Cancer of the Gastrointestinal Tract

23

Cancer of the Gastrointestinal Tract SECTION A: ORAL TUMORS JULIUS M. LIPTAK

Incidence and Risk Factors Oral tumors are common in both cats and dogs, with cancers of the oral cavity accounting for 3% to 12% and 6% of all tumors in these species, respectively.1–5 Oropharyngeal cancer is 2.6 times more common in dogs than in cats, and male dogs have a 2.4 times greater risk of developing oropharyngeal malignancy compared with female dogs.6,7 A male sex predisposition has also been reported for dogs with malignant melanoma (MM), tonsillar squamous cell carcinoma (SCC), and peripheral odontogenic fibromas,8,9 and a female sex predisposition has been reported for dogs with axial osteosarcoma (OSA).10 Dog breeds with the highest risk of developing oropharyngeal cancer include the cocker spaniel, German shepherd dog, German shorthaired pointer, Weimaraner, golden retriever, Gordon setter, miniature poodle, Chow Chow, and boxer.3,8,11 In one study, German shepherd dogs and boxers had a decreased risk of developing oral melanoma.11 In dogs, the most common malignant oral tumors are, in descending order, MM, SCC, and fibrosarcoma (FSA),12–24 although in other studies SCC is more common than MM.25 SCC is the most common oropharyngeal cancer in cats, followed by FSA, which accounts for 13% of feline oral tumors.5 Other malignant oral tumors in dogs include OSA, chondrosarcoma, anaplastic sarcoma, multilobular osteochondrosarcoma (MLO), intraosseous carcinoma, myxosarcoma, hemangiosarcoma, lymphoma, mast cell tumor, and transmissible venereal tumor.12–28 Tumors or tumor-like lesions of unusual sites, types, and biologic behavior (e.g., peripheral odontogenic fibroma, acanthomatous ameloblastoma [AA], odontogenic tumors, tonsillar SCC, tongue tumors, malignancy of young dogs, viral papillomatosis, canine and feline eosinophilic granuloma complex, and nasopharyngeal polyps) will be covered at the end of this chapter. A general summary of the common oral tumors is found in Table 23.1. 

Pathology and Natural Behavior The oral cavity is a very common site for a wide variety of malignant and benign cancers. Although most cancers are fairly straightforward histologically, some have confusing nomenclature or extenuating circumstances that warrant discussion. 432

Malignant Melanoma In comparison to other malignant oral tumors, MM tends to occur in smaller body weight dogs. Cocker spaniel, miniature poodle, Anatolian sheepdog, Gordon setter, Chow Chow, and golden retriever are overrepresented breeds.11 The mean age at presentation is 11.4 years.11 MM occurs in cats, but is uncommon.29 MM can present a confusing histopathologic picture if the tumor or the biopsy section does not contain melanin (Fig. 23.1A), and amelanotic melanomas (see Fig. 23.1B) represent up to 38% of cases.30 A histopathologic diagnosis of undifferentiated or anaplastic sarcoma or even epithelial cancer should be viewed with suspicion for possible reclassification as melanoma. Several immunohistochemical antibodies can be applied to biopsy specimens to help differentiate melanoma from other poorly differentiated tumors and an immunodiagnostic cocktail using antibodies against PNL2, Melan A, TRP-1, and TRP-2 was found to have 100% specificity and 94% sensitivity and may be helpful in differentiation.11,31 Melanoma of the oral cavity is a highly malignant tumor with frequent metastasis to the regional lymph nodes (LNs) and then the lungs.9,30–68 There is a small subset of dogs with well-differentiated oral melanomas and these may have a more benign biologic behavior.41,69 The metastatic rate is site, size, and stage dependent and reported in up to 80% of dogs.12,20,30–68 The World Health Organization (WHO) clinical staging system for oral tumors in dogs may have prognostic significance in dogs with oral melanoma (Table 23.2).30–68,70 MM is a highly immunogenic tumor, and molecular and immunomodulatory approaches to treatment are active areas of research and treatment.56–68 A review of the biology and molecular mechanisms of canine melanoma development and progression is provided in Chapter 20.71,72 

Squamous Cell Carcinoma SCC is the most common oral tumor in cats (Fig. 23.2) and the second most common in dogs.1,4,5,20–24 There are five different histologic subtypes of SCC in dogs: conventional, papillary, basaloid, adenosquamous, and spindle cell.73 Papillary SCCs typically occur in the rostral oral cavity of dogs less than 9 months old, although cases in older dogs have also been reported.73–77 The metastatic rate for nontonsillar SCC in dogs is 5% to 29%,43,76–85 but the metastatic risk is site dependent, with the rostral oral cavity having a low metastatic rate and the caudal tongue and tonsil having a high metastatic potential.77

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TABLE 23.1  Summary of Common Oral Tumors in the Dog and Cata CANINE

FELINE

Malignant Melanoma

SCC

Fibrosarcoma

Acanthomatous Ameloblastoma

SCC

Fibrosarcoma

Frequency

30%–40%

17%–25%

8%–25%

5%

70%–80%

13%–17%

Median age (years)

12

8–10

7–9

8

10–12

10

Sex predisposition

None to male

None

Male

None

None

None

Animal size

Smaller

Larger

Larger

None

—

—

Site predilection

Gingival, buccal, and labial mucosa

Rostral mandible

Maxillary gingiva and hard palate

Rostral mandible

Tongue, pharynx, and tonsils

Gingiva

Lymph node metastasis

Common (41%–74%)

Rare (<40%) Tonsil SCC up to 73%

Occasional (9%–28%)

None

Rare

Rare

Distant metastasis

Common (14%–92%)

Rare (<36%)

Occasional (0%–71%)

None

Rare

Rare (<20%)

Gross appearance

Pigmented (67%) or amelanotic (33%), ulcerated

Red, cauliflower, ulcerated

Flat, firm, ulcerated

Red, cauliflower, ulcerated

Proliferative, ulcerated

Firm

Bone involvement

Common (57%)

Common (77%)

Common (60%–72%)

Common (80%– 100%)

Common

Common

Surgery response

Fair to good

Good

Fair to good

Excellent

Poor

Fair

 Local recurrence

0%–59%

0%–50%

31%–60%

0%–11%

 MST

5–17 months

9–26 months

10–12 months

>28–64 months

45 days

 1-Year survival rate

21%–35%

57%–91%

21%–50%

72%–100%

<10%

Radiation response

Good

Good

Poor to fair

Excellent

Poor

 Response rate

83%–94%

—

—

—

 Local recurrence

11%–27%

31%–42%

32%

8%–18%

 MST

4–12 months

16–36 months

7–26 months

37 months

 1-Year survival rate

36%–71%

72%

76%

>85%

Best treatment

Surgery and/ or radiation ± chemotherapy ± immunotherapy

Surgery and/or radiation

Surgery and/or radiation

Surgery

Surgery and radiation ± sensitizer

Surgery and/or radiation

Prognosis

Fair to good

Good to excellent

Good

Excellent

Poor to fair

Fair

MST

<36 months

26–36 months

18–26 months

>64 months

14 months

Cause of death

Distant disease

Local or distant disease

Local disease

Rarely tumor related

Local disease

Poor

90 days

Local disease

MST, Mean survival time; SCC, squamous cell carcinoma. aReferences

  

11–21, 28–32, 37, 53, 57–60, 78, 84–86, 104–111.

In cats, the risk of developing oral SCC is significantly increased by 4-fold with the use of flea collars and high intake of either canned food in general or canned tuna fish specifically.86 Exposure to household tobacco smoke increases the risk of oral SCC by 2-fold in cats,86 and although this was not statistically significant, smoke exposure is associated with

a significant increase in expression of p53 in SCC lesions compared with cats with oral SCC not exposed to environmental smoke.87 For this reason, mutations of p53 may be involved in the development and progression of smoke-related oral SCC in cats.

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TABLE 23.2  Clinical Staging (TNM) of Oral Tumors in

Dogs and Cats70

Clinical Staging System for Oral Tumors Primary Tumor (T) Tis Tumor in situ T1 Tumor <2 cm in diameter at greatest dimension T1a Without evidence of bone invasion T1b With evidence of bone invasion T2 Tumor 2–4 cm in diameter at greatest dimension T2a Without evidence of bone invasion T2b With evidence of bone invasion T3 Tumor >4 cm in diameter at greatest dimension T3a Without evidence of bone invasion T3b With evidence of bone invasion

A

Regional Lymph Nodes (N) N0 No regional lymph node metastasis N1 Movable ipsilateral lymph nodes N1a No evidence of lymph node metastasis N1b Evidence of lymph node metastasis N2 Movable contralateral lymph nodes N2a No evidence of lymph node metastasis N2b Evidence of lymph node metastasis N3 Fixed lymph nodes

Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis [specify site(s)]

Stage Grouping

B •

Fig. 23.1 (A) A malignant melanoma arising from the rostral mandible. (B) An amelanotic malignant melanoma arising from the caudal maxilla.

I II III IV

  

Tumor (T)

Nodes (N)

Metastasis (M)

T1 T2 T3 Any T Any T Any T

N0, N1a, N2a N0, N1a, N2a N0, N1a, N2a N1b N2b, N3 Any N

M0 M0 M0 M0 M0 M1

SCC frequently invades bone in both cats and dogs, and bone invasion is usually severe and extensive in the cat. Increased tumor expression of parathyroid hormone–related protein in cats with oral SCC may play a role in bone resorption and tumor invasion.88 Control of local disease is the most challenging aspect in cats with oral SCC because of the extent of the local tumor89–112; [not superscript] however, metastasis has been reported to the mandibular LNs and lungs in 31% and 10% of cats, respectively,95 and hence treatment for this metastatic potential may be warranted for cats in which local tumor control is achieved. 

Fibrosarcoma Oral FSA is the second most common oral tumor in cats and the third most common in dogs.2,5, 20–24,90 In dogs, oral FSA tends to occur in large breed dogs, particularly golden and Labrador retrievers.20–24,113–117 The median age at diagnosis is 7.3 to 8.6 years and there may be a male predisposition.113–116 Oral FSA may look surprisingly benign histologically and, even with large biopsy samples, the pathologist can find it difficult to differentiate fibroma from low-grade FSA.113 This syndrome, which is common on the hard palate (Fig. 23.3) and maxillary arcade between the canine and carnassial teeth

• Fig. 23.2  Typical appearance of an oral squamous cell carcinoma in a cat. Although these can be proliferative and firm, ulceration is more common.

of large-breed dogs, has been termed histologically low-grade but biologically high-grade FSA.113 Even with a biopsy result suggesting fibroma or low-grade FSA, the treatment should be aggressive, especially if the cancer is rapidly growing, recurrent,

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435

• Fig. 23.3  Typical appearance of a biologically high-grade but histologically low-grade fibrosarcoma. These often appear histologically benign or low-grade, but have an aggressive local behavior. Wide surgical resection and possibly postoperative radiation therapy are required for adequate local tumor control.

or invading bone. FSA is locally invasive, but metastasis to the lungs and occasionally regional LNs occurs in fewer than 30% of dogs.12,20–24,43,113–117 

Osteosarcoma OSA of axial sites is less common than appendicular OSA and represents approximately 25% of all cases.10 Of the axial OSA, the mandible and maxilla are involved in 27% and 16% to 22% of cases, respectively.10,118 OSA is the fourth most common malignant oral tumor in dogs. The metastatic potential for axial OSA is less than appendicular OSA.10,119–122 A female sex predisposition has been reported.10 

Peripheral Odontogenic Fibroma Peripheral odontogenic fibroma is the preferred term for a group of benign tumors previously known as epulides.123 Four types of epulides have been described in the dog: acanthomatous, fibromatous, ossifying, and giant cell.123–135 Acanthomatous epulis has been renamed acanthomatous ameloblastoma, and the fibromatous and ossifying epulides have been renamed peripheral odontogenic fibroma.123 Peripheral odontogenic fibromas are relatively common in dogs, but rare in cats.135 Multiple epulides have been described in cats, with 50% of cases occurring in cats younger than 3 years.135 They are benign gingival proliferations arising from the periodontal ligament and appear similar to focal fibrous hyperplasia of the gingiva.123 Unlike AAs, they do not invade into underlying bone. The mean age at presentation for dogs with peripheral odontogenic fibromas is 8 to 9 years, and a male predisposition has been reported.123–127 Peripheral odontogenic fibromas are slow-growing, firm masses and usually are covered by intact epithelium. They have a predilection for the maxilla rostral to the third premolar teeth.123–127 

•

Fig. 23.4 An intraoral radiograph of the rostral mandible of a cat with a squamous cell carcinoma. Note the extensive bone lysis resulting in tooth loss, which is very common in cats with this type of tumor.

Acanthomatous Ameloblastoma AA is a benign tumor, but has an aggressive local behavior and frequently invades bone of the underlying mandible or maxilla. Medium- to large-breed dogs are most commonly affected, and Shetland sheepdogs, Old English sheepdogs, and golden retrievers are overrepresented.123–130 The mean age at presentation is 7 to 10 years, and a sex predisposition is unlikely, with three studies reporting conflicting results.125,128–130 The rostral mandible is the most common site, representing 51% of all cases in one study of 263 dogs with AA, with other sites being the caudal mandible (22%), rostral maxilla (22%), and caudal maxilla (6%).128,129 They do not metastasize. AA is the preferred term, but some pathologists will refer to these tumors by their previous terminology of acanthomatous epulis or adamantinoma.124 

History and Clinical Signs Most cats and dogs with oral cancer present with a mass in the mouth noticed by the owner. Cancer in the caudal pharynx, however, is rarely seen by the owner and the animal will present with signs of increased salivation, exophthalmos or facial swelling, epistaxis, weight loss, halitosis, bloody oral discharge, dysphagia or pain on opening the mouth, or occasionally cervical lymphadenopathy (especially SCC of the tonsil).20–24,91 Loose teeth, especially in an animal with generally good dentition, should alert the clinician to possible underlying neoplastic bone lysis (Fig. 23.4), particularly in the cat. Although paraneoplastic syndromes associated with oral tumors are rare, hypercalcemia has been reported in two cats with oral SCC87 and hyperglycemia in a cat with a gingival vascular hamartoma.136 

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Diagnostic Techniques and Workup The diagnosis and clinical staging of animals with oropharyngeal masses is imperative before definitive surgical excision. A biopsy is required for definitive diagnosis and this will assist the clinician in determining biologic behavior and prognosis. Clinical staging consists of evaluating the extent of the local tumor and the presence of metastatic disease. The regional LNs and lungs are the two most common sites of metastasis in cats and dogs with oral tum ors.30–68,76–85,89–122 The procedures required for the diagnosis and clinical staging of animals with oral cancer can usually be performed under a short general anesthesia. 

Diagnosis A large incisional biopsy is often required for a definitive diagnosis. Fine-needle aspirate (FNA) or impression smear cytology has traditionally been considered unrewarding because many oral tumors are associated with a high degree of necrosis and inflammation; however, one prospective study of 114 cats and dogs with oral masses showed that, in comparison to definitive histopathologic results, FNA cytology had a diagnostic accuracy rate of 98% in dogs and 96% in cats, and impressions smear cytology had a diagnostic accuracy rate of 92% in dogs and 96% in cats.137 Dogs with exophytic or ulcerated masses will generally tolerate a deep wedge or core punch biopsy without general anesthesia. Biopsy is recommended in the diagnostic workup of cats and dogs with an oral mass to differentiate benign from malignant disease, for owners basing their treatment options on prognosis, and when other treatment modalities, such as radiation therapy (RT), may be preferable. Oral cancers are commonly infected, inflamed, or necrotic, and it is important to obtain a large representative specimen. Cautery may distort the specimen and should be used for hemostasis only after blade incision or punch biopsy. Large samples of healthy tissue at the edge and center of the lesion will increase the diagnostic yield, but care must be taken not to contaminate normal tissue, which cannot be removed with surgery or included in the radiation field. Biopsies should always be performed from within the oral cavity and not through the lip to avoid seeding tumor cells in normal skin and compromising curative-intent surgical resection. For small lesions (e.g., epulides, papillomas, or small labial mucosal melanoma), curative-intent resection (excisional biopsy) may be undertaken at the time of initial evaluation. However, accurate notes should be included in the medical records, and/or photographic evidence, to detail the size and anatomic location of the mass if excision is incomplete and further treatment is required. For more extensive disease, waiting for biopsy results is recommended so that appropriate treatment plans can be formulated.

•

Fig. 23.5 A computed tomography image of a dog with a maxillary fibrosarcoma. Advanced imaging allows better planning of surgery and radiation therapy, as the extent of bone involvement and extension into the nasal cavity is often much greater than can be appreciated grossly.

the cortex is destroyed and hence apparently normal radiographs do not exclude bone invasion. Advanced imaging modalities are now widely available and these are recommended for imaging of oral tumors, particularly tumors arising from the maxilla, palate, and caudal mandible (Fig. 23.5).143–145 Computed tomography (CT) scans are generally preferred to magnetic resonance imaging (MRI) because of superior bone detail, but both CT or MRI scans will provide more information on the local extent of the tumor than regional radiographs. In one study, invasion into adjacent structures was noted in only 30% of dogs imaged with radiographs compared with more than 90% of dogs imaged with contrast-enhanced CT.145 In another study, MRI provided more accurate information on invasion into adjacent structures, MRI and CT showed similar accuracy in assessing bone invasion, and calcification and cortical bone erosion were better assessed with CT scan.144 Although not widely available, positron emission tomography (PET)/CT provided valuable information on the extent of soft tissue infiltration and presence of LN metastasis in cats with oral SCC in comparison to CT.146,147 This information is important for planning the definitive surgical procedure (or RT if indicated). 

Clinical Staging: Local Tumor

Clinical Staging: Regional Lymph Nodes

Tumor size is an important prognostic factor for some types of oral tumors, such as MM, SCC, and tongue tumors,40,41,78,138–142 and hence an accurate measurement of tumor size should be recorded. Cancers that are adherent to or arising from bones of the mandible, maxilla, or palate should be imaged under general anesthesia to determine the presence of bone lysis and the extent of local disease. Regional radiographs include open mouth, intraoral, oblique lateral, and ventrodorsal or dorsoventral projections. Bone lysis is not radiographically evident until 40% or more of

Regional LNs should be carefully palpated for enlargement or asymmetry. However, caution should be exercised when making clinical judgments based on palpation alone because LN size is not an accurate predictor of metastasis. In one study of 100 dogs with oral MM, 40% of dogs with normal sized LNs had metastasis and 49% of dogs with enlarged LNs did not have metastasis.34 Furthermore, the regional LNs include the mandibular, parotid, and medial retropharyngeal LNs; but the parotid and medial retropharyngeal LNs are not externally palpable.148–151 In addition,

CHAPTER 23  Cancer of the Gastrointestinal Tract

only 55% of 31 cats and dogs with metastasis to the regional LNs had metastasis to the mandibular LNs.149 CT and PET/CT can be useful to determine LN metastasis and guide further diagnostics.143,147,148 LN aspiration should be performed in all animals with oral tumors, regardless of the size or degree of fixation of the LNs.34,149 The accuracy of LN aspirates for the detection of metastatic cancer in cats and dogs is 77%.152 Resection of some or all of the regional LNs has been described and, although the therapeutic benefit of this approach is unknown, it may provide valuable staging information.148–151 The major concerns with nontargeted LN resection are the possibility of missing a metastatic lesion and the potential morbidity associated with excision of multiple LNs. Lymphatic drainage of the oral cavity is highly variable in humans and likely in dogs and cats,151 and the first draining LN can be ipsilateral or contralateral to the tumor and include any one of the mandibular, medial retropharyngeal, parotid, or minor LNs, such as the buccal LN.149,151 For these reasons, sentinel LN (SLN) mapping and biopsy is becoming the preferred technique for LN staging of oral tumors. SLN mapping and biopsy is the assessment of LN metastasis without more aggressive en bloc surgical excisions of the regional LNs. The SLN is the first draining LN and the status of this LN is representative of the entire LN bed. Furthermore, the SLN is not necessarily the regional anatomic LN. In one study of dogs with cutaneous mast cell tumors, the SLN was different from the regional anatomic LN in 40% of dogs.153 Methods to detect SLN in people with head and neck cancer include lymphoscintigraphy, intraoperative blue dyes, and intraoperative gamma probes.154 Lymphoscintigraphy, intraoperative dyes, and contrast-enhanced ultrasonography have been described in dogs with various tumors, including head and neck cancer.154,155 The use of lipid-soluble and water-soluble contrast agents has also been reported as methods of detecting the location of the SLN preoperatively, and then combining this with methylene blue to aide in the identification of the SLN intraoperatively (Fig. 23.6).156 The advantage of this latter technique is that radioactive materials are not required and hence this is a more widely applicable SLN mapping technique. 

Clinical Staging: Distant Metastasis The final step in the clinical staging of animals with oral tumors is imaging of the thoracic cavity for metastasis to the lungs. Three-view thoracic radiographs (right and left lateral projections, and either dorsoventral or ventrodorsal projection) are generally recommended. CT scans should be considered for animals with highly metastatic tumor types, such as oral MM, as they are significantly more sensitive in detecting pulmonary metastatic lesions compared with radiographs.157–160 Based on these diagnostic steps, oral tumors are then clinically staged according to the WHO staging scheme (see Table 23.2).70 

Treatment Surgery Surgery and RT are the most common treatments used for the local control of oral tumors. Surgical resection is the most economic, expeditious, and curative treatment. The type of oral surgery depends on tumor histology and location. Except for peripheral odontogenic fibromas, most oral tumors have some underlying bone involvement and surgical resection should include bony margins to increase the likelihood of local tumor

437

control. More aggressive surgeries such as mandibulectomy, maxillectomy, and orbitectomy are generally well tolerated by cats and dogs. These procedures are indicated for all aggressive and/or invasive oral tumors, particularly lesions with extensive bone invasion, with poor sensitivity to RT (Tables 23.3 and 23.4).13–24,161–164 Margins of at least 2 cm are generally necessary for malignant cancers such as SCC, MM, FSA, and OSA in the dog. If possible, FSA in the dog and SCC in the cat should be treated with surgical margins greater than 2 cm because of high local recurrence rates. Bone reconstruction after bony resection has been described,165–172 but is rarely necessary in dogs because of good postoperative function and cosmetic appearance with mandibulectomy alone.13–24 Furthermore, a high complication rate has been reported after reconstruction and these complications often require revision surgeries for their management.24,172 In contrast to dogs, cats frequently have poor postoperative function after mandibulectomy90 and hence mandibular reconstruction may improve postoperative functional outcome in cats.173 Rostral and segmental resections (e.g., mandibulectomy and maxillectomy) may be sufficient for benign lesions and rostral SCC in dogs. Rim resections, in which the ventral cortex of the mandible is preserved, may be possible for small benign tumors localized to the alveolar margin of the mandible (Fig. 23.7).174–176 Larger resections, including hemimandibulectomy, hemimaxillectomy, orbitectomy, and radical maxillectomy, are necessary for more aggressive tumors, especially FSA, and malignant tumors with a more caudal location.13–24,161–164 Although these large resections carry some morbidity, owner satisfaction with the cosmetic and functional outcomes is in excess of 85%.13–24,90,161–164 Cosmesis is usually very good after most mandibulectomy and maxillectomy procedures (Fig. 23.8), but can be challenging with aggressive bilateral rostral mandibulectomies and radical maxillectomies.13–24,161–164,177 Blood loss and hypotension are the most common intraoperative complications, particularly during caudal or aggressive maxillectomy procedures.21,162,177 Postoperative complications include incisional dehiscence and oronasal fistula formation, epistaxis, increased salivation, mandibular drift and malocclusion, lip trauma, infection, and difficulty prehending food, particularly after bilateral rostral mandibulectomy caudal to the second premolar teeth.13–24,161–164,177 Elastic training, consisting of an orthodontic elastic rubber chain between an orthodontic button on the lingual aspect of the intact mandible tooth and buccal aspect of the maxillary fourth premolar tooth, has been described to maintain occlusion and prevent mandibular drift after mandibulectomy in dogs.178 Enteral feeding tubes are not usually required after oral surgery in dogs; however, they are recommended for cats treated with any type of mandibulectomy because eating can be difficult for 2 to 4 months after surgery and 12% of cats never eat voluntarily after mandibulectomy.89,90 Local disease control is the goal of treatment for most animals with oral tumors. Regional LN resection has been described in cats and dogs; although it adds to clinical staging information, its effectiveness in controlling local and metastatic disease is unknown.148–151 

Radiation Therapy RT can be effective for locoregional control of oral tumors. RT can be used as a primary treatment, with either palliative or curative intent, as an adjunct for incompletely resected tumors, or as an adjunct for locally aggressive tumors regardless of the completeness of excision, such as oral FSA. MM,42–49 canine oral SCC,80,81,179

A

C

B

D

E • Fig. 23.6  Indirect lymphography for sentinel lymph node mapping. (A) A lipid-soluble, radio-opaque con-

trast agent is being injected peritumorally in four quadrants around a malignant melanoma in a dog. (B) The lipid-soluble contrast agent is taken up slowly into the lymphatics. A regional radiograph is taken 24 hours postinjection to identify the sentinel lymph node, which was the ipsilateral mandibular lymph node in this case (arrow). (C) To confirm the sentinel lymph node, methylene blue is injected in four quadrants peritumorally during surgery. (D) Methylene blue is rapidly taken up into the lymphatics. A surgical approach is made to the sentinel lymph node identified radiographically. Blue discoloration of the afferent lymphatics and lymph node assist in identifying this node as the sentinel lymph node. The sentinel lymph node is submitted for histopathologic assessment to determine whether there is evidence of metastatic disease. (E) Regional radiograph of a cat with a malignant melanoma of the lip 24 hours after peritumoral injection of a lipid-soluble contrast agent. The sentinel lymph node is the buccal lymph node. Note that the mandibular lymph nodes are the only palpable regional lymph nodes; however, malignant oral tumors can metastasize the ipsilateral or contralateral mandibular, medial retropharyngeal, parotid, and minor lymph nodes. Aspiration or excision of only the mandibular lymph node may result in metastatic lymph nodes being missed.

CHAPTER 23  Cancer of the Gastrointestinal Tract

TABLE 23.3  Various Mandibulectomies

Mandibulectomy Procedure

Indications

Comments

Unilateral rostral

Lesions confined to rostral hemimandible; not crossing midline

Most common tumor types are squamous cell carcinoma and adamantinoma that do not require removal of entire affected bone; tongue may lag to resected side.

Bilateral rostral

Bilateral rostral lesions crossing the symphysis

Tongue will be “too long,” and some cheilitis of chin skin will occur; has been performed as far back as PM4 but preferably at PM1.

Vertical ramus

Low-grade bony or cartilaginous lesions confined to vertical ramus

These tumors are variously called chondroma rodens or multilobular osteosarcoma; temporomandibular joint may be removed; cosmesis and function are excellent.

Complete unilateral

High-grade tumors with extensive involvement of horizontal ramus or invasion into medullary canal of ramus

Usually reserved for aggressive tumors; function and cosmesis are good.

Segmental

Low-grade midhorizontal ramus cancer, preferably not into medullary cavity

Poor choice for highly malignant cancer in medullary cavity because growth along mandibular artery, vein, and nerve is common.

   TABLE 23.4  Various Maxillectomies

Maxillectomy Procedure

Indications

Comments

Unilateral rostral

Lesions confined to hard palate on one side

One-layer closure.

Bilateral rostral

Bilateral lesions of rostral hard palate

Needs viable buccal mucosa on both sides for flap closure.

Lateral

Laterally placed midmaxillary lesions

Single-layer closure if small defect, two-layer if large.

Bilateral

Bilateral palatine lesions

High rate of closure dehiscence because lip flap rarely reaches from side to side; may result in permanent oronasal fistula.

  

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but can include permanent alopecia, skin fibrosis, bone necrosis and oronasal fistula formation, development of a second malignancy within the radiation field, keratoconjunctivitis sicca, cataract formation, xerostomia, and retinal atrophy.43,130–132 Orthovoltage radiation may be associated with a higher incidence of second malignancies and bone necrosis than megavoltage irradiation.32,130,131 

Chemotherapy The major problem with most oral tumors is control of local disease; however, chemotherapy may be indicated for some tumors with higher metastatic potential, especially oral MM in dogs,9,30– 68 tonsillar SCC in cats and dogs, OSA in dogs,122 and possibly oral SCC in cats.89–112  • Fig. 23.7  Rim resection of an acanthomatous ameloblastoma in a dog. The rim resection has been performed with a 24-mm biradial saw to preserve the ventral cortex of the mandibular body and hence prevent postoperative mandibular drift.

•

Fig. 23.8 The typical appearance of a dog 6 months postoperatively after subtotal unilateral mandibulectomy for an osteosarcoma. The tongue will often hang out and the remaining hemimandible will drift toward the resected side.

and some benign tumors, such as AA,130–132 are known to be radiation responsive, and RT should be considered in the primary treatment of these tumors. RT can also be used for the palliation of oral SCC in cats and a variety of hypofractionated, accelerated, and stereotactic RT protocols have been described.96–106 Acute effects are common but self-limiting. These include alopecia and moist desquamation, oral mucositis, dysphagia, and ocular changes, such as blepharitis, conjunctivitis, keratitis, and uveitis.43,80,81,116,117,130 The acute effects of coarse fractionation are less than experienced with the full-course protocols used for oral SCC and dental tumors and usually resolve rapidly.44–49,96–104 Late complications are rare, occurring in fewer than 5% of cases,

Prognosis Clinical series of more than 750 dogs with various oral malignancies treated with either mandibulectomy or maxillectomy have been described.13–24,161–164 The majority of cases were treated with surgery alone. Unfortunately, the methods of reporting and outcome results vary with each paper. Overall, the lowest rates of local tumor recurrence and best survival times (STs) are reported in dogs with AA and SCC, whereas FSA and MM are associated with the least favorable results.13–24 Most of these reports suggest that histologically complete resection, smaller diameter, and a rostral location are favorable prognostic factors.24 In two studies of 142 dogs treated with either mandibulectomy or maxillectomy, tumor-related deaths were 10 to 21 times more likely with malignant tumors, up to five times more likely with tumors located caudal to the canine teeth, and two to four times more likely after incomplete resection.22,23 Rostral locations are usually detected at an earlier stage and are more likely to be resectable with complete surgical margins. Local tumor recurrence is more frequent after incomplete resection with 15% to 22% and 62% to 65% of tumors recurring after complete and incomplete excision, respectively.22,23 Recurrent disease negatively affects ST because further treatment is more difficult and the response to treatment is poorer.31 FSA continues to have high local recurrence rates in most studies, and more aggressive surgical approaches or adjuvant therapies, such as postoperative RT, should be considered.24,115 On the other hand, MM is controlled locally in 75% of cases, but metastatic disease requires more effective systemic adjuvant therapy.

Malignant Melanoma The prognosis for dogs with oral MM is guarded. Metastatic disease is the most common cause of death, with metastasis to the lungs reported in 14% to 67% of dogs.9,13–24, 30–68 Surgery or RT can provide good local control, but the majority of dogs will fail treatment because of metastatic disease and hence the search for effective adjuvant immunotherapy holds the most promise to ultimately improve outcomes. Surgery is the most common treatment for management of the local tumor. The median survival time (MST) for untreated dogs with oral MM is 65 days,31 whereas tumor control and STs are significantly better when surgery is included in the treatment plan.32 The overall local tumor recurrence rate after surgery is up to 45%,24,40,41 with local tumor recurrence rates of 22% after mandibulectomy and 48% after maxillectomy.7,18,19 The median ST (MST) for dogs with MM treated with surgery alone varies

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TABLE 23.5  Prognostic Factors for Dogs with Oral Malignant Melanoma Treated with Surgery, with or without

Radiation Therapy, Chemotherapy, and/or Immunotherapy

Prognostic Factor

Median Progression-Free Survival

Median Survival Time

Age40

—

630 days if <12 years 224 days if ≥12 years

Tumor size56

—

511 days if >2 cm 164 days if >2 cm

Tumor size40

—

630 days if <2 cm 240 days if 2–4 cm 173 days if >4 cm

Tumor size41

>567 days if <3 cm 245 days if >3 cm

874 days if <3 cm 396 days if >3 cm

Metastasis at diagnosis41

567 days if no metastasis 187 days if metastasis

818 days if no metastasis 131 days if metastasis

Clinical stage40,41

>567 days for stage I >187 days for stage II 245 days for stage III

874 days for stage I 818 days for stage II 207 days for stage III

PDGFRs-α and -β coexpression30

239 days if no coexpression 159 days if no coexpression

335 days if no coexpression 183 days if no coexpression

Ki6730

484 days if Ki67 <19.5% 188 days if Ki67 >19.5%

484 days if Ki67 <19.5% 224 days if Ki67 >19.5%

PDGFR, Platelet-derived growth factor receptor.

  

considerably from 150 to 874 days with 1-year survival rates less than 35%.9,13–24,30–68 In a recent study, the median progressionfree interval (PFI) and MST after surgery alone for oral MM were greater than 567 days and 874 days, respectively.41 Variables which are known to have prognostic significance in dogs treated with surgery alone or in combination with other modalities include age, tumor size, clinical stage, the ability of the first treatment to achieve local control, and histologic and immunohistochemical criteria such as the degree of differentiation, mitotic index, nuclear atypia score, pigment quantification, COX-2 expression, PDGFR expression, Ki67 expression, and c-kit expression (Table 23.5).9,13–24,30–68 In some studies, tumor location has prognostic importance with rostral mandibular and caudal maxillary sites having a better prognosis than other sites.32,37,53 MSTs are significantly shorter for dogs with recurrent oral MM compared with dogs with previously untreated oral MM.31 In one study, dogs treated with adjunctive RT had significantly longer STs, but this result may have been confounded by age, which was also prognostic in this study.40 In 64 dogs with surgically treated well-differentiated melanomas of the lips and oral cavity, 95% of dogs were either alive or had died of unrelated causes at the end of the study period.69 Prognostic information for melanocytic tumors in dogs has recently been reviewed.39 Oral melanoma is responsive to hypofractionated RT protocols. A number of different hypofractionated RT protocols have been described: (1) 3 weekly 8 to 10 Gy fractions for a total dose of 24 to 30 Gy,44,47 (2) 4 weekly fractions of 9 Gy for a total dose of 36 Gy,45,47 (3) 6 weekly 6 Gy fractions for a total dose of 36 Gy,46 (4) 5 fractions of 6 Gy over 2.5 weeks,49 and (5) 8 weekly 6 Gy fractions for a total dose of 48 Gy.42 Response rates are excellent, with 81% to 100% of tumors responding and a complete response observed in up to 70% of melanomas.42–49 Local recurrence is reported in 15% to 26% of dogs experiencing a complete response with a median

time to local recurrence of 139 days.44–49 In one study progressive local disease was observed in all dogs that did not achieve a complete response.44 The most common cause of death is metastasis, and this is reported in 58% of dogs with a median time of metastasis of 311 days.46 The MST for dogs treated with RT is 192 to 401 days, with a 1-year survival rate of 36% to 48% and a 2-year survival rate of 21%.44–49 Local tumor control and ST are significantly improved with rostral tumor location, smaller tumor volume, no radiographic evidence of bone lysis, postoperative irradiation of microscopic disease, and megavoltage irradiation.43,45,47,48 In one series of 140 dogs with oral MM, the MST was 21 months if none of these risk factors were present compared with an MST of 11 months with one risk factor, 5 months with two risk factors, and three months with all three risk factors.47 Tumor size is important with median PFS for dogs with T1 oral melanomas of 19 months compared with less than 7 months for T2 and T3 tumors.43 In one study of 111 dogs treated with either orthovoltage or megavoltage hypofractionated protocols, tumor size and clinical stage had a significant effect on outcome with MSTs for dogs with stage I, II, III, and IV oral malignant melanoma of 758, 278, 163, and 80 days, respectively.48 In this study, there was a greater risk of death and decreased STs overall (MSTs of 233 days compared with 122 days) and for dogs with stage III melanoma (MSTs of 210 days compared with 99 days) when treated with orthovoltage rather than megavoltage RT.48 The median PFI was significantly prolonged in one study of 27 dogs when hypofractionated RT was combined with adjuvant oral temozolomide compared with hypofractionated RT alone.49 Hypofractionated RT has also been described in five cats with oral melanoma, resulting in a 60% response rate and MST of 146 days (range: 66–224 days).29 Effective systemic adjuvant therapies (e.g., immunotherapy, chemotherapy) are ultimately necessary for successful management

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of dogs with oral MM owing to the high metastatic risk. Unfortunately, these tumors, in dogs and people, are generally poorly responsive to cytotoxic chemotherapy and effective immunotherapies that result in meaningful immunologic responses in the majority of patients are currently lacking. In a small study of 17 dogs treated with surgery and adjuvant carboplatin, the median PFS was 259 days (with 41% of dogs developing local tumor recurrence and 41% of dogs developing metastasis) and the MST was 440 days.52 However, two recent studies have shown no benefit in STs with the use of adjunctive chemotherapy,40,41 with overall MSTs of 335 days and 352 days in dogs that were and were not treated with systemic adjuvant therapy.41 Immunotherapy holds the most promise for effective management in dogs with MM and this is an area of very active research in both veterinary and physician-based oncology. The use of DNA vaccinations with either murine or human tyrosinase in dogs with advanced stages of oral MM (clinical stage II–IV) results in MSTs of 224 to 389 days.61–66 In one study of nine dogs treated with DNA vaccine encoded for human tyrosinase, complete response was observed in one dog with lung metastasis, two dogs with stage IV disease and bulky metastasis lived for greater than 400 days, and two dogs with stage II or III disease died of other causes approximately 500 days after treatment with no evidence of tumor at necropsy.61 The MST is significantly improved to 589 days when the primary oral site and regional LNs are controlled with surgery or RT.61 In a prospective study of dogs with surgically excised stage II or III oral MM that compared 58 dogs treated with DNA vaccine encoded for human tyrosinase with a historical control of 53 unvaccinated dogs, the MST was significantly longer for dogs in the vaccinated group (not reached compared with 324 days) with tumor-related deaths in only 26% of vaccinated dogs compared with 64% of unvaccinated dogs.62 In two prospective studies investigating human recombinant chondroitin sulfate proteoglycan-4 DNA–based electrovaccination after surgical resection in dogs with stage II or III oral MMs, the survival outcomes were significantly longer in vaccinated dogs.67,68 For vaccinated and unvaccinated dogs, respectively, the local recurrence rates were 21% to 35% and 39% to 42%; the metastatic rates were less than 36% and 79% to 90%; the 6-month survival rates were 96% to 100% and 63% to 69%; the 12-month survival rates were 64% to 74% and 15% to 26%; the 24-month survival rates were 30% and 5%; the median disease-free intervals (DFIs) were 477 days and 180 days; and the MSTs were 653 to 684 days and 200 to 220 days.67,68 For vaccinated dogs, outcomes were significantly better for dogs weighing less than 20 kg.68 A thorough discussion of MM and its prognosis after definitive treatment with surgery, RT, chemotherapy, and/or immunomodulatory agents is provided in Chapter 20. The location of MM may also have some prognostic significance. Melanomas of the lip and tongue may have a lower metastatic rate, with survival more dependent on local control of the tumor. In one series of 60 dogs with oral MMs at various sites treated with combinations of surgery, RT, chemotherapy, and immunotherapy, the MST for dogs with lip and tongue MMs was 580 days and was greater than 551 days, respectively.9 In comparison, the MST was 319 days for maxillary MMs and 330 days for MMs of the hard palate.9 In another study, the MST was significantly longer for dogs with labial mucosal MMs (310 days) than mandibular and maxillary MMs (123 days).38 In another study, only 5% of 64 dogs with well-differentiated melanomas of the mucous membranes of the lips and oral cavities treated with surgery alone had died from tumor-related causes,

with an overall MST of 34 months.69 This improved prognosis may reflect the location of these lesions (lip compared with oral cavity) or the degree of differentiation. Nuclear atypia and mitotic index have also been shown to be prognostic in dogs with oral MM.35 

Canine Oral Squamous Cell Carcinoma The prognosis for dogs with oral SCC is good, particularly for rostral tumor locations. Local tumor control is usually the most important challenge, although metastasis to the regional LNs is reported in up to 10% of dogs and to the lungs in 3% to 36% of dogs.24,43,76–85,179 In contrast, SCC of the tonsils and base of the tongue are highly metastatic, with metastasis reported in up to 73% of dogs, and locoregional recurrence is common.138–141,180,181 Surgery and RT can both be used for locoregional control of oral SCC in dogs. Photodynamic therapy has also been reported with fair-to-good results in 11 dogs with smaller oral SCC.182 Surgery is the most common treatment for nontonsillar SCC.13–24,74,78,79,179 Overall local recurrence rates vary from 18% to 23%24,179 and, in one study, local recurrence was significantly associated with incomplete histologic excision.24 After mandibulectomy, the local recurrence rate is 0% to 10% and the MST varies from 19 to 43 months with 88% to 100%, 79%, and 58% 1-, 2-, and 3-year STs, respectively.20,74,78,79 In comparison, the local recurrence rate is 14% to 29% after maxillectomy, with an MST of 10 to 39 months and a 1-, 2- and 3-year survival rates of 57% to 94%, 69%, and 38%, respectively.21,78,79 The reason for the higher local control and survival rates with mandibular resections is probably that the rostral mandible is the most common location for oral SCC in dogs and complete surgical resection is more likely for these rostral tumors. However, tumor location (both mandibular vs. maxillary and location within the oral cavity) was not prognostic after surgical excision in three recent studies.77–79 In one study, the MST for untreated dogs was 54 days, with a 0% 1-year survival rate.78 In comparison, the 1-year survival rate for dogs with surgically excised oral SCC was 94%, with MSTs not reached for dogs with stage I oral SCC and 420, 365, and 50 days for dogs with stage II, III, and IV oral SCC, respectively.78 The presence of tumor-associated inflammation and risk score of 2 or ≥3 (combination of tumor-associated inflammation, lymphatic or vascular invasion, and peripheral nerve invasion) were associated with a significantly worse prognosis.78 In two studies of dogs with surgically resected mandibular and maxillary SCC, overall median disease-free STs were not reached with 1- and 2-year disease-free survival rates of 75% to 79% and 61% to 76%, respectively.76,179 The median disease-free survival was significantly shorter for dogs with grade III SCCs (138 days) and SCCs with a proliferating cell nuclear antigen expression greater than 65% (155 days) compared with dogs with grade II SCCs and SCCs with a proliferating cell nuclear antigen expression ≤65% (not reached).77 In one study, incomplete histologic margins were associated with a significantly worse outcome (MST 1140 days compared with not reached for dogs with complete histologic excision), but dogs with incomplete histologic margins treated with adjuvant hypofractionated RT were significantly less likely to die of tumor-related reasons than dogs not treated with adjuvant RT.179 Full-course RT, either alone or as an adjunct after incomplete surgical resection, is also a successful treatment modality for the management of oral SCC in dogs.43,80,81,179 The local tumor recurrence rate is 31%.80,81 The MST for RT alone is 15 to 16 months and increases to 34 months when combined with surgery.80,81

CHAPTER 23  Cancer of the Gastrointestinal Tract

In one series of 39 dogs with oral SCC, the overall median PFS time was 36 months, with 1- and 3-year PFS rates of 72% and 55%, respectively.43 Local tumor control was more successful with smaller lesions; the median PFS time for T1 tumors (<2 cm diameter) was not reached and greater than 68 months compared with 28 months for T2 tumors (2–4 cm diameter) and 8 months for dogs with T3 tumors (>4 cm diameter).43 Other favorable prognostic factors for dogs receiving orthovoltage irradiation include rostral tumor location, maxillary SCC, and young age.80 Rostral tumors (MST of 28 months compared with 2–10 months for caudal to extensive tumors), nonrecurrent tumors (MST 29 months compared with 7 months for recurrent SCC), portal size less than 100 cm2/m2 (MST 24 months compared with 7 months), and age less than 6 years (MST of 39 months compared with 10 months) are good prognostic factors for dogs treated with orthovoltage RT.80 Younger age is also prognostic for dogs treated with megavoltage RT, as the MST of 315 days for dogs with oral SCC and older than 9 years is significantly shorter than the 1080 day MST for dogs younger than 9 years.81 Chemotherapy is indicated for dogs with metastatic disease, dogs with bulky disease, and when owners decline surgery and RT; however, although responses are noted in the macroscopic (gross disease) setting, durability of response is expected to be short (2–3 months). As the metastatic potential of oral SCC in dogs is relatively low, the role of adjuvant chemotherapy in minimizing the risk of metastatic disease is unknown. In a series of 17 dogs treated with piroxicam alone, the response rate was 17%, with one complete response and two partial responses.82 The median PFI for dogs responding to piroxicam was 180 days and significantly longer than the 102 days for dogs with stable disease.82 The outcome is better when piroxicam is combined with either cisplatin or carboplatin. In a series of nine dogs treated with piroxicam and cisplatin, the overall MST was 237 days, with the 56% of dogs responding to this chemotherapy protocol having a significantly better MST (272 days) than nonresponders (116 days).83 However, renal toxicity was reported in 41% of dogs in this study and such toxicities limit the clinical usefulness of this protocol. In another small series of seven dogs with T3 oral SCC treated with piroxicam and carboplatin, a complete response was observed in 57% of dogs and this response was sustained in all dogs at the median follow-up time of 534 days.84 Novel therapies under investigation include the combination of intralesional bleomycin and feline interleukin-12 (IL-12) DNA with translesional electroporation.54 

Feline Oral Squamous Cell Carcinoma The prognosis for cats with oral SCC is poor. There is no known effective treatment that consistently results in durable control or survival. Local control is the most challenging problem. In one series of 52 cats, the 1-year survival rate was less than 10%, with MSTs of 3 months or less for surgery alone, surgery and RT, RT and low-dose chemotherapy, or RT and hyperthermia.91 However, 42% of these cats had SCC involving the tongue, pharynx, or tonsils. In another series of 54 cats treated in general practice, the MST was 44 days, with a 10% 1-year survival rate.94 The oncologic outcome may be better for cats with mandibular SCC. The MST for seven cats treated with a combination of mandibulectomy and RT was 14 months, with a 1-year survival rate of 57%.89 Local recurrence was the cause of failure in 86% of these cats between 3 and 36 months after therapy. In another series of 22 cats treated with mandibulectomy alone, the median DFI was 340 days.90 Tumor location and extent of resection had prognostic importance, with an MST of 911 days for rostral mandibulectomies,

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217 days after hemimandibulectomy, and 192 days when more than 50% of the mandible was resected.90 Expansile, blastic, and discrete lesions are often more resectable than invasive, lytic, and ill-defined lesions. The use of esophagostomy or gastrostomy tubes may be necessary to provide supplemental nutrition in these cats for up to 4 months postoperatively.90 RT alone is generally considered ineffective in the management of cats with oral SCC. In nine cats treated with an accelerated radiation protocol (14 fractions of 3.5 Gy delivered twice daily for 9 days), the overall MST was 86 days and, although not significant, the MST for cats with a complete response was 298 days.100 The combination of RT with radiation sensitizers or chemotherapy improves response rates and STs. Using the same accelerated radiation protocol with carboplatin resulted in a 52% complete and 22% partial response rate at 30 days with a MST of 163 days in 31 cats.101 Intratumoral etanidazole, a hypoxic cell sensitizer, resulted in a 100% partial response rate in nine cats completing the RT course, with a median decrease in tumor size of 70% and a MST of 116 days.96 Gemcitabine was used at low doses as a radiation sensitizer in eight cats with oral SCC, with an overall response rate of 75%, including two cats with complete responses, for a median duration of 43 days and an MST of 112 days.98 However, gemcitabine is not recommended as a radiosensitizer in cats because of significant hematologic and local tissue toxicities.99 The combination of RT with mitoxantrone holds some promise; in two series of 18 cats, a complete response was observed in 73%, with a median duration of response of 138 to 170 days and an MST of 184 days.97,107 Tumor location, clinical stage, and the completeness of response are reported prognostic factors.101,103 Location was a prognostic factor in this study, with significantly longer MSTs in cats with SCC of the tonsils (not reached, mean 724 days) and cheek (not reached) than other locations.101 A complete response at 30 days was also associated with a significantly longer ST (379 days) than non- or partial responders (115 days).101 Hypofractionated RT has also been reported in cats with oral SCC. An overall response rate of 81%, with an MST of 174 days, was reported in 21 cats treated with an accelerated hypofractionated RT protocol consisting of 10 daily fractions of 4.8 Gy for a total dose of 48 Gy.103 In 54 cats treated with 8 to 10 Gy weekly fractions for a total dose of 24 Gy to 40 Gy, the radiation-induced adverse effects were considered mild, with the majority of owners reporting a subjectively improved quality of life.104 The overall MST was 92 days and cats with sublingual SCCs had a longer MST (135 days) than cats with mandibular SCC (80 days).104 Palliative stereotactic RT has been investigated in 20 cats with a 39% overall response rate and a median PFI and MST of 87 and 106 days, respectively; however, there was a high complication rate with mandibular fracture in 6 of 11 cats, fibrosis in three of six cats with lingual SCC, and oronasal fistula in one of three cats with maxillary SCC.105,106 In this study, cats with a low Bmi-1 percentage, which is an oncogene responsible for suppression of cell-cycle inhibitors and confers resistance to both chemotherapy and RT, had a significantly better outcome with longer median PFI than cats with a higher Bmi-1 percentage.106 Other prognostic factors for cats with oral SCC treated with stereotactic RT include sex, tumor microvascular density, and degree of keratinization.105 Localized irradiation with strontium-90 may be effective for selected cats with very superficial disease.183 Chemotherapy appears to be largely ineffective in the management of cats with oral SCC. No responses were observed in 18 cats treated with liposome-encapsulated cisplatin or 13 cats treated

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with piroxicam.108,110 However, nonsteroidal antiinflammatory drugs (NSAIDs) and toceranib have been shown to significantly improved outcomes in cats with measureable oral SCC.94,111 In one study of 23 cats with oral SCC with no previous treatments, toceranib and/or an NSAID resulted in a biologic response rate of 57%, with a complete response in 4% of cats, partial response in 9% of cats, and stable disease in 43% of cats.111 The MST of cats treated with toceranib and/or an NSAID (123 days) was significantly longer than the 45-day MST for cats not treated with toceranib.111 Cats with a biologic response to treatment with toceranib and/or an NSAID had significantly better median PFS (112 days) and overall MSTs (202 days) than cats that did not respond to treatment (29 days and 73 days, respectively).111 Cats treated with an NSAID also had a significantly improved MST (169 days) than cats not treated with an NSAID (55 days).111 As most of these small case series are retrospective in nature, caveats as to the true efficacy of these therapeutic approaches await conformation in controlled, randomized trial settings. Pamidronate, a bisphosphonate drug with antiosteoclastic activity, has been shown to reduce proliferation of feline cancer cells in vitro and palliate cats with bone-invasive tumors, including oral SCC.112 In a pilot study of five cats with oral SCC treated with pamidronate, some of which were treated with other modalities including NSAIDs, the median PFS time and overall MST were 71 days and 170 days, respectively.112 

Fibrosarcoma The prognosis for dogs with oral FSA is guarded. These are locally aggressive tumors and local control is more problematic than metastasis. Metastasis is reported to the regional LNs in 19% to 22% of dogs and to the lungs in up to 27% of dogs. 12,20–24,43,113– 117,179 Multimodality treatment of local disease appears to afford the best survival rates, with combinations of surgery and RT or RT and hyperthermia.115 Surgery is the most common treatment for oral FSA. Local recurrence has been reported in up to 54% of dogs overall,24,179 up to 59% of dogs after mandibulectomy,20 and up to 40% of dogs after maxillectomy.21 However, a recent retrospective series reported local recurrence in 24% of 29 dogs with mandibular and maxillary FSA.114 Local tumor recurrence was significantly associated with incomplete excision and breed (golden retriever or golden retriever mixed breed dogs).114 Two of the seven dogs with local tumor recurrence developed recurrence after incomplete excision and adjunctive RT.114 In older reports, the 1-year survival rates rarely exceed 50% with surgery alone;13–23 however, the MST in a recent retrospective series was 743 days with a median PFI of greater than 653 days and 1- and 2-year survival rates of 88% and 58%, respectively.114 The median DFI for five cats treated with mandibulectomy was 859 days.90 The combination of surgery and RT may provide the best opportunity to control local disease in dogs regardless of completeness of excision.115 Oral FSAs are considered radiation resistant in the macroscopic (gross) disease setting.116 The mean ST of 17 dogs treated with RT alone was only 7 months.116 When RT is used as an adjunct to surgical resection, local tumor recurrence was reported in 32% of dogs overall and the MST increased to 18 to 26 months with a 1-year PFS rate of 76%.43,117 In one study, 17 of 48 dogs with oral FSA were treated with adjuvant hypofractionated RT and RT did not provide a protective effect with significantly poorer STs in dogs treated with RT.179 However, in another study, the addition of RT to surgery resulted in significantly longer median PFS

(301 days compared with 138 days) and overall MSTs (505 days compared with 220 days) than mandibulectomy or maxillectomy alone.115 A smaller tumor size improves the outcome after RT, with a median PFS time of 45 months for dogs with T1 tumors compared with 31 months and 7 months for T2 and T3 tumors, respectively.43 

Osteosarcoma OSA of axial sites is less common than appendicular OSA and represents approximately 25% of all cases.10 Of the axial OSA, the mandible and maxilla are involved in 27% and 16% to 22% of cases, respectively.10,118 The prognosis for dogs with oral OSA is better than for those with appendicular OSA because of an apparent lower metastatic potential.10,119–122 In one study, only 4% of 183 dogs with maxillary, mandibular or calvarial OSA had evidence of metastasis at the time of diagnosis,12 with distant metastasis reported in 32% to 46% of dogs after definitive treatment.12,24 The outcome after mandibulectomy alone is variable, with MSTs of 14 to 18 months and 1-year survival rates of 35% to 71%.10,20,119 After mandibulectomy, local recurrence and metastasis has been reported in 15% to 28% and 35% to 58% of dogs, respectively.20,121,122 The median metastasis-free interval and MST were 627 days and 525 days, respectively, in one study of 50 dogs.122 After maxillectomy, local recurrence and metastasis were reported in 58% and 32% of 69 dogs, respectively.121 The MST for dogs with maxillary OSA varies from 5 to 10 months, with a 1-year survival rate of 17% to 27% and with local tumor recurrence rather than distant metastasis being the most common cause of death.10,21,118,121 Local tumor control is the most challenging problem and resecting oral OSAs with complete surgical margins is imperative. The completeness of excision was prognostic for both local tumor recurrence and survival in multivariate analyses in one study.121 The combination of surgery with either RT or chemotherapy has not resulted in improved outcomes in dogs with incompletely resected tumors, highlighting the necessity for an aggressive surgical approach.120,121 These results are supported by another study of 45 dogs with axial OSA in which favorable prognostic factors included complete surgical excision, mandibular location, and smaller body weight dogs.118 Other poor prognostic factors for dogs with mandibular, maxillary, and/or calvarial OSA include serum alkaline phosphatase levels greater than 140 units/L, increased monocyte counts, telangiectatic histologic subtype, mitotic index, histologic grade, and local tumor recurrence.121,122 The role of chemotherapy in the management of dogs with oral OSA was considered controversial because local tumor recurrence was the most common cause of tumor-related deaths; however, adjuvant chemotherapy results in significantly longer metastasisfree intervals and STs in dogs with mandibular OSA.122 

Peripheral Odontogenic Fibroma The prognosis for dogs with peripheral odontogenic fibromas is excellent after treatment with either surgery or RT. These are benign tumors, and metastasis has not been reported; hence, local tumor control is the principal goal of therapy. The local tumor recurrence rate after surgical resection without bone removal varies from 0% to 17%,125,126 whereas a 4% local recurrence rate was reported in one study of dogs treated with either mandibulectomy or maxillectomy.24 RT is also effective, with an 3-year PFS

CHAPTER 23  Cancer of the Gastrointestinal Tract

rate of 86%.131 However, definitive RT is usually not required, as these tumors can be adequately managed with simple surgical resection.127 Local recurrence is common in cats with multiple peripheral odontogenic fibromas and is reported in 73% of 11 cats 3 months to 8 years after surgical resection.135 

Acanthomatous Ameloblastoma Surgery or RT is also used in the management of dogs with AA. Mandibulectomy or maxillectomy is required for surgical resection of AAs because of frequent bone invasion by this benign tumor. In one study, 91% of AAs recurred at a mean of 32 days after marginal excision.127 Local recurrence rates after either mandibulectomy or maxillectomy with appropriate margins are less than 5%.13–24,125,128,129 In one study of 263 dogs with AA, complete histologic excision was reported in 67%, 75%, and 100% of dogs with 1.0 cm, 1.5 cm, or 2.0 cm surgical margins, respectively. Despite incomplete histologic excision, the local recurrence rate was 0%, with a mean follow-up of 33 months.129 Megavoltage RT, consisting of an alternate day protocol of 4 Gy per fraction to a total of 48 Gy, results in a 3-year PFS rate of 80% in dogs with AAs.131 The overall local recurrence rate with RT varies from 8% to 18% in two studies of 39 dogs and recurrence was eight times more likely with T3 tumors compared with T1 and T2 tumors.130,131 The majority of tumors recur within the radiation field, which suggests a higher radiation dose may be required to achieve higher rates of local tumor control, particularly for tumors greater than 4 cm in diameter.131 Other complications associated with RT include malignant transformation in 5% to 18% of dogs and bone necrosis in 6% of dogs.130–132 Intralesional bleomycin has been reported in two studies of dogs with AA.133,134 In total, 10 dogs were treated with curativeintent intralesional bleomycin and all had complete responses. In one study of six dogs,134 1 to 16 (median, 5) intralesional injections were administered before a complete response was achieved. The median time to complete response was 1.5 months. There was no evidence of recurrence at 1 year in one study and after a median follow-up of 842 days in another study.134 

Selected Sites or Cancer Conditions in the Oral Cavity Tonsillar Squamous Cell Carcinoma Tonsillar SCC is 10 times more common in animals living in urban versus rural areas, implying an etiologic association with environmental pollutants.184 The most common tonsillar tumor is SCC.185,186 Tonsillar SCC has a significantly higher proportion of grade III lesions and metastatic disease at diagnosis compared with oral SCC at other sites.77 Lymphoma can affect the tonsils, but bilateral tonsillar involvement is more common and this is usually accompanied by generalized lymphadenopathy.185,186 Other cancers, especially MM, can metastasize to the tonsils.185,186 Cervical lymphadenopathy is a common presenting sign, even with very small primary tonsillar cancers. FNA of the regional LNs or excisional biopsy of the tonsil are required for definitive diagnosis. Up to 20% of cases have evidence of pulmonary metastasis at presentation. In spite of disease apparently confined to the tonsil, this disease is considered systemic at diagnosis in more than 90% of cats and dogs.185,186 The CT features of pharyngeal neoplasia have been described, and these are useful in determining the extent of local disease and the presence of LN

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and distant metastasis.185,186 If disease is localized to the tonsils and not infiltrative, then surgery should be considered as part of a multimodal treatment protocol. Simple tonsillectomy is almost never curative, but probably should be done bilaterally because of the high percentage of bilateral disease.10 Cervical lymphadenectomy, especially if the regional LNs are large and fixed, is rarely curative and should be considered diagnostic only. Regional RT of the pharyngeal region and cervical LNs can achieve locoregional control in more than 75% of cases; however, survival still remains poor with 1-year survival rates of only 10%.180,181 Local tumor control and STs were significantly improved in one study of 22 dogs with tonsillar SCC when RT was combined with a variety of different chemotherapy drugs.181 Cause of death is local disease early and systemic disease (usually lung metastasis) later. To date, no known effective chemotherapeutic agents exist for canine or feline SCC, although cisplatin, carboplatin, doxorubicin, vinblastine, and bleomycin have been used with limited success.85,181 In one study of 44 dogs with tonsillar SCC treated with surgery, RT, and/or chemotherapy, the MST was 179 days and dogs presenting with either anorexia or lethargy had significantly shorter STs.187 

Lingual Lingual tumors are uncommon in cats and dogs. In dogs, tongue tumors account for up to 4% of all oropharyngeal neoplasms.188 Neoplasia accounts for up to 54% of canine lingual lesions with 64% of these being malignant tumors.138,140,188 The majority of these tumors are located on the dorsal surface of the tongue, and are evenly distributed between the rostral, mid, and caudal portions of the tongue.138,141 For unknown reasons, 16% of dogs and up to 29% of people with tongue tumors have a second primary tumor.189 Hence, thorough physical examination and clinical staging are important in animals with tongue tumors. White dogs appear to be at higher risk for SCC, even though lack of pigment would not be intuitive as an etiologic contributor as it is in other more sunlight-exposed areas of the body (e.g., nose, eyelids, and ears).139 Other reported breed predilections include Chow Chow and Chinese Shar-Pei for MM; poodle, Labrador retriever, and Samoyed for SCC; border collie and golden retriever for hemangiosarcoma and FSA; and cocker spaniel for plasma cell tumors.188 The most common cancer of the canine tongue is SCC, accounting for up to 50% of cases, followed by MM, mast cell tumor, hemangiosarcoma and hemangioma, granular cell myoblastoma, FSA, adenocarcinoma, neurofibrosarcoma, leiomyosarcoma, rhabdomyoma and rhabdomyosarcoma, myxoma, and lipoma.139,141,188,190 Feline tongue tumors are usually SCCs, and most are located on the ventral surface near the frenulum. Presenting signs are similar to those of other oral tumors. Ulceration is common with SCC. An incisional biopsy, such as a punch or wedge biopsy, is recommended for the diagnosis of tongue lesions in cats and dogs. A biopsy is necessary to differentiate malignant tumors from nonneoplastic lesions, such as eosinophilic granuloma and calcinosis circumscripta, and because a knowledge of the definitive diagnosis may change treatment options (i.e., surgical dose or multimodality therapy with either RT and/or chemotherapy) or the willingness of the owner to pursue curative-intent treatment. Ultrasonography can be useful in delineating the margins of tongue masses to determine surgical resectability.191 Regional LNs should be aspirated for staging purposes and three-view thoracic radiographs evaluated for lung metastasis.

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Surgical resection is recommended,141 whereas RT is reserved for MMs, inoperable cancer, or tumors metastatic to the regional LNs. Surgical resection, involving either marginal excision, subtotal glossectomy, or total glossectomy, was well tolerated in one study of 97 dogs.141 Complications included postoperative bleeding (10%), partial tongue paralysis (2%), and incisional dehiscence (2%); and no dog had long-term prehension difficulties.141 Resection of 50% to 100% of the tongue or avulsion of the tongue was reported in five dogs with minimal postoperative problems, which suggests that more aggressive resections may be possible without compromising quality of life.189 Feeding tubes are recommended for enteral nutrition during postoperative recovery after total glossectomy but, in the long term, eating and drinking are usually only mildly impaired and good hydration and nutrition can be maintained postoperatively.139,189 Hypersalivation is the most common complaint after aggressive resections.189 Thermoregulation can be a problem in hot and humid environments. Grooming in cats will be compromised and may result in poor hair-coat hygiene. The prognosis for tongue tumors depends on the site, size, type, and grade of cancer, completeness of excision, local tumor recurrence, and metastasis.139–141 Cancer in the rostral tongue has a better prognosis, possibly because rostral lesions are detected at an earlier stage, the caudal tongue may have richer lymphatic and vascular channels to allow metastasis, and rostral tumors are easier to resect with wide margins.139 Tumor size was prognostic in two studies. In one study, dogs with tongue tumors greater than 4 cm2 were 10 times more likely to develop local recurrence and/ or distant metastasis and up to 19 times more likely to die of their tongue tumor than dogs with tumors ranging from 1 cm2 to 4 cm2.140 In another study, tumor size was the only variable prognostic on multivariate analysis; dogs with tumors less than 2 cm had a MST of 818 days compared with 207 days for dogs with tumors 2 cm or greater.141 Complete surgical excision was significantly more likely with smaller tumors and tumors located in the rostral free portion of the tongue.139,140 Furthermore, complete surgical excision was significantly associated with increased STs and dogs with incomplete histologic margins were significantly more likely to develop local recurrence and/or distant metastasis and die of their tumor.139,140 Local tumor recurrence has been reported in 26% to 28% of dogs after glossectomy, and is more likely with incomplete histologic excision, large tumors, and malignant tumors.140,141 Dogs with local tumor recurrence were 33 times more likely to die as a result of their tumor than dogs without local recurrence.140 Dogs with benign tongue tumors have a significantly longer DFI and MST than dogs with malignant tongue tumors.140 In one study, the MST for dogs with benign tongue tumors was not reached and greater than 1607 days compared with 286 days for dogs with malignant tongue tumors.140 Dogs with malignant tongue tumors were eight times more likely to have local recurrence and/or distant metastasis and 15 times more likely to die of their tumor than dogs with benign tongue tumors.140 Dogs with metastatic disease have a significantly worse outcome, with an MST of 241 days compared with a MST of 661 days for dogs without metastatic disease.141 Tongue SCCs in dogs are graded from I (least malignant) to III (most malignant) based on histologic features such as degree of differentiation and keratinization, mitotic rate, tissue and vascular invasion, nuclear pleomorphism, and scirrhous reaction.139 The MST for dogs with grade I tongue SCC is 16 months after surgical resection, which is significantly better than the MSTs

of 4 and 3 months reported for grade II and III SCC, respectively.139 The 1-year survival rate is 50% after complete surgical resection and approaches 80% with complete histologic excision of low-grade SCCs.139 Long-term control of feline tongue tumors is rarely reported with 1-year survival rates for tongue SCC less than 25%. The MST for dogs with tongue MM is variable, with 222 days reported in one study,140 but not reached and was greater than 551 days in another study.9 The metastatic rate ranges from 29% to 45%.9,138,140,141 The overall MST for 20 dogs with surgically treated lingual hemangiosarcoma was 553 days.142 Lingual hemangiosarcomas are typically small, located on the ventral aspect of the tongue, and low to intermediate histologic grade.142 Prognostic factors included tumors causing clinical signs and larger tumors. Dogs with clinical signs associated with their lingual hemangiosarcoma had a significantly shorter MST (159 days) than asymptomatic dogs (633 days).142 The MST for dogs with lingual hemangiosarcomas less than 2 cm (633 days) was significantly longer than for dogs with tumors 2 cm to 4 cm (150 days).142 Granular cell myoblastoma is a curable cancer.192 These cancers may look large and invasive, but are almost always removable by conservative and close margins (Fig. 23.9). Permanent local control rates exceed 80%.192 They may recur late, but serial surgeries are usually possible. Metastasis is rare with this cancer. 

•

Fig. 23.9 This large granular cell myoblastoma was easily removed surgically. The dog had a recurrence 2 years postoperatively, which was resected again, and the dog is tumor free 3 years after the second surgery.

CHAPTER 23  Cancer of the Gastrointestinal Tract

Undifferentiated Malignancy of Young Dogs Undifferentiated malignancy is seen in dogs under 2 years of age (range, 6–22 months).193 Most dogs are large breeds and there is no sex predilection. The disease is manifest by a rapidly growing mass in the area of the hard palate, upper molar teeth, maxilla, and/or orbit.193 Biopsies reveal an undifferentiated malignancy of undetermined histiogenesis. The majority of dogs present with metastasis to the regional LNs and distant sites. An effective treatment has not been identified, although chemotherapy would be necessary considering the high metastatic rate. Most dogs are euthanatized within 30 days of diagnosis because of progressive and uncontrolled tumor growth.193 Papillary SCC has been reported to occur in the oral cavity of young dogs (mean age, 3.9 years).74 The most common location is the rostral maxilla, and bone invasion is frequently noted on CT.74 Treatment recommendations include complete surgical resection or surgical cytoreduction and curettage followed by RT (40 Gy in 20 fractions). In two studies, no dogs developed either local tumor recurrence or regional or distant metastasis after treatment with either surgery alone or cytoreductive surgery and RT.74,194 

Multilobular Osteochondrosarcoma MLO is an infrequently diagnosed bony and cartilaginous tumor that usually arises from the canine skull, including the mandible, maxilla, hard palate, orbit, and calvarium.27,28 Histologically, these tumors are characterized by multiple lobules with a central cartilaginous or bone matrix surrounded by a thin layer of spindle cells.27,28 On imaging, MLO is characterized by a typical “popcorn” appearance (Fig. 23.10). Surgery is recommended for management of the local tumor. The overall rate of local recurrence after surgical resection is 47% to 58% and depends on completeness of surgical resection and histologic grade.27,28 The median DFI for completely resected MLO is 1332 days and significantly better than the 330 days reported for incompletely

• Fig. 23.10  A computed tomography image of a multilobular osteochon-

drosarcoma of the vertical ramus of the mandible. Note the characteristic “popcorn” appearance of the mass. After resection of the vertical ramus, this dog was tumor free 3 years after surgery.

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excised tumors.28 In terms of tumor grade, the local recurrence rate for grade III tumors is 78% and significantly worse than the recurrence rates of 30% and 47% for grade I and II MLO, respectively.28 This tumor has a moderate metastatic potential (usually to the lung), which is grade dependent, but usually occurs late in the course of disease. Metastasis is reported in up to 58% of dogs with the median time to metastasis of 426 to 542 days.27,28 Metastasis is significantly more likely after incomplete surgical resection with a 25% metastatic rate in completely excised tumors and 75% after incomplete resection.28 Tumor grade also has a significant effect on metastatic rate with metastasis reported in 78% of grade III MLO compared with 30% of grade I and 60% of grade II tumors.28 There is no known effective chemotherapy treatment for metastatic disease, but STs greater than 12 months have been reported with pulmonary metastasectomy because of the slow-growing nature of this tumor.28 The overall MST is 21 months and is grade dependent, with reported MSTs of 50 months, 22 months, and 11 months for grade I, II, and III tumors, respectively.27,28 Tumor location also has prognostic significance because the outcome for dogs with mandibular MLO is significantly better, with an MST of 1487 days compared with 587 days for these tumors at other sites.28 

Odontogenic Tumors Odontogenic tumors originate from epithelial cells of the dental lamina. They account for up to 2.4% of all feline oral tumors,5 but are rare in dogs. They are broadly classified into two groups depending on whether the tumors are able to induce a stromal reaction.195,196 Inductive odontogenic tumors include ameloblastic fibroma, feline inductive odontogenic tumor, and complex and compound odontomas.196 Ameloblastomas, AAs, and amyloid-producing odontogenic tumors are examples of noninductive odontogenic tumors.195,196 Additional odontogenic tumor groups include tumors composed primarily of odontogenic ectomesenchyme (cementoma and cementifying fibroma), tumors derived from the periodontal ligament (peripheral odontogenic fibroma), cysts of the jaw (dentigerous cyst and radicular cyst), and tumorlike lesions (giant cell epulis and gingival hyperplasia.196 Inductive fibroameloblastoma is the most common odontogenic tumor in cats, usually occurs in cats less than 18 months of age, and has a predilection for the region of the upper canine teeth and maxilla.5,124,195–197 Radiographically the tumor site shows variable degrees of bone destruction, production, and expansion of the mandibular or maxillary bones (Fig. 23.11). Teeth deformity is common. Smaller lesions are treated with surgical debulking and cryosurgery or premaxillectomy. Larger lesions will respond to RT. Local treatment needs to be aggressive, but control rates are good and metastasis has not been reported.5,124 Odontomas are benign tumors arising from the dental follicle during the early stages of tooth development.198 Odontomas induce both enamel and dentin within the tumor. Odontomas have a biologic behavior similar to ameloblastomas. Dentigerous cysts are nonneoplastic, circumscribed cystic lesions originating from islands of odontogenic epithelium.195 They contain one or more teeth embedded in the cyst wall. Radiographs show a characteristic radiolucent halo surrounding the nonerupted tooth originating at the cementoenamel junction and enveloping the crown of the tooth.199 Odontogenic cysts may represent an early stage of malignant epithelial tumors.195 Surgical treatment is recommended, consisting of surgical removal of nonerupted teeth and the cyst lining with possible cancellous bone grafting, to prevent local tumor recurrence.199 

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SECTION B: SALIVARY GLAND NEOPLASIA SARAH E. BOSTON

Incidence and Risk Factors Salivary gland neoplasia in dogs and cats is rare; however, it is a significant cause of salivary disease. In a study of the histopathologic diagnosis of salivary gland biopsies in dogs and cats, 30% were diagnosed with neoplasia.203 The second most common diagnosis in that study was sialadenitis (26%). 

Pathology

• Fig. 23.11  An intraoral radiograph of the rostral mandible in a dog with

an ameloblastoma. Note the expansile mandibular mass. The tumor was curetted and filled with cancellous bone graft and the dog was tumor free 1 year after surgery.

Osteomas Osteomas have been described in both dogs and cats.200,201 Osteomas are benign tumors of histologically normal mature compact and/or trabecular bone.201 They are slow growing and rarely cause clinical signs unless the mass interferes with adjacent structures or prevents occlusion.200,201 Radiographically, osteomas are typically proliferative masses with no evidence of bone lysis.200,201 They are classified as peripheral, central, or extraskeletal in people, and peripheral and central osteomas have been described in dogs.200,201 Surgical excision is usually curative.200,201 

Comparative Aspects202 SCC accounts for the vast majority of oral cancer in humans. Oral tumors are associated with alcohol and tobacco use and usually occur in patients more than 40 years old. Patients with oral cancer have an increased risk of developing esophageal and lung cancer. Tumors are staged similar to animals and clinical stage influences both treatment options and prognosis. Surgery and RT are the only options that provide the opportunity for a cure. Surgery and radiation are occasionally combined, especially because neither modality is likely to achieve a cure rate greater than 70% when used as sole therapy. Chemotherapy has a limited role for control of local disease but has shown promise, often in combination with radiation, for advanced stage cancer. Prognosis is strongly correlated to histologic grade, stage, and site. Metastasis, particularly to the regional LNs, is more frequent with tonsillar and pharyngeal SCC and larger sized tumors. Tumors of the pharynx and caudal tongue are associated with a worse prognosis than cancers of the rostral tongue and oral cavity because of the higher incidence of nodal metastasis and difficulty in controlling disease once it has spread beyond the primary site. 

Salivary gland neoplasms are primarily malignant epithelial tumors. Simple adenocarcinoma is the most common histopathologic diagnosis, with other types of carcinomas being represented second most commonly.204 Other reported tumors in this location include oncocytoma205 and carcinosarcoma in cats206; and pleomorphic adenoma,207 myoepithelioma,208 OSA,209 and mast cell tumor in dogs210; however, these are single case reports and are rare. 

History and Clinical Signs Clinical signs of salivary neoplasia and sialadenitis may be similar. The most common presenting complaint in a retrospective of salivary gland neoplasia in dogs and cats was the presence of a mass.204 Other presenting complaints included halitosis, weight loss, anorexia, dysphagia, exophthalmos, Horner’s syndrome, sneezing, and dysphonia.204 In one retrospective study of dogs and cats, there appeared to be a predilection for male sex and Siamese breed in cats.204 In that study, the mandibular salivary gland was most commonly affected in cats and the parotid salivary gland was most commonly affected in dogs.204 

Diagnostic Techniques and Workup An FNA for cytology should be performed as a first step in attempting to distinguish between benign and malignant disease.211 If this is not successful, a needle-core, incisional, or possibly an excisional biopsy can be considered for histopathology. Salivary gland adenocarcinoma is both locally aggressive and has metastatic potential, and hence local and distant staging should be considered before definitive treatment. Thoracic radiographs or CT can be performed to assess the lungs for metastatic disease. An ultrasound of the affected area can also be performed for initial staging and possibly to obtain an ultrasound-guided aspirate of the mass and/or regional LNs.212 The medial retropharyngeal LNs are the primary lymphatic drainage center of the salivary glands and should be evaluated cytologically and/or biopsied for histopathology.213 Ultimately, a CT scan of the head and thorax is recommended for staging and surgical planning.212 In cases where surgery may not be possible, the patient should be positioned for a concurrent radiation planning CT for potential RT alone. In one retrospective study, cats presented at a more advanced stage of disease than dogs, suggesting that this disease may be more aggressive in cats.204 

Therapy Surgery is the mainstay of therapy. Using a CT scan for surgical planning, the affected salivary gland is removed. By definition,

CHAPTER 23  Cancer of the Gastrointestinal Tract

this is a marginal excision. However, the degree of tumor encapsulation will help guide whether or not adjunctive RT is indicated. Regional LNs should be sampled for staging purposes. The surgical approach to the affected mandibular or parotid salivary gland is generally straightforward. If the parotid salivary gland is removed, care must be taken to identify and protect the facial nerve. If this is not possible, facial nerve paralysis may occur. In rare cases of zygomatic salivary neoplasia,214,215 the zygomatic salivary gland is approached via an orbitotomy and removal of the zygomatic arch.214 

Prognosis In one retrospective study of dogs and cats with salivary gland neoplasia, the median survival times were 550 days and 516 days for dogs and cats, respectively.204 In that study, patients were treated with surgery alone or in combination with RT or chemotherapy.204 The small number of patients treated with adjunctive therapy in that study makes it difficult to make a general recommendation for adjunctive therapy. Postoperative RT is generally recommended, especially in cases where the tumor is invasive and has extended beyond the capsule.216 Recommendations for chemotherapy are less defined due to the paucity of information in the literature, but may be indicated in cases with evidence of metastatic disease and with highly malignant histopathology. 

Comparative Aspects Salivary gland adenocarcinoma has been reported in many other mammalian species other than dogs and cats.217–225 Treatment of salivary carcinoma in humans is commonly surgery followed by RT.226–229 Factors that have been associated with a negative prognosis in one study included male sex, perineural invasion, high risk pathology, and late stage.226 Another study found that age, sex, stage, site, and skin or bone invasion were significantly associated with survival.227 The use of postoperative RT has been shown to improve locoregional control.227 Local control has been shown to be significantly associated with tumor stage and treatment type, with the combination of RT and surgery being superior to surgery alone.228 Tumor stage was significantly associated with survival.228 Five- and 10-year survival rates are 68%229 and 50%, respectively.227 A 20-year actuarial rate of local control of 57% was reported in one study with a 12-year probability of distant metastasis of 40%.227 

SECTION C: ESOPHAGEAL TUMORS PIERRE M. AMSELLEM AND JAMES P. FARESE

Incidence and Risk Factors Esophageal neoplasia is rare in dogs and cats. Esophageal sarcomas have been reported in association with infestation by the nematode Spirocerca lupi.230–237 Although this parasite has been reported worldwide (South Africa, Kenya, India, Israel, the southeastern United States), Spirocerca lupi–associated esophageal granulomas and sarcomas are reported mainly in Israel.230–237 Leiomyomas may have a genetic component, as a high incidence was reported in a colony of laboratory beagle dogs.238 Most animals with esophageal tumors are middle-aged or older and there does not seem to be a gender predisposition. 

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Pathology and Behavior It is postulated that with spirocercosis-associated sarcomas, a parasitic esophageal granuloma undergoes malignant transformation leading to the development of an esophageal sarcoma, typically in the caudal thoracic portion of the esophagus.234 Histologic types of spirocercosis-associated sarcomas include OSAs, fibrosarcomas, and undifferentiated sarcomas.239 Metastasis to the lungs was reported in 5 of 11 dogs at necropsy.234 Additional metastatic sites included kidneys, adrenals, stomach, regional LNs, tongue, and the heart.234 Complicating factors include the presence of megaesophagus and hypertrophic osteopathy.234 Plasmocytoma,240 adenomatous polyp,241 leiomyosarcoma,242 carcinoma,243 adenocarcinoma,243 adenosquamous carcinoma,244 and squamous cell carcinoma245 have also been reported in dogs, but these are rare. Squamous cell carcinoma is the most common esophageal tumor in cats, typically occurring in the middle third of the esophagus just caudal to the thoracic inlet.246,247 Leiomyomas are benign tumors of the muscularis of the esophagus. They have been reported in the distal esophagus near the gastroesophageal junction in dogs.238,248 In some cases, multiple leiomyomas can occur in the distal esophagus and the stomach.232,233 Leiomyomas do not invade the esophageal mucosa. In contrast, low-grade leiomyosarcomas occasionally penetrate the esophageal mucosa.242 Paraesophageal tumors, such as thyroid, thymic, or heart base tumors, can invade the esophagus.249,250 

History and Clinical Signs Clinical signs are usually related to obstruction of the esophagus, leading to regurgitation and weight loss. The presence of ulceration of the mass can cause melena and secondary anemia. Respiratory signs can occur if aspiration pneumonia or metastatic disease develops. Leiomyomas often are an incidental finding but can occasionally cause signs associated with esophageal obstruction.232,233,243 

Diagnostic Tests and Workup Diagnostic tests for esophageal masses usually include survey thoracic radiographs, contrast esophagram, esophagoscopy (Fig. 23.12), and CT scan (Fig. 23.13).242 Survey radiographs may show retention of gas within the esophageal lumen, a mass, or esophageal dilatation proximal to the mass (Fig. 23.14). Spondylitis on the ventral aspect of the vertebral body T6 to T12 was detected radiographically in 12 of 15 dogs with spirocercosis-associated esophageal sarcoma.234 A positive-contrast esophagram may show a stricture or mass lesion in the esophageal lumen. Ultrasound- or CT-guided aspirates can be performed for cytologic evaluation. Endoscopic biopsies of esophageal masses are possible; however, for smooth muscle tumors, such as leiomyomas and leiomyosarcomas, they are usually unrewarding, as these tumors do not penetrate the esophageal mucosa.242,248 A surgical approach may be needed in these cases to obtain an incisional biopsy; however, given the invasive nature of the surgical approach, most biopsies are excisional. A fecal flotation test may be performed in dogs with esophageal masses to test for Spirocerca lupi eggs, particularly in areas where the parasite is endemic. This is a poorly sensitive test; eggs were detected in only two of eight dogs in one study of spirocercosisassociated sarcomas.234 

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• Fig. 23.14  Lateral

thoracic radiographic image of a large (8 cm long × 6 cm wide) leiomyosarcoma in the caudal esophagus, just cranial to the diaphragm. (From Farese JP, Bacon NJ, Ehrhart NP, et al. Oesophageal leiomyosarcoma in dogs: surgical management and clinical outcome of four cases. Vet Comp Oncol. 2008;6(1):31–38.)

• Fig. 23.12 Esophagoscopic

view of an esophageal leiomyosarcoma in a dog. (From Farese JP, Bacon NJ, Ehrhart NP, et al. Oesophageal leiomyosarcoma in dogs: surgical management and clinical outcome of four cases. Vet Comp Oncol. 2008;6(1):31–38)

Esophageal tumor

Right

Left

Heart

• Fig. 23.13  Computed tomographic image of an esophageal leiomyosar-

coma in a dog. (From Farese JP, Bacon NJ, Ehrhart NP, et al. Oesophageal leiomyosarcoma in dogs: surgical management and clinical outcome of four cases. Vet Comp Oncol. 20089;6(1):31–38.)

Treatment Options Most esophageal cancers have extensive local involvement that typically precludes curative-intent therapy. In dogs with esophageal sarcomas, partial esophagectomy has been reported.251 The authors’ preferred approach is to perform an esophagotomy opposite to the esophageal mass to visualize the mass from

within the esophageal lumen.251 A full-thickness esophagectomy can then be performed to resect the mass with a minimum of 1-cm margins.251 Endoscopic laser or electrocautery debulking of esophageal sarcomas has also been reported.236 In one study, there was no difference in survival times between dogs treated with surgery and dogs treated with endoscopic ablation.233 Leiomyomas and low-grade leiomyosarcomas can be marginally excised via an intercostal thoracotomy or laparotomy.248 Marginal excision appears to provide good long-term local tumor control for most dogs with esophageal leiomyomas. In contrast, marginal excision resulted in incomplete histologic excision in three of four dogs with esophageal leiomyosarcomas; however, local tumor recurrence was confirmed in only one dog and clinical signs of recurrence may not develop because of the slow-growing nature of this tumor.242 More aggressive excision with end-to-end resection of esophageal tumors can be curative,240 but this is often not possible because of the extent of the resection required and/or the location of the mass. Resection of caudal esophageal masses is possible with gastric advancement through the diaphragm,243 but persistent gastroesophageal reflux and esophagitis can occur.250 Nonsurgical treatment options for esophageal tumors have not been established. There are no published reports in dogs or cats documenting successful treatment with either chemotherapy or radiation therapy, either alone or as an adjuvant therapy. Successful palliative treatment by placement of esophageal stents has been reported in the management of a squamous cell carcinoma252 and of a leiomyoma in dogs.253 

Prognosis Except for leiomyoma and low-grade leiomyosarcomas, the overall prognosis for dogs and cats with esophageal tumors is guarded to poor because of the extent of local disease and/or the presence of metastasis at the time of diagnosis. In one study on 17 dogs with spirocercosis-associated esophageal sarcomas, five dogs treated with partial esophagectomy and adjuvant doxorubicin survived a median of 267 days.234

CHAPTER 23  Cancer of the Gastrointestinal Tract

The prognosis for dogs and cats with esophageal carcinomas seems to be poor, as most tumors are unresectable.243,250 The prognosis for dogs with esophageal leiomyomas after marginal excision appears to be good in a small case series of three dogs248 and an additional case report,243 although local recurrence was reported in one dog. Similarly, dogs with low-grade leiomyosarcomas had good long-term resolution of clinical signs after marginal excision, despite incomplete histologic margins in three of four dogs.242 

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Diagnostic Techniques and Workup

Almost all cancers of the pancreas are epithelial and most are malignant adenocarcinoma of ductular or acinar origin. Nodular hyperplasia is a common asymptomatic finding in older dogs and cats. Benign pancreatic pseudocysts and adenomas have been diagnosed by ultrasonography or surgery in dogs and cats.256,263 In the vast majority of cases, malignant pancreatic cancer has metastasized to regional or distant sites before a diagnosis can be made.260,264 

Most hematologic and biochemical evaluations are nonspecific, but may include mild anemia, hyperglycemia, neutrophilia, and bilirubinemia (if occluding the common bile duct).256 Elevations of serum amylase and lipase are inconsistent.269 In extreme cases, signs of pancreatic insufficiency may be exhibited.270 In the dog, most tumors are not palpable through the abdominal wall. In the cat, late-stage, large palpable masses may be present. Positive-contrast upper GI radiographs may reveal slowed gastric emptying and occasionally compression or invasion of the duodenum. Ultrasonography should be a useful diagnostic tool for localization of the primary tumor, documentation, and aspiration of fluid, as well as metastasis to liver and regional LNs.271 Ascites may be a clinical sign and, when present, may reveal malignant cells on cytologic examination (carcinomatosis). A large (>2 cm) solitary mass is suggestive of pancreatic cancer rather than nodular hyperplasia in cats.272 Contrast ultrasound has been assessed for distinguishing between pancreatic adenocarcinoma or insulinoma in four dogs.273 In B-mode ultrasound, a hypoechoic nodule was present in the pancreas in three dogs, whereas heterogeneous pancreatic tissue was evident in the other dog. Contrast ultrasound could differentiate between the two tumors: adenocarcinomas appeared as hypoechoic and hypervascular lesions whereas insulinomas showed uniformly hypervascular lesions.273 The utility of advanced imaging such as CT and MRI has not been documented for exocrine pancreatic tumors in veterinary patients. At present, most diagnoses are made at exploratory celiotomy. Immunohistochemical markers have been evaluated for aiding diagnosis of pancreatic carcinoma in dogs. More specifically, the expression patterns of claudin-4, a tight junction molecule, and claudin-5, an endothelium specific tight junction protein, were compared between well-differentiated and poorly differentiated pancreatic acinar cell carcinomas and normal pancreatic tissues.274,275 Claudin-4 was present laterally in normal pancreatic acinar cells and intense apical lateral position in cells from a well-differentiated exocrine pancreatic carcinoma. Poorly differentiated exocrine pancreatic adenocarcinomas demonstrated a loss of claudin-4 expression.274 The authors concluded claudin-4 immunohistochemistry may be useful to distinguish well-differentiated and undifferentiated exocrine pancreatic carcinomas.274 Claudin-5 has also been evaluated in this manner with expression documented in lateral membranes of exocrine acinar cells and the endothelial cells of vessels and lymphatics within the stroma of the intact pancreas. The well- and poorly differentiated carcinomas showed loss of claudin-5 expression.275 

History and Clinical Signs

Therapy

The history and clinical signs of exocrine pancreatic cancer are vague and nonspecific and may mimic or be accompanied by pancreatitis. Weight loss and anorexia (marked in cats),265 paraneoplastic alopecia in cats,266,267 vomiting, rare associated diabetes mellitus,265,268 abdominal distension due to a mass effect or abdominal effusions secondary to tumor implantation on the peritoneum (i.e., carcinomatosis; common in cats), icterus (with common bile duct obstruction), and lethargy are common symptoms.265 Alternatively, patients may present for symptoms of metastatic disease. 

Most non–islet cell carcinomas of the pancreas are locally invasive and metastatic to regional LNs and liver at diagnosis. If liver, peritoneal cavity, or draining LNs are positive for tumor, aggressive surgery should generally not be performed. Total pancreatectomy or pancreaticoduodenectomy (Whipple’s procedure) have been described in humans and dogs,276 but carries a high operative morbidity and mortality without significant cure rates and is not recommended. Bypass procedures, such as gastrojejunostomy or cholecystoduodenostomy, are short-term palliative options for patients with

Comparative Aspects A high mortality rate is associated with esophageal cancers in humans.254 The American Cancer Society predicts that 17,290 new cases of esophageal cancers will occur in 2018, causing 15,850 deaths.254 The most common esophageal cancer in the United States of America is adenocarcinoma followed by squamous cell carcinoma.254 Adenocarcinoma has a predilection for the distal esophagus.255 Risk factors include obesity, male gender, alcohol and tobacco consumption, gastroesophageal reflux, and Barrett esophagus.255 Barrett esophagus consists of metaplasia of the esophageal mucosa secondary to severe gastroesophageal reflux and may be a preneoplastic lesion.255 

SECTION D: EXOCRINE PANCREATIC CANCER LAURA E. SELMIC

Incidence and Risk Factors Cancer of the exocrine pancreas is very rare (<0.5% of all cancers) in the dog and the cat.256,257 Incidence rates of pancreatic cancer have been estimated at 17.8 per 100,000 patient years for dogs and 12.6 per 100,000 patient years for cats.258 Older female dogs and spaniels have been described as being at higher risk.259–261 Experimentally, N-ethyl-N′-nitro-N-nitrosoguanidine has been shown to induce pancreatic duct adenocarcinoma when administered intraductally in dogs.262 

Pathology and Natural Behavior

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imminent or present gastrointestinal or common bile duct obstruction, respectively. Radiation therapy and chemotherapy have shown limited value in humans and animals. Occasionally, uncomfortable effusions from carcinomatosis can be diminished with systemic or intracavitary chemotherapy (see Chapter 12); however, the palliative response tends to be short lived. 

Prognosis The outlook for this disease in companion species is very poor because of its critical location and advanced stage at diagnosis. In a recent study evaluating the outcome for 34 cats with pancreatic carcinoma, the overall median survival time was 97 days and, for cats treated with either chemotherapy or surgery, the median survival time was 165 days.265 Cats with abdominal effusion at diagnosis survived a median of 30 days.265 Only three cats survived greater than 1 year.265 

Comparative Aspects277–279 Pancreatic exocrine carcinoma accounted for an estimated 53,670 new cases and 43,090 deaths in the United States in 2017.278 Several risk factors have been identified, including older age, inherited susceptibility, cigarette smoking, obesity, and diabetes mellitus. Most patients have disease progression beyond the pancreas at the time of initial diagnosis. Seventy-five percent are located in the head of the pancreas and the remainder in the body and tail of the pancreas. Direct extension to duodenum, bile duct, and stomach, as well as common metastasis to LNs and liver, make treatment difficult. Treatments that are currently used include surgery (curative or palliative), radiotherapy (as an adjuvant or for treatment of advanced local disease), and systemic chemotherapy. Surgical resection is the mainstay of treatment for pancreatic carcinoma in humans, especially if the patient has a small tumor localized to the pancreas. Depending on the extent of disease within the pancreas, other surgical procedures include pancreaticoduodenectomy (Whipple’s procedure) or total pancreatectomy. With recent advances in surgical technique, the mortality associated with these procedures has decreased; however, considerable patient morbidity still exists. Removal of the entire pancreas necessitates management of the patient for exocrine pancreatic insufficiency and diabetes mellitus. After surgery, chemotherapy is recommended to improve survival, but there is no superior single chemotherapeutic approach. In patients whose tumors are determined to be borderline resectable, chemotherapy is administered for 2 to 4 months and then, if the patient is still free from metastases, surgery or chemoradiation can be considered. Treatments for locally advanced or widely metastatic disease are palliative, but include chemotherapy alone or chemoradiation. If biliary outflow is obstructed, several procedures may be indicated including surgical bypass, endoscopic biliary stenting, or percutaneous biliary decompression. Palliative bypass of gastric outflow obstruction can be performed by open gastrojejunostomy, laparoscopic gastrojejunostomy, duodenal stenting, or decompressive gastrostomy tube. Despite recent developments and research into treatment of this disease, the prognosis remains poor, with overall 5-year survival rates for all patients less than 6%.280 

SECTION E: GASTRIC CANCER OWEN T. SKINNER

Incidence and Risk Factors Gastric cancer is rare in small animals, comprising 0.16% of cancers in one large study.281 The causes of gastric cancers have not been identified in dogs.281–284 Gastric carcinoma has been experimentally induced in dogs with nitrosamines; however, the clinical relevance of these findings is unclear.285 Hypergastrinemia is a risk factor in humans, typically associated with atrophic gastritis caused by Helicobacter pylori.286 Although gastrin levels have not been reported to be increased in small populations of dogs with gastric carcinoma, individual dogs have been noted with substantial increases in serum gastrin.287,288 H. pylori infection is rare in dogs.289 Non–H. pylori Helicobacter species are highly prevalent in dogs, although the clinical significance of these organisms is uncertain, with both mild gastritis and asymptomatic presentations reported.289–291 Gastric carcinoma is the most common nonhematopoietic gastric tumor in dogs.292–294 Breeds at higher risk of gastric carcinoma include the Tervueren, Bouvier des Flandres, Groenendael, collie, standard poodle, Norwegian elkhound, and Norwegian lundehund.281,287,295–297 Mean age at presentation is typically 8 to 10 years.281,283,284,293,294 Male dogs are consistently overrepresented, with a male-to-female ratio of approximately 1.5:1.281,292– 294,298 The most common mesenchymal tumors of the stomach are smooth muscle tumors (leiomyomas and leiomyosarcomas) and gastrointestinal stromal tumors (GISTs). These occur with similar frequency in male and female dogs, with a mean age at diagnosis of approximately 11 years.299 Other reported canine gastric tumors include mast cell tumor (MCT),300 histiocytic sarcoma,301,302 plasmacytoma,303 and undifferentiated sarcoma.304 Lymphoma is the most common primary gastric malignancy in cats.305 Gastric carcinoma is rare in cats, representing fewer than 5% of feline gastrointestinal carcinoma cases.306–308 Gastritis and Helicobacter have been proposed as risk factors for feline gastric carcinoma and lymphoma.309,310 Other reported feline gastric tumors include MCT,311 carcinoid,312 hamartoma,313 and polyps.314 

Pathology and Natural Behavior Gastric carcinoma is classified as either “intestinal” (with papillary, acinar, or solid subtypes) or “diffuse” (with undifferentiated or glandular subtypes).298,315 Intestinal type tumors in humans are thought to arise from sequential progression through gastritis, metaplasia, and dysplasia, whereas diffuse type tumors may be associated with mutation or methylation of CDH1.316 The diffuse histologic type is more common in dogs.283,287,298 Canine gastric carcinoma commonly arises in the pylorus or lesser curvature, although some carcinomas may lead to diffuse, firm thickening of the stomach (linitis plastica).281,293,296,298,317 Ulceration is common and may progress to full-thickness perforation and peritonitis.294 Metastasis to regional LNs is common (32% at presentation and 77% at postmortem), with liver and lungs less frequently affected.292,298 Many mesenchymal tumors previously diagnosed as leiomyosarcomas have been reclassified as GISTs.299,304 Gastric leiomyoma and leiomyosarcoma are typically focal, with or

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453

without cavitating ulceration, and are most often found at the cardia or pylorus.293,318–321 Paraneoplastic hypoglycemia has been reported with leiomyoma and leiomyosarcoma, possibly due to excessive release of IGF-2.320,321 Although smooth muscle tumors are more common in the stomach, approximately 10% to 20% of GISTs arise at this site.299,304,322 GISTs arise from the interstitial cells of Cajal, which normally express c-Kit (CD117) and may also express CD34, and hence immunohistochemistry (IHC) is required to differentiate leiomyosarcomas from GISTs.322,323 Mutations in exon 11 of the c-kit gene are common in canine GIST and mutations in exon 9 have been reported.299,324–327 GISTs are rare in cats.328 Gastric involvement of feline alimentary lymphoma is relatively uncommon.329,330 Readers should refer to Chapter 33, Section B (Feline Lymphoma and Leukemia) for further information regarding gastric lymphoma. 

History and Clinical Signs

• Fig. 23.15  Dorsal plane computed tomography image of a dog with an ulcerated and cavitated pyloric leiomyosarcoma (white arrowhead).

Vomiting is the most common clinical sign, with or without associated hematemesis, in cats and dogs with gastric tumors.284,292 Weight loss, anorexia, melena, diarrhea, and abdominal pain may also be encountered. Gastric cancer should be considered as a potential cause of septic peritonitis or pneumoperitoneum. Duration of clinical signs may vary widely, but is commonly in the order of 1 to 2 months.292,294 

Diagnostic Techniques and Workup Routine blood tests are not expected to be diagnostic, but may reveal anemia, hypoalbuminemia, thrombocytopenia, or thrombocytosis in patients with hemorrhage associated with ulceration.284,292 Hepatocellular leakage enzymes may be increased with liver metastasis. Abdominal radiographs may identify changes such as a cranial abdominal mass, loss of serosal detail, or apparent thickening of the gastric wall. Contrast radiography may be helpful to identify delayed gastric emptying. Given the limited detail typically observed on radiographs, this modality has been largely superseded by abdominal ultrasound and, increasingly, CT (Fig. 23.15).292,331–333 Gastric carcinomas tend to be broad-based on imaging, whereas mesenchymal tumors and benign lesions may be more focal or pedunculated.314,334 Intraluminal gas can make ultrasonography challenging.335 Thoracic imaging, whether radiographs or CT, should be assessed as part of the clinical staging protocol, but pulmonary metastasis at presentation is rare in patients with gastric cancer.292,304 Gastroscopy can provide complementary information to the findings of diagnostic imaging (Fig. 23.16).335 Multiple biopsies of any gastric lesions should be obtained, given the potential for acquisition of nondiagnostic samples in dogs and cats with gastric pathology.336 If the disease process does not involve the mucosa, diagnosis from endoscopic biopsies can be challenging. Surgical biopsies may be considered if a diagnosis cannot be obtained with gastroscopy. Histopathology is the gold standard for diagnosis; however, squash preparation cytology, with assessment for the presence of signet ring cells and/or cytoplasmic microvacuolation, is sensitive (94%) and specific (94%) for gastric carcinoma.337 IHC should be considered if there is doubt regarding tumor type.299,304 FNA cytology of gastric masses has poor agreement (50%) with definitive histopathology in dogs and cats.308 

• Fig. 23.16  Ulcerated gastric carcinoma seen at gastroscopy in a dog.

Treatment Resection of local disease may be considered in patients with solid tumors without evidence of either diffuse disease or distant metastasis. Surgery, if feasible, typically consists of various partial gastrectomy procedures. For tumors located in the pyloric region, surgical resection often requires a gastroduodenostomy (Billroth I).293,338 Gastrojejunostomy (Billroth II) has been performed for patients with more extensive disease; however, outcomes are guarded because of persistent vomiting, poor appetite, and progressive disease with poor survival times of only 4 to 5 weeks.293,339 Partial gastrectomy is recommended for tumors located in the gastric body. If surgery is pursued, complete abdominal exploration should be performed to assess for metastasis, with particular attention paid to all abdominal LNs and the liver. Benign lesions, such as leiomyomas, can be excised with a marginal approach.319 Adjuvant RT is used in humans after resection of gastric carcinomas, but RT has played a minimal role in dogs because of the proximity of sensitive tissues.340

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PA RT I V     Specific Malignancies in the Small Animal Patient

The role of chemotherapy for animals with solid gastric tumors is unclear. Response of carcinomas to chemotherapy has typically been poor, although multiple protocols have been attempted.284,292,293 Expression of HER-2 is common in canine gastric carcinoma (58%), and this may represent a therapeutic target in dogs; however, clinical data are not available.341 Responses to imatinib have been reported in dogs with GISTs, but large-scale studies are lacking.324,325 

TABLE 23.6  Morphologic Types of Canine Hepatic

Tumors

Massive (%)

Nodular (%)

Diffuse (%)

Hepatocellular carcinoma

53–84

16–25

0–19

Bile duct carcinoma

37–46

0–46

17–54

Prognosis

Neuroendocrine tumor

0

33

67

Gastric carcinoma typically carries a poor prognosis because of the difficulty in achieving local tumor control and a moderateto-high metastatic rate. Long-term survival is possible after partial gastrectomy, but survival times are usually less than 6 months.292–294,297,338,342,343 Given the challenges with controlling systemic disease, few dogs with gastric carcinoma are good surgical candidates and careful case selection is critical. Improvements in systemic therapies may increase the number of animals considered candidates for surgery. The median survival times for dogs with GIST, leiomyosarcoma, and undifferentiated sarcoma, provided they survive the perioperative period, are 37.4 months, 8 to 12 months, and 2.9 months, respectively.304,318 The prognosis is excellent after surgical resection of leiomyoma, with the majority of dogs cured.319,344 The median survival times for dogs and cats with gastrointestinal MCTs are less than 1 month300 and 531 days, respectively.311 

Sarcoma

36

64

0

Comparative Aspects In 2012 gastric cancer was the third most common cause of cancer-related death in men worldwide and the fifth most common cause of cancer-related death in women.345 Men are approximately twice as likely to be affected as women.346 Approximately 89% of noncardia gastric cancer in humans is associated with H. pylori.347 Significant geographic differences are observed in the incidence of gastric carcinoma and this may be a result of H. pylori prevalence, socioeconomic status, and likely genetic susceptibility.316,347 Mortality rates are approximately 60% to 80%, reflecting advanced disease at presentation and an aggressive disease course.348 Treatment of local gastric tumors varies from endoscopic mucosal resection for superficial lesions to partial or total gastrectomy for more infiltrative and advanced lesions.349,350 Adjuvant therapy, particularly chemoradiotherapy, is common in patients with advanced gastric cancer, although improvements in survival are often limited.340,351 Targeted therapies, including trastuzumab targeting of HER-2, have shown promise, but improvements in outcome are still small for most patients.352 

SECTION F: HEPATOBILIARY TUMORS JULIUS M. LIPTAK

Incidence and Risk Factors Primary hepatic tumors are uncommon and account for fewer than 1.5% of all canine tumors and 1.0% to 2.9% of all feline tumors, but up to 6.9% of nonhematopoietic tumors in cats.353– 356 Metastasis to the liver from nonhepatic neoplasia is more common and occurs 2.5 times more frequently than primary liver

• Fig. 23.17  A solitary hepatocellular carcinoma with classic massive liver

tumor morphology. A liver lobectomy is being performed using a thoracoabdominal surgical stapling device.

tumors in dogs, particularly from primary cancer of the spleen, pancreas, and GI tract.353,354 Primary hepatobiliary tumors are more common than metastatic disease in cats.356 The liver can also be involved in other malignant processes, such as lymphoma, malignant histiocytosis, and systemic mastocytosis.354,355 Nodular hyperplasia is a relatively common diagnosis in older dogs but is benign and probably does not represent a preneoplastic lesion.356 There are four basic categories of primary malignant hepatobiliary tumors in cats and dogs: hepatocellular, bile duct, neuroendocrine (or carcinoid), and mesenchymal.356 Malignant tumors are more common in dogs, whereas benign tumors occur more frequently in cats.354–360 There are three morphologic types of these primary hepatic tumors: massive, nodular, and diffuse (Table 23.6).357 Massive liver tumors are defined as a large, solitary mass confined to a single liver lobe (Fig. 23.17); nodular tumors are multifocal and involve several liver lobes (Fig. 23.18); and diffuse involvement may represent the final spectrum of neoplastic disease with multifocal or coalescing nodules in all liver lobes or diffuse effacement of the hepatic parenchyma (Fig. 23.19).356,357 The prognosis for cats and dogs with liver tumors is determined by histology and morphology. The prognosis is good for massive hepatocellular carcinomas (HCC) and benign tumors because complete surgical resection is usually achievable and their biologic behavior is relatively nonaggressive with an indolent growth rate.359–363 In contrast, the prognosis is poor for cats with any type of malignant tumor, dogs with malignant tumors other than massive HCC, and cats and dogs with nodular and diffuse liver tumors because resection is less feasible and/or metastasis is more common.354–366

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455

Pathology and Natural Behavior Hepatocellular Tumors

• Fig. 23.18  Nodular morphologic appearance of a bile duct carcinoma in a cat.

• Fig. 23.19  Diffuse morphologic appearance in a dog with a bile duct carcinoma.

Hepatocellular tumors include HCC, hepatocellular adenoma (or hepatoma), and hepatoblastoma.356 Hepatoblastoma is a rare tumor of primordial hepatic stem cells and has only been reported in one dog.369 Hepatocellular adenoma is usually an incidental finding and rarely causes clinical signs.354 Of the hepatocellular tumors, hepatocellular adenoma is more common in cats and HCC occurs more frequently in dogs.354,357,358 HCC is the most common primary liver tumor in dogs, accounting for up to 77% of cases, and the second most common in cats.354–360,367 Etiologic factors implicated in the development of HCC in humans include infection with hepatitis virus B or C and cirrhosis.370 A viral etiology has also been demonstrated in woodchucks but not in cats or dogs, and cirrhosis is rare in dogs with HCC.358–361 A link between progressive vacuolar hepatopathy and HCC has been proposed in Scottish terriers, with HCC diagnosed in 34% of Scottish terriers with progressive vacuolar hepatopathy.371 In one study, 20% of dogs with HCC were diagnosed with additional tumors although most were benign and endocrine in origin.357 A breed and sex predisposition has not been confirmed in dogs with HCC, but miniature schnauzers and male dogs are overrepresented in some studies.357,361,363,372 Morphologically, 53% to 83% of HCCs are massive (see Fig. 23.17), 16% to 25% are nodular, and up to 19% are diffuse.354,357 The left liver lobes, which include the left lateral and medial lobes and papillary process of the caudate lobe, are involved in more than two-thirds of dogs with massive HCC,357,361–363 but tumors are equally distributed between the left and right liver lobes in cats.373 Metastasis to regional LNs, peritoneum, and lungs is more common in dogs with nodular and diffuse HCC.354,357,361 Other metastatic sites include the heart, kidneys, adrenal glands, pancreas, intestines, spleen, and urinary bladder.354,357,361 The metastatic rate varies from 0% to 37% for dogs with massive HCCs and 93% to 100% for dogs with nodular and diffuse HCCs.354,357–363 

Bile Duct Tumors In people, primary liver tumors have been reclassified according to the presence of hepatic progenitor cells and immunohistochemical markers to differentiate hepatocytic and cholangiocytic lineages.367 Liver tumors with hepatic progenitor cell characteristics are typically more poorly differentiated and biologically aggressive, resulting in a poorer prognosis.367 Primary liver tumors in dogs and cats have also been reclassified according to these criteria.367,368 Based on histologic findings and the degree of immunoreactivity to keratin 19, hepatocellular tumors were divided into well-differentiated, scirrhous, and poorly differentiated tumors.367 HCCs expressing less than 5% of keratin 19 were more likely to be derived from mature hepatocytes with minimal evidence of cellular pleomorphism, infiltrative growth, and rare metastasis,367 and this accounted for 79% of canine HCCs and all feline HCCs.367,368 In contrast, primary liver tumors with keratin 19 expression, which included poorly differentiated HCCs and cholangiosarcomas, were characterized by a high grade of cellular pleomorphism, infiltrative growth, vascular invasion, and intra- or extrahepatic metastasis.367,368 These tumors were probably derived from either hepatic progenitor cells or dedifferentiation of mature hepatocytes.367 

Bile Duct Adenoma (Biliary Cystadenoma) There are two types of bile duct tumors in cats and dogs: bile duct adenoma and carcinoma.354,357–360,364,365,374–378 Bile duct adenomas are common in cats, accounting for more than 50% of all feline hepatobiliary tumors, and are also known as biliary or hepatobiliary cystadenomas because of their cystic appearance (Fig. 23.20).358–360,374–376 Male cats may be predisposed.374,376 Bile duct adenomas usually do not cause clinical signs until they reach a large size and compress adjacent organs.374–376 There is an even distribution between single and multiple lesions.358–360,374–376 Malignant transformation has been reported in humans, and anaplastic changes have been observed in some feline adenomas.358,374  Bile Duct Carcinoma (Cholangiocarcinoma) Bile duct carcinoma is the most common malignant hepatobiliary tumor in cats and the second most common in dogs.354,357–360 Bile duct carcinomas account for 9% to 41% of all malignant liver tumors in dogs.357,368,379 In humans, trematode infestation, cholelithiasis, and sclerosing cholangitis are known risk factors for bile duct carcinoma.380 Trematodes may also be involved in the etiology of bile duct carcinoma in cats and dogs, but they are

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• Fig. 23.20  Intraoperative image of a bile duct cystadenoma in a cat. Surgical resection was curative in this cat.

unlikely to be a major contributor because bile duct carcinomas also occur in geographic regions outside the normal distribution of trematodes.356,360,365 A predilection for Labrador retrievers has been proposed.365 A sex predisposition has been reported for female dogs.357,364,372 In cats, however, the sex predisposition is conflicting.358–360 The distribution of morphologic types of bile duct carcinoma is similar to HCC, with 37% to 46% massive, up to 54% nodular (see Fig. 23.18), and 17% to 54% diffuse.354,357,364,365 Bile duct carcinomas can be intrahepatic, extrahepatic, or within the gall bladder.354,357–360,364,365 Intrahepatic carcinomas are more common in dogs,357,364,365 whereas an equal distribution of intrahepatic and extrahepatic tumors to extrahepatic predominance has been reported in cats.358–360 Solid and cystic (or cystadenocarcinoma) bile duct carcinomas have been reported, but this distinction does not influence either treatment or prognosis.364 Bile duct carcinoma of the gall bladder is rare in both species.354,357–360,364,365 Bile duct carcinomas have an aggressive biologic behavior. Metastasis is common in dogs, with up to 88% metastasizing to the regional LNs and lungs (Fig. 23.21); other sites include the heart, spleen, adrenal glands, pancreas, kidneys, and spinal cord.354,357,364,365 In cats, diffuse intraperitoneal metastasis and carcinomatosis occur in 67% to 80% of cases.358–360 

Neuroendocrine Tumors Neuroendocrine tumors, also known as carcinoids, are rare in cats and dogs.354,357–360,367,368 These tumors arise from neuroectodermal cells and are histologically differentiated from carcinomas with the use of silver stains.355,366 Neuroendocrine hepatobiliary tumors are usually intrahepatic, although extrahepatic tumors have been reported in the gall bladder.366,377,378,381 Carcinoids tend to occur at a younger age than other primary hepatobiliary tumors.357,366 Morphologically, carcinoids are nodular in 33% and diffuse in the remaining 67% of cases.357,366 Primary hepatic neuroendocrine tumors have an aggressive biologic behavior with frequent involvement of more than one liver lobe and metastasis to the regional LNs, peritoneum, and lungs in cats and dogs.357,366,381 Other metastatic sites include the heart, spleen, kidneys, adrenal glands, and pancreas.366 

• Fig. 23.21  Lung metastasis in the cat with bile duct carcinoma depicted in Fig. 23.18. This cat also had diffuse peritoneal metastasis.

Sarcomas Primary and nonhematopoietic hepatic sarcomas are rare in cats and dogs.354,357–360,380 The most common primary hepatic sarcomas are hemangiosarcoma (HSA), leiomyosarcoma, and fibrosarcoma, with HSA the most frequently diagnosed primary hepatic sarcoma in cats and leiomyosarcoma the most common in dogs.354,357–360,380,382–385 The liver is a common site for metastatic HSA in dogs, whereas only 4% to 6% of HSA occur primarily in the liver.384,385 Other primary hepatic sarcomas include rhabdomyosarcoma, liposarcoma, OSA, and malignant mesenchymoma.354–360 The liver, with lungs, LNs, spleen, and bone marrow, is commonly involved in dogs with disseminated histiocytic sarcoma (HS).386,387 Benign mesenchymal tumors such as hemangiomas are rare.354–360 There are no known breed predispositions, although a male predilection has been reported.357 Diffuse morphology has not been reported, with massive and nodular types accounting for 36% and 64% of sarcomas, respectively.357,380 Hepatic sarcomas have an aggressive biologic behavior, with metastasis to the spleen and lungs reported in 86% to 100% of dogs.357,380 

Other Primary Hepatic Tumors Myelolipoma is a benign hepatobiliary tumor in cats.355,356 Histologically, myelolipomas are composed of well-differentiated adipose tissue intermixed with normal hematopoietic elements.356 Chronic hypoxia has been proposed as an etiologic factor because myelolipomas have been reported in liver lobes entrapped in diaphragmatic herniae.356 Myelolipomas can be either single or multifocal.356 

History and Clinical Signs Hepatobiliary tumors are symptomatic in approximately 50% of cats and 75% of dogs, especially in animals with malignant

CHAPTER 23  Cancer of the Gastrointestinal Tract

tumors.353–366,373 With respect to the massive form of HCC, most clinical signs are related to the mechanical mass effect of the tumor and only rarely to any systemic effects of the tumor or hepatic insufficiency. The most common presenting signs are nonspecific, such as inappetence, weight loss, lethargy, vomiting, polydipsia–polyuria, and ascites.353–366,373 Weakness, ataxia, and seizures are uncommon and may be caused by hepatic encephalopathy, paraneoplastic hypoglycemia, or central nervous system metastasis.357,361,388 Icterus is more common in dogs with extrahepatic bile duct carcinomas and diffuse neuroendocrine tumors.354,357,364 Hemoperitoneum secondary to rupture of massive HCC has been reported in two dogs.389 Physical examination findings are often unrewarding. A cranial abdominal mass is palpable in up to 75% of cats and dogs with liver tumors, although palpation can be misleading because hepatic enlargement may be either absent in nodular and diffuse forms of liver tumors or missed because of the location of the liver in the cranial abdominal cavity deep to the costal arch.353–366 

Diagnostic Techniques and Workup Laboratory Tests Hematologic and serum biochemical abnormalities are usually nonspecific. Leukocytosis, anemia, and thrombocytosis are common in dogs with liver tumors.353–366 Anemia is usually mild and nonregenerative.357,363 Thrombocytosis is seen in approximately 50% of dogs with massive HCC.363Anemia and thrombocytopenia are relatively common in dogs with primary and metastatic hepatic HSAs.355 Prolonged coagulation times (e.g., increased prothrombin time, thrombin time, and activated partial thromboplastin time) and specific clotting factor abnormalities (e.g., decreased factor VIII:C and increased factor VIII:RA and fibrinogen degradation products) have been identified in dogs with hepatobiliary tumors, although these are rarely clinically relevant.390 Liver enzymes are commonly elevated in dogs with hepatobiliary tumors (Table 23.7). Increased activity of liver enzymes probably reflects hepatocellular damage or biliary stasis and is not specific for hepatic neoplasia.356 There is also no correlation between the degree of hepatic involvement and magnitude of liver enzyme alterations.356,363 The type of liver enzyme abnormalities may provide an indication of the type of tumor and differentiate primary and metastatic liver tumors.391 Alkaline phosphatase (ALP) and alanine transferase (ALT) are commonly increased in dogs with primary hepatic tumors, whereas aspartate aminotransferase (AST) and bilirubin are more consistently elevated in dogs with metastatic liver tumors.353,391 Furthermore, an ASTto-ALT ratio less than one is consistent with HCC or bile duct carcinoma, whereas a neuroendocrine tumor or sarcoma is more likely when the ratio is greater than one.357 In general, however, liver enzyme elevations are not specific for the diagnosis of hepatobiliary diseases.392 Other changes in the serum biochemical profile in dogs with hepatic tumors may include hypoglycemia, hypoalbuminemia, hyperglobulinemia, and increased preprandial and postprandial bile acids.353,354,357,361–366 Hypoglycemia is a paraneoplastic syndrome reported secondary to hepatic adenoma and management is described in more detail in Chapter 5. In contrast to dogs, azotemia is often present in cats with hepatobiliary tumors and may be the only biochemical abnormality, although liver enzyme abnormalities, especially ALT, AST, and total bilirubin, are also common and are significantly higher in cats with malignant tumors.358–360

457

TABLE 23.7  Common Clinicopathologic

Abnormalities in Cats and Dogs with Hepatobiliary Tumors

Parameter

Cat (%)

Dog (%)

Leukocytosis

54–73

Anemia

27–51

Hypoalbuminemia

52–83

Increased ALP

10–64

61–100

Increased ALT

10–78

44–75

Increased AST

15–78

56–100

Increased GGT

78

39

Increased total bilirubin

33–78

18–33

Increased serum bile acids

67

50–75

ALP, Alkaline phosphatase; ALT, alanine transferase; AST, aspartate aminotransferase; GGT, γ-glutamyltransferase.

  

α-Fetoprotein, an oncofetal glycoprotein, is used in the diagnosis, monitoring response to treatment, and prognostication of HCC in humans.370 In dogs, serum levels of α-fetoprotein are increased in 75% of HCC and 55% of bile duct carcinomas.393,394 However, α-fetoprotein has limited value in the diagnosis and treatment monitoring of canine HCC, as serum levels of α-fetoprotein are also increased in other types of liver tumors, such as bile duct carcinoma and lymphoma, and nonneoplastic hepatic disease.394,395 Hyperferritinemia is common in dogs with HS and immune-mediated hemolytic anemia (IMHA); thus, once IMHA has been excluded, serum ferritin levels may be useful in differentiating HS from other causes of liver disease.396 

Imaging Radiographs, ultrasonography (US), and advanced imaging can be used for the diagnosis, staging, and surgical planning of cats and dogs with hepatobiliary tumors. A cranial abdominal mass, with caudal and lateral displacement of the stomach, is frequently noted on abdominal radiographs of cats and dogs with massive liver tumors.362,363,372 Mineralization of the biliary tree is a rare finding in dogs with bile duct carcinoma.356 Sonographic or CT examination is recommended because these radiographic findings are not specific for the diagnosis of a hepatic mass and do not provide information on the relationship of the hepatic mass with regional anatomic structures. Abdominal US or triphasic (arterial, venous, and delayed contrast phases) CT are preferred for identifying and characterizing hepatobiliary tumors in cats and dogs.397 US examination is useful in determining the presence of a hepatic mass and defining the tumor as massive, nodular, or diffuse398–402 and, in the case of cats, whether the tumor is cystic or not.372 If focal, the size and location of the mass and its relationship with adjacent anatomic structures, such as the gall bladder or caudal vena cava, can be assessed.376,398–402 Tumor vascularization can be determined using Doppler imaging techniques or triphasic CT, although the latter is superior.356,402 The US appearance of hepatobiliary tumors varies and does not correlate with histologic tumor type.376,397–406 However, US-guided FNA or needle-core biopsy of hepatic masses is

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a useful, minimally invasive technique to obtain cellular or tissue samples for diagnostic purposes.398–401 A coagulation profile is recommended before hepatic biopsy because mild-to-moderate hemorrhage is the most frequent complication, occurring in approximately 5% of cases.398–401 A correct diagnosis is obtained in up to 60% of hepatic aspirates and 90% of needle-core biopsies.398–401,407 The most useful cytologic features for the diagnosis of well-differentiated HCCs include dissociation of hepatocytes, acinar or palisading arrangement of neoplastic cells, and the presence of naked nuclei and capillaries, together with mild anisocytosis, anisokaryosis, multinuclearity, and increased N:C ratios.408,409 More invasive techniques, such as laparoscopy and open keyhole approaches, can also be used for the biopsy and staging of cats and dogs with suspected liver tumors. In humans, laparoscopy is recommended for local staging, as up to 20% of cases do not proceed with open surgery because of either nodular or diffuse tumors or unresectable disease.410 However, for solitary and massive hepatic masses, surgical resection can be performed without a preoperative biopsy because both diagnosis and treatment can be achieved in a single procedure. Advanced imaging techniques, such as triphasic CT and MRI, are preferred in humans for the diagnosis and staging of liver tumors and many veterinary centers also use this methodology.370,397 Unlike US, imaging appearance may provide an indication of tumor type.370 Furthermore, CT and MRI are more sensitive for the detection of small hepatic lesions and determining the relationship of liver masses with adjacent vascular and soft tissue structures.370 In dogs, there are CT features that can be used to differentiate nodular hyperplasia, hepatic adenomas, and HCCs based on enhancement patterns during arterial and portal venous phases.411,412 However, in another study, there were no features on dual-phase CT scans that differentiated benign and malignant hepatic lesions.413 Triphasic CT was reported to be more than 90% accurate in differentiating benign from malignant masses in 44 dogs and was superior to color-flow, power, and pulse-wave Doppler US, but could not differentiate the histologic type of malignant tumor.397 MRI with a liver-specific contrast agent, gadoxetate disodium, has been described in seven dogs with HCC, but imaging findings were variable.414 Imaging is also important for the staging of cats and dogs with liver tumors. Local extension and regional metastasis can be assessed with abdominal US, CT, MRI, or laparoscopy. The sonographic and sometimes gross appearance of nodular hyperplasia and metastatic disease is similar. In two studies, 25% to 36% of dogs with ultrasonographically detectable focal hepatic lesions were diagnosed with nodular hyperplasia.415,416 Biopsy of such lesions is recommended before definitively diagnosing metastatic disease and excluding animals from curative-intent surgery.417 Although rare at the time of diagnosis, three-view thoracic radiographs or advanced imaging techniques should be assessed for evidence of lung metastasis before treatment. 

Therapy and Prognosis Hepatocellular Tumors Liver lobectomy is recommended for cats and dogs with any hepatic tumor that has a massive morphologic appearance, particularly HCC. Surgical techniques for liver lobectomy include finger fracture, mass ligation, mattress sutures, bipolar vessel sealant devices, and surgical stapling.417 Mass ligation is not recommended for large dogs, tumors involving either the central or right

• Fig. 23.22  Liver lobectomy using a bipolar vessel sealing device. liver divisions, or tumors with a wide base.417 The finger-fracture technique, involving blunt dissection through hepatic parenchyma and individual ligation of bile ducts and vessels, is acceptable for smaller lesions. Surgical staplers or bipolar vessel sealant devices are preferred for liver lobectomy because operative time is shorter with fewer complications (see Fig. 23.17; and 23.22).363,417 A hilar dissection technique may be required for larger tumors extending to the hilus of the liver lobe because adequate margins may not be achievable with a surgical stapler.418 Complete histologic excision of massive HCCs is associated with significantly better local tumor control and survival times,419 and the use of real-time fluorescent imaging has been described to assess the completeness of excision intraoperatively in dogs with massive HCCs.420 Advanced imaging and intraoperative US may provide information on the relationship of right-sided and central liver tumors with the caudal vena cava before liver lobectomy. Right-sided liver tumors can be excised even if intimately associated with the caudal vena cava, with or without an ultrasonic aspirator, but the surgeon should be familiar with the course of the caudal vena cava through the hepatic parenchyma. En bloc resection of the caudal vena cava with a right-sided HCC has been reported.421 In one report of 42 dogs with massive HCC treated with liver lobectomy, the intraoperative mortality rate was 4.8% and the complication rate was 28.6%.363 Complications include hemorrhage, vascular compromise to adjacent liver lobes, and transient hypoglycemia and reduced hepatic function.356,363,417 In one single institution study, blood transfusions were required in 17% of dogs and 44% of cats treated with liver lobectomy for various hepatic conditions,422 which highlights the importance of preoperative cross-matching or blood typing before liver lobectomy to be more adequately prepared to manage intraoperative bleeding. The prognosis for dogs and cats with massive HCC is good (Fig. 23.23). Local tumor recurrence is reported in 0% to 13% of dogs with massive HCC after liver lobectomy.362,363 In a recent study investigating the effect of the completeness of histologic excision in 37 dogs with massive HCC, local tumor recurrence was reported in 12% of dogs with complete histologic excision and 58% of dogs with incomplete histologic excision.419 The median progression-free and overall survival times were significantly longer in dogs with complete histologic excision (1000 days and greater than 1836 days, respectively) than incomplete histologic excision (521 days and 765 days, respectively) although both groups enjoyed durable postsurgical

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Survival (proportion)

1 0.8 0.6 0.4 0.2 0 0

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1250

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Surgery No surgery

• Fig. 23.23  Kaplan–Meier survival curve for dogs with massive hepatocel-

lular carcinoma. The median survival time for dogs with surgically resected tumors is significantly better than dogs not treated with curative-intent liver lobectomy. (Reprinted with permission from Liptak JM, Dernell WS, Monnet E, et al. Massive hepatocellular carcinoma in dogs: 48 cases (1992– 2002). J Am Vet Med Assoc. 2004;225:1225–1230.)

survival.419 Metastasis to other regions of the liver and lungs has been documented in 0% to 37% of dogs, but metastasis is rare in recent clinical reports and most deaths are unrelated to HCC.357,362,363,419 The MST for dogs with massive HCC after liver lobectomy are greater than 1460 to 1836 days,363,419 and the MST was 2.4 years for six cats with HCC treated with liver lobectomy.373 In comparison, the MST of 270 days was significantly decreased for six dogs managed conservatively, and these dogs were 15.4 times more likely to die of tumor-related causes than dogs treated surgically.363 Prognostic factors in dogs with massive HCC include surgical treatment, side of liver involvement, ALT and AST activity, ratios of ALP-to-AST and ALT-toAST, and completeness of histologic excision.363,419 Right-sided liver tumors, involving either the right lateral lobe or caudate process of the caudate lobe, had a poorer prognosis because intraoperative death was more likely due to caudal vena cava trauma during surgical dissection.363 There was no difference in survival time if dogs with right-sided massive HCC survived surgery.363 Increased ALT and AST were associated with a poor prognosis in one study, which may reflect more severe hepatocellular injury secondary to either large tumor size or more aggressive biologic behavior.363 In contrast, the prognosis for dogs with nodular and diffuse HCC is poor. Surgical resection is usually not possible because of involvement of multiple liver lobes. Treatment options for nodular and diffuse HCC in humans include liver transplantation or minimally invasive procedures for regional control, such as ablation or embolization.370 Bland embolization and chemoembolization have been reported with moderate success in the palliation of four dogs and one cat with HCC,423–425 and microwave ablation has been described in five dogs with diffuse hepatic neoplasia, including one dog with HCC.426 The role of RT and chemotherapy in the management of HCC is largely unknown. Traditional RT is ineffective in the management of liver tumors, as the canine liver cannot tolerate cumulative doses greater than 30 Gy356,370; however, three-dimensional (3-D) conformal RT, which enables targeted high-dose RT to the tumor while sparing

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adjacent normal hepatic tissue, has been described in 6 dogs with nonresectable HCC.427 In this study, 3-D conformal RT was delivered at 6 to 10 Gy per fraction to a total dose of 18 to 42 Gy with 1 to 2 fractions per week for a total of 3 to 7 fractions.427 This RT protocol resulted in partial responses in five of the six dogs, and an MST of 567 days.427 HCC is considered chemoresistant in humans because response rates are usually less than 20%.356,370 The poor response to systemic chemotherapy is probably a result of rapid development of drug resistance due to either the role of hepatocytes in detoxification or expression of P-glycoprotein, a cell membrane efflux pump associated with multidrug resistance.356 However, single-agent gemcitabine has been investigated in dogs with unresectable HCC with encouraging results.428 In one this study, 18 dogs with mostly nodular and diffuse well-differentiated HCCs were treated with gemcitabine for 5 weeks.428 The overall MST was 983 days, but depended on the morphology and resectability of the tumor.428 The MSTs were 1339 days for dogs with massive HCC, 983 days for dogs with nodular HCC, and 113 days for dogs with diffuse HCC; and the MSTs were 1339 days for dogs with incompletely excised HCC, which included all four dogs with massive HCC and 9 of 10 dogs with nodular HCC, and 197 days for dogs with nonresectable HCC, including all four dogs with diffuse HCC.428 Novel treatment options currently being investigated in human medicine include immunotherapy, hormonal therapy with tamoxifen, and antiangiogenic agents.370 

Bile Duct Tumors Bile duct adenomas can present as either single (e.g., massive) or multifocal lesions. Liver lobectomy is recommended for cats with single bile duct adenoma (cystadenoma) or multifocal lesions confined to one to two lobes.358–360,374–376 The prognosis is very good after surgical resection with resolution of clinical signs and no reports of local recurrence or malignant transformation.360,374,375 Liver lobectomy is also recommended for cats and dogs with massive bile duct carcinoma. However, survival time has been poor in cats and dogs treated with liver lobectomy because the majority have died within 6 months as a result of local recurrence and metastatic disease.360,429 There is no known effective treatment for cats and dogs with nodular or diffuse bile duct carcinomas because these lesions are not amenable to surgical resection and other treatments are often not successful. 

Neuroendocrine Tumors Carcinoids have an aggressive biologic behavior and are usually not amenable to surgical resection because solitary lesions and massive morphology are rare.357,366 The efficacy of RT and chemotherapy is unknown. Prognosis is poor because metastasis to the regional LNs, peritoneum, and lungs occurs in 93% of dogs and usually early in the course of disease.357,366 

Sarcomas Liver lobectomy can be attempted for solitary and massive sarcomas. However, the prognosis is poor because metastatic disease is often present at the time of surgery.357,380 Chemotherapy has not been investigated in the treatment of primary hepatic sarcomas, although, similar to other solid sarcomas, response rates are likely to be poor. Doxorubicin-based protocols and ifosfamide

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have shown some promise with sarcomas in other locations and warrant consideration for cats and dogs with primary hepatic sarcomas.430,431 

Other Primary Hepatic Tumors Surgical resection with liver lobectomy is recommended for cats with primary hepatic myelolipoma, and the prognosis is excellent with prolonged survival time and no reports of local recurrence.356 

Comparative Aspects HCC is one of the most common malignancies in humans as a result of viral infections with hepatitis viruses B and C and cirrhosis induced by alcohol consumption and other disease.370 A number of paraneoplastic syndromes have been described including hypoglycemia, erythrocytosis, and hypercalcemia.368 US is considered a good screening imaging modality, but advanced imaging with contrast-enhanced CT or MRI is preferred to determine the location, size, and extent of hepatic lesions.368 Other tests include serum α-fetoprotein, serologic tests for hepatitis B and C viruses, and histologic confirmation with core liver biopsies.368 Unlike HCC in dogs, the morphology of HCC in humans is often nodular or diffuse, which makes definitive treatment more problematic. Treatment options depend on the stage of disease and include surgery (e.g., liver lobectomy and liver transplantation), local ablative therapies (e.g., cryosurgery, ethanol or acetic acid injection, and microwave or radiofrequency ablation), regional therapies (e.g., transarterial chemotherapy, embolization, chemoembolization, or RT), and systemic treatment with chemotherapy or immunotherapy.368 Response rates to single- and multiple-agent chemotherapy protocols are less than 25%, and chemotherapy is no longer recommended for human patients with HCC.370 Bile duct carcinomas are rare and, similar to those in cats and dogs, often associated with a poor prognosis.382 Risk factors include primary sclerosing cholangitis, the liver flukes Opisthorchis viverrini and Clonorchis sinensis in endemic areas of Southeast Asia and China, and cholelithiasis.382 Surgical resection is preferred but, because of the high rate of local or regional recurrence, adjuvant treatment with RT or chemotherapy is recommended.382 However, because of the rarity of this tumor, studies supporting the efficacy of these adjuvant treatments are lacking. Papillary histology, extrahepatic location, and complete resection are favorable prognostic factors in humans with bile duct carcinomas.432 

SECTION G: INTESTINAL TUMORS LAURA E. SELMIC, KIM A. SELTING AND JENNIFER K. REAGAN

Incidence and Risk Factors Intestinal tumors are rare in dogs and cats.433–435 In a survey of insured dogs in the United Kingdom, a standardized incidence rate of 210/100,000 dogs was reported for alimentary tumors and this accounted for 8% of all tumor submissions.436 Incidence of feline digestive neoplasia in a South African survey comprised 13.5% of all tumors, which likely included oral tumors.437 In the United States, a query of more than 300,000

cat submissions to the Veterinary Medical Database found 8% to relate to cancer and less than 1% (13% of the cancer cases) to be intestinal neoplasia.438 Regarding specific tumor types, lymphoma comprises nearly 30% of all feline tumors and 6% of all canine tumors and is the most common intestinal tumor in most reports.434,439–441 In 163 cases of feline lymphoma, the intestine was the most commonly affected site.442 Adenocarcinoma is the second most frequent tumor in both species, with mast cell tumors (MCTs) in cats and leiomyosarcomas or gastrointestinal stromal tumors (GISTs) in dogs the third most common tumors. As with many cancers, the incidence of intestinal neoplasia increases in older dogs and cats. Mean ages of affected cats for small and large intestinal neoplasia generally range between 10 and 12 years, and increasing risk after 7 years of age has been reported.434,438,442–448 Dogs are also usually middle aged or older, with mean ages most often between 6 and 9 years and possibly older (12 years) for dogs with leiomyosarcoma.443,448–452 Overall, there may be a slight sex predilection for males to develop intestinal tumors. Many studies report a near equal incidence among male and female dogs,452–455 although one study did find 76% of dogs with intestinal adenocarcinoma to be male.456 Males also appear overrepresented for smooth muscle tumors,448 comprising 82% of gastrointestinal (GI) leiomyomas457 and 76% of dogs with leiomyosarcoma.451 In addition, 90% of dogs with GI lymphoma were male448 and there was a slight male predominance in nonlymphomatous tumors.441,458,459 In cats, males have greater representation in some studies,446,460 while only slightly exceeding or equaling females in other studies.445,446,460–462 Siamese cats are 1.8 times more likely to develop intestinal neoplasia438 and are overrepresented in studies of intestinal adenocarcinoma, up to eight times greater than other breeds.434,438,444,458,461 Although small numbers of Siamese cats are included in many series of feline intestinal lymphoma, one study did show a significant overrepresentation.443 Otherwise, there is no breed predilection for intestinal lymphoma in cats. In dogs, few studies of intestinal neoplasia report an overrepresentation of specific breeds. Large-breed dogs in general constituted most cases in a series of smooth muscle tumors.454 Collies and German shepherd dogs are overrepresented in some reports for intestinal tumors, especially adenocarcinoma, rectal carcinoma, and rectal polyps.449,463 In a recent Czech necropsy study, breed predispositions were identified in the pug, Leonberger, and English setter for intestinal adenoma; in the English setter and Hovawart for intestinal adenocarcinoma; and the Doberman and Hovawart for intestinal lymphoma.448 MCTs have been reported primarily in Maltese. Although these reports came from Japan, where small breeds are popular, more than 50% of reported cases in two series were in Maltese dogs with a male predominance.464,465 With the exception of retroviral influence on the development of feline lymphoma, there are no known etiologic organisms or chemical agents that reliably contribute to the development of spontaneously occurring intestinal neoplasia in dogs and cats. A recent retrospective study in 55 cats with intestinal carcinoma showed significant association between the presence of Helicobacter species and development of poorly differentiated large intestinal mucinous adenocarcinoma.466 The findings of this study suggest Helicobacter spp. may play a possible role in intestinal carcinoma formation and determining site of development in cats.466 However, it has also been suggested Helicobacter species in the feces may represent normal flora rather than pathogens.467 

CHAPTER 23  Cancer of the Gastrointestinal Tract

Pathology and Natural Behavior Epithelial, mesenchymal, neuroendocrine, and discrete/round cell neoplasias can all be found in the intestinal tract. Although most small intestinal tumors are malignant in dogs, most rectal tumors are benign polyps, adenomas, or carcinomas in situ (Fig. 23.24).455,468 When tumors of the GI system metastasize, sites of predilection in decreasing frequency include mesenteric LNs (especially adenocarcinoma), liver (especially leiomyosarcoma), mesentery, omentum, spleen, kidney, bone, peritoneum (e.g., carcinomatosis), and lung.441,458,462,469 Interestingly, metastasis from intestinal adenocarcinoma was discovered in three dogs initially presented for testicular masses.470 One dog was presented for multiple cutaneous masses that IHC confirmed were epithelial in origin and a primary small intestinal adenocarcinoma with additional visceral metastasis was diagnosed at necropsy.471 GI

• Fig. 23.24  Cobblestone appearance to a rectal adenocarcinoma. Dogs

with this tumor type live an average of 12 months after surgical excision. (Courtesy Dr. Eric Pope, Ross University, College of Veterinary Medicine.)

A

461

lymphoma is often a systemic disease; 25% of dogs and 80% of cats will have concurrent involvement of other organs.443,450

Lymphoma Lymphoma is the most common type of small intestinal neoplasia in cats and dogs. For feline intestinal lymphoma, subtypes include lymphocytic, lymphoblastic, epitheliotropic, and large granular lymphocyte (LGL) types. Intestinal lymphoma in dogs occurs in the stomach and small intestine equally and more often in both of these sites than in the large intestine. For additional information regarding canine and feline lymphoma the reader is referred to Chapter 33, Sections A and B. 

Adenomatous Polyps and Adenocarcinoma Most alimentary adenocarcinoma in cats is found in the small intestine433,456,462; however, the colon and rectum are more common sites in dogs.472,473 For colorectal adenocarcinomas, the rectum is a more common site than the colon.474 The cecum is more likely to develop leiomyosarcomas or GISTs than adenocarcinoma.451,473 Histologic descriptors for carcinoma of the intestine include adeno- (forming glands), mucinous (>50% mucin), signet ring (>50% of cells have intracellular mucin), and undifferentiated or solid (no evidence of gland formation).472 Grossly, colorectal adenocarcinomas may demonstrate a pedunculated (especially in the distal rectum), cobblestone (middle rectum), or annular (middle rectum) appearance, which may relate to behavior and prognosis (Fig. 23.25).469,473,474 Adenomatous polyps are found in the rectum of dogs and carcinomas in situ are found in both the colon and rectum. Most lesions are solitary, although multiple and diffuse lesions can be seen and are associated with increased recurrence rates.455 A case series of 31 dogs with colorectal carcinoma found that most were B-cell, high-grade, and caused hematochezia.475 Miniature dachshunds are overrepresented for inflammatory colorectal ­polyps, suggesting a breed predisposition in multiple case series from Japan.476,477 The

B • Fig. 23.25  An annular form of colonic adenocarcinoma causing a structure. The thick band of tissue (B) creating the stricture is seen on cross-section (A). In one study, dogs with this type of tumor survived an average of only 1.6 months. (Courtesy Dr. Eric Pope, Ross University, College of Veterinary Medicine.)

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inflammatory polyps presented as multiple small polyps, whereas other colorectal polyps generally presented as either solitary or multiple lesions.476,477 In cats, polyps are more common in the duodenum and intestinal obstruction resulting from a duodenal Brunner’s gland adenoma has been reported in a dog.478 

Leiomyomas, Leiomyosarcomas, and GISTs Leiomyomas occur more commonly in the stomach, but have also been reported in the esophagus, small intestine, and colorectum.457 GISTs are well documented in humans and have been reported in dogs and cats.479–481 These nonlymphoid tumors of mesenchymal origin were originally diagnosed as leiomyosarcomas and some, but not all, were leiomyomas. Histologically, GISTs are highly cellular mesenchymal tumors that do not show ultrastructural characteristics consistent with smooth muscle differentiation. GISTs are thought to arise from multipotential stem cells phenotypically similar to interstitial cells of Cajal, driven by activating mutations of c-Kit (a proto-oncogene). Although these cells can differentiate into smooth muscle cells if deprived of KIT (a receptor tyrosine kinase), GISTs are a discrete clinical entity from leiomyosarcoma.482 Leiomyosarcomas are positive for smooth muscle actin and desmin and negative for KIT. GISTs are distinguished by high vimentin immunoreactivity, low alpha smooth muscle actin reactivity, and CD117 (KIT) reactivity, and arise primarily in the small and large intestine.457,483,484 c-Kit exon 11 mutations have been found to occur frequently in canine GISTs, which is similar to human GISTs, where exon 11 mutations occur in 60% to 70% of cases and mutations in exon 9 occur in 5% to 10% of cases.457,485 To date, only one dog with an exon 9 mutation has been reported.486 CD117 (KIT) reactivity is considered a major diagnostic criterion and is used to distinguish GISTs from leiomyosarcomas in many studies.487,488 When stratified as such, 28 of 42 leiomyosarcomas in dogs were reclassified as GISTs and only 2 of the 28 cases of GIST metastasized (7%), with those dogs living longer than dogs with leiomyosarcoma.487 These investigators also found that GISTs were significantly more likely to occur in the large intestine, specifically the cecum, and leiomyosarcomas in the stomach and small intestine,487 yet a recent study contradicted this finding with GISTs occurring primarily in the small intestine.484 Considering these findings, the incidence of true leiomyosarcoma is likely low because many previously reported cases may have actually been GISTs. The inclusion of GISTs as leiomyosarcomas will also have caused confounding of clinical behavior in these studies. In addition to the effect on incidence, conflicting reports of biologic behavior are problematic. Although the study cited earlier found a 7% rate of metastasis for dogs with GISTs and a worse prognosis for dogs with leiomyosarcoma, a recent study reported a higher rate of metastasis (27%) in GISTs and no metastasis in dogs with leiomyosarcomas.484 

Mast Cell Tumors Intestinal MCTs are the third most common tumor after lymphoma and adenocarcinoma in cats, but their incidence and behavior are poorly reported. For further details, the reader is referred to Chapter 21. 

Other Tumor Types The term carcinoid refers to tumors that arise from the diffuse endocrine system rather than the intestinal epithelium, despite

histologic similarity to carcinomas. Carcinoid cells arise from enterochromaffin cells of the intestinal mucosa and contain secretory granules that may contain substances such as 5-hydroxytryptamine (serotonin), secretin, somatostatin, and gastrin, among others.472 IHC for cytokeratin and for secretory substances, such as serotonin, may be positive, and serum concentration of serotonin has been documented at 10 times the normal range in one dog with a carcinoid.489 Carcinoids have been described in many species and may occur in both the large and the small intestines and frequently metastasize to the liver.434,473,489 Carcinoids may follow an aggressive and debilitating clinical course.489 Extramedullary plasmacytomas (EMPs) are solitary tumors with no evidence of systemic multiple myeloma and the reader is referred to Chapter 33, Section D , where they are covered in detail. Another uncommon tumor type is extraskeletal OSA, which has been reported in the duodenum of a cat.490 This cat had no evidence of metastasis at diagnosis and did well for 4 months after surgery when clinical signs recurred and the cat died.490 Three of 55 extraskeletal and 145 total cases of feline OSA were of intestinal origin.491 A series of four cats was reported with intestinal hemangiosarcoma arising from four different locations within the intestines; no cat survived greater than 1 week.492 Finally, one dog was diagnosed with ganglioneuroma of the rectum and experienced long-term survival after surgical resection.493 Small intestinal ganglioneuromatosis has also been reported in a dog with a similar good outcome after surgical resection.494 

Molecular Aspects With an increasing armamentarium of molecular diagnostics, insights into the pathogenesis, progression, and prognosis of tumors are constantly emerging. Cellular adhesion and invasion (e.g., Tenascin-C,463,495 versica, hyaluronan,496 β-catenin, and E-cadherin497–499), stromal remodeling, and alterations in tumor suppressor genes (e.g., p53497,499–501) may play a role in the development and progression of intestinal neoplasia. The importance of the relationship between a tumor cell and its stroma should not be underestimated. Although molecular markers/targets likely play an important role in intestinal tumors, the utility of these in diagnostics, prognostication, and therapy in companion animal species, with the exception of GIST and CD117 expression, is limited.481 COX enzymes are responsible for prostaglandin synthesis and COX-2 is overexpressed in many head/neck and genitourinary tumors, creating a possible therapeutic target. COX-2 has been identified in both benign and malignant small intestinal and colorectal epithelial tumors in dogs, although the number of positive cells varies and was very low in some studies.502,503 In addition, one study found no COX-2 staining in 13 intestinal tumors in cats.504 COX inhibitors are thus of questionable value in treating intestinal tumors. 

History and Clinical Signs The duration of clinical signs before presentation typically averages 6 to 8 weeks, but can range from less than 1 day to several months.441,450,451 Clinical signs include (in varying order of frequency): weight loss, diarrhea, vomiting, and anorexia, and, less frequently, melena, anemia, and hypoglycemia (with smooth muscle tumors).434,441,444,453,460,461,505–508 Clinical signs often relate to location of the tumor within the GI tract. Proximal lesions more commonly result in vomiting;

CHAPTER 23  Cancer of the Gastrointestinal Tract

small intestinal lesions in weight loss; and large bowel lesions in hematochezia and tenesmus.456,458 Although carcinoids may secrete endocrine substances, clinical signs do not always reflect hypersecretion.472 Dogs and cats may present with clinical signs relating to intestinal obstruction, such as anorexia, weight loss, and vomiting. In dogs with cecal GISTs, 25% to 32% cause perforation which results in a localized peritonitis and clinical signs of an acute abdomen.487,488 Smooth muscle tumors are located within the muscular layer of the intestines and not within the lumen and evidence of GI bleeding is often absent, but anemia and melena have been reported.451,452 Clinical signs of chronic small bowel disease should not be ignored in cats, as 96% to 99% had abnormalities on biopsy consistent with inflammatory bowel disease (IBS) or neoplasia (lymphoma, MCT, adenocarcinoma).507,508

Paraneoplastic Syndromes One dog was presented for alopecia and Cheyletiella infection within 2 months of euthanasia for abdominal carcinomatosis from intestinal carcinoma. The neoplasia was not identified with abdominal US at the original workup, but immunosuppression resulting from an underlying neoplasia was thought to lead to opportunistic Cheyletiella infection. Although pruritus resolved with ivermectin therapy, alopecia persisted, suggesting a paraneoplastic origin.509 Alopecia has also been reported as a paraneoplastic syndrome secondary to a metastasizing colonic carcinoma in a cat.510 Neutrophilic leukocytosis (in one dog associated with monocytosis and eosinophilia) has been reported in dogs with rectal tumors. Resolution or improvement of hematologic abnormalities occurred after treatment for adenomatous rectal polyps.502,511 Hypereosinophilia and eosinophilic tumor infiltrates have been reported in a cat and several dogs with intestinal T-cell lymphoma; the suggested cause was IL-5 secretion by the neoplastic lymphocytes.512–514 EMP may lead to a hyperviscosity syndrome resulting from overproduction of immunoglobulin.515 Erythrocytosis managed with periodic phlebotomy was related to a cecal leiomyosarcoma in a 14-year-old dog. The diagnosis was made at postmortem 2 years later; erythropoietin mRNA and protein were isolated from tumor cells, suggesting ectopic erythropoietin production as the cause of the erythrocytosis.516 Hypoglycemia has also reported with intestinal smooth muscle tumors as a paraneoplastic syndrome.517 Nephrogenic diabetes insipidus has also been documented in one dog with intestinal leiomyosarcoma.518 

Diagnostic Techniques and Workup Physical Examination An abdominal mass may be palpated on initial examination in approximately 20% to 40% of dogs with lymphoma450,453 and 20% to 50% of dogs with nonlymphomatous solid intestinal tumors.441,456,458 Pain and fever were reported in 20% of dogs with lymphoma in one report.450 Digital rectal examination may identify masses or annular strictures due to rectal tumors or polyps in as high as 63% of dogs.456,474 Abdominal masses are also often readily palpated in cats with both lymphoma and adenocarcinoma.444,445,458,460 Dehydration is also common and occurs in 30% to 60% of cats with nonlymphomatous tumors.444,458 

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Clinical Pathology Complete Blood Count Anemia is common in dogs and cats with intestinal tumors and is often not characterized, but may occur in conjunction with melena and elevated blood urea nitrogen (BUN). Anemia affects nearly 40% of dogs in most studies and as low as 15% but up to 70% of cats.441,445,451,452,456,458,460 Leukogram changes are also common including leukocytosis in 25% to 70% of dogs and 40% of cats.441,444,452,458 A left shift may be seen as well as monocytosis in some patients.458,460  Chemistry Profile Biochemical abnormalities are similar between dogs and cats with intestinal tumors. As a result of malabsorption, hypoproteinemia may be present in one-fourth to one-third of patie nts.441,444,445,452,453,456 Other common abnormalities include elevated liver enzymes, specifically alkaline phosphatase in 15% to 33% of dogs and up to 85% of cats with nonlymphomatous neoplasia.441,452,456,458,460 In one series, high cholesterol was seen in 41% of cats with nonlymphomatous tumors.458 An elevated BUN has been reported in 13% of dogs and 30% of cats with intestinal adenocarcinoma.441,444 This may be a result of concurrent renal insufficiency, intestinal bleeding due to the tumor, or dehydration. Although some cats may have hyperglycemia,458 smooth muscle tumors can cause up to 55% of patients to be hypoglycemic as a result of insulin-like growth factor secretion.451 Dogs may also have increased amylase and electrolyte disturbances,456 and patients with lymphoma may be hypercalcemic.445 Serum alpha 1-acid glycoprotein, an acute-phase reactant protein, may be increased in cats with cancer, but this lacks specificity and prognostic relevance.519,520  Cytology and Histopathology As with other anatomic sites, cytology of the intestinal tract can help differentiate major tumor types. In addition, lymphocyte accumulations can be tested using polymerase chain reaction (PCR) for antigen receptor rearrangement (PARR) for clonality (see Chapter 33, Section A and B for further details). In cats, mucosal biopsies of the upper GI tract are commonly obtained in a minimally invasive fashion using endoscopy. Despite the superiority of full thickness biopsies (because submucosal and muscularis infiltration can be characterized), the ease of endoscopic biopsy has resulted in rigorous evaluation of ancillary diagnostics to improve accuracy on these samples. Because of reported eosinophilia with intestinal lymphoma and reports of MCT with concurrent small T-cell lymphoma in cats, it may be challenging to distinguish between the two tumor types.512,521,522 

Imaging Abdominal Radiographs and Ultrasound In dogs and cats with intestinal lymphoma, concurrent enlargement of liver, spleen, and/or mesenteric LNs may be seen.450 Plain abdominal radiographs may reveal an abdominal mass in approximately 40% of both dogs and cats, although some reports are higher for solid tumor types and lower for lymphoma.441,444,445,450,452,458 An obstructive pattern may also be seen on plain radiographs in 10% to 75% of cats and dogs.441,452,456,458 Other abnormalities may include poor serosal detail and thickened stomach wall.445

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Contrast radiography, although used less after advances in US, has often been used to evaluate patients with signs of primary GI disease. US can help facilitate noninvasive localization of the tumor and identification of other sites of metastasis or involvement. It also can guide needle aspiration or needle biopsy or assist in treatment planning. US is a more sensitive diagnostic test than radiographs for identifying a mass.441,451,454,523 US is also less time consuming than contrast radiography, and the increased use, availability, and operator skill for the former has diminished the need for the latter. US findings in dogs and cats with intestinal neoplasia most consistently include bowel wall thickening and loss of normal wall layering.456,523,524 Intestinal lymphoma in dogs more often results in long segments of involved bowel and either a solitary mass or diffusely thickened bowel loops with thickening of the muscularis propria in cats.506,524,525 However, the normal appearance of intestine does not rule out the presence of lymphoma, as one study showed 26% of dogs diagnosed with GI lymphoma did not have sonographic abnormalities.526 Adenocarcinoma in cats has been described as having mixed echogenicity and was asymmetric in three of five cats.523 In one study, two-thirds of dogs with intestinal adenocarcinoma had hypoechoic tumors and most had decreased motility.456 These masses averaged 4 cm long with a median wall thickness of 1.2 cm.456,473 MCTs have an eccentric appearance with alteration, but not loss of wall layering, commonly involving the muscularis propria.522 Smooth muscle tumors are characteristically large (median diameter 4.8 cm) and anechoic/hypoechoic, and a muscular layer origin may be identified. Leiomyomas may have a smooth contour.454 One report of metastatic mammary carcinoma to the small intestine described the appearance as multiple, hypoechoic, well-defined or marginated nodules within the muscularis layer of the jejunum that did not disrupt the intestinal layering.527 Degree of thickening, distribution of lesion(s), and symmetry are used to help differentiate neoplastic from nonneoplastic disease.528 In one study, 99% of dogs with neoplasia had a loss of wall layering and this was associated with a 50 times greater likelihood of neoplasia than enteritis (Fig. 23.26).524 In addition, dogs with

walls thicker than 1 cm are nearly four times as likely to have a tumor and those with focal lesions are nearly 20 times as likely to have a tumor.524 Nevertheless, possible differential diagnoses include fungal (pythiosis and histoplasmosis) masses, as these can mimic neoplasia.528 In general, neoplasia exhibits more dramatic thickening with loss of wall layering and greater LN enlargement, as well as more frequent focal lesions than nonneoplastic intestinal disease.528 Similar changes (thickened muscularis propria, and ratio of muscularis to mucosa >1) can be seen in cats with intestinal lymphoma, but do not reliably distinguish neoplasia from IBD.529 In a series of 14 cats with carcinomatosis, three of which were a result of small intestinal tumors (two carcinomas and one lymphoma), the hallmark ultrasonographic finding was the presence of masses in the double sheet portion of peritoneum that connects the visceral and parietal portions (100% of cats); all cats also had free peritoneal fluid.530 

Thoracic Radiographs Thoracic radiographs are critical to the complete evaluation of the cancer patient. For dogs with nonlymphomatous intestinal tumors, yield is low, with very few patients presenting with pulmonary metastasis.441 This may be due to a bias in reporting because many reports detail outcome of treatment and patients with metastatic disease may not receive treatment. In fact, many case series report no evidence of metastasis on initial evaluation for solid tumors of the intestine in dogs.441,451,452,456,458 Two of 14 cats in one series and no cats in another series had pulmonary nodules at initial evaluation.444,458 For cats and dogs with lymphoma, enlarged sternal or perihilar LNs, pleural effusion, or diffuse interstitial changes may be seen.445,450  Endoscopy, Colonoscopy, and Laparoscopy Minimally invasive methods of collecting tissues to aid in diagnosis are increasingly used. Endoscopic findings in dogs with intestinal lymphoma include an irregular cobblestone or patchy erythematous appearance to the duodenal mucosa and poor distensibility and elasticity of the duodenal wall.453 Colonoscopy can be considered to evaluate for multiple colorectal masses as well as

BOWEL BOWEL Muscularis Submucosa Mucosa

Lumen

Mucosa

Lumen

Muscularis

A

B •

Fig. 23.26 A cross-sectional ultrasound image of a segment of small intestine with lymphoma (A) is compared with a longitudinal view of a segment of normal small intestine (B). Note that the clearly defined intestinal layers in the normal tissue are completely effaced in the tumor tissue. A loss of layering is strongly supportive of neoplasia. The diseased bowel is also markedly thickened, suggesting neoplasia. (Courtesy Dr. Stephanie Essman, University of Missouri, College of Veterinary Medicine.)

Submucosa

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obtain biopsy samples; however, single rectal masses appear to be more common in dogs and these masses were not present beyond the colorectal border.531 Therefore proctoscopy or transanal single laparoscopic port evaluation may provide information regarding mass number and characteristics without the need for extensive bowl preparation and surgical delay.531 Of note, 5 of 16 dogs (31%) had different colonoscopy biopsy results compared with the final histopathology results with a tendency to underdiagnose malignancy.531 Interobserver variation is likely to be more pronounced with small tissue samples and this is a limitation of these less invasive approaches. 

Exploratory Laparotomy When noninvasive or minimally invasive diagnostics fail to confirm a diagnosis, an exploratory laparotomy may be indicated for dogs and cats with persistent signs of GI disease. Benefits include direct visualization of all abdominal viscera and the ability to collect full-thickness biopsies of all segments of intestines and other viscera. Patients with resectable solid tumors may be both diagnosed and treated in a single procedure with intestinal resection and anastomosis. In a series of dogs with GI lymphoma, endoscopic biopsies were sometimes difficult to interpret because of lymphoplasmacytic infiltrate, but surgical biopsies obtained by laparotomy confirmed the diagnosis in all cases.450 In a study evaluating 367 dogs and cats undergoing GI biopsies, the risk of GI dehiscence was found to be very low (1% dogs, <3% cats) with possible risk factors in cats being neoplasia and hypoalbumenia, although these had wide confidence intervals.532 It should be noted that carcinomatosis should not always be seen as an indication for euthanasia (Fig. 23.27). After removal of the primary intestinal adenocarcinoma, two cats with malignant effusion lived 4.5 and 28 months after surgery.444 

Therapy and Prognosis Surgery With the exception of lymphoma, surgical resection is the primary treatment for intestinal tumors. Lymphoma is treated primarily

A •

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with chemotherapy except when intestinal perforation or the need for a biopsy necessitates surgery (Fig. 23.28). As long as severe extraserosal invasion and/or adhesions do not complicate the surgical approach, complete excision of intestinal tumors is often possible. For dogs and cats without evidence of local or distant metastasis, long-term survival is possible, although some tumors may later metastasize. Overall, the 1-year survival rate is approximately 40% for dogs with solid small intestinal tumors.441 For cats with adenocarcinoma, approximately 50% will metastasize to the local LNs, 30% to the peritoneal cavity (carcinomatosis), and 20% or less to the lungs.434,458,462 Dogs have similar rates of metastasis to LNs for both adenocarcinoma and leiomyosarcoma, although the liver is usually the second most frequent site.441,458,473 Perioperative mortality can approach 30% to 50% as a result of sepsis, peritonitis, or owner decision for euthanasia when nonresectable tumors are present.441,451

Small Intestine Intestinal resection and anastomosis is the most common surgical technique for tumors of the small intestine. Stapling techniques have been shown to be equivalent to hand suturing in both the large and small intestine.533,534 Canine small intestinal adenocarcinoma has a guarded prognosis with a mean survival time (ST) of only 12 days without treatment and a mean ST of 114 days after surgical resection, though others report median STs (MSTs) of 7 and 10 months.441,456,458 Dogs with leiomyosarcoma who survive the perioperative period have MSTs of 1.1 to almost 2 years.451,452 One case series found the MST for 28 dogs with GIST to be approximately 38 months (1 year if postoperative deaths were included) versus an MST of 8 months for 10 dogs with leiomyosarcoma, although this difference was not statistically significant.487 Another study found no difference in survival between dogs with GIST and leiomyosarcoma with 1-year survival rates of approximately 80% for both tumor types (Fig. 23.29).488 The benefit of surgery is questionable for dogs with intestinal MCTs. In two case series, most dogs died within the first month. Only 2 of 49 dogs (combined total for two series with almost all being GI MCTs) lived past 180 days and prednisone was not helpful in most cases.465,466

B

Fig. 23.27  Carcinomatosis discovered at exploratory laparotomy. Note the irregular peritoneal surface instead of a normal glossy appearance (A) and the multiple serosal implants (B). (Courtesy Dr. F. A. Mann, University of Missouri, College of Veterinary Medicine.)

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In cats with small intestinal adenocarcinoma, there is significant perioperative risk, but cats that live beyond 2 weeks may experience long-term control with surgery alone (Fig. 23.30). In two series, all cats that did not have their tumors resected were euthanized or died within 2 weeks of surgery.444,458 After surgical resection, one-half of cats in one report and all cats in another study died within 2 weeks of surgery, and 4 of 11 cats surviving beyond 2 weeks died within 2 months of complications or other nontumor causes.444,458,462 For eleven of the 12 cats that survived 2 weeks beyond surgery, mean ST was 15 months, although in another report the MST was 2.5

months.444,461 For details about outcome after treatment for alimentary lymphoma see Chapter 33, Sections A and B. 

Large Intestine There are various approaches for removal of tumors from the large intestine based on the size, location, and depth of penetration of the mass. Generally, for rectal mucosal masses suspected to be benign polyps, the masses can be removed via mucosal eversion and submucosal resection.535 Transrectal endoscopic removal of benign canine rectal tumors can be considered if more extensive surgery is required because of the location of the tumor. Using this technique, five of six dogs showed significant improvement in quality of life and three dogs were cured; however, one dog died due to rectal perforation, which is a known complication of this procedure.536 The other disadvantage of this technique is there is often incomplete removal of the mass, as it is usually removed piecemeal. In a recent case report, this technique was modified to inject saline to separate the mucosa from the submucosa to improve visibility and the ability to completely remove

A

• Fig. 23.29  Cecal gastrointestinal stromal tumor seen at exploratory lapa-

rotomy. Note the darkly colored perforated area of the tumor that led to septic peritonitis in this dog. (Courtesy Dr. E. A. Maxwell, University of Illinois, College of Veterinary Medicine.)

B

C • Fig. 23.28  Intestinal lymphoma in a dog (A). The specimen is shown after resection and anastomosis (B) and on cross-section (C) to illustrate the marked thickening of the bowel wall. (Courtesy Dr. Eric Pope, Ross University, College of Veterinary Medicine.)

•

Fig. 23.30 Intestinal obstruction as a result of adenocarcinoma (white arrow). Note the distention of the jejunum oral to the mass compared with the normal diameter aboral to the mass. There is also an enlarged lymph node (black arrow). (Courtesy Dr. Eric Pope, Ross University, College of Veterinary Medicine.)

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the mass.537 For malignant rectal tumors, full-thickness removal of the rectum is generally indicated. Rectal-pull through is commonly performed for rectal adenocarcinomas. This can be performed through either a perineal or combined perineal-abdominal approach.538,539 Complications are relatively common, including fecal incontinence (57% total with 40% permanent fecal incontinence), diarrhea (43%), tenesmus (31%), stricture formation (21%), rectal bleeding (11%), dehiscence (8%), and infection (5%).538 Colostomy use has been reported to aid in management of dogs with nonresectable rectal tumors. In one report, skin excoriation was the most common complication, but colostomy bags were managed for up to 7 months.540 For rectal polyps and carcinomas in situ, depending on the surgical technique used for resection, local recurrence of clinical signs is reported in up to 41% of dogs and 18% of dogs had malignant transformation associated with tumor recurrence.455 Surgical removal of duodenal polyps in cats is typically curative.446 For dogs with colorectal adenocarcinoma, local excision results in MSTs of 2 to more than 4 years compared with 15 months for stool softeners alone;474,475,539,541 colorectal EMPs and polyps also fare well with MSTs of 15 months and 2 years or more, respectively, after surgical excision.464,542 In cats with large intestinal neoplasia, STs after surgery alone are approximately 3.5 months for lymphoma, 4.5 months for adenocarcinoma, and 6.5 months for MCT. Subtotal colectomy has been recommended for cats with colonic adenocarcinoma.447,543 Adjuvant chemotherapy has improved STs for cats with adenocarcinoma, but not for lymphoma.447 

Chemotherapy No randomized studies exist to investigate the efficacy of adjuvant chemotherapy after resection of epithelial intestinal tumors in dogs and cats. The benefit of adjuvant chemotherapy in humans is questionable, although current fluorouracil-based regimens are often considered to be the standard of care. When attempted, adjuvant chemotherapy typically includes doxorubicin in veterinary medicine. One retrospective study in cats with colonic adenocarcinoma treated with subtotal colectomy did show a significant survival advantage for cats receiving adjuvant doxorubicin; MSTs were 280 days with and 56 days without chemotherapy.447 In another retrospective study using adjuvant carboplatin, the MST was 269 days, but no controls were included to evaluate treatment without chemotherapy.543 Distant and nodal metastases were found to be negative prognostic indicators, with an MST of 200 days versus 340 days and 178 days versus 328 days, respectively.543 For carcinomatosis, intracavitary therapy may be helpful with carboplatin for cats or cisplatin or 5-fluorouracil (5-FU) for dogs.544 For further details about treatment of alimentary lymphoma please see Chapter 33, Sections A and B. Individual case reports in dogs using receptor tyrosine kinase inhibitors (TKIs, imatinib and toceranib phosphate) to treat GISTs in the setting of metastatic disease, nonresectable disease, or recurrent disease have shown good responses with partial (PR, n = 1) or complete responses (n = 2) for greater than 140 days, greater than 9 months, and greater than 4 years, respectively.486,545,546 The only toxicity seen was in one dog, and this manifested as an increase in ALT resulting in dose reduction of imatinib.546 After this dose decrease, the PR ceased, which could have been due to the lower dose or emergence of resistance as has been documented in human GISTs due to a second site mutation in c-kit.546 Imatinib has also been reported in the treatment of canine intestinal

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MCT with metastasis to the spleen. A strong PR was seen but was brief in duration.547 A reduction in the size and clinical signs of rectal polyps in 8 dogs was noted after piroxicam therapy, either orally or in suppository form. Clinical response did not relate to whether there was inflammation associated with the tumor.502 

Radiation Therapy RT is seldom used in the treatment of intestinal tumors because of the concern regarding toxicity to surrounding abdominal viscera, the ability to often obtain adequate local control via surgery, and the inability to reliably irradiate the same tissue each day because of the mobility of the intestine. 

Prognostic Factors Intestinal perforation does not appear to be a negative prognostic factor for leiomyosarcoma because dogs surviving the perioperative period had prolonged STs in one series.451 For colorectal tumors, treatment is prognostic, with local excision resulting in significantly better outcomes than palliative care. Gross appearance, although not statistically examined, may determine outcome because dogs with annular, obstructing masses survived a mean ST of 1.6 months whereas dogs nodular/cobblestone masses or single pedunculated masses had mean STs of 12 and 32 months, respectively.474 For nonlymphomatous small intestinal tumors in dogs, metastasis at the time of surgery resulted in significantly shorter STs (3 months vs. 15 months). The 1-year survival rates for dogs with and without LN metastasis were 20% and 67%, respectively.441 In another study, however, dogs with and without visceral metastasis from leiomyosarcoma survived equally as long after surgical resection (21 months).451 Male dogs with small intestinal adenocarcinoma had a significantly better outcome; however, the number of female dogs in that study was low.456 Cats with adenocarcinoma, however, survived significantly longer if they were treated with subtotal colectomy (138 days vs. 68 days with mass excision), received postoperative doxorubicin (280 days with vs. 56 days without doxorubicin), and had no LN metastasis at surgery (259 days for no LN metastasis vs. 49 days with LN metastasis).447 For further details about prognosis for dogs and cats with intestinal MCT see Chapter 21. For prognostic factors for canine and feline alimentary lymphoma see Chapter 33, Sections A and B. 

Comparative Aspects Although cancer of the large intestine and rectum is well characterized in humans, small intestinal neoplasia is rare. Theories for this discrepancy include more rapid small intestinal transit time compared with the large intestine (creating less contact time for carcinogens), dilution of carcinogens with fluid compared with solid stool, differences in pH, relative lack of bacteria to allow transformation of procarcinogens, presence of detoxifying enzymes, and increased presence of immunoglobulin A promoting local immunosurveillance of damaged cells as a result of increased lymphocytes in the small intestine. This is in contrast to veterinary medicine where in cats and sometimes dogs, malignant neoplasia is more common in the small intestine than the large intestine. This may reflect differences in physiology, diet, or genetics. As in animals, tumors of the small intestine of humans are usually malignant. Diagnostic evaluation is similar to that described in

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animals, although advanced imaging modalities, such as CT, are more often used. Most diagnoses are made at surgery and 5-year survival rates average approximately 20%.548 Large bowel/colorectal cancer is one of the most frequently diagnosed cancers in both men and women. Risk factors include genetic predisposition/familial history, tobacco and alcohol intake, advanced age, and predisposing medical conditions, among others. Colorectal cancer development may further be influenced by intake of red meat (especially fried), low-fiber and/or high-fat diets, obesity, fecal pH, and fecal mutagens. Among genetic risk factors, polymorphism in colonic enzymes and mutations leading to familial adenomatous syndromes are uncommon but are important as models of carcinogenesis. In most familial polyposis syndromes, the adenomatous polyposis coli (APC) gene is mutated. The multistage progression from benign polyp to carcinoma is well understood and underscores the importance of early detection.549 Recently, the APC gene was found to be altered in about 70% of tested canine colorectal tumor samples, suggesting a similar molecular pathogenesis.550 In contrast, hereditary nonpolyposis colon cancer develops without known premalignant polyps; this is inherited via autosomal dominance with high penetration and is characterized by microsatellite instability.551 In human medicine, GISTs are also subcategorized by the histopathologic morphology, a recent publication on canine intestinal tumor classification divided canine GISTs into 2 morphologic groups: spindlyloid/storiform and epitheloid, with the majority of GISTs in this study being spindlyloid.484 In addition, it has been suggested in humans there may be a subset of GISTs that are KIT negative.484 A recent study evaluated the use of protein 1 (DOG1) IHC marker to identify GISTs and it was found to have an increased specificity and sensitivity compared with KIT IHC.552 In this study, 2 tumors were negative for KIT and positive for DOG1. This may indicate there is a subpopulation of GISTs in dogs that are also KIT negative. The authors concluded that utilizing diagnostic panels with KIT and DOG1 markers would improve the accuracy of diagnosis.552 The most clinically important aspects of comparative oncology when considering intestinal neoplasia in humans are the use of COX inhibitors in the treatment and prevention of colorectal neoplasia, and the use of TKIs. In people, KIT mutations in GISTs have led to the use of imatinib mesylate, a TKI that inhibits KIT.553 This illustrates the notion of therapy directed at the molecular defect rather than the histologic diagnosis. KIT is mutated in some canine GISTs and thus TKIs may benefit this population as well. COX inhibition byNSAIDs decrease the incidence of colorectal cancer and mortality by 40% to 50%.554 Among the proposed mechanisms of action, prostaglandin production may be related to tumor progression and therefore inhibition leads to cancer prevention. In addition, non-COX pathways include inhibition of transcription factors and induction of nuclear hormone receptors that lead to cellular differentiation.554 Interestingly, a retrospective study found a significantly reduced incidence of cancer in dogs with a history of NSAID use (71% reduced risk).555 Therapy in humans is similar to that in companion animals. Surgical resection is the primary mode of therapy with adjuvant targeted or traditional chemotherapy in many cases, especially if patients present with LN metastasis or unresectable disease. TKIs may improve prognosis for unresectable and metastatic GISTs.556 Adjuvant chemotherapy is used in colon cancer, with oxaliplatin in combination with capecitabine or with leukovorin and 5-FU,

but without a convincing increase in overall STs.557 RT is used primarily for areas of the GI tract that are not very mobile, such as the stomach and rectum. 

SECTION H: PERIANAL TUMORS JULIUS M. LIPTAK AND MICHELLE M. TUREK The perianal area of dogs contains several glands and structures from which tumors may develop. Perianal, or circumanal, glands are located in the dermis in a circular fashion around the anus and are also scattered in areas on the prepuce, tail, pelvic limbs, and trunk.558 These are commonly referred to as hepatoid glands as a result of their cellular morphologic resemblance to hepatocytes and are considered nonsecretory sebaceous glands in the adult dog.558,559The anal sacs represent blind cutaneous diverticula that are located on each side of the anus at the 4 o’clock and 8 o’clock positions. Located in the connective tissue surrounding these diverticula are distinct apocrine sweat glands that empty their secretions into the lumen of the anal sacs. The most frequently observed tumors of this region in dogs include perianal sebaceous adenoma, perianal sebaceous adenocarcinoma, and apocrine gland anal sac adenocarcinoma (AGASAC). Other tumors arising from the anal sacs include squamous cell carcinoma (SCC) and malignant melanoma,560–563 but benign tumors of the anal sac are rare.564 Any cutaneous or subcutaneous tumor can affect the perianal region, including mast cell tumor, soft tissue sarcoma, squamous cell carcinoma, hemangiosarcoma, lymphoma, melanoma, leiomyoma, and transmissible venereal tumor. Because cats do not have glands analogous to the perianal sebaceous glands in the dog, perianal adenoma and perianal adenocarcinoma are uncommonly recognized in this species. Apocrine gland adenocarcinoma of the anal sac occurs rarely in the cat.565–567 

Perianal Adenoma and Adenocarcinoma Incidence and Risk Factors Perianal adenomas (circumanal, hepatoid tumors) represent the majority of canine perianal tumors (58%–96%).558,568 Development and progression of these benign tumors appear to be sex hormone–dependent, with growth stimulated by androgenic hormones and supressed by estrogenic hormones.558,569,570 Older, intact male dogs are at higher risk.558,568,569 The mean reported age is 10 years.568 A high incidence of associated testicular interstitial cell tumors has been reported for males with perianal adenomas, supporting testosterone production as a cause569; however, a true cause-and-effect relationship has not been clarified because interstitial cell tumors are also a common incidental finding in non– adenoma-bearing, older intact males. Perianal adenomas in the female occur almost exclusively in ovariohysterectomized animals in which low levels of estrogen do not suppress tumor growth. Rarely, androgenic steroid secretion from the adrenal glands, occasionally accompanied by signs of hyperadrenocorticism, may stimulate perianal adenoma formation in female dogs.571,572 Cocker spaniels, beagles, bulldogs, and Samoyeds may be predisposed.558,569 Some authors have proposed the term epithelioma to describe a subset of perianal sebaceous gland tumors.573 Epitheliomas are considered low-grade malignancies with a greater

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tendency to be locally invasive and to recur after surgical excision.574,575 To date, there is little clinical information to support a distinction between adenoma and epithelioma. Perianal adenocarcinoma, a malignant tumor of the perianal glands, occurs much less frequently than its benign counterpart, representing only 3% to 21% of all tumors in this region.558,568 The mean age of affected dogs is 11 years.568,576 Tumors occur in castrated or intact males, as well as in females, implying no hormonal dependency; however, this does not preclude earlier hormonal initiation.569,576 Large-breed male dogs appear to be overrepresented.576 

Pathology and Natural Behavior Perianal adenoma is benign. These are slow-growing tumors and, although local disease may be extensive, metastasis does not occur.558,576 Perianal adenocarcinoma is generally associated with a low rate of metastasis (<15%) at the time of diagnosis.576 Metastasis may be more likely to develop later in the course of disease as the primary tumor becomes larger and more invasive.576 The most frequent site of metastasis is the regional LNs.558,576 Distant metastasis is rare, but has been reported in the lungs, liver, kidney, and bone.569,576 This tumor tends to be more rapidly growing, fixed, and firmer than the more common benign perianal adenoma. The pathogenesis of canine perianal tumors is not known. In a large study evaluating tumor growth characteristics of 240 perianal gland tumors, cell proliferation and apoptosis were quantified by proliferating cell nuclear antigen (PCNA) IHC and microscopic detection of apoptotic corpuscles.577 Increases in both parameters were observed in perianal adenocarcinomas compared with perianal adenomas.577 Ki67 immunoreactivity has also been evaluated and was found to increase from benign to malignant lesions, being highest in perianal adenocarcinomas and recurrent tumors.574,575,578 Collectively, these results suggest that a high proliferative index may be related to tumor aggressiveness. Other IHC studies have attempted to elucidate possible molecular mechanisms involved in canine perianal gland tumorigenesis. Nuclear p53 accumulation was detected in 50% of perianal sebaceous gland adenocarcinomas in one study, suggesting that expression of a mutated p53 tumor suppressor protein may play a role.579 Discordant results were reported in another study in which p53 reactivity was found in none of 11 perianal gland adenocarcinomas and in only a small percentage of adenomas.580 In the same tumor samples, Mdm2 expression was observed in both adenomas and adenocarcinomas.580 A study that evaluated androgen receptor expression found no difference between perianal adenomas and adenocarcinomas; the authors concluded that the mechanism by which androgens influence carcinogenesis is still unknown.581 Vascular endothelial growth factor (VEGF) may also be involved in tumorigenesis. Serum VEGF levels corresponded with tumor aggressiveness and tumor burden in one study.575 The same study suggested a correlation between serum 17-β-estradiol and VEGF levels, supporting the role of hormones in carcinogenesis in some perianal tumors.575 Another proposed mediator of tumor development is growth hormone. Growth hormone was detected with IHC in 96% of perianal adenomas and 100% of perianal sebaceous gland adenocarcinomas.582 Finally, serum magnesium levels were found to be higher in dogs with malignant perianal tumors than in those with benign tumors.583 

History and Clinical Signs Benign perianal adenomas tend to be slow-growing (over months to years) masses that are nonpainful and usually asymptomatic.

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They may be single, multiple, or diffuse (similar to generalized hyperplasia or hypertrophy of the perianal tissue).558 Most occur on the hairless skin around the anus, although they may extend to haired regions and can develop on the prepuce, scrotum, or tail head (stud tail or “caudal tail gland”).558 Benign lesions may ulcerate and become infected but are rarely adherent or fixed to deeper structures.558 They are usually fairly well circumscribed, on average 0.5 to 3 cm in diameter, and elevated from the perineum.558 Perianal adenocarcinoma may have a similar gross appearance to perianal adenoma; however, they tend to have a faster growth rate, present more commonly as a larger and firmer mass with some degree of ulceration and fixation to deeper tissues, and they are more likely to recur after conservative surgical resection.576 Perianal adenocarcinomas can be multiple.573 Obstipation, dyschezia, or perianal pain or irritation can be seen with larger masses.576 Rarely, clinical signs are related to obstruction of the pelvic canal by LN metastasis. Castrated male dogs with a new or recurrent perianal tumor may have an increased risk for malignant rather than benign disease because, unlike perianal adenoma, perianal adenocarcinomas are not hormonally dependent. 

Diagnostic Techniques and Workup Signalment, history, and physical examination findings will assist in developing a preliminary suspicion of tumor type as well as treatment planning. The mass should be palpated and a rectal examination performed to assess the degree of fixation and extent of the mass as well as the presence of enlarged LNs. Physical examination findings may provide some indication of whether a perianal mass is benign or malignant; however, there is a degree of overlap in the gross appearance of perianal adenoma and adenocarcinoma. FNA cytology to differentiate benign from malignant tumors can be unrewarding, although it is helpful in ruling out other tumor types. Incisional biopsy is recommended for definitive diagnosis and to better direct clinical staging tests and treatment options.584 Malignant disease is more likely in tumors showing invasiveness into surrounding tissue, disorderly arrangement of cells, increased nuclear pleomorphism, and increased numbers of mitotic figures.584 In some cases, a definitive diagnosis may not be possible histologically, and IHC with monoclonal antibodies against carcinoma-associated antigens 4A9, 1A10, as well as PCNA, and Ki67 may assist in differentiating perianal adenoma from adenocarcinoma.573–578,585 In the rare event that differentiation from AGASAC is needed, cytokeratin expression patterns may be helpful.586 Clinical validation is needed to confirm the utility of these IHC approaches. For dogs with perianal adenocarcinoma, abdominal and thoracic imaging is recommended to investigate for the presence of metastatic disease. Up to 15% of dogs with perianal adenocarcinoma have evidence of metastatic disease at the time of diagnosis, and the regional LNs and lungs are the most common sites of metastasis.558,569,576 Based on studies of canine AGASAC, advanced imaging modalities, such as CT andMRI, are superior to abdominal ultrasonography for the detection of enlarged LNs, particularly those within the pelvic canal. Although distant metastasis is uncommon, three-view thoracic radiographs or thoracic CT is recommended for the detection of pulmonary metastasis. 

Treatment Surgical resection is the recommended treatment for dogs with perianal adenomas and adenocarcinomas. Perianal adenomas can be excised with minimal margins of less than 1 cm, whereas larger

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margins are recommended for perianal adenocarcinomas because of their propensity for local recurrence after more conservative resections.574 Castration is also recommended in intact male dogs with perianal adenomas because of the role of testosterone in the tumorigenesis of these tumors.569,587 For diffuse or large perianal adenomas located on or in the anal sphincter, staged surgery may be preferable with castration initially to decrease tumor volume followed by surgical resection when the perianal adenoma is small enough that it can be more easily and safely resected. More than 90% of male dogs will be cured with castration and local resection of the perianal adenoma.558,569 Cryosurgery and carbon dioxide laser ablation are possible alternative treatment options for perianal adenomas, especially if small,588,589 but the major limitation of these techniques is an inability to assess the surgical margins for the completeness of excision. Hyperthermia and RT have also been used successfully.590,591 The cost, added morbidity, and limited availability of these modalities make them a poor alternative to standard surgical resection. Electrochemotherapy has been described in dogs with perianal adenoma and consists of intratumoral injections of chemotherapy followed by local delivery of electric pulses to potentiate drug uptake by tumor cells.587,592 Treatments are delivered in 1 or 2 weekly sessions. Based on limited studies, the reported overall response rate is greater than 90%, with 65% complete responses.587,592 Smaller tumors (<5 cm) generally respond better than larger tumors.587,592 Larger tumors are more likely to develop local complications, including focal necrosis, erythema, and inflammation.587,592 Systemic effects are not reported.587,592 Perianal adenoma may also regress after estrogen therapy575; however, its use is associated with a risk of myelosuppression. Cyclosporin is reported to have had a palliative effect in one dog with multiple ulcerated perianal adenomas and a measurable reduction in tumor size was observed.593 Perianal sebaceous gland adenocarcinoma is more locally invasive and generally does not respond to castration.569 Aggressive surgical resection with a minimum of 1-cm lateral margins is recommended. Removal of one-half or more of the anal sphincter is possible with only rare transient loss of fecal continence. Preoperative incisional biopsy is recommended to differentiate perianal adenoma from adenocarcinoma because this differentiation may not be possible based on history, gross tumor characteristics, or cytology. If an excisional biopsy is performed, then there is a risk of incomplete histologic excision and local tumor recurrence. The rate of local tumor recurrence is unknown after incomplete histologic excision, but further surgery is complicated by the regional anatomy with a greater risk of treatment-associated morbidity. Adjuvant RT may improve local tumor control after incomplete excision; however, data for this approach are lacking. The use of electrochemotherapy has been reported in a small series of dogs.587,592 Favorable outcomes have been reported, but additional clinical studies are needed to validate the efficacy of electrochemotherapy.587,592 

Prognosis The vast majority of dogs with perianal adenoma are cured with surgical resection and, if indicated, castration.558,561 Serum VEGF levels may correlate with biologic behavior of this tumor type.576 In a series of 41 dogs with perianal adenocarcinoma, stage of tumor had a significant influence on DFI and overall survival times (OSTs).576 Tumors less than 5 cm in diameter (T2) were associated with 2-year tumor control rates in excess of 60%,576 suggesting that surgical removal of these masses at an early stage

is relatively successful with respect to disease control. The rate of metastasis at diagnosis is 15% and is a poor prognostic factor for survival.576 The MST for dogs with LN or distant metastasis was 7 months; however, aggressive treatment was not attempted in five of six dogs.576 In a smaller study, tumor recurrence occurred in 75% of dogs; however, tumor size, surgical approach, and completeness of excision were not reported.574 If present, regional LN metastasis may be resected and this may result in improved ST. The use of RT and/or chemotherapy, including actinomycin D, has been reported anecdotally, but their role in local or distant control is undefined.576,594,595 Nuclear size, as measured by computer-assisted image analysis in cytologic tumor samples, and Ki67 expression may correlate with biologic behavior of perianal adenocarcinoma.574,596 

Apocrine Gland Anal Sac Adenocarcinoma and Other Tumors of the Anal Sac Incidence and Risk Factors AGASAC accounts for 17% of perianal malignancies and 2% of all skin and subcutaneous tumors.568,597 Spaniels, particularly English cocker spaniels, German shepherds, Alaskan malamutes, and dachshunds have been reported to have an increased risk of AGASAC.598–601 A female predilection was reported in earlier studies601–604; however, an approximately equal sex distribution has been shown in multiple larger series.598–601,605 Neutering may be associated with increased incidence of AGASAC in male dogs.598 The mean age of dogs at diagnosis of AGASAC is 9 to 11 years.568,599–606 Tumors in dogs as young as 5 years have been reported, suggesting that evaluation of the perineum and palpation of the anal sacs should be a routine part of the physical examination of every adult dog. AGASAC is a rare tumor in the cat, representing 0.5% of all feline skin and subcutaneous neoplasms.565 The median age of affected cats is 13 years, although animals as young as 6 years have been reported.565,566 Siamese cats may be at higher risk.565,566 

Pathology and Natural Behavior AGASACs are distinct from perianal gland adenocarcinomas histologically and clinically. Histologic patterns of tumor cell arrangement in AGASAC have been classified as solid (closely packed neoplastic cells in lobules or nests with minimal stroma), tubules/rosettes/pseudorosettes (cells are radially arranged around a central tubule or a collection of cytoplastic processes or a small blood vessel), and papillary (elongated tree-like projections with a fibrovascular stalk).607,608 The solid and tubules/rosettes/pseudorosettes patterns occur in about 95% of cases.607,608 AGASACs are usually unilateral, although bilateral AGASACs have been reported.564,603–606,609–611 The overall incidence of bilateral AGASACs, either simultaneously or temporally separated, is up to 14%.603,604,606,611,612 Paraneoplastic hypercalcemia is reported in 16% to 53% of dogs with AGASAC.564,581–602,605–607,609,613–617 Hypercalcemia is caused by the synthesis and secretion of parathyroid hormone– related peptide from neoplastic tissue.618–620 Hypertrophic osteopathy in association with pulmonary involvement has been reported in two dogs.621,622 Metastasis is common in dogs with AGASAC. Overall, metastasis is reported in 26% to 96% of dogs at the time of diagnosis, with 26% to 89% of dogs having metastasis to the regional LNs and 0% to 42% with metastasis to distant

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sites.564,568,599–602,605,606,610,616 Metastasis can be present even when the primary tumor is small (<1 cm).607 The medial iliac and internal iliac LNs (collectively called sublumbar LNs) and sacral LNs are the most common sites of metastasis,564,599–601,605,606,609 whereas distant sites include lungs, liver, spleen, bone, and, less commonly, heart, adrenal glands, stomach, omentum, pancreas, kidneys, urinary bladder, and the mediastinum.564,568,599–604 AGASAC micrometastases were detected incidentally in the bone marrow in one of four dogs in one study.623 Tumor behavior can vary, because some dogs with large primary tumors may present without metastatic disease, whereas others may have a small primary tumor that has already metastasized.607 In one study, dogs with clinical signs were more likely to have LN metastasis at diagnosis compared with dogs whose tumors were detected incidentally.607 Histologic features including marked peripheral infiltration into surrounding tissue (neoplastic aggregates separated from the main tumor nodule), lymphovascular invasion, and solid pattern of cell arrangement were also associated with nodal metastasis at diagnosis, whereas mitotic index and presence of necrosis were not.607 In another study, E-cadherin, a protein that mediates adhesion and communication between cells and the extracellular matrix, was evaluated as a prognostic marker in dogs with AGASAC.624 A positive relationship between survival and the proportion of cells expressing E-cadherin immunoreactivity was observed, suggesting that loss of E-cadherin expression may play a role in tumor progression.624 p53 expression has been detected via IHC in a low-to-moderate proportion of AGASAC samples; however, no clinical implications have come from these findings.579 A genetic analysis study in English cocker spaniels showed a higher frequency of AGASAC in dogs with the major histocompatibility complex DLA–DBQ1 allele, suggesting that a genetic factor may play a role in tumor development in this breed.625 COX-2 expression also has been evaluated in AGASAC.626 All tumor samples evaluated in one study showed positive immunoreactivity, as did ductal cells in normal anal sacs.626 Neuroendocrine differentiation, suggested by expression of markers including synaptophysin, chromogranin A, and neuron-specific enolase, was detected via IHC in 30% of AGASAC.608,627 To further dissect the molecular basis of AGASAC and its reported sensitivity to the tyrosine kinase inhibitor toceranib phosphate (Palladia), expression of key toceranib targets has been evaluated.628,629 In one study, mRNA for vascular endothelial growth factor receptor (VEGFR)-2, platelet-derived growth factor receptor (PDGFR)-α and -ß, and KIT was detected in all 24 tumors evaluated, but protein expression assessed by IHC was less consistent.629 Protein expression of VEGFR-2 and PDGFR-α was present in most tumors; however, only one third expressed KIT. PDGFR-ß was strongly expressed in stroma.629 Interestingly, RET expression was observed at both the mRNA and phosphorylated protein levels.629 Phosphorylation of other receptor tyrosine kinases, including EGFR, Dtk/TYRO3, ROR-1, ROR-2, Tie1, insulin-R, and RON, was observed in more than half of the tumors, suggesting that these may also have a role in AGASAC tumorigenesis.629 A case series of 11 dogs with anal sac melanoma suggests a moderate to aggressive biologic behavior.560 Primary tumors were unilateral in all cases with a mean diameter of 3.4 cm. At the time of diagnosis, four of eight dogs had confirmed or suspected sublumbar LN metastasis, and 1 of 11 dogs had pulmonary metastasis.560 The median mitotic index of the primary tumors was 50 per 10 high-power fields. Ten of 11 dogs died due to tumor progression.560 Squamous cell carcinoma has also been reported arising

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from the anal sac in nine dogs, all with unilateral disease.561–563 Four of these dogs were clinically staged and none had evidence of regional LN or distant metastasis. Tumors recurred in four of five dogs after surgical excision.561–563 The biologic behavior of feline AGASAC has not been clearly defined. Most reports suggest that it is a locally invasive disease associated with a moderate-to-high risk of tumor recurrence after surgery.565–567 The rate of metastasis is variable between studies.565–567 Metastasis to the regional LNs was suspected at the time of diagnosis in 20% of surgically treated cats with AGASAC.566 Metastatic sites include regional LNs, liver, diaphragm, and lungs.565,567 Paraneoplastic hypercalcemia is relatively rare in cats with AGASAC, being reported in 11% of cats in one series.565,566 Bilateral tumors have not been reported. 

History and Clinical Signs Clinical signs in dogs with AGASAC are often referable to either the presence of the primary mass (perianal discomfort, swelling [Fig. 23.31A], discharge, bleeding, scooting, perianal licking), obstruction of the pelvic canal by LN metastasis (tenesmus, abnormal stool shape, constipation, lethargy, anorexia), or to hypercalcemia (polyuria, polydipsia, hyporexia, lethargy, vomiting).599,600,607 The primary tumor is an incidental finding on physical examination in up to 47% of reported dogs.600,603 Rarely, dogs present with pain or lameness as a result of bone metastasis or direct extension of metastatic LNs into the lumbar or sacral vertebrae. In one study, presence of clinical signs was associated with the size of the primary tumor.616 Dogs with anal sac melanoma or SCC present with clinical signs related to the primary tumor.561–563 Common signs include hemorrhagic discharge and perineal licking.561–563 Tenesmus and constipation may be less common than in dogs with AGASAC.561–563 In one study, all dogs with anal sac melanoma presented with clinical signs; none of the tumors were detected incidentally.560 Of nine dogs with anal sac SCC, one dog was diagnosed incidentally.561–563 In cats with AGASAC, the most common clinical sign is perineal ulceration or discharge and this is present in up to 85% of cats (see Fig. 23.31B).566 Other clinical signs include tenesmus, constipation, scooting, and excessive grooming of the perineal area.565–567 Lethargy and/or hyporexia may be secondary to severe constipation. Not all cats present with clinical signs, and tumors can be detected incidentally during a routine physical examination, although this is rare.565 It is not uncommon for an AGASAC to be misdiagnosed as an anal sac abscess based on the presence of ulceration and discharge in the perineal region.565,566 

Diagnostic Techniques and Workup Because dogs with AGASAC may present with signs unrelated to perianal disease (i.e., polyuria and polydipsia due to hypercalcemia), assessment of animals with suspicious clinical signs requires a careful rectal examination, including palpation of both anal sacs and evaluation for possible regional lymphadenomegaly. Although a definitive diagnosis requires either an FNA or biopsy, the likelihood of AGASAC is high in animals with a firm and discrete mass in the anal sac. AGASAC has a characteristic “neuroendocrine” cytologic appearance consisting of polyhedral to roundish epithelial cells with uniform round nuclei and light blue-gray, slightly granular cytoplasm (see Fig. 7.18). Cytologic criteria of malignancy are often subtle or absent. FNA cytology

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Fig. 23.31 (A) The typical appearance of a large apocrine gland anal sac adenocarcinoma in a dog. (B) The typical appearance of an apocrine gland anal sac adenocarcinoma in a cat. Ulceration with an associated discharge is the most common finding in cats with apocrine gland anal sac adenocarcinomas.

is valuable for ruling out impaction, infection, or inflammatory disease of the anal sac, although AGASAC can become secondarily infected or inflamed. Although special stains are almost never needed to confirm the diagnosis, a small study of cytokeratin immunoreactivity in perianal tumors showed a repeatable pattern of expression (CK7+/CK14–) in AGASAC.586 Clinical staging in dogs and cats with AGASAC includes assessing the size of the anal sac mass, evaluating for hypercalcemia, and investigating the abdomen and thorax for metastatic disease. Serum ionized calcium levels are preferred to total calcium concentrations for the assessment of hypercalcemia. Accurate tumor staging in the abdomen and pelvic canal is important, because presence of metastasis affects prognosis and treatment decisions. Abdominal radiographs may reveal regional lymphadenomegaly in advanced cases, but are inadequate for the assessment of smaller metastatic LNs and metastasis to other abdominal organs such as the liver and spleen. Abdominal ultrasonography is commonly used to evaluate the abdomen and is more sensitive than radiography.630 Despite its superiority to radiography, ultrasound has limitations. In one study, the only sonographic feature that separated benign from malignant LNs was LN size.631 Changes in shape, contour, cavitation, echogenicity, and parenchymal uniformity did not reliably distinguish metastatic LNs.631 Identification of nodal metastasis by ultrasound is further limited by anatomy, because the pelvic floor precludes visualization of LNs in the pelvic canal. Advanced imaging, including CT and MRI, allows for evaluation of LNs in the pelvic canal and can detect lymphadenomegaly in dogs deemed normal by ultrasound (Fig. 23.32).632 Furthermore, studies have shown that advanced imaging detects a greater number of enlarged LNs than ultrasonograpy.632–634 Sentinel LN mapping, using indirect CT lymphography, has been described in 18 dogs with AGASAC.635 This study, along with the advanced imaging studies, suggests that patterns of LN metastasis can vary, and do not always follow lymphatic drainage linearly from the perineum.633–635

Lymphadenopathy related to AGASAC can involve any of the three LN centers (medial iliac, internal iliac, or sacral), and often skips LNs. The sacral LN was deemed the sentinel LN in only 25% of cases.635 Collectively, these findings suggest that advanced imaging is necessary for optimal treatment planning to thoroughly assess the extent of disease. Importantly, these studies also bring to light that outcomes of treatment studies can be significantly affected by choice of staging tests. Three-view thoracic radiographs or thoracic CT are recommended for detection of pulmonary metastasis or rare mediastinal involvement. In rare instances, pulmonary metastasis can be present without obvious regional LN disease. Lameness or bone pain should be evaluated with radiography, advanced imaging, and/or nuclear scintigraphy to rule out bone metastasis. Workup should also include complete blood count, serum biochemistry panel, and urinalysis. Hypercalcemia of malignancy can result in renal damage, which may modify prognosis and anesthetic risk. Medical management of hypercalcemia or impaired renal function may be necessary before surgery or for nonresectable disease (see Chapter 5). Diagnosis of anal sac melanoma or SCC requires a tissue biopsy for histopathologic confirmation; however, cytology can be highly suggestive.560 Although the biologic behavior of these less common anal sac tumors is not clearly defined, abdominal and thoracic imaging are recommended for complete tumor staging.561–563 Metastasis appears common in dogs with anal sac melanoma, but not with SCC.560–563 

Treatment Surgery is considered the mainstay of treatment for dogs with nonmetastatic AGASAC or AGASAC metastatic to the regional LNs.564,600,605,606,612 Excision of the primary tumor can be daunting because of the location of the anal sacs relative to the rectum, external anal sphincter, and perineal neurovascular structures;

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Metastatic Medial lliac Lymph Node

Internal lliac Artery Internal lliac Vein

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Fig. 23.32 Transverse computed tomography (CT) images at the level of the pelvic canal in two dogs with apocrine gland anal sac adenocarcinoma. Small (A) and large (B) ipsilateral sacral lymphadenomegaly is noted (arrow), and both of these were not detected during abdominal ultrasonography. Three-dimensional advanced imaging, such as CT or magnetic resonance imaging, is preferred for tumor staging because it allows better visualization of the sacral lymph nodes within the pelvic canal.

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however, the majority of AGASACs can be resected with a closed anal sacculectomy and a low risk of postoperative complications (Fig. 23.33A).605 The complication rate after local AGASAC excision is 5% to 24%, with the most common complications being wound dehiscence, rectal perforation, rectocutaneous fistulation, incisional infection, and transient fecal incontinence.605,606,610 Risk of complications may be related to tumor size.610 In an older study, mild to severe fecal incontinence was reported in 19% of dogs, and this incontinence was transient in 40% and permanent in 60%603; however, the surgical approach used in this study was more aggressive than what is currently recommended, with resections involving 120° to 270° anoplasties.603 Local resection of AGASAC is almost always marginal because of the location of these masses within the perineal space.616 As a result, the completeness of histologic excision is determined by tumor biology rather than the surgical approach; incomplete histologic excisions are expected when tumors have ruptured through their capsule either microscopically or macroscopically. Lymphadenectomy is recommended for excision of metastatic sublumbar and sacral LNs because STs appear to be significantly improved when metastatic LNs are removed.601 When nodal enlargement is obstructing the pelvic canal or contributing

to hypercalcemia, lymphadenectomy relieves clinical signs and improves quality of life. The sublumbar LNs include the paired medial and internal iliac LNs.630,631 These LNs are located in close proximity to the terminal branches of the aorta and caudal vena cava in the dorsal aspect of the caudal abdomen (see Fig. 23.33B). The majority of metastatic sublumbar and sacral LNs are solid, although occasionally they can be cystic.636 Excision can be complicated by their location, regional anatomic structures, invasion into lumbar vertebrae, and if they are cystic. Omentalization of an unresectable cystic nodal metastasis was reported in one dog with good results.636 Iatrogenic trauma to the terminal branches of the aorta or, more commonly, the thin-walled caudal vena cava, can result in significant intraoperative bleeding and the need for blood products. As a result, cross-matching is recommended before surgery in dogs treated with surgical excision of metastatic LNs. The complication rate after LN extirpation varies from 0% to 12%, with the most commonly reported complications being intraoperative hemorrhage, unresectable metastatic LNs, LN rupture, and abdominal wall dehiscence.605,606,612 Sacral LNs are more difficult to expose, but can usually by extirpated with careful digital dissection. Pelvic osteotomies are rarely required to provide additional exposure for removal of metastatic sacral LNs. Multiple studies

Fig. 23.33 Surgical management of dogs with apocrine gland anal sac adenocarcinoma depends on the stage of disease. (A) Closed anal sacculectomy for excision of an apocrine gland anal sac adenocarcinoma in a dog. (B) View of the dorsal aspect of the caudal abdomen during surgical extirpation of a metastatic sublumbar lymph node. Resection of metastatic lymph nodes can be complicated by regional vasculature (pictured), deep location within the abdominal cavity and pelvic canal, and the nature of the metastatic lymph nodes (such as invasion into regional musculature or being cystic).

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have shown that there is a survival advantage associated with treatment of progressive disease in dogs with AGASAC.605,606,612,637 Therefore excision of recurrent tumors or progressive nodal metastasis is recommended, especially when it can be done with low morbidity. Although surgery rarely has a role in the management of distant metastatic disease, particularly at the time of diagnosis, splenectomy may be considered in dogs with splenic metastasis in the context of slowly progressive disease when there is no evidence of metastasis to other distant sites.607 The roles for adjuvant chemotherapy and RT are controversial and not fully defined. Chemotherapy has traditionally been recommended for the treatment of canine AGASAC because of the risk of metastasis. Drugs with demonstrated antitumor activity in the gross disease setting include carboplatin, cisplatin, and actinomycin D.594,598,599 Other drugs reported in the postoperative setting include mitoxantrone and melphalan.564,609 However, no controlled study has shown a survival advantage with the use of adjuvant chemotherapy in dogs with AGASAC.600,601,605,606 In one study of 113 dogs with AGASAC, there was no significant difference in outcome between dogs treated with surgery alone and dogs treated with surgery and chemotherapy, with MSTs of 500 days and 540 days, respectively.600 Similarly, in another study of 74 dogs, there was no significant difference in either MST or time to progression for dogs treated with surgery alone (581 days and 402 days, respectively) and surgery and carboplatin (723 days and 384 days, respectively).606 In fact, in another study, the use of adjuvant chemotherapy had a negative effect on DFI and no effect on ST.605 In these retrospective studies, it is possible chemotherapy was more often offered or chosen in patients with more advanced disease, which could have resulted in a bias against chemotherapy effectiveness. Until controlled clinical trials are performed to definitively define the role of chemotherapy in the management of dogs with AGASAC, there is little evidence to support its use in the adjuvant setting. Toceranib has been associated with modest tumor responses in canine AGASAC.638 In a retrospective study of 32 dogs with multiple prior failed therapies, use of toceranib resulted in tumor response durations of 10 to 47 weeks.638 A 25% partial response rate was noted and an additional 63% of dogs maintained stable disease, for a total clinical benefit rate of 88%. Resolution of hypercalcemia has also been reported with toceranib treatment.638 The antitumor effect of toceranib may be mediated through inhibition of the PDGFR-β or vascular endothelial growth factor receptor 2, both of which are expressed in canine AGASAC.628,629 Controlled clinical trials are needed to determine the role of toceranib in the treatment of dogs with AGASAC. COX-2 is expressed in the glandular epithelial cells of AGASAC,626 and this may suggest a potential role for COX-2 inhibitors in the management of dogs with AGASAC. Adjuvant electrochemotherapy using cisplatin has been reported in a single dog after an incomplete primary tumor excision.639 RT has been described for both palliation and multimodal, curative-intent treatment of dogs with AGASAC.600,601,609,611,617 Measurable response rates of 38% to 75% have been observed in dogs with bulky disease treated with hypofractionated or fractionated protocols, suggesting radiosensitivity in the gross disease setting609,611,617,640; however, the role of RT for tumor control in the microscopic setting after surgical resection of primary or nodal AGASAC remains poorly defined. In a study of 113 variably treated dogs, the use of adjuvant RT did not result in a significant improvement in STs in 15 dogs.600 This may have been due to low statistical power, as the MST of these dogs was longest among the

treatment groups at 742 days.600 Radiation protocols, treatment intent, and tumor stage were not described.600 In the only report of standardized curative-intent adjuvant RT, the MST of 15 dogs was 956 days.609 Dogs received 15 daily fractions of 3.2 Gy (total dose of 48 Gy) to the primary site and regional LN beds using a nonconformal technique in combination with mitoxantrone chemotherapy. Although STs were favorable, late complications developed in half of the dogs.609 Subsequent radiation toxicity studies showed that late radiation effects such as rectal stricture, rectal perforation, and chronic colitis are more likely to occur when radiation doses per fraction of 3 Gy or greater are used.641,642 Therefore future curative-intent protocols should include pelvic irradiation at doses less than 3 Gy per fraction.641,642 Use of conformal radiation technology, such as intensity-modulated RT, should further reduce the risk of toxicity by optimizing avoidance of critical structures. Dose-dependent, self-limiting acute effects reported in the study of nonconformal curative-intent irradiation of this region included mild to severe moist desquamation of the perianal area and colitis resulting in perianal discomfort lasting 1 to 4 weeks.609,642 The role of palliative-intent RT for relief of clinical signs associated with bulky AGASAC is better defined. Various hypofractionated protocols have been described including 5 daily fractions of 4 Gy, 3 to 4 weekly fractions of 6 to 9 Gy, 8 fractions of 3.8 Gy on a Monday–Wednesday–Friday schedule, and 5 biweekly fractions of 5 Gy.601,611,617,640 These palliative RT protocols resulted in an improvement in clinical signs in up to 63% of dogs, including resolution of obstipation in some dogs.611,617,640 Hypercalcemia resolved with RT alone in 31% of dogs and in an additional 46% of dogs when RT was combined with prednisone and a bisphosphonate.617,640 The reported median progression-free intervals (PFIs) for dogs treated with palliative-intent hypofractionated protocols were 10 to 11 months, and MSTs ranged from 8 to 15 months.601,611,617,640 Acute effects were mild and infrequent with grade I–II acute colitis in 8% to 27% of dogs, and grade I–II acute skin effects in 17% to 21% of dogs.611,617 Late effects were rare in one study and included suspected rectal stricture in 3% of dogs and grade I late skin effects in 6% of dogs; these occurred in dogs treated with fractions of 5 Gy or greater.617 In contrast, late effects were not observed in dogs treated with 8 fractions of 3.8 Gy delivered on a Monday–Wednesday–Friday schedule.611 Severely hypofractionated RT should be used cautiously because late effects, such as rectal stricture, rectal perforation and chronic colitis, are related to dose per fraction.611,617,641,642 When interpreting the results of RT studies, it is important to consider that tumor control probability and risk of RT complications are affected by radiation dose distributions in the patient. A radiation treatment planning study showed that computerized, CT-based, 3-D conformal RT planning results in improved radiation dose distributions, with greater dose homogeneity in neoplastic tissues and better control of exposure of critical normal structures compared with nongraphic manual RT planning.643 This has important implications for the interpretation of tumor control and toxicity profiles of older studies in which manual treatment planning was used.643 It is possible that contemporary and future studies that take advantage of sophisticated treatment planning systems and conformal radiation delivery techniques may achieve different tumor control rates and complication risks than those described in older reports. Radiation studies should also be evaluated in the context of the regions that are irradiated, with reported radiation fields including the perianal region alone, perianal region and

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enlarged LNs,611,617 or perianal region and regional lymphatic chain regardless of the size of the regional LNs.609,617 These differences could affect clinical outcomes and should be considered when studies are compared. There may be a role for RT in the curative-intent management of dogs with incompletely excised AGASAC or dogs with surgically excised regional LN metastasis, or in the palliative management of dogs with measureable disease600,601,609,619; however, further studies are required to determine how RT should be optimized. The majority of published studies have not standardized therapy for AGASAC according to clinical stage, and there is some evidence that the treatment approach may be stage dependent.601 In one study, a clinical stage system and treatment algorithm were developed on the basis of a retrospective analysis of 80 dogs, and then these were evaluated in a prospective cohort of 50 dogs.601 The proposed treatment algorithm included various combinations of surgery, carboplatin chemotherapy, and hypofractionated RT. However, this staging system has not been widely accepted, likely because it does not prioritize surgical excision on the basis of resectability. Surgery, according to the algorithm, is recommended only for primary tumors smaller than 2.5 cm and for metastatic LNs smaller than 4.5 cm when the primary tumor is smaller than 2.5 cm. In light of the increasing evidence of the importance of surgery in the treatment of AGASAC and its positive effect on survival,600,601,605–607,612,637 surgical excision, including resection of recurrent disease, has become the mainstay of treatment for resectable AGASAC irrespective of size. Further studies are required to investigate the optimal combinations of surgery, chemotherapy, and RT in the management of dogs with various clinical stages of AGASAC. 

Prognosis Although dogs with metastatic AGASAC are rarely cured, longterm survival may be achieved in many cases after surgery-based treatments of the primary tumor and metastatic LNs both at presentation and in the face of recurrence. The reported DFIs for dogs treated surgically, with or without adjuvant therapy, range from 262 to 443 days.605–607 Local recurrence rates vary widely from 5% to 44%.603,605–607,612 Local recurrence is not associated with completeness of excision,603,607 and this highlights the difficulty in using the completeness of excision to determine whether adjuvant therapies, such as RT or revision surgery, are required after incomplete histologic excision. Metastasis to regional LNs and to distant sites after surgery has been reported in 31% to 69% and 14% to 18% of dogs, respectively.603,606,607,612 Multiple studies have reported shorter median DFIs in dogs with LN metastasis at diagnosis (134–197 days) compared with dogs without LN metastasis (529–760 days).603,606,607 Dogs with LN metastasis at the time of surgery have a 2.5-fold hazard of disease progression compared with dogs without LN metastasis.603 For dogs with either local recurrence or postoperative LN metastasis, further treatment can improve STs.606,610,637 In one study of 74 dogs with AGASAC treated surgically, with or without adjuvant chemotherapy, 55% developed either local recurrence and/or LN metastasis.606 Of these dogs, 68% were treated with additional surgery, RT, and/or chemotherapy. The MST for dogs in which recurrent or metastatic disease was treated was 374 days after treatment for progressive disease, compared with 47 days for dogs in which the recurrent or metastatic disease was not treated.606 In another study, the additional MST associated with a second surgical intervention was 283 days.612

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Overall, the reported MSTs for dogs with AGASAC range from 386 to 960 days,564,599–603,605–607,609–611,615,616 with estimated 1and 2-year survival rates of 65% and 29%, respectively.600 Tumorrelated deaths vary widely between studies, with 41% to 81% of dogs dying as a result of AGASAC.600,601,605,606 The prognosis for dogs with AGASAC is dependent on a number of factors, especially clinical stage. In one study, dogs with no metastasis and primary tumor size less than 2.5 cm treated with surgery alone had overall favorable outcomes with the MST not reached and with only 9% of dogs experiencing tumor-related deaths.601 In other studies, dogs with LN metastasis treated surgically, with or without adjuvant chemotherapy, had significantly shorter OSTs compared with dogs without metastasis.605–607 OST was 293 to 448 days in dogs with LN metastasis and 529 to 925 days in dogs without metastasis.605–607 In a study of 28 dogs with advanced LN metastasis (larger than 4.5 cm), treatment with hypofractionated RT resulted in a better median PFI and MST (347 days and 447 days, respectively) than did surgery with extirpation of metastatic LNs (159 days and 182 days, respectively).611 Based on these collective findings, the role of a stage-dependent treatment algorithm is attractive and may become a future direction in the treatment of dogs with AGASAC. Poor prognostic factors reported in various studies include primary tumor size,600,601,607,617 presence of clinical signs,607 presence of LN metastasis,601,605–607 size of LN metastasis,601 presence of distant metastasis,600,601,624 nonpursuit of surgery,600,601 treatment with chemotherapy alone,600 lack of any therapy at all,601 histologic features of the primary tumor,607,608 E-cadherin immunoreactivity,624 and, in some studies, hypercalcemia.600,602,607 Tumor size is prognostic for survival in a number of studies, but the threshold varies.600,601,606,615,616 In one study of 113 dogs, dogs with tumors less than 10 cm2 had a better MST (584 days) than dogs with AGASAC greater than 10 cm2 (292 days).600 In another study, a maximal tumor dimension of 2.5 cm was found to be prognostic.601 In the retrospective arm of this study, the MSTs were 1205 and 722 days for dogs with nonmetastatic AGASAC less and greater than 2.5 cm, respectively.601 In a study of 77 dogs treated with palliative-intent hypofractionated RT, the only negative predictor for survival was tumor size greater than 2.5 cm.617 In another study, a tumor size of 2.5 cm was not predictive of survival in 39 dogs, but a 4-cm cutoff was prognostic.607 Dogs with AGASAC smaller than 4 cm had a longer PFI and MST (518 and 773 days, respectively) than dogs whose tumors were greater than 4 cm (251 and 433 days, respectively). These discrepancies in prognostic tumor size could reflect differences in how tumors are measured, the difficulty in using an absolute metric measurement across a wide range of dog sizes and body weights, and/or the inherent difficulty in identifying consistent prognostic factors using nonstandardized cohorts. Tumor size was associated with the presence of clinical signs in one study.607 Dogs with clinical signs were more likely to have local recurrence after surgery and shorter OSTs compared with dogs diagnosed incidentally.607 Compared with asymptomatic dogs or dogs with local signs, dogs with systemic clinical signs (e.g., anorexia, polyuria/polydipsia, abnormal stool shape, tenesmus, constipation, and/or lethargy) had significantly shorter PFIs and OSTs.607 Metastatic disease, both to the regional LNs and distant sites, is associated with a worse prognosis in dogs with AGASAC (Fig. 23.34).600,601,605–607,624 The reported MSTs for dogs with LN metastasis at diagnosis treated with various modalities

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•

Fig. 23.34 Estimated Kaplan–Meier survival curves for overall survival times in dogs with apocrine gland anal sac adenocarcinoma with (dashed) and without (solid) metastasis at the time of diagnosis. The median overall survival times for dogs with metastasis (448 days) was significantly shorter than for dogs without metastasis (761 days, p = 0.042). (Reprinted with permission from Wouda RM, Borrego J, Keuler NS, et  al. Evaluation of adjuvant carboplatin chemotherapy in the management of surgically excised anal sac apocrine gland adenocarcinoma in dogs. Vet Comp Oncol. 2016;14:67–80.)

range from 293 to 448 days and this is significantly worse than the MSTs of 529 to 1205 days for dogs without LN metastasis.601,605,606 Dogs with LN metastasis at the time of diagnosis have a 2.3-fold increased risk of tumor-related death.605 Although the prognosis is worse for dogs with LN metastasis,601 MSTs improve after excision of the metastatic LNs.601 The role of chemotherapy in dogs with LN metastasis disease remains undefined. The MST for dogs with distant metastasis ranges from 71 to 82 days in one study to 219 days in another study, and this is significantly worse than the MST in dogs without distant metastasis.600,601 Treatment also has an effect on STs in dogs with AGASAC. Overall, when considering all dogs with AGASAC, those treated with surgery have a significantly better outcome (MST 548 days) than those treated with either chemotherapy (MST 202 days) or those for which surgery was not part of the treatment protocol (MST 402 days).600 However, when dogs with advanced LN metastasis (>4.5 cm) were expressly evaluated, treatment with hypofractionated RT resulted in significantly better outcomes compared with surgical extirpation.611 AGASAC has been classified histologically according to its tumor cell arrangement, including solid, rosette, tubular, papillary, and mixed patterns.607,608 In one study of 39 dogs, dogs with a predominantly solid pattern had shorter PFIs and OSTs compared with dogs with other histologic patterns, corroborating a prior study that also associated tumor-related death with solid histologic pattern.607,608 Other histologic features of the primary tumor that have been associated with shorter PFIs and OSTs include increased peripheral infiltration into surrounding tissue, presence of necrosis, and lymphovascular invasion.607 In an IHC study, the expression of E-cadherin in greater than 75%

of AGASAC cells was associated with a longer MST (1168 days) than in dogs whose AGASAC expressed E-cadherin in fewer than 75% of cells (448 days).624 In a study of 113 dogs with AGASAC, MSTs for dogs with and without hypercalcemia were 256 days and 584 days, respectively.600 Although hypercalcemia is a poor prognostic factor in some studies,600,602,607 other studies have found no difference in survival between hypercalcemic and normocalcemic dogs.599,605,606,609 Dogs with hypercalcemia require complete or near-complete removal of the tumor burden, including metastatic disease, to resolve the hypercalcemia.603,613,637 Tumor responses to hypofractionated RT and toceranib have resulted in resolution of hypercalcemia in some dogs.611,617,640 Medical management with corticosteroids and/or bisphosphonates may be needed to improve control of hypercalcemia. Recurrence of hypercalcemia after tumor-ablating treatment is typically associated with recurrent or metastatic disease.600,603,614 In 11 dogs with anal sac melanoma treated with various combinations of surgery, RT, chemotherapy, immunotherapy, and supportive medical management, the median PFI and OST were only 3 months and 3.5 months, respectively.560 Ten of 11 dogs died due to local or distant tumor progression.560 One dog with a small, 1.5 cm primary tumor survived at least 58 months after surgery and adjuvant chemotherapy.560 Six of nine dogs with anal SCC survived 0 to 7 months after diagnosis.561–563 Two dogs were lost to follow-up 7 months after diagnosis and one dog was disease-free 1 year after treatment with hypofractionated RT and carboplatin for a recurrent SCC.561–563 Of five dogs that underwent surgical resection of the primary tumor, four dogs had recurrence within 1 to 5 months of surgery.561,563 The MST for 30 cats treated surgically, with or without adjunctive chemotherapy and/or RT, is 260 days.566 The 1-, 2-, and 3-year survival rates were 42%, 27%, and 18%, respectively, with a tumor-related mortality rate of 53%.566 Poor prognostic factors for survival in treated cats with AGASAC include local tumor recurrence and increased nuclear pleomorphic score. The risk of tumor-related death increased by 8 times for cats with local tumor recurrence and 10 times for cats with increased nuclear pleomorphic score.566 The MSTs for cats with a nuclear pleomorphic score of 2 and 3 were 909 days and 187 days, respectively, and this was significantly different.566 The role of chemotherapy and RT are unknown, but RT would theoretically be indicated because of the high rate of local tumor recurrence, especially after incomplete histologic excision. A short-lived partial response to carboplatin was reported in one cat with recurrent AGASAC.644 In another report, adjuvant curative-intent RT (48 Gy) and carboplatin resulted in local recurrence and/or metastasis within 6 months of treatment in two cats.567 In both cats, RT was well tolerated with minimal acute effects.567 

Comparative Aspects645–648 No similar hormonally dependent perianal disease state exists in humans. The most common cancer of the anal margin is squamous cell (epidermoid) carcinoma. These tumors arise from the junction of haired skin and mucous membrane of the anal canal. Risk of developing cancer in this location is positively correlated with sexual activity, and most tumors are associated with human papillomavirus infection. Precancerous changes (dysplasia) in the epithelium of the anal canal may precede tumor development. Regional LNs are the most common site of metastasis. Previously considered a surgical disease requiring a permanent

CHAPTER 23  Cancer of the Gastrointestinal Tract

colostomy, improved outcomes have been achieved with definitive chemoradiation. The standard approach to therapy is concomitant RT and chemotherapy using 5-FU and mitomycin C. Surgery is reserved for locally recurrent or persistent disease. The mean 5-year disease-free survival and overall survival rates are 60% and 75%, respectively. Size and degree of invasion of the primary tumor, regional LN involvement, and presence of distant metastases are important prognostic factors. Identification of biomarkers that may serve as predictors of outcome or targets for therapy is being explored.

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CHAPTER 23  Cancer of the Gastrointestinal Tract

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CHAPTER 23  Cancer of the Gastrointestinal Tract

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