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Neoplasms of the Anus
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ANORECTAL SURGERY
NEOPLASMS OF THE ANUS Gregory C. Oliver, MD, and Samuel B. Labow, MD
ANATOMY
The anal area is often misunderstood by clinicians because its boundaries and anatomic features are variously defined. Terms such as "surgical anal canal" and "anatomic anal canal" serve to confuse the issue. For the purposes of this discussion of anal cancers (Fig. I), we define the anal canal as extending from the anorectal ring at the floor of the pelvis proximally to the anal verge distally. The anal verge is the transition point at which, with the patient at rest, the skin of the anal margin meets and the anal canal cannot be visualized. The skin of the anal margin contains all elements of normal skin, that is, hair follicles and glandular structures, whereas the squamous lining of the distal anal canal is devoid of these appendages. 2 The anal canal is encircled along its length by a complex of muscular sphincters. Over the length of the anal canal, the inner circular smooth muscle layer of the gastrointestinal tract thickens to form the internal anal sphincter and provides resting, involuntary muscular continence. At the proximal extent of the canal, the puborectalis surrounds the canal posteriorly and laterally. Distal to the puborectalis and deep to the internal sphincter, the three-muscle complex that constitutes the external anal sphincter provides additional voluntary control over fecal continence. Another topographic landmark that assists the clinician in evaluatFrom the Division of Colon and Rectal Surgery, Department of Surgery, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School and the Muhlenberg Regional Medical Center, Plainfield, New Jersey (GCO); and the Department of Surgery, Cornell University College of Medicine, New York, New York (SBL), and the North Shore University Hospital, Great Neck, New York (SBL)
SURGICAL CLINICS OF NORTH AMERICA VOLUME 74 • NUMBER 6 • DECEMBER 1994
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puborectalis: anorectal ring
-&,?""-- internal hemorrhoids
anorectal transitional zone
column of
9-:-&~ morgagni
anal canal anal crypt external ----*7 sphincter
dentate line anal gland
internal sphincter
external hemorrhoids
anal margin
Figure 1. Anatomy of the anal canal.
ing patients with anal malignancies is the dentate line or the pectinate line. This is the site at which fusion of the endoderm and ectoderm occurs during embryologic development. 18 This landmark is important in regard to the lymphatic drainage in this area. Proximal to the dentate line, lymphatics drain into the pelvis along the middle rectal vessels to the pelvic side walls and internal iliac chains and superiorly via the superior rectal vessels and the periaortic nodes. Distal to the dentate line, lymphatics drain along cutaneous pathways to the inguinal and then femoral nodal chains. 43 Only when there is advanced lymphatic obstruction due either to prior lymphatic disease or lymphatic malignant spread does retrograde lymphatic drainage occur.
HISTOLOGY
Because the anal area is the junction of embryologic layers, it is rich in cellular diversity. The anal margin, that skin bearing normal appendages distal to the anal verge, consists of squamous epithelium and eccrine and apocrine glands. It is subject to all malignant conditions that may normally involve the skin and its structures. The skin here is keratinized. 37 More complex yet is the histologic variation present in the anal
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canal. Distally, the appendage-free epidermis becomes more cuboidal as it reaches the dentate line. It is generally devoid of keratin. Proximal to the dentate line and over a length of up to 20 mm, the cellular histology is in transition and so is known as the anal transition zone (ATZ). Therein elements of squamous mucosa intermix with transitional cellular elements and columnar rectal mucosa. Approximately 20 mm proximal to the dentate line, the rectal columnar epithelium predominates and accounts for the majority of cancers afflicting this area?3 The ATZ gives rise to multiple cell types, each of which is subject to potential malignant involvement and so must be considered here. The ATZ harbors transitional cells, squamous cells, columnar cells, endocrine cells, melanocytes, and anal glandular cellsY The latter arise at the base of the columns of Morgagni at the level of the dentate line. The secretory portions of these glands arise in the intersphincteric space and so are not visible within the anal canal.23 When malignancies of these cell lines occur, histologic and histochemical studies permit accurate diagnosis, which, in turn, suggests therapeutic options (Table 1).
Table 1. TREATMENT OPTIONS FOR ANAL CANCERS Malignancies involving the anal margin Squamous cell cancers
Basal cell cancer Bowen's disease Perianal Paget's disease Malignant melanoma Malignancies of the anal canal Epidermoid cancer
Adenocarcinoma Rectal type
Anal gland type Endocrine cancers Carcinoids Small cell carcinoma Melanoma
Wide local excision Radiation Combined modality' Wide local excision Wide local excision Wide local excision Wide local excision Combined modality (biopsy and chemoradiation) Wide local excisiont Radiation APR APR Wide local excision or electrocoagulation:j: Radiation APR Wide local excision APR (for advanced lesions) Combination chemotherapy Radiation/APR§ Wide local excisionll APR~
'Combination chemotherapy and radiation therapy. tWhen size is < 2 cm and no involvement with the dentate line. :j:For lesions confined to the bowel wall, < 4 cm and without identifiable adenopathy. §As local palliation of obstructive symptoms. IIlf confined to wall and < 2 mm in depth. llAs palliation for bleeding or obstruction.
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EPIDEMIOLOGIC FACTORS AND THE DEVELOPMENT OF ANAL CANCER
Epidermoid carcinomas of the anus account for I % to 2% of all large bowel malignancies. 9 These tumors are somewhat more common in women than men, with a ratio approaching 2:1. Ample evidence in the medical literature links various risk factors with an increased incidence of anal cancer. Briefly, we review these major factors as they relate to increased risk for the development of anal cancer. For years, clinicians have appreciated that chronic anal wounds or irritation predisposes to an increased risk of anal malignancy. 10, 29, 42 Human papilloma viruses (HPV) and herpes simplex virus type 2 have been linked to malignant development in the anogenital region. 14,78 Investigators have linked cigarette smoking and its amount to an increased incidence of anal cancer in men and women. 14, 30 The association of anal intercourse with the subsequent development of anal cancer has been studied with some interesting data derived. Engaging in anal intercourse appeared to pose a 12-fold increased risk for anal cancer in anally receptive males but not in females. 29 When the data were corrected for co-risk factors such as smoking, concomitant anogenital infections, and chronic benign anal condition, Holly et aP9 concluded that anal intercourse alone was not a risk factor for subsequent development of anal cancer. Chronic inflammatory diseases affecting the anal area have been found to be associated with an increased incidence of anal cancer. Such is the case with Crohn's disease, for which Slater et al69 reported a IO-fold increase in incidence. Lastly, immunosuppression may predispose to an increased incidence of anal cancer. Penn55 studied a group of renal transplant patients who were maintained on chronic immunosuppressive drug regimens. He noted a 200-fold greater incidence of anal cancer in this group. Whether the immunosuppression of the normal host immune system allowed normal cellular mutations to malignant cells to go unrecognized or immune suppression opens the door for oncogenic viral or chemical stimulants is not yet known. These two factors may work in synergy to increase the risk of developing anal cancer. Likewise, the stimulus of chronic anal wounds, radiation exposure, or infections may increase the likelihood of malignant cellular growth. This may be due to increased cellular growth rates, a reduction in local host immune defenses, or both. The exact mechanism is yet to be determined. For the present, it seems prudent to recommend that risk factors for anal cancer be recognized early. Attempts to remove or correct these factors ought to be made. Where these risk are ongoing, increased surveillance should be encouraged. NEOPLASMS OF THE ANAL MARGIN Squamous Cell Cancer
Squamous cell cancer of the anal margin is the most common malignancy found in this area. Lesions are found in association with
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chronic local irritation and poor hygiene. Fenger17 points out that a spectrum of precancerous to frankly malignant growth in this cell line is frequently associated with HPV DNA-condylomata acuminata, bowenoid papulosis, anal intraepithelial neoplasia (AIN), leukoplakia, and Bowen's disease. Clinically, these lesions may differ in appearance, but all may progress to invasive squamous cell carcinoma. The similarity of this spectrum of disease to that of the female genital tract is inescapable. 20 Because HPV may be readily demonstrated using current immunohistochemical and hybridization techniques, a great deal of new insight into this disease spectrum is developing. HPV 16 is frequently found in squamous anal cancers and HPV 18 in adenocarcinomas of the anus. 39. 66 Patients whose tumors carry the HPV DNA are on average 9 years younger than patients with squamous anal cancer and no HPV DNA.27 Malejczyk and co-workers40 have suggested that HPV-infected cells elaborate proteins that inhibit the host cells' natural immune surveillance system. Hiorns et aP8 theorized that carcinogens, such as cigarette smoke, then act to cause genetic abnormalities that the immune system does not recognize. Additional studies published by Ogunbiyi's groupSl demonstrate that expression of the c-myc oncogene is associated with the progression from benign to malignant squamous change. Developments in tumor molecular biology may one day permit us to stabilize the cellular environment to prevent or reverse malignant potential. Currently, our therapies are aimed at treatment of the malignant condition. Fortunately, most squamous cancers of the anal margin are well differentiated and have a biologic behavior like squamous cancers found elsewhere on the skin. Metastases are usually a late feature and have been related to size. 4s Pintor et al S6 reported that lesions of the anal margin less than 5 cm in size carried a better prognosis for cure and survival than larger lesions. It is rare today in our practice to find such an advanced lesion. In fact, treatment options depend upon the clinical staging of the lesion. Because metastases may be deep to involve the sphincter muscles or, more likely, the ipsilateral groin lymph nodes, the lesion should be assessed for either possibility. Smaller, mobile lesions without clinically apparent groin nodes can be treated by local excision with clear margins or by radiation therapy. Surgical series report 5-year survivals ranging from 100% in highly selected casesS to 68% in another group.2S QuanS8 points out that if synchronous groin nodes are present with an as yet untreated primary lesion, groin dissection may be contemplated but the prognosis is poor. In the Memorial Hospital experience, 5-year survivors are rare. When metachronous groin nodes are found, therapeutic groin dissection is carried out, resulting in an 83% 5-year survival. Prophylactic groin dissection is not recommended because only about 20% of patients with an anal margin squamous cancer go on to develop groin node metastases, and the morbidity of a prophylactic groin lymph node dissection is significant. Radiation has been administered via the Curie radium implant technique,S3 external beam radiation,B and as a combination of radiation with chemotherapy, adding conservative surgical excision of primary
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lesions for tumors judged by clinical staging to have a poor prognosis.H Using radon seed implantation, the 5-year survival rate was 68%. The more recent series from the Curie Institute employs a mixed bag of techniques including external beam cobalt-60 and/or electron beam via the linear accelerator. Just as the radiation delivery methods were mixed, so too were the tumors, which ranged from Tl to T4. Five-year survivors reached 52%. Cummingsll reserves combined chemoradiation with local surgery for patients demonstrating poorly differentiated tumor, tumor greater than 4 cm in diameter, and a high risk of groin node involvement. In a limited number of cases, he reports an 85% crude 5-year survival rate. In our practice and experience, the vast majority of patients presenting with squamous carcinoma of the anal margin have limited lesions that carry a good prognosis for cure by wide local excision. Without doubt, this is also more cost-effective than chemotherapy and radiation therapy. For large lesions, lesions that locally involve the anal sphincters, or lesions that demonstrate positive groin nodes by needle aspiration, combined chemoradiation with or without local surgical excision is our preference over abdominal perineal excision. Therapeutic groin lymph node dissection is of benefit if clinically detectable disease persists after the combined-modality approach. Basal Cell Cancer of the Anal Margin
Grossly similar to basal cell cancer found elsewhere on the skin, these lesions are rare in our practice. Nielson and Jensen48 reported on 34 cases and found this lesion to constitute 0.2% of all anorectal neoplasms. These tumors grow slowly and metastasize late. Wide local excision is most often curative. 57 Local recurrence may occur and should be treated by repeated adequate wide local excision. Bowen's Disease
Bowen's disease and bowenoid papulosis are examples of squamous cell carcinoma in situ (CIS)P Bowen's disease clinically appears as a plaquelike lesion, either scaly or crusted, usually erythematous but occasionally pigmented. Bowenoid papulosis, in contrast, appears as multiple small, domed lesions in the perianal area. These lesions may be differentiated by means of their histologic appearance. Some years ago, these lesions were believed to be important as markers for an increased incidence of internal malignancies. Graham and Helwig24 reported that 70% to 80% of patients with Bowen's disease would at some time manifest another visceral or cutaneous malignancy. More recent work by Arbesman and RansohofP has cast significant doubt on this association. This latter view is more in keeping with our limited personal experience. What must be kept in mind, however, are recent reports in
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which CIS of this type has progressed under observation to become frankly invasive squamous carcinoma. 34, 61 In one case, this occurred in an immunocompromised male homosexual with stage IV HIV infection. Another patient developed invasive squamous cancer in Bowen's disease subsequent to treatment for HPV 16-associated cervical cancer. Awareness of these risks should prompt increased surveillance. Beck and Fazio7 and others60 have reviewed their experience with this disorder and recommend wide local excision as adequate treatment. We agree with this. A note of caution should be observed. Although we agree that subsequent visceral cancers are less common than previously believed in this disorder, the association of Bowen's lesions with HPV infections in patients with both intact and compromised immune systems makes it prudent to closely follow both male and female patients for HPV-associated cancers of the anogenital areas.
Perianal Paget's Disease
Perianal Paget's disease may actually represent two different cancers that histologically appear as one. Grossly, these lesions appear as red, slightly raised, eczematous perianal patches that are generally quite pruritic. Most often the diagnosis is made after protracted attempts at medical therapy for pruritus ani have failed. 8 Histologically, Paget's cells appear as large hyperchromatic nuclei surrounded by a halo of clear, pale cytoplasm. Immunohistochemical evaluation suggests that there may be two distinct origins for these cells, each with a distinctly different prognosis. 4, 17, 32, 41,67,72 The classic description of this disorder relates the process to the development of carcinoma within the intraepithelial perianal skin. Immunohistochemical analysis demonstrates "gross cystic disease fluid glycoproteins," a marker for apocrtne cell origin. However, the alternative origin for the cancerous development is from invasion of the perianal skin by adenocarcinoma arising in the rectum or anus. This second mechanism is supported by histochemical studies demonstrating cytokeratins and carcinoembryonic antigens characteristic of bowel cancers without glycoproteins associated with apocrine cell origin.4, 32, 41, 72 Regardless of the cell of origin, clinicians should search carefully for an underlying large bowel malignancy, which occurs in 59%32 to 100%6 in reported series. When no bowel malignancy is found, treatment consists of adequate wide local excision with careful follow-up to detect early local recurrence or the more serious development of a large bowel malignancy?' 32 When a synchronous cancer of the large bowel is present, therapy should be selected to first deal with this more serious lesion and secondarily with the Paget's disease. The results of treatment of the underlying bowel malignancy depend upon locoregional and distant metastasis. On a practical note, when no associated large bowel tumor is present, we have found it very helpful to map the extent of Paget's disease in the perianal skin, which is difficult to detect grossly. The method we prefer was reported by Goldberg et aP1 and consists of
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perianal washing with 1% acetic acid followed by painting of the area with toluidine blue, a supravital dye that is picked up and retained within the nuclei of the Paget's cells. Rewashing the area with 1% acetic acid removes all toluidine blue not within the Paget's cells and so clearly demarcates the areas for wide excision. Malignant Melanoma
These lesions are characterized by their occult nature and early distant metastases. Morson and Volkstadf46 early on documented the dismal outlook for these lesions. More recently, Wanebo and co-workers 74 reported on the Memorial Hospital-Sloan-Kettering experience. The lesion may develop on the perianal skin, in the anorectal transition zone, or within the colonic mucosa. In fact, it may arise anywhere melanocytes are normally found. The lesions are usually pigmented but may be amelanotic. Lesions may be sessile or pedunculated, the latter being confused with hemorrhoidal enlargement. 58 Patients usually present because of symptoms of pressure, mass, or pain. By the time symptoms develop, metastases have invariably occurred. In Quan's experience,58 survival was 12% and correlated best with the depth of tumor penetration. Lesions deeper than 2 mm were uniformly fatal before 5 years. In the Memorial Hospital experience, the treatment selected did not correlate with survival. This is to say that local therapies, node dissections, cryotherapy, abdominal perineal resection, radiation therapy, and chemotherapy all had similar, dismal results. Until effective treatments for disseminated melanoma can be found, treatment should be aimed at adequate palliation of symptoms When suspicious, asymptomatic lesions are encountered during routine anorectal examination, wide local excision is likely to be therapeutic as well as diagnostic as long as metastases have not occurred. NEOPLASMS OF THE ANAL CANAL Epidermoid Cancers
Grouped herein are tumors that in the past were considered separate entities. These are squamous cell cancers, basaloid (cloacogenic or transitional) carcinomas, and mucoepidermoid carcinomas. Although these tumors generally share a favorable prognosis when appropriately treated,22 poor outcomes are common owing to the late patient presentation and/or delayed physician diagnosis. In the British study by Edwards and co-workers,16 76% of anal canal epidermoid carcinomas were initially diagnosed as benign conditions. Eighty-one percent had lesions over 2 em in size at diagnosis. Unfortunately, the tendency of patients to attribute rectal bleeding and mucous discharge to "hemorrhoids" often delays diagnosis and definitive treatment of epidermoid carcinoma.
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Although histologically different in appearance, these tumors all arise between the anal verge and the proximal ATZ. Presenting complaints are bleeding in 50% of patients,S anal pain, or anal swelling. Initial clinical assessment demonstrates an anal canal mass or an ulcerated, indurated lesion. Anoscopic visualization should be performed and directed biopsies obtained. As these tumors spread primarily to the inguinal lymph nodes, a careful assessment of these should be made. Suspicious lymph nodes should be aspirated with a fine needle for cytologic evaluation. As these tumors may arise in the ATZ proximal to the dentate line, lymphatic drainage may be lateral within the pelvis or superiorly toward the para-aortic nodal chain. Digital palpation should evaluate these areas as well within the limitation of finger length. When available, intra-anal and intrarectal ultrasonography assists in assessing depth of tumor penetration as well as perirectal lymph nodes suspicious for neoplastic spread. Wade and co-workers73 reported that 14% of the lymph nodes histologically shown to contain metastases were less than 5 mm in size. Palpation alone cannot be definitive in nodes of this size. Cummingsll points out that at initial presentation, 20% of patients have inguinal nodal spread and 30% have intrapelvic nodal involvement, depending upon their location in relation to the dentate line. Distant metastases are present on initial assessment in less than 10% of cases. Recent retrospective studies on archived specimens by Shepherd et al 64 demonstrated again that depth of tumor penetration and lymph node involvement were the most useful prognostic factors. DNA ploidy also stood out under statistical review in that diploid tumors had better 5-year survivals than did nondiploid (aneuploid) tumors. The treatment of epidermoid cancers of the anal canal has undergone a dramatic evolution over the last 20 years. Initially, the only option for treatment of anal canal lesions was surgical. Radiation as primary treatment came into vogue in the 1970s initially in Europe. Then, in the 1980s, treatment evolved to the combined-modality approach. As each regimen has its advocates, a brief review of each is presented. Local excision of anal canal lesions may be an acceptable option when prognostic factors are favorable, that is, a lesion less than 2 cm, distal to the dentate line, well differentiated, and not involving muscle?O According to Quan,S8 local excision employing these guidelines results in a 66% 5-year cure rate. For larger lesions, deeper lesions, and lesions proximal to the dentate line, abdominoperineal resection (APR) with or without pelvic lymphadenectomy and with therapeutic groin dissection when positive nodes are known to exist was the standard of treatment and still provides good control over locoregional disease. In experienced hands, operative mortality was 1.7% for patents under 70 and 8.5% for those over 70. Five-year surgical cure in the Memorial series58 was 58%. Interestingly, however, Welsh and Male6 reported that in 43 patients they operated on with APR for cure, 39% developed recurrence. Because of the significant mortality in the older age patient, the sexual dysfunction,
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the urinary continence problems, the need for a permanent colostomy, and the high rate of locoregional recurrence, combined modality therapy has its appeal. Radiation therapy was popularized by Papillon. Initially, small, favorable anal canal cancers were treated by radium implants and then external beam irradiation was added to treat potential metastatic spread to lymph node drainage areas. In fact, in well-selected patients, Papillon and Montbarbon54 were able to achieve a 65% 5-year cure rate, about the same as Quan58 achieved with local excision. However, for those patients presenting with more advanced lesions, radiation alone produced 5-year survivals of 73% when no nodes were detectable and 36% when nodes were involved. 63 Developments in chemotherapy set the stage for our current practice in treating anal canal cancer. In 1968, Moertel et al44 reported that mitomycin C produced a favorable response in gastrointestinal tumors. Li and Ross38 reported similar gastrointestinal tumor responses to 5fluorouracil (5-FU). Nigro and co-workersso published their results of preoperative radiation to the pelvis combined with chemotherapy consisting of mitomycin C and 5-FU. In this initial group, 24 patients had an APR performed following chemoradiotherapy. Of these, 22 had no residual tumor in the specimen. Five-year survival rates were 83%.49 From this initial success, many groups have joined the field and are experimenting with radiation dosage and fractions, as well as chemotherapeutic drugs, dosage, duration, and cycles. n . 15. 35. 52. 68. 71 The current regimen being employed by Nigro49 consists of external beam radiation, 3000 cGy to the tumor bed and pelvic and inguinal node beds on days 1 through 15. Mitomycin C is given as a bolus on day 1 at a dose of 15 mg/m2. 5-FU is begun at a dose of 1000 mg/m2 and administered as a continuous infusion on days 2 through 5 (4 days). The 5-FU dose is repeated on days 28 through 31 (4 days). We have modified Nigro's protocol only in that if gross tumor is still present on day 28, another 1000 to 1500 cGy is administered to the tumor bed at 200 cGy/day. To our knowledge, no other regimen has achieved a better 5-year cure rate than Nigro has reported. Severe toxicity in our experience is rare and, when present, is related to mitomycin C's suppressive effect on hematopoiesis. Abdominal perineal resection is used as a salvage procedure when persistent or recurrent disease proves amenable. As to treatment failure, Boman et al9 reported that after curative APR for epidermoid anal cancer, 37% experienced tumor recurrence. Of these, 73% were confined to the pelvis. In the Cummings et aP2 experience with recurrent disease after radiation therapy, 68% were confined to the pelvis. In the same report, inguinal recurrence fell to 2.6% in 38 patients in whom the groins were prophylactically irradiated. This compares with inguinal recurrence rates of 15% to 25% in nonirradiated inguinal nodes. 9. 54 Although prophylactic lymph node dissections do not appear warranted based upon their low tumor yield and substantial associated morbidity, prophylactic radiation treatment to the groin areas does appear efficacious and indicated in this group of patients.
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ADENOCARCINOMA Colorectal Type
According to Fenger,!7 this is the most common carcinoma involving the anal canal. Whether the origin of this lesion is rectal or anal is a moot point because histologically and immunohistochemically these tumors are identicaU8 In a recent report by Koulos and co-workers,36 HPV 18 DNA was found in two of six archived surgical specimens of anal adenocarcinoma. No HPV-associated DNA was found with adenocarcinomas of the rectum or colon, a finding in agreement with previous studies. The relationship of HPV 18 to the development of anal adenocarcinoma has yet to be delineated but again raises the possibility, as with HPV 16 and epidermoid anal cancer, that the viral genome predisposes to subsequent malignant transformation. Treatment for this condition is selected on the basis of careful clinical staging of the tumor. For tumors that are well to moderately well differentiated, confined to the wall of the anus, free of encroachment on the dentate line, less than 4 em in size, and free of regional adenopathy, we consider the patient for electrocoagulation according to the technique of Salvati et al 62 or for local excision. Unfortunately, invasion of the sphincters is frequently present, making APR the more commonly performed procedure. Ramming and co-workers59 reported on eight patients with distal anorectal adenocarcinoma who were treated by wide local excision with subsequent external beam radiotherapy. Via anterior and posterior ports, 4500 cGy were administered. In a limited follow-up of 24 months, no recurrences were noted. Increasingly, surgeons are using transanal ultrasonography to more accurately stage these distal lesions in order to select the more favorable cancers for local treatment and adjuvant radiation and possibly chemotherapy. At present, clinical trials are in progress to compare sphincter-saving local surgical procedures combined with chemoradiotherapy, either preoperatively or postoperatively, with traditional APR. Conclusive data are not available at this time but give promise for the future.
Anal Gland Type
To date, only about 100 cases of this entity have been reported in the literature. The origin of these cancers is still debatableY Some authors believe that this tumor arises as a primary carcinoma of the anal gland. 26 Others suggest that these tumors arise in anorectal duplications and, as such, are mucinous. 33 Jensen et aPl reported 21 cases, 9 of which supported the former hypothesis and 5 the latter. Seven cases were so advanced as to make their origin impossible to determine. In fact, both scenarios may develop and present as an extramucosal mass in the anal canal or in the ischiorectal, extra sphincteric fossa. Our personal experience is limited to three cases. In the first, a I-em ischiorectal
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adenocarcinoma was discovered during wide local excision of perianal Paget's disease. Subsequent APR demonstrated lateral pelvic node involvement. This patient died 18 months later with disseminated cutaneous and visceral metastases. In the second case, the patient was found to have a new primary mucinous adenocarcinoma at the dentate line while being followed up 1 year after an anterior resection for rectal cancer at 10 cm. After APR, the pathologist demonstrated the tumor origin in what was thought to be a small anorectal duplication. The third patient was seen for complaints of anal swelling and pain of 1 month's duration. A submucosal mass at the level of the dentate line was palpated. Through the anoscope, deep biopsies using a rigid proctoscopic biopsy forceps demonstrated mucinous adenocarcinoma. An APR was performed after 45 cGy to the anorectum, bilateral groins, and pelvic nodal drainage and demonstrated the cancer involving the internal and external sphincters but without evidence of metastatic spread. Because these tumors tend to spread aggressively to the groin and pelvic nodes, we believe that preoperative radiation therapy to the primary tumor and to the nodal drainage areas is indicated. APR is still the only viable solution to tumor removals because these cancers invariably involve the sphincter mechanism. Clinical staging is irrelevant because the cancer arises extramucosally. ENDOCRINE CANCERS Carcinoid Type
The ATZ contains cells of neuroectodermal origin that may give rise to carcinoids. Immunohistochemical analysisl demonstrates that these tumors may contain active peptides and neurotransmitters. Generally, these tumors are nonfunctional. As elsewhere in the gastrointestinal tract, cancers over 2 cm in size behave more aggressively and should be considered for APR if wide local excision is not possible. 47 Small Cell Carcinoma Type
Boman et al9 reported on 13 small cell cancers of the anus, only one of which survived 5 years. More recently, other small series have confirmed this finding. 6s,77 In most, they have been hormonally inactive but have shown aggressive local growth patterns. Most cancers have been unresectable at the time of diagnosis. Because their histochemistry is similar to that of oat cell lesions of the lung, similar regimens of chemotherapy have been recommended. Unfortunately, our recent experience with one such case demonstrated a failure in response to chemotherapy and radiation treatment to the pelvis. Because of tumor growth within the pelvis, outlet obstruction necessitated laparotomy and APR. The tumor was resectable. Fortunately, these cancers are rare. Chemotherapy
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is thought to be the first choice in treatment, with surgery and radiation reserved as palliative measures?5
SUMMARY
Anal cancers can be grouped into three major categories. First, anal margin lesions are usually well-differentiated, keratinized squamous cell carcinomas that are amenable to local treatment measures. Second, anal canal cancers distal to the dentate line are mostly epidermoid, nonkeratinizing, moderately differentiated tumors. They are usually best treated with a multimodality approach using chemoradiotherapy and reserving surgery for clinical failures. Third, cancers arising in the ATZ are usually adenocarcinomas, and their treatment depends upon local factors. APR is in order for locally aggressive lesions, but newer protocols are studying multimodality therapy for this entity as well. Other, less common cancers of this region should be evaluated based upon their biologic potential and local involvement, with treatments selected accordingly.
References 1. Alumets J, AIm P, Falkner S, et al: Immunohistochemical evidence of peptide hormones in endocrine tumor of the rectum Cancer 48:2409, 1981 2. American Joint Committee on Cancer: Manual for Staging of Cancer, ed 3. Philadelphia, JB Lippincott, 1988 3. Arbesman H, Ransohoff DF: Is Bowen's disease a predictor for the development of internal malignancy? A methodological critique of the literature. JAMA 257:516, 1987 4. Armitage NC, Jass JR, Richman PI, et al: Paget's disease of the anus: A clinicopathological study. Br J Surg 76:60, 1989 5. Beahrs OH, Wilson SM: Carcinoma of the anus. Ann Surg 184:422, 1976 6. Beck DE, Fazio VW: Perianal Paget's disease. Dis Colon Rectum 30:263, 1987 7. Beck DE, Fazio VW: Premalignant lesions of the anal margin. South Med J 82:470,1989 8. Berardi RS, Lee S, Chen HP: Perianal extramammary Paget's disease. Surg Gynecol Obstet 167:359, 1988 9. Boman BM, Moertel CG, O'Connell MJ, et al: Carcinoma of the anal canal. Cancer 54:114,1984 10. Buchwalter JA, Jurayj MN: Relationship of chronic anorectal disease to carcinoma. Arch Surg 75:352, 1957 11. Cummings BJ: Anal cancer. Int J Radiat Oncol BioI Phys 19:1309, 1990 12. Cummings BJ, Thomas GM, Keane TJ: Primary radiation therapy in the treatment of anal canal carcinoma. Dis Colon Rectum 25:778, 1982 13. Cutuli B, Fenton J, Labib A, et al: Anal margin carcinoma: 21 cases treated at the Institute Curie by exclusive conservative radiotherapy. Radiother Oncol 11:1, 1988 14. Daling JR, Weiss NS, Hislop TG, et al: Sexual practices, sexually transmitted disease and the incidence of anal cancer. N Engl J Med 317:973, 1987 15. Doci R, Zucali R, Bombelli L, et al: Combined chemoradiation therapy for anal cancer: A report of 56 cases. Ann Surg 215:150, 1992 16. Edwards AT, Moues LC, Foster ME, et al: Anal cancer: The case for earlier diagnosis. J Soc Med 84:395, 1991 17. Fenger C: Anal neoplaSia and its precursors: Facts and controversies. Semin Diagn Pathol 8:190, 1991 18. Fenger C: Histology of the anal canal. Am J Surg Pathol 12:41, 1988
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19. Fenger C, Filipe MI: Pathology of the anal glands with special reference to their mucin histochemistry. Acta Pathol Microbiol Scand 85:273, 1977 20. Fenger C, Neilsen VT: Intraepithelial neoplasia in the anal canal: The appearance and relation to genital neoplasia. Acta Pathol Microbiol Immunol Scand 94:343, 1986 21. Goldberg SM, Gordon PH, Nivatvongs S: Neoplasms of the anal canal. In Essentials of Anorectal Surgery. Philadelphia, JB Lippincott, 1980, p 164 22. Goldman S, Glimelius B, Pahlman L, et al: Anal epidermoid carcinoma: A population based clinico-pathological study of 164 patients. Int J Colorectal Dis 3:109, 1988 23. Gordon PH, Nivatvongs S: Surgical anatomy. In Principles and Practice of Surgery for the Colon, Rectum, and Anus. St. Louis, Quality Medical Publishers, 1992, p 11 24. Graham JH, Helwig EG: Bowen's disease and its relationship to systemic cancer. Arch Dermatol 83:738, 1961 25. Greenall MJ, Quan SHQ, Stearns MW, et al: Epidermoid cancer of the anal margin: Pathologic features, treatment and clinical results. Am J Surg 149:95, 1985 26. Hagihara P, Vazquez MD, Parker JC, et al: Carcinoma of anal-duct origin: Report of a case. Dis Colon Rectum 19:694, 1976 27. Higgins GD, Uzelin DM, Phillips GE, et al: Differing characteristics of human papillomavirus RNA-positive and RNA-negative anal carcinomas. Cancer 68:561, 1991 28. Hiorns LR, Scholefield JH, Palmer JG, et al: Ki-ras oncogene mutations in non-HPVassociated anal carcinoma. J Pathol 161:99, 1990 29. Holly EA, Whittemore AS, Ashton DA, et al: Anal cancer incidence: Genital warts, anal fissure or fistula, hemorrhoids and smoking. J Natl Cancer Inst 81:1726, 1989 30. Holmes F, Borek D, Owen-Kummer M, et al: Anal cancer in women. Gastroenterology 95:107, 1988 31. Jensen SL, Shikouh-Amiri MH, Hagen K, et al: Adenocarcinoma of the anal ducts: A series of 21 cases. Dis Colon Rectum 31:268, 1988 32. Jensen SL, Sjolin KE, Shokouh-Amiri MH, et al: Paget's disease of the anal margin. Br J Surg 75:1089, 1988 33. Jones EA, Morson BC: Mucinous adenocarcinoma in an anorectal fistulae. Histopathology 8:279, 1984 34. Kato T, Kawashima M: Detection of human papillomavirus type 16 in bowenoid papulosis and invasive carcinoma occurring in the same patient with a history of cervical carcinoma. Arch DermatoI124:851, 1988 35. Knecht BH: Combined chemotherapy and radiotherapy for carcinomas of the anus. Am J Surg 159:518, 1990 36. Koulous J, Fraser S, Chumas J, et al: Human papillomavirus detection in adenocarcinoma of the anus. Mod PathoI4:58, 1991 37. Leichman LP, Cummings BJ: Anal carcinoma. Curr Probl Cancer 14:122, 1990 38. Li MC, Ross ST: Chemoprophylaxis for patients with colorectal cancer: Prospective study with five year follow-up. JAMA 235:2825, 1976 39. Loning T, Riviere A, Henke R, et aI: Penile/anal condylomas and squamous cancer: An HPV-DNA hybridization study. Virchows Arch [A] 412:491, 1988 40. Malejczyk J, Majewski S, Jablonska S, et al: Abrogated NK-celllysis of human papillomavirus (HPV)-16-bearing keratinocytes in patients with pre-cancerous HPV-induced anogenitallesions. Int J Cancer 43:209, 1989 41. Miller LR, McCunniff AJ, Randall ME: An immunohistochemical study of perianal Paget's disease. Cancer 69:2166, 1992 42. Milliken JC: Squamous carcinoma arising in anal fistula. Br J Surg 89:224, 1960 43. Miscusi G, Masoni L, Dell'Anna A, et al: Normal lymphatic drainage of the rectum and the anal canal revealed by lymphoscintigraphy. Coloproctology 9:171, 1987 44. Moertel CG, Reitemier RJ, Hahn RG: Mitomycin C therapy in advanced gastrointestinal cancer. JAMA 204:1045, 1968 45. Morson BC: The pathology and results of treatment of squamous cell carcinoma of the anal canal and anal margin. Proc R Soc Med 53:416, 1960 46. Morson BC, Volkstadt H: Malignant melanoma of the anus and rectum. Am J Surg 103:191, 1962 47. Naunheim KS, Zeitels J, Kaplan EL, et al: Rectal carcinoid tumors-Treatment and prognosis. Surgery 94:670, 1983
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48. Nielsen OV, Jensen SL: Basal cell carcinoma of the anus-A clinical study of 34 cases. Br J Surg 68:856, 1981 49. Nigro NO: An evaluation of combined therapy for squamous cell cancer of the anal canal. Dis Colon Rectum 27:763, 1984 50. Nigro NO, Vaitkevicuis VK, Considine B: Combined therapy for cancer of the anal canal: A preliminary report. Dis Colon Rectum 17:354, 1974 51. Ogunbiyi OA, Scholefield JH, Rogers K, et al: C-myc oncogene expression in anal squamous neoplasia. J Clin Pathol 46:23, 1993 52. Papillon J: Effectiveness of combined radio-chemotherapy in the management of epidermoid carcinoma of the anal canal. J Radiat Oncol Bioi Phys 19:1217, 1990 53. Papillon J: Radiation therapy in the management of epidermoid carcinoma of the anal region. Dis Colon Rectum 17:181, 1974 54. Papillon I, Montbarbon JF: Epidermoid carcinoma of the anal canal: A series of 276 cases. Dis Colon Rectum 30:324, 1987 55. Penn I: Cancers of the anogenital region in renal transplant patients: Analysis of 65 cases. Cancer 58:611, 1986 56. Pintor MP, Northover JMA, Nicholls RJ: Squamous cell carcinoma of the anus at one hospital from 1948 to 1984. Br J Surg 76:806, 1989 57. Quan SHQ: Anal and para-anal tumors. Surg Clin North Am 58:591, 1978 58. Quan SHQ: Cancer of the anus. In Beahrs OH, Higgins GA, Weinstein JJ (eds): Colorectal Tumors. Philadelphia, JB Lippincott, 1986, p 217 59. Ramming KP, Juillard G, Parker R, et al: Management of carcinoma of the rectum and anus without abdominoperineal resection. Am J Surg 152:16, 1986 60. Rassmussen 00, Christiansen J: Conservative management of Bowen's disease of the anus. Int J Colorectal Dis 4:164, 1989 61. Rudlinger R, Buchmann P: HPV16-positive bowenoid papulosis and squamous-cell carcinoma of the anus in an HIV-positive man. Dis Colon Rectum 32:1042, 1989 62. Salvati EP, Rubin RI, Eisenstat TE, et al: Electrocoagulation of selected carcinoma of the rectum. Surg Gynecol Obstet 166:393, 1988 63. Schlienger M, Krzisch C, Pene F, et al: Epidermoid carcinoma of the anal canal: Treatment results and prognostic variables in a series of 242 cases. Int J Radiat Oncol Bioi Phys 17:1141, 1989 64. Shepherd NA, Scholefield JH, Love SB, et al: Prognostic factors in anal squamous carcinoma: A multivariate analysis of clinical, pathological and flow cytometric parameters in 235 cases. Histopathology 16:545, 1990 65. Shirouzu K, Morodomi T, Isomoto H, et al: Small-cell carcinoma of the rectum. Dis Colon Rectum 28:434, 1985 66. Shrager KR, Kim JG, Manos MM, et al: Papillomavirus found in anorectal squamous carcinoma, not in colon adenocarcinoma. Arch Surg 127:741, 1992 67. Shutze WP, Gleysteen JJ: Perianal Paget's disease: Classification and review of management: Report of two cases. Dis Colon Rectum 33:502, 1990 68. Sischy B, Doggett RLS, Krall JM, et al: Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: Interim report on radiation therapy oncology group study No. 8314. J Nat! Cancer Inst 81:850, 1989 69. Slater G, Greenstein A, Aufses A: Anal carcinoma in patients with Crohn's disease. Ann Surg 199:348, 1984 70. Stearns MW, Quan SHQ: Epidermoid carcinoma of the anorectum. Surg Gynecol Obstet 131:953, 1970 71. Tanum G: Diagnosis and treatment of anal carcinoma. Acta Oncol 32:513, 1992 72. Tjandra J: Perianal Paget's disease: Report of three cases. Dis Colon Rectum 32:462, 1988 73. Wade OS, Herrera L, Castillo NB, et al: Metastases to the lymph nodes in epidermoid carcinoma of the anal canal studied by a clearing technique. Surg Gynecol Obstet 169:238, 1989 74. Wanebo HI, Woodruff JM, FaIT GH, et al: Melanoma. Cancer 47:1891,1981 75. Waugh DE: Anal and perianal malignancies. Surg Clin North Am 66:841, 1986 76. Welsh JP, Malt RA: Appraisal of the treatment of carcinoma of the anus and anal canal. Surg Gynecol Obstet 145:837, 1977
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77. Wick MR, Weatherby RP, Weiland LH: Small cell neuroendocrine carcinoma of the colon and rectum. Hum PathoI18:9, 1987 78. zur Hausen H: Human genital cancer: Synergism between two virus infections or synergism between a virus infection and initiating events. Lancet 2:1370, 1982
Address reprint requests to Gregory C. Oliver, MD Associated Colon and Rectal Surgeons 1010 Park Avenue Plainfield, NJ 07060
ANORECTAL SURGERY
NEOPLASMS OF THE ANUS Gregory C. Oliver, MD, and Samuel B. Labow, MD
ANATOMY
The anal area is often misunderstood by clinicians because its boundaries and anatomic features are variously defined. Terms such as "surgical anal canal" and "anatomic anal canal" serve to confuse the issue. For the purposes of this discussion of anal cancers (Fig. I), we define the anal canal as extending from the anorectal ring at the floor of the pelvis proximally to the anal verge distally. The anal verge is the transition point at which, with the patient at rest, the skin of the anal margin meets and the anal canal cannot be visualized. The skin of the anal margin contains all elements of normal skin, that is, hair follicles and glandular structures, whereas the squamous lining of the distal anal canal is devoid of these appendages. 2 The anal canal is encircled along its length by a complex of muscular sphincters. Over the length of the anal canal, the inner circular smooth muscle layer of the gastrointestinal tract thickens to form the internal anal sphincter and provides resting, involuntary muscular continence. At the proximal extent of the canal, the puborectalis surrounds the canal posteriorly and laterally. Distal to the puborectalis and deep to the internal sphincter, the three-muscle complex that constitutes the external anal sphincter provides additional voluntary control over fecal continence. Another topographic landmark that assists the clinician in evaluatFrom the Division of Colon and Rectal Surgery, Department of Surgery, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School and the Muhlenberg Regional Medical Center, Plainfield, New Jersey (GCO); and the Department of Surgery, Cornell University College of Medicine, New York, New York (SBL), and the North Shore University Hospital, Great Neck, New York (SBL)
SURGICAL CLINICS OF NORTH AMERICA VOLUME 74 • NUMBER 6 • DECEMBER 1994
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puborectalis: anorectal ring
-&,?""-- internal hemorrhoids
anorectal transitional zone
column of
9-:-&~ morgagni
anal canal anal crypt external ----*7 sphincter
dentate line anal gland
internal sphincter
external hemorrhoids
anal margin
Figure 1. Anatomy of the anal canal.
ing patients with anal malignancies is the dentate line or the pectinate line. This is the site at which fusion of the endoderm and ectoderm occurs during embryologic development. 18 This landmark is important in regard to the lymphatic drainage in this area. Proximal to the dentate line, lymphatics drain into the pelvis along the middle rectal vessels to the pelvic side walls and internal iliac chains and superiorly via the superior rectal vessels and the periaortic nodes. Distal to the dentate line, lymphatics drain along cutaneous pathways to the inguinal and then femoral nodal chains. 43 Only when there is advanced lymphatic obstruction due either to prior lymphatic disease or lymphatic malignant spread does retrograde lymphatic drainage occur.
HISTOLOGY
Because the anal area is the junction of embryologic layers, it is rich in cellular diversity. The anal margin, that skin bearing normal appendages distal to the anal verge, consists of squamous epithelium and eccrine and apocrine glands. It is subject to all malignant conditions that may normally involve the skin and its structures. The skin here is keratinized. 37 More complex yet is the histologic variation present in the anal
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canal. Distally, the appendage-free epidermis becomes more cuboidal as it reaches the dentate line. It is generally devoid of keratin. Proximal to the dentate line and over a length of up to 20 mm, the cellular histology is in transition and so is known as the anal transition zone (ATZ). Therein elements of squamous mucosa intermix with transitional cellular elements and columnar rectal mucosa. Approximately 20 mm proximal to the dentate line, the rectal columnar epithelium predominates and accounts for the majority of cancers afflicting this area?3 The ATZ gives rise to multiple cell types, each of which is subject to potential malignant involvement and so must be considered here. The ATZ harbors transitional cells, squamous cells, columnar cells, endocrine cells, melanocytes, and anal glandular cellsY The latter arise at the base of the columns of Morgagni at the level of the dentate line. The secretory portions of these glands arise in the intersphincteric space and so are not visible within the anal canal.23 When malignancies of these cell lines occur, histologic and histochemical studies permit accurate diagnosis, which, in turn, suggests therapeutic options (Table 1).
Table 1. TREATMENT OPTIONS FOR ANAL CANCERS Malignancies involving the anal margin Squamous cell cancers
Basal cell cancer Bowen's disease Perianal Paget's disease Malignant melanoma Malignancies of the anal canal Epidermoid cancer
Adenocarcinoma Rectal type
Anal gland type Endocrine cancers Carcinoids Small cell carcinoma Melanoma
Wide local excision Radiation Combined modality' Wide local excision Wide local excision Wide local excision Wide local excision Combined modality (biopsy and chemoradiation) Wide local excisiont Radiation APR APR Wide local excision or electrocoagulation:j: Radiation APR Wide local excision APR (for advanced lesions) Combination chemotherapy Radiation/APR§ Wide local excisionll APR~
'Combination chemotherapy and radiation therapy. tWhen size is < 2 cm and no involvement with the dentate line. :j:For lesions confined to the bowel wall, < 4 cm and without identifiable adenopathy. §As local palliation of obstructive symptoms. IIlf confined to wall and < 2 mm in depth. llAs palliation for bleeding or obstruction.
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EPIDEMIOLOGIC FACTORS AND THE DEVELOPMENT OF ANAL CANCER
Epidermoid carcinomas of the anus account for I % to 2% of all large bowel malignancies. 9 These tumors are somewhat more common in women than men, with a ratio approaching 2:1. Ample evidence in the medical literature links various risk factors with an increased incidence of anal cancer. Briefly, we review these major factors as they relate to increased risk for the development of anal cancer. For years, clinicians have appreciated that chronic anal wounds or irritation predisposes to an increased risk of anal malignancy. 10, 29, 42 Human papilloma viruses (HPV) and herpes simplex virus type 2 have been linked to malignant development in the anogenital region. 14,78 Investigators have linked cigarette smoking and its amount to an increased incidence of anal cancer in men and women. 14, 30 The association of anal intercourse with the subsequent development of anal cancer has been studied with some interesting data derived. Engaging in anal intercourse appeared to pose a 12-fold increased risk for anal cancer in anally receptive males but not in females. 29 When the data were corrected for co-risk factors such as smoking, concomitant anogenital infections, and chronic benign anal condition, Holly et aP9 concluded that anal intercourse alone was not a risk factor for subsequent development of anal cancer. Chronic inflammatory diseases affecting the anal area have been found to be associated with an increased incidence of anal cancer. Such is the case with Crohn's disease, for which Slater et al69 reported a IO-fold increase in incidence. Lastly, immunosuppression may predispose to an increased incidence of anal cancer. Penn55 studied a group of renal transplant patients who were maintained on chronic immunosuppressive drug regimens. He noted a 200-fold greater incidence of anal cancer in this group. Whether the immunosuppression of the normal host immune system allowed normal cellular mutations to malignant cells to go unrecognized or immune suppression opens the door for oncogenic viral or chemical stimulants is not yet known. These two factors may work in synergy to increase the risk of developing anal cancer. Likewise, the stimulus of chronic anal wounds, radiation exposure, or infections may increase the likelihood of malignant cellular growth. This may be due to increased cellular growth rates, a reduction in local host immune defenses, or both. The exact mechanism is yet to be determined. For the present, it seems prudent to recommend that risk factors for anal cancer be recognized early. Attempts to remove or correct these factors ought to be made. Where these risk are ongoing, increased surveillance should be encouraged. NEOPLASMS OF THE ANAL MARGIN Squamous Cell Cancer
Squamous cell cancer of the anal margin is the most common malignancy found in this area. Lesions are found in association with
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chronic local irritation and poor hygiene. Fenger17 points out that a spectrum of precancerous to frankly malignant growth in this cell line is frequently associated with HPV DNA-condylomata acuminata, bowenoid papulosis, anal intraepithelial neoplasia (AIN), leukoplakia, and Bowen's disease. Clinically, these lesions may differ in appearance, but all may progress to invasive squamous cell carcinoma. The similarity of this spectrum of disease to that of the female genital tract is inescapable. 20 Because HPV may be readily demonstrated using current immunohistochemical and hybridization techniques, a great deal of new insight into this disease spectrum is developing. HPV 16 is frequently found in squamous anal cancers and HPV 18 in adenocarcinomas of the anus. 39. 66 Patients whose tumors carry the HPV DNA are on average 9 years younger than patients with squamous anal cancer and no HPV DNA.27 Malejczyk and co-workers40 have suggested that HPV-infected cells elaborate proteins that inhibit the host cells' natural immune surveillance system. Hiorns et aP8 theorized that carcinogens, such as cigarette smoke, then act to cause genetic abnormalities that the immune system does not recognize. Additional studies published by Ogunbiyi's groupSl demonstrate that expression of the c-myc oncogene is associated with the progression from benign to malignant squamous change. Developments in tumor molecular biology may one day permit us to stabilize the cellular environment to prevent or reverse malignant potential. Currently, our therapies are aimed at treatment of the malignant condition. Fortunately, most squamous cancers of the anal margin are well differentiated and have a biologic behavior like squamous cancers found elsewhere on the skin. Metastases are usually a late feature and have been related to size. 4s Pintor et al S6 reported that lesions of the anal margin less than 5 cm in size carried a better prognosis for cure and survival than larger lesions. It is rare today in our practice to find such an advanced lesion. In fact, treatment options depend upon the clinical staging of the lesion. Because metastases may be deep to involve the sphincter muscles or, more likely, the ipsilateral groin lymph nodes, the lesion should be assessed for either possibility. Smaller, mobile lesions without clinically apparent groin nodes can be treated by local excision with clear margins or by radiation therapy. Surgical series report 5-year survivals ranging from 100% in highly selected casesS to 68% in another group.2S QuanS8 points out that if synchronous groin nodes are present with an as yet untreated primary lesion, groin dissection may be contemplated but the prognosis is poor. In the Memorial Hospital experience, 5-year survivors are rare. When metachronous groin nodes are found, therapeutic groin dissection is carried out, resulting in an 83% 5-year survival. Prophylactic groin dissection is not recommended because only about 20% of patients with an anal margin squamous cancer go on to develop groin node metastases, and the morbidity of a prophylactic groin lymph node dissection is significant. Radiation has been administered via the Curie radium implant technique,S3 external beam radiation,B and as a combination of radiation with chemotherapy, adding conservative surgical excision of primary
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lesions for tumors judged by clinical staging to have a poor prognosis.H Using radon seed implantation, the 5-year survival rate was 68%. The more recent series from the Curie Institute employs a mixed bag of techniques including external beam cobalt-60 and/or electron beam via the linear accelerator. Just as the radiation delivery methods were mixed, so too were the tumors, which ranged from Tl to T4. Five-year survivors reached 52%. Cummingsll reserves combined chemoradiation with local surgery for patients demonstrating poorly differentiated tumor, tumor greater than 4 cm in diameter, and a high risk of groin node involvement. In a limited number of cases, he reports an 85% crude 5-year survival rate. In our practice and experience, the vast majority of patients presenting with squamous carcinoma of the anal margin have limited lesions that carry a good prognosis for cure by wide local excision. Without doubt, this is also more cost-effective than chemotherapy and radiation therapy. For large lesions, lesions that locally involve the anal sphincters, or lesions that demonstrate positive groin nodes by needle aspiration, combined chemoradiation with or without local surgical excision is our preference over abdominal perineal excision. Therapeutic groin lymph node dissection is of benefit if clinically detectable disease persists after the combined-modality approach. Basal Cell Cancer of the Anal Margin
Grossly similar to basal cell cancer found elsewhere on the skin, these lesions are rare in our practice. Nielson and Jensen48 reported on 34 cases and found this lesion to constitute 0.2% of all anorectal neoplasms. These tumors grow slowly and metastasize late. Wide local excision is most often curative. 57 Local recurrence may occur and should be treated by repeated adequate wide local excision. Bowen's Disease
Bowen's disease and bowenoid papulosis are examples of squamous cell carcinoma in situ (CIS)P Bowen's disease clinically appears as a plaquelike lesion, either scaly or crusted, usually erythematous but occasionally pigmented. Bowenoid papulosis, in contrast, appears as multiple small, domed lesions in the perianal area. These lesions may be differentiated by means of their histologic appearance. Some years ago, these lesions were believed to be important as markers for an increased incidence of internal malignancies. Graham and Helwig24 reported that 70% to 80% of patients with Bowen's disease would at some time manifest another visceral or cutaneous malignancy. More recent work by Arbesman and RansohofP has cast significant doubt on this association. This latter view is more in keeping with our limited personal experience. What must be kept in mind, however, are recent reports in
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which CIS of this type has progressed under observation to become frankly invasive squamous carcinoma. 34, 61 In one case, this occurred in an immunocompromised male homosexual with stage IV HIV infection. Another patient developed invasive squamous cancer in Bowen's disease subsequent to treatment for HPV 16-associated cervical cancer. Awareness of these risks should prompt increased surveillance. Beck and Fazio7 and others60 have reviewed their experience with this disorder and recommend wide local excision as adequate treatment. We agree with this. A note of caution should be observed. Although we agree that subsequent visceral cancers are less common than previously believed in this disorder, the association of Bowen's lesions with HPV infections in patients with both intact and compromised immune systems makes it prudent to closely follow both male and female patients for HPV-associated cancers of the anogenital areas.
Perianal Paget's Disease
Perianal Paget's disease may actually represent two different cancers that histologically appear as one. Grossly, these lesions appear as red, slightly raised, eczematous perianal patches that are generally quite pruritic. Most often the diagnosis is made after protracted attempts at medical therapy for pruritus ani have failed. 8 Histologically, Paget's cells appear as large hyperchromatic nuclei surrounded by a halo of clear, pale cytoplasm. Immunohistochemical evaluation suggests that there may be two distinct origins for these cells, each with a distinctly different prognosis. 4, 17, 32, 41,67,72 The classic description of this disorder relates the process to the development of carcinoma within the intraepithelial perianal skin. Immunohistochemical analysis demonstrates "gross cystic disease fluid glycoproteins," a marker for apocrtne cell origin. However, the alternative origin for the cancerous development is from invasion of the perianal skin by adenocarcinoma arising in the rectum or anus. This second mechanism is supported by histochemical studies demonstrating cytokeratins and carcinoembryonic antigens characteristic of bowel cancers without glycoproteins associated with apocrine cell origin.4, 32, 41, 72 Regardless of the cell of origin, clinicians should search carefully for an underlying large bowel malignancy, which occurs in 59%32 to 100%6 in reported series. When no bowel malignancy is found, treatment consists of adequate wide local excision with careful follow-up to detect early local recurrence or the more serious development of a large bowel malignancy?' 32 When a synchronous cancer of the large bowel is present, therapy should be selected to first deal with this more serious lesion and secondarily with the Paget's disease. The results of treatment of the underlying bowel malignancy depend upon locoregional and distant metastasis. On a practical note, when no associated large bowel tumor is present, we have found it very helpful to map the extent of Paget's disease in the perianal skin, which is difficult to detect grossly. The method we prefer was reported by Goldberg et aP1 and consists of
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perianal washing with 1% acetic acid followed by painting of the area with toluidine blue, a supravital dye that is picked up and retained within the nuclei of the Paget's cells. Rewashing the area with 1% acetic acid removes all toluidine blue not within the Paget's cells and so clearly demarcates the areas for wide excision. Malignant Melanoma
These lesions are characterized by their occult nature and early distant metastases. Morson and Volkstadf46 early on documented the dismal outlook for these lesions. More recently, Wanebo and co-workers 74 reported on the Memorial Hospital-Sloan-Kettering experience. The lesion may develop on the perianal skin, in the anorectal transition zone, or within the colonic mucosa. In fact, it may arise anywhere melanocytes are normally found. The lesions are usually pigmented but may be amelanotic. Lesions may be sessile or pedunculated, the latter being confused with hemorrhoidal enlargement. 58 Patients usually present because of symptoms of pressure, mass, or pain. By the time symptoms develop, metastases have invariably occurred. In Quan's experience,58 survival was 12% and correlated best with the depth of tumor penetration. Lesions deeper than 2 mm were uniformly fatal before 5 years. In the Memorial Hospital experience, the treatment selected did not correlate with survival. This is to say that local therapies, node dissections, cryotherapy, abdominal perineal resection, radiation therapy, and chemotherapy all had similar, dismal results. Until effective treatments for disseminated melanoma can be found, treatment should be aimed at adequate palliation of symptoms When suspicious, asymptomatic lesions are encountered during routine anorectal examination, wide local excision is likely to be therapeutic as well as diagnostic as long as metastases have not occurred. NEOPLASMS OF THE ANAL CANAL Epidermoid Cancers
Grouped herein are tumors that in the past were considered separate entities. These are squamous cell cancers, basaloid (cloacogenic or transitional) carcinomas, and mucoepidermoid carcinomas. Although these tumors generally share a favorable prognosis when appropriately treated,22 poor outcomes are common owing to the late patient presentation and/or delayed physician diagnosis. In the British study by Edwards and co-workers,16 76% of anal canal epidermoid carcinomas were initially diagnosed as benign conditions. Eighty-one percent had lesions over 2 em in size at diagnosis. Unfortunately, the tendency of patients to attribute rectal bleeding and mucous discharge to "hemorrhoids" often delays diagnosis and definitive treatment of epidermoid carcinoma.
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Although histologically different in appearance, these tumors all arise between the anal verge and the proximal ATZ. Presenting complaints are bleeding in 50% of patients,S anal pain, or anal swelling. Initial clinical assessment demonstrates an anal canal mass or an ulcerated, indurated lesion. Anoscopic visualization should be performed and directed biopsies obtained. As these tumors spread primarily to the inguinal lymph nodes, a careful assessment of these should be made. Suspicious lymph nodes should be aspirated with a fine needle for cytologic evaluation. As these tumors may arise in the ATZ proximal to the dentate line, lymphatic drainage may be lateral within the pelvis or superiorly toward the para-aortic nodal chain. Digital palpation should evaluate these areas as well within the limitation of finger length. When available, intra-anal and intrarectal ultrasonography assists in assessing depth of tumor penetration as well as perirectal lymph nodes suspicious for neoplastic spread. Wade and co-workers73 reported that 14% of the lymph nodes histologically shown to contain metastases were less than 5 mm in size. Palpation alone cannot be definitive in nodes of this size. Cummingsll points out that at initial presentation, 20% of patients have inguinal nodal spread and 30% have intrapelvic nodal involvement, depending upon their location in relation to the dentate line. Distant metastases are present on initial assessment in less than 10% of cases. Recent retrospective studies on archived specimens by Shepherd et al 64 demonstrated again that depth of tumor penetration and lymph node involvement were the most useful prognostic factors. DNA ploidy also stood out under statistical review in that diploid tumors had better 5-year survivals than did nondiploid (aneuploid) tumors. The treatment of epidermoid cancers of the anal canal has undergone a dramatic evolution over the last 20 years. Initially, the only option for treatment of anal canal lesions was surgical. Radiation as primary treatment came into vogue in the 1970s initially in Europe. Then, in the 1980s, treatment evolved to the combined-modality approach. As each regimen has its advocates, a brief review of each is presented. Local excision of anal canal lesions may be an acceptable option when prognostic factors are favorable, that is, a lesion less than 2 cm, distal to the dentate line, well differentiated, and not involving muscle?O According to Quan,S8 local excision employing these guidelines results in a 66% 5-year cure rate. For larger lesions, deeper lesions, and lesions proximal to the dentate line, abdominoperineal resection (APR) with or without pelvic lymphadenectomy and with therapeutic groin dissection when positive nodes are known to exist was the standard of treatment and still provides good control over locoregional disease. In experienced hands, operative mortality was 1.7% for patents under 70 and 8.5% for those over 70. Five-year surgical cure in the Memorial series58 was 58%. Interestingly, however, Welsh and Male6 reported that in 43 patients they operated on with APR for cure, 39% developed recurrence. Because of the significant mortality in the older age patient, the sexual dysfunction,
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the urinary continence problems, the need for a permanent colostomy, and the high rate of locoregional recurrence, combined modality therapy has its appeal. Radiation therapy was popularized by Papillon. Initially, small, favorable anal canal cancers were treated by radium implants and then external beam irradiation was added to treat potential metastatic spread to lymph node drainage areas. In fact, in well-selected patients, Papillon and Montbarbon54 were able to achieve a 65% 5-year cure rate, about the same as Quan58 achieved with local excision. However, for those patients presenting with more advanced lesions, radiation alone produced 5-year survivals of 73% when no nodes were detectable and 36% when nodes were involved. 63 Developments in chemotherapy set the stage for our current practice in treating anal canal cancer. In 1968, Moertel et al44 reported that mitomycin C produced a favorable response in gastrointestinal tumors. Li and Ross38 reported similar gastrointestinal tumor responses to 5fluorouracil (5-FU). Nigro and co-workersso published their results of preoperative radiation to the pelvis combined with chemotherapy consisting of mitomycin C and 5-FU. In this initial group, 24 patients had an APR performed following chemoradiotherapy. Of these, 22 had no residual tumor in the specimen. Five-year survival rates were 83%.49 From this initial success, many groups have joined the field and are experimenting with radiation dosage and fractions, as well as chemotherapeutic drugs, dosage, duration, and cycles. n . 15. 35. 52. 68. 71 The current regimen being employed by Nigro49 consists of external beam radiation, 3000 cGy to the tumor bed and pelvic and inguinal node beds on days 1 through 15. Mitomycin C is given as a bolus on day 1 at a dose of 15 mg/m2. 5-FU is begun at a dose of 1000 mg/m2 and administered as a continuous infusion on days 2 through 5 (4 days). The 5-FU dose is repeated on days 28 through 31 (4 days). We have modified Nigro's protocol only in that if gross tumor is still present on day 28, another 1000 to 1500 cGy is administered to the tumor bed at 200 cGy/day. To our knowledge, no other regimen has achieved a better 5-year cure rate than Nigro has reported. Severe toxicity in our experience is rare and, when present, is related to mitomycin C's suppressive effect on hematopoiesis. Abdominal perineal resection is used as a salvage procedure when persistent or recurrent disease proves amenable. As to treatment failure, Boman et al9 reported that after curative APR for epidermoid anal cancer, 37% experienced tumor recurrence. Of these, 73% were confined to the pelvis. In the Cummings et aP2 experience with recurrent disease after radiation therapy, 68% were confined to the pelvis. In the same report, inguinal recurrence fell to 2.6% in 38 patients in whom the groins were prophylactically irradiated. This compares with inguinal recurrence rates of 15% to 25% in nonirradiated inguinal nodes. 9. 54 Although prophylactic lymph node dissections do not appear warranted based upon their low tumor yield and substantial associated morbidity, prophylactic radiation treatment to the groin areas does appear efficacious and indicated in this group of patients.
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ADENOCARCINOMA Colorectal Type
According to Fenger,!7 this is the most common carcinoma involving the anal canal. Whether the origin of this lesion is rectal or anal is a moot point because histologically and immunohistochemically these tumors are identicaU8 In a recent report by Koulos and co-workers,36 HPV 18 DNA was found in two of six archived surgical specimens of anal adenocarcinoma. No HPV-associated DNA was found with adenocarcinomas of the rectum or colon, a finding in agreement with previous studies. The relationship of HPV 18 to the development of anal adenocarcinoma has yet to be delineated but again raises the possibility, as with HPV 16 and epidermoid anal cancer, that the viral genome predisposes to subsequent malignant transformation. Treatment for this condition is selected on the basis of careful clinical staging of the tumor. For tumors that are well to moderately well differentiated, confined to the wall of the anus, free of encroachment on the dentate line, less than 4 em in size, and free of regional adenopathy, we consider the patient for electrocoagulation according to the technique of Salvati et al 62 or for local excision. Unfortunately, invasion of the sphincters is frequently present, making APR the more commonly performed procedure. Ramming and co-workers59 reported on eight patients with distal anorectal adenocarcinoma who were treated by wide local excision with subsequent external beam radiotherapy. Via anterior and posterior ports, 4500 cGy were administered. In a limited follow-up of 24 months, no recurrences were noted. Increasingly, surgeons are using transanal ultrasonography to more accurately stage these distal lesions in order to select the more favorable cancers for local treatment and adjuvant radiation and possibly chemotherapy. At present, clinical trials are in progress to compare sphincter-saving local surgical procedures combined with chemoradiotherapy, either preoperatively or postoperatively, with traditional APR. Conclusive data are not available at this time but give promise for the future.
Anal Gland Type
To date, only about 100 cases of this entity have been reported in the literature. The origin of these cancers is still debatableY Some authors believe that this tumor arises as a primary carcinoma of the anal gland. 26 Others suggest that these tumors arise in anorectal duplications and, as such, are mucinous. 33 Jensen et aPl reported 21 cases, 9 of which supported the former hypothesis and 5 the latter. Seven cases were so advanced as to make their origin impossible to determine. In fact, both scenarios may develop and present as an extramucosal mass in the anal canal or in the ischiorectal, extra sphincteric fossa. Our personal experience is limited to three cases. In the first, a I-em ischiorectal
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adenocarcinoma was discovered during wide local excision of perianal Paget's disease. Subsequent APR demonstrated lateral pelvic node involvement. This patient died 18 months later with disseminated cutaneous and visceral metastases. In the second case, the patient was found to have a new primary mucinous adenocarcinoma at the dentate line while being followed up 1 year after an anterior resection for rectal cancer at 10 cm. After APR, the pathologist demonstrated the tumor origin in what was thought to be a small anorectal duplication. The third patient was seen for complaints of anal swelling and pain of 1 month's duration. A submucosal mass at the level of the dentate line was palpated. Through the anoscope, deep biopsies using a rigid proctoscopic biopsy forceps demonstrated mucinous adenocarcinoma. An APR was performed after 45 cGy to the anorectum, bilateral groins, and pelvic nodal drainage and demonstrated the cancer involving the internal and external sphincters but without evidence of metastatic spread. Because these tumors tend to spread aggressively to the groin and pelvic nodes, we believe that preoperative radiation therapy to the primary tumor and to the nodal drainage areas is indicated. APR is still the only viable solution to tumor removals because these cancers invariably involve the sphincter mechanism. Clinical staging is irrelevant because the cancer arises extramucosally. ENDOCRINE CANCERS Carcinoid Type
The ATZ contains cells of neuroectodermal origin that may give rise to carcinoids. Immunohistochemical analysisl demonstrates that these tumors may contain active peptides and neurotransmitters. Generally, these tumors are nonfunctional. As elsewhere in the gastrointestinal tract, cancers over 2 cm in size behave more aggressively and should be considered for APR if wide local excision is not possible. 47 Small Cell Carcinoma Type
Boman et al9 reported on 13 small cell cancers of the anus, only one of which survived 5 years. More recently, other small series have confirmed this finding. 6s,77 In most, they have been hormonally inactive but have shown aggressive local growth patterns. Most cancers have been unresectable at the time of diagnosis. Because their histochemistry is similar to that of oat cell lesions of the lung, similar regimens of chemotherapy have been recommended. Unfortunately, our recent experience with one such case demonstrated a failure in response to chemotherapy and radiation treatment to the pelvis. Because of tumor growth within the pelvis, outlet obstruction necessitated laparotomy and APR. The tumor was resectable. Fortunately, these cancers are rare. Chemotherapy
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is thought to be the first choice in treatment, with surgery and radiation reserved as palliative measures?5
SUMMARY
Anal cancers can be grouped into three major categories. First, anal margin lesions are usually well-differentiated, keratinized squamous cell carcinomas that are amenable to local treatment measures. Second, anal canal cancers distal to the dentate line are mostly epidermoid, nonkeratinizing, moderately differentiated tumors. They are usually best treated with a multimodality approach using chemoradiotherapy and reserving surgery for clinical failures. Third, cancers arising in the ATZ are usually adenocarcinomas, and their treatment depends upon local factors. APR is in order for locally aggressive lesions, but newer protocols are studying multimodality therapy for this entity as well. Other, less common cancers of this region should be evaluated based upon their biologic potential and local involvement, with treatments selected accordingly.
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Address reprint requests to Gregory C. Oliver, MD Associated Colon and Rectal Surgeons 1010 Park Avenue Plainfield, NJ 07060