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Biology and Management of Salivary Gland Cancers
Biology and Management of Salivary Gland Cancers David J. Adelstein, MD,* Shlomo A. Koyfman, MD,† Adel K. El-Naggar, MD, PhD,‡,§ and Ehab Y. Hanna, MD§ The salivary gland cancers are uncommon neoplasms of the head and neck, which exhibit considerable pathologic, biological, and clinical diversity. Surgical resection, often with postoperative radiation, is the standard therapeutic approach, and the results after treatment vary widely depending on the tumor histology. Chemotherapy has been of only limited palliative benefit in patients with advanced disease, and there has been little exploration of its use in definitive management. Recent investigation has focused on identification of the characteristic molecular signatures and genomic alterations of the specific histologic subtypes. These efforts have suggested the potential for molecularly targeted therapies, and clinical trials exploring this approach are currently underway. Semin Radiat Oncol 22:245-253 © 2012 Elsevier Inc. All rights reserved.
S
alivary gland cancers represent fewer than 5% of all newly diagnosed malignancies and exhibit a broad-spectrum of phenotypic, biological, and clinical heterogeneity. This heterogeneity poses significant challenges to the investigation of these diseases. Recent progress in our understanding of the biology and management of these cancers will be reviewed. The major salivary glands are the parotid, submandibular, and sublingual glands. The parotid gland is the site of origin of approximately 70% of salivary gland tumors, although less than half of these are malignant. Benign diagnoses, including pleomorphic adenomas and Warthin tumors, are more common. The submandibular glands account for 10% of salivary gland neoplasms, of which approximately 50% are malignant. Primary tumors of the sublingual glands comprise ⬍1% of all cases and will not be further discussed. The remaining 20% of salivary gland tumors arise from the minor salivary glands, which can be found throughout the upper aerodigestive tract and are, in general, malignant.1
*Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH. †Department of Radiation Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH. ‡Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX. §Department of Head and Neck Surgery, University of Texas, MD Anderson Cancer Center, Houston, TX. Address reprint requests to David J. Adelstein, MD, Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Desk R-35, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: [email protected]
1053-4296/12/$-see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2012.03.009
Histogenesis and Histopathology Salivary tumors are believed to arise from progenitor cells residing within the different ductal tributaries of the salivary glands. Based on their segmented origin, salivary carcinomas can be broadly segregated into tumors arising from the main ductal segments and those derived from the terminal branches and acini.2 Carcinomas originating from the main ducts are purely epithelial and highly malignant, whereas those developing from the terminal ducts are composed of epithelial and myoepithelial cells and behave less aggressively. The different biology of these subtypes has been attributed to the modulating role of myoepithelial cells. Salivary gland carcinomas have been classified into 24 well-defined diagnostic entities by the World Health Organization classification based on their cellular, organizational, and architectural composition.3 Table 1 details the histologic distribution described by Spiro in his large series from Memorial Sloan-Kettering Cancer Center.1 Mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (ACC), and adenocarcinoma are the most frequent diagnoses, representing ⬎75% of the tumors. Although primary squamous cell carcinomas of the parotid gland are sometimes described, the existence of this disease has been subject to question. It is more likely that squamous cell cancer of the parotid represents metastatic intraparotid lymph node involvement from a cutaneous squamous cell malignancy and not a primary glandular tumor. This has important implications when designing radiotherapy treatment fields.
Adenoid Cystic Carcinoma ACC develops in both major and minor salivary glands of the head and neck regions and rarely, in other sites, such as 245
D.J. Adelstein et al
246 Table 1 Histopathology of Salivary Gland Cancer1
Molecular Biomarkers
Diagnosis
Frequency
Mucoepidermoid carcinoma Adenoid cystic carcinoma Adenocarcinoma Malignant mixed tumors Acinic cell carcinoma Other
34% 22% 18% 13% 7% 6%
bronchial tree, breast, cervix, and skin. Three overlapping morphologic patterns have been described, including the tubular, cribriform (Swiss-cheese), and the solid forms, and the behavior of this disease varies based on both the dominant histopathologic pattern identified and the site of origin. Tumors of breast, skin, and airway appear less aggressive than those of salivary, cervical, and vaginal origin, and those with solid morphology are more aggressive than the cribriform or tubular forms.4
Mucoepidermoid Carcinoma MEC derives from the main duct segment and is composed of basal, intermediate, and differentiated cells in varying combinations. It may also develop in non– head and neck sites, including lung, skin, breast, cervix, and thyroid. This entity is graded based on the architectural formation, cellular, and cytologic features into 3 distinct grades. Low-grade tumors are predominantly cystic with focal cellular formations, intermediate grade tumors are focally cystic with solid tumor nests that lack cellular anaplasia, and high-grade tumors are composed of solid tumor nests with cellular anaplasia and tumor necrosis. Histologic grading is of recognized prognostic importance, although most of these tumors have overlapping and mixed components.5 This not uncommonly leads to arbitrary grading.
Adenocarcinoma/Salivary Duct Carcinoma Adenocarcinoma/salivary duct carcinoma is considered a spectrum of the same entity. It is composed of purely epithelial cells and runs a more aggressive clinical course. Both phenotypes may arise de novo, or as a malignant transformation of a long-standing or recurrent pleomorphic adenoma.6 The salivary duct carcinomas bear a pathologic resemblance to mammary adenocarcinoma and share hormonal and growth factor alterations. However, the salivary adenocarcinomas present predominantly in older males and in later stages.
Recent work has focused on the identification and characterization of the molecular and hormonal profiles of these tumors, with the hope that this will lead to more targeted therapeutic approaches. Reports of the rates of overexpression of hormonal receptors and molecular markers, including the epidermal growth factor receptor (EGFR), HER2, and c-kit, have varied according to the published series, staining method, and histology as noted in Table 2. Several of the more important markers are discussed later in the text.
C-kit Kit is a transmembrane cell surface receptor encoded by the c-kit gene. This gene is associated with the regulation of cell migration, differentiation, and proliferation. Of the numerous biomarkers investigated in ACC, overexpression of c-kit was consistently reported in 90%. However, mutations in the c-kit gene have not been consistently identified in ACC.7 Although it remains a potential target, further efforts to define its biological role in ACC are needed. Recently, the restricted expression of this gene in the epithelial cells rather than in the myoepithelium has been emphasized and may impact triaging patients for kit-directed therapy.8
Epidermal Growth Factor Receptor The incidence of EGFR overexpression in ACC has varied from 0% to 37%.8,9 Although activated mutations and amplification have been identified and linked to therapeutic response in other solid tumors, no mutations and/or amplifications have been detected in ACC.9 As such, the role of EGFR as a therapeutically relevant marker in ACC remains uncertain. In salivary adenocarcinoma, however, EGFR overexpression has been reported, and in some of these tumors, an associated EGFR mutation has been found.10 This suggests a potential role for anti-EGFR therapy in the treatment of this subset of patients.
Her2 In contrast to EGFR, HER2 expression in ACC is rare, and the effectiveness of anti-Her2 treatment of patients with this cancer is likely limited. As in mammary carcinoma, however, HER2 is overexpressed in approximately 25% of adenocarcinoma/salivary duct carcinomas.10 The frequent overexpression of EGFR and HER2 in salivary gland carcinomas provides the rationale for clinical trials of agents directed against these targets.9,11 MEC shares phenotypic features with ade-
Table 2 Hormonal and Molecular Markers in Common Salivary Gland Cancers Histopathology
EGFR
HER2
C-kit
VEGF
Androgen
Mucoepidermoid Adenoca/salivary duct carcinoma Adenoid cystic
40% 30%-40% 20%
25%-35% 20%-30% Rare
Rare Rare 80%-90%
50% 65% 85%
Rare 15%-40% Rare
EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor.
Salivary gland cancers: biology and management nocarcinoma, including frequent expression of EGFR and HER2.
PI3K-AKT-Mammalian Target of Rapamycin Pathway The PI3K axis plays a critical role in tumorigenesis. Although the dysregulation of this pathway is complex, it involves alterations of AKT, PTEN, the mammalian target of rapamycin, and several known upstream tumor-associated growth factors, including EGFR, HER2, Platelet derived growth factor (PDGF), and Vascular endothelial growth factor (VEGF).12 The availability of small molecule inhibitors for different components of this pathway renders it an attractive therapeutic target. The recent finding that activation of the mammalian target of rapamycin pathway in Adenomatous polyposis coli (APC)/PTEN transgenic mice resulted in the formation of acinar salivary gland malignancy, and that treatment with rapamycin produced tumor regression suggests the possibility of a similar approach in human salivary carcinomas.13
Androgen Receptor Androgen receptor expression has been reported in a high percentage of salivary duct carcinomas and can serve as a pathologic marker for this disease.14 Similar to the use of antiestrogen therapy in estrogen-receptor–positive breast cancer, the identification of androgen receptors in salivary duct carcinoma suggests a potential role for antiandrogen therapy. Anecdotal success has been reported.15
Genomic Rearrangements Although reciprocal chromosomal translocations are uncommon in solid tumor malignancies, this alteration has been identified in 2 of the more frequent salivary carcinomas. Because of the critical role of gene fusion in tumor evolution and biology, efforts are underway to determine their implications in this disease. In ACC, Persson et al have described a tumorspecific translocation, t(6;9) (q22-23; p23-24), in 6 patients.16 This translocation fuses the MYB oncogene to the transcription factor gene NFIB leading to the potential activation of MYB targets, which include genes associated with apoptosis, cell cycle control, and cell growth. This observation has potential diagnostic and therapeutic implications.17 Similarly, characterization of the t(11;19) and the associated CTRC/MAML2 fusion gene in MEC of salivary gland and other sites supports the importance of this alteration in disease development.18 Tumors with this fusion gene are generally less aggressive than those lacking this fusion.19 Therapeutic strategies aimed at aberrant transcriptional pathways in fusion carrying tumors are attractive. Thus, however, transcriptional factors and chimeric fusion proteins have been difficult to target with small molecule inhibitors because of their protein/protein and protein/Deoxyribonucleic acid (DNA) interaction. Alternatively, approaches that target downstream effectors of these fusion proteins may prove successful, as reported in other solid tumors. Future concerted efforts to conduct deep sequencing of these tumors and to
247 integrate these data with other genomic information may lead to the development of functionally annotated molecular therapeutic targets for the treatment of patients with these tumors.
Patient Evaluation Tumors of the parotid gland usually present as a painless swelling. The presence of facial nerve paresis or paralysis, pain, fixation of the mass to the overlying skin or underlying structures, and associated cervical adenopathy usually indicate the presence of local or regional extension of a malignancy. The diagnosis of parotid malignancy should not await the development of these signs and symptoms, however, and the possibility of malignancy should be ruled out in patients presenting with any mass in the parotid gland. This will usually require cytologic or histologic evaluation with a fine needle aspiration biopsy (FNAB) or parotidectomy, respectively. Tumors of the submandibular gland are relatively uncommon and usually present as a painless, mobile mass in the submandibular triangle. Involvement of the overlying skin or fixation to the mandible often indicates local extension of a malignant tumor. Ipsilateral weakness or numbness of the tongue indicates perineural spread of malignancy along the hypoglossal or lingual nerves, respectively. Weakness of the marginal mandibular branch of the facial nerve would also suggest perineural extension. Tumors arising from the minor salivary glands are usually malignant. Their clinical presentation depends on the site of origin, most commonly the palate, parapharyngeal space, and lacrimal gland.
Fine Needle Aspiration Biopsy FNAB has been widely recognized and well established as an accurate technique in the diagnosis of salivary gland masses.20 Numerous studies have reported an exceptionally high degree of sensitivity, specificity, and predictive value for FNAB. In general, diagnostic accuracy is higher for benign than for malignant salivary gland tumors. The accuracy of FNAB, however, depends greatly on the experience of the cytopathologist, and the overall volume of patients with salivary neoplasms evaluated at any given institution. The most common source of diagnostic error of FNAB is inadequate sampling. The use of ultrasound-guided FNAB may be of help in cases in which it is difficult to obtain a representative sample.
Imaging Salivary gland tumors with clinical findings suggestive of malignancy, tumors arising from the deep lobe of the parotid gland or the parapharyngeal space, and, tumors of the submandibular and minor salivary glands should be evaluated with high-resolution imaging. The goal of imaging is to provide an accurate delineation of the location and extent of the tumor, its relation to major neurovascular structures, perineural spread, skull base invasion, and intracranial extension. Imaging
248 should also provide accurate staging of the regional lymph nodes and evaluate for the presence of distant metastases in high-risk patients. Magnetic resonance imaging (MRI) is superior to computerized tomography (CT) in demonstrating the internal architecture of salivary gland tumors in a multiplanar manner and in delineating the interface between tumor and normal salivary gland. In contrast to benign tumors, which are invariably well defined, malignant tumors may exhibit irregular margins. The T1-weighted images are particularly helpful. Extension of the tumor beyond the fascial confines of the gland can be adequately seen on both CT and MRI and should raise the suspicion of malignancy. Bone destruction of the mandible or skull base is best visualized on CT, whereas bone marrow involvement is better demonstrated on MRI. Both studies can adequately evaluate the neck for metastatic adenopathy. Although parapharyngeal space masses are well visualized by both techniques, they are better delineated with MRI than CT. Patients with high-grade or locoregionally advanced cancers are at high risk of distant metastasis, and in such patients, body imaging may be warranted for complete disease staging. The use of positron emission tomography scanning or of fused positron emission tomography/CT scans in this disease is currently undergoing clinical investigation.21
Surgery The principal treatment for cancer of the salivary glands in the absence of distant hematogenous metastases is surgical resection. The goal of surgical treatment is the complete excision of the tumor, while avoiding unnecessary morbidity. Risk factors for disease recurrence after surgical resection have been reported by multiple authors and include locally advanced disease extent, incomplete surgical resection, bone invasion, named nerve involvement, positive surgical margins, nodal involvement, and unfavorable histopathologic grading.22,23 The surgical approach and the scope of resection depend on the location and extent of the tumor.24
Primary Tumor Resection Tumors located in the superficial lobe of the parotid gland will require a superficial parotidectomy. Tumors that also extend to or originate from the deep lobe will require a total parotidectomy. The facial nerve is dissected and preserved, unless it is directly infiltrated or encased by the tumor, and facial nerve monitoring is often used to minimize injury to the facial nerve during surgery. Preoperative weakness or paralysis of the facial nerve usually indicates tumor involvement, and in these instances, the main trunk or the involved nerve branches may have to be sacrificed. The nerve or its involved branches should also be sacrificed if there is intraoperative evidence of gross invasion or microscopic infiltration of the nerve by tumor, even in the presence of normal preoperative facial nerve function. This is more likely to occur with larger and higher-grade tumors, and in tumors that extend from the superficial to the deep lobe, transgressing the
D.J. Adelstein et al plane of the facial nerve. Surgical margins on both the distal and proximal nerve stumps should be confirmed because of the possibility of perineural spread for some distance from the area of the primary tumor. Achieving negative surgical margins on the proximal stump of the facial nerve may require a mastoidectomy and facial nerve dissection along its course in the temporal bone. Tumor extension outside the parotid gland may require resection of surrounding skin or masseter muscle, mastoidectomy, temporal bone resection, mandibulectomy, or resection of the contents of the infratemporal fossa. If the facial nerve is sacrificed, nerve repair may be done using either direct neurorrhaphy of the cut edges or a cable graft, depending on the length of the resected segment. Immediate rehabilitation of the paralyzed face requires diligent eye care to prevent exposure keratitis. This will involve the liberal use of artificial tears, lubricating ointment, and protection with an appropriate eye dressing and eyewear. An upper eyelid gold weight implant should be considered in patients with complete facial paralysis. This simple reanimation technique allows for prevention of dry eye symptoms and for protection of the cornea from exposure keratitis. Consideration can also be given for tarsorrhaphy or a lower eyelid shortening procedure, to provide additional corneal protection and rehabilitation of the lower eyelid. If the facial nerve is not repaired or grafted, then surgical reconstruction for static or dynamic rehabilitation of the paralyzed face may be indicated. Patients undergoing radical parotidectomy with facial nerve sacrifice often require complex reconstruction that may include local skin flaps, myocutaneous flaps, or free tissue transfer. Tumors located in the submandibular gland will require en bloc resection of the involved gland and any involved structures in the submandibular triangle, including hypoglossal or lingual nerves, digastric or mylohyoid muscles, floor of mouth, or mandible. Special attention should be given to the lingual, hypoglossal, and marginal mandibular nerves since they may be involved by perineural spread of tumor. Thickening and nodularity of these nerves may indicate perineural involvement, and in such cases, histologic confirmation by frozen section may be useful in both establishing nerve invasion and obtaining negative surgical margins. Surgical resection of cancer of the minor salivary glands depends on their site of origin and extent of the disease. In the oral cavity, this may only require wide local excision of a localized low-grade tumor. Larger and high-grade tumors may require more radical excision, including marginal or segmental mandibulectomy, and/or partial or total resection of the hard or soft palate. Salivary gland cancer involving the sinonasal tract is usually high grade and presents at an advanced stage. Surgical resection may require partial or total maxillectomy, infratemporal fossa dissection, and/or anterior craniofacial resection. The branches of the second (V2) and third (V3) divisions of the trigeminal nerve are at high risk for perineural spread of minor salivary gland malignancy. These nerves may provide an avenue for early skull base invasion.
Salivary gland cancers: biology and management
249
Resection of the cranial base may be required in some cases to eradicate the tumor and obtain negative margins.
Neck Dissection Patients with clinical or radiographic evidence of lymph node metastasis will require a therapeutic comprehensive neck dissection. Even in the absence of clinical evidence of nodal involvement, the increased incidence of occult regional disease in patients with advanced primary site tumors or highgrade histology (such as undifferentiated carcinoma, highgrade mucoepidermoid, adenocarcinoma, or salivary duct carcinoma) suggests the need for an elective neck dissection. A selective (supraomohyoid) neck dissection may be used as a staging procedure in such cases. Suspicious nodes should be sent for frozen-section diagnosis, and if positive for metastatic carcinoma, a comprehensive neck dissection should then be performed.
Radiation Therapy Adjuvant Treatment For small or low-grade cancers, surgical resection alone with good margin control is adequate. Although never tested in a prospective randomized clinical trial, the use of adjuvant postoperative radiotherapy (RT) is indicated in patients who have close or positive margins, lymph node metastases, locally advanced disease, bone or nerve involvement, recurrent disease, or a combination of other adverse features, such as high nuclear grade, perineural invasion, and lymphovascular invasion. Several older retrospective series provide a limited evidence base for the use of postoperative radiotherapy in highrisk patients by demonstrating a local control advantage when compared with surgery alone (Table 3). A matchedpair analysis from Memorial Sloan-Kettering Cancer Center reported that patients with major salivary gland cancer who had stage III/IV disease, positive lymph nodes, or high-grade tumors had improved local control and, in some instances, improved survival with the addition of adjuvant radiotherapy. However, patients with low-grade or early-stage (I/II) disease did not appear to benefit.25 Other studies, including a large review by the Dutch Head and Neck Oncology Coop-
erative Group, confirmed this improvement in local control with the addition of adjuvant RT.26-29 Contemporary series also report excellent results with a combined approach. A recent review of 50 patients with parotid gland cancer treated in the United Kingdom demonstrated excellent local control (96%) with conservative facial nerve–sparing surgery and postoperative RT.30 Benefit has also been suggested in patients with submandibular gland and minor salivary gland cancers.28,31,32
Definitive Radiation in Unresectable Disease Radiotherapy also has an important role in the management of locally advanced, unresectable, or recurrent salivary gland cancer when surgery is not feasible. Although radiotherapy can be very effective in achieving tumor shrinkage and symptomatic palliation, curative nonoperative approaches have been challenging. Several methods of radiation enhancement have been investigated to improve tumor control rates. Fast neutron therapy was studied as a promising method of radiation enhancement given its higher relative biological effectiveness compared with traditional photon or electron beam therapy. A phase III study demonstrated that neutron therapy did improve local control compared with photon (with or without electron beam) therapy (56% vs 17%; P ⫽ 0.009). However, distant metastases and overall survival were inferior in the neutron arm, and severe late side effects were noted in long-term survivors.33 Other single institution experiences confirmed similar findings. With the limited number of neutron capable facilities, as well as the higher incidence of late side effects, neutron therapy has fallen out of favor. Other methods of radiation enhancement or of increasing the radiation dose have included carbon ion therapy,34 altered fractionation schedule,35 hyperthermia,36 proton beam radiation,37 and brachytherapy.
Target Volumes and Radiation Dose In the postoperative setting, the tumor and involved lymph node bed constitute the primary target volume and are generally treated to 60 Gray (Gy) in 30 fractions. Preoperative imaging and examination findings should guide radiation field design to ensure that all areas originally involved with
Table 3 Selected Retrospective Nonrandomized Comparisons of Surgery Alone and Surgery With Postoperative Radiotherapy (RT) in Salivary Gland Cancer Author Armstrong et al25 Stage I/II Stage III/IV Node positive High grade North et al26 Bissett28 Chen et al29 aCause-specific
survival.
Number of Patients
Local Control: Surgery
Local Control: Surgery/RT
Overall Survival: Surgery
Overall Survival: Surgery/RT
92
66% 79% 17% 40% 44% 74% 30% 61%
78% 91% 51% 69% 63% 96% 69% 84%
55% 96% 10% 19% 28% 59% 60%a 60%
69% 82% 51% 49% 57% 75% 65%a 65%
69 84 140
250 disease are targeted. For patients with parotid tumors who undergo a superficial parotidectomy, the deep lobe of the gland should be included in the clinical target volume. For those with deep lobe involvement, the parapharyngeal space and infratemporal fossa should be targeted. Patients with close (⬍1 mm) or positive margins or extracapsular nodal extension are either treated with an additional boost of 6 Gy to those areas of highest recurrence risk or with a simultaneous-integrated boost using intensity-modulated radiotherapy. Alternatively, a single large dose of intraoperative radiation (10-20 Gy) directed at areas of expected close or positive margins, or extracapsular extension can be safely combined with fractionated external beam radiotherapy to improve local control.38 In the definitive nonoperative setting, treatment volumes follow similar principles, but the total dose used may be ⱖ70 Gy. Ipsilateral cervical lymph nodes are routinely targeted when involved. For patients without clinical or pathologic lymph node involvement, elective nodal irradiation to a dose of 50-54 Gy is usually reserved for patients with larger or higher-grade tumors. A review of 474 such patients demonstrated that tumors ⬎4 cm and high-grade tumors had significantly higher risks of occult lymph node metastases than those with smaller and low-grade disease.39 Although carcinoma of the parotid gland most frequently involves periparotid and level II lymph nodes, skip metastases to levels III and IV have been observed, and these nodal stations should be routinely targeted when treating the neck. Level Ib nodes should be included when level IIa is involved, and level V nodes should be targeted when levels IIb, IIIb or IVb are involved. When treating submandibular gland cancers postoperatively, levels I-III are at highest risk and are targeted electively when indicated. Minor salivary gland cancers can often be midline and may necessitate bilateral lymph node irradiation. Treatment of the contralateral neck should also be considered for patients who have multiple ipsilateral lymph nodes involved. Histology is another important factor to consider during radiation planning. ACC rarely metastasizes to lymph nodes but frequently spreads along cranial nerves. Consequently, although elective nodal irradiation is not necessary for these patients, particular attention must be paid to ensuring coverage of involved nerves up to their exit point from the brainstem at the base of skull.40 Conversely, undifferentiated carcinomas of the salivary glands are highly malignant, exhibit frequent lymphatic metastases, and should be treated accordingly.
Systemic Treatments Chemotherapy The use of systemic chemotherapy in advanced salivary gland cancer has, in general, been confined to those patients with advanced and incurable disease. Meaningful exploration of this treatment modality has been hampered by the diversity of histologic subtypes and the disease infrequency. The published literature contains several small patient series, report-
D.J. Adelstein et al ing results from clinical trials using a number of different chemotherapeutic agents; often in mixed populations, including patients with many different histologic subtypes. Cisplatin and cisplatin-based regimens have been most frequently explored, but the response rates have been modest, and the impact, if any, on survival has been impossible to discern. Several recent reviews have summarized these data.41-45 Many of the reported series include large number of patients with ACC, reflecting the long natural history of this disease, even when metastatic. It is this long, indolent natural history, however, that makes such patients less likely to exhibit an objective disease response, and makes any interpretation of the experience after chemotherapy difficult. Disease stability after a short course of chemotherapy in patients with such an indolent disease would be expected, and likely has little meaning. In addition, most reported series were published ⬎20 years ago. Several of the more recent studies are of interest. The first was a phase II trial of single-agent paclitaxel, conducted by the Eastern Cooperative Oncology Group in 45 patients with advanced, MEC, adenocarcinoma, or ACC of the salivary gland.46 Eight partial responses were observed among the 31 patients with MEC or adenocarcinoma, but no responses were identified in the 14 patients with ACC. Notably, the median survival for the entire group was 12.5 months, with a 3-year projected survival of 11% for the MEC patients and 20% for the adenocarcinoma patients. The 3-year projected survival for the 14 adenoid cystic patients was 43%, however, despite their lack of responsiveness to the chemotherapeutic agent. Similarly, a phase II trial of singleagent gemcitabine reported no responses among 21 patients with advanced ACC, despite disease stability for at least 6 months in 48%.47 A more recent report from the National Cancer Institute of Canada assessed the use of gemcitabine in combination with either cisplatin or carboplatin in 33 patients with advanced salivary gland cancer. Two of the 10 patients (20%) with ACC experienced an objective response to treatment, as did 6 of the 23 patients (26%) with other histologic diagnoses (mostly adenocarcinomas).48 Similar to most other chemotherapy trials, the response rates were modest, and the regimen did not meet the predefined criteria for antitumor activity. Concurrent chemotherapy and radiation have achieved notable success in the more common squamous cell head and neck cancers. There has been only limited exploration of this approach in the salivary gland cancers, again because of their infrequency. Small single-arm trials have been reported detailing the use of chemotherapy and concurrent radiation after primary surgical resection in high-risk patients,49 after surgical resection for recurrence,50 and in inoperable patients.51 Concurrent chemoradiotherapy has also been used before planned surgical resection in a 17-patient prospective trial.52 All of these reports demonstrated significant activity of concurrent chemoradiotherapy suggesting possible benefit from this approach. The Radiation Therapy Oncology Group (RTOG) has recently opened a prospective phase II randomized trial (RTOG 1008) comparing radiation and concurrent cisplatin with radiation therapy alone in high-risk patients
Salivary gland cancers: biology and management
251
Table 4 Phase II Trials of Targeted Therapy for Salivary Gland Cancer Author al53
Haddad et Glisson et al54 Hotte et al7 Pfeffer et al55 Agulnik et al9 Locati et al56
Year
Number
Target (s)
Drug
Response Rate (%)
Stable Disease (%)
2003 2005 2005 2007 2007 2009
14 28 16 10 36 30
HER2 EGFR C-kit C-kit HER2/EGFR EGFR
Trastuzumab Gefitinib Imatinib Imatinib lapatinib Cetuximab
8% 0 0 0 0 0
Not reported 67% 60% 20% 64% 80%
EGFR, epidermal growth factor receptor.
after surgical resection, with the hope of better defining the role of concurrent chemoradiotherapy in this disease.
Molecular Targeting of Salivary Gland Malignancies Perhaps of greater interest in recent years has been the attempt to use our increasing understanding of the biology of these tumors to identify specific molecular targets that might be amenable to molecularly targeted therapies. Although potential molecular targets have been identified, the results of this approach have, in general, been disappointing (Table 4).7,9,41-44,53-56 A good example is the imatinib experience in c-kit-positive ACC. ACC is characterized by a high frequency of c-kit overexpression, and there has been an occasional case report of responsiveness to the c-kit inhibitor, imatinib. This observation led to the initiation of 2 separate trials of imatinib as treatment for patients with advanced ACC.7,55 Both of these studies were closed, however, with no evidence of tumor response and with moderate toxicity. Stable disease as the best response was frequently observed. A probable explanation for the lack of activity of this agent is that although patients with ACC overexpress c-kit, unlike patients with gastrointestinal stromal tumors, they do not commonly harbor activating c-kit mutations.7 A phase II study of lapatinib, an oral tyrosine kinase inhibitor of both EGFR and HER2, reported similar findings.9 Patients with progressive salivary gland cancer were eligible for this study only if their tumor expressed either EGFR or HER2. None of the 36 evaluable patients experienced a response to therapy, although 79% of the patients with ACC and 47% of the patients with other histologies experienced stable disease. In 36% of the evaluable patients, disease stability continued for ⬎6 months. The investigators considered this disease stability a positive result, but there has been little enthusiasm for further study of this agent. Similar trials have been conducted using the EGFR inhibitors gefitinib54 and cetuximab,56 and the anti-HER2 agent trastuzumab.53 Despite marker overexpression, there has been no meaningful or reproducible response rate demonstrated to these therapies. Discordance in the immunohistochemical evidence of marker overexpression and the rate of genetic mutations of both EGFR and HER2 has been described and may help explain these observations.57,58 In the series of patients with salivary duct carcinoma reported by Williams et al, although 70% of the tested tumors evidenced immunohistochemical EGFR overexpression, only 10% of
the tumors contained an EGFR gene mutation.58 Similarly, 26% of these tumors overexpressed HER2, but fewer than half demonstrated any HER2 gene amplification. A more sophisticated approach to identifying putative molecular targets will be required before any useful clinical application of targeted therapy will be possible.
Conclusions Salivary gland cancer is an uncommon and heterogeneous disease, with considerable variability in its natural history. Surgery with postoperative radiation for high-risk patients remains the standard of care. Systemic chemotherapy has been of only limited benefit, although an exploration of the role of concurrent chemotherapy and radiation is currently under way. Recent progress in our understanding of the molecular biology of salivary gland cancers promises the possibility that more specific targeted therapies might prove useful. The careful design and conduct of prospective clinical trials will be critical to improving our treatments for this disease.
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malignant tumors of the salivary glands. J Clin Oncol 25:3978-3984, 2007 Williams MD, Roberts D, Blumenschein GR Jr, et al: Differential expression of hormonal and growth factor receptors in salivary duct carcinomas: Biologic significance and potential role in therapeutic stratification of patients. Am J Surg Pathol 31:1645-1652, 2007 Locati LD, Perrone F, Losa M, et al: Treatment relevant target immunophenotyping of 139 salivary gland carcinomas (SGCs). Oral Oncol 45:986-990, 2009 Guertin DA, Sabatini DM: Defining the role of mTOR in cancer. Cancer Cell 12:9-22, 2007 Diegel CR, Cho KR, El-Naggar AK, et al: Mammalian target of rapamycin-dependent acinar cell neoplasia after inactivation of APC and PTEN in the mouse salivary gland: Implications for human acinic cell carcinoma. Cancer Res 70:9143-9152, 2010 Nasser SM, Faquin WC, Dayal Y: Expression of androgen, estrogen, and progesterone receptors in salivary gland tumors. Frequent expression of androgen receptor in a subset of malignant salivary gland tumors. Am J Clin Pathol 119:801-806, 2003 Jaspers HC, Verbist BM, Schoffelen R, et al: Androgen receptor-positive salivary duct carcinoma: A disease entity with promising new treatment options. J Clin Oncol 29:e473-e476, 2011 Persson M, Andrén Y, Mark J, et al: Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck. Proc Natl Acad Sci U S A 106:18740-18744, 2009 Mitani Y, Li J, Rao PH, et al: Comprehensive analysis of the MYB-NFIB gene fusion in salivary adenoid cystic carcinoma: Incidence, variability, and clinicopathologic significance. Clin Cancer Res 16:4722-4731, 2010 Tonon G, Modi S, Wu L, et al: t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a notch signaling pathway. Nat Genet 33:208-213, 2003 Tirado Y, Williams MD, Hanna EY, et al: CRTC1/MAML2 fusion transcript in high grade mucoepidermoid carcinomas of salivary and thyroid glands and Warthin’s tumors: Implications for histogenesis and biologic behavior. Genes Chromosomes Cancer 46:708-715, 2007 Postema RJ, van Velthuysen ML, van den Brekel MW, et al: Accuracy of fine-needle aspiration cytology of salivary gland lesions in the Netherlands Cancer Institute. Head Neck 26:418-424, 2004 Razfar A, Heron DE, Branstetter BF, et al: Positron emission tomography-computed tomography adds to the management of salivary gland malignancies. Laryngoscope 120:734-738, 2010 Garden AS, El-Naggar AK, Morrison WH, et al: Postoperative radiotherapy for malignant tumors of the parotid gland. Int J Radiat Oncol Biol Phys 37:79-85, 1997 Terhaard CH, Lubsen H, Van der Tweel I, et al: Salivary gland carcinoma: Independent prognostic factors for locoregional control, distant metastases, and overall survival: Results of the Dutch head and neck oncology cooperative group. Head Neck 26:681-693, 2004 Hanna EY, Suen JY: Malignant tumors of the salivary glands, in Myers EN, Suen JY, Myers JN, Hanna EY (eds): Cancer of the Head and Neck. Philadelphia, PA, Saunders, 2003 Armstrong JG, Harrison LB, Spiro RH, et al: Malignant tumors of major salivary gland origin. A matched-pair analysis of the role of combined surgery and postoperative radiotherapy. Arch Otolaryngol Head Neck Surg 116:290-293, 1990 North CA, Lee DJ, Piantadosi S, et al: Carcinoma of the major salivary glands treated by surgery or surgery plus postoperative radiotherapy. Int J Radiat Oncol Biol Phys 18:1319-1326, 1990 Terhaard CH, Lubsen H, Rasch CR, et al: The role of radiotherapy in the treatment of malignant salivary gland tumors. Int J Radiat Oncol Biol Phys 61:103-111, 2005 Bissett RJ, Fitzpatrick PJ: Malignant submandibular gland tumors. A review of 91 patients. Am J Clin Oncol 11:46-51, 1988 Chen AM, Bucci MK, Weinberg V, et al: Adenoid cystic carcinoma of the head and neck treated by surgery with or without postoperative radiation therapy: Prognostic features of recurrence. Int J Radiat Oncol Biol Phys 66:152-159, 2006 Shah K, Javed F, Alcock C, et al: Parotid cancer treatment with surgery
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followed by radiotherapy in Oxford over 15 years. Ann R Coll Surg Engl 93:218-222, 2011 Garden AS, Weber RS, Ang KK, et al: Postoperative radiation therapy for malignant tumors of minor salivary glands. Outcome and patterns of failure. Cancer 73:2563-2569, 1994 Parsons JT, Mendenhall WM, Stringer SP, et al: Management of minor salivary gland carcinomas. Int J Radiat Oncol Biol Phys 35:443-454, 1996 Laramore GE, Krall JM, Griffin TW, et al: Neutron versus photon irradiation for unresectable salivary gland tumors: Final report of an RTOG-MRC randomized clinical trial. Radiation Therapy Oncology Group. Medical Research Council. Int J Radiat Oncol Biol Phys 27:235240, 1993 Schulz-Ertner D, Nikoghosyan A, Jäkel O, et al: Feasibility and toxicity of combined photon and carbon ion radiotherapy for locally advanced adenoid cystic carcinomas. Int J Radiat Oncol Biol Phys 56:391-398, 2003 Wang CC, Goodman M: Photon irradiation of unresectable carcinomas of salivary glands. Int J Radiat Oncol Biol Phys 21:569-576, 1991 Gabriele P, Amichetti M, Orecchia R, et al: Hyperthermia and radiation therapy for inoperable or recurrent parotid carcinoma. A phase I/II study. Cancer 75:908-913, 1995 Pommier P, Liebsch NJ, Deschler DG, et al: Proton beam radiation therapy for skull base adenoid cystic carcinoma. Arch Otolaryngol Head Neck Surg 132:1242-1249, 2006 Freeman SB, Hamaker RC, Singer MI, et al: Intraoperative radiotherapy of head and neck cancer. Arch Otolaryngol Head Neck Surg 116:165168, 1990 Armstrong JG, Harrison LB, Thaler HT, et al: The indications for elective treatment of the neck in cancer of the major salivary glands. Cancer 69:615-619, 1992 Garden AS, Weber RS, Morrison WH, et al: The influence of positive margins and nerve invasion in adenoid cystic carcinoma of the head and neck treated with surgery and radiation. Int J Radiat Oncol Biol Phys 32:619-626, 1995 Papaspyrou G, Hoch S, Rinaldo A, et al: Chemotherapy and targeted therapy in adenoid cystic carcinoma of the head and neck: A review. Head Neck 33:905-911, 2011 Laurie SA, Licitra L: Systemic therapy in the palliative management of advanced salivary gland cancers. J Clin Oncol 24:2673-2678, 2006 Surakanti SG, Agulnik M: Salivary gland malignancies: The role for chemotherapy and molecular targeted agents. Semin Oncol 35:309319, 2008 Vattemi E, Graiff C, Sava T, et al: Systemic therapies for recurrent and/or metastatic salivary gland cancers. Expert Rev Anticancer Ther 8:393-402, 2008 Rizk S, Robert A, Vandenhooft A, et al: Activity of chemotherapy in the palliative treatment of salivary gland tumors: Review of the literature. Eur Arch Otorhinolaryngol 264:587-594, 2007 Gilbert J, Li Y, Pinto HA, et al: Phase II trial of taxol in salivary gland malignancies (E1394): A trial of the Eastern Cooperative Oncology Group. Head Neck 28:197-204, 2006 van Herpen CM, Locati LD, Buter J, et al: Phase II study on gemcitabine in recurrent and/or metastatic adenoid cystic carcinoma of the head and neck (EORTC 24982). Eur J Cancer 44:2542-2545, 2008 Laurie SA, Siu LL, Winquist E, et al: A phase 2 study of platinum and gemcitabine in patients with advanced salivary gland cancer: A trial of the NCIC Clinical Trials Group. Cancer 116:362-368, 2010 Tanvetyanon T, Qin D, Padhya T, et al: Outcomes of postoperative concurrent chemoradiotherapy for locally advanced major salivary gland carcinoma. Arch Otolaryngol Head Neck Surg 135:687-692, 2009 Pederson AW, Haraf DJ, Blair EA, et al: Chemoreirradiation for recurrent salivary gland malignancies. Radiother Oncol 95:308-311, 2010 Haddad RI, Posner MR, Busse PM, et al: Chemoradiotherapy for adenoid cystic carcinoma: Preliminary results of an organ sparing approach. Am J Clin Oncol 29:153-157, 2006 Katori H, Tsukuda M: Concurrent chemoradiotherapy with cyclophos-
Salivary gland cancers: biology and management phamide, pirarubicin, and cisplatin for patients with locally advanced salivary gland carcinoma. Acta Otolaryngol 126:1309-1314, 2006 53. Haddad R, Colevas AD, Krane JF, et al: Herceptin in patients with advanced or metastatic salivary gland carcinomas. A phase II study. Oral Oncol 39:724-727, 2003 54. Glisson BS, Blumenschein G, Francisco M, et al: Phase II trial of gefitinib in patients with incurable salivary gland cancer. J Clin Oncol 23:508s, 2005; abstr 5532 55. Pfeffer MR, Talmi Y, Catane R, et al: A phase II study of imatinib for advanced adenoid cystic carcinoma of head and neck salivary glands. Oral Oncol 43:33-36, 2007
253 56. Locati LD, Bossi P, Perrone F, et al: Cetuximab in recurrent and/or metastatic salivary gland carcinomas: A phase II study. Oral Oncol 45:574-578, 2009 57. Vidal L, Tsao MS, Pond GR, et al: Fluorescence in situ hybridization gene amplification analysis of EGFR and HER2 in patients with malignant salivary gland tumors treated with lapatinib. Head Neck 31:10061012, 2009 58. Williams MD, Roberts DB, Kies MS, et al: Genetic and expression analysis of HER-2 and EGFR genes in salivary duct carcinoma: Empirical and therapeutic significance. Clin Cancer Res 16:2266-2274, 2010
S
alivary gland cancers represent fewer than 5% of all newly diagnosed malignancies and exhibit a broad-spectrum of phenotypic, biological, and clinical heterogeneity. This heterogeneity poses significant challenges to the investigation of these diseases. Recent progress in our understanding of the biology and management of these cancers will be reviewed. The major salivary glands are the parotid, submandibular, and sublingual glands. The parotid gland is the site of origin of approximately 70% of salivary gland tumors, although less than half of these are malignant. Benign diagnoses, including pleomorphic adenomas and Warthin tumors, are more common. The submandibular glands account for 10% of salivary gland neoplasms, of which approximately 50% are malignant. Primary tumors of the sublingual glands comprise ⬍1% of all cases and will not be further discussed. The remaining 20% of salivary gland tumors arise from the minor salivary glands, which can be found throughout the upper aerodigestive tract and are, in general, malignant.1
*Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH. †Department of Radiation Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH. ‡Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX. §Department of Head and Neck Surgery, University of Texas, MD Anderson Cancer Center, Houston, TX. Address reprint requests to David J. Adelstein, MD, Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Desk R-35, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: [email protected]
1053-4296/12/$-see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2012.03.009
Histogenesis and Histopathology Salivary tumors are believed to arise from progenitor cells residing within the different ductal tributaries of the salivary glands. Based on their segmented origin, salivary carcinomas can be broadly segregated into tumors arising from the main ductal segments and those derived from the terminal branches and acini.2 Carcinomas originating from the main ducts are purely epithelial and highly malignant, whereas those developing from the terminal ducts are composed of epithelial and myoepithelial cells and behave less aggressively. The different biology of these subtypes has been attributed to the modulating role of myoepithelial cells. Salivary gland carcinomas have been classified into 24 well-defined diagnostic entities by the World Health Organization classification based on their cellular, organizational, and architectural composition.3 Table 1 details the histologic distribution described by Spiro in his large series from Memorial Sloan-Kettering Cancer Center.1 Mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (ACC), and adenocarcinoma are the most frequent diagnoses, representing ⬎75% of the tumors. Although primary squamous cell carcinomas of the parotid gland are sometimes described, the existence of this disease has been subject to question. It is more likely that squamous cell cancer of the parotid represents metastatic intraparotid lymph node involvement from a cutaneous squamous cell malignancy and not a primary glandular tumor. This has important implications when designing radiotherapy treatment fields.
Adenoid Cystic Carcinoma ACC develops in both major and minor salivary glands of the head and neck regions and rarely, in other sites, such as 245
D.J. Adelstein et al
246 Table 1 Histopathology of Salivary Gland Cancer1
Molecular Biomarkers
Diagnosis
Frequency
Mucoepidermoid carcinoma Adenoid cystic carcinoma Adenocarcinoma Malignant mixed tumors Acinic cell carcinoma Other
34% 22% 18% 13% 7% 6%
bronchial tree, breast, cervix, and skin. Three overlapping morphologic patterns have been described, including the tubular, cribriform (Swiss-cheese), and the solid forms, and the behavior of this disease varies based on both the dominant histopathologic pattern identified and the site of origin. Tumors of breast, skin, and airway appear less aggressive than those of salivary, cervical, and vaginal origin, and those with solid morphology are more aggressive than the cribriform or tubular forms.4
Mucoepidermoid Carcinoma MEC derives from the main duct segment and is composed of basal, intermediate, and differentiated cells in varying combinations. It may also develop in non– head and neck sites, including lung, skin, breast, cervix, and thyroid. This entity is graded based on the architectural formation, cellular, and cytologic features into 3 distinct grades. Low-grade tumors are predominantly cystic with focal cellular formations, intermediate grade tumors are focally cystic with solid tumor nests that lack cellular anaplasia, and high-grade tumors are composed of solid tumor nests with cellular anaplasia and tumor necrosis. Histologic grading is of recognized prognostic importance, although most of these tumors have overlapping and mixed components.5 This not uncommonly leads to arbitrary grading.
Adenocarcinoma/Salivary Duct Carcinoma Adenocarcinoma/salivary duct carcinoma is considered a spectrum of the same entity. It is composed of purely epithelial cells and runs a more aggressive clinical course. Both phenotypes may arise de novo, or as a malignant transformation of a long-standing or recurrent pleomorphic adenoma.6 The salivary duct carcinomas bear a pathologic resemblance to mammary adenocarcinoma and share hormonal and growth factor alterations. However, the salivary adenocarcinomas present predominantly in older males and in later stages.
Recent work has focused on the identification and characterization of the molecular and hormonal profiles of these tumors, with the hope that this will lead to more targeted therapeutic approaches. Reports of the rates of overexpression of hormonal receptors and molecular markers, including the epidermal growth factor receptor (EGFR), HER2, and c-kit, have varied according to the published series, staining method, and histology as noted in Table 2. Several of the more important markers are discussed later in the text.
C-kit Kit is a transmembrane cell surface receptor encoded by the c-kit gene. This gene is associated with the regulation of cell migration, differentiation, and proliferation. Of the numerous biomarkers investigated in ACC, overexpression of c-kit was consistently reported in 90%. However, mutations in the c-kit gene have not been consistently identified in ACC.7 Although it remains a potential target, further efforts to define its biological role in ACC are needed. Recently, the restricted expression of this gene in the epithelial cells rather than in the myoepithelium has been emphasized and may impact triaging patients for kit-directed therapy.8
Epidermal Growth Factor Receptor The incidence of EGFR overexpression in ACC has varied from 0% to 37%.8,9 Although activated mutations and amplification have been identified and linked to therapeutic response in other solid tumors, no mutations and/or amplifications have been detected in ACC.9 As such, the role of EGFR as a therapeutically relevant marker in ACC remains uncertain. In salivary adenocarcinoma, however, EGFR overexpression has been reported, and in some of these tumors, an associated EGFR mutation has been found.10 This suggests a potential role for anti-EGFR therapy in the treatment of this subset of patients.
Her2 In contrast to EGFR, HER2 expression in ACC is rare, and the effectiveness of anti-Her2 treatment of patients with this cancer is likely limited. As in mammary carcinoma, however, HER2 is overexpressed in approximately 25% of adenocarcinoma/salivary duct carcinomas.10 The frequent overexpression of EGFR and HER2 in salivary gland carcinomas provides the rationale for clinical trials of agents directed against these targets.9,11 MEC shares phenotypic features with ade-
Table 2 Hormonal and Molecular Markers in Common Salivary Gland Cancers Histopathology
EGFR
HER2
C-kit
VEGF
Androgen
Mucoepidermoid Adenoca/salivary duct carcinoma Adenoid cystic
40% 30%-40% 20%
25%-35% 20%-30% Rare
Rare Rare 80%-90%
50% 65% 85%
Rare 15%-40% Rare
EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor.
Salivary gland cancers: biology and management nocarcinoma, including frequent expression of EGFR and HER2.
PI3K-AKT-Mammalian Target of Rapamycin Pathway The PI3K axis plays a critical role in tumorigenesis. Although the dysregulation of this pathway is complex, it involves alterations of AKT, PTEN, the mammalian target of rapamycin, and several known upstream tumor-associated growth factors, including EGFR, HER2, Platelet derived growth factor (PDGF), and Vascular endothelial growth factor (VEGF).12 The availability of small molecule inhibitors for different components of this pathway renders it an attractive therapeutic target. The recent finding that activation of the mammalian target of rapamycin pathway in Adenomatous polyposis coli (APC)/PTEN transgenic mice resulted in the formation of acinar salivary gland malignancy, and that treatment with rapamycin produced tumor regression suggests the possibility of a similar approach in human salivary carcinomas.13
Androgen Receptor Androgen receptor expression has been reported in a high percentage of salivary duct carcinomas and can serve as a pathologic marker for this disease.14 Similar to the use of antiestrogen therapy in estrogen-receptor–positive breast cancer, the identification of androgen receptors in salivary duct carcinoma suggests a potential role for antiandrogen therapy. Anecdotal success has been reported.15
Genomic Rearrangements Although reciprocal chromosomal translocations are uncommon in solid tumor malignancies, this alteration has been identified in 2 of the more frequent salivary carcinomas. Because of the critical role of gene fusion in tumor evolution and biology, efforts are underway to determine their implications in this disease. In ACC, Persson et al have described a tumorspecific translocation, t(6;9) (q22-23; p23-24), in 6 patients.16 This translocation fuses the MYB oncogene to the transcription factor gene NFIB leading to the potential activation of MYB targets, which include genes associated with apoptosis, cell cycle control, and cell growth. This observation has potential diagnostic and therapeutic implications.17 Similarly, characterization of the t(11;19) and the associated CTRC/MAML2 fusion gene in MEC of salivary gland and other sites supports the importance of this alteration in disease development.18 Tumors with this fusion gene are generally less aggressive than those lacking this fusion.19 Therapeutic strategies aimed at aberrant transcriptional pathways in fusion carrying tumors are attractive. Thus, however, transcriptional factors and chimeric fusion proteins have been difficult to target with small molecule inhibitors because of their protein/protein and protein/Deoxyribonucleic acid (DNA) interaction. Alternatively, approaches that target downstream effectors of these fusion proteins may prove successful, as reported in other solid tumors. Future concerted efforts to conduct deep sequencing of these tumors and to
247 integrate these data with other genomic information may lead to the development of functionally annotated molecular therapeutic targets for the treatment of patients with these tumors.
Patient Evaluation Tumors of the parotid gland usually present as a painless swelling. The presence of facial nerve paresis or paralysis, pain, fixation of the mass to the overlying skin or underlying structures, and associated cervical adenopathy usually indicate the presence of local or regional extension of a malignancy. The diagnosis of parotid malignancy should not await the development of these signs and symptoms, however, and the possibility of malignancy should be ruled out in patients presenting with any mass in the parotid gland. This will usually require cytologic or histologic evaluation with a fine needle aspiration biopsy (FNAB) or parotidectomy, respectively. Tumors of the submandibular gland are relatively uncommon and usually present as a painless, mobile mass in the submandibular triangle. Involvement of the overlying skin or fixation to the mandible often indicates local extension of a malignant tumor. Ipsilateral weakness or numbness of the tongue indicates perineural spread of malignancy along the hypoglossal or lingual nerves, respectively. Weakness of the marginal mandibular branch of the facial nerve would also suggest perineural extension. Tumors arising from the minor salivary glands are usually malignant. Their clinical presentation depends on the site of origin, most commonly the palate, parapharyngeal space, and lacrimal gland.
Fine Needle Aspiration Biopsy FNAB has been widely recognized and well established as an accurate technique in the diagnosis of salivary gland masses.20 Numerous studies have reported an exceptionally high degree of sensitivity, specificity, and predictive value for FNAB. In general, diagnostic accuracy is higher for benign than for malignant salivary gland tumors. The accuracy of FNAB, however, depends greatly on the experience of the cytopathologist, and the overall volume of patients with salivary neoplasms evaluated at any given institution. The most common source of diagnostic error of FNAB is inadequate sampling. The use of ultrasound-guided FNAB may be of help in cases in which it is difficult to obtain a representative sample.
Imaging Salivary gland tumors with clinical findings suggestive of malignancy, tumors arising from the deep lobe of the parotid gland or the parapharyngeal space, and, tumors of the submandibular and minor salivary glands should be evaluated with high-resolution imaging. The goal of imaging is to provide an accurate delineation of the location and extent of the tumor, its relation to major neurovascular structures, perineural spread, skull base invasion, and intracranial extension. Imaging
248 should also provide accurate staging of the regional lymph nodes and evaluate for the presence of distant metastases in high-risk patients. Magnetic resonance imaging (MRI) is superior to computerized tomography (CT) in demonstrating the internal architecture of salivary gland tumors in a multiplanar manner and in delineating the interface between tumor and normal salivary gland. In contrast to benign tumors, which are invariably well defined, malignant tumors may exhibit irregular margins. The T1-weighted images are particularly helpful. Extension of the tumor beyond the fascial confines of the gland can be adequately seen on both CT and MRI and should raise the suspicion of malignancy. Bone destruction of the mandible or skull base is best visualized on CT, whereas bone marrow involvement is better demonstrated on MRI. Both studies can adequately evaluate the neck for metastatic adenopathy. Although parapharyngeal space masses are well visualized by both techniques, they are better delineated with MRI than CT. Patients with high-grade or locoregionally advanced cancers are at high risk of distant metastasis, and in such patients, body imaging may be warranted for complete disease staging. The use of positron emission tomography scanning or of fused positron emission tomography/CT scans in this disease is currently undergoing clinical investigation.21
Surgery The principal treatment for cancer of the salivary glands in the absence of distant hematogenous metastases is surgical resection. The goal of surgical treatment is the complete excision of the tumor, while avoiding unnecessary morbidity. Risk factors for disease recurrence after surgical resection have been reported by multiple authors and include locally advanced disease extent, incomplete surgical resection, bone invasion, named nerve involvement, positive surgical margins, nodal involvement, and unfavorable histopathologic grading.22,23 The surgical approach and the scope of resection depend on the location and extent of the tumor.24
Primary Tumor Resection Tumors located in the superficial lobe of the parotid gland will require a superficial parotidectomy. Tumors that also extend to or originate from the deep lobe will require a total parotidectomy. The facial nerve is dissected and preserved, unless it is directly infiltrated or encased by the tumor, and facial nerve monitoring is often used to minimize injury to the facial nerve during surgery. Preoperative weakness or paralysis of the facial nerve usually indicates tumor involvement, and in these instances, the main trunk or the involved nerve branches may have to be sacrificed. The nerve or its involved branches should also be sacrificed if there is intraoperative evidence of gross invasion or microscopic infiltration of the nerve by tumor, even in the presence of normal preoperative facial nerve function. This is more likely to occur with larger and higher-grade tumors, and in tumors that extend from the superficial to the deep lobe, transgressing the
D.J. Adelstein et al plane of the facial nerve. Surgical margins on both the distal and proximal nerve stumps should be confirmed because of the possibility of perineural spread for some distance from the area of the primary tumor. Achieving negative surgical margins on the proximal stump of the facial nerve may require a mastoidectomy and facial nerve dissection along its course in the temporal bone. Tumor extension outside the parotid gland may require resection of surrounding skin or masseter muscle, mastoidectomy, temporal bone resection, mandibulectomy, or resection of the contents of the infratemporal fossa. If the facial nerve is sacrificed, nerve repair may be done using either direct neurorrhaphy of the cut edges or a cable graft, depending on the length of the resected segment. Immediate rehabilitation of the paralyzed face requires diligent eye care to prevent exposure keratitis. This will involve the liberal use of artificial tears, lubricating ointment, and protection with an appropriate eye dressing and eyewear. An upper eyelid gold weight implant should be considered in patients with complete facial paralysis. This simple reanimation technique allows for prevention of dry eye symptoms and for protection of the cornea from exposure keratitis. Consideration can also be given for tarsorrhaphy or a lower eyelid shortening procedure, to provide additional corneal protection and rehabilitation of the lower eyelid. If the facial nerve is not repaired or grafted, then surgical reconstruction for static or dynamic rehabilitation of the paralyzed face may be indicated. Patients undergoing radical parotidectomy with facial nerve sacrifice often require complex reconstruction that may include local skin flaps, myocutaneous flaps, or free tissue transfer. Tumors located in the submandibular gland will require en bloc resection of the involved gland and any involved structures in the submandibular triangle, including hypoglossal or lingual nerves, digastric or mylohyoid muscles, floor of mouth, or mandible. Special attention should be given to the lingual, hypoglossal, and marginal mandibular nerves since they may be involved by perineural spread of tumor. Thickening and nodularity of these nerves may indicate perineural involvement, and in such cases, histologic confirmation by frozen section may be useful in both establishing nerve invasion and obtaining negative surgical margins. Surgical resection of cancer of the minor salivary glands depends on their site of origin and extent of the disease. In the oral cavity, this may only require wide local excision of a localized low-grade tumor. Larger and high-grade tumors may require more radical excision, including marginal or segmental mandibulectomy, and/or partial or total resection of the hard or soft palate. Salivary gland cancer involving the sinonasal tract is usually high grade and presents at an advanced stage. Surgical resection may require partial or total maxillectomy, infratemporal fossa dissection, and/or anterior craniofacial resection. The branches of the second (V2) and third (V3) divisions of the trigeminal nerve are at high risk for perineural spread of minor salivary gland malignancy. These nerves may provide an avenue for early skull base invasion.
Salivary gland cancers: biology and management
249
Resection of the cranial base may be required in some cases to eradicate the tumor and obtain negative margins.
Neck Dissection Patients with clinical or radiographic evidence of lymph node metastasis will require a therapeutic comprehensive neck dissection. Even in the absence of clinical evidence of nodal involvement, the increased incidence of occult regional disease in patients with advanced primary site tumors or highgrade histology (such as undifferentiated carcinoma, highgrade mucoepidermoid, adenocarcinoma, or salivary duct carcinoma) suggests the need for an elective neck dissection. A selective (supraomohyoid) neck dissection may be used as a staging procedure in such cases. Suspicious nodes should be sent for frozen-section diagnosis, and if positive for metastatic carcinoma, a comprehensive neck dissection should then be performed.
Radiation Therapy Adjuvant Treatment For small or low-grade cancers, surgical resection alone with good margin control is adequate. Although never tested in a prospective randomized clinical trial, the use of adjuvant postoperative radiotherapy (RT) is indicated in patients who have close or positive margins, lymph node metastases, locally advanced disease, bone or nerve involvement, recurrent disease, or a combination of other adverse features, such as high nuclear grade, perineural invasion, and lymphovascular invasion. Several older retrospective series provide a limited evidence base for the use of postoperative radiotherapy in highrisk patients by demonstrating a local control advantage when compared with surgery alone (Table 3). A matchedpair analysis from Memorial Sloan-Kettering Cancer Center reported that patients with major salivary gland cancer who had stage III/IV disease, positive lymph nodes, or high-grade tumors had improved local control and, in some instances, improved survival with the addition of adjuvant radiotherapy. However, patients with low-grade or early-stage (I/II) disease did not appear to benefit.25 Other studies, including a large review by the Dutch Head and Neck Oncology Coop-
erative Group, confirmed this improvement in local control with the addition of adjuvant RT.26-29 Contemporary series also report excellent results with a combined approach. A recent review of 50 patients with parotid gland cancer treated in the United Kingdom demonstrated excellent local control (96%) with conservative facial nerve–sparing surgery and postoperative RT.30 Benefit has also been suggested in patients with submandibular gland and minor salivary gland cancers.28,31,32
Definitive Radiation in Unresectable Disease Radiotherapy also has an important role in the management of locally advanced, unresectable, or recurrent salivary gland cancer when surgery is not feasible. Although radiotherapy can be very effective in achieving tumor shrinkage and symptomatic palliation, curative nonoperative approaches have been challenging. Several methods of radiation enhancement have been investigated to improve tumor control rates. Fast neutron therapy was studied as a promising method of radiation enhancement given its higher relative biological effectiveness compared with traditional photon or electron beam therapy. A phase III study demonstrated that neutron therapy did improve local control compared with photon (with or without electron beam) therapy (56% vs 17%; P ⫽ 0.009). However, distant metastases and overall survival were inferior in the neutron arm, and severe late side effects were noted in long-term survivors.33 Other single institution experiences confirmed similar findings. With the limited number of neutron capable facilities, as well as the higher incidence of late side effects, neutron therapy has fallen out of favor. Other methods of radiation enhancement or of increasing the radiation dose have included carbon ion therapy,34 altered fractionation schedule,35 hyperthermia,36 proton beam radiation,37 and brachytherapy.
Target Volumes and Radiation Dose In the postoperative setting, the tumor and involved lymph node bed constitute the primary target volume and are generally treated to 60 Gray (Gy) in 30 fractions. Preoperative imaging and examination findings should guide radiation field design to ensure that all areas originally involved with
Table 3 Selected Retrospective Nonrandomized Comparisons of Surgery Alone and Surgery With Postoperative Radiotherapy (RT) in Salivary Gland Cancer Author Armstrong et al25 Stage I/II Stage III/IV Node positive High grade North et al26 Bissett28 Chen et al29 aCause-specific
survival.
Number of Patients
Local Control: Surgery
Local Control: Surgery/RT
Overall Survival: Surgery
Overall Survival: Surgery/RT
92
66% 79% 17% 40% 44% 74% 30% 61%
78% 91% 51% 69% 63% 96% 69% 84%
55% 96% 10% 19% 28% 59% 60%a 60%
69% 82% 51% 49% 57% 75% 65%a 65%
69 84 140
250 disease are targeted. For patients with parotid tumors who undergo a superficial parotidectomy, the deep lobe of the gland should be included in the clinical target volume. For those with deep lobe involvement, the parapharyngeal space and infratemporal fossa should be targeted. Patients with close (⬍1 mm) or positive margins or extracapsular nodal extension are either treated with an additional boost of 6 Gy to those areas of highest recurrence risk or with a simultaneous-integrated boost using intensity-modulated radiotherapy. Alternatively, a single large dose of intraoperative radiation (10-20 Gy) directed at areas of expected close or positive margins, or extracapsular extension can be safely combined with fractionated external beam radiotherapy to improve local control.38 In the definitive nonoperative setting, treatment volumes follow similar principles, but the total dose used may be ⱖ70 Gy. Ipsilateral cervical lymph nodes are routinely targeted when involved. For patients without clinical or pathologic lymph node involvement, elective nodal irradiation to a dose of 50-54 Gy is usually reserved for patients with larger or higher-grade tumors. A review of 474 such patients demonstrated that tumors ⬎4 cm and high-grade tumors had significantly higher risks of occult lymph node metastases than those with smaller and low-grade disease.39 Although carcinoma of the parotid gland most frequently involves periparotid and level II lymph nodes, skip metastases to levels III and IV have been observed, and these nodal stations should be routinely targeted when treating the neck. Level Ib nodes should be included when level IIa is involved, and level V nodes should be targeted when levels IIb, IIIb or IVb are involved. When treating submandibular gland cancers postoperatively, levels I-III are at highest risk and are targeted electively when indicated. Minor salivary gland cancers can often be midline and may necessitate bilateral lymph node irradiation. Treatment of the contralateral neck should also be considered for patients who have multiple ipsilateral lymph nodes involved. Histology is another important factor to consider during radiation planning. ACC rarely metastasizes to lymph nodes but frequently spreads along cranial nerves. Consequently, although elective nodal irradiation is not necessary for these patients, particular attention must be paid to ensuring coverage of involved nerves up to their exit point from the brainstem at the base of skull.40 Conversely, undifferentiated carcinomas of the salivary glands are highly malignant, exhibit frequent lymphatic metastases, and should be treated accordingly.
Systemic Treatments Chemotherapy The use of systemic chemotherapy in advanced salivary gland cancer has, in general, been confined to those patients with advanced and incurable disease. Meaningful exploration of this treatment modality has been hampered by the diversity of histologic subtypes and the disease infrequency. The published literature contains several small patient series, report-
D.J. Adelstein et al ing results from clinical trials using a number of different chemotherapeutic agents; often in mixed populations, including patients with many different histologic subtypes. Cisplatin and cisplatin-based regimens have been most frequently explored, but the response rates have been modest, and the impact, if any, on survival has been impossible to discern. Several recent reviews have summarized these data.41-45 Many of the reported series include large number of patients with ACC, reflecting the long natural history of this disease, even when metastatic. It is this long, indolent natural history, however, that makes such patients less likely to exhibit an objective disease response, and makes any interpretation of the experience after chemotherapy difficult. Disease stability after a short course of chemotherapy in patients with such an indolent disease would be expected, and likely has little meaning. In addition, most reported series were published ⬎20 years ago. Several of the more recent studies are of interest. The first was a phase II trial of single-agent paclitaxel, conducted by the Eastern Cooperative Oncology Group in 45 patients with advanced, MEC, adenocarcinoma, or ACC of the salivary gland.46 Eight partial responses were observed among the 31 patients with MEC or adenocarcinoma, but no responses were identified in the 14 patients with ACC. Notably, the median survival for the entire group was 12.5 months, with a 3-year projected survival of 11% for the MEC patients and 20% for the adenocarcinoma patients. The 3-year projected survival for the 14 adenoid cystic patients was 43%, however, despite their lack of responsiveness to the chemotherapeutic agent. Similarly, a phase II trial of singleagent gemcitabine reported no responses among 21 patients with advanced ACC, despite disease stability for at least 6 months in 48%.47 A more recent report from the National Cancer Institute of Canada assessed the use of gemcitabine in combination with either cisplatin or carboplatin in 33 patients with advanced salivary gland cancer. Two of the 10 patients (20%) with ACC experienced an objective response to treatment, as did 6 of the 23 patients (26%) with other histologic diagnoses (mostly adenocarcinomas).48 Similar to most other chemotherapy trials, the response rates were modest, and the regimen did not meet the predefined criteria for antitumor activity. Concurrent chemotherapy and radiation have achieved notable success in the more common squamous cell head and neck cancers. There has been only limited exploration of this approach in the salivary gland cancers, again because of their infrequency. Small single-arm trials have been reported detailing the use of chemotherapy and concurrent radiation after primary surgical resection in high-risk patients,49 after surgical resection for recurrence,50 and in inoperable patients.51 Concurrent chemoradiotherapy has also been used before planned surgical resection in a 17-patient prospective trial.52 All of these reports demonstrated significant activity of concurrent chemoradiotherapy suggesting possible benefit from this approach. The Radiation Therapy Oncology Group (RTOG) has recently opened a prospective phase II randomized trial (RTOG 1008) comparing radiation and concurrent cisplatin with radiation therapy alone in high-risk patients
Salivary gland cancers: biology and management
251
Table 4 Phase II Trials of Targeted Therapy for Salivary Gland Cancer Author al53
Haddad et Glisson et al54 Hotte et al7 Pfeffer et al55 Agulnik et al9 Locati et al56
Year
Number
Target (s)
Drug
Response Rate (%)
Stable Disease (%)
2003 2005 2005 2007 2007 2009
14 28 16 10 36 30
HER2 EGFR C-kit C-kit HER2/EGFR EGFR
Trastuzumab Gefitinib Imatinib Imatinib lapatinib Cetuximab
8% 0 0 0 0 0
Not reported 67% 60% 20% 64% 80%
EGFR, epidermal growth factor receptor.
after surgical resection, with the hope of better defining the role of concurrent chemoradiotherapy in this disease.
Molecular Targeting of Salivary Gland Malignancies Perhaps of greater interest in recent years has been the attempt to use our increasing understanding of the biology of these tumors to identify specific molecular targets that might be amenable to molecularly targeted therapies. Although potential molecular targets have been identified, the results of this approach have, in general, been disappointing (Table 4).7,9,41-44,53-56 A good example is the imatinib experience in c-kit-positive ACC. ACC is characterized by a high frequency of c-kit overexpression, and there has been an occasional case report of responsiveness to the c-kit inhibitor, imatinib. This observation led to the initiation of 2 separate trials of imatinib as treatment for patients with advanced ACC.7,55 Both of these studies were closed, however, with no evidence of tumor response and with moderate toxicity. Stable disease as the best response was frequently observed. A probable explanation for the lack of activity of this agent is that although patients with ACC overexpress c-kit, unlike patients with gastrointestinal stromal tumors, they do not commonly harbor activating c-kit mutations.7 A phase II study of lapatinib, an oral tyrosine kinase inhibitor of both EGFR and HER2, reported similar findings.9 Patients with progressive salivary gland cancer were eligible for this study only if their tumor expressed either EGFR or HER2. None of the 36 evaluable patients experienced a response to therapy, although 79% of the patients with ACC and 47% of the patients with other histologies experienced stable disease. In 36% of the evaluable patients, disease stability continued for ⬎6 months. The investigators considered this disease stability a positive result, but there has been little enthusiasm for further study of this agent. Similar trials have been conducted using the EGFR inhibitors gefitinib54 and cetuximab,56 and the anti-HER2 agent trastuzumab.53 Despite marker overexpression, there has been no meaningful or reproducible response rate demonstrated to these therapies. Discordance in the immunohistochemical evidence of marker overexpression and the rate of genetic mutations of both EGFR and HER2 has been described and may help explain these observations.57,58 In the series of patients with salivary duct carcinoma reported by Williams et al, although 70% of the tested tumors evidenced immunohistochemical EGFR overexpression, only 10% of
the tumors contained an EGFR gene mutation.58 Similarly, 26% of these tumors overexpressed HER2, but fewer than half demonstrated any HER2 gene amplification. A more sophisticated approach to identifying putative molecular targets will be required before any useful clinical application of targeted therapy will be possible.
Conclusions Salivary gland cancer is an uncommon and heterogeneous disease, with considerable variability in its natural history. Surgery with postoperative radiation for high-risk patients remains the standard of care. Systemic chemotherapy has been of only limited benefit, although an exploration of the role of concurrent chemotherapy and radiation is currently under way. Recent progress in our understanding of the molecular biology of salivary gland cancers promises the possibility that more specific targeted therapies might prove useful. The careful design and conduct of prospective clinical trials will be critical to improving our treatments for this disease.
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