Overview
Malignant salivary gland tumors are rare, accounting for <1% of all cancers and 3–5% of head and neck cancers. It encompasses a diverse group of disease entities with heterogeneous histologies and clinical behaviors. Advances in genomic and molecular pathology techniques have improved tumor characterization and expanded our understanding of tumor biology. In addition, classification of salivary gland tumors has recently been updated. In the 4th edition of the World Health Organization (WHO) Classification published in 2017, new entities have been described and added while others have been removed or collapsed into another category. Diagnostic criteria for existing lesions have also been refined and new treatment strategies have emerged. This chapter summarizes contemporary approaches and recent advances in the characterization, diagnosis, and management of malignant salivary gland tumors.
Epidemiology
Based on Surveillance, Epidemiology, and End Results (SEER) data, the current age-adjusted incidence rate of salivary gland malignancies in the United States is 1.3 new cases per 100,000. A significant increase in incidence has been reported in recent decades within the US and Europe. Peak incidence typically occurs during the sixth and seventh decades of life. Incidence rate is higher among men than women. Pediatric malignant salivary gland malignancies are extremely rare but the risk of malignancy associated with salivary gland masses is higher in children than in adults.
Salivary gland tumors most commonly arise within the parotid gland. In general, the risk of malignancy is inversely associated with the size of the gland. While 15–32% of parotid tumors are malignant, approximately 41–45% of submandibular, 70–90% of sublingual, and 50% of minor salivary gland tumors are malignant. In addition, malignant salivary gland tumors can arise from ectopic salivary tissues found within head and neck lymph nodes or bones.
Etiology
The etiology of primary salivary gland malignancies remains largely unknown. However, radiation exposure appears to be a risk factor. For example, a higher incidence of malignant salivary gland tumors has been reported in patients with a history of Hodgkin lymphoma treated with radiotherapy and in patients exposed to radiation from atomic weapons. Occupational exposures to rubber, nickel alloys, silica dust, kerosene, and hair dyes have also been suggested to play a role. Although conflicting data exists, alcohol consumption, smoking, and a diet high in processed meats have been associated with elevated risks of salivary gland malignancy. Moreover, a history of pleomorphic adenoma is associated with a risk of malignant transformation that significantly increases over time. An association between patients with a history of breast cancer and tumors of salivary gland origin has been previously reported. A recent report noted a higher incidence of salivary gland cancers in patients with BRCA mutation.
Sequencing studies have revealed that genomic alterations play an important role in the oncogenesis of salivary gland malignancies. Somatic mutations, chromosomal rearrangements, copy number aberrations, and epigenetic alterations have been identified in a variety of tumor types, including mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (ACC), salivary duct carcinoma (SDC), hyalinizing clear cell carcinoma (HCCC), carcinoma ex-pleomorphic adenoma, and acinic cell carcinoma. A new entity, mammary analog secretory carcinoma (MASC), has also been recently defined based on a key molecular alteration, t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 fusion. Although evidence on targeted therapies in salivary gland malignancies remain limited, recently discovered alterations with potential for therapeutic intervention are discussed in this chapter.
Clinical Presentation
Benign and malignant salivary gland tumors commonly present as painless, slow-growing masses. Minor salivary gland tumors may arise from the oral cavity, palate, paranasal sinuses, nasopharynx, nasal cavity, pharynx, larynx, and trachea. Features suggestive of malignancy include pain, ulceration, rapid growth, facial nerve or other cranial nerve paralysis, paresthesia, fixation to underlying structures, and cervical lymphadenopathy. However, a lack of symptoms does not exclude the possibility of malignancy. Tumors can be asymptomatic and found incidentally on imaging. In advanced tumors, skin involvement and distant metastases can develop. Clinical presentation also depends on anatomic location. For example, involvement of the parapharyngeal space by deep lobe parotid tumors or minor salivary gland tumors can present as an oropharyngeal mass, “hot potato voice”, unilateral eustachian tube obstruction, dysphagia, or obstructive sleep apnea.
Diagnosis
Diagnostic work-up should include complete history and physical examination, as well as imaging studies and biopsy. Computed tomography (CT) is readily assessible and can be used to define tumor extent, detect metastatic cervical lymphadenopathy, and assess for cortical bone involvement. In addition to contrast enhanced head and neck CT, a chest CT scan should be considered for high-grade and locally advanced tumors to exclude lung metastases. Magnetic resonance imaging (MRI) is particularly useful for assessing large tumors with deep lobe or parapharyngeal space involvement, for minor salivary gland tumors with submucosal extension, and if perineural invasion is suspected. Positron emission tomography (PET) imaging is not routinely recommended since malignant salivary neoplasms demonstrate variable 18 F fluorodeoxyglucose (FDG) uptake. As such, it cannot be used to reliably detect tumors or to distinguish malignant from benign lesions. While advanced malignancies with invasion of surrounding structures, involvement of cranial nerves, and metastatic disease can be suspected based on physical examination and/or imaging findings, pathologic diagnosis is usually required to distinguish malignant from benign conditions.
Fine needle aspiration biopsy (FNAB) is a well-established diagnostic tool in salivary gland neoplasms. In general, the diagnostic accuracy of FNAB is lower for malignant salivary gland tumors compared with benign and depends greatly on the experience of the cytopathologist. Ultrasound can be used to improve accuracy of FNAB, particularly for necrotic or cystic tumors. The lack of uniform reporting guidelines also contributes to the challenges of cytopathologic diagnosis. Recently, the Milan System for Reporting Salivary Gland Pathology was proposed with goals of facilitating standardized reporting and improving the overall effectiveness of FNAB across institutions. Six categories were defined with associated risks of malignancy. In cases where lymphoma is suspected, core biopsy can be performed, and fresh samples can be sent for flow cytometry. Open biopsies are generally not recommended due to the risks of facial nerve injury, tumor rupture, and seeding. Complete tumor excision (i.e., parotidectomy with facial nerve dissection or submandibular gland excision) can be utilized for cases where a diagnosis is uncertain. Intraoperative frozen section can be considered when an experienced pathologist is available. However, frozen section has a reported accuracy rate of 85.9% for malignant tumors and a false-negative rate of 2.6%.
Treatment
Treatment approaches for malignant salivary gland neoplasms require individualized approaches and depend on histology, tumor grade, and stage. Primary surgical resection is the standard treatment for resectable carcinomas of the major and minor salivary glands. For advanced and/or high-grade carcinomas, multimodality therapy, including radiotherapy and systemic therapies is required. Mesenchymal-derived malignancies, such as sarcomas, rarely occur in salivary glands and require a multidisciplinary approach. Lymphomas are treated nonsurgically. Metastatic disease involving the parotid gland can occur in cutaneous malignancies, including squamous cell carcinoma and malignant melanoma. While surgical resection is utilized for regional control, treatment algorithms are evolving with expanding investigation of checkpoint inhibitors and targeted therapies in both neoadjuvant and adjuvant settings.
Surgical resection of the primary tumor balances oncologic control and adequate margins with functional preservation. For carcinomas occurring within the superficial lobe of the parotid gland, the treatment of choice is superficial parotidectomy with complete tumor resection with a cuff of normal glandular tissue. Total parotidectomy is indicated for tumors involving or arising within the deep lobe. Radical parotidectomy with sacrifice of the facial nerve is indicated for infiltrative tumors involving or surrounding the facial nerve, particularly in the setting of a preoperative facial nerve paralysis. If facial nerve function is intact preoperatively, every effort should be made to preserve the facial nerve without compromising oncologic outcomes. A guiding surgical principal is to leave no gross disease behind. In the setting of malignancy if the facial nerve is encased in tumor and a plane of dissection cannot be developed to avoid leaving gross disease, the nerve should be resected. For tumors with involvement of the skin, temporal bone, mandible, masticator space, or infratemporal fossa, an extended parotidectomy with reconstruction is indicated. Tumors involving the parapharyngeal space may require a combination of approaches, including transcervical and/or transparotid approaches. Larger tumors or those with close proximity to the carotid artery may require mandibulotomy for access. Transoral approaches are rarely indicated for malignant tumors.
For malignant tumors involving the submandibular gland, excision of the entire gland with level IA and IB contents is advocated over excision of the gland alone, to achieve adequate soft tissue margins and to remove the primary echelon of lymph nodes that might harbor metastatic disease. The marginal mandibular branch of the facial nerve, lingual nerve, and hypoglossal nerve should be identified and preserved unless directly infiltrated by tumor. Sublingual gland tumors should be treated with excision of the entire gland along with the surrounding tissue for margin control. Depending on tumor extent, excision of the submandibular gland, floor of the mouth mucosa, floor of the mouth musculature, and mandible may be required. Lingual and hypoglossal nerves may be preserved if not directly involved by tumor.
Minor salivary gland tumors vary in location. In general, wide local resection with adequate margins is the treatment of choice. The oral cavity and oropharynx are the most commonly involved sites. For malignant tumors involving the palate, maxillectomy may be indicated for bony involvement or to achieve margin control. Soft palate resection can lead to velopharyngeal insufficiency and may require soft tissue or obturator reconstruction. In selected cases with limited disease, tumors involving the oropharynx, nasal cavity/paranasal sinuses, or larynx may be amendable to transoral robotic surgery, endoscopic resection, or conservative laryngeal surgery, respectively. However, advanced tumors generally require an open approach with reconstruction.
Therapeutic neck dissections are performed for cases with clinically positive nodal disease. Levels of the neck dissected depend on locations of the primary tumor and involved nodes. The indications for prophylactic neck dissection are controversial as evidence varies regarding incidence of occult nodal metastases. In general, prophylactic neck dissection for a clinically N0 neck may be advocated for high-grade tumors and locally advanced T3 or T4 disease, or when exposure of the neck is required for reconstructive purposes.
Mucoepidermoid Carcinoma
Clinical Features
MEC has been reported as the most common malignant tumor of the salivary glands in multiple large retrospective cohorts of children and adults. MEC is associated with a female preponderance with a mean age at presentation of ~45 years. The parotid gland is the most commonly involved major salivary gland, where MEC represents up to 50% of all parotid malignancies. In the minor salivary glands, MEC most commonly occurs on the palate but can be found in a variety of locations including the oral cavity, oropharynx, larynx, nasal cavity, and paranasal sinuses. MECs occurring within the mandible or maxilla, known as central MECs, are thought to arise from heterotopic salivary tissue. Although rare, this disease entity should be included in the differential diagnosis of unicystic or multicystic lesions of the mandible or maxilla. MEC is the salivary gland malignancy most frequently associated with a false-negative frozen section diagnosis. Clinical behavior of MEC ranges from indolent to rapid growth with metastatic spread. Prognosis depends on stage and tumor grade. Advanced stage and high-grade tumors are associated with significantly worse survival outcomes compared with low-grade tumors.
Histology
MEC tumors are characterized by the presence of two populations of cells – the mucus cells and the epidermoid cells, the proportion of which helps to define the grade of the tumor. Low-grade MEC is characterized by prominent cystic structures and mature cellular elements. This tumor contains proportionally more mucus cells, which may form gland-like structures, and fewer epidermoid cells ( Fig. 45.1 ). Intermediate-grade tumors display fewer and smaller cysts and occasional solid islands of epidermoid tumor cells. Although mucus cells are still present, there is an increasing proportion of epidermoid cells and occasional keratin pearl formation ( Fig. 45.2 ). The high-grade carcinomas are hypercellular, solid tumors with noticeable cellular atypia and frequent mitotic figures. These tumors will often be mistaken for a squamous cell carcinoma and the differentiation between the two can be quite difficult ( Fig. 45.3 ). Positive immunohistochemical staining for mucin indicates a high-grade MEC rather than a squamous cell carcinoma.
Molecular Alterations
MEC is characterized by frequent and unique translocation that may constitute an initiating event in the development of a subset of these tumors. Several cytogenetic analyses of MEC have shown translocation t(11;19) (q21;p13) either alone or with other nonspecific alterations. Cloning of this translocation has identified a fusion oncogene composed of exon 1 of the MECT1 (CRTC1/WAMTP) gene on chromosome 19p13 and exons 2–5 of the MAML2 gene on chromosome 11q21 regions. MAML2 , a member of the mastermind gene family, encodes a nuclear protein that binds to the CSL transcriptional factor and the intracellular domain of the Notch receptor to activate the Notch target gene. The fusion partner is the CRTC1 (MECT1) , a member of the highly conserved CREß/cAMP coactivator gene family. Studies of this fusion transcript in a series of MEC have reported a correlation between fusion positive tumors and low tumor grade and better behavior. CRTC1/MAML2 translocations are seen in 50–88% of MECs. Fusion-negative MEC may evolve from a different evolutionary pathway and may represent a biologically distinctive category. The results also suggest that tumors lacking the fusion transcript behave more aggressively. In addition to CRTC1/MAML2 translocations, next generation sequencing studies have also identified frequent mutations in TP53 , CDKN2A , PIK3CA , BAP1 , BRCA1/S , and POU6F2 . Compared with low-grade tumors, high-grade tumors tend to harbor more genetic alterations per tumor, as well as more frequent mutations in TP53 and PIK3CA/mTOR pathway genes.
Treatment
Complete surgical resection is the primary treatment modality for MEC. For low-grade tumors, surgical resection of the primary tumor alone is often curative. Given a high risk of occult cervical nodal metastasis, elective neck dissections are warranted for high-grade tumors in the N0 setting. In contrast, low- and intermediate-grade MEC do not require elective neck dissection in the absence of other risk factors given significantly lower risks of occult nodal disease. Postoperative radiotherapy is indicated for high-grade tumors, stage III/IV disease, extensive perineural invasion, and close or positive margins. Lymphovascular invasion, involvement of the deep lobe of the parotid, and extraglandular extension are also risk factors considered in treatment decision making. At present, systemic therapies are mainly utilized in the recurrent and/or metastatic setting for high-grade tumors. Cisplatin-based regimens are commonly used. An ongoing clinical trial, RTOG 1008, is evaluating the utility of adjuvant concurrent chemoradiation with weekly cisplatin versus radiation alone in high-risk salivary carcinomas.
Adenoid Cystic Carcinoma
Clinical Features
ACC accounts for up to one-third of all salivary gland malignancies. It is the most common malignancy affecting minor salivary glands. The most frequent location is the palate. In addition to the head and neck, ACC has been reported to occur in the secretory glands of other tissues including the breast, vulva, esophagus, and tracheobronchial tree. Most cases develop during the fifth and sixth decades of life. No consistent gender predilection has been identified. ACC generally exhibits slow growth. Paradoxically, it is also a clinically relentless malignancy characterized by an affinity for nerve invasion, recurrence, and distant metastases. Patients may present with a slow-growing mass accompanied by pain, paresthesia, and/or cranial nerve paralysis. While cervical lymph node metastases are generally uncommon, distant metastases occur in 35–50% of patients. Metastases most commonly occur in the lung, followed by bone and liver and can occur after a long period of indolent disease. Lung only metastasis is associated with significantly better prognosis compared with involvement of other organs (i.e., bone and liver). Intracranial disease is rare and usually occurs as a result of direct tumor extension or invasion along cranial nerves, rather than hematogenous spread.
Histology
ACC manifests three phenotypic subtypes, which are nearly always present in the majority of tumors but with variable proportions. These include cribriform, tubular, and the solid morphologic variants ( Figs. 45.4–45.6 ). The cribriform pattern is the most common and most easily recognizable. It is often referred to as the “Swiss cheese” pattern. Tumor cells are arranged in nests around cylindrical spaces that may contain a mucinous or hyalinized material. Cells that are arranged in layers and form ductal structures characterize the tubular pattern. The solid pattern contains sheets of tumor cells with no intervening spaces. In both the tubular and the cribriform phenotypes, the tumor units consist of myoepithelial and ductal epithelial cells. The percentages of each pattern form the basis of the grading system composed by Szanto et al. High-grade tumors are defined as those containing >30% solid component. Although controversy exists regarding the prognostic significance of the proposed staging system, presence of a solid component has been consistently associated with poor outcomes in multiple case series. In addition, perineural and intraneural invasion are common features of ACC associated with recurrence and poor prognosis. Invasion along nerves can be seen far beyond the clinically apparent boundaries of the primary tumor.
Molecular Alterations
Cytogenetic studies of ACC have reported frequent alterations at chromosomes 6p, 9p, and 17p, with the most consistent alteration at the 6q regions (1,2,3, 4). A reciprocal t (6;9) (q22–23; p23–24) translocation resulting in formation of a fusion oncogene between the myeloblastosis (MYB) and the nuclear factor 1 B-type (NFIB) transcription factor has been described in ACC (1–3). MYB is a leucine zipper transcription factor at 6q22–24 that participates in the regulation of cell proliferation, apoptosis, and differentiation. MYB-NFIB fusion results in loss of the MYB 3’-untranslated region (exon 15), which normally contains highly conserved target sequences for certain microRNAs; these target sites negatively regulate MYB expression (1). Loss of MYB repression results in overexpression of the fusion transcripts and protein, thereby inducing transcriptional activation of MYB target genes (1). MYB-NFIB fusions have been found in ~50% of ACC cases and can be detected via FISH. Additional MYB mutations and translocations have recently been identified via whole genome sequencing, thereby increasing the overall percentage of MYB alterations in ACC to ~75%. MYB translocations are the most frequent recurrent genetic alteration in ACC. In addition, whole genome and whole exome sequencing studies have revealed that ACC harbors a very low overall mutation rate of ~0.3–0.4 mutations per megabase. ACC exhibits wide mutational diversity with very few recurrent mutations. Identified recurrent mutations can be grouped into those affecting NOTCH , fibroblast growth factor (FGF) , and epigenetic pathways, particularly those involved in chromatin remodeling.
Treatment
Although the optimal treatment algorithm for ACC has not been established, the current standard for localized disease is complete surgical excision. Neck dissection is performed for clinically positive disease. While opinions vary, elective neck dissections are considered within the authors’ institution for tumors with high risk features such as high-grade, T3/T4, or extensive perineural invasion. Given the high prevalence of perineural invasion, postoperative radiotherapy is frequently utilized to improve locoregional control. Radiotherapy has also shown effectiveness in controlling unresectable disease involving the skull base. For patients with advanced unresectable disease, concurrent chemo-radiotherapy has been shown to provide durable local regional control. Systemic therapies are currently utilized for metastatic disease and are being examined for advanced disease within clinical trials. ACC is in general not a chemotherapy-sensitive disease. Single-agent treatments with cytotoxic agents generally do not generate significantly objective responses. Combinatorial chemotherapy can provide higher response rates of up to ~25% but is generally toxic and limited in response duration. Since ACC grows slowly, the timing of treatment initiation for metastatic disease is controversial. Watchful waiting is a common initial approach for patients with distant metastases. Active treatment is initiated when patients become symptomatic or develop rapidly progressive disease. Lung metastasectomy has been utilized in ACC with success and can be considered in selected patients. A number of targeted therapies have been examined in ACC. Despite findings of c-KIT overexpression in ACC, imatinib, a tyrosine kinase inhibitor targeting c-KIT, has shown very limited response in ACC, suggesting that c-KIT overexpression is not a driver event. Tyrosine kinase inhibitors targeting epidermal growth factor receptor (EGFR) overexpression do not demonstrate significant activity as single agents but might improve response rate when combined with platinum-based cytotoxic chemotherapies. Vascular endothelial growth factor (VEGF) is highly expressed in ACC and many clinical studies have been conducted with VEGF receptor inhibitors in the metastatic setting, with response rates of ~10% and most patients achieving disease stability. Recent studies have examined targeting FGF and NOTCH given findings of sequencing studies. Clinical trials examining FGF receptor inhibition have not yielded significant responses. Activating NOTCH1 mutations have been found to characterize a subgroup of ACC with solid histology, advanced disease, non-lung distant metastases, and have been associated with decreased survival. NOTCH1 inhibitors have shown promising activity in preclinical studies and within a phase I trial (NCT02784795). Single agent anti-PD1 has rendered no responses in the subgroup of metastatic ACC included in a phase II salivary gland trial. Additional clinical studies are investigating pan-NOTCH inhibitors, MDM2 inhibitors, checkpoint inhibitors combinations, and histone deacetylase inhibitors in ACC.
Acinic Cell Carcinoma
Clinical Features
Acinic cell carcinoma is the third most common salivary gland malignancy overall and the second most common salivary gland malignancy in children. Women are more frequently affected than men. The median age at diagnosis is 44 years, although all age groups are affected ranging from children to the elderly. Familial predisposition has been reported. Since acinic cell carcinomas are derived from serous acinar cells, the vast majority, over 80%, arise within the parotid gland. It can also occur within the submandibular gland and minor salivary glands. Given that the sublingual glands are mostly composed of mucinous acini, acinic cell carcinoma very rarely occurs in that location. In 3% of cases, acinic cell carcinoma can present as bilateral lesions. It typically presents as a slowly enlarging mass that is mobile and well-circumscribed. Pain can occur as a presenting symptom in a proportion of patients. Although acinic cell carcinoma is generally considered as a low-grade malignancy, recent studies suggest that a subset of tumors are associated with poor prognosis. Cervical lymph node metastases and distant metastases can occur, typically involving the lungs. In addition, acinic cell carcinoma is associated with a rate of locoregional recurrence of ~35% and recurrences can occur many years after initial diagnosis. Dedifferentiation within a low-grade tumor to a high-grade malignancy has also been reported and is associated with decreased survival. Presence of distant metastases is associated with poor prognosis.
Histology
Four main subtypes are described microscopically: solid, microcystic, papillocystic, and follicular. As with many other tumors, the different patterns and cell types may coexist in variable proportions within one tumor. The cells of the solid variant ( Fig. 45.7 ) closely mimic normal acinar cells with abundant basophilic cytoplasm containing fine vacuoles with or without intracytoplasmic granules, and small, eccentric nuclei. The granules will be periodic acid Schiff (PAS) positive, diastase resistant. The other three patterns contain low cuboidal cells with eosinophilic cytoplasm and occasional cytoplasmic vacuoles reminiscent of intercalated duct cells ( Figs. 45.8 , 45.9 ). The vacuoles will be mucicarmine-negative. Acinic cell carcinomas are generally low-grade indolent carcinomas, occasionally presenting as high-grade carcinomas with high mitotic figures, necrosis, and lymph node metastasis ( Fig. 45.10 ).
Molecular Alterations
Structural alterations and loss of heterozygosity have been reported in acinic cell carcinomas. Loss of heterozygosity has been identified on chromosomes 4p, 5q, 6p, and 17p. In addition, targeted next generation sequencing revealed alterations in PTEN , BRAF , FBXW7 , ATM , and NF1 . Similar to other low-grade salivary gland malignancies, the overall mutation burden in acinic cell carcinoma is low. However, no consistent translocations and fusion oncogenes have been identified. Before its recognition as a distinct disease entity, a proportion of secretory carcinomas (previous MASC) were categorized as acinic cell carcinoma due to their morphologic overlap. In contrast to secretory carcinoma, which harbors ETV6 translocations, acinic cell carcinoma is characterized by intact ETV6 .
Treatment
Low-grade acinic cell carcinoma can be treated with surgical resection alone. Therapeutic neck dissections are performed in patients with clinically apparent cervical lymph node involvement. Adjuvant radiotherapy is indicated for advanced tumors, lymph node involvement, positive margins, and high-grade or undifferentiated tumors. Deep lobe involvement and extraparotid extension are also considered. Inoperable tumors, incompletely excised tumors, and recurrent tumors also require radiotherapy. Management of advanced metastatic acinic cell carcinoma remains challenging due to limited data. No specific chemotherapy regimen has been identified as the treatment of choice and management is largely based on anecdotal experience. Platinum-based chemotherapy regimens are the mostly commonly used.
Carcinoma Ex-Pleomorphic Adenoma
Clinical Features
Carcinoma ex-pleomorphic adenoma (Ca-ex-PA) is defined as a carcinoma arising from a primary or recurrent benign pleomorphic adenoma (PA). It constitutes ~12% of all malignant salivary gland tumors. The prevalence of Ca-ex-PA transformation from PA reported in the literature ranges from 1.5% to 13.8%. Malignant transformation from PA is rare and occurs most frequently in patients with longstanding tumors. The risk of malignant transformation in PA is 1.5% within the first 5 years of diagnosis, but increases to ~10% after 15 years. Malignant forms of PA include Ca-ex-PA, carcinosarcoma, metastasizing PA, and high-grade sarcoma ex-PA, with Ca-ex-PA being the most common. Carcinoma ex-PA can present as an asymptomatic mass similar to PA. It can also present as rapid growth in the setting of a known PA and/or new onset of pain, facial nerve paralysis, skin ulceration or fixation, or lymphadenopathy. Patients may also have a history of prior surgeries for PA. Patients typically present in the sixth and seventh decades of life, which is significantly later than the average age of onset for PA. No gender predilection has been reported. The parotid is the most commonly involved salivary gland. The prognosis of Ca-ex-PA depends on stage, histologic grade, and degree of invasion. Patients with minimally invasive tumors have an excellent prognosis. Patients with invasive tumors have a worse prognosis, with distant metastases reported in 60–70% of patients.
Histology
The histopathologic features of Ca-ex-PA typically includes both benign PA and malignant components. The malignant component may show different carcinoma subtypes, of which adenocarcinoma not otherwise specified (NOS) is the most common. Almost all other malignant varieties of salivary gland tumors have been described (i.e., SDC, MEC, ACC, squamous cell carcinoma, myoepithelial carcinoma, and epithelial myoepithelial carcinoma). A mixture of subtypes can be seen within the malignant component ( Figs. 45.11 , 45.12 ). In some tumors, the original benign PA components are difficult to detect. In such cases, Ca-ex-PA is based on prior biopsy or clinicopathologic correlation. Ca-ex-PA is further classified based on the extent of invasion of the carcinoma component beyond the fibrous capsule and can be subdivided into noninvasive, minimally invasive (<1.5 mm beyond the capsule), and invasive (>1.5 mm beyond the capsule). Tumor grade is determined and scored according to the grade of the malignant component. An infiltrative and destructive growth pattern is common. Nuclear hyperchromasia, pleomorphism, necrosis, and mitoses are frequent. Low-grade tumors may demonstrate minimal atypia and harbor better prognosis.
