Salivary Gland

Abstract

The major and minor salivary glands are the sites of numerous inflammatory and neoplastic processes. Molecular advances and the expanding body of literature have led to the reclassification and addition of new entities which will be discussed in this chapter. While ancillary studies are helpful, many of the tumors in this category rely on histomorphologic features for the diagnosis. The biphasic nature of salivary gland tumors are a source of many overlapping morphologies and immunoprofiles. This chapter will focus on the differential diagnosis and distinguishing features to aid in the diagnosis of salivary gland tumors.

List of Frequently Asked Questions

• 1. What are the basic histologic components of the salivary gland and how are they characterized?

• 2. How has the terminology of salivary gland lesions changed and what are the newest entities described in this group?

• 3. What are some of the unusual morphologic changes that are seen in pleomorphic adenomas and what is their significance?

• 4. What is the biologic behavior of “benign” metastasizing pleomorphic adenoma and are there any risk factors for its development?

• 5. What are the malignant forms of pleomorphic adenoma and how are they diagnosed?

• 6. What are the grading systems for mucoepidermoid carcinoma and their correlation with clinical outcomes?

• 7. What are the three types of adenoid cystic carcinoma and how do they relate to tumor grade?

• 8. What are the histologic features of acinic cell carcinoma?

• 9. What is mammary analogue secretory carcinoma and how is it characterized?

• 10. What are clues to the diagnosis of polymorphous adenocarcinoma (polymorphous low-grade adenocarcinoma) and which entities are in the differential diagnosis?

• 11. What are the morphologic subtypes of basal cell adenomas, their clinical relevance, and differential diagnosis?

• 12. What are the criteria used to diagnose myoepithelial tumors, their subtypes, and the differential diagnoses?

• 13. What is the differential diagnosis of oncocytic lesions of salivary gland?

• 14. What is the differential diagnosis of clear cell tumors of the salivary gland?

• 15. What are the different ductal carcinomas and how are they distinguished?

• 16. Are there specific histologic features for the diagnosis of adenocarcinoma, not otherwise specified?

• 17. What is high-grade transformation, how is it different from dedifferentiation, and which salivary gland tumors can undergo such changes?

• 18. What are the principal papillary tumors of the salivary gland and their differential diagnosis?

• 19. Does primary squamous cell carcinoma of salivary gland exist and how is it diagnosed?

• 20. What are the common metastases to salivary gland?

• 21. Which primary tumors of salivary gland are identical to their counterparts at other sites?

• 22. Which clinicopathologic features predict behavior in salivary gland carcinomas and how does tumor type relate to behavior?

• 23. What is the distribution of salivary gland tumors in the minor salivary glands?

• 24. What are the most common salivary gland tumors in children?

• 25. What are the most common benign mesenchymal tumors of salivary gland and their characteristics?

• 26. What are the most common primary malignant mesenchymal tumors of salivary gland?

• 27. What is the differential diagnosis of benign cystic lesions of the salivary gland?

• 28. What are the major inflammatory lesions of the salivary gland?

• 29. What are the common lymphomas of salivary gland?

• 30. Which nonneoplastic lesion of salivary gland may represent a premalignant process?

• 1. What are the basic histologic components of the salivary gland, and how are they characterized?

  Many salivary gland (SG) tumors are biphasic, composed of at least two cell types, ductal and myoepithelial cells. An understanding of how the different components of normal salivary gland express various immunohistochemical markers will help inform the pathologist of a specific tumor type and aid in the correct diagnosis. Not all of the markers expressed in normal tissue are present in its neoplastic counterpart. In addition, among the normal SG components, there are different types of ducts, acini, and supporting cells including serous and mucinous acini, intercalated ducts, striated ducts, excretory ducts, and two types of supporting cells (myoepithelial and basal cells). Figure 5.1 depicts the normal acinar-ductal unit. Table 5.1 shows the immunohistochemical profile of the different components and their variations.

  Reference: [1]

• 2. How has the terminology of salivary gland tumors changed and what are the newest entities described in this group?

  A handful of old and new tumors were either reclassified or added to the 4th edition of the World Health Organization (WHO) Classification of Head and Neck Tumors published in 2017. Some novel entities have been excluded, pending further studies, but are worthy of discussion here (Table 5.2). The questions that follow in this chapter will use the newer terminology and include older terms for clarification, when needed.

  References: [2, 3]

• 3. What are some of the unusual morphologic changes that are seen in pleomorphic adenomas and what is their significance?

  Conventional pleomorphic adenomas have an admixture of myoepithelial and ductal cells with varying amounts of chondromyxoid stroma. Metaplastic changes can display both epithelial and stromal differentiation.

  • The most well-described epithelial change in PA is squamous metaplasia. The squamous cells show abundant, eosinophilic cytoplasm, and bland nuclear features, with or without keratin pearl formation (Fig. 5.2).

  • Cystic change within the ducts and associated keratin is referred to as adnexal-like differentiation.

  • On small biopsy material, mucoepidermoid carcinoma (MEC) enters the differential diagnosis. However, keratinization is not a feature of MEC and is rarely seen, even in its high-grade form.

  Most stromal metaplasias seen in PA are due to the pluripotent differentiation of the myoepithelial cell.

  • Fatty metaplasia is not an uncommon finding, and it usually comprises less than 20% of the tumor but may be as much as 80%. It is seen almost exclusively in the major salivary glands.

  • Ultrastructural studies show myoepithelial cells with abundant intracellular lipid. Consequently, these fatty areas express cytokeratins and myoepithelial markers.

    • Sebaceous metaplasia is commonly seen alongside fatty metaplasia.

  • Other mesenchymal changes include bony metaplasia and schwannian change.

    • Such areas will demonstrate myoepithelial differentiation by immunohistochemistry.

  Various case series and reports have described intravascular tumor in pleomorphic adenomas.

  • Epithelium and stroma can be seen in small, thin-walled vessels and large, muscular vessels. The proposed mechanism is artifactual tumor spillage into the vasculature as a result of biopsy or surgical manipulation.

  • None of the reported cases have been associated with tumor metastasis or aggressive behavior. The phenomenon is observed most commonly in major salivary glands and is characterized by:

    • An absence of platelet meshwork

    • Involvement of vessels at the tumor periphery

    • Involvement of more than one vessel

  References: [4,5,6,7,8,9,10,11,12,13]

• 4. What is the biologic behavior of “benign” metastasizing pleomorphic adenoma and are there any risk factors for its development?

  • Metastasizing pleomorphic adenoma (MPA) is a rare entity with less than 100 cases reported in the English literature.

  • The old terminology of benign metastasizing PA has fallen out of favor, as estimated mortality rates are 20% and disease-free survival approaches 50%.

  • The latency period between diagnosis and metastasis averages 15 years (range: 3–51 years).

  • Knight et al. reported metastases most commonly in the bone (37%), lung (34%), and cervical lymph nodes (20%). There are also reports of MPA to the kidney, skin, and brain.

  • There are no definitive histopathologic features to distinguish MPA from conventional PA (Fig. 5.3). The morphology of the metastases is identical to the primary tumor and shows no cytologic atypia or malignant transformation. A few factors are associated with increased risk:

    • Repeated surgical manipulation – up to 80% are associated with at least one, though typically multiple, recurrences at the primary site. Recurrent tumors may show multiple nodules (Fig. 5.4).

    • Metastasis occurs only after resection of the primary tumor, raising the possibility of tumor spillage into the vasculature as a possible mechanism.

  References: [14,15,16,17,18,19]

• 5. What are the malignant forms of pleomorphic adenoma and how are they diagnosed?

  Up to 15% of untreated PA will undergo malignant transformation. The malignant forms of PA are carcinoma ex pleomorphic adenoma (CEXPA) and carcinosarcoma. CEXPA is a rare tumor primarily seen in the parotid gland with a minority of cases presenting in the submandibular gland and the palate. Patients present with rapid growth of a long-standing, preexisting mass. Regardless of histologic subtype, CEXPA is a high-grade tumor.

  • The type of carcinoma which arises in a CEXPA should always be specified and usually takes the form of adenocarcinoma, not otherwise specified (NOS) or salivary duct carcinoma (SDC).

  • Evidence of PA must be present either by histologic evaluation or clinical documentation of a previous PA at the same site. Extensive hyalinization or fibrosis in the tumor only suggests a previous PA (Fig. 5.5).

  • CEXPA is broadly divided into three categories: intracapsular, minimally invasive, and widely invasive.

    • Intracapsular carcinoma exhibits overt, cytologically malignant features (i.e., atypical mitoses, pleomorphism, necrosis) within the capsule of the PA. It can look like anything from ductal carcinoma in situ to an infiltrative carcinoma.

      • Random atypia or areas that resemble cytologically low-grade carcinomas (e.g., mucoepidermoid or adenoid cystic carcinoma) are not sufficient for a diagnosis of intracapsular carcinoma.

    • Minimally invasive CEXPA shows invasion of the PA capsule. By definition, the distance of invasion beyond the capsule must be less than 1.5 mm.

    • Widely invasive CEXPA shows invasion ≥1.5 mm beyond the PA border with an associated mortality rate of 35–65%.

  • Tumors with less than 1.5 mm of invasion show few or no recurrences, no distant metastases or tumor-associated deaths. Several studies that proposed a cutoff of 4–6 mm show similar outcomes.

  • The proportion of carcinoma, type of carcinoma, tumor size, grade, and extent of invasion all have prognostic significance and should be reported.

  Carcinosarcoma is a biphasic tumor composed of malignant epithelial and mesenchymal components. It may arise de novo or from a preexisting PA (up to 30%). They account for less than 1% of all SG malignancies with less than 100 reported cases.

  • Over 70% occur in the parotid gland; minor SG sites include palate and tongue.

  • There is a male predominance and mean age at diagnosis is in the sixth decade.

  • The carcinomatous component is usually a poorly differentiated adenocarcinoma, NOS or SDC.

  • The sarcomatous portion is usually a high-grade chondrosarcoma. Osteosarcoma, fibrosarcoma, and unspecified spindle sarcoma are also seen.

  • Carcinosarcomas have a poor prognosis with distant metastases and subsequent death in 60% of patients.

  • Histologic grade and distance of invasion beyond the capsule of a preexisting PA strongly correlate with clinical behavior.

  References: [13, 19,20,21,22,23,24,25,26,27]

• 6. What are the grading systems for mucoepidermoid carcinoma and their correlation with clinical outcomes? Are there any independent histopathologic features that correlate with clinical outcomes?

  • Mucoepidermoid carcinoma (MEC) is the most common malignancy of the salivary glands in adults and children.

  • MEC is characterized by a variably solid and cystic tumor with three cell types (Fig. 5.6):

    • Intermediate cell: most common cell type ranges from a small basaloid cell to a large cell with a moderate amount of eosinophilic cytoplasm, small, dark to slightly vesicular nucleus.

    • Squamous/epidermoid cell: large, polygonal cell with abundant eosinophilic cytoplasm scattered singly and in small nests.

    • Mucous cells: large cell with clear, mucinous cytoplasm and eccentric, dark nucleus.

  • Grading of MEC relies on several histomorphologic features. There are three popular grading systems, all with a three-tiered approach (Table 5.3).

    • Despite this lack of standardization, tumor grade significantly correlates with survival in each system, and it is an important determinant of therapy.

    • High-grade tumors are usually treated with surgery, radiation, and neck dissection.

    • The Brandwein system tends to bundle low and intermediate tumors together and upgrades individual tumors. The AFIP system does the opposite, generally downgrading tumors and bundling intermediate and high-grade tumors.

    • 70–80% of MEC will be low or intermediate grade (LG, IG).

    • Population-based studies show no statistically significant difference in overall or disease-free survival between LG and IG tumors.

  • Regardless of the grading system, a high tumor grade is an independent predictor of decreased survival. Other independent predictors of a worse prognosis include:

    • Advanced age

    • Tumor size

    • Positive lymph node metastases

    • Positive surgical margins

  • 40–80% of LG and IG MECs are positive for the fusion product between the Mastermind-like 2 gene (MAML2) and the CREB-regulated transcription coactivator gene (CRTC), resulting in the t(11; 19)(q21; p13) translocation.

    • Several smaller studies have shown that the (MAML2) gene rearrangement partnered with either CRTC1(MECT1) or CRTC3 conveys a favorable prognosis.

    • The specificity of the MAML2 rearrangements approaches 100% for MEC and may aid in the diagnosis of high-grade tumors.

  References: [28,29,30,31,32,33,34,35,36,38]

• 7. What are the three types of adenoid cystic carcinoma and how do they relate to tumor grade?

  • Adenoid cystic carcinoma (AdCC) has a classic biphasic cellular composition of myoepithelial cells and ductal cells.

    • The predominant cells are small, uniform myoepithelial cells with scant, pale cytoplasm and bland, hyperchromatic, round to angulated nuclei. Ductal cells are low, cuboidal with regular, round nuclei, and a more dispersed chromatin.

    • Perineural invasion (PNI) is frequent.

  • AdCC has three growth patterns (in order of frequency):

    • 1.  Cribriform: nests of basaloid cells with sieve-like, punched out spaces containing pale, basophilic glycosaminoglycans or eosinophilic basement membrane material. Small ducts are scattered throughout the stroma and within the basaloid nests (Fig. 5.7).

    • 2.  Tubular: small duct proliferation with surrounding myoepithelial cells and dense, hyaline stroma.

    • 3.  Solid: large, solid nests and lobules of basaloid cells with minimal stroma. Nuclei are slightly larger than other types and more vesicular.

  • Histologic grading is based on type:

    • Low-grade: tubular, no solid component

    • Intermediate grade: cribriform (with or without minor solid component)

    • High-grade: at least 30% solid type

      • A higher percentage of solid type correlates with worse prognosis.

      • Some authors contend that any amount of a solid component will impact prognosis. As a result, this feature should be reported in clinical cases.

  • The MYB-NIFB translocation (t(6;9)) is present in approximately 30% of cases but has no impact on behavior.

    • Eighty percent of AdCC (including fusion negative cases) will express MYB by immunohistochemistry (IHC).

  • AdCC is a locally aggressive tumor characterized by a protracted clinical course of recurrences, late metastases, and death. Regardless of grade, most patients are treated with radiation therapy for local control. Lymph node metastases are seen in about 20% of patients. While 5-year survival rates approach 80%, 15-year survival rates are less than 20%.

  References: [39,40,41,42,43,44]

• 8. What are the histologic features of acinic cell carcinoma?

  Acinic cell carcinoma (AcCC) represents approximately 10% of all salivary gland carcinomas. It most commonly occurs in the parotid gland (85–90%) with a slight female predominance. AcCC is grossly well-circumscribed, non-infiltrative and may be lobulated.

  • Morphologic subtypes include solid, microcystic/cystic, follicular, and papillo-cystic (Fig. 5.8). None of the morphologic variants correlate with clinical behavior.

  • The non-acinar cells in AcCC are of intercalated duct origin and seen in the papillary, microcystic, and follicular types. These subtypes generally express CK7.

    • The cells have a moderate amount of eosinophilic cytoplasm with variably sized, intracytoplasmic vacuoles that may coalesce to form lumina (Fig. 5.9a).

    • Cells show minimal atypia and may form sheets with small cystic spaces or large, thyroid-like, follicular spaces.

    • The eosinophilic, luminal material reacts with PAS and may show weak mucicarmine staining.

  • The solid type comprises sheets of acinar cells with granular, basophilic cytoplasm and intracytoplasmic, zymogen granules. Nuclei range from small, dark, dot-like to round with fine chromatin and conspicuous nucleoli (Fig. 5.9b). This subtype generally lacks duct differentiation and is negative for CK7.

  • Cells may have a hobnail-type appearance; this should not be mistaken for apocrine-type, apical snouting.

  • Strong cytoplasmic and canalicular staining for DOG-1 is a characteristic.

  • AcCC is sometimes associated with a prominent lymphoid stroma.

  • A small subset of cases occurs in minor salivary glands (5%), mainly the lip and buccal mucosa. Many of these, as well as zymogen granule-poor types, harbor the ETV6-NTRK3 translocation and have been reclassified as secretory carcinomas; see question 9.

  References: [45,46,47,48,49]

• 9. What is mammary analogue secretory carcinoma and how is it characterized?

  Mammary analogue secretory carcinoma is a recently described tumor derived from intercalated duct epithelium that resembles secretory carcinoma of the breast. The 4th edition of the WHO Classification of Head and Neck Tumors uses the term secretory carcinoma (SC). It is primarily a tumor of the major salivary glands (80%). Patients are typically middle-aged with a slight male predominance.

  • SC is circumscribed, unencapsulated tumors with invasive growth. The cells are arranged in tubular, papillary, microcystic, and solid growth patterns (Fig. 5.10). Fibrous septa separate the tumor lobules. The luminal pink, bubbly (colloid-like) material is positive for mucicarmine and PAS stains with and without diastase.

  • The tumor cells are cuboidal with small, bland vesicular nuclei with conspicuous, central nucleoli, mild atypia, and vacuolated or granular, eosinophilic cytoplasm. Mitoses, necrosis, and lymphovascular invasion are rare.

  • SC is characterized by the ETV6-NTRK3, t(12;15)(p13;q25) translocation, identical to that seen in mammary secretory carcinoma. Other translocation partners include t(12;XX).

  • The primary differential diagnostic consideration with SC is acinic cell carcinoma. Table 5.4 summarizes the differences between SC and AcCC.

    • A subset of zymogen granule-poor AcCC and those in minor SG have been retrospectively reclassified as SC based on molecular findings.

    • The clinical significance of this distinction is unclear given the limited number of cases. However, SC may have a slightly higher rate of lymph node metastases (20%).

  • SC can undergo high-grade transformation . High-grade tumors express p53 and membranous beta-catenin.

  References: [46, 49,50,51,52,53,54,55,56,57]

• 10. What are the clues to the diagnosis of polymorphous adenocarcinoma (polymorphous low-grade adenocarcinoma) and which entities are in the differential diagnosis?

  Polymorphous adenocarcinoma (PAC) is a monotypic tumor comprising cells of terminal/intercalated duct origin. It is classically described as cytologically uniform but architecturally diverse. It shows a relatively even distribution among intraoral and major salivary gland sites. There is twofold female predominance with a mean age of 60 years old.

  • PAC is the second most common intraoral salivary gland carcinoma after adenoid cystic carcinoma.

  • The palate is the most common location (approximately 60%).

  • The different growth patterns include solid, lobular, papillary, ductal, and tubular; cribriform and papillary growth are less common.

  • PAC is usually unencapsulated with a more solid, lobular center and small nests and cords of single cells radiating toward the tumor periphery in an infiltrative pattern. This arrangement creates the classic, concentric, targetoid appearance (Figs. 5.11 and 5.12).

  • The cells are small to intermediate in size with bland, oval nuclei, delicate nuclear membranes and pale chromatin.

  • Perineural invasion is common and necrosis is rare.

  • Mutations in PRKD1 E710D are present in up to 70% of cases.

  • Overall 5- and 10-year survival rates are 91% and 73%, respectively. Distant metastases and deaths due to disease are rare.

  • Locoregional recurrences, including cervical lymph node metastases, approach 30% and can have long latency periods in excess of 15 years. For this reason, and because of reports of occasional high-grade transformation, the “low-grade” moniker has been removed from the name in the 4th edition of WHO classification system.

  The major differential diagnoses with PAC arise primarily because the diagnosis is made on limited biopsy samples typically from the oral cavity (Table 5.5). Its polymorphous architecture has many mimics that are greatly reduced on excision specimens.

  • Cribriform adenocarcinoma of (minor) salivary gland (CASG) shows significant morphologic overlap with PAC but a distinct clinical picture. Less than 100 cases have been reported in the literature. It occurs primarily in the minor salivary glands, and patients typically present with cervical lymph node metastases. However, the tumor has an excellent prognosis with no reported distant metastasis or deaths due to disease.

  • CASG (Fig. 5.13) is not currently classified by the WHO but is probably best regarded as a cribriform variant of PAC. A subset harbor translocations of PRKD1-3 with ARID1A and DDX3X.

  References: [2, 58,59,60,61,62,63,64,65,66]

• 11. What are the morphologic subtypes of basal cell adenomas, their clinical relevance, and differential diagnosis?

  Basal cell adenomas are rare, accounting for 1–3% of all salivary gland tumors. They present primarily in the parotid gland, with a minority of cases in intraoral sites (upper lip) and submandibular gland. There is a slight female predominance with a wide age range and a peak incidence in the seventh decade.

  • BCA is a well-circumscribed, encapsulated tumor composed of bland, basaloid cells that show some degree of nuclear palisading. Mitoses are rare, and necrosis is absent.

  • There are four morphologic types (Table 5.6) of BCA; most tumors will show at least two types (Fig. 5.14).

  • The two main cell types are abluminal with varying amounts of ductal cells:

    • Myoepithelial cells: small, dark cells with round to oval, hyperchromatic nuclei and scant cytoplasm.

      • Muscle markers: positive

      • Basal markers: positive (p63, CK5/6, CK14)

    • Basal cells: larger, abluminal cells with oval, more pale nuclei and more abundant, eosinophilic cytoplasm. They typically align at the epithelial-stromal interface and demonstrate palisading.

      • Muscle markers: negative

      • Basal markers: positive (p63, CK5/6, and CK14)

  Basal cell adenocarcinoma (BCAC) poses the most significant diagnostic challenge with BCA. BCAC only differs from BCA by demonstrating infiltrative growth, including capsular, vascular or perineural invasion. Increased mitotic activity, pleomorphism, and necrosis may be seen but are not prominent features.

  • Some authors suggest that a BCA with mitoses in excess of three per ten high-power fields should be carefully examined and completely submitted for histologic evaluation to exclude BCAC.

  • The solid variant is the most common type of BCAC, and palate is the most common intraoral site.

  • The differential diagnosis of BCAC depends on type and location. Immunohistochemical stains and morphologic features can help make the correct diagnosis.

    • Adenoid cystic carcinoma

    • Basaloid squamous cell carcinoma

    • Basal cell carcinoma

  References: [67,68,69,70,71,72]

• 12. What are the criteria used to diagnose myoepithelial tumors, their subtypes, and the differential diagnoses?

  Myoepithelial tumors are rare tumors accounting for less than 2% of all salivary gland neoplasms. The parotid gland is the most common site (40–60%) with up to 20% of cases presenting in minor salivary gland, usually palate. Myoepitheliomas and myoepithelial carcinomas (MyEC) present as a slow-growing, painless masses.

  • Myoepithelial tumors are encapsulated and composed almost exclusively of myoepithelial cells. Some authors do not accept any ductal elements, while others will allow for as much as 10% duct formation. Given the morphologic overlap with so many SG tumors, we prefer the former, more stringent criteria.

  • There are five different cell types: epithelioid, spindled (Fig. 5.15), plasmacytoid or hyaline (Fig. 5.16), clear cell, and mucinous. Tumor variants generally comprise at least 75% of one cell type, but a mixed pattern is the rule.

    • The cell type is not clinically significant, but awareness of the different morphologies and their mimics is important in making an accurate diagnosis (Table 5.7).

    • The stroma can be positive for Alcian blue but usually negative for mucicarmine.

  • The diagnosis of myoepithelial tumors requires demonstration of myoepithelial lineage by immunohistochemistry or ultrastructural analysis.

  • Myoepithelial tumors co-express keratins and muscle markers to varying degrees:

    • Keratins: AE1/3, 34BetaE12, Cam5.2, CK14

    • Muscle markers: calponin, smooth muscle actin, SMA, MSA, calponin

    • Other positive markers: vimentin, S100, p63, GFAP

    • Negative markers: CK7

  • A few notable exceptions to the classic immunoprofile:

    • Spindle variant is negative for pan-cytokeratin.

    • Mucinous variant expresses CK7, mucicarmine, with variable p63 and calponin.

    • Plasmacytoid variant may only weakly express muscle markers.

    Myoepithelial carcinoma (MyEC) is distinguished from myoepitheliomas by:

    • An infiltrative border, multinodular growth

    • Frequent or atypical mitoses (see Fig. 5.15d)

    • Tumor nodules with a hypercellular periphery and a necrotic center (see Fig. 5.16c, d)

  • Histologic parameters such as grade, cell type, mitotic rate, the presence of necrosis, nerve or vascular invasion do not consistently correlate with prognosis.

  • Clinically, MyEC has high metastatic rates, averaging 40–50% and frequent recurrences. Common sites of metastases are the lungs and cervical lymph nodes.

  References: [1, 73,74,75,76,77,78,79,80]

• 13. What is the differential diagnosis of oncocytic lesions of salivary gland?

  The three principal oncocytic lesions of the salivary gland are oncocytoma (Fig. 5.17), nodular oncocytic hyperplasia (or oncocytosis), and oncocytic carcinoma (Fig. 5.18). Among these, less than 10% represent oncocytic carcinomas. Table 5.8 summarizes the features of each.

  • All three lesions occur in older patients (sixth to seventh decades) with no gender preference.

  • Care should be taken to distinguish the clear cell variant of oncocytoma from other primary and secondary clear cell tumors (see question 14).

  • The infiltrative growth pattern of oncocytic carcinoma is a key feature in the diagnosis, as pleomorphism and atypia may be focal.

  Oncocytic change occurs in a variety of salivary gland entities; a few tumors are notable for having oncocytic variants. These variants are generally defined as having at least 50% oncocytic change and should be considered in the differential diagnosis of oncocytic tumors.

  • The oncocytic variant of epithelial-myoepithelial carcinoma (EMCA) shows the classic biphasic pattern of outer myoepithelial cells and inner ductal cells. When both ductal and myoepithelial cells are oncocytic, immunohistochemical stains may be necessary to appreciate the biphasic pattern.

    • Seethala et al. noted that oncocytic EMCA has a tendency toward papillary growth and frequently demonstrates sebaceous differentiation.

    • The immunoprofile is similar to that of the usual type of EMCA: p63 and muscle markers will highlight the myoepithelial layer, and various keratins will stain the ductal component.

    • In oncocytomas, p63 only stains cells at the periphery of the tumor nodules.

  • The oncocytic variant of mucoepidermoid carcinoma (oncMEC) is a rare tumor with only a few cases described in the literature.

    • The oncocytes are arranged in sheets and nests in a fibrotic stroma.

    • The majority of cases are low to intermediate grade.

    • The tumors are mostly solid; conventional areas of MEC may be scarce, and mucous cells may be difficult to find without special stains.

    • The Warthin tumor-like variant of MEC typically shows disorganized, multilayered, oncocytic epithelium lining cysts and papillae with a dense lymphoid stroma and occasional mucus cells.

    • Awareness of both of these variants is essential in avoiding an incorrect diagnosis but conveys no prognostic value. Both variants stain strongly and diffusely with p63 and harbor MAML2 gene rearrangements.

  References: [69, 81,82,83,84,85,86,87,88,89,90]

• 14. What is the differential diagnosis of clear cell tumors of the salivary gland?

  Clear cell carcinoma is a rare, low-grade tumor of primarily minor salivary gland, with 80% occurring in intraoral sites (tongue and palate). Immunohistochemical stains and electron microscopy support a squamous origin.

  • CCC is characterized by small nests, cords, and single files of clear cells separated by a dense, eosinophilic, hyaline stroma. The cells are small with a high nuclear to cytoplasmic ratio, bland nuclei, and clear to pale pink cytoplasm. Necrosis and mitoses are rare (Fig. 5.19).

  • CCC rarely shows a predominance of optically clear cells.

  • A myxoid, fibrocellular stroma may be present in lieu of the hyalinized stroma.

  • CCC harbors the EWSR1-AFT1 rearrangement in 80–90% of cases. The same alteration is seen in clear cell odontogenic carcinomas, a postulated, intraosseous relative of CCC.

  • Perineural invasion is frequent (40–50%).

  • Increased mitotic activity or necrosis should raise concern for high-grade transformation.

  • Metastatic rates to regional lymph nodes are estimated at 25%. However, CCC are considered low-risk tumors with metastases to distant sites and subsequent deaths at less than 4%.

  Areas of clear cell change can be seen in a wide variety of benign and malignant salivary gland tumors. A few SG tumors such as epithelial-myoepithelial carcinoma (Fig. 5.20) and mucoepidermoid carcinoma (Fig. 5.21) are notable for their clear cell variants. The list in Table 5.9 is not comprehensive, and metastatic lesions, like squamous cell carcinoma and renal cell carcinoma, should also be considered.

  References: [73, 91,92,93,94,95,96,97,98]

• 15. What are the different ductal carcinomas and how are they distinguished?

  Salivary duct carcinoma (SDC) is a high-grade tumor of salivary duct origin. It is a disease of the elderly with a marked male predominance. As many as 60% occur in the parotid gland, though submandibular and minor salivary glands can also be involved. Up to 10% of cases arise in a carcinoma ex pleomorphic adenoma.

  • SDC resembles high-grade ductal carcinoma in situ of the breast. It comprises large ducts/cysts lined by pleomorphic cells with coarse chromatin, prominent nucleoli, and moderate to abundant eosinophilic cytoplasm. The cells are arranged in a cribriform pattern with Roman-bridge architecture and comedo necrosis. Apical snouting, typical of apocrine differentiation, is characteristic (Fig. 5.22).

  • Distinction from squamous cell carcinoma and high-grade transformation of other salivary gland carcinomas is critical, as the latter are more aggressive. Immunohistochemical stains and careful sampling to exclude a preexisting low-grade component are useful in arriving at the correct diagnosis.

  • Regardless of gender, SDC expresses androgen receptors (AR), a marker of apocrine change. Williams et al. contend that AR-negative SDC is sufficiently rare enough to question the diagnosis.

  • SDC has a poor prognosis with high rates of lymph node metastasis (50–70%), distant metastases (50%), and local recurrences (40–50%). Five-year survival ranges from 23% to 64%.

  Intraductal carcinoma (IDC) is an in situ, ductal proliferation that resembles atypical ductal hyperplasia or low-grade ductal carcinoma in situ of the breast. IDC is rare, shows a slight female predominance, and overwhelmingly occurs in the parotid gland.

  • IDC is predominantly cystic with round smooth contours and a micropapillary, solid, or cribriform architecture. The cribriform lesions can show irregular or slit-like spaces with larger cells at the periphery and small, dark cells crowded toward the lumen center.

  • The cells have a moderate to abundant amount of eosinophilic cytoplasm that may have vacuoles, apical snouts, or PASD-positive globules. The nuclei are bland with a finely dispersed chromatin and variable nucleolar prominence.

  • The sine qua non of the diagnosis is the demonstration of a myoepithelial layer surrounding the cysts and ducts.

  • Intermediate- and high-grade cytology occurs in 13–17% of cases. Tumors show increased mitotic activity and pleomorphism; rare foci of necrosis may be present.

  • Foci of limited stromal invasion can be seen in 20–23% of cases. Even with this finding, IDC has an excellent prognosis.

    • Cases with limited invasion should be diagnosed as “IDC with focal invasion.”

    • Thorough sampling should be done to assess the amount or presence of invasion.

  • Rare local recurrences are attributed to incomplete excision, and no reports of distant metastases or death due to disease have been described. Table 5.10 compares SDC to low- and high-grade IDC.

  References: [3, 99,100,101,102,103,104,105,106,107,108]

• 16. Are there specific histologic features for the diagnosis of adenocarcinoma, not otherwise specified?

  By definition, adenocarcinoma, not otherwise specified (ACA, NOS) is a glandular carcinoma that does not meet histologic criteria for any other SG carcinoma; it is a diagnosis of exclusion. All cases show an infiltrative glandular or ductal proliferation; more specific histologic features are not established. Table 5.11 summarizes the clinicopathologic features of ACA, NOS.

  • Tumors comprise cuboidal or columnar cells of different subtypes, including mucinous and oncocytic. The 2017 WHO classification includes mucinous and intestinal types of adenocarcinoma in the ACA, NOS category (see question 2).

  • The growth patterns are numerous, including cribriform and solid architectures, papillae, nest, cords, and tubules.

  • ACA, NOS are generally aggressive tumors, though low-grade tumors have a better prognosis.

  • High-grade tumors show frequent mitoses , pleomorphism, and necrosis.

  References: [109,110,111]

• 17. What is high-grade transformation, how is it different from dedifferentiation, and which salivary gland tumors can undergo such changes?

  Dedifferentiation of any tumor is characterized by the sharp demarcation of a well-differentiated tumor from a high-grade component that shows none of the histomorphologic features of the original. When salivary gland carcinomas undergo “dedifferentiation,” the high-grade component is typically a poorly differentiated adenocarcinoma or an undifferentiated carcinoma. Because the high-grade component is recognized as being similar to the lower-grade component and there may be a transition from the low-grade area, the term dedifferentiation is not wholly accurate. In such a setting, high-grade transformation (i.e., from a low-grade adenocarcinoma to a higher-grade carcinoma) is the preferred term.

  • Tumors with high-grade transformation (HGT) characteristically show:

    • Marked nuclear pleomorphism

    • High mitotic activity

    • Necrosis

  • The percentage of tumor that is needed for the HGT designation has not been defined for any of the tumor types. Despite the lack of standardization, all reported cases, regardless of tumor type, are associated with clinical progression.

  • Table 5.12 summarizes the features and diagnostic considerations of transformed SG carcinomas. HGT is very rare, and most of the information is based on only a handful of reported cases for each tumor.

  References: [54, 112,113,114,115,116,117,118,119]

• 18. What are the principal papillary tumors of the salivary gland and their differential diagnosis?

  There are four main entities in the group of papillary tumors of the salivary gland: inverted ductal papillomas (InvDP), intraductal papillomas (IDP), sialadenoma papilliferum (SAP), and papillary cystadenoma lymphomatosum (Warthin tumor).

  The ductal papillomas occur within the salivary duct system, at the intersection of the excretory duct and surface epithelium. So, their primary location is in the minor salivary glands. The lip, usually upper, is the most common site, followed by the buccal mucosa, palate, floor of mouth, and tongue. The ductal papillomas include inverted ductal papillomas (InvDP)and intraductal papillomas (IDP). Both are rare entities described in small series and case reports. Table 5.13 summarizes the different papillary lesions and the most common entities in the differential diagnosis.

  • Inverted ductal papillomas (IDP) are well-circumscribed tumors with endophytic growth and pushing borders.

    • The junction of the tumor and the surface epithelium may show a dilated, pore-like orifice.

    • The papillae are broad and lined by basaloid cells that show epidermoid differentiation with squamous, transitional or mucous-type, columnar epithelium.

    • Mitoses are infrequent, and cellular atypia is minimal.

  • Intraductal papillomas show an exophytic growth of complex, branching papillae that protrude into a well-circumscribed, unicystic cavity.

  • Sialadenoma papilliferum extends from the mucosal surface and presents as a slow-growing, papillary, verrucoid mass:

    • Unencapsulated, biphasic tumor composed of complex papillae.

    • The base shows an endophytic proliferation of ducts with varying amounts of ectasia.

  • Cystadenomas are a diagnostic consideration for IDP. Cystadenomas are typically well-circumscribed, multicystic tumors of major and minor salivary gland.

    • Thin, fibrous bands separate the cysts which are lined by an oncocytic, cuboidal to columnar epithelium; mucous and squamous cells may also be present.

    • Papillary growth may be focal or predominate.

  • Warthin tumor (WT) is the second most common tumor of salivary gland, after pleomorphic adenoma. It occurs exclusively in the parotid gland and rarely in the peri-parotid lymph nodes. WT have a slight male predominance and may be multifocal and bilateral.

    • The tumor comprises papillae with fibrovascular cores containing a dense lymphoid stroma (Fig. 5.23).

    • A characteristic bilayer of inner columnar and outer cuboidal oncocytes lines the papillae which protrude into cystic spaces. The cells are cytologically bland and may show squamous, sebaceous, or mucous cell metaplasia.

  References: [120,121,122,123,124,125,126]

• 19. Does primary squamous cell carcinoma of salivary gland exist and how is it diagnosed?

  Primary squamous cell carcinoma (SCC) of the salivary gland is exceedingly rare and occurs in the parotid gland. Case reports involving the submandibular gland have been difficult to confirm. Many historical cases likely represent salivary duct carcinomas or metastatic squamous cell carcinomas from the skin. Most reports do not give detailed information about the clinicopathologic features, raising questions about the rigor of the diagnosis. It is essentially a diagnosis of exclusion; adherence to strict criteria is essential.

  • Primary SCC of the parotid is thought to arise from squamous metaplasia involving Stensen’s duct.

  • One should suspect a primary SCC of the salivary gland in the following settings:

    • No history of previous skin carcinoma.

    • SCC is not solely confined to intraparotid lymph nodes.

    • Keratinization is present.

    • Other head and neck primary sites have been excluded.

    • History of radiation to the parotid.

    • Duct obstruction or elongated mass (i.e., growing along/in the main duct)

    • The presence of squamous dysplasia or arising from a large duct origin

  • The handful of cases that are most plausible have a few features in common:

    • Patients are predominantly male, between 50 and 70 years old.

    • Variable smoking history.

    • Facial nerve paralysis and regional lymph node involvement at presentation.

  • Other salivary gland carcinomas with squamous differentiation or metaplasia, especially those that may undergo high-grade transformation, must be excluded.

    • High-grade mucoepidermoid carcinoma (MEC) is a common mimic of SCC.

    • MEC should not show keratinization, and mucicarmine staining helps to identify mucous cells.

  References: [127,128,129,130]

• 20. What are the common metastases to salivary gland?

  Nonlymphoid metastases to the salivary glands account for about 15% of all malignant SG tumors. The majority of metastases to salivary gland are from the head and neck sites (80–90%), most commonly involve the parotid gland (90–95%), and are squamous cell carcinomas (40–60%).

  • The most common metastases are listed in order of frequency:

    • Head and neck cutaneous squamous cell carcinoma (30–65%)

    • Head and neck cutaneous melanomas (20–30%)

    • Infraclavicular sites (10–15%)

  • Metastases to intra- and peri-parotid lymph nodes occur via lymphatic spread.

  • Metastases to submandibular gland are typically intraparenchymal and spread hematogenously.

  • The most common distant sites are the lung, breast, and kidney, accounting for over 90% of distant secondary tumors.

    • Melanomas and tumors from distant sites are more likely to present as occult primaries.

    • Latency periods of up to several years may exist between initial diagnosis and the SG metastases.

  • Primary SG tumors must be excluded with a thorough clinical history and examination. Ancillary studies can aid in this distinction, but there is some overlap in the immunoprofile and histomorphology of primary and secondary tumors (Table 5.14).

  References: [131,132,133,134,135,136,137,138]

• 21. Which primary tumors of salivary gland are identical to their counterparts at other sites?

  Some rare primary salivary gland carcinomas exist which are best known as primary tumors at other anatomic sites (e.g., small cell lung carcinoma). Due to their rarity in SG, all of these tumors should be distinguished from metastases, and this is best done by relying on clinical history. Primary SG lymphoepithelial carcinoma, squamous cell carcinoma, and sebaceous carcinoma are histomorphologically indistinguishable from their counterparts in other locations (Table 5.15).

  • SG is the second most common site (after larynx) for neuroendocrine tumors of the head and neck.

  • Under the current 4th edition of the WHO, poorly differentiated NEC and undifferentiated carcinomas all fall under the moniker of poorly differentiated carcinoma, regardless of NE marker expression:

    • Poorly differentiated NEC is divided into small cell and large cell types:

      • The most common subtype in the SG is the small cell type.

      • Behavior does not appear to differ much between the small and large cell NEC, though the number of cases are limited.

      • PD NEC of salivary gland may stain for CK20, and this helps to distinguish it from primary lung tumors.

    • Undifferentiated carcinomas are composed of large cells that show no light microscopic evidence of glandular or squamous differentiation:

      • Some are known to have ultrastructural evidence of neuroendocrine differentiation but don’t usually demonstrate such features by immunohistochemistry.

  References: [139,140,141,142,143]

• 22. Which clinicopathologic features predict behavior in salivary gland carcinomas and how does tumor type relate to behavior?

  Factors effecting clinical behavior and prognosis in SG carcinomas are similar to other carcinomas. Table 5.16 lists the clinical and pathologic factors that predict survival in SG carcinomas.

  • As discussed earlier, tumor grade correlates with survival. But only a handful of SG carcinomas are routinely graded and include:

    • Mucoepidermoid carcinoma

    • Adenoid cystic carcinoma

    • Adenocarcinoma, NOS

  • For the remainder of SG carcinomas, specific tumor types have an implied histologic grade. But unlike grade, tumor type inconsistently correlates with survival.

  • The relationship between grade, histologic type, and behavior among the more common SG carcinomas is summarized in Table 5.17.

    • Broadly, low- to intermediate-risk and high-risk tumors have a 5-year survival of ≥80% and ≤50%, respectively.

    • The aggressive local behavior of adenoid cystic carcinoma, regardless of grade, is considered high risk.

  References: [38, 144,145,146,147,148,149]

• 23. What is the distribution of salivary gland tumors in the minor salivary glands?

  Diagnosing minor SG tumors is a particular challenge because the readily accessible location encourages acquisition of small biopsies which create diagnostic difficulties. Knowing the frequency of tumors by site (Table 5.18) and other clinicopathologic features can be helpful.

  • The common biphasic tumors of minor SG were discussed earlier (see Table 5.5).

  • The squamoid lesions of minor SG are compared in Table 5.19.

  • Common among most minor SG tumors:

    • Unencapsulated.

    • Mucosal involvement does not equate with malignancy.

  • A few clinical correlates are worth noting:

    • There is at least a slight female predominance for minor SG tumors in the United States, regardless of type or site.

    • Cystadenomas are the most common benign lower lip tumor.

    • The most common site for canalicular adenomas is the upper lip.

    • There is a higher risk of malignancy for any tumor occurring in minor SG when compared to major SG.

    • The percentage of benign versus malignant tumors in minor SG varies among authors.

      • In the largest series, benign tumors are slightly more common in minor SG (51–61%).

      • On average, benign and malignant tumors represent approximately 55% and 45% of minor SG tumors, respectively.

  References: [150,151,152,153,154,155]

• 24. What are the most common salivary gland tumors in children?

  • There are some unique characteristics of salivary gland tumors in children when compared to adults. Table 5.20 highlights notable findings between the two groups.

  • Several authors eliminate vasoformative tumors (hemangiomas and lymphangiomas) from their study design, as many of these lesions will not undergo surgery. But when these lesions are taken into consideration, their incidence exceeds that of pleomorphic adenoma.

  References: [156,157,158,159,160,161,162,163,164,165]

• 25. What are the most common benign (nonlymphoid) mesenchymal tumors of salivary gland and their characteristics?

  • Lymphomas of salivary gland account for almost 8% of all SG tumors and will be addressed separately in Chap. 10. Here we discuss the common nonlymphoid mesenchymal tumors of SG.

  • Hemangiomas are by far the most common benign mesenchymal tumor of SG.

    • Hemangiomas occur in children and represent the most common salivary gland tumor in children under 1 year old.

    • The tumors comprise thin-walled, nonmuscular, vascular spaces lined by bland endothelial cells. Mitoses may be frequent, but atypia is absent.

    • Most lesions undergo involution by age 10, obviating the need for surgery.

  • Lipomas represent about 20% of benign mesenchymal tumors of SG. They occur primarily in the major SG of adults (>85% parotid) with an average age of 55 years and a male predominance.

    • Lipomas of SG are histologically identical to those of soft tissue, composed of encapsulated, mature fatty tissue. They should be devoid of salivary gland structures, except for rare residual acini or ducts at the tumor periphery.

    • Variants of lipomas (e.g., spindled lipoma, angiolipoma) are seen less commonly in SG but do occur. Table 5.21 lists the morphologic features which distinguish the benign lipomatous tumors.

    • Several SG tumors may show fatty metaplasia, most especially pleomorphic adenomas and myoepitheliomas.

  • Peripheral nerve sheath tumors (Table 5.22) are ranked among the top three benign mesenchymal lesions, after vascular and fatty tumors.

    • Schwannomas are more common than neurofibromas.

    • As much as 35% of neurofibromas in SG are associated with neurofibromatosis type 1.

  References: [6, 166,167,168,169,170]

• 26. What are the most common primary malignant mesenchymal tumors of salivary gland?

  • Primary sarcomas of the salivary gland are rare, representing approximately 0.5% of all salivary gland tumors and 2% of malignant salivary gland tumors.

  • Approximately 80% occur in the parotid gland. There is male predominance, and the average age is 40 years old.

  • Patients present with a painless mass that may show rapid growth and eventual tenderness.

  • Luna et al. outlined four criteria used to classify a sarcoma as primary to salivary gland:

    • 1.  The patient must not have a history of a similar sarcoma at any other site.

    • 2.  Metastatic disease to the salivary gland must be excluded.

    • 3.  Gross and microscopic examination must establish the salivary gland, and not adjacent soft tissues, as the primary site.

    • 4.  Carcinosarcoma must be excluded.

  • Cockerill et al. reported 17 primary sarcomas of salivary gland along with a literature review of an additional 170 cases. The most common tumor types (Table 5.23) are listed in order of frequency.

  • Salivary gland sarcomas, as a group, carry a poor prognosis related to tumor size, type, and histologic grade. The behavior of individual tumor types, when compared to their soft tissue counterparts, is variable.

    • SG sarcomas have high rates of recurrence (30–35%), distant metastases (25–40%), and mortality (28–40%).

    • The lung is the most frequent metastatic site.

  • An accurate diagnosis is critical, given the prognostic implications. Carcinosarcoma and myoepithelial carcinoma should be excluded.

  References: [169, 171,172,173,174,175,176]

• 27. What is the differential diagnosis of benign cystic lesions of the salivary gland?

  Lymphoepithelial (LE) cysts are squamous-lined lesions with an associated dense, lymphoid population. They occur almost exclusively in the parotid gland with rare cases reported in the floor of mouth. The demographics vary depending on the presence of HIV (human immunodeficiency virus) infection. Table 5.24 compares LE cysts in HIV-positive and HIV-negative patients. Surgical excision is the treatment of choice.

  • The differential diagnosis of LE cyst includes a cystic metastatic squamous cell carcinoma to intra- or peri-parotid lymph nodes.

    • The more common metastatic squamous cell carcinoma to this area is from the skin, and it is typically not cystic.

    • The epithelium of LE cysts lacks the atypia and keratinization seen in squamous cell carcinoma .

  The remaining, nonneoplastic cystic lesions are all related to duct obstruction or trauma. They typically present as a compressible, painless mass. Table 5.25 compares the primary nonneoplastic cysts of salivary gland.

  • Mucoceles are the most common nonneoplastic lesion of the salivary gland. They lack epithelium and are, therefore, not true cysts (Fig. 5.24). They are essentially a cystic space created by extravasated mucin into the submucosa.

    • Large mucoceles of the floor of mouth are called ranulas.

  • Mucus retention cysts and salivary duct cysts represent true cysts, lined by an attenuated or metaplastic epithelium.

    • The pathogenesis is related to intermittent, partial duct obstruction or mucus stasis with subsequent dilatation.

    • Salivary duct cysts (Fig. 5.25) may show oncocytic, squamous, or mucinous metaplasia raising concern for mucoepidermoid carcinoma or cystadenoma.

      • Unlike MEC, the cyst is generally unilocular and the lining is typically attenuated or lined by a single-cell layer.

      • Cystadenomas are typically multicystic.

  References: [1, 177,178,179,180,181]

• 28. What are the major inflammatory lesions of the salivary gland?

  • Lymphoepithelial sialadenitis (LESA) is characterized by an extensive lymphoid infiltrate primarily involving the parotid gland. Bilateral disease and isolated submandibular disease are very uncommon.

    • LESA has a strong female predilection and is associated with, but not exclusive to Sjögren syndrome.

    • A diagnosis of Sjögren syndrome requires confirmation of various clinical and laboratory findings. Focal lymphocytic sialadenitis is usually diagnosed on a labial biopsy and requires one or more aggregates of ≥50 lymphocytes with minimal plasma cells (focus score ≥1).

    • The hallmark of LESA is the lymphoepithelial lesion: proliferative, slightly spindled duct epithelium infiltrated by slightly enlarged lymphocytes.

    • Extranodal marginal zone B-cell lymphoma of SGs is typically preceded by LESA.

  • Chronic sclerosing sialadenitis (CSS, Kuttner tumor) is an inflammatory process that most commonly affects the submandibular gland.

    • Recent studies show that most cases of CSS are a manifestation of IgG4-related diseases, an inflammatory disorder resulting in tumor-like, fibro-inflammatory lesions in multiple organs (e.g., pancreas, SG, orbit, kidneys, lung).

    • CSS-/IgG4-related sialadenitis must be clinically distinguished from obstructive chronic sialadenitis given the far-reaching clinical implications and its therapeutic response to corticosteroids.

  • A subset of cases previously labeled as CSS is best classified as an obstructive chronic sialadenitis and is likely related to sialolithiasis. Table 5.26 highlights the salient features of the different types of sialadenitis.

    References: [182,183,184,185,186,187,188]

• 29. What are the common lymphomas of salivary gland?

  Lymphomas of salivary gland account for almost 8% of all salivary gland tumors. Here we highlight salient features of hematolymphoid lesions in the SG, but the reader is referred to Chap. 10 for a more detailed discussion.

  • Salivary gland accounts for 5% of all extranodal lymphomas.

  • Eighty percent of SG lymphomas occur in the parotid.

  • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is the most common lymphoma of salivary gland, followed by follicular lymphoma and diffuse large B-cell lymphoma.

    • Lymphoepithelial sialadenitis (LESA) is a precursor of MALT and is associated with Sjögren syndrome (see question 28).

  • A subset of follicular lymphomas occur primarily in intraparotid LNs and is, therefore, not always of an extranodal origin.

  References: [189,190,191,192,193,194]

• 30. Which nonneoplastic lesion of salivary gland may represent a premalignant process?

  Sclerosing polycystic adenosis (SPA) is a rare fibroproliferative lesion of SG with only a handful of cases reported in the literature. It occurs predominantly in the parotid gland with a wide age range. Average age at presentation is in the fourth decade, and there is a slight female predominance. Patients usually present with a painless, slow-growing mass and occasional minor nerve pain and tingling.

  • SPA is well-circumscribed with a pseudocapsule; prominent, cystically dilated ducts in a dense, sclerotic stroma; and variable amounts of chronic inflammation.

  • Cystic spaces are lined by apocrine, clear, or oncocytic-like cells. Attenuated or denuded epithelium is replaced by foamy histiocytes. Large, serous acinar cells with abundant eosinophilic cytoplasm and PAS-D-positive granules are distinctive. The granules may coalesce to form intracytoplasmic globules.

  • The intraductal proliferations in SPA may be exuberant with cribriform architecture and atypia. An associated myoepithelial layer expresses p63 but may be negative for muscle markers.

  • Atypical SPA is clonal and some regard it as neoplastic with a low malignant potential.

    • High-grade atypia should be regarded as an intraductal carcinoma. The significance of mild to moderate cytologic atypia is unclear.

  • Densely fibrotic areas may resemble radial scars of the breast and should not be mistaken for carcinoma. The normal lobular architecture should be maintained.

  • Recurrence rates approach 20% and may occur over several years. A single report of an associated invasive carcinoma exists.

  References: [195,196,197,198,199,200,201,202]

Fig. 5.1

Normal parotid gland. Serous acini predominate. A large interlobular excretory duct (E) with a second layer of abluminal basal cells (arrow) gives rise to striated ducts (ST) with cuboidal cells and subnuclear striations (inset, arrow). Smaller intercalated ducts (IC) are found among the acini

Table 5.1 Histology and immunoprofile of normal salivary gland cell types

Table 5.2 Changes in WHO terminology for salivary gland tumors

Fig. 5.2

Pleomorphic adenoma with squamous metaplasia. Chondromyxoid stroma (right) contains nests of hyperchromatic, small, angulated, myoepithelial cells surrounding eosinophilic ductal cells with squamous metaplasia and keratin pearl formation

Fig. 5.3

Pleomorphic adenoma

Fig. 5.4

Recurrent pleomorphic adenoma . Multiple nodules of predominantly chondromyxoid stroma are scattered within normal parotid gland parenchyma

Fig. 5.5

Carcinoma ex pleomorphic adenoma . (a) Residual tubules of pleomorphic adenoma are seen at the periphery of a large, hyalinized, fibrotic nodule. (b) Salivary duct carcinoma arising in a pleomorphic adenoma shows cribriform glands with punched out lumens, Roman arches, and comedo necrosis

Fig. 5.6

Mucoepidermoid carcinoma . (a) Predominantly cystic tumor in a fibrotic stroma with smaller daughter cyst. (b) Sheets of eosinophilic intermediate cells (arrowhead) show minimal atypia. Rare squamous cells (arrow) and numerous mucous cells are present

Table 5.3 Comparison of grading systems for mucoepidermoid carcinoma

Fig. 5.7

Adenoid cystic carcinoma . (a) Areas of solid ACC have basaloid myoepithelial cells and demonstrate perineural invasion (arrow). Cribriform regions with lightly basophilic stroma are seen on the right. (b) Higher magnification shows the hyperchromatic, angulated myoepithelial cells, focally surrounding ductal structures (arrows)

Fig. 5.8

Acinic cell carcinoma . Acinar cells are arranged in sheets and contain basophilic, granular cytoplasm (left) as well as finely reticulated, pale cytoplasm (right) with small, round, dark nuclei. In contrast, the normal parotid gland (top) shows small acini in a normal lobular architecture with intervening ducts

Fig. 5.9

Acinic cell carcinoma . (a) Microcystic pattern, with numerous small cysts, lined by cuboidal, intercalated duct-type cells. (b) Solid type with the “blue dot” appearance of small nuclei in acinar cells with deeply basophilic granules

Fig. 5.10

Secretory carcinoma . (a) Microcystic pattern with variably sized spaces and pale eosinophilic secretions. (b) Tumor cytoplasm is finely vacuolated and lacks basophilic zymogen granules. (c) The tumor is strongly positive for S100 and (d) mammaglobin

Table 5.4 Contrasting features between secretory carcinoma and acinic cell carcinoma

Fig. 5.11

Polymorphous adenocarcinoma . (a) Low magnification shows a variegated architecture with papillary structures toward the center and small tubules (top), single cells (bottom left), and lobules (right) at the periphery. (b) A tumor lobule shows a concentric targetoid arrangement and nuclear monotony with oval, bland, pale nuclei. (c) Tumor cells are arranged in single files and (d) tubules

Fig. 5.12

Polymorphous adenocarcinoma . (a) S100 is strongly and diffusely positive. (b) SMA shows rare, scattered positive cells

Table 5.5 Tumors in the differential diagnosis of polymorphous adenocarcinoma

Fig. 5.13

Cribriform adenocarcinoma of the salivary gland. Tumor cell aggregates retract from basal cells at the stromal interface and form glomeruloid structures. Nuclei are oval, pale, and grooved reminiscent of papillary thyroid carcinoma

Table 5.6 Clinicopathologic features of the morphologic types of basal cell adenoma

Fig. 5.14

Basal cell adenoma . (a) Solid type with tumor nests arranged in lobules. (b) Tubulo-trabecular pattern with ribbons of tumor cells and scattered tubular lumens. (c) Membranous type, cells are surrounded by hyalinized, eosinophilic basement membrane material

Fig. 5.15

Spindled myoepithelial tumors . (a–c) Myoepithelioma. A well-circumscribed spindle cell tumor composed of bland spindle cells arranged in intersecting fascicles with vague palisading similar to a schwannoma. Foci of tumor cell cords (c arrow) in a mucoid stroma offer a clue to the diagnosis. (d) Spindled myoepithelial carcinoma, in contrast, shows increased nuclear atypia and mitoses

Fig. 5.16

Hyaline type myoepithelial tumors . (a, b) Myoepithelioma. Sheets of monotonous tumor cells with brightly eosinophilic, plasmacytoid cytoplasm and tufts of hyaline, basement membrane material (b center). (c, d) Myoepithelial carcinoma. Submucosal tumor lobules with necrotic centers and tumor cells surrounded by hyaline, basement material

Table 5.7 Variants of myoepithelial tumors, their features, and tumors in the differential diagnosis

Fig. 5.17

Oncocytoma . (a) A well-circumscribed, solid tumor. (b) Cells with abundant, granular, eosinophilic cytoplasm are arranged in trabeculae with scattered duct lumens

Fig. 5.18

Oncocytic carcinoma . Sheets of atypical tumor cells with a high N-C ratio, granular pink cytoplasm, and nuclear pleomorphism

Table 5.8 Pathologic features of oncocytic salivary gland lesions

Fig. 5.19

Clear cell carcinoma . (a) Infiltrative nests of polygonal cells with clear cytoplasm, distinct cell borders, and atypical nuclei in a fibrous stroma. (b) Intracytoplasmic glycogen is (left) PAS-positive and (right) diastase sensitive

Fig. 5.20

Epithelial-myoepithelial carcinoma . (a) Large, irregular tumor lobules in a fibrous stroma. (b) Areas of clear cell change separated by thin, fibrous bands. (c) Higher magnification shows a distinct two cell population of cuboidal, pink luminal cells (arrows) and clear, abluminal myoepithelial cells (arrowhead). (d) Immunohistochemistry for (left) p63 highlights myoepithelium and (right) pan-cytokeratin strongly stains ductal cells

Fig. 5.21

Mucoepidermoid carcinoma . Clear cells can be seen but are usually not the predominant or only cell type

Table 5.9 Characteristics of clear cell carcinomas of salivary gland

Fig. 5.22

Salivary duct carcinoma . (a) Cribriform, large ducts are (b) positive for androgen receptors

Table 5.10 Histologic features of ductal carcinomas of salivary gland

Table 5.11 Clinicopathologic features of adenocarcinoma, NOS

Table 5.12 Features and staining of tumors with high-grade transformation

Table 5.13 Differential diagnosis of papillary tumors of salivary gland

Fig. 5.23

Warthin tumor . A papillary and cystic neoplasm with a lymphoid stroma and eosinophilic cyst debris composed of (inset) a bilayer of oncocytic cells

Table 5.14 Metastatic tumors to salivary gland and their differential diagnosis

Table 5.15 Primary carcinomas of salivary gland with identical counterparts from other locations

Table 5.16 Factors impacting survival in salivary gland carcinomas

Table 5.17 Clinical behavior of salivary gland carcinomas by histologic type

Table 5.18 Most common findings in minor salivary gland tumors

Table 5.19 Differential diagnosis of squamoid lesions of minor salivary gland

Table 5.20 Comparison of salivary gland tumors in children and adults

Table 5.21 Clinicopathologic features of fatty tumors of salivary gland

Table 5.22 Comparison of schwannomas and neurofibromas

Table 5.23 Frequency of sarcomas in salivary gland

Table 5.24 Comparison of lymphoepithelial cysts relative to HIV status

Table 5.25 Clinicopathologic features of common salivary gland cysts

Fig. 5.24

Mucocele . The submucosa of the lower lip squamous epithelium contains a pseudocyst filled with proteinaceous fluid and inflammatory cells. A true epithelial lining is absent

Fig. 5.25

Salivary duct cyst. Chronic sialadenitis with salivary duct cyst lined by (inset) ductal epithelium with focal goblet cell metaplasia

Table 5.26 Clinicopathologic features of inflammatory lesions of salivary gland

Case Presentations

Case 1

Learning Objectives

• 1. To become familiar with the morphologic features of a salivary gland adenocarcinoma

• 2. To develop a differential diagnosis for a parotid gland adenocarcinoma

Case History

A 68-year-old female presents with a firm, painless, preauricular mass.

Gross Findings

Poorly circumscribed 2.0 cm mass of the parotid gland with attached skin. The cut surface is solid, tan-white, and homogeneous. Extra-glandular extension is present into adjacent skin.

Histologic Findings (Fig. 5.26)

Large sheets and lobules of tumor are composed of back-to-back glands with foci of cribriform architecture. Tumor cells are columnar with oval nuclei, fine chromatin, and absent nucleoli. Focal single-cell necrosis is present, but geographic and comedo necroses are absent.

Fig. 5.26

Adenocarcinoma, NOS. (a) Infiltrative lobules of tumor (b) are composed of complex glands with cigar-shaped nuclei, luminal mucin, and single-cell necrosis

Differential Diagnosis

• Metastatic adenocarcinoma

• Adenocarcinoma, not otherwise specified

• Neuroendocrine carcinoma, large cell type

• Salivary duct carcinoma

IHC and Other Ancillary Studies (Not Shown)

• Positive: pan-cytokeratin, strong CK7, weak, focal CK20

• Negative: TTF-1, CDX2, synaptophysin, chromogranin, p63, CK5/6

Final Diagnosis

High-grade adenocarcinoma, not otherwise specified (NOS)

Follow-Up

4 months later the patient had disease progression with lung and lymph node metastases while receiving chemotherapy.

Take-Home Messages

• 1. Adenocarcinoma, NOS must demonstrate glandular or duct differentiation. By definition, it cannot meet criteria for the diagnosis of any named carcinoma of salivary gland. It is a diagnosis of exclusion. Metastases from other sites should be excluded clinically and by immunohistochemistry.

• 2. Intestinal-type of adenocarcinoma, NOS has a similar appearance to this case and may express CK20 or CDX2. A primary gastrointestinal carcinoma should be excluded clinically but is highly unlikely to present as an unknown primary with parotid metastasis and strong CK7 expression.

• 3. Large cell neuroendocrine carcinoma will not show such clear glandular differentiation. Salivary duct carcinoma has a high nuclear grade, more cribriform structures, and comedo necrosis.

References: [109, 110, 203]

Case 2

Learning Objectives

• 1. To generate a differential diagnosis of squamous malignancies of the parotid

• 2. To become familiar with the grading of salivary gland carcinomas

Case History

A 58-year-old female presents with a firm, painless, posterior auricular mass.

Gross Findings

A 1.8 cm solid, tan-white circumscribed, but invasive mass in the parotid gland. Areas of necrosis are identified on sectioning. Cysts are not present.

Histologic Findings (Fig. 5.27a, b)

Nodules of tumor cells with areas of necrosis and a rounded, infiltrative border. The tumor cells are relatively monotonous with mild to moderate nuclear atypia and a moderate amount of eosinophilic cytoplasm. Mucus cells are not identified. Foci of lymphovascular invasion (LVI) are present. Rare clear cells and squamous cells are seen. Perineural invasion (PNI) and extra-glandular extension are present (not shown). Three peri-parotid lymph nodes are positive for carcinoma.

Fig. 5.27

Mucoepidermoid carcinoma, high-grade. (a) Solid nodules of intermediate cells with (b) foci of infiltrative nests, extensive necrosis, and LVI (upper left). (c) Tumor cells are strongly positive for CK5/6

Differential Diagnosis

• Squamous cell carcinoma

• Oncocytic carcinoma

• Mucoepidermoid carcinoma

IHC and Other Ancillary Studies

• Positive: CK5/6 (Fig. 5.27c), p63 strongly positive

Final Diagnosis

High-grade mucoepidermoid carcinoma

Take-Home Messages

• 1. The three principal grading systems for mucoepidermoid carcinoma (MEC) all show correlation with patient outcomes. The most important features are solid growth, pleomorphism, necrosis, mitoses, and perineural invasion. This case is difficult to grade because, despite lymphovascular invasion (LVI) and extensive necrosis, the cytologic features are relatively bland (e.g., minimal pleomorphism and mitotic activity). Application of the three main grading systems for this MEC yielded the following results:

  • (a) Modified Healy: high-grade (HG) – solid growth, lymphovascular invasion, PNI, soft tissue extension. Using a “best fit” approach, this tumor would qualify as high-grade despite the absence of pleomorphism and frequent mitoses.

  • (b) Brandwein: 13 pts, HG: less than 25% cystic (2 pts), necrosis (3 pts), PNI (3 pts), lymphovascular invasion (3 pts), and infiltrative border (2 pts).

  • (c) AFIP, 7 pts; HG, less than 20% cystic (2 pts); necrosis (3 pts); and PNI (2 pts).

• 2. The tumor shows a predominance of intermediate cells with scattered clear and squamous cells. This varied population helps to exclude oncocytic carcinoma

• 3. The absence of keratin and a known squamous cell carcinoma of a head and neck site make this diagnosis highly unlikely.

References: [32, 37, 38, 204]

Case 3

Learning Objective

• 1. To generate a differential diagnosis of squamous malignancies of the parotid

Case History

An 80-year-old male complains of a firm mass in the preauricular region. Physical exam reveals marked actinic changes of the skin on his face and head. He reports having several “small cancers burned off of his face” over the years.

Gross Findings

A large 2.6 cm, circumscribed mass is present in the parotid gland with two to three similar appearing, smaller masses in other areas of the gland. The largest is tan-white and firm and associated with a caseous, white material.

Histologic Findings (Fig. 5.28)

A circumscribed, partially encapsulated, but infiltrative mass is present. The tumor shows nests of polygonal cells with abundant eosinophilic cytoplasm, hyperchromatic nuclei with coarse chromatin, and occasional pleomorphism. Keratin pearls are easily identified. Additional intraparotid lymph nodes show similar tumor cells.

Fig. 5.28

Metastatic squamous cell carcinoma. (a) Infiltrative sheets of squamous cell carcinoma involving parotid gland parenchyma. (b) High magnification shows keratinizing tumor cells with keratin pearls

Differential Diagnosis

• Primary squamous cell carcinoma (SCC)

• Metastatic squamous cell carcinoma

• High-grade mucoepidermoid carcinoma

IHC and Other Ancillary Studies

None

Final Diagnosis

Metastatic squamous cell carcinoma of the skin

Take-Home Messages

• 1. There are no markers to definitively distinguish the source of a squamous cell carcinoma, especially if it is a keratinizing carcinoma.

• 2. Squamous cell carcinoma of the major salivary gland should be considered a metastasis until proven otherwise. A primary SCC at this site is exceedingly rare and should adhere to specific criteria, previously discussed in question 19.

• 3. High-grade mucoepidermoid carcinomas are rarely keratinizing and should only be focal. This patient’s history of multiple skin “cancers” and multiple intraparotid lymph node metastases supports a diagnosis of metastatic SCC from the skin. This is one of the most common metastases to the parotid gland.

References: [127, 129, 133, 205]

Case 4

Learning Objectives

• 1. To understand the criteria used to subclassify neuroendocrine carcinomas of the salivary gland (SG)

• 2. To develop a differential diagnosis for neuroendocrine carcinomas of SG

Case History

A 57-year-old male present with a mass at the angle of his mandible and cervical lymphadenopathy.

Gross Findings

A large, fleshy, necrotic tumor mass diffusely infiltrates the parotid parenchyma. Several peri-parotid lymph nodes also show tumor involvement.

Histologic Findings (Fig. 5.29a–c)

The tumor comprises large sheets of cells with extensive areas of necrosis. The cells are small to intermediate sized with scant to more appreciable, pale cytoplasm. The nuclei range from oval to slightly spindled with a fine, stippled chromatin, and an absence of nucleoli. There are frequent mitoses and single-cell necrosis. LVI and PNI are present (not shown).

Fig. 5.29

Small cell carcinoma. (a) Large areas of necrosis alternate with ribbons of carcinoma. (b) The tumor cells show slight spindling and single-cell necrosis. (c) Tumor nuclei have a finely stippled chromatin and frequent mitoses. Cell size is at the upper limit for small cell carcinoma, but the absence of nucleoli and pleomorphism do not favor a large cell NEC. (d) Pan-cytokeratin shows a dot-like, cytoplasmic staining pattern. (e) CD56 is strongly positive. (f) Synaptophysin is diffusely positive with focal granular staining

Differential Diagnosis

• Metastatic small cell carcinoma

• Primary small cell carcinoma

• Large cell neuroendocrine carcinoma

• Metastatic Merkel cell carcinoma

IHC and Other Ancillary Studies (Fig. 5.29d–f)

• Positive: pan-cytokeratin (dot-like), CK5/6 (dot-like), synaptophysin, neuron-specific enolase (NSE)

• Negative: CK7, CK20, TTF-1, CD45

• Merkel cell oncoprotein serum antibody is negative

Final Diagnosis

Primary neuroendocrine carcinoma (NEC), small cell type (small cell carcinoma)

Follow-Up

A neck dissection was performed and yielded 6 positive lymph nodes out of 18 throughout levels 2 through 5.

Take-Home Messages

• 1. Primary small cell carcinomas, though well-defined, fall under the category of poorly differentiated carcinomas. This is primarily because they are all undifferentiated (e.g., no glandular or squamous differentiation) and may show variable or no neuroendocrine differentiation at all. The presence of two neuroendocrine markers, epithelial differentiation, and typical morphology support a diagnosis of small cell carcinoma.

• 2. NSE and CD56 alone are non-specific for neuroendocrine differentiation. The addition of synaptophysin or chromogranin expression is required for a diagnosis of NEC.

• 3. Small cell carcinomas can show a range of cell size. This patient’s tumor has cells that are at the upper limit of size for small cell carcinomas (30 μ). Large cell NEC tends to have more pleomorphism; larger, polygonal cells; rosette formation with palisading; and prominent nucleoli. The distinction in head and neck sites does not appear to be clinically relevant as outcomes are equally dismal in both groups.

• 4. Merkel cell carcinomas are usually positive for CK20, but primary NEC of the parotid can also express CK20. Co-expression with CK7 and a negative CK20 excludes Merkel cell carcinoma. Salivary NECs may even express TTF-1, so clinical history is essential in arriving at the correct diagnosis.

References: [139,140,141,142,143, 206,207,208]

Case 5

Learning Objectives

• 1. To understand the classification of poorly differentiated carcinomas of the salivary gland

• 2. To generate a differential diagnosis of poorly differentiated carcinomas

Case History

An 81-year-old female complains of a right cheek mass. CT scan shows a right cheek mass with duct dilatation and possible duct derivation versus involvement.

Gross Findings

A 1.7 cm firm, tan-gray tumor mass is present in the buccal submucosal. The tumor is infiltrative with a tan-white cut surface. The overlying mucosa shows no gross lesions. Chest and neck CT scans are negative for metastatic disease.

Histologic Findings (Fig. 5.30a, b)

The tumor is composed of sheets of small- to intermediate-sized cells with scant, pale cytoplasm. The cells are arranged in cords and trabeculae. Glands, tubules, ducts, and squamous features are not identified. The nuclei are round with prominent, central nucleoli. Mitotic activity is brisk. Perineural invasion is present. Necrosis is not identified.

Fig. 5.30

Poorly differentiated carcinoma. (a) Sheets of tumor cells adjacent to minor salivary gland of the cheek. (b) The tumor shows a vaguely organoid pattern. The cells are small, with a high N-C ratio, scant pale to basophilic cytoplasm, vesicular nuclei, and prominent nucleoli. Frequent mitoses and single-cell necrosis are present. (c) CK7 immunohistochemistry is strongly positive. (d) CD56 shows focal staining

Differential Diagnosis

• Primitive neuroectodermal tumor

• Undifferentiated carcinoma

• Lymphoma

• Melanoma

IHC and Other Ancillary Studies (Fig. 5.30c, d)

• Positive: pan-cytokeratin (strong), CK7, CD56 (weak, focal)

• Negative: synaptophysin, chromogranin, androgen receptors

Final Diagnosis

Poorly differentiated carcinoma

Follow-Up

5 months later, the patient presents with a new neck mass in level 2. PET (positron emission tomography) scan shows liver and bone metastases.

Take-Home Messages

• 1. According to the WHO classification, poorly differentiated carcinomas include undifferentiated carcinomas like this case. By definition, undifferentiated carcinomas show no evidence of squamous or glandular differentiation. They may or may not demonstrate neuroendocrine features. The CD56 expression and morphologic features of this case are not sufficient for a diagnosis of NEC.

• 2. Lymphoma and melanoma are easily excluded with IHC stains.

• 3. As with all the tumors in this category, metastatic carcinomas must be excluded.

References: [2, 209]