Salivary gland neoplasms

Clinical findings

• This occurs in the sixth decade and presents as a painless nodule or mass on the lips (most common site), and buccal and palatal mucosa ( Fig. 13.2 ).

  

Etiopathogenesis and histopathologic features

Genomic changes have yet to be identified.

• This lesion arises within a cystically dilated excretory salivary duct and consists of a benign papillary proliferation of cuboidal and columnar cells (especially on the luminal aspect), squamous cells, and mucous cells, with fibrovascular cores; microcysts are often present and the point of origin/attachment to the duct lumen may be evident ( Fig. 13.2 ).

• Solid tumors that completely fill the lumen of the duct are likely to represent some other papillary neoplasm.

Differential diagnosis

• Papillary cystadenoma consists of a proliferation of multiple cystic (infrequently unicystic) structures of varying size within which is ductal adenomatous hyperplasia composed of cuboidal-columnar or oncocytic cells forming papillary structures.

• Mucinous adenocarcinoma, papillary type, has similar papillary structures composed of mucous cells but with solid and complex architecture. These exhibit AKT -E17K mutation.

• Inverted ductal papilloma is endophytic and forms bulbous fronds of epithelium that invaginates into the connective tissue.

Management and prognosis

• Excision is curative.

Clinical findings

• This occurs most frequently in the sixth and seventh decades and 60% occur in the lips and approximately 30% in the buccal mucosa as a painless nodule, sometimes with a punctum from which mucus may be expressed.

Etiopathogenesis and histopathologic features

This lesion is similar to a sinonasal inverted papilloma in histopathology but without malignant potential and there are too few cases to determine if these also exhibit EGFR mutation seen in 78% to 88% of sinonasal inverted papillomas.

• There is an unencapsulated, discrete endophytic or “inverted”, lobular proliferation of squamous epithelium arising from an excretory salivary duct; clefts within the lobules represent extensions of the duct and the main duct often opens onto the surface. The lobules are composed of predominantly squamous cells, scattered mucous cells, and oncocytes, and ductal structures may be present lined by low cuboidal-to-columnar cells; microcysts are often seen ( Fig. 13.3 ).

  

• Some cases show the presence of human papillomavirus (HPV)-6 and -11.

Differential diagnosis

• Intraductal papillomas exhibit one large cystically dilated lumen with an intraluminal papillary epithelial proliferation, rather than the lobular endophytic proliferation of an inverted papilloma.

• Papillary cystadenoma consists of a proliferation of multiple cystic structures each of which exhibits papillary and adenomatous hyperplasia.

• Mucoepidermoid carcinoma may have a predominantly epidermoid component with only a few mucous and intermediate cells but is infiltrative and often forms small and large cysts. It exhibits CRTC1/3:: MAML2 fusion.

Management and prognosis

• Excision is curative and the lesion does not tend to recur.

Clinical findings

• This occurs most frequently in the sixth and seventh decades with a 1.5:1 male predilection and the most common location is the hard palatal mucosa (60%–70% of cases) with the buccal mucosa affected in 10% of cases.

• The lesion has a rough, warty appearance similar to a squamous papilloma.

Etiopathogenesis and histopathologic features

Seventy to 100% of conventional sialadenoma papilliferum show BRAF V600E mutation while the oncocytic type does not; 12.5% show HRAS mutation. BRAF mutations are also common in syringocystadenoma papilliferum, the skin counterpart.

• Conventional type: There is a benign, nonencapsulated, exophytic papillary proliferation of surface squamous epithelium similar to a papilloma, in continuity with deep adenomatous and ductal hyperplasia that does not show stromal infiltration. There may be a subtle cribriform pattern and the ducts are irregularly shaped and branching, and are lined with bilayered cuboidal and myoepithelial cells, or with multiple cell layers, sometimes with papillary epithelial hyperplasia of ductal epithelium. Occasional mucous cells are present ( Fig. 13.4 ).

  

• Oncocytic type: This is similar in all aspects to the conventional type except that the ductal epithelium is composed of oncocytic cells with abundant eosinophilic, granular cytoplasm, and round nuclei.

• Luminal cells are K7+ and abluminal cells are p63+; BRAF is positive within both the glandular and squamous components.

• Although cases have been reported showing dysplasia/carcinoma-in-situ and development of malignancy, these may represent de novo papillary carcinomas or cystadenocarcinomas.

Differential diagnosis

• Squamous papilloma does not show the deep adenomatous hyperplasia but this may be the rendered diagnosis if the biopsy is small and superficial.

• Papillary cystadenoma consists of multiple cystic (infrequently unicystic) structures within which protrude simple papillary structures lined by bland cuboidal bilayered epithelium bordered by a continuous layer of p63 positive abluminal cells; there is no surface exophytic papillary component.

• Intraductal papillary mucinous neoplasm, noninvasive type, contains nucous cells and exhibits AKT1 mutation

Management

• Excision is the treatment of choice and there is an up to 7% recurrence rate.

Etiopathogenesis and histopathologic features

Over 90% of pleomorphic adenomas are positive for PLAG1 or HMGA2 rearrangements. The fusion partners are listed in Table 13.1 .

• There is a partially encapsulated or nonencapsulated but discrete tumor with a biphasic pattern exhibiting a proliferation of ducts composed of low cuboidal cells with a surrounding cuff of epithelioid myoepithelial cells, with the myoepithelial cells streaming into the myxochondroid stroma. Pseudopod-like extensions into the capsule are not infrequent. Solid and cribriform patterns are common; rarely, tumors have a reticulated pattern. The cellular variant consists of sheets of myoepithelial cells and ducts with little stroma, although most tumors have abundant stroma ( Figs. 13.6–13.9 ).

  
  
  
  

• Oncocytes, squamous metaplasia, keratin pearls, keratin cysts, clusters of sebaceous cells, and foci of mucous cells may be present. A pure oncocytic variant exists but is not usually seen in the minor glands of the oral cavity ( Fig. 13.10 ).

  

• Myoepithelial cells may be epithelioid, spindled, stellate, plasmacytoid, or clear; plasmacytoid myoepithelial cells have abundant eosinophilic cytoplasm and eccentric nuclei that vary in shape and size, dispersed chromatin, and small or inconspicuous nucleoli ( Fig. 13.11 ).

  

• The stroma which may be myxoid or hyalinized may exhibit osteochondroid material, mature adipocytes, and tyrosine crystals ( Figs. 13.6 and 13.10 ).

• Myoepithelial cells are positive for S100 protein, vimentin, calponin, smooth muscle actin (SMA), maspin, smooth muscle myosin long chain, GFAP, p63, p40, and SOX10 ( Fig. 13.12 ).

  

• Significant cytologic atypia (not just variation in nuclear shape and size) is seen in intracapsular, in situ carcinoma, or noninvasive carcinoma ex pleomorphic adenoma; these are usually strongly associated with the presence of stromal hyalinization, hyaline nodules, and dystrophic calcifications.

Differential diagnosis

• Apocrine chondroid syringoma of the skin (presenting on the lip) may appear similar, although there may be apocrine decapitation secretion within ducts and follicular and sebaceous differentiation.

• Spindle cell lipoma or other benign mesenchymal neoplasm with bone, cartilage, and fat differentiation such as osteolipoma do not show immunopositivity for keratin within the spindle cells.

• Adenoid cystic carcinoma may be considered if the tumor has significant cribriform architecture but there are true ducts and pseudoducts, and cells exhibit hyperchromatic and angular nuclei, that are positive for MYB by immunohistochemistry.

• The presence of significant hyalinization and calcifications must prompt a search for carcinoma ex pleomorphic adenoma , the two most common of which are salivary duct carcinoma and myoepithelial carcinoma. Hyalinized nodules within salivary duct carcinoma or myoepithelial carcinoma are often associated with PLAG1 and HMGA2 in 80% to 90% of cases, suggesting that these nodules represent senescent areas of pleomorphic adenoma ( Fig. 13.13 ).

  • Intracapsular carcinoma ex pleomorphic adenoma is the term used for a carcinoma or adenocarcinoma that develops within the pleomorphic adenoma that does not invade the capsule while the intracapsular intraductal carcinoma exhibits malignant cells that replace benign ductal cells of the pleomorphic adenoma

  • Minimally invasive carcinoma exhibits less than 6 mm of capsular invasion although this number varies depending on the study.

  • Invasive carcinoma extends beyond 6 mm of the capsule. As expected, invasive carcinoma has a worse outcome than intracapsular and minimally invasive lesions.

  

• Myoepithelial carcinomas rarely occur intraorally and most are of the epithelioid or clear cell type; tumor cells exhibit significant cytologic atypia.

Management and prognosis

• Excision with clear margins is the treatment of choice for pleomorphic adenoma, and the recurrence rate is insignificant for intraoral lesions.

• Malignant transformation occurs in long-standing lesions in less than 5% of cases.

• Tumors with copy gains of both EGFR and HER2 may have poor prognosis but most of these have been reported within the parotid gland.

Etiopathogenesis and histopathologic features

A few cases show EWSR1 rearrangements and the oncocytic variant exhibits NTF3::PLAG1 , FBXO32::PLAG1 , and GEM::PLAG1 fusions.

• This is a well-circumscribed monophasic tumor that consists of a proliferation of myoepithelial cells that may be epithelioid, spindled and stellate, plasmacytoid, clear or a combination of these cell types ( Fig. 13.14 ). The plasmacytoid variant has large, polyhedral cells with abundant eosinophilic cytoplasm and eccentric nuclei that may vary in size and shape but do not show mitotic figures. Tumor cells may be arranged in sheets, cords, and trabeculae and rarely may exhibit a reticulated pattern. Ducts are not present.

  

• The stroma may be myxoid, myxochondroid, or hyalinized, and bone and cartilage may be present.

• An oncocytic variant exists where the tumor cells have abundant brightly eosinophilic cytoplasm but is positive for markers for myoepithelial differentiation by immunostaining.

• Cells are positive for keratin especially K14, S100 protein, SOX10, p63, SMA, and calponin.

Differential diagnosis

• Pleomorphic adenoma is a biphasic tumor and always contains ducts even if they are few in number.

• Plasmacytoma has coarse “clock-face” chromatin and a distinct perinuclear zone of Hopf, and tumor cells are CD138+, MUM1+, and negative for S100 protein, p63, and keratin.

• Interestingly, soft tissue myoepithelioma exhibits PLAG1 rearrangement in approximately 30% of cases and EWSR1 rearrangements in approximately 45% of cases.

• Myoepithelial carcinoma exhibits significant cytologic atypia and there is a variant termed secretory myoepithelial carcinoma that contains strands, cords, and sheets of vacuolated signet ring cells positive for K7 and mucin, and variably positive for p63, S100 protein, calponin, and SMA. These had been previously classified as signet ring adenocarcinoma or even mucinous myoepithelioma and these likely represent mucinous adenocarcinoma (see later).

Clinical findings

• This occurs most frequently in the seventh decade with a 2:1 female predilection; 80% occur as a mobile, firm nodule in the upper lip mucosa with approximately 10% occurring in the buccal mucosa; multifocal tumors occur infrequently.

Etiopathogenesis and histopathologic features

Genomic changes have yet to be identifed.

• This is a monophasic tumor composed of an encapsulated proliferation of cuboidal-to-columnar cells, usually in two layers, in interconnected trabeculae and ribbon-like strands forming narrow, elongated ducts and channels (canaliculi); where two strands meet, knots or beads of cells form. Some tumors have thicker bands of cells resulting in a trabecular pattern. Cells have slightly palisaded, pseudostratified, ovoid nuclei with dispersed chromatin and small nucleoli; occasional mitotic figures, oncocytes, and mucous cells may be seen and there may be luminal epithelial spherules or morules. Cystic change may be associated with papillary epithelial protrusions. ( Figs. 13.15 and 13.16 ).

  
  

• The stroma is collagen-poor and mucinous/myxoid with prominent ectatic capillaries; other findings include hemorrhage and psammomatoid spherical calcifications.

• Cells are positive for AE1/3, K7, K19, EMA, S100 protein, vimentin, CD117, and SOX10, and negative for SMA ( Fig. 13.16 C–D); the epithelial spherules are positive for p16 and p63, and GFAP is present in tumor cells at the tumor-capsule interface.

• Foci of early canalicular adenoma within adjacent gland lobules is not unusual ( Fig. 13.17 ).

  

Differential diagnosis

• Trabecular basal cell adenoma is a biphasic tumor that is rare in the minor glands and exhibits hyalinized stroma, and contains both ductal and myoepithelial cell populations with positivity for myoepithelial markers such as p63 in the abluminal cells, as well as nuclear positivity for β-catenin and LEF-1.

• Eccrine spiradenoma, a skin adnexal tumor that may occur on the lip forms lobules and broad trabeculae of tumor cells with two cell populations, and hyalinized material and lymphocytes are present.