Tumors of salivary gland

tumors of salivary glands

1. TUMORS OF SALIVARY GLAND AZFAR NEYAZ, JUNIOR RESIDENT SGPGIMS, LUCKNOW

2. Anatomy and histology 3 pairs of major salivary glands Other locations: lateral margin of tongue, palate, lips, buccal mucosa. Seromucinous glands of nasal cavity, larynx, and bronchi histologically similar to minor salivary glands.

3. The fundamental structure of all salivary glands is the acinar -ductal unit. Acini are variably composed of serous or mucous cells or both. Ductal unit- intercalated, striated, intralobular , interlobular and main excretory duct. Acini and intercalated ducts are surrounded by myoepithelial cells. Preservation of the lobular architecture is an important feature favouring a diagnosis of a non-neoplastic process over a tumor.

4. Myoepithelial cells: Physiolgically and functionally modified epithelial cells. Possess a dual epithelial & smooth muscle phenotype. Produce extracellular matrix. Anti-invasive effect in neoplasms by promoting epithelial differentiation, secreting proteinase inhibitors & suppressing angiogenesis. Basal cells : maintain multidirectional differentiation & play a role in the process of regeneration & metaplastic changes.

5. Parotid gland The parotid gland - largest of the three major glands and weighs on average between 14 and 30 g. Composed almost entirely of serous cells. Sebaceous glands may be observed in 10% to 42%of normal parotid glands . The parotid glands contain 3 to 32(average: 20) intraglandular lymph nodes.

6. The submandibular gland is the second largest salivary gland, weighing approximately 7 to 8 g. Mixed, with both serous and mucous cells; serous units predominate, accounting for approximately 90% of the acinar cells. sublingual gland is poorly encapsulated ,smallest major salivary gland, weighing approximately 2 to 3 gm.

7. Serous-type acini of a parotid gland with dense secretory granules Histologic section of a submaxillary gland.

8. Portion of a parotid gland demonstrating multiple foci of sebaceous differentiation.

9. The intercalated ducts (arrows) (sectioned longitudinally) lie in contact with the acinus . The striated ducts (sectioned transversely) are lined with a oncocytic columnar cells.

10. WHO histological classification of tumors of salivary glands Mucoepidermoid carcinoma Adenoid cystic carcinoma Acinic cell carcinoma Polymorphous low grade adenocarcinoma Salivary duct carcinoma Epithelial myoepithelial carcinoma Basal cell adenocarcinoma Sebaceous carcinoma Sebaceous lymphadenocarcinoma Oncocytic carcinoma Myoepithelial carcinoma Lymphoepithelial carcinoma Malignant epithelial tumors

11. Sialoblastma Clear cell carcinoma NOS Cystadenocarcinoma Low grade cribriform cystadenocarcinoma Mucinous adenocarcinoma Adenocarcinoma NOS Carcinoma ex pleomorphic adenoma Carcinosarcoma Metastasising pleomorphic adenoma Squamous cell carcinoma Small cell carcinoma Large cell carcinoma Malignant epithelial tumors

12. Pleomorphic adenoma Myoepithelioma Basal cell adenoma Warthin tumor Oncocytoma Canalicular adenoma Sebaceous adenoma Lymphadenoma Sebaceous non-sebaceous Ductal papillomas Inverted ductal papilloma Intraductal papilloma Sialadenoma papilliferum Cystadenoma Benign epithelial tumors

13. Hodgkin lymphoma Diffuse large B-cell lymphoma Extranodal marginal zone B-cell lymphoma Soft tissue tumors Hemangioma Haematolymphoid tumors Secondary tumors

14. General features of salivary gland tumors in adults and children

15. Behaviour of salivary gland carcinomas

16. Predilection for major/minor salivary glands as a clue to diagnosis : Major salivary gland Minor salivary gland Warthin tumor Polymorphous low grade adenocarcinoma (palate) Acinic cell carcinoma Canalicular adenoma (lip, buccal mucosa) Oncocytoma/oncocytic carcinoma Cystadenoma/ cystadenocarcinoma Epithelial- myoepithelial carcinoma Inverted papilloma Basal cell adenoma/ adenocarcinoma Intraductal papilloma Salivary duct carcinoma Lymphoepithelial carcinoma Sialadenoma papilliferum (palate)

17. Pleomorphic adenoma Characterized microscopically by architectural rather than cellular pleomorphism . Consist of cells with epithelial and myoepithelial differentiation along with variable amounts of characteristic stroma . H ighly variable morphology results from amalgamation of cellular and stromal components.

18. Clinical features 4 th – 6 th decade F>M 75% : parotid, 5-10% : submandibular & 10% : minor salivary glands. Can also occur in various mucosal sites(bronchus & nasal cavity), skin ( chondroid syringoma ), breast & soft tissues.

19. Benign mixed tumor of the submandibular gland demonstrating a firm, whitish tan, well-encapsulated mass Gross specimen of pleomorphic adenoma. The external surfaces have been marked with blue dye. The cut surface of the tumor is tan-colored and interspersed with brown areas. Note the glistening quality of the tumor.

20. Microscopic appearance Thinly encapsulated. Highly variable growth pattern. Prototypic histologic appearance : tubular structures enveloped by myoepithelial mantles submerging in a chondromyxoid stroma. Melting phenomenon : characteristic

21. Epithelial component: Form anastamosing tubules, cysts, ribbons & solid sheets.

22. Plasmacytoid hyaline cells : restricted to pleomorphic adenoma and Myoepithelioma–diagnostic. Stroma : produced by modified myoepithelial cells. Chondroid, myxoid, chondromyxoid, hyalinized, osseous, & adipose tissues. Chondromyxoid stroma is pathognomonic of pleomorphic adenoma.

23. There is a small satellite nodule immediately outside the thin capsule of the tumor. This represents a tumor protuberance . This finding is still compatible with a diagnosis of benign pleomorphic adenoma. Double-layered duct-like structures with a conspicuous abluminal layer of clear myoepithelial cells.

24. An intimate mixture of epithelial and stromal elements is seen in this mixed tumor. The stroma exhibits cartilaginous differentiation. Plasmacytoid cells

25. Cellular mixed tumor : Because of its extreme cellularity, this tumor may be mistaken for a malignant tumor Pleomorphic adenoma with a focus resembling adenoid cystic carcinoma . There are some cribriform structures and tubules sharply demarcated from the stroma.

26. Pleomorphic adenoma showing a focus of mucous metaplasia. Focal squamous differentiation with keratinization is seen amidst complex glandular structures.

27. Lipomatous pleomorphic adenoma . Pleomorphic adenoma showing bone forming by osseous metaplasia in stroma.

28. Spindly and stellate cells are disposed in a lattice-like fashion within the myxoid matrix . A myoepithelioma can show a similar appearance.

29. Pleomorphic adenoma: immunohistochemical profile. Staining for epithelial membrane antigen highlights the ductal lumens. calponin highlights myoepithelial & modified myoepithelial cells.

30. Recurrent pleomorphic adenoma Possible reasons for recurrences or persistence in pleomorphic adenoma include: The diffluent nature of predominantly mucoid tumors. The variability of the thickness of the capsule, together with the tendency of the tumour to invade the capsule. Tumour protuberances bulging through the capsule. Intratumoral splitting beneath the capsule. It is probable that the tumour cells have low biological requirements and this enables them to survive when spilt into the operative site.

31. Recurrent pleomorphic adenoma Typical multinodular growth pattern .

32. Differential diagnosis Diagnosis is challenging in limited biopsy material from salivary glands. Polymorphous low-grade adenocarcinoma. Adenoid cystic carcinoma. Pleomorphic adenoma showing squamous or mucoepidermoid metaplasia- Squamous cell carcinoma or mucoepidermoid carcinoma.

33. A histologically benign pleomorphic adenoma that inexplicably manifests local or distant metastasis. Probable mechanism :vascular permeation sec. to mechanical implantation. Common sites – bone, lung, lymph nodes. Characteristically retains the benign histologic features of pleomorphic adenoma. Metastasizing pleomorphic adenoma

34. Malignant mixed tumor refers to two different entities: carcinoma ex pleomorphic adenoma (which is more common ). carcinosarcoma Carcinoma ex pleomorphic adenoma is defined as a pleomorphic adenoma from which an epithelial malignancy is derived. Signs of malignant transformation: Rapid growth, F ixation, U lceration, F acial nerve palsy & R egional lymphadenopathy. Malignant mixed tumor

35. The malignant component is most commonly classifiable as: Poorly differentiated adenocarcinoma PLGA . S alivary duct carcinoma . SCC. M ucoepidermoid carcinoma . M alignant myoepithelioma . A denoid cystic carcinoma . C lear cell carcinoma . Most important prognostic factor are the extent of extra capsular invasion and h istologic grade of the malignant component .

36. Noninvasive carcinoma ex pleomorphic adenoma showing more extensive dysplastic change Noninvasive carcinoma ex pleomorphic adenoma showing dysplastic cells replacing the inner duct layer leaving a benign myoepithelial layer.

37. Perineural invasion next to remnant of scarred pleomorphic adenoma. Note the benign component with numerous small irregular ducts in a hyalinized stroma (upper left) and a focus of adenocarcinoma with associated necrosis (lower right).

38. Carcinosarcoma Carcinosarcoma is a malignant tumour composed of a mixture of both carcinomatous and sarcomatous elements. Most common sarcomatous elements are chondrosarcoma, osteosarcoma and fibrosarcoma. Moderate to poorly differentiated adenocarcinoma (NOS) or an undifferentiated carcinoma are the most common carcinomatous components.

39. Carcinosarcoma showing mixture of adenocarcinomatous and osteosarcomatous differentiation

40. Basal cell adenoma It is a benign tumor comprising of basaloid cells sharply delineated from stroma by basement membrane-like material.(1 to 3%) Mesenchymal component or chondromyxoid stroma should be absent. 6 th – 7 th decades, female preponderence. 70% - parotid gland .

41. Gross : small, well-circumscribed, encapsulated nodules measuring between 1-3 cm. Cut section : solid and homogeneous or cystic, with a greyish-white to brown color. Cut surface of the parotid gland tumor shows well-circumscribed, grayish-white, solid mass.

42. Histologically subclassified according to their cellular growth pattern. Solid Trabecular Tubular, Membranous (dermal analogue) types

43. Trabecular type : Narrow epithelial islands forming an interconnecting cord-like architecture. Solid type : Large sheets & broad bands of basaloid cells with peripheral palisading. Detail of a squamous diff. frequently found in the solid variant ( inset).

44. Tubular type. Prominent duct-like structures with intraluminal eosinophilic secretion. Membranous type. Thick, hyaline, basement membrane like material surrounds large lobules. This material is also present within the epithelial nests forming coalescing, hyaline droplets.

45. Differential diagnosis Basal cell adenocarcinoma - (infiltrative borders) Adenoid cystic carcinoma- ( invasive growth, perineural invasion, absence of squamous eddies) Pleomorphic adenoma- ( chondromyxoid stroma, plasmacytoid hyaline cells.)

46. Basal cell adenocarcinoma It is cytologically and histologically similar to basal cell adenoma but is an infiltrative epithelial neoplasm with potential for metastasis. Average age 60 years. 90% - occur in the parotid gland and they are rare in the minor salivary glands of the oral cavity.

47. Basal cell adenocarcinoma. Islands of basaloid cells infiltrate a fibrous stroma . Distinction from basal cell adenoma is based on the presence of unequivocally infiltrative growth . As is typical of basal cell adenocarcinoma, some cells have darker nuclei and some have larger paler nuclei. A focus of perineural invasion is seen ( right of center).

48. Basal cell adenocarcinoma. Solid nests of mildly atypical basaloid cells with peripheral palisading Basal cell adenocarcinoma. Focal squamous differentiation with keratin pearl formations .

49. Differential diagnosis

50. Myoepithelioma Myoepithelioma is a benign salivary gland tumour. Composed almost exclusively of sheets, islands or cords of cells with myoepithelial differentiation that may exhibit spindle, plasmacytoid, epithelioid or clear cytoplasmic features. Age- 4 th to 5 th decade Site- parotid, palate.

51. Myoepithelioma. The cut surface of a tumor presents as a well-circumscribed, yellow-tan colored, solid mass in the parotid gland.

52. 6 growth patterns - Solid Nodular Mucinous Trabecular Pseudoglandular Reticulated IHC : p 63, S100, calponin, SMA, smooth muscle actin, calponin, CD10 .

53. Spindle cell type. The spindle cells are arranged in an interlacing fascicular pattern. Plasmacytoid cell type. The plasmacytoid cells exhibiting eccentrically located nuclei and abundant eosinophilic cytoplasm are surrounded by a myxoid matrix.

54. Epithelioid cell type : Solid and trabecular growth patterns of polygonal epithelial cells with central nuclei and eosinophilic cytoplasm Clear cell type : Solid growth of polygonal shaped clear cells with intercellular hyaline depositions.

55. Spindle-shaped myoepithelial cell forming a neurilemmoma -like pattern. Myoepithelial cells forming a reticular pattern.

56. Differential diagnosis Various mesenchymal lesions: eg.nerve sheath tumor , nodular fasciitis . Myoepithelial carcinoma. Pleomorphic adenoma.

57. Myoepithelial carcinoma characterized by infiltrative growth and potential for metastasis. <2% of all salivary gland carcinomas. Age – 50 to 60 years. 75% arise in the parotid

58. Gross : 3.5 to 5 cm, show infiltrative growth into adjacent parenchyma, haemorrhage and necrosis. Histologic features of malignancy : cellular pleomorphism, >7 mitosis/10 hpf perineural or lymphovascular invasion necrosis. Neoplastic lobules with central coagulative type necrosis, focal squamous differentiation.

59. Reactivity for cytokeratin and at least one of the other myoepithelial markers, including SMA , GFAP, CD10, calponin and smooth muscle actin is required for diagnosis. Differentials : Myoepithelioma, Sarcomas, Clear cell tumors.

60. Myoepithelial carcinoma. Low-power view showing multinodular architecture. Spindle cell type. The spindle cells arranged in a vaguely interlacing fascicular pattern.

61. Oncocytoma Benign tumour of salivary gland origin composed exclusively of large epithelial cells with characteristic bright eosinophilic granular cytoplasm (oncocytic cells). Age – 6 th to 8 th decade. History of radiation exposure - in 20% of patients. Site : 84% occur in the parotid followed by submandibular gland.

62.   Gross appearance of oxyphilic adenoma. The tumor is well circumscribed, solid, and light brown.

63. Oncocytoma consisting of characteristic light and dark cells . Oncocytoma with clear cell change.

64. Oncocytic carcinoma A proliferation of cytomorphologically malignant oncocytes and adenocarcinomatous architectural phenotypes, including infiltrative qualities. These may arise de novo, but are usually seen in association with preexisting oncocytoma. Mean age- 60years, M>F. Site- parotid (80%) and submandibular glands (10%).

65. Oncocytic carcinoma. This is a destructive infiltrating tumor. Oncocytic carcinoma showing neural invasion.

66. Differential Diagnosis : Multifocal nodular oncocytic hyperplasia. Oncocytoma. Salivary duct carcinoma.

67. Practical approach to assessment of the malignant potential of myoepithelial, basal cell and oncocytic neoplasms of the salivary gland.

68. Canalicular adenoma Tumor composed of columnar epithelial cells arranged in thin, anastomosing cords often with a beaded pattern and a characteristic paucicellular stroma. Peculiar predilection to involve the upper lip (about 80% of tumors). Mean age 65 years, F>M. Size 0.5-2.0 cm in diameter and are grossly well circumscribed.

69. Canalicular adenoma is made up of double rows of interconnecting & branching cords of tumor composed of bland, basaloid, cuboidal to columnar cells. The surrounding stroma is acellular with very sparse collagen production

70. Warthin tumor Also known as adenolymphoma or papillary cystadenoma lymphomatosum. Tumour composed of glandular and often cystic structures, sometimes with a papillary cystic arrangement. Lined by characteristic bilayered epithelium, comprising inner columnar eosinophilic or oncocytic cells surrounded by smaller basal cells. The stroma contains a variable amount of lymphoid tissue with germinal centres.

71. 2 nd mc tumor in salivary gland. Almost exclusively restricted to the parotid glands and the periparotid lymph nodes. Mean age-62 years, M>F . Etiology- Radiation & smoking. Clinically multicentric in 12-20%, bilateral in 5- 14% of patients.

72. Gross appearance of Warthin tumor of parotid gland. The presence of multiple large cystic spaces is characteristic of this lesion. Warthin tumor is typically tannish brown, often with cystic spaces. In addition, this tumor demonstrates areas of degeneration and necrosis (yellowish foci).

73. Warthin’s tumor showing papillary cystic tumor with dense lymphoid stroma The papillae and glands are typically lined by columnar oncocytic luminal cells in which the nuclei are often polarized towards the lumen. Beneath the luminal cells is a layer of basal cells, which are sharply demarcated from the underlying lymphoid stroma.

74. Metaplastic variant- 6-7% of Warthin tumors . Nonkeratinizing squamous metaplasia , mucinous metaplasia. Cellular atypia and a pseudo-infiltrative appearance of the metaplastic squamous epithelium in the residual tumor often invite an erroneous diagnosis of squamous cell or mucoepidermoid carcinoma. Extensive necrosis, in which a ghost architecture of papillary structures is often identified; this can be highlighted with a reticulin stain.

75. Malignant change in Warthin tumors Incidence - 1% Epithelial component: squamous cell carcinoma, oncocytic carcinoma, adenocarcinoma, undifferentiated carcinoma & mucoepidermoid carcinoma. Lymphoid stroma : Various types of non-Hodgkin's lymphoma and Hodgkin's lymphoma have been reported. D/Ds: oncocytoma, lymphoepithelial cysts, squamous cell carcinoma , Mucoepidermoid carcinoma.

76. Sebaceous neoplasms Well-circumscribed tumor composed of irregularly sized and shaped nests of sebaceous cells without cytologic atypia, often with areas of squamous differentiation and cystic change. Mean age is 58 years . 50% of tumors arise in the parotid gland, 17% in the buccal mucosa, 13% in the retromolar region. Size -0.4- 3.0 cm. Well circumscribed to encapsulated and are greyish-white to yellow.

77. Sebaceous adenoma showing nests of sebaceous cells with peripheral squamous differentiation. Sebaceous adenoma consisting solely of sebaceous cells of varying sizes.

78. Sebaceous adenocarcinoma Well-differentiated sebaceous carcinoma consisting of non-specific glandular cells and cells showing conspicuous sebaceous differentiation.

79. Sebaceous lymphadenoma : well-circumscribed to encapsulated tumour composed of variably sized and shaped nests of sebaceous glands without atypia often intermixed with different proportions of variably sized ducts, within a background of lymphocytes and lymphoid follicles . Lymphadenoma is a similar tumour lacking sebaceous differentiation.

80. Sebaceous lymphadenoma : Variably shaped epithelial nests with multiple cystic formations, containing sebaceous cells ,in a lymphoid stroma. Sebaceous glands in a diffuse lymphoid background

81. Lymphadenoma. A well-circumscribed tumor in the parotid gland. Lymphadenoma, nonsebaceous type. There are multiple nests of basaloid tumor cells with focal ductal differentiation in a lymphoid background.

82. Cystadenoma “Rare benign epithelial tumour characterized by predominantly multicystic growth in which the epithelium demonstrates adenomatous proliferation”. The epithelial lining is frequently papillary and rarely mucinous. Site- minor salivary glands( lips and buccal mucosa) Age – 57 years, F>M.

83. Cystadenoma. Well-circumscribed tumor composed of variably sized, multiple cysts with focal papillary configurations. The cyst lining epithelium consists of columnar or cuboidal cells. The cysts contain eosinophilic, proteinaceous material

84. Oncocytic cystadenoma . Papillary-cystic proliferation of oncocytic epithelium in the parotid gland. Note the absence of lymphoid infiltration in fibrous stroma separating cystic spaces. The cysts are lined by a double-layered oncocytic epithelium, resembling that seen in Warthin tumor.

85. Cystadenocarcinoma “ Rare malignant tumour characterized by predominantly cystic growth that often exhibits intraluminal papillary growth. It lacks any additional specific histopathologic features that characterize the other types of salivary carcinomas showing cystic growth papillary growth” Malignant nature of the tumor is manifested by invasion of surrounding tissue Age > 50 years, site- 65% occur in the major salivary glands. Gross : partially circumscribed, multicystic mass, ranging in size from 0.4 to 6.0 cm with an average size of 2.4cms .

86. Cystadenocarcinoma. Tumor with multiple papillary-cystic structures invades into the surrounding salivary gland parenchyma. Cyst formations accompanied by prominent intracystic papillary projections of columnar cells.

87. Duct papilloma Predominantly arising from minor salivary glands. Occur in 6-8 th decade, M>F Encompasses three benign tumors: Inverted duct papilloma Intraductal papilloma Sialadenoma papilliferum Inverted duct papilloma : luminal papillary proliferation arising at the junction of a salivary gland duct and the oral mucosal surface epithelium and exhibits an endophytic growth pattern that forms a nodular mass.

88. Inverted ductal papilloma. This tumor is continuous with the overlying surface epithelium and grows in an inverting pattern, forming a smooth-edged, broad-based mass. It is composed of immature squamous or basaloid epithelium In addition, numerous mucinous goblet cells are often intermixed with the basaloid and squamous cells.

89. Intraductal papilloma is a luminal papillary proliferation of duct epithelium that arises from a segment of the interlobular or excretory duct and causes unicystic dilatation. Grossly, intraductal papillomas are well-circumscribed, unicystic nodules that range in size from 0.5-2.0 cm. Intraductal papilloma

90. Intraductal papilloma. A cystically dilated duct with papillary epithelial projections into the cystic space. Extending into the lumen of the cystic space are fronds of columnar epithelium supported by a central fibrovasacular core.

91. Sialadenoma papilliferum : characterized by a biphasic growth pattern of exophytic squamous and endophytic glandular components. 80% of the neoplasms occur on the hard and/or soft palate. Buccal mucosa is the second most common site. It has a high (10–15%) risk of postoperative recurrence.

92. Sialadenoma papilliferum demonstrating the typical exophytic papillary surface and deeper ductal components. The bland surface squamous epithelium communicates with the underlying columnar epithelium lining the ductal structures.

93. Salivary gland anlage tumor manifests in newborns or within the first few weeks of life with respiratory distress. The tumor is postulated to be a hamartoma because the histologic features are reminiscent of developing salivary gland in embryo. Although some investigators favor a teratomatous interpretation. Salivary gland anlage tumor The surface is covered by nonkeratinizing squamous epithelium which extends downwards into the submucosal tissue , giving rise to squamous nests, branching ducts and cystic structures.

94. MUCOEPIDERMOID CARCINOMA 5% of all salivary gland tumors. Commonest malignant tumor in adult and childhood . 1 st -9 th decade, females, peaking in 4-5 th decade. Parotid gland(45%) & palate (21%). Malignant glandular epithelial neoplasm characterized by mucous cells, intermediate and epidermoid cells, with columnar, clear cell and oncocytoid features .

95. Cut surface of the intermediate-grade tumor shows gray white, solid mass accompanied by multiple small cystic structures and infiltrative borders. Low-grade mucoepidermoid carcinomas may have a distinctly cystic gross appearance.

96. Low-grade mucoepidermoid carcinoma: with a prominent cystic component. The tumor contains goblet, intermediate and squamous cells.

97. Intermediate grade mucoepidermoid carcinoma. Solid nests with focal cystic structures consisting of intermediate cells as well as epidermoid cells & a few mucous cells Low-grade mucoepidermoid carcinoma

98. Tumor is composed primarily of markedly pleomorphic epidermoid cells and a small proportion of mucous cells. Periodic acid–Schiff (PAS) stain showing scattered positive mucous cells in the solid nests.

99. Mucoepidermoid carcinoma. Clear cell variant Oncocytic variant .

100. Mucoepidermoid carcinoma. Abundant hyalinized stroma is evident. Extensive secondary lymphoid cell infiltration, referred to as tumor-associated lymphoid proliferation.

101. Brandwein Mucoepidermoid Carcinoma Criteria

102. 1. Warthin's tumor with squamous/mucinous metaplasia 2. Pleomorphic adenoma with squamous differentiation 3. Cystadenoma or cystadenocarcinoma 4. Poorly differentiated adenocarcinoma (versus high grade mucoepidermoid carcinoma) 5. Squamous cell carcinoma (versus high-grade mucoepidermoid carcinoma). Differential diagnosis

103. Adenoid cystic carcinoma Most common malignant tumor of submandibular gland and minor salivary glands. 4 th -6 th decade, female preponderence. Marked propensity for perineural invasion. Adenoid cystic carcinoma is a “basaloid tumour consisting of epithelial and myoepithelial cells in variable morphologic configurations, including tubular, cribriform and solid patterns”.

104. Adenoid cystic carcinoma of the parotid gland has deceptively well-delineated outlines. Microscopically, the tumor extends well beyond the grossly apparent edges of the tumor. Tan, fleshy, firm, invasive tumor

105. The classic cribriform pattern of adenoid cystic carcinoma. At higher magnification, the cells are haphazardly arranged around the extracellular spaces

106. Adenoid cystic carcinoma. Tubular variant (20-30%) showing morphologically similar luminal and abluminal cells. Adenoid cystic carcinoma. Tubular variant showing morphologically clear abluminal cells .

107. Adenoid cystic carcinoma. Solid variant higher power showing scattered duct-like structures within the tumor sheet. Adenoid cystic carcinoma. Solid variant showing extensive comedo necrosis.

108. Adenoid cystic carcinoma with prominent perineurial invasion Adenoid cystic carcinoma showing bone invasion

109. Adenoid cystic carcinoma with hyalinization or myxoid change, mimicking pleomorphic adenoma. The cribriform island shows deposits of abundant hyaline material with strangulation " of the tumor cells. This pattern differs from the hyalinization seen in pleomorphic adenomq in that the process is confined to the cellular island, which itself is sharply delineated from the fibrous stroma .

110. Adenoid cystic carcinoma. P63 staining of myoepithelial component.

111. Dedifferentiated adenoid cystic carcinoma : Transformation of adenoid cystic ca into another high grade neoplasm represented by poorly differentiated adenocarcinoma or sarcomatoid carcinoma. The left field depicts the pre-existing adenoid cystic carcinoma, comprising Basaloid cells with interspersed pseudocystics paces. The right field shows the poorly differentiated (dedifferentiated) solid tumor composed of much larger, pleomorphic and mitotically active cells, associated with coagulative necrosis

112. DIFFERENTIAL DIAGNOSIS : PLG adenocarcinoma Basaloid sq. cell carcinoma Pleomorphic adenoma BC adenocarcinoma

113. Acinic cell carcinoma “Malignant epithelial neoplasm of salivary glands in which at least some of the neoplastic cells demonstrate serous acinar cell differentiation , which is characterized by cytoplasmic zymogen secretory granules.” 3% to 6% of all salivary gland tumors. Site – parotid(80%),minor salivary glands of oral cavity. It is the most common malignant salivary gland tumor to arise bilaterally (3%)

114. Age- 2 nd to 7 th decade. F > M Gross : rubbery or firm, round or lobulated, circumscribed masses that are usually less than 3 cm in diameter. Microscopy- wide range of cell types and architectural configurations.

115. Sections through a superficial parotidectomy for an acinic cell carcinoma reveal a sharply demarcated tumor with a partially cystic appearance.

116. Acinic cell carcinoma. The cells have an abundant cytoplasm filled with basophilic zymogen granules Acinic cell carcinoma. Periodic acid Schiff stain highlighting zymogen granules on the luminal aspect

117. Some tumor cells contain basophilic granules (left lower field). Most cells are polygonal and many resemble intercalated duct cells. Note the bland appearances of the nuclei. Acinic cell carcinoma with extensive psammoma body formation

118. Microcystic variant. Follicular variant

119. Acinic cell carcinoma showing focal clear cell change. Papillary cystic variant . There are many hobnail cells and some vacuolated cell

120. Well-differentiated acinic cell carcinoma with abundant lymphoid stroma. favorable prognosis This otherwise typical acinic cell carcinoma shows an area (upper) of higher grade carcinoma with small-cell features. This phenomenon has been referred to as “dedifferentiation.”

121. Differential diagnosis Well differentiated tumor- normal salivary gland Papillary cystic variant - cystadenocarcinoma. Follicular variant- metastatic follicular carcinoma of thyroid. Oncocytoma

122. Polymorphous low grade adenocarcinoma The commonest site of occurrence is the palate (60-70 %), followed by buccal mucosa (16%), upper lip, retromolar area, base of tongue . Also known as Lobular carcinoma, terminal duct carcinoma and low-grade papillary adenocarcinoma Age - 5 th -6 th decades. PLGA occurs almost exclusively in the minor salivary glands. Gross - firm, circumscribed, but non-encapsulated, yellow tan lobulated nodule, average size 2.2cms

123. Tumor invades into the minor salivary gland parenchyma. A malignant infiltrative tumor characterized by diverse architectural patterns but unified by bland-looking tumor cells.

124. Sheet-like solid growth of the tumor cells exhibiting uniform oval nuclei without any pleomorphism. Polymorphous low-grade adenocarcinoma. Low power view showing histologic diversity within the tumor. Mainly solid and tubular growth patterns with focal cribriform and papillary areas.

125. Tubular structures are predominantly lined by a single layer of small cuboidal cells. Multiple pseudocystic spaces with pale staining amphophilic mucoid contents resulting in a cribriform appearance

126. Papillary configurations of columnar or cuboidal cells Polymorphous low-grade adenocarcinoma ‘‘Indian-file’’ growth pattern.

127. Perineural invasion with concentric targetoid appearance. Fascicular growth pattern

128. Differential Diagnosis : Pleomorphic adenoma . (non infiltrative tumor with dual luminal & abluminal cell differentiation) Adenoid cystic carcinoma ( basaloid cells with a high n/c ratio and more hyperchromatic angulated nuclei , presence of a prominent abluminal component.) So variability of growth pattern is the most consistent architectural feature of the tumor.

129. Epithelial myoepithelial carcinoma 7 th -8 th decade, female preponderance Site -parotid (60%), submandibular gland (10–12%). Gross : a multinodular mass, with expansive borders ,lacking a true capsule, average size of 3cms. A malignant tumour composed of variable proportions of two cell types, which typically form duct-like structures. The biphasic morphology is represented by an inner layer of duct lining, epithelial type cells and an outer layer of clear, myoepithelial-type cells.

130. The myoepithelial component is represented by the cells with clear cytoplasm The tumor characteristically invades in broad fronts (normal salivary g land tissue seen in right field)

131. Epithelial- myoepithelial carcinoma with trabecular arrangement & predominantly non-canalized ducts. Epithelial- myoepithelial carcinoma. Not uncommonly some glandular structures have dilated lumens or are thrown into papillary folds. This feature is practically never seen in adenoid cystic carcinoma.

132. A) Cytokeratin stain highlighting the luminal cells. (B) Calponin staining highlighting abluminal myoepithelial cells. Epithelial- myoepithelial carcinoma showing neural invasion

133. Differentials- Tubular variant of adenoid cystic ca. Pleomorphic adenoma.

134. Salivary duct carcinoma “An aggressive adenocarcinoma which resembles high-grade breast ductal carcinoma” Consist of solid, papillary cystic, and cribriform patterns. M>F, after 50 years of age. Site- parotid(~80%). P resent with a rapidly enlarging parotid mass associated with facial nerve palsy , pain and cervical lymphadenopathy .

135. Cut surface of the tumor shows gray-white, solid mass with foci of necrosis

136. Intraductal component comprised of cribriform structures. Note that the central portion of the ductal cell nests undergoes comedo -like necrosis The invasive component consists of irregular glands and cords of cells that elicit a prominent desmoplastic reaction.

137. Carcinoma cells exhibiting large pleomorphic nuclei with coarse chromatin and prominent nucleoli. The cytoplasm is abundant and granularly eosinophilic Sarcomatoid salivary duct carcinoma. There are several nests of typical salivary duct carcinoma with a prominent cribriform pattern surrounded by a markedly pleomorphic, atypical spindle cell population of tumor cells

138. Mucin -rich variant. Mucin lakes containing islands of carcinoma cells (right) in addition to the typical salivary duct carcinoma component. Invasive micropapillary variant. Morula -like small cell clusters without fibrovascular cores, surrounded by a clear space.

139. Salivary duct carcinoma. Immunohistochemistry. Carcinoma cells are diffusely positive for androgen receptor in their nuclei. Diffuse and strong membranous staining for HER-2/ neu .

140. Differential Diagnosis : Metastasis : breast ( N egative estrogen receptor together with diffuse intense staining for CEA favors a diagnosis of salivary duct carcinoma over breast cancer. Oncocytic adenocarcinoma High grade mucoepidermoid carcinoma. ( epidermoid cells & goblet cells is not seen in salivary duct carcinoma) Papillary cystic variant of acinic cell ca and cystadenocarcinoma. ( lack the comedo necrosis & intraductal -like pattern typically seen in salivary duct carcinoma)

141. CLEAR CELL CARCINOMA NOS “Malignant epithelial neoplasm composed of a monomorphous population of cells that have optically clear cytoplasm”. Age 40 to 70 years. Site: minor glands of the mouth (60%) particularly in the base of tongue and palate.

142. The majority of tumors with a predominant population of clear cells have been diagnosed as epithelial-myoepithelial carcinomas. Other differentials: clear cell oncocytoma mucoepidermoid carcinoma acinic cell carcinoma sebaceous carcinoma metastatic renal cell carcinoma are needed to be excluded. It is a diagnosis by exclusion.

143. cl Hyalinizing clear cell carcinoma. Uniform population of cells with clear cytoplasm forming discrete nests in a dense fibrous stroma.

144. Lymphoepithelial carcinoma “Lymphoepithelial carcinoma (LEC) is an undifferentiated carcinoma accompanied by a prominent non-neoplastic lymphoplasmacytic infiltrate”. Less than 1% of all salivary gland tumors. Striking racial predilection for Eskimos, south-eastern Chinese and Japanese. The tumor is associated with Epstein-Barr virus in almost all cases in Eskimos , Chinese and Japanese

145. Etiology- EBV. Site- parotid gland(80%), submandibular gland. Morphologically indistinguishable from nasopharyngeal carcinoma. Gross- fleshy and firm, and range from 1-10 cm in size (mean 2-3 cm)

146. Undifferentiated lymphoepithelioma-like carcinoma of the parotid gland. The tumor has sharply demarcated margins and grossly resembles a lymphoma.

147. Undifferentiated, lymphoepithelioma-like carcinoma. A large component of tumor (left) is surrounded by a brisk lymphoplasmacytic reaction (right). The neoplastic cells have large, vesicular, but relatively uniform nuclei. Mitotic figures are typically easily identified. Cell borders are indistinct. The epithelial cells are mixed in a complex fashion with the reactive lymphoplasmacytic elements

148. In situ hybridization for EBV-encoded small RNA (EBER). Almost all of the carcinoma cells express strong nuclear EBER hybridization signals. Note complete absence of signal in the surrounding lymphoid stroma .

149. Differential Diagnosis : Metastatic lymphoepithelial carcinoma. Large cell carcinoma Lymphoma( DLBCL) Lymphadenoma.

150. Undifferentiated carcinoma Rare tumors composed of primitive/anaplastic cells which exhibit no obvious line of differentiation. Focal isolated glandular formation or squamous differentiation does not exclude this diagnosis. Undifferentiated carcinoma can be further subclassified into: small cell carcinoma large cell undifferentiated carcinoma lymphoepithelioma-like carcinoma

151. Small cell carcinoma Small cells are defined as tumor cells with diameter less than 30 um. Characterized by a proliferation of small anaplastic cells with scant cytoplasm, fine nuclear chromatin, and inconspicuous nucleoli”. Extremely rare , Age - fifth and seventh decades of life, M>F. Site – parotid(most common). D ivided into neuroendocrine and ductal types largely depending on the presence or absence of neurosecretory granules

152. Small cell carcinoma. High-power view showing the tumor cells with scant cytoplasm and inconspicuous nucleoli. Mitotic figures are readily identified. Small cell carcinoma. Tumor cells are diffusely immunopositive for chromograninA .

153. Paranuclear dot-like pattern of immunoreactivity for cytokeratin 20. The tumor cell nuclei are round to oval, with pale, dispersed chromatin and a well-defined nuclear membrane

154. DD- Metastatic small cell carcinoma Solid variant of adenoid cystic ca. Metastatic malignant melanoma.

155. Large cell carcinoma Very rare, Age >60 years , site – parotid. Morphologically they are similar to anaplastic carcinoma of the lung, thyroid or pancreas. C onsist of sheets and irregular islands of large pleomorphic cells with well defined cell borders, copious cytoplasm and large nuclei containing prominent nucleoli. Mitoses, tumor necrosis, lymphatic and vascular invasion are seen.

156. Large cell carcinoma. Sheet-like growth pattern of large pleomorphic cells with abundant eosinophilic cytoplasm and prominent nucleoli Solid growth with peripheral palisading and several rosette-like structures. The tumor cells have large and polygonal nuclei with vesicular chromatin and prominent nucleoli

157. Differential diagnosis : Metastatic undifferentiated carcinoma. Metastatic malignant melanoma. Anaplastic large cell lymphoma of intraparotid lymph node. Lymphoepitheliomalike carcinoma.

158. Adenocarcinoma NOS Exhibits ductal differentiation but lacks any of the histomorphologic features that characterize the other defined types of salivary carcinoma. Age- 6 th to 7 th decade. F >M. Site – parotid(60%), minor salivary glands(40%). The growth patterns are protean, the single unifying feature being the lack of recognisable patterns diagnostic of other specific neoplasms Small areas of the tumor may show features of specific neoplasms

159. Adenocarcinoma NOS: Low grade tumor. Prominent well-formed glandular formations. Intermediate-grade tumor. Fused glandular formations with focal solid areas.

160. High-grade tumor. Irregularly shaped islands and strands of anaplastic carcinoma cells. Glandular formations are inconspicuous.

161. Mucinous adenocarcinoma “ Malignant tumour composed of epithelial clusters within large pools of extracellular mucin. The mucin component usually occupies the bulk of the tumour mass”. Age >50yrs,M>F. Site- palate and the sublingual gland.

162. Colloid carcinoma Composed of multiple pools of mucin in a delicate fibrous stroma that surrounds atypical pleomorphic carcinoma cells. Detail of carcinoma nests demonstrating prominent nucleoli and moderate amounts of eosinophilic cytoplasm

163. Squamous cell carcinoma Primary salivary gland SCC is very rare(<1%) Parotid (80%), submandibular gland(20%) Age : 60 to 65years, M:F= 2:1. History of previous radiotherapy. Differential Diagnosis- Metastatic squamous cell carcinoma High grade Mucoepidermoid carcinoma. Warthin's tumor and oncocytoma with florid atypical squamous metaplasia.

164. Low-power view showing multilocular cystic lesions filled with lamellar keratin material. Portion of the cyst wall consists of stratified squamous epithelium with keratinization through parakeratotic cells.

165. Sialoblastoma Also known as embryoma , congenital carcinoma or congenital basal cell adenoma Present at birth or within first few months of life. C omposed of primitive-appearing cells with occasional ductal formation, recapitulating the embryonic salivary tissue. Parotid /submandibular gland = 3:1. Associated with facial palsy, congenital nevi, & concomitant hepatoblastoma .

166. The tumor forms sheets of basaloid cells with focal ductal differentiation separated by fibromyxomatous stroma . . The tumor cells are uniform without mitotic figures or pleomorphism.

167. Soft tissue tumors Non-epithelial tumors comprise about 10% of all salivary glands tumors Benign vascular tumors ( hemangioma and lymphangioma ) are the commonest mesenchymal tumors >50% mesenchymal lesion. Benign tumors> malignant tumors. Major salivary glands. Benign tumors: vascular tumors > lipomas > neural >sarcoma.

168. Juvenile hemangioma It is the most common salivary gland tumor in infants. Also known as capillary hemangioma,juvenile hemangioendothelioma or infantile hemangioendothelioma . Site- parotid gland Involute spontaneously by 6 to 7 years of age. Gross : hypertrophic lobules of salivary gland with a gray-reddish color, the basic structure of the parotid gland is maintained and a tumor mass is indistinct .

169. Tumor diffusely and uniformly involves the parotid gland lobules, leaving scattered striated ducts. Proliferation of the plump endothelial cells with mild nuclear atypia.

170. Haematolymphoid tumors Primary salivary gland non-Hodgkin lymphomas- 5% of all primary extranodal NHL . Most commonly affected gland-parotid gland (75% of all cases), followed by the submandibular gland (20%). Extranodal marginal zone B-cell lymphomas (MALT lymphomas)- 80% of lymphoma cases. BLEL is a known risk factor for the development of salivary gland lymphoma.

171. well-developed stage of MALT lymphoma showing scattered lymphoepithelial lesions in diffuse sheets of monocytoid cells Lymphoepithelial lesion formed by the infiltration of monocytoid cells in the proliferation of duct epithelial cells.

172. MALT lymphoma.Immunohistochemistry . (A) The lymphoid tumor cells at both inside and outside of the lymphoepithelial lesion diffusely\ express CD20 (left) but are negative for CD3 (right). Immunoglobulin light chain restriction. Many kappa light chain-positive cells are seen in the left, whereas only scattered lambda positive cells are identified in the right

173. SECONDARY TUMORS Comprise about 5% of all malignant tumours of salivary glands. 80%of sec.of parotid are from head & neck tumors . 85% of mets in submandibular gland are from distant sites . 60% - SCC , 15% - melanomas. Lung carcinoma (especially the small cell carcinoma type), kidney and breast carcinomas are the most common.

174. Most important features taken into consideration before making a diagnosis are : Tumor borders Cellular composition Architectural arrangement Cytologic features Stromal components Analytic approach to diagnosis of epithelial tumors of salivary glands

175. Some acinic cell ca and ca-ex-PA have circumscribed borders. Pushing type of infiltration – Epithelial myoepithelial carcinoma, Basal cell adenocarcinoma, acinic cell carcinoma. Morphologically bland looking myoepithelial , basal cell, oncocytic neoplasm if having invasive borders : malignant . Warthin's tumor complicated by infarction or inflammation can result in adhesions to the surrounding tissues , mimicking a -malignant neoplasm clinically or grossly. Invasive or not?

176. Cellular differentiation in various salivary gland neoplasms

177. References Diagnostic histopathology of tumors. Christopher D.M Fletcher.3 rd edition p: 239-316 WHO Head & neck tumors. 2005, p no: 210-281 Diagnostic surgical pathology . Stephen.S.Sternberg.5 th edition volume 1. Diagnostic surgical pathology of head and neck. Douglas R. Gnepp . 2 nd edition. Page no 413- 536. Surgical pathology of head and neck. Leon Barnes.3 rd edition, volume 1. page no 475- 607.

178. Thank you