BASALOID/ BLUE SALIVARY GLAND TUMORS RAJA R. SEETHALA, M.D. UNIVERSITY OF PITTSBURGH

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1 LIST OF COMMONLY USED ABBREVIATIONS BASALOID/ BLUE SALIVARY GLAND TUMORS RAJA R. SEETHALA, M.D. UNIVERSITY OF PITTSBURGH PLGA Polymorphous Low Grade Adeno CASG Cribriform Adeno of Salivary Gland ACC Adenoid Cystic Carcinoma EMCA Epithelial Myoepithelial Carcinoma BCA/BCAC Basal Cell Adenoma/Basal Cell Adeno PA Pleomorphic Adenoma HGT High Grade Transformation SCC Squamous Cell Carcinoma 1 2 TOPICS Basaloid Tumors 001 Applications of Salivary Tumor Basics Basaloid Tumors 101 PLGA/CASG vs ACC Basaloid Tumors 400 Biphasic Basaloid Tumors BASALOID TUMORS 001 APPLICATIONS OF SALIVARY TUMOR BASICS Basaloid Tumors 1337 Pleomorphic Basaloid Tumors and Beyond 3 4 CLEAR CELL, MYXOID Sebaceous Tumors Clear Cell Carcinoma Mucinous Adeno Epithelial- Myoepithelial Oncocytic Metastatic Renal Cell Carcinoma Pleomorphic Adenoma Myoepithelioma Myoepithelial Salivary Duct Squamous cell Polymorphous low grade adeno ONCOCYTIC/ ONCOCYTOID Mammary Analogue Secretory Carcinoma Mucoepidermoid Oncocytoma Epithelial- Myoepithelial Pleomorphic Adenoma Myoepithelioma Myoepithelial Squamous cell Polymorphous low grade adeno Acinic cell Basal Cell Adenoma Basal Cell Adeno Adeno, NOS Acinic cell Basal Cell Adenoma Basal Cell Adeno Adeno, NOS OTHER NON SALIVARY TUMORS/ METASTASES * Common entities Adenoid cystic BASALOID 5 * Common entities Adenoid cystic BASALOID 6 1

2 CALPONIN Acinic Cell CA blue because of the cytoplasm Blue dot tumor Myoepithelioma blue because of the high N/C ratio 7 8 TOOLS FOR RESOLUTION OF ENTITIES - BORDER THE IMPORTANCE OF BORDER IN BASALOID TUMORS Pleomorphic Adenoma Myoepithelioma Acinic cell Squamous cell Adeno, NOS OTHER NON SALIVARY TUMORS/ METASTASES Tubulotrabecular, Solid and Cribriform Types Basal Cell Adenoma Membranous Type RECURRENCES OF Basal Cell Adeno BENIGN TUMORS Epithelial- Myoepithelial Myoepithelial Polymorphous low grade adeno Adenoid cystic Likelihood of Malignancy 9 Palate tumor 1986 Biopsy called Adenoid Cystic Carcinoma Resection same year Cellular Pleomorphic Adenoma; Free of disease 21 years 10 TOOLS FOR RESOLUTION OF ENTITIES - PHENOTYPE ACINUS INTERCALATED DUCT Ductal luminal cells STRIATED DUCT EXCRETORY DUCT Bilayered arrangement of luminal (ductal) cells and abluminal (basal and/or myoepithelial cells) Components often visible on H&E Delineation between cell components is sharp and organized IHC: pronounced phenotypic distinction between components BASALOID TUMORS 101 PLGA/CASG VS ACC Myoepithelial cells Myoepithelial, Acinar tumors Basal cells Ductal tumors Squamoid, Mucous cell containing STILL A CHALLENGE??? BIPHASIC TUMORS tumors

3 POLYMORPHOUS LOW GRADE ADENOCARCINOMA (PLGA) ADENOID CYSTIC CARCINOMA (ACC) Originally coined by Evans and Batsakis Almost exclusively minor salivary (palate 60-80%) Recurrences in 1/3 of patients 0-17% nodal metastasis rate Distant metastases and deaths from disease rare Historically confused with ACC Subgroup (mostly base of tongue) now considered by many as Cribriform Adeno of (+/- minor) 13 Salivary Gland (CASG) (or other synonyms) Biphasic Salivary Gland Tumor (Ducts surrounded by myoepithelial cells) Tubular, Cribriform and Solid growth patterns Slow but relentless progression 5 year survival = 75-80% 15 year survival = <15% 14 SIMILAR GROWTH PATTERNS DIFFERENT CYTONUCLEAR FEATURES AND PHENOTYPE SIMILARITIES Border Growth Patterns MORPHOLOGIC DISTINCTION PLGA/CASG NOT BIPHASIC Ovoid vesicular (classic PLGA) to clear (CASG pattern) CASG pattern also has more of a papillary glomeruloid growth ACC BIPHASIC Angulated hyperchromatic nuclei Stromal clefting 15 PLGA ACC BOTH SHOW INFILTRATIVE BORDERS 16 PLGA ACC SHARED TUBULAR GROWTH 17 PLGA ACC SHARED CRIBRIFORM GROWTH 18 3

4 BILAYER BILAYER PLGA ACC 19 CASG PATTERN PAPILLARY GLOMERULOID 20 IMMUNOPHENOTYPE AND OTHER FINDINGS PLGA/CASG S100 diffusely positive C-kit variable ACC S100 Focally positive C-kit moderately to strongly positive, ductal accentuation Modern IHC p63 variably positive (random pattern)/ ΔNp63 (p40) negative Molecular alterations PRKD family P63 and P40 positive (abluminal pattern) Molecular alterations MYB, MYBL1 Other markers CD43, BCL-2, Ki-67 are unnecessary and of dubious value 21 PLGA S100 ACC S PLGA c-kit ACC c-kit 23 PLGA p63 older staining protocols 24 4

5 25 26 PLGA p63 modern staining protocol PLGA p40 PLGA PANKER ACC p63 IT COULD BE CHALLENGING ON BIOPSY HOWEVER Sampling may limit distinction between monophasic and biphasic Decalcification (Decal) may clear out nuclei and make cells pinker ACC (and almost any salivary tumor) may show surface alterations at minor salivary and sinonasal sites ACC AE1_3 5

6 Decal Section PREVIOUS SLIDE PLGA like area in ACC Deeper in the lesion 33 Recurrence (No Decal) 34 ACC Connecting to Surface Oncocytic Columnar areas near surface

7 ACC Connecting to Surface Squamoproliferative changes at surface Cellular PA EMCA BASALOID TUMORS 400 BIPHASIC BASALOID TUMORS THE REAL EVERYDAY CHALLENGE BCA ACC EPITHELIAL MYOEPITHELIAL CARCINOMA (EMCA) Formally described by Donath et al 1972 Age 6 th decade Female to male ratio - ~1.5:1. Site parotid 60-80% submandibular 8-15% sinonasal 5-10% other up to 5% Outcome very favorable (5 yr survival -94%) 41 HISTOLOGIC FEATURES Multinodular growth (can be partly encapsulated) Biphasic tubules with clear polygonal outer myoepithelial cells and inner eosinophilic cuboidal ductal cells Hyaline stroma Can have overgrowth of either component Non- clear cell variants (i.e. oncocytic) exist 42 7

8 43 Clear cell EMCA with myoepithelial overgrowth 44 A Blue EMCA with myoepithelial overgrowth 45 Biphasic Areas 46 DISTINCTION FROM CELLULAR PA Cellular Pleomorphic Adenoma Epithelial-myoepithelial Carcinoma Encapsulated non infiltrative Small indistinct myoepithelial cells that stream into a myxoid stroma Chondroid elements Multinodular permeation Larger Polygonal myoepithelial cells embedded in hyaline stroma with no streaming CAM 5.2 Actin p63 8

9 ACC (TUBULAR) VS EMCA ACC EMCA Very infiltrative Tubular pattern rarely seen in isolation Typically multinodular pushing permeation Streaming Cellular PA EMCA 49 Small dark angulated myoepithelial cells, scant cytoplasm Clefting between tumor nests and stroma MYB alterations Large polygonal myoepithelial cells Occasional single cell dyshesion but no clefting between tumor and stroma RAS mutations 50 Both can be c-kit +!! BASAL CELL ADENOMA (BCA, HISTORICALLY MONOMORPHIC ADENOMA) Age 5 th decade, F:M 2:1 Parotid>>>submandibular>>>other sites Solitary slow growing mass Tubular ACC EMCA BCA BCA Dermal analogue (Membranous type) Often Multifocal Can be associated with Brooke Spiegler syndrome (multiple trichoepithelioma, cylindroma) Molecular findings: CYLD1 gene, chromosome 16q Presumed tumor suppressor gene, mutated or lost in sporadic and germline tumors Tubulotrabecular type CTTNB1 mutations Nuclear β catenin and LEF-1 expression Recurrence rate Very low <2% Exception Dermal analogue 25% May really be multifocality rather than recurrence

10 1/11/2016 HISTOLOGIC FEATURES MONOMORPHIC IS A MISNOMER Patterns: Tubulotrabecular, Solid, Cribriform, Membranous Basal cells Dark cells outermost palisaded layer Cytokeratin +/-, P63+, Actin+ Pale cells immediately adjacent to dark cells and can have squamoid features Cytokeratin weak+, P63+, Actin- Tubulotrabecular Solid Ductal cells -vary in proportion Cytokeratin+, P63-, Actin- Squamous and sebaceous elements can be present Peculiar S100+ spindled myoepithelial derived stroma in tubulotrabecular tumors Cribriform Membranous TRIPHASIC PHENOTYPE KERATIN 57 P63 58 S100 myoepithelial derived stroma ACTIN 59 Beta Catenin 60 LEF-1 10

11 DISTINCTION FROM CELLULAR PA Cellular PA BCA At most focal palisading Small indistinct myoepithelial cells that stream into a myxoid stroma Chondroid elements Prominent peripheral palisading Distinct from surrounding hyaline or cellular myoepithelial derived stroma Sebaceous elements Nuclear Beta Catenin Cellular PA BCA with myoepithelial derived stroma BASAL CELL ADENOCARCINOMA (BCAC) HISTOLOGIC FEATURES Same morphologic patterns but invasive Age ~ one decade older than BCAC, M=F Usually de novo, but can arise from BCA (usually membranous type) Solid and membranous most common patterns Infiltrative Mitosis>4/10hpf Ki-67 >5% PNI (~1/3) High grade morphology is rare Tubulotrabecular Transition to Solid 65 Invading Fascia 66 11

12 BCA AND BCAC (TUBULOTRABECULAR) VS EMCA EMCA BCA and BCAC No prominent palisading Abundant (clear) cytoplasm in outer layer P63 actin Prominent peripheral palisading Outer layers can be subdivided into dark and pale cells with scant cytoplasm P63> actin (only dark layer) Nuclear Beta Catenin 67 Epithelial Myoepithelial Carcinoma Basal Cell Adeno 68 EMCA P63-Actin double stain BCAC Tubular BCA or EMCA? B-catenin LEF-1 ACC (CRIBRIFORM AND SOLID) VS BCAC (MEMBRANOUS AND CRIBRIFORM) ACC Highly infiltrative BCAC Variable border often cystic or partly encapsulated Cylinders are thicker Small droplets of matrix in membranous pattern Small dark angulated myoepithelial cells, scant cytoplasm Vesicular with peripheral palisading, triphasic staining frequent 71 Pure, rarely any metaplasia Both can be c-kit +!! Squamous and sebaceous elements 72 12

13 73 74 Adenoid Cystic Carcinoma Membranous Basal Cell Adeno Adenoid Cystic Carcinoma Cribriform Basal Cell Adeno BASALOID TUMORS 1337 PLEOMORPHIC BASALOID TUMORS AND BEYOND 75 HIGH GRADE TRANSFORMATION (HGT) IN BASALOID SALIVARY GLAND TUMORS Rare HGT= progression from any conventional type to a pleomorphic high grade Desmoplasia, necrosis common Blue tumors reported to undergo grade transformation ACC EMCA Acinic Cell Carcinoma PLGA/CASG Key to diagnosis, recognition of a conventional component ACC-HGT ACC-HGT 13

14 P63 loss of biphasic phenotype in ACC-HGT 79 Acinic cell - HGT Courtesy of Drs. Simon Chiosea and Lindsay Williams 80 PAS-D COMMON DIFFERENTIAL DIAGNOSES Entities Salivary Duct Carcinoma Resolution Apocrine thus pink not blue. AR+. Basaloid and Non-Keratinizing SCC (Primary and Metastasis) Other Non-Salivary Tumors and Metastases Primary Surface dysplasia/in situ component. p63 diffuse, not abluminal or with rare cells Metastasis Clinical history/ possibly viral markers (EBV/HPV) Index of suspicion if a tumor strays from previously mentioned characteristics Salivary Duct CA AR Surface Component Basaloid SCC 14

15 1/11/2016 A basaloid tumor of the parotid OR IS IT??? Basaloid SCC Solid ACC P63 p16 HPV ish 87 Another basaloid tumor of the parotid 88 P40 Glands or something else? TAKE HOME POINTS Like other salivary gland tumors, basaloid or blue salivary tumors can be stratified by their border and cell type PLGA/CASG is not a biphasic tumor and is thus fairly simple to differentiate from ACC when given adequate material ACC, EMCA, PA, and BCA/BCAC are biphasic tumors that have key discriminatory morphologic characteristics EWSR1 FISH ++ Adamantinoma like Ewing Sarcoma Almost all basaloid salivary tumors can undergo HGT and are best recognized by searching for the differentiated component; otherwise non salivary tumors and metastases should be considered CD99 15

16 REFERENCES: Basaloid/ Blue Salivary Gland Tumors Diseases of the salivary gland. Seethala RR, In: Wick MD, LiVolsi VA, Pfeifer JD, Stelow EB, Wakely PE, editors: Silverberg's Principles and Practice of Surgical Pathology and Cytopathology, Cambridge Univesity Press, Polymorphous low-grade adeno of minor salivary glands. A study of 14 cases of a distinctive neoplasm. Evans HL, Batsakis JG. Cancer 1984;53(4): Polymorphous low grade adeno: a clinicopathologic study of 164 cases. Castle JT, Thompson LD, Frommelt RA, Wenig BM, Kessler HP. Cancer 1999;86(2): Cribriform adeno of minor salivary gland origin principally affecting the tongue: characterization of new entity. Skalova A, Sima R, Kaspirkova-Nemcova J, Simpson RH, Elmberger G, Leivo I, Di Palma S, Jirasek T, Gnepp DR, Weinreb I, Perez-Ordoñez B, Mukensnabl P, Rychly B, Hrabal P, Michal M. Am J Surg Pathol Aug;35(8): Polymorphous low grade adeno has a consistent p63+/p40- immunophenotype that helps distinguish it from adenoid cystic and cellular pleomorphic adenoma. Rooper L, Sharma R, Bishop JA. Head Neck Pathol Mar;9(1):79-84 Epithelial-myoepithelial : a review of the clinicopathologic spectrum and immunophenotypic characteristics in 61 tumors of the salivary glands and upper aerodigestive tract. Seethala RR, Barnes EL, Hunt JL. Am J Surg Pathol Jan;31(1):44-57 A comparative analysis of LEF-1 in odontogenic and salivary tumors. Bilodeau EA, Acquafondata M, Barnes EL, Seethala RR. Hum Pathol Feb;46(2): Trabecular and solid-cribriform types of basal cell adenoma. A morphologic study of two cases of an unusual variant of monomorphic adenoma. Dardick I, Lytwyn A, Bourne AJ, Byard RW. Oral Surg Oral Med Oral Pathol Jan;73(1): Current concepts on dedifferentiation/high-grade transformation in salivary gland tumors. Costa AF, Altemani A, Hermsen M. Patholog Res Int. 2011;2011: Adenoid cystic with high-grade transformation: a report of 11 cases and a review of the literature. Seethala RR, Hunt JL, Baloch ZW, Livolsi VA, Leon Barnes E. Am J Surg Pathol Nov;31(11): Dedifferentiated adenoid cystic : a clinicopathologic study of 6 cases. Nagao T, Gaffey TA, Serizawa H, Sugano I, Ishida Y, Yamazaki K, Tokashiki R, Yoshida T, Minato H, Kay PA, Lewis JE. Mod Pathol Dec;16(12):

17 Acinic cell with high-grade transformation: a report of 9 cases with immunohistochemical study and analysis of TP53 and HER-2/neu genes. Skálová A, Sima R, Vanecek T, Muller S, Korabecna M, Nemcova J, Elmberger G, Leivo I, Passador-Santos F, Walter J, Rousarova M, Jedlickova K, Curik R, Geierova M, Michal M. Am J Surg Pathol Aug;33(8): Epithelial-myoepithelial with high grade transformation. Roy P, Bullock MJ, Perez-Ordoñez B, Dardick I, Weinreb I. Am J Surg Pathol Sep;34(9): Polymorphous low-grade adeno of the salivary glands with transformation to high-grade. Simpson RH, Pereira EM, Ribeiro AC, Abdulkadir A, Reis-Filho JS. Histopathology 2002;41(3): Salivary duct : the predominance of apocrine morphology, prevalence of histologic variants, and androgen receptor expression. Williams L, Thompson LD, Seethala RR, Weinreb I, Assaad AM, Tuluc M, Ud Din N, Purgina B, Lai C, Griffith CC, Chiosea SI. Am J Surg Pathol May;39(5): p63 Immunohistochemistry in the distinction of adenoid cystic from basaloid squamous cell. Emanuel P, Wang B, Wu M, Burstein DE. Mod Pathol May;18(5): Adamantinoma-like Ewing sarcoma mimicking basal cell adeno of the parotid gland: a case report and review of the literature. Lezcano C, Clarke MR, Zhang L, Antonescu CR, Seethala RR. Head Neck Pathol Jun;9(2):280-5.