A Cutaneous Facial Mass Identified as the New Entity Mammary Analogue Secretory Carcinoma of Probable Salivary Gland Origin

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1 A Cutaneous Facial Mass Identified as the New Entity Mammary Analogue Secretory Carcinoma of Probable Salivary Gland Origin Scott W. Binder, MD Professor and Senior Vice Chair Chief, Dermatopathology Geffen/UCLA Healthcare

2 Case Presentation A 50 year-old man presents with a 7 mm erythematous papule on the right face Developed over a few months Asymptomatic No history of prior neoplasms including salivary gland tumors Lesion located just lateral to nose

3 Clinical Impression Rule out bug bite

4 Histopathology 4

5 Histopathology 5

6 Histopathology 6

7 Histopathology 7

8 Histopathology 8

9 Histopathology 9

10 Differential Diagnoses Acinic cell carcinoma Apocrine or eccrine sweat duct tumor Mammary analogue secretory carcinoma Benign oncocytic neoplasms Mucoepidermoid carcinoma Metastasis from a visceral primary

11 Outside Special Stains S-100 EMA CK 7 CK 20 p63 Mucicarmine

12 Additional Immunohistochemistry Mammaglobin CEA CK 5/6 Thyroglobin TTF-1 PSA Ki67

13 Diagnosis Mammary Analogue Secretory Carcinoma (MASC)? Primary salivary gland origin v. primary cutaneous tumor Rule out metastasis

14 Background MASC first described in 2010 by Skalova et al. Morphologic overlap between acinic cell carcinoma and secretory carcinoma of the breast Tumors affect all ages (range 14-77), slightly male-predominant

15 MASC Presents as slowly growing mass, often near parotid gland No evidence of primary cutaneous origin, as of yet Most treated with non-radical excision +/-radiotherapy Cases of lymph node metastases, local recurrences, low mortality Chiosea et al, Histopathology 2012

16 Histology of MASC Unencapsulated, lobulated Intercalated duct cells in tubular, microcystic, papillary patterns Lumina with ample bubbly secretions (mucicarmine +) Absence of serous acinar granules

17 Immunohistochemistry of MASC Staining Usually positive S100 CK7 Vimentin Often positive EMA GCDFP Mammaglobin Negative CK5/6, CK20 P63, TTF-1, PSA, Thyroglobulin 17

18 Immunohistochemistry of most apocrine tumors Cytokeratin 5/6+, p63+ S100+/-, cytokeratin 7+ Mammaglobin +/-, EMA+ (patchy, highlights ducts) CEA+, GCDFP 15+/- 18

19 Key Differential Diagnoses of MASC Diagnosis Benign oncocytic neoplasms (oncocytoma, oncocytic cystadenoma, Warthin tumor) Key Cytomorphologic Features Lack vacuolated cytoplasm, more cohesive Ancillary Testing Features S-100 negative, antimitochondrial antibody positive Acinic cell carcinoma Usually lacks mucin PAS-D+ cytoplasmic granules, DOG-1 strongly positive, mammaglobin negative Mucoepidermoid carcinoma Metastatic carcinoma Epidermoid differentiation High grade nuclei, many show necrosis p63 positive, S100 negative, MAML2 translocation Staining variable 19

20 Fusion Gene Almost all MASC had fusion gene ETV6-NTRK3 Normal Cells No ETV6 Split Signals Abnormal ETV6 split signals

21 Clinical Course Patient had neoplasm completely excised by the ENT service Work-up for primary underlying neoplasm is on-going and imaging studies are negative for primary salivary gland tumor

22 Summary MASC is likely an under-recognized diagnosis and can present a diagnostic pitfall, easily being confused with a primary adnexal tumor given that it is a newly-described entity and too bland to be immediately interpreted as a metastasis or recurrence. The origin of this particular tumor is still uncertain, as no salivary gland primary has been detected in this patient. Immunohistochemical stains for S100, CK7, p63, cytokeratin 5/6, mammaglobin, and identification of the ETV6-NTRK3 fusion gene would be required to completely evaluate tumors of this type? Primary cutaneous/subcutis MASC v. unusual primary apocrine sweat duct tumor (solid and cystic hidradenoma)

23 Cutaneous Metastases v. Adnexal Primary Carcinoma: A Practical Approach 23

24 Cutaneous Metastases Clinical Considerations Mean age at presentation is 62 Most common primary tumors Lung 30% Melanoma 18% G.I. Tract 14% Breast 5% Lymphoma 5% In approximately 10% of cases, the primary is unknown Histologic Types Adenocarcinoma 40% Melanoma 15% Squamous carcinoma 15% Other 30% 24

25 Cutaneous Metastases v. Primary Adnexal Carcinoma Histopathologic Characteristics of Metastases Tumor growth often concentrated in the deep dermis - bottom heavy appearance Sparing of epidermis common Ulceration and pagetoid spread rarely noted (colonic and melanoma) Tumor necrosis sometimes present Lymph/vascular invasion sometimes observed High grade tumor cells with numerous mitoses 25

26 Cutaneous Metastases v. Primary Adnexal Carcinoma Immunohistochemical Considerations Battery may include Cytokeratin 7 Cytokeratin 20 S-100 MART-1/Melan-A/MITF or SOX-10 PSA TTF-1 ER/PR/Her-2-neu CDX-2 Cytokeratin 5/6, p63* 26

27 Cutaneous Metastases v. Primary Adnexal Carcinoma Recent studies have shown that CK5/6 and p63 may help distinguish primary adnexal neoplasms (CK5/6+/p63+) from most metastatic carcinomas (CK5/6-/p63-) P63 especially helpful D2-40 not been especially helpful in my lab 27

28 46 yo F with history of breast cancer x7 years 28

29 Histopathology 29

30 Histopathology 30

31 Histopathology 31

32 IHC Results CK7 32

33 IHC Results ER 33

34 IHC Results HER2/neu 34

35 IHC Results CK5/6 35

36 IHC Results P63 36

37 68 yo M w paranasal mass present x 1 yr rapid recent growth 37

38 Histopathology 38

39 Histopathology 39

40 Histopathology 40

41 IHC Results CK5/6 41

42 IHC Results p63 42

43 Cutaneous Metastases v. Primary Adnexal Carcinoma Impossible to reliably distinguish primary or metastatic eccrine/apocrine tumors from cutaneous metastases of breast carcinomas, especially apocrine or mucinous types Immunohistochemical Staining of Breast v. Metastases ER (estrogen receptor) PR (progesterone receptor) GCDFP-15 (gross cystic disease fluid protein) CEA Her-2-neu None of these may reliably separate primary sweat duct tumors from breast metastases 43

44 Cutaneous Metastases v. Primary Adnexal Carcinoma Aberrant staining of metastases Technical Antibody Technique Therapeutic effect chemo and/or radiation/immune modulators Tumor metastases may have different immuno phenotypes than the primary Tumors don t always read the books Another tumor/primary is responsible for the aberrant staining 44

45 Cutaneous Metastases v. Primary Adnexal Carcinoma Take Home H&E considerations and clinical information most important for diagnostic purposes Immunohistochemistry stains are useful ancillary studies, especially cytokeratin 5/6 and p63 but be careful as these may lead you astray Be sure to eliminate the possibility of a basal cell carcinoma demonstrating unusual growth patterns Always think of the possibility of a primary adnexal CA in the appropriate clinical and histologic context Occasional inability to differentiate a primary adnexal CA from a visceral metastasis 45

46 References Saliva A, Vanecek T, Sima R, Laco J, Weinreb I, Perez-Ordonez B, Starek I, Geierova M, Simpson RH, Passador-Santos F, Ryska A, Leivo I, Kinkor Z, Michal M. Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol May;34(5): Griffith C, Seethala R, Chiosea SI. Mammary analogue secretory carcinoma: a new twist to the diagnostic dilemma of zymogen granule poor acinic cell carcinoma. Virchows Arch Jul;459(1): Fehr A, Löning T, Stenman G. Mammary analogue secretory carcinoma of the salivary glands with ETV6- NTRK3 gene fusion. Am J Surg Pathol Oct;35(10): Rastatter JC, Jatana KR, Jennings LJ, Melin-Aldana H. Mammary analogue secretory carcinoma of the parotid gland in a pediatric patient. Otolaryngol Head Neck Surg Mar;146(3): Connor A, Perez-Ordoñez B, Shago M, Skálová A, Weinreb I. Mammary analog secretory carcinoma of salivary gland origin with the ETV6 gene rearrangement by FISH: expanded morphologic and immunohistochemical spectrum of a recently described entity. Am J Surg Pathol Jan;36(1): Chiosea SI, Griffith C, Assaad A, Seethala RR. Clinicopathological characterization of mammary analogue secretory carcinoma of salivary glands. Histopathology Sep;61(3): Griffith CC, Stelow EB, Saqi A, Khalbuss WE, Schneider F, Chiosea SI, Seethala RR. The cytological features of mammary analogue secretory carcinoma: a series of 6 molecularly confirmed cases. Cancer Cytopathol May;121(5): Bishop JA. Unmasking MASC: bringing to light the unique morphologic, immunohistochemical and genetic features of the newly recognized mammary analogue secretory carcinoma of salivary glands. Head Neck Pathol Mar;7(1):35-9.

47 References Jung MJ, Song JS, Kim SY, Nam SY, Roh JL, Choi SH, Kim SB, Cho KJ. Finding and characterizing mammary analogue secretory carcinoma of the salivary gland. Korean J Pathol Feb;47(1): Hwang MJ, Wu PR, Chen CM, Chen CY, Chen CJ. A rare malignancy of the parotid gland in a 13- year-old Taiwanese boy: case report of a mammary analogue secretory carcinoma of the salivary gland with molecular study. Med Mol Morphol Aug 18. Knezevich SR, Garnett MJ, Pysher TJ, et al. ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer Res. 1998;15: Makretsov N, He M, Hayes M, et al. A fluorescence in situ hybridization study of ETV6-NTRK3 fusion gene in secretory breast carcinoma. Genes Chromosomes Cancer. 2004;40: Rastatter JC, Jatana KR, Jennings LJ, Melin-Aldana H. Mammary analogue secretory carcinoma of the parotid gland in a pediatric patient. Otolaryngol Head Neck Surg Mar;146(3): Connor A, Perez-Ordoñez B, Shago M, Skálová A, Weinreb I. Mammary analog secretory carcinoma of salivary gland origin with the ETV6 gene rearrangement by FISH: expanded morphologic and immunohistochemical spectrum of a recently described entity. Am J Surg Pathol Jan;36(1): Chiosea SI, Griffith C, Assaad A, Seethala RR. Clinicopathological characterization of mammary analogue secretory carcinoma of salivary glands. Histopathology Sep;61(3):

48 References Griffith CC, Stelow EB, Saqi A, Khalbuss WE, Schneider F, Chiosea SI, Seethala RR. The cytological features of mammary analogue secretory carcinoma: a series of 6 molecularly confirmed cases. Cancer Cytopathol May;121(5): Bishop JA. Unmasking MASC: bringing to light the unique morphologic, immunohistochemical and genetic features of the newly recognized mammary analogue secretory carcinoma of salivary glands. Head Neck Pathol Mar;7(1):35-9. Jung MJ, Song JS, Kim SY, Nam SY, Roh JL, Choi SH, Kim SB, Cho KJ. Finding and characterizing mammary analogue secretory carcinoma of the salivary gland. Korean J Pathol Feb;47(1): Hwang MJ, Wu PR, Chen CM, Chen CY, Chen CJ. A rare malignancy of the parotid gland in a 13-year-old Taiwanese boy: case report of a mammary analogue secretory carcinoma of the salivary gland with molecular study. Med Mol Morphol Aug 18. Knezevich SR, Garnett MJ, Pysher TJ, et al. ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer Res. 1998;15: Makretsov N, He M, Hayes M, et al. A fluorescence in situ hybridization study of ETV6-NTRK3 fusion gene in secretory breast carcinoma. Genes Chromosomes Cancer. 2004;40:

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