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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
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 glad tumors
Clinical Impression
“Rule out bug bite”
Differential Diagnoses
• Acinic cell carcinoma
• Apocrine or eccrine sweat duct tumor
• Mammary analogue secretory carcinoma
• Benign oncocytic neoplasms • Oncocytoma, Oncocytic cystadenoma, Warthin tumor
• Mucoepidermoid carcinoma
• Salivary duct carcinoma
Diagnosis
Mammary Analogue Secretory Carcinoma (MASC)
? Primary salivary gland origin v. primary cutaneous tumor
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
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
Histology of MASC
• Unencapsulated, lobulated
• Intercalated duct cells in tubular, microcystic, papillary patterns
• Lumina with ample “bubbly” secretions (mucicarmine +)
• Absence of serous acinar granules
Immunohistochemistry of MASC Staining • Usually positive
• S100
• CK7
• Vimentin • Often positive
• EMA
• GCDFP
• Mammoglobin
• Negative
• CK5/6, CK20
• P63, TTF-1, PSA, Thyroglobulin
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Differentiating Features of MASC
Griffith et al, Cancer Cytopathology 2012
Differentiating Features of MASC
Griffith et al, Cancer Cytopathology 2012
Fusion Gene
• Almost all MASC had fusion gene ETV6-NTRK3
Normal Cells No ETV6 Split Signals Abnormal ETV6 split signals
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
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, vimentin, mammaglobin, GCDFP, and identification of the ETV6-NTRK3 fusion gene would be required to completely evaluate tumors of this type.
Cutaneous Metastases v. Adnexal Primary Carcinoma: A Practical Approach
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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%
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Cutaneous Metastases
• Relative frequencies of involvement of different skin sites •Face & Scalp 22%
•Abdomen 18%
•Back 12%
•Chest 10%
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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
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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*
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Cutaneous Metastases v. Primary Adnexal Carcinoma
• Most common patterns of staining: •Lung adenocarcinoma: CK7+/CK20-, S-100-, TTF-1+ •Melanoma: CK7-/CK20-/S-100+/MART-1+/MITF •Bladder (TCC): CK7+/CK20+/S-100- •Renal Cell CA: CK7+/CK20-/S-100-/EMA+/CA-9+ •Breast: CK7+/CK20-/ER/PR+/Her-2-neu+/- •Prostate: CK7-/CK20-/PSA+
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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
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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 from breast metastases
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Cutaneous Metastases v. Primary Adnexal Carcinoma
• Of these, the best combination: •Her-2-neu: more commonly positive in metastatic breast CA than adnexal/sweat duct primaries
•Androgen receptor: more common in sebaceous tumors than breast metastases
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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
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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
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. 2010 May;34(5):599-608. • 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. 2011 Jul;459(1):117-8. • Fehr A, Löning T, Stenman G. Mammary analogue secretory carcinoma of the salivary glands with
ETV6-NTRK3 gene fusion. Am J Surg Pathol. 2011 Oct;35(10):1600-2. • 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. 2012 Mar;146(3):514-5. • 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. 2012 Jan;36(1):27-34. • Chiosea SI, Griffith C, Assaad A, Seethala RR. Clinicopathological characterization of mammary
analogue secretory carcinoma of salivary glands. Histopathology. 2012 Sep;61(3):387-94. • 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. 2013 May;121(5):234-41. • 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. 2013 Mar;7(1):35-9.
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. 2013 Feb;47(1):36-43. • 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. 2013 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;15:5046–5048. • 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;40:152–157. • 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. 2012 Mar;146(3):514-5. • 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. 2012 Jan;36(1):27-34. • Chiosea SI, Griffith C, Assaad A, Seethala RR. Clinicopathological characterization of
mammary analogue secretory carcinoma of salivary glands. Histopathology. 2012 Sep;61(3):387-94.
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. 2013 May;121(5):234-41. • 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. 2013 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. 2013 Feb;47(1):36-43. • 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. 2013 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;15:5046–5048. •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;40:152–157.