Evening Specialty Conference: Cytopathology

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1 : Cytopathology N. Paul Ohori, M.D. University of Pittsburgh Medical Center Disclosure of Relevant Financial Relationships Disclosure of Relevant Financial Relationships USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. N. Paul Ohori declares he has no conflict of interest to disclose. August 2014 Clinical History: A 71 year old woman presented with hoarseness and dyspnea. Biopsy of a tracheal mass and FNA of a cervical lymph node showed a carcinoma with ETV6/NTRK3 gene fusion. In addition, a 4.6 cm left thyroid mass and a 2.6 cm right thyroid mass were identified. FNA of the left thyroid mass was performed. 1

2 What is the significance of ETV6/NTRK3 gene fusion? ETV6/NTRK3 gene fusion Neoplasms with ETV6/NTRK3 gene fusion Fusion of ETS variant 6 gene on chromosome 12 to the neurotrophic tyrosine receptor kinase 3 gene on chromosome 15. The resulting transcript encodes for a chimeric protein product that is a constitutively active tyrosine kinase. ETV6/NTRK3 gene fusion has been found in a variety of neoplasms. Infantile (Congenital) Fibrosarcoma (1998) Congenital Mesoblastic Nephroma (1998) Acute Myeloid Leukemia (1999) Secretory Breast Carcinoma (2002) Chronic Eosinophilic Leukemia (2011) Inflammatory Myofibroblastic Tumor (ALK-negative) (2016) Neoplasms with ETV6/NTRK3 gene fusion Mammary Analogue Secretory Carcinoma (MASC) (2010) Salivary gland MASC Parotid Submandibular Minor Skin MASC Thyroid MASC (2015) Papillary Thyroid Carcinoma with ETV6/NTRK3 gene fusion (2014) Differential Diagnosis Salivary gland MASC Thyroid MASC Papillary Thyroid Carcinoma Metastasis from other neoplasms with ETV6/NTRK3 2

3 Previous Specimens Tracheal Biopsy: Carcinoma with ETV6/NTRK3 Tracheal biopsy (1 month prior) Carcinoma with ETV6/NTRK3 Lymph Node FNA (2 weeks prior) Carcinoma PAX-8 Tracheal Biopsy: Carcinoma with ETV6/NTRK3 TTF-1 GCDFP-15 Mammaglobin Other immunohistochemistry results: Positive PanCK, CK7, CK5/6, GCDFP (focal), Mammaglobin (focal) Negative S100, ER, p63, Calponin, Napsin-A, CK20, p63, WT-1 Lymph Node FNA: Carcinoma PAX-8 Lymph Node FNA: Carcinoma Mammaglobin 3

4 Differential Diagnosis based on Tracheal Biopsy and Lymph Node FNA Carcinoma in tracheal biopsy and lymph node FNA sample with similar morphologic features. PAX-8 positive TTF-1 negative GCDFP/Mammaglobin positive Differential Diagnosis: Papillary Thyroid Carcinoma (favored diagnosis) MASC (salivary gland vs thyroid) August 2014 Back to our index case: Left Thyroid FNA Cytopathology Diagnosis: Papillary Thyroid Carcinoma [No cell block available for IHC] Molecular Studies (ThyroSeq): ETV6/NTRK3 Cytology and Molecular Test Summary Tracheal biopsy: Carcinoma with ETV6/NTRK3 (with DDx) Lymph Node FNA: Carcinoma (with DDx) Left Thyroid FNA: PTC with ETV6/NTRK3 Tracheal biopsy, lymph node biopsy, and thyroid FNA specimens with shared features. Involved with the same gene fusion. Is all of this Papillary Thyroid Carcinoma with ETV6/NTRK3? What have we learned about Head and Neck carcinomas with ETV6/NTRK3 gene fusion recently? Salivary Gland MASC Skalova (2010): Mammary Analogue Secretory Carcinoma (~Sec Br Ca) Tubular, microcystic, and solid patterns may mimic thyroid carcinoma In salivary glands, ETV6/NTRK3 t(12;15) (p13;q25) is specific for MASC. Other fusion partners discovered - ETV6-X Prior MASC Dx - Zymogen-poor Acinic Cell Carcinoma or ADC, NOS. Positive IHC: Mammaglobin, GCDFP, S100, GATA-3, CK7, CK19, DOG-1 Negative IHC: Calponin, SMA, p63, CK5/6 High-grade MASC: necrosis, prominent nucleoli and pleomorphism Low-grade MASC: may mimic Salivary Gland Adenoma Prognosis: overall mo DFS; high-grade mo DOD. Skálová A, et al. Am J Surg Pathol. 2010;34(5):

5 Cytopathology of MASC Skálová A, et al. Am J Surg Pathol. 2010;34(5): Bishop JA, et al. Cancer Cytopathol May;121(5): Griffith CC, et al. Cancer Cytopathol May;121(5): Takeda M, et al. Diagn Cytopathol Feb;43(2): Pusztaszeri MP, Faquin WC. Semin Diagn Pathol. 2015;32: Thyroid MASC Histology, IHC, and Molecular features ~ Salivary gland MASC Positive IHC: Mammaglobin, GCDFP, S100, p63, GATA-3, weak PAX-8 Negative IHC: TTF-1, Thyroglobulin Large, infiltrative, extra-thyroidal extension, locally aggressive can invade into trachea, high stage May be associated with synchronous PTC Classic or FVPTC; ETV6/NTRK3 in both MASC and PTC (?PTC >>> MASC) Frequent recurrence but associated with long term survival Role of Tyrosine kinase inhibitors (TKI) (e.g. entrectinib) Papillary Thyroid Carcinoma with ETV6/NTRK3 ETV6/NTRK3 is the second most common genetic alteration in radiation-related thyroid carcinoma ~14% (after RET/PTC). ~1-2% among sporadic well-differentiated PTCs (higher in pediatric population). Rad associated: FVPTC or Classic PTC +/- solid growth pattern Non-rad associated: Mixed follicular and papillary patterns (occ pure Classic PTC or FVPTC) Infiltrative and multinodular Clear cell or oncocytic features Cytoplasmic vacuoles (similar to MASC) Locally aggressive, can metastasize Lymph node metastasis Psammoma bodies Overt nuclear features of PTC Metastasis from other carcinomas with ETV6/NTRK3 Secretory Breast Carcinoma (SBC) Tubular, microcystic, solid patterns, intra and extracellular eosinophilic secretions Usually low-grade with mild to moderate nuclear atypia Occasional high-grade SBC with numerous mitoses and necrosis Triple-negative breast carcinoma ETV6/NTRK3 is specific for SBC in the breast In the current case, breast carcinoma was excluded by negative imaging studies. Tracheal Resection (2 months after index case) Left Neck Dissection Total Thyroidectomy 5

6 Tracheal Resection Tracheal Resection Lymph Node MASC with High Grade Transformation Arising from Minor Salivary Glands Metastatic MASC Thyroidectomy: MASC extending into and metastasizing to Thyroid Left Lobe 5.0, 1.7cm; Right 2.5cm S-100 DOG-1 Mammaglobin PAX-8 TTF-1 SOX-10 Pertinent Issues for the Thyroid FNA case MASC has many masks ETV6/NTRK3 is a specific marker in the appropriate context. More helpful with single organ involvement (e.g. salivary gland). More complicated with thyroid gland involvement. High-grade MASC vs higher grade transformation of PTC. May mask the typical morphologic features of MASC. Therapeutic implications High stage PTC/MASC treated with surgery and/or chemotherapy/radiation TKI (e.g. entrectinib) Acquired resistance (NTRK3 G623R mutation) Summary Tracheal biopsy (1 month prior) Carcinoma with ETV6/NTRK3 Lymph Node FNA (2 weeks prior) Carcinoma (similar to tracheal biopsy) Left Thyroid FNA (index case) Papillary Thyroid Carcinoma with ETV6/NTRK3 Tracheal Resection MASC with LN metastasis and extension into Thyroid 6

7 Message 1 ETV6/NTRK3 gene fusion is found in a variety of neoplasms Infantile (Congenital) Fibrosarcoma (1998) Congenital Mesoblastic Nephroma (1998) Acute Myeloid Leukemia (1999) Secretory Breast Carcinoma (2002) Mammary Analogue Secretory Carcinoma (MASC) (2010) Chronic Eosinophilic Leukemia (2011) Papillary Thyroid Carcinoma (2014) Inflammatory Myofibroblastic Tumor (ALK-negative) (2016) Message 2 MASC can mimic Papillary Thyroid Carcinoma with ETV6/NTRK3 gene fusion Distinguishing features: Cyto-histologic features Mammaglobin, GCDFP, DOG-1, TTF-1, Thyroglobulin MASC with high-grade transformation may mask characteristic features Solid pattern with high-grade nuclear features may be from MASC or PTC Sometimes, you will not know until it comes out. Message 3 Most MASCs are indolent although some may behave aggressively. Most are comparable to other low-grade salivary gland carcinomas. High stage MASC treated by chemotherapy/radiation Therapeutic implications of ETV6/NTRK3 gene fusion (TKI e.g. entrectinib) References Skálová A, et al. Am J Surg Pathol. 2010;34(5): Griffith C, et al. Virchows Arch Jul;459(1): Griffith CC, et al. Cancer Cytopathol May;121(5): Williams L, Chiosea SI. Head Neck Pathol Dec;7(4): Skálová A, et al. Am J Surg Pathol Jan;38(1): Sethi R, et al. Laryngoscope Jan;124(1): Leeman-Neill RJ, et al. Cancer Mar 15;120(6): Takeda M, et al. Diagn Cytopathol Feb;43(2): Ito Y, et al. Am J Surg Pathol May;39(5): Pusztaszeri MP, Faquin WC. Semin Diagn Pathol. 2015;32: References Stevens TM, et al. Mod Pathol Aug;28(8): Del Castillo M, et al. Am J Surg Pathol Nov;39(11): Skálová A, et al. Am J Surg Pathol Jan;40(1):3-13. Picarsic JL, et al. Pediatr Dev Pathol Mar-Apr;19(2): Drilon A, et al. Ann Oncol May;27(5): Stevens TM, Parekh V. Arch Pathol Lab Med. 2016;140(9): Dogan S, et al. Mod Pathol Sep;29(9): Reynolds S, et al. Head Neck Pathol Sep;10(3): Dettloff J, et al. Head Neck Pathol Jul 11. [Epub ahead of print] Seethala RR, et al. Am J Surg Pathol Jan 25. [Epub ahead of print] 7

8 Important Information Regarding CME/SAMs The Online CME/Evaluations/SAMs claim process will only be available on the USCAP website until September 30, No claims can be processed after that date! After September 30, 2017 you will NOT be able to obtain any CME or SAMs credits for attending this meeting. 8