4/17/2015. Case 1. A 37 year old man with a 2.2 cm solitary left thyroid mass.

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1 Case 1 A 37 year old man with a 2.2 cm solitary left thyroid mass. Case 1 Case 1 1

2 Case 1: Diagnosis? A. Benign B. Atypia of undetermined significance/follicular lesion of undetermined significance C. Suspicious for a follicular neoplasm D. Suspicious for malignancy E. Malignant Case 1: Cytologic Diagnosis Suspicious for a follicular neoplasm (FVPTC cannot be ruled out) 2

3 3

4 Case 1: Histologic Diagnosis Encapsulated follicular variant of papillary thyroid carcinoma Endocrine Pathology Society Working Group on Encapsulated FVPTC Led by Dr. Yuri Nikiforov 25 endocrine pathologists from 7 countries Including Drs. Asa, LiVolsi, Rosai, Lloyd 2 endocrinologists 1 endocrine surgeon 1 psychiatrist/ethicist 1 thyroid cancer survivor 8 teleconferences, 1.5 day meeting Follow up of Encapsulated FVPTC >200 tumors with long term follow up 1 metastases (primary had only limited sampling) 1 local recurrence (tumor had a positive surgical margin) 4

5 Conference Terminology Proposal Non invasive follicular thyroid neoplasm with papillary like nuclear features (NIFT) Capsule must be adequately sampled Typically no further treatment after excision of nodule How are encapsulated FVPTC/ NIFT lesions classified on cytology? N=72 cases Cytologic Number (% total) diagnosis ND 3 (4%) Benign 9 (13%) AUS/FLUS 13 (18%) FN/SFN 7 (10%) SUS 35 (49%) Malignant 5 (7%) Howitt et al Am J Clin Pathol. In press. How would NIFT alter malignancy rate? FNA Diagnosis Total Cases (%) Benign Diagnoses Malignant Diagnoses NNFVPTC Diagnoses ROM ROM if NNFVPTCs Non Malignant Absolute Decrease in ROM Relative Decrease in ROM Non Diagnostic* 53 (8.1 %) % 17.0 % 1.9 % 10% Benign** 167 (25.5 %) % 5.4 % 7.8 % 59% AUS/FLUS 97 (14.8 %) % 22.7 % 17.5 % 44% SFN 88 (13.4 %) % 37.5 % 8.0 % 18% SUS 94 (14.4 %) % 45.7 % 41.5 % 48% POS 156 (23.8 %) % 93.6 % 5.1 % 5% Total % 40.0 % 13.0 % 25% * Referred for surgery because of persistent non diagnostic cytology or suspicious clinical or sonographic findings. ** Referred for surgery because of large nodule size, compressive symptoms, or suspicious clinical or sonographic findings. Strickland et al. Unpublished data. 5

6 NIFT and Thyroid FNA NIFT terminology would decrease malignancy rates for all FNA categories Would especially impact SUS and AUS/FLUS categories Requires clinician, patient, and pathologist education Refine criteria for Malignant category? Consider reclassifying indeterminate categories? Increased role for mutation testing to determine extent of surgery (RAS vs BRAF mutations)? Case 2 A 27 year old woman with a right neck mass. 6

7 Case 2 Case 2 Case 2 7

8 Case 2: Diagnosis? A. Metastatic medullary carcinoma B. Metastatic moderately differentiated neuroendocrine carcinoma of the larynx (atypical carcinoid) C. Metastatic melanoma D. Paraganglioma Calcitonin positive Thyroid primary subsequently identified Case 2 Case 2: Diagnosis Metastatic medullary carcinoma 8

9 Medullary carcinoma 7% of all thyroid cancers C cell derived neuroendocrine carcinoma 15% inherited (MEN IIa and IIb syndromes) >70% develop LN metastasis Notoriously variable appearance Medullary carcinoma Variants Oncocytic Spindle cell Papillary Mixed follicular and MTC Clear cell Small cell Giant cell (anaplastic) MTC Monotonous, dyshesive cells Plasmacytoid Spindled Epithelioid Neuroendocrine nuclei Speckled, granular chromatin Amyloid (50 80%) Medullary carcinoma Cytologic features 9

10 Medullary carcinoma Medullary carcinoma Medullary carcinoma 10

11 Medullary carcinoma Medullary carcinoma Melanoma 11

12 Medullary carcinoma Immunohistochemistry Calcitonin (85 90%) CEA Keratin Synaptophysin Chromogranin TTF 1 Use caution if not able to confirm Check serum calcitonin Hürthle cell neoplasm Neuroendocrine tumors Medullary carcinoma Paraganglioma Keratin negative Laryngeal atypical carcinoid (moderately differentiated neuroendocrine carcinoma) May be calcitonin positive Serum calcitonin elevated in medullary ca TTF 1 negative 12

13 Case 3 A 79 year old woman with a 5 month history of a firm, mobile 2 cm non tender parotid mass. 13

14 14

15 Case 3: Diagnosis A. Adenoid cystic carcinoma B. Basal cell adenoma C. Pleomorphic adenoma D. Pilomatrixoma E. Basaloid squamous cell carcinoma Basaloid neoplasms Immature looking cells with scanty cytoplasm 15

16 Basaloid neoplasms The most problematic differential diagnosis Benign: Basal cell adenoma Myoepithelioma Pleomorphic adenoma Pilomatrixoma Low grade malignant Basal cell adenocarcinoma Basal cell carcinoma High grade malignant Adenoid cystic carcinoma Metastatic small cell carcinoma/merkel cell carcinoma Metastatic basaloid squamous cell carcinoma Adenoid cystic carcinoma may be deceptively bland Adenoid cystic carcinoma Tubular, cribriform, and solid growth patterns Hyaline matrix globules and linear branching structures Acellular Variably sized Sharp borders Matrix is surrounded by basaloid cells Adenoid cystic carcinoma, solid variant More aggressive clinically Most difficult variant to identify on cytology Can only identify by finding characteristic matrix material 16

17 Basal cell adenoma/adenocarcinoma Cytologic features Solid, trabecular, tubular, membranous patterns Can only distinguish benign vs malignant by infiltrative growth in resected specimen Trabecular type Basaloid cells Nuclear pallisading No atypia No necrosis No mitoses Lacks PA matrix material Diagnosis Basal cell adenoma, membranous type 17

18 Basal cell adenoma 2% of benign salivary gland tumors Adults Parotid (75%) Path: Basaloid cells without chondromyxoid matrix Variants: Solid, trabecular, tubular, membranous Basal cell adenoma, membranous type Conspicuous basal lamina Similar to dermal cylindroma Predilection for developing skin adnexal tumors More aggressive behavior: Recurrence 25% Malignant transformation 28% DDx: adenoid cystic carcinoma, PA, basaloid squamous cell carcinoma Beta catenin alterations Nuclear beta catenin CTNNB1 point mutation Basal cell adenoma Genetics Diagnosis # Positive / Total # of Cases (%) Basal Cell Adenoma 12/16 (75 %) Basal Cell Adenocarcinoma 0/1 Adenoid Cystic Carcinoma 0/13 Pleomorphic Adenoma 0/10 Epithelial Myoepithelial Carcinoma 1/2 Jo et al; unpublished data 18

19 Basaloid neoplasms Diagnostic clues Look for atypia, necrosis, and mitotic activity in high grade malignancies Basaloid SCC Small cell ca Pilomatrixoma Squamous whorls Basaloid squamous cell carcinoma Basal cell adenoma/adenocarcinoma Not seen in adenoid cystic carcinoma Characteristic matrix material of adenoid cystic Ghost cells in pilomatrixoma History, clinical, and radiologic findings Case 4 58 year old female presenting with an 8 month history of right sided facial swelling first noticed after an upper respiratory tract infection 19

20 MRI: T1 axial and sagittal views reveal a 3.2 x 2.2 cm well circumscribed cystic and partially enhancing mass centered in the deep lobe of the right parotid gland 20

21 Case 4: Diagnosis A. Acinic cell carcinoma B. Adenocarcinoma, NOS C. Mucoepidermoid carcinoma D. Salivary duct carcinoma E. Mammary analogue secretory carcinoma 21

22 Cytologic findings Mucoid background Dense secretory droplets Clear/oncocytic cells Intracytoplasmic vacuoles Low N:C ratio Round nuclei Variably prominent nucleoli Degenerated cells/necrosis? Oncocytic/clear cell neoplasms Abundant cytoplasm/mild cytologic atypia Oncocytic/clear cell neoplasms Differential diagnosis Warthin tumor Oncocytoma Acinic cell carcinoma Mucoepidermoid carcinoma 22

23 Mucoepidermoid carcinoma Oncocytic variant Clear cell variant Mucoepidermoid carcinoma Low grade Mucus cells (predominate in low grade) Epidermoid cells (predominate in high grade) Intermediate cells Mucinous background Acinic Cell Carcinoma 23

24 Cell blocks are very helpful Cell blocks are very helpful Mucicarmine (MEC) PAS D (Acinic) Immunostains P63 + MEC /+ Oncocytoma DOG 1 +Acinic Acinic cell carcinoma, PAS D H&E PAS-D Mucicarmine 24

25 Am J Surg Pathol 2010;34: case series salivary gland tumors with morphologic similarities to secretory carcinoma of the breast Skalova. Am J Surg Pathol 2010;34: Mammary Analogue Secretory Carcinoma MASC Acinic Cell Carcinoma 25

26 Mammary Analogue Secretory Carcinoma Positive for S 100 and mammaglobin IHC Extracellular secretory material positive for mucicarmine and PAS ETV6 gene rearrangement Mammary Analogue Secretory Carcinoma Variable architecture Clusters, papillary groups, singly dispersed Eosinophilic cells Vacuolated cytoplasm Intracytoplasmic vacuoles Luminal mucin Colloid like secretions Mammary Analogue Secretory Carcinoma Mammaglobin S

27 Mammary Analogue Secretory Carcinoma Cytologic diagnosis POSITIVE FOR MALIGNANT CELLS. Mammary analogue secretory carcinoma. 27

28 MASC: Clinical summary Broad age range M>F Minor and major glands More frequent lymph node metastases Low grade High grade transformation has been described Salivary gland genetics Tumor Translocation Involved genes Pleomorphic Adenoma 8q12 12q13 15 PLAG1 HMGA2 Mucoepidermoid Carcinoma t(11;19)(q21;p13) MECT1 MAML2 Adenoid Cystic Carcinoma t(6;12)(p21;q13) MYB NFIB Mammary Analogue Secretory Carcinoma t(12;15)(p13;q25) ETV6 NTRK3 Hyalinizing Clear Cell t(12;22)(q13;q12) EWSR1 ATF1 Carcinoma Cribriform Adenocarcinoma t(1;14) ARID1A PRKD1 Point mutations in basal cell neoplasms (CTNNB1) and PLGA (PRKD1) 28

29 Case 5 A 59 year old man presents with a left parotid mass Case 3 Case 3 29

30 Case 3 Case 3 Case 3 30

31 Case 3 Case 5: Diagnosis? A. Large cell lymphoma B. Hodgkin lymphoma C. Undifferentiated (lymphoepithelial carcinoma) D. Squamous cell carcinoma E. Sebaceous lymphoadenoma A Case 3 EBNA CK5/6 P16 P63 31

32 Case 3 EBER Case 5: Diagnosis Lymphoepithelial carcinoma Nasopharyngeal carcinoma 32

33 Nasopharyngeal carcinoma Nasopharyngeal carcinoma Nasopharyngeal carcinoma 33

34 Large cells with small lymphocytes Salivary gland Warthin tumor Acinic cell carcinoma Mucoepidermoid carcinoma Lymphadenoma Lymphoepithelial carcinoma Large cells with small lymphocytes Large cell lymphoma Hodgkin Disease Seminoma NPC Thymoma FDC sarcoma Seminoma Morphologic variants: Undifferentiated (lymphoepithelioma like) EBER HPV ISH 34

35 Site of origin Nasopharynx EBV positive Oropharynx HPV positive Salivary gland EBV +/ Diagnosis of exclusion if EBV+ Rare! 35

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