04/09/2018. Salivary Gland Pathology in the Molecular Era Old Friends, Old Foes, & New Acquaintances
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1 Salivary Gland Pathology in the Molecular Era Old Friends, Old Foes, & New Acquaintances Jennifer L. Hunt, MD, MEd Aubrey J. Hough Jr, MD, Endowed Professor of Pathology Chair of Pathology and Laboratory Medicine University of Arkansas for Medical Sciences 1 1
2 Agenda Old Friends Old Foes Shifty Acquaintances 4 Old Friends 5 Mucoepidermoid Carcinoma Incidence Most common malignant salivary gland tumor (children and adults) Major and minor salivary glands Peak incidence 5th to 6th decades Clinical Mass lesion Surgical treatment with margins 6 2
3 Histology Mucus cells and cysts Epidermoid cells Intermediate cells 7 Mucus cells and Cysts I M E Cell types 9 3
4 Salivary Gland Tumors Tumor specific General grading Grading by Definition Mucoepidermoid Adenoid cystic carcinoma Epithelialmyoepithelial Adenocarcinoma, NOS Salivary Duct carcinoma Polymorphous low-grade No Grading Acinic cell carcinoma 10 Mucoepidermoid Translocation t(11;19)(q21;p13) MECT1-MAML2 MECT1: also known as CRTC1, TORC1, WAMTP1 camp response element binding protein (CREB) regulated transcriptional coactivator MAML2: Notch coactivator Translocation activates Notch target genes independent of Notch ligands 11 MECT-MAML2 Translocation Courtesy of Dr. Sanja Dacic University of Pittsburgh 12 4
5 Translocation Analysis in MEC 80% 69/97 28/40 71% 70% 60% 11/24 46% 40% 20% 5/39 13% 0% Low Grade Intermediate High Grade Seethala High Grade Fehr, Genes Chrom Canc 47:203, 2008 Behboudi, Genes Chrom Canc 45:470, 2006 Okabe, Clin Cancer Res 12:3902, 2006 Martins, J Molec Diag 6:205, 2004 Seethala, AJSP 34:1106, Variant Morphology Oncocytic MEC Clear cell MEC Sclerosing MEC Psammomatous MEC Warthin-like variant? 14 Oncocytic MEC Site Gender Mean Age Our Series 8/11 Parotid (73%) 5 Male Literature 12/17 Parotid (71%) 10 Male 6 Female 6 Female 58 years 59 years Weinreb I, AJSP 33:409,
6 Oncocytic MEC Histology Predominant epithelioid oncocytic cells Focal muceopidermoid carcinoma areas or prominent mucinous differentiation IHC p63 positive in the oncocytic cells Mucin and PASD positive in mucus cells 16 Oncocytic Mucoepidermoid Carcinoma Oncocytic Mucoepidermoid Carcinoma, mucin 6
7 Oncocytic Mucoepidermoid Carcinoma, p63 Oncocytic MEC Molecular 10/14 (71%) positive for MECT1-MAML2 translocation Negative, 29% Positive, 71% Garcia J, Human Path, 42:2001, Clear cell Mucoepidermoid Carcinoma 7
8 Clear cell Mucoepidermoid Carcinoma, mucin Clear cell Mucoepidermoid Carcinoma, p63 Differential Diagnosis Clear cell (hyalinizing) carcinoma 24 8
9 Clear Cell Carcinoma Incidence Rare <1% of salivary gland tumors Clinical Minor >> major 21% in parotid Peak in 6th to 8th decades 25 Clear Cell Carcinoma Cytology Clear cells Glycogen content variable Focal eosinophilia, rare squamous Mucocytes usually absent 26 Clear Cell Carcinoma Other histologic features Duct and gland lumens absent Invasion Perineural Stromal Stromal hyalinization Clear cell hyalinizing carcinoma 27 9
10 Clear cell carcinoma 28 Clear cell carcinoma 29 Clear Cell Carcinoma Immunohistochemistry CEA + EMA + Myoepithelial markers negative p63 uniformly positive CK5/6 uniformly positive 30 10
11 Clear Cell Carcinoma Treatment Surgical resection with clear margins Prognosis Excellent prognosis Rarely metastasizes or causes death Aggressive cases Increased anaplasia Increased mitotic activity 31 Clear Cell Carcinoma t(12;22) EWSR1-ATF1 Translocation Similar to the translocation seen in clear cell sarcomas of tendons and aponeuroses, angiomatoid fibrous hystioctyoma, and clear-cell sarcomas of the gastrointestinal tract 32 Variant Morphology Oncocytic MEC Clear cell MEC Sclerosing MEC Psammomatous MEC Warthin-like variant? 33 11
12 Old Foes 34 Adenoid Cystic Carcinoma Incidence Relatively common Any salivary gland location Clinical Mass lesion Nerve palsies Surgical treatment with margins 36 12
13 Adenoid Cystic Carcinoma Histology Tubular, cribriform, solid patterns Solid has worse behavior Perineural invasion Nuclei small, dark, and angulated 37 Adenoid cystic carcinoma, cribriform Adenoid cystic carcinoma, tubular 39 13
14 Adenoid cystic carcinoma, solid 40 Adenoid Cystic Carcinoma, perineural invasion Adenoid Cystic Carcinoma IHC CKIT and bcl-2 positive Epithelial cells: cytokeratins Myoepithelial cells: p63, SMA, CK5/
15 Adenoid Cystic Translocation t(6;9) (q22-23; p23-24) MYB-NFIB MYB Transcription factor with an important role in cell proliferation, apoptosis, and differentiation Highly expressed in immature proliferating cells, and down-regulated as cells become more differentiated Expressed in translocation in myoepithelial cells NFIB: nuclear factor 1B 43 Translocation: FISH & IHC 100% 80% 60% 40% 20% Translocation No translocation Abnormal 0% Adenoid cystic Other salivary tumors West R, Am J Surg Pathol 2011;35: High Grade Transformation Clinical Tumor progression with aggressive disease May have clinical history of adenoid cystic carcinoma Histology Low grade areas and high grade areas Epithelial predominance Necrosis Vascular invasion 45 15
16 Adenoid cystic carcinoma with high grade transformation 46 Adenoid cystic carcinoma with high grade transformation High Grade Transformation Immunohistochemistry Loss of myoepithelial component SMA, p63, calponin negative All cells stain with cytokeratin Strong p53 staining High proliferative rate (Ki-67) 48 16
17 Epithelial-Myoepithelial Carcinoma Incidence: Rare Clinical: Mass lesion 30% are encapsulated Parotid 60%, palate 10% Histology Epithelial: Tubules and ducts Myoepithelial: Surrounds epithelial cells Dense basement membrane material 49 Epithelial-myoepithelial carcinoma 50 Epithelial-myoepithelial carcinoma 51 17
18 Epithelial-Myoepithelial Carcinoma IHC Epithelial markers Myoepithelial markers CKIT positive (70%) Bcl-2 positive (70%) 52 EMC, Cytokeratin 53 EMC, p63 Epithelial-Myoepithelial Carcinoma Prognosis 95% disease specific prognosis Poor prognostic markers Necrosis Angiolymphatic invasion Positive surgical margins 54 18
19 Polymorphous Low Grade Histology Mixed growth patterns Open nuclei, bland Perineural and stromal invasion 55 Polymorphous Low Grade Incidence Usually in oral cavity, palate Clinical Mass lesion Surgical treatment with margins 56 Polymorphous low grade adenocarcinoma 19
20 Polymorphous low grade adenocarcinoma Polymorphous low grade adenocarcinoma Polymorphous Low Grade Immunohistochemistry GFAP negative Bcl-2 positive S100 positive CKIT +/
21 Shifty Acquaintances 61 Acinic Cell Carcinoma Histology--variable Serous Papillary-cystic Tubulolobular Special stains Cytoplasmic zymogen granules PAS, diastase resistant DOG1 and carbonic anhydrase VI 62 Acinic cell carcinoma 63 21
22 Acinic cell carcinoma, H&E PAS after diastase 64 Zymogen Poor Acinic Cell Carcinoma Major differential diagnoses Acinic cell carcinoma 12% on re-review were MASC ~50% of zymogen poor were MASC Adenocarcinoma, NOS 38% on re-review were MASC Mammary analog secretory carcinoma Low grade cribriform cystadenocarcinom Chiosea SI, AJSP 36:343,
23 Mammary Analogue Secretory Carcinoma Clinical Rare tumor, but not well described yet Mean age 45 Males > Females 69% in major salivary glands 22% with nodal metastasis 92 month disease free survival Skalova A, AJSP. May 2010;34(5): Connor A, AJSP. Jan 2012;36(1): Chiosea SI, Histopathology. Feb Mammary Analogue Secretory Carcinoma Histology Circumscribed, but not encapsulated Lobulated mass divided by fibrous septae Microcystic or tubular Occasional unusual growth Solid or macrocystic Bubbly secretion in microcysts (PAS +) 69 23
24 Mammary Analogue Secretory Carcinoma 70 Mammary Analogue Secretory Carcinoma Mammary Analogue Secretory Carcinoma 24
25 Mammary Analogue Secretory Carcinoma Mammary Analogue Secretory Carcinoma, PAS Mammary Analogue Secretory Carcinoma Immunohistochemistry Strong cytokeratin (7, 8, 18) Strong diffuse S100 GCDFP (70%) Mammoglobin (100%) 75 25
26 Mammary Analogue Secretory Carcinoma, S100 Mammary Analogue Secretory Carcinoma ETV6-NTRK3 t(12;15) FISH image courtesy of Julia Bridge, MD 77 Mammary Analogue Secretory Carcinoma Major differential diagnoses Acinic cell carcinoma Adenocarcinoma, NOS Other ductal derived tumors 78 26
27 Agenda Old Friends Mucoepidermoid Carcinoma Variants of MEC Old Foes Adenoid cystic carcinoma Epithelial myoepithelial carcinoma Shifty Acquaintances Acinic cell carcinoma Mammary analog secretory carcinoma 79 27
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