This document discusses a case of a 52-year-old woman with a slow-growing, painless buccal tumor. The original diagnosis was low-grade adenocarcinoma, not otherwise specified (NOS). The document provides background on adenocarcinoma NOS, noting that while recent advances have improved classification, about 5-10% of salivary gland adenocarcinomas still fall into this category. Molecular analysis may reveal that some NOS tumors are variants of established types or facilitate discovery of new tumor types within the NOS group.
This document discusses a case of a 52-year-old woman with a slow-growing, painless buccal tumor. The original diagnosis was low-grade adenocarcinoma, not otherwise specified (NOS). The document provides background on adenocarcinoma NOS, noting that while recent advances have improved classification, about 5-10% of salivary gland adenocarcinomas still fall into this category. Molecular analysis may reveal that some NOS tumors are variants of established types or facilitate discovery of new tumor types within the NOS group.
This document discusses a case of a 52-year-old woman with a slow-growing, painless buccal tumor. The original diagnosis was low-grade adenocarcinoma, not otherwise specified (NOS). The document provides background on adenocarcinoma NOS, noting that while recent advances have improved classification, about 5-10% of salivary gland adenocarcinomas still fall into this category. Molecular analysis may reveal that some NOS tumors are variants of established types or facilitate discovery of new tumor types within the NOS group.
This document discusses a case of a 52-year-old woman with a slow-growing, painless buccal tumor. The original diagnosis was low-grade adenocarcinoma, not otherwise specified (NOS). The document provides background on adenocarcinoma NOS, noting that while recent advances have improved classification, about 5-10% of salivary gland adenocarcinomas still fall into this category. Molecular analysis may reveal that some NOS tumors are variants of established types or facilitate discovery of new tumor types within the NOS group.
Entities, Old Enemies Justin A. Bishop, MD UT Southwestern Medical Center Dallas, Texas @ENTPathology Salivary Gland Tumors
• One of the most difficult areas of ENT pathology
• Rare – few pathologists see high volumes • Tremendous variety • Even a single tumor type (e.g., pleomorphic adenoma) may show marked morphologic variability • Difficult to stay up-to-date on new findings altering classification Selected Genetic Alterations in Salivary Gland Tumors Tumor Alteration % cases Acinic cell carcinoma NR4A3 rearrangements 95% HTN3::MSANTD3 fusion 5% Adenoid cystic carcinoma MYB, MYBL1, and/or NFIB fusions ~80% MYB activation/amplification Basal cell adenoma/ CTNNB1 or CYLD mutation 40-80% (adenoma) Basal cell adenocarcinoma 5-30% (carcinoma) Clear cell carcinoma EWSR1::ATF1, rare others ~80-90% Epithelial-myoepithelial carcinoma PLAG1 or HMGA2 fusions ~50% HRAS mutations Intraductal carcinoma NCOA4::RET, ~50% (intercalated duct, mixed, oncocytic) TRIM27::RET, TRIM33::RET, other fusions BRAF V600E mutation Mucoepidermoid carcinoma MAML2 fusions ~70-80%
Mucinous adenocarcinoma AKT1 and TP53 mutations >90%
Pleomorphic adenoma and carcinoma ex- PLAG1 or HMGA2 fusions ~60-90%
pleomorphic adenoma
Polymorphous adenocarcinoma PRKD1, PRKD2 and PRKD3 fusions or 80-90%
mutations Sialadenoma papilliferum BRAF V600E mutations 80% Salivary duct carcinoma (also apocrine TP53, HRAS, PIK3CA, PTEN mutations 90-100% intraductal carcinoma and sclerosing ERBB2 amplification polycystic adenoma) PLAG1 or HMGA2 fusions, rare others Secretory carcinoma ETV6::NTRK3 100% ETV6::RET, ETV6::MET, others Case 1 13-year-old boy with a parotid mass Original Diagnosis
• Warthin tumor MAML2 FISH Current Diagnosis
“Warthin like” variant of mucoepidermoid carcinoma.
Mucoepidermoid Carcinoma
• Most common salivary gland
carcinoma. • Both adults and children. • Major or minor salivary glands. • Low, intermediate, or high-grade. • Prognosis grade-dependent • CRTC1::MAML2 or CRTC3::MAML2 found in ~80% low-intermediate grade MECs, and 46-85% of high grade MECs. Mucoepidermoid Carcinoma Difficult-to-Diagnose Variants of Mucoepidermoid Carcinoma Warthin Tumor
• 2nd most common salivary gland
tumor (after PA). • 6th-7th decade (very rare in children). • Slight male predominance. • Linked to cigarette smoking. • May arise from lymph nodes. MAML2 in Warthin tumor?
• Bullerdiek J, et al. Translocation t(11;19)(q21;p13.1) as the sole
chromosome abnormality in a cystadenolymphoma (Warthin's tumor) of the parotid gland. Cancer Genet Cytogenet. 1988;35(1):129-32. • Mark J, et al. Chromosomal patterns in Warthin's tumor. A second type of human benign salivary gland neoplasm. Cancer Genet Cytogenet. 1990;46(1):35-9. • Enlund F, et al. Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors. Exp Cell Res. 2004;292(1):21-8.
Very Bland MEC Cystadenoma (CRTC3::MAML2) (no fusions) Oncocytic Variant of Mucoepidermoid Carcinoma Sclerosing Variant of Mucoepidermoid Carcinoma Sclerosing Variant of Mucoepidermoid Carcinoma Ciliated Variant of Mucoepidermoid Carcinoma Courtesy Ilan Weinreb
Mucoepidermoid Carcinoma with Acinar Differentiation
Spindled Variant of Mucoepidermoid Carcinoma p40/p63-Negative Mucoepidermoid Carcinoma p40 Mucoepidermoid Carcinoma with No “Ep” MAML2 FISH Metatypical Adenoid Cystic Carcinoma “Funny Sinonasal” Adenoid Cystic Carcinoma “Pinky Duct” Adenoid Cystic Carcinoma Case 2 78-year-old woman with a slow-growing, painless lower lip tumor CK7 CK20 Original Diagnosis
• Papillary mucinous cystadenocarcinoma, rule out metastasis
Mucinous Salivary Gland Carcinomas
• Include mucoepidermoid carcinoma, mucin-rich variant salivary duct carcinoma. • Tumors not fitting into other categories are rare and have historically been called many different names in case reports or small series. • Mucinous adenocarcinoma, colloid carcinoma, signet ring carcinoma, intestinal adenocarcinoma, mucinous cystadenocarcinoma, etc. • Cystadenocarcinoma and mucinous adenocarcinoma were in 2005 WHO, but removed for 2017 and lumped into adenocarcinoma, NOS. CK7 CK20 Mucinous Adenocarcinomas
Rooper, et al. AJSP. 2021; 45:1337-47.
NGS Results Mucinous Adenocarcinomas
• Metastases only seen in colloid and signet ring patterns
AJSP. 2021; 45:1337-47.
• Mucin-producing salivary adenocarcinomas represent a histologically
diverse, single entity. • We propose a unified mucinous adenocarcinoma category subdivided into papillary, colloid, signet ring, and mixed subtypes to facilitate better recognition and classification of these tumors. • Back in the 2022 WHO. Final Diagnosis
• Mucinous adenocarcinoma, papillary type
Salivary IPMN? Salivary IPMN? Case 3 70-year-old woman with base of tongue fullness and dysphagia. CK5/6 p40 p16 Original Diagnosis
• Described in 1994 as “hyalinizing clear cell carcinoma.” • Variably named • Clear cell carcinoma, NOS (WHO 2005) • “Clear cell adenocarcinoma” (AFIP 2008) • Now “clear cell carcinoma” in WHO 2017 and 2022. Clear cell carcinoma
• Originally regarded as a diagnosis of exclusion. • Discovery of consistent EWSR1::ATF1 gene fusion has helped define this tumor type more precisely. • Subset with alternate fusions. • Same translocation as OCCC, clear cell sarcoma, myoepithelial carcinoma of ST. Clear cell carcinoma
• Most common in oral cavity (especially base of tongue and palate),
but may be seen in other minor or major salivary glands. • Slight female predominance. • Usually 5th-8th decades, rare in children. • Submucosal swelling, +/- ulcer and pain. Clear cell carcinoma
• Low-grade by definition • Very rare cases of high-grade transformation • Good prognosis, only occasional recurrences or lymph node metastases. • Distant metastases and tumor-related deaths are rare. Clear Cell Carcinoma Clear Cell Carcinoma Clear Cell Carcinoma Clear Cell Carcinoma Clear Cell Carcinoma Clear Cell Carcinoma Can be eosinophilic!
Clear Cell Carcinoma
Can be mucinous!
Clear Cell Carcinoma
Clear Cell Carcinoma Is squamoid (sometimes overtly!)
(especially base of tongue) • 16 of 16 showed some p16- positivity • All HPV RNA ISH negative, EWSR1-rearranged. • Significant treatment difference: • p16+ OPSCC: often chemo- Am J Surg Pathol. 2018;42(3):367-371. radiation only. • CCC: surgery only. CCC HPV+ SqCC MEC CCC Mucoepidermoid Carcinoma Mucoepidermoid CCC carcinoma EWSR1 in ~75% MAML2 in ~80% Case 4 52-year-old woman with a slow-growing, painless buccal tumor Original Diagnosis
• Low-grade adenocarcinoma, NOS
Adenocarcinoma, NOS
• Despite recent advancements in classification, a significant
group (5-10%) of salivary gland adenocarcinomas still cannot be placed in a specific diagnostic category and are termed adenocarcinoma, not otherwise specified (NOS).
• With new diagnostic tools, this group is expected to
shrink. Adenocarcinoma, NOS
• Molecular analysis may:
• Reveal that some tumors in the NOS category, particularly low-intermediate-grades, are better classified as variants of an already-established tumor type
• Facilitate the discovery of novel tumor types within the
adenocarcinoma NOS category that have not yet been recognized • Before its description, many cases of secretory carcinoma were diagnosed as low- or intermediate-grade adenocarcinoma NOS Am J Surg Pathol. 2019. 43(8):1023-32. Updated Experience Head Neck Pathol. 2021; 15:1192-1201.
• 24 total cases • 13 women, 11 men • 17 to 83 years (mean, 49.5) • 23 of 24 oral cavity • Palate (n=14) and buccal mucosa (n=6) most frequent • 1 Parotid gland • MEF2C::SS18 fusion demonstrated in 21 of 24 • Identical breakpoints • In the remaining 3 cases, SS18 break apart FISH was positive • Treatment information available in 17 • All managed with surgery only • In 14 cases with follow-up (1-216 months, mean 30), none recurred or metastasized Microsecretory Adenocarcinoma Microsecretory Adenocarcinoma Microsecretory Adenocarcinoma Microsecretory Adenocarcinoma Microsecretory Adenocarcinoma Microsecretory Adenocarcinoma Microsecretory Adenocarcinoma Microsecretory Adenocarcinoma Microsecretory Adenocarcinoma Microsecretory Adenocarcinoma S100 Microsecretory Adenocarcinoma SOX10 Microsecretory Adenocarcinoma p63 p40 Microsecretory Adenocarcinoma SMA SMA Microsecretory Adenocarcinoma Mammaglobin Differential Diagnosis
Microsecretory Polymorphous adenocarcinoma: adenocarcinoma: • MEF2C::SS18 • PRKD1, 2, or 3 rearrangements or mutations Conclusions
• We identified a novel salivary gland neoplasm
which we named “microsecretory adenocarcinoma” • Consistent, unique histologic, immunohistochemical, and molecular features • Propensity for oral cavity • Indolent behavior Conclusions
• Combined histologic/IHC/molecular approach may
serve as a model for further refining salivary gland tumor classification and decreasing the number of tumors diagnosed as adenocarcinoma, NOS. Microcribriform Adenocarcinoma
• In the original MSA paper, there was one case in the control group with SS18::ZBTB7A. • In retrospect, some overlap, but sufficiently different that we did not feel confident including as MSA. • Now 4 cases, unique and reproducible Microcribriform adenocarcinoma • AJSP, in press. Microcribriform Adenocarcinoma
• 3 women, 1 man • 24-65 years (mean, 52) • Non-oral sites: • 2 parotid, 1 submandibular, 1 bronchus • All cases treated surgically, with two receiving post-operative radiation • Follow-up data available for two cases, both NED 12-66 months after surgery Microcribriform Adenocarcinoma Microcribriform Adenocarcinoma Microcribriform Adenocarcinoma Microcribriform Adenocarcinoma p40 SMA Thank you!
