ModPath Chat

Currently, PAX8 is the most commonly used immunomarker for gynecologic carcinomas; however, it lacks specificity. By mining The Cancer Genome Atlas mRNA expression profile data, Drs. Ding and Liu’s team identified SOX17 as a potential specific marker for gynecologic tumors. The authors performed immunohistochemical staining on tissue microarrays from 416 ovarian and endometrial cancer cases and 1544 solid tumors from other organs. Like PAX8, SOX17 was highly expressed in most subtypes of ovarian carcinoma (97.5% vs 97% for PAX8 in serous carcinoma, 90% vs 90% in endometrioid carcinoma, and 100% vs 100% in clear cell carcinoma), except for mucinous carcinoma (0% vs 27%). SOX17 was also highly expressed in endometrial carcinoma subtypes (88% vs 84% in endometrioid carcinoma, 100% vs 100% in serous and clear cell carcinoma). Importantly, SOX17 was not expressed in thyroid carcinomas, renal cell carcinomas, and mesotheliomas.

Primary ovarian mucinous tumors represent a heterogeneous group of neoplasms that can be diagnostically challenging. Our guest, Dr. Pavel Dundr and his coauthors analyzed 124 tumors that were originally diagnosed as mucinous borderline tumors (MBTs) or mucinous carcinomas (MCs), with an emphasis on interobserver diagnostic agreement and assessment of the potential utility of molecular profiling.

Only a moderate agreement in diagnosis was found between the 13 observers on the study (k 0.524, for mucinous cystadenoma vs MBT vs MC). A perfect agreement for the distinction between mucinous cystadenoma/MBT - as a combined category - and MC was found in only 36.3% of cases. Differentiating between MBTs and MCs with expansile invasion was particularly problematic.

A comparison of molecular findings between the MBT and MC groups did not show major unequivocal differences. Interestingly, HER2 overexpression or amplification was found in 5.3% of MBTs, 35.3% of all MCs and in 45% of MCs with expansile invasion.

Extranodal extension (ENE) is a significant prognostic factor for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma. However, it remains controversial whether ENE is prognostically relevant in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). The host discusses with Dr. Nora Katabi from Memorial Sloan Kettering Cancer Center her team’s recent study on the topic.

Patients with ENE had shortened overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). The 5-year OS, DSS, and DFS were 95%, 97%, and 90% for the group without ENE, and 64%, 71%, and 65% respectively for the group with ENE. On multivariate survival analysis, the presence of ENE was an independent adverse prognostic factor for OS, DSS, and DFS. The authors propose to document the presence and extent of ENE for these tumors and give consideration for the American Joint Committee on Cancer (AJCC) 9th edition to include ENE into pN stage of HPV-positive OPSCC.

Immunohistochemistry (IHC) and microsatellite instability (MSI) testing constitute the two major test modalities currently in use for detecting deficient mismatch repair (dMMR). Each is associated with caveats and limitations that can be consequential. Most notably, the traditional approach of defining mismatch repair protein IHC abnormality by complete loss of staining in all tumor cells is evolving. Partial or clonal loss is becoming recognized as a manifestation of gene abnormality; in some cases, such clonal loss is associated with germline pathogenic variants. Non-colorectal cases, and occasionally even colorectal tumors, that are MMR deficient by IHC but not MSI-high by current standards are being recognized. Recent data suggest that these immunohistochemistry abnormal/non-microsatellite instability-high cases warrant further genetic workup for Lynch syndrome detection. In this episode, we discuss with Dr. Jinru Shia of Memorial Sloan Kettering Cancer Center her team's view on what constitutes the most optimal strategy in test selection and how best to utilize case context to enhance the interpretation of the dMMR test results.

The group of precursors that lead to HPV-independent, p53-wild-type squamous cell carcinoma is largely unexplored. Nonetheless, a subset of lesions with verruciform acanthosis and altered squamous maturation has been characterized using diverse nomenclature such as VAAD, vLSC, DEVIL, and VAM. These lesions are associated with invasive squamous cell carcinoma and verrucous carcinoma of the vulva, and they harbor recurrent alterations in oncogenes like PIK3CA, HRAS, and NOTCH1.

Dr. Carlos Parra-Herran from the department of Pathology at Brigham and Women's Hospital discusses the importance of reproducibly in distinguishing these lesions from other squamous vulvar precursors and non-neoplastic mimickers with acanthosis or verruciform growth. In order to align with the WHO classification, his group proposes the unifying term of HPVi (p53wt) vaVIN.

Adenoid Ameloblastoma is a very rare benign odontogenic tumor characterized microscopically by epithelium resembling conventional ameloblastoma, with additional duct-like structures, epithelial whorls, and cribriform architecture. Dentinoid deposits, clusters of clear cells, and ghost-cell keratinization may also be present.These tumors do not harbor BRAF or KRAS mutations and their molecular basis appears distinct from conventional ameloblastoma but remains unknown. Dr. Carolina Cavalieri Gomes from the Universidade Federal de Minas Gerais in Brazil, discusses her team’s discovery of CTNNB1 (beta-catenin) exon 3 mutations in 4 of 9 primary cases and 2 additional recurrences.

While the occasional presence of ghost cells keratinization was the feature that led the team to initially investigate beta-catinin, this feature was present in only 2/6. Furthermore, nuclear beta-catenin immunoexpression (IHC) was found in 7 of 8 tested samples including some with wild type CTNNB1. The findings support the classification of adenoid ameloblastoma as a separate entity, and not as a subtype of ameloblastoma. The use of beta-catenin IHC could help in establishing the diagnosis in challenging cases.

Flat lesions of the urothelium with histologic features that falls short of the threshold for urothelial carcinoma in situ (CIS) remains a challenging problem in diagnostic surgical pathology. Among these are flat urothelial hyperplasia, urothelial dysplasia, and atypia of unknown significance; lesions that have struggled under evolving classifications, changing criteria, and limited clinical actionability, all confounded by the recognized lack of diagnostic reproducibility.

In this episode of ModPath Chat, Dr. Gladell Paner discusses with the host his recently published "Controversies in Pathology" article in Modern Pathology on the pros and cons of keeping the previous terminology of this group of lesions. 

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