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Novel immunohistochemical markers in the differential diagnosis of endocervical and endometrial adenocarcinoma: The added benefit of CAIX and PAX8.

ABSTRACT: In a biopsy specimen, adenocarcinomas of the endometrium and uterine cervix may demonstrate significant morphologic overlap. The distinction between these two entities prior to surgical resection is clinically significant as assigning the primary site dictates treatment and prognosis. This diagnostic dilemma is approached by the application of a panel of immunohistochemical stains, traditionally composed of CEA, vimentin, p16, ER, and PR. Most cases are successfully managed with this panel; however, in difficult cases additional tools are needed to suggest a more definitive diagnosis. In this study, we reviewed the efficacy of the customary panel of stains, as well as the added value of new stains in the diagnosis of endocervical adenocarcinoma. Our cohort included biopsy samples of 90 patients (81 endometrial and 9 endocervical adenocarcinomas) with a subsequent hysterectomy for confirmation of diagnosis. This study validated the customary panel of stains and suggests additional markers to aid in the differential diagnosis (PAX8 and CAIX). The addition of PAX8 to the traditional panel increases PPV from 85.71% to 100%. A PPV of 100% may also be attained with fewer stains (five total), with the application of a proposed new panel, which includes PAX8, CAIX, CEA, p16 and ER. This is the first-time differential expression of CAIX has been suggested in the distinction between endocervical and endometrial adenocarcinomas.

SUBMITTER: Hernandez-Caballero AI

PROVIDER: S-EPMC7397698 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Novel immunohistochemical markers in the differential diagnosis of endocervical and endometrial adenocarcinoma: The added benefit of CAIX and PAX8.

Hernandez-Caballero Ana I AI Vierkoetter Koah R KR Ahn Hyeong Jun HJ Shimizu David D Terada Keith K

Gynecologic oncology reports 20200727

In a biopsy specimen, adenocarcinomas of the endometrium and uterine cervix may demonstrate significant morphologic overlap. The distinction between these two entities prior to surgical resection is clinically significant as assigning the primary site dictates treatment and prognosis. This diagnostic dilemma is approached by the application of a panel of immunohistochemical stains, traditionally composed of CEA, vimentin, p16, ER, and PR. Most cases are successfully managed with this panel; howe ...[more]

PMID: 32775591

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Project description:BackgroundEndocervical adenocarcinoma (ECA) is further classified as human papillomavirus (HPV)-associated (HPVA) or non-HPVA (NHPVA), per the International Endocervical Adenocarcinoma Criteria and Classification (IECC). HPVA is a glandular tumor with stromal invasion and/or exophytic expansile-type invasion, associated with the typical molecular characteristics of high-risk HPV (HR-HPV) infection. Transforming acidic coiled-coil protein-3 (TACC3),an oncogene that is frequently abnormally expressed,represents a vital biomarker for multiple human malignancies. This study aimed to examine the role of TACC3 in the diagnosis and prognosis of ECA.MethodsWe analyzed 264 patients with ECA who underwent surgical resection, classifying their tumors into HPVA and NHPVA subtypes. The expression levels of TACC3, P16, MLH1, PMS2, MSH2, MSH6 and Ki-67 in tumors were evaluated by tissue microarray using immunohistochemistry (IHC). HPV subtypes were identified in formalin-fixed paraffin-embedded (FFPE) ECA tissues by the polymerase chain reaction (PCR).ResultsECA samples showed increased TACC3 expression relative to adjacent non-carcinoma samples. TACC3 expression was higher in HPVA than in NHPA. In the HPVA subtype, high TACC3 expression was significantly correlated with P16-positive, Ki-67-high expression. Furthermore, TACC3 levels were significantly related to tumor histological type (P = 0.006), nerve invasion (P = 0.003), differentiation (P = 0.004), surgical margin (P = 0.012), parametrium invasion (P = 0.040), P16 expression (P < 0.001), and Ki-67 (P = 0.004). Additionally, Kaplan-Meier analysis showed that TACC3 upregulation was associated with poor overall survival (OS, P = 0.001), disease-free survival (DFS, P < 0.001), and recurrence survival (P < 0.001). Multivariate analysis indicated that elevated TACC3 expression served as a marker to independently predict ECA prognosis. ROC curve analyses indicated that TACC3, P16, and HPV subtypes showed similar utility for distinguishing HPVA from NHPVA, with areas under the ROC curves of 0.640, 0.649, and 0.675, respectively. The combination of TACC3 and HPV subtypes improved the diagnostic performance of ECA compared with TACC3, P16, and HPV subtypes alone.ConclusionsTaken together, our findings identify that TACC3 is a promising complementary biomarker for diagnosis and prognosis for patients with ECA.

Project description:Previously, our international team proposed a three-tiered pattern classification (Pattern Classification) system for endocervical adenocarcinoma of the usual type that correlates with nodal disease and recurrence. Pattern Classification-A tumors have well-demarcated glands lacking destructive stromal invasion or lymphovascular invasion, Pattern Classification-B tumors show localized, limited destructive invasion arising from A-type glands, and Pattern Classification-C tumors have diffuse destructive stromal invasion, significant (filling a 4 × field) confluence, or solid architecture. Twenty-four cases of Pattern Classification-A, 22 Pattern Classification-B, and 38 Pattern Classification-C from the tumor set used in the original description were chosen using the reference diagnosis originally established. One H&E slide per case was reviewed by seven gynecologic pathologists, four from the original study. Kappa statistics were prepared, and cases with discrepancies reviewed. We found a majority agreement with reference diagnosis in 81% of cases, with complete or near-complete (six of seven) agreement in 50%. Overall concordance was 74%. Overall kappa (agreement among pathologists) was 0.488 (moderate agreement). Pattern Classification-B has lowest kappa, and agreement was not improved by combining B+C. Six of seven reviewers had substantial agreement by weighted kappas (>0.6), with one reviewer accounting for the majority of cases under or overcalled by two tiers. Confluence filling a 4 × field, labyrinthine glands, or solid architecture accounted for undercalling other reference diagnosis-C cases. Missing a few individually infiltrative cells was the most common cause of undercalling reference diagnosis-B. Small foci of inflamed, loose or desmoplastic stroma lacking infiltrative tumor cells in reference diagnosis-A appeared to account for those cases up-graded to Pattern Classification-B. In summary, an overall concordance of 74% indicates that the criteria can be reproducibly applied by gynecologic pathologists. Further refinement of criteria should allow use of this powerful classification system to delineate which cervical adenocarcinomas can be safely treated conservatively.

Dataset Information

Novel immunohistochemical markers in the differential diagnosis of endocervical and endometrial adenocarcinoma: The added benefit of CAIX and PAX8.

Publications

Novel immunohistochemical markers in the differential diagnosis of endocervical and endometrial adenocarcinoma: The added benefit of CAIX and PAX8.

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