The Application and Pitfalls of Immunohistochemical Markers in Challenging Diagnosis of Genitourinary Pathology

Abstract

Context.— The morphologic features of different entities in genitourinary pathology overlap, presenting a diagnostic challenge, especially when diagnostic materials are limited. Immunohistochemical markers are valuable when morphologic features alone are insufficient for definitive diagnosis. The World Health Organization classification of urinary and male genital tumors has been updated for 2022. An updated review of immunohistochemical markers for newly classified genitourinary neoplasms and their differential diagnosis is needed. Objective.— To review immunohistochemical markers used in the diagnosis of genitourinary lesions in the kidney, bladder, prostate, and testis. We particularly emphasized difficult differential diagnosis and pitfalls in immunohistochemistry application and interpretation. New markers and new entities in the 2022 World Health Organization classifications of genitourinary tumors are reviewed. Recommended staining panels for commonly encountered difficult differential diagnosis and potential pitfalls are discussed. Data Sources.— Review of current literature and our own experience. Conclusions.— Immunohistochemistry is a valuable tool in the diagnosis of problematic lesions of genitourinary tract. However, the immunostains must be carefully interpreted in the context of morphologic findings with a thorough knowledge of pitfalls and limitations.

Diagnostic Biomarkers in Renal Cell Tumors According to the Latest WHO Classification: A Focus on Selected New Entities

“…A variable degree of CAIX staining can be seen in several nonrenal tumors, including neuroendocrine tumors, mesotheliomas, and tumors of the endometrium, stomach, cervix, breast, lung, liver, testis, and brain, which is a pitfall in distinguishing renal versus nonrenal carcinomas [3].…”

“…In renal tumors, the most common CK is CK7, a low-molecular-weight CK which is highly expressed in most papillary renal cell carcinomas (PRCCs), ChrRCCs, collecting duct carcinomas (CDCs), and almost all CPRCTs and mucinous tubular and spindle cell carcinomas (MTSCCs) [59]. Conversely, CK7 staining is a rare and focal finding in CCRCC and tubulocystic RCC, and it is very focal to almost absent in RO [3]. CK7 is also a marker of urothelial carcinoma; therefore, an upper tract urothelial carcinoma should be always taken into account when assessing a CK7-positive renal neoplasm.…”

“…Urothelial carcinoma cells express other CKs, namely CK20 and 34βE12 as well, which are low-molecular-weight and high-molecular-weight CKs, respectively. However, CK20 expression is lacking in the vast majority of renal cell tumors, except ESC-RCC, whereas 34βE12 is a marker of CDC, renal medullary carcinoma (RMC), and most CCPRCTs [3]. CD10 (also known as acute lymphocytic leukemia antigen or CALLA) is a cell-surface glycoprotein expressed on the brush border of the proximal renal tubular epithelial cells and podocytes.…”

“…CD10 (also known as acute lymphocytic leukemia antigen or CALLA) is a cell-surface glycoprotein expressed on the brush border of the proximal renal tubular epithelial cells and podocytes. It has been traditionally regarded as a marker of CRCC, PRCC, and CDC [3]. Other renal tumors can at least partly express CD10, such as ChrRCC and RO [56].…”

“…Overall, this new classification provides a more precise distinction of the various subgroups of tumors and emphasizes the importance of their biological and molecular characterization alongside traditional cytological and architectural features. In this setting, immunophenotyping (i.e., the identification of tissue biomarkers through immunohistochemistry (IHC)) plays an even greater role than in the past, as it represents a bridge between morphology and genetics through the determination of diagnostic protein biomarkers identifiable in tissue sections [3]. Since there is no specific immunophenotypic biomarker for a particular histotype of renal tumor, it is essential to apply a panel of markers that, based on morphological characteristics, allow us to favor or rule out the diagnostic hypotheses formulated on a case-by-case basis.…”