New developments in diagnosis of an aggressive form of renal cancer

By Dr. Michelle S. Hirsch

Kidney cancer is a disease that affects over 400,000 patients worldwide each year. However, there are at least 15 different subtypes of renal cell tumors, called renal cell carcinomas, that arise from epithelial structures (tubules) within the kidney. Some of these renal cell carcinoma subtypes are associated with aggressive behavior and spread to other organs, leading to death in a subset of patients; whereas other are more indolent and are cured when surgically removed. It is the pathologist’s job to accurately diagnose and subtype specific kidney tumors so that the urologist and/or oncologist can treat the patients with appropriate therapies. After surgical removal, treatment may range from no further therapy to specific chemotherapy depending on the tumor type. Additionally, it is known that a subset of renal cell carcinoma occurs in patients who have inherited a gene mutation from a parent, which can result in a specific genetic syndrome (also called a familial mutation/disease). This contrasts with a spontaneous/non-inherited gene mutation (also known as a somatic mutation). One such example is mutation of a Krebs cycle enzymatic gene called fumarate hydratase. The fumarate hydratase gene can undergo somatic or familial gene mutation, both of which can lead to kidney tumor formation; however, only a familial gene mutation is associated with the specific syndrome, ‘hereditary leiomyomatosis and renal cell carcinoma syndrome’ (HLRCC, also known in the past as Reed’s syndrome; Home - HLRCC Family Alliance (hlrccinfo.org)).

Those with HLRCC can develop benign smooth muscle tumors, called leiomyomas, in their skin and uterus, as well as malignant kidney tumors called fumarate hydratase-deficient renal cell carcinomas. The specific diagnosis of a fumarate hydratase deficient renal cell carcinoma can be challenging, as it can look similar to other subtypes of kidney cancer. However, over the past decade, awareness of this kidney tumor subtype has grown, and diagnostic biomarkers (such as immunohistochemistry and molecular tests) can be used to help make the diagnosis of a fumarate hydratase deficient renal cell carcinoma more readily. More specifically, labeling with an antibody to fumarate hydratase should be present in all normal cells when viewed with the microscope; however, in mutated tumors, this marker is typically absent. In contrast, a more recently developed antibody to S-(2-succino)-cysteine (2SC) is only positive in the tumor cells from fumarate hydratase deficient renal cell carcinoma and not in non-tumor cells.

In a recent study in the International Journal of Surgical Pathology (A Clinicopathological and Molecular Analysis of Fumarate Hydratase (FH)-deficient Renal Cell Carcinomas with Heterogeneous Loss of FH Expression - William J. Anderson, Harrison K. Tsai, Lynette M. Sholl, Michelle S. Hirsch, 2022 (sagepub.com)), Anderson et al demonstrates that although fumarate hydratase staining is expected to be lost/negative in these renal tumors, sometimes the staining is not perfect, meaning that it is still positive in the tumor or it is positive in some cells and not in other cells (i.e., heterogeneous or patchy loss of staining). This can make the diagnosis more challenging for the pathologist. This study, however, confirmed that even when there is patchy fumarate hydratase positivity, the 2SC staining is still present, and the molecular alterations seen in other fumarate hydratase deficient renal cell carcinomas are still present. This study helps clarify the ambiguous staining pattern, which in turn helps pathologists make an accurate diagnosis of a fumarate-hydratase deficient renal carcinoma. Accordingly, the patients can then be treated appropriately (usually surgery plus surveillance or surgery plus chemotherapy). They often also undergo genetic testing to evaluate for a familial mutation; if the latter is found, family members can also be evaluated and screened for tumor formation (i.e., early detection).

Article details

A Clinicopathological and Molecular Analysis of Fumarate Hydratase (FH)-deficient Renal Cell Carcinomas with Heterogeneous Loss of FH Expression
William J. Anderson, MBChB, Harrison K. Tsai, MD, PhD, Lynette M. Sholl, MD, Michelle S. Hirsch, MD, PhD
First Published: January 20, 2022
International Journal of Surgical Pathology

About the Author

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Dr. Michelle S. Hirsch is an Associate Professor of Pathology at Harvard Medical School and Chief of the Genitourinary Pathology Division at Brigham and Women’s Hospital, Boston, Massachusetts. Prior to practicing as a pathologist, Dr. Hirsch is originally from Palo Alto, California and she earned her undergraduate B.S. in physiology from UC Davis. She then moved to Boston where she obtained her Ph.D. in Anatomy and Cell Biology and an M.D., both from Boston University School of Medicine. Her residency and fellowship training were completed at the Brigham and Women’s Hospital, where she now still works as both a Genitourinary and Women’s & Perinatal Pathologist. Dr. Hirsch’s research focuses on tumors from all of the genitourinary organs, with an emphasis on kidney cancer and biomarkers. Dr. Hirsch is also very proud of the trainees and junior faculty she has mentored.

Michelle S. Hirsch, MD, PhD - Brigham and Women's Hospital (brighamandwomens.org)