Clues to recognition of fumarate hydratase‐deficient renal cell carcinoma: Findings from cytologic and limited biopsy samples

Abstract

Background Fumarate hydratase (FH)‐deficient renal cell carcinoma (RCC) is rare and highly aggressive and is believed to arise mostly in the setting of hereditary leiomyomatosis‐RCC syndrome with a germline mutation of FH. Because of the aggressiveness of these tumors and a frequent lack of ascertainable family history, these tumors may first present as metastases and be sampled by cytology. The cytologic findings of FH‐deficient RCC have not previously been reported. Methods Cytologic and limited biopsy samples from patients with FH‐deficient RCC were reviewed retrospectively. Results In total, 24 cytologic and limited biopsy samples from 19 patients (6 women and 13 men; age range, 22‐69 years) who had FH‐deficient RCC and metastasis at presentation were evaluated. These included 21 cytology samples ranging from malignant effusions (n = 7) to metastases (n = 11), to samples of primary kidney tumors (n = 3). The samples exhibited cells, often in clusters and abortive papillae, with voluminous, finely vacuolated cytoplasm and large, pleomorphic nuclei with prominent, viral inclusion‐like nucleoli. A distinctive finding of peripheral cytoplasmic clearing frequently was apparent, and intranuclear cytoplasmic pseudoinclusions were less frequent. Of 7 cell block and biopsy samples, several of which represented sampling from the same patient, all demonstrated tissue fragments that had discernable morphologic patterns associated with FH‐deficient RCC, including tubulocystic and intracystic papillary growth. Conclusions Features characteristic and suggestive of FH‐deficient RCC may be identified in cytologic and small biopsy samples. Although the current samples were identified retrospectively in well characterized cases of FH‐deficient RCC, the authors argue that, with appropriate clinical correlation, these features are sufficiently distinctive to trigger recognition and confirmatory workup.

New entities, new technologies, new findings: A review of the cytologic features of recently established subtypes of renal cell carcinoma

“…75,80,82 We recently studied the features of well characterized FH-deficient RCCs, including large numbers of bona fide HLRCC-RCCs in individuals who had Cancer Cytopathology February 2019 proven germline FH mutations. 83 Across a wide variety of sample types, including effusions and aspirations of primary or metastatic, FH-deficient RCCs, we noted that cytologic samples, which frequently were moderately cellular, exhibited large, pleomorphic cells, often in tridimensional clusters or abortive papillae. The character of the cytoplasm, which usually was most apparent in Diff-Quik-stained samples, was voluminous and finely vacuolated, and a few cases had larger vacuoles.…”

“…We recently studied the features of well characterized FH‐deficient RCCs, including large numbers of bona fide HLRCC‐RCCs in individuals who had proven germline FH mutations . Across a wide variety of sample types, including effusions and aspirations of primary or metastatic, FH‐deficient RCCs, we noted that cytologic samples, which frequently were moderately cellular, exhibited large, pleomorphic cells, often in tridimensional clusters or abortive papillae.…”

“…Although consensus recommendations regarding the use of FH immunostains for triage of RCC cases are not available, for prospective workup of cytologic samples, we emphasize a careful review of cytologic features (nucleolar prominence, suggestion of perinucleolar halo, intranuclear pseudoinclusions, two-toned cytoplasm) 83 or hints at architectural patterns characteristic of these tumors (tubulocystic pattern, intracystic papillary with hyalinized cores) 99 as morphologic triggers for this stain. Certainly in the setting of any syndromal stigmata or history, young age, or early metastasis from a clinically small tumor would trigger an FH immunostain in our practice as well.…”

Molecular Genetics of Renal Cell Tumors: A Practical Diagnostic Approach

“…Histologically, they show marked intratumoral heterogeneity with papillary, tubulocystic, solid or cribriform patterns, and usually the presence of large nuclei with deep red nucleoli ( Figure 3A,B). However, no single or a combination of histologic features are diagnostic of FH-deficient RCCs/HLRCCs [101,108,[122][123][124][125][126][127][128].…”

“…Immunohistochemically, FH-deficient RCCs show loss of staining for fumarate hydratase (FH) (sensitivity 80 to 90%) [101,108,[123][124][125][126][127][128][129]. Positive immunohistochemical staining for 2SC (2-Succinocysteine) is supportive feature, however antibody for 2SC is not currently commercially available [123,125,129].…”