<p class="first" id="d6862318e226">Hereditary leiomyomatosis and renal cell carcinoma
syndrome is characterized by an
increased risk of agressive renal cell carcinoma, often of type 2 papillary histology,
and is caused by FH germline mutations. A prominent eosinophilic macronucleolus with
a perinucleolar clear halo is distinctive of hereditary leiomyomatosis and renal cell
carcinoma syndrome-associated renal cell carcinoma according to the 2012 ISUP and
2016 WHO kidney tumor classification. From an immunohistochemistry perspective, tumors
are often FH-negative and S-(2-succino)-cysteine (2SC) positive. We performed a pathology
review of 24 renal tumors in 23 FH mutation carriers, and compared them to 12 type
2 papillary renal cell carcinomas from FH wild-type patients. Prominent eosinophilic
nucleoli with perinucleolar halos were present in almost all FH-deficient renal cell
carcinomas (23/24). Unexpectedly, they were also present in 58% of type 2 papillary
renal cell carcinomas from wild-type patients. Renal cell carcinoma in mutation carriers
displayed a complex architecture with multiple patterns, typically papillary, tubulopapillary,
and tubulocystic, but also sarcomatoid and rhabdoid. Such pattern diversity was not
seen in non-carriers. FH/2SC immunohistochemistry was informative as all hereditary
leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas were either
FH- or 2SC+. For FH and 2SC immunohistochemistries taken separately, sensitivity of
negative anti-FH immunohistochemistry was 87.5% and specificity was 100%. For positive
anti-2SC immunohistochemistry, sensitivity, and specificity were 91.7% and 91.7%,
respectively. All FH wild-type renal cell carcinoma were FH-positive, and all but
one were 2SC-negative. In conclusion, multiplicity of architectural patterns, rhabdoid/sarcomatoid
components and combined FH/2SC staining, but not prominent eosinophilic nucleoli with
perinucleolar halos, differentiate hereditary leiomyomatosis and renal cell carcinoma-associated
renal cell carcinoma from type 2 papillary renal cell carcinoma with efficient FH
gene. Our findings are crucial in identifying who should be referred to Cancer Genetics
clinics for genetic counseling and testing.
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