Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome secondary to germline fumarate hydratase (FH) mutation presents with cutaneous and uterine leiomyomas, and a distinctive aggressive renal carcinoma. Identification of HLRCC patients presenting first with uterine leiomyomas may allow early intervention for renal carcinoma. We reviewed the morphology and immunohistochemical (IHC) findings in patients with uterine leiomyomas and confirmed or presumed HLRCC. IHC was also performed on a tissue microarray of unselected uterine leiomyomas and leiomyosarcomas. FH-deficient leiomyomas underwent Sanger and massively parallel sequencing on formalin-fixed paraffin-embedded tissue. All 5 patients with HLRCC had at least 1 FH-deficient leiomyoma: defined as completely negative FH staining with positive internal controls. One percent (12/1152) of unselected uterine leiomyomas but 0 of 88 leiomyosarcomas were FH deficient. FH-deficient leiomyoma patients were younger (42.7 vs. 48.8 y, P=0.024) and commonly demonstrated a distinctive hemangiopericytomatous vasculature. Other features reported to be associated with FH-deficient leiomyomas (hypercellularity, nuclear atypia, inclusion-like nucleoli, stromal edema) were inconstantly present. Somatic FH mutations were identified in 6 of 10 informative unselected FH-deficient leiomyomas. None of these mutations were found in the germline. We conclude that, while the great majority of patients with HLRCC will have FH-deficient leiomyomas, 1% of all uterine leiomyomas are FH deficient usually due to somatic inactivation. Although IHC screening for FH may have a role in confirming patients at high risk for hereditary disease before genetic testing, prospective identification of FH-deficient leiomyomas is of limited clinical benefit in screening unselected patients because of the relatively high incidence of somatic mutations.

We present 11 cases of spindle and cuboidal renal cell carcinoma, which is believed to be a distinctive morphological entity. Our cases were histologically, immunohistochemically and ultrastructurally similar to the previously reported cases of spindle and cuboidal renal cell carcinoma. In contrast to all previously reported cases of spindle and cuboidal renal cell carcinoma, we observed an association with nephrolithiasis in three of our cases; moreover, one of our tumours had a conventional renal cell carcinoma component and another revealed a metastatic focus in a regional lymph node. None of our patients died of the disease. This study confirms that spindle and cuboidal renal cell carcinoma has a low malignant potential.

No abstract

We have studied the viability of targeted molecular screening for the identification of female patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Affected patients harbor a germ-line heterozygous mutation of the fumarate hydratase (FH) gene. Clinically, some patients present with aggressive renal cell carcinoma. Concerning women, in almost all cases, this is preceded by symptomatic uterine leiomyoma. We aimed to identify women operated on for symptomatic leiomyoma by the age of 30. Archived paraffin-embedded leiomyoma tissue was tested for the FH gene mutation in 14 cases. Two patients with multiple leiomyomas and with the confirmed germ-line mutations c.1433_1434dupAAA, p.(Lys477dup) and c.953A>T, p.(His318Leu) were identified and enrolled in a surveillance program. Statistically significant correlation between the presence of multiple uterine leiomyomas (more than seven in our experience) and the FH gene mutation was found. The immunohistochemical expression pattern, of simultaneous FH absence and S-(2-succino)cysteine (2SC) positivity, correlated with the results of the molecular genetic study in only one case. The histomorphologically simultaneous detection of enlarged nucleoli with a clear halo of leiomyocyte nuclei, their fibrillary cytoplasm, the presence of eosinophilic globules, and staghorn vessels proved to be only a partially sensitive indicator of HLRCC-associated leiomyoma and fully correlated with immunohistochemistry and molecular genetic study only in one case. Molecular genetic testing is presently the only reliable diagnostic tool able to identify HLRCC patients. The sensitivity and specificity of the presence of multiple leiomyomas in women with the FH gene mutation who are younger than 30 years old should be confirmed in larger scale studies. The applied targeted molecular screening protocol proved to be effective, resulting in identification of two positive patients out of fourteen tested individuals.