Review of hereditary leiomyomatosis renal cell carcinoma with focus on clinical and pathobiological aspects of renal tumors

Abstract

The entity of hereditary leiomyomatosis renal cell carcinoma (HLRCC)-associated RCC has been proposed and integrated into the recent International Society of Urologic Pathology (ISUP) of renal tumors. This tumor is characterized by presence of cutaneous and/or uterine leiomyomas and RCC and autosomal dominant hereditary form. Grossly, HLRCC arising in the kidney show the solid tumor with frequent partial cystic area. Microscopically, the tumor typically shows papillary RCC, type 2, with eosinophilic large nucleoli reminiscent of cytomegaloviral inclusion and perinuclear clearing/haloes. Immunohistochemically, tumor cells show the overexpression for 2SC and reduced expression of FH. Germline mutation of <i>fumarate hydratase </i>(FH) gene, the HLRCC responsible gene mapped to chromosome 1q43, has been identified in patients with HLRCC. As the renal cancer in patients with HLRCC generally behave aggressively even in a small size, complete surgical resection and retroperitoneal lymph node resection should be performed promptly when the tumor is discovered. The surveillance of renal tumor in FH gene germline mutation-positive patients should be started from the early age using ultrasound sonography or magnetic resonance imaging.

The Differential Diagnosis of Medullary-Based Renal Masses

“…54,146 In patients with HLRCC, 5% to 35% develop FH-d RCC, while 10% to 100% have cutaneous leiomyomas, and~80% have a history of uterine leiomyomas. 17,37,[146][147][148][149][150] The median patient age at diagnosis is~43 years with a range of 11 to 69 years. 54,146 Men are affected more than women in most cohorts (~2:1), 54,146,149,151 but some have suggested no sex predilection.…”

“…8,85 The most common clinical presentation for an FH-d RCC includes abdominal, back, or flank pain; weight loss; and hematuria. 146,148 For those with HLRCC, an FH-d RCC can be identified with renal surveillance imaging and/or following the diagnosis of an FH-d leiomyoma (patients typically present with uterine bleeding and/or menorrhagia or during reproductive workup).…”

“…8,17,54,146 Most tumors progress, either developing metastases or proving fatal with short follow-up intervals, including progressions of 26% to 65% and death from disease in 27% to 74% of cases. 17,54,146,148,149,151 Although data are very scarce, tumors with an entirely low-grade appearance may have a more favorable prognosis. 153…”

“…There is a slight predominance of left-sided tumors and a median tumor size of 6.5 to 9.2 cm (range, 0.9-28 cm). 1,8,17,54,146,148,149 FH-d RCC has a wide morphologic range, with most tumors showing mixed growth patterns (Figure 6, B through D). 6,54,146 Architectural patterns include papillary (most frequent), tubular, tubulopapillary, solid sheets/nests/cords, tubulocystic, intracystic papillary, infiltrating glandular, sievelike/cribriform, and reticular/yolk sac-like.…”

“…Other nonspecific biomarkers include PAX8, showing uniform positivity (confirms renal epithelial origin); CD10, showing variable positivity; CK7 (Figure 6, G) and AMACR, usually showing negativity. [146][147][148][149] Of note, AMACR nearly always shows positivity in PRCC, which may help with this differential diagnosis. CAIX can show focal to diffuse expression in a subset of cases (Figure 6, H).…”