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Year : 2017  |  Volume : 60  |  Issue : 1  |  Page : 108-110
Hereditary leiomyomatosis and renal cell cancer syndrome associated renal cell carcinoma

Department of Pathology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India

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Date of Web Publication14-Feb-2017


Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a recently described entity with unknown exact prevalence. The affected individuals are predisposed to have multiple leiomyomas and renal cancer due to germline mutation in fumarate hydratase gene on chromosome 1. The knowledge of this rare tumour is essential for early recognition and institution of appropriate therapy, since they have a grave prognosis. Herein, we present the first case from India of HLRCC in a 42 year old lady who presented with a renal mass and metastasis with consequent fulminant course of disease. We discuss the detailed histomorphologic features and iunique immunohistochemical signature of this unusual renal tumour with discussion of differential diagnosis.

Keywords: Hereditary, immunohistochemistry, leiomyomatosis, renal

How to cite this article:
Adamane S, Desai S, Menon S. Hereditary leiomyomatosis and renal cell cancer syndrome associated renal cell carcinoma. Indian J Pathol Microbiol 2017;60:108-10

How to cite this URL:
Adamane S, Desai S, Menon S. Hereditary leiomyomatosis and renal cell cancer syndrome associated renal cell carcinoma. Indian J Pathol Microbiol [serial online] 2017 [cited 2020 Aug 12];60:108-10. Available from: http://www.ijpmonline.org/text.asp?2017/60/1/108/200025

   Introduction Top

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant syndrome, characterized by the development of cutaneous and uterine leiomyomas as well as renal cell carcinoma (RCC). The association of RCC with HLRCC syndrome was first described by Launonen et al. in two Finnish families.[1] The hallmark mutation in this syndrome is the fumarate hydratase ([FH], 1q42.3–q43) gene, a Krebs cycle enzyme.[2] HLRCC has been identified and is now recognized as a separate entity in the new International Society of Urologic Pathology Vancouver classification.[3] Herein, we present the first case of renal cancer in HLRCC syndrome to be reported from India with immunohistochemical confirmation.

   Case Report Top

A 42-year-old lady presented with abdominal pain of 3 months duration. Contrast-enhanced computerized tomographyic scan of abdomen revealed a 6 cm × 4.3 cm mass lesion in the right kidney with multiple retroperitoneal nodal and liver metastases. The patient underwent radical nephrectomy elsewhere, and the specimen was sent to our institute for pathological evaluation. The tumor was grayish white with focal spongy areas, with multiple confluent tumors encroaching almost entire cortex and medulla of the right kidney with satellite tumor nodules in the surrounding normal renal parenchyma throughout. Areas of hemorrhage and necrosis were not visible grossly. Microscopically, the tumor had myriad of patterns including tubulocystic areas of variable size, infiltrating tubuloglandular structures reminiscent of collecting duct carcinoma and papillary areas [Figure 1]. The tumor cells were cuboidal with enlarged nuclei, prominent cherry red nucleoli, and characteristic perinucleolar halo/clearing [Figure 2] and [Figure 3]. Areas of necrosis, hemorrhage, and sarcomatoid change were not seen in the tumor, and a morphologic possibility of tubulocystic RCC with admixed areas of papillary RCC was favored. Immunohistochemistry revealed positivity for vimentin, E-cadherin, and Alpha-methylacyl-CoA racemase, whereas negative for CD10 and CK7. On further immunohistochemistry (at Memorial Sloan Kettering Cancer Center, New York, USA), the tumor marked strongly with S-(2-succino)-cysteine (2SC) and was negative for FH, thereby confirming renal cancer associated with HLRCC syndrome [Figure 4]. Tumor invaded the renal vein and perinephric fat, and a concomitant liver biopsy confirmed metastasis (TNM AJCC pT3b Nx M1); the patient expired within 2 months of diagnosis owing to progressive disease.
Figure 1: (a) Morphological features of the renal carcinoma in hereditary leiomyomatosis and renal cell carcinoma syndrome showing tubulocystic areas of variable sizes (H and E, ×40) (b) collecting duct like areas with desmoplastic stroma (H and E, ×40) (c) papillary areas (H and E, ×40) and (d) solid confluent and cribriforming areas (H and E, ×40)

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Figure 2: (a-c) High power view of tubulocystic areas showing high grade nuclear features with prominent eosinophilic nucleoli and perinucleolar clearing (H and E, ×200) and (d) focal hobnailing of nuclei (H and E, ×200)

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Figure 3: High power view depicting the prominent cytomegalovirus inclusion like nucleoli in this case of hereditary leiomyomatosis and renal cell carcinoma (Arrow; H and E, ×400)

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Figure 4: (a and b) Immunohistochemical staining in hereditary leiomyomatosis and renal cell carcinoma renal cancer demonstrating strong positivity for S-(2-succino)-cysteine (indirect immunoperoxidase, ×100 and × 200) and (c and d) negative staining in tumor with fumarate hydratase (indirect immunoperoxidase, ×10 and × 200)

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   Discussion Top

Many syndromic associations have been found with different variants of RCCs, including the more common Von Hippel–Lindau disease with clear cell histology, hereditary papillary RCC of Type 1 papillary histology, and Birt-Hogg-Dubé syndrome with hybrid chromophobe-oncocytomas, chromophobe RCC, clear cell RCC, and oncocytomas and tuberous sclerosis with angiomyolipomas.[4],[5],[6],[7] HLRCC is a rare hereditary cancer syndromes in which the affected individuals are at risk of developing RCC with aggressive features as well as cutaneous and uterine leiomyomas. This syndrome is found to have germline mutation of gene FH with incomplete phenotypic penetrance; 90% penetrance for development of uterine leiomyomas and about 20% penetrance for renal cancer.[1],[8],[9] HLRCC has predilection for women in the third or fourth decades. Most of the cases present as high stage disease with nodal or systemic dissemination, as was also seen in the present case.[1],[9]

The histomorphological features of renal tumors in HLRCC patients were initially described to have resemblance to papillary RCC.[5] Merino et al.[8] expanded and expanded the morphologic spectrum of the renal tumors in the largest study of HLRCC cases with variety of tumor patterns such as papillary, tubular, tubulo-papillary, solid, or mixed. They described the histological hallmark of tumor nuclei with prominent inclusion such as orangophilic or eosinophilic nucleoli, surrounded by a clear halo, reminiscent of the one seen in cytomegalovirus infections. In the present case, there was admixture of a Type 2 papillary RCC like areas and areas with tubulocystic growth patterns with the characteristic nuclear features.

Leiomyoma in the patients suffering with HLRCC is found at variable sites including the skin (multiple or single in 76% of affected individuals) and uterus, which tend to be multiple and present an earlier age with a mean age of 30 years. They have predilection for malignant transformation into leiomyosarcomas.[1],[2],[8] In the current patient, the presence of leiomyomas could not be confirmed as the radiology of abdomen and pelvis was reported elsewhere and was unavailable.

Differential diagnosis on histology include Type 2 papillary RCC, tubulocystic RCC, eosinophilic variant of clear cell RCC, collision between a RCC and a rare angioleiomyoma. Papillary RCC, Type 2 variant is the closest mimic. In fact, all tumors which have Type 2 papillary RCC like morphology need to be carefully assessed for characteristic nuclear features and history so as not to miss an HLRCC. Tubulocystic RCC is more common in males and is a low-grade tumor, with the majority of tumors presenting as stage pT1.[3],[8],[10]

Until recently, there were no established specific immunohistochemical markers for confirming renal tumors seen in HLRCC. Molecular confirmation for the FH enzyme was done either by studying activity in cultured skin fibroblasts or lymphoblastoid cells showing reduced activity (≤60%) or the loss of heterozygosity study was the only definitive means of establishing the correct diagnosis in HLRCC cases. However, Chen et al.[10] have recently observed that diffuse 2SC and absent FH immunostaining was confirmatory to diagnose renal cancers in HLRCC. They found that these two markers had almost 100% concordance with germline mutational studies to detect FH gene mutation. FH is one of the key enzymes in the Krebs cycle and catalyzes the conversion of fumarate to malate. Loss of FH leads to abnormal intracellular accumulation of fumarate. Increased level of fumarate in cells can spontaneously react with the cysteine sulfhydryl group of proteins to form a stable chemical modification, 2SC, by a process called protein succination.[10]

   Conclusion Top

We have described the first case of HLRCC from India, which was confirmed by characteristic immunohistochemical features. Most of these renal tumors behave aggressively and hence the need to diagnose them early cannot be overemphasized. The pathologists need to be aware and recognize the characteristic histomorphological features to ensure correct diagnosis of these patients.


We would like to sincerely thank Dr. Mahul B. Amin, Professor and Chairman, Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Editor-In-Chief, AJCC Cancer Staging System, 8th Edition, and Dr. Ying-Bei Chen, MD, PhD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, for the generous help in performing S-(2-succino)-cysteine and fumarate hydratase immunohistochemistry evaluation for the special interesting case.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 2001;98:3387-92.  Back to cited text no. 1
Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002;30:406-10.  Back to cited text no. 2
Srigley JR, Delahunt B, Eble JN, Egevad L, Epstein JI, Grignon D, et al. The International Society of Urological Pathology (ISUP) vancouver classification of renal neoplasia. Am J Surg Pathol 2013;37:1469-89.  Back to cited text no. 3
Teh BT, Giraud S, Sari NF, Hii SI, Bergerat JP, Larsson C, et al. Familial non-VHL non-papillary clear-cell renal cancer. Lancet 1997;349:848-9.  Back to cited text no. 4
Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 1997;16:68-73.  Back to cited text no. 5
Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B, Linehan WM, et al. Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol 2002;26:1542-52.  Back to cited text no. 6
Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell 2002;2:157-64.  Back to cited text no. 7
Merino MJ, Torres-Cabala C, Pinto P, Linehan WM. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol 2007;31:1578-85.  Back to cited text no. 8
Kiuru M, Lehtonen R, Arola J, Salovaara R, Järvinen H, Aittomäki K, et al. Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. Cancer Res 2002;62:4554-7.  Back to cited text no. 9
Chen YB, Brannon AR, Toubaji A, Dudas ME, Won HH, Al-Ahmadie HA, et al. Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: Recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. Am J Surg Pathol 2014;38:627-37.  Back to cited text no. 10

Correspondence Address:
Santosh Menon
Department of Pathology, 8th Floor, Annexe Building, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.200025

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