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Syndromic Renal Epithelial Tumors


================= Summary ===============

von Hippel-Lindau (VHL) syndrome

  • VHL gene mutations
  • Abnormal VHL protein function
  • HIF1-alpha accumulation
  • Retinal and CNS hemangioblastomas
  • Endolymphatic sac tumors
  • RCC in 70% patients by age 60
  • Renal clear cell cysts or clusters

Birt-Hogg-Dubé (BHD) Syndrome

  • Mutations in BHD gene
  • Follicular & skin lesions
  • Pulmonary cysts, pneumothorax & bronchiectasis
  • Medullary thyroid carcinoma
  • RCCs in 15-27% patients
  • Hybrid of oncocytoma and chromophobe RCC

Tuberous Sclerosis Complex

  • Mutations in TSC1 and TSC2
  • Abnormal mTOR pathway signaling
  • Neurocutaneous disorders
  • Multiple benign CNS and skin tumors
  • PEComas are typical component
  • RCCs in 2-4% patients

Hereditary Papillary Renal Carcinoma Syndrome

  • Mutations of c-MET proto-oncogene
  • Ligand-independent kinase activity
  • Multiple, bilateral papillary renal cell carcinomas
  • No extra-renal lesion

Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome

  • Leiomyomas of skin and uterus
  • RCC in 20-35% patients
  • Characteristic large nucleoli with peri-nucleolar halos

Syndromic renal epithelial tumor denotes a tumor or tumor-like lesion of the kidney as an integral component of a constellation of pathophysiologic presentations that form a specific clinical syndrome. Several clinical syndromes are known to have such a renal component. They are von Hippel-Lindau syndrome, tuberous sclerosis syndrome or complex, Birt-Hogg-Dubé syndrome, hereditary papillary renal carcinoma syndrome, and hereditary leiomyomatosis and renal cell cancer syndrome.  All of them are transmitted in an autosomal dominant manner.  The importance of studying these syndromes associated with renal epithelial lesions is at least 3-fold.  First, these studies historically have taught us a great deal of tumorigenesis of related renal cell carcinomas and will continue to contribute to our understanding of these tumors.  Second, the syndrome offers an excellent model to further delineate tumorigenesis with other disease processes.  Third, the associated components of the syndrome can provide invaluable clues to the diagnosis of the tumor and its subtype vital for therapeutic intervention. Conversely, recognizing these components clinically or morphologically in a surgical specimen can help identify these underlying syndromes.

von Hippel-Lindau (VHL) syndrome

von Hippel-Lindau (VHL) syndrome is characterized by retinal hemangioblastomas, cerebellar and spinal hemangioblastoma, clear cell renal cell carcinomas, pheochromocytomas, pancreatic cysts and endocrine pancreatic tumors, endolymphatic sac tumors of ear and epididymal cystadenomas. It is associated with alterations in a tumor suppressor, VHL, gene located on on chromosome 3p25. VHL gene mutations are also found in at least 50% of cases of clear cell RCCs. In fact, a deletion on chromosome arm 3p, where the VHL gene resides, is present in most sporadic and familial tumors.  The VHL gene product, pVHL, normally targets hypoxia-inducible factors, HIF1-alpha, for degradation. Absence of pVHL or abnormal pVHL functional status leads to HIF1-alpha accumulation, which in turn activates multiple downstream signaling pathways involved in tumorigenesis. 30-70% patients with VHL develop renal lesions including cysts, infiltrative clear cell clusters, cystic clear cell RCCs and solid clear cell RCCs. The syndromic RCCs prior to age 20 are very rare. The frequency increases after 20 years of age with the mean age of onset at age 44. By age 60, 70% patients develop RCC. In practice, when finding multiple clear cell RCCs with or without clear cell-lined cysts and infiltrative clear cell clusters in the kidney, von Hippel-Lindau syndrome should be considered.

Tuberous Sclerosis Complex (TSC)

Tuberous Sclerosis complex (TSC) includes tumors or tumor-like lesions in multiple anatomic sites. Although it is largely viewed as a genetic neurocutaneous disorder characterized by multiple benign tumors of the CNS and skin, tumors of visceral organs also occur with high frequency. A group of such tumors such as angiomyolipomas, pulmonary lymphangioleiomyomatosis and clear cell "sugar" tumors collectively named as PEComas are typical component of tuberous sclerosis complex. In addition, cardiac rhabdomyomas, subependymomas, giant cell astrocytomas and retinal hamartomas are also constituents of this syndrome. TSC results from mutations in two related tumor suppressor genes, tuberous sclerosis complex (TSC1 and TSC2); TSC1 encode hamartin, whereas TSC2 encodes tuberin. Mutation in TSC1 and TSC2 leads to abnormal mTOR pathway signaling. About 50% of patients with Tuberous Sclerosis Complex show renal involvement in the form of renal cysts, angiomyolipomas and RCCs. But renal cell tumors, particularly multifocal, with voluminous clear cytoplasm and/or large eosinophilic cells are also typical. Fortunately, only 2-4% TSC patients develop RCCs that are predominantly clear cell type.

Birt-Hogg-Dubé (BHD) Syndrome

Birt-Hogg-Dubé (BHD) Syndrome is inherited in an autosomal dominant pattern with incomplete penetrance.  The syndrome is characterized by renal tumors, cutaneous lesions (fibrofolliculomas, trichodiscomas, and acrochordons), pulmonary cysts, spontaneous pneumothorax, bronchiectasis, and bronchospasm, colonic neoplasms, medullary thyroid carcinoma and lipomas. Syndrome involves mutations in BHD gene on chromosome 17p12-q11.2 which encodes for folliculin protein. 15-27% of the patients develop renal cells tumors, usually in the 6th decade of life (range: 31-73 years) while skin lesions occurs in the 3rd decade of life.

Although all types of renal cell carcinomas can occurs in BHD syndrome, the most common is the hybrid of oncocytoma and chromophobe renal cell carcinoma. Characteristically, many oncocytic tumors show scattered clusters of cells with clear cytoplasm. Pure chromophobe RCC and renal oncocytomas are also common. A very helpful clue is the presence of renal oncocytosis in surrounding renal parenchyma, i.e. multiple microscopic oncocytic nodules, cluster of oncocytic cells percolating between non-neoplastic parenchyma and cysts lined by oncocytic cells

Hereditary papillary renal carcinoma syndrome (HPRC)

Hereditary papillary renal carcinoma syndrome is inherited in autosomal dominant pattern with incomplete penetrance. Less than 50% of members of affected families develop disease. The syndrome is associated with activating mutations of c-MET proto-oncogene on chromosome 7q31. c-Met gene product is a tyrosine kinase protein that mediate cell proliferation. The mutation leads to ligand-independent constitutive activation of the kinase activity that results in tumorogenesis.

Tumors in HPRC syndrome manifest at relatively late age (50 to 70 years). It is characterized by multiple, bilateral papillary renal cell carcinomas. No extrarenal manifestation has been reported. Renal tumors associated with syndromic c-MET mutations are all type 1 papillary RCC. Thus, finding of multiple papillary RCC in old patient should raise the suspicion of this syndrome. However, it is important to remember that papillary RCC is also the most common multifocal tumor in sporadic setting and in kidney with chronic diseases.

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome is characterized by leiomyomas of skin and uterus and renal carcinomas. Inactivation of the fumarate hydratase gene due to germline mutation forms the genetic basis of the syndrome. Most patients develop cutaneous leimyomas and, in women, uterine leimyomas at young age. About 20-35% patients develop renal cell carcinomas. Renal cell carcinomas associate with this syndrome tend to be of aggressive type, such as type-2 papillary carcinoma or “collecting duct carcinoma”, and tend to metastasize even when tumor size is small. Histologically, the carcinomas show infiltrative growth with papillary, solid, tubular, and often a mixture of growth pattern (architectures). Large nucleoli with peri-nucleolar halos are reported to be very characteristic. Unlike other syndromic RCC, renal tumor in HLRCC syndrome is solitary and unilateral.

References / Suggested Readings

W.M. Linehan, et al.: Hereditary kidney cancer: unique opportunity for disease-based therapy. Cancer. 115(10 Suppl): 2252-61, 2009.

T.K. Choueiri.: Hereditary kidney cancer syndromes. Uptodate (Accessed on July 2012).

S. Sudarshan, et al.: Mechanisms of disease: hereditary leiomyomatosis and renal cell cancer--a distinct form of hereditary kidney cancer. Nat Clin Pract Urol. 4(2):104-10, 2007.

E.P. Henske.: Tuberous sclerosis and the kidney: from mesenchyme to epithelium, and beyond. Pediatr Nephrol. 20(7):854-7, 2005.

H. Ross, et al.: Renal Cell Carcinoma With Clear Cell and Papillary Features. Arch Pathol Lab Med. 136(4):391-9, 2012.