Familial Cancer Syndromes



Familial Cancer Syndromes


Satish K. Tickoo, MD

Victor E. Reuter, MD








Graphic representation of abdominal lesions in von Hippel-Lindau syndrome shows bilateral, multiple renal cysts image, renal tumors image, pancreatic cysts image, and adrenal pheochromocytoma image.






Besides the larger, macroscopic clear cell renal cell carcinomas, VHL kidneys often show numerous microscopic aggregates or tumorlets of clear cells, frequently with irregular outlines image.


TERMINOLOGY


Abbreviations



  • von Hippel-Lindau (VHL) syndrome


  • Hereditary papillary renal carcinoma (HPRC) syndrome


  • Birt-Hogg-Dubé (BHD) syndrome


  • Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome


  • Tuberous sclerosis (TS) syndrome


SYNDROMES


General Considerations



  • In all forms of inherited renal neoplasms, tumors are usually diagnosed at earlier age and are more likely to be multifocal and bilateral



    • At present, only exception to multifocality and bilaterality appears to be HLRCC syndrome


  • Because of consistent defects within tumor groups, genetic profiles of inherited neoplasms are relatively easier to study



    • Knowledge thus gained may be applied in similar, more common sporadic tumors



      • This has resulted in better understanding of genetic mechanisms involved in various sporadic tumor subtypes


      • Most targeted therapies currently in use/under investigation have been direct consequence of this better understanding of tumor genetics


SYNDROMIC RENAL TUMORS


von Hippel-Lindau Syndrome



  • Autosomal dominant syndrome, characterized by



    • Retinal hemangioblastomas


    • Clear cell renal cell carcinomas (RCC) and multiple renal cysts


    • Cerebellar and spinal hemangioblastomas


    • Pheochromocytomas


    • Pancreatic cysts and endocrine pancreatic tumors


    • Endolymphatic sac tumors of ear


    • Epididymal cystadenomas


  • VHL, unlike most other familial renal cancer syndromes, shows high degree of genetic penetrance


  • Estimated incidence: 1/36,000-1/45,500


  • Syndrome is associated with alterations in tumor suppressor VHL gene



    • Gene located at chromosome 3p25


    • Inactivated by various mutations, loss of heterozygosity (LOH), hypermethylations, or alterations in VHL modifier genes


    • In VHL syndrome, germline mutation present in 1 allele of VHL gene



      • Clinical manifestations of disease result when mutations/silencing occur in other wild-type allele


  • VHL gene product pVHL essential for proteosomic degradation of hypoxia-inducible factor-1α (HIF-1α)



    • Absence of functional pVHL results in overexpression of HIF-1α


    • Activated HIF-1 heterodimers localize to nucleus and regulate transcription of multiple genes by binding to hypoxia-responsive elements (HRE); activated targets include



      • Vascular endothelial and platelet-derived growth factors (VEGF and PDGF) and receptors


      • Glucose transporter protein-1 (GLUT1)


      • Erythropoietin


      • Carbonic anhydrase-IX (CA9)


      • Transforming growth factor-alpha (TGF-α)


      • C-X-C chemokine receptor type 4 (CXCR4)


      • C-mesenchymal-epithelial transition factor (c-MET)


    • Many of these factors associated with angiogenesis, tumorigenesis, and tumor metastasis



  • Depending on whether pheochromocytomas are present or not, VHL disease can be divided into 2 major types



    • Type 1 is not associated with pheochromocytomas



      • It involves “loss of function” mutations, including deletion, microinsertion, and nonsense mutations


    • Type 2 has high risk for pheochromocytomas and is divided into 3 subtypes



      • Type 2A, associated with low risk for RCC


      • Type 2B, associated with high risk for RCC


      • Type 2C, with pheochromocytomas only


      • Mutations that predispose to type 2 VHL are mainly of missense type that result in conformationally altered pVHL


      • These mutant pVHLs still may be able to retain some of their functions or may gain other novel functions


  • Renal lesions in VHL syndrome include multiple bilateral benign cysts, atypical cysts, cystic RCCs, and solid RCCs


  • Kidneys are usually of normal size and weight, chiefly because most cysts and RCCs are small


  • Renal cysts



    • Cysts are usually few (3-30 in number; mean: 7.8 per kidney), usually small (almost all < 1.5 cm, mean size: 0.7 cm)


    • Cysts may be unilocular or multilocular


    • They are almost entirely lined by clear cells; focal or predominant granular cytoplasm is rarely present



      • Cysts are designated as benign cysts (1 layer of clear cells without atypia) or atypical cysts (2 or 3 cells thick ± atypia)


      • Focal proliferations more than 3 cells thick are regarded as cystic RCCs


    • Increased vascularity is often seen around cysts


  • Clear cell renal cell carcinoma



    • Mean age for development of renal carcinoma: 37 years (range: 16-67)


    • By age 70, chance of kidney cancer is 70%


    • Retinal and CNS hemangioblastomas usually manifest at earlier mean ages (25 and 30 years)



      • Renal lesions are earlier manifestation in only 7%


    • In spite of relatively few patients developing metastasis, metastatic RCC is leading cause of death from VHL


    • In addition to macroscopically identifiable tumors, numerous microscopic nodules of clear cells seen in

      VHL kidneys



      • Some nodules well circumscribed


      • Others present as aggregates of clear cells, with irregular outlines


      • Clusters and sheets of clear cells appearing to percolate between nephrons also common


    • Screening for renal tumors in VHL patients recommended after age 10


  • Management of renal tumors



    • Current strategies advocate conservative management for all genetic, multifocal, bilateral tumors



      • Nephron-sparing surgery/tumor ablation strategy is used with intent to remove all solid and semicystic lesions from kidney


      • Procedure is usually delayed until tumors grow beyond 3 cm in size


      • During follow-up, as new tumors develop, repeat procedures are performed


      • Main intent of this approach is to preserve renal function as much and as long as possible


    • Targeted therapies currently being investigated to potentially reduce tumor burden of even localized tumors in VHL


Hereditary Papillary Renal Carcinoma Syndrome



  • Autosomal dominant syndrome, with incomplete penetrance, characterized by



    • Multiple, bilateral papillary renal cell carcinomas



      • Hundreds to thousands of tumors known to occur in each kidney


  • Syndrome is associated with activating mutations of c-MET proto-oncogene



    • Gene is located at chromosome 7q31


    • Hepatocyte growth factor (a.k.a. scatter factor) acts as ligand for MET trans-member tyrosine kinase protein


    • Normally, binding to hepatocyte growth factor activates MET tyrosine kinase protein



      • Tyrosine phosphorylation induces proliferation and differentiation of epithelial and endothelial cells, cell branching, and invasion


  • c-MET mutations result in ligand-independent constitutive activation of MET tyrosine kinase



    • Activated tyrosine kinase then binds to and activates several signal transducers and adaptors, such as



      • Phosphatidylinositol 3 kinase (PI3K)


      • pp60src


      • Growth factor receptor-bound protein 2 (Grb2)


      • GRB2-associated binding protein 1 (Gab1)


    • This constitutive activation results in tumorigenesis


  • Renal tumors associated with syndromic c-MET mutations are all type 1 papillary RCC



    • Tumors show papillary or tubulo-papillary architecture, similar to type 1 sporadic carcinomas


    • Foamy macrophages and calcifications commonly present


  • Tumors often manifest at relatively late age (50 to 70 years)



    • Recently, early onset form of disease has also been described


  • Low genetic penetrance is supported by relatively low proportion of cases demonstrating syndrome manifestations



    • Approximately 50% of members of affected families develop disease


  • Tumors are multifocal and bilateral


  • No extrarenal manifestations of HPRC are known at present


Birt-Hogg-Dubé Syndrome



  • Autosomal dominant syndrome with incomplete penetrance, characterized by



    • Renal tumors



    • Cutaneous lesions (fibrofolliculomas, trichodiscomas, and acrochordons)


    • Pulmonary cysts, spontaneous pneumothorax, bronchiectasis, and bronchospasm


    • Colonic neoplasms


    • Medullary thyroid carcinoma


    • Lipomas


  • Syndrome involves mutations in BHD gene



    • BHD gene maps to chromosome 17p12-q11.2


    • Gene codes for folliculin protein


    • Multiple mutations, including germline and somatic, have been reported in BHD gene


    • Usually, germline mutation in 1 allele is inherited, followed by somatic-type mutation in the other allele that may result in tumorigenesis



      • This supports the role of BHD as a tumor suppressor gene


    • Renal tumors in BHD syndrome usually have oncocytic cytoplasm



      • Most common tumor type displays hybrid features of renal oncocytoma and chromophobe RCC


      • Characteristically, many oncocytic tumors show scattered clusters of cells with clear cytoplasm


      • Pure chromophobe RCC and renal oncocytomas are other common tumor types


      • Other types of renal cell carcinoma are also seen, including clear cell and papillary RCC


    • Renal oncocytosis is evident in surrounding renal parenchyma in large proportion of cases


    • Morphologic spectrum of renal oncocytosis includes



      • Numerous microscopic oncocytic nodules: May have features of chromophobe RCC, oncocytoma, or even hybrid tumors


      • Cysts lined by oncocytic cells


      • Oncocytic changes in nonneoplastic renal tubules


      • Clusters and sheets of oncocytic cells percolating between nonneoplastic nephrons


    • Skin tumors usually appear before renal manifestations

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Jul 6, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Familial Cancer Syndromes

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