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  Disease summary:

  
  
  
  
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    Approximately 50,000 new cases of renal cell carcinoma (RCC) are diagnosed each year.

    
    
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    RCCs are adenocarcinomas derived from renal tubular epithelium. Renal carinoma is comprised of several different types of cancer, each with a different histologic type, with a different clinical course, responding differently to therapy, and caused by different genes.

  
  
  
  
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  Histologically, there are five subtypes:

  
  
  
  
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    Conventional (clear cell) (70%-80%)

    
    
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    Chromophile (papillary) (10%-15%). Papillary is further classified into type 1 (5%) and type 2 (10% of cases) based on further genetic alterations, histologic, and genetic criteria

    
    
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    Chromophobe (3%-5%)

    
    
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    Collecting duct (1%)

    
    
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    Unclassified (1%)

  
  

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  RCC can be hereditary as well as sporadic or nonhereditary. While sporadic RCC is often a solitary lesion and most commonly presents in individuals in their 60s, inherited forms tend to be multifocal, bilateral, and have an earlier onset.

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  Hereditary basis:

  
  
  
  
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    Renal cancer is hereditary in up to 4% of cases, and follows an autosomal dominant inheritance pattern with incomplete penetrance. In the absence of a diagnosed syndrome, the risk for family members of patients with RCC may increase fivefold. The highest risk appears to be confined to siblings of renal cell cancer patients, arguing for the potential of low penetrance genes acting in concert to elevate the risk of disease.

  
  

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  Differential diagnosis:

  
  
  
  
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    It is important to distinguish the multiorgan system syndromes that include renal cancer as a single feature (ie, von Hippel-Lindau [VHL], Birt-Hogg-Dubé [BHD], and hereditary leiomyomatosis renal cell cancer [HLRCC]) from the familial tumor predispositions (ie, hereditary papillary renal carcinoma [HPRC]), in which renal cancer is the only major finding. Thus, it is imperative to inquire about associated features if there is clinical suspicion for an inherited syndrome in order to establish a clinical diagnosis or indication for genetic (germline) testing (Table 50-1).

  
  

Diagnostic Criteria for Hereditary Renal Cancer

Inherited forms tend to be multifocal, bilateral, and have an early onset (<60 years of age). The histologic type of renal cancer can help delineate the associated syndrome(s) and guide further evaluation (Table 50-2).

Diagnostic Evaluation

Clear Cell

If a patient presents with predominantly clear cell RCC and has features suggestive of an inherited predisposition (young age of onset, multiple lesions), it is important to investigate for signs and symptoms suggestive of VHL. To establish a clinical diagnosis of VHL in a patient, without a known family history, two or more characteristic lesions as noted above are required. The majority of individuals with VHL (70%) develop retinal hemangioblastomas (which can be asymptomatic) by their mid-twenties. These can be detected on routine ophthalmoscopic examination and are often the initial manifestation of VHL, thus providing an important clinical clue for targeting the evaluation. In the absence of retinal findings, further imaging can assist in arriving at a diagnosis of VHL or potentially point to other hereditary renal carcinoma syndromes.

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  Computed tomographic (CT) scan or magnetic resonance imaging (MRI) to establish the presence of

  
  
  
  
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    Central nervous system (CNS) hemangioblastomas (VHL)

    
    
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    Pheochromocytomas that exhibit high signal intensity on T2-weighted MRI, which may help differentiate them from adrenal cortical nodules (VHL, SBHD)

    
    
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    Paragangliomas particularly in the head and neck region (SBHD)

    
    
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    Endolymphatic sac tumors identified with high signal intensity with T1 imaging on MRI as a mass on the posterior wall of the petrous part of the temporal bone (VHL)

    
    
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    Multiple, bilateral lung cysts which can lead to unexplained spontaneous pneumothoraces (BHD)

    
    
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    Subependymal glial nodules, cortical tubers, and subependymal giant cell astrocytomas (tuberous sclerosis complex [TSC])

  
  

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  Ultrasound examination for evaluation of the epididymis and broad ligament, and for less expensive screening of the kidneys (VHL)

  
  
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  Measurement of urinary catecholamine metabolites (VMA, metanephrine, and total catecholamine) to detect elevations that may suggest pheochromocytoma even in the absence of hypertension (VHL, SBHD)

Papillary Type 1