Definition

Several clinico-pathologic syndromes exist, defined by distinct genetic abnormalities

Diagnostic Criteria

Syndrome	Genetic Abnormality	Extra-renal	Renal Carcinoma
von Hippel Lindau	VHL 3p25 dominant	Retinal and CNS hemangioblastomas, pancreatic and other cystadenomas, pheochromocytomas	Multiple clear cell carcinomas
Birt Hogg Dubé	FLEN 17p11.2 dominant	Cutaneous fibrofolliculomas, trichodiscomas, skin tags, lung cysts & pneumothorax	Multiple hybrid chromophobe-oncocytomas
Hereditaary leiomyomatosis and renal cell carcinoma	FH 1q42-43 dominant	Cutaneous and uterine leiomyomas, rare kindreds with uterine leiomyosarcoma	Aggressive papillary RCC
Hereditary papillary RCC	MET 7q31 dominant	None	Multiple type 1 papillary RCC
Constitutional chromosome 3 translocation	Various dominant	None	Multiple clear cell RCC
Succinate dehydrogenase B	SDHB 1p36 may be recessive	Pheochromocytomas, head & neck paragangliomas	Bubbly pale to clear cytoplasm

von Hippel Lindau
- Most common renal carcinoma syndrome
  - Prevalence 1:35,000
- Multifocal clear cell carcinomas
- Surrounding kidney parenchyma frequently has innumerable microscopic foci of clear cells
- Renal cysts frequent
Birt Hogg Dubé
- Various types of renal cell carcinomas may occur (Pavlovich 2002)
  - Most (84%) are chromophobe or hybrid chromophobe-oncocytoma
    - Very low incidence of aggressive behavior
    - Hybrid tumors have also been reported in non-syndromic cases (Petersson)
  - Most others are clear cell carcinomas
    - Frequently high grade
    - Behavior same as non-syndromic cases
- Frequent microscopic foci of oncocytosis
  - Clusters of cells with eosinophilic cytoplasm, sharp cell borders and large nuclei
  - Not restricted to kidneys with chromophobe or hybrid tumors
    - May be seen even in BHD syndrome kidneys with clear cell carcinomas
Hereditary leiomyomatosis and renal cell carcinoma
- Usually solitary tumors
- Papillary or tubulopapillary pattern lined by tall cells with abundant eosinophilic cytoplasm (Merino)
  - Large pleomorphic nuclei
    - Large inclusion-like eosinophilic nucleoli
- May have focal clear cells
- In the past, some cases reported as type 2 papillary carcinoma or as collecting duct carcinoma
- Negative for mucin, ulex lectin binding, CK7, CD10
- Clinically aggressive
Hereditary papillary renal cell carcinoma
- Very rare
- Type 1 papillary renal cell carcinomas (Schmidt)
  - Papillae lined by cuboidal cells
  - Usually low cytologic grade
Constitutional chromosome 3 translocation carcinomas
- Very rare
- Multiple clear cell carcinomas
Succinate dehydrogenase mutation carcinomas
- Very rare
- Various patterns reported, including oncocytoid tumors
- Most recent report describes distinctive features (Gill 2011)
  - Circumscribed but not encapsulated
    - Not infiltrative but may surround occasional normal elements
  - Numerous clear to pale cytoplasmic inclusions imparting a bubbly appearance to cytoplasm
    - Inclusions are actually giant mitochondria
  - Frequently cystic
  - Good behavior unless sarcomatoid (1 of 4 cases)

Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates:: 2/24/11, 11/11/11