World Health Organization Classification of Tumours Pathology and ...

Fig. 1.08 Hereditary papillary renal cancer (HPRC)with multiple, bilateral papillary RCC.Fig. 1.09 Germline mutations of the MET oncogenein hereditary papillary renal cell carcinoma (HPRC).members develop the disease by theago of 55 years {2327}. Extrarenal manifestationsof HPRC have not been identified.Papillary renal cell carcinomaBHD patients develop myriad papillarytumours, ranging from microscopiclesions to clinically symptomatic carcinomas{1979}. The histological pattern hasbeen termed papillary renal carcinomatype 1 and is characterized by papillaryor tubulo-papillary architecture verysimilar to papillary renal cell carcinoma,type 1.GeneticsResponsible for the disease are activatingmutations of the MET oncogenewhich maps to chromosome 7q31. METcodes for a receptor tyrosine kinase{799,1212,1213,1570,2326,2327,2926,2928}. Its ligand is hepatocyte growthfactor (HGFR). Mutations in exons 16to 19, ie the tyrosine kinase domain causesa ligand-independent constitutiveactivation.Duplication of the mutant chromosome 7leading to trisomy is present in a majorityof HPRC tumours {768,845,1996,2032,2937}.ManagementFor patients with confirmed germlinemutation, annual abdominal CT imagingis recommended.Hereditary leiomyomatosis andrenal cell cancer (HLRCC)DefinitionHereditary leiomyomatosis and renal cellcancer (HLRCC, MIN no: 605839) is anautosomal dominant tumour syndromecaused by germline mutations in the FHgene. It is characterized by predispositionto benign leiomyomas of the skin andthe uterus. Predisposition to renal cellcarcinoma and uterine leiomyosarcomais present in a subset of families.MIM No. 605839 {1679}.Diagnostic criteriaThe definitive diagnosis of HLRCC relieson FH mutation detection. The presenceof multiple leiomyomas of the skin andthe uterus papillary type 2 renal cancer,and early-onset uterine leiomyosarcomaare suggestive {51,52,1330,1450,1469,2632}.Renal cell cancerAt present, 26 patients with renal carcinomashave been identified in 11 familiesout of 105 (10%) {52,1329,1450,1469,2632}. The average age at onset is muchearlier than in sporadic kidney cancer;median 36 years in the Finnish and 44years in the North American patients,(range 18-90 years). The carcinomas aretypically solitary and unilateral {1450,2632}. The most patients have died ofmetastatic disease within five years afterdiagnosis. The peculiar histology of renalcancers in HLRCC originally led to identificationof this syndrome {1450}.Typically, HLRCC renal cell carcinomasdisplay papillary type 2 histology andlarge cells with abundant eosinophiliccytoplasm, large nuclei, and prominentinclusion-like eosinophilic nucleoli. TheFuhrman nuclear grade is from 3 to 4.Most tumours stain positive for vimentinand negative for cytokeratin 7. Recently,three patients were identified havingeither collective duct carcinoma or oncocytictumour {52,2632}. Regular screeningfor kidney cancer is recommended,but optimal protocols have not yet beendetermined. Computer tomography andabdominal ultrasound have been proposed{1328,2632}. Moreover, as renalcell carcinoma is present only in a subsetof families, there are no guidelines yet,whether the surveillance should be carriedout in all FH mutation families.AFig. 1.10 Hereditary papillary renal cell carcinoma (HPRC) A Tumours have a papillary or tubulo-papillaryarchitecture very similar to papillary renal cell carcinoma, type 1. Macrophages are frequently present inthe papillary cores. B Hereditary papillary renal cell carcinoma frequently react strongly and diffusely withantibody to cytokeratin 7.BLeiomyomas of the skin and uterusLeiomyomas of the skin and uterus arethe most common features of HLRCC,the penetrance being approximately85% {1328,2632}. The onset of cutaneousleiomyomas ranges from 10-47years, and uterine leiomyomas from 18-52 years (mean 30 years) {2632}.Clinically, cutaneous leiomyomas present18Tumours of the kidney