Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype

Abstract

Germline mutations of c-met oncogene at 7q31 have been detected in patients with hereditary papillary renal cell carcinoma. In addition, c-met mutations were shown to play a role in 13% of patients with papillary renal cell carcinoma and no family history of renal tumors. The histopathology of papillary renal cell carcinoma with c-met mutations has not been previously described. We analyzed the histopathology of 103 bilateral archival papillary renal cell carcinomas and 4 metastases in 29 patients from 6 hereditary papillary renal cell carcinoma families with germline c-met mutations and 6 papillary renal cell carcinomas with c-met mutations from 5 patients with no family history of renal tumors. Twenty-five sporadic renal tumors with prominent papillary architecture and without somatic c-met mutations were evaluated for comparison. All papillary renal cell carcinomas with c-met mutations were 75 to 100% papillary/tubulopapillary in architecture and showed chromophil basophilic, papillary renal cell carcinoma type 1 histology. Fuhrman nuclear grade 1-2 was seen in tumors from 23 patients, and nuclear grade 3 was observed focally in 8 patients. Seventeen patients had multiple papillary adenomas and microscopic papillary lesions in the surrounding renal parenchyma. Clear cells with intracytoplasmic lipid and glycogen were focally present in tumors of 94% papillary renal cell carcinoma patients. Clear cells of papillary renal cell carcinoma had small basophilic nuclei, and clear cell areas lacked a fine vascular network characteristic of conventional (clear) cell renal cell carcinoma. We conclude that papillary renal cell carcinoma patients with c-met mutations develop multiple, bilateral, papillary macroscopic and microscopic renal lesions. Renal tumors with c-met genotype show a distinctive papillary renal cell carcinoma type 1 phenotype and are genetically and histologically different from renal tumors seen in other hereditary renal syndromes and most sporadic renal tumors with papillary architecture. Although all hereditary and sporadic papillary renal cell carcinomas with c-met mutations share papillary renal cell carcinoma type 1 histology, not all type 1 sporadic papillary renal cell carcinomas harbor c-met mutations.

Figure 1.

A: Pedigree of hereditary PRC family 150. Solid symbols indicate individuals with renal tumors. Diagonal slash indicates patient is deceased. Patient numbers correspond to individuals listed in Table 2 ▶ . B: Gross photograph of multiple renal tumors in a nephrectomy specimen from hereditary PRC patient 4599 (family 150) with H1112R mutation (from Zbar et al¹²). The tumors display prominent yellow color. C: Interphase FISH on a tumor cell touch preparation from hereditary PRC patient 4599 with H1112R mutation (family 150). Three copies of MET (trisomy 7; rhodamine, red signal) are seen in the tumor cell, using c182b3 combined with a centromeric α-satellite probe (FITC, green signal) specific for chromosome 17¹⁹; D: DNA sequence of hereditary PRC patient 5946 (family 5946) showing germline mutation C to T transition (antisense, arrow) at nucleotide 3522, resulting in a valine to isoleucine change at codon 1110.

Figure 2.

Representative PRC from patient 4599 (family 150) with H1112R mutation. The tumors show type 1 PRC (chromophil basophilic) histology and Fuhrman nuclear grade 1–2. A: Papillary architecture characterized by delicate fibrovascular cores lined by small cells with basophilic nuclei and scant amphophilic cytoplasm (H&E, ×400). B: Tubulopapillary architecture and small cells with basophilic nuclei and amphophilic cytoplasm (H&E, ×400). C: Psammoma bodies and foamy hemosiderin-laden macrophages are prominent microscopic features (H&E, ×400). D: Papillary architecture, foamy macrophages in fibrovascular cores and cells with small basophilic nuclei and scant amphophilic and focal clear cytoplasm (H&E, ×200).

Figure 3.

Histopathology of representative PRC and an ultrastructure of clear cells in hereditary PRC patients 5946 with V1110I mutation and 4599 with H1112R mutation. A: Fibrous pseudocapsule surrounds a 4 cm tumor from patient 5946; a retraction artifact gives an impression of a “cyst wall lined by a layer of tumor cells” (H&E, ×200). B: A tumor from patient 4599 shows a “metanephric adenoma-like” architecture and contains cells with low grade basophilic nuclei and amphophilic and eosinophilic cytoplasm (H&E, ×400). C: A tumor from patient 5946 demonstrates an area composed of sheets of cells with basophilic Fuhrman nuclear grade 1 nuclei and clear cytoplasm and adjacent cells with Fuhrman nuclear grade 3 nuclei and eosinophilic cytoplasm. Thin fibrovascular papillary cores are seen in cross-section in the area of clear cells (H&E, ×400). D: Electron micrograph of clear cells from a hereditary PRC patient 5946 shows prominent intracytoplasmic lipid droplets and glycogen (magnification, ×6600).

Figure 4.

Multiple adenomas and microscopic papillary lesions in the surrounding kidney parenchyma and PRC metastases in hereditary PRC patients with c-met mutations have the architecture and histology which is similar to the architecture and histology of PRC. A: Papillary adenoma in patient 5946 with V1110I mutation (H&E, ×200). B: A microscopic papillary lesion in patient 4599 with H1112R mutation (H&E, ×400). C: Microscopic papillary lesions in patient 5946 with V1110I mutation (H&E, ×400). D: A lymph node metastasis in patient 3740 with H1112R mutation (family 150) (H&E, ×200).