Renal Neoplasia: Diagnostic Problems and Recently Recognized Entities
Case 2 -
Papillary Renal Cell Carcinoma Type 1
John N Eble, M.D.
Holger Moch, M.D.
62 year old man. The tumor was detected incidentally by
ultrasound. There were no specific signs or symptoms. Renal angiography showed relative hypovascularity
of the tumor. The tumor was treated by nephrectomy. Macroscopic findings:
The kidney specimen contained a 3.5 x 2 x 1.5 cm tumor. There was tumor hemorrhage and
Papillary renal cell carcinoma Type 1
Papillary renal cell carcinomas comprise approximately 10% of renal cell carcinoma. The reported mean
age at presentation ranges from 52 to 66 years. Signs and symptoms are similar to clear cell renal
carcinomas. Renal angiography studies have shown relative hypovascularity for papillary renal cell
carcinomas. Histopathologically, papillary renal cell carcinoma is characterized by malignant epithelial
cells forming papillae and tubules in at least 70% of the tumor areas. The tumor papillae contain a
delicate fibrovascular core and aggregates of foamy macrophages and cholesterol crystals may be present.
Necrosis and hemorrhage is frequently seen and hemosiderin granules may be present. Calcified
concretions are common in papillary cores. Two morphological types of papillary renal cell carcinomas
have been described: Type1 tumors have papillae covered by small cells with scanty cytoplasm, arranged
in a single layer on the papillary basement membrane. Type 2 tumor cells are often of higher nuclear
grade with eosinophilic cytoplasm and pseudostratified nuclei on papillary cores. Type1 tumors are more
frequently multifocal. Type 1 tumors have a better prognosis than type 2 tumors. Solid variants of
papillary renal cell carcinomas have also been described. They consist of tubules with short papillae
Papillary adenomas are tumors with papillary or tubular architecture of low nuclear grade and 5mm in
diameter or smaller. Autopsy studies have found papillary adenomas increase in frequency from 10% in
patients younger than 40 years to 40% in patients older than 70 years. Papillary adenomas frequently
develop in patients on long term hemodialysis and occur in 33% of patients with acquired renal cystic
disease. Usually, papillary adenomas are solitary, but occasionally they are multiple and bilateral.
When they are very numerous, this has been called "renal adenomatosis". While grade I tubulo-papillary
tumors between 0.5 and 1 cm are strictly defined as carcinomas, many pathologists prefer to report them
as papillary epithelial neoplasms of low malignant potential for practical reasons.
Papillary type 1 renal carcinomas are found in the hereditary papillary renal carcinoma syndrome
(HPRC). The MET- proto-oncogene is inactivated by germline-activating
mutations in the HPRC-syndrome. Papillary type-2 renal carcinomas are found in the hereditary
leiomyomatosis and renal cell cancer syndrome (HLRCC), which is caused by germline loss-of-function
mutations in the fumarate-hydratase (FH) gene.
The MET-proto-onco gene encodes a receptor tyrosine kinase that is activated
by hepatocyte growth factor (HGF). Met-HGF
signaling is important for the epithelial-mesenchymal transition, cell proliferation and integration of
these pathways causes invasive growth. Phosphorylation of tyrosines in MET generates a docking site for
second messengers (Figure 2) which activate several signaling pathways involving RAS, STATS and phospholipase C. MET is over-expressed in many cancers.
Figure 3: Activating missense mutations in MET lead
to papillary renal carcinoma
a) In normal cells, hepatocyte growth factor (HGF) binds the MET
receptor to induce MET dimerization and release auto-inhibition by the MET carboxyl terminus. This
permits transphosphorylation of catalytic tyrosine (Tyr) 1234 and Tyr 1235. Subsequent phosphorylation
of the multisubstrate docking sites Tyr 1349 and Tyr 1356 promotes binding of second-messenger molecules,
such as GRB2, GAB1, phosphatidylinositol 3-kinase (not shown), and downstream signalling leading to
morphogenic, motogenic and mitogenic programs
b) Renal cells from patients with hereditary papillary renal carcinoma
(HPRC) can harbor germline mutations (star) in the tyrosine domain of MET.
These mutations are predicted to release the auto-inhibition by the MET carboxyl terminus, allowing the
receptor to transition to the active kinase form in the absence of ligand stimulation. However, addition
of HGF fully activates mutant MET kinase by stimulation of transphosphorylation of Tyr 1235 only.
Signals for proliferation, invasion and survival occur after docking-site phosphorylation and
second-messenger binding. Additional steps such as duplication of mutant MET-bearing chromosome 7 and
trisomy of chromosomes 16, 17 and 20 might be necessary for the development of these late-onset papillary
renal carcinomas. from: Nature 4, 2004, 381-393
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