Correlation Between Morphologic and Molecular Phenotypes of Renal Neoplasms. The Importance of the Surgical Pathologist in Recognizing New Hereditary Renal Syndromes
Maria J. Merino
NCI, National Institutes of Health
In the United States there are approximately 30,000 new cases of kidney cancer each year, and 12,000
individuals die from the disease. Kidney cancer is made up of a number of different cell types of
cancers that develop from different portions of the collecting system.
Each type of kidney cancer is characterized by a specific morphology, is caused by a different
gene, and has a different clinical course. Among the most common types of kidney cancer are clear
cell renal carcinoma, papillary renal carcinoma, chromophobe renal carcinoma and oncocytoma.
Can Morphology assist in the Discovery of novel familial syndromes and their genetic
Birt, Hogg and Dubé had described the appearance of multiple cutaneous fibrofolliculomas in a large
Canadian family in 1977. The syndrome, which goes by the name Birt Hogg Dubé, or BHD, was initially
defined as an autosomal dominant inherited syndrome in which affected individuals are known
to be affected with cutaneous lesions. The predisposition to develop this cutaneous hamartomas, was
inherited as an autosomal dominant Mendelian trait. Birt Hogg Dubé syndrome kindreds have been described
in which affected family members had health problems involving the lungs, colon, and rarely
kidneys. In some of these kindreds affected members developed spontaneous pneumothorax and colon
cancer. The incidence of associated Renal tumors was unknown.
The morphologic type of the renal tumors remained unknown
To test whether kidney cancers were significantly associated with familial fibrofolliculoma, families
were recruited on the basis of fibrofolliculomas and determined the frequency of renal tumors and
spontaneous pneumothorax. To detect occult renal malignancies, family members were examined by renal
ultrasound, and abdominal CT scans.
We have found, that about 14.4 % of those affected with the syndrome have renal tumors compared
to 1.8% not affected (p = 0.0002). The odds of developing a renal tumor was 9.3 times greater for
persons affected with BHD. Age was associated with the development of renal tumors (p = 0.0054). 11.9 %
of patients over 40 years of age developed renal tumors compared to 2.3% younger patients (<41 years).
When the renal cell carcinoma phenotype was evaluated, it became clear that it was notable in a
number of ways. We have found renal cell carcinoma in 36/152 (24%)
patients affected with BHD. In a group of 30 BHD patients with renal tumors, we found an average
5.3 macroscopic tumors (up to 6 cm in size) per patient (range 1-28). Multiple and bilateral tumors
were also detected in most patients.
Specific tumor phenotypes are associated with the BHD syndrome
The pathologic evaluation of 130 BHD
renal tumors revealed a predominance of unusual phenotypes such as oncocytic and/or “hybrid”
neoplasms (65/130, 50%) or chromophobe renal cell carcinomas (44/130, 34%). Twelve clear cell renal
cell carcinomas (9%) were found in 9 patients. Marked microscopic oncocytosis was found in the
renal parenchyma of most patients. (Pavlovich et al, in press). This unusual type of tumor had not
previously been reported in association with familial syndromes.
spectrum of lesions from were those recognizable as oncocytomas to yellowish masses with the
characteristic appearance of Clear cell RCC. The histologic evaluation revealed different cell types and
suggested tumor progression from oncocytomas to hybrid lesions to chromophobe RCC and finally Clear Cell
In order to confirm that the BHD renal tumors with clear cells were true conventional RCC, molecular
analyses were undertaken on specimens from 7 BHD renal tumors of conventional (clear-cell)
histology. LOH flanking VHL at 3p was noted in 4/7 (57%) tumors, and VHL mutations were noted in 2
of 6 (33%) tumors analyzed (both of which also demonstrated 3p LOH. BHD tumors of other histologies were
also analyzed for 3p LOH and VHL mutations; of 16 chromophobe RCC, 4 hybrids, and 4 oncocytomas assayed,
none had LOH at D3S1110 or D3S1038, and 0/3chromophobe, 0/6 hybrid, and 0/1 oncocytomas demonstrated VHL
These findings raise the question whether renal oncocytosis and hybrid renal neoplasms are precursors
of chromophobe and conventional RCC in BHD kidneys, and perhaps in some cases of sporadic renal
neoplasia. Recognition of these tumors by the pathologist, may assist in recognition of this syndrome.
Eighteen individuals with BHD (from 13 different families) who had partial or radical nephrectomies for
renal cell carcinoma(s) (RCC) provided material for genetic analysis. Tumor and normal tissues were
microdissected for LOH studies. Microsatellite analyses at five 17p11 markers in the BHD locus (D17S740,
D17S2196, D17S620, D17S805, D17S2187) were performed. 15/88 tumors (17%) demonstrated loss of
heterozygosity (LOH) at all informative 17p markers, while microsatellite instability (MSI) was only
noted in 1 tumor. Seven tumors with 17pLOH came from six patients in whom BHD had been linked to
specific 17p alleles: in each of these cases, the wild type rather than BHD-linked 17p11 alleles were
lost in the tumors (p=0.008).
CGH analyses corroborated either whole-arm 17p or whole chromosome losses in the tumors with 17pLOH
irrespective of histology.
2- Morphology leads to the characterization of Hereditary Leiomyomatosis Renal
Cell Carcinoma (HLRCC), a new hereditary syndrome and to conduct genotype/phenotype analysis.
As members of the same family with unknown familial forms of renal cell carcinoma were evaluated,
three kindreds with what appeared to be an inherited form of papillary renal carcinoma that was
distinct from HPRC were identified. Affected individuals in these kindreds were found to have an
extraordinarily aggressive form of Type II renal cell carcinoma. We also noted that many affected
family members have cutaneous leiomyomas. This syndrome has been characterized by investigators in
Northern Europe and named Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC),9 which is related
to another syndrome, Multiple Cutaneous Leiomyoma (MCL). Affected individuals in HLRCC and MCL
kindreds are also at risk to develop multiple uterine leiomyomas (fibroids). A Finnish/Northern
European consortium recently identified an HLRCC/MCL locus on chromosome 1q and subsequently reported the
identification of mutations of the Krebs cycle enzyme, fumarate hydratase (FH), as a gene mutated in the
germline of some of the kindreds affected by HLRCC/MCL. This syndrome is rarely recognized in our
country thus the importance of pursuing the studies.
In order to characterize the clinical phenotype and to study the genetic basis of Type II papillary
renal carcinoma we have recruited MCL/HLRCC kindreds. To date 67 patients have been screened
affected or at risk from 14 HLRCC/MCL kindreds (41 patients at NIH and 26 on field trips). In four
of these kindreds Type II papillary RCC appeared, in 10 kindreds no evidence of renal carcinoma has yet
Definition of morphological phenotypes
It is now known that there are two morphologic types (Type I and Type II) of sporadic
papillary renal carcinoma. Sporadic Type I papillary renal carcinoma tends to be a moderately
indolent cancer with a decreased propensity to metastasize early and therefore good prognosis.
Sporadic Type II papillary carcinoma is an aggressive form of cancer that spreads early and is
refractory to any form of therapy. We have found c-Met mutations in tumors from patients with Type
I papillary renal carcinoma, but not from patients with Type II papillary renal carcinoma. The
cytogenetic abnormalities in tumors from patients with type II papillary renal carcinoma are
characterized by translocations involving the long arm of chromosome 1. We suspect that these
translocations could result in loss of the translocated arm of chromosome 1 and subsequent mutation of
the remaining FH gene in these tumors.
It is clear, that morphologic evaluation of Renal tumors can be the initial step to identify new syndromes, and
provide the basis for the discovery of related new genes.
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