Moderators: Dr. John Eble and Dr. Brett Delahunt
Section 1 -
Hybrid Tumors, Oncocytomas and Chromophobe Renal Cell Carcinomas
Guido Martignoni, Stefano Gobbo, Matteo Brunelli
Universitŕ di Verona
Renal tumors with abundant eosinophilic cytoplasm are fairly common and can pose problems because
their differential diagnosis includes both benign and malignant tumors.
This differential diagnosis can be particularly difficult in core needle biopsies of renal masses, a
procedure that is being increasingly performed with the advent of new minimal invasive forms of
therapies, such as cryoteraphy and diathermocoagulation which require a pre-operative diagnosis
The most frequent of these tumors are chromophobe renal cell carcinoma and oncocytoma.
Recently tumors showing combined zones of chromophobe renal cell carcinoma and oncocytoma patterns have
been described and named hybrid tumors. It has been proposed that these tumors could represent a link
between oncocytoma and chromophobe renal cell carcinoma and could validate the hypothesis that
chromophobe tumors may represent a genetic/morphologic progression from oncocytoma
Chromophobe renal cell carcinoma was first recognized in 1985 by Thoenes and his collaborators .
It comprises approximately 5 per cent of surgically removed renal epithelial tumors . Grossly, it is
a solid well circumscribed neoplasm with a light brown colour on the cut surface. The morphologic
features of chromophobe renal cell carcinoma include a solid, "cobblestone" growth pattern whereas the
acinar architecture surrounded by a rich vascular network as seen in clear cell renal cell carcinoma is
lacking. A tubular architecture may be occasionally seen. Focal calcifications and broad fibrotic septa
are frequently present. Nuclei ranged from vesicular to wrinkled and can exhibit marked pleomorphism.
The neoplastic cells can display binucleation. The peripheral portion of the cytoplasm shows a variable
degree of granularity and eosinophilia resulting in an accentuation of the cellular membrane. A
perinuclear "halo" may be observed . Mitotic figures can be found in an highly amount ranging from
none to twenty-five x 50 high power fields .
At electron microscopy chromophobe renal cell carcinoma is typically characterized by a cytoplasm
containing scant numbers of mitochondria, which have tubulovesicular christae, and by the presence of
innumerable 150-300-microm microvesicles scattered between the mitochondria; these microvesicles are
responsable for the perinuclear halo and flocculent cytoplasm in the chromophobic neoplastic cells .
In 1988, ten cases of eosinophilic variant out of 32 chromophobe renal cell carcinomas have been
In our experience this variant represents roughly the 10% of this histotype .
Hale's colloidal iron stain has been considered a diagnostic hallmark, but in some cases it can not
be contributory. C hromophobe renal cell carcinoma immunohistochemically expresses cytokeratins, in
particular cytokeratin 7 shows a strong immunoreactivity in nearly all of the neoplastic cells with an
accentuation of the staining at the plasma membrane. Epithelial membrane antigen, parvalbumin, c-Kit,
EpCam and in a subset of cases RCC antigen and CD10 are also positive
A unique feature seen in chromophobe renal cell carcinoma is the loss of multiple chromosomes leading
to hypodiploid tumor cells. The most common loss involves chromosome 1, 2, 6, 10, 13, 17 and 21. These
genetic losses have been found by classical cytogenetic methods, comparative genomic hybridization and
fluorescence in situ hybridization
The eosinophilic and classic variants of chromophobe renal
cell carcinoma have similarly highly frequent losses of chromosomes 1, 2, 6, 10, and 17 in contrast with
renal oncocytomas .
At the molecular level p53 mutation have been demonstrated in 27% of chromophobe renal cell carcinoma
Chromophobe renal cell carcinoma is considered a low grade malignancy with a much better prognosis
than clear cell renal cell carcinoma, the five years disease free survival being upwards of 90%
However a few distant metastases have been reported and sarcomatoid changes in chromophobe renal cell
carcinoma vary from 9 to 55 per cent in the literature . Recently Brunelli et al. found more than
one signal in both epithelial and sarcomatoid components by fluorescence in situ hybridization analysis
using centromeric probes for chromosomes 1, 2, 6, 10 and 17 .
Oncocytoma of the kidney has been described by Klein and Valensi in 1976 . It represents about 5%
of renal cortical neoplasms. They are well circumscribed nonencapsulated tan neoplasm and show a central
scar in one third of the cases. Rare oncocytomas extend into perirenal fat and sometimes into blood
vessels. They are formed by tumor cells arranged in nests, cords or tubules whereas papillary growth
pattern is absent. The neoplastic cells are round to polygonal with a deeply eosinophilic granular
cytoplasm. The nucleus is round and usually contains a prominent nucleolus. Nuclear features are
homogeneous from cell to cell although a small population of cells with scanty cytoplasms and
hyperchromatic nuclei, so called oncoblasts, can be seen. In most of the oncocytomas no mitotic figures
are detectable. Necrosis is constantly absent .
Electron microscopy reveals a cytoplasm loaded with mitochondria . This fact is responsible for
the cytoplasmic eosinophilia.
In oncocytoma there is no diffuse Hale's colloidal iron stain  and the cytokeratin 7 stains single
or small cluster of neoplastic cells with positive cytoplasmic reaction. Eighty per cent of the
oncocytomas are positive for the calcium binding protein parvalbumin and more than 90% for S100A1,
another calcium binding protein, which is interestingly negative in 96 % of the chromophobe renal cell
Cytogenetically renal oncocytomas fall into three categories, namely characterized by normal
karyotype, monosomy 1 and or 14, often with Y chromosome loss, and structural abnormalities of 11q13
which include cyclin D1 locus .
Loss of chromosome 1 has been reported by Polascik et al. (57%
with loss of heterozygosity (LOH) at 1p and 30% LOH at 1q in 13 cases), Crotty et al. (33%, karyotyping
study on six cases), Presti et al. (45%, CGH study on 13 cases), Thrash-Bingham et al. (75%, LOH at 1p
on four cases), Brown et al. (50%, FISH study on 20 cases), Herbers et al. (10%, LOH with two markers
on 1p/1q in a study performed on 41 cases)
and Fusezi .
The majority of oncocytomas behave in a benign fashion; only a few questionable reported cases have
Renal oncocytomatosis is a rare condition described by Warfel and Eble in 1982 . It is
characterized by the presence of bilateral numerous oncocytomas and oncocytic changes in the renal
tubules. Recently Tickoo et al have reported a group of patients with multiple oncocytic lesions and
they called this disease oncocytosis. Some of these tumors had a hybrid morphology between oncocytoma
and chromophobe renal cell carcinoma, suggesting that these neoplasms can be related and that chromophobe
renal cell carcinoma can represent a progression from oncocytoma .
Birt-Hogg-Dubč syndrome is a genodermatosis inherted as an autosomal dominant trait which could shed a
light between the possible relationship between oncocytoma and chromophobe renal cell carcinoma and the
genetic progression from one to the other. This disorder, first recognized in 1977 by three Canadian
physicians is characterized by the presence of multiple fibrofolliculomas, which are considered
hamartomas of the hair follicles, on the skin of the head and neck accompanied by acrochordons and
trichodiscomas. Later, pulmonary cysts with spontaneous pneumothorax and multifocal renal tumors were
recognized in patients affected by this syndrome. The patients are adults (V decade) and predominantly
males (80%). The renal tumors from 30 patients have been described in detail. The most common
histologic type is a hybrid tumor showing combined zones of chromophobe renal cell carcinoma and
oncocytoma patterns. The other tumors were chromophobe renal cell carcinoma (35%), clear cell renal cell
carcinoma (9%), oncocytomas 5% and papillary renal cell carcinoma (2%)
The gene responsible for this syndrome has been localized on chromosome 17p11.2 by linkage analysis
in Birt-Hogg-Dubč syndrome families and encodes a protein called folliculin.
Although the progression oncocytoma/chromophobe renal cell carcinoma seems higly suggestive in renal
tumors occurring in patients with Birt-Hogg-Dubč syndrome, some data obtained from sporadic chromophobe
renal cell carcinomas, sporadic oncocytomas and renal oncocytosis in patients without Birt-Hogg-Dubč
syndrome are not in accord with this hypothesis .
In sporadic chromophobe renal cell carcinoma and sporadic oncocytoma the Birt-Hogg-Dubč syndrome gene
is involved in 11% and 29% of the cases and these percentages are smaller than those observed in the
other renal cell neoplasia such as clear cell carcinoma and papillary renal cell carcinoma (33% and 36%
. Recently Al Saleem et al reported a case of apparently nonfamilial oncocytomatosis
in which they demonstrated by cytogenetic analysis that the genetic findings differs from that of
Birt-Hogg-Dubč syndrome and is characterized by losses involving chromosomes 1, 14, 21, and Y .
In conclusion, we need to collect more cases of hybrid tumors and perform further immunohistochemical
and genetic studies on these neoplasms to better understand the biology of the renal epithelial tumors
with abundant eosinophilic cytoplasm.
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