Victor E. Reuter
Memorial Sloan Kettering Cancer Center
New York, NY
Renal Cell Carcinoma is not a rare disease, having an incidence of approximately 10 cases per 100,000
population. Currently, approximately 32,000 new cases will be diagnosed and 12,000 patients will die of
Unfortunately there has been very little progress in the management of these tumors with
surgery being the only time-proven therapeutic option. Despite this lack of progress in the management
of RCC, during the past 10 years we have gained a better understanding of the biology, morphology, and
clinical behavior of these tumors.
Many cells types and growth pattern characteristics may be seen in renal epithelial neoplasms,
| Cell Types ||Growth Pattern|
| Clear cell ||Acinar|
| Granular Cell ||Tubular/glandular|
| Oncocytic || Papillary|
| Spindled || Sarcomatoid|
| Rhabdoid || Solid|
While it is certainly true that virtually all renal cell carcinomas contain one or more of these cell
types and growth patterns, a classification based solely on these distinctions is not very precise. For
example, "sarcomatoid carcinoma" does not exist as an entity since we now know that sarcomatous features
may be present not only in clear cell carcinomas but also in other types such as collecting duct,
chromophobe, and papillary RCC. "Granular cell" features may be observed in tubulo-papillary, oncocytic,
and collecting duct tumors as well as high grade clear cell carcinomas, all of which have very different
natural histories. In 1986 Dr. W. Thoenes described a renal tumor which he called Chromophobe renal
cell carcinoma.  During the ensuing years he and his collaborators proceeded to reevaluate the
classification of renal tumors based on morphologic, histochemical, immunohistochemical, and electron
microscopic data.  At the same time, advances in laboratory methodology allowed us, for the first
time, to establish cell cultures and perform karyotypes on solid tumors, including RCC. During the
interim many investigators worked on the molecular characterization of renal tumors. We should not
underestimate the contributions made to our understanding of the genetic basis of renal epithelial
neoplasms by our colleagues studying hereditary tumors, particularly the group from the National
Institutes of Health led by Drs. Zbar, Linehan and Merino. Their work, combined with work done on
sporadic tumors by others, has translated into a new morphologic classification which has been, at least
in part, validated by genetics and molecular genetics.
Interestingly, the findings made by the
morphologists and basic scientists seemed to validate each other, leading to a revised classification
with greater scientific merit. More recently, clinical studies have provided further validity to the
Epithelial Tumors of the Kidney
|Benign || Malignant|
Papillary (chromophil) adenoma
Metanephric (embryonal) adenoma
|RCC, conventional type (clear cell)|
Papillary (chromophil) RCC
Collecting duct carcinoma - medullary carcinoma
Tumors of undetermined malignant potential
Multilocular cystic RCC
Hereditary Renal Tumors
The majority of renal neoplasms are sporadic, although a small percentage may be hereditary, such as
those clear cell (conventional} carcinomas associated with von Hippel-Lindau disease.
forms of inherited renal neoplasms, tumors are more likely to be diagnosed at an earlier age and are more
likely to be multifocal and bilateral.  Von Hippel-Lindau disease is an autosomal dominant syndrome
characterized by retinal hemangiomas, clear cell (conventional) renal cell carcinomas and multiple renal
cysts, cerebellar and spinal hemangioblastomas, phaeochromocytomas, endocrine pancreatic tumors and
epididymal cystadenomas. The tumor-suppressor VHL gene is located at
chromosome 3p25, and can be inactivated by various mutations, loss of heterozygosity, hypermethylation,
or alterations in VHL modifier genes. Lack of normal VHL protein increases the Hypoxia Induced Factor
(HIF)-1a levels, resulting in overexpression of endothelial growth factors and culminating in a
hypervascular state seen in most VHL-related tumors, and possible tumorigenesis. Other familial non-VHL
clear cell (conventional) RCC have been reported, most of which involve translocations of chromosome 3
including 3p14 (Fragile Histidine Triad-FHIT), 3q13.3 and 3q21 genes, while a few others do not involve
Hereditary forms of papillary renal cell carcinoma are sometimes associated with tumors of the
breast, pancreas, lung, skin and stomach. The syndrome is associated with activating mutations of c-MET proto-oncogene at chromosome 7q34.  Upregulation of the gene results in
the activation of a heterodimeric membrane-spanning tyrosine kinase that is a receptor for hepatocyte
growth factor/scatter factor, and is involved in angiogenesis, cellular motility, growth, invasion, and
cellular differentiation. The renal tumors with trisomy 7 in this syndrome have been shown to harbor
c-MET mutants in 2 of the chromosome copies. 
Birt-Hogg-Dubé syndrome (BHD) is another syndrome recently recognized to be related to multifocal and
bilateral renal tumors. This autosomal dominant syndrome is characterized by cutaneous lesions
(fibrofolliculomas, trichodiscomas and acrochordons), spontaneous pneumothorax, bronchiectasis, and
bronchospasm, colonic neoplasms, and lipomas, which occur in conjunction with the renal tumors.
The renal tumors have variably been reported as renal oncocytomas or chromophobe RCC. However, in our
experience, these tumors are predominantly oncocytic neoplasms displaying hybrid features of both types,
or tumors with some unusual morphologic features. A recent study on a large number of renal tumors from
patients with BHD syndrome revealed similar findings.  The BHD gene has
been mapped to chromosome 17p12-q11.2, and the exact mode of tumorigenesis is not yet completely
elucidated.  Of the families identified with familial renal oncocytoma (FO), a number of these have
been subsequently found to have BHD syndrome.
Rarely, a constitutional reciprocal translocation
between 8q24.1 and 9q34.3 has been reported in cases of bilateral, multifocal renal oncocytoma. 
Sporadic Renal Cell Tumors
Clear Cell (Conventional) Renal Cell Carcinoma:
Conventional (clear cell) carcinoma comprises approximately 60%-65% of all RCC.  They are
characterized by tumor cells with clear cytoplasm (due to increased lipid and glycogen) and an acinar
growth pattern. The "clearing" of the cytoplasm extends from the nucleus to the cytoplasmic membrane,
especially in low grade tumors. In higher grade lesions the cytoplasm may be only partially clear or
mostly "granular", that is to say eosinophilic. It is in these areas where one is likely to see a loss
of the acinar growth pattern, the tumor now being either solid or sarcomatous. It is important to look
for areas of transition to a lower grade so as to establish the correct diagnosis. These tumors may take
on a papillary or pseudopapillary appearance focally, but this is due to degenerative changes rather than
true papillae formation.
Many investigators have attempted to establish grading schemes for RCC with mixed results. In 1981
Fuhrman and her collaborators published a four-tiered classification and showed good correlation with
clinical outcome.  Grade I tumors have small (< than 7 microns}, regular hyperchromatic nuclei
without nucleoli. At the other extreme, grade 4 tumors had markedly enlarged pleomorphic nuclei with
prominent and irregular nucleoli. Despite the fact that this classification is very cumbersome to apply
in general practice (due in great part to the fact that it depends on the actual measurement of
neoplastic nuclei), we have found it to be very useful in predicting clinical behavior, but only in cases
of clear cell carcinoma. Its application to any of the other tumor types is controversial for reasons
that will be discussed later. Tumors with sarcomatous features, irrespective of its tumor type of
origin, should be considered high grade.
Clear cell RCCs are characterized by the loss of genetic material of the short arm of chromosome 3
(3p) and mutations in VHL gene.
In patients with von Hippel-Lindau disease, such losses and
mutations are described in virtually all cases. Interestingly, somatic mutations/hypermethylations in
the same region can be found in 75 to 80% of the more common sporadic, unilateral, and unifocal tumors as
Papillary (chromophil) renal cell carcinoma:
Papillary (chromophil) renal cell carcinoma is an enigmatic group, which includes mostly the cases
previously considered to be tubulo-papillary type.  We now know that there are at least two distinct
types of papillary RCC, both at the morphologic and genetic level and that they appear to have distinct
clinical behaviors as well. As a group they constitute approximately 13% of all renal cortical
neoplasms. As you might expect, most of these tumors have a papillary, tubular or tubulo-papillary
growth pattern. Some tumors have a "solid" growth pattern due to compression of the papillary
structures, making them difficult to identify. Other tumors have a striking "glomeruloid" appearance.
The cytoplasm may be basophilic, eosinophilic or partially clear. It is not unusual for these tumors to
be multifocal, with one or several dominant masses and other minute tumors throughout the cortex
(so-called papillary-tubular adenomas). This is the most common type to present with bilateral disease.
Papillary tumors often exhibit abundant lipid laden macrophages within the interstitium of the
fibrovascular cores. This feature is very helpful in making the correct diagnosis. One must be very
careful since some clear cell RCC may undergo focal necrosis in which the viable cells are seen adjacent
to a blood vessel, thus producing a pseudo-papillary appearance. Since this phenomenon is likely to be
seen in higher grade tumors, it is very likely that the tumor cells do not exhibit a clear cytoplasm,
confounding the problem. Again, looking at many areas of the lesion will allow us to classify these
Many experts feel that the Fuhrman grading scheme is well suited for papillary RCC but others
Drs. Delahunt and Eble have suggested a two-tiered system (types 1 and 2} based
on nuclear features and growth pattern characteristics, which may end up being clinically useful. They
seem to correspond to the type 1 and 2 tumors described molecularly by Zbar and his group. To date
whether these tumors should be graded and, if so, what system to use remains controversial.
Cytogenetic and molecular studies have revealed distinct findings in PRCC that distinguishes them from
other renal epithelial tumors.
The majority of sporadic PRCC are characterized by trisomy of
chromosomes 7 and 17 (type 1 tumors) as well as loss of chromosome Y
. Some investigators have
suggested that tumors exhibiting trisomy 7/17 only are likely to be benign, whereas those tumors
exhibiting additional genetic abnormalities will behave aggressively, a hypothesis that has not been
confirmed in the literature. Recently the group from NIH described the genetic abnormality associated
with type 2 papillary RCC, that being mutations in the fumarate hydratase gene. 
t(X;1}(p11;q21} has been encountered in a subgroup of PRCC.
This translocation results in
the fusion of the TFE3 gene on chromosome X to a novel gene, PRCC, on chromosome 1.
The gene product is believed to play a role in
disrupting normal mitotic spindle checkpoints, with resultant tumorigenesis.  Interestingly, the
TFE3 gene at Xp11.2 has been recently shown to be involved in translocations
with the ASPL gene at 17q25 in a group of renal tumors in young people, a
translocation also seen in alveolar soft part sarcoma.
Approximately 10% of the sporadic PRCC
have also been reported to show somatic mutations in c-MET gene, a genetic
abnormality that is commonly seen as a germline mutation in familial cases. 
Chromophobe Renal Cell Carcinoma:
Chromophobe RCC is an interesting group of neoplasms that was first described in 1985 by Dr. W.
Thoenes and his collaborators and which constitutes approximately 6% of renal cortical neoplasms.
These tumors had been previously classified under the "granular" RCC category but in fact
constitute a distinct morphologic and genetic entity. The morphologic features include a solid,
"pavement" or "cobblestone" growth pattern. The acinar architecture surrounded by a rich vascular
network as seen in clear cell tumors is lacking. Occasionally one may encounter a tubular or cord-like
growth pattern focally, even mimicking a neuroendocrine neoplasm. Nuclei are vesicular or sharply
angulated, located centrally, and rarely exhibit marked pleomorphism. Binucleated cells are a common
finding. Characteristically one sees perinuclear clearing (perinuclear "halo"). The peripheral portions
of the cytoplasm exhibit variable degrees of eosinophilia and granularity, these features being most
prominent adjacent to the cytoplasmic membrane. The end result is accentuation of the cytoplasmic
membrane which enhances the cobblestone appearance of the tumor. Ultrastructurally the neoplastic cells
exhibit "distended vesicles" around the nucleus, giving rise to perinuclear clearing.  The nature of
these vesicles is unclear but some investigators think that they represent aberrant mitochondria or
altered endoplasmic reticulum. The remaining cytoplasmic organelles are compressed to the periphery,
giving rise to the granularity observed by light microscopy. Dr. Thoenes and his group also described
an eosinophilic variant with similar morphologic features and growth pattern but in which the cytoplasmic
eosinophilia is more pronounced. 
The cytoplasm of Chromophobe RCC stains for Hale's colloidal iron but contains sparse amounts of lipid
or glycogen.  For this reason the gross appearance is tan or light brown rather than yellow. CRCC
are characterized genetically by loss of chromosomes 1 and Y as well as combined chromosomal losses,
usually affecting chromosomes 1, 6, 10, 13, 17, and 21.
Loss of multiple chromosomes leads to
hypodiploid tumor cells, a unique feature seen in many of these tumors.  Abnormalities in
mitochondrial DNA may be observed, but its specificity remains controversial. 
These tumors have a much better prognosis than conventional renal cell carcinomas, with the five-year
disease free survival being upwards of 90%.
This fact is supported by several large series, both
published and in press.
Oncocytomas of the kidney also constitute approximately 6% of renal cortical neoplasms.
are characterized by tumor cells arranged in nests, cords, or tubules but never exhibit a papillary
growth pattern. The cytoplasm must be deeply eosinophilic and the nucleus should be round or vesicular
and may contain a prominent, regular nucleolus. Chromatin is finely granular or stippled. Nuclear
features are fairly homogeneous from cell to cell although occasional isolated or groups of cells may
exhibit marked hyperchromasia and pleomorphism. These features are usually accompanied by increased
cytoplasm and never associated with mitotic activity. In fact, rarely, if ever, will you encounter
mitotic activity in an oncocytoma. Tumor necrosis is also absent. A central, stellate scar has been
considered to be characteristic of this type of tumor. While it is true that many oncocytomas contain
such a scar, this feature may also be found in other low grade renal epithelial neoplasms, including
clear cell and chromophobe carcinomas. It is a sign of slow growth rather than a feature of a specific
tumor type. Microscopically, the scar is composed of loose or dense hyalinized connective tissue
containing occasional entrapped tumor cells. Tumor cells may infiltrate perirenal soft tissue and may
occasionally be present within small vessels, although renal vein invasion has not been described.
Some investigators have suggested that the term oncocytoma should be reserved for tumors containing
grade 1 nuclei (Fuhrman classification) only,  but virtually all well preserved oncocytomas exhibit
nucleoli and should not be graded. The diagnosis is based on the cytologic features as well as growth
pattern, not the presence or absence of nucleoli. If one follows these strict criteria, the overwhelming
majority of oncocytomas behave in a benign fashion; only a few questionable reported cases have
metastasized. We know of no case that has died of disease. Electron microscopy reveals a cytoplasm
loaded with mitochondria.
This fact is responsible for the cytoplasmic eosinophilia and the
mahogany brown gross appearance.
Genetically, oncocytomas do not exhibit 3p-, trisomy 7/17 or multiple combined chromosomal losses.
They commonly exhibit loss of chromosomes Y and 1 and a few cases have been described containing a
translocation involving chromosome 11. Some investigators have suggested that mutation in mitochondrial
DNA may lead to increased proliferation of mitochondria and possibly to the proliferation of neoplastic
cells. This hypothesis has yet to be proven. Recently we have described a group of patients with
multiple oncocytic lesions ("Oncocytosis). Among several characteristic morphologic features, some had a
hybrid morphology between oncocytomas and chromophobe renal cell carcinoma, suggesting that these tumors
may be genetically related. In fact, there is a hypothesis that chromophobe tumors may represent a
genetic/morphologic progression from oncocytoma. It is very likely that many if not all of those
patients belonged to BHD families.
Collecting Duct Carcinoma:
Collecting duct (Bellini duct) carcinoma is a very rare and enigmatic tumor.
It may present
at any age although it tends to occur in younger patients. These tumors are thought to arise from the
collecting ducts within the renal medulla and commonly exhibit a papillary/tubular growth pattern. The
original description of this tumor and its possible relationship to ducts of Bellini of the renal medulla
can be traced to Pierre Masson. More recently, other authors have described an intraductal growth
pattern or dysplastic changes in adjacent collecting ducts to support the hypothesis that these tumors
arise in collecting ducts. They differ from papillary carcinomas of the renal cortex by their location,
lack of multifocallity, and higher nuclear grade. They tend to be light tan or gray in color, reflecting
the fact that they contain little glycogen. They may contain intracytoplasmic mucin but one may have to
stain several sections to identify it. Some authors suggest that this tumor is likely to react
immunohistochemically with high molecular weight cytokeratin (for example, 34BE12), peanut lectin
agglutinin (PNA), and Ulex europaeus (UEA).
As previously mentioned, these tumors may occur at any age but usually present in a younger patient
population. They are very aggressive tumors, a third exhibiting metastases at the time of presentation.
Most patients die of disease within three years of diagnosis.
Since collecting duct carcinomas are rare, very few have been studied cytogenetically. Füzesi et al
studied three cases, all of which were characterized by monosomies, including chromosomes 1, 6, 14, 15,
and 22.  This fact suggests that they are different from papillary renal cortical tumors which, as
we have seen, are characterized by trisomy of chromosome 17 and/or 7.
Another tumor which some investigators believe to be a particularly virulent variant of Collecting
Duct carcinoma is the so-called medullary carcinoma.
This highly aggressive tumor develops
preferentially in young patients with sickle cell trait. They have rather distinctive morphologic
features that overlap with those seen in collecting duct carcinomas and high grade urothelial tumors
arising in the renal pelvis.
Renal Cell Carcinoma, Unclassified:
This diagnostic category includes the renal carcinomas that do not fit into any of the above-described
categories, even after genetic analysis.  Thus, tumors of unrecognizable cell or architectural types,
or those with apparent composites of the recognized types are all included in this.
These form up to 6% of all renal epithelial tumors.  While many of the tumors from this
category are of high cytomorphological grade and aggressive clinical behavior,  by definition, they
are not a pure entity, including highly aggressive tumors as well as less aggressive types. An example
of the latter group would be those cases which are difficult to classify as oncocytoma or an eosinophilic
variant of CRCC.
In summary, recent advances in the study of renal neoplasms have allowed us to modify the
classification of these tumors. It is now possible to correlate the morphological phenotype to the
genotype in a more accurate manner. In addition, it has allowed us to do away with entities such as
"granular" and "sarcomatoid" RCC since we now know that these cytological features are non-specific and
may be found in tumors of different types. We have also come to realize that well accepted grade schemes
such as that of Fuhrman et al. are applicable to Clear Cell RCC but its application to grade other tumor
types is debatable and should be submitted to further study.
Renal Epithelial Neoplasms
|"Granular" Features || Sarcomatoid Features || Papillary Or Tubulopapillary Features|
|Collecting Duct Ca.|
|Collecting Duct Ca.|
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