Epithelial Tumors of the Kidney
Classification

Benign	Malignant
Oncocytoma Papillary (chromophil) adenoma Metanephric (embryonal) adenoma Nephrogenic Adenofibroma	RCC, conventional type (clear cell) Papillary (chromophil) RCC Chromophobe RCC Collecting duct carcinoma - medullary carcinoma RCC, unclassified
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. [10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21] In all 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. [22] 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 chromosome 3. [22, 23]

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. [24] 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. [22]

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. [25, 26] 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. [27] The BHD gene has been mapped to chromosome 17p12-q11.2, and the exact mode of tumorigenesis is not yet completely elucidated. [26] Of the families identified with familial renal oncocytoma (FO), a number of these have been subsequently found to have BHD syndrome. [22, 23] Rarely, a constitutional reciprocal translocation between 8q24.1 and 9q34.3 has been reported in cases of bilateral, multifocal renal oncocytoma. [28]

Sporadic Renal Cell Tumors

Clear Cell (Conventional) Renal Cell Carcinoma:
Conventional (clear cell) carcinoma comprises approximately 60%-65% of all RCC. [29] 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. [30] 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. [31, 32, 33, 34, 35] 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 well. [36]

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. [37] 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 tumors correctly.

Many experts feel that the Fuhrman grading scheme is well suited for papillary RCC but others disagree. [8, 29, 38, 39] 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. [40, 41] The majority of sporadic PRCC are characterized by trisomy of chromosomes 7 and 17 (type 1 tumors) as well as loss of chromosome Y [40, 42, 43, 44, 45, 46, 47] . 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. [48]

t(X;1}(p11;q21} has been encountered in a subgroup of PRCC. [23, 49, 50] This translocation results in the fusion of the TFE3 gene on chromosome X to a novel gene, PRCC, on chromosome 1. [23, 50, 51] The gene product is believed to play a role in disrupting normal mitotic spindle checkpoints, with resultant tumorigenesis. [52] 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. [53, 54] 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. [55]

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. [3, 56, 57, 58] 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. [56] 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. [57]

The cytoplasm of Chromophobe RCC stains for Hale's colloidal iron but contains sparse amounts of lipid or glycogen. [59] 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. [60, 61, 62, 63] Loss of multiple chromosomes leads to hypodiploid tumor cells, a unique feature seen in many of these tumors. [64] Abnormalities in mitochondrial DNA may be observed, but its specificity remains controversial. [65]

These tumors have a much better prognosis than conventional renal cell carcinomas, with the five-year disease free survival being upwards of 90%. [8, 66] This fact is supported by several large series, both published and in press.

Oncocytomas:
Oncocytomas of the kidney also constitute approximately 6% of renal cortical neoplasms. [67, 68, 69, 70] They 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, [68] 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. [69, 71, 72] 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. [73, 74] 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. [75] 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. [76, 77, 78, 79] 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. [6] 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. [8] While many of the tumors from this category are of high cytomorphological grade and aggressive clinical behavior, [80] 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

Differential Diagnosis:

"Granular" Features	Sarcomatoid Features	Papillary Or Tubulopapillary Features
Conventional RCC Chromophobe RCC Papillary RCC Oncocytoma	Conventional RCC Papillary RCC Chromophobe RCC Collecting Duct Ca. Urothelial Ca.	Conventional RCC Chromophobe RCC Papillary RCC Collecting Duct Ca. Urothelial Ca.

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