2009 update on the classification of renal epithelial tumors in adults

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1 International Journal of Urology (2009) 16, doi: /j x Review Article 2009 update on the classification of renal epithelial tumors in adults Antonio Lopez-Beltran, 1 Jose C Carrasco, 2 Liang Cheng, 3 Marina Scarpelli, 4 Ziya Kirkali 5 and Rodolfo Montironi 4 1 Anatomical Pathology Unit, Department of Surgery, Faculty of Medicine, 2 Urology Service, Reina Sofia University Hospital, Cordoba, Spain; 3 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA; 4 Section of Pathological Anatomy and Histopathology, Polytechnic University of the Marche Region, School of Medicine, Ancona, Italy; and 5 Department of Urology, School of Medicine, Dokuz Eylül University, Izmir, Turkey Abstract: The classification of kidney tumors in adults expands rapidly with new categories recently incorporated. This will result in the modification of the current 2004 World Health Organization (WHO) classification of the adult renal epithelial neoplasms. Emphasis should be placed in defining risk groups categorized as malignant or benign tumors, including a category of tumors with low malignant potential to accommodate recently recognized categories with extremely good prognosis after surgery. Unusual tumors such as familial renal cell carcinoma (RCC), translocation RCC, renal cell carcinoma after neuroblastoma, tubular mucinous and spindle cell carcinoma, and mixed epithelial and stromal tumors are also presented. A number of recently described entities and morphologic variants of classical categories deserve recognition since they can be important in differential diagnosis. This review emphasizes clinical, pathological and genetic features defining renal epithelial tumors in adults. Key words: classification, genetics, histological subtypes, kidney cancer, pathology. Introduction Current classification of renal cell tumors in adults was proposed in 2004 by the World Health Organization (WHO) classification. 1,2 This classification summarizes the achievements and contributions of previous classifications, in particular the Mainz (1986) and Heidelberg (1997) classifications. 3,4 It describes categories and entities based on pathological and genetic analyses. 2 Since this is a rapidly expanding field, a number entities and morphologic variants of the main tumor categories have recently been described; 1,3 43 these may be important in patients prognoses and differential diagnoses, and therefore, are important in patients clinical management. 2,5,44 91 This review gives an overview on recent developments in the classification of adult epithelial kidney tumors. Familial renal cancer Inherited or familial predisposition to renal neoplasia is present in less than 4% of renal tumors. 10,12,20,27,36,37,39,41,58 Table 1 lists the known inherited syndromes that predispose to renal tumors as presented in the 2004 WHO classification. 1,2 Each of these syndromes predisposes to a distinct histologic type of renal cell carcinoma (RCC) or other kidney tumor. Clinically, hereditary renal cancers show a tendency to be multiple and bilateral, may have a family history, and present at an earlier age than the non-familial and non-hereditary renal neoplasms. There are four major types of inherited kidney epithelial tumors. VHL clear cell RCC Correspondence: Professor Antonio Lopez-Beltran MD PhD, Unit of Anatomical Pathology, Department of Surgery, Faculty of Medicine, Avda. Menendez Pidal s/n, E-14004, Cordoba, Spain. em1lobea@uco.es Received 4 July 2008; accepted 15 July Online publication 20 April 2009 Like its sporadic counterpart, von Hippel Lindau (VHL) clear cell RCC harbors defective VHL tumor suppressor genes. Genetic alteration in the VHL gene in the tumor can include deletion, nonsense or frame-shift mutations or mis-sense mutations. 10 Hereditary papillary RCC Hereditary papillary RCC (HPRCC) are typically bilateral, multifocal type 1 papillary RCCs. Genetic alterations involve a proto-oncogene, c-met, located at 7q31.1. Similar to what is found in sporadic papillary RCC, trisomy 7 and 17 are characteristically identified in these tumors. 27 Hereditary leiomyomatosis RCC Hereditary leiomyomatosis RCC (HLRCC) patients develop cutaneous and uterine leiomyomas and type 2 papillary RCC. The pathologic findings in this disease are caused by mutations in the fumarate hydratase gene located at 1q Gross et al. reported that chromosomal 1q42-44 single copy was found in 82% of patients. Several different architectural patterns have been described at the histologic level, that is papillary (most common), tubulo-papillary, tubular, and solid. Mixed patterns can also be present. The most important histologic feature of these neoplasms, which is suggested being the hallmark of the HLRCC tumors, is the presence of a characteristic large nucleus with a very prominent eosinophilic nucleolus, surrounded by a clear halo. 15 Immunohistochemical studies are non-specific; however, loss of heterozygosity at 1q32 and 1q42-44 is a frequent finding. These tumors are associated with poor prognosis and frequent spread to regional lymph nodes. 15 Birt-Hogg-Dube syndrome Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant cancer syndrome characterized by benign skin tumors, renal tumors, and spontaneous pneumothorax. 37 The disease-related gene has been mapped to chromosome 17p11.2. A common chromosome 17p11.2 deletion interval is identified in 70% of individuals. BHDS is characterized by a spectrum of mutations, and clinical heterogeneity both among and The Japanese Urological Association

2 Updated classification of renal tumors Table 1 Known inherited syndromes that predispose to renal tumors as presented in the 2004 World Health Organization (WHO) classification Syndrome Gene Tumor Von Hippel-Lindau (VHL) VHL (3p25) Clear cell Tuberous sclerosis TSC1, TSC2 Angiomyolipoma, clear cell, other Constitutional chromosome 3 translocation Responsible gene not found Clear cell Familial renal carcinoma Gene not identified Clear cell Hereditary PRCC c-met Papillary type 1 Birt-Hogg-Dube (BHD) BHD Chromophobe Familial oncocytoma Loss of multiple chromosomes Oncocytoma Hereditary leiomyoma-rcc FH Papillary type 2 VHL gene mutated in some families. Renal oncocytomas, hybrid oncocytic and clear cell carcinomas may occur. PRCC, papillary RCC; RCC, renal cell carcinoma. within families. Renal epithelial tumors with hybrid features are seen in this syndrome (e.g. oncocytic tumor with clear cell carcinoma). 37,45 Malignant renal cell tumors Clear cell RCC All kidney tumors of the clear cell type of any size are considered malignant according to 2004 WHO classification (Table 2). 1,2,84 Most clear cell RCCs are solitary cortical neoplasms that occur with equal frequency in either kidney. Multicentricity (4%) and bilaterality (0.5 to 3.0%) may be seen. 84 The size is variable, but the frequency of small lesions increases due to imaging techniques. Clear cell RCC is typically golden yellow (Fig. 1). Necrosis, cystic degeneration, hemorrhage, calcification, ossification, extension into the renal vein and sarcomatoid change may occur. 48 Microvascular invasion might be a relevant clinical prognostic parameter for low clinical stage RCC and could be the only independent predictor of disease-recurrence after radical surgery (Fig. 2). 2,4,17,18,84 RCC clear cell type may progress into a sarcomatoid carcinoma, which is an ominous prognostic sign. Clear cell RCC has a worse prognosis when compared with chromophobe or papillary subtypes. Fuhrman nuclear grade after stage is the most important prognostic predictor in RCC. 48 Sporadic clear cell RCC displays frequent chromosome 3p losses (Table 3). 4 Loss of chromosome 9p has been reported as an independent prognostic factor in patients with clear cell RCC. 63 The term granular cell indicates RCC with acidophilic cytoplasm, a specific tumor category in the 1998 WHO classification. 92 RCCs with this morphology are now included among the clear cell type based in the absence of genetic and clinical differences between both types. 2 Clear cell RCC with pseudo-papillary architecture is difficult to distinguish from conventional papillary RCC. Fuzesi et al. 81 studied three clear cell RCCs with papillary architecture, and found chromosomal aberrations characteristic of clear cell RCC, with 3p loss and monosomy 14. None of the tumors exhibited trisomy of chromosomes 7 or 17, or loss of Y chromosome, as would have been expected in papillary RCC. 14 Genotyping is the tool of choice for differentiation. The potentially aggressive epithelioid angiomyolipoma as a major differential diagnostic consideration regarding high grade RCC, has been recently recognized. 79 Recently, five cases of RCC of clear cell type Fuhrmann s grade 2, associated with a peculiar stromal proliferation having angioleiomyoma-like features have recently been reported. 9 This proliferation was particularly prominent at the interphase between the Table 2 Modified classification of renal cell tumors in adults Familial renal cancer Malignant renal cell tumors Clear cell RCC Papillary RCC Chromophobe RCC Carcinoma of the collecting ducts of Bellini Tubulocystic carcinoma Renal medulary carcinoma Renal carcinoma associated with Xp11.2 translocations/tfe3 gene fusions (MiTF/TFE family translocation carcinomas) RCC in long-term survivors after neuroblastoma Mucinous tubular and spindle cell carcinoma Thyroid follicular carcinoma-like tumor of kidney RCC unclassified Renal cell neoplasms in end-stage renal disease RCC associated to acquiered cystic disease Clear cell papillary RCC Renal cell neoplasms of low malignant potential Multilocular cystic renal cell neoplasm of low malignant potential (multilocular clear cell RCC) Benign renal cell tumors Papillary adenoma Oncocytoma Metanephric adenoma and adenofibroma Mixed stromal and epithelial tumors (renal epithelial and stromal tumor) Cystic nephroma Mixed epithelial and stromal tumor RCC, renal cell carcinoma. tumor edge and the surrounding normal tissues. It has been postulated that this angioleiomyoma-like change is a tumor epiphenomenon and that it represents yet another manifestation of the well-documented capacity of RCC to induce vascular proliferation. 9 A major advance in RCC is the finding of molecular pathways for the pathogenesis of RCC that can also be used in targeted therapy protocols. Two key pathways are essential to the pathophysiology of the clear cell RCC subtype: (i) the hypoxia-inducible pathway associated with frequent mutations of the VHL tumor suppressor gene; and (ii) the mammalian target of rapamycin (mtor) signaling pathway. 22 Recently 2009 The Japanese Urological Association 433

3 A LOPEZ-BELTRAN ET AL. (a) (b) (c) (d) (e) Fig. 1 Gross features of main epithelial tumors of the kidney. Clear cell renal cell carcinoma (RCC) (a); papillary RCC (b); multilocular cystic RCC (c); chromophobe RCC (d); oncocytoma (e). reported clinical data with inhibitors targeting various aspects of these pathways suggest the onset of a new therapeutic era for patients with metastatic clear cell RCC. The utility of these novel therapies in nonclear cell subtypes of RCC needs to be established. 22 An in depth study of these mechanisms is beyond the scope of this review. Papillary RCC Papillary RCC has a less aggressive clinical course than clear cell RCC. 1,2 Papillary RCC has variable proportions of papillae and may be bilateral or multifocal with frequent hemorrhage, necrosis and cystic degeneration (Fig. 1). 2 The papillae contain a fibrovascular core with aggregates of foamy macrophages, calcified concretions and frequent hemosiderin granules. 85 Cellular type 1 and type 2 tumors have been recognized with papillae covered by small cells with scant cytoplasm arranged in a single layer in type 1, and tumor cells of higher nuclear grade, eosinophilic cytoplasm and pseudostratified nuclei in type 2 (Fig. 2). 75,76 This terminology is preferred in the current WHO classification, to previous terms such as basophilic (type 1) or eosinophilic (type 2) chromophilic papillary RCC in previous classifications. 2,3,49 There are prognostic differences between type 1 and 2 categories with high grade lesions (type 2) better characterized at histologic evaluation. Type 1 tumors have longer survival. 75 Associated sarcomatoid change is rare. 25,74 Trisomy or tetrasomy 7, trisomy 17 and loss of chromosome Y are the earliest karyotypic change. 26,61 Fuhrman s tumor grade, stage, tumor proliferation and sarcomatoid change are correlated with outcome. One recent study showed nucleolar grade to be superior to classic Fuhrman grade in papillary RCC. 28 Age and sex distribution of papillary RCC is similar to clear cell RCC. Recent molecular genetic studies provide evidence for the independent origin of multifocal papillary tumors in patients with papillary RCCs. 90 A variant of papillary carcinoma, oncoytic papillary RCC, has recently been proposed. 11 The cytoplasm of the neoplastic cells was filled by mitochondria with lamellar cristae. 11,86 All cases were positive for the The Japanese Urological Association

4 Updated classification of renal tumors (a) (b) (c) (d) (e) (f) Fig. 2 Main histologic types of renal cell carcinoma (RCC). Clear cell RCC (a); papillary RCC type 1 (b) and type 2 (c); multilocular cystic RCC (d); chromophobe RCC, usual type (e) and the eosinophilic variant (f). antimitochondrial antigen and racemase and showed variable immunoreactivity for cytokeratins (AE1/AE3, CK8-18, CK7, CK19), EMA, CD10, vimentin, and parvalbumin. Interphase cytogenetics showed three or more signals for chromosome 7 and 17, a finding that can be useful in cases mimicking an oncocytoma. 11,86 Within this category, one patient died of metastases on follow-up. 11 Chromophobe RCC Less aggressive than other RCCs, the chromophobe type is characterized by huge pale cells with reticulated cytoplasm and prominent cell membrane (Fig. 2). 1,78 It accounts for 5% of renal epithelial tumors. 3,33,47,59,76 Chromophobe RCC is solid and appears orange turning grey or sandy after fixation (Fig. 1). The eosinophilic variant needs to be differentiated from oncocytoma (Fig. 2). 62 Sarcomatoid transformation is associated with aggressive disease. 47,64,67 Diffuse cytoplasmic Hale s iron colloid stain is characteristic. The relationship between oncocytoma and chromophobe RCC is still under investigation. Both are considered to be derived from the intercalated cell of the collecting duct, both have alterations of mitochondria, that is, rearrangement of mitochondrial DNA and increased mitochondria in oncocytoma 19 and numerous mitochondria-derived microvesicles in chromophobe RCC, and both are frequently observed in the oncocytosis with or without BHD syndrome. 59 In addition, there are reports of hybrid tumor composed of oncocytic and chromophobe elements. 13 Therefore, oncocytoma might be the benign counterpart of chromophobe RCC. 14,62 Loss of several chromosomes characterizes chromophobe RCC (Table 3). 7,29 Recognizing occasional occurrence of metastases and 10% mortality rate represents an advance with clinical relevance. At diagnosis most patients are in the sixth decade, stage T1 or T2 (86%) with a similar gender incidence. Fuhrman grading seems not to be appropriated to grade chromophobe RCC. 76 Carcinoma of the collecting ducts of Bellini Collecting duct carcinoma (CDC) is centrally located in the kidney, ranges 2.5 to 12.0 cm and typically shows a firm grey-white appearance. 6,30,66 When small, CDC origin within a medullary pyramid may be seen. Most tumors are in advanced stage with metastasis at diagnosis. The cells of CDC display Fuhrman 3 and 4 nuclear features (Fig. 3). CDC is positive for keratins of low molecular weight (LMW) and high molecular weight (HMW) and vimentin, but molecular alterations of CDC are poorly understood. 6,30,66 The main differential diagnoses of CDC include type 2 PRCC, renal pelvic adenocarcinoma or urothelial carcinoma with glandular differentiation. CDC accounts for <1% of renal malignancies and derives from the principal cells of the collecting duct. Mean patient age is 55 years with a slight male predominance. 6,66 Upper tract imaging often suggests urothelial carcinoma and patients may have positive urine cytology. Tubulocystic carcinoma The nature of tubulocystic carcinoma, a rare renal tumor composed of tubular and cystic structures, is poorly understood (Fig. 3). 42 It has been suggested that it may represent a low-grade collecting duct carcinoma of the kidney despite the lack of sufficient molecular and pathologic evidence. 42 Tubulocystic carcinoma is a rare tumor, which is composed of tubular and cystic structures. The genomic alterations of tubulocystic carcinoma are alike but not identical to those of papillary RCC. Like papillary RCC, it often exhibits trisomy of chromosome 17, but it does not show trisomy It does not exhibit monosomy of chromosomes 1, 6, 14, 15, and 22 and frequent allelic loss on chromosomal arms 1q, 6p, 8p, 13q, and 21q, which are frequently seen in collecting duct cancer. 42 Immunohistochemistry studies showed that the tumor expresses CD10 (85%), a-methylacyl coenzyme A Racemase (AMACR) (77%), parvalbumin (100%), 34bE12 (15%) and CK19 (100%). A recent report on 13 cases showed, one of the 13 cases with metastasis to the pelvic lymph nodes. 42 Five of the 13 cases coexisted with papillary RCC (n = 3) or papillary adenoma (n = 2). 42 At the present time it is considered a poorly defined entity. Renal medullary carcinoma Renal medullary carcinoma is a rapidly growing but rare tumor of the renal medulla, regarded as an aggressive variant of collecting duct 2009 The Japanese Urological Association 435

5 A LOPEZ-BELTRAN ET AL. Table 3 Main clinico-pathological and genetic features of renal cell tumors in adults RCC subtype Incidence Development Cell/tissue characteristics Growth pattern Prognosis Genetic Clear cell 75% Solitary, rare multicentric or bilateral Clear cytoplasm; cells with eosinophilic cytoplasm occasionally) Multilocular cystic Rare Solitary, rare bilateral Clear cytoplasm, small dark nuclei Papillary 10% Multicentric, bilateral or solitary Type 1 (basophilic) or type 2 (eosinophilic) Chromophobe 5% Solitary Pale or eosinophilic granular cytoplasm Solid, tubular, cystic, rare papillae Aggressiveness according to grade, stage and sarcomatoid change -3p, +5q22, -6q, -8p, -9p, -14q Cystic, no solid component No progression or metastases VHL gene mutation Tubulo-papillary, solid Aggressiveness according to grade, stage and sarcomatoid change +3q, +7, +8, +12, +16, +17, +20, -Y Solid 10% mortality -1, -2, -6, -10, -17, -21, hypodiploidy Collecting ducts of Bellini 1% Solitary Eosinophilic cytoplasm Irregular channels Aggressive, 2/3 of patients die within 2 years Medulary Rare Solitary Eosinophilic cytoplasm Reticular pattern Mean survival of 15 weeks after diagnosis -1q, -6p, -8p, -13q, -21q, -3p (rare) Rare loss of chromosome 22 Xp11 translocation Rare Solitary Clear and eosinophilic cells Tubulo-papillary Indolent t(x;1)(p11.2;q21), t(x;17)(p11.2;q25), Other After neuroblastoma Rare Solitary Eosinophilic cells with oncocytoid features Mucinous tubular and spindle cell Rare Solitary Tubules, extracellular mucin and spindle cells Solid Related to grade and stage Allelic imbalance at 20q13 Solid Rare metastases, -1, -4, -6, -8, -13, , +11, +16, +17 Unclassified 4% to 6% Solitary Variable, sarcomatoid Solid High mortality Unknown Renal cell neoplasms in end-stage renal disease Thyroid follicular carcinoma-like tumor of kidney Rare Solitary Clear cells or eosinophilic cells Solid Unknown Variable gains chromosomes 7 and 17 Rare Solitary Clear cells Solid and papillary Unknown Gains 7q36, 8q24, 12, 16, 17p11-q11, 17q24, 19q, 20q13, 21q22.3, and Xp. Losses of 1p36, 3, 9q21-33 Tubulocystic carcinoma Rare Solitary Eosinophilic cells Tubulocystic Unknown Variable trisomy of chromosome 17 RCC, renal cell carcinoma; VHL, von Hippel Lindau The Japanese Urological Association

6 Updated classification of renal tumors (a) (b) (c) (d) Fig. 3 Uncommon histologic types of renal cell carcinoma (RCC). Collecting duct carcinoma (Bellinis tumor) (a); medullary carcinoma (b); tubular, mucinous and spindle cell carcinoma (c); Tubulocystic carcinoma (d). carcinoma that was initially considered of renal pelvis origin. Some may have solid or rhabdoid phenotype (Fig. 3). 73 With few exceptions this tumor is seen in young black males with sickle cell trait (mean age 22 years), presenting with hematuria, flank pain, weight loss and palpable mass. Metastatic deposits may be the initial clinical evidence and the reported prognosis is poor. 73 (a) Renal carcinoma associated with Xp11.2 translocations/tfe3 gene fusions Renal carcinoma associated with Xp11.2 translocations/tfe3 gene fusions (MiTF/TFE family translocation carcinomas) is defined by different translocations involving chromosome Xp11.2, all resulting in gene fusions involving the TFE3 gene (Table 3) This carcinoma predominantly affects children and young adults, but may be seen in adults. The ASPL-TFE3 translocation carcinomas characteristically present at an advanced stage associated with lymph node metastases RCC associated with Xp11.2 translocations resemble clear cell RCC on gross examination and seem to have an indolent evolution, even with metastasis. 65 The histopathologic appearance is that of a papillary carcinoma with clear cells and cells with granular eosinophilic cytoplasm; these cells display nuclear immunoreactivity for TFE3 protein (Fig. 4). Another subset of renal tumors are associated with a translocation t(6;11)(p21;q12) involving the transcription factor EB (TFEB). Argani and Ladanyi have recently proposed to regroup these neoplasms under the category of the MiTF/TFE family of translocation carcinomas. Translocation involving TFE3 and TFEB can be specifically identified by immunohistochemistry, but diagnosis may also be carried out by cytogenetic examination of fresh material A recent report on 31 such cases showed 29 cases that were diagnosed as TFE3 and two as TFEB renal translocation carcinomas, including 13 males and 18 females, mean age 24.6 years. Two patients had a previous history of chemotherapy and one had a history of renal failure. Mean size of the tumor was 6.9 cm. 65 Thirteen cases were pt3 stage. Twelve patients were N+ or M+ and five died of the disease. Mixed (b) Fig. 4 Renal cell carcinoma in a case of Xp.11 translocation showing (a) histological features and (b) papillary architecture, and (c) nuclear immunoreactivity for TFE-3 protein. (c) 2009 The Japanese Urological Association 437

7 A LOPEZ-BELTRAN ET AL. (a) (c) (b) Fig. 5 Unclassified renal cell carcinoma (RCC) showing pure (a) sarcomatoid carcinoma or unrecognizable cell types (b,c). papillary and nested patterns with clear and/or eosinophilic cells represented the most common histologic appearance with foci of calcifications regardless of the type of translocation (Fig. 4). TFE3 immunostainings were positive in only 82% of TFE3 translocation carcinomas. 65 Both TFE3 and TFEB renal translocation carcinomas expressed CD10 and alpha-methylacyl-coenzyme-a racemase in all cases. Unsupervised clustering on the basis of the gene expression profiling indicated a distinct subgroup of tumors. TRIM 63 glutathione S-transferase A1 and alanyl aminopeptidase are the main differentially expressed genes for this group of tumors. 65 Renal cell carcinoma in long term survivors after neuroblastoma A few cases of RCC arise in long-term survivors of childhood neuroblastoma. 8 This group is heterogeneous and shows oncocytoid features. Allelic imbalances occur at the 20q13 locus. 8,78 The prognosis is similar to other RCCs. Males and females are equally affected with a mean age of 13.5 years, being uni- or bilateral. 78 Mucinous, tubular and spindle cell carcinoma Mucinous, tubular and spindle cell carcinoma, included for the first time in the current WHO classification, 2 is a low-grade carcinoma composed of tightly packed tubules separated by pale mucinous stroma and a spindle cell component (Fig. 3). 68,78,80 It seems to derive from the distal nephron. This tumor has a combination of losses involving chromosomes 1, 4, 6, 8, 13 and 14 and gains of chromosome 7, 11, 16 and ,80 A recent immunohistochemical analysis found a significant immunophenotypic overlap with papillary RCC, 21 and some authors believe this is a variant of papillary RCC with spindle cell differentiation. 21 There is a female predominance and the mean age is 53 years at diagnosis. 80 It presents as a circumscribed asymptomatic mass on ultrasound examination. 68,78 One patient developed metastases on follow-up. It is currently considered a poorly-defined entity. Thyroid follicular carcinoma-like tumor of the kidney Two cases of unusual renal tumor, which have not been classified under a known subtype of RCC and characteristically show similar histology to thyroid follicular carcinoma, have recently been reported. 5 Both patients were 29- and 32-year-old asymptomatic women that had no lesions in the thyroid. 31 Immunohistochemically, the tumor cells showed intensive staining for cytokeratin AE1/AE3 and CD10 and were not reactive to thyroid transcription factor-1 and thyroglobulin. 5,31 Chromosomal gains of 7q36, 8q24, 12, 16, 17p11-q11, 17q24, 19q, 20q13, 21q22.3, and Xp and losses of 1p36, 3, and 9q21-33 were detected by comparative genomic hybridization. 5 Chromosomal losses of 1, 3, 7, 9p21, 12, 17, and X were detected by fluorescence in situ hybridization (FISH) in another case. 31 These findings are dissimilar to previously classified renal neoplasm. 5 Until more experience is made available, it is better to consider it as a poorly defined entity. Renal cell carcinoma, unclassified In surgical series, 4 6% of renal tumors are unclassified at presentation, and most are of high grade and stage at diagnosis with poor survival. 2 Features that might place a carcinoma in this category include: (i) composites of recognized types; (ii) pure sarcomatoid morphology without recognizable epithelial elements; (iii) mucin production; (iv) rare mixtures of epithelial and stromal elements; and (v) unrecognizable cell types (Fig. 5). 2 Limited reported data suggest that this is an aggressive form of RCC, mainly because most cases are at advanced stages at presentation. 43 RCC with sarcomatoid change Sarcomatoid change may be seen in all types of RCC with no evidence supporting the notion that RCC develops de novo as sarcomatoid carcinoma; therefore, the 2004 WHO classification does not consider it as an entity, but rather as a progression of any RCC main type. 2,25,67,74 As mentioned above, pure sarcomatoid morphology without recognizable epithelial elements falls into the unclassified category. 2,25,47 RCC with sarcomatoid elements shows higher proliferative activity than other RCC types and usually exhibit highly malignant behavior with a predilection for increased local invasiveness and a higher likelihood of distant metastasis. 67,74 Sarcomatoid components have been seen in all of the common types of RCCs: clear cell, papillary, chromophobe and collecting duct. 2,64,67 It is speculated that the sarcomatoid components of RCCs represent areas of dedifferentiation, and it follows that the The Japanese Urological Association

8 Updated classification of renal tumors genomic changes associated with a specific type of RCC should be conserved within the dedifferentiated sarcomatoid RCC component. 25,67,74 The clonal origin of sarcomatoid RCC has been recently investigated. Jones et al. 91 examined the pattern of allelic loss in clear cell and sarcomatoid components of RCCs from 22 patients who had tumors with both components. Clonality analysis showed the same pattern of non-random X-chromosome inactivation in both clear cell and sarcomatoid components in 13 of the 14 cases studied. 91 However, different patterns of allelic loss were seen in the clear cell and co-existing sarcomatoid components in 15 cases. The results suggested that both clear cell and sarcomatoid components of RCCs are derived from the same progenitor cell. Different patterns of allelic loss in multiple chromosomal regions in clear cell and sarcomatoid components represent genetic divergence during clonal evolution. 91 While loss of 3p has been found in the sarcomatoid components of some clear cell RCCs, the chromosomal changes in sarcomatoid RCCs vary from case to case and some appear to be unrelated to those that are characteristic of the classic types of RCC. 64,67,71,91 The specific molecular mechanisms responsible for sarcomatoid transformation of a renal tumor are unknown, although some studies suggest a link between mutation of the P53 tumor suppressor gene and sarcomatoid morphology. Renal cell neoplasms of low malignant potential Multilocular cystic renal cell neoplasm of low malignant potential The 2004 WHO classification of kidney tumors recognizes multilocular cystic renal cell carcinoma (MCRCC) as a rare variant of clear cell RCC with a good prognosis. 2 This is a tumor with excellent outcome and entirely composed of cysts of variable size separated from the kidney by a fibrous capsule (Fig. 1). The cysts are lined by a single layer of clear to pale cells but occasionally show a few small papillae. 2 The septa are composed of fibrous tissue that may have epithelial cells with clear cytoplasm that resemble those lining the cysts (Fig. 2). Cases with expansive nodules are excluded. VHL gene mutations in MCRCC (a) Renal cell neoplasms in end-stage renal disease Two new histologic subtypes of RCC have been seen recently to occur in patients with end-stage renal disease, that is, RCC associated with acquired cystic disease and clear cell papillary RCC. 34,70,82 Acquired cystic disease-associated renal tumors Acquired cystic disease-associated RCCs are composed of cells with abundant eosinophilic cytoplasm and variably solid, cribriform, tubulocystic and papillary architecture. 70 Information concerning chromosomal changes in these tumors is limited. Tickoo et al. 34 analyzed the status of the VHL gene and chromosomes 7 and 17 with FISH in 43 tumors arising in patients with end-stage renal disease, and found no VHL gene deletions, although gains of chromosomes 7 and 17 were observed in some cases. Cossu-Rocca et al. 70 studied three eosinophilic epithelial tumors arising in kidneys with acquired cystic disease from three patients. 70 Deposits of calcium oxalate crystals were present in each tumor. FISH analysis showed no losses or gains of chromosomes 1, 2, 6, 10, or 17 in one tumor; gains of chromosomes 1, 2, and 6 were noted in two tumors, and one of these tumors also showed gains of chromosome ,82 These gains are in contrast to the multiple chromosomal losses that are typical of chromophobe RCCs, and the loss of chromosome 1 found in approximately 10% of renal oncocytomas. (b) (c) Clear cell papillary renal cell carcinoma These recently described RCCs are composed mainly of papillary structures proliferating within cystic spaces, lined by cells with clear cytoplasm, and occurring in patients with and without end-stage kidney disease. 93,94 Gobbo et al. investigated a group of seven tumors from five patients with interphase FISH and immunohistochemistry. 82 All tumors lacked the gains of chromosome 7 and loss of Y that are typical for papillary RCC and furthermore lack the 3p deletion, which is typical of clear cell RCC. 70,82 Fig. 6 Benign epithelial tumor of the kidney including papillary adenoma (a), oncocytoma (b), and metanephric adenoma (c) The Japanese Urological Association 439

9 A LOPEZ-BELTRAN ET AL. supports its classification as a type of clear cell RCC. 32 No progression of MCRCC has been observed and the diagnostic criteria and its good prognosis have been noticed in the current WHO classification, which considers it a specific entity. A recent report by our group on 45 MCRCC cases, 32 classified according to the 2004 WHO criteria and modified to accept Furhman grade 2 cases, showed that most patients with unilateral MCRCC and no side predominance found incidentally were men (62%). 32 MCRCC occurred slightly more often in men than in women (1.7:1). 32 At diagnosis, 82% of patients had stage T1 and 16%, stage T2; one patient had stage T3. 32 The Fuhrman grade was 1 (62%) or 2 (38%), with smaller tumors 4 cm) most likely Fuhrman grade 1. All 45 patients were alive with no evidence of disease at mean follow-up of 66 months, confirming an extremely good prognosis after surgery and a 5-year disease-specific survival rate of 100%. 32 To rename this tumor as multilocular cystic renal cell neoplasm of low malignant potential might help urologists approach the patients conservatively in selected cases. 32 Benign tumors Papillary adenoma Papillary adenoma (0.5 cm or smaller) is usually a solitary, well circumscribed, greyish or white lesion in the renal cortex that shows a tubulo-papillary architecture similar to cellular types 1 and 2 in papillary RCC (Fig. 6). 85 Papillary adenoma is the most common neoplasm of the epithelium of the renal tubules. 61 It is found in 10% to 40% of specimens and shows genetic alterations similar to papillary RCC, but is less extensive. Renal adenomatosis refers to the occasional occurrence of multiple and/or bilateral papillary adenomas. 61,85 Oncocytoma Oncocytoma is a benign renal epithelial neoplasm that derives from the intercalated cells. 50 It is well circumscribed, non-encapsulated, mahogany-brown or pale yellow with a central stellate scar. The oncocyte has densely granular eosinophilic cytoplasm and round and regular nuclei (Fig. 6). Mitotic activity and necrosis are uncommon. Chromosomes 1 and/or 14 loss and alterations of mitochondrial DNA are frequent. Oncocytoma comprises 3% to 9% of all primary renal neoplasms. 50 Males are affected twice as often as females. Most are incidental and sporadic but few are symptomatic. The eosinophilic variants of chromophobe RCC are frequently difficult to distinguish from renal oncocytomas on hematoxylin and eosin stained histologic sections. 50 The distinction is important, as chromophobe RCC is a malignant tumor while oncocytoma is considered to be a benign lesion. Reports of malignant or metastatic oncocytomas are postulated to actually represent misdiagnosed chromophobe RCCs. 88 The Hale s colloidal iron stain shows a diffuse and strong reticular pattern in almost 100% of chromophobe RCC, and it is frequently patchy and focal in oncocytoma. 50 Chromophobe RCC frequently shows loss of chromosomes 1 and Several groups of investigators have reported that chromosome 3p loss is not detectable in oncocytoma. 23 The term oncocytosis (oncocytomatosis) refers to a small subset of oncocytic tumors removed surgically because of a dominant mass that microscopically has the features of oncocytoma, although some may have either chromophobe RCC or hybrid features. 35,69 Metanephric adenoma and adenofibroma This group includes metanephric adenoma and metanephric adenofibroma and represents a novelty in the current WHO classification. 2,72 Metanephric adenoma is an epithelial neoplasm that occurs in children and adults (fifth and sixth decades). 51,89 There is a female preponderance, half are incidental but may present with polycythemia. An exceptional case with metastasis has been reported, and therefore, appropriate follow-up is advised. 77 Patients range in age from 5 months to 36 years and may coexist with Wilms tumor or RCC. 72,85 A case of high grade sarcoma arising in association with metanephric adenoma (metanephric adenosarcoma) has been described. Metanephric adenomas are 3 6 cm, usually solitary and not encapsulated (Fig. 6). 89 Metanephric adenofibroma shows an epithelial component identical to that of metanephric adenoma, which is embedded in a fibroblast-like stroma. Metanephric adenoma has a normal karyotype. 60,61,72,83 (a) (b) Fig. 7 Benign epithelial and stromal tumor of the kidney. Gross (a) and histologic features (b) The Japanese Urological Association

10 Updated classification of renal tumors Cystic nephroma and mixed epithelial and stromal tumors Cystic nephroma is a benign mixed epithelial and stromal neoplasm frequently unilateral, solitary and multilocular. 46 It is encapsulated with no solid areas or necrosis. 16,78 Adult cases present after age 30 with female predominance. Some are associated with pleuropulmonary blastoma. 87 Non-random X chromosome inactivation supports its neoplastic nature. 16,46,78 Mixed epithelial and stromal tumor of kidney is a rare renal neoplasm composed of a mixture of stromal solid areas and epithelial (mostly cystic) elements previously reported as cystic hamartoma of renal pelvis or adult mesoblastic nephroma (Fig. 7). 46 Some stromal cells react with antibodies to estrogen and progesterone. There is a female predominance with history of estrogen therapy. All cases have been seen in adults. Some are incidental but others have flank pain or hematuria. Some may experience malignant transformation. A recent report suggests that cystic nephroma and mixed epithelial and stromal tumors are part of the same spectrum of lesions, and therefore, they should be named as renal epithelial and stromal tumors. 38 This hypothesis awaits confirmation. 16 Conclusions Unlike our knowledge of RCC a decade ago, we now know that it is not a single disease, since biological and clinical properties define a number of entities, the recognition of which is of value in daily clinical practice. The classification of epithelial tumors of the kidney has been expanded in recent years and a modified classification is now used in daily practice. The fact that different histologic subtypes have different clinical outcomes, and show different responses to therapy, represents an important advance in recent years. 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