Recent developments in the pathology of renal tumors: morphology and molecular characteristics of select entities.
Abstract: Context.--Renal cell carcinoma is a heterogeneous group of tumors with distinct histopathologic features, molecular characteristics, and clinical outcome. These tumors can be sporadic as well as familial or associated with syndromes. The genetic abnormalities underlying these syndromes have been identified and were subsequently found in corresponding sporadic renal tumors.

Objective.--To review the recent molecular and genetic advancements relating to sporadic and familial renal carcinomas as well as those related to Xp11.2 translocation-associated renal cell carcinoma and renal medullary carcinoma.

Data Sources.--Literature review, personal experience, and material from the University of Chicago.

Conclusions.--Molecular genetic diagnostic techniques will continue to introduce new biomarkers that will aid in the differential diagnosis of difficult cases. The identification of specific signaling pathways that are defective in certain renal tumors also makes possible the development of new therapies that selectively target the aberrant activity of the defective proteins.

(Arch Pathol Lab Med. 2009;133:1026-1032)
Article Type: Report
Subject: Kidney diseases (Diagnosis)
Kidney diseases (Genetic aspects)
Kidney diseases (Development and progression)
Immunohistochemistry (Usage)
Immunohistochemistry (Analysis)
Gene expression (Research)
Gene expression (Physiological aspects)
Morphology (Analysis)
Authors: Yan, Benjamin C.
Mackinnon, A. Craig
Al-Ahmadie, Hikmat A.
Pub Date: 07/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: July, 2009 Source Volume: 133 Source Issue: 7
Topic: Event Code: 310 Science & research
Accession Number: 230152034

The most recent classification of renal cell carcinoma (RCC) encompasses the distinct morphologic features as well as the molecular and genetic characteristics of these tumors. (1) The most common subtype, clear cell RCC, comprises approximately 60% of renal cancers and is characterized by an encapsulated solid mass with alveolar or acinar arrangement of clear polygonal cells. (2) Although this tumor is a typical manifestation of von Hippel-Lindau (VHL) disease, it can be seen sporadically or as part of other familial renal cancer syndromes. Most clear cell RCCs have deletions of the short arm of chromosome 3, mostly related to loci corresponding to VHL disease gene VHL. von Hippel-Lindau disease is an autosomal-dominant syndrome characterized by bilateral, multifocal clear cell RCC; bilateral, multifocal pheochromocytomas; hemangioblastomas and cavernous hemangiomas of the brainstem, cerebellum, or retina; malignant neuroendocrine tumors of the pancreas; epididymal cystadenomas; and hepatic, renal, and pancreatic cysts. (3,4) Tumors of the VHL disease usually have one copy of VHL mutated and the second copy inactivated, most often by deletion of the gene. Similarly, it was subsequently found that a significant number of sporadic clear cell RCCs have one inactivated copy of the VHL gene by mutation, and the other copy is lost by deletion, (5,6) making the VHL gene a classic example of the 2-hit tumor-suppressor gene. (7)

Furthermore, xenografts of clear cell RCC containing homozygous loss-of-function mutations in VHL gene ([VHL.sup.-/-]) caused tumor formation in mice. However, introduction of wild-type copies of the VHL gene into the cell lines that were injected in mice resulted in no or minimal tumor formation. (8)

The VHL protein has been shown to form a ubiquitin ligase complex with the proteins Elongin B, Elongin C, and Cul-2, which targets the hypoxia-inducible factor 1[alpha] (HIF-1[alpha]) for degradation in the proteasome in normoxic conditions. (9-12) In oxygenated and iron-replete cells, the enzyme HIF-[alpha]-prolyl hydroxylase hydroxylates a proline residue (P564) on HIF-1[alpha], rendering HIF-1[alpha] susceptible to ubiquitination and subsequent proteasomal destruction.13 However, because HIF-[alpha]-prolyl hydroxylase requires oxygen as a cofactor, this enzyme is inactivated under hypoxic or iron-deficient conditions. Under such conditions, HIF-1[alpha] is stabilized and capable of translocating to the nucleus, where it heterodimerizes with its partner, the constitutively expressed aryl hydrocarbon receptor nuclear translocator7HIF-1[alpha]. (14,15) The HIF-1 heterodimer, a basic helix-loop-helix-Per-Arnt-Sim transcription factor, can then bind to gene regulatory sequences termed hypoxia-response elements of several target genes downstream from HIF-1[alpha], including the genes encoding vascular endothelial growth factor (VEGF), the glucose transporter (GLUT1), platelet-derived growth factor (PDGF), transforming growth factor a, and erythropoietin. (15-21) Furthermore, renal carcinoma cells lacking the VHL protein were found to produce mRNA transcripts encoding the VEGF, GLUT1, and PDGF proteins, whereas the introduction of wild-type VHL protein into these cells abolished production of these

gene transcripts. (22) Therefore, abrogation of normal VHL function with consequent stabilization of HIF-1 leads to the transcriptional activation of a suite of genes involved in vascular proliferation and glycolytic metabolism that promote and support tumor growth. (16) By understanding this pathway in clear cell RCC, a number of biomarkers have been identified to aid in the diagnosis and treatment of such tumors. One such example is carbonic anhydrase IX, which identifies a membranous enzyme/protein whose normal function is to regulate both intracellular and extracellular pH and whose expression is induced by hypoxic conditions. It also has been reportedly shown to influence the regulation of cell proliferation, oncogenesis, and tumor progression. (23-25) Downstream from HIF-1[alpha],the expression of carbonic anhydrase IX is VHL-HIF pathway dependent. This marker has been shown to be consistently and preferentially expressed in clear cell RCC (Figure 1), unlike its expression in some other tumors, which tends to be focal and around areas of necrosis. (26-28) Interestingly, this pattern of expression is maintained in clear cell RCC with high nuclear grade as well as those with sarcomatoid morphology. (26,29) New agents that target selective molecules in the VHL-HIF pathway have been developed and are being applied to advanced and metastatic cases of clear cell RCC, the results of which are promising. (30)




Papillary RCC is the second most common type of renal carcinoma, constituting 10% to 15% of renal cancers, and can be morphologically classified into 2 types. (2,31) Type I is characterized architecturally by fibrovascular papillae lined by a single layer of cuboidal neoplastic cells with small, uniform, oval nuclei with inconspicuous nucleoli and pale basophilic cytoplasm (Figure 2, A). In contrast, type II papillary carcinomas are composed of fibrovascular papillae lined by a pseudostratified layer of larger neoplastic cells that have large spherical nuclei with prominent nucleoli and abundant eosinophilic cytoplasm (Figure 2, B). Papillary carcinomas containing histologic features of both types are occasionally encountered. Because of the difficulty in classifying these tumors with mixed features, clinical studies examining the survival of patients with these carcinomas often do not distinguish between types I and II. (32,33) It has been suggested that type II papillary RCC is associated with a more aggressive behavior, usually presenting at higher stage, and carries worse survival than type I papillary RCC. (34-36) However, this concept is not entirely agreed upon, and more studies are needed to further solidify the association between type II and an aggressive behavior.

Conventionally, the most common chromosomal abnormality of papillary RCC involves trisomies of chromosomes 7 and 17 and loss of chromosome Y. (37) Additionally, loss of 9q correlated with reduced survival in these tumors.38,39 By comparative genomic hybridization analyses, it was found that full-length gains of chromosomes 7 and 17 are more frequently detected in type I papillary RCC than in type II tumors. (40)

Recently, comparative genomic hybridization using microarray technology was employed in an attempt to classify papillary renal carcinomas according to genome-wide expression profiles. (41) Despite the presence of significant overlap of the expression profiles of these 2 types, it was noted that the expression patterns of mixed type I and type II tumors resembled that of type I tumors after data analysis, whereas the expression patterns of type II tumors consistently grouped together. It was consequently proposed that papillary RCC be reclassified into 2 molecular classes rather than the established morphologic types. Class 1 papillary RCC includes morphologic type I, a low-grade variant of type II, and the mixed type I/low-grade type II tumors, whereas class 2 papillary RCC corresponds to high-grade type II tumors. Computational analysis of the expression profiles of class 1 versus class 2 papillary tumors demonstrated distinct patterns of gene expression, thereby allowing accurate discrimination between class 1 and class 2 tumors. By inferring cytogenetic aberrations from the differential mRNA expression patterns, both classes were found to exhibit full-length gains in chromosomes 7, 12, 16, 17, and 20. However, class 2 tumors contained more frequent gains in 1q, 2, and 8q and more frequent losses of 3p, 6q, 9q, and 14q, whereas class 1 tumors showed more frequent gains of chromosomes 3, 7, and 16.

In addition, it was found that class 1 tumors demonstrated greater expression of genes involved in [G.sub.1]-S-phase checkpoint regulation (specifically, the genes encoding cyclin D2, cyclin-dependent kinase 6, retinoblastoma-like 2, and [p21.sup.Cip1]) and of c-Met compared with class 2 tumors. (41) In contrast, class 2 tumors demonstrated greater expression of genes involved in [G.sub.2]-M-phase checkpoint regulation (cyclin B1, cyclin B2, and TopII[alpha]). This classification, however, requires further validation by other studies and more cases. If the results are reproducible and the distinction between these 2 types based on gene expression profiles proves helpful in separating the 2 types into distinct clinicopathologic entities, then special considerations should be given to incorporating these profiles into future classification schemes of renal tumors. The challenge that still remains is to consistently be able to find the morphologic correlates and reduce interobserver variability in identifying and assigning papillary tumors to these classes.

The detection of elevated mRNA transcription of the gene encoding TopII[alpha] was confirmed by immunohistochemical detection of the TopII[alpha] protein in type II tumors. (41) Previous immunohistochemical studies had determined that cytokeratin 7 is expressed in more than 97% of type I papillary RCCs but rarely detected in type II papillary neoplasms. (42) No specific marker of type II papillary RCCs had been identified previously. Thus, the use of antibodies against the TopII[alpha] protein may help in the distinction between class 1 and class 2 papillary RCCs. Furthermore, the identification of this protein as an upregulated gene product in class 2 papillary RCCs raises the possibility that this enzyme, in addition to fumarate hydratase, may be targeted by pharmaceutical agents for therapeutic purposes in treating papillary RCC. Clinical trials examining the effects of topoisomerase II inhibitors in patients with clear cell RCC have yielded disappointing results. (43,44) However, these compounds have yet to be tested in patients with papillary RCC.

Mutations in the MET gene had been identified previously in both familial and sporadic type I papillary RCCs. (45-47) Cell cycle dysregulation arising as a result of MET mutations has been documented in experimental animals: conditionally inactivating MET mutations in mice has been shown to cause hepatocytes to transition from [G.sub.0] to [G.sub.1] phase. (48) However, the same murine hepatocytes carrying inactivating MET mutations could not transition into S phase. Further investigation of the mechanisms governing cell cycle regulation involving MET are required to explain the role of these pathways in carcinogenesis.

The syndrome of hereditary papillary renal carcinoma type I is a recently described entity that is inherited in an autosomal-dominant manner and predisposes patients to the development of bilateral, multifocal, type I papillary RCC. (49) Genetic linkage analysis showed that the gene carrying mutations in patients with this familial syndrome mapped to the q31 locus of chromosome 7, the same chromosomal locus where the tyrosine kinase receptor c-Met is located. (45) Sequencing of the MET gene identified mis-sense mutations in patients with hereditary papillary renal carcinoma type I and in sporadic papillary RCC, suggesting that constitutive tyrosine kinase activity leads to the development of type I papillary RCC.

Renal carcinogenesis has been noted to have an increased incidence in patients with hereditary leiomyomatosis RCC, an autosomal-dominant syndrome that is also associated with multiple cutaneous and uterine leiomyomata, as well as uterine leiomyosarcomas. (50-54) Histologically, the renal tumors consisted of type II papillary RCC. The hereditary leiomyomatosis RCC gene was mapped by linkage analysis to chromosome 1q42.3-43 and was subsequently identified as the gene encoding the Krebs cycle enzyme fumarate hydratase. (53-56)


Birt-Hogg-Dube (BHD) syndrome is a rare condition inherited in an autosomal-dominant fashion and characterized by unique skin lesions (multiple fibrofolliculomas, trichodiscomas, and acrochordons) and associated internal organ lesions, such as intestinal polyps, renal and lung cysts, and medullary thyroid carcinoma in the original description. (57,58) However, the association of renal tumors with this syndrome was not recognized until later, when a patient with BHD syndrome was found to have bilateral kidney tumors with variable histopathologic features, including clear cell and chromophobe RCC, with areas of mixed clear and eosinophilic cells in the same tumor. (59)

This syndrome was later shown to segregate together with the development of familial renal tumors that are typically bilateral and multifocal with variable histologies, including chromophobe RCC, clear cell RCC, oncocytomas, papillary RCC and, most commonly, tumors defined as hybrid oncocytic neoplasms. (60-62) Patients with BHD were also predisposed to developing pulmonary cysts. Genetic linkage analysis in families with BHD determined that the BHD trait mapped to 17p11.2. (63) Shortly thereafter, the gene containing pathogenic mutations in BHD patients was identified and called folliculin. (64) The function of folliculin is still largely unknown, but it is thought to serve as a tumor-suppressor gene. Of note is that numerous mutations have been described in the BHD gene, most of which have been located within a hypermutable 8 cytosine tract and result in a truncated form of folliculin. Current clinical management of these syndromes involves careful clinical monitoring and numerous surgical resections.


Recently, a subset of RCC carrying chromosomal translocations involving the short arm of the X chromosome--specifically, Xp11.2--has been characterized, which result in fusions involving the TFE3 transcription factor gene that maps to this locus. The transcription factor binding to IGHM enhancer 3 (TFE3) protein belongs to a family of basic helix-loop-helix/leucine zipper transcription factors that also includes transcription factor EB (TFEB), transcription factor EC, and microphthalmia-associated transcription factor. (65-74) These proteins may homodimerize or heterodimerize to bind DNA.

The most common translocations associated with these tumors are t(X;17)(p11.2;q25), the same cytogenetic abnormality (with identical breakpoints) observed in alveolar soft part sarcomas, which gives rise to the ASPL-TFE3 fusion gene, and t(X;1)(p11.2;q21), which results in the PRCC-TFE3 fusion gene. (75-85) Both the ASPL-TFE3 and the PRCC-TFE3 fusion genes encode chimeric gene products that retain the ability of the TFE3 protein to migrate to the nucleus and participate in transcription. (86,87)

Other, less common translocations involving the TFE3 gene include t(X;1)(p11.2;p34), which results in the PSF-TFE3 chimera; inv(X)(p11.2;q12), which fuses the NonO([p54.sup.nrb])and TFE3 genes; and t(X;17)(p11.2;q23), which gives rise to the fusion of the TFE3 gene with CLTC. (88,89)

Although most translocation RCCs are related to Xp11.2, another variant harboring a different translocation, t(6;11)(p21;12), has been described, which produces a fusion between the Alpha and the TFEB genes. (84,90-92)

Originally thought to affect the pediatric age group, it was later shown that these tumors occur in both pediatric and adult populations. The age at diagnosis ranges from 17 months to 78 years. (84,93,94) Although pediatric tumors show no particular sex bias, adult tumors demonstrate a strong female predilection. (84,93) Patients present with abdominal masses, flank pain, and hematuria, but also can develop outflow obstruction with consequent pyelonephritis, or they may be misdiagnosed with renal cysts or nephroliths. (93)

Grossly, the tumors are well circumscribed but unencapsulated, with soft, yellow-tan cut surfaces. (84) Necrosis, hemorrhage, calcification, and cystic change may also be present. The histopathologic features include papillary architecture, with clear cells attached to a fibrovascular core and with occasional organoid nests of cells separated by delicate fibrovascular septa (Figure 3, A). The neoplastic cells are polygonal, with clear to eosinophilic cytoplasm and slightly irregular, eccentric nuclei with vesicular chromatin and prominent nucleoli. (84,93) This morphology is similar to that of alveolar soft part sarcoma, in which fusion of the ASPL (also known as RCC17 and ASPSCR1) and TFE3 genes was originally identified. (85) Pseudopapillary architecture and psammomatous calcification may be present. (84) Ultrastructural examination revealed the presence of numerous electron-dense, membrane-bound cytoplasmic granules, as well as membrane-bound rhomboid crystals identical to those found in alveolar soft part sarcoma.

Renal cell carcinoma containing the PRCC-TFE3 fusion gene generally demonstrates a more nested architecture containing tumor cells that have less-voluminous cytoplasm with fewer psammoma bodies and fewer hyaline nodules. Some of these tumors have been shown by electron microscopy to contain intracisternal microtubules identical to those seen in extraskeletal myxoid chondrosarcoma. (83)

The diagnosis of translocation RCC should be suspected when some of the above-mentioned features are encountered in a renal tumor, especially if the patient is young. In the absence of cytogenetic or molecular genetic analyses, immunohistochemistry on formalin-fixed, paraffin-embedded tissue is essential to confirm the diagnosis of translocation RCC. These tumors consistently exhibit nuclear labeling of TFE3 protein when an antibody to the C-terminal portion of TFE3 is applied. This pattern of expression (nuclear labeling for TFE3 protein) is specific for the diagnosis of Xp11 translocation RCC in archival material (Figure 3, B). Besides Xp11 translocation RCC and alveolar soft part sarcoma, no other tumor types or normal tissues express TFE3. (93,95) As for RCC associated with translocation t(6;11), nuclear labeling with TFEB serves as the diagnostic marker. (96)

Additionally, translocation RCCs have been found to commonly express CD10, RCC marker [alpha]-methylacyl coenzyme-A racemase, melanocytic markers HMB-45 and Melan-A, and E-cadherin, but typically either lack expression of keratins AE1/AE3, CAM 5.2, and cytokeratin 7 and epithelial membrane antigen or show only focal weak expression. (84,93,95)

Although these tumors have been reported at advanced stages, it is still early to draw compelling clinical outcome and prognostic data, mainly because of the overall low incidence and relatively recent identification and characterization of this entity.


Renal medullary carcinoma is a rare and highly aggressive tumor of the renal medulla that affects young patients with sickle cell disease or sickle cell trait at a mean age of 22 years (range, 10-40 years) and demonstrates a male predilection. (97,98) The patients are mostly African American and usually present with gross hematuria, abdominal or flank pain, and commonly weight loss. (96,99) Metastases are also common to lymph nodes, liver, or lung, and may be the initial presentation of the disease. (100,101) The prognosis of these tumors is poor, with a mean survival of 15 weeks. Chemotherapy and radiation therapy do not alter the clinical course. (97)

Grossly, these tumors are poorly circumscribed, centrally situated renal masses ranging in size from 4 to 12 cm with a mean size of 7 cm. Tumor necrosis, resulting in communication with the collecting system, and hemorrhage are frequent findings. (98,102) Renal medullary carcinomas are associated with a wide spectrum of histologic features, including solid, reticular, tubular, trabecular, cribriform, and micropapillary architecture as well as sarcomatoid morphology. (98,103-108) Neutrophils are often scattered throughout the tumor, and lymphocytes are present at the infiltrating border. Stromal sclerosis and edema are also common features, and sickled erythrocytes are found in most cases. An example is shown in Figure 4, A. The immunoprofile of these tumors includes positivity for cytokeratins AE1/AE3 and CAM 5.2, epithelial membrane antigen, and carcinogenic embryonic antigen, but negativity for high-molecular weight cytokeratins. (101,109)



In a recent immunohistochemical study, 5 renal medullary carcinomas exhibited loss of expression of the INI1 (Snf5/Baf47/SmarcB1) protein from tumor cells (Figure 4, B), in contrast to what was observed in high-grade RCC and urothelial carcinoma of the renal pelvis, including those with rhabdoid features, which retained strong INI1 immunoreactivity. (101) INI1 is a highly conserved and ubiquitously expressed protein that acts as a part of the SWI/ SNF chromatin-remodeling complex. (110) Biallelic loss of INI1 leads to the development of aggressive lethal neoplasms, either lymphomas or rhabdoid tumors, in transgenic mice in which one INI1 allele had been deleted and the remaining allele inactivated. (111,112) It has been shown previously that this protein is lost in other aggressive tumors, such as renal and extrarenal rhabdoid tumors, atypical teratoid/rhabdoid tumors of the central nervous system, and epithelioid sarcomas. (113-117) Moreover, in a recent series, 6 of 38 rhabdoid tumors carried wild-type INI1 genes and retained immunoreactivity for the protein. Conversely, 7 tumors that did not meet the diagnostic criteria of rhabdoid tumors exhibited a lack of INI1 immunoreactivity, yet led to clinical courses similar to those of rhabdoid tumors. (118) These studies suggest that tumors lacking INI1 expression may follow an aggressive clinical course, even if they do not necessarily have rhabdoid morphology, such as renal medullary carcinoma. Tumors characterized by INI1 inactivation, therefore, may in the future be classified into a separate category of entities in which the loss of this protein may identify an underlying molecular aberration accounting for the aggressive clinical behavior.


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Benjamin C. Yan, MD, PhD; A. Craig Mackinnon, MD, PhD; Hikmat A. Al-Ahmadie, MD Accepted for publication February 11, 2009.

From the Department of Pathology, University of Chicago, Chicago, Illinois. Dr Al-Ahmadie is now with the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.

Presented in part at the Current Issues in Diagnostic Pathology conference, University of Chicago, Chicago, Illinois, November 2007.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Hikmat A. Al-Ahmadie, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (e-mail:
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