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Renal cell carcinoma is an adenocarcinoma of the kidney. Its classic presentation is with costovertebral pain, palpable mass, and hematuria (blood in the urine). However, this triad is present in only 10% of cases. Many times, the tumor is asymptomatic and may be found as an incidental finding on radiologic studies. In other cases, constitutional symptoms of fever, weakness, weight loss, and malaise may occur. In the medical literature, it has often been referred to as the great mimic of medicine since it may present with a variety of symptoms that may not be traced to the kidney. Please refer to the laboratory findings to see the diversity of presentations. Unfortunately, this tumor may also present with metastasis before the primary tumor is detected. Metastases are found by radiologic examination in 25% of newly diagnosed cases.


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Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
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SYNONYMS Hypernephroma
Adenocarcinoma of the kidney
INCIDENCE 1-3% of visceral cancers
30,000 new cases per year
12,000 deaths per year
AGE RANGE AND MEDIAN 6-7th decades
Pediatric renal cell carcinoma: clinical, pathologic, and molecular abnormalities associated with the members of the mit transcription factor family.

Department of Pediatrics, Division of Haematology/Oncology, Division of Pathology, Hospital for Sick Children, Toronto, Canada.


Am J Clin Pathol. 2006 Sep;126(3):349-64. Abstract quote

We describe the clinical features, outcome, pathology, cytogenetics, and molecular aspects of 13 pediatric papillary renal cell carcinomas during a 19-year period. Seven cases (54%) had translocations involving Xp11.2 (TFE3). They were identified by cytogenetic, molecular, and/or immunohistochemical analyses. All Xp11.2+ translocations were TFE3+ by immunostaining. Cytogenetic and/or polymerase chain reaction analyses identified 3 cases with t(X17) and 1 case with t(1;17), and all had additional translocations. Histologic features in common in TFE3+ tumors also were present in some TFE3- tumors. One TFE3- tumor had complex cytogenetic abnormalities, 55XY,+2,del(3)(p14),+7,+8,+12,+13,+16,+17,+20[11 ], and 2 cases had normal karyotypes. None had t(6;11)/TFEB+ immunostaining. Five cases had focal, weak MITF tumor immunostaining.

The key clinical findings were as follows: (1) The presence of an Xp11.2 (TFE3) translocation frequently is associated with advanced stage at initial examination. (2) All patients who underwent complete, partial nephrectomy with clear margins (adequate only for stage 1) and resection of metastases were alive and relapse-free at last follow-up. (3) The mean +/- SD event-free survival and overall survival rates at 5 years were both 92% +/- 7.4%. (4) One patients with a TFE3+ and MITF+ tumor and 66-87,XXY,der(1)t(1;8)del(4)(q?) der(11)t(11;15)der17t(X;17 abnormalities died 9 months after diagnosis.
Renal neoplasms in younger adults: analysis of 112 tumors from a single institution according to the new 2004 World Health Organization classification and 2002 American Joint Committee on Cancer Staging System.

Cao Y, Paner GP, Perry KT, Flanigan RC, Campbell SC, Picken MM.

Department of Pathology, Loyola University Chicago Medical Center, Maywood, Ill 60153, USA.

Arch Pathol Lab Med. 2005 Apr;129(4):487-91. Abstract quote  

CONTEXT: Adult renal neoplasms have a predilection for older patients and are clinically and morphologically distinct from renal neoplasms found in pediatric age groups. Relatively rare tumors occur in younger adults (18-45 years of age). Whether these renal tumors are morphologically and clinically distinct from those of older adults has been the subject of controversy. Recent modification of the World Health Organization histologic classification and the American Joint Committee on Cancer staging system of adult renal tumors further highlighted the need for case analysis in this age group.

OBJECTIVE: To analyze renal tumors in younger adults based on a large surgical series from a single institution.

DESIGN: Of 780 renal mass nephrectomy (partial, total, or radical) specimens that were available for evaluation and had been obtained between 1986 and 2004 at Loyola University Medical Center, 112 specimens were from patients between 18 and 45 years of age. The tumors were reevaluated according to the 2004 World Health Organization classification and the 2002 American Joint Committee on Cancer staging system.

RESULTS: The likelihood of clear cell renal cell carcinoma was significantly reduced from 65% in older adults to 53% in younger adults (18-45 years, P = .04). The reduction trend was more significant when comparing an even younger age group. The majority (64%) of clear cell renal cell carcinoma in younger adults was low stage, T1a. Seventeen percent of these tumors had multilocular cystic features involving more than 50% of the tumor volume (55%-85%). The number of oncocytomas was also significantly lower in younger adults than in older adults (2% vs 11%, P < .001), and this presumably age-related benign neoplasm was not identified in patients younger than 40 years in this study. In contrast, the miscellaneous tumor category showed a remarkable increase, from 4% in older adults to 26% in younger adults (P < .001). The youngest patient group (18-35 years) had a higher incidence of miscellaneous tumors, 37%. Younger female adults tended to have more benign miscellaneous neoplasms than did their male counterparts (64% vs 36%, P < .001). Clear cell and chromophobe renal cell carcinoma occurred more frequently in younger male adults than in female adults (2:1 and 8:1, respectively).

CONCLUSIONS: Renal neoplasms are more heterogeneous in younger adults and have a different distribution pattern compared with that in older adults. Malignant and benign renal neoplasms tend to have a contrasting sex distribution in younger adults.
SEX Males 2:1
Tobacco 2x incidence in smokers
Obesity Esp. in women
Unopposed estrogen therapy  
Exposure to asbestos  
Exposure to heavy metals  
Exposure to petroleum products  
Chronic renal failure  
Acquired cystic disease  
Tuberous sclerosis  


Calcium Oxalate Deposition in Renal Cell Carcinoma Associated With Acquired Cystic Kidney Disease: A Comprehensive Study.

Sule N, Yakupoglu U, Shen SS, Krishnan B, Yang G, Lerner S, Sheikh-Hamad D, Truong LD.

From the Departments of *Pathology, daggerUrology, and double daggerMedicine, Renal Section, Baylor College of Medicine, Houston, TX; and section signMethodist Hospital, Houston, TX.
Am J Surg Pathol. 2005 Apr;29(4):443-451. Abstract quote  

The main complication of acquired cystic kidney disease (ACKD) is frequent development of renal tumors, including renal cell carcinoma (RCC). Intratumoral deposition of calcium oxalate (CaOx) is a distinct feature of ACKD-associated RCCs, but several features of this type of RCC are not known. Features of the 30 end-stage renal disease (ESRD)-associated RCCs identified within a 13-year period, including eight with CaOx deposition, were analyzed.

Pathologic and clinical features of CaOx positive (+) and negative (-) RCCs were evaluated and compared. The CaOx+ RCCs showed higher tendency for bilaterality and multifocality. Seven tumors displayed distinctive morphologic features characterized by tumor cells with ill-defined cell membrane, abundant granular eosinophilic cytoplasm, large nuclei, and prominent nucleoli. One tumor was of clear cell type. Regardless of histologic type, all tumors displayed a proximal tubular differentiation. No significant difference was noted for tumors' stage, proliferation, and apoptosis rate between the CaOx+ and CaOx- RCCs. CaOx+ RCCs account for a significant portion of all ESRD-associated RCCs.

The majority of these RCCs display a distinctive morphologic profile. Proximal tubular cell differentiation in conjunction with ESRD-mediated high serum level may be pathogenetically important for intratumoral CaOx deposition. These RCCs seems to have a relatively good prognosis.

Proliferative activity of renal cell carcinoma associated with acquired cystic disease of the kidney: Comparison with typical renal cell carcinoma.

Ikeda R, Tanaka T, Moriyama MT, Kawamura K, Miyazawa K, Suzuki K.

Departments of Urology and Pathology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.

Hum Pathol 2002 Feb;33(2):230-5 Abstract quote

To assess the proliferative activity of renal cell carcinoma (RCC-A) in patients with acquired cystic disease of the kidney (ACDK) after long-term hemodialysis, we analyzed cell cycle, DNA ploidy, and S-phase fraction by flow cytometry (FCM) and proliferating cell nuclear antigen (PCNA) labeling index by immunohistochemistry.

The data were compared with those of typical RCC (tRCC). Sixteen (88.9%) of 18 RCC-As showed a diploid pattern. The values of cells at each phase in the cell cycle in RCC-A group (S, 4.36% + 2.16%; G2M, 5.06% + 1.90%; S+G2M, 9.41% + 2.81%; P <.05) were significantly different from those of tRCCs (S, 8.91% + 6.58%; G2M, 8.77% + 5.73%; S+G2M; 17.67% + 7.61%). The PCNA labeling index was statistically significantly lower in the RCC-As (24.01% +/- 13.4%; P <.05) than in tRCCs (42.27% +/- 26.1%).

These results indicate that the RCC-As are less proliferative than tRCC and are consistent with the observation that RCC-As are less aggressive neoplasms.


Concurrent Angiomyolipoma and Renal Cell Neoplasia: A Study of 36 Cases

Rafael E. Jimenez, etal.

Mod Pathol 2001;14:157-163 Abstract quote

Little is known about the association of angiomyolipoma and adult renal-cell neoplasia.

We studied the clinicopathologic features of 36 patients with concurrent angiomyolipoma and renal-cell neoplasia from the consultation and surgical pathology files of nine institutions. HMB-45 immunoreactivity was analyzed in both neoplasms.

Twenty-five sporadic cases of patients with angiomyolipoma and renal-cell neoplasia and 11 cases of patients with tuberous sclerosis, as defined by Gomez’ criteria, had mean ages of 59 and 53 years, respectively, and female–male ratios of 2:1 and 5:1, respectively. The mean size of the angiomyolipomas was 1 cm in the sporadic cases and 3 cm in those patients with tuberous sclerosis (medians: 0.5 and 3 cm, respectively, P = .002). The mean sizes of the renal-cell neoplasms were 5 cm in sporadic cases and 6 cm in patients with tuberous sclerosis (medians: 4 and 5 cm, respectively; P = .88).

In both clinical settings, angiomyolipoma was more commonly the incidental tumor. Clear-cell (conventional) renal-cell carcinoma was the most common renal-cell neoplasm in both groups of patients, accounting for approximately two thirds of the tumors.

In patients with tuberous sclerosis, 27% of renal-cell neoplasms were oncocytomas, compared with 8% in sporadic cases (P = .15). Papillary neoplasia, chromophobe, and collecting-duct renal-cell carcinoma were found only in sporadic cases. All of the 22 renal-cell neoplasms studied were negative for HMB-45, whereas all 25 angiomyolipomas studied were positive.


Renal tumors in the birt-hogg-dube syndrome.

Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B, Linehan WM, Merino MJ.


Am J Surg Pathol 2002 Dec;26(12):1542-52 Abstract quote

Birt-Hogg-Dube (BHD) syndrome is an autosomal dominant genodermatosis characterized by the development of small dome-shaped papules on the face, neck, and upper trunk (fibrofolliculomas). In addition to these benign hair follicle tumors, BHD confers an increased risk of renal neoplasia and spontaneous pneumothorax.

To date, there has been no systematic pathologic analysis of the renal tumors associated with this syndrome. We reviewed 130 solid renal tumors resected from 30 patients with BHD in 19 different families. Preoperative computed tomography scans demonstrated a mean of 5.3 tumors per patient (range 1-28 tumors), the largest tumors averaging 5.7 cm in diameter (+/- 3.4 cm, range 1.2-15 cm). Multiple and bilateral tumors were noted at an early age (mean 50.7 years). The resected tumors consisted predominantly of chromophobe renal cell carcinomas (44 of 130, 34%) or of hybrid oncocytic neoplasms that had areas reminiscent of chromophobe renal cell carcinoma and oncocytoma (65 of 130, 50%). Twelve clear cell (conventional) renal carcinomas (12 of 130, 9%) were diagnosed in nine patients. These tumors were on average larger (4.7 +/- 4.2 cm) than the chromophobe (3.0 +/- 2.5 cm) and hybrid tumors (2.2 +/- 2.4 cm). Microscopic oncocytosis was found in the renal parenchyma of most patients, including the parenchyma of five patients with evidence of clear cell renal cell carcinoma.

Our findings suggest that microscopic oncocytic lesions may be precursors of hybrid oncocytic tumors, chromophobe renal cell carcinomas, and perhaps clear cell renal cell carcinomas in patients with BHD syndrome. Recognition by the pathologist of the unusual renal tumors associated with BHD may assist in the clinical diagnosis of the syndrome.


The Morphologic Spectrum of Kidney Tumors in Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) Syndrome.

*Laboratory of Pathology †Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD.


Am J Surg Pathol. 2007 Oct;31(10):1578-1585. Abstract quote

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial syndrome characterized by the development of cutaneous and uterine leiomyomas as well as renal tumors. The mutation of this condition has been identified in the fumarate hydratase (FH, 1q42.3-q43) gene. The histology of the renal cancers has not been well described or illustrated because of the newness of the syndrome.

We reviewed 40 renal tumors resected from 38 patients belonging to HLRCC families with proven fumarate hydratase germline mutation. Patients ranged in age from 17 to 75 years of age. Tumors were unilateral in all but 2 cases. The size of the tumors varied between 2.3 and 20 cm and there was no laterality preference. Several different architectural patterns were recognized: papillary (25 cases), tubulo-papillary (8 cases), tubular (2 cases), and solid (1 case). Mixed patterns were also present in 4 cases.

The most important histologic feature of these neoplasms, which we believe to be the hallmark of the HLRCC tumors, is the presence of a characteristic large nucleus with a very prominent inclusion like orangiophilic or eosinophilic nucleolus, surrounded by a clear halo. Immunohistochemical studies did not provide a specific marker for these tumors, however, loss of heterozygosity at 1q32 and 1q42-44 was frequently found. These tumors are associated with poor prognosis and frequent spread to regional lymph nodes.

At the moment, morphology is the best tool to recognize these tumors. Proper diagnosis of this syndrome by the pathologist may assist in early detection of these tumors.
VON HIPPEL-LINDAU SYNDROME Up to 2/3 of patients develop multiple renal cysts and bilateral multiple renal cell CA
VHL gene

Mutational analysis of the von hippel lindau gene in clear cell renal carcinomas from tuberous sclerosis complex patients.

Duffy K, Al-Saleem T, Karbowniczek M, Ewalt D, Prowse AH, Henske EP.

Medical Oncology Division (KD, MK, AHP, EPH) and Department of Pathology (TA-S), Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Mod Pathol 2002 Mar;15(3):205-10 Abstract quote

Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder characterized by seizures, mental retardation, autism, and tumors of multiple organs. Renal disease in TSC includes angiomyolipomas, cysts, and renal cell carcinomas. It is known that somatic mutations in the von Hippel Lindau (VHL) tumor suppressor gene occur in most clear cell renal carcinomas.

To determine whether TSC-associated clear cell carcinomas also contain VHL mutations, we analyzed six tumors for loss of heterozygosity in the VHL gene region of chromosome 3p and for mutations in the VHL gene. Four of the patients were women between the ages of 34 and 68 years, and two were males under the age of 21 years. The loss of heterozygosity analysis was performed using polymorphic microsatellite markers, and the mutational analysis was performed using direct sequencing. Chromosome 3p loss of heterozygosity was not detected, and no VHL mutations were identified.

These findings suggest that mutations in the TSC1 and TSC2 genes lead to clear cell renal carcinogenesis via an alternate pathway not involving VHL mutations.


Renal Carcinomas With the t(6;11)(p21;q12): Clinicopathologic Features and Demonstration of the Specific Alpha-TFEB Gene Fusion by Immunohistochemistry, RT-PCR, and DNA PCR.

Argani P, Lae M, Hutchinson B, Reuter VE, Collins MH, Perentesis J, Tomaszewski JE, Brooks JS, Acs G, Bridge JA, Vargas SO, Davis IJ, Fisher DE, Ladanyi M.

From the *Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD; the daggerDepartment of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY; double daggerDepartment of Pathology and section signDivision of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; ||Department of Pathology, University of Pennsylvania Medical Center, Philadelphia, PA; paragraph signDepartment of Pathology, University of Nebraska Medical Center, Omaha, NE; #Department of Pathology and **Pediatric Hematology, Children's Hospital Boston, Boston, MA.
Am J Surg Pathol. 2005 Feb;29(2):230-240. Abstract quote  

A highly distinctive subset of renal neoplasms of children and young adults contains a t(6;11)(p21;q12), a translocation recently been shown to result in fusion of Alpha, a gene on 11q12, with the transcription factor gene TFEB on 6p21.

To define the clinicopathologic spectrum of this nascent entity and to establish immunohistochemical (IHC) and molecular methods for the detection of the specific Alpha-TFEB fusion, we studied 7 renal neoplasms that showed the t(6;11) by cytogenetic or molecular analysis (patient age: range, 9-33 years; mean, 17 years). While all tumors were confined to the kidney, 3 tumors demonstrated vascular invasion. In limited follow-up, none has metastasized.

We postulated that the Alpha-TFEB gene fusion may result in deregulated expression of TFEB protein that would be detectable by IHC. Using a polyclonal antibody to TFEB on formalin-fixed, paraffin-embedded tissue sections, we found that all 7 renal neoplasms with the t(6;11) demonstrated moderate (2 cases) or strong (5 cases) nuclear TFEB immunoreactivity. In contrast, none of 1089 other tumors (of 74 histologic types from 16 sites) labeled significantly for TFEB. Nuclear immunoreactivity for TFEB in normal tissues was extremely rare, limited to weak labeling of scattered benign lymphocytes. We also show that the Alpha-TFEB fusion RNAs are highly variable in size and structure, making detection by reverse-transcriptase polymerase chain reaction (RT-PCR) less reliable than for other gene fusions. Because Alpha is an intronless gene and therefore lacks splice signals, we hypothesized that DNA PCR and RT-PCR products would be identical, allowing for the use of more robust molecular assays based on genomic DNA. Indeed, in 2 cases with available frozen tissue, we showed the genomic Alpha-TFEB junction detected by DNA PCR to be identical to the Alpha-TFEB fusion mRNA detected by RT-PCR.

In summary, renal neoplasms with the t(6;11) are a distinctive neoplastic entity with many similarities to the Xp11 translocation carcinomas, and together with the latter form a growing "MiTF/TFE family" of translocation carcinomas. Nuclear immunoreactivity for TFEB protein is a highly sensitive and specific diagnostic marker for these renal neoplasms. Finally, the special molecular features of the Alpha-TFEB gene fusion allow its molecular detection by DNA PCR as a robust alternative to RT-PCR in clinical tumor samples.
Mismatch repair genes in renal cortical neoplasms.

Baiyee D, Banner B.

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305-5324, USA.

Hum Pathol. 2006 Feb;37(2):185-9. Epub 2005 Dec 15. Abstract quote  

Mutation of human mutL homolog 1 (MLH-1) and human mutS homolog 2 (MSH-2) has been linked with the pathogenesis of colorectal carcinoma in hereditary nonpolyposis colorectal cancer syndrome and other carcinomas. Mutations of these genes in renal cell carcinomas were recently described.

The aim of this study was to examine the expression of MLH-1 and MSH-2 in renal cortical neoplasms of various histological types by immunohistochemistry. Thirty-eight (n = 38) resected renal tumors were obtained from the surgical pathology files of the UMass Memorial Healthcare, including clear cell carcinomas (CLEARs, n = 20), papillary carcinomas (PAPs, n = 8), chromophobe carcinomas (CHRs, n = 4), and oncocytomas (ONCs, n = 6). Positive immunostaining for MLH-1 and MSH-2 was graded by the number of positive tumor cell nuclei, as follows: 0, negative; 1, up to one third of positive nuclei; 2, one to two thirds positive; and 3, greater than two thirds positive. Loss of MLH-1 or MSH-2 was defined as a tumor with grade 0 or 1, compared with the normal tubules. Normal tubules and intercalated ducts contained cells positive for MLH-1 and MSH-2 in all cases.

For both antibodies, positive staining in tumors ranged from grade 1 to 3 in the CLEAR and PAP but was only grade 2 to 3 in the CHR and ONC. Loss of MLH-1 and/or MSH-2 occurred in malignant tumors but not in ONC. Loss of MLH-1 was present in 8 (40%) of 20 CLEARs and 4 (50%) of 8 PAPs, compared with loss of MSH-2 in 4 (20%) of 20 CLEARs and 1 (25%) of 4 CHRs.

Our results suggest that loss of mismatch repair genes is involved in the malignant transformation in some renal carcinomas, particularly those derived from the proximal tubules.

Renal cell carcinoma: Allelic loss at chromosome 9 using the fluorescent multiplex-polymerase chain reaction technique.

Fukunaga K, Wada T, Matsumoto H, Yoshihiro S, Matsuyama H, Naito K.

Department of Urology, Yamaguchi University School of Medicine, Ube, Japan.

Hum Pathol 2002 Sep;33(9):910-4 Abstract quote

Loss of tumor-suppressor genes on both arms of chromosome 9 appears to be common in many types of cancer. Chromosome 9q is often partially deleted in bladder cancer, lung cancer, and basal cell carcinoma. However, little data are available on allelic loss on chromosome 9 in renal cell carcinoma (RCC).

One hundred and nine nonpapillary RCCs were studied for loss of heterozygosity (LOH) at 13 loci on chromosome 9 by using the fluorescent multiplex-polymerase chain reaction method to compare DNA from tumor samples and peripheral blood lymphocytes. At the loci tested, LOH was found in from 2.3% (9q31, D9S938) to 17% (9q22, 1AJL) of informative cases, and 27 (24.8%) of the 109 RCCs had LOH at 1 or more loci of chromosome 9. LOH was more often detected at 9q22 within the PTCH gene (17%) when compared with LOH at the other 12 loci (P = 0.0172). Regarding the relationship with clinical parameters, however, there were no statistically significant associations between this LOH and tumor stage or grade. Among the 109 tumors, 6 (5.5%) showed replication errors.

Our results suggest that LOH of the PTCH gene may be related to the development of nonpapillary RCC, although the clinical relevance has not been not clarified.

MET protooncogene in papillary carcinomas Gene found in chromosome 7, with trisomy 7 a frequent abnormality in these tumors

This protein is the tyrosine kinase receptor for hepatocyte growth factor which mediates growth, cell mobility, invasion, and morphogenetic differentiation
PRCC gene in papillary carcinomas Found on chromosome 1
Implicated in childhood sporadic tumors with X;1 translocation
VHL gene in clear cell carcinomas 98% of these tumors, regardless of sporadic or familial cases have a deletion or unbalanced translocation
t(3;6) t(3;8) t(3;11)

This causes a loss of a region of chromosome 3 which harbors the VHL gene (3p25.3). The gene acts as a tumor suppressor gene and encodes a protein called elongin which inhibits the generation of transcriptional elongation complex
80% of tumors alos have a second nondeleted allele of the VHL gene with somatic mutations or hypermethylated inactivation

SPARC expression in primary human renal cell carcinoma: Upregulation of SPARC in sarcomatoid renal carcinoma

Naoki Sakai, MD
Masaya Baba, MD
Yoji Nagasima, MD, etal.

Hum Pathol 2001;32:1064-1070. Abstract quote

SPARC (secreted protein acidic and rich in cysteine, also called osteonectin, BM-40, and 43K protein) is a matricellular protein and is associated with cell–matrix interactions during cell proliferation and extracellular remodeling. It is also implicated in the neovascularization, invasion, and metastasis of human malignancies.

To investigate a potential role of the SPARC in renal tumorigenesis, we examined primary renal cell carcinomas (RCCs) for SPARC expression by Northern blot analysis and for protein distribution by immunohistochemistry.

We found that 6 (100%) of 6 sarcomatoid and 25 (70%) of 36 clear-cell carcinomas had enhanced SPARC transcription compared with that of the corresponding normal kidney tissue. In contrast, papillary and chromophobe RCCs characterized by a hypovascular or avascular tumor phenotype had undetectable SPARC expression. Immunohistochemical analysis showed that SPARC was strongly stained in the cytoplasm of the sarcomatoid neoplastic cells in sarcomatoid RCCs, whereas it was expressed only in the vascular endothelial cells and fibroblasts in clear-cell RCCs. SPARC staining intensity in the stromal cells was increased in the invading portion in some clear-cell RCCs. These findings suggest that tumor development, including neovascularization and invasion in clear-cell RCCs, might be regulated by SPARC from stromal endothelial cells and fibroblasts and that sarcomatoid transformation from common-type RCCs is associated with upregulation of SPARC expression; SPARC may contribute to its aggressive tumor phenotype.

Xp11 TRANSLOCATION t(6:11)(p21;q12)


Hepatic dysfunction  
Cushing syndrome  
Leukemoid reactions  


Renal cell carcinoma in South Korea: a multicenter study.

Kim H, Cho NH, Kim DS, Kwon YM, Kim EK, Rha SH, Park YW, Shim JW, Lee SS, Lee SN, Lee J, Lee JS, Lee TJ, Jung SJ, Jung SH, Chung JH, Cho HY, Joo HJ, Choi YJ, Choi C, Han WS, Hur B, Ro JY; Genitourinary Pathology Study Group of the Korean Society of Pathologists.

Department of Pathology, Yonsei Unviersity College of Medicine, Seoul, Korea.

Hum Pathol. 2004 Dec;35(12):1556-63 Abstract quote.

The incidence of renal cell carcinoma (RCC) in South Korea is steadily becoming similar to that in Western countries. This study summarizes the results of a 3-year multicenter survey of RCC in South Korea, conducted by the Korean Genitourinary Pathology Study Group. A total of 795 cases of RCC were collected from 20 institutes between 1995 and 1997, including 686 clear cell RCCs (86.3%), 58 papillary RCCS (7.30%), 49 chromphobe RCCs (6.16%), and 2 collecting duct RCCs (0.25%). At least 5 years of follow-up was available for 627 clear cell, 54 papillary, and 49 chromophobe RCCs. All subtypes presented most frequently with stage T3aN0M0 at the time of operation, and papillary RCCs demonstrated more frequent lymph node metastasis.

Overall survival was not significantly related to the histological subtype (clear cell vs papillary, P = 0.8651; clear cell vs chromophobe, P = 0.0584; papillary vs chromophobe, P = 0.0743). For clear cell RCCs, statistically significant associations were found between overall survival and sex (P = 0.0153), multiplicity (P = 0.0461), necrosis (P = 0.0191), age, sarcomatoid change, TNM stage, nuclear grade, and modality of treatment (all P <0.0001). Overall survival was significantly associated with tumor size (P = 0.0307), nuclear grade (P = 0.0235), multiplicity, sarcomatoid change, and TNM stage (all P <0.0001) for papillary RCCs and with the presence of sarcomatoid change (P = 0.0281), nuclear grade (P = 0.0015), treatment modality (P = 0.0328), and TNM stage (P <0.0001) for chromophobe RCCs. Age (P = 0.0125), nodal stage (P = 0.0010), and treatment modality (P = 0.0001) were significant independent prognostic indicators for clear cell RCC on multivariate analysis.

This is the first multicenter study of RCC in South Korea, demonstrating the general patterns and prognostic factors of Korean RCCs.
Most common in upper poles Often bulge into calyx and pelvis
Clear cell tumors Solitary unilateral lesions
3-15 cm
Bright yellow-gray-white
Large areas of necrosis
Papillary tumors May be multifocal and bilateral
Hemorrhagic and cystic
Papillae grossly present
HEREDITARY TUMORS Confined to the kidney
No stigmata of VHL but defects in the VHL gene
Hereditary papillary carcinoma Autosomal dominant form with multiple bilateral tumors
Mutations in the MET protooncogene

Concurrent angiomyolipomas and renal cell carcinoma harboring metastatic foci of mammary carcinoma in the same kidney: An incidental autopsy finding in a patient with a follow-up of thirty years

J. Fernando Val-Bernal, MD, PhD
Fernando Villoria, MD
M. Angeles Pérez-Expósito, MD

Ann Diagn Pathol 2001;5:293-299 Abstract quote

The synchronous occurrence of three different types of renal tumor in a patient is rare.

We report a case of conventional (clear cell) renal cell carcinoma harboring metastatic foci of mammary carcinoma associated with two angiomyolipomas in the left kidney incidentally discovered at the autopsy. The patient was a 75-year-old woman, without the tuberous sclerosis complex, who had undergone left radical mastectomy and radiotherapy for an infiltrating duct carcinoma of breast 30 years before. This tumor was widely disseminated at autopsy, but the nontumorous renal parenchyma was free of metastases.

To the best of our knowledge this combination of neoplasms has not been described before. This case shows the important role played by autopsy in the accurate investigation of interrelations among coexisting tumors.


Morphologic and Molecular Characterization of Renal Cell Carcinoma in Children and Young Adults.

Bruder E, Passera O, Harms D, Leuschner I, Ladanyi M, Argani P, Eble JN, Struckmann K, Schraml P, Moch H.

Institutes and Departments of Pathology of the Universities of *Basel, daggerKiel, double daggerMemorial Sloan-Kettering Cancer Center, New York, and section signJohns Hopkins Medical Institutions, Baltimore, MD; and paragraph signIndiana University School of Medicine, Indianapolis, IN.
Am J Surg Pathol. 2004 Sep;28(9):1117-1132. Abstract quote  

A new WHO classification of renal cell carcinoma has been introduced in 2004. This classification includes the recently described renal cell carcinomas with the ASPL-TFE3 gene fusion and carcinomas with a PRCC-TFE3 gene fusion. Collectively, these tumors have been termed Xp11.2 or TFE3 translocation carcinomas, which primarily occur in children and young adults.

To further study the characteristics of renal cell carcinoma in young patients and to determine their genetic background, 41 renal cell carcinomas of patients younger than 22 years were morphologically and genetically characterized. Loss of heterozygosity analysis of the von Hippel-Lindau gene region and screening for VHL gene mutations by direct sequencing were performed in 20 tumors. TFE3 protein overexpression, which correlates with the presence of a TFE3 gene fusion, was assessed by immunohistochemistry. Applying the new WHO classification for renal cell carcinoma, there were 6 clear cell (15%), 9 papillary (22%), 2 chromophobe, and 2 collecting duct carcinomas. Eight carcinomas showed translocation carcinoma morphology (20%). One carcinoma occurred 4 years after a neuroblastoma. Thirteen tumors could not be assigned to types specified by the new WHO classification: 10 were grouped as unclassified (24%), including a unique renal cell carcinoma with prominently vacuolated cytoplasm and WT1 expression. Three carcinomas occurred in combination with nephroblastoma. Molecular analysis revealed deletions at 3p25-26 in one translocation carcinoma, one chromophobe renal cell carcinoma, and one papillary renal cell carcinoma. There were no VHL mutations. Nuclear TFE3 overexpression was detected in 6 renal cell carcinomas, all of which showed areas with voluminous cytoplasm and foci of papillary architecture, consistent with a translocation carcinoma phenotype.

The large proportion of TFE3 "translocation" carcinomas and "unclassified" carcinomas in the first two decades of life demonstrates that renal cell carcinomas in young patients contain genetically and phenotypically distinct tumors with further potential for novel renal cell carcinoma subtypes. The far lower frequency of clear cell carcinomas and VHL alterations compared with adults suggests that renal cell carcinomas in young patients have a unique genetic background.



Interobserver and intraobserver variability using the Fuhrman grading system for renal cell carcinoma.

Al-Aynati M, Chen V, Salama S, Shuhaibar H, Treleaven D, Vincic L.

Department of Pathology, St Joseph's Hospital, Hamilton Health Sciences Corporation and McMaster University, Hamilton, Ontario.

Arch Pathol Lab Med 2003 May;127(5):593-6 Abstract quote

CONTEXT: Histologic grading of renal cell carcinoma has been shown to be second to staging in prognostic significance. A 4-tier grading scheme proposed by Fuhrman et al and based on nuclear features is the system used most frequently in North America. There are, however, very few studies in the literature assessing the interobserver variability for this system, and to our knowledge, none addressing intraobserver variability.

OBJECTIVE: To assess the interobserver and intraobserver agreement among 4 pathologists using the Fuhrman nuclear grading scheme for renal cell carcinoma.

DESIGN: Representative hematoxylin-eosin-stained slides of 99 consecutive primary renal cell carcinoma cases diagnosed between 1994 and 1999 at St Joseph's Hospital, Hamilton, Ontario, were independently graded by 4 pathologists on 2 occasions with a minimum period of 3 months separating the 2 readings.

RESULTS: Intraobserver kappa values ranged from 0.29 to 0.62 (mean = 0.45), and interobserver kappa values ranged from 0.19 to 0.38 and from 0.09 to 0.44 for the first and second rounds, respectively (combined mean kappa value = 0.29). When combining Fuhrman grades 1 and 2 as low-grade tumors and grades 3 and 4 as high-grade tumors, the intraobserver kappa values ranged from 0.4 to 0.64 (mean = 0.53) and interobserver kappa values ranged from 0.28 to 0.59 and from 0.26 to 0.58 for the first and second rounds, respectively (combined mean kappa value = 0.45). The admixture of 2 grades in the same tumor was observed in 53% of cases.

CONCLUSIONS: We found only moderate intraobserver and interobserver agreement using the 4-grade Fuhrman scheme. After collapsing the diagnostic grades to 2, the intraobserver agreement changed from moderate to substantial. The collapsing of the 4-category Fuhrman grades into 2 categories is useful in improving intraobserver agreement.

Potential Pitfalls in the Frozen Section Evaluation of Parenchymal Margins in Nephron-Sparing Surgery

Teresa McHale, MD,1 S. Bruce Malkowicz, MD,2 John E. Tomaszewski, MD,1 and Elizabeth M. Genega, MD

Am J Clin Pathol 2002;118:903-910 Abstract quote

With advances in radiographic imaging, there has been an increase in the incidental detection of small renal cell carcinomas, with a resultant increase in partial nephrectomies for these tumors. Partial nephrectomy often necessitates assessment of renal parenchymal margins by frozen section.

To determine the most common problematic "lesions" encountered on renal parenchymal margins, we evaluated all diagnostically challenging frozen sections that had been referred to a genitourinary pathologist.

Frozen sections with detached atypical cells and crushed tubules were the most common lesions that presented diagnostic uncertainty. We found that normal constituents of renal parenchyma, namely tubules and glomeruli, can be mistaken for neoplasia. Neoplastic tubules of low-grade renal cell carcinomas may be misinterpreted as thickly cut, crushed benign tubules, and the significance of tubulopapillary "adenomas" in frozen sections is unclear.

The present report highlights diagnostic difficulties that pathologists may encounter on frozen sections of renal parenchymal margins.


Cytology of morcellated renal specimens: significance in diagnosis and dissemination.

Meng MV, Miller TR, Cha I, Stoller ML.

Department of Urology, University of California School of Medicine, San Francisco, CA, USA.


J Urol. 2003 Jan;169(1):45-8. Abstract quote

PURPOSE: Controversy surrounds the process of morcellation for retrieving laparoscopically removed specimens. The inability to assess tumor stage, increased difficulty in pathological examination and the potential for tumor spillage are cited as significant disadvantages of the technique. We examined cytological findings in bag washings after laparoscopic nephrectomy for benign and malignant diseases.

MATERIALS AND METHODS: We prospectively obtained cytology washings from the retrieval bag after laparoscopic nephrectomy and manual morcellation. In 22 consecutive cases after specimen fragmentation in a LapSac (Cook Urological, Spencer, Indiana) the bag was thoroughly irrigated with 30 cc normal saline. This wash was then processed by ThinPrep (Cytyc Corp., Marlborough, Massachusetts) and stained with Papanicolaou stain. Standard pathological examination of the morcellated specimen was performed to determine renal histology.

RESULTS: The histological diagnosis was clear cell renal carcinoma in 10 cases, multicystic renal carcinoma in 2, papillary renal cell carcinoma in 1, angiomyolipoma in 1, and oncocytoma in 1. Bag cytological results were accurate in 9 of 13 patients with carcinoma (69%), while in 3 cytological study provided additional information. In all 9 cases of benign histology, cytological findings were consistent with benign cellular features. Neoplastic cells were easily detected and classified into type and grade.

CONCLUSIONS: Cytological examination of LapSac washings after specimen morcellation provided a pathological diagnosis in the majority of patients. This method may complement existing techniques and be useful for increasing the accuracy of pathological analysis of morcellated specimens. In addition, these data suggest that malignant cells are liberated during the morcellation process, which has significant implications for potential tumor dissemination.

Renal papillary adenoma--a putative precursor of papillary renal cell carcinoma.

Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.


Hum Pathol. 2007 Feb;38(2):239-46. Epub 2006 Oct 23. Abstract quote

The precursor lesions of renal cell carcinoma (RCC) are unknown. The purpose of this study is to determine the incidence, histomorphological features, and immunohistochemical features of papillary adenoma and elucidate its potential relationship to RCC.

We reviewed 542 consecutive nephrectomy specimens over an 8-year period. Immunohistochemistry was carried out with antibodies specific for alpha-methyl-coenzyme A racemase (AMACR) and glutathione S-transferase alpha (clear-cell RCC marker). Thirty-eight (7%) nephrectomy specimens showed histologic evidence of papillary adenoma. Of these 38 cases, 18 (47%) arose in the setting of papillary RCC (PRCC). Seven papillary adenomas (18%) occurred in the setting of acquired polycystic kidney disease (APKD), 6 in clear-cell RCCs, 3 in chromophobe RCCs, 2 in end-stage kidney disease, 1 in oncocytoma, 1 in angiomyolipoma, and 1 in renal schwannoma. Furthermore, papillary adenomas were more commonly found in kidneys removed for PRCC (25%, 18/71) than in kidneys harboring clear-cell RCC (1.9%, 6/318).

Histomorphologically, papillary adenomas were characterized by varying proportions of papillae and tubules formed by cuboidal cells with scant basophilic cytoplasm similar to those in type 1 PRCC. Adenomas associated with PRCC tend to be multiple in number (61% [11/18] of cases had >2 adenomas; mean, 5). In contrast, 100% of papillary adenomas arising in other conditions had less than 2 adenomas. Most of the adenomas (82%, 31/38) stained strongly for AMACR in a fashion similar to that of PRCC. The 7 AMACR-negative cases all arose in the setting of APKD.

In this study of surgical specimens, the high coincidence, multifocality, and histologic and immunohistochemical similarities between papillary adenoma and PRCC suggest that the 2 are strongly associated and may represent a continuum of 1 biologic process. In contrast, adenomas associated with APKD exhibit distinct morphological and immunohistochemical features and, therefore, may have an entirely different pathogenesis.

Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents.

Argani P, Antonescu CR, Illei PB, Lui MY, Timmons CF, Newbury R, Reuter VE, Garvin AJ, Perez-Atayde AR, Fletcher JA, Beckwith JB, Bridge JA, Ladanyi M.

Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland 21231-2410, USA.

Am J Pathol 2001 Jul;159(1):179-92 Abstract quote

The unbalanced translocation, der(17)t(X;17)(p11.2;q25), is characteristic of alveolar soft part sarcoma (ASPS). We have recently shown that this translocation fuses the TFE3 transcription factor gene at Xp11.2 to ASPL, a novel gene at 17q25.

We describe herein eight morphologically distinctive renal tumors occurring in young people that bear the identical ASPL-TFE3 fusion transcript as ASPS, with the distinction that the t(X;17) translocation is cytogenetically balanced in these renal tumors. A relationship between these renal tumors and ASPS was initially suggested by the cytogenetic finding of a balanced t(X;17)(p11.2;q25) in two of the cases, and the ASPL-TFE3 fusion transcripts were then confirmed by reverse transcriptase-polymerase chain reaction. The morphology of these eight ASPL-TFE3 fusion-positive renal tumors, although overlapping in some aspects that of classic ASPS, more closely resembles renal cell carcinoma (RCC), which was the a priori diagnosis in all cases. These tumors demonstrate nested and pseudopapillary patterns of growth, psammomatous calcifications, and epithelioid cells with abundant clear cytoplasm and well-defined cell borders.

By immunohistochemistry, four tumors were negative for all epithelial markers tested, whereas four were focally positive for cytokeratin and two were reactive for epithelial membrane antigen (EMA) (one diffusely, one focally). Electron microscopy of six tumors demonstrated a combination of ASPS-like features (dense granules in four cases, rhomboid crystals in two cases) and epithelial features (cell junctions in six cases, microvilli and true glandular lumens in three cases). Overall, although seven of eight tumors demonstrated at least focal epithelial features by electron microscopy or immunohistochemistry, the degree and extent of epithelial differentiation was notably less than expected for typical RCC. We confirmed the balanced nature of the t(X;17) translocation by fluorescence in situ hybridization in all seven renal tumors thus analyzed, which contrasts sharply with the unbalanced nature of the translocation in ASPS.

In summary, a subset of tumors previously considered to be RCC in young people are in fact genetically related to ASPS, although their distinctive morphological and genetic features justify their classification as a distinctive neoplastic entity. Finally, the finding of distinctive tumors being associated with balanced and unbalanced forms of the same translocation is to our knowledge, unprecedented.

Renal Cell Carcinoma Associated With Prominent Angioleiomyoma-like Proliferation: Report of 5 Cases and Review of the Literature.

*Centro Consulenze Anatomia Patologica Oncologica, Centro Diagnostico Italiano, Milan, Italy daggerDepartment of Pathology, Institute National of Pediatrics, Mexico City, Mexico double daggerDepartment of Pathology, University of Bologna, Bologna, Italy section signDepartment of Pathology, Johns Hopkins Medical Institutions, Baltimore parallelGenzyme Genetics, Inc, New York, NY.

Am J Surg Pathol. 2006 Nov;30(11):1372-1381. Abstract quote

Five cases of renal cell carcinoma of clear cell type are presented, Fuhrmann's grade 2, associated with a peculiar stromal proliferation having angioleiomyoma-like features. This proliferation was particularly prominent at the interphase between the tumor edge and the surrounding normal tissues, in which it acquired the configuration of a tumor capsule. Four similar cases were taken from the literature.

We postulate that this angioleiomyoma-like change is a tumor epiphenomenon and that it represents yet another manifestation of the well-documented capacity of renal cell carcinoma to induce vascular proliferation, probably through the secretion of angiogenic and other growth factors by the tumor cells.
70-80% of all types
Cells with clear or granular cytoplasm staining for glycogen and lipid
Delicate branching vasculature

Low-grade tubular-mucinous renal neoplasms: morphologic, immunohistochemical, and genetic features.

Rakozy C, Schmahl GE, Bogner S, Storkel S.

Department of Pathology, University Witten Herdecke (CR,GES, SS), Wuppertal, Germany.

Mod Pathol 2002 Nov;15(11):1162-71 Abstract quote

The current classification system of renal tumors is based on morphologic criteria, as supported by genetic findings.

We present a group of previously unclassified tumors with similar morphologic and genetic features, suggesting a new entity within renal neoplasms. Seven renal tumors from five patients (ages 31-67 years) were analyzed. All cases were stained with periodic acid-Schiff, Hale's colloidal iron (HCI), and Alcian blue (AB) at pH 2.5/1.0 with and without hyaluronidase (HA) digestion. Immunohistochemical (IHC) stains were performed for CK8, CK18, CK19, vimentin, villin, Tamm-Horsfall protein (THP), renal cell carcinoma marker (RCC), epithelial membrane antigen (EMA), ulex europaeus agglutinin (UEA-1), soy bean agglutinin (SBA), peanut agglutinin (PNA), and MIB-1.

Comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) studies were performed on all cases.

All tumors showed circumscribed growth, a tubular growth pattern with focal solid areas, no significant nuclear atypia and absence of necrosis, desmoplasia, or inflammation. Abundant extracellular mucin was present. Immunohistochemistry stains support collecting duct origin (EMA+, PNA+, SBA+/-, CK 8/18/19+, vimentin+/-, UEA-1-, RCC-, villin-, THP-). The proliferative rate was low (<1%). CGH showed multiple consistent chromosomal losses (-1,-4, -6, -8, -9, -13, -14, -15, -22). Clinical outcome was favorable, with recurrences but no known distant metastases or death of disease. These findings are distinct from all previously classified renal neoplasms.

Our data suggest the presence of a unique tumor entity within tumors of probable collecting duct origin: tubular-mucinous renal tumors of low malignant potential.


Extensively Necrotic Cystic Renal Cell Carcinoma A Clinicopathologic Study With Comparison to Other Cystic and Necrotic Renal Cancers

David A. Brinker, M.D.; Mahul B. Amin, M.D.; Mariza de Peralta-Venturina, M.D.; Victor Reuter, M.D.; David Y. Chan, M.D.; Jonathan I. Epstein, M.D.

From the Department of Pathology and the James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, Baltimore, Maryland (D.A.B., D.Y.C., J.I.E.); Department of Pathology, Emory University Hospital, Atlanta, Georgia (M.B.A.); Department of Pathology, Henry Ford Health System, Detroit, Michigan (M.P.-V.); and Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (V.R.)

Am J Surg Pathol 2000;24:988-995 Abstract quote

Renal cell carcinomas often show varying degrees of necrosis and cystic change. The prognostic importance of necrosis so extensive that only a few tumor cells can be identified is not clear. We gathered clinicopathologic and follow-up data on a group of eight such cases (``type I'').

These patients were compared with two other groups of renal cell carcinomas: those with extensive necrosis (>50%), yet with readily identifiable tumor (``type II''), and cancers with extensive cystic change not resulting from necrosis, usually multiloculated (``type III'').

The groups showed similar demographic characteristics, and within each group there was great variation in tumor size. Conventional (clear cell) histology was more common than papillary morphology in all groups. The type II neoplasms tended to be of higher nuclear grade and pathologic stage than the other groups. While one of six type I patients with follow up progressed 131 months after diagnosis, eight of 20 type II patients showed progression. None of the six type III patients with follow up progressed.

We conclude that renal cell carcinomas showing extensive necrosis are capable of aggressive behavior, and patients with these lesions cannot be assured of cure following surgery. Pathologists must be aware of this entity and extensively sample any renal lesion showing extensive necrosis. The tumors showing a greater amount of viable neoplastic cells yet at least 50% necrosis had a higher rate of progression than did the type I patients. The lack of progression of any of the type III cases supports the idea that type III multiloculated cystic renal cell carcinomas may carry a distinctly better prognosis than other forms of renal cell carcinoma.

Renal medullary carcinoma: report of seven cases from Brazil.

1State University of Campinas, São Paulo, Brazil.


Mod Pathol. 2007 Sep;20(9):914-20. Abstract quote

We report seven cases of renal medullary carcinoma collected from several institutions in Brazil. In spite of a relatively high incidence of sickle cell trait in Brazil, this is a rare tumor.

All patients were males between the ages of 8 and 69 years (mean 22 years). From the collected information, the most frequent presenting symptoms were gross hematuria and flank or abdominal pain. The duration of symptoms ranged from 1 week to 5 months. Most of the tumors were poorly circumscribed arising centrally in the renal medulla. Size ranged from 4 to 12 cm (mean 7 cm) and hemorrhage and necrosis were common findings.

All seven cases described showed sickled red blood cells in the tissue and six patients were confirmed to have sickle cell trait. All cases disclosed the characteristic reticular pattern consisting of tumor cell aggregates forming spaces of varied size, reminiscent of yolk sac testicular tumors of reticular type. Other findings included microcystic, tubular, trabecular, solid and adenoid-cystic patterns, rhabdoid-like cells and stromal desmoplasia.

A peculiar feature was suppurative necrosis typically resembling microabscesses within epithelial aggregates. The medullary carcinoma of the 69-year-old patient was associated with a conventional clear cell carcinoma.

To our knowledge, this association has not been previously reported and the patient is the oldest in the literature. The survival after diagnosis or admission ranged from 4 days to 9 months. The 8-year-old African-Brazilian patient with a circumscribed mass is alive and free of recurrence 8 years after diagnosis.

This case raises the question whether a periodic search for renal medullary carcinoma in young patients who have known abnormalities of the hemoglobin gene and hematuria could result in an early diagnosis and a better survival.
Expanding the Histologic Spectrum of Mucinous Tubular and Spindle Cell Carcinoma of the Kidney.

*Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY daggerDepartment of Pathology, The Johns Hopkins Hospital, Baltimore, MD double daggerDepartment of Pathology, Wellington School of Medicine, Wellington South, New Zealand section signDepartment of Pathology, Mayo Clinic, Rochester, MN.


Am J Surg Pathol. 2006 Dec;30(12):1554-1560. Abstract quote

Mucinous tubular and spindle cell carcinomas (MTSCs) are polymorphic neoplasms characterized by small, elongated tubules lined by cuboidal cells and/or cords of spindled cells separated by pale mucinous stroma. Nonclassic morphologic variants and features of MTSC have not been well studied.

We identified 17 previously unreported MTSCs from Surgical Pathology and consultative files of the authors and their respective institutions and studied their morphologic features. A total of 10/17 cases were considered "classic," as described above, with 5/10 showing at least focal (20% to 50%) tubular predominance without apparent mucinous matrix. Alcian blue staining revealed abundant (>50%) mucin in all classic cases. Seven of 17 MTSCs were classified as "mucin-poor," with little to no extracellular mucin appreciable by hematoxylin and eosin.

Four of these cases showed equal tubular and spindled morphology, 2 cases showed spindle cell predominance (70%; 95%), and 1 case showed tubular predominance (90%). In 5/7 mucin-poor cases, staining for Alcian blue revealed scant (<10%) mucin in cellular areas with the other 2 cases having 30% mucin. Unusual histologic features identified in the 17 cases were: foamy macrophages (n=8), papillations/well formed papillae (n=6/n=1), focal clear cells in tubules (n=3), necrosis (n=3), oncocytic tubules (n=2; 40%, 5%), numerous small vacuoles (n=2), heterotopic bone (n=1), psammomatous calcification (n=1), and nodular growth with lymphocytic cuffing (n=1).

An exceptional case contained a well-circumscribed, HMB45-positive angiomyolipoma within the MTSC. MTSCs may be "mucin-poor" and show a marked predominance of either of its principal morphologic components, which coupled with the presence of other unusual features such as clear cells, papillations, foamy macrophages, and necrosis, may mimic other forms of renal cell carcinoma.

Pathologists must be aware of the spectrum of histologic findings within MTSCs to ensure their accurate diagnosis.
Immunohistochemical Analysis of Mucinous Tubular and Spindle Cell Carcinoma and Papillary Renal Cell Carcinoma of the Kidney: Significant Immunophenotypic Overlap Warrants Diagnostic Caution.

Paner GP, Srigley JR, Radhakrishnan A, Cohen C, Skinnider BF, Tickoo SK, Young AN, Amin MB.

From the *Department of Pathology, Emory University Hospital, Atlanta, GA; daggerDepartment of Pathology, Credit Valley Hospital, Mississauga, Ontario, Canada; double daggerDepartment of Pathology, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada; section signDepartment of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY; and parallelDepartment of Pathology, Atlanta VA Medical Center, Atlanta, GA.

Am J Surg Pathol. 2006 Jan;30(1):13-19. Abstract quote  

Mucinous tubular and spindle cell carcinoma, a rare, recently described distinctive subtype of renal cell carcinoma, may have some morphologic similarities to the more common papillary renal cell carcinoma, particularly the basophilic (type 1) tumors with prominent solid growth pattern. Tumor circumscription, compact tubular architecture, focal papillations, mucin production and foam cells (features seen in both papillary renal cell carcinoma and mucinous tubular and spindle cell carcinoma), as well as spindle cell morphology, have resulted in some cases sent to us in consultation with a question of possible sarcomatoid papillary renal cell carcinoma.

In this study, tissue microarrays with triplicate samples each from 27 mucinous tubular and spindle cell carcinomas and 20 papillary renal cell carcinomas were created to simulate experience in renal biopsy specimens. From immunohistochemistry (IHC) data, published in the contemporary literature, a panel consisting of alpha-methylacyl-CoA racemase (AMACR), cytokeratin 7 (CK7), epithelial membrane antigen (EMA), renal cell carcinoma marker (RCC Ma), CD10, high molecular weight cytokeratin (HMWK), and c-kit was designed to test its utility in differential diagnosis. The immunoreactivity in mucinous tubular and spindle cell carcinoma was AMACR 93%, CK7 81%, EMA 95%, RCC Ma 7%, CD10 15%, HMWK 15%, and c-kit 5% and in papillary renal cell carcinoma was AMACR 95%, CK7 65%, EMA 88%, RCC Ma 25%, CD10 80%, HWMK 15%, and c-kit 18%. This largest study to date on IHC of mucinous tubular and spindle cell carcinoma dispels the specificity of AMACR for papillary renal cell carcinoma among the RCC subtypes. The histogenesis of mucinous tubular and spindle cell carcinoma from the distal nephron continues to be debatable, as our study showed the expression of the proximal convoluted tubule-related marker AMACR among these tumors.

Thus, in tumors with predominant compact tubular growth and focal papillary architectures, careful attention to the presence of a low-grade spindle cell population may be helpful in the distinction of mucinous tubular and spindle cell carcinoma, as the key immunohistochemical stains for papillary renal cell carcinoma are also expressed in this subtype of renal cell carcinoma.
Multilocular cystic renal cell carcinoma : a report of 45 cases of a kidney tumor of low malignant potential.

Suzigan S, Lopez-Beltran A, Montironi R, Drut R, Romero A, Hayashi T, Gentili AL, Fonseca PS, Detorres I, Billis A, Japp LC, Bollito E, Algaba F, Requena-Tapias MJ.

Laborclin Laboratory, Sao Jose do Rio Preto, Brazil.

Am J Clin Pathol. 2006 Feb;125(2):1-6. Abstract quote  

The 2004 World Health Organization (WHO) classification of kidney tumors recognizes multilocular cystic renal cell carcinoma (MCRCC) as a rare variant of clear cell renal cell carcinoma with a good prognosis. Available information on its clinical significance is limited.

The study cohort included 45 MCRCC cases classified according to 2004 WHO criteria obtained through a multi-institutional international search. Most patients had unilateral MCRCC with no side predominance that was found incidentally; 62% were men, but women had tumors at an earlier age (P = .385). MCRCC occurred slightly more often in men than in women (1.7:1). At diagnosis, 82% of patients had stage T1 and 16%, stage T2; 1 patient had stage T3. The Fuhrman grade was 1 (62%) or 2 (38%), with smaller tumors ( pound4 cm) most likely Fuhrman grade 1 (P = .911). All 45 patients were alive with no evidence of disease at mean follow-up of 66.1 months, confirming an extremely good prognosis after surgery and a 5-year disease-specific survival rate of 100%.

To rename this tumor as multilocular cystic renal cell neoplasm of low malignant potential might help urologists approach the patients conservatively.
Adult Papillary Renal Tumor With Oncocytic Cells: Clinicopathologic, Immunohistochemical, and Cytogenetic Features of 10 Cases.

Lefevre M, Couturier J, Sibony M, Bazille C, Boyer K, Callard P, Vieillefond A, Allory Y.

From the Departments of Pathology, *Tenon, double daggerCochin, section signHenri Mondor, paragraph signLariboisiere Hospitals, Assistance Publique-Hopitaux de Paris; the daggerDepartment of Genetics, Institut Curie, Paris, and the parallelEMI 337, INSERM, Creteil, France.
Am J Surg Pathol. 2005 Dec;29(12):1576-1581. Abstract quote  

We report a series of 10 oncocytic renal papillary tumors, with the aim of determining their clinicopathologic features. All patients were male (median age, 71 years), treated by radical nephrectomy and free of recurrence or metastasis (median follow-up, 62 months).

Tumors (median size, 3.3 cm) were intrarenal and well limited, with no extrarenal extension. They consisted of thin, nonfibrotic papillae lined by a single layer of oncocytic cells, with finely granular eosinophilic cytoplasm and round regular nucleus exhibiting central nucleolus (Fuhrman grade II, except for one grade III). Foci of necrosis were present in most cases. All tumors were immunoreactive for alpha-methylacyl-coenzyme A racemase, vimentin, and CD10; 4 expressed renal cell carcinoma antigen and 3 cytokeratin 7. There were a low number of cytogenetic changes in the 5 analyzed cases (median, 4; range, 1-7), with no trisomy 7 or 17. Papillary architecture, necrosis, and immunohistochemical profiles argued against the diagnosis of oncocytoma and suggested our cases to be part of the papillary renal cell carcinoma group. However, the cases were atypical for type 1 papillary carcinoma (due to oncocytic cells and absence of trisomy 17) and for type 2 (due to a good outcome).

These results suggest that adult papillary renal tumors with oncocytic cells might be a distinct variant in the papillary renal cell carcinoma group.
C-kit expression in renal oncocytomas and chromophobe renal cell carcinomas.

Huo L, Sugimura J, Tretiakova MS, Patton KT, Gupta R, Popov B, Laskin WB, Yeldandi A, Teh BT, Yang XJ.
Hum Pathol. 2005 Mar;36(3):262-8. Abstract quote  

Summary C- kit encodes the membrane-bound tyrosine kinase KIT, whose expression has been identified in several types of human neoplasms. Recently, KIT has been reported to be a marker for chromophobe renal cell carcinoma (RCC) and renal angiomyolipoma. However, expression of this molecule has not been adequately studied in other renal tumors, particularly oncocytoma, which may morphologically resemble chromophobe RCC.

In this study, we analyzed c- kit messenger RNA (mRNA) levels in 17 chromophobe RCCs and 20 renal oncocytomas obtained from complementary DNA (cDNA) microarrays. Furthermore, comprehensive immunohistochemical analysis of KIT protein using a monoclonal antibody was performed in 226 renal tumors including chromophobe RCC (n = 40), oncocytoma (n = 41), clear-cell RCC (n = 40), renal angiomyolipoma (n = 29), and papillary RCC (n = 21) on tissue microarrays (TMAs) and was compared with immunostaining results from 25 chromophobe RCCs and 30 oncocytomas using standard sections. The staining intensity was semiquantitatively graded on a 3-tier scoring system. All chromophobe RCCs and oncocytomas showed significant overexpression of c- kit mRNA. The average increase of mRNA compared with normal kidney tissue was 7.4-fold for chromophobe RCCs and 7.4-fold for oncocytomas. Immunohistochemical expression of KIT was found in most chromophobe RCCs (95% in TMAs and 96% in conventional sections) and oncocytomas (88% in TMAs and 100% in conventional sections) but was infrequently observed in renal angiomyolipomas (17%), papillary RCCs (5%), and clear-cell RCCs (3%). Furthermore, the average KIT immunoreactivity in TMAs was stronger in chromophobe RCC (1.93) and oncocytoma (2.07) than in other subtypes of renal tumors tested, including angiomyolipomas (0.17), papillary RCCs (0.05), and clear-cell RCCs (0.03).

In conclusion, we found a significant elevation of c- kit mRNA by cDNA expression microarrays and overexpression of KIT protein by immunohistochemistry not only in chromophobe RCCs but also in oncocytomas. In contrast, immunohistochemical expression of KIT was not detected in most other types of renal cell tumors evaluated. The differential expression of c- kit in these renal tumors may have diagnostic and therapeutic implications.
Expression of RON Proto-oncogene in Renal Oncocytoma and Chromophobe Renal Cell Carcinoma.

Patton KT, Tretiakova MS, Yao JL, Papavero V, Huo L, Adley BP, Wu G, Huang J, Pins MR, Teh BT, Yang XJ.

*Department of Pathology, Northwestern University, Feinberg School of Medicine, and daggerDepartment of Pathology, University of Chicago Chicago, IL; Departments of double daggerPathology and section signUrology, University of Rochester, Rochester, NY; and paragraph signLaboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI.
Am J Surg Pathol. 2004 Aug;28(8):1045-1050. Abstract quote  

Recently, it was reported that RON proto-oncogene, encoding a receptor tyrosine kinase, was strongly expressed in renal oncocytomas but not in any renal cell carcinomas, including 5 chromophobe renal cell carcinomas, which morphologically resemble oncocytomas.

To determine its diagnostic value, we studied Ron protein expression by immunohistochemistry in a larger number of renal cell neoplasms with emphasis on chromophobe renal cell carcinomas. Tissue microarrays containing 141 renal cell neoplasms, including 55 oncocytomas and 52 chromophobe renal cell carcinomas, were constructed. In addition, conventional sections from 15 cases of oncocytoma and 5 cases of chromophobe renal cell carcinoma were analyzed. Immunohistochemistry was carried out with a monoclonal mouse anti-human Ron-alpha antibody. Staining intensity was scored on a 0 to 3 scale. Ninety-nine percent of oncocytomas (69 of 70) and 96% of chromophobe renal cell carcinomas (55 of 57) showed moderate to strong, diffuse cytoplasmic Ron immunoreactivity with intensities >/=2, while only 17% of other renal cell carcinoma subtypes stained with intensities >/=2.

Our study indicates that Ron immunostaining cannot be used to distinguish oncocytoma from chromophobe renal cell carcinoma.

The Ron Proto-oncogene Product Is a Phenotypic Marker of Renal Oncocytoma.

Rampino T, Gregorini M, Soccio G, Maggio M, Rosso R, Malvezzi P, Collesi C, Canton AD.

Am J Surg Pathol. 2003 Jun;27(6):779-85. Abstract quote

The proto-oncogene product Ron is the receptor for macrophage stimulating protein, a scatter factor that stimulates cell proliferation, prevents apoptosis, and induces an invasive cell phenotype.

We investigated the expression of Ron, Ki-67 (proliferation index), p53, and bcl-2 (proapoptotic and antiapoptotic proteins, respectively) in 50 renal tumors (19 clear cell carcinomas, 18 oncocytomas, 7 papillary cell carcinomas, 5 chromophobe cell carcinomas, and 1 carcinoma with sarcomatoid areas). In addition, we studied Ron in normal kidney and in the renal carcinoma cell line Caki-1. Immunostaining and Western blot showed Ron in normal kidney and in all oncocytomas but never in renal cell carcinomas or in Caki-1.

In addition, Western blot showed that Ron was expressed in phosphorylated, i.e., active, form. Bcl-2 was strongly expressed in oncocytomas, whereas Ki-67 and p53 were much less expressed in oncocytomas than in carcinomas. These results indicate in Ron a marker that differentiates oncocytoma from the other renal epithelial tumors.

We therefore think that Ron may prove to be a new tool for a sound and precise diagnosis of oncocytoma, a benign tumor that cannot always be distinguished from carcinomas at histologic examination. The overexpression of bcl-2, but not p53 in oncocytoma, suggests that the MSP/Ron system sustains the growth of oncocytoma by opposing apoptosis.

PAPILLARY Cuboidal or low columnar cells arranged in papillae
Psamomma bodies may be present
Nucleolar Grade But Not Fuhrman Grade is Applicable to Papillary Renal Cell Carcinoma.

*Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, Wellington, New Zealand daggerDepartment of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand.


Am J Surg Pathol. 2006 Sep;30(9):1091-1096 Abstract quote

This study was undertaken to determine the validity of Fuhrman grading in a series of papillary renal cell carcinomas (PRCCs), to examine the interrelationship and prognostic significance of the individual components of the grading system, and further to determine whether any observed predictive value was independent of other prognostic indicators.

Ninety cases of PRCC were studied. Fifty-nine tumors were of type 1 and 31 were of type 2. There were 33 TNM stage 1, 26 stage 2, 18 stage 3, and 12 stage 4 tumors, whereas division of cases according to pT category showed 14 pT1a, 20 pT1b, 25 pT2, 15 pT3a, 4 pT3b, and 11 pT4 tumors. Ten tumors were grade 1, 58 grade 2, and 22 grade 3 when predominant Fuhrman grade was assigned, whereas grading according to the high-power field containing the highest grade (focal grade) showed 40 grade 2, 49 grade 3, and 1 grade 4 tumors. Measurements of nuclear size (area, major axis, perimeter) and shape (shape factor, compactness) were undertaken using image analysis. Nuclear area ranged from 27.63 to 116.39 muM, major axis length 6.70 to 14.06 muM, and nuclear perimeter 20.05 to 41.77 muM. Shape factor ranged from 0.805 to 0.878 and compactness from 14.33 to 15.66. Predominant nucleolar grade using the criteria of the Fuhrman classification was nucleolar grade 1 for 13 tumors, nucleolar grade 2 for 56 tumors, and nucleolar grade 3 for 21 tumors. Focal nucleolar grade based on the high-power field showing the greatest degree of nuclear pleomorphism, was grade 2 for 38 tumors and grade 3 for 52 tumors. pT category, TNM stage, focal Fuhrman grade, and PRCC type were significantly associated with survival. Of the various measures of the components of the Fuhrman classification, only focal nucleolar grade was associated with survival, on univariate analysis.

On multivariate analysis, focal nucleolar grade and tumor diameter were independently associated with survival, whereas TNM stage retained significance independent of other parameters.

It is concluded that assessment of nucleolar prominence rather than Fuhrman grade is applicable for stratification of tumors within TNM stage or pT category for PRCC and that this should be based upon the high-power field showing the greatest degree of nuclear pleomorphism.
A distinct expression pattern and point mutation of c-kit in papillary renal cell carcinomas.

Lin ZH, Han EM, Lee ES, Kim CW, Kim HK, Kim I, Kim YS.

1Department of Pathology, Korea University Ansan Hospital, College of Medicine, Korea University, South Korea
Mod Pathol. 2004 Jun;17(6):611-6. Abstract quote

KIT is expressed not only in tumors derived from hematopoietic stem cells, melanocytes, germ cells, mast cells, and interstitial cells of Cajal, but also in other malignancies such as chromophobe renal cell carcinoma. This pattern of KIT expression prompted us to investigate the expression and mutation of c-kit gene exons 9, 11, 13, 17, and intron 17 in the different subtypes of renal cell carcinomas (n=66) and non-neoplastic kidneys (n=12).

We found that KIT showed strong immunoreactivity in the cytoplasm of papillary renal cell carcinomas (100%), but on the cell membranes of chromophobe renal cell carcinomas (100%). Interestingly, a specific point mutation of the c-kit intron 17 (T->A) was found only in papillary renal cell carcinomas (94%).

Our study demonstrates that the expression pattern and one mutation of c-kit may distinguish papillary renal cell carcinomas.

Gains of chromosomes 7, 17, 12, 16, and 20 and loss of Y occur early in the evolution of papillary renal cell neoplasia: a fluorescent in situ hybridization study.

Brunelli M, Eble JN, Zhang S, Martignoni G, Cheng L.

Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202-5120, USA.
Mod Pathol. 2003 Oct;16(10):1053-9. Abstract quote  

It has been suggested that gains of chromosomes 7 and 17 and loss of Y occur in renal papillary adenoma and that progression to papillary renal cell carcinoma is marked by gains of additional chromosomes, most frequently 12, 16, and 20. Previous studies have included very few lesions of <5 mm in diameter, a requirement of the present definition of papillary adenoma.

Ten papillary adenomas (ranging from 1 to 5 mm in diameter) from autopsy material and 10 surgically resected papillary renal cell carcinomas were studied with fluorescence in situ hybridization in paraffin sections using centromeric probes for chromosomes 7, 12, 16, 17, 20, and Y diluted 1:100 with tDenHyb1 buffer. The signals in 50 to 150 nuclei were counted in each tumor. Controls for all the probes were normal renal tissues from the same patients. Three or more signals per nucleus were frequently observed in papillary adenomas: chromosome 7 (range, 10 to 50%; > or = 30% in 9 of 10), 17 (range, 10 to 47%; > or = 30% in 7), 16 (range, 1 to 63%; > or = 10% in 5), 12 (range, 0 to 32%; > or =10% in 4), and 20 (range, 5 to 49%; > or = 10% in 5). Loss of the Y chromosome was observed in 80 to 90% of nuclei in 9 adenomas from males. Three or more signals were frequent in papillary renal cell carcinomas: chromosome 7 (range, 32 to 63%; > or =30% in 10 of 10), 17 (range, 28 to 61%; > or = 30% in 7), 16 (range, 0 to 45%; > or = 10% in 6), 12 (range, 1 to 37, > or = 10% in 5), 20 (range, 2 to 44%; > or = 10% in 4). No signal for Y was observed in 12 to 88% (> or = 81% in 6) of nuclei in 7 carcinomas from males. Statistical analysis showed no difference between adenomas and carcinomas.

Gains of chromosomes 7, 17, 16, 12, and 20 and loss of the Y chromosome occur early in the evolution of papillary renal cell neoplasia in tumors that are only a few millimeters in diameter. Progressive gains of these chromosomes do not appear to correlate with the transition from adenoma to carcinoma.

Morphologic typing of papillary renal cell carcinoma: Comparison of growth kinetics and patient survival in 66 cases

Brett Delahunt, MD, FRCPA, John N. Eble, MD, Margaret R.E. McCredie, PhD, Peter B. Bethwaite, PhD, FRCPA, John H. Stewart, MBChB, FRCP, A. Michael Bilous, MBChB, FRCPA

Hum Pathol 2001;32:590-595 Abstract quote

Whereas papillary renal cell carcinoma is now established as a subtype of renal cell neoplasia, division of these tumors into 2 distinctive morphotypes has been proposed. Type 1 tumors have cells with scanty pale cytoplasm arranged in a single layer on the basement membrane of papillary cores. In these tumors, psammoma bodies and foamy macrophages are frequently seen, and the tumors frequently express cytokeratin 7. Type 2 tumor cells have pseudostratified nuclei and usually have voluminous eosinophilic cytoplasm. Recent studies have supported this subclassification of papillary renal cell carcinoma by demonstrating differing genotypes for type 1 and 2 tumors. To further study the subclassification of papillary renal carcinoma, we compared clinical features, nuclear grade, stage, tumor growth kinetics, and survival in a series of 50 type 1 and 16 type 2 papillary renal cell carcinomas. Comparison of patient age at presentation, sex, and primary tumor size shows no significant difference between the 2 tumor types.

Type 1 tumors were of significantly lower Fuhrman grade (P = .0001) and higher Robson stage (P = .009) than type 2 tumors. There was no significant difference when tumors were staged according to the TNM classification. Assessment of tumor growth kinetics showed significantly different mean silver-staining nucleolar organizer region (AgNOR) scores and Ki-67 indices (AgNOR type 1, 3.83, type 2, 7.24, P = .0001; Ki-67 type 1, 3.17%, type 2, 6.01%, P = .0002). Multivariate analysis showed tumor type (P = .03), presence of metastases (P = .04), AgNOR score (P = .001), and Ki-67 index (P = .03) to be independently associated with survival.

These results provide evidence of the clinical utility of dividing papillary renal cell carcinomas into 2 types according to histologic characteristics.

Renal translocation carcinomas: clinicopathologic, immunohistochemical, and gene expression profiling analysis of 31 cases with a review of the literature.

HIA Val de Grace, Van Andel Research Institute, Paris, France.


Am J Surg Pathol. 2008 May;32(5):656-70. Abstract quote

We report clinicopathologic features of a large series of renal translocation carcinomas from a multicentric study. Diagnosis was performed by cytogenetic examination of fresh material and/or by immunochemistry with antibodies directed against the C-terminal part of transcription factor E3 (TFE3) and native transcription factor EB (TFEB) proteins. Clinical data, follow-up, and histologic features were assessed. Antibodies against CK7, CD10, vimentin, epithelial membrane antigen, AE1-AE3, E-cadherin, alpha-methylacyl-coenzyme A racemase, melan A, and HMB45 were tested on tissue microarrays. Whole-genome microarray expression profiling was performed on 4 tumors.

Twenty-nine cases were diagnosed as TFE3 and 2 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 1 had a history of renal failure. Mean size of the tumor was 6.9 cm. Thirteen cases were >/=pT3 stage. Twelve cases were N+ or M+. Mean follow-up was 29.5 months. Three patients presented metastases and 5 have died. Mixed papillary and nested patterns with clear and/or eosinophilic cells represented the most consistent histologic appearance, with common foci of calcifications regardless of the type of translocation. Using a 30 mn incubation at room temperature, TFE3 immunostainings were positive in only 82% of our TFE3 translocation carcinomas. Both TFE3 and TFEB renal translocation carcinomas expressed CD10 and alpha-methylacyl-coenzyme A racemase in all cases. An expression of E-cadherin was observed in two-third of cases. Cytokeratins were expressed in less than one-third of cases. Melanocytic markers were expressed at least weakly in all cases except two.

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.

Our results suggest that these differentially expressed genes may serve as novel diagnostic or prognostic markers.
Xp11 Translocation Renal Cell Carcinoma in Adults: Expanded Clinical, Pathologic, and Genetic Spectrum.

Departments of *Pathology †Oncology ¶Urology, The Johns Hopkins University, Baltimore, MD ‡Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY §Department of Pathology, Hackensack University Medical Center, Hackensack, NJ ∥Department of Pathology, University Hospital, Zürich Switzerland ♯Department of Pathology, Indiana University, Indianapolis, IN **Pathology, Hospital del Mar, Autonomous University of Barcelona ††Pathology, Hospital del Mar, Universitat Pompeu Fabra, Barcelona, Spain ‡‡Dep. de Anatomia Pathológica, Fac. De Ciências Médicas-UNICAMP, Brazil.


Am J Surg Pathol. 2007 Aug;31(8):1149-1160 Abstract quote

The recently recognized Xp11 translocation renal cell carcinomas (RCCs), all of which bear gene fusions involving the TFE3 transcription factor gene, comprise at least one-third of pediatric RCC. Only rare adult cases have been reported, without detailed pathologic analysis.

We identified and analyzed 28 Xp11 translocation RCC in patients over the age of 20 years. All cases were confirmed by TFE3 immunohistochemistry, a sensitive and specific marker of neoplasms with TFE3 gene fusions, which can be applied to archival material. Three cases were also confirmed genetically.

Patients ranged from ages 22 to 78 years, with a strong female predominance (F:M=22:6). These cancers tended to present at advanced stage; 14 of 28 presented at stage 4, whereas lymph nodes were involved by metastatic carcinoma in 11 of 13 cases in which they were resected. Previously not described and distinctive clinical presentations included dense tumor calcifications such that the tumor mimicked renal lithiasis, and obstruction of the renal pelvis promoting extensive obscuring xanthogranulomatous pyelonephritis. Previously unreported morphologic variants included tumor giant cells, fascicles of spindle cells, and a biphasic appearance that simulated the RCC characterized by a t(6;11)(p21;q12) chromosome translocation. One case harbored a novel variant translocation, t(X;3)(p11;q23). Five of 6 patients with 1 or more years of follow-up developed hematogenous metastases, with 2 dying within 1 year of diagnosis.

Xp11 translocation RCC can occur in adults, and may be aggressive cancers that require morphologic distinction from clear cell and papillary RCC. Although they may be uncommon on a percentage basis, given the vast predominance of RCC in adults compared with children, adult Xp11 translocation RCC may well outnumber their pediatric counterparts.

PRCC-TFE3 Renal Carcinomas: Morphologic, Immunohistochemical, Ultrastructural, and Molecular Analysis of an Entity Associated With the t(X;1)(p11.2;q21).

Argani P, Antonescu CR, Couturier J, Fournet JC, Sciot R, Debiec-Rychter M, Hutchinson B, Reuter VE, Boccon-Gibod L, Timmons C, Hafez N, Ladanyi M.

Am J Surg Pathol 2002 Dec;26(12):1553-66 Abstract quote

The reappraisal of genetically defined subsets of renal tumors can help to highlight the key pathologic features of specific neoplastic entities.

We report the morphologic, immunophenotypic, ultrastructural, and molecular features of 11 renal carcinomas bearing a t(X;1)(p11.2;q21) and/or the resulting PRCC-TFE3 gene fusion. The male/female ratio was 4:7. Ten patients were in the age range of 9-29 years and one was 64 years old (mean 21.3 years, median 15 years).

The predominant histologic pattern was nested, with islands of tumor cells compartmentalized by thin-walled capillary vasculature. Minor variations on this pattern yielded solid, acinar, alveolar, and tubular architecture. Papillary architecture was seen in nine cases, usually as a minor component. Neoplastic cells were typically characterized by irregularly shaped nuclei with vesicular chromatin and small nucleoli not visible with a 10x objective, and cytoplasm that ranged from clear to densely granular and eosinophilic. Mitoses were extremely rare; 5 were found in 900 high power fields examined from the 11 neoplasms.

The most distinctive immunohistochemical feature of these neoplasms was moderate to intense nuclear labeling for TFE3 protein. These tumors were also consistently immunoreactive for the RCC antigen (10 of 11) and CD10 (9 of 9), whereas cytokeratin and epithelial membrane antigen were negative in four cases and were positive focally in the others. Ultrastructurally, all of the six neoplasms examined showed features consistent with conventional-type (clear cell) renal carcinoma, although two demonstrated distinctive intracisternal microtubules. Both tumors tested contained PRCC-TFE3 fusion transcripts.

The differential diagnosis includes conventional-type papillary renal cell carcinoma, conventional-type (clear cell) renal carcinoma, and the ASPL-TFE3 renal carcinomas associated with the t(X;17)(p11.2;q25), with the latter two being morphologically the most similar to the t(X;1) renal carcinomas.

Aside from their distinctive clinicopathologic features described here, there is experimental evidence suggesting that these tumors may show differential sensitivity to certain chemotherapeutic agents.


Renal Cell Carcinoma With Rhabdoid Features

Neriman Gökden, M.D.; Oscar Nappi, M.D.; Paul E. Swanson, M.D.; John D. Pfeifer, M.D., Ph.D.; Robin T. Vollmer, M.D.; Mark R. Wick, M.D.; Peter A. Humphrey, M.D., Ph.D.

From the Lauren V. Ackerman Laboratory of Surgical Pathology (N.G., P.E.S., J.D.P., M.R.W., P.A.H.), Barnes–Jewish Hospital and the Washington University School of Medicine, St. Louis, MO, U.S.A.; Laboratory Medicine (R.T.V.), VA and Duke University Medical Centers, Durham, NC, U.S.A.; and the Department of Pathology (O.N.), Cardarelli Hospital and the University of Naples, Italy.

Am J Surg Pathol 2000;24:1329-1338 Abstract quote

Neoplasms with rhabdoid features have been reported at many anatomic sites. In the kidney, rhabdoid tumors are typically found in children, whereas only rare examples have been reported in adults. Little is known of renal cell carcinomas (RCCs) that exhibit rhabdoid features.

The objective of this study was to determine the incidence of RCC with rhabdoid attributes and characterize the histologic, immunophenotypic, and ultrastructural features by retrospective analysis of 480 consecutively identified cases of RCC in radical nephrectomy specimens.

Immunohistochemical evaluation was performed in cases with rhabdoid foci using a panel of antibodies to pan-cytokeratin (pan-CK), CK7, CK20, epithelial membrane antigen (EMA), S-100 protein, desmin, vimentin, neuron-specific enolase (NSE), muscle-specific actin (MSA), smooth muscle actin (SMA), human melanoma, black-45 (HMB-45), and glial fibrillary acidic protein (GFAP). Electron microscopy was also performed in selected cases. The presence and extent of rhabdoid foci in relation to pathologic stage and grade were assessed. Twenty-three of 480 cases of RCC (4.7%) exhibited rhabdoid features. The 23 patients were all adults with a mean age of 61.8 years (age range, 33–84 yrs). Fifteen of the patients were men and eight were women.

Histologically, the rhabdoid foci were typified by sheets and clusters of variably cohesive, large epithelioid cells with vesicular and often eccentric nuclei, prominent nucleoli, and large, paranuclear intracytoplasmic hyaline globules (inclusions). The presence of these rhabdoid features was related to high histologic Fuhrman grade of the nonrhabdoid carcinoma component, with an incidence of 0 of 84 grade 1 cases, eight of 300 grade 2 cases (2.6%), six of 70 grade 3 cases (8.9%), and nine of 26 grade 4 cases (34.6%; p = 3 ×10–9). The rhabdoid foci were all high grade. The presence of rhabdoid foci was also found in higher stage carcinomas. A total of 52% (12 of 23) of RCC cases with rhabdoid features exhibited extrarenal extension compared with 28% (24 of 92) of contemporary RCCs without rhabdoid features (p = 0.03). The size of the rhabdoid component ranged from 1 mm to more than 2 cm and comprised 1% to 50% of the renal mass. Immunoreactivity for vimentin (100%), NSE (79%), and pan-CK (56%) was present in the majority of cases. Substantial percentages of cases were immunopositive for EMA (47%) and S-100 protein (37%), with minimal to no immunohistochemical reactivity for CK7 (5%), SMA (5%), CK20 (0%), desmin (0%), MSA (0%), HMB-45 (0%), and GFAP (0%). A distinctive globular, paranuclear reaction pattern was found for the cytokeratin, EMA, and vimentin immunostains. Ultrastructurally, the rhabdoid cells had paranuclear intermediate filament aggregates or paranuclear condensation of organelles, often associated with peripheral vacuolization. Adult RCCs may harbor a rhabdoid component, and these neoplasms can be regarded as ``composite'' tumors. Rhabdoid elements are important to identify because of their high-grade nature, and association with high stage.

Adult RCC with rhabdoid elements should be distinguished from pure rhabdoid tumors of kidney, in light of their clinicopathologic differences. Rhabdoid differentiation in adult renal cell carcinoma may represent clonal divergence and/or evolution, and emergence of a particularly aggressive element.


Sarcomatoid renal cell carcinoma: an examination of underlying histologic subtype and an analysis of associations with patient outcome.

Cheville JC, Lohse CM, Zincke H, Weaver AL, Leibovich BC, Frank I, Blute ML.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
Am J Surg Pathol. 2004 Apr;28(4):435-41. Abstract quote  

A sarcomatoid component can occur in all histologic subtypes of renal cell carcinoma (RCC) and indicates an aggressive tumor.

We studied 2381 patients treated with radical nephrectomy for RCC between 1970 and 2000. A urologic pathologist reviewed the microscopic slides from all tumor specimens for the presence of a sarcomatoid component, defined as a RCC with any malignant spindle cell component. All tumors with a sarcomatoid component were classified as nuclear grade 4. A total of 120 (5.0%) patients had RCC with a sarcomatoid component, including 94 who died of RCC at a mean of 1.4 years following nephrectomy (median 8 months; range 44 days to 10 years). Cancer-specific survival rates at 2 and 5 years following nephrectomy were 33.3% and 14.5%, respectively.

The presence of distant metastases at the radical nephrectomy and histologic tumor necrosis were significantly associated with death from RCC among patients with sarcomatoid RCC. Patients with clear cell (conventional) RCC and chromophobe RCC were more likely to have tumors with a sarcomatoid component (5.2% and 8.7%, respectively) compared with patients with papillary RCC (1.9%).

The presence of a sarcomatoid component was significantly associated with death from RCC for all three subtypes (P < 0.001). Even among patients with grade 4 clear cell RCC, the presence of a sarcomatoid component was significantly associated with outcome, both univariately (risk ratio 1.59; P = 0.010) and after adjusting for TNM stage, tumor size, and histologic tumor necrosis (risk ratio 1.46; P = 0.037).
Sarcomatoid renal cell

Am J Surg Pathol 2001;25:275-284 (Abstract quote)

Of 952 consecutively histologically subtyped renal cell carcinomas, the incidence of sarcomatoid differentiation was 8% in conventional (clear cell) renal carcinoma, 3% in papillary renal carcinoma, 9% in chromophobe renal carcinoma, 29% in collecting duct carcinoma, and 11% in unclassified renal cell carcinoma.

One hundred one renal cell carcinomas with sarcomatoid change were studied, and clinicopathologic parameters were correlated with outcome. The mean age of patients was 60 years (range, 33–80 years), and the male-to-female ratio was 1.6:1. The median tumor size was 9.2 cm (range, 3–25 cm). The primary histologic subtype of the carcinoma component was conventional (clear cell) renal carcinoma in 80 cases, papillary renal carcinoma in eight, chromophobe renal carcinoma in seven, collecting duct carcinoma in two, and unclassified renal cell carcinoma in four.

The sarcomatoid component resembled fibrosarcoma in 54 cases, malignant fibrous histiocytoma in 44, undifferentiated sarcoma (not otherwise specified) in three with focal rhabdomyosarcomatous component in two of them. The spindled elements accounted for 1% to 99% of the sampled tumor (median, 40%; mean 45%). The histologic grade of the spindled elements was intermediate to high in 92 cases and low in nine cases. Most cases were TNM stages III and IV (seven stage I, six stage II, 63 stage III, and 25 stage IV).

Follow-up was available in 88 patients; 61 (69%) patients died of disease and had a median survival time of 19 months. Distant metastases, most frequently to the lungs, were documented in 51 (66%) of 77 patients who had available clinical information regarding distant metastasis. The disease-specific survival rate was 22% and 13% after 5 and 10 years, respectively, compared with a cohort of renal cell carcinomas without sarcomatoid change with a 5-and 10-year disease-specific survival of 79% and 76%, respectively. Kaplan–Meier survival analysis showed that tumors with high TNM stage (p = 0.0027), at least 50% sarcomatoid component (p = 0.0453), and angiolymphatic invasion (p = 0.0282) were associated with decreased survival rates.

The primary histologic subtype of the carcinoma component and the type and grade of the sarcomatoid component did not affect survival.
In a Cox proportional hazard regression model, TNM stage appeared to be the only significant variable in predicting outcome among renal cell carcinomas with sarcomatoid change (p = 0.018; risk ratio, 6.984 and 8.439).
Compared with a cohort of renal cell carcinomas without sarcomatoid change, sarcomatoid tumors tended to present at a more advanced stage (p = 0.0001). Also, when adjusted for stage, necrosis, and tumor size, patients with tumors with sarcomatoid differentiation had a worse prognosis than did patients with tumors without sarcomatoid change (p = 0.0001)

Sarcomatoid change in renal cell carcinoma portends a worse prognosis. Because tumors with even a small component of sarcomatoid change may have an adverse outcome, this finding, when present, should be noted in the surgical pathology report.


PAS with diastase sensitivty
Reveals glycogen within the clear cells
Sudan black, oil red o Reveals fat within the clear cells

Tumor classification by tissue microarray profiling: random forest clustering applied to renal cell carcinoma.

Shi T, Seligson D, Belldegrun AS, Palotie A, Horvath S.

[1] 1Department of Human Genetics, University of California, Los Angeles, CA, USA [2] 2Department of Biostatistics, University of California, Los Angeles, CA, USA.
Mod Pathol. 2005 Apr;18(4):547-57 Abstract quote.  

We describe a novel strategy (random forest clustering) for tumor profiling based on tissue microarray data. Random forest clustering is attractive for tissue microarray and other immunohistochemistry data since it handles highly skewed tumor marker expressions well and weighs the contribution of each marker according to its relatedness with other tumor markers. This is the first tumor class discovery analysis of renal cell carcinoma patients based on protein expression profiles.

The tissue array data contained at least three tumor samples from each of 366 renal cell carcinoma patients. The eight tumor markers explore tumor proliferation, cell cycle abnormalities, cell mobility, and the hypoxia pathway. Since the procedure is unsupervised, no clinicopathological data or traditional classifications are used a priori. To explore whether the tissue microarray data can be used to identify fundamental subtypes of renal cell carcinoma patients, we first carried out random forest clustering of all 366 patients. By analyzing the tumor markers simultaneously, the procedure automatically detected classes that correspond to clear- vs non-clear cell tumors (demonstration of proof-of-principle). The resulting molecular grouping provides better prediction of survival (logrank P=0.000090) than this classical pathological grouping (logrank P=0.023). We then sought to extend the class discovery by searching for finer subclasses of clear cell patients.

The procedure automatically discovered: (a) two classes corresponding to low- and high-grade patients (demonstration of proof-of-principle); (b) a subgroup of long-surviving clear cell patients with a distinct molecular profile and (c) two novel tumor subclasses in low-grade clear cell patients that could not be explained by any clinicopathological variables (demonstration of discovery).

Beta defensin-1, parvalbumin, and vimentin: a panel of diagnostic immunohistochemical markers for renal tumors derived from gene expression profiling studies using cDNA microarrays.

Young AN, De Oliveira Salles PG, Lim SD, Cohen C, Petros JA, Marshall FF, Neish AS, Amin MB.

Am J Surg Pathol 2003 Feb;27(2):199-205 Abstract quote

The common histopathologic subtypes of renal epithelial neoplasms include conventional, or clear cell, renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, and renal oncocytoma. These subtypes differ clinically and pathologically, making accurate classification important. However, this differential diagnosis can be challenging because of overlapping morphology, suggesting a potential utility for ancillary immunohistochemical markers.

We used cDNA microarrays to identify candidate markers for distinguishing renal tumor subtypes. In this report we validated differential expression of three candidate markers, beta defensin-1, parvalbumin, and vimentin, and evaluated the use of this immunohistochemical panel as a potential diagnostic tool.

Consistent with our cDNA microarray data, chromophobe RCCs and oncocytomas exhibited similar expression profiles: 8 of 8 examples of each subtype were immunohistochemically positive for beta defensin-1 and parvalbumin and negative for vimentin (sensitivity 100%, specificity 100%); 4 of 7 papillary RCCs were positive for beta defensin-1, parvalbumin, and vimentin (sensitivity 57%, specificity 97%); and 22 of 23 conventional RCCs were negative for beta defensin-1, parvalbumin, or both markers (sensitivity 96%, specificity 96%) as well as positive for vimentin (sensitivity 83%). The immunohistochemical panel distinguished renal tumor subtypes with greater specificity than any marker used alone.

This work demonstrates that a useful panel of immunohistochemical markers can be derived from differential gene expression profiles determined using cDNA microarrays.


Expression of Alpha-Methylacyl-CoA Racemase in Papillary Renal Cell Carcinoma.

Tretiakova MS, Sahoo S, Takahashi M, Turkyilmaz M, Vogelzang NJ, Lin F, Krausz T, Teh BT, Yang XJ.

Departments of Pathology and dagger Medicine, University of Chicago, Chicago, IL; double dagger Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI; and section sign Department of Pathology, Geisinger Health System, Danville, PA.

Am J Surg Pathol. 2004 Jan; 28(1): 69-76. Abstract quote  

SUMMARY: Alpha-methylacyl-CoA racemase (AMACR) was first discovered by using cDNA microarray technology as a molecular marker for prostate cancer. Our recent microarray analysis of renal cell carcinomas showed a significant increase of AMACR mRNA levels in papillary renal cell carcinomas, but not in other subtypes.

To investigate the value of this marker in pathologic diagnosis, we analyzed AMACR mRNA levels in cDNA microarrays from 70 kidney tumors. Furthermore, we evaluated the AMACR expression in 165 kidney tumors on tissue microarrays and 51 papillary carcinomas of other organs by immunohistochemistry. AMACR mRNA was significantly overexpressed in 7 of 8 papillary renal cell carcinomas with an average of 5.2-fold increase, and only in 2 of 62 nonpapillary kidney tumors.

Immunohistochemistry demonstrated strong AMACR positivity in all cases of papillary renal cell carcinomas (41 of 41, 100%), including 6 metastatic papillary renal cell carcinomas, but only focal or weak reactivity in the minority (18 of 124, 15%) of other renal tumors including 13 of 52 clear cell renal cell carcinomas, 3 of 20 oncocytomas, and 2 of 17 urothelial carcinomas. All chromophobe (0 of 18) and sarcomatoid components of renal cell carcinomas (0 of 15) were negative for AMACR. Weak or focal AMACR immunoreactivity was detected in only 4 of 51 (8%) papillary carcinomas arising in other organs (2 of 14 thyroid, 2 of 13 lung, 0 of 6 breast, 0 of 6 endometrium, 0 of 6 ovary, and 0 of 6 pancreas).

Using a combination of cDNA microarrays, tissue microarrays, and immunohistochemistry, we identified AMACR as a marker for papillary renal cell carcinoma, which could be valuable in subclassification of renal cell carcinomas and in the differential diagnosis of a metastatic papillary carcinoma.
Distribution of Cytokeratins and Vimentin in Adult Renal Neoplasms and Normal Renal Tissue: Potential Utility of a Cytokeratin Antibody Panel in the Differential Diagnosis of Renal Tumors.

Skinnider BF, Folpe AL, Hennigar RA, Lim SD, Cohen C, Tamboli P, Young A, de Peralta-Venturina M, Amin MB.

From the *Department of Pathology, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada; daggerDepartment of Pathology, Emory University School of Medicine, Atlanta, GA; double daggerDepartment of Pathology, William Beaumont Hospital, Detroit, MI; and the section signDepartment of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX.

Am J Surg Pathol. 2005 Jun;29(6):747-754. Abstract quote  

Adult renal epithelial neoplasms (RENs) comprise several distinct clinicopathologic entities with potential prognostic and therapeutic differences. Individual cases can show overlapping morphologic features, necessitating the use of ancillary methods.

The purpose of this study was to determine the diagnostic utility of cytokeratin (CK) subtype expression pattern in a wide range of adult RENs. RENs (including clear cell [conventional] renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, renal oncocytoma, collecting duct carcinoma (CDC), renal medullary carcinoma (RMC), urothelial carcinoma, metanephric adenoma (MA), tubulocystic carcinoma (TC) (also known as low-grade collecting duct carcinoma), and mucinous tubular and spindle cell carcinoma) were immunostained for CK subtypes (CK5/CK6, 7, 8, 13, 14, 17, 18, 19, 20), high molecular weight CKs 1, 5, 10, 14 (HMWCK), and vimentin (Vim). The expression pattern of normal kidney was also examined and correlated with RENs. Although there is some overlap, subtypes of RENs show distinctive CK expression profiles that may be useful in several differential diagnostic settings. Clear cell RCCs typically showed a restricted expression pattern of CK8, CK18 and Vim. Papillary RCCs typically expressed CK7, CK8, CK18, CK19, and Vim and could be distinguished from MA (CK7-). Chromophobe RCCs were typically CK7+, CK8+, CK18+, and Vim-, and could be distinguished from oncocytomas (typically CK7-).

In oncocytomas, nonspecific staining of unblocked endogenous biotin is a potentially significant diagnostic pitfall. CDC, RMC, and TC demonstrated similar CK expression profiles (with the exception of HMWCK expression limited to CDC), supporting a close relationship between these entities. A panel of CK5/CK6, CK17, and Vim may be helpful in distinguishing CDC (typically CK5/CK6-, CK17-, Vim+) and urothelial carcinoma (typically CK5/CK6+, CK17+, Vim-).

In conclusion, CK expression patterns may be helpful in several differential diagnostic situations when dealing with adult RENs.

Expression of MUC1 (EMA) and E-cadherin in renal cell carcinoma: a systematic immunohistochemical analysis of 188 cases.

Langner C, Ratschek M, Rehak P, Schips L, Zigeuner R.

Institute of Pathology, University of Graz, Medical School, Graz, Austria.
Mod Pathol. 2004 Feb;17(2):180-8 Abstract quote.  

MUC1 (epithelial membrane antigen) is a membrane-associated mucin known to interfere with both cell-cell and cell-matrix adhesions. Overexpression has been associated with poor prognosis in a variety of cancers.

We investigated the expression of MUC1 (using two different antibodies, MA695 and E29) and E-cadherin in renal cell carcinomas (137 conventional, 23 chromophobe, 20 papillary, and eight unclassified tumors) with respect to diagnostic and prognostic significance using a tissue microarray technique.

Immunoreactivity was correlated with histological subtype, pT-stage, and grade using the chi2 test or the Fisher's exact test, respectively. Impact on disease-free survival was analyzed using the Kaplan-Meier method and the log-rank test. Immunoreactivity of more than 10% of cancer cells with MA695, E 29, and E-cadherin antibodies was found in 112/133 (84%), 86/133 (65%), and 7/131 (5%) conventional, 20/22 (91%), 19/22 (86%), and 21/22 (95%) chromophobe, 13/20 (65%), 8/20 (40%), and 3/20 (15%) papillary as well as 5/8 (63%), 5/8 (63%), and 4/8 (50%) unclassified carcinomas, respectively. The two different MUC1 antibodies yielded comparable staining results. A diffuse cytoplasmic staining pattern for MUC1 was found exclusively in chromophobe carcinomas, whereas conventional and papillary subtypes showed predominantly membranous staining (P<0.0001).

Regarding papillary carcinomas, MUC1 was predominantly associated with type 1 (P=0.0001), and E-cadherin with type 2 (P=0.049) tumors. The cellular staining pattern of MUC1 in conventional tumors was related to pT-stage (P=0.002) and tumor grade (P=0.001): Low-stage (pT1/pT2) and grade (G1/G2) tumors showed a predominantly apical membranous staining, high-stage (pT3a/pT3b) and grade (G3/G4) tumors a predominantly circumferential membranous staining (with or without additional diffuse cytoplasmic immunoreactivity), which, in the conventional subtype, was associated with poor prognosis (P<0.0001).

In conclusion, MUC1 and E-cadherin are diagnostically and prognostically useful markers in renal tumor pathology, especially when cellular staining patterns are considered.
Expression of Epithelial Cell Adhesion Molecule (EpCam) in Renal Epithelial Tumors.

Went P, Dirnhofer S, Salvisberg T, Amin MB, Lim SD, Diener PA, Moch H.

From the *Institute of Pathology, University of Basel, Basel, Switzerland; daggerInstitute of Pathology, Kantonsspital, St. Gallen, Switzerland; double daggerEmory University, School of Medicine, Atlanta, GA; and section signDepartment of Pathology, University Hospital, Zurich, Switzerland.

Am J Surg Pathol. 2005 Jan;29(1):83-88. Abstract quote

EpCam is an epithelial adhesion molecule expressed in a broad range of carcinomas. Clinical trials with specific humanized anti-EpCam antibodies have shown promising results and have been inaugurated in renal cell carcinoma (RCC) therapy.

To study the EpCam expression profile, primary renal cell neoplasms as well as corresponding metastases were evaluated by immunohistochemistry in tissue microarrays. EpCam expression in oncocytomas and chromophobe RCCs was determined on conventional large sections. Moderate or strong EpCam expression was found in eighteen percent of clear cell (n = 147), 75% of chromophobe (n = 12), and 55% of papillary RCCs (n = 20), but not in oncocytomas (n = 3). On large sections, 90% of chromophobe RCCs (n = 20) showed a strong and homogeneous positivity, whereas oncocytomas (n = 15) revealed EpCam positivity in single tumor cells or small clusters. Fourteen percent of RCC metastases (n = 97) showed EpCam expression. Patients with EpCam expressing clear cell RCC showed a trend toward a better prognosis in a Cox regression analysis including stage, grade, and necrosis.

The data suggest EpCam as a potential therapeutic target in a subset of patients with RCC. In addition, expression patterns of EpCam could become a helpful tool in the discrimination of chromophobe RCC and oncocytoma.
Overexpression of glutathione s-transferase a in clear cell renal cell carcinoma.

Chuang ST, Chu P, Sugimura J, Tretiakova MS, Papavero V, Wang K, Tan M, Lin F, Teh BT, Yang XJ.

Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL.
Am J Clin Pathol. 2005 Mar;123(3):421-9. Abstract quote  

To determine its diagnostic value, we evaluated glutathione S-transferase a (GST-a) expression in a large number of renal cell carcinomas (RCCs).

GST-a messenger RNA (mRNA) levels from 70 renal neoplasms were analyzed with complementary DNA (cDNA) microarray chips containing 21,632 cDNA clones. Furthermore, 348 primary renal tumors and 24 metastatic RCCs were subjected to immunohisto-chemical analysis with a GST-a-specific antibody. GST-a mRNA was elevated significantly (11.4-fold) in a majority of clear cell RCCs (28/43 [65.1%]; 28/39 [71.8%] with adjustments for informative spots) compared with other kidney tumors (1/27 [3.7%]).

Strong and diffuse GST-a immunoreactivity was demonstrated in a majority of clear cell (166/202 [82.2%]; mean intensity, 2.41) and metastatic clear cell RCCs (17/24 [70.8%]; mean intensity, 2.62). Other renal tumor types did not exhibit significant GST-a immunoreactivity, confirming mRNA results.

Through cDNA microarrays and immunohistochemical analysis, we demonstrated GST-a as a biomarker for clear cell RCCs.
Human Kidney Injury Molecule-1 (hKIM-1): A Useful Immunohistochemical Marker for Diagnosing Renal Cell Carcinoma and Ovarian Clear Cell Carcinoma.

*Department of Laboratory Medicine, Geisinger Medical Center, 100 N. Academy Avenue, Danville, PA 17822 daggerDepartment of Pathology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 double daggerShanghai Institute of Cardiovascular Disease, Shanghai Zhongshan Hospital, Fudan University, Shanghai, P. R. of China section signDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 parallelDepartment of Pathology and Immunology, Washington University in St Louis, St Louis, MO 63110-1093 paragraph signDepartment of Pathology, The Methodist Hospital, Affiliated with Weil Medical College of Cornell University, Houston, TX 77030 musical sharpVan Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503

Am J Surg Pathol. 2007 Mar;31(3):371-381. Abstract quote

Human kidney injury molecule-1 (hKIM-1), a type I transmembrane glycoprotein expressed in injured renal proximal tubules, was also found in renal cell carcinoma (RCC).

The current study attempts to evaluate the diagnostic utility of hKIM-1 in a large series of 480 neoplasms including defined subtypes of renal cell tumors, metastatic RCCs, and nonrenal tumors. Tissue microarray (TMA) sections containing 179 renal cell tumors (73 clear cell RCC, 30 papillary RCC, 16 chromophobe RCC, 15 oncocytoma, and 45 metastatic RCC) were included in this study. In addition, 80 cases of renal cell neoplasm and 221 nonrenal tumors in routine tissue sections were also included. Both TMA and routine sections were incubated with anti-hKIM-1 monoclonal antibody using an EnVision-HRP kit.

The results demonstrated that a membranous/cytoplasmic staining pattern for hKIM-1 was observed in 54 of 73 (74%) clear cell RCCs and 28 of 30 (93%) papillary RCCs on TMA sections. Zero of 54 chromophobe RCCs and 4 of 41 (9.75%) oncocytomas were positive for hKIM-1 when combining TMA and routine sections. Similar staining results were observed in 35 of 45 (78%) metastatic RCCs. Data from cDNA microarray expression and Western blot demonstrated similar findings. Fifteen of 16 cases (93.8%) of clear cell carcinoma of the ovary demonstrated positive reactivity for hKIM-1.

These data indicate that hKIM-1: (1) is a relatively sensitive and specific marker for papillary, clear cell, and metastatic RCCs, (2) can be used to distinguish clear cell from chromophobe RCC, and (3) may serve as a diagnostic marker for clear cell carcinoma of the ovary.

Inhibin alpha distinguishes hemangioblastoma from clear cell renal cell carcinoma.

Hoang MP, Amirkhan RH.

Am J Surg Pathol. 2003 Aug;27(8):1152-6 Abstract quote

Inhibin alpha subunit (inhibin A) expression in hemangioblastomas has not been previously reported in the literature.

We analyzed the expression of inhibin A in 25 hemangioblastomas from 22 patients. Eleven cases were from 8 patients with von Hippel-Lindau disease, and these tumors were multicentric and/or recurrent. The remaining 14 cases from 14 patients were sporadic. The male-to-female ratio was 8:3, and the age at presentation ranged from 19 to 78 years (mean 35 years; median 45 years). Eighteen tumors were located in the cerebellum/posterior fossa, 1 in the medulla, 1 in the occipital lobe, and 5 in the spinal cord. Four metastatic renal cell carcinomas in brain, 10 renal cell carcinomas from 8 patients with von Hippel-Lindau disease, and 5 sporadic clear cell renal cell carcinomas were also included. Two patients with von Hippel-Lindau disease had both renal cell carcinoma and hemangioblastoma. The stromal cells of all 25 cases of hemangioblastoma expressed inhibin A. Strong, moderate, and weak cytoplasmic immunoreactivity was noted in 17, 5, and 3 cases, respectively. In contrast, none of the 19 renal cell carcinomas, primary as well as metastatic, expressed inhibin A. There was no difference in the inhibin A staining pattern between the sporadic hemangioblastoma and those associated with VHL.

These findings demonstrate inhibin A to be a useful marker in distinguishing hemangioblastoma from metastatic clear cell renal cell carcinoma. While the diagnostic importance is evident, the pathophysiology of inhibin A expression by the stromal cells of hemangioblastoma remains unknown and further investigation is required.


Parvalbumin Is Constantly Expressed in Chromophobe Renal Carcinoma

Guido Martignoni, M.D., Maurizio Pea, M.D., Marco Chilosi, M.D., Matteo Brunelli, M.D., Aldo Scarpa, M.D., Chiara Colato, M.D., Regina Tardanico, M.D., Giuseppe Zamboni, M.D. and Franco Bonetti, M.D.

Dipartimento di Patologia-Sezione Anatomia Patologica (GMMP, MC, MB, AS, CC, GZ, FB), Università di Verona, Verona, Italy; Istituto di Anatomia Patologica, Università di Brescia (RT), Brescia, Italy

Mod Pathol 2001;14:760-767 Abstract quote

Chromophobe renal carcinoma is composed of neoplastic cell showing several features similar to those found in the intercalated cells of the collecting ducts. Because the distal nephron expresses calcium-binding proteins playing a role in calcium homeostasis, we reasoned that these proteins could be expressed by chromophobe carcinoma and therefore represent a diagnostic marker.

We studied the immunohistochemical expression of different calcium-binding proteins (parvalbumin, calbindin-D28K, and calretinin) in 140 renal tumors, including 75 conventional (clear cell) carcinomas, 32 chromophobe carcinomas, 17 papillary renal cell carcinomas, and 16 oncocytomas.

Parvalbumin was strongly positive in all primary chromophobe carcinomas and in one pancreatic metastasis; it was positive in 11 of 16 oncocytomas and absent in conventional (clear cell) and papillary renal cell carcinomas, either primary or metastatic. Calbindin-D28K and calretinin were negative in all tumors, with the exception of two chromophobe carcinomas, four oncocytomas, and two papillary renal cell carcinomas showing inconspicuous calretinin expression.

Our data demonstrate that parvalbumin may be a suitable marker for distinguishing primary and metastatic chromophobe carcinoma from conventional (clear cell) and papillary renal cell carcinoma. Moreover, they suggest a relationship between chromophobe renal carcinoma and renal oncocytoma and indicate that chromophobe carcinoma exhibits differentiation toward the collecting-duct phenotype.


Expression of CD9/motility-related protein 1 (MRP-1) in renal parenchymal neoplasms: Consistent expression in papillary and chromophobe renal cell carcinomas

Naoto Kuroda, MD
Keiji Inoue, MD
Limei Guo, MD, etal.


Hum Pathol 32:1071-1077 Abstract quote

CD9 is a glycoprotein that is abundant in hematopoietic cells. Recently, it has been reported that CD9 is also present in the human kidney.

In this article, we investigated the expression of CD9 using an immunohistochemical technique. We also studied the expression of CD9 protein and messenger RNA (mRNA) in tissue samples of some renal tumors using immunoblotting and reverse-transcription polymerase chain reaction (RT-PCR) analysis.

Immunohistochemically, all tumors of papillary and chromophobe renal cell carcinomas (RCCs) and oncocytomas expressed CD9. In addition, CD9 was expressed in 31 of 66 conventional RCCs and 1 of 4 collecting duct carcinomas. On immunoelectron microscopy, CD9 was identified on the plasma membrane of a conventional RCC. The presence of CD9 protein in normal kidneys and various renal tumors, except for a collecting duct carcinoma and an oncocytoma, was confirmed by immunoblotting. On RT-PCR analysis, the expression of CD9 mRNA was observed in 1 normal kidney, 2 conventional RCCs, and 1 oncocytoma. The frequency of immunohistochemical CD9 positivity was significantly higher in papillary and chromophobe RCCs than in collecting duct carcinomas and conventional RCCs, respectively.

These results suggest that CD9 may be a beneficial marker in the differential diagnosis between papillary RCCs and collecting duct carcinomas and also between chromophobe and conventional RCCs.


Diagnosing Primary and Metastatic Renal Cell Carcinoma The Use of the Monoclonal Antibody `Renal Cell Carcinoma Marker'

David K. McGregor, M.D. ; Kamal K. Khurana, M.D. ; Christine Cao, B.S. ; Chun Chui Tsao, M.D. ; Gustavo Ayala, M.D. ; Bhuvaneswari Krishnan, M.D. ; Jae Y. Ro, M.D. , Ph.D. ; Juan Lechago, M.D. , Ph.D. ; Luan D. Truong, M.D.

From the Departments of Pathology, Baylor College of Medicine (D.K.M., C.C.T., G.A., B.K., J.L., L.D.T.), Methodist Hospital (J.L., L.D.T.), VA Medical Center (B.K.), M.D. Anderson Cancer Hospital (J.Y.R.) Houston, Texas, and Upstate Medical University (K.K.K.), Syracuse, New York, U.S.A.

Am J Surg Pathol 2001;25:1485-1492 Abstract quote

The diagnosis of primary or metastatic renal cell carcinoma (RCC) can be difficult, especially in small biopsies, because of the wide variety of histologic appearances and clinical presentations that RCC can assume. An immunomarker specific for RCC is currently not available.

We tested the relevant diagnostic use of the Renal Cell Carcinoma Marker (RCC Ma), a monoclonal antibody, against a normal human proximal tubular brush border antigen. Immunostaining using RCC Ma and the avidin-biotin-peroxidase complex technique was performed on archival tissues from primary and metastatic tumors of renal or nonrenal origin. A total of 122 of 153 primary RCCs (79.7%) were positive [clear cell (84%), papillary (96%), chromophobe (45%), sarcomatoid (25%), and collecting duct (0%)], with 10% of tumor cells stained in 93% of cases. None of the 64 primary renal tumors other than RCC, including 15 oncocytomas, was positive. Fifteen of 146 (10.2%) nonrenal primary tumors were positive (5 of 17 breast tumors, 8 of 8 parathyroid adenomas, and 2 of 7 embryonal carcinomas). Forty-two of 63 (67%) metastatic RCCs were positive with 10% of cells being stained in 83% of them. Two of 108 (2%) metastases from tumors other than RCCs were positive, both of which were metastatic breast carcinomas; however, only 10% (2 of 19) of metastatic breast carcinomas were positive.

RCC Ma is an excellent marker for primary RCC, which should facilitate its diagnosis in a small biopsy. Although RCC Ma remains highly specific (98%) for metastatic RCC, a negative result may not rule out metastatic RCC because of a rather low sensitivity and a focal staining pattern in some of the positive cases. RCC Ma may also facilitate the differential diagnosis between oncocytoma and other types of RCC when they are composed mostly of eosinophilic cells.


Ultrastructural Observations on Mitochondria and Microvesicles in Renal Oncocytoma, Chromophobe Renal Cell Carcinoma, and Eosinophilic Variant of Conventional (Clear Cell) Renal Cell Carcinoma

Satish K. Tickoo, M.D.; Min W. Lee, M.D.; John N. Eble, M.D.; Mitual Amin, M.D.; Thomas Christopherson, B.S.; Richard J. Zarbo, M.D.; Mahul B. Amin, M.D. Sternberg SS, ed. Bostwick DG, Elble JN, eds. Tyler D, ed. Tyler D, ed.

Departments of Pathology, Henry Ford Hospital, Detroit, Michigan (S.K.T., M.W.L., M.A., T.C., R.J.Z.), Emory University Hospital, Atlanta, Georgia (M.B.A.), and Roudebush VA Medical Center, Indiana University, Indianapolis, Indiana (J.N.E.), U.S.A.

Am J Surg Pathol 2000;24:1247-1256 Abstract quote

On light microscopic examination, the morphologically overlapping features of granular eosinophilic cytoplasm in renal oncocytoma and the eosinophilic variants of chromophobe renal cell carcinoma and conventional (clear cell) renal cell carcinoma may pose difficulties in diagnosis.

We investigated the ultrastructure of 5 renal oncocytomas, 7 eosinophilic variants of chromophobe renal cell carcinoma, and 5 eosinophilic variants of conventional (clear cell) renal cell carcinoma. Special attention was paid to mitochondria and microvesicles and interrelations thereof. The electron microscopic features were correlated with the light microscopic findings.

All of the tumors had abundant mitochondria. Although abundant microvesicles were present in all of the chromophobe renal cell carcinomas, scant numbers of microvesicles were also sometimes present in renal oncocytomas (2 of 5) and in the eosinophilic variant of conventional (clear cell) renal cell carcinoma (1 of 5). The mitochondria in all three types of renal neoplasms studied differed in morphology, being predominantly uniform and round with predominantly lamellar cristae in renal oncocytoma, variable in shape and size with predominantly tubulocystic cristae in chromophobe renal cell carcinoma, and swollen and pleomorphic with rarefied matrix and attenuated cristae in the eosinophilic variant of conventional (clear cell) renal cell carcinoma. Variable numbers of mitochondria in all of the chromophobe renal cell carcinomas had outpouchings of the outer membranes, some of which carried parts of inner membrane within them. These outpouchings closely resembled the nearby cytoplasmic microvesicles, as did the tubulocystic cristae of the mitochondria. Some microvesicles contained homogeneous, electron-dense, finely granular matrix, similar to that seen in mitochondria. In one of seven chromophobe renal cell carcinomas, microvesicles were present in rough endoplasmic reticulum, and in two others, mitochondria were present within some vesicles. These features strongly suggest a close relationship between the microvesicles and mitochondria.

Based on the role of vesicle formation in normal mitochondriogenesis, and some of our observations, we propose that defective mitochondriogenesis may be the source of microvesicles in chromophobe renal cell carcinomas.

Renal epithelial neoplasms: The diagnostic implications of electron microscopic study in 55 cases

Bhuvaneswari Krishnan, MD
Luan D. Truong, MD

Hum Pathol 2002;33:68-79. Abstract quote

Several unsettled histogenetic, nosologic and diagnostic considerations for renal epithelial tumors may have ultrastructural ramifications. Yet, a comprehensive electron microscopic study of renal epithelial neoplasms, in light of the recent classification, is not available.

The ultrastructural findings from fifty-five renal epithelial neoplasms [31 clear cell renal cell carcinomas (RCC), 11 papillary RCC, 5 chromophobe RCC, 3 sarcomatoid RCC and 5 oncocytomas] were correlated with their light microscopic appearance. Clear cell RCC showed long microvilli similar to the brush border of the normal proximal tubules, with abundant cytoplasmic lipid and glycogen. Papillary RCC showed variably sized microvilli, and small amounts of cytoplasmic lipid, but no glycogen. Chromophobe RCC showed many cytoplasmic vesicles and abnormal mitochondria, with rare short and stubby microvilli. Renal oncocytoma showed many mitochondria with a few vesicles in the apical portion of the cytoplasm and rare short and stubby microvilli. The eosinophilic cell variants of clear cell RCC, papillary RCC and chromophobe RCC showed ultrastructural features similar to those of their respective prototypes, except for an increased numbers of mitochondria in the cytoplasm. One sarcomatoid clear cell RCC showed skeletal muscle differentiation. Two types of cytoplasmic inclusions, i.e. hyaline globules and granules similar to those in the Paneth cells (PC-like granules) were identified only in clear cell RCC, which displayed distinctive ultrastructural features.

The current EM study demonstrates distinctive ultrastructural features of renal epithelial neoplasms. The findings lend additional support to the current classification of the pertinent tumor types, facilitate the differential diagnoses, and provide insights into the possible histogenesis of renal epithelial neoplasms.



Primary Carcinoid Tumor Arising in a Mature Teratoma of the Kidney.

Yoo J, Park; S, Jung Lee H, Jin Kang S, Kee Kim B.

Department of Pathology, St Vincent's Hospital, Catholic University, South Korea.


Arch Pathol Lab Med 2002 Aug;126(8):979-981 Abstract quote

Primary carcinoid tumor, especially that arising in a mature teratoma of the kidney, is extremely rare; only 3 cases have been reported in the world literature to date. Because of the rarity of the lesion, its histogenesis and prognosis are unknown.

We report a case of primary renal carcinoid tumor occurring in a mature teratoma in a 30-year-old woman. A computed tomographic scan of the abdomen revealed a mass in the left kidney containing dense calcification with minimal contrast enhancement. Histologically, the tumor was composed of trabecular and anastomosing ribbonlike nests, identical to the features of carcinoid tumors of other sites. Immunohistochemical stainings were positive for cytokeratin, neuron-specific enolase, and chromogranin. In addition, there were mature teratoid tissues, such as columnar epithelium, smooth muscle, and bone.

The carcinoid tumor was under and closely apposed to the lining of the cysts. The patient did not have clinical manifestations of the carcinoid syndrome and had an uneventful recovery.

Renal Cystic Diseases: A REVIEW.

Bisceglia M, Galliani CA, Senger C, Stallone C, Sessa A.

From the *Division of Anatomic Pathology and the daggerDivision of Nephrology and Dialysis, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo (FG), Italy; the double daggerDepartment of Pathology, Cook Children's Medical Center, Fort Worth, TX; the section signDepartment of Pathology and Laboratory Medicine, Children's & Women's Health Centre of British Columbia, Vancouver, Canada; and the parallelDivision of Nephrology and Dialysis, City Hospital, Vimercate-Milan, Italy.

Adv Anat Pathol. 2006 Jan;13(1):26-56 Abstract quote.  

This review aims to assist in the categorization of inherited, developmental, and acquired cystic disease of the kidney as well as to provide a pertinent, up-to-date bibliography.

The conditions included are autosomal-dominant polycystic kidney disease, autosomal-recessive polycystic kidney disease, unilateral renal cystic disease (localized cystic disease), renal simple cysts, multicystic dysplastic kidney, pluricystic kidney of the multiple malformation syndromes, juvenile nephronophthisis and medullary cystic disease, medullary sponge kidney, primary glomerulocystic kidney disease, and glomerulocystic kidney associated with several systemic disorders mainly of genetic or chromosomal etiology, cystic kidney in tuberous sclerosis, and in von Hippel-Lindau syndrome, cystic nephroma, cystic variant of congenital mesoblastic nephroma, mixed epithelial stromal tumor of the kidney, renal lymphangioma, pyelocalyceal cyst, peripylic cyst and perinephric pseudocyst, acquired renal cystic disease of long-term dialysis, and cystic renal cell carcinoma and sarcoma.

Whereas the gross and histologic appearance of some of these conditions may be diagnostic, clinical and sometimes molecular studies may be necessary to define other types.
Hum Pathol. 2004 Jun;35(6):697-710. Abstract quote

Both mesotheliomas and renal cell carcinomas can present a wide variety of morphological patterns. Because of this, renal cell carcinomas that metastasize to the pleura and lung may be confused with mesotheliomas.

The aim of the present study was to compare the value of the various immunohistochemical markers currently available for the diagnosis of mesothelioma and renal cell carcinoma. A total of 48 mesotheliomas (40 epithelioid, 8 sarcomatoid), and 48 renal cell carcinomas (24 conventional, 12 chromophobe, 8 papillary, 4 sarcomatoid) were investigated for the expression of the following markers: calretinin, mesothelin, cytokeratin 5/6, WT1, thrombomodulin (TM), N-cadherin, CD15 (leu-M1), MOC-31, Ber-EP4, BG-8 (Lewis(y)), CD10, renal cell carcinoma marker (RCC Ma), carcinoembryonic antigen (CEA), and B72.3. All (100%) of the epithelioid mesotheliomas reacted for calretinin, mesothelin, and cytokeratin 5/6; 93% for WT1; 78% for TM; 75% for N-cadherin, 48% for CD10, 15% for Ber-EP4, 8% for MOC-31, 8% for RCC Ma, 5% for BG-8, and none for CEA, B72.3, or CD15. Of the sarcomatoid mesotheliomas, 88% expressed calretinin, 75% N-cadherin, 38% CD10, and 13% each expressed cytokeratin 5/6, WT1, and TM. All of the remaining markers were negative. Among the RCCs, 81% expressed CD10, 75% N-cadherin, 63% CD15, 50% RCC Ma, 50% MOC-31, 42% Ber-EP4, 8% BG-8, and 2% TM. The remaining markers were negative.

The results indicate that calretinin, mesothelin, and cytokeratin 5/6 are the best positive mesothelioma markers for differentiating epithelioid mesotheliomas from renal cell carcinomas. The best discriminators among the antibodies considered negative markers for mesothelioma are CD15, MOC-31, and RCC Ma. An accurate differential diagnosis can be reached with the use of any 2 of the 3 recommended positive markers, which should be selected based on availability and on which ones yield the best staining results in a given laboratory. One of the recommended negative markers may be added to the panel if deemed necessary. If confirmation of renal origin is needed, RCC Ma could be useful.

Calretinin is the only marker that appears to have any utility in distinguishing between sarcomatoid mesotheliomas and sarcomatoid renal cell carcinomas.

Mixed Epithelial and Stromal Tumor of the Kidney

N. Volkan Adsay, M.D.; John N. Eble, M.D.; John R. Srigley, M.D.; Edward C. Jones, M.D.; David J. Grignon, M.D.

From Harper Hospital and Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, U.S.A. (V.A., D.J.G.); VA Medical Center and Indiana University, Indianapolis, Indiana, U.S.A. (J.N.E.); The Credit Valley Hospital and McMaster University, Hamilton, Ontario, Canada (J.R.S.); and Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada (E.C.J.).

Am J Surg Pathol 2000;24:958-970 Abstract quote

We describe the clinicopathologic features of 12 patients with a distinctive tumor of the kidney characterized by a mixture of epithelial and stromal elements that form solid and cystic growth patterns.

Similar tumors were reported previously in the literature under various names, including adult mesoblastic nephroma. All but one of the patients were women. The only man had a long history of treatment with lupron and diethylstilbesterol. Seven of the women had histories of long-term oral estrogen use of whom six had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy several years prior, and the seventh patient had been using oral contraceptives for many years. Another woman had this operation but did not receive any hormone therapy. Ages ranged from 31 to 71 years (mean, 56 yrs). Six patients presented with symptoms, including pain and infections attributable to mass effect, and in six the tumor was detected incidentally.

Grossly, the tumors were well-circumscribed (mean size, 6 cm; range, 3–12 cm) and consisted of solid and cystic components, most often in equal proportions but in variable distribution.

Microscopically, the spindle cell component ranged in appearance from scar-like fibrous tissue to leiomyoma-like interlacing fascicles; usually there was a mixture of both. More cellular foci reminiscent of ovarian stroma or solitary fibrous tumor were also present. No blastema was present. Epithelial elements (composed of clusters of tubules with variable lining) were scattered amidst the spindle cells, and focally transformed into large cysts lined by cells with abundant pink cytoplasm and a hobnail appearance. Immature epithelial elements typical of Wilms' tumor were not present. Muscle markers (desmin and smooth muscle actin) were positive diffusely and strongly in the spindle cells of all tumors, whereas HMB-45 and CD34 were absent. Estrogen receptors were detected in the nuclei of spindle cells in seven tumors and progesterone receptors in three.

The distinctive clinicopathologic characteristics of these lesions warrant their classification as a separate category of kidney tumor. We suggest the descriptive term ``mixed epithelial and stromal tumor'' for this group until its nature and relationship to other kidney lesions are further clarified. Its preponderance in females with a history of long-term estrogen replacement and the history of long-term sex-steroid use in the only male patient, combined with the frequent content of estrogen and progesterone receptors in the spindle cells, suggest that the hormonal milieu plays a role in the evolution of these tumors.

The clinical and pathologic parallels with mucinous cystic tumors of pancreas and liver raise the possibility of a common pathogenetic mechanism that may be linked to the periductal fetal mesenchyme. We think this entity is a benign composite neoplasm in which stroma and epithelium are both integral neoplastic components.


Spiradenocylindroma of the Kidney Clinical and Genetic Findings Suggesting a Role of Somatic Mutation of the CYLD1 Gene in the Oncogenesis of an Unusual Renal Neoplasm

Philipp Ströbel, M.D. ; Andreas Zettl, M.D. ; Zhou Ren, M.D. ; Petr Starostik, M.D. ; Hubertus Riedmiller, M.D. ; Stephan Störkel, M.D. ; Hans Konrad Müller-Hermelink, M.D. ; Alexander Marx, M.D.

From the Institute of Pathology (P.S., A.Z., Z.R., P.S., H.K.M.-H., A.M.) and the Department of Urology (H.R.), University of Würzburg, Würzburg, and the Institute of Pathology (S.S.), Klinikum Wuppertal, Wuppertal, Germany

Am J Surg Pathol 2002;26:119-124 Abstract quote

We describe the morphology and comparative genomic hybridization findings in a tumor for which we propose the term “spiradenocylindroma” of the kidney.

The tumor arose in the wall of a renal cyst in an otherwise healthy male patient who had a favorable clinical course after nephrectomy. Tumor cells formed either large nodules exhibiting a solid or trabecular architecture with conspicuous perivascular spaces or cylindromatous small tumor cell islands arranged in a jigsaw pattern. Focally, there were interspersed tubular structures and tumor cell rosettes with central deposits of periodic acid–Schiff-positive material. A minor tumor component showed epidermoid differentiation. The tumor cells were strongly positive for cytokeratins 5/6, high molecular weight cytokeratins 34E12 and AE1/3, and E-cadherin, but only weakly positive for cytokeratins 7, 8, 18, 19, and epithelial membrane antigen. Focal reactivity for actin, vimentin, and S-100 protein or lysozyme and 1 -antichymotrypsin within tubular and cylindromatous areas suggested myoepithelial and apocrine differentiation, respectively.

By comparative genomic hybridization, the only abnormality was loss of the long arm of chromosome 16 and gain of genetic material on the short arm of chromosome 16, suggesting isochromosome i(16p). This finding is unique among renal neoplasms and implies loss of heterozygosity at 16q12–13 of the CYLD1 gene that is critically involved in the oncogenesis of familial cylindromatosis and some sporadic spiradenocylindromas.

We conclude that somatic mutation of the CYLD1 gene outside the skin can have a role in the oncogenesis of tumors with cylindromatous features.

Renal cell carcinomas in children and young adults: increased incidence of papillary architecture and unique subtypes.

Renshaw AA, Granter SR, Fletcher JA, Kozakewich HP, Corless CL, Perez-Atayde AR.

Brigham and Women's Hospital, Harvard University Medical School, Boston, Massachusetts, USA.

Am J Surg Pathol. 1999 Jul;23(7):795-802. Abstract quote  

Renal cell carcinomas in children and young adults are rare, and the pathologic features of these tumors have not been well described.

We reviewed 24 renal cell carcinomas in children and young adults ages 6 to 29 years, 14 of whom were younger than 18 years of age. Fourteen were female. In 19 (79%) of 24 cases, the tumor met histologic criteria for papillary renal cell carcinoma, with at least 50% papillary architecture. Four of the remaining five cases were typical clear cell tumors in patients known to have von Hippel Lindau syndrome, and one case was of chromophobe type. In the papillary tumors, calcifications, high nuclear grade, extracapsular extension (American Joint Commission on Cancer stage T3), and lymph node metastases were common. Among these papillary tumors, four distinct histologic patterns could be identified.

Collecting duct-like tumors (two cases) involved the large collecting ducts, were multifocal and predominantly papillary, and had focal tubular and solid areas. These tumors were reactive for epithelial membrane antigen (EMA) and keratins, including CK7, but negative for Ulex europeaus and high molecular weight keratin 34BE12.

Voluminous cell tumors (four cases) were composed of cells with extremely voluminous clear cytoplasm and, although predominantly papillary, had areas that also resembled clear cell tumors. These tumors were reactive for keratins AE1/AE3 but were otherwise negative for all other keratins, EMA, and U. europeaus. One of these tumors showed an X;7 translocation. Adult type tumors (12 cases) resembled papillary tumors of adults. These tumors were reactive for EMA and keratins, including CK7, and all but one were negative for U. europeaus and keratin 34BE12. This last case had trisomies of chromosomes 7, 16, 17, and 20. The final neuroendocrinelike case was multifocal, organoid, and composed of nests of small cells in a neuroendocrinelike pattern. Three of 13 patients were alive with disease at last follow-up, and three additional patients died of disease, all within 2 years. Progression was highly associated with lymph node involvement at the time of resection.

We conclude that the clinicopathologic features of renal cell carcinomas in children and young adults differ from those arising in older adults. These tumors are characteristically high-grade, high-stage, papillary tumors with numerous calcifications, and several subtypes can be identified based on histologic, immunohistochemical, and cytogenetic features. Some subtypes appear to be unique to this age group.
Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents.

Argani P, Antonescu CR, Illei PB, Lui MY, Timmons CF, Newbury R, Reuter VE, Garvin AJ, Perez-Atayde AR, Fletcher JA, Beckwith JB, Bridge JA, Ladanyi M.

Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland 21231-2410, USA.
Am J Pathol. 2001 Jul;159(1):179-92. Abstract quote  

The unbalanced translocation, der(17)t(X;17)(p11.2;q25), is characteristic of alveolar soft part sarcoma (ASPS). We have recently shown that this translocation fuses the TFE3 transcription factor gene at Xp11.2 to ASPL, a novel gene at 17q25.

We describe herein eight morphologically distinctive renal tumors occurring in young people that bear the identical ASPL-TFE3 fusion transcript as ASPS, with the distinction that the t(X;17) translocation is cytogenetically balanced in these renal tumors. A relationship between these renal tumors and ASPS was initially suggested by the cytogenetic finding of a balanced t(X;17)(p11.2;q25) in two of the cases, and the ASPL-TFE3 fusion transcripts were then confirmed by reverse transcriptase-polymerase chain reaction. The morphology of these eight ASPL-TFE3 fusion-positive renal tumors, although overlapping in some aspects that of classic ASPS, more closely resembles renal cell carcinoma (RCC), which was the a priori diagnosis in all cases. These tumors demonstrate nested and pseudopapillary patterns of growth, psammomatous calcifications, and epithelioid cells with abundant clear cytoplasm and well-defined cell borders.

By immunohistochemistry, four tumors were negative for all epithelial markers tested, whereas four were focally positive for cytokeratin and two were reactive for epithelial membrane antigen (EMA) (one diffusely, one focally). Electron microscopy of six tumors demonstrated a combination of ASPS-like features (dense granules in four cases, rhomboid crystals in two cases) and epithelial features (cell junctions in six cases, microvilli and true glandular lumens in three cases). Overall, although seven of eight tumors demonstrated at least focal epithelial features by electron microscopy or immunohistochemistry, the degree and extent of epithelial differentiation was notably less than expected for typical RCC. We confirmed the balanced nature of the t(X;17) translocation by fluorescence in situ hybridization in all seven renal tumors thus analyzed, which contrasts sharply with the unbalanced nature of the translocation in ASPS.

In summary, a subset of tumors previously considered to be RCC in young people are in fact genetically related to ASPS, although their distinctive morphological and genetic features justify their classification as a distinctive neoplastic entity. Finally, the finding of distinctive tumors being associated with balanced and unbalanced forms of the same translocation is to our knowledge, unprecedented.


PROGNOSIS Chromophobe renal carcinomas have best prognosis

Prognostic implications of CD95 receptor expression in clear cell renal carcinomas.

Ramp U, Bretschneider U, Ebert T, Karagiannidis C, Willers R, Gabbert HE, Gerharz CD.

Institute of Pathology, Department of Urology, and Computer Center, Heinrich Heine University, Duesseldorf, Germany.


Hum Pathol 2003 Feb;34(2):174-9 Abstract quote

The CD95 (Apo-1/Fas) receptor-ligand system is a key regulator of apoptosis. Down-regulation of CD95 receptor and up-regulation of CD95 ligand has been reported in a variety of human tumors and is thought to confer a selective survival advantage.

To explore the relevance of the CD95 system for tumor progression and prognosis in clear cell renal cell carcinomas (RCCs), we analyzed CD95 receptor and ligand expression in formalin-fixed tissue from 149 clear cell RCCs by immunohistochemistry. CD95 ligand expression could not be detected in nonneoplastic tubule epithelia and in clear cell RCCs. In contrast, CD95 receptor expression was found in the great majority of clear cell RCCs, and no down-regulation of CD95 receptor protein was evident when compared with nonneoplastic tubule epithelia. Although a significant increase (P = 0.004) of CD95 receptor expression was evident from well-differentiated (G1) to poorly differentiated (G3) RCCs, CD95 receptor expression was not correlated with tumor stage or survival of RCC patients.

In conclusion, clear cell RCCs differ from other types of human cancer by their failure to down-regulate CD95 receptor expression or up-regulate CD95 ligand expression during tumor progression. These ex vivo observations suggest that down-regulation of CD95 receptor expression may not provide an additional selective growth advantage to RCC cells and thus further confirm our previous in vitro observations on a functional impairment of CD95-mediated apoptosis in RCC.


Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma.

Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML.


Am J Surg Pathol 2003 May;27(5):612-24 Abstract quote

Our objective was to compare cancer-specific survival and to examine associations with outcome among the histologic subtypes of renal cell carcinoma (RCC).

We studied 2385 patients whose first surgery between 1970 and 2000 was a radical nephrectomy for sporadic, unilateral RCC. All RCC tumors were classified following the 1997 Union Internationale Contre le Cancer and American Joint Committee on Cancer guidelines. There were 1985 (83.2%) patients with clear cell, 270 (11.3%) with papillary, 102 (4.3%) with chromophobe, 6 (0.3%) with collecting duct, 5 (0.3%) with purely sarcomatoid RCC and no underlying histologic subtype, and 17 (0.7%) with RCC, not otherwise specified. Cancer-specific survival rates at 5 years for patients with clear cell, papillary, and chromophobe RCC were 68.9%, 87.4%, and 86.7%, respectively.

Patients with clear cell RCC had a poorer prognosis compared with patients with papillary and chromophobe RCC (p <0.001). This difference in outcome was observed even after stratifying by 1997 tumor stage and nuclear grade. There was no significant difference in cancer-specific survival between patients with papillary and chromophobe RCC (p = 0.918). The 1997 TNM stage, tumor size, presence of a sarcomatoid component, and nuclear grade were significantly associated with death from clear cell, papillary, and chromophobe RCC. Histologic tumor necrosis was significantly associated with death from clear cell and chromophobe RCC, but not with death from papillary RCC.

Our results demonstrate that there are significant differences in outcome and associations with outcome for the different histologic subtypes of RCC, highlighting the need for accurate subtyping.

Prognostic Impact of Histologic Subtyping of Adult Renal Epithelial Neoplasms
An Experience of 405 Cases

Mahul B. Amin, M.D.; Mitual B. Amin, M.D.; Pheroze Tamboli, M.D.; Javid Javidan, M.D.; Hans Stricker, M.D.; Mariza De-Peralta Venturina, M.D.; Anita Deshpande, M.B.B.S.; Mani Menon, M.D.

From the Departments of Pathology (Mitual B.A., P.T., M.D.-P.V., A.D.) and Urology (J.J., H.S., M.M.), Henry Ford Hospital, Detroit, Michigan; the Department of Pathology and Laboratory Medicine and Department of Urology (Mahul B.A.), Emory University School of Medicine, Atlanta, Georgia.

Am J Surg Pathol 2002;26:281-291 Abstract quote

Just two and a half decades ago adult renal cell neoplasms, i.e., those arising from the renal tubules or collecting duct epithelium, were subdivided into two major subtypes: “clear cell carcinoma” and “granular cell carcinoma.” Subsequent detailed morphologic and/or cytogenetic studies have resulted in the recognition of several distinctive subtypes of adult renal epithelial neoplasms, which has led to the promulgation of a refined contemporary histologic classification of these tumors.

This study examines the prognostic significance of histologic subtyping in accordance with the new classification in a consecutive series of 405 cases treated at a single institution. Cases were histologically classified into 28 (7%) benign tumors [27 (6.7%) renal oncocytomas, 1 (0.2%) metanephric adenoma] and 377 (93%) malignant tumors [255 (63%) conventional (clear cell) renal cell carcinoma, 75 (18.5%) papillary renal cell carcinoma, 24 (5.9%) chromophobe renal cell carcinoma, and 23 (5.7%) renal cell carcinoma, unclassified]. A total of 25 (6.6%) malignant tumors showed evidence of sarcomatoid change. Kaplan–Meier survival analysis with log-rank test showed histologic type (p = 0.002), Fuhrman's nuclear grade (p = 0.001), TNM stage (p = 0.001), vascular invasion (p = 0.001), and necrosis (p = 0.001) to be significantly associated with disease-specific survival and progression-free survival, based on follow-up of 368 patients (mean 64.5 months, median 56 months). The 5-year disease-specific survival for chromophobe renal cell carcinoma, papillary renal cell carcinoma, conventional (clear cell) renal cell carcinoma, and renal cell carcinoma, unclassified was 100%, 86%, 76%, and 24%, respectively; no patient with a benign tumor diagnosis progressed or died of disease.

The 5-year progression-free survival for chromophobe renal cell carcinoma, papillary renal cell carcinoma, conventional (clear cell) renal cell carcinoma, and renal cell carcinoma, unclassified was 94%, 88%, 70%, and 18%, respectively. Malignant tumors with sarcomatoid change had a 35% and 27%, 5-year disease-specific and progression-free survival, respectively. Cox proportional hazards regression analysis showed TNM stage (p = 0.001), nuclear grade (p = 0.01), and necrosis (p = 0.05) to be significant predictors of disease-specific survival.

In conclusion, our study shows that the histologic categorization of adult renal epithelial neoplasms performed by routine light microscopic hematoxylin and eosin-based examination in accordance with the contemporary classification scheme has prognostic utility.

Comparison of Standardized and Nonstandardized Nuclear Grade of Renal Cell Carcinoma to Predict Outcome Among 2,042 Patients

Christine M. Lohse
Michael L. Blute, MD
Horst Zincke, MD, PhD
Amy L. Weaver, MS
John C. Cheville, MD

Am J Clin Pathol 2002;118:877-886 Abstract quote

We compared the ability of original nuclear grades from surgical pathology reports and grades reviewed by a urologic pathologist to predict death due to renal cell carcinoma (RCC) for 2,042 patients treated with radical nephrectomy between January 1970 and December 1998.

Reviewed grade 1 tumors had small, round nuclei with inconspicuous nucleoli visible at ×400; grade 2 contained round to slightly irregular nuclei with mildly enlarged nucleoli visible at ×200; grade 3 had round to irregular nuclei with prominent nucleoli visible at ×100; grade 4 contained enlarged pleomorphic or giant cells. Predictive abilities were compared using R2 values from Cox proportional hazards models. There were 1,733 (84.87%) clear cell, 222 (10.87%) papillary, and 87 (4.26%) chromophobe tumors.

Reviewed grades were more predictive of death due to RCC than original grades for clear cell (R2, 21% vs 16%), papillary (R2, 16% vs 13%), and chromophobe (R2, 39% vs 27%) RCC. Among patients with clear cell and papillary RCC, this difference was apparent even after adjusting for the 1997 TNM stage.

Standardized nuclear grades were more predictive of death due to RCC than nonstandardized grades for all subtypes studied.

Morphologic Subtyping of Papillary Renal Cell Carcinoma: Correlation with Prognosis and Differential Expression of MUC1 between the Two Subtypes.

Leroy X, Zini L, Leteurtre E, Zerimech F, Porchet N, Aubert JP, Gosselin B, Copin MC.

Departments of Pathology (XL, EL, MCC, BG), Urology (LZ), Molecular Biology (FZ, NP, JPA), Lille University Hospitals and the Unity INSERM U560 (XL, EL, MCC, NP, JPA), CHR-U, Lille, France.

Mod Pathol 2002 Nov;15(11):1126-30 Abstract quote

Papillary renal cell carcinoma is now a well-established entity with distinct histological and cytogenetic features. A subdivision has been proposed in correlation with prognosis. Type 1 is the most frequent subtype and appears to have a better prognosis than Type 2. The subdivision is based on microscopic criteria.

To investigate these 2 types of papillary renal cell carcinoma, we have compared the clinical features, ancillary factors (TNM stage, Fuhrman grade), survival and MUC1 expression in 25 Type 1 and 12 Type 2 papillary renal cell carcinomas. Type 2 tumors were significantly associated with a higher Fuhrman grade (Grade III frequent; P <.001). Type 2 tumors were also associated with a poorer prognosis than Type 1 (P <.005). Fuhrman grade was significantly associated with prognosis (P <.005). The type and the prognosis were not correlated with the TNM stage.

We have shown a differential expression of MUC1 between Type 1 and Type 2 with a polarized expression in Type 1 and a rare expression in Type 2. In conclusion we confirm that the morphologic sub-typing and Fuhrman grade are valuable factors of outcome of papillary renal cell carcinomas and that MUC1 immunostaining is useful in differentiating Type 1 and Type 2 tumors.


High expression levels of insulin-like growth factor-I receptor predict poor survival among women with clear-cell renal cell carcinomas.

Parker AS, Cheville JC, Janney CA, Cerhan JR.

Departments of Health Sciences Research and Anatomic Pathology, Mayo Clinic, Rochester, MN.

Hum Pathol 2002 Aug;33(8):801-5 Abstract quote

Currently, tumor stage and grade remain the only widely accepted prognostic indicators of clear-cell renal cell carcinoma (CC-RCC). As such, there is a need to identify other prognostic markers because behavior of CC-RCC cannot always be determined by stage alone. Recent studies of human CC-RCC cell lines suggest that insulin-like growth factor-I receptor (IGF-IR) may have some prognostic value for patients with CC-RCC.

Using a population-based cohort of 48 female patients with CC-RCC and long-term follow-up, we tested the hypothesis that the immunohistochemical detection of IGF-IR expression in CC-RCC is associated with poorer cancer-specific survival after adjustment for stage and age at diagnosis. Kaplan-Meier analysis suggested that patients with CC-RCC that exhibited greater than 50% IGF-IR expression experienced a significantly poorer cancer-specific survival compared with patients with CC-RCC that exhibited less than 50% IGF-IR expression. The difference in survival was apparent at 2 years and remained throughout follow-up. Based on a Cox proportional hazard model that adjusted for stage and age at diagnosis, patients with tumors that exhibited greater than 50% IGF-IR staining were 4 times more likely to die of CC-RCC compared with patients whose tumors exhibited less than 50% staining (HR = 4.2; 95% confidence interval [CI]; 1.1-17.1). A smoothing spline with 4 degrees of freedom supported the results from the categorical analysis.

Evidence from this population-based pilot investigation is consistent with laboratory data suggesting that expression of IGF-IR may have some prognostic implication for patients presenting with CC-RCC; however, confirmation in a larger study is needed.


Intragenic PTEN/MMAC1 Loss of Heterozygosity in Conventional (Clear-Cell) Renal Cell Carcinoma is Associated with Poor Patient Prognosis.

Velickovic M, Delahunt B, McIver B, Grebe SK.

Department of Pathology and Molecular Medicine (MV, BD, SKGG), Wellington School of Medicine and Health Sciences, Wellington, New Zealand.

Mod Pathol 2002 May;15(5):479-85 Abstract quote

Inactivation of the PTEN/MMAC1 tumor suppressor gene has been linked to tumor progression in several human malignancies. However, the role of PTEN/MMAC1 in the development and progression of the major renal cell carcinoma morphotypes remains controversial.

We examined microdissected specimens from 80 conventional (clear cell) renal cell carcinomas (cRCC), 27 papillary renal cell carcinomas (pRCC), and 16 chromophobe renal cell carcinomas (chRCC) for loss of heterozygosity (LOH) at and around the PTEN/MMAC1 locus and for mutations in the PTEN/MMAC1 gene. The results of the molecular studies were correlated with tumor stage, grade, and patient survival. LOH at one or more of the examined loci occurred in 37.5% of cRCC, 29.6% of pRCC and 87.5% of chRCC specimens. The chRCC specimens showed increasing rates of LOH the further that a marker was located toward the q telomer of chromosome 10, consistent with nonspecific genetic disarray in genomically highly unstable tumors. No such pattern was discernible in the cRCC and pRCC. In the cRCC, LOH at intragenic PTEN/MMAC1 microsatellite markers (indicating deletional events involving the actual PTEN/MMAC1 gene) was significantly associated with tumor death, with 85.7% of such patients dying, whereas only 45.3% of patients without intragenic LOH died (P =.018). There were no PTEN/MMAC1 mutations in our specimens.

We conclude that PTEN/MMAC1 inactivation may play a role in the progression of cRCC. Biallelic inactivation may preferentially occur by nonmutational mechanisms, or, alternatively, haploinsufficiency of PTEN/MMAC1 may be sufficient to affect tumor progression in cRCC.


MUC1 mucin and trefoil factor 1 protein expression in renal cell carcinoma: Correlation with prognosis

Sigurd Kraus, MD
Paul D. Abel, FRCS
Christian Nachtmann
Hans-Jörg Linsenmann, etal

Hum Pathol 2002;33:60-67 Abstract quote

This study examines the coexpression of MUC1 mucin and trefoil factor 1 TFF1) and their relationship to progression of renal cell carcinoma (RCC). Immunohistochemistry was performed on tumor and adjacent normal tissue from clear-cell RCC (n = 60) and tissues from normal controls (n = 5) using a set of well-characterized monoclonal antibodies recognizing different epitopes of MUC1 and TFF1. Results of immunohistochemistry were compared with clinical parameters, including tumor grade, tumor size, presence of metastasis, and progression-free survival of patients after surgery.

In normal tissue, MUC1 and TFF1 were absent from the normal proximal tubular epithelium but were identified in distal and collecting tubular epithelium. In RCC, increased MUC1 expression positively correlated to tumor progression. MUC1 recognized by HMFG1 was associated with large tumor size (P < .05), distant metastasis (P < .05), and invasion of large veins (P < .05). Expression of the under-glycosylated form of MUC1 recognized by SM3 was found to correlate to time to progression (recurrence, metastasis, or death of patient; P < .001). Expression of TFF1 did not significantly correlate with any prognostic parameters. However, there was a significant correlation (P < .01) between TFF1 and MUC1 expression (HMFG2 epitope) in RCCs.

These results are consistent with the following conclusions: (1) MUC1 may be an independent prognostic marker in RCC; (2) TFF1 is frequently coexpressed with MUC1 and may act synergistically; and (3) RCC may originate from distal tubular epithelium.

MUC1 Expression Is Correlated With Nuclear Grade and Tumor Progression in pT1 Renal Clear Cell Carcinoma

Xavier Leroy, MD, etal.

Am J Clin Pathol 2002;118:47-51 Abstract quote

We studied, by immunohistochemical analysis, the expression of MUC1 and epithelial membrane antigen in 44 stage pT1 renal cell carcinomas (RCCs). Six patients had a metastatic evolution.

The percentage of stained cells was determined for each tumor. All tumors and normal adjacent renal parenchyma were stained. In normal kidney, distal convoluted tubules and collecting ducts stained strongly with an apical distribution. In tumors, there was a significant statistical correlation of the MUC1 expression level with the nuclear grade and with tumor progression. High-grade tumors had more stained cells than did low-grade tumors. Metastatic tumors also were more stained than nonmetastatic lesions. By using the Kaplan-Meier method and the log-rank test, we observed that patients with fewer than 10% of stained cells had no metastatic evolution. In contrast, patients with 70% or more stained cells had significantly lower metastasis-free survival rates.

We conclude that MUC1 is expressed in RCC and is associated with tumor progression in pT1 RCC.


Neural cell adhesion molecule expression in renal cell carcinomas: Relation to metastatic behavior.

Daniel L, Bouvier C, Chetaille B, Gouvernet J, Luccioni A, Rossi D, Lechevallier E, Muracciole X, Coulange C, Figarella-Branger D.

Hum Pathol. 2003 Jun;34(6):528-32. Abstract quote

Neural cell adhesion molecule (NCAM), a member of the immunoglobulin superfamily, is expressed by a subgroup of renal cell carcinomas (RCCs) and by a limited number of adult organs, including the central nervous system (CNS) and adrenal gland. Because the major function of NCAM is homophilic adhesion between homotypic and heterotypic cells, we hypothesized that NCAM-expressing RCCs should preferentially metastasize to the CNS and adrenal gland.

We did a retrospective immunohistochemical analysis of NCAM expression both in 338 primary renal tumors, including 249 conventional RCCs and 31 metastases of conventional RCCs. In primary renal tumors, NCAM was expressed by only 38 (15.2%) conventional RCCs and by no other histological subtypes of renal tumor. This expression correlated with a higher risk of adrenal and CNS metastases (P <0.001). NCAM expression also correlated with tumor size (P <0.001), renal vein involvement (P = 0.02), perirenal invasion (P = 0.02), and Fuhrman grading (P < 0.001). Finally, patients with NCAM-expressing RCCs had a lower survival rate (P = 0.006), especially in the first 2 years after surgery.

NCAM expression is of interest both for evaluating the prognosis of patients with conventional RCCs and for determining a subgroup of patients at high risk for adrenal and CNS metastases.


Pax-2 expression in adult renal tumors

Laurent Daniel, etal.

Hum Pathol 2001;32:282-287. (Abstract quote)

To assess the expression of the homeogene Pax-2 in adult renal cell carcinomas, we did a retrospective immunohistochemical analysis of 56 frozen tumor samples representing all major histologic subtypes of renal tumors. There were 33 conventional renal cell carcinomas (58.9%), 12 papillary renal cell carcinomas (21.4%), 4 chromophobe cell renal carcinomas, 4 urothelial cell renal carcinomas, and 3 oncocytomas. Forty-five tumors (62.5%) were localized, and 21 tumors had extrarenal involvement. Eight patients (14%) had metastatic disease at the end of the follow-up.

We searched for relationships between Pax-2 expression and nuclear grading, TNM staging, Ki-67 proliferation index, expression of transforming growth factor-1 (TGF-1), an in vitro down-regulator of Pax-2 expression, and finally cytogenetic abnormalities.

All histologic subtypes expressed Pax-2 protein, except urothelial renal carcinomas. The highest expression was in papillary renal cell carcinomas. In this subtype, all tumors and 83.3% ± 12.3% of tumor cells were immunoreactive for Pax-2. All but 2 conventional renal cell carcinomas expressed Pax-2, but with 26.3% ± 29.6% of immunoreactive cells (P < .001). Pax-2 expression was not correlated with nuclear grading (P = .6), tumor size (P = .3), and TGF-1 expression (P = .1). Nevertheless, Pax-2 expression correlated with the Ki-67 proliferation index only for the conventional histologic subtype (P = .03). In this histologic subtype, Pax-2 expression was higher in patients with metastatic disease than in those without (P = .02). Pax-2 expression was not associated with specific cytogenetic abnormalities like trisomy 7 (P = .1), 3p deletion (P = .5), and hyperdiploidy (P = .2). TGF-1 expression, positive in 33 tumors (59%), was not correlated with either Pax-2 expression (P = .1) or current prognostic factors such as nuclear grading (P = .2). Interestingly, we also observed an expression of TGF-RI and TGF-RII in the tumors with high nuclear grading (P = .005).

We conclude that Pax-2 protein is expressed in all major histologic subtypes of renal cell carcinomas. The pattern of expression differs between these subtypes. Pax-2 expression in conventional renal cell carcinomas is correlated with the proliferation index and is significantly higher in patients with metastatic disease.

Expression of Platelet-Derived Growth Factor-aa Receptor Is Associated With Tumor Progression in Clear Cell Renal Cell Carcinoma

Irene Sulzbacher, MD, Peter Birner, MD, Margit Träxler, Michael Marberger, MD, and Andrea Haitel, MD

Am J Clin Pathol 2003:120:107-112 Abstract quote

Platelet-derived growth factors (PDGFs) exert their biologic function by binding to 3 different tyrosine kinase receptor isoforms. Especially the PDGF-aa receptor binds PDGF proteins with high specificity, which results in growth stimulation.

The expression of the receptor and its ligand was studied in human renal cell carcinomas (RCCs) by immunohistochemical analysis, and the expression of PDGF-aa receptor and PDGF-AA was correlated with clinicopathologic parameters of patients with clear cell RCC (CCRCC).

In CCRCC, the mean expression of PDGF-aa receptor and PDGF-AA was 38.8% (range, 0.0%-96.0%) and 18.4% (range, 0.0%-90.0%), respectively. PDGF-aa receptor expression was significantly higher in grade 3 and grade 4 tumors compared with grade 1 and grade 2 tumors (P = .027; Mann-Whitney test), and high receptor expression correlated with tumor progression in univariate analysis (P = .0253; log-rank test), while PDGF-AA expression had no prognostic influence on the outcome of patients with CCRCC.

Therefore, immunohistochemical detection of high PDGF-aa receptor expression in CCRCC is associated with adverse outcomes. Furthermore, the PDGF receptor-factor interaction loop may be considered as a possible target for novel therapeutic strategies.

Clinical significance of cell proliferation, microvessel density, and CD44 adhesion molecule expression in renal cell carcinoma

Nathalie Rioux-Leclercq, MD
Jonathan I. Epstein, MD
Jean-Yves Bansard
Bruno Turlin, MD
Jean-Jacques Patard, MD, PhD
Andréa Manunta, MD
Theresa Chan, MD
Marie-Paule Ramee, MD
Bernard Lobel, MD
Jacques-Philippe Moulinoux, MD, PhD

Hum Pathol 2001;32:1209-1 Abstract quote

Renal cell carcinoma (RCC) is known to have a wide variation in clinical outcome despite the use of conventional prognostic factors, such as staging or grading. A better knowledge of the biologic aggressiveness of RCC could facilitate the selection of patients at high risk of tumor progression.

The aim of this study was to determine if use of measurements of vascular density, cell proliferation, and cell adhesion could better predict the biologic behavior of RCC. We immunohistochemically analyzed CD34, Ki-67, and CD44H expression on formalin-fixed, paraffin-embedded tissues from 73 RCCs for quantifying microvessel density (MVD), Ki-67 labeling index (LI), and CD44H LI, respectively. Univariate cancer-specific survival analysis showed that tumor stage (P < .01), tumor size (P < .001), nuclear grade (P < .01), metastasis (P < .001), MVD (P < .03), Ki-67 LI (P < .001), and CD44H LI (P < .0001) were predictors of tumor-related death. There was a statistical correlation between CD44H LI and both Ki-67 LI (r' = .3) and MVD (r' = –44). Ki-67 LI (P < .04) and CD44H LI (P < .02), as well as metastasis (P < .008), emerged as independent predictors of cancer-specific survival in multivariate analysis in patients with metastases (P < .04 and P < .02, respectively) and in patients without metastases (P < .006 and P < .00001, respectively).

Our study suggests that vascular density, cell proliferation, and cell adhesion represent a complex tumor–host interaction that may favor progression of RCC. Cell proliferation and CD44H expression appear to be powerful markers to identify patients with an adverse prognosis.

The renal sinus is the principal invasive pathway: a prospective study of 100 renal cell carcinomas.

Bonsib SM.

From the Department of Pathology and Laboratory Medicine, Indiana University Medical Center University Hospital, Indianapolis, Indiana.
Am J Surg Pathol. 2004 Dec;28(12):1594-600. Abstract quote  

A total of 100 renal cell carcinomas were prospectively examined for renal sinus invasion, 74 clear cell renal cell carcinomas (CC), 3 renal cell carcinomas, unclassified (RUC), 16 papillary renal cell carcinomas (PapC), and 7 chromophobe renal cell carcinomas (ChC).

Using the 2002 TNM staging formulation, 49 tumors were T1, 5 were T2, and 46 were T3 or T4. Renal sinus invasion occurred more often than renal capsule invasion. No tumor invaded the capsule that did not also invade the sinus. Renal sinus invasion correlated with Fuhrman grade; 17% of grades 1/2 tumors invaded the sinus, while 71% of grade 3/4 tumor invaded the sinus (P < 0.001). Sinus invasion correlated with tumor type; 2 of 23 PapC and ChC invaded the sinus compared with 44 of 77 CC and RUC. Sinus invasion occurred in approximately 16% of tumors 1 to 4 cm in size, then abruptly increased for larger tumors (P < 0.001).

When tumors are staged by the 1997 and 2002 TNM formulation, renal sinus invasion upstaged 28% of cases stage T1 or T2 by the 1997 formulation, to T3 using the 2002 criteria. In conclusion, renal sinus invasion is the most common site of extrarenal extension of renal carcinoma and correlates with tumor type, grade and size.

Appropriate evaluation for sinus invasion reduces the incidence of T1b and T2 CC tumors, limiting prognostic utility and suggesting reassessment of the T1 and T2 stage designations.
5 year survival 45%
70% in absence of distant mets
15-20% with renal vein invasion or extension into perinephric fat
Sites of metastasis Lungs 50%
Bones 33%
Regional lymph nodes

Kidney Morcellation in Laparoscopic Nephrectomy for Tumor Recommendations for Specimen Sampling and Pathologic Tumor Staging

Joseph T. Rabban, M.D., M.P.H.; Maxwell V. Meng, M.D.; Ben Yeh, M.D.; Theresa Koppie, M.D.; Linda Ferrell, M.D.; Marshall L. Stoller, M.D.

From the Departments of Pathology (J.T.R., L.F.), Urology (M.V.M., T.K., M.L.S.), and Radiology (B.Y.), University of California, San Francisco, California,

Am J Surg Pathol 2001;25:1158-1166 Abstract quote

Laparoscopic nephrectomy is a novel approach for small renal tumors in selected patients; however, removal of the kidney through the small laparoscopic abdominal wall incision site requires the kidney to be morcellated into small fragments while still in situ. Morcellation presents two problems for the pathologist. First, guidelines for optimal sampling of morcellated fragments have not been described. Second, morcellation precludes complete pTNM tumor staging, in particular, tumor size, margins, and renal vein involvement.

Based on our initial experience with 23 laparoscopic nephrectomies/nephroureterectomies (13 clinically suspected neoplasms, confirmed pathologically as renal cell carcinoma [RCC, n = 7], urothelial carcinoma of the renal pelvis [n = 3], angiomyolipoma [n = 1], and cystic nephroma [n = 1], and 10 clinically benign entities) and a conservative statistical model, we present a decision analysis model of various specimen sampling protocols that optimize cost, labor, or time to diagnosis (single vs sequential sampling). Using the tumor-to-kidney volume ratio (TKR), calculated from preoperative radiologic imaging and specimen gross weight, several specimen sampling algorithms were compared. For the average situation in which TKR is 0.15, the algorithm that most significantly optimizes cost and labor is one that initially samples 5% of the morcellated specimen. However, additional sampling may be required in one fourth of the cases. The optimal amount of sampled tissue may indeed be less than 5% because this assumes no suspicious tissue is grossly visible and in all our cases of RCC grossly visible tumor was identified. Additional nomograms for a spectrum of TKR, sampling success, and cost are presented to allow pathologists their own discretion in determining optimal sampling of the morcellated kidney.

Tumor staging is severely limited by morcellation. Tumor size, renal capsule involvement, and renal vein involvement cannot be fully pathologically evaluated for RCC, whereas invasion cannot be definitively assessed for urothelial carcinoma of the renal pelvis. Knowledge of the radiologic features (lesion size, capsule, and vein involvement) is important in sampling and staging morcellated kidneys removed laparoscopically.


Radical nephrectomy with and without lymph node dissection: preliminary results of the EORTC randomized phase III protocol 30881. EORTC Genitourinary Group.

Blom JH, van Poppel H, Marechal JM, Jacqmin D, Sylvester R, Schroder FH, de Prijck L.

EORTC Data Center, Brussels, Belgium.

Eur Urol 1999 Dec;36(6):570-5 Abstract quote

OBJECTIVE: The authors present demographic and surgical data from a randomized phase III trial, instituted by the EORTC Genitourinary Group in 1988, the aim of which was to assess whether complete lymph node dissection in conjunction with radical nephrectomy for renal cell cancer is more effective than radical nephrectomy alone.

METHODS: Before surgery, the renal cell carcinoma was staged and judged to be nonmetastatic and resectable. The patients were randomized prior to surgery into those having radical nephrectomy combined with complete lymph node dissection or into those having radical nephrectomy alone. Postoperatively all patients were followed until progression of disease or death.

RESULTS: Of the 772 randomized patients, 41 were not eligible. 383 had a complete lymph node dissection together with a radical nephrectomy. 389 had a radical nephrectomy alone. The complication rate did not differ significantly between the two groups. A complete lymph node dissection in 336 patients revealed absence of lymph node metastases in 325 of them.

CONCLUSIONS: The present study shows that complete lymph node dissection does not add morbidity to the radical nephrectomy. After proper preoperative staging, the incidence of unsuspected lymph node metastases is low (3.3%).

Blood loss and the need for transfusion in patients who undergo partial or radical nephrectomy for renal cell carcinoma.

Shvarts O, Tsui KH, Smith RB, Kernion JB, Belldegrun A.

Department of Urology, University of California Los Angeles School of Medicine, Los Angeles, California 90095-1738, USA

J Urol 2000 Oct;164(4):1160-3 Abstract quote

PURPOSE: We assessed blood loss and subsequent transfusion associated with nephrectomy performed for suspected renal cell carcinoma to establish guidelines for preoperative autologous blood donation and identify a subgroup of patients that may benefit from erythropoietin administration.

MATERIALS AND METHODS: We retrospectively reviewed the charts of 211 patients who underwent partial (73%) or radical (23%) nephrectomy for presumed renal cell carcinoma at our institution between 1990 and 1999. Patients were divided into groups 1-44.5% treated with radical nephrectomy for localized disease, 2-21.3% radical nephrectomy for metastatic lesions invading the renal vasculature or inferior vena cava, 3-8% radical nephrectomy for metastatic disease with locally extensive lesions and 4-26.5% partial nephrectomy for localized lesions. Patient charts were evaluated for preoperative and postoperative hematocrit, estimated blood loss, transfusions received, surgical complications and underlying disease.

RESULTS: Median estimated blood loss was 200, 400, 250 and 555 cc in groups 1 to 4, respectively. However, patients in groups 2 and 3 had a substantially greater range of blood loss than those in groups 1 and 4, respectively. The incidence of those with a blood loss of greater than 1 l. was 7%, 36%, 24% and 11% in groups 1, to 4, respectively. The incidence of those requiring transfusion was significantly lower in group 1 than in groups 2 to 4 (18% versus 44%, 24% and 30%, respectively, p <0.009). Mean transfusion requirement plus or minus standard deviation was significantly greater in groups 2 and 3 than in 1 and 4 (2.3 +/- 1.08, 5.5 +/- 4.4, 11.3 +/- 9.6 and 2.3 +/- 1.7 units, respectively, p <0.05). No significant difference was noted in the change in hematocrit as a result of surgery in the 4 groups (p >0.05). Similarly underlying disease and operative complications did not have a significant effect on blood loss or transfusion (p >0. 05).

CONCLUSIONS: Radical or partial nephrectomy for localized renal cell carcinoma leads to consistent and well tolerated operative blood loss that rarely results in the need for substantial transfusion. In contrast, nephrectomy for advanced disease may cause a risk of greater blood loss and subsequent need for the transfusion of multiple units of blood. While preoperative autologous blood donation may have limited value in this regard due to the high cost and number of units needed, preoperative erythropoietin administration may be a viable option. Prospective randomized studies are currently planned.


Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma.

Motzer RJ, Murphy BA, Bacik J, Schwartz LH, Nanus DM, Mariani T, Loehrer P, Wilding G, Fairclough DL, Cella D, Mazumdar M.

Genitourinary Oncology Service, Division of Solid Tumor Oncology, and the Departments of Medical Imaging and Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

J Clin Oncol 2000 Aug;18(16):2972-80 Abstract quote

PURPOSE: A randomized phase III trial was conducted to determine whether combination therapy with 13-cis-retinoic acid (13-CRA) plus interferon alfa-2a (IFNalpha2a) is superior to IFNalpha2a alone in patients with advanced renal cell carcinoma (RCC).

PATIENTS AND METHODS: Two hundred eighty-four patients were randomized to treatment with IFNalpha2a plus 13-CRA or treatment with IFNalpha2a alone. IFNalpha2a was given daily subcutaneously, starting at a dose of 3 million units (MU). The dose was escalated every 7 days from 3 to 9 MU (by increments of 3 MU), unless >/= grade 2 toxicity occurred, in which case dose escalation was stopped. Patients randomized to combination therapy were given oral 13-CRA 1 mg/kg/d plus IFNalpha2a. Quality of life (QOL) was assessed.

RESULTS: Complete or partial responses were achieved by 12% of patients treated with IFNalpha2a plus 13-CRA and 6% of patients treated with IFNalpha2a (P =.14). Median duration of response (complete and partial combined) in the group treated with the combination was 33 months (range, 9 to 50 months), versus 22 months (range, 5 to 38 months) for the second group (P =.03). Nineteen percent of patients treated with IFNalpha2a plus 13-CRA were progression-free at 24 months, compared with 10% of patients treated with IFNalpha2a alone (P =.05). Median survival time for all patients was 15 months, with no difference in survival between the two treatment arms (P =.26). QOL decreased during the first 8 weeks of treatment, and a partial recovery followed. Lower scores were associated with the combination therapy.

CONCLUSION: Response proportion and survival did not improve significantly with the addition of 13-CRA to IFNalpha2a therapy in patients with advanced RCC. 13-CRA may lengthen response to IFNalpha2a therapy in patients with IFNalpha2a-sensitive tumors. Treatment, particularly the combination therapy, was associated with a decrease in QOL.

A randomized phase II trial comparing two different sequence combinations of autologous vaccine and human recombinant interferon gamma and human recombinant interferon alpha2B therapy in patients with metastatic renal cell carcinoma: clinical outcome and analysis of immunological parameters.

Schwaab T, Heaney JA, Schned AR, Harris RD, Cole BF, Noelle RJ, Phillips DM, Stempkowski L, Ernstoff MS.

Norris Cotton Cancer Center, Department of Surgery, Lebanon, New Hampshire, USA.

J Urol 2000 Apr;163(4):1322-7 Abstract quote

PURPOSE: The clinical observation of spontaneous regression in patients with renal cell carcinoma (RCC) and the response to various immunotherapeutic therapies strongly suggest a role for the host immune system in this disease. Prior studies showed that sequential administration of interferon (IFN) gamma and IFN alpha to RCC patients was safe. Clinical responses as well as immune changes in the peripheral blood mononuclear cell compartment were observed. Autologous tumor cell vaccines (AV) have also demonstrated activity in renal cell carcinoma. We hypothesize that the addition of AV to sequential IFN gamma and a therapy might improve the tumor-specific immune response by providing an appropriate source of antigen in the appropriate cytokine environment. To our knowledge, this is the first trial using AV combined with IFN alpha and IFN gamma. The purpose of this study was to evaluate the feasibility of manufacturing and administering (AV) from resected tumor samples, and administration of AV with combination IFN gamma and IFN alpha therapy. Finally, the impact on immunological parameters of these treatment options was assessed.

MATERIALS AND METHODS: Patients with metastatic RCC were randomly assigned to receive AV plus bCG along with a sequential administration of IFN gamma and a either together or after initiation of vaccine. Toxicity and clinical responses were evaluated. Modulations of the immune system were investigated by analyzing phenotype, cytokine mRNA expression, T cell proliferation and cytotoxicity in the peripheral blood mononuclear cell compartment.

RESULTS: Fourteen patients with metastatic renal cell carcinoma were enrolled in this study; 9 were available for response evaluation. In a 70 day period, 3 (33%) showed mixed responses, 5 (56%) stable disease and 1 (11%) progression of disease. Toxicities were consistent with previous clinical reports. In the flow-cytometry phenotype analysis, stimulation of distinct subsets of circulating T-lymphocytes and a decrease of CD8+ T cell subsets was demonstrated. T-cell proliferation to allogeneic tumor cell stimulation improved following treatment. IL-4 and IL-5 mRNA levels were reduced in all patients after treatment. Patients who responded to treatment did not produce any IL-4 mRNA at all, before or after treatment.

CONCLUSIONS: AV with IFNgamma and IFNalpha therapy might induce a MHC class-mediated cytotoxic T lymphocyte (CTL) response. We suggest that adequate therapy might direct T cell response toward a Th1 type response. We hypothesize a state of improved immune readiness in patients who might eventually respond to immunotherapy.

Placebo-associated remissions in a multicentre, randomized, double-blind trial of interferon gamma-1b for the treatment of metastatic renal cell carcinoma.

The Canadian Urologic Oncology Group. Elhilali MM, Gleave M, Fradet Y, Davis I, Venner P, Saad F, Klotz L, Moore R, Ernst S, Paton V.

Department of Urology at the Royal Victoria Hospital (MUHC), Canada.

BJU Int 2000 Oct;86(6):613-8 Abstract quote

OBJECTIVE: To determine the validity of using an historical maximum spontaneous regression rate (reportedly 0-1.1% in those with lung metastases after nephrectomy) in clinical trials of treatments for patients with metastatic renal cell carcinoma (RCC), as the eligibility criteria for most studies will select patients with better performance status (and thus excluding those who are unlikely to respond) and more modern staging methods would potentially reduce the number of false-positives.

PATIENTS AND METHODS: A multicentre randomized,placebo-controlled, double-blind trial was recently completed in which 197 patients with metastatic RCC from 17 study centres across Canada were randomized to receive placebo or recombinant interferon gamma-1b (60 microg/m2) subcutaneously once every 7 days until disease progression. All tumour responses were validated by an independent response committee unaware of the treatment.

RESULTS: The median (95% confidence interval) overall response rate (complete, CR, and partial, PR) for those on interferon-gamma was 4 (1.4-11.5)% and for those on placebo was 6 (2. 5-13.2)% (P = 0.75). In the six patients who were receiving placebo the CR and PR (three each) was considered to represent spontaneous remission. Of these six patients (aged 44-64 years) five had undergone nephrectomy, one a tumour embolization, four had clear cell carcinoma and one an adenocarcinoma, and all had regression of lung and/or lymph node metastases.

CONCLUSION: The lack of efficacy of interferon-gamma in this trial underlines the importance of continued research to identify alternative therapeutic agents or combinations of agents in phase II studies. However, the threshold response rate for initiating phase III trials should be increased to 18% in the phase II trials, i.e. three times the response rate on placebo.

Randomized multicenter phase II trial of subcutaneous recombinant human interleukin-12 versus interferon-alpha 2a for patients with advanced renal cell carcinoma.

Motzer RJ, Rakhit A, Thompson JA, Nemunaitis J, Murphy BA, Ellerhorst J, Schwartz LH, Berg WJ, Bukowski RM.

Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

J Interferon Cytokine Res 2001 Apr;21(4):257-63 Abstract quote

Recombinant human interleukin-12 (rHuIL-12) is a pleiotropic cytokine with anticancer activity against renal cell carcinoma (RCC) in preclinical models and in a phase I trial.

A randomized phase II study of rHuIL-12 compared with interferon-alpha (IFN-alpha) evaluated clinical response for patients with previously untreated, advanced RCC. Patients were randomly assigned 2:1 to receive either rHuIL-12 or IFN-alpha2a. rHuIL-12 was administered by subcutaneous (s.c.) injection on days 1, 8, and 15 of each 28-day cycle. The dose of IL-12 was escalated during cycle 1 to a maintenance dose of 1.25 microg/kg. IFN was administered at 9 million units by s.c. injection three times per week. Serum concentrations of IL-12, IFN-gamma, IL-10, and neopterin were obtained in 10 patients treated with rHuIL-12 after the first full dose of 1.25 microg/kg given on day 15 (dose 3) of cycle 1 and again after multiple doses on day 15 (dose 6) of cycle 2.

Thirty patients were treated with rHuIL-12, and 16 patients were treated with IFN-alpha. Two (7%) of 30 patients treated with rHuIL-12 achieved a partial response, and the trial was closed to accrual based on the low response proportion. IL-12 was absorbed rapidly after s.c. drug administration, with the peak serum concentration appearing at approximately 12 h in both cycles. Serum IL-12 concentrations remained stable on multiple dosing. Levels of IFN-gamma, IL-10, and neopterin increased with rHuIL-12 and were maintained in cycle 2. rHuIL-12 is a novel cytokine with unique pharmacologic and pharmacodynamic features under study for the treatment of malignancy and other medical conditions.

The low response proportion associated with rHuIL-12 single-agent therapy against metastatic RCC was disappointing, given the preclinical data. Further study of rHuIL-12 for other medical conditions is underway. For RCC, the study of new cytokines is of the highest priority.


Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma.

Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P, Steinberg GD, Belldegrun AS.

University of California, Los Angeles, Los Angeles, CA, USA.

J Clin Oncol 1999 Aug;17(8):2521-9 Abstract quote

PURPOSE: To prospectively evaluate in a multicenter randomized trial the antitumor activity of CD8(+) tumor-infiltrating lymphocytes (TILs) in combination with low-dose recombinant interleukin-2 (rIL-2), compared with rIL-2 alone, after radical nephrectomy in metastatic renal cell carcinoma patients.

PATIENTS AND METHODS: Between December 1994 and March 1997, 178 patients with resectable primary tumors were enrolled at 29 centers in the United States and Europe. Patients underwent total nephrectomy, recovered, and were randomized to receive either CD8(+) TILs (5 x 10(7) to 3 x 10(10) cells intravenously, day 1) plus rIL-2 (one to four cycles: 5 x 10(6) IU/m(2) by continuous infusion daily for 4 days per week for 4 weeks) (TIL/rIL-2 group) or placebo cell infusion plus rIL-2 (identical regimen) (rIL-2 control group). Primary tumor specimens were cultured at a central cell-processing center in serum-free medium containing rIL-2 to generate TILs.

RESULTS: Of 178 enrolled patients, 160 were randomized (TIL/rIL-2 group, n = 81; rIL-2 control group, n = 79). Twenty randomized patients received no treatment after nephrectomy because of surgical complications (four patients), operative mortality (two patients), or ineligibility for rIL-2 therapy (14 patients). Among 72 patients eligible for TIL/rIL-2 therapy, 33 (41%) received no TIL therapy because of an insufficient number of viable cells. Intent-to-treat analysis demonstrated objective response rates of 9.9% v 11.4% and 1-year survival rates of 55% v 47% in the TIL/rIL-2 and rIL-2 control groups, respectively. The study was terminated early for lack of efficacy as determined by the Data Safety Monitoring Board.

CONCLUSION: Treatment with CD8(+) TILs did not improve response rate or survival in patients treated with low-dose rIL-2 after nephrectomy.

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