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Background
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.
OUTLINE
EPIDEMIOLOGIC ASSOCIATIONS CHARACTERIZATIONS SYNONYMS Hypernephroma
Adenocarcinoma of the kidneyINCIDENCE 1-3% of visceral cancers
30,000 new cases per year
12,000 deaths per yearAGE RANGE AND MEDIAN 6-7th decades
Department of Pediatrics, Division of Haematology/Oncology, Division of Pathology, Hospital for Sick Children, Toronto, Canada.
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 GEOGRAPHIC DISTRIBUTION Worldwide 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
DISEASE ASSOCIATIONS CHARACTERIZATION ACQUIRED CYSTIC DISEASE (HEMODIALYSIS)
- 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.
AMYLOIDOSIS 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.
BIRT-HOGG-DUBE SYNDROME
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.
HLRCC SYNDROME (HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CARCINOMA)
*Laboratory of Pathology †Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
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.
PATHOGENESIS CHARACTERIZATION ALPHA-TFEB GENE
- 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
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.PTCH GENE
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 GENE 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 PRCC gene in papillary carcinomas Found on chromosome 1
Implicated in childhood sporadic tumors with X;1 translocationVHL GENE 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 inactivationSPARC 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)
(TFE3 FUSION)
LABORATORY/
RADIOLOGICCHARACTERIZATION Polycythemia Hypercalcemia Hepatic dysfunction Cushing syndrome Eosinophilia Leukemoid reactions
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
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, MDAm 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
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.VARIANTS ADENOMA
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.ALVEOLAR SOFT-PART SARCOMA-LIKE (ASPL-TFE3 FUSION GENE) 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.
ANGIOLEIOMYOMA-LIKE
*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.
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.CHROMOPHOBE CLEAR CELL (NONPAPILLARY) Most common type
70-80% of all types
Cells with clear or granular cytoplasm staining for glycogen and lipid
Delicate branching vasculatureCOLLECTING DUCT CARCINOMA
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.
CYSTIC AND NECROTIC 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.
MEDULLARY CARCINOMA
1State University of Campinas, São Paulo, Brazil.
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.MUCINOUS TUBULAR AND SPINDLE CELL CARCINOMA
*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.
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
- 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.ONCOCYTOMA
- 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
*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.
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,