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.

EPIDEMIOLOGIC ASSOCIATIONS	CHARACTERIZATIONS
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
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)
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.
von Hippel-Lindau (VHL) syndrome	Up to 2/3 of patients develop multiple renal cysts and bilateral multiple renal cell CA VHL gene
Hereditary clear cell carcinoma	Confined to the kidney No stigmata of VHL but defects in the 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.
Hereditary papillary carcinoma	Autosomal dominant form with multiple bilateral tumors Mutations in the MET protooncogene

 

PATHOGENESIS	CHARACTERIZATION
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
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
Chromophobe cells in chromophobe renal carcinoma	Cells are derived from the intercalated cells of the collecting duct
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.

 

LABORATORY/RADIOLOGIC/OTHER TESTS	CHARACTERIZATION
Polycythemia
Hypercalcemia
Hepatic dysfunction
Cushing syndrome
Eosinophilia
Leukemoid reactions

 

GROSS APPEARANCE	CHARACTERIZATION
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
METASTATIC TUMORS
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.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
ALVEOLAR SOFT-PART SARCOMA-LIKE
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.
CHROMOPHOBE	Pale eosinophilic cells with a perinuclear halo Solid sheets with concentration of largest cells around blood vessels
The utility of epithelial membrane antigen and vimentin in the diagnosis of chromophobe renal cell carcinoma. Khoury JD, Abrahams NA, Levin HS, MacLennan GT. Department of Pathology, Case Western Reserve University/University Hospitals of Cleveland; the and Department of Anatomic Pathology, The Cleveland Clinic Foundation, Cleveland, OH.	Ann Diagn Pathol 2002 Jun;6(3):154-8 Abstract quote We evaluated the immunohistochemical expression of epithelial membrane antigen (EMA) and vimentin (VMT) in chromophobe renal cell carcinoma (CHRCC). We also studied the utility of EMA and VMT immunostains in helping differentiate CHRCC from renal oncocytoma and conventional (clear cell) renal cell carcinoma with granular morphology (GCRCC). Immunohistochemical staining for EMA and VMT was performed on 21 cases of CHRCC, 16 cases of renal oncocytoma, and 28 cases of GCRCC. The diagnosis in all cases was by concurrence of all pathologists involved in the study and was based entirely on examination of routinely stained slides. All cases were classic examples of these tumor types and presented no diagnostic difficulties. The intensity of immunohistochemical staining was graded on a scale of 0 to 3 (0 = no staining; 1 = equivocal; 2 = unequivocal, moderate intensity; and 3 = unequivocal, high intensity). Positive immunohistochemical staining was defined as unequivocal staining of at least 20% of the neoplastic cells. All cases of CHRCC were positive for EMA and negative for VMT. The same immunophenotype was observed in 75% of renal oncocytoma and 21% of GCRCC. In summary, all CHRCC cases in our study demonstrated immunohistochemical staining for EMA and not VMT. However, we also found that the same immunophenotype is observed in 75% of renal oncocytoma and in 21% of GCRCC, precluding its utility for positive identification of CHRCC. Nevertheless, the lack of such an immunophenotype is a reliable indication that a neoplasm under consideration is not CHRCC.
Cytokeratins 7 and 20 immunoreactivity in chromophobe renal cell carcinomas and renal oncocytomas. Wu SL, Kothari P, Wheeler TM, Reese T, Connelly JH. Department of Pathology and Laboratory Medicine, University of Texas-Houston Medical School (SLW, JHC).	Mod Pathol 2002 Jul;15(7):712-7 Abstract quote Chromophobe renal cell carcinomas and renal oncocytomas share morphologic similarities and may present a diagnostic challenge on routine hematoxylin-eosin staining. Currently recommended additional studies of Hale's colloidal iron staining and electron microscopy are often difficult to interpret and technically challenging and may not be readily available. Previous studies have reported conflicting results with regard to the cytokeratin 7 staining pattern in chromophobe renal cell carcinomas and renal oncocytomas. Cytokeratin 20 expression in chromophobe renal cell carcinomas has not pre-viously been studied. Formalin-fixed paraffin-embedded tissue of 11 chromophobe renal cell carcinomas and 21 renal oncocytomas were retrieved from the archived files (1984-2000) of four teaching hospitals. Of the 11 chromophobe renal cell carcinomas, eight stained positive (73%) for cytokeratin 7, one stained focally positive (9%), and two cases (18%) were completely negative. Cytokeratin 7 staining of the 21 oncocytomas revealed 4 positive (19%), 7 focally positive (33%), and 10 negative cases (48%). Cytokeratin 20 was uniformly negative on all 11 cases of chromophobe renal cell carcinomas and all 21 cases of oncocytomas. Cytokeratin 7 does not appear to show the consistent immunoreactivity in chromophobe renal cell carcinomas and renal oncocytomas, as has been previously suggested. ytokeratin 20 immunostaining in chromophobe renal cell carcinomas and renal oncocytomas is uniformly negative. Despite the technical and interpretive challenges of Hale's colloidal iron, it is still the most useful stain in differentiating chromophobe renal cell carcinomas from renal oncocytomas.
Chromophobe renal cell carcinoma with extensive calcification and ossification. Wu SL, Fishman IJ, Shannon RL. Department of Pathology and Laboratory Medicine, University of Texas-Houston Medical School; the Department of Urology, Baylor College of Medicine, Houston; and the Department of Pathology, St. Luke's Episcopal Hospital, Houston, TX.	Ann Diagn Pathol 2002 Aug;6(4):244-7 Abstract quote A 39-year-old woman presenting with microscopic hematuria was found to have an extensively calcified mass in the upper pole of the right kidney. Gross and histologic examination of the nephrectomy specimen revealed a 9.3-cm renal tumor composed of solid trabecular sheets of polygonal epithelial cells with clear cytoplasm and distinct cell borders characteristic of a chromophobe renal cell carcinoma. Electron microscopy showed the presence of numerous intracytoplasmic microvesicles, thereby confirming the diagnosis. However, the unique additional feature of this tumor included the presence of dense calcification and ossification throughout the tumor. To our knowledge, we report the first case of chromophobe renal cell carcinoma with the concomitant presence of extensive calcification and ossification. A literature review on chromophobe renal cell carcinoma with either calcification or ossification is performed.
Chromophobe renal cell carcinoma with osteosarcoma-like differentiation. Itoh T, Chikai K, Ota S, Nakagawa T, Takiyama A, Mouri G, Shinohara N, Yamashita T, Suzuki S, Koyanagi T, Nagashima K.	Am J Surg Pathol 2002 Oct;26(10):1358-62 Abstract quote Sarcomatoid differentiation in renal cell carcinoma is thought to be the result of the dedifferentiation of the parent tumor, and it can be found in the chromophobe renal cell carcinoma just as other subtypes. We report a case of chromophobe renal cell carcinoma, which showed osteosarcoma-like differentiation. This is the first known case ever to be clearly identified as such. The patient was a 74-year-old man, and the CT scan revealed a huge retroperitoneal mass, which protruded from the lower half of the kidney and directly invaded the colon. Intraabdominal dissemination and metastases to the liver and lungs were also found. The resected tumor histologically showed sarcoma-like spindle cell proliferation and partly produced massive osteoid, which simulated the osteosarcoma. In addition, a typical histology of chromophobe renal cell carcinoma was found in part of the tumor. Immunohistochemically, spindle cells were reactive for epithelial membrane antigen, cytokeratin, and vimentin. The cell nests that were labeled by epithelial membrane antigen and cytokeratin were also found in the osteosarcoma-like area. We think that these phenomena were the result of "dedifferentiation" and metaplasia of the chromophobe renal cell carcinoma.
CLEAR CELL (NONPAPILLARY)	Most common type 70-80% of all types Cells with clear or granular cytoplasm staining for glycogen and lipid Delicate branching vasculature
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.
PAPILLARY	Cuboidal or low columnar cells arranged in papillae Psamomma bodies may be present
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.
RHABDOID FEATURES
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
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) Conclusion: 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.

 

SPECIAL STAINS/IMMUNOPEROXIDASE/OTHER	CHARACTERIZATION
PAS with diastase sensitivty	Reveals glycogen within the clear cells
Sudan black, oil red o	Reveals fat within the clear cells
PARVALBUMIN
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.
MRP-1
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.
RENAL CELL CARCINOMA MARKER
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.
ELECTRON MICROSCOPY
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.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
CARCINOID TUMOR
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.
MIXED EPITHELIAL AND STROMAL TUMOR
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
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.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS	Chromophobe renal carcinomas have best prognosis
GENERAL
HISTOPATHOLOGY
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.
INSULIN-LIKE GROWTH FACTOR-1 RECEPTOR
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.
LOSS OF HETEROZYGOSITY
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
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.
PAX-2
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.
PROLIFERATION MARKERS
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.
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 Liver Adrenals Brain Skin
Staging
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.
TREATMENT
SURGERY
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.
INTERFERONS
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.
TUMOR INFILTRATING LYMPHOCYTES
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.

Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.

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