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Background
This is rare type of kidney cancer. Chromophobe RCC is a well-circumscribed, light brown tumor that only rarely demonstrates hemorrhage or necrosis.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION AGE Adults SEX Equal
DISEASE ASSOCIATIONS CHARACTERIZATION ACQUIRED CYSTIC DISEASE
Chromophobe cell renal carcinoma with acquired cystic disease of the kidney in a long-term hemodialysis patient.
Fujimoto K, Anai S, Okajima E, Cho M, Yoshida K, Ozono S, Hirao Y, Kikkawa A.
Department of Urology, Nara Medical University, Kashihara, Ikoma, Japan.
Int J Urol. 2003 Feb;10(2):99-102 Abstract quote.
We report a rare case of chromophobe cell renal carcinoma found in a 52-year-old female who had received hemodialysis therapy for 13 years. She was diagnosed as having a left renal tumor 7.5 cm in diameter with acquired cystic disease of the kidney (ACDK) by ultrasonographic examination during periodical systemic screening.As abdominal computed tomography scanning and enhanced color Doppler ultrasonography suspected that the hypervascular tumor was renal cell carcinoma, she underwent translumbar nephrectomy in July 2000. The histopathological diagnosis was chromophobe cell carcinoma with pT2 and grade 2 malignancy.
Chromophobe cell carcinoma is uncommon among renal tumors with ACDK found in long-term hemodialysis patients.
PATHOGENESIS CHARACTERIZATION Chromophobe cells in chromophobe renal carcinoma Chromophobe cells are derived from the intercalated cells of the collecting duct CHROMOSOMAL ALTERATIONS
- Eosinophilic and classic chromophobe renal cell carcinomas have similar frequent losses of multiple chromosomes from among chromosomes 1, 2, 6, 10, and 17, and this pattern of genetic abnormality is not present in renal oncocytoma.
Brunelli M, Eble JN, Zhang S, Martignoni G, Delahunt B, Cheng L.
[1] 1Department of Pathology and Laboratory Medicine, Universita di Verona, Verona, Italy [2] 2Dipartimento di Patologia, Universita di Verona, Verona, Italy.
Mod Pathol. 2004 Oct 01; Abstract quote
That chromophobe renal cell carcinoma has an uncommon eosinophilic variant has been recognized for more than a decade. In sections stained with hematoxylin and eosin, the eosinophilic variant of chromophobe renal cell carcinoma and renal oncocytoma are similar in appearance. While it is well established that chromophobe renal cell carcinoma and renal oncocytoma have different patterns of genetic anomalies, little is known of the genetics of the eosinophilic variant of chromophobe renal cell carcinoma.
This study was undertaken to elucidate the genetic lesions of eosinophilic chromophobe renal cell carcinoma and to compare them with those found in classic chromophobe renal cell carcinoma and in renal oncocytoma. A total of 29 renal neoplasms-nine eosinophilic chromophobe renal cell carcinomas, 10 classic chromophobe renal cell carcinomas, and 10 oncocytomas-were investigated by fluorescence in situ hybridization on 5 mum paraffin-embedded tissue sections with centromeric probes for chromosomes 1, 2, 6, 10, and 17. Signals were counted in 100-200 neoplastic nuclei from each tumor. Chromophobe renal cell carcinomas frequently showed loss of chromosomes 1 (70% of classic, 67% of eosinophilic), 2 (90% classic, 56% eosinophilic), 6 (80% classic, 56% eosinophilic), 10 (60% classic, 44% eosinophilic), and 17 (90% classic, 78% eosinophilic); Among the classic chromophobe renal cell carcinomas, only one had no loss of any of the chromosomes, while 50% had loss of all five chromosomes. Among the eosinophilic chromophobe renal cell carcinomas, one of nine had no loss and 44% had loss of all five chromosomes. One oncocytoma had loss of chromosome 1. No other chromosomal loss was detected in the oncocytomas. In conclusion, losses of chromosomes 1, 2, 6, 10, and 17 are frequent in both eosinophilic and classic chromophobe renal cell carcinomas. Loss of chromosome 1 occurs occasionally in oncocytoma but losses of chromosomes 2, 6, 10, and 17 are not found in oncocytomas.
When the differential diagnostic problem is oncocytoma vs eosinophilic chromophobe renal cell carcinoma, detection of losses of chromosomes 2, 6, 10, or 17 effectively excludes the diagnosis of oncocytoma and supports the diagnosis of chromophobe renal cell carcinoma.RON PROTO-ONCOGENE 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.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL
Review of chromophobe renal cell carcinoma with focus on clinical and pathobiological aspects.
Kuroda N, Toi M, Hiroi M, Enzan H.
First Department of Pathology, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan.
Histol Histopathol. 2003 Jan;18(1):165-71. Abstract quote
In recent years, the concept of chromophobe renal cell carcinoma (RCC) has been established. Chromophobe RCCs account for about 4-6% of all renal tumors.Macroscopically, the cut surface of the tumor is generally grey-beige in color. Histologically, there are two variants (typical and eosinophilic). In the typical variant, large tumor cells with architecture of a compact tubulo-cystic pattern proliferate. The cytoplasm is abundant and shows a fine reticular translucent pattern. The cell border is thick, prominent and eosinophilic. In the eosinophilic variant, tumor cells are smaller and markedly eosinophilic, and a perinuclear halo is often seen.
Histochemically, the tumor cells generally show a diffuse and strong reaction for Hale's colloidal iron staining. Ultrastructurally, tumor cells contain many cytoplasmic microvesicles (150-300 nm). In chromosomal analysis, a low chromosome number is characteristic of chromophobe RCCs, due to the frequent occurrence of a combined loss of chromosomes 1, 2, 6, 10, 13, 17, and 21.
In differential diagnosis, histological distinction from oncocytomas, which share a common phenotype (intercalated cells of the collecting duct system), is most important. In this diagnostic setting, recent studies have given rise to several problems. Firstly, some cases of coexistent chromophobe RCC and oncocytoma (so-called renal oncocytosis) or cases of oncocytoma with metastasis have recently been reported.
Secondly, the existence of chromophobe adenoma, which is the benign counterpart of chromophobe RCC, and an oncocytic variant of chromophobe RCC has recently been suggested. Therefore, further studies are needed to elucidate the relationship between chromophobe RCCs and oncocytomas, to confirm whether chromophobe adenoma actually exists or not, and to identify the key gene that causes chromophobe RCCs.
Chromophobe renal cell carcinoma: clinical, pathological and molecular biological aspects.
Nagashima Y.
Department of Pathology, Yokohama City University School of Medicine, Yokohama, Japan.
Pathol Int. 2000 Nov;50(11):872-8 Abstract quote.
Chromophobe renal cell carcinoma (RCC), a newly established subtype of renal neoplasm, is composed of tumor cells with characteristically cloudy, weakly eosinophilic and reticular cytoplasm.The tumor should be distinguished from the common clear cell RCC, because of the unique clinicopathological and molecular biological features. The tumor does not show gender bias. Patient ages are similar to those of clear cell RCC, but might occur in the 20- to 40-year-old age group. Grossly, the tumor tends to be beige in color, which is different from the yellowish color of common RCC. Electron microscopy and immunohistochemistry indicate the intercalated cell of the collecting duct as the cellular origin. Cytogenetic study shows non-random multiple chromosome loss, with mitochondrial DNA rearrangement.
Alteration of the von Hippel-Lindau (VHL) gene, a cancer suppressor gene relating with clear cell RCC, has not yet been observed. In order to adopt the most appropriate treatment, including gene therapy, recognition and correct pathological diagnosis of chromophobe RCC are extremely important.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL Pale eosinophilic cells with a perinuclear halo
Solid sheets with concentration of largest cells around blood vesselsSolid architecture is the most predominant pattern
Most tumors are nuclear grades III and IV
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.
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.
VARIANTS HYBRID
- Hybrid chromophobe renal cell neoplasm.
Mai KT, Dhamanaskar P, Belanger E, Stinson WA.
Division of Anatomical Pathology, Department of Laboratory Medicine, The Ottawa Hospital-Civic Campus, 1053 Carling Avenue, Ottawa, Ont., Canada, K1Y 4E9.
Pathol Res Pract. 2005;201(5):385-9. Abstract quote
Hybrid renal cell neoplasms (HRCNs) containing areas of tumor cells displaying cytological features of chromophobe renal cell carcinoma (CHRCC) and renal oncocytoma (RO) have been recently described in patients with renal oncocytosis and Birt-Hogg-Dube (BHD) syndrome (autosomal dominant genodermatosis). In this study, we identified cases of sporadic HRCN.
We reviewed 425 consecutive renal cell carcinomas (RCC), 18 CHRCC, six HRCN, and 25 RO. Five HRCN were identified, including four from the group of RCC and two from RO. Patient age ranged from 40 to 68 years (mean age: 54 years), and the male:female ratio was 4:1. Tumors measured from 1.8 to 5 cm (mean diameter: 3.0 cm). Tumoral necrosis was not seen. Vascular invasion into medium-sized veins was identified in one HRCN. Chromophobe cells accounted for 20-80% of the tumors. Hale's colloidal stain showed weak to moderate diffuse cytoplasmic staining in scattered cells corresponding to those displaying routine staining features of chromophobe cells. Areas of oncocytic cells in studied tumors and control oncocytomas showed negative or focal cytoplasmic staining usually bordering extra- or intra-cytoplasmic lumina. Immunostaining for cytokeratin 7 and vimentin showed focal immunoreactivity in three cases and negative reactivity in all six cases, respectively.
None of the study cases had microscopic RO, as commonly seen in renal oncocytosis, or were associated with BHD syndrome Sporadic HRCN accounted for 1% of RCC. They were of smaller size than RCC and were associated with a favorable prognosis.OSTEOSARCOMA
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.
RHABDOID
Rhabdoid differentiation of chromophobe renal cell carcinoma.
Shannon BA, Cohen RJ.
Tissugen Pty Ltd, Perth, Western Australia.
Pathology. 2003 Jun;35(3):228-30. Abstract quote
AIMS: Rhabdoid change represents an aggressive form of divergent differentiation previously reported in conventional (clear-cell) and papillary renal cell carcinoma. This study aims to characterise rhabdoid differentiation in a case of chromophobe renal cell carcinoma (ChRCC) and to investigate its origin by genetic analysis.METHODS: A large tumour mass arising in the right kidney of a 76-year-old male was investigated using routine stains (H&E, Hale's colloidal iron), immunostains (vimentin, cytokeratin) and genetic analysis for loss of heterozygosity (LOH) on chromosomes 1, 2, 3p, 6q, 10q, 13q, 17q, 17p and 21q.
RESULTS: The tumour mass was comprised of the following histological subtypes: (i) typical ChRCC, (ii) eosinophilic variant ChRCC and (iii) rhabdoid variant RCC. Tumour cells of all three different histological subtypes had a positive reaction to Hale's colloidal iron stain, negative immunostaining for vimentin and LOH on chromosomes 2, 10q, 13q and 17p. These results are consistent with a diagnosis of ChRCC and indicate a common genetic origin for all three histological cell types.
CONCLUSIONS: This study confirms that the aggressive rhabdoid variant can arise from ChRCC, as has been previously demonstrated for conventional (clear-cell) and papillary RCC.
SARCOMATOID
Chromophobe renal cell carcinoma with sarcomatoid transformation.
Abrahams NA, Ayala AG, Czerniak B.
Ann Diagn Pathol. 2003 Oct;7(5):296-9. Abstract quote
We present a rare case of a chromophobe renal cell carcinoma that progressed to a high-grade spindle cell sarcoma. The tumor affected a 50-year-old man who had presented with right upper quadrant discomfort and hematuria and subsequently underwent a right radical nephrectomy.Microscopically, the tumor was composed of two distinct components, a chromophobe renal cell carcinoma and a sarcomatoid component. The sarcomatoid component had exhibited aggressive behavior by spreading to a regional lymph node.
This case report shows that chromophobe carcinoma can develop a sarcomatoid transformation with a high propensity for invasive growth and metastasis.
Renal cell carcinoma, chromophobe type, with collecting duct carcinoma and sarcomatoid components.
Gong Y, Sun X, Haines GK 3rd, Pins MR.
Department of Pathology, Northwestern University Medical School, Chicago, Ill 60611, USA.
Arch Pathol Lab Med. 2003 Jan;127(1):e38-40. Abstract quote
We report a case of a 72-year-old man with a chromophobe renal cell carcinoma that had both sarcomatoid and collecting duct carcinoma components. The 7-cm tumor occupied the entire lower pole of the kidney and infiltrated the renal parenchyma and the pelvic-calyceal system.Histologically, it had an area of classic chromophobe renal cell carcinoma that merged into a sarcomatoid component. Closely intermixed with the sarcomatoid component was a collecting duct carcinoma component characterized by highly pleomorphic, epithelioid cells arranged in cords, nests, and tubulomicrocystic structures. The cords, nests, and tubules were associated with a florid desmoplastic stromal response and numerous inflammatory cells. In addition, dysplastic changes were noted in adjacent nonneoplastic collecting duct epithelium. Immunohistochemical studies confirmed the presence of 3 distinct components in this patient's tumor.
To the best of our knowledge, this is the first reported case of a chromophobe renal cell carcinoma with sarcomatoid and collecting duct carcinoma components.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION SPECIAL STAINS Hale's colloidal iron stain reveals strong blue cytoplasmic staining
IMMUNOPEROXIDASE
Department of Pathology Unit, Mediterranean Institute of Oncology, Catania, Italy.
Immunohistochemical staining for cytokeratin 7 (CK7), KIT, and PAX2 expression was performed on 91 renal neoplasms, 37 conventional (clear cell) renal cell carcinomas (CRCCs), 20 papillary RCCs (PRCCs), 11 chromophobe RCCs (ChCs), and 23 oncocytomas, with available karyotypes.
All ChCs, 19 PRCCs, 2 CRCCs, and 1 oncocytoma were CK7+; all ChCs, 22 oncocytomas, 2 CRCCs, and no PRCCs expressed KIT; PAX2 was positive in 31 CRCCs, 17 PRCCs, 20 oncocytomas, and 1 ChC. The predominant expression profiles were as follows: CRCC, CK7-/KIT-/PAX2+ (26/37); PRCC, CK7+/KIT-/PAX2+ (17/20); ChC, CK7+/KIT+/PAX2- (10/11); and oncocytoma, CK7-/KIT+/PAX2+ (19/23).
Cytogenetic analysis showed that the sole PAX2+ ChC had a retained chromosome 10, and all ChCs with chromosome 10 loss were PAX2-.
These results identify specific staining patterns of the 4 major histologic subtypes of renal neoplasms and raise the question of a relationship between chromosome 10 loss and loss of PAX2 expression in ChC.Chromophobe renal cell carcinoma: an immunohistochemical study of 21 Japanese cases.
Taki A, Nakatani Y, Misugi K, Yao M, Nagashima Y.
Department of Pathology, Yokohama City University School of Medicine, Yokohama, Japan
Mod Pathol. 1999 Mar;12(3):310-7. Abstract quote
Chromophobe renal cell carcinoma (RCC) is a newly established category of RCC composed histologically of characteristic "chromophobe" tumor cells. Although ultrastructural and immunohistochemical studies showed that these tumor cells present several features similar to those found in the intercalated cells of the collecting duct, immunohistochemical studies using antibody panels on a large number of cases are limited.
We performed an immunohistochemical study of 21 Japanese cases of chromophobe RCC, along with cases of clear RCC and renal oncocytoma, to find hallmarks useful for precise differential diagnosis of these tumors. Chromophobe RCC was positive for epithelial membrane antigen but negative for vimentin. Cytokeratins did not show constant immunoreactivity in the three types of renal tumors. Furthermore, all of the chromophobe RCCs and renal oncocytomas were positive for E-cadherin but not for N-cadherin, whereas all of the clear RCCs were negative for E-cadherin, and 58% were positive for N-cadherin. The Ki-67 labeling indices were significantly lower in cases classified as (pT1) or Grade 2 chromophobe RCC than in cases of clear RCC.
Immunoreaction for E-cadherin was demonstrated to be useful for distinguishing chromophobe RCC from clear RCC, and a low Ki-67 labeling index might indicate a favorable prognosis, as reported in several previous studies.c-KIT
- KIT and RCC Are Useful in Distinguishing Chromophobe Renal Cell Carcinoma From the Granular Variant of Clear Cell Renal Cell Carcinoma.
Wang HY, Mills SE.
From the Robert E. Fechner Surgical Pathology Laboratory, Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, VA. The current address of Dr. Wang is Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
Am J Surg Pathol. 2005 May;29(5):640-646. Abstract quote
The distinction between chromophobe renal cell carcinoma, the granular cell variant of clear cell renal cell carcinoma, and renal oncocytoma is a common diagnostic dilemma.
The usefulness of KIT, CD10, RCC, and RON in the differential diagnosis of these renal epithelial tumors was investigated. KIT was 100% positive in chromophobe renal cell carcinoma (11 of 11) and renal oncocytoma (12 of 12). The KIT staining pattern was identical in both tumor types, with cytoplasmic membrane attenuation, and fine granular cytoplasmic staining. In contrast, KIT was absent in all granular cell variants of clear cell renal cell carcinoma (0 of 6). RCC was observed in more than 80% of the granular cell variant of clear cell renal cell carcinoma (5 of 6) but was negative in all chromophobe renal cell carcinomas (0 of 11) and renal oncocytomas (0 of 12). CD10 was expressed in 100% of the granular cell variant of clear cell renal cell carcinoma (6 of 6), 72% of chromophobe renal cell carcinomas (8 of 11), and 58% of renal oncocytomas (7 of 12). RON was 100% positive in the chromophobe renal cell carcinomas (11 of 11) and renal oncocytomas (12 of 12) but only 50% positive in the granular cell variant of clear cell renal cell carcinoma (3 of 6). Colloidal iron was diffusely and strongly positive in more than 80% of the chromophobe renal cell carcinomas (9 of 11), focally and weakly positive in 41% of the renal oncocytomas (5 of 12) but negative in all granular cell variant of clear cell renal cell carcinoma (0 of 6).
The above results demonstrate that: 1) KIT is a very sensitive marker for both chromophobe renal cell carcinoma and renal oncocytoma; 2) immunohistochemistry using antibodies to KIT combined with RCC was sufficient to discriminate between chromophobe renal cell carcinoma and the granular cell variant of clear cell renal cell carcinoma; and 3) neither RON, nor KIT, nor a combination of this panel can be used to distinguish chromophobe renal cell carcinoma from renal oncocytoma. Colloidal iron staining aided in this distinction for the majority of the chromophobe renal cell carcinomas (more than 80% positive) and renal oncocytomas (close to 60% negative).
- 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.
KIT Expression in Chromophobe Renal Cell Carcinoma: Comparative Immunohistochemical Analysis of KIT Expression in Different Renal Cell Neoplasms.
Petit A, Castillo M, Santos M, Mellado B, Alcover JB, Mallofre C.
Departments of *Pathology, Oncology, and Urology, Hospital Clinic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain.
Am J Surg Pathol. 2004 May;28(5):676-678. Abstract quote
The overexpression of c-Kit in chromophobe renal cell carcinoma (ChRCC) has been described by comparative gene expression analyses and has been proposed as a possible specific hallmark of this neoplasm. The aim of our study was to establish its immunohistochemical expression in a large series of ChRCC and to compare it with other renal neoplasms.
In our study, immunohistochemical characterization of KIT was performed in 87 renal neoplasms including 25 cases of ChRCC, 13 cases of renal oncocytoma, and 39 renal cell carcinomas (21 cases of conventional RCC [CRCC], 8 cases of CRCC with granular cell differentiation, and 10 cases of papillary RCC [PRCC]). Eighty-eight percent ChRCC and 71% oncocytomas showed immunohistochemical expression of KIT, while the other types of RCC studied were all negative. The meaning of immunohistochemical expression of KIT in ChRCC and oncocytomas is still unknown, but its immunohistochemical staining appears to be useful in distinguishing ChRCC from PRCC, CRCC, and its granular cell variant. Moreover, our findings support current models that consider that there is a histopathogenic relationship between oncocytoma and ChRCC.
Finally, it should be determined whether KIT plays a role in the tumorigenesis of ChRCC and oncocytoma and whether targeted therapy with STI-571, an inhibitor of KIT, could be effective in exceptional cases of ChRCC with metastatic extension or recurrence.CADHERIN-KIDNEY SPECIFIC
Mod Pathol. 2005 Jul;18(7):933-40. Abstract quote
Renal cell neoplasms are presumably derived from different cell types of the nephron. Clear cell and papillary renal cell carcinoma (RCC) are thought to be of proximal tubular origin, whereas oncocytoma and chromophobe RCC are derived from intercalated cells of distal nephron. A few molecules, such as RCC marker and CD10, have been shown to be markers for clear cell RCC and papillary RCC. Such markers are not yet available for renal tumors presumably of the distal nephron.
The expression of kidney-specific (Ksp) cadherin, a recently cloned gene thought to be transcribed exclusively in the kidney, was studied in normal human kidney, as well as in 105 primary renal neoplasms, including 42 clear cell RCC, 30 papillary RCC, 13 chromophobe RCC, and 20 oncocytomas. The expression patterns were compared with those of RCC marker. The Ksp-cadherin expression was noted preferentially in distal convoluted tubules with a basolateral membrane stain in normal kidney. All 13 chromophobe RCC and 19 of 20 oncocytomas showed diffuse and strong immunoreactivity for Ksp-cadherin, while only 14% clear cell RCC and 13% papillary RCC showed focal positivity. The RCC marker expression was detected in 85%, 98%, 15% and 0% of clear cell RCC, papillary RCC, chromophobe RCC, and oncocytoma, respectively. A few clear cell RCC and papillary RCC showed dual expression of both RCC marker and Ksp-cadherin, which appear to have distinct histologic features.
These results demonstrated high sensitivity and specificity of Ksp-cadherin for distal convoluted tubules, which can be used as adjunct for diagnosis of chromophobe RCC.
- Expression of kidney-specific cadherin distinguishes chromophobe renal cell carcinoma from renal oncocytoma.
Mazal PR, Exner M, Haitel A, Krieger S, Thomson RB, Aronson PS, Susani M.
Hum Pathol. 2005 Jan;36(1):22-8 Abstract quote.
Summary Distinguishing renal oncocytoma from chromophobe and other renal carcinomas is essential, considering their differing biological potentials. Although renal oncocytoma is considered a benign tumor, chromophobe renal cell carcinoma has potentially malignant biological behavior. The numerous reported studies on distinguishing these 2 entities have been based on morphological, histochemical, immunohistochemical, ultrastructural, and cytogenetic features. But none of these features has proven to be reliably specific, especially in tumors with overlapping phenotypes.
We report a novel immunohistochemical approach based on the expression of a recently described kidney-specific cadherin (Ksp-cadherin) for the differential diagnosis of these 2 tumors. We compared Ksp-cadherin expression in 212 renal tumors, including 102 clear cell renal carcinomas, 46 papillary renal cell carcinomas, 30 chromophobe carcinomas, 3 collecting duct carcinomas, and 31 oncocytomas. In addition, we examined the expression of epithelial membrane antigen, vimentin, CK7, and Hale's colloidal iron staining.
We found that chromophobe renal cell carcinomas consistently (96.7% of cases) demonstrated a distinctive membrane pattern of Ksp-cadherin expression, whereas renal oncocytomas (3.2%), clear cell renal cell carcinomas (0%), papillary renal cell carcinomas (2.2%), and collecting duct carcinomas (0%) usually did not express Ksp-cadherin. CK7 expression was found in 90.0%, 6.5%, 7.8%, 76.1%, and 33.3% of these tumor cases, respectively. Whereas CK7 was detected in different types of renal cell carcinomas, Ksp-cadherin was expressed almost exclusively in chromophobe renal cell carcinomas.
Immunohistochemical analysis of Ksp-cadherin offers a fast, reliable approach for the distinguishing between renal oncocytoma and chromophobe renal cell carcinoma that is applicable for routine pathology laboratory studies without the need for time-consuming and costly ancillary studies.CD10
- CD10 is expressed in a subset of chromophobe renal cell carcinomas.
Martignoni G, Pea M, Brunelli M, Chilosi M, Zamo A, Bertaso M, Cossu-Rocca P, Eble JN, Mikuz G, Puppa G, Badoual C, Ficarra V, Novella G, Bonetti F.
1Anatomia Patologica, Universita di Sassari, Sassari, Italy.
Mod Pathol. 2004 Dec;17(12):1455-63. Abstract quote
CD10 has been considered a useful marker in the diagnosis of renal carcinomas, because of its expression in clear cell and papillary renal cell carcinomas and its absence in chromophobe renal cell carcinomas. On the other hand, chromophobe renal cell carcinoma expresses parvalbumin, which is absent in clear cell and papillary renal cell carcinomas.
To further address the relevance of these markers, we studied the expression of CD10 and parvalbumin in 42 samples of chromophobe renal cell carcinoma (seven of which had aggressive features, including invasion beyond the renal capsule, renal vein invasion, metastases, or sarcomatoid transformation), 75 clear cell renal cell carcinomas (eight metastatic) and 51 papillary renal cell carcinomas (two metastatic). CD10 was found in 100% of clear cell renal cell carcinomas, 63% of papillary renal cell carcinomas and in all metastatic cases of both types. At variance with previous studies, we found CD10 expression in from 30 to 90% of the neoplastic cells, in 11 of 42 (26%) chromophobe renal cell carcinomas. The CD10-positive cases included five of the seven (71%) chromophobe renal cell carcinoma with aggressive features. Statistical analysis showed significant association of CD10-positive tumors with clinicopathologic aggressiveness (P=0.003) and mitotic figures (P=0.04). Parvalbumin was strongly expressed in all primary and metastatic chromophobe renal cell carcinomas.
Western blot analysis was utilized to confirm the expression of both CD10 and parvalbumin in chromophobe renal cell carcinomas.CYTOKERATIN
- Distribution of Cytokeratins and Vimentin in Adult Renal Neoplasms and Normal Renal Tissue: Potential Utility of a Cytokeratin Antibody Panel in the Differential Diagnosis of Renal Tumors.
Skinnider BF, Folpe AL, Hennigar RA, Lim SD, Cohen C, Tamboli P, Young A, de Peralta-Venturina M, Amin MB.
From the *Department of Pathology, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada; daggerDepartment of Pathology, Emory University School of Medicine, Atlanta, GA; double daggerDepartment of Pathology, William Beaumont Hospital, Detroit, MI; and the section signDepartment of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX.
Am J Surg Pathol. 2005 Jun;29(6):747-754. Abstract quote
Adult renal epithelial neoplasms (RENs) comprise several distinct clinicopathologic entities with potential prognostic and therapeutic differences. Individual cases can show overlapping morphologic features, necessitating the use of ancillary methods.
The purpose of this study was to determine the diagnostic utility of cytokeratin (CK) subtype expression pattern in a wide range of adult RENs. RENs (including clear cell [conventional] renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, renal oncocytoma, collecting duct carcinoma (CDC), renal medullary carcinoma (RMC), urothelial carcinoma, metanephric adenoma (MA), tubulocystic carcinoma (TC) (also known as low-grade collecting duct carcinoma), and mucinous tubular and spindle cell carcinoma) were immunostained for CK subtypes (CK5/CK6, 7, 8, 13, 14, 17, 18, 19, 20), high molecular weight CKs 1, 5, 10, 14 (HMWCK), and vimentin (Vim). The expression pattern of normal kidney was also examined and correlated with RENs. Although there is some overlap, subtypes of RENs show distinctive CK expression profiles that may be useful in several differential diagnostic settings. Clear cell RCCs typically showed a restricted expression pattern of CK8, CK18 and Vim. Papillary RCCs typically expressed CK7, CK8, CK18, CK19, and Vim and could be distinguished from MA (CK7-). Chromophobe RCCs were typically CK7+, CK8+, CK18+, and Vim-, and could be distinguished from oncocytomas (typically CK7-).
In oncocytomas, nonspecific staining of unblocked endogenous biotin is a potentially significant diagnostic pitfall. CDC, RMC, and TC demonstrated similar CK expression profiles (with the exception of HMWCK expression limited to CDC), supporting a close relationship between these entities. A panel of CK5/CK6, CK17, and Vim may be helpful in distinguishing CDC (typically CK5/CK6-, CK17-, Vim+) and urothelial carcinoma (typically CK5/CK6+, CK17+, Vim-).
In conclusion, CK expression patterns may be helpful in several differential diagnostic situations when dealing with adult RENs.
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.
Cytokeratin 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.
EMA
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, OH, USA.
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.EPITHELIAL CELL ADHESION MOLECULE (EpCAM)
- Expression of Epithelial Cell Adhesion Molecule (EpCam) in Renal Epithelial Tumors.
Went P, Dirnhofer S, Salvisberg T, Amin MB, Lim SD, Diener PA, Moch H.
From the *Institute of Pathology, University of Basel, Basel, Switzerland; daggerInstitute of Pathology, Kantonsspital, St. Gallen, Switzerland; double daggerEmory University, School of Medicine, Atlanta, GA; and section signDepartment of Pathology, University Hospital, Zurich, Switzerland.
Am J Surg Pathol. 2005 Jan;29(1):83-88. Abstract quote
EpCam is an epithelial adhesion molecule expressed in a broad range of carcinomas. Clinical trials with specific humanized anti-EpCam antibodies have shown promising results and have been inaugurated in renal cell carcinoma (RCC) therapy.
To study the EpCam expression profile, primary renal cell neoplasms as well as corresponding metastases were evaluated by immunohistochemistry in tissue microarrays. EpCam expression in oncocytomas and chromophobe RCCs was determined on conventional large sections. Moderate or strong EpCam expression was found in eighteen percent of clear cell (n = 147), 75% of chromophobe (n = 12), and 55% of papillary RCCs (n = 20), but not in oncocytomas (n = 3). On large sections, 90% of chromophobe RCCs (n = 20) showed a strong and homogeneous positivity, whereas oncocytomas (n = 15) revealed EpCam positivity in single tumor cells or small clusters. Fourteen percent of RCC metastases (n = 97) showed EpCam expression. Patients with EpCam expressing clear cell RCC showed a trend toward a better prognosis in a Cox regression analysis including stage, grade, and necrosis.
The data suggest EpCam as a potential therapeutic target in a subset of patients with RCC. In addition, expression patterns of EpCam could become a helpful tool in the discrimination of chromophobe RCC and oncocytoma.ELECTRON MICROSCOPY Numerous oval cytoplasmic microvesicles measuring from 150 to 300 nm in diameter
Considered diagnostic
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES GRANULAR CELL VARIANT OF CLEAR CELL RENAL CELL CARCINOMA RENAL ONCOCYTOMA
PROGNOSIS CHARACTERIZATION GENERAL
- Histological Subtyping and Nuclear Grading of Renal Cell Carcinoma and Their Implications for Survival: A Retrospective Nation-Wide Study of 629 Patients.
Gudbjartsson T, Hardarson S, Petursdottir V, Thoroddsen A, Magnusson J, Einarsson GV.
Departments of Urology and Surgery, Landspitali University Hospital, Hringbraut, IS 150 Reykjavik, Iceland.
Eur Urol. 2005 Jun 15; [Epub ahead of print] Abstract quote
OBJECTS:: The aim of this study was to evaluate the prognostic significance of the current WHO histological subtyping and Fuhrman nuclear grading on the survival of patients with renal cell carcinoma (RCC).
MATERIALS AND METHODS:: A retrospective population-based study was carried out on all patients with a histopathologically confirmed diagnosis of RCC in Iceland between 1971 and 2000. Fuhrman grade, TNM stage, and survival were evaluated and multivariate analysis applied in order to determine prognostic factors.
RESULTS:: Out of 629 patients (387 males, 242 females, mean age 64 years), 558 (88.7%) had clear cell, 53 (8.4%) papillary, and 13 (2.1%) chromophobe RCC. Patient demographics were comparable for the two major subtypes, but chromophobe RCCs were larger in size and were diagnosed at a younger age. Clear cell RCCs were more often of higher grades (G3+G4, 48.4%) and at advanced TNM stages (III+IV, 59.3%) than papillary RCCs (22.6% and 34% respectively, p<0.001). Linear regression analysis showed a strong correlation between grade, tumor size, and stage (p<0.001). Chromophobe RCCs had a better survival in univariate analysis than both papillary and clear cell RCCs (84.6% vs. 66.5% and 54.9% 5-year disease specific survival, p<0.001). However, in the multivariate analysis, only the patient's age, calendar year of diagnosis, TNM stage, and nuclear grade were independent prognostic factors of survival.
CONCLUSION:: In this complete nation-wide series nuclear grading is important in predicting survival of patients with RCC. It is strongly related to both tumor size and stage, with stage being by far the strongest prognostic factor. Different histological subtypes confer different survival. However, in spite of the distinctive cytogenetic and molecular characteristics of the subtypes, the survival difference is to a large extent due to differences in grade and particularly stage.
Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma.
Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Am J Surg Pathol. 2003 May;27(5):612-24. Abstract quote Our objective was to compare cancer-specific survival and to examine associations with outcome among the histologic subtypes of renal cell carcinoma (RCC).
We studied 2385 patients whose first surgery between 1970 and 2000 was a radical nephrectomy for sporadic, unilateral RCC. All RCC tumors were classified following the 1997 Union Internationale Contre le Cancer and American Joint Committee on Cancer guidelines. There were 1985 (83.2%) patients with clear cell, 270 (11.3%) with papillary, 102 (4.3%) with chromophobe, 6 (0.3%) with collecting duct, 5 (0.3%) with purely sarcomatoid RCC and no underlying histologic subtype, and 17 (0.7%) with RCC, not otherwise specified.
Cancer-specific survival rates at 5 years for patients with clear cell, papillary, and chromophobe RCC were 68.9%, 87.4%, and 86.7%, respectively. Patients with clear cell RCC had a poorer prognosis compared with patients with papillary and chromophobe RCC (p <0.001). This difference in outcome was observed even after stratifying by 1997 tumor stage and nuclear grade. There was no significant difference in cancer-specific survival between patients with papillary and chromophobe RCC (p = 0.918). The 1997 TNM stage, tumor size, presence of a sarcomatoid component, and nuclear grade were significantly associated with death from clear cell, papillary, and chromophobe RCC. Histologic tumor necrosis was significantly associated with death from clear cell and chromophobe RCC, but not with death from papillary RCC.
Our results demonstrate that there are significant differences in outcome and associations with outcome for the different histologic subtypes of RCC, highlighting the need for accurate subtyping.
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Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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