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Sarcomatoid renal carcinoma: the final common dedifferentiation pathway of renal epithelial malignancies
Pathology (1999) 31, pp. 185 ± 190
SARCOMATOID RENAL CARCINOMA: THE FINAL COMMON DEDIFFERENTIATION PATHWAY OF RENAL EPITHELIAL MALIGNANCIES BR E T T DE LA H U N T Department of Pathology, Wellington School of Medicine, University of Otago, Wellington, New Zealand
Summary Sarcomatoid renal carcinoma (SRC) is an aggressive neoplasm with an age and gender distribution similar to that of conventional (clear cell) renal cell carcinoma (RCC). Genetic and morphologic evidence indicates that the tumor results from de-differentiation of renal epithelial malignancy and associations with RCC, papillary renal carcinoma, chromophobe renal carcinoma and collecting duct carcinoma have been reported. The tumor is composed of sheets of malignant spindle cells that have immunohistochemical and ultrastructural features of both stromal and epithelial cells, and may contain myxoid areas containing osteoclast-like giant cells or pleomorphic sarcomatoid spindle cells resembling rhabdomyoblasts. Rare cases of osteogenic SRC have been described. The tumor shows marked proliferative activity in growth kinetic studies and is usually associated with a poor patient survival that is best predicted by staging. Key words: Renal cell carcinoma, renal tumor, sarcomatoid renal carcinoma,
tumor
metaplasia,
prognosis,
p53,
ultrastructure,
transformation of malignant epithelial cells, and because of this the term SR C was considered appropriate.5 W hile the m ajority of SRCs are found in association with conventional RCCs, sarcomatoid transformation is not confined to this subgroup of tumors. Sarcom atoid metaplasia has also been described in papillary renal carcinom a,6 collecting duct carcinom a 7 and in occasional series of chrom ophobe renal carcinom a.8 ±1 0 Akhtar et al. reported a high incidence of chromophobe renal carcinoma in their series of SRC and thus speculated that this variant of renal malignancy frequently underwent sarcom atoid transformation. 8 In the M ainz classification of renal parenchymal tum ors, evolution into a spindle cell morphology was considered to be the result of extensive chromosomal rearrangement, leading to an identical spindle cell morphology regardless of the parent type of renal epithelial malignancy. 11 This concept has been reinforced in recent consensus classifications of renal parenchymal tumors in which SRC was not considered to be a separate tumor type, but was recognized as occurring in a of a variety of epithelial malignancies.1 2,1 3
immunohistochemistry. Abbreviations: RCC, renal cell carcinoma; SRC, sarcomatoid renal carcinoma. Accepted 8 April 1999
INTRODUCTION The nature of sarcom atoid renal carcinom a (SRC) was not appreciated in early classifications of renal malignancy as these tumors were considered to be true sarcomas, being derived from fibroblasts and smooth m uscle cells of the renal interstitium or capsule.1 This confusion regarding the characterization of SRC was further complicated by the inclusion of the tum or as a variant of nephroblastom a in some classifications 1 and the mistaken conclusion that what is now recognized as conventional (clear cell) renal cell carcinoma (RCC) was of stromal origin.2 The earliest evidence as to the true nature of SR C was derived from the finding that many so-called renal sarcom as had associated foci of renal carcinoma, 3 and the term carcinosarcom a was applied. 4 Understanding of the pathogenesis of SRC was further refined by the observation that areas in some tumors were transitional in morphology between carcinoma and sarcom a. These transitional foci were considered to provide evidence that the sarcomatous areas adjacent to RCC were the result of metaplastic
CLINICAL AND PATHOLOGICAL FEATURES The criteria for defining SRCs vary from series to series, with the majority of studies requiring the identification of an epithelial component within the tumor. The percentage of spindle cells necessary to permit designation of a tumor as a SRC varies considerably, with some series accepting any proportion, no m atter how small, while others base their definition on the presence of a minimum percentage of spindle cells which range up to 80% of the tumor.1 4,15 This variation in the definition of SR C has contributed to considerable inter-study differences in the proportion of these tumors present in different series of renal tumors. This varies between 0.9% 15 and 42% ,1 6 with tumors in the latter study being defined by the presence of at least 1% of spindle cells. SRC occurs in a clinical setting similar to that of conventional RCC, being most com monly found in the elderly. The age distribution of patients reported in large case series ranges from 29 to 81 years, while the median age in these studies ranges from 56 to 61 years. As with conventional RCC, SR C is most commonly found in males, although in some series a near equal gender distribution has been recorded. The clinical features of SR C are sum marized in Table 1. SRCs show no predilection for any part of the renal architecture and are often of large dimensions and of
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TA B L E 1
Clinical features of sarcomatoid renal cell carcinoma from reported series No. of Cases s% of RCCd in series
Sex (M /F)
Age range (median) in years
Farrow, et al., 1968 5
37 (1.5%)
21/16
29 ±76 (59)
Tomara et al., 1983 1 7
13 (1%)
11/2
34 ±78 (56)
Bertoni et al., 1987 1 8
19 (6%)
11/8
50 ±75 (61)
Sella et al., 1987 1 9 Ro et al., 1987 2 0
44 (4.8%)
24/20
30 ± 81 (56)
Oda et al., 1993 2 1
12 (6%)
12/0
32 ±77 (56.3)
Series
advanced stage at the time of diagnosis (Table 1). The macroscopic appearance of the tumor is not diagnostic, although they are usually solid and grey/white and have a firm to hard consistency on sectioning. Cystic areas and a gross appearance sim ilar to conventional RCCs are also frequently observed. On m icroscopic examination, the majority of tumors are composed of spindle cells arranged in sheets, although they occasionally exhibit a storiform pattern, simulating either fibrosarcoma or malignant fibrous histiocytoma (Fig. 1). Occasional vascular SRCs have been noted to resemble hemangiopericytom a.2 0 A number of tumors also have myxoid foci containing cells showing marked nuclear pleom orphism with varying numbers of tum or and/or osteoclast-like giant cells (Fig. 2). Rarely SRC contains areas of osteoid with mineralized bony trabeculae in association with more typical sheets of malignant spindle cells and foci of malignant cartilage. These tumors have been designated osteogenic SRC and in the m ajority of the 17 cases reported to date, areas of typical conventional RCC have been found adjacent to the sarcom atoid cells. 5,2 2,2 3 In those instances where epithelial elem ents are not present, osteogenic SR C m ust be differentiated from true renal osteogenic sarcoma by ultrastructural or imm unohistochemical studies. Sporadic reports of rhabdomyomatous differentiation in SR Cs have appeared, with the diagnosis being based on the identification of strap cells that may show poorly formed cross-striations on light m icroscopic examination. 24 In our experience, sarcomatoid cells with rhabdoid appearance most com monly occur in myxoid foci of SRCs (Fig. 3). Although the m orpholo gy of these cells is suggestive of rhabdomyoblastic differentiation, we have been unable to confirm this either by electron m icroscopy or imm unohistochemical studies. SRCs have been found to show a marked degree of nuclear pleomorphism, although in the m ajority of reported series, a specific grade is not usually assigned to each of the cases.17 ±1 9 In the 42 case series of Ro et al. 2 0 six tumors were classified as exhibiting m ild nuclear pleom orphism , while 21 and 15 tum ors were classified as showing moderate and m arked pleom orphism respectively. These findings parallel the results of Harris et al., who classified
Tumor stage: number of cases Robson
3a : 23 3b : 3 Not stated : 11 Robson 1 :2 2 :5 3b : 1 4 :5 Robson 1 :1 2 :6 3 :4 4 :8 Robson 1± 3 : 19 4 : 25 UICC pT 2 b: 3 pT 3 : 8 pT 4 : 1
Fig. 1 Sarcomatoid renal carcinoma showing features of fibrosarcoma. (H & E, original magnification 3 240).
their seven cases into grade 3 (four tumors) and grade 4 (three tumors), although the criteria of their grading system were not stated.2 5 In som e series, spindle cells were treated as a variant of cell type along with clear and granular epithelial tumor
SARC OMATOID RENAL CAR CINOM A
187
Fig. 2 Osteoclast-like giant cells within sarcomatoid renal carcinoma. (H & E, original magnification 3 240).
Fig. 3 Sarcomatoid renal carcinoma showing rhabdomyoblast-like differentiation. (H & E, original magnification 3 510).
cells,1 4,1 5,2 6 while in other series, spindle cells were analysed as a variant of architectural pattern. 2 7 In composite grading systems for conventional RCC, SRCs have been assigned to the highest grade regardless of nuclear pleomorphism, 28 ,2 9 and the validity of this has been supported by survival studies which show the presence of spindle cells within a tum or to have progno stic significance independent of nuclear grade. 30 For SR C derived from conventional RCC, the grade of epithelial cells adjacent to sarcomatoid foci shows considerable variation, although high grade tumors predominate. Aggregation of cases from two reported series shows a distribution of: six grade 1, 15 grade 2, 24 grade 3 and 15 grade 4 tum ors, 20 ,3 1 indicating that sarcom atoid metaplasia of RCC cannot be predicted by degree of nuclear pleomorphism of the original tumor.
peripheral and intralum inal microvilli within tumor cells.3 2 ± 34 There is often marked nuclear indentation and the tum or cell cytoplasm contains abundant rough endoplasmic reticulum, free ribosomes and m itochondria. In som e tum ors intracytoplasmic glycogen and lipid have been identified, and in areas basal lamina m ay also be seen.3 3 Im munohistochemistry also provides evidence as to the pathogenesis of SR C, with the m ajority of tumors expressing a variety of epithelial markers. In various series cytokeratin AE1/AE3 was found to be positive in almost all cases,31 ,35 while cytokeratins 8 and 18,1 0 CAM 5.2 3 1,35 ,36 and PKK1 25 positivity, and negative staining for high molecular weight cytokeratin 3 1 have been reported. Epithelial membrane antigen labeling is variable in SR Cs, with the antigen being expressed by malignant spindle cells in approximately 50% of cases.8 ,25 ,31 ,35 Stromal markers also show variable expression in SRC, with vimentin positivity being noted in 33 to 100% of cases. 8,22 ,25 ,31 Cytoplasmic vim entin staining usually occurs in a patchy distribution within the tumor, and the frequency of staining is usually greater than that seen within conventional RCC. 25 Occasional tumors have been shown to exhibit actin positivity, a feature which has been interpreted as being suggestive of myofibroblastic differentiation of epithelial cells.3 1
ULTRASTRUCTURE AND IMMUNOHISTOCHEMISTRY Convin cing evidence as to the epithelial nature of SR C has been provided by ultrastructural studies which have dem onstrated the presence of desmosomes (Fig. 4) and occasional
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beyond G 0 .3 7 PC NA shows significantly increased expression with increasing tumor grade for conventional RCC.21 ,39 In those studies that have com pared PCNA indices of conventional RCC with SRC, no difference was noted between high grade (grade 3 of 3) RCC and SR C, implying that each of the tumors has a similar level of S-phase activity.2 1,39 Identical results were obtained from studies on conventional RCC and SRC growth kinetics utilizing fixation resistant pK i-67.40 These results have confirmed that SR C has a high proliferative activity, and this correlates well with the rapid clinical progression of this variety of renal malignancy.
GENETIC AND MOLECULAR STUDIES
Fig. 4 Sarcomatoid renal carcinoma with poorly formed desmosomes (arrow). (Original magnification 3 17,000.)
TUMOR PROLIFERATION KINETICS Several studies have investigated the growth kinetics of SR C using markers of interphase and cell cycle activity. Enum eration of silver staining nucleolar organizer regions (AgN ORs) provides a valid measure of interphase interval and is of utility in the estimation of tum or proliferation rate. 37 In studies comparing AgN OR scores of SR Cs with conventional RCCs, divided according to tumor grade, the m ean AgN OR scores for SRCs were found to be significantly higher than those obtained for grade 1 and 2 conventional RCCs, and were similar to those derived from carcinomas exhibiting m arked nuclear pleomorphism (grade 3).38 In a similar study, identical findings were observed when AgN OR scores were compared with those of low and intermediate grade tumors, however AgN OR scores for SR Cs were also found to be significantly higher than those obtained for high grade conventional RCCs, characterized by the presence of tumor giant cells. 21 SRC proliferative activity has also been quantified by evaluation of imm unohistochemical expression of proliferating cell nuclear antigen (PCNA) and polyclonal antibody to Ki-67 antigen (pKi-67). PC NA is primarily a marker of S-phase activity, although in rapidly proliferating cells, antigen may persist into the G 2 -and M -phases, while Ki-67 is expressed in cells that have entered the cell cycle
There is limited information available regarding the genetic changes associated with sarcomatoid transformation of renal carcinoma. Detailed analysis of one case of SR C, associated with high grade conventional RCC, showed complex chromosomal rearrangem ents including those usually associated with progression of RCC to a more malignant phenotype.4 1 In addition to these changes, rearrangements of chromosom es 1, 2 and 4 were also demonstrated. As these mutations are not characteristic of changes associated with any subtype of renal carcinoma, the findings suggest that loci in one or more of these chromosomes m ay be involved in the development of SR C. The retention of chromosomal rearrangements associated with the developm ent of a specific variant of renal carcinoma within the cells of the SR C component of the tum or in this single case report, further provides evidence that cytogenetic analysis may be of value in determining the original subtype of an SR C, even in the absence of a differentiated carcinom a component. The association between p53 gene mutation and sarcom atoid transform ation of renal carcinoma has also been investigated in a sm all series of tumors. In this study, mutation of the p53 gene was demonstrated in 86% of tum ors, 42 while in a separate study, 76% of cases of SRC showed im munoreactivity to the p53 protein. 43 In cases consisting of both conventional RCC and SR C, mutant p53 protein was seen in only 14% of the epithelial components of these biphasic tumors.4 2 These features are unlikely to be specific for sarcom atoid transformation of renal carcinoma, however as in a further series of renal epithelial malignancies, p53 mutations were noted in 48% of carcinomas, with the changes being unrelated to histologic tumor type. 44 M ore recently, expression of the cell adhesion molecule cadherin-6 has been studied in a variety of renal carcinomas. Loss of im munostaining was noted in high grade carcinomas and in SR C, and it was suggested that this loss of expression may be associated with tum or progression to a more malignant phenotyp e.45
PROGNOSIS The poor prognos is of SRC has been confirmed in clinical outcome studies, with median survivals of six months 1 4,1 7,20 and 24-, 30- and 36-month survival rates of 28.6% ,2 0 19.5% 1 4 and 19.1% 2 0 respectively, being reported for cases not stratified according to tumor stage. The most important
SARC OMATOID RENAL CAR CINOM A
Fig. 5
189
Parenchymal renal tumors associated with sarcomatoid renal carcinoma.
predictor of survival for SR C is tumor stage, with Robson stage 1 tumors having a significantly longer 20 and stage 4 tum ors having a significantly shorter, median survival.1 9 Although the m ajority of published series contain insufficient cases of SRC to perm it multivariate analysis of survival-related data, it has been suggested that a greater percentage of sarcomatoid cells within the tum or is associated with a less favorable prognosis. 18 The validity of this suggestion has been confirmed in part, although independent prognos tic significance for percentage of sarcom atoid cells was found to be confined to stage 1 and 2 tum ors only.2 0 Tumor grade, based on the degree of nuclear pleomorphism, has been shown to be of no progno stic value for SR C,2 0 although prolonged survival in a patient with Fuhrman grade 2, Robson stage 1 disease has prompted speculation that low grade tumors m ay have a more favorable prognos is.34
which may occur in a variety of renal epithelial malignancies (Fig. 5). In the recent consensus conferences assem bled to consider the establishment of guidelines regarding the classification of renal malignancies, it was recom mended that for SR C with associated carcinoma, the tum or should be classified according to original tumor type.1 2 For those SR Cs where the sarcomatoid component has completely overgrown and obliterated the original carcinoma, it was agreed that the tumor be placed in an unclassified category. As noted earlier, in cases where the m orpholo gy of the original tumor has been lost, cytogenetic studies may assist in determining the correct classification category for these morphologically undifferentiated tumors. Address for correspondence: B .D., Department of Pathology, Wellington School of Medicine, University of Otago, PO Box 7343, Wellington South, New Zealand. E-mail: [email protected]
References CONCLUSION Although SR C is an uncom mon form of renal m alignancy it is of importance because of its typically late presentation, short clinical course and frequently fatal outcome. Histologically, SRC is characterized by the presence of malignant spindle cells that usually express markers of both epithelial and stromal differentiation. Despite this uniformity of appearance, it is clear that these tumors are of diverse pathogenesis. Convincing evidence as to the true nature of SR C has been obtained from both m orpholo gic and cytogenetic studies, which suggest that the developm ent of a sarcomatoid phenotype is the result of genetic rearrangement leading to profound morphologic dedifferentiation,
1. Weisel W, Dockerty M D, Priestley JT. Sarcoma of the kidney. J Urol 1943; 50: 564 ±73. 2. Wilson LB. A comparative study of the histology of the so-called hypernephromata and the embryology of the nephridial and adrenal tissues. J Med Res 1911; 24: 73 ± 90. 3. Griffiths IH, Thackeray AC. Parenchymal carcinoma of the kidney. B J Urol 1949; 21: 128 ± 51. 4. Saphir O, Vass A. Carcinosarcoma. Am J C ancer 1938; 33: 221± 361. 5. Farrow GM , Harrison EG, Utz DC. Sarcomas and sarcomatoid and mixed malignant tumors of the kidney in adults. Part III. Cancer 1968; 22: 556± 63. 6. Renshaw AA, Corless CL. Papillary renal cell carcinoma: gross features and histologic correlates. J Urol Pathol 1997; 7: 9 ± 20. 7. M atz LR, Latham BI, Fabian VA, Vivian JB. Collecting duct carcinoma of the kidney, a report of three cases and a review of the literature. Pathology 1997; 29: 354 ± 9.
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8. Akhtar M, Tulbah A, Kandar AH, Ali MA. Sarcomatoid renal cell carcinoma: the chromophobe connection. Am J Surg Pathol 1997; 21: 1188 ± 95. 9. Aizawa S, Chigusa M , Ohno Y, Suzuki M. Chromophobe cell renal carcinoma with sarcomatoid component. A report of two cases. J Urol Pathol 1997; 6: 51± 9. 10. Gomez-Roman JT, Mayorga-Fernandez M, Fernandez-Fernandez F, Val-Bernal JF. Sarcomatoid chromophobe cell renal carcinoma: immunohistochemical and lectin study on one case. Gen Diag Pathol 1997; 143: 63 ±9. 11. St orkel È S, van den Berg E. M orphological classification of renal cancer. World J Urol 1995; 13: 153 ± 8. 12. St orkel È S, Eble JN, Adlahka K, et al. Classification of renal cell carcinoma. Cancer 1997; 80: 987± 9. 13. Kovacs G, Akhtar M, Beckwith JB, et al. The Heidelberg classification of renal cell tumors. J Pathol 1997; 183: 131± 3. 14. Theil KS, Schinella RA, Golimbu M, Waisman J. Prediction of survival in renal tubular adenocarcinoma. Lab Invest 1985; 52: 67A. 15. Selli C, Hinshaw W M, Woodward BH, Paulson DF. Stratification of risk factors in renal cell carcinoma. Cancer 1983; 52: 899 ± 903. 16. Boxer RJ, Waisman J, Lieber MM , et al. Renal carcinoma: computer analysis of 96 patients treated by nephrectomy. J Urol 122: 1979; 598 ±601. 17. Tomera KM , Farrow GM , Lieber M M. Sarcomatoid renal carcinoma. J Urol 1983; 130: 657± 9. 18. Bertoni F, Ferri C, Benati P, et al. Sarcomatoid carcinoma of the kidney. J Urol 1987; 137: 25 ± 8. 19. Sella A, Logothetis CJ, Ro JY, et al. Sarcomatoid renal cell carcinoma. A treatable entity. Cancer 1987; 60: 1313 ± 8. 20. Ro JY, Ayala AG, Sella A, et al. Sarcomatoid renal cell carcinoma: clinicopathologic. A study of 42 cases. Cancer 1987; 59: 516 ± 26. 21. Oda H, M achinami R. Sarcomatoid renal cell carcinoma. A study of its proliferative activity. Cancer 1993; 71: 2292 ±8. 22. Bastacky S, M cBee A, Fusca F, Becich M J. Sarcomatoid renal carcinoma with malignant osseous and chondroid differentiation: case report and literature review. J Urol Pathol 1996; 5: 119± 38. 23. Nasu M , Yamazaki S, Kishi H, et al. Sarcomatoid clear cell renal cell carcinoma with chondroid and osteoid differentiation: Immunohistochemical and ultrastructural findings. J Urol Pathol 1997; 6: 171± 80. 24. M enzies DW. Carcinoma and rhabdomyosarcoma in the same kidney, a study in the classification and histogenesis of mixed renal tumors. Aust NZ J Surg 1955; 25: 214 ±24. 25. Harris SC, Hird PM, Shortland JR. Immunohistochemistry and lectin histochemistry in sarcomatoid renal cell carcinoma: a comparison with classical renal cell carcinoma. Histopathology 1989; 15: 607±16. 26. Skinner DG, Colvin RB, Vermillion CD, et al. Diagnosis and management of renal cell carcinoma. A clinical and pathologic study of 309 cases. Cancer 1971; 28: 1165 ±77. 27. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982; 6: 655 ± 63.
Pathology (1999), 31, August 28. Arner O, Blanck C, von Schreeb T. Renal adenocarcinoma. Morphology ±grading of malignancy ±prognosis. A study of 197 cases. Acta Clin Scand 1965; 346: 7± 52. 29. Hermanek P, Sigel A, Chlepas S. Histological grading of renal cell carcinoma. Eur Urol 1976; 2: 189 ± 91. 30. Delahunt B, Nacey JN. Renal cell carcinoma. Histological indicators of prognosis. Pathology 1987; 19: 258 ± 63. 31. De Long W, Grignon DJ, Eberwein P, et al. Sarcomatoid renal cell carcinoma. An immunohistochemical study of 18 cases. Arch Pathol Lab Med 1993; 117: 636 ±40. 32. M acke RA, Hussain MB , Imray TJ, et al. Osteogenic and sarcomatoid differentiation of a renal cell carcinoma. C ancer 1985; 56: 2452 ±7. 33. Bonsib SM , Fischer J, Plattner S, Fallon B. Sarcomatoid renal tumors. Clinico-pathologic correlation of three cases. C ancer 1987; 59: 527± 32. 34. Lloreta J, Corominas JM, Munne A, et al. Low grade spindle cell carcinoma of the kidney. Ultrastruct Pathol 1998; 22: 83 ± 90. 35. M edeiros LJ, Michie SA, Johnson DE, et al. An immunoperoxidase study of renal cell carcinomas: correlation with nuclear grade, cell type and histologic pattern. Hum Pathol 1988; 19: 980 ±7. 36. Fleming S, M atthews TJ. Renal tubular antigens in regenerative epithelium and renal carcinoma. Br J Urol 1987; 60: 103 ±9. 37. Brugel G. Interpretation of proliferation markers. Virchows Arch 1996; 427: 323 ± 41. 38. Delahunt B, Nacey JN, Hammett GD, Frater W J. Nucleolar organizer regions in renal cell carcinoma, renal oncocytomas and renal adenoma. Anal Cell Pathol 1989; 1: 185 ±90. 39. Delahunt B, Bethwaite PB, Nacey JN, Ribas JL. Proliferating cell nuclear antigen (PC NA) expression as a prognostic indicator for renal cell carcinoma: comparison with tumor grade, mitotic index and silver staining nucleolar organizer region numbers. J Pathol 1993; 170: 471±7. 40. Delahunt B, Bethwaite PB, Thornton A. Proliferation of renal cell carcinoma assessed by fixation-resistant polyclonal Ki-67 antibody labelling: correlation with clinical outcome. Cancer 1995; 75: 2714 ± 9. 41. Dijkhuizen T, van den Berg E, van den Berg A, et al. Genetics as a diagnostic tool in sarcomatoid renal cell cancer. Int J Cancer 1997; 72: 265 ±9. 42. Oda H, Nakatsuru Y, Ishikawa T. M utations of the p53 gene and p53 protein overexpression are associated with sarcomatoid transformation in renal cell carcinomas. C ancer Res 1995; 55: 658 ± 62. 43. Kattar M M, Grignon DJ, Sarkar FH, et al. p53 gene expression in sarcomatoid renal cell carcinoma: a clinicopathologic study with review of the literature. J Urol Pathol 1996; 5: 207± 21. 44. Presti JC, Rao PH, Chen Q, et al. Histopathological, cytogenetic and molecular characterization of renal cortical tumors. Cancer Res 1991; 51: 1544 ± 52. 45. Paul R, Ewing CM, Robinson JC, et al. Cadherin-6, a cell adhesion molecule specifically expressed in the proximal renal tubule and renal cell carcinoma. C ancer Res 1997; 57: 2741± 8.
SARCOMATOID RENAL CARCINOMA: THE FINAL COMMON DEDIFFERENTIATION PATHWAY OF RENAL EPITHELIAL MALIGNANCIES BR E T T DE LA H U N T Department of Pathology, Wellington School of Medicine, University of Otago, Wellington, New Zealand
Summary Sarcomatoid renal carcinoma (SRC) is an aggressive neoplasm with an age and gender distribution similar to that of conventional (clear cell) renal cell carcinoma (RCC). Genetic and morphologic evidence indicates that the tumor results from de-differentiation of renal epithelial malignancy and associations with RCC, papillary renal carcinoma, chromophobe renal carcinoma and collecting duct carcinoma have been reported. The tumor is composed of sheets of malignant spindle cells that have immunohistochemical and ultrastructural features of both stromal and epithelial cells, and may contain myxoid areas containing osteoclast-like giant cells or pleomorphic sarcomatoid spindle cells resembling rhabdomyoblasts. Rare cases of osteogenic SRC have been described. The tumor shows marked proliferative activity in growth kinetic studies and is usually associated with a poor patient survival that is best predicted by staging. Key words: Renal cell carcinoma, renal tumor, sarcomatoid renal carcinoma,
tumor
metaplasia,
prognosis,
p53,
ultrastructure,
transformation of malignant epithelial cells, and because of this the term SR C was considered appropriate.5 W hile the m ajority of SRCs are found in association with conventional RCCs, sarcomatoid transformation is not confined to this subgroup of tumors. Sarcom atoid metaplasia has also been described in papillary renal carcinom a,6 collecting duct carcinom a 7 and in occasional series of chrom ophobe renal carcinom a.8 ±1 0 Akhtar et al. reported a high incidence of chromophobe renal carcinoma in their series of SRC and thus speculated that this variant of renal malignancy frequently underwent sarcom atoid transformation. 8 In the M ainz classification of renal parenchymal tum ors, evolution into a spindle cell morphology was considered to be the result of extensive chromosomal rearrangement, leading to an identical spindle cell morphology regardless of the parent type of renal epithelial malignancy. 11 This concept has been reinforced in recent consensus classifications of renal parenchymal tumors in which SRC was not considered to be a separate tumor type, but was recognized as occurring in a of a variety of epithelial malignancies.1 2,1 3
immunohistochemistry. Abbreviations: RCC, renal cell carcinoma; SRC, sarcomatoid renal carcinoma. Accepted 8 April 1999
INTRODUCTION The nature of sarcom atoid renal carcinom a (SRC) was not appreciated in early classifications of renal malignancy as these tumors were considered to be true sarcomas, being derived from fibroblasts and smooth m uscle cells of the renal interstitium or capsule.1 This confusion regarding the characterization of SRC was further complicated by the inclusion of the tum or as a variant of nephroblastom a in some classifications 1 and the mistaken conclusion that what is now recognized as conventional (clear cell) renal cell carcinoma (RCC) was of stromal origin.2 The earliest evidence as to the true nature of SR C was derived from the finding that many so-called renal sarcom as had associated foci of renal carcinoma, 3 and the term carcinosarcom a was applied. 4 Understanding of the pathogenesis of SRC was further refined by the observation that areas in some tumors were transitional in morphology between carcinoma and sarcom a. These transitional foci were considered to provide evidence that the sarcomatous areas adjacent to RCC were the result of metaplastic
CLINICAL AND PATHOLOGICAL FEATURES The criteria for defining SRCs vary from series to series, with the majority of studies requiring the identification of an epithelial component within the tumor. The percentage of spindle cells necessary to permit designation of a tumor as a SRC varies considerably, with some series accepting any proportion, no m atter how small, while others base their definition on the presence of a minimum percentage of spindle cells which range up to 80% of the tumor.1 4,15 This variation in the definition of SR C has contributed to considerable inter-study differences in the proportion of these tumors present in different series of renal tumors. This varies between 0.9% 15 and 42% ,1 6 with tumors in the latter study being defined by the presence of at least 1% of spindle cells. SRC occurs in a clinical setting similar to that of conventional RCC, being most com monly found in the elderly. The age distribution of patients reported in large case series ranges from 29 to 81 years, while the median age in these studies ranges from 56 to 61 years. As with conventional RCC, SR C is most commonly found in males, although in some series a near equal gender distribution has been recorded. The clinical features of SR C are sum marized in Table 1. SRCs show no predilection for any part of the renal architecture and are often of large dimensions and of
ISSN 0031±3025 printed/ISSN 1465-3931 online/99/030185 ± 06 Royal College of Pathologists of Australasia
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Pathology (1999), 31, August
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TA B L E 1
Clinical features of sarcomatoid renal cell carcinoma from reported series No. of Cases s% of RCCd in series
Sex (M /F)
Age range (median) in years
Farrow, et al., 1968 5
37 (1.5%)
21/16
29 ±76 (59)
Tomara et al., 1983 1 7
13 (1%)
11/2
34 ±78 (56)
Bertoni et al., 1987 1 8
19 (6%)
11/8
50 ±75 (61)
Sella et al., 1987 1 9 Ro et al., 1987 2 0
44 (4.8%)
24/20
30 ± 81 (56)
Oda et al., 1993 2 1
12 (6%)
12/0
32 ±77 (56.3)
Series
advanced stage at the time of diagnosis (Table 1). The macroscopic appearance of the tumor is not diagnostic, although they are usually solid and grey/white and have a firm to hard consistency on sectioning. Cystic areas and a gross appearance sim ilar to conventional RCCs are also frequently observed. On m icroscopic examination, the majority of tumors are composed of spindle cells arranged in sheets, although they occasionally exhibit a storiform pattern, simulating either fibrosarcoma or malignant fibrous histiocytoma (Fig. 1). Occasional vascular SRCs have been noted to resemble hemangiopericytom a.2 0 A number of tumors also have myxoid foci containing cells showing marked nuclear pleom orphism with varying numbers of tum or and/or osteoclast-like giant cells (Fig. 2). Rarely SRC contains areas of osteoid with mineralized bony trabeculae in association with more typical sheets of malignant spindle cells and foci of malignant cartilage. These tumors have been designated osteogenic SRC and in the m ajority of the 17 cases reported to date, areas of typical conventional RCC have been found adjacent to the sarcom atoid cells. 5,2 2,2 3 In those instances where epithelial elem ents are not present, osteogenic SR C m ust be differentiated from true renal osteogenic sarcoma by ultrastructural or imm unohistochemical studies. Sporadic reports of rhabdomyomatous differentiation in SR Cs have appeared, with the diagnosis being based on the identification of strap cells that may show poorly formed cross-striations on light m icroscopic examination. 24 In our experience, sarcomatoid cells with rhabdoid appearance most com monly occur in myxoid foci of SRCs (Fig. 3). Although the m orpholo gy of these cells is suggestive of rhabdomyoblastic differentiation, we have been unable to confirm this either by electron m icroscopy or imm unohistochemical studies. SRCs have been found to show a marked degree of nuclear pleomorphism, although in the m ajority of reported series, a specific grade is not usually assigned to each of the cases.17 ±1 9 In the 42 case series of Ro et al. 2 0 six tumors were classified as exhibiting m ild nuclear pleom orphism , while 21 and 15 tum ors were classified as showing moderate and m arked pleom orphism respectively. These findings parallel the results of Harris et al., who classified
Tumor stage: number of cases Robson
3a : 23 3b : 3 Not stated : 11 Robson 1 :2 2 :5 3b : 1 4 :5 Robson 1 :1 2 :6 3 :4 4 :8 Robson 1± 3 : 19 4 : 25 UICC pT 2 b: 3 pT 3 : 8 pT 4 : 1
Fig. 1 Sarcomatoid renal carcinoma showing features of fibrosarcoma. (H & E, original magnification 3 240).
their seven cases into grade 3 (four tumors) and grade 4 (three tumors), although the criteria of their grading system were not stated.2 5 In som e series, spindle cells were treated as a variant of cell type along with clear and granular epithelial tumor
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Fig. 2 Osteoclast-like giant cells within sarcomatoid renal carcinoma. (H & E, original magnification 3 240).
Fig. 3 Sarcomatoid renal carcinoma showing rhabdomyoblast-like differentiation. (H & E, original magnification 3 510).
cells,1 4,1 5,2 6 while in other series, spindle cells were analysed as a variant of architectural pattern. 2 7 In composite grading systems for conventional RCC, SRCs have been assigned to the highest grade regardless of nuclear pleomorphism, 28 ,2 9 and the validity of this has been supported by survival studies which show the presence of spindle cells within a tum or to have progno stic significance independent of nuclear grade. 30 For SR C derived from conventional RCC, the grade of epithelial cells adjacent to sarcomatoid foci shows considerable variation, although high grade tumors predominate. Aggregation of cases from two reported series shows a distribution of: six grade 1, 15 grade 2, 24 grade 3 and 15 grade 4 tum ors, 20 ,3 1 indicating that sarcom atoid metaplasia of RCC cannot be predicted by degree of nuclear pleomorphism of the original tumor.
peripheral and intralum inal microvilli within tumor cells.3 2 ± 34 There is often marked nuclear indentation and the tum or cell cytoplasm contains abundant rough endoplasmic reticulum, free ribosomes and m itochondria. In som e tum ors intracytoplasmic glycogen and lipid have been identified, and in areas basal lamina m ay also be seen.3 3 Im munohistochemistry also provides evidence as to the pathogenesis of SR C, with the m ajority of tumors expressing a variety of epithelial markers. In various series cytokeratin AE1/AE3 was found to be positive in almost all cases,31 ,35 while cytokeratins 8 and 18,1 0 CAM 5.2 3 1,35 ,36 and PKK1 25 positivity, and negative staining for high molecular weight cytokeratin 3 1 have been reported. Epithelial membrane antigen labeling is variable in SR Cs, with the antigen being expressed by malignant spindle cells in approximately 50% of cases.8 ,25 ,31 ,35 Stromal markers also show variable expression in SRC, with vimentin positivity being noted in 33 to 100% of cases. 8,22 ,25 ,31 Cytoplasmic vim entin staining usually occurs in a patchy distribution within the tumor, and the frequency of staining is usually greater than that seen within conventional RCC. 25 Occasional tumors have been shown to exhibit actin positivity, a feature which has been interpreted as being suggestive of myofibroblastic differentiation of epithelial cells.3 1
ULTRASTRUCTURE AND IMMUNOHISTOCHEMISTRY Convin cing evidence as to the epithelial nature of SR C has been provided by ultrastructural studies which have dem onstrated the presence of desmosomes (Fig. 4) and occasional
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beyond G 0 .3 7 PC NA shows significantly increased expression with increasing tumor grade for conventional RCC.21 ,39 In those studies that have com pared PCNA indices of conventional RCC with SRC, no difference was noted between high grade (grade 3 of 3) RCC and SR C, implying that each of the tumors has a similar level of S-phase activity.2 1,39 Identical results were obtained from studies on conventional RCC and SRC growth kinetics utilizing fixation resistant pK i-67.40 These results have confirmed that SR C has a high proliferative activity, and this correlates well with the rapid clinical progression of this variety of renal malignancy.
GENETIC AND MOLECULAR STUDIES
Fig. 4 Sarcomatoid renal carcinoma with poorly formed desmosomes (arrow). (Original magnification 3 17,000.)
TUMOR PROLIFERATION KINETICS Several studies have investigated the growth kinetics of SR C using markers of interphase and cell cycle activity. Enum eration of silver staining nucleolar organizer regions (AgN ORs) provides a valid measure of interphase interval and is of utility in the estimation of tum or proliferation rate. 37 In studies comparing AgN OR scores of SR Cs with conventional RCCs, divided according to tumor grade, the m ean AgN OR scores for SRCs were found to be significantly higher than those obtained for grade 1 and 2 conventional RCCs, and were similar to those derived from carcinomas exhibiting m arked nuclear pleomorphism (grade 3).38 In a similar study, identical findings were observed when AgN OR scores were compared with those of low and intermediate grade tumors, however AgN OR scores for SR Cs were also found to be significantly higher than those obtained for high grade conventional RCCs, characterized by the presence of tumor giant cells. 21 SRC proliferative activity has also been quantified by evaluation of imm unohistochemical expression of proliferating cell nuclear antigen (PCNA) and polyclonal antibody to Ki-67 antigen (pKi-67). PC NA is primarily a marker of S-phase activity, although in rapidly proliferating cells, antigen may persist into the G 2 -and M -phases, while Ki-67 is expressed in cells that have entered the cell cycle
There is limited information available regarding the genetic changes associated with sarcomatoid transformation of renal carcinoma. Detailed analysis of one case of SR C, associated with high grade conventional RCC, showed complex chromosomal rearrangem ents including those usually associated with progression of RCC to a more malignant phenotype.4 1 In addition to these changes, rearrangements of chromosom es 1, 2 and 4 were also demonstrated. As these mutations are not characteristic of changes associated with any subtype of renal carcinoma, the findings suggest that loci in one or more of these chromosomes m ay be involved in the development of SR C. The retention of chromosomal rearrangements associated with the developm ent of a specific variant of renal carcinoma within the cells of the SR C component of the tum or in this single case report, further provides evidence that cytogenetic analysis may be of value in determining the original subtype of an SR C, even in the absence of a differentiated carcinom a component. The association between p53 gene mutation and sarcom atoid transform ation of renal carcinoma has also been investigated in a sm all series of tumors. In this study, mutation of the p53 gene was demonstrated in 86% of tum ors, 42 while in a separate study, 76% of cases of SRC showed im munoreactivity to the p53 protein. 43 In cases consisting of both conventional RCC and SR C, mutant p53 protein was seen in only 14% of the epithelial components of these biphasic tumors.4 2 These features are unlikely to be specific for sarcom atoid transformation of renal carcinoma, however as in a further series of renal epithelial malignancies, p53 mutations were noted in 48% of carcinomas, with the changes being unrelated to histologic tumor type. 44 M ore recently, expression of the cell adhesion molecule cadherin-6 has been studied in a variety of renal carcinomas. Loss of im munostaining was noted in high grade carcinomas and in SR C, and it was suggested that this loss of expression may be associated with tum or progression to a more malignant phenotyp e.45
PROGNOSIS The poor prognos is of SRC has been confirmed in clinical outcome studies, with median survivals of six months 1 4,1 7,20 and 24-, 30- and 36-month survival rates of 28.6% ,2 0 19.5% 1 4 and 19.1% 2 0 respectively, being reported for cases not stratified according to tumor stage. The most important
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Fig. 5
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Parenchymal renal tumors associated with sarcomatoid renal carcinoma.
predictor of survival for SR C is tumor stage, with Robson stage 1 tumors having a significantly longer 20 and stage 4 tum ors having a significantly shorter, median survival.1 9 Although the m ajority of published series contain insufficient cases of SRC to perm it multivariate analysis of survival-related data, it has been suggested that a greater percentage of sarcomatoid cells within the tum or is associated with a less favorable prognosis. 18 The validity of this suggestion has been confirmed in part, although independent prognos tic significance for percentage of sarcom atoid cells was found to be confined to stage 1 and 2 tum ors only.2 0 Tumor grade, based on the degree of nuclear pleomorphism, has been shown to be of no progno stic value for SR C,2 0 although prolonged survival in a patient with Fuhrman grade 2, Robson stage 1 disease has prompted speculation that low grade tumors m ay have a more favorable prognos is.34
which may occur in a variety of renal epithelial malignancies (Fig. 5). In the recent consensus conferences assem bled to consider the establishment of guidelines regarding the classification of renal malignancies, it was recom mended that for SR C with associated carcinoma, the tum or should be classified according to original tumor type.1 2 For those SR Cs where the sarcomatoid component has completely overgrown and obliterated the original carcinoma, it was agreed that the tumor be placed in an unclassified category. As noted earlier, in cases where the m orpholo gy of the original tumor has been lost, cytogenetic studies may assist in determining the correct classification category for these morphologically undifferentiated tumors. Address for correspondence: B .D., Department of Pathology, Wellington School of Medicine, University of Otago, PO Box 7343, Wellington South, New Zealand. E-mail: [email protected]
References CONCLUSION Although SR C is an uncom mon form of renal m alignancy it is of importance because of its typically late presentation, short clinical course and frequently fatal outcome. Histologically, SRC is characterized by the presence of malignant spindle cells that usually express markers of both epithelial and stromal differentiation. Despite this uniformity of appearance, it is clear that these tumors are of diverse pathogenesis. Convincing evidence as to the true nature of SR C has been obtained from both m orpholo gic and cytogenetic studies, which suggest that the developm ent of a sarcomatoid phenotype is the result of genetic rearrangement leading to profound morphologic dedifferentiation,
1. Weisel W, Dockerty M D, Priestley JT. Sarcoma of the kidney. J Urol 1943; 50: 564 ±73. 2. Wilson LB. A comparative study of the histology of the so-called hypernephromata and the embryology of the nephridial and adrenal tissues. J Med Res 1911; 24: 73 ± 90. 3. Griffiths IH, Thackeray AC. Parenchymal carcinoma of the kidney. B J Urol 1949; 21: 128 ± 51. 4. Saphir O, Vass A. Carcinosarcoma. Am J C ancer 1938; 33: 221± 361. 5. Farrow GM , Harrison EG, Utz DC. Sarcomas and sarcomatoid and mixed malignant tumors of the kidney in adults. Part III. Cancer 1968; 22: 556± 63. 6. Renshaw AA, Corless CL. Papillary renal cell carcinoma: gross features and histologic correlates. J Urol Pathol 1997; 7: 9 ± 20. 7. M atz LR, Latham BI, Fabian VA, Vivian JB. Collecting duct carcinoma of the kidney, a report of three cases and a review of the literature. Pathology 1997; 29: 354 ± 9.
190
DELAHU NT
8. Akhtar M, Tulbah A, Kandar AH, Ali MA. Sarcomatoid renal cell carcinoma: the chromophobe connection. Am J Surg Pathol 1997; 21: 1188 ± 95. 9. Aizawa S, Chigusa M , Ohno Y, Suzuki M. Chromophobe cell renal carcinoma with sarcomatoid component. A report of two cases. J Urol Pathol 1997; 6: 51± 9. 10. Gomez-Roman JT, Mayorga-Fernandez M, Fernandez-Fernandez F, Val-Bernal JF. Sarcomatoid chromophobe cell renal carcinoma: immunohistochemical and lectin study on one case. Gen Diag Pathol 1997; 143: 63 ±9. 11. St orkel È S, van den Berg E. M orphological classification of renal cancer. World J Urol 1995; 13: 153 ± 8. 12. St orkel È S, Eble JN, Adlahka K, et al. Classification of renal cell carcinoma. Cancer 1997; 80: 987± 9. 13. Kovacs G, Akhtar M, Beckwith JB, et al. The Heidelberg classification of renal cell tumors. J Pathol 1997; 183: 131± 3. 14. Theil KS, Schinella RA, Golimbu M, Waisman J. Prediction of survival in renal tubular adenocarcinoma. Lab Invest 1985; 52: 67A. 15. Selli C, Hinshaw W M, Woodward BH, Paulson DF. Stratification of risk factors in renal cell carcinoma. Cancer 1983; 52: 899 ± 903. 16. Boxer RJ, Waisman J, Lieber MM , et al. Renal carcinoma: computer analysis of 96 patients treated by nephrectomy. J Urol 122: 1979; 598 ±601. 17. Tomera KM , Farrow GM , Lieber M M. Sarcomatoid renal carcinoma. J Urol 1983; 130: 657± 9. 18. Bertoni F, Ferri C, Benati P, et al. Sarcomatoid carcinoma of the kidney. J Urol 1987; 137: 25 ± 8. 19. Sella A, Logothetis CJ, Ro JY, et al. Sarcomatoid renal cell carcinoma. A treatable entity. Cancer 1987; 60: 1313 ± 8. 20. Ro JY, Ayala AG, Sella A, et al. Sarcomatoid renal cell carcinoma: clinicopathologic. A study of 42 cases. Cancer 1987; 59: 516 ± 26. 21. Oda H, M achinami R. Sarcomatoid renal cell carcinoma. A study of its proliferative activity. Cancer 1993; 71: 2292 ±8. 22. Bastacky S, M cBee A, Fusca F, Becich M J. Sarcomatoid renal carcinoma with malignant osseous and chondroid differentiation: case report and literature review. J Urol Pathol 1996; 5: 119± 38. 23. Nasu M , Yamazaki S, Kishi H, et al. Sarcomatoid clear cell renal cell carcinoma with chondroid and osteoid differentiation: Immunohistochemical and ultrastructural findings. J Urol Pathol 1997; 6: 171± 80. 24. M enzies DW. Carcinoma and rhabdomyosarcoma in the same kidney, a study in the classification and histogenesis of mixed renal tumors. Aust NZ J Surg 1955; 25: 214 ±24. 25. Harris SC, Hird PM, Shortland JR. Immunohistochemistry and lectin histochemistry in sarcomatoid renal cell carcinoma: a comparison with classical renal cell carcinoma. Histopathology 1989; 15: 607±16. 26. Skinner DG, Colvin RB, Vermillion CD, et al. Diagnosis and management of renal cell carcinoma. A clinical and pathologic study of 309 cases. Cancer 1971; 28: 1165 ±77. 27. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982; 6: 655 ± 63.
Pathology (1999), 31, August 28. Arner O, Blanck C, von Schreeb T. Renal adenocarcinoma. Morphology ±grading of malignancy ±prognosis. A study of 197 cases. Acta Clin Scand 1965; 346: 7± 52. 29. Hermanek P, Sigel A, Chlepas S. Histological grading of renal cell carcinoma. Eur Urol 1976; 2: 189 ± 91. 30. Delahunt B, Nacey JN. Renal cell carcinoma. Histological indicators of prognosis. Pathology 1987; 19: 258 ± 63. 31. De Long W, Grignon DJ, Eberwein P, et al. Sarcomatoid renal cell carcinoma. An immunohistochemical study of 18 cases. Arch Pathol Lab Med 1993; 117: 636 ±40. 32. M acke RA, Hussain MB , Imray TJ, et al. Osteogenic and sarcomatoid differentiation of a renal cell carcinoma. C ancer 1985; 56: 2452 ±7. 33. Bonsib SM , Fischer J, Plattner S, Fallon B. Sarcomatoid renal tumors. Clinico-pathologic correlation of three cases. C ancer 1987; 59: 527± 32. 34. Lloreta J, Corominas JM, Munne A, et al. Low grade spindle cell carcinoma of the kidney. Ultrastruct Pathol 1998; 22: 83 ± 90. 35. M edeiros LJ, Michie SA, Johnson DE, et al. An immunoperoxidase study of renal cell carcinomas: correlation with nuclear grade, cell type and histologic pattern. Hum Pathol 1988; 19: 980 ±7. 36. Fleming S, M atthews TJ. Renal tubular antigens in regenerative epithelium and renal carcinoma. Br J Urol 1987; 60: 103 ±9. 37. Brugel G. Interpretation of proliferation markers. Virchows Arch 1996; 427: 323 ± 41. 38. Delahunt B, Nacey JN, Hammett GD, Frater W J. Nucleolar organizer regions in renal cell carcinoma, renal oncocytomas and renal adenoma. Anal Cell Pathol 1989; 1: 185 ±90. 39. Delahunt B, Bethwaite PB, Nacey JN, Ribas JL. Proliferating cell nuclear antigen (PC NA) expression as a prognostic indicator for renal cell carcinoma: comparison with tumor grade, mitotic index and silver staining nucleolar organizer region numbers. J Pathol 1993; 170: 471±7. 40. Delahunt B, Bethwaite PB, Thornton A. Proliferation of renal cell carcinoma assessed by fixation-resistant polyclonal Ki-67 antibody labelling: correlation with clinical outcome. Cancer 1995; 75: 2714 ± 9. 41. Dijkhuizen T, van den Berg E, van den Berg A, et al. Genetics as a diagnostic tool in sarcomatoid renal cell cancer. Int J Cancer 1997; 72: 265 ±9. 42. Oda H, Nakatsuru Y, Ishikawa T. M utations of the p53 gene and p53 protein overexpression are associated with sarcomatoid transformation in renal cell carcinomas. C ancer Res 1995; 55: 658 ± 62. 43. Kattar M M, Grignon DJ, Sarkar FH, et al. p53 gene expression in sarcomatoid renal cell carcinoma: a clinicopathologic study with review of the literature. J Urol Pathol 1996; 5: 207± 21. 44. Presti JC, Rao PH, Chen Q, et al. Histopathological, cytogenetic and molecular characterization of renal cortical tumors. Cancer Res 1991; 51: 1544 ± 52. 45. Paul R, Ewing CM, Robinson JC, et al. Cadherin-6, a cell adhesion molecule specifically expressed in the proximal renal tubule and renal cell carcinoma. C ancer Res 1997; 57: 2741± 8.