- Email: [email protected]
Sarcomatoid renal cell carcinoma
Urologic Oncology 6 (2001) 231–238
Review article
Sarcomatoid renal cell carcinoma: basic biology, clinical behavior and response to therapy Debby Chaoa, Amnon Zismana, Stephen J. Freedlanda, Allan J. Pantucka, Jonathan W. Saidb, Arie S. Belldegruna,* a
Division of Urologic Oncology, Department of Urology, University of California School of Medicine, Los Angeles, CA 90095-1738, USA b Department of Pathology and Laboratory Medicine, University of California School of Medicine, Los Angeles, CA 90095-1738, USA Received 9 November 2000; received in revised form 25 January 2001; accepted 2 March 2001
Abstract All histological subtypes of renal cell carcinoma (RCC) are capable of undergoing sarcomatous transformations that result in tumors with distinctive appearances and aggressive biologic behavior. The history of sarcomatoid renal cell carcinoma (SRCC) is traced from the time when it was thought to be a true sarcoma to the present when its epithelial origin is fully appreciated. The distinctive macroscopic and microscopic features as well as various diagnostic methods are reviewed. A description of the complex genetic aberrations associated with various types of RCC are summarized. It is apparent that the chromosomal changes known at this time are common to both SRCC and classic RCC while the unique alterations that lead to the sarcomatoid transformation remain unknown. The mode of presentation, the clinical behavior, and the prognostic factors common to SRCC are also reviewed. Finally, the various modalities that have been examined for the treatment of SRCC are detailed to evaluate for patient response and overall improvement in survival. A comparison of the treatment methods suggest that high-dose recombinant interleukin-2 may hold the greatest promise in improving the dismal prognosis associated with this disease. © 2001 Elsevier Science Inc. All rights reserved. Keywords: Sarcomatoid renal cell carcinoma; Genetic aberrations; Prognostic factors; Treatment, IL-2
1. Introduction Sarcomatous transformation of typical renal cell carcinoma (RCC) occurs in 1–13% of RCC patients [1–4]. Because it is an uncommon malignancy, few large-scale studies are available. The largest series from one study has been just 44 patients [3]. A comparison of sarcomatoid renal cell carcinoma (SRCC) to classic RCC reveals similarities in age, sex, and side distributions with differences in biologic behavior and clinical outcomes. The aggressive nature and dismal prognosis associated with RCC displaying these sarcomatous alterations has been clearly and consistently demonstrated since it was first recognized as a distinct entity. 2. Historical perspectives The classification of tumors displaying both carcinomatous and sarcomatous features has been debated since Virchow first introduced the term “carcinosarcoma” in 1864 * Corresponding author. 10833 Le Conte Ave., Room 66-118 CHS Los Angeles, CA 90095-1738. Tel.: 1-310-794-6584; Fax: 1-310206-5343. E-mail address: [email protected] (A.S. Belldegrun).
[5,6]. Initially, it was believed that simultaneous malignant growth of epithelial and stromal cells gave rise to these unusual tumors. The spindle cells that were consistently seen on microscopy were believed by some investigators to originate from fibroblasts or smooth muscle cells [7]. However, others raised the possibility that the spindle-shaped elements were derived from epithelial cells that had undergone severe metaplastic transformations. Another hypothesis pointed to the possibility that chronic inflammation in the carcinomatous tumor caused the structural changes, reactive fibrosis, and lymphocytic infiltration that gave rise to the sarcoma-like appearance. A classification of “pseudosarcomatous carcinoma” was even suggested [7]. Eventually, tumors previously diagnosed as carcinosarcomas were reexamined and the majority were given new classifications of adenocarcinoma with sarcoma-like features [8], thereby defining the progression of transformation from typical malignant epithelial cells to less differentiated but clearly carcinomatous cells, and finally, to poorly differentiated spindle and giant cells. Ultimately, the term sarcomatoid renal cell carcinoma was coined by Farrow et al. who studied 38 cases of kidney tumors with mixed malignant elements. They concluded
1078-1439/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S1078-1439(01)00 1 2 5 - 9
232
D. Chao et al. / Urologic Oncology 6 (2001) 231–238
that a diagnosis of SRCC required the co-existence of adulttype carcinoma with a component of undifferentiated pleomorphic cells displaying morphologically sarcomatous features [9]. 3. Macroscopic features The macroscopic features of SRCC are not diagnostic for the disease [10]. Farrow described the gross features of SRCC as predominately parenchymal, unencapsulated, and locally invasive [9]. The tumors are usually large with an average size of approximately 10 cm [2,11,12]. They can demonstrate a bimorphic appearance with the yellow, friable, multi-nodular, and often times, hemorrhagic areas typical for renal cell carcinoma while other regions may have a more solid and fibrous appearance typical for the sarcomatoid component. The proportion of sarcomatous and carcinomatous components can vary in different tumors and the two regions may be well demarcated or appear unrecognizably blended [13]. 4. Microscopic features The typical microscopic appearance of SRCC is that of a mixed tumor having a bimorphic pattern containing various degrees of high-grade sarcoma-like elements with classic malignant epithelial components that can intermingle or abut with one another (Fig. 1). Based on cytogenetic and pathologic research done over the last two decades, it is evident that renal cortical tumors are not a single tumor but rather a group of distinct malignancies. These findings were summarized in the Hiedelberg classification of renal cortical tumors which accurately describes the major variants of
RCC. Therefore the histology of the carcinomatous region in SRCC containing tumors can involve all types of RCC, including clear cell, chromophil (previously known as papillary, both typical and eosinophil), chromophobe, collecting duct carcinoma and unclassified tumors [4,11,12,14–16]. There have been several reports on the possible propensity for chromophobe RCC to undergo sarcomatoid transformation [4,17–19], suggesting that chromophobe RCC may represent the most common carcinomatous component in SRCC [4]. Nevertheless, the larger studies have all shown that the most common carcinomatous components are clear cell and chromophil [3,11,12]. This discrepancy can be due to sample sizes or to the under-diagnosis of chromophobe RCC, a relatively new entity [4]. The histology of the sarcomatoid component may vary, but the presence of pleomorphic spindle cells and/or giant cells is seen in most tumors [13]. The majority of SRCC show abundant mitoses [11], a high degree of nuclear pleomorphism [10,11] and large areas of necrosis confined mostly to the sarcomatous region [11]. Silver staining for nucleolar organizer regions demonstrated unusually high proliferative activity within SRCC [20]. Multiple sarcomatoid variants have been described. The two most common types closely resemble malignant fibrous histiocytoma and fibrosarcoma [2,11]. In the former, cells are arranged irregularly in whorls or interlacing fascicles with variable amounts of collagen and fibrous stroma. In the latter, the spindle cells are arranged in a monomorphic pattern [2,10,13]. Less commonly, SRCC may mimic rhabdomyosarcoma [9,10], hemangiopericytoma [11,13,21], osteogenic sarcoma [8,9,14,22], or contain foci of myxoid tissue containing multi-nucleated osteoclast-like giant cells with a background of sarcomatous elements [10,11]. An un-
Fig. 1. Typical H & E appearance of SRCC (200 magnification) demonstrating (A) a predominate sarcomatoid component [S] with a minor malignant epithelial element [E], (B) a clear demarcation (broken line) between the sarcomatoid [S] and malignant epithelial components [E], and (C) a pure sarcomatoid tumor with mostly spindle cells and a cluster of giant cells [G].
D. Chao et al. / Urologic Oncology 6 (2001) 231–238
usual angiosarcomatoid-type RCC with anastomosing vascular channels lined by an atypical single layer of endothelial-like cells has also been reported [23]. Microscopic examination of primary tumors and their associated metastatic growths or involved lymph nodes may demonstrate similar or vastly different histologies [9,22,24]. The primary tumor may have no indication of sarcomatous elements while the metastatic tumor or node can feature mixed or pure sarcomatoid histology. The reverse can also be true. No pattern of histologic variations between primary tumors and the associated metastasis has been found so far. 5. Ultrastructure and immunohistochemistry Electron microscopy can be used to determine the presence of epithelial features in tumors having sarcomatoid characteristics. It is also useful when the cell type(s) of a bimorphic tumor cannot be adequately ascertained and the diagnosis of a true carcinosarcoma cannot be ruled out. In the electron micrographs, the presence of multiple desmosomes, cell interdigitations, abundant microvilli, basal lamina, papillary ridges and a complex pleated pattern of opposing plasma membranes analogous to true renal tubular cells are the features indicative of a true epithelial origin [2,22,24,25]. Because true sarcomas and carcinosarcomas are exceedingly rare, ultrastructural findings play an important role in making the correct diagnoses [11]. Immunohistochemical studies have shown that many epithelial markers are common to SRCC and classic RCC. Expression of cytokeratins 8, 18, 19 and epithelial membrane antigen (EMA) and binding to various antibodies such as AE1/AE3 (anti-cytokeratin 1–8, 10, 14–17) and CAM 5.2 (anti-cytokeratin 8 and 18) can often be detected in both [4,26]. Conversely, vimentin over-expression is usually more prevalent in the sarcomatoid elements relative to the carcinomatous elements. The cytokeratin kidney-associated simple epithelial antigen, a low molecular weight cytokeratin, is also expressed more frequently by sarcomatoid tumors [26]. Thus, despite the fact that a specific and pathognomonic immunohistochemical pattern for SRCC does not exist, when hematoxylin-eosin staining is insufficient to distinguish SRCC from a true sarcoma or carcinosarcoma, the co-expression of vimentin and at least one cytokeratin is strongly suggestive of SRCC [15,26,27]. 6. Radiographic characteristics CT and angiography are useful tools in distinguishing SRCC from true sarcomas. SRCC typically arise from the renal parenchyma, are consistently hypervascular in nonnecrotic regions, have abundant neovascularization [15] and often extend into the renal vein or inferior vena cava, may have direct extension into the para-aortic regions, and are commonly associated with retroperitoneal lymphadenopathy [28]. SRCC tumors are usually larger in size and may exhibit a mass effect causing an expansion or distortion of
233
the renal outline. Hypovascular tumors arising from the renal capsule or renal sinus that remain capsule-confined with no involvement of the renal vein or inferior vena cava are features more typical for true sarcomas. Tumors exhibiting fat density range are highly suspicious for a liposarcoma. Although radiographic findings are useful when the differential is between sarcoma and SRCC, they cannot be used to distinguish SRCC from typical RCC [15,28].
7. Genetic aberrations The accumulation of multiple genetic alterations leading to genetic instability is thought to be one of the mechanisms resulting in the conversion of a normal cell to a malignant one. There are an average of 8.6 genetic aberrations per sarcomatoid tumor [29]. Elfving et al. showed that RCC patients who have greater than 5 genetic alterations had higher degrees of cytogenetic complexity directly associated with worse prognosis [30]. The presence of spindle cells has not been found to be associated with any cytogenetic patterns [30]. The chromosomal changes detected in SRCC are nonspecific and can be seen in many variants of highly aggressive and metastatic RCC. The most common genetic aberration in RCC is the loss of the short arm of chromosome 3. Loss of heterozygosity (LOH) and other alterations involving chromosome 3p can be detected in the majority of sporadic non-papillary RCC regardless of histologic type or tumor stage [31–36]. Multiple loci have been found on chromosome 3p that may have some role in the development of RCC. One study reported that the most common breakpoint that can be seen in all types of non-papillary RCC is located between 3p11–21 [34]. LOH or other alterations of the non-papillary renal carcinoma-1 (NRC-1), a tumor suppressor loci found on 3p12, can be detected in the majority of non-papillary RCC cell types [36]. Another study reported that the minimal common deletion in sporadic RCC was located on chromosome 3p21–26 [32]. The von Hippel Lindau (VHL) gene is located on 3p25 and mutations of this gene occur in up to 57% of sporadic RCC cases [37]. Chromosome 17 is unique in that both its loss and gain have been implicated in the progression of RCC [32,34, 38,39]. Jiang et al. found the most common gain of DNA in SRCC tumors involved chromosome 17 [29]. Oda et al. reported a strong association between p53 gene alteration on chromosome 17p and sarcomatoid transformation in RCC [38]. A majority of the tumors (79%) had mutations of the p53 region in the sarcomatoid portion of the mixed tumors while less than 15% of the tumors showed similar mutations in the carcinomatous components. The study concluded that the genetic heterogeneity within a single tumor is suggestive of a role in sarcomatous transformation and progression. Kanamaru et al., on the other hand, did not find substantial variations in immunoreactivity for the p53 protein in the sarcomatoid and carcinomatous regions and con-
234
D. Chao et al. / Urologic Oncology 6 (2001) 231–238
Table 1 RCC cytogenetics: genetic alterations associated with SRCC are not specific [58,59] RCC histologic type
Loss of heterozygosity
Non-papillary RCC
3p*, 6q, 8p, 9p, 10q, 11q, 14q, 17p, 19p Y 11p, 13q*, 14, 17, 18 4q, 6q, 9p, 11q, 13q*
Papillary RCC Advanced RCC Sarcomatoid RCC
from any subtype of RCC. The genetic changes leading to the unique transformation of classic RCC to SRCC remain unknown.
Chromosomal gain 16
8. Patient presentation and clinical behavior 7, 17* 3p, 5q, 7, 17 7, 8q, 12q, 17*
The poor prognosis associated with SRCC is well established. Patients with SRCC usually present with the signs and symptoms typical for classic RCC. The most common symptoms at diagnosis are identical to the classic triad for RCC; flank/abdominal pain, palpable mass, and hematuria [2,4,9,13]. There have been no reported cases of bilateral SRCC and no associations with VHL disease or tuberous sclerosis have been found. The rate of incidental diagnosis for SRCC is also unknown. Few SRCC tumors are capsule-confined. Overall, the incidence of Stage 1 disease is 5–19%, Stage 2 is 20–38%, Stage 3 is 21–31%, and Stage 4 is 38–57% [2–4,11,13]. This is in comparison to classic RCC where approximately half of the patients are diagnosed with the 1997 classification of Stage T1-2 disease [46]. The incidence of renal vein and inferior vena cava involvement, regional nodal involvement and distant metastasis has varied between studies and is summarized in Table 2. The most common sites of metastasis are lung and bone [3,11,12] but any organ may be affected. There have been three case reports of SRCC metastasizing to the heart and infiltrating the endocardium without evidence of tumor thrombus in the inferior vena cava [47–49]. The possible mechanism for these unusual metastasis include retrograde lymphatic spread, lymphohematogenous spread along the thoracic duct to the superior vena cava, hematogenous spread of tumor cell emboli, or via small pulmonary arteriovenous shunts. The presence of spindle cells was reported to be an independent poor prognostic indicator for RCC [1,50]. Several other prognostic factors have also been proposed for SRCC. Several studies have found that pathologic stage was the
* Denotes most common genetic alteration.
cluded that p53 did not have a specific role in sarcomatoid transformation [40]. The long arm of chromosome 13 is also a common site of aberration in advanced RCC, including SRCC [29,32]. Jiang et al. reported that loss of all or part of chromosome 13q was the most common genetic alteration detected in SRCC, occurring in 75% of the tumors examined [29] with a deletion in a susceptible region commonly located at 13q12–14 (89%) . Two genes located in this region are the retinoblastoma (Rb) and BRCA-2. However, subsequent studies have found that Rb gene mutations were uncommon in RCC (less than 2%) and normal expression of the Rb protein is detected in the majority of tumor cells [41,42]. It is, therefore, possible that other undetected genes in the 13q12–14 region are directly involved in the progression and transformation of RCC to its sarcomatoid variant. The hyperploidy of chromosome 7 can often be detected in SRCC and other types of advanced RCC [29,34]. Extra copies of chromosome 7 have been significantly correlated with Ki-67 over-expression in RCC cells [43]. The overexpression of Ki-67 is hypothesized to be associated with poor prognosis and increase potential for biologic aggressiveness and progression [44,45]. Table 1 summarizes the genetic aberrations detected in various types of RCC. In this regard, the overlap between SRCC and RCC is clearly demonstrated and is consistent with the current understanding that SRCC can be derived
Table 2 Common clinical features of sarcomatoid RCC based on larger-scale studies (n 10). Number of SRCC patients % of patients with SRCC Male (%) Female (%) Mean size of tumor (cm) Most common epithelial component Stage T1-2 (%) Stage T3 (%) Stage T4 (%) RV/IVC involvement (%) Regional nodal involvement (%) Distant metastasis (%) Nephrectomy done (%) Median survival (mos)
Farrow [9]
Tomera [2]
Ro [11]
Sella [3]
Culine [55]
Akhtar [4]
Cangiano [12]
37
13 1 11 (85) 2 (15) 10
42
44 4.8 24 (55) 22 (45)
14 1.1 11 (79) 3 (21)
11 5.8 5 (45) 6 (55)
31
21 (57) 16 (43) Clear
2 (15)
23 (62) 3 (8) 36 (97) 6.0
RV renal vein; IVC inferior vena cava.
1 (8) 5 (38) 12 (92) 6.3
24 (57) 18 (43) 10.2 Clear 6 (14) 34 (81) 2 (5) 15 (36) 14 (33) 10 (24) 6.8
Chromophobe 3 (30) 3 (30) 4 (40)
25 (57) 40 (91) 6.6
13 (93)
23 (74) 8 (26) 9 Clear 3 (10) 19 (61) 8 (26) 9 (29) 7 (23) 26 (84) 31 (100)
D. Chao et al. / Urologic Oncology 6 (2001) 231–238
single most important prognostic factor [3,11,12], with a median survival for Stage 1 disease of 50 months and just 4–5 months for Stage 3–4 disease [11]. Other factors associated with poor prognosis include lymph node involvement and distant metastasis [3,12]. When only one organ is involved with metastatic disease, lung is associated with the worst prognosis and involvement of three or more organs was also a poor prognostic indicator [3]. Other factors are apparently non-prognostic. These include the presence of renal vein or inferior vena cava involvement [11,12], pattern of sarcomatoid growth (e.g., malignant fibrous histiocyte-like vs. fibrosarcoma-like), type of sarcomatoid cell (spindle vs. giant cell), level of cellularity, the degree of fibrosis within the tumor, and the presence and density of lymphocytic infiltration [11,51]. Finally, nephrectomy and other types of surgical resections were not shown to impact patient outcomes [3,12,13]. Reports on the prognostic roles of grade, mitotic rate and degree of necrosis have been discrepant [11,15,51]. Female sex and age greater than 59 were poor prognostic indicators in the study by Sella et al. [3], while Cangiano et al. determined that age and sex do not influence prognosis [12]. The relative proportion of sarcomatous component to the carcinomatous component is one of the most disputed prognostic factors. One study found that the proportion of the sarcomatous component did impact patient prognosis but only for Stage 1–2 disease [11]. Another study concluded that pure sarcomatoid RCC behaved more aggressively than mixed clear and sarcomatoid RCC with the latter having a better prognosis similar to pure clear cell RCC [52]. Finally, Bertoni et al. determined that patients with tumors exhibiting less than 5% sarcomatoid regions had improved prognosis but no difference was found when the comparison was made between patients having more than or less than 50% sarcomatoid component [13]. Other studies did not demonstrate a prognostic role for the proportion of sarcomatoid component [12,15,51]. The prognosis of patients with SRCC is uniformly dismal with a median survival of only 4–7 months after diagnosis [2,3,9,11,12,29]. In contrast, the median survival for RCC patients is 19 months (Fig. 2) [3]. There are sporadic reports of Stage 1 SRCC patients with long-term survival [2,11]. One patient with a small (5 cm) capsule confined tumor had a survival time of 81 months [11] while two patients with Stage 2 disease, having tumors that contained 5% or less of the sarcomatous component, were still alive after 69 and 77 months [13]. A case report described a patient with recurrent disease at 1 and 7 years after initial nephrectomy, with all pathology specimens demonstrating SRCC, who was still alive 1 year after the last surgical resection [53]. In perhaps the most unusual case, a patient with capsule confined SRCC had spontaneous regression of his pulmonary metastasis after undergoing nephrectomy. He received no other form of treatment during the interval time and was alive and well without evidence of disease 1 year after the spontaneous regression [54]. Despite these rare
235
Fig. 2. Kaplan-Meier survival plot for 661 patients undergoing nephrectomy at UCLA for RCC between 1989–1999 comparing the survival of SRCC vs. non-SRCC histologic subtypes (median follow-up 44 months).
cases of prolonged survival and positive outcomes, the overall prognosis for SRCC remains poor. 9. Treatment Effective treatment for SRCC remains elusive with surgery being the mainstay. A compilation of studies (13 patients) shows that 151 of 158 patients underwent surgical resections [2–4,9,12,13]. Sella et al. found that surgery alone resulted in a slight improvement of survival for Stage 4 patients from 3 months to 6 months but no Stage 1–3 patients achieved complete cures [3]. The overall survival for patients treated only with surgery was 5–6.6 months [2,3, 9,12]. Because the vast majority of SRCC patients had their primaries removed, it is difficult to compare potential differences in survival with patients who still have their primaries in place. Based on the overall survival however, one can conclude that the difference between the two groups is small and neither group appears to fare well. In an effort to improve the survival of SRCC patients, a number of systemic therapies, including hormone therapy, chemotherapy, and immunotherapy, have been attempted with differing results. The various studies have included only those patients with Stage 4 disease. Sella et al. found that independent of nephrectomy, Stage 4 patients who received some form of systemic therapy had a higher median survival of 13 months compared to those who did not receive systemic therapy (3.8 months) [3]. Hormone therapy for SRCC patients with Stage 4 disease, including medroxypregesterone and androgen therapy, resulted in no measurable response and a median survival of 12–13 months [3]. Chemotherapy for SRCC can be sub-categorized into doxorubicin-based and non-doxorubicinbased therapy. Patients treated with non-doxorubicin-based chemotherapy, including CCNU (lomustine), streptozotocin, hydroxyurea, vincristine, BAF (boc-aspartyl [Ome]-flu-
236
D. Chao et al. / Urologic Oncology 6 (2001) 231–238
oromethylketone) and elliptinium, did not respond to therapy and survived for approximately 6–8 months [3,55]. Doxorubicin-based therapies including CYVADIC (cyclophosphamide, vincristine, doxorubicin, and dacarbazine), DECAV (dacarbazine, cyclophosphamide, cisplatin, doxorubicin, and vindesine), and DI (doxorubicin and isosfamide) have yielded poor response and survival rates in most patients. Median survival has been reported at 7–12 months [3,55]. Despite mediocre results seen in the majority of patients, a small population of patients appeared to respond. Culine et al. reported three patients having partial responses with average durations of 7.8 months. The patients had prolonged survival periods of 20, 29, and 60 months in comparison to the 11 non-responders who had an overall median survival of 9 months [55]. Sella et al. reported on a complete response in two of eight patients treated with doxorubicinbased therapy [3]. Both patients had Stage 1 disease at diagnosis and were still alive with no evidence of disease at 46 and 50 months. Lupera et al. also observed a complete remission in an SRCC patient treated with DECAV [56]. Overall, the majority of patients do not respond well to doxorubicin-based chemotherapy and non-responders have only limited improvements in survival. However, a small and still uncharacterized subset of patients do benefit significantly from this form of treatment. More studies are needed to elucidate the parameters leading to these positive outcomes. Numerous types of immunotherapy have been explored for the treatment of SRCC patients, but the outcomes have been heterogeneous. Interferon-alpha (INF-) as a single agent did not yield measurable clinical response in patients [3,52,55] but did result in prolongation of median survival to 35–41 months [3,55]. Of the nine patients treated with a combination regimen consisting of INF-, tumor infiltrating lymphocytes (TIL), and low-dose interleukin-2 (IL-2), one patient had a complete response and two had partial responses [12]. The overall median survival for these nine patients was 9 months. Low-dose IL-2 was also used as a single agent but no responses were noted [12,52] and median survival was just 3 months [12]. Single-agent high-dose IL-2 has demonstrated promising results for the treatment of SRCC. Cangiano et al. concluded that not receiving highdose IL-2 was one variable significantly correlated with an increased relative risk of death (RR 10.4) [12]. However, Wu et al. noted that patients with pure sarcomatoid tumors responded differently to high-dose IL-2 than those with mixed sarcomatoid and clear cell tumors having median survivals of 14 and 35 months, respectively [52]. Nevertheless, high-dose IL-2 appears to benefit the largest proportion of SRCC patients, especially in prolonging overall survival, and should be considered for all Stage 4 patients who have no contraindications and can tolerate acceptable degrees of the associated toxicities. The data on treatment modalities for SRCC has been limited by the relatively few cases studied. So far, only patients with Stage 4 disease have been treated with the various types of systemic therapies. With the poor prognosis associ-
ated with all stages of this disease and the lack of definite cure with surgery alone, the role of high-dose IL-2 may need to be expanded to include all SRCC patients. The role of nephrectomy prior to the administration of high-dose IL-2 remains unanswered. Reports on systemic therapies given to SRCC patients did not differentiate between the responses seen in patients who underwent nephrectomies from those who did not. This is probably due to the small number of patients who forego surgery. However, it will be important to make this distinction for the benefit of future patients. If aggressive resection does increase the efficacy of high-dose IL-2, a patient who undergoes a partial nephrectomy and is then diagnosed with SRCC may benefit from supplemental surgery. If surgery does not improve on the survival of patients receiving high-dose IL-2, an invasive procedure associated with some degree of morbidity and mortality can be avoided. This suggests that a role for prenephrectomy biopsy may exist for patients with large tumors to assist in treatment decision processes. Although the role of nephrectomy and high-dose IL-2 for the treatment of SRCC is still unclear, it has been shown that high-dose IL-2 following surgery resulted in improved efficacy and survival when compared to either modality alone for the treatment of RCC [57]. It is possible that similar findings could hold true for SRCC. 10. Conclusion Significant progress has been made in characterizing the sarcomatous transformation of renal cell carcinoma since it was first recognized as a distinct entity from true sarcomas. With a large array of diagnostic tools available, it is now accepted that SRCC is a transformed continuum of the various subtypes of RCC. However, the specific factors resulting in the aggressive biologic behavior of SRCC remain unclear. The current data seems to suggest that radical nephrectomy followed by high-dose IL-2 holds the greatest promise in prolonging survival. Similar to Wilms’ tumor, a large multicentric cooperative study may be able to provide answers to the unsolved questions regarding SRCC. References [1] Skinner DG, Colvin RB, Vermillion CD, Pfister RC, Leadbetter WF. Diagnosis and management of renal cell carcinoma: a clinical and pathologic study of 309 cases. Cancer 1971;28:1165–77. [2] Tomera KM, Farrow GM, Lieber MM. Sarcomatoid renal carcinoma. J Urol 1983;130:657–9. [3] Sella A, Logothetis CJ, Ro JY, Swanson DA, Samuels ML. Sarcomatoid renal cell carcinoma. A treatable entity. Cancer 1987;60:1313–8. [4] Akhtar M, Tulbah A, Kardar AH, Ashraf M. Sarcomatoid renal cell carcinoma: the chromophobe connection. Am J Surg Pathol 1997;21: 1188–95. [5] Saphir O, Vass A. Carcinosarcoma. Am J Cancer 1938;33:331. [6] Fauci PA, Therhag HG, Davis JE. Carcinosarcoma of the renal pelvis. J Urol 1961;85:897–902. [7] Weisel W, Dockerty MB, Priestley JT. Sarcoma of the kidney. J Urol 1943;50:654–573.
D. Chao et al. / Urologic Oncology 6 (2001) 231–238 [8] Hou LT, Willis RA. Renal carcino-sarcoma, true and false. J Pathol Bacteriol 1963;85:139–44. [9] Farrow GM, Harrison EGJ, Utz DC. Sarcomas and sarcomatoid and mixed malignant tumors of the kidney in adults. 3. Cancer 1968;22: 556–63. [10] Delahunt B. Sarcomatoid renal carcinoma: the final common dedifferentiation pathway of renal epithelial malignancies. Pathology 1999;31:185–90. [11] Ro JY, Ayala AG, Sella A, Samuels ML, Swanson DA. Sarcomatoid renal cell carcinoma: clinicopathologic. A study of 42 cases. Cancer 1987;59:516–26. [12] Cangiano T, Liao J, Naitoh J, Dorey F, Figlin R, Belldegrun A. Sarcomatoid renal cell carcinoma: biologic behavior, prognosis, and response to combined surgical resection and immunotherapy. JCO 1999;17:523–8. [13] Bertoni F, Ferri C, Benati A, Bacchini P, Corrado F. Sarcomatoid carcinoma of the kidney. J Urol 1987;137:25–8. [14] Young RH, Dunn J, Dickersin GR. An unusual oncocytic renal cell tumor with sarcomatoid foci and osteogenic differentiation. Arch Pathol Lab Med 1988;112:937–40. [15] Auger M, Katz RL, Sella A, Ordonez NG, Lawrence DD, Ro JY. Fine-needle aspiration cytology of sarcomatoid renal cell carcinoma: a morphologic and immunocytochemical study of 15 cases. Diag Cytopathol 1993;9:46–51. [16] Baer SC, Ro JY, Ordonez NG, et al. Sarcomatoid collecting duct carcinoma: a clinicopathologic and immunohistochemical study of 5 cases. Hum Pathol 1993;24:1017–22. [17] Kuroda N, Hayashi Y, Itoh H. A case of chromophobe renal cell carcinoma with sarcomatoid foci and a small daughter lesion. Patholo Int 1998;48:812–7. [18] Mai KT, Veinot JP, Collins JP. Sarcomatous transformation of chromophobe cell renal carcinoma. Histopathology 1999;34:557–9. [19] Tardio JC. Chromophobe cell renal carcinomas with sarcomatoid areas. Histopathology 2000;36:184–5. [20] Oda H, Machinami R. Sarcomatoid renal cell carcinoma: a study of its proliferative activity. Cancer 1993;71:2292–8. [21] DeLong W, Gringnon DJ, Eberwein P, Shum DT, Wyatt JK. Sarcomatoid renal cell carcinoma: an immunohistochemical study of 18 cases. Arch Pathol Lab Med 1993;117:636–40. [22] Macke RA, Hussain MB, Imray TJ, Wilson RB, Cohen SM. Osteogenic and sarcomatoid differentiation of a renal cell carcinoma. Cancer 1985;56:2452–7. [23] Kragel PJ, Travis WD, Luibel FJ. Sarcomatoid renal carcinoma with angiosarcomatoid component. Urology 1992;40:381–4. [24] Bonsib SM, Fischer J, Plattner S, Fallon B. Sarcomatoid renal tumors: clinicopathologic correlation of three cases. Cancer 1987;59:527–32. [25] Deitchman B, Sidhu GS. Ultrastructural study of a sarcomatoid variant of renal cell carcinoma. Cancer 1980;46:1152–7. [26] 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. [27] Markovic-Lipkovski J, Brasanac D, Todorovic V, Muller CA, Muller GA. Immunomorphological characteristics of renal cell carcinoma. Histol Histopathol 1995;10:651–9. [28] Shirkhoda A, Lewis E. Renal sarcoma and sarcomatoid renal cell carcinoma: CT and angiographic features. Radiology 1987;162:353–7. [29] Jiang F, Moch H, Richter J, et al. Comparative genomic hybridization reveals frequent chromosome 13q and 4q losses in renal carcinomas with sarcomatoid transformation. J Pathology 1998;185:382–8. [30] Elfving P, Mandahl N, Lundgren R, et al. Prognostic implications of cytogenetic findings in kidney cancer. Br J Urol 1997;80:698–706. [31] Zbar B, Bruch T, Talmadge C, Linehan M. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature 1987; 327:721–7. [32] Anglard PKT, Brauch H, Weiss GH, et al. Molecular analysis of genetic changes in the origin and development of renal cell carcinoma. Cancer Res 1991;51:1071–7.
237
[33] Morita R, Ishikawa J, Tsutsumi M, et al. Allelotype of renal cell carcinoma. Cancer Res 1991;51:820–3. [34] Presti JC, Rao PH, Chen Q, et al. Histopathological, cytogenetic, and molecular characterization of renal cortical tumors. Cancer Res 1991; 51:1544–52. [35] Moch H, Presti JC, Sauter G, et al. Genetic aberrations detected by comparative genomic hybridization are associated with clinical outcome in renal cell carcinoma. Cancer Res 1996;56:27–30. [36] Lovell M, Lott ST, Wong P, El-Naggar A, Tucker S, Killary AM. The genetic locus NRC-1 within chromosome 3p12 mediates tumor suppression in renal cell carcinoma independently of histological type, tumor microenvironment, and VHL mutation. Cancer Res 1999;59: 2182–9. [37] Crossey PA, Richards FM, Foster K, et al. Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet 1994;3: 1303–8. [38] Oda H, Nakatsuru Y, Ishikawa T. Mutations of the p53 gene and p53 protein overexpression are associated with sarcomatoid transformation in renal cell carcinomas. Cancer Res 1995;55:658–62. [39] Wada Y, Yokogi H, Moriyama-Gonda N, Shigeno K, Shiina H, Igawa M. Chromosome aberrations in renal tumors detected by fluorescence in situ hybridization. Cancer Genet Cytogenet 1997;99:38–44. [40] Kanamaru H, Li B, Miwa Y, Akino H, Okada K. Immunohistochemical expression of p53 and bcl-2 proteins is not associated with sarcomatoid change in renal cell carcinoma. Urol Res 1999;27:169–73. [41] Walther MM, Guarra JR, Elwood L, et al. Loss of heterozygosity occurs centromeric to RB without associated abnormalities in the retinoblastoma gene in tumors from patients with metastatic renal cell carcinoma. J Urol 1995;153:2050–4. [42] Presti JC, Reuter VE, Cordon-Cardo C, et al. Expression of the retinoblastoma gene product in renal tumors. Anticancer Res 1996;16: 549–56. [43] Wada Y, Igawa M, Shiina H, et al. Comparison of chromosomal aberrations detected by fluorescence in situ hybridization with clinical parameters, DNA ploidy and Ki67 expression in renal cell carcinoma. Br J Cancer 1998;77:2003–7. [44] Aaltomaa S, Lipponen P, Ala-Opas M, Eskelinen M, Syrjanen K. Prognostic value of Ki-67 expression in renal cell carcinoma. Eur Urol 1997;31:350–5. [45] Rioux-Leclercq N, Turlin B, Bansard J, et al. Value of immunohistochemical Ki-67 and p53 determinations as predictive factors of outcome in renal cell carcinoma. Urology 2000;55:501–5. [46] Tsui K, Shvarts O, Smith RB, Figlin RA, deKernion JB, Belldegrun A. Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria. J Urol 2000;163:1090–5. [47] Bird DJ, Semple JP, Seiler MW. Sarcomatoid renal cell carcinoma metastatic to the heart: report of a case. Ultrastruct Pathol 1991;15:361–6. [48] Riccioni L, Damiani S, Pasquinelli G, Scarani P. Solitary left ventricle metastasis by renal cell carcinoma with sarcomatoid features. Tumori 1996;82:266–9. [49] Santo-Tomas M, Mahr NC, Robinson MJ, Agatston AS. Metastatic renal cell carcinoma invading right ventricular myocardium without caval involvement. J Cardiovasc Surg 1998;39:811–2. [50] Mani S, Todd MB, Katz K, Poo W. Prognostic factors for survival in patients with metastatic renal cancer treated with biological response modifiers. J Urol 1995;154:35–40. [51] Delahunt B, Nacey JN. Renal cell carcinoma II. Histological indicators of prognosis. Pathology 1987;19:258–63. [52] Wu J, Caliendo G, Hu X, Dutcher JP. Impact of histology on the treatment outcome of metastatic or recurrent renal cell carcinoma. Medical Oncol 1998;15:44–9. [53] Goessl C, Muller M, Heicappell R, Perez-Canto A, Miller K. Longterm survival after surgery for recurrent advanced sarcomatoid renal carcinoma. BJU Int 1999;84:888–9. [54] Garcia-Del-Muro X, Cardenal F, Romagosa V, Gil M. Sarcomatoid
238
D. Chao et al. / Urologic Oncology 6 (2001) 231–238
renal cell carcinoma: a case of spontaneous regression of metastasis. Eur Urol 1993;24:300–1. [55] Culine S, Bekradda M, Terrier-Lacombe MJ, Droz JP. Treatment of sarcomatoid renal cell carcinoma: is there a role for chemotherapy? Eur Urol 1995;27:138–41. [56] Lupera H, Theodore C, Ghosn M, Court BH, Wibault P, Droz JP. Phase II trial of combination chemotherapy with decarbazine, cyclophosphamide, cisplatin, doxorubicin, and vindesine (DECAV) in advanced renal cell cancer. Urology 1989;34:281–3.
[57] Belldegrun A, Shvarts O, Figlin RA. Expanding the indications for surgery and adjuvant IL-2-based immunotherapy in patients with renal cell carcinoma. Cancer J Sci Am 2000;6(Suppl 1):S88–92. [58] Mirghomizadeh F, Kupka S, Blin N. Assessing genetic heterogeneity of renal cell tumors. Anticancer Res 1999;19:1467–70. [59] Steiner G, Sidransky D. Molecular differential diagnosis of renal carcinoma from microscopes to micro satellites. Am J Pathol 1996;149: 1791–5.
Review article
Sarcomatoid renal cell carcinoma: basic biology, clinical behavior and response to therapy Debby Chaoa, Amnon Zismana, Stephen J. Freedlanda, Allan J. Pantucka, Jonathan W. Saidb, Arie S. Belldegruna,* a
Division of Urologic Oncology, Department of Urology, University of California School of Medicine, Los Angeles, CA 90095-1738, USA b Department of Pathology and Laboratory Medicine, University of California School of Medicine, Los Angeles, CA 90095-1738, USA Received 9 November 2000; received in revised form 25 January 2001; accepted 2 March 2001
Abstract All histological subtypes of renal cell carcinoma (RCC) are capable of undergoing sarcomatous transformations that result in tumors with distinctive appearances and aggressive biologic behavior. The history of sarcomatoid renal cell carcinoma (SRCC) is traced from the time when it was thought to be a true sarcoma to the present when its epithelial origin is fully appreciated. The distinctive macroscopic and microscopic features as well as various diagnostic methods are reviewed. A description of the complex genetic aberrations associated with various types of RCC are summarized. It is apparent that the chromosomal changes known at this time are common to both SRCC and classic RCC while the unique alterations that lead to the sarcomatoid transformation remain unknown. The mode of presentation, the clinical behavior, and the prognostic factors common to SRCC are also reviewed. Finally, the various modalities that have been examined for the treatment of SRCC are detailed to evaluate for patient response and overall improvement in survival. A comparison of the treatment methods suggest that high-dose recombinant interleukin-2 may hold the greatest promise in improving the dismal prognosis associated with this disease. © 2001 Elsevier Science Inc. All rights reserved. Keywords: Sarcomatoid renal cell carcinoma; Genetic aberrations; Prognostic factors; Treatment, IL-2
1. Introduction Sarcomatous transformation of typical renal cell carcinoma (RCC) occurs in 1–13% of RCC patients [1–4]. Because it is an uncommon malignancy, few large-scale studies are available. The largest series from one study has been just 44 patients [3]. A comparison of sarcomatoid renal cell carcinoma (SRCC) to classic RCC reveals similarities in age, sex, and side distributions with differences in biologic behavior and clinical outcomes. The aggressive nature and dismal prognosis associated with RCC displaying these sarcomatous alterations has been clearly and consistently demonstrated since it was first recognized as a distinct entity. 2. Historical perspectives The classification of tumors displaying both carcinomatous and sarcomatous features has been debated since Virchow first introduced the term “carcinosarcoma” in 1864 * Corresponding author. 10833 Le Conte Ave., Room 66-118 CHS Los Angeles, CA 90095-1738. Tel.: 1-310-794-6584; Fax: 1-310206-5343. E-mail address: [email protected] (A.S. Belldegrun).
[5,6]. Initially, it was believed that simultaneous malignant growth of epithelial and stromal cells gave rise to these unusual tumors. The spindle cells that were consistently seen on microscopy were believed by some investigators to originate from fibroblasts or smooth muscle cells [7]. However, others raised the possibility that the spindle-shaped elements were derived from epithelial cells that had undergone severe metaplastic transformations. Another hypothesis pointed to the possibility that chronic inflammation in the carcinomatous tumor caused the structural changes, reactive fibrosis, and lymphocytic infiltration that gave rise to the sarcoma-like appearance. A classification of “pseudosarcomatous carcinoma” was even suggested [7]. Eventually, tumors previously diagnosed as carcinosarcomas were reexamined and the majority were given new classifications of adenocarcinoma with sarcoma-like features [8], thereby defining the progression of transformation from typical malignant epithelial cells to less differentiated but clearly carcinomatous cells, and finally, to poorly differentiated spindle and giant cells. Ultimately, the term sarcomatoid renal cell carcinoma was coined by Farrow et al. who studied 38 cases of kidney tumors with mixed malignant elements. They concluded
1078-1439/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S1078-1439(01)00 1 2 5 - 9
232
D. Chao et al. / Urologic Oncology 6 (2001) 231–238
that a diagnosis of SRCC required the co-existence of adulttype carcinoma with a component of undifferentiated pleomorphic cells displaying morphologically sarcomatous features [9]. 3. Macroscopic features The macroscopic features of SRCC are not diagnostic for the disease [10]. Farrow described the gross features of SRCC as predominately parenchymal, unencapsulated, and locally invasive [9]. The tumors are usually large with an average size of approximately 10 cm [2,11,12]. They can demonstrate a bimorphic appearance with the yellow, friable, multi-nodular, and often times, hemorrhagic areas typical for renal cell carcinoma while other regions may have a more solid and fibrous appearance typical for the sarcomatoid component. The proportion of sarcomatous and carcinomatous components can vary in different tumors and the two regions may be well demarcated or appear unrecognizably blended [13]. 4. Microscopic features The typical microscopic appearance of SRCC is that of a mixed tumor having a bimorphic pattern containing various degrees of high-grade sarcoma-like elements with classic malignant epithelial components that can intermingle or abut with one another (Fig. 1). Based on cytogenetic and pathologic research done over the last two decades, it is evident that renal cortical tumors are not a single tumor but rather a group of distinct malignancies. These findings were summarized in the Hiedelberg classification of renal cortical tumors which accurately describes the major variants of
RCC. Therefore the histology of the carcinomatous region in SRCC containing tumors can involve all types of RCC, including clear cell, chromophil (previously known as papillary, both typical and eosinophil), chromophobe, collecting duct carcinoma and unclassified tumors [4,11,12,14–16]. There have been several reports on the possible propensity for chromophobe RCC to undergo sarcomatoid transformation [4,17–19], suggesting that chromophobe RCC may represent the most common carcinomatous component in SRCC [4]. Nevertheless, the larger studies have all shown that the most common carcinomatous components are clear cell and chromophil [3,11,12]. This discrepancy can be due to sample sizes or to the under-diagnosis of chromophobe RCC, a relatively new entity [4]. The histology of the sarcomatoid component may vary, but the presence of pleomorphic spindle cells and/or giant cells is seen in most tumors [13]. The majority of SRCC show abundant mitoses [11], a high degree of nuclear pleomorphism [10,11] and large areas of necrosis confined mostly to the sarcomatous region [11]. Silver staining for nucleolar organizer regions demonstrated unusually high proliferative activity within SRCC [20]. Multiple sarcomatoid variants have been described. The two most common types closely resemble malignant fibrous histiocytoma and fibrosarcoma [2,11]. In the former, cells are arranged irregularly in whorls or interlacing fascicles with variable amounts of collagen and fibrous stroma. In the latter, the spindle cells are arranged in a monomorphic pattern [2,10,13]. Less commonly, SRCC may mimic rhabdomyosarcoma [9,10], hemangiopericytoma [11,13,21], osteogenic sarcoma [8,9,14,22], or contain foci of myxoid tissue containing multi-nucleated osteoclast-like giant cells with a background of sarcomatous elements [10,11]. An un-
Fig. 1. Typical H & E appearance of SRCC (200 magnification) demonstrating (A) a predominate sarcomatoid component [S] with a minor malignant epithelial element [E], (B) a clear demarcation (broken line) between the sarcomatoid [S] and malignant epithelial components [E], and (C) a pure sarcomatoid tumor with mostly spindle cells and a cluster of giant cells [G].
D. Chao et al. / Urologic Oncology 6 (2001) 231–238
usual angiosarcomatoid-type RCC with anastomosing vascular channels lined by an atypical single layer of endothelial-like cells has also been reported [23]. Microscopic examination of primary tumors and their associated metastatic growths or involved lymph nodes may demonstrate similar or vastly different histologies [9,22,24]. The primary tumor may have no indication of sarcomatous elements while the metastatic tumor or node can feature mixed or pure sarcomatoid histology. The reverse can also be true. No pattern of histologic variations between primary tumors and the associated metastasis has been found so far. 5. Ultrastructure and immunohistochemistry Electron microscopy can be used to determine the presence of epithelial features in tumors having sarcomatoid characteristics. It is also useful when the cell type(s) of a bimorphic tumor cannot be adequately ascertained and the diagnosis of a true carcinosarcoma cannot be ruled out. In the electron micrographs, the presence of multiple desmosomes, cell interdigitations, abundant microvilli, basal lamina, papillary ridges and a complex pleated pattern of opposing plasma membranes analogous to true renal tubular cells are the features indicative of a true epithelial origin [2,22,24,25]. Because true sarcomas and carcinosarcomas are exceedingly rare, ultrastructural findings play an important role in making the correct diagnoses [11]. Immunohistochemical studies have shown that many epithelial markers are common to SRCC and classic RCC. Expression of cytokeratins 8, 18, 19 and epithelial membrane antigen (EMA) and binding to various antibodies such as AE1/AE3 (anti-cytokeratin 1–8, 10, 14–17) and CAM 5.2 (anti-cytokeratin 8 and 18) can often be detected in both [4,26]. Conversely, vimentin over-expression is usually more prevalent in the sarcomatoid elements relative to the carcinomatous elements. The cytokeratin kidney-associated simple epithelial antigen, a low molecular weight cytokeratin, is also expressed more frequently by sarcomatoid tumors [26]. Thus, despite the fact that a specific and pathognomonic immunohistochemical pattern for SRCC does not exist, when hematoxylin-eosin staining is insufficient to distinguish SRCC from a true sarcoma or carcinosarcoma, the co-expression of vimentin and at least one cytokeratin is strongly suggestive of SRCC [15,26,27]. 6. Radiographic characteristics CT and angiography are useful tools in distinguishing SRCC from true sarcomas. SRCC typically arise from the renal parenchyma, are consistently hypervascular in nonnecrotic regions, have abundant neovascularization [15] and often extend into the renal vein or inferior vena cava, may have direct extension into the para-aortic regions, and are commonly associated with retroperitoneal lymphadenopathy [28]. SRCC tumors are usually larger in size and may exhibit a mass effect causing an expansion or distortion of
233
the renal outline. Hypovascular tumors arising from the renal capsule or renal sinus that remain capsule-confined with no involvement of the renal vein or inferior vena cava are features more typical for true sarcomas. Tumors exhibiting fat density range are highly suspicious for a liposarcoma. Although radiographic findings are useful when the differential is between sarcoma and SRCC, they cannot be used to distinguish SRCC from typical RCC [15,28].
7. Genetic aberrations The accumulation of multiple genetic alterations leading to genetic instability is thought to be one of the mechanisms resulting in the conversion of a normal cell to a malignant one. There are an average of 8.6 genetic aberrations per sarcomatoid tumor [29]. Elfving et al. showed that RCC patients who have greater than 5 genetic alterations had higher degrees of cytogenetic complexity directly associated with worse prognosis [30]. The presence of spindle cells has not been found to be associated with any cytogenetic patterns [30]. The chromosomal changes detected in SRCC are nonspecific and can be seen in many variants of highly aggressive and metastatic RCC. The most common genetic aberration in RCC is the loss of the short arm of chromosome 3. Loss of heterozygosity (LOH) and other alterations involving chromosome 3p can be detected in the majority of sporadic non-papillary RCC regardless of histologic type or tumor stage [31–36]. Multiple loci have been found on chromosome 3p that may have some role in the development of RCC. One study reported that the most common breakpoint that can be seen in all types of non-papillary RCC is located between 3p11–21 [34]. LOH or other alterations of the non-papillary renal carcinoma-1 (NRC-1), a tumor suppressor loci found on 3p12, can be detected in the majority of non-papillary RCC cell types [36]. Another study reported that the minimal common deletion in sporadic RCC was located on chromosome 3p21–26 [32]. The von Hippel Lindau (VHL) gene is located on 3p25 and mutations of this gene occur in up to 57% of sporadic RCC cases [37]. Chromosome 17 is unique in that both its loss and gain have been implicated in the progression of RCC [32,34, 38,39]. Jiang et al. found the most common gain of DNA in SRCC tumors involved chromosome 17 [29]. Oda et al. reported a strong association between p53 gene alteration on chromosome 17p and sarcomatoid transformation in RCC [38]. A majority of the tumors (79%) had mutations of the p53 region in the sarcomatoid portion of the mixed tumors while less than 15% of the tumors showed similar mutations in the carcinomatous components. The study concluded that the genetic heterogeneity within a single tumor is suggestive of a role in sarcomatous transformation and progression. Kanamaru et al., on the other hand, did not find substantial variations in immunoreactivity for the p53 protein in the sarcomatoid and carcinomatous regions and con-
234
D. Chao et al. / Urologic Oncology 6 (2001) 231–238
Table 1 RCC cytogenetics: genetic alterations associated with SRCC are not specific [58,59] RCC histologic type
Loss of heterozygosity
Non-papillary RCC
3p*, 6q, 8p, 9p, 10q, 11q, 14q, 17p, 19p Y 11p, 13q*, 14, 17, 18 4q, 6q, 9p, 11q, 13q*
Papillary RCC Advanced RCC Sarcomatoid RCC
from any subtype of RCC. The genetic changes leading to the unique transformation of classic RCC to SRCC remain unknown.
Chromosomal gain 16
8. Patient presentation and clinical behavior 7, 17* 3p, 5q, 7, 17 7, 8q, 12q, 17*
The poor prognosis associated with SRCC is well established. Patients with SRCC usually present with the signs and symptoms typical for classic RCC. The most common symptoms at diagnosis are identical to the classic triad for RCC; flank/abdominal pain, palpable mass, and hematuria [2,4,9,13]. There have been no reported cases of bilateral SRCC and no associations with VHL disease or tuberous sclerosis have been found. The rate of incidental diagnosis for SRCC is also unknown. Few SRCC tumors are capsule-confined. Overall, the incidence of Stage 1 disease is 5–19%, Stage 2 is 20–38%, Stage 3 is 21–31%, and Stage 4 is 38–57% [2–4,11,13]. This is in comparison to classic RCC where approximately half of the patients are diagnosed with the 1997 classification of Stage T1-2 disease [46]. The incidence of renal vein and inferior vena cava involvement, regional nodal involvement and distant metastasis has varied between studies and is summarized in Table 2. The most common sites of metastasis are lung and bone [3,11,12] but any organ may be affected. There have been three case reports of SRCC metastasizing to the heart and infiltrating the endocardium without evidence of tumor thrombus in the inferior vena cava [47–49]. The possible mechanism for these unusual metastasis include retrograde lymphatic spread, lymphohematogenous spread along the thoracic duct to the superior vena cava, hematogenous spread of tumor cell emboli, or via small pulmonary arteriovenous shunts. The presence of spindle cells was reported to be an independent poor prognostic indicator for RCC [1,50]. Several other prognostic factors have also been proposed for SRCC. Several studies have found that pathologic stage was the
* Denotes most common genetic alteration.
cluded that p53 did not have a specific role in sarcomatoid transformation [40]. The long arm of chromosome 13 is also a common site of aberration in advanced RCC, including SRCC [29,32]. Jiang et al. reported that loss of all or part of chromosome 13q was the most common genetic alteration detected in SRCC, occurring in 75% of the tumors examined [29] with a deletion in a susceptible region commonly located at 13q12–14 (89%) . Two genes located in this region are the retinoblastoma (Rb) and BRCA-2. However, subsequent studies have found that Rb gene mutations were uncommon in RCC (less than 2%) and normal expression of the Rb protein is detected in the majority of tumor cells [41,42]. It is, therefore, possible that other undetected genes in the 13q12–14 region are directly involved in the progression and transformation of RCC to its sarcomatoid variant. The hyperploidy of chromosome 7 can often be detected in SRCC and other types of advanced RCC [29,34]. Extra copies of chromosome 7 have been significantly correlated with Ki-67 over-expression in RCC cells [43]. The overexpression of Ki-67 is hypothesized to be associated with poor prognosis and increase potential for biologic aggressiveness and progression [44,45]. Table 1 summarizes the genetic aberrations detected in various types of RCC. In this regard, the overlap between SRCC and RCC is clearly demonstrated and is consistent with the current understanding that SRCC can be derived
Table 2 Common clinical features of sarcomatoid RCC based on larger-scale studies (n 10). Number of SRCC patients % of patients with SRCC Male (%) Female (%) Mean size of tumor (cm) Most common epithelial component Stage T1-2 (%) Stage T3 (%) Stage T4 (%) RV/IVC involvement (%) Regional nodal involvement (%) Distant metastasis (%) Nephrectomy done (%) Median survival (mos)
Farrow [9]
Tomera [2]
Ro [11]
Sella [3]
Culine [55]
Akhtar [4]
Cangiano [12]
37
13 1 11 (85) 2 (15) 10
42
44 4.8 24 (55) 22 (45)
14 1.1 11 (79) 3 (21)
11 5.8 5 (45) 6 (55)
31
21 (57) 16 (43) Clear
2 (15)
23 (62) 3 (8) 36 (97) 6.0
RV renal vein; IVC inferior vena cava.
1 (8) 5 (38) 12 (92) 6.3
24 (57) 18 (43) 10.2 Clear 6 (14) 34 (81) 2 (5) 15 (36) 14 (33) 10 (24) 6.8
Chromophobe 3 (30) 3 (30) 4 (40)
25 (57) 40 (91) 6.6
13 (93)
23 (74) 8 (26) 9 Clear 3 (10) 19 (61) 8 (26) 9 (29) 7 (23) 26 (84) 31 (100)
D. Chao et al. / Urologic Oncology 6 (2001) 231–238
single most important prognostic factor [3,11,12], with a median survival for Stage 1 disease of 50 months and just 4–5 months for Stage 3–4 disease [11]. Other factors associated with poor prognosis include lymph node involvement and distant metastasis [3,12]. When only one organ is involved with metastatic disease, lung is associated with the worst prognosis and involvement of three or more organs was also a poor prognostic indicator [3]. Other factors are apparently non-prognostic. These include the presence of renal vein or inferior vena cava involvement [11,12], pattern of sarcomatoid growth (e.g., malignant fibrous histiocyte-like vs. fibrosarcoma-like), type of sarcomatoid cell (spindle vs. giant cell), level of cellularity, the degree of fibrosis within the tumor, and the presence and density of lymphocytic infiltration [11,51]. Finally, nephrectomy and other types of surgical resections were not shown to impact patient outcomes [3,12,13]. Reports on the prognostic roles of grade, mitotic rate and degree of necrosis have been discrepant [11,15,51]. Female sex and age greater than 59 were poor prognostic indicators in the study by Sella et al. [3], while Cangiano et al. determined that age and sex do not influence prognosis [12]. The relative proportion of sarcomatous component to the carcinomatous component is one of the most disputed prognostic factors. One study found that the proportion of the sarcomatous component did impact patient prognosis but only for Stage 1–2 disease [11]. Another study concluded that pure sarcomatoid RCC behaved more aggressively than mixed clear and sarcomatoid RCC with the latter having a better prognosis similar to pure clear cell RCC [52]. Finally, Bertoni et al. determined that patients with tumors exhibiting less than 5% sarcomatoid regions had improved prognosis but no difference was found when the comparison was made between patients having more than or less than 50% sarcomatoid component [13]. Other studies did not demonstrate a prognostic role for the proportion of sarcomatoid component [12,15,51]. The prognosis of patients with SRCC is uniformly dismal with a median survival of only 4–7 months after diagnosis [2,3,9,11,12,29]. In contrast, the median survival for RCC patients is 19 months (Fig. 2) [3]. There are sporadic reports of Stage 1 SRCC patients with long-term survival [2,11]. One patient with a small (5 cm) capsule confined tumor had a survival time of 81 months [11] while two patients with Stage 2 disease, having tumors that contained 5% or less of the sarcomatous component, were still alive after 69 and 77 months [13]. A case report described a patient with recurrent disease at 1 and 7 years after initial nephrectomy, with all pathology specimens demonstrating SRCC, who was still alive 1 year after the last surgical resection [53]. In perhaps the most unusual case, a patient with capsule confined SRCC had spontaneous regression of his pulmonary metastasis after undergoing nephrectomy. He received no other form of treatment during the interval time and was alive and well without evidence of disease 1 year after the spontaneous regression [54]. Despite these rare
235
Fig. 2. Kaplan-Meier survival plot for 661 patients undergoing nephrectomy at UCLA for RCC between 1989–1999 comparing the survival of SRCC vs. non-SRCC histologic subtypes (median follow-up 44 months).
cases of prolonged survival and positive outcomes, the overall prognosis for SRCC remains poor. 9. Treatment Effective treatment for SRCC remains elusive with surgery being the mainstay. A compilation of studies (13 patients) shows that 151 of 158 patients underwent surgical resections [2–4,9,12,13]. Sella et al. found that surgery alone resulted in a slight improvement of survival for Stage 4 patients from 3 months to 6 months but no Stage 1–3 patients achieved complete cures [3]. The overall survival for patients treated only with surgery was 5–6.6 months [2,3, 9,12]. Because the vast majority of SRCC patients had their primaries removed, it is difficult to compare potential differences in survival with patients who still have their primaries in place. Based on the overall survival however, one can conclude that the difference between the two groups is small and neither group appears to fare well. In an effort to improve the survival of SRCC patients, a number of systemic therapies, including hormone therapy, chemotherapy, and immunotherapy, have been attempted with differing results. The various studies have included only those patients with Stage 4 disease. Sella et al. found that independent of nephrectomy, Stage 4 patients who received some form of systemic therapy had a higher median survival of 13 months compared to those who did not receive systemic therapy (3.8 months) [3]. Hormone therapy for SRCC patients with Stage 4 disease, including medroxypregesterone and androgen therapy, resulted in no measurable response and a median survival of 12–13 months [3]. Chemotherapy for SRCC can be sub-categorized into doxorubicin-based and non-doxorubicinbased therapy. Patients treated with non-doxorubicin-based chemotherapy, including CCNU (lomustine), streptozotocin, hydroxyurea, vincristine, BAF (boc-aspartyl [Ome]-flu-
236
D. Chao et al. / Urologic Oncology 6 (2001) 231–238
oromethylketone) and elliptinium, did not respond to therapy and survived for approximately 6–8 months [3,55]. Doxorubicin-based therapies including CYVADIC (cyclophosphamide, vincristine, doxorubicin, and dacarbazine), DECAV (dacarbazine, cyclophosphamide, cisplatin, doxorubicin, and vindesine), and DI (doxorubicin and isosfamide) have yielded poor response and survival rates in most patients. Median survival has been reported at 7–12 months [3,55]. Despite mediocre results seen in the majority of patients, a small population of patients appeared to respond. Culine et al. reported three patients having partial responses with average durations of 7.8 months. The patients had prolonged survival periods of 20, 29, and 60 months in comparison to the 11 non-responders who had an overall median survival of 9 months [55]. Sella et al. reported on a complete response in two of eight patients treated with doxorubicinbased therapy [3]. Both patients had Stage 1 disease at diagnosis and were still alive with no evidence of disease at 46 and 50 months. Lupera et al. also observed a complete remission in an SRCC patient treated with DECAV [56]. Overall, the majority of patients do not respond well to doxorubicin-based chemotherapy and non-responders have only limited improvements in survival. However, a small and still uncharacterized subset of patients do benefit significantly from this form of treatment. More studies are needed to elucidate the parameters leading to these positive outcomes. Numerous types of immunotherapy have been explored for the treatment of SRCC patients, but the outcomes have been heterogeneous. Interferon-alpha (INF-) as a single agent did not yield measurable clinical response in patients [3,52,55] but did result in prolongation of median survival to 35–41 months [3,55]. Of the nine patients treated with a combination regimen consisting of INF-, tumor infiltrating lymphocytes (TIL), and low-dose interleukin-2 (IL-2), one patient had a complete response and two had partial responses [12]. The overall median survival for these nine patients was 9 months. Low-dose IL-2 was also used as a single agent but no responses were noted [12,52] and median survival was just 3 months [12]. Single-agent high-dose IL-2 has demonstrated promising results for the treatment of SRCC. Cangiano et al. concluded that not receiving highdose IL-2 was one variable significantly correlated with an increased relative risk of death (RR 10.4) [12]. However, Wu et al. noted that patients with pure sarcomatoid tumors responded differently to high-dose IL-2 than those with mixed sarcomatoid and clear cell tumors having median survivals of 14 and 35 months, respectively [52]. Nevertheless, high-dose IL-2 appears to benefit the largest proportion of SRCC patients, especially in prolonging overall survival, and should be considered for all Stage 4 patients who have no contraindications and can tolerate acceptable degrees of the associated toxicities. The data on treatment modalities for SRCC has been limited by the relatively few cases studied. So far, only patients with Stage 4 disease have been treated with the various types of systemic therapies. With the poor prognosis associ-
ated with all stages of this disease and the lack of definite cure with surgery alone, the role of high-dose IL-2 may need to be expanded to include all SRCC patients. The role of nephrectomy prior to the administration of high-dose IL-2 remains unanswered. Reports on systemic therapies given to SRCC patients did not differentiate between the responses seen in patients who underwent nephrectomies from those who did not. This is probably due to the small number of patients who forego surgery. However, it will be important to make this distinction for the benefit of future patients. If aggressive resection does increase the efficacy of high-dose IL-2, a patient who undergoes a partial nephrectomy and is then diagnosed with SRCC may benefit from supplemental surgery. If surgery does not improve on the survival of patients receiving high-dose IL-2, an invasive procedure associated with some degree of morbidity and mortality can be avoided. This suggests that a role for prenephrectomy biopsy may exist for patients with large tumors to assist in treatment decision processes. Although the role of nephrectomy and high-dose IL-2 for the treatment of SRCC is still unclear, it has been shown that high-dose IL-2 following surgery resulted in improved efficacy and survival when compared to either modality alone for the treatment of RCC [57]. It is possible that similar findings could hold true for SRCC. 10. Conclusion Significant progress has been made in characterizing the sarcomatous transformation of renal cell carcinoma since it was first recognized as a distinct entity from true sarcomas. With a large array of diagnostic tools available, it is now accepted that SRCC is a transformed continuum of the various subtypes of RCC. However, the specific factors resulting in the aggressive biologic behavior of SRCC remain unclear. The current data seems to suggest that radical nephrectomy followed by high-dose IL-2 holds the greatest promise in prolonging survival. Similar to Wilms’ tumor, a large multicentric cooperative study may be able to provide answers to the unsolved questions regarding SRCC. References [1] Skinner DG, Colvin RB, Vermillion CD, Pfister RC, Leadbetter WF. Diagnosis and management of renal cell carcinoma: a clinical and pathologic study of 309 cases. Cancer 1971;28:1165–77. [2] Tomera KM, Farrow GM, Lieber MM. Sarcomatoid renal carcinoma. J Urol 1983;130:657–9. [3] Sella A, Logothetis CJ, Ro JY, Swanson DA, Samuels ML. Sarcomatoid renal cell carcinoma. A treatable entity. Cancer 1987;60:1313–8. [4] Akhtar M, Tulbah A, Kardar AH, Ashraf M. Sarcomatoid renal cell carcinoma: the chromophobe connection. Am J Surg Pathol 1997;21: 1188–95. [5] Saphir O, Vass A. Carcinosarcoma. Am J Cancer 1938;33:331. [6] Fauci PA, Therhag HG, Davis JE. Carcinosarcoma of the renal pelvis. J Urol 1961;85:897–902. [7] Weisel W, Dockerty MB, Priestley JT. Sarcoma of the kidney. J Urol 1943;50:654–573.
D. Chao et al. / Urologic Oncology 6 (2001) 231–238 [8] Hou LT, Willis RA. Renal carcino-sarcoma, true and false. J Pathol Bacteriol 1963;85:139–44. [9] Farrow GM, Harrison EGJ, Utz DC. Sarcomas and sarcomatoid and mixed malignant tumors of the kidney in adults. 3. Cancer 1968;22: 556–63. [10] Delahunt B. Sarcomatoid renal carcinoma: the final common dedifferentiation pathway of renal epithelial malignancies. Pathology 1999;31:185–90. [11] Ro JY, Ayala AG, Sella A, Samuels ML, Swanson DA. Sarcomatoid renal cell carcinoma: clinicopathologic. A study of 42 cases. Cancer 1987;59:516–26. [12] Cangiano T, Liao J, Naitoh J, Dorey F, Figlin R, Belldegrun A. Sarcomatoid renal cell carcinoma: biologic behavior, prognosis, and response to combined surgical resection and immunotherapy. JCO 1999;17:523–8. [13] Bertoni F, Ferri C, Benati A, Bacchini P, Corrado F. Sarcomatoid carcinoma of the kidney. J Urol 1987;137:25–8. [14] Young RH, Dunn J, Dickersin GR. An unusual oncocytic renal cell tumor with sarcomatoid foci and osteogenic differentiation. Arch Pathol Lab Med 1988;112:937–40. [15] Auger M, Katz RL, Sella A, Ordonez NG, Lawrence DD, Ro JY. Fine-needle aspiration cytology of sarcomatoid renal cell carcinoma: a morphologic and immunocytochemical study of 15 cases. Diag Cytopathol 1993;9:46–51. [16] Baer SC, Ro JY, Ordonez NG, et al. Sarcomatoid collecting duct carcinoma: a clinicopathologic and immunohistochemical study of 5 cases. Hum Pathol 1993;24:1017–22. [17] Kuroda N, Hayashi Y, Itoh H. A case of chromophobe renal cell carcinoma with sarcomatoid foci and a small daughter lesion. Patholo Int 1998;48:812–7. [18] Mai KT, Veinot JP, Collins JP. Sarcomatous transformation of chromophobe cell renal carcinoma. Histopathology 1999;34:557–9. [19] Tardio JC. Chromophobe cell renal carcinomas with sarcomatoid areas. Histopathology 2000;36:184–5. [20] Oda H, Machinami R. Sarcomatoid renal cell carcinoma: a study of its proliferative activity. Cancer 1993;71:2292–8. [21] DeLong W, Gringnon DJ, Eberwein P, Shum DT, Wyatt JK. Sarcomatoid renal cell carcinoma: an immunohistochemical study of 18 cases. Arch Pathol Lab Med 1993;117:636–40. [22] Macke RA, Hussain MB, Imray TJ, Wilson RB, Cohen SM. Osteogenic and sarcomatoid differentiation of a renal cell carcinoma. Cancer 1985;56:2452–7. [23] Kragel PJ, Travis WD, Luibel FJ. Sarcomatoid renal carcinoma with angiosarcomatoid component. Urology 1992;40:381–4. [24] Bonsib SM, Fischer J, Plattner S, Fallon B. Sarcomatoid renal tumors: clinicopathologic correlation of three cases. Cancer 1987;59:527–32. [25] Deitchman B, Sidhu GS. Ultrastructural study of a sarcomatoid variant of renal cell carcinoma. Cancer 1980;46:1152–7. [26] 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. [27] Markovic-Lipkovski J, Brasanac D, Todorovic V, Muller CA, Muller GA. Immunomorphological characteristics of renal cell carcinoma. Histol Histopathol 1995;10:651–9. [28] Shirkhoda A, Lewis E. Renal sarcoma and sarcomatoid renal cell carcinoma: CT and angiographic features. Radiology 1987;162:353–7. [29] Jiang F, Moch H, Richter J, et al. Comparative genomic hybridization reveals frequent chromosome 13q and 4q losses in renal carcinomas with sarcomatoid transformation. J Pathology 1998;185:382–8. [30] Elfving P, Mandahl N, Lundgren R, et al. Prognostic implications of cytogenetic findings in kidney cancer. Br J Urol 1997;80:698–706. [31] Zbar B, Bruch T, Talmadge C, Linehan M. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature 1987; 327:721–7. [32] Anglard PKT, Brauch H, Weiss GH, et al. Molecular analysis of genetic changes in the origin and development of renal cell carcinoma. Cancer Res 1991;51:1071–7.
237
[33] Morita R, Ishikawa J, Tsutsumi M, et al. Allelotype of renal cell carcinoma. Cancer Res 1991;51:820–3. [34] Presti JC, Rao PH, Chen Q, et al. Histopathological, cytogenetic, and molecular characterization of renal cortical tumors. Cancer Res 1991; 51:1544–52. [35] Moch H, Presti JC, Sauter G, et al. Genetic aberrations detected by comparative genomic hybridization are associated with clinical outcome in renal cell carcinoma. Cancer Res 1996;56:27–30. [36] Lovell M, Lott ST, Wong P, El-Naggar A, Tucker S, Killary AM. The genetic locus NRC-1 within chromosome 3p12 mediates tumor suppression in renal cell carcinoma independently of histological type, tumor microenvironment, and VHL mutation. Cancer Res 1999;59: 2182–9. [37] Crossey PA, Richards FM, Foster K, et al. Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet 1994;3: 1303–8. [38] Oda H, Nakatsuru Y, Ishikawa T. Mutations of the p53 gene and p53 protein overexpression are associated with sarcomatoid transformation in renal cell carcinomas. Cancer Res 1995;55:658–62. [39] Wada Y, Yokogi H, Moriyama-Gonda N, Shigeno K, Shiina H, Igawa M. Chromosome aberrations in renal tumors detected by fluorescence in situ hybridization. Cancer Genet Cytogenet 1997;99:38–44. [40] Kanamaru H, Li B, Miwa Y, Akino H, Okada K. Immunohistochemical expression of p53 and bcl-2 proteins is not associated with sarcomatoid change in renal cell carcinoma. Urol Res 1999;27:169–73. [41] Walther MM, Guarra JR, Elwood L, et al. Loss of heterozygosity occurs centromeric to RB without associated abnormalities in the retinoblastoma gene in tumors from patients with metastatic renal cell carcinoma. J Urol 1995;153:2050–4. [42] Presti JC, Reuter VE, Cordon-Cardo C, et al. Expression of the retinoblastoma gene product in renal tumors. Anticancer Res 1996;16: 549–56. [43] Wada Y, Igawa M, Shiina H, et al. Comparison of chromosomal aberrations detected by fluorescence in situ hybridization with clinical parameters, DNA ploidy and Ki67 expression in renal cell carcinoma. Br J Cancer 1998;77:2003–7. [44] Aaltomaa S, Lipponen P, Ala-Opas M, Eskelinen M, Syrjanen K. Prognostic value of Ki-67 expression in renal cell carcinoma. Eur Urol 1997;31:350–5. [45] Rioux-Leclercq N, Turlin B, Bansard J, et al. Value of immunohistochemical Ki-67 and p53 determinations as predictive factors of outcome in renal cell carcinoma. Urology 2000;55:501–5. [46] Tsui K, Shvarts O, Smith RB, Figlin RA, deKernion JB, Belldegrun A. Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria. J Urol 2000;163:1090–5. [47] Bird DJ, Semple JP, Seiler MW. Sarcomatoid renal cell carcinoma metastatic to the heart: report of a case. Ultrastruct Pathol 1991;15:361–6. [48] Riccioni L, Damiani S, Pasquinelli G, Scarani P. Solitary left ventricle metastasis by renal cell carcinoma with sarcomatoid features. Tumori 1996;82:266–9. [49] Santo-Tomas M, Mahr NC, Robinson MJ, Agatston AS. Metastatic renal cell carcinoma invading right ventricular myocardium without caval involvement. J Cardiovasc Surg 1998;39:811–2. [50] Mani S, Todd MB, Katz K, Poo W. Prognostic factors for survival in patients with metastatic renal cancer treated with biological response modifiers. J Urol 1995;154:35–40. [51] Delahunt B, Nacey JN. Renal cell carcinoma II. Histological indicators of prognosis. Pathology 1987;19:258–63. [52] Wu J, Caliendo G, Hu X, Dutcher JP. Impact of histology on the treatment outcome of metastatic or recurrent renal cell carcinoma. Medical Oncol 1998;15:44–9. [53] Goessl C, Muller M, Heicappell R, Perez-Canto A, Miller K. Longterm survival after surgery for recurrent advanced sarcomatoid renal carcinoma. BJU Int 1999;84:888–9. [54] Garcia-Del-Muro X, Cardenal F, Romagosa V, Gil M. Sarcomatoid
238
D. Chao et al. / Urologic Oncology 6 (2001) 231–238
renal cell carcinoma: a case of spontaneous regression of metastasis. Eur Urol 1993;24:300–1. [55] Culine S, Bekradda M, Terrier-Lacombe MJ, Droz JP. Treatment of sarcomatoid renal cell carcinoma: is there a role for chemotherapy? Eur Urol 1995;27:138–41. [56] Lupera H, Theodore C, Ghosn M, Court BH, Wibault P, Droz JP. Phase II trial of combination chemotherapy with decarbazine, cyclophosphamide, cisplatin, doxorubicin, and vindesine (DECAV) in advanced renal cell cancer. Urology 1989;34:281–3.
[57] Belldegrun A, Shvarts O, Figlin RA. Expanding the indications for surgery and adjuvant IL-2-based immunotherapy in patients with renal cell carcinoma. Cancer J Sci Am 2000;6(Suppl 1):S88–92. [58] Mirghomizadeh F, Kupka S, Blin N. Assessing genetic heterogeneity of renal cell tumors. Anticancer Res 1999;19:1467–70. [59] Steiner G, Sidransky D. Molecular differential diagnosis of renal carcinoma from microscopes to micro satellites. Am J Pathol 1996;149: 1791–5.