Clear Cell Sarcoma of the Kidney

Am J Surg Pathol. 2007 Oct;31(10):1459-1468. Abstract quote

We report 20 cases of a distinct, previously unrecognized renal neoplasm, anaplastic sarcoma of the kidney with polyphenotypic features. The tumors were identified by rereviewing tumors with unusual anaplastic features from the National Wilms Tumor Study Pathology Center, the International Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group trials.

Patients ranged in age from 10 months to 41 years (median age 5 y, mean age 12 y) and females predominated (1.5:1). Twelve tumors presented in the right kidney, and 5 in the left (laterality was unknown in 3 cases). The most common presentation was a renal mass. Grossly, most tumors were large, measured 4 to 21 cm (mean 12.7 cm) and weighed 115 to 1820 g (mean 835 g). Seven out of 12 tumors suitable for assessment had a distinct cystic component. The tumors involved the pelvi-calyceal system in 5 of the cases.

Histologically, all tumors showed a spindle cell component which contained either multiple foci or diffuse, widespread anaplastic changes with bizarre pleomorphic cells and very atypical mitotic figures. Chondroid differentiation was seen in 16 cases, usually in the form of islands of hyaline cartilage (13 cases) or chondroid matrix (3 cases). The nodules of cartilage showed both benign and malignant features, often within the same tumor. In 2 cases small foci of osteoid were found whereas osteoclastlike giant cells were seen in 4 cases. Only 3 of the tumors exhibited a primitive blastemalike area. No neoplastic epithelial structures were identified. No nephrogenic rests were found. Limited immunohistochemical studies showed vimentin positivity in 5/5 cases, desmin was positive in 4/6 cases, MYF4 showed focal weak nuclear positivity in 1/4 cases, but MyoD1 was negative in all cases (0/5). PGP9.5 was focally, strongly positive in 4/5 cases and p53 was strongly positive in 3/6 cases. Cytokeratin, using the antibody CAM5.2, was uniformly negative within the tumor cells. Finally, CD56 was focally positive in 1/6 tumors, whereas all other markers were negative including NB84a (4/4), CD34 (5/6), CD99 (5/5), and WT1 (6/6 cases).

In 4 tumors reverse transcriptase-polymerase chain reaction was performed to detect the SYT-SSX fusion transcript produced by the t(x;18), and the ETV6-NTRK3 fusion transcript using RNA extracted from archived paraffin blocks-results were negative in all 4 specimens. Tumor stage was known in 15 patients including 7 stage I, 4 stage II, 3 stage III, and 1 stage IV tumors. They were usually diagnosed as anaplastic Wilms tumors and treated accordingly.

Of the 13 patients with a minimum of 2 years follow-up, 4 patients developed distant metastases and 1 had local recurrence including 1 patient with stage IV, 2 with stage III, and 2 with stage I at presentation. Three of them died and 2 were lost to follow-up. One patient with stage I tumor developed widespread metastases and died. Another stage I patient developed local recurrence after 3 months of diagnosis, but was lost to follow-up. Five stage I patients were alive and free of tumor at last follow-up. The most common sites of metastases were lung (3 cases), and liver and bones (2 cases each).

These tumors showed pathologic features similar to the pleuropulmonary blastoma of childhood and undifferentiated (embryonal) sarcoma of the liver. In the differential diagnosis, anaplastic Wilms tumor, primary renal synovial sarcoma, malignant mesenchymoma, ectomesenchymoma, and mesenchymal chondrosarcomas have been considered but none of these tumors shared the same features as the 20 cases described here which represent a distinct clinicopathologic entity with morphologic features of a polyphenotypic anaplastic sarcoma of the kidney. Further molecular studies are needed to better understand its nature and more accurate classification.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	CCSK

HISTOLOGICAL TYPES	CHARACTERIZATION
General	Am J Surg Pathol 2000;24:4 91% of the tumors had the classic pattern as either a predominant or a secondary morphology, a majority also demonstrated one or more variant patterns These patterns usually blended smoothly with the classic pattern or another variant pattern 1. Myxoid pattern (50%) 2. Sclerosing pattern (35%) 3. Cellular pattern (26%) 4. Epithelioid pattern (trabecular or acinar type) (13%) 5. Palisading (verocay-body) pattern (11%) 6. Spindle cell pattern (7%) 7. Storiform pattern (4%) 8. Anaplastic pattern (2.6%)
Clear Cell Sarcoma of the Kidney A Review of 351 Cases From the National Wilms Tumor Study Group Pathology Center Pedram Argani, M.D.; Elizabeth J. Perlman, M.D.; Norman E. Breslow, Ph.D.; Nancy G. Browning, M.S.; Daniel M. Green, M.D.; Giulio J. D'Angio, M.D.; J. Bruce Beckwith, M.D. From the Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland (P.A., E.J.P.); the Department of Biostatistics, University of Washington, Seattle, Washington (N.E.B.); the Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, California (N.G.B., J.B.B.); the Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, New York (D.M.G.); and the Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. (G.J.D.).	Am J Surg Pathol 2000;24:4 Abstract quote We reviewed 351 cases of clear cell sarcoma of the kidney (CCSK), including 182 cases entered on National Wilms Tumor Study Group (NWTSG) trials 1�4 for which clinical follow-up information was available. Tumors were restaged using NWTS 5 criteria. Mean age at diagnosis in the NWTS group was 36 months with a range of 2 months to 14 years. The male to female ratio was 2:1. Typical gross features included large size (mean diameter 11.3 cm), a mucoid texture, foci of necrosis, and prominent cyst formation. Nine major histologic patterns were identified (classic, myxoid, sclerosing, cellular, epithelioid, palisading, spindle, storiform, and anaplastic); virtually all tumors contained multiple patterns that blended with one another. Immunohistochemical stains were performed on 45 cases; only vimentin was consistently immunoreactive. Consistently negative results with other antibodies helped exclude other tumors in the differential diagnosis; all CCSKs were cytokeratin-negative, including epithelioid tumors that mimicked Wilms tumor, and MIC2-negative, including cellular tumors that mimicked primitive neuroectodermal tumor. The p53 gene product was rarely overexpressed in non-anaplastic CCSKs, but strikingly overexpressed in two of three anaplastic CCSKs. Overall survival was 69%. Multivariate analysis revealed four independent prognostic factors for survival: treatment with doxorubicin, stage, age at diagnosis, and tumor necrosis. Of note, stage 1 patients had a remarkable 98% survival rate. No other histologic or clinical variable independently correlated with survival.
VARIANTS
Clear cell sarcoma of the kidney: report of a case with mandibular metastasis simulating a benign myxomatous tumor	Oral Surg Oral Med Oral Pathol 1988;65:567�74.
Anaplastic subset	Am J Surg Pathol 2000;24:4 Defined by nuclear hyperchromasia, nuclear gigantism, and atypical mitoses Anaplasia appears to arise de novo Dramatic p53 overexpression in the anaplastic foci of two tumors in which the non-anaplastic regions did not overexpress p53

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
ANAPLASTIC SARCOMA OF THE KIDNEY
Anaplastic Sarcoma of the Kidney: A Clinicopathologic Study of 20 Cases of a New Entity With Polyphenotypic Features. Vujanić GM, Kelsey A, Perlman EJ, Sandstedt B, Beckwith JB. *Department of Histopathology, School of Medicine, Cardiff University, Cardiff †Department of Pediatric Pathology, Royal Manchester Childrenʼs Hospital, Manchester, UK ‡Department of Pathology, Childrenʼs Memorial Hospital, Chicago, IL §Childhood Cancer Research Unit, Karolinska Institute, Astrid Lindgrenʼs Childrenʼs Hospital, Stockholm, Sweden ∥Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA.	Am J Surg Pathol. 2007 Oct;31(10):1459-1468. Abstract quote We report 20 cases of a distinct, previously unrecognized renal neoplasm, anaplastic sarcoma of the kidney with polyphenotypic features. The tumors were identified by rereviewing tumors with unusual anaplastic features from the National Wilms Tumor Study Pathology Center, the International Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group trials. Patients ranged in age from 10 months to 41 years (median age 5 y, mean age 12 y) and females predominated (1.5:1). Twelve tumors presented in the right kidney, and 5 in the left (laterality was unknown in 3 cases). The most common presentation was a renal mass. Grossly, most tumors were large, measured 4 to 21 cm (mean 12.7 cm) and weighed 115 to 1820 g (mean 835 g). Seven out of 12 tumors suitable for assessment had a distinct cystic component. The tumors involved the pelvi-calyceal system in 5 of the cases. Histologically, all tumors showed a spindle cell component which contained either multiple foci or diffuse, widespread anaplastic changes with bizarre pleomorphic cells and very atypical mitotic figures. Chondroid differentiation was seen in 16 cases, usually in the form of islands of hyaline cartilage (13 cases) or chondroid matrix (3 cases). The nodules of cartilage showed both benign and malignant features, often within the same tumor. In 2 cases small foci of osteoid were found whereas osteoclastlike giant cells were seen in 4 cases. Only 3 of the tumors exhibited a primitive blastemalike area. No neoplastic epithelial structures were identified. No nephrogenic rests were found. Limited immunohistochemical studies showed vimentin positivity in 5/5 cases, desmin was positive in 4/6 cases, MYF4 showed focal weak nuclear positivity in 1/4 cases, but MyoD1 was negative in all cases (0/5). PGP9.5 was focally, strongly positive in 4/5 cases and p53 was strongly positive in 3/6 cases. Cytokeratin, using the antibody CAM5.2, was uniformly negative within the tumor cells. Finally, CD56 was focally positive in 1/6 tumors, whereas all other markers were negative including NB84a (4/4), CD34 (5/6), CD99 (5/5), and WT1 (6/6 cases). In 4 tumors reverse transcriptase-polymerase chain reaction was performed to detect the SYT-SSX fusion transcript produced by the t(x;18), and the ETV6-NTRK3 fusion transcript using RNA extracted from archived paraffin blocks-results were negative in all 4 specimens. Tumor stage was known in 15 patients including 7 stage I, 4 stage II, 3 stage III, and 1 stage IV tumors. They were usually diagnosed as anaplastic Wilms tumors and treated accordingly. Of the 13 patients with a minimum of 2 years follow-up, 4 patients developed distant metastases and 1 had local recurrence including 1 patient with stage IV, 2 with stage III, and 2 with stage I at presentation. Three of them died and 2 were lost to follow-up. One patient with stage I tumor developed widespread metastases and died. Another stage I patient developed local recurrence after 3 months of diagnosis, but was lost to follow-up. Five stage I patients were alive and free of tumor at last follow-up. The most common sites of metastases were lung (3 cases), and liver and bones (2 cases each). These tumors showed pathologic features similar to the pleuropulmonary blastoma of childhood and undifferentiated (embryonal) sarcoma of the liver. In the differential diagnosis, anaplastic Wilms tumor, primary renal synovial sarcoma, malignant mesenchymoma, ectomesenchymoma, and mesenchymal chondrosarcomas have been considered but none of these tumors shared the same features as the 20 cases described here which represent a distinct clinicopathologic entity with morphologic features of a polyphenotypic anaplastic sarcoma of the kidney. Further molecular studies are needed to better understand its nature and more accurate classification.
Blastemal Wilms tumor and PNET	More aggressively invasive than CCSK, entrapping whole islands of native renal parenchyma as opposed to the single tubules entrapped by CCSK Coarser chromatin than CCSK Consistent MIC2 negativity in CCSK
	Distinction of epithelioid CCSK patterns, particularly acinar types, from the true tubular differentiation of a Wilms tumor No CCSK expressed cytokeratin regardless of how epithelioid the appearance
Plump cell variant of cellular congenital mesoblastic nephroma, metanephric stromal tumor	Predominantly spindled CCSKs can be difficult to distinguish Characteristic fine chromatin of CCSK All CCSKs in our study stained negatively for desmin and S100 protein, A significant percentage of congenital mesoblastic nephromas stain with desmin
Metanephric Stromal Tumor Report of 31 Cases of a Distinctive Pediatric Renal Neoplasm Pedram Argani, M.D.; J. Bruce Beckwith, M.D. From the Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland, U.S.A. (P.A.); the Department of Pathology, Loma Linda University School of Medicine, Loma Linda, California, U.S.A. (J.B.B.); and the National Wilms Tumor Study Group Pathology Center.	Am J Surg Pathol 2000;24:917-926 Abstract quote We report 31 cases of a novel pediatric renal neoplasm, metanephric stromal tumor (MST). Mean patient age was 2 years, and the most common presentation was that of an abdominal mass. Gross examination typically revealed a fibrous lesion centered in the renal medulla containing smooth-walled cysts (mean tumor size, 5.5 cm). MST is histologically identical to the stromal component of metanephric adenofibroma (MAF, previously termed nephrogenic adenofibroma) and is an unencapsulated spindle cell lesion that entraps native kidney. Characteristic histologic features of MST include alternating cellularity that imparts a nodular low-power appearance, onion-skin cuffing around entrapped renal tubules, heterologous differentiation (glia or cartilage), and vascular alterations (angiodysplasia of entrapped arterioles, juxtaglomerular cell hyperplasia in entrapped glomeruli). Three tumors in which the vascular alterations were particularly florid were associated with extrarenal vasculopathy and attendant morbidity. A majority of cases stained for CD34, although the degree of staining was variable. Most patients were treated with surgical excision alone, and none experienced recurrence or metastasis. Recognition of this entity can spare a child potentially toxic adjuvant chemotherapy that might be used for lesions in its differential diagnosis, specifically clear cell sarcoma of the kidney.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
Prognostic Factors	Am J Surg Pathol 2000;24:4 Only histologic variable that independently correlated with survival was the presence of necrosis, typically a feature of aggressive high-grade sarcomas
Survival	Am J Surg Pathol 2000;24:4 High survival rate (98%) for patients with revised stage 1 disease Updated NWTS 5 criteria, invasion of renal sinus vasculature, not gross protrusion beyond the hilar plane, is a basis of upstaging from stage 1 to stage 2 The long-held concept that stage 1 CCSKs disseminate early seems at variance with their slow growth rate, as reflected by the relatively low MIB-1 staining indices we obtained, the documented long intervals to recurrence, and the low percentage of patients who initially presented with stage 4 disease Four revised stage 1 patients in this study who did not receive the benefit of doxorubicin therapy all survived, suggesting that these tumors were not disseminated and may have been cured by surgical excision
Metastasis	Am J Surg Pathol 2000;24:4 Bone is a favored site Approximately 20% of documented CCSK metastases occurred 3 years or more after diagnosis and some as long as 10 years later High (29%) frequency of lymph node metastases identified at presentation
Treatment
Treatment of children with clear-cell sarcoma of the kidney: a report from the National Wilms' Tumor Study Group	J Clin Oncol 1994;12:2132�7. Addition of doxorubicin (Adriamycin) to vincristine and dactinomycin improved the 6-year relapse-free survival for patients with CCSK All patients with CCSK on NWTS trial 5 are now treated with doxorubicin regardless of stage