Clear Cell Sarcoma of the Kidney 

Clear cell sarcoma of the kidney (CCSK) represents one of the most common tumors with "unfavorable histology" listed in the National Wilms Tumor Study Group (NWTSG) clinical protocols.[1] In 1970, Kidd initially recognized clear cell sarcoma of the kidney as a distinct clinicopathologic entity, noting its propensity to metastasize to bone. The distinctive histopathologic features of clear cell sarcoma of the kidney were reported simultaneously in 1978 by Morgan and Kidd,[2] Marsden et al,[3] and Beckwith and Palmer.[1] These reports confirmed the propensity of the tumor to metastasize to bone, poor clinical outcome, and the sarcomatous nonepithelial nature of the tumor.

Unlike Wilms tumor, clear cell sarcoma of the kidney has not been associated with intralobar nephrogenic rests. In a series of 351 cases from the NWTSG that was reviewed by Argani et al, only one case of clear cell sarcoma of the kidney was associated with a perilobar nephrogenic rest.[4] Gene expression profiles of clear cell sarcomas of the kidney suggest the cell of origin to be a renal mesenchymal cell with neural markers. Only one case has been associated with renal dysplasia, and no familial cases or syndromes have been identified in association with clear cell sarcoma of the kidney. Using the fifth National Wilms Tumor Study (NWTS-5) criteria for tumor staging, 25% of patients had localized stage I tumors, most patients presented with stage II (37%) or stage III (34%) disease, and only 4% of patients presented with distant metastases (see Wilms Tumor for staging information).[5]

Patients presenting with bilateral CCSK at diagnosis are rare but have been reported.[6, 7]

The most common site of metastasis at the time of presentation in patients with clear cell sarcoma of the kidney is the ipsilateral renal hilar lymph nodes. Skip metastases to periaortic lymph nodes have been reported in patients with clear cell sarcoma of the kidney in the presence of hilar lymph nodes that were histologically confirmed with negative results.

Approximately 5% of patients present with distant metastases. Bone is the most common distant site of metastases (15%), followed closely by lung, abdomen, retroperitoneum, brain, and liver. Unusual soft tissue sites (scalp, epidural, nasopharynx, neck, paraspinal, ovary, abdominal wall, axilla) and other sites (orbit) have been reported.  Approximately 20% of documented clear cell sarcoma of the kidney metastases occurred at least 3 years after diagnosis; some occurred as long as 10 years later.[8, 9]    

The histogenesis of clear cell sarcoma of the kidney is unclear and appears to be unrelated to Wilms tumor.

Genomics of clear cell sarcoma of the kidney

Several biological features of clear cell sarcoma of the kidney have been described. They include the following:

• Internal tandem duplications in exon 15 of the  BCOR gene (BCL6 corepressor) were reported in 100% (20 of 20 cases) of clear cell sarcoma of the kidney cases but in none of the other pediatric renal tumors evaluated. ^[10]  Other reports have confirmed the finding of  BCOR internal tandem duplications in clear cell sarcoma of the kidney. ^{[11, 12, 13]}  Hence,  BCOR internal tandem duplications appear to play a key role in the tumorigenesis of clear cell sarcoma of the kidney, and their identification should aid in the differential diagnosis of renal tumors. ^[10]
• The  YWHAE-NUTM2 fusion (involving either  NUTM2B or  NUTM2E) resulting from t(10;17) was reported in 12% of cases of clear cell sarcoma of the kidney. ^[14] The presence of the  YWHAE-NUTM2 fusion appears to be mutually exclusive with the presence of  BCOR internal tandem duplications; this observation is based on a study of 22 cases of clear cell sarcoma of the kidney that included two cases with the  YWHAE-NUTM2 fusion and 20 cases with  BCOR internal tandem duplications. ^[11]  The gene expression profiles for cases with the  YWHAE-NUTM2 fusion were distinctive from those with  BCOR internal tandem duplications.
• The t(10;17)q22;p13) results in an in-frame fusion of the genes YWHA (encoding14-3-3ɛ) and  NUTM2 as fusion partners in the resultant in-frame transcript. ^[14]   This fusion protein confers migratory advantage on cells through the up-regulation of EGFR, IGF1R or PDGFα.  By blocking these pathways using neutralizing antibodies, the migratory advantage conferred by the transcript was abrogated.  This holds potential for novel therapeutic approaches in CCSK. ^[15]
• Evaluation of 13 clear cell sarcoma of the kidney tumors for changes in chromosome copy number, mutations, and rearrangements found a single case with the  YWHAE-NUTM2 fusion and 12 cases with  BCOR internal tandem duplications. ^{[13, 16]}   No other recurrent segmental chromosomal copy number changes or somatic variants (single nucleotide or small insertion/deletion) were identified, providing further support for the role of  BCOR internal tandem duplication as the primary oncogenic driver for clear cell sarcoma of the kidney. ^[16]

United States statistics

Clear cell sarcoma of the kidney represents less than 3% of pediatric renal tumors. Approximately 20 new cases are diagnosed each year in the United States. Clear cell sarcoma of the kidney is extremely rare in infants younger than 6 months and in young adults. Most patients are aged 1-4 years. A male predominance is observed. Fifty percent of cases are diagnosed in children aged 2-3 years. Around 5% of patients have metastatic disease at presentation.

International statistics

Hadley et al concluded that in a developing country, such as South Africa, the disease is rare, clinically and radiologically indistinguishable from Wilms tumor, and commonly accompanied by hypertension. Treatment results are poor and difficult to sustain.[17]

Race-, sex-, and age-related demographics

Whites and Blacks are affected in equal numbers.

A male predominance has been noted, with a male-to-female ratio of 2.04:1.

Age of presentation ranges from 2 months to 14 years, with a mean age of 36 months. The highest incidence of clear cell sarcoma of the kidney is in children aged 2-3 years, in which 50% of the cases are diagnosed. A sharp decline in incidence occurs in children older than 3 years. Clear cell sarcoma of the kidney is extremely rare in infants younger than 6 months and in young adults, although it has been reported. The oldest reported patient was aged 57 years.[18]  Zhang et al reported the case of a 62-year-old man with clear cell sarcoma of the kidney, who presented with generalized pruritus.[19]

Patients who have stage I tumors, are aged 2-4 years, and have no tumor necrosis tend to have a better prognosis.[20]

Patients who present with distant metastases or multifocal disease have a poor prognosis, with a 50% long-term 6-year survival rate.

An Austrian study found that the most common site of relapse associated with poor survival was the brain.[21]

Treatment with doxorubicin has resulted in a 66% reduction in the tumor-related mortality rate.

Morbidity/mortality

In the fourth National Wilms Tumor Study (NWTS-4), patients were randomized between 6 months of chemotherapy and 15 months of chemotherapy.[22]  Patients randomized to 15 months of therapy had a better outcome compared with patients who received the shorter course of chemotherapy. The 8-year relapse-free survival and overall survival were 87.8% and 87.5%, respectively, for patients receiving 15 months of chemotherapy.

Complications

Cardiomyopathy results primarily from anthracycline (doxorubicin) use. Patients should obtain routine follow-up echocardiograms after the completion of therapy.

Patients are at risk for renal failure because they have a single kidney.

Radiation effects have decreased but, in the past, have consisted of asymmetry of the muscle mass in the back.

Secondary malignant neoplasms may arise as a result of chemotherapy (particularly alkylating agents in combination with radiotherapy).

Infertility may occur as a result of the alkylating agents.

A risk of intestinal obstruction is noted.

Parents and patients must undergo formal chemotherapy instruction to learn about the adverse effects of medication. They must be encouraged to call with any questions and to become educated regarding the expectations of chemotherapy.

Parents must be taught regarding flushing schedules and how to maintain and care for the central venous catheter if it exits the skin and the procedure to follow if the patient develops a fever.

Patients who have undergone abdominal surgery are at risk for developing intestinal obstructions or scar tissue related to the surgery. Families must be educated to call when abdominal pain or vomiting develop that are not related to an infectious cause. All members of the pediatric oncology team also must have a heightened awareness of the risk of obstruction in these patients so that an abdominal radiograph is obtained if any suggestion of obstruction exists.

For excellent patient education resources, visit eMedicineHealth's Cancer Center. Also, see eMedicineHealth's patient education article Renal Cell Cancer.

Manifestations in patients with clear cell sarcoma of the kidney (CCSK) are similar to those in patients with Wilms tumor. Patients present with an abdominal mass (see the image below), which is usually identified by a caregiver or family relative who has not seen the child in some time.

Large right-sided heterogeneous renal mass in a 9-month-old infant. Biopsy findings were consistent with clear cell sarcoma of the kidney.

Often, abdominal swelling or the presence of an abdominal mass is noticed by a parent while bathing or dressing the child. Abdominal pain, gross hematuria, fever, and hypertension are other frequent findings.

Physical findings include a large palpable unilateral abdominal mass. Patients may have accompanying findings, such as hypertension and/or hematuria (gross or microscopic), depending on the size of the tumor. Extrarenal tumors with histologic features identical to those of clear cell sarcoma of the kidney have been reported.

No specific laboratory study confirms the diagnosis of clear cell sarcoma of the kidney (CCSK); therefore, most testing pertains to the workup of an abdominal mass. The following investigations should be included in the workup:

• Complete blood cell (CBC) count: CBC counts should be performed to evaluate for evidence of anemia.

• Creatinine levels: Serum creatinine levels are tested to assess the patient's renal function.

• Standard preoperative laboratory studies: Prothrombin time and activated partial thromboplastin time should be checked in preparation for surgery, and urinalysis should be performed.

There are no radiological features of CCSK that can reliably distinguish CCSK from other pediatric renal tumors.[23]  CT scans of the chest (before surgery) and abdomen should be performed initially to define the extent of the tumor. Examples are shown below.

Large right-sided heterogeneous renal mass in a 9-month-old infant. Biopsy findings were consistent with clear cell sarcoma of the kidney.

Recurrent clear cell sarcoma of the kidney occurring in a lymph node 18 months after therapy.

Abdominal ultrasound should be performed to evaluate the status of the inferior vena cava and any gross extension into the renal vein. Tumor thrombus in the renal vein is present in approximately 5% of patients with clear cell sarcoma of the kidney.

Bone scan and brain CT scan or MRI are also part of the workup.

Whole-body FDG-PET, whole-body MRI, or 99mTc bone scan are recommended since bone is one of the common metastatic sites at diagnosis. Brain MRI should also be part of the initial workup.

Clear cell sarcoma of the kidney usually presents as a large unicentric mass markedly distorting or almost completely replacing the kidney. The mean diameter of measured tumors in the NWTSG series was 11.3 cm, with a range of 2.3-24 cm. The mean weight of the kidney tumor was 661 g. When an epicenter could be determined, the renal medulla was the most common location. No case of multicentric origin was identified in the NWTSG series. Sections of tumors appear grossly as tan-gray, soft, and mucoid. Cystic foci are almost universally present and occasionally represent the dominant feature, so that the diagnosis of multilocular renal cyst is made. Discrete foci of necrosis and hemorrhage may be present.

Histologically, clear cell sarcoma of the kidney shows 3 components, namely, (1) cord cells, which are small round-to-oval cells with deceptively bland cytologic features, including mitotic figures; (2) septal cells, which are spindle-shaped cells along the fibrovascular septa (fibrovascular septa can be demonstrated more convincingly using reticulum stain); and (3) an intercellular matrix composed of mucopolysaccharide, which ranges from minute indiscernible droplets to large pools imparting the clear appearance of clear cell sarcoma of the kidney.

Depending on the amount, distribution, and variation in morphology of the 3 components, the tumor shows a classic clear cell sarcoma of the kidney pattern or the variant histologic patterns. Variant histologic patterns may also be observed in the metastases. The classic pattern usually represents the predominant pattern in most clear cell sarcoma of the kidney tumors; the patterns blend smoothly with one or more of the following variant patterns:

• Myxoid pattern (50%)

• Sclerosing pattern (35%)

• Cellular pattern (26%)

• Epithelioid pattern (trabecular or acinar type) (13%)

• Palisading (Verocay body) pattern (11%)

• Spindle cell pattern (7%)

• Storiform pattern (4%)

• Anaplastic pattern (2.6%)

The anaplastic pattern is defined by nuclear hyperchromasia, nuclear gigantism, and atypical mitoses. Overexpression of p53 (>75% of the nuclei) has been demonstrated in 2 of 3 anaplastic clear cell sarcoma of the kidney lesions. The classic histologic pattern of clear cell sarcoma of the kidney is characterized by cord cells arranged in cords, nests, or groups surrounded by thin fibrovascular septa. A moderate amount of clear intercellular matrix separates the cord cells, giving a clear appearance, hence the designation clear cell sarcoma of the kidney. The term clear cells is doubly a misnomer because the clear cell appearance is caused by loose spacing of the round or oval cord cells with intervening intercellular clear mucoid matrix and because the clear appearance may be absent in many cases.[24]

The diagnosis of clear cell sarcoma of the kidney should be considered, even if no real or apparent clear appearance is noted in the tumor cells in an unusual renal tumor. The classic pattern described is observed at least focally in most patients. However, in a minority of cases, such as in resected tumors or in small biopsy specimens, the classic pattern is absent and only the variant pattern is seen. Therefore, the practicing pathologist must be familiar with the variant pattern.

Diffuse strong nuclear labeling for BCOR is now the single best IHC marker for CCSK.  Historically, IHC has had little role in supporting the diagnosis of CCSK except to exclude various entities in the differential diagnosis. CCSK is uniformly negative for vascular markers (CD34), neural markers (S100), protein muscle markers (desmin) and epithelial markers (cytokeratins and epithelial membrane antigens).[25]  

Electron microscopy reveals features of primitive mesenchymal cells with abundant pale extracellular matrix, containing scant collagen fibers, and occasional septa, containing myofibroblasts or pericytes. The main contribution of immunohistochemistry and electron microscopy is to exclude other diagnostic possibilities.

Staging for renal tumors is as follows:

• Stage I: The tumor is limited to the kidney and is completely resected. The renal capsule is intact, and no evidence of rupture is observed. The vessels of the renal sinus are not involved, and no evidence of tumor at or beyond the margins of resection exists.

• Stage II: The tumor extends beyond the kidney but is completely resected. Regional extension of tumor has occurred. Blood vessels outside the renal parenchyma (including those of the renal sinus) may contain tumor. Biopsy is performed on tumors (except by fine needle aspiration), or spillage of the tumor occurs before or during surgery; spillage is confined to the flank and does not involve the peritoneal surface. No evidence of tumor at or beyond the margins of resection is noted.

• Stage III: Residual tumor is nonhematogenous and is confined to the abdomen. Stage III criteria are (1) the presence of lymph nodes within the abdomen (renal hilar, para-aortic, or beyond) that demonstrate positive results for tumor, (2) the tumor penetrates the peritoneal surface, (3) the tumor implants on the peritoneal surface, (4) gross or microscopic evidence of the tumor is present after resection, (5) resection is incomplete because of involvement of vital structures, or (6) tumor spillage is not confined to the flank.

• Stage IV: Hematogenous metastases (eg, lung, liver, bone, brain) or lymph node metastases extend outside of the abdominopelvic region.

• Stage V: Bilateral renal involvement is discovered at diagnosis. Each side is staged individually using the above criteria.

The approach for treating clear cell sarcoma of the kidney (CCSK) is different from the approach for Wilms tumor because the overall survival of children with clear cell sarcoma of the kidney remains considerably lower than that of patients with favorable-histology Wilms tumor. In the third National Wilms Tumor Study (NWTS-3), the addition of doxorubicin to the combination of vincristine, dactinomycin, and radiation therapy resulted in an improvement in disease-free survival in patients with clear cell sarcoma of the kidney.[26]

NWTS-4 showed that patients treated with vincristine, doxorubicin, and dactinomycin for 15 months had an improved relapse-free survival rate compared with patients treated for 6 months (87.5% vs 60.6% at 8 y).[22] The overall survival has improved for patients with clear cell sarcoma of the kidney from NWTS-3 to NWTS-4 (83% vs 66.9% at 8 y). The 8-year relapse-free survival rate for localized clear cell sarcoma of the kidney stages I-III is 88%, but late relapses have been known to occur. In the NWTS-5 protocol, patients with all stages of CCSK are treated with the same regimen used in patients who have Wilms tumor with diffuse anaplasia (excluding stage I);[26] this treatment consists of a radical nephrectomy followed by radiotherapy and chemotherapy with cyclophosphamide, etoposide, vincristine, and doxorubicin for 24 weeks.

In the NWTSG series that was reviewed by Argani et al, a better prognosis was indicated in the subset of patients with clear cell sarcoma of the kidney that was characterized by stage I tumors in patients aged 2-4 years in whom no tumor necrosis was identified.[4]

In the completed Children's Oncology Group protocol (AREN0321), all patients with clear cell sarcoma of the kidney, except patients with stage IV, were treated as in NWTS-5 with regimen I. However, patients with stage I who undergo lymph node sampling did not undergo radiation therapy to the tumor bed. Any patient with stage I who did not have a lymph node sampling was upstaged to stage II.[20] Patients with stage IV were treated with irinotecan and vincristine in an upfront window approach before treatment with cyclophosphamide, etoposide, vincristine, and  doxorubicin.

At presentation, radical nephrectomy is the initial treatment of choice if the lesion is resectable. If the size or extension of the lesion is in question, a biopsy is performed, and chemotherapy is administered, followed by surgical resection after a response has been obtained.

Radiation oncologist

Once the tumor has been resected, the tumor bed and any other sites of disease are irradiated.

Pediatric oncologist

Primary care physicians should consult with a pediatric oncologist to determine standard and investigational treatment protocols.

Diet

No special diet is required.

Activity

Activity recommendations are made on an individual basis.

Patients with clear cell sarcoma of the kidney (CCSK) are treated with combination chemotherapy. The addition of doxorubicin to chemotherapeutic regimens has been shown to improve disease-free survival rates. Physicians caring for a patient with clear cell sarcoma of the kidney should consult a pediatric oncologist affiliated with a cancer center that participates in national or international trials to determine the current standard treatment protocol and to determine whether the patient is eligible for an investigational protocol.

Class Summary

Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (ie, gap 1 [G1]), followed by DNA synthesis (ie, S phase), a premitotic phase (ie, gap 2 [G2]), and, finally, mitotic cell division (ie, M phase).

The rate of cell division varies among tumors. Most lesions of common cancers increase very slowly in size compared to normal tissues, and the rate of growth may even be slower in large tumors. This difference allows normal cells to recover more quickly from chemotherapy than malignant cells, and provides the rationale behind current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism in many antineoplastic agents.

Refer to the specific protocols for duration of therapy with each drug and timing of administration within each treatment cycle.

Vincristine (Oncovin)

A vinca alkaloid that inhibits cellular mitosis by inhibiting intracellular tubulin function, binding to microtubules, and inhibiting the synthesis of spindle proteins.

Doxorubicin (Adriamycin, Rubex)

Inhibits topoisomerase II and produces free radicals, which may cause the destruction of DNA. The combination of these 2 events can, in turn, inhibit the growth of neoplastic cells.

Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Etoposide (Toposar, VePesid, VP-16)

Inhibits topoisomerase II and causes DNA strand breakage causing cell proliferation to arrest in late S or early G2 portion of the cell cycle.

Class Summary

Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide and cyclophosphamide.

In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, the ifosfamide or cyclophosphamide metabolite considered responsible for urotoxicity.

Mesna (Mesnex)

Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity. Dose is dependent on dose of ifosfamide or cyclophosphamide, typically 60-100% of the antineoplastic agent used. May be administered as an initial bolus followed by IV continuous infusion or as intermittent IV infusions before and following chemotherapy regimen.

Class Summary

These act as a hematopoietic growth factor that stimulates the development of granulocytes. They are used to treat or prevent neutropenia in patients receiving myelosuppressive cancer chemotherapy and to reduce the period of neutropenia associated with bone marrow transplantation. They are also used to mobilize autologous peripheral blood progenitor cells for bone marrow transplantation and to manage chronic neutropenia.

Filgrastim (Neupogen, G-CSF)

Granulocyte colony-stimulating factor that activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils.

After completing chemotherapy, patients should continue to have regular blood work and radiographic scans on an outpatient basis, which decreases in frequency over time. The ideal follow up schedule has not been established particularly for the length of follow up. Generally, these visits occur every 1-3 months for the first year, every 3-6 months for the second and third years, then yearly thereafter. Investigators in Europe and in North America have reported an increase in number of CNS recurrences of clear cell sarcoma of the kidney (CCSK). The brain should be routinely scanned with other areas (such as lungs).

Clear cell sarcoma of the kidney tumors are associated with late recurrence; the most common site of recurrence is the brain and then the lung. Unlike Wilms tumors, patients remain at risk for recurrence after 2 years posttherapy. Tumors may recur as long as 10 years after completion of treatment. However, with the recent treatment approaches, most recurrences occur within 3 years of the completion of therapy.

Treatment of patients with recurrent clear cell sarcoma of the kidney depends on initial therapy. Cyclophosphamide and carboplatin should be considered if not used initially.[27]  Patients with recurrent clear cell sarcoma of the kidney that involves the brain have responded to treatment with ifosfamide, carboplatin, and etoposide (ICE), coupled with local control consisting of either surgical resection and/or radiation.[28]  Patients with recurrent clear cell sarcoma of the kidney should be considered for treatment on available pediatric phase I and phase II clinical trials and NCI-COG Pediatric MATCH study (NCI-COG Pediatric MATCH - National Cancer Institute).

Patients require follow-up evaluation in a late-effects clinic and monitoring with appropriate tests because they have a single kidney. Patients are assessed for toxic effects resulting from chemotherapy, radiotherapy, or both. Follow-up visits should include renal, psychosocial, cardiac, and hormonal evaluations.

Inpatient and outpatient medications

Trimethoprim-sulfamethoxazole is indicated in patients who have undergone irradiation therapy to the lung. This drug therapy should continue throughout the course of treatment and for 6 months posttherapy.

Deterrence/prevention

No preventive measures for childhood cancers currently are known.

Pediatricians often refer patients with an abdominal mass to a pediatric general surgeon or urologist (if a known renal mass is present). These specialists should involve pediatric oncologists preoperatively. Chest CT scans should be obtained before surgery to eliminate confusion regarding areas of atelectasis that may be difficult to separate from metastases. In addition, if abnormal findings are revealed on chest CT scans, a biopsy of lung tissue can be planned at the time of surgery.

Chemotherapy may be administered on an outpatient (depending on the facilities) or inpatient basis.

Fever and neutropenia may occur, requiring hospitalization for intravenous antibiotics and monitoring.

Although the major therapy for cancer should occur at a center staffed by pediatric oncologists, referring physicians should continue to play an important role in the child's care throughout treatment. The referring physician can be critical in performing the first evaluation of an illness, particularly if the child lives far from the oncology center.

Patients may be referred to pediatric general surgeons and urologists.