History: Manifestations in patients with CCSK are similar to those in patients with Wilms tumor. Patients present with an abdominal mass, which usually is identified by a caregiver or family relative who has not seen the child for a while.
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:

• 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 CCSK have been reported.

Causes: The histogenesis of CCSK is unknown and appears to be unrelated to Wilms tumor. No specific chromosomal translocation has been associated with CCSK; a finding that generally indicates a normal karyotype.

Lab Studies:

• Since no specific laboratory study exists to confirm the diagnosis of CCSK, most testing pertains to the workup of an abdominal mass.

• Complete blood count: Complete blood 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.

Imaging Studies:

• CT scans of the chest (before surgery) and abdomen should be performed initially to define the extent of the tumor.

• 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 CCSK.

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

Histologic Findings: CCSK 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, CCSK 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 CCSK.

Depending on the amount, distribution, and variation in morphology of the 3 components, the tumor shows a classic CCSK pattern or the variant histologic patterns. Variant histologic patterns also may be observed in the metastases. The classic pattern usually represents the predominant pattern in most CCSK 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 CCSK lesions. The classic histologic pattern of CCSK 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 CCSK. 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.

The diagnosis of CCSK should be considered, even if no real or apparent clear appearance exists 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, it is essential that the practicing pathologist be familiar with the variant pattern.

Unfortunately, no diagnostically useful immunohistochemical features exist. Tumor cells usually test positive for vimentin and negative for cytokeratin, factor VIII–associated antigen, epithelial membrane antigen, desmin, S100, factor XIIIa, c-kit, polyclonal carcinoembryonic antigen (CEA), and MAC387. Positive staining results for cytokeratin, a₁-antitrypsin, and a₁-antichymotrypsin have been described.

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: 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 exists. 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 exists of tumor at or beyond the margins of resection.
• 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.

Medical Care: CCSK tumors are aggressive and respond poorly to treatment with vincristine and actinomycin alone. The addition of doxorubicin in aggressive chemotherapy regimens has improved survival rates. 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); this treatment consists of a radical nephrectomy followed by radiotherapy and chemotherapy with cyclophosphamide, etoposide, vincristine, and doxorubicin for 24 weeks.

Results from the first 3 NWTSG trials suggest that the addition of doxorubicin to vincristine and actinomycin D improved the 6-year relapse-free survival rate in patients with CCSK. All patients with CCSK who are treated using the NWTS-5 regimen currently are treated with doxorubicin as well.

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

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

Consultations:

• Radiotherapist: 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.

Patients with 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 CCSK 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.
 

Drug Category: Antineoplastic agents -- 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.

Drug Category: Uroprotective antidote -- 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.

Drug Category: Colony-stimulating growth factors -- Act as a hematopoietic growth factor that stimulates the development of granulocytes. Used to treat or prevent neutropenia in patients receiving myelosuppressive cancer chemotherapy and to reduce the period of neutropenia associated with bone marrow transplantation. Also used to mobilize autologous peripheral blood progenitor cells for bone marrow transplantation and to manage chronic neutropenia.

Further Inpatient Care:

• 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 IV antibiotics and monitoring.

Further Outpatient Care:

• Monitoring for recurrence

• After completing chemotherapy, patients should continue to have regular blood work and radiographic scans on an outpatient basis, which decreases in frequency over time. 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.

• As noted previously, CCSK tumors are associated with late recurrence; thus, in some settings, patients with CCSK need to be monitored even more closely. The most common site of recurrence is bone. Unlike Wilms tumor, patients remain at risk for recurrence after 2 years posttherapy. Tumors may recur up to 10 years after completion of treatment. 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.

In/Out Patient Meds:

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

Transfer:

• Pediatrician or general practitioner: 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.

Deterrence/Prevention:

• No preventive measures for childhood cancers currently are known.

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.

Prognosis:

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

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

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

Patient Education:

• 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 abdominal 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.