–Postnatal MRI is also useful in outlining the site and size of the tumor properly as well as its relation to other intra-abdominal organs.

4.3.7Treatment and Prognosis

•The majority of these tumors are benign tumors and have a favorable outcome.

•The cellular variant can at times be aggressive.

•Surgical resection of congenital mesoblastic nephroma is the treatment of choice and this is curative.

•Most cases of mesoblastic nephroma are clinically benign. However, there are reports of local recurrence in incompletely resected tumors, and metastases to the brain, lung, heart and bone.

–In such cases, patients may be treated with chemotherapy and/or radiation therapy.

•When diagnosed in the first 7 months of life, the 5-year event-free survival rate is 94 % and the overall survival rate is 96 %.

•Patients at increased risk of recurrence and/or metastasis are those showing incomplete resection with positive resection margins, cellular type, and age at diagnosis of more than 3 months

4.4Clear Cell Sarcoma of the Kidney (CCSK)

4.4.1Introduction

•In the past, clear cell sarcoma of the kidney was considered as a subtype of Wilms’ tumor.

•Clear cell sarcoma is now considered a distinct clinical and histologic entity.

•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, Marsden et al, and Beckwith and Palmer.

•Clear cell sarcoma of the kidney is also known as bone metastasizing renal tumor of childhood because of its tendency to metastasize to bones.

•Clear cell sarcoma of the kidney (CCSK), is an uncommon renal tumor of childhood.

•It accounts for 4–5 % of all primary renal tumors in childhood.

•Approximately 20 new cases are diagnosed each year in the United States.

•It is difficult to differentiate clear cell sarcoma from Wilms’ tumors both clinically and radiologically.

•Age of presentation of CCSK ranges from 2 months to 14 years, with a mean age at diagnosis of 36 months.

•Clear cell sarcoma of the kidney is extremely rare in infants younger than 6 months old.

•The highest incidence (50 % of the cases) of clear cell sarcoma of the kidney is in children aged 2–3 years.

•It occurs more in males than females, with a male-to-female ratio of 2.04:1.

•CCSK arises from a renal mesenchymal cell that possesses neural markers.

•Grossly, the tumor is soft and well circumscribed.

•Histologic analysis show small cells with inconspicuous nucleoli and ill-defined cell membranes and a prominent capillary network.

•The Clinical presentation includes abdominal pain, hypertension, and hematuria.

•Radiologically, it is difficult to differentiate this from Wilms tumor but a sharply demarcated solid intrarenal mass without intra-vascular extension is most radiological finding.

•Clear cell sarcoma of the kidney is characterized by:

–Its propensity to metastasize to bones.

–Poor prognosis.

–The sarcomatous nonepithelial nature.

–CCSK may also recur many years after its initial diagnosis.

•The tumor is characterized by its aggressive behavior and is associated with a higher rate of relapse and mortality than Wilms tumor. It may metastasize to the bones, lymph nodes, brain, liver, and lungs, in some cases long after nephrectomy.

•CCSK is an aggressive renal tumor with a unique propensity to metastasize to bone and brain, as well as lung and abdomen.

•Only 4–5 % of patients with CCSK present with distant metastases.

•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.

•Bone is the most common site of distant metastases (15 %).

•This is followed by the lungs, abdomen, retroperitoneum, brain, and liver.

•Unusual soft tissue sites (scalp, epidural, nasopharynx, neck, paraspinal, ovary, abdominal wall, and axilla) and other sites (orbit) have also been reported.

•Since bone metastases may occur with this disease, bone scintigraphy or FDG-PET scan is recommended and Brain CT scan or MRI are part of the workup of these patients.

•Overall, the prognosis of clear cell sarcoma is poor when compared with that of patients with Wilms’ tumors.

•The treatment consists of radical nephrectomy, chemotherapy, and radiotherapy.

•The prognosis of CCSK is generally poor, but the development of newer treatment regimens has improved survival and currently the relapse-free and cancer-specific survival rate for revised stage 1 CCSK is about 90–100 %.

•Currently, the overall survival rate for patients with CCSK is about 83 %.

4.4.2Pathophysiology

•Clear cell sarcoma of the kidney originates from renal mesenchymal cells with neural markers.

•It is not associated with intralobar nephrogenic rests.

•CCSK is usually unilateral affecting only one kidney and no bilateral cases have been reported.

•At the time of presentation:

–25% of patients presented with stage I tumors

–37% of patients presented with stage II tumors

–34 % of patients presented with stage III tumors

–4 % of patients presented with distant metastases

•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.

•Bone is the most common 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, and 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.

4.4.3Clinical Features

•The clinical manifestations of patients with clear cell sarcoma of the kidney (CCSK) are similar to those patients with Wilms tumor.

•The usual presentation is with an abdominal mass that was noticed by the parents or primary care physician or pediatrician. Sometimes, the mass is discovered accidently during an abdominal ultrasound that was ordered for something else. The mass may be discovered by the mother while dressing or giving bath to the child.

•Other clinical presentations include:

–Abdominal pain

–Gross or microscopic hematuria

–Fever

–Hypertension

•Clinically, the patient has a large palpable unilateral abdominal mass.

•No specific chromosomal translocation or syndromes have been associated with clear cell sarcoma of the kidney.

•The proto-oncogene c-kit is overexpressed in clear cell sarcoma of the kidney but is not accompanied by gene amplification or activating mutations.

•The t(10;17)(q22;p13) and deletion 14q have been described.

4.4.4Investigations

•CBC

•Serum electrolytes, BUN and creatinine levels

•Liver function testes

•Prothrombin time and activated partial thromboplastin time

•Abdominal ultrasound:

–This is important to define the tumor, its origin and extent.

–It is also important 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.

•CT scans of the chest and abdomen:

–To define the origin and extent of the tumor

–To define secondaries in the lymph nodes, liver and lugs

•Bone scan is important to exclude secondaries

•Brain CT scan or MRI are also important to detect secondaries

4.4.5Histopathology

•Clear cell sarcoma of the kidney usually presents as a large mass markedly distorting or almost completely replacing the kidney.

•The tumor can reach a large size with a mean tumor diameter of 11.3 cm (2.3–24 cm).

•The mean weight of the kidney tumor is about 661 g.

•CCSK is an epicenteric tumor and the renal medulla is the most common location.

•No case of multicentric tumor was identified.

•On cut sections of the tumor:

–It appears as tan-gray, soft, and mucoid.

–There are multiple cystic areas and sometimes these cysts represent the dominant feature.

–Discrete foci of necrosis and hemorrhage may be present.

•Histologically, clear cell sarcoma of the kidney shows three components:

–Cord cells:

•These are small round-to-oval cells with deceptively bland cytologic features, including mitotic figures.

–Septal cells:

•These are spindle-shaped cells along the fibrovascular septa (fibrovascular septa can be demonstrated more convincingly using reticulum stain).

–An intercellular matrix:

•This is 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, CCSK is divided histologically into two types:

–Classic clear cell sarcoma of the kidney

–Variant clear cell sarcoma of the kidney

–The classic pattern usually represents the predominant pattern in most clear cell sarcoma of the kidney tumors.

–The classic histologic pattern 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 most common variant is the myxoid CCSK.

–The variant patterns include:

•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 anaplastic clear cell sarcoma of the kidney.

–The 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, α 1 -antitrypsin, and α 1 -antichymotrypsin have also been described.

4.4.6Treatment

•The overall survival of children with clear cell sarcoma of the kidney remains considerably lower than that of patients with favorablehistology Wilms tumor.

•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 year).

•This is attributed to the use of chemotherapy for prolonged periods.

•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 year).

•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 reported.

•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 chemotherapy with cyclophosphamide, etoposide, vincristine, and doxorubicin for 24 weeks.

–And radiotherapy

–CCSK commonly responds poorly to treatment with vincristine and actinomycin alone, but the addition of doxorubicin to chemotherapy regimens has improved survival rates.

•In the current Children’s Oncology Group protocol (AREN0321), all patients with clear cell sarcoma of the kidney, except patients with stage IV, continue treatment as in NWTS-5.