Clear-cell sarcoma of the kidney (CCSK) was first reported by Kidd in 1970, and is characterized by its bone metastasizing tendencies and propensity for late recurrences.
3-4% of all primary pediatric renal tumours are clear cell sarcoma of the kidney (CCSK); they are classified separately from Wilms tumour. Approximately 20 new cases are diagnosed each year in the United States.
Unlike Wilms tumour, it is not associated with hemihypertrophy and sporadic aniridia.
The genetics of CCSK are entirely different from Wilms tumor. A t(10;17)(q22;p13) and deletion 14q have been found in some patients. Alterations in the p53 tumour suppressor gene are sometimes seen in CCSK. EGFR pathway regulatory abnormalities have been seen in CCSK. The proto-oncogene c-kit is overexpressed in CCSK. However, the is no gene amplification or activating mutations.
CCSK tumours are usually fairly large and are unilateral and unicentric, often arising from the central or medullary portion of the kidney. They have a mucoid texture, foci of necrosis and prominent cyst formation. Intracytoplasmicvesicles are often found and are the basis for the term clear cell sarcoma. The tumor kidney junction is classically well-defined. Any area of nephroblastoma excludes the diagnosis of CCSK.
There are 3 types of components:
- Septal cell (spindle-shaped) in fibrovascular septa
- Cord cell (round or oval)
- Intercellular matrix (it has MPS or mucopolysaccharide, hence the name clear cell)
Most tumours have a classic pattern: monomorphous with cords/nests of a few cells divided by evenly dispersed small vascular septa. There are multiple other histologic 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%)
In most cases more than one pattern is seen.
Classic Pattern
Metastases may exhibit variant histologic patterns.
NWTS-4 - 86 (59 males and 27 females) CCSK patients were in this study. No patient had bilateral disease (stage V).
|
Age |
|
|
<1y |
33% |
|
1-2y |
34% |
|
> 2y |
19% |
|
Male:Female |
59:27 |
|
Stage |
|
|
I |
35% |
|
II |
21% |
|
III |
28% |
|
IV |
2% |
Table 1. Characteristics of CCSK patients in NWTS-4
CCSK has a peak incidence between 3 – 5 years of age with a M:F ratio of 2:1.
1/21 patients in NWTS-4 developed brain mets, compared with 11% of patients in earlier studies. More than 30% of the recurrences occurred between 2 years and 37 months; however, none have been reported after 37 months, in contrast to other prior studies. Bone scans are now standard at diagnosis for CCSK patients in NWTS-5.
These tumors have a propensity to metastasise to bone (15 – 17% incidence) giving it the name “bone metastasising renal tumour of childhood” (bone mets are seen in < 2% with Wilms tumor). The other sites of metastasis, in order of frequency are: lung, abdomen, retroperitoneum, brain, and liver. Late onset of first relapse is a distinctive feature even in stage-I tumours and regular post-operative follow up is essential. Earlier reports noted that nearly 20% of CCSKmetastases occurred at least 3 years after diagnosis; rarely even up to 10 years later.
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.
[from ref 1]
All stages of CCSK are treated with radical nephrectomy. Chemotherapy typically is VCR, cyclophosphamide, doxorubicin and etoposide for 24 weeks. Almost all receive radiation therapy (see below)
Only children who are a) Stage I and b) had negative lymph node biopsies are able to avoid radiation therapy to the tumor bed. (Stage 1 children without lymph node sampling are upstaged to stage II.
One study found that children treated on arm DD-RT of NWTS-3 (longer treatment duration – 15 months) had a 64.6% 6-year RFS (relapse free survival), and concluded that longer tx with vincristine, doxorubicin, and dactinomycin for patients with CCSK provides better RFS than a shorter course (6 months), but unfortunately no improvement in overall survival.
COG protocol (AREN0321) for all CCSK non-stage IV patients recommends continued treatment as in NWTS-5.
Patients with stage IV undergo treatment with irinotecan and vincristine in an upfront window approach before treatment with cyclophosphamide, etoposide, vincristine, doxorubicin, and cyclophosphamide.
Overall survival is 69%. In one review, 4 independent prognostic factors were identified after multivariate analysis:
- Treatment with doxorubicin
- Stage
- Age at diagnosis
- Tumour necrosis
Long term follow up is essential – there are late relapses, even in stage 1 disease. Under current treatment protocols most recurrences are seen within 3 years of the completion of therapy. Best outcome is in Stage I tumors, in kids from 2-4 years of age, and who have no tumor necrosis. Stage IV (distant metastases) or multifocal disease have a worse prognosis – 50% long-term 6-year survival rate.
|
Agent |
MOA |
|
Cyclophosphamide (Cytoxan, Neosar) |
N2 Mustard relative. Alkylating agent. Cross-links DNA |
|
Etoposide (Toposar, VP-16) |
Inhibits topoisomerase II and causes DNA strand breakage. There is ‘freezing’ of cell proliferation in late S or early G2 cell cycle |
|
Vincristine (Oncovin) |
A vinca alkaloid that mainly inhibits mitosis by inhibiting intracellular tubulin function -> binds to microtubules. |
|
Doxorubicin (Adriamycin, Rubex) |
Produces free radicals (DNA degradation). Inhibits topoisomerase II. |
|
Mesna (Mesnex) |
Blocks acrolein (a metabolite of cyclophosphamide or iphosphamide that causes hemorrhagic cystitis) by virtue of its free thiol groups. |