Answer: Clear cell sarcoma of the kidney

Histology: At low-power, this appears to be a well defined neoplasm with a pushing border with the native kidney: however, within the lesion are single entrapped nephrons, indicating a subtly-infiltrative growth pattern. Some of these entrapped tubules have primitive appearing nuclei, indicative of embryonal hyperplasia. The neoplasm is predominantly composed of epithelioid cells with ill- defined clear cytoplasm, separated by regularly capillary vasculature pattern. The nuclei are open and hypochromatic. These are the typical features of clear cell sarcoma of the kidney.

Discussion: A biphasic Wilms tumor is mimicked by the embryonal hyperplasia of the entrapped tubules in clear cell sarcoma of the kidney. However, the nuclei of a Wilms tumor would be uniformly hyperchromatic. Renal cell carcinoma would feature more cellular capillary vasculature, and would not entrap single nephrons in the manner of clear cell sarcoma of the kidney. Congenital mesoblastic nephroma of the classic type would entrap islands of native nephrons, and would feature more hyperchromatic nuclei with abundant collagen formation.

Clear cell sarcoma of the kidney (CCSK) comprises about 3 percent of pediatric renal neoplasms. The mean age at presentation is 2 years but I have seen bonafide cases in adults. There is a 2:1 male to female ratio, and all tumors arise unicentrically within the kidney. CCSK has a distinctive behavior. The tumor has a proclivity to metastasize to bone such that it is also known to some as “bone metastasizing renal tumor of childhood.” It may also metastasize to other usual sites such as brain and soft tissue; remember, Wilms tumor almost never metastasizes to these places. CCSK has traditionally been considered an aggressive cancer with survival in the range of 20%. However, the addition of Adriamycin to chemotherapy regimens has improved survival to approximately 70%. Nonetheless, CCSK has the potential to recur late, more than ten years after diagnosis. In contrast, Wilms tumor, if it recurs, usually does so within two years.

The classic pattern of CCSK features a characteristic vasculature composed of evenly placed branching capillaries separating tumor cells into cords or nests, 6 to 10 cells in width. The cells within the cords are well spaced apart by what appears to be clear cytoplasm; however, this is in fact extracellular mucopolysaccharide that is between rather than within cells. Cell processes are in fact thin and tenuous, surrounding this extracellular matrix. Most characteristic is the nuclear chromatin of the tumor cells, which is finely granular and open, often with an “orphan Annie eye” appearance. Nucleoli are not prominent. In many cases the extracellular mucopolysaccharide coalesces to form myxoid pools, and the septa can be thickened and cellular. Unlike Wilms tumor, which is usually encapsulated, CCSK is often subtly infiltrative and scalloped at its border, entrapping single native nephrons. Occasional entrapped nephrons undergo embryonal metaplasia, mimicking the primitive tubules of a Wilms tumor showing epithelial differentiation. Entrapped tubules may be highlighted by cytokeratin immunostaining, since CCSK is negative for most immunohistochemical markers, including cytokeratins. Entrapped tubules may dilate massively, creating a mimic of cystic nephroma.

The diagnosis of CCSK would not be so hard if it always had the classic pattern throughout. Unfortunately, CCSK is often dominated by one or more variant histologic patters, which allow it to mimic and be mimicked by all other pediatric renal neoplasms. These patterns are summarized below:

In the cellular pattern of CCSK, the intercellular mucopolysaccharide and capillary vasculature are less apparent, so the tumor mimics other small round cell tumors of the kidney, specifically blastemal Wilms tumor and renal PNET. Blastemal Wilms tumor is a major problem in differential diagnosis since it may have a vascular pattern like that of CCSK. In contrast to the former two lesions, CCSK has the most uniform chromatin, and its nuclei are spaced furthest apart. Immunohistochemistry can also be helpful, since CCSK is always negative for cytokeratins and CD99 (MIC2).

In the epithelioid pattern of CCSK, the cord cells form thin trabeculae or ribbons, and may even cluster like tubules, which mimics the epithelial component of Wilms tumor. The open chromatin is again helpful here, as is the preservation of the regular capillary vasculature. Additionally, epithelioid foci of CCSK are non-immunoreactive for cytokeratin, while Wilms tumor would be cytokeratin-positive.

In the sclerosing pattern of CCSK, bands of hyaline collagen are deposited adjacent to the vascular septa. In extreme cases this sclerosis mimics osteoid. The open chromatin and the absence of mineralization help establish the diagnosis in such cases.

In the storiform pattern, CCSK mimics a fibrohistiocytic lesion such as dermatofibrosarcoma protuberans (DFSP). The open chromatin of the tumor cell nuclei helps in the differential diagnosis, as does the fact that CCSKs are negative for CD34.Other spindled CCSK can show a fascicular pattern. The differential diagnosis would range from stromal predominant Wilms tumor to synovial sarcoma and congenital mesoblastic nephroma.

In the palisading pattern of CCSK, the spindle cell nuclei are aligned to simulate the Verocay body pattern of schwannoma. Unlike schwannoma, CCSK is non-immunoreactive for S-100 protein.

The most helpful features in making a diagnosis of CCSK include the fine nuclear chromatin and regular capillary vasculature, which are characteristic. However, proper fixation is required to appreciate the nuclear chromatin of CCSK. Another helpful fact is that, while the variant patterns of CCSK are confusing, they often occur together, so seeing a mixture of one or more characteristic variant patterns can help. Therefore, thorough sampling of these neoplasms can be very useful. Finally, as alluded to above, CCSK is essentially inert with most immunohistochemical markers. Hence, absence of labeling for specific markers of other tumors, such as cytokeratin, CD99, desmin, S-100 protein, and CD34, helps establish the diagnosis.

Reference(s):
– Am J Surg Pathol 2000;24: 4-18