Answer: Ewing sarcoma/PNET

Histology: This is a monotonous small round blue cell tumor which affects the kidney. There is extensive necrosis. The cells are fairly uniform, and focally form Homer Wright Rosettes. CD99 diffusely demonstrated membranous labeling. This neoplasm demonstrated the EWS/FLI1 gene fusion typical of Ewing sarcoma/PNET.

Discussion: None of the entities in the differential diagnosis would demonstrate the EWS/FLI1 gene fusion of Ewing sarcoma. Blastemal Wilms tumor would feature more tightly packed hyperchromatic small round blue cells. This does not label for CD99. Neuroblastoma may affect the kidney of very young patients; however, it would not demonstrate labeling for CD99. Malignant lymphoma features more discohesive cells with irregular nuclear contours.

Given the numerical predominance of Wilms tumor and its known capacity to demonstrate extensive neural differentiation, the diagnosis of primary renal primitive neuroectodermal tumor (PNET) has always been difficult to defend. However, the entity of primary renal PNET has recently been established by molecular demonstration of the characteristic EWS-FLI1 gene fusion that results from the t(11;22)(q24;q12) chromosome translocation within these neoplasms.

These tumors are most common in young adults and adolescents. They tend to present at high stage and have a poor outcome. Review of 15 cytogenetically and/or molecularly confirmed well-documented cases in the literature reveals a mean age of 27 years and a Male/Female ratio of 10:4. While staging information is often incomplete in these reports, the mean tumor diameter reported was 16.1cm. Five of 10 patients for whom stage information was provided presented with distant metastases, while 2 other patients had incomplete excisions with residual tumor at the surgical margin. Of the 11 patients for whom follow up information was reported, 6 have died of disease (mean time to death of 9 months), 1 patient developed pulmonary metastases at 6 months, while 4 are reported to have no evidence of disease on follow up. The latter may be somewhat optimistic, since the reported follow-up was 1 year or less in all but one of these 4 survivors. The data gleaned from genetically confirmed cases have been corroborated by a recent series of 11 well-characterized tumors that were diagnosed by morphology and extensive immunohistochemistry. In this series, mean age at presentation was 34 years, and mean tumor diameter was 11cm. While none of the patients presented with distant metastasis, in 5 of 11 cases, renal vein invasion was identified grossly, and “most” cases demonstrated vascular invasion microscopically. Of the 8 patients will follow up, 5 died of disease (mean time to death, 17.6 months), while 3 were alive with no evidence of recurrent disease (mean follow up of 28 months, including one patient with only 4 months of follow-up). Hence, even clinically localized renal PNETs have an aggressive clinical course.

It is likely that many tumors previously classified as adult blastemal-predominant Wilms tumors in the past are in fact renal PNETs. In fact, in young adults, renal PNET is a more likely diagnosis than blastemal WT (J. Bruce Beckwith, personal communication). The kidney may be the most common site for PNET outside of the bone and soft tissue. As PNET is typically a more aggressive neoplasm than Wilms tumor and requires more intensive chemotherapy, it is likely that such cases (along with primary renal synovial sarcomas) contribute to the prevailing view among oncologists that “adult Wilms tumors” are more aggressive than their pediatric counterparts.

Renal PNET are morphologically identical to their soft tissue counterparts. Uniform sheets of primitive small round blue cells characterize these tumors. Necrosis and mitoses are frequent. Tumors demonstrating neural differentiation feature Homer Wright rosettes and a more lobular architecture. Such rosettes must be distinguished from the early tubular differentiation of Wilms tumor, where a lumen has not yet formed. True tubular differentiation that would support the diagnosis of WT requires the presence of lumens with rigid cytoplasmic luminal borders.

The primary differential diagnoses for renal PNET consists of blastemal WT and cellular CCSKs. The diagnosis of renal PNET is more likely in young adults, since both CCSK and WT typically affect patients under the age of 5. Like blastemal WT, PNET features an aggressively invasive border, engulfing islands of renal parenchyma, while CCSK entraps single native nephrons. Thorough sampling of tumors is helpful, since PNETs have a uniform morphology throughout while CCSK and WT may show distinctive patterns of growth in other parts of the neoplasm that establishes their diagnoses. Otherwise, at the H and E level, the distinction is best made cytologically. The nuclei of PNET are more evenly spaced than those of blastemal WT, which often aggregate into nodules and mold to each other. CCSK nuclei are generally spaced further apart than those of PNET, separated by stromal mucopolysaccharide. Additionally, the chromatin of PNET nuclei is less coarse than that of WT, but more coarse than the characteristic open chromatin of CCSK. Immunohistochemistry is also very helpful. Over 95% of PNETs demonstrate complete membranous labeling for CD99 (MIC2, O13), while CCSKs and WT virtually never do. One must be aware that both of the latter may show nonspecific cytoplasmic labeling for this marker. Additionally, one should be aware that true PNET may show focal cytokeratin immunoreactivity that can lead to confusion with WT.

Molecularly confirmed renal PNET have demonstrated the EWS-FLI1 gene fusion that is characteristic of the ES/PNET family of tumors. In bone and soft tissue ES/PNET, the precise translocation breakpoints on these genes vary, resulting in variability in the exons included in the resulting fusion transcript. In approximately 70% of EWS/FLI1 gene fusions, EWS exon 7 is fused to FLI1 exon 6 (so called type 1 fusion), while variant fusions make up the minority of cases. It has been shown that non-type 1 gene fusions in ES/PNET of soft tissue are associated with poor outcome. Of 23 molecularly confirmed renal PNET cases [which comprises 10 of the previously discussed 15 cases and an additional 13 described by Parham et al.], 12 (52%) have demonstrated the type 1 fusion, while 11 (48%) have demonstrated variant fusions. The slightly-increased predilection for variant gene fusions to occur in the renal cases may contribute to their adverse prognosis as described above.