Ewing sarcoma/primitive neuroectodermal tumor arising in the adrenal gland

To the Editor: Ewing sarcoma (ES)/primitive neuroectodermal tumor (PNET) is a malignant small round blue cell neoplasm of presumed neuroectodermal origin that affects bones and soft tissue in children and young adults. Nearly 80% of the patients are younger than 20 years. The tumor cells characteristically express CD99 (MIC2 antigen), a glycoprotein localized on cell membrane. The defining feature of ES/PNET is a characteristic translocation t(11;22)(q24;q12) involving the EWSR1 gene on chromosome 22 and the FLI1 gene on chromosome 11. ES/PNET in parenchymal organs are rare, and those arising in the adrenal gland have been reported in a limited number of case reports. We present a case of ES/PNET arising in the adrenal medulla and discuss the clinicopathological and molecular features that differentiated it from neuroblastoma, and helped determine appropriate therapy with excellent response. A 26 year-old woman presented with constant dull leftsided flank pain for three days. Ultrasound revealed an 11.3 ¥ 10 ¥ 5.2 cm retroperitoneal left adrenal mass with mixed echogenicity and internal vascularity, and a 9 ¥ 2.2 cm echogenic oval thrombus in the inferior vena cava. CT scan demonstrated a heterogeneously enhancing mass with central area of necrosis and a thrombus extending into the left adrenal vein, renal vein and inferior vena cava. The patient’s plasma metanephrines, aldosterone and renin levels were within normal limits. Staging work up (chest CT, bone scan, bone marrow aspirate and biopsy) did not reveal any metastasis. A left adrenalectomy with inferior vena cava thrombectomy, left nephrectomy and splenectomy was performed. A postoperative fluorodeoxyglucose-positron emission tomography (FDG-PET) showed limited uptake in the proximal inferior vena cava suggesting residual tumor thrombus. The patient received 10 cycles of chemotherapy with cytoxan, adriamycin and vincristine alternating with ifosfamide and etoposide every 2 weeks, followed by radiation therapy. She was alive and free of disease 8 months after surgery. Gross pathology examination revealed a 12 cm suprarenal mass separate from the kidney. The tumor was nodular and showed a tan-yellow cut surface with areas of cystic degeneration, necrosis and hemorrhage (Fig. 1b). A tumor thrombus extended into the adrenal and renal veins, and the inferior vena cava (Fig. 1a). Microscopically, the adrenal medulla was completely replaced by a malignant small round blue cell tumor with a compressed rim of adrenal cortex at the periphery. The tumor consisted of sheets of monomorphic, briskly mitotic cells with scant cytoplasm (Fig. 1c). A Periodic Schiff’s stain with diastase revealed focal intracytoplasmic granules consistent with glycogen. Extensive areas of tumor necrosis with peritheliomatous survival pattern were seen associated with organizing hemorrhage. Rosettes or rosettelike structures, neurofibrillary matrix, neuronal or any other differentiation were not present. Extra-adrenal extension into fat was identified but the tumor did not infiltrate the kidney or the spleen. A single lymph node was negative for metastasis. Immunohistochemistry showed that the tumor cells were strongly and diffusely positive for CD99 (membranous expression), positive for chromogranin-A (dot-like paranuclear expression), vimentin, and neuron-specific enolase (NSE), and negative for synaptophysin, CD30, CD45, CD56, CD57, cytokeratin, S-100 protein, melan-A, desmin, myogenin and neurofilament (Fig. 1d). Fluorescence in-situ hybridization (FISH) evaluating 30 cells with dual colored breakapart probes and using a 20% cutoff value confirmed EWSR1 gene rearrangement signals in 23% (7 out of 30) of the tumor cells. A review of the English literature revealed 12 additional cases, and confirmed that ES/PNETof the adrenal gland is a rare, aggressive and lethal tumor (Table 1). The patients ranged in age from 4 to 57 years (median age 22), most were children (5/13) or young adults (6/13), and only two patients were older than 30 years. There was no particular predilection for gender (6 males, 7 females) or laterality (right 5, left 5, unknown 3). The tumors were large (range 5 to 17 cm), solid and cystic, hemorrhagic and necrotic. Interestingly, four of the tumors including the present case showed involvement of the inferior vena cava by direct extension of tumor thrombus that in one case reached the right atrium, a feature that appears to be unique to adrenal ES/PNET. Follow-up in 12 cases shows that the tumors were aggressive and lethal, leading to death in seven and progression in three patients within two years of diagnosis. Eight patients had metastasis at presentation or developed it during follow-up. Only two patients including the present case achieved complete remission after surgery, chemotherapy and radiotherapy (Table 1). ES/PNET of the adrenal gland needs to be differentiated from neuroblastoma, an embryonic neoplasm of the sympathetic nervous system. Both tumors share the morphology of The study was approved by the institutional human investigation committee with waiver for patient consent. Pathology International 2013; 63: 283–286 doi:10.1111/pin.12063 bs_bs_banner