Primary renal primitive neuroectodermal tumor.

Primitive Neuroectodermal Tumor of the kidney is a rare entity. Very few cases of primary renal PNET have been reported to date. Most literature about rPNET is isolated case reports. We report a case of rPNET in a 39-year-old male with a pre-operative diagnosis of renal cell carcinoma with renal vein thrombosis. The patient underwent radical nephrectomy with thrombolectomy, and histopathological examination revealed a highly aggressive tumor composed of monotonous sheets of round cells. Tumor cells were positive for CD 99 and FLI-1, hence confirming the diagnosis of Primitive Neuroectodermal Tumor. Post-surgery, patient was given VAC/IE-based adjuvant chemotherapy. In view of highly aggressive nature of this tumor, prompt diagnosis and imparting effective chemotherapy regimen to the patient is required, and it is important to differentiate PNET from other small round-cell tumors because of different therapeutic approach.

Introduction

Primitive Neuroectodermal Tumor (PNET), a highly aggressive tumor of the kidney is a rare malignancy with only few cases being reported in literature.[1] It generally occurs in adolescents and young adults with isolated pediatric cases.[23] Boys and men are more likely to suffer rPNET (renal PNET), and the sex ratio (male: female) is about 3:1.[4] It usually presents at an advanced stage, with distant metastasis and is associated with a poor prognosis. We report in this paper, a case of primary renal PNET in a young male.

Case Report

A 39-year-old male presented with complaints of hematuria and heaviness in the right flank since 15 days. Physical examination revealed a soft lump in the right hypochondrium. Ultrasound examination of the abdomen showed an irregular cystic structure in the right kidney at lower pole with few internal echoes. Size of the mass lesion was 25 × 30 mm. CT scan of the abdomen demonstrated a large significantly enhancing right renal lower polar mass with necrosis with thrombosis in right renal vein. On the basis of these clinico-radiological findings, diagnosis of right side renal cell cancer was made, and right radical nephrectomy with thrombolectomy was performed. Gross examination revealed a friable, grayish-white, lobulated mass (7 × 5 cm) with multiple foci of hemorrhage and necrosis. The mass extended from mid to lower pole of the right kidney and infiltrated into the renal pelvis and was limited to the renal capsule The renal vein and ureter were free of the tumor. There was a thrombus inside the renal vein, which was not adherent to intima of renal vein. No lymph nodes were dissected from aortocaval region. Microscopically, the tumor was composed of monotonous sheets of round cells with scant cytoplasm, hyperchromatic vesicular nuclei, coarse chromatin and few conspicuous nucleoli, transverse by thin fibrous bands infiltrating and entrapping the renal glomeruli and tubules [Figure 1]. Brisk mitosis and apoptosis was noted. Areas of necrosis were present. Lympho-vascular embolization was present. No extension into the peri-renal fat was seen. On immunohistochemistry, the tumor cells were positive for CD99 [Figure 2a], FLI-1 [Figure 2b], NSE [Figure 2c], and synaptophysin [Figure 2d], but negative for desmin, CK, EMA, and LCA. A diagnosis of PNET was made based on the above findings, and patient was started on VAC (vincristine, adriamycin, and cyclophosphamide) alternating with IE (ifosfamide and etoposide)-based adjuvant chemotherapy regimen which he tolerated well. After 6 cycles of chemotherapy, a PET scan showed absence of any metabolically active focal uptake in whole body. Bone marrow aspiration and biopsy was done, which revealed uninvolved bone marrow. Chemotherapy with VAC (vincristine, actinomycin D, and cyclophosphamide) alternating with IE (ifosfamide and etoposide) for a year was planned.

Figure 1

Section showing malignant round cells arranged in pattern sheets infiltrating and entrapping the renal glomeruli and tubules {Figure 1a: H&E; ×100, Figure 1b: H&E; ×200}

Figure 2

(a) The tumor cells express membranous expression of CD99 {DAB; ×200} (b) The tumor cells express nuclear positivity for FLI-1{DAB; ×200} (c) The tumor cells express cytoplasmic positivity for neuron-specific enolase (NSE) {DAB; ×200} (d) The tumor cells expressing cytoplasmic positivity for synaptophysin {DAB; ×200}

Discussion

The Primitive Neuroectodermal Tumor (PNET), was first recognized by Arthur Purdy Stout in 1918, and is a member of the family of “small round-cell tumors.”[5] PNET arising in the kidney was first reported by Mor in 1994.[6] Primitive Neuroectodermal Tumors occurs preferentially in the soft-tissues of the paravertebral region and chest wall, less frequently in extremities, with a slight male predominance. rPNET appears to be an unique clinical entity that behaves more aggressively than PNET arising at other sites.[7]

The presenting symptoms and images of rPNET are non-specific and similar to other renal tumors. rPNET show a male predominance with 85% cases being diagnosed during the second to fourth decade. It is an aggressive tumor that tends to recur locally and to metastasize to lymph nodes, lung, liver, bone, and bone marrow, which entail a worse prognosis.[8]

The differential diagnosis of rPNET includes other small round cell tumors like neuroblastoma, adult nephroblastoma, malignant lymphoma, rhabdoid tumor, small cell carcinoma and monophasic, poorly differentiated, round cell variant of synovial sarcoma, carcinoid, rhabdomyosarcoma, clear cell sarcoma of the kidney, the small cell variant of osteosarcoma, and desmoplastic small round cell tumor.[9]

Grossly, rPNET are typically very large tumors with about 65% measuring >10 cm in diameter.[10] They tend to be grayish in color, encapsulated, and contain focal areas of hemorrhage or necrosis. Microscopically, the tumor is composed of sheets of round cells; individual cells have a round nucleus with a distinct nuclear membrane, fine powdery chromatin, and 1 or 2 small nucleoli. The cytoplasm is ill-defined, scanty, usually PAS-positive, and mitosis are variable. Perivascular pseudo rosettes and Homer-Wright rosettes are common.

To better address the diagnosis, an immunohistochemical analysis is necessary. Immunohistochemical markers to be used to confirm diagnosis are cytokeratin (for nephroblastoma, small cell carcinoma, and synovial sarcoma), LCA (for Lymphoma), NSE/chromogranin A (for neuroblastoma), and CD-99 for PNET. CD99 (the product of MIC2 gene) greatly aids in recognizing the ES/PNET family of tumors.[11] Many PNET also stain for neural markers, including NSE, Leu-7, S-100 protein, synaptophysin, and PGP9.5.[12]

The most frequent translocation in PNET is t(11;22)(q24;q12), detected in approximately 90% of cases, resulting in EWS-FLI fusion gene. Monoclonal antibodies to FLI1 can be used to detect these tumors.[13]

The 5-year disease-free survival rate of rPNET is about 45% to 55%.[14] The overall survival in patients who had localized rPENT was longer than that in the patients who had rPENT with regional nodes or distant metastases.[15] The preferred treatment for rPENT is surgical resection associated with chemotherapy and radiotherapy treatment. The role of radiotherapy is not clear, but it may be advocated in locally advanced disease and involvement of Gerota's fascia.[15] Post-operative chemotherapy for rPENT is usually used and can improve the prognosis of rPNET.[7] The most commonly used chemotherapeutics are adriamycin, etoposide, dactinomycin, vincristine, cyclophosphamide, and ifosfamide.[714] A multimodality management is recommended.