Primitive neuroectodermal tumor of the kidney: A rare case with unusual presentation

Introduction

Primitive neuroectodermal tumors (PNETs) are malignant, small round cell tumors of neural crest origin which typically arises from bone or soft tissue in the trunk/axial skeleton/paraspinal regions in adolescents and young adults and comprises of <1% of all sarcomas. Incidence of extraosseous PNET involving genitourinary system such as kidney, bladder, epididymis, and prostate is extremely rare.^{1, 2} The diagnosis of renal PNET is based on histomorphology and immunohistochemistry, supported by cytogenetic analysis, therefore preoperative diagnosis is challenging. Multidisciplinary treatment strategies including surgery, adjuvant chemotherapy, and radiotherapy are favored. Owing to the high aggressiveness, presence of >50% cases with local recurrence and metastasis at the time of presentation lead to overall poor prognosis of renal PNET (rPNET). Ewing sarcoma (ES) and PNET represent morphologic spectrum of same disease process; however, cases with, Flexnere Wintersteiner or Homer Wright rosettes were initially diagnosed as PNET. Genetically, this tumor is characterized by recurrent chromosomal translocations of EWSR1 gene on chromosome 22, i.e. t (21;22) (q24;q12) resulting in fusion of EWSR1 (22q12) and Friend leukemia virus integration 1 (FLI1 genes 11q24) in 90–95% of rPNET/EWS.² Here we are discussing the clinical, histopathological, immunohistochemical findings and treatment outcomes of rPNET in a young male with preoperative diagnosis of clear cell type of renal cell carcinoma (RCC).

Case report

A 35-year-old male patient presented with left lower flank pain radiating to back, painless hematuria, dysuria, and weight loss and managed initially as a case of left ureteric colic. Ultrasonography of abdomen revealed bilateral renal calculus with a mass lesion at upper pole of left kidney. Contrast enhanced computed tomography (CECT) showed a hypodense lesion measuring 80 × 67 mm in upper pole of left kidney with variegated post contrast enhancement and extension into the left renal vein; a possibility of RCC with right non-obstructive renal calculi was considered. Hematological and biochemical profiles were within normal limits. The patient underwent left robotic radical nephrectomy. Gross examination of the specimen showed a lobulated, variegated tumor measuring 9.1 × 5.8 × 4 cms occupying the upper pole. Renal pelvis and left renal vein appears involved on gross. Histopathological examination revealed a tumor composed of sheets, cords of small, round, and monomorphic cells having high N:C ratio, poorly defined cytoplasmic membrane, hyperchromatic nuclei, and inconspicuous nucleoli (Fig. 1). Immunohistochemical analysis showed positivity for vimentin, CD 99, WT1, and Ki67 80–90%, while negativity for CD45, pancytokeratin, synaptophysin, and chromogranin (Table 1). A diagnosis of rPNET with involvement of renal sinus, perirenal fat, left renal vein, and two positive regional lymph nodes was confirmed (pT3aN1My: stage III). After nephrectomy, the patient started, from 29 May 2017, VAC/IE regiment adjuvant chemotherapy comprised of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide and has received 11 cycles till 16 Jan 2018. On follow-up, our patient is disease-free till now.

Fig. 1.

Photomicrographs show sheets of small monomorphic round cells on right side (arrow head) with normal renal parenchyma on left side (arrow) [a H&E 40x], Tumor cells with high N:C ratio, poorly defined cytoplasmic membrane [b, H&E 100x], Tumor cells with lymphovascular invasion (star) [c H&E 200x], Tumor cells with pseudorossete formation [d Haematoxylin & Eosin (H&E) 400x]. These tumor cells are immunopositive for CD99 [e 100x], Neuron-specific enolase [f 100x] while immunonegative for PANCK [g 100x], however Ki67 index was 80–90% [h 100x].

Table 1.

Immunohistochemical and genetic characteristics of small round blue cell tumors.

Diagnosis	CD99	FLI1	CD45	TdT	WT1	Cytokeratin	Desmin	Myogenin	Genetic alterations
ES/PNET	+	+	–	–	Rare	Rare	Rare	–	t(11;22) (q24;q12) EWS-FLI1
LBL	Variable	Variable	+	+	–	–	–	–	Numerous
WT	-/Rare	–	–	–	+	+	–	–	NA
SS	–	–	–	–	Variable/-	Variable	Rare	–	t(X;18) (p11.23;q11) SS18-SSX1
RMS	Variable	–	–	–	Variable	–	+	+	t(2;13) (q35;q14) PAX3-FKHR
NB	–	–	–	–	–	–	–	–	MYCN gene (2p24) amplification (25%)
DSRCT	Variable	–	–	–	–	+	+	–	t(11;22) (p13;q12) EWS-WT1

ES/PNET: Ewing sarcoma/peripheral neuroectodermal tumor; LBL: lymphoblastic lymphoma; WT: Wilms' tumor, SS: synovial Sarcoma; RMS: rhabdomyosarcoma; NB: neuroblastoma; DSRCT: desmoplastic small round cell tumor; TdT: terminal deoxynucleotidyl transferase; NA: Not applicable; FLI1: Friend leukemia virus integration 1.

Reference: Celli R, Cai G. Ewing Sarcoma/Primitive Neuroectodermal Tumor of the Kidney: A Rare and Lethal Entity. Arch Pathol Lab Med. 2016;140:281–5.

Discussion

Primary renal PNET was first reported by Seemayer et al in 1975.⁷ The possible etiology of rPNET is based on the theory of neural cell intussusception in the kidney during development that initiates the tumorigenesis.¹ rPNET most commonly affects young adults, with a mean age of 30.4 years and male predominance of 61%.^{1, 2} The presenting symptoms of rPNET are non-specific as noted in our patient include left flank pain, hematuria followed by dysuria, and weight loss. Laboratory parameters are mostly within normal range except altered level of lactate dehydrogenase and neuron-specific enolase. Radiological computed tomography features revealed solitary, large, lobulated, ill-defined, or heterogeneous structures with areas of hemorrhage, necrosis, and dystrophic calcification; however, no parenchyma infiltration was noted.^{3, 4} Preoperative fine needle aspiration cytology plays an important role due to advent of preoperative chemotherapy. Fine Needle Aspiration Cytology (FNAC) showed cellular smears comprising of densely dispersed, monomorphic, small round cells with round nuclei, fine nuclear chromatin, and scanty clear cytoplasm in a clean background. Many cells revealed glycogen as irregularly vacuolated cytoplasm with intense periodic acid Schiff positivity. Its diagnosis is mainly based on histopathology, immunohistochemistry (IHCs) as well as cytogenetic profile. Histomorphologically, rPNET shows nests, Homer–Wright pseudorosettes (clusters of cells with neurofibrillary stromal core), cord-like arrangements of predominantly small round cells having scanty cytoplasm, hyperchromatic, irregular nuclei, and small nucleoli. The histological pattern mimics solid acini of clear cell RCC, trabeculae of papillary RCC, and cobblestone appearance of chromophobe RCC.^{1, 2} Other histological differential diagnoses include blastema-predominant Wilms' tumor, monophasic synovial sarcoma, lymphoblastic lymphoma, neuroblastoma, clear cell sarcoma, neuroendocrine small cell carcinoma, small cell subtype of osteosarcoma, desmoplastic small round cell tumor (DSRCT), and rhabdomyosarcoma.^{1, 2} Immunohistochemical profile as diffuse membrane positivity on CD99 present in >90% of rPNET cases; however, its specificity for differentiation from neuroendocrine small cell carcinoma, Wilm's tumor, rhabdomyosarcoma, synovial sarcoma, and non-Hodgkin's lymphoma is limited where CD99 albeit weaker cytoplasmic staining is present.^{1, 2, 5} FLI-1 is a DNA-binding transcription factor that showed strong nuclear positivity in 71% of ES/PNET cases; however, its positive staining in small proportion of rhabdomyosarcomas, desmoplastic small round cell tumors, lymphoblastic lymphomas, and synovial sarcomas makes it non-specific.^{5, 6} Neuron-specific enolase (NSE) is positive in 95% of cases of rPNETs as well in most of the neuroblastoma cases.^{1, 2} Other IHCs expressed by rPNET include FLI-1, synaptophysin, S-100, Leu-7, and vimentin in 48%–70% of cases.⁷ Blastemal Wilms' tumor is seen in young age with immunopositivity of tumor cells for epithelial membrane antigen, WT1, while immunonegativity for CD99 and FLI1. Renal neuroblastoma generally occurs at age of 5 years with immunopositivity for NSE, chromogranin, while immunonegative for CD99. Rhabdomyosarcoma is more commonly present in young children who are immunopositive for desmin, myogenin, and MyoD1 while immunonegative for CD99. Lymphoblastic lymphoma is immunopositive for CD45 and other hematopoietic markers. Synovial sarcoma and DSRCT are immunopositive for Bcl2 and desmin, respectively. Chromosomal translocation t (11; 22) (q 24; q 12) can be observed in 90–95% of rPNET/EWS.² Heterogeneity in EWSR1-FLI1 fusion gene depends upon chromosomal breakpoint location. In 50% cases, type 1 rearrangement comprises of fusion of first seven exons of EWSR1 with exons six to nine of FLI1. In 25% cases, for type 2 rearrangement, there is fusion of EWSR1 to exon 5 of FLI1. As a chimeric transcription factor, EWS-FLI1 regulates downstream target genes of Sonic Hedgehog, DAX-1 (NR0B1), forkhead box proteins, cholecystokinin, lysyl oxidases, and GLI1 pathways. Other significantly altered intracellular signal transduction pathways include insulin-like growth factor receptor 1 (IGF-IR) and phosphatidylinositol-3 kinase–mTOR pathway. Primary rPNET are usually very aggressive tumors with distant metastasis to lymph nodes, lungs, liver, bone, and local recurrence in more than 50% of patients.⁸ The combination of surgery and chemotherapy is the most common therapeutic approach for the patient with rPNET. Radiotherapy in rPNET is indicated in cases with extracapsular spread of tumors/tumor residues/positive surgical margins.⁸ The overall 5-year disease-free survival rate is about 45%–55% in patients with tumors localized in the kidney.⁸ Patients with rPNET diagnosed in the advanced stage have a median relapse-free survival of 2 years.⁸ Risi et al. in their retrospective study observed the median overall survival time of 24 months (95% confidence interval 4.5–15.1).⁹ In a preclinical model of EWS, a small molecule that blocks the oncogenic protein interaction of EWS-FLI1 with RNA helicase A inhibited tumor growth.¹⁰ YK-4-279 blocks RNA helicase A (RHA) interaction with EWS-FLI1. This induces apoptosis in EWS cells and reduced the growth of EWS orthopic xenografts. IMC-A12 (cixutumumab) is a fully human IgG1 monoclonal antibody that targets IGF-IR with high affinity and antagonizes IGF-I and IGF-II ligand binding and signaling. It blocks IGF-IR pathway by effecting internalization and degradation of IGF-IR, resulting in reduction of surface receptors. rPNET is extremely rare entity with variable presentation and an aggressive behavior and should be included in differential diagnoses in younger symptomatic patients, as correct timely diagnosis has a significant impact on specific treatment strategy and prognosis.

Conflicts of interest

The authors have none to declare.