Primitive neuroectodermal tumours (PNET) are small round cell tumors that originate from the cells of the primitive neural crest. It was first coined for a group of embryonal tumors located in the central nervous system (cPNET) such as medulloblastoma, pineoblastoma and cerebral neuroblastoma. More recently, the PNET concept has been expanded to include histologically similar, peripherally located tumours, referred to as peripheral PNET (pPNET). Although pPNETs can occur in numerous solid organs such as the kidney, ovary, vagina, testis, uterus, cervix, urinary bladder, parotid gland, heart, lung, rectum and pancreas, it is an extremely rare tumor entity, one case of splenic carcinoid had been described previously (1) and 12 reported cases involving the pancreas (2).
We report a case of pPNET involving the spleen and the tail of the pancreas in a 7 year old boy who presented with a rapidly enlarging painful mass at the left hypochondriac region.
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A 7 year old boy presented to a private hospital with underlying history of abdominal pain, progressive left upper quadrant distention and pain for 3 months after taking food, associated with loss of weight and appetite. The child was previously well, full term normal delivery with uneventful antenatal and post natal history. Clinical examination revealed a firm mass at the left upper quadrant of the abdomen. His blood hemoglobin, total white cell count, renal and liver profile were unremarkable.
A contrast enhanced CT scan was performed, which showed a large encapsulated heterogeneously enhancing mass measuring 14.8 x 12 x 16.7cm with areas of necrosis adjacent to the splenic hilum, pushing the splenic parenchyma into a thin rim. No clear fat plane was seen between this mass and the spleen There is also no clear margin between this mass and the tail of pancreas (Figure 1 and 2). This mass was displacing the left kidney downwards and the left adrenal gland was seen at the medial aspect with no clear fat plane between the mass and the adrenal (Figure 3). The stomach is pushed supero-medially and the bowel loops are displaced to the right and inferiorly. No evidence of distant metastases was seen. Based on the CT findings a diagnosis of a large left adrenal mass was made and biopsy performed in that hospital revealed peripheral neuroendocrine tumour.
He was referred to our centre with a diagnosis of PNET of left adrenal gland for further management. Re-biopsy of the mass in our centre also stated as PNET. He underwent elective laparoscopy converted to laparotomy, left thoracotomy, splenectomy, distal pancreatectomy and repair of the left diaphragm. Intra-operative findings were a large splenic tumour measuring about 16 x 14 x 10cm adherent to the tail of pancreas and left hemi-diaphragm with normal left kidney and adrenal gland. Macroscopically the specimen demonstrated tumour at the splenic hilum, well demarcated from the splenic parenchyma causing flattening of the splenic parenchyma into a thin rim. It was firm and had a nodular yellow orange cut surface. Histopathological examination of the lesion revealed sheets and clusters of uniform malignant cells, separated by desmoplastic fibrous tissue. The cells were arranged mainly in insular and acinar pattern. The cells showed mildly pleomorphic vesicular nuclei. A broad pushing edge with the splenic parenchyma was seen. The malignant cells were positive for MNF-116, synaptophysin and chromogranin. Mucicarmine and PAS/diastase were negative. These findings concluded the tumour as PNET involving the splenic hilum and tail of pancreas.
Post-op was uneventful apart from developing left pleural effusion on day 2, which was drained with chest tube. He underwent 4 cycles of chemotherapy up to date. Follow-up CT scans was done, which did not show any residual tumour or recurrence, neither evidence of distant metastasis.
Figure 1: Coronal reformatted image showing a large heterogeneously enhancing tumour with areas of necrosis at the region of splenic hilum (black arrows), pushing the splenic parenchyma into a thin rim (white arrows).
Figure 2: Axial image showing the head and body of pancreas (black arrows) and the porto-splenic confluence (white star) No clear demarcation is seen between this tumour and the tail of pancreas.
Figure 3: Coronal reformatted image showing the tumour displacing the left kidney
downwards (black arrow). The black star pointing to the left adrenal gland and the white arrow showing the spleen.
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PNET form a subset of the "small-round-cell tumors" in childhood that comprise lymphomas, neuroblastoma and soft tissue sarcomas including rhabdomyosarcomas. Peripheral PNET (pPNET) have been further classified into neuroendocrine carcinoma and carcinoid. Neuroendocrine carcinoma is a malignant epithelial neoplasm characterized by high mitotic activity, a high metastatic rate, and poorer prognosis. However, carcinoid tumors tend to show a low-grade malignancy characterized by rare mitosis, slow growth, and good prognosis (1). Peripheral PNET was first described by Stout as a tumor of the ulnar nerve with the gross features of a sarcoma but composed of small round cells focally arranged as rosettes in 1918(2). pPNET makes up approximately 1% of all sarcomas (2).
Clinical symptoms depend on the site of presentation but invariably present with a rapidly enlarging often painful mass as was seen in our patient. At times of diagnosis, 25-50% of PNETs present with metastatic disease, and metastases spread rapidly to the lung, lymph nodes, liver, and bones (4). Most PNETs are well to moderately differentiated and can be classified as those associated with a clinical syndrome caused by excessive hormone production (functional PNETs) or those without such an association (nonfunctional PNETs). Carcinoid syndrome is uncommon, occurring in only 0.3%-10.0% of patients with all carcinoid tumors(1).
Imaging wise these tumors are commonly large and show heterogeneous enhancement with internal hemorrhage and necrosis as also was present in this case. They might be locally aggressive with vascular invasion and invasion of adjacent organs. Sometimes these tumors may show internal septations or calcification. Although the imaging appearance of peripheral PNETs is nonspecific, these tumors should be considered in the differential diagnosis when a large mass with aggressive features are encountered. Differentiation between benign and malignant PNETs can be difficult, although the presence of local invasion of adjacent organs or distant metastasis usually indicates malignant behavior. Hence a stepwise preoperative imaging evaluation for PNET localization is very important for potentially curative surgery (6).
The diagnosis of PNET necessitates histopathological and immunohistochemical analysis. The gross appearance of the excised tumor may be pale and soft with central necrosis. PNET show a high expression of the cell surface glycoprotein MIC2 (also named CD99) which is considered to be important in cell adhesion (2-4). However, other neoplasms as well as normal tissue including pancreatic endocrine tumors, pancreatic islet cells tumors, T lymphoblastic lymphomas, poorly differentiated synovial sarcomas, stromal tumors and rare rhabdomyosarcomas may express express the MIC2 protein, thus limiting specificity of the test (2-6).
Many tumors in the PNET spectrum show immunohistochemical evidence of neuroectodermal differentiation to varying degrees. Besides MIC2 (CD 99), immunohistochemical positivism for neural markers - neurofilament, synaptophysin, chromogranin, NSE, protein gene product 9.5 (PGP 9.5), Leu 7 - are more specific for neural differentiation (1-7). To name a tumor as PNET, it should display rosette formations, and should be positive for at least two of the neural markers. We diagnosed the tumor in the present case to be a PNET based on its characteristic insular and pseudorosette patterns, low mitotic activity, and its reactivity to both synaptophysin and chromogranin
Once PNET is diagnosed, the standard treatment is a systemic multi-agent chemotherapy combined with surgery and/or radiotherapy. Tumor dissemination at the time of diagnosis is associated with a poorer outcome compared to localized disease (2,3). In previously reported series the 5-year survival rate ranges from 61% to 77% (2). Intensive preoperative multi-agent chemotherapy may further improve the prognosis of these tumors (8).
In conclusion, PNET involving the spleen and pancreas is an extremely rare tumor and mainly affects children or young adults. As a rule PNETs are highly aggressive but early chemotherapy, immediate surgical interventions and close follow-up lead to regression and prolongation of the survival period.
The most significant prognostic factor is the presence or absence of metastatic disease, with the former group of patients having a dismal long-term prognosis. In the absence of metastases wide resection of the primary tumour shows excellent prognosis as seen in our patient. Significant advances in the chemotherapeutic regimens, as well as improved facility in diagnosing these tumors through imaging, cytogenetic and immunohistochemical analysis, should improve long-term disease-free survival.