Journal of the Pancreas Open Access

Keywords

Neuroectodermal Tumors, Primitive; Pancreas; Sarcoma, Ewing

Abbreviations

ES/PNET Ewing’s sarcoma / primitive neuroectodermal tumor

INTRODUCTION

Ewing’s sarcoma (ES), a malignant osteolytic tumor, characterized as small round cell tumors was first documented by James Ewing in the year 1921 as diffuse endothelioma of bone. Rarely, it also has extra osseous manifestations which resemble intraosseous ES. This extra osseous forms of ES was first described by Tefft in 1969 [1]. Ewing’s sarcoma (ES) family of tumors include: classical ES (osseous origin), atypical ES (extra osseous), Primitive neuroectodermal tumor (PNET) and Askin tumor [2]. All these tumors have common morphology, immunophenotypic features and cytogenetics, hence included in the same family of tumors. These tumors were believed to be derived from a primitive cell. The primitive cell can be either the neural crest or mesenchymal stem cells. The definitive origin is yet to be determined [3]. ES occurs due to cytogenetic alterations – t (11:22) translocation which led to the formation of the fusion protein (EWS-FLI1). Osseous ES are more commonly found in the diaphysis of long bones of pelvis, distal femur, proximal tibia, femoral diaphysis, and proximal humerus. Rarely, ES/PNETs can also have extra osseous manifestations. Similar cases have been reported to arise from solid organs like lung, gall bladder, kidney, urinary bladder, uterus, and vagina. Extra osseous manifestation of PNETs in the pancreas is extremely rare.

DISCUSSION

We aimed to focus on Pancreatic Ewing’s Sarcoma (ES/ PNET) in this literature review. In total, only 24 cases have been reported world-wide up-to-date (Table 1). From the review of all 24 cases, we found that the age ranged from 2 years to 60 years. The average age was 23 years. There was no significant difference in the sex within these reported cases. The most common signs and symptoms of these patients were abdominal pain, jaundice, abdominal mass, vomiting, and dyspepsia. 10 patients out of 24 showed positive cytogenetic analysis t(11; 12) (q24; q12). The main treatment of the disease from our review was surgery along with chemotherapy +/- radiotherapy. 17 out of 24 patients received chemotherapy after surgery. 5 out of 24 patients had multiple recurrences after combined surgery and chemotherapy.

The incidence of Ewing sarcoma is 1 per million for people of all ages in the United States and it has remained unchanged for 30 years [4, 5]. It is most common in whites, less frequently seen in Asians [5, 6]. The occurrence of extra osseous Ewing’s Sarcoma in the Pancreas (ES/PNET) is very rare. From the world-wide literature review, only 24 cases of have been reported up to date.

The fusion partner of EWS is FLI1 gene on chromosome 11 and ERG gene on chromosome 22 in approximately 90% and 10% respectively. Rarely, many other genes from the family members of ETS have also been identified as the fusion partners of EWS [7]. According to Lin et al. 95% of cases of ES occur from EWS/FLI1 fusion gene formation as a result of transformation. Due to the difference in the locations of the EWS and FLI1 genomic breakpoints, it resulted in the existence of alternative forms of the chimeric gene. There are two most common forms, type 1 and type 2 accounting to 60% and 25% of the cases respectively. Type 1 consists of the first 7 exons of EWS joined to exons 6-9 of FLI1 and type 2 includes FLI1 exon 5 also [8]. The prognosis of type 1 fusion is significantly better prognosis than the other fusion types as observed by Lin et al. a less active chimeric transcription factor is encoded by the type 1 fusion gene explaining the heterogeneous forms of ES at the molecular level. Particular chromosomal translocations are strongly associated with the development of PNET. The products of the fusion genes resulted from the translocations are specific to the type of tumors. In ES/PNETs, karyotype of t(11;22)(q24;q12), which results from the EWS-FLII gene infusion and t(21;22)(q22;q12), which results from EWSERG gene infusion account for 85% and 10% respectively [9, 10, 11]. In reports of ES/PNETs, there are eight cases which chromosome translocation are t(11;22)(q24; q12) while three cases with t(21;22)(q22;q12) and loss of cosmids F7 and E4 distal of the EWS-R1 breakpoint in nearly all cells in one case [2, 12, 13, 14, 15, 16, 17, 18].

ES is an undifferentiated tumor lacking neural differentiation in the primitive cells, but some tumors have cells with neural differentiation as they contain Homer-Wright rosettes. The classic ES appears like that of a primitive, undifferentiated neoplasm morphologically. Histologically, there are small round blue cells in the form of monotonous sheets with hyperchromatic nuclei and scant cytoplasm [8]. All the 24 cases in this review satiate these histologic criteria (Table 1) [19, 20, 21]. The tumor consists of extensive necrotic areas but viable tumor is usually preserved around blood vessels. Some tumor cells can also invade blood vessels. Some features are absent typically like nuclear atypia, palisading, and formation of rosettes (where the tumor cells are arranged in a circle about a central fibrillary space, indicative of neural differentiation or pseudo rosettes. The markers like P30/32MlC2 and at least two kinds of neuronal markers are the immunohistochemical criteria for the diagnosis of PNET [12]. Monoclonal antibodies like CD99, O13, HBA71, 12E7, RFB1 are also tested although none of them are actually specific for PNETs [12]. The neural markers like Neuron Specific Enolase (NSE), Chromogranin A (CgA), Synaptophysin (Syn) are usually positive but markers such as desmin, actin, S-100, insulin, glucagons, somatostatin are rarely positive.

In extra osseous Ewing’s sarcoma, the mean age is 20(0- 39), male: female is 53%: 47%. Other characteristics are 85% in whites, 73% in axial primary sites, and 20% in pelvic primary sites [22]. ES clinically presents with abdominal pain with abdominal mass. They can also have associated jaundice, vomiting, dyspepsia, severe anemia, hemorrhage of the upper gastrointestinal tract, hypoglycemia (Table 1). Ewing sarcoma is not restricted to any particular location, it can occur anywhere. They may also have back pain indicating a para-spinal, retroperitoneal, or deep pelvic tumor and patients with metastatic disease often have systemic symptoms of fever and weight loss [23]. ES/PNETs do not have specific signs and symptoms different from ES in general. Head of the pancreas is the most common site for peripheral PNETs (pPNETs) and the size ranged from 3.5 cm to 11 cm (Table 1). Due to the necrotic areas in the tumor, a tumor of variable density is noticed on the CT scan of the abdomen. Although there is no close relationship of the tumors with the arteries, some tumors may have intensification in the focal areas on CT in the arterial phase. In the advanced stages of the tumor, invasion to the surrounding organs and metastasis may be seen [24].

There are no established pathological criteria for the diagnosis of the pPNETs. The combination of clinical symptoms like abdominal pain with abdominal mass, jaundice, vomiting dyspepsia, pathological characteristics like sheets of small round blue cells with hyperchromatic nuclei and scant cytoplasm; immunohistochemical features positive for CD99, O13, HBA71, 12E7, RFB1 and neural markers like Neuron Specific Enolase (NSE), Chromogranin A, Synaptophysin; and cytogenetic analysis for MIC-2 gene and t(11;22)(q24;q12) suggest the diagnosis of PNETs. Histological features and distinction from other small round cell tumors are the principle criteria for the diagnosis of PNET. In pancreatic PNETs, specific characters of PNET like Homer-Wright (H-W) rosette or atypical rosette array of the cells are rarely present under light microscopy. The important criteria for the diagnosis of ES/PNETs are the cell cytoplasm containing neuronal secretory granules, neurofilaments, and pyknic nucleus granules [12]. From our present review, neural markers were positive for NSE (10 cases), synaptophysin (2 cases), vimentin (6 cases) out of 24 cases.

Differential diagnosis based on histomorphology is ES/PNET, Desmoplastic Small Round Cell Tumor (DSRCT), Small Cell Neuroendocrine Carcinoma (SNSC) and pancreatoblastoma. The ES family of tumors consists of small monomorphic round cells histologically, with small nuclei and scant cytoplasm. The same pattern is observed in a large group of tumors. In DSRCT's, which are multicentric tumors, desmopasia is noticed in the cellular phase which resembles the soft tissue in ES. The tumor cells are positive for CK and desmin [25]. World Health Organisations defined small cell carcinomas as malignant epithelial tumors consisting of small cells with scant cytoplasm, ill-defined borders, granular nuclear chromatin, absent nucleoli with extensive necrosis, and high mitotic count [26]. The tumor often stains positive for neuroendocrine markers such as synaptophysin, CD 56, and chromogranin A. Cell to cell molding is usually seen in SCNC [25]. Pancreatoblastomas are typically solid, soft masses. When observed under the microscope, cells with “acinar” differentiation and cells forming small “squamoid” nests are noticed [27].

pPNETs are known to be extremely malignant tumors with unavoidable relapse and metastasis. There have been reported cases of metastasis to lung, liver, bone marrow, lymph nodes and other organs. There have been five reported cases of pancreatic PNETs with local recurrence [2, 12, 13, 28, 29] and three cases with lung metastasis [16, 28, 30], one case with bone metastasis [16]. High dose radiation therapy and surgical resection with chemotherapy have been present acceptable treatments for pPNETs. The acceptable forms of chemotherapy protocols that promote the efficiency of the treatment are CAV (cyclophosphamide, adriamycin, vincristine) and neoadjuvant chemotherapy (vincristine, actinomycin, adriamycin, cyclophosphamide, isophosphamide, etoposide). Radiation therapy is used with some therapeutic efficacy. There is no appropriate treatment protocol yet for these tumors and unfortunately, all of the above mentioned treatments are unsatisfactory [31].

ES/PNETs being rare, there is only a little reported data on the prognosis and survival of these patients. Improvements in the detection of PNETs and their early surgical removal had significant impact on the survival rate of these patients. From the literature, it has been observed that patients treated with surgery combined with chemotherapy were alive after 5 years of treatment in 80% of individuals. The 5 year survival rate dropped to 29% in patients with metastasis to liver or unresectable tumor. Advancing age, tumors in advanced stage, nonfunctioning tumors and those with rapid growth generally have poor outcome. In patients with advanced PNETs with metastasis, the development of the new therapeutic options that arrest the tumor growth and progression have shown to be promising [32]. From our review, 4 out of 24 cases deceased with disease within the range of 6 months to 50 months from the time of diagnosis. One case deceased with post-operative complications. Rests of the cases were alive with or without disease, with some patients having multiple metastasis and recurrences.

CONCLUSION

PNET is a very rare malignant tumor with unavoidable recurrences. Being rare, we only have 24 reported cases of PNET up-to-date from our review. Due to lack of established diagnostic pathological criteria for this tumor, it is possible to misdiagnose this tumor. Hence, in the cases of pancreatic tumors, it is necessary to highlight the importance of considering ES/PNET in the differential diagnosis. For the better management, and improved pronosis and survival of these patients, it is necessary to understand the biological characteristics of this tumor in detail.

Conflict of Interest

The authors declare that there is no conflict of interests regarding the publication of this paper.

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