Extraosseus Ewing's Sarcoma in Pancreas: A Review

Primitive neuroectodermal tumors (PNET, previously referred to as peripheral neuroepithelioma) are rare malignant tumors with various degrees of differentiation belonging to the Ewing’s family of sarcomas. They are classified as round cell tumors arising from soft tissues. In rare instances, PNETs may arise from solid organs containing neuroendocrine cells of kidney, bladder, heart, lungs, parotid glands and pancreas. Most cases occur in the second decade of life with a slight preponderance in males. PNET of the pancreas is an aggressive tumor with multiple recurrences and a relatively poor prognosis. These tumors should be considered in the differential diagnosis, especially in a diagnosed pancreatic tumor in individuals less than 35 years of age. Due to the nature of the tumor, surgery with subsequent chemoradiation are widely accepted modalities despite the poor prognosis. In this article, we review 25 cases of extraosseous Ewing’s sarcoma (ES) of the pancreas which to the best of our knowledge, enlists most cases reported in the literature thus far.


Introduction And Background
Ewing sarcoma is a poorly differentiated, aggressive, malignant, round cell tumor without cellular or structural differentiation more commonly diagnosed in children younger than ten. It is the second most common malignant bone tumor in children, after osteosarcoma. The incidence of Ewing sarcoma is 1 per million for people of all ages in the United States and has remained unchanged for 30 years [1]. It is most common in Caucasians, and less frequently seen in Asians and African Americans [2,3] The clinical entity of PNET was identified by Stout in 1918, initially seen in the peripheral nerves [3]. Tefft described the extraosseous form of Ewing's sarcoma (EES) in 1964. PNETS have also been found in other sites such as the kidney, urinary bladder, uterus, gallbladder, lung, and vagina, and vulva [4][5][6][7][8][9]. Peripheral primitive neuroectodermal tumors rarely arise in organs and it is extremely uncommon for PNETs to originate in the pancreas. Batsakis et al. divided the PNET family of tumors into the following three groups, based on the origin of the tissuecentral nervous system tumors including primitive neuroectodermal tumors in the brain and spinal cord, tumors derived from the autonomic nervous system called neuroblastomas, and tumors originating outside the central and autonomic nervous system called Peripheral primitive neuroectodermal tumors (PPNETs) [4].
The ES/PNET family also includes several other related clinicopathologic neoplastic entities such as malignant small-cell tumors of the thoracic pulmonary region (Askin's tumor, described by Askin in 1979), paravertebral small-cell tumor, atypical ES, PNET of bone, and extraosseous ES. These neoplasms exhibit a neural phenotype, express the MIC2-protein (CD99) and display the same chromosomal translocation t (11; 22) (q24; q12) in about 85% of the cases and hence, can be helpful in diagnosis and have a prognostic value [1,2] PNETs usually originate in soft tissues and bone. Luttges, et al. found that only two cases among 600 primary pancreatic neoplasms were pancreatic PNETs [9]. The tumor is of insidious onset and patients usually have no specific clinical symptoms. The most common presentation of an extraosseous tumor is a rapidly growing mass associated with localized pain. The diagnosis of peripheral primitive neuroectodermal tumors of the pancreas encompasses clinical symptoms, pathological characteristics, immunohistochemical features, and molecular genetic analysis. Complete surgical resection followed by radiation and chemotherapy is the currently accepted treatment, although the prognosis remains poor due to the highly aggressive nature of this cancer [7]. Chemotherapeutic regimens that have been used in various combinations include vincristine, cyclophosphamide, actinomycin D and doxorubicin. The prognosis of the extraosseous sites of PNETs is poor due to the delay in diagnosis, and also due to the age of the patient, tumor bulk, location and the highly aggressive nature of the tumor [10] .

Review
This literature review talks about Pancreatic Ewing's Sarcoma (ES/PNET). In total, 25 cases have been reported in the literature to our knowledge. From the review of the 25 cases, we observed that ages ranged from 2 years to 60 years while the average age was around 23 years. No significant sexual predominance was identified in the literature review (13 male patients and 12 female patients). The most common symptoms reported were abdominal pain (68%), jaundice (20%), nausea (16 %), and anemia (16 %). Endocrine disorders such as hyperglycemia and precocious puberty were accompanied in some cases [11] . Ten patients out of 25 had documented chromosomal translocations t(11; 12) (q24; q12). The most common site for peripheral PNET was the head of the pancreas with the size ranging from 3.5 cm to 11 cm.
Abdominal CT and MRI are the two most common modalities to visualize pancreatic tumors, with MRI being the more sensitive imaging study. Tan et al. reported that the radiographic characteristics of the lesion have an isodense or hypodense on unenhanced CT, isointense on T1WI, and can be either isointense or hyperintense on T2WI as revealed by MRI [12]. Pancreatic tumors have ill-defined borders and irregular shapes with heterogeneous enhancement. Due to necrotic areas within the tumor, variable densities have been noticed on the CT scan of the abdomen. Although there is no close relationship 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 into the surrounding organs and metastasis may be seen [13][14][15].
Gene studies have shown that the fusion of the FLI1 gene on chromosome 11 and the ERG gene on chromosome 22 to be associated with PNES. The products of the fusion genes resulting from the translocations are specific to the type of tumors. In reports of ES/PNETs, there are eight cases in which chromosome translocation is t (11;22) (q24;q12) while three cases had t (21;22) (q22; q12). Loss of cosmids F7 and E4 distal of the EWS-R1 breakpoint in nearly all cells was noted in one case [5,10,[16][17][18][19][20] .
ES is an undifferentiated tumor lacking neural differentiation in the primitive cells. However, some tumors have cells with neural differentiation in the form of Homer-Wright rosettes. Histologically, there is a presentation of small round blue cells in the form of monotonous sheets with hyperchromatic nuclei and scant cytoplasm [16]. All 25 cases in this review meet these histologic criteria. The tumor consists of extensive necrotic areas with viable tissue usually preserved around blood vessels [18][19][20][21]. A known marker for the diagnosis of PNET are p30/32MlC2 [20]. Nonspecific monoclonal antibodies like CD99, O13, HBA71, 12E7, RFB1 were also tested, although none of them are specific for PNETs [21]. Neural markers like Neuron Specific Enolase (NSE), Chromogranin A (CgA), Synaptophysin (Syn) can also be positive [22][23][24].
There are no definite guidelines for the pathological criteria for the diagnosis of the peripheral PNETs. The combination of clinical signs and symptoms such as abdominal pain with an abdominal mass, jaundice, vomiting, dyspepsia, pathological characteristics like sheets of small round blue cells with hyperchromatic nuclei and scant cytoplasm; immune-histochemical features stained positive for CD99, O13, HBA71, 12E7, RFB1 and neural markers like Neuron Specific Enolase (NSE), Chromogranin A, Synaptophysin; cytogenetic analysis for MIC-2 gene and t [11;22] [q24; q12] suggest a 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 is the cell cytoplasm containing neuronal secretory granules, neurofilaments, and pyknic nucleus granules [25,26]. From our present review, neural markers were positive for NSE (10/25 cases), synaptophysin (2/25 cases) and vimentin (6/25 cases).
Differential diagnoses that are considered based on histomorphology are 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, desmoplasia is noticed in the cellular phase which resembles the soft tissue in ES. The tumor cells are positive for Creatine kinase (CK) and desmin [8]. The tumor often stains positive for neuroendocrine markers such as synaptophysin, CD56, and chromogranin. There have been five reported cases of pancreatic PNETs with local recurrence, three cases with lung metastasis and one case with bone metastasis [27][28][29][30].
Surgical resection with chemoradiation is the widely accepted treatment protocol for PNETs. The commonly used chemotherapeutic agents include doxorubicin, cyclophosphamide, vincristine, actinomycin-D, ifosfamide, and etoposide. A randomized study by Grier et al. compared treatment with three drug regimen (VDC: vincristine, doxorubicin, and cyclophosphamide) versus a five-drug therapy (VDC plus ifosfamide, and etoposide). Subsequently the five drug regimen was established as the gold standard for treatment of PNET's [20]. Dactinomycin is no longer used in the United States but continues to be used in the Euro-Ewing studies. Increased dose intensity of doxorubicin during the initial months of therapy was associated with an improved outcome in a meta-analysis done prior to the standardization of ifosfamide and etoposide. Radiation therapy has a role in those patients with residual disease after surgery and chemotherapy. Hyperfractionated radiation therapy has not shown to be of any extra benefit; whereas proton-beam radiation therapy and intensitymodulated radiation therapy (IMRT) treatment seem to be promising but lack randomized data.
The main treatment of the disease from our review was surgery along with chemotherapy with or without adjunctive radiotherapy. 18 out of 25 patients received chemotherapy after surgery. Five out of 25 patients had multiple recurrences after combined surgery and chemotherapy.
There is only a little-reported data on the prognosis and survival of these patients who have ES/PNETS. Improvements in the detection of PNETs and their early surgical removal has had a 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 the liver or unresectable tumor. Advancing age, advanced stage tumors, non-functioning tumors and those with rapid growth generally have poor outcomes. In patients with advanced PNETs with metastasis, the development of new therapeutic options that arrest tumor growth and progression have shown to be promising [7,29,30,31,32,33,34]. From our review, 4 out of 25 cases died with the disease within the range of 6 months to 50 months from the time of diagnosis while one died with postoperative complications. The rest were alive with or without disease, with some having multiple metastasis and recurrences.

Conclusions
PNET is an aggressive malignant tumor with unavoidable recurrences. Our review of 25 reported cases of PNET till date indicates that from the lack of concrete diagnostic pathological criteria, it is easy to misdiagnose PNET. In cases of pancreatic tumors, it is necessary to highlight the importance of considering ES/PNET early on in the differential diagnosis for improved prognosis and better longevity.