INTRODUCTION

Ewing’s sarcoma/primitive neuroectodermal tumour (ES/PNET) is an unusual malignant neoplasm. In rare cases, PNETs may arise in solid organs that contain neuroendocrine cells. James Ewing first described Ewing’s sarcoma (ES) in 1921, while the extra osseous Ewing’s sarcoma or PNET was first described by Tefft in 1969.^1,2 ES/PNET comprises four sub-types: peripheral primitive neuroectodermal tumour (pPNET), Ewing’s sarcoma of bone (ESB), Askin’s tumour, and extraosseous Ewing’s sarcoma (EES). ES/PNET has been reported in several case reports and series with unusual sites such as the salivary glands, oral cavity, adrenal gland, jejunum, pericardium, lung, stomach biliary tract, kidney, heart, prostate, cervix, vagina, gonads, uterine corpus, and pancreas.³ Here, we report a rare case of ES/PNET in the pancreas of a 51-year old woman with synchronous carcinoma cervix. Reporting on such a rare form will help us in improving the characterization of the pathology, while contributing to cancer treatment advancement. In the future, it will also serve as guidance in the treatment of such rare cases.

CASE PRESENTATION

A 51-year-old female presented to our hospital in July 2018 with a history of vaginal bleeding accompanied with leukorrhea. She also complained of lower back pain.

Her speculum examination showed an ulceroproliferative growth over the cervix which bled on touch. Computed tomography (CT) revealed a large 7x6.8x6.6 cm mass lesion involving lower uterine segment and upper vagina with multiple iliac nodes. A biopsy was carried out. The patient was diagnosed with squamous cell carcinoma of the cervix (Figure 1A). On immunohistochemistry, tumour cells showed strong nuclear positivity for P40 (Figure 1B).

The patient completed concurrent radiotherapy (50 Gray in 25 fractions) along with five cycles of cisplatin. The patient also received three fractions of intracavitary brachytherapy.

Magnetic resonance imaging (MRI) was performed on routine follow-up after two months. A regression in the previously visualized cervical lesion was noted. There was a resolution of the previously mentioned pelvic nodes. A well-defined altered signal intensity heterogeneously enhancing tissue lesion measuring 58x44x50mm in size arising from the tail of the pancreas was noted. The possibility of a second primary of neoplastic origin rather than a metastatic one was suspected.

A whole body PET-CT scan showed a large FDG avid mass involving the tail of pancreas with metabolically active left para-aortic nodes just below the level of left renal hilum [maximum standardized uptake value (SUV_max): 12.7].

Tumour markers, CA-19.9 and carcinoembryonic antigen (CEA test) were tested to rule out pancreatic adenocarcinoma and were found to be within normal limits. Fine needle aspiration cytology (FNAC) was positive for malignant cells.

The patient underwent laparoscopic distal pancreatic splenectomy. Gross analysis of the specimen showed a pancreatic segment of 13x12x7.5 cm infiltrated by a vague nodular grey mass measuring 6.2x5.5x4 cm at the tail end.

On histology, the tumour showed diffuse sheets of round cells (Figure 2A). The tumour cells exhibited small round cells with a large central nucleus and scanty cytoplasm. (Figure 2B). The tumour cells showed minimal nuclear pleomorphism. Brisk mitosis was noted.

On immunohistochemistry, these tumour cells showed perinuclear dot-like positivity for Pan-CK (Figure 2C); CD99 (Mic-2) showed cytoplasmic membranous positivity (Figure 2D), and Fli-1 showed strong nuclear staining (Figure 2E). Immunohistochemically, the cells were negative for CD-56, Desmin, LCA, AR, ER, Cyclin D1. Hence the diagnosis of Ewing/ PNET was made. 

The patient had received one cycle of vincristine, doxorubicin (Adriamycin), and cyclophosphamide (VAC) and one cycle of ifosfamide and etoposide (IE). The patient is scheduled for three cycles of VAC and three cycles of IE followed by radiation therapy with vincristine. The patient is currently doing well.

DISCUSSION

PNETs comprise nearly 1% of all sarcomas with an estimated five-year survival rate of 50%.^4-7 PNETs have been reported to develop in solid organs, although this is rare. In some cases, PNETs have been found arising from the pelvis, thoracopulmonary region, and the lower limbs of children and young adults.⁶ In organs that contain neuroendocrine cells such as the pancreas, PNETs are extremely rare and account for only 0.3% of all primary tumours.^8,9 To the best of our knowledge, there are only a few pancreatic ES/PNET cases seen with synchronous tumours reported in the literature.^1-20 Herein, we present the first synchronous case of PNET with a squamous cell carcinoma of the cervix.

Patients with such neoplasms are often asymptomatic or have a poorly symptomatic course even in advanced stages, as observed in our case.^8,9

ES/PNET is comprised of small round cell tumours, morphologically. They are poorly differentiated tumours. There are several entities that have small round cell morphology such as desmoplastic small round cell tumour (DSRCT), lymphoma, extra-adrenal neuroblastoma, pancreatic endocrine tumour (PET), visceral small cell neuroendocrine carcinoma (SCNC), extra-renal Wilm’s tumour, and pancreatoblastoma.^14-17

In terms of imaging tests, abdominal MRI and CT are the most useful in the detection of such tumours. However, their diagnosis is not easy as there are no specific patterns in the radiological findings as shown in Table 1.¹³ A histopathological test with immunohisotchemistry is required to confirm the diagnosis of ES/PNET as in our case, but it varies from case to case (Table 1).¹³

Although pancreatic ES/PNETs are an extremely rare disease, they should be considered in the differential diagnosis of the pancreatic mass panel. We also suggest that cases with pancreatoblastoma, undifferentiated small cell carcinoma, and neuroendocrine carcinomas should be investigated for ES/PNET.¹⁷ The clinical presentation of the tumour is diffuse while its histological findings are not exclusive.

In our case, the pathologic diagnosis was based on the positive immunoreactivity for CD99, Fli-1, and PAN-CK in many of the tumour cells. The diagnosis of pancreatic ES/PNET is made by a combination of clinical, pathological, immunohistochemical, and cytogenetic features. However, in our case, cytogenetic features were not taken into account due to limited resources.

Molecular analysis of translocation and cytogenetic evaluation have been a recognized and dominant adjunct for sarcoma diagnosis and classification. As per the evidence, ES/PNET demonstrate chromosomal translocations including the EWS gene on chromosome 22 and a member of the ETS family of genes. The most common translocation include t (11; 22) (q24; q12) that results in the fusion product EWS-FLI1 which is observed in 85%–95% of cases.⁷ The second most common translocation is t (21; 22) (q22; q12) which is observed in nearly 5%–10% of cases.⁷

The standard treatment of PNET involves the use of systemic multi-agent chemotherapy along with surgery and/or radiotherapy.¹² Poor outcomes are associated with tumour dissemination in comparison to a localized disease at the time of diagnosis.¹²

In conclusion, Ewing’s sarcoma/PNET of the pancreas is a rare pancreatic malignancy. To the best of our knowledge, this is the first case of Ewing’s sarcoma synchronously diagnosed in a patient with carcinoma cervix. Round cell tumours of the pancreas can be diagnosed as lymphomas, neuroendocrine carcinomas or PNET. Thus, a combination of histology and immunohistochemistry is required to differentiate PNET from other round cell tumours of the pancreas. We think that our case may contribute to the literature for this rare and unusual entity.

ACKNOWLEDGEMENTS

The authors would like to thank Dr. Yasam Venkata Ramesh from HCG Manavata cancer center, Center for difficult cancers (CDC), Nashik, India, for his medical writing assistance.

MAIN POINTS

• Ewing’s sarcoma/primitive neuroectodermal tumor (ES/PNET) is an unusual malignant neoplasm.

• ES/PNET synchronous with carcinoma cervix is extremely rare and reporting it can help in improving the characterization of the pathology, while contributing to the cancer treatment advancement.

ETHICS

Informed Consent: There is informed consent of patient for this case report.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Concept: R.P., S.G., R.N., Design: R.P., S.G., Y.V.R., R.N., Supervision: S.G., R.N., Data Collection and/or Processing: R.P., S.G., Y.V.R., R.N., Analysis and/or Interpretation: R.P., S.G., Y.V.R., R.N., Literature Search: Y.V.R., Writing: Y.V.R., Critical Review: R.P., S.G., R.N.

DISCLOSURES

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The author declared that this study had received no financial support.