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  Table of Contents    
Year : 2021  |  Volume : 64  |  Issue : 5  |  Page : 184-187
Primary non hodgkin lymphoma and Ewing's sarcoma/PNET: Two rare pancreatic round cell tumors with diverse clinical outlook

1 Department of Nuclear Medicine and Bone Densitometry, Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India
2 Department of Histopathology, Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India

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Date of Submission20-Sep-2019
Date of Decision16-Oct-2019
Date of Acceptance09-Mar-2020
Date of Web Publication7-Jun-2021

How to cite this article:
Bakshi N, Dhawan S, Bhalla S, Verma R. Primary non hodgkin lymphoma and Ewing's sarcoma/PNET: Two rare pancreatic round cell tumors with diverse clinical outlook. Indian J Pathol Microbiol 2021;64, Suppl S1:184-7

How to cite this URL:
Bakshi N, Dhawan S, Bhalla S, Verma R. Primary non hodgkin lymphoma and Ewing's sarcoma/PNET: Two rare pancreatic round cell tumors with diverse clinical outlook. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Dec 1];64, Suppl S1:184-7. Available from: https://www.ijpmonline.org/text.asp?2021/64/5/184/317921

Dear Editor,

A vast majority (85–90%) of pancreatic malignancies are adenocarcinomas arising in exocrine glands, followed by pancreatic endocrine tumors (<5%).[1] Primary pancreatic lymphoma and Ewing's sarcoma/primitive neuroectodermal tumor (PNET) are exceedingly rare tumors comprising less than 0.5% and 0.3% of all pancreatic neoplasms, respectively.[2],[3],[4] Herein, we present a report of two patients with these rare tumors.

Case history

Case 1

A 64-year-old female patient presented with a 2-month history of passing dark, tarry stools, with intermittent dull aching pain in the epigastrium. Contrast-enhanced computed tomography (CECT) abdomen revealed a well-defined lobulated homogenously enhancing mass lesion involving the pancreaticoduodenal area closely abutting the D2 segment of the duodenum [Figure 1]a. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) from the lesion yielded scant lymphoid aspirate and was nondiagnostic. Gross examination of the resected Whipple's pancreaticoduodenectomy specimen showed a solid, fleshy tumor in the head of the pancreas measuring 7 × 5 cm [Figure 1]b, with infiltrating margins replacing most of the preexisting pancreatic parenchyma as well and ulcerating the overlying duodenal mucosa. Microscopic examination revealed the tumor to be composed of loose discohesive sheets of medium to large-sized atypical lymphoid cells [Figure 1]c. The cells had hyperchromatic, round to oval nuclei with clumped nuclear chromatin, small to prominent nucleoli and scant eosinophilic cytoplasm [Figure 1]d. Brisk mitosis and areas of necrosis were seen. The tumor was infiltrating the wall of the common bile duct as well as the overlying duodenum with ulceration of the mucosal epithelium. Twenty-six regional lymph nodes were free of tumor and showed reactive hyperplasia. Tumor cells were diffusely positive for LCA, CD20, and CD79a [Figure 1]e. CD3 [Figure 1]f, CD5, CD10, BCL2, and BCL6 were negative. Ki67 proliferation index was 45–50%. CK, synaptophysin, chromogranin, vimentin, and desmin were also negative ruling out other differential diagnoses. A final impression of Non-Hodgkin's lymphoma showing diffuse large B-cell lymphoma (DLBCL) pancreas was rendered.
Figure 1: A panel of photographs depicting: (a) CECT abdomen showing a well-defined lobulated homogeneously enhancing soft tissue density mass lesion involving the pancreaticoduodenal area. (b) Gross image showing an infiltrating tumor in the head of the pancreas with a fleshy grey-brown cut surface replacing most of the pancreatic parenchyma. (c) Loose discohesive sheets of medium to large-sized atypical lymphoid cells [HE × 10×]. (d) Tumor cells have hyperchromatic, round to oval nuclei with clumped nuclear chromatin, small to prominent nucleoli and scant eosinophilic cytoplasm [HE × 40×]. (e) Tumor cells are diffusely positive for CD20 [IHC, 20×]. (f) Tumor cells are negative for CD3 [IHC, 20×]

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Case 2

A 17-year-old girl presented with yellowish discoloration of sclera and itching with loss of weight and appetite for 2 months. Positron emission tomography-computed tomography (PET/CT) scan revealed a large lobulated mildly DOTA-NOC-avid mass lesion in the head and uncinate process of pancreas, closely abutting and compressing the common bile duct (CBD) and 2nd and 3rd part of duodenum [Figure 2]a. A clinico-radiological impression of neuroendocrine tumor/solid pseudopapillary neoplasm of pancreas was made and the patient underwent Whipple's pancreaticoduodenectomy with regional lymph node resection. Grossly, a 7.5 × 5.5 cm tumor in the head of the pancreas with infiltration into the wall of duodenum, was seen. Microscopic examination of the tumor showed uniform small round cells arranged in loosely cohesive sheets around delicate vascular channels, trabeculae, and focal organoid pattern [Figure 2]b. The cells had enlarged round to oval nuclei, fine stippled chromatin, inconspicuous nucleoli, and scant eosinophilic cytoplasm [Figure 2]c. Brisk mitosis, apoptosis, and areas of tumor necrosis were observed. Tumor cells were positive for cytokeratin (CK), CD99 (membranous), and Cyclin D1 [Figure 2]d. In view of the patient's age, gender, and tumor location, multiple differential diagnoses were considered that excluded using histological features and IHC results. Solid pseudopapillary neoplasm of the pancreas was ruled out by membranous expression of beta-catenin and negativity for alpha 1 antitrypsin, CD10, and PR. The high-grade pancreatic neuroendocrine neoplasm was ruled out by negativity for synaptophysin and chromogranin. The morphological features were not characteristic of acinar cell carcinoma and the tumor was negative for alpha 1 antitrypsin. DOG1 negativity ruled out gastrointestinal stromal tumor; rhabdomyosarcoma/leiomyosarcoma was ruled out by negativity for desmin. The presentation and morphology were not characteristic of desmoplastic small round cell tumor and the tumor was negative for WT1 and desmin. Based on the morphology and the immunohistochemistry (IHC) findings, a final diagnosis of Ewing's sarcoma/PNET was rendered. Interphase fluorescence in situ hybridization (FISH) and reverse transcriptase-polymerase chain reaction (RT-PCR) using RNA extracted from the tumor confirmed translocation t(11;22)(q24;q12), typical of Ewing's sarcoma.
Figure 2: A panel of photographs depicting: (a) PET CT scan showing large lobulated mildly DOTA NOC avid mass lesion in the head and uncinate process of the pancreas (arrow). (b) A tumor composed of uniform small round cells arranged in loosely cohesive sheets around delicate vascular channels and trabeculae (HE × 10×). (c) Tumor cells having round to oval nuclei with finely stippled chromatin and inconspicuous nucleoli, scant cytoplasm and brisk mitosis (HE × 40×). (d) Diffuse membranous CD99 positivity (IHC, 10 ×)

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   Discussion Top

Non-ductal neoplasms of pancreas are rare tumors, comprising only 1%–2% cases.[1],[2],[3] However, these tumors span a wide range of histological features that need to be recognized by pathologists due to the distinctly varied prognosis of various entities in this group. This especially holds for pancreatic lymphomas which are associated with a distinctly better prognosis and may be curable even in advanced stages.

Primary pancreatic lymphoma (PPL) is defined as an extranodal lymphoma arising in the pancreas with the bulk of the disease localized to this site.[2],[3] Clinical manifestations are similar to those associated with ductal carcinoma such as abdominal pain (83%), palpable abdominal mass (58%), weight loss (50%), jaundice (37%), acute pancreatitis (12%), small bowel obstruction (12%), and diarrhea (12%).[5] Clinical manifestations commonly associated with Non-Hodgkin lymphoma (NHL) such as fever, chills, and night sweats are rare in primary pancreatic lymphoma.[6] Laboratory and radiographic findings are often nonspecific.[5],[6] EUS-FNA of the pancreas is a useful technique that may provide the diagnosis while avoiding an open surgical procedure. However, sampling and interpretation error, as well as inability to subclassify the lymphoma remain important diagnostic limitations. CT-guided or EUS-guided biopsy is another minimally invasive option for diagnosis. In a review of 269 percutaneous biopsies of pancreatic lesions with CT or ultrasound guidance, the combined diagnostic accuracy was 93%, major complications were seen in only three cases and no biopsy related death occurred.[7] In our case EUS-FNA yielded scant material composed predominantly of lymphoid cells and was nondiagnostic, necessitating surgery. Histologically, PPLs are usually of B phenotype and commonly high grade; though low-grade lymphomas such as follicle center cell and MALT lymphoma have been described.[8] Pancreatic T-cell lymphomas are exceedingly rare in western literature comprising only 4% cases, but a higher rate of 21% is reported in Japan.[8],[9] Chemotherapy and/or radiotherapy are the mainstay of treatment in PPL.[10] Surgery is often difficult in PPL because tumors are large, and often associated with an otherwise histologically normal pancreas, carrying a high risk of postoperative pancreatic fistula.[11] Therefore, the first treatment choice for PPL should be a combination of chemotherapy and radiotherapy and surgery is now preferred only when EUS guided FNA/biopsy fails to provide a preoperative diagnosis.[10],[11]

The Ewing's family of tumors (EFT) comprises a molecularly defined group of “small round blue cell tumors,” consisting of Ewing's sarcoma of bone (ESB), extraosseous Ewing's sarcoma (EES), peripheral primitive neuroectodermal tumor (pPNET), and Askin's tumor.[12] These are poorly differentiated neoplasms that arise from primitive neuroepithelial stem cells, showing morphologic, histological, immunohistochemical and ultrastructural evidence of neuroectodermal differentiation. Although these tumors seldom arise in solid organs, they have been reported in the kidney, urinary bladder, uterus, gall bladder, lung, and vagina. Metastatic spread to pancreas from Ewing sarcoma, infiltration of pancreas by a pPNET arising in the retroperitoneum, and a widely disseminated PNET of unknown primary site that involved pancreas have been reported.[12] However, pancreas is an exceedingly rare primary site for PNET, with only a handful of cases reported worldwide.[12–14] A literature review by Kumar et al. in 2016 revealed only 24 reported cases of pancreatic Ewing's/PNET, age range of 2 to 60 years (average age of 23 years).[13]

Abdominal CT and MRI are the commonly used radiological tests; however, preoperative diagnosis is difficult, as there is no pattern of radiological findings and therefore histopathology, IHC, and cytogenetic analysis are needed for a comprehensive diagnosis.[3],[13] EFTs is a prototype of the “small round cell” tumor group, composed of sheets of small cells with high nuclear to cytoplasmic ratio. IHC is essential since the family of small round cell tumors is large with considerable morphological overlap. EFTs show a membranous expression of CD99 or MIC2 and nuclear expression of FLI1 and these remain the most commonly used markers for this group of tumors, although their accuracy remains controversial.[15],[16] Depending on the degree of neuroectodermal differentiation, the tumor cells may also express neuron-specific enolase (NSE), synaptophysin, and S-100 protein. In vitro studies have shown that cyclin D1 is overexpressed in Ewing' sarcoma, while cyclins D2, D3, and E1 do similarly in rhabdomyosarcoma which is an important differential for EFTs especially in pediatric/adolescent patients.[17] Due to broad histologic differentials and lack of specific IHC markers, there is an increasing reluctance among oncologists to accept the diagnosis of EWS/pPNET without cytogenetic and molecular genetic analysis.

On cytogenetic analysis using FISH or RTPCR, Ewing sarcoma is defined by chromosomal translocations that fuse EWS (EWSR1), located at 22q12, and a gene of the ETS family of transcription factors.[18],[19] In 90% of cases, the fusion gene is EWS-FLI1, which encodes the N-terminal portion of EWS and the C-terminal portion of FLI1 (located at 11q24). The product of the gene EWS-FLI1 drives the growth of these tumors through the deregulation of transcription and apoptosis.[19] In approximately 10% of cases, the fusion gene is EWS-ERG, in which the ERG gene from 21q22 substitutes for FLI1. Rare cases of Ewing sarcoma show fusions of EWS to other ETS-family genes (such as ETV1, E1AF [ETV4], and FEV), or similar fusions of the EWS-related gene FUS (FUS-ERG or FUS-FEV).[15],[19] In our case, RT PCR using RNA extracted from the tumor was positive for EWS-FLI1 type 3 fusion transcript indicating a t (11;22)(q24;q12) translocation. Ewing's sarcoma/PNET is an aggressive tumor, with detectable metastatic disease in 25–30% cases at the time of diagnosis, most often to lung, bone, and bone marrow.[3],[20] Pancreatic PNETs reported in literature have shown local recurrence, lung and bone metastasis. Despite improved results with multimodality treatment, pancreatic PNETs are highly aggressive tumors with a dismal overall prognosis.[3],[15],[20]

In summary, we have presented two very rare pancreatic tumors with vastly different clinical outlook. A high index of suspicion with timely use of histopathology, IHC and cytogenetics can aid in early diagnosis leading to earlier treatment and improved outcome in pancreatic PNETs. Similarly, awareness among clinicians and an attempt to obtain preoperative tissue diagnosis can be vital in avoiding radical surgery in patients with pancreatic lymphoma.

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Conflicts of interest

There are no conflicts of interest.

   References Top

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Mao Y, Sang X, Liang N, Yang H, Lu X, Yang Z, et al. Peripheral primitive neuroectodermal tumors arising in the pancreas: The first case report in Asia and a review of the 14 total reported cases in the world. Hepatobiliary Surg Nutr 2013;2:51-60.  Back to cited text no. 3
Kim JY, Song JS, Park H, Byun JH, Song KB, Kim KP, et al. Primary mesenchymal tumors of the pancreas: Single-center experience over 16 years. Pancreas 2014;43:959-68.  Back to cited text no. 4
Hai L, Li SD, Hu XG, Li ZS. Primary pancreatic lymphoma: Report of six cases. World J Gastroenterol 2006;12:5064-67.  Back to cited text no. 5
Arcari A, Anselmi E, Bernuzzi P, Bertè R, Lazzaro A, Moroni CF, et al. Primary pancreatic lymphoma. Report of five cases. Haematologica 2005;90:ECR09.  Back to cited text no. 6
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Koniaris LG, Lillemoe KD, Yeo CJ, Abrams RA, Colemann J, Nakeeb A, et al. Is there a role for surgical resection in the treatment of early-stage pancreatic lymphoma? J Am Coll Surg 2000;190:319-30.  Back to cited text no. 11
Bose P, Murugan P, Gillies E, Holter JL. Extraosseous Ewing's sarcoma of the pancreas. Int J Clin Onco 2012;17:399-46.  Back to cited text no. 12
Kumar J, Agrawal S, Agarwal RK, Dayama K. A review of a rare entity in pancreas- Extraosseous ewing's Sarcoma. JOP 2016;17:574-9.  Back to cited text no. 13
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[PUBMED]  [Full text]  
Magro G, Brancatob F, Musumecic G, Alaggiod R, Parentie R, Salvatorelli L. Cyclin D1 is a useful marker for soft tissue ewing's sarcoma/peripheral primitive meuroectodermal tumor in children and adolescents: A comparative immunohistochemical study with rhabdomyosarcoma. Acta Histochemica 2015; Available from: http://dx.doi.org/10.1016/j.acthis. 2015.01.005. [Last accessed on 2019 Oct 24].  Back to cited text no. 16
Zhang J, Hu S, Schofield DE, Sorensen PH, Triche TJ. Selective usage of D-type cyclins by ewing's tumors and rhabdomyosarcomas. Cancer Res 2004;64:6026–34.  Back to cited text no. 17
Fuchs B, Inwards CY, Janknecht R. Vascular endothelial growth factor expression is up-regulated by EWS-ETS oncoproteins and Sp1 and may represent an independent predictor of survival in Ewing's sarcoma. Clin Cancer es 2004;10:1344-53.  Back to cited text no. 18
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Correspondence Address:
Shashi Dhawan
Department of Histopathology, Sir Ganga Ram Hospital, Rajender Nagar, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_730_19

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