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A Nonpediatric Extraosseous Ewing Sarcoma of the Pancreas: Differential Diagnosis and Therapeutic Strategies

A Nonpediatric Extraosseous Ewing Sarcoma of the Pancreas: Differential Diagnosis and Therapeutic... Hindawi Case Reports in Oncological Medicine Volume 2020, Article ID 2792750, 4 pages https://doi.org/10.1155/2020/2792750 Case Report A Nonpediatric Extraosseous Ewing Sarcoma of the Pancreas: Differential Diagnosis and Therapeutic Strategies Binoy Yohannan and Mark Feldman Department of Internal Medicine, Texas Health Presbyterian Hospital Dallas, Texas 75231, USA Correspondence should be addressed to Mark Feldman; markfeldman@texashealth.org Received 7 June 2019; Accepted 10 January 2020; Published 31 January 2020 Academic Editor: Mauro Cives Copyright © 2020 Binoy Yohannan and Mark Feldman. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Extraosseous Ewing’s sarcoma is a rare and aggressive malignant tumor with a poor prognosis. The pancreas is an extremely uncommon primary site, with only 27 cases that have been published worldwide. We report a 26-year-old female who presented with 5 days of left upper quadrant pain, nausea, and vomiting. On examination, she was anicteric and had epigastric and left upper quadrant tenderness without guarding, rebound tenderness, or a palpable mass. She had slightly elevated serum aminotransferase and lipase levels. Abdominal computerized tomography revealed a multilobulated tumor arising from the body and tail of the pancreas. A biopsy confirmed a small round cell tumor, and immunohistochemistry was positive for CD99 in approximately 70% of the tumor cells. A fluorescence in situ hybridization (FISH) assay showed a 22q12 rearrangement. She was diagnosed with extraosseous Ewing sarcoma of the pancreas and underwent multiagent neoadjuvant chemotherapy followed by surgical resection, but subsequent imaging revealed evidence of systemic disease progression. She chose to go on hospice care and died a few weeks later. 1. Introduction 2. Case Presentation The Ewing sarcoma (ES) family of tumors (ESFT) includes A 26-year-old Caucasian woman presented with 5 days of left ES of bone (ESB) and extraosseous ES (EES) [1]. ESB was upper quadrant abdominal pain, nausea, and vomiting. She first described by James Ewing in 1921 [2]. EES was first had no fever, chills, night sweats, jaundice, dysphagia, early reported by Tefft et al. in 1969 [3]. ESB is more commonly satiety, constipation, melena, hematochezia, anorexia, or seen in males, with a peak age between 10 and 20. EES is weight loss. She denied tobacco or alcohol use, radiation also most commonly seen in the second decade of life, exposure, or family history of cancer. Her vital signs were but all age groups can be affected, and there is no gender normal. She had no pallor, icterus, or lymphadenopathy. predilection [4]. Tenderness was present in the epigastrium and left upper Approximately 30% of all ESFTs are extraosseous, most quadrant without guarding, rebound tenderness, or palpable commonly arising in the soft tissues of the trunk or extrem- mass. She had normal bowel sounds. Rectal and pelvic exam- ities, but rarely in various locations in the gastrointestinal inations were negative. She had a normal complete blood tract including the biliary tree, stomach, esophagus, and oral count, coagulation profile, and inflammatory markers. Serum cavity. The pancreas is an extremely uncommon extraoss- testing revealed slightly elevated AST, ALT, and lipase levels. eous location, with only 27 cases reported worldwide [5, 6]. Computerized tomography of the abdomen with oral and We report a lethal case of cytogenetically confirmed EES intravenous contrast showed a large (10 cm × 9 cm × 7 cm) of the pancreas in a young woman who presented with multilobulated upper abdominal mass inseparable from the abdominal pain. body and tail of the pancreas, filling the lesser sac, and 2 Case Reports in Oncological Medicine (a) (b) Figure 1: CT of the abdomen and pelvis with oral and IV contrast showing a large multilobulated upper abdominal mass (arrow) inseparable from the body and tail of the pancreas (a). The tumor (10 cm × 9 cm × 7 cm) filled the lesser sac (arrow) and wrapped around the gastric fundus (b). onstrated residual ES with only 30% tumor necrosis and a continued high mitotic rate (>20 mitoses/10 HPF). Resected margins were negative for a tumor. Postoperative CT showed evidence of disease recurrences in the right diaphragmatic crus and the rectosigmoid junction. She received 3 additional cycles of adjuvant chemotherapy with vincristine, temozolo- mide, and irinotecan, but subsequent CT imaging showed metastatic disease in the liver and retroperitoneum. She chose hospice care and died a few weeks later. 3. Discussion EES of the pancreas is a rare and aggressive malignant tumor Figure 2: Histopathology with hematoxylin and eosin staining with a poor prognosis. They usually arise from the head of showing small round blue cells with hyperchromatic nuclei and the pancreas [5]. The most common sign or symptom is scant amounts of ill-defined cytoplasm (×100). abdominal pain, followed in frequency by jaundice [5]. Affected patients can present with anemia, or rarely, hyper- wrapping around the gastric fundus (Figure 1). Positron glycemia or precocious puberty [5]. When compared to the emission tomography-CT scan confirmed a fludeoxyglucose infiltrative growth pattern of pancreatic adenocarcinoma, F 18-avid pancreatic mass and showed a separate 2.2 cm left EES of the pancreas has an expansile growth pattern; it tends subdiaphragmatic nodule suspicious for metastatic disease. to present late in the disease course [6]. Histologically, there She underwent a CT-guided core biopsy of the pancreatic are small round cells (blue on H&E stain) with hyperchro- mass which showed small round cells with hyperchromatic matic nuclei and scant cytoplasm containing neuronal secre- nuclei and scant amounts of ill-defined cytoplasm (Figure 2). tory granules, neurofilaments, and pyknotic nuclear granules Immunohistochemistry was positive for CD99 (membrane [7]. These malignant cells show a high expression of single- staining pattern in approximately 70% of tumor cells), chain type-1 glycoprotein (MIC2, also called CD99) and are cytokeratin AE1/AE3, NKX2.2, CD 56, SOX10, and synap- one of the best diagnostic immunohistochemical markers tophysin. A FISH assay of tumoral tissue showed a 22q12 for this disease [8]. Other immunohistochemical markers rearrangement. A diagnosis of extraosseous ES of the pancreas include O13, HBA71, 12E7, RFB1, and neuronal markers was made. The patient then received 5 cycles of neoadjuvant such as neuron specific enolase, chromogranin A, and synap- chemotherapy with vincristine, ifosfamide, and doxorubicin. tophysin. In 90% of cases, these tumors share a unique and However, a postchemotherapy CT showed evidence of disease specific 11;22 chromosomal translocation that involves fusion progression. She then underwent laparotomy which showed a between EWS on chromosome 22 and FLI-1 on chromosome dominant retrogastric tumor mass involving 70 percent of the 11. This chimeric gene product can be detected by FISH or posterior gastric wall, a 3.5 cm separate lesion just left of the reverse transcription polymerase chain reaction. In the rest pancreatic anatomic neck, and two soft tissue pericolic lesions of the cases, there is a mutation or rearrangement in ERG adjacent to the splenic flexure. An en bloc distal pancrea- on chromosome 22 [7, 9]. tectomy with splenectomy, subtotal gastrectomy with Roux- The differential diagnosis of a small round blue cell en-Y gastrojejunostomy, and left colectomy with primary tumor includes Wilms’ tumor, neuroblastoma, hepatoblas- anastomosis were performed. Surgical histopathology dem- toma, rhabdomyosarcoma, small-cell lymphoma, visceral Case Reports in Oncological Medicine 3 with metastatic disease at the time of diagnosis [19]. Also, small-cell neuroendocrine carcinoma, desmoplastic small round cell tumor, pancreatic neuroendocrine tumor, and the existing chemotherapies are highly toxic and poorly pancreatoblastoma, with the latter four arising from the tolerated by patients. Hence, there is an unmet need for newer therapies with better clinical response and a favorable pancreas [10]. On ultrasonography, EES lesions are most frequently safety profile. hypoechoic, although anechoic areas may also be present, Pazopanib, a multitargeted tyrosine kinase inhibitor, is likely representing areas of hemorrhage or necrosis [11]. approved for the treatment of advanced soft tissue sarcomas, EES appears hypodense or isodense on noncontrast CT including EES [20]. There are few case reports of successful treatment of retroperitoneal and paravertebral EES with depending on the degree of necrosis; one-third of tumors may have calcification. On MRI, these tumors are isointense pazopanib [21, 22]. Assuming that this data can be extrapo- on T1-weighted images and either isointense or hyperin- lated to EES of the pancreas, pazopanib could provide a tense on T2-weighted images. The tumors have irregular new treatment option for patients who have failed multiple shapes with ill-defined borders and have heterogeneous lines of therapy. Furthermore, there are newer promising drugs with a novel mechanism of action that could poten- enhancement with contrast [12]. Bone metastasis can be bet- ter detected by FDG-PET rather than by bone scintigraphy, tially transform the treatment paradigm for ES in the future. whereas contrast-enhanced helical CT is superior to FDG- The EWS-FLI1 is a tumor-specific translocation seen in ESFT PET for the detection of pulmonary metastases due to the and has a great potential as a molecular target for therapy. small size of the pulmonary nodules [13]. However, EWS-FLI1 has been a very difficult target to ana- lyze in vitro due to poor solubility [23]. TK216 is a novel The diagnosis of EES is based on clinical symptoms, his- topathology, immunohistochemical features, and cytogenetic small-molecule that directly binds to EWS-FLI1 and inhibits analysis. A core biopsy of the tumor is usually sufficient for its function by blocking binding to RNA helicase A. TK216 diagnostic purposes; however, immunohistochemistry and demonstrates potent antiproliferative effects on ES cell lines cytogenetic analysis are essential to rule out other small and xenografts and is currently being tested in clinical trials [24]. Another exciting target is the enzyme lysine-specific round cell tumors listed earlier. EES is a highly aggressive tumor, and almost all patients demethylase 1 (LSD1) which is highly expressed in ES cell have occult or gross disseminated disease at the time of diag- lines, and inhibitors of LSD1 could offer a ray of hope against this lethal disease [25]. In preclinical studies, it has been nosis. Prior to the era of chemotherapy, the prognosis was dismal, but survival has improved substantially with the shown that focal adhesion kinase (FAK) inhibitors and Aurora kinase B inhibitors synergistically impair Ewing sar- advent of chemotherapy. It is crucial that affected patients are treated with a multidisciplinary approach at centers of coma cell growth and significantly inhibit tumor progres- excellence with expertise in managing these rare tumor types. sion; this treatment approach needs to be validated in clinical trials [26]. Intriguingly, in vitro studies have shown The standard treatment is systemic neoadjuvant or adjuvant multiagent chemotherapy combined with surgery and radio- that ES cells are highly sensitive to cyclin-dependent kinase (CDK) 7/12/13 inhibitors that impair DNA damage repair therapy [4, 14]. With ES being a rare tumor in adults, most chemotherapy protocols have been adapted from published in fusion-positive ES [27]. Also, CDK12/13 inhibitors and pediatric studies. Unfortunately, adult patients with ES do PARP inhibitors such as olaparib are highly synergistic in ES [27]. Ganitumab (monoclonal antibody against insulin poorly when compared to children treated with the same reg- imen. The popular chemotherapy regimen includes vincris- growth factor-1R) has been granted an orphan drug desig- nation by the FDA and is currently being investigated in tine, doxorubicin (or dactinomycin), and cyclophosphamide (VDC) [15]. Adding alternate cycles of ifosfamide and etopo- phase III clinical trials as a first-line therapy for patients side (IE) to the standard regimen significantly improves the with newly diagnosed metastatic ES (http://www.fda.gov). The other novel drugs that are being studied include a outcome for patients with localized disease but does not affect the outcome for patients with metastatic disease [16]. NEDD8-activating enzyme (NAE) inhibitor (pevonedistat), Alternately, a VDI regimen (vincristine, doxorubicin, and immune checkpoint inhibitors, and chimeric antigen recep- ifosfamide) in the neoadjuvant setting, as used in our patient, tor (CAR) T-cell therapy. followed by an adjuvant therapy based on posttreatment per- cent necrosis has a favorable outcome when compared to his- 4. Conclusion torical adult controls treated with VDC-IE [17]. Local control of disease can be achieved surgically with negative tumor Extraosseous Ewing’s sarcoma is a rare soft tissue sarcoma margins or with radiation therapy in unresectable tumors with poor prognosis. This case highlights the importance of or patients with positive tumor margins. Aggressive surgical considering EES in the differential diagnosis of a young treatment with negative surgical margins is associated with patient presenting with a pancreatic mass. Despite aggressive overall survival benefit [18]. The dose of radiation recom- therapy, the outcome remains unsatisfactory and there is an mended for EES is 45 Gy to the initial tumor volume plus a unmet need for newer therapies. 2 cm margin area, followed by a boost of 5.4 Gy to a total dose of 50.4 Gy [15]. Consent Despite these aggressive measures, the outcome of EES is unsatisfactory with an overall 5-year survival rate of 60-80% The patient’s mother signed an informed consent form to in patients with localized disease and below 30% in patients publish this case report and all related figures. 4 Case Reports in Oncological Medicine [15] L. Granowetter, R. Womer, M. Devidas et al., “Dose-intensi- Conflicts of Interest fied compared with standard chemotherapy for nonmetastatic The authors have no conflicting interest. Ewing sarcoma family of tumors: a Children's Oncology Group Study,” Journal of Clinical Oncology, vol. 27, no. 15, pp. 2536–2541, 2009. Acknowledgments [16] H. E. Grier, M. D. Krailo, N. J. Tarbell et al., “Addition of ifos- famide and etoposide to standard chemotherapy for Ewing's The authors would like to thank the Division of Hematology sarcoma and primitive neuroectodermal tumor of bone,” The & Oncology and the Pathology Department at Texas Health New England Journal of Medicine, vol. 348, no. 8, pp. 694– Presbyterian Hospital of Dallas for their help and support. 701, 2003. [17] M. J. Wagner, V. Gopalakrishnan, V. Ravi et al., “Vincristine, References ifosfamide, and doxorubicin for initial treatment of Ewing sar- coma in adults,” The Oncologist, vol. 22, no. 10, pp. 1271–1277, [1] R. Carvajal and P. Meyers, “Ewing's Sarcoma and Primitive Neuroectodermal Family of Tumors,” Hematology/oncology [18] R. B. Raney, L. Asmar, W. A. Newton Jr. et al., “Ewing's sar- Clinics of North America, vol. 19, no. 3, pp. 501–525, 2005. coma of soft tissues in childhood: a report from the Intergroup [2] J. Ewing, “Diffuse endothelioma of bone,” in Proceedings of the Rhabdomyosarcoma Study, 1972 to 1991,” Journal of Clinical New York Pathological Society, vol. 21, p. 17, 1921. Oncology, vol. 15, no. 2, pp. 574–582, [3] M. Tefft, G. F. Vawter, and A. Mitus, “Paravertebral ‘round [19] Y. Eralp, S. Bavbek, M. Başaran et al., “Prognostic factors and cell’ tumors in children,” Radiology, vol. 92, no. 7, pp. 1501– survival in late adolescent and adult patients with small round 1509, 1969. cell tumors,” American Journal of Clinical Oncology, vol. 25, [4] R. Ahmad, B. R. Mayol, M. Davis, and B. T. Rougraff, “Extra- no. 4, pp. 418–424, 2002. skeletal Ewing’s sarcoma,” Cancer, vol. 85, no. 3, pp. 725–731, [20] W. T. A. van der Graaf, J.-Y. Blay, S. P. Chawla et al., “Pazopa- nib for metastatic soft-tissue sarcoma (PALETTE): a rando- [5] P. Bose, P. Murugan, E. Gillies, and J. L. Holter, “Extraosseous mised, double-blind, placebo-controlled phase 3 trial,” The Ewing's sarcoma of the pancreas,” International Journal of Lancet, vol. 379, no. 9829, pp. 1879–1886, 2012. Clinical Oncology, vol. 17, no. 4, pp. 399–406, 2012. [21] Y. Yamamoto, M. Nozawa, N. Shimizu, T. Minami, [6] N. Nishizawa, Y. Kumamoto, K. Igarashi et al., “A peripheral K. Yoshimura, and H. Uemura, “Pazopanib for recurrent primitive neuroectodermal tumor originating from the pan- extraosseous Ewing's sarcoma of the retroperitoneum,” Inter- creas: a case report and review of the literature,” Surgical Case national Journal of Urology, vol. 21, no. 11, pp. 1183-1184, Reports, vol. 1, no. 1, pp. 1–8, 2015. [7] T. G. P. Grünewald, F. Cidre-Aranaz, D. Surdez et al., “Ewing [22] T. Alcindor, “Response of refractory Ewing sarcoma to pazo- sarcoma,” Nature Reviews Disease Primers, vol. 4, no. 1, p. 5, panib,” Acta Oncologica, vol. 54, no. 7, pp. 1063-1064, 2015. [23] A. Üren and J. A. Toretsky, “Ewing’s sarcoma oncoprotein [8] A. Rocchi, M. C. Manara, M. Sciandra et al., “CD99 inhibits EWS–FLI1: the perfect target without a therapeutic agent,” neural differentiation of human Ewing sarcoma cells and Future Oncology, vol. 1, no. 4, pp. 521–528, 2005. thereby contributes to oncogenesis,” The Journal of Clinical Investigation, vol. 120, no. 3, pp. 668–680, 2010. [24] N. Federman, P. A. Meyers, N. C. Daw et al., “A phase I, first- in-human, dose escalation study of intravenous TK216 in [9] U. Yamaguchi, T. Hasegawa, Y. Morimoto et al., “A practical patients with relapsed or refractory Ewing sarcoma,” Journal approach to the clinical diagnosis of Ewing’s sarcoma/primi- of Clinical Oncology, vol. 35, article TPS11626, 15_Supple- tive neuroectodermal tumour and other small round cell ment, 2017. tumours sharing EWS rearrangement using new fluorescence in situ hybridisation probes for EWSR1 on formalin fixed, par- [25] K. I. Pishas, C. D. Drenberg, C. Taslim et al., “Therapeutic tar- affin wax embedded tissue,” Journal of Clinical Pathology, geting of KDM1A/LSD1 in Ewing sarcoma with SP-2509 vol. 58, no. 10, pp. 1051–1056, 2005. engages the endoplasmic reticulum stress response,” Molecular Cancer Therapeutics, vol. 17, no. 9, pp. 1902–1916, 2018. [10] Q. R. Chen, G. Vansant, K. Oades et al., “Diagnosis of the small round blue cell tumors using multiplex polymerase chain reac- [26] S. Wang, E. E. Hwang, R. Guha et al., “High-throughput chem- tion,” The Journal of Molecular Diagnostics, vol. 9, no. 1, ical screening identifies focal adhesion kinase and Aurora pp. 80–88, 2007. kinase B inhibition as a synergistic treatment combination in [11] F. O'Keeffe, J. G. Lorigan, and S. Wallace, “Radiological fea- Ewing sarcoma,” Clinical Cancer Research, vol. 25, no. 14, tures of extraskeletal Ewing sarcoma,” The British Journal of pp. 4552–4566, 2019. Radiology, vol. 63, no. 750, pp. 456–460, 1990. [27] A. B. Iniguez, B. Stolte, E. J. Wang et al., “EWS/FLI confers [12] M. R. Robbin, M. D. Murphey, J. S. Jelinek, H. T. Temple et al., tumor cell synthetic lethality to CDK12 inhibition in Ewing “Imaging of soft tissue Ewing sarcoma and primitive neuroec- sarcoma,” Cancer Cell, vol. 33, no. 2, pp. 202–216.e6, 2018. todermal tumor,” Radiology, vol. 209, p. 311, 1998. [13] T. Györke, T. Zajic, A. Lange et al., “Impact of FDG PET for staging of Ewing sarcomas and primitive neuroectodermal tumours,” Nuclear Medicine Communications, vol. 27, no. 1, pp. 17–24, 2006. [14] N. P. Rud, H. M. Reiman, D. J. Pritchard, F. J. Frassica, and W. A. Smithson, “Extraosseous Ewing’s sarcoma. A study of 42 cases,” Cancer, vol. 64, no. 7, pp. 1548–1553, 1989. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Oncological Medicine Hindawi Publishing Corporation

A Nonpediatric Extraosseous Ewing Sarcoma of the Pancreas: Differential Diagnosis and Therapeutic Strategies

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Copyright © 2020 Binoy Yohannan and Mark Feldman. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Case Reports in Oncological Medicine Volume 2020, Article ID 2792750, 4 pages https://doi.org/10.1155/2020/2792750 Case Report A Nonpediatric Extraosseous Ewing Sarcoma of the Pancreas: Differential Diagnosis and Therapeutic Strategies Binoy Yohannan and Mark Feldman Department of Internal Medicine, Texas Health Presbyterian Hospital Dallas, Texas 75231, USA Correspondence should be addressed to Mark Feldman; markfeldman@texashealth.org Received 7 June 2019; Accepted 10 January 2020; Published 31 January 2020 Academic Editor: Mauro Cives Copyright © 2020 Binoy Yohannan and Mark Feldman. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Extraosseous Ewing’s sarcoma is a rare and aggressive malignant tumor with a poor prognosis. The pancreas is an extremely uncommon primary site, with only 27 cases that have been published worldwide. We report a 26-year-old female who presented with 5 days of left upper quadrant pain, nausea, and vomiting. On examination, she was anicteric and had epigastric and left upper quadrant tenderness without guarding, rebound tenderness, or a palpable mass. She had slightly elevated serum aminotransferase and lipase levels. Abdominal computerized tomography revealed a multilobulated tumor arising from the body and tail of the pancreas. A biopsy confirmed a small round cell tumor, and immunohistochemistry was positive for CD99 in approximately 70% of the tumor cells. A fluorescence in situ hybridization (FISH) assay showed a 22q12 rearrangement. She was diagnosed with extraosseous Ewing sarcoma of the pancreas and underwent multiagent neoadjuvant chemotherapy followed by surgical resection, but subsequent imaging revealed evidence of systemic disease progression. She chose to go on hospice care and died a few weeks later. 1. Introduction 2. Case Presentation The Ewing sarcoma (ES) family of tumors (ESFT) includes A 26-year-old Caucasian woman presented with 5 days of left ES of bone (ESB) and extraosseous ES (EES) [1]. ESB was upper quadrant abdominal pain, nausea, and vomiting. She first described by James Ewing in 1921 [2]. EES was first had no fever, chills, night sweats, jaundice, dysphagia, early reported by Tefft et al. in 1969 [3]. ESB is more commonly satiety, constipation, melena, hematochezia, anorexia, or seen in males, with a peak age between 10 and 20. EES is weight loss. She denied tobacco or alcohol use, radiation also most commonly seen in the second decade of life, exposure, or family history of cancer. Her vital signs were but all age groups can be affected, and there is no gender normal. She had no pallor, icterus, or lymphadenopathy. predilection [4]. Tenderness was present in the epigastrium and left upper Approximately 30% of all ESFTs are extraosseous, most quadrant without guarding, rebound tenderness, or palpable commonly arising in the soft tissues of the trunk or extrem- mass. She had normal bowel sounds. Rectal and pelvic exam- ities, but rarely in various locations in the gastrointestinal inations were negative. She had a normal complete blood tract including the biliary tree, stomach, esophagus, and oral count, coagulation profile, and inflammatory markers. Serum cavity. The pancreas is an extremely uncommon extraoss- testing revealed slightly elevated AST, ALT, and lipase levels. eous location, with only 27 cases reported worldwide [5, 6]. Computerized tomography of the abdomen with oral and We report a lethal case of cytogenetically confirmed EES intravenous contrast showed a large (10 cm × 9 cm × 7 cm) of the pancreas in a young woman who presented with multilobulated upper abdominal mass inseparable from the abdominal pain. body and tail of the pancreas, filling the lesser sac, and 2 Case Reports in Oncological Medicine (a) (b) Figure 1: CT of the abdomen and pelvis with oral and IV contrast showing a large multilobulated upper abdominal mass (arrow) inseparable from the body and tail of the pancreas (a). The tumor (10 cm × 9 cm × 7 cm) filled the lesser sac (arrow) and wrapped around the gastric fundus (b). onstrated residual ES with only 30% tumor necrosis and a continued high mitotic rate (>20 mitoses/10 HPF). Resected margins were negative for a tumor. Postoperative CT showed evidence of disease recurrences in the right diaphragmatic crus and the rectosigmoid junction. She received 3 additional cycles of adjuvant chemotherapy with vincristine, temozolo- mide, and irinotecan, but subsequent CT imaging showed metastatic disease in the liver and retroperitoneum. She chose hospice care and died a few weeks later. 3. Discussion EES of the pancreas is a rare and aggressive malignant tumor Figure 2: Histopathology with hematoxylin and eosin staining with a poor prognosis. They usually arise from the head of showing small round blue cells with hyperchromatic nuclei and the pancreas [5]. The most common sign or symptom is scant amounts of ill-defined cytoplasm (×100). abdominal pain, followed in frequency by jaundice [5]. Affected patients can present with anemia, or rarely, hyper- wrapping around the gastric fundus (Figure 1). Positron glycemia or precocious puberty [5]. When compared to the emission tomography-CT scan confirmed a fludeoxyglucose infiltrative growth pattern of pancreatic adenocarcinoma, F 18-avid pancreatic mass and showed a separate 2.2 cm left EES of the pancreas has an expansile growth pattern; it tends subdiaphragmatic nodule suspicious for metastatic disease. to present late in the disease course [6]. Histologically, there She underwent a CT-guided core biopsy of the pancreatic are small round cells (blue on H&E stain) with hyperchro- mass which showed small round cells with hyperchromatic matic nuclei and scant cytoplasm containing neuronal secre- nuclei and scant amounts of ill-defined cytoplasm (Figure 2). tory granules, neurofilaments, and pyknotic nuclear granules Immunohistochemistry was positive for CD99 (membrane [7]. These malignant cells show a high expression of single- staining pattern in approximately 70% of tumor cells), chain type-1 glycoprotein (MIC2, also called CD99) and are cytokeratin AE1/AE3, NKX2.2, CD 56, SOX10, and synap- one of the best diagnostic immunohistochemical markers tophysin. A FISH assay of tumoral tissue showed a 22q12 for this disease [8]. Other immunohistochemical markers rearrangement. A diagnosis of extraosseous ES of the pancreas include O13, HBA71, 12E7, RFB1, and neuronal markers was made. The patient then received 5 cycles of neoadjuvant such as neuron specific enolase, chromogranin A, and synap- chemotherapy with vincristine, ifosfamide, and doxorubicin. tophysin. In 90% of cases, these tumors share a unique and However, a postchemotherapy CT showed evidence of disease specific 11;22 chromosomal translocation that involves fusion progression. She then underwent laparotomy which showed a between EWS on chromosome 22 and FLI-1 on chromosome dominant retrogastric tumor mass involving 70 percent of the 11. This chimeric gene product can be detected by FISH or posterior gastric wall, a 3.5 cm separate lesion just left of the reverse transcription polymerase chain reaction. In the rest pancreatic anatomic neck, and two soft tissue pericolic lesions of the cases, there is a mutation or rearrangement in ERG adjacent to the splenic flexure. An en bloc distal pancrea- on chromosome 22 [7, 9]. tectomy with splenectomy, subtotal gastrectomy with Roux- The differential diagnosis of a small round blue cell en-Y gastrojejunostomy, and left colectomy with primary tumor includes Wilms’ tumor, neuroblastoma, hepatoblas- anastomosis were performed. Surgical histopathology dem- toma, rhabdomyosarcoma, small-cell lymphoma, visceral Case Reports in Oncological Medicine 3 with metastatic disease at the time of diagnosis [19]. Also, small-cell neuroendocrine carcinoma, desmoplastic small round cell tumor, pancreatic neuroendocrine tumor, and the existing chemotherapies are highly toxic and poorly pancreatoblastoma, with the latter four arising from the tolerated by patients. Hence, there is an unmet need for newer therapies with better clinical response and a favorable pancreas [10]. On ultrasonography, EES lesions are most frequently safety profile. hypoechoic, although anechoic areas may also be present, Pazopanib, a multitargeted tyrosine kinase inhibitor, is likely representing areas of hemorrhage or necrosis [11]. approved for the treatment of advanced soft tissue sarcomas, EES appears hypodense or isodense on noncontrast CT including EES [20]. There are few case reports of successful treatment of retroperitoneal and paravertebral EES with depending on the degree of necrosis; one-third of tumors may have calcification. On MRI, these tumors are isointense pazopanib [21, 22]. Assuming that this data can be extrapo- on T1-weighted images and either isointense or hyperin- lated to EES of the pancreas, pazopanib could provide a tense on T2-weighted images. The tumors have irregular new treatment option for patients who have failed multiple shapes with ill-defined borders and have heterogeneous lines of therapy. Furthermore, there are newer promising drugs with a novel mechanism of action that could poten- enhancement with contrast [12]. Bone metastasis can be bet- ter detected by FDG-PET rather than by bone scintigraphy, tially transform the treatment paradigm for ES in the future. whereas contrast-enhanced helical CT is superior to FDG- The EWS-FLI1 is a tumor-specific translocation seen in ESFT PET for the detection of pulmonary metastases due to the and has a great potential as a molecular target for therapy. small size of the pulmonary nodules [13]. However, EWS-FLI1 has been a very difficult target to ana- lyze in vitro due to poor solubility [23]. TK216 is a novel The diagnosis of EES is based on clinical symptoms, his- topathology, immunohistochemical features, and cytogenetic small-molecule that directly binds to EWS-FLI1 and inhibits analysis. A core biopsy of the tumor is usually sufficient for its function by blocking binding to RNA helicase A. TK216 diagnostic purposes; however, immunohistochemistry and demonstrates potent antiproliferative effects on ES cell lines cytogenetic analysis are essential to rule out other small and xenografts and is currently being tested in clinical trials [24]. Another exciting target is the enzyme lysine-specific round cell tumors listed earlier. EES is a highly aggressive tumor, and almost all patients demethylase 1 (LSD1) which is highly expressed in ES cell have occult or gross disseminated disease at the time of diag- lines, and inhibitors of LSD1 could offer a ray of hope against this lethal disease [25]. In preclinical studies, it has been nosis. Prior to the era of chemotherapy, the prognosis was dismal, but survival has improved substantially with the shown that focal adhesion kinase (FAK) inhibitors and Aurora kinase B inhibitors synergistically impair Ewing sar- advent of chemotherapy. It is crucial that affected patients are treated with a multidisciplinary approach at centers of coma cell growth and significantly inhibit tumor progres- excellence with expertise in managing these rare tumor types. sion; this treatment approach needs to be validated in clinical trials [26]. Intriguingly, in vitro studies have shown The standard treatment is systemic neoadjuvant or adjuvant multiagent chemotherapy combined with surgery and radio- that ES cells are highly sensitive to cyclin-dependent kinase (CDK) 7/12/13 inhibitors that impair DNA damage repair therapy [4, 14]. With ES being a rare tumor in adults, most chemotherapy protocols have been adapted from published in fusion-positive ES [27]. Also, CDK12/13 inhibitors and pediatric studies. Unfortunately, adult patients with ES do PARP inhibitors such as olaparib are highly synergistic in ES [27]. Ganitumab (monoclonal antibody against insulin poorly when compared to children treated with the same reg- imen. The popular chemotherapy regimen includes vincris- growth factor-1R) has been granted an orphan drug desig- nation by the FDA and is currently being investigated in tine, doxorubicin (or dactinomycin), and cyclophosphamide (VDC) [15]. Adding alternate cycles of ifosfamide and etopo- phase III clinical trials as a first-line therapy for patients side (IE) to the standard regimen significantly improves the with newly diagnosed metastatic ES (http://www.fda.gov). The other novel drugs that are being studied include a outcome for patients with localized disease but does not affect the outcome for patients with metastatic disease [16]. NEDD8-activating enzyme (NAE) inhibitor (pevonedistat), Alternately, a VDI regimen (vincristine, doxorubicin, and immune checkpoint inhibitors, and chimeric antigen recep- ifosfamide) in the neoadjuvant setting, as used in our patient, tor (CAR) T-cell therapy. followed by an adjuvant therapy based on posttreatment per- cent necrosis has a favorable outcome when compared to his- 4. Conclusion torical adult controls treated with VDC-IE [17]. Local control of disease can be achieved surgically with negative tumor Extraosseous Ewing’s sarcoma is a rare soft tissue sarcoma margins or with radiation therapy in unresectable tumors with poor prognosis. This case highlights the importance of or patients with positive tumor margins. Aggressive surgical considering EES in the differential diagnosis of a young treatment with negative surgical margins is associated with patient presenting with a pancreatic mass. Despite aggressive overall survival benefit [18]. The dose of radiation recom- therapy, the outcome remains unsatisfactory and there is an mended for EES is 45 Gy to the initial tumor volume plus a unmet need for newer therapies. 2 cm margin area, followed by a boost of 5.4 Gy to a total dose of 50.4 Gy [15]. Consent Despite these aggressive measures, the outcome of EES is unsatisfactory with an overall 5-year survival rate of 60-80% The patient’s mother signed an informed consent form to in patients with localized disease and below 30% in patients publish this case report and all related figures. 4 Case Reports in Oncological Medicine [15] L. Granowetter, R. Womer, M. Devidas et al., “Dose-intensi- Conflicts of Interest fied compared with standard chemotherapy for nonmetastatic The authors have no conflicting interest. Ewing sarcoma family of tumors: a Children's Oncology Group Study,” Journal of Clinical Oncology, vol. 27, no. 15, pp. 2536–2541, 2009. Acknowledgments [16] H. E. Grier, M. D. Krailo, N. J. 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Case Reports in Oncological MedicineHindawi Publishing Corporation

Published: Jan 31, 2020

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