Primary Pancreatic Undifferentiated Pleomorphic Sarcoma

ABSTRACT Primary pancreatic sarcomas are rare malignancies with an incidence of 0.1%. This case report is of a 48-year-old man who presented with this condition. The patient's treatment plan consisted of distal pancreatectomy and splenectomy with intraoperative immunohistochemistry and adjuvant chemotherapy. To correctly identify and treat undifferentiated pleomorphic sarcoma, a stepwise strategy involving cross-sectional imaging and extensive histopathology analysis is necessary.


INTRODUCTION
Abdominal pain is a common presenting symptom of pancreatic malignancy related to neurovisceral irritation. 1 Primary pancreatic sarcomas with an incidence of 0.1% often present with abdominal pain. The term "sarcoma" refers to a diverse group of malignancies that originate in the soft tissues and bones. We report a case of high-grade, undifferentiated pleomorphic sarcoma (UPS) of the pancreas.

CASE REPORT
A 48-year-old man presented to the emergency department with nonradiating, left lower quadrant abdominal pain for 2 days. The pain was aggravated by ingestion of food and accompanied by low-grade fever, malaise, loose stool, and 10 lbs. weight loss over 3 months. He denied nausea, emesis, melena, jaundice, recent trauma, infections, travel, alcohol, or drug or non-steroidal anti-inflammatory drug use. His family history was notable for prostate and colon cancer in his father. He was found to have tachycardia, but no hypotension or fever. His weight was 77 kg (169 lb 12.8 oz), and body mass index was 22.4 kg/m 2 . Physical examination revealed tenderness in the left lower quadrant without a palpable mass. Laboratory examination revealed the patient to present with neutrophilic leukocytosis (14.3 thou/mcL); microcytic, hypochromic anemia (hemoglobin 11.1 gm/dL, hematocrit 35.2%, mean corpuscular volume 24.3 pg); and elevated HbA1C (7.1%). The patient's liver profile revealed elevated alkaline phosphatase (245 U/L), and elevated alanine transaminase (58 U/L). CA 19-9 was normal. An abdominal computed tomography (CT) scan with intravenous contrast revealed a 6.8 cm complex cystic pancreatic mass suspicious for malignancy with mild pancreatic duct dilatation seen within the tail of the pancreas (Figure 1). Abdominal magnetic resonance imaging (MRI) showed a 9.2 cm macrolobulated mass involving the pancreas without local extension or metastasis. On MRI, the pancreatic tail was identified to have upstream atrophy with ductal dilatation, which continued to the ventral pancreatic level. Positron emission tomography-CT (PET-CT) showed a large fluorodeoxyglucose-avid centrally necrotic pancreatic mass without metastasis. Subsequent endoscopic ultrasound revealed a round mass identified in the pancreatic body. The mass was hypoechoic and heterogeneous and not completely cystic but not completely solid in nature. The mass measured 65 by 49 mm in maximal cross-sectional diameter with well-defined endosonographic borders. An intact interface was seen between the mass and the celiac trunk suggesting a lack of invasion. The endosonographic appearance of parenchyma and the upstream pancreatic duct indicated duct dilation and parenchymal atrophy. The pancreatic duct measured 2.4 mm in the head, 4.4 mm in the body, and 3.2 mm in the tail. Fine-needle biopsy of the mass was performed, which demonstrated malignant spindle cells. Immunohistochemistry (IHC) performed on this specimen was unable to characterize the neoplasm's lineage, being negative for antibodies directed against CKAE1AE3, CD163, synaptophysin, CD117, CD34, CD31, SMA, S-100, and SOX-10. In a patient with an intrapancreatic mass of this morphology without involvement of the retroperitoneum or lymph nodes, the differential diagnosis remained broad but included sarcomatoid carcinoma or sarcoma.
He underwent distal pancreatectomy and splenectomy (Figures 2 and 3). Intraoperative frozen section showed a highgrade, predominantly spindled but focally epithelioid malignancy ( Figure 4). Subsequent IHC was negative for multiple epithelial markers, including epithelial membrane antigen, broad-spectrum keratin cocktails (AE1/AE3 and OSCAR), and high molecular weight keratin (34betaE12) This combination of clinical, histomorphologic, and immunophenotypic features yielded a diagnosis of undifferentiated pleomorphic sarcoma. The mass measured 10.5 cm in the greatest dimension, and surgical margins were negative. He underwent adjuvant chemotherapy with 4 cycles of doxorubicin/ifosfamide. Surveillance with chest/abdominal/pelvic CT every 3 months was recommended. His most recent follow-up imaging obtained 15 months after therapy completion showed no pancreatic ductal dilatation, normal pancreatic parenchyma, and no cystic of arterially enhancing pancreatic lesions. Moreover, there was no evidence of recurrent or metastatic disease in the abdomen. The patient had an unremarkable clinical examination at follow-up and remained under a surveillance protocol for 4 additional months. The entire length of follow-up was 24 months from the time he presented to the emergency department until the present time.

DISCUSSION
Primary UPS is an exceptionally rare subtype of pancreatic sarcoma. 2 Pancreatic sarcomas are aggressive and are often associated with poor prognosis. 3 The first case of pancreatic UPS was reported in 1986, which had good outcome with only distal pancreatectomy and splenectomy without radiotherapy or chemotherapy. 4 Ambe et al and Feather et al described cases of pancreatic sarcoma noting that they are more commonly seen in younger individuals and more frequently involve the pancreatic tail and the body. 3,5 Similarly, our case involved a relatively young individual with the tumor localized to the pancreatic body. Pancreatic sarcomas are usually large in size and present with abdominal pain, nausea, vomiting, and weight loss. These features were present in our case. 2 An English-language literature   search revealed 20 cases of UPS with a very similar clinical presentation as our patient (Table 1). Of the 20 cases that we found in the English literature, 11 presented primarily with abdominal pain and 4 presented abdominal pain as an associated symptom to the discomfort or other diagnosis.
There are 2 main hypotheses regarding the genesis of primary UPS of the pancreas. The first hypothesis is that these tumors are not a distinct entity, but rather a common morphologic pattern that many neoplasms share. As tumors become more undifferentiated, this shared morphologic pattern perhaps implies a common development pathway of malignancy. Under this hypothesis, UPS can arise from sarcomas and carcinomas. The second hypothesis is that UPS results from malignant transformation of mesenchymal stem cells that do not show differentiation markers at the outset.
UPS can mimic many entities and is essentially a diagnosis of exclusion. 2 UPS may clinically mimic any mass-forming lesions of the pancreas such as autoimmune pancreatitis, tuberculosis, sarcoidosis, and other malignancies. Likewise, they can histomorphologically mimic many high-grade carcinomas or sarcomas based on which features predominate in a given tumor. By definition, they do not diffusely express any characteristic immunophenotype, so IHC serves mainly to exclude other entities which enter the clinical or morphologic differential. For example, in our case, IHC chiefly served to exclude sarcomatoid carcinoma, gastrointestinal stromal tumor, neuroendocrine carcinoma, angiosarcoma, leiomyosarcoma, and melanoma. Genetic alterations are common in pancreatic carcinomas/ sarcomas, and molecular testing may reveal amplification of SAS, MDM2, CDK4, DDIT3, and HMGIC. 6 Mutations of the genes TP53, RB1, and CDKN2A also play a role in UPS growth. 2 Multimodal treatment with chemotherapy, radiofrequency ablation, and surgery improves the prognosis and survival of patients with primary pancreatic UPS. 7 The chemotherapy regimen in our case was recommended based on histology and currently existing data on adjuvant chemotherapy in soft-tissue sarcoma. Primary pancreatic sarcomas are not common and given the heterogeneity of primary sarcoma location; decision making regarding systemic therapy is largely driven by histology. UPS is one of the most common soft-tissue sarcomas, thus routinely included in clinical trials assessing the utility of treatment. Prospective studies assessing the role of adjuvant chemotherapy using anthracycline with ifosfamide (EORTC 62931) have failed to show an overall survival advantage and thus is not considered a standard of care for all patients. 8 However, the National Comprehensive Cancer Network guidelines recommends adjuvant chemotherapy may be considered in some cases. 9 Reassessment of data from EORTC 62931 for those considered to have high-risk disease or a 10year predicted probability of overall survival , 51% based on the Sarculator risk stratification nomogram noted improvement in risk of recurrence (hazard ratio [HR] 0.46) and risk of death (HR 0.46). 10 Using the Sarculator nomogram for our patient, he was deemed to have very high risk of recurrence (estimated 7-year overall survival of 39% and 7-year diseasefree survival of 14% using one of our nomograms). Therefore, we recommended anthracycline-based chemotherapy. Most of the cases in Table 1 describes middle-aged men with pleomorphic malignancies in the body and/or tail of the pancreas who did well with surgery. Despite the reported similarity of the cases, an evidence base to inform management of this malignancy is lacking because of its rareness. A stepwise approach with cross-sectional imaging and biopsy is important to appropriately diagnose and manage UPS.