A patient with chronic hepatitis C and a pancreatic mass in endoscopic ultrasound.

We report a rare case of pancreas tumor (lymphoma) in a patient with a history of chronic hepatitis C virus (HCV) infection without treatment, with a high viral load (20,199,805 IU/ml). He presented with abdominal pain, jaundice, weight loss and sweating. Computed tomography showed a hypodense mass located in the head of the pancreas, and immunohistochemistry of a specimen obtained by endoscopic ultrasound-guided fine needle aspiration revealed non-Hodgkin's lymphoma of the pancreas, B cell type. An association of HCV infection with pancreatic lymphoma has only been reported rarely in the literature and its clinical significance is uncertain.

Introduction

Primary pancreatic lymphoma (PPL) is extremely rare, comprising 2.2% of non-Hodgkin's lymphomas (NHLs) and 4.9% of all pancreatic malignancies [1]. Clinical manifestations and imaging findings of PPL are similar to adenocarcinoma, but PPL must be distinguished from it because unlike pancreatic adenocarcinoma, PPL is potentially treatable [2, 3, 4]. Hepatitis C virus (HCV) infection has been associated with the development of B cell NHL (including diffuse large B cell lymphoma, marginal zone lymphoma and extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue) [5, 6, 7, 8, 9]. An association of hepatitis C and hepatic and splenic marginal zone lymphoma has been reported [7, 10], however its association with pancreatic lymphomas is unknown. We report a case of pancreatic lymphoma with HCV infection.

Case Report

The patient was a 49-year-old man admitted to the hospital with the complaint of epigastric abdominal pain, icterus, significant weight loss, fever and sweating since 1.5 months prior to admission. He had a history of chronic HCV infection without treatment. He had no history of smoking or alcohol consumption.

On admission, blood pressure was 120/80 mm Hg, pulse rate was 88 bpm and temperature was 37.9°C. Physical examination revealed icteric sclera and mild tenderness in the epigastric abdomen. Hemoglobin level was 14 g/dl with a leukocyte count of 5,400/mm3 (neutrophils 57%, lymphocytes 35%) and a platelet count of 245,000/mm3. Aspartate aminotransferase was 85 U/l, alanine aminotransferase 105 U/l, total bilirubin 12 mg/dl, direct bilirubin 8 mg/dl, alkaline phosphatase 735 U/l, serum lactate dehydrogenase (LDH) 725 IU/l and serum carbohydrate antigen 19-9 (CA19-9) 25 U/ml. HCV genotype was 1a and viral load was 20,199,805 IU/ml.

Abdominal ultrasound showed a hypoechoic mass adjacent to the head of the pancreas and the common bile duct was dilated with a diameter of 12 mm. Computed tomography (CT) of the abdomen showed a hypodense mass located in the head of the pancreas (fig. ). Chest X-ray was normal. Endoscopic ultrasound (EUS) showed a 3 × 3 cm mass in the head of the pancreas with portal invasion, and fine needle aspiration (FNA) was performed (fig. ). Endoscopic retrograde cholangiopancreatography was performed and showed dilated common and hepatic bile ducts, thus a metallic biliary stent was placed. Bone marrow aspiration and biopsy was performed and its pathologic examination was normal.

Microscopic pathologic examination was done on cell block specimen and reported a malignant undifferentiated tumor (fig. ); immunohistochemistry of the specimen revealed positive leukocyte common antigen in tumor cells (fig. 3b), diffuse and strong membrane staining for the B cell marker protein CD20 (fig. 3c), scattered CD3 in nontumoral lymphocytes and negative cytokeratin in tumoral cells (fig. 3d), compatible with NHL of the pancreas, B cell type. We started Peg-interferon plus ribavirin and the patient was referred to radiotherapy.

Fig. 3

Microscopic pathologic examination and immunohistochemistry of the pancreas tumor specimen (magnification ×400): a EUS-FNA cytology showing malignant undifferentiated tumor. b Positive leukocyte common antigen in tumor cells. c Diffuse and strong membrane staining for the B cell marker protein CD20. d Scattered CD3 in nontumoral lymphocytes and negative cytokeratin in tumor cells compatible with NHL of the pancreas, B cell type.

Discussion

PPL is extremely rare, comprising 2.2% of NHLs and 4.9% of all pancreatic malignancies [1]. PPL can be confounded with pancreatic adenocarcinoma [2, 3]. In a study by Mishra et al. [11] based on the Surveillance, Epidemiology, and End Results database, 523 cases of PPL were identified. The median age range at diagnosis was 65–69 years. The most common histologic type was diffuse large B cell lymphoma. The head of the pancreas is the most common location. T cell lymphomas are very uncommon [3, 12, 13]. Presenting symptoms are nonspecific, including abdominal pain, weight loss, jaundice, nausea and vomiting [1, 4, 13, 14]. This 49-year-old man presented with abdominal pain, weight loss, jaundice, fever and sweating. Systemic B symptoms are uncommon in pancreatic lymphoma [4, 13], but this patient had B symptoms.

CT is the most common imaging method for the detection of PPL. The combination of a bulky localized tumor in the pancreatic head without significant dilatation of the main pancreatic duct strengthens a diagnosis of pancreatic lymphoma over adenocarcinoma. The presence of calcification or necrosis is a reliable finding for ruling out NHL [15, 16]. Our reported case had none of the above-mentioned imaging findings.

EUS can visualize pancreatic tumor dimension and anatomic location in relation to surrounding structures. EUS-guided fine needle biopsy of tumors can also be performed and provide a histological diagnosis of PPL in some cases [17]. EUS-guided FNA (EUS-FNA) of pancreatic masses is as accurate as CT/ultrasound-guided sampling and surgical biopsies [18], and immunocytochemistry examination of the specimen can improve the accuracy of EUS-FNA cytology [19].

In this case, microscopic examination of EUS-FNA of the pancreas mass did not provide a definite diagnosis, but immunohistochemistry was compatible with B cell NHL. CA19-9 is usually normal and sometimes slightly elevated [20, 21]. LDH is a useful marker for the diagnosis of PPL and also an important prognostic factor. PPL should be suspected in a patient with pancreatic mass and elevated LDH and b2 microglobulin serum markers [13, 22]. In this case serum CA19-9 was normal and serum LDH was high.

This case met the criteria for the definition of PPL as used by Dawson et al. [23]. These criteria include: (1) neither superficial lymphadenopathy nor enlargement of mediastinal lymph nodes on chest radiography; (2) a normal leukocyte count in peripheral blood; (3) main mass in the pancreas with lymph node involvement confined to the peripancreatic region; (4) no hepatic or splenic involvement.

The etiology of PPL is unknown. Epstein-Barr virus can contribute to the development of lymphomas. Stomach mucosa-associated lymphoid tissue lymphoma is known to be caused by Helicobacter pylori; no such association with PPL is known to date. Familial pancreatic lymphoma has also been reported to be associated with pancreatic lymphoma [13, 24, 25]. A causative role of HCV in B cell lymphoproliferative disorders has been suggested by several reports [5, 6, 7, 8, 9]. In a study by Mizorogi et al. [26], among 123 patients with B cell lymphoproliferative disorders, 38 patients with non-B cell lymphoproliferative disorders and 516 patients with miscellaneous diseases, the prevalence of HCV infection was higher in patients with B cell NHL than in those with non-B cell NHL and the control group.

Despite these strong associations, an association of HCV infection with pancreatic lymphoma has only been shown by few reports. Takagi et al. [9] in Japan reported a case of pancreas lymphoma with chronic hepatitis C. Visco et al. [27] in Italy analyzed 156 previously untreated consecutive HCV-positive patients with diffuse large B cell lymphoma observed from 1994 to 2004. The spleen was the most frequently involved extranodal site, followed by liver and stomach. They observed one case of pancreas lymphoma.

The reason of association between HCV and lymphomas is uncertain. Lymphoproliferation induced by HCV may occur due to binding of the virion to receptors on the surface of B lymphocytes, which might lower their threshold for antigen response or induce DNA mutations [28]. In patients with HCV infection and splenic marginal zone NHL, treatment of HCV infection leads to regression of NHL [10]. Moreover, HCV infection can directly drive lymphoproliferation [29].

In a large study by Giordano et al. [30] among military veterans infected with HCV, they found a 20–30% increased overall risk of NHL. HCV infection was associated with an increased risk of cryoglobulinemia, supporting the hypothesis that chronic HCV infection serves as an immunological stimulus for progression to hematological malignancy.

Our patient had a high HCV viral load and he did not have other risk factors for lymphoma, therefore HCV infection may have played a role in the pathogenesis of lymphoma. Because of the patient's high viral load and probability of hepatitis exacerbation after chemotherapy initiation, we started Peg-interferon plus ribavirin and he was initially referred to radiotherapy and then chemotherapy was started. More research is needed to clarify the relationship between HCV and PPL.