Pancreatitis and Probable Paraneoplastic Cholestasis as Presenting Manifestations of Pancreatic Lymphoma in a Child

Abstract

INTRODUCTION Lymphomas are the third most common malignancy in childhood. Although they may involve extranodal organs (1), the pancreas is rarely a primary site. Lymphomas comprise less than 0.7% of pancreatic malignancies and primary pancreatic lymphoma represents only 1% of all non-Hodgkin lymphomas (2,3). Cholestasis as a paraneoplastic phenomenon is equally unusual. Although idiopathic, intrahepatic cholestasis has been reported in a wide range of neoplasms, including renal cell carcinoma (4), lung cancer (5) and Hodgkin and non-Hodgkin lymphomas (6,7), it remains a very rare occurrence. A better understanding of cholestasis as a paraneoplastic phenomenon has followed the identification of tumor synthesized proinflammatory cytokines that have both direct and indirect deleterious effects on biliary secretion. We present a 10-year-old boy admitted to our institution with anaplastic large T cell lymphoma of the head of the pancreas who presented with acute pancreatitis. During his hospital stay, progressive jaundice and dilatation of the large bile ducts required biliary stenting. Despite stenting, however, cholestasis worsened and responded only to radiotherapy and chemotherapy. CASE REPORT A previously healthy 10-year-old boy developed anorexia, intermittent shoulder and back pain, epigastric pain, vomiting and a pruritic, erythematous, maculopapular rash on his arms and legs. There was no history of fever, diarrhea, generalized pruritus, dark urine or acholic stools. On physical examination, he was afebrile and anicteric. Vital signs were normal. His weight was greater than the 95% for age and his height was greater than the 50% for age. Mild epigastric tenderness was elicited on palpation without rebound or guarding. The liver and spleen were not palpable. The initial complete blood count included a white blood cell count of 11.5 × 109/L, a hemoglobin concentration of 10.6 g/dL and a platelet count of 330,000/mm3. The differential white cell count was normal. The stool was guaiac negative. The serum albumin concentration was 4 g/dL, and the total bilirubin concentration was 0.7 mg/dL with a direct fraction of 0.2 mg/dL. The serum aspartate aminotransferase and alanine aminotransferase were 104 U/L and 183 U/L, respectively (normal ranges, 12-38 and 7-41 U/L). The alkaline phosphatase was 358 U/L (normal range for age, 100-390 U/L) and the gamma glutamyl transpeptidase was 432 U/L (normal range, 9-58 U/L). The serum amylase was 75 IU/L and lipase 199 U/dL (normal range, 20-96 IU/L and 3-43 U/dL). The serum lactate dehydrogenase was 192 U/L (normal range, 115-221 U/L). His admitting diagnosis was pancreatitis and he was treated with intravenous fluids and complete restriction of oral intake. An abdominal ultrasound (Fig. 1) revealed a mass-like lesion in the head of the pancreas and a cavernous transformation of the portal vein but no splenomegaly (13.1 cm in its greatest dimension). An abdominal computed tomographic (CT) scan showed an edematous head and uncinate process of the pancreas, collateralization of veins in the region of the porta hepatis and a small amount of ascites (Fig. 2). There was no pancreatic or biliary ductal dilation. A central venous line was placed and intravenous nutrition was instituted.FIG. 1: Abdominal ultrasound. Note pancreatic head mass and cavernous transformation of the portal vein.FIG. 2: CT scan of abdomen. Conforming enlargement of pancreatic head and collateralization of the portal vein.Despite bowel rest and analgesics, his abdomen remained tender and became distended. Fever developed with temperatures to 102°F. The serum amylase and lipase values peaked on hospital day 14 (408 IU/L and 1980 U/dL, respectively). From hospital days 14 to 28, as the serum amylase and lipase gradually decreased, serum transaminases and bilirubin concentrations steadily increased. A magnetic resonance image of the liver and pancreas (Fig. 3) revealed homogenous enlargement of the pancreatic head without a focal enhancing mass. There was mild dilation of the left intrahepatic ducts and the pancreatic duct with distension of the gall bladder. An attempt to perform endoscopic retrograde cholangiopancreatography failed because of gastric outlet obstruction and compression of the duodenum by the pancreatic head. During the next month, he gradually developed tachypnea, anasarca and ascites. A spiral CT of the chest showed no pulmonary emboli but did reveal calcified perihilar and peritracheal nodes and a large effusion in the right hemithorax.FIG. 3: MRCP of abdomen. Gallbladder is distended. Pancreatic duct and left intrahepatic ducts are dilated.One month after his admission transhepatic cholangiography was successful in demonstrating both the right and left biliary systems. Cholangiography revealed ectasia of the intrahepatic ducts and diffuse narrowing of the central portion of the left main hepatic duct with similar generalized narrowing of the common hepatic and common bile ducts (Fig. 4). Bilateral biliary drainage catheters were placed and allowed to drain externally by gravity. Under ultrasound guidance, a chest tube was placed and the large right-sided pleural effusion was drained. Amylase concentration of the pleural fluid was 10 IU/L and the lactate dehydrogenase was 277 U/L. Cytological examination revealed lymphocytes and a few mesothelial cells but no neoplastic cells. Pancreatic and liver biopsies were obtained at this time.FIG. 4: Transhepatic cholangiogram. Common bile duct is dilated and intrahepatic ducts are dilated.The liver biopsy revealed features compatible with acute large bile duct obstruction and ascending cholangitis. Pancreatic biopsies showed an anaplastic large T-cell lymphoma with ALK-1 positivity. Subsequently, bone marrow aspirate and biopsy, CSF cell count and cytology and bone scan were negative normal. Despite patent bile ducts demonstrated on two subsequent CT scans and a cholangiogram performed 2 weeks after drain placement (Fig. 5), and despite external biliary drainage of over 500 cc/d, the serum bilirubin continued to increase, peaking at 40.3 mg/dL (direct 19.3 mg/dL); the aspartate aminotransferase and alanine aminotransferase increased to the 200-400 U/L range and the gamma glutamyl transferase peaked at 290 U/L. A liver biopsy obtained 1 month thereafter revealed persistent marked intrahepatic cholestasis with feathery degeneration of hepatocytes. Evidence of cholangitis had resolved and there was substantial diminution of the portal inflammatory infiltrate.FIG. 5: Cholangiogram following biliary drain placement. A two-week follow up cholangiogram following internal/external drain placement revealed a patent common bile duct and resolution of intrahepatic ductal dilation.The dramatically increased total and direct bilirubin began to decline 3 weeks after the initiation of pre-phase chemotherapy with dexamethasone and cyclophosphamide. The anasarca, ascites and abdominal pain also slowly resolved. Chemotherapeutic options remained limited because of the patient's persistent elevation of serum bilirubin. He therefore received localized radiation therapy, followed by high-dose methotrexate with leucovorin rescue. After high-dose methotrexate, the total bilirubin decreased to approximately 9-10 mg/dL (direct bilirubin, 4-5 mg/dL). Multiagent chemotherapy was then continued based on ACLC-99, an international protocol for the treatment of anaplastic large-cell lymphoma. For 3 months therapy was limited to dexamethasone, ifosfamide, cyclophosphamide and high-dose methotrexate with leucovorin rescue, as these agents are not excreted through the hepatobiliary system. Four months after initiation of therapy, the serum bilirubin was normal and treatment was completed, employing the previous agents with additional etoposide, vinblastine and doxorubicin. During episodes of fever and neutropenia, he experienced transient increases in total and direct bilirubin, which resolved with treatment of infection and/or resolution of febrile neutropenia. Biliary drains were removed 9 months after diagnosis, and all subsequent CT scans have shown normal bile ducts without dilatation or obstruction. His most recent CT scans have shown persistence of the apparent portal venous malformation and a mildly enlarged spleen (14 cm). He completed chemotherapy and was in complete remission 18 months after treatment. DISCUSSION Anaplastic large-cell lymphoma is an uncommon type of non-Hodgkin lymphoma, accounting for 2% to 8% of all lymphomas. It is typified by expression of the CD30 antigen and large neoplastic cells. In approximately 80% of cases, anaplastic large-cell lymphoma has also been shown to display the t (2,5) translocation. The product of this gene is the NPM-ALK fusion protein. These tumors are generally T cell or null cell proliferations (8). Anaplastic large-cell lymphoma is particularly rare in the pediatric population (13). Unlike pancreatoblastoma (22), the most common pancreatic tumor in childhood and adolescence, lymphomas of the pancreas account for less than 0.7% of all pancreatic malignancies and 1% of non-Hodgkin lymphomas (3,9). Malignant lymphomas of the pancreas are generally large and often invade surrounding tissue, making it difficult to decide whether the pancreas is the primary site (10). A pancreatic mass is more likely to be a lymphoma if it is >6 cm, if lymphadenopathy is present adjacent to the mass and if splenomegaly and other signs of lymphoma are noted (11). The location of the tumor in the pancreas is not helpful in differentiating carcinoma from lymphoma. The average age of patients with pancreatic carcinoma is in the seventh decade. In childhood and adolescence a lymphoma is a much more likely, albeit still rare, malignancy in this site. Pancreatic lymphomas involve the head of the gland in 53% of cases. At presentation according to one survey, 75% had abdominal pain, 50% had weight loss, 42% had jaundice, 54% had a palpable mass, 20% had fever and 20% had night sweats (11). Most are B-cell tumors, although four cases of T-cell lymphoma of the pancreas have been described (11,12). Pancreatitis is rarely the presenting symptom of pancreatic lymphoma. In reported cases it has not been clear whether the tumor arose from the pancreas itself or from surrounding bowel (9). A recent report describes a 14-year-old boy with pancreatic non-Hodgkin lymphoma who presented with pancreatitis (2). This patient, like ours, had several weeks of abdominal pain and clinical and biochemical evidence of pancreatitis, hyperbilirubinemia and elevation of serum transaminases. He also had dilated bile ducts. Ultrasound and CT scan revealed global pancreatic enlargement with intrapancreatic masses and a dilated pancreatic duct. Masses were also found in both kidneys. Renal and pancreatic masses were highly malignant B-cell non-Hodgkin lymphomas (diffuse large cell). The prognosis for patients with pancreatic lymphoma is better than for those with pancreatic carcinoma. Because choice of therapy depends upon the specific cell type involved, histologic evaluation of tumor in any large pancreatic mass is essential. Studies of pediatric patients with anaplastic large-cell lymphoma report survivals of 57% to 90%. The prognosis is poorer in patients with visceral (including lung, liver or spleen) involvement, mediastinal involvement, skin lesions or central nervous system disease at diagnosis. There are insufficient cases to comment specifically on the impact of pancreatic involvement. However, we would assume the outcome is similar to those with visceral disease (13-17). Lymphoma must be included in the differential diagnosis of any child with a pancreatic mass. A tissue diagnosis before surgical resection is mandatory. Surgical approaches to pancreatic lymphomas are not clearly defined, although some reports favor gastric or biliary bypass with chemotherapy. Total pancreatectomy is not recommended and carries great morbidity (18). In view of the systemic nature of lymphoma in childhood and adolescence surgery without chemotherapy should not be considered in childhood lymphoma. This case describes a child with what we suspect was a paraneoplastic cholestasis associated with a lymphoma of the pancreas. His persistent hyperbilirubinemia in the face of adequate drainage without bile duct dilation and the resolution of jaundice with radiation and chemotherapy all support our suspicion that the patient's cholestasis was metabolic rather than obstructive and probably related to lymphoma-associated cytokines. Proinflammatory cytokines such as tumor necrosis factor alpha and interleukin-1 beta have recently been shown to down-regulate bile salt transporters (19,20), and these cytokines may be produced by malignant lymphomas (21).