Primary Non-Hodgkin Lymphoma of the Extrahepatic Biliary Tract and Gallbladder in a Child

Lymphoma constitutes the third most frequently diagnosed malignancy after leukemia and brain tumors in children younger than 15 years of age (1). Lymphoma may be associated with bile duct obstruction in several ways: nodal enlargement secondary to lymphomatous infiltration or extranodal tumor compressing the common bile duct (2), secondary infiltration of the hepatobiliary tract in the case of disseminated lymphoma narrowing the bile duct lumen (3), and paraneoplastic bile duct paucity reported to produce cholestasis in patients treated for lymphoma (4). Primary non-Hodgkin lymphoma of the extrahepatic biliary tract has rarely been recorded. A literature review revealed only 12 reported cases of patients with lymphomatous infiltration of the extra-hepatic biliary tract, the youngest of whom was a 25-year-old woman (5–15). In these cases, the diagnosis was frequently missed at the onset of the disease. Before pathological studies confirmed the diagnosis of lymphoma it was suspected that most of the patients had adenocarcinoma or primary sclerosing cholangitis. Here, we describe an unusual case of a child with a lymphoma infiltrating the extrahepatic biliary tract without extrabiliary localization. The main challenge presented by this exceptional case was the differential diagnosis suggested by the patient's clinical presentation and radiologic studies. We compare the patient's evolution with previously reported cases. CASE REPORT A 4-year-old boy who presented with fluctuating but progressive jaundice was transferred to our institution. For 6 weeks before consultation, the child reported intermittent right upper abdominal pain and nausea. During this period, his mother noticed progressive jaundice, tea-colored urine, and clay-colored stools. The patient was tired and had generalized pain and arthralgia. He did not report fever, night sweat, weight loss, pruritus, skin rash, or respiratory symptoms. His past medical and familial histories were irrelevant. He did not travel and was never in contact with patients suffering from viral hepatitis. Physical examination showed jaundice but no skin lesion. The boy's abdomen was soft with moderate sensitivity in the upper right quadrant. The left lobe of the liver was slightly enlarged, but there were no signs of portal hypertension. The spleen was not palpable and there was no lymphadenopathy. Initial laboratory examinations confirmed cholestasis, with total bilirubin of 4.3 mg/dL, direct bilirubin of 2.7 mg/dL, gamma-glutamyl-transferase (GGT) of 82 U/L (normal: 4–23 U/L), alanine-aminotransferase (ALT) of 3 U/L (normal: 5–25 U/L), and aspartate-aminotransferase (AST) of 77 U/L (normal: 5–60 U/L). The boy's erythrocyte sedimentation rate was elevated at 32 mm/h but his complete blood count, amylase, coagulation studies, and factor V results were normal. Serologic test results were negative for hepatitis A, B, and C viruses, Epstein-Barr virus, cytomegalovirus, and adenovirus. Autoantibody serologic screening results were negative. Throat and stool viral culture results were negative. Ultrasonography and abdominal CT showed a thickened common bile duct and gallbladder wall, and enlarged lumens of the intrahepatic ducts (Fig. 1 and 2). There was no lymph node enlargement or hepatic nodule. Gallium scintigraphy demonstrated radioactive tracer activity only in the region of the hepatic hilum.FIG. 1.: Ultrasonograph of the abdomen. Transverse scan at the level of the gallbladder (gb) and head of the pancreas (p) showing marked thickening of the gallbladder wall (curved arrow) and apparent enlargement of the distal common bile duct (small arrow) caused by hypoechoic infiltration surrounding the lumen (A). Longitudinal scan along the axis of the common bile duct: infiltration of the choledocal wall (small arrow) compresses the lumen (large arrow) of the distal duct (B).Figure 1: ContinuedFIG. 2.: Computed tomograph at the same level as shown in in Figure 1A. Showing marked thickening of the gallbladder (gb) wall (small arrow) and enlargement of the common bile duct (large arrow).During the following weeks, the patient's condition slowly improved. Total bilirubin decreased to 2.2 mg/dL but hepatic enzyme and erythrocyte sedimentation rates remained elevated (AST, 131 U/L; ALT, 137 U/L; ESR, 60 mm/h). A bone marrow aspirate did not show the presence of malignant cells. Exploratory laparotomy was performed. There was infiltration of the hepatic hilum and gallbladder. The tumoral process had involved all the extrahepatic biliary tract. No other mass was found. An incisional biopsy of the gallbladder wall was performed and showed marked lymphocytic infiltration. Lymphoid nodules with germinative centers were seen. Immunohistochemistry performed on paraffin sections revealed that all cells expressed leucocyte common antigen and that a portion of them expressed either a T-cell marker (UCHL-1) or a B-cell marker (L-26). Immunophenotype studies by flow cytometry could not be performed because of specimen deterioration. The final report concluded that there was massive lymphoid hyperplasia without signs of lymphoma. Two weeks after admission, the patient felt better and the decision was made to follow the evolution of his disease. One month after biopsy, the boy again reported abdominal pain, pale stools, and dark urine. His total bilirubin was 2.0 mg/dL, and hepatic enzyme levels were similar to those measured in the previous month. No CT changes were reported. A laparotomy similar to the first and a cholecystectomy were performed. Macroscopically, the gallbladder was recognizable but its lumen was severely narrowed by a markedly thickened wall (up to 1.1 cm thick). The extrahepatic biliary tract was patent but also showed thickened walls. Microscopically, a diffuse lymphoproliferative process was infiltrating the walls of the gallbladder and the cystic duct (Fig. 3A). The tumor cells had round or slightly indented hyperchromatic nuclei with small nucleoli (Fig. 3B). The tumor-cell nuclei were smaller than those of the surrounding macrophages and mitoses were numerous. Few remnants of lymphoid nodules were found.FIG. 3.: Pathology studies. Microscopic examination reveals massive lymphomatous infiltration of the gallbladder wall (A). High-power magnification (40 ×) discloses multiple tumoral nucleated cells (B). Multiple mitoses are evident with higher enlargement (100 ×). Flow cytometry shows that cells expressed HLA-DR protein without CD3 protein (C) and that cells had CD19 surface protein without CD10 protein (D).Immunohistochemistry of paraffin sections revealed that, although all cells expressed leucocyte-common antigen, few expressed a T-cell marker (UCHL-1) or B-cell marker (L-26). Immunophenotype studies by flow cytometry showed that the proliferating cells expressed CD19, CD45, and human leukocyte antigen (HLA-DR) proteins but not CD10 and CD21 surface proteins or Kappa or Lambda chains (Fig. 3C and D). These results confirmed that a lymphoblastic lymphoma of the pre-B type developed in the biliary tract of this child. Extensive work-up failed to find any other localization of the tumor. The patient was started on chemotherapy with prednisone, vincristine, doxorubicine, and methotrexate. During 18 months of treatment, he was hospitalized only for chemotherapy and isolated fever; all clinical and radiological exams failed to show a relapse of the lymphoma. His bilirubin and hepatic enzyme levels returned to normal. DISCUSSION The patient described here was hospitalized because of cholestasis of unknown cause. In most cases, history, physical examination, simple blood tests, and ultrasonography will elucidate the cause (16). Intermittent jaundice associated with a slight elevation of liver enzymes, increased direct bilirubin, and gamma-glutamyl-transpeptidase (GGT) in children suggests extrahepatic obstruction. Radiologic studies are part of the basic evaluation in such cases. In our case, computed tomography revealed an enlarged common bile duct but did not differentiate between a dilated common bile duct lumen and an infiltrated wall with collapsed lumen. Ultrasound studies provided differential diagnosis by showing a narrow lumen with thickening of the wall of the main bile ducts. From an imaging standpoint, the differential diagnosis included primary sclerosing cholangitis, histiocytosis X, inflammatory pseudo-tumor, and lymphoma. Cholangiocarcinoma of the extrahepatic biliary tract is a mucus-secreting tumor with an inflammatory reaction that can mimic the radiologic images of sclerosing cholangitis. Adenocarcinoma or cholangiocarcinoma would have been considered a possible diagnosis in an adult but is rare in children. Without histologic studies, it is difficult to establish the true nature of the lesion. Takehara et al. (13) suggest that a homogenous hypoechoic mass in the lumen of the duct is more suggestive of lymphoma; unfortunately, because of the limited number of patients with that disease, this statement cannot be confirmed or refuted. Many authors have reported the relevance of endoscopic retrograde cholangiopancreatography to complete the investigation in these cases. Biliary tract lymphoma usually shows an irregular narrowed segment of the main bile duct followed by dilated intrahepatic bile ducts. This procedure would be of little help in differentiating the causes of the infiltrative process. Consequently, surgical biopsy is the diagnostic procedure of choice. A cholecystectomy is usually necessary to provide enough material for analysis. Because primary lymphoma of the extrahepatic biliary tract is uncommon, diagnosis of frozen sections may be difficult. The first recorded patients were initially diagnosed as having chronic nonspecific inflammation (8,11), which may be confused with an inflammatory pseudo-tumor. One patient was presumed to have a nonepithelial neoplasm before final pathologic studies revealed lymphoma (10). In the present case, intraoperative frozen sections were suspected for lymphoma twice, but the first biopsy was not specific enough to confirm the malignancy. The specimen was denatured because of nonoptimal preservation and delayed preparation of the material. The lack of reliable immunophenotype studies by flow cytometry and of immunologic investigations of paraffin sections and the presence of reactive lymphoid nodules prevented a firm diagnosis of lymphoma. Because of the recurrence of symptoms, cholecystectomy was indicated. Histological tissue examination and flow cytometry then confirmed the diagnosis of lymphoma. The identification of cell-surface proteins by flow cytometry allows for better characterization of lymphoid cells. During its differentiation from pluripotent stem cell to mature B cell, a lymphoid cell acquires and loses surface proteins. In the case reported, a tumoral process was suspected because the cells expressed all the same surface proteins. Expression of CD19, CD45, and HLA-DR proteins suggest that the cells are of the lymphoid pathway, but the absence of Kappa or Lambda chains confirms that they did not reach the mature B-lymphocyte stage. The absence of CD10 and CD21 surface proteins confirmed that the proliferating cells were from a pre–B-lymphoblastic lymphoma. B-cell lymphoma is the most common type of lymphoma affecting the digestive tract. In the 12 cases reported, all lymphoma types (non-Hodgkin or Hodgkin, B cell or T cell) were found to originate from the common bile duct. Only time will permit us to determine the lymphoma type most often originating from the biliary tract. The patient described in this paper responded well to chemotherapy. Eighteen months after beginning treatment, he seemed to be free of disease. This correlates well with previously recorded cases. If left untreated, primary non-Hodgkin lymphoma of the extrahepatic biliary tract has a bad prognosis; there was lymphoma recurrence in the four cases recorded where surgery was not immediately followed by chemotherapy (6,8,11,14). Of the four patients, only two survived after chemotherapy was started. Of the seven cases initially treated with surgery and chemotherapy (the present case and (5,7,9,10,13,15)), four were disease-free at the time of publication, one was lost to follow-up, and two died in the following months. One of the two patients to die was a man with AIDS who died of a meningeal lymphoma 10 months after initial surgery (7), and the other was a patient who died of pneumonia 4 months after surgery but showed infiltrative pancreatic lymphoma at autopsy (15). These are small numbers, but most cases of primary non-Hodgkin lymphoma of the extrahepatic biliary tract appear to respond well to chemotherapy treatment after initial surgery. Evaluation of this interesting pediatric case of intermittent jaundice illustrates the differential diagnosis of extrahepatic biliary-tract–wall infiltration. Final histologic studies confirmed that primary lymphoma of the bile duct must be considered in this kind of presentation, even in the absence of other signs of tumor. Because the diagnosis is difficult to establish with simple pathologic studies, more aggressive management should be proposed. Large surgical biopsy is necessary to organize rapid and satisfactory treatment.

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