Introduction

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma (NHL), which accounts for 30–40% of NHL [1]. DLBCL can be cured with rituximab-based therapy as the first-line treatment in approximately two thirds overall and more than 50% cases even in advanced stages. The International Prognostic Index (IPI) can predict the treatment effect, which consists of age at diagnosis, serum lactate dehydrogenase (LDH) level, ECOG performance status, Ann Arbor stage of disease and number of extranodal disease sites [2]. Therefore, evaluation of solid organs or extranodal involvement is essential for prediction of prognosis.

Obstructive jaundice is a rare complication with DLBCL and seen in only 1–2% as an initial presentation [3]. The most common cause of biliary obstruction is compression of the biliary tract by enlarged lymph nodes. In such cases, the existence of bile duct invasion of lymphoma cells is rarely mentioned or proven pathologically, so the ratio of bile duct invasion to the total cases of obstructive jaundice is still unknown. Thus, the significance of bile duct invasion is not clear and might be underestimated. Here we present two cases of DLBCL presenting as obstructive jaundice due to bile duct invasion confirmed by endoscopic retrograde cholangiopancreatography (ERCP). Our cases suggest that ERCP may be useful as a diagnostic procedure and this evaluation method can elucidate the influence of bile duct invasion on the prognosis.

Case report

Case 1 is a 73-year-old male with the history of multiple hepatic and renal cysts. He was admitted to our hospital with fever and enlargement of multiple intraabdominal lymph nodes. Laboratory data revealed elevated liver enzymes [aspartate transaminase (AST) 111 U/L, alanine transaminase (ALT) 105 U/L, gamma-glutamyl transpeptidase (γGTP) 628 U/L, alkaline phosphatase (ALP) 1218 U/L, total bilirubin (T-bil) 3.0 mg/dL, direct bilirubin (D-bil) 1.8 mg/dL]. Abdominal ultrasonography showed dilatation of common bile duct (CBD) up to 14 mm. Endoscopic ultrasonography (EUS) showed distal CBD stricture due to extrinsic compression with dilated proximal CBD up to 18 mm (Fig. 1a). Endoscopic plastic stent placement released the biliary obstruction and the biopsy from the wall of CBD demonstrated the invasion of large B cells into the subepithelial connective tissue of CBD (Fig. 2a). Immunohistochemical staining of the biopsy from the wall of CBD and right cervical lymph node showed positive for CD5, CD20, CD79a, MUM1, BCL-2, BCL-6, and c-MYC. Ki-67 staining ranged from 60 to 70% in the B cells, c-MYC-positive cells accounted for 60% and BCL-2-positive cells accounted for 90% (Fig. 2b–j). The diagnosis was stage IIIE, CD5-positive, triple expression DLBCL [4]. Positron emission tomography (PET) scan showed multiple enlargement of supraclavicular, mediastinal, para-aortic and mesenteric lymph nodes (SUV max 26.3). Hyperbilirubinemia resolved after plastic stent placement (T-bil 0.9 mg/dL), and he received combination chemotherapy including rituximab, cyclophosphamide, adriamycin, vincristine and predonisolone (R-CHOP therapy). After three courses of R-CHOP, biliary stricture was resolved and a plastic stent was removed. He accomplished chemotherapy and achieved complete remission. However, he had a relapse soon after and is now undergoing salvage chemotherapy.

Fig. 1
figure 1

EUS findings. a EUS findings of case 1 and b case 2 showed common bile duct stricture due to enlarged lymph nodes. EUS; endoscopic ultrasonography, LN; lymph node

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Fig. 2
figure 2

Pathological findings. a HE staining of the biopsy from the wall of common bile duct (CBD) in case 1 showed the bile duct epithelium (blue arrows) and the invasion of large lymphoma cells with crush artifact into the subepithelial connective tissue of CBD. Immunohistochemical staining showed b CD20-positive and c CD5 weakly-positive. d HE staining of the biopsy from right cervical lymph node in case 1 showed diffuse large atypical lymphoma cell invasion. Immunohistochemical staining showed e CD20-positive, f CD5 weakly-positive, g cyclinD1-negative, h CD10-negative, i BCL-2-positive and j c-MYC-positive. k, l HE staining of the biopsy from the wall of CBD in case 2 showed the bile duct epithelium (blue arrows) and the invasion of large lymphoma cells with crush artifact into the subepithelial connective tissue of CBD. Immunohistochemical staining showed m CD20-positive, n CD10 partially-positive and o BCL-6 positive (× 400 at original magnification)

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Case 2 is a 78-year-old male with the history of hepatocellular carcinoma due to chronic hepatitis B. He was admitted to our hospital with jaundice. Laboratory data revealed elevated liver enzymes (AST 230 U/L, ALT 251 U/L, γGTP 992 U/L, ALP 1915 U/L, T-bil 7.6 mg/dL, D-bil 5.0 mg/dL). He had received transcatheter arterial embolization (TAE) and radiofrequency ablation (RFA) several times for hepatocellular carcinoma, thus we suspected the relapse of carcinoma. However, ERCP showed common bile duct stricture due to extrinsic compression by a mass with dilated proximal CBD up to 13 mm (Fig. 1b). Endoscopic plastic stent placement released the biliary obstruction and biopsy from the wall of CBD demonstrated invasion of lymphoma cells into the subepithelial connective tissue of CBD, positive for CD10, CD20, BCL-2, and BCL-6, and negative for CD5 and cyclinD1 (Fig. 2k–o). Ki-67 staining ranged from 70 to 80% in the B cells. The diagnosis was stage IIE, GCB-type DLBCL. PET scan showed multiple lesions around the duodenum, kidneys, and enlarged lymph nodes at mesentery and peritoneum (SUV max 8.1). Hyperbilirubinemia did not resolve even after placing a plastic stent because of impaired liver function. Chemotherapy was not given because of patient’s poor general condition.

Discussion

Obstructive jaundice is rare as an initial presentation of NHL, accounting for only 1–2% [5]. Jaundice in lymphoma can be caused by several ways, including extrahepatic bile duct obstruction due to enlarged lymph nodes, direct hepatic involvement of lymphoma, vanishing bile duct syndrome, primary bile duct lymphoma, primary hepatic lymphoma, drug-induced hepatitis, tumor-related hemolysis, and bile duct stricture after radiation [6]. Ödemiş recently reported seven patients with biliary tract obstruction secondary to malignant lymphoma. Six of seven cases were caused by extrinsic bile duct pressure due to enlarged lymph nodes and the other case was due to direct hepatic involvement [3].

Although obstructive jaundice with malignant lymphoma is mostly caused by extrahepatic bile duct obstruction due to enlarged lymph nodes, the presence of direct invasion of lymphoma cells into the bile duct has rarely examined and the diagnostic procedure has not been established. In general, direct invasion from adjacent lymph node is not necessarily associated with poor prognosis and not counted as an extranodal site. However, the extent of local tumor invasion predicts prognosis in some extranodal lymphomas, such as extranodal NK/T-cell lymphoma [7]. Until now, the existence of bile duct invasion has been rarely mentioned and the significance of bile duct invasion has never been evaluated, thus the influence of bile duct invasion on prognosis is still unknown. It might reflect the aggressive feature of lymphoma and our cases suggest that ERCP is useful as a diagnostic procedure. Especially in case 1, the surface of the bile duct appeared to be smooth macroscopically through ERCP, but pathology showed bile duct invasion. Therefore, macroscopically non-invasive findings cannot be used to deny the microscopic invasion. Since ERCP is necessary to release the obstruction of CBD, and endoscopic biopsy is minimally invasive, it should be done in all cases with obstructive jaundice.

Case 1 has CD5-positive DLBCL, which accounts for 5–10% of DLBCL [8] and has poorer prognosis in comparison with CD5-negative DLBCL [9]. CD5 positivity is correlated with old age, female predominance, elevated serum LDH level, more than one extranodal site, poor performance status, B symptoms, advanced stage, and high IPI [2, 10]. Case 1 has all characteristic features of CD5-positive DLBCL except for the sex, and bile duct invasion might reflect the aggressive nature of CD5 positivity.

The initial treatment of DLBCL with obstructive jaundice is controversial. Doxorubicin is predominantly metabolized by the liver and excreted by the bile, so it shows increased half-lives in patients with obstructive jaundice. Therefore, dose modifications based on the total bilirubin and hepatic transaminases are required [11, 12]. Some papers conclude that biliary drainage procedures before chemotherapy are only recommended in patients with associated symptoms or infectious complications of obstruction and the use of doxorubicin should be delayed until the bilirubin level gets sufficiently low by chemotherapy [5]. On the other hand, biliary drainage before chemotherapy can reduce the risk of obstructive cholangitis and enables to treat with the standard therapy R-CHOP from the beginning. William et al. reported that obstructive jaundice as an initial symptom was resolved in 10 of 13 cases (77%) [13]. In most cases, resolution of stricture was achieved within 90 days of intervention and start of chemotherapy, thus the transient placement of plastic stent is sufficient. As for our case 1, placing plastic stent with ERCP and biliary decompression allowed to use R-CHOP from the first cycle without any complications, and the stent was removed safely after 3 cycles of chemotherapy. Plastic stent placing is a safe approach and reduces the risk of cholangitis and allows to use full dose of the key drug, doxorubicin from the first cycle, therefore it has become a standard of care for obstructive jaundice caused by malignancy. Furthermore, it can be used to evaluate the bile duct invasion by biopsy of the wall of CBD at the same time.

In conclusion, the significance of the bile duct invasion of lymphoma cells has not been evaluated in the cases of lymphoma with biliary obstruction. The diagnostic procedure is not established, and the influence of bile duct invasion on prognosis is still unknown. Our cases clarified the bile duct invasion of lymphoma cells with ERCP, which suggest that ERCP may be useful as a diagnostic procedure for bile duct invasion. The ratio of bile duct invasion to the total cases of obstructive jaundice, the influence on the prognosis and the utility of ERCP as a diagnostic procedure should be further investigated.