Hodgkin's lymphoma-related vanishing bile duct syndrome: A case report and literature review

Kaohsiung Journal of Medical Sciences (2013) 29, 636e641

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CASE REPORT

Hodgkin’s lymphoma-related vanishing bile duct syndrome: A case report and literature review Kiong-Ming Wong a, Chao-Sung Chang b,*, Chun-Chieh Wu c, Hsin-Ling Yin c a

Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan b Division of HematologyeOncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan c Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Received 11 July 2012; accepted 26 September 2012 Available online 9 August 2013

KEYWORDS Ductopenia; Hodgkin’s lymphoma; Vanishing bile duct syndrome

Abstract We report the case of a 38-year-old man who developed vanishing bile duct syndrome in association with Hodgkin’s lymphoma. He was noted to have cervical lymphadenopathy and marked elevation of total serum bilirubin at diagnosis. He achieved complete remission with normalization of serum bilirubin after eight courses of Adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy followed with autologous hematopoietic cell transplantation. Consecutive liver biopsies performed at diagnosis and at the stage of complete remission revealed the disappearance and regeneration of interlobular bile ducts, respectively. Our case provides pathological evidence that Hodgkin’s lymphoma-related vanishing bile duct syndrome is a reversible bile duct injury disease. Bilirubin is a reliable serum marker to monitor the treatment response of these cases. The mechanism to develop hyperbilirubinemia with vanishing bile duct in such a case of Hodgkin’s lymphoma remains to be studied. A literature review was carried out. Copyright ª 2013, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. All rights reserved.

Introduction * Corresponding author. Division of HematologyeOncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Number 100, Tzyou 1st Road, Kaohsiung City 807, Taiwan. E-mail address: [email protected] (C.-S. Chang).

Jaundice related to Hodgkin’s lymphoma (HL) has been reported to occur in 3e13% patients [1,2]. The common causes of abnormal liver function in these patients include extrahepatic bile duct obstruction or hepatic infiltration by

1607-551X/$36 Copyright ª 2013, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.kjms.2013.05.002

HL-related vanishing bile duct syndrome lymphoma cells, viral hepatitis, or complications of chemotherapeutic treatment [2]. A rare paraneoplastic syndrome in association with HL, called vanishing bile duct syndrome (VBDS), was first described in 1993 by Hubscher et al. [3]. This syndrome presents with severe icterus and hepatic abnormalities as a result of loss of normal bile duct. The mechanism of hyperbilirubinemia in HL-related VBDS and its resolution remain unclear. Few studies have described the pathogenesis of VBDS in such a case. Our case provides evidence of ductopenia at diagnosis and its resolution postchemotherapy by serial liver biopsies. A literature review of HL-related VBDS was carried out.

Case report A 38-year-old man was admitted to our ward with complaints of abdominal pain and jaundice for 1 week. Past history showed that he had dyslipidemia and depressive disorder and had been under Bupropion treatment. The

637 associated symptoms and signs included nausea sensation, watery diarrhea, and fever. He had consumed some alcohol over recent days, and had travelled to China and Japan recently. He denied receiving blood transfusion, intravenous drug abuse, high-risk sexual behavior, or exposure to drugs or viral hepatitis. Physical examination showed icteric sclera, right neck lymph node swelling, and mild upper abdomen tenderness. Laboratory tests revealed bilirubin (total/direct), 14.8/9.39 mg/dL; alanine transaminase (ALT), 181 IU/L; aspartate aminotransferase (AST), 53 IU/L; alkaline phosphatase, 155 IU/L; and gammaglutamyl transferase, 317 IU/L. The hemogram was normal. The virology tests were negative for hepatitis A virus, hepatitis B virus, hepatitis C virus, EpsteineBarr virus, herpes simplex virus, human immunodeficiency virus, and cytomegalovirus. Immunology tests revealed normal levels of b2-microglobulin, complement component 3 (C3), complement component 4 (C4), and immunoglobulin, and the test was negative for antinuclear antibody. Ceruloplasmin level was normal. Neck computed tomography (CT)

Figure 1. Portal tract devoid of bile duct, as highlighted by a lack of HE stain- and CK 19 stain-positive structure within the tract on pretreatment liver biopsy. Normal portal tract with regeneration bile duct was present at the periphery of tract (white arrows) on post-treatment liver biopsy. Parallel hepatic artery branches (red arrows) were demonstrated. (A) Grade I portal and lobular inflammatory activity and no fibrosis with steatohepatitis and cholestasis. Loss of normal interlobular bile duct around the portal tract. (HE, original magnification: 400
). (B) Grade II portal and lobular inflammatory activity. Arrows show interlobular bile ducts. (HE, original magnification: 400
). (C) Focal decrease numbers of bile duct in portal tract area (CK 19, original magnification: 400
). (D) Increased numbers of interlobular bile ducts in portal tract area demonstrated by CK 19 immunohistochemical stain. Arrows show interlobular bile ducts (CK 19, original magnification: 400
). CK Z cytokeratin; HE Z hematoxylin and eosin.

638

K.-M. Wong et al. Serial changes of liver biochemical levels in response to clinical treatments 250

400

200

300 250

150

200 100

150 100

Bil level

AST and ALP levels

350

50

50 0

0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70

Weeks Aspartate transaminase (AST) (U/L)

Alkaline phosphatase (ALP) (U/L)

Total bilirubin (bil) (mg/L)

Figure 2. Serial changes in liver biochemical levels in response to clinical treatments. The patient was treated with eight cycles of ABVD regimen chemotherapy (a black arrow for each cycle) from Week 4 to Week 32 after diagnosis of Hodgkin’s lymphoma. The patient received autologous hematopoietic cell transplantation in Week 55 (open arrow). Liver biochemical levels normalized in Week 70 after clinical treatment. ABVD Z adriamycin, bleomycin, vinblastine, and dacarbazine; ALP Z alkaline phosphatase; AST Z aspartate aminotransferase; Bil Z bilirubin.

scan showed enlarged lymph nodes over the right jugulodigastric, posterior cervical, and supraclavicular areas. Abdominal CT scan revealed normal intrahepatic biliary duct and unremarkable intra-abdominal lymphadenopathy. Positron emission tomographyecomputed tomography (PET-CT) scan revealed involvement of cervical regions, mediastinum, and bilateral axillary basins. Suspicious spleen and bone marrow involvement were also noted. Neck lymph node biopsy was performed, and the pathology revealed classical HL with mixed cellular subtype. Bone marrow biopsy was found negative for lymphoma involvement. Due to persistent jaundice, a liver biopsy was carried out; the pathology showed cholestasis with absent or focally decreased numbers of bile ductules in the portal tract areas in the whole specimen (Fig. 1A and C) rather than proliferative ones and no Hodgkin cell was identified, which addressed the possibility of HL-related VBDS. After diagnosis of HL Stage IIA, the patient was treated with standard adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen chemotherapy biweekly. The dosage of chemotherapy was adjusted according to the reference for Truven Heath Analytics Micromedex version 1.0 (Healthcare Series) due to hepatic insufficiency. A total of eight courses (4 cycles) of ABVD chemotherapy were given over 28 weeks. The patient’s total bilirubin level returned to nearly normal on Week 28 (Fig. 2). Liver biopsy repeated on Week 36 revealed regeneration of interlobular bile ducts (Fig 1B and D). Three months after chemotherapy had been completed, the patient received peripheral blood stem cell mobilization with cyclophosphamide 4 g/m2 followed by peripheral blood stem cell harvest. Autologous hematopoietic cell transplantation with BEAM (Bischloroethylnitrosourea (BCNU), etoposide, cytosine arabinoside, and melphalan) conditioning regimen was carried out 3 months after peripheral blood stem cell harvest. Total nuclear cell count 6.42
108/kg and CD34 count 1.67
106/ kg body weight were administered during the autologous hematopoietic cell transplantation. Full engraftment was

reached on Day 19 after autologous hematopoietic cell transplantation. The patient has maintained remission state up to the time of writing (more than 7 months) and is regularly followed up at our outpatient service.

Discussion VBDS is a common pathologic manifestation resulting from various etiologies such as autoimmune disease, medications, infections, neoplastic disorders, and genetic abnormalities [4]. HL-related VBDS was first reported by Hubscher et al. [3] in three Hodgkin disease patients with intrahepatic cholestasis and ductopenia in 1993. Ductopenia was defined as a decreasing of bile duct numbers in pathology. The bile duct numbers were determined as a percentage by counting the number of portal tracts with ducts and dividing it by the total number of portal tracts present. Following Hubscher et al’s work, we performed a literature search in PubMed database using “vanishing bile duct syndrome”, “Hodgkin’s lymphoma”, and “ductopenia” as keywords. The search yielded a total of 23 HL-related VBDS cases from 1993 to 2011 (Table 1) [3e19], which included both English and non-English publications. An overview of the clinical presentations of the aforementioned 23 patients is given in Table 2. Patients tended to be young with a mean age of 28 years (range, 3.5e54 years), and there was a male predominance (maleefemale ratio, 3.6:1). All patients had jaundice (100%) and pruritus (100%). Other common symptoms and signs were weight loss (93%), night sweats (78%), and fever (70%). Most patients had palpable neck lymphadenopathy (84%), whereas fewer patients presented with hepatomegaly (50%) and splenomegaly (33%). Total bilirubin levels were elevated in all cases, with a mean of 305 mmol/L (range, 34e856 mmol/L). Serum alkaline phosphatase levels were increased markedly in many cases, with a mean of 960 IU/L (range, 155e5724 IU/L). AST levels seldom exceeded 200 IU/L in those patients, with a

Ref

[3] [3] [3] [10] [8] [13] [14] [14] [15] [7] [5] [9] [9] [6] [16] [11] [17] [12] [18] [19] [4] [4] This study

Review cases of Hodgkin’s lymphoma-related vanishing bile duct syndrome. Year

1993 1993 1993 1997 1997 1997 1998 1998 2000 2000 2001 2002 2002 2004 2004 2005 2006 2007 2007 2008 2008 2008 2010

Stage

IA NR IIB IIIB IIA IB IIIB IIIB IA IIIB IIIB IIA IIA IIA IIIB NR IIIA IIA IIIB IIIA IIIB IIIB IIA

Tx

CRS C CS C CRS CS CS CS CS C CS CRS CRS R C CS NT CRS C C CR CR CT

Age

44 26 37 21 3.5 5 27 50 38 54 3.5 28 23 43 46 17 46 22 17 39 10 12 38

Sex

M M F F M M F F M M M F M M M M M M M M M M M

Pretreatment

Post-treatment

Outcome

Biopsy

Bil (mmol/L)

AST (IU/L)

ALP (IU/L)

Biopsy

Bil (mmol/L)

AST (IU/L)

ALP (IU/L)

Ductopenia Nil Ductopenia Ductopenia Ductopenia Ductopenia Ductopenia Ductopenia Ductopenia Ductopenia Nil Ductopenia Ductopenia Nil Ductopenia Ductopenia Ductopenia Ductopenia Ductopenia Ductopenia Ductopenia Ductopenia Ductopenia

300 400 NR 245 856 NR 399 370 34 51 105 559 NR NR 266 57 217 444 473 501 85 184 252

100 100 NR 108 100 67 83 78 203 NR 55 68 NR NR 86 120 36 134 148 157 208 151 53

210 200 NR 198 500 998 NR NR 2041 138 210 619 NR NR 384 5724 170 236 964 1144 2434 NR 155

HD Ductopenia NIL DR Ductopenia NIL NIL NIL NIL Ductopenia Ductopenia Ductopenia Ductopenia Ductopenia NIL DR NIL NIL NIL NIL Ductopenia NIL DR

700 800 NR 11 682 NR 646 430 46 NR NR 653 459 215 300 4.8 NR 27 13 409 NR 433 22

300 80 NR 193 300 NR 98 102 210 NR NR NR 174 40 180 56 NR 40 46 NR NR NR 50

600 100 NR 469 700 NR NR NR 7970 360 NR 2925 2481 348 1200 1084 NR 117 390 NR NR NR 247

D: liver failure D: sepsis D: sepsis Alive D: liver failure D: liver failure Alive D: sepsis D: liver failure Alive D: liver failure D: HD Alive Alive D: sepsis Alive D: sepsis Alive Alive D: unknown D: unknown Alive Alive

HL-related vanishing bile duct syndrome

Table 1

ALP Z alkaline phosphatase; AST Z aspartate aminotransferase; Bil Z bilirubin; C Z chemotherapy alone; CR Z chemotherapy þ radiotherapy; CRS Z chemotherapy þ radiotherapy þ steroids; CT Z chemotherapy þ autologous hematopoietic cell transplantation; D Z died; DR Z ductal regeneration; F Z female; HD Z Hodgkin’s disease; M Z male; Nil Z not performed; NR Z not reported in the article; NT Z no treatment for Hodgkin’s lymphoma as diagnosis was made after autopsy; R Z radiotherapy alone; Tx Z treatment.

639

640 Table 2 Summary of clinical features of 23 patients with Hodgkin’s lymphoma-related vanishing bile duct syndrome. Basic demographic Age (y) (mean, range) 28 (3.5e54) Gender (M:F) 18:5 Symptoms/signs (n/N, %)a Jaundice 23/23 (100) Pruritus 12/12 (100) Weight loss 13/14 (93) Night sweats 7/9 (78) Fever 7/10 (70) Neck lymphadenopathy 16/19 (84) Hepatomegaly 8/16 (50) Splenomegaly 6/18 (33) Initial liver biochemical values (mean, range) Aspartate transaminase (U/L) 152 (36e208) Alkaline phosphatase (U/L) 960 (155e5724) Total bilirubin (mmol/L) 305 (34e856) Staging, treatment, and outcome Stage (I/II/III/IV/NR) (n) (3/7/11/0/2) Treatment (6/1/2/7/5/1/1) (C/R/CR/CS/CRS/CT/NT) (n) C Z chemotherapy alone; CR Z chemotherapy þ radiotherapy; CRS Z chemotherapy þ radiotherapy þ steroids; CS Z chemotherapy þ steroid; CT Z chemotherapy þ autologous hematopoietic cell transplantation; F Z female; M Z male; NT Z no treatment; R Z radiotherapy alone. a Percentage is expressed as the number of positive cases divided by the number of total cases with definite record; n Z number of positive cases; N Z total cases with definite record.

mean of 152 IU/L (range, 36e208 IU/L). Liver biopsies prior to treatment were performed in 20 cases (Table 1); for these cases, ductopenia was found in pathology. Three cases did not receive liver biopsy prior to treatment. Two received liver biopsy after chemotherapy treatment due to persistent cholestasis [3,5]. The other case suffered from VBDS at the remission stage of HL; therefore, liver biopsy was performed after lymphoma had been treated [6]. Most of these cases were in Stage III (44%) and Stage II (26%), which constituted 70% of all the cases (Table 2). Thirteen percent of these patients were in Stage I, 4% in Stage IV, 4% with relapsed disease, and 8% in unreported stage. Treatments for these cases included chemotherapy alone (26%); radiotherapy alone (4%); chemotherapy combined with radiotherapy (8%); chemotherapy combined with steroid (30%); a combination of chemotherapy, radiotherapy, and steroid (22%); and no treatment as HL was diagnosed by autopsy (4%). To the best of our knowledge, our study is the first to demonstrate cases who received autologous hematopoietic cell transplantation in addition to chemotherapy for HL with a presentation of VBDS. Autologous hematopoietic cell transplantation is considered a feasible treatment choice in such a rare case, although its long-term benefit needs further observation. After treatment, 44% of the cases survived. Survival cases demonstrate apparent improvement of total bilirubin and AST levels. The modest improvement of ALP levels in surviving cases may be due to longer half-life of ALP and usage

K.-M. Wong et al. of steroid in some of the cases. Refractory response to treatment for HL subsequently led to mortality in these cases. Liver failure (42%) and sepsis (42%) were two main causes of death. The remaining causes of death (16%), however, were unidentifiable as death was sudden. As expected, fatal cases showed deterioration of total bilirubin, AST, and ALP levels (Table 1). Twelve cases had liver biopsies following treatment. Among these, one case had repeated liver biopsy owing to new liver nodules being found, which disclosed involvement of the liver in Hodgkin’s disease [3]. Eight cases showed persistent ductopenia and four of them met with mortality due to sepsis, progressive liver failure, or HL [3e9]. Three cases showed ductal regeneration and all remain alive to date [[10,11], and this case] (Table 1). Two possible mechanisms to explain HL-related VBDS have been postulated: direct bile duct damage by infiltrated lymphoma cells and paraneoplastic toxic cytokine released by lymphoma cells [20]. The latter mechanism has been accepted more due to the disparity between the minor load of lymphoma and severe cholestasis seen in those cases of HL-related VBDS and documented liver biopsies prior to the initiation of chemotherapy [8,10,12,13]. The paraneoplastic effect may be related to mediators released by inflammatory cells surrounding or infiltrating the tumor [21,22]. In the past, patients with HD-related VBDS were speculated to gain poor survival outcome, with low regenerative capacity of injured bile ducts, leading to irreversible damage, liver failure, and death [4]. Our review gives pathological evidence to support the potential reversibility of these diseases and survival in those cases who respond to cancer treatment. In conclusion, HL-related VBDS is a reversible paraneoplastic injury if the cancer responds to medical treatment. Bilirubin is a more reliable cholestasis marker compared to alkaline phosphatase in monitoring treatment response. Autologous hematopoietic cell transplantation is a feasible treatment of choice in such a rare case, although its longterm benefit needs further observation.

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