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 Table of Contents  
Year : 2023  |  Volume : 3  |  Issue : 2  |  Page : 81-85

Isolated Hepatobiliary Involvement in an Infant with Langerhans Cell Histiocytosis: A Case Report with Review of Literature

1 Department of Pediatric Medicine, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India
2 Department of GI and Hepatobiliary Pathology, School of Digestive and Liver Disease, Kolkata, West Bengal, India

Date of Submission18-Jan-2023
Date of Decision29-Mar-2023
Date of Acceptance25-Apr-2023
Date of Web Publication24-May-2023

Correspondence Address:
Dr. Niva Lakra
Bhatia Basti, Main Road, Kadma, Jamshedpur, Jharkhand
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_18_23

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Background: Langerhans cell histiocytosis (LCH) is a rare condition in which there is the proliferation of cells of the monocyte-dendritic cell lineage, including Langerhan's cells, with variable clinical manifestations and outcomes. Hepatic involvement is often seen as a part of multi-system LCH and is associated with a fulminant course. Isolated hepatobiliary involvement in LCH is rare. Clinical Description: We report an 11-month-old female infant presenting with prolonged fever associated with progressive jaundice, clay-colored stools, and a massive hepatomegaly. Liver biopsy showed CD1a and Langerin positivity. There was no other system involvement, and hence, the infant was diagnosed with a case of single-system LCH with isolated hepato-biliary LCH. Management and Outcome: A customized chemotherapeutic regimen was started with cytarabine and prednisolone. The patient has responded and there has been gradual improvement in the general clinical condition as well as the laboratory parameters. Conclusions: This case report creates the awareness of possible presentation of pediatric LCH with isolated liver involvement. A high index of suspicion, carefully customized chemotherapeutic regimen may help in the timely diagnosis and successful management.

Keywords: Children, hepatic LCH, single-system Langerhan's cell histiocytosis

How to cite this article:
Lakra N, Paul A, Ghosh R, Datta S. Isolated Hepatobiliary Involvement in an Infant with Langerhans Cell Histiocytosis: A Case Report with Review of Literature. Indian Pediatr Case Rep 2023;3:81-5

How to cite this URL:
Lakra N, Paul A, Ghosh R, Datta S. Isolated Hepatobiliary Involvement in an Infant with Langerhans Cell Histiocytosis: A Case Report with Review of Literature. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Jun 6];3:81-5. Available from: http://www.ipcares.org/text.asp?2023/3/2/81/377508

Langerhans cell histiocytosis (LCH), earlier known as Histiocytosis X, is the most common histiocytic disorder. The hallmark is aberrant clonal proliferation of cells of the monocyte-dendritic cell lineage involving Langerhans cells, containing the typical organelles called Birbeck granules.[1] The disorder has a wide spectrum of clinical manifestations, varying from self-limited disease to severe multisystem dysfunction and failure. Skeletal involvement is seen in as high as 80% of affected individuals and this maybe the only affected site, especially in those above 5 years of age. Other common symptoms include skin lesions (50%), lymphadenopathy (33%), and hepatosplenomegaly (20%).[1]

Hepatobiliary involvement is seen in around 15% of LCH patients and may present as jaundice, sclerosing cholangitis, biliary cirrhosis, and end-stage liver disease requiring transplantation.[1] However, presentation of LCH with isolated hepatobiliary disease is rare.[2],[3],[4],[5],[6] We report the case of an infant with LCH presenting with isolated hepatobiliary involvement.

  Clinical Description Top

An 11-month-old, female infant, first born, out of a nonconsanguineous marriage, was admitted to our institute with the chief complaints of continuous moderate-to-high-grade fever for 3 months, along with progressive abdominal distension, yellowish discoloration of eyes, and urine with clay-colored stool for a month. History of poor feeding with progressive weight loss was also present. There was no history of contact with tuberculosis, any rash, blood transfusion, any surgery, bleeding manifestations, or family history of liver disease.

Three weeks ago, the infant had presented to a local hospital with fever and loose stools. Echocardiography had revealed cardiac dysfunction with chink of pericardial effusion with an ejection fraction of 50%. The infant was treated as a case of multisystem inflammatory syndrome in children and administered intravenous methylprednisolone at a dose of 10 mg/kg/day for 5 days and immunoglobulin at a dose of 2 g/kg over 24 h along with aspirin. The infant recovered, fever and loose stools subsided and was discharged after 10 days.

On re-appearance of high-grade fever, after a period of 3 weeks, the infant presented to us, this time being associated with progressive jaundice and abdominal distension. On examination, the infant was sick-looking, icteric, febrile, with a temperature of 38.8°C, normal volume pulses of 118/min, and respiratory rate of 42/min. She had a body-weight of 6.5 Kg (−2.47 Z-score for age) and length of 70 cm (−1.45 Z-score for age). Her left arm showed Bacillus Calmette-Guerin (BCG) scar mark. There was neither lymphadenopathy nor rash. Her abdomen was distended with venous prominence [Figure 1], and an enlarged liver extending up to the right iliac fossa, firm in consistency, with palpable left lobe and a liver span of 12.5 cm was present. There was no splenomegaly. Other systems examined revealed no abnormality.
Figure 1: (a) Child with cachectic look and hugely distended abdomen, (b) clay-coloured stool of the child

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  Management and Outcome Top

The possibilities of infection and malignancies were considered. Laboratory investigations showed progressive anemia, persistent neutrophilic leukocytosis, thrombocytosis, raised erythrocyte sedimentation rate, and C-reactive protein, along with evidence of cholestasis and hypoalbuminemia [Table 1]. Infectious etiologies were ruled out by dual antigen test, smear for malarial parasite, rk39 immunochromatography for kala azar, urine and blood culture, hepatitis B surface antigen, hepatitis C antibody, anti-Epstein–Barr viral capsid antigen, and TORCH immunoglobulin IgG and IgM ELISA, respectively. Mantoux test was negative and chest X-ray was normal. Skeletal radiograph survey was normal with no lytic bone lesions. Abdominal ultrasonography revealed massive hepatomegaly with heterogeneous echogenicity. The contrast-enhanced computed tomography whole abdomen revealed similar findings of hepatomegaly with heterogeneous enhancement, minimal ascites and no obvious focal lesion or calcification in the liver. Bone marrow aspiration and biopsy study showed cellular reactive marrow. Alpha fetoprotein and autoimmune liver profile (anti-nuclear antibody, anti-smooth muscle antibody, and anti-liver kidney microsome antibody) also came out to be negative.
Table 1: Trends of laboratory parameters of the infant with isolated liver involvement in Langerhans cell histiocytosis

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In the meantime, the child was started empirically on intravenous antibiotics (cefotaxime and doxycycline) and other supportive management. In view of clinical deterioration with persisting high grade fever, intravenous antibiotics were upgraded to cefepime and amikacin and anti-tubercular drugs were started as life-saving measures.

Subsequently, the results of histopathology of percutaneous liver biopsy were obtained, which showed partial distortion of lobular architecture with canalicular and cytoplasmic cholestasis, periportal bridging fibrosis, portal triads showing edema, ductal proliferation, and cholestasis, along with infiltration by polymorphs, few eosinophils and many histiocytes with nuclear grooves; histologically compatible with LCH [Figure 2] Immunohistochemistry showed CD1a and Langerin positivity confirming the diagnosis of hepatic LCH.
Figure 2: (a) Nodular infiltration of inflammatory cells in the lobule H and E × 100, (b) nodule formation in lobule highlighted by reticulin stain H and E × 100, (c) canalicular cholestasis in lobule H and E × 400, (d) infiltrate in lobule composed of eosinophils, histiocytes and polymorphs H and E × 400, (e) histiocytes show presence of nuclear grooves H and E × 400, (f) histiocytes with nuclear groove in between interlobular bile ducts of portal triads H and E × 400

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As no standard treatment regimens for LCH localized only to the hepatobiliary system have yet been described, treatment was started with a modified chemotherapeutic protocol consisting of cytarabine and prednisolone (modified induction regimen of low dose cytarabine [100 mg/m2] every 3 weeks along with prednisolone [40 mg/m2/day] daily for 4 weeks tapered over the next 2 weeks [one cycle consists of 6 weeks]).[7] She has received three such cycles and started showing response after the second cycle. The child was also given high doses of Vitamin A, D, E, K, folic acid, zinc, and multivitamin supplementation. High calorie and high protein diet (initially 100kcal/kg/day gradually escalated to 200kcal/kg/day with 3–4 g/kg/day of protein) was advised.

As per the last follow-up, after 3 months, there has been a gradual improvement in the clinical condition. Serum bilirubin and alkaline phosphatase are in a decreasing trend. Hepatomegaly has reduced from before with liver size reduced to 5 cm below right costal margin and bilirubin improved to 4.1 mg/dL. There have not been any new symptoms pertaining to affection of any other organ-system. Our further plan is to start on maintenance therapy for LCH, as per the standard guidelines.[7]

  Discussion with Review of Literature Top

The infant described above is a case of single-system LCH with isolated hepatic involvement. LCH is a disorder in which there is an abnormal proliferation and accumulation of dendritic antigen-presenting histiocytes, Langerhans cells. When one organ or system is involved, it is termed single system (SS-LCH), while involvement of two or more systems is termed multisystem (MS-LCH).[7]

Overall, LCH is rare, with an annual incidence of LCH of around 2–5 per million per year with peak incidence between the age of 1 and 4 years. However, clinical presentation can occur at any age and a male preponderance is seen.[8] Isolated hepatic involvement in LCH is extremely rare with only a few pediatric cases reported [Table 2].[2],[3],[4],[5],[6] Our patient was a female infant, whereas the majority of articles reported the condition in male children above 2 years of age.
Table 2: Review of literature showing reports of children with isolated hepatobiliary involvement in Langerhans cell histiocytosis

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The disease course and outcome of LCH depend on the age, organs involvement, including degree of organ dysfunction at the time of initial diagnosis. A long-term follow-up study of children with LCH showed that those with SS-LCH had a 100% regression rate and low relapse rate, compared to 73% regression in MS-LCH.[9]

Hepatic involvement can be a primary or secondary process.[1] The enzyme gamma-glutamyl transferase acts as a sensitive indicator of direct liver infiltration in LCH. However, LCH in other sites can indirectly affect the liver via the accompanying macrophage activation syndrome, resulting in hepatomegaly and hypoalbuminemia, without direct infiltration.[10]

The histologic picture can be diverse, with findings as lobular Langerhan's cell infiltration, cholangitis-like pattern, and also cirrhosis at later stages. According to the WHO classification of tumors, if histiocytes are positive for CD1a or langerin on immunohistochemistry, a definitive diagnosis can be obtained.[11] The LCH cells are predominantly seen in early lesions. In late lesions, there can be decrease in the number of LCH cells, with increased foamy macrophages along with fibrosis. There may be little or no CD1a or langerin (CD207) histiocytes in biopsy due to its patchy distribution.

The diagnosis of hepatic LCH is based on one or more of the following parameters:[12] (1) hepatomegaly (at least 3 cm below the costal margin, confirmed by ultrasound), (2) liver dysfunction defined either by serum bilirubin >3 times the upper limit of normal, protein <5.5 g/dL, albumin <3 g/dL, transaminases above three times normal, or presence of an intrahepatic nodular mass or ascites or edema, not due to other causes; or (3) histopathological findings of active disease. Our case fits into isolated hepato-biliary involvement due to the presence of hepatomegaly, hepatic dysfunction as well as histopathological findings suggestive of LCH. No features of any other system involvement were seen.

Treatment for LCH ranges from observation to chemotherapy or hematopoietic stem cell transplantation, depending upon the clinical classification of the disease. In SS-LCH, monotherapy is used with agents such as oral 6-mercaptopurine and methotrexate, indomethacin, bisphosphonates, and hydroxyurea. For MS-LCH, the standard regimen includes intravenous vinblastine and oral prednisolone with an initial course for 6–12 weeks, followed by continuation phase of at least 12 months. Nonresponders, particularly those with progressive disease in a high-risk organ, are administered salvage therapy with a combination of cladribine and cytarabine with or without bone marrow and/or solid organ transplantation.[7] Newer targeted therapy with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors such as vemurafenib and dabrafenib have a role in refractory patients.[13]

The prognosis of LCH depends on the presentation and organ involvement. An age of presentation above 2 years, or disease restricted to skin, lymph nodes, or bones has a good prognosis, compared to those presenting at younger ages and having multisystem involvement, especially those with involvement of risk organs (the hematopoietic system, liver, or spleen). The prognosis for SS-LCH is usually good. However, hepatic involvement can drastically affect the patient's prognosis. The 5-year overall survival rate in those with hepatic involvement is only 25%.[12] We plan to follow up the patient with clinical examination, complete blood count and liver function tests at 3 monthly interval, and Anthropometry and ultrasound of whole abdomen every 6 monthly. A follow-up for at least 5 years is required.[7]

  Conclusions Top

An isolated hepatic involvement in LCH is rare and usually carries a poor prognosis. A high index of suspicion, carefully customized chemotherapeutic regimen may help in timely diagnosis and successful management.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Jezierska M, Stefanowicz J, Romanowicz G, et al. Langerhans cell histiocytosis in children – A disease with many faces. Recent advances in pathogenesis, diagnostic examinations and treatment. Postepy Dermatol Alergol 2018;35:6-17.  Back to cited text no. 1
Buza N, Lagarde DC, Dash S, et al. Langerhans cell histiocytosis: Report of a single organ involvement in a child. J Cell Mol Med 2004;8:397-401.  Back to cited text no. 2
Wang Q, Jin S, Xiang B, et al. Liver transplantation in a child with liver cirrhosis caused by langerhans cell histiocytosis: A case report. BMC Pediatr 2022;22:18.  Back to cited text no. 3
Pratap T, Jalal MJ, Rashmi R, et al. Hepatobiliary and gastrointestinal involvement in langerhans cell histiocytosis-spectrum of three cases. Indian J Radiol Imaging 2021;31:670-7.  Back to cited text no. 4
Kaplan KJ, Goodman ZD, Ishak KG. Liver involvement in Langerhans' cell histiocytosis: A study of nine cases. Mod Pathol 1999;12:370-8.  Back to cited text no. 5
Finn LS, Jaffe R. Langerhans' cell granuloma confined to the bile duct. Pediatr Pathol Lab Med 1997;17:461-8.  Back to cited text no. 6
LCH-IV International Collaborative Treatment Protocol for Children and Adolescents with Langerhans Cell Histiocytosis. Available from: https://www.uhs.nhs.uk/Media/UHS-website-2019/Docs/PaediatricOncology/Solids/LCH-IV-protocol-vs-1-4-Nov-2016.pdf/. [Last accessed on 2023 Jan 01].  Back to cited text no. 7
Yi X, Han T, Zai H, et al. Liver involvement of Langerhans' cell histiocytosis in children. Int J Clin Exp Med 2015;8:7098-106.  Back to cited text no. 8
İnce D, Demirağ B, Özek G, et al. Pediatric langerhans cell histiocytosis: Single center experience over a 17-year period. Turk J Pediatr 2016;58:349-55.  Back to cited text no. 9
Jaffe R. Liver involvement in the histiocytic disorders of childhood. Pediatr Dev Pathol 2004;7:214-25.  Back to cited text no. 10
Nakamine H, Yamakawa M, Yoshino T, et al. Langerhans cell histiocytosis and langerhans cell sarcoma: Current understanding and differential diagnosis. J Clin Exp Hematop 2016;56:109-18.  Back to cited text no. 11
Fu Z, Li H, Arslan ME, et al. Hepatic Langerhans cell histiocytosis: A review. World J Clin Oncol 2021;12:335-41.  Back to cited text no. 12
Suh JK, Kang S, Kim H, et al. Recent advances in the understanding of the molecular pathogenesis and targeted therapy options in Langerhans cell histiocytosis. Blood Res 2021;56:S65-9.  Back to cited text no. 13


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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