Introduction

Langerhans cell histiocytosis LCH encompasses a syndrome with a broad range of clinical manifestations and a prognosis that varies according to the number of organs involved. The only feature that all forms of this disease have in common is the proliferation of histiocytic cells and infiltration of these cells into normal tissues. The most commonly affected tissues are bone skin and lymph nodes. Langerhans cells may also invade and proliferate in the liver lung spleen and bone marrow as well as other organs. Hepatic involvement in LCH is incompletely understood. Hepatic manifestations might be the initial presentation in patients with LCH and this might sometimes be indistinguishable from primary sclerosing cholangitis.

A histiocytic infiltrate with accompanying surrounding inflammation and prominent eosinophils of portal areas cholangiolar destruction ductopenia sclerosing cholangitis and chronic cholestasis should prompt use of stains for S 100 and CDla because demonstration of Langerhans cells is important to establish the correct diagnosis.

Case Report

A 34 year old man high school teacher by profession reported to the hospital with complaints of itching of 4 months duration yellowish discoloration of sclera and dark urine of 3 months duration. He also reported low grade fever with evening rise of temperature of 1 month duration. On further questioning he reported loss of appetite and weight loss of about 8 kg in the preceding 6 months generalized weakness easy fatigability and arthralgia.

On review of symptoms he had no night sweats chills acholia ascites or pedal edema. He declined any history of substance abuse jaundice transfusion of blood or blood products gastrointestinal bleed. Physical examination revealed averagely built male with stable vital signs. His sclerae were icteric. There was no palpable lymphadenopathy. Abdominal examination revealed enlarged liver palpable 2 cm below the right costal margin. The liver was firm in consistency with a span of 14 cm. Rest of systemic examination was within normal limits. Laboratory data revealed hemoglobin of 10.6 g dL total leukocyte count of 18 230 cells 956 L with neutrophils 76 lymphocytes 18 monocytes 4 eosinophils 2 and platelet count of 6.62 lakhs 956 L. His prothrombin time was 15.3 sec C 13.5 sec INR 1.2 . Peripheral smear showed microcytic hypochromic red blood cells neutrophilic leukocytosis with toxic granules and few transformed lymphocytes. His liver function tests were abnormal with total bilirubin 3.7 mg dL direct bilirubin 1.9 mg dL indirect bilirubin 1.8 mg dL alanine transaminase ALT 25 IU L aspartate transaminase AST 49 IU mL alkaline phosphatase ALP 509 IU L total protein 8.4 g dL albumin 3.1 g dL 947 glutamyl transpeptidase 126 IU L. Alpha fetoprotein AFP was 1.35 ng mL urea 9 mg dL creatinine 0.6 mg dL serum sodium 137 mMol L potassium 4.2 mMol L. Cancer antigen CA 19 9 was 13.6 U mL. Blood and urine samples were cultured and did not show any growth of microorganisms. Viral screening for hepatitis C virus hepatitis B virus and human immunodeficiency virus HIV was negative.

Bone marrow examination demonstrated cellular marrow with M E ratio of 9 1 normoblastic erythropoiesis and orderly maturation of myeloid series. He had received numerous courses of antibiotics in the past but continued to remain symptomatic. USG abdomen revealed hepatomegaly coarse echopattern of the liver mild surface nodularity with multiple hypo to hyperechoic irregular ill defined focal lesions randomly scattered in both lobes of liver Fig. 1 . The lesions measured between few mm up to 18 mm few of them showing cystic necrotic components. No intrahepatic biliary radical dilatation IHBRD was observed. Portal vein measured 9 mm with hepatopetal flow. Spleen was bulky with a span of 11.3 cm. No collaterals were noted. Triple phase CT of the liver Fig. 2a showed that the lesions were hypodense on noncontrast phase with no enhancement on arterial portal venous and delayed phase.

Portal vein and its intrahepatic branches as well as hepatic veins were patent. Few enlarged periportal and aortocaval nodes largest 3.2 1.8 cm were also noted. No focal lesion was noted elsewhere in the abdomen and chest Fig. 2b . An ultrasound guided liver biopsy was performed. This revealed extensive replacement of liver parenchyma extending from portal to centrilobular regions with multiple large collections of Langerhans cells demonstrating large pale contorted or lobulated reniform vesicular nuclei finely dispersed chromatin and abundant slightly eosinophilic or amphophilic cytoplasm. Nucleoli were not prominent. In addition to Langerhans cells the infiltrate also contained eosinophils and variable numbers of lymphocytes epithelioid macrophages including foam cells neutrophils and plasma cells Figs. 3 5 . The remaining liver showed maintained portal and lobular architecture. There was patchy sinusoidal dilatation and congestion. Regenerative changes with twinning of hepatocyte cell plates were also noted. No significant duct injury ductopenia or cholestasis was noted. Immunohistochemistry IHC revealed strongly positivity for CD1a and S 100 Fig. 6 . Few cells were positive for CD68 but pancytokeratin was negative. On the basis of liver biopsy and IHC findings the patient was diagnosed with LCH. Skeletal survey of patient s skull chest dorsal lumbar spine long bones and pelvis with hips showed no focal osteolytic lesion vertebra plana intramedullary lesion or periosteal reaction.

Discussion

Langerhans cell histiocytosis encompasses a syndrome with a broad range of clinical manifestation and a prognosis that varies according to the number of organs involved.1 Solitary bone lesions usually affecting the skull have a favorable prognosis whereas multisystem organ involvement carries a poor prognosis. In the pediatric age group the most common presentation is a multisystem disease with pyrexia and failure to thrive. Mortality in this subgroup of patients is 60 .2 Older children often present with solitary bone involvement that can regress spontaneously or require minimal treatment.1 In adults the disease occurs infrequently.3 4 Almost every organ in the body can be involved in LCH. Bone followed by skin lymph nodes ears bone marrow and peripheral blood are the common sites of involvement. Less often affected are liver spleen lung endocrine organs and the gastrointestinal tract. The infiltrates of Langerhans cells are nearly always associated with an inflammatory response consisting of mature lymphocytes neutrophils eosinophils plasma cells and occasionally mast cells. Dense fibrosis might surround these infiltrates with replacement of normal tissue and distortion of the surrounding architecture. Hepatic involvement in LCH is incompletely understood. Previous literature on Letterer Siwe disease old name for LCH is difficult to evaluate because many of those cases probably represented other diseases notably various forms of leukemia and lymphoma.3 Hepatic manifestations might be the initial presentation in patients with LCH and this might sometimes be indistinguishable from primary sclerosing cholangitis.5 Histopathology in many cases shows some degree of active bile duct infiltration injury and destruction by Langerhans cells. Small and medium sized bile ducts show infiltration by the Langerhans cells with displacement of the epithelial cells. Almost complete replacement of some ducts by aggregates of Langerhans cells within the pre existing basement membrane has also been reported.

When large bile ducts are injured by the Langerhans cells they may produce cystic dilatation ulceration and rupture with a secondary xanthogranulomatous inflammatory response. Therefore it is important to consider this disease in differential diagnosis of primary sclerosing cholangitis particularly in children. The correct diagnosis can be made if one is aware of the entity and seeks and recognizes the common components of the disease process. A histiocytic infiltrate with accompanying surrounding inflammation and prominent eosinophils of portal areas cholangiolar destruction ductopenia sclerosing cholangitis and chronic cholestasis should prompt use of stains for S 100 and CDla because demonstration of Langerhans cells is important to establish the correct diagnosis.6 7 CD1a is important as activated Kupffer cells may acquire S 100 positivity.

References

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