Ramya Iyyadurai1, Ruth Asirvatham2, Sowmya Satyendra1, V Surekha3 1 Department of Medicine, CMC, Vellore, Tamil Nadu, India 2 Department of Pathology, University of Michigan, USA 3 Department of Geriatrics, CMC, Vellore, Tamil Nadu, India
Langerhans cell histiocytosis is a group of disorders caused by proliferation of the histiocytes. This is a rare neoplastic disease with multisystem involvement. We present a case of an adult male with intermittent fever, recurrent jaundice suggestive of predominant liver involvement. He had undergone multiple courses of anti-tuberculosis treatment with no improvement. Biopsy of the lymph node in our hospital showed Langerhan's cell histiocytosis and liver biopsy showed bridging fibrosis. This case report highlights liver involvement in Langerhans cell histiocytosis with lung and lymph node involvement occurring later, which is an uncommon presentation of this rare disease.
Keywords: Langerhans cell histiocytosis, Langerhans cell histiocytosis prognosis, liver Langerhans cell histiocytosis
Design with Ease
Langerhans cell histiocytosis (LCH) is a disease caused by clonal proliferation and migration of dendritic antigen presenting histiocytes. Involvement of the liver in children is well recognized; however, in adults, liver involvement is poorly understood and a cause of severe morbidity and mortality.
A 38-year-old grocer from Orissa presented to us in February 2009 with the history of swelling in his neck on the right side associated with intermittent fever and jaundice. He also complained of abdominal distension with vomiting and weight loss of 12 kg since 2006. Fine-needle aspiration cytology of the neck swelling (lymph node) revealed granulomatous inflammation, and he was initiated on anti-tuberculosis therapy (ATT) with rifampicin (450 mg), isoniazid (300 mg), pyrazinamide (750 mg), and ethambutol (600 mg) to be taken once daily.
After 3 months, he was still feeling unwell; hence, he went to a tertiary care hospital where he underwent a barium meal follow through which showed thickened bowel loops and computed tomography scan of the abdomen which showed multiple hypoechoic lesions in the liver. A histopathological examination of biopsy of the hypoechoic lesions in the liver was suggestive of granulomatous hepatitis. He was restarted on nonhepatotoxic antituberculous therapy (injection amikacin 500 mg intravenous once a day, levofloxacin 750 mg once a day, and ethambutol 800 mg once a day) as his transaminase levels were high.
In April 2007 since his symptoms did not improve an upper gastrointestinal endoscopy was done which showed Grade II esophageal varices. He was advised to start taking oral steroids which he took for 1 week and then stopped and came to our hospital for further management. He is neither an alcohol consumer nor a smoker.
At admission in our hospital, the patient was febrile, icteric, and pale. He had a firm, fixed 3 cm × 3 cm right submandibular swelling. His pulse and blood pressure were normal. His liver was enlarged, and his respiratory and cardiovascular examination was normal.
The patient was admitted to the ward where investigations showed deranged liver function tests, deranged bleeding parameters [Table 1], and chest X-ray showed cystic changes in the left lower zone [Figure 1]. Tests done for hepatitis-causing viruses were negative.
Differential diagnosis and investigations
At this junction, we considered whether the patient had sarcoidosis, multidrug-resistant tuberculosis (TB) or non-Hodgkins lymphoma (NHL) or LCH since all these illness can cause granulomatous inflammation. Multidrug-resistant TB was considered because the patient had not responded to adequate doses of ATT. Sarcoidosis can involve the liver and causes noncaseating granulomatous inflammation which can involve the lung, liver lymph node. NHL involves the reticuloendothelial system and can cause granuloma formation.
A biopsy of the submandibular lymph node and transjugular liver biopsy was done, after transfusing fresh frozen plasma since the patient had deranged bleeding parameters. The histopathological examination of the liver showed features suggestive of prolonged cholestatic injury with focal periportal bridging and diffuse perisinusoidal fibrosis and Kupffer cell siderosis. A gastroscopy was repeated which showed mild portal gastropathy. Histopathological examination (HPE) of the cervical lymph node showed histiocytes which were CD1a [Figure 2] and [Figure 3] and CD43 positive and for S100 protein, suggestive of an LCH.
Diagnosis, management, and course of illness
Considering that patient had an earlier liver biopsy suggestive of granulomatous inflammation and second liver biopsy showing prolonged cholestatic fibrosis, and lung showing cystic changes with lymph node biopsy suggestive of LCH, a diagnosis of LCH with multisystem involvement was considered. The patient was initiated on high-dose steroids (prednisolone 1 mg/kg). He was also asked to continue his ursodeoxycholic acid (UDCA) and was discharged.
He was symptomatically better with corticosteroids and so went back home. However, he returned to the hospital after 2 months with complaints of hemoptysis. A repeat chest X-ray [Figure 4] followed by a computed tomogram [Figure 5] of the chest showed extensive cystic changes in both the lung bases. Since the patient's disease continued to be active and progressive on oral steroids, he was started on chemotherapy with vincristine.
After three cycles of chemotherapy, the patient developed high-grade fever and cough with purulent expectoration. He was found to have hypotension, and a right-sided pneumonia and required management in the Intensive Care Unit with mechanical ventilation, ionotropic support, and broad spectrum antibiotics. He deteriorated very rapidly and expired.
LCH is a group of disorders of unknown origin with a widely variable clinical presentation and outcome. Although known by various terms including histiocytosis X, eosinophilic granuloma, Letterer–Sewe disease, Hand–Schüller–Christian syndrome, the currently preferred name for these group of diseases is LCH. The estimated incidence of LCH is one to two cases per 1 million, being more common between the ages of 21 and 69 with an average age of 32 years.
LCH can be classified as a single-system disorder or multisystem disorder. Single-system LCH involves any one of these areas; bone, skin, lymph node, lungs, or rarely the thyroid or thymus. In multisystem LCH, there is involvement of two or more organs. Individuals with multisystem LCH are further subdivided into low-risk and high-risk categories on the basis of the “risk organs” involved. Involvement of liver, spleen, and bone marrow (considered “risk organs”) in LCH and are associated with a poor prognosis.
In adults, bone is the most commonly involved organ (80% of cases). Extraosseous sites most commonly involved are the hypothalamic-pituitary axis and the skin in 50% of patients, lymph nodes in 10%. Lung involvement is frequent in multisystem disease but seen in only 5% of all patients while the liver and spleen involvement are seen in 1% of the patients. Liver involvement is usually seen in the later stage of the disease or is associated with a more fulminant disease process as seen in our patient. Failure to control the disease in early stages can lead to liver fibrosis or biliary cirrhosis.
The individual in this discussion had elevated thyroid-stimulating hormone (TSH) and low T3 and T4 levels. Thyroid involvement in LCH is extremely rare. Most cases have an anterior pituitary syndrome with secondary hypothyroidism which presents as low TSH, low T3, and low T4. Patients with thyroid involvement in LCH present with diffuse thyroid swelling. Thyroid involvement may rarely precede multisystem involvement. This individual had thyroid swelling and may have had thyroid involvement which we were not able to prove by biopsy.
The definitive diagnosis of LCH is based histological examinations and histochemical staining. Literature has shown that S100 protein positivity, Ki-67 immunostaining is helpful in diagnosis, and CD1a is considered the most specific marker for LCH. While CD1a the most specific marker was positive in our patient, S100 was negative.
Liver involvement in Langerhans cell histiocytosis
Involvement of the liver in LCH is frequent but often missed. The most common histological finding is sclerosing cholangitis. The initial biochemical tests usually reveal cholestasis with transaminitis. There appears to be two stages in the progression of LCH - an early stage with infiltration of the liver with histiocytes and a late stage where there is sclerosis of the biliary tree. The previous studies show that liver involvement has a negative impact on patient survival. There are no studies on therapy for liver involvement in LCH, but UDCA has been suggested for relief of symptoms. Histopathological examination of the liver in the patient discussed also showed features of prolonged cholestatic injury. The presence of CD1a will help in identifying liver involvement, especially if the liver biopsy is done in late stages and shows only fibrosis  as in this patient.
Treatment of Langerhans cell histiocytosis
Treatment of individuals with LCH depends on the extent of the disease and the organ systems involved. Skin lesions and single bony lesions tend to resolve spontaneously. Steroids may help to slow or even stop the progression of disease. In lung LCH, smoking cessation is crucial to prevent disease recurrence or progression. However, for severely symptomatic disease, in which there are complications associated with vital organ dysfunction involving the liver, lungs, and central nervous system, the use of a variety of immunosuppressive treatments have been suggested. Chemotherapeutic agents, such as vinblastine, methotrexate, cyclophosphamide, etoposide, and cladribine, have been used with limited success in patients with progressive disease unresponsive to corticosteroids and in those with multiorgan involvement. The treatment of hepatic LCH consists of systemic chemotherapy, but the therapy is not effective once cirrhosis develops. In patients with advanced liver involvement, liver transplantation is a curative option.,
There are no randomized trials in the management of LCH. The current practice is to use cytarabine 100 mg/m . This regiment is considered to be more effective (complete remission in 80%) than cladribine or vincristine/prednisolone which was used in our patient.
Recent studies have identified newer marker for LCH such as BRAF, V600E, and MAP2K1. These markers can identify high-risk patients. They have also been used to develop targeted therapy and newer drugs such as vemurafenib, which is a BRAF inhibitor.,
Langerhans cell histiocytosis and tuberculosis
Diagnosis may be missed and needs a high index of clinical suspicion, especially in patients who have been diagnosed to have TB based on granulomatous inflammation of multiple organs and who do not respond to antituberculous therapy. Studies in individuals with pulmonary TB show that sputum conversion occurs at a median of 5.5 weeks and maximum at 6 weeks. If this can be extrapolated to patients with disseminated TB, then it can be assumed that patients with TB of other organ systems are expected to improve by 6 weeks. In case, the clinician does not see clinical improvement then an alternative diagnosis should be suspected and in a patient who does not improve with adequate ATT an alternative diagnosis must be considered. Referral to a higher center where additional HPE techniques are available may lead to diagnosis and appropriate care.
Diagnosis of LCH is difficult since it is a rare illness and it requires special staining techniques. Even if the patient presents with hepatitis as in our patient involvement of the liver is often missed in patients with systemic LCH. Liver involvement is associated with adverse outcomes. Liver biopsy with appropriate histochemical tests such as CD1a is the cornerstone in diagnosis. It is very important to identify liver involvement early for improved outcomes. UDCA is an adjuvant to treatment and patients who present late with liver involvement may require liver transplantation.
In countries like India, where TB is endemic, a person who is suspected of TB based on granulomatous inflammation of multiple organs and started on ATT should be evaluated for other causes, especially when adequate response to ATT does not occur within the expected time frame.
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Conflicts of interest
There are no conflicts of interest.