Adult Hepatic Langerhans Cell Histiocytosis: Report of Two Cases With Different Clinico-pathological Manifestations

Langerhans cell histiocytosis (LCH), a clonal neoplasm of myeloid dendritic cells more commonly involves the pediatric population than the adults.^1,2 Hepatic involvement by LCH, especially when isolated, is prone to misdiagnosis as it can have a wide range of clinical presentation and mimics other primary liver diseases. We describe the clinical and histopathological spectrum of two exceptional cases of adult hepatic LCH with variable presentations and outcomes.

The first individual was a 31-year-old gentleman who presented to the adult gastroenterology outpatient department with a complaint of dull aching right upper quadrant pain in abdomen for the last one year along with a weight loss of 12 kg since the onset of symptoms. On examination, the liver was not palpable though the spleen was just palpable below the left costal margin. Additionally, acneiform papules and a few pustules with hyperpigmentation were noted over the face, upper limb, body, and scalp. The hematological investigations and the liver function tests highlighted mild anemia, leucocytosis, raised ESR, elevated serum ferritin and ceruloplasmin, mildly elevated transaminases, and reversal of albumin: globulin ratio while the serum total bilirubin, conjugated bilirubin, total protein, albumin, prothrombin time, and international normalized ratio (INR) were within normal limits (Supplementary Table). Viral serology for HBV, HCV, and HIV, tTG-IgA, and autoimmune serology for ANA, SMA, LKM, PCA, and AMA was negative. Transabdominal ultrasound (TA-US) showed coarse echotexture of liver and mild splenomegaly. On transient elastography (Fibroscan), Liver stiffness measurement (LSM) was 14.1 kPa. Controlled attenuation parameter score (CAP) was 178 dB/m. FDG-PET CT scan showed a mildly FDG avid cutaneous thickening in the posterior chest wall, (SUV max 4.9), right anterior chest wall, few sites in the pubic region as well as on the medial aspect of the right leg. Upper GI endoscopy did not reveal any varices.

The second individual was a 32-year-old gentleman who presented with a history of shortness of breath increasing on exertion (Modified Medical Research Council grade II) which was insidious in onset and slowly progressive over 5 months. He was diagnosed with bilateral recurrent pneumothorax, managed with intercostal chest drain placement on multiple occasions, and right-sided pleurodesis. He also started noticing yellowish discoloration of eyes and urine starting within one month of onset of dyspnea. This was also gradually progressive and was associated with episodes of clay-colored stool and pruritus. There was no history of fever, abdominal distension, or gastrointestinal bleeding. The patient also developed bullous skin lesions involving scalp, nodular lesions over the forehead, and macular skin lesions involving the chest, anterior torso, and back. This was associated with the fragility of the fingernails. The patient also had a history of recurrent gingivitis and dental caries for the last two years requiring multiple tooth extractions and placement of artificial dentures. The hematological investigations and the liver function tests highlighted mild anemia, raised ESR, elevated serum ferritin and a cholestatic profile with conjugated hyperbilirubinemia, 3–4 times elevation of serum alkaline phosphatase, mildly elevated transaminases, elevated INR, and reversal of albumin: globulin ratio (Supplementary Table). TA-US showed hepatomegaly (liver span 18.5 cm) with bilateral lobar and peripheral intrahepatic biliary radicle dilatation (IHBRD) as well as a prominent common bile duct (CBD). Magnetic resonance imaging with cholangiopancreratography (MRCP) showed many T1 hypointense and T2 hyperintense lesions in the liver. There were multiple peripherally enhancing cystic hepatic lesions with prominent IHBRD and narrowing of left hepatic duct (LHD) near the primary confluence. CECT chest revealed centriacinar emphysema with multiple air-filled cystic lesions in both lungs and bilateral pneumothoraces (Supplementary Figure 1). A few lytic lesions were also noted in the vertebrae. Endoscopic retrograde cholangiopancreatography (ERCP) and biliary stenting were done to alleviate the progressive jaundice. However, it worsened over time without any evidence of cholangitis.

EUS-guided liver biopsies were performed from both lobes using a 19-G biopsy needle in both cases. The liver biopsies in both these cases showed expansion of the portal tracts by fibrosis with occasional porto-portal bridging septa (Figure 1a), an eosinophil-rich inflammatory infiltrate along with occasional eosinophilic microabscesses, admixed with variable aggregates of atypical histiocytoid cells (Figure 1b). These atypical cells showed abundant pale, eosinophilic cytoplasm, eccentrically placed nuclei, frequent nuclear grooves, evenly dispersed chromatin, and inconspicuous nucleoli (Figure 1b). These atypical cells were focally seen impinging on the bile ducts causing their destruction (Figure 1c). In contrast to the first case, the second case showed marked hepatocanalicular cholestasis (Figure 1d) and extravasated bile with giant cell reactions around it. The atypical cells showed diffuse, strong immunopositivity for CD1a (membranous) (Figure 1e) and langerin/CD207 (cytoplasmic) (Figure 1f). CK7 immunostain highlighted the destruction of the bile ducts (Figure 1g). Immunohistochemistry for BRAFV600E was negative in the first case and was not performed in the second case. The skin biopsy in the second case showed infiltration by the atypical cells in contrast to the first case. The bone marrow aspirate and biopsy in both cases did not show any infiltration. The second case showed histological features of large bile duct obstruction, and chronic cholestasis in the form of intrahepatocytic copper retention (rhodanine stain) and biliary metaplasia (CK7 immunostain) compared to the first one which did not show any feature of chronic cholestasis (Supplementary Figure 2). Thus, the overall morphological and immunophenotypic findings in these two cases were consistent with a diagnosis of single system-LCH (SS-LCH) and multisystem LCH (MS-LCH) (liver, skin, bone, and the lungs) respectively with high-risk organ (liver) involvement.

Figure 1.

Histopathology and immunohistochemistry: Dense portal fibrosis with porto-portal bridging fibrosis (a, Masson trichrome, 20×), eosinophil-rich inflammation (black star) with collection of atypical histiocytoid cells (thick black arrows) (b, Hematoxylin and eosin, 400×), destruction of the bile ducts (thin black arrow) by the tumor cells and inflammatory cells (c, Hematoxylin and eosin, 400×), and hepatocanalicular cholestasis (d, Hematoxylin and eosin, 400×). CD1a (e, 400×) and CD207 (f, 400×) showing diffuse immunopositivity of the Langerhans cells while CK7 highlighting the bile duct with ongoing destruction (g, 400×). Note the interlobular bile duct with ongoing damage (thin black arrow).

The first patient received an induction chemotherapy regimen using DAL HX83 protocol comprising vinblastine, etoposide, and prednisone, with a subsequent plan to treat with methotrexate and 6-Mercaptopurine. The patient is doing well and tolerating the treatment till date (3 months after the beginning of treatment and 4 months after the initial presentation). The second patient received 5 cycles of vinblastine and prednisolone. However, he was readmitted after 2 months with worsening jaundice and cholestatic symptoms. Repeat MRCP suggested a possibility of sclerosing cholangitis, possibly resulting from infiltration by LCH. Following a multidisciplinary discussion, the patient was referred for liver transplantation awaiting the same.

LCH is a clonal neoplasm of myeloid dendritic cells with a characteristic Langerhans cell immunophenotype and atypical histiocytoid morphology, in the form of positivity for CD1a and CD207 (langerin, a surrogate of Birbeck granules, characteristic of LCH). The disease occurs predominantly in children, with an annual incidence of 5–9 cases per million while the occurrence in adults is much rarer with an annual incidence of only 1–2 new cases per 1 million.¹ Its classification is based on a number of involved sites (single or multisystem LCH), each of which accounts for half of the patients. The most commonly involved organs are the skeletal system, skin, or the pituitary gland while the involvement of other organs such as liver, spleen, lungs, lymph nodes, or central nervous system usually occurs as a part of multisystem LCH (MS-LCH). Involvement of the bone marrow, liver, or spleen is categorized as high-risk disease, and is associated with a poor prognosis.²

Adult LCH usually presents after the fourth decade, and approximately two-thirds of patients have multisystem involvement at diagnosis.² Isolated liver involvement, as in the first case, is particularly unusual, with only a handful of cases reported in literature.3, 4, 5 Patients often present with hepatomegaly, hypoalbuminemia, or features of cholestasis.⁶ The first case was unusual as the individual was asymptomatic other than the weight loss along with mild elevation of the transaminases. Besides, the features of cholestasis were subtle despite histological evidence of bile duct destruction by the Langerhans cells. However, the LSM value and the reversal of the A: G ratio corroborated with the advanced fibrosis during the diagnosis. In contrast, the second case showed frank features of cholestasis with evidence of duct destruction and stricture formation simulating a sclerosing cholangitis-like picture.

The diagnosis of unsuspected hepatic LCH on liver biopsy is challenging. The pattern of involvement varies depending on the stage of disease. Early stages are characterized by portal or lobular infiltration by atypical histiocytes with periductal and duct-destructive collection of neoplastic cells. The late stages show a sclerosing cholangitis-like pattern akin to the second case with extensive periductal fibrosis and rare to absent neoplastic cells. A subset of these patients progresses to cirrhosis.^7,8 The atypical histiocytes show complex nuclear contours with grooves, fine chromatin, and moderate to abundant eosinophilic cytoplasm in an eosinophil-rich background. Ultrastructural examination reveals Birbeck granules, a tennis racket/zipper-shaped subcellular structure.¹ BRAFV600E mutation can occur in 40–70% cases of LCH although the incidence can be low, especially in the adulthood.^9,10

Treatment of LCH depends on the extent of organ involvement. Patients with solitary disease can be kept on close observation or given local therapy in form of single lymph node resection or curettage of solitary bone lesion. On the other hand, patients with MS-LCH are treated with systemic steroids and chemotherapy, comprising of vinblastine, methotrexate, and cladribine.² Advanced-stage disease and cirrhosis do not respond well to chemotherapy. At later stages, liver transplantation may be indicated.⁸ Hepatic LCH has a relatively poor prognosis, with a fatality rate of 30% and may also portend the onset of MS- LCH. Thus, it is important to keep the patient on a close follow-up.

Credit authorship contribution statement

GK, AC, and SaM were involved in the collection and analysis of the data along with the first draft of the manuscript, JS, GP, PM, and AD were involved in the clinical management and follow-up of the patient and critically reviewed the manuscript. PG was involved in the radiological evaluation and diagnosis of the cases and critically reviewed the manuscript. KG was involved in the diagnosis of a case and critically reviewed the manuscript. SuM was involved in the conceptualization, diagnosis, preparation, and finalization of the manuscript.

Conflicts of interest

The authors declare no conflict of interest.

Funding

The authors received no funds for this study.

Appendix A. Supplementary data

The following are the Supplementary data to this article:

Fig. S1.

Radiology of Case 2: MRI of the liver highlighting multiple peripherally enhancing cystic hepatic lesions (S1a) with prominent intrahepatic biliary radicle dilatation (IHBRD) and narrowing of left hepatic duct (LHD) near the primary confluence (white arrow, S1b). CECT chest highlighting centriacinar emphysema with multiple air-filled cystic lesions in both lungs and pneumothorax (S1c)

Fig. S2.

Comparison of rhodanine stain and CK7 immunostain between Case 1 and Case 2: No rhodanine positivity (S2a) and nil to occasional biliary metaplasia (S2b) in Case 1 compared to diffuse periportal hepatocytic rhodanine positive granules (black arrows, S2c) and panacinar biliary metaplasia (S2d) in Case 2