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Year : 2022  |  Volume : 59  |  Issue : 1  |  Page : 119--122

Langerhans cell sarcoma with BRAF-V600E mutation and hemophagocytosis: An autopsy report

Manoj G Madakshira1, Navneet Sharma2, Pankaj Malhotra3, Amanjit Bal1,  
1 Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Internal Medicine and Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Correspondence Address:
Amanjit Bal
Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh


Langerhans cell sarcoma (LCS) is a rare high-grade neoplasm of langerhans cell phenotype having unambiguous malignant cytological features. We report such a rare case in a 20-year-old man who presented with dyspnea and high-grade fever. On evaluation, he had generalized lymphadenopathy, hepatosplenomegaly, and a large anterior mediastinal mass. Fine needle aspiration from the mediastinal mass and bone marrow aspirate showed numerous atypical cells, many of which showed grooved nuclei. In addition, the bone marrow showed prominent hemophagocytosis. The patient had a stormy hospital stay and succumbed to the illness. The autopsy revealed a rare multisystem involvement by LCS involving the lymph nodes, liver, spleen, lungs, and intestine, which harbored a BRAFV600E mutation and was associated with hemophagocytosis.

How to cite this article:
Madakshira MG, Sharma N, Malhotra P, Bal A. Langerhans cell sarcoma with BRAF-V600E mutation and hemophagocytosis: An autopsy report.Indian J Cancer 2022;59:119-122

How to cite this URL:
Madakshira MG, Sharma N, Malhotra P, Bal A. Langerhans cell sarcoma with BRAF-V600E mutation and hemophagocytosis: An autopsy report. Indian J Cancer [serial online] 2022 [cited 2022 Aug 17 ];59:119-122
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Langerhans cell sarcoma (LCS) is a rare malignant neoplasm characterized by unambiguous malignant cytology, brisk mitosis, and immunophenotype of CD1a, CD207, and S100p.[1] It has an incidence of 0.2 per 10,000,000.[2] The tumor can manifest with single or multiple sites involvement.[2] BRAFV600E mutation is reported in a subset of cases.[3] We discuss the autopsy findings with the involvement of lymph nodes, liver, spleen, gut, and lungs with sparing of the skin and concomitant hemophagocytosis as part of a rare constellation in LCS.[2]

 Case Report

A 20-year-old man presented with dyspnea, preceded by high-grade fever. On examination, he had generalized lymphadenopathy, hepatosplenomegaly, free fluid in the peritoneal cavity, and decreased breath sounds in the right infrascapular region. During the 11 days of hospital stay, he had persistent tachycardia and tachypnoea. Investigations revealed macrocytic anemia with a rising leukocytosis (9500 to 14300 per mm3, Reference range: 5000 to 10000 per mm3) and worsening of thrombocytopenia (56000 to 13000 per mm3, Reference range: 150000 to 450000 per mm3). Clinical chemistry showed increasing transaminitis (Aspartate aminotransferase/Alanine aminotransferase: 319/265 units per liter to 2740/1038 units per liter, Reference range: 7 to 55 units per liter/8 to 48 units per liter), a rise in unconjugated hyperbilirubinemia (Total Bilirubin/Direct Bilirubin: 2.04/0.7 to 4.16/1.77 mg per deciliter, Reference range: 0.3 to 1.0 mg per deciliter/0 to 0.4 mg per deciliter) and hypoalbuminemia (Total protein/Albumin: 5.6/2.3 gm per deciliter, Reference range: 6 to 8 gm per deciliter/3.5 to 5.0 gm per deciliter). There was a persistent rise in serum lactate dehydrogenase (1728 to 4736 units per liter, Reference range: 140 to 280 units per liter) with a terminal rise in d-dimer levels Reference range: 3676 IU/ml (less than 0.5 IU/ml). Also noted was a rise in serum procalcitonin (2.3 to 7.3 ng per ml, Reference range: 0.10 to 0.49 mg per milliliter) with maintained renal function (blood urea nitrogen/creatinine; 18/0.74 mg per deciliter, Reference range: 7 to 20 mg per deciliter/0.84 to 1.21 mg per deciliter). Computed tomography showed an anterior mediastinal mass with consolidation of right middle and lower lobe of lung, bilateral pleural effusion, hepatosplenomegaly with mild intra-hepatic biliary radical dilation, cholelithiasis, nodular thickening of the gut wall and mesenteric lymphadenopathy [Figure 1]a. Serum ascitic-albumin gradient was 1.4. Bone marrow showed prominent histiocytes with evidence of hemophagocytosis and clusters of atypical cells with vesicular grooved nuclei. Fine needle aspiration from mediastinal mass showed similar atypical cells. The patient was managed with assisted ventilation under broad-spectrum antibiotic cover and platelet replacement. With a suspicion of high-grade lymphoma and secondary hemophagocytosis, he was started empirically on intravenous corticosteroids on day 8. The patient had a stormy course with copious blood on endotracheal suction leading to cardiorespiratory arrest on Day 11.{Figure 1}

On partial clinical autopsy, the serous cavities yielded about 1 liter of peritoneal and 500 ml fluid in each pleural cavity. There was generalized lymphadenopathy involving the cervical, axillary, inguinal, paratracheal, hilar, carinal, paraaortic, periportal, para-aortic and mesenteric groups. The mediastinal mass was measuring 6 × 5 × 4 cm having a variegated cut surface [Figure 1]b. Histology showed near-total replacement of the nodal architecture by sheets of atypical cells [Figure 1]c. These cells had large reniform, lobulated, grooved nuclei with moderate eosinophilic cytoplasm [Figure 1]d. Scattered polylobate and multinucleated cells were seen [Figure 1]e. Brisk mitosis was present (5-6 per high per field) with many atypical mitotic figures [Figure 1]f. The background population were of lymphocytes, plasma cells, and eosinophils. The atypical cells were positive for CD45, CD68 [Figure 1]i, S100p, CD1a [Figure 1]j and CD56, while being negative for CD3, CD20 and CD30 [Figure 1]g and [Figure 1]h. The tumor tissue was positive for BRAF-V600E mutation by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and sanger sequencing [Figure 3]a. The liver was enlarged (2200 gm) and the cut surface showed diffuse greyish white areas which corresponded to expanded portal tracts with infiltration by similar atypical cells [Figure 2]b and [Figure 3]c. In addition, the Kupffer cells showed hemophagocytosis. The spleen was heavy (450 gm) and showed multiple infarcts with intervening greyish white nodules, which corresponded to diffuse infiltration of the red pulp by similar atypical cells [Figure 2]b. Bone marrow showed similar atypical cells, with evidence of hemophagocytosis [Figure 3]b. The small and large intestine showed nodular mucosal thickening which correlated to infiltration of similar atypical cells in the lamina propria [Figure 2]c, [Figure 2]d, and [Figure 3]d. Both the lungs together weighed 1200 gm with bilateral hemorrhagic consolidation [Figure 2]a. Microscopy confirmed the extensive intra-alveolar hemorrhage with patchy hyaline membrane formation. There was infiltration by similar atypical cells in the peribronchiolar and inter-alveolar interstitium [Figure 3]e. The heart, kidneys, adrenals, testes, prostate, and bladder did not show any specific pathology. In view of the histology, immunophenotype, and BRAF mutation status, a diagnosis of multisystem LCS with secondary hemophagocytosis was made.{Figure 2}{Figure 3}


LCS is an extremely rare malignant neoplasm arising from the langerhans cell, with an estimated incidence of 0.2 per 10,000,000 and can present in a wide age range (congenital - 88 yrs.).[2] A single site is involved in 60% of cases, and the remainder have disseminated disease. The common sites of involvement include skin, lymph node, bone and nasopharynx.[2] In cases with dissemination, there has been documented involvement of lungs, liver and spleen. However, there is no instance of involvement of the intestines described in the literature.[4] LCS may occur denovo, or transform from an underlying langerhans cell histiocytosis or transdifferentiate from a hematolymphoid neoplasm.[2],[5] The histology is characterized by tumor cells exhibiting nuclear pleomorphism with occasional longitudinal grooving and moderate pale eosinophilic cytoplasm.[5] The location of the tumor cells recapitulates the migratory path of langerhans cells with involvement of subcapsular sinus, paracortex, and sinuses of lymph node; red pulp of spleen; portal tracts of liver; peribronchiolar area of lungs and lamina propria of intestines.[3] The ultrastructure of these neoplastic cells may fail to demonstrate the birbeck granules which are pathognomonic of langerhans cell, indicating possible dedifferentiation. The immunophenotype, however, faithfully replicates the langerhans cell profile with positive staining for CD1a, S100p, and CD207.[5] However, the staining pattern may not be uniform in comparison with langerhans cell histiocytosis. Also documented is the aberrant expression of CD30 and CD56 in LCS which suggests a poor prognosis.[5] Molecular analysis shows some LCS to harbor the BRAFV600E mutation.[2] No case of LCS has been described with concomitant hemophagocytosis. However, there have been reports of concomitant langerhans cell histiocytosis and hemophagocytosis, with a proposed mechanism of macrophage activation through T lymphocytes.[6] Hemophagocytosis secondary to hematolymphoid neoplasms portends a very poor prognosis and is often the cause of worsening.[7] Multi-modality management with a combination of surgery and chemo-radiotherapy is suggested for LCS, with surgery being used as an option for cases with single site involvement. Bone marrow transplantation is considered as the most well-founded method of treatment but is associated with problems of patient selection, tolerance and toxicity.[2] The overall median survival in LCS is dismal at 19 months.[1] However, early detection of underlying BRAFV600E mutation and subsequent therapy with BRAF inhibitors have shown encouraging results.[8]


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