Leukemic transformation of Langerhans cell sarcoma
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- Sumida, K., Yoshidomi, Y., Koga, H. et al. Int J Hematol (2008) 87: 527. doi:10.1007/s12185-008-0063-x
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A 57-year-old man became aware of left supraclavicular lymph node swelling, which was subsequently diagnosed as Langerhans cell sarcoma, based on a positive immunophenotype for CD1a, S-100 protein, and langerin, and histologically bizarre pleomorphism. The tumor became leukemic 3 months later. Despite intensive chemotherapy, he died of disease progression 7 months after the initial diagnosis. Tumor cells in the leukemic phase expressed CD5, CD7, CD13, CD33, CD34, CD68, and CD123. These findings suggested leukemic transformation from Langerhans cell sarcoma. Leukemic transformation may be a clinical manifestation of advanced Langerhans cell sarcoma, and should be differentiated from acute myelogenous leukemia.
KeywordsLangerhans cell sarcomaLeukemic transformationAcute myelogenous leukemia
Langerhans cells, uniquely present in the epidermis of the skin, are members of a family of the professional antigen-presenting cells called dendritic cells. Langerhans cells are myeloid-lineage dendritic cells, which originate from the bone marrow [1, 2]. Neoplastic proliferations of Langerhans cells are classified by the World Health Organization (WHO) into Langerhans cell histiocytosis and Langerhans cell sarcoma . Langerhans cell sarcoma is considered to be a higher-grade variant of Langerhans cell histiocytosis, and is rarely reported . Bohn et al.  summarized 20 Langerhans cell sarcoma cases reported in the English-language literature; most of the patients revealed lymph node and skin involvement, although the lungs, liver, spleen, and bone marrow may also be involved. They showed a poor prognosis and a short survival period, despite conventional combination chemotherapy, surgery, and radiotherapy. We describe a patient who developed leukemic transformation from Langerhans cell sarcoma.
2 Case report
Histologic immunostaining and flowcytometric analysis of tumor cells
LN Flowcytometry (%)
BM Flowcytometry (%)
Kappa light chain
Lambda light chain
The tumor of the present patient was diagnosed as Langerhans cell sarcoma based on the presence of large cells with bizarre pleomorphism, and positivity for CD1a, S-100 protein, and langerin. The diagnosis of Langerhans cell tumors, which include Langerhans cell histiocytosis and Langerhans cell sarcoma, requires the expression of both CD1a and S-100 protein . The expression of some histiocytic markers is also frequent, such as CD68 and some focal, weak expression of lysozyme . Langerhans cell sarcoma is considered a higher grade variant of Langerhans cell histiocytosis, showing overtly malignant cytological features and striking pleomorphism .
Langerhans cell sarcoma is rare. It can present de novo or progress from antecedent Langerhans cell histiocytosis [3, 6]. Lee et al.  summarized 19 patients with Langerhans cell sarcoma reported in the English-language literature from 1973 to 2006. In addition to the skin, the lymph nodes, spleen, liver, bone marrow, thymus, lung, and kidney were frequently involved. Similarly, Bohn et al.  summarized 20 Langerhans cell sarcoma cases reported in the English-language literature (including 4 cases reported by Lee et al. ) from 1992 to 2007. These cases were diagnosed according to the immunophenotype of the tumor cells (CD1a and S-100 protein expression) and the WHO criteria [3, 5]. The ages of the patients ranged between 10 and 81 years, with a male–female ratio of 1:1. Most of the patients showed lymph node and skin involvement, although the lungs, liver, spleen, and bone marrow may also be involved . Only four cases were unifocal, with the disease mainly affecting the skin. In our patient, tumor cells were observed at a rate of more than 90% in peripheral blood and bone marrow, in addition to lymph nodes, tonsils, and the spleen. Langerhans cell tumors have been reported to be associated with other neoplasms such as follicular center lymphoma, adenocarcinoma, and mediastinal germ cell tumor . Therefore, acute myelogenous leukemia (AML) may have developed coincidently in our patient. However, the tumors were positive for CD68, CD123, CD5, CD7, CD13, and CD33, as were the tumor cells of lymph nodes, although CD1a, S-100 protein, and langerin were not expressed. Moreover, the tumor became leukemic only 3 months after the initial diagnosis. These findings suggested the leukemic transformation of Langerhans cell sarcoma in our patient.
Interaction between granulocyte–macrophage colony-stimulating factor and tumor necrosis factor (TNF)-alpha is crucial for the generation of human dendritic/Langerhans cells from CD34+ hematopoietic progenitors . Cultures of cord blood CD34+ hematopoietic progenitor cells with interleukin-3 + TNF-alpha also yield CD1a+ cells . Moreover, CD1a+ dendritic cells acquire Langerhans cell characteristics such as E-cadherin, langerin, Lag Ag, and Birbeck granules, when cultured in the presence of cytokines [8, 9]. Therefore, the tumor cells of our patient may have lost their immunophenotype, such as CD1a, S-100 protein, or langerin, in the leukemic phase, as they became less differentiated and more atypical.
Imamura et al.  described a 9-year-old girl with leukemic infiltration of Langerhans’ granule-containing histiocytes characterized by indented nuclei and abundant, faintly acidophilic cytoplasm. The initial diagnosis of this patient was acute granulocytic leukemia, because the peripheral WBC count was 69,200 μL−1, with 62% myeloblast-like, abnormal cells. Henderson et al.  also reported a 22-year-old man who developed histiocytic leukemia at an advanced stage. Rod-shaped structures consistent with Langerhans’ cell granules were detected in the cytoplasm of atypical histiocytes by electron microscopy. Kawase et al.  reported a 62-year-old patient with Langerhans cell sarcoma who developed AML (French–American–British classification, M2) after chemotherapy for Langerhans cell sarcoma, although it was not described whether or not AML was related to Langerhans cell sarcoma. These clinical observations suggest that a significant proportion of Langerhans cell sarcomas may become leukemic at an advanced stage.
Bohn et al.  reported that it is important to differentiate Langerhans cell sarcoma from tumors with a pleomorphic component. Because of the marked cytologic atypia and bizarre pleomorphism, hematologic and non-hematologic entities must be considered in the differential diagnosis, which includes malignant melanoma, anaplastic carcinoma, diffuse large cell lymphoma, anaplastic large cell lymphoma, T-cell lymphoma, and dendritic cell tumors. Similarly, the leukemic transformation of Langerhans cell sarcoma should also be differentiated from AML, because tumor cells share myeloid antigens. Immunophenotypic analysis such as of CD1a, S-100 protein, langerin, or CD68, and electron microscopy may be useful in differentiating the leukemic phase of Langerhans cell sarcoma from AML.
Our patient died of disease progression 7 months after the initial diagnosis. The overall survival of Langerhans cell sarcoma patients is reported to be approximately 50% . In the review by Lee et al. , 11 of the 19 patients died within 2 years and 1 died at 40 months. Of the remaining 7 patients who survived, the skin was the only organ involved in 3 patients, and 4 of the patients had been followed-up for less than 1 year . The course of the disease is generally related to the number of organs affected at presentation . On the other hand, Kawase et al.  reported that CD56 may be a clinically relevant biologic marker for predicting an intractable course of Langerhans cell neoplasm, although the tumor cells of our patient did not express CD56. Due to the poor prognosis of Langerhans cell sarcoma, a novel therapeutic approach, including stem cell transplantation, should be considered at an early stage.
We are grateful to Hidenori Tsukiji for technical assistance.