Unusual cutaneous Langerhans cell sarcoma without extracutaneous involvement
© Li et al.; licensee BioMed Central Ltd. 2013
Received: 31 October 2012
Accepted: 21 January 2013
Published: 6 February 2013
Langerhans cell sarcoma (LCS) typically presents as cytologic atypia and clinical aggressiveness and may involve multiple organs during the progression of the disease. Primary skin LCS without any extra-cutaneous site association is extremely rare and only a few such cases have been described in the literature. We present a case of unusual primary LCS in skin occurring in a middle-aged male patient. Physical examination revealed a large ulcerated cutaneous lesion and a smaller nodular lesion were located in the skin of the extensor side of his right knee. There was no regional lymph node or any other extra-cutaneous organ involvement. Histologically, typical large and pleomorphological tumor cells with epithelioid appearance and significantly malignant cytological features were observed to infiltrate in dermis and subcutaneous tissue. By immunohistochemistry, the tumor cells were positive for CD1a, S-100 protein and largerin strongly and diffusely. However, these cells were negative for CD3, CD20, CD21, pan-cytokeratin, HMB-45, Melan-A, and MPO. A diagnosis of primary cutaneous LCS was made. The patient received systemic chemotherapy of CHOP regimen, and was on a regular follow-up period for 12 months. There was no sign of relapse of tumor or any other extra-cutaneous organ involvement by whole body positron emission tomography/computed tomography (PET/CT) study. Because LCS is a high-grade malignancy with poor prognosis, it suggests that strict histological analysis and thorough radiographic examination are necessary for accurately diagnosing this tumor even if cutaneous involvement presented only.
KeywordsLangerhans cell sarcoma (LCS) Langerhans cell tumor Cutaneous involvement Differential diagnosis
According to the degree of cytologic atypia and clinical aggressiveness, Langerhans cell tumors are divided into two main subgroups: Langerhans cell histiocytosis (LCH) and Langerhans cell sarcoma (LCS) . LCS is a rare high-grade neoplasm with overtly malignant cytologic features and aggressive clinical course. It can occur at any age and may involve multiple systems or tissues. Skin and underlying soft tissue are the most common involvement, but other unusual locations, such as bone , lung , gallbladder and peritoneal lymph nodes  have also been described in the literature. LCS may be limited to cutaneous involvement or may progress to affect other organs. However, to our knowledge, primary cutaneous LCS without any extra-cutaneous association is extremely rare and so far only a few such cases with immunohistochemical and/or ultrastructural confirmation have been described in the literature [5, 6]. Due to its rareness in skin, the accurate diagnosis of cutaneous LCS could be difficult to be made because similar microscopic features may be encountered in metastatic cancer, malignant melanoma, anaplastic large cell lymphoma and myeloid sarcoma. Therefore, it is indeed a challenge for clinicians to make a correct diagnosis when the LCS presents as a solitary cutaneous mass because inaccurate diagnosis may lead to improper treatment. Herein we describe an additional case of primary cutaneous LCS arising in the skin in a middle-aged male patient without any extra-cutaneous manifestation in order to provide valuable information in this field.
Clinical presentation and management
Material and methods
The surgical specimens, including large ulcerated plaque and small nodular mass, were routinely fixed in 10% neutral buffered formalin. The tissues were embedded in paraffin. Four micrometer-thick sections were stained with H&E. Immunohistochemical analyses were performed using the ChemMate Envision/HRP Kit (Dako, Glostrup, Denmark). The antibodies used in this study included a broad panel of antibodies against CD1a, CD3, CD5, CD20, CD21, CD30, CD38, CD56, CD68, CD79a, ALK, S-100 protein, Langerin, pan-cytokeratin, HMB-45, Melan-A, MPO and ki-67. The antibodies were obtained from Dako Cytomation (Dako, Glostrup, Denmark), Santa Cruz Biotechnology (Santa Cruz, CA, USA) and Novocastra laboratories LTD (Hong Kong, China).
For detection of Epstein-Barr virus (EBV) infection in the tissues, in situ hybridization for EBERs (EBV-encoded RNAs) was performed. The EBERs detection kit was purchased from Dako (Glostrup, Denmark). The detection process was conducted according to the manufacturer’s instructions.
Langerhans cell sarcoma (LCS) is a rare but distinct tumor derived from dendritic cell lineage. It was firstly recognized by Wood and colleagues in 1984 as malignant histiocytosis X to describe a rapidly fatal cutaneous mass with massive tumor infiltration of multiple organs occurring in an elderly male patient . In 1992, Tani et al. defined it as a “malignant neoplasm of Langerhans cells with the following criteria: (i) proliferation of typical Birbeck granule-containing tumor cells, and (ii) malignant cytological features such as atypia and frequent mitotic figures” . The classification of tumor of dendritic cells is indeed controversial, and there are overlapped features among various entities of the histiocytic and dendritic cell lesions, making definitive diagnosis difficult . According to the WHO classification, tumors of dendritic cell lineage include follicular dendritic cell tumors, interdigitating dendritic cell tumors, Langerhans cell tumors and other rare dendritic cell tumors. Langerhans cells and interdigitating dendritic cells share a common hematopoietic CD34+ precursor; in contrast, follicular dendritic cells do not have a hematopoietic origin. Langerhans cell tumors show expression of both CD1a and S-100 protein, however, interdigitating cells are positive for S-100 but negative for CD1a. Follicular dendritic cells express CD21 consistently, but never express CD1a. These specific immunophenotypes of tumor cells may be helpful to identify the accurate diagnosis of dendritic cell tumors. However, indeterminate dendritic cell tumor, a rare type of dendritic cell tumor and originate from the alleged precursor cells of Langerhan cells, is indeed difficult to distinguish from Langerhans cell tumor because both tumors consistently express S-100 protein and CD1a. By definition, indeterminate dendritic cells lack Birbeck granules on ultrastructural examination . However, not all cases diagnosed as Langerhans cell tumors had ultrastructural studies to confirm the presence of Birbeck granules. Ben-Ezra et al. reported that only 3 cases presented Birbeck granules among 9 cases of LCS . Deng et al. also described a cutaneous LCS without Birbeck granules and doubted it might be an indeterminate cell sarcoma . Therefore, it is possible that some previously reported LCS might be confused with indeterminate cell neoplasms, and indeterminate cell neoplasms are actually underreported.
Recent studies suggest that langerin (CD207) represents a very specific marker for Langerhans cells and derived tumors [4, 12], and it has been negative in reported indeterminate cell neoplasms [13, 14]. Langerin is a type II Ca2+-dependent lectin and induces the formation of Birbeck granules, the presence of which supports a Langerhans cell origin. However, Wang et al. recently demonstrating a langerin-positive LCS did not indicate Birbeck granules in the cytoplasm of the neoplastic cells on ultrastructural examination . Verdijk et al. found a lack of Birbeck granules in Langerhans cells to be associated with a mutation in the langerin gene . The lack of Birbeck granules under the electron microscopy might be due to the damage of Birbeck granules during histological process  or poor differentiation of tumor cells . Thus, langerin is a useful marker for distinguishing Langerhans cell tumors from indeterminate cell tumors even in Birbeck granules-negative cases [12, 17]. In the present case, we found that the tumor cells exhibited remarkably cellular atypia and higher mitotic activity with co-expression of CD1a, S-100 protein and langerin. This is consistent with a typical primary LCS in spite of the presence of Birbeck granules in tumor cells.
Clinicopathological features of Langerhans cell sarcoma with only cutaneous involvement described in present and previous reports
Pileri SA (2002) 
Langerhans cell sarcoma
Multiple nodular lesions on skin
Pileri SA (2002) 
Langerhans cell sarcoma
Single nodular lesion on skin
Surgery and radiotherapy
Alive in complete remission
Misery L (2003) 
Malignant Langerhans cell tumor
Single red, hardened nodular lesion on skin
Surgery with large excision
2-year follow-up, no relapse/alive
The present case
Langerhans cell sarcoma
Ulcerated and nodular lesion on skin
Surgery and chemotherapy with CHOP regimen
PR, 1-year follow-up, no relapse/alive
As its rareness in skin and poorly differentiated morphologic features, cutaneous LCS should be differentially diagnosed from other epithelial or mesenchymal malignancy of skin, including metastatic cancer, malignant melanoma, anaplastic large cell lymphoma and myeloid sarcoma. All of these diseases exhibit skin lesion and a frankly malignant cytologic appearance with highly aggressive clinical course and a poor prognosis, which may sometimes cause diagnostic confusion with LCS. However, cutaneous squamous cell carcinoma or metastatic cancer shows an obvious nest structure with epithelial phenotype, such as pan-cytokeratin, CK7 or CK20. Melanoma might share S-100 protein positivity, but also expresse other melanocytic markers, such as HMB45 and melan-A. Anaplastic large cell lymphomas are CD30+ and EMA+ and may show ALK positivity. Occasionally, myeloid leukemia can firstly present in skin, in which CD68 and lysozyme positivity could be observed and sometimes difficult to be distinguished from LCS. The presence of myeloid specific markers, such as MPO, CD117, CD99 and CD34 should be helpful in making a diagnosis of myeloid leukemia first presenting in skin or cutaneous myeloid sarcoma. In our case, the tumor cells strongly expressed CD1a, S-100 protein and langerin, which were Langerhans cell-specific marker, arguing against other cutaneous hematological neoplasma.
In conclusion, LCSs are extremely rare and only a few cases of LCSs with only cutaneous involvement have been reported in the literature. Our additive case also presented its rarity of site. The diagnosis of primary cutaneous LCS is difficult and should be made cautiously, particularly for those cases with clinically localized disease, but lacking the extra-cutaneous manifestation. LCS is a highly aggressive hematopoietic malignancy with poor prognosis. We suggest a long period of follow-up is necessary and radiographic examination is helpful for demonstrating organ involvement to inspect the progression even if the patient had complete remission at initial chemotherapy.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Langerhans Cell Histiocytosis
Langerhans Cell Sarcoma
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