Complexity of diagnosing and treating langerhans cell sarcoma: A case report.

INTRODUCTION: Langerhans cell sarcoma (LCS) is a very rare malignant tumor of Langerhans cells that may metastasize to many organs. The diagnosis of this tumor is difficult and its prognosis is poor. AIM: To report the difficulty to diagnose LCS, and discuss therapeutic management of this rare entity. CASE PRESENTATION: We report a case of LCS in a 52-year-old man who presented with an axillar lymphadenopathy. The diagnosis of nodular sclerosis type Hodgkin's disease was established after histologic examination. The patient was treated with chemotherapy (ABVD regimen: Doxorubicin, Bleomycin, Vinblastine, Dacarbazine) and radiotherapy with a partial response. However, disease recurrence was observed and histological analysis confirmed the diagnosis of Langerhans cell sarcoma. A revision of the initial histological examination concluded to the diagnosis of sarcoma from the beginning. We chose the ESHAP (Etoposide, Methylprednisolone, Aracytine, Cisplatin) regimen and clinical improvement of LCS was obtained after 2 cycles but the patient had a fatal outcome and died by disease progression. CONCLUSION: Because of its rarity, diagnosis is difficult and an optimal treatment strategy for this disease has not yet been identified. Polychemotherapy can be an effective modality for the treatment of LCS.

The Expression of Insulin-Like Growth Factor 2 Messenger RNA-Binding Protein 3 in Langerhans Cell Histiocytosis and Langerhans Cell Sarcoma.

Langerhans cell neoplasms, which include Langerhans cell histiocytosis and Langerhans cell sarcoma, are tumors that originate from dendritic cells. Langerhans cell sarcoma is defined as a high-grade neoplasm with overtly malignant cytological features and the Langerhans cell-like phenotype, and generally has a poorer prognosis and more aggressive phenotype than Langerhans cell histiocytosis. Insulin-like growth factor 2 messenger RNA-binding protein 3 (IGF2BP3 or IMP3) is an oncofetal protein that is expressed in various cancer types; its expression is often associated with a poor prognosis and aggressive phenotype. Here, we used immunohistochemistry to evaluate IGF2BP3 expression in Langerhans cell neoplasms. IGF2BP3 expression was scored as negative (< 1%) or positive (≥ 1%) by immunohistochemistry. All 4 patients with Langerhans cell sarcoma (100%) and 6 of 22 pediatric (age < 18 years) patients with Langerhans cell histiocytosis (27.3%) had positive results for IGF2BP3; however, 16 of 22 pediatric patients with Langerhans cell histiocytosis (72.7%) and all 15 adult (age ≥ 18 years) patients with Langerhans cell histiocytosis (100%) had a negative result. Among patients with Langerhans cell histiocytosis, IGF2BP3 expression was independent of sex, location, prognosis, and BRAF V600E staining results. Taken together, these results indicate that IGF2BP3 expression may be a helpful marker for distinguishing Langerhans cell sarcoma from Langerhans cell histiocytosis in adult patients.

From the archives of MD Anderson Cancer Center: A case of concurrent follicular lymphoma and Langerhans cell sarcoma with a review of the literature.

Transdifferentiation of follicular lymphoma to a Langerhans cell neoplasm is rarely reported and not well understood. Here we present a case, review the literature and discuss some of the biological underpinnings of lineage switch of B cells to histiocytes/Langerhans cells. A 31-year-old woman had follicular lymphoma (FL) and Langerhans cell sarcoma (LCS) co-localized above and below diaphragm. The FL was low-grade, had typical morphologic features, and was positive for CD10, BCL-2, and BCL-6. The LCS was cytologically atypical with necrosis and a high mitotic rate, and the immunophenotype supported Langerhans cell lineage positive for CD1a, CD207/langerin, and S-100 protein. Both tumors carried IGH-BCL2 and the LCS cells had immunophenotypic evidence of a residual B cell program, supporting the notion that these neoplasms are clonally related. The case reported is unusual because the patient was young and both diseases presented simultaneously, before any therapy. In addition, immunohistochemical analysis showed that the LCS was negative for BRAF V600E and phospho-ERK, suggesting that the LCS belongs to the known subset of Langerhans cell tumors lacking BRAF V600E and MAP2K1 mutations. Concurrent occurrence of FL and Langerhans cell neoplasm is an unusual phenomenon, with 10 cases reported previously: 4 Langerhans cell histiocytosis and 6 Langerhans cell sarcoma, including this case.

Langerhans cell sarcoma involving skin and showing epidermotropism: A comprehensive review.

Langerhans cell sarcoma (LCS) is rare and aggressive; patients have an overall survival rate of less than 50%. We present a 62-year-old man with a history of superficial spreading melanoma of the upper back with sentinel lymph node metastasis, Langerhans cell histiocytosis, and LCS. The patient presented with erythematous papules and scaly areas on his face, neck, arms, chest, abdomen, and legs. A skin biopsy revealed a proliferation of large neoplastic cells involving the dermis and with epidermotropism. These cells had atypical bean-shaped nuclei, with ample cytoplasm and abundant mitotic figures including atypical forms. Immunohistochemical studies showed the tumor to be diffusely positive for CD1a, S100 protein, and langerin (CD207) and negative for melanocytic markers. Some tumor cells were positive for cyclin D1. A diagnosis of LCS involving the skin was established. The present study is a very unusual case of LCS showing epidermotropism. The patient's history of metastatic melanoma posed additional challenges for diagnosis, underlying the need of immunophenotyping in these cases. Consensus for optimal standard therapy has not been established in LCS, and thus, early recognition is important since these neoplasms tend to recur and metastasize. LCS in skin is discussed and published cases are comprehensively reviewed.

A case of Langerhans cell sarcoma on the scalp: Whole-exome sequencing reveals a role of ultraviolet in the pathogenesis.

Langerhans cell sarcoma (LCS) is a high-grade neoplasm with overtly malignant cytological features and a Langerhans cell phenotype. The underlying genetic features are poorly understood, and only a few alterations, such as those of the MARK pathway-related genes, CDKN2A and TP53 have been reported. Here we present a 70-year-old male with LCS on the scalp and pulmonary metastasis. The multinodular tumor, 3.0 cm in diameter, consisted of diffusely proliferated pleomorphic cells with numerous mitoses (53/10 HPFs). Immunohistochemically, the tumor cells were positive for CD1a, Langerin and PD-L1, and the Ki-67 labeling index was 50%. These pathological features were consistent with LCS, and were also observed in the metastatic tumor. Whole-exome sequencing revealed that both the primary and metastatic tumors harbored a large number of mutations (>20 mutations/megabase), with deletion of CDKN2A and TP53 mutation, and highlighted that the mutational signature was predominantly characteristic of ultraviolet (UV) exposure (W = 0.828). Our results suggest, for the first time, that DNA damage by UV could accumulate in Langerhans cells and play a role in the pathogenesis of LCS. The high mutational burden and PD-L1 expression in the tumor would provide a rationale for the use of immune checkpoint inhibitors for treatment of unresectable LCS.

Concurrent cutaneous localization of Langerhans cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma in a patient with a history of chronic lymphocytic leukemia/small lymphocytic lymphoma.

The phenomenon of histiocytic/dendritic cell sarcomas arising through transformation of a pre-existed lymphoproliferative disease is called transdifferentiation. Langerhans cell sarcoma transdifferentiating from chronic lymphocytic leukemia/small lymphocytic lymphoma is extremely rare and all the reported cases were localized in lymph nodes. We present a case of concurrent cutaneous localization of Langerhans cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, in which the chronic lymphocytic leukemia/small lymphocytic lymphoma preceded the development of the Langerhans cell sarcoma. A cutaneous lesion from a 63-year-old patient with a history of chronic lymphocytic leukemia/small lymphocytic lymphoma was biopsied. The histologic examination revealed a mixture of two cell populations infiltrating diffusely the dermis. The first was composed of small lymphoid cells with somewhat monotonous appearance and mild nuclear atypia positive for PAX5, CD79a, CD20, CD23, CD5, and LEF1. The second was composed of large cells with abundant cytoplasm and pleomorphic nuclei. These cells were positive for CD1a, CD207, and S100 protein and exhibited a high mitotic rate and a high MIB-1 immunostaining index. Therefore, two different entities, chronic lymphocytic leukemia/small lymphocytic lymphoma and Langerhans cell sarcoma, were detected in the same skin fragment. The patient died 3 years after initial diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma.

Incidence, Clinical Features, and Outcomes of Langerhans Cell Sarcoma in the United States.

BACKGROUND: Limited knowledge exists on the incidence, treatment patterns, and long-term outcomes of Langerhans cell sarcoma (LCS) in the United States. PATIENTS AND METHODS: We performed a retrospective study of LCS patients diagnosed between 2001 and 2014 using the Surveillance, Epidemiology, and End Results (SEER) and National Cancer Data Base (NCDB) databases. Incidence was calculated from SEER, and treatment patterns and outcomes were calculated from NCDB. RESULTS: A total of 25 and 52 cases of LCS were reported to SEER and NCDB, respectively. The overall incidence of the disease was 0.2 per 10,000,000 and did not differ by race (P = .56) or sex (P = .33). The median age at diagnosis was 62 (range, 19-90) years. Of the 52 patients from NCDB, 20 (39%) received chemotherapy as first-line therapy, 24 (46%) received surgery, and 15 (29%) received radiotherapy. The 1-year overall survival (OS) rate was 62%, and the median OS was 19 months. After censoring the patients with bone marrow and reticuloendothelial system involvement, no significant difference in OS was noted between the patients who were managed with or without surgery (P = .75). Postsurgical radiation or chemotherapy were not associated with improvement in median OS (P = .25). Patients who were managed with radiotherapy had a better OS compared to those who received no radiotherapy (P = .03). CONCLUSION: This dual-national registry study shows that LCS is extremely rare and has a poor prognosis. Radiotherapy may offer a survival advantage to patients with locoregional disease without bone marrow and reticuloendothelial system involvement.

Liquid-based cytology in the diagnosis of Langerhans cell sarcoma: A case report.

Langerhans cell sarcoma (LCS) is an extremely rare malignant dendritic cell neoplasm with Langerhans cell differentiation. Conventional cytology, based on cell morphology alone, cannot render a cytological diagnosis of LCS because immunochemical analysis is essential to identify the Langerhans cell immunophenotype. We present a case illustrating the value of liquid-based cytology with immunocytochemistry as compared with conventional cytology, along with histological and immunohistochemical findings. A 92-year-old woman presented with a 1-month history of progressive right cervical lymphadenopathy. Cytology of a fine needle aspiration sample from the right superior internal jugular lymph node revealed proliferation of atypical, pleomorphic, and histiocytoid cells with one or more irregular-shaped nuclei. Compared with conventional cytology, liquid-based cytology demonstrated more clustered and spatial cells, slightly less marked nuclear atypia, more intense light green staining of the cytoplasm, and a clearer background. Immunocytochemical analysis of the abnormal cells revealed expression of vimentin, CD1a, langerin, CD68, and S-100. The combined morphologic and immunocytochemical results strongly indicated LCS. Histological and immunohistochemical examination of a subsequent excisional biopsy specimen closely coincided with the results of liquid-based cytology. Thus, this technique, including the use of immunocytochemistry, is very useful and valuable for the pathological diagnosis of nonepithelial and hematopoietic neoplasms. There are subtle but considerable differences in cell morphology between conventional and liquid-based cytology; these differences include clusterability, spatial findings, dyeability, and atypism as illustrated in this case of LCS.

A Case of Pulmonary Langerhans Cell Sarcoma Simultaneously Diagnosed with Cutaneous Langerhans Cell Histiocytosis Studied by Whole-Exome Sequencing.

Langerhans cell histiocytosis (LCH) and Langerhans cell sarcoma (LCS) are clonal proliferations of Langerhans-type cells. Unlike in LCH, the pathophysiology and clinical course of LCS are unclear due to its rarity. Here, we report the case of a 73-year-old male patient who was diagnosed with cutaneous LCH and pulmonary LCS at the same time. Pathological review of these 2 tumors revealed similar immunohistochemical findings. However, the tumor cells in LCS had more aggressive cytological features than those in LCH. Results of BRAF mutation analysis using real-time PCR were negative for both tumors. In whole-exome sequencing (WES), stop-gain mutations in TP53 gene were discovered only in LCS cells. The mechanism of development of LCS from various progenitor cells is currently unclear. According to the results of the WES study, changes in TP53 gene might have contributed to the malignant features of LCS.

Cytological findings of langerhans cell sarcoma in a case of quintuple cancer.

Langerhans cell sarcoma (LCS) and quintuple cancers are extremely rare. In this report, a case of quintuple cancers including LCS was described. An 80-year-old man had squamous cell carcinoma of the nasal skin, colon and rectum adenocarcinomas, and T-cell/histiocyte-rich large B-cell lymphoma. As swelling of multiple submental lymph nodes was observed, fine-needle aspiration was carried out. Many large cells with high-grade nuclear atypia and abundant cytoplasm were observed. Lymphocytes and eosinophils were observed in the background. Although a malignant tumor was suspected, a definite diagnosis could not be made. In a biopsy sample, the tumor cells were positive for vimentin, CD68, S-100, CD1a, and CD163 and negative for epithelial, lymphocyte, and melanoma markers in immunohistochemistry. A diagnosis of LCS was made from the immunohistochemical findings and high mitotic rate with atypical forms. The patient died about 2 months after the first medical examination. Metastasis of LCS was confirmed in many organs by autopsy. LCS has a poor prognosis. In cases with the above-described cytological findings, LCS should be added to the list of differential diagnosis. The cytological findings presented here may be useful for determining appropriate clinical management such as staging of the disease and follow-up of the neoplasm. Diagn. Cytopathol. 2017;45:441-445. © 2017 The Authors Diagnostic Cytopathology Published by Wiley Periodicals, Inc.

Langerhans Cell Histiocytosis and Langerhans Cell Sarcoma: Current Understanding and Differential Diagnosis.

Langerhans cell (LC) histiocytosis (LCH) and LC sarcoma (LCS) are proliferative processes consisting of cells having morphologic and phenotypic features of Langerhans cells (LCs), although the latter may have lost some of these features. Because neoplastic nature of LCH as well as LCS is more likely by recent studies, a category of LC hyperplasia can be better characterized. LCH and LCS are rarely seen in daily pathology practice, but it is important to accurately characterize these lesions. For this purpose, an outline covering proliferations of LC and related cells was constructed. The scheme of this outline is based especially on evaluating borderline lesions, neoplastic trans-differentiation, and degree of similarity with the normal counter-parts. In addition, the organization and update of the current classification scheme for histiocytic and dendritic-cell proliferations is presented.

Langerhans cell sarcoma: an unusual microscopic presentation.

A 70-year-old Caucasian male presented to our clinic for a pruritic eruption progressing over several months. He complained of fatigue with a 20-pound weight loss over the past year. On presentation, the patient had browny-yellow to violaceous, purpuric, macular and papular lesions on the legs, arms, lower abdomen and back. Initial biopsy showed an angiocentric infiltrate with a suggestion of intraluminal proliferation; CD31 and Fli-1 positivity suggested either reactive angioendotheliomatosis or an unusual intravascular histiocytosis. Further excisional biopsies demonstrated perivascular collections of cells with ample cytoplasm, prominent nuclear pleomorphism and mitotic activity. The nuclei demonstrated nuclear folding, grooves and indentations. The atypical cells were S100, CD1a and CD56 positive with immunohistochemistry. A diagnosis of Langerhans cell sarcoma (LCS) was made. LCS is a rare, aggressive malignancy that can involve multiple organs including the skin, lymph nodes, lung, bone marrow, spleen, heart, and brain. The skin and lymph nodes are commonly involved, and the cutaneous presentation varies greatly. Immunohistochemistry characteristically shows CD1a and S100 positivity. CD56 expression is uncommon and often portends a poor prognosis. There is no established treatment of LCS due to its rarity. Surgery, radiation, and chemotherapy have been used with varied outcomes. Our patient was treated with prednisone with improvement of cutaneous disease. He did not develop systemic involvement, but died 1.5 years later from complications associated with heart failure. Langerhans cell sarcoma should be considered when faced with an unusual angiocentric infiltrate in which initial immunohistochemical staining results may be misleading.

Leucemización de sarcoma de células de Langerhans / Leukemic transformation of Langerhans cell sarcoma

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Diagnostic value of Wilms tumor 1 and CD44 in Langerhans cell sarcoma: case series of 4 patients.

Langerhans cell sarcoma (LCS) is a rare tumor with markedly malignant cytological features originating from Langerhans cells. LCS diagnosis is difficult and requires differentiation from other malignant tumors and Langerhans cell histiocytosis (LCH). Immunochemical antibodies, such as langerin, S-100 protein, and CD1a, have been used to diagnose LCS, but the results are crossed with LCH. To determine more significant biomarkers of LCS, we studied the expression and distribution pattern of Wilms tumor 1 (WT1) and cluster of differentiation 44 (CD44) in LCS. A broad panel of antibodies was used for immunohistochemical technology. Simultaneously, dual immunofluorescence staining examination and fluorescence in situ hybridization staining methods were used to study the location of WT1 and CD44 in LCS tumor cells. The results showed that tumor cells expressed WT1, CD44, and other special Langerhans cell markers (langerin, CD1a, and S-100 protein). LCS cells in all the cases showed normal cytogenetic findings without overexpression of WT1 and CD44. The expression of WT1 and CD44 was observed on langerin tumor cells by dual immunofluorescence staining examination in LCS. Our results suggest that WT1 and CD44 are potential biomarkers for LCS diagnosis. Clear understanding of their functional roles may further explain the pathogenesis of this highly malignant tumor and develop some novel immunotherapy strategies.