Langerhans cell sarcoma with an aberrant cytoplasmic CD3 expression
- 6.1k Downloads
Langerhans cell sarcoma is a rare and aggressive high grade hematopoietic neoplasm with a dismal prognosis. It has a unique morphological and immunotypic profile with a CD1a/ langerin/S100 + phenotype. T cell lineage markers except for CD4 in Langerhans cell sarcoma have not been documented previously. We report a case of 86 year-old male of Caucasian descent who presented with an enlarging right neck mass over 2 months with an underlying unknown cause of anemia. Computed tomography scan of the neck, chest and abdomen revealed generalized lymphadenopathy and mild splenomegaly suspicious for lymphoma. Diagnostic core biopsy performed on right neck mass revealed a possible T cell lymphoma with expression of T cell lineage specific marker CD3 but conclusive diagnosis could not be made due to insufficient core biopsy sample. Further excisional biopsy performed on a left inguinal node showed a hematopoietic neoplasm with features of Langerhans cell sarcoma with a focal cytoplasmic CD3 expression in 30-40% of the tumor cells. PCR for T cell receptor (TCR) gene rearrangement failed to demonstrate a clonal gene rearrangement in the tumor cells arguing against a T cell lineage transdifferentiation, suggesting an aberrant CD3 expression. To the best of our knowledge, this case represents the first report of Langerhans cell sarcoma with an aberrant cytoplasmic CD3 expression.
KeywordsLangerhans cell sarcoma (LCS) Langerhans cell histiocytosis (LCH) CD3 Aberrant expression Lineage plasticity Transdifferentiation
According to the most recent WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (2008) , Langerhans cell sarcoma (LCS) belongs to the category of histiocytic and dendritic cell neoplasms. It is a rare subtype of tumors derived from Langerhans cells with a female predominance.
Clinically, LCS is often an extranodal tumor with skin and bone involvement, but it may present with multi-organ involvement including lymph node, lung, liver and spleen. 11% of the reported cases patients had pancytopenia. Compared to more commonly known Langerhans cell histiocytosis (LCH), also a clonal neoplastic proliferation of Langerhans cells, LCS has a much higher degree of cytological atypia and prominent proliferation rate with an aggressive clinical course. Both LCH and LCS have a similar immunophenotype including CD1a/langerin/S100+ [2, 3] but without B- and T-cell lineage markers except for CD4 . LCS with a cytoplasmic T cell specific marker CD3 has heretofore not been reported in the English literature. Herein we provide the first report of LCS with an aberrant cytoplasmic CD3 expression.
An 86 year old Caucasian male who had been relatively healthy with medically controlled diabetes on insulin, treated temporal arteritis and myocardial infarction in 1987 without ongoing angina was referred to hematology/Oncology service for possible T cell lymphoma at Ottawa Hospital in July 2011. The patient had a short history of a rapidly growing right neck mass, an anemia of unknown cause, mild weight loss and generalized weakness. Laboratory investigations showed a bicytopenia with a normocytic anemia, Hb 89 g/L (reference interval 115–155 g/L) and thrombocytopenia, PLT 86 x 109/L (reference interval 125–400 x 109/L). He also had a neutrophilia with WBC 19.8 x 109/L (reference interval 3.0-10.5 x 109/L). LDH was mildly elevated with a value of 240 u/L(reference interval 100–205 u/L). CT of neck/thorax/abdomen demonstrated diffuse lymphadenopathy involving the neck, mediastinum, lung, abdomen and pelvic and mild splenomegaly. Two previous right neck core biopsies at another hospital suggested a peripheral T cell lymphoma based on the expression of T cell specific marker CD3 with negative CD20 and cytokeratin AE1/3. Definitive diagnosis could not be made due to insufficient tissue. An excisional left inguinal node biopsy was performed at the Ottawa Hospital.
Immunohistochemical staining of Langerhans cell sarcoma
Langerhans cell sarcoma in our case
Typical immunophenotype of tumors derived from Langerhans cells
30-40% + cytoplasm
Langerhans cells are one subset of hematopoietic cells, thought to derive from monocyte-macrophage lineage. They are specialized dendritic cells in skin or mucosal sites devoted to antigen presentation to T cells upon activation. They are then thought to migrate to lymph node through lymphatics. Physiologically, Langerhans cells can respond in a non-clonal fashion to certain reactive stimuli such as smoking, in the lung [8, 9]. Alternatively, they can proliferate in a clonal pattern, forming tumors designated as LCH and much less commonly as LCS. LCH can also be associated with other disease processes such as malignant lymphoma, and myasthenia gravis [10, 11], but there is still debate about whether these represent a clonal or non-clonal reactive process in those situations.
LCH and LCS have been believed to originate from myeloid stem cells [12, 13, 14, 15, 16] rather than lymphoid stem cells, but some recent experimental and clinical evidence has argued against this belief [17, 18]. Furthermore, some clinical reports have suggested that both B- and T-cell neoplasms can transdifferentiate into LCH and LCS after prolonged treatment of the original disorders [19, 20, 21, 22, 23], suggesting that in these hematolymphoid neoplasms the tumor cells have some potential for lineage plasticity, somewhat comparable to the leukemias with lineage plasticity, acute leukemias of ambiguous lineage in the 2008 WHO hematolymphoid tumour classication. Because of its linkage to the T-cell receptor molecules surface membrane CD3 is felt to be the most specific T lineage marker along with cytoplasmic epsilon chain, although CD3 epsilon chain can be expressed in cytoplasm of NK cells and thymocytes. Furthermore aberrant CD3 expression has been reported in other hemotopoietic tumours such as diffuse large B cell lymphoma, primary mediastinal large B cell lymphoma, plasmablastic lymphoma and classical Hodgkin’s lymphoma [24, 25, 26, 27] but not in histiocytic sarcoma. In addition, LCH can co-exist with T cell lymphoblastic lymphoma in the same tissue, making the correct diagnosis difficult [28, 29].
In our case, because of the expression of cytoplasmic CD3 and CD4, we performed T cell receptor (TCR) gene arrangement studies for gamma, delta and beta chains by PCR to rule out the possibility of T cell lineage transdifferentiation or lineage plasticity. The results failed to demonstrate a clonal rearrangement pattern, suggesting that the LCS tumor cells had an aberrant cytoplasmic CD3 expression rather than a T cell transdifferentiation phenomenon.
As a rare subtype of sarcoma, LCS has a poor prognosis . Although the prognostic factors in LCS were not known, they might include prognostic factors common to other rare sarcomas, such as patient age, tumor size, tumor cell grade, proliferation rate, and/or stage. [31, 32, 33]. DNA ploidy had been proposed as one of the prognostic factors in some subtypes of sarcoma [31, 34], although another study does not show ploidy status to be an independent prognostic factor . The prognostic role of DNA ploidy in LCS had never been explored. In our case, due to the rarity of LCS and finesse of the technique, DNA ploidy study was not performed.
Among the reported LCS cases , patients had a predominantly female distribution with a median age of 39 years old, ages ranging from 10 to 72 years. Our patient, at 86 was thus the oldest reported to date.
In summary, we reported the first case of Langerhans cell sarcoma with an aberrant cytoplasmic CD3 expression, which initially with insufficient immunophenotyping created diagnostic difficulty, especially about lineage assignment. Recognizing the cytomorphologic features characteristic of Langerhans cells prompted use of markers enabling the correct diagnosis.
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.
- 1.Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW: WHO classification of tumors of haematopoietic and lymphoid tissues. 2008, France: International Agency for Research on CancerGoogle Scholar
- 4.Pileri SA, Gaidano G, Zinzani PL, Pileri SA, Grogan TM, Harris NL, Banks P, Campo E, Chan JK, Favera RD, Delsol G, De Wolf-Peeters C, Falini B, Gascoyne RD, Gaulard P, Gatter KC, Isaacson PG, Jaffe ES, Kluin P, Knowles DM, Mason DY, Mori S, Müller-Hermelink HK, Piris MA, Ralfkiaer E, Stein H, Su IJ, Warnke RA, Weiss LM: Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases. Histopathology. 2002, 41: 1-29.CrossRefPubMedGoogle Scholar
- 6.Forero-Torres A, Leonard JP, Younes A, Rosenblatt JD, Brice P, Bartlett NL, Bosly A, Pinter-Brown L, Kennedy D, Sievers EL, Gopal AK: A Phase II study of SGN-30 (anti-CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Br J Haematol. 2009, 146: 171-179. 10.1111/j.1365-2141.2009.07740.x.CrossRefPubMedGoogle Scholar
- 13.Geissmann F, Prost C, Monnet JP, Dy M, Brousse N, Hermine O: Transforming growth factor beta1, in the presence of granulocyte ⁄ macrophage colony-stimulating factor and interleukin 4, induces differentiation of human peripheral blood monocytes into dendritic Langerhans cells. J Exp Med. 1998, 187: 961-966. 10.1084/jem.187.6.961.PubMedCentralCrossRefPubMedGoogle Scholar
- 14.Hoshino N, Katayama N, Shibasaki T, Ohishi K, Nishioka J, Masuya M, Miyahara Y, Hayashida M, Shimomura D, Kato T, Nakatani K, Nishii K, Kuribayashi K, Nobori T, Shiku H: A novel role for Notch ligand Delta-1 as a regulator of human Langerhans cell development from blood monocytes. J Leukoc Biol. 2005, 78: 921-929. 10.1189/jlb.1204746.CrossRefPubMedGoogle Scholar
- 19.Feldman AL, Berthold F, Arceci RJ, Abramowsky C, Shehata BM, Mann KP, Lauer SJ, Pritchard J, Raffeld M, Jaffe ES: Clonal relationship between precursor T-lymphoblastic leukaemia/lymphoma and Langerhans-cell histiocytosis. Lancet Oncol. 2005, 6: 435-437. 10.1016/S1470-2045(05)70211-4.CrossRefPubMedGoogle Scholar
- 20.Feldman AL, Arber DA, Pittaluga S, Martinez A, Burke JS, Raffeld M, Camos M, Warnke R, Jaffe ES: Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone. Blood. 2008, 111: 5433-5439. 10.1182/blood-2007-11-124792.PubMedCentralCrossRefPubMedGoogle Scholar
- 21.Shao H, Xi L, Raffeld M, Feldman AL, Ketterling RP, Knudson R, Rodriguez-Canales J, Hanson J, Pittaluga S, Jaffe ES: Clonally related histiocytic/dendritic cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: a study of seven cases. Mod Pathol. 2011, 24: 1421-1432. 10.1038/modpathol.2011.102.PubMedCentralCrossRefPubMedGoogle Scholar
- 22.Ratei R, Hummel M, Anagnostopoulos I, Jähne D, Arnold R, Dörken B, Mathas S, Benter T, Dudeck O, Ludwig WD, Stein H: Common clonal origin of an acute B-lymphoblastic leukemia and a Langerhans' cell sarcoma: evidence for hematopoietic plasticity. Haematologica. 2010, 95: 1461-1466. 10.3324/haematol.2009.021212.PubMedCentralCrossRefPubMedGoogle Scholar
- 23.Feldman AL: Langerhans cell sarcoma, clonally related to the original follicular lymphoma, so called “Transdifferentiation” of the follicular lymphoma clone. USCAP. 2010, hematopathology specialty conference handoutGoogle Scholar
- 26.Wallentine JC, Perkins SL, Tripp SR, Bruggman RD, Bayerl MG: Diffuse large B-cell lymphoma with coexpression of CD3 in a pediatric patient: a case report, review of the literature, and tissue microarray study. J Pediatr Hematol Oncol. 2009, 31: 124-127. 10.1097/MPH.0b013e31818b354a.CrossRefPubMedGoogle Scholar
- 30.Kawase T, Hamazaki M, Ogura M, Kawase Y, Murayama T, Mori Y, Nagai H, Tateno M, Oyama T, Kamiya Y, Taji H, Kagami Y, Naoe T, Takahashi T, Morishima Y, Nakamura S: CD56/NCAM-positive Langerhans cell sarcoma: a clinicopathologic study of 4 cases. Int J Haematol. 2005, 81: 323-329. 10.1532/IJH97.04142.CrossRefGoogle Scholar
- 31.Balogh Z, Szemlaky Z, Szendroi M, Antal I, Pápai Z, Fónyad L, Papp G, Changchien YC, Sápi Z: Correlation between DNA ploidy, metaphase high-resolution comparative genomic hybridization results and clinical outcome of synovial sarcoma. Diagn Pathol. 2011, 6: 107-114. 10.1186/1746-1596-6-107.PubMedCentralCrossRefPubMedGoogle Scholar
- 34.Mertens F, Stromberg U, Mandahl N, Dal Cin P, de Wever I, Fletcher CD, Mitelman F, Rosai J, Rydholm A, Sciot R, Tallini G, van den Berghe H, Vanni R, Willen H: Prognostically important chromosomal aberrations in soft tissue sarcomas: a report of the Chromosomes and Morphology (CHAMP) study group. Cancer Res. 2002, 62: 3980-3984.PubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.