Hematology Reports 2019; volume 11:7841 phoma with specific tropism for skin that exhibits an aggressive clinical behavior. Silent T-cell receptor cutaneous Correspondence: Silvana Novelli, Department T-cell lymphoma associated They are resistant to chemotherapy and/or of Hematology, Hospital de la Santa Creu i to a clonal plasma cell radiation, and have a poor prognosis with a Sant Pau, Carrer Mas Casanovas, 90. 4th 5-year overall survival of 10%. Although Floor, 08041 Barcelona, Spain. even rarer, there have been reports of E-mail: snovelli@santpau.cat proliferation Ana Caballero,1 Silvana Novelli,1 PTCLs with loss of expression of the TCR, Key words: silent TCR, gamma-delta T-cell Anna Mozos,2 Pilar Garcia Muret,3 which have been termed PTCL TCR-silent lymphoma, PTCL. type.3,4 Jorge Sierra,1 Javier Briones1 1Hematology Contributions: AC and SN wrote the case Department, 2Pathology report; AC, SN and PG treated the patient; AM Department, 3Dermatology Department, and PG revised all biopsies, AM, JS and JB Hospital de la Santa Creu i Sant Pau, Case Report revised the clinical record and all authors Barcelona, Spain revised the final manuscript. A 72-year-old male with a previous heart transplant in 2000 was diagnosed with Conflict of interest: the authors declare no a PCGDTL. At the time of diagnosis, he potential conflict of interest. Abstract was receiving immunosuppressive drugs. In a control in September 2014 he presented Funding: none. Within T-cell lymphomas (TCL) there are 2 entities expressing gamma-delta TCR: with 2 nodular lesions about 2 cm in the Received for publication: 21 August 2018. hepatosplenic gamma-delta T-cell lym- anterior and lateral surfaces of his lower Accepted for publication: 7 December 2018. phoma (HSGDTL) and the primary cuta- limbs. The skin biopsy revealed a diffuse neous gamma-delta T-cell lymphoma cell infiltration of the dermis (predominant- This work is licensed under a Creative (PCGDTL). PCGDTL is a rare form of T- ly of perivascular and peri-adnexal). The Commons Attribution-NonCommercial 4.0 cell lymphoma with specific tropism for tissue was composed by a medium-size International License (CC BY-NC 4.0). skin that have a dismal prognosis. lymphoid population with irregular nuclei and prominent nucleoli. Some cells occa- ©Copyright A. Caballero et al., 2019 Although even rarer, there have been sionally had large cytoplasm. The immuno- Licensee PAGEPress, Italy reports of TCL with loss of expression of Hematology Reports 2019; 11:7841 the TCR, which have been termed peripher- histochemical (IHC) stains showed a pre- doi:10.4081/hr.2019.7841 al TCL TCR-silent type. We report the case dominant T-cell population (CD2, CD3 and of a cutaneous TCR-silent type lymphoma CD5 positive) with an intense and diffuse associated to a clonal plasma cell prolifera- expression of CD8. There was a loss of CD7 expression. In situ hybridization for platin, with no response. Radiotherapy was tion with an ominous outcome that led to a mRNA of Epstein-Barr virus (EBERs) was administered (20 Gy) with temporal remis- lot of discussion in its classification. Due to the aggressiveness of the disease and the negative. Staining for TCR beta-F1 chain sion of the disease. At the end of treatment, scant evidence about therapy in this strange was also negative. TCR gamma and delta a new PET-CT reported the presence of an entity the outcome was fatal. We report a proteins expression studied by IHC in adenopathy at the left external iliac chain. unique case of a TCR-silent cutaneous TCL paraffin-embedded tissue were no assess- The lymph node biopsy showed a dense with an exceptional histopathology, pro- able. The Ki67 index was 50%. TCR molec- plasma cell infiltrate with lambda light longed clinical evolution and a subsequent ular studies showed a gamma rearrange- chain restriction (Figure 2). plasma cell clonal expansion. ment with a predominant peak at 208 bp. Plasma cells were EBERs negative. The Thus, the patient was diagnosed with a study of B-cell receptor rearrangement PCGDTL. The complete blood count and showed a monoclonal peak in the FR3 PET-CT were normal (Figure 1). region. The serum/urine protein elec- Introduction The patient received 4 cycles of COP trophoresis and bone marrow biopsy were chemotherapy (cyclophosphamide-vin- Peripheral T-cell lymphomas (PTCLs) cristine-prednisone) reaching a stable dis- normal. are a group of complex entities, comprising ease followed by radiotherapy (30 Gy) that On October 2015, a new follow-up less than 10% of non-Hodgkin lymphomas. eliminated skin infiltration. PET-CT showed a diffuse infiltration of the PTCLs are subclassified based on histolog- Two months later, new nodular lesions skull, left humerus, and right femur. A biop- ic, immunophenotypic, and genetic find- appeared above the previously irradiated sy of one of the bone lesions showed the ings. PTCLs frequently involve the skin, field. The new skin biopsy showed atypical presence of infiltration of the inter-trabecu- either as primary or secondary manifesta- T cells (CD2+, CD3+ and CD5+) with loss lar spaces by a proliferation of medium-size tion of the disease. Most of these cutaneous of CD7 expression and diffuse expression lymphoid cell, occasional mitotic figures T-cell lymphomas (CTCLs) express an of CD8. The beta-F1 staining remained neg- and apoptotic bodies. IHC stains showed a alpha-beta T-cell receptor (TCR) while only ative; IHC for gamma and delta TCR pro- T-cell population CD3+ CD5+ and CD7-; 2-4% express a gamma-delta TCR. The teins were negative. The study of TCR- CD8 was positive on some atypical cells. WHO classification recognizes only two gamma rearrangement showed the same monoclonal peak than the previous biopsy. CD4 and CD138 were negative distinct entities of gamma-delta T-cell lym- phoma: the hepatosplenic gamma-delta T- The previous diagnosis was revised and a In summary, we report a complex case cell lymphoma (HSGDTL) and the primary new diagnosis of CTCL TCR silent subtype of a CTCL with an exceptional histopathol- cutaneous gamma-delta T-cell lymphoma was established. A new PET-CT did not ogy, prolonged clinical evolution and a sub- (PCGDTL).1,2 show disease dissemination. The patient sequent plasma cell clonal expansion. PCGDTL is a rare form of T-cell lym- received 4 cycles of gemcitabine-oxali- [page 6] [Hematology Reports 2019; 11:7841] Case Report Discussion In this report, we describe an infrequent form of disseminated CTCL with loss of expression of the TCR (TCR silent type) associated with a clonal plasma cell expan- sion. The most frequent TCR is made up of alpha and beta chains. The other form com- prises gamma and delta chains, which are expressed approximately on 4% of T-cells. Gamma-delta T-cells tend to concen- trate in the mucosa, lymphoid tissues and epithelial barriers as well as in the red pulp of the spleen. These T-cells develop from CD4-/CD8- thymic precursors in the bone marrow and, unlike alpha-beta T-cells, they typically lack the major histocompatibility complex restriction. In contrast to TCR alpha-beta cells, these cells usually have a CD4-/CD8- phenotype.5 The 2016 WHO classification recog- nizes two main types of gamma-delta PTCL namely, gamma-delta hepatosplenic T-cell lymphoma and primary cutaneous gamma- delta T-cell lymphoma (PCGDTL).6 PCGDTL is a lymphoma composed of a clonal proliferation of mature, activated gamma delta T-cells with a cytotoxic phe- Figure 1. A) Skin biopsy showing a diffuse lymphoid infiltration of the dermis (original magnification ×10). B) Immunohistochemical stain for CD3 highlighting medium and notype. PCGDTL represents approximately occasionally large neoplastic T cells (original magnification ×10). C, D) Diffuse negative 1% of all CTCL. immunohistochemical stain for TCR beta-F1 chain of neoplastic population (original The disease may be predominantly epi- magnification ×10 and ×40). dermotropic and presents with patches and plaques. The lesions are most often located on the extremities. Dissemination to mucos- al and other extranodal sites is frequently observed, but involvement of lymph nodes, spleen or bone marrow is uncommon. Cells of PCGDTL have a beta-F1-, CD3+, CD2+, CD5-, CD7+/-, CD56+ phe- notype with strong expression of cytotoxic proteins. But some cases with CD5+ have been reported.7,8 Most, lack both CD4 and CD8, although CD8 may be expressed in some cases. The cells are strongly positive for delta TCR with appropriate detection methods. If staining for delta TCR cannot be performed, the absence of beta-F1 may be used to establish the diagnosis. TCR beta may be either rearranged or deleted, but it is not expressed. Epstein-Barr virus is usually negative.9 Prognosis of PCGDTL is poor, with a median survival of 15 months and a 5-year overall survival of 10%.2 With the histopathology, IHC, and because of the gamma-delta TCR studies were not assessable the patient was diag- nosed with a PCGDTL. The second skin biopsy showed negative beta-F1 and a neg- ative gamma and delta TCR. These new Figure 2. A, B) Loss of lymph node architecture. Two different cell populations: a lym- findings lead us to reconsider our first diag- phoid population accompanied by clusters of mature plasma cells (original magnification nosis as a TCR silent type lymphoma. ×4 and ×20). C) Immunohistochemical stain for CD138 highlighting extensive infiltra- tion by mature plasma cells (original magnification ×4). D) Lambda light chain restric- These PCGDTL that lacks a TCR tion (original magnification ×10). [Hematology Reports 2019; 11:7841] [page 7] Case Report expression by IHC studies have been desig- tions associated with T-cell lymphomas are Microabscess Ann Dermatol 2017;29: nated as “TCR silent PTCL”. It has been uncommon and not well characterized.15 229-32. proposed that the TCR silent phenotype rep- 8. Sindhu H, Chen R, Chen H, et al. resents a common phenomenon of “TCR Gamma-delta (γδ) T-cell lymphoma - instability” in different tumor types, rather another case unclassifiable by World than representing a distinct entity. In favor Conclusions Health Organization classification: a to this hypothesis there is a previous report case report. J Med Case Rep 2017;11: of a TCR alpha-beta hepatosplenic T-cell In summary, we show a CTCL TCR 163. lymphoma that evolved to a TCR silent phe- silent associated with an EBV-negative 9. Langerak AW, Groenen PJ, Brügge- notype.10,11 clonal plasma cell proliferation, which rep- mann M, et al. EuroClonality/BIO- The lack of TCR expression may repre- resents an example of the heterogeneity of MED-2 guidelines for interpretation sent a phenotypic aberration in PTCL, usu- the PTCLs. The clonal plasma cell expan- and reporting of Ig/TCR clonality test- ally found at the time of progression. This sion in addition to the presence of bone dis- ease may lead to a misdiagnosis of multiple ing in suspected lymphoproliferations. finding indicates that the lack of beta TCR Leukemia 2012;26:2159-71. chain expression cannot be used to infer a myeloma making the diagnosis of a TCR- silent PTCL a real challenge. 10. Harrington L, Sokol L, Holdener S, et gamma-delta T-cell origin with certainty. A al. Cutaneous gamma-delta T-cell lym- first explanation could be that the βF1 - phoma with central nervous system TCR-γδ- cases represent a more ‘immature’ involvement: report of a rarity with step, before or during cytoplasmic CD3 expression. A second hypothesis is that References review of literature. J Cutan Pathol 2014;41:936-43. some cases may represent neoplasms of NK 1. Swerdlow SH, Campo E, Pileri SA, et 11. Thériault C, Galoin S, Valmary S, et al. cells. This is supported by another report al. The 2016 revision of the World PCR Analysis of Immunoglobulin showing that NKH-1 is preferentially Health Organization classification of Heavy Chain(IgH) and TcR-gamma expressed on peripheral T-cell lymphomas lymphoid neoplasms. Blood 2016;127: Chain Gene Rearrangements in the with CD3-/βF1- phenotype, which seems to 2375-90. Diagnosis of Lymphoproliferative be the usual phenotype of “true” NK cells.5 2. Foppoli M, Ferreri AJ. Gamma-delta t- Disorders: Results of a Study of 525 Regardless of whether it is a separate cell lymphomas. Eur J Haematol Cases. Mod Pathol 2000;13:1269-79. entity or a transition due to disease progres- 2015;94:206-18. 12. Campidelli C, Sabattini E, Piccioli M, sion, our case is even more unique because 3. Vin H, Talpur R, Tetzlaff MT, Duvic M. et al. Simultaneous occurrence of it is associated with a clonal plasma cells T-cell receptor-γ in gamma-delta pheno- peripheral T-cell lymphoma unspecified proliferation. type cutaneous T-cell lymphoma can be and B-cell small lymphocytic lym- The coexistence of PTCLs and B-cell accompanied by atypical expression of phoma. Report of 2 cases. Hum Pathol clonality occurs in 9 to 16% of cases and CD30, CD4, or TCRβF1 and an indo- represents a diagnostic dilemma. This find- 2007;38:787-92. lent clinical course. Clin Lymphoma ing is more frequent in immature T cell 13. Hodges E, Quin CT, Wright DH, Smith Myeloma Leuk 2014;14:e195-200. lymphoid neoplasms.12 JL. Oligoclonal populations of T and B 4. Gaulard P, Bourquelot P, Kanavaros P, There are some possible explanations cells in a case of angioimmunoblastic T- et al. Expression of the alpha/beta and for the detection of coexisting B and T cell lymphoma predominantly infiltrat- gamma/delta T-cell receptors in 57 clones. The first is the so-called lineage ed by T cells of the VB5.1 family. Mod cases of peripheral T-cell lymphomas. infidelity of a single clone that results of the Pathol 1997;50:15-7. Identification of a subset of recombination of TCR and IGH genes in the 14. Venizelos J, Papadopoulos N, gamma/delta T-cell lymphomas. Am J same clone. The second is the presence of Pathol 1990;137:617-28. Lambropoulou M, et al. Metachronous two different clones’ coexistence, which 5. Garcia-Herrera A, Song JY, Chuang SS, extranodal marginal zone B-cell lym- may happen in up to 35% of PTCL et al. Nonhepatosplenic γδ T-cell lym- phoma of mucosa-associated lymphoid cases.12,13 Another possibility is that phomas represent a spectrum of aggres- tissue (MALT lymphoma) and peripher- tumoral cells could secrete factors that sive cytotoxic T-cell lymphomas with a al T-cell lymphoma unspecified: histo- might produce a second neoplasia, in this mainly extranodal presentation. Am J logic, immunophenotypic, and molecu- case a new lymphoma.14 B-cell expansions Surg Pathol 2011;35:1214-25. lar documentation. Onkologie are ranging from isolated or small clusters 6. Swerdlow S, Campo E, Harris N, et al. 2005;28:423-6. of large activated B-cells to focally conflu- WHO classification of tumours of 15. Balagué O, Martínez A, Colomo L, et ent transformed B-cells that may obscure haematopoietic and lymphoid tissues- al. Epstein-Barr virus negative clonal the T-cell proliferation. International Agency for Research on plasma cell proliferations and lym- A recent study described that EBV-neg- Cancer – 2017 phomas in peripheral T-cell lym- ative B-cell proliferations associated with 7. Kato K, Namiki T, Ueno M, et al. A phomas: a phenomenon with distinctive PTCL had a marked plasma cell differentia- Case of Primary Cutaneous Gamma- clinicopathologic features. Am J Surg tion. Nevertheless, EBV-negative prolifera- Delta T-Cell Lymphoma with Pautrier Pathol 2007;31:1310-22. [page 8] [Hematology Reports 2019; 11:7841]