EBV Negative Angioimmunoblastic T–Cell Lymphoma with Sequential Development of Diffuse Large B–Cell Lymphoma in Course of Progression

Dear Editor,

A 55–year–old male presented with generalized lymphadenopathy, fatigue and night sweats. Inguinal node biopsy revealed AITL with a typical immunoprofile: CD2 + , CD3 + , CD4 + , bcl2 + , CD10 + , EBV (LMP-1)-, Ki67 > 80% %  Fig. 1a–i. The EBV encoded RNA in situ hybridization (EBER ISH) was negative. The bone marrow biopsy and laboratory parameters (including LDH) were normal at presentation, except elevated β2microglobulin level which was 4.7 mg/L. The patient was HIV, HCV and HBsAg negative. The Multi Slice Computed Tomography (MSCT) scan of thorax revealed mediastinal lymph node conglomerates measuring 34 × 27 mm in size with bilateral pleural effusion. MSCT of abdomen and pelvis depicted retroperitoneal conglomerates in left parailiacal region measuring 35 mm in size. The right inguinal lymph node conglomerates were "Bulky" in size and approximately measured 84 mm (a target point for biopsy), whereas left sided nodes were 26 mm. He was assigned advanced "Bulky" stage III disease. The patient received 6 induction courses of CHOEP₂₁ (Doxorubicin, Cyclophosphamide, Vincristine, Etoposide, Prednisone), followed by 2 additional cycles (Doxorubicin omitted due to cardio-toxicity). The “dose–dense” schedule as bi–weekly induction (recommended by ESMO guidelines) was not applicable. The patient refused to undergo autologous stem cell transplantation (ASCT). A partial response was obtained. We continued systemic treatment with 3 cycles of Chlorambucil + Prednisone. Considering the fact that the patient achieved a non- progressive state, further treatment was suspended for approximately an year. During the treatment-free period episodes of pneumonia and urinary infections occurred due to immunosuppression. Subsequently, the patient developed refractory pancytopenia and ascites accompanied by the appearance of a cauliflower-like cutaneous infiltration on his back measuring 25 × 15 mm in diameter. The tumor was surgically removed and a new bone marrow biopsy was performed. Histology revealed the occurrence of a composite lymphoma. The massive bone marrow infiltration was CD3 + leukemic AITL, whereas the cutaneous tumor appeared to be diffuse large B–cell lymphoma (DLBCL), non–GCB, not otherwise specified (NOS). The tumor immunophenotype was: LCA + , CD20 + , CD10-, bcl2 + , MUM1 + , CD43 ± , bcl6-, CD5-, CD23-, CD8-, CD3-, CD30-, ALK-, CD68-, TdT-, S-100-, CD34-, EBV (LMP-1)-, EBER ISH-, Ki67 > 60%  Fig. 1j–o. Regarding the DLBCL co–occurrence, Rituximab was introduced to “salvage” chemotherapy, i.e. DHAP. Irrespective of initial improvement, refractory thrombocytopenia occurred during the fifth cycle causing lethal hemorrhagic diathesis. The overall survival of the patient was 2.9 years.

Fig. 1.

a, b, c Micromorphology of AITL (H & E stain). There is a subtotal effacement of nodal architecture by polymorphic cellular infiltrate that surrounds the prominent proliferation of arborizing small vessels. The atypical T cells are small to medium-sized, have mildly irregular nuclei and clear cytoplasm, and are admixed with small reactive lymphocytes, histiocytes, plasma cells, eosinophils, and large transformed immunoblasts. Neoplastic T cells show immunohistochemical positivity to CD3 d, follicular (germinal center) T cell marker CD10 (e), and T helper cell marker CD4 f. Nuclear staining to Ki67 demonstrates high proliferative activity > 80% g. Immunostaining to CD31 h highlights the marked proliferation of high endothelial venules, while CD21 i detects the expansion of follicular dendritic cell meshwork. The patient had diffuse involvement of bone marrow by AITL (H & E stain) j,k. Polymorphic infiltrate occupying medullary spaces was rich in CD3+ neoplastic T-cells l. The bottom row m n, o depicts diffuse large B cell lymphoma of the skin of AITL patient. The skin lesion showed diffuse infiltration by large blastoid CD20 positive n, and CD3 negative cells o.

Angioimmunoblastic T–cell lymphoma (AITL) is an aggressive primary nodal T–cell lymphoma that originates from CD4 + follicular helper T–cells [1]. Its pathological diagnosis relies on distinct immunophenotype and unique architecture comprised of arborizing high endothelial venules, follicular dendritic cell hyperplasia with a scattered reactive Epstein–Barr virus (EBV) + B–cell blasts [1]. Progression to EBV + , and more rarely to EBV-, B–cell neoplasms (BCN) may occur in a subset of cases [2]. The natural course of AITL is characterized by a median survival of less than 3 years accompanied by profound immunodeficiency, making the delivery of aggressive therapy difficult [1, 3].

We presented a patient with a EBV negative AITL followed by sequential development of the DLBCL during leukemic AITL transformation. Although rare, sequential development of DLBCL may occur in AITL patients [4]. A significant proportion of reactive EBV + B–cell blasts present in a tumor microenvironment represent a morphological basis for DLBCL development. The underlying mechanism may include EBV infection and reactivation along with the immunosuppressive background of AITL as a trigger point [4]. However, it has not yet been defined what may trigger the development of DLBCL in EBV negative cases. In respect of the data above, our case was all the more interesting, from scientific point, given that both the AITL and DLBCL histology samples were EBV negative by using EBER-ISH. There are extremely rare publications regarding EBV negative AITL cases, so data are reduced to the extent of single cases and no conclusion can be drawn. We suppose that the profound immunodeficiency particularly in a setting of AITL accompanied by previous chemotherapy exposure had a major impact on secondary BCN development. A significant proportion of reported cases pointed to cutaneous DLBCL involvement [5]. Whether it was just a coincidence or there is some regularity regarding the site of BCN development in a setting of preexisting AITL has not yet been clarified.