Peripheral T-cell and NK-cell lymphomas and their mimics; taking a step forward - report on the lymphoma workshop of the XVIth meeting of the European Association for Haematopathology and the Society for Hematopathology

Abstract

Mature T-cell and T/NK-cell neoplasms are both uncommon and heterogeneous, among the broad category of non-Hodgkin lymphomas. Owing to the lack of specific genetic alterations in the vast majority, most currently defined entities show overlapping morphological and immunophenotypic features, and therefore pose a challenge to the diagnostic pathologist. In the light of recent immunophenotypic, cytogenetic and molecular genetics advances in the field of T-cell and T/NK-cell lymphomas, the focus of the lymphoma workshop of the European Association for Haematopathology/Society for Hematopathology meeting in Lisbon, Portugal, in October 2012 was to refine existing diagnostic criteria and clarify the borders between overlapping entities. The panel reviewed over 200 submitted cases, which were grouped into five categories: (i) angioimmunoblastic T-cell lymphoma and T-follicular-helper-cell-associated lymphomas; (ii) CD30-positive T-cell lymphomas/lymphoproliferative diseases; (iii) extranodal T-cell and NK-cell neoplasms; (iv) EBV-associated T-cell/NK-cell lymphomas/lymphoproliferative diseases; and (v) peripheral T-cell lymphoma, not otherwise specified, post-transplant lymphoproliferative disorders, and mimics. This report summarizes the discussions and conclusions of the workshop, which question current diagnostic criteria and provide recommendations for refining existing classifications.

Keywords: CD30; Epstein-Barr virus; T-cell lymphoma; angioimmunoblastic; follicular T-helper.

Figure 1.

A, B. A case of ‘typical’ angioimmunoblastic T-cell lymphoma (AITL) (case 337, Dr Vornanen, Fimlab, Finland). A, H&E shows a polymorphous infiltrate with clear cells amidst hyperplastic high endothelial venules (HEVs). B, CD21 staining (left panel) fails to show significant expansion of follicular dendritic cell (FDC) meshworks, whereas CD23 staining (right panel) shows florid FDC hyperplasia. C, D, A case of AITL, pattern I (case 328, Dr Nelson, Caris Diagnostics, USA). A 73-year-old female presented with systemic symptoms, generalized lymphadenopathy, and skin changes, and had polyclonal hypergammaglobulinaemia. C, H&E shows florid perifollicular monomorphous proliferation of medium-sized lymphoid cells. The inset shows the paracortex with a prominence of HEVs. D, The perifollicular neoplastic T cells express PD1. E, F, A case that showed typical AITL on initial biopsy and a tumour cell-rich pattern of AITL on follow-up biopsy (case 55, Dr Tzankov, University Hospital Basel, Switzerland). E, Second biopsy showing a tumour cell-rich morphology (left panel) with florid FDC expansionon CD21 staining (right panel). F, First biopsy showing ‘typical’ AITL (left panel) with florid FDC expansion on CD21 staining (right panel). G, H, A case of AITL with an unusual pattern (case 168, Dr Dogan, Mayo Clinic, USA). A 66-year-old presented with generalized lymphadenopathy, skin rash, and pleural effusion. G, H&E shows partial effacement of nodal architecture by paracortical clusters of clear cells amidst hyperplastic HEVs; amidst the clusters, there are many nodules of small lymphoid cells. H, left panel, PD1 staining highlights the neoplastic TFH cells corresponding to the clusters of clear cells. H, right panel, the nodules of small lymphocytes are IgD-positive

Figure 2.

A, B, A case of AITL showing overlap with the follicular variant of PTCL NOS (PTCL-F) (case 225, Dr Sabatini, S. Orsola-Malpighi Hospital, University of Bologna, Italy). Pax5 (red) and CD10 (brown) double staining highlights the CD10-positive neoplastic T cells distributed in a follicular pattern (A) and also occasionally around a regressed follicle (B), B, Inset shows the details of the regressed follicle on H&E staining. C-E, A case of PTCL-F showing overlap with AITL (case 305, Dr Burke, Alta Bates Summit Medical Center, USA); the follow-up biopsy showed no follicular growth pattern or features of typical AITL. C, H&E of the first biopsy shows a follicular growth pattern. The inset shows the neoplastic lymphoid cells to be of small to medium size. D, CD2 3 staining highlights focal FDC expansion. E, H&E of the follow-up biopsy shows a monotonous infiltrate of larger atypical lymphoid cells, amidst hyperplastic HEVs. F, A case of typical AITL with a prominence of EBV-negative Hodgkin/Reed-Sternberg (HRS) cells (case 35, Dr Vijnovich-Baron, Centro de Patologi’a CEPACIT, Argentina). CD10 staining highlights the neoplastic T cells, which form rosettes around the HRS cells. F inset: H&E staining, which shows an HRS cell surrounded by medium-sized neoplastic lymphoid cells.

Figure 3.

A, ALK-positive anaplastic large-cell lymphoma confined to the central nervous system (case 256, Dr Park, Gil Medical Centre, South Korea). Staging did not reveal any other manifestation except right-side hemisphere and brainstem (H&E, insert ALK1). It is of note that ALK staining was purely cytoplasmic. B, C, Involvement of a lymph node by CD30-positive lymphoproliferative disease (case 37, Dr Jaffe, National Institute of Health, USA). This process resembles classical Hodgkin lymphoma, which was the diagnosis originally proposed (B, H&E). The patient’s skin lesions were not appreciated at the time of initial diagnosis, and were only recognized some years after treatment for a presumed diagnosis of Hodgkin’ lymphoma. The skin lesions were later biopsied and recognized as lymphomatoid papulosis (C, H&E). An identical clonal T-cell gene rearrangement was identified in DNA from the lymph node and the subsequent skin biopsies (C, inserts according to BIOMED2 protocols). In both biopsies, the blasts were positive for CD30 and CD15 as well as cytotoxic proteins, but lacked Pax5 or detectable EBV. D-G, Peripheral T-cell lymphoma mimicking Hodgkin lymphoma (case 253, Dr Bacon, Newcastle upon Tyne Hospitals, UK). The patient was a 60-year-old with left axillary and supraclavicular lymph node swelling, generalized itch, but no B symptoms. After the diagnosis of classical Hodkin lymphoma, the patient was treated accordingly, but relapsed 6 years later. Histologically, nodules separated by fibrous bands harboured varying numbers of large mononuclear Hodgkin-like cells in a background of small lymphocytes, numerous histiocytes, plasma cells, and small numbers of eosinophils (D, H&E). In some nodules, the large cells were relatively sparse (E, CD30 staining), whereas in others they were more numerous and almost confluent (F, CD30 staining). The Hodgkin/Reed-Sternberg-like cells showed expression of CD30 and CD15 in combination with cytotoxic proteins such as perforin (G) but no Pax5 (H) or LMP1.

Figure 4.

A, EATL type I shows prominent epitheliotropism by atypical lymphocytes (case 100, Dr Ananthanarayanan, University of Chicago, USA) B, The infiltrate is polymorphous with admixed eosinophils. The cells show variation in size and shape. C, This case was positive for TCRc, and was negative for TCRb (not shown). D, This example of EATL type II shows the characteristic prominent epitheliotropism by monomorphic small to medium-sized lymphoid cells (E) (case 244, Drs Brar and Jagmohan, UHS Hospitals, USA). Interestingly, the tumour cells were positive for TCRb, and negative for TCRc. F, This case was classified as PTCL NOS, and presented in the stomach in a patient with marked eosinophilia (41 000/mm3). However, the patient had widespread disease, with involvement of multiple extranodal sites. Atypical CD30-positive T cells are associated with numerous eosinophils (case 252, Dr Parrens, Bordeaux University Hospital, France). G, NK-cell enteropathy (case 329, Dr Aline-Fardin, Bordeaux University Hospital, France): atypical lymphoid cells with abundant pale cytoplasm within the lamina propria of a colonic biopsy. H, Indolent CD8-positive T-cell lymphoproliferative disease can involve multiple sites in the gastrointestinal tract. In this example, the cells infiltrate the colonic mucosa. Note that the glandular epithelium is spared. I, Cells are CD8-positive. (H) and (I) were contributed by Dr Jaffe).

Figure 5.

Subcutaneous panniculitis-like T-cell lymphomas with bone marrow involvement at presentation (case 193, Dr Brown, University of Michigan, USA). This 28-year-old woman presented with subcutaneous nodules associated with adenopathies, splenomegaly, B symptoms, pancytopenia, and haemophagocytic syndrome. A, Biopsy of a subcutaneous nodule disclosed typical features of SPTCL. In the concomitant bone marrow biopsy, atypical lymphoid cells with abundant pale cytoplasm surround adipocytes (typical rimming). B, Cells are CD8-positive. C, This example of γ/δ T-LGL in the spleen (case 61, Dr Nagendra, Memorial Medical Center, USA) shows the characteristic sparse and minimal infiltrate of the red pulp by small lymphocytes without significant atypia (inset), with remnants of follicles in the white pulp. D, Cells are CD8-positive. Note that this case showed restricted expression of a single killer cell immunoglobulin-like receptor (KIR) isoform, CD158b. E, Nodal involvement by T-cell large granular lymphocytic leukaemia (case 185, Dr Wotherspoon, Royal Marsden Hospital, UK). A dense monotonous infiltrate of small lymphocytes is seen. F, Cells with a CD8-positive phenotype. Note the presence of residual B-cell (CD8-negative) follicles. This 51-year-old man presented with abdominal discomfort, and was found to have mesenteric lymphadenopathy and mild splenomegaly. The lymph node biopsy was initially regarded as PTCL NOS, but was revised to T-LGL when the patient developed lymphocytosis with an excess of clonal large granular lymphocytes 2 years later. The patient was well at last follow-up 38 months after initial presentation, with no treatment. G, Hepatosplenic T-cell lymphoma in a 66-year-old man with pancytopenia and splenomegaly (case 313, Dr Oliviera, Mayo Clinic, USA). The spleen shows an expanded red pulp with a dense proliferation of monotonous medium-sized cells with moderately abundant cytoplasm within splenic cords and sinuses. H, The bone marrow core with CD3 immunostaining is of critical diagnostic value: there is prominent or exclusive distribution of the neoplastic cells within more or less dilated sinuses (left), and this distribution is emphasized by CD3 staining (right). In this case, cells had an α/β phenotype, and were CD5-negative/CD56-positive, with a non-activated cytotoxic (TIA1-positive, granzyme B-negative) profile.

Figure 6.

A-C, Extranodal NK-cell/T-cell lymphoma, nasal type. A, H&E-stained section shows infiltration by atypical lymphocytes with necrosis and haemorrhage (case 32, Dr Goodlad, Western General Hospital & University of Edinburgh, UK). The patient, a 70-year-old Caucasian man, presented with facial swelling and induration. The tumour involved paranasal sinuses, skin, and testis. B, Perforin-positive neoplastic cells show prominent angioinvasive growth. C, Almost all tumour cells are EBER-positive. D-F, Nodal EBV-positive T-cell/NK-cell lymphoma. D, H&E section shows diffuse infiltration by monomorphic small to medium-sized lymphoid cells. The patient was a 53-year-old Asian man who presented with fever, systemic lymphadenopathy, splenomegaly, and haemophagocytosis. E, Tumour cells are CD8-positive, and positive for TCRβ and TIA-1 (not shown). F, They are also diffusely positive for EBER (D-F contributed by Dr Y. H. Ko). G-I, Chronic active EBV infection. G, Colonic mucosa shows a mixed inflammatory infiltrate in the lamina propria (case 192, Dr Oh, Hanyang University Hospital, Republic of Korea). The patient was a 5-year-old boy who presented with recurrent bowel perforation and wound dehiscence with fever, abnormal liver function, and NK lymphocytosis (68% of lymphocytes). EBV PCR showed a high viral load (11 450 copies per 5 μl of whole blood). The patient had a waxing and waning clinical course, with subsequent development of mosquito bite hypersensitivity. H, EBER in-situ hybridization highlights EBV-infected lymphocytes. I, EBER-positive cells of colonic mucosa are positive for CD3 (red, CD3; brown, EBER).

Figure 7.

A, B, Thyroid mass from a 44-year-old male with a 10-year history of Hashimoto’s thyroiditis. A section shows residual reactive lymphoid follicles and prominent T-zone proliferation. The panel diagnosis was T-lymphoproliferative disorder/indolent peripheral T-cell lymphoma, and illustrates the difficulty in characterizing this type of extranodal T-cell proliferation. B shows staining for PD1, suggesting Tfh cell proliferation. Note that the staining is less intense than in the hyperplastic germinal centre, which is highlighted (case 314, Dr Sarah Ondrejka, Cleveland Clinic, USA). C, D, Lymph node biopsy from a 35-month-old boy with fever and cervical adenopathy, and referred with an outside diagnosis of PTCL. An H&E photomicrograph (C) shows sheets of blasts and plasmacytoid dendritic cells, and the panel diagnosis was Kikuchi-Fujimoto disease. Stain for CD123 (D) highlights plasmacytoid dendritic cells (case 306, Dr Nancy Harris, Massachusetts General Hospital, USA). E, F, A 49-year-old Jamaican woman presented with enlarged cervical lymph nodes, fever and weight loss, and positive HTLV-I serology. A lymph node biopsy shows features of ATLL, with numerous large anaplastic cells, staining for CD30 in F. CD30-positive anaplastic cells are not uncommon in ATLL, and should not lead to misclassification as ALCL in the setting of HTLV-I infection (case 41, Dr S. Choi, Hospital of the University of Pennsylvania, USA).

Figure 8.

A, A two-step algorithm for the diagnostic strategy for T-cell lymphoma. The primary staining panel (first round) for all suspected T-cell lymphomas will help to distinguish reactive and neoplastic conditions. In any case of T-cell lymphoma the second round of staining can be used to arrive at a final classification. Regarding the use of CD21 and CD23 for FDC detection, see also Figure 1A,B and the corresponding section in the text. B-F, A 76-year-old male presented with generalized lymphadenopathy (case 190, Dr L. Ruco, Dr A. Di Napoli and Dr M. C. Cox, Rome, Italy). The panel diagnosis was peripheral T-cell lymphoma, NOS (B). The case shows varying expression of CD20 (C). Moreover, the tumour cells were positive for PD1 (D) in the absence of other Tfh markers. Moreover, this case illustrates the presence of an EBV-driven population of Hodgkin-like cells positive for CD30 (E) and LMP1 (F). G,H, The lymph node of a 43-year-old man with submandibular lymphadenopathy after a renal transplant was diagnosed as peripheral T-cell lymphoma, NOS, and showed monoclonal T-cell proliferation with aberrant PAX5 expression (G), but in the absence of PAX5 amplification (H) (case 364, Dr M. Lew, Boston, USA; FISH performed by Dr A. L. Feldman, Mayo Clinic, USA). I,J, The case of a 61-year-old female, presenting with abdominal lymphadenopathy, a jejunal mass and colonic involvement (I), was also was diagnosed as peripheral T-cell lymphoma, NOS, and illustrates isolated expression of FOXP3 (J) in the context of a cytotoxic T-cell phenotype (CD3-positive, CD25-positive, CD4-positive, CD8-negative, CD30-negative). There were no signs of enteropathy, and HTLV-I serology was negative (case 151, C. Lome-Maldonado, Mexico).