Case 3 -

Peripheral T-cell Lymphoma, Not Otherwise Ppecified, Follicular Variant (WHO 2008) Laurence de Leval University of Lausanne Lausanne, Switzerland

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Clinical History A Caucasian man born in 1953 presented in January 2010 because of small submaxillary and submental lymphadenopathies. The patient was otherwise well, with no systemic symptoms and no fever. He had no significant past medical history except a notion of poorly charactertized colitis with intermittent diarrhea. An ultrasonography (US) of the neck failed to reveal abnormally enlarged lymph nodes. In June 2010 he presented with tumefaction of the right cervical region. MRI confirmed cervical lymphadenopathies up to 2.5 cm on the right side. Workup in the search of a primary lesion in the upper aerodigestive tract and respiratory tree remained negative. Serologic studies were negative for HIV, HTLV-I, HTLV-II, CMV, toxoplasma, treponema, and showed evidence of previous EBV infection. A control MRI in September 2010 showed mild decrease in size of the cervical lymphadenopathies, but clinical examination revealed inguinal lymphadenopathies. Two inguinal lymph nodes, 1.1 and 1.3 cm were excised (representative section submitted). Blood analysis showed normal blood cell counts, no increase in LDH levels and normal immunoglobulin levels. The differential count of the white blood cells (8100/mm3) was normal with 17% lymphocytes, 70% neutrophils and 9% monocytes. Flow cytometry immunophenotyping of the peripheral blood revealed a CD4 to CD8 ratio of about 5 to 1 and a small proportion of T cells (0.2%) coexpressing CD4 and CD10. The bone marrow was histologically normal; examination of the smear revealed a few atypical lymphoid cells. A staging Pet-CT showed a moderate hypermetabolism involving right cervical, left axillary, retroperitoneal and right inguinal lymph nodes (maximal standardized uptake value, SUV = 1.6). A man aged 57 with no previous medical history presented with generalized lymphadenopathy. The biopsy is from an inguinal lymph node, 1.5 cm. Case 3 - Figure 1 Histology The caspule was slightly fibrosed and the periperal sinus was inconspicuous. The lymph nodes showed marked architectural distorsion into large vaguely nodular structures, while some areas showed a preserved architecture comprising subcapsular follicles and interfollicular/paracortical areas. The large nodules were composed predominantly of small lymphoid cells but also contained scattered aggregates or larger sheets of pale cells. The latter consisted of medium to large atypical lymphoid cells with roud to oval nuclei, open chromatin, small mucleoli and abundant clear cytosplasm. Mitoses were easily seen among these cells. Aggregates or bands of these atypical cells were also seen in a perifollicular/marginal zone distribution around smaller follicles. In some places outside the large nodules, aggregates of atypical cells were seen in association with hyperplastic veinules. No significant eosinophilia was observed. Immunophenotype and genetic studies The nodules were mainly composed of small CD20+ IgD+ IgM+ cells with polytypic expression of immunoglobulin light chains, and comprised dense dendritic meshworks highlighted by CD21 and CD23. CD20 did not stain extrafollicular large cells. The aggregates of clear cells were CD2+ CD3+ CD4+ CD5+ CD7- CD8- CD10+ CD20- CD43+(dim) CD57- PD-1+ Bcl-6+ c-Maf+ CXCL13+. CyclinD1 produced no staining in lymphoid cells. Ki67 stained a high proportion of the nuclei in the clear cell aggregates. In situ hybridization with EBER probes was negative. A monoclonal rearrangement of the TCR gamma chain was demonstrated by PCR with the use of the Biomed-A TCRG primers and with a homemade multiplex assay. FISH assays with break-apart probes for ITK (5q33) and SYK (9q22) showed colocalized fluorescent signals at the two loci, indicating the absence of the t(5;9)/ITK-SYK translocation. Differential diagnosis and discussion Based on the peculiar histologic features of this lymphoproliferation and the dominant pattern consisting of large irregular nodules, a broad list of differential diagnoses could be considered: (1) a reactive process such as progressive transformation of the germinal centers; (2) nodular lymphocyte predominance Hodgkin's lymphoma; (3) small B-cell lymphomas such as mantle cell lymphoma, follicular lymphoma or marginal zone lymphoma; (4) another unusual form of atypical or neoplastic lymphoproliferation. After a first basic round of immunostains for demonstration of B-cell and T-cell markers, identification of the T-cell phenotype of the atypical clear cells narrowed down the differential diagnosis to the fourth possibility, and more specifically to the category of T-cell lymphoproliferative processes. Taken together, the cytologic atypicality of the CD4+ T cells, their aberrant immunophenotype with negativity for CD7 expression and elevated proliferation fraction, were considered diagnostic for peripheral T-cell lymphoma, which was corroborated by the documentation of a monoclonal TCR gene rearrangement. Lymphomas derived from mature T cells display wide clinical and pathological heterogeneity and comprise numerous entities. Those typically presenting with nodal involvement comprise anaplastic large cell lymphomas, angioimmunoblastic T-cell lymphoma, and peripheral T-cell lymphoma, not otherwise specified, a category defined by default and comprising the cases not fulfilling the criteria for a «more specific» disease entity. In this case the T-cell lymphoma was developed in a peculiar histopathological settingin association with large primary-type B-cell follicles and follicular dendritic cell meshworks, with a perifollicular growth pattern and involvement of the mantle zone. There have been several reports in the literature of peripheral T-cell lymphomas with a pattern of growth related to follicular structures, and either a «follicular» or «perifollicular» distribution, in which the neoplastic cells localize within follicles (follicular lymphoma-like), or are distributed within the marginal zone with a so-called perifollicular distribution, or involve expanded mantle zones of the follicles (progressive transformation of germinal centers-like). Peripheral T-cell lymphomas with such a growth pattern are referred to as the follicular variant of peripheral T-cell lymphoma, not otherwise specified, in the 2008 WHO classification of hematologic malignancies. According to the largest case series reported in the literature, the neoplastic cells of follicular peripheral T-cell lymphomas are almost always CD4-positive with frequent coexpression of CD10 (70% of the cases) and constant expression of one or several markers normally expressed by follicular helper T cells. Follicular helper T cells (TFH), previously designated germinal center T cells, represent a peculiar subset of CD4+ T cells normally located in the light zone of reactive germinal centers where they provide functional help to germinal center B cells for antibody production. Distinctive markers of TFH cells include: (1) the CXCL13 chemokine (which promotes follicular homing by B and T cells by B and T cells and the migration of a subset of dendritic cells into B-cell follicles in a lymphotoxin-dependent fashion); (2) several cell surface molecules including CD57, CXCR5, CD154, programmed death-1 (PD-1) (a member of the CD28 costimulatory receptor family resulting in negative regulation of T-cell activity), and inducible costimulator (ICOS) (a CD28 homologue with costimulatory function in T-cell activation and expansion); (3) the transcription factors Bcl-6 and c-Maf. Accordingly in the current case the neoplastic T cells were CD4+ CD10+ and expressed several TFH markers (CXCL13, PD-1, Bcl-6 and c-MAF). CD57 which is a marker of normal TFH cells is in fact uncommonly positive in follicular T-cell lymphomas, and was also negative in this case. The demonstration of the TFH immunophenotype of the lymphoma cells raises the differential diagnosis with angioimmunoblastic T-cell lymphoma, an entity that has been recently characterized as derived from TFH cells. Our patient did not present with the clinical or immunological features typical of angioimmunoblastic T-cell lymphoma, such as constitutional symptoms ( fever, weight loss), hepatomegaly and/or splenomegaly, skin rash, anemia and hypergammaglobulinemia. Histologically, the pattern at low power did not correspond to any of the classical patterns described by Attygalle and the "sinus sign" often seen in angioimmunoblastic T-cell lymphoma was not observed; a polymorphous reactive infiltrate of eosinophils, histiocytes and/or plasma cells was not present; EBV-infected B-cell blasts were not demonstrated. Careful morphologic assessment, however, disclosed some common features with angioimmunoblastic T-cell lymphoma: small foci comprised tumor cells in association with hyperplastic veinules; and although the neoplastic T cells were in general medium to large with frank atypia, a subset were found to be smaller and less atypical. The presence of a small percentage of circulating tumor cells demonstrated in this case, has been reported as a common feature of angioimmunoblastic T-cell lymphoma. In addition to the common TFH derivation, other overlapping clinical and/or pathological features between follicular peripheral T-cell lymphoma and angioimmunoblastic T-cell lymphoma have indeed been observed in a significant proportion of the cases analyzed in the literature, and there are several reports of patients who underwent sequential biopsies showing alternatively one or the other histology. Although these findings supporting a link between follicular peripheral T-cell lymphoma and angioimmunoblastic T-cell lymphoma, in the current WHO classification follicular peripheral T-cell lymphoma has been introduced as a variant of peripheral T-cell lymphoma, not otherwise specified. The t(5;9)(q33;q22) translocation involving ITK (at 5q33) and SYK (at 9p22) and resulting in an ITK-SYK fusion transcript was first reported by Streubel et al. in 2006. This translocation is recurrent peripheral T-cell lymphomas not otherwise specified and is predominantly found in association with «follicular» cases. Overall the translocation is detected in about 20% of the follicular peripheral T-cell lymphoma cases, and has not been detected in angioimmunoblastic T-cell lymphoma. Although the transforming and oncogenic properties of the fusion gene have been demonstrated in vitro and in a conditional mouse model, the biological significance of detecting hte translocation in a given tumor remains unknown. Accordingly, its specificity remains unclear. Follicular peripheral T-cell lymphoma tends to occur in elderly patients, similar to other peripheral T-cell lymphomas. The majority of patients have disseminated disease (stage III or IV) at the time of the diagnosis. The disease seems to carry an overall dismal prognosis with about 50% surival at two years, but there are examples of long-term persistent complete remissions after multiagent chemotherapy. Final diagnosis Peripheral T-cell lymphoma, not otherwise specified, follicular variant (WHO 2008) Take home points A subset of peripheral T-cell lymphoma present with a follicular growth pattern, morphologically mimicking follicular B-cell lymphoma, marginal zone lymphoma or progressive transformation of the germinal centers. Peripheral T-cell lymphomas with a follicular pattern resembling progressive transformation of the germinal centers and those with a perifollicular/marginal zone pattern, may be difficult to identify because of an abundant reactive small B-cell component Follicular peripheral T-cell lymphomas are usually CD4+ CD10+ and have an immunophenotype of follicular helper T cells, and the use of TFH markers (CXCL13, PD-1, Bcl-6) is mandatory to confirm the diagnosis. Follicular T-cell lymphomas, currently classified as a variant of peripheral T-cell lymphoma, not otherwise specified, show overlapping features with angioimmunoblastic T-cell lymphoma A subset of follicular T-cell lymphomas carry a t(5;9) translocation fusing ITK and SYK Pertinent references Attygalle A, Al-Jehani R, Diss TC, Munson P, Liu H, Du MQ, et al. Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10. Blood. 2002 Jan 15;99(2):627-33. Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR, Rolph MS, et al. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J Immunol. 2004 Jul 1;173(1):68-78. de Leval L, Rickman DS, Thielen C, Reynies A, Huang YL, Delsol G, et al. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood. 2007 Jun 1;109(11):4952-63. de Leval L, Savilo E, Longtine J, Ferry JA, Harris NL. Peripheral T-cell lymphoma with follicular involvement and a CD4+/bcl-6+ phenotype. Am J Surg Pathol. 2001 Mar;25(3):395-400. Huang Y, Moreau A, Dupuis J, Streubel B, Petit B, Le Gouill S, et al. Peripheral T-cell lymphomas with a follicular growth pattern are derived from follicular helper T cells (TFH) and may show overlapping features with angioimmunoblastic T-cell lymphomas. Am J Surg Pathol. 2009 May;33(5):682-90. Ikonomou IM, Tierens A, Troen G, Aamot HV, Heim S, Lauritzsen GF, et al. Peripheral T-cell lymphoma with involvement of the expanded mantle zone. Virchows Arch. 2006 Jul;449(1):78-87. Streubel B, Vinatzer U, Willheim M, Raderer M, Chott A. Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma. Leukemia. 2006 Feb;20(2):313-8. Swerdlow S, Campo E, Harris N, Jaffe E, Pileri S, Stein H, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Swerdlow S, Campo E, Harris N, Jaffe E, Pileri S, Stein H, et al., editors. Lyon: IARC Press; 2008. Vinuesa CG, Tangye SG, Moser B, Mackay CR. Follicular B helper T cells in antibody responses and autoimmunity. Nat Rev Immunol. 2005 Nov;5(11):853-65.