T follicular helper cell (TFH) is a type of CD4 + helper T cell subset, located in the follicular germinal center to promote B cell expansion and differentiation. The 2008 World Health Organization (WHO) Classification scheme broadly grouped PTCLs into Angioimmunoblastic T-cell lymphoma (AITL) and PTCL, not otherwise specified (NOS). At that time lymphoma of T follicular helper cell origin(TFH-NL) was belong to PTCL, NOS. However, the 2017 World Health Organization (WHO) Classification scheme turned to grouped PTCLs into TFH-NL and PTCL, NOS. Currently identified categories of T-follicular helper cell-derived lymphomas include AITL, follicular T-cell lymphoma (FTL) (equivalent to the follicular variant of the original peripheral T), and NPTCL-TFH[1, 11]. The diagnostic criteria of NPTCL-TFH are: a) shared immunophenotypic features with AITL; b) expressed at least 2(ideally 3) TFH markers; c) lack of Inflammatory/polymorphous background; d) few HEV proliferation; e) no follicular dendritic cell(FDC) meshwork expansion. In a review by Parwiz J et al., T- and NK-cell lymphomas comprise only about 6% of all lymphoproliferative disorders, and the most frequent type is the not otherwise specified (NOS) category, NPTCL-TFH only account for less than 1% of all T-cell neoplasms[14, 15], therefore our case is very rare. Although our case is not the first NPTCL-TFH case reported, we firstly found CD20 expressed in this disease. All of the morphologic features, immunohistochemical results, scattered EBV + cells and T-cell arrangement positive proved our case to be a NPTCL-TFH. What interest us is CD20 get strong staining on the tissue. As a recognized B cell marker, CD20 is less well positive on T cells. The first case of CD20-positive peripheral T-cell lymphoma was reported by Yokose et al. in 2000, then CD20-positive AITL by Tachibana et al. in 2011. Recently there were more cases observed in NPTCL[18, 19], however we report the very first case presented CD20 positive in NPTCL-TFH after 2017 WHO Classification scheme. CD20 positivity in T-cell lymphomas may include derivation from subsets of CD20 positive T-cells undergoing neoplastic transformation or CD20-acquisition following neoplastic transformation of the T-cells. We suppose that T-follicular helper cells may have a supporting effect on B cells in the germinal center, and thus differentiate into CD20-expressing cells. Or TFH cells have uncertain direction of differentiation of progenitor B cells.
NPTCL-TFH should be distinguished from other types of peripheral T cell lymphomas, especially AITL. The clinical difference between AITL and NPTCL-TFH remains unclear, for they both have the symptoms of multiple lymphadenopathies, splenomegaly, B symptoms, hypergammaglobulinemia, eosinophilia, or a positive Coombs test. In regards of pathology, AITL are disorganized and show a diffuse polymorphous infiltrate that includes a variable proportion of medium-sized neoplastic T cells with abundant clear cytoplasm. these common characteristics in morphology often messed up with NPTCL-TFH, only through immunohistochemistry and molecular features can separate them[21–23]. With the new criteria, about 70% AITL can be redefined as NPTCL-TFH[21, 22]. AITL and TFH-NPTCL, may represent a morphologic continuum is further strengthened by the reported observations of transitions from one diagnosis to the other[2, 12, 23]. Our case’s morphological feature is similar to AITL, but the exact expression of CD4, Bcl-6, PD-1 and CXCL-13, scattered EBV positive cells and the T cell receptor arrangement positive proved it T follicular helper cell phenotype.
PTCL-NOS is another rare T-cell lymphoma needing to be distinguished. As the most common subtype of mature T cell lymphoma, it is a diagnosis of exclusion. There is no particular morphological aspect of this tumor. The lymph node often consists of numerous medium-sized or large cells with irregular, pleomorphic, hyperchromatic, or vesicular nuclei. Clear cells and Reed-Sternberg―like cells can also be seen. Unlike PTCL-TFH, PTCL-NOS has a very important inflammatory background in morphology, while hyperplasia of high endothelial venules and/or follicular dendritic cells are not usually seen. Although our case displays similar cell feature with PTCL-NOS, it does not have a prominent polymorphic inflammatory background, and the expression of TFH markers instead of CD30, a possible marker of PTCL-NOS also supports our diagnosis.
Moreover, follicular T cell lymphoma (FTCL) has some similar features with PTCL-TFH, because they both derived from T follicular helper cells. Sang Eun Yoon et al. classified 207 cases diagnosed with nodal lymphomas of T follicular helper (Tfh) cell origin into 111 cases of AITL, 68 cases of PTCL-NOS, 19 cases of FTCL and 10 cases of PTCL-TFH phenotype, but they cannot analyze FTCL and PTCL-TFH as different diseases with immunolabeling. In FTCL, two distinct growth patterns are recognized: one that mimics follicular lymphoma and one that mimics progressive transformation of germinal canters. The interfollicular areas lack the polymorphic infiltrates and vascular proliferation characteristic of AITL. Our case shows no FDC expansion on CD21, which highlights the diagnose is not FTCL.
We did the immunohistochemical labeling of CD30 and ALK was to make a differential diagnosis with anaplastic large cell lymphoma(ALCL). ALCL can be divided into ALK-positive and ALK-negative subtypes based on expression of ALK or ALK gene rearrangement. The neoplastic cells were mainly medium to large size with moderate basophilic cytoplasm, which mimics with our case. However, most of them had hyperchromatic nuclei and prominent nucleoli. So added the negative expression of CD30 and ALK, we eliminate the consideration of ALCL.
Since some of the tumor cells were CD20 positive, we should not ignore some B-cell neoplasms such as Hodgkin lymphoma, High-grade B-cell lymphoma. It’s just that the positive T cell markers and TCR rearrangement in our case confirmed that it was derived from T cells. Mantle T-cell lymphoma or other non-Hodgkin lymphomas such as Hepatosplenic T-cell lymphoma, Primary cutaneous anaplastic lymphoma, Primary cutaneous peripheral T-cell lymphomas also have some distinguishment points in our case. However, in general, it’s the molecular feature, expression of Bcl-6, CD4, PD-1 and CXCL-13 and positive of TCR arrangement that confirms our diagnose.