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[10]. 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[12]. 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[13], 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,[16] then CD20-positive AITL by Tachibana et al. in 2011[17]. 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[19]. 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.[20]
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[14]. 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[24]. 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[1]. 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[25]. In FTCL, two distinct growth patterns are recognized: one that mimics follicular lymphoma and one that mimics progressive transformation of germinal canters[14]. The interfollicular areas lack the polymorphic infiltrates and vascular proliferation characteristic of AITL[26]. 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[1]. 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[27]. 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.