Primary cutaneous peripheral T-cell lymphomas with a T-follicular helper phenotype: an integrative clinical, pathological and molecular case series study

Abstract

Summary Background Primary cutaneous peripheral T‐cell lymphomas with a T‐follicular helper phenotype (pcTFH‐PTCL) are poorly characterized, and often compared to, but not corresponding with, mycosis fungoides (MF), Sézary syndrome, primary cutaneous CD4+ lymphoproliferative disorder, and skin manifestations of angioimmunoblastic T‐cell lymphomas (AITL). Objectives We describe the clinicopathological features of pcTFH‐PTCL in this original series of 23 patients, and also characterize these cases molecularly. Methods Clinical and histopathological data of the selected patients were reviewed. Patient biopsy samples were also analysed by targeted next‐generation sequencing. Results All patients (15 men, eight women; median age 66 years) presented with skin lesions, without systemic disease. Most were stage T3b, with nodular (n = 16), papular (n = 6) or plaque (atypical for MF, n = 1) lesions. Three (13%) developed systemic disease and died of lymphoma. Nine (39%) patients received more than one line of chemotherapy. Histologically, the lymphomas were CD4+ T‐cell proliferations, usually dense and located in the deep dermis (n = 14, 61%), with the expression of at least two TFH markers (CD10, CXCL13, PD1, ICOS, BCL6), including three markers in 16 cases (70%). They were associated with a variable proportion of B cells. Eight patients were diagnosed with an associated B‐cell lymphoproliferative disorder (LPD) on biopsy, including Epstein–Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (n = 3), EBV+ LPD (n = 1) and monotypic plasma cell LPD (n = 4). Targeted sequencing showed four patients to have a mutated TET2–RHOAG17V association (as frequently seen in AITL) and another a TET2/DNMT3A/PLCG1/SETD2 mutational profile. The latter patient, one with a TET2–RHOA association, and one with no detected mutations, developed systemic disease and died. Five other patients showed isolated mutations in TET2 (n = 1), PLCG1 (n = 2), SETD2 (n = 1) or STAT5B (n = 1). Conclusions Patients with pcTFH‐PTCL have pathological and genetic features that overlap with those of systemic lymphoma of TFH derivation. Clinically, most remained confined to the skin, with only three patients showing systemic spread and death. Whether pcTFH‐PTCL should be integrated as a new subgroup of TFH lymphomas in future classifications is still a matter of debate. What is already known about this topic? There is a group of cutaneous lymphomas that express T‐follicular helper (TFH) markers that do not appear to correspond to existing World Health Organization diagnostic entities. These include mycosis fungoides, Sézary syndrome, or primary cutaneous CD4+ small/medium‐sized T‐cell lymphoproliferative disorder or cutaneous extensions of systemic peripheral T‐cell lymphomas (PTCL) with TFH phenotype. What does this study add? This is the first large original series of patients with a diagnosis of primary cutaneous PTCL with a TFH phenotype (pcTFH‐PTCL) to be molecularly characterized. pcTFH‐PTCL may be a standalone group of cutaneous lymphomas with cli...

Follicular T helper cells and cutaneous T-cell lymphomas

“…In this issue of the BJD , Wang et al . present in their study 23 cases characterized by the expression of TFH markers indicating a TFH phenotype, but that do not belong to one of the well‐defined CTCL entities 8 . Clinically, these cases present with papulonodular lesions or plaques.…”

“…In this issue of the BJD, Wang et al present in their study 23 cases characterized by the expression of TFH markers indicating a TFH phenotype, but that do not belong to one of the well-defined CTCL entities. 8 Clinically, these cases present with papulonodular lesions or plaques. Histologically, they show a dense and diffuse dermal infiltrate of atypical CD4 + T cells that express at least two, and often three TFH markers.…”

Primary cutaneous T‐follicular helper lymphoma

“…Clinically, cutaneous TFH neoplasms will present as nodules rather than plaques, and without erythroderma. Histologically, epidermotropism (the hallmark of MF) should not be seen [7]. A lack of nodal involvement on staging imaging studies will differentiate a primary cutaneous TFH lesion from secondary skin involvement by a nodal TFH neoplasm, something which may be seen, particularly in the case of angioimmunoblastic T-cell lymphoma [8,9].…”

Cutaneous T‐cell lymphomas: 2023 update on diagnosis, risk‐stratification, and management

“…An important goal during a patient's initial diagnostic evaluation is to distinguish non-MF/SS CTCL subtypes from MF/SS, as the natural history, prognosis, and treatment approach for each of the non-MF/ SS lymphomas is highly variable, including a recently described subset of primary CTCL with a T follicular helper immunophenotype with histopathologic and genetic characteristics similar to angioimmunoblastic T-cell lymphomas. 91 A detailed description of these CTCL subtypes is beyond the scope of this update, but the salient features of each have been previously summarized. 2,92 3 | RISK-STRATIFICATION…”