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

Abstract

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 clinicopathological and molecular characteristics that overlap with those of systemic TFH lymphomas, such as angioimmunoblastic T-cell lymphoma, and does not belong to known diagnostic groups of cutaneous lymphoma. This has an impact on the treatment and follow-up of patients; the clinical behaviour needs to be better clarified in further studies to tailor patient management.

Figure 1

Case selection and inclusion criteria. EBV, Epstein–Barr virus; GFELC, Groupe Francais d’Etude des Lymphomes Cutanés [French Study Group of Cutaneous Lymphomas network]; MF, mycosis fungoides; PTCL, peripheral T‐cell lymphoma; TFH, T‐follicular helper; SS; Sézary syndrome.

Figure 2

Representative clinical and histopathological aspects of pcTFH‐PTCL. Clinical photographs show multiple erythematous nodules on the trunk and the right arm in patient 5, with a ‘dome‐shaped’ erythematous and slightly squamous nodule, strongly resembling a pcSMLPD (inset). Erythematous papules on the cheek and chin were the manifestation of disease in patient 17. In patient 11’s biopsy, there is a dermal infiltrate, made of small/medium‐sized atypical lymphocytes. The neoplastic T cells show a full TFH phenotype, with positivity for CD3, PD1, CD10, CXCL13 and BCL6. pcTFH‐PTCL, primary cutaneous peripheral T‐cell lymphomas with a TFH phenotype; pcSMLPD, primary cutaneous CD4⁺ small‐/medium‐sized cell lymphoproliferative disorder; TFH, T‐follicular helper. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3

pcTFH‐PTCL associated with an EBV⁺ lymphoproliferation in the skin (patient 1). Erythematous nodule on the left thigh. The fluorodeoxyglucose positron emission/computed tomography imaging shows two subcutaneous hypermetabolic nodules (arrows) on the trunk and the right thigh, in addition to a skin lesion of the left thigh (circle). Histology shows a dense lymphocytic infiltrate involving all layers of skin. The superficial part of the lesion shows a T‐cell component made of small CD3⁺ and CXCL13⁺ lymphocytes with hyperchromatic nuclei. In the deep dermis and hypodermis, there are sheets of large atypical immunoblast‐like CD20⁺ EBV⁺ lymphocytes (EBER⁺). pcTFH‐PTCL, primary cutaneous peripheral T‐cell lymphomas with a T‐follicular helper phenotype; EBV, Epstein–Barr virus. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 4

Representation of molecular data with correlation to relevant clinicopathological features. EBV, Epstein–Barr virus; LPD, lymphoproliferative disorder. [Colour figure can be viewed at wileyonlinelibrary.com]