Nodal Marginal Zone Lymphoma with Prominent Expansion of PD-1+ T-Follicular Helper Cells - A Persistent Diagnostic Challenge with a Heterogeneous Mutational Architecture

Sep 30, 2026

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Nodal marginal zone lymphoma (NMZL) is an indolent B-cell lymphoma that can be difficult to diagnose because distinct markers may be absent. In rare atypical cases, abundant PD1+ T follicular helper (TFH) cells can mimic peripheral T-cell lymphoma of TFH origin, complicating interpretation. A 72-year-old woman with progressive lymphadenopathy showed disrupted nodal architecture and proliferating CD4+/PD1+ T cells. Bone marrow contained CD20+ B-cell aggregates mixed with CD3+/CD4+/PD1+ T cells. NGS demonstrated immunoglobulin clonality in both compartments, polyclonal T-cell receptor genes, and NMZL-associated mutations with tissue-specific distribution, highlighting the need for NGS-based clonality and spatial mutational profiling.

LanguageEnglish

CategoryHealthcare

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Reading Time45 min

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Abstract

Introduction

Communication Nodal Marginal Zone Lymphoma with Prominent Expansion of PD-1+ T-Follicular Helper Cells: A Persistent Diagnostic Challenge with a Heterogeneous Mutational Architecture Stefania Crisci 1, Annarosaria De Chiara 2, Maria Oro 1, Maria Rivieccio 1, Annalisa Altobelli 1, Sara Mele 1, Letizia Sirica 1, Daniela Donnarumma 1, Matteo Bonanni 1, Annarosa Cuccaro 1, Alberto Fresa 1, Rosaria De Filippi 3 and Antonio Pinto 1, * Academic Editor: Hans Knecht Received: 21 November 2025 Revised: 9 December 2025 Accepted: 18 December 2025 Published: 20 December 2025 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Hematology-Oncology and Stem Cell Transplantation Unit, Istituto Nazionale Tumori-IRCCS-Fondazione‘G. Pascale’, Via Mariano Semmola 49, 80131 Naples, Italy; [s.crisci@istitutotumori.na.it](s.crisci@istitutotumori.na.it) (S.C.); [maria.oro@istitutotumori.na.it](maria.oro@istitutotumori.na.it) (M.O.); [maria.rivieccio@istitutotumori.na.it](maria.rivieccio@istitutotumori.na.it) (M.R.); annalisa.altobelli@istitutotumori.na.it (A.A.); [s.mele@istitutotumori.na.it](s.mele@istitutotumori.na.it) (S.M.); [letizia.sirica@istitutotumori.na.it](letizia.sirica@istitutotumori.na.it) (L.S.); d.donnarumma@istitutotumori.na.it (D.D.); matteo.bonanni@istitutotumori.na.it (M.B.); annarosa.cuccaro@istitutotumori.na.it (A.C.); [alberto.fresa@istitutotumori.na.it](alberto.fresa@istitutotumori.na.it) (A.F.) 2 Pathology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione ‘G. Pascale’, 80131 Naples, Italy; [a.dechiara@istitutotumori.na.it](a.dechiara@istitutotumori.na.it) 3 Department of Pharmacy, Università degli Studi Federico II, 80131 Naples, Italy; [rosaria.defilippi@istitutotumori.na.it](rosaria.defilippi@istitutotumori.na.it) * Correspondence: [a.pinto@istitutotumori.na.it](a.pinto@istitutotumori.na.it); Tel.: +39-(0)-81-17770368 Abstract Nodal marginal zone lymphoma (NMZL) is an indolent B-cell lymphoma that may pose diagnostic challenges due to the absence of distinct markers. In rare atypical cases, an overabundance of PD1+ T follicular helper (TFH) cells in tumor tissue may mimic peripheral T-cell lymphoma (PTCL) of TFH origin, further complicating the diagnosis. A 72-year-old woman with progressive lymphadenopathy had a cervical lymph node biopsy showing a disrupted architecture with monomorphic nodules of CD20+/MNDA+ B-cells and a prominent central population of proliferating CD4+/PD1+ T-cells, initially suggestive of a PTCL-TFH. The bone marrow contained aggregates of CD20+ B-cells intermixed with CD3+/CD4+/PD1+ T-cells. Next-generation sequencing (NGS) revealed clonal immunoglobulin heavy-chain rearrangements in the lymph node and bone marrow, with T-cell receptor genes displaying a polyclonal pattern. Targeted NGS showed no PTCLrelated alterations but identified NMZL-associated mutations with different distributions across lymph node and bone marrow compartments. NOTCH2 mutations (c.6418C>T; p.Gln2140*) were found in both tissues, while the (c.69+2T>A; p.?) TNFRSF14 gene mutation was only detected in the lymph node. The KMT2D gene displayed a frameshift variant in the lymph node (c.4801_4802delinsT; p.Arg1601Leufs*3) and an in-frame deletion (c.11756_ 11758del; p.Gln3919del) in the bone marrow. Notably, NGS and digital droplet PCR confirmed a TP53 frameshift mutation (c.902del; p.Pro301Glnfs*44) with a fractional abundance of 0.31% in the lymph node and a (c.742C>T; p.Arg248Trp) mutation (0.309%) in the bone marrow. Results underscore the importance of NGS-based clonality to diagnose NMZL with prominent PD1+ T-cell hyperplasia, and prompt further investigation into tissue-specific mutational signatures in these unusual cases. Keywords: nodal marginal zone lymphoma; PD-1; T-follicular helper cells; next-generation sequencing; clonality asse

FAQs

Why can nodal marginal zone lymphoma (NMZL) be challenging to diagnose in some cases?

NMZL is an indolent B-cell lymphoma that may lack distinct diagnostic markers. In atypical cases, excessive PD1+ T follicular helper cells can resemble peripheral T-cell lymphoma of TFH origin.

What did the biopsy and bone marrow findings suggest initially?

The lymph node biopsy showed disrupted architecture with CD20+/MNDA+ B-cell nodules and a prominent central population of proliferating CD4+/PD1+ T cells, initially suggestive of PTCL-TFH. The bone marrow contained CD20+ B-cell aggregates intermixed with CD3+/CD4+/PD1+ T cells.

How did next-generation sequencing (NGS) clarify the diagnosis?

NGS identified clonal immunoglobulin heavy-chain rearrangements in both lymph node and bone marrow, while T-cell receptor genes were polyclonal. Targeted NGS did not find PTCL-related alterations but detected NMZL-associated mutations with different distributions across compartments.

Sep 30, 2026

Uploaded by Asher