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Mature T/NK cell disorders

T follicular helper phenotype

Nodal PTCL with a TFH phenotype


Luiz Paulo de Lima Guido, M.D.
Catalina Amador, M.D.

Last author update: 4 November 2024
Last staff update: 4 November 2024

Copyright: 2021-2024, PathologyOutlines.com, Inc.

PubMed Search: Nodal PTCL with a TFH phenotype

Luiz Paulo de Lima Guido, M.D.
Catalina Amador, M.D.
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Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Clinical features | Diagnosis | Laboratory | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: de Lima Guido LP, Amador C. Nodal PTCL with a TFH phenotype. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomaPTCLTFH.html. Accessed December 17th, 2024.
Definition / general
  • Mature T cell lymphoma with a T follicular helper (TFH) phenotype, defined by the expression of CD4 and at least 2 (ideally 3) TFH markers, primarily involving lymph nodes
  • Must not fulfill the diagnostic criteria for other defined mature T cell lymphoma entities, including other nodal TFH lymphomas (Leukemia 2022;36:1720, Blood 2016;127:2375)
Essential features
  • Aggressive, mature T cell lymphoma
  • Expression of CD4 and at least 2, preferably 3, T follicular helper markers (such as PD-1, CD10, BCL6, CXCL13 and ICOS)
  • Part of a spectrum of T cell lymphomas with TFH phenotype, which also includes nodal TFH cell lymphoma, angioimmunoblastic type (nTFHL-AI), formerly angioimmunoblastic T cell lymphoma and nodal TFH cell lymphoma, follicular type (nTFHL-F), formerly known as follicular T cell lymphoma
  • Other mature T cell lymphomas must be excluded
  • Frequent mutations in RHOA and epigenetic regulators such as TET2 and DNMT3A
Terminology
  • Current terminology
    • Nodal T follicular helper (TFH) cell lymphoma, not otherwise specified in the 5th edition of the World Health Organization Classification of Hematolymphoid Tumors: Lymphoid Neoplasms (WHO HAEM5) (Leukemia 2022;36:1720)
    • Follicular helper T cell lymphoma, NOS in the International Consensus Classification of Mature Lymphoid Neoplasms (ICC 2022) (Mod Pathol 2022;35:306)
  • Historical names
    • These cases were classified initially within peripheral T cell lymphoma, not otherwise specified (PTCL, NOS) in the 4th edition of the WHO classification (WHO 2008)
    • Posteriorly renamed as nodal PTCL with a TFH phenotype in the revised 4th edition of the WHO classification (WHO 2017), where it was grouped with angioimmunoblastic T cell lymphoma (AITL) and T follicular lymphoma under the provisional umbrella category of nodal lymphomas of TFH origin (Blood 2016;127:2375)
ICD coding
  • ICD-O: 9702/3 - nodal TFH cell lymphoma, NOS
  • ICD-11: 2A90 & XH6SR1 - mature T cell lymphoma, specified types, nodal or systemic & nodal peripheral T cell lymphoma with T follicular helper phenotype
Epidemiology
Sites
  • nTFHL, NOS is characterized by disseminated disease similar to nTFHL-AI (Leukemia 2022;36:1720)
  • Nearly all cases involve lymph nodes
Pathophysiology
  • Proposed origin from TFH cells (a T cell subset essential for germinal center reactions and B cell specialization)
  • nTFH, NOS has a gene expression profile more comparable to nTFH-AI than PTCL, NOS (Blood 2016;127:2375, Haematologica 2017;102:e148)
  • Similarly, the mutational landscape resembles that of nTFH-AI
  • Physiologically, RHOA mediates migration and polarity of T cells
    • RHOA also functions in thymocyte development and activation of pre-T cell receptor (pre-TCR) signaling in thymocytes
    • G17V RHOA protein is considered to be a loss of function mutant on RhoA signaling pathway
    • Physiologic functions of RHOA are presumably abrogated in the G17V mutant, as the protein cannot be converted to the active GTP bound form
    • Its mutation may drive naive CD4+ T cells to differentiate to TFH cells and facilitate neoplasia
    • TET2 and DNMT3A are considered early mutations in TFH cells (Leukemia 2018;32:694)
Clinical features
  • Lymphadenopathy with typical advanced stage disease at presentation
  • Similar bone marrow involvement to nTFHL-AI and PTCL, NOS (Blood 2021;137:2161)
Diagnosis
  • Must not fulfill the required histopathological criteria for nTFHL, angioimmunoblastic type (nTFHL-AI) such as extrafollicular follicular dendritic cell expansion or high endothelial venule hyperplasia or nTFHL, follicular type (nTFHL-F), which displays a follicular growth pattern
  • Desirable clonal TCR gene rearrangement or mutation involving RHOA p.G17V
  • Staging performed according to the Lugano modification of the Ann Arbor staging system (J Clin Oncol 2014;32:3059)
Laboratory
  • nTFH, NOS has been linked to Coombs positive hemolytic anemia and polyclonal hypergammaglobulinemia but not as strongly as nTFH-AI (Blood 2021;137:2161)
Prognostic factors
  • Similar overall survival (OS) and progression free survival (PFS) to nTFHL-AI but better than PTCL, NOS, based on limited data (Haematologica 2017;102:e148)
  • Male gender, an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher and thrombocytopenia are related to poor OS (Haematologica 2017;102:e148)
Case reports
Treatment
  • Cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like chemotherapy is used in most patients
  • Ifosfamide, mesna, carboplatin, etoposide (ICE) gemcitabine based chemotherapy is less commonly used
  • Epigenetic modifiers, such as histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors, have shown a better treatment response rate than other PTCLs in the relapsed setting (Blood 2018;132:2305, Blood Adv 2020;4:4640, Am J Surg Pathol 2019;43:1282)
Microscopic (histologic) description
  • Lymph node architecture is effaced by a tumor cell rich infiltration of varying sized lymphoid cells (typically medium to large sized)
  • 2 recognized patterns: diffuse infiltration or proliferation around follicles in a paracortical T zone infiltration
  • Lack of a prominent polymorphic inflammatory background, high endothelial venule hyperplasia or follicular dendritic cell meshwork proliferation; however, some of these features typical of nTFH-AI may be present (Am J Surg Pathol 2016;40:1249)
  • Secondary B cell proliferations, unlike nTFH-AI, have not been thoroughly studied (Leukemia 2022;36:1720)
  • Lymphoepithelioid (Lennert morphology) may be encountered (Am J Surg Pathol 2007;31:1695)
Microscopic (histologic) images

Contributed by Catalina Amador, M.D.
Effacement of nodal architecture

Effacement of nodal architecture

Medium to large sized lymphocytes

Medium to large sized lymphocytes

Clear cell morphology

Clear cell morphology

Absent expansion of follicular dendritic cell meshworks   Absent expansion of follicular dendritic cell meshworks

CD21 and CD23: absent expansion of follicular dendritic cell meshworks


CD20 negative for B cell markers

CD20 negative for B cell markers

Positive membranous expression of CD4

Positive membranous expression of CD4

ICOS membranous positivity

ICOS membranous positivity

PD1 membranous positivity

PD-1 membranous positivity

BCL6 nuclear positivity

BCL6 nuclear positivity

Positive stains
Negative stains
Molecular / cytogenetics description
  • Clonal TCR gene rearrangement in most cases
  • Similar gene expression profile to nTFH-AI and normal TFH cells (Blood 2007;109:4952)
  • Mutational profiles of nPTCL-TFH overlap with nTFH-AI, except for IDH2, which is restricted to nTFH-AI
  • Mutations in RHOA
    • Mutations in G17V locus specific to TFH lymphomas
    • Loss of RHOA GTPase activity
  • Up to 60% frequency in nTFHL, NOS, similar to nTFH-AI (Blood 2021;137:2161)
  • Mutations in epigenetic regulators
    • Nonspecific for TFH lymphomas; seen in other T cell lymphomas and hematolymphoid neoplasms
    • TET2
      • Loss of function mutations
      • 50 - 75% frequency in nTFH, NOS (comparable to 75% in nTFHL-F and 50 - 80% in nTFHL-AI)
    • DNMT3A
      • Loss of function mutations
      • 7 - 10% frequency (compared with 25% in nTFHL-F and 20 - 40% in nTFHL-AI)
  • Mutations in TCR signaling pathway genes
    • Not specific, as they are also seen in other T cell lymphomas
    • PLC gamma: up to 10% and FYN < 5%
    • CD28 is absent as it seems restricted to nTFHL-AI (Blood Adv 2020;4:4640)
  • Cytogenetic abnormalities
    • Copy number gains in chromosomes 5 and 7 occur with a similar frequency to nTFH-AI (~10%) (Blood 2021;137:2161)
  • Negative serologic or molecular evidence of HTLV-1
Sample pathology report
  • Right inguinal lymph node, excisional biopsy:
    • Lymph node with nodal T follicular helper cell lymphoma, not otherwise specified (WHO HAEM5) / follicular helper T cell lymphoma, not otherwise specified (see comment)
    • Comment: The overall morphological features, including the expression of CD4 and 3 T follicular helper cell markers (ICOS, PD-1 and BCL6) by the neoplastic cells, support the diagnosis of a TFH lymphoma. The diagnosis of nTFH, NOS is favored over angioimmunoblastic T cell lymphoma due to the lack of polymorphism, expanded follicular dendritic cell meshworks and high endothelial venules. Given the patient's origin, adult T cell leukemia / lymphoma was also considered, given that these cases can express TFH markers. However, the serology study for HTLV-1 yielded negative results, excluding this possibility. T cell receptor gamma gene rearrangement studies were positive and the next generation sequencing panel revealed mutations in RHOA, TET2 and DNMT3, supporting the morphologic findings.
    • Microscopic description: The biopsy shows sections of lymph node with effaced architecture by an abnormal lymphoid infiltrate with a diffuse growth pattern. The neoplastic cells are composed of a spectrum of small, intermediate and large lymphoid cells with minimally associated inflammatory background. Immunohistochemistry shows that the neoplastic cells express CD3 and CD4, PD-1, BCL6 and ICOS and are negative for CD20, CD8, CD10, ALK and EBER in situ hybridization. CD30 is positive in 30% of the neoplastic cells. CD21 highlights the absence of expanded follicular dendritic cell meshworks. Ki67 proliferation is 50%. EBER in situ hybridization is negative.
Differential diagnosis
Board review style question #1
 


Which option describes characteristic features of nodal peripheral T cell lymphomas with T follicular helper phenotype?

  1. Increased expression of CD21 and CD23
  2. MYC and BCL2 gene rearrangements
  3. Polymorphic inflammatory background with expanded follicular dendritic cell meshwork
  4. Predominance in the young population
  5. Proliferation around follicles in a T zone infiltration pattern of the paracortex
Board review style answer #1
E. Proliferation around follicles in a T zone infiltration pattern of the paracortex. nTFHL, NOS characteristically presents with 2 recognized patterns: diffuse infiltration or proliferation around follicles in a paracortical T zone infiltration. Answer A is incorrect because CD21, CD23, CD35 or clusterin do not highlight expanded follicular dendritic cell meshworks. Answer B is incorrect because MYC and BCL2 gene rearrangements are characteristic of double hit high grade B cell lymphomas. Answer D is incorrect because this entity predominates in the elder population. Answer C is incorrect because this finding is characteristic of nodal TFH cell lymphoma, angioimmunoblastic type (nTFHL-AI).

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Reference: Nodal PTCL with a TFH phenotype
Board review style question #2
Which option describes a typical feature of nodal peripheral T cell lymphomas with T follicular helper phenotype?

  1. Expression of CD8 and TdT
  2. Formation of well defined aggregates surrounded by numerous small IgD+ mantle zone B cells arranged into large irregular nodules
  3. Indolent progression with a low incidence of disseminated disease
  4. Lack of TCR gene rearrangements
  5. RHOA and TET2 gene mutations
Board review style answer #2
E. RHOA and TET2 gene mutations. Detection of RHOA p.G17V mutation is observed in up to 60% of nTFHL, NOS and is a useful adjunct, as it supports the diagnosis of a nTFHL over PTCL, NOS. TET2 loss of function mutations have a 50 - 75% frequency in nTFH, NOS, comparable to 75% in nTFHL-F and 50 - 80% in nTFHL-AI. Answer A is incorrect because CD8 and TdT are mature T cell lymphomas, hence TdT is characteristically negative. CD8 is typically not expressed in these tumors but the expression does not exclude diagnosis. Answer B is incorrect because these findings describe nodal TFH cell lymphoma, follicular type (nTFHL-F). Answer C is incorrect because these tumors typically present as advanced disease. Answer D is incorrect because clonal TCR gene rearrangement is detected in most cases.

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Reference: Nodal PTCL with a TFH phenotype
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