Introductory Chapter: Updates and New Insights from WHO 2017 Peripheral T-Cell Lymphoma Classification

*Pier Paolo Piccaluga*

## **1. Introduction**

Peripheral T-cell lymphomas (PTCLs) are relatively rare disorders, representing around 10% of all lymphomas worldwide; however, they are relatively common in specific geographic areas, including Asia, the Caribbean basin, and scattered areas in Europe where HTVL1 is endemic.

In the latest edition of the World Health Organisation (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues, edited in 2017, nodal, extra nodal and leukaemia forms are listed. Specifically, as many as 31 entities are listed among PTCLs [1]. Compared with the previous edition, in the current classification, a few but quite relevant novelties have been introduced. Generally speaking, as already observed for B-cell derived malignancies, recent discoveries from molecular genetic studies led to a better definition of certain entities and clearly defined a pivotal role for cellular derivation in tumour classification. In the following, the main updates concerning non-cutaneous PTCLs will be briefly discussed.

## **2. T-follicular helper cell-related lymphomas**

Among nodal PTCLs, that overall constitute the majority of PTCL cases, a new subgroups has been defined based on the corresponding to a specific cellular counterpart, namely the T-follicular helper (TFH) lymphocytes. The latter is physiologically represented within germinal centres of secondary follicles, providing costimulatory signalling to B-lymphocytes through many different singling pathways [2]. These cells, at immunophenotyping, are characterised by the expression of selected markers, including BCL6, SAP, ICOS, CXCL13 and CD10. Consistently, tutors derived from TFH cells express these molecules. However, likely due to the aberrancy in phenotype, which is typical of PTCLS [3], some of them may lack in a single case. Therefore, an extended panel should be tested to confirm the diagnosis. On the other hand, since non-TFH-derived PTCLs may express one of these markers, it is recommended to detect positive staining for at least two (better would be three) of them to claim a TFH derivation [4]. TFH-related PTCLs currently include three main nodal PTCL types, namely angioimmunoblastic T-cell lymphoma (AITL, the commonest PTCL in northern Europe), follicular T-cell lymphoma (FTCL, formerly accounted among PTCLS not otherwise specified/NOS), and PTCL/NOS not fulfilling the diagnostic criteria for the previous tutors but showing a clear TFH-phenotype. Such cases were characterised and associated to TFHlymphocyte at both transcriptional and protein level [5–7].

Beside the cell of origin, *per se* relevant criteria for tumour classification, TFHrelated PTCLs also share, at least for a certain extent, the genetic background and, therefore, the molecular pathogenesis. Particularly, genes controlling epigenetic regulation of gene expression as well as gene involved in T-cell receptor (TCR) signalling appeared to be more commonly deregulated [8, 9]. The presence of *TET2, IDH2* and *DNMT3A/B* somatic mutations is detected in about 20–80% of cases [10, 11]. Intriguingly, it was recently shown that treatment with 5-azacytidine, a well-known demethylating agent, currently approved for acute myeloid leukaemia therapy, was strikingly effective in patients affected by TFH-PTCL, with sustained clinical responses observed in previously relapsed/refractory cases [12]. Second, mutations affecting *RHOA* were observed in up to 70% of AITL cases and in a variable percentage of other PTCLs [9, 11]. By deregulating the RHOA GTPase protein, the TCR signalling is eventually affected. Similar effects are determined by *VAV1* rearrangements that are mutually exclusive with *RHOA* mutations. Less frequently, other genetic events can inter with TCR singling, including *PLCG1* (14%), *CD28* (9–11%) and *FYN* (3–4%) [8].

Finally, ITK/SYK rearrangements, due to the t(5;9) translocation, are quite common in FTCL, being only occasionally recorded in AITL.

Therapeutic strategies designed against aberrant TCR are currently under investigation.

#### **3. Extra-nodal, non-cutaneous PTCL**

As far as this category of PTCLs is concerned, the main novelties regard anaplastic large cell lymphomas (ALCLs) and intestinal PTCLs.

Among ALCLs, first of all, ALCL ALK-negative has been regarded as an independent entity, mainly based on gene expression data [13-15] and more recent genetic data acquired through next generation sequencing [16]. In fact, ALCL ALKnegative was shown to have a global gene expression profile (GEP) different from other PTCLs and specially PTCL/NOS, carrying recurrent genetic rearrangements eventually leading to STAT3 activation [16]. Noteworthy, this finding provides the molecular basis for the similarities between ALCL ALK-positive and negative, since STAT3 is the main downstream of ALK as well.

Second, a new provisional entity has been introduced, the breast-implantassociated (BI) ALCL. This tumour, although very uncommon, solicited great attention for the social impact. In fact, it selectively arises in patients who received a breast implant after oncologic or simply aesthetic surgery. The tumour can present as wither a serum (i.e. with malignant cells floating in a serous fluid around the capsule) or as tumbrel mass, the latter cases being more aggressive. Of note, recent GEP studies indicated that BI-ALCL is distinct from ALK-positive and negative cases, but presents with the same typical features including STAT3 activation and TCR singling downregulation [17]. The genetic background of the disease needs, however, to be fully elucidated.

As far as intestinal PTCLs are concerned, it has become apparent that the two subtypes formerly designated as variants of enteropathy-associated T-cell lymphoma (EATL) are distinct [18–20]. Type I EATL, now designated as EATL, is closely related to coeliac disease and is mainly encountered in people from the northern part of Europe. Type II EATL, now designated as *monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)*, shows no link with coeliac disease and appears relatively more common in Hispanic and Asian populations. Genetically,

**3**

Italy

**Author details**

communities.

Pier Paolo Piccaluga1,2,3

Medicine, Bologna, Italy

Technology, Nairobi, Kenya

provided the original work is properly cited.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology and Medical Oncology "L&A Seràgnoli", Bologna University School of

2 Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo,

3 Department of Pathology, Jomo Kenyatta University of Agriculture and

\*Address all correspondence to: pierpaolo.piccaluga@unibo.it

*Introductory Chapter: Updates and New Insights from WHO 2017 Peripheral T-Cell Lymphoma…*

gains in chromosome 8q24 involving MYC are seen in a high proportion of cases of MEITL but not EATL. On the clinical ground, both forms of intestinal T-cell

Overall, a new road towards molecular classification and possibly more targeted therapy has been initiated for PTCLs, as it happened for acute leukemias and B-cell lymphomas in the last decade. Despite the large amount of still unsolved issues, hopefully, this will be translated soon into significant benefit for patients and

lymphoma are aggressive and almost always occur in adults [18].

*DOI: http://dx.doi.org/10.5772/intechopen.86262*

*Introductory Chapter: Updates and New Insights from WHO 2017 Peripheral T-Cell Lymphoma… DOI: http://dx.doi.org/10.5772/intechopen.86262*

gains in chromosome 8q24 involving MYC are seen in a high proportion of cases of MEITL but not EATL. On the clinical ground, both forms of intestinal T-cell lymphoma are aggressive and almost always occur in adults [18].

Overall, a new road towards molecular classification and possibly more targeted therapy has been initiated for PTCLs, as it happened for acute leukemias and B-cell lymphomas in the last decade. Despite the large amount of still unsolved issues, hopefully, this will be translated soon into significant benefit for patients and communities.

## **Author details**

*Peripheral T-cell Lymphomas*

(9–11%) and *FYN* (3–4%) [8].

investigation.

a clear TFH-phenotype. Such cases were characterised and associated to TFH-

Beside the cell of origin, *per se* relevant criteria for tumour classification, TFHrelated PTCLs also share, at least for a certain extent, the genetic background and, therefore, the molecular pathogenesis. Particularly, genes controlling epigenetic regulation of gene expression as well as gene involved in T-cell receptor (TCR) signalling appeared to be more commonly deregulated [8, 9]. The presence of *TET2, IDH2* and *DNMT3A/B* somatic mutations is detected in about 20–80% of cases [10, 11]. Intriguingly, it was recently shown that treatment with 5-azacytidine, a well-known demethylating agent, currently approved for acute myeloid leukaemia therapy, was strikingly effective in patients affected by TFH-PTCL, with sustained clinical responses observed in previously relapsed/refractory cases [12]. Second, mutations affecting *RHOA* were observed in up to 70% of AITL cases and in a variable percentage of other PTCLs [9, 11]. By deregulating the RHOA GTPase protein, the TCR signalling is eventually affected. Similar effects are determined by *VAV1* rearrangements that are mutually exclusive with *RHOA* mutations. Less frequently, other genetic events can inter with TCR singling, including *PLCG1* (14%), *CD28*

Finally, ITK/SYK rearrangements, due to the t(5;9) translocation, are quite com-

As far as this category of PTCLs is concerned, the main novelties regard anaplas-

Among ALCLs, first of all, ALCL ALK-negative has been regarded as an independent entity, mainly based on gene expression data [13-15] and more recent genetic data acquired through next generation sequencing [16]. In fact, ALCL ALKnegative was shown to have a global gene expression profile (GEP) different from other PTCLs and specially PTCL/NOS, carrying recurrent genetic rearrangements eventually leading to STAT3 activation [16]. Noteworthy, this finding provides the molecular basis for the similarities between ALCL ALK-positive and negative, since

Second, a new provisional entity has been introduced, the breast-implantassociated (BI) ALCL. This tumour, although very uncommon, solicited great attention for the social impact. In fact, it selectively arises in patients who received a breast implant after oncologic or simply aesthetic surgery. The tumour can present as wither a serum (i.e. with malignant cells floating in a serous fluid around the capsule) or as tumbrel mass, the latter cases being more aggressive. Of note, recent GEP studies indicated that BI-ALCL is distinct from ALK-positive and negative cases, but presents with the same typical features including STAT3 activation and TCR singling downregulation [17]. The genetic background of the disease needs,

As far as intestinal PTCLs are concerned, it has become apparent that the two subtypes formerly designated as variants of enteropathy-associated T-cell lymphoma (EATL) are distinct [18–20]. Type I EATL, now designated as EATL, is closely related to coeliac disease and is mainly encountered in people from the northern part of Europe. Type II EATL, now designated as *monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)*, shows no link with coeliac disease and appears relatively more common in Hispanic and Asian populations. Genetically,

Therapeutic strategies designed against aberrant TCR are currently under

lymphocyte at both transcriptional and protein level [5–7].

mon in FTCL, being only occasionally recorded in AITL.

tic large cell lymphomas (ALCLs) and intestinal PTCLs.

**3. Extra-nodal, non-cutaneous PTCL**

STAT3 is the main downstream of ALK as well.

however, to be fully elucidated.

**2**

Pier Paolo Piccaluga1,2,3

1 Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology and Medical Oncology "L&A Seràgnoli", Bologna University School of Medicine, Bologna, Italy

2 Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy

3 Department of Pathology, Jomo Kenyatta University of Agriculture and Technology, Nairobi, Kenya

\*Address all correspondence to: pierpaolo.piccaluga@unibo.it

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of tumors of hematopoietic and lymphoid tissues. 5th ed. Vol. 1. Lyon: IARC; 2017

[2] CG1 V, Linterman MA, Yu D, MacLennan IC. Follicular helper T cells. Annual Review of Immunology. 2016;**34**:335-368

[3] Went P, Agostinelli C, Gallamini A. Marker expression in peripheral T-cell lymphoma: A proposed clinical-pathologic prognostic score. Journal of Clinical Oncology. 2006;**24**(16):2472-2479

[4] Dogan A, Gaulard P, Jaffe ES. Angioimmunoblastic T-cell lymphoma and other nodal lymphomas of T follicular helper cell origin. In: WHO Classification of tumors of hematopoietic and lymphoid tissues. 5th ed. Vol. 1. Lyon: IARC; 2017. pp. 407-412

[5] Rudiger T, Geissinger E, Muller-Hermelink HK. 'Normal counterparts' of nodal peripheral T-cell lymphoma. Hematological Oncology. 2006;**24**(4):175-180

[6] de Leval L, Rickman DS, Thielen C, et al. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood. 2007;**109**(11):4952-4963

[7] Piccaluga PP, Agostinelli C, Califano A, et al. Gene expression analysis of angioimmunoblastic lymphoma indicates derivation from T follicular helper cells and vascular endothelial growth factor deregulation. Cancer Research. 2007;**67**(22):10703-10710

[8] Vallois D, Dobay MP, Morin RD, et al. Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas. Blood. 2016;**128**(11):1490-1502

[9] Palomero T, Couronne L, Khiabanian H, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nature Genetics. 2014;**46**(2):166-170

[10] Lemonnier F, Couronne L, Parrens M, et al. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood. 2012;**120**(7):1466-1469

[11] Odejide O, Weigert O, Lane AA. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood. 2014;**123**(9):1293-1296

[12] Lemonnier F, Dupuis J, Sujobert P. Treatment with 5-azacytidine induces a sustained response in patients with angioimmunoblastic T-cell lymphoma. Blood. 2018;**132**(21):2305-2309

[13] Piccaluga PP, Agostinelli C, Califano A, et al. Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets. The Journal of Clinical Investigation. 2007;**117**(3):823-834

[14] Piva R, Agnelli L, Pellegrino E. Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms. Journal of Clinical Oncology. 2010;**28**(9):1583-1590

[15] Iqbal J, Weisenburger DD, Greiner TC, et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood. 2010;**115**(5):11

[16] Crescenzo R, Abate F, Lasorsa E. Convergent mutations and kinase

**5**

*Introductory Chapter: Updates and New Insights from WHO 2017 Peripheral T-Cell Lymphoma…*

*DOI: http://dx.doi.org/10.5772/intechopen.86262*

fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell.

[17] Di Napoli A, De Cecco L,

[18] Jaffe ES, Chott A, Ott G. Intestinal T-cell lymphoma. In: WHO Classification of tumors of hematopoietic and lymphoid tissues. 5th ed. Vol. 1. Lyon: IARC; 2017. pp. 372-380

[19] Attygalle AD, Cabegadas J, Gaulard P, et al. Peripheral T-cell and NK-cell lymphomas and their mimics; taking a step forward - report on the lymphoma workshop of the XVIth meeting of the European Association for Haematopathology and the Society for Hematopathology. Histopathology.

[20] Swerdlow SH, Jaffe ES, Brousset P, et al. Cytotoxic T-cell and NK-cell lympho mas: Current questions and controversies. The American Journal of Surgical Pathology. 2014;**38**:e60-e71

2014;**64**:171-199

Piccaluga PP. Transcriptional analysis distinguishes breast implant-associated anaplastic large cell lymphoma from other peripheral T-cell lymphomas. Modern Pathology. 2019;**32**(2):216-230

2015;**27**(4):516-532

*Introductory Chapter: Updates and New Insights from WHO 2017 Peripheral T-Cell Lymphoma… DOI: http://dx.doi.org/10.5772/intechopen.86262*

fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell. 2015;**27**(4):516-532

[17] Di Napoli A, De Cecco L, Piccaluga PP. Transcriptional analysis distinguishes breast implant-associated anaplastic large cell lymphoma from other peripheral T-cell lymphomas. Modern Pathology. 2019;**32**(2):216-230

[18] Jaffe ES, Chott A, Ott G. Intestinal T-cell lymphoma. In: WHO Classification of tumors of hematopoietic and lymphoid tissues. 5th ed. Vol. 1. Lyon: IARC; 2017. pp. 372-380

[19] Attygalle AD, Cabegadas J, Gaulard P, et al. Peripheral T-cell and NK-cell lymphomas and their mimics; taking a step forward - report on the lymphoma workshop of the XVIth meeting of the European Association for Haematopathology and the Society for Hematopathology. Histopathology. 2014;**64**:171-199

[20] Swerdlow SH, Jaffe ES, Brousset P, et al. Cytotoxic T-cell and NK-cell lympho mas: Current questions and controversies. The American Journal of Surgical Pathology. 2014;**38**:e60-e71

**4**

*Peripheral T-cell Lymphomas*

[1] Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of tumors of hematopoietic and lymphoid tissues. 5th helper T-cell-derived lymphomas. Blood. 2016;**128**(11):1490-1502

H, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nature Genetics. 2014;**46**(2):166-170

2012;**120**(7):1466-1469

[9] Palomero T, Couronne L, Khiabanian

[10] Lemonnier F, Couronne L, Parrens M, et al. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood.

[11] Odejide O, Weigert O, Lane AA. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma.

[12] Lemonnier F, Dupuis J, Sujobert P. Treatment with 5-azacytidine induces a sustained response in patients with angioimmunoblastic T-cell lymphoma.

[14] Piva R, Agnelli L, Pellegrino E. Gene expression profiling uncovers molecular

[15] Iqbal J, Weisenburger DD, Greiner TC, et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma.

[16] Crescenzo R, Abate F, Lasorsa E. Convergent mutations and kinase

classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms. Journal of Clinical Oncology. 2010;**28**(9):1583-1590

Blood. 2014;**123**(9):1293-1296

Blood. 2018;**132**(21):2305-2309

[13] Piccaluga PP, Agostinelli C, Califano A, et al. Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets. The Journal of Clinical Investigation.

2007;**117**(3):823-834

Blood. 2010;**115**(5):11

ed. Vol. 1. Lyon: IARC; 2017

[2] CG1 V, Linterman MA, Yu D, MacLennan IC. Follicular helper T cells. Annual Review of Immunology.

[3] Went P, Agostinelli C, Gallamini A. Marker expression in peripheral T-cell lymphoma: A proposed clinical-pathologic prognostic score. Journal of Clinical Oncology.

**References**

2016;**34**:335-368

2006;**24**(16):2472-2479

[4] Dogan A, Gaulard P, Jaffe ES. Angioimmunoblastic T-cell

[5] Rudiger T, Geissinger E, Muller-Hermelink HK. 'Normal counterparts' of nodal peripheral T-cell lymphoma. Hematological Oncology.

[6] de Leval L, Rickman DS, Thielen C, et al. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood. 2007;**109**(11):4952-4963

[7] Piccaluga PP, Agostinelli C, Califano A, et al. Gene expression analysis of angioimmunoblastic lymphoma indicates derivation from T follicular helper cells and vascular endothelial growth factor deregulation. Cancer Research. 2007;**67**(22):10703-10710

[8] Vallois D, Dobay MP, Morin RD, et al. Activating mutations in genes related to TCR signaling in

angioimmunoblastic and other follicular

2006;**24**(4):175-180

lymphoma and other nodal lymphomas of T follicular helper cell origin. In: WHO Classification of tumors of hematopoietic and lymphoid tissues. 5th ed. Vol. 1. Lyon: IARC; 2017. pp. 407-412

**7**

**Chapter 2**

**Abstract**

November 2018.

**1. Introduction**

**2. Background**

**2.1 WHO classification**

**Keywords:** T-cell lymphoma, transplant

of T-cell lymphoma has led to advances in management.

Overview of T-cell Lymphomas

T-cell lymphomas are a mixed bag of diseases with a similar origin but diverse in biology and behavior. This review aims to highlight the key changes to the WHO classification and summarize the therapeutic paradigm as of the time of writing in

T- and natural killer (NK)-cell lymphomas are a heterogeneous group of lymphoproliferative diseases that represent 10–15% of non-Hodgkin lymphomas (NHL). T-cell lymphomas in general have worse outcomes as compared to their B-cell counterparts. Over recent years, the understanding of the different subtypes

T- and NK-cell lymphomas can be subclassified according to nodal, extranodal, cutaneous, or leukemic subtypes based on the 2008 World Health Organization (WHO) classification of lymphoid malignancies (**Table 1**) [1]. The 2016 update of the WHO classification saw the addition of three provisional entities and changes in designation to five entities, reflecting the advancements in the understanding of

The update in the classification saw follicular T-cell lymphoma coming under the umbrella of angioimmunoblastic T-cell lymphoma (AITL), given the common genetic mutations such as *TET2*, *IDH2*, *DNMT3A*, *RHOA*, and *CD28* and fusions such as *ITK-SYK* and *CTLA4-CD28* nodal peripheral T-cell lymphoma (PTCL), previously classified under peripheral T-cell lymphoma, not otherwise specified (PTCL NOS) was

The diagnosis of PTCL NOS is made when a lymphoproliferative disorder is of the T-cell lineage without any distinctive features that fit into the subtypes. Two distinct molecular subgroups have been identified in PTCL NOS with differing clinical outcomes and prognosis. High expression of transcription factor *GATA3* was associated with worse clinical outcomes, while TBX2 expression enriched by IFNgamma and NfKB pathways was associated with better survival. These findings provide insight into a disease which has been a diagnosis of exclusion, with poor

this group of diseases [2, 3]. The major changes are highlighted below.

reclassified under the AITL classification given the similar genetic landscape.

clinical outcomes and minimal advances in treatment.

*Nagavalli Somasundaram and Soon Thye Lim*

## **Chapter 2**
