PTCLC81-C96

According to the current WHO classification in its 4th revised edition of 2017, PTCL distinguishes mature peripheral T-cell lymphomas from immature peripheral T-cell neoplasms (lymphoblastic T-NHL, T-ALL) (Swerdlow S CE et al. 2017). Due to their particular clinic and therapy, primary cutaneous T-cell lymphomas are assigned a distinct order. In PTCL, histological entities occur in varying frequencies depending on age and geographies. The following entities occur most frequently in Europe (Vose J et al 2008):

Mycosis fungoides with versch. Variants (MF)

PTCL without further specification (PTCL, NOS)

Angioimmunoblastic T-cell lymphoma (AITL)

Large cell anaplastic lymphoma (ALCL, ALK+ and ALK-).

Peripheral T-cell lymphomas (PTCL) are tabulated below according to the 2017 WHO classification:

T-cell prolymphocytic leukemia (T-PLL).

T-cell leukemia with large granular lymphocytes (T-LGL).

Chronic lymphoproliferative disorder of NK cells (CLPD-NK)

Aggressive NK cell leukemia (ANKL)

Systemic EBV+ T-cell lymphoma in childhood * (EBVT)

Hydroa-vacciniforme-like lymphoproliferative disorder * (HV-like LPDs)

Adult T-cell lymphoma/leukemia (HTLV+) (ATLL)

Extranodal NK-/T-cell lymphoma, nasal type (ENKTL)

Enteropathy-associated T-cell lymphoma (EATL)

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) *

Indolent T-cell lymphoproliferative disorder of the GI tract * (ITCLD-GT)

Hepatosplenic T-cell lymphoma (HSTL)

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL)

Mycosis fungoides (MF)

Sézary syndrome (SS)

Primary cutaneous CD30+ T-cell lymphoproliferative disorders (PCTPD)

- Lymphomatoid papulosis (LyP)

- Primary cutaneous CD30 positive anaplastic large T-cell lymphoma (PCALCL)

Cutaneous gamma/delta T-cell lymphoma (PCGDTCL)

Primary cut aneousaggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (PCACETL)

Primary cutaneous acral CD8+ T-cell lymphoma * (PCATCL)

Primary cutaneous small-medium pleomorphic T-cell lymphoproliferative disorder (provisional)* (PCSM-LPD)

Peripheral T-cell lymphoma, NOS (PTCL, NOS) = heterogeneous group of peripheral T-cell lymphomas

Angioimmunoblastic T-cell lymphoma (AITL) - high cutaneous presence

Follicular T-cell lymphoma * (FTCL)

Nodal peripheral T-cell lymphoma with TFH phenotype * (PTCLTFH)

Anaplastic large cell lymphoma, ALK+ (ALCL, ALK+)

Anaplastic large cell lymphoma, ALK- * (ALCL, ALK-) (see below Anaplastic large cell lymphoma, ALK+)

Breast implant-associated anaplastic large cell lymphoma *(BIA-ALCL)

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* change compared to WHO classification of 2008, italic: provisional entity

PTCL account for <10% of all newly diagnosed NHL worldwide and represent very rare lymphomas in Europe and North America with incidences totaling <1 in 100,000 people per year. Men are more commonly affected than women (1.7:1). The incidence of extranodal NK/T-cell lymphomas of the nasal type (ENKTL) is highest in the Asian region.

ALCL, ALK+ is characterized by reciprocal translocation of the anaplastic lymphoma kinase (ALK) gene on chromosome 2p23 and the most common fusion partner nucleophosmin (NPM) on chromosome 5q35 corresponding to translocation t(2;5)(p23;q35). New in the 2017 WHO classification is that Anaplastic Large Cell Lymphoma (ALCL), ALK- is now recognized as a distinct entity.

A subset of Anaplastic large cell lymphoma, ALK- with DUSP22/IRF4 rearrangement on chromosome 6p25 is characterized by a non-cytotoxic immunophenotype, a defined gene expression and methylation profile, and recurrent point mutations in the MSC gene (Parrilla Castellar ER et al. 2014; Luchtel RA et al. 2018).

This entity, which accounts for approximately 30% of all cases of ALCL, ALK-, appears to be associated with a better prognosis, similar to that of anaplastic large cell lymphoma, ALK+ (Parrilla Castellar ER et al. 2014; Luchtel RA et al. 2018). Anaplastic large cell lymphoma, ALK- with a rearrangement of TP63 are overall less common but associated with a worse prognosis (Parrilla Castellar ER et al. 2014).

Furthermore, breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) has been added to the current classification as a new provisional entity. Breast implant-associated anaplastic large cell lymphoma is ALK-negative and does not carry the gene rearrangements typical of systemic anaplastic large cell lymphoma ALK- (Oishi N et al. 2018). Its genetic background includes characteristic epigenetic mutations and mutations in the JAK/STAT pathway, as well as typical chromosomal imbalances.

The most common group of nodal T-cell lymphomas derived from CD4+ T-follicular helper cells (TFH) (now provisional group) includes angioimmunoblastic T-cell lymphoma (AITL) and other entities. The latter are the very rare "follicular T-cell lymphoma" and nodal peripheral T-cell lymphoma (PTCL) with a Tfh phenotype, previously classified as PTCL, NOS.

In addition to a Tfh immunophenotype and corresponding gene expression profiles, these lymphomas are characterized by mutations that describe a "multistep tumorigenesis" common to them. Epigenetic dysregulation and mutations in TET2 with or without DNMT3A mutations are typical, as they are also frequently found in early hematopoietic progenitors (Lemonnier F et al. 2012).

Second-hit mutations include hotspot RHOAG17V mutations, which occur in up to 80% of cases (Sakata-Yanagimoto M et al. 2014) and other gain-of-function mutations in the T-cell receptor signal transduction pathway(PLCG1, CD28, PIK3, CARD11).

In addition, fusions involving SYK and ITK, CD28 and CTLA4, CD28 and ICOS, or FYN and TRAF3IP1, respectively, are found with variable frequency (Palomero T et al. 2014). IDH2 mutations are found in approximately 30% of angioimmunoblastic T-cell lymphomas (AITL). These cause the production of the oncometabolite 2HG and correlate with a typical morphology (clear cells).

Very heterogeneous cases of T-cell lymphomas are subsumed under "PTCL, NOS", with some of these cases being Epstein-Barr virus (HHV-4) (EBV)-positive and not fulfilling the criteria for one of the specific entities.

Tumors with a Tfh phenotype are excluded by definition and are classified as nodal lymphomas derived from Tfh cells (see above).

Using gene expression analysis, two molecular subgroups can be distinguished in the group of PTCL, NOS characterized by overexpression of the transcription factors GATA3 and TBX21; the latter subgroup partially expresses cytotoxic genes (Iqbal J et al.2014).

Patients with GATA3 expression appear to have a worse prognosis. The PTCL-GATA3 subgroup has a higher genetic complexity. Loss or mutation of tumor suppressor genes affecting the CDKN2A/B-TP53 and PTEN/PI3Ksignal transduction pathway is common.

The PTCL-TBX2 subset has less aberrant DNA copy number variation; clustered mutations are found in genes regulating DNA methylation (Heavican TB et al. 2019). Loss of CDKN2A CDKN2A (CDKN2A is the acronym for "Cyclin Dependent Kinase Inhibitor 2A") is associated with poor prognosis in all PTCL, NOS (including the GATA3 subgroup).

In the enteropathy-associated T-cell lymphoma (EATL) group, the current classification uses the term EATL only for the form formerly described as EATL, Type I. Only this entity is associated with the presence of gluten-sensitive enteropathy (sprue, celiac disease). The entity previously described as EATL, type II is now referred to as monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) (Swerdlow S CE et al. 2017). At the genomic level, MEITL is characterized by frequent loss-of-function mutations in the methyltransferase SETD2 gene (Roberti A et al. 2016).

Alterations in SETD2 are also frequently found in hepatosplenic T-cell lymphoma (HSTL), another highly aggressive lymphoma that is mostly derived from gamma-delta T cells . In EATL and MEITL, mutations in genes of the JAK-STAT signal transduction pathway are also found. Alterations in STAT3 and JAK1 are more common in EATL, and alterations in STAT5B and JAK3 are more common in MEITL (Moffitt AB et al. 2017).

Overall, molecular alterations are becoming increasingly important for more accurate diagnosis of T-cell lymphomas. Individual aberrations also appear to have prognostic significance.

Risk factors: Prolonged immunosuppression is associated with an increased incidence of non-Hodgkin lymphoma, including PTCL. An example is hepatosplenic T-cell lymphoma (HSTL), where pre-existing immunosuppression, often extending over prolonged periods (iatrogenic), is found in approximately 20% of cases. Pre-existing celiac disease is a risk factor for the occurrence of EATL. Specific genetic polymorphisms as risk factors for PTCL have not yet been described in genome-wide association studies.

HTLV-1 infections: Patients with adult T-cell leukemia/lymphoma (ATLL) are typically sero-positive for HTLV-I, therefore prevention of vertical transmission of HTLV-I is likely to reduce the incidence of this entity.

EBV infections: In contrast, the pathogenetic significance of EBV infection or reactivation for the occurrence of various lymphomas, such as extranodal NK-/T-cell lymphomas, nasal type (ENKTL), is unclear.

With the exception of ALCL, ALK+, the probability of developing the disease increases with age.

As in aggressive B-cell lymphomas, the initial manifestations are usually progressive painless lymph node enlargement and/or extranodal manifestations. The extranodal manifestations are found in the gastrointestinal tract in EATL and MEITL, in the ENT area in extranodal NK-/T-cell lymphomas of the nasal type (ENKTL), and in the subcutaneous lymph nodes in cutaneous T-cell lymphomas. In panniculitis-like T-cell lymphomas, subcutaneous indurations are manifested in the skin. B-symptomatology is typical. A tendency to infection, sometimes with opportunistic pathogens, is common. Patients with angioimmunoblastic T-cell lymphoma (AITL) may present with polyclonal hypergammaglobulinemia, Coombs-positive hemolytic anemia or EBV+ clonal B-cell proliferations up to diffuse large B-cell lymphoma (Swerdlow S CE et al. 2017).

A CT scan of the neck, thorax and abdomen is required for diagnostic imaging. CT or MRI of the skull or lumbar puncture are recommended only in cases of clinical suspicion. PET/CT has superior sensitivity to CT for extranodal noncutaneous manifestations, particularly in the GI tract. Thus, additional manifestations can often be found when staging PTCL using FDG-PET. The diagnostic PET/CT examination corresponds to international standards in aggressive lymphomas and has high prognostic significance.

PTCL are not only rare but also very heterogeneous, so many pathologists may have limited experience in diagnosing such lymphomas. Especially in cases where neoplastic cells are rare and destruction of normal lymph node architecture is discrete, it can be difficult to prove malignancy of lymphoproliferative changes. Another problem is that Reed-Sternberg cells and/or an expansion of B cells may be found in PTCL, which can lead to the (mis)diagnosis of Hodgkin lymphoma or another B-cell lymphoma. Reference pathology is useful in the therapeutic consequences of the diagnosis. It is recommended to remove a lymph node or a sufficiently large tissue sample in order to be able to perform immunohistochemistry and molecular investigations in addition to a comprehensive histopathological evaluation, which can be decisive for the diagnosis.

PTCL express pan-T-cell antigens (CD2, CD3, CD7) to varying degrees, T-cell receptor structures (more commonly of the alpha-beta, less commonly of the gamma-delta type) as well as antigens found in T-cells of varying function (CD4, CD8). The study of markers differentiating TFH PTCL (CD10, BCL6, PD1, ICOS, CXCL13) is becoming increasingly important in the diagnosis of nodal non-anaplastic PTCL, since a Tfh phenotype (expression of at least two markers) triggers the diagnosis of TFH lymphoma and excludes PTCL, NOS (de Leval L 2020).

Loss or very weak expression of T-cell antigens and/or the appearance of pathological phenotypes, e.g. cells with double positivity or negativity for CD4 and CD8, are relatively common and may support the diagnosis of malignancy. Clonality detection by analysis of rearrangement of T-cell receptor genes may be helpful. Other methods such as FISH, PCR for fusion transcripts and panel sequencing are now part of the investigations. For the detection of EBV in ENKTL, aggressive NK cell leukemia, a part of PTCL, NOS, in situ hybridization is recommended.

In the presence of ALCL, a strong and homogeneous expression of CD30 as well as the presence of an ALK translocation is necessary. Besides the most common translocation t(2;5) and the resulting NPM-ALK fusion gene, other fusion partners of ALK, such as TMP3, TFG, CLTCL or TRAF can be found. Immunohistochemistry provides a sensitive method to detect ALK fusion protein expression; the type of translocation determines the subcellular localization of ALK when stained appropriately. Variant translocations have no proven clinical significance or impact on disease prognosis [32].

The diagnosis of spread and staging of T-cell lymphomas is analogous to that of aggressive B-cell lymphomas. Bone marrow diagnostics (aspiration and biopsy) including subsequent flow cytometry and histochemistry for immunophenotyping is mandatory.

PTCL are usually rapidly progressive without treatment, except for T-LGL, MF or LyP; indolent forms of AITL are exceptions. With systemic chemotherapy, PTCL can be cured in a proportion of patients (5-year overall survival approx. 30% across all entities). For patients in whom full-dose systemic therapy cannot be administered due to limited tolerability, individually adapted therapies with palliative intent may be useful. For cutaneous T-cell lymphomas, there are therapy regimens adapted to the stage of the disease.

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3. Iqbal J et al.(2014) Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood 123:2915-2923
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