Peripheral T-cell lymphoma not otherwise specifiedC84.4

Peripheral T-cell lymphoma, not otherwise specified (PTL-NOS), represents a heterogeneous category of aggressive, nodal and extranodal, mature T-cell lymphomas recovered from other WHO-defined peripheral T-cell lymphoma entities (Swerdlow SH et al.2017). Besides angioimmunoblastic T-cell lymphoma (AITL), PTL-NOS, is the second most common non-(primary) cutaneous peripheral T-cell lymphoma (de Leval L et al.2001).

Most patients are in middle and advanced adulthood

Onset with generalized lymphadenopathy, sometimes also with primary or secondary involvement of skin and gastrointestinal tract. The clinical manifestation can mean significant differential diagnostic problems with regard to differentiation from specific cutaneous and gastrointestinal entities. B symptoms (weight loss, fever, night sweats) are common.

Skin lesions are uncharacteristic and resemble those of angioblastic T-cell lymphoma. Initially, maculo-papular exanthema is described, which sometimes resembles drug exanthema. The recurrent course with the formation of papules, plaques and later nodules proves the lymphatic genesis of the skin changes.

The cytological spectrum is very broad, with medium and large pleomorphic cells predominating. An inflammatory background is often present with eosinophilic granulocytes, plasma cells and histiocytic cells. Most PTL-NOS express the α/β-T cell receptor, are CD3+CD4+ with variable loss of CD5 and CD7. Frequently, a proportion of cells are CD30+. A small group of PTL-NOS show a cytotoxic immunophenotype (TIA1+, Granzyme B+), even more rarely there is an EBV association.

Differentiation from non-neoplastic, reactive processes may pose problems in individual cases. For the differential diagnostic evaluation it is important that entity overlapping genetic alterations can occur between PTL-NOS as well as angioimmunoblastic T-cell l ymphoma and ALK-negative large cell anaplastic lymphoma , which suggests a close relationship of these lymphoma entities. Uniform strong CD30 expression, frequent reactivity for epithelial membrane antigen (EMA) and the cytotoxic immunophenotype of anaplastic large cell lymphoma, ALK negative, are indicative for differential diagnosis.

Anthracycline-based combination chemotherapy remains the most commonly used first-line strategy with overall response rates (ORR) of 50-60% and complete response rates (CRR) of 20-30%.

Prospective studies with intent-to-treat analyses have shown that consolidation with high-dose chemotherapy and autologous stem cell transplantation (ASCT) results in progression-free survival (PFS) comparable to historical cohorts and may improve OS in selected patient populations. However, randomized data are still lacking (Oluwasanjo A et al. 2019).

Based on the gene signature defining each group, the 5-year survival rate is 38% for the TBX21- group.

High expression of a cytotoxic gene signature in the TBX21 subgroup was also associated with poor clinical outcome in larger studies (Boddicker RL et al. 2016).

For the GATA3 group, it is 19%.

By gene expression studies, PTL-NOS can be divided into two main groups that show significant survival differences.

• One group is characterized by strong GATA3 expression and associated with a high MYC and proliferation signature.
• The other group (49% of all PTL-NOS) is characterized by TBX21 (T-bet) expression.

Since both transcription factors GATA3 and TBX21 are also detectable at the protein level, immunohistochemistry may have prognostic significance (Iqbal J et al.2014).

Molecular biology: Detectable frequent mutations (about 25%) in epigenetic regulators (MLL28, KDM6A, MLL, TET1, TET2, DNMT3A) (Schatz JH et al.2015).

Approximately 10% of PTL NOS show the fusion product t(5;9)(q33;q22). VAV1 fusion products involved in T cell receptor signaling were found in 11% of PTL-NOS (but they are also detectable in 11% of ALK-negative large cell anaplastic lymphomas) (Boddicker RL et al.2016).

Recurrent mutations of TET2, IDH2, DNMT3A, RHOA and CD28 were found in PTL-NOS and, after correlation with histology and immunophenotype, help to assign follicular helper T cell-derived lymphomas to a new category in the 2017 WHO classification ("nodal peripheral T cell lymphomas with T follicular helper phenotype"). (Sandell R et al.2017; Lone W et al. 2018).

Immunohistochemically verified CD30 expression is highly variable among PTL-NOS and correlates very well with mRNA level.

Furthermore, gene expression studies were able to differentiate two biologically distinct groups.

PTL-NOS-CD30+

and

PTL-NOS-CD30-

The PTL-NOS-CD30+ group shows decreased expression of T cell differentiation/activation genes (CD28, CD52, CD69, NFATc2) and T cell signal transduction genes (tyrosine kinases Lck, Fyn, Itk), but increased expression of transcription factors such as JunB and MUM1/IRF4. This expression pattern is shared by the PTL-NOS-CD30+ group with ALK-negative large cell anaplastic lymphomas, whereas the PTL-NOS-CD30- group shows an inverse expression profile. Moreover, PTL-NOS-CD30- not only occupy a special position at the molecular level, but also have by far the worst prognosis with a median overall survival of 10.5 months (Bisig B et al (2013)

The division of PTL-NOS into the two main groups.

• GATA3+

and

• TBX21+

identifies a high-risk group within the PTL-NOS with the GATA3+ collective.

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