Peripheral T-cell lymphomas

Account for 5-10% of lymphoid malignancies.

Represent a diverse set of leukemias, extranodal lymphomas involving liver, spleen, mucosa and skin.

Heterogeneous lymphoproliferative group disorder or arising from immunologic mature T cells, as opposed to pre-T cells or thymic T cells.

The World Health Organization 2017 classification describes 29 distinct subtypes of PTCL.

These diseases typically are divided into 1 of 4 categories, including: 1) disseminated or leukemic disease; 2) nodal disease; 3) extranodal disease; and 4) cutaneous disease.

PTCLs, carry a poor prognosis, than aggressive B cell lymphomas, because they are less  responsive to and have less frequent durable remissions with standard anthracycline based chemotherapy regimens.

T cell lymphomas that present in the skin tend to be indolent.

T cell lymphomas with blood involvement, nodal involvement or extranodal involvement tend to be much more aggressive.

The more modern classifications now refer to them as the mature T‐cell neoplasms (MTCLs), a designation that reflects the fact that these cells have undergone TCR gene rearrangement in the thymus.

Mature T-cell lymphomaa (MTCL) are considered aggressive diseases, although several may have a more indolent course.

The diversity of normal T lymphocytes in the immune system is the basis for the intrinsic heterogeneity of diseases we categorize as PTCL.

The most common types of skin T cell inform include mycosis fungoides and CD30 positive lymphoproliferative disorders.

Nodal T cell lymphomas include peripheral T cell lymphoma not otherwise specified, and T follicular helper lymphoma, and anaplastic large cell lymphoma.

The PTCLs account for only approximately 6% to 10% of all cases of NHL, making them exceedingly rare.

PTCL-NOS and angioimmunoblastic T-cell are the two most common forms and have an incidence of only 2500 and 1800 cases per year, respectively, in the US.

Changes in classification: peripheral T cell lymphomas with T follicular helper phenotype includes angioimmunoblastic  lymphoma and the previously grouped PTCL-NOS.

World Health Organization classification PTCL neoplasms is divided into those that are predominantly leukemic, those that are predominantly nodal, and those that are predominantly extranodal.

The predominantly nodal subtypes consist of angioimmunoblastic T cell lymphomas, anaplastic large cell lymphomas, and peripheral T-cell lymphomas, and not otherwise specified PTCL lymphomas (PTCL-NOS).

PTC-NOS often involves nodal sites, but many patients have extranodal involvement including the liver, bone marrow, G.I. tract, and skin.

PTC-NOS is associated with poor overall survival an event free survival rates compared with aggressive B cell lymphomas.

PTC-NOS hastwo major molecular subgroups GATA3 or TBX21.

Patients with PTCL‘s demonstrate more aggressive clinical features in patients with B-cell lymphoma, including B-symptoms, diffuse disease, extranodal disease, increased serum lactate dehydrogenase levels, increased beta-2 microglobulin levels, bulky disease, elevated Ki-67, and overexpression of p53.

The most common subtypes are peripheral T-cell lymphoma not otherwise classified, angioimmunoblastic T cell lymphoma and anaplastic large cell lymphoma.

Approximately 12-15% of all non-Hodgkin’s lymphoma.

Higher incidence varies geopgraphically reflecting differening exposures to pathogenic viruses.

Increased incidence in Asian countries may be due to higher infection rate with human T-cell leukemia virus1 (HTLV-1) and Epstein Barr virus.

Peripheral T cell lymphomas have a higher incidence in the Caribbean and Far East.

Most subtypes carry an inferior prognosis compared to B- cell counterparts.

Evaluation: work up a similar to lymphoid neoplasm‘s with determination of stage, routine, lab studies, bone marrow, biopsy and aspirate, CBC, metabolic panel, physical examination to include skin and imaging studies; PET/CT scan, and or chest/abdominal pelvic CT with contrast of diagnostic quality is essential.

Echocardiogram or MUGA scan is usually recommended.

There are a few or no therapies specifically for this disease.

More likely to involve extranodal sites than B cell lymphomas.

T-cell phenotype associated with a negative prognosis.

Patients with peripheral T-cell lymphomas have a particularly poor prognosis due to aggressive course and lack of effective treatments.

Approximately 6000 cases diagnosed each year in the US.

Incidence increases with age and has a higher incidence in men with a male:female ratio of 1.8:1.

Incidence varies with geographic location with 4% in Vancouver and to 21% in Hong Kong.

In the United States, the highest incidence is found among American Indians, Alaskan natives, and the lowest in Utah.

Some subtypes of PTCL and a higher incidence in blacks, Asians, and Pacific Islanders, compared to whites.

The incidence has increased significantly in the past two decades, with a 7.9% annual increase from 1992 I and 2005 (Abouyabis AN).

More then 50% of of Asians present with stage III or four disease.

Five year relative survival rates are poor, ranging from 29-48%.

The various ides have differing biology and response to therapy.

The subtype anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma associated with a good response to anthracycline based chemotherapy.

Most subtypes associated with poor prognosis very

A heterogeneous group commonly misdiagnosed in approximately 10% of cases.

Most common misdiagnosed subtypes are hepatosplenic, ALK- negative anaplastic large cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma.

Prognosis for such lymphomas after conventional treatment 9-42 months.

Subgroup anaplastic large cell lymphoma expressing anaplastic lymphoma kinase has a favorable outcome compared to other peripheral T cell lymphomas.

Histology of PTCL reflects nodal effacement by diffuse growth of malignant T cells, are often accompanied by reactive histiocytes and endothelial venules.

The malignant cells have clear cytoplasm, irregular nuclei and multi-nucleated giant tumor cells and Reed-Sternberg like cells may be seen.

Marked inflammatory component that histiocytes, eosinophils, plasma cells and B lymphocytes are generally present.

The most common T-cell marker is CD3, a pan T.-cell marker because it is generally present in all types of T cells.

Other subset T cell markers are CD2, CD5 and CD7 which are expressed by nonmalignant T cells.

Normal T cells express CD3, CD2, CD5, and CD7.

The most common genomic abnormality in T-cell lymphomas is the loss of some T cell markers most commonly CD7, followed by CD5 and in CD2.

CD 30 expression is universal among patients with systemic anaplastic large cell lymphoma.

Across all PTCL subtypes approximately 50% of patients tumors express CD30.

Most PTCL-NOS cells ARE CD4 positive, although some are positive for CD8.

About 97% of PTCL-NOS have alpha/beta T-cell receptors and stains positive for T-cell receptor betaF1 when her exposed to anti-BF1 antibody.

Gamma/DELTA T-cell lymphomas and natural killer(NK) cell lymphomas are negative for alpha-beta T-cell receptors.

Most common presentation of extranodal NK/T cell lymphoma nasal type in an adult with a destructive nasal and midline lesion.

NK/T-cell lymphoma has a median age of diagnosis of 50 years and is most common in invasion or central and South American individuals.

NK/T-cell lymphoma extranodal type may also present in the skin, soft tissues, the testes, the upper respiratory tract and the GI tract.

Extranodal NK/T-cell lymphoma is a chemotherapy resistant type of PTCL.

Extranodal NK/T. cell lymphoma response to radiation in the early stages with a 5 year overall survival of 83%, but not useful in later stage disease (You JP).

Extranodal NK/T lymphoma as an overall survival for patients with advanced disease of only 20-40% (Bekkenk MW).

PTCL are difficult to treat, and are less responsive to chemotherapy regimens then are diffuse large cell B-cell lymphomas, and are associated with a poor prognosis.

Diagnostic accuracy increased by immunohistochemistry testing, occasional pathognomonic cytogenetic results and molecular studies.

PET/CT staging increasingly essential.

Diagnosis of systemic disease requires multi agent chemotherapy.

No standard chemotherapy approaches exists.

Treatment has traditionally been similar to that for diffuse large B-cell lymphoma, however outcomes are poor with this type of treatment, associated with early relapse, progression free survival of less than one year at an overall survival of less than two years.

Anthracycline-based chemotherapy regimens  are the most commonly used first line regimens associated with a significant mortality reduction.

CHOP chemotherapy is most commonly used front-line, but responses are poor and cure is seen only in a small minority of cases.

CHOP chemotherapy associated with limited durability in responses.

Adding agents such as etoposide, alemtuzumab and denileukin difitox to CHOP can improve outcome.

In patients who have a favorable response to induction therapy with a hematopoietic stem cell transplant can produce a 2 year overall survival of 84% and a 2 year progression free survival rate of 63% (Rodriguez J).

High dose therapy and autologous transplantation roles remain undefined.

Drugs approved for the treatment of relapsed PTCL include:pralatrexate, romidepsin, brentuximab (for ALCL only),  belinostat and JAK2 inhibitor.

Brentuximab added to cyclophosphamide, doxorubicin, and prednisone showed significant improvement in response rate.

Pralatrexate (Folotyn) used as a single agent for patients with relapsed or refractory peripheral T cell lymphoma.

Pralarexate In Patients with Relapsed or refractory peripheral T-cell lymphoma (PROPEL) study treated patients with 30 mg three square IV weekly in seven-week cycles: of 109 of evaluable patients 27% responded with a median duration of response of 9.4 months.

In a phase 2 study in progressive or relapsed peripheral T-cell lymphomas following prior systemic therapy 131 patients with a mean age of 59.4 years and the median time since diagnosis of 1.25 years receiving 14 mg for meter squared of romidepsin by four hour infusion on days one, eight, and 15 of the 28 day cycle for up to six cycles: 26% response rate, with CR and 13% and 13% with PR (Coiffer B et al).

In a study of single agent romidepsin in patients with relapsed or refractory PTCLhad an overall response rate of 38%, median duration of response of 8.9 months (Piekarz RL et al).

The use of more intensive chemotherapy regimens has not resulted in favorable outcomes in patients with PTCL, with the exception of anaplastic large cell lymphoma.


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