Peripheral T-cell and NK-cell Lymphomas
Dr. Elaine S. Jaffe
Dr. Philippe Gaulard
Case 1 -
Introduction to Peripheral T-cell lymphomas and Angioimmunoblastic T-cell
Elaine S. Jaffe, M.D
National Cancer Institute
Bethesda , MD
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The patient is a 60 year old male with fever, skin rash, thrombocytopenia, leukocytosis, and generalized lymphadenopathy. The patient was found to have a monoclonal IgM spike in serum and urine, with plasma cell infiltrates in bone marrow and a presumptive diagnosis of Waldenstrom's macroglobulinemia. The patient was treated with high dose steroids, had transient response and the symptoms recurred. A lymph node biopsy was obtained.
Case 1 - Figure 1
Classification of T-cell and NK-cell lymphomas
Mature T-cell and NK-cell neoplasms are relatively uncommon, accounting for fewer than 10% of all
non-Hodgkin's lymphomas (NHL) on a worldwide
basis.  The most common subtypes of mature T-cell
lymphomas are peripheral T-cell lymphoma, unspecified (PTLU) and anaplastic large cell lymphoma (ALCL)
Table 1: WHO Classification of Mature T-cell and NK-cell neoplasms
T-cell and NK-cell lymphomas show significant variations in incidence in different
geographical regions and racial populations. For example, T/NK-cell lymphomas comprise a higher
proportion of NHL in Asians populations. These differences result from both a true increased incidence,
as well as a relative decrease in the frequency of many B-cell lymphomas, such as follicular lymphoma,
seen commonly in North America and Europe . HTLV-1 accounts for an increased of adult T-cell leukemia/
lymphoma (ATLL) risk in regions where it is endemic, including southwestern Japan and the Caribbean
Often leukemic or disseminated|
T-cell prolymphocytic leukemia
T-cell granular lymphocytic leukemia
Aggressive NK-cell leukemia
Adult T-cell lymphoma/leukemia (HTLV1+)
Hepatosplenic T-cell lymphoma
Extranodal NK/T-cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Muco-cutaneous gδ T-cell lymphoma (Provisional WHO/EORTC 200547)
Primary cutaneous anaplastic large cell lymphoma
Peripheral T-cell lymphoma, unspecified
Angioimmunoblastic T-cell lymphoma
Anaplastic large cell lymphoma (systemic)
Another major factor affecting the incidence of T-cell and NK-cell lymphomas is racial predisposition.
Extranodal NK-cell lymphomas, nasal-type and aggressive NK-cell leukemia are much more common in Asians
than they are in other races.  Other groups at increased risk for these EBV-associated diseases are
individuals of Native American descent in Central and South America, and Mexico.  Other rare
EBV-positive lymphomas derived from T-cells showing a similar racial and geographic distribution include
fulminant EBV-positive T-cell lymphoproliferative disorder,  which has overlapping features with
severe chronic active EBV-infection, and Hydroa vacciniforme-like lymphoma, a form of EBV-positive
T-cell or NK-cell lymphoma seen mainly in children.  Genetic factors linked to defective surveillance
of EBV have been postulated to play a role in these epidemiological differences. High viral load at the
time of initial viral infection may be an additional risk factor.
T-cell lymphomas manifest the immunophenotypic features of post-thymic T lymphocytes, being derived
from both aβ T-cells and gδ T-cells.  This distinction is based on the structure of the T-cell
receptor. Gamma-delta T-cells, along with NK-cells are components of the innate immune system, and do
not require antigen sensitization to be active.
The innate immune system is functional based
only on genes encoded in the host genome. It is distinguished from the adaptive or antigen-specific
immune system; most T-cells in peripheral blood and peripheral lymphoid organs belong to the latter.
The T-cells of the adaptive immune system are heterogeneous and functionally complex, and include
na´ve, effector (regulatory and cytotoxic), and memory T-cells. CD4-positive T-cells are primarily
regulatory, acting via cytokine production, while CD8-positive (and double negative) T-cells are
primarily cytotoxic. Recently much has been learned about a unique T-cell subset found in the normal
germinal center. These cells, termed follicular T-helper cells (TFH), provide help to B-cells
in the context of the germinal center reaction. They have a unique phenotype, expressing the germinal
center-associated markers BCL6 and CD10, normally found on B-cells. TFH express CD4, CD57,
produce the chemokines CXCR5 and CXCR13. CXCL13 causes induction and proliferation of follicular
dendritic cells, and is involved in B-cell recruitment to the lymph node, by facilitating the adhesion of
T-cells to high endothelial venules and allowing them to transit the vessel wall.
PTLs show great morphological diversity, and a spectrum of histological appearances can be seen within
individual disease entities. The cellular composition can range from small cells with minimal atypia to
large cells with anaplastic features. Such a spectrum is seen in ALCL, ATLL, and extranodal NK/T-cell
lymphoma, as selected examples. However, cytological atypia does not necessarily correlate with clinical
behavior. For these reasons, it has been difficult to apply cytological principles to the
classification of PTLs. In a similar vein, immunophenotypic markers have been less useful in
classification T-cell lymphomas than B-cell lymphomas, as often one marker is sharing by multiple disease
entity. As an example, CD30, a hallmark of ALCL, is found in diverse lymphoid malignancies of T- and
B-cell types. Finally, the molecular pathogenesis for most T-cell lymphomas is as yet undiscovered. For
the above reasons, clinical features have played a major role in defining many of the specific entities
included in the WHO classification. 
Angioimmunoblastic T-cell lymphoma (AILT)
Angioimmunoblastic T-cell lymphoma (AILT) has emerged
as a distinctive subtype of PTL with unique pathobiological features. This disease is seen mainly in
elderly adults with an equal male : female ratio. Originally thought to be a form of abnormal immune
response, most patients present with generalized lymphadenopathy, hepatosplenomegaly, skin rash, and
marked constitutional symptoms. Polyclonal hypergammaglobulinemia is an almost constant finding and the
lymph nodes usually contain polyclonal plasma cells, as well as frequent large B immunoblasts, despite
the absence of well-formed follicles with germinal centers. The neoplastic T-cells have clear cytoplasm,
and are distributed in a marked inflammatory background. Other features include prominent arborizing
high endothelial venules (HEV) and expansion of dendritic meshworks outside the follicle, usually arising
from the prominent HEV. The neoplastic T-cells are CD4-positive T-cells that express CD10 and sometimes
BCL6, features that suggested the neoplastic cells might be derived from germinal center based T-cells
Most recently, two groups have identified increased expression of CXCL13 in AILT, a finding that helps
to link together many of these clinical and pathological features.
CXCL13 is associated with
expansion of follicular dendritic cells, and facilitates the entry of B-cells into the lymph node through
their attachment to the HEV, thus helping to clarify the B-cell expansion characteristic of this disease.
Another almost constant finding in AILT is the presence of EBV-positive B-cells. It has been
postulated that this finding is secondary to decreased immune surveillance and reactivation of EBV in the
setting of a compromised immune system.  However, EBV-positive B-cells are found even very early in
the course of the disease. In some cases this phenomenon progresses to an EBV-positive B-cell
lymphoproliferative disorder resembling post-transplant polymorphic B-cell lymphoma. In other instances
the EBV-positive B-cells may resemble Reed-Sternberg cells, leading to an erroneous diagnosis of
classical Hodgkin's lymphoma. 
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