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Elsayes, K.M. Mature T-Cell Lymphomas. Encyclopedia. Available online: https://encyclopedia.pub/entry/15700 (accessed on 23 June 2024).
Elsayes KM. Mature T-Cell Lymphomas. Encyclopedia. Available at: https://encyclopedia.pub/entry/15700. Accessed June 23, 2024.
Elsayes, Khaled M.. "Mature T-Cell Lymphomas" Encyclopedia, https://encyclopedia.pub/entry/15700 (accessed June 23, 2024).
Elsayes, K.M. (2021, November 03). Mature T-Cell Lymphomas. In Encyclopedia. https://encyclopedia.pub/entry/15700
Elsayes, Khaled M.. "Mature T-Cell Lymphomas." Encyclopedia. Web. 03 November, 2021.
Mature T-Cell Lymphomas
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The most recent WHO 2016 classification of lymphoid tumors now recognizes 29 discrete types of mature T-cell lymphomas (MTCLs). According to the initial site of involvement, MTCLs can clinically be broadly classified into one of four categories, including (1) leukemic disease; (2) nodal disease; (3) extranodal disease; and (4) cutaneous disease. The most common MTCLs subtypes include PTCL, not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma (AITL), other subtypes include hepatosplenic gamma delta T-cell lymphoma (HSTCL), anaplastic large-cell lymphoma (ALCL), and subcutaneous panniculitis-like T-cell lymphoma (SPTCL), the primary T-cell lymphoma of the intestine.

MTCLs mature-T-cell lymphoma imaging

1. Introduction

Lymphomas can be generally classified into Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphomas (NHL), and either B-cell or T-cell lymphoma, based on their cellular origin. Virtually all systems can be involved including nodal and extranodal sites. However, in HL, at onset, nodal and splenic involvement is more common, while extranodal manifestation is more commonly seen in NHL [1]. The incidence of extranodal involvement in NHL has been continuously rising due to many factors including immunosuppression and increased use of chemotherapy [2][3]. Historical advances in our understanding of lymphoma behavior and pathogenesis have been restricted largely to BCLs and HL compared with mature T-cell lymphomas (MTCLs). The cellular origin of MTCL is complex and not fully understood. T cells emerge from the bone marrow and experience maturation within the thymus by undergoing T-cell-receptor (TCR) gene rearrangement. Diversity of MTCLs is attributed to different types of T cells, each secreting different sets of cytokines signaling other cascades of immune cells. T cells include T-helper (Th) cells, suppressor T cells, cytotoxic cells, memory cells, γδ T cells and natural killer (NK) cells, which is considered a subtype of T cell [4]. The most recent WHO 2016 classification of lymphoid tumors now recognizes 29 discrete types of MTCLs. According to the initial site of involvement, MTCLs can clinically be broadly classified into one of four categories, including (1) leukemic disease; (2) nodal disease; (3) extranodal disease; and (4) cutaneous disease. The most common MTCLs subtypes include PTCL, not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma (AITL), other subtypes include hepatosplenic gamma delta T-cell lymphoma (HSTCL), anaplastic large-cell lymphoma (ALCL), and subcutaneous panniculitis-like T-cell lymphoma (SPTCL), the primary T-cell lymphoma of the intestine [5]. Generally, cutaneous T-cell lymphoma (CTCL) without distant metastatic disease is associated with a favorable prognosis of a 90% 5-year survival rate. Later in the course of the disease, progression, as manifested by nodal and visceral involvement, can be seen with a markedly decreased 5-year survival to almost 0%. Prognosis of most PTCL subtypes is generally poor [6].

Imaging in general, and specifically FDG PET/CT, plays an essential role in the management of lymphomas. The use of FDG-PET/CT can change the tumor staging in almost 30% of cases. FDG-PET/CT can impact management by further subclassifying lymphomas clinically into aggressive or indolent subtypes based on standardized uptake values (SUVs) and heterogeneity of disease [7]. Aggressive lymphomas often display higher SUV (>10–13) on the baseline, or focal disease in nodal or extranodal sites, or diffuse disease within extranodal sites such as the spleen, liver, or bone marrow [8]. FDG PET/CT can also help with detecting transformation of lymphomas into more aggressive counterparts by detecting an increase in SUVs of lymphomatous masses despite adequate treatment received, directing the physician to change the management and treatment plan. FDG-PET has been shown to be useful in identifying active residual sites of disease by demonstration of persistent metabolic activity with those masses [9][10]. In general, both TCLs and BCLs are FDG-avid on PET/CT. Although FDG avidity has been found to correlate with aggressiveness and clinical behavior of BCLs, the relationship between FDG uptake and different TCL subtypes has not been unquestionably settled. TCLs usually have a poorer prognosis compared to BCLs with a 5-year survival rate of less than 20% [6].

2. Changes Contained in the Updated 2016 WHO Classification of T-Cell Lymphoid Malignancies

The updated 2016 World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissue ( Table 1 ) [11] account for significant changes in our understanding of lymphoma behavior including both B-cell and T-cell lymphomas since 2008, and refines the pathogenesis and molecular biology of different types of lymphoma and lymphoma-like disorders [5][12]. Significant advances have occurred in the classification of TCLs, which has prompted revisions in the 2016 updated WHO classification ( Table 2 ). TCLs can be broadly divided into peripheral (PTCL) and cutaneous types (CTCL). Compared to BCLs, TCLs are relatively rare neoplasms ranging from indolent to aggressive lymphomas. TCLs account for less than 1% and nearly 12% of all lymphomas and NHL cases, respectively [13]. Compared to BCL, TCLs have a more aggressive clinical course and are more challenging to diagnose and treat given their rarity.

Table 1. 2016 WHO classification of mature T-cell and natural killer cell (NK) neoplasms, with highlights of molecular, immunophenotype and clinical features of most common subtypes.
Histologic Subtype Molecular Change &
Characteristic Immunophenotype
Clinical Characteristic
  • T-cell prolymphocytic leukemia
  • T-cell large granular lymphocytic leukemia
  • Chronic lymphoproliferative disorder of NK cells Aggressive NK-cell leukemia
  • Systemic EBV1 T-cell lymphoma of childhood
  • Hydroa vacciniforme-like lymphoproliferative disorder
   
  • Adult T-cell leukemia/lymphoma
  • HTLV-1 infection leads to the clonal expansion and immortalization of CD4+ T cells and CD 24+ cells
  • Transformation of Tax and HBZ, modulating signal transduction pathways (CREB/ATF, NF-κB, JAK-STAT, mTOR-AKT
  • More endemic in Japan
  • 2/3 cases present as leukemia, 1/3 as lymphoma
  • Organomegaly and skin involved
  • Extranodal NK-/T-cell lymphoma, nasal type
  • Clonal episomal EBV infection of NK or T cells
  • Overexpression of cytotoxic proteins (granzyme H) and PDGFRA.
  • Occurs in nasopharynx (nasal type) and less frequently at other anatomic sites (extranasal)
  • Enteropathy-associated T-cell lymphoma
  • Monomorphic epitheliotropic intestinal T-cell lymphoma
  • Indolent T-cell lymphoproliferative disorder of the GI tract
  • HLA DQ2 or DQ8 haplotypes.
  • TCRγδ phenotype, and a lack of TCR expression
  • Not fitting EATL or MEITL
  • Associated with celiac
  • Not associated with celiac
  • Ulcerative bowel mass
  • Hepatosplenic T-cell lymphoma
  • It is most commonly of γδ _T-cell lineage
  • Isochromosome 7q [i(7)(q10)] is reported to be a frequent recurrent chromosomal aberration
  • History of immune dysfunction
  • Hepatosplenomegaly with lack of adenopathy
  • Subcutaneous panniculitis-like T-cell lymphoma
  • T-cell infiltration of the subcutaneous fat without dermal or epidermal involvement
  • Prolonged course of recurrent panniculitis
  • Hemophagocytic syndrome
  • Mycosis fungoides (MF)
  • Sézary syndrome (SS)
  • Most common cutaneous subtypes
  • Memory T-lymphocyte (CD45RO+)
  • MF: Localized skin
  • SS: Skin and dissmentated disease
  • Primary cutaneous CD30 1 T-cell lymphoproliferative disorders
  • Lymphomatoid papulosis
  • Primary cutaneous anaplastic large-cell lymphoma
  • Primary cutaneous gd T-cell lymphoma
   
  • Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphomas
   
  • Primary cutaneous acral CD8+ T-cell lymphoma
  • New provisional entity
  • Described in ear
  • Primary cutnaeous CD4 1 small/medium T-cell lymphoproliferative disorder
   
  • Peripheral T-cell lymphoma, NOS
  • Most common subtype
  • Lacks specific morphologic and phenotypic features of other PTCL subtypes
  • Associatedwith translocation t(5:9)(q33:32)
  • Most commonly cutaneous symptoms
  • B symptoms in systemic involvement
  • Follicular T-cell lymphoma
   
  • Angioimmunoblastic T-cell lymphoma
  • 2nd most common subtype
  • Associated with immune dysregulation of T-follicular helper (TFH) cells
  • Recurrent gains of chromosomes 3q, 5q, and 21
  • Generalized lymphadenopathy
  • B symptoms
  • Nodal peripheral T-cell lymphoma with TFH phenoytpe
   
  • Anaplastic large-cell lymphoma, ALK+ and ALK-subtypes
  • ALK gene located on chromosome 2p23, with the nucleophosmin gene (NPM), on 5q35
  • Overexpression of MYC i
  • Can be differentiated based on initial site of presentation: systemic ALCL, primary cutaneous ALCL, and breast implant-associated ALCL (BIA-ALCL).
  • ALK+ has better clinical course compared to ALK-variant
  • Breast implant–associated anaplastic large-cell lymphoma
  • New entitiy
  • A subtype of ALK + ve cases
  • Cells express CD30 and frequent marker for cytotoxic T-cells.
  • Excellent prognosis
  • Two forms, either preimplant effusion or axillary adenopathy
Table 2. Summary of changes contained in the updated 2016 WHO classification of T-cell lymphoid malignancies. New entities have been included, former entities have been reclassified, and some provisional entities have been “promoted” to reflect the advancement of our understanding of lymphoma molecular biology and clinical behavior.
Entiry/Category Updates
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL)
  • No updates
Hepatosplenic delta T-cell lymphoma (HSTCL)
  • No updates
Angioimmunoblastic T-cell lymphoma (AITL)
  • New subtypes
Enteropathy-associated T-cell lymphoma (EATL)
  • Previously designated EATL type 1
Monomorphic epitheliotropic intestinal T-cell
Lymphoma (MEITL)
  • Formerly known as EATL type 2 segregated from type I EATL and given a new name due to its distinctive nature
Indolent T-cell lymphoproliferative disorder of the
GI tract
  • Subtype of Primary T-cell lymphoma of the bowel
Primary cutaneous acral CD8+ T-cell lymphoma
  • New provisional entity
Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS)
  • New subgroups identified
ALK anaplastic large-cell lymphoma (ALCL)
  • ALK, +ve, no updates
  • ALK, −ve, new subgroups
Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL)
  • New provisional entity

3. Uncommon Mature T-Cell Lymphoma Variants

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of MTCL originating from mature cytotoxic cells. The first case was reported by Gonzalez et al., in 1991 [14]. Distinction from the more aggressive primary cutaneous gamma delta TCL was made in the updated WHO classification [5].

The two described histopathological aspects of Breast implant associated anaplastic large cell lymphoma include in situ BIA-ALCL (confined to implant capsule), mostly presenting with delayed implant effusion. The second form is infiltrative BIA-ALCL (infiltrating the capsule) mostly related to mass-forming lesions years after surgery [15]. Both clinicopathologic forms may coexist in the same patient. In case of late peri-implant seroma, aspiration of at least 50 mL must be performed and sent for culture, cytology and flow cytometry. Fine needle aspiration cytology samples play an important role, and cell block is also crucial as they provide the basis for immunohistochemistry to evaluate for BIA-ALCL versus other entities such as infections/scar/granuloma formation. In cases of mass-forming lesions, core needle should be the preferential approach, and cores should be submitted in saline for flow cytometry if BIA-ALCL is a diagnostic consideration [16]. Morphology of cells shows large, atypical lymphoid cells with inflammatory background and eccentric, kidney-shaped nuclei, with homogeneous eosinophilic cytoplasm “hallmark cells” [17]. Cells express CD30 and frequent markers for cytotoxic T-cells. The precise pathogenic mechanisms of this type of lymphoma are still to be established. Chronic bacterial antigen stimulation or chronic irritation from implant characteristics may play a role in tumorigenesis [18].

Hepatosplenic gamma delta T-cell lymphoma (HTSL) is a very rare, lethal subtype of TCL-NHL, accounting for less than 1% of NHL [19]. Although the pathogenesis of HSTL is not completely understood, up to 20% of cases of are seen in long-term immunosuppressed patients, most often post-organ transplantation and in patients receiving immunosuppressive agents for autoimmune disorders such as Crohn disease and rheumatoid arthritis [20]. The origin of HSTL in most instances has been hypothesized to be related to immature cytotoxic γδ T cells residing in the spleen. The exact function of this cell is still unclear; however, it is believed to act as the hinge between both the innate and adaptive immune system. It is hypothesized that the pathophysiology of HTSL arises from upregulation of those cytotoxic γδ T cells via the JAK/STAT pathway, induced by various immunomodulator therapies such as azathioprine and monoclonal antibodies that inhibit TNF-α inhibitors (such as infliximab) [21][22]. Histologically, the malignant lymphocytes show a spectrum of features, such as cytoplasm devoid of azurophilic granules, nuclei with condensed chromatin and inconspicuous nucleoli, high nucleus-to-cytoplasm ratio, and fine chromatin. HSTL cells can often resemble lymphoblasts encountered in acute leukemia. Malignant lymphocytes initially involve and infiltrate the sinusoids and cords of the red pulp of the spleen. Uncontrolled proliferation within the red pulp causes atrophy of the white pulp.

Most lymphomas affecting the gastrointestinal (GI) tract are B-cell in origin, such as diffuse large B-cell lymphoma (DLBCL), mantle cell, marginal zone, and follicular lymphomas. TCLs of the GI tract are exceedingly rare. A unique subtype of the latter is known as enteropathy-associated T-cell lymphoma, which primarily involves the proximal jejunum and ileum, and represents a diagnostic challenge.

4. Conclusions

The updated fourth edition WHO classification of lymphoid malignancies released in 2016 contains important information for both radiologists and oncologists. Certain rare lymphomas may be occasionally encountered in clinical practice. Although some of those disorders have distinct clinical and imaging features, many overlap with more common disorders, thus causing delay in diagnosis and management. However, early diagnosis of many of these disorders is key as many of these are potentially treatable and early intervention may be lifesaving.

References

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  11. Silberstein, L.; Anastasi, J. Chapter 85—T-Cell Lymphomas. In Hematology, 7th ed.; Hoffman, R., Benz, E., Heslop, H., Weitz, J., Eds.; Elsevier: Amsterdam, The Netherlands, 2018; pp. 1343–1380.
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