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T-Cell Lymphoma

Editor: Saud Alsubait Updated: 3/13/2024 2:09:45 PM

Introduction

The lymphoid system is the pillar of the human immune response. It comprises innate immunity covered by NK cells and adaptive immunity by the B and T-cells. Non-Hodgkin lymphoma (NHL) is a disorder of these immune cells. The understanding of these cells from their formation to maturation is necessary for the diagnosis and management of this disease spectrum.

T-cell lymphomas consist of a wide variety of uncommon diseases that can be indolent or aggressive and comprise 12% of all NHL. Since NK-cells are closely related to the T-cells, their malignancies are also included in the classification. WHO released a revised lymphoma classification in 2016, which broadly divided T-cell/NK-cell lymphomas as the precursor and mature T-cell neoplasms. The mature subgroup is further divided into leukemic, nodal, extranodal, and cutaneous.[1]

NHL can also be divided into indolent or aggressive diseases. Indolent lymphomas are characterized by a long disease course and are generally resistant to standard chemotherapy, whereas aggressive disease usually has an acute presentation with B symptoms and rapid progression. Cutaneous T-cell lymphoma (CTCL) is considered indolent, whereas peripheral mature lymphomas (PTCL), which include the rest, are considered aggressive. Two-thirds of the CTCLs are comprised of mycosis fungoides (MF) and Sezary syndrome (SS). PTCL-NOS (not otherwise specified) is the most common among the PTCL, followed by anaplastic large cell lymphoma (ALCL) and angioimmunoblastic T-cell lymphoma (AITL).[2]

Etiology

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Etiology

The cause of the majority of T-cell Lymphoma remains unexplained. CTCL is considered to arise secondary to the dysregulation of genes (cancer-testis genes and B lymphoid tyrosine kinase) and signaling pathways(Jak-3/STAT and NOTCH1). There have been reports suggesting an association between chronic cutaneous inflammation (eg, chronic urticaria, chemical exposure) and CTCL development.

Infectious etiology has also been considered for both CTCL and PTCL, which include bacterial (staphylococcal enterotoxin) and viral association (retrovirus-like Human T-cell leukemia virus (HTLV)1 and HTLV2, HIV, EBV, CMV, HHV8), with a specific association of HTLV1 with adult T-cell lymphoma/leukemia and EBV with Natural-killer cell/T-cell lymphoma, and AITL.[3] Enteropathy associated T-cell lymphoma(ETAL) is seen in association with celiac disease. T-cell activating autoimmune disease and family history of myeloma increases the risk of T-cell lymphoma.[4]

Epidemiology

The incidence of T-cell lymphoma increases with advancing age. Geographic location and ethnic variability have an impact on the distribution of the disease. The usual age group of PTCL is between 55 to 74 years at the time of diagnosis, and it is more common in males. PTCL-NOS is more common in North America, whereas EBV-associated lymphomas are in Asia and Central and South America.  

Adult T-cell lymphoma is endemic to Japan and the Caribbean islands. ETAL is found to have an association with HLA DQ2 and DQ8, which in turn is related to celiac disease. ALK-positive ALCL and hepatosplenic T-cell lymphoma can be seen in younger people.[5] MF and SS have slightly greater incidences in the African-American population and are less common in Asia.[4]

Pathophysiology

The lymphoid progenitors exit out of the thymus to form the T-cells. Their antigen detection is mediated through t-cell receptors (TCR).

CTCL pathogenesis includes inhibition of apoptosis and promoting oncogenesis by targeting the tumor suppressor genes. Alteration of key signaling pathways, which include NOTCH overexpression, which helps in cell differentiation and proliferation, Fas underexpression, and dysregulation of JaK3/STAT by decreasing function and expression of negative regulators. The affinity of CTCL to the skin is thought to be mediated through the adhesion receptor mechanism. The cells migrate using the interaction between E selectin present in the endothelium and cutaneous lymphocyte-associated antigen(CLA) expressed in CTCL cells. These interactions are through chemokine receptors, the most common being CCR4, which is overexpressed here. CTCL has been shown to have distinct microRNA expression(miR-21 and miR155), which resists apoptosis and thus promotes proliferation.

MF and SS mostly consist of helper memory or effector T-cells. They are usually positive for all T-cell markers. CD7 is expressed early in the differentiation process, but they are absent in T-cells homing to the skin, but marked deletion of CD7 is considered an ancillary confirmatory test. Malignant T-cells activate the T-cell receptor (TCR) pathway, which leads to the release of T-helper cell cytokines and persistent proliferation through alteration of Fas-mediated apoptosis and TGF beta related growth suppression.[4]

PTCLs arise from post thymic T-cells/Natural killer (NK) cells, and the pathogenesis is poorly understood. Some studies of gene expression profiling have shown us that pathways altered are nuclear factor kappa B signaling and cell cycle deregulation, but those were underpowered studies. Most of them have a clonal expansion of TCR rearranged lymphocytes. This may not be seen in NK cell neoplasms. Some cytogenic aberrations seen in PTCL-NOS include gains in chromosome 7q and rearrangements of TP63, which results in oncogenic p63. Some other mechanisms include altering the microenvironment and remodeling the T-cell genome by viral molecules. Anaplastic large cell lymphoma(ALCL) is divided into two categories depending on the presence or absence of anaplastic lymphoma kinase protein(ALK). This distinction is necessary for clinical and prognostic assessment. Adult T-cell lymphoma, caused by HTLV-1, is spread through bodily fluids and causes clonal expansion and antiapoptosis of the CD4 cells by incorporating viral proteins that alter the signaling pathways, including but not limited to JAK-STAT and NFkB, thus leading to impaired cytokine production and host immunity.[6][7]

Histopathology

Histologic features of CTCL are subtle and can mimic benign inflammation. Usual findings are haloed lymphocytes, exocytosis, epidermotropism, Pautrier microabscess, severely convoluted, and hyperchromatic lymphocytes in the epidermis and lymphocytes within the basal layer.[4]

Bone marrow biopsy assists in diagnosis, ruling out other diseases, and prognostic assessment of PTCL. PTCL has diverse histological patterns and can have overlapping features of diseases like B-cell lymphoma and Hodgkin disease. Adult T-cell lymphoma shows peripheral circulating lymphocytes with abnormally convoluted nuclei (feather nuclei, cloverleaf cell). ALCL is characterized by hallmark cells with horseshoe-shaped nuclei. Some common and universal findings include polymorphous infiltrates with the tumor cells, eosinophils, plasma cells, histiocytes, and blood vessels.[8]

History and Physical

This disease spectrum usually presents late and in aggressive stages because the initial symptoms or signs almost always have benign conditions as the top differentials.

CTCL, as their name suggests, presents as skin lesions. MF is usually restricted to the skin in the early stages, as macules and patches. But when the disease progresses, skin lesions become plaques, tumors, or nodules with associated adenopathy and other organ infiltration. Usually seen in the sun-protected area. But in the advanced stage, SS can arise de-novo or from MF, characterized by erythroderma, lymphadenopathy, and Sezary cells seen in peripheral blood, skin, and lymph nodes. SS is more aggressive, symptomatic, and with lower remission rates. Some of the precursor lesions associated with or that evolve into MF are clonal dermatitis/cutaneous lymphoid dyscrasias, follicular mucinosis,  lymphoid papulosis, pagetoid reticulosis, and granulomatous slack skin.[4]

PTCL, as mentioned earlier, presents with nodal, extranodal, involving liver, spleen, leukemic, and cutaneous involvement. Extranodal is a common presentation. Sometimes, patients exhibit B symptoms(fever, night sweats, weight loss). Paraneoplastic syndromes associated with PTCL include eosinophilia, hemophagocytic syndrome, and autoimmune phenomena. AITL has associated underlying immune deficiency, leading to opportunistic infections. Subcutaneous panniculitis-like T-cell lymphoma, which is very rare, can present as painless nodules or plaques, easily confused for an infectious/inflammatory process. Extranodal NK/T-cell lymphoma is characterized by the involvement of the aero-digestive tract, especially the nasal region, leading to nasal obstruction, epistaxis, and bony destruction. Adult T-cell lymphoma can have cutaneous and extracutaneous manifestations, with the acute phase of the disease having hypercalcemia and lytic bone lesions. As its name suggests, hepatosplenic T-cell lymphoma involves the bone marrow and is associated with marked hepatosplenomegaly.[2]

Evaluation

Since the clinical picture of CTCL has a significant overlap with benign conditions, it takes an average of almost 6 years to diagnose the disease from the onset.

To diagnose, peripheral smear examination and bone marrow aspirate are necessary. Immunophenotyping and molecular cytogenetics to understand the clonality is important to assist in diagnosis and management. Combining the results from immunophenotyping, like cell lineage identification and aberrant antigen expression, with morphologic findings helps in diagnosis. If these results are inconclusive, molecular cytogenetics can be used to assess the clonality. Peripheral blood analysis for malignant T-cells is invaluable in the early stage of the disease. Lymph node or extranodal specimen biopsy findings augment the immunohistochemistry analysis and thus help in diagnosis.

Malignant cells arise CD4+/CD8- in ATCL and AITL. In PTCL NOS cells are CD4/CD8. Detection of malignant T-cell clones provides a definite diagnosis through T-cell receptor (TCR) PCR and flow cytometry analysis. Cell surface marker also has diagnostic value in diagnosis. CD25+ in ARCL, pan T-cell antigen expression in AITL. EBV+ cells are found in AITL. ATCL ALK+ has t(2,5). Loss of CD26, CD27, CD7, and overexpression of CD 164 is commonly seen, later specifically in SS.[4] PCTCL-NOS shows the loss of almost all T-cell antigens, CD7, CD3, CD10, CD56+, and CD30 + expression. The progression of the disease is characterized by the expression of Ki67, CD34, and AgNORs. T-cell specific soluble IL-2 receptor is considered a marker of severity and to measure prognosis. Other markers used for the same include miRNA profiling, TOX gene, and EPHA4. ALCL has cells that are mostly CD30+.[2]

Treatment / Management

Management starts with the correct identification of subtypes with a biopsy of the specific site for histopathological and immunophenotype analysis, calculation of the prognostic index, assessment of the extent of the disease by imaging, and the patient's performance status. If a specific subtype is suspected, testing for EBV PCR, HTLV-1 PCR, and celiac disease should be done.

Computed tomography (CT) is used to assess and stage the disease as it is commonly available. FDG PET/CT scan is considered to have superior sensitivity because of the FDG avidity in some  T-cell lymphomas and helps in staging and treatment response assessment. MRI is used particularly in soft tissue involvement in extranodal NK/T-cell lymphoma and subcutaneous panniculitis T-cell lymphoma.

The treatment options available for CTCL are palliative, not curative. Therapy can be divided into skin directed for early-stage disease, systemic therapy for later-stage disease (advanced nodal or visceral disease), and disease refractory to localized treatments. Topical therapy includes UV A with psoralen (PUVA), UV B, external beam radiation, total skin radiation, topical chemotherapy, and topical retinoids. Systemic therapy is achieved by Interferon-alpha, oral retinoids, targeted therapies, single or combination chemotherapy, and stem cell transplant. Corticosteroids are also used as both targeted and systemic therapy.[4](B3)

Retinoids help through their antiproliferative and antiapoptotic properties. Commonly used topical regimens are bexarotene (FDA-approved) and tazarotene. Severe hyperlipidemia and central hypothyroidism are side effects of bexarotene. Systemic retinoids include acitretin, isotretinoin, and bexarotene. Topical chemotherapy commonly used are mechlorethamine (nitrogen mustard), an alkylating agent, and carmustine. Systemic chemotherapy commonly used is methotrexate, pralatrexate, chlorambucil, gemcitabine, pegylated doxorubicin, and antimetabolite like fludarabine phosphate, 2-deoxycoformycin. PUVA inhibits DNA and RNA synthesis, but it will affect both normal and neoplastic cells; thus, the side effect profile is secondary malignancies of the skin. Histone deacetylase inhibitors (HDACi) are the newer group of therapeutic options available for the treatment of CTCL, which have both transcription-dependent and independent mechanisms of action for the expression of tumor suppressor genes. Vorinostat and romidepsin are FDA-approved, with an overall response rate of almost 50% with a tolerable side effect profile, the prominent one being cardiac arrhythmias from QTc prolongation. Targeted therapies include imiquimod (Toll-like receptor agonist), denileukin diftitox (recombinant fusion protein), alemtuzumab (a monoclonal antibody against CD52), and everolimus ( mTOR pathway target). Agents that are still undertrial are proteasome inhibitors like bortezomib. Allogenic stem cell transplant is used in advanced stages, usually appropriate for young patients with relapsing disease.[9]

Because of the rarity of the disease and the lack of randomized trials, there are no optimal treatment options for PTCL, but it is dependent on the small trials. Standard chemotherapy is CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone) or a CHOP-like regimen( addition of etoposide). Etoposide based regimens are CHOEP and EPOCH. These are better tolerated by younger patients and people with higher performance status. Other chemotherapy regimens that have been tried include ACVBP(dose-intensified doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) plus consolidation with autologous stem cell transplantation (ASCT) and hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone). Other treatment modalities have been made by improving CHOP by adding newly approved/under trial medications. These include the addition of anti-CD-52 antibody (alemtuzumab) and denileukin diftitox (fusion protein between IL-2 and diphtheria toxin) to the CHOP/CHOP-like regimen; both are in phase II and had a significant side effect profile.[9]

Treatment regimens now under phase III are  Brentuximab Vedotin (anti CD30 monoclonal antibody)[10] and CHP vs. CHOP,  Romidepsin (HDAC inhibitor) CHOP (Ro-CHOP) Versus CHOP, these two for induction and Pralatrexate Versus Observation Following CHOP-based Chemotherapy for maintenance. In ALCL, CD 30 expression is assessed; if positive, the treatment regimen brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (BV +CHP), is considered superior to CHOP.ALK positivity in ALCL also plays an important role as ALK inhibitors(Crizotinib, Alectinib). Extranodal NK/T-cell lymphoma is generally refractory to CHOP regimens because of the presence of the P-glycoprotein gene. For localized variants, chemoradiotherapy using dexamethasone, carboplatin, ifosfamide, and etoposide, whereas for advanced disease, L-asparaginase with ifosfamide, etoposide, dexamethasone, and methotrexate (SMILE). Adult T-cell lymphoma-leukemia has a very poor prognosis. Because of the rapid progression of the disease, the most appropriate treatment modality is unclear, and the patient should be enrolled in a clinical trial. The current treatment modality is VCAP (vincristine, cyclophosphamide, doxorubicin, and prednisone), AMP (doxorubicin, ranimustine, and prednisone), VECP (vindesine, etoposide, carboplatin, prednisone), and intrathecal chemotherapy with the addition of anti-CCR4 antibody mogamulizumab.[11](A1)

For those who are more than 70 years old, CHOP is used. Interferon-alpha plus zidovudine for HTLV1 has proven effective in acute, chronic, and smoldering ATL, not in the lymphoma stage. ALCL Stem cell transplant is considered in the consolidation phase after achieving first remission, complete or partial. Transplant in second or third remission is less studied. In the case of ALCL with a low prognostic score, we should hold off on the stem cell transplant because of their good response to chemotherapy.[11](B3)

Relapsed or refractory PTCL is managed with ASCT if the patient is a candidate for the same. No chemotherapy has been proven superior over the other. The decision should be made about transplants before starting the treatment. Multiagent chemotherapy includes ifosfamide, carboplatin, etoposide or dexamethasone, cytarabine, and cisplatinum, which induces remission but cannot be continued for long because of the side effect profile and is thus useful pre-transplant. If the patient is transplant-ineligible, chemotherapy regimens like romidepsin and pralatrexate are more tolerable.

Differential Diagnosis

The common differentials for CTCL are erythroderma like atopic/contact dermatitis, drug eruptions, erythrodermic psoriasis, lichen planus, cutaneous B-cell lymphoma, subcutaneous panniculitis t-cell lymphoma.[4]

PTCL differentials include other subtypes of T-cell lymphoma, B-cell lymphoma, granulomatous histiocytosis, and paracortical hyperplasia.

Radiation Oncology

Radiation is very effective in the treatment of CTCL since these lymphocytes are sensitive to radiation therapy. External beam radiation is used in stages I to III and whole-body skin electron beam for advanced disease.

Radiation in setting on PTCL is given in cases of a limited-stage disease, early and upfront in the consolidation phase, and palliation to alleviate the symptoms. 17919841. In cases of extranodal NK/T-cell lymphoma, radiation therapy as a primary treatment, especially in the indolent phase, has been found to have a favorable prognosis.[12]

Staging

Lugano classification is a staging system used for all types of lymphomas. It is divided into limited vs. advanced.[13]

Limited

  • I: Involvement: One node or a group of adjacent nodes.  Extranodal status: Single extranodal lesions without nodal involvement.
  • II: Involvement: Two or more nodal groups on the same side of the diaphragm. Extranodal status: Stage I or II by nodal extent with limited contiguous extranodal involvement.

Advanced

  • III: Involvement: Nodes on both sides of the diaphragm; nodes above the diaphragm with spleen involvement.
  • IV: Involvement: Additional noncontiguous extra lymphatic involvement.

Prognosis

CTCL, at initial stages, has the same life expectancy as healthier adults. But when the disease progresses to more infiltrative and visceral involvement, it has bad prognostic effects. MF is a lifelong disease and recurs after stopping the treatment. Many patients who have a chronic course die from an unrelated disease. SS has a poor prognosis, with median survival between 3-4 years.[4]

PTCL has a poor prognosis compared to its B-cell counterpart. The international prognostic index, which has age, performance status, LDH, stage, and extranodal involvement, helps in determining the prognosis. Even if the IPI index is low, it is still considered to have a poorer prognosis. The presence of some markers, including p53, Ki-67, BCL-2, BCl-X, CD 26, and EBV, denotes poor prognosis, whereas AKL, NFkB, CCR3, and TCR BF1 presence shows good prognosis.[6]

Complications

The patients are at high risk of infection due to altered immune systems and high rates of secondary cancers, especially lymphomas. Hypercalcemia and lytic bone lesions are involved in acute T-cell lymphoma/leukemia. Bony destruction is also seen in Extranodal Nk/T-cell lymphoma, nasal type. Visceral involvement of skin, GI tract, lungs, and adrenals are seen. Large cell transformation, which means more aggressive transformation, is seen in CTCL. Precursor T-cell lymphoblastic lymphoma can cause superior vena cava syndrome, tracheal obstruction, and pleural/pericardial effusion. Ulceration of the lesion can be seen in MF.[6]

Consultations

A team approach is necessary for the diagnosis and management of the various T-cell lymphomas. While the microscopic diagnosis is established by the hematopathologist, the medical oncology should know when to discuss the patient's treatment options with a radiation oncologist. A multidisciplinary conference with the surgeon, medical, and radiation oncologist will help in deciding the appropriate management options for these patients.

Deterrence and Patient Education

Patients should be educated about the etiology, disease course, and prognosis. Reversible factors that have been studied are chronic chemical exposure/pesticides and HTLV-1 infection, which is transmissible. They should be advised to stop the exposure to the chemicals, be careful in handling bodily fluids, and have safe sex practices.

Enhancing Healthcare Team Outcomes

Since it is a rare spectrum of disease,  an interprofessional approach is needed, including the medical and radiation oncologist and hematopathologist. We should be familiar with the common subtypes seen in the respective endemic areas. Because the initial presentation can be very subtle, the treatment team should suspect this disease after ruling out the top differential diagnosis.

References


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