Peripheral T-Cell Lymphoma
Peripheral T cell lymphoma (PTCL) is a heterogeneous group of lymphomas accounting for 5% to 15% of non-Hodgkin lymphomas (NHL), in the western world. It is comprised of peripheral (systemic) and cutaneous forms developed from T-cells and natural killer (NK) cells. Clinically, these lymphomas are often aggressive.
Angioimmunoblastic T cell lymphoma (AITL) is nowadays considered a separate subtype of PTCL. This form, described in 1974 by Frizzera et al., was previously known by several synonyms such as 'angioimmunoblastic lymphadenopathy with dysproteinemia', 'immunoblastic lymphadenopathy', and 'lymphogranulomatosis X'. The follicular T helper cell, based on molecular analyses, is considered the cell of origin for AITL.
Cutaneous lymphomas are NHLs manifesting in the skin in the absence of extracutaneous manifestations at the time of diagnosis. Further subdivided into cutaneous B-cell lymphoma (CBCL) and cutaneous T-cell lymphoma (CTCL), CTCLs comprise up to four-fifths of all primary cutaneous lymphomas. Of note, CTCLs are classified separately from the group of PTCLs.
Among the CTCLs there are Mycosis fungoides (MF), Primary cutaneous anaplastic large cell lymphoma, and Sezary syndrome (SS). MF also termed 'Alibert-Bazin syndrome' or 'granuloma fungoides', represents the most common type of CTCL while remaining a rare type of NHL. Primary cutaneous anaplastic large cell lymphoma is another form of CTCL. Both contribute to roughly four-fifths of all CTCLs.
Large Cell Cutaneous Ki-1 Anaplastic Lymphoma also termed as 'Anaplastic large cell lymphoma' (ALCL) or 'CD30 positive anaplastic large cell lymphoma' is a rare and aggressive type of PTCL (NHL). This form is encompassed among the group of CD30-positive lymphoproliferative disorders and can affect lymph nodes and extranodal sites. Usually, based on the expression of the anaplastic lymphoma kinase (ALK) protein, two sub-types are described: ALK-positive and ALK-negative Large Cell Cutaneous Ki-1 Anaplastic Lymphoma.
SS is a rare leukemic form of CTCL. It is historically identified as a triad of pruritic erythroderma, generalized lymphadenopathy, and the presence of distinct “Sezary cells” in the skin, lymph nodes, and peripheral blood. Although MF is a primary subtype of CTCL, it has historically and inappropriately been used interchangeably with CTCL. It is an aggressive form of CTCL.
This chapter will address:
- Angioimmunoblastic T cell lymphoma
- Large Cell Cutaneous Ki-1 Anaplastic Lymphoma
- Cutaneous T-cell lymphoma:
- Mycosis fungoides
- Sezary syndrome
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A pooled analysis from 15 case-control studies identified the following risk factors as associated with a high overall statistically significant risk of developing PTCL, including a family history of hematologic malignancies, eczema, psoriasis, celiac disease, heavy smoking, certain occupations (textile worker, electrical fitter).
The etiology of the Large Cell Cutaneous Ki-1 Anaplastic Lymphoma is unknown. Molecular investigation proved that in the ALK-positive sub-type, the tyrosine kinase receptor ALK gene (2p23) is overexpressed due to a t(2;5)(p23;q35) translocation.
The etiological picture of MS and SS is uncertain. Environmental factors, immunological alterations, infections, and other tumors are possible factors that could favor the onset of CTCLs. Considering that subjects affected by these pathologies have a familial predisposition to tumors, it seems that genetic factors are more involved in the onset of MF and SS than other lymphomas.
AITL comprises up to 2% of all NHL cases; however, it represents one out of every five PTCL cases per annum. After PTCL not otherwise specified (NOS), it is considered the most common PTCL subtype. It carries a 1:1 male to female ratio, is more common in Europe than in Asia or North America, and has a median age of 65-70 yrs. in the United States (US) and worldwide.
Retrospective studies showed that the incidence of CTCL increased steadily between 1973 and 1998 and has stabilized since then. Moreover, CTCL incidence is twice in males compared to females. It is common in African Americans, metropolitan areas, and patients with higher income and education levels. Increased incidence was observed in patients following organ transplants and those with HIV.
MF, the commonest CTCL subtype, comprise about 50% of all CTCLs. The incidence rate is almost twice as common in males with a median age at diagnosis between 55 and 60. Hispanic patients were observed to present at younger ages, higher stage, and aggressive clinical course. Sezary syndrome represents about 3-5% of all CTCLs and is more common in non-Hispanic whites.
Large cell cutaneous Ki-1 anaplastic lymphoma represents about 25% to 30% of all CTCLs and is the second most common subtype after MF. It is seen most among non-Hispanic whites and has an excellent prognosis. It can occur at any age with a peak incidence in the 60s.
History and Physical
Common clinical features of AITL includes B-symptoms (drenching night sweats, fever, weight loss) and lymphadenopathy. Enlargement of the liver and spleen may be present at diagnosis. Rashes may be the antecedent finding in about 20% to 50% of AITL patients, with skin manifestations ranging from urticarial lesions to nodular tumors.
Patients with CTCLs often present with “chronic dermatitis,” that is resistant to therapy and often misdiagnosed as chronic nonspecific dermatoses. The lesions of MF may progress from “patch” to “plaque” to “tumor.” A patch is a flat lesion with varying degrees of erythroderma, and plaque is a raised, well-demarcated lesion less than a cm in size. In contrast, the tumor is defined as a raised lesion greater than a centimeter. The clinical-stage determines the distribution of lesions with early-stage having a predilection for folds and non-exposed sun areas.
Lesions are usually pruritic, with severity known for determining the quality of life in these patients. Sezary syndrome, the aggressive leukemic form of CTCLs, is characterized by pruritic erythroderma, generalized lymphadenopathy, and circulating leukemic “Sezary cells” in the peripheral blood. PCALCL usually presents as a brownish to violaceous nodule or tumor and may be solitary to generalized in distribution.
Angioimmunoblastic T cell lymphoma
Initial evaluation, in addition to physical examination, should include complete blood count, comprehensive metabolic panel, LDH, HTLV-1, systemic imaging such as CT chest, abdomen, pelvis with contrast, or positron emission tomographic [PET-CT] scan, bone marrow evaluation, echocardiogram (before anthracycline therapy).
Diagnosis is based on clinical features, histopathologic features, immunophenotyping, and molecular studies.
Some of the hematological abnormalities include polyclonal hypergammaglobulinemia, direct coombs positive autoimmune hemolytic anemia, peripheral eosinophilia.
The cell of origin of AITL is the follicular T helper cell. There is dysregulation of T helper cells resulting in unchecked B cell activation and development of AITL. It is histologically characterized by effacement of normal lymphoid architecture, accompanied by a pleomorphic cellular infiltrate, resulting in loss of follicles and extensive intranodal revascularization. The cellular infiltrate includes B cells, plasma cells, histiocytes, eosinophils. Some of the B cells are EBV+ reflecting the immunodeficient state.
Immunophenotyping and molecular studies
Immunophenotyping reveals that the malignant cells are CD3+, CD4+, and CD10+. CXCL13, uniformly expressed in neoplastic cells, is diagnostically significant, whereas CD30+, which is seen in about 20% of all AITLs, is therapeutically relevant.
A diagnosis of diffuse large B-cell lymphoma may be uncovered concomitantly at the time of diagnosis of AITL or at relapse, warranting the need for re-biopsy if a relapse is suspected.
Large Cell Cutaneous Ki-1 Anaplastic Lymphoma
The diagnosis depends on clinical and histopathological findings. Histopathology usually reveals large cells, with about 75% expressing CD30. Immunophenotyping reveals that mostly these cells are CD4+ with loss of pan-T markers such as CD2, CD3, and CD 5. In contrast to systemic ALCL, the cells in PCALCL are usually negative for CD15 and epithelial membrane antigen.
Mycosis fungoides and Sezary Syndrome
Diagnosis is usually based on clinical and histopathologic findings. Once a diagnosis is made, accurate staging is essential as it provides prognostic significance. Initial workup includes biopsy of the skin and/or lymph nodes, bone marrow biopsy (if cytopenia or extracutaneous disease is suspected), flow cytometry, and systemic imaging. The purpose of flow cytometry is to assess the clonality of T-cells.
Histopathology: The classic MF skin lesion appears as a superficial lichenoid lymphocytic infiltrate. The lymphocytes range from small to large and characteristically reveal cerebriform nuclei. The hallmark of this malignant infiltrate is epidermotropism (lymphocytes frequent the epidermis without any obvious spongiosis) and clusters of lymphocytes around the Langerhans cell in the epidermis, what is known as the Pautrier microabscesses. In the advanced stages, there is a lack of epidermotropism, and the lymphocytes are characteristically large, atypical, and extend deeper into the dermis.
Immunophenotyping plays a vital role in diagnosis, with cells expressing CD3+CD4+CD45RO+CD8-. Loss of maturation markers on the CD4+ cell, such as CD7 and CD26, indicates malignant clonality of the T-lymphocyte.
Treatment / Management
Angioimmunoblastic T cell Lymphoma
Despite the seemingly disappointing failure-free survival rates, CHOP (cyclophosphamide, daunorubicin, vincristine, prednisone) therapy is the most employed backbone in the upfront setting based on data from three large retrospective studies. CHOP for six cycles every three weeks is considered the standard therapy for patients newly diagnosed with AITL over the age of 60. A recent double-blind, placebo-controlled randomized clinical trial comparing brentuximab vedotin plus CHP (cyclophosphamide, hydroxydaunorubicin, prednisone) versus CHOP for CD30+ peripheral T-cell lymphomas, revealed significantly better progression-free survival and overall survival with the former. CHOP with etoposide (CHOEP) was seen to improve event-free survival in a cohort consisting of AITL patients, but this was statistically insignificant. CHOEP may provide the ability to achieve deeper remission, which would ensure that the patient receives a transplant. Nonrandomized data supports the use of High dose therapy and autologous stem cell transplantation in the upfront setting.
Treatment of relapsed/refractory AITL
Management of relapsed/refractory (primary progressive) AITL is currently evolving. If patients are eligible for transplant and have not received it during initial treatment, divergent treatment patterns have evolved. These include short course combination regimens borrowed from relapsed, aggressive B-cell lymphomas such as ICE (ifosfamide, carboplatin, etoposide) and DHAP (dexamethasone, cisplatin, cytarabine) with an overall response rate (ORR) of up to 70%, and the other is continuous therapy which includes the Histone Deacetylase (HDAC) inhibitors such as romidepsin and belinostat. The overall response rate to romidepsin was 30%, whereas belinostat had an ORR of 45% in AITL. For patients who are “transplant-ineligible” with relapsed/refractory AITL, median OS is 5.5 months, and continuous therapy, as mentioned above, are options.
Large Cell Cutaneous Ki-1 Anaplastic Lymphoma
Anthracycline-based chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimen, is the treatment of the first choice. This approach can be combined with radiotherapy in stage I/II disease. Pediatric patients follow different protocols, similar to those used for B-cell lymphomas, and in combination with other drugs such as methotrexate, etoposide, and cytarabine. Also, high-dose chemotherapy, followed by autologous stem cell transplantation, may be offered, usually in the case of relapses or as a first-choice treatment in the case of a poor prognosis. Conjugated antibodies (brentuximab vedotin) may be given when at least one chemotherapy protocol has proved ineffective.
Mycosis fungoides and Sezary Syndrome
Management of MF and SS is heavily reliant on the accurate staging of this condition. Staging of MF and SS is essential for choosing therapy and for prognostication. It is unique as it incorporates atypical circulating cells in the blood (B) and tumor, nodes, and metastases (TNMB classification).
Tumor or “T” is further classified into four types and classified based on the appearance of skin lesions. T1 means limited patches/papules/plaques involving less than 10% skin area, T2 describes generalized patches/papules/plaques involving greater than 10% of skin area, T3 is any tumor greater than or equal to 1 cm in size, and T4 is generalized erythroderma over at least 80% of surface area. Nodes (N) are classified based on clinical examination and histopathological grade of lymph nodes (LN). N0 means no clinically abnormal appearing LN. N1 is abnormal appearing lymph node in addition to histopathological Dutch grade 1 or NCI grade 0 to 2, N2 is abnormal LN in addition to Dutch grade 2/NCI grade 3, and N3 is abnormal LN in addition to Dutch grade 3 to 4/NCI grade 4. Metastases or “M” are classified based on visceral involvement, with M0, which means no visceral involvement and M1, which implies visceral organ involvement. Blood or “B” is subdivided into B0, B1, and B2. B0 is circulating atypical cells (Sezary cells) less than 5%, B1 is defined as Sezary cells greater than 5%. B2 is defined as Sezary cells greater than 1000 cells/mm3, CD4/CD8 ratio higher than 10, and evidence of a T cell clone.
Based on the revised staging by ISCL/EORTC in 2007, blood involvement (B) is incorporated into the clinical staging. Stage I is determined mainly by skin involvement (T) and is divided into IA (T1 N0 M0 B0/1) and IB (T2 N0 M0 B0/1). Stage II is determined mainly by skin involvement (T) and nodal involvement; it is subdivided into IIA (T1/2 N1/2 M0 B0/1) and IIB (T3 N1/2 M0 B0/1). Stage III is characterized by erythroderma (T4) and is subdivided into IIIA (T4 N0-2 M0 B0) and IIIB (T4 No-2 M0 B1). Stage IV is determined by blood involvement and metastases; it is subdivided into IVA1 (T1-4 N0-2 M0 B2), IVA2 (T1-4 N3 M0 B0-2), and IVB (T1-4 N0-3 M1 B0-2).
Treatment approaches for MF and SS involve local and systemic therapy. Local therapy or skin-directed therapy includes topical glucocorticoids, topical nitrogen mustard, topical tacrolimus, topical carmustine, topical retinoids, imiquimod, phototherapy, photodynamic therapy, and electron beam therapy. Options for systemic therapy includes oral retinoids, histone deacetylase inhibitors (vorinostat, romidepsin), interferon-alpha, extracorporeal photopheresis, monoclonal antibodies (anti CD52, alemtuzumab), monoclonal antibody conjugate (anti CD30 therapy, brentuximab vedotin), chemotherapy.
The general treatment philosophy is that skin-directed therapy is used in early stages (IA and IB) or combination with systemic agents in advanced disease. Topical glucocorticoids are rarely used as monotherapy, and they have the disadvantage of causing skin atrophy. Topical carmustine, tacrolimus, and nitrogen mustard are used infrequently. Phototherapy utilizes ultraviolet radiation (UVA and UVB) and is considered an effective treatment for early-stage (IA and IB) MF and SS. However, it has not been FDA-approved due to a lack of prospective trials. Photodynamic therapy is a form of photochemotherapy utilizing porphyrin induced selective, localized production of cytotoxic oxygen species at the tumor site. Electron beam therapy is localized radiation therapy using electron beams and is known to have a complete remission of up to 80 percent.
Systemic agents are used for advanced disease (stage III/IV) and maybe also be used in persistent/relapsed stage I disease. Oral bexarotene is a retinoid used as a first-line systemic agent in MF, with an overall response rate of 45 to 57 percent. It has many adverse effects such as hypertriglyceridemia and central hypothyroidism and should never be used in pregnancy or anticipated pregnancy due to its teratogenic effects. Histone deacetylase inhibitors such as romidepsin and interferon-alpha have been used as monotherapy or combination therapy with other systemic options. As monotherapy, their overall response rate ranges between 35 to 50 percent. Extracorporeal photopheresis (ECP) involves the administration of Psoralens, which is a photoactive compound followed by UVA radiation, also known as PUVA. Retrospective reviews have revealed improved survival advantage with ECP.
Alemtuzumab, a humanized monoclonal antibody of CD52, depletes leukemic cells and is highly effective in SS. Brentuximab vedotin, a monoclonal antibody conjugate of CD30, recently showed an overall response rate of 54 percent in MF. Chemotherapy options include alkylating agents (cyclophosphamide, chlorambucil), Antimetabolites (pralatrexate), and anthracyclines (doxorubicin). Treatment with single-agent chemotherapy resulted in a higher incidence of large cell transformation associated with a poor prognosis than the original diagnosis. Combined multimodality therapy was associated with much better outcomes.
Angioimmunoblastic T Cell Lymphoma
Given the presentation of type B symptoms, rash, lymphadenopathy, differential diagnoses include cutaneous lymphoid neoplasms (including cutaneous lymphomas), infections, an autoimmune disease. The pathological examination of suspicious lesions clinches the diagnosis.
Large Cell Cutaneous Ki-1 Anaplastic Lymphoma
Differential diagnosis includes Hodgkin's lymphoma and T-cell lymphomas, in which CD30 can be expressed.
Cutaneous T-cell Lymphoma
Benign dermatoses seem to be the most prominent differential diagnoses for cutaneous T-cell lymphomas. These conditions include psoriasis, contact dermatitis, drug eruption. Several of these benign dermatoses may even have T-cell rearrangements (TCR).
Angioimmunoblastic T-cell Lymphoma
They are classified according to Lugano classification for non-Hodgkin lymphoma. Divided into four stages: Stage I is a single lymph node region or one extra lymphatic region or site. Stage II is two lymph node regions on the same side of the diaphragm or with localized involvement of an extra lymphatic organ. Stage III refers to lymph node involvement on both sides of the diaphragm. Stage 4 refers to the widespread involvement of one or more extra lymphatic organs (lung, bone marrow).
Cutaneous T Cell Lymphomas
Staging has been discussed above under the management section.
Angioimmunoblastic T Cell Lymphoma
Up to 4 prognostic scoring systems are currently in use for AITL. These include IPI (International prognosis index), mPIT (Modified prognostic index for PTCL), IPTCLP (International peripheral T cell lymphoma project score). The use of Age and performance status as markers is consistent among these scoring systems mentioned above. IPTCLP uses platelet count in addition to above, whereas mPIT uses Ki-67%.
Large Cell Cutaneous Ki-1 Anaplastic Lymphoma
When treated, ALK-positive patients (5-year survival of 70-80%) have a better prognosis than ALK-negative patients (5-year survival of 33% to 49%). Relapses worsen the prognosis.
Mycosis Fungoides and Sezary Syndrome
The commonest cause of death is an infection in both AITL and CTCLs. It contributes to roughly half of the death in these patients. Septicemia and bacterial pneumonia are the most common etiology. About 10% with advanced MF develop herpes virus infection. After infection, widespread visceral involvement seems to be the most frequent cause of death.
Peripheral T cell lymphomas are relatively rare hematologic malignancies and need interdisciplinary involvement. This team should comprise a hematologist specializing in lymphomas, hematopathologist, oncologist, primary care physician, oncology nurse, oncological pharmacist, Infectious disease expert, Social worker. Depending on the type of peripheral T cell lymphoma (cutaneous or AITL), this team can also include a dermatologist, radiation oncologist, and palliative medicine specialist.
Deterrence and Patient Education
Patients should be educated about the type of cancer, its prognosis, treatment options, and possible treatment side effects before beginning therapy.
Enhancing Healthcare Team Outcomes
There is no cure for AITL outside the realm of bone marrow transplantation. Early involvement of a hematologist specializing in malignant hematology to choose an ideal chemotherapy regimen to induce remission (either complete or partial remission) in the “transplant eligible” patient is important. In patients who are “transplant-ineligible,” the strategy should be to choose an ideal regimen to increase progression-free survival. A dermatologist, radiation oncologist, and hematologist should evaluate patients with cutaneous T cell lymphomas (MF and PCALCL) to choose an ideal therapeutic regimen that involves a combination of skin directed therapy and systemic therapy or one of them.
A clean line of communication needs to be maintained between these key players mentioned above to provide optimal care to these patients. Treatment of Peripheral T cell lymphomas can result in a lot of drug toxicity; these should be monitored with frequent follow-ups, especially during active chemotherapy.
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