Sezary Syndrome

Etiology

The exact cause for mycosis fungoides and Sezary syndrome has not been established. 

Epidemiology

Mycosis fungoides tend to affect the older population. Generally, patients older than 50 years are predisposed as well as males compared to females with a ratio of 2:1. The incidence of Sezary syndrome in the United States is about 0.8 to 0.9 cases per million persons per year. Like mycosis fungoides, it tends to affect the elderly population and males more commonly. The incidence is higher in Whites compared to Blacks. There is no genetic predisposition and thus no increased risk of developing Sezary syndrome in families of affected patients.[7]

Pathophysiology

The pathogenesis of most of the cases of Sezary syndrome is still unknown. However, a small percentage of cases of Sezary syndrome are associated with human T-lymphotropic viruses type 1 and 2 (HTLV-I/II), which are endemic in southern Japan, the Caribbean islands, and part of the Middle East. The typical immunophenotype of abnormal peripheral T-cell population in Sezary syndrome is CD3+, CD4+, CD7-, CD26-, CD8-. Occasionally, sezary syndrome can occur when the malignant population demonstrates a CD8+ phenotype or even a CD4-CD8 phenotype. Sezary syndrome with CD8+ phenotype may be associated with HTLV-I/II or HIV. The tumor cells originate from memory T-cells or skin-homing CD4+ T-cells expressing cutaneous lymphocyte antigen (CLA) and chemokine receptors CCR4 and CCR7. Patients with Sezary syndrome have suppressed immunity, as the malignant cells produce type-2 T-cell (Th2) cytokines, which suppress Th1 immunity by decreasing the production of interleukin-12. The role of interleukin-12 is to stimulate the production of interferon-gamma and tumor necrosis factor-alpha (TNF-a), thus protecting against tumors.

Histopathology

Generally, there are atypical lymphocytes in a sparse dermal infiltrate along with epidermotropism (movement of the atypical lymphocytes into the epidermis), which is suggestive, but not diagnostic, of mycosis fungoides; epidermotropism may be completely absent in biopsies from patients with Sezary syndrome. The more diagnostic intraepidermal aggregates of atypical cells (ie, Pautrier microabscesses) may or may not be present. Significant edema and a nonspecific infiltrate of inflammatory T-cells may predominate, making diagnosis more difficult.[8] Clonality of T-cell receptor gene rearrangement in the skin by polymerase chain reaction is consistent with, but not diagnostic of, mycosis fungoides and SS. 

History and Physical

The early lesions of mycosis fungoides mimic psoriasis, chronic eczema, atopic dermatitis, leprosy, or lichenoid pityriasis. The typical skin involvement is thin erythematous plaques or flat patches. They present as single or multiple lesions in the gluteal region or thighs. The lesions can be pruritic and remain stable for many years, go into remission, or grow slowly.

Sezary syndrome is an erythrodermic cutaneous T-cell lymphoma with a leukemic component. Erythroderma is an intense, widespread, pruritic, exfoliative rash that represents new lesions or progression of prior patches or plaques.

It is characterized by erythroderma, lymphadenopathy, Sezary or Lutzner cells, atypical circulating lymphocytes, and cutaneous and systemic dissemination of CD4+ T-cells in the blood and the lymph nodes. Mycosis fungoides are like a patch or a plaque, whereas Sezary syndrome presents as a diffuse skin rash. During the disease, it tends to involve about 80% of the total body surface area. Sezary syndrome can be considered a leukemic phase of cutaneous T-cell lymphoma without any bone marrow compromise. Involvement of the bone marrow can be seen in advanced disease. The other skin lesions associated with Sezary syndrome include alopecia, keratoderma, hypertrophied nails, lichenification, and ectropion (outward turning of the lower eyelid). Very rarely, it could also involve the visceral organs. Pruritus is intense and can be debilitating. Even high doses of antihistamines cannot provide relief. Treatment of underlying cancer with steroids has shown to be effective in controlling pruritus. Due to suppressed immunity, affected people are at higher risk for secondary infections (bacterial and viral) and secondary cancers, including Hodgkin and non-Hodgkin lymphomas.

Evaluation

Any patient presenting with erythroderma should raise the suspicion of Sezary syndrome. Though the skin involvement is diffuse in Sezary syndrome, it is not as dense as in mycosis fungoides. Therefore, a skin biopsy should be performed without any interventions for the lesions, and the site with the greatest induration should be biopsied.[9][10][11]

Excisional lymph node biopsy is preferred, and it can show reactive changes, dermatopathic changes, or features suggestive of lymphoma. Peripheral blood shows atypical circulating lymphocytes with grooved nuclei, called Sezary or Lutzner cells. A rarely smaller variant of Sezary cells can be seen in normal people or people with known malignancy.[12][13]

Immunophenotyping confirms that T-cell origin (CD3+ and CD4+) and lack of expression of CD2, CD3, CD5, and CD7 (mature T-cell antigens) are supportive of Sezary syndrome. The diagnosis is made by erythroderma involving greater than 80% body surface area, clonal T-cell receptor rearrangement confirmed by polymerase chain reaction or Southern blot, and absolute Sezary cell count of at least 1000 cells/μL, or 1 of the following 2 criteria:

1. Increased CD4+ or CD3+ with CD4/CD8 ratio of 10 or more
2. Increased CD4+ cells with abnormal phenotype (CD4+CD7- ratio of 40% or more or CD4+CD26- ratio of 30% or more)

The staging of Sezary syndrome and mycosis fungoides involves evaluating the skin (T), lymph nodes (N), visceral organ involvement (M), and blood (B). The types of skin lesions and the extent of their involvement determine the "T" stage. Blood involvement depends on the tumor burden of the blood. Patients with Sezary syndrome are considered to have stage IVA1, IVA2, and IVB, depending on the presence of nodal and visceral involvement.

Treatment / Management

The treatment options are based on the stage of the disease. Given the leukemic involvement in Sezary syndrome, the treatment is generally systemic. It can be given alone or in combination with skin-based therapy. Stage IVA (no visceral involvement) patients are usually treated with extracorporeal phototherapy combined with biological response modifiers (retinoids and interferons). Other alternatives include low-dose methotrexate and histone deacetylase inhibitors (vorinostat and romidepsin). Various combinations of the above can be used along with skin-directed therapy.

• Skin-directed therapy includes topical or systemic steroids, topical nitrogen mustard, phototherapy (UVB and PUVA), and total skin electron beam therapy.
• Radiation therapy can be used for local control of skin and nodal disease.
• Patients with stage IVB (visceral involvement) are usually treated with histone deacetylase inhibitors or targeted therapy like brentuximab vedotin.
• Targeted agents approved for mycosis fungoides/Sezary syndrome include brentuximab vedotin and mogamulizumab. BV is an anti-CD30 monoclonal antibody conjugated with the tubulin inhibitor monomethylauristatin E approved by the FDA for patients who have received prior therapy. Its approval is based on the ALCANZA trial.[14] Moga is a defucosylated humanized antibody directed against the chemokine receptor CCR4 overexpressed on malignant T-cells. Its approval is based on MAVORIC trial.[15]
• In the relapsed and refractory setting, various single-agent chemotherapies can be used, like doxorubicin, gemcitabine, and purine/pyrimidine analogs. FDA-approved drugs in this setting include intermediate-dose methotrexate and pralatrexate. Other options include pembrolizumab, alemtuzumab, bortezomib, and lenalidomide. 
• Young patients with high-risk diseases should be offered allogeneic hematopoietic stem cell transplantation at experienced centers.
(A1)

Besides these disease-directed treatment options, pruritis is a big concern in patients with Sezary syndrome. Various local or systemic options can be used to control the pruritis.[16]

Differential Diagnosis

Sezary syndrome should be differentiated from mycosis fungoides, psoriasis, pityriasis rubra pilaris, dermatitis, hypereosinophilic syndrome, and adult T-cell leukemia. Primary skin disorders like scabies, drug eruption, and graft-versus-host disease are also in the differential. 

Prognosis

Skin classification, stage of disease, elevated LDH, advanced age and comorbidities, race, male sex, peripheral eosinophilia, large cell transformation, and folliculotropic mycosis fungoides have each been associated with poor prognosis and have been variably compiled into validated prognostic indices, including the CTCL Severity Index, the Cutaneous Lymphoma International Prognostic Index, and the Cutaneous Lymphoma International Consortium Prognostic Index.[17]