Continuing Education Activity

Sezary syndrome and mycosis fungoides are the most common forms of cutaneous T-cell lymphoma (CTCL). This can be a diagnostic challenge to clinicians as it can mimic benign skin disorders. It is hypothesized that Sezary syndrome can evolve gradually from mycosis fungoides or occur spontaneously. Patients with this condition have skin involvement characterized by erythematous plaques or flat patches which may be single or multiple. The patients need a skin biopsy to evaluate this condition, along with an excisional lymph node biopsy and peripheral smear. This activity describes the presentation of Sezary syndrome and highlights the role of the interprofessional team in managing this malignancy.

Objectives:

• Identify the etiology of Sezary syndrome.
• Review the pathophysiology of Sezary syndrome.
• Describe the workup of a patient suspected of having Sezary syndrome.
• Summarize the importance of improving care coordination among the interprofessional team members to educate patients on the management of their severe pruritis and prescribe medications to relieve the itch which will enhance the delivery of care for those with Sezary syndrome.

Introduction

Sezary syndrome and mycosis fungoides are the most common forms of cutaneous T-cell lymphoma (CTCL) and can mimic benign skin disorders. This can be a diagnostic challenge to clinicians. Though mycosis fungoides is the most common cutaneous lymphoma, it constitutes less than 1% of total non-Hodgkin lymphoma  (NHL) cases. Researchers hypothesize that Sezary syndrome can evolve gradually from mycosis fungoides or occur spontaneously. Significant evidence has been established that both Sezary syndrome and mycosis fungoides are closely related and constitute the broad spectrum of cutaneous lymphomas.[1][2][3]

Primary cutaneous lymphomas (PCL) are localized to the skin, without any extracutaneous involvement at the time of initial diagnosis and are a subset of non-Hodgkin lymphoma. They can originate either from T or B lymphocytes and are called cutaneous T-cell lymphomas or cutaneous B-cell lymphomas (CBCL) respectively. Cutaneous T-cell lymphoma is further categorized into 2 types.[4][5][6]

• An indolent form that includes mycosis fungoides (MF), lymphomatoid papulosis, and anaplastic large T-cell primary cutaneous lymphoma
• An aggressive form that includes Sezary syndrome (SS)

Etiology

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

Epidemiology

Mycosis fungoides tends 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 white compared to African Americans. 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 SS 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 SS is CD3+, CD4+, CD7-, CD26-, CD8-. Occasionally SS can occur with the malignant population demonstrating a CD8+ phenotype or even a CD4-CD8- phenotype. SS 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 IL-12. The role of IL-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 MF; epidermotropism may be completely absent in biopsies from SS patients. The more diagnostic intra-epidermal aggregates of atypical cells (ie, Pautrier's 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 (PCR) is consistent with, but not diagnostic of MF 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 either as single or multiple lesions in the gluteal region or thighs. The lesions can be pruritic and can remain stable for many years, go into remission, or grow slowly.

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

It is characterized by erythroderma, lymphadenopathy, Sezary, or Lutzner cells which are atypical circulating lymphocytes and cutaneous and systemic dissemination of CD4+ T cells in the blood and the lymph nodes. Mycosis fungoides is 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 as 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 have shown to be effective in controlling the 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 it is 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 or 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 confirming 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% BSA, clonal TCR rearrangement confirmed by PCR or Southern blot, and absolute Sezary cell count of at least 1000 cells/microL, or one of the following 2 criteria:

• Increased CD4+ or CD3+ with CD4/CD8 ratio of 10 or more
• 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 is done by evaluating the skin (T), lymph nodes (N), visceral organ involvement (M), and blood (B). Types of skin lesions and extent of its involvement determines 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 a combination of skin-based therapy. Stage IVA (no visceral involvement) patients are usually treated with extracorporeal phototherapy (ECP) 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 (TSEBT).
• 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 (HDAC) inhibitors or targeted therapy like brentuximab vedotin.
• Targeted agents approved for MF/SS include brentuximab vedotin (BV) and mogamulizumab (Moga). BV is an anti-CD30 monoclonal antibody conjugated with the tubulin inhibitor monomethylauristatin E that is 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 which is 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.

Besides these disease-directed treatment options, pruritis is a big concern in patients with Sezary syndrome. Various local and/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, 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 MF have each been associated with poor prognosis and have been variably compiled into validated prognostic indices including the CTCL Severity Index (CTCL-SI), the Cutaneous Lymphoma International Prognostic Index (CLIPi), and the CLIC Prognostic Index. [17]

Enhancing Healthcare Team Outcomes

Cutaneous T cell lymphomas are best managed by an interprofessional team that includes oncology nurses. Clinicians looking after patients with cutaneous T cell malignancies should not forget that improve the quality of life. These patients have severe pruitus, which can be disabling. Thus, the patient should be educated on how to moisturize the skin and prescribed medications to relieve the itch. During treatment of the malignancy, the patient's quality of life should be a consideration.

The outlook for most patient is guarded.