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Sezary Syndrome


Sezary Syndrome

Article Author:
Anusha Vakiti
Article Author:
Sandeep Padala
Article Editor:
Daulath Singh
Updated:
8/16/2020 3:05:57 AM
For CME on this topic:
Sezary Syndrome CME
PubMed Link:
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][4]

  • 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 elderly population and males more commonly. The incidence is higher in whites 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. Few cases in Japan, Caribbean islands, and the Middle East have been associated with human T-lymphotropic viruses types 1 and 2 (HTLV1 and HTLV2). 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.

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.[8][9][10]

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.[11][12]

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 single-agent chemotherapy.
  • 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 investigational options include pembrolizumab, alemtuzumab, bortezomib, and brentuximab vedotin.
  • Young patients with the high-risk disease 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.[13]

Differential Diagnosis

Sezary syndrome should be differentiated from mycosis fungoides, psoriasis, pityriasis rubra pilaris, dermatitis, hypereosinophilic syndrome, and adult T-cell leukemia.

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.


References

[1] Cristofoletti C,Bresin A,Caprini E,Russo G,Narducci MG, Loss of β-arrestin-2 gene and possible functional consequences on Sezary Syndrome. Cell cycle (Georgetown, Tex.). 2019 May 20;     [PubMed PMID: 31106661]
[2] Maitre E,Le-Page AL,Comoz F,Truquet F,Damaj G,Cornet E,Verneuil L,Salaün V,Troussard X, Usefulness of Flow Cytometry for the Detection of Cutaneous Localization in Malignant Hematologic Disorders. Cytometry. Part B, Clinical cytometry. 2019 May 3;     [PubMed PMID: 31050147]
[3] Molloy K,Jonak C,Woei-A-Jin FJSH,Guenova E,Busschots AM,Bervoets A,Hauben E,Knobler R,Porkert S,Fassnacht C,Cowan R,Papadavid E,Beylot-Barry M,Berti E,Alberti Violetti S,Estrach T,Matin R,Akilov O,Vakeva L,Prince M,Bates A,Bayne M,Wachsmuch R,Wehkamp U,Marschalko M,Servitje O,Turner D,Weatherhead S,Wobser M,Sanches JA,McKay P,Klemke D,Peng C,Howles A,Yoo J,Evison F,Scarisbrick J, Characteristics associated with significantly worse quality of life in mycosis fungoides/Sézary syndrome from the Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study. The British journal of dermatology. 2019 May 2;     [PubMed PMID: 31049926]
[4] Johnson LDS,Banerjee S,Kruglov O,Viller NN,Horwitz SM,Lesokhin A,Zain J,Querfeld C,Chen R,Okada C,Sawas A,O'Connor OA,Sievers EL,Shou Y,Uger RA,Wong M,Akilov OE, Targeting CD47 in Sézary syndrome with SIRPαFc. Blood advances. 2019 Apr 9;     [PubMed PMID: 30962222]
[5] Van-de-Velde V,Zhou Y, Existing and Emerging Therapies for Cutaneous T-Cell Lymphoma. Journal of cutaneous medicine and surgery. 2019 May/Jun;     [PubMed PMID: 30943788]
[6] Mycosis Fungoides (Including Sézary Syndrome) Treatment (PDQ®): Patient Version 2002;     [PubMed PMID: 26389317]
[7] Lim HLJ,Tan EST,Tee SI,Ho ZY,Boey JJJ,Tan WP,Tang MBY,Shen L,Chan YH,Tan SH, Epidemiology and prognostic factors for mycosis fungoides and Sézary syndrome in a multi-ethnic Asian cohort: a 12-year review. Journal of the European Academy of Dermatology and Venereology : JEADV. 2019 Feb 23;     [PubMed PMID: 30801779]
[8] Damasco FM,Geskin LJ,Akilov OE, Nail Changes in Sézary Syndrome: A Single-Center Study and Review of the Literature. Journal of cutaneous medicine and surgery. 2019 Mar 27;     [PubMed PMID: 30917680]
[9] Alpdogan O,Kartan S,Johnson W,Sokol K,Porcu P, Systemic therapy of cutaneous T-cell lymphoma (CTCL). Chinese clinical oncology. 2019 Feb;     [PubMed PMID: 30818958]
[10] Wain T,Venning VL,Consuegra G,Fernandez-Peñas P,Wells J, Management of cutaneous T-cell lymphomas: Established and emergent therapies. The Australasian journal of dermatology. 2019 Feb 26;     [PubMed PMID: 30809800]
[11] Justiz Vaillant AA,Stang CM, Lymphoproliferative Disorders 2019 Jan;     [PubMed PMID: 30725847]
[12] Shalabi D,Bistline A,Alpdogan O,Kartan S,Mishra A,Porcu P,Nikbakht N, Immune evasion and current immunotherapy strategies in mycosis fungoides (MF) and Sézary syndrome (SS). Chinese clinical oncology. 2019 Feb;     [PubMed PMID: 30691274]
[13] Cristofoletti C,Narducci MG,Russo G, Sézary Syndrome, recent biomarkers and new drugs. Chinese clinical oncology. 2019 Feb;     [PubMed PMID: 30525758]