Sezary syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2]

Overview

Sezary syndrome (SS) is one of the most common subtypes of cutaneous T cell lymphoma (CTCL). Sezary syndrome is an erythrodermic cutaneous T-cell lymphoma with a leukemic involvement of malignant T cells with or without lymphnod and visceral organ involvement. SS is closely related to mycosis fungoides (MF), and the two disorders are diagnosed and staged by the same criteria .Cutaneous T cell lymphoma arises from T-cell lymphocytes, which are normally involved in the cell mediated immune response. Sezary Syndrome constitute the broad spectrum of cutaneous T cell lymphoma.

Historical Perspective

• Sezary syndrome (SS) was first described by Albert Sézary in 1938.
• The association between cell count of lymphocytes in the peripheral blood with grooved, lobulated (that is, “cerebriform”) nuclei and Sezary syndrome was made in the early to mid-20th century.

Classification

• The staging of sezazry syndrome is based on the TNMB:
• Sezary syndrome is defined by T4 erythroderma of body surface area (BSA) more than of 80 percent, Sezary cell is more than 1000 cells/microL in B2 involvement of peripheral blood staged of Sezary syndrome is based on the presence of nodal and/or visceral involvement

Staging for mycosis fungoides and Sezary syndrome
Skin (T)
T1	Limited patches, papules, and/or plaques covering <10% of the skin surface. May further stratify into T1a (patch only) versus T1b (plaque patch)
T2	Patches, papules, or plaques covering 10% of the skin surface. May further stratify into T2a (patch only) versus T2b (plaque patch).
T3	One or more tumours (1-cm diameter)
T4	Confluence of erythema covering 80% body surface area
Node (N)
N0	No clinically abnormal peripheral lymph nodes; biopsy not required
N1	Clinically abnormal lymph nodes; histopathology Dutch grade 1 or NCI LN0-2
N1a	Clone negative
N1b	Clone posetive
N2	Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 2 or NCI LN3
N2a	Clone negatove
N2b	Clone posetive
N3	Clinically abnormal peripheral lymph nodes; histopathology Dutch grades 3e4 or NCI LN4; clone positive or negative
NX	Clinically abnormal peripheral lymph nodes; no histologic confirmation
Visceral (M)
M0	No visceral organ involvement
M1	Visceral involvement (must have pathology confirmation and organ involved should be specified)
Blood (B)
B0	0 Absence of significant blood involvement: 5% of peripheral blood lymphocytes are atypical (Sezary) cells B0a Clone negative B0b Clone positive
B1	Low blood tumour burden: >5% of peripheral blood lymphocytes are atypical (Sezary) cells but does not meet the criteria of B2 B1a Clone negative B1b Clone positive
B2	High blood tumour burden: 1000/mL Sezary cells with positive clone

The staging of Sezary syndrome is based on the clinical stages:

clinical stages
Stage	T	N	M	B	DDS
IA	1	0	0	0/1	98
IB	2	0	0	0/1	89
IIA	1.2	1.2	0	0/1	89
IIB	3	0-2	0	0/1	56
IIIA	4	0-2	0	0	54
IIIB	4	0-2	0	1	48
IVA1	1-4	0-2	0	2	41
IVA2	1-4	3	0	0-2	23
IVB	1-4	0-3	1	0-2	18

• [5-year disease free survival (DSS)]

Pathophysiology

• The exact pathogenesis of Sezary syndrome is not fully understood.
• Sezary syndrome is an erythrodermic cutaneous T-cell lymphoma with a leukemic involvement of malignant T cells.
• Cutaneous T cell lymphoma arises from T-cell lymphocytes, which are normally involved in the cell mediated immune response.
• Sezary syndrome's patients 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.
• 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.
• A few patients of Sezary syndrome are associated with human T-lymphotropic virus types 1 and 2 (HTLV1 and HTLV2) In Japan, Caribbean islands, and the Middle East.
• In Sezary syndrome's patients blood flow cytometry shown measurement of the CD4+CD26- population of lymphocytes is a valuable tool for monitoring and CD26 seen in >90% of patients and CD7 loss in 50% of patients.
• In majority of Sezary syndrome's patients peripheral blood T cell seen CD3+, CD4+, CD7-, CD26-, CD8-.
• In some Sezary syndrome patients CD8+ phenotype seen with retroviral infections (HTLV-1/2 or HIV).
• Sezary syndrome cells are T-cells that have pathological quantities of mucopolysaccharides.
• When Sezary cells move from the blood into the skin, the skin problem is seen and Sezary cells are finded in rash.
• In sezary syndrome maybe one or more chromosomal abnormalities, such as the loss or gain of genetic.

Microscopic pathology

• Light microscopic findings : On microscopic histopathological analysis, movement of the atypical lymphocytes into the epidermis, atypical cells in intra epidermal, and infiltrate of inflammatory T cells are characteristic findings of Sezary syndrome.
• Sezary cells are aypical mononuclear cells with moderately to highly grooved nuclei, termed seen in prepheral blood morphology, Sezary cell is large than normal lymphocyt cell.
• Clonality of the T cell receptor (TCR) gene rearrangement : Clonality of the T cell receptor (TCR) gene rearrangement by polymerase chain reaction.
• High throughput TCR sequen is more sensitive technique than T cell receptor (TCR).

Causes

• The cause of Sezary syndrome has not been identified.
• Sezary syndrome might have one or more of the chromosomal abnormalities, such as the loss or gain of genetic.

Clinical Features

History

• The majority of sezary syndrome patients present with developing lymphadenopathy and erythroderma for weeks to months.
• Cutaneous T cell lymphoma is usually initially seen by dermatologists with patients presenting with skin lesions such as erythematous patches or plaque.
• Sezary syndrome is known as leukemic form of cutaneous T cell lymphoma (CTCL) that associated with erythroderma.
• Early clinical features of Sezary syndrome include:

• Mimic psoriasis
• Chronic eczema
• Atopic dermatitis
• Leprosy
• Lichenoid pityriasis

• In Sezary syndrome single or multiple lesions( thin erythematous plaques or flat patche) is a typucal skin involvement in the gluteal region or thighs.
• The lesions of Sezary syndrome can be pruritic or remain stable for many years, go into remission, or grow slowly
• Patients with Sezary syndrome have a positive history of pruritic, infection, second malignancy such as hodgkin lymphoma, non-Hodgkin lymphoma, melanoma, urinary cancer.
• Patients with Sezary syndrome often have a history of several years of eczematous or dermatitis skin lesions before the diagnosis is finally established.
• The skin lesions then progress from the patch stage to the plaque stage to cutaneous tumors, skin is often pruritic and affected on quality of life of patients.

Signs

Common signs of Sezary syndrome include:

• Widespread erythema
  • In Sezary syndrome widespread erythema can be finely scaly, indurated, or even resemble livido reticularis
• Indurated
• Resemble livido reticularis
• Erythema(Not seen in some patients)
• The severity of erythema body surface area (BSA) involved may wax and wane(>80% of BSA)

Skin lesions

The other skin lesion symptoms of Sezary syndrome are:

• Patches and plaques to erythroderma
• Keratosis pilaris
• Alopecia (hair loss)
• Ectropion
• Keratoderma
• Hypertrophic nails
• Erosions
• Lichenification
• Trouble regulating body temperature
• Abnormalities of fingernails and toenails

Other Signs

Some patients with Sezary syndrome have

• Lymphadenopathy
• Viscer

Differentiating Sezary syndrome from other Diseases

• Sezary syndrome must be differentiated from other diseases that cause:
  • Mycosis fangoides
    • Sezaruy syndrome is more symptoI contrast to patch or plaque MF, SS is much more symptomatic. Sezary syndrome patients tend to present with diffuse skin involvement,not like mycosis fungoides usually evolve through patches and plaques to erythroderma
    • In Sezary syndrome infiltration of skin is generally much less dense than plaque in mycosis fungoides (MF)
  • Eczema
  • Psoriasis
  • Pityriasis rubra pilaris
  • dermatitis
  • Hypereosinophilic syndrome
  • Adult T-cell leukemia
  • Atopic dermatitis
  • Contact dermatitis
  • Chronic actinic dermatitis
  • Scabies
  • Drug eruption
  • Graft versus host disease

Epidemiology and Demographics

• The prevalence of Sezary syndrome is exact unknown.
• In 2005 and 2009 the incidence of Sezary syndrome was estimated to be 0/08 and 0/09 cases per 100,000 individuals in the United States.

Age

• The median age at diagnosis of Sézary syndrome is 60 years of age(SS).
• Sezary syndrome is more commonly observed among elderly patients.

Gender

• Males are more commonly affected with Sezary syndrome than females(2:1).

Race

• Sezary syndrome usually affects individuals of the whites race.
• Sezary syndrome is rare disease that tends to affect Whites but in this study African american has more percentage

Risk Factors

• Common risk factors in the developme Sezary syndrome are AIDS, pneumonias , bacterial cutaneous infections were frequen.

Complications and Prognosis

• Common complications of Sezary syndrome include infection, second malignancies ( Hodgkin lymphoma, Non-Hodgkin lymphoma, melanoma, urinary cancer) and especially lymphoma.
• Prognosis is depended on stage of disease, elevated LDH, race, sex (male), peripheral eosinophilia and generally is poor.

Diagnosis

• The diagnosis of Sezary syndrome is made through examination of total body surface area (BSA) and the following of result of blood tests, biopsy of lymph node and bone marrow should be done.
• Patients are presenting with maycosis fangoides (MF) may evolve to Sezary syndrome (SS) after 6-30 monthes.
• The ISCL/EORTC recommends diagnostic criteria:

1. Erythroderma covering body surface area (BSA) >80%
2. By PCR or southern blot analysis a clonal TCR rearrangement identified in blood
3. Sezary cell count >1000 cells/microL or one of the following two criteria :
   1. Increased CD4+ or CD3+ cells with a CD4 to CD8 ≥ 10
   2. Increased CD4+ cells with an abnormal phenotype ( CD4+CD7- ≥40 % or CD4+CD26- ≥30%)

• CT scan may be helpful in the diagnosis of Sezary syndrome. Findings on CT scan a node larger than 1.5 cm.

Symptoms

• Symptoms of Sezary syndrome may include the following:
  • Most common symtom of Sezary syndrome is pruritus.
    • There is not related between pruritis and the degree of blood involvement or the extent and depth of erythema .
    • Pruritus may exacerbate sleep dysfunction, anxiety, and depression.

Physical Examination

• Patients with Sezary syndrome usually appear with skin signs and symptoms.
• Physical examination may be remarkable for:

• Skin lesions
• Enlarged lymph nodes
• Fingernails and toenails abnormalities
• lower eyelides
• trouble regulating body temperature
• Splenomegaly
• Hepatomegaly
• Gastrointestinal trac

Laboratory Findings

• In sezary syndrome, B0, sezary cells are defined less than 5.
• A majority of number atypical mononuclear cells with moderately to highly groove nuclei, termed Sezary cells concentration of peripheral blood of Sezary syndrome patients .
• Other laboratory findings consistent with the diagnosis of Sezary syndrome include PCR, southern blot, and High throughput TCR sequencing, immunophenotyping confirming T cell origin (CD3+, CD4+), lymph node biopsy, peripheral blood test (morphology, felow cytometry)

Laboratory tests for cutaneous T cell lymphoma include:

• Complete blood count (CBC)
• Peripheral blood smear

• Atypical T-cells (Sezary cells)

• Blood chemistry studies
• Flow cytometry
• Immunohistochemistry
• Immunophenotyping: Beta F1+, CD2-/+, CD3+, CD3- (CD4-positive variant), CD4+ (CD4-positive variant), CD4-, CD5-, CD7+/-, CD8+, CD8- (CD4-positive variant), Granzyme B+, and Perforin+
• Bon marrow
  • In advanced disease of Sezary syndrome, bone marrow involvement can be seen.
  • Considered as a leukemic phase of cutaneous T-cell lymphoma without any bone marrow compromise.
• Biopsy:
  • More than 4 cm of punch

Treatment

The mainstay of therapy for Sezarey syndrome (SS) is similar to treatment for mycosis fungoides (MF).

Medical Therapy

• Pharmacologic medical therapy is recommende radiotherapy, biological therapy mycosis fungoides (MF) for Sezary syndrome (SS) plus photopheresis (ECP) and low dose alemtuzumab, and the need for adjuvant treatment to control pruritus.
  • In patients with severe pruritus; topical and systemic anti pruritics are recommended.
• Systemic treatments are generally required in the leukemic blood involvement Sezary syndrome patients.
• In new diagnosed Sezary syndrome patients with slowly progressive disease munomodulatory therapies are recommended.
• Pharmacologic medical therapies for Sezary syndrome include primary treatment and secodanry treatment and allogenic hematopoietic cell transplantation
  • Primary: Extracorporeal photopheresis (ECP), Retinoids (bexarotene, acitretin, isotretinoin, all-trans retinoic acid), Histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin), Low dose methotrexate
  • Secondary: Pegylated liposomal doxorubicin,Gemcitabine, Alemtuzumab, Chlorambucil, Fludarabine, Cladribine, Pentostatin, Intermediate dose methotrexate, Pralatrexate (low dose) , Brentuximab vedotin, Pembrolizumab

Primary treatment
Agent	Combination therapy	Comment
ECP	Systemic therapy can be combined with ECP: Retinoid, low dose methotrexate, HDAC inhibitor, interferon skin directed therapy (phototherapy, topicals, TSEBT)	this therapy is only in some specialized centers.
Retinoids (bexarotene, acitretin, isotretinoin, all-trans retinoic acid)	Systemic therapy can be combined such as: ECP Interferon Skin direct therapy( PUVA, TSEBT)	Teratogenic Side effects such as: Hyperlipidemia Central hypothyroidism (bexarotene)
Interferon alpha Interferon gamma	Systemic therapy can be combined : ECP Bexarotene ECP Skin directed therapy: Topicals, PUVA	It is useful for concomitant autoimmune conditions or solid transplant patients
Methotrexate (Low dose)	Systemic therapy can be combined: ECP Interferon HDAC inhibitor Skin directed therapy	Side effects: Teratogenic Mild generalized immunosuppression liver toxcity
Histone deacetylase HDAC inhibitors (vorinostat, romidepsin)	Systemic therapy can be combined: IECP Interferon Skin directed (TSEBT) therapy	Side effect: Fatigue Nausea Diarrhea Thrombocytopenia Nonspecific electrocardiogram effects
Secondary treatment
Secondary treatment recomanded after inadequate response, refractory disease or progression despite primary treatment ( Pegylated liposomal doxorubicin, Gemcitabine, Alemtuzumab, Chlorambucil, Fludarabine, Cladribine, Pentostatin, Methotrexate(intermediate dose), Low dose pralatrexate, Brentuximab vedotin, Pembrolizumab)

• For immediate control in patients with rapidly progressive disease, chemotherapeutic agents or targeted therapies are recommanded. If possible immune enhancing or preserve agent recommanded to use before chemotherapy.
• The predominant therapy for cutaneous T cell lymphoma is PUVA. Adjunctive chemotherapy, radiotherapy, biological therapy, retinoid therapy, and photophoresis may be required

Prevention

• There are no primary preventive measures available for [disease name].

• Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

• Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].
• Pneumococcal vaccination ld be systematically recommended
• Prophylaxis with co-trimoxazole and valaciclovir is when the CD4 count is < 0·2 × 109 cells L-1