Introduction: 

• It is a malignant proliferation of mature memory T cells of helper type. 
• Sezary syndrome is a generalized mature T cell lymphoma characterized by the presence of erythroderma, lymphadenopathy and neoplastic T-lymphocytes in the blood.

Epidemiology: 

• Account for 50% of all cutaneous lymphomas 
• M:F= 2:1 
• Usually seen in adults 
• Median age- 55 years 
• Account for 1.5% of all lymphomas in US 

Etiology:

• HTLV-1 in some cases 
• Occupational exposure to petrochemicals 

Pathogenesis: 

• Prolonged antigenic stimulation leads to enhanced immune response, subsequently there are mutations affecting apoptotic pathway. 
• Homing of tumor cells in skin by following mechanisms 
  • Cutaneous lymphocyte antigen binds to e-selectin of dermal venules 
  • CCR4 chemokine receptor on tumor cells binds to c-c chemikines ligands (17 and 22) in skin. 
  • CXC chemokine receptor 3 and 4- Binds to integrin receptors on dermal Langerhans cells

Clinical Features:

• Inflammatory premycotic phase
  • Widespread, patchy, scaly, erythematosus pruritic eruptions 
  • Bathing trunk distribution- Folds and non-sun exposed body areas
• Plaque phase
  • Well demarcated plaques especially over the trunk, measuring >5cm
  • Associated with lymphadenopathy
• Tumor phase 
  • Skin tumors are formed which ulcerate and fungate 
  • Nonspecific scaly eruptions 
• Dissemination erythroderma (Overlap with Sezary syndrome) 
• Sezary syndrome: Erythroderma, Pruritus, Alopecia, Palmar or plantar hyperkeratosis, Onychodystrophy 
• D’emblee lesions – skin tumors without preceding patch / plaque stage 
• Lesions may lead to insomnia, weight loss, depression and suicidal ideations 
• 50% deaths occur due to infections, usually due to staphylococcus/ pseudomonas. They start as cutaneous infections and then cause septicemia. 

Investigations: 

•  Skin biopsy
  • Epidermotropic infiltrates containing small to medium sized cells  These cells contain irregular (cerebriform) nuclei. 
  • Poutrier microabscesses – Aggregates of cerebriform cells in the epidermis 
  • Epidermal involvement with single cell exocytosis. 
  • In the dermis, infiltrates may be patchy, band like or diffuse depending upon the stage of disease 
  • Inflammatory infiltrate consisting of small lymphocytes and eosinophils may be present. 
  • Large cell transformation: Large cells are present in >25% of lymphoid/ tumor cell infiltrates in skin lesion biopsy. 
• Lymph node biopsy
  • Category 1 (No involvement)-   Dermatopathic lymphadenopathy, scattered cerebriform lymphocytes may be present, but clusters are not seen 
  • Category 2 (Early involvement)- Focal obliteration of architecture with clusters of atypical, cerebriform lymphocytes, often mainly paracortical in distribution.
  • Category 3 (massive involvement)- Complete replacement of architecture with diffuse infiltrates of atypical, cerebriform lymphocytes
• Peripheral smear 
  • Neoplastic cells contain markedly convoluted nuclei. Cytoplasm is scanty, sometimes vacuolated 
  • Sometimes predominantly small (Lutzner cells) or large (Classical Sezary cell) are seen. 
  • Minimum of 1000 such cells / cmm must be present for diagnosis of Sezary syndrome
• Immunophenotyping 
  • Positive- CD2, CD3, CD5, CD4, TCRbeta, HECA antigen, Cutaneous lymphocyte antigen 
  • Negative – CD8, CD7, CD26, Cytotoxic associated proteins 
• Molecular studies
  • Clonal rearrangement of TCR genes
  • Inactivation of CDK N2A/p16, PTEN 
• Cytogenetics
  • Complex karyotypes: usually involve chromosomes 6, 2, 1 and 17q 

Criteria for Diagnosis: 

• For Sezary syndrome: 
  • Presence of T cells with clonal T cell receptor gene rearrangement in blood 
  • Any one of following 3 
    • Absolute Sezary count >1000cells/cmm 
    • Increased CD4+ or CD3+ cell count with CD4/CD8 ratio of 10 or more. 
    • Increased CD4+ cells with abnormal phenotype (>40%- CD4+/CD7- or >30% CD4+/CD26- of total lymphocytes) 

Staging of Mycosis fungoides :

 (Patient's palm without digits is equivalent to 0.5% of body surface area and with all 5 digits is equivalent to 1% of BSA) 

Poor Prognostic Markers: 

• Stage III or more
• Age > 60 years 
• Increased LDH Levels 
• Transformation to large T-cell lymphoma 
• Presence of extracutaneous disease 
• Peripheral blood involvement 

Pretreatment Work-up:  

• History 
• Examination 
  • LN: 
  • Spleen: 
  • Skin-% BSA involved: 
• WHO P. S. 
• BSA 
• IHC/Flow cytometry 
• BMA and Bx 
• Biopsy of suspected node 
• CT (CAP)/ PET 
• Stage 
• Hemoglobin 
• TLC, DLC 
• Platelet count 
• PS for Sezary Cells count 
• LFT: Bili- T/D   SGPT:     SGOT: Albumin:    Globulin: 
• Creatinine 
• Electrolytes: Na:    K:    Ca: Mg:     PO4: 
• Uric acid: 
• LDH 
• HIV: 
• HBsAg:
• HCV: 
• Serology for HTLV-1 (For high-risk population) 
• UPT
• Chemotherapy consent after informing about disease, prognosis, cost of therapy, side effects, hygiene, food and contraception
• Fertility preservation
• PICC line insertion and Chest X ray after line insertion
• Tumor board meeting and decision
• Attach supportive care drug sheet
• Inform primary care physician

Treatment Plan: 

Goals of therapy include:

• Reduce and control symptoms
• Minimise risk of progression
• Avoid treatment related toxicities. If chemotherapy is required, give single agents, rather than combination chemotherapies.

About Each Modality of Treatment: 

• Skin directed therapies: 
  • Topical steroids
    • Effective during early stages of MF 
    • Role is limited to temporary short-term use because of suppression of collagen synthesis (leading to skin atrophy), striae formation, skin fragility and secondary infections. 
  • Topical tacrolimus 
    • Advantage compared steroids is, it does not suppress collagen synthesis 
  • Topical imiquimod (Aldara) 
    • Topical immunomodulator 
    • Induces TNF alpha and INF 
    • Applied 3 times per week for 3 months 
  • Topical mechlorethamine 
  • Topical retinoids 
    • Bexarotene- 1% gel - LA- BD 
    • Binds to nuclear retinoid X receptors and alters gene expression 
    • Should not be given to pregnant ladies 
  • ISRT- 8-12 Gy 
    • Useful for localized plaques 
  • Phototherapy: UVB, PUVA/UVA1 
    • Given 3 times a week 
    • Minimum 4-8 weeks are required to achieve response 
    • Maintenance response is required after response (Once a week UVB) 
  • Electron beam therapy: 
    • Linear accelerator generated electron beams are scattered by penetrable plate placed at the collimeter site. Energy of electrons is reduced to 4-7 MeV which allows adequate field distribution 
    • Can be used for localized disease or entire skin surface. 
    • Remission rate- 80% 
    • 4Gy per week, to a total dose of 36 Gy in 8-9 weeks 
    • Advantages: Durable complete responses without systemic toxicity 
    • Disadvantages: 
      • Alopecia 
      • Atrophy, edema, dermatitis 
      • Increased risk of cutaneous malignancy 
• Systemic therapy- Category 1 
  • Interferon alpha 2b 
    • Response rate: 50-70% 
    • Dose: 3-5x 10⁶ Units/day or 3 times a week 
    • Side effects- Flu like symptoms, fatigue 
  • Methotrexate- <50mg/week 
  • Vorinostat 
    • Response rate: 30% 
    • Median time for recurrence- 56 days 
    • Side effects: Dairrhea, fatigue, nausea 
  • Brentuximab 
  • Bexarotine 
    • 300mg/m2 per day 
    • Response rate- 45-57% 
    • Side effects: Central hypothyroidism, pseudotumor cerebri, leucopenia, pruritus,  
  • Extracorporeal photopheresis 
    • 8-methoxy psoralen (0.6mg/kg) PO is given to patient 
    • White cells are collected, exposed to UVA and then reinfused 
    • It has direct cytotoxic effect on tumor cells and it also activates lymphocytes against tumor cells. 
    • Administered every 2-4 weekly until clearance of disease 
    • Response rate- 64% 
• Systemic therapy- Category 2 
  • Gemcitabine 
  • Liposomal doxorubicin 
  • Pralatrexate 
    • Novel antifolate agent 
    • Dose: 15-30mg/m2- IV- Weekly- for 6-7 weeks 
    • Supplement folic acid 
    • Adverse effect- Mucosal inflammation, thrombocytopenia 
• Systemic therapy for Relapse/ Refractory cases 
  • Chlorambucil 
  • Cyclophosphamide 
  • Etoposide 
  • Pentostatin 
  • Bortezomib 
  • Multiagent chemotherapy: Regimens similar to Peripheral T cell lymphoma (Results in increased immunosuppression with high risk of serious infections, resulting in death of patients in majority of patients) 
• Regimens for Eryhtrodermic lesions/ Sezary syndrome 
  • Phototherapy with Interferon alpha 2 b 
  • Phototherapy with retinoid 
  • Extracorporeal photopheresis with interferon/retinoid 
  • If high tumor burden (Absolute Sezary cell count- >5000/cmm) 
    • Same as above 
    • Mogamulizumab + Skin directed therapy 
    • Romidepsin + Skin directed therapy 

Supportive Care: 

• Pruritus 
  • Moisturizers, emollients and barrier protection 
  • Topical steroids with or without occlusion 
  • Optimize skin directed therapy 
  • Antihistaminics, Gabapentin 
  • Apprepitant, SSRI in selected patients 
  • Infections: 
    • Intranasal mupirocin 
    • Oral dicloxacillin 
    • Cotrimoxazole/ Doxycycline- if suspect MRSA 
    • Bleach baths or soaks 
    • Avoid central lines 

Recent advances:

Allogeneic stem cell transplant for treatment of mycosis fungoides and Sezary syndrome

This meta-analysis assessed allo-HSCT outcomes for advanced-stage MF or SS based on 557 patients from 2010 to 2023. The results showed a 1-year overall survival (OS) of 51%, 3+year OS of 40%, and progression-free survival at 1 year and 3+ years of 42% and 33%, respectively. Non-relapse mortality was 18%, and relapse occurred in 47% of cases with a median time to relapse of 7.9 months. Rates of acute and chronic graft-versus-host disease were 45% and 40%. Reduced-intensity conditioning was associated with superior OS compared to myeloablative conditioning (58% vs. 30%). Donor lymphocyte infusion after relapse led to complete remission in 46% of cases. 

https://doi.org/10.1038/s41409-023-02122-0