Mycosis fungoides and Sézary syndrome.

IN A NUTSHELL
Cutaneous T‐cell lymphomas (CTCL) are extra‐nodal non‐Hodgkin lymphomas primarily involving the skin at diagnosis.
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Mycosis fungoides (MF) is typically an indolent skin‐limited lymphoma, accounting for ~60% of CTCL cases, whereas Sézary syndrome (SS) is a rare and aggressive disease representing only ~2%–3% of cases.
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PATHOGENESIS

The pathogenesis of MF and SS remains incompletely understood.

Oncogenesis is multifactorial, involving genetic, immunological and microbial factors.
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MF and SS are mature CD4+ memory T‐cell neoplasms: SS was initially considered a leukaemic form of MF, but accumulating evidence indicates that they are distinct diseases, arising from mutations in extra‐cutaneous precursors that secondarily infiltrate the skin.
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CLINICAL FINDINGS

MF often follows an indolent course, which may include patch, plaque and tumour stages, although progression to advanced disease occurs in only 20%–25% of patients:
Early stages commonly present with erythematosquamous patches and plaques, mostly on non‐sun‐exposed areas (‘bathing‐trunk’ distribution), with variable pruritus.

In a subset of patients, over time (often many years), tumorous lesions or erythroderma can develop.
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MF displays several additional clinical phenotypes:
Classical variants include:
Folliculotropic MF: follicular lesions, commonly with associated alopecia, predominantly on the head and neck.

Pagetoid reticulosis (extremely rare): localized patch or plaque, usually on the extremities.

Granulomatous slack skin (extremely rare): lax skin affecting flexural regions such as the axillae and groin.
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Other rare clinical variants include hypopigmented, hyperpigmented, poikilodermatous, bullous, ichthyosiform, pigmented purpuric‐like, papular, pustular and solitary forms.
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SS is a systemic disease, characterized by:
Erythroderma (widespread erythema and scaling in >80% of the body surface area), typically with intense pruritus and frequently with palmoplantar keratoderma and nail dystrophy.

Lymphadenopathy.

Atypical circulating T cells (Sézary cells) in peripheral blood.
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DIAGNOSIS

Diagnosis is challenging and relies on integrated clinicopathological, immunophenotypic and molecular assessment.
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Multiple skin biopsies are often necessary for confirmation:
In MF, histological features vary by lesion stage:
Patches show a superficial band‐like infiltrate of atypical T cells with cerebriform nuclei that migrate into the epidermis (epidermotropism).

Plaques display more pronounced epidermotropism, sometimes with Pautrier microabscesses (small intraepidermal clusters of atypical lymphocytes).

Tumours form dense dermal infiltrates of atypical cells with loss of epidermotropism.

Rapidly progressive forms may show large‐cell transformation, defined by >25% large atypical lymphocytes (transformed MF).
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In SS, atypical circulating T cells (Sézary cells) are characterized by large, hyperconvoluted (‘cerebriform’) nuclei with condensed chromatin and scant cytoplasm. In erythrodermic skin, these atypical cells may be difficult to identify, and epidermotropism is usually absent.
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Immunophenotyping (by immunohistochemistry or flow cytometry) shows that, in both MF and SS, neoplastic cells are mature T memory cells, typically CD3+, CD4+ and CD45RO+, with frequent loss of CD7 and CD8. CD30 expression should be assessed in all cases.
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T‐cell receptor (TCR) gene analysis, performed by polymerase chain reaction and high‐throughput sequencing (HTS) of T‐cell receptor genes, may identify the malignant clone, thereby increasing diagnostic sensitivity.
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Diagnosis of SS is based on cutaneous and haematological criteria (Table 1). Given that skin biopsy may be non‐diagnostic in up to one‐third of cases, peripheral blood flow cytometry is mandatory in erythrodermic patients and may represent the only route to diagnosis.
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Except in patients with stage I disease (see below), evaluation for extra‐cutaneous disease is recommended:
Flow cytometry of peripheral blood.

Serum lactate dehydrogenase (LDH) levels; β2‐microglobulin and/or soluble interleukin‐2 receptor (disease markers).

CT or positron emission tomography‐computed tomography scan.
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CLASSIFICATION AND STAGING

MF and SS are classified among mature T‐ and natural killer‐cell neoplasms (World Health Organization 5th edition) and staged using the European Organisation for Research and Treatment of Cancer/International Society for Cutaneous Lymphomas tumor‐node‐metastasis‐blood (EORTC/ISCL) TNMB system (Table 2), in which SS is at least stage IVA1.
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MANAGEMENT

In MF/SS, therapy aims to reduce disease burden and improve quality of life. Management is ideally delivered in a multidisciplinary setting, with therapeutic choice depending on disease stage, patient factors, drug availability and access to clinical trials:
Skin‐directed therapies
Topical corticosteroids.

Topical chemotherapy (e.g. chlormethine).

Radiotherapy—localized or total skin electron beam therapy (TSEBT).

Phototherapy—narrow‐band ultraviolet B (UVB) (nbUVB), psoralen plus ultraviolet A (UVA) (PUVA).
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Systemic therapies
Interferons‐alpha (e.g. pegylated interferon α2a).

Retinoids (e.g. bexarotene).

Methotrexate.

Monoclonal antibodies—brentuximab vedotin (anti‐CD30), mogamulizumab (anti‐C‐C chemokine receptor 4), alemtuzumab (anti‐CD52), pembrolizumab (anti‐programmed cell death protein 1; investigational).

Chlorambucil.

Histone deacetylase inhibitors (HDACi)—vorinostat, romidepsin, chidamide.

Denileukin diftitox.
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Extra‐corporeal photopheresis (ECP), wherein mononuclear cells are UVA‐irradiated and reinfused—mostly used in patients with blood involvement, particularly in SS.
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Intravenous chemotherapy agents:
Monochemotherapy with gemcitabine or pegylated liposomal doxorubicin.

Cyclophosphamide, doxorubicin, vincristine, and prednisone (generally avoided).
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Allogeneic haematopoietic stem cell transplantation.
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For early‐stage MF (I–IIA), treatment focuses on symptom control and quality of life. Aggressive regimens are not recommended and may instead increase mortality. Management typically involves skin‐directed therapies, with systemic agents reserved for widespread and/or refractory disease. Localized radiotherapy can be particularly useful in unilesional disease.
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For advanced‐stage MF (≥IIB) and SS, therapy usually combines systemic treatments with skin‐directed strategies, including localized radiotherapy for paucilesional tumoral disease, with TSEBT reserved for extensive skin involvement.
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Supportive care is fundamental at all stages of MF/SS. This includes pruritus control and prompt treatment of secondary infections.
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Allogeneic haematopoietic stem cell transplantation remains the only potentially curative option, but is limited to carefully selected patients with advanced‐stage disease, due to high treatment‐related morbidity and mortality.
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PROGNOSIS

In MF, prognosis reflects clinical stage and prognostic indices, such as the Cutaneous Lymphoma International Prognostic Index (CLIPI)
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Early‐stage disease (IA–IIA) carries an excellent prognosis, with life expectancy comparable to the general population in most patients.

Advanced‐stage disease (≥IIB) has a poorer prognosis, with median survival <5 years.
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In SS, prognosis is generally poor, with median survival of 2–4 years.
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Unfavourable outcomes are associated with older age (>60 years), higher stage, large‐cell transformation and elevated LDH.
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CONCLUSIONS

MF and SS are cutaneous T‐cell lymphomas that require integration of clinical, histopathological and immunogenetic findings for accurate diagnosis.

Management is multimodal and stage‐based, aiming to reduce disease burden and control symptoms, as cure remains uncommon.

AUTHOR CONTRIBUTIONS

Joana Calvão: Supervision; writing – review and editing. Francisco Martins: Conceptualization; writing – original draft.

CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest to disclose.

PATIENT CONSENT STATEMENT
Patient consent was not required as this manuscript does not include identifiable patient data.

PERMISSION TO REPRODUCE MATERIAL FROM OTHER SOURCES
No material from other sources has been reproduced in this manuscript.