Mycosis Fungoides and Sézary Syndrome

• The malignant cell is a mature, skin-homing CD4-positive T cell expressing CLA (cutaneous lymphocyte antigen) and CCR4, receptors that direct trafficking into the skin and account for the disease being confined there for years
• In mycosis fungoides the cell resembles a tissue-resident memory T cell, which explains its persistence in fixed skin sites and the tendency of lesions to recur in the same places
• In Sézary syndrome the cell resembles a central memory T cell, which recirculates between blood, lymph nodes and skin — explaining the leukaemic, erythrodermic and nodal picture rather than fixed plaques
• Epidermotropism — malignant T cells migrating into the epidermis — is the histological hallmark. Clusters of these cells within the epidermis form Pautrier microabscesses
• Loss of pan-T-cell antigens, particularly CD7 and later CD5 and CD2, is characteristic and is used diagnostically
• Genomic changes are dominated by chromosomal instability and mutations in the JAK/STAT, NF-κB and T-cell receptor signalling pathways, along with TP53 and CDKN2A loss in advanced disease. There is no single defining translocation, unlike most B-cell lymphomas
• As disease advances, malignant cells lose skin-homing restriction and disseminate to nodes, blood and viscera
• Progressive loss of the normal T-cell repertoire produces immunosuppression, and infection — typically staphylococcal sepsis through a compromised skin barrier — is the leading cause of death, rather than tumour bulk

• Age — median at diagnosis around 55-60; uncommon but well described in children and young adults
• Male predominance of roughly 2:1
• Higher incidence in Black populations, with earlier onset and more advanced disease at presentation
• No infectious cause is established for mycosis fungoides. HTLV-1 causes a different disease (adult T-cell leukaemia/lymphoma) which can closely mimic it and must be excluded serologically
• Occupational and environmental exposures have been proposed and none is confirmed
• Chronic antigenic stimulation is hypothesized as a driver but remains unproven
• There is no established familial predisposition, though rare familial clusters are reported

The stages, which unfold over years

• Patch stage: flat, erythematous, finely scaling patches, often subtly atrophic or wrinkled ("cigarette paper"), typically in sun-protected areas — buttocks, lower trunk, upper thighs, breasts — the so-called bathing-trunk distribution. Frequently pruritic, often diagnosed and treated as eczema or psoriasis for years
• Plaque stage: raised, indurated, well-demarcated plaques, sometimes annular or arciform, with more intense pruritus
• Tumour stage: nodules and tumours which may ulcerate, classically arising within pre-existing plaques. Facial involvement produces leonine facies
• Erythrodermic disease: generalized erythema involving more than 80% of body surface, with scaling, intense pruritus, and impaired thermoregulation

Sézary syndrome

• The triad of erythroderma, generalized lymphadenopathy, and circulating Sézary cells
• Intractable pruritus, often the dominant and most distressing symptom
• Palmoplantar keratoderma, alopecia, ectropion from facial skin tightening, and onychodystrophy
• Hypothermia or temperature instability, high-output cardiac failure and fluid loss from erythroderma — erythroderma is a genuine medical emergency at its extreme

Other features

• Poikiloderma — mottled hyper- and hypopigmentation with atrophy and telangiectasia
• Hypopigmented mycosis fungoides, more common in darker skin and in children, easily mistaken for vitiligo or pityriasis alba
• Folliculotropic mycosis fungoides — follicular papules, alopecia, often head and neck, more treatment-resistant
• Lymphadenopathy in advanced disease; visceral involvement is late
• Recurrent skin infection, particularly Staphylococcus aureus, from barrier failure

Skin biopsy — and expect to repeat it

• Multiple biopsies from untreated lesions are often needed; early patch-stage histology can be nonspecific for years, and a negative biopsy does not exclude the diagnosis
• Withhold topical steroids for at least two weeks before biopsy where feasible, as they obscure the infiltrate
• Histology: a band-like (lichenoid) infiltrate of atypical lymphocytes in the papillary dermis with epidermotropism — atypical lymphocytes within the epidermis, often aligned along the basal layer with surrounding clear haloes and disproportionate to the degree of spongiosis. Pautrier microabscesses — intraepidermal clusters of atypical cells — are highly characteristic but present in a minority
• Cells show cerebriform (convoluted) nuclei

Immunophenotype and clonality

• CD2, CD3, CD4 and CD45RO positive; CD8 negative in the great majority
• Loss of CD7 is the most useful aberrancy; loss of CD5 and CD2 occurs later
• An increased CD4:CD8 ratio within the infiltrate
• T-cell receptor gene rearrangement demonstrating clonality supports the diagnosis — but a clone can be found in benign inflammatory dermatoses, so clonality alone is not diagnostic and must be interpreted with clinical and histological findings

Blood, staging and the specific tests for Sézary syndrome

• Peripheral blood flow cytometry for an expanded CD4-positive population, with loss of CD7 or CD26, and an elevated CD4:CD8 ratio (10 or more)
• Sézary cell count, with an absolute Sézary count of 1000 cells/µL or more defining B2 blood involvement
• TNMB staging (tumour, node, metastasis, blood) — the blood compartment is staged explicitly, unlike other lymphomas
• CT or PET-CT for nodal and visceral disease in advanced stages; lymph node biopsy where nodes are enlarged
• LDH, full blood count and film
• HTLV-1 serology in every patient with suspected cutaneous T-cell lymphoma, particularly those from endemic regions — adult T-cell leukaemia/lymphoma mimics mycosis fungoides closely and is a different disease

Differential diagnosis

• Eczema, psoriasis, chronic contact dermatitis, drug eruption — the usual and lengthy prelude to diagnosis
• Adult T-cell leukaemia/lymphoma (HTLV-1 positive, hypercalcaemia, "flower cells")
• Erythroderma of other causes: drug reaction, psoriasis, pityriasis rubra pilaris, atopic dermatitis
• Lymphomatoid papulosis and primary cutaneous CD30-positive lymphoproliferative disorders, which may coexist with mycosis fungoides
• Parapsoriasis, which exists on a continuum with early mycosis fungoides

Match intensity to stage — this is the central principle

• Early-stage disease (patches and plaques, no blood or nodal involvement) has an excellent prognosis and is treated with skin-directed therapy. Systemic chemotherapy neither prolongs survival nor prevents progression at this stage, and its toxicity is real. Overtreatment is the commonest error

Skin-directed therapy

• Topical corticosteroids, potent and superpotent, for patch and plaque disease
• Phototherapy: narrowband UVB for patch-stage disease, PUVA for thicker plaques — highly effective and a mainstay
• Topical chemotherapy: mechlorethamine (nitrogen mustard) gel; topical bexarotene
• Localized radiotherapy to individual tumours — mycosis fungoides is exquisitely radiosensitive
• Total skin electron beam therapy for extensive cutaneous disease, giving high response rates with skin-limited toxicity

Systemic therapy for advanced, refractory or erythrodermic disease

• Retinoids: oral bexarotene (expect central hypothyroidism and hypertriglyceridaemia, which require pre-emptive management)
• Interferon-alfa
• Extracorporeal photopheresis, particularly effective in erythrodermic disease and Sézary syndrome, and often combined with interferon or retinoids
• Histone deacetylase inhibitors: vorinostat, romidepsin
• Brentuximab vedotin for CD30-positive disease
• Mogamulizumab, an anti-CCR4 antibody, with particular efficacy in blood compartment disease and Sézary syndrome
• Methotrexate at low dose; gemcitabine or liposomal doxorubicin for more aggressive disease
• Allogeneic stem cell transplantation is the only potentially curative option and is considered in young patients with advanced disease
• Multi-agent chemotherapy produces high but very short-lived response rates and is reserved for rapidly progressive visceral disease

Supportive care, which matters as much as the antineoplastic therapy

• Aggressive management of pruritus — often the single greatest determinant of quality of life — with emollients, antihistamines, gabapentinoids, aprepitant and mirtazapine
• **Skin barrier care and prompt treatment of *Staphylococcus aureus*** colonization and infection, including decolonization strategies
• Temperature and fluid management in erythroderma
• Psychological support: this is a visible, disfiguring, chronic and incurable disease

• **Infection, particularly Staphylococcus aureus bacteraemia and sepsis through a disrupted skin barrier — the leading cause of death**, and the reason skin care is not a cosmetic issue
• Intractable pruritus with sleep deprivation, excoriation and severe impairment of quality of life
• Erythroderma with hypothermia, fluid and protein loss, and high-output cardiac failure
• Large cell transformation — conversion to a CD30-positive large T-cell phenotype, marking a sharp deterioration in prognosis
• Visceral dissemination to lung, liver, spleen and CNS in advanced disease
• Immunosuppression from disease and treatment, with opportunistic infection
• Treatment toxicity: bexarotene-induced central hypothyroidism and severe hypertriglyceridaemia; secondary cutaneous malignancy after prolonged PUVA; mogamulizumab-associated rash and increased graft-versus-host disease risk if transplanted afterwards
• Ectropion, alopecia, nail loss and keratoderma with functional and cosmetic consequences
• Psychosocial morbidity — disfigurement, social withdrawal, depression

• Mycosis fungoides is a CD4-positive skin-homing T-cell lymphoma with no fungus involved, evolving through patch → plaque → tumour over years to decades, and typically misdiagnosed as eczema or psoriasis for several years first
• Pautrier microabscesses — intraepidermal clusters of atypical lymphocytes — are the classic histological finding, along with epidermotropism and cerebriform nuclei
• Patches favour sun-protected, bathing-trunk areas — buttocks, lower trunk, upper thighs
• Loss of CD7 is the most useful immunophenotypic aberrancy; the cells are CD4-positive and CD8-negative
• T-cell receptor clonality alone does not make the diagnosis — clones occur in benign dermatoses. Correlate with clinical and histological findings, and expect to need repeated biopsies
• Sézary syndrome is the triad of erythroderma, generalized lymphadenopathy and circulating Sézary cells, with an absolute Sézary count of 1000/µL or more, loss of CD7 or CD26, and a CD4:CD8 ratio of 10 or more
• Staging is TNMB — the blood compartment is staged explicitly, unlike other lymphomas
• Early-stage disease is treated with skin-directed therapy — topical steroids, narrowband UVB or PUVA, topical mechlorethamine, local radiotherapy. Systemic chemotherapy does not prolong survival and should not be used for early disease
• Mycosis fungoides is exquisitely radiosensitive, and total skin electron beam therapy is highly effective for extensive skin disease
• Infection through the damaged skin barrier — usually staphylococcal — is the leading cause of death, not tumour bulk. Skin care is life-prolonging treatment
• Bexarotene causes central hypothyroidism and hypertriglyceridaemia — anticipate and manage both from the start
• Extracorporeal photopheresis and mogamulizumab are particularly useful when blood is involved — that is, in Sézary syndrome and erythrodermic disease
• Check HTLV-1 serology — adult T-cell leukaemia/lymphoma mimics mycosis fungoides closely and is an entirely different disease
• Large cell transformation to a CD30-positive phenotype signals a marked worsening of prognosis and opens the door to brentuximab vedotin