Synonym: cutaneous T-cell lymphoma (CTCL)

Classification

Classification of cutaneous T-cell lymphomas by the World Health Organization (WHO) and the European Organisation for Research and Treatment of Cancer (EORTC).¹

Epidemiology

Mycosis fungoides accounts for about 72% of cutaneous T-cell lymphomas.²

• The incidence is approximately 0.36 cases per 100,000 population per year.³
• Most often presents in those aged 45 to 60 years but has been diagnosed in children and adolescents.³
• 50% more common in black than in white patients and twice as frequent in men than in women.
• Some occupational factors may be associated, e.g. glass formers, pottery and ceramics workers.³
• There is some clustering in families.⁴

Presentation

• Patches and plaques may affect any area of the skin, but are often distributed asymmetrically in the bathing suit area, i.e. hips, buttocks, groin, lower trunk, axillae and breasts. Involvement of the scalp often causes alopecia.
• In its early stages, mycosis fungoides mimics many benign dermatoses. The cutaneous eruptions wax and wane.
• The skin disease generally progresses from:
  • Patch phase (up to 15 cm across): flat, erythematous pink-brown macules that may have a fine scale, may be single or multiple and may be pruritic. In dark-skinned individuals, the patches may appear as hypopigmented or hyperpigmented areas. As patches become more infiltrative, they evolve into palpable plaques.
  • Plaque phase: tend to be raised, with fine scale, well-demarcated, erythematous shapes with irregular borders. Annular patterns with central clearing and pruritus are common.
  • Mycotic or tumour phase: with later visceral involvement and infection as the skin turns into ulcerating, necrotic tumours.

Differential diagnosis

Early in the course of disease, skin lesions may be non-specific, with a non-diagnostic biopsy result, and so confusion with benign conditions is common.

Investigations

• Liver function tests: lactate dehydrogenase (LDH) is a marker of bulky or biologically aggressive disease. Abnormal transaminase values may indicate hepatic involvement.
• Uric acid: may be raised in aggressive disease.
• Consider HIV testing (but the vast majority of patients are HIV-negative).³
• Chest X-ray.
• CT scan of the abdomen and pelvis: in patients with advanced disease (stage IIB to stage IVB) or in patients with clinically suspected visceral disease.
• Skin biopsy: for a definitive diagnosis, skin biopsy shows mycosis or "Sézary cells" (convoluted lymphocytes), a band-like upper dermal infiltrate, and epidermal infiltrations of neoplastic lymphocytes (Pautrier's abscesses). Multiple biopsies may be required before the diagnosis is certain.
• Bone marrow examination: only if the patient has proven blood or nodal involvement.
• Lymph node biopsy: if the nodes are palpable.

The diagnosis of early mycosis fungoides often needs integration of clinical, histological and molecular features since it can be confused with benign eczematous skin disease. Algorithms are often used.²

Associated diseases

The CTCLs comprise a heterogeneous group of entities. Indolent low-risk entities, including mycosis fungoides and Sézary syndrome are distinguished from aggressive entities, including peripheral T-cell lymphoma and its variants and HTLV-1 associated acute T-cell leukaemia/lymphoma.⁵

Sézary syndrome

Sezary syndrome is a variant of mycosis fungoides, occurring in about 5% of cases, in which the patient has generalised erythroderma and more than 1000 per mm³ atypical T lymphocytes circulating in the peripheral blood - Sézary cells - CD4+ T lymphocytes with a highly convoluted and bizarre morphological appearance.
It is characterised by erythroderma, leukaemia, generalised lymphadenopathy and hepatosplenomegaly. It occurs most frequently in middle-aged males. Patients have a median survival of less than 5 years

Staging

• Primary tumour (T)
  • T1: eczematous patches, papules, or limited plaques <10% of the skin surface
  • T2: erythematous patches, papules or generalised plaques covering 10% or more of the skin's surface
  • T3: tumours, one or more
  • T4: generalised erythroderma
• Nodes (N)
  • N0: no nodes
  • N1: clinically abnormal peripheral lymph nodes (record nodes involved) but biopsy negative for CTCL
  • N2: peripheral lymph nodes positive for CTCL - but not abnormal clinically
  • N3: Abnormal nodes - CTCL Bx positive
• Distant metastasis (M)
  • M0: no visceral organ involvement
  • M1: visceral involvement (with pathological confirmation)
• Equivalent stages:
  • Stage IA = T1, N0, M0
  • Stage IB = T2, N0, M0
  • Stage II = T1 or T2, N1, M0
  • Stage III = T4, N0 or N1, M0
  • Stage IVA = T1-4, N2 or N3, M0
  • Stage IVB = T1-T4, N0-N3, M1

Management

Mycosis fungoides and Sézary syndrome are rarely curable; the goal of treatment is to control the disease while keeping toxic effects to a minimum.

• Symptomatic treatments: emollients or antipruritics in combination with specific topical and systemic treatment.
• Topical treatments:
  • Topical steroids
  • Topical chemotherapy, e.g. nitrogen mustard or bischloroethylnitrosourea
  • Ultraviolet B or ultraviolet A treatment, enhanced with psoralen and UVA (PUVA) or total body electron beam radiation in the patch or plaque phase. These modalities are also used in the tumour phase combined with systemic therapies, e.g. PUVA plus interferon.⁶
• Systemic treatment:
  • For patients who have relapsed or whose disease is refractory to topical treatments or who have tumours, erythroderma, or nodal or visceral disease.
  • Extracorporeal photopheresis (leucopheresis with PUVA treatment for the collected white blood cells and then reinfusion of treated cells).
  • Recombinant alfa interferon
  • Of the chemotherapeutic agents, pentostatin, gemcitabine, doxorubicin and oral retinoids seem to be particularly effective.⁷ Activity against CTCL has been shown at relatively lower doses with less myelosuppression.⁸
  • The monoclonal antibody alemtuzumab leads to responses in at least half of patients with advanced disease.⁹
  • Combination chemotherapy: is generally not used because the infectious complications and short response duration outweigh the modest response rates (compared to other non-Hodgkin lymphomas). Increased survival is not demonstrated with the use of combination chemotherapy compared to sequential topical agents.
• Bone marrow transplantation: allogenic transplants are reported in the literature as case reports or small groups of patients.

Several novel systemic therapies have emerged; retinoids like bexarotene, the fusion toxin denileukin diftitox, lenalidomide, and toll-like receptor agonists. Other important novel or emerging agents include the histone deacetylase inhibitors; a novel antifolate, pralatrexate; the proteasome inhibitor bortezomib; and the purine nucleoside phosphorylase inhibitor forodesine.⁸

Complications

• Infection
• High-output cardiac failure
• Anaemia of chronic disorders
• Oedema
• Secondary malignancies
• Skin cancer
• Melanoma
• Colon cancer
• Hodgkin's lymphoma
• Non-Hodgkin's lymphomas

Prognosis

• Incurable in most patients, with the exception of those with stage IA disease.
• Mycosis fungoides represents the most benign of the cutaneous T-cell lymphomas, with 10-year relative survival ranging from 100% to 41%, depending on the degree of skin involvement.¹⁰
• Probability of progression to extracutaneous disease within 20 years of diagnosis can be up to 40%, depending on stage.¹⁰
• Mortality and prognosis are related to stage at diagnosis:¹¹
  • Patients diagnosed with stage IA disease (patch or plaque skin disease limited to less than 10% of the skin surface area) who undergo treatment, have a normal life expectancy.
  • The median survival is 11 years for patients with extensive patch/plaque (stage IB or IIA).
  • Cutaneous tumours (stage IIB): median survival 3.2 years.
  • Erythroderma (stage III): median survival 4.6 years.
  • Pathologic nodal involvement (stage IVA): median survival 1.2 years.
  • Visceral disease (stage IVB): median survival 0.9 years.
• Mycosis fungoides may progress to Sézary syndrome or transform to large-cell histology.
• Late-stage mycosis fungoides is associated with increasing immunosuppression, and death most often results from systemic infection. Other causes of increased mortality include secondary malignancies (e.g. higher-grade non-Hodgkin's lymphoma, Hodgkin disease, colon cancer), and cardiopulmonary complications (e.g. high output failure).