3.3.12 Cutaneous Lymphomas

Code: nil (group of diseases).

Cutaneous lymphomas are officially listed as rare diseases. The age adjusted incidence of CTCL is 6.4 per 1,000,000 persons and this incidence rate is highest between the ages of 70-79 years of age. The incidence rate of CBCL is reported to be approximately 3 per 1,000,000 persons.

Cutaneous lymphomas are a heterogeneous group of non-Hodgkin lymphomas that primarily involve the skin. They can be classified into primary cutaneous lymphomas (only affecting the skin) and secondary cutaneous lymphomas (with systemic involvement).

The aetiology of cutaneous lymphomas is not known in most cases. Older age is a risk factor. Some cutaneous lymphomas have been associated with a viral infection (HTLV-1 for adult T-cell lymphoma/ leukemia, EBV for EBV-associated lymphoproliferative diseases). Typical mutations of mycosis fungoides have the fingerprint of ultraviolet irradiation.

Pathophysiology could also involve lymphoproliferation related to antigen persistence and secondary occurrence of mutations leading to more aggressive clones.

Symptoms of primary cutaneous lymphomas vary depending on the subtype.

Erythematous, hypopigmented or poikilodermic macules or patches with mild scaling can be found in mycosis fungoides (the most frequent CTCL). 70-80% of patients remain at this indolent stage. 20-30% of patients evolve towards a more aggressive stage with development of nodules or tumors or develop extracutaneous progression (leukemic, lymph node or visceral involvement). Erythroderma is present in erythrodermic mycosis fungoides and Sézary syndrome, a rare form of CTCL characterized by the presence of circulating malignant blood T-cells. Patients often develop ectropion, alopecia and palmoplantar keratoderma. Pruritus is a common symptom. Enlarged adenopathies are frequent.

B-cell lymphomas characteristically appear with dome-shaped bluish-red papules and nodules, which may become large aggregates. Follicular B-cell lymphoma realize infiltrated plaques and tumor, usually non ulcerating. Marginal zone lymphoproliferative disease more often presents as usually non ulcerating nodules and predominate on members. Primary cutaneous B cell lymphoma leg type realize tumors and infiltrated plaques, which are often ulcerated.

Cutaneous lymphomas can appear anywhere on the body, localisation may depend on the subtype of lymphoma. Early lesions of mycosis fungoides are frequently found on sun—protected areas. Follicular B-cell lymphoma predominate on scalp and trunk. Marginal zone lymphoma predominates on the members. Primary cutaneous B cell lymphoma leg type are located mainly on legs and buttocks.

Primary cutaneous lymphomas are classified by the WHO-EORTC classification system. The classification relies on clinical and histological features and is obtained by clinico-pathological correlation.

• Cutaneous T-cell lymphomas account for approximately 75% of the cases. Mycosis fungoides and its variants represent 50% of CTCL. The group of CD30 lymphoproliferative disorders represents 30% of CTCL cases. This group comprises lymphomatoid papulosis and anaplastic large cell lymphoma. The remaining cases are various rare types of CTCL.

• 25% of primary cutaneous lymphoma are CBCL, comprising primary cutaneous follicular lymphoma, primary cutaneous marginal zone lymphoproliferative disease, and primary cutaneous large B cell lymphoma, leg-type.

Laboratory tests can be useful for the diagnosis. Serologic testing for lymphotropic viruses (HIV, EBV, HTLV-1) should be considered depending on the clinical form. In advanced cases of CTCL or in case of erythroderma, flow cytometry (CD3, CD4, CD8, loss of CD26 and CD7) should be used. LDH is a useful reflect of tumor mass. A T or B-cell clonal pattern can be identified in skin +/- blood by PCR tests or high throughput sequencing. Staging should be precised according to the TNMB (Tumor nodes metastasis blood) classification in mycosis fungoides or Sézary syndrome and according to TNM classification in the rest of primary cutaneous lymphomas. CT scan (or PET-CT) can be recommended to study extracutaneous dissemination.

Cutaneous lymphomas are a proliferation of lymphocytes with variable size, atypia, architecture, and immunophenotype, depending on the subtype.

Histological features of mycosis fungoides, the most frequent form, include a dense infiltrate of small to medium mononuclear cerebriform cells with mild to moderate atypia in the upper dermis with epidermotropism (spread of lymphocytes into the epidermis), without spongiosis, typically at the dermo-epidermal junction with an “indian file” lining up of the lymphocytes or forming Pautrier’s microabscesses (intraepidermal collections of primarily atypical lymphocytes). Sézary cells (atypical lymphocytes with cerebriform nuclei) can be found in the skin or in the peripheral blood (by cytomorphological examination of the peripheral blood smear) of patients with Sézary syndrome. Immunohistochemistry is used to describe the cell of origin and the histological subtype.

The group of CD30 lymphoproliferative disorders is characterized by the expression of CD30 by tumor T-cells.

CBCL express CD20. In primary cutaneous large B cell lymphoma, immunochemistry with bcl-2, bcl-6, MUM and search for MyD88 mutation are mandatory to differentiate indolent lymphoma from aggressive lymphoma.

Prognosis of primary cutaneous lymphomas depends on the subtype and stage and is generally considered better than primary nodal lymphomas. The majority of mycosis fungoides cases are early stage and have an indolent evolution. Advanced stage mycosis fungoides have a worse prognosis. CD30 lymphoproliferative disorders have a good prognosis.

As concerns CBCL, follicular B cell lymphoma and marginal zone B cell lymphoma have an indolent evolution, whereas large B cell lymphoma, leg type have a more aggressive evolution.

Many cutaneous lymphomas have an indolent evolution. Erythroderma types are accompanied with severe pruritus and often loss of protein and trace elements via desquamation as well as risk of hypo- or hyperthermia due to inadequate temperature control. Patients with cardiac insufficiency can have aggravation of the problem because maintaining the skin red requires a very important increase of the cardiac output. Large nodular aggregates at groin or axillar region can stop lymph drainage. In case of advanced-stage or aggressive form, immunosuppression (primary, and secondary to the treatments) combined with the presence of ulcerated lesions or the erythroderma (erythrodermic skin is not able to stop the bacteria to cross and increases the risk of sepsis. Lymphoma progression (nodal involvement, visceral or peripheral blood involvement at leukemic level) may occur.

Differential diagnoses includein patch stage: contactdermatitis, atopicdermatitis, psoriasis, parapsoriasis, dermatomycoses, pseudolymphomas. In tumour stage CTCL or CBCL: other primary or secondary lymphomas or other tumours. In erythrodermic patients, with psoriasis, drug reactions, pityriasis rubra pilaris or eczema.

The treatment should be adjusted to the subtype (indolent or aggressive) and stage (early or advanced).

Skin directed treatments are used in early-stage mycosis fungoides, they include topical corticosteroids, phototherapy (narrow band UVB or PUVA), and topical chlormethin. Radiation therapy (localized or full skin irradiation with electrons (Total Skin Electron Beam) can be used in advanced cases. Systemic treatments include methotrexate, bexarotene, pegylated interferon. In more advanced cases, HDAC (histone deacethylase) inhibitors, immunotherapies (e.g., anti-CD30, anti-CCR4) or chemotherapy are used. Photopheresis are used in erythrodermic mycosis fungoides. Allogeneic stem cell transplantation is considered in aggressive cases.

Indolent B-cell lymphomas may be treated by surgical excision, radiation therapy, topical steroids, or rituximab (anti-CD20 antibody) in disseminated cases. Aggressive B-cell lymphomas usually require rituximab and polychemotherapy.