Mycosis fungoides is the most common form of cutaneous T-cell lymphoma. The cutaneous T-cell lymphomas are an assorted group of cancers with varying genotypes and phenotypes. Mycosis fungoides is a rare form of cancer, but it is considered to be the most frequent form of cutaneous lymphoma. Mycosis fungoides is predominantly a disease of abnormal CD4+ lymphocytes that have become malignant and have moved into the skin, causing the characteristic lesions. Advances with immunophenotyping and gene rearrangement studies have helped to characterize the disease and are used for diagnostic and prognostic purposes. Altogether, mycosis fungoides is a rare condition afflicting approximately 1 in 500,000 people.
CLINICAL SUBTYPES OF CUTANEOUS T-CELL LYMPHOMA
Clinical Findings: Mycosis fungoides often manifests as a slowly progressing rash that occurs in doublecovered areas such as the groin and breast skin. The buttocks are a very common area of involvement. There is a 2 : 1 male predominance. Mycosis fungoides is seen in all races, with a predominance in the African American population compared with the Caucasian or Asian population. It is infrequently encountered in children. Mycosis fungoides is staged based on its appearance, the body surface area (BSA) involved, and the involvement of lymph nodes, blood, and other organ systems. The most common stage of mycosis fungoides is stage IA.
Stage IA mycosis fungoides carries an excellent prognosis, with most patients leading a normal life span and dying from another cause. Stage IA disease is typically described as patches of involvement totaling less than 10% of the BSA and no lymph node involvement. The rash of stage IA disease appears as thin, atrophic patches on the buttocks, breasts, or inner thighs. There are often areas of poikiloderma (hyperpigmentation and hypopigmentation as well as telangiectasias and atrophy). The atrophy has been described as “cigarette paper” atrophy: The skin exhibits a fine crinkling similar to freshly rolled cigarette paper. The rash is often asymptomatic, but pruritus can be problematic for some. The diagnosis of mycosis fungoides is based on the clinical and pathological findings.
Patch-stage mycosis fungoides can go undiagnosed for years to decades because of its indolent nature and often bland appearance. It often appears as psoriasis, a nonspecific form of dermatitis, and initial biopsies are often nonspecific. The application of topical steroids before a skin biopsy is obtained may alter the histological picture enough to make the diagnosis of mycosis fungoides impossible. Often, serial biopsies over years are required until one shows the characteristic features of mycosis fungoides. It is best to biopsy a previously untreated area. In addition to being a very slowdeveloping cancer, it is possible that mycosis fungoides may start as a form of dermatitis and over many years transform into a malignant CD4+ process.
At the other end of the spectrum is the Sézary syndrome. This is an erythrodermic variant of mycosis fungoides with peripheral blood involvement. Circulating Sézary cells are the hallmark of this syndrome. The Sézary cells are enlarged lymphocytes with cerebriform nuclei. The cerebriform nuclei can best be appreciated under electron microscopy. It is considered to be a leukemic phase of mycosis fungoides. Sézary syndrome has a poor prognosis.
There are many varying stages of disease between these two extremes. The morphology of cutaneous lymphoma changes from patches to plaques to nodules or tumors. Varying amounts of ulceration may be present. The natural history of progression of mycosis fungoides is variable and difficult to predict clinically. The most accurate way to predict the course is based on the type of involvement and the BSA involved. The smaller the BSA of involvement, the better the prognosis. A worse prognosis is seen with the nodular form as opposed to the plaque type or the patch form of mycosis fungoides.
Histological Analysis Of Cutaneous T-Cell Lymphoma
Pathogenesis: The etiology of mycosis fungoides is unknown. The pathomechanism that causes the responsible lymphocytes to transform into malignant cells is unknown. Significant work has looked at various causes including retroviruses, environmental insults, gene deletions, and chronic antigen stimulation. However, the exact mechanism of malignant transformation for this disease, which was originally described in 1806, remains unresolved.
Histology: Stage IA disease shows the characteristic histological findings of mycosis fungoides. There is a lichenoid infiltrate of abnormal lymphocytes with cerebriform nuclei. There are varying amounts of epidermotropism without spongiosis. The epidermotropic cells are the abnormal lymphocytes that have entered the epidermis. Occasionally, collections of the lymphocytes occur within the epidermis as small groupings called Pautrier’s microabscesses. Immunophenotyping of the cells present reveals the infiltrate to be predominantly CD4+ lymphocytes with a loss of the CD7 and CD26 surface molecules. Clonality of the infiltrate can be determined by performing a Southern blot analysis. The presence or lack of clonality is not diagnostic, and this test is not routinely performed.
Peripheral blood can be analyzed by flow cytometry for the presence of circulating lymphoma cells. This is a rare finding in low-stage disease and a near-universal finding in Sézary syndrome.
Treatment: Treatment of mycosis fungoides is based on the stage of disease. Stage IA disease is often treated with a combination of topical corticosteroids, nitrogen mustard ointment, narrow-band ultraviolet B (UVB) phototherapy, or psoralen + ultraviolet A (PUVA) phototherapy. As the BSA of involvement increases, the use of creams becomes difficult. Phototherapy is often used for those with widespread patch disease.
Isolated tumors respond well to local radiotherapy. Often, systemic treatments are employed as well. These systemic agents include the retinoids (bexarotene, acitretin, and isotretinoin) and interferon, both α and γ types. Extracorporeal photophoresis has been used for all stages of mycosis fungoides, especially Sézary syndrome. The patient is given intravenous psoralen and then has peripheral blood removed and separated into its components. The white blood cells are isolated, exposed to UVA light, and then returned to the patient. The exposed leukocytes that have been damaged by the psoralen and UVA are believed to induce a vaccine-like immunological response.
Total skin electron-beam therapy can be used in special cases in institutions that have the technical capability. Denileukin diftitox is an approved therapy for refractory disease. This drug is created by fusion of the interleukin-2 (IL-2) molecule and the diphtheria toxin. Cells that express the CD25 molecule (IL-2 receptor) are selectively killed by this medication. Denileukin diftitox can cause severe side effects and should be administered only by specialists adept at its use. Many new medications are being used with variable success in the treatment of mycosis fungoides, including an anti-CD52 monoclonal antibody, alemtuzumab, and various investigational mediations. Bone marrow transplantation is another option for life-threatening refractory disease.
Despite the many therapies available, no treatment has been shown to increase survival in patients with mycosis fungoides. It is therefore inadvisable to treat stage IA disease with a medication that has acute, potentially life-threatening side effects.