MYCOSIS FUNGOIDES
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.
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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.
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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.
