Mycosis fungoides

Mycosis Fungoides

I. What every physician needs to know.

Mycosis fungoides (MF) is the most common type of cutaneous T cell lymphoma which manifests as patches, plaques, or nodules on non-sun exposed areas of the skin. These skin lesions may slowly evolve into tumors. In severe cases, MF also involves extracutaneous tissues such as the lymph nodes, lungs, liver, spleen and gastrointestinal tract. Classic MF is considered an indolent disease that progresses slowly over years to decades.

Sézary syndrome is the aggressive and leukemic cutaneous T-cell lymphoma variant, characterized by circulating atypical T cells (Sézary cells), diffuse erythema (erythroderma), and severely disabling pruritus with or without lymphadenopathy.

Patients with MF and Sézary syndrome are at a significantly increased risk of developing a second lymphoma, particularly Hodgkin lymphoma and the cutaneous T-cell lymphoma subtype lymphomatoid papulosis, as well as nonhematologic malignancies.

II. Diagnostic Confirmation: Are you sure your patient has MF?

A considerable number of reports have documented MF mimicking other dermatoses, leading to some clinicians labeling MF as “the great imitator.”

MF is diagnosed on clinical, histological, and immunopathological grounds supported by molecular biological criteria, based on the guidelines from The International Society for Cutaneous Lymphoma (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC).

A total of 4 points is required for the diagnosis of mycosis fungoides based on any combination of points from the clinical, histopathologic, molecular, and immunopathologic criteria. Clinical and histopathologic sections are further divided into basic and additional criteria:

If basic criteria and two additional points are met, 2 points are given.

If basic criteria and one additional criterion are met, 1 point is given.

1) Clinical

Basic criterion is the presence of persistent skin patches/thin plaques.

Additional clinical criteria include:

Presence of these lesions in the non-sun exposed areas
Variation in size and shape of these lesions and
Poikiloderma (areas of increased and decreased pigmentation, prominent blood vessels, and thinning of the skin).

2) Histopathologic

Basic criterion is the presence of superficial lymphoid infiltrates on skin biopsy.

Additional criteria include:

Epidermotropism without spongiosis (see further details discussed below)

Presence of enlarged hyperchromatic nuclei with irregular nuclear contours on the biopsy specimen

Because concordance rates among pathologists are low for the diagnosis of early MF, serial biopsy specimens are needed from various clinical sites to render a definitive diagnosis.

3) Molecular biological

Clonal rearrangement of T- Cell Receptor gene by PCR qualifies for 1 point. This is absent in 50% of cases.

4) Immunopathologic

Presence of any of the below mentioned immunopathologic criteria qualifies for 1 point:

Less than 50% of T-cells of the lesional infiltrates express CD2, CD3, and/or CD5.
For total lesional infiltrates, less than 10% of T-cells express CD7.
Discordance of the dermal and epidermal cells (deficiency in the epidermis) in the expression of CD2, CD3, CD5, or CD7.

In the past, the diagnosis of Sézary syndrome (aggressive leukemic phase of mycosis fungoides) was made when a high number of Sézary cells (abnormal lymphocytes with cerebriform nuclei and unique morphologic appearance) were found circulating in the blood. However, this has largely been replaced by flow cytometry because of high interobserver variability in cell counts.

A. History Part I: Pattern Recognition:

Typically, patients present with complaints of chronic, pruritic and scaly skin patches or plaques on non-sun exposed areas, or “bathing suit” areas of the skin. This includes the breasts, buttocks, lower trunk, and groin. Pruritis is often, but not always, present and can be so severe that it can affect quality of life.

Diagnosis may be complicated by the premycotic phase (presence of skin lesions that are nonspecific and biopsies that are non-diagnostic). This phase can precede the diagnosis and can last for months. Sometimes, these skin lesions progress to infiltrated plaques followed by ulcerative lesions or tumerous growths. Patients can also present with skin patches, plaques, tumors and ulceration at the same time.

Hospitalization may result from generalized erythroderma, which can be the presenting complaint in patients with more advanced disease. Rarely in some patients, MF is associated with alopecia, or pigmented purpura-like skin lesions. Multiple recurrent cutaneous infections may be the presenting complaint. In some patients multiple recurrent cutaneous infections may be the presenting complaint. Cases of patients with advanced disease presenting with large areas of necrotic skin, cutaneous and blood stream bacterial infections are also present in the literature.

B. History Part 2: Prevalence:

MF usually presents at the age of 55-60 years but can also be seen in younger individuals. It affects men more than women, and blacks more than whites. Roughly, MF has an incidence of 3.6 per 100,000 person years. MF is believed to result from chronic antigenic stimulation that leads to uncontrolled clonal expansion and the accumulation of T-cell helper memory cells in the skin. Genetic abnormalities and environmental triggers have been implicated as predisposing factors. It has been proposed that there is an association between MF and human T-lymphotropic virus type I (HTLV-I). To date, however, this relationship has not been confirmed.

C. History Part 3: Competing diagnoses that can mimic MF.

MF can present similarly to other papulosquamous and eczematous skin disorders. The following disease processes can mimic MF: eczema, psoriasis, lichen planus, photodermatitis, drug reactions, primary cutaneous lymphoma and folliculotropic MF. Careful history, physical examination and skin histo and immunopathology are needed to make the correct diagnosis. Even tinea corporis has been reported to mimic MF.

D. Physical Examination Findings.

Typical physical findings include chronic, pruritic and scaly skin patches mainly on non-sun exposed areas such as buttock and breast. Skin lesions can also be found as plaques, or as ulcerative or tumorous growths. These skin lesions may be hypo or hyperpigmented and/or atrophied. Other findings include focal or generalized erythyroderma. Alopecia can also be found on clinical examination. Alopecia arreata is most commonly associated but in rare cases total body hair loss can also be seen.

In advanced cases, lymphadenopathy and organomegaly (such as hepatosplenomegaly) can also be found on clinical examination.

E. What diagnostic tests should be performed?

There are no physical examination findings or examination maneuvers which can confirm the diagnosis of MF. Diagnosis of MF is made on the combination of clinical, histopathologic, biological and immunopathologic criteria (see above).

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Basic laboratory studies, such as complete blood count (CBC) with peripheral smear (to evaluate for Sézary syndrome), complete metabolic panel and lactate dehydrogenase (LDH), should be obtained first.

Skin biopsy and histology are needed to establish the diagnosis. Multiple skin biopsies are recommended to confirm the diagnosis. Presence of aggregates of mononuclear cells with cerebriform nuclei in the epidermis surrounding Langerhans cells, also known as Pautrier microabscesses, is a rare finding but is diagnostic. Mostly, skin biopsy reveals atypical lymphocytes found in the epidermis or superficial dermis. Lymph node biopsies can be obtained and have prognostic significance.

Immunophenotyping follows skin histopathology. The detailed discussion of immuno-phenotyping is beyond the scope of this chapter, but briefly, absence of one or more of mature T cell markers on the lymphocytes favors the diagnosis of lymphoma.

PCR or southern blot is used next to evaluate for T-cell receptor gene rearrangement to support the diagnosis of mycosis fungoides.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

No imaging study is necessary to establish the diagnosis of MF, but chest x-ray, computed tomography (CT) scan of the chest, abdomen and pelvis can be obtained to evaluate the involvement of internal organs. Positron emission tomography (PET) is known to have a higher sensitivity. For patients who cannot have PET scanning, magnetic resonance imaging (MRI) studies may be requested.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

III. Default Management.

Once diagnosis is made, staging of the tumor should be followed next. This includes careful examination of the skin lesions and evaluation of the involvement of the lymph nodes and other organs by imaging studies. Lymph node and, rarely, bone marrow biopsies can also be obtained in advanced cases.

Management subsequently depends on the extent of involvement of the disease.

A. Immediate management.

MF is an indolent non-Hodgkin T-cell lymphoma and usually does not need any immediate management. Detailed work-up should be completed before treatment is initiated. Treatment and management decisions of MF should be made in consultation with hematology/oncology and dermatology experts.

Rarely, MF can present with complications such as pneumonia or septicemia (from skin infections associated with immune deficiency) or cardiovascular failure. Treatment of complications should be initiated immediately.

B. Physical Examination Tips to Guide Management.

Physicians should monitor changes in skin lesions and lymphadenopathy after treatment is initiated. If involvement of internal organs was established during staging, they should be closely followed by imaging studies.

It is important to know that topical therapy such as nitrogen mustard and corticosteroids can exacerbate pruritus after the treatment is initiated.

Histone deacetylase (Romedepsis and vorinostat) is known to cause ST/T wave and QT changes on EKG and needs frequent monitoring of EKG when infused.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

During treatment with systemic retinoids, lipid panel and thyroid function tests should be closely monitored. Gemfibrozil should be avoided because of the known side effects of the combined therapy; fish oil tablets can be used instead. Some authors have also documented liver toxicities associated with administration of retinodis, and liver function tests (LFTs) should also be monitored in these patients.

Romedepsis and vorinostat, histone deacetylase are also known to cause blood dyscrasias, ST/T wave and QT changes on EKG and GI side effects. In these patients, baseline EKG, complete metabolic panel (CMP) and complete blood count need to be obtained before infusion is initiated.

Pulmonary function tests and comprehensive metabolic panel (including liver and kidney function) should be monitored during treatment with methotrexate.

D. Long-term management.

The details about treatment of MF are beyond the scope of this chapter, and should be developed along with a Hematology/Oncology expert. Briefly, localized disease can be treated with topical chemotherapy (nitrogen mustard or carmustine), topical corticosteroids (usually used as add-on treatment), total skin electron beam therapy (TSEBT) for the localized area, and phototherapy (UVB or PUVA).

Extensive disease is treated with either one or combination of any of the following: total skin electron beam therapy (TSEBT), systemic retinoid, interferon, histone deacetylase inhibitors, Denileukin diftitox, extracorporeal photochemotherapy (ECP, photopheresis), and systemic chemotherapy. Treatment usually continues until the skin lesions are resolved. In some cases treatment duration ranging from 3-5 years to indefinite is documented in the literature.

E. Common Pitfalls and Side-Effects of Management.

Over a period of time, lymphocytes may lose their predilection for the epidermis, and may target the dermis, lymph nodes and other organs, converting MF into a more aggressive and resistant leukemia. At times, MF can undergo large cell transformation (anaplastic cells or immunoblasts) associated with a worse prognosis.

Romedepsis and vorinostat are potent inhibitors of the CYP enzyme system and can lead to serious toxicities of medications which are metabolized by similar CYP enzymes.

Treatment with systemic retinoids are associated with hypertriglyceridemia, hypercholesterolemia, thyroid and liver abnormalities, requiring replacement of thyroid hormone and lipid-lowering treatment during management.

Ultra-potent glucocorticoids should not be used on the face and neck as these areas are susceptible to steroid-induced complications. Also, use of steroids for prolonged periods of time is associated with skin breakdown and cutaneous infections.

Nitrogen mustard is commonly associated with allergic skin reactions, and carmustine can lead to skin hyperpigmentation.

Phototherapy is associated with acute skin burning and has been shown to increase chances of other skin cancers if used for longer periods of time.

Interferon treatment is well known to be associated with flu-like symptoms.

Denileukin diftitox is associated with multiple side effects, including cardiac arrhythmias, liver dysfunction, myalgia, flu-like symptoms and capillary leak syndrome (a rare medical condition in which extravasation of fluid through the capillaries from blood to the interstitial space results in hypotension, edema, and multi-organ failure).

Finally, systemic chemotherapy is associated with gastrointestinal side effects and myelosuppression; methotrexate can cause pulmonary, hepatic, and renal toxicities. Pulmonary function tests, liver function tests, and renal panel should be monitored during treatment.

Pegylated liposomal doxorubicin is associated with blood disorders and palmo-plantar erythrodysesthesias (painful feeling in the palms and soles, associated with tenderness or swelling).

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

Methotrexate dose needs to be decreased in patients with renal insufficiency.

B. Liver Insufficiency.

Methotrexate dose needs to be decreased in patients with liver dysfunction.

C. Systolic and Diastolic Heart Failure.

Romedepsis and vorinostat may prolong QTc; they should be infused carefully in patients with underlying heart failure.