Dermatology

Mycosis Fungoides and Sézary Syndrome

Are You Confident of the Diagnosis?

  • What you should be alert for in the history

Be observant for a patient who has had a long history of a questionable rash or a benign skin condition, particularly in areas of non–sun-exposed skin, unresponsive to medications indicated for that disease. The clinical course of mycosis fungoides (MF) is very indolent and can at times be mistaken for benign skin conditions such as chronic eczema, allergic contact dermatitis, or psoriasis. As a result, in these patients, it can take many years (median duration to diagnosis = 6 years) before an accurate diagnosis is made.

Sezary syndrome (SS) is classically defined as the triad of erythroderma, generalized lymphadenopathy, and the presence of malignant T-cells in the skin, lymph nodes, and peripheral blood. Patients usually present with an abrupt onset of itching and non-specific erythroderma. Rarely, patients have a preceding history of MF.

  • Characteristic findings on physical examination

The initial skin lesions in MF will generally appear in sun-protected areas, including bathing trunk areas, and the insides of the arms. The clinical presentation is divided morphologically into patches, plaques and tumors.

Patches are characterized by variably sized, erythematous lesions, at times with fine overlying scale (Figure 1). They may have a "cigarette paper-like" appearance. In early phases, lesions can appear more "digitate."

Figure 1.

Typical patch.

Plaques are characterized by infiltrative, at times scaly, reddish-brown lesions that can become confluent. (Figure 2) These lesions can resemble psoriasis, a subacute dermatitis, or even a granulomatous process such as granuloma annulare, although MF typically has associated epidermal change (scale).

Figure 2.

Typical plaque.

Tumors are characterized by solitary, localized, or at times generalized lesions that can ulcerate (Figure 3). Patients may present with patches, plaques or tumors (Figure 4) which may ulcerate. Only rarely do tumors appear de novo (called d'emblee form). As a result, if only tumors are present without preceding or concurrent patches or plaques, consideration of a less common variant of cutaneous T-cell lymphoma (CTCL) should be made.

Figure 3.

Typical tumor.

Figure 4.

Patient with evidence of patches, plaques and tumors.

Patients who have erythema covering over 80% of their body surface area (BSA) (erythroderma) have a greater risk of leukemic involvement (Figure 5).

Figure 5.

Erythrodermic patient.

Although patients may classically present with patch, plaque or tumor stage disease, there are many variants that may make a clinical diagnosis difficult. Some of these variants include: the classical form, hypopigmented, follicular, syringotropic, granulomatous (including granulomatous slack skin), palmo-plantar, pigmented purpuric-like, bullous/vesicular, interstitial, verrucous, vegetating, unilesional, erythrodermic, poikilodermatous, pustular, zosteriform and ichthysiform-like.

Folliculotropic MF: Patients can present with grouped follicular papules (Figure 6), acneiform lesions, including comedonal lesions, indurated plaques, and sometimes tumors. Lesions can be associated with alopecia given involvement of the hair follicle. The presentation may be more pronounced in the head and neck area, but lesions may occur anywhere on the skin surface. Pruritus may be very severe.

Figure 6.

Folliculotropic lesion.

SS by definition presents with erythroderma, which can be associated with exfoliation, edema, lichenification and intense pruritus. Patients may also commonly have lymphadenopathy, alopecia, onychodystrophy, ectropion, and palmoplantar hyperkeratosis.

Formal estimation of a patient's cutaneous involvement is important to track disease burden and response to therapy. This can be done using a modified severity-weighted assessment tool (mSWAT). Patch, plaque and tumor body surface area (BSA) are determined and multiplied by a factor of 1, 2 and 4 respectively to establish their standardized mSWAT score.

In addition to accurate assessment of their skin lesions, patients should undergo palpation for lymphadenopathy and organomegaly. Lymph nodes greater than 1.5 cm in size that are firm, irregular, clustered or fixed, are of most concern.

  • Expected results of diagnostic studies

Biopsy:

In order to confirm the diagnosis, a tissue biopsy is necessary, and if possible, of two distinct lesions with at least one representing a more indurated lesion. Patients should be off of topical steroids for at least two weeks prior to biopsy to enhance diagnostic yield. The histopathology may differ slightly with progressive disease. Early patch lesions can demonstrate a superficial bandlike or lichenoid infiltrate consisting of lymphocytes and histiocytes. Atypical cells with small to medium-sized cerebriform nuclei may be identified, and can be found in the epidermis (epidermotropism).

Another important diagnostic clue is the presence of atypical lymphocytes hugging the dermal, epidermal junction. A psoriasiform hyperplasia of the epidermis can be seen. The papillary dermis shows fibrosis with coarse bundles of collagen. Diagnostic clue: presence of epidermotropic lymphocytes in the basal layer of the epidermis and with nuclei slightly larger than those within the upper dermis.

In plaques, the epidermotropism can be more pronounced. The clustered atypical lymphocytes surrounding Langerhans cells present in the epidermis are called Pautrier microabscesses (Figure 7). There can be a dense band-like infiltrate within the upper dermis (Figure 8). Progression to tumor stage disease reveals dense, nodular or diffuse infiltrates which can involve all levels of the dermis. Epidermotropism may be lost. Angiocentricity and/or angiodestruction may exist. Transformation to a diffuse large cell lymphoma may occur (CD30+ or CD30-). It is defined as the presence of large cells exceeding 25% of the infiltrate or large cells forming microscopic nodules.

Figure 7.

Close-up of a pautrier's microabscess.

Figure 8.

Dense infiltrate of atypical lymphocytes with epidermotropism.

In SS, there is often a psoriasiform spongiotic pattern with a band-like infiltrate of lymphocytes (Figure 9).The infiltrate tends to be more monotonous. Although a lymphocytic infiltrate within the upper dermis is common, the typical findings of lymphocytes hugging the dermal, epidermal junction with or without epidermotropism may be absent in as many as 50% of cases, making the histologic diagnosis of SS quite difficult. However, the ultimate distinction from MF must be made via clinical correlation and other diagnostic features. In erythrodermic cases, it is always recommended that peripheral blood flow cytometry be performed (see below under Bloodwork).

Figure 9.

Dense lymphocytic infiltrate with tagging of atypical lymphocytes at the D-E junction and epidermotropism.

Folliculotropic MF is characterized histopathologically by folliculotropic infiltrates with relative sparing of the epidermis and evidence of follicular mucinosis. Occasionally the epidermis may also be involved. In some cases, there may be infiltration of both follicular epithelium and eccrine sweat glands.

Bloodwork:

Blood involvement is determined by flow cytometric analysis and detection of a clonal T-cell population. The typical immunophenotype of the abnormal peripheral blood T-cell population is CD3+, CD4+, CD7- (loss in about 50% of cases), CD26- (loss in more than 90% of cases), CD8-. Occasionally MF or SS can occur where the malignant population demonstrates a CD8+ phenotype. SS with the CD8 phenotype can be associated with retroviral infections (HTLV-1/2 or HIV), and it is recommended that these serologies be obtained.

For a diagnosis of SS, peripheral blood analysis must reveal one or more of these: absolute sezary count of more than 1000 cells/mm3, CD4:CD8 ratio greater than 10, loss of any or all of the T-cell antigens CD2, CD3, CD4 and CD5, loss of CD26 or CD7, in the setting of a positive T-cell clone. However, one should note that clonality may not be detected in early cases with the use of standard TCR/PCR (T-cell receptor gene rearrangement assays).

The malignant cells generally have a Beta-F1+(alpha/beta T-cell), CD3+, CD4+, CD5+, CD45RO+, CD8- phenotype. The ratio of CD4:CD8 can be greater than 4:1. The cells may lack expression of certain T-cell antigens such as CD7 and CD26.

Expression of cytotoxic proteins (TIA-1, granzyme B) are identified in 10% of patients with plaques, but is more common in tumors with blastic transformation.

Gene Rearrangement:

Tissue and blood may also be sent for T-cell receptor gene rearrangement by polymerase chain reaction (PCR). A clonal population is commonly identified in the skin of patients with plaque or tumors, but only in 50-60% of early patch stage disease. One should be aware that a dominant clone can also be identified in patients with autoimmune inflammatory dermatoses. With an equivocal flow cytometry result, it is important to be able to identify whether a clonal population exists in the peripheral blood and whether it matches with that in the skin, which is more suggestive of a diagnosis of some form of cutaneous T-cell lymphoma. A newer modality, high throughput sequencing of the T-cell receptor (HTS), may enhance diagnostic specificity and sensitivity aiding in a more accurate initial diagnosis and in the assessment of disease progression and minimal residual disease activity.

Radiologic studies:

Radiologic evaluation is not always necessary in patients, especially those with early stage disease. In patients with early stage disease including Stage IA or patients with limited T2 skin disease and lack of lymphadenopathy or blood involvement, a CXR and/or ultrasound of peripheral nodal basins can be performed though may be of low yield. In more advanced stage patients, CT scan of the chest, abdomen, and pelvis +/- FDG-PET are recommended for further evaluation.

Lymph Node Evaluation:

Any lymph node that is 1.5 cm or greater in size, and/or is fixed, firm, or irregular would be considered suspicious for lymphoma and an excisional biopsy (preferred for staging) vs core biopsy would be of diagnostic value.

Once all the diagnostic data are obtained, comprehensive staging is possible. Since staging of the disease is constantly modified, please see the National Comprehensive Cancer Network ((NCCN) website (www.nccn.org/professionals/physician_gls/f_guidelines.asp) under guidelines for Non Hodgkins Lymphoma for the most up-to-date staging data.

  • Diagnosis confirmation

In early-stage disease, the histopathologic diagnosis of MF may be very difficult, as it can appear similar to benign dermatoses such as psoriasis and chronic contact dermatitis or eczema. As a result, clinical correlation and repeated follow-up biopsies are crucial.

Differentiation of SS from non-neoplastic erythrodermas is at times very difficult. The differential includes atopic dermatitis, psoriasis, drug reactions and pityriasis rubra pilaris (PRP) among many others. Identification of a clonal T-cell population in the blood allows for differentiation of SS from other benign forms of erythroderma. Performing peripheral blood flow cytometry is critical as an expanded population of phenotypically abnormal T-cells can be found in more than 80% of patients with SS, whereas this finding is quite unusual in the other disorders.

It can be difficult to clinically differentiate between tumor stage MF and anaplastic large cell lymphoma (ALCL) as both can be CD30+. Typically, ALCL is associated with the new onset of a limited number of tumor nodules (often single lesions or several). It is also quite unusual for MF tumors to spontaneously regress whereas this can occur in a small percentage of cases of ALCL.

Accurate diagnosis is important given the risk of disease progression of CTCL when immunosuppressive medications are used for a presumed different diagnosis.

Who is at Risk for Developing this Disease?

Mycosis fungoides (MF) is the most common type of CTCL. It generally presents in older adults (median age 55-60), however it may also occur in children and adolescents and has a male predominance. It has an Incidence rate of 6.4-9.6/1,000,000 persons. While the incidence is increasing, it is unclear how much of that increase is due to more accurate diagnosis.

MF accounts for approximately 1% of all non-Hodgkin's lymphomas. SS accounts for about 10% of cases of CTCL. A subset of patients diagnosed with LyP have an increased risk of developing a secondary lymphoproliferative disorder including MF.

What is the Cause of the Disease?

  • Etiology

The exact etiology of MF/SS remains unknown though it is thought that chronic antigenic stimulation may lead to uncontrolled clonal expansion of T-cell helper memory cells in the skin. Some patients may have a genetic predisposition: there are rare cases of familial occurrence. An environmental factor is not necessarily thought to play a role, given that the development of MF in unrelated married individuals is rare. However, in view of the rising incidence and cluster areas of occurrence, environmental factors should be sought. Immunosuppression may also predispose patients to developing CTCL.

The role of cytomegalovirus (CMV), Epstein-Barr virus (EBV), HHV-8 and Borrelia burgdorferi have been suggested, but not confirmed. HTLV-1/2, the cause of adult T-cell leukemia/lymphoma, produces a clinical condition that mimics mycosis fungoides and Sezary syndrome. HTLV-1/2 are endemic in southern Japan, the Caribbean islands, and part of the Middle East. In rare patients, the same T-cell clone has been detected in those who have second lymphomas questioning a common origin of disease.

  • Pathophysiology

Skin-homing: MF cells express cutaneous lymphocyte antigen (CLA), the ligand for E-selectin, which is expressed on endothelial cells in the setting of an inflammatory process. Skin associated chemokines such as CC-chemokine ligands 17 and 22 help facilitate skin-trafficking.

Epidermotropic: The chemokine receptor CCR4 is increased on MF cells. CCL 17, produced in the epidermis, is a critical ligand for CCR4 leading to recruitment of cells into the epidermis.

Increased Th2 environment: The malignant CD4+ T-cells produce Th2 cytokines. This results in decreased Th1 helper T-cell function, reduced delayed-type hypersensitivity, elevated IgE and eosinophilia, with increased levels of IL-4 and IL-5. Activated T-cells also produce IL-10, IL-13 and TGF-beta which can inhibit cell-mediated immunity. In SS, the transcription factors important for a Th2 environment such as GATA-3 and JUNB are overexpressed. Patients also have a defect in Th1 cytokine production with decreased levels of IL-12, IFN-alpha, and IFN-gamma. IL-13 may serve as an autocrine and paracine growth factor for the malignant T-cells.

Activated malignant T-cells: They express several activation markers including CD45RO, proliferating-cell nuclear antigen, and CD25. They fail to express CD40L upon engagement of the TCR resulting in a reduction of dendritic cell (DC) activation and cytokine production.

Clonal dominance: Chromosomal rearrangment hotspots have been detected that may allow for a clonal population to emerge (deletions on 1p, 17p, 10q, and 19 and gains at 4q, 18, and 17q).

Defective apoptosis: Early patch and plaque stage MF lesions, as well as circulating malignant T-cells may show defects in Fas expression or constitutive STAT 3 or 5 activation. Tumors have been shown to have p-53 expression defects, microsatellite instability, and p16/p15 alterations. Amplification of JUNB has been noted which plays a role in T-cell proliferation, differentiation and apoptosis.

Decreased normal lymphocyte populations: As the disease progresses, the levels of cytotoxic CD8+ T-cells, CD56+ NK cells, and myeloid and plasmacytoid dendritic cells decrease. In addition, it is thought that MF/SS patients have a reduction in their T-cell receptor repertoire/complexity.

Molecular changes: Patients with CTCL may have distinct microRNA changes allowing them to be differentiated from benign dermatoses with >90% accuracy (miRNAs 155. 203, 205, 326, 663, and 711). Programmed death 1 (PD1) is expressed on neoplastic cells in Sezary syndrome and may decrease with appropriate treatment.

In summary, Sezary syndrome is characterized by certain immunologic findings. There are increased levels of CD4+/CCR4+/CD26- T-cells. There is a systemic increase in IL-4, IL-5 and IL-10 levels, which leads to an increase in peripheral eosinophilia and elevated IgE levels. Sezary syndrome is also associated with a decrease in CD8+ T-cells, dendritic cells, and CD56+NK cells. A decrease in systemic levels of IL-12, IFN-alpha, and INF-gamma leads to a decrease in cell mediated cytotoxicity.

Systemic Implications and Complications

  • Extracutaneous Disease

The most frequent sites of extracutaneous involvement are the lymph nodes, lung, spleen, and liver. Other than focal involvement in advanced disease, the bone marrow is usually spared. SS may be associated with involvement of any organ, including the central nervous system (CNS). Microscopic involvement may occur early, prior to overt disease. Thus, CNS and other organ involvement may be subtle at its earliest involvement. Please refer to patient management section for appropriate work-up of extracutaneous disease.

  • Complications

Since these patients can have extensive breakdown of their skin, they are at higher risk for infection. In addition, they may be immune deficient due to both their disease and medications. As a result, septicemia and/or pneumonia are common causes of death. Patients with erythroderma are often carriers of Staphylococcus aureus with a high rate of infection with MRSA.

In SS, involvement of the bone marrow, other than focally, is rare in early stages, but may be found in later stages.

Patients with MF/SS are at increased risk of developing a secondary malignancy including non-melanoma skin cancers, melanoma, colonic carcinoma and second lymphoproliferative disorders. Because of the endogenous immune suppression associated with SS, these patients may be at greater risk for more rapid dissemination of a second malignancy.

  • Associated Systemic Disorders

MF can be associated with other hematologic disorders such as lymphomatoid papulosis (LyP), CD30+ anaplastic large cell lymphoma (ALCL), and Hodgkins Lymphoma and other B-cell lymphomas. Their onset may or may not coincide with the diagnosis of MF or SS. Rarely, the same clone may be identified in MF and an associated T-cell lymphoproliferative process.

  • Prognosis

Patients with limited T1 stage have a life expectancy similar to that of the general population.

All patients with MF/SS have a risk of disease progression (RDP) of 34%. The risk increases with advancing stage of disease. For example, patients with stage IIIA disease without peripheral Sezary cells (B0a) have a lower risk of disease progression than those with stage IIIB disease with peripheral blood involvement (B1).

Predictors of reduced survival and increased RDP:

  • Advanced skin (T) stage: the presence of plaques has a worse prognosis than patches (T2b vs T2a); those with thick plaques have a worse prognosis than those with thin

  • Overall clinical stage: patients with N1 nodes have poorer survival in comparison to those with N0; patients with stage Nx have a greater relative risk of death stressing the importance of lymph node biopsies for those with palpable or radiologically enlarged nodes

  • Increased age

  • Male sex

  • Level of peripheral blood tumor burden

  • Presence of a T-cell clone in the peripheral blood in patients with B0 disease

  • Increased lactate dehydrogenase (LDH)

  • Folliculotropic MF: these patients may have a resistance to skin-directed therapy or a differing underlying biology

  • Large cell transformation: has more significance for disease progression

  • Beta-2-microglobulin levels

Predictors of improved survival and decreased RDP:

  • Hypopigmented MF

  • MF with LyP

  • Poiklodermatous MF

  • Earlier stage, particularly IA

  • In the setting of a malignant CD4 phenotype, many CD8+ T-cells in the cutaneous infiltrate

Treatment Options

Treatment options are summarized in Table I, Table II, and Table III.

Table I.

Skin-directed treatment with common side effects
Therapy Common Side Effects
Topical corticosteroids Atrophy
Topical chemotherapy (Nitrogen Mustard, Carmustine) Allergic contact and irritant contact dermatitis
Local radiation Acute dermatitis, chronic radiodermatitis
Topical retinoids (Bexarotene, Tazarotene) Irritation
Phototherapy (UVB, PUVA) Increased risk of squamous cell and basal cell carcinoma. Likely increased risk of melanoma
Topical Imiquimod Irritation
Total skin electron beam (TSEB) Irritant dermatitis

Table II.

Systemic treatment options with important side effects
Therapy Common side effects
Retinoids (Bexarotene, ATRA, Isotretinoin) Hypothyroidism with bexarotene, hypertriglyceridemia, dryness, teratogenic
Interferons (IFN-alpha, IFN-gamma) Depression, fatigue, flu-like symptoms
HDAC-inhibitors (Vorinostat, Romidepsin) Pulmonary embolism -rare
Extracorporeal photopheresis Well tolerated, transient hypotension, low grade fever
Denileukin difitox Pulmonary leak syndrome
Methotrexate Liver damage, anemia, pulmonary fibrosis
Chemotherapy (single or multi-agent) Numerous potential side effects dependent on specific agent
Bone marrow transplant Graft versus host disease, infection

Table III.

Commonly used combination therapies in the treatment of mycosis fungoides
Combination therapy
Phototherapy + Retinoid
Phototherapy + IFN
Phototherapy + Photopheresis
TSEB + Photopheresis
Retinoid + IFN
Bexarotene + denileukin diftitox
Photopheresis + Retinoid
Photopheresis + IFN
Photopheresis + Retinoid + IFN

Optimal Therapeutic Approach for this Disease

General guidelines

Treatment recommendations vary depending on the stage of disease (Table VII). Therefore, it is important to perform a comprehensive clinical history, physical examination, and appropriate laboratory studies to determine the accurate staging for a patient. When possible, preservation of the immune response should occur. For other than stage IA, combination therapy, consisting of both skin-directed and systemic therapy (preferably immune potentiating therapy) may lead to a more rapid and more sustained clinical responses.

Should patients have more advanced disease that is progressing rapidly, then consideration should be given to the use of therapeutics which can initially rapidly debulk the patient's disease. A return to immune modulatory therapy should be undertaken whenever possible, although those with profound immune suppression may no longer respond to immune manipulation.

Comprehensive treatment options are given in Table IV-Table X.

Table IV.

Mycosis fungoides therapeutic options based on stage of disease, including common side effects
  Stage First-Line Therapy Common Side Effects Second-Line Therapy Common Side Effects
IA, IB, IIA Expectant therapy (for stage IA)   Bexarotene Hypothyroidism, hypertriglyceridemia, teratogenic
  PUVA Burning, NMSC, PUVA lentigines Interferon alpha Depression, flu-like symptoms
  UVB Burning, NMSC (nonmelanoma skin cancer) Interferon alpha + retinoids *
  Topical corticosteroids Skin atrophy Denileukin diftitox Pulmonary leak syndrome
  Localized radiation therapy Irritant dermatitis, chronic radiation dermatitis Low-dose methotrexate Liver cirrhosis, anemia, pulmonary fibrosis, increased risk of infection
  Topical retinoids Irritation Interferon alpha + PUVA *
  Topical nitrogen mustard Irritant and allergic contact dermatitis Retinoids + PUVA *
  Topical carmustine Irritant and allergic contact dermatitis Bexarotene + PUVA *
  Imiquimod Irritation    
IIB PUVA + Interferon alpha * BexaroteneBexarotene + Interferon alpha or gamma *
  TSEB and superficial X-irradiation * Denileukin diftitox +Romidepsin *
  PUVA + Bexarotene or Isotretinoin * Chemotherapy Numerous potential side effects dependent on specific agent
III PUVA + Interferon alpha * Bexarotene Hypothyroidism, hypertriglyceredemia, teratogenic
  Interferon alpha Depression, flu like symptoms Chemotherapy Numerous potential side effects dependent on specific agent
  Methotrexate Liver damage, anemia, pulmonary fibrosis Vorinostat Pulmonary embolism
  TSEB Irritant dermatitis, chronic radiation dermatitis Romidepsin Altered electrolytes, cardiac conduction defects, infections, anemia
  Nitrogen mustard Irritant and allergic contact dermatitis Alemtuzumab Severe infections
  Photopheresis Well tolerated, transient hypotension, low grade fever Photopheresis + Interferon alpha *
  PUVA + bexarotene or isotretinoin * Photopheresis + Interferon gamma *
IV TSEB and/or X-irradiation * Allogeneic stem cell transplant GVHD, Infection
  Bexarotene Hypothyroidism, hypertriglyceredemia, teratogenic Interferon alpha or gamma + bexarotene *
  Denileukin diftitox Pulmonary leak syndrome Interferon + photopheresis + bexarotene *
  Chemotherapy Numerous potential side effects dependent on specific agent    
  Interferon alpha Depression, flu like symptoms    
  Alemtuzumab Severe infections    
  Low to moderate dose Methotrexate Liver cirrhosis, anemia, pulmonary fibrosis, increased risk of infection    

Table X.

Various second- and third-line therapies for Sézary syndrome, including common side effects
Systemic therapies   Common Side Effects
  Alemtuzumab Severe infections
  Chlorambucil + corticosteroid Anemia, leukopenia, infection, infertility + Corticosteroid side effects
  Liposomal doxorubicin Infection, anemia, bleeding
  HDAC inhibitors (vorinostat, romidepsin) Infection, anemia, leukopenia, pulmonary embolism
  Gemcitabine Anemia, leukopenia, flu-like symptoms
  Deoxycoformycin Infection, potential to induce secondary cancers
  High-dose methotrexate (>100 mg/week) Chemical hepatitis, renal insufficiency, anemia, leukopenia
  Fludarabine +/- cyclophosphamide *
  Mechlorethamine Infection, extravasation reactions, anemia, loss of fertility
  Consider allogeneic transplantation as appropriate GVHD
  Clinical trial  

Topical corticosteroids

  • Indication: May result in remission in T1 disease or provide symptomatic relief in more advanced stages

  • Use: Apply to affected areas 1-2x/daily (clobetasol 0.05% ointment) or apply as a soak and smear (triamcinolone 0.1% ointment), 1-2.5% hydrocortisone for the face or intertriginous areas

  • Side effects: Increased atrophy, and depending on percentage of BSA applied, may result in temporary and reversible suppression of the hypothalamic-pituitary axis.

Topical nitrogen mustard (NM) 0.01-0.04%

  • Indication: For patients with patch/plaque disease or erythroderma

  • Pharmacologic category: Alkylating agent (completely metabolized in the skin)

  • Use: Apply this topical chemotherapeutic daily (sparing the axilla and groin, and will wash off after 8 hours) until complete clearing occurs. It is recommended to continue application 2-3 months after the last active lesion resolves. Some patients may relapse after discontinuation, so some physicians will opt to continue maintenance therapy with applications on a weekly, or monthly basis. For highly localized lesions, the local application is recommended by some (as opposed to total skin application from the neck down).

  • Side effects: Cutaneous intolerance and an allergic contact dermatitis occurs in about 20%. There is a concern, unproven, that it may lead to an increase in non-melanoma skin cancers. Small amounts absorbed through the skin are rapidly catabolized.

Topical carmustine (BICNU) 0.03-0.04%

  • Indication: Patients with patch/plaque disease or erythroderma. It is a good alternative to nitrogen mustard.

  • Pharmacologic category: Nitrosourea

  • Use: Application and length of therapy are similar to NM. Avoid application to the face given potential adverse cosmetic effects

  • Side effects: Bone marrow suppression may occur in less than 10% of patients (usually only with high-strength aqueous solution), permanent and severe telangiectasias, skin irritation

  • Monitoring: Regular CBC to monitor for bone marrow suppression

Bexatorine (Targetrin Gel or Tazarotene cream or gel)

  • Indication: Patients with early stage disease and localized lesions

  • Use: Apply a thin film daily to affected areas. Not to exceed >20% of BSA

  • Side effects: Limited to the site of application with burning, stinging, erythema or photosensitivity. Contraindicated in pregnant women.

Imiquimod 5% cream (Aldara)

  • Indication: Patients with localized patch or plaque disease

  • Pharmacologic category: Toll-like receptor 7 agonist

  • Use: Apply three to seven times a week to affected areas

  • Side effects: Hypersensitivity, irritation (some irritation is desirable as it reflects the local activation of the immune response)

Narrow band UVB (nbUVB)

  • Indication: Patients with patch-stage disease given its limited extent of penetration

  • Use: Present two to three times a week until observe a clinical response, then slowly taper after patient clears. It is better tolerated than broadband therapy. It tends to have a lower risk of carcinogenesis than PUVA but relapses are more frequent after nbUVB.

  • Effective maintenance requires at least every other week exposure.

  • Side effects: Sunburn, use with caution in patients with fair skin or strong history of both melanoma and nonmelanoma skin cancers; attempt to avoid burning

PUVA

  • Indication: Patients with plaque-stage disease because of its deeper penetration. Used carefully, it may also have benefit for erythrodermic patients.

  • Use: Present two to three times a week until lesions clear then slowly taper. Patients may frequently relapse after discontinuation, therefore monthly maintenance therapy may be beneficial. Side effects: nausea and abdominal discomfort with ingestion of psoralen, and increased sensitivity to light. PUVA therapy is associated with an increased risk of nonmelanoma and melanoma skin cancer (should be used with caution in patients with strong personal history of melanoma or non-melanoma skin cancer). Attempt to avoid burning.

Localized radiation therapy

  • Indication: Palliation of individual lesions (MF cells are radiosensitive and can be killed with low doses of radiation with more superficial penetration) - patients will need referral to radiation oncology

  • Use: Doses range from 10-30Gy for each treatment field; low dose 4Gy X 2 can be very effective for most individual skin lesions

  • Side effects: burn, dermatitis, radiation recall

Total skin electron beam

  • Indication: Palliation with the hopes of achieving a durable response - patients will need referral to radiation oncology

  • Use: Dose ranges from 12-36 Gy. Low dose (12 Gy) is well-tolerated and can be repeated multiple times, but relapses occur more rapidly in comparison to high-dose (36 Gy). Usually high-dose TSEB is not performed more than twice for any given patient.

  • Side effects: Alopecia, nail stasis (absent growth), nail dystrophy, edema of hands and feet, generalized hyperpigmentation, radiation recall, fatigue, aging of skin

Oral bexarotene (Targetrin)

  • Indication: Patients with advanced stage MF and SS, or refractory early stage

  • Pharmacologic category: Retinoid RXR receptor agonist

  • Use: The manufacturer's recommended dosing is 300mg/m2/day. Due to the significant hyperlipidemia that occurs, lower doses are recommended by many treating physicians depending upon the cardiovascular risk profile. For patients who show a response, treatment is usually continued indefinitely unless patients become intolerant to the side effects or eventually progress. Among non-responders or progressers, consideration can be given to adding another treatment (such as phototherapy or interferon) before abandoning bexarotene.

  • Side effects: severe central hypothyroidism with suppression of TSH and hyperlipidemia. As a result, Bexarotene should be used with caution in patients with a significant cardiovascular history or pre-existing hyperlipidemia with the concern that the resulting or worsening hyperlipidemia may exacerbate their underlying condition. Typically, a statin, if tolerated, and levothyroxine are co-administered with Bexarotene. Fish oil, fenofibrate and niacin are other lipid lowering agents which may be used together with or instead of statins to control lipids.

  • Monitoring: Baseline and monthly or bimonthly CBC, serum Free T4 and lipid profile. Patients may require additional medications including levothyroxine and a lipid lowering agent. Gemfibrozil is contraindicated because it can increase plasma concentrations of Bexarotene due to inhibition of P450 3A4. Bexarotene may rarely be associated with cholestatic jaundice. There is a risk of pancreatitis if severe hyperlipidemia occurs.

  • Lower doses of Bexarotene may be used in combination therapy with interferons, photopheresis or phototherapy in an effort to reduce the adverse effect of hyperlipidemia. Combination therapy may lead to more rapid clinical responses.

Retinoids (ATRA and isotretinoin)

  • Indication: Patients who are intolerant to bexarotene and cannot undergo more intensive therapeutic regimens

  • Pharmacologic category: Retinoid RAR receptor agonists

  • Use: For ATRA (all-trans retinoic acid) the starting doses are 10-20 mg/day and for isotretinoin they are 0.5/mg/kg/day

  • Side effects: teratogenic, therefore they should be used with caution for young women of child bearing potential.

  • Monitoring: Urine pregnancy test, CBC and CMP upon initiation of medication and serial lipid and CMP profiles on a monthly basis along with pregnancy testing

Denileukin diftitox (Ontak)

  • Indication: Patients with advanced stage MF or SS

  • Pharmacologic category: Fusion protein comprised of diptheria toxin fragments and IL-2. This drug demonstrates the greatest benefit in patients whose malignant cells have increased expression of the high-affinity IL2Receptor (CD25 positivity).

  • Use: Administered via IV for four to five consecutive days at 9 or 18 mcg/kg/day with 2 weeks rest in between for as long as patient responds.

  • Side effects: One-quarter of patients in trials developed a vascular leak syndrome (2 or more of hypotension, edema or hypoalbuminemia). As a result, it should be avoided in patients with poorly controlled hypertension, heart failure, or impaired renal or hepatic function. Tachycardia, chest pain, headache, pain, nervousness, dizziness, hypocalcemia, and weight loss may occur. Severe fatigue can occur after the first cycle. Transient inhibition of hepatic production of albumin can lead to severe edema and orthostatic hypotension.

  • Monitoring: Regular CBC, CMP including LFTs and albumin

  • Once tolerated, combination therapy with Bexarotene and/or interferon may be beneficial.

Interferon (IFN)-alpha (Intron A Recombinant) (PegIntron or Pegasys Pegylated)(Alferon [consensus interferon]

  • Indication: As a second-line therapy in patients with stage IA and IB disease and a first-line therapy for those with more advanced stages

  • Pharmacologic category: Biologic response modifier/Immune potentiator

  • Use: Average treatment dose is 3 million units (miu) three times per week of the recombinant or 0.5 to 1.5micrograms/kg of pegylated once weekly. Administration is continued until complete response is observed. Patients may also benefit from continued biweekly administration to prevent relapse or progression. If a patient does not respond in 6 months, consider using a multimodality approach with addition of PUVA or Bexarotene or photopheresis if leukemic. Interferon plus methotrexate may also be considered for refractory patients.

  • Side effects: Elevated transaminases, leukopenia, thrombocytopenia, depression, and suicidal ideation, neuropathy, cognitive difficulties in the elderly. Patients also typically experience a flu-like syndrome upon initial administration of the medication which diminishes in intensity with continued use. It is recommended that without other contraindications, they should take acetominophen with their injection dose. Avoid in patients who have anaphylactic sensitivity to mouse immunoglobulin (IgG), egg protein, or neomycin. It can also rarely induce autoimmune hepatitis or thyroiditis or aggravate other autoimmune conditions.

  • Monitoring: Regular CBC, CMP including LFTs

Interferon (IFN)-gamma (Actimmune)

  • Indication: As a second-line therapy in patients with stage IA and IB disease and a first-line therapy for those with more advanced stages. IFN-gamma is not FDA approved (but recommended among the NCCN Guidelines for advanced disease) for use in patients with CTCL, therefore, IFN-alpha is generally offered first.

  • Pharmacologic category: Biologic response modifier/Immune potentiator

  • Use: Average treatment dose of 1-2 milion units (miu) three times per week. Administration is continued until complete response is observed. Patients may also benefit from continued biweekly administration. If a patient does not respond in 6 months, to consider stopping or using a multimodality approach with addition of PUVA or Bexarotene or both or photopheresis if leukemic. In advanced disease, may be used together with interferon alpha as well as Bexarotene and/or photopheresis.

  • Side effects: Flu-like symptoms, leukopenia, elevated liver enzymes, mild anemia (interferon gamma appears to be better tolerated than interferon alpha in the elderly population with fewer cognitive effects and less frequent neuropathy or autoimmunity; however, it should not be used in patients with multiple sclerosis)

  • Monitoring: Regular CBC, CMP including LFTs

Methotrexate

  • Indication: Patients with early stage disease as a second line agent or more advanced disease as a first line agent

  • Pharmacologic category: Dihydrofolate reductase inhibitor

  • Use: 5-40 mg/week

  • Side effects: Can have toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems, including cytopenias and liver disease. It should not be used in patients with underlying liver disease or alcohol use.

  • Monitoring: CBC counts monthly and liver and renal function every 1-3 months during therapy or whenever dose changes are made.

Vorinostat

  • Indication: Patients with more advanced disease as a second line agent

  • Pharmacologic category: HDAC inhibitor

  • Use: Dose at 400 mg daily if patient can tolerate. If dose reductions are necessary, may decrease to 300 mg daily or 300 mg for 5 days out of each week

  • Side effects: Nausea, vomiting, diarrhea, abdominal discomfort, anorexia, weight loss, dose-related thrombocytopenia and anemia (reversible upon decrease in dose or discontinuation), and elevated creatinine (reversible upon decrease in dose or discontinuation)

  • Monitoring: Regular CBC and CMP

  • May be used in combination with interferons gamma or alpha and photopheresis

Romidepsin

  • Indication:Patients with more advanced disease as a first or second line agent

  • Pharmacologic category: HDAC inhibitor

  • Use: Dose of 14 mg/M squared infused over 4 hours once weekly for three weeks then skip one week. May continue as long as patient responds

  • Side effects: Nausea, gastrointestinal distress, anorexia, thrombocytopenia. Use cautiously in those with long Q-T.

  • May be used in combination with interferons

Alemtuzumab (Campath)

  • Indication: Patients with advanced stage MF or more often SS - patients will need referral to oncology

  • Pharmacologic category: Monoclonal antibody against CD52 (an antigen found on B-cells, T-cells, monocytic cells)

  • Use: Administer 3-10 mg IV over 2 h initially; titrate slowly to 15 mg as tolerated and administer three times/week for up to 12 weeks if no adverse effects

  • Side effects: pancytopenia, thrombocytopenia, autoimmune hemolytic anemia, and serious infusion reactions. Fatal bacterial, viral, fungal, and protozoan infections have been reported.

  • Administer with prophylaxis against bacterial, fungal and Herpes viral infections

  • Low doses (10-15 mg subcutaneously may be associated with a lower infection rate)

  • Monitoring: Regular CBC, CMP with LFTs, and CMV quantification

Chemotherapy

  • Patients will need referral to oncology

  • May use single agent including Gemcitabine, Liposomal Doxorubicin, Moderate dose methotrexate or multidrug combinations of CHOP, HyperCVAD, or others.

Table V. Therapeutic options for mycosis fungoides, including common side effects.

Table V.

Therapeutic options for mycosis fungoides, including common side effects
Treatment Notes Common Side Effects
First-Line    
PUVA For patch/plaque disease. Treat 2-3x/week. Can be combined with retinoids/rexinoids or interferon. Burning, PUVA lentigines, increased NMSC
UVB For patch disease. Treat 2-3x/week. Burning, increased NMSC
Topical corticosteroids For early disease or symptomatic relief. Atrophy
Topical bexarotene For limited disease sites. Especially useful so as not to overuse topical steroids. Irritant dermatitis
Topical Nitrogen mustard Spot therapy for limited disease, or full body application for extensive involvement. Irritant and Allergic contact dermatits
Topical carmustine Can try if patients develop allergic reaction to NM. Irritant and Allergic contact dermatits
Localized radiotherapy For limited number of lesions, including thickened plaques, tumors. Irritant dermatitis, chronic radiation dermatitis
TSEB For patients with Stage IB or IIA disease with progression or refractory disease Irritant dermatitis, chronic radiation dermatitis
Second-Line    
Oral bexarotene Can be combined with multiple other modalities to achieve a response Hypothyroidism, hypertriglyceridemia, teratogenic
IFN-alpha Can be combined with PUVA, retinoids, or bexarotene Depression, flu like symptoms
Low-dose methotrexate Can be combined with steroids, ECP, PUVA and IFN-alpha Liver damage, anemia, pulmonary fibrosis
Vorinostat Can be combined with PUVA, IFN-alpha or IFN-gamma Pulmonary embolism
Denileukin diftitox It is usually considered after a trial of Bexarotene and/or Vorinostat Pulmonary leak syndrome

Patients with folliculotropic MF may be less responsive to the traditional skin directed therapies given evidence of a deeper infiltrate. PUVA combined with retinoids (isotretinoin preferably) and Interferon gamma may be successful. TSEB may also result in clearing of cutaneous disease, however, sustained remissions are rare and continued systemic therapy with an interferon and/or isotretinoin is recommended. Topical carmustine appears to be more effective than topical nitrogen mustard for FMF.

Table VI. Stage IIB therapeutic options, including common side effects

Table VI.

Stage IIB therapeutic options, including common side effects
Treatment Notes Common Side Effects
First-Line    
IFN-alpha Can be combined with PUVA, retinoids, Bexarotene, and Methotrexate Depression, flu like symptoms
TSEB and superficial radiation To help clear thickened plaques/tumors Irritant dermatitis, chronic radiation dermatitis
PUVA Can be combined with Retinoids, Bexarotene, or IFN-alpha Burning, PUVA lentigines, Increased NMSC
Second-Line    
Bexarotene Can be combined with multiple other modalities to achieve a response Hypothyroidism, Hypertriglyceridemia, teratogenic
Vorinostat Can be combined with PUVA, IFN-alpha, or IFN-gamma Pulmonary embolism
Denileukin Diftitox It is usually considered after a trial of Bexarotene and/or Vorinostat Pulmonary leak syndrome
Novel agents Consider novel clinical trial agents before initiation of chemotherapy Numerous potential side effects dependent on specific agent
Chemotherapy This is considered a last resort unless rapid progression. Transplantation may be considered in certain patients. Numerous potential side effects dependent on specific agent

Table VII. Therapeutic options for Sezary syndrome along with Stage III disease, including common side effects

Table VII.

Therapeutic options for Sezary syndrome along with Stage III disease, including common side effects
Treatment Notes Common Side Effects
First-Line    
ECP Can be combined with oral steroids (short-term), IFN-alpha, IFN- gamma, Bexarotene, or low-dose Methotrexate Transient hypotension, fevers
IFN-alpha Can be combined with PUVA, Retinoids, Bexarotene and ECP Depression, Flu-like symptoms
PUVA + IFN-alpha For Stage III disease. Would not recommend PUVA alone *
Methotrexate Can be combined with steroids, ECP, PUVA and IFN-alpha Liver cirrhosis, anemia, pulmonary fibrosis, increased risk of incfection
Second-Line    
Bexarotene Can combine with ECP or IFN-alpha or IFN gamma Hypothyroidism, Hypertriglyceredemia, teratogenic
Vorinostat Can be combined with PUVA, IFN-alpha, or IFN gamma Pulmonary embolism
Denileukin Diftitox It is usually considered after a trial of Bexarotene and/or Vorinostat Pulmonary leak Syndrome
Alemtuzumab Monoclonal antibody against CD52 Severe infections
Novel agents Consider novel clinical trial agents before initiation of chemotherapy Numerous potential side effects dependent on specific agent
Chemotherapy This is considered a last resort. Allogeneic Transplantation may be considered in certain patients. Numerous potential side effects dependent on specific agent

Table VIII. Non-Sezary syndrome Stage IVA and IVB therapeutic options, including their common side effects

Table VIII.

Non-Sezary syndrome Stage IVA and IVB therapeutic options, including their common side effects
Treatment Notes Common Side Effects
Chemotherapy Allogeneic transplantation should be considered for patients after course of therapy Numerous potential side effects dependent on specific agent
TSEB and/or X-irradiation To help clear thickened plaques/tumors Irritant dermatitis, chronic radiation dermatitis
Bexarotene Can be combined with multiple other modalities to achieve a response Hypothyroidism, Hypertriglyceredemia, teratogenic
Denileukin Diftitox It is usually considered after a trial of Bexarotene and/or Vorinostat Pulmonary leak syndrome
IFN-alpha Can be combined with PUVA, retinoids, or bexarotene Depression, flu like symptoms
Alemtuzumab Monoclonal antibody against CD52 for leukemics Severe infections
Vorinostat Can be combined with PUVA, IFN-alpha, or IFN gamma Pulmonary embolism
Novel agents Consider novel clinical trial agents before initiation of chemotherapy Numerous potential side effects dependent on specific agent
Methotrexate Can be combined with steroids, ECP, PUVA and IFN-alpha or TSEB Liver cirrhosis, anemia, pulmonary fibrosis, increased risk of infection

Table IX. Initial therapeutic options for the treatment of Sezary syndrome, including common side effects

The clinician needs to be aware to use the disease burden and the rate of progression when determining therapy. Always try to preserve immune function by the use of immunomodulatory therapies before systemic chemotherapies. Multimodal therapies tend to always work better than monotherapy. Look for and treat staphylococcal infection to help prevent life threatening sepsis. Itching is often severe and can be a major cause of morbidity. Alway treat pruritus aggressively.

Table IX.

Initial therapeutic options for the treatment of Sezary syndrome, including common side effects
Systemic therapies (monotherapies)   Common Side Effects
  ECP Well tolerated, transient hypotension, low grade fever
  Interferon alfa Depression, Flu like symptoms
  Bexarotene Hypothyroidism, hypertriglyceredemia, teratogenic
  Low-dose methotrexate (< 100mg/week) Liver cirrhosis, anemia, pulmonary fibrosis, increased risk of incfection
  Denileukin diftitox (plus corticosteroid) Pulmonary leak syndrome
Combination therapies    
Systemic plus skin directed    
  Interferon alfa or gamma + PUVA or topical nitrogen mustard *
  Methotrexate (low dose) + topical nitrogen mustard *
  Bexarotene + PUVA *
  Immunomodulators (ECP, interferon alfa or gamma, bexarotene alone or in combination) + Total skin electron beam *
Systemic plus systemic    
  Interferon alpha + Bexarotene *
  ECP + other immunomodulators (bexarotene, interferon alfa, interferon gamma, low-dose methotrexate alone or in combination) *
  Methotrexate (low dose) + Interferon alfa *

Patient Management

If you are suspicious of a diagnosis of MF/SS, perform a confirmatory biopsy to send for routine microscopy with H+E and appropriate immunophenotyping.

Send blood for complete blood cell count, comprehensive metabolic panel including liver function tests, lactate dehydrogenase.

Patients who present with plaques, tumors, erythroderma or significant lymphadenopathy (>1.5cm), should be screened for extracutaneous involvement: Flow cytometry, PCR/TCR on the blood and skin to determine if there is a matching clone, CT of the chest, abdomen and pelvis with contrast or whole body PET/CT scan.

Bone marrow involvement is usually focal, therefore, biopsy is usually of low yield unless patients have evidence of significant blood or nodal disease.

Patients should return for follow-up every 2-3 months for a complete physical exam and appropriate laboratory studies according to their therapeutic regimen.

Unusual Clinical Scenarios to Consider in Patient Management

CD8+ CTCL:A small percentage of cases of MF or SS may be characterized by a CD8+ malignant phenotype. In these cases interferons, particularly interferon gamma, should be used with caution as they have the capacity to activate CD8+ T-cells. In the setting of a CD8+ lymphoma, serologies should be obtained for HTLV-1 and 2 and for HIV to rule out a retroviral cause of the lymphoma.

Multimodality therapy: Among patients with advanced MF or SS, the immune response should be preserved whenever possible and a multimodality approach should be pursued. Examples include treating SS patients with photopheresis in combination with an interferon and bexarotene. Occasionally, both interferon alpha and gamma may be used together to stimulate the immune response and to suppress the growth of the malignant population. Furthermore, one important property of interferon gamma is the ability of this cytokine to prime dendritic cells, thus, making it advantageous to use interferon gamma together with photopheresis leading to enhancement of the ability of antigen presenting cells to process the large numbers of apoptotic tumor cells that are generated from the photopheresis procedure.

Use of skin directed therapies along with systemic multimodality therapies is also encouraged. Thus, patients receiving photopheresis and interferon may also receive PUVA or total skin electron beam to enhance clearing of the skin. This approach may lead to more prolonged responses and remissions. If PUVA or TSEB will not be used, then topical chemotherapy may be employed along with systemic therapies in an effort to further debulk the skin of malignant T-cells.

Allogeneic stem cell transplantation: Patients with advanced stage CTCL should be introduced to the concept of allogeneic transplantation at the earliest possible time during their care. At the time of this writing it appears that the optimal candidates are those with SS who have not had bulky nodal disease or extensive tumor disease manifesting large cell transformation. Transplantation should be considered for those where it likely will not be possible to induce a long term remission with multimodality biologic therapies plus skin directed therapy. Disease burden should be minimal at the time of transplantation.

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