Clinical Presentation

Mycosis fungoides and Sézary syndrome are neoplasias of malignant T lymphocytes that usually possess the helper/inducer cell surface phenotype. These kinds of neoplasms initially present as skin involvement and, as such, have been classified as cutaneous T-cell lymphomas. Cutaneous T-cell lymphomas should be distinguished from other T-cell lymphomas that involve the skin, such as anaplastic large cell lymphoma (CD30 positive), peripheral T-cell lymphoma (CD30 negative, with no epidermal involvement), adult T-cell leukemia/lymphoma (usually with systemic involvement), or subcutaneous panniculitic T-cell lymphoma. These histologic types of T-cell lymphomas are discussed in Peripheral T-Cell Non-Hodgkin Lymphoma Treatment.

Typically, the natural history of mycosis fungoides is indolent. Symptoms of the disease may present for long periods, in a range of 2 to 10 years, because cutaneous eruptions wax and wane before they receive a biopsy confirmation. Mycosis fungoides and Sézary syndrome are treatable with available topical therapy, systemic therapy, or both. To date, curative modalities have proven elusive, with the possible exception of patients with minimal disease confined to the skin.

In addition, several benign or indolent conditions can be confused with mycosis fungoides. Consultation with a pathologist who has expertise in distinguishing these conditions is important.

Prognosis and Survival

The prognosis of patients with mycosis fungoides and Sézary syndrome is based on the extent of disease (stage) at presentation. The presence of lymphadenopathy and involvement of peripheral blood and viscera increase in likelihood with worsening cutaneous involvement and define poor prognostic groups. The Cutaneous Lymphoma International Consortium retrospectively reviewed 1,275 patients and found the following four independent prognostic markers indicate a worse survival:

• Stage IV disease.
• Age older than 60 years.
• Large cell transformation.
• Elevated lactate dehydrogenase.

The median survival following diagnosis varies according to stage. Patients with stage IA disease have a median survival of 20 years or more. Most deaths for this group are not caused by, nor are they related to, mycosis fungoides. In contrast, more than 50% of patients with stage III through stage IV disease die of mycosis fungoides, with a median survival of approximately 5 years. The Cutaneous Lymphoma International Prognostic index used male gender, age older than 60 years, plaques, lymph nodes, blood involvement, and visceral involvement as poor prognostic factors to define predicted overall survival (OS) and progression-free survival in both early-stage and advanced-stage groups.

A report on 1,798 patients from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program database found an increase in second malignancies (standardized incidence ratio, 1.32; 95% confidence interval , 1.15–1.52), especially for Hodgkin lymphoma, non-Hodgkin lymphoma, and myeloma. Another report on 4,459 patients from the SEER database found that the 19.2% of African American patients with mycosis fungoides have a shorter OS, potentially attributable to disease characteristics, socioeconomic status, and type of therapy (hazard ratio, 1.47; 95% CI, 1.25–1.74; P .001).

Cutaneous disease can manifest itself as an eczematous patch or plaque stage covering less than 10% of the body surface (T1), a plaque stage covering 10% or more of the body surface (T2), or as tumors (T3) that frequently undergo necrotic ulceration. Several retrospective studies showed that 20% of patients progress from stage I or II disease to stage III or IV disease. Sézary syndrome presents with generalized erythroderma (T4) and peripheral blood involvement. However, there is some disagreement about whether mycosis fungoides and Sézary syndrome are actually variants of the same disease. The same retrospective study with a median follow-up of 14.5 years found that only 3% of 1,422 patients progressed from mycosis fungoides to Sézary syndrome.

There is consensus that patients with Sézary syndrome (leukemic involvement) have a poor prognosis (median survival, 4 years), with or without the typical generalized erythroderma. Cytologic transformation from a low-grade lymphoma to a high-grade lymphoma (large cell transformation) occurs rarely (5%) during the course of these diseases and is associated with a poor prognosis. A retrospective analysis of 100 cases with large cell transformation found reduced disease-specific survival with extracutaneous transformation, increased extent of skin lesions, and CD30 negativity. A common cause of death during the tumor phase is septicemia caused by chronic skin infection with staph species, herpes simplex, herpes zoster, and fungal skin infections.

Folliculotropic mycosis fungoides is a variant of mycosis fungoides marked by folliculotropic, rather than epidermotropic, neoplastic infiltrates, with preferential location in the head and neck area. Early plaque-stage folliculotropic mycosis fungoides have a very indolent prognosis, while extracutaneous disease portends a very poor prognosis.

The histologic diagnosis of mycosis fungoides and Sézary syndrome is usually difficult to determine in the initial stages of the disease and may require the review of multiple biopsies by an experienced pathologist.

A definitive diagnosis from a skin biopsy requires the presence of mycosis fungoides and Sézary syndrome cells (convoluted lymphocytes), a band-like upper dermal infiltrate, and epidermal infiltrations with Pautrier abscesses (collections of neoplastic lymphocytes). A definitive diagnosis of Sézary syndrome may be made from a peripheral blood evaluation when skin biopsies are consistent with the diagnosis. Supportive evidence for circulating Sézary cells is provided by T-cell receptor gene analysis, identification of the atypical lymphocytes with hyperconvoluted or cerebriform nuclei, and flow cytometry with the characteristic deletion of cell surface markers such as CD7 and CD26. However, none of these is individually pathognomonic for lymphoma.

The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification to define mycosis fungoides. Peripheral blood involvement with mycosis fungoides or Sézary syndrome cells is correlated with more advanced skin stage, lymph node and visceral involvement, and shortened survival.

Mycosis fungoides and Sézary syndrome also have a formal staging system proposed by the International Society for Cutaneous Lymphomas (ISCL) and the European Organisation for Research and Treatment of Cancer (EORTC).

Table 1. Histopathologic Staging of Lymph Nodes in Mycosis Fungoides and Sézary Syndromea

Table 2. Definitions of TNM Stages IA and IBa

Table 3. Definitions of TNM Stages IIA and IIBa

Table 4. Definitions of TNM Stages III, IIIA, and IIIBa

Table 5. Definitions of TNM Stages IVA1, IVA2, and IVBa

Treatment options for patients with mycosis fungoides and Sézary syndrome include the following:

Photodynamic Therapy

1. Psoralen and ultraviolet A radiation (PUVA).
   • Therapeutic trials with PUVA have shown an 80% to 90% complete remission rate with early cutaneous stages achieving the best responses. PUVA may be used in conjunction with systemic treatment. Continued maintenance therapy with PUVA at more protracted intervals is generally required to prolong remission duration. PUVA combined with interferon alpha-2a is associated with a high response rate.
2. Narrowband ultraviolet B radiation.
   • Single-arm and retrospective comparisons confirm narrowband ultraviolet B with 80% to 90% complete remission rates, especially for patients with early cutaneous stages.
   • A Cochrane systematic review and meta-analysis compared PUVA with narrowband ultraviolet B radiation in 778 patients with early-stage mycosis fungoides (stage IA, IB, and IIA). Significantly higher complete responses were seen in patients treated with PUVA (73.8% versus 62.2%; HR, 1.68; 95% CI, 1.02–2.76; P = .04), with no significant differences in adverse effects.
3. Extracorporeal photophoresis (ECP) alone or in combination with total-skin electron-beam radiation (TSEB). ECP is particularly applicable for Sézary syndrome and erythrodermic mycosis fungoides.
   • In a retrospective analysis of 65 patients, with a median follow-up of 48 months, use of ECP in the first to third line of treatment yielded a longer median time-to-needing-treatment than other systemic options (P .03).

Radiation Therapy

1. TSEB.
   • Electron-beam radiation of appropriate energies will penetrate only to the dermis, and thus the skin alone can be treated without systemic effects. This therapy requires a radiation therapy facility with physics support and considerable technical expertise to deliver precise dosimetry. TSEB can result in short- and long-term cutaneous toxic effects and is not widely available.
   • This therapy can provide excellent palliation, with complete response rates of as much as 80%, and may be combined with systemic treatment. Based on the long-term survival of these early-stage patients, electron-beam radiation therapy is sometimes used with curative intent. Long-term disease-free survival (DFS) can be achieved in patients with unilesional mycosis fungoides treated with local radiation therapy.
2. Local electron-beam radiation or orthovoltage radiation therapy may be used to palliate areas of bulky or symptomatic skin disease.

Biologic Therapy

1. Interferon alpha or interferon gamma alone or in combination with topical therapy.
   • A retrospective review of 198 patients with mycosis fungoides and Sézary syndrome compared time to next treatment (TTNT) between interferon alpha and conventional chemotherapy. Interferon alpha provided a longer TTNT of 8.7 months (95% confidence interval , 6.0–18.0) than did chemotherapy, with a TTNT of 3.9 months (95% CI, 3.2–5.1) and P .00001.

Chemotherapy

1. Topical chemotherapy with mechlorethamine (nitrogen mustard).
   • This form of treatment may be used palliatively or to supplement therapeutic approaches directed against nodal or visceral disease. Topical application of mechlorethamine has produced regression of cutaneous lesions, with particular efficacy in early stages of disease. The overall complete remission rate is related to skin stage; 50% to 80% of TNM classification T1 patients, 25% to 75% of T2 patients, as many as 50% of T3 patients, and 20% to 40% of T4 patients have complete responses. The overall complete remission rate in 243 patients was 64% and was related to stage; as many as 35% of stage IV patients had complete responses. Treatments are usually continued for 2 to 3 years. Continuous 5-year DFS may be possible in as many as 33% of T1 patients.
2. Oral methotrexate (NCT00425555).
3. Pegylated liposomal doxorubicin.
4. Fludarabine, 2-chlorodeoxyadenosine, and pentostatin are active agents for mycosis fungoides and Sézary syndrome.
   • Chemotherapeutic agents generally demonstrate short durations of response. In a retrospective review of 198 patients with advanced-stage disease, the median time before patients required new therapy was 4 months. However, these comparisons may be confounded by the order in which the agents were introduced.
5. Single-agent chemotherapy or combination systemic chemotherapy (chlorambucil plus prednisone, mechlorethamine, cyclophosphamide, methotrexate, and combination chemotherapy) are often combined with treatment directed at the skin.
   • Chemotherapeutic agents generally demonstrate short durations of response. In a retrospective review of 198 patients with advanced-stage disease, the median time before patients required new therapy was 4 months. However, these comparisons may be confounded by the order in which the agents were introduced.
6. Pralatrexate (folate analog).
   • Chemotherapeutic agents generally demonstrate short durations of response. In a retrospective review of 198 patients with advanced-stage disease, the median time before patients required new therapy was 4 months.

Other Drug Therapy

1. Symptomatic management with topical corticosteroids. Low potency steroids can be used on the face with safety and efficacy.
2. Bexarotene, an oral or topical retinoid (NCT00255801).
3. Lenalidomide.
4. Vorinostat or romidepsin or other histone deacetylase inhibitors (HDACi).
   • A retrospective review of 198 patients with mycosis fungoides and Sézary syndrome compared TTNT between HDACi and conventional chemotherapy. HDACi provided a longer TTNT of 4.5 months (95% CI, 4.0–6.1) than did chemotherapy, with a TTNT of 3.9 months (95% CI, 3.2–5.1; P = .01).

Targeted Therapy

1. Brentuximab vedotin.
   • Two phase II trials of 58 patients with variable CD30 expression showed a 50% to 70% response rate with 50% of patients still in remission after 1 year.
2. Mogamulizumab.
   1. In a prospective randomized trial, 372 previously treated patients received either mogamulizumab, a monoclonal antibody directed against C-C chemokine receptor 4, or vorinostat, the HDACi.
      • With a median follow-up of 17 months, the median PFS favored mogamulizumab at 7.7 months versus 3.1 months for vorinostat (HR, 0.53; 95% CI, 0.41−0.69; P .0001).
      • In a preliminary study such as this, no overall survival (OS) was seen.

Transplantation

1. Allogeneic or autologous bone marrow transplantation.
   • Among these highly selected patients, the 5-year OS rate ranges from 30% to 50%, with a relapse-free survival rate of 15% to 25%.

Checkpoint Inhibitors

1. Pembrolizumab.
   • Anecdotal responses have been seen in patients with advanced relapsed or refractory mycosis fungoides. In a single-arm, multicenter, phase II trial of 24 patients treated with pembrolizumab, the overall response rate was 38%.

Anecdotal responses, some lasting for months, can be seen with aggressive antibiotic treatment of Staphylococcus aureus, with corresponding decreased expression of interleukin-2 receptors, STAT signaling, and T-cell proliferation.

These types of treatments produce remissions, but long-term remissions are uncommon. Treatment, therefore, is considered palliative for most patients, although major symptomatic improvement is regularly achieved. Survival in excess of 8 years, however, is common for patients with early stages of disease. All patients with mycosis fungoides and Sézary syndrome are candidates for clinical trials evaluating new approaches to treatment.

Because several forms of treatment can produce complete resolution of skin lesions in this stage, the choice of therapy is dependent on local expertise and the facilities available. With therapy, the survival of patients with stage IA disease can be expected to be the same as for age- and gender-matched controls.

There is no curative therapy and no clear difference in overall survival (OS) among the treatment options for patients with stage I and stage II mycosis fungoides.

A randomized study of 103 patients compared combined total-skin electron-beam radiation (TSEB) plus combination chemotherapy with sequential topical therapies. In the latter group, combination chemotherapy was reserved for symptomatic extracutaneous disease or for disease that was refractory to topical therapies. Patients with any disease stage were eligible. Although the complete response rate was higher with combined therapy, toxic effects were considerably greater, and no difference was seen in disease-free or OS between the two groups.

Treatment Options for Stage I and Stage II Mycosis Fungoides

Treatment options for stages I and II mycosis fungoides include the following:

1. Photodynamic therapy.
   • Psoralen and ultraviolet A (PUVA) radiation.
   • Narrowband ultraviolet B radiation.
2. Radiation therapy.
   • TSEB.
   • Local electron-beam radiation or orthovoltage radiation therapy may be used to palliate areas of bulky or symptomatic skin disease.
3. Biologic therapy.
   • Interferon alpha or interferon gamma alone or in combination with topical therapy.
4. Chemotherapy.
   • Topical chemotherapy with mechlorethamine (nitrogen mustard).
   • Oral methotrexate (NCT00425555).
   • Pegylated liposomal doxorubicin.
   • Fludarabine, 2-chlorodeoxyadenosine, and pentostatin are active agents for MF.
   • Single-agent chemotherapy or combination systemic chemotherapy (chlorambucil plus prednisone, mechlorethamine, cyclophosphamide, methotrexate, and combination chemotherapy) often combined with treatment directed at the skin.
   • Pralatrexate (folate analog).
5. Other drug therapy.
   • Symptomatic management with topical corticosteroids. Low potency steroids can be used on the face with safety and efficacy.
   • Bexarotene, an oral or topical retinoid (NCT00255801).
   • Lenalidomide.
   • Vorinostat or romidepsin or other histone deacetylase inhibitors.
6. Targeted therapy.
   • Brentuximab vedotin.

Mycosis Fungoides

There is no curative therapy and no clear difference in overall survival (OS) among the treatment options for patients with stage III and stage IV disease.

The use of single alkylating agents has produced objective responses in 60% of patients, with a duration of less than 6 months. One of the alkylating agents (e.g., mechlorethamine , cyclophosphamide, or chlorambucil), or the antimetabolite methotrexate is the most frequently used. Single agents have not been shown to cure any patients, and insufficient data exist to determine whether these agents prolong survival. Combination chemotherapy is not definitely superior to single agents. Even in stage IV disease, treatments directed at the skin may provide significant palliation.

A randomized study of 103 patients compared combined total-skin electron-beam radiation (TSEB) plus combination chemotherapy with conservation therapy consisting of sequential topical therapies. In the latter group, combination chemotherapy was reserved for symptomatic extracutaneous disease or for disease refractory to topical therapies. Patients with any stage were eligible. Although the complete response rate was higher with combined therapy, toxic effects were considerably greater, and no difference was seen in disease-free survival or OS between the two groups.

Sézary Syndrome

Sézary syndrome is a rare leukemic variant of cutaneous T-cell lymphoma characterized by erythroderma, circulating Sézary cells with cerebriform nuclei, lymphadenopathy, and pruritus. This condition typically progresses rapidly with only short duration of response to most therapies. A retrospective review of 176 patients with SS identified the following poor prognostic factors:

• High lactate dehydrogenase.
• Previous diagnosis of mycosis fungoides.
• Presence of T-cell receptor gene rearrangements in skin, blood, or both.

Remissions attained by using extracorporeal photophoresis, alpha interferon, or retinoids may be followed by allogeneic stem cell transplantation. In an anecdotal series of 16 patients with Sézary syndrome after allogeneic transplant, 9 were in complete remission after 4 years.

Treatment Options for Stage III and Stage IV Mycosis Fungoides (Including Sézary Syndrome)

Treatment options for stages III and IV mycosis fungoides and Sézary syndrome include the following (note that in this clinical setting, the skin is easily injured; any of the topical therapies must be administered with extreme caution):

1. Photodynamic therapy.
   • Psoralen and ultraviolet A (PUVA) radiation.
   • Narrowband ultraviolet B radiation.
   • Extracorporeal photophoresis (ECP) alone or in combination with TSEB. ECP is particularly applicable for Sézary syndrome and erythrodermic mycosis fungoides.
2. Radiation therapy.
   • TSEB.
   • Local electron-beam radiation or orthovoltage radiation therapy may be used to palliate areas of bulky or symptomatic disease.
3. Biologic therapy.
   • Interferon alpha alone or in combination with other agents, such as topical therapy.
4. Chemotherapy.
   • Oral methotrexate (NCT00425555).
   • Fludarabine, 2-chlorodeoxyadenosine, and pentostatin are active agents for mycosis fungoides and Sézary syndrome.
   • Single-agent chemotherapy or combination systemic chemotherapy (chlorambucil plus prednisone, mechlorethamine, cyclophosphamide, methotrexate, and combination chemotherapy) often combined with treatment directed at the skin.
   • Topical chemotherapy with mechlorethamine.
   • Pegylated liposomal doxorubicin.
   • Pralatrexate (folate analog).
5. Other drug therapy.
   • Symptomatic management with topical corticosteroids. Low potency steroids can be used on the face with safety and efficacy.
   • Lenalidomide.
   • Bexarotene, an oral or topical retinoid.
   • Vorinostat or romidepsin or other histone deacetylase inhibitors.
6. Targeted therapy.
   • Brentuximab vedotin.
7. Checkpoint inhibitors.
   • Pembrolizumab.

The treatment of relapsed patients with mycosis fungoides and Sézary syndrome who have cutaneous T-cell lymphomas involves the joint decisions of the dermatologist, medical oncologist, and radiation oncologist. It may be possible to re-treat localized areas of relapse in the skin with additional electron-beam radiation or possibly to repeat total-skin electron-beam radiation therapy (TSEB). Photon radiation to bulky skin or nodal masses may prove beneficial. If these options are not possible, then continued topical treatment with other modalities such as mechlorethamine or psoralen and ultraviolet A radiation (PUVA) may be warranted to relieve cutaneous symptoms.

Clinical trials, if possible, should be considered as the next therapeutic option.

Treatment Options for Recurrent Mycosis Fungoides (Including Sézary Syndrome)

Treatment options under clinical evaluation for recurrent mycosis fungoides and Sézary syndrome include the following:

1. Radiation therapy.
   • Additional electron-beam radiation or a repeat of TSEB.
   • Photon radiation to bulky skin or nodal masses.
2. Photodynamic therapy.
   • Topical treatment with mechlorethamine (nitrogen mustard) or PUVA.
   • PUVA combined with interferon alpha-2a is associated with a high response rate.
   • Narrowband ultraviolet B radiation.
   • Extracorporeal photophoresis has produced tumor regression in patients resistant to other therapies.
3. Chemotherapy.
   • Pralatrexate (folate analog).
   • Pegylated liposomal doxorubicin.
   • Systemic chemotherapy: chlorambucil plus prednisone, mechlorethamine, cyclophosphamide, methotrexate, and combination chemotherapy.
4. Other drug therapy.
   • Symptomatic management with topical corticosteroids.
   • Bexarotene, an oral or topical retinoid.
   • Lenalidomide.
   • Vorinostat or romidepsin or other histone deacetylase inhibitors.
5. Biologic therapy.
   • Interferon alpha alone or in combination with other agents, such as topical therapy.
6. Transplantation.
   • Allogeneic bone marrow or stem cell transplantation.
7. Targeted therapy.
   • Brentuximab vedotin.
   • Mogamulizumab.