Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL), a form of cancer that mainly affects the skin. It is a slow-growing cancer where abnormal T-lymphocytes, a type of white blood cell, build up in the skin. This causes specific skin rashes and, over time, may spread to other parts of the body. The name “mycosis fungoides” originally referred to the advanced stage of the disease, when the skin lesions looked like a fungal infection, but the condition actually includes a range of skin problems with different levels of severity and progression. CTCL is not just one disease, but a group of related conditions that all involve problems with T-cells, which are important for immune function.

Pathophysiology of Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphoma (CTCL) is a type of cancer where certain T-lymphocytes, a type of immune cell, grow out of control and invade the skin. Over time, these cancerous cells may spread to other parts of the body. T-cells normally help protect the body from infections, but in CTCL, they stop working properly and cause problems like skin rashes.

CTCL often develops in stages, starting with patches and plaques on the skin. As it gets worse, it can form tumors and affect other organs. MF is the most common type of CTCL, but there are other forms, like Sezary syndrome, which is more aggressive. Sezary syndrome causes widespread redness of the skin, changes in the blood, and swollen lymph nodes. In some cases, MF can appear as hypopigmented mycosis fungoides or lymphomatoid papulosis, which each have different signs and progress in their own way.

Clinical Presentation and Staging

• Early Stages (Patch and Plaque): The initial signs of MF often mimic other dermatologic conditions, leading to delays in diagnosis. Early lesions typically appear as red, scaly patches or plaques, often on the trunk, upper arms, and thighs. These lesions can be itchy or asymptomatic, and may be mistaken for psoriasis or eczema in the early stages. The patch stage is characterized by superficial infiltration of the skin, while the plaque stage involves thicker, more elevated lesions that may spread over larger areas.
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• Advanced Stages (Tumor): As the disease progresses, the patches and plaques may evolve into tumors or nodules that can ulcerate. In these advanced stages, the skin lesions may resemble fungal infections due to their appearance, which led to the historical naming of the condition as “mycosis fungoides.” Tumor formation typically occurs after several years of disease progression.
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• Sezary Syndrome: Sezary syndrome is a more aggressive form of CTCL characterized by erythroderma, widespread skin redness, and the presence of Sezary cells (abnormal T-lymphocytes) in the blood. Sezary syndrome is often associated with generalized lymphadenopathy, pruritus, and systemic symptoms such as fever and weight loss.

Diagnosis

Diagnosing MF and other forms of CTCL requires a combination of clinical evaluation, histopathology, and molecular techniques.

• Skin Biopsy: A skin biopsy is an important test to confirm the diagnosis of CTCL. The biopsy can show unusual T-cells that move into the outer layer of the skin and form clusters called Pautrier microabscesses. Special staining techniques and molecular tests are used to look for signs that the T-cells are abnormal and to check for specific markers like CD4 and CD8, which are often found in higher amounts in CTCL. These tests help dermatologists confirm the disease and understand its characteristics.
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• Blood Tests and Imaging: Sezary syndrome can be diagnosed by finding Sezary cells in the blood. To check if the disease has spread, doctors may also do a bone marrow biopsy or lymph node biopsy. In more advanced cases, imaging tests like CT scans or PET scans may be used to look at how much the lymph nodes or other organs are affected. 

Treatment Options

Treatment for mycosis fungoides and related CTCL subtypes depends on the stage and extent of the disease. Management approaches range from topical therapies for localized disease to systemic treatments for more advanced or widespread disease.

• Topical Therapies: For early-stage MF (patch or plaque stage), potent topical corticosteroids are the first-line treatment. These medications help reduce inflammation and slow the growth of malignant T-cells in the skin. Additionally, topical chemotherapy agents such as nitrogen mustard and Carmustine can be used, although they are less commonly utilized due to potential side effects and limited efficacy in advanced disease. Another option is bexarotene gel, a topical retinoid that can help normalize the skin and reduce malignant T-cell activity.
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• Phototherapy: Phototherapy is an important treatment for widespread skin lesions in conditions like mycosis fungoides and Sezary syndrome. Two common types are narrowband UVB and PUVA (psoralen plus ultraviolet A) therapy. These treatments use light to target and kill abnormal T-cells, while also helping to reduce skin inflammation. For cases that are more widespread or do not respond to other treatments, extracorporeal photopheresis (ECP) may be used, especially in Sezary syndrome. ECP is a special type of light treatment that can be more effective for these challenging cases.
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• Systemic Therapies: For more advanced disease or for cases resistant to topical treatments, systemic therapies are often necessary.
  • Bexarotene: An oral retinoid that has shown efficacy in treating CTCL by modulating retinoic acid receptors.
  • Interferon-alpha: An immune-modulating agent that has been used to treat advanced CTCL, particularly in cases with widespread skin involvement.
  • Methotrexate: A chemotherapy drug that is occasionally used for advanced CTCL.
  • Alemtuzumab and Brentuximab vedotin are newer immunotherapies being explored for resistant CTCL.
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• Radiotherapy: Total skin electron beam radiation is an important treatment for extensive or resistant CTCL, especially when other treatments haven’t worked. It uses targeted radiation to treat large areas of the skin. While it can be very effective, one limitation is that it can’t be used repeatedly in patients with widespread disease, as too much radiation can cause harm.
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• Bone Marrow Transplantation: In cases of refractory or advanced CTCL that do not respond to other treatments, hematopoietic stem cell transplantation (bone marrow transplantation) has been used in select cases.

Prognosis

Early-stage CTCL, like when it’s in the patch or plaque phase, has a very good prognosis, and many patients can live normal life spans with the right treatment. However, more advanced forms, especially Sezary syndrome, have a less certain prognosis because the disease can spread to other parts of the body. Relapses are common, so ongoing treatment is often needed to control the disease and manage flare-ups.

Conclusion

Mycosis fungoides and related forms of cutaneous T-cell lymphoma represent a spectrum of diseases with diverse clinical manifestations and treatment responses. While early-stage disease can often be managed effectively with topical therapies and phototherapy, advanced cases may require systemic treatments and radiotherapy. Multidisciplinary care, including dermatologists, oncologists, and specialized centers, is critical for optimal management, particularly in cases of advanced or refractory disease. Advances in immunotherapy and biologic agents offer promising prospects for future treatment strategies.

References

1. Guthrie, T. H., Gutzmer, R., & Dummer, R. (2020). Cutaneous T-cell lymphoma: Pathogenesis, clinical presentation, and management. Lancet Oncology, 21(6), 853-861. https://doi.org/10.1016/j.lancet.2020.04.007
2. Kadin, M. E. (2017). Cutaneous T-cell lymphoma: Pathogenesis and clinical management. Journal of Clinical Oncology, 35(15), 1589-1599. https://doi.org/10.1200/JCO.2016.70.2215
3. Lehman, D., & Lebwohl, M. (2018). Mycosis fungoides and Sezary syndrome: A review of the literature and management strategies. Journal of Dermatologic Treatment, 29(7), 655-666. https://doi.org/10.1080/09546634.2017.1343709
4. Swerdlow, S. H., Campo, E., Harris, N. L., et al. (2016). WHO classification of tumours of haematopoietic and lymphoid tissues (4th ed.). IARC Press.