Mycosis fungoides

by Jason Wasserman MD PhD FRCPC and Zuzanna Gorski MD FRCPC
October 26, 2024

Mycosis fungoides is a type of cancer called lymphoma that starts in the skin. A lymphoma is a cancer of lymphocytes, white blood cells that help protect the body from infections. In mycosis fungoides, the cancerous cells are a type of lymphocyte called T cells, which build up in the skin, leading to rashes, patches, or other skin changes. The disease develops slowly in most people, starting with mild skin changes that may be mistaken for eczema or other skin conditions. Over time, if the condition worsens, the cancerous T cells invade deeper layers of the skin, forming tumours, or spreading beyond the skin to the blood, lymph nodes, or other organs.

What are the symptoms of mycosis fungoides?

The symptoms of mycosis fungoides depend on the stage of the disease.

Some common symptoms include:

• Red, scaly patches that are often itchy (early stage).
• Thickened, raised plaques (later stage).
• Tumours on the skin that can grow and spread (advanced stage).
• Enlarged lymph nodes or fatigue if the disease spreads beyond the skin.

These symptoms usually develop slowly over time, which can make diagnosing mycosis fungoides challenging in its early stages.

What causes mycosis fungoides?

The exact cause of mycosis fungoides is not known. It is not contagious, meaning it cannot spread from person to person. Some research suggests that changes in the immune system may trigger the condition, but no specific cause has been confirmed. Genetic factors might also play a role, though these are still under investigation.

How is the diagnosis of mycosis fungoides made?

The diagnosis is usually made by examining a small skin sample under the microscope, called a biopsy. Because mycosis fungoides can look like other skin conditions, multiple biopsies may be needed to confirm the diagnosis. Pathologists look for abnormal lymphocytes in the tissue to make the diagnosis.

What are the microscopic features of mycosis fungoides?

The appearance of mycosis fungoides changes with the progression of the disease. Pathologists divide it into stages based on how the abnormal cells appear under the microscope.

Patch stage

In the early patch stage, abnormal lymphocytes collect in a layer of the skin called the epidermis. These small- to medium-sized lymphocytes have dark, folded (cerebriform) nuclei and tend to line up along the base of the epidermis. Surrounding these cancer cells, normal immune cells may cause mild inflammation in the skin.

Plaque stage

In the plaque stage, the lymphocytes spread into the upper layers of the epidermis. They can gather into small clusters called Pautrier microabscesses, which are held together by structures in the skin called Langerhans cells. In some cases, other immune cells form granulomas around the cancer cells, making it harder to diagnose.

Tumour stage

In the tumour stage, the cancer cells lose their connection to the skin’s surface and grow deep into the dermis, forming large clusters or sheets of cells. These tumours contain different-sized lymphocytes, including larger, abnormal cells.

Large cell transformation

Large cell transformation occurs when more than 25% of the cancer cells grow larger and become more abnormal. This transformation is often a sign that the disease is becoming more aggressive and may need more intensive treatment. Large cell transformation usually happens in advanced stages; dense tumours can make the diagnosis more difficult.

Immunohistochemistry

Pathologists use immunohistochemistry to identify proteins in cancer cells. This helps confirm the diagnosis and provides information about the disease’s behaviour.

• CD2, CD3, CD5, and CD4: These proteins are typically found on T cells, the type of lymphocytes involved in mycosis fungoides.
• CD7: This marker is often reduced or lost in advanced disease.
• CD30: This marker can be positive or negative; its levels can vary over time.
• Cutaneous lymphocyte antigen (CLA) and CCR4: These proteins indicate that the lymphocytes are targeting the skin.
• PD-1: This protein shows that the immune cells may be exhausted and no longer functioning correctly.
• TOX: This marker helps pathologists confirm early-stage disease.

In more advanced stages, additional changes may occur, including the loss of T cell markers (like CD2 and CD5) or increased levels of Ki-67, which indicates rapid cell growth. Some forms of mycosis fungoides, such as those with CD8-positive lymphocytes, are more common in children and specific populations and tend to have a slower disease course.

How is mycosis fungoides staged?

The stage of mycosis fungoides describes how much the disease has progressed. Doctors use a system developed by the International Society of Cutaneous Lymphomas (ISCL) and the European Organisation for Research and Treatment of Cancer (EORTC) to classify the disease. This system considers several factors, including the condition of the skin, involvement of lymph nodes, spread to other organs (metastasis), and the presence of cancer cells in the blood. Each component has specific criteria that help determine the overall stage of the disease.

Skin involvement (T)

• T1: Small patches, papules (raised spots), or plaques (thicker skin) covering less than 10% of the skin. This can be further divided as follows:
  • T1a: Only patches are present.
  • T1b: Both plaques and patches may be present.
• T2: Patches, papules, or plaques covering 10% or more of the skin surface.
  • T2a: Only patches are present.
  • T2b: Both plaques and patches may be present.
• T3: One or more tumours, each at least 1 cm in size.
• T4: Redness (erythema) covering at least 80% of the skin.

Lymph node involvement (N)

• N0: No abnormal lymph nodes; a biopsy is not needed.
• N1: Abnormal lymph nodes are present but with low levels of cancerous involvement:
  • N1a: No evidence of cancer cells (clone-negative).
  • N1b: Cancer cells are found (clone-positive).
• N2: Abnormal lymph nodes with moderate cancerous involvement:
  • N2a: No cancer cells found (clone-negative).
  • N2b: Cancer cells are present (clone-positive).
• N3: Abnormal lymph nodes with severe cancerous involvement, regardless of clone status.
• Nx: Lymph nodes appear abnormal, but no biopsy was performed to confirm cancer.

Visceral (organ) involvement (M)

• M0: No signs of cancer spreading to other organs.
• M1: Cancer has spread to internal organs, confirmed through biopsy.

Blood involvement (B)

• B0: No significant blood involvement; fewer than 5% of white blood cells are cancerous.
  • B0a: No cancerous clone detected in the blood.
  • B0b: A cancerous clone is detected.
• B1: Low levels of cancer cells in the blood; more than 5% of white blood cells are cancerous but do not meet the criteria for B2.
  • B1a: No cancerous clone detected.
  • B1b: A cancerous clone is detected.
• B2: High levels of cancer cells in the blood; at least 1000 cancerous cells per microliter are found, with a positive clone.

Clinical stages and survival

The overall clinical stage helps doctors predict how the disease will progress and the likely outcome (5-year disease-specific survival or DSS). The clinical stage incorporates information on skin involvement (T), lymph node involvement (N), visceral organ involvement (M), and blood involvement (B).

The following table summarizes the stages:

What is the prognosis for a person diagnosed with mycosis fungoides?

The prognosis depends on how advanced the disease is at the time of diagnosis. The TNMB system, which assesses the size of the tumour, involvement of lymph nodes, spread to other organs, and blood involvement, helps predict the disease’s course.

• Early stages (IA, IB, IIA): In these stages, the disease is usually limited to the skin, and the prognosis is very good, with many people having a normal life expectancy.
• Advanced stages (IIB and beyond): The outlook becomes more serious as the disease progresses and involves tumours, lymph nodes, blood, or internal organs.

Other factors that can affect prognosis include older age (over 60), high levels of lactate dehydrogenase (LDH), and the presence of cancer cells in the blood without apparent symptoms. Regular follow-ups with a healthcare provider are essential to monitor for any changes and provide the best possible care.

With early diagnosis and appropriate treatment, many people with mycosis fungoides can manage the disease for years. Advanced care, including chemotherapy or targeted therapies, may be necessary for those with more aggressive forms of the disease.