Cutaneous T-cell lymphomas (CTCL)
The two most common types of CTCL are:
• mycosis fungoides (MF); and
• Sézary syndrome (SS).
Other forms of CTCL include:
• primary cutaneous CD30+ lymphoproliferative disorders;
• subcutaneous panniculitis-like T-cell lymphoma;
• extranodal NK/T-cell lymphoma, nasal type (very rare in western countries, but more common in Asia and Central and South America).
• primary cutaneous peripheral T-cell lymphoma-not otherwise specified.
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Most CTCLs are indolent (ie, chronic) lymphomas – non-curable, but treatable and usually not life-threatening.
In CTCL, malignant T-cells travel to the upper layers of the skin, causing a rash, which leads to diagnosis. CTCL is sometimes wrongly referred to as a skin cancer because it affects the skin, but this is not a precise use of the term “skin cancer”. Skin cancer is the designation for cancers that develop from other, non-lymphoid cells of the skin, including epidermal cells (which lead to squamous cell carcinoma) and melanocytes or pigment cells (which lead to melanoma).
Classic mycosis fungoides (MF)
Mycosis fungoides is the most common form of CTCL. It is an indolent type, following a slow, chronic course, often over many years or decades, and very often does not spread beyond the skin. Over time, in about 10% of cases, it can progress beyond the skin. Most people will have the classic form of MF, but there are several rarer forms. Many patients lead normal lives while treating their disease, some remaining in remission for long periods of time.
MF can appear anywhere on the body but tends to affect areas of the skin protected from sun by clothing. Classic MF will usually start in the form of irregularly shaped, oval or ringlike (annular), dry or scaly patches (usually flat and either discoloured or pale). The patches vary in how they behave; disappearing suddenly, staying the same shape and size or gradually enlarging. They can appear anywhere on the body but will generally be found on the torso or buttocks.
It can also appear as thicker and slightly raised areas of skin, called plaques, which can itch and sometimes ulcerate (break down/weep). These will tend to appear on the buttocks or in the folds of the skin, and may cause hair loss in affected areas. In rarer cases, larger nodules or raised lumps may appear, called tumours, which can ulcerate or weep and be painful.
In a very few people, erythroderma may develop, where the skin becomes red, thickened and sore all over.
While it is possible to have all these types of lesions at the same time, most people who have had the disease for many years experience only one or two types of lesions, generally patches and plaques (see photograph).
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Although generally an indolent, chronic disease, the course of MF in individual patients is unpredictable. It can be slow, rapid or static. Most patients will only experience skin symptoms without serious complications. About 10% will see the disease progress with serious complications. Unlike types of skin cancer, chiefly melanoma, MF almost never progresses to lymph nodes and internal organs without showing very obvious signs of progression in the skin.
Rarer forms of mycosis fungoides
Apart from the classic form of mycosis fungoides there are 3 other, rarer forms that behave slightly differently and look different under a microscope:
• folliculotropic mycosis fungoides affects hair follicles in particular. It commonly affects the head and neck and can cause hair loss. There may just be one patch, plaque or
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tumour but most people have several. There may be small cysts or blocked pores. These are sometimes called ‘comedomes’ (whiteheads) or ‘milia’ (milk spots) as they look like white bumps on the skin. Topical therapies, such as PUVA and chemotherapy ointments, don’t work well for this type of skin lymphoma. The suggested treatment may be totalskin electron beam therapy, PUVA combined with retinoid drugs, interferon or radiotherapy.
• pagetoid reticulosis (Woringer-Kolopp disease) usually shows up as a single scaly plaque, often on an arm or leg. It never spreads beyond the skin. It may be treated with surgery or a low dose of radiotherapy.
• granulomatous slack skin (GSS) is an extremely rare form of mycosis fungoides. Loose folds of skin develop in the armpits and groin. There is no agreed standard treatment for this type of CTCL. Surgery, radiotherapy, PUVA, steroid creams or interferon may be suggested.
For more information on treatments, see Section 5 of this guide.
Sézary syndrome (SS)
Sézary syndrome is a less common but more aggressive type of CTCL that is related to MF but presents with very severe itching, total body redness (erythroderma), intense scaling of the skin and frequent hair loss. People with SS often lose large amounts of skin during the night and may find their bedding covered with skin flakes in the morning. They may also feel tired, have a fever and have enlarged lymph nodes. The malignant T-cells found in the skin are also seen circulating in the bloodstream.
SS is the only type of CTCL that always affects the skin and the blood. The skin may be hot, sore, extremely itchy, occasionally flaking and burning. Oozing of clear fluid from the skin is common. Because much heat is lost through the skin, people often feel cold. Symptoms may be accompanied by changes in nails, hair or eyelids.
Primary cutaneous CD30-positive lymphoproliferative disorders
(PCCD30+LPD)
There are two main types of these disorders, accounting for almost one-third of all diagnosed CTCLs:
• lymphomatoid papulosis (LyP); and
• primary cutaneous anaplastic large-cell lymphoma (PCALCL).
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In both types a CD30 protein is found on the surface of the abnormal lymphocytes. Both disorders can be well-managed and have an excellent prognosis, with a 10-year survival of 100% for LyP and 90% for PCALCL.
Lymphomatoid papulosis (LyP)
Lymphomatoid papulosis (LyP) manifests itself with self-healing small red-brown bumps and spots on the skin (papules) that come and go. Lesions can be unnoticed or itchy and painful, taking 2-3 months to run their course. It can be persistent with frequent, recurring eruptions or it can disappear for an extended period of time before showing up again. Stress is often reported to trigger the breakouts.
LyP is usually classified as non-malignant or as a CTCL precursor (ie, about 1 in 20 people with LyP will go onto develop another lymphoma such as PCALCL, MF or Hodgkin lymphoma), though some experts say it is a very low-grade form of CTCL.
The disease can happen at any time in life – from early childhood to middle age, affecting both genders equally. Black-skinned individuals seem less affected than other racial groups.
Primary cutaneous anaplastic large cell lymphoma (PCALCL)
Primary cutaneous ALCL (PCALCL) is an indolent, slow-growing type of CTCL, with characteristic features that include single or multiple raised red skin lesions and nodules, which do not typically crust and have a tendency to ulcerate. These lesions may appear anywhere on the body and grow very slowly, so they may be present for a long time before being diagnosed.
Rare types of cutaneous T-cell lymphoma
There are several rare types of CTCL, including:
• Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is slow-growing and can occur at any age. It is slightly more common in women. It starts in the fatty layer of the skin, just below the surface. There may be one or more plaques or nodules, often on the legs. Other more general symptoms may be present, such as fevers, low blood counts and weight loss. This condition responds very well to steroid tablets, which may be the only treatment needed. If further treatment is required, this may be in the form of local
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radiotherapy (only to the affected area) or chemotherapy with doxorubicin. If the SPTCL is faster growing, suggested treatment may be a combination of chemotherapy drugs such as CHOP or even a stem cell transplant.
• Extranodal NK/T-cell lymphoma, nasal type, is a fast-growing type of lymphoma that is very rare in western countries but more common in Asia and Central and South America. It is sometimes seen in the skin, but can also start elsewhere and involve the skin. People with this type of lymphoma usually test positive for Epstein-Barr virus (EBV). In most cases, this type of lymphoma is treated with a systemic (whole body) chemotherapy regimen, such as SMILE (dexamethasone, methotrexate, ifosfamide, Lasparaginase and etoposide), combined with radiotherapy for localised disease.
Primary cutaneous T cell lymphoma-not otherwise specified
The ESMO Clinical Practice Guidelines include the following cutaneous lymphoma subgroups within the category of primary cutaneous T cell lymphoma-not otherwise specified:
• primary cutaneous CD4-positive small/medium T-cell lymphoma is a slow-growing lymphoma with a good prognosis (outlook). It usually appears as a single plaque or nodule on the face, neck or upper torso. Treatment is usually to remove the plaque or nodule surgically or attack it with radiotherapy. If the lymphoma is more widespread, suggested treatment may be either a chemotherapy drug called cyclophosphamide or an immunotherapy drug, interferon alpha.
• primary cutaneous gamma/delta T-cell lymphoma is a faster-growing type of skin lymphoma that usually occurs in adults. It most commonly shows up as patches and plaques on the arms or legs. Symptoms may also include night sweats, fevers and weight loss. Some people develop low blood counts and an enlarged liver and spleen. Suggested treatment is most likely to be a combination of chemotherapy drugs, or, in some circumstances, a stem cell transplant.
• primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma is a faster growing lymphoma that occurs mainly in adults. It appears as widespread spots (papules), plaques and tumours on the skin. Affected areas may ulcerate. It can also affect the lining of the mouth. Your doctor is most likely to suggest treatment with a combination of chemotherapy drugs, or, in some circumstances, a stem cell transplant.
For more information on treatments, see Section 5 of this guide.
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Cutaneous B-cell lymphomas (CBCL)
The three primary types of CBCL are:
• primary cutaneous follicle centre lymphoma (PCFCL);
• primary cutaneous marginal zone B-cell lymphoma (PCMZL); and
• primary cutaneous diffuse large cell lymphoma, leg type (also known as PCLBCL-LT).
PCFCL and PCMZL are slow growing, indolent types with a good prognosis (10-year survival exceeds 90%), while PCLBCL-LT has a more unfavourable prognosis (with a disease-related 5-year survival of approximately 50%).
Primary cutaneous follicle centre lymphoma (PCFCL)
PCFCL is the most common type of CBCL, most often being found on the head, neck or upper torso. Lesions are pink or red nodules, or slowly-developing tumours. They rarely become open sores or ulcers. Some patients find nodules in many locations on the body, but more often it is a single tumour or small group of nodules.
PCFCL responds well to radiation. You may have radiotherapy if 1 or just a few areas of your skin are affected. Occasionally, you may have surgery if the lymphoma is confined to 1 area. Both treatments work very well.
If the lymphoma is more widespread, treatment depends on how much skin is involved. If you have just a few scattered areas of affected skin, your specialist may monitor it and keep treatment in reserve for when you need it. This is called ‘watch and wait’. People often feel anxious about ‘watch and wait’ because they feel as if nothing is being done to treat them. Rest assured that doctors know from research that the disadvantages of early treatment can outweigh the advantages.
If you have lymphoma in several areas of skin you may receive rituximab. This is an immunotherapy drug that you have intravenously (through a drip into a vein). Some people might have rituximab by subcutaneous injection (injection under the skin). A few people have treatment with a chemotherapy regimen (several drugs), often along with rituximab.
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Immunotherapy drugs do not kill lymphoma directly. They stimulate your immune system to recognise the lymphoma cells as foreign to your body and kill them. Interferon alpha is another immunotherapy drug that you may have.
If primary cutaneous follicle centre lymphoma relapses (comes back), it can often be successfully treated with the same treatment you had the first time.
For more information on treatments, see Section 5 of this guide.
Primary cutaneous marginal zone B-cell lymphoma (PCMZL)
PCMZL is the second most common form of CBCL and is related to a type of non-Hodgkin’s lymphoma known as extranodal lymphoma of mucosa-associated lymphoid tissue (MALT) type. Patients find pink or red papules, nodules or, less frequently, tumours. It can occur anywhere on the skin but tends to show up on arms, legs or torso.
This is one of the few skin lymphomas with a known cause. Some people with a MALT lymphoma have evidence of a bacterial infection called Borrelia burgdorferi. If you have this infection, you have treatment with antibiotics first. When there is no infection, treatment is usually with radiotherapy or surgery, particularly if the lymphoma is only in 1 area.
In other respects, the treatment approach of PCMZL will be the same as for PCFCL (see above), as recommended in the ESMO Clinical Practice Guidelines.
For more information on treatments, see Section 5 of this guide.
Primary cutaneous diffuse large cell lymphoma, leg type (also known as PCLBCL-LT)
PCLBCL-LT is a rare and more dangerous type of CBCL that looks much different under the microscope, and most of the time is found in the lower legs, more commonly in older women, where it can reach a very significant size.
PCLBCL-LT often grows into large tumours that extend deep into the fat of the body, growing quickly and becoming open sores. Unlike slow-growing types of lymphoma, this one has a high likelihood of spreading outside the skin.
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Treatment is usually chemotherapy, with or without radiotherapy. The chemotherapy most commonly used is R-CHOP (rituximab together with cyclophosphamide, hydroxydaunorubicin, vincristine (Oncovin®) and prednisolone). You may have rituximab alone. If the lymphoma relapses, your doctor will probably suggest more chemotherapy.
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3 Diagnosis
Introduction
One of the challenges in definitively diagnosing cutaneous lymphoma is that its signs and symptoms are not the same for all patients, combined with the fact that some of the symptoms, especially when they are milder, are commonly confused with conditions like eczema or psoriasis, or fungal skin reactions (such as ringworm), or various skin reactions to drugs, certain substances or allergies.
Key symptoms
Patches, plaques, papules and tumours are clinical names for a variety of skin presentations (also known as lesions) that can be clues that lead to diagnosis.
Patches are usually flat, possibly scaly, and look like a rash. Plaques are thicker, raised lesions. Papules are small, raised solid areas of skin that look like a rash. Tumours are raised bumps or nodules which may or may not ulcerate. To be called a tumour, generally a nodule has to be at least 1 cm in size, or greater. It is possible to have one or all of these types of lesions. Some people have the disease for years and only experience one.
Some people also have swollen lymph nodes, usually in the neck, armpits or groin.
A common symptom is itching, although some patients do not experience this.
Process of diagnosis
In primary care
Diagnosis of the many subtypes of cutaneous lymphomas can vary and sometimes it takes a long time before it is confirmed. Regardless, the process for diagnosis is similar for all types.
Healthcare systems vary from country to country, hence the exact diagnostic process or system may look different depending upon which country you live in. However, usually someone who may have cutaneous lymphoma is most likely to go to a general practitioner (a doctor in primary or frontline care) if they have red or itchy patches of skin or if they have lumps anywhere. Many skin lymphomas look like more common skin conditions such as eczema or psoriasis. Many of them also develop very slowly, some over as long as 10–40 years. It may take a long time for the primary care doctor to rule out other conditions and then make a referral to a specialist. This might be a specialist in skin diseases
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(dermatologist) or a specialist in diseases of the blood and lymphatic system (haematologist).
Assessment
At the hospital or specialist clinic, the specialist will ask how and when the skin problem developed and how it affects you. They will carry out a physical examination, looking carefully at skin patches or lumps. A medical photographer might take pictures of the affected areas of skin. The specialist will also ask about your general health and about any other symptoms, such as weight loss or fevers.
Biopsy
The doctor may suspect what the problem is, but will have to confirm the diagnosis with a skin biopsy. In a biopsy, the doctor numbs an area of affected skin with a local anaesthetic and removes a small piece of the skin. The sample is then examined under a microscope and sent for specialised tests to look at the cells and their genes and proteins in detail. These tests sometimes have to be done in a laboratory at another centre. Results of the biopsy can take 2–3 weeks to come back.
Diagnosing skin lymphoma is not always straightforward, even for a specialist. Further skin biopsies might be needed over the following few weeks or months. In some people, the skin rash does not look typical of lymphoma. In this case, there might need to be several biopsies taken over a few years before a full diagnosis can be made. This can be a frustrating and anxious time. It is important that the doctors make an accurate diagnosis and find out as much as possible about your skin condition so that you can have the most suitable treatment.
Tests, scans and examinations
The history of how and when the skin problem developed, the physical examination and the results of skin biopsies help the medical team to diagnose the lymphoma. To find out more about the lymphoma and how it is affecting your body, you also need to have a full physical examination and blood tests. These tests are needed for ‘staging’ of the lymphoma. During the physical examination, the doctor will feel for enlarged lymph nodes in the neck, under the arms and in the groin. No internal examinations will be needed. The blood tests will include blood cell counts and measurements of levels of some chemical substances found in the blood, including lactate dehydrogenase (LDH). This is an enzyme in the body that is used in the process of turning sugar into energy.
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Further tests depend on exactly the type of lymphoma that is diagnosed and on the patient’s general health. If the diagnosis is of the most common T-cell skin lymphoma, mycosis fungoides, and the physical examination and blood tests are normal, only a chest X-ray is needed.
Scans for T-cell skin lymphomas are not done as often as they are for other types of non- Hodgkin lymphoma. Scans may be needed if other investigations suggest there are lymphoma cells in the blood or lymph nodes (glands).
The most common type of scan for skin lymphoma is a computed tomography (CT) scan of your chest, abdomen and pelvis (area between your hip bones). Some people may have another scan called positron-emission tomography (PET), which may be combined with CT into a PET/CT scan. These scans capture images of the internal organs in great detail. Patients usually have them as an outpatient and they can take anything from 30 minutes to 2 hours. Not all hospitals or treatment centres can carry out PET/CT scans so it may be necessary to go to a larger medical centre rather than a local hospital.
A few people with suspected skin lymphoma have a bone marrow biopsy. A bone marrow biopsy involves taking a small sample of the bone marrow (the spongy tissue in the centre of some of the large bones of the body where blood cells are made) from the hip bone with a needle. The doctor numbs the skin over the bone with a local anaesthetic first. The sample is then examined under a microscope to see if it contains lymphoma cells. Painkilling medication can be taken to help with any discomfort after the procedure.
If the lymph nodes are enlarged, a lymph node biopsy may be necessary, which involves having a node removed under a local or general anaesthetic. This is sometimes called an ‘excision biopsy’. The node is then sent to the laboratory to be examined under a microscope.
Some people may also have a fine needle aspirate (FNA) of a lymph node. This is where a fine needle is used to remove some cells from the enlarged lymph node without it being removed. An FNA is sometimes done before referral to the specialist clinic. However, after an FNA, a lymph node biopsy is still likely to be necessary as a FNA only samples some of the cells in the lymph node. This means abnormal cells might be missed.
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All these tests are done to find out which parts of the body the lymphoma is affecting. They are also done to make sure that the lymphoma definitely started in the skin rather than spread there from somewhere else. This is important. Lymphomas that start inside the body behave differently to skin lymphomas and need different treatment. Once all the results are back, the medical team can decide on the best course of treatment.
The appearance of the skin, together with the physical examination and other test results usually provide:
• a diagnosis of the exact type of skin lymphoma – whether it is a T-cell or a B-cell skin lymphoma and exactly which type;
• information on whether the lymphoma is a slow-growing (low-grade or ‘indolent’) type or faster-growing (high-grade or ‘aggressive’) type;
• an indication of the stage of the disease.
