Understanding
Cutaneous Lymphomas

Lymphomas that arise in tissues or organs outside of the lymphatic system (tissues and organs that produce, store, and carry white blood cells) are called extranodal lymphomas. Extranodal lymphomas that arise and manifest primarily in the skin are called cutaneous lymphomas. When lymphomas start in the skin and there is no evidence of disease outside of the skin when the disease is first diagnosed, they are called primary cutaneous lymphomas. Primary cutaneous lymphomas are a form of non-Hodgkin lymphoma (NHL)

Cutaneous T-cell lymphoma (CTCL) starts in the T-cells of the skin and is the most common type of primary cutaneous lymphoma. Most forms of CTCL begin as indolent (slow growing) diseases and involve only skin symptoms, although some more aggressive forms of CTCL can affect blood, lymph nodes (small bean-shaped structures that help the body fight disease), and the function of other organs. CTCL affects men more often than women and usually occurs in people in their 50s and 60s.

Cutaneous B-cell Lymphoma (CBCL) is often indolent andrare, representing approximately 2% of the NHLs and 20-25% of all primary cutaneous lymphomas. CBCL starts in the B-cells of the skin and may appear on the skin as a rash, reddish bump, lump, or nodule, usually with a raised and smooth appearance. CBCL affects men and women equally and can occur in any age group.

Symptoms, Staging, and Diagnostic Procedure

Cutaneous T-cell lymphoma (CTCL)

CTCL skin lesions often look red and dry, can be of any size, and can affect any part of the body, although more often they arise on the trunk, buttocks, and thighs. Aside from the skin, CTCL can also affect the blood, lymph nodes, and other internal organs. Symptoms can include:

• Red rash or skin discoloration.
• Dry skin.
• Itching (which can be severe) sometimes with a burning sensation.
• Swelling (due to enlarged lymph nodes).
• Hair loss including at times eyebrows and eyelashes.
• Nail changes.
• Thickening and cracking of the skin of palms and soles.

Blood flow cytometry (a technique that detects and counts different types of cells in bodily fluids, according to their physical and chemical characteristics and the surface markers they express) is essential to diagnose and stage CTCL. Whole-body imaging is often needed to determine if the cancer has spread to the lymph nodes or other organs. These tests may include a computed tomography (CT) scan, a positron emission tomography (PET, a form of imaging that uses a special tracer to locate cancer cells in the body) scan, and/or magnetic resonance imaging (MRI, a procedure that takes detailed pictures of areas inside the body using a powerful magnet and radio waves). Swollen lymph nodes for reasons other than CTCL can be positive on a PET scan so a biopsy (a procedure in which a piece of the abnormal tissue is removed from the body and examined under a microscope) is necessary to confirm if CTCL cells are present in the lymph node. A bone marrow biopsy (a procedure to collect small samples of the spongy tissue inside the bone) may also be performed, if blood counts are abnormal, but is not always necessary.

Once the diagnosis is made, patients undergo exams to assess the disease stage (how much the cancer has grown, what is the extent and pattern of growth in the skin [patch, plaque or tumor], and if it has spread to other parts of the body). The clinical stages of CTCL are detailed in Table 1.

Table 1. Clinical Stages of CTCL

Stages	A	B
I. (disease limited to the skin)	Skin: Less than 10% covered in patches or plaques. Lymph nodes, blood, and internal organs not involved.	Skin: 10%-79% covered in patches or plaques. Lymph nodes, blood, and internal organs not involved.
II. (disease limited to the skin)	Skin: Up to 79% covered with patches or plaques. Lymph nodes enlarged but not involved on biopsy.	Skin: Up to 79% covered with patches, plaque, and/or tumors. Lymph nodes may be enlarged but not involved on biopsy.
III. (erythroderma but without significant blood involvement)	Skin: >80 covered with patches or plaques, with or without tumors. Lymph nodes may be enlarged but are not involved on biopsy. Blood and internal organs are not involved.	Skin: >80% covered with patches or plaques, with or without tumors. Lymph nodes may be enlarged but are not involved on biopsy. Low-level of blood involvement. Internal organs are not involved.
IV. (disease has spread to the lymph nodes and/or the bloodstream)	IVA1: Covered to any degree with patches, plaques, or tumors; blood is involved. Lymph nodes may be enlarged but are not involved on biopsy. Internal organs are not involved. IVA2: Skin: Covered to any degree with patches, plaques, or tumors. Blood may or may not be involved. Biopsy-proven lymph node involvement. Internal organs are not involved.	Skin: Covered to any degree with patches, plaques, or tumors. Blood may or may not be involved. Lymph nodes may or may not be involved. Internal organs, including the bone marrow (the spongy tissue inside the bones), are involved.

Because it is a rare disease, patients with CTCL should be referred to a health care team that specializes in this type of lymphoma. The patients’ clinical stage is important to select the best treatment. The treatment is individually chosen for each patient and may be adjusted frequently depending on how effective the treatment is and how well the patient tolerates it.

The clinical stage is also important to determine the prognosis (how well the patient will do with standard treatment) and treatment options. Keep in mind that no two patients are alike and that statistics can only predict how a large group of patients will do (not what will happen to an individual patient). The doctor most familiar with the patient’s situation is in the best position to interpret these statistics and understand how well they apply to a patient’s particular situation.

Subtypes

Cutaneous T-cell lymphoma (CTCL)

There are different subtypes of CTCL, and the most common ones are mycosis fungoides (MF), CD30-positive lymphoproliferative disorders, and Sézary syndrome (SS). Other subtypes of CTCL are less frequent and can be more aggressive (fast-growing).

The most common subtype of CTCL is MF and represents around half of all skin lymphomas. Most patients with MF initially experience only skin symptoms. This type of CTCL is usually indolent. In many patients, the disease is limited to the skin. However, MF may progress (become worse or spread in the body) more rapidly in some patients and spread to the lymph nodes, blood, and/or internal organs. MF may look different in each patient as skin symptoms can appear in different forms.

It is possible to have more than one type of skin symptom. For instance, patients with erythrodermic MF also have scaly red skin lesions that can be very itchy but may also have tumors.

A medical history, physical examination, and skin biopsy (a procedure to collect small samples of the affected skin) are needed for diagnosis. A physician will examine lymph nodes, order various blood tests, and may conduct other screening tests, such as blood flow cytometry or a whole-body imaging study (such as a CT or PET scan).

MF is difficult to diagnose in its early stages because symptoms can be minimal and the skin biopsy findings can be similar to those of other skin conditions.

SS is more aggressive and harder to treat than MF. Patients with SS by definition have stage IV lymphoma, and may experience the following signs and symptoms:

Cutaneous B-cell Lymphoma (CBCL)

Symptoms depend on the tumor location (where the tumor is located in the body) and the extent (cancer stage and how far it has spread) of the disease. The most common symptoms include:

CBCL can appear as a single lesion (area that looks abnormal or different from the surrounding skin) or multiple lesions in either one or several body regions (areas). Many skin conditions may look similar but are not CBCLs. The disease can relapse (return after treatment) or occur in new places on the skin, but it rarely spreads outside the skin. Almost 100% of patients with single lesions achieve remission (no signs or symptoms of disease) after radiation therapy (uses high-energy radiation to kill cancer cells). However, patients with multiple lesions are more likely to continue to have new lesions appear. This fact does not affect prognosis (how well the patient will do), which remains very good.

To diagnose CBCL, blood tests and a bone marrow biopsy are usually performed.

Cutaneous B-cell Lymphoma (CBCL)

The most common CBCL subtypes are:

Primary Cutaneous Follicle Center Lymphoma (PCFCL) is the most common type of CBCL. This skin lymphoma is indolent, developing slowly over months or years. It usually appears on the head, neck, or torso (upper body or chest) of the body as red pimples, nodules, or plaques. In some cases, it can also be found on the legs. This type of CBCL is usually diagnosed in middle-aged adults and responds well to treatment.

Primary Cutaneous Marginal Zone B-Cell Lymphoma (PCMZL) is the second most common form of CBCL. This indolent lymphoma can have a similar appearance to cutaneous follicle center lymphoma, often as red to purplish large pimples, plaques, or nodules on the arms or upper body. Some cases are linked to an infection with Borrelia burgdorferi, a type of bacteria carried by ticks that causes Lyme disease. This type of CBCL is more common in older adults.

First Treatment after Diagnosis

For MF, treatment is directed either at the skin (skin directed therapy) or at the entire body (systemic therapy, treatment with drugs that are absorbed or injected, travel through the bloodstream and reach all parts of the body). Skin directed therapy can be topical (treatment locally applied to the skin in the form of creams, ointments, or gels) or full skin (ultraviolet light, skin radiation). The disease is not considered curable and follows a chronic course (lasting for a long period of time), but it can be managed with treatment and sometimes becomes undetectable (remission). Some patients with early-stage MF are able to can remain in remission for long periods of time.

Since SS is systemic (cancer has spread to the bloodstream), it should not be treated with skin-directed therapies alone. The remaining treatments approved for SS may be prescribed alone or in combination to achieve the best long-term treatment response.

Topical therapies generally are used for earlier-stage disease and are useful to treat patients who have patches and limited plaques. These therapies include:

• Topical corticosteroids (most frequently used topical therapy).
• Topical chemotherapy (drugs that stop the growth of or kill cancer cells) with, for example, mechlorethamine (Valchlor).
• Topical retinoids like bexarotene (Targretin).
• Topical immunotherapy (drugs that use the body’s immune system to fight cancer) with imiquimod (Zyclara).
• Local or total skin radiation therapy.
• Phototherapy (with ultraviolet light).

Corticosteroids are the most commonly used topical treatment for CTCL. Bexarotene gel (Targretin) and mechlorethamine gel (Valchlor) have been approved by the U.S. Food and Drug Administration (FDA) as a topical treatment for Stages IA and IB CTCL in patients who have received previous skin treatment.

Systemic treatment may be used in more advanced-stage disease and in patients with earlier stage disease who did not respond to or did not tolerate topical therapies.

Systemic treatments include:

Chemotherapy, including:

• Methotrexate
• Pralatrexate
• Pegylated liposomal doxorubicin
• Fludarabine
• 2chlorodeoxyadenosine
• Pentostatin
• Folate analogues, like pralatrexate (Folotyn)

Immunotherapy

• Immunomodulatory agents (drugs that work on the immune system directly by regulating [activating or slowing down] the activity of specific proteins) such as interferon alfa or gamma (with or without topical therapies)
• Antibody-drug conjugate (ADC) such as brentuximab vedotin (Adcetris) which is a monoclonal antibody (a protein made in the laboratory that bind to cancer cells and help the immune system destroy them) attached to a chemotherapy drug. The monoclonal antibody in the ADC recognizes and binds to a protein called CD30 on the cancer cell surface.
• Monoclonal antibodies such as mogamulizumab (Poteligeo).

Oral retinoids like bexarotene (Targretin).

Targeted therapy (drugs that target molecules that the cancer cells use to grow and spread) with histone deacetylase (HDAC) inhibitors such as vorinostat (Zolinza) or romidepsin (Istodax).

Extracorporeal photopheresis (the blood of the patient is removed, and the white blood cells are isolated, exposed to UV radiation and returned to the patient).

Stem cell transplantation (SCT), the patient is treated with high-dose chemotherapy or radiation to remove their blood-forming cells or stem cells and then receives healthy stem cells to restore the bone marrow’s ability to make new blood cells. There are two types of SCT:

• Autologous: The patient receives his/her own stem cells after high dose chemotherapy and/or radiation. This is very rarely used in CTCL.

• Allogeneic: The patients receive stem cells from a donor, usually a family member or an unrelated donor). Allogeneic SCT not only restores the bone marrow’s ability to make new blood cells but also transplant a new donor-derived immune system.

Targeted therapy (drugs that target molecules that the cancer cells use to grow and spread) with histone deacetylase (HDAC) inhibitors such as vorinostat (Zolinza) or romidepsin (Istodax).

Cutaneous B-cell Lymphoma (CBCL)

Upon CBCL diagnosis, appropriate staging work-up (a procedure to evaluate how much the cancer has grown and if it has spread) should be done to make sure that the disease is limited to the skin. In general, this includes routine laboratory tests (like blood testing) and whole-body imaging studies (like CT scans). Bone marrow biopsies are not recommended for all patients with indolent CBCLs.

Treatment selection for CBCL depends on the type of CBCL, and whether the skin lesion is solitary/ regional (single lesion or lesions that are limited to one region of the skin) or multifocal (widespread). Treatment also depends on how fast the lymphoma grows (indolent vs aggressive).

For indolent lymphomas with solitary/regional lesions, the most common treatment is local radiation therapy. Surgical treatment can be an option, but may result in wide, unnecessary scars.

Common treatments for CBCL include:

• Intralesional corticosteroids (applied directly into the lesion).
• Radiation therapy (applied directly to the lesions).
• Almost 100% of patients with single lesions achieve remission after radiation therapy. However, patients with multiple lesions are more likely to continue to have new lesions appear. This fact does not affect prognosis, which remains very good.

Indolent CBCLs that present as multiple lesions may be observed through an approach known as “active surveillance” or “watchful waiting,” in which patients’ overall health and disease are monitored through regular checkup visits that can include laboratory and imaging tests. For more information on active surveillance, view the Active Surveillance fact sheet on the Foundation’s website (lymphoma.org/publi-cations).

If lesions are very widespread and symptomatic, systemic therapies may be appropriate. This includes monoclonal antibodies like rituximab (Rituxan), with or without chemotherapy.

Regular skin examinations are very important, especially for indolent CBCLs, as the skin is the most common site of new lesions. General laboratory tests may also be done, but imaging is not needed unless there is a concern of systemic (widespread) disease.

 Relapsed and Refractory

Many yet-to-be-approved treatments (also referred to as investigational drugs) are currently being tested in clinical trials for CTCL and/or CBCL. Results from these clinical trials may improve or change the current standard of care (the proper treatment that is widely used by health care professionals and accepted by medical experts). The table below lists some of these treatments that can be accessed through a clinical trial. For more information about clinical trials, view the Understanding Clinical Trials publication on the Foundation’s website (lymphoma.org/publications).

Table 2. Selected Agents Under Investigation for CTCL and CBCL in Phase 2 or 3 Clinical Trials.

Agent (drug)	Class (type of treatment)	Type of Lymphoma
DR-01	Immunotherapy; monoclonal antibody, anti-CD94	R/R CTCL of cytotoxic T-cells Untreated CTCL
Durvalumab (Imfinzi)	Immunotherapy; immune checkpoint inhibitor, anti-PD-L1	R/R CTCL
Hypericin (HyBryte)	Topical therapy; photosensitizer	Untreated CTCL
Lacutamab (IPH4102)	Immunotherapy; monoclonal antibody, anti- KIR3DL2	R/R CTCL
Nivolumab (Opdivo)	Immunotherapy; immune checkpoint inhibitor, anti-PD-1	R/R CTCL and R/R CBCL
Pembrolizumab (Keytruda)	Immunotherapy; immune checkpoint inhibitor, anti-PD-1	R/R CTCL
Ruxolitinib	Targeted therapy; JAK3 inhibitor	R/R CTCL
Talimogene laherparepvec (Imlygic)	Immunotherapy; oncolytic viral therapy	R/R CTCL
Tofacitinib	Topical targeted therapy; JAK3 inhibitor	Untreated R/R CTCL
Zanubrutinib (Brukinsa)	Targeted therapy, BTK inhibitor	R/R CBCL

It is important to remember that scientific research is always evolving. Treatment options may change as new treatments are discovered, and current treatments are improved. Therefore, it is important that patients check with their physician or with the Foundation for any treatment updates that may have re-cently appeared. It is also very important that all patients with CTCL or CBCL consult a specialist to clear up any questions.

Clinical trials are important in finding effective drugs and the best treatment doses for patients with cutaneous lymphomas. They are not a “last resort” for patients. Every drug available today had to be tested in clinical trials before it was approved for general use, and all new and emerging treatments.

There are four main types or phases of clinical trials. The phase is based on the study’s objective and the number of participants.

Patients interested in participating in a clinical trial should view the Understanding Clinical Trials fact sheet on the Foundation’s website (visit lymphoma.org/publications), talk to their physician, or contact the Foundation’s Lymphoma Resource Center for an individualized clinical trial search by calling (800) 500-9976 or emailing [email protected].

How to Be a Self-Advocate?

Being a self-advocate and an active participant in healthcare decisions can be a positive experience. It may help patients regain a sense of control that they may have lost following the lymphoma diagnosis by making sure patients receive the best care. Patients and caregivers should remember they are partners in their treatment plan.

• Do not be afraid to ask your doctors or nurses questions about your care. An educated patient asking questions is not ‘being a challenge to your physician’ (or ‘being a difficult patient’).
• Learn more about lymphoma by asking your doctor for information and visiting reliable websites, such as the Foundation’s at www.lymphoma.org.
• Take advantage of counseling, support groups, nutritional counseling, fitness classes, expressive arts, and other services offered at your doctor’s office, cancer center, or hospital.
• Consider joining the Foundation’s Lymphoma Support Network, a nationwide peer support program that matches patients and caregivers with people who have had similar experiences. For information about the program, call (800) 500-9976 or email [email protected].
• Finally, it is important that patients not be afraid to talk with the healthcare team about nonmedical issues such as transportation, finances, insurance, working through treatment or taking time off, and childcare. There are nurses, social workers, physician’s assistants that are be able to provide the support and resources to help.

Survivorship

As a cancer survivor, it is important that you practice self-care regularly to reset your physical and emotional well-being. Adopting routines of self-care will help you recharge your batteries and stay healthy. Talk with your healthcare team about developing a wellness plan to help you stay physically and emotionally healthy and improve your mood. Consider the following suggestions:

• Watch your health. Stay up-to-date with your own medical appointments and take any medications as prescribed.
• Exercise. Stay active with short periods of daily exercise (30 minutes of power walking, jogging or biking). If not possible, take the stairs instead of the elevator or park farther away than usual.
• Eat well. Include fruits and vegetables in your meals and maintain a balanced diet.
• Cut down on risk factors. Quit smoking and reduce alcohol intake.
• Sleep. Try to get 7 hours of sleep per night, or take naps when needed.
• Rest. Meditation, deep breathing and stretching can help you relax and reduce stress.
• Write it down. Keeping a journal with thoughts and feelings may help to let go of worries and fears.

View the Foundation’s Survivorship Series factsheet on the Foundation’s website atl ymphoma.org/publication for more info.

Long Term Follow-Up Care Plan

All lymphoma survivors should have a long term follow up plan (also called a “survivorship care plan”) after treatment ends. This plan is arranged by your healthcare team and includes a summary of the treatments you received, recommendations for follow-up care based on your medical history, and schedules for medical exams to check if the lymphoma has come back (recurrence). This allows your healthcare team to monitor your overall health and look out for long-term effects or other problems that may occur at any point after treatment. Your doctor will let you know how often you need to return for checkup appointments and which physical exams and blood tests are necessary. These checkups usually include a review of your medical history, physical exam and bloodwork, as well as specific exams or screenings recommended by your doctor (see Health Screenings to Consider on next page).

A follow-up care plan may also provide information to help you meet any emotional, social, legal, and/or financial needs. Your health care team can help you decide which doctor to see for your follow-up care plan (the same doctor who treated your lymphoma, a health care provider specialized in caring or cancer survivors, or your primary care provider [PCP]). Some clinics specialized in follow-up cancer plans offer comprehensive support to cancer survivors (called “survivorship clinics”). You can visit oncolink.org/clinics/search to check for survivorship clinics in your area.

View the Foundation’s Survivorship Series fact sheet on the Foundation’s website at lymphoma.org/publication for more info.

Health Screenings To Consider

As a survivor, there are specific health screenings and exams that you may do at an earlier age than the general population. These will be adapted to the type of lymphoma you had and the treatment you received. For instance, due to the increased risk of secondary breast cancer from radiation therapy, women who received radiation therapy to the chest area during childhood, adolescence, or young adulthood should have clinical breast examinations yearly until age 25, then every six months thereafter. In addition, these women should receive yearly mammograms and breast magnetic resonance imaging (MRI) beginning at age 25 or eight years after completion of the radiation therapy, whichever comes last.

Other health screenings the physician may suggest include:

• Bone density scans
• Cardiovascular monitoring
• Chest or whole body imaging
• Screening for other cancers (e.g. colorectal or skin)
• Dental screenings
• Eye exams
• Lipid blood tests
• Thyroid function tests

Because everyone is different, survivors should talk with their physicians about which screenings are most appropriate and when they should be started.

Care Partners

There are many ways you can help a loved one with lymphoma, as follows:

• Be present. The most important thing that a care partner can do is to “just show up.”
• Be prepared. Talk with the healthcare team so that you know what to expect throughout the treatment, how to manage symptoms and when to ask for help.
• Listen. Each person asks for help in different ways, verbally (through words) and nonverbally, and some may require more comfort while others are more action oriented.
• Avoid “cheerleading”. Do not disregard your love one’s negative feelings (sadness, anger or worry).
• Organize the help. A rush of sudden help upon diagnosis can make the situation harder to manage and create unproductive tension.
• Set up remote access with computer and/or phone access. This is helpful for regular communication with your loved one.
• Offer rides. This is important for people with decreased mobility or limited resources.
• Take notes. If you go into the appointments, write down notes with the doctor’s plan, medications, potential side effects and other relevant information.

Patients and their care partner are encouraged to keep copies of all medical records. This includes test results as well as information on the types, amounts, and duration of all treatments received. Medical records are important for keeping track of any side effects resulting from treatment or potential disease recurrences. The Foundation can help patients manage this documentation.

View the Care Partners factsheet on the Foundation’s website at lymphoma.org/publication for more info.

• What is my exact diagnosis? What subtype of lymphoma do I have? May I have a copy of the report from the pathologist?
• What is the stage of my disease? In what area of the body is it specifically located?
• What are my treatment choices? Which do you recommend for me and why? Would choosing one treatment prevent me from getting a different kind of treatment later on? How are the different treatments administered?
• Do I need more than one type of treatment?
• What is the goal of treatment? What are the expected benefits of each type of treatment?
• How will we know if the treatment is working? What tests will I need to determine if treatment is working, and how often will I need to be tested?
• How long will the treatment last?
• What are the chances the treatment will be successful?
• What is a clinical trial? Are clinical trials available that are studying new treatments for my type of lymphoma? Would a clinical trial be appropriate for me? How would I benefit? Are there any drawbacks of participating in a clinical trial?
• Will I be able to work during treatment? Will I be able to drive or take public transportation during my treatment?
• Should I take care of other medical or dental issues before I start treatment?
• How much will the treatment cost? Will my insurance cover some or all of it? What will my out-of-pocket costs be?