Peripheral T-Cell Lymphoma

What is Peripheral T-Cell Lymphoma ?

Peripheral T cell lymphoma (PTCL) is a type of cancer that comes in many forms, making up 5% to 15% of non-Hodgkin lymphomas – a type of cancer that originates in your lymph system – in the western world. It’s made up of system-wide and skin-related forms developed from T-cells and natural killer (NK) cells, types of white blood cells that share many features. These cancers are often aggressive in nature.

One variety of PTCL, called Angioimmunoblastic T cell lymphoma (AITL), is now considered a unique kind. This variety was first identified in 1974 and was previously known by several different terms. Today, we know it develops from a type of cell called the follicular T helper cell.

There’s another group of lymphomas – called cutaneous lymphomas – that show up in the skin without signs of cancer elsewhere in the body at the time of diagnosis. These further break down into cutaneous B-cell lymphoma (CBCL) and cutaneous T-cell lymphoma (CTCL) categories—with CTCLs making up the majority of all primary skin lymphomas. These CTCLs are classified separately from PTCLs.

Among the CTCLs, there are Mycosis fungoides (MF), Primary cutaneous anaplastic large cell lymphoma, and Sezary syndrome (SS). MF is the most common type of CTCL, even though it’s a rare type of non-Hodgkin lymphoma. Primary cutaneous anaplastic large cell lymphoma is another form of CTCL. Both account for about 80% of all CTCLs.

One particularly rare and aggressive type of PTCL is known as Large Cell Cutaneous Ki-1 Anaplastic Lymphoma, which is sometimes referred to as ‘Anaplastic large cell lymphoma’ (ALCL) or ‘CD30 positive anaplastic large cell lymphoma’. It belongs to the group of CD30-positive lymphoproliferative disorders, conditions characterized by an overproduction of lymphocytes. It can affect both lymph nodes and areas outside the lymphatic system. There are two key sub-types differentiated by whether the anaplastic lymphoma kinase (ALK) protein is present.

SS is a rare type of CTCL that looks like a type of leukemia. It’s typically known for a triad of signs: itchy red skin, swollen lymph nodes throughout the body, and distinct “Sezary cells” found in the skin, lymph nodes, and bloodstream. While MF is a primary subtype of CTCL, it has often been inaccurately used interchangeably with CTCL. In reality, it’s an aggressive form of CTCL.

The topics addressed include:

• Angioimmunoblastic T cell lymphoma
• Large Cell Cutaneous Ki-1 Anaplastic Lymphoma
• Cutaneous T-cell lymphoma:
• Mycosis fungoides
• Sezary syndrome

What Causes Peripheral T-Cell Lymphoma ?

A combined analysis of 15 separate studies identified several risk factors that can greatly increase the likelihood of developing PTCL (Peripheral T cell lymphoma). These include having a family history of blood-related cancers, having skin conditions like eczema or psoriasis, having celiac disease, smoking heavily, and working in certain jobs like textile manufacturing and electrical fitting.

The cause of Large Cell Cutaneous Ki-1 Anaplastic Lymphoma, a type of skin lymphoma, is not known yet. However, research at the molecular level has found that in a subtype of this lymphoma that is ALK-positive, there is an overexpression of the ALK gene, which is a type of protein involved in cell growth. This overexpression happens due to a specific change in the genetic code, referred to as t(2;5)(p23;q35) translocation.

The causes behind the occurrence of Mycosis fungoides (MF) and Sezary syndrome (SS), two other types of skin lymphoma, are not clear. It’s thought that factors like exposure to certain environmental elements, alterations in the immune system, infections, and presence of other cancers might contribute to the development of these lymphomas. Considering that people with these conditions often have a family history of tumors, it seems likely that genes play a higher role in the occurrence of MF and SS compared to other lymphomas.

Risk Factors and Frequency for Peripheral T-Cell Lymphoma

• Anaplastic large cell lymphoma (AITL) accounts for up to 2% of all non-Hodgkin’s lymphoma (NHL) cases, and one in five of peripheral T-cell lymphoma (PTCL) cases annually.
• AITL is as common in men as it is in women, is seen more often in Europe than Asia or North America, and typically affects people aged between 65 and 70.
• Cutaneous T-cell lymphoma (CTCL) has become more common between 1973 and 1998, with the incidence now stable; it seems to be twice as common in men as women.
• CTCL is more prevalent among African Americans, people living in cities, and those with a higher income and education level.
• People who have had organ transplants or are living with HIV also have a higher incidence of CTCL.
• Mycois fungoides (MF), a type of CTCL, accounts for about 50% of all CTCL cases, seems to be almost twice as common in men, and typically affects people in their mid-50s to early 60s.
• Hispanic patients typically present with MF at a younger age, with more severe disease, and a more aggressive course of the disease.
• Sezary syndrome constitutes about 3-5% of all CTCL cases and is more prevalent among non-Hispanic white individuals.
• Large cell cutaneous Ki-1 anaplastic lymphoma, the second most common form of CTCL after MF, makes up 25% to 30% of all cases; it is more common in non-Hispanic whites, and has a good prognosis.
• This type of lymphoma can occur in people of any age, but most often affects people in their 60s.

Signs and Symptoms of Peripheral T-Cell Lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) has common symptoms, including “B symptoms,” such as excessive sweating during sleep, a fever, and weight loss. There might also be enlargement of the liver and spleen at diagnosis. Some patients will have rashes as the first symptoms, which can vary from hives to nodular tumors. About 20 to 50 percent of patients with AITL will have rashes.

Nearly all patients with cutaneous T-cell lymphomas (CTCLs) will have symptoms that seem similar to “chronic dermatitis.” These symptoms may often be misdiagnosed as chronic nonspecific skin conditions. The skin lesion of mycosis fungoides (MF), a type of CTCL, tend to progress from “patch” to “plaque” to “tumor.” A “patch” is a flat, red skin lesion. A “plaque” is a raised, well-defined skin lesion less than a centimeter in size. A “tumor” is a raised lesion larger than a centimeter. As the disease progresses, the lesions may preferentially appear in skin folds and areas not exposed to the sun.

• Flat, red skin lesion (“patch”).
• Raised, well-defined skin lesion less than a centimeter in size (“plaque”).
• Raised lesion larger than a centimeter (“tumor”).

The skin lesions can be itchy, and the severity of this itchiness can affect a patient’s overall quality of life. Sezary syndrome, an aggressive type of CTCL, typically presents as itchy red skin (erythroderma), enlarged lymph nodes (generalized lymphadenopathy), and the presence of “Sezary cells” in the blood. Primary cutaneous anaplastic large cell lymphoma (PCALCL), another type of lymphoma, often appears as a brownish or violet nodule or tumor, and can be either a single lesion or multiple lesions spread across the body.

Testing for Peripheral T-Cell Lymphoma

When it comes to diagnosing a type of cancer known as Angioimmunoblastic T cell lymphoma, you will have to undergo several tests. This includes a physical examination, blood tests, a metabolic panel, and LDH test, which checks for damage in the body. Your doctor may also test you for a virus (HTLV-1) that can increase your risk for this type of cancer. Imaging tests like a CT scan of the chest, abdomen, and pelvis or a PET-CT scan, which produces detailed 3D images of the inside of the body, are also used.

The ultimate diagnosis will depend on your clinical symptoms, what the doctor observes under the microscope on your tissue samples (histopathology), the types of cells found in your body’s immune response (immunophenotyping), and DNA tests (molecular studies).

There are certain blood irregularities that may point to this type of cancer, such as higher than normal levels of certain types of protein in the blood (polyclonal hypergammaglobulinemia), blood cells breaking down too quickly (autoimmune hemolytic anemia), and high levels of a type of white blood cell (peripheral eosinophilia).

In the tissue samples tested, doctors may note changes in the lymph nodes and an increase in certain types of cells. There might also be changes seen in certain protein markers on the cells and abnormalities in chromosomes, which are structures in cells that contain genes. Sometimes, a diagnosis of another type of lymphoma (diffuse large B-cell lymphoma) might be made at the same time or after the initial diagnosis, which may require a repeat biopsy if the cancer comes back.

If you have a certain type of skin lymphoma (called Mycosis fungoides and Sezary Syndrome), the diagnosis process is quite similar. The doctor again looks at your clinical symptoms and tissue samples, takes a biopsy of the skin and/or lymph nodes, and imaging is done as well. They might also ask for a bone marrow biopsy (a test that measures the amount of bone marrow and fat in a specific area of the bone) if they suspect that the disease has spread. The purpose of flow cytometry, a process used to measure properties of cells, is to assess the unique characteristics of the T-cells.

The tissue samples may show changes in the skin cells and in the skin’s lymphocyte cells, which are a type of immune cell. Doctors are particularly looking at the presence of cerebriform nuclei, which are oddly shaped cell structures. For this type of lymphoma, they also look for epidermotropism, which is when lymphocytes start to migrate to the skin. Immunophenotyping helps complete the diagnosis, where doctors will again look out for certain markers on cells and note any that are missing that should typically be there.

Treatment Options for Peripheral T-Cell Lymphoma

Angioimmunoblastic T cell lymphoma (AITL) is a type of cancer that commonly affects the lymphatic system. Even though the success rate seems quite low, current treatment typically involves the use of a four-drug regimen that includes cyclophosphamide, daunorubicin, vincristine, and prednisone, also known as CHOP therapy. CHOP therapy has been shown to be most effective in individuals diagnosed with AITL who are over the age of 60. 

Recent trials have also shown that combining brentuximab vedotin (another medication) with a slightly modified version of CHOP therapy can yield better results, including slower disease progression and improved chances of survival. 

For AITL that has come back (relapsed) or doesn’t respond (refractory) to initial treatments, other regimens, such as ICE (ifosfamide, carboplatin, etoposide) or DHAP (dexamethasone, cisplatin, cytarabine), can be used. These options have shown an overall response rate of up to 70%. Other treatments showing promise include drugs designed to inhibit a certain protein involved in cancer growth (histone deacetylase inhibitors).

Anaplastic Lymphoma is another type of lymphoma that can affect the skin, also known as Large Cell Cutaneous Ki-1 Anaplastic Lymphoma. CHOP or similar treatments are often the first choice of treatment. In early stages, it can be combined with radiation therapy. For cases of relapse (cancer returns after treatment) or poor prognosis (outlook is less favorable), high-dose chemotherapy, followed by autologous stem cell transplantation, may be offered. This treatment involves harvesting healthy stem cells from the patient before the high-dose chemotherapy, then re-infusing them back into the patient to help rebuild their immune system. 

Mycosis fungoides and Sezary syndrome are types of cancer that primarily affect the skin and are largely treated based on accurate staging of the disease. Staging involves assessing how far the disease has spread in the body. Treatment involves local and systemic therapy. Local therapy treats a specific location, and may involve topical creams or gels, phototherapy, or photodynamic therapy– a treatment that uses a drug and a specific type of light to kill cancer cells. Electron beam therapy, a type of radiation therapy using electron beams, also has a shown to be effective.

Systemic therapy treats the whole body and is used for more advanced stages of these disorders. This could involve oral retinoids, histone deacetylase inhibitors, interferon-alpha, apheresis procedures which filter the blood, monoclonal antibodies which are designed to target specific cells, and chemotherapy. Treatment with oral retinoids or chemotherapy is often recommended for advanced disease but comes with potential side effects such as high cholesterol and potential harm to a developing fetus in pregnancy. Alemtuzumab, a special type of medication designed to target and eliminate certain immune cells, has shown to be particularly effective in SS, a severe form of the disease. Brentuximab vedotin, a medication that directly targets cancer cells, also showed promising results in MF. Chemotherapy can be a treatment option, but its use as a single agent has been linked to a worsening of the prognosis. Multimodal therapy, which involves the use of several different treatments, tends to be associated with better outcomes.

What else can Peripheral T-Cell Lymphoma be?

In the case of Angioimmunoblastic T Cell Lymphoma, doctors typically look for signs such as persistent fever, skin rash, and swollen lymph nodes. To pinpoint the correct diagnosis, they’ll need to rule out other conditions that can cause similar symptoms. The common alternatives could include:

• Skin cancer (cutaneous lymphoid neoplasms, including cutaneous lymphomas)
• Infections
• An autoimmune disease

Examining suspicious skin lesions will usually confirm the diagnosis.

Another condition, Large Cell Cutaneous Ki-1 Anaplastic Lymphoma, is often mistaken for different types of lymphomas like Hodgkin’s lymphoma and T-cell lymphomas, due to the presence CD30, a protein often expressed in these conditions.

As for Cutaneous T-cell Lymphoma, it is frequently confused with harmless skin conditions, which are the frequently identified alternative diagnoses that can have similar symptoms. The common alternative diagnoses include:

• Psoriasis
• Contact dermatitis
• Drug rash

These conditions may even show T-cell rearrangements (TCR) similar to Cutaneous T-cell Lymphoma.

What to expect with Peripheral T-Cell Lymphoma

Angioimmunoblastic T Cell Lymphoma

Angioimmunoblastic T Cell Lymphoma (AITL) is gauged by up to 4 scoring systems that help determine the possible outcome or prognosis of the condition. These systems are: IPI (International prognosis index), mPIT (Modified prognostic index for PTCL), and IPTCLP (International peripheral T cell lymphoma project score). These guides consistently use a patient’s age and physical well-being in their calculations. Additional factors considered are platelet count by the IPTCLP, and a protein called Ki-67% by mPIT.

Large Cell Cutaneous Ki-1 Anaplastic Lymphoma

Regarding Large Cell Cutaneous Ki-1 Anaplastic Lymphoma, patients with ALK-positive (a specific gene mutation) have better chances of survival compared to those who are ALK-negative. The 5-year survival rate for ALK-positive patients is 70-80%, compared to 33%-49% for ALK-negative patients. Unfortunately, chances of recovery worsen if the disease reoccurs.

Mycosis Fungoides and Sezary Syndrome

For conditions such as Mycosis Fungoides and Sezary Syndrome, the patient’s outlook greatly depends on the stage of the disease. If the disease progresses to transform into large T-cell lymphoma (a type of blood cancer), whether it is CD30+ or CD30-, the prognosis is generally less favorable.

Possible Complications When Diagnosed with Peripheral T-Cell Lymphoma

The most common cause of death in both Angioimmunoblastic T-Cell Lymphoma (AITL) and Cutaneous T-Cell Lymphoma (CTCL) is typically caused by an infection, which is responsible for about half of all patient deaths. The most common types of these infectious diseases are septicemia, otherwise known as blood poisoning, and bacterial pneumonia. In about 10% of advanced Mycosis Fungoides (a form of CTCL) cases, the herpes virus infection is reported. After these infections, the most common cause of death is usually due to the infection spreading widely to other organs.

Severe Symptoms and Risks:

• Infections (responsible for about half of all patient deaths)
• Septicemia (blood poisoning)
• Bacterial pneumonia
• Herpes virus infection (in about 10% of advanced Mycosis Fungoides cases)
• Widespread infection to other organs (leading cause of death post infections)

Preventing Peripheral T-Cell Lymphoma

Patients need to have the right information about their specific cancer type, its likely outcome, the different treatment choices they have, and any possible side effects of these treatments before their therapy starts. This information helps them understand their illness better and prepare for what to expect during the course of their treatment.