Rare Lymphoma Challenges VA Clinicians from Diagnosis to Treatment

by U.S. Medicine

May 21, 2014
An estimated 5-10% of all cutaneous T-cell lymphoma (CTCL) diagnosed each year occurs in veterans treated by the VA. The cancer, classified as presumptively caused by Agent Orange exposure, is notoriously difficult to diagnose and often tricky to treat. That is changing with important new drugs on the market and a spate of new clinical trials. By Annette M. Boyle DURHAM, NC—Even for experienced dermatologists, cutaneous T-cell lymphoma (CTCL) remains a mystery disease. CTCL comprises several related conditions, but in total, they account for less than 4% of all non-Hodgkins lymphomas. Physicians at the VA, however, have the greatest chance of ever seeing a patient with CTCL, as 5-10% of new cases diagnosed each year occur in patients seen at VA medical facilities.
Mycosis fungoides is the most common form of cutaneous t-cell lymphoma.

Mycosis fungoides is the most common form of cutaneous t-cell lymphoma.

The VA classifies CTCL as presumptively caused by Agent Orange exposure. The incidence of CTCL rose nearly 5.7% per year from 1973 until 1998 and has since stabilized at 7.7 per 1 million person years. The disease occurs twice as often in men as in women and incidence increases with age, with first diagnosis typically in individuals over the age of 50. Mycosis fungoides (MF), the most common form of CTCL, gets its name from the mushroom-like skin tumors that sometimes develop in the advanced stage of the disease. MF is typically indolent in its early stages. The second most common subtype, Sezary syndrome (SS), is a more aggressive, leukemic form of the disease. Rarer subtypes include cutaneous CD30-expressing anaplastic large cell lymphoma, panniculitis-like T-cell lymphoma, CD8-expressing aggressive epidermotropic T-cell lymphoma and gamma-delta T-cell lymphoma. “Mycosis fungoides is difficult to diagnose in its early stages because the symptoms and skin biopsy finding are similar to those of other skin conditions,” said Michael Kelley, MD, National Program Director for Oncology for the VA. “The disease looks different in each patient with skin symptoms that can appear as patches, plaques or tumors. These skin lesions may be mistaken for eczema, psoriasis or dermatitis.”
Click the above table to expand it to full-size in a new table

Click the above table to expand it to full-size in a new table

Symptoms for MF and SS may include:
  • Scaly red rash or discolored patches in unexposed skin
  • Thin, reddened, eczema-like rash
  • Thickened scaly, red skin or psoriasis-like rash
  • Tumors on the skin, which may ulcerate and become infected
  • Total body redness, often with scaling and erythroderma1
Because CTCL often resembles other, more common diseases, diagnosis includes physical examination and history and other tests. “Sites of biopsy may include skin, lymph node, bone marrow, or other involved organs. Patients with very advanced stage CTC can have malignant cells circulating in the blood (Sezary syndrome), which can be detected by blood tests such as routine examination of a peripheral blood smear or immunophenotyping of a blood sample,” Kelley told U.S. Medicine. To determine whether CTCL involves lymph nodes or other organs, imaging may also be used. Many patients diagnosed in the early stages of the disease with MF or SS may never progress to tumor lesions. “The course of the disease is widely variable between patients with some individuals having disease limited to the skin that waxes and wanes over many years or decades, while other individuals have disease that involves lymph nodes, bone marrow, and other organs, in addition to skin,” Kelley said.
Click the above table to expand to full-size in a new tab

Click the above table to expand to full-size in a new tab

In early stage disease, topical treatments may keep the disease in check indefinitely. Patients with more advanced disease will typically require both topical and systemic therapies. Kelley noted that there are many effective treatments currently available for CTCL, but none are thought to be curative. Frequently, patients will find symptomatic relief or remission from a treatment for several months or longer before requiring additional treatment or new therapies. The VA employs a variety of therapeutic options to treat CTCL patients, with the most appropriate treatment determined by the extent of the spread of the lymphoma cells, the aggressiveness of the disease, and the general and medical condition of the patient. Topical treatments for early stage disease with involvement limited to the skin include corticosteroids, chemotherapy agents such as nitrogen mustard and carmustine, retinoids such as bexarotene, radiation therapy to the skin and phototherapy.
The main goal in treating cutaneous t-cell lymphoma, shown above, is to induce a long term remission with minimal impairment of the patient’s quality of life or immune system.

The main goal in treating cutaneous t-cell lymphoma, shown above, is to induce a long term remission with minimal impairment of the patient’s quality of life or immune system.

For more advanced stage disease, VA treatment options include systemic use of retinoids, histone deacetylase inhibitors such as romidepsin and vorinostat, immunomodulatory agents such as interferon and lenalidomide, chemotherapy, stem cell transplant and extracorporeal photopheresis, according to Kelley. In the absence of a known cure and the presence of multiple effective treatment agents, the main goal of CTCL treatment today is to induce a long-term remission with minimal impairment of the patient’s quality of life or immune system. That goal may change in the near future, though, as the number of clinical trials in this field has recently exploded. From 1996-2000, ClincialTrials.gov listed 66 trials for CTCL.2 Currently, 109 clinical trials are in process, according to the site. Drugs in clinical trials include the novel HDAC inhibitors, belinostat and panobinostat; a proteasome inhibitor, bortezomib; forodesine, a purine nucleoside phophorylase inhibitor; and vaccinations.  In 2013, the Food and Drug Administration approved mechlorethamine (nitrogen mustard), an alkylating agent, in gel formation as a topical treatment for the mycosis fungoides type of CTCL in patients who had received one or more previous skin-directed therapies. The drug was previously approved for intravenous use in CTCL. 1 Leukemia & Lymphoma Society. Cutaneous T-cell Lymphoma Facts. October 2011. 2 Akilov OE, Geskin L. Therapeutic Advances in Cutaneous T-cell Lymphoma. Skin Therapy Letter. 2011;16(2).

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