Progress is slow in improving diagnosis of CTCL

Cutaneous T-cell lymphoma (CTCL) is a complex disease that is difficult to diagnose and manage, but advances in research and technology are raising hopes of finding reliable tests and biomarkers for earlier diagnosis. These advances were examined Saturday during “Management Issues in Cutaneous Lymphoma” (F066).

“There is a lot that is not known, but there are many great developments coming out now, including high throughput sequencing and transcriptional profiling. We are also learning about dysregulation of certain pathological pathways and how we can manipulate them to treat the disease,” Larisa J. Geskin, MD, associate professor of dermatology and director of the Cutaneous Oncology Center at Columbia University, New York, said in an interview about her presentation.

The most common types of CTCL are mycosis fungoides and Sezary syndrome. Mycosis fungoides is often confused with conditions such as eczema and psoriasis, and is frequently misdiagnosed, with an average diagnosis taking eight years, she said. Sezary syndrome patients are often misdiagnosed as having peripheral T-cell lymphoma and mistakenly treated with aggressive chemotherapy.

“The reason for the delay in diagnosis is that the current methods rely on a constellation of findings, including immunohistochemistry, phenotyping, evidence of clonality, and clinical presentation. They are not very specific or sensitive,” Dr. Geskin said.Mycosis fungoides is considered to be an incurable disease, but there are many new promising therapies coming out. Early diagnosis is beneficial because it can provide appropriate therapies so patients feel better.”

Keys to earlier diagnosis would be the development of reliable testing and finding biomarkers. Dr. Geskin reviewed research modalities being used to improve diagnosis, including proteomic approaches, micro RNA (mRNA) classification, evaluations of copy number variations, transcriptional profiling, and T-cell receptor clonality (TCR).

In 2012, Dr. Geskin’s laboratory reported increased TOX and decreased RUNX3 tumor suppressor gene expressions based on high throughput sequencing and genetic profiling. This finding was confirmed by the protein expression in the tissue, and it has led to the discovery of the TOX gene as a useful marker for CTCL diagnosis.

“TOX is very important because it was shown to be present in the tissue biopsies of these patients,” Dr. Geskin said, adding that it may be a more specific marker in the detection of CTCL.

TOX plays a role in CD4+ T-cell development, and it regulates RUNX3, a known tumor suppressor gene. In CTCL, TOX acts as an oncogene, which suppresses RUNX3, dysregulating the TOX-RUNX3 pathway, a novel oncogenic pathway recently described by Dr. Geskin’s group and others.

Other developments in the diagnosis and pathogenesis of CTCL are the use of FISH (fluorescence in situ hybridization) to assess copy number variations, transcriptional profiling, and high throughput sequencing of TCR. Researchers are discovering patterns in these patients, Dr. Geskin said.

“There are no dependable biomarkers in CTCL, but we are finding frequently dysregulated pathways, and proteomic and genomic abnormalities. We have new methods and technologies coming out that detect new markers that were not previously known,” she said. “We are searching for new diagnostic tests, and in the process, we learn about disease pathogenesis and dysregulation of normal pathways in cutaneous T-cell lymphoma.”

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