John Zic, MD, dermatologist, Tennessee Valley VAMC,
professor, Vanderbilt University School of Medicine

Chronic rash in a sun-protected area that doesn’t respond to topical treatment likely needs to be evaluated for mycosis fungoides, the most common variant of cutaneous T-cell lymphoma. Now, a new VA study reports that a protein expression can help make the diagnosis.

By Annette M. Boyle

NASHVILLE, TN—In its early stages, mycosis fungoides can easily be mistaken for a number of other skin conditions such as eczema and psoriasis. The most common variant of cutaneous t-cell lymphoma (CTCL) has one tell-tale sign that can help physicians identify it much more reliably—and years sooner.

“Mycosis fungoides often take six to 10 years to diagnose, not because healthcare providers are missing the diagnosis, but because it takes time for enough changes to take place in the skin for the malignancy to be detected by a pathologist,” explained John Zic, MD, a dermatologist at the Tennessee Valley VAMC and professor at the Vanderbilt University School of Medicine.

In its early stages, mycosis fungoides can easily be mistaken for a number of other skin conditions such as eczema and psoriasis.

Indolent malignancy occurs most often in older males, “so we would expect there to be a higher percentage of veterans with mycosis fungoides and CTCL than in the general population,” Zic noted.

In an article published in the Journal of the European Academy of Dermatology and Venereology, Zic and his Vanderbilt colleagues, led by Laura McGirt, MD, confirmed that mycosis fungoides (MF) increases expression of thymocyte selection-associated HMG box protein (TOX). In addition, they found that large plaque parapsoriasis (LPP) also increases TOX expression. While LPP is not considered a malignancy itself, 10-20% of people who have it will go on to develop MF. 1

The team stained and analyzed samples with MF (53), other forms of cutaneous t-cell lymphoma (20), large plaque parapsoriasis (10), normal skin (2) and benign inflammatory dermatoses (17). Of the 53 MF samples, 73.6% stained positively and 62.3% showed strong positive results. The benign conditions, in contrast, picked up any TOX expression in 31.6% of samples and only one (5.3%) was strongly positive.

“If there is a strong expression of the TOX marker with staining on skin biopsies, then the positive predictive value for MF is almost 97%,” Zic told U.S. Medicine. “That’s significant because many skin disease have lots of t-cell lymphocytes in the skin. This helps us distinguish which ones are likely MF, an early lymphoma of the skin, and which are benign.” TOX has a negative predictive value of 47%, he added.

Better Identification

TOX can also facilitate identification of non-MF types of CTCL. The researchers stained samples of cutaneous anaplastic large cell lymphoma (8), systemic anaplastic large cell lymphoma (3) and lymphomatoid papulosis (9). Half of these CTCL sample stained at all and just 5% had strongly positive TOX staining, much lower than seen in MF.

TOX helps identify LPP, too. The researchers found a nearly equal number of biopsies for LPP and MF had TOX staining, 70% and 75%, respectively. Half of LPP samples had strong TOX staining. As a result, TOX will not clearly differentiate between those two conditions, but it will help distinguish them from other benign skin problems.

The similar response in LPP and MF might help in other ways, however. “If we start to understand why LPP evolves into MF in some patients, we might learn some important information about why some patients get MF in the first place,” Zic pointed out.

Studies that looked at exposure to chemicals as a potential factor in MF development produced conflicting results, he noted, and the disease occurs across all socio-economic strata.

TOX expression might be part of the answer. The authors noted that previous research had shown that overexpression of TOX increased CTCL cell growth and that follow up with the patients who have LPP indicated high TOX levels could reveal whether they progress to MF at a higher rate or more quickly than others. Samples with MF that were exposed to agents such as retinoid, bexarotene or depsipeptide that inhibit CTCL proliferation had lower TOX levels, which also indicated a relationship between the protein’s expression and cell growth.

MF tends to occur more often and more aggressively in blacks than in whites. All of the slides from black patients with MF had positive TOX expression, compared to 65.9% of those from whites, according to the report. The authors caution that the small sample size may skew the conclusions, but other studies have shown an association between higher TOX expression and worse outcomes.

The best marker for MF until now has been negative—the loss of CD7. “Determination of a positive tumour marker would be instrumental in the timely and appropriate diagnosis of MF, particularly in the early stages of the disease,” the authors wrote.

TOX simplifies the differential. “If a pathologist is suspicious for MF, a strongly positive result for TOX may lead to an earlier and more confident diagnosis,” Zic said.

Attention to unusual rashes could also help with diagnosis.

“Veterans or active duty force patients who might be suspected of having MF would be those with pink to red patches or plaques on sun-protected areas, such as the buttocks, arm pits, groin or breasts. It doesn’t wax and wane and often doesn’t itch, so patients may not bring it to the attention of a physician because it doesn’t bother them,” Zic suggested.

For nonpathologists, one of the best early signs of MF is very straightforward. As Zic put it, “If you have a chronic rash in a sun-protected area that doesn’t respond to topical treatment, it may need to be evaluated for MF.”

  1. McGirt LY, Degesys CA, Johnson VE, Zic JA, Zwerner JP, Eischen CM. TOX expression and role in CTCL. J Eur Acad Dermatol Venereol. 2016 Sep;30(9):1497-502. doi: 10.1111/jdv.13651. Epub 2016 Jun 26.