الفهرس 
PATHOGENESIS OF MYCOSIS FUNGOIDESOnly 14 pages are availabe for public view
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Abstract
M
ycosis fungoides represents the most common type of CTCL. There is continued and substantial increase in the incidence of MF in the last years especially among Arab populations. The diagnosis of early MF (stage I, IIA) is one of the greatest challenges in clinical dermatology and dermatopathology. The lack of a standardized and reliable method for diagnosing MF presents significant difficulties in the assessment and management of patients suspected to have MF.
To solve this problem, the ISCL (2005) has proposed an algorithm for the diagnosis of early MF. This algorithm relies on integration of several diagnostic parameters (clinical, histopathological, immunophenotypical and molecular). Although, the proposed algorithmic scoring provides a degree of diagnostic standardization, it lacks positive identification markers for better establishment of the diagnosis.
TOX is a candidate diagnostic marker for MF. It showed significant expression in early MF lesions versus dermatitis. TOX encodes a nuclear protein of the HMG family that act as transcription factor and is highly but transiently expressed in thymic tissue. TOX is a critical regulator of early T-cell development, specifically during the transition from CD4+/CD8+ precursors to CD4 + T cells. After leaving the thymus, it is tightly suppressed. However, it was found to be expressed in various tumors including cutaneous lymphomas
To the best of our knowledge, no studies have investigated the differential expression of TOX in both classical and hypopigmented MF. We aimed to evaluate TOX as a positive identification marker for classical and hypopigmented MF and correlate it with their CD4/CD8 immune profile.
To achieve our goal, we included 30 patients with early stage MF (15 patients with classical MF; 15 patients with hypopigmented variant) and compare them with 15 patients with BID (chronic dermatitis) as a control group. Both cases and controls were sex and age matched. Patients were recruited from the cutaneous lymphoma clinic at the Dermatology department, Ain Shams University.
Patients were diagnosed and staged according to the ISCL guidelines. Immunohistochemical evaluation of TOX was done for both cases and controls. Specimens showing >10% nuclear staining of lymphocytes were considered positive (weak positive: 10-50%; strong positive: >50%). CD4 and CD8 expression was also studied among cases to detect the predominant phenotype expression.
In our study, the mean age among all MF cases was 34.1±18.4 with male predominance (70%). The mean age of onset in the MF group was 29.5 years. Most of the patients (76.7%) had lesions on sun-protected sites. There is highly significant difference between classic and hypopigmented MF cases as regards the age, as it was found that in classic MF the mean age was 46.3 years, while in hypopigmented MF cases was 21.8 years. There was also highly significant difference as regards age at time of disease onset as the mean in the classic type was 40.8 years, while it was 11.8 years in the hypopigmented variant. These data confirmed the results of previous studies that hypopigmented MF affects younger age group with earlier age of onset.
In our study, histopathology of both MF variants revealed that interface type of epidermotropism was found in 53.3%, while 46.7% had pagetoid epidermotropism. No significant difference was found between the classic MF and hypopigmented MF regarding duration of the disease, sex, site of MF and epidermotropism type. However, statistically significant difference was found between classical and hypopigmented MF regarding CD4/CD8 expression, where majority of classical variant express CD4 (73.3%), while CD8 expression was predominant in hypopigmented variant (73.3%). Our results were in agreement with previous studies that showed that CD8 is the predominant phenotype in hypopigmented MF, whereas CD4 is more common in classic MF.
Regarding TOX expression, highly significant difference was found between MF cases and controls, as 96.7% of cases had positive expression compared to 26.7% of controls. TOX was found to have 96.7% sensitivity and 73.3% specificity in differentiating cases from controls. Highly significant difference was found between classic MF cases and controls, where 93.3% of classic MF cases showed positive TOX expression comparable to 26.7% of controls with 93.3% sensitivity and 73.3% specificity.
The aberrant TOX expression in MF was previously confirmed in MF without significant expression in chronic dermatitis by most studies. Besides immunohistochemistry, previous studies showed that TOX was overexpressed by immunofluorescence, real time quantitative-PCR and gene profiling. TOX was found to promote the cell cycle and suppress tumor suppressor genes. All these confirm that TOX is a potential diagnostic marker for early MF and has a vital role in promoting early MF.
As regards hypopigmented MF, highly significant difference was found between cases and controls regarding TOX expression, where all hypopigmented cases showed positive TOX expression comparable to 26.7% of controls. Sensitivity and specificity was 100% and 73.3%, respectively. To the best of our knowledge, no similar case control studies had been previously reported in literature.
In the current study, there was no significant difference in TOX expression as regards age, sex, site of MF, stage of MF, epidermotropism type. In addition, no significant difference was found as regards MF clinical type (classical vs. hypopigmented) or CD4/ CD8 expression. This shows that TOX expression is not only restricted to CD4+ cells and it can also be expressed by CD8+ MF variants.
It seems that TOX is a promising diagnostic marker with high sensitivity and specificity, not only in classical MF, but also in hypopigmented variant. TOX was found to be expressed among MF cases regardless of their immune profile. This highlights that a more complex underlying mechanisms exists that can promote tumorigenesis among MF variants regardless of their immune profile.