FOXP3 Can Predict Disease Progression and Risk of Transformation in Uniformly Treated Patients with Mycosis Fungoides

Mycosis fungoides (MF) is a heterogeneous lymphoid neoplasm with a variable clinical course. In early stages MF often runs an indolent course. A small but significant part of these patients develop an aggressive course frequently associated with inferior survival. No consistent biological markers are predictive of survival or risk of transformation (RT). Foxp3 belongs to a novel forkhead transcription factor essential for the development and regulation of regulatory T-cells (Treg). Recent studies have shown conflicting results when expression of Foxp3 was analyzed as a prognostic factor in MF. We hypothesized that Foxp3 could be an important marker in predicting for overall survival (OS), progression-free (PFS) survival and RT in MF patients managed by uniform treatment regimens.

42 patients with newly diagnosed MF were retrieved form the record files. All patients were managed and treated at our institute. Complete follow-up and pathological material (paraffin blocks) was available for 35/42 patients. In all 35 cases the diagnostic biopsies were reviewed concurrently by an expert dermatopathologist and hematopathologist and diagnosis fully confirmed. The diagnostic biopsies were immunostained with CD3, CD4, CD7, CD8, CD30 and CD56 specific antibodies. Clonality for TCR gamma was performed for most of the cases in the study (85%). FOXP3 antibody (clone 221D/D3) that recognizes the Foxp3 in the nucleus (but does not cross react with other Foxp proteins) was utilized for studying the Foxp3 expression by the tumor cells and or peritumoral lymphocytes. 20 cases of reactive non-neoplastic dermal lesions including lichen planus, lupus and dermatitis were also immunostained for Foxp3 for comparison. Only high intensity nuclear staining was accepted as positive expression. The Foxp3 staining was further semi quantitatively estimated as no expression (0), 0–10% (1+), 10–50% (2+) and >50% (3+). Both the cell content and immuno-architectureal pattern were determined. Age, sex, clinical presentation, stage of disease was compared to Fox3 expression by chi-square and Fishers's exact test. The Kaplan-Meyer method and log rank test were used to evaluate survival data.

34 of 35 (97%) patients were alive at 8 years. Tumor stage at the time of diagnosis as defined by ISCL-EORTC, 2008 was as follows: stage 1A (57%), 1B (25%), 2A (6%), 2B (6%), 3 (6%). 19/35 (54%) were female and 16/35 (46%) were male. The median age at diagnosis was 44.0 years (range 7–80 years). The median follow-up period was 37 months (range 12– 96 months). Foxp3 expression showed predominantly intraepidermal or basal localization of tumor cells. In most of the cases the epidermotropism and the nuclear atypia was helpful in easily discerning tumor cells from reactive non-neoplastic Tregs. Reactive dermal lesions served as an excellent control in that the distribution of Tregs in these lesions was predominantly dermal and rarely basal. Overall 28/35 (80%) and 7/35 (20%) cases were positive and negative for Foxp3 respectively. There was no significant correlation between disease pattern, clinical presentation, stage, age or sex and marker expression. In the Foxp3 positive patients 17/28(61%) showed disease progression whereas 11/28 (39%) were free of disease at last follow-up (FU period 12–96 months) (p=0.05, Fisher's exact test). 13/28 (46%) Foxp3+ patients were found to have relapse of disease after initial response compared to only 2/7 (28.5%) patients, who relapsed but lacked Foxp3 expression (p=0.242, Fisher's exact test). Comparing disease progression and aggressiveness as evidenced by lymph node metastasis and transformation to Sezary syndrome: only Foxp3 positive cases (4 versus 0) had evidence of disease progression (3 lymph node metastasis alone and one Sezary syndrome) thus indicating increased RT. One patient who died of widespread disease showed >30% Foxp3 expression in the neoplastic lymphoid cells.

Specific biological markers for outcome and prognosis in MF remain elusive. A regulatory T-cell (Treg) phenotype defines a subset of MF patients who might carry a different prognosis and might require more aggressive and or targeted therapy. More data on Foxp3 expression in cutaneous T-cell lymphomas and its clinical significance is needed.

No relevant conflicts of interest to declare.