الفهرس 
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Abstract
Mycosis fungoides is the most common type of cutaneous T Cell lymphomas. It has unclear cause, but various hypotheses are proposed. The clinical presentation of MF varies with the stage of the disease either patch, plaque or tumor stage. Janus kinases are non-receptor intracellular tyrosine kinases that play a key role in the pathogenesis of inflammatory skin disorders and several hematological malignancies. Deregulated JAK signaling appears to play an important role in survival of malignant T cells. JAK inhibitors have proved efficacy when used in treatment of some dermatological diseases including psoriasis and atopic dermatitis. The aim of the present study was to evaluate the expression of JAK1 and JAK3 in MF patients in comparison to normal healthy controls to highlight a possible role of JAK1 and JAK3 in the pathogenesis of different stages of MF, prognosis and severity of mycosis fungoides. Patients and methods: This study included (53) patients diagnosed clinically, dermoscopically and histopathologically as MF, collected from the outpatient clinic of Dermatology & Venereology Department and Clinical Oncology department, Tanta University Hospitals, and (53) healthy subjects were obtained during multiple plastic surgeries from the Plastic Surgery Department, Faculty of Medicine, Tanta University & from healthy volunteers and were served as controls, matching the age and sex of MF patients. All patients were subjected to the following: 1- Detailed history taking. 2- Thorough general and dermatological examinations. 3- Written informed consents and photographing of the skin lesions at first clinical presentation. 4- Dermoscopic examination of the lesions using manual dermoscopy. 5- MF staging according to TNMB classification system recognized by ISCL/EORTC staging. 6- Routine laboratory investigations and imaging for staging of MF 7- Skin biopsies from the obvious skin lesions in MF patients and from healthy subjects were obtained and submitted for: • Routine H & E examination. • Immunohistochemical staining using CD3 & CD4 immunostains. • Immunohistochemical staining using JAK1 and JAK3 monoclonal antibodies. • Real-time Quantitative Reverse Transcription Polymerase Chain Reaction (RT-PCR) for JAK 1 and JAK3. The results of this study revealed the following: 1-Clinical Results: The age of MF patients ranged from 5 to 70 years, while in controls, the age ranged from 18 to 65 years with no statistically significant difference in age between MF patients and controls (P=0.309). MF patients included 18 males (34%) and 35 females (66%) while in control group there were 15 males (28.3%) and 38 females (71.7%) with no statistically significant difference in sex between the MF patients and controls (P=0.529). The duration of lesions ranged from 0.08 to 25 years with a mean of 4.82 ± 5.23 years. MF patients included: 22 patients (41.6%) suffering from classic MF:10 patients with patch stage (18.9%), 9 with plaque stage (17%) and 3 with tumor stage (5.7%). The remaining 31 patients (58.5%) were: 16 patients with hypopigmented MF (30.2%), 7 with hyperpigmented MF (13.2%), 5 with poikilodermatous MF (9.4%) and 3 with erythrodermic MF (5.7%). Patients with classic MF had a mean age of 48.86±12.9, and hypopigmented MF patients hadmean age was 22.1 ± 14.2. 46 MF patients were early stage MF (86.8%), and 7 patients with late stage MF (13.2%). 2-Dermoscopic results: 1) Vascular changes: Fine short linear vessels were found in 29 patients (54.7%), dotted blood vessels in 16 patients (30.2%), spermatozoa like vessels (dotted and a short curved linear vessel, giving a shape like a spermatozoon) in 16 patients (30.2%), thick linear vessels ( longer linear curved or branched vessels with a diameter larger than the fine vessels) in 12 patients (22.6%), polymorphous pattern of blood vessels in 17 patients (32.1%) and purpuric dots in 7 patients (13.2%). 2) Scales: White scales were found 37 patients (69.8%), geometric white scales (linear scales occupying skin furrows or scales with rhomboid or triangular morphology) in 34 patients (64.2%), perifollicular white scales in 20 patients (37.7%) and lamellar scales in 8 patients (15.1%). 3) Color changes: Orange yellowish patches were found in 25 patients (47.2%), white structureless patches in 36 patients (67.9%), whitish pink areas in 30 patients (56.6%), and pigmentary changes included disturbed pigment network (partial loss of the skin normal pigment network) in 16 patients (30.2%), brownish pigmentation in the form of brownish dots and brownish pigmented patches in 26 patients (49.1%), perifollicular and peri-eccrine duct openings hyperpigmented halo in 5 patients (9.4%) and follicular pigmentation in 2 patients (3.8%). 4) Other findings: included prominent eccrine duct openings in 8 patients (15%), follicular plugging in one patient (1.9%) and ulceration in one patient (1.9%). 3-Histopathological results (H&E): All patients (100%) had dermal lymphocytic infiltrate with variable density, 31 patients (58.5%) had mild degree of lymphocytic atypia (1), 17 patients (32.1%) had moderate atypia (2), and 5 patients (9.4%) had severe atypia (3), 51 patients (96.2%) had epidermotropism, 9 patients (17.0%) had Pautrier microabscess, 5 patients (9.4%) had epidermal atrophy, 9 patients (17.0%) showed prominent vascularity in the dermis and 12 patients (22.6%) showed accentuated hyperpigmentation. 4- Immunohistochemical staining for confirmation of MF diagnosis: All MF cases showed positive staining for CD3 and CD4 with variable intensity of staining (Moderate and strong). 5-Immunohistochemical staining using JAK monoclonal antibodies: JAk1 and JAK3 were detected as homogenous brown stain. JAK1 expression was nuclear, while the JAK3 was cytoplasmic. Immunoreactivity score for JAK1 in MF patients ranged from 6 to 12 with a mean of 8.4 ± 2, while in healthy controls, it ranged from 2 to 3 with a mean of 2.5 ± 0.5 and there was statistically significant increase in MF patients than controls with P value (<0.001).The mean of JAK1 IRS in patch, plaque and tumor stage MF was 7.20 ± 1.55, 10.33 ± 1.58 and 12.0 ± 0.0 respectively. There was significant higher expression of JAK1 in tumor stage than patch and plaque stage MF (P7=0.001). JAK1 IRS in patients with epidermotropism had a mean of 8.22 ± 1.88, and in patients with papillary and reticular dermal lymphocytes had a mean of 12.0 ± 0.0, while patients with Pautrier microabcesses had a mean of 10.33 ± 1.58. In MF patients with mild degree of lymphocytic atypia, JAK1 IRS ranged from 6 to 9. In patients with moderate atypia, JAK1 IRS had a mean of 8.82 ± 1.98. In patients with severe degree lymphocytic atypia, JAK1 IRS ranged from 9 to 12. There was statistically significant increase of JAK1 IRS in patients with severe atypia than moderate and mild atypia (P=0.001). Immunoreactivity score for JAK3 in MF patients ranged from 3 to 12 with a mean of 5.1 ± 2 ,while in healthy controls, it had a mean of 3 ± 0 and there was statistically significant increase in MF patients than controls with P value (<0.001), The mean of JAK3 expression in patch, plaque and tumor stage MF was 4.50 ± 1.35, 7.22 ± 1.56 and 8.67 ± 3.06 respectively. There was statistically significant higher expression of JAK3 in tumor stage than patch and plaque stage MF (P7=0.004). JAK3 IRS in patients with epidermotropism had a mean of 4.92 ± 1.75, and in patients with papillary and reticular dermal lymphocytes had a mean of 8.67± 3.06 , while patients with Pautrier microabcesses had a mean of 7.22 ± 1.20 .In MF patients with mild degree of lymphocytic atypia, JAK3 IRS had a mean of 4.58 ± 1.52, in patients with moderate atypia, JAK3 IRS had a mean of 5.29 ± 1.93, while in patients with severe degree lymphocytic atypia, JAK3 IRS had a mean of 7.80 ± 3.03 with There was statistically significant increase of JAK3 IRS in patients with severe atypia than moderate and mild atypia (P=0.025). Immunoreactivity score of JAK1 was higher in all clinical types of MF than Immunoreactivity score of JAK3 with statistically significant increase in patch and plaque stage MF, hypopigmented, hyperpigmented and poikilodermatous MF and with no statistically significant difference in tumor stage MF and erythrodermic MF. In early stage MF, JAK1 IRS ranged from 6 to 12 with a mean of 8.0 ± 1.79, while JAK3 IRS ranged from 3 to 9 with a mean of 4.80 ± 1.76. In late stage MF, JAK1 IRS ranged from 9 to 12 with a mean of 10.71 ± 1.60, while JAK3 IRS ranged from 4 to 12 with a mean of 7.14 ± 2.54. There was statistically significant increase in the IRS of JAK1 than JAK3 IRS in early stage (P<0.001), and statistically significant increase in JAK1 IRS than JAK3 IRS in late stage MF (P=0.027). 6- Results of RT-PCR: Both JAK1 and JAK3 showed a stepwise upregulation in lesional MF skin than the normal control skin as follows: • The fold change of JAK1 in MF patients ranged from 1.1 to 6.6 with a mean of 3.1 ± 1.4, while in healthy controls, it had a mean of 1 ± 0 and there was statistically significant increase of JAK3 fold change in MF patients than healthy controls with P value <0.001. • JAK3 fold change ranged from 1.1 – 5.2 in MF patients with a mean of 1.8 ± 0.8 while in healthy controls it had a mean of 1 ± 0 and there was statistically significant increase of JAK3 fold change in MF patients than healthy controls with P value <0.001.