الفهرس 
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Abstract
NMSC is the most frequently detected cancer. The most common NMSC
are BCC and cSCC. The process of skin carcinogenesis is still not fully
understood. However, several studies have been conducted to explain better the
mechanisms that lead to malignancy. The JAK/STAT pathway is a signaling
pathway initiated by diverse cytokines, interferons, growth factors, and related
molecules. This pathway provides a smart mechanism by which extracellular
factors control gene expression. JAK has been associated with essential proteins,
including signal transducers and activators of transcription (STATs), which in
turn regulate the expression of a variety of proteins involved in apoptosis. Thus,
the JAK/STAT signaling axis plays a chief role in the proliferation and survival of
different cancer cells.
Despite extensive research focused on the protein structure and
mechanisms of activation of JAKs and signal transduction through these proteins,
their importance in cancer initiation and progression seems to be underestimated,
so that this study aims to investigate the role of JAK1 and STAT3 in the
pathogenesis of NMSC through its immunohistochemical (IHC) expression in
cases and to correlate its expression with the clinical and histopathological
parameters.
This prospective case-control study was done on 128 cases presented with
NMSC, 47 age, and gender-matched apparently healthy volunteers. Skin biopsies
from the control group and cases were taken to detect histopathological and
immunohistochemical JAK1 and STAT3 expression.
Regarding BCC cases:
The age of cases is ranged between 15 and 90 years with a median value of
60. The selected patients were 38 males (47.5%) and 42 females (52.5%), with a
male to female ratio of 1: 1.1. Regarding the site, 68 of patients (85%) at head and
neck, 12 of patients were at the trunk (15%), and none of them (0.0%) were in the
extremities. Regarding the clinical subtypes, 33 of patients (41.2%) were
presented with an ulcer. 19 of the patients (23.8%) were presented with mass.
The size 0.2 to 12 cm ranged from with mean of 2.75. 47 (58.6%) of cases
had a free margin, while 4 (5%) of them had involved margin. Lymphovascular
and perineural invasion were absent in all cases.
Regarding SCC cases:
The age of cases is ranged between 6 and 78 years with a median value of
53.5. The selected patients were 24 males (50%) and 24 females (50%), with a
male to female ratio of 1:1. Regarding the site, 30 of patients (62.5%) at head and
neck, 12 of patients were at the trunk (25%), and 6 of them (12.5%) were in the
extremities. Regarding the clinical subtypes, 32 of patients (66.7%) were
presented with Mass. 14 of patients (29.2%) were presented with an ulcer.
The size 0.5 to 15 cm ranged from with mean of 3. 32 (66.7%) of cases
had a free margin, while 4 (8.3%) of them had involved margin. Lymphovascular
and perineural invasion were found in all cases. 22(45.8%) of cases were of grade
1, while18 (37.5%) of cases were of grade 2, and only 8 (16.7%) cases were of
grade 3.22 (45.8%) of cases were of stage 1, while18 (37.5%) of cases were of
stage 2, and only 8 (16.7%) cases were of stage 3.
Summary
92
Regarding JAK1:
- JAK1 was expressed in the epithelium of all control cases and 92.8% of
NMSC cases, with a significant difference between the studied groups. (P<
0.001).
- Regarding the cellular localization of JAK1 in the epithelium, all positive
control cases show nucleocytoplasmic JAK1 localization, while 98.3 of
NMSC showed cytoplasmic expression, with a significant difference between
the studied groups. (P< 0.001).
- There was a significant difference between the studied groups regarding
epithelial and stromal H score (P< 0.001 and P= 0.02, respectively).
- In the epithelium, 57.4% of cases in the control group had belonged to the
high H score group, while 71.2% of NMSC cases had belonged to the low H
score group with a significant positive difference between the two groups.
(P= 0.001), whereas in the stroma, 64.3% of cases in the control group had
belonged to the low H score group, while 55.4% of NMSC cases had
belonged to the high H score group with a significant positive difference
between the two groups. (P= 0.03).
- There was a significant positive difference between the studied groups
regarding epithelial and stromal H score (P<0.001 and P= 0.02, respectively).
- 80% and 70% of control cases had belonged to the low H score group in the
epithelium and stroma, respectively, whereas 61.9% and60.8 % of NMSC
cases had belonged to the high H score group in the epithelium and stroma,
respectively, with a significant positive difference between the studied group
both in the epithelium or stroma (P< 0.0001 and P= 0.001, respectively).
- All control cases displayed mild expression both in the epithelium and
stroma. None of them had a moderate and strong expression, whereas 74.6%,
65.8% of NMSC cases displayed mild expression in the epithelium and
stroma, respectively with 25.4% and34.2 % showed moderate or strong
expression with a significant difference between the studied groups both in
the epithelium and surrounding stroma (P=0.01 and P= 0.003, respectively).
- JAK1 was expressed in all control cases, whereas it was expressed only in
83.8% of SCC cases with a significant difference between the two studied
groups (P2= 0.003).
- JAK1 was expressed in 97.5% of BCC cases, whereas it was expressed only
in 83.8% of SCC cases with a significant positive difference between the two
studied groups (P3= 0.004).
- JAK1 showed nucleocytoplasmic expression in all cases of the control group,
whereas it showed cytoplasmic expression in all cases of the BCC group and
95% of cases of the SCC group in the epithelium with a significant difference
between the studied groups (P1 and P2< 0.001).
- There was a significant relationship between control and BCC group JAK1 H
score both in the epithelium and stroma (P1= 0.003 and 0.01, respectively).
In contrast, there was a significant relationship between control and SCC
group only in the epithelium (P2< 0.001).
Summary
93
- 57.4% of control cases belonged to the high H score group, whereas 67.9% of
BCC cases and 77.5% of SCC cases belonged to low H score group with a
significant positive difference between the studied groups (P1= 0.005 and
P2< 0.001, respectively)
Regarding STAT3:
- STAT3 was expressed in 85.1% of control cases, whereas it was expressed in
97.5% of BCC cases with a significant difference between the two studied
groups (P1= 0.008).
- STAT3 was expressed in 97.5% of BCC cases, whereas it was expressed only
in 83.4% of SCC cases with a significant positive difference between the two
studied groups (P3= 0.004).
- STAT3 showed nucleocytoplasmic expression in all cases of the control
group, whereas it showed cytoplasmic expression in 88.5% and 98.7% of
cases of BCC group in the epithelium and stroma, respectively, with a
significant difference between the two studied groups (P1< 0.001 for both).
- STAT3 showed nucleocytoplasmic expression in all cases of the control
group, whereas it showed cytoplasmic expression in 80% and 100% of cases
of SCC group in the epithelium and stroma, respectively, with a significant
difference between the two studied groups (P2< 0.001 for both).
- There was a significant relationship between H score in control and BCC
group both in the epithelium and stroma (P1< 0.001 and 0.001, respectively).
- There was a significant relationship between BCC and SCC group only in the
epithelium (P3< 0.001). In BCC, the H score ranged from 30-220 with a
median of 100, whereas in SCC, H score ranged from 20-160 with a median
of 60.
- 80% of control cases belonged to the low H score group, whereas 74.4% and
61.8% of BCC cases in the epithelium and stroma, respectively, belonged to
the high H score group with a significant positive difference between the
studied groups (P1<0.001 and 0.001, respectively).
- 74.5% of BCC cases belonged to the high H score group, whereas 62.5% of
SCC cases belonged to the low H score group in the epithelium with a
significant positive difference between the studied groups (P3< 0.001).
- 70% of control cases belonged to the low H score group, whereas 61.8% of
SCC cases belonged to the high H score group in the stroma with a significant
positive difference between the studied groups (P2= 0.007).
- The Intensity of expression in BCC cases varied from mild in 69.2% of cases,
to moderate in 25.6% of cases with 5.2% of cases displayed strong intensity,
while in control cases; they displayed mild intensity in all cases, with no
cases displayed moderate or severe intensity with a significant difference
between the two groups in the epithelium (P1< 0.001).
- The Intensity of expression in BCC cases varied from mild in 64.5% of cases,
to moderate in 13.2% of cases with 22.3% of cases displayed severe intensity,
while in control cases, they displayed mild intensity in all cases, with no
cases displayed moderate or severe intensity with a significant difference
between the two groups in the stroma (P1= 0.001).
Summary
94
- Regarding the intensity of expression of STAT3 in the stroma, there was a
significant positive association between control and SCC group (P2< 0.001).
The Intensity of expression in SCC cases varied from mild in 68.2% of cases,
to moderate in 22.7% of cases with 9.1% displayed severe intensity, while in
control cases, they displayed mild intensity in all cases, with no cases
displayed moderate or severe intensity.
- There was a significant relationship between stromal H- score expression of
JAK1and the patients’ male gender (P= 0.03).
- There was a significant positive relationship between JAK1 stromal H score
and the male gender in the stroma (P=0.03)
- There was a negative correlation between the JAK1 epithelial H score and the
size of BCC (r= -0.31, P= 0.006).
- There was a significant positive correlation between stromal JAK1
overexpression and the age of SCC (r= 0.36 and P= 0. 01)
- There was a significant relationship between epithelial JAK1 overexpression
and the free margin of SCC. (P= 0.04)
- There was a significant positive correlation between stromal STAT3 H score
and the age of patients (r= 0.18, P= 0.04).
- A significant association was found between STAT3 overexpression and the
margin of NMSC.
- There was a significant positive relationship between STAT3 overexpression
and the female gender of BCC patients in the tumor tissue (P= 0.001).
- There was a positive correlation between epithelial and stromal STAT3 H
score and the age of SCC cases (r= 0.31 and P= 0.049 & r =0.43 and P=
0.003, respectively). Also, There was a significant association between the
STAT3 stromal H score and the male gender of SCC cases (P= 0.03).
- A significant relationship between the STAT3 epithelial H score and (high
grade and advanced stage) of SCC was also noted (P= 0.001and P< 0.001
respectively).
- Another significant relationship between STAT3 epithelial and stromal H
score and the free margin of SCC was also Noted (P= 0.04 and P= 0.001
respectively).
- There was a significant positive correlation between epithelial and stromal
JAK1 expression in NMSC cases (r= 0.26 and P= 0.003).
- There was a significant positive correlation between epithelial and stromal
JAK1 expression in BCC cases (r=0.32 and P= 0.004).
- There was a significant positive correlation between epithelial and stromal
STAT3 H score in NMSC cases (r= 0.45 and P< 0.001).
- There was a significant positive correlation between epithelial and stromal
STAT3 H score in SCC cases (r= 0.73 and P< 0.001).
- There was a significant positive correlation between JAK1 and STAT3
stromal H score in NMSC cases (r= 0.29 and P= 0.001)