Abstract
Background
The objective of this study was to examine the association between SOX2 expression and diagnostic and prognostic data in precancerous and cancerous lesions of the cervix uteri. It was postulated that SOX2 immunohistochemistry has the potential to serve as a diagnostic marker for classifying squamous intraepithelial lesions and as a predictor of invasion.
Methods
The immunohistochemical staining of SOX2 was investigated in 210 cervical biopsies obtained from the archives of the Pathology Department of Gaziantep University Faculty of Medicine between January 2017 and June 2022. The samples were grouped according to their diagnosis, namely benign (normal/squamous metaplasia) (n = 28), cervical intraepithelial neoplasia 1 (CIN1) (n = 50), cervical intraepithelial neoplasia 2 (CIN2) (n = 50), cervical intraepithelial neoplasia (CIN3) (n = 50) and squamous cell carcinoma (SCC) (n = 32). The correlation between the expression status and prognostic parameters was analyzed.
Results
The expression of SOX2 was observed in 62.5% of SCC cases, 70% of CIN3 cases and 26% of CIN2 cases. A statistically significant difference in expression was observed between the CIN1 and CIN2/3 groups and the noninvasive-invasive group. No significant correlation was identified between SOX2 expression and prognostic parameters in SCC group.
Conclusions
A notable increase in SOX2 expression was evident as the lesions progressed from normal squamous epithelial cells to those exhibiting CIN1, CIN2, CIN3, and finally, SCC. The results of this study suggest that SOX2 may be utilized as a diagnostic tool to facilitate the differentiation between low grade squamous intraepithelial lesion (LSIL or CIN1) and high grade squamous intraepithelial lesion (HSIL or CIN2/CIN3). Moreover, it has the potential to assist in the differentiation of CIN2 from CIN3 and SCC in cases where the invasion is debatable.
Keywords: Cervical cancer, CIN, HSIL, LSIL, SOX2
Introduction
Cervical cancer represents the fourth most common cancer in women, with 606,127 new cases and 341,831 deaths worldwide in 2020 [1]. It is estimated that between 80 and 90% of cervical cancers are squamous cell carcinomas (SCCs), with the majority of these cases (> 90–95%) associated with the human papilloma virus (HPV) [2]. Human papillomavirus (HPV) infection is a significant contributing factor in the development of cervical pre-cancerous lesions and cervical cancer [3]. The high-risk (HR) HPV group is responsible for the development of cervical intraepithelial neoplasia (CIN) and invasive cervical cancer. In the high-risk group, HPV 16 is the most commonly associated with the development of cervical cancer [4–7]. Additionally, other established risk factors include multiparity, pregnancy at a young age [8], tobacco use, and lack of cervical cancer screening [9]. SOX2 is a member of the SOX family of transcription factors [10] and interacts with other transcription factors such as Nanog and Oct4 to maintain the pluripotency and self-renewal properties of embryonic stem cells (ESCs) [11]. Cervical reserve cells, which are squamous epithelial precursors, are postulated to play a role in cervical carcinogenesis. It is hypothesized that HR-HPV infection initiates oncogenesis by affecting stem cells, particularly in the transformation zone, thereby causing cervical carcinogenesis [12]. Nanog, Musashi-1, nucleostemin [13], Sox2 [14], prostate stem cell antigen (PSCA), piwi-like protein 1 (PIWIL1) and TBX2 [15] are the principal stem cell markers that demonstrate reactivity in normal cervical epithelium and cervical SCC. In recent years, SOX2 has been identified as a key factor in numerous cancer-related studies. Aberrant expression of SOX2 has been observed in a number of different cancer types, including glioblastoma, lung carcinoma, esophageal carcinoma, oral cavity carcinoma, prostate carcinoma and sinonasal carcinoma. Elevated levels of SOX2 have been linked to tumor proliferation, metastasis, poor prognosis and resistance to treatment [16]. Distinguishing reactive processes from dysplasia, grading dysplasia and detecting invasive disease in cervical biopsy samples may prove challenging. The objective of this study was to test the hypothesis that SOX2 immunohistochemistry can be employed in the diagnosis and grading of precancerous lesions and the diagnosis of squamous cell carcinoma (SCC) in cervical biopsies. The relationship between SOX2 expression and prognostic entities, including the presence of HPV infection, HPV type, multiparity and parametrial involvement, lymph node, distant organ metastasis and the presence of lymphovascular invasion, was compared in SCC cases.
Material and method
Patient selection
In the present retrospective study, we reviewed the medical records of cervical biopsies performed at the Pathology Department of Gaziantep University Faculty of Medicine between June 2017 and January 2022. The study population comprised patients diagnosed with LSIL (low-grade squamous intraepithelial lesion, cervical intraepithelial lesion- CIN 1, n:50), HSIL (high-grade squamous intraepithelial lesion, CIN 2, n:50 and CIN 3, n:50), SCC (n:32) and normal/squamous metaplasia (n:28), resulting in a total of 210 patients. The biopsies that had already been subjected to immunohistochemistry for p16 INK4A and Ki67 were selected for analysis. The following variables were documented: age at diagnosis, gravidity status, high risk HPV DNA determination by molecular PCR (High risk HPC cocktail including Type 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, cobas HPV, Roche Diagnostics), HPV type, presence and result of smear screening prior to biopsy, and presence and result of conization/hysterectomy after biopsy. The study protocol had been approved by the institutional ethics committee of Gaziantep University Faculty of Medicine.
Immunohistochemical analysis
For immunohistochemical analysis, 4-micrometer-thick sections were cut from formalin fixed and paraffin embedded cervical biopsies and mounted on adhesive slides. The tissue sections were then deparaffinized and hydrated. An incubation period of eight minutes at 95 °C was employed for the Ultra Conditioner. A retrieval time of 52 min was selected (Cell Conditioning 1; Ventana). SOX2 (clone EP103, Cell Marque) was incubated at a dilution of 1:100 for 40 min (Ultra-BenchMark ULTRA system, Roche Diagnostics), followed by a 16-minute incubation with hematoxylin and a subsequent 4-minute incubation with ground staining reagent. Subsequently, the staining was visualized with DAB (Ventana Medical Systems). Only nuclear SOX2 staining was considered to be indicative of a positive result. The percentage of positive cells was scored in accordance with the staining rate of the cells. The percentage of cells exhibiting staining was quantified as follows: 0% staining (score 0); 10–25% staining (score 1); 26–50% staining (score 2); 51–75% staining (score 3); and 76–100% staining (score 4). The intensity of the staining was classified as strong nuclear positivity (score 3), moderate nuclear positivity (score 2), weak nuclear positivity (score 1) and no staining (score 0). The final score was calculated by multiplying the staining intensity score by the positive cell ratio score. Final score of greater than or equal to 4 was taken to indicate positive SOX2 expression [17]. The extent of SOX2 expression in the epithelial layer and its relationship with Ki-67 and p16 immunohistochemistry were analyzed in SOX2-positive cases.
In the p16 evaluation, both cytoplasmic and nuclear immunoreactivity, i.e., block staining, were considered positive. The p16 expression percentage scores were determined as follows: Score 0 (no expression), Score 1 (staining in the lower 1/3 of the epithelium), Score 2 (staining in the lower 2/3 of the epithelium), and Score 3 (complete staining of the epithelium). Ki67 staining was considered positive for nuclear immunoreactivity. The determination of Ki67 expression percentage scores was conducted in the following manner: Score 0 (no expression increase—staining only in the basal layer), Score 1 (staining in the lower 1/3 of the epithelium), Score 2 (staining in the lower 2/3 of the epithelium), and Score 3 (complete staining of the epithelium) [16].
Follow-up and statistical analysis
Data pertaining to the follow-up period were available for thirty patients in the SCC group, with the follow-up period extending from one to fifty-nine months. All statistical analyses were conducted using the statistical software package SPSS 22.0 (SPSS Inc., Chicago). The Student’s t-test was employed to compare numerical data in two normally distributed independent groups, whereas the Mann-Whitney U test was used to compare non-normally distributed variables in two groups. Continuous variables were expressed as mean ± standard deviation, while categorical variables were expressed as numbers and percentages. A chi-squared analysis was employed to identify discrepancies between categorical variables. In all analyses, a p-value of less than 0.05 was considered statistically significant.
Results
The mean age was 39.3 years for CIN 1, 38.3 years for CIN 2, 44.9 years for CIN 3, 55.7 (27–81) years in the group of patients diagnosed with SCC and 37.1 years in the group of patients diagnosed with normal/squamous metaplasia (N/SM). A significant difference was identified when the mean age of the group of SILs (CIN 1, CIN 2, CIN 3) and SCC was compared (p = 0.001).
Information regarding parity and the number of live births was available for 193 of the 210 patients. The proportion of women with five or more pregnancies (multiparity) was 33% (15/44) in the CIN1 group, 30% (14/47) in the CIN2 group, 38% (19/49) in the CIN3 group, 43% (12/28) in the SCC group and 4% (1/25) in the N/SM group. The statistical analysis revealed a significant correlation between multiparity and the development of SIL and SCC (p = 0.019).
Only high-risk HPV types (Type 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) are tested by PCR. The results of HPV DNA testing were available for total 164 patients who were tested at our center an additional patients who were tested at an external center and subsequently referred to us (Table-1).
Table 1.
HPV positivity rates in N/SM, CIN1, CIN2, CIN3 and SCC groups
| N/SM | CIN1 | CIN2 | CIN3 | SCC | |
|---|---|---|---|---|---|
| HPV positive | 18/24 (75%) | 41/44 (93.2%) | 46/48 (95.8%) | 35/38 (92.1%) | 10/10 (100%) |
| HPV negative | 0 (0%) | 3/44 (6.8%) | 2/48 (4.2%) | 3/38 (7.9%) | 0 (0%) |
CIN 1: Cervical intraepithelial neoplasia 1, CIN 2: Cervical intraepithelial neoplasia 2, CIN 3: Cervical intraepithelial neoplasia 3, SCC: Squamous cell carcinoma, N/SM: Normal/squamous metaplasia, HPV: Human Papilloma virus
A single case (2%) within the N/SM diagnosis group exhibited an high score of 6 and was thus classified as SOX2 positive. (Figure 1A and B) The HPV test yielded a negative result for this case. The remaining 27 cases (92%) were found to be SOX2 negative. (Figure 1C and D) SOX2 expression was not observed in cervical glandular epithelium and stromal cells.
Fig. 1.
The presence of SOX2 in cervical epithelium is demonstrated in the following images: A: Ectocervical squamous epithelium (H&E, x100) B: SOX2 final score (6), positive in ectocervical squamous epithelium (x200) C: Squamous metaplasia (H&E, x200). D: SOX2 final score (1) negative in ectocervical squamous epithelium (x200)
In the CIN 1 group, SOX2 staining was observed to be weak to moderate, predominantly expressed in basal/parabasal cells, and SOX2 was classified as negative in all 50 cases (Fig. 2A and B).
Fig. 2.
The expressions of SOX2 in SILs A: CIN 1 (LSIL) (H&E, x100), B: SOX2 final score (3) negative in CIN1 (x200). C: CIN 2 (HSIL) (H&E, x200), D: SOX2 final score (9) positive in CIN2 (x200). E: CIN 3 (HSIL) (H&E, x100), F: SOX2 final score (12) positive in CIN3 (x100)
In the CIN 2 group, SOX2 expression was positive in 13 of 50 cases (26%) (Fig. 2C and D) and negative in 37 (74%) cases.
In patients with CIN 3, the SOX2 score was negative in 15 cases (30%), while the SOX2 score was positive in 35 cases (70%) (Fig. 2E and F).
SOX2 was positive in 20 cases (62.5%), whereas it was negative in 12 samples (37.5%) in the SCC group (Fig. 3). The expression of SOX2 increased in a stepwise manner, from normal squamous epithelium and precancerous lesions to cervical carcinoma. A statistically significant difference was observed between the CIN 1 (LSIL) and CIN 2 and CIN 3 (HSIL) groups (p = 0.001), as well as between the cervical precancerous lesions and SCC groups (p = 0.001). (Table 2)
Fig. 3.
SOX2 positivity in SCC A: SCC (H&E, x100), B: SOX2 final score (12) positive (x100)
Table 2.
Expression of SOX2 in diagnostic groups
| SOX2 |
N/SM (n = 28) |
CIN 1 (n = 50) |
CIN 2 (n = 50) |
CIN 3 (n = 50) |
SCC (n = 32) |
Total (n = 210) |
|---|---|---|---|---|---|---|
|
Positive (FS:>4) |
1 (3.5%) |
0 (0%) |
13 (26%) |
35 (70%) |
20 (62.5%) |
69 (32.9%) |
|
Negative (FS: 0–4) |
27 (96.5%) |
50 (100%) |
37 (74%) |
15 (30%) |
12 (37.5%) |
141 (67.1%) |
| p value* | 0,001 |
(CIN 1: Cervical intraepithelial neoplasia 1, CIN 2: Cervical intraepithelial neoplasia 2, CIN 3: Cervical intraepithelial neoplasia 3, SCC: Squamous cell carcinoma, N/SM: Normal/squamous metaplasia), FS: Final score
*Significant at p < 0.05, Chi-square test
A comparison of cases included in the study from the N/SM and premalignant categories (CIN1, 2, and 3) revealed a positive predictive value of SOX2 expression of 97.9%, while the negative predictive value was 20.9%. When the cases were examined as SCC and others, the positive predictive value of SOX2 for invasive cases was determined to be 28.9%, and the negative predictive value was determined to be 91.4%.
The present study sought to ascertain whether there were any associations between clinicopathological features and SOX2 expression. Additonally, there was no association between SOX2 expression and HPV type.
The results demonstrated that five of the 32 SCC cases exhibited keratinization (15.6%), while 27 cases were non-keratinized (84.4%). When the keratinized and non-keratinized cases were evaluated together, 19 cases (59.4%) were found to be differentiated, while 13 cases (40.6%) were undifferentiated.
Information on tumor size was unavailable for five cases. Of the remaining 23 cases, tumor size was determined by vaginal examination, imaging, or macroscopic measurement and ranged from 20 mm to 87 mm.
Three patients (9.3%) exhibited solely parametrial involvement, whereas eight patients (25%) demonstrated local invasion, characterized by parametrial involvement and spread to surrounding organs. A total of six patients (18.7%) exhibited distant organ metastases. Seventeen patients (53%) exhibited evidence of lymphovascular invasion, including involvement of lymph nodes.
Information on the follow-up of the 32 cases was available for 30 of them, with the follow-up period ranging from one month to 59 months. During the follow-up period, four patients were found to have died within a minimum of one and a half months and a maximum of 15 months. One of the deceased patients had synchronous cervical SCC and biliary adenocarcinoma, and the cause of death was complications from biliary adenocarcinoma. When classified according to the International Federation of Gynecology and Obstetrics (FIGO) staging system, 12 cases (37.5%) were classified as stage I, five cases (15.6%) were classified as stage II, three cases (9.4%) were classified as stage III, and 12 cases (37.5%) were classified as stage IV. No correlation was identified between SOX2 expression and prognostic factors, including tumor differentiation, tumor size, the presence of lymphovascular invasion and distant metastasis, survival and FIGO stage (Table 3).
Table 3.
Expression of SOX2 of clinicopathological features in SCC
| SOX2 | ||||
|---|---|---|---|---|
| Positive | Negative | |||
| n (%) | n (%) | p* | ||
| Tumor Type | Nonkeratinized | 16 (80) | 11 (91.7) | 0.360 |
| Keratinized | 4 (20) | 1 (8.3) | ||
| Differentiation | Differentiated | 13 (65) | 7 (58.3) | 0.707 |
| Undifferentiated | 7 (35) | 5 (41.7) | ||
| Tumor diameter (mm) | ≤40 | 8 (50) | 5 (45.5) | 0.816 |
| > 40 | 8 (50) | 6 (54.5) | ||
| Lymphovascular Invasion | Yes | 11 (55) | 4 (33.3) | 0.234 |
| No | 9 (45) | 8 (66.7) | ||
| Distant Metastasis | Yes | 3 (15) | 3 (25) | 0.488 |
| No | 17 (85) | 9 (75) | ||
| Survival | Alive | 16 (94.1) | 10 (83.3) | 0.351 |
| Death | 1 (5.9) | 2 (16.7) | ||
| Clinical stages (FIGO stages) | I-IIA | 7 (35) | 6 (50) | 0.404 |
| IIB-IV | 13 (65) | 6 (50) | ||
*Significant at p < 0.05, Chi-square test
The p16 results for the cases included in the study are summarized in Table 4.
Table 4.
p16 expression in N/SM, CIN1, CIN2, CIN3 and SCC
| N/SM | CIN 1 | CIN 2 | CIN 3 | SCC | Total | ||
|---|---|---|---|---|---|---|---|
| p16 | (n = 28) | (n = 50) | (n = 50) | (n = 50) | (n = 32) | (n = 210) | |
|
Negative Score 0 (96.5%) |
27 96.5% |
25 (50%) |
2 (4%) |
1 (2%) |
0 (0%) |
56 (26.7%) |
|
| Positive | |||||||
| Score 1 |
0 (0%) |
12 (24%) |
1 (2%) |
0 (0%) |
0 (0%) |
13 (6.2%) |
|
| Score 2 |
1 (3.5%) |
4 (8%) |
24 (48%) |
0 (0%) |
0 (0%) |
28 (13.3%) |
|
| Score 3 |
0 (0%) |
9 (18%) |
23 (46%) |
49 (98%) |
32 (100%) |
113 (53.8%) |
|
| p-value* | 0.001 | ||||||
CIN 1: Cervical intraepithelial neoplasia 1, CIN 2: Cervical intraepithelial neoplasia 2, CIN 3: Cervical intraepithelial neoplasia 3, SCC: Squamous cell carcinoma, N/SM: Normal epithelium/squamous metaplasia)
Significant at p < 0.05, Chi-square test
Among the 27 p16-negative cases in the N/SM group, all were SOX2-negative, while one SOX2-positive case exhibited a p16 score of 2. Of the 13 cases that were positive for SOX2 in the CIN2 group, 11 exhibited p16 score 3 staining. This finding was replicated in the CIN3 group, where all SOX2-positive cases (35/50) demonstrated p16 score 3 staining. A similar trend was observed in the SCC group, with all SOX2-positive cases (20/32) exhibiting p16 score 3 staining. A total of 48 cases were identified as SOX2-positive in the CIN2 and CIN3 groups, and these cases exhibited p16 score 3 staining. SOX2 positivity exhibited a significant correlation with p16 score 3 positivity (p < 0.05). The results of the study are summarized in the following Table-5.
Table 5.
SOX2 and p16 expression
| p16 score 0 (n = 56) | p16 score 1 (n = 13) |
p16 score 2 (n = 28) |
p16 score 3 (n = 113) |
|
|---|---|---|---|---|
| SOX2 positive | 0/56 (0%) | 0/13 (0%) | 3/28 (10.7%) | 66/113 (58.4%) |
| SOX2 negative | 56/56 (100%) | 13/13 (100%) | 25/28 (89.3%) | 47/113 (41.6%) |
The Ki-67 results for the cases included in the study are summarized in Table 6.
Table 6.
Ki-67 expression in N/SM, CIN1, CIN2, CIN3 and SCC
| N/SM | CIN 1 | CIN 2 | CIN 3 | SCC | Total | |
|---|---|---|---|---|---|---|
| Ki-67 | (n = 28) | (n = 50) | (n = 50) | (n = 50) | (n = 32) | (n = 210) |
| Score 0 |
28 (100%) |
2 (4%) |
0 (0%) |
0 (0%) |
0 (0%) |
30 (14.3%) |
| Score 1 |
0 (0%) |
40 (80%) |
0 (0%) |
0 (0%) |
0 (0%) |
40 (19%) |
| Score 2 |
0 (0%) |
6 (12%) |
34 (68%) |
0 (0%) |
0 (0%) |
40 (19%) |
| Score 3 |
0 (0%) |
2 (4%) |
16 (32%) |
50 (100%) |
32 (100%) |
100 (47.7%) |
| p-value* | 0.001 |
CIN 1: Cervical intraepithelial neoplasia 1, CIN 2: Cervical intraepithelial neoplasia 2, CIN 3: Cervical intraepithelial neoplasia 3, SCC: Squamous cell carcinoma, N/SM: Normal epithelium/squamous metaplasia)
Significant at p < 0.05, Chi-square test
In the study, 27 cases were found to be SOX2-negative, while one case was found to be SOX2-positive. All 27 SOX2-negative cases and all 1 SOX2-positive case in the SE/SM group showed a Ki-67 staining score of 0. In contrast, all 11 SOX2-positive cases in the CIN2 group, all 35 SOX2-positive cases in the CIN3 group, and all 20 SOX2-positive cases in the SCC group showed a Ki-67 score of 3. These findings suggest a significant correlation between SOX2 positivity and Ki-67 score 3 staining (p < 0.05). The results of the study are summarized in the following Table-7.
Table 7.
SOX2 and Ki-67 expression
| Ki-67 score 0 (n = 30) |
Ki-67 score 1 (n = 40) |
Ki-67 score 2 (n = 40) |
Ki-67 score 3 (n = 100) |
|
|---|---|---|---|---|
| SOX2 positive | 1/30 (3.3%) | 0/40 (0%) | 2/40 (5%) | 66/100 (66%) |
| SOX2 negative | 29/30 (96.7%) | 40/40 (100%) | 38/40 (95%) | 34/100 (34%) |
Discussion
This study examines the expression and diagnostic potential of SOX2, a marker of embryonic stem cells, in normal squamous epithelium, squamous metaplasia, low-grade squamous intraepithelial lesions (LSIL, CIN 1), high-grade squamous intraepithelial lesions (HSIL, CIN 2, CIN 3) and squamous cell carcinoma (SCC) in cervical biopsies.
The relationship between SOX2 and cancer has been the subject of numerous studies in recent years, with data reported on a range of topics including SOX2 and tumorigenesis, prognosis and drug resistance in at least 25 different cancers [16]. In these studies, SOX2 expression has been detected in both genetic material (RNA) and at the cellular protein level, thus allowing it to be measured immunohistochemically [16].
Immunohistochemically, SOX2 is positive in 14–25% of cases with normal squamous epithelium, predominantly in the basal layer [14, 18]. Conversely, SOX2 staining is absent in immature squamous metaplasia and endocervical glandular cells [19–21]. In our study, SOX2 expression was negative in 26 cases (92.8%) of normal cervical squamous epithelium and squamous metaplasia, with low to moderate intensity in basal/parabasal cells. Furthermore, no staining was observed in endocervical glandular cells.
A rise in SOX2 expression from low-grade CIN 1 to high-grade CIN 3 in cervical squamous intraepithelial lesions (SIL) has been documented in numerous studies [20–22]. In cases of CIN 1, SOX2 staining is typically observed as a weak staining in the lower third of the epithelium [19, 20, 22]. In our study, we evaluated SOX2 expression using a histological score, with examples of this method available in the literature [23]. In this study, 26 (52%) of CIN 1 cases exhibited low to moderate nuclear SOX2 expression, with an excess in basal/parabasal cells.
SOX2 expression has been documented in the lower two-thirds of the dysplastic epithelium in HSIL [24] or in full thickness [20, 25, 26]. It was yielded no statistically significant results with regard to SOX2 staining in cases of CIN 2 and CIN 3 [24]. In our study, a positive SOX2 score was observed in 26% of the CIN 2 group, while SOX2 was positive in 70% of the CIN 3 group. A statistically significant difference was observed in SOX2 score positivity between the CIN 2 and CIN 3 diagnostic categories. It was demonstrated that a statistically significant difference was observed between SOX2 and OCT4 expression levels across the categories of normal cervical epithelium, LSIL, HSIL and cervical cancer [26].
In our study, the proportion of SCC samples exhibiting high levels of SOX2 expression was 62.5%. In the existing literature, the rate of SOX2 expression in cervical cancer is reported to range from 73% to 100%. The high level of SOX2 expression in cervical cancer has been supported by numerous studies [19, 22, 24, 26, 27]. Conversely, the SOX2 score was negative in 37.5% of the cases in our study. In contrast to the findings of the majority of previous studies, one study reported that the majority of SCC cases (65%) were SOX2 negative [25]. Furthermore, the same study revealed that SOX2 positivity was more prevalent in areas of CIN 3 with SCC than in those without invasion. This result was evaluated in correlation with the findings of several studies in the literature indicating a correlation between SOX2 downregulation and increasing tumor grade [28].
The majority of cases exhibiting SOX2 expression exhibited a score of 3 staining (complete positivity) in p16 and Ki-67 immunohistochemistry. Research in the field has also demonstrated a correlation between p16 and SOX2 expression [22].
No correlation has been reported in the literature between SOX2 IHC expression and prognostic parameters such as age, lymph node status, tumor diameter and tumor stage [14, 18, 26, 29, 30]. It is, however, noteworthy that tumor differentiation is observed to decrease in cases where high SOX2 expression is present [14, 27]. It was demonstrated that, although no significant correlation was observed between tumor differentiation and SOX2 expression, SOX2 expression decreased with increasing tumor size [26]. The present study did not identify any statistically significant differences in SOX2 expression between tumor types, tumor differentiation, tumor size, the presence of lymphovascular invasion and distant metastasis, survival and FIGO stage. The relatively small number of SCC cases compared to other case groups and the lack of HPV results for all cases are limiting factors of the study.
Conclusions
The results demonstrated that SOX2 expression was a significant factor in the diagnostic discrimination of squamous metaplasia, precancerous lesions and cervical SCC in cervical biopsies when classified according to histological score. Despite the utility of SOX2 immunohistochemistry in differentiating LSIL from HSIL in cervical biopsies, its unaided use is limited. We believe that SOX2 may be an adjunct and alternative to p16 and Ki-67 in routine use due to its high correlation with full-thickness positivity of p16 and Ki-67 in cervical lesions.
Acknowledgements
Not applicable.
Abbreviations
- CIN1
Cervical intraepithelial neoplasia 1
- CIN2
Cervical intraepithelial neoplasia 2
- CIN3
Cervical intraepithelial neoplasia 3
- SCC
Squamous cell carcinoma
- LSIL
Low grade squamous intraepithelial lesion
- HSIL
High grade squamous intraepithelial lesion
- HPV
Human Papilloma Virus
- HR
High risk
- ESC
Embryonic stem cell
- N/SM
Normal/squamous metaplasia
- PCR
Polymerase chain reaction
- FIGO
Federation of gynecology and obstetrics
Authors’ contributions
Hypothesis: EU, Literature Review: MB, Data collection: MB, EU, Data analysis and histopathologic examination: MB, EU, writing: MB, EU.
Funding
This study was supported by Gaziantep University Scientific Research Unit.
Data availability
All data generated or analyzed during this study are included in this published article.
Declarations
Ethics approval and consent to participate
This study was approved by the research Ethics Committee of Gaziantep University Medical Faculty. All procedures involving human participants in this study were in accordance with the ethical standards of the institutional research committee and the 1964 Helsinki Declaration. Written informed consent was obtained from all participants.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Data Availability Statement
All data generated or analyzed during this study are included in this published article.