In addition to the histomorphological and immunohistochemical classifications in ovarian cancer, it was determined that tumors developed from different pathways by molecular findings, and a new classification was proposed according to their molecular characteristics. Epithelial tumors are grouped as Type 1 and Type 2 tumors, and the cell groups, precursor lesions and prognostic information of these groups are categorized and compared. BRAF and KRAS mutations are high in type 1 tumors and they do not show TP53 mutations. Type 2 tumors show TP53 mutation in almost all cases (2, 14)
When the studies on FGFR1 expression in ovarian tumors were searched in the literature, Valve et al. in their study on 51 ovarian tumors, it was observed that an expression increase of 91% was detected in 24 serous carcinoma cases with RT-PCR (7). Birrer et al. In the study, FGF1 amplification was detected in 66% of 42 HGSC cases with RT-PCR, and increased FGF1 mRNA expression was associated with a poor prognosis (15). In the study conducted by Helsten et al. with the new generation sequencing method, the rate of FGFR1 amplification in 233 ovarian tumors was reported as 5-9%, and no subtype information was given (4). In our study, the rate of FGFR1 amplification (95%) in serous ovarian carcinomas was found to be higher than other studies. When we look at the amplification rates, we found 98.31% amplification in the HGSC group and 57.14% in the Borderline/LGSC group.When we evaluated the fold change rates, it was seen that there was a statistically significant increase in favor of HGSC in the HGSC group compared to the Borderline/LGSC and SC groups.
In the study by Cole et al., it was shown that the anti-tumor activity of cisplatin increased when FGFR1 inhibition was applied together with cisplatin in 10 serous ovarian carcinomas and 5 normal ovaries by in situ hybridization method, and in 40 serous ovarian carcinomas and 10 normal ovaries by immunohistochemistry method. With cell cycle analyses, it was stated that this effect was achieved by increasing the apoptosis of both agents (14). This provides support for the use of FGFR-1 as a target in therapy.
The effects of FGFR1 amplification have been demonstrated in many studies on other tumor types. FGFR1 expression in squamous cell lung carcinomas is directly proportional to lymph node metastasis (16), and FGFR1 expression is inversely proportional to chemosensitivity in small cell lung carcinomas (17); it is an independent prognostic indicator in breast tumors (18), it increases tamoxifen sensitivity when used together with tamoxifen (19); It has been proven that increased expression of FGFR receptors in diffuse gastric carcinomas is associated with depth of invasion, distant metastasis, histological grade, and recurrence (20).
It is known that BSTs with micropapillary morphology have a relatively poor prognosis compared to BSTs without micropapillary morphology. Micropapillary morphology was detected in 2 of the borderline serous tumor cases. When the FGFR1 fold changes of these cases were examined, it was seen that they were 7.06 and 4.55. The fact that these 2 cases have FGFR1 expression at the level of HGSCs, different from the mean of BST cases and LGSC cases, supports that micropapillary variant BSTs are a higher grade tumor with a worse prognosis than other BST cases. Conditions such as ischemia, hemorrhage and necrosis can affect the amount of evaluable cells in the tissue and cause false negativity. In our study, hemorrhage and ischemia findings were observed in 1 LGSC and 1 BST case. In the evaluation made with light microscope, it was seen that most of the cells in the tissue were not degenerated and unaffected. However, fold change values were found to be lower than expected for the relevant diagnosis group. This difference was thought to occur because the cells were affected by ischemia. Since 1 of the HGSC cases had a fold change of less than 1, the clinical information and histological findings were re-examined. However, no additional clinical or pathological features were observed in the case. This case, whose FGFR1 amplification was not detected, was found to be ex within 1 month.
FGFR1 expression fold changes detected by RT-PCR in all cases were statistically correlated with immunohistochemically determined cytoplasmic H score (p<0.05). However, statistical significance could not be determined with positivity/negative criteria such as staining of more than 1% tumor cells, staining of more than 10% tumor cells or being considered positive when the H score is greater than 100 in previous publications (p>0.05) (8–13).
Various studies are being conducted to create microarrays in epithelial ovarian tumors, and in our study, 1 core of 5 mm diameter was examined from 100 cases. Hecht et al. CK7, CK20, p53, WT-1, ER, PR, Ki-67 immunohistochemical stains were studied and compared with the whole block section in the study performed by taking 3 samples with a diameter of 0.6 mm from each of 174 epithelial ovarian tumors. When comparing single-core, two-cores and three-cores, respectively, it is reported that results with 91%, 95% and 96% accuracy are obtained. The tissue size (5 mm in diameter) we used in the microarray was found to be sufficient to perform immunohistochemical studies with the support of the data in the literature. It is emphasized that antigenicity may be affected as the age of paraffin block progresses (grouping as >10 years and ≤10 years) and the importance of site selection in borderline tumors (21). In our study, the oldest paraffin block in terms of tissue age was 10 years ago. On microarray, in the study of Permuth et al., complete block section examination in 59 epithelial ovarian cancers and 1 core examination of 1 mm diameter taken from the central region were compared in terms of mismatch repair (MMR) gene expression loss. In 17 cases with loss of MMR gene expression in the central chord, 5 more cores of 1 mm diameter are sampled from the peripheral region. In 11 of these cases, there is loss of expression in the center, while expression is detected in the periphery. It is interpreted that this situation may be related to fixation (22). In our study, relevant areas from H&E sections were selected considering fixation and staining in previous immunohistochemical staining. Tissue was taken from subcapsular areas in appropriate cases. Tissue integrity was confirmed by H&E re-staining in sections taken after the immunohistochemistry method.
As a result of the immunohistochemical examination performed with the FGFR1 antibody, it was determined that the cytoplasmic staining decreased, respectively, and was observed at varying rates in the HGSC, LGSC/Borderline and SC groups. In this regard, there are not enough studies on ovarian carcinomas with the FGFR1 immunohistochemistry method in the literature.