There are few reports in the literature about normal-sized ovary carcinoma syndrome [1] (NOCS). The expression of CA125, Ber-EP4, Calretinin and CK7 in NOCS has not been reported. Thirty-three cases of NOCS treated in our hospital between 1992 and 2002 with complete data were selected for immunohistochemical analysis.
1. Materials and methods
1.1 Source of data
The clinical data of 33 cases of NOCS were obtained from the complete medical records archived in the Department of Obstetrics and Gynecology of the Fourth Hospital of Hebei Medical University from January 1992 to December 2002. 839 cases of ovarian epithelial carcinoma treated by surgery in 10 years, among which 33 cases met the diagnostic criteria of NOCS as described by Hata et al [2] and the wax specimens were well preserved, including primary epithelial carcinoma of the ovary (hereinafter referred to as ovarian primary carcinoma) in 19 cases, extraovarian peritoneal serous papillary carcinoma (EPSPC) in 8 cases, and metastatic ovarian carcinoma of unknown organ in 6 cases. Fourteen cases were randomly selected as controls from 806 (839-33) cases of common ovarian epithelial carcinoma (hereafter referred to as ovarian cancer) during the same period.
1,2 Methods
Pathological sections were reviewed anew, and double-blind method was used to read the sections. For the same sections, those with inconsistent diagnosis were discarded. The expression of CA125, calcium-binding protein calretinin (abbreviated as calretinin), keratin CK7 (abbreviated as CK7), and epithelial antigen Ber-EP4 (abbreviated as Ber-EP4) were detected in 33 cases of NOCS and 14 cases of ovarian cancer by immunohistochemical Streptomyces antibiotin protein-peroxidase ligation (SP method). the SP method kit and Mouse anti-CA125 and CK7 monoclonal antibodies and rabbit anti-human Calretinin polyclonal antibody were purchased from Beijing Zhongshan Biotechnology Co. and Ber-EP4 antibody was purchased from DAKO. The kit instructions were strictly followed. The results were determined: positive staining for CA125 protein was localized in the cell membrane and appeared brownish-yellow staining; positive staining for Calretinin, CK7 and Ber-EP4 protein was localized in the cell plasma and appeared brownish-yellow staining. The number of positive cells was defined as negative if it was less than 5%, and positive if it was greater than or equal to 5%.
1. 3 Statistical treatment The exact probability method of the four-compartment table in SPSS10.0 statistical package was used for statistics.
2. Results
2, 1 Clinical characteristics Age 35-70 years, median age 54 years. According to the 1986 FIGO staging: 5 cases of stage I-II and 28 cases of stage III-IV.
2, 2 Pathological characteristics of NOCS
According to the original surgical records, the maximum diameter of both ovaries did not exceed 4 cm, and the surface was nodular, with small papillae or cauliflower-like superfluous organisms locally visible. Microscopic observation: (1) Primary carcinoma of ovary: components of carcinoma were seen in the ovarian peritoneum and parenchyma, with glandular, papillary or stripe-like arrangement, varying cell size and obvious heterogeneity. (2) EPSPC: tumor invaded the ovarian surface epithelium without mesenchymal infiltration in 5 cases; tumor invaded the ovarian surface epithelium and the cortical mesenchyme under it, but the tumor was less than 5 mm×5 mm
2, 3 Immunohistochemical analysis of NOCS
In NOCS, the expression rates of CA125 and Ber-EP4 were higher in ovarian primary carcinoma than their expression in EPSPC, which were significantly different by the exact probability method of the four-compartment table (P<0.01,P<0.05). the expression of CA125, CK7, Calretinin, and Ber-EP4 in ovarian carcinoma and ovarian primary carcinoma were not significantly different (x2= 1.11, P>0.05)
3, Discussion
3, 1 Diagnostic criteria and clinicopathological features of NOCS The definition of normal-sized ovarian cancer syndrome (NOCS) was first proposed by Feuer et al [3] in 1989 (now confusingly named in domestic reports) and is characterized by the presence of diffuse cancer foci in the pelvic and abdominal cavities with normal-sized ovaries bilaterally, and/or the presence of small granules on its surface. There are four types of tissue origin, namely (1) primary carcinoma of the ovary. (2) EPSPC.(3) Metastatic carcinoma of unknown organ. (4) Malignant mesothelioma of the peritoneum. Most scholars currently use the diagnostic criteria of Hata et al. for NOCS: (1) Extensive carcinoma foci in the abdominal cavity were found by open exploration, while the ovaries were normal in size bilaterally, with or without superfluous organisms on their surfaces. (2) Postoperative pathological examination of the ovaries was primary cancer or metastatic cancer of unknown organ. (3) No other primary foci were found on preoperative imaging and surgical exploration. (4) No preoperative chemotherapy or radiation treatment for ovarian disorders and no recent surgery involving the ovaries.
The diagnostic criteria for EPSPC by the Gynecologic Oncology Group (GOG): (1) normal size of both ovaries; (2) extra-ovarian lesions larger than those invading the ovarian surface; (3) microscopic examination with one of the following conditions: 1) no lesions in the ovaries; 2) tumor invading the ovarian surface epithelium without interstitial infiltration; 3) tumor invading the ovarian surface epithelium and the cortical interstitium underneath, but the tumor is less than 5mm×5mm. (4) The pathological type and cytological features must be similar or consistent with ovarian plasmacytoid cystic adenocarcinoma, regardless of the degree of pathological differentiation of the tumor. In our group, there were 15 cases of EPSPC meeting the above diagnostic criteria. The age of menarche of the patients was earlier than that of ovarian primary carcinoma, and the survival rate and incidence of ascites over three years were basically the same as that of ovarian primary carcinoma, and the two were not easily distinguishable from each other in terms of symptoms and clinical manifestations, and the efficacy of chemotherapy was similar to that of ovarian primary carcinoma.
3,2 3 Molecular markers of NOCS
CA125 (The Mullerianmarker) is a high molecular weight glycoprotein recognized by monoclonal antibody OC125 with a molecular weight of 200 kDa, which is a widely used biomarker in ovarian cancer and is not expressed in normal ovarian cells. It is highly sensitive in ovarian plasmacytoid papillary carcinoma, but its specificity is not strong.Ber-EP4 (EpithelialAntigen), an epithelial membrane antigen extracted from thymic carcinoma cell line MDF-7, is a strong positive marker for cancer, and according to a recent report [23], Ber-EP4 in ovarian plasmacytoid papillary carcinoma exhibited .95% sensitivity and 91% specificity in ovarian plasmacytoma. Therefore, CA125 and Ber-EP4 were selected as tumor markers to detect their expression in NOCS, and common ovarian cancer was used as a control, and their expression in primary ovarian cancer and common ovarian cancer was compared. The results showed that the expression of CA125 was similar in NOCS and common ovarian cancer, so CA125 can be used as an effective indicator for preoperative diagnosis and postoperative monitoring of NOCS patients. of specificity, which is basically the same as that reported in the literature [23]. Therefore, Ber-EP4 can be used as a good marker for ovarian cancer, and if it can be widely used in clinical practice, its combination with CA125 can improve the detection rate of primary ovarian cancer in NOCS and reduce the rate of misdiagnosis.CK7 (Cytokeratin7) is a basic cytokeratin extracted from human OTN11 ovarian cancer cell line with a molecular weight of 54 kDa and an isoelectric point of CK7 has a high affinity for primary ovarian cancer and is positive in 100% of cases, while ovarian cancers metastasized from the intestine are negative. Therefore, CK7 was selected as a tumor marker to detect its expression in NOCS. The results showed that CK7 was positive in 19 cases of primary ovarian cancer and in 2 cases of 6 cases of ovarian metastases from unknown organs (Fig12), while the follow-up results showed that these 2 patients finally died of gastric cancer, but both of them were negative for CA125 (Fi13), therefore, there are two possibilities for the positive results of CK7: (1) primary ovarian cancer. (2) Metastatic carcinoma of ovary of gastric origin. In this case, a positive CA125 would support primary cancer of the ovary and a negative CA125 would support metastatic cancer of the ovary of gastric origin. According to the literature [29], it is generally not easy to differentiate pathologically whether ovarian tumors are primary or metastatic, especially those originating from the gastrointestinal tract and the breast. By detecting CK7 protein expression in tissues, combined with CA125 assay results, a preliminary differentiation between primary ovarian cancer and metastatic ovarian cancer in NOCS, especially metastatic cancer of gastrointestinal origin, can be made, thus providing information for the selection of targeted chemotherapeutic agents after surgery.
Calretinin is a calcium-binding protein with a molecular weight of 29 kDa and is expressed mainly in the nervous system and to a lesser extent in non-neural tissues Doglioni et al [30] reported that Calretinin is 100% sensitive and 90% specific for malignant mesothelioma Attanoos [23] also concluded that Calretinin is a highly specific and sensitive marker. Since EPSPC has the same origin as peritoneal malignant mesothelioma, Calretinin was selected as a tumor marker to detect its expression in EPSPC and compared with the expression of Calretinin in ovarian primary carcinoma, and the results showed that Calretinin showed 62.5% sensitivity and 66.6% specificity in EPSPC. There was no significant difference in the expression of Calretinin in ovarian primary carcinoma and EPSPC. Thus, it is clear that although Calretinin is highly sensitive in malignant mesothelioma, it does not serve as a specific marker for EPSPC and does not distinguish ovarian primary carcinoma from EPSPC.
Molecular markers of NOCS It was reported [7] that Ber-EP4 showed 95% sensitivity and 91% specificity in ovarian plasmacytic papillary carcinoma. The results of the present study showed similar expression of CA125 in NOCS and ovarian carcinoma.
Ber-EP4 showed 89.5% sensitivity in ovarian primary carcinoma and 92.9% in ovarian carcinoma and 83.3% specificity in both ovarian primary and ovarian carcinoma.Takekawa et al [8] found no difference in the expression of Keratin, EMA, Vimentin and PCNA in NOCS and ovarian carcinoma. Both primary ovarian cancer and ovarian cancer showed ascites, extensive implantation metastasis in the pelvic abdomen, and essentially the same molecular marker expression, but the difference in tumor volume between the two may be due to intrinsic genetic changes [8]. The results of the study showed that the expression of CA125 and Ber-EP4 in EPSPC was significantly lower than that in ovarian primary carcinoma, i.e., both positive CA125 and Ber-EP4 were more likely to be ovarian primary carcinoma. Ovarian primary carcinoma and EPSPC are two different types of tumors, but their histological types, cytological features, and tumor behaviors are similar, and their clinical manifestations are not easily distinguishable.
CK7 has a high affinity for ovarian primary carcinoma and is 100% positive, while all ovarian carcinomas metastasized from the intestine are negative[9] . Results of the study.
All 19 cases of ovarian primary carcinoma were positive for CK7, and 2 cases of ovarian metastatic carcinoma from unknown organs were positive for CK7, while the follow-up results of these 2 patients who finally died of gastric cancer were negative for CA125, therefore, there are two possibilities for positive results for CK7: (1) primary carcinoma of ovarian origin. (2) Ovarian metastatic cancer of gastric origin. In this case, a positive CA125 would support primary ovarian cancer and a negative CA125 would support metastatic ovarian cancer of gastric origin, thus providing valuable information for the selection of targeted chemotherapeutic agents after surgery.Attanoos et al [7] concluded that Calretinin is a highly specific and sensitive marker for malignant mesothelioma.EPSPC has the same origin as peritoneal malignant mesothelioma, but the study The results showed that Calretinin exhibited 62.5% sensitivity and 66.6% specificity in EPSPC, and there was no significant difference in the expression of Calretinin between ovarian primary carcinoma and EPSPC, which shows that it does not serve as a specific marker for EPSPC and does not distinguish ovarian primary carcinoma from EPSPC.