[Abstract] OBJECTIVE: To investigate the clinicopathological characteristics, survival and prognostic factors influencing the expression of molecular markers of NOCS in normal-sized cancer of the ovary syndrome (NOCS). METHODS: A retrospective analysis of 55 patients with NOCS was performed, and the expression of CA125, Ber-EP4 Calretinin and CK7 in ovarian cancer and NOCS was detected by immunohistochemical SP method. RESULTS: NOCS accounted for 6, 56% of ovarian cancers in the same period, and there was an increasing trend in recent years. the mean time from initial diagnosis to surgery in patients with NOCS was (127, 8±255, 6) d, while the corresponding time in patients with ovarian cancer was (58, 7±57, 6) d. The difference between the two was significant (t=2, 01, P<0, 05). The accuracy rate of vaginal ultrasound for NOCS was 93, 5%. The mean survival time for chemotherapy ≥3 courses and residual foci <2 cm in diameter was significantly different (P<0, 05) compared to chemotherapy <3 courses and residual foci ≥2 cm in diameter. The mean survival time of patients after surgery was not related to age, abdominal volume, clinical stage, or pathological grade. 1-year, 3-year, and 5-year survival rates for NOCS were 67, 9%, 29, 1%, 10, and 2%, respectively. the expression of CA125 and Ber-EP4 was higher in ovarian primary carcinoma than in EPSPC (P<0, 01, P<0, 05), while in ovarian cancer and ovarian primary carcinoma there was no significant difference in the expression of Conclusion: Ovarian primary carcinoma is the main component of NOCS. middle-aged and elderly women over 50 years old with unexplained gastrointestinal symptoms, accompanied by a large amount of ascites, and a non-palpable mass on gynecological examination should be considered as NOCS and promptly undergo vaginal color ultrasound and other examinations and perform an exploratory dissection.
There are few reports on normal-sized ovary carcinoma syndrome (NOCS) in the literature. In our hospital, 55 cases of NOCS were treated from 1992 to 2002. Now, we summarize and analyze the clinicopathological characteristics of NOCS from multiple perspectives, aiming to enable clinicians to better understand this disease, improve the diagnosis and treatment, reduce the preoperative misdiagnosis rate and improve the survival rate.
1. Materials and methods
1.1 Sources The clinical data of 55 cases of NOCS were obtained from the complete medical records archived in the case room of the Department of Obstetrics and Gynecology, Fourth Hospital of Hebei Medical University from January 1992 to December 2002. 839 cases of ovarian epithelial carcinoma were treated surgically in 10 years, among which 52 cases met the diagnostic criteria of Hata et al [2] for NOCS, 33 cases had well-preserved wax specimens, including primary epithelial carcinoma of the ovary Among them, 52 cases met the diagnostic criteria of NOCS by Hata et al [2], 33 cases had well preserved wax specimens, including 19 cases of primary epithelial carcinoma of the ovary (hereinafter referred to as primary ovarian carcinoma), 18 cases of extraovarian peritoneal serous papillary carcinoma (EPSPC), and 6 cases of metastatic ovarian carcinoma of unknown organ. Three other cases did not meet the diagnostic criteria of Hata et al. One case each of endodermal sinus tumor, granulosa cell tumor and follicular membrane granulosa cell tumor were also included in the NOCS because of the normal size of the ovary. Fourteen cases were randomly selected as controls from 787 (839-52) cases of common ovarian epithelial carcinoma (hereafter referred to as ovarian cancer) during the same period.
1, 2 Methods The clinicopathological data of 55 patients were retrospectively analyzed, and 47 of them were followed up for more than 1 year, and 8 cases were lost due to unknown address or relocation. The pathological sections were reviewed again and double-blinded method was used to read the sections, and those with inconsistent diagnosis were discarded for the same sections. The expression of CA125, calcium-binding protein calretinin (referred to as calretinin), keratin CK7 (referred to as CK7), and epithelial antigen Ber-EP4 (referred to as Ber-EP4) were detected in 33 cases of NOCS and 14 cases of ovarian cancer by immunohistochemical streptavidin anti-biotin protein-peroxidase ligation (SP method). the SP method kit and murine anti-human CA125 and CK7 monoclonal antibodies and rabbit anti-human Calretinin polyclonal antibody were purchased from Beijing Zhongshan Biotechnology Co. 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 SPSS10, 0 statistical software was used to perform one-way t-test, logistic multi-factor regression analysis, and multiple linear regression analysis for factors affecting the prognosis of NOCS, respectively. Survival rate was calculated by Kaplan-Meier survival curve method, and Log-rank test was used for comparison of survival between two groups. Immunohistochemical positive expression rates were calculated using the exact probability method with a four-compartment table as well as the X2 test. The percentage composition of diseases was calculated according to the following formula.
Number of new cases of a disease in the same period
Percentage composition of a disease = × 100G
Total number of all new cases in a given period
2. Results
2.1 Clinical characteristics of NOCS
2.1.1 Clinical characteristics Age of onset 38-73 years, median age 56 years, 15 cases <50 years (27.3%), 40 cases ≥50 years (72.7%), percentage of disease composition of NOCS in ovarian cancer was 6.56% (55/839), and there is an increasing trend in recent years, 2.63% in 1992-1997, 9.56% in 1998-2002. There were 53 cases with ascites (96,4%), 200-6500mL of ascites, 22 cases with <2000mL (40,0%), 31 cases with ≥2000mL (56,4%), and 2 cases without ascites (3,6%) (open abdomen for other reasons). According to the 1986 FIGO staging: 7 cases in stage I-II and 48 cases in stage III-IV. The frequencies of various clinical symptoms are shown in Table 1, mainly abdominal distension and digestive system symptoms. in NOCS, the age at menarche was (16,1±2,4) years and (14,5±1,5) years in patients with primary carcinoma of ovary and EPSPC, respectively, and the difference between them was significant (t=11,85,P<0,01), while the difference between the incidence of ascites was not significant (P>005).
2,1,2 Adjuvant examinations Preoperative abdominal ultrasound was performed in 55 cases and found small papillary abnormalities on the ovarian surface and metastatic masses in the pelvic and abdominal cavities in 23 cases, mostly in the greater omentum, colon, liver and spleen area, with an accuracy rate of 41,8%. 46 cases were also examined by vaginal ultrasound and 43 cases were found to have uneven ovarian surface or small papillary abnormalities, with an accuracy rate of 93,5%. The accuracy of combined abdominal and vaginal ultrasound increased to 97.8%, and cancer cells were found in ascites in 47 cases (88.7%). Blood count: Platelets were higher than 400×109/L in 23 cases (41,8%) and up to 598×109/L.
2,1,3 Misdiagnosis rate 21 cases (38,2%) were misdiagnosed preoperatively, including 18 cases in external hospitals and 3 cases in our hospital. There were 14 cases of tuberculous peritonitis, 6 cases of cirrhotic ascites, and 1 case of pelvic inflammatory disease, respectively.
2, 1, 4 Time from initial diagnosis to surgery The mean time from initial diagnosis to surgical confirmation in 55 cases of NOCS was (127, 8±255, 6) d, while the corresponding time in 14 patients with common ovarian cancer was (58, 7±57, 6) d. The difference was significant (t=2, 01,
P<0,05).
2, 2 Pathological features 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 the 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 beneath it, but the tumor was less than 5mm×5mm in 4 cases; lesions within the ovarian parenchyma were less than 5mm×5mm in 6 cases.
The 55 cases of NOCS had four types of tissue origin, ovarian primary tumor, EPSPC, metastatic cancer of unknown organ and malignant mesothelioma in 32 cases (58,2%), 15 cases (27,3%), 7 cases (12,7%) and 1 case (1,8%), respectively. Primary tumors of the ovary were the main component of NOCS, including 29 cases of primary carcinoma of the ovary and 1 case each of endothelial sinus tumor, granulosa cell tumor and follicular membrane granulosa cell tumor. Grading: 10 cases were graded G1, 34 cases were graded G2~G3, and 11 cases were not graded (metastatic carcinoma of unknown organ, malignant mesothelioma, endodermal sinus tumor, granulosa cell tumor and follicular membrane granulosa cell tumor).
2.3 Treatment of NOCS All 55 cases were treated surgically with total uterus + bilateral adnexa + large omentum + metastases resection, of which the residual foci were <2 cm in 40 cases and ≥2 cm in 15 cases. 43 cases were treated with postoperative chemotherapy, 33 with PC regimen, 5 with VPC regimen, 3 with VAC regimen, 2 with TP regimen (P: cisplatin, C: cyclophosphamide, V: vincristine, T: Tysol); 17 cases with <3 courses and 26 cases with ≥3 courses. 5 of 55 cases were given 1~3 courses of chemotherapy preoperatively.
2, 4 Prognostic factors of NOCS The relationship between the mean survival time after surgery and age, number of chemotherapy, residual foci size, abdominal volume, staging and grading is shown in Table 2. by univariate t-test: the mean survival time of those with ≥3 courses of postoperative chemotherapy was significantly different from those with <3 courses (t=3, 38, P<0, 05); the mean survival time of those with residual foci <2 cm in diameter was significantly different from those with ≥2 cm (t=3, 51, P<0, 05); the mean postoperative survival time was not related to patient age, abdominal volume, staging, or grading (t=1, 29, t=0, 74, t=0, 91, t=1, 81, P>0, 05).
By logistic multifactorial regression analysis and multiple linear regression analysis, the number of courses of chemotherapy and residual foci diameter were the main factors affecting the prognosis of NOCS ( OR number of chemotherapy=0, 752, OR residual foci=0, 781, P<0, 05, regression coefficient chemotherapy=1, 6319, regression coefficient residual foci=1, 5123, P<0, 05).
2, 5 Survival rates of NOCS The overall 1-, 3-, and 5-year survival rates of NOCS were 67, 9%, 29, 1%, and 10, 2%, respectively. among NOCS, the 1-, 3-, and 5-year survival rates of EPSPC and primary ovarian cancer were 76, 9%, 20, 4%, and 10, 1%, respectively, and 72, 4%, 19, 9%, and 13, 3%, respectively, with no significant survival rate comparison between the two groups There was no significant difference between the survival rates of the two groups (P>0, 05).
2, 6 Immunohistochemical analysis of NOCS In NOCS, the expression of CA125 and Ber-EP4 in primary carcinoma of ovary was higher than their expression in EPSPC, and there was a significant difference by the exact probability method of four-compartment table (P<0, 01,P<0, 05).The expression of CA125, CK7, Calretinin, Ber-EP4 in ovarian carcinoma versus ovarian There was no significant difference in the expression of CA125, CK7, Calretinin, and Ber-EP4 in primary cancer and ovarian cancer (x2=1, 11, P>0, 05) see Table 3.
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 (the name is now confusingly reported in China), and is characterized by the presence of diffuse cancer foci in the pelvic and abdominal cavities with normal-sized ovaries bilaterally, and/or the phenomenon 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) They had not received chemotherapy or radiation therapy for ovarian disorders before surgery, nor had they undergone any recent surgery involving the ovaries.
In this group, 29 cases of primary carcinoma of the ovary, 15 cases of EPSPC, 7 cases of metastatic carcinoma of unknown organ, and 1 case of peritoneal malignant mesothelioma met the Hata diagnostic criteria. In addition, there were 3 cases that did not meet the above diagnostic criteria: 1 case was 46 years old with endodermal sinus tumor, showing abdominal distension, rapid increase in abdominal circumference, significant wasting with decreased urine output, NOCS was considered, and a large amount of ascites was found on abdominal dissection. One case of granulosa cell tumor of the follicular membrane. In these 3 cases, there were two inconsistencies with the definition and diagnostic criteria: first, ovarian cancer of non-epithelial origin, but germ cell tumors and gonadal mesenchymal cell tumors. Second, there were no extensive pelvic and abdominal metastases, but both ovaries were normal in size, and no primary foci were found on preoperative imaging and surgical exploration. We believe that such cases of ovarian malignancy without pelvic-abdominal metastasis and normal size of both ovaries should also be classified as NOCS, that is, it may be better to change the definition of primary carcinoma of the ovary to primary tumor of the ovary. Therefore, NOCS is not a simple disease, but a combination of multiple diseases.
The percentage of disease composition of NOCS in ovarian cancer varies among reports, ranging from 1,92% to 15%, and 6,56% in our data, with an increasing trend in recent years. The misdiagnosis rate of NOCS in our data was 38, 2%, which was much lower than the 50%~100% reported in the literature [4]. The reason may be that the awareness of this disease has increased in our hospital in recent years, and when patients, especially middle-aged and elderly women over 50 years of age, present with unexplained abdominal distension, abdominal pain, ascites, and wasting, promptly perform examinations related to ovarian cancer, such as finding cancer cells in ascites, blood CA125 determination, ultrasound, especially vaginal color ultrasound, and when the possibility of NOCS is considered to be high, promptly perform a dissection and exploration, thus The rate of misdiagnosis has been greatly reduced.
Vaginal color ultrasound has high resolution and is not disturbed by factors such as obesity, older bladder not easily filled, posterior uterus, repetitive reflection of air in the intestinal cavity, etc. It can detect small papillary protrusions on the surface of normal-sized ovaries, or nodules and uneven internal echogenicity, etc. Combined with color power angio imaging (CPA) to observe ovarian tumors, In combination with color power angio imaging (CPA), the hematologic characteristics of ovarian tumors can be observed, which further improves the reliability of vaginal color ultrasound in the diagnosis of NOCS. In our data, the accuracy of vaginal color ultrasound for NOCS was 93,5%, and the combined detection of abdominal ultrasound and vaginal color ultrasound can increase the accuracy of NOCS to 97,8%, which is similar to that reported in the literature [5]. Therefore, vaginal color ultrasound is an important screening tool for patients with suspected NOCS.
The diagnostic criteria of the American Gynecologic Oncology Group (GOG) for EPSPC: (1) normal size of both ovaries; (2) extra-ovarian lesions larger than those invaded on the ovarian surface; (3) microscopic examination with one of the following: 1) no lesion present in the ovary. 2) tumor invading the ovarian surface epithelium without interstitial infiltration. 3) tumor invading the ovarian surface epithelium and the cortical interstitium under it, but the tumor (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 that met the above diagnostic criteria. The age of menarche of the patients was earlier than that of ovarian primary carcinoma, and the survival rate of more than three years and the incidence of ascites 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.
In our data, NOCS was treated with the same treatment method as ovarian cancer, that is, surgery combined with chemotherapy, and the prognosis of surgery alone was poor. The effect of chemotherapy alone was not shown in our data. Therefore, the best treatment choice for NOCS, whether chemotherapy alone is superior to surgery-chemotherapy, and whether chemotherapy-surgery-chemotherapy is the best treatment are yet to be studied in more depth by expanding the sample size.
Treatment of metastatic ovarian cancer with resection of only the whole uterus + bilateral adnexa without resection of the primary lesion has poor efficacy and extremely poor prognosis, with an average survival time of only 3 months after surgery. Therefore, for metastatic cancer with pathologically confirmed metastases to unknown organs, the primary lesion should be identified as much as possible and targeted treatment should be given. Ovarian metastases from digestive system tumors are mostly treated with combination chemotherapy based on 5-fluorouracil [1].
There are few reports on the survival rate of NOCS. The present data show that the 5-year survival rate of NOCS is 10,2%, which is lower than the 20% reported in the literature [6] and lower than the 37% for common ovarian cancer. The reasons for this may be: older age of onset, more advanced cases, poor sensitivity to chemotherapy, high preoperative misdiagnosis rate and long time between initial diagnosis and surgery in NOCS.
3.2 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 cancer.Ber-EP4 showed 89,5% sensitivity in primary ovarian cancer and 92,9% specificity in ovarian cancer and 83,3% specificity in both primary and ovarian cancer.Takekawa et al [8] showed that Keratin, EMA, Vimentin and PCNA were not differentially expressed in NOCS and ovarian cancer. 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 positive in 100%, while all ovarian carcinomas metastasized from the intestine are negative[9] . The results of the study: 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, the positive results for CK7 have the following two possibilities: (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 results of the study showed that Calretinin showed 62,5% sensitivity and 66,6% specificity in EPSPC.Calretinin expression in primary carcinoma of the ovary and EPSPC There was also no significant difference in the expression of calretinin in ovarian primary carcinoma and EPSPC, thus it cannot be used as a specific marker for EPSPC and cannot distinguish ovarian primary carcinoma from EPSPC.