Among gynecologic tumors, ovarian malignancy is the most life-threatening disease for women. Normal-sized ovary carcinoma syndrome (NOCS) is relatively rare in clinical practice, with a preoperative misdiagnosis rate of almost 100% [1] and a worse prognosis than ovarian cancer, with a 5-year survival rate of 10% compared to 37% for ovarian cancer [2]. In recent years, the incidence of this disease has been on the rise, mainly due to the lack of awareness of the disease and the low chance of surgery, but with the gradual recognition of the disease, the diagnosis rate has increased, and the incidence has risen. Since the first report of this disease by Feuer et al [3] in 1989, a number of reports have appeared one after another at home and abroad, with the largest sample size of 20 cases. In this paper, the clinicopathological features, diagnostic points, and factors influencing treatment and prognosis of NOCS are reviewed as follows.
I. Definition
In 1989, Feuer et al. first reported 11 cases of ovarian malignant tumors of different histological origins, characterized by diffuse pelvic and abdominal extensive carcinoma with normal size of bilateral ovaries and/or small granules on its surface, and named them NOCS. there are four types of histological origins, namely: (1) peritoneal mesothelioma; (2) extra-gonadal mullerian duct tumor; (3) metastatic carcinoma of unknown organ (3) metastatic cancer of unknown organ; (4) primary ovarian cancer. The incidence of NOCS varies, ranging from 1.92% to 21.5% [5-7], and the names are confusing, such as (1) normal large ovarian cancer syndrome (NOCS) [1]; (2) primary ovarian epithelial carcinoma syndrome with normal-sized ovaries [1]; and (3) primary ovarian cancer with normal-sized ovaries [3]. epithelial carcinoma syndrome [5]; (3) normal large ovarian cancer [8]; (4) ovarian liquid surface cancer [9]; and (5) ovarian cancer syndrome of normal ovarian size [7]. Because NOCS is not a simple disease, but a combination of multiple diseases, and the ovaries are normal in size to the naked eye, we believe that it is more appropriate to call it normal-sized ovarian cancer syndrome (NOCS).
Clinicopathological features of NOCS
The clinical features of NOCS are: high prevalence over the age of 50 years, most patients present with abdominal distension, poor appetite, wasting, and increased abdominal circumference as the first symptoms; some patients present with abdominal pain [1]; almost every patient has a large amount of ascites; there are implanted nodules in the rectal fossa of the uterus, positive ascites exfoliation cytology, normal size ovaries with a nodular surface and small papillary superfluous organisms locally, and widely implanted corn-like nodules in the pelvic abdomen The pelvic abdominal cavity had widely planted corn-like nodules, which were locally aggregated in a pie shape. Pathological type: predominantly plasmacytic cystic adenocarcinoma with a pathological grade of G2 or higher [5].
Diagnostic criteria of NOCS: most scholars adopted the diagnostic criteria of Hata et al [10]: (1) extensive metastases in the abdominal cavity were found by open exploration, while the ovaries were normal in size bilaterally with or without superfluous growths on their surfaces; (2) the ovaries were examined postoperatively on pathology as primary carcinoma or metastatic carcinoma of unknown organs; (3) no other primary foci were found on preoperative imaging and surgical exploration; (4) there was no preoperative cancer due to (4) no preoperative chemotherapy or radiotherapy for ovarian disease, and no recent surgery involving the ovaries.
NOCS has an insidious onset, late presentation and difficult diagnosis, with a misdiagnosis rate of 40% to 100% [5, 7]. To avoid misdiagnosis, a thorough preoperative physical examination, pelvic and abdominal examinations (including ultrasound, CT, and gastrointestinal tract radiographs), routine laboratory tests, vaginal ultrasound and lumpectomy are important because vaginal ultrasound has high resolution and is not disturbed by factors such as somatic obesity, age, bladder filling, and posterior uterus, making the observation of the disease clearer and more intuitive, and combined with more specific blood flow information that significantly improves the accuracy of the diagnosis of the disease [11]. The tumor marker CA125 is generally elevated in EPSPC and ovarian epithelial carcinoma, and it can be used as an effective indicator for preoperative diagnosis and postoperative disease monitoring. calretinin is a characteristic marker for mesothelioma, with a positive rate of 88%-100% [12].
III. 4 types of NOCS
(A) EPSPC
EPSPC is the main type of NOCS. EPSPC is called EPSPC because it originates on the peritoneal surface, has normal size of bilateral ovaries or has only a small infiltration on the surface, and has a histological pattern similar to ovarian plasmacytoma papillary carcinoma, so it accounts for 7.2%-15% of ovarian cancer in the same period [13].
The diagnostic criteria of the American Gynecologic Oncology Group (GOG) for EPSPC [9] are: (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 conditions: 1) no lesion present on the ovary; 2) tumor invading the ovarian surface epithelium without interstitial infiltration; 3) tumor invading the ovarian surface epithelium and the cortical interstitium underneath, but (4) The pathological type and cytological features must be similar or consistent with those of ovarian plasmacytoid cystic adenocarcinoma, regardless of the degree of tumor differentiation.
Koutselinin et al [14] concluded that EPSPC is a primary, rare, peritoneal tumor of multicentric origin. The clinical presentation is like advanced ovarian plasmacytoma papillary carcinoma. Pathological features: the tumor mostly grows in the greater omentum, bilateral pelvis and abdominal peritoneum, forming multiple or multiple tumor nodules, and the greater omentum is mostly pancake shaped. Microscopically, the histological structure is consistent with ovarian plasmacytic cystic adenocarcinoma, but sand granules are more common [9]; the tumor tissue is often poorly differentiated and above G2.
EPSPC originates from mesothelial tissue with müllerian duct differentiation potential outside the ovary, i.e. EPSPC is a malignant tumor of müllerian duct origin originating from the peritoneal mesothelium [15], which shares a common ontogenetic and embryologic basis with ovarian epithelial tumors. The female peritoneum is also derived from the somatic epithelium and its subepithelial mesenchyme, and it not only has a common embryologic origin with the female epithelium, but also has a tendency to differentiate into the epithelium and the mesenchyme of the somatic duct [9]. Therefore, both the histomorphology of the tumor and the histochemical and immunohistochemical features of the tumor cells are very similar to those of primary plasmacytoid papillary carcinoma of the ovary [13]. Although it can be differentiated by morphological criteria, with postoperative pathology showing only superficial cortical infiltration of the ovary, it is not possible to distinguish whether a peritoneal tumor is a primary or ovarian cancer metastasis when there is a malignant tumor in the ovarian mesenchyme [3]. To date, there is no good tumor marker that can distinguish these two tumors with the same histogenesis and immunophenotypic and immunohistochemical characteristics [12]. The literature reports that the positive expression rates of epithelial membrane antigen (EMA), epithelial antigen (Ber-EP4), placental alkaline phosphate (PLAP), vimentin, TAG-72, S-100, Leu-M1, and calretinin in EPSPC and ovarian plasmacytoid cystic adenocarcinoma tissues are essentially the same [9].CA125 and Ber- EP4 had high expression rates in primary ovarian cancer, 100% and 95%, respectively; while the expression rates in EPSPC were relatively lower, 67% and 33%, respectively [12]. The rate of BRCA1 gene mutation was slightly higher in primary peritoneal carcinoma than in ovarian carcinoma [13];; while Halperin et al [16] used immunohistochemistry to confirm that EPSPC and ovarian carcinoma were two types of plasmacytic papillary carcinoma with significantly lower expression of estrogen receptor and progesterone receptor in the former than in the latter (P=0.001), and significantly lower Ki-67 expression in the former than in the latter (P=0.019). The proportion of hypofractionation was significantly greater in the former than in the latter (P=0.012); the former had a younger age at menarche, a higher incidence of ascites, more pelvic and abdominal metastases, and a lower survival rate of more than 3 years than the latter. Therefore, it is believed that EPSPC and ovarian cancer may be two different types of malignant tumors, and EPSPC can be regarded as a new type of epithelial tumor.
(II) Metastatic carcinoma of unknown organ
Among common tumors, ovarian metastasis has the highest chance if the primary focus is stomach, breast or colon. Metastatic ovarian cancer accounts for about 5.0%-12.7% of ovarian malignant tumors [9, 17]. However, those with unknown primary foci account for 3.0% to 13.6% of ovarian metastatic tumors [18]. In contrast, the percentage of metastatic carcinoma of the ovary with unknown primary foci in normal size of the ovary as a percentage of metastatic carcinoma of the ovary has not been exactly reported.
Clinicopathologic features: (1) Normal size ovaries with small granules or ectopic papillae on the surface and microscopic findings of tumors in one or both ovaries [9]; tumor emboli were seen in the lymphatic vessels; most of them were bilateral. (2) Most ovarian metastatic carcinomas are secondary to gastrointestinal tumors, so they usually have gastrointestinal symptoms, such as abdominal distension and abdominal pain; in addition, ascites is also common, but the cause of its formation is unknown [9]. (3) Metastatic ovarian tumors have not yet seen the phenomenon of pancake shaped thickening of the greater omentum, while primary ovarian tumors often have varying degrees of thickening of the greater omentum or even pancake shaped, which is the main point of differentiation between primary and metastatic ovarian tumors [17]. (4) Cytokeratin 7 (CK7) was positive in primary ovarian cancer but negative in metastatic ovarian cancer of the intestine [18]. CA125 was highly expressed in primary ovarian cancer (84%) but only 4% in metastatic cancer of the intestine of the gastrointestinal tract [18]. (5) It is generally not easy to identify microscopically whether ovarian malignant tumors are primary or metastatic, especially those originating from the gastrointestinal tract and breast [19]. Immunohistochemistry can identify, for example, CK7. metastatic carcinoma of unknown organ, the metastatic route of which is still unknown. The general preference is for lymphatic metastasis. Because ovarian metastasis has occurred when the primary focus of gastric cancer is quite limited or confined to the submucosa, with a metastasis rate of 18.9% [9]; the ovaries are normal in appearance and tumor emboli are visible in the lymphatic vessels microscopically.
(iii) Primary ovarian cancer
Almost all primary ovarian cancers are epithelial tumors [1-4] and are mostly seen in middle-aged and elderly women.
Clinicopathologic features: normal size ovaries with nodular surface and locally visible papillary redundancy; pelvic and abdominal cavities with widely planted cornu nodules; pie-like thickening of the greater omentum [5]; predominantly plasmacytic adenocarcinoma with a pathologic grade of G2 or higher.
Ovarian plasmacytic surface carcinoma is a specific type of plasmacytic adenocarcinoma; the tumor consists entirely of ectopic papillae originating from the ovarian surface, which is less common and is often associated with extensive abdominal dissemination; the ovarian tumor itself is often small, with only small foci or even no interstitial infiltration [9]. It may represent a tumor of multicentric origin of the ovarian surface epithelium and extra-ovarian peritoneum, usually bilateral. Extensive peritoneal dissemination is present at the time of presentation [9].
(iv) Malignant mesothelioma
Malignant mesothelioma is a relatively uncommon tumor. It accounts for a relatively small proportion of NOCS, ranging from 9.0% to 36% [1].
IV. Treatment and prognosis
For the treatment of NOCS, surgery is mostly advocated to remove extensive cancer foci in the pelvic and abdominal cavities, including total uterus + bilateral adnexa + greater omentum + appendix, or tumor cytoreductive surgery [6, 7]. Individual cases reported pelvic lymph node dissection [6]. After tumor cytoreductive surgery, the size of the residual foci is the most critical factor affecting the prognosis of ovarian cancer, and postoperative chemotherapy is supplemented with effective chemotherapy for the tumor pathology type. The vast majority of scholars believe that EPSPC and ovarian epithelial carcinoma, due to the same origin and similar histological features, are both treated well with APC or PC regimens (A: adriamycin, P: cisplatin, C: cyclophosphamide) for more than 6 courses of chemotherapy [5, 6]. The addition of radiotherapy to postoperative chemotherapy for EPSPC has been shown to be effective, with a postoperative tumor-free survival time of more than 87 months [1]. In addition, the survival of patients treated with platinum-based combination chemotherapy was significantly longer than that of patients treated without platinum-based chemotherapy [2]. Most 5-Fu-based combination chemotherapy is used for metastatic tumors in the gastrointestinal tract. In conclusion, thorough tumor cytoreductive surgery and systematic multi-course chemotherapy are two important factors to achieve a better prognosis.
The prognosis of NOCS is worse than that of ovarian cancer, with survival times ranging from 1 month to 7 years after surgery [5]. The reason for this is that during gynecological examination, both ovaries are of normal size, which is not easily detected by ultrasound and CT, and by the time the patient develops symptoms, the pelvic and abdominal cavities are full of lesions. In addition, EPSPC is the main type of NOCS, while the success rate of tumor cytoreductive surgery is 65.5% for EPSPC and 79% for ovarian plasmacytoid papillary carcinoma (P=0.049) [2]. Generally EPSPC is less effective and has a short disease-free survival, typically only 3.4 months, with a mean survival time of 19 months, while ovarian plasmacytoid papillary carcinoma has a disease-free survival and a mean survival time of 11.7 months and 31 months, respectively [2]. In view of the limited successful implementation of tumor cytoreductive surgery in EPSPC, the short tumor-free survival, and the short survival time, these differences should further lead to the search for new and better treatment options different from those for ovarian cancer. It is believed that the prognosis of NOCS will improve with better understanding of the disease, improved diagnostic techniques, and improved treatments.