To our knowledge, ovarian metastases of pancreatic cancer are rare and not widely reported. Ovarian metastases commonly originate from malignant tumors of the colorectum, breast, endometrium, stomach, cervix, appendix, etc. However, pancreatic cancer metastasis to the ovaries is quite rare[3, 9-12]. In fact, pancreatic primary tumors account for an estimated 7% of nongenital ovarian metastases[4, 7]. The great majority of these cases are PDAC, with sporadic case reports of metastatic PNEC. We discovered from the Surveillance, Epidemiology, and End Results (SEER) Database that the rate of female pancreatic cancer metastasis was 39.6% in the liver, 15.4% in the lung, 4.4% in the brain and 7.0% in bone between 2010 and 2016. The SEER database does not contain data on ovarian metastasis in pancreatic cancer; however, among the female pancreatic cancer patients of our hospital, the proportion of ovarian metastasis was only 2.39‰ (9/3757). Most were PDAC patients (6/9), and the others were PCC (2/9) and PNEC (1/9) patients.
Pancreatic cancer that first presents as ovarian metastases is extremely difficult to diagnose. Most of these patients were diagnosed as having ovarian neoplasms evidenced by inferior abdominal symptoms and ultrasound/CT examination results. Patients with ovarian metastatic tumors usually complain of abdominal or pelvic pain and abdominal distension (possibly due to ascites). In other cases, ovarian metastases can also manifest as affecting the menstrual cycle or causing vaginal bleeding, even in postmenopausal women[14-16]. Patients in our study were also treated for lower abdominal pain or lumps, with the vast majority diagnosed at gynecological clinics. Among these cases, the vast majority (8/9) of pancreatic tumors were located in the body or tail of the pancreas. Because tumors in the pancreatic body and tail often have difficulty triggering specific clinical symptoms, they are difficult to detect in the early stage. In contrast, pelvic masses make it easier for patients to identify signs and symptoms of compression, discomfort, pain, and a palpable lower abdominal mass.
At the time of the patients’ first visit, pelvic CT scanning or ultrasound of the uterus and ovaries may be performed. Pelvic enhanced CT may reveal ovarian masses that are characterized by an uneven and slightly low density, uneven edges, and uneven enhancement (Fig 1). However, CT and ultrasound can often help to locate ovarian lesions but may not accurately identify the nature of ovarian tumors. If the inspection is more comprehensive, there may be additional findings. Most of the time, abdominal enhancement CT can identify pancreatic tumors, which generally exhibit low densities, uneven edges, and an unclear mass shadow in the pancreas (Fig 2). However, in clinical work, some pancreatic surgeons and gynecologists only focus on pancreatic tumors or ovarian neoplasms, respectively, without the benefit of whole abdomen and pelvic enhancement CT, resulting in a missed diagnosis. Theoretically, PET-CT is still the best method to identify metastatic lesions. However, it is still expensive and not routinely performed before surgery. Regarding tumor markers, the sensitive indicator for ovarian tumors is serum CA125, and for pancreatic tumors, it is serum CA19-9. Elevated serum CA19-9 is also a common phenomenon in these patients. This is worthy of the attention of more gynecologists, so that when they endeavor to identify the origin of ovarian tumors, they will also simultaneously screen for digestive tract-related serum tumor markers, especially CA19-9.
The main treatment for pancreatic cancer with ovarian metastases is surgery as soon as possible, with the goal of complete resection. Even if the primary pancreatic cancer is unresectable, resection of the ovarian metastasis is still necessary, as this can not only effectively relieve the clinical symptoms of the patient but also prolong the survival time[17-20]. The median survival time of patients with metastatic ovarian tumors is generally closely related to the primary site of the tumor; in addition, the median survival time is also related to the timing of the diagnosis, whether surgical resection of the metastatic lesions is performed, and other factors[11, 21-25]. All of the patients in our study had their ovarian metastases resected. The median survival of these patients with ovarian metastases was 7 months, suggesting that patients with ovarian metastases did have a poor prognosis.
In some cases of this study, ovarian metastases were revealed to be mucinous tumors. For some pathologists, cases are misdiagnosed as primary ovarian mucinous carcinomas because pancreatic adenocarcinoma can produce large metastatic multicystic ovarian tumors that appear similar to primary ovarian mucinous neoplasms. Ovarian metastases are characterized by multiple cysts containing mucoid material and an external surface lobulated with small gray to pale yellow nodules. Upon microscopic examination, the neoplasms strikingly resemble primary cystic mucinous tumors (Fig 3). They are composed predominantly of mucinous cysts that are usually large and dilated. The stroma between the cysts contains compact aggregates of glands and single glands. An infiltrative pattern with destructive stromal invasion is typically not prominent. Usually, fewer than 3% of primary ovarian carcinomas are mucinous, and most of them are unilateral and at stage I at diagnosis. Therefore, mucinous carcinoma of the ovary may suggest the presence of a nonovarian primary tumor[26, 27]. In addition to morphological characteristics, immunohistochemical markers may be helpful in distinguishing between primary and metastatic neoplasms of the ovaries[28-31]. Currently, the most commonly used immunohistochemical tumor markers in diagnosing metastatic ovarian tumors are CK20 and CK7. CEA and CA125 may also be routinely examined by the pathology department, but these two markers do not seem to distinguish between primary ovarian and metastatic tumor[33-36].
At present, the mechanism by which pancreatic cancer metastasizes to the ovary remains controversial. Some clinicians consider the metastatic path of pancreatic cancer to the ovary to resemble that of Krukenberg tumors, and the possible sources of ovarian metastases are peritoneal spread, lymphatic spread and hematogenous diffusion[37-42]. The pancreas is a peritoneal interpositional organ. When pancreatic cancer is located in the pancreatic body or tail, the most common lymphatic metastatic pathway is hilar or splenic lymph node metastasis, and the liver tops the list of distant metastatic organs of pancreatic cancer. In addition, by local infiltration, cancer cells may also enter the lymphatic reflux system of the posterior peritoneum. In this study, we found that 5 patients had no evidence of liver metastases when ovarian metastasis was found. Multiple miliary nodules located in the posterior peritoneum were also found during the operation (Fig 4). This suggested that pancreatic cancer cells may have undergone retrograde migration. Pancreatic cancer tissue can mechanically block the lymphatic vessels of the posterior peritoneum; therefore, diffuse pancreatic cancer cells can migrate along this pathway to para-aortic and pelvic lymph nodes, eventually forming an ovarian metastasis. Furthermore, pancreatic cancer spreading to the ovaries usually results in bilateral ovarian metastases, and intraductal cancer emboli are commonly seen in lymphatic vessels by microscopy[43, 44].