Pancreatic Cancer With Ovarian Metastasis: Clinical Features, Diagnosis and Management

Background: To summarize the clinical features, diagnosis and management of pancreatic cancer with ovarian metastasis. Methods: We retrospectively analyzed the clinical data of patients with ovarian metastases of primary pancreatic cancer who were admitted to our hospital from 01/01/1985 to 04/01/2020. Results: In total, there were 3757 female pancreatic-cancer patients. 9 of them were diagnosed with ovarian metastasis at an average age of 51.89 (38-69) years. The reason for the patients’ visit was generally a mass in the lower abdomen and/or abdominal pain. 7 patients had signicantly higher serum CA19-9 levels. 8 patients had pancreatic tumors located in the body or tail; 1 patient, in the pancreatic head. All patients underwent excision of ovarian tumors and resection or biopsy of pancreatic tumors. 6 patients had pancreatic ductal adenocarcinoma (PDAC), 2 had pancreatic cystadenocarcinoma (PCC), and 1 had pancreatic neuroendocrine carcinoma (PNEC), all revealed by the pathological results. Ovarian tumors were assessed by pathology and were consistent with pancreatic metastasis. Currently, 2 patients are still alive (followed until 04/2020). The median survival time for all patients was 7 months (2.9-22 months). Conclusions: Pancreatic cancer with ovarian metastases is rare and easily misdiagnosed. When ovarian tumors are suspected to be metastatic, elevated serum CA19-9 may indicate that the primary cancer is pancreatic. Enhanced CT can facilitate diagnostic localization. In addition, if the pancreatic tumor cannot be removed, the ovarian tumor should still be resected to reduce the tumor load and improve quality of life.


Background
It is well known that pancreatic cancer is the fourth most common cause of cancer-related death and is an extremely in ltrative neoplasm that usually presents with vascular and perineural invasion [1]. Longterm survival is possible only in patients who present with disease diagnosed at the local stage (accounting for only approximately 20% of cases), and radical resection still represents the only hope for a cure. Pancreatic cancer usually metastasizes through the lymphoid system to areas such as the liver, lung, spleen, bone and other organs [2]. However, ovarian metastases in female patients are exceedingly rare in clinical practice.
Pancreatic cancer that has metastasized to the ovaries is found in 4% to 6% of patients at autopsy but is rarely diagnosed clinically [3][4][5]. Similar cases have been reported in several retrospective studies of nongenital cancers that have metastasized to the ovaries. Pancreatic cancer was identi ed as the primary malignancy in 2% to 19% of these patients [6][7][8]. Such patients with an ovarian metastasis generally have no distinguishing clinical symptoms or signs. Most patients are nally diagnosed with primary pancreatic tumors because of pelvic symptoms when they go to the gynecological clinic. It is easy to miss this diagnosis in clinical work, and the true prevalence of the clinical diagnosis, optimal therapeutic protocol, prognosis and survival rates are still not clear. Therefore, we collected and summarized all of the medical records for pancreatic cancer patients with ovarian metastases who were admitted to our hospital from 01/01/1985 to 04/01/2020 to provide a common education and consultation resource for clinical surgeons and gynecologists.

Methods
From 01/01/1985 to 04/01/2020, 3757 female patients with pancreatic cancer were admitted to our hospital. Nine of them had been diagnosed with ovarian metastases in which the primary tumor was pancreatic cancer. We collected disease-relevant information, including clinical symptoms, imaging examination, laboratory tests, tumor features, pathological features, surgery and adjuvant treatments. To date, 2 of these patients have remained alive. All patients were followed until death, and the surviving patients were followed until April 2020.
The respective ethics committees approved the collection of these materials. Written informed consent was obtained from the surviving patients. The cases were retrieved from our consultation les. None of these cases have been reported before.

Clinical characteristics
We summarize the clinical characteristics of these 9 patients in Table 1. All patients were female with an average age of 51.89 (range: 38-69) years at the time of discovery of ovarian metastasis). Among these patients, 8 were found to have pancreatic cancer and ovarian metastasis at the same time; 1 patient was rst diagnosed with and treated for pancreatic cancer and developed ovarian metastasis 2 years later.
The reason for the patients' visit was generally a mass in the lower abdomen and/or abdominal pain.
There were 5 patients with lower abdominal masses and 6 patients with abdominal pain. The lumps were all self-palpable, and the pain was not severe but was a long-term, moderate pain; it was often only after several weeks of pain that the patients came to the hospital. The rst diagnostic department was the gynecology department for Patients 1-8, and the primary malignant tumor of the pancreas was found after the gynecological outpatient or inpatient complete examination. Patient 9 was admitted to the oncology outpatient department and was considered to have pancreatic tumor ovarian metastasis after the completion of the examination.

Imaging and laboratory tests
The optional auxiliary examination of the abdominal pelvic cavity is generally ultrasound or CT scanning. Five patients underwent CT scanning, and 4 patients underwent color ultrasound of the uterus and ovaries at the rst diagnosis. Through these tests, ovarian masses were found and suspected to be malignant. The status of ovarian involvement can be assessed before surgery by CT-scan and ultrasound results. Five patients had bilateral ovarian tumors, 3 had only right ovarian involvement and 1 had only left ovarian involvement. According to the CT scanning or PET/CT results, there was no evidence of metastatic liver cancer in Patients 1-5, and in Patients 6-9, the results were clearly suggestive of metastatic liver cancer. PET/CT results for Patient 8 suggested retroperitoneal lymph node metastasis at the same time. At the rst visit, these patients were also tested for serum CA19-9 indicators at the same time. Patients 1-8, except for Patient 6, were negative, and the rest of the patients had noticeably increased serum CA19-9 to varying degrees. The serum level of CA19-9 was high in Patient 9 when she was rst diagnosed with a pancreatic tumor (PNEC) but was normal when she was diagnosed with ovarian metastasis 2 years later.

Tumor characteristics, treatment and follow-up
Pancreatic tumors of Patient 3 were located in the head of the pancreas, and the rest were located in the pancreatic body or tail. All patients underwent surgical treatment, and unilateral or bilateral ovaries and fallopian tubes were removed. The speci c surgical modalities and subsequent treatment are shown in Table 1. Pancreatic tumors in Patients 2-9 were found to be unresectable at the time of diagnosis, so they underwent either aspiration biopsy or intraoperative biopsy. The pathological ndings were pancreatic ductal adenocarcinoma (PDAC) in Patients 1-6, pancreatic cystadenocarcinoma (PCC) in Patients 7 and 8, and PNEC in Patient 9. Ovarian tumors in all patients were assessed by pathology and were consistent with pancreatic metastasis. The speci c pathological types and immunohistochemistry of the ovarian tumors are detailed in Table 2.
We followed all patients to the status of death, and the overall survival time was de ned as the period from the rst onset of the disease to death. At present, Patients 5 and 6 are still alive, and both follow-up periods ended on 04/22/2020. The median survival time was 7 months (from the onset of the ovarian tumors to death).

Discussion
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][10][11][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 [13]. 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 rst presents as ovarian metastases is extremely di cult 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][15][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 di culty triggering speci c clinical symptoms, they are di cult 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' rst 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 ndings. 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 bene t 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 tractrelated 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][18][19][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][22][23][24][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 [3]. 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 in ltrative 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][29][30][31]. Currently, the most commonly used immunohistochemical tumor markers in diagnosing metastatic ovarian tumors are CK20 and CK7 [32]. 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][34][35][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][38][39][40][41][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 in ltration, cancer cells may also enter the lymphatic re ux 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]. Tables  Table 1 Clinical characteristics, treatment methods and follow-up of all 9 patients.  Consent for publication: We con rm that this work is original and has not been presented or published elsewhere, nor is it currently under consideration for publication elsewhere.
Availability of data and material: The datasets used or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests: The authors of this article have no con ict of interest.  Pelvic enhanced CT showed two masses in the bilateral ovaries, with uneven and slightly low density, uneven edges, and uneven enhancement; the largest sections measured 12.2 x 9.7 cm and 4.9 x 4.4 cm, respectively.
Page 19/21 Figure 2 Abdominal enhanced CT showed a low-density mass, which had uneven edges, in the pancreatic body and tail, and the largest cross section was 4.1 x 2.3 cm.

Figure 3
Hematoxylin-eosin staining of the metastatic ovarian tumors. Figure 4 During the operation, many scattered metastatic nodules were observed to be present on the patient's peritoneum (indicated by forceps), and the size of these nodules ranged from 3-5 mm.