Pancreatic cancer with ovarian metastasis: cases report and literature review

Abstract

Background: 

Pancreatic cancer with ovarian metastases is rare and easily misdiagnosed. Patients with ovarian metastases are first diagnosed with ovarian cancer and may miss the opportunity to receive surgical operation. We report 7 rare cases of ovarian metastases secondary to pancreatic adenocarcinoma and review the literature to analyze clinical characteristics, diagnostic methods, and potential therapeutic strategies for the rare malignancy.

Cases Summary: 

We retrospectively analyzed the clinical data of 7 female patients with ovarian metastases of primary pancreatic cancer who were admitted to our hospital from January 01, 1985, to April 1, 2020. These 7 patients were diagnosed with ovarian metastasis at an average age of 52.28 (38–69) years. The reason for the patient’s visit was generally a mass in the lower abdomen and/or abdominal pain. Six of them had significantly higher serum Carbohydrate antigen19-9 (CA19-9) levels, 6 patients had pancreatic tumors located in the body or tail, and 1 patient had one in the head of the pancreas. All patients underwent excision of ovarian tumors and resection or biopsy of pancreatic tumors. Five patients had pancreatic ductal adenocarcinoma (PDAC), and 2 had pancreatic cystadenocarcinoma (PCC), all of which were revealed by the pathological results. Ovarian tumors were assessed by pathology and were consistent with pancreatic metastasis. Currently, all 7 patients have died (follow-up to January 2, 2021). The median survival time for all patients was 13.7 months (2.9–27 months).

Conclusions: 

For this rare tumor, elevated serum CA19-9 may indicate that the primary lesion is in the pancreas. Enhanced pancreatic Computed Tomography (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 the quality of life.

Introduction

It is well known that pancreatic cancer (PC) is the fourth most common cause of cancer-related death and is an extremely infiltrative neoplasm that usually presents with vascular and perineural invasion.^[1] Long-term survival is possible only in patients who present with a disease diagnosed at the local stage (accounting for only approximately 20% of cases), and radical resection still represents the only hope for a cure. PC usually metastasizes through the lymphoid system to areas such as the liver, lung, spleen, bone, and other organs. However, ovarian metastases in female patients are exceedingly rare in clinical practice.^[2]

PC that has metastasized to the ovaries is found in 4% to 6% of patients at autopsy but is rarely diagnosed clinically.^[3] Similar cases have been reported in several retrospective studies of nongenital cancers that have metastasized to the ovaries. PC was identified as the primary malignancy in 2% to 19% of these patients.^[4] Such patients with ovarian metastasis generally have no distinguishing clinical symptoms or signs. Most patients are finally 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 PC patients with ovarian metastases who were admitted to our hospital from January 1, 1985, to December 1, 2020, to provide a common education and consultation resource for clinical surgeons and gynecologists.

Case presentation

Clinical characteristics

The clinical characteristics of these 7 patients are in Table 1. All 7 patients were female with an average age of 52.28 (range: 38–69) years at the time of discovery of ovarian metastasis. All the patients were diagnosed with PC in combination with ovarian metastases at the same time.

Table 1 - Clinical characteristics, treatment methods and follow-up of all 7 patients

Case	Age (y)	Abdominal symptom		Examination at first-time diagnose		CA19-9/CA125 (U/ml)	Location of the tumor	Pathology (pancreas)	Operation	Adjuvant treatment	Outcome	Follow-up (M)(last time)
		mass	pain	CT	Echo
1	43	√	√		√	213.4/40.9	Pancreatic tail; Bilateral ovaries	PDAC	Biopsy of pancreatic tumor; Resection of ovarian tumors	Chemotherapy	Die	5.7
2	58	√			√	63/51.5	Pancreatic head; Bilateral ovaries	PDAC	Biopsy of pancreatic tumor; Resection of bilateral accessories	Chemotherapy	Die	2.9
3	46		√	√		442/109.7	Pancreatic body; Bilateral ovaries	PDAC	Resection of bilateral accessories	None	Die	13.4
4	69		√		√	49/35.6	Pancreatic tail; Right ovary	PDAC	Resection of bilateral accessories	Chemotherapy; radiotherapy	Die	27
5	66		√	√		10.9/28.7	Pancreatic body; Right ovary	PDAC	Resection of uterus, bilateral accessories, omentum, appendix	None	Die	5
6	38	√			√	3775/423.5	Pancreatic tail; Bilateral ovaries	PCC	Resection of bilateral accessories	Chemotherapy	Die	20
7	46	√	√	√		12708/109.6	Pancreatic body and tail; Right ovary	PCC	Resection of right accessory	Chemotherapy	Die	22

PCC = pancreatic cystadenocarcinoma, PDAC = pancreatic ductal adenocarcinoma.

Chief complaints

The reason for the patient’s visit was generally a mass in the lower abdomen and/or abdominal pain. There were 4 patients with lower abdominal masses and 5 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 first diagnostic department was the gynecology department for the 7 patients.

History of past illness

These 7 patients denied any history of hypertension, coronary heart disease, diabetes, or coronary heart disease. They reported no history of smoking, alcohol intake, or a hereditary disorder.

Physical examination

The abdominal examination of the 7 patients was all diffusely soft, with no distention or tenderness. No other positive sign was observed.

Laboratory examinations

At the first visit, these patients were tested for serum CA19-9 indicators at the same time. The patients 1–7, except for patient 5, were negative, the rest of the patients had varying degrees of increase in serum CA19-9.

Imaging examinations

The optional auxiliary examinations of the abdominal pelvic cavity are generally ultrasound or CT scanning. Three patients underwent CT scanning, and 4 patients underwent color ultrasound of the uterus and ovaries at the first diagnosis. Through these tests, ovarian masses were found and suspected as malignant. The status of ovarian involvement can be assessed by CT scanning and ultrasound results before surgery. Four patients had bilateral ovarian tumors and 3 patients had only right ovarian involvement. According to the CT scanning or PET/CT results, there was no evidence of metastatic liver cancer in patients 1–4, and in patients 5–7, the results were suggestive of metastatic liver cancer. PET/CT results for patient 7 suggested retroperitoneal lymph node metastasis at the same time.

Tumor characteristics, treatment, and follow-up

Pancreatic tumors of patient 2 were located in the head of the pancreas, and the rest were located in the pancreatic bodies or tails. All patients underwent surgical treatment, and unilateral or bilateral ovaries and fallopian tubes were removed. The specific surgical modalities and subsequent treatment are shown in Table 1. All the patients underwent either aspiration biopsy or intraoperative biopsy of pancreatic tumors because of unresectable pancreatic tumors. The pathological results were pancreatic ductal adenocarcinoma (PDAC) in patients 1–5, and pancreatic cystadenocarcinoma (PCC) in patients 6 and 7. Ovarian tumors in all patients were assessed by pathology and were consistent with pancreatic metastasis. The specific pathological types and immunohistochemistry of the ovarian tumors are detailed in Table 2.

Table 2 - Pathological and immunohistochemical features of ovarian tumors in all 7 patients

Case	Pathology of ovarian tumors	Grade	CDX2	CK20	CK7	CEA	ER	PR	p53	P16	PAX-8	WT-1	Ki67
1	Metastatic mucinous adenocarcinoma	I	+	—	+		—	—	+	—	—	—
2	Metastatic adenocarcinoma	III				+	—	—
3	Metastatic adenocarcinoma	I		+	+	+	—	—	—	Partial+	—	—	30%
4	Metastatic adenocarcinoma	II	+	—	Partial+		—	—			—
5	Metastatic adenocarcinoma	II	—	—	+		—	—	—	—	—	—	20%
6	Metastatic mucinous adenocarcinoma	I	+	+	+	+	—	—	+	—		—	60%
7	Metastatic mucinous adenocarcinoma	I	—	—	—		—	—	—	—			5%

The significance for + was defined by intensity and extent of IHC staining. Staining intensity was scored 0 (negative), 1 (low), 2 (medium), and 3 (high). Staining extent was scored 0 (0% stained), 1(1%–25% stained), 2 (26%–50% stained), and 3 (51%–100% stained). The final score was determined by multiplying the intensity scores with staining extent and ranged from 0 to 9. The tissues of final scores less than or equal 3 were considered as low expression(-), 3–5 were considered as medium expression (partial+), and more than 5 were high expression(+).

We followed all patients to the status of death, and the overall survival time was defined as the period from the first onset of the disease to death. At present, all of the patients have died and the median survival time was 13.7 months (from the onset of the ovarian tumors to death).

Discussion

To our knowledge, ovarian metastases of PC are rare and not widely reported. To investigate this rare disease, we systematically searched the literature databases from 2012 to 2022. The keywords used were “ovarian carcinoma/cancer,” “pancreatic carcinoma/cancer/adenocarcinoma,” “ovarian metastasis,” and “ovary.” The inclusion criteria were any form of publication focusing on PDAC with ovarian metastases and a sufficient description of clinicopathological characteristics. Studies published in languages other than English, those with duplicate data from the same patient, and those for which the full text was unavailable were excluded. Eight studies were yielded from the systematic search and 8 patients were included.^[5–12] The characteristics of all cases are summarized in Table 3. The summary and analysis of the clinicopathological characteristics from these cases may provide a comprehensive description for surgeons and gynecologists.

Table 3 - Clinical features of pancreatic cancer with ovarian metastasis (8 cases from 2012 to 2022)

Year	Case	Age (y)	Abdominal pain	Abdominal mass	Nausea/Vomiting		Weight loss	Jaundice	Abdominal distension	Anorexia	Ovarian metastasis at initial presentation	Location of pancreatic tumor	Pathology of pancreas	Laterality of metastasis	Pancreatic surgery	Ovarian surgery	Chemotherapy
2012	1	41	Yes	Yes		Yes	No	No	Yes	No	Yes	Body and tail	Cystadenocarcinoma	Bilateral	Yes	Yes	Yes (GEMOX)
2016	2	63	Yes	Yes		No	No	No	No	Yes	No	Body	Adenocarcinoma	Right	No	Yes	Yes (S-1/GEM)
2020	3	69	Yes	Yes		No	Yes	No	No	No	Yes	Tail	Adenocarcinoma	Right	Yes	Yes	Yes (GEM+PTX)
2020	4	38	No	Yes		No	No	No	Yes	No	Yes	Tail	Cystadenocarcinoma	Bilateral	No	No	Yes (GEM+CIS)
2020	5	48	No	Yes		No	No	No	No	No	Yes	Tail	Adenocarcinoma	Right	Yes	Yes	Yes
2021	6	64	Yes	Yes		No	No	No	Yes	No	Yes	Tail	Adenocarcinoma	Left	Yes	Yes	Yes (FOLFIRINOX)
2022	7	55	Yes	Yes		Yes	Yes	No	No	No	No	Unknown	Adenocarcinoma	Right	Yes	Yes	Yes (GEM+PTX)
2022	8	42	No	Yes		No	No	No	No	No	No	Body	Adenocarcinoma	Bilateral	No	Yes	No (immunotherapy)

Ovarian metastases commonly originate from malignant tumors of the colorectum, breast, endometrium, stomach, cervix, appendix, etc. However, PC metastasis to the ovaries is quite rare.^[3,13–16] In fact, pancreatic primary tumors account for an estimated 7% of nongenital ovarian metastases.^[17,18] The great majority of these cases are PDAC, with sporadic case reports of metastatic PNEC.^[19] We discovered from the Surveillance, Epidemiology, and End Results (SEER) Database that the rate of female PC metastasis was 39.6% in the liver, 15.4% in the lung, 4.4% in the brain, and 7.0% in the bone between 2010 and 2016. The SEER database does not contain data on ovarian metastasis in PC; however, among the female PC patients of our hospital, the proportion of ovarian metastasis was only 1.86% (9/3757).

PC that first presents as ovarian metastases are 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 about abdominal or pelvic pain and abdominal distension (possibly due to ascites). In other cases, ovarian metastases can also be manifested as affecting the menstrual cycle or causing vaginal bleeding, even in postmenopausal women.^[20–22] 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 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. Given the poor prognosis and difficult clinical management of ovarian metastases from PC, we should screen key populations for early diagnosis in clinical practice. These include adult women with lower abdominal pain accompanied by gastrointestinal symptoms, elevated tumor markers (such as CA125, CA19-9), postmenopausal or nonmenstrual irregular vaginal bleeding accompanied by gastrointestinal symptoms, and palpable masses in the lower abdomen.

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, Supplementary Fig.1, https://links.lww.com/JP9/A23). 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.

Figure 1.: 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 × 9.7 cm and 4.9 × 4.4 cm, respectively.

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 × 2.3 cm.

The main treatment for PC with ovarian metastases is surgery as soon as possible, with the goal of complete resection. Even if the primary PC 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.^[23–26] 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.^[15,27–29] All of the patients in our study had their ovarian metastases resected. The median survival of these patients with ovarian metastases was 13.7 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 multicyclic 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 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.^[30,31] In addition to morphological characteristics, immunohistochemical markers may be helpful in distinguishing between primary and metastatic neoplasms of the ovaries.^[32–34] Currently, the most commonly used immunohistochemical tumor markers in diagnosing metastatic ovarian tumors are CK20 and CK7.^[35] carcinoembryonic antigen (CEA) and CA125 may also be routinely examined by the pathology department, but these 2 markers do not seem to distinguish between primary ovarian and metastatic tumors.^[36–38]

Figure 3.: Hematoxylin-eosin staining of the metastatic ovarian tumors.

At present, the mechanism by which PC metastasizes to the ovary remains controversial. Some clinicians consider the metastatic path of PC to the ovary to resemble that of Krukenberg tumors, and the possible sources of ovarian metastases are peritoneal spread, lymphatic spread, and hematogenous diffusion.^[39–43] The pancreas is a peritoneal interpositional organ. When PC 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 PC. In addition, by local infiltration, cancer cells may also enter the lymphatic reflux system of the posterior peritoneum. In this study, we found that 4 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 PC cells may have undergone retrograde migration. PC tissue can mechanically block the lymphatic vessels of the posterior peritoneum; therefore, diffuse PC cells can migrate along this pathway to para-aortic and pelvic lymph nodes, eventually forming ovarian metastasis. Furthermore, PC spreading to the ovaries usually results in bilateral ovarian metastases, and intraductal cancer emboli are commonly seen in lymphatic vessels by microscopy.^[44]

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 to 5 mm.

Conclusions

In conclusion, the probability of ovarian metastasis from PC is small; the condition is rare in clinical practice and is difficult to diagnose early. Most patients develop lower abdominal symptoms at the later stage of the disease. On the basis of our study, we suggest that at the time of discovering ovarian tumors and suspected metastasis, doctors should be more active in screening abdominal and pelvic enhancement CT scans and evaluating serum CA19-9. Additionally, we believe that even if PC is already unresectable, the ovarian tumors should still be excised, thereby reducing the tumor load and improving the quality of life in patients.

Acknowledgment

Not applicable

Author contributions

WW and CQ contributed to the conception of the study; ZL and BZ contributed significantly to manuscript preparation; ZZ, XZ, and ZL performed the data analyses and wrote the manuscript; HX, XL, and XZ helped perform the analysis with constructive discussions. All authors have read and approved the manuscript.

Financial support

This article was supported by National Natural Science Foundation of China, No. 81773215 and CAMS Innovation Fund for Medical Sciences (No. 2021-I2M-1-002).

Conflicts of interest

The authors declare no conflicts of interest.

Ethics approval

This case report represents a fully anonymized retrospective presentation. Therefore, the need for ethical approval was waivedaccording to the regulation of the Ethics Committee of PekingUnion Medical College Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College.