Clinical characteristics and management of metastatic ovarian tumors

Introduction

Solid adnexal masses in postmenopausal patients are highly suspicious of malignancy with a background risk of 65% [1]. Apart from primary ovarian cancer and metastases to the ovary, the differential diagnosis should include relatively common benign lesions such as fibroma and fibrothecoma as well as potentially malignant, rare, hormonally active tumors like sertolioma/leydigoma or granulosa cell tumor [1].
Metastatic lesions account for 5–28% of malignant tumors described in the ovary [1–3]. The primary neoplasms are most often cancers of the gastrointestinal tract (colon – 30–33%, stomach – 30–39%, appendix 11–13%, pancreas – 12%, biliary tract –15% and liver – 4%) [1–4]. Other non-gynecologic cancers include breast cancer (13%) and, less commonly, lung, kidney, bladder and thyroid cancers, as well as lymphomas, melanomas and sarcomas [1–4]. Among gynecological cancers, endometrial cancer (23%) is the most common source of ovarian metastases, while cervical cancer accounts for only about 4% of cases [1–4].
Primary cancers metastasize to the ovary via three main routes: blood-borne, lymph-borne and by means of circulation of peritoneal fluid [5]. Increased ovarian blood supply in premenopausal women facilitates metastasizing, therefore blood-borne ovarian metastatic tumors, like from breast cancer, appear statistically 10–15 years earlier than primary ovarian cancers [6, 7]. Patients with metastases from the gastrointestinal tract constitute a generally older population [6]. Gastric cancer uses mainly the retrograde spread via the lymphatic vascular pathway [6]. Interestingly, recent studies have indicated significant clinical and histopathological differences regarding ovarian metastases from left-sided and right-sided colorectal and rectal cancers [8]. Left-sided colorectal and rectal neoplasm appears to metastasize mainly via the blood and lymphatic vascular pathways, is more likely to yield distant metastases, and ovarian metastases are usually unilateral [8]. In contrast, right-sided colorectal cancer primarily uses intraperitoneal spread; peritoneal implants, bilateral ovarian metastases and infiltration on the surface of the ovary have been observed more frequently [8]. However, no relationship has been shown between the side of the colorectal cancer and the ovary to which the cancer is more likely to metastasize [8].
In almost half of the patients, ovarian metastases are metachronous, i.e. occurring after a longer time interval after treatment of the primary nonmetastatic disease [7]. The earliest metastases, which occur on average about 1–2 years after the diagnosis of the primary neoplasm derive from the gastrointestinal tract and non-small cell lung cancer and the slowest metastatic spread to the ovary is reported from the urinary bladder and the appendix, which occur about 10 years after the primary diagnosis [7, 9–11].
Metastatic ovarian tumors are usually smaller (<10 cm in diameter) than primary ovarian can- cers [12] and usually occur bilaterally (up to 69% of cases) [6]. However, the morphology differs depending on the original mass. Histologically, metastatic tumors of the ovary most often correspond to mucinous adenocarcinomas [12]. “Maturation phenomenon” observed in intestinal adenocarcinoma refers to the tendency of neoplastic cells to transform into mature epithelial cells [13], which may lead to histological similarity with borderline tumors and even to cystadenomas [13]. The most-studied metastatic tumor of the ovary is the Krukenberg tumor, which accounts for 30–40% of metastatic lesions found in the ovary [14]. According to the World Health Organization (WHO), the term Krukenberg tumor refers to a metastatic lesion of the ovary with mucinous adenocarcinoma/signet ring cell carcinoma originating from the gastrointestinal tract [15]. Mucus-filled signet ring cells should occupy at least 10% of the tumor tissue [13]. Krukenberg tumor in 70% derives from gastric adenocarcinoma, poorly cohesive type [16].
The symptoms are highly nonspecific, yet present in 70% of patients at the time of diagnosis and include abdominal bloating (39%), abdominal pain (38–42%), ascites (27–39%), postmenopausal bleeding (18%), increased abdominal girth (15%), weight loss (6%) and, less frequently, abnormal uterine bleeding associated with ovarian dysfunction or sex hormone production by the developing metastasis [6, 7, 11, 12]. Often, in about 38–42% of cases, the diagnosis of a metastatic ovarian lesion precedes the diagnosis of the primary tumor [13]. Moreover, up to 32–36% of ovarian metastases originating from the gastrointestinal tract are initially diagnosed as primary ovarian cancer [11, 14], reaching 73% for synchronous ovarian metastases in gastric cancer and 65% for synchronous ovarian metastases in colorectal and rectal cancer [7]. Therefore preoperative assessment is extremely important in order to tailor the treatment plan to the patient’s specific condition.
Transvaginal ultrasound is the gold standard for diagnosing pelvic masses. Sonographic appearance of ovarian metastases differs depending on their origin and has been extensively described in the literature [6, 17, 18]. The International Ovarian Tumor Analysis Group (IOTA) developed and validated several mathematical models for differentiating between benign and malignant adnexal masses based on sonographic features of the tumor. According to a recently published consensus of four international societies (European Society of Gynaecological Oncology, International Society of Ultrasound in Obstetrics and Gynecology, IOTA, European Society of Gastrointestinal Endoscopy), the IOTA ADNEX model, which has a similar accuracy to subjective assessment by an expert sonographer, is recommended for preoperative assessment of all adnexal masses. ADNEX is easy to use, can be applied to all adnexal lesions and with the use of Ca-125 it can discriminate between primary and metastatic ovarian cancers. It is superior to all previously developed methods, including the risk of ovarian malignancy algorithm (ROMA) and the risk of malignancy index, which are mainly based on tumor marker levels.
Elevated levels of carcinoembryonic antigen (CEA) and CA-72-4 may indicate a primary origin in the gastrointestinal tract, CA-19-9 is a marker characteristic for pancreatic cancer, stomach cancer, colorectal cancer as well as cholangiocarcinoma, whereas CA-15-3 is a marker for breast cancer. Upper and lower endoscopy is not routinely recommended. However, given that most ovarian metastases originate from the gastrointestinal tract, it is worth considering, especially in countries with a high incidence of gastrointestinal cancers [6]. Noteworthy, the frozen section can only determine the malignant character of the lesion and has very low specificity with regard to differentiating between primary and metastatic ovarian cancer. Definitive diagnosis can only be made on the basis of histopathological examination, often using immunohistochemical methods [6]. These assays can aid in the precise identification of the tumor’s origin by detecting specific markers that are indicative of different types of cancer cells. Primary ovarian cancers are generally larger and have more often cystic-solid appearance, patients more frequently present with ascites, while metastatic tumors are smaller and have a solid appearance in the ultrasound examination, moreover patients with metastatic ovarian tumors present higher levels of CEA and often have a history of malignancy [13]. There are no differences in bilateralism or carcinomatosis between primary and metastatic ovarian tumors [13]. In about 15% of cases, the primary cancer cannot be determined [14].
The presence of ovarian metastases is prognostically unfavorable, but the final prognosis depends largely on the primary lesion [6, 7, 9]. The mean survival is longer for primary cancers originating from the reproductive tract in comparison to non-gynecologic cancers (48 months vs. 12–20 months, respectively) [6, 7, 12]. Several prognostic factors have been identified such as preoperative CA-125 level, age at diagnosis, type of primary tumor, presence of intraperitoneal spread, complete cytoreduction and presence of unilateral vs. bilateral ovarian metastases [6, 9, 12, 19–21].
There is no single treatment algorithm for patients with metastatic ovarian tumors. Clinical management should focus on making the correct diagnosis, localizing the primary tumor and staging.
For premenopausal women who wish to retain fertility, unilateral adnexectomy with intraoperative biopsy and histopathologic examination of the other ovary is acceptable [10, 20]. However, these patients should be aware of the risk of micrometastases in the contralateral ovary [10, 22]. Achieving optimal cytoreduction is a crucial prognostic factor. Studies have shown that residual tumors of 2 cm or larger significantly decrease mean survival 25–14 months [9, 19, 23]. Postoperative adjuvant therapy, primarily chemotherapy, has also been shown to improve mean survival rates [7, 9].
Although the benefit of cytoreductive surgery is not definitively established, it should always be considered for patients with disease confined to the ovaries where complete resection is possible [8]. Surgery is not recommended when the disease has spread extensively beyond the ovaries and complete resection is unattainable [8]. Additionally, resection of both ovaries should be performed in all postmenopausal women, even if a unilateral mass is identified through imaging as these methods often miss micrometastases in the contralateral ovary [8]. This is particularly true for right-sided primary tumors, where bilateral metastatic involvement is more common.

Case report

A 72-year-old patient with coronary disease, hypertension and obesity (body mass index 32 kg/m²) was admitted to the clinic due to bilateral solid adnexal masses detected on routine transvaginal ultrasound. Tumor markers Ca-125 and HE4 were within the normal range (ROMA index – 21%). The patient had a history of cholecystectomy and partial gastrectomy due to benign lesions.
Basic laboratory tests were normal. Tumor marker CA-15-3 was mildly increased 33.5 (normal range 0–28.5) but CA-19-9 was extremely elevated – 3669.0 (normal range 0–34), which led to a suspicion of metastatic origin of the ovarian masses and the patient was scheduled for an extended differential diagnosis in order to establish the primary cancer.
Transvaginal ultrasound examination revealed bilateral solid masses in the ovaries with a marked flow in color Doppler examination (Fig. 1 A, B). Magnetic resonance imaging of the pelvis and abdomen confirmed bilateral oval, smoothly contoured heterogeneous solid adnexal lesions (Fig. 2 A–C). Computed tomography revealed disseminated osteosclerotic lesions in the vertebral column, most likely metastatic. No lesions in the lungs or mediastinum were detected. Lymphadenopathy and peritoneal metastasis were excluded. Colonoscopy with biopsy revealed diverticulosis of the sigmoid colon and nests of low-grade cancer cells in the lamina propria of the colorectal mucosa, immunohistochemistry showed CK7(+) but Ca-125(–).
Gastroscopy with biopsy reported gastroesophageal reflux without esophagitis, hernia of the esophageal foramen, hypertrophic gastropathy of the fungus and body of the stomach, gastric ulcers and biliary reflux. Additionally, focal necrosis of the epithelium of the gastric antrum and body was described. Pathomorphological examination revealed nests of low-grade cancer cells underneath epithelium and in the lamina propria, immunohistochemistry showed CK7(+) but Ca-125(–).
The patient was diagnosed with disseminated colon cancer with bilateral metastases to the ovaries and multiple bone metastases. Due to the advanced stage of the disease the patient was referred to palliative care.
Due to the advanced stage of the disease and the patient’s comorbidities, a comprehensive palliative care plan was initiated to enhance her quality of life. Given the multiple bone metastases causing significant pain, the patient was started on a personalized analgesic regimen following the WHO analgesic ladder. This included non-opioid analgesics and opioids for moderate to severe pain, and adjuvant therapies like bisphosphonates were considered to reduce bone pain and prevent skeletal-related events. To address nausea, vomiting, and potential gastrointestinal discomfort from both the disease and previous surgeries, antiemetic medications were prescribed. Proton pump inhibitors were continued to manage gastric ulcers and prevent further gastric irritation. Recognizing the risk of malnutrition due to reduced appetite and previous partial gastrectomy, a dietitian provided nutritional counseling, and supplements were recommended to maintain caloric intake and address specific nutrient deficiencies.
Emotional and psychological support was offered to help the patient and her family cope with the emotional stress of the diagnosis. Spiritual care was made available to address existential concerns and provide comfort if desired.
The palliative care team facilitated conversations about the patient’s wishes, priorities, and goals, including discussions about preferred settings for care, understanding of the prognosis, and expectations.
A multidisciplinary approach was adopted, with regular meetings held among oncologists, primary care providers, nurses, social workers, and other specialists to ensure coordinated and continuous care. The patient’s symptoms and quality of life indicators were regularly assessed to adjust the care plan as needed, and education and resources were offered to family members to help them understand the disease process and how best to support the patient.
By integrating palliative care early and focusing on the patient’s individual needs, the care plan aimed to provide holistic support, alleviate suffering, and improve the overall quality of life.

Conclusions

Solid adnexal lesions are associated with a high risk of malignancy estimated over 65% [1] and should always raise a suspicion of metastases, especially if bilateral. Making a correct diagnosis is clinically challenging. The prognosis is generally unfavorable, but is highly dependent on the location of the primary neoplasm, the possibility of optimal cytoreduction and adjuvant chemotherapy.

Disclosures

1. Institutional review board statement: Not applicable.
2. Assistance with the article: None.
3. Financial support and sponsorship: None.
4. Conflicts of interest: None.

References