Metastases to the Gynecologic Tract
Metastases to the genital tract may occur as a result of recognizable widely disseminated disease from another site or as an isolated lesion. In the latter case, it may be difficult to distinguish between a primary tumor of the gynecologic tract or metastases to the gynecologic tract from a nongynecologic site. Because treatment planning and appropriateness of surgery may be dictated by the primary site of the tumor, it is important to make the distinction between primary and metastatic disease. This chapter focuses on common sites of metastases to the gynecologic tract, characteristic clinical presentations, and radiologic and pathologic considerations that may be clinically helpful in treatment planning.
EPIDEMIOLOGY
Key Points
1. Metastatic disease to the gynecologic organs most commonly arises from colorectal, breast, gastric, and appendiceal primary malignancies.
2. Within the reproductive tract, the ovaries and vagina are the organs most commonly affected by metastatic disease.
3. Malignant masses or lesions in the gynecologic organs should be considered as potential sites of metastases if an established primary malignancy is of advanced stage or demonstrates poor prognostic factors.
Metastatic disease to the genital tract from nongenital tract malignancies is relatively uncommon but is influenced by geographic differences in cancer incidence. For instance, in Asian countries where gastric cancer is more common, metastatic disease to the genital tract is more prevalent. In Japan, 18% to 29% of tumors found in the reproductive organs may be non-gynecologic in origin; in Thailand, where cholangiocarcinoma is quite prevalent, 7% of all metastases to the genital tract may arise from the gallbladder or extrahepatic biliary tract.1 A single-institution review from the United States of 445,000 accessioned cases identified 325 metastatic tumors to the genital tract over a 32-year time period; 149 (45.8%) were from extragenital sites including the colon and rectum, breast, stomach, and appendix. Additional primary sites included the bladder, ileum, and cutaneous melanoma. The remaining sites of metastases originated from other areas within the genital tract such as the endometrium.2
The ovaries and vagina are, by far, the structures most commonly involved with nongenital tract metastases. Although percentages may vary by geographic area, the most common primary sites of disease metastatic to the ovaries typically arise from the gastrointestinal (GI) tract (large intestine and stomach, pancreas, biliary tract, and appendix) and breast. These sites comprise 50% to 90% of the metastatic cancers to the ovaries (Table 17-1). Although the histology of a metastatic breast cancer may look uniquely like breast cancer, metastases from other sites, such as the pancreas and appendix, are mucinous and can be difficult to distinguish from a primary mucinous tumor of the ovary. Endometrioid-appearing histologies in the ovary can arise from metastatic colon cancer, and clear cell histology can be confused with signet ring cells from a gastric cancer or a metastatic clear cell renal carcinoma. In the case of breast cancer, metastases to the ovary may remain completely occult and are detected only at autopsy or when they become symptomatic to the patient or identified on examination by her physician. With mucinous tumors, the metastases in the ovary can become quite large, leading to significant symptoms and typically dominating the clinical picture for the patient and the clinician.
Table 17-1 Metastatic Tumor to the Ovaries
Reproductive tract lesions are most likely to reflect metastatic disease when there is an established nongynecologic primary malignancy, especially if the primary tumor is advanced or has poor prognostic factors. This is true of metastatic breast, pancreatic, and colon cancer. In the case of some metastatic GI tract malignancies, however, the primary tumor may not be found for many years after the metastasis. The classic signet ring cell adenocarcinoma of the ovary is called a Krukenberg tumor, which represents fewer than 6% to 7% of all ovarian tumors in Western countries. The signet ring morphology was initially described in 1896 by a German pathologist and gynecologist, Friedrich Krukenberg. However, the extragenital origin of the Krukenberg tumor was not described until 6 years later. The stomach is the primary site of malignancy in 70% of cases of Krukenberg tumor. The route of spread to the ovaries is believed to be lymphatic due to the copious lymphatic plexus surrounding the gastric mucosa and submucosa. This lymphatic plexus, which communicates with the lymphatics along the ovarian vessels, provides a direct conduit for even small gastric cancers to spread to the hilum and cortex of the ovary.3
Primary appendiceal neoplasms, including low-grade mucinous neoplasms, signet ring adenocarcinomas, and mucinous carcinoid tumors, also may remain occult until they present with symptomatic ovarian masses or disseminated mucin consistent with pseudomyxoma peritonei. The rupture site of a primary low-grade appendiceal neoplasm may be small and contained with fibrotic mucus.4 When this occurs, the resulting ovarian metastases are frequently bilateral and occur as a result of implantation of tumor cells and mucin on the surface of the ovaries, which can then invade into the stroma. If there is unilateral involvement of the ovary, it is more frequently on the right side, adjacent to the appendix.5
Most patients with colorectal cancer, similar to those with breast cancer, will have their primary malignancy detected before the diagnosis of metastatic disease to the ovaries. In colorectal cancers, only 3% of patients initially present with an ovarian mass. In general, the majority of primary colon cancers occur distally in the sigmoid or rectum. In patients who develop ovarian metastases, most have a primary lesion in the colon that has full-thickness invasion of the bowel wall, direct invasion into adjacent structures, multiple positive lymph nodes, and/or involvement of other non-ovarian sites such as the omentum or liver.6 Although ovarian involvement can occur by direct extension, other processes such as angio-genesis and stromal cell–cancer cell interaction have been proposed for the predilection of colorectal cancer to metastasize to the ovaries. In patients with pancreatic cancer, 4% to 6% will have ovarian metastases during the course of their disease.4 In a small series of patients with metastatic pancreatic cancer, all patients had other sites of intraperitoneal disease, such as the omentum and bowel mesentery, when the ovarian involvement was detected.7
Carcinomas of the extrahepatic bile ducts and gallbladder are far more common in Asian countries. Ovarian metastases may present in a heterogenous manner, with nearly equal number of patients presenting at the time of primary tumor diagnosis and before or after detection of the primary tumor site. The vast majority of metastases are bilateral and mucinous, but the tumor may be infiltrative or primarily present on the surface of the ovaries and can be cystic, solid, or mixed in morphology.8
After the gastrointestinal tract, breast cancer is the most common site of origin of metastatic disease, especially to the ovaries. Because there are genetic mutations in BRCA1, BRCA2, and the DNA mismatch repair genes that predispose women to develop ovarian cancer, distinguishing a primary ovarian malignancy from a metastatic breast or colon cancer in women who harbor these genetic mutations may create a diagnostic dilemma. Nearly 10% of women who develop breast cancer before the age of 50 years will harbor a mutation in BRCA1 or BRCA2 that will place them at risk for ovarian cancer.9 Distinguishing advanced primary ovarian cancer from metastatic breast cancer is critical in providing recommendations for the appropriateness of cytoreductive surgery, chemotherapy, or hormonal therapy.
In a review of 79 women with a history of breast cancer who presented with carcinomatosis and underwent surgery, the majority of patients (75%) were diagnosed with primary ovarian, tubal, or peritoneal cancers.10 Although not statistically significant, the authors suggested a trend favoring a new primary ovarian cancer in women with longer intervals since their breast cancer diagnosis and higher CA-125 values. In autopsy studies, 10% of patients with breast cancer have ovarian metastases.11 The most significant risk factor for ovarian involvement is advanced-stage breast cancer. In a series of 31 patients with stage IV breast cancer who underwent laparoscopy for either an adnexal mass or therapeutic bilateral salpingo-oophorectomy, 21 patients (68%) were diagnosed with metastatic breast cancer.12 Conversely, women diagnosed with early-stage breast cancer are more likely to have benign adnexal disease than metastatic disease in their ovaries. In a series of 129 women with breast cancer who underwent surgery for an adnexal mass, 88% were found to have benign ovarian cysts; of the remaining patients with malignant lesions, the majority were primary ovarian cancers rather than metastatic breast cancer.10
Metastatic melanoma and renal cell carcinoma frequently pose diagnostic problems. When metastatic to the ovaries or uterus, the majority of patients with melanoma have disseminated disease in other areas. The ovaries represent the majority (75%) of metastases. Usually, there is a history of removal of a cutaneous lesion or an ocular lesion. The time span to the development of metastatic disease that involves the ovaries and becomes clinically significant may be many years.
Metastases to the uterus, cervix, vagina, and vulva are exceedingly rare, with individual reports scattered throughout the literature. Primary sites that can metastasize to the uterine corpus or cervix include breast, stomach, colon, rectum, melanoma, lung, and kidney.13 In patients with a history of breast cancer, distinguishing between a primary uterine malignancy and metastatic breast cancer can be challenging if the patient has received hormonal therapy for her breast cancer. Tamoxifen is associated with known uterine pathology, including hyperplasias, highly irregular polyps, and primary endometrial cancers, all of which may also present with vaginal bleeding. In general, women with metastatic breast cancer to the uterus have a poor prognosis, as the uterus is rarely the only site of disseminated disease.14 Isolated metastases to the vagina have been described in breast, renal, pancreatic, biliary tract, and colon cancer. Reports of metastases to the vulva are even more unusual.
DIAGNOSIS
Key Points
1. Metastatic lesions to the reproductive organs typically present with similar symptoms of primary gynecologic cancers and include abnormal bleeding, pelvic pain, and bloating.
2. Ultrasound imaging may identify solid and bilateral ovarian masses that are suggestive of metastatic disease.
3. In women with pelvic masses or vaginal lesions, elevated serum markers, such as carcinoembryonic antigen (CEA) or CA–19-9, may suggest a nongynecologic primary malignancy.
Whenever a patient has a history of cancer and presents with a mass or lesion in the gynecologic tract, metastatic disease must be considered in the differential. Patients with metastatic disease to the ovaries are frequently younger than patients with primary ovarian cancer. On average, patients with Krukenberg tumors are in the 40- to 50-year age range.15 Symptoms associated with ovarian involvement can include abdominal bloating, abdominal or pelvic pain, and weight loss. Gastric cancers, because of luteinization of the ovarian stroma, may produce virilization or, on occasion, irregular vaginal bleeding.16 Occasionally, the patient may be asymptomatic and have a mass discovered on routine physical examination.17 This can occur with metastatic breast cancer. In 30% of cases of metastatic disease to the ovaries, the mass may be the initial presenting feature before the diagnosis of the actual primary tumor site.16 Any metastatic tumor that involves the uterus, cervix, vagina, or vulva may lead to symptoms of irregular or postmenopausal bleeding, discomfort due to the presence of a mass, or pain.
Symptoms or the finding of an unexplained mass in the reproductive tract should trigger a diagnostic work-up in the form of imaging and appropriate laboratory studies. Ultrasound or CT is usually the initial imaging study performed. Features of ovarian tumors on ultrasound that suggest a metastatic origin include bilateral involvement of the ovaries, a solid appearance, and a differential in the size of the ovaries. These features occur in 80% of patients of Krukenberg tumor. When there is a combined solid and cystic component, or cystic features only, distinction from a primary ovarian cancer becomes challenging (Figure 17-1). On CT scan or MRI, many of the same features found on ultrasound will be present, including a primarily solid component or solid and cystic components with septations (Figure 17-2). In the face of bilateral cystic ovarian masses and copious fluid on imaging studies, a low-grade appendiceal neoplasm resulting in pseudo-myxoma peritonei should be suspected.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
