Gynecologic Oncology: Clinical Practice and Surgical Atlas, 1st Ed.

Metastases to the Gynecologic Tract

S. Diane Yamada and Nita K. Lee

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

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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 BRCA1BRCA2, 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.

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FIGURE 17-1. Transvaginal ultrasound of Krukenberg tumor involving the left ovary, metastatic cholangiocarcinoma.

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FIGURE 17-2. CT scan, Krukenberg tumor involving ovaries, metastatic colorectal carcinoma.

CT scan may identify the primary site of disease if a suspicious mass is found elsewhere in the GI tract. In addition, a radiographic abnormality on upper GI series may suggest an underlying gastric cancer. However, tumors in the gastric mucosa may be quite small when they metastasize and remain undetected for many years. Endoscopic examination may miss a small tumor that has extensively infiltrated into the submucosa. Tumors arising from the pylorus may also be difficult to detect given their location.

Serum markers may help to distinguish the primary site of disease. CA-125 is elevated in 70% of advanced-stage ovarian cancers. Although CA-125 may be elevated in a patient with a Krukenberg tumor, it may not be elevated to the degree of epithelial ovarian cancers.18 CEA is a marker for colon, appendiceal, and gastric cancers, whereas CA–19-9 can be a marker for pancreatic cancer. A CA-125 to CEA ratio of greater than 25 has also been used to help distinguish ovarian from metastatic colorectal cancer with an overall test accuracy of 94%.19

Metastatic lesions to the ovary from the breast frequently present as solid masses or generalized ovarian enlargement in postmenopausal women. This occurs more frequently in women who have stage IV breast cancer. When the masses are cystic and solid, however, differentiating a primary ovarian cancer from a metastasis is more difficult. Positron emission tomography (PET)-CT, which is often used in breast cancer staging and restaging, can detect incidental lesions in the pelvis that require further investigation. The sensitivity and specificity of PET for metastatic lesions to the ovary is not well established. Although the standardized uptake value (SUV) is higher in breast cancer metastases to the ovaries compared with GI cancers, these results are based on very limited numbers of patients with overlapping SUV levels and should not be used to distinguish primary cancers from metastatic disease at this time.20

PATHOLOGY

Key Points


1. Mucinous adenocarcinomas of the ovary may represent metastases from a primary malignancy in the gastrointestinal tract or pancreas.

2. Krukenberg tumors are characteristically bilateral, solid, and exhibit a bosselated outer surface.

3. Immunohistochemical profiling, including CK7, CK20, CDX2, and S100, may distinguish a primary gynecologic malignancy from metastatic disease.


The majority of primary ovarian cancers are of papillary serous histology. In any instance where the ovarian cancer is a mucinous or endometrioid histology, it may be challenging to distinguish a primary malignancy of the ovary from a metastatic tumor. Metastatic colorectal cancers can mimic primary endometrioid ovarian carcinomas, whereas metastatic appendiceal and pancreatic cancers can be confused with primary mucinous or mucinous borderline tumors of the ovary. Frequently, however, primary mucinous or endometrioid cancers of the ovary are unilateral, not bilateral. When the tumor is bilateral, or small (< 10 cm) and unilateral, metastatic disease should be suspected. The classic Krukenberg tumor has pathologic criteria defined by the World Health Organization to include the presence of mucin-producing signet ring cells, stromal involvement, and ovarian stromal sarcomatoid proliferation.21The intracytoplasmic mucin of the signet ring cells typically stains with mucicarmine or a periodic acid-Schiff stain. Although Krukenberg tumors have typically been classified as metastatic gastric cancers, more recently the term has been applied to all metastatic GI cancers and can include colon or pancreatic cancers as well as metastatic tumors of any nongenital tract origin. When they result from metastatic gastric cancer, they are grossly solid with a smooth nodular or bosselated outer surface (Figure 17-3A). When cut, the surface is white or tan with areas of red or brown discoloration and a firm or gelatinous appearance (Figure 17-3B). Histologically, the tumors have an infiltrative, irregular growth pattern with single-cell invasion, signet ring cells, and surface mucin (Figure 17-4A4B).22 Metastatic mucinous cancers tend to have a multinodular growth pattern that involves the ovarian surface. The presence of necrotic debris or “dirty necrosis,” a higher degree of nuclear atypia in the well-formed glands, and desmoplasia are features of metastatic colon cancer and can be used to distinguish a metastatic lesion from a primary mucinous or endometrioid cancer (Figure 17-5A-C).11 The size of the ovarian metastasis does not seem to be a distinguishing factor in metastatic colorectal cancer, as the lesions can get quite large (> 10 cm) and be unilateral.6

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FIGURE 17-3. A. Krukenberg tumor, gastric cancer, gross section. B. Krukenberg tumor, gastric cancer, cut surface.

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FIGURE 17-4. A. Krukenberg tumor, metastatic gastric cancer, AE1/AE3 stain, ×40. B. Krukenberg tumor, metastatic gastric cancer, AE1/AE3 stain ×400.

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FIGURE 17-5. A. Krukenberg tumor, colon cancer, gross section. B. Metastatic colon cancer in the stroma of the fallopian tube demonstrating desmoplasia. C. Metastatic colon cancer involving the ovary, low power. D. Metastatic colon cancer involving the ovary, high power.

Pancreatic ductal adenocarcinomas and cholangio-carcinomas (Figures 17-6A and 17-6B) are another source of mucinous tumors. Four to 6% of patients with pancreatic cancer will have metastases to the ovaries. They more commonly arise from the tail of the pancreas and may be confused with primary ovarian cancers, especially when there is diffuse peritoneal and omental involvement. The ovaries may become quite large (average size, 12.5 cm) and contain large mucinous cysts with smaller glands in the intervening stroma.23

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FIGURE 17-6. A. Metastatic cholangiocarcinoma to the ovary, low power. B. Metastatic cholangiocarcinoma to the ovary, high power.

The classification of appendiceal mucinous tumors has gone through some evolution. Tumors that are confined to the appendix have been called adenomas or low-grade appendiceal mucinous neoplasms. If there is a breach in the muscularis mucosa, the tumor has been called a mucinous tumor of uncertain malignant potential. Tumors with high-grade cytology or with destructive invasion of the appendiceal wall are called appendiceal adenocarcinomas or invasive adenocarcinomas.24 Primary appendiceal carcinomas are quite rare, representing fewer than 1% of all GI tract cancers. The primary tumor in the appendix may be small, or the appendix may rupture, leading to obliteration of the tumor altogether. In pseudomyxoma peritonei, there is diffuse gelatinous material present in the peritoneal cavity. Mucinous low-grade appendiceal neoplasms may produce secondary neoplasms in the ovary. Most commonly, there is bilateral involvement of the ovaries; if unilateral involvement is found, it is usually right sided. On cut section of the ovary, there is mucinous material in the stroma of the ovary (pseudo-myxoma ovarii) and multiple cysts lined by low-grade, bland-appearing mucinous cells with minimal nuclear atypia. In a small number of cases, primary appendiceal carcinomas in the form of signet ring histology can metastasize to the ovaries as a Krukenberg tumor.

Application of an immunohistochemical profile using cytokeratin stains and other markers can distinguish the primary site of disease (Table 17-2). Primary ovarian carcinomas are typically cytokeratin (CK) 7 positive and CK 20 negative. In contrast, colon cancer is typically CK 7 negative and CK 20 positive. Other GI primaries such as appendiceal, gastric, and small intestinal cancers, like ovarian cancer, can be CK 7 positive. CA-125 is expressed in the majority of papillary serous ovarian cancers but is also positive in half of mucinous ovarian cancers, making it a less useful immunostain for mucinous tumors. Although CEA is positive in most mucinous tumors, this can occur regardless of whether the origin is ovarian or GI, also making it a less useful distinguishing marker. CDX2 is a nuclear transcription marker that is frequently positive in lower GI tract cancers, which can be helpful in differentiating a metastatic GI primary from a primary mucinous ovarian cancer.25 Other studies of mucinous markers such as MUC2 and MUC5AC have shown variable results. S100 is a marker for melanoma that is characteristically diffusely positive in metastatic lesions. Although immunostain profiles can be helpful, they are not mutually exclusive, and the patient’s entire clinical picture must be taken into account when interpreting the results of stains.

Table 17-2 Immunostain Profile of Primary Versus Metastatic Carcinomas Involving the Ovaries

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In autopsy studies, metastatic breast cancer has been found in the ovaries in 10% of patients. Lobular carcinomas have a greater propensity to spread to the ovaries than infiltrating ductal carcinomas; however, given the higher overall frequency of ductal carcinomas, most metastases to the ovaries will be ductal in nature. The ovaries may be quite small when involved with metastatic disease. If the histology of the ovarian cancer is papillary serous, it is more likely to be a separate primary ovarian cancer. Lobular carcinomas can present with solid nests of tumor that may appear similar to adult type ovarian granulosa cell tumors. Ductal carcinomas can be challenging to differentiate from adenocarcinomas of the ovary or peritoneum and often require further work-up, including specific immunohistochemical stains. Breast carcinomas tend to have a similar cytokeratin profile to ovarian cancers and are often CK 7 positive and CK 20 negative. CA-125, WT1, and gross cystic disease fluid protein 15 (GCDFP-15) may be helpful in distinguishing primary ovarian cancer from metastatic breast cancer. In primary ovarian cancers, CA-125 is positive in 92% of cases, and WT1 is positive in 76% of cases, whereas GCDFP-15 tends to be negative in comparison with the breast cancer lesions.26 More recently, PAX8, a transcription factor necessary for organogenesis in the thyroid, kidney, and Mullerian system, has been studied with WT1 to distinguish ovarian cancers from breast cancers. PAX8 staining performed better than WT1 and was diffusely positive in 87% of known ovarian cancers, whereas none of the breast cancers stained positive for Pax8.27 Although it is a rare occurrence, when breast cancer metastasizes to the uterus, it often involves the myometrium and stroma while sparing the endometrial glands.

Renal cell carcinoma metastatic to the ovaries is quite rare, but when it occurs, it is invariably of the clear cell type. Therefore, making a distinction between a primary ovarian clear cell cancer from a metastatic renal cell carcinoma becomes a dilemma. In primary clear cell cancers of the ovary, there is a heterogeneity in the appearance of the cells, as there is an admixture of flattened cells, hobnail cells, and cuboidal cells. Primary clear cell cancers of the ovary may also be associated with endometriosis. In metastatic tumors, there is more homogeneity to the clear cells, and there may be a sinusoidal vascular pattern. Positive CK 7 immunostaining may help to distinguish a primary ovarian cancer from a metastatic renal cell cancer, which tends to be CK 7 negative.28

Cutaneous malignant melanoma can metastasize to nearly any organ in the body. Approximately 20% of such patients develop recurrent disease. However, metastases to the genital tract are exceedingly rare and represent only 2.5% of cases. Although the most frequent sites of recurrence are the primary site of disease followed by the regional lymph nodes, visceral spread can occur. In the genital tract, the ovaries are the most common metastatic site, but metastases to the endometrium and myometrium of the uterus have also been described.

Only 30% of ovarian metastases are pigmented. Immunostains such as S-100, HMB-45, and MART1 are positive in most melanomas and may be helpful in identifying the primary sites of disease.11

TREATMENT AND PROGNOSIS

Key Points


1. Surgical resection of metastatic lesions should be considered in symptomatic patients with good performance status and isolated masses.

2. Limited evidence suggests a potential survival benefit with resection of metastatic disease in colorectal, pancreatic, and breast cancers.


The treatment of patients with metastases to the genital tract depends on the performance status of the patient, whether the patient has a known primary site of disease, and whether the metastatic lesions are isolated or diffusely disseminated. Overall, the survival of patients with metastases to the ovaries is poor. Nearly 80% of patients succumb to their disease within 2 years. Despite this, metastatic tumor to the ovaries can create significant symptoms to warrant removal for palliation. In one recent retrospective series of patients, there was a significant difference in survival if patients had isolated metastases to the ovaries or disseminated disease. In patients with isolated ovarian metastases, median survival was 30.7 months as compared with those with extensive, disseminated disease, for whom the median survival was 10 months (P = .02). Patients with colon cancer had longer survivals compared with patients with gastric cancer (29.6 months vs. 13 months, respectively), and patients who underwent surgery and were left with microscopic disease also experienced longer survival as compared with those left with visible residual disease.29 In another study of metastatic pancreatic cancer to the ovaries, the mean patient age was only 49 years. Those who underwent resection of their ovarian metastases had a median survival of 16.5 months, as compared with 8.5 months in those who received chemotherapy alone. In patients who received only chemotherapy, the ovarian metastases did not respond to treatment.23 Patients with known ovarian metastases from colon cancer also showed a lack of response to chemotherapy, which may suggest that the ovaries are a sanctuary for metastatic disease.30 In a Korean study of patients with a history of gastric cancer who developed Krukenberg tumors, the median age was also only 41 years. Patients who underwent either bilateral salpingo-oophorectomy or hysterectomy with bilateral salpingo-oophorectomy had median survivals of 10.9 months if there was no gross residual disease or 7.5 months if left with gross residual disease. There were 2 patients in this series of 34 patients who survived longer than 4 years after complete resection of their Krukenberg tumors. Additionally, there was a significant difference if the patient had disease confined to the ovaries (median survival, 13.1 months) as compared with disease in the pelvis (median survival, 7.5 months) or intra-abdominal disease (median survival, 3.6 months).31 Therefore, a reasonable approach in a patient with good performance status and isolated metastatic disease would be to consider surgery to remove the ovaries.

Many of the same treatment strategies observed in metastatic GI cancer hold true for metastatic breast cancer. Several retrospective studies have identified a trend toward longer progression-free survival in women who can be optimally debulked even in the setting of metastatic breast cancer. This typically occurs in the setting of isolated metastatic disease and in patients without evidence of other metastatic disease. Garg et al32 showed that in 19 patients who were found to have abdominal carcinomatosis due to breast cancer, those undergoing successful cytoreductive surgery (5 patients) had a longer median survival time than those with larger volume residual disease (14 patients; 34.4 vs. 3.9 months; P = .0001).32 In another small study of 29 patients, 62% underwent nonoptimal surgery or biopsies and the remainder underwent complete resection of metastatic disease; median survival was 2 years in the former group and had not been reached at 2 years of follow-up in the latter group.33 The subsequent development of metastatic disease in other sites such as the pelvis and liver occurred in the majority of patients after surgery. This should be considered in counseling patients about the risks and benefits of undergoing surgery and effect on palliation of symptoms. As chemotherapy regimens improve for nongynecologic cancers, however, the survival of these patients may be expected to improve.

Management of metastases to other areas of the genital tract will clearly depend on the patient’s overall prognosis and symptoms. If a patient develops significant problems with vaginal bleeding from uterine or cervical metastases, it would be reasonable to perform a hysterectomy. A complete hysterectomy also allows for definitive diagnosis of the disease. Metastases to the vagina and vulva must be managed individually and with attention paid to minimizing complications in the face of a disease with poor prognosis. Primary resection and radiation have been described in the management of disease involving the vagina, but the numbers of patients treated are too small to provide any meaningful conclusions about the effectiveness of treatment.

FUTURE DIRECTIONS

In conclusion, patients who develop metastatic disease to the genital tract frequently have primary malignancies arising from the GI tract or breast, and the primary disease is usually advanced stage. Ovarian metastases are frequently bilateral; mucinous histologies, in particular, may be difficult to distinguish from primary mucinous ovarian cancers. Surgery to cyto-reduce the metastatic lesions appear to be associated with longer survival if the metastatic disease is isolated and able to be completely cytoreduced. As molecular markers improve, it may become easier to distinguish primary gynecologic malignancies from nongynecologic malignancies. Although it would be preferable to have serum markers that could adequately determine the primary site of disease, often the decision to operate or treat with chemotherapy or hormonal therapy tailored to the primary site of disease becomes a function of patient performance status, symptoms, and the presence of other sites of disease.

REFERENCES

1. Khunamornpong S, Suprasert P, Chiangmai WNA, et al. Metastatic tumors to the ovaries: a study of 170 cases in northern Thailand. Int J Gynecol Cancer. 2006;16:132-138.

2. Mazur MT, Hsueh S, Gersell DJ. Metastases to the female genital tract. Analysis of 325 cases. Cancer. 1984;53:1978-1984.

3. Al-Agha OM, Nicastri AD. An in-depth look at Krukenberg tumor. Arch Pathol Lab Med. 2006;130:1725-1730.

4. Hart WR. Diagnostic challenge of secondary (metastatic) ovarian tumors simulating primary endometrioid and mucinous neoplasms. Pathol Int. 2005;55:231-243.

5. Young R, Gilks B, Scully R. Mucinous tumors of the appendix associated with mucinous tumors of the ovary and pseudomyxoma peritonei: a clinicopathologic analysis of 22 cases supporting an origin in the appendix. Am J Surg Pathol. 1991;15:415-429.

6. Lewis MR, Euscher ED, Deavers MT, Silva EG, Malpica A. Metastatic colorectal adenocarcinoma involving the ovary with elevated serum CA125: a potential diagnostic pitfall. Gynecol Oncol. 2007;105:395-398.

7. Young RH, Hart WR. Metastases from carcinomas of the pancreas simulating primary mucinous tumors of the ovary: a report of seven cases. Am J Surg Pathol. 1989;13:748-756.

8. Khunamornpong S, Lerwill MF, Siriaunkgul S, et al. Carcinoma of the extrahepatic bile ducts and gallbladder metastatic to the ovary: a report of 16 cases. Int J Gynecol Pathol. 2008;3:366-379.

9. Kwon JS, Gutierrez-Barrera AM, Young D, et al. Expanding the criteria for BRCA mutation testing in breast cancer survivors. J Clin Oncol. 2010;28(27):4214-4220.

10. Simpkins F, Zahurak M, Armstrong D, et al. Ovarian malignancy in breast cancer patients with an adnexal mass. Obstet Gynecol. 2005;105:507-513.

11. Young RH. From Krukenberg to today: the ever present problems posed by metastatic tumors in the ovary. Part II. Adv Anat Pathol. 2007;14:149-177.

12. Quan ML, Fey J, Eitan R, et al. Role of laparoscopy in the evaluation of the adnexa in patients with stage IV breast cancer. Gynecol Oncol. 2004;92(1):327-330.

13. Kumar NB, Hart WR. Metastases to the uterine corpus from extragenital cancers: a clinicopathologic study of 6 cases. Cancer. 1982;50:2163-2169.

14. Hara F, Kiyoto S, Takabatake D et al. Endometrial metastasis from breast cancer during adjuvant endocrine therapy. Case Rep Oncol. 2010;3:137-141.

15. Yook JH, Oh ST, Kim BS. Clinical prognostic factors for ovarian metastasis in women with gastric cancer. Hepatogastroenterology. 2007;54:955-959.

16. Kiyokawa T, Young RH, Scully RE. Krukenberg tumors of the ovary. A clinicopathologic analysis of 120 cases with emphasis on their variable pathologic manifestations. Am J Surg Pathol. 2006;30:277-299.

17. Moore RG, Chung M, Granai CO et al. Incidence of metastases to the ovaries from nongenital tract primary tumors. Gynecol Oncol. 2004;93:87-91.

18. Lewis MR, Deavers MT, Silva EG, Malpica A. Ovarian involvement by metastatic colorectal adenocarcinoma: still a diagnostic challenge. Am J Surg Path. 2006;30:177-184.

19. Yedema CA, Kenemans P, Wobbes T, et al. Use of serum tumor markers in the differential diagnosis between ovarian and colorectal adenocarcinomas. Tumour Biol. 1992;13:18-26.

20. Kitajima K, Suzuki K, Senda M, et al. FDG PET/CT features of ovarian metastasis. Clin Radiol. 2011;66:264-268.

21. Serov SF, Scully RE. Histologic typing of ovarian tumours, vol. 9. Geneva, Switzerland: World Health Organization; 1973: 17-18.

22. Lee KR, Young RH. The distinction between primary and metastatic mucinous carcinomas of the ovary: gross and histologic findings in 50 cases. Am J Surg Pathol. 2003;27:281-292.

23. Falchook GS, Wolff RA, Varadhachary GR. Clinicopathologic features and treatment strategies for patients with pancreatic adenocarcinoma and ovarian metastases. Gynecol Oncol. 2008; 108:515-519.

24. Misdraji J. Appendiceal mucinous neoplasms. Controversial issues. Arch Pathol Lab Med. 2010;134:864-870.

25. Vang R, Gown AM, Wu LSF. Immunohistochemical expression of CDX2 in primary ovarian mucinous tumors and metastatic mucinous carcinomas involving the ovary: comparison with CK20 and correlation with coordinate expression of CK7. Modern Pathol. 2006;19:1421-1428.

26. Tornos C, Soslow R, Chen S, et al. Expression of WT1, CA125 and GCDFP-15 as useful markers in the differential diagnosis of primary ovarian carcinomas versus metastatic breast cancer to the ovary. Am J Surg Pathol.2005;29:1482-1289.

27. Nonaka D, Chiriboga L, Soslow RA. Expression of Pax8 as a useful marker in distinguishing ovarian carcinomas from mammary carcinomas. Am J Surg Pathol. 2008;32;10:1566-1571.

28. McCluggage WG, Wlkinson N. Metastatic neoplasms involving the ovary: a review with emphasis on morphological and immunohistochemical features. Histopathology. 2005;47:231-247.

29. Joang R, Tng J, Cheng X, Zang RY. Surgical treatment for patients with different origins of Krukenberg tumors: outcomes and prognostic factors. Eur J Surg Oncol. 2009;35:92-97.

30. Goere D, Daveau C, Elias D, et al. The differential response to chemotherapy of ovarian metastases from colorectal carcinoma. Eur J Surg Oncol. 2008;34:1335-1339.

31. Kim HK, Heo DS, Bang YJ, Kim NK. Prognostic factors of Krukenberg’s tumor. Gynecol Oncol. 2001;82:105-109.

32. Garg R, Zahurak ML, Trimble ET, et al. Abdominal carcinoma-tosis in women with a history of breast cancer. Gynecol Oncol. 2005;99:65-70.

33. Bigorie V, Morice P, Duvillard P, et al. Ovarian metastases from breast cancer. Cancer. 2010;799-804.

34. Prat J. Ovarian carcinomas, including secondary tumors: diagnostically challenging areas. Mod Pathol. 2005;18:S99-S111.



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