Metastatic Tumors of the Ovary

Chapter Outline
General Features 694
Mode of Spread 694
Site of Origin 696
- Intestinal Carcinomas 696
- Krukenberg Tumor 699
- Carcinoid Tumors 701
- Breast Carcinoma 702
- Tumors of the Pancreas, Biliary Tract, and Liver 703
- Tumors of the Appendix 704
- Renal Tumors 705
- Tumors of the Urinary Tract 706
- Adrenal Gland Tumors 707
- Malignant Melanoma 707
- Pulmonary and Mediastinal Tumors 707
- Uterine Tumors 707
- Lymphoma and Leukemia 709
- Peritoneal Tumors 710
- Extragenital Sarcomas 711
Summary 712

General Features

The ovaries are involved by metastatic tumors more often than any other organ in the female genital tract, regardless of the location of the primary neoplasm. Tumors that extend to the ovary directly from adjacent organs or tissues are also included in the category of secondary tumors; however, most ovarian carcinomas associated with uterine cancers of similar histologic type are independent primary neoplasms (see Chapter 27 ).

Metastatic tumors to the ovary are common and occur in approximately 30% of women dying of cancer. About 6–7% of all adnexal masses found during physical examination are actually metastatic ovarian tumors, frequently unsuspected by gynecologists. The metastasis often masquerades as a primary ovarian tumor and may even be the initial manifestation of the patient's cancer. Pathologists also tend to mistake metastatic tumors for primary ovarian neoplasms, even after microscopic examination, because the existence of a concurrent or prior tumor in another organ is either not known or disregarded. Also, all metastatic tumors may have a functioning ovarian stroma with clinical or pathologic evidence of hyperestrogenism simulating a primary ovarian tumor.

The frequencies of various sites of origin of secondary ovarian tumors differ among different countries according to the incidence of various cancers therein. Carcinomas of the colon, stomach, breast, and endometrium, as well as lymphomas and leukemias, account for the vast majority of cases. Rectal or sigmoid colon cancer accounts for 75% of the metastatic intestinal tumors to the ovary, and probably constitutes the most common cause of misdiagnosis. The Krukenberg tumor is almost always secondary to a gastric adenocarcinoma, but may occasionally originate in the intestine, appendix, breast, or other sites. Rarely, breast cancer metastatic to the ovary presents clinically as an ovarian mass. In fact, in patients with a history of breast cancer, especially BRCA -positive cases, clinically detected ovarian tumors are usually independent primaries and not metastases. In recent years, attention has been drawn to mucinous tumors of the appendix, pancreas, and biliary tract that often spread to the ovary and closely simulate ovarian mucinous borderline tumors or carcinomas. Resemblance to borderline tumors or even benign cystadenofibromas is due to the so-called maturation phenomenon by which the epithelium of the metastatic carcinoma differentiates and appears flattened and benign. A wide variety of other tumors may metastasize to the ovary.

General features of ovarian metastasis include: bilaterality, multinodularity, involvement of the ovarian surface, extensive extraovarian spread, unusual patterns of dissemination, unusual histologic features, blood vessel and lymphatic invasion, and desmoplastic stromal reaction ( Table 30.1 ).

Table 30.1

Metastatic Tumors to the Ovary (Clues to the Diagnosis)

1.
Bilaterality (mucinous and endometrioid-like)
2.
Small, superficial, multinodular tumors
3.
Vascular invasion
4.
Desmoplastic reaction
5.
Unusual histology
6.
Extensive extraovarian spread
7.
Unusual clinical history

Mode of Spread

The routes of tumor spread to the ovary are variable. Lymphatic and hematogenous metastasis to the ovaries is the most common form of dissemination. The importance of hematogenous spread is supported by the higher frequency of ovarian metastases in the well-vascularized ovaries of young patients. Embolic spread often produces multiple nodules within the substance of the ovary and commonly is accompanied by prominent intravascular nests of tumor cells in the ovarian hilum, meso-ovarium, and mesosalpinx.

Direct extension is also a common form of spread from adjacent tumors of the fallopian tube, uterus, and colorectum, for mesotheliomas, and for occasional retroperitoneal sarcomas. Transtubal spread provides an explanation for some surface ovarian implants from carcinomas of the uterine corpus, but may also account for some cases of spread from the uterine cervix. Neoplasms may also reach the ovary by the transperitoneal route from abdominal organs, such as the appendix. The metastatic tumor is found on the surface of the ovary or in the superficial cortex. Ovulation orifices may possibly represent a portal of entry for tumor cells.

Clinical Features

Ovarian metastases can be discovered in patients during follow-up after treatment of a primary tumor, or unexpectedly diagnosed during a surgical procedure for treatment of an abdominal tumor, or fortuitously found at autopsy. The age distribution of patients with ovarian metastases depends to a great extent on that of the corresponding primary tumors, but patients with metastases to the ovaries tend to be younger than those with primary ovarian neoplasms. This partly reflects the propensity of tumors to seed to the richly vascularized ovaries of young women and partly that tumors commonly metastasizing to the ovaries, especially intestinal, gastric, and mammary carcinomas, occur in younger women.

The circumstances leading to the discovery of the ovarian metastases depend on the site of the primary tumor. Ovarian metastases are detected before the breast cancer in only 1.5% of cases. In patients with a rectal or sigmoid colon cancer, the ovarian metastases and the primary tumor are discovered simultaneously, or more often, the intestinal tumor has been resected months or, years previously (50–75% of cases). Less frequently, the colorectal adenocarcinoma is discovered several months to years after resection of the ovarian metastases (3–20% of cases). In contrast, in about two-thirds of patients with Krukenberg tumor the diagnosis of the ovarian metastases precedes the discovery of the primary carcinoma. When a patient presents with abdominopelvic symptoms leading to suspicion of an ovarian tumor, the symptoms are nonspecific and similar to those of ovarian cancer, i.e., pelvic masses, ascites, or vaginal bleeding. Some patients with ovarian metastases have menstrual abnormalities, postmenopausal bleeding, and virilization, or they deliver a masculinized female fetus. These endocrine manifestations result from hormonally active luteinized stromal cells found in approximately one-third of metastatic tumors. Stromal luteinization occurs most frequently in association with metastatic mucinous carcinomas, particularly of colorectal or gastric origin.

Approximately 80% of patients with a Krukenberg tumor have bilateral ovarian metastases, and 73% of patients with ovarian metastases from breast carcinomas have extraovarian metastases. Radiologically, patients with a Krukenberg tumor more often have a solid mass with an intratumoral cyst, whereas primary ovarian cancers are predominantly cystic.

Macroscopic Features

Ovarian metastases are bilateral in over 70% of cases ( Figure 30.1 ). In contrast, the ovarian carcinomas most commonly mimicked by metastases (i.e., mucinous, endometrioid, and clear cell carcinomas) are bilateral in less than 15% of cases. Metastatic tumors grow as superficial or parenchymatous solid nodules or, frequently, as cysts. The size of ovarian metastases varies even from one side to the other. The ovaries may be only slightly enlarged or measure 10 cm or more. Intraoperative assessment of size and laterality may serve as a helpful guideline in distinguishing primary from metastatic mucinous tumors: bilateral tumors of any size or unilateral tumors under 10 cm have a high probability of being metastatic, whereas unilateral tumors over 10 cm are usually primary. However, there are many exceptions, especially in cases of colorectal and endocervical primaries. It is also noteworthy that metastases involving the ovary are often larger than their corresponding primary tumors.

Figure 30.1, Metastatic carcinoma from the colon. The ovaries are replaced by solid multinodular tumors.

Microscopic Features

The microscopic appearance of the metastases varies depending on the nature of the primary tumor. The identification of surface implants is extremely helpful in the recognition of secondary ovarian tumors that spread through the abdominal cavity and tubal lumen. Other features more commonly observed in metastatic tumors include multinodular infiltrative growth, single cell infiltration, follicle-like spaces (due to inadequate lymphatic drainage), and intravascular tumor emboli. Presence of a desmoplastic stroma and prominent stromal luteinization around tumor glands are also suspicious for metastasis.

Site of Origin

Intestinal Carcinomas

Most intestinal metastases originate in the large intestine and, much less frequently, in the small bowel. Whereas at autopsy metastases from intestinal carcinomas are less common than those from gastric carcinomas (14% vs 38%, respectively), at the time of operation metastases from intestinal carcinomas are almost five times as frequent as those from gastric carcinomas. Up to 45% of colorectal metastases to the ovary are clinically thought to be primary ovarian tumors, and many are misinterpreted as such on microscopic examination. Metastasis from the large bowel to the ovary is seen relatively more frequently when this cancer develops in women under 40 years of age. In one large series, one-fourth of patients were less than 40 years old and in another about 43% were under 50 years. In the latter study, it was found that patients initially presenting with an ovarian mass were significantly younger than those having ovarian spread in the setting of a known colorectal primary (average 48 vs 61 years). Not infrequently, patients have luteinized stromal cells in the ovarian tumor with resultant hormone production and endocrine symptoms.

The ovarian tumors are bilateral in approximately two-thirds of cases ( Figure 30.1 ). Smaller tumors are usually solid, whereas larger tumors are composed of friable gray, yellow, or red tissue with cysts that contain necrotic tumor, mucinous fluid, or blood ( Figure 30.2 ).

Figure 30.2, Metastatic carcinoma from the colon. Solid and cystic tumor with extensive necrosis and focal hemorrhage.

Microscopically, the metastatic tumors may be confused with primary endometrioid or mucinous carcinoma depending on whether the colonic carcinoma is predominantly non-mucinous or mucinous. Features that help distinguish colon cancer from endometrioid carcinoma include luminal necrotic debris (‘dirty necrosis’), focal segmental necrosis of the glands ( Figures 30.3–30.5 ), occasional presence of goblet cells, and absence of müllerian features (squamous differentiation, an adenofibromatous component, or association with endometriosis). Also the nuclei lining the glands of metastatic colon carcinoma exhibit a higher degree of atypia than those of endometrioid carcinoma ( Figure 30.5 ). The stroma may be desmoplastic ( Figure 30.6 ), edematous, or myxoid, but frequently resembles ovarian stroma. Stromal luteinization is most frequently found in metastatic colorectal carcinomas.

Figure 30.3, Metastatic adenocarcinoma from the colon. Garland-like glandular pattern with focal segmental necrosis of glands and abundant necrotic debris.

Figure 30.4, Metastatic adenocarcinoma from the colon. Focal segmental necrosis of glands and luminal necrotic debris (‘dirty necrosis’).

Figure 30.5, Metastatic adenocarcinoma from the colon. The glandular epithelium shows papillary growth and striking nuclear atypia (grade 3).

Figure 30.6, Metastatic adenocarcinoma from the colon. Neoplastic glands lying in a desmoplastic stroma.

Metastatic tumors may also resemble closely primary mucinous ovarian tumors both grossly ( Figure 30.7 ) and microscopically. The metastases may be moderately differentiated ( Figure 30.8 ) or so well differentiated that they can be mistaken for mucinous borderline or less often benign ovarian tumors. Generous sampling (at least one block per 1–2 cm of tumor diameter) is recommended. Metastatic mucinous tumors to the ovary can originate in the large intestine, stomach, pancreas, gallbladder, biliary tract, appendix, and even, exceptionally, urachus and lung. Features supportive of the diagnosis of a metastasis already discussed include bilaterality, histologic surface involvement by epithelial cells (surface implants) ( Figure 30.9 ), irregular infiltrative growth with desmoplasia ( Figure 30.6 ), single cell invasion, signet-ring cells, vascular invasion ( Figure 30.10 ), coexistence of benign-appearing mucinous areas with foci showing a high mitotic rate and nuclear hyperchromasia, and histologic surface mucin. In some cases, the intestinal metastases contain cells with abundant clear cytoplasm and may simulate either primary clear cell carcinoma or the secretory variant of endometrioid carcinoma ( Figure 30.11 ).