Section 4 -

Metastatic Tumors To The Female Genital Tract, With Emphasis To Metastatic Tumors To The Ovary Esther Oliva Massachusetts General Hospital Boston , MA

Metastases to the female genital tract occur not infrequently, the ovary being the most common site. Vulva and vagina: Secondary involvement occurs from primary tumors in other pelvic sites including in order of frequency cervix, endometrium, colon and rectum, ovary, and urinary bladder or urethra. Patients with gestational trophoblastic disease may present with vaginal metastases and patients with uterine choriocarcinoma have vaginal metastases in up to 50 of cases. Uterus: It may be involved either by direct extension (tubal, ovarian, peritoneal or cervical carcinoma) or by metastatic carcinoma. In the latter circumstance the primary malignancy is usually widely disseminated. Extragenital carcinomas that more frequently involve the uterus include breast, stomach and colon, although any other malignancy can rarely metastasize to the uterus, the cervix being more commonly involved than the uterine corpus. Ovary: Metastases to the ovary account for 6 to 7-17% of all ovarian cancers among different series. Because of the relatively high frequency with which metastases are bilateral (2/3 to 3/4 of the cases), the possibility of metastasis should always be considered when one is evaluating bilateral ovarian tumors. The most common tumors that metastasize to the ovary arise in the colorectum, breast, endometrium, stomach, cervix, pancreas, appendix, and biliary tract. In general, about 15 to 20% of bilateral ovarian tumors will prove to be metastatic. Several studies have evaluated various gross and microscopic features of metastatic and primary ovarian tumors in an attempt to establish diagnostic criteria that would reliably distinguish between them. Features that favor metastasis to the ovary: Bilateral ovarian involvement Multinodular growth on gross or microscopic examination Surface involvement frequently associated with a desmoplastic reaction Hilar vascular invasion as primary ovarian tumors, even when high grade, uncommonly exhibit extensive lymphatic or vascular invasion Infiltration of preexistent structures as well as single cells Different histologic patterns of the tumor in different nodules Features that favor a primary ovarian tumor: Expansile pattern of invasion Complex papillary pattern Size > 10 cm Smooth external surface Borderline or benign appearing areas at least in most cases Microscopic cystic glands The finding of a cystic ovarian tumor, a feature that at first glance may be considered characteristic of a primary ovarian tumor is not an infrequent presentation in metastasis and in fact some metastatic tumors are predominantly cystic. This feature may be seen in metastatic colonic cancer, pancreatic carcinoma, endocervical carcinoma, and metastatic carcinoid tumors among others. Metastatic adenocarcinoma from the large intestine: The ovaries are prone to involvement by metastatic colorectal carcinoma. Approximately 3.5% of women with colon carcinoma are found to have ovarian involvement at some point in the course of their disease, however, interestingly up to 45% of metastases from the large intestine are clinically interpreted as primary ovarian carcinomas and on microscopic examination, these tumors may so closely mimic a primary ovarian adenocarcinoma that the correct diagnosis can be overlooked. On gross examination, even though they are frequently bilateral, in the most recent series reported by Lewis and colleagues, unilateral involvement was seen in 33 out of 86 cases and in 20 of these 33 cases the ovarian tumor measured >10 cm in largest dimension. These tumors have typically a necrotic appearance in the ovary. On microscopic examination they may mimic either primary endometrioid (EC) or mucinous carcinomas (MC) of the ovary, and less frequently some metastatic intestinal adenocarcinomas to the ovary may be entirely composed of clear cells and may suggest a primary clear cell carcinoma of the ovary.Typical microscopic features in metastatic colon cancer to the ovary include dirty necrosis, focal segmental necrosis of epithelium lining glands and cysts, garland pattern and glands that show severe nuclear atypia and stratification but still good preservation of the glandular architecture, although it is important to remember that some of these features may be also seen in EC. The clinical history is very important, however, a significant minority of women with colorectal carcinoma present with an adnexal mass and at that time are not known to have a primary tumor in the intestine. In the frozen section the pathologist may suggest the diagnosis of metastasis so the surgeon may look for the source of the tumor based on the pathologic findings. Thus careful gross examination is crucial in these cases. In difficult cases the combined use of CK7 and CK20 allows the discrimination of most metastatic colorectal carcinomas from ECs of the ovary. Endometrioid adenocarcinomas are almost always positive for CK7 and negative for CK20 whereas the opposite pertains to colorectal carcinomas, with the exception of right-sided and high-grade colon cancers which more often express CK7. Ovarian MCs show an inconsistent immunophenotype but are almost always positive for CK7 and show variable positivity for CK20, which is often patchy in distribution, in 40 % to 73 % of tumors. Exceptions include mucinous tumors arising in mature cystic teratomas typically negative for CK7 and positive for CK20, suggesting that they arise from gastrointestinal elements of the teratoma. As CK7 and CK20 are not always discriminatory, particularly in mucinous tumors, CEA may be added to the immunohistochemical panel as colonic carcinomas are typically CEA+ and approximately 35% of ovarian MCs are CEA negative. Other potential antibodies that may help in this differential diagnosis include: Cdx-2 which shows consistent strong and diffuse nuclear positivity in colorectal carcinomas. However, staining is also seen in ovarian carcinomas, most often in MCs (in up to 93% of cases), and rarely in ECs. Cdx-2 is an extremely sensitive marker of colorectal cancer, but due to its relative lack of specificity, it is best used in conjunction with other stains. β-catenin has a relatively limited utility in the diagnosis of metastatic colorectal carcinoma is as it is not a very sensitive marker for colon cancer even though Ov-ECs and MCs rarely express it. P504S is overexpressed particularly colorectal cancer and prostate cancer and in their precursor lesions. However, experience in ovarian cancer is very limited and requires additional evaluation. Breast carcinoma is one of the most common tumors that metastasizes to the ovary. The frequency of ovarian metastases in women with breast cancer ranges from 10 to 20% at autopsy to about 30% in therapeutic oophorectomy specimens. Although the ovarian involvement is frequently accompanied by other intraabdominal disease, tumor is confined to the ovary in 15% of the cases. Lobular carcinoma spreads more commonly to the ovary than ductal carcinoma, however, about 75% of ovarian metastases from breast cancer are from ductal cancer, as this is the most common type of breast cancer. Although these tumors frequently show typical growth patterns that include tubules, cords or single cells some being of the signet ring cell type, differentiating a primary ovarian carcinoma from a metastatic breast carcinoma may be difficult particularly in women with an inherited breast/ovarian cancer syndrome. Patients with hereditary ovarian cancer belong mostly to the BRCA I group (70%) or BRCA 2 (20%). Those patients are at a higher risk of developing breast cancer at an earlier age but also ovarian, fallopian tube and peritoneal carcinoma. It is important to differentiate between the two categories of tumors as the 5-year survival rate for patients with primary ovarian carcinoma between 5 and 90% depending on tumor stage and residual amount of tumor after primary surgery while patients with metastatic breast cancer to the ovary have a 5-year survival rate of < 10%. It is important to keep in mind that an ovarian tumor in a woman with breast cancer is more likely to be a new ovarian surface epithelial carcinoma (either poorly differentiated serous or endometrioid carcinoma) and not a metastasis from her breast cancer. The use of differential cytokeratins is not helpful as both breast and ovarian cancers are positive for CK7, but the presence of cytokeratin 20 positivity in a metastatic carcinoma is strongly suggestive of a carcinoma of non-breast origin. Gross cystic fluid disease protein 15 (GCDFP-15) is a marker of apocrine differentiation that is expressed in the majority of breast carcinomas as well as in tumors of the salivary glands, sweat glands, and prostate. Since salivary and skin adnexal tumors involving the ovary are very rare, a GCDFP-15 positive tumor in the ovary is almost certainly of breast origin. However, a negative GCDFP-15 tumor does not exclude a breast origin, as approximately 30-40% of breast carcinomas are negative for this marker. WT1 expression has been shown to be highest in serous carcinomas (93%) and transitional cell carcinomas (82%) among ovarian cancers while it is only rarely positive in breast carcinomas. Thus, it may be helpful in distinguishing serous carcinoma from breast carcinoma, especially when the tumor is poorly differentiated. In a very recent series reported by Tornos and colleagues, none of the 39 metastatic breast carcinomas to the ovary expressed WT1 while 31 out of 33 serous carcinomas were WT1 positive. Finally CA-125 may be added to this panel, as most ovarian carcinomas are CA-125 positive while only 5 out 39 metastatic breast carcinomas to the ovary were only weakly and focally positive in the same study. Gastric carcinoma including Krukenberg tumor. The latter implies a tumor with a prominent component of signet ring cells containing abundant mucin typically lying in a background of cellular stroma. Most Krukenberg tumors arise in the stomach and more frequently in the pylorus. In the largest series reported to date by Kiyokawa and colleagues, 2/3 of the primary tumors (total=120) originated in the stomach, with other primary sites by order of frequency being appendix, colon, breast, small intestine, rectum, gallbladder and urinary bladder. Signet ring cell carcinomas metastasize to the ovary more than twice as often as intestinal-type carcinomas. This is the most common form of ovarian metastatic carcinoma in young women. . It is important to note that some of these patients may have signs or symptoms related to ovarian stromal luteinization particularly during pregnancy with androgenic manifestations. It is also important to know that the primary gastric tumor may be extremely small and that sometimes it may be detected years after the diagnosis of the ovarian metastasis. On gross examination the tumors are frequently large, solid and edematous to gelatinous. On microscopic examination although signet ring cells are numerous in most tumors, they may be inconspicuous or absent in significant areas of the tumor, and some tumors may have a predominant tubular pattern or may show a wide variety of patterns. The differential diagnosis includes a clear cell carcinoma with signet ring cells, primary mucinous carcinoids of the ovary (almost always associated with a dermoid cyst) and in tubular Krukenberg tumors the main differential diagnosis is with a Sertoli Leydig cell tumor, however, the latter is not characterized by the presence of signet ring cells. Lastly metastases from intestinal-type gastric adenocarcinoma are rare, and in contrast to Krukenberg tumors it seems that these patients are older, have a known history of gastric cancer and concomitant widespread disease, although experience is very limited. Studies of CK7 expression in gastric carcinomas vary greatly, with some studies showing up to 96% CK7 positivity and up to 40% CK20 expression. Similarly, in small bowel carcinomas, a very recent study has shown that these tumors are typically CK7 positive, although 75% of the cases also express CK20. The use of immunohistochemistry in the differential diagnosis of gastric carcinoma versus primary ovarian mucinous carcinoma is very limited. Pancreaticobiliary carcinoma. It accounts for 10% of ovarian metastases that manifest clinically as an ovarian mass. It can closely mimic a primary mucinous tumor of the ovary as it may have extremely well differentiated, even benign appearing glands or areas with a borderline appearance. On gross examination they may appear as a unilocular cyst. On microscopic examination they can mimic a benign, borderline mucinous tumor with or without intraepithelial carcinoma or a MC. In these cases, the clinical history and search for surface implants are extremely helpful. Dpc4 is a tumor suppressor gene inactivated by allelic loss in 55% of pancreatic cancers. This finding can be demonstrated by lack of immunostaining. In a recent study, Dpc4 was found to be positive in 100% of primary mucinous tumors of the ovary, in the vast majority of colorectal carcinomas (89%), and in 100% of primary appendiceal carcinomas. It is extremely important carefully inspect the surface of the ovary to look for implants. Negative staining for Dpc4 in a mucinous tumor involving the ovary is supportive of metastatic pancreatic tumor. Carcinoid tumor. It accounts for approximately 2% of metastases that form ovarian masses. Carcinoid tumors that metastasize to the ovary are more commonly from the appendix or small intestine. Forty percent of women in whom metastases are found at the time of operation have the carcinoid syndrome and in most cases there are extraovarian metastases. Only 1/3 of patients with primary carcinoids have symptoms or signs related to the carcinoid syndrome and they disappear after surgery. In contrast, in patients with metastatic carcinoids and carcinoid syndrome, the carcinoid syndrome persists because 90% of the patients have extraovarian metastases. On gross examination these tumors have frequently a yellow to tan cut-surface and some of them may be predominantly cystic. On microscopic examination, the patterns are insular, trabecular or mucinous as seen in primary carcinoids of the ovary. However, a typical feature is the association with an extensive fibromatous stromal proliferation. Primary ovarian carcinoids are always unilateral, form a single nodule frequently in the wall of a mature cystic teratoma, but they can also be associated with mucinous tumors or Brenner tumors in the same ovary. In rare occasions where the opposite ovary is enlarged, this is due to the presence of a dermoid cyst or a mucinous tumor. It is important to distinguish metastatic from primary carcinoids as patients with metastatic carcinoid have a 20% survival rate compared to the 95% survival for patients with primary carcinoids. Immunohistochemical stains are not helpful. Metastatic carcinoid more frequently are cystic and are associated with the carcinoid syndrome Endocervical carcinoma: The vast majority of endocervical adenocarcinomas are high-risk human papillomavirus (HPV)-related neoplasms, characterized by p16 expression and frequent loss of hormone receptor expression, which infrequently metastasize to the ovaries. In a recent series of 10 cases reported by Elishaev and colleagues the ovarian metastases presented prior to diagnosis or concurrently with the primary endocervical tumors in 2 and 5 cases respectively; 7 tumors measured ³ 10 cm; and they were unilateral in 8 cases. In all cases, the ovarian tumors were initially diagnosed as or thought to represent independent primary ovarian borderline tumors or well-differentiated ECs or MCs. As illustrated in this investigation, it may be quite difficult to separate primary versus metastases in these cases. HPV staining may be helpful in the discrimination of a MC of the cervix metastatic to the ovary from a primary mucinous tumor. Elishaev and colleagues have recently looked at HPV types in cases of metastatic endocervical adenocarcinoma initially misdiagnosed as primary ovarian carcinoma. The endocervical and ovarian tumors were positive for either HPV 16 or HPV 18 with concordance of HPV types in the cervical and ovarian tumors in each case. A second study has shown concordance of HPV expression, either 16 or 18, in women with metastatic cervical cancer to sites other than the ovary using in situ hybridization for HPV DNA and reverse transcriptase in situ polymerase chain reaction for HPV RNA, thus supporting the promising role of HPV testing in identifying metastatic cervical carcinoma. Recently, it has been shown that p16, a tumor suppressor gene that plays an important role in the regulation and differentiation of the cell cycle, is a reliable surrogate marker for HPV. Elishaev and colleagues showed that all tested tumors were diffusely positive for p16. Furthermore, they found absent or limited expression of ER and PR in most cases. HPV typing and p16 may assist in detecting metastatic endocervical adenocarcinoma. Lung carcinoma: Despite the fact that lung carcinoma is common and well known to metastasize widely, ovarian spread is not as frequent and from a literature review secondary ovarian neoplasia from primary lung carcinoma accounted for 0.4%. In the most recent series reported by Irving and Young, a history of prior lung carcinoma was documented in only 53% of cases, five (16%) ovarian tumors were detected up to 26 months before the lung cancer, and small cell carcinoma was the most common subtype to be associated with ovarian manifestations. In that series, 44% of the tumors were small cell carcinomas (14 of 32), 34% adenocarcinomas (11 of 32), and 16% large cell carcinomas (5 of 32). As small carcinoma is the most common variant metastasizing to the ovary, in these cases the differential diagnosis includes primary small cell carcinomas of the ovary. In difficult cases, TTF-1 may be used to aid in this differential diagnosis. This is a specific and sensitive marker of most lung adenocarcinomas including bronchioloalveolar adenocarcinoma (non-mucinous type) as well as at least 50% of lung small cell carcinomas. Studies of TTF-1 expression in lung metastases from primary tumors in the colon, breast, stomach, endometrium, and ovary have shown them to be negative; the subtypes of ovarian carcinoma were not specified in these studies. A recent study evaluated TTF-1 expression in 53 ovarian surface epithelial carcinomas. The results showed that 3/8 endometrioid, 6/25 serous, 4/10 clear cell, and 2/10 mucinous carcinomas were positive, although strong expression was seen in only 2 clear cell carcinomas (7.5% of the total cases). Although the pattern of TTF-1 expression in primary ovarian tumors has not been well studied, an adenocarcinoma of pulmonary origin should be strongly considered when a metastatic adenocarcinoma involving the ovary shows TTF-1 positivity. 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