Ovarian Mucinous Tumors

General Features

Mucinous tumors show cysts and glands lined by epithelial cells containing intracytoplasmic mucin. The tumor cells may resemble those of the endocervix, gastric pylorus, or intestine. They are typically diastase resistant PAS positive, and mucicarmine positive. Mucinous tumors account for 10–15% of all primary ovarian tumors. Approximately 80% are benign and the remainder are borderline tumors, noninvasive carcinomas, and invasive carcinomas. Although they generally occur in older women (mean ages 51–54 years), mucinous borderline tumors and carcinomas are more common in the first two decades than their serous counterparts. Mucinous tumors, especially the borderline tumors, tend to be the largest of all ovarian tumors. Many of them are 15–30 cm in diameter and weigh up to 4000 g or more.

Mucinous ovarian tumors are difficult to interpret. Over the past 40 years, their classification has changed considerably as a result of the following: (1) the separation of mucinous borderline tumors from mucinous carcinomas, (2) the recognition of mucinous borderline tumors with intraepithelial carcinoma (IEC), (3) the evidence that most ovarian mucinous cystic tumors associated with pseudomyxoma peritonei are low-grade appendiceal mucinous neoplasms that involve the ovary secondarily, and (4) the increasing recognition of metastatic adenocarcinomas of intestinal and pancreatic origin that closely resemble primary ovarian mucinous tumors.

Although mucinous ovarian tumors are currently classified as surface epithelial tumors, their origin is unclear in most cases. Some mucinous tumors are of germ cell origin (monodermal teratomas), but neometaplasia of the ovarian surface epithelium is an alternative explanation for their development. In fact, transitions between mucinous tumors and serous and endometrioid tumors are occasionally seen. Also, serous and endometrioid tumors may secrete mucin from the apical pole of the epithelial cells, resulting in abundant intracystic mucus, but are not generally intracytoplasmic. Mucinous tumors may be associated with dermoid cysts (3–5%), Brenner tumors, and mucinous tumors of other organs such as the uterine cervix and appendix. In patients with the Peutz–Jeghers syndrome, well-differentiated mucinous ovarian tumors may be accompanied by minimal deviation adenocarcinomas (‘adenoma malignum’) of the cervix. Occasionally, mucinous cystic ovarian tumors may develop from heterologous gastrointestinal elements in a Sertoli–Leydig cell tumor.

Mucinous ovarian tumors are among the most common non-endocrine neoplasms presenting hormonal manifestations. Most times, the endocrine symptoms are due to the secretion of steroid hormones, which the ovarian stroma adjacent to the tumor produces. The serum level of inhibin (a hormone produced by ovarian granulosa and lutein cells that inhibits the secretion of follicle-stimulating hormone by the anterior pituitary gland) is considered to be a tumor marker for mucinous borderline tumors and carcinomas, possibly due to the reactive luteinized cells that develop in the adjacent stroma. Less frequently, patients present with Zollinger–Ellison syndrome, secondary to gastrin secretion by neuroendocrine cells in the gastrointestinal mucinous epithelium, and rarely, the carcinoid syndrome (see Chapter 29 ). CA125, carcinoembryonic antigen (CEA), and CA19-9 are often elevated in mucinous carcinomas.

Ovarian mucinous tumors are subdivided into benign, borderline, and malignant categories depending on their degree of cell proliferation, nuclear atypia, and the presence or absence of stromal invasion. In contrast to serous tumors, which are characteristically homogeneous in their degree of differentiation, mucinous tumors often are heterogeneous. Benign-appearing, borderline, and invasive patterns may coexist within an individual neoplasm; also, not infrequently, the degree of malignancy of the carcinomatous component varies from noninvasive to invasive and from well-differentiated to poorly differentiated or even undifferentiated (anaplastic) carcinoma. Such morphologic continuum suggests that tumor progression occurs from cystadenoma and borderline tumor to noninvasive, microinvasive, and invasive carcinoma. This hypothesis is supported by studies of K-RAS mutations, which are common in mucinous ovarian tumors and represent an early event in mucinous ovarian tumorigenesis. Mucinous borderline tumors have a higher frequency of K-RAS mutations than that of mucinous cystadenomas, but lower than mucinous carcinomas. Using microdissection, the same K-RAS mutation has been detected in benign-appearing, borderline, and malignant areas of the same tumor. From a practical viewpoint, the prognostic evaluation of mucinous ovarian tumors other than benign cystadenomas is difficult because of their typical large size, and the great variation in the degree of differentiation of individual tumors. Exten­sive sampling is important, especially of areas that appear nodular or solid.

Benign Mucinous Tumors

Clinical Profile

Benign mucinous cystadenomas constitute approximately 80% of ovarian mucinous tumors. They occur most frequently during the third to sixth decades, although may also be encountered in younger women. This age distribution accounts for their frequent occurrence during pregnancy.

Macroscopic Features

Mucinous cystadenomas are often large (mean size, 10 cm), unilateral, multilocular, but sometimes unilocular cystic tumors containing mucoid material. The outer cyst wall is often thick with a smooth or bosselated surface. The rare mucinous cystadenofibromas and adenofibromas are partly to almost completely solid with small cysts ( Figure 26.1 ). Benign mucinous tumors are typically unilateral in 95% of cases.

Microscopic Features

Mucinous cystadenomas are composed of glands and cysts lined by a single layer of columnar cells with abundant intracellular mucin. Cellular stratification is minimal, and nuclei are basally located with only mild atypia ( Figure 26.2 ). If epithelial proliferation resembling a borderline mucinous tumor is present, this feature must be limited to <10% of the epithelial volume for the tumor to qualify as a cystadenoma. Papillae are unusual except in rare cases of mucinous cystadenomas of endocervical type, which are conspicuously papillary. Goblet cells, neuroendocrine cells, and, rarely, Paneth cells may be encountered in mucinous cystadenomas of gastrointestinal type. However, gastric foveolar-type epithelium or intestinal epithelium with goblet cells is found more often in mucinous borderline tumors and carcinomas. Reactive nuclear atypia and mitotic activity can be seen in peripheral crypt-like structures. The stroma is fibrocollagenous and exhibits variable cellularity. Occasionally, marked prominence of the stroma occurs between glands, giving rise to patterns of adenofibroma ( Figure 26.3 ). Stromal cellularity may be increased in the vicinity of the epithelium where lutein-like cells are seen in 25% of cases. Rare benign tumors may show definite Leydig cells (with crystals) in the adjacent stroma. Smooth muscle may develop sometimes in the stroma running parallel to the cyst linings.

Rupture of mucinous glands and cysts is common, resulting in extravasation of mucin into the stroma, and often a marked inflammatory response. Such a finding must be distinguished from large pools of dissecting mucin (pseudo­myxoma ovarii), which is a characteristic feature of mucinous ovarian tumors associated with pseudomyxoma peritonei (see later). In about 5% of mucinous cystadenomas, the mucin in the stroma typically elicits a histiocytic and foreign body giant cell response (mucin granuloma) ( Figure 26.4 ). Extruded neoplastic epithelium from an adjacent ruptured gland, particularly if accompanied by a mucin granuloma, should be distinguished from stromal microinvasion (see later). Mucinous cystadenomas and adenofibromas are benign but can recur if incompletely excised. Tumor rupture is not associated with recurrence.

Mucinous cystadenomas are associated with dermoid cysts in 5% of cases and with Brenner tumors in 18%. Accordingly, it has been suggested that mucinous tumors of intestinal type may be of germ cell origin or arise from Brenner tumors.

Mucinous Borderline Tumors

Mucinous borderline tumors (MBTs) exhibit an epithelial proliferation of mucinous-type cells greater than that seen in their benign counterparts, but without destructive stromal invasion. The proliferative areas must constitute greater than 10% of the epithelial volume of the tumor. In the Western world, MBTs are less common than serous borderline tumors (SBTs). Of the 20% of primary mucinous tumors that are not cystadenomas, MBTs outnumber the invasive carcinomas. MBTs have been subclassified into two different clinicopathologic forms: the most common form is composed of gastrointestinal-type epithelium and is designated MBT of gastrointestinal type . A second and less common variant of MBT contains endocervical-type epithelium and has been named MBT endocervical-like ( Figure 26.5 ).

Mucinous Borderline Tumors, Endocervical-Like

Endocervical MBTs, also designated as müllerian MBTs, account for 10–15% of MBTs. About 140 cases have been reported. These tumors differ in many respects from intestinal MBTs, as shown in Table 26.1 . The average age of the patients with endocervical MBTs is 40 years, with a range of 15–84 years. An association with endometriosis is frequent (35–50%). At the time of diagnosis, most tumors are confined to the ovary and approximately 20% have spread to the peritoneum or regional lymph nodes. No association with pseudomyxoma peritonei has been described.

Table 26.1

Mucinous Borderline Tumors

	Endocervical-like MBT (%)	Intestinal-type MBT (%)
Frequency	15	85
Average age (years)	34	41
Bilaterality	40	6
Diameter (cm)	8	19
Multilocular	20	72
Goblet cells	0	100
Grimelius +ve cell	3	86
Acute inflammation	100	0
Endometriosis	30	6
Stage II–III	24	10
Impl +/or LN Mets	20	0
Pseudomyxoma P	0	17

Macroscopic Features

The tumors average 8–10 cm in diameter, with a range from 2 to 36 cm. About 80% are unilocular or contain three or fewer locules. Most of them show grossly visible intracystic papillae ( Figure 26.6 ). From 12% to 40% are bilateral at presentation and the contralateral ovary is subsequently involved by an endocervical-type MBT in an additional 7% of cases.

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