Epithelial ovarian tumors are heterogeneous neoplasms primarily classified according to cell type. They are further subdivided into benign, borderline, and malignant (carcinomas), and this subdivision is very important as it correlates with behavior. Borderline ovarian tumors show epithelial proliferation higher than that seen in their benign counterparts and variable nuclear atypia; however, in contrast to carcinomas, there is no destructive stromal invasion, and their prognosis is much better. Ovarian carcinomas are the most common ovarian cancers and the most lethal gynecological malignancies. On the basis of histopathology and molecular genetics, they are divided into five types (high-grade serous (70%), endometrioid (10%), clear cell (10%), mucinous (3%), and low-grade serous carcinomas (<5%)), which are morphologically diverse and account for over 95% of cases. These tumors are essentially distinct diseases, as indicated by differences in epidemiological and genetic risk factors, precursor lesions, patterns of spread, molecular alterations, response to chemotherapy, and prognosis. For a successful specific treatment, reproducible histopathological diagnosis of the tumor cell type is critical.
Highlights
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Epithelial ovarian tumors are heterogeneous neoplasms primarily classified according to cell type.
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These tumors are further subdivided into benign, borderline, and malignant, correlates with prognosis.
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Borderline ovarian tumors lack destructive stromal invasion.
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The five main types of ovarian carcinoma are essentially distinct diseases.
Introduction
Epithelial ovarian tumors account for approximately two-thirds of all ovarian tumors and about 90% of all ovarian cancers in the Western World . They comprise a group of heterogeneous neoplasms, which are primarily classified according to cell type into serous, mucinous, endometrioid, clear cell, transitional, and squamous cell tumors . Paradoxically, benign counterparts of these cells are not found in the normal ovary and their development during neoplasia has long been attributed to mullerian “neometaplasia” of the ovarian surface epithelium (mesothelium), which derives from the coelomic epithelium. Specifically, since the coelomic epithelium gives rise to the müllerian ducts, it was proposed that, as the surface epithelium becomes malignant, it would acquire the morphologic features of the müllerian duct epithelium, that is, serous (fallopian tube-like), endometrioid (endometrium-like), and mucinous (endocervical-like). This aberrant differentiation constitutes the basis for ovarian tumor classification. Currently, tumors are thought to originate from embryonic stem cells of the ovarian surface epithelium . However, there is now evidence that a number of tumors thought to be primary ovarian cancers actually originate in other pelvic organs and involve the ovary secondarily. It has been recognized that high-grade serous carcinomas (HGSCs, the most common type of ovarian cancer) may sometimes arise from precursor epithelial lesions in the fimbriated end of the fallopian tube , whereas endometrioid and clear cell carcinomas (CCCs) originate from ovarian endometriosis . The relative importance of the fallopian tube mucosa compared with the ovarian surface epithelium in the genesis of high-grade serous ovarian cancer is still a subject of debate. On the contrary, it can be argued that tumors originating in endometriosis are ultimately of endometrial origin. Thus, in some cases, the term ovarian cancer may not be accurate and it has been suggested that it should be replaced with the terms “pelvic” or “peritoneal” cancer. However, given the confusion that might follow in the literature, the author thinks that it is best to keep the term ovarian cancer until the various possible origins of these diseases are known better.
Borderline tumors
Epithelial ovarian tumors are subdivided into benign, borderline, and malignant (carcinomas), and this subdivision is very important as it correlates with behavior . Borderline ovarian tumors show epithelial proliferation higher than that seen in their benign counterparts and variable nuclear atypia; however, in contrast to carcinomas, there is no destructive stromal invasion, and their prognosis is much better than that of carcinomas. In spite of the lack of stromal invasion, serous borderline tumors, particularly those with exophytic growth, can implant on peritoneal surfaces and, rarely (about 10% of peritoneal implants), progress to low-grade serous carcinoma (LGSC) and invade the underlying tissues .
Although favorable in the vast majority of cases, the biologic behavior of the borderline tumors differs from that of the obviously benign tumors of the same cell type(s) and, rarely (<1–3%), progression to invasive carcinoma occurs justifying the term “borderline tumor.” Alternative terms such as atypical proliferative are not recommended since they are nonspecific, that is, all nonbenign epithelial tumors (borderline and carcinomas) are, by definition, proliferative neoplasms, which exhibit nuclear atypia. Furthermore, this term is misleading as it does not consider the malignant potential of a small but significant number of these tumors and discourage follow-up . Although the term “borderline” may suggest uncertainty, it accurately describes the ambiguous histological and biological features of these neoplasms and remains the most appropriate term. Accordingly, it has been recommended by the World Health Organization (WHO) for the last four decades . The majority of these tumors are associated with a favorable prognosis and the term “tumors of low malignant potential” is no longer recommended.
The distinction between borderline tumors and carcinomas is one of the most common problems in ovarian tumor pathology, yet the literature on borderline tumors is confusing, particularly with regard to their diagnostic features and treatment. With the exception of squamous cell tumors, the borderline concept applies to all types of ovarian epithelial tumors listed before; however, most data in the literature refer to the serous and mucinous intestinal categories, which are the two most common types and show striking clinicopathological differences.
Serous and mucinous borderline tumors
Serous borderline tumors (SBTs) account for 5–10% of ovarian serous tumors and occur at an average of 42 years. Approximately 70% are confined to one or both ovaries (stage I) at the time of diagnosis; the remaining tumors have spread within the pelvis (stage II) or upper abdomen (stage III). One-third of stage I tumors are bilateral . Macroscopically, SBTs have one or more cysts that are lined by polypoid excrescences and closely packed papillae (endophytic growth). In almost half of SBTs, the papillary growth covers the outer surface of the ovary (exophytic growth). Microscopically, SBTs show stromal polyps, glands, and papillae lined by stratified cuboidal to columnar epithelial cells and ciliated cells resembling those of the fallopian tube ( Fig. 1 ). The arborizing papillae form increasingly smaller branches ending in epithelial cells clusters apparently detached from the stroma (hierarchical branching); the tumor cells show varying degrees of nuclear atypia; and there is no “destructive” stromal invasion or solid sheets of tumor with a cribriform pattern .
Mucinous borderline tumors (MBTs) have been subclassified into two different clinicopathologic forms: the most common form (85–90%) is composed of gastrointestinal-type epithelium and is designated MBT of gastrointestinal type ( Fig. 2 ). A second and less common variant of MBT contains endocervical-type epithelium and has been named endocervical-like MBT ( Fig. 3 ) .
Endocervical-like 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. The average age of the patients with endocervical MBTs is 40 years and 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 . The prognosis of endocervical-type MBT is excellent and approximates that of SBTs. Recent studies report that foci of intraepithelial carcinoma (IEC) or microinvasion do not influence the prognosis . No deaths from these tumors have been well documented .
MBTs of intestinal type account for 10–15% of ovarian mucinous tumors and are more common in the first two decades than their serous counterparts . About 80–90% are stage I and only 5% are bilateral . Of note, metastatic mucinous tumors in the ovary often mimic primary ovarian mucinous neoplasms, particularly adenocarcinomas of the pancreas and large intestine . Nearly all stage II–III MBTs are associated with pseudomyxoma peritonei and, in these patients, the ovarian tumor is virtually always secondary from a primary appendiceal tumor . On gross examination, MBTs average 19 cm in diameter, are usually cystic and multilocular, and contain mucinous fluid. Microscopically, the tumor consists of cysts and glands lined by atypical epithelium of gastric pyloric-type ( Fig. 2 ). The cysts may contain papillae that are typically thin and branching. The lining epithelium almost always contains goblet cells and may have argyrophil cells and occasional Paneth cells. The epithelial cells are usually stratified to two or three layers, nuclear atypia is mild to moderate, and mitotic figures vary from few to numerous. High-grade nuclear features are absent and stromal invasion is not seen ( Fig. 2 ).
MBTs of intestinal type may exhibit areas of epithelial cell proliferation of four or more layers, scattered foci of cribriform or stroma-free papillary architecture, and moderate (grade 2) or severe atypical (grade 3) nuclei ( Fig. 4 ). Numerous studies have shown that these tumors are almost always clinically benign, and we recommend classifying them as MBTs with IEC .
In contrast to serous tumors, which are usually homogeneous, mucinous intestinal tumors are often heterogeneous. Benign-appearing, borderline, and invasive patterns may coexist within an individual neoplasm; this continuum suggests that progression occurs from cystadenoma and borderline tumor to noninvasive, microinvasive, and invasive carcinoma . This is supported by studies of K-RAS mutations, which represent an early event in mucinous ovarian tumorigenesis .
The overall outcome of SBTs is very favorable. The 5-year survival rates of patients with stage I–IIIb disease are between 88% and >95% . For patients with stage I tumors, the risk of recurrence or the development of a second SBT has been estimated to be only 5–10% . Risk factors for recurrence include conservative treatment, particularly cystectomy, bilaterality (stage IB), and incomplete staging. In SBTs, the presence of tumor at the resection margin of the cystectomy specimen and multifocality with removal of more than one cyst are strong predictors of failure of cystectomy to control the disease . Transformation of SBT to LGSC occurs in 6–7% of patients in the late stage of the disease . Other than the adverse effect of invasive implants, there is no agreement in the literature as to which prognostic factors are important . Subdivision of SBTs into benign and malignant, based on the presence of a micropapillary architecture , is artificial since SBTs with or without micropapillary pattern may rarely be associated with invasive peritoneal implants and poor outcome . The term “micropapillary” is flawed as all SBTs have micropapillae descriptively and their extension may range from a few papillae to a large number of them. Bilaterality, ovarian surface growth, and advanced stage (mainly noninvasive peritoneal implants) are more common features of extensively micropapillary SBTs than of typical SBTs, but a strong association of the former tumors with invasive implants and poor outcome has been inconsistent . According to most investigators, SBTs with micropapillary pattern or SBTs with microinvasion have a prognosis similar to that of tumors lacking these features . Similarly, focal lymph node involvement has not demonstrated any effect on survival. The 5-year survival rate of patients with stage I MBT is approximately 100%. In a recent report, six of 144 patients (4.2%) had tumor recurrence. Risk factors for recurrence included FIGO stage IC, microinvasive carcinoma, age < 45 years, and IEC .
In young patients who undergo fertility-sparing surgery, the nature of the recurrent tumor varies according to the histological type. In these patients, MBTs of intestinal type recur less frequently than SBTs, but when they do, it is more often as an invasive carcinoma . Most SBTs maintain their microscopic features and usually do not progress to frankly invasive carcinoma . In contrast, MBTs of intestinal type represent intermediate stages of mucinous tumorigenesis and, even if an MBT per se is essentially a benign neoplasm, it may be accompanied by or may progress to intraepithelial and frankly invasive carcinoma . However, in patients with MBTs initially treated by unilateral salpingo-oophorectomy, recurrences that occur in the contralateral ovary most likely represent independent primary mucinous tumors, which are typically heterogeneous and may contain benign-appearing, borderline, and carcinomatous elements. In other words, SBTs and MBTs of intestinal type are different diseases with different biologic behavior .
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70% of SBTs are confined to one or both ovaries (stage I)
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Most SBTs are associated with favorable prognosis
- •
Recurrence of SBT in the contralateral ovary occurs in 5–10% of cases
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Progression of SBT to low-grade serous carcinoma occurs in 6–7% of cases
- •
Benign noninvasive peritoneal implants are frequently associated with exophytic SBTs
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Invasive peritoneal implants are rare (10% of peritoneal implants) and represent superficial and small foci of low-grade serous carcinoma
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Almost all MBTs are stage IA tumors associated with excellent prognosis
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After fertility-sparing surgery, MBTs may “recur” as carcinomas in the contralateral ovary.
- •
These tumors most likely represent independent primary MBTs that have progressed to carcinoma
- •
Ovarian mucinous tumors with pseudomyxoma peritonei may resemble ovarian MBT, but almost always originate in the appendix or elsewhere in the gastrointestinal tract
- •
Endocervical-like MBTs (mullerian MBTs) are often bilateral and usually arise from endometriosis. Prognosis is favorable.
Borderline tumors
Epithelial ovarian tumors are subdivided into benign, borderline, and malignant (carcinomas), and this subdivision is very important as it correlates with behavior . Borderline ovarian tumors show epithelial proliferation higher than that seen in their benign counterparts and variable nuclear atypia; however, in contrast to carcinomas, there is no destructive stromal invasion, and their prognosis is much better than that of carcinomas. In spite of the lack of stromal invasion, serous borderline tumors, particularly those with exophytic growth, can implant on peritoneal surfaces and, rarely (about 10% of peritoneal implants), progress to low-grade serous carcinoma (LGSC) and invade the underlying tissues .
Although favorable in the vast majority of cases, the biologic behavior of the borderline tumors differs from that of the obviously benign tumors of the same cell type(s) and, rarely (<1–3%), progression to invasive carcinoma occurs justifying the term “borderline tumor.” Alternative terms such as atypical proliferative are not recommended since they are nonspecific, that is, all nonbenign epithelial tumors (borderline and carcinomas) are, by definition, proliferative neoplasms, which exhibit nuclear atypia. Furthermore, this term is misleading as it does not consider the malignant potential of a small but significant number of these tumors and discourage follow-up . Although the term “borderline” may suggest uncertainty, it accurately describes the ambiguous histological and biological features of these neoplasms and remains the most appropriate term. Accordingly, it has been recommended by the World Health Organization (WHO) for the last four decades . The majority of these tumors are associated with a favorable prognosis and the term “tumors of low malignant potential” is no longer recommended.
The distinction between borderline tumors and carcinomas is one of the most common problems in ovarian tumor pathology, yet the literature on borderline tumors is confusing, particularly with regard to their diagnostic features and treatment. With the exception of squamous cell tumors, the borderline concept applies to all types of ovarian epithelial tumors listed before; however, most data in the literature refer to the serous and mucinous intestinal categories, which are the two most common types and show striking clinicopathological differences.
Serous and mucinous borderline tumors
Serous borderline tumors (SBTs) account for 5–10% of ovarian serous tumors and occur at an average of 42 years. Approximately 70% are confined to one or both ovaries (stage I) at the time of diagnosis; the remaining tumors have spread within the pelvis (stage II) or upper abdomen (stage III). One-third of stage I tumors are bilateral . Macroscopically, SBTs have one or more cysts that are lined by polypoid excrescences and closely packed papillae (endophytic growth). In almost half of SBTs, the papillary growth covers the outer surface of the ovary (exophytic growth). Microscopically, SBTs show stromal polyps, glands, and papillae lined by stratified cuboidal to columnar epithelial cells and ciliated cells resembling those of the fallopian tube ( Fig. 1 ). The arborizing papillae form increasingly smaller branches ending in epithelial cells clusters apparently detached from the stroma (hierarchical branching); the tumor cells show varying degrees of nuclear atypia; and there is no “destructive” stromal invasion or solid sheets of tumor with a cribriform pattern .
Mucinous borderline tumors (MBTs) have been subclassified into two different clinicopathologic forms: the most common form (85–90%) is composed of gastrointestinal-type epithelium and is designated MBT of gastrointestinal type ( Fig. 2 ). A second and less common variant of MBT contains endocervical-type epithelium and has been named endocervical-like MBT ( Fig. 3 ) .
Endocervical-like 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. The average age of the patients with endocervical MBTs is 40 years and 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 . The prognosis of endocervical-type MBT is excellent and approximates that of SBTs. Recent studies report that foci of intraepithelial carcinoma (IEC) or microinvasion do not influence the prognosis . No deaths from these tumors have been well documented .
MBTs of intestinal type account for 10–15% of ovarian mucinous tumors and are more common in the first two decades than their serous counterparts . About 80–90% are stage I and only 5% are bilateral . Of note, metastatic mucinous tumors in the ovary often mimic primary ovarian mucinous neoplasms, particularly adenocarcinomas of the pancreas and large intestine . Nearly all stage II–III MBTs are associated with pseudomyxoma peritonei and, in these patients, the ovarian tumor is virtually always secondary from a primary appendiceal tumor . On gross examination, MBTs average 19 cm in diameter, are usually cystic and multilocular, and contain mucinous fluid. Microscopically, the tumor consists of cysts and glands lined by atypical epithelium of gastric pyloric-type ( Fig. 2 ). The cysts may contain papillae that are typically thin and branching. The lining epithelium almost always contains goblet cells and may have argyrophil cells and occasional Paneth cells. The epithelial cells are usually stratified to two or three layers, nuclear atypia is mild to moderate, and mitotic figures vary from few to numerous. High-grade nuclear features are absent and stromal invasion is not seen ( Fig. 2 ).
MBTs of intestinal type may exhibit areas of epithelial cell proliferation of four or more layers, scattered foci of cribriform or stroma-free papillary architecture, and moderate (grade 2) or severe atypical (grade 3) nuclei ( Fig. 4 ). Numerous studies have shown that these tumors are almost always clinically benign, and we recommend classifying them as MBTs with IEC .
In contrast to serous tumors, which are usually homogeneous, mucinous intestinal tumors are often heterogeneous. Benign-appearing, borderline, and invasive patterns may coexist within an individual neoplasm; this continuum suggests that progression occurs from cystadenoma and borderline tumor to noninvasive, microinvasive, and invasive carcinoma . This is supported by studies of K-RAS mutations, which represent an early event in mucinous ovarian tumorigenesis .
The overall outcome of SBTs is very favorable. The 5-year survival rates of patients with stage I–IIIb disease are between 88% and >95% . For patients with stage I tumors, the risk of recurrence or the development of a second SBT has been estimated to be only 5–10% . Risk factors for recurrence include conservative treatment, particularly cystectomy, bilaterality (stage IB), and incomplete staging. In SBTs, the presence of tumor at the resection margin of the cystectomy specimen and multifocality with removal of more than one cyst are strong predictors of failure of cystectomy to control the disease . Transformation of SBT to LGSC occurs in 6–7% of patients in the late stage of the disease . Other than the adverse effect of invasive implants, there is no agreement in the literature as to which prognostic factors are important . Subdivision of SBTs into benign and malignant, based on the presence of a micropapillary architecture , is artificial since SBTs with or without micropapillary pattern may rarely be associated with invasive peritoneal implants and poor outcome . The term “micropapillary” is flawed as all SBTs have micropapillae descriptively and their extension may range from a few papillae to a large number of them. Bilaterality, ovarian surface growth, and advanced stage (mainly noninvasive peritoneal implants) are more common features of extensively micropapillary SBTs than of typical SBTs, but a strong association of the former tumors with invasive implants and poor outcome has been inconsistent . According to most investigators, SBTs with micropapillary pattern or SBTs with microinvasion have a prognosis similar to that of tumors lacking these features . Similarly, focal lymph node involvement has not demonstrated any effect on survival. The 5-year survival rate of patients with stage I MBT is approximately 100%. In a recent report, six of 144 patients (4.2%) had tumor recurrence. Risk factors for recurrence included FIGO stage IC, microinvasive carcinoma, age < 45 years, and IEC .
In young patients who undergo fertility-sparing surgery, the nature of the recurrent tumor varies according to the histological type. In these patients, MBTs of intestinal type recur less frequently than SBTs, but when they do, it is more often as an invasive carcinoma . Most SBTs maintain their microscopic features and usually do not progress to frankly invasive carcinoma . In contrast, MBTs of intestinal type represent intermediate stages of mucinous tumorigenesis and, even if an MBT per se is essentially a benign neoplasm, it may be accompanied by or may progress to intraepithelial and frankly invasive carcinoma . However, in patients with MBTs initially treated by unilateral salpingo-oophorectomy, recurrences that occur in the contralateral ovary most likely represent independent primary mucinous tumors, which are typically heterogeneous and may contain benign-appearing, borderline, and carcinomatous elements. In other words, SBTs and MBTs of intestinal type are different diseases with different biologic behavior .
- •
70% of SBTs are confined to one or both ovaries (stage I)
- •
Most SBTs are associated with favorable prognosis
- •
Recurrence of SBT in the contralateral ovary occurs in 5–10% of cases
- •
Progression of SBT to low-grade serous carcinoma occurs in 6–7% of cases
- •
Benign noninvasive peritoneal implants are frequently associated with exophytic SBTs
- •
Invasive peritoneal implants are rare (10% of peritoneal implants) and represent superficial and small foci of low-grade serous carcinoma
- •
Almost all MBTs are stage IA tumors associated with excellent prognosis
- •
After fertility-sparing surgery, MBTs may “recur” as carcinomas in the contralateral ovary.
- •
These tumors most likely represent independent primary MBTs that have progressed to carcinoma
- •
Ovarian mucinous tumors with pseudomyxoma peritonei may resemble ovarian MBT, but almost always originate in the appendix or elsewhere in the gastrointestinal tract
- •
Endocervical-like MBTs (mullerian MBTs) are often bilateral and usually arise from endometriosis. Prognosis is favorable.
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