This chapter updates several important issues pertaining to epithelial malignancies of the ovary. These include: (1) origins, including fallopian tube and updates on the potential significance of and interpretive pitfalls with serous tubal intraepithelial carcinoma (STIC), (2) subdivisions of high-grade serous carcinoma (HGSC) that have clinical and possibly pathogenetic importance, (3) molecular parameters useful in subclassification, (4) recent data on the outcome of stage I noninvasive low-grade serous carcinomas (LGSCs; also known as micropapillary borderline tumors), and (5) the spectrum of borderline tumors of mixed epithelial type. As always mucinous tumors include both endocervical and intestinal type, with an additional gastric variant that must be kept in mind that can be associated with Peutz-Jeghers syndrome.
Keywordshigh-grade serous carcinoma (HGSC), micropapillary borderline, low-grade serous carcinoma (LGSC), noninvasive low-grade serous carcinoma (LGSC), invasive implants, borderline tumors
Tumor Origin, Terminology, and Classification
This chapter addresses pelvic epithelial malignancies that are commonly held synonymous with “ovarian cancer.” To maintain consistency, the term ovarian will be used as a generic term but this category encompasses tumors that might arise from the fallopian tubes and peritoneal surfaces. This view is manifest in the new International Federation of Gynecology and Obstetrics (FIGO) staging.
Epithelial tumors constitute about half of ovarian tumors, often include both an epithelial and a stromal component (hence the often-used term epithelial-stromal ), and are subdivided into serous, mucinous, endometrioid, clear cell, transitional cell, squamous, mixed epithelial, and undifferentiated types. The addition of the term stromal reflects the fact that many of these tumors have a conspicuous stromal component that is derived from the specialized stroma of the ovary, which, unlike the nonspecific stroma within most other epithelial tumors, is capable of hormone synthesis, sometimes inducing a paraneoplastic syndrome, usually related to hyperestrogenism. This is most conspicuous in the benign and borderline tumors (adenofibromas). Except for squamous and undifferentiated tumors, there are benign, borderline, and malignant subcategories within all of these divisions. The designation “borderline” is unique in the nosology of human tumors. Use of the term is controversial and merits some discussion.
As implied in Chapters 21 and 24 , the origin of ovarian cancer has undergone some revision with the discovery that the fallopian tube is the primary site of origin for incidentally detected high-grade serous carcinomas (HGSCs), be they in women with BRCA mutations or the general population. A few important ground concepts are reviewed to update our knowledge of this group of neoplasms. They include the following ( Figs. 25.1 and 25.2 ):
One group of tumors, specifically well to moderately differentiated endometrioid, clear cell, mucinous, and borderline or low-grade serous tumors, arise most commonly in the ovarian cortex, presumably from cortical inclusions (or endosalpingiosis) or endometriosis.
A second group of tumors, and the most common malignant tumors, are generically termed high-grade müllerian carcinomas, a term synonymous with HGSC. These tumors invariably contain mutations in TP53 , a significant percentage harbor defects in DNA repair, and approximately 20% of these patients have a germ-line mutation in either BRCA1 or BRCA2 (see Chapter 24 ). Tumors previously termed high-grade endometrioid and transitional carcinomas that contain TP53 mutations are largely included in the HGSC group under the category of SET (solid, endometrioid-like, or transitional). The “classic” HGSCs seem to be closely associated with the distal fallopian tube, with coexisting serous tubal intraepithelial carcinoma (STIC) found in up to 75% of cases. In contrast the SET group is associated with an STIC in 25%. Alternative sites of origin include the ovary, endometriosis, adenofibromas, peritoneal or ovarian surface epithelium, and (equally possible) occult precursors in the fallopian tube. It should be emphasized at this point that the tube contains the only well-defined precursor, although the reader is cautioned that not all intramucosal STICs are necessarily primary lesions. What is important is that HGSCs have a remarkable propensity for growth on ovarian and peritoneal surfaces.
A small number of tumors appear to arise from the region of the peritoneal surfaces and precisely where they come from is controversial. The most likely source is in müllerian inclusions (endosalpingiosis) or endometriosis. These tumors include borderline serous tumors and occasional endometrioid carcinomas. Whether HGSCs arise from extraovarian müllerian inclusions is uncertain, inasmuch as a serous carcinogenic sequence has not been clearly described in these sites. The reader will encounter tumors classified as “primary peritoneal” serous carcinomas. This designation pertains to their apparent origin beyond the tube or ovary but is not a declaration that these tumors actually arose from the mesothelium.
In recent years the molecular footprints of epithelial ovarian tumors have been increasingly refined, permitting investigators to uncover pathways and biomarkers that distinguish the individual groups and provide both pathogenetic information as well as potential diagnostic and therapeutic targets (see Fig. 25.1 ). They will be referred to under each tumor type within the chapter as appropriate.
The Continuum of Borderline and Low-Grade Malignancy
The World Health Organization (WHO) selected the designation “tumors of borderline malignancy” in 1973 and applied it to all epithelial types, defining borderline tumors as those with epithelial or architectural atypia but without obvious stromal invasion.
However, although they have often been considered a single entity in clinical follow-up studies, borderline tumors of different epithelial types are not equivalent and can be subdivided into the following categories:
In the most frequently encountered borderline tumors, those of the serous type, the intermediate microscopic appearance correlates with a clinical behavior that is also somewhere between benign and malignant. The tumor might undergo microinvasion, spread to the peritoneum or to lymph nodes, and recur in a significant minority, but most of the time they do not harm the patient or do so only after a prolonged period.
In the case of the second most common mucinous borderline tumor, many cases previously thought to have spread to the peritoneum (usually in the form of pseudomyxoma peritonei) are now believed to have been metastases to both the ovaries and the peritoneum from a gastrointestinal (usually appendiceal) primary and are not ovarian tumors at all. This invites scrutiny of the origin of any low-grade intestinal type mucinous tumor, particularly those that are bilateral or exhibit extra-ovarian spread.
Finally, the much less common endometrioid, clear cell, and transitional cell borderline tumors that typically have a favorable outcome.
On the basis of these observations and to discourage an overly aggressive clinical response to tumors that behave in a benign fashion in the majority of cases, some authorities recommend that the category of borderline tumors be abandoned and replaced by the term atypical proliferative. This term has now been included in the 2014 WHO classification where tumors can be designated as serous borderline tumor (SBT) or atypical proliferative serous tumor (APST). The presence of micropapillary/cribriform growth patterns in borderline tumors have also been described and are held synonymous with noninvasive low-grade serous carcinoma (LGSC). Whatever terms one uses in clinical practice, it is important for pathologists to be familiar with the gross and microscopic appearances of borderline tumors to avoid an erroneous intraoperative diagnosis of carcinoma on a frozen section. SBTs can present as dramatic proliferations on the ovarian surface, mucinous borderline tumors may present as massive tumors, and rare endometrioid borderline tumors may exhibit areas that closely resemble malignancies. Yet many borderline tumors can be safely treated with unilateral oophorectomy or cystectomy in young patients who wish to retain their fertility. An intraoperative report that a tumor is borderline will then lead to thorough operative staging and generous sampling of the tumor for permanent sections.
Resolving the Paradox of Peritoneal Implants
Peritoneal implants are a common feature of borderline, low- and high-grade serous tumors of the ovary and generate a “visceral” response in both clinician and pathologist, as well as the obvious questions:
Why should a tumor that is not overtly malignant or has not invaded the ovarian stroma have the ability to metastasize to the peritoneum?
How does one consistently predict which implants are going to behave in an aggressive fashion?
These questions can be addressed, if not answered completely, if the reader accepts that the peritoneal surface is not only a prime site for serous tumor implantation but is also more susceptible to invasion than ovarian or tubal stroma. Thus, there is a sequence of increasingly malignant biologic potential as shown in Box 25.1 and Table 25.1 . Because the peritoneum is accessible to many of these tumors and because classification systems cannot always predict biologic behavior, an occasional “borderline” tumor can be expected to successfully establish invasive implants on the peritoneal surface. The risk increases further with noninvasive low-grade carcinomas (micropapillary) of the ovary—provided they have access to the peritoneum—increases further in frankly invasive (in their own stroma) LGSCs, and culminates in HGSCs of the ovary or fallopian tube. The criteria for these entities will be discussed later, but readers can take comfort in the fact that they are witnessing a spectrum of tumor aggressiveness that may or may not always be easy for the practitioner to sort out by examination of the primary tumor alone. Thus, the nature of the implants has the most weight as an outcome predictor in well-differentiated serous tumors of the ovary.
Benign serous tumor
Benign serous tumor with peritoneal implants/endosalpingiosis
Borderline (proliferative) serous tumor
Borderline serous tumor with noninvasive implants
Borderline serous tumor with invasive implants (uncommon)
Noninvasive low-grade serous carcinoma (LGSC; micropapillary borderline)
Noninvasive LGSC with micropapillary/invasive implants
Invasive LGSC of the ovary
LGSC of the ovary with extra ovarian metastases
Serous intraepithelial carcinoma confined to the fallopian tube (most commonly discovered in asymptomatic women undergoing risk reduction procedures)
High-grade serous carcinoma (HGSC) confined to the fallopian tube (rare)
HGSC confined to the ovary (rare)
HGSC involving ovarian, fallopian tube, and other serosal or peritoneal surfaces (most common clinical presentation)
|Surface involvement||Increases the risk of peritoneal implants|
|Microinvasion||By itself not a risk factor for adverse outcome if criteria strictly applied; however, it co-segregates with additional variables of adverse outcome (e.g., peritoneal involvement, invasive implants, well-differentiated serous carcinomas)|
|Lymph node spread||Does not alter survival but in one study has been associated with decreased disease-specific survival|
|Noninvasive implants||Increases slightly the risk of adverse outcome|
|Micropapillary/microcribriform||Synonymous with a noninvasive low-grade serous carcinoma (LGSC); risk of adverse outcome increased slightly in stage I tumors (5%) relative to conventional borderline tumors (1%)|
|Invasive implants||Adverse outcome in over 30%|
Strengths and Weaknesses of Tumor Typing and Grading
There are two internationally recognized grading systems: those of the FIGO and the WHO. In the former, tumor architecture is the sole determinant of grade (less than 5% solid growth = grade 1; more than 50% solid growth = grade 3). The WHO system uses both architectural and cytologic features but does not give details, relying on the pathologist’s impression to determine grade in a three-tier system. In the United States, the Gynecologic Oncology Group employs a modified FIGO system wherein grade is determined by differing criteria depending on the epithelial subtype. Silverberg and Shimizu have proposed a system of grading for all cell types, modeled on the Nottingham system for grading breast cancer, using architectural features (glandular, papillary, solid), nuclear grade, and mitotic count with each scored as 1 to 3 and then the total score determining the grade. However, in some histologic types, particularly clear cell carcinoma, no grading system appears to be effective in prognostication.
Are these detailed grading systems necessary for routine management? Perhaps, but with several caveats.
Most serous carcinomas can be managed with a two-grade system that parallels their biology: Malpica et al. studied serous carcinomas using a simplified two-grade system (high grade and low grade) and found grade to be an independent prognostic indicator in a multivariate analysis. In this study, the Silverberg and Shimizu system correlated closely with their two grades (very few Silverberg grade 2 tumors were found). The FIGO system, however, correlated poorly. Vang et al. recommended a two-grade system for serous carcinomas that parallels the biologic differences between these tumors. They observed that most tumors in the grade 2 category (similar to Silverberg) typically belonged in the high-grade category. Using this or other systems has identified low-grade tumors and linked them to a higher likelihood of platinum resistance.
Despite this, the reader is forewarned that occasional serous tumors cannot be so readily classified into low and high grade. Some low-grade tumors will be associated with higher grade components suggesting progression and p53 immunostains, which typically separate LGSCs (wild type pattern) from HGSCs (diffuse or null staining) might be inconclusive. An example of such a tumor is illustrated later in the chapter.
Stage supersedes cell type and grade in serous carcinomas: In a study by Gilks et al., who compared the prognostic significance of histologic cell type and grade in maximally debulked pelvic epithelial carcinomas, stage, followed by cell type (e.g., serous versus endometrioid), was the most powerful prognostic indicator, and tumor grade did not independently correlate with outcome. The reproducibility for cell type was good (kappa = 0.77). Combined with the previously discussed studies, it is reasonable that a two-tier system for serous tumors would be more reproducible and clinically applicable for all epithelial subtypes than the various three-tier systems currently used.
Lower and higher grade endometrioid tumors are distinguishable biologically: Grades 1 and 2 endometrioid carcinomas easily segregate to molecular pathways in the so-called type I tumors, similar to LGSCs. True grade 3 endometrioid adenocarcinomas of the ovary also exist but are uncommon and must be distinguished from tumors in the SET category of HGSC, and an argument can be made for combining grades 1 and 2.
In our practice, we use the following approach:
We classify serous carcinomas as high or low grade on the pathology report as required by the clinical management team. Similar to others, our experience has been that most (but not all) grade 2 serous carcinomas will justify classification in the high-grade group. LGSCs (grade 1) often are associated with borderline tumors. The two can be distinguished from HGSCs by p53 immunostaining and, to some degree, p16 immunostaining. Occasional cases in which an LGSC merges with a high-grade component should be immunostained and will require a descriptive note to alert the oncologist to this, inasmuch as management and outcome expectations following chemotherapy will differ between low- and high-grade tumors.
We grade endometrioid carcinomas as we do in the uterus, using the FIGO system of architectural grading and upgrading FIGO grade 1 and grade 2 tumors by one grade on the basis of high nuclear grade. True grade 3 endometrioid adenocarcinomas of the ovary are uncommon. High-grade adenocarcinomas with pseudoendometrioid, solid, or transitional (SET group) share TP53 mutations with HGSC and are classified by most as equivalent to HGSC. If we are uncertain about the cell type, we classify these tumors as high-grade müllerian adenocarcinomas and are mindful of these distinctions inasmuch as the association with STIC seems to be less with the SET patterned tumors.
We determine whether mucinous carcinomas have infiltrative or expansile invasion. If the latter, we grade based on nuclear atypia. If there is infiltrative invasion, even focally, we grade the entire tumor based on this component using the same system as for endometrioid carcinomas.
With a few exceptions, clear cell carcinomas are high grade. They can be quite small, emerging within a clear cell adenofibroma or an endometriotic cyst, with minimal invasion. In these instances, this information will be conveyed in the report inasmuch as stage I tumors confined to a cyst have a favorable outcome.
We grade transitional cell carcinomas on the basis of their nuclear features, being mindful that an uncommon subset of these tumors are associated with true endometrioid tumors or Brenner tumors and may have lower grade cytology. The remainder belong in the SET group of HGSC.
Serous tumors are composed of cells and patterns of growth that resemble those of the fallopian tube. This cell population is normally composed of both secretory and ciliated cells, the latter signifying terminal differentiation. Both populations are conspicuous at the benign and borderline end of the spectrum, and non-ciliated immature cells typify the high-grade tumors. Low-grade carcinomas exhibit features of ciliated differentiation, but actual cilia are less prominent. In essence, the higher the grade, the less capable the cells are of maturing, similar to other epithelia.
Sites of origin for pelvic serous neoplasms include the following:
The ovarian surface epithelial cortical endosalpingiosis or cortical inclusion cysts: This source is considered the most plausible for the majority of benign, borderline, and low-grade serous malignancies.
The distal fallopian tube: This site accounts for a significant number of HGSCs, including some that have been previously assumed to originate on the surface of the ovary and peritoneum. Presumably clonal papillary proliferations have been described in the distal tube but their relationship to borderline tumor is unclear.
Müllerian epithelial rests in the pelvis: This source has been implicated in so-called primary peritoneal serous carcinomas, specifically those that are not associated with a plausible site of origin in the distal tube.
Serous tumors are the most common subtype of epithelial-stromal neoplasms. In the West, they account for about 30% of all ovarian neoplasms and over 60% of the malignant epithelial tumors, but they are relatively less common in Asia. Approximately 60% are benign, 10% are borderline, and 30% are malignant. Benign serous tumors occur across the age spectrum but are most common in the fourth to sixth decades. The average age of patients with borderline tumors is approximately 45 years, but these tumors may occur in women in their late teens and early 20s. The average age of patients with serous carcinoma is the mid-to-late 50s ; they are very rare in teenagers and uncommon in patients younger than 30 years old.
Benign Serous Tumors (Cystadenomas, Cystadenofibromas, Adenofibromas, Papillary Adenofibromas, Surface Papillary Adenofibromas)
Benign serous tumors are bilateral in 10% to 20% of cases. Most are either partially or completely cystic. A cystadenoma is arbitrarily distinguished from a cortical inclusion cyst if it exceeds 1 cm in diameter. A typical cystic tumor has one or more locules containing watery or pale fluid (occasionally mucoid) with a thick collagenized capsule ( Fig. 25.3 ). Adenofibromatous elements convey multiple smooth, knobby papillae lining the surface of a cyst, to confluent firm white to pale yellow areas that may contain smaller cysts ( Fig. 25.4 ), to tumors that essentially appear entirely solid on the ovarian surface ( Fig. 25.5 ). The terms cystadenoma or cystadenofibroma are acceptable and choosing one or the other depends on the degree of fibrous component. The glands, cysts, and broad-based papillae of benign serous tumors are lined with a mixture of secretory and ciliated cells similar to what is seen in the fallopian tube, with rare mitotic figures ( Fig. 25.6 ). In some adenofibromas, the epithelium is cuboidal and without cilia, resembling the ovarian surface epithelium. These cases are customarily included in the serous category.
Invariably, the practitioner will be faced with small foci of more complex growth, either papillae or more pseudostratified epithelium. If these areas exceed 10% of the tumor epithelium, a diagnosis of SBT or APST is justified. If not, we note their presence and classify the tumor as a serous cystadenoma with focal proliferative activity.
Noninvasive Low-Grade Serous Tumors With Potential for Adverse Outcome
Borderline (Atypical Proliferative) Serous Tumors
SBTs are bilateral in about 25% of cases. They are usually partly cystic with watery or mucinous cyst fluid and contain intracystic or surface soft white to tan cauliflower-like papillary projections ( Fig. 25.7 ). The papillae are usually more extensive than the firmer, smooth, bosselated papillae of benign tumors. However, one cannot reliably predict the histologic findings on the basis of the gross appearance, and frozen section examination of either type of projection is warranted.
The following characterize SBTs:
About 70% of patients with SBTs have no evidence of spread beyond the ovary at the time of initial staging; the disease-free survival in these patients is 98.2%.
The remaining 30% of patients have pelvic or abdominal peritoneal implants upon initial staging. These account for the great majority who suffer serious morbidity or death.
However, in marked contrast to serous carcinomas, only 15% to 30% of these higher-stage tumors recur; even when they do, many of them still do not cause harm. Thus, since the late 1970s, the primary focus of research on SBTs has been to discover predictors of a poor outcome in these higher-stage cases.
Studies have examined the prognostic significance of the histopathologic features of the primary tumor, the morphology of the implants, lymph node metastases, minor foci of invasion in the ovarian tumor, flow cytometry, and p53 expression in the tumor cells. These are discussed in greater detail later.
The main finding that predicts outcome in higher-stage SBTs is the type of extraovarian peritoneal implants: whether they are “invasive” or “noninvasive.” The 7-year disease-free survival in patients with noninvasive implants is 95.3%; with invasive implants it is 66%.
SBTs are characterized by broad, branching papillae focally covered with highly stratified epithelial cells, some of which appear to be free floating in the extracellular space ( Figs. 25.8 and 25.9 ). This space is usually clear, but some tumors may elaborate mucin ( Fig. 25.10 ). The epithelial cells consist of a mixture of polygonal or columnar and exhibit variable potential for ciliated differentiation. The latter may manifest as abundant cilia or as eosinophilic cytoplasm that is sometimes ciliated or has surface blebs ( Fig. 25.11 ; see Fig. 25.9 ). In some cases, the cytoplasm is abundant, especially in tumors from pregnant women ( Fig. 25.12 ). Nuclear atypia varies among and within cases from mild to moderate, but it is generally less severe than that of LGSCs (see Figs. 25.9, 25.11, and 25.12B ). Mitotic figures are infrequent. The stroma is fibrous and variably cellular; it may be edematous, particularly in the papillary cores. There may be few or many psammoma bodies. Benign-appearing areas, either cystadenomatous or adenofibromatous, are often present and may account for the majority of the tumor.
Borderline tumors are distinguished from low-grade carcinomas by the absence of both micropapillary or cribriform (noninvasive low-grade carcinomas) growth and frank stromal invasion. In addition, the reader will note that (noninvasive) LGSCs often display a more irregular branching pattern, with large blunt papillae terminating abruptly into micropapillary growth patterns. Because of the oblique sectioning of complex papillae, there are areas where epithelial cells are included within the stroma. This appearance should not be mistaken for invasion, because there is no stromal reaction and one can easily conceptualize the included areas as secondary to the plane of section. It must be acknowledged that, aside from tumors that have the micropapillary/cribriform patterns described later, there are occasional low-grade serous tumors that lack obvious stromal invasion but have a particularly exuberant epithelial growth pattern ( Fig. 25.13 ). Experienced pathologists may differ on whether to interpret these as borderline tumors or as LGSCs with “expansile growth-type invasion.”
Having diagnosed an SBT, the pathologist may encounter five other features, the first four of which do not alter management but may slightly increase the overall risk of recurrence and in some cases, adverse outcome:
Surface involvement ( Fig. 25.14A ): Exclusion of surface involvement depends on a careful gross examination and orientation such that the surface is evident on the slide, usually by its being inked prior to cutting into the tumor. These have a “stuck on” appearance and are identical to extraovarian noninvasive desmoplastic implants. These “auto implants” are associated with an increased frequency of high-stage tumors, but they do not alter the prognosis in stage I and are not currently considered to represent invasion. The presence or absence of surface involvement should be included in the final report.
Stromal microinvasion: Most SBTs are homogeneous. However, generous and judicious sampling is required to exclude focal areas of invasion. In most cases, this requires at least one section per centimeter of tumor diameter. Invasive foci measuring less than 10 mm 2 and less than 3 mm in greatest dimension are present in as many as 10% of cases. These should be reported as foci of microinvasion. Microinvasive areas consist either of dyshesive eosinophilic cells in the cores of the papillae (see Fig. 25.14B ) or small aggregates of cells with a cribriform or microcystic pattern, usually with a reactive-appearing stroma (see Fig. 25.14C ). Microinvasion does not by itself appear to alter the overall behavior of a borderline tumor but will co-segregate with more aggressive tumors (LGSCs), in which case certain patterns, such as micropapillae, may be more ominous. Vascular space invasion has also been observed in a few cases with microinvasion, but thus far it has not been demonstrated to worsen the prognosis. A borderline tumor with invasive areas that are larger than microinvasive areas should be reported as LGSCs associated with an SBT. Patients with these tumors often—but not invariably—have invasive extraovarian implants and a high mortality, albeit sometimes only after many years.
Lymph node involvement: Lymph nodes are not examined in many cases, and whether nodal involvement by SBTs carries significant weight in terms of overall outcome has not been well established. Pelvic and paraortic lymph node involvement has been found in as many as 25% of cases in which nodes are examined. The tumor is generally present in sinusoidal spaces rather than in the substance of the node, distinguishing them from müllerian rests (endosalpingiosis) that may also be present ( Fig. 25.15 ). The presence of lymph node involvement has not been shown to alter the prognosis of SBTs. However, there may be a relationship to lower disease-free survival.
Noninvasive implants on the peritoneal surfaces: Sometimes the surface of the tumor or the lining of a cyst within the tumor may have plaques of reactive-appearing fibrous stroma containing psammoma bodies and epithelial cells lying singly or in small groups. They are illustrated later. Noninvasive implants on the peritoneal surfaces impart a slightly greater risk of an adverse outcome than when absent, but the differences are small. This will be discussed further later.
Salpingoliths: The fallopian tubes in patients with borderline tumors may contain concentric calcifications trapped within the lamina propria, termed salpingoliths ( Fig. 25.16 ). When detected in tubal specimens, these concentric calcifications should raise the possibility of a coexisting borderline serous tumor in the ovary or pelvic surfaces.
In all, the prognostic impact of the preceding findings is low (see Table 25.1 ). Studies of stromal microinvasion and lymph node spread in borderline tumors have shown little impact on 5- to 6-year survival, although some feel that disease-free survival is reduced with lymph node involvement. Recurrence rates for noninvasive implants are less than 10%. Surface involvement is significant insofar as it enables peritoneal spread, the outcome ultimately being a function of the biology of tumor.
Borderline Serous Tumors With Micropapillary/Cribriform Architecture (Noninvasive Low-Grade Serous Carcinomas)
Women with SBTs that contain extensive areas of micropapillary or cribriform epithelial overgrowth have an increased frequency of bilateral tumors and invasive peritoneal implants, with the attendant risk of the latter for subsequent recurrence and death (discussed later). In the micropapillary pattern, epithelial cells surround a prominent, nonbranching fibrous stalk and protrude radially as long, thin micropapillae without stromal cores such that the low-power appearance resembles a Medusa head ( Fig. 25.17A and B ). When the micropapillae merge, they take on a ramifying appearance; alternatively the pattern can take on a cribriform pattern (see Fig. 25.17C ). The epithelial cells in these foci generally differ from those in other areas or in ordinary borderline tumors in that the cells are monomorphous and “clonal appearing” with scant cytoplasm (see Fig. 25.17D ). They are mostly cuboidal but may also have a hobnail, columnar, or flattened appearance. Cilia may be retained, particularly in the areas of cribriform growth (see Fig. 25.17C ). Nuclei are round and slightly more hyperchromatic than in the usual borderline tumor.
Ample data exist to consider the micropapillary pattern synonymous with noninvasive LGSCs. In a study examining 400 borderline tumors and well-differentiated carcinomas, 17 borderline tumors had micropapillary/cribriform foci at least 5 mm in extent. Of the 13 patients with follow-up data in this group, three had no implants and none recurred; three had noninvasive implants and one had a recurrence; six had invasive implants (defined so as to include micropapillary in the implant itself as invasive), four of these patients had a recurrence, and two died of their tumors.
In a companion study of 65 advanced-stage borderline tumors, 11 ovarian tumors had micropapillary/cribriform areas, 10 of which had invasive implants. Seven of the 10 patients had recurrences, and four died of their tumors. The frequency of invasive implants and recurrences in this group was much greater than in the remaining cases. Because of these findings and subsequent correlative molecular analyses, these authors concluded that SBTs with micropapillary/cribriform areas greater than 5 mm belong in a separate category that they designated “micropapillary serous carcinoma.”
Four subsequent studies of tumors with micropapillary/cribriform areas totaling 59 cases recorded noninvasive implants in 28 cases, three of which recurred, and invasive implants in five cases, all of which recurred. There were no recurrences in the 26 cases without implants. Another study of 99 advanced-stage SBTs contained 18 cases with micropapillary/cribriform areas. Only three of these 18 patients had invasive implants, but 14 of them had disease progression or recurrence, and five of them died. This compared with 25 recurrences and 12 deaths in 81 patients without micropapillary/cribriform areas in their ovarian tumors.
Taken together, these observations indicate that patients with micropapillary/cribriform foci in an SBT have a higher risk than those with ordinary SBTs for both noninvasive and invasive implants and thus for subsequent recurrence. The question that has persisted is whether micropapillary tumors without implants imposed a greater risk of recurrence. The earlier studies did not provide consistent outcome information; however, it is important to note a study by Hannibal et al. surveying registry data from Denmark between 1978 and 2002. Their study encompassed 946 women with APST and 80 with noninvasive LGSC. Given the extent of the population studied, several findings in their study merit notation:
They found that the 5-year and 20-year risk of metastatic serous cancer (mostly LGSC) outcome following a micropapillary borderline (or noninvasive LGSC) was several fold higher than that for SBT/APST (5.0% and 13.9% vs. 0.9% and 3.7%). Thus, although spread from the ovary or invasive implants is still the most powerful predictor of adverse outcome, the risk of adverse outcome for stage I tumors is still elevated relative to ordinary borderline tumors (see Fig. 25.17E and F ).
The recurrence rate for all SBTs/APSTs was only 5.3%, increasing steadily up to 10 years following surgery and then leveling off.
Although an LGSC outcome was infrequent for APSTs, it was nonetheless significantly greater than the expected rate of serous cancer in the population (34 for APSTs vs. 2.5 in the general population). Moreover, the risk of metastatic LGSC outcome for noninvasive LGSC was significantly higher than for APSTs with a hazard ratio (HR) of 4.3. Factors contributing to LGSC outcome risk for women with APSTs were surface involvement (HR = 4.8), residual disease following surgery (HR = 3.8), bilaterality (HR = 7.7), noninvasive implants (HR = 9.3), and, most telling, invasive implants (HR = 115.9). Less information is available on risk factors for adverse outcome following noninvasive LGSC given the small numbers, but nonsignificant risks were linked to advanced stage (HR = 2.6), surface involvement (HR = 2.2), and invasive implants (HR = 4.5).
For the purposes of management, our strategy is to adhere to the spirit of the WHO classification and classify these tumors as SBTs with complex or micropapillary architecture, noting their alternate designation of noninvasive LGSC, the latter important to convey their biologic potential. Both terms are included in Table 25.2 . Naturally, cases with micropapillary/cribriform areas must be sampled and sectioned thoroughly to exclude invasion within the ovarian tumor, and we extensively sample the omentum. Moreover, we append a note to the diagnostic report indicating the presence of micropapillary/cribriform foci and the fact that these foci slightly increase the risk of an LGSC outcome, as recently described.
|Serous Tumors||Most common epithelial tumor group|
|Adenocarcinoma||More than 85% involve the ovarian surface or adjacent structures|
|Includes low (≈10%) and high (≈90%) grade carcinomas|
|Noninvasive low-grade serous carcinoma (LGSC)||Grade 1, synonymous with micropapillary/cribriform borderline|
|Borderline||Can be intracystic or involve the ovarian surface|
|Mucinous Tumors||Include intestinal (common) and müllerian (less common) types|
|Adenocarcinoma||Includes borderline tumors with “intraepithelial carcinoma”|
|With mural nodules|
|Adenocarcinoma||High-grade carcinomas overlap with high-grade serous carcinomas (HGSCs)|
|Borderline||Also known as proliferative cystadenoma/adenofibroma; including squamous morules|
|Clear Cell Tumors|
|Adenocarcinoma||Papillary and adenofibromatous types|
|Borderline||Occur in adenofibromas|
|Transitional Cell Tumors|
|Malignant||Includes malignant Brenner tumors and the rare transitional cell carcinoma|
|Borderline||Typically proliferating Brenner tumors|
|Benign||Usually Brenner tumors|
|Squamous Cell Tumors|
|Malignant||Rare squamous carcinomas with or without a coexisting teratoma|
|Mixed Epithelial Tumors|
|Malignant||Commonly a mixture of high-grade serous and endometrioid (high-grade müllerian)|
|Borderline and benign||Overlap with serous and müllerian mucinous tumors, also called “seromucinous borderline tumors”|
|Undifferentiated or Unclassified|
It is important to stress that micropapillary-like mimics can be seen in not only noninvasive LGSCs but also ordinary borderline tumors ( Fig. 25.18A ), frank low serous carcinomas (see Fig. 25.18B ), and HGSCs (see Fig. 25.18C ). Thus, attention must be paid to the histologic criteria, the surrounding tumor, and the cytologic features of the tumor epithelium.
Assessment of Peritoneal Involvement
Peritoneal deposits are present in approximately 30% of cases of ovarian SBTs. Tumors with surface involvement are associated with a much higher frequency of these foci than those without surface involvement, which suggests that the extraovarian deposits are derived from the ovarian tumor. Thus, by convention they are designated as “implants.” The current evidence supports both a single and multicell origin:
Borderline tumors can arise in the peritoneum without any ovarian involvement.
Some X chromosome inactivation studies, comparing the implants with the ovarian tumor, have documented clonality differences between them. However, others support a single cell of origin, as studies looking at BRAF and KRAS mutations also found a shared clonality in most, but not all, SBTs.
Rarely, LGSCs develop in the abdomen following borderline serous tumors that are confined to the ovaries at initial staging, often after many years.
TP53 and KRAS mutations in ovarian borderline tumors and subsequent peritoneal serous carcinomas tend to differ, suggesting that the carcinomas and the borderline tumors arise independently. In this sense, one might think of an SBT as a marker for a patient at increased risk for the development of peritoneal carcinoma, rather than the cause of it, at least in some cases. Regardless of their derivation, the presence of peritoneal implants and whether or not they are invasive are the most important indicators of outcome in SBTs.
As implied earlier and in Box 25.1 , peritoneal implants are essentially the earliest manifestation of metastatic potential, and in their mildest form, these “metastases” can be biologically insignificant, essentially growing at such a slow or indolent rate that they fail to expand and cause significant morbidity. This would be the conceptual definition of noninvasive as opposed to invasive implants. However, because the peritoneum is more susceptible to tumor growth and invasion than the ovarian stroma, the biology of some borderline tumors and many noninvasive (micropapillary) carcinomas (also termed “borderline tumors with complex or micropapillary architecture”) will be more readily appreciated by examining the peritoneal surfaces. In our experience and that of others, distinguishing two strict categories of implants—“invasive” and “noninvasive”—is not a simple task. The criteria for this distinction and current recommendations are addressed later in the microscopic description of borderline tumors and their implants.
Implants Versus Benign Mimics
Implants must be distinguished from florid mesothelial hyperplastic reactions, which may form glandlike structures, contain psammoma bodies, and be associated with a fibrous reaction, similar to true implants. Mesothelial cell nuclei are paler than epithelial cell nuclei, and, when lining a surface, hyperplastic mesothelial cells often have a hobnail arrangement with spaces between them ( Fig. 25.19 ). Although usually not necessary, a positive calretinin stain will confirm their mesothelial nature.
Glandular, cystic, or small papillary inclusions, sometimes with psammoma bodies, are not uncommonly present on peritoneal surfaces, in lymph nodes, and in the omentum ( Fig. 25.20 ) in women with or without borderline tumors. Although some can question the benign nature of these foci in lymph nodes, as well as their link to the borderline tumor when present in the omentum, their presence has not been shown to alter the prognosis of an SBT, and they should not be diagnosed as implants or metastases. True implants have a more exuberant and complex epithelial cell proliferation than do these foci of endosalpingiosis.
It is important to reiterate here that the status of the peritoneal cytology will not determine the nature of the peritoneal involvement. Low-grade serous tumors, be they SBT or LGSC, may not be distinguishable on cytology alone. In general, we refer to a positive peritoneal cytology in such cases as “positive for low grade serous neoplasia” ( Fig. 25.21 ) and leave the distinction of the nature of the tumor up to histology.
Invasive Versus Noninvasive Implants
Implants may or may not invade pelvic or abdominal structures. On the basis of this distinction, implants are divided into invasive and noninvasive types. These may coexist. Criteria to distinguish the implant types are given here and summarized in Table 25.3 .
|Epithelial||Desmoplastic||Accepted Criteria b||Proposed Additional Qualifying Criteria c|
|Papillary epithelium similar to that of the usual borderline tumor in submesothelial invaginations or between lobules of adipose tissue||Papillae, glands, cell clusters, or single cells within inflamed, reactive-appearing fibrous tissue that appears to be plastered on to serosal surfaces or in fibrous septae of adipose tissue||Proliferative epithelium resembling low-grade serous carcinoma (LGSC) invading abdominal/pelvic organs or omental fat, usually with a desmoplastic reaction and an infiltrative margin||Micropapillary architecture whether or not there is obvious invasion, or solid epithelial nests with surrounding clefts in a fibrous stroma|
c Bell KA, Smith Sehdev AE, Kurman RJ: Refined diagnostic criteria for implants associated with ovarian atypical proliferative serous tumors (borderline) and micropapillary serous carcinomas. Am J Surg Pathol 25(4):419-432, 2001.
Noninvasive implants consist of two subtypes—epithelial and desmoplastic. Epithelial implants are composed of papillae resembling those within a borderline tumor. They are found either in mesothelial-lined invaginations of a peritoneal surface or between lobules of fat ( Fig. 25.22A and B ). Desmoplastic noninvasive implants consist of single cells, small epithelial islands, papillae, or cribriform glands encased in stroma, usually with inflammatory cells and psammoma bodies. The entire implant appears well circumscribed and has a “plastered on” rather than invasive infiltrative appearance (see Fig. 25.22C ). Early in their evolution, desmoplastic noninvasive implants may appear necrotic and inflammatory.
Invasive implants are composed of cells and cell patterns similar to those of well-differentiated serous carcinomas. They are almost always associated with stromal desmoplasia but, in addition, have an irregular, infiltrative-appearing border. They appear to invade underlying structures or replace fatty tissue rather than sitting indolently on the peritoneal surface or between fat lobules ( Fig. 25.23 ).
If underlying tissue is absent in a biopsy, the lesion is classified as noninvasive by default. However, because this is a common scenario, one reported study of implant morphology classified either a micropapillary pattern alone or solid epithelial nests surrounded by clear spaces or clefts in a fibrous stroma ( Fig. 25.24 ) as invasive in the absence of an obvious infiltrative pattern. Using their expanded criteria, these authors found that of 60 patients with implants, 31 had the invasive type. Nineteen of these 31 patients had progressive disease, and six of them died. Of the 29 remaining patients, three had progression and two died. A caveat is that 25 of the 60 patients (45%) had micropapillary/cribriform areas in their primary tumor. This is a higher frequency than was found in two other studies of high-stage borderline tumors (where micropapillary/cribriform foci were present in only 21% of 146 ovarian tumors), suggesting that case selection may have skewed the data toward the finding of micropapillary foci in the implants. Nevertheless, these results suggest that an expanded definition of invasive implants is warranted.
Low- and High-Grade Serous Carcinomas
Serous carcinomas account for 39% to 62% of all epithelial carcinomas. Approximately 15% were originally considered to be stage I, versus 6% stage II, 49% stage III, and 30% stage IV. However, in current practice, it is unusual to encounter an HGSC without some form of extraovarian spread, because these tumors either arise in the distal fallopian tube with ready access to the perineal cavity or in a site that permits rapid spread, be it the superficial ovarian cortex, ovarian surface, or adjacent peritoneal surface. Thus, although the 5-year disease-free survival in stages I and II combined is estimated in the range of 80% versus 20% for stages III and IV, few HGSCs fall into the former category.
Serous carcinomas are bilateral in approximately 70% of cases. They range from a few centimeters to approximately 20 cm. They are much more variable grossly than benign or borderline tumors. Most are both cystic and solid, with a variable predominance of one or the other. The surface may be smooth but in most cases is irregular, with variably sized tumor masses growing on the capsule ( Fig. 25.25 ). Some tumors may be entirely superficial in their growth pattern; many of these probably arise in the distal fallopian tube ( Fig. 25.26A ). Early tumors or those previously treated with neoadjuvant chemotherapy can be exceedingly subtle (see Fig. 25.26B ).
Invasive Low-Grade Serous Carcinomas
On the basis of their nuclear features, almost all serous carcinomas can be divided into low-grade and high-grade types (grade 1 or grade 3), with the latter constituting the great majority of cases. LGSCs are often associated with areas that merge morphologically with SBTs ( Fig. 25.27A ); they typically combine the features of both an extensive papillary architecture (often with many psammoma bodies) and evidence of stromal invasion (see Fig. 25.27B ). The latter may consist of infiltrating gland-like structures or more commonly, multiple papillae projecting into a space or embedded in a fibrous stroma that may also contain glands, cysts, irregular islands of tumor cells, or cribriform glands (see Fig. 25.27B ). Often the invasive papillae are surrounded by a clear space, possibly caused by fluid secreted by tumor cells (see Fig. 25.27C ) and occasionally demonstrate a “macropapillary” invasive architecture ( Fig. 25.27D ). Nuclei are uniform, round, or oval with evenly distributed chromatin, with or without a prominent nucleolus ( Fig. 25.28 ). At this point in the spectrum of low-grade serous tumors, cilia are inconspicuous. The mitotic index is usually less than 10 per 10 high-power fields. In some cases, a conspicuous micropapillary or cribriform component may be present ( Fig. 25.29 ; see Fig. 25.27A ) with underlying invasion.
Peritoneal invasion by LGSC is an extension of the spectrum of invasive implants in borderline tumors. In contrast to the latter, the abundance of metastatic deposits and its nuclear morphology are more in keeping with a frankly malignant process. This can take the form of numerous nests of invasive tumor, more loosely arranged clusters of papillae ( Fig. 25.30A ), the latter of which might be delicate and might mimic a noninvasive implant (see Fig. 25.30B ). A rare variant of low-grade carcinoma and one that appears to predominate, if not originate in, the peritoneum is the “psammocarcinoma.” This tumor contains a marked preponderance of psammoma bodies to the point where the epithelial cells may be overlooked (see Fig. 25.30C ). Peritoneal metastases from either of these low-grade malignancies can focally mimic adhesions or noninvasive implants from a borderline tumor, but they will invariably demonstrate invasion into underlying tissues that equals or exceeds that seen in invasive implants described previously.
Nodal metastases can occur in LGSCs. They are typically more confluent and actively replace the nodal parenchyma (see Fig. 25.30D ).
Low- Versus High-Grade Serous Carcinoma
The pathologist who is contemplating the diagnosis of an HGSC of the ovary typically must make two distinctions: (1) whether the tumor is high- or low-grade serous and (2) whether it is an endometrioid carcinoma. As mentioned earlier, the separation of LGSC from HGSC might be difficult for two reasons. First, some tumors fall into a category of intermediate grade. Second, some LGSCs have areas virtually indistinguishable from HGSC.
LGSCs should not display accumulation of nuclear p53 protein, because they arise independent of perturbations in this pathway. Thus, they typically display focal or patchy staining ( Fig. 25.31A ). In fact, the presence of some staining, as will be discussed later, is helpful in that it implies the presence of an intact TP53 gene. Tumors displaying greater degrees of nuclear atypia might still be considered low-grade carcinomas (see Fig. 25.31B ). However, if they contain strong (or completely absent) staining for p53, they are best placed in the HGSC category (see Fig. 25.31C ). In essence, designation of grade 2, although justifiable for tumors that fall into a morphologic gray zone, has little practical value. Using p53 immunohistochemistry, the pathologists must attempt to determine the tumor grade for the purposes of prognosis and management.
High-Grade Serous Carcinomas
HGSCs display a range of morphologic patterns including (1) classic HGSC and (2) SET patterns. The two are distinguished primarily based on growth pattern and the fundamental, consistent feature is enlarged nuclei, usually with prominent nucleoli and many mitoses, which are often abnormal.
Classic HGSC is immediately recognized as “serous carcinoma.” The range of pleomorphism is broad and may include bizarre cells ( Figs. 25.32 through 25.34 ). The architectural features are more variable, including large papillae (see Fig. 25.31B ); smaller papillae may be frequent or sparse, small, or large ( Fig. 25.35A ) and micropapillary architecture devoid of supporting stroma (see Fig. 25.35B ). Foci showing neither distinct papillary nor glandular architecture with slit-forming fenestrations are common ( Fig. 25.36 ). The stroma is fibrous, desmoplastic, edematous, or myxoid. Psammoma bodies may be plentiful, infrequent, or absent. There may be extensive necrosis. Additional patterns that are distinctly “nonserous” in their appearance include foci of squamous differentiation, osseous metaplasia, intracytoplasmic lumina with mucinous inclusions, a microcystic appearance ( Fig. 25.37A ), intracellular or extracellular hyaline globules, multinucleated cells sometimes resembling syncytiotrophoblasts (often beta–human chorionic gonadotropin [β-hCG] positive), an adenoid cystic–like pattern, a yolk sac tumor–like reticular pattern, and mural nodules of sarcoma or anaplastic carcinoma.
SET (solid, endometrioid-like, and transitional) patterns of HGSC are the group that are not always readily classified as HGSC, because they lack the striking features attributed to the classic group, mainly they show a predominance of more solid growth with less striking atypia. In addition to their morphologic features, SET variants have the following attributes: (1) they have been described somewhat more frequently in association with BRCA1 inactivation or germ-line mutations, (2) they have been observed to have a higher rate of chemoresponsiveness, and (3) they a significantly lower frequency of association with STIC than the classic type.
SET patterns include the following: (1) solid resembling grade 3 endometrioid, with the exception of somewhat higher nuclear grade; (2) pseudoendometrioid, with well-defined glands with partial preservation of pseudostratified epithelium; and (3) transitional, essentially a solid pattern with stromal cores lending a resemblance to a urothelial tumor yet retaining a müllerian immunophenotype (PAX8, WT1, CK7, p53 positive, and CK20 negative) (see Fig. 25.37B and C ). Another pattern that might be encountered is “undifferentiated.” Typical serous morphology may not be seen and the diagnosis may require immunostaining. In such cases, we simply apply the term “high-grade müllerian adenocarcinoma.”
Determining the Origin of High-Grade Pelvic Serous Carcinoma
Potential origins for HGSC are detailed earlier in this chapter, and there are a number of recent publications promoting algorithms to ascertain the probable origin of HGSCs. To summarize what is known:
The only epithelium that contains a serous carcinogenic sequence that can be agreed on is the distal fallopian tube and endometrial lining, the former being the putative source in a very high percentage of incidentally discovered extrauterine HGSCs in asymptomatic women.
An STIC cannot be found in approximately 60% of symptomatic women with HGSC.
Some STICs are very likely intramucosal metastases rather than primary lesions.
Other sources, including ovarian adenofibromas and endometriomas, as well as endosalpingiosis and pelvic ovarian surface epithelium, are under consideration but have yet to yield a definable carcinogenic sequence. We do recommend noting the presence of any potential precursor sequence, including STIC ( Fig. 25.38 ). For management purposes and staging, STIC is not a critical component unless found in isolation, and we do not resort to the more traditional approaches to sorting out origin at this time.
In our diagnostic practice, we adhere to the following guide:
Stage I tumors involving the ovary or fallopian tube are classified as such and assigned to the organ of origin.
Higher stage tumors are simply classified as HGSC, irrespective of whether they are on the ovary, mesosalpinx, pelvic peritoneum, or endosalpinx.
If STIC or a serous tubal epithelial proliferation/lesion is identified, it is noted in the report.
If the endosalpinx is involved by tumor, it is noted in the report.
Any associated ovarian or extraovarian features, including borderline or lower grade serous tumors, adenofibromas, endometriosis, or benign mullerian remnants (endosalpingiosis), are noted in the report.
The tumor is staged according to the FIGO guidelines.
This approach provides for the acquisition of data that might be relevant to site of origin, should this become an important management issue in the future. At this time, staging does not require assigning a specific site of origin; however, many advocate assigning the site of origin to the fallopian tube, ovary, or peritoneum.
Differential Diagnosis of Serous Neoplasms
Benign Serous Tumors
The principal issue with benign serous tumors is their distinction from non-neoplastic cysts or surface epithelial changes . Serous surface papillary adenofibromas should be at least 1 cm in greatest extent to be considered neoplastic. Small, knobby, fibrous protrusions on the surface of the ovary are common. Sometimes they are submitted for frozen section with the clinical suspicion of an implant or small carcinoma.
The rare rete cystadenoma resembles a serous cystadenoma. However, it is located in the ovarian hilus and lined by nonciliated cuboidal, columnar, or flattened epithelial cells, often forming an undulating or creviced appearance. There is smooth muscle in the wall, and hilus cells are often present.
The epithelium of an endometrioid adenofibroma can resemble serous epithelium except for the lack of cilia. The distinction in some cases is arbitrary. When uncertain, we simply classify these as benign cystadenofibromas.
Many borderline epithelial tumors of the ovary consist of both ciliated and secretory cells, or both and endometrioid differentiation, and it can be argued that the classification of a given tumor will depend on the direction in which the differentiation pathway is tilting. Endocervical-like (müllerian) mucinous and mixed epithelial (mucinous, ciliated, and endometrioid) borderline tumors, as well as lower grade mixed endometrioid and serous carcinomas, typify this spectrum and are classified accordingly. This group may be associated with endometriosis or hemorrhagic cysts, suggesting at least a form of endometriosis.
The retiform variant of Sertoli-Leydig cell tumor is papillary and may simulate an SBT or LGSC ( Fig. 25.39 ). However, it contains other features of a Sertoli-Leydig cell tumor, is usually found in teenagers and young women, and may be androgenic.
Because of overlapping features, serous carcinomas are most commonly confused with other epithelial-stromal tumors, either of the endometrioid, clear cell, or transitional cell type. Less frequently, other papillary neoplasms, such as the retiform Sertoli-Leydig cell tumor (discussed earlier), mesothelioma (discussed later), metastatic serous carcinomas from elsewhere in the female genital tract, or papillary carcinomas from distant sites, such as the breast, can mimic ovarian serous carcinoma.
Unlike serous carcinomas, low-grade endometrioid carcinomas may have squamous foci or aggregates of low-grade spindle cells without obvious keratinization blending with glandlike spaces. Psammoma bodies are rare in endometrioid carcinomas, and endometrioid papillary areas are usually villous rather than broad based and complex as in serous carcinomas. Endometriosis may accompany endometrioid tumors but is only rarely demonstrated with serous tumors. Immunostaining for the Wilms tumor gene, WT-1 , may be of assistance but in lower grade tumors is less likely to be needed. There is strong WT-1 nuclear staining in most serous carcinomas, but most endometrioid carcinomas stain only weakly or not at all. An equally promising biomarker is p16, which is diffusely positive in HGSCs and patchy in distribution in low-grade serous tumors and low-grade endometrioid carcinomas. However, it will not distinguish between high-grade serous and high-grade endometrioid carcinomas.
Clear cell carcinomas with papillary architecture can resemble serous carcinomas. However, most of the epithelial cells have either clear or oxyphilic cytoplasm and a characteristic nucleus with an angular periphery and a prominent nucleolus. The papillary cores are often hyalinized in clear cell carcinomas, and there are almost always other characteristic patterns. As with endometrioid carcinomas, residual endometriosis may be present. Immunohistochemistry may aid in this distinction, as clear cell carcinomas uncommonly demonstrate aberrant p53 staining, and are often positive for HNF1-B, Napsin A, and AMACR. Additionally, WT-1 is typically strongly positive in the nuclei of HGSC, whereas it is generally negative in clear cell carcinoma.
Transitional cell carcinomas associated with Brenner tumors or endometrioid adenocarcinomas conceivably might be confused with the transitional (SET) pattern of HGSC. The latter display greater nuclear atypia and will be p53 positive, and the associated benign Brenner tumor will not be seen.
Malignant mesotheliomas may sometimes be primarily or exclusively confined to the ovaries ( Fig. 25.40 ). They are often both papillary and solid and may simulate either an SBT or a carcinoma. The papillae of mesotheliomas have hyaline cores and are less complex than those of serous tumors. Although there are exceptions, mesothelioma cells are usually less stratified and pleomorphic than those of serous carcinomas. They have a round to oval nucleus with fine chromatin, a small nucleolus, and densely eosinophilic cytoplasm. The majority of serous carcinomas mark positively for a variety of epithelial markers, including epithelial membrane antigen (EMA), CAM-5.2, AE-1/AE-3, CK-7, B-72.3, LeuM-1, CA-125, Pax8, and WT-1 (nuclear staining), some of which overlap with mesothelioma. Serous carcinomas are negative for CK-20, calretinin, D2-40, and other mesothelial markers. Additionally, Bap1 loss by immunohistochemistry supports a diagnosis of malignant mesothelioma.
Serous carcinomas of the endometrium may metastasize to the ovaries, bringing up the question of origin when both organs are involved. These cases are best evaluated by assessing the volume of tumor, depth of penetration, and vascular invasion in the uterus compared with the location and extent of the tumor in the ovaries. WT-1 immunostaining may be helpful. It is generally strongly and diffusely positive in primary ovarian serous carcinomas and either negative or only focally positive in uterine serous carcinomas. One study showed that nearly all peritoneal serous carcinomas scored positive for WT-1, whereas only 20% of uterine tumors did. In another study, small carcinomas in a uterine polyp were typically WT-1 negative, even when associated with considerable peritoneal disease. Thus, the percentage of superficial uterine serous carcinomas that can be attributed to a peritoneal primary is considered small. Conversely, with increasing use of the Sectioning and Extensively Examining the FIMbriated End (SEE-FIM) protocol for evaluating tubes in uterine serous carcinomas, it is accepted that associated STICs are often mucosal metastases from the uterus.
Cervical “Papillary Serous Carcinoma,” p53 and p16 Staining
A small subset of cervical adenocarcinomas have been classified as papillary serous carcinomas owing to their close resemblance to their counterparts in the upper genital tract. Like the latter, they are intensely positive for p16, and this marker will not distinguish the two groups. However, TP53 mutations do not characterize the cervical carcinomas, and a p53 stain should be weakly positive and heterogeneous (“wild-type” pattern) ( Fig. 25.41A ). If the stain is either diffuse and intensely positive or completely negative (“mutation-type” pattern), a diagnosis of a metastasis from the upper genital tract should be considered (see Fig. 25.41B and C ). The latter is an important distinction. We have seen examples of HGSCs that have metastasized to the cervix but were devoid of p53 staining because the antigenic targets on the protein had been lost due to mutation, resulting in a null “mutation-type” staining pattern.
Serous Versus Endometrioid Carcinoma
The distinction of serous from endometrioid carcinoma is a common conundrum in the endometrium due to both the spectrum of morphologies that might defy precise separation and some immunophenotypic overlap. p53 staining may help in some cases, and the presence of squamous differentiation will exclude a serous neoplasm. If a case proves impossible to classify, a diagnosis of “high-grade müllerian carcinoma” is permissible. Examples of such endometrioid tumors are illustrated under the section on high-grade endometrioid carcinomas (see Fig. 25.107 , later).
General Features and Clinical Aspects
Mucinous tumors of the ovary, which represent the second most common type of epithelial-stromal neoplasm, are characterized by mucin-containing epithelial cells that resemble the mucinous epithelium of the endocervix (endocervical-type) or gastrointestinal tract (intestinal type). In the United States and Europe, they account for 12% to 15% of all ovarian tumors; however, in Japan, they account for a higher percentage of ovarian tumors overall. About 80% of mucinous ovarian tumors are benign, 10% are borderline, and 10% are malignant. Mucinous carcinomas have been reported to account for 9% to 13% of malignant epithelial-stromal tumors ; however, the relative and absolute frequencies of both borderline and malignant mucinous tumors are not known (and have been changing) because of (1) differing criteria that have been used to distinguish them and (2) the likelihood that many mucinous carcinomas that were actually metastatic to the ovaries were considered to be primary tumors (both borderline and malignant) before criteria to separate these two possibilities were better understood. For instance, in a report in which the authors took these more recent insights into account, mucinous carcinomas accounted for only 2.4% of 124 ovarian epithelial carcinomas in Washington, DC.
The average age of patients with carcinomas and borderline tumors is the early to mid-50s, whereas patients with benign mucinous tumors are somewhat younger. In contrast to other epithelial-stromal tumors, ovarian mucinous tumors may occur in teenagers and young adults as well, although their occurrence in this age range is still uncommon.
Mucinous tumors usually cause signs and symptoms that are similar to those of ovarian tumors in general. However, they are the most common of the non-endocrine-cell ovarian tumors to be accompanied by hormonal manifestations—most often estrogenic or androgenic. This is likely caused by activation of tumor stromal cells to produce steroids. Rarely, neoplastic neuroendocrine cells from the cyst lining may secrete gastrin or serotonin, causing the Zollinger-Ellison or carcinoid syndrome. About 5% of mucinous tumors have a separate component of dermoid cyst ; less commonly, they are associated with a Brenner tumor.
Serum CA-125 levels have not been as sensitive for mucinous carcinomas as for other epithelial malignancies; in one study, only six of 17 patients with both advanced-stage and localized mucinous carcinomas had elevated CA-125 levels. Conversely, serum carcinoembryonic antigen (CEA) CA-19-9 and CA-72-4 were more sensitive for mucinous carcinomas than for other tumor types.
Mucinous epithelial stromal tumors are currently classified into the following general categories ( Table 25.4 ; see Table 25.2 ): (1) benign, (2) borderline, (3) malignant, (4) mucinous cystic tumors with mural nodules, and (5) mucinous cystic tumors associated with pseudomyxoma peritonei. Benign mucinous tumors consist of cystadenomas (by far the most common), adenofibromas, and cystadenofibromas. Mucinous borderline tumors are further subclassified into two major histologic subtypes: the intestinal type, accounting for about 85% of the total, and the endocervical-like (müllerian) type. A third type is characterized by pyloric differentiation, is rare, and has been associated with Peutz-Jeghers syndrome. These tumors are present for gastric markers including MUC6. Variants of the first two types—intestinal and endocervical mucinous borderline tumors—include those with (1) atypia only, (2) intraepithelial carcinoma, and (3) microinvasion. Mucinous carcinomas are classified into two subtypes based upon their growth pattern: (1) expansile and (2) infiltrative.
|Intestinal Type (With Atypia Only)||Intestinal Type With Intraepithelial Carcinoma||Endocervical-Like|
|Gross||Large, smooth-surfaced multilocular cyst, cyst linings smooth to rough, bilateral in 5%||Same||Smaller, fewer cysts, may be associated with endometriosis, bilateral in 40%|
|Microscopic||Cysts or glands lined with slightly stratified mucinous columnar cells and goblet cells, thin papillae with stromal cores, mild nuclear atypia||Same, with foci of malignant-appearing nuclei, often highly stratified, papillary, or cribriform||Cysts with broad papillae lined by endocervical-like mucinous cells and stratified eosinophilic cells, numerous neutrophils|
|Appearance of extraovarian disease||Pseudomyxoma peritonei (PP) a||Invasive peritoneal implants without PP b||Noninvasive or invasive peritoneal implants, no PP|
|Usual behavior in cases with extraovarian disease||Variable; usually persistent or recurrent over many years, eventually fatal in 40% to 50%||Similar to carcinomas, most are fatal in a few years or less||Benign c|
Stage I mucinous borderline tumors (with atypia only) are almost always benign, with a recorded recurrence rate of less than 1%. Many reported cases of intestinal mucinous borderline tumor higher than stage I at the time of initial staging have had the clinical appearance of pseudomyxoma peritonei. However, in the majority of these cases, the ovarian tumor(s) were metastatic from the appendix or, less commonly, from elsewhere in the gastrointestinal tract (see the “ Pseudomyxoma Peritonei ” section for further information). Some have reported recurrence of stage I mucinous borderline tumors associated with surgical adhesiolysis. A small subset of patients with endocervical mucinous borderline tumors also present with extraovarian disease; however, the clinical course appears to be indolent and no deaths have been reported. Nevertheless, relatively few cases with long-term (more than 10 years) follow-up have been reported. Therefore, continued clinical follow-up is mandatory to exclude the possibility of recurrence.
For stage I intestinal mucinous borderline tumors with intraepithelial carcinoma, the recurrence rate is approximately 6.5%. In cases with recurrence, or in cases that are higher than stage I, the metastases have been in the form of invasive abdominal implants (rather than pseudomyxoma peritonei) and the prognosis has been poor, similar to that of high-stage invasive mucinous carcinomas. In these cases, it is likely that areas of invasion in the primary tumor were not sampled. The presence of intraepithelial carcinoma and microinvasion in endocervical-like mucinous borderline tumors does not appear to have an adverse effect on patient outcome, because no recurrences have been reported (however, very few cases have been reported).
Stage I mucinous carcinomas have recurred in 10.8% of cases, whereas persistence or recurrence and often a fatal outcome have been reported in 92% of higher stage cases.
Mucinous tumors are the largest of all ovarian tumors. One was reported to weigh more than 300 pounds. Only about 5% of cystadenomas and intestinal-type borderline tumors are bilateral, and stage I mucinous carcinomas are almost always unilateral. However, endocervical-like borderline tumors are bilateral in 30% to 40% of cases. They are smaller than other mucinous tumors and may be adjacent to or within an endometriotic cyst.
Most mucinous tumors are smooth-surfaced, variably solid, but typically multicystic masses that are filled with translucent viscous fluid ( Figs. 25.42 and 25.43 ). They may also be unilocular cysts and when smooth and brown to cream in color are often of the müllerian (endocervical) type ( Fig. 25.44 ). Because mucinous tumors are notorious for their histologic heterogeneity, with malignant foci sometimes representing only a small component, it is extremely important to open and carefully examine each cyst and select areas that are most likely to correspond to the malignant foci, especially at the time of frozen section. In general, areas of malignant growth are usually solid or form readily identifiable papillary structures. It is important to note that borderline foci may be solid but typically reside within fleshy polypoid areas or excrescences in the cyst wall ( Fig. 25.45 ). Entirely malignant tumors (i.e., mucinous adenocarcinoma) may be predominantly solid with only small cysts and include both primary and metastatic tumors ( Figs. 25.46 and 25.47 ). The latter is an immediate concern at the frozen section bench if an obviously malignant mucinous tumor is bilateral. For practical purposes, if the tumor appears grossly benign (no solid or papillary growth, with smooth lined cyst[s]) and only morphologically benign foci are found in one or two frozen sections, we report it as a “mucinous cystadenoma.” However, if the frozen section(s) contains borderline areas, the clinician is notified that foci of carcinoma may be discovered on permanent sections, and a thorough intraoperative examination of the pelvis and abdomen for potential metastases should be performed. The decision to remove the uterus and opposite ovary depends on the clinical circumstances. At least two permanent sections per centimeter of maximal diameter tumor has been recommended to adequately sample mucinous tumors. This protocol may be excessive if the tumor is entirely cystic, with smooth cyst walls throughout it.
As mentioned earlier, cystic ovarian mucinous tumors are sometimes a component of the clinical syndrome of pseudomyxoma peritonei. In this setting, they are more frequently bilateral; they may be grossly similar to the usual mucinous tumor but are sometimes gelatinous, thin-walled, multicystic masses that differ from the tumors described previously ( Fig. 25.48 ). In either case, the ovarian tumors are almost always metastatic, with the primary tumor most often residing in the appendix, which should be removed and completely examined microscopically in all cases of pseudomyxoma peritonei (see the next section for further discussion).
Benign Mucinous Tumors: Cystadenomas, Cystadenofibromas, and Adenofibromas
These three tumors form a spectrum with varying proportions of epithelial-lined cysts, glands, and stroma. The cystadenoma is by far the most common, being composed of one or more thin-walled cysts that are lined by a single layer of mucinous columnar cells with benign-appearing, basally located nuclei ( Fig. 25.49 ). Mitotic figures may be present. There may also be occasional goblet cells and neuroendocrine cells, the latter requiring special stains for visualization. Sometimes small papillae with stromal cores project into the cysts; however, there is no associated epithelial stratification or tufting. The stroma may be fibrous or resemble ovarian stroma. In some instances, it may contain smooth muscle, luteinized cells ( Fig. 25.50 ), or calcifications. Because of cyst rupture and mucin extravasation, large areas of necrosis accompanied by histiocytes and inflammatory cells may be present ( Fig. 25.51 ). Adenofibromas and cystadenofibromas contain a grossly observable solid stromal component. Microscopically, they contain mucinous glands and small cysts uniformly distributed in a fibromatous stroma ( Fig. 25.52 ).
Borderline Mucinous Tumors: Intestinal and Endocervical-Like Types
About 85% of mucinous borderline tumors are of the intestinal type. These in turn make up three subtypes: (1) with atypia only, referred to simply as “borderline,” (2) with intraepithelial carcinoma, and (3) with stromal microinvasion.
Intestinal-Type Mucinous Borderline Tumors With Atypia Only
These differ from cystadenomas and cystadenofibromas in that, in addition to benign-appearing areas with a single layer of mucinous columnar cells with banal, basally located nuclei, other areas are characterized by the presence of epithelial cells that are crowded and stratified and often form either stroma-free papillary tufts or papillae with thin fibrous cores ( Figs. 25.53 and 25.54 ). In these foci, the nuclei are slightly enlarged and hyperchromatic and have increased mitotic activity, most noticeably at the base of the papillae ( Fig. 25.55 ). The epithelium has the morphologic appearance of intestinal epithelium with goblet cells ( Fig. 25.56 ) and sometimes Paneth cells. Neuroendocrine cells are also present but may require special stains for visualization. The gland and cyst lumens contain mucin, sometimes admixed with histiocytes and inflammatory cells. There may be areas of necrosis secondary to mucin extravasation .
Intestinal-Type Mucinous Borderline Tumors With Intraepithelial Carcinoma
If the epithelial cell nuclei appear cytologically malignant (significant nuclear enlargement, nuclear hyperchromasia, often prominent nucleoli) and there is no obvious stromal invasion, the suffix “with intraepithelial carcinoma” should be added to the diagnosis of mucinous borderline tumor ( Fig. 25.57 ). In most cases, there is prominent stratification of the malignant-appearing cells with stroma-free papillae or a cribriform pattern of growth ( Figs. 25.58 through 25.60 ).
Intestinal-Type Mucinous Borderline Tumors With Microinvasion
One or several small foci of stromal invasion, often inciting a desmoplastic response, may be present in a borderline tumor ( Fig. 25.61 ). If the invasive areas are all less than 10 mm 2 and less than 3 mm in any linear dimension, the tumor should be interpreted as “borderline with focal microinvasion,” further specifying the number of invasive foci. Areas of mucin extravasation with a fibrous and histiocytic response containing entrapped benign epithelial cells may be misinterpreted as invasion ( Fig. 25.62 ). Generally, true invasion will have more developed desmoplasia, fewer histiocytes, and more obviously malignant epithelial cells arranged in an infiltrative pattern. All reported stage I cases with microinvasion have had a benign clinical behavior.
Endocervical-Like Borderline Tumors
The low-power microscopic appearance, with broad bulbous papillae, associated with cell stratification and epithelial tufting, is similar to that of serous rather than the multicystic appearance of an intestinal-type mucinous borderline tumor ( Fig. 25.63 ). The papillae, however, are lined by both mucinous columnar cells resembling those of the endocervix and stratified polygonal eosinophilic cells ( Figs. 25.64 and 25.65 ). Characteristically, many acute inflammatory cells are present in the epithelial cell cytoplasm and in the extracellular mucin (see Fig. 25.65 ). Adjacent endometriosis may be present, and sometimes the tumor appears to arise from an endometriotic cyst. Nuclei are usually only slightly atypical, but rare cases with areas of intraepithelial carcinoma or microinvasion have been reported; the behavior of these has been benign. Even in the absence of identifiable stromal invasion, approximately 6% of endocervical-like borderline tumors have had either noninvasive or invasive-appearing abdominal and peritoneal implants ( Figs. 25.66 and 25.67 ) and rarely lymph node metastases. These have not, however, led to recurrences.