Molecular Pathogenesis

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.

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.

Serous borderline tumor (SBT). A, An opened cyst contains myriad small papillae. B, A surface borderline tumor projects from the cortex of the ovary (bottom).

The following characterize SBTs:

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  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%.

  
  
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  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.

  
  
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  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.

  
  
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  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.

  
  
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  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.

Serous borderline tumor (SBT). Broad, edematous papillae with numerous smaller daughter papillae projected into a cystic space.

Serous borderline tumor (SBT). Bland epithelial cells around the smaller papillae appear to be free floating in the extracellular space.

Serous borderline tumor (SBT) with mucoid material. A, Gross pathology. B, Stringy mucinous material occupies the extracellular space around the papillae.

Serous borderline tumor (SBT). Bland columnar cells with surface blebs surround the papilla.

Serous borderline tumor (SBT) in a pregnant woman. A, There is exuberant epithelial growth around the papillae. B, The epithelial cells are large with abundant eosinophilic cytoplasm.

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.”

Exuberant growth in a serous borderline tumor (SBT).

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:

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  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.

  
  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  A, Surface involvement by a borderline serous tumor. B, Microinvasion in a serous borderline tumor (SBT). Several round cells, some with a peripheral space, percolate through the stroma of a papilla. As in this example, they are often inconspicuous and easily overlooked. They may be highlighted with a keratin stain. C, Microinvasion in an SBT. Irregular epithelial islands in a stroma that appears to be reactive.

  
  
  
  
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  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.

  
  
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  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.

  
  

  
  

  
  

  

  
  

  
  

  Lymph node metastases in a borderline tumor (right). A focus of endosalpingiosis is on the left for comparison.

  
  
  
  
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  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.

  
  
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  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.

  
  

  
  

  
  

  

  
  

  
  

  Microcalcifications (salpingoliths) in the fallopian tube associated with a borderline serous tumor.

  
  

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.

Micropapillary growth pattern in a serous borderline tumor (SBT). A, Low-power image of numerous micropapillary clusters in an ovary. B, At higher power, long slender papillae radiate from a large central core. C, Cribriform growth pattern in an SBT. Complex ramifying cords and slim papillae are evident. D, Micropapillary growth pattern in an SBT at higher magnification. The nuclei are monomorphous. In this case, they are vesicular with small nucleoli. E, Cystic borderline tumor of the ovary with no surface or peritoneal involvement. F, There is single intracystic cribriform area in E (intraepithelial carcinoma). However, the risk of recurrence approximates that of a conventional borderline tumor.

( E, Courtesy of Dr. Eleanor Y. Chang.)

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:

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  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 ).

  
  
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  The recurrence rate for all SBTs/APSTs was only 5.3%, increasing steadily up to 10 years following surgery and then leveling off.

  
  
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  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.

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.

Micropapillary features can be mimicked or found in all serous tumors, including borderline tumors (A); low-grade serous carcinomas (LGSCs; B ); and high-grade serous carcinomas (HGSCs; C ).

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.

Reactive mesothelial cells in the peritoneum. The formation of small glandlike structures and cytoplasmic vacuoles is distracting, but the nuclei are bland.

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.

Omentum with endosalpingiosis. There is benign müllerian inclusion without papillarity or nuclear atypia within the omental fat.

Peritoneal Cytology

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.

A, Low-grade serous neoplasm in a peritoneal cytology. B, The cell block preparation suggests a borderline serous tumor, but ultimately the diagnosis must be made on tissue biopsy in such cases.

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 .

Table 25.3

Invasive Versus Noninvasive Implants of Serous Borderline Tumors

Noninvasive a		Invasive
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

 

a If underlying tissue is not present in the biopsy, the implant is considered noninvasive.

b Konstantinopoulos PA, Matulonis UA: Current status and evolution of preclinical drug development models of epithelial ovarian cancer. Front Oncol 3:296, 2013.

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.

Epithelial, noninvasive implant of a serous borderline tumor (SBT). A, Papillae with psammoma bodies, similar to those of an ovarian borderline tumor, appear to be free floating in the interstices of the omental fat. There is no stromal reaction. B, Another noninvasive implant loosely attached to the underlying adipose tissue. C, Desmoplastic noninvasive implant from an SBT. Two small islands of epithelial cells are present in a fibrovascular stroma that appears “plastered on” to the surface of the omentum.

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 ).

Invasive implants from a serous borderline tumor (SBT). A, Numerous epithelial islands are present in a fibrous and edematous stroma. The lesion appears to be expanding into and replacing the omental fat. B, Another invasive implant from a borderline tumor.

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.

A, Micropapillary implant. This has been added to the invasive implant group. B, Peritoneal implant with retraction artifact from a low-grade serous tumor. Some authors consider this finding in itself evidence of invasion.

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.

Low-grade serous carcinoma (LGSC). A, An exophytic component closely resembles a borderline tumor. B, An adjacent focus with stromal invasion. C, LGSC. The tumor at left is embedded in a desmoplastic stroma. On the right there is prominent retraction artifact, a feature associated with well-differentiated serous carcinomas. D, An unusual but easily recognized example of “macropapillary” invasion of the ovarian stroma by an LGSC. Large papillae of tumor are suspended in the stroma within spaces that are largely unlined in keeping with retraction artifact.

A, Low-grade serous carcinoma (LGSC). The papillae are lined by nuclei with only slight atypia. Mitotic figures are absent in this field. Cilia are typically inconspicuous but can be present in areas of the tumor that appear to be more benign. B, Papillary LGSC. An extensive micropapillary component (center) is associated with adjacent stromal invasion (right).

Low-grade serous carcinoma (LGSC) merging with a higher grade component. A, At lower magnification the growth pattern is characteristic of LGSC. B, The p53 immunostain is characteristic of wild-type. Another area of tumor has a different growth pattern (C) and exhibits conspicuous atypia (D). This may not be synonymous with high-grade serous carcinoma (HGSC) but reflects biologic progression of the tumor and might include regional acquired mutations in TP53 in some cases.

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.

Patterns of peritoneal invasion by low-grade serous tumors. A, Loosely arranged but dense cellular aggregates. B, Smaller papillae at high density in loose connective tissue. C, Massive involvement of the peritoneal surface by invasive well-differentiated tumor with psammoma bodies (psammocarcinoma). D, Lymph node metastasis from a low-grade serous carcinoma (LGSC).

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.

p53 immunostaining patterns in serous carcinoma. A, A low-grade tumor displays focal staining consistent with an intact TP53 gene. B, Moderately differentiated (grade 2) serous carcinoma. There is focal micropapillary morphology. C, At higher power, the tumor exhibits uniform epithelial clusters. However, they are strongly p53 positive in keeping with a high-grade serous tumor (inset).

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.

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  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.

  
  

  
  

  
  

  

  
  

  
  

  High-grade serous carcinoma (HGSC). The nuclei are large with prominent nucleoli.

  
  

  
  

  
  

  

  
  

  
  

  High-grade serous carcinoma (HGSC). This illustrates a moderate degree of pleomorphism.

  
  

  
  

  
  

  

  
  

  
  

  A further example of a high-grade serous carcinoma (HGSC). In this case, there is extreme pleomorphism with bizarre, convoluted nuclear shapes.

  
  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  Papillary serous carcinoma. A, Papillary architecture and high-grade nuclei are evident. B, Fine micropapillae in a high-grade serous carcinoma (HGSC).

  
  

  
  

  
  

  

  
  

  
  

  Papillary serous carcinoma. Papillae are less evident and growth is more solid with interspersed ramifying slitlike spaces.

  
  

  
  

  
  

  

  
  

  
  

  SET (solid, endometrioid-like, and transitional) patterns of high-grade müllerian carcinoma that are considered by many to be variants of serous carcinoma. A, Grade 3 endometrioid adenocarcinoma for comparison. B, Solid pattern of high-grade serous carcinoma (HGSC). Note the greater variation in nuclear morphology and staining. C, Endometrioid-like pattern of HGSC shows some preservation of pseudostratification. D, The “transitional” preserves some papillary morphology. Note however the high nuclear grade in keeping with a variant of HGSC.

  
  
  
  
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  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:

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  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.

  
  
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  An STIC cannot be found in approximately 60% of symptomatic women with HGSC.

  
  
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  Some STICs are very likely intramucosal metastases rather than primary lesions.

  
  
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  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.

  
  

  
  

  
  

  

  
  

  
  

  Coexistence of serous tubal intraepithelial carcinoma (STIC) and high-grade serous carcinoma (HGSC). A, HGSC. B, Coexisting STIC. C, Hemorrhagic cyst of the ovary with HGSC. D, At higher magnification. Strong p53 staining is seen in the inset.

  
  

In our diagnostic practice, we adhere to the following guide:

• 1.
  

  Stage I tumors involving the ovary or fallopian tube are classified as such and assigned to the organ of origin.

  
  
• 2.
  

  Higher stage tumors are simply classified as HGSC, irrespective of whether they are on the ovary, mesosalpinx, pelvic peritoneum, or endosalpinx.

  
  
• 3.
  

  If STIC or a serous tubal epithelial proliferation/lesion is identified, it is noted in the report.

  
  
• 4.
  

  If the endosalpinx is involved by tumor, it is noted in the report.

  
  
• 5.
  

  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.

  
  
• 6.
  

  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.

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.

Borderline Tumors

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.

Retiform variant of Sertoli-Leydig cell tumor.

Serous Carcinomas

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.

Malignant mesothelioma involving the peritoneum (A), involving the ovarian surface (B), and at high grade involving the ovarian surface (C).

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.

A, Papillary “serous” carcinoma of the cervix retains a wild-type pattern of p53 immunopositivity (lower right inset). However, like high-grade ovarian serous carcinomas, it will stain strongly for p16 (lower left inset). B, A high-grade serous carcinoma (HGSC) is intensely and diffusely positive. C, Another HGSC is devoid of p53 staining, consistent with a truncating mutation.

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).

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 ).

Mucinous cystadenoma. The cyst lining cells are columnar with pale cytoplasm and basal nuclei.

Mucinous cystadenoma with stromal luteinization. The pale luteinized stromal cells cling to the periphery of the epithelial lining cells. These cells may sometimes be the source of hormone production in mucinous tumors.

Mucinous borderline tumor with extravasation of mucin and histiocytes.

Mucinous adenofibroma. Benign-appearing glands are present in a fibrous stroma.

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 .

Mucinous borderline tumor, intestinal type. Two benign cysts flank a cyst lined with proliferative epithelium.

Mucinous borderline tumor, intestinal type. The proliferative cells line papillae with thin fibrous cores.

Mucinous borderline tumor, intestinal type. Low-grade mucinous epithelial cells with pseudostratification resulting from the plane of sectioning of the papillae.

Mucinous borderline tumor, intestinal type. Columnar cells and goblet cells are present.

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 ).

Mucinous borderline tumor with intraepithelial carcinoma. Malignant-appearing epithelial cells with only minimal stratification.

Mucinous borderline tumor with intraepithelial carcinoma. At low power, the cysts are lined by stratified epithelium with and without mucinous cytoplasm.

Mucinous borderline tumor with intraepithelial carcinoma. There is marked stratification of crowded cells that have a cytologically malignant appearance.

Mucinous borderline tumor with intraepithelial carcinoma. A cribriform intracystic growth pattern is present.

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.

Mucinous borderline tumor with microinvasion. Single cells appear to break off into the stroma from adjacent glands.

Mucinous borderline tumor with pseudoinvasion. A strip of benign-appearing mucinous cells is present in a large field of histiocytes secondary to cyst rupture and mucin extravasation.

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.

Endocervical-like mucinous borderline tumor. The low-power appearance mimics a serous borderline tumor (SBT) with bulbous papillae.

Endocervical-like mucinous borderline tumor. The papillae are lined by benign-appearing mucinous cells that resemble those of the endocervix.

Endocervical-like mucinous borderline tumor. In this focus, highly stratified eosinophilic cells line the papillae. There are numerous leukocytes in the papillae and in the mucin.

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