Epithelial Ovarian Tumors: Serous Tumors, Mucinous Tumors, and the Approach to Ovarian Tumor Diagnosis

Gross features ( Figs. 13.1 – 13.2 )

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  Serous cystadenomas are composed of one or more thin-walled cysts with watery fluid and a lining that is smooth or with soft to firm, polypoid excrescences composed almost entirely of stroma. The tumors are bilateral in up to 20% of cases.

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  Serous surface papillomas appear as polypoid excrescences on the outer surface of one or both ovaries.

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  Serous adenofibromas and cystadenofibromas are typically hard, white to yellow-white, predominantly solid, fibromatous tumors that contain glands or fluid-filled cysts that may bear polypoid excrescences that vary from firm to soft.

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  The excrescences and the hard consistency of the stromal component in some tumors may prompt an erroneous gross impression of carcinoma.

Microscopic features ( Figs. 13.3–13.5 )

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  The cysts and polypoid stromal excrescences (that may be densely collagenous or markedly edematous) are typically lined by an epithelium similar to that of the fallopian tube, including ciliated cells and less numerous nonciliated secretory cells.

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  There is usually a single layer of cells but particularly when the wall is somewhat fibrous, benign glands may involve the cyst wall and even exhibit a cribriform pattern.

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  Tumors lined entirely by nonspecific, cuboidal or columnar nonciliated epithelium are also generally classified as serous, but some may actually be of endometrioid type, the distinction being subjective in some cases. A search for often subtle foci of endometriosis usually indicates an endometrioid nature.

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  Focal limited proliferation less than that of a borderline tumor may be seen and the suffix ‘with focal atypia’ or ‘with focal proliferation’ may be added.

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  Psammoma bodies may be present, but are generally inconspicuous.

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  The stroma of some tumors, presumably due to denudation of the cyst lining, may contain histiocytes.

Differential diagnosis

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  Epithelial inclusion cyst with serous features. This distinction is based arbitrarily on size, the lesion being considered neoplastic if >1 cm.

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  Surface stromal proliferations ( Chapter 12 ). These, in contrast to surface serous papillomas, are usually multifocal and microscopic.

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  Endometriotic cyst. This diagnosis may be suggested by collections of foamy and/or pigmented histiocytes, but endometriotic epithelium and stroma are absent.

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  Endometrioid adenofibroma. These tumors have stratified, predominantly nonciliated epithelial cells; squamous differentiation may be present.

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  Rete cystadenoma ( Chapter 17 ). Differential features include a hilar location, mural hilus cells or smooth muscle, and a lining with small crevices and cells with rare or no cilia.

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  Cystic struma ovarii ( Chapter 15 ). Follicles (often rare and attenuated within the cyst wall) with colloid, an absence of cilia, and reactivity for TTF1 or thyroglobulin establish the diagnosis.

Gross features ( Fig. 13.6 )

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  SBTs are bilateral in 25–40% of cases and typically unilocular or multilocular cystic masses with a mean diameter of 10 cm. The intracystic fluid is usually watery, but may be mucoid, suggesting a mucinous tumor. Solid areas, present in a third of tumors, usually represent a fibromatous component (serous adenofibroma or cystadenofibroma of borderline malignancy).

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  Polypoid to papillary excrescences (imparting a velvety appearance) usually form part or most of the cyst lining, the ovarian surface (serous surface papilloma of borderline malignancy), or both. Surface involvement is present in 30% (stage I) to 50% (all stages) of tumors.

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  Occasional tumors are a serous surface papillary tumor of borderline malignancy in which velvety surface tumor often covers an otherwise normal ovary.

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  Proposed sampling recommendations are:

  • Primary tumors: at least 1 block/cm of tumor diameter for tumors <10 cm and 2 blocks/cm for larger tumors. Sections should also be taken from areas that differ in appearance (fleshy, necrotic, hemorrhagic) to exclude serous carcinoma. Blocks of exophytic (surface) tumor and ruptured locules should be separately identified.

  • Omentum (if grossly negative): at least 1 block/2 cm of the largest dimension.

Usual microscopic features of primary tumors ( Figs. 13.7–13.19 )

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  Low-power examination typically reveals intracystic or serosal papillae with fibrous or edematous cores often accompanied by an orderly invagination of papillae and glands into a fibromatous stroma.

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  The papillae are typically complex with a hierarchical branching pattern in which progressively smaller fibrous-cored papillae are in turn covered by stratified tumor cells that form cellular tufts or buds. Some tumor cells are exfoliated or appear detached because their point of attachment is not in the plane of section.

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  The tumor cells are mostly columnar with a modest amount of cytoplasm. Some cells, typically apical, contain copious eosinophilic cytoplasm; ciliated cells are also usually present and hobnail cells may also be seen. Some glands may have an endometrioid-like appearance. Luminal mucin may be conspicuous and cytoplasmic mucin, if present, is confined to the tips of the cells.

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  The nuclear atypia varies from mild to moderate, but rare cells with greater atypia may be present. Mitotic figures are usually infrequent and nucleoli are only occasionally conspicuous.

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  Luminal or stromal psammoma bodies are often present and may be numerous. Stromal infiltrates of foamy histiocytes, sometimes in response to denudation of the epithelial lining cells, should not be misinterpreted as indicating an origin from endometriosis with which SBTs are only rarely associated.

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  Infarction of the fibrous-cored papillae may be seen that may elicit a desmoplastic response with entrapment of tumor cells, potentially mimicking an autoimplant (see next heading) or invasion.

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  Small foci of borderline tumor may be a focal or multifocal finding in an otherwise typical serous cystadenoma.

  • When <10% of the tumor is borderline tumor, some have used the terms ‘focally proliferative’ or ‘focally atypical’ serous cystadenoma because of an uneventful follow-up in some studies. Allison et al. found that when the borderline foci accounted for <20% of the tumor and were exclusively intracystic, there were no associated implants.

  • Ramalingam et al., however, found that rare tumors with these features have been associated with extraovarian implants. Additionally, Longacre et al. have found that some tumors with <10% borderline component are followed by an ipsilateral or contralateral typical SBT.

  • Descriptive diagnoses such as ‘serous cystadenoma with focal proliferation’ may be used with an accompanying notation specifying the proportion of the tumor that is proliferative (borderline appearing). Some may prefer to designate such a tumor as ‘benign serous tumor with a minor borderline component’.

  • Whatever terminology is used for these neoplasms, the proportion of the tumor that is composed of borderline neoplasia and whether or not the latter involves the ovarian surface should be specified. Irrespective of the specific term elected, communication with the treating physician is most important.

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  The stroma of SBTs usually is paucicellular and fibrous but may have a loose edematous appearance and/or contain inflammatory cells. A hypercellular stroma (that is most common in endometrioid tumors) is only occasionally seen and rarely may suggest a granulosa cell tumor although in one reported case of this type that component was FOXL2 negative.

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  Florid mesothelial hyperplasia in the wall and on the surface of the tumor is occasionally present ( Chapter 20 ).

Unusual microscopic features of primary tumors ( Figs. 13.20–13.25 )

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  Micropapillary (including cribriform) pattern.

  • This pattern, which occurs in 5–10% of SBTs, is synonymously referred to in the 2014 WHO classification as ‘noninvasive low-grade serous carcinoma’. We and others prefer and continue to use (and do so here) ‘micropapillary SBT’ (MSBT) to denote this finding as long as cytologic findings do not warrant a diagnosis of carcinoma.

  • A size requirement of ≥5 mm for the micropapillary focus was initially proposed for a diagnosis of MSBT, although Vang et al. (2017) in a later study with long follow-up found that even a 1 mm micropapillary focus was prognostically significant.

  • Compared to typical SBTs, MSBTs more often exhibit or are associated with bilaterality, a surface component, microinvasion, stage II or III disease due to extraovarian implants (even in entirely intracystic tumors), invasive implants, and lymph node involvement that may represent metastases or independent primaries.

  • Long (arbitrarily defined as 5× longer than wide), filiform, nonbranching papillae with minimal or absent stromal cores emanate directly from large, smoothly contoured, stromal-cored papillae or from the cyst lining, resulting in a nonhierarchical, often filigree, pattern.

  • A cribriform pattern, which may be pure or coexist with the micropapillary pattern, is included in the MSBT category by most investigators.

  • The neoplastic cells with micropapillary and cribriform foci are more monomorphic than those of typical SBTs, being round, nonciliated, and with scanty cytoplasm, mild to moderate nuclear atypia, and often a small, occasionally prominent, nucleolus. High-grade atypia, other than in rare cells, is absent. If the latter is more than minimal, caution must be taken to exclude noninvasive serous carcinoma.

  • Rare MSBTs are associated with an invasive serous carcinoma that is usually low-grade (LGSC, see corresponding heading) and thus should be thoroughly sampled. May et al. have found that MSBTs and LGSCs have similar gene expression profiles.

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  Solid patterns. Rare SBTs have florid cellular stratification to the extent that the tumor cells fill and even obliterate the cyst lumens, resulting in solid sheets of cells.

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  Autoimplants. These mimic the noninvasive desmoplastic implants that occur on the extraovarian peritoneum (see below), appearing as sharply delimited desmoplastic foci that typically occur on the serosal surface but occasionally on the inner (cystic) surface of the tumor. In some cases, an appearance similar to that of an autoimplant may be a result of infarction.

  • In 90% of cases, the autoimplants are associated with extraovarian implants that are usually noninvasive.

  • The desmoplasia within an autoimplant can suggest serous carcinoma. Features favoring an autoimplant include a location between tumor papillae or on the ovarian surface, circumscription, a high stromal:epithelial ratio, and epithelial cells like those of typical SBT.

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  Microinvasion (in 5–10% of SBTs).

  • The foci of microinvasion, which are often multifocal, are characterized by tumor cells that often have abundant eosinophilic cytoplasm and are disposed singly or as small clusters, cribriform arrangements, and small papillae.

  • There is usually little or no stromal response. The invasive cells may occupy spaces that may result from fluid secretion by the tumor cells or may represent lymphatics (see last point below).

  • Upper size limits for each focus of 3 mm or 5 mm in maximal dimension or 10 mm ² in area have been suggested, although found that microinvasion exceeding these size limits was not a prognostically adverse finding (see Prognostic Factors).

  • Maniar et al. found that the eosinophilic cells in microinvasive foci (and lymph nodes) showed loss of ER, PR, WT1, and Ki-67 and staining for M30 (an apoptotic marker) suggesting that these cells are senescent. The opposite findings were found in the noneosinophilic cuboidal/columnar cells of SBTs as well as in LGSCs.

  • Lymphatic invasion has been associated with microinvasion in several studies.

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  Focal ‘noninvasive’ carcinoma. Most SBTs are homogeneous throughout but occasional tumors have focal high-grade cytologic atypia indicating transformation to carcinoma. We have seen cases of this type with extraovarian invasive tumor confirming that the primary focus was frank carcinoma.

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  Invasive serous carcinoma.

  • Occasional SBTs are admixed with an invasive serous carcinoma that is usually low-grade, either micropapillary or as discrete small, rounded nests lacking the eosinophilic cells of microinvasion and with more cytologic atypia. Rare SBTs are associated with an invasive HGSC. The proportion of the tumor that is carcinomatous and whether it involves the surface should be noted.

  • Some SBTs are followed by a serous carcinoma that in at least some cases likely represents direct progression from the SBT (Xing, Zeppernick et al.)

Microscopic features of implants of serous borderline tumors ( Figs. 13.26–13.35 )

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  Extraovarian serous peritoneal lesions associated with SBTs include: endosalpingiosis ( Chapter 19 ), a finding that does not affect the stage; noninvasive implants; invasive implants; and low- or high-grade serous carcinomas. The last, in particular, are likely independent primary tumors. As noted earlier, implants are present in about 30% of SBTs; in some studies, the frequency is higher.

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  That extraovarian implants are metastatic in most cases is suggested by their much higher frequency in SBTs with a surface component than in those that are entirely intracystic: 62% vs 4% (Segal and Hart) and 69% vs 16% (Longacre et al.). However, MSBTs without a surface component are associated with implants in up to 35% of cases.

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  Implants may be grossly visible as small nodules or plaques, but are often microscopic.

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  Noninvasive implants, which account for ~90% of implants, are composed predominantly of neoplastic epithelial cells (epithelial implants) or of desmoplastic stroma (desmoplastic implants). Psammoma bodies may be absent, occasional, or conspicuous. The implants involve the peritoneal surface including invaginations between omental fat lobules that may be misinterpreted as invasion.

  • Noninvasive epithelial implants resemble the primary ovarian tumor with absent or limited stromal response that may include adhesions. Occasionally, likely due to maturation, glands indistinguishable from endosalpingiosis may be seen.

  • Noninvasive desmoplastic implants form generally well-delineated peritoneal plaques or nodules and are composed of small nests, glands, papillae, or singly disposed tumor cells within a desmoplastic or granulation tissue-type stroma that almost always exceeds the volume of the epithelial component, sometimes accounting for most of the implant. Fibrin and acute inflammatory cells may be conspicuous, particularly superficially.

  • If the biopsy specimen does not include underlying tissue, the lesion is considered ‘consistent with a noninvasive implant’ on the assumption that it has been stripped off with ease.

  • Noninvasive implants may have a micropapillary pattern or small nests of cells surrounded by a clear zone or cleft. The micropapillary pattern may be exophytic (as in primary tumors) or endophytic, with a complex network of irregular spaces; Bell KA et al. consider these patterns ‘invasive’ even without invasion of underlying tissues. found them to be more frequent in implants that were invasive by usual criteria but were not independently prognostic.

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  Invasive implants account for no more than 5% of implants; the frequency is even lower in some studies.

  • The 2014 WHO classification has replaced the term ‘invasive implants’ with ‘low-grade serous carcinoma’ but some prefer the former term. As Prat states, ‘the term “invasive peritoneal implant” fits better with the synchronous presence of a noninvasive ovarian tumor and describes more properly a small and superficial tumor that may or may not progress to peritoneal carcinomatosis (LGSC) after several years’.

  • Low-power examination reveals destructive invasion and replacement of underlying tissue by an irregular and haphazard infiltration of small nests (sometimes surrounded by clefts), cribriform glands, and micropapillae, usually within a desmoplastic stroma. The epithelial:stromal ratio is usually higher than in noninvasive desmoplastic implants.

  • The tumor cells may have more basophilic cytoplasm and more uniformly atypical nuclei than in noninvasive implants, in some cases resembling those of a low-grade serous carcinoma.

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  In some cases, an implant cannot be confidently classified as invasive or noninvasive; such implants were considered ‘indeterminate’ in the Longacre study. Given the rarity of invasive implants, the bias should be towards diagnosing noninvasive implants unless there is convincing evidence to the contrary.

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  Differential diagnosis and/or associated features of implants:

  • Endosalpingiosis ( Chapter 19 ). This is a common finding involving pelvic and omental peritoneum in the reproductive era, and is especially common in women with SBTs. Endosalpingiotic glands are lined by bland tubal-type epithelium without the cellular stratification, papillarity, tufting, and nuclear atypia of SBT implants.

  • Primary extraovarian SBT ( Chapter 19 ).

  • Mesothelial hyperplasia ( Chapter 20 ). This common finding associated with SBTs may complicate determining if cells in a peritoneal biopsy specimen are tumor cells or mesothelial cells, or both. The former usually immunoreact with epithelial markers (we prefer claudin-4; only membranous staining is considered positive) but not for calretinin, whereas the opposite findings indicate mesothelial cells.

  • Histiocytic infiltrates ( Chapter 20 ). An implant will sometimes elicit a striking peritoneal histiocytic infiltrate (sometimes with admixed hyperplastic mesothelial cells) that may obscure the neoplastic cells of the implant. Immunostains for histiocytic markers (such as CD68) and epithelial markers can be helpful.

  • Implants of low-grade serous carcinoma. These can occasionally appear noninvasive but usually have a higher epithelial:stromal ratio than noninvasive desmoplastic implants of a SBT, and typically have the morphologic features of low-grade serous carcinoma (see below) including uniformly atypical nuclei.

Common associated tubal findings ( Fig. 13.36 )

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  Involvement of the fallopian tube lumen or mucosa by psammoma bodies is common in SBTs. found psammoma bodies in 24% of stage I SBTs and in 51% of stage II and III cases; Wolsky et al. had similar findings. The latter authors also found intraluminal detached papillae, buds, clusters, or nests of tumor cells in 42% of stage IC–III SBTs but in none of their stage IA or IB tumors suggesting spread of detached tumor cells into the tubal lumina.

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  Endosalpingiosis. Wolksy et al. found tubal serosal endosalpingiosis in 18% of stage IC–III SBTs but in none of the stage IA–B tumors.

Immunohistochemical and molecular findings

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  The tumor cells are positive for most epithelial markers, and ER, PR, WT1, and p53 (wild-type pattern), but these are rarely needed for diagnosis.

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  found that only 8% of SBTs exhibit functional p53 mutations compared to 51% of HGSCs.

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  Ho et al. found that almost 90% of SBTs harbor BRAF or KRAS mutations that were also present in adjacent cystadenomatous epithelium, suggesting that the mutations precede the development of SBT.

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  Most peritoneal implants are clonal (with the same KRAS or BRAF mutations as in the primary SBT) supporting metastatic spread (Ardigheiri et al., Horn et al., Sieben et al.) (also see molecular findings below). Zuo et al. found KRAS mutations in 61% of invasive implants vs 22% of noninvasive implants.

Lymph node involvement by serous borderline tumor ( Figs. 13.37 – 13.38 )

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  Nodal involvement (LNI) has been found in 20–40% of patients with SBTs undergoing lymphadenectomy. Patients with LNI have been reported to be younger than those without it.

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  Maniar et al. found that LNI had a strong association with ovarian surface involvement and peritoneal implants, suggesting that LNI in some cases may be due to spread of exfoliated tumor cells rather than via lymphatics from the primary tumor.

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  found that the involved nodes were, in order of frequency, pelvic, mesenteric/omental, para-aortic, and supradiaphragmatic. The number of involved nodes varied from 1 to 20 (mean, 3).

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  found four patterns of intranodal SBT:

  • Individual cells, nests, and simple papillae within sinuses or the parenchyma (90% of cases).

  • Intraglandular pattern within the parenchyma: epithelium-lined spaces containing complex hierarchical papillae (68% of cases), sometimes with contiguous foci of microinvasion similar to that in primary SBTs.

  • Tumor cells with copious eosinophilic cytoplasm (52% of cases) in the sinuses and/or parenchyma similar to those seen in primary SBTs and their implants.

  • Micropapillary pattern (16% of cases) in the parenchyma consisting of delicate papillae without fibrovascular cores and/or a complex maze of slit-like spaces.

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  LNI has a strong association with intranodal endosalpingiosis, from which the intranodal SBT may arise, usually with the second pattern noted above. Features favoring metastatic intranodal SBT include an absence of endosalpingiosis; sinus involvement; intranodal SBT as single cells, nests, or papillae; and microinvasion, sometimes with LVI, in the primary tumor. Occasionally, LNI may be a result of both synchronous primary neoplasia and metastasis.

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  Most studies have found that LNI is not an adverse prognostic factor independent of stage. , however, found that nodules (>1 mm in size) of confluent tumor without intervening lymphoid tissue, often with a micropapillary pattern and a desmoplastic stroma, may be an adverse prognostic factor, although we would consider this pattern to represent LGSC.

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  The differential of LNI in SBT includes, in addition to endosalpingiosis and primary intranodal SBT, intranodal hyperplastic mesothelial cells (see Chapter 20 ).

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  Lymph nodes may be the site of a recurrence (see below). In such cases, the involved nodes may be supradiaphragmatic and the intranodal tumor may resemble the primary SBT, LGSC, or even, rarely, HGSC.

Lymph node involvement by low-grade serous carcinoma in patients with serous borderline tumors ( Figs. 13.39 – 13.40 )

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  reported 5 cases of LNI by LGSC in women with ovarian SBTs. The LNI was synchronous (one case) or metachronous (4 cases) being found from 7 months before to 5 months after the ovarian SBT.

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  The LGSCs were supraclavicular (2 cases) and cervical, intramammary, and para-aortic nodes (1 case each) and replaced the lymph node or diffusely involved the sinusoids or cortices. Two patients also had extensive intranodal SBT and endosalpingiosis in pelvic nodes.

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  The ovarian SBTs exhibited surface excrescences (4 cases) and microinvasion (3 cases) but lacked micropapillary/cribriform patterns. All had noninvasive implants and one also had invasive implants.

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  Two patients had local recurrences and died of disease. Another patient, who initially had supraclavicular LNI by LGSC, developed abdominopelvic lymphadenopathy and was alive with disease at last follow-up.

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  The authors concluded that, as with intranodal SBTs, intranodal LGSCs may arise from intranodal endosalpingiosis and progress independently of the ovarian SBT.

Differential diagnosis

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  Müllerian borderline tumors of mixed cell type (see Chapter 14 ). These tumors often contain foci resembling SBT but also have cells with intracellular mucin and in some cases, endometrioid and squamous elements.

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  LGSCs. These differ from SBTs by the presence of stromal invasion greater than microinvasion. Additionally, there are small nests, more uniform papillae than in most SBTs, and greater cytologic atypia, an appearance differing from that of microinvasion of an SBT.

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  HGSC lacking stromal invasion. These can be misdiagnosed as a SBT if severe cytologic atypia is overlooked. Most such tumors, however, also have more florid epithelial proliferations off the surfaces of papillae with the formation of slit-like spaces and other typical formations of serous carcinoma unacceptable for an SBT.

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  Endometrioid papillary tumor of borderline malignancy and endometrioid and clear cell carcinomas ( Chapter 14 ).

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  Retiform Sertoli–Leydig cell tumors ( Chapter 16 ).

Prognostic factors in serous borderline tumors