Berek and Hacker's Gynecologic Oncology, 5th Edition
Christina S. Kong
Teri A. Longacre
Michael R. Hendrickson
The individual organs within the genital tract make up an extended müllerian system that can give rise to a wide variety of histologically similar tumors. Because of this extended müllerian system, tumor classification and assignment of primary site can be problematic. This chapter provides an overview of the main tumors that are encountered in the female genital tract, emphasizing key histopathologic features and pertinent ancillary diagnostic studies.
To maximize the information provided by pathologic examination, it is important that the treating clinician understand basic concepts of gynecologic oncologic pathology. It is similarly important for the pathologist to understand basic clinical, radiologic, and serologic data. The integration of clinical, radiologic, and pathologic information is central to intraoperative evaluation and ultimately to treatment planning, and it occurs best within the framework of the multidisciplinary tumor board seen in most major cancer centers.
Squamous Lesions of the Cervix
There are several systems for classifying preneoplastic lesions of the cervix, so it is useful to be familiar with all the systems because the terms can be used interchangeably (Table 5.1). Over the years, the classification systems have moved toward fewer, more clinically relevant categories. The most recent is the Bethesda system, which was developed for providing uniform diagnostic terminology for cervical cytologic specimens but is now also used for histologic diagnoses. It has two categories: low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL). The LSIL category encompasses condyloma and cervical intraepithelial neoplasia (CIN) grade 1, whereas the HSIL category encompasses CIN 2 and CIN 3. CIN 1 is equivalent to mild dysplasia, CIN 2 to moderate dysplasia, and CIN 3 to severe dysplasia and carcinoma in situ. The Bethesda system and CIN terminology are the most widely used.
Low-Grade Squamous Intraepithelial Lesion
There are three main subtypes of LSIL. Flat condylomas lack the exophytic growth pattern and are more frequently associated with intermediate and high-risk HPV types. These are the most common in the cervix. Condyloma acuminatum is the classic genital wart with an exophytic growth pattern. It is typically associated with low-risk HPV types 6 and 11.Immature condylomas are the least common and exhibit a filiform, papillary growth pattern; they are associated with low-risk HPV types.
Table 5.1 Terminology for Cervicovaginal Squamous Intraepithelial Lesions
LSIL is characterized by thickened mucosa with enlarged, dark cells that have low nuclear-tocytoplasmic ratios in the upper layers (Fig. 5.1). Binucleation can be seen in 90% of LSIL, and when the nuclei are surrounded by an irregularly shaped and sharply punched out halo, they are known as koilocytes. However, binucleation and halos both can be seen as part of a reactive process. With reactive change, the nucleus is minimally enlarged and not hyperchromatic, and the halo is less distinct, round, and uniform. Glycogen vacuoles can also appear as round, uniform halos. In addition, LSIL can be mimicked by a squamous papilloma (also known as an ectocervical or fibroepithelial polyp). Squamous papillomas lack koilocytes and have central fibrovascular cores that are not typical of condylomas.
The ASCUS-LSIL Triage Study studied interobserver variability in the diagnosis of squamous intraepithelial lesion (SIL) on biopsy (1). More than 2,700 cervical biopsies and loop electrosurgical excision procedure (LEEP) specimens were examined by one to two staff pathologists at one of four centers across the United States and then reviewed by one of four quality control (QC) pathologists. There was agreement on the diagnosis of LSIL in 43% of cases, but 41% of the cases diagnosed by the staff pathologists as LSIL were downgraded by the QC pathologists to negative. Of note, most of the downgraded cases were positive for high-risk HPV, raising the question of which diagnosis was correct. The significance of this finding was not addressed by the study.
High-Grade Squamous Intraepithelial Lesion
HSIL are characterized by atypical, dark cells with high nuclear-to-cytoplasmic ratios that involve one-third to two-thirds of the epithelium in cases of CIN 2 (Fig. 5.2) or more than twothirds in cases of CIN 3 (Fig. 5.3). The involved mucosa is notable for disorderly arrangement of cells with loss of polarity and crowding. Mitotic figures in the upper half of the mucosa are commonly identified.
Figure 5.1 Low-grade squamous intraepithelial lesion (mild dysplasia, CIN 1). The mucosa is thickened with dysplastic cells and koilocytes in the upper layers.
Figure 5.2 High-grade squamous intraepithelial lesion (moderate dysplasia, CIN 2). Dysplastic cells with high nuclear-to-cytoplasmic ratios involve less than two-thirds of the mucosa.
Figure 5.3 High-grade squamous intraepithelial lesion (severe dysplasia, CIN 3). The squamous mucosa is notable for full thickness atypia and extension of the dysplastic cells down into endocervical glands.
Immature squamous metaplasia and atrophy can be difficult to distinguish from HSIL because they are also characterized by cells with high nuclear-to-cytoplasmic ratios. However, the nuclei in squamous metaplasia and atrophy should lack crowding and appear uniform with smooth nuclear membranes. Mitotic figures can be seen near the basal layer but not in the upper half of the mucosa. In indeterminate cases, immunohistochemical stain for p16INK4a, a surrogate marker for high-risk HPV, can be helpful (2). In some cases, for various reasons (e.g., tangential sectioning, small dissociated fragment, cautery artifact), a distinction cannot be made between LSIL and HSIL. These are best characterized as SIL of indeterminate grade.
The ALT study found good reproducibility for the histologic diagnosis of HSIL with concordance in 76.9% of cervical biopsies and 80.2% of LEEP specimens (1).
Squamous Cell Carcinoma
Cervical squamous cell carcinomas (SCCs) can be subdivided into two main groups: microinvasive carcinomas and invasive carcinomas. Microinvasive carcinoma (FIGO* stage IA1) is defined as microscopic disease with ≤3.0 mm stromal invasion and ≤7.0 mm horizontal extent. For accurate measurements, the entire lesion needs to be visible with requires negative surgical margins. Although lymphatic-vascular invasion (LVI) is acknowledged as a poor prognostic factor, the presence or absence of LVI does not change the FIGO stage. The depth of invasion is measured from the basement membrane at the point of invasion to the deepest invasive focus (Fig. 5.4). Morphologically, microinvasive carcinoma is characterized by jagged fingers extending from the base of HSIL into the submucosa and surrounded by chronic inflammation and loose, fibroblastic stroma (i.e., desmoplasia). Often at the point of invasion, the neoplastic cells become more differentiated and have abundant eosinophilic cytoplasm that may be keratinizing. Microinvasive carcinoma can be difficult to distinguish from HSIL, especially when HSIL involves endocervical glands or is associated with previous biopsy site changes. Examining multiple-level sections of the same focus can be helpful.
Squamous cell carcinomas that are clearly invasive can be keratinizing or nonkeratinizing and range from well differentiated to poorly differentiated. Well- to moderately differentiated invasive SCC is characterized by cohesive nests and sheets of neoplastic cells with abundant eosinophilic cytoplasm and distinct cell borders (Fig. 5.5). Keratin pearl formation, central keratinization, and necrosis within nests may also be identified. With poorly differentiated carcinomas, keratinization may be minimal or absent, and they may be difficult to distinguish from other types of poorly differentiated carcinomas (e.g., adenocarcinoma). Grade and type have not been found to be prognostically significant.Instead, depth of invasion, lymphatic or vascular invasion, and size are important prognostic variables.
Figure 5.4 Microinvasive squamous cell carcinoma of the cervix. Invasion is measured from the basement membrane at the point of invasion (upper arrow) to the deepest invasive focus (lower arrow). FIGO* Stage IA1 cervical cancer is defined by a depth of invasion ≤3 mm and horizontal extent ≤7 mm in a specimen with negative margins.
Figure 5.5 Invasive squamous cell carcinoma of the cervix, moderately differentiated keratinizing. Keratinization and necrosis within nests of malignant squamous cells are present.
Human Papilloma Virus
Human papilloma virus (HPV) DNA has been detected in virtually all cases of cervical dysplasia and carcinoma, and it is considered to be a necessary but not sufficient cause for the development of the vast majority of invasive cervical carcinomas. Although a variety of HPV types may infect epithelial cells, the risk of oncogenic transformation is most strongly linked to several specific high-risk types. In 2003, a large epidemiologic study by the International Agency for Research on Cancer (IARC) pooled data from nine countries and identified 15 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), three probable high-risk types (26, 53, and 66), and 12 low-risk types (6, 11, 40, 42,43, 44, 54, 61, 70, 72, 81, and CP6108). The IARC met again in 2005 to reassess the carcinogenicity of HPV and revised the original list of high-risk types to include 13 types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66 (3). Most investigators now believe that persistent infection with high-risk HPV types is associated with the subsequent development of high-grade dysplasia and invasive carcinoma (4). A substantial proportion of LSIL are also associated with infection by high-risk HPV types, but many infections are transitory (4,5).
Cervicovaginal Cytology (Pap Testing)
Specimen Preparation Methods
There are two main specimen types for cervicovaginal cytology: conventional smear and liquid-based preparation. Conventional smears involve directly smearing material onto a glass slide and then immediately fixing the specimen with ethanol. The advantages of conventional smears are their low cost and the lack of need for specialized equipment to process specimens. The disadvantages are lack of uniformity in specimen preparation and unsatisfactory smears because of obscuring inflammation, obscuring blood, or thick areas in the smear.
Liquid-based preparations involve placing the cytologic material in a liquid fixative instead of directly smearing it on a glass slide. The two most commonly used are ThinPrep(Hologic, Bedford, MA) and SurePath (BD Diagnostics, Burlington, NC). ThinPrep uses a methanolbased fixative and a filter preparation for making the slide. SurePath uses an ethanol-based fixative and a Ficoll gradient. SurePath also employs a detachable head for the collection device so the entire specimen is submitted for processing. The advantages of liquid-based preparations are uniformity in slide preparation and fewer unsatisfactory specimens. The disadvantages are significantly higher cost and the necessity for specialized processing equipment for each liquid-based method.
Who Signs Out Pap Tests?
Cervicovaginal cytologic specimens are predominantly screened by board-certified cytotechnologists. In some small laboratories, the primary screening of the slides is performed by a pathologist. If the Pap test is negative for intraepithelial lesion or malignancy and lacks reactive or reparative changes, then the final report can be issued by the cytotechnologist.Quality control review by a second senior cytotechnologist or a pathologist is performed on at least 10% of all negative cases and on all cases for patients with a history of an abnormal Pap test. If any reactive, reparative, or epithelial abnormalities are found, then the slide is reviewed by a pathologist who will issue the final report.
The Clinical Laboratory Improvement Act of 1988 set limits on the number of Pap tests that can be reviewed by a cytotechnologist in a 24-hour period. The nationwide limit is 100 nonimaged or 200 imaged slides per day, but individual states can set lower limits (e.g., 80 nonimaged or 160 imaged slides in California). Currently, there is a requirement that all pathologists and cytotechnologists who interpret Pap tests pass an annual proficiency test.
The Bethesda System
In 1988, the National Cancer Institute sponsored a workshop in Bethesda, Maryland, to develop uniform diagnostic terminology for Pap tests. The resulting classification system has undergone multiple revisions, and the system currently in use is Bethesda 2001 (6) (Table 5.2).
According to the Bethesda system, the Pap test report should include the following categories: specimen type (e.g., conventional, liquid based), specimen adequacy, and interpretation or result. A general categorization category and educational notes and suggestions are optional. If automated screening is performed (e.g., ThinPrep Imager or BD FocalPoint), then the device and result are also reported. If ancillary testing is performed, then the results may be indicated in the Pap test report or reported separately.
Table 5.2 2001 Bethesda System
Table 5.3 Lubricants Less Likely to Interfere with ThinPrep Samples
Specimen adequacy is divided into “satisfactory for evaluation” and “unsatisfactory for evaluation.” The presence or absence of transformation zone cells (i.e., endocervical cells or squamous metaplastic cells) and quality indicators (e.g., obscuring blood or inflammation, scant cellularity) are indicated under the umbrella of “satisfactory for evaluation.” Specimens can be unsatisfactory for a variety of reasons, and this will be indicated on the report. Some specimens are rejected and not processed; these are usually the result of a broken slide or empty collection vial. Others are found to be unsatisfactory after processing and examination of the slide. A common cause of unsatisfactory ThinPrep specimens is the use of lubricants containing carbomers or carbopol polymers when obtaining the sample. Cytyc has distributed a nonexhaustive list of lubricants that are less likely to interfere with processing (Table 5.3). Another common cause of unsatisfactory specimens is obscuring blood. Although liquid-based systems can remove blood from the sample, the ThinPrep system is able to handle less blood than the SurePath Ficoll gradient.
Squamous Cell Abnormalities
LSIL in cervical cytology specimens is characterized by enlarged (more than three times the size of an intermediate cell nucleus), dark nuclei with irregular, thickened nuclear membranes. When the cells are binucleated and surrounded by a sharply defined, irregularly shaped halo with a peripheral rim of thickened cytoplasm, then the cell is known as akoilocyte (Fig. 5.6). Although koilocytes are pathognomonic for a diagnosis of LSIL, they are not required. LSIL can be diagnosed based on cells with enlarged, dark, irregular nuclei and no cytoplasmic halo. Koilocytes can be mimicked by prominent glycogen vacuoles or inflammatory halos (Fig. 5.7). In these cases, the area of perinuclear clearing is not sharply demarcated and tends to be round and regular with the nucleus centrally located. When the findings fall short of LSIL, the diagnosis of atypical squamous cells of undetermined significance (ASC-US) is used (Fig. 5.8). Usually, this is because one of the nuclear features is lacking: The nuclei are not quite large enough (2.5 to 3 times the size of an intermediate cell nucleus), dark enough, or irregular enough.
HSIL is characterized by cells with dark nuclei, irregular nuclear membranes and high nuclearto-cytoplasmic ratios (Fig. 5.9). The dysplastic cells can occur singly, in sheets, or as syncytial aggregates. The chromatin ranges from coarse to bland, and the cytoplasm from delicate to dense. The nuclei vary in size and are frequently smaller than those seen with LSIL. With liquid-based preparations, dispersed abnormal single cells are more common than aggregates. In addition, with ThinPrep, the nuclei may not be dark; the diagnosis relies on finding single cells with irregular nuclear membranes and high nuclear-to-cytoplasmic ratios.
Mimics of HSIL include squamous metaplasia, atrophy, repair, endometrial cells, histiocytes, and endocervical cells. Atrophy and squamous metaplasia can be especially difficult to distinguish from HSIL. With atrophic changes, the basal and parabasal cells have high nuclear-to-cytoplasmic ratios with enlarged, dark nuclei, and the background can resemble tumor diathesis (Fig. 5.10). The distinction from HSIL relies on finding smooth nuclear membranes, flat monolayer sheets, and lack of variability in nuclear size and shape. Squamous metaplastic cells have high nuclear-to-cytoplasmic ratios and dense cytoplasm but smooth nuclear membranes. If the cytologic features fall short of a diagnosis of HSIL, then the diagnosis of atypical squamous cells-cannot exclude HSIL (ASC-H) is used. If dysplastic cells are clearly present but do not quite meet criteria for HSIL, then the changes are characterized as LSIL cannot exclude HSIL.
Figure 5.7 Inflammatory halos. Perinuclear clearing with a centrally located nucleus and hazy edges can be seen with infections (e.g., trichomonas) and can be mistaken for koilocytes. (Papanicolaou stain)
Figure 5.6 Low-grade squamous intraepithelial lesion. Koilocytes have sharply delineated, irregular halos and multiple, dark nuclei with irregular nuclear borders. (Papanicolaou stain)
Figure 5.8 Atypical squamous cells of undetermined significance (ASC-US). The nucleus is 2.5 times the size of the intermediate cell nucleus, and the nuclear membranes are smooth. (Papanicolaou stain)
Figure 5.9 High-grade squamous intraepithelial lesion. The dysplastic cells have dark nuclei with focal nuclear membrane irregularities and high nuclear-to-cytoplasmic ratios. (Papanicolaou stain)
Figure 5.10 Atrophy. Atrophic vaginitis is characterized by sheets of parabasal cells and an inflammatory background that can mimic squamous cell carcinoma. (Papanicolaou stain)
The cytologic diagnosis of squamous cell carcinoma implies invasive carcinoma because carcinoma in situ is encompassed within the category of HSIL. Keratinizing SCC has single cells with dense, dark nuclei and dense, orangeophilic (i.e., orange-colored) cytoplasm. Nonkeratinizing SCC has syncytial aggregates as well as single cells with coarse chromatin and poorly defined cell borders with delicate basophilic (i.e., blue-colored) cytoplasm. Macronucleoli and tumor diathesis (i.e., necrosis, degenerating blood, inflammation) can be seen with both but more frequently with nonkeratinizing SCC. With liquid-based preparations, tumor diathesis is seen as necrotic material clinging to the edges of cell groups and is less apparent than on conventional smears where it is spread across the background (Fig. 5.11). SCC can be difficult to distinguish from HSIL because there is significant morphologic overlap between these two entities. Because keratinization can be seen with both, the findings of macronucleoli and tumor diathesis are more reliable indicators of SCC but are not always present. However, for both HSIL and SCC, the next step is colposcopy with biopsy, which will provide material for more definitive assessment for invasive carcinoma.
Glandular Cell Abnormalities
The diagnosis of “atypical glandular cells” accounts for less than 1% of all Pap tests. However, significant disease is present in 9% to 38% of cases with HSIL as the most common abnormal finding (7). Other findings include endocervical adenocarcinoma in situ, cervical carcinoma, endometrial pathology including carcinoma, and extrauterine carcinoma. Postmenopausal women have a higher rate of abnormality with a significant cervical or endometrial abnormality found in more than 30% of cases.
Endocervical adenocarcinoma in situ (AIS) is characterized by enlarged, elongated nuclei with irregular nuclear membranes and coarse chromatin arranged radially as rosettes or in strips as crowded palisades (Fig. 5.12). When the cytoplasm is partially stripped away, the palisading nuclei can resemble an array of feathers. This feature is referred to asfeathering and is considered characteristic of AIS. Mitotic figures are also commonly present.
Endocervical AIS can be closely mimicked by tubal metaplasia, direct sampling of the endometrium, and HSIL involving endocervical glands. Tubal metaplasia is distinguished by the lack of nuclear crowding and smooth nuclear membranes. The presence of cilia is characteristic but not always seen. Direct sampling of endometrium can yield strips and sheets of atypical glandular cells with feathering, rosette formation, and frequent mitotic figures.
Figure 5.11 Squamous cell carcinoma. Necrosis in liquid-based preparations is characterized by granular debris that clings to the edges of tumor cell clusters. (Papanicolaou stain)
Figure 5.12 Endocervical adenocarcinoma in situ. Palisading nuclei stripped of cytoplasm (“feathering”) is a characteristic feature. The nuclei are enlarged and elongated with coarse chromatin. (Papanicolaou stain)
Identifying small, tightly cohesive endometrial stromal cells can help in the distinction from AIS. Sampling of endometrial tissue can occur as the result of cervical endometriosis or inadvertent sampling of the lower uterine segment or endometrial cavity (Fig. 5.13). The latter occurs more frequently in patients who have a shortened cervix resulting from previous LEEP or cone biopsy. The presence of glands embedded in stroma should raise the possibility of direct endometrial sampling. HSIL involving endocervical glands can be distinguished from AIS by the lack of palisading, presence of single cells with high nuclear-to-cytoplasmic ratios and irregular nuclear membranes, or evidence of keratinization. AIS and HSIL can coexist. If the features fall short of a diagnosis of AIS, depending on the degree of atypia present, the following Bethesda diagnoses may be used: “Atypical endocervical cells, not otherwise specified (NOS)” or “Atypical endocervical cells, favor neoplastic.” The latter diagnosis is associated with a higher likelihood of finding a clinically significant lesion on biopsy.
Figure 5.13 Endometriosis. Direct sampling of endometrial glands can mimic endocervical adenocarcinoma in situ. The smooth nuclear membranes and lack of nuclear crowding support a benign process. (Papanicolaou stain)
Adenocarcinomas most commonly originate from the endocervix or endometrium but can also represent spread from an extrauterine source (e.g., ovary, breast, stomach, colon, kidney, or bladder). Invasive endocervical adenocarcinomas resemble AIS but are distinguished by the presence of a tumor diathesis in the background. Endometrial carcinoma is characterized by three-dimensional groups or papillary clusters of cells with enlarged nuclei and often vacuolated cytoplasm (Fig. 5.14). Intracytoplasmic neutrophils are common. When the tumor cells have large cytoplasmic vacuoles and are associated with psammoma bodies, then the findings are suggestive of a serous carcinoma. Adenocarcinoma cells in a clean background or with unusual morphology that is not typical of a uterine primary raise the possibility of metastatic disease (Fig. 5.15).
The diagnosis of atypical endometrial cells is used when endometrial cell clusters are noted for mild nuclear enlargement, vacuolated cytoplasm, or cytoplasmic neutrophils. If it cannot be determined whether the atypical cells are endocervical or endometrial in origin, then the diagnosis of atypical glandular cells (NOS) or atypical glandular cells, favor neoplastic can be used.
The diagnosis of “endometrial cells in a woman 40 years of age and older” is used when benign-appearing exfoliated endometrial stromal or glandular cells are identified in a cervical cytology specimen from a woman aged 40 or older. The age cutoff was set by the Bethesda system 2001 because menstrual data, menopausal status, hormonal therapy, and clinical risk factors are frequently unknown to the laboratory. For asymptomatic, premenopausal women, no further studies are recommended. However, endometrial sampling is recommended for symptomatic premenopausal women and all postmenopausal women (7).
HPV testing has become routine since the ASCUS LSIL Triage (ALT) Study (8) and the publication of the American Society for Colposcopy and Cervical Pathology (ASCCP) Consensus Guidelines for the Management of Women with Cervical Cytological Abnormalities. Initially, Digene Hybrid Capture II was the only commercially available HPV test and had the additional distinction of being the assay used in the ALT study. In the intervening time, several different assays that use multiple different methodologies have become commercially available.
Figure 5.14 Endometrial carcinoma. Three-dimensional papillary clusters of cells with enlarged nuclei. (Papanicolaou stain)
Figure 5.15 Metastatic breast carcinoma. Adenocarcinoma cells in a background without inflammation and necrosis raise the possibility of spread from an extrauterine source. (Papanicolaou stain)
Some are direct tests for HPV such as in situ hybridization (ISH), whereas others are surrogate markers such as p16INK4A and ProEx C. Polymerase chain reaction (PCR) is the traditional gold standard for HPV detection, and two assays by Roche, currently available in Europe, are undergoing FDA approval in the United States.
Digene Hybrid Capture II (HC2) has been approved by the FDA for use in triaging patients with a cervical cytology diagnosis of ASC-US and for triaging patients over age 30 with negative cervical cytology (8). It can be performed on cervical swabs or liquid-based cervical cytology samples. The method involves hybridization of the full genomic HPV RNA probe with the target DNA, followed by capture onto a solid phase and chemiluminescent detection. The FDA-approved threshold for a positive result is 1.0 RLU/PC (relative light unit to positive control specimen ratio), which corresponds to approximately ~1 pg/mL or 5,000 HPV DNA copies per test well (9).
HC2 utilizes two RNA probes, one directed at low-risk HPV types (6, 11, 42, 43, 44) and another at high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68). Only the high-risk HPV assay has clinical utility because low-risk HPV has no oncogenic potential. Since HC2 was developed, HPV 68 has been reclassified out of the high-risk category, whereas HPV 66 is now considered high risk. Although the high-risk probe does not directly target HPV 66, studies have shown that HPV 66 is detected through cross-reactivity. One of the main criticisms of HC2 is decreased specificity because of cross-reactivity, but the benefit of crossreactivity is increased clinical sensitivity. As exemplified by HPV 66, cross-reactivity can allow for the detection of HPV types not currently classified as high risk.
Positive results with HC2 testing for high-risk HPV have been reported in many patients who have no cytologic or histologic evidence of dysplasia. False positive results with HC2 can occur as the result of cross-reactivity or signal leak. De Cremoux et al. reported a false positive rate of 6.2% with 1.9% because of cross-reactivity and 4.3% because of signal leak (10). Cross-reactivity with high-risk HPV DNA occurred in cases that had very high loads of low-risk HPV; similar cross-reactivity with low-risk types occurred with high loads of highrisk HPV. In addition, the chemiluminescent signal in cases with high viral loads also led to false positive results in contiguous samples because of leaking of the signal.
Currently, HC2 results are usually reported as positive or negative based on the assigned cutoff of 1.0 RLU/PC. Although HC2 testing has been shown to have good interlaboratory reproducibility, there is poor reproducibility near the cutoff point of 1.0 RLU/PC (11). In a significant portion of cases with borderline positive HC2 results, PCR analysis for HPV is negative (12). This would argue for including a borderline category when reporting HC2 results to flag cases that are near the cutoff point and may represent a false positive result.
Other slide-based HPV assays such as in situ hybridization, p16INK4A and ProEx C are also available but these assays lack the extensive validation of Digene HC2. Limited studies comparing Ventana HPV ISH with Digene HC2 have shown insufficient sensitivity for HPV ISH to replace HC2 for ASC-US triage (13,14). Assays intended for triage or screening purposes should be very sensitive with a low false negative rate and high negative predictive value.
The main impetus behind developing automated screening systems was to increase productivity and improve quality. Both ThinPrep and SurePath have imaging systems that can be used with their liquid-based preparations. The ThinPrep Imaging System was approved by the FDA in 2003 for dual review of ThinPrep cervical cytology slides. After the imaging system screens the slide, the cytotechnologist reviews 22 selected fields of view. If any abnormal cells are seen, then the slide is manually rescreened by the cytotechnologist.Studies have shown the ThinPrep system to have equivalent or better sensitivity than manual screening for the detection of LSIL and HSIL, and higher specificity for the diagnosis of HSIL (15). The BD FocalPoint Slide Profiler is FDA approved for primary screening of SurePath or conventional cervical cytology slides. It functions as a triage device, allowing a portion of slides to be archived with no further review by a cytotechnologist and identifying cases that are more likely to contain significant abnormalities, requiring further review. The BD FocalPoint GS Imaging System is a new location-guided screening system that can be used in conjunction with the Slide Profiler. The guided screener will direct the cytotechnologist to the fields of view containing the abnormal areas detected by image analysis.
Glandular Lesions of the Cervix
A variety of terms have been used to describe preinvasive glandular lesions of the cervix, including atypia, dysplasia, and adenocarcinoma in situ. Unlike cervical squamous lesions, cervical glandular dysplasia is a poorly defined and controversial entity. Glandular lesions that exhibit some but not all the features of adenocarcinoma in situ have been associated with in situ and invasive adenocarcinoma, but the diagnostic criteria, clinical implications, prevalence, and progression rate of these lesions are not uniformly agreed upon (16).
Adenocarcinoma In Situ
The histological diagnosis of adenocarcinoma in situ (ACIS) requires unequivocal dysplastic changes, which are typically manifested by low-power basophilia, nuclear hyperchromasia with either fine or coarsely granular chromatin, nuclear apoptotic or karyorrhectic debris, apical mitotic figures, and loss of polarity (which may be subtle) (Fig. 5.16). The involved glands exhibit a lobular architecture that may appear more pronounced than adjacent uninvolved endocervical glands, but irregular infiltration into stroma is absent. Partial gland involvement is common. Recently, a superficial form of ACIS has been described in the superficial columnar mucosa featuring similar cytologic alterations but less pronounced atypia. This lesion is thought to occur more commonly in a younger age group (mean, 26 years) and so has been interpreted as an “early” form of ACIS (17).
A variety of processes mimic ACIS, including tubal or tuboendometrial metaplasia, endometriosis, and reactive endocervical cells, as well as several endocervical cell alterations that do not necessarily appear to represent a reactive process (18). These latter alterations often pose the most diagnostic difficulty and are classified on the basis of the abnormality present: endocervical glandular hyperplasia, mitotically active endocervical mucosa, stratified endocervical mucosa, and atypical oxyphilic metaplasia.
In recent years, the use of biomarkers, particularly a combination of Ki-67 and p16, has been used in the differential diagnosis of ACIS. In general, strong, diffuse expression of p16 in conjunction with increased Ki-67 is more commonly associated with ACIS, whereas weak or focal p16 expression with or without increased Ki-67 is more supportive of an ACIS mimic (19). Exceptions occur, so it is important to be thoroughly aware of the variant expression patterns of these markers in the individual lesions in order to prevent overinterpretation on the basis of staining patterns alone (20).
Figure 5.16 Adenocarcinoma in situ of the cervix. In situ carcinoma exhibits nuclear hyperchromasia, stratification, irregular chromatin, and apical mitotic figures. A normal endocervical gland is present on the right.
Figure 5.17 Invasive adenocarcinoma of the cervix. Deeply infiltrative glands are irregular in contour and surrounded by edematous stroma. (top, low power; bottom, high power)
The diagnosis of invasive cervical adenocarcinoma can be very difficult in early or superficially invasive lesions as well as in limited (superficial) biopsy specimens. Unlike squamous carcinoma of the cervix, invasion may not be associated with a significant stromal reaction; in these instances, identification of invasion is based on the presence of significant glandular irregularity, an infiltrative gland pattern, and the presence of enlarged, complex neoplastic glandular structures deep to the normal endocervical crypts (Fig. 5.17).
Because of the difficulties in diagnosing early invasive lesions, the concept of “microinvasive adenocarcinoma” is not as well accepted as it is for microinvasive squamous cell carcinoma; nevertheless, a maximum depth of invasion of 3 mm with negative margins and no lymphovascular invasion is considered by most clinicians as the upper limit for consideration for conservative management. Measurements are made from the surface and expressed in millimeters.
Invasive adenocarcinoma of the usual or endocervical type accounts for 60% to 70% of cervical adenocarcinomas. Two variants—adenoma malignum (minimal deviation adenocarcinoma) and villoglandular adenocarcinoma—are very uncommon but the source of frequent diagnostic problems. Other histologic subtypes include serous, clear cell, endometrioid, mesonephric, intestinal type, adenoid basal, adenoid cystic, and neuroendocrine carcinoma (18,21). Only those with distinctive clinical or differential diagnostic problems that affect prognosis or treatment are discussed.
Minimal Deviation Carcinoma (Adenoma Malignum)
This tumor, which is characterized by a deceptively benign histologic appearance, accounts for <10% of all cervical adenocarcinomas. Patients present with irregular bleeding, diffuse cervical enlargement, or vaginal mucus discharge. An association with Peutz-Jeghers syndrome has been reported (21). A wide age range has been reported, but virtually all patients are older than 20 years of age.
Microscopically, the tumor features cystically dilated, irregular (claw-shaped) glands with minimal cytologic atypia and minimal stromal reaction (Fig. 5.18). The diagnosis is most easily established by careful search for foci of cytologic atypia, stromal reaction, or conventional-type adenocarcinoma. This tumor can replace normal endocervical and endometrial glandular tissue, mimicking mucinous metaplasia in uterine curettings and biopsy. Intracytoplasmic carcinoembryonic antigen (CEA) staining may he helpful is some cases, but not all adenoma malignum carcinomas are CEA positive and normal endocervical glands may express CEA on occasion, although usually only along the surface (glycocalyx). These carcinomas do not stain for p16.
This tumor occurs predominantly in young women and is characterized by villoglandular architectural growth pattern and low nuclear grade. These tumors have a good prognosis but only if they are exophytic with minimal or no invasion (Fig. 5.19). An association with HPV has been reported, and these tumors may be p16 positive.
Clear Cell Carcinoma
Clear cell carcinoma may occur in young (diethystilbestrol exposure in utero) or older women and may arise in the ectocervix (typically, associated with diethystilbestrol exposure) or endocervix. A variety of patterns—including tubulocystic, glandular, solid, and papillary—may be seen (21).
Mesonephric remnants may develop hyperplasia and carcinoma; often a spectrum of these changes is seen in the carcinomas (21). The carcinomas often pose significant diagnostic difficulty because of their lateral and deep location within the cervix. There may be no surface component. Ductal, retiform, tubular, solid, and spindle patterns may be seen in the carcinomas. Most are low to moderate nuclear grade, so some cases may be difficult to distinguish from florid mesonephric hyperplasia. The distinction is often based on loss of lobular architecture and infiltrative pattern. Diagnosis of higher-grade mesonephric adenocarcinoma is based on identification of residual normal or hyperplastic mesonephric tubules with their characteristic eosinophilic luminal material. Prognosis is uncertain because of the limited numbers of cases but probably similar to usual endocervical adenocarcinoma. These tumors are not known to be associated with HPV, and most are p16 negative.
Figure 5.18 Minimal deviation adenocarcinoma (adenoma malignum). Large, irregular mucinous glands typically show bland or minimally atypical cytological features. (top, low power; bottom, high power)
Neuroendocrine carcinoma, small- and large-cell variants, account for less than 5% of all cervical carcinomas. These highly aggressive tumors may present as small lesions, but most are deeply invasive. They exhibit the usual features of a neuroendocrine carcinoma; high mitotic rates and necrosis are common (Fig. 5.20). Neuroendocrine carcinoma is often associated with ACIS, HSIL, and conventional invasive cervical adenocarcinoma. Most harbor HPV-18 and are p16-positive. Rarely, well-differentiated neuroendocrine carcinoma (carcinoid) may occur in the cervix, and the prognosis for this tumor may be better. Metastasis should always be excluded.
Figure 5.19 Villoglandular adenocarcinoma of cervix. Slender, elongate villi are lined by well-differentiated epithelium with an exophytic growth pattern. This tumor is associated with a good prognosis, provided there is minimal or no cervical stromal invasion. (top, low power; bottom, high power)
Adenoid Basal Carcinoma (Adenoid Basal Epithelioma)
Adenoid basal cell carcinoma (epithelioma) occurs in postmenopausal, elderly women (mean age 65 years). Most are asymptomatic, and the tumor is discovered during evaluation of an atypical Pap smear. Indeed, it is often associated with HSIL. The cervix is often normal on colposcopic and physical examination. The tumor is cytologically bland (often looks like “bland squamous cell carcinoma”) and features basaloid, adenoid, and squamoid differentiation. The adenoid areas consist of small, closely packed tubules, occasionally with intraluminal secretions reminiscent of mesonephric tubules (Fig. 5.21). There is typically no stromal response. Mitotic figures are rare or absent. The tumor has a favorable prognosis and needs to be distinguished from the adenoid cystic pattern of cervical adenocarcinoma, which does not have a favorable prognosis (21). Because of the extremely favorable prognosis associated with adenoid basal carcinoma, the diagnostic term adenoid basal epithelioma is preferred.
Figure 5.20 Neuroendocrine carcinoma of cervix. Malignant cells with high mitotic index are arranged in a sheetlike growth pattern. Necrosis is often present in these clinically aggressive tumors.
Adenoid Cystic Carcinoma
Unlike adenoid basal carcinoma (epithelioma), adenoid cystic carcinoma is a clinically aggressive neoplasm. It is composed of cribriform nests containing eosinophilic hyaline material within the gland lumens, resembling adenoid cystic carcinoma of the salivary gland
Localization of Adenocarcinoma: Primary versus Metastasis
Distinction between primary endometrial and primary endocervical adenocarcinoma may be difficult in biopsy and curettage specimens, especially when no precursor lesion is present. When clinical and histologic evaluation fails to clearly identify a carcinoma as cervical or endometrial in origin, an immunohistochemical panel that includes several markers, such as estrogen receptor (ER), progesterone receptor (PgR), vimentin, CEA, and p16 is often useful (19,22,23). Using this particular panel (Table 5.4), glandular proliferations that are ER/PgR-positive, vimentin-positive, CEA-negative, and p16-negative are almost always endometrial origin (Fig. 5.22), whereas those that are ER and PgR negative, vimentin negative, CEA positive, and p16 positive are very likely to be endocervical in origin (Fig. 5.23). However, overexpression of p16 can occur in a variety of other carcinomas independent of HPV status, including uterine (as well as cervical) serous carcinoma. Because the distinction between these two sites of origin may be based on whether a strong staining pattern with p16 is focal or diffuse in an individual case, this pattern of reactivity is most useful in whole tissue sections. In limited samplings, such as are encountered in routine biopsy and curettage specimens, these patterns may be misleading.
Figure 5.21 Adenoid basal carcinoma (epithelioma). This variant of cervical adenocarcinoma is characterized by nests of bland basaloid and squamoid cells in the cervical stroma. A squamous intraepithelial lesion is typically present in the overlying mucosa. This neoplasm is often referred to as adenoid basal epithelioma because it has a very favorable prognosis. (top, low power; bottom, high power)
The most common sites of origin for metastatic carcinomas presenting in uterine curettings are breast, stomach, ovary, and colon. Most patients have a previous history of carcinoma, and the metastasis is not the first presentation of disease. Lymphoma and melanoma, although rare, also continue to pose diagnostic problems when encountered in this location because of their mimicry of undifferentiated carcinoma or sarcoma. Use of a basic panel for undifferentiated tumors and a low threshold for suspecting metastasis will prevent most misclassifications.
Table 5.4 Distinguishing Endometrial from Endocervical Adenocarcinoma
Figure 5.22 Endometrial adenocarcinoma (upper left). Endometrial adenocarcinoma is typically ER/PgR-positive (upper right), vimentin-positive (lower right), and p16-negative (lower left).
Stromal and smooth muscle tumors may occur in the cervix; they resemble their more common uterine counterparts. Although the vagina is the more common site, embryonal rhabdomyosarcoma may also occur in the cervix; in contrast to vaginal rhabdomyosarcoma, which is more common in children, cervical rhabdomyosarcoma tends to occur in young adults. Most are embryonal, but spindle and alveolar variants may also be seen.
Mixed Epithelial and Mesenchymal Tumors
The same mixed epithelial and mesenchymal tumors that occur in the uterine corpus may occur in the cervix. They tend to exhibit the same patient demographics as their uterine counterparts, but cervical adenosarcomas tend to occur at a younger age (24). Most present during the reproductive years with abnormal bleeding and recurrent polyps. Data are limited, but most appear to have a more favorable prognosis, possibly because of the early detection of low-stage disease in the majority of patients. As in uterine corpus tumors, depth of invasion and sarcomatous overgrowth are adverse prognostic indicators.
Figure 5.23 Endocervical adenocarcinoma (upper left). In contrast to endometrial adenocarcinoma (see Figure 5.22), endocervical adenocarcinoma is typically Er/PgR negative (upper right), vimentin negative (lower left), and p16 positive (lower right).
A variety of other neoplasms may arise in the uterine cervix. These include alveolar soft part sarcoma, rhabdomyoma, and nerve sheath tumors. Alveolar soft part sarcomas of the female genital tract appear to have a better prognosis than their counterparts in other sites. Yolk sac tumors may also occur in the cervicovaginal region. Melanoma, lymphoma, and leukemia usually involve the cervix secondarily either as metastases or in the setting of widespread disease (18).
Squamous Lesions of the Vagina
Squamous Intraepithelial Lesion
Preneoplastic lesions of the vagina are termed vaginal intraepithelial neoplasia (VAIN) and graded from 1 to 3. Similar to the cervix, condyloma and VAIN 1 correlate with LSIL andVAIN 2 and VAIN 3 correlate with HSIL. LSIL and HSIL in the vagina have the same morphologic features as those in the cervix. LSIL can be mimicked by vaginal papillomatosis, which exhibits papillary architecture, parakeratosis, and cytoplasmic halos. However, papillomatosis lacks significant acanthosis and nuclear atypia. HSIL can be mimicked by atrophy and immature squamous metaplasia, but can be distinguished by a lack of nuclear atypia in the latter two entities.
Squamous Cell Carcinoma
Primary squamous cell carcinoma of the vagina is uncommon. Vaginal SCC more frequently occurs as a result of secondary involvement by extension from the cervix or vulva. The morphologic features are the same as for the cervix. In patients with vaginal adenosis, immature squamous metaplasia involving areas of adenosis can be mistaken for invasive SCC, but the two entities can be readily distinguished by the lack of cytologic atypia and lack of desmoplastic response with the benign process.
Figure 5.24 Clear cell adenocarcinoma of vagina. In this solid pattern of clear cell carcinoma, sheets of malignant cells with clear cytoplasm extensively replace normal tissue.
Glandular Lesions of the Vagina
Clear cell adenocarcinoma is the most common malignant glandular lesion in the vagina, followed by endometrioid, mucinous, and mesonephric subtypes. The latter histologic subtypes occur predominantly in perimenopausal women.
Clear Cell Adenocarcinoma
Clear cell carcinoma of the cervicovaginal region is strongly linked to in utero exposure to diethylstilbestrol (DES) and has decreased in incidence with decreased use of this teratogen. It typically occurs in association with adenosis. Although the upper vagina is the most common site of involvement in DES-exposed women, the cervix is the most commonly affected site in non-DES-exposed women. The appearance is the same as the ovarian counterpart (Fig. 5.24). Prognosis is determined by tumor size, depth of invasion, and lymph node involvement.
The presence of glandular epithelium in the vagina is termed adenosis. Adenosis may exhibit mucinous endocervical-like epithelium or tuboendometrioid epithelium. It is often asymptomatic but may be detected by colposcopic examination. Atypical adenosis, which exhibits architectural and cytological atypia, is often seen in association with clear cell adenocarcinoma.
Fibroepithelial Stromal Polyp
Fibroepithelial stromal polyp is a common, typically small, exophytic polypoid lesion occurring in reproductive-aged women, most commonly in the vagina, but also in the vulva and cervix. Almost one-third occur during pregnancy. The polyps often occur in the anterior wall and range in size from 0.5 cm to 4.0 cm. Histologically, they are characterized by small spindle cells and enlarged, stellate multinucleated cells in a myxoid stroma (Fig. 5.25). Mitotic figures can be prominent and may raise the suspicion for a malignant process. However, fibroepithelial stromal polyps are distinguished from sarcoma botryoides by the absence of a cambium layer.
Figure 5.25 Fibroepithelial stromal polyp. Atypical stromal cells (inset) may simulate a malignancy, but this is a benign, probably reactive process. Although the lesion extends to the surface epithelium, there is no cellular condensation (forming a so-called cambium layer) at the surface; the absence of a cambium layer helps to distinguish this lesion from sarcoma botyroides on a limited sampling (see Figure 5.26). This polyp occurs most commonly in the vagina but can also be seen in the vulva and cervix.
Embryonal rhabdomyosarcoma is the most common vaginal sarcoma; it occurs almost always in infants and children, but rare cases have been reported in young adults and postmenopausal women. The tumors present as polypoid vaginal masses, often protruding through the introitus, that may vary in size from 0.2 cm to 12 cm. Microscopically, the tumor is composed of small, round to oval or spindle cells surrounded by an edematous, myxoid stroma (Fig. 5.26). A characteristically dense, cellular cambium layer can be seen in the subepithelial zone. Rhabdomyoblasts (strap cells) are present but may be sparse or ill defined. Identification of rhabdomyoblasts can be facilitated by immunostaining for myogenin or Myo-D1.
Figure 5.26 Sarcoma botyroides (embryonal rhabdomyosarcoma). Top left: Botyroid growth pattern of cervical embryonal rhabdomyosarcoma. Courtesy of Dr. Matthew Quick. Top right: Stellate cells set in myxoid stroma are more condensed beneath the surface epithelium, forming a distinct cambium layer. Bottom: Small cells with hyperchromatic nuclei are punctuated by larger cells with more abundant eosinophilic cytoplasm.
Wide local excision and combination chemotherapy is the preferred treatment for sarcoma botyroides. Staging in children is based on the Intergroup Rhabdomyosarcoma Study group classification; adults are staged according to the TNM and FIGO system. Most rhabdomyosarcomas in the vulvovaginal region are of the embryonal type, but rare tumors are of the alveolar type, which has a worse prognosis.
Melanoma is the second most common malignancy to occur in the vagina (after squamous cell carcinoma). Affected patients are typically 60 years of age and present with vaginal bleeding. Most, but not all lesions are pigmented, nodular or flat, and measure 2 cm to 3 cm in size at diagnosis; ulceration may be present. The anterior wall of the lower third of the vagina is the most common site. The diagnosis may be difficult on small biopsies because an in situ component or pagetoid spread is often absent. Epithelioid cell lesions may resemble carcinoma, whereas spindle cell lesions may create confusion for sarcoma. Immunohistochemical stains for melanoma markers are often required to establish a diagnosis. The prognosis is poor.
Postoperative Spindle Cell Nodule
A variety of reactive processes may occur within the vagina, particularly following surgical procedures. One such lesion is composed of a cellular, spindle cell proliferation that may simulate a neoplastic process. This lesion has been designated as postoperative spindle cell nodule.
Squamous Cell Lesions of the Vulva
Similar to the cervix, different terminology systems are in use to describe preneoplastic lesions of the vulva (25) (Table 5.5). These systems resemble the ones used for the cervix. Low-grade vulvar intraepithelial lesion (LVIL) encompasses condyloma acuminatum and VIN 1, whereas high-grade vulvar intraepithelial lesion (HVIL) encompasses VIN 2, VIN 3, and carcinoma in situ. The main difference lies in whether VIN is graded. The latest 2003 World Health Organization (WHO) classification grades VIN on a scale of 1 to 3, with VIN 3 further subdivided into classic type and simplex type. In contrast, the International Society for the Study of Vulvovaginal Disease (ISSVD) decided in 2004 to eliminate the category of VIN 1 and to abolish grading of VIN. This decision was based on the lack of evidence that condylomas, which account for the majority of VIN 1 lesions, progress to carcinoma and the lack of interobserver reproducibility for diagnosing VIN 1 or for distinguishing between VIN 2 and VIN 3 (26). The ISSVD retained the distinction between classic VIN and simplex (differentiated) VIN. Given the variability in terminology, it is best to determine what terminology system the pathologist is using, especially if the diagnosis is “vulvar intraepithelial neoplasia (VIN)” with no further specification.
Vulvar Intraepithelial Neoplasia
The two-tiered Bethesda-like system is a simple way to view precursor lesions of the vulva. LVIL consists predominantly of condyloma acuminata, which are associated with low-risk HPV types 6 and 11 (Fig. 5.27) Flat condylomas are uncommon in the vulva but may be associated with high-risk HPV. Fibroepithelial polyps (skin tags) and hymenal mucosa can be mistaken for exophytic condylomas. Nonspecific inflammatory atypia or psoriasis can be misdiagnosed as flat condylomas.
Table 5.5 Terminology for Precursor Lesions of Vulvar Squamous Cell Carcinoma
Figure 5.27 Condyloma. Exophytic condylomas are common in the vulva and are associated with low-risk HPV types 6 and 11.
HVIL can be subdivided into two main types of VIN 3: classic (Bowenoid) VIN and simplex (differentiated) VIN. These two types of VIN 3 underscore the two different pathways—HPV related and HPV unrelated—that lead to the development of vulvar squamous cell carcinoma. High-risk HPV is identified in 53% to 90% of cases of classic VIN 3, with HPV 16 as the most common type (27). However, HPV 18, 31, 33, 35, 51, 52, and 68 have also been isolated from cases of classic VIN (28). In contrast, HPV is rarely identified in simplex VIN (28).
Classic VIN is commonly multicentric with extension to the perineum and involvement of the cervix and vagina. There are three patterns or subtypes of classic VIN: warty, basaloid, and pagetoid. The warty pattern is characterized by prominent koilocytosis or warty architecture (Fig. 5.28), whereas the basaloid is more poorly differentiated (Fig. 5.29). The atypia involves two-thirds or more of the epithelium and is notable for disorganization, cells with high nuclear-to-cytoplasmic ratios, dark irregular nuclei, and numerous mitotic figures, including abnormal forms. Dyskeratotic cells are often present, and the dysplastic cells frequently extend down pilosebaceous units, which can mimic invasive carcinoma. The pagetoid subtype is rare but important to recognize because it can closely mimic extramammary Paget's disease. The distinction between these two entities requires special stains because histologically they are both characterized by single cells and clusters of cells with pale cytoplasm involving the squamous epithelium of the vulva.
Simplex VIN is localized to the vulva and usually identified adjacent to areas of invasive carcinoma in elderly patients. It is rarely identified prospectively (29). The morphologic changes of simplex VIN are subtle and characterized by nuclear atypia of the basal cell layer and expansion of the basal layer into elongated, narrow, branching rete ridges (Fig. 5.30) The nuclei can range from relatively small, dark and irregular to enlarged and pleomorphic. Maturation is also abnormal as exhibited by the presence of enlarged keratinocytes with large, pleomorphic nuclei and abundant, markedly eosinophilic cytoplasm in the mid- to superficial layers. These abnormal keratinocytes can also extend into the basal layer and involve the rete ridges (29). The thickness of the epithelium is variable and can be atrophic or acanthotic (i.e., thickened). The differential diagnosis for simplex VIN includes lichen sclerosus with squamous hyperplasia and other benign dermatologic conditions such as lichen simplex chronicus, psoriasis, spongiotic dermatitis, and candida vulvitis.
Figure 5.28 Classic VIN, warty. Prominent koilocytosis is present on the surface and overlies severe atypia involving two-thirds of the underlying epithelium.
Figure 5.29 Classic VIN, basaloid. Cells with high nuclear-to-cytoplasmic ratios and dark, irregular nuclei involve the full thickness of the squamous epithelium.
Lichen sclerosus is considered a risk factor for the development of vulvar squamous cell carcinoma. It appears to play a role in the HPV-independent pathway. Lichen sclerosus is negative for HPV and is more frequently identified in association with simplex VIN than with classic VIN (27,28).
Squamous Cell Carcinoma
Primary invasive squamous cell carcinomas of the vulva can be subdivided into two main types: conventional squamous cell carcinoma and verrucous carcinoma. Conventional squamous cell carcinomas can exhibit different growth patterns, including warty, basaloid, and keratinizing (Fig. 5.31). Invasive squamous cell carcinomas that have warty or basaloid features are typically associated with classic VIN and high-risk HPV, whereas well-differentiated keratinizing squamous cell carcinomas are more commonly associated with simplex VIN (27).
Figure 5.30 Simplex VIN. Abnormal keratinocytes with abundant, markedly eosinophilic cytoplasm involve the mid- to superficial layers and extend into the elongated, branching rete ridges.
Figure 5.31 Conventional keratinizing squamous cell carcinoma of the vulva. Nests of well-differentiated tumor cells jaggedly invade into the stroma on microscopic examination.
Verrucous carcinoma is a rare special variant of squamous cell carcinoma that is slow growing and has minimal metastatic potential. It is typically exophytic, well circumscribed, and composed of hyperkeratotic fronds of cytologically bland squamous epithelium. The interface with the underlying stroma characteristically consists of a pushing border with associated chronic inflammation (Fig. 5.32).
Figure 5.32 Verrucous carcinoma of the vulva. Top:Vulvectomy specimen shows exophytic verrucous tumor. Bottom:The tumor is exophytic with hyperkeratotic fronds of bland squamous epithelium and well circumscribed with a pushing border with the underlying stroma.
Bartholin duct cyst is the most common cystic growth in the vulva. It occurs posteriorly in the vulvar vestibule. Excision is usually reserved for those lesions that fail to respond to conservative management. However, some investigators recommend excision of Bartholin gland cysts to exclude adenocarcinoma when cysts or abscesses occur in patients more than 40 years of age. The cyst lining is often variable: Endocervical-like mucinous, squamous, and transitional epithelium is often present. The presence of atypia, cellular stratification, or mitotic figures are concerning features and should warrant full pathologic examination of the entire cyst wall to exclude carcinoma.
Bartholin Gland Adenocarcinoma
An uncommon tumor, this neoplasm affects women 50 years of age and older. The clinical impression is usually that of a Bartholin duct cyst. Histologic types include adenocarcinoma, squamous cell carcinoma, adenoid cystic carcinoma, and hybrid types. A transition zone to adjacent Bartholin gland confirms the diagnosis. Approximately 20% of patients have ipsilateral groin lymph node metastases at initial diagnosis.
Fibroepithelial Stromal Polyp
Fibroepithelial stromal polyps also occur on the vulva but are most commonly seen in the vagina. They may be single or multiple. Fibroepithelial stromal polyps probably represent a reactive lesion rather than a true neoplasm.
A rare benign glandular neoplasm, papillary hidradenoma usually occurs in the region of the intralabial sulcus in adult women. The tumor is well circumscribed and composed of complex, branching papillae lined by a double layer of outer myoepithelial and inner epithelial cells (31).
Extramammary Paget's Disease
Paget's disease of the vulva is an intraepithelial neoplasm characterized by large, round cells with abundant, pale cytoplasm, often forming small intracytoplasmic lumina or glandlike structures (31). Vulvar Paget's disease may be primary or secondary and presents clinically as a red, eczematous lesion. Postmenopausal women are most commonly affected. Approximately 90% are primary and noninvasive (cutaneous), whereas 10% are associated with an underlying invasive carcinoma (cutaneous, anorectal, urothelial). All forms of Paget's disease are immunoreactive for cytokeratin and epithelial membrane antigen. Classic primary cutaneous vulvar Paget's disease also expresses CK7 and HER-2/neu(Fig. 5.33), whereas secondary Paget's often exhibits an immunophenotype of the primary site of origin.
A variety of specialized genital stromal neoplasms occur in the vulvovaginal region of reproductive-aged women (32). Most are small, hormonally responsive, and clinically indolent. The most common specialized genital stromal tumors are angiomyofibroblastoma, cellular angiofibroma, and superficial angiomyxoma (33). Often mistaken clinically for a Bartholin gland cyst, these specialized genital stromal lesions may recur locally if incompletely excised, but they are not associated with aggressive clinical behavior.
Prepubertal vulval fibroma is unlikely to be confused with any of the typical vulvar mesenchymal lesions because of its predilection for prepubertal females. This lesion, which most commonly involves the labia majora, presents as a unilateral or, rarely, bilateral, illdefined, and painless subcutaneous vulvar mass with microscopic features that suggest a hamartomatous process.
Other mesenchymal neoplasms that behave in a clinically benign fashion include lipoma, neurofibroma, schwannoma, granular cell tumor, glomus tumor, and hemangioma.
Dermatofibrosarcoma protuberans is a low-grade cutaneous tumor with a high risk for recurrence if incompletely excised. High-grade sarcomas that most commonly occur in the vulva include rhabdomyosarcoma, proximal epithelioid sarcoma, alveolar soft part sarcoma, Ewing's sarcoma and peripheral primitive neuroectodermal tumor, and postradiation angiosarcoma.
Rarely, smooth muscle tumors may involve the vulvar region. Criteria for malignancy differ from those for uterine smooth muscle tumors and are based on size (>5 cm), mitotic index (>5 mitotic figures per 10 high-power fields), infiltrative margins, and cellular atypia.
Figure 5.33 Paget's disease of vulva. Top: Paget cells are confined to the intraepidermal compartment, forming small glandlike structures. Bottom:The Paget cells express cytokeratin 7.
Aggressive angiomyxoma occurs in the deep vulvar and inguinal soft tissue and is characterized by a paucicellular spindle cell proliferation separated by loose myxoid stroma (Fig. 5.34). Mitotic activity is low. Despite the bland histologic appearance, it is an infiltrative tumor that may locally invade deep pelvic structures if incompletely excised (31). Aggressive angiomyxoma occurs most commonly during the third to fifth decades. The clinical impression frequently includes Bartholin's gland cyst or hernia; the extent of disease is often underestimated.
Figure 5.34 Aggressive angiomyxoma of vulva. Paucicellular spindle cell proliferation separated by loose myxoid stroma. Despite the bland appearance, this is an infiltrative tumor with a propensity for recurrence if incompletely excised.
Malignant melanoma accounts for less than 10% of all vulvar malignancies and consists of three types: mucosal or acral lentiginous, nodular, and superficial spreading. As many as 25% are unclassified. Vulvar melanoma occurs more commonly in elderly, white women and typically presents as a nodular mass that may be pigmented; satellite lesions are common. Melanomas express S-100 protein, HMB-45, and Melan A (Fig. 5.35). Clark levels and Breslow thickness should be reported for all vulvar melanomas.
Benign, atypical, and dysplastic nevi occur in the vulva. Benign nevi may be congenital or acquired. Atypical vulvar nevi (atypical melanocytic nevi of the genital type) occur primarily in young, reproductive-aged women and are characterized by atypical superficial melanocytes and variably sized junctional melanocytic nests. They are distinguished from melanoma on the basis of small size, circumscription, absence of pagetoid spread, significant cytological atypia and mitotic activity in the deeper dermal melanocytes. Atyical vulvar nevi may appear more atypical during pregnancy. They are not associated with dysplastic nevi elsewhere. Dysplastic nevi also occur predominantly in younger women but exhibit an irregular border; microscopically, clusters of atypical spindled and epithelioid nevus cells with prominent nucleoli and nuclear pleomorphism are seen. Unlike atypical vulvar nevi, dysplastic vulvar nevi may be associated with dysplastic nevi elsewhere on the trunk and extremities.
Other tumors that occur in the vulva include cutaneous adnexal tumors, tumors that arise from specialized anogenital mammary-like glands, and tumors of minor vestibulary gland and Skene gland origin (31).
Figure 5.35 Vulvar melanoma. Top: Nests of epithelioid cells extensively replace normal vulvar tissue. Bottom: Strong expression of S100 protein.
The endometrial morphologic changes with which the gynecologic oncologist is concerned are limited and chiefly involve endometrial carcinoma and its precursors. This section focuses on these proliferations and those that figure in their differential diagnosis.
In discussing endometrial nonsecretory proliferations it is helpful to realize that the endometrium can give rise to a variety of epithelial phenotypes that are more commonly encountered in other parts of the müllerian-derived system: the ovary, the fallopian tubes and the endocervix. The term metaplasia is used for benign epithelial proliferations of this type, and special variant carcinomas is used for the malignant patterns. Endometrial epithelial proliferations, whether benign or malignant, typically feature mixtures of these differentiated epithelial types. The carcinoma precursors feature this mixed epithelial phenotype in varying degrees, hence the full designation hyperplasia/metaplasia, which is to be understood when hyperplasia is used unmodified.
The term endometrial hyperplasia denotes a proliferating endometrium featuring glandular architectural abnormalities that result in glandular crowding and take the form of eithercystic dilatation of glands (simple hyperplasia) or glandular budding (complex hyperplasia). Current taxonomy further stratifies hyperplastic endometria on the basis of their cytologic features into atypical endometrial hyperplasia and nonatypical endometrial hyperplasia, the latter term implying that significant cytologic atypia is absent. The risk posed by hyperplasia for the subsequent development of endometrial carcinoma is roughly correlated with the degree of cytologic atypia present. The assessment of atypia is subject to observer disagreement. The WHO classification is simplified to simple without atypia, complex without atypia, and atypical hyperplasia (simple or complex) (Table 5.6) (Figs. 5.36and 5.37).
Table 5.6 Features of Endometrial Hyperplasias
Figure 5.36 Simple endometrial hyperplasia without atypia. An increased number of round glands is seen, some of which are cystically dilated. There is no cytologic atypia.
Figure 5.37 Complex atypical hyperplasia. Crowded, irregular glands show little intervening stroma. The glands show rounded, pleomorphic nuclei with prominent nucleoli. (top, low power; bottom, high power)
Atrophic or Weakly Proliferative Endometrium with the Architecture of Hyperplasia When a complex hyperplasia is the last unshed endometrium of a postmenopausal woman and the epithelium subsequently becomes atrophic in the wake of estrogen withdrawal, then the pattern often mimics hyperplasia. Confusion is avoided when it is noted that the epithelium is atrophic and not proliferating.
Well-Differentiated Adenocarcinoma (Usual or Special Variant) This is the chief differential diagnostic consideration and, unfortunately, the one that exhibits among the highest levels of expert disagreement in gynecologic pathology. The reasons for this are set out elsewhere, (41) and the differential diagnosis is discussed below.
First, carcinomas may be classified in terms of their differentiated histopathologic features (Table 5.7). The endometrium gives rise to a variety of differentiated carcinomas, but more than 80% are glandular neoplasms that resemble the epithelium found in endometrial hyperplasia. Squamous or squamoid (morular) differentiation is commonly encountered in this endometrioid or usual adenocarcinoma. The term endometrioid is used to denote this histologic pattern and to distinguish it from endometrial, which is the generic term for carcinomas that originated anatomically in the endometrium. Other müllerian-differentiated types (e.g., serous, clear cell, mucinous) make up the remainder of endometrial carcinomas, the so-called special variants.
Endometrial carcinomas may also be grouped with an eye to the hormonal (and associated epidemiologic) background in which they arise: hyperestrogenic settings (type I) or hypoestrogenic settings (type II).
Patients in the first group (type I) tend to be between 40 and 60 years of age (although carcinoma can develop in younger women, including, in rare instances, those in their 20s).They may have a history of chronic anovulation or estrogen hormone-replacement therapy, and the carcinomas are usually well differentiated, stage I, nonmyoinvasive tumors associated with endometrial hyperplasia/metaplasia (found either concurrently or in previous endometrial samplings). Most of the tumors are estrogen and progesterone receptor (ER and PgR) positive and p53 negative and express low levels of the proliferation antigen Ki-67. Patients in this first group have a very favorable prognosis after hysterectomy.
In contrast, patients in the second group (type II) tend to be elderly and typically have no history of hyperestrogenism. In these cases, the surrounding nonneoplastic endometrium is almost always atrophic or only weakly estrogen supported, but there may be an in situ component with high-grade cytologic features. The carcinomas that develop in this group of patients are usually of the special variant type with a poor prognosis or are high-grade endometrioid neoplasms that are high stage with deep myoinvasion. They tend to be ER and PgR negative, strongly express p53, and show high Ki-67 labeling.
Table 5.7 Classification of Endometrial Carcinoma
Most endometrial adenocarcinomas are of endometrioid type. In these tumors, malignant glands are lined by stratified, often elongated, nuclei, reminiscent of benign endometrial epithelium. A distinct subtype of endometrioid carcinoma is villoglandular carcinoma, in which there are long, slender papillae lined by relatively bland cells with cigar-shaped nuclei (Fig. 5.38).
Figure 5.38 Villoglandular carcinoma. Delicate, elongated papillae (analogous to villous structures in villous adenomas of the large bowel) are lined by small, complex, epithelial buds. (top, low power; bottom, high power)
Figure 5.39 Well-differentiated endometrioid adenocarcinoma. Back-to-back glands with minimal or no intervening stroma (upper left) and cytologic atypia (note prominent nucleoli, upper right) are features of usual endometrial carcinoma. Glandular nests with extensive cribriforming is another common pattern seen in endometrioid adenocarcinoma (lower left and lower right). Note that in this example, the cytologic atypia is not significantly different from that seen in endometrial hyperplasia (lower right) and the diagnosis of carcinoma is based on complex architecture.
Villoglandular carcinoma is a low-grade tumor with an excellent prognosis; the main reason for recognizing this subtype is that it should not be confused with serous carcinoma of the endometrium (see below), which is also papillary but has a much worse prognosis.
Well-Differentiated Adenocarcinoma versus Atypical Hyperplasia or Metaplasia
A variety of morphologic definitions of well-differentiated adenocarcinoma have been published over the years and differ in various respects (34,35). Most require a certain level of cytologic atypia or architectural complexity. Architectural complexity usually takes the form of one or more of the following: extensive budding and branching of glands and papillary structures with superimposed secondary structures (buds or secondary papillae) and a cribriform pattern (Fig. 5.39). Expert disagreement over cases in this gray zone is common. Fortunately, this disagreement impedes clinical decision making in only a small subset of patients, including those with comorbidities or those for whom uterine conservation is important.
Adenocarcinoma with Squamous Elements
Squamous elements are very common in endometrioid adenocarcinoma of all grades (Fig. 5.40). The presence of squamous differentiation does not affect the prognosis. Of importance, the squamous areas (benign or malignant), which typically form sheets, are excluded when determining architectural grade (see below).
Secretory and Ciliary Carcinomas
Other subtypes of endometrioid adenocarcinoma include the rare secretory carcinoma and ciliated carcinomas. These are well differentiated and have a favorable prognosis. These morphologic patterns can also be seen focally in an otherwise ordinary endometrioid carcinoma.
Mucinous adenocarcinoma (Fig. 5.41) is usually low-grade and low-stage and is frequently seen in women treated with tamoxifen. If this pattern is seen in an endometrial sampling, the anatomic origin—cervix or endometrium—may be in doubt. Strategies for illuminating this issue are set out in Table 5.5.
Serous Carcinoma This tumor makes up between 5% and 10% of all endometrial carcinomas and is known for its aggressive behavior (36,37,38). It typically affects postmenopausal women and arises in the setting of endometrial atrophy. The hallmarks of this carcinoma are a tendency for myometrial invasion, extensive lymphatic space invasion, and early (and clinically inapparent) dissemination beyond the uterus (most often in the form of diffuse peritoneal involvement). Microscopically, the tumor is composed of complex papillary fronds lined by highly malignant cells possessing prominent, eosinophilic nucleoli (Fig. 5.42). Uterine serous carcinoma generally lacks ER and PgR and is strongly immunoreactive for p53. Serous carcinoma of endometrium is not graded; it is regarded as a high-grade tumor by definition.
Figure 5.40 Endometrioid adenocarcinoma with squamous elements. A solid area of benign-appearing squamous cells is seen in the right half of the field.
Only a minority of papillary proliferations of the endometrium are serous carcinomas; more frequent are papillary hyperplasia/metaplasias and villoglandular endometrioid carcinomas. All of these are benign or low-grade proliferations and must be distinguished from serous carcinoma (Table 5.8). Metastatic serous carcinoma to the endometrium must also be excluded.
In Situ Serous Carcinoma (Endometrial Intraepithelial Carcinoma)
This lesion is characterized by replacement of benign (often atrophic) endometrial epithelium by highly malignant cells resembling serous carcinoma (Fig. 5.43) (38). It is regarded as a precursor of serous carcinoma and is sometimes seen adjacent to it (39).
Clear Cell Carcinoma
Primary clear cell carcinoma of the endometrium is histologically indistinguishable from clear cell carcinoma in the ovary. This neoplasm combines high-grade cytologic features characterized by enlarged, angulated nuclei and large, irregular nucleoli with cytoplasmic clearing (at least in focal areas). The architecture may be papillary, glandular, or sheetlike. When it is glandular, the tumor cell nuclei often protrude into the luminal space, giving rise to a hobnail or tombstone appearance (Fig. 5.44). The differential diagnosis includes first, the hypersecretory change (Arias-Stella reaction) (Fig. 5.45) seen both in pregnancy and with the use of progestational medication; and, second, the clinically nonaggressive secretory variant of endometrioid carcinoma.
Squamous Cell Carcinoma
Primary squamous cell carcinoma of the endometrium is very rare and is much less common than extension of a primary uterine cervical carcinoma to the endometrium. Primary squamous cell carcinoma of the endometrium may be associated with cervical stenosis and pyometra.
Figure 5.41 Mucinous adenocarcinoma. Confluent and cribriform glands are lined by mucinous epithelium. (top, low power; bottom, high power)
This is a tumor that shows no glandular or squamous differentiation. It represents 1% to 2% of all endometrial carcinomas and has epidemiologic features similar to those of endometrioid carcinoma.
Tumor heterogeneity is, of course, ubiquitous and a well-established consequence of tumor progression; endometrial carcinomas are no exception. When differences between components become sufficiently striking, the term mixed is employed. To qualify for this diagnosis, the minor component(s) should compose 10% or more of the tumor.
Figure 5.42 Serous carcinoma of the endometrium. Papillae and glands are composed of malignant cells with marked nuclear atypia. (top, low power; bottom, high power)
Histologic Grading of Endometrioid Carcinoma
The histologic grade is assigned according to the percentage of solid epithelial growth (not including areas of squamous differentiation).
- FIGO grade 1: The tumor exhibits well-formed glands and has 5% or less of solid growth pattern.
Table 5.8 Papillary Proliferations of the Endometrium
Figure 5.43 In situ serous carcinoma of the endometrium. High-grade nuclear atypia of serous carcinoma contrasts with benign, inactive glandular epithelium of the adjacent, nonhyperplastic endometrium.
- FIGO grade 2: The solid growth pattern occupies between 6% and 50% of the tumor.
- FIGO grade 3: Tumors display more than 50% solid epithelial growth.
Severe nuclear atypia raises the grade by one, but the possibility of a nonendometrioid (serous or clear cell) carcinoma should always be excluded in this situation.
Figure 5.44 Clear cell carcinoma of the endometrium. Malignant glands are lined by anaplastic hobnail cells with clear cytoplasm. (top, low power; bottom, high power)
Pathologic Staging of Endometrial Carcinoma
Endocervical involvement is usually diagnosed on the hysterectomy specimen. Infrequently, it may be diagnosed from an endocervical curettage, but the cancer present in the endocervical curettage is usually a contamination from the uterine cavity.
Figure 5.45 Arias-Stella reaction of the endometrium. The glandular lining shows enlarged hobnail cells with clear cytoplasm and “smudged” nuclei, a pattern that may mimic clear cell carcinoma.
The depth of myometrial invasion is expressed as a proportion of the myometrium invaded by carcinoma; in the FIGO staging system, this is reported as inner or outer half. The presence of lymphatic or vascular space invasion is not used to determine the depth of invasion. Involvement of adenomyosis by adenocarcinoma may resemble myometrial invasion on intraoperative visual examination; the presence of residual endometrial stroma or benign basalis glands between the tumor and myometrium is a helpful microscopic differentiating feature.
Simultaneous primary involvement should be considered before diagnosing ovarian metastases with well differentiated uterine endometrioid carcinoma. In most such cases, the uterine tumor shows minimal or no myometrial invasion and there is no lymphovascular or cervical stromal invasion.
Endometrial stromal tumors and smooth muscle tumors account for the majority of mesenchymal neoplasms in the uterine corpus. Although most endometrial stromal neoplasms are easily separated from smooth muscle neoplasms, there is a range over which clear distinction is not possible using conventional light microscopy and immunohistochemistry. These “mixed” tumors are occasionally referred to as stromomyomas; however, when such lesions remain ambiguous despite immunohistochemical analysis and the probability of an endometrial stromal proliferation is high on other grounds, they should be assigned to the endometrial stromal group for management purposes (40).
Smooth Muscle Tumors
Smooth muscle tumors are the most common mesenchymal neoplasm in the uterus. Most are composed of interlacing fascicles of spindle-shaped smooth muscle fibers (Fig. 5.46), but epithelioid (Fig. 5.47) and myxoid (Fig. 5.48) variants are also seen.
Leiomyomas represent the most common tumor of the uterus. They present during reproductive years and are often multiple. The typical gross appearance is that of a well circumscribed, solid, white to tan myometrial nodule with a trabeculated surface on cut sections.
Figure 5.46 Uterine smooth muscle tumor (leiomyoma), standard morphology. The usual smooth muscle tumor forms a discrete intramyometrial fibrous mass. Bland spindle cell histology features ovoid, blunt-ended nuclei with no atypia.
Figure 5.47 Uterine smooth muscle tumor (leiomyoma), epithelioid morphology. Some smooth muscle tumors exhibit pronounced epithelioid histology, mimicking epithelial processes.
Figure 5.48 Uterine smooth muscle tumor (leiomyoma), myxoid morphology. Rarely, smooth muscle tumors undergo extensive myxoid change. In these cases, a myxoid leiomyosarcoma must be excluded.
Degenerative changes may alter this appearance, and edema, hemorrhage, fibrosis, and hyaline (infarction-type) necrosis are commonly seen. Occasionally, mitotically active leiomyomas containing 15 or more mitotic figures per 10 high-power fields may be encountered; in the absence of other atypical features (i.e., coagulative tumor cell necrosis or significant cytologic atypia), these neoplasms are clinically benign (41).
Leiomyomas exhibiting dense cellularity without tumor cell necrosis or significant cytologic atypia are designated cellular leiomyomas; these cellular neoplasms are clinically benign but may be confused with endometrial stromal neoplasms (Fig. 5.49). They are distinguished from stromal tumors by the presence of diffuse expression of the smooth muscle markers desmin and caldesmon with minimal or absent expression of CD10 (41).
Leiomyomas that exhibit diffuse or multifocal moderate to severe cytologic atypia, but no tumor cell necrosis or increased mitotic index (>10 mitotic figures per 10 high-power fields) are designated atypical leiomyomas with low potential for recurrence (Fig. 5.50). Most such tumors are clinically benign, although local recurrence may rarely occur (42).
Leiomyosarcomas are uncommon uterine tumors but are the most common sarcoma in the uterus. They typically affect adult women in the perimenopausal years. Leiomyosarcomas are typically solitary, fleshy, and necrotic intramural tumors. The presence of coagulative tumor cell necrosis, moderate to severe cytologic atypia, and numerous mitotic figures distinguish leiomyosarcoma from leiomyoma (Fig. 5.51). Leiomyosarcoma is a highly malignant neoplasm, and the prognosis is poor.
Epithelioid leiomyosarcomas exhibit patterns of epithelioid differentiation in addition to the usual features of malignancy seen in the more conventional leiomyosarcoma: cytologic atypia, tumor cell necrosis, and increased mitotic index (5 mitotic figures per 10 high-power fields) (41).
Figure 5.49 Cellular leiomyoma. Leiomyomas with marked cellularity may mimic endometrial stromal differentiation (see Figures 5.53 and 5.54). (top, low power; bottom, high power)
Myxoid leiomyosarcoma is a large, gelatinous neoplasm that usually appears to be circumscribed on gross examination. Microscopically, the smooth muscle cells are usually widely separated by myxoid material (Fig. 5.52). The characteristic low cellularity partly accounts for the presence of only a few mitotic figures per 10 high-power fields in most myxoid leiomyosarcomas. Despite the low mitotic counts, myxoid leiomyosarcoma has the same unfavorable prognosis as typical leiomyosarcoma (41).
Figure 5.50 Atypical leiomyoma. Diffuse, marked nuclear atypia in the absence of tumor cell necrosis and increased mitotic index is classified as atypical leiomyoma, which has a low risk of recurrence.
Smooth Muscle Tumor of Uncertain Malignant Potential
Uterine smooth muscle tumors that cannot be reliably diagnosed as benign or malignant are designated as tumors of uncertain malignant potential. This diagnosis is used when there is uncertainty concerning the type of necrosis (hyaline versus coagulative), the subtype of smooth muscle differentiation (standard versus epithelioid versus myxoid), the degree of cytologic atypia or the mitotic index (41).
Smooth Muscle Neoplasms with Unusual Growth Patterns
Uterine smooth muscle tumors may demonstrate unusual patterns of distribution. As in other uterine smooth muscle neoplasms, the tumors showing these unusual patterns of distribution may exhibit standard spindle, epithelioid, or myxoid histology (41).
Diffuse leiomyomatosis refers to the presence of numerous, histologically benign small smooth muscle nodules diffusely distributed throughout the uterus. The nodules range up to 3 cm in diameter, but most are less than 1 cm. This condition is benign.
This condition is characterized by the presence of cords of histologically benign smooth muscle growing within venous channels beyond the confines of a leiomyoma. Extension into pelvic veins and, on occasion, the inferior vena cava and right heart may be seen.
Benign Metastasizing Leiomyoma
This clinicopathologic condition consists of the presence of histologically benign smooth muscle tumors in the lung, pelvic lymph nodes, or abdomen in association with a histologically benign uterine smooth muscle tumor. Typically, the uterine tumor is removed years before the extrauterine tumors are detected.
Disseminated Peritoneal Leiomyomatosis
Disseminated peritoneal leiomyomatosis is a rare condition characterized by widespread nodules of histologically benign smooth muscle in the omentum and peritoneum, often numbering in the tens to hundreds. The nodules are usually small, firm, gray to white, and cover the peritoneal surfaces, clinically simulating a disseminated malignancy. This condition typically occurs during the reproductive years and many patients are pregnant at the time of diagnosis. Despite the alarming appearance, disseminated peritoneal leiomyomatosis is usually associated with an indolent clinical course and can be treated conservatively with long-term follow-up.
Figure 5.51 Uterine leiomyosarcoma. Diagnostic criteria for uterine leiomyosarcoma are diffuse atypia, tumor cell necrosis, and increased mitotic index. (top, low power; bottom, high power)
Endometrial Stromal Tumors
Neoplasms in the endometrial stromal group resemble the stroma of normal proliferative phase endometrium. In the uterus, they are divided into two main categories: endometrial stromal nodule and endometrial stromal sarcoma. Both are composed of a monomorphous population of ovoid to spindled cells possessing scanty cytoplasm and small, bland, uniform nuclei with evenly distributed chromatin. These cells are embedded in an abundant reticulin framework that contains a highly characteristic, delicate, arborizing vasculature. Focal hyaline thickening of the vessel walls and collagen bands may be present. Endometrial stromal nodule is clinically benign, whereas endometrial stromal sarcoma may recur, sometimes many years after the primary tumor has been removed.
Figure 5.52 Uterine myxoid leiomyosarcoma. This rare variant of uterine leiomyosarcoma may exhibit clinically aggressive behavior in the absence of significant mitotic activity (>2 mitotic figures per 50 high-power fields). The presence of cytologic atypia and tumor cell necrosis distinguishes this infiltrative lesion from myxoid leiomyoma. (top, low power; bottom, high power)
Endometrial Stromal Nodule
Endometrial stromal nodule is well circumscribed, usually small, and intramural (Fig. 5.53). Infiltration of the myometrium or uterine vasculature is absent. Because diagnosis is based on complete circumscription and absence of lymphovascular invasion, the distinction between stromal nodule and stromal sarcoma can usually be made only at the time of hysterectomy.
Figure 5.53 Endometrial stromal nodule. Endometrial stromal tumors are composed of small, uniform cells with scant cytoplasm similar to stromal cells in normal proliferative phase endometrium. When an endometrial stromal tumor is well circumscribed and there is no lymphovascular invasion, it is clinically benign and classified as an endometrial stromal nodule.
Endometrial Stromal Sarcoma (Low Grade)
Endometrial stromal sarcoma accounts for less than 20% of all uterine sarcomas, occurs almost exclusively in adults, and has a peak incidence in the fifth decade; more than three-quarters of women are premenopausal. There is no association with previous irradiation nor do patients share the risk profile of patients with endometrial carcinoma. Endometrial stromal sarcoma is an indolent neoplasm with a protracted clinical course. At the time of clinical presentation, most tumors are confined to the uterus. Extrauterine disease is associated with a higher risk for recurrence but is still compatible with long-term survival. Patients come to clinical attention because of a mass that may be associated with abdominal pain or uterine bleeding. When advanced, the uterus is asymmetrically enlarged by a typically yellow or tan tumor mass that infiltrates the surrounding normal myometrium, often extending into the endometrial cavity as a polypoid growth. The neoplasm is distinguished from endometrial stromal nodule by (i) the presence of infiltrating margins or (ii) vascular invasion (Fig. 5.54). In most cases, mitotic figures are difficult to find, but occasional tumors have in excess of 10 mitotic figures per 10 high-power fields. Although it was traditional to grade endometrial stromal sarcoma based on mitotic index, this classification currently has relatively little utility in diagnostic practice and patient management (43). Endometrial stromal sarcoma should be distinguished from “undifferentiated sarcoma,” a clinically highly aggressive neoplasm, which shares with endometrial stromal sarcoma a generally undifferentiated appearance but has a greater degree of cytologic atypia.
Undifferentiated Uterine Sarcoma
Undifferentiated uterine sarcoma is much less common than low-grade endometrial stromal sarcoma (44). Undifferentiated uterine sarcomas are easily recognized as cytologically malignant and are composed of highly cellular, often pleomorphic, undifferentiated rounded to spindled cells with a high mitotic index (Fig. 5.55). Most resemble the undifferentiated malignant stroma often encountered in carcinosarcomas. Undifferentiated uterine sarcomas, in sharp contrast to endometrial stromal sarcomas, are aggressive neoplasms with a high incidence of metastases.
Figure 5.54 Endometrial stromal sarcoma. The presence of infiltrative margins and lymphovascular invasion distinguish low-grade endometrial stromal sarcoma from benign stromal nodule. (top, low power; bottom, high power)
Mixed Müllerian Neoplasms
Mixed müllerian neoplasms are biphasic epithelial-mesenchymal proliferations that exhibit a range of clinical behaviors from benign to highly malignant. Adenofibroma, adenomyoma, and atypical polypoid adenomyoma are the common biphasic epithelial-mesenchymal lesions at the benign end of the spectrum, whereas adenosarcoma andcarcinosarcoma represent the malignant end of the spectrum (Table 5.9).
Figure 5.55 Undifferentiated uterine sarcoma. Mesenchymal tumors showing marked cellularity, cytologic atypia, and high mitotic index are classified as undifferentiated uterine sarcomas. Heterologous elements may also be present.
Table 5.9 Mixed Müllerian Neoplasms
Adenofibromas are considered to be clinically benign with little risk for recurrence once they are completely excised. They typically have broad, fibrotic to mildly cellular stroma with intervening cleftlike epithelial-lined surfaces morphologically similar to phyllodes tumor of the breast (Fig. 5.56). Authorities differ on the appropriate mitotic index for distinguishing adenofibroma from adenosarcoma. Zaloudek and Norris advocate a threshold of 4 mitotic figures per 10 high-power fields (45), whereas Clement and Scully suggest a threshold of 2 mitotic figures per 10 high-power fields (46). In most instances, the 4 mitotic figures per 10 high-power fields criterion is sufficient to diagnose adenosarcoma, but tumors with particularly cellular stroma or borderline mitotic counts are best regarded as being of uncertain malignant potential, particularly if subepithelial condensation is present (see Adenosarcoma below).
Atypical Polypoid Adenomyoma
Atypical polypoid adenomyoma is a polypoid endometrial proliferation composed of irregular glands set in a stroma composed of smooth muscle or, more commonly, smooth muscle and fibrous tissue (Fig. 5.57). Morular or squamous metaplasia is present in most cases and is often florid. The endometrial samplings typically consist of large fragments or chunks of tissue simulating carcinoma. The condition occurs in premenopausal or perimenopausal women; a clinical history of infertility is not uncommon. These lesions can recur locally but do not have metastatic potential. Reproductive conservation utilizing procedures short of hysterectomy is warranted for the conventional APA, provided there is continual follow-up (47).
Figure 5.56 Adenofibroma of uterus. Irregular, clefted glands are surrounded by prominent paucicellular and mitotically inactive stroma.
Adenosarcoma is an uncommon, predominantly low-grade malignant biphasic tumor that is composed of benign epithelial elements and sarcomatous stroma. Most patients with uterine corpus adenosarcoma are postmenopausal. An association with unopposed estrogen and tamoxifen therapy has been reported.
Uterine corpus adenosarcoma typically presents as a polypoid growth that protrudes through the cervical os or appears to arise from the cervix or lower uterine segment; often there is a history of recurrent polyps, which in retrospect may represent early or subtle forms of adenosarcoma. Microscopically, the tumor consists of uniformly distributed, often cystic, and irregularly contoured glandular elements, often with internal papillations scattered throughout a variably cellular stroma. The stroma forms a characteristic hypercellular collar or cuff (socalled cambium layer) around the glands, often producing irregular, stellate glandular configurations (Fig. 5.58).
Approximately 25% of adenosarcomas are myoinvasive. Most patients with uterine adenosarcoma are cured by hysterectomy. However, deep myoinvasion, lymphovascular invasion, high-grade heterologous stroma, stromal overgrowth, and extrauterine spread are associated with disease recurrence. Stromal overgrowth is defined as pure stromal proliferation constituting greater than 25% of the tumor. Approximately 10% to 25% of patients with uterine adenosarcoma die of their disease. This figure rises to 50% for those whose tumors contain stromal overgrowth.
Adenosarcoma often represents a challenge for the pathologist because of significant overlap with adenofibroma and other forms of benign polyp. Most adenosarcomas arise in the uterine corpus, but cervical, vaginal, tubal, ovarian, and primary peritoneal adenosarcomas also occur. Involvement of additional extragenital sites in women has been linked to endometriosis.
Figure 5.57 Atypical polypoid adenomyoma. This polyp typically occurs in the lower uterine segment and is composed of complex endometrioid glands with squamous metaplasia set in a fibromuscular stroma. (top, low power; bottom, high power)
Despite the long entrenched terminology of “malignant mixed müllerian tumor,” carcinosarcoma is the current preferred designation for mixed neoplasms composed of carcinoma and sarcoma. With rare exceptions, carcinosarcoma is a disease of elderly menopausal women; there is an association with prior pelvic radiation. Most patients present with uterine bleeding; the typical appearance is that of a fleshy, necrotic and hemorrhagic, polypoid mass that fills the uterine cavity and extends through the cervical os. The cardinal rule for diagnosing carcinosarcoma requires the presence of a distinct biphasic neoplasm, composed of separate but admixed malignant-appearing epithelial and mesenchymal elements (Fig. 5.59). The mesenchymal and epithelial elements should not merge with one another. Both the high-grade nuclear features and the biphasic pattern of this neoplasm are obvious in the typical case. The stromal components may be homologous (leiomyosarcoma, stromal sarcoma, fibrosarcoma) or heterologous (chondrosarcoma, rhabdomyosarcoma, osteosarcoma, liposarcoma). Although tradition holds that heterologous elements do not bear on prognosis, a recent study from Memorial Sloan-Kettering suggests that surgical stage I uterine carcinosarcoma with heterologous elements may be more aggressive than carcinosarcoma without heterologous elements (48). Prognosis is also dependent on stage, the size of the tumor, and the depth of myometrial invasion.
Four broad histogenetic categories of ovarian tumors are observed: surface epithelial-stromal tumors (65% to 70%), sex cord-stromal tumors (15% to 20%), germ cell tumors (5% to 10%), and metastases (5%).
Figure 5.58 Adenosarcoma of uterus. In contrast to adenofibroma, the stroma in adenosarcoma is cellular and mitotically active. Stromal condensation around the glandular component forms a characteristic cambium layer.
Surface Epithelial-Stromal Tumors
Surface epithelial-stromal tumors are the most common neoplasms of the ovary (Table 5.10). They consist of six types: serous, mucinous, endometrioid, clear cell, transitional, and undifferentiated (49,50). Tumors with squamous differentiation have also historically been included among the surface epithelial-stromal tumors, but pure squamous tumors are rare; most arise in teratomas.
Tumors with serous differentiation represent 45% of surface epithelial-stromal ovarian neoplasms; they are characterized by epithelial cells resembling those of the fallopian tube and encompass a group of three biologically distinct entities: benign serous cystadenofibroma, serous tumor of low malignant potential (serous borderline tumor), and serous carcinoma.
Benign Serous Tumors
Benign serous cystadenomas or cystadenofibromas constitute almost one-half of all serous ovarian neoplasms. Benign serous tumors occur over a wide age range but are most common in the reproductive age group. They are often bilateral and composed of varying amounts of fibrous stroma and cysts. They range in size from 1 cm to 10 cm (rarely as large as 30 cm). The cysts are unilocular or multilocular and may contain papillary projections. Surface papillomas may also be present. Microscopically, the cysts are lined by a simple layer of epithelium that recapitulates the ciliated epithelial cells of the fallopian tube.
Serous Tumors of Low Malignant Potential (Serous Borderline Tumors)
Serous tumors of low malignant potential constitute approximately 15% of all ovarian serous neoplasms and account for the vast majority of all borderline surface epithelial-stromal neoplasms. They occur at a slightly younger age than serous carcinoma (mean 45 years versus 60 years). They are more often bilateral and larger than benign serous tumors and may present with disease beyond the confines of the ovary. Serous neoplasms in the low malignant potential group are predominately cystic with variable amounts of papillary epithelial projections, although solid tumors with surface papillary excrescences may also occur. Microscopically, serous tumors of low malignant potential are composed of architecturally complex branching papillary and micropapillary structures not unlike that of low-grade serous carcinomas, but they do not feature destructive invasion of the ovarian stroma. The nuclei are uniform or mildly atypical (Fig. 5.60). Mitotic activity is low. Psammoma bodies are often present but are not diagnostic.
Figure 5.59 Carcinosarcoma of uterus. Biphasic lesion composed of malignant glands and stroma (top). Heterologous elements, such as cartilage depicted here, may be present in carcinosarcoma (bottom).
Micropapillary Pattern Approximately 10% of serous tumors of low malignant potential contain foci of significant micropapillary architecture, defined as nonhierarchical branching of slender, elongated papillae that are at least five times as long as they are wide (Fig. 5.61) or a sievelike cribriform pattern occupying a continuous 5-mm extent. The micropapillary variant is more frequently associated with bilaterality, ovarian surface involvement, and the presence of extraovarian disease (51). When the extraovarian disease is invasive, serous tumors of low malignant potential with micropapillary architecture have a poorer prognosis.
Table 5.10 Histologic Classification of Surface-Epithelial Stromal Tumors
Figure 5.60 Serous borderline tumor (low malignant potential). Papillae are lined by stratified tubal type epithelium with tufting. Mitotic activity is minimal, and cytologic atypia is mild to moderate. There is no stromal invasion.
Stromal Microinvasion Stromal microinvasion, defined as 5 mm in linear extent or 10 mm2 in area, may be found in 10% to 15% of serous tumors of low malignant potential. Stromal microinvasion is characterized by eosinophilic cells or small micropapillae lying within stromal spaces beneath larger papillae (Fig. 5.62). It is seen more frequently during pregnancy. Although it may be associated with a small, long-term risk of disease recurrence when occurring in patients who are not pregnant, the overall prognosis is favorable. Stromal microinvasion appears to represent a histologic link between serous tumors of low malignant potential and low-grade serous carcinoma and is likely a bona fide form of early invasion (52).
Figure 5.61 Serous borderline tumor with micropapillary pattern. In this variant, the papillae are elongated and at least fivefold longer than their width. Ovarian surface involvement, bilaterality, and extraovarian implants are more common in this variant than in the usual serous borderline tumor.
Figure 5.62 Stromal microinvasion in serous borderline tumor. Small foci of intrastromal single cells and small, nonbranching papillae may be seen in 10% to 15% of serous borderline tumors. Although such foci likely represent early stromal invasion, their presence does not warrant a diagnosis of carcinoma, provided they are small (_5 mm) and show no significant cytologic atypia.
Figure 5.63 Top: Noninvasive implant of serous borderline tumor. Bottom: Invasive implant of serous borderline tumor. Unlike noninvasive implants, invasive implants have an irregular stromal interface.
Extraovarian Disease Approximately 30% to 40% of serous tumors of low malignant potential are associated with similar-appearing lesions in the pelvis and intraabdominal sites, including lymph nodes. These lesions, termed implants, may be microscopic or macroscopic and are subclassified as noninvasive or invasive types, based on the presence of destructive infiltration into underlying normal tissue structures (Fig. 5.63). Noninvasive implants are divided into epithelial and desmoplastic types, depending on whether or not there is an associated stromal response. The distinction between noninvasive and invasive implants is important because extraovarian invasive disease is associated with a significantly poorer prognosis (53). At times it is difficult to determine whether an implant is invasive or not; in these instances, the implants may be classified as indeterminate. Implants that are indeterminate for invasion appear to have a prognosis that is intermediate to that of noninvasive and invasive implants (54).
Figure 5.64 Lymph node involvement by serous borderline tumor. Lymph node involvement by serous borderline tumor can be florid but does not confer a poorer prognosis.
Lymph node involvement (Fig. 5.64) occurs in 20% to 30% of cases of ovarian serous tumor of low malignant potential (55), but the presence of lymph node involvement does not confer a worse prognosis unless it exhibits an invasive pattern.
Endosalpingiosis frequently coexists with serous low malignant potential (borderline) lesions in the peritoneum and lymph nodes, but the presence of endosalpingiosis alone does not upstage disease. The frequent coexistence of endosalpingiosis with “implants” of ovarian serous tumor of low malignant potential would seem to support the concept that serous tumors may arise in endosalpingiosis in at least a subset of cases.
Serous Carcinoma Serous carcinoma accounts for 35% to 40% of all serous ovarian neoplasms and approximately 75% of ovarian surface epithelial-stromal carcinomas. Ovarian serous carcinoma tends to occur in the sixth to seventh decades (mean 56 years). Grossly, serous carcinoma is bilateral in 60% of cases and is solid and cystic or mostly solid. Microscopically, serous carcinomas exhibit fine papillae (low-grade carcinoma) that can become fused and form solid sheets of cells with slitlike spaces (high-grade carcinoma). Marked nuclear atypia and numerous mitotic figures, which may be atypical, are characteristic in the high-grade tumors (Fig. 5.65). Psammoma bodies are often present but are not specific.
Ovarian serous carcinoma is graded using either a three-tiered system based on architecture and cytology or a two-tiered system based on the degree of nuclear atypia and the mitotic index (56,57). The high-grade (grades 2 and 3) serous carcinomas are the most common surface epithelial carcinomas and are associated with p53 mutations and somatic or germ-line abnormalities of BRCA1 or BRCA2. Low-grade (grade 1) serous carcinomas (Fig. 5.66) are much less common than high-grade serous carcinomas, accounting for less than 10% of serous carcinomas. The low-grade (grade 1) serous carcinomas exhibit mutations in B-RAF and K-RAS, similar to those seen in serous tumors of low malignant potential (58).
Figure 5.65 High-grade serous carcinoma of ovary. Sheets and papillae show marked nuclear pleomorphism and frequent mitotic figures.
Figure 5.66 Low-grade serous carcinoma of ovary. Simple and branching papillae invade stroma but show moderate cytologic atypia and low mitotic activity.
High-grade serous carcinoma is the most common gynecologic tumor to occur in women with germ-line BRCA1 and BRCA2 mutations; serous carcinoma may also develop in the fallopian tubes and on the surface of the peritoneum.
Serous psammocarcinoma, a very rare variant of low-grade serous carcinoma, is defined by the presence of massive psammomatous calcification (at least 75% of the tumor cell nests contain a psammoma body), predominant extraovarian disease distribution, and low-grade cytologic atypia. The prognosis for serous psammocarcinoma is favorable (59).
Surface epithelial tumors with mucinous differentiation account for 15% of all ovarian neoplasms in the United States and Europe. These tumors are characterized by epithelial cells resembling those of the endocervix (endocervical-like) or gastrointestinal tract (intestinal type). Like the serous tumors, they encompass a group of three distinct entities: benign mucinous cystadenoma or adenofibroma, mucinous borderline tumor (tumor of low malignant potential), and mucinous carcinoma (50,60).
Benign Mucinous Tumors
Almost 80% of all mucinous ovarian neoplasms are benign unilocular or multilocular cystadenomas. They occur in a wide age range but are most commonly diagnosed in the reproductive age group. Benign mucinous tumors are typically unilateral and can reach a very large size, extending to 30 cm or more in diameter. Microscopically, the tumors are composed of a columnar epithelial lining with abundant, pale-staining intracellular mucin that resembles endocervical or gastric-type epithelium. Goblet cells may be present but are uncommon in benign mucinous tumors (in contrast to intestinal-type mucinous tumors of low malignant potential or mucinous carcinomas).
Mucinous Tumors of Low Malignant Potential (Mucinous Borderline Tumors), Intestinal Type
Mucinous borderline tumors account for 10% to 15% of all mucinous ovarian tumors; the intestinal type is most common. Mucinous borderline tumors of intestinal type are unilateral and often larger than benign mucinous tumors. They occur most commonly during the late reproductive years (mean 45 years). Microscopically, the multilocular cysts are lined by variably stratified mucinous epithelium forming complex papillary folds. The individual cells show mild to moderate cytological atypia with increased mitotic figures (Fig. 5.67). Goblet cells are present. The presence of marked or severe nuclear atypia involving the full thickness of stratified epithelium (i.e., not limited to the crypts) is classified asintraepithelial carcinoma.
Two patterns of microinvasion are recognized in mucinous borderline tumors of intestinal type. The first pattern consists of infiltration of stroma by individual cells or small nests of cells that are cytologically similar to the cells elsewhere in the borderline tumor. Such foci must not exceed 5 mm in linear extent or 10 mm2 in area. This is an uncommon finding in mucinous borderline tumors (in comparison to the frequency of microinvasion in serous borderline tumors). The second, more common pattern of microinvasion consists of one or more small foci (≤5 mm in linear extent or ≤10 mm2 in area) of nests, individual cells, and glands exhibiting cytological features of high-grade carcinoma cells; this latter pattern is classified as microinvasive carcinoma. Foci of microinvasive carcinoma are of uncertain prognostic significance, but their presence should prompt a search by the pathologist for larger foci of invasive carcinoma (49).
Mucinous Tumors of Low Malignant Potential (Mucinous Borderline Tumors), Endocervical-Like
Mucinous borderline tumors of müllerian (endocervical) type are bilateral in as much as 40% of cases and have a strong association with endometriosis, which is present in as much as 50% of cases. The mean age of patients with endocervical-like mucinous borderline tumors is mid-30s. These tumors are composed of complex papillae, architecturally similar to those of serous borderline tumors, lined by columnar mucin-secreting epithelium and ciliated eosinophilic epithelium. Nuclear atypia is mild to moderate, and mitotic figures may be present. Typically, there is a prominent neutrophilic infiltrate in the stroma of the papillae. Stromal microinvasion, similar to that in serous borderline tumors may be present. Extraovarian implants may also be present in as much as 20% of cases, but their presence has not been associated with a poorer prognosis.
Mucinous Carcinoma, Intestinal Type
Mucinous carcinomas account for less than 10% of all mucinous ovarian neoplasms. Two different patterns of invasion are recognized, both of which may coexist in a single tumor. The confluent glandular or expansile invasive pattern is recognized by marked glandular crowding with little intervening stroma (Fig. 5.68). The destructive stromal invasive pattern, which is less common, is recognized by irregular nests and single cells with malignant cytological features infiltrating stroma (Fig. 5.69). The presence of stromal invasion, whether of destructive or confluent type, must exceed 5 mm in linear extent or 10 mm2 in area in order to be classified as carcinoma; otherwise a diagnosis of microinvasive carcinoma is warranted.
Figure 5.67 Mucinous borderline tumor, intestinal type. Papillary growth pattern, stratification, and nuclear atypia distinguish these tumors from cystadenoma. Intestinal differentiation is exemplified by goblet cells and, in some cases, Paneth cells. There is no stromal invasion. (top, low power; bottom, high power)
Figure 5.68 Mucinous adenocarcinoma of ovary. Expansile stromal invasion in a mucinous ovarian tumor is classified as mucinous carcinoma, but it does not appear to confer the same ominous prognosis as mucinous ovarian tumors with destructive stromal invasion (see Figure 5.69). (top, low power; bottom, high power)
Most primary mucinous carcinomas of the ovary are confined to the ovary at the time of diagnosis; an advanced stage mucinous carcinoma involving the ovary at first diagnosis should be evaluated as a possible metastasis from other sites, particularly the gastrointestinal tract (49).
Figure 5.69 Mucinous adenocarcinoma of ovary. Destructive stromal invasion in a mucinous ovarian tumor is classified as mucinous carcinoma. Metastasis—for example, from the gastrointestinal tract—should always be considered, especially in the presence of high-stage disease or bilateral ovarian involvement.
Mucinous Tumor with Pseudomyxoma Peritonei
Although ovarian mucinous tumors associated with pseudomyxoma peritonei are listed as a distinct category by the WHO, most of these tumors are metastases from primary mucinous tumors of the vermiform appendix (Fig. 5.70). Rarely, primary ovarian mucinous tumors of the intestinal type are associated with pseudomyxoma peritonei; these tumors typically have an associated teratomatous component in the ovary (61,62). The natural history of these tumors is not well understood.
Surface epithelial tumors with endometrioid differentiation exhibit the glandular or stromal histologic features of endometrial glands and stroma. Ovarian tumors showing endometrioid differentiation account for less than 10% of all surface epithelial-stromal tumors.
Benign Endometrioid Tumors and Endometrioid Tumors of Low Malignant Potential (Endometrioid Borderline Tumors)
Benign endometrioid tumors are rare and, when present, typically unilateral. Borderline endometrioid tumors may be bilateral (30%). Both are clinically benign. The tumors resemble their uterine counterparts and are composed of glandular or villoglandular proliferations, which may show cytoplasmic clearing or secretory-type changes with sub- or supranuclear vacuolization. Squamous metaplasia is common. The changes in borderline endometrioid tumors are analogous to those seen in complex atypical hyperplasia of the endometrium, in that there is both cytological and architectural atypia but no stromal invasion.
The typical ovarian endometrioid carcinoma is comparable to FIGO grade 1 or 2 endometrioid adenocarcinoma of the uterus, although occasional tumors have a higher-grade, more solid growth pattern. Squamous metaplasia is common, as are other metaplastic changes (secretory, ciliated cell, oxyphilic, mucinous). Endometrioid carcinomas of the ovary exhibit a wide array of patterns that may pose differential diagnostic problems for the pathologist; these include spindled, tubular, insular, trabecular, microglandular, adenoid basal, and adenoid cystic. When prominent, these patterns may mimic Sertoli cell or Sertoli-Leydig cell tumors, carcinoid tumors, or granulosa cell tumors (Fig. 5.71). Metastases from the gastrointestinal tract may also simulate a primary endometrioid carcinoma. An association with endometriosis, either ovarian or elsewhere in the pelvis, is observed in as much as 40% of cases. Simultaneous primary endometrioid carcinomas in the uterus are present in 20% of cases (49).
Figure 5.70 Pseudomyxoma peritonei. Cytologically low-grade mucinous epithelium is present within pools of mucin in the ovarian stroma (top), peritoneum (middle), and within the appendix (bottom) in this condition. Most cases are associated with an appendiceal mucinous neoplasm; rarely, this condition is encountered in mucinous ovarian tumors arising in a mature teratoma.
Figure 5.71 Endometrioid adenocarcinoma of ovary. Ovarian endometrioid carcinoma has similar morphology to endometrial endometrioid carcinoma, including squamous cell differentiation.
Clear Cell Tumors
Surface epithelial stromal tumors with clear cell differentiation are characterized by epithelial cells containing glycogen-rich clear cytoplasm and hobnail cells with varying degrees of fibrous stroma. Once considered to be of mesonephric origin, clear cell surface epithelial tumors are now recognized as derivatives of the müllerian tract. Clear cell tumors account for 3% of all surface epithelial stromal tumors. Almost all are malignant.
Benign Clear Cell Tumors and Clear Cell Tumors of Low Malignant Potential (Borderline Clear Cell Tumors)
The benign and borderline clear cell adenofibromatous tumors are extremely rare (<1% of clear cell tumors) and present in the second to seventh decade of life.
Clear Cell Carcinoma
Clear cell carcinomas tend to occur in the fifth to seventh decade (10% in the fourth decade). There is an unexplained increased prevalence of clear cell carcinoma in Japan relative to Western countries. Two-thirds of women with clear cell carcinoma are nulliparous. More than one-half have associated endometriosis involving the ovary or other pelvic sites. When associated with endometriosis, mixed clear cell and endometrioid carcinoma may occur. Patients with clear cell carcinoma are at risk for developing paraneoplastic hypercalcemia or pelvic venous thromboses. Most clear cell carcinomas, even when advanced stage, are unilateral (49). The tumors are composed of glands, tubules, cysts, or solid sheets of polyhedral cells with optically clear or eosinophilic granular cytoplasm (Fig. 5.72). Hobnail cells are characteristic. Psammoma bodies may be present, and as much as 25% of cases contain eosinophilic hyaline bodies. Clear cell carcinomas of the ovary are not graded (49).
Transitional Cell (Brenner) Tumors
Transitional cell tumors are thought to arise through metaplasia of the ovarian surface epithelium and are analogous to Walthard nests, which are transitional-type epithelial inclusions occurring beneath the serosa of the fallopian tubes and in the hilar regions of the ovaries. They are uncommon (3% of all surface epithelial-stromal tumors). Most are clinically benign.
Figure 5.72 Clear cell adenocarcinoma of ovary. Glands are lined by polygonal cells with clear cytoplasm and enlarged, hyperchromatic, and pleomorphic nuclei. (top, low power; bottom, high power)
Benign Transitional Cell (Brenner) Tumor
Brenner tumors are the most common type of ovarian transitional cell tumor. They are often microscopic or incidental findings discovered at laparotomy for unrelated pelvic conditions. They affect patients during the fourth to eighth decades (mean 50 years). They are typically solid, unilateral tumors with small cysts on cut section; most are less than 2 cm. A gritty consistency may be present because of flecks of calcification (Fig. 5.73). They may be associated with a mucinous cystic tumor. Microscopically, they contain nests of cytologically bland cells with urothelial appearance surrounded by a prominent fibromatous stroma. The individual nests may be solid or microcystic with an inner mucinous epithelial lining.
Figure 5.73 Brenner tumor of ovary. Nests of transitional epithelium are set in fibrous stroma. Stromal calcifications may impart a gritty texture.
Transitional Cell (Brenner) Tumor of Low Malignant Potential (Borderline)
Borderline tumors are typically unilateral, solid and cystic, and usually larger (10 cm to 25 cm) than benign Brenner tumors. Microscopically, they feature coarse papillary fronds lined by multilayered uroepithelium that resembles low-grade papillary urothelial carcinoma of the urinary tract. Despite their epithelial proliferation, these tumors are clinically benign.
Malignant Brenner Tumor
Malignant transitional cell tumors with benign or atypical proliferating transitional elements are designated as malignant Brenner tumors. These tumors show nuclear pleomorphism, hyperchromasia, and numerous mitotic figures, as well as destructive stromal invasion.
Transitional Cell Carcinoma
Malignant transitional cell tumors without benign or atypical proliferating transitional elements are designated as transitional cell carcinomas. The diagnosis of transitional cell carcinoma is highly subjective.
Undifferentiated Epithelial Tumors
Undifferentiated carcinomas lack histological features of a specific müllerian cell type. They are invariably high grade. Because undifferentiated areas are common in high-grade ovarian carcinomas that contain specific features of serous, clear cell, or other differentiation elsewhere, pure undifferentiated carcinomas are infrequent (49).
Mixed Surface Epithelial-Stromal Tumors
Mixed surface epithelial-stromal tumors have two or more differentiated histologic cell types, each of which account for at least 10% of the tumor.
Sex Cord-Stromal Tumors
Sex cord-stromal tumors demonstrate ovarian, testicular, or a mixture of ovarian and testicular cell differentiation (63). Many of the tumors of this subtype variably express inhibin,a feature that is often used in confirming the presence of sex cord-stromal differentiation.
Adult Granulosa Cell Tumors
Adult granulosa cell tumor is the most common sex cord-stromal tumor in the ovary. This tumor occurs in females over a wide age range (mean 52 years) but is more common in late reproductive years than in the pediatric age group. Patients often present with estrogenic symptoms (50).
Figure 5.74 Adult granulosa cell tumor. Top: Ribbons of cells with coffee-bean nuclei surround a macrofollicle. The mitotic index is usually low in these tumors. Bottom: Microfollicular pattern with Call-Exner bodies.
Adult granulosa cell tumors are unilateral and solid, solid and cystic, or predominantly cystic. Microscopically, they are characterized by a proliferation of ovoid, predominantly uniform cells with an open chromatin pattern and nuclear grooves (Fig. 5.74). Mitotic figures are present but typically few in number. A variety of patterns can be observed, including trabecular, insular, diffuse (sarcomatoid), and microfollicular, featuring characteristic Call-Exner bodies (small round spaces filled with eosinophilic material formed by the surrounding granulosa cells). Macrofollicles are also present in most adult granulosa cell tumors. Adult granulosa cell tumor is a neoplasm of low malignant potential; recurrences may occur many years after initial diagnosis. The most important prognostic feature is stage of disease.
Figure 5.75 Juvenile granulosa cell tumor. Macrofollicles in this tumor are surrounded by cells with more hyperchromatic and often more mitotically active nuclei than those in the adult type.
Juvenile Granulosa Cell Tumors
Juvenile granulosa cell tumors tend to occur in younger women (97% occur in females younger than age 30). Patients often present with isosexual pseudoprecocity or menstrual irregularities.
Most juvenile granulosa cell tumors are unilateral and low stage with a macroscopic appearance similar to the adult granulosa cell tumor. They are distinguished from the adult variant by the presence of larger, more irregular follicles and rounded, more atypical nuclei that are euchromatic or hyperchromatic and nongrooved (Fig. 5.75). Mitotic figures are often numerous. Most juvenile granulosa cell tumors are clinically benign; approximately 10% of patients develop recurrences, typically within the first 5 years of initial diagnosis (63).
Sertoli-Leydig Cell Tumors
Sertoli-Leydig cell tumors occur most commonly in women in their mid-20s but can occur in females as young as 2 and as old as 75 years. Approximately one-third of patients present with virilization; estrogenic manifestations are less frequent. Almost one-half of patients exhibit no endocrinologic manifestations (64).
Sertoli-Leydig cell tumors are typically unilateral and low stage, but 10% may have ovarian surface involvement. Less than 5% exhibit extraovarian spread at diagnosis. Most are solid or solid and cystic, and pale yellow or tan in color. The characteristic features are tubules or cords of Sertoli cells with interspersed nests of Leydig cells enmeshed in primitive gonadal stroma (Fig. 5.76). Rarely, a Sertoli-only cell tumor can be seen. Approximately 20% have heterologous elements, which may be epithelial or mesenchymal and include mucinous, cartilaginous, neuroendocrinological (carcinoid tumor), or skeletal muscular (rhabdomyosarcoma) differentiation. Retiform elements resembling rete testis are seen in 15% of cases. The tumors are graded on the basis of the degree of Sertoli tubule formation and the extent of primitive stroma. Well-differentiated tumors have a mitotic index of less than 5 mitotic figures per 10 high-power fields, whereas poorly differentiated tumors have a mitotic index greater than 10 mitoses per 10 high-power fields, and intermediate tumors have an intermediate mitotic index.
Figure 5.76 Sertoli-Leydig cell tumor. Sertoli tubules with interspersed Leydig cells form this well-differentiated tumor.
Sex-Cord Tumor with Annular Tubules
A rare variant of Sertoli cell tumor, the sex-cord tumor with annular tubules is distinguished by the presence of simple or complex annular tubules composed of Sertoli cells arranged antipodally around hyaline material (Fig. 5.77). Tumors are unilateral and often associated with hormonal manifestations. As much as 25% are clinically malignant (50).One-third occur in patients with Peutz-Jeghers syndrome; when they occur in this setting, sex-cord tumor with annular tubules are clinically benign, bilateral, and small, often incidental findings.
When sex cord-stromal tumors contain minor components of other types of sex cord-stromal tumor, the tumor is usually designated by the major component. However, when a tumor is composed of an admixture of well differentiated Sertoli cell tubules and granulosa cell elements, and the second cell population makes up at least 10% of the tumor, the tumor is classified as gynandroblastoma, and the relative contribution and subtypes are reported. Most such tumors are benign.
This group of stromal tumors is composed of spindle or oval cells with scant (fibroma) or more abundant, pale, lipid-rich cytoplasm (thecoma) associated with varying degrees of collagen. Estrogenic manifestations are generally absent in fibromas but occur in as many as 60% of patients with thecomas. Tumors in this group tend to occur in middle age (fibroma) or after menopause (thecoma). Most are unilateral, solid, or solid and microcystic, and they vary from gray or white (fibroma) to bright yellow (thecoma). Microscopically, the tumors are composed of cells arranged in fascicles or a storiform pattern; calcification and hyaline plaques may be seen (Fig. 5.78). Patients with nevoid basal cell carcinoma syndrome develop ovarian fibromas at a younger age; in this setting, the fibromas are bilateral, multinodular, and calcified. Almost all fibromas and thecomas are clinically benign. Some fibromas present with ascites and pleural effusion (Meigs syndrome), which resolves on removal of the tumor.
Sclerosing Stromal Cell Tumors
These stromal tumors occur in young women and are rarely associated with endocrine manifestations. They are unilateral and clinically benign. Sclerosing stromal tumors are distinguished by the presence of alternating, relatively hypercellular and hypocellular areas of stromal proliferation arranged in a pseudolobular pattern. An extensive, thin-walled vascular pattern is often present.
Figure 5.77 Sex-cord tumor with annular tubules. Prominent hyaline bodies are surrounded by a proliferation of complex annular tubules. This tumor may be associated with Peutz-Jeghers syndrome and is typically incidental and clinically benign in that setting. Those tumors that are not associated with the syndrome may recur and demonstrate clinically aggressive behavior.
Figure 5.78 Fibroma-thecoma of ovary. Spindle-shaped cells are dispersed in a variably fibrous stroma.
Figure 5.79 Steroid cell tumor of ovary. Nests of polygonal cells with central rounded nuclei may exhibit finely vacuolated, eosinophilic, or, less commonly, optically clear cytoplasm.
Steroid Cell Tumors, Not Otherwise Specified
Steroid cell tumors tend to occur in young, reproductive-aged women (25% younger than 30 years of age). These tumors are unilateral. Most are confined to the ovary at diagnosis, but as many as 20% have extraovarian spread at diagnosis and 30% are clinically malignant. Endocrine manifestations, when present, tend to be androgenic, although estrogenic, progestogenic, and Cushingoid manifestations may also be seen (63). Most are solid and pale yellow or orange, with the color depending on the steroid content. Microscopically, the tumors are composed of solid nests of uniform, round, or polygonal cells with distinct cell borders and central nuclei that contain small but distinct nucleoli (Fig. 5.79). The cytoplasm may be finely vacuolated or eosinophilic and granular. Most tumors are mitotically inactive with fewer than 2 mitotic figures per 10 high-power fields; tumors with a high mitotic index may be more aggressive.
Leydig Cell Tumors and Stromal Luteomas
Steroid cell tumors, not otherwise specified, must be distinguished from Leydig cell tumors and stromal luteomas, both of which tend to exhibit a benign clinical course. Leydig cell tumors are recognized by the presence of Reinke crystals. They are either small and typically hilar in location or large and replacing most of the ovarian parenchyma. Stromal luteomas are typically small (less than 3 cm), well-circumscribed tumors that occur within (and are circumscribed by) the ovarian stroma. A size criterion of 1 cm has been imposed to distinguish Leydig cell tumors and stromal luteomas from benign, nonneoplastic ovarian steroid cell proliferations (see below).
Germ Cell Tumors
These tumors are derived from the primordial germ cells of the ovary. Most are mature cystic teratomas and are clinically benign. The remaining germ cell tumors are malignant; most occur in children or adolescent females (63).
Mature Cystic Teratoma
Mature teratomas are typically cystic, although solid variants do occur. They have a wide age range, occurring in females from 2 to 80 years (mean 32 years). As many as 15% are bilateral at presentation. Mature teratomas are one of the most common ovarian neoplasms, accounting for 30% to 45% of all ovarian tumors and as much as 60% of all benign ovarian tumors. Recurrences may occur in the residual ipsilateral ovary following cystectomy, particularly when the tumors are multiple or ruptured. The presence of mature glial implantsin the peritoneum (grade 0 implants) does not adversely affect prognosis (50) (Fig. 5.80).
Figure 5.80 Mature teratoma. Cystic neoplasm contains teeth, hair and sebaceous material.
Monodermal mature teratomas are not uncommon in the ovary and include struma ovarii (thyroid), carcinoid, strumal carcinoid, ependymoma, and primitive neuroectodermal tumor.
The development of a secondary somatic carcinoma may rarely occur in mature teratomas in postmenopausal women. Squamous carcinoma and adenocarcinoma, usually of intestinal type, account for most cases of secondary carcinoma. Secondary sarcomas are less common and tend to occur in younger patients.
Immature teratomas are distinguished from mature teratomas by the presence of variable amounts of immature embryonal tissue, typically in the form of immature neuroectodermal tissue (Fig. 5.81). Prognosis is dependant on grade and stage of disease. Tumors are graded on the basis of the amount of immature tissue present. Grading is traditionally based on a threetiered system, although a two-tiered system may be more reproducible. Treatment of immature teratomas has evolved in recent years. Surgery alone is considered curative in children and adolescent patients with immature teratomas regardless of the grade. Chemotherapy is used for patients who relapse.
Figure 5.81 Immature teratoma. Top: Teratomas are graded on the amount of immature tissue, most commonly manifested by immature neural tissue, that is present. Bottom: In contrast, the presence of mature glial tissue does not affect prognosis, even when it forms nodular deposits throughout the peritoneum (gliomatosis).
Dysgerminoma is identical to its testicular counterpart, the seminoma. The ovarian tumors are unilateral in 80% of patients, large (mean 15 cm), solid, and tan in appearance; cyst formation is seen in areas of infarction. Most occur in the second and third decade, although 5% present in children less than 5 years of age. The tumors are composed of a diffuse proliferation of rounded cells with discrete cell membranes and central nuclei with one to four prominent nucleoli (Fig. 5.82). Lymphocytes and granulomas are often present. Some tumors contain syncytiotrophoblastic cells, which may be associated with elevated serum beta-human chorionic gonadotropin. The neoplastic cells express placental alkaline phosphatase, CD117, and OCT 3/4. Calcifications should prompt consideration for the presence of concomitant gonadoblastoma (50).
Figure 5.82 Dysgerminoma. Top left: Solid, pale tan lobulated growth pattern is characteristic of dysgerminoma. Top right and bottom: The tumor is composed of sheets of ovoid to polygonal cells with clear cytoplasm, prominent cell borders and central nuclei with multiple small nucleoli. Interspersed mature lymphocytes are characteristic.
Figure 5.83 Yolk sac tumor of ovary. Top: Microcystic reticular pattern of yolk sac tumor. Bottom: These tumors express AFP (left) and glypican-3, as well as SALL4 (right).
Yolk Sac Tumor
Yolk sac tumor (endodermal sinus tumor) occurs in females from as young as 17 months to 43 years (mean 20 years). The tumor is usually unilateral, solid, and cystic with areas of hemorrhage and necrosis. A reticular or tubulocystic pattern with Schiller-Duval bodies is characteristic, but microcystic, macrocystic, solid, and glandular patterns are also seen (Fig. 5.83). Yolk sac tumors are associated with elevated serum alpha fetoprotein (AFP). The tumors express AFP, cytokeratin, and glypigan-3, and SALL4 (65).
This tumor is composed of dysgerminoma cells admixed with sex-cord derivatives resembling Sertoli or granulosa cells. Gonadoblastoma is typically diagnosed in children or young adults. Most are bilateral, but this may not be macroscopically apparent. Calcifications within hyalinized bodies of the sex-cord component are seen in more than 80% of cases. Almost all gonadoblastomas are associated with an underlying gonadal disorder, either pure or mixed dysgenesis, with a Y chromosome being detected.
Pure embryonal carcinoma is rare in the ovary but may be admixed with other germ cell tumors; this appears to be particularly common in gonadoblastomas. Embryonal carcinoma expresses cytokeratin, CD117, OCT 3/4, and CD30.
Miscellaneous Ovarian Tumors
The ovary gives rise to a variety of other benign and malignant tumors that do not easily sort into one or another of the major ovarian tumor categories. Most of these tumors are extremely rare and include such diverse entities as paraganglioma; myxoma; small cell carcinoma, hypercalcemic type; small cell carcinoma, pulmonary type; and large-cell neuroendocrine carcinoma, among others (66). Only small cell carcinoma, hypercalcemic type occurs with sufficient frequency to warrant discussion in this chapter.
Small Cell Carcinoma, Hypercalcemic Type
This is an uncommon, highly malignant tumor presenting in young women, often in association with paraneoplastic hypercalcemia. The tumors are usually large and unilateral, even in the presence of advanced stage disease. Approximately 50% of tumors are confined to the ovary at presentation, and these tumors appear to have a better prognosis than tumors with extraovarian spread. Small cell carcinoma, hypercalcemic type is typically composed of small, undifferentiated and mitotically active cells (Fig. 5.84), although large cells may be present and, in some cases, form the predominant cell type. The tumor cells grow in solid sheets punctuated by variably sized follicle-like spaces. Mucinous epithelium may be seen in as many as 15% of tumors (66).
Small cell carcinoma, hypercalcemic type should not be confused with small cell carcinoma, pulmonary type. The latter tumor occurs in postmenopausal women and is histologically and immunohistologically similar to small cell neuroendocrine carcinoma of the lung.
Secondary Tumors of the Ovary (Metastases)
Tumors secondarily involving the ovary include carcinoma, lymphoma or leukemia, melanoma, and sarcoma. The tubular gastrointestinal tract, particularly the colon, is the most common source of metastatic carcinoma (Fig. 5.85), followed by the breast and pancreatobiliary tract. However, tumors arising in any site may secondarily spread to the ovary; the relative frequency of the primary site varies in different countries, depending on the relative incidence of various types of cancer and on changing patterns in the treatment of these cancers. The classic Kruckenberg tumor refers to metastatic signet-ring carcinoma involving the ovaries (Fig. 5.86), which typically arises in the stomach, appendix, or large bowel. A variety of features may suggest an ovarian metastasis; these include bilateral disease, surface nodules, extensive lymphatic involvement, and diameter smaller than 10 cm.
Figure 5.84 Small cell carcinoma, hypercalcemic type of ovary. Sheets of immature small cells with high mitotic index are punctuated by follicle-like spaces containing eosinophilic material.
Figure 5.85 Metastatic colorectal adenocarcinoma. Top: Metastatic colorectal carcinoma often simulates a primary ovarian tumor. Note the smooth external capsule. Bottom: A garland gland pattern and the presence of extensive “dirty cell” necrosis secondary to the presence of necrotic cellular debris within gland lumens are characteristic of metastatic colorectal carcinoma.
Figure 5.86 Metastatic gastric signet-ring adenocarcinoma (Kruckenberg tumor). Metastatic signet-ring carcinomas are often associated with ovarian stromal hyperplasia, which may mimic a stromal process.
Nonneoplastic Lesions of the Ovary
Many nonneoplastic lesions of the ovary may mimic an ovarian neoplasm. Most occur during the reproductive years. Some are associated with infertility. These include cysts of follicular origin, massive ovarian edema, stromal hyperplasia and hyperthecosis, endometriosis, and a variety of pregnancy-associated changes (67).
Cysts of Follicular Origin
Cysts of follicular origin are classified as follicular or luteal, depending on whether the cyst lining is composed of nonluteinized or luteinized granulosa and theca cells. By definition larger than 3 cm, most cysts of follicular origin do not exceed 8 cm in diameter. Rupture of a follicular or corpus luteal cyst may cause abrupt abdominal pain or hemoperitoneum.
Polycystic Ovarian Disease (Sclerocystic Ovaries)
Sclerocystic ovaries show bilateral ovarian enlargement with numerous cortical cysts, most measuring less than 3 cm, underlying a white fibrous band of cortical tissue. The etiology of this relatively common condition is heterogeneous, but in many cases the underlying defect has been attributed to insulin resistance of peripheral tissue or an abnormality of the hypothalamicpituitary-ovarian axis. Patients present with anovulation, menstrual dysfunction, and hyperandrogenemia (Polycystic Ovarian Syndrome, Stein-Leventhal syndrome).
Massive Ovarian Edema
Massive ovarian edema occurs predominantly in children, adolescents, and young women. The etiology is uncertain but is thought to be the result of partial lymphatic or venous obstruction leading to accumulation of edema fluid and ovarian enlargement. Patients present with abdominal pain, abdominal distention, or menstrual irregularities. Affected patients may show features of virilism, hirsutism, and, rarely, precocious pseudopuberty. The affected ovary is gelatinous because of fluid accumulation within the interstitium of the ovary, separating and sometimes involving preexisting follicular structures (67).
Stromal hyperplasia is found predominantly in the postmenopausal age group. The ovaries are enlarged bilaterally by hyperplastic stroma, which may contain luteinized cells. The condition is benign and generally asymptomatic, often discovered incidentally during surgery for other causes.
Stromal hyperthecosis may be seen in association with stromal hyperplasia in postmenopausal women but can also occur in reproductive-age women. Virilization, acne, obesity, hypertension, and glucose intolerance may be seen in association with stromal hyperthecosis in premenopausal women. A small percentage of patients have HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome. The ovaries are bilaterally enlarged by a proliferation of theca cells similar to those of the theca interna.
Endometriois commonly presents during the reproductive years and ranges from single or multiple microscopic deposits of ectopic endometrial glands and stroma to large hemorrhagic cysts (endometriomas) simulating a tumor mass. The larger cysts should be carefully examined to exclude the presence of an occult clear cell or endometrioid carcinoma.
Rarely, foci of endometriois may form large, polypoid masses on the ovary, fallopian tube, bowel, or peritoneum (Fig. 5.87). Most of the reported lesions have followed a benign clinical course (68), but complete excision and thorough microscopic examination should be performed to exclude adenosarcoma, stromal sarcoma, or adenocarcinoma arising in the setting of endometriosis.
Pregnancy luteoma is a benign condition that occurs in the second half of pregnancy and regresses after delivery. One or both ovaries are enlarged by single or multiple nodules of steroid cells with abundant, eosinophilic cytoplasm. Necrosis and degenerative changes may be present. Most are discovered during cesarean section.
Figure 5.87 Polypoid endometriosis. When large and multifocal, these polypoid masses of ectopic endometrial tissue may simulate a neoplasm.
Large Solitary Luteinized Cyst of Pregnancy and the Puerperium
Large solitary luteinized follicular cyst of pregnancy and the puerperium is a rare, unilateral, thin-walled cyst lined by large cells with abundant cytoplasm with focal pleomorphic and hyperchromatic nuclei. These atypical cells are thought to be degenerative. A distinct theca layer is absent.
Hyperreactio luteinalis is characterized by bilateral ovarian enlargement secondary to the development of multiple luteinized cysts. This condition is rare in normal pregnancy but may occur in 10% to 40% of women with gestational trophoblastic disease and in women undergoing ovulation induction (especially those with preexisting polycystic ovaries).
The traditional, admittedly arbitrary criteria to distinguish serous carcinoma of the ovary from serous carcinoma of the peritoneum are based on the presence of at least 5 mm of ovarian parenchymal involvement or, in the case of low-stage disease, by the exclusive presence of ovarian (surface or parenchymal) involvement. Primary serous carcinoma of the fallopian tube, once considered to be very rare, has been based on the exclusion of primary ovarian and uterine disease. The historical basis for these distinctions rests largely on the hypothesis that most serous carcinomas arise either from the surface epithelium of the ovary or from inclusion glands within the ovarian parenchyma.
This hypothesis has been challenged in the last several years by the revival of the alternative theory that serous carcinoma arises from the epithelium of the fimbria of the fallopian tube. The detection of tubal intraepithelial carcinoma (Fig. 5.88) in women undergoing riskreducing salpingo-oophorectomy, in women with ovarian serous carcinoma, and in women with peritoneal serous carcinoma has buffeted this claim and generated renewed interest in the tubal fimbria as a candidate source of serous carcinoma. Whether all such examples reflect primary tubal epithelium as the source of carcinoma or secondary involvement by carcinoma arising elsewhere is currently unanswerable, except in those cases in which the fallopian tube is the only site of involvement. A p53 signature has been identified in the fimbriated tubal epithelium that may represent a precursor lesion of tubal intraepithelial carcinoma (Fig. 5.89), but this requires further study (69). Metastases not uncommonly involve the fallopian tube mucosa and serosa.
Figure 5.88 Serous tubal intraepithelial carcinoma. Tubal mucosa is focally replaced by stratified cells with markedly pleomorphic nuclei. The lesion is confined to the mucosa and typically occurs in the fimbria and distal fallopian tube in women with BRCA germ-line mutations.
Figure 5.89 Fallopian tube with “p53 signature.” Histologically normal tubal mucosa (left) may exhibit nuclear over-expression of p53 (top right), but low Ki-67 proliferation rate (bottom right). Although it has been proposed that this lesion may be a precursor to serous tubal carcinoma, it is not known to be associated with an adverse prognosis in the absence of morphological carcinoma.
The fallopian tubes from all risk-reducing salpingo-oophorectomy specimens should be serially sectioned and completely examined microscopically in order to exclude occult tubal intraepithelial carcinoma (70).
Primary Tubal Carcinoma
Serous carcinoma is the most common histologic subtype of carcinoma to occur in the fallopian tube (Fig. 5.90), but endometrioid neoplasms (adenofibroma, borderline, and carcinoma) may also occur. The distinction among the three types of endometrioid tumor and serous tumors is based on the criteria for these distinctions that are used elsewhere in the female genital tract.
Adenomatoid tumors are common, benign mesothelial neoplasms arising in the subserosa of the paratubal region, but they may also be seen in the uterus and, rarely, in the ovary. When occurring in the fallopian tube, they are small, firm tan white nodules, often measuring less than 1 cm in diameter. The uterine tumors are usually larger and arise in the myometrium. The presence of tubular and signet-ring-like cells may simulate a metastatic carcinoma (Fig. 5.91).
Gestational Trophoblastic Disease
Gestatational trophoblastic disease arises as a result of abnormal placental development with a resultant proliferation of syncytiotrophoblastic, cytotrophoblastic, or intermediate trophoblastic tissue (71).
Hydatidiform mole is the most common form of gestatational trophoblastic disease and is divided into complete or partial moles. The complete mole is diploid (46XX or 46XY) and derived entirely from paternal chromosomes because of fertilization of an empty ovum by a single spermatozum, whereas partial mole is triploid (69XXX, 69XXY, or 69XYY) and derived from fertilization of a normal egg by two spermatozoa.
Figure 5.90 Invasive serous carcinoma, fallopian tube. Superficial invasion into the tubal stroma is seen in this early invasive serous tubal carcinoma.
Figure 5.91 Adenomatoid tumor, fallopian tube. Signet-ring appearance may simulate metastatic carcinoma.
Complete Hydatidiform Mole
Complete moles exhibit uniformly enlarged, hydropic villi with variable degrees of circumferential trophoblastic proliferation. The well-developed, second-trimester complete moles are visualized as transparent, grapelike vesicles on macroscopic examination, but complete moles in early trimester abortuses may be difficult to detect even on microscopic examination. Because complete moles are paternally derived, proteins encoded by paternally imprinted genes are not expressed in the villous stromal tissue or cytotrophoblast of complete moles. One of these proteins, p57, may be used to establish the diagnosis of complete moles in diagnostically more difficult cases (Fig. 5.92).
Complete moles may progress to invasive mole or choriocarcinoma. Progression is associated with progressively rising serum beta human chorionic gonadotropin levels.
Partial Hydatidiform Mole
Partial moles exhibit a dimorphic population of small and larger villi with lesser degrees of trophoblastic proliferation. Most are associated with a fetus. Progression of partial mole to invasive mole or choriocarcinoma is rare or nonexistent.
Invasive mole is diagnosed on the basis of invasion into myometrium or its blood vessels (Fig. 5.93). Common sites of extrauterine spread include the vagina, vulva, and lung.
Choriocarcinoma is a highly malignant tumor composed of syncytiotrophoblastic and cytotrophoblastic cells arranged in a bilaminar configuration (Fig. 5.94). Chorionic villi are almost always absent. Hemorrhage and necrosis are common. Patients often present with profuse vaginal bleeding. Distant lung, brain, or liver metastases may also be present.
Placental Site Trophoblastic Tumor
This very uncommon form of gestational trophoblastic disease is composed of intermediate trophoblastic cells (Fig. 5.95). The tumor may form a discrete mass or irregularly infiltrate the myometrium, causing uterine enlargement. Although most placental site trophoblastic tumors follow a benign clinical course, the behavior is unpredictable, and occasional tumors spread throughout the uterus and metastasize to distant sites.
An epithelioid variant, composed of smaller, more epithelioid cells resembling squamous cell carcinoma, appears to be more aggressive (71).
Exaggerated Placental Site
Exaggerated placental site is a benign condition marked by an exuberance of intermediate trophoblastic cells that may simulate placental site trophoblastic tumor. The lesion is no different from the usual implantation site, but the individual intermediate trophoblastic cells are larger and more numerous; nuclear hyperchromasia may also be present. Unlike placental site trophoblastic tumor, chorionic villi and syncytiotrophoblastic giant cells are typically present, mitotic figures are rare or absent, and there is no necrosis.
Placental Site Nodule and Plaque
Placental site nodules are essentially hyalinized implantation sites. They occur during the reproductive years and may be a cause of uterine bleeding or an incidental finding. They are discrete lesions, forming nodules or plaques, but occasionally they may present as multiple fragments or lesions in a uterine sampling (Fig. 5.96). A history of pregnancy may be remote or even absent. Placental site nodule or plaque is a benign process and not to be confused with placental site trophoblastic tumor.
Figure 5.92 Complete hydatidiform mole. Top: Enlarged, hydropic villi correspond to the grapelike vesicles seen in curettage specimens. Bottom: Villous stromal cells and cytotrophoblast cells do not express paternally imprinted nuclear p57 in complete hydatidiform mole.
Figure 5.93 Invasive mole. Complete hydatidiform mole with exuberant trophoblastic proliferation invades the myometrium in this hysterectomy specimen.
Figure 5.94 Choriocarcinoma. Bilaminar pattern of syncytiotrophoblastic and cytotrophoblastic cells is diagnostic of this tumor.
Figure 5.95 Placental site trophoblastic tumor. Top: Large, atypical eosinophilic and polygonal cells diffusely infiltrate the deep myometrium. Bottom: Human placental lactogen is expressed by the neoplastic intermediate trophoblastic cells.
Figure 5.96 Placental site nodule. Discrete nodules or plaques of hyalinized intermediate trophoblastic tissue may be seen in curettage specimens.
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