Pseudoneoplastic lesions of the female genital tract.

Context.—Numerous benign, proliferative, or reactive processes, often related to hormone stimulation or inflammation, occur throughout the female genital tract and may mimic benign or malignant tumors. Several of the more common pseudoneoplastic lesions are discussed in this article, including microglandular hyperplasia of the cervix mimicking well-differentiated endometrial adenocarcinoma, reactive epithelial changes in the fallopian tubes mimicking adenocarcinoma or carcinoma in situ, and pregnancy changes in the ovary including pregnancy luteoma and large solitary luteinized follicular cyst of pregnancy and puerperium that may mimic ovarian neoplasms. Objectives.—To discuss and illustrate several common lesions of the female genital tract that mimic neoplasms. Data Sources.—Material derived from consultation cases and review of the literature. Conclusions.—Many benign hyperplastic or reactive processes that occur in the female genital tract may be mistaken for neoplasms both clinically and pathologically. Awareness of the features of such lesions will aid in their correct diagnosis and prevent overtreatment of benign processes. A variety of reactive and hyperplastic processes due to inflammation or repair and hormone or gonadotropin stimulation may mimic neoplasms throughout the female genital tract. Although many of these proliferative processes are difficult to distinguish from neoplasms, frequently their morphologic features allow their identification. Several such entities are discussed in this review, including microglandular hyperplasia of the cervix mimicking well-differentiated endometrial and endocervical adenocarcinoma, reactive epithelial changes in the fallopian tubes mimicking adenocarcinoma or carcinoma in situ, atypical and hyperplastic changes in endometriosis, and pregnancy changes in the ovary including pregnancy luteoma and large solitary luteinized follicular cyst of pregnancy and puerperium. Recognition of these pseudoneoplastic entities is of crucial importance in preventing overtreatment of such lesions that often occur in young women of reproductive age. MICROGLANDULAR HYPERPLASIA The distinction between benign endocervical glandular proliferations and adenocarcinoma in both endocervical and endometrial specimens continues to represent a diagnostic challenge. Several entities have been recognized as mimics of malignancy; amongst those, microglandular hyperplasia probably represents the most prominent example. This entity was first recognized in a study of cervical changes in pregnant women.1 The term microglandular hyperplasia was first used by Kyriakos and coworkers2 in 1968 for a cohort of patients taking oral contraceptives. Surprisingly, 1 year before this landmark publication, the lesion was already recognized as bearing histopathologic resemblance with endocervical adenocarcinoma.3 Currently, it is controversial whether microglandular hyperplasia bears true association with endogenous or exogenous hormones.4,5 The lesion usually occurs in women of reproductive age, but a small percentage of patients are postmenopausal.6 Microglandular hyperplasia is frequently an incidental finding but can present as a polyp or erosion. At low-power view, the architecture is variable; the lesion can be polypoid or not, single or multifocal, superficial or deeply located. Characteristically, it is composed of closely packed, small tubular or irregular glands with areas of cystic dilatation (Figure 1, A). There is scant intervening stroma and no sharp separation between glands and stroma (Figure 1, B). Admixed acute and chronic inflammation is typically associated with the lesion and is often present within the luminal secretions (Figure 1, C). The lining epithelium is cuboidal or low columnar and mucinous, with variable degrees of squamous metaplasia and reserve cell hyperplasia (Figure 1, D). Cytoplasmic vacuoles are common and are characteristically subnuclear, but supranuclear vacuoles are also encountered. In most instances, the nuclei are bland; when present, atypia is usually focal (Figure 1, C). Mitotic figures are rare or absent. The typical histopathologic features of microglandular hyperplasia are well established, but uncommon patterns can pose problems in the differential diagnosis. These include solid, sheetlike proliferations of cells, pseudoinfiltrative growth, signet ring cells, hobnail-like cells, increased nuclear atypia, and mitotic figures7,8 (Figure 2, A and B). We have recently encountered an example of florid microglandular hyperplasia in a pregnant patient, associated with Arias-Stella reaction, that closely simulated adenocarcinoma. Importantly, these unusual patterns merge with areas of typical microglandular hyperplasia, thus facilitating the correct diagnosis in well-sampled specimens. However, a greater diagnostic challenge is faced in small and fragmented biopsy samples. The difficult distinction of endocervical microglandular hyperplasia and well-differentiated endometrial adenocarcinoma in biopsy and curettage specimens is a common reason for consultation in gynecologic pathology. Particularly concerning are well-differentiated endometrial adenocarcinomas with mucinous differentiation, either in pure form or, more commonly, intermixed with endometrioid adenocarcinoma. The architectural pattern can be confusingly similar and can feature small crowded glands. The presence of nuclear atypia and mitotic figures is certainly helpful in favoring endometrial adenocarcinoma; yet the latter may be deceptively bland. Both conditions may display associated squamous differentiation, in the form of central squamous morules in endometrioid adenocarcinoma and immature squamous metaplasia in microglandular hyperplasia. Intraluminal mucin and polymorphonuclear infiltration can be seen in both conditions.9 It is often very helpful to characterize the normal epithelium in the same fragment as the lesion in question; if endometrial or endocervical, as an indication of endometrial adenocarcinoma or microglandular hyperplasia, respectively. Table 1 and Figure 3, A through D, provide a comparison between endocervical microglandular hyperplasia and endometrial adenocarcinoma and demonstrate the difficulty in this distinction. Above all, considering the age of the patient is of major importance. The diagnosis of microglandular hyperplasia in endometrial samples of postmenopausal women should be exercised with extreme caution.9,10 Overall, the presence of even mild nuclear atypia or mitotic activity in a complex glandular proliferation in a sample confirmed to be from the endometrium (by the presence of endometrial tissue) in a perimenopausal or postmenopausal woman should raise the concern of well-differentiated adenocarcinoma and prompt further investigation.10 Microglandular hyperplasia may also simulate invasive endocervical adenocarcinoma.7,11 As in the differential with endometrial carcinoma, the presence of nuclear atypia and mitotic activity strongly favors malignancy. Architecturally, invasive adenocarcinomas tend to have more irregular and haphazardly arranged glands with surrounding desmoplastic stroma. Identification of adjacent adenocarcinoma in situ would be consistent with a neoplastic process in a questionable focus. Finally, if morphologic examination does not suffice, p16 immunostaining or human papilloma virus in situ hybridization may be used; positivity would be diagnostic of neoplasia in this particular setting. Some studies12,13 have explored the application of immunohistochemistry for carcinoembryonic antigen as an adjunct to the morphologic diagnosis. They report more frequent and diffuse expression in adenocarcinoma versus microglandular hyperplasia. Despite the positive results, these studies comprised a few cases. This may be the reason why, to our knowledge, this complementary method has not been widely used in the differential diagnosis of microglandular hyperplasia. The diagnosis of clear cell carcinomas may be entertained in rare instances. This tumor typically occurs in older women in contrast to the predominantly reproductive-age population for microglandular hyperplasia. Clear cell carcinoma shows marked cytologic atypia and numerous mitotic figures, at least focally. Both lesions may contain tubular, cystic, and solid patterns but the papillary growth seen in some clear cell carcinomas is not found in microglandular hyperplasia. The solid growth of clear cell carcinoma displays cells with abundant clear cytoplasm, while the cells in microglandular hyperplasia tend to be smaller and have bland nuclei, containing subnuclear vacuoles and lacking intracytoplasmic glycogen. Microglandular hyperplasia is a reactive process of endocervical glands that occurs most commonly in women of reproductive age. The importance of its recognition lies in the distinction from malignant processes, primarily endometrial and endocervical adenocarcinomas. The examination of scant biopsy specimens remains a challenge. FALLOPIAN TUBE LESIONS The fallopian tube has a limited variety of neoplastic and pseudoneoplastic processes when compared to other organs of the female genital tract and has traditionally received modest interest regarding histopathologic findings. However, it has become a focus of greater attention during the last few years, after the recognition of its role in the development of serous carcinoma in women with germline BRCA mutations who undergo risk-reducing salpingo-oophorectomy.14,15 Recent contributions have progressively pinpointed the tubal epithelium as the potential origin of tubal, ovarian, and peritoneal carcinomas, not only in the BRCA mutation setting but also in sporadic adnexal epithelial tumors.16–18 This knowledge has led pathologists to heighten their index of suspicion regarding tubal atypia and has resulted in an appreciation of subtle neoplastic changes occurring in the fallopian tube epithelium, as well as the propensity of reactive atypia to mimic serous carcinoma in situ. BRCA-related neoplasms are usually clinically and grossly occult, often microscopic, and in situ, leading to difficulty in differential diagnosis with reactive changes.19 The distinction is of major importance and guides decisions regarding staging, surgery, chemotherapy, and follow-up.20,21 The fallopian tube epithelium shows morphologic changes in response to hormonal status.22–24 During the estrogenic phase of the menstrual cycle, the tubal ciliated cells show increased height and number, and mitotic figures are slightly more frequent. Despite these features, mitotic figures are extremely rare in normal tubal epithelium.23 Normal tubal lining cells have scant cytoplasm and can appear dark and crowded at low-power view. However, the nuclear features are bland (Figure 4). Mild degree of mucosal epithelial proliferation is frequent in fallopian tubes removed for a diversity of reasons, and it can be found in up to 66% of tubal ligations.25 More prominent reactive changes involving the fallopian tube have been referred to as atypical or adenomatous hyperplasia.25–27 They can be encountered in association with a variety of conditions, including inflammation, hyperestrogenic states, and neoplastic processes involving other gynecologic sites.28–30 These findings have been reported in 7% to 16% of unselected salpingectomy specimens.31,32 Reactive tubal epithelial changes are characterized by mucosal hyperplasia with crowding and stratification of the epithelium, tufting, and nuclear atypia (Figure 5). The nuclear atypia is mild to moderate, but can be focally severe. Mitotic figures are infrequent and often absent. The cells maintain the nuclear to cytoplasmic ratio and cilia. Early tubal carcinoma is typically of serous type and arises most commonly in the fimbriae but other histologic variants have been described and other fallopian tube segments may be affected.17 Serous carcinoma in situ of the fallopian tube reveals a hypercellular stratified epithelium with nuclear crowding, enlargement and hyperchromasia, loss of polarity, increased nuclear to cytoplasmic ratio, and often numerous mitotic figures (Figure 6, A). Factors classically used in the distinction of a malignant versus a pseudoneoplastic process, such as young age, absence of gross tumor, and lack of solid areas, are not as helpful in the BRCA era. Therefore, this differentiation has to rely on a constellation of clinicopathologic features (Table 2). In reactive changes, the nuclear atypia is less alarming than in tubal serous carcinoma in situ that displays severe nuclear atypia in all cells comprising the lesion. The identification of cilia and terminal bars in the apical surface of the cells in question is very helpful, as those are invariably absent in high-grade serous carcinoma. A high mitotic activity has been regarded by some as the only single diagnostic criteria for carcinomas, as mitotic figures are absent or infrequent in reactive conditions.23,28 In a simplistic way, the diagnosis of serous carcinoma in situ requires unequivocal cytologic atypia that cannot be explained by a reactive process. In case of doubt, immunostains for MIB-1 and p53 can be applied. The nuclear positivity for p53 should be strong and diffuse and MIB-1 proliferation index should be high to support a diagnosis of serous carcinoma.18 It is often useful to compare the area in question to the rest of the epithelium (Figure 6, A through F). According to the literature and also in our experience, patients with BRCA mutations frequently have epithelial atypia that does not reach the criteria for carcinoma.33,34 It is conceivable that these lesions could progress to carcinoma, but currently this is merely speculation. It is very important to strictly apply the criteria. Only carcinomas in situ should be considered diagnosable lesions until a general consensus is reached for the diagnostic features of the earlier morphologically recognizable stages of tubal carcinogenesis, such as dysplasia. These alterations are of uncertain significance at this point; only time and growing experience will reveal their significance. A more florid example of reactive change in the fallopian tube that mimics invasive adenocarcinoma has been termed pseudocarcinomatous hyperplasia.35,36 It may be encountered in tuberculous salpingitis and nontuberculous salpingitis. It is characterized by crowding and stratification of the epithelium, apparent gland formation or cribriforming, tufting, and nuclear atypia (Figure 7, A through C). This is associated with glandular infiltration of the muscularis propria with desmoplastic reaction and pseudoglandular hyperplasia of tubal serosal mesothelial cells, mimicking transmural extension of carcinoma. However, florid tubal epithelial hyperplasia almost invariably is accompanied by marked chronic and sometimes acute inflammation. Mitotic activity in tubal hyperplasia generally is low. It must be emphasized that inflammation can be occasionally present in tubal carcinomas, highlighting again the importance of the cytologic features in the differential diagnosis. Metaplastic papillary tumor is a peculiar and uncommon incidental finding in the fallopian tube during pregnancy or postpartum period. The lesion is microscopic and composed of papillary structures lined by large epithelial cells, with abundant eosinophilic cytoplasm with mild nuclear atypia (Figure 8). Because of its distinct appearance, it is easily differentiated from borderline tumors or adenocarcinoma.36,37 ENDOMETRIOSIS The histopathologic diagnosis of endometriosis is usually straightforward and is based on the recognition of endometriotic glands and stroma in aberrant sites. However, several unusual aspects may raise concern for a neoplasm, including atypical endometriosis, mass-forming lesions, polypoid growth, lymphovascular or perineural involvement, and necrotic pseudoxanthomatous nodules, all of which will be discussed below. The pathogenic mechanisms of endometriosis have not been completely elucidated and are probably multifactorial. Many investigators38,39 have shown clonality in endometriotic cysts, and a wide range of cytogenetics and molecular genetic alterations have been described, including partial or total chromosomal losses and gains.40,41 For the purpose of this review, endometriosis and associated lesions will be considered pseudoneoplastic, pertinent to the focus of this article; however, future investigations may prove a true neoplastic nature for some of these tissue processes. Atypical endometriosis refers to the presence of cytologic atypia within the glandular epithelial cells, particularly within the lining of endometriotic cysts. The frequency has been reported to be between 12% and 22%, depending on the criteria for atypia.42,43 The cells are enlarged, and have varied amounts of dense eosinophilic cytoplasm and atypical hyperchromatic nuclei. They are usually arranged in a single layer but can, on occasion, be stratified or form small papillary structures. A hobnail appearance is common. The presence of cytologic atypia in endometriotic cysts does not appear to have a negative impact on prognosis.44 However, it has been documented adjacent to endometrioid or clear cell carcinomas arising within endometriotic cysts, suggesting that it may potentially be a precursor occasionally prone to malignant transformation45 (Figure 9). Clear cell carcinoma represents the main differential diagnosis for atypical endometriosis because of the nuclear atypia, hobnail appearance, and association with endometriotic cysts. Distinguishing features are absence of a mass, infiltration of the cyst wall, or mitotic activity in atypical endometriosis. Polypoid endometriosis shows histopathologic findings very similar to those of endometrial polyps occurring within the endometrial cavity and featuring irregular and often cystic endometrial glands, fibrotic endometrial stroma, and prominent, thick-walled blood vessels. Reported sites include the walls of endometriotic cysts, omentum, serosal surfaces of the bowel and uterus, and mucosal surfaces of the vagina and bowel, among others.46 These lesions are most commonly associated with usual endometriosis and have been linked to estrogenic stimulation, including tamoxifen use.46,47 The main differential diagnosis is müllerian adenosarcoma, which characteristically shows leaflike glandular architecture, periglandular stromal hypercellularity, and atypical stromal cells, features absent in polypoid endometriosis. Intestinal endometriosis is believed to affect about one-third of patients with endometriosis.48 On occasion, it forms mass lesions or infiltrates the bowel wall, mimicking a neoplasm, primarily colonic adenocarcinoma. Useful features that distinguish endometriosis from malignancy are the predominantly mural location with an outward to inward growth, minimal or absent mucosal involvement, and the identification of endometrial stroma and old hemorrhage. Immunostains are certainly helpful in this differentiation, as large intestinal epithelium is usually positive for CK20 and CDX2, and müllerian epithelium is usually negative for these markers but positive for CK7 and estrogen receptor protein. Although most examples of endometriosis involving the digestive tract occur in the small bowel and colon, it has been described in other sites. We recently encountered a case of very extensive decidualized endometriosis in a pregnant patient that formed a large abdominal mass, infiltrating the stomach and spleen.49 Endometrial tissue can be encountered within lymphatic and blood vessels, unrelated to menstruation, leading to the differential of lymphovascular involvement by carcinoma. It has been reported in the myometrium, urethra, and ovary and almost invariably is concurrent with adenomyosis or endometriosis.50,51 The bland cytologic features of the focus in question and the absence of malignancy elsewhere strongly argue against adenocarcinoma. Perineural involvement by nonneoplastic endometrial glands has also been described and is not considered to be evidence of malignancy.52 Necrotic pseudoxanthomatous nodules are composed of an area of central necrosis, surrounded by histiocytes and hyalinization (Figure 10). The histiocytes have abundant foamy or granular cytoplasm, often pigmented, thereby the denomination pseudoxanthomatous. More typical foci of endometriosis are not usually found adjacent to these areas but often in other sites in the same patient.53 Rarely, these cases may raise the question of a neoplasm because of the presence of necrosis, but any other features suggestive of malignancy are absent. Finally, a wide range of müllerian neoplasms are know to arise in association with endometriosis, including endometrioid and clear cell carcinoma, endometrial stromal tumors, adenosarcoma, and carcinosarcoma54,55; these diagnostic possibilities must be excluded in cases of extensive endometriosis. OVARY Several pseudoneoplastic conditions occur in the ovary during pregnancy as a result of stimulation of stromal or sex cord elements, or both, by pregnancy hormones. Two such entities that may be mistaken clinically and pathologically for neoplasms are pregnancy luteoma and solitary luteinized follicle cyst of pregnancy and the puerperium.56 Pregnancy Luteoma Pregnancy luteoma is a benign, hyperplastic lesion that may be mistaken for a neoplasm, thus leading to unnecessary oophorectomy. Between 100 and 200 cases have been reported in the literature, although the true incidence is probably underestimated, as most of these lesions likely remain undetected.56–66 Pregnancy luteoma occurs in the second half of pregnancy, often among African American women, and is usually an incidental finding at cesarean delivery or during postpartum tubal ligation.56,58–60 In rare cases, a pelvic mass has been detected or the lesion has become symptomatic because of torsion, rupture, or obstruction of the pelvic outlet during labor.61,62 Recently, cases have been detected sonographically63,64 or by magnetic resonance imaging.65 Pregnancy luteomas are associated with virilization of the mother in about 25% of cases, and female infants are virilized as well in 60% to 70% of cases.64–66 Macroscopically, pregnancy luteomas are solid masses that may be mistaken for ovarian neoplasms because of this feature. Bilateral masses are present in approximately one-third of cases and multiple nodules are present within the ovary in about 50% of patients. Pregnancy luteomas range in size from microscopic up to 20 cm in maximal diameter, with a mean diameter of 7 cm in 1 study.59 The cut surfaces reveal 1 or more solid, brown, reddish, or tan nodules with a pushing margin. Foci of hemorrhage are often present.56,59,67,68 Microscopic examination reveals well-circumscribed nodules of steroid hormone–producing cells, intermediate in size between luteinized granulosa cells and luteinized theca interna cells. The cells are arranged in sheets, trabeculae, and follicle-like structures (Figure 11, A). The cells are polygonal with round, centrally located nuclei, which often contain a prominent nucleolus. Nuclear atypia may be present. Mitotic figures are often present, with a mitotic count of up to 7 mitotic figures per 10 high-power fields (Figure 11, B). Rarely, colloid droplets similar to those seen in the corpus luteum of pregnancy are identified.56,59 Reticulum invests nests and groups of cells. Pregnancy luteomas are generally thought to arise from nodular hyperplasia of theca interna cells (theca-lutein hyperplasia),59,67,69 although others56 have proposed an origin from stromal cells. More recently, it has been suggested that these tumorlike lesions may be clonal proliferations that have a growth advantage in pregnancy.70 The differential diagnosis includes sex cord–stromal tumors such as luteinized thecoma, steroid cell tumor, and hilus cell tumor and metastatic neoplasms such as carcinomas and melanoma. Sex cord–stromal tumors are occasionally seen in pregnancy and often become at least partially luteinized. They differ from pregnancy luteoma in that they are usually unilateral and solitary, as opposed to the multinodular and bilateral lesions seen in pregnancy luteoma. Microscopically, luteinized thecomas generally have at least focal residual spindle cell areas even in pregnancy. Reticulum stains invest single cells in thecomas rather than groups of cells, as seen in pregnancy luteoma. Several features that may aid in distinguishing pregnancy luteoma from steroid cell tumors include the presence of multiple nodules and numerous mitotic figures in pregnancy luteomas, features that are not usually seen in steroid cell tumors. Steroid cell tumors often have a distinctive prominent vascular pattern (Figure 12). Despite these features, the 2 entities may be impossible to distinguish morphologically in many cases. For practical purposes, a solid, lipid-poor, steroid hormone cell–type tumor in pregnancy should be considered a pregnancy luteoma56 unless there is substantial data to the contrary. Metastatic carcinomas are often multinodular and bilateral and may present in pregnancy; however, they would show a greater degree of nuclear atypia than is seen in pregnancy luteomas. Immunostains are helpful in distinguishing primary and metastatic carcinomas from pregnancy luteoma. Carcinomas, either primary or metastatic, are positive for keratins and epithelial membrane antigen and for other respective antigens based on their primary site of origin, and they are negative for inhibin. Pregnancy luteomas are positive for inhibin and may be positive for Melan-A, but are negative for HMB-45 and S100, which would differentiate them from malignant melanoma. Since pregnancy luteomas usually spontaneously regress within weeks of delivery, and the ovaries return to normal size,56,59 minimal intervention is appropriate. Solid nodules with radiologic findings of pregnancy luteoma (solid nodules, multinodularity, and bilaterality) discovered in the second half of pregnancy have been followed clinically.64 When encountered during surgery at the time of cesarean delivery or postpartum tubal ligation, a biopsy to determine the pathologic diagnosis is sufficient. Large Solitary Luteinized Follicle Cyst of Pregnancy and Puerperium Another benign lesion of the ovary that occurs during pregnancy and may be mistaken for a neoplasm is an uncommon, large, unilocular cyst first described by Clement and Scully71 in 1980 as large solitary luteinized follicle cyst of pregnancy and puerperium. The patients with this lesion are young, with an average age of 26 years.71 The cysts are often discovered incidentally on routine physical or ultrasound examinations during pregnancy or puerperium, or as incidental findings during cesarean delivery. They have been detected from the third month of pregnancy to the third month postpartum, and in rare cases, seemed to have developed or enlarged after delivery.71,72 Neither the patients nor their infants have shown endocrinologic manifestations.71–76 Macroscopically, the cysts are unilateral and large, with smooth external surfaces; they measure from 8 to 55 cm in greatest diameter. The cysts are unilocular, with thin walls measuring up to 5 mm in thickness, and contain clear, serosanguinous or mucoid fluid. The inner cyst lining is smooth.71–76 Microscopic examination reveals 1 to 10 layers of luteinized cells, presumably granulosa cells, without a clear distinction between the granulosa and theca lutein layers. The cells are polygonal and may be uniform or highly variable in size, with eosinophilic to clear cytoplasm. Most of the cells have uniform, round nuclei and often have a single prominent nucleolus. A characteristic feature is the presence focally of enlarged, hyperchromatic, bizarre nuclei in 10% to 50% of the cyst-lining cells. Mitotic figures are not seen (Figure 13). The lining cells may desquamate into the cyst lumen, and the wall in these areas is fibrous or lined by fibrin. Luteinized cells are also often seen in the underlying fibrous wall of the cyst. Call-Exner bodies or colloid bodies are not identified. The histologic features of the cysts are similar when resected during pregnancy, at term, or during the puerperium.71–76 Although the pathogenesis of these cysts is unknown, the timing of their development would suggest that human chorionic gonadotropin stimulation is involved in their development. High levels of gonadotropins during postpartum may play a role, as well as for those lesions that develop or enlarge in the postpartum period.71 The presence of large cysts lined by atypical cells raises the possibility of a neoplasm both clinically and pathologically. The major neoplasms in the differential diagnosis are cystic granulosa cell tumor and cystic serous or mucinous neoplasms. The cystic granulosa cell tumor is a rare variant that presents as a unilocular or paucilocular cyst lined by multiple layers of granulosa cells. The granulosa cells are smaller, more uniform, and without pleomorphism and are usually not strikingly luteinized; they form Call-Exner bodies and have grooved nuclei when of adult type. Although granulosa cell tumors often become luteinized during pregnancy, the luteinization is usually not as pronounced as in the solitary luteinized cyst of pregnancy, and Call-Exner bodies have not been reported in the latter entity. Although the stroma of mucinous epithelial neoplasms may be extensively luteinized in pregnancy, the mucin-containing columnar lining cells are usually unaffected. On the other hand, the lining cells of benign and borderline serous tumors may become polygonal or hobnail shaped, with abundant eosinophilic cytoplasm and enlarged hyperchromatic nuclei. Features that allow the recognition of serous neoplasms are the presence of cilia on some cells, the uniform single layer of cells lining the cysts in a cystadenoma, and the presence of the distinctive architecture of serous borderline tumors, whereas solitary luteinized follicle cysts of pregnancy are usually at least focally lined by stratified polygonal cells. Immunostains are also helpful; the cells of solitary luteinized follicle cyst of pregnancy are positive for inhibin and calretinin. CONCLUSIONS A number of benign entities may be difficult to distinguish from neoplasms in the female genital tract. Being aware of the spectrum of such lesions may allow their correct diagnosis and prevent overdiagnosis and excessive treatment. The authors have no relevant financial interest in the products or companies described in this article. Copyright: College of American Pathologist 2010 Figure 1 Typical histopathologic features of microglandular hyperplasia. A, Low-power view of crowded glands with focal cystification. B, Poor demarcation between glands and stroma. C, Reserve cell hyperplasia and squamous metaplasia is associated with the glands D, Bland cuboidal mucinous cells without nuclear atypia and mitosis; also note the inflammatory infiltrate (hematoxylin-eosin, original magnifications ×100 [A], ×200 [B and C], and ×400 [D]). Figure 2. Unusual morphologic variants of microglandular hyperplasia. A, Nuclear atypia in microglandular hyperplasia. B, Microglandular hyperplasia with solid growth pattern (hematoxylin-eosin, original magnifications ×400 [A] and ×200 [B]). Figure 3 A and C, Endometrial adenocarcinoma (left). B and D, Microglandular hyperplasia (right). Both lesions have a similar low-power appearance with closely packed glands. However, the glands of endometrial adenocarcinoma tend to be more irregularly shaped (A) than those in microglandular hyperplasia (B). The cells of endometrial adenocarcinoma have greater pleomorphism and irregular chromatin (C), while in microglandular hyperplasia, the nuclei are bland and regular (D). Also note the mitotic figure (C, arrow) in the endometrial adenocarcinoma (hematoxylin-eosin, original magnifications ×100 [A and B] and ×400 [C and D]). Figure 4. Normal fallopian tube epithelium showing the ciliated cells with clear cytoplasm and round nuclei and intermixed secretory cells; they are taller with oval nuclei (hematoxylin-eosin, original magnification ×400). Figure 5. Reactive tubal epithelial changes. Note that despite the severe nuclear enlargement and atypia, the cells maintain nuclear to cytoplasmic ratio and, more importantly, the cilia. Mitoses are absent (hematoxylin-eosin, original magnification ×400). Figure 6 A, Tubal serous carcinoma in situ showing stratification, loss of polarity, and severe nuclear atypia. B, Normal tubal epithelium from the same case. Immunohistochemistry for p53 shows strong and diffuse nuclear staining in the in situ carcinoma (C) and focal weak staining in the normal tubal epithelium (D). MIB-1 immunostain shows higher proliferation index in the in situ carcinoma (E) compared to the normal tubal epithelium (F) (hematoxylin-eosin, original magnifications ×400 [A and B]; original magnifications ×200 [C through F]). Figure 7 Pseudocarcinomatous hyperplasia. A, Prominent mucosal proliferation with architectural complexity and cellular stratification. B, Tubal epithelium within the muscular wall. C, Mesothelial hyperplasia with a focus of transitional cell metaplasia (Walthard cell rest) (hematoxylin-eosin, original magnifications ×400 [A and C]; and ×200 [B]). Figure 8. Metaplastic papillary tumor featuring papillary structures lined by large epithelial cells with abundant eosinophilic cytoplasm and bland nuclei (hematoxylin-eosin, original magnification ×400). Figure 9. Well-differentiated endometrioid adenocarcinoma arising in a focus of endometriosis (hematoxylin-eosin, original magnification ×400). Figure 10. Necrotic pseudoxanthomatous nodule characterized by a central area of necrosis surrounded by hemosiderin-laden histiocytes (hematoxylin-eosin, original magnification ×200). Figure 11 A, Pregnancy luteoma showing nodules of steroid hormone–producing cells arranged in sheets and follicle-like structures. B, The cells are polygonal with round, centrally located nuclei and prominent nucleoli (hematoxylin-eosin, original magnifications ×200 [A] and ×400 [B]). Figure 12. Ovarian stromal luteoma is very similar in appearance to the luteoma of pregnancy and the two may sometimes be indistinguishable in pregnancy. Ovarian steroid cell tumors often have a more prominent vascular pattern as seen here (hematoxylin-eosin, original magnification ×400). Figure 13. Large, solitary luteinized follicle cyst of pregnancy and the puerperium. The cyst is lined by polygonal cells with a moderate amount of cytoplasm. Scattered cells are large with enlarged, hyperchromatic, bizarre nuclei (hematoxylin-eosin, original magnification ×400). Contributor Notes From the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Debra A Bell, MD, Department of Laboratory Medicine and Pathology, Mayo Clinic, Hilton Bldg 11th floor, 200 First St SW, Rochester, MN 55905, e-mail: [email protected]