Hysteroscopy: Visual Perspectives of Uterine Anatomy, Physiology & Pathology
3rd Edition

Chapter 6
Pathology of the Uterus
Nilsa C. Ramirez
W. Dwayne Lawrence
The Normal Endometrium
The typical 28-day menstrual cycle can be divided into menstrual, proliferative, and secretory phases without a distinct demarcation between the end of one phase and the beginning of the next. The first day of menstrual bleeding is designated day 1 of the cycle. The menstrual phase lasts for an average of 4 days, during which a variable amount of tissue is sloughed and fluid is lost from the residual endometrial tissue; regeneration of the glands and surface epithelium has already begun before the midpoint of the menstrual phase. During the proliferative phase, which averages 10 days but can vary considerably in length from one individual to another and from one cycle to another in the same individual, the endometrial glands and stroma proliferate under the influence of rising levels of estrogens secreted by developing graafian follicles. Ovulation occurs typically on day 14 with the formation of a corpus luteum; progesterone secretion by the corpus luteum induces the onset of the secretory phase of the cycle. During this phase, the endometrium is primed for reception of the fertilized ovum. Glandular secretion is at its height from days 20 to 23, and progressive transformation of stromal cells into large predecidual cells dominates the last third of the secretory phase. If implantation does not occur, the corpus luteum degenerates, with progressively decreasing production of estrogens and progesterone. When these hormones have fallen to very low levels, the spiral arterioles of the endometrium undergo spasm and then dilation; the endometrial tissue undergoes degeneration, and menstruation begins. Evaluation of the architectural and cytologic variations in the glands, stroma, and spiral arterioles of the endometrium permits assessment of its phase of development.
Gross Examination
Hysteroscopic examination has demonstrated that menstruation usually begins in the cornual and fundal regions; in one study, sloughing was occasionally noted before the clinical onset of menstrual bleeding. Fragments of desquamated endometrial tissue appear gray-white, whereas the remaining mucosa is red and focally covered by white necrotic tissue. The late menstrual endometrium is thin and congested, with multiple punctate hemorrhages. Proliferative endometrium is pink-gray, smooth, and glistening; it increases progressively in height from 1 or 2 mm to 3 or 4 mm and occasionally is 6 or 7 mm just prior to ovulation. Secretory endometrium is yellow-white and glistening and may attain a thickness of 5 mm or more. About 5 days before the onset of menstruation or sometimes earlier in the cycle, the endometrium may have a polypoid appearance, simulating hyperplasia (Fig. 6.1). Around day 24 the endometrium begins to shrink, and by the onset of menstruation it is only one half to three quarters of its maximum height. This loss of tissue volume, resulting in a premenstrual thickness of about 2 mm, is caused principally by a loss of stroma fluid. If fertilization occurs, the endometrium continues to thicken. The ovum, which usually implants on day 20 of the cycle, may be visible on the endometrial surface as a slightly elevated red spot less than 1 mm in diameter.
The postmenopausal endometrium may be paper-thin if glandular atrophy with fibrosis of the stroma has occurred; however, if atrophy is less marked or irregular in its distributions, as often occurs during the first 10 or more years after the onset of menopause, the endometrium may be 1 or 2 mm thick. Thin-walled cystic glands are occasionally visible and are generally more numerous in elderly women.
Microscopic Examination
In the early proliferative phase, the glands are small, straight, and tubular and are lined by low columnar cells with basal nuclei, which may be slightly pseudostratified. Mitotic figures are uncommon. The stroma is composed of delicate stellate and spindle cells with sparse cytoplasm. As the endometrium continues to proliferate, mitotic activity increases in both the glands and the stroma and pseudostratification of the epithelial nuclei and enlargement and slight tortuosity of the glands are evident (Fig. 6.2).
In the early secretory phase, the first morphologic evidence of ovulation appears within 36 to 48 hours in the form of subnuclear vacuoles in the glandular epithelium. Mitotic activity and pseudostratification of nuclei disappear within approximately 3 days after ovulation as secretion begins to appear in the gland lumens; maximal glandular secretion and stromal edema are achieved between days 20 and 22 (6 to 8 days after ovulation). The beginning of the late secretory phase is heralded by prominence of the spiral arterioles,

around which mitotic activity recommences in the endometrial stromal cells on day 23. The arterioles coil extensively, and the stromal cells acquire increasing amounts of pale cytoplasm, becoming predecidual cells. This change spreads throughout the upper part of the endometrium, and the glands assume a sawtooth configuration (Fig. 6.3). Subsequently, fluid escapes from the stroma and the endometrium decreases in thickness. Endometrial granular lymphocytes accumulate in increasing numbers as menstruation approaches. The latter cells (also known as endometrial granulocytes, metrial cell, K cells, and stromal granulocytes) were once considered to be derived from endometrial stroma, but further studies have demonstrated their origin from the large granular T-lymphocyte series. If implantation occurs, the endometrium becomes increasingly congested, the secretion and edema persist, and the predecidual cells become progressively larger to form decidual cells.
FIGURE 6.1 Secretory phase. The endometrium is yellow-white, glistening, and polypoid. Microscopic examination revealed this endometrium to be at day 19 of the cycle.
FIGURE 6.2 Proliferative phase. The endometrium is relatively thin, with straight or slightly tortuous glands. (×64.)
FIGURE 6.3 Secretory endometrium. The endometrium is thick, and its glands are tortuous with serrated border (×24.)
The postmenopausal endometrium varies from a relatively thick layer, with glands of varying sizes lined by mitotically inactive pseudostratified epithelium and abundant fibrous stroma, to a very thin layer containing small glands lying in a sparse component of fibrotic stroma (Fig. 6.4). The atrophic glands may be cystically dilated and lined by flattened epithelium. Varying combinations of these changes may be seen within individual endometria after the menopause. In general, the thicker endometria, which have been designated as showing inactive hyperplasia, are seen in the earlier postmenopausal years; simple atrophy (predominance of small atrophic glands) in later years; and cystic atrophy (predominance of cystic atrophic glands) in the most elderly age group.
Endometrial Hyperplasia
Diffuse hyperplasia of the endometrium results from a continuous exposure to estrogens unopposed by progesterone. This disorder may be encountered in women of a wide age

range in various clinical conditions. Women of reproductive age with anovulatory cycles, perimenopausal and postmenopausal women on estrogen therapy, obese women with a high rate of peripheral conversion of androgens to estrogens, and women of all ages with estrogen-producing ovarian tumors are among those subject to the development of endometrial hyperplasia. The drug tamoxifen, a nonsteroidal antiestrogenic compound that is used widely in the treatment of breast adenocarcinoma, has been implicated in some studies with the development of endometrial polyps, endometrial hyperplasia, and carcinoma.
FIGURE 6.4 Atrophic endometrium. Small and inactive-appearing glands are set in a fibrotic stroma. (×64.)
Focal hyperplasia, differing only in its extent from diffuse hyperplasia, is occasionally seen within an otherwise normal endometrium. The pathogenesis of this lesion is unclear; presumably, it results from a localized exaggerated response to estrogens or deficiency of progesterone receptors. Most examples of endometrial hyperplasia can be assigned to one of two major categories: simple hyperplasia and the complex forms. The latter have been known by various terms, among which are adenomatous hyperplasia, atypical hyperplasia, atypical adenomatous hyperplasia, architectural atypicality, cellular atypicality and carcinoma in situ. Simple hyperplasia, which includes cystic hyperplasia, is thought to have a very low malignant potential, whereas the more severe forms of complex hyperplasia are regarded as significantly precancerous.
The system of classification of endometrial hyperplasia proposed by the World Health Organization (WHO) and the International Society of Gynecological Pathologists (ISGP) takes into consideration both architectural and cytologic features of the glands. It divides endometrial hyperplasia into four categories: simple hyperplasia, complex (adenomatous) hyperplasia, simple atypical hyperplasia, and complex atypical hyperplasia (adenomatous hyperplasia with atypia). The terms simple and complex refer to the architectural features of the hyperplastic glands, whereas the term atypia is used only if cytologic atypia is identified. Despite poor reproducibility, the use of this classification system has been widely accepted. Recent advances in the field of cytogenetics may assist in the development of a new classification system with better reproducibility and correlation with clinical outcome.
Gross Pathology
Although the hyperplastic endometrium may retain the glistening, mucoid, pink-gray appearance of the normal proliferative endometrium, it is usually thicker and is occasionally polypoid (Fig. 6.5). Small cysts may be visible, and dilated congested sinusoids may be seen just beneath the surface; although small red foci of hemorrhage and yellow foci of necrosis are sometimes seen, the latter finding should raise the suspicion of focal carcinoma.
Microscopic Pathology
Simple hyperplasia typically has a characteristic Swiss cheese appearance on low-power magnification. Variably sized dilated glands, lined by flattened to pseudostratified columnar epithelium, are found either diffusely or focally on the background of a proliferative endometrium (Fig. 6.6). The stroma appears abundant and active with naked nuclei. Mitotic figures vary from few to numerous. If cytologic atypia is identified, the term simple atypical hyperplasia is used.
FIGURE 6.5 Endometrial hyperplasia. The endometrial cavity is occupied by thickened, irregularly polypoid, yellow-tan tissue without evidence of necrosis.
Complex hyperplasia may be superimposed on simple hyperplasia but is also encountered in pure or almost pure form. This category includes various architectural abnormalities. If cytologic atypicality is also present, the term complex atypical hyperplasia is used.

In most cases, architectural and cellular abnormalities coexist to a parallel degree. The most common mild manifestation of the former is the presence of outpouchings from cystic glands, creating a so-called finger-in-glove pattern; the outpouchings may appear as small glands pinched off by stroma from the adjacent cystic glands. Despite varying degrees of glandular crowding, clearly recognizable stroma remains between the glands. With increasing severity of architectural atypia, epithelial stratification and glandular crowding become more prominent until only thin wisps of stroma separate thick-walled glands of distorted shapes (Fig. 6.7). Rarely, the lumens of the glands are obliterated focally by proliferation of the lining cells. Another form of complexity is the presence of papillae with fibrovascular stalks within dilated glands. Cytologic atypicality is characterized by nuclear rounding, hyperchromatism, pleomorphism, and loss of polarity. Mitotic activity is usually but not invariably increased, and the nucleoli may be enlarged and prominent.
FIGURE 6.6 Simple hyperplasia. Variably sized, generally rounded cystic glands lie in a cellular endometrial stroma. (×64.)
Various metaplastic changes may be encountered in association with hyperplasia, including the acquisition of abundant eosinophilic cytoplasm (eosinophilic metaplasia), the appearance of cilia on the cell surfaces (ciliated cell metaplasia), and squamous metaplasia (acanthosis), with the formation of “morules” of small, immature squamous cells, which may be centrally necrotic. These alterations do not of themselves indicate a premalignant state, but alert the pathologist to scrutinize closely the architectural and nuclear characteristics of the associated glandular epithelium, since metaplasia may occur in atypical hyperplasia as well as adenocarcinoma. Focal or diffuse glandular secretory changes may also be present.
In some laboratories the degree of complexity and cellular abnormalities within a specimen of endometrium are graded as mild, moderate, or severe, and the extent of the lesion within the entire specimen is determined. When cytologic and architectural features are indistinguishable from those of adenocarcinoma but the lesion forms a single focus of disseminated small foci without obvious invasion of the surrounding stroma, the designation carcinoma in situ has been used. The definition of carcinoma in situ of the endometrium is controversial, however, and most pathologists do not use the term, including for these lesions within the category of complex atypical hyperplasia.
FIGURE 6.7 Endometrial hyperplasia with severe architectural and cytologic atypia (complex atypical hyperplasia). The glands are crowded, and most are separated by only thin wisps of stroma. The nuclei are stratified, and many are rounded and vesicular. (×250.)
Endometrial Polyps
Although endometrial polyps have been reported to occur in prepubertal girls, they are encountered almost always in older patients, particularly those in their fifth decade. These lesions may be asymptomatic or may be associated with abnormal uterine bleeding. Their frequency is increased in cases of endometrial carcinoma.
Gross Pathology
Endometrial polyps occur singly in about three fourths of cases. Although they may occur at any location within the endometrial cavity, they are found most often in the fundus, particularly in the cornual areas. They range from lesions a few millimeters in diameter to larger masses that occupy the entire endometrial cavity and simulate cancer. Some of them are sessile, whereas others have long, slender stalks (Figs. 6.8 and 6.9). Occasionally a large polyp protrudes through the external cervical os and very rarely through the introitus, mimicking procidentia. Most polyps are pink-gray to white with smooth, glistening surfaces, beneath which small cysts may be visible. Occasionally the entire polyp or only its tip is hemorrhagic or infarcted. It must be emphasized that various

lesions other than glandular polyps may have a polypoid configuration, including carcinoma, sarcomas, carcinosarcomas, adenosarcomas, leiomyomas, fragments of retained placenta (placental polyps), and even secretory endometrium.
FIGURE 6.8 Endometrial polyp. Virtually the entire endometrial cavity is occupied by a large, broad-based, sessile polyp. (×13.)
Microscopic Pathology
The endometrial glands within polyps may have various appearances, which depend in part on the age and hormonal status of the patient. In women in the reproductive age group, they are often out of phase with those of the adjacent endometrium. Although they may be secretory during the luteal phase of the cycle, more typically they have a weakly proliferative pattern, and often they are cystically dilated. In postmenopausal patients, cystic glands lined by low cuboidal to flattened epithelium are most frequently encountered (Fig. 6.10). The stroma within polyps may resemble that of a proliferative endometrium but is often fibrotic. A consistent feature of a fully developed polyp is the presence of large, thick-walled blood vessels throughout its core. Occasionally, smooth muscle is present within the stroma of a polyp; if it is the predominant component, the term adenomyomatous polyp or polypoid adenomyoma is appropriate.
FIGURE 6.9 Endometrial polyp. An elongated slender polyp is attached to the fundus and extends to the internal cervical os. The surrounding endometrium appears flattened and atrophic.
Various degrees of glandular atypicality and even carcinoma may be encountered within otherwise benign polyps. Serous and clear cell carcinomas have been reported to arise in endometrial polyps, as have malignant müllerian mixed tumors. When glandular atypicality, usually associated with acanthosis, occurs within an adenomyomatous polyp, the term atypical polypoid adenomyoma has been used. In a curettage specimen, this lesion is distinguishable from a low-grade adenocarcinoma or adenoacanthoma that has invaded the myometrium by the pattern of its smooth muscle, which resembles a leiomyoma and lacks the orientation of bundles seen in the normal myometrium.
FIGURE 6.10 Endometrial polyp containing numerous variably sized glands, many of which are dilated, within a fibrous stroma. The adjacent endometrium is thin and atrophic.
Endometrial Carcinomas
Carcinoma of the endometrium occurs over a wide age range. Exceptional examples have been encountered in prepubertal girls, and fewer than 10% are seen in women of reproductive age; the great majority occurs in postmenopausal women. Just as in cases of endometrial hyperplasia, unopposed estrogenic stimulation has been shown

by numerous investigations to increase significantly the risk of endometrial carcinoma. Many of these tumors arise on a background of complex atypical hyperplasia, but some originate within an otherwise normal-appearing endometrium.
FIGURE 6.11 Endometrial adenocarcinoma. The endometrial cavity is occupied by a bulging, irregularly polypoid tumor with a pebbly surface. Opaque yellow foci are visible.
Gross Pathology
Endometrial carcinomas may be localized or involve the entire endometrium; when they are diffuse they typically terminate abruptly at the internal cervical os. Localized tumors may be polypoid and either sessile or pedunculated (Figs. 6.11 and 6.12). Although small carcinomas may be occult within a normal or hyperplastic endometrium or an endometrial polyp, the typical tumor is composed of irregularly heaped up tissue, which often has a pebbly or granular surface (Fig. 6.13). In contrast to the glistening, mucoid gray, elastic features of proliferative or hyperplastic endometrium, carcinomatous tissue appears opaque, dry, pale-yellow or white, and friable. Dark-yellow areas are often conspicuous as a result of necrosis of the accumulation of lipid-filled cells of stromal origin between the neoplastic glands. Hemorrhage and ulceration are common, particularly when the tumor is poorly differentiated, and abnormal vascular patterns may be seen on the surface of the tumor.
FIGURE 6.12 Endometrial adenocarcinoma. The anterior and posterior endometrial surfaces are occupied by yellow-tan, irregularly piled-up tumor, which terminates abruptly at the internal cervical os.
FIGURE 6.13 Higher magnification of tumor in Fig. 6.12 shows the opaque, pale-yellow, irregularly polypoid surface of the tumor.
Microscopic Pathology
Although they have not been correlated to any significant extent with specific gross features, various histologic patterns and cell types may be encountered in cases of endometrial carcinoma. Adenocarcinomas of the usual endometrioid type, characterized by the presence of tubular glands lined by stratified mucin-free or mucin-poor epithelial cells, account for most of the cases (Fig. 6.14). The criteria for separating severely atypical hyperplasia from low-grade adenocarcinoma of the endometrium are not sharply defined, but atypical glandular proliferations that have the following features are accepted as adenocarcinomas by almost all observers: a back-to-back arrangement of glands without recognizable intervening stroma; a cribriform pattern (bridging of epithelial lining cells to form multiple lumens within an enlarged gland); a complex papillary architecture; stratification, loss of polarity, rounding and pleomorphism of nuclei; irregular clumping of chromatin

alternating with clear foci within the nuclei; mitotic figures, which may be relatively few in well-differentiated tumors; and a desmoplastic reaction of the stroma separating the glands. One or more of these features may be absent in individual cases.
FIGURE 6.14 FIGO grade I adenocarcinoma with cribriform arrangement of glands, which are closely packed without intervening stroma. (×400.)
Squamous cell differentiation is often encountered in endometrial carcinomas, particularly in low-grade endometrioid tumors, in which rounded nodules of cytologically benign, small, immature squamous cells partially occupy or replace varying numbers of the neoplastic glands (Fig. 6.15). The presence of these nodules or morules in an adenocarcinoma engendered the designation adenoacanthoma. When the squamous component is cytologically malignant and typical of that seen in squamous cell carcinoma, and also invades the stroma independently of the glandular component of the tumor, the term adenosquamous carcinoma has been recommended and subsequently widely used (Fig. 6.16). This tumor is typically associated with a less well-differentiated glandular component than the adenoacanthoma and has a much worse prognosis. Although some investigators have concluded that the presence of malignant squamous cells per se in the adenosquamous carcinoma explains its poor prognosis, others have attributed the latter to the typically higher grade of the accompanying glandular component. Recent studies have supported the latter view based on the observation in a large series of cases that the prognosis of endometrioid carcinomas with both glandular and squamous components depends on the grade of the glandular component rather than the benign or malignant appearance of the squamous component. The WHO favors the term endometrioid adenocarcinoma with squamous differentiation with grading of the glandular component.
FIGURE 6.15 Adenocarcinoma with squamous differentiation. FIGO grade 1. Malignant endometrial glands contain rounded nodules (morules) of small cytologically benign squamous cells. (×256.)
FIGURE 6.16 Adenocarcinoma with squamous differentiation. FIGO grade 2. Sheets of malignant squamous cells (right portion of figure) abut malignant glands. (×256.)
Relatively rare subtypes of endometrial carcinoma are also encountered. The clear cell carcinoma closely resembles that found in other portions of the genital tract such as the ovary, cervix, and vagina. This tumor may have papillary, tubular, cystic, or solid patterns or mixtures thereof. It is characterized by two predominant cell types: polyhedral or rounded clear cells with abundant intracytoplasmic glycogen (Fig. 6.17A), and hobnail cells, characterized by scanty cytoplasm and bulbous, hyperchromatic nuclei that protrude into the glandular lumens (Fig. 6.17B). The serous papillary carcinoma has microscopic features similar to those of the serous papillary carcinoma of the ovary, with thick fibrous papillary fronds usually lined by markedly

atypical cells with nuclear pleomorphism and macronucleoli and small cellular buds that appear to be detached from the larger polypoid excrescences (Fig. 6.18). This tumor has a poor prognosis, related to the frequent presence of deep invasion of the myometrium, often extensive vascular invasion or transtubal spread that may result in peritoneal implantation. Serous papillary carcinoma should not be confused with the villoglandular variant of endometrioid adenocarcinoma, a lesion with villous papillary architecture that behaves more like low-grade nonvillous endometrioid carcinomas than serous carcinomas. In this unusual pattern, the papillary fronds have delicate fibrovascular cores lined by mild to moderately atypical cells that resemble those of nonvillous endometrioid adenocarcinoma; cellular budding is typically absent or minimal. Other rare forms of endometrioid carcinoma include the secretory type, a well-differentiated adenocarcinoma with subnuclear vacuolization similar to that observed in normal early secretory endometrium, and the mucin-rich carcinoma, characterized by the presence of abundant mucin, which is primarily intraluminal but may be additionally present in the cytoplasmic apices of the neoplastic cells. In contrast, in mucinous adenocarcinomas of the endometrium, which are rarer than those of the cervix, mucin fills the cytoplasm, depressing the nucleus to the base of the cell. Another very rare type of endometrial carcinoma is the pure squamous cell form, which may arise on a background of cervical stenosis, pyometra, and squamous metaplasia.
FIGURE 6.17 A; Clear cell carcinoma. The solid pattern is composed of polygonal and rounded cells with clear cytoplasm and relatively small dark eccentric nuclei. The clear cytoplasm stains positively for glycogen. (×256.) B: Clear cell adenocarcinoma. Variably sized glandular spaces are lined by prominent hobnail cells with scanty cytoplasm and large, bulbous nuclei that protrude into the lumina. (×260.)
FIGURE 6.18 Serous papillary adenocarcinoma. The tumor contains delicate papillae with small buds of neoplastic appearing to lie free within the lumen. Psammoma bodies are present in the left portion of the micrograph. (×160.)
Both the WHO and the International Federation of Gynecology and Obstetrics (FIGO) recommend grading endometrioid carcinoma of the endometrium on the basis of both the architectural and the nuclear features of the tumor. Accordingly, well-differentiated tumors composed almost entirely of well-formed glands lined by slightly to moderately atypical cells are grade 1. Tumors with a 6% to 50% solid arrangement of nonsquamous epithelial cells are grade 2 and >50%, grade 3. If the degree of a nuclear atypia is more severe than expected for tumors with a grade 1 architectural pattern, the grade is increased by one (Fig. 6.19). It must be emphasized also that the grade assigned to a tumor in an endometrial curettage specimen is often lower than that revealed by thorough examination of the subsequently removed uterus. Since 1989, the FIGO has recommended surgicopathologic staging of carcinomas of the endometrium. The evaluation of pelvic and para-aortic lymph nodes, adnexa, and peritoneal fluid cytology is combined with the depth of myometrial invasion and the presence or absence of endocervical involvement to determine the stage.

Smooth Muscle Tumors
Leiomyomas are the most common tumors of the uterus, occurring most often in women of reproductive age, especially those in the forth and fifth decades. In the postmenopausal period these tumors typically undergo atrophy, occasionally accompanied by extensive calcification; rarely, they enlarge progressively. Leiomyosarcomas, which are much rarer but account for about 45% of sarcomas and malignant müllerian mixed tumors (carcinosarcomas) of the uterus, reach their peak incidence in the fifth and sixth decades.
FIGURE 6.19 Adenocarcinoma, high grade. The tumor is composed of sheets of poorly differentiated cells with rare to absent glandular differentiation. (×256.)
Gross Pathology
Leiomyomas may occur in any portion of the myometrium and present as intramural, subserosal, or submucosal masses. They vary in size from microscopic to massive. Submucosal leiomyomas appear as rounded masses that bulge to varying extents into the endometrial cavity; they may also form pedunculated tumors on stalks, sometimes presenting as soft or firm polypoid masses protruding through the external cervical os or rarely through the introitus (Fig. 6.20). The overlying endometrium may be atrophic, congested, ulcerated, or hemorrhagic. The tumor tissue itself may undergo various degenerative changes, including infarction and cyst formation.
Leiomyosarcomas are typically softer and more often necrotic and hemorrhagic than leiomyomas. Approximately 20% are predominantly submucosal, protruding into the endometrial cavity in a polypoid fashion.
Microscopic Pathology
The typical leiomyoma is composed of interlacing bundles of spindle-shaped cells with eosinophilic cytoplasm and cigar-shaped pale nuclei (Fig. 6.21). Focal or diffuse hyalinization and edema are common. Calcification is frequent, particularly after menopause. The epithelioid smooth muscle tumor, sometimes referred to as the leiomyoblastoma, a subtype, is composed predominantly or exclusively of smooth muscle cells resembling epithelial cells, with abundant eosinophilic or clear cytoplasm, and growing diffusely or in cords or trabeculae.
FIGURE 6.20 Submucosal leiomyoma. The tumor forms a pedunculated rounded mass attached to the endometrium by a short broad pedicle.
The diagnosis of leiomyosarcoma is usually obvious but may be difficult in borderline cases. The presence of coagulative tumor cell necrosis, significant cellular atypicality, and increased mitotic activity (ten or more mitotic figures per ten high-power fields) are the most useful criteria according to Bell et al. (Fig. 6.22). If any two of these criteria are present, a diagnosis of leiomyosarcoma is warranted. The authors classified as “leiomyomas with increased mitotic activity” tumors with 5 to 20 mitotic figures per 10 high-power fields, absent or mild cellular atypicality, and no evidence of coagulative tumor cell necrosis. Tumors with zero to ten mitotic figures per ten high-power fields, moderated to severe cellular atypicality, and no evidence of cellular coagulative necrosis, were classified as “atypical leiomyomas with a low risk of recurrence.” Epithelioid smooth muscle tumors are benign in the great majority of cases; the histologic criteria for malignancy are less clear-cut than those of typical smooth muscle tumors.
Endometrial Stromal Tumors
Endometrial stromal tumors include benign forms, low-grade sarcomas, and high-grade sarcomas. The benign tumors are the very rare stromal nodules, 75% of which

occur in women of reproductive age. Endometrial stromal sarcomas (ESS) account for 10% to 15% of uterine sarcomas and carcinosarcomas. The low-grade variety (formerly known both as endolymphatic and stromal myosis and endometrial stromatosis) occurs over a wide age range of patients, but is encountered in women of reproductive age in more than half of the cases, with a mean age in the early forties. High-grade sarcomas occur in slightly older women, with the average age being approximately 50 years. A different designation for high-grade ESS was recently recommended owing to several reasons. Included among those are the facts that mitotic counts are no longer used to differentiate between the low- and high-grade ESS and that tumors traditionally classified as high-grade ESS usually fail to show endometrial stromal differentiation and may not be of endometrial stromal origin. The recommended terms include poorly differentiated endometrial sarcoma, undifferentiated endometrial sarcoma, and undifferentiated uterine sarcoma. The term undifferentiated endometrial sarcoma is recommended by the WHO for these high-grade sarcomas.
FIGURE 6.21 Leiomyoma. The tumor is well demarcated (A) and composed of interlacing bundles of well-differentiated spindle-shaped cells (B). (A: ×64; B: ×256.)
FIGURE 6.22 Leiomyosarcoma. The tumor is composed of spindle cells with enlarged pleomorphic nuclei. Mitotic figures are numerous (arrows). (×256.)
FIGURE 6.23 Low-grade endometrial stromal sarcoma (formerly endolymphatic stromal myosis). Tumor bulges into endometrial cavity and may be seen as wormlike extensions protruding from the vessels within the myometrium.
Gross Pathology
Although most stromal nodules are intramural, approximately 20% form soft polypoid masses that bulge into the endometrial cavity. The uterus is typically enlarged in cases of endometrial stromal sarcoma regardless of its grade. The low-grade tumors usually form smooth-surfaced polypoid masses that fill the endometrial cavity (Fig. 6.23); in the underlying

myometrium, they grow as yellow-tan, serpiginous, and nodular masses or as wormlike structures protruding from the lumens of myometrial vessels. Sectioning of the broad ligament and adnexa may reveal extrauterine extension, including intravascular wormlike prolongations. In some cases, the tumor appears to blend almost imperceptibly with the surrounding myometrium and a clearly defined mass is not appreciated.
High-grade stromal sarcomas characteristically form large polypoid masses that fill the endometrial cavity. They are more apt to exhibit hemorrhage and necrosis than the low-grade tumors and are less prone to extend as wormlike structures within the uterine and extrauterine vessels.
Microscopic Pathology
The stromal nodule is composed of bland cells closely resembling the stromal cells of normal proliferative endometrium. The diagnostic feature of this tumor is its sharp demarcation from the adjacent myometrium. The mitotic rate is generally very low. The tumor must be distinguished from a highly cellular leiomyoma, with which it has been often confused. The low-grade stromal sarcoma invades the myometrium in a serpiginous fashion, typically extending within vascular spaces (Fig. 6.24). Numerous small blood vessels, similar in appearance to the spiral arterioles of a secretory endometrium, are a characteristic feature of the tumor, and sharply etched foci of hyalinization may be present. The neoplastic cells are similar to those of the stromal nodule. Stromal sarcomas with high-grade features usually have brisk mitotic activity, with more than 10 and usually more than 20 mitotic figures per 10 high-power fields. The cells of these tumors have less resemblance to the stromal cells of normal proliferative endometrium than those of a low-grade sarcoma and may assume nonspecific features of a round cell or spindle cell sarcoma or may be one of various specific subtypes of soft tissue such as malignant fibrous histiocytoma.
FIGURE 6.24 Low-grade endometrial stromal sarcoma (formerly endolymphatic stromal myosis). Tongues of tumor permeate the myometrium and its vessels. (×44.)
Mixed Epithelial and Stromal Tumors
Mixed epithelial and stromal tumors contain epithelial as well as stromal elements. The epithelial component is occasionally benign, but the stromal component is rarely so. The adenosarcomas and the much more common carcinosarcomas (malignant müllerian mixed tumors) generally occur in postmenopausal women, although in one series approximately one third of the patients were premenopausal and three were 16, 17, and 22 years of age. Malignant müllerian mixed tumors account for about 35% of uterine sarcomas.
Gross Pathology
Most mixed tumors partly or completely fill the endometrial cavity in the form of irregular single or multiple polypoid masses (Figs. 6.25 and 6.26). They may be soft or firm, depending on the degree of malignancy of either the epithelial or stromal component. Necrosis and hemorrhage are common in the malignant müllerian mixed tumors.
FIGURE 6.25 Malignant müllerian mixed tumor; homologous (carcinosarcoma). Tumor bulges into the endometrial cavity and may be seen as wormlike extensions protruding from the vessels within the myometrium.
Microscopic Pathology
The rare adenofibroma is characterized by club-shaped polypoid masses lined by low columnar or cuboidal epithelium projecting from the surface or into cysts within the tumor. The stroma is composed of cytologically benign cells, which may have the appearance of endometrial stromal cells

or fibroblasts. Mitotic figures are rare or absent in both the epithelium and the stroma. In contrast, the müllerian adenosarcoma contains benign or atypical-appearing glands and a sarcomatous stroma that exhibits more than an occasional mitotic figure (Fig. 6.27). A characteristic feature is collaring of the glandular component by cellular foci of stromal neoplasia. The epithelium may be endometrioid, mucinous, or squamous.
FIGURE 6.26 Malignant müllerian mixed tumor; heterologous. The large polypoid tumor exhibits extensive areas of yellow-to-green necrotic tissue.
In homologous malignant müllerian mixed tumors the sarcomatous component may be similar to that of an endometrial stromal sarcoma, but other types of sarcoma, such as fibrosarcoma and leiomyosarcoma, are occasionally encountered. The malignant epithelial element is most commonly of müllerian type such as endometrioid, serous, clear cell, or squamous cell carcinoma (Fig. 6.28). The malignant müllerian mixed tumors with heterologous elements may include rhabdomyoblasts, malignant-appearing cartilage or bone, or a combination of these elements (Fig. 6.29). In one series rhabdomyosarcoma was present in 68% of the cases, chondrosarcoma in 29%, and osteogenic sarcoma in the remainder.
FIGURE 6.27 Adenosarcoma. Irregularly branching cleftlike glands are surrounded by a cellular sarcomatous stroma imparting a collaring effect. (×28.)
FIGURE 6.28 Malignant müllerian mixed tumor; homologous (carcinoma). A gland lined by irregularly stratified malignant cells is surrounded by a highly cellular stroma with numerous, often atypical mitotic figures.
FIGURE 6.29 Malignant müllerian mixed tumor; heterologous. A nest carcinoma (arrow) is present within an area of spindle cell sarcoma. An island of malignant cartilage is present on the left. (×100.)
Gestational Trophoblastic Disease
According to the most recent WHO classification (2003), the term gestational trophoblastic disease (GTD) encompasses the following: the molar pregnancies (hydatidiform mole [complete, partial, invasive, metastatic]), the trophoblastic

neoplasms (choriocarcinoma, placental site trophoblastic tumor/PSTT, epithelioid trophoblastic tumor/ETT) and the nonneoplastic, nonmolar trophoblastic lesions (the exaggerated placental site, the placental site nodule and plaque). The hydatidiform mole has been reported to occur in approximately one of every 2,000 pregnancies and choriocarcinoma in one of every 20,000 to 40,000 pregnancies. GTD can also be seen in association with ectopic pregnancy. Studies show that 2.5% of all gestation-associated choriocarcinomas develop following an ectopic pregnancy. The choriocarcinoma, which is composed of malignant cytotrophoblast and syncytiotrophoblast cells growing in concert (sometimes with a component of intermediate type trophoblast), follows a hydatidiform mole in approximately one third to one half of the cases; in the remainder, it follows some other form of pregnancy, including a full-term delivery and a spontaneous or therapeutic abortion. Moles often cause vaginal bleeding and are detected in the first trimester of pregnancy. Complete hydatidiform moles show hydropic swelling of most of the chorionic villi, the karyotype is usually 46XX, and a fetus is almost always absent. Clinically, the uterus is larger than expected for the estimated gestational age (EGA) in approximately half the patients; in the remainder, the uterus is either of normal size or smaller than normal. Serum hCG levels are elevated (sometimes markedly) for the EGA. In partial hydatidiform moles, two populations of chorionic villi are identified: one hydropic and the other of a smaller (“normal”) size; the karyotype is usually triploid, and there is almost always fetal development. Clinically, the uterine size is usually small for the EGA.
The PSTT is composed of intermediate trophoblast cells of the type normally encountered in the implantation site. Patients typically present with amenorrhea and uterine enlargement and are often thought to be pregnant. The patient’s last known intrauterine pregnancy may be recent or remote, and a past history of a molar pregnancy is reported in 5% to 8% of patients. The tumor generally secretes only small amounts of chorionic gonadotropin and has a benign, self-limited, clinical course; however, occasional tumors, which typically contain numerous mitotic figures, have an aggressive clinical behavior with metastatic spread and a fatal outcome.
The ETT is a tumor composed of intermediate trophoblast cells of the type normally encountered in the chorion. Abnormal uterine bleeding is the usual clinical presentation. The patient’s last known intrauterine pregnancy may be recent or remote, and a past history of a molar pregnancy is reported in approximately 14% of patients. Serum hCG levels are usually low (<2,000 mIU/mL). The clinical behavior and response to chemotherapy is variable and similar to that of PSTT. The recommended treatment modality for both PSTT and ETT is hysterectomy.
An exaggerated placental site (formerly known as syncytial endometritis) represents an exuberant infiltration of the myometrium by intermediate trophoblast cells mixed with syncytiotrophoblastic giant cells at the site of placental implantation of a normal or molar gestation. It is a physiologic process, not to be confused with a PSTT.
Placental site nodules or plaques are discrete foci of hyalinized placental implantation sites that are encountered mainly as incidental microscopic findings in endometrial curettings. The patients are usually of reproductive age and have had at least one previous (sometimes remote) intrauterine pregnancy. These lesions have no apparent clinical significance.
The term unclassified trophoblastic lesion (UTL) is recommended when a trophoblastic lesion does not conform to the established histologic criteria for specific entities in gestational trophoblastic disease. For example, an abnormal trophoblastic proliferation not associated with a villous component but lacking the classic histopathologic features of a choriocarcinoma or a PSTT would qualify for this diagnosis.
Gross Pathology
The uterus containing a complete hydatidiform mole is typically distended by many thin-walled, fluid-filled vesicles up to 1 to 2 cm in diameter; the vesicles are usually connected by thin strands of connective tissue. The invasive mole can be recognized grossly if intramyometrial vesicles are identified. The most characteristic features of a choriocarcinoma are hemorrhage and necrosis. The tumor may form a bulky, soft, friable mass filling the uterine cavity, with multiple nodules of hemorrhagic tumor involving the myometrium (Fig. 6.30). The PSTT may present as a polypoid tumor protruding into the endometrial cavity or may primarily involve the myometrium, with extension to or beyond the serosa. Sectioning reveals soft, tan masses; hemorrhage and necrosis are usually not prominent features except in the occasional malignant forms of the tumor. ETTs are usually solitary and discrete invasive tumors that range in size from 0.5 to 4.0 cm. They may be solid or cystic, with varying degrees of hemorrhage and necrosis.
FIGURE 6.30 Choriocarcinoma. The endometrial cavity is filled with soft markedly hemorrhagic tumor.

Microscopic Pathology
The histologic hallmarks of the complete hydatidiform mole are hydropic swelling of the great majority of the chorionic villi and circumferential proliferation of the overlying of atypical trophoblastic cells. The generally avascular villi are enlarged, round, and filled with pale edematous tissue that frequently contains central cavities known as cisterns. There are varying degrees of trophoblastic proliferation and atypicality. In partial hydatidiform moles, the hydropic villi are characterized by a scalloped contour and focal (rarely atypical) trophoblastic hyperplasia. Cistern formation is not as prominent as in the complete moles. “Normal-size” chorionic villi are also present and are usually fibrotic, but may contain vessels filled with nucleated red blood cells. Partial moles may be difficult to distinguish from complete moles; in such cases, flow cytometry to characterize the DNA content may be helpful in making the distinction. The histologic features of invasive moles are generally similar to those of noninvasive forms, although the villi within the myometrium may be relatively few and tend to be less edematous.
Choriocarcinoma is characterized by proliferation of malignant cytotrophoblast and syncytiotrophoblast (sometimes with a component of intermediate-type trophoblast), without associated chorionic villi. The better-differentiated tumors grow in a typical biphasic pattern with a central core of mononuclear trophoblast (malignant cytotrophoblast or a combination of malignant cytotrophoblast and intermediate-type trophoblast) cells rimmed by syncytiotrophoblast cells (Fig. 6.31). In contrast, poorly differentiated forms are characterized by a proliferation of large, bizarre cells with poor delineation between mononuclear trophoblast and syncytiotrophoblastic cells, although the latter can be recognized in small numbers. Numerous typical and atypical mitotic figures can be identified, especially in more poorly differentiated lesions. Extensive hemorrhage is a common finding.
FIGURE 6.31 Choriocarcinoma. The typical biphasic pattern is composed of a central core of malignant cytotrophoblast with a rim of syncytiotrophoblast (arrow).
FIGURE 6.32 Placental site trophoblastic tumor. Sheets and strands of polygonal trophoblastic cells invade the smooth muscle of the myometrium, splitting muscle bundles. (×256.)
The cells of the placental site trophoblastic tumor have features similar to those of the implantation site, appearing polygonal to fusiform, with abundant eosinophilic to amphophilic cytoplasm. The nuclei range from small, vesicular, and rounded to large, hyperchromatic, and pleomorphic. Some cells are binucleate, trinucleate, or multinucleate. Fibrinoid change is usually present. The tumors characteristically invade the myometrium as single cells or as small groups of cells interposed between bundles of smooth muscle fibers or individual fibers (Fig. 6.32). They are not associated with chorionic villi. Vascular space invasion is due to the replacement of smooth muscle by hyalinelike material. The immunohistochemical profile of PSTT is similar to the one of intermediate-type trophoblast, which demonstrates predominantly hPL (human placental lactogen) immunopositivity and only small amounts of hCG. Conversely, most choriocarcinomas are strongly immunopositive for hCG and only focally for hPL.
On the basis of an analysis of a few cases, mitotic activity appears to be the most reliable, but not exclusive, criterion for differentiating the clinically benign cases of PSTT from those with a malignant course. In the benign tumors, the mitotic rate is usually four or less per ten high-power fields (HPFs). In contrast, several tumors that have shown an aggressive clinical behavior have had mitotic rates ranging from 8 to 12 per 10 HPFs.
The cells of the ETT have features similar to those of the chorionic type intermediate trophoblast, appearing small and round, with eosinophilic or clear cytoplasm. Mitotic activity is variable, and ranges from one to ten per ten HPFs. They grow in epithelioid nests or cords, or as solid masses.

Hemorrhage, fibrinoid change, and calcification are usually present, and extensive necrosis is a prominent feature. The tumor margins are usually circumscribed. They are not associated with chorionic villi. Vascular invasion is not a common feature. The immunohistochemical profile of ETT includes focal staining for hPL. Immunostaining for hCG is randomly distributed, noted in single cells or small clusters of cells.
Nonneoplastic Gestational Disorders
Nonneoplastic disorders associated with gestation that may occupy the endometrium include products of conception retained after an incomplete abortion, which occasionally take on the configuration of a polyp, and fetal remnants. Placental “polyps” are almost always found in women of reproductive age, but at least one example was not discovered until 5 years after the menopause. Abnormal uterine bleeding is a common presenting symptom and may be manifested as severe postpartum hemorrhage when a “polyp” is of recent origin and as menometrorrhagia in cases of longer duration. Occasionally, fetal remnants, particularly fragments of bone, are found in the presence or absence of trophoblastic tissue.
Gross Pathology
Placental polyps appear as pedunculated firm or soft, mottled, red or yellow necrotic tissue, which may be located anywhere within the uterine cavity, although in one series more than one half of them occurred in the fundus or in a cornu (Fig. 6.33). They may attain a diameter of 5 to 6 cm.
FIGURE 6.33 Placental polyp. The endometrial cavity contains soft, polypoid, yellow-red tissue.
FIGURE 6.34 Placental polyp. Hyalinized avascular chorionic villi are lined by a flat layer of trophoblast and enveloped in a mass of fibrin. (×100.)
FIGURE 6.35 Irregular yellow-brown fragments of bone are embedded within the endometrium. A fragment protruding from the endometrium in the left portion of the photograph has a tubular configuration.
Microscopic Pathology
Placental polyps may contain either well-preserved chorionic villi with viable-appearing trophoblast and decidua or hyalinized villi with degenerated trophoblast and decidua (Fig. 6.34). In one series of 20 cases, the chorionic villi were not found within the myometrium, but in some reported cases their presence therein has suggested a focal process similar to placenta accreta. Sectioning of bony fragments in the endometrium generally reveals their fetal character (Fig. 6.35). Very rarely, glial tissue is found within the endometrium and sometimes the myometrium; it is usually

interpreted as retained fetal tissue, but in some cases it is truly neoplastic and may even spread beyond the uterus.
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