I. NORMAL ANATOMY. The uterus is a pear-shaped hollow organ with a normal weight of between 40 and 80 g in adults. It is divided into the corpus, the lower uterine segment, and the cervix. The uterine cavity is triangular, measuring on average 6 cm in length. It is composed of the inner endometrial lining and the myometrium or muscular wall, with a serosal covering which extends to the peritoneal reflection. The peritoneal reflection is shorter anteriorly than posteriorly and so can be used for orienting hysterectomy specimens.
II. GROSS EXAMINATION, TISSUE SAMPLING, AND HISTOLOGIC SLIDE PREPARATION
A. Endometrial biopsy and curettage specimens. The most common endometrial tissue samplings examined in surgical pathology are endometrial biopsy and curettage specimens, obtained from cervical dilation and curettage procedures. Endometrial biopsy samples are obtained from a relatively limited office sampling procedure in which no cervical dilation is required. The dimension (size range of the largest tissue fragments, or the dimensions of the tissue in aggregate) and/or volume of the specimen should be documented. The entire specimen should be submitted for microscopic examination and three H&E stained levels prepared for microscopic examination.
B. Products of conception specimens are usually obtained by curettage (although the tissue is often spontaneously passed). The dimension (size range of the largest tissue fragments, or the dimensions of the tissue in aggregate) and/or volume of the specimen should be documented. At least three cassettes should be submitted, focused on any villous tissue that is grossly present, to optimize microscopic identification chorionic villi both for confirmation of the presence of an intrauterine pregnancy and to rule out a molar gestation. If the initial three blocks do not contain villi, the remainder of the specimen should be submitted; if villi are still not identified, the possibility of an ectopic pregnancy exists, a result that should be immediately communicated to the clinician.
C. Hysterectomy specimens. The type of hysterectomy (abdominal or vaginal, with or without salpingo-oophorectomy) should be determined and the size, weight, and shape of the uterus recorded (the processing of radical hysterectomy specimens, which differs substantially, is discussed in Chap. 34). The uterine serosa should be carefully examined for any abnormalities, which should be sampled. The uterus is next bivalved in the coronal plane to show the endometrial cavity and endocervical canal, which are examined and measured. The maximum thickness of the endometrium and myometrium should also be noted. Both halves of the uterus are then serially sectioned parallel to the long axis of the uterus.
1. For specimens excised for benign disease, sections of the anterior cervix, posterior cervix, anterior endomyometrium, and posterior endomyometrium are submitted. Additional sections of any identified lesions must also be submitted.
2. For specimens excised for malignancies, contiguous sections of both anterior and posterior endomyometrium, lower uterine segment, and cervix should be submitted to assess for tumor involvement of the lower uterine segment and cervix. In addition, at least one full thickness section of the uterine wall containing tumor from both anterior and posterior uterus (including the serosa from the deepest area of myometrial invasion by the
tumor) are submitted to enable calculation of the depth of invasion. Representative sections from any other lesions must also be submitted.
1. The endometrial mucosa is composed of glands and stroma. It is divided into the functional (luminal) layer and the basal (inner) layer. The basal cell layer acts as a reserve cell layer and is responsible for the regeneration of the endometrium after menses. The stroma is composed of endometrial stromal cells and blood vessels.
2. The menstrual cycle is divided into menstrual phase, proliferative phase, and secretory phase. Menstrual endometrium, present for the first 4 days of the 28-day cycle, is characterized by glandular (karyorrhectic debris in glandular cells) and stromal (dense balls of collapsed stroma with surrounding neutrophils and reactive epithelium) breakdown, glandular secretory exhaustion, and background inflammation (e-Figs. 33.1 and 33.2).*
Day 1 of menstrual bleeding is defined as day 1 of the cycle; the menstrual phase lasts for 3 to 4 days. Proliferative phase begins on day 4 and in an idealized situation lasts until day 14. Although it usually lasts about 11 days, it may greatly vary. During the early proliferative phase, the endometrium is thin and composed of straight, evenly spaced glands in a loose stroma (e-Fig. 33.3). By day 8 to 10, stromal edema due to estrogen causes increased endometrial thickening, and the glands become more coiled as the glandstroma growth rate increases (e-Fig. 33.4). Throughout the proliferative phase, the epithelium lining the glands shows nuclear stratification, with a high mitotic rate in both glands and stroma (e-Fig. 33.5).
The secretory phase begins with ovulation. In an idealized 28-day cycle, secretory phase begins at day 14 and lasts 14 days, although it may range from 11 to 18 days. Following an interval phase from day 14 to day 15 (during which there are no dateable changes), the first dateable feature of early secretory phase is the appearance of subnuclear vacuoles on day 16, which appear as a clear zone between the basement membrane and the nucleus pushing the nucleus toward the glandular lumen. On day 17 the epithelium exhibits uniform subnuclear vacuoles, giving the appearance of “piano keys” (e-Fig. 33.6). The vacuoles then move to the supranuclear position (day 18) and eventually are secreted into the glandular lumen (e-Fig. 33.7). Maximal stromal edema occurs during the mid-secretory phase, around day 22. At day 23, the stroma begins to condense, and the first signs of periarteriolar decidualization (where stromal cells acquire abundant, eosinophilic cytoplasm under the influence of progesterone) become apparent (e-Fig. 33.8). On day 25, this decidualization extends beneath the surface epithelium. Prominent glandular saw-toothing and maximal stromal decidualization occur on days 26 to 27 (e-Fig. 33.9). Numerous granular lymphocytes, marked stromal decidual change, and glandular breakdown are the features of day 28 of late secretory phases.
1. The earliest gestation-related changes occur following the implantation of the blastocyst. These changes are characterized by decidualization of the stroma with edema; the glands exhibit distension with increased secretion and a serrated architecture (e-Fig. 33.10). By 4 to 8 weeks post implantation, the endometrial epithelium often exhibits a physiologic response known as the Arias-Stella reaction characterized by glands that have a
hypersecretory pattern and are lined by cells with enlarged, hyperchromatic nuclei that often jut into the gland lumens (e-Fig. 33.11).
2. The placental implantation site, often seen in curettage specimens obtained because of a missed abortion, is characterized by decidualized stroma infiltrated by intermediate trophoblast. Intermediate trophoblast have hyperchromatic, angulated nuclei and amphophilic cytoplasm and are often multinucleated (e-Fig. 33.12). Intermediate trophoblast also normally infiltrates maternal spiral arteries causing fibrinoid deposition in the vessel wall which serves to dilate the vessels and increase blood flow to the placenta (e-Fig. 33.13). Intermediate trophoblast also normally infiltrates myometrium which can occasionally be present in curettage specimens (e-Fig. 33.14).
3. Placental site nodules are incidental, usually microscopic findings that are characterized by small foci of hyalinized material with entrapped intermediate trophoblast cells, often with vacuolated cytoplasm (e-Fig. 33.15). They are thought to arise from the chorionic type intermediate trophoblast of the fetal membranes which is also vacuolated. Placental site nodules are occasionally encountered in endometrial biopsies and curettage specimens but may also be seen in cervical specimens.
4. Abnormalities of implantation. Placenta accreta occurs when a layer of decidua is not present between the placental villi and the myometrium at the implantation site (e-Fig. 33.16); fibrin and intermediate trophoblast may be present between villi and myometrium in accreta. Cytokeratin, which will be positive in trophoblast and negative in decidua, can be used if the distinction is difficult on H&E. Placenta increta is present when villi invade into the myometrium, and transmural extension of villi with perforation is termed placenta percreta.
Risk factors for placenta accreta include prior Cesarean section, placenta previa, and prior instrumentation, among others. All forms of accreta may be associated with life-threatening hemorrhage, which may require immediate hysterectomy.
C. Exogenous hormone therapy
1. Estrogen causes proliferation of endometrial glands and stroma. Persistent exposure to estrogen (exogenous as well as endogenous estrogen, as occurs with anovulatory cycles, obesity, or an estrogen-secreting tumor) causes endometrial proliferation with subsequent glandular and stromal breakdown, often clinically interpreted as irregular menstrual bleeding. Microscopically, the findings include stromal condensation with formation of so-called exodus bodies or stromal blue-balls, glandular degeneration and apoptosis of the glandular epithelial cells, and fibrin thrombi in stromal vessels (e-Fig. 33.17).
2. Prolonged exposure to progestogens results in endometrium with a characteristic pattern that includes underdeveloped, inactive glands in a background of a stroma that shows marked decidual change (e-Fig. 33.18).
3. Tamoxifen is primarily used for the treatment of breast cancer. In the endometrium, tamoxifen competitively binds to estrogen receptors and acts as an agonist. It increases the risk of endometrial hyperplasia and adenocarcinomas (Ann NY Acad Sci. 2001;949:237), and up to 20% of women on tamoxifen develop endometrial polyps (Cancer. 2001;92:1151).
IV. COMMON BENIGN DISEASES OF THE ENDOMETRIUM
1. Acute endometritis is defined by the presence of acute neutrophilic inflammation in the stroma of the nonmenstruating endometrium. In severe cases, the neutrophils are present throughout the stroma, the endometrial epithelium, and the glandular lumina (e-Fig. 33.19). Acute inflammation present during the menstrual phase of the endometrium should not be misdiagnosed as
active infection. Acute endometritis is uncommon and is usually seen only in postpartum or postabortive endometrium.
2. Chronic endometritis is defined by the presence of plasma cells in the endometrial stroma. Associated features include glandular and stromal breakdown, and dyssynchronous glandular and stromal development (e-Fig. 33.20). The most common causes of chronic endometritis include Chlamydia trachomatis, Ureaplasma urealyticum, cytomegalovirus, and herpes virus infection. Infection by Actinomyces israelii or Neisseria gonorrheae usually causes a mixed acute and chronic pattern of inflammation. Granulomatous inflammation is rare; common causes include Mycobacterium tuberculosis infection, fungal infection, sarcoidosis, and hysteroscopic ablation therapy.
B. Atrophy is most commonly seen in postmenopausal women. Premenopausal causes include treatment with oral contraceptives or gonadotropin agonists (Lupron). Patients with premature menopause also show an atrophic pattern. Microscopically, the endometrium is composed of a thin layer of endometrial glands lined by an attenuated layer of inactive epithelial cells surrounded by thin stroma. No mitotic activity is present (e-Fig. 33.21).
C. Metaplasia is the presence of any type of glandular epithelium other than the normal columnar type. Metaplasia is a common finding in perimenopausal and postmenopausal women and is often associated with abnormal uterine bleeding or recent use of exogenous hormonal therapy.
1. Tubal metaplasia consists of foci of normal tubal epithelium within the endometrial glands, including ciliated, nonciliated secretory, and intercalated cells. The ratio of the ciliated to nonciliated cells is cyclical and depends on hormonal influences.
2. Ciliated cell metaplasia is the most common form of metaplasia. It is composed of a layer of ciliated columnar cells with round to oval nuclei and abundant pale eosinophilic cytoplasm (e-Fig. 33.22). Ciliated cell metaplasia is a normal response of endometrial epithelium to various hormonal exposures. It is most commonly found in perimenopausal endometrium and is associated with endometrial polyps, anovulatory cycles, and exogenous hormonal therapy.
3. Squamous metaplasia (e-Fig. 33.23) is often caused by chronic irritation and often takes the form of squamous morules or rounded, swirling nests of squamous cells. Squamous metaplasia must not be confused with endometrial hyperplasia or malignancy, although it can occur as a secondary change in both.
4. Eosinophilic metaplasia or eosinophilic change refers to glandular epithelium with abundant eosinophilic cytoplasm and a central round to oval nucleus (e-Fig. 33.24). It is often associated with a neutrophilic infiltrate, the formation of small epithelial papilla, and mild nuclear atypia.
5. Mucinous metaplasia is rare. It is morphologically similar to endocervical mucinous epithelium in that it consists of columnar epithelium with basally located oval nuclei and abundant apical mucin (e-Fig. 33.25).
6. Clear cell metaplasia is also rare. It is characterized by columnar cells with round nuclei and clear cytoplasm.
D. Endometrial polyps are local overgrowths of endometrial glands and stroma that protrude into the endometrial cavity. Polyps are present in about 20% to 25% of women and are frequently found in the perimenopausal and postmenopausal period. Grossly, polyps appear as broad-based to pedunculated lesions; some pedunculated polyps can extend into the endocervical canal, and even through the os. Microscopically, polyps are composed of endometrial glands within a fibrous stroma; the presence of thick-walled blood vessels within the fibrous stroma is the most common key to the diagnosis (e-Fig. 33.26). Frequently, the glands are variably shaped and irregularly distributed.
Although endometrial polyps in postmenopausal women usually contain dilated glands lined by one layer of atrophic epithelium, foci of metaplastic or hyperplastic epithelium, as well as frank adenocarcinoma, may be present. Consequently, endometrial polyps should be entirely submitted for microscopic examination.
1. Polyps with stromal smooth muscle are referred to as adenomyomatous polyps.
2. Atypical polypoid adenomyoma is a polypoid lesion characterized histologically by crowded irregular endometrial glands with a complex architecture and cytologic atypia in stroma that is predominantly composed of smooth muscle (e-Fig. 33.27). The lesion has a high rate of recurrence after incomplete surgical removal and mainly occurs in premenopausal, nulliparous women. It is associated with a clinical history of infertility.
E. Disordered proliferative endometrium predominantly exhibits a normal proliferative pattern, with mild irregular branching and budding and some cystic dilation. However, the glands to stroma ratio is not increased—the main factor that helps to differentiate a disordered proliferative pattern from simple hyperplasia. The epithelium lining the glands is composed of stratified and columnar cells with no atypia. Mitotic activity is similar to that of normal proliferative endometrium (e-Fig. 33.28).
V. ENDOMETRIAL HYPERPLASIA AND ENDOMETRIAL INTRAEPITHELIAL CARCINOMA. Endometrial hyperplasia is thought to develop as a result of unopposed estrogenic stimulation. Any disorder that causes an increase in endogenous or exogenous estrogenic stimulation such as polycystic ovarian disease, obesity, or ovarian neoplasms (e.g., thecomas, granulosa cell tumors) can therefore predispose to endometrial hyperplasia. Abnormal bleeding is the major clinical symptom.
A. Endometrial hyperplasia is subclassified as simple or complex on the basis of the architectural pattern, and as with or without atypia on the basis of the cytologic features. Numerous studies have demonstrated that the risk of progression to adenocarcinoma (specifically, endometrioid adenocarcinoma and its variants) is more highly correlated with the presence of cytologic atypia than the degree of glandular crowding.
1. Simple hyperplasia shows a glands to stroma ratio that is slightly increased (more than 1:1) with prominent variability in size of the glands, glandular budding, and cystic glandular dilatation (e-Fig. 33.29).
2. Complex hyperplasia is composed of crowded, architecturally complex glands with little intervening stroma. The glands to stroma ratio is elevated (at least 3:1) (e-Fig. 33.30).
3. Cytologic atypia, which may be a feature of simple or complex hyperplasia, is based on the nuclear cytology of the glandular epithelium. The most reliable indicators of cytologic atypia are an enlarged nucleus that is round rather than oval, that has coarse clumped chromatin, and that has a prominent nucleolus (e-Fig. 33.31). A diagnosis of hyperplasia should be made with extreme caution during the secretory phase of the endometrium because of the usual crowding of the glands in this phase of the menstrual cycle. The presence of cytologic atypia must be distinguished from the cellular changes that accompany metaplasias, and from Arias-Stella reaction.
B. Endometrial intraepithelial neoplasia (EIN) represents an alternative classification scheme for premalignant endometrial lesions. EIN is defined as a proliferation of islands of endometrial glands which have cytological and architectural abnormalities and are considered to be premalignant. The EIN scheme has been proposed both as an approach to simplify the diagnosis of premalignant changes and as a classification more closely linked to the genetic changes in premalignant endometrial epithelium (Gynecol Oncol. 2000;76:287) preceding transformation into endometrial adenocarcinoma. Studies have shown
that some of these lesions harbor PTEN tumor suppressor gene inactivation, mutations of k-ras, and microsatellite instability. EIN is considered to be a monoclonal proliferation composed of cells in early stages of carcinogenesis.
Diagnostic criteria for EIN (www.endometrium.org) are based on size of the lesion, nuclear cytology, and glandular architecture (including glandular crowding with an increased glands to stroma ratio, cytologic differences between the neoplastic glands and the adjacent normal glands, and an area of glandular crowding that is >1 mm in greatest dimension). EIN can have squamous, mucinous, or clear cell differentiation. The treatment of these lesions is similar to the clinical management of atypical endometrial hyperplasia.
C. Endometrial intraepithelial carcinoma (EIC) is thought to represent the precursor lesion to serous carcinoma. Microscopically, EIC is composed of glands lined by cells with the same cytologic abnormalities as serous carcinoma, but without evidence of myometrial stromal invasion (e-Fig. 33.32). The development of EIC is independent of prior unopposed estrogenic stimulation and typically arises in a setting of atrophic endometrium.
VI. EPITHELIAL MALIGNANCIES. Epithelial malignancies are the most common gynecological malignancy in women in developed countries. Endometrial cancer can be divided into two broad categories which have differences in their clinical and pathologic features, as well as their underlying genetic abnormalities.
A. Type I tumors consist of endometrioid adenocarcinoma and its variants. They account for over 80% of endometrial tumors and usually develop in postmenopausal women in their fifth and sixth decades in the background of longterm estrogen stimulation. Type I tumors are strongly associated with diabetes and obesity and have a relatively good prognosis. The endometrial glands and stroma in Type I tumors are strongly positive for estrogen and progesterone receptors. In addition, the stromal cells show diffuse strong immunopositivity for CD10 (CALLA) antigen. Genetically, they show microsatellite instability, and mutations in the PTEN tumor suppressor gene, k-ras, and CTNNB1, but assessment for these genetic abnormalities is not necessary for diagnosis.
B. Type II tumors, for example serous papillary carcinoma, usually occur in women in their sixth and seventh decades and are not associated with estrogen stimulation, and therefore do not occur in a background of complex atypical hyperplasia but rather in atrophic epithelium. They are more likely than Type I tumors to be at an advanced stage at the time of presentation and so have a relatively poor prognosis. Genetically they are characterized by TP53 mutations.
The WHO classification of uterine corpus malignancies is presented in Table 33.1, and the pathologic staging of uterine corpus carcinomas is shown in Table 33.2 and Figure 33.1.
1. Endometrioid adenocarcinoma usually arises in the uterine corpus and grossly usually consists of a raised to exophytic, pink tan, hemorrhagic mass that projects into the endometrial cavity.
Microscopically, the tumor consists of irregular, confluent, complex glandular or villoglandular structures lined by pleomorphic stratified columnar cells with pleomorphic nuclei. The presence of areas with definitive cribriform architecture is a microscopic feature that can be used to distinguish well-differentiated endometrioid adenocarcinoma from complex hyperplasia with cytologic atypia. Foci of squamous differentiation, which should not be mistaken as solid component of the tumor, are often encountered.
Myometrial invasion is recognized by the presence of an irregular endometrial-myometrial border or by an associated desmoplastic and inflammatory stromal response (e-Fig. 33.33). The depth of myometrial invasion compared with the full thickness of the myometrium and the presence or absence of lymphovascular space invasion should be noted.
TABLE 33.1 WHO Histologic Classification of Tumors of the Uterine Corpus
Epithelial tumors and related lesions
Variant with squamous differentiation
Ciliated cell variant
Clear cell adenocarcinoma
Mixed cell adenocarcinoma
Squamous cell carcinoma
Transitional cell carcinoma
Small cell carcinoma
Endometrial stromal and related tumors
Endometrial stromal nodule
Endometrial stromal sarcoma, low grade
Undifferentiated endometrial sarcoma
Smooth muscle tumors
Smooth muscle tumors of uncertain malignant potential
Leiomyoma, not otherwise specified
Mitotically active variant
Hemorrhagic cellular variant
Growth pattern variants
Miscellaneous mesenchymal tumors
Mixed endometrial stromal and smooth muscle tumors
Perivascular epithelioid cell tumor
Other malignant mesenchymal tumors
Other benign mesenchymal tumors
Mixed epithelial and mesenchymal tumors
Carcinosarcoma (malignant mixed mullerian tumor)
Atypical polypoid variant
Gestational trophoblastic disease
Placental site trophoblastic tumor
Epithelioid trophoblastic tumor
Nonneoplastic, nonmolar trophoblastic lesions
Placental site nodule and plaque
Exaggerated placental site
Sex cord-like tumors
Tumors of germ cell type
Lymphoid and hematopoietic tumors
From: Tavassoli FA, Devilee P, eds. World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Breast and Female Genital Organs. Lyon: IARC Press; 2003. Used with permission.
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