Clinical Features

Most tumors develop slowly in the setting of hyperestro­genism against a background of non-atypical endometrial hyper­plasia, although some arise in atrophic endometrium. Endometrioid carcinoma is predominantly a disease of the sixth and seventh decades and 75% of cases occur after the menopause. Only 5% occur in women less than 40 years old. They are low-grade, non-myoinvasive, associated with a good prognosis and often develop after a long history of anovulatory cycles or estrogen therapy. Endometrial carcinoma rarely occurs in pregnancy.

Women with endometrioid carcinoma most often present with abnormal vaginal bleeding, which means in the majority of cases postmenopausal bleeding. The fact that they bleed, however, simply means that the tumor is often large or advanced. Smaller carcinomas may be asymptomatic. Surprisingly frequently, asymptomatic tumor is documented in women who have an endometrial biopsy before instituting hormone replacement therapy, or had the tumor discovered initially at autopsy. Patients with advanced disease may complain of pelvic pain, which reflects tumor spread.

The diagnosis is made by endometrial biopsy or curettage, but imaging techniques and hysteroscopy are being used more and can play an important role. Outpatient endometrial sampling techniques (Pipelle biopsy) have an excellent diagnostic rate for endometrial carcinoma, similar to that for curettage.

Gross Features

Endometrioid carcinoma can present variously to the naked eye when the uterus is opened. The uterus may be slightly or grossly enlarged but it may be of normal size or even small and atrophic, particularly in a postmenopausal woman. Most tumors arise in the corpus but some originate in the lower uterine segment. The tumor may present as a single mass or there may be multiple separate masses ( Figure 18.5 ) or a diffuse thickening of the endometrium. Carcinomas are situated more frequently on the posterior than the anterior wall. The most common appearance is of an exophytic, rough, perhaps papillary area of the endometrium with a shaggy surface and ulceration ( Figure 18.6 ). Sometimes the tumor is polypoid, with a fairly narrow base. When this is the case, its surface may be smooth and hemorrhagic and the uterine cavity distended, with concomitant thinning of the uterine wall. When the tumor is polypoid, the remaining endometrium usually appears thin. Myometrial invasion may be obvious to the naked eye ( Figure 18.6 ), with either pushing or infiltrating borders, but frequently it is difficult to appreciate the degree of myometrial invasion grossly. There seems to be no correlation between the degree of exophytic growth of the tumor within the uterine cavity and the presence of myometrial invasion. However, a tumor diameter of more than 2 cm generally is associated with poorer prognosis and a higher frequency of distant failure.

Endometrial adenocarcinoma. The tumor involves only part of the endometrium and appears as apparently separate foci.

Endometrial adenocarcinoma. A section through the wall of a uterus shows carcinoma protruding into the lumen (*) and invading deeply into the myometrium (black arrow). A leiomyoma is also present (+).

Microscopic Features

The glandular pattern and cellular features generally resemble the proliferative endometrium. Carcinoma is recognized within the endometrial compartment by the presence of at least one of the following: meandering interconnected lumens formed by folded sheets of neoplastic epithelium ( Figure 18.7 ), irregular angulated and tapering glandular contours ( Figure 18.8 ), a cribriform pattern of the glands ( Figures 18.9 and 18.10 ), or a solid area of glandular epithelium ( Figures 18.10 and 18.11 ). Several features may be present together. These points are summarized in Figure 18.12 .

Endometrial adenocarcinoma, endometrioid type, grade 1 (well differentiated). The branching glands with maze-like lumens indicate an architecture of folded sheets of neoplastic epithelium, rather than dense packing of tubular structures.

Endometrial adenocarcinoma, endometrioid type. Well-differentiated (grade 1) tumor with confluent glands.

Endometrial adenocarcinoma, endometrioid type. Moderately differentiated (grade 2) tumor, with solid and cribriform areas.

Endometrial adenocarcinoma, endometrioid type. Moderately differentiated (grade 2) tumor, with solid and cribriform areas.

Endometrial adenocarcinoma, endometrioid type. Poorly differentiated (grade 3) tumor.

(A–E) Intraendometrial adenocarcinoma. Glandular architectural patterns that may be seen in non-myoinvasive areas. (A) Cribriform glands; (B) Maze-like or meandering lumens; (C) Villoglandular; (D) Confluent polygonal molded glands; (E) Solid growth.

Stratification of epithelial cells is almost always seen. Occasionally, cribriform fragments have a microglandular appearance easily confused with a cervical lesion ( Figure 18.13 ). The individual epithelial cells are larger than would be expected in the proliferative phase. Compared with the normal endometrium, the carcinoma cells have a distinctly altered cytology that varies between cases and even within areas of a single tumor, but may include rounded nuclei, clumped chromatin, and prominent nucleoli. Individual tumors frequently show patchy changes in differentiation to mucinous, squamous, tubal, or other cytologies, and in these cases cytoplasmic as well as nuclear features stand out from the normal background. Some endometrioid adenocarcinomas secrete abundant mucin (‘mucin-rich’ variant), and these may or may not have identifiable intracytoplasmic mucin. Mitotic figures are usually present but may be scanty in well-differentiated tumors.

Endometrial adenocarcinoma, endometrioid type, with microglandular cribriform architecture. These delicate lesions tend to be exophytic, and may appear highly fragmented in biopsy specimens.

Endometrioid adenocarcinomas, like their precursor EIN lesions, spread within the endometrial compartment by extension of newly formed, well-differentiated neoplastic glands into the adjacent stroma (centripetal growth). In turn, the adjacent endometrial stroma responds by remodeling, rarely showing a desmoplastic change. For this reason, qualitatively assessing the character of the endometrial stroma within the endometrial compartment itself is noncontributory in distinguishing noninvasive from invasive carcinoma.

Foamy histiocytes are commonly seen in the endometrial stroma of patients with a carcinoma. Nearly one-fifth of cases contain stromal cells laden with lipid ( Figure 18.14 ), but there is no correlation between the presence of these cells and the grade of the tumor or the survival of the patient. This change is simply a reactive response to tumor cells. The presence of such histiocytic cells in endometrial biopsies showing EIN should always lead to further diagnostic work-up for coexistent carcinoma.

Endometrial adenocarcinoma. Foam cells in the stroma.

Histologic Grading

The most commonly used histologic grading system is that of the International Federation of Gynecology and Obstetrics (FIGO) and is recommended by the World Health Organization (WHO; Table 18.3 ). This three-tiered grading system is applied to endometrioid adenocarcinomas which are classified, as well differentiated (grade 1), moderately differentiated (grade 2), or poorly differentiated (grade 3). The grading procedure is based on the amount of solid non-squamous areas within a tumor. Squamous components are excluded. Grade 1 tumors ( Figure 18.15 ) show 5% or less solid growth and often there is no solid tumor at all. Grade 2 tumors ( Figure 18.16 ) show solid growth in 6–50% of the tumor. More than 50% solid growth is considered grade 3 ( Figure 18.17 ). Most endometrioid adenocarcinomas are grade 1 or 2.

Endometrial adenocarcinoma, endometrioid type, grade 1 (well differentiated). Grade 1 tumors have less than 5% solid growth.

Endometrial adenocarcinoma, endometrioid type, grade 2 (moderately differentiated). Grade 2 tumors have between 5% and 50% solid areas.

Endometrial adenocarcinoma, endometrioid type, grade 3 (poorly differentiated). Grade 3 tumors have more than 50% (non-squamous) solid growth.

Although the FIGO grading system of endometrioid carcinoma relies first and foremost on the architectural pattern of the glands, the histologic grade should be raised by one level beyond that determined by architecture alone in those cases exhibiting severe nuclear atypia ( Table 18.4 and Figure 18.18 ). Usually the architectural and nuclear grades correspond, but, when at variance, the nuclear grade is often the more reliable indicator of prognosis. When the final grade is elevated due to severe nuclear atypia, a note should appear in the report so that the clinician is alerted that the patient falls into this special category.

High-grade nuclear atypia in this tumor with no solid growth (grade 1 architecture) is the basis to increase the reported grade by one unit, to grade 2 (moderately differentiated).

Myoinvasion

Myoinvasion is diagnosed when the malignant glands have transgressed the endomyometrial junction and extend into the underlying myometrium. The normal junction, however, is not a straight line, but a rather vague and irregular border. Thus, in many cases, tumors confined to the endometrium cannot be distinguished microscopically from tumors invading the superficial myometrium. In fact, myoinvasion is overdiagnosed in routine practice in as much as 25% of cases; in contrast, failure to diagnose true myoinvasion is extremely rare. This is supported by recent FIGO data, which indicate almost identical 5 year survival rates for women with noninvasive tumors and those with tumors invading less than half of the myometrial thickness. In contrast, the distinction of inner half invasion from outer half invasion is usually straightforward, and the probability of recurrence is markedly increased for women with deeply invasive tumors. Thus, in the 2009 FIGO staging classification of endometrial carcinoma, tumors with no myometrial invasion and tumors with less than 50% invasion are combined under stage IA.

Occasionally, endometrial carcinoma appears confined to foci of adenomyosis. Adenomyosis is really a ‘diverticulum’ of endometrium deep into the myometrium, and carcinoma can extend into these foci without invading the myometrium. Tumor involvement of adenomyotic foci occurs in about 25% of cases and is not associated with an adverse prognosis. When tumor cells extend outward into the myometrium, depth of invasion is measured not from the point of transgression in adenomyosis, but from the superficial endomyometrial junction.

The decision to perform pelvic and para-aortic lymph node dissection is largely based on depth of myometrial invasion (also on cell type and histologic grade). Intraoperatively, the pathologist may be requested to assess these features by frozen section.

Maximum depth of myoinvasion is measured in milli­meters from the endomyometrial junction, and expressed as the percentage of the total myometrial thickness. Problems arise, however, when the boundary is distorted by the tumor itself or other lesions such as leiomyomas. Residual areas of normal endometrium ( Figure 18.19 ) or overrun normal glands are informative landmarks, when available. Bulky exophytic tumors can be difficult to orient in a single histologic section and, in such cases, assessment of the endomyometrial boundary at the site of deepest invasion requires a combination of gross and histologic evaluation.

This tumor is entirely intraendometrial, but the irregular junction between the endometrium and myometrium imparts a false impression of myoinvasion. Endometrial stroma (arrows) surrounds the tumor.

Myoinvasion is assessed by evaluation of the topographical distribution of glands and the appearance of adjacent stroma. Invasion across a broad front (21% of cases) may be difficult to distinguish from an irregular endomyometrial interface unless it can be compared to the adjacent uninvolved endomyometrium. This is sometimes evident by a ‘shoulder’ formed at the juncture of a zone of myoinvasion with an area of surface involvement ( Figure 18.20, arrow ). Most common (67%) are irregular groups of glands with or without a stromal response ( Figure 18.21 ). ‘Adenomyosis-like’ invasion (7% of cases) ( Figure 18.22 ) can be distinguished from non-myoinvasive tumor extending into foci of adenomyosis ( Figures 18.23 and 18.24 ) by its lack of accompanying endometrial stroma. Unfortunately, CD10 immuno­reaction occurs focally in the cells surrounding tumor clusters in the myometrium of women without adenomyosis, and this limits utility. A distinctive pattern of microcystic, elongated or slit-like, and fragmented (MELF) invasive glands is often accompanied by individual invading cells and a loose stromal response with marked inflammation ( Figures 18.25 and 18.26 ). The MELF pattern of invasion has some features of epithelial–mesenchymal transition, including a greatly reduced proliferative activity and acquisition of a cytokeratin (CK)7-positive immunophenotype. Least common of all (1%) are widely spaced individual glands lacking any stromal response, akin to adenoma malignum of the endocervix ( Figures 18.27 and 18.28 ).

Broad front myoinvasion, showing a ‘shoulder’ (arrow) between myoinvasive (left) and surface (right) involvement.

Irregular infiltrating glands with no stromal response.

(Courtesy of Dr. Marisa R. Nucci.)

Myoinvasion by blunt tumor structures in an ‘adenomyosis-like’ pattern.

(Courtesy of Dr. Marisa R. Nucci.)

Tumor extension into adenomyosis, non-myoinvasive. Two areas of adenomyosis are seen, one with only benign glands (left), and one with extension of adenocarcinoma from the surface (right).

Tumor extension into adenomyosis, non-myoinvasive. Detail showing focus of carcinoma and benign glands. A thin layer of intervening stroma is seen.

Myoinvasion by microcystic elongated (slit-like) glands (MELF).

(Courtesy of Dr. Marisa R. Nucci.)

Individual invasive cells in MELF-type invasion are eosinophilic or squamous like, and somewhat obscured by the combined stromal and inflammatory response.

(Courtesy of Dr. Marisa R. Nucci.)

‘Adenoma malignum’ pattern of myoinvasion.

(Courtesy of Dr. Marisa R. Nucci.)

There is little stromal response to these well-differentiated adenoma malignum-type invasive glands.

(Courtesy of Dr. Marisa R. Nucci.)

Accessibility of sampling devices to deeper tissues limits the ability to diagnose myoinvasive disease by biopsy or curettage, even when present.

Cytologic Correlation

There are no established guidelines for routine endometrial cytologic screening, but exfoliated neoplastic endometrial cells are sometimes encountered in cervical Pap smears. Up to two-thirds of women with endometrial adenocarcinoma have malignant cells in their cervical cytology specimen and high-grade as well as high-stage tumors seem to be detected more frequently. In cervical smears, malignant endometrial cells characteristically appear as small clusters with darkly stained nuclei ( Figure 18.31 ) or perhaps as single discrete cells that are easily overlooked. On rare occasions following the recognition of malignant glandular cells in a cervical Pap smear, the endocervical curettage and endometrial biopsy may be negative. The possibility of an ovarian lesion should be considered and excluded.

Endometrial adenocarcinoma, cytology. Malignant glandular cells in a cervical smear.

Transcervical cytology sampling devices such as the Tao brush have been designed to directly access the endometrium. With this device malignant cells in an endometrial brushing are freshly removed and rapidly fixed so the features are well preserved. Appearance is widely variable, from large single cells to small clusters as well as sheets ( Figure 18.32 ). Although superior to a cervical Pap smear specimen, transcervical instrumentation with a brush introduces many of the potential morbidities of the Pipelle biopsy while yielding less tissue.

Transcervical brush cytology of endometrioid endometrial adenocarcinoma. Carcinoma showing bubble-like mucin-filled cytoplasm.

(Courtesy of John Maksem.)

Shed tumor DNA incidentally collected by liquid cervical Pap smear may be sequenced to demonstrate mutations known to be present in a coincident endometrial carcinoma. Because the DNA may be shed from anywhere above it is not possible to localize a lesion, nor is the sensitivity and specificity of such a screen known when large numbers of mutations are screened in the asymptomatic patient.

Differential Diagnosis

Well-differentiated endometrioid adenocarcinoma may be difficult to distinguish from EIN/AH. This problem has been discussed in detail in Chapter 17 . EIN consists of individual lumen-bearing glands grouped together, whereas a cribriform pattern, solid growth, meandering interconnected lumens, or villoglandular architecture ( Figure 18.12 ) generally are diagnostic of adenocarcinoma.

Myoinvasion clearly favors a diagnosis of carcinoma, but as biopsy and curettage devices rarely sample the myometrial wall it is a criterion only available in hysterectomy specimens and therefore only of use in establishing the final diagnosis. Several groups have systematically examined endometrial biopsy material in women with and without myoinvasive adenocarcinoma to discover features associated with myoinvasion. Variation in nuclear size (anisokaryosis, measured as standard deviation of nuclear diameter) emerged as the single variable most associated with deep myoinvasion. This finding confirms the earlier observation that the presence of extreme nuclear pleomorphism worsens clinical outcome relative to that expected by architectural features alone.

Well-differentiated endometrioid adenocarcinoma with myometrial invasion may be difficult to distinguish from atypical polypoid adenomyoma , particularly in curettings ( Figure 18.46 ). This is an obviously important distinction since most atypical polypoid adenomyomas are treated conservatively. Postmenopausal age of the patient and marked nuclear atypia favor a myoinvasive adenocarcinoma, because atypical polypoid adenomyoma usually shows no more than mild to moderate nuclear atypia. In contrast to the elongated fibers of the normal myometrium, the stromal component of atypical polypoid adenomyoma grows in short interlacing fascicles. Furthermore, in curettings or biopsy from an atypical polypoid adenomyoma, there are usually also fragments of normal background endometrium; in contrast, on a biopsy of an endometrioid adenocarcinoma, it would be most unusual to obtain only fragments of myoinvasive neoplasm without free tumor fragments. Immunohistochemistry is helpful in distinguishing between atypical polypoid adenomyoma and a myoinvasive endometrioid adenocarcinoma; whereas the stromal component of atypical polypoid adenomyoma is CD10 negative, the myoinvasive glands of endometrioid adenocarcinoma are typically surrounded by CD10 immunoreactive stromal cells.

Atypical polypoid adenomyoma. Neoplastic glands with squamous morules are offset by a densely muscular stroma.

Although atypical polypoid adenomyoma has an excellent prognosis, there is a risk of recurrence (around 45%) if curettage or polypectomy is undertaken. There is also a small, but definite, risk of transition to endometrioid adenocarcinoma, which has been estimated at 8.8% in one meta-analysis.

Metaplastic changes as described in Chapter 16 may be seen in benign, premalignant (EIN/AH), or carcinoma states. Hormonally induced metaplasias, such as tubal metaplasia resulting from estrogen stimulation, have a distinctive topography in which metaplastic glands are diffusely interspersed among non-metaplastic glands. This differs from the expanding geographic foci of premalignant and malignant neoplastic processes in which the metaplastic component itself may be cohesive and geographic. Even if metaplastic changes are frequently associated with cancer, the benign cytologic features, architectural pattern, and lack of invasion help to make the correct diagnosis of hormonally induced metaplasias.

Poorly differentiated carcinomas composed of extensive solid tumor may show spindled cells and give a ‘pseudo­sarcomatous’ appearance. Just the presence of recognizable glands does not mean the tumor is biphasic and, in such cases, a diagnosis of carcinosarcoma would be unjustified. Conversely, it is also apparent that the mesenchymal and epithelial elements of carcinosarcomas may both show reactivity with cytokeratins and vimentin. Thus, cytokeratin reactivity in the stromal element does not necessarily mean that a carcinomatous component is present in a sarcoma and, in some cases, a distinction is impossible to make.

The interpretation of menstrual endometrium or en­dometrium with glandular and stromal breakdown in curettings may be difficult, especially in distinguishing it from adenocarcinoma. The absence of stroma between the glandular elements may give the impression of confluent glands or in some cases even of solid epithelial growth. The piled up epithelium may lose nuclear polarity and acquire prominent nucleoli. However, the coarse chromatin and nuclear pleomorphism of malignancy are lacking and a genuine cribriform pattern and invasion are never present. Mitoses are also lacking. Furthermore, the glands of menstrual endometrium regularly exhibit some residual secretory change and a careful search will identify typical areas of stromal fragmentation as opposed to areas of coagulative necrosis (see Chapter 14 ).

The distinction between endometrial adenocarcinoma and endocervical adenocarcinoma may be difficult, if not impossible, to make in curettings. Fractional curettage assists in delimiting the site of involvement, but surface extension along the lower uterine segment may occur. Even though most endometrial carcinomas are of endometrioid type and most endocervical carcinomas are of mucinous type, endometrioid carcinomas may arise in the cervix and mucinous adenocarcinomas not uncommonly arise in the endometrium. The stroma of the tumor may also help; in cervical adenocarcinomas it is typically fibrous whereas endometrial carcinomas usually contain very little stroma. An immunostain panel of three markers can be used in the differential diagnosis. ER and vimentin are more likely to be expressed in endometrial than cervical adenocarcinomas, whereas cervical adenocarcinomas more frequently show strong immunoreactivity for p16. In endometrial adenocarcinomas p16 immunostaining is weak or patchy. Reactivity for integrated human papillomavirus (HPV) in DNA isolated from tumor tissue strongly supports a cervical origin, as it is present in 80–90% of cervical, and essentially no endometrial, adenocarcinomas. Tissue processing and HPV polymerase chain reaction testing for this purpose are not generally available, however.

The term ‘papillary carcinoma’ is imprecise and should not be used for endometrial tumors. Villoglandular endometrioid adenocarcinoma, serous carcinoma, clear cell adenocarcinoma, and mucinous adenocarcinoma may all have a papillary architecture. Villoglandular endometrioid adenocarcinoma shows the columnar and darkly staining cells characteristic of endometrioid carcinoma. Nuclear grade is usually low. The cells of serous carcinoma tend to be small and cuboidal rather than columnar, and nuclear atypia is marked. Indeed, an immediately obvious discrepancy between high-grade nuclear changes in an apparently well-differentiated adenocarcinoma (irrespective of growth pattern) should alert the pathologist to the possibility of a serous carcinoma (see below). Clear cell adenocarcinomas rarely show papillary areas exclusively. Usually tubulocystic areas with a ‘hobnail’ pattern or solid areas of clear cells are frequently present. The morphology of the epithelial cells in mucinous adenocarcinoma, with regular, basal nuclei and abundant, mucinous cytoplasm allows the distinction to be made easily.

Behavior and Treatment

Endometrioid adenocarcinoma and its variants present early as postmenopausal bleeding, which is both obvious and alarming. Eighty percent of patients present with clinical stage 1 disease, although some patients are found to have more advanced disease at surgery. Five year survival rates are currently 96% for stage 1 disease, 67% for stage 2, and 23% for stage 3. The behavior of the endometrioid histologic variants is the same, grade for grade, as that of typical endometrioid adenocarcinoma.

The standard treatment is surgical, consisting of hysterectomy with bilateral salpingo-oophorectomy, with or without adjuvant radiotherapy. Practices vary regionally regarding pelvic and para-aortic lymph node dissection. It is doubtful whether lymphadenectomy has any added benefit in the patient whose primary lesion is well differentiated and superficially invasive. Lymph node dissections are commonly carried out, however, if frozen section of the hysterectomy specimen demonstrates deep myometrial invasion, cervical involvement, or a non-endometrioid histology. Local delivery of high-dose progestins by hormone-impregnated intrauterine devices may be effective in controlling well-differentiated local disease with a low rate of systemic complications. Systemic treatment with progestins may be beneficial but, as the tumors that respond are those with ER and PRs that are of early stage and low grade with a favorable outcome anyway, practical use of these agents is limited. Chemotherapy and adjuvant radiotherapy are used for advanced and recurrent disease.

Appearances Following Radiation

Curetted specimens may be received following radiation therapy for endometrial carcinoma. Currently, however, this is an infrequent event since radiotherapy is predominantly given postoperatively. The tumor’s histologic response to radiation varies and sometimes no changes can be detected. Changes may be seen in both neoplastic and non-neoplastic epithelial cells. Most prominent among these are nuclear enlargement, pleomorphism, and hyperchromasia, often resulting in markedly bizarre forms ( Figure 18.47 ). As these alterations are seen in both benign and malignant cells, identifying residual carcinoma can be difficult.

Endometrial adenocarcinoma. Appearance following radiation.