Revisión Carcinoma de Endometrio

Advances in Anatomic Pathology Vol. 9, No. 3, pp. 145184 2002 Lippincott Williams & Wilkins, Inc.
, Philadelphia
Review Article
Endometrioid Carcinoma of the Uterine Corpus: A Review of Its Pathology With Emphasis on Recent Advances and Problematic Aspects
*Philip B. Clement and Robert H. Young
*Departments of Pathology, Vancouver General Hospital and Health Sciences Center and the University of British Columbia, Vancouver, British Columbia, Canada; and James Homer Wright Pathology Laboratories of the Massachusetts General Hospital and Department of Pathology, Harvard Medical School, Boston, Massachusetts, U.S.A.
Summary: This review considers the pathologic features of endometrioid carcinoma of the uterine corpus, which accounts for approximately 80% of endometrial adenocarcinomas, with an emphasis on its histologic features, recent advances, and problematic aspects. In addition to typical endometrioid carcinoma, the variants of endometrioid carcinoma covered include secretory carcinoma, villoglandular endometrioid carcinoma, endometrioid carcinoma with small nonvillous papillae, endometrioid carcinomas with microglandular and sertoliform patterns, and endometrioid carcinomas with metaplastic changes. These changes include a variety of different appearances of squamous epithelia (ranging from mature and keratinizing to immature with only subtle evidence of a squamous nature), clear cells, surface changes resembling syncytial metaplasia or microglandular hyperplasia, ciliated cells, oxyphilic cells, and spindled epithelial cells (sarcomatoid carcinoma). The last is one of several variants that may cause a biphasic appearance, all of which should be distinguished from the malignant mllerian mixed tumor. Rare findings in endometrioid carcinomas include hyalinization, psammoma bodies, and foci of stromal metaplasia such as osteoid. Unusual growth patterns of endometrioid carcinomas include involvement of adenomyosis, the diffusely infiltrating pattern of myoinvasion, and a previously unemphasized pattern of myoinvasion with pinched off glands that may be cystic or have a pseudovascular appearance, often with a myxoid stromal reaction. Other aspects of endometrioid carcinoma discussed are its immunoprofile, grading, cervical involvement (including a hitherto undescribed burrowing pattern of extension within the cervix that can result in underdiagnosis of stage IIB disease), carcinoma arising in the lower uterine segment, carcinoma arising in polyps and adenomyomas, carcinoma in young women, tamoxifen-related carcinoma, associated ovarian endometrioid carcinoma, and peritoneal keratin granulomas. Finally, the differential diagnosis of endometrioid carcinoma is briefly considered with a section on benign mimics, including curettage-related changes, menstrual changes, adenomyosis-related problems, metaplastic changes, atypical polypoid adenomyoma, radiation atypia, and papillary proliferations, and a section on metastatic colonic carcinoma. Key Words: UterusEndometriumCarcinomaEndometrioid.
Address correspondence and reprint requests to Dr. Robert H. Young, Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114.
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P. B. CLEMENT AND R. H. YOUNG HISTORICAL PERSPECTIVE AND INTRODUCTION became accepted and was incorporated in the 1994 World Health Organization classification of endometrial carcinomas (9). Serous carcinoma subsequently received so much attention in the coverage of endometrial carcinoma that although some attention was focused on nuances of the morphology of endometrioid carcinoma, some aspects of its pathologic characterization have been overlooked or underemphasized. It is the purpose of this review to highlight unusual aspects and to discuss timehonored issues in the pathology of endometrioid carcinoma. A subsequent review also to appear in this Journal considers nonendometrioid carcinomas of the corpus (10). Our primary purpose here is to discuss in detail the histologic features of endometrioid adenocarcinomas of the corpus (which account for approximately 80% of endometrial adenocarcinomas) with emphasis on histologic variants. Although the histologic distinction of typical endometrioid carcinoma from other histologic types of endometrial carcinoma is usually straightforward, the wide variety of subtypes of endometrioid carcinoma, some recently described, can result in diagnostic problems, including their potential misclassification as a more aggressive histologic type of endometrial carcinoma. The differential diagnosis of endometrioid adenocarcinoma with complex atypical endometrial hyperplasia is not considered here, because it is a topic unto itself and has been extensively discussed in the recent literature. CLASSIFICATION OF MORPHOLOGIC VARIANTS OF ENDOMETRIOID ADENOCARCINOMAS OF THE UTERINE CORPUS The listing in Table 1 is used to highlight the various patterns, cell types, and miscellaneous other changes that may be encountered in endometrioid carcinomas of the uterine corpus. Knowledge of these features is important to the pathologist so as to facilitate correct recognition of the tumor, but some of them would not necessarily require specific mention in the pathology report, because their presence has no bearing on behavior or treatment; a notation may be indicated, particularly when a feature is conspicuous. Two or even more of these variant features may be present in individual tumors, sometimes making the diagnosis particularly challenging, but for convenience of coverage, each change is considered on its own. Endometrioid carcinomas with a significant component of a second cell type (arbitrarily defined as >10%) are placed in the category of a carcinoma of mixed cell type according to the recommendations of the World Health Organization. As such, they organizationally be-
As with almost all major forms of neoplasia, the first certain mention of endometrial carcinoma is lost in the sands of time. Much of the nineteenth century literature on uterine cancer was dominated by coverage of cancer of the uterin cervix, and discussion of carcinoma of the corpus was either nonexistent or cursory at best. In 1900, cancer of the corpus received its first detailed analysis in what we consider to be the first major text on uterine cancer. That work transformed knowledge of this subject by the extent, depth, and quality of the coverage. In that book, one of Dr. Thomas S. Cullens great trilogy of gynecologic pathology texts (1,2) entitled Cancer of the Uterus (3), 8 of 26 chapters were devoted to the topic. Two chapters dealt with symptomatology and treatment, and the remaining chapters were exclusively or predominantly on gross and microscopic features (Fig. 1), with separate chapters on differential diagnosis and squamous cell carcinoma. Approximately 220 pages were devoted to the subject, and they are accompanied by the beautiful illustrations of the legendary medical illustrator Max Brdel (4) and his colleagues. Subsequent to Cullens timeless work, there were relatively few advances of great note until the last three decades. Until recently, endometrial adenocarcinoma was considered relatively homogeneous, and discussion of morphologic variants in standard texts up to circa 1980 was usually limited and restricted to issues such as the significance of squamous elements being of benign (adenoacanthoma) or malignant (adenosquamous carcinoma) appearance, the presence of secretory change or mucinous differentiation in some cases, and the existence of occasional clear cell carcinomas. There has, however, been a great expansion of interest in the topic dating to the recognition of serous carcinoma, which became established as an entity during the late 1970s and early 1980s (57). Entry into the lexicon of serous carcinoma required that the usual form of endometrial carcinoma receive its own designation. We are not certain who first applied the term endometrioid (used in the ovary since 1961, *) to these tumors, but the earliest use of it in the literature pertaining to endometrial carcinoma that we have been able to find was by Hendrickson and Kempson (8) in their well-known book of 1980. The term quickly
* According to Long and Taylor, the term endometrioid was introduced in 1961 by Santesson to refer to ovarian tumors with the appearance of endometrial carcinoma. Santesson was the first investigator to note the relatively high frequency of these tumors in the ovary (24.4% in his study). (Long ME, Taylor HC Jr. Endometrioid carcinoma of the ovary. Am J Obstet Gynecol 1964;90: 936950.)
Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002
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FIG. 1. (A) Typical endometrioid adenocarcinoma with branching tubular glands. (B) Endometrioid carcinoma with squamous differentiation of the morular type (adenoacanthoma). The typical intraglandular location of the squamous elements is seen. (Reproduced, from Cullen TS. Cancer of the uterus. Philadelphia: WB Saunders, 1909; Figs. 189 and 200.)
long in the second part of this exploration of the pathologic characterization of endometrial carcinoma to be published later (10). Endometrioid carcinomas with a component of another subtype accounting for less than 10% of the tumor (which nosologically still belong in the endometrioid group) are discussed in a later section, because even a minor component of a second cell type may be associated with diagnostic problems. GROSS FEATURES The variants of endometrioid carcinoma are indistinguishable on gross examination. In some cases, particularly those in which most of the tumor has been removed by curettage, grossly visible tumor may not be apparent despite obvious tumor on microscopic examination. Conversely, one should not mistake the lush thick endometrium of the late secretory phase for carcinoma. Visible tumors vary from sessile polypoid masses that may fill the endometrial cavity (Plate 1A) to nodules or irregular thickened plaques that may be localized or diffuse. The
TABLE 1. Endometrioid carcinomas of the uterine corpus

Typical Secretory With papillae Villoglandular Small nonvillous papillae Microglandular Sertoliform With metaplastic changes Squamous differentiation Clear cell change, not otherwise specified Surface changes resembling syncytial metaplasia or microglandular hyperplasia Ciliated cells Oxyphilic (or oncocytic) cells With spindled epithelial cells (sarcomatoid) With a poorly differentiated carcinomatous component With other patterns Diffuse growth with low-grade cytology Extensive hyalinization Pinched off glands that may be cystic or pseudovascular With other rare findings Psammoma bodies Stromal metaplasia (e.g., osteoid) With <10% component of one or more other cell types of endometrial carcinoma (e.g., serous, mucinous)
ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS surface of the tumor is typically irregular or shaggy. Some high-grade tumors may diffusely infiltrate the myometrium with limited mucosal abnormality. Gross evaluation is sometimes difficult when numerous large leiomyomas distort and bulge irregularly into the endometrial cavity. In such cases, small foci of carcinoma between the leiomyomas may be overlooked. Occasional tumors are confined to the lower uterine segment as discussed later. The neoplastic tissue is typically pale tan to white and soft, but it is occasionally firm or even gritty. Foci of hemorrhage, necrosis, or both are often visible, especially in poorly differentiated tumors. Myometrial invasion by similar tissue is grossly evident in some cases but is often only detectable microscopically. A similar comment pertains to cases in which carcinoma involves adenomyosis, an issue discussed in detail later. Rarely, tumor involving adenomyosis is evident grossly as white neoplastic tissue that cuffs small cysts (Fig. 2). Assiduous gross inspection of the cervix should be performed to detect tumor spread, but the latter is often discovered only on microscopic examination of routinely submitted sections of cervix. Rare endometrioid carcinomas have been confined to one horn of a bicornuate uterus (11). MICROSCOPIC FEATURES OF TYPICAL ENDOMETRIOID CARCINOMA The amount of tumor and its topography in hysterectomy specimens are highly variable. Most of the endometrium may be lined but not thickened by tumor, or the tumor may have striking focality and an abrupt interface with nonneoplastic endometrium. In other cases, the tumor may be multifocal within a background of endometrial hyperplasia. In some cases, there is striking polypoid intracavitary growth of tumor without any myometrial invasion, whereas in other cases, striking myometrial invasion may be seen in cases with minimal tumor in the endometrium or none at all if curettage has removed it. In occasional cases of small-volume disease, a biopsy or curettage entirely removes the tumor, and the hysterectomy specimen is negative. Specific aspects related to patterns of invasion, including occasional differences in the morphology of the neoplastic glands when they invade, are considered separately later.
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FIG. 2. Endometrioid carcinoma involving adenomyosis. The sectioned surface of the myometrium shows many white foci of tumor, mostly with well-defined margins and some with central cysts representing the foci of adenomyosis involved by the carcinoma.
Typical endometrioid carcinomas (see Plate 1B) are composed of tubular glands, most of which are medium sized but may range from small to large and cystic. The glands are generally round to oval but may be angulated
< PLATE 1. (A) The endometrial cavity is filled by papillary yellow neoplastic tissue. (B) Typical glandular pattern of endometrioid adenocarcinoma. This tumor is grade 1. (C) Secretory variant. Subnuclear vacuoles are conspicuous. (D) Villoglandular papillary pattern. (E) Endometrioid carcinoma with small nonvillous papillae. The cells have appreciable cytoplasm, and the cytologic features are low grade. (F) Endometrioid carcinoma with small nonvillous papillae. The pattern is more complex than in the previous illustration. (G) Endometrioid carcinoma with microglandular pattern and luminal mucin with neutrophils, imparting a superficial resemblance to microglandular hyperplasia. (H) Endometrioid carcinoma with microglandular hyperplasia-like pattern on high-power examination.
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P. B. CLEMENT AND R. H. YOUNG metrioid carcinoma has been used for such tumors (Fig. 4). Ciliated cells may occasionally be seen lining the neoplastic glands in an otherwise typical and almost always well-differentiated endometrioid carcinoma (14), but they are inconsequential (Fig. 5); we reserve the term ciliated carcinoma for the distinctive tumor described by Hendrickson and Kempson (15) as discussed later. The tumors may show focal or confluent necrosis of the glands or necrotic debris in gland lumens, particularly in poorly differentiated tumors, and neutrophils may be conspicuous. Stromal foamy histiocytes occur in approximately 15% of endometrioid carcinomas, which are usually well differentiated (Fig. 6) (16). Although a nonspecific finding, the presence of these histiocytes in an endometrial specimen, especially if unaccompanied by the other inflammatory cells that occur in xanthomatous endometritis, should always raise the possibility of an accompanying endometrioid adenocarcinoma. Associated endometrial hyperplasia is present in 18% to 45% of endometrioid adenocarcinomas (1721).
FIG. 3. Endometrioid carcinoma that is FIGO grade 2 because of the cytologic features. Contrast with the nuclear features depicted in Plate 1A.
or branched. They may grow singly but usually form anastomosing cribriform masses with fusion of the neoplastic glands (see Plate 1B), sometimes resulting in long, often labyrinthine, gland lumens. The endometrial stroma between the neoplastic glands may be replaced by a desmoplastic stroma, although in our experience, a desmoplastic stroma is uncommon in endometrioid carcinomas confined to the endometrium. The glands are lined by stratified or pseudostratified columnar cells with rounded nuclei and variably prominent nucleoli (Fig. 3). Nuclear pleomorphism is variable but is most often only mild to moderate. The cytoplasm is usually not a striking feature, being modest in amount and pale to lightly eosinophilic. Mucin is usually absent or confined to luminal tips of the cells, but minor foci of mucinous differentiation (cells with intracellular mucin) are present in approximately 40% of tumors on routine staining (12) or in approximately 50% with the use of mucin stains (13). Luminal mucin may be prominent in endometrioid carcinomas and the term mucin-rich endoAdvances in Anatomic Pathology, Vol. 9, No. 3, May, 2002
FIG. 4. Mucin-rich endometrioid carcinoma. Gland lumens are filled with material that was basophilic.
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intestinal type cells, including goblet and argentaffin cells (28). SECRETORY CARCINOMA The term secretory carcinoma is applied to rare wellor moderately differentiated endometrioid carcinomas in which glycogen vacuoles (subnuclear, supranuclear, or both) are present within most of the neoplastic cells (see Plate 1C). These tumors are rare, with fewer than 30 examples reported in detail (2931). Tumors with a minor secretory component are more common but still infrequent. In the only two series of secretory carcinomas in the literature, two thirds of the patients were postmenopausal, with an age of 35 to 79 years (mean 57 years) (30,31). In some cases, the vacuoles seem to represent a transitory response to an endogenous or exogenous progestational stimulus; in such cases, a secretory pattern within an adenocarcinoma obtained by curettage may not be present within the tumor at the time of hys-
FIG. 5. Endometrioid carcinoma in which some of the glands are lined by ciliated cells.
Many otherwise typical endometrioid adenocarcinomas contain argyrophilic cells that are apparent only on Grimelius staining (2227), a finding of only academic interest. In some of these tumors, the argyrophilia is apical and related to mucin granules (22). In other cells, diffuse cytoplasmic argyrophilia in columnar or squamous cells is caused by glycogen granules. Argyrophilia in approximately 10% of endometrioid carcinomas is caused by enterochromaffin cells that appear as round, ovoid, or flask-shaped cells individually disposed within the glandular epithelium; occasional cells contain long cytoplasmic processes (27). Enterochromaffin cells are typically immunoreactive for chromogranin, serotonin, and, occasionally, one or more polypeptide hormones, including calcitonin, somatostatin, and corticotropin. Ultrastructural examination of enterochromaffin cells reveals granules 80 nm in diameter. No patients with endometrioid carcinomas containing enterochromaffin cells have had endocrine manifestations. Rare otherwise typical endometrioid carcinomas have contained other
FIG. 6. Endometrioid carcinoma with prominent stromal foamy histiocytes.
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P. B. CLEMENT AND R. H. YOUNG distinguished from rare endometrioid carcinomas in which clear cells line tubules but lack even a focal secretory pattern as discussed later.
terectomy or vice versa. In cases encountered in premenopausal women who are not on hormone therapy, a corpus luteum has typically been present when the ovaries have been available for histologic examination. The adjacent uninvolved endometrium in such cases usually has a secretory pattern more advanced than that of a 17-day secretory endometrium. Additionally, a disproportionate number of secretory carcinomas were encountered during the 1970s among adenocarcinomas occurring in young women using Oracon, a sequential oral contraceptive agent with a large estrogen and relatively small progesterone content (29). In other cases, a secretory pattern is encountered in endometrial adenocarcinomas during the course of treatment with progestins. Most cases of secretory carcinoma, however, have occurred in women with no known source of excess progesterone. The tumors have a behavior similar to that of other welldifferentiated endometrioid adenocarcinomas; only 3 of 24 patients in the two series cited previously died of tumor (30,31). Secretory carcinomas should be distinguished on histologic examination from other endometrial cancers with clear cells (Table 2) such as clear cell adenocarcinoma, which, in contrast, typically has a more aggressive behavior and is composed of tumor cells that are polygonal and clear (without subnuclear vacuoles), flattened, or of hobnail type and usually contain higher grade nuclei. Clear cell carcinoma also more typically has a diffuse growth of clear cells, and the distinctive tubulocystic and papillary patterns of clear cell carcinoma rule out secretory carcinoma. We have encountered occasional otherwise typical secretory carcinomas with foci of solid growth, however (Fig. 7). Although the latter raise the possibility of clear cell carcinoma when considered in isolation, the merging of these foci with typical secretory carcinoma and the presence of grade 1 nuclear features in the solid areas lead us to favor the interpretation that these foci represent an unusual growth pattern in a secretory carcinoma. Secretory carcinoma should also be
TABLE 2. Endometrial carcinomas and nonneoplastic endometrial lesions with clear cells
Carcinomas Secretory cells in secretory endometrioid carcinoma Glycogentated squamous cells in endometrioid carcinoma with squamous differentiation Clear cells, not otherwise specified, in endometrioid carcinoma Lipid-rich endometrioid carcinoma Clear cells in clear cell carcinoma Metastatic renal cell and potentially other metastatic tumors Nonneoplastic lesions Arias-Stella reaction Clear cell change of pregnancy
VILLOGLANDULAR ENDOMETRIOID CARCINOMA A variety of papillae can be seen in endometrial carcinomas and nonneoplastic endometrial proliferations (Table 3). This section focuses on the most common papillary pattern that is found in endometrioid carcinomas. Such tumors, preferably referred to as villoglandular endometrioid carcinoma (VGECs), accounted for 13% and 31% of endometrioid carcinomas in the two largest studies in the literature (3234); our experience is closer to the lower figure. In one of the studies (33), 40% of the tumors were pure VGEC, and the rest were mixed with typical endometrioid carcinoma. Villoglandular endometrioid carcinomas are characterized by long, slender, villous papillae with thin fibrovascular cores (see Plate 1D) usually admixed with a variable proportion of endometrioid glands, although rare tumors are purely or almost purely villous. The cells lining the villi and glands resemble those of typical endometrioid carcinoma. Ninety-seven percent of the tumors in one study (33) were grade 1 or 2; the corresponding figure for typical endometrioid carcinomas was 74%. Squamous differentiation may also be present, as can potentially any other variant feature of endometrioid carcinoma. The villous pattern may be seen in myoinvasive foci (Fig. 8), although it tends to be most conspicuous in superficial tumor. Villoglandular endometrioid carcinomas should be distinguished from other papillary endometrial lesions (see Table 3). The highly stratified cells, complex papillae often lacking stromal cores, and epithelial buds of serous papillary carcinoma of the endometrium are usually absent. Also, high-grade nuclei are generally lacking in VGECs. Although mucinous, clear cell, and transitional cell carcinomas of the endometrium are often papillary, at least focally, other features of the tumors readily facilitate their distinction from VGECs. One nonneoplastic papillary endometrial lesion in the differential diagnosis recently described by Lehman and Hart (35) is considered in a separate section on mimics of endometrioid carcinoma near the end of this review. The behavior of VGECs was similar to that of typical endometrioid carcinoma of similar grade in a large Gynecologic Oncology Group study (33). Ambros et al. (32) found that myoinvasive VGECs (see Fig. 8) had a
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FIG. 7. (A) Endometrioid carcinoma with focal prominent solid growth of clear cells. (B) High-power view of clear cells. Adjacent areas of this tumor were typical secretory endometrioid adenocarcinoma, and the neoplasm was classified by us as belonging to that category (see text for further explanatory comments).
higher frequency of vascular invasion and nodal involvement and a worse outcome than myoinvasive endometrioid carcinoma of usual type. The two types, however, had a similar behavior when confined to the endometrium. The more aggressive behavior of myoinvasive VGECs in that study was independent of grade and stage (32). Since the publication of that report, Ambros has found that most well-differentiated endometrioid carcinomas that have recurred or metastasized have had a component of myoinvasive VGEC (R.A. Ambros, personal communication, 2002). ENDOMETRIOID CARCINOMAS WITH SMALL NONVILLOUS PAPILLAE This variant of endometrioid carcinoma, which is particularly likely to be confused with serous papillary carcinoma, has recently been described by Murray et al. (36). Those authors found that this subtype accounted for
8% of their endometrioid carcinomas. The mean age of the patients was intermediate between that of patients with endometrioid carcinoma of usual type and that of patients with papillary serous carcinoma. These tumors are characterized by small papillae within glands of otherwise typical endometrioid carcinomas (usually grade 1 or 2) or on the villous projections of VGECs. Most of the papillae are in the form of buds of cells with ample eosinophilic cytoplasm (see Plate 1E) and a low nuclearto-cytoplasmic ratio, but some papillae have a more complex pattern (see Plate 1F). Overt squamous differentiation is present in half of the cases, and the eosinophilic cells in the buds likely reflect abortive squamous differentiation. The tumors had a prognosis identical to that of other endometrioid adenocarcinomas of similar grade in contrast to the generally poor prognosis of serous adenocarcinomas in some cases. The distinction from papillary serous carcinoma rests on the recognition that the small nonvillous papillae occur in the background of an otherAdvances in Anatomic Pathology, Vol. 9, No. 3, May, 2002
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P. B. CLEMENT AND R. H. YOUNG two of the tumors were mixed endometrioid-mucinous carcinomas (the others were pure mucinous carcinomas), but we have subsequently seen microglandular changes in tumors that would be classified as pure endometrioid carcinomas because they contained a mucinous component that accounted for less than 10% of the tumor (see Plate 1G,H). The distinction of microglandular carcinomas from microglandular hyperplasia rests on the merging of the microglandular pattern with that of a typical endometrioid carcinoma and a degree of nuclear atypia and mitotic activity in the microglandular areas that exceeds that allowable in microglandular hyperplasia. The age of the patient may be helpful, because microglandular hyperplasia is rare in postmenopausal women who are not on hormonal treatment. In one case of endometrioid adenocarcinoma with a microglandular pattern, strong immunoreactivity of the tumor for MIB-1 and carcinoembryonic antigen (CEA) facilitated its distinction from microglandular hyperplasia (39). SERTOLIFORM ENDOMETRIOID CARCINOMAS These are rare endometrioid carcinomas with a focal to predominant pattern resembling that of ovarian Sertoli cell tumors (40,41). The sertoliform component is composed of small hollow or solid tubules and short slender cords lined by or composed of columnar cells with apical, occasionally clear, cytoplasm (Plate 2A). The reported tumors have been of low grade. The cells in the sertoliform component are immunoreactive for cytokeratin, epithelial membrane antigen, and vimentin but not for actin or desmin. Based on a small number of cases, the behavior of these tumors does not differ from that of endometrioid carcinomas of usual type of similar grade. These tumors should be distinguished from endometrial stromal sarcomas with sex cordlike elements and uterine tumors resembling ovarian sex cord tumors by the presence of typical endometrioid carcinoma and squamous elements as well as nonimmunoreactivity of the sertoliform component for smooth muscle antigens. Sertoliform endometrioid carcinomas represent the uterine counterpart of the much more common ovarian endometrioid carcinomas that resemble sex cord tumors, and any sex cordlike patterns seen in the ovarian tumors could potentially be seen in the endometrial tumors. ENDOMETRIOID CARCINOMAS WITH SQUAMOUS DIFFERENTIATION These tumors account for approximately 25% of endometrioid carcinomas. Squamous change, albeit some-
TABLE 3. Endometrial carcinomas and nonneoplastic endometrial lesions with papillary patterns
Carcinomas Endometrioid villoglandular (thin papillae with fibrous cores; epithelial buds absent; usually grade 1 or 2) with small nonvillous papillae (bud-like to filiform papillae without fibrous cores; usually not detached; cells often have eosinophilic cytoplasm; usually grade 1, occasionally grade 2, rarely grade 3) Serous (bud-like epithelial papillae, often detached; usually grade 3) Mucinous (usually villous; mostly grade 1, occasionally grade 2, rarely grade 3) Clear cell (small papillae with hyalinized cores; larger papillae, typically nonvillous, often with stromal cores that are relatively acellular; papillae often have hobnail cells; usually grade 2 or 3) Transitional (tall and thick; any grade but most often grade 2) Squamous (broad, may be hyperkeratotic; any grade [may even be cytologically benign], rarely grade 3) Nonneoplastic lesions Papillary proliferations (fibrous cores, covered by metaplastic cells; bland nuclei; often within or on the surface of a polyp) Syncytial change (confined to surface or superficial glands; stroma-free papillae; eosinophilic to squamoid cells with typically bland nuclei, but nucleoli and mitoses may be seen; neutrophilic infiltrate, nuclear debris, and compact dense stroma common) Arias-Stella reaction (stroma-free papillae, clear and hobnail cells; invariable association with pregnancy or hormone therapy)
wise typical carcinoma or VGEC that lacks the typical cellular buds or classic slit-like spaces of serous carcinoma. The typically low-grade nuclear features of the papillae contrast with the almost invariably high-grade nuclear features of the cells in the papillae of serous carcinomas. Rare high-grade endometrioid carcinomas can have small nonvillous papillae, but a variety of differences, including lack of conspicuous budding and slitlike spaces, enable distinction even in these cases. ENDOMETRIOID CARCINOMAS WITH A MICROGLANDULAR PATTERN In 1992, five endometrial carcinomas that histologically simulated microglandular hyperplasia were described (37). This phenomenon was previously noted to be a problem in a review of microglandular hyperplasia by Leslie and Silverberg (38). The tumors occurred in postmenopausal patients ranging from 57 to 69 years of age. Two of the patients were or had been receiving Premarin and Provera, and two were receiving only Premarin. The clinical presentation was identical to that of patients with typical low-grade endometrioid adenocarcinoma. The neoplasms had conspicuous microglandular patterns with luminal eosinophilic secretion and luminal and stromal neutrophils. In the hysterectomy specimens,
ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS times only abortive, in endometrioid carcinomas can have numerous diverse overlapping appearances but is considered here in several groups for convenience of discussion: 1) rounded intraluminal aggregates (morules) (see Plate 2B); 2) infiltrating nests resembling conventional squamous cell carcinoma (see Plate 2C); 3) plaque-like foci (see Plate 2D); 4) oval, round, columnlike, or wedge-shaped foci of well-differentiated and often glycogenated cells (Fig. 9A); 5) micropapillae; 6) individual cell keratinization (see Fig. 9B); and 7) solid foci in which cells are often fusiform to spindled and show varying degrees of subtle evidence of squamous differentiation (see Fig. 9C,D), including occasional small whorls or eddies of immature squamous cells. Some of these patterns of squamous change overlap with findings described in the next section when they are located on the surface of the tumor. The first two of the patterns listed here have received the most attention (4247). Tumors in these categories were formerly classified as adenoacanthomas and adenosquamous carcinomas, respectively, but use of these terms has decreased in recent years for reasons discussed below. Adenocarcinoma with squamous differentiation is the preferred term in the 1994 World Health Organization classification (9), although adenoacanthoma and adenosquamous designations are still listed as alternate designations. Adenoacanthoma was used to refer to endometrioid adenocarcinomas (usually grade 1) containing rounded nests (morules) of squamous cells that typically occupy the lumens of the neoplastic glands (see Plate 2B). The morules are sometimes extensive and confluent (Fig. 10), and they may obscure the glandular component. They are typically composed of immature polygonal to occasionally spindled squamous cells with bland nuclear features. Sometimes, the cells, especially in the centers of the nests, undergo maturation and even keratinization. Necrosis can also be seen in the centers of the morules (see Fig. 10). In adenosquamous carcinomas, which usually have a glandular component of higher grade than that of adenoacanthomas, the squamous epithelium may be intraglandular but is often independently invasive of the endometrium or myometrium in contrast to the morules of adenoacanthoma (see Plate 2C). Occasionally, the squamous cells may have clear glycogen-rich cytoplasm, a finding that should be distinguished from clear cell carcinoma by the absence of the tubulocystic and papillary patterns and hobnail cells characteristic of the latter tumor. The malignant squamous cells may also assume a spindled shape, occasionally resulting in a sarcomatoid appearance. The squamous elements in some endometrioid carcinomas have features that are intermediate be-
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tween those of the typical adenoacanthoma and those of the typical adenosquamous carcinoma; this observation (in conjunction with the issue considered in the next paragraph) led to the conclusion that the subcategorization should be abandoned. In early studies of endometrial carcinomas with squamous differentiation, adenoacanthomas were found to have a significantly better prognosis than adenosquamous carcinomas (4244). One of these studies (43) and several subsequent studies (4547) found that the behavior of endometrioid carcinomas with squamous differentiation is dependent on the grade of the glandular component and depth of myometrial invasion as is the case with typical endometrioid carcinomas. Adenoacanthomas thus have a better prognosis than adenosquamous carcinomas because they are associated with a better differentiated glandular component and they are more frequently confined to the endometrium than are adenosquamous carcinomas. The behavior of an endometrioid
FIG. 8. Villoglandular endometrioid carcinoma invading the myometrium.
ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS carcinoma with squamous differentiation is therefore similar to that of typical endometrioid carcinomas when matched for grade and depth of myometrial invasion. Peritoneal keratin granulomas, present in rare cases of endometrioid carcinoma with squamous differentiation, are discussed later in this review. Plaque-like squamous metaplasia, often a surface phenomenon (see Plate 2D), usually occurs as isolated small patches but may be striking in aggregate; this finding may be seen with other surface metaplastic changes as discussed in the next section. Occasionally, the superficial or deeper portion of an endometrioid carcinoma has masses of well-differentiated and sometimes glycogenated squamous epithelium. The small nonvillous papillae of endometrioid carcinomas are occasionally taller and filiform and may exhibit squamous change. Individual cell keratinization is seen in some small nonvillous papillae but may be ubiquitous in other settings. Finally, in solid foci of some endometrioid carcinomas, small whorls reflecting abortive squamous change are seen, which is a finding that may be a clue to an endometrioid nature just as it is in some ovarian endometrioid carcinomas. ENDOMETRIOID CARCINOMAS WITH CLEAR CELL CHANGE, NOT OTHERWISE SPECIFIED Most endometrioid carcinomas with clear cells are in the category of a tumor with squamous change in which prominently glycogenated squamous cells appear clear (the most common cause of clear cells in endometrioid adenocarcinoma in our opinion) or in that of the much less common secretory variant of endometrioid carcinoma (see Table 2). Rarely, nonspecific clear cell change that cannot be attributed to glycogenated squamous cells or secretory change is seen. In some of these tumors, it may be related to the presence of abundant cytoplasmic lipid. ENDOMETRIOID CARCINOMAS WITH SURFACE METAPLASTIC CHANGES A constellation of surface metaplastic changes may be seen in endometrioid carcinoma. Jacques and colleagues
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(48) encountered them in almost 50% of their endometrioid carcinomas. In 30% of the tumors with surface metaplastic changes, syncytial aggregates of bland, eosinophilic, sometimes squamoid cells were present, often in a papillary pattern, simulating papillary syncytial change (see Plate 2E). In 12% of such cases, the surface change resembled microglandular hyperplasia (as described previously), and in the remaining 58% of the cases, a mixture of patterns was seen. The degree of nuclear atypia in these surface changes was usually less than that of the underlying tumor. Careful attention to cytologic detail in these cases and awareness that the specimens are from the endometrium rather than the endocervix should facilitate the diagnosis of carcinoma or prompt a request for additional tissue if the initial specimen is too scanty for a definite diagnosis. CILIATED CARCINOMA As noted earlier, rare otherwise typical welldifferentiated endometrioid adenocarcinomas may contain glands that are lined predominantly by ciliated cells (14). There has been no sizable series of such cases reported, but it is likely that such tumors would have the same prognosis as typical endometrioid adenocarcinoma of similar grade and depth of invasion, and it is not our practice to label such tumors as ciliated carcinomas. Hendrickson and Kempson (15) have described an unusual type of ciliated carcinoma with a distinctive appearance characterized by sheets of cells punctured by small lumina imparting a cribriform appearance (Fig. 11A,B). The tumor cells had grade 1 nuclear features and cilia that projected into extracellular and intracellular lumina. The behavior of the tumors in their study was similar to that of typical endometrioid carcinoma. OXYPHILIC (INCLUDING ONCOCYTIC) ENDOMETRIOID CARCINOMAS Pitman and co-workers (49) described a series of otherwise typical endometrioid carcinomas that were composed predominantly or entirely of cells with abundant oxyphilic cytoplasm (see Plate 2F). Subsequently, a series of similar cases was reported by Silver et al. (50).
< PLATE 2. (A) Endometrioid carcinoma with sertoliform pattern. (B) Endometrioid carcinoma with squamous morules characterized by rounded aggregates of cells with bland cytologic features (adenoacanthoma). (C) Neoplastic endometrioid glands are seen at the bottom, and infiltrating squamous carcinoma is seen at the top (adenosquamous carcinoma). (D) Endometrioid carcinoma with plaque-like squamous differentiation seen at the upper right. Typical endometrioid carcinoma is seen best at the upper left. This tumor had a peculiar pattern of hyalinization as discussed in the text and illustrated in Figure 14. (E) Surface component of endometrioid carcinoma resembling so-called papillary syncytial metaplasia. (F) Endometrioid carcinoma with cells with abundant eosinophilic cytoplasm (oxyphilic endometrioid carcinoma). (G) Endometrioid carcinoma with spindle cell epithelial component (sarcomatoid carcinoma). Conventional endometrioid neoplasia is seen at the top left but merges with a solid pattern in which many of the cells are spindled at the bottom right. (H) Endometrioid carcinoma with minor component of mucinous cells.
ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS Although no distinctive findings were found ultrastructurally in the first series, Silver et al. (50) found that the neoplastic cells in the tumors in their study contained abundant mitochondria; hence, their preferred designation of oncocytic carcinoma. All the reported oxyphilic and oncocytic endometrioid carcinomas have been grade 1 or 2 (4952), but we have seen solid nests of cells with striking eosinophilic cytoplasm in occasional high-grade carcinomas. The clinical presentation of these tumors does not seem to differ from that of typical endometrioid carcinoma. Several of the reported tumors invaded the myometrium or were stage II or III. One tumor that was well differentiated was associated with deep myoinvasion and labeled a minimal deviation oncocytic carcinoma (52). ENDOMETRIOID CARCINOMAS WITH SPINDLED EPITHELIAL CELLS In some endometrioid carcinomas (53), the neoplastic epithelial cells, like those of ovarian endometrioid carcinomas (54), are focally spindled; rarely, such foci are conspicuous (see Plate 2G). The spindle cells are almost always less atypical (Fig. 12) than the sarcomatous spindle cells of a malignant mllerian mixed tumor (MMMT), and a biphasic pattern (so typical of the latter tumor), although seen, is generally not as striking. It is only rarely difficult to distinguish a sarcomatoid carcinoma from an MMMT on routinely stained slides, and immunostains are not needed. We object to the trend in some quarters to consider an MMMT a sarcomatoid carcinoma. They are of epithelial histogenesis, but tumors are classified on the basis of their morphology rather than only on their cell lineage; otherwise, all tumors of endometrial cell lineage would be classified as one. Although the MMMT is the best known biphasic tumor, it is worth noting that pure endometrioid carcinomas of various subtypes (Table 4) may descriptively be biphasic, a feature that can result in a misdiagnosis of MMMT. ENDOMETRIOID CARCINOMAS WITH A POORLY DIFFERENTIATED CARCINOMATOUS COMPONENT Rare otherwise typical endometrioid carcinomas may be associated with a poorly differentiated carcinomatous
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FIG. 10. Endometrioid carcinoma with striking squamous differentiation in the form of round to oval aggregates, one of which exhibits central necrosis.
component that may exhibit signet-ring differentiation (55), trophoblastic differentiation (including choriocarcinoma) (56), hepatoid differentiation (resembling hepatocellular carcinoma) (5760), or giant cell carcinoma (61). All these tumors are considered mixed endometrial carcinomas or are most closely related to undifferentiated carcinoma, and they are covered in our subsequent review (10). OTHER RARE PATTERNS The solid foci of high-grade endometrioid carcinomas usually have the nonspecific morphologic features of pleomorphic epithelial cells. Occasional grade 1 or 2
< FIG. 9. Patterns of squamous differentiation. (A) Large nests of mature metaplastic squamous epithelium. (B) Small clusters of cells and individual cells with eosinophilic cytoplasm reflecting squamous differentiation. (C) Immature squamous differentiation forms an elongated curvilinear focus (right). The fusiform to spindle-shaped cells forming a solid area (middle-left) probably also represent cells that are differentiating toward a squamous type because of their merging with foci of more obvious squamous change. (D) High-power view of solid area of growth similar to that present in C in which there is a vague whorling, an occasional subtle manifestation of abortive squamous differentiation in endometrioid tumors of both the uterine corpus and ovary.
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FIG. 11. Ciliated endometrioid carcinoma of the type described by Hendrickson and Kempson (15). (A) Solid sheets of cells are interrupted by occasional glands with small lumens. (B) On higher power, some of the lumens are intracellular and contain cilia (arrows). (The slide from which these photographs were taken was kindly provided by Dr. Michael Hendrickson, Stanford University Medical Center, CA).
tumors may also have solid foci but with less atypical cytologic features (Fig. 13). The solid foci in these tumors may merge with sarcomatoid foci. A sharp distinction of the solid foci from the neoplastic endometrioid glands may impart a biphasic pattern (see Table 4). In some cases, either the solid rounded or spindled foci merge with areas in which the stroma is extensively hyalinized (Fig. 14). Epithelial cells in varying arrangements (e.g., clusters, cords, trabeculae) may be embedded in the hyaline material. This is another feature of endometrioid carcinoma that may result in a biphasic pattern (see Fig. 14B). Another peculiar pattern of neoplasia we have seen only in myoinvasive tumor is discussed later in a separate section. OTHER RARE FINDINGS Psammoma bodies can occur in otherwise typical endometrioid carcinomas (Fig. 15); Cullen (3) illustrates
such a tumor (his Fig. 203). Parkash and Carcangiu (62) have noted that the presence of psammoma bodies seems to be related to inflammation and necrosis within the tumor. Rare endometrioid carcinomas may contain benign heterologous elements in the stroma (e.g., fat, osteoid) (Fig. 16), the presence of which should not result in a misdiagnosis of MMMT (63). ENDOMETRIOID CARCINOMAS WITH A SMALL COMPONENT (<10%) OF ANOTHER CELL TYPE Strictly speaking, an endometrioid carcinoma with a component of a second cell type that accounts for less than 10% of the tumor should be classified as endometrioid. Nevertheless, because even a tiny component of some cell types (e.g., serous, clear cell, small cell, undifferentiated) may have an adverse prognostic significance, such a finding should be highlighted in the report,
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FIG. 12. Sarcomatoid endometrioid carcinoma. This high-power view of an area in which the cells are focally spindled shows cytologic features that are less atypical than in a sarcomatous component of a malignant mllerian mixed tumor.
and we have included this category as the last one in Table 1. The presence of a second cell type of no known clinical or prognostic significance such as mucinous (see Plate 2H) or squamous need not be mentioned if minimal
TABLE 4. Tumors with endometrioid glands and a biphasic appearance
Endometrioid carcinoma With spindled epithelial cells (sarcomatoid carcinoma) With interglandular diffuse growth Small cells with low-grade cytology Small cell carcinoma Undifferentiated carcinoma, NOS With extensive hyalinization With stromal osteoid Malignant mu llerian mixed tumors With high-grade sarcomatous component (MMMT, NOS) With low-grade sarcomatous component (mu llerian adenosarcoma) With benign mesenchymal stromal component (mu llerian adenofibroma) MMMT, malignant mu llerian mixed tumor; NOS, not otherwise specified.
FIG. 13. Endometrioid carcinoma with solid growth of small cells in a diffuse distribution, resulting in a biphasic pattern. Foci with this appearance often merge with areas of spindle cells that, in turn, may merge with foci showing squamous differentiation. Although biphasic, the appearance is distinct from that of malignant mllerian mixed tumor.
(<10%), but the presence of such a component can cause diagnostic confusion by sometimes producing peculiar and occasionally complex microscopic patterns. For example, when these cell types are associated with unusual architectural features such as villous papillae, one can encounter tumors that are partially conventional endometrioid carcinoma with other areas that are villous with mucinous cells and still other areas that consist of squamous epithelium. Indeed, some such tumors can resemble a mllerian mixed epithelial borderline tumor of the ovary, and we have seen rare endometrial tumors in which this pattern has predominated. Because there is no borderline category in endometrial neoplasia, we believe such tumors are best classified as low-grade carcinomas, with a notation indicating the specific elements and the relative proportion of each. These tumors are technically
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FIG. 15. ies.
Endometrioid carcinoma with occasional psammoma bod-
FIG. 16. plasia.
Endometrioid carcinoma with striking stromal osteoid meta-
of mixed cell type and are discussed further in our next review (10). EFFECTS OF TREATMENT Radiation-induced changes in endometrial carcinomas are quite variable, probably because of differences in response between tumors, radiation dosage levels, and intervals between treatment and hysterectomy (6466). These changes may include complete disappearance of the tumor; necrosis within residual tumor; tumor cell cytoplasm that is increased in amount and degree of vacuolation; nuclei that are bizarre (Fig. 17), pyknotic, or
karyorrhectic; and enlarged nucleoli (64,65). The tumor may become more differentiated, and squamous elements absent in the pretreatment specimen may become prominent (65). Progestins can also induce changes in endometrioid carcinomas. Well-differentiated tumors have been successfully treated with progestins, suggesting that at least some of them disappear entirely. Those that persist may become better differentiated, with the appearance of squamous metaplasia within the tumor (65). The glands may become smaller with an atrophic appearance (Fig. 18), there may be an increase in the ratio of stroma to tumor, and the former is usually decidualized.
< FIG. 14. Endometrioid carcinomas with stromal hyalinization. (A) This tumor shows small ball-like foci of hyaline punctuating an otherwise solid growth of cells, some of them spindled. This focus is, in turn, mantled by typical endometrioid adenocarcinoma with focal squamous differentiation. (B) The striking stromal hyalinization imparts a peculiar appearance on low-power examination. (C) Prominent stromal hyalinization surrounds numerous small clusters of epithelial cells. (D) The hyalinization in this field has segregated the epithelial cells and resulted in a palisaded arrangement.
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P. B. CLEMENT AND R. H. YOUNG Colposcopic and hysteroscopic findings as well as the presence of an associated atypical endometrial hyperplasia or endocervical adenocarcinoma in situ can be helpful, as can the different immunoprofiles of the two tumors (6775). As recently summarized by Zaino (74), a limited panel of vimentin, estrogen receptor (ER), and CEA can localize the site of origin in most problematic cases. Endometrial adenocarcinomas (including those of endometrioid type) are characterized by a vimentinpositive, ER-positive, and CEA-negative profile, whereas endocervical adenocarcinomas (including those of endometrioid type) are characterized by the opposite findings (vimentin-negative, ER-negative, CEApositive). In another study, however, Kamoi et al. (75) found that CEA was not helpful and that only a combination of strong vimentin and strong ER staining in an endometrioid carcinoma predicted (with approximately 95% accuracy) an endometrial origin for the tumor. When the results of these various markers are inconclu-
FIG. 17. Endometrioid carcinoma with giant cells after intracavitary radiation therapy of endometrioid carcinoma.
IMMUNOPROFILE OF ENDOMETRIOID CARCINOMAS The distinction between an endometrial endometrioid adenocarcinoma and an endocervical endometrioid adenocarcinoma in a fractional dilatation and curettage specimen may be challenging when both components of the specimen contain similar tumor. This distinction is important, because the treatment of endometrial and endocervical adenocarcinomas generally differs. In our experience, however, endometrioid carcinomas of the cervix are rare, and the typical endometrial endometrioid carcinoma has a distinctly different histologic appearance from the typical endocervical primary adenocarcinoma (i.e., so-called endocervical-type adenocarcinoma of the cervix). The glands of the latter are generally smaller, and their lining cells tend to have more intense amphophilic to eosinophilic cytoplasm, are more mitotically active, and show more apoptosis. Despite these morphologic differences in most cases, there are some tumors in which morphologic overlap is such that other findings may aid in this distinction.
FIG. 18. Endometrioid carcinoma with small atrophic neoplastic glands separated by edematous stroma in a patient treated with hormonal therapy for low-grade endometrioid carcinoma.
ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS sive, the detection of human papillomavirus by in situ hybridization favors an endocervical origin, although its presence was found in only 45% of endocervical adenocarcinomas in one study (71) and in 70% in another (69). Human papillomavirus was not detected in any of the endometrial adenocarcinomas in either of these two studies. The immunoprofile of the tumor may also help to determine if an endometrioid adenocarcinoma in the area of the lower uterine segment and/or upper endocervix in a hysterectomy specimen is of endometrial or endocervical origin. Other immunohistochemical studies have compared the immunoprofile of endometrial endometrioid adenocarcinomas with that of endometrial serous carcinomas. Kounelis et al. (70) reported that endometrioid carcinomas have a much lower expression of p53 than do serous carcinomas (35% versus 76%). Most of the p53-positive endometrioid carcinomas were of high grade; similar findings have been reported in other studies (76,77). In the same study (70), ER and progesterone receptor were much more commonly present (in 70% and 72.5%, respectively) in endometrioid carcinomas than in serous carcinomas (in 23.8% and 19%, respectively). PATTERNS OF INVASION AND ASSOCIATED ISSUES Invasion of endometrial carcinoma is first manifested within the endometrium by the presence of one or more architectural features that indicate there has been invasion of the endometrial stroma. Even in carcinomas of small volume, a confluent arrangement of glands or the presence of clearly malignant glands in an abnormal arrangement generally makes the diagnosis straightforward. In general, intraendometrial carcinoma (stage Ia) is composed of fused, often cribriform, masses without the tendency for separation of the neoplastic glands that occurs when the tumor invades the underlying myometrium. Occasionally, however, as noted previously, the neoplastic aggregates are separated by a desmoplastic stroma (Fig. 19). The amount of carcinoma invasive of the endometrium and of the underlying myometrium, and the ratio between the two, is quite variable. In some cases, there is a relatively limited volume of intraendometrial carcinoma but striking invasion of the subjacent myometrium. In other cases, there is abundant intraendometrial carcinoma but no underlying invasion; indeed, in some cases, the endometrium is effaced by carcinoma with an exclusive exophytic growth pattern without any invasion of the myometrium. Factors that cause these discrepant situations are unknown. Recognizing myometrial invasion by endometrial car-
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FIG. 19.
Endometrioid carcinoma with a desmoplastic stroma.
cinomas is straightforward when glands that are often irregularly shaped, haphazardly distributed, and surrounded by a desmoplastic stroma have an infiltrative border with the myometrium (Fig. 20). Other growth patterns of the tumors may create problems in determining the presence and depth of myometrial invasion, however. A carcinoma that has overgrown the endometrium but has not invaded the myometrium may accentuate the normally irregular endomyometrial junction. In such cases, well-circumscribed and rounded nests of tumor seem to bulge into the superficial myometrium, an appearance that is often misinterpreted as superficial myometrial invasion (Fig. 21). Awareness of this appearance, the presence of occasional noncancerous endometrial glands or foci of endometrial stroma between the tumor and the myometrium, and the absence of a reactive stroma facilitate the correct interpretation. Some myoinvasive tumors have a well-circumscribed, expansile, or pushing border with the myometrium. In such cases, the myometrial invasion may not be recognizable if the normal endomyometrial junction is not included in the tissue
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P. B. CLEMENT AND R. H. YOUNG below. In their system, however, the diffusely infiltrating pattern is defined more broadly than in the other studies (7880), being characterized by irregularly distributed glands, masses, cords, or nests of tumor cells infiltrating the myometrium haphazardly (81). When an endometrial carcinoma and adenomyosis coexist in the same uterus (see Fig. 2), the latter process is involved by the carcinoma in approximately 25% of cases (Fig. 23) (82,83). In rare cases, the adenomyotic involvement may represent a multifocal origin of the carcinoma, but in most cases, it represents direct invasion by the endometrial carcinoma. The fact that some carcinomas arise from adenomyotic glands is suggested by the rare confinement of the adenocarcinoma to adenomyosis (8486) or, more often, by the finding of precancerous changes within adenomyotic glands next to foci of adenocarcinoma. A number of studies have found that the prognosis of an endometrial adenocarcinoma is
FIG. 20. Endometrioid carcinoma that is deeply invasive of the myometrium. One congerie of glands is growing as a large rounded aggregate, whereas the central focus has an elongated shape. There is a conspicuous stromal reaction.
section. A different pattern of myoinvasion is that referred to as diffusely infiltrating invasion (78,79) or the single gland pattern of invasion (80) in which most or all of the invasive tumor takes the form of individually disposed glands widely scattered through the myometrium (Fig. 22A,B). In such cases, especially when the neoplastic glands are well differentiated and associated with little or no stromal response, the process can be misdiagnosed as adenomyosis with atrophy of its stroma. The term adenoma malignum pattern of invasion has been applied to some such cases (79). Although two earlier studies suggested that the diffusely infiltrating pattern might have an adverse prognostic significance (78,80), a larger more recent study found that it did not (79). Lax et al. (81) have used the pattern of myoinvasion (expansile versus diffusely infiltrating) as one parameter in the assessment of grade in their recently proposed grading system for endometrioid carcinoma as discussed
FIG. 21. Endometrioid carcinoma confined to the endometrium. Note the irregularity of the base of the lesion (left), which reflects the irregularity that is common at the endomyometrial junction.
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FIG. 22. Endometrioid carcinoma with so-called diffusely infiltrating pattern. (A) Low-power view shows the typical morphology and conspicuous lack of any stromal reaction. (B) High-power view of glands showing low-grade nuclear features.
not adversely affected when myometrial involvement by the carcinoma is confined to the adenomyosis (82,83,87). It should be noted, however, that these studies contained only a small number of cases of carcinomatous involvement of deep adenomyotic foci. The pathologist should carefully distinguish between carcinomatous involvement of adenomyosis and true myometrial invasion. Jacques and Lawrence (87) found one or more features useful in identifying involvement of adenomyotic foci by carcinoma, including the presence of a smooth rounded contour with the surrounding myometrium, the presence of nonneoplastic glands or endometrial-type stroma within the foci in question, the absence of desmoplasia or an inflammatory response, and the presence of adjacent uninvolved islands of adenomyosis. Problems in interpretation may persist in older women, however, in whom the adenomyotic stroma is frequently atrophic. In such cases, it may be difficult or impossible to determine if the malignant glands are in direct contact with the myometrium or are surrounded by thin wisps of atrophic stroma.
Although adenomyotic stromal cells are immunoreactive for CD10, CD10 is also frequently expressed immediately around nests of myoinvasive adenocarcinoma; thus, CD staining is not usually helpful in the differential diagnosis (8890). In difficult cases, low-power evaluation may show that the spatial arrangement of the carcinomatous foci is consistent with islands of adenomyosis involved by cancer. In other cases, the number of epithelial islands, their relation to one another, their irregular borders, and an absence of the surrounding hyperplastic smooth muscle characteristic of adenomyosis may strongly favor myometrial invasion. Criteria similar to those just outlined apply in the rare cases in which a carcinoma spreads to involve the epithelium of an underlying adenomyoma. Residual myomatous stroma between the glands is a clue to the process. The possibility of endometrioid carcinomas arising in adenomyomas is discussed later in this review. Cullen (3) noted that carcinomatous involvement of a leiomyoma is rare, an observation that is in accord with our experience.
FIG. 23. Endometrioid carcinoma involving adenomyosis. (A) The striking nature of the abnormality on low power suggests myometrial invasion. Note the smoothly contoured periphery of most of the islands. At this magnification, small foci of residual endometrial stroma or benign endometrioid glands, which are often helpful supportive findings in establishing the diagnosis of tumor involving adenomyosis, are not appreciable. (B) The dark blue cuff around most of the neoplastic aggregates in this illustration represents endometrial stroma at the periphery of the adenomyotic foci that are involved by the low-grade carcinoma. (C) This high-power view shows many residual benign endometrioid glands in a focus of tumor involving adenomyosis. Many neoplastic glands are also evident.
ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS Morphologic Differences Between Intraendometrial and Myoinvasive Endometrioid Carcinomas Although invasive carcinoma is usually at least focally gland forming, any potential appearance of invasive carcinoma can be encountered, ranging from fused glands to large sheets, nests, small clusters (Fig. 24), or single cells. Although the gland patterns of most endometrioid carcinomas invading the myometrium are similar to those seen in the endometrium, some differences in the morphology of the glands of myoinvasive adenocarcinoma as compared to intraendometrial carcinomas merit comment. As noted previously, in the so-called diffusely infiltrating pattern of myoinvasion, there is more separation of the glands than is typically seen within the endometrium. Also, a desmoplastic reaction, a lymphocytic response (see below), or both are generally more conspicuous in the myometrium, and sometimes the stromal response is myxoid (Fig. 25). Occasionally, the myoinvasive endometrioid glands undergo a peculiar but distinctive change (Fig. 26) characterized by microcystic or slit-like glands with a lining of flattened epithelial
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FIG. 25. Endometrioid carcinoma invading myometrium and associated with a prominent somewhat myxoid stromal reaction.
FIG. 24. Endometrioid carcinoma invading myometrium in the form of small clusters of tumor cells.
cells (see Fig. 26C,D) that often have appreciable eosinophilic cytoplasm. The lumens may or may not contain detached clusters of carcinoma cells. The flat linings of the slit-like glands have been referred to as endotheliallike (see Fig. 26D) in one of the rare comments on this pattern in the literature (80). The cysts seem to evolve and become pinched off from pointed projections that emanate from the conventional parent endometrioid glands (see Fig. 26B). In some cases, the cystic glands break down, becoming represented by rare tumor cells associated with a myxoid or edematous stromal reaction that may draw attention to the foci in question. Sometimes, these foci and the better preserved foci of this phenomenon lie beyond the main margin of the tumor and can potentially be overlooked, leading to an underestimation of the depth of invasion. This appearance has received scant attention in the literature, although we are aware of at least one article in which it is illustrated (Figs. 6 and 7 of that work) (80). Whether this pattern of invasion has any significance prognostically remains to
ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS be investigated. We have recently seen a grade 1 endometrioid carcinoma confined to the inner third of the myometrium with this pattern that was associated with lymph node metastases. In some cases with the peculiar pinched off glands, the striking stromal reaction is an initial clue to the presence of the invasive tumor. In addition to a desmoplastic reaction, as noted previously, other types of reaction to the invasive tumor may be seen occasionally. In some cases, there is a lymphocytic response around myoinvasive tumor nests. Occasionally, in such cases, depending on the plane of section, these inflammatory cells are unassociated with tumor, but the latter may become apparent on deeper sectioning. In some cases, the lymphocytes surround blood vessels as discussed later. Finally, in some cases, as with any invasive adenocarcinoma that may contain mucin within gland lumens, gland rupture may result in mucin pools (Fig. 27) (91). This finding, referred to as free mucin, was associated with an increased risk of vascular invasion in the only study of the phenomenon of which we are aware (91). The mucin is epithelial mucin in contrast to the acidic mucin of the myxoid stromal response noted previously. CERVICAL INVOLVEMENT Cervical involvement in endometrial carcinoma is usually a result of direct surface or stromal extension, although it is occasionally secondary to implantation or lymphatic spread. In a recent study of spread by implantation (92), the following criteria were proposed: 1) the tumor is embedded in the endocervical epithelium or superficial stroma surrounded by inflammatory cells and granulation tissue; 2) the cervical tumor is similar histologically to that within the endometrial cavity; 3) the cervical tumor is separate from the endometrial tumor with no evidence of direct extension; and 4) the cervical tumor is surrounded by nonneoplastic endocervical glands with no transition between the two. The implanted tumor is considered to be secondary to implantation of endometrial carcinoma in the denuded endocervix after fractional dilatation and curettage. The finding was present in 5% of hysterectomy specimens removed for endometrial carcinoma in patients who had undergone fractional curettage.
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FIG. 27. Endometrioid carcinoma with abundant luminal mucin and gland rupture with mucin pools lying in the stroma.
In stage IIa disease, tumor is confined to the endocervical epithelium (Fig. 28), whereas in stage IIb disease, tumor is invasive of the endocervical stroma. In most studies, stage IIb disease is associated with a worsened prognosis, whereas stage IIa disease is not. The diagnosis of stage II disease in the 1988 FIGO staging system for endometrial carcinoma is based on examination of the hysterectomy specimen. In some institutions, however, preoperative radiation treatment is still given for patients in whom stage II disease is diagnosed by clinical examination in conjunction with endocervical curettage. Histologic diagnosis of stage II disease on the basis of the findings within an endocervical curettage specimen can be difficult, because these specimens are often artifactu-
< FIG. 26. Endometrioid carcinoma with a peculiar myoinvasive pattern in which small glands become pinched off from larger glands, become altered in morphology, and are often associated with a prominent stromal reaction. (A) Gland at the upper left shows an eccentric constriction with a pointed projection at the 5:00 oclock position. (B) High-power view of phenomenon seen in A in which the gland at the top has become detached from the larger and more typical endometrioid gland at the bottom. (C) Cystic gland with flattened lining cells that often results in cases of this type. (D) Peculiar elongated gland lined by flattened epithelial cells with focally appreciable (eosinophilic) cytoplasm and potentially mimicking a blood vessel.
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ally contaminated by tumor from the endometrial cavity. Artifactual contamination most commonly takes the form of tumor fragments unattached to stroma (freefloating tumor) admixed with normal endocervical tissue. In such cases, we diagnose detached fragments of adenocarcinoma, definite cervical involvement by tumor is not identified. Failure to include this disclaimer in the pathology report can result in the tumor being inappropriately considered stage II by the clinician, potentially leading to overly aggressive treatment. For example, Abeler and Kjorstad (93) reviewed 278 endocervical curettage specimens initially considered positive for involvement by endometrial carcinoma and concluded that only 24% of them represented unequivocal stage IIb disease as indicated by the presence of stromal invasion in tissue fragments that were covered by normal squamous or endocervical glandular epithelium. The diagnosis of cervical involvement by an endometrial endometrioid carcinoma is usually more straightforward in a hysterectomy specimen, as is the distinction between stage IIa and stage IIb disease. We have encountered a peculiar pattern of spread of endometrioid endometrial adenocarcinoma to the cervix that can lead to diagnostic problems. We refer to this as the burrowing pattern, because the tumors seemingly burrow within the cervix from the corpus. In these cases, the endometrial carcinomas, which are usually grade 1 or 2, invade preferentially within the deep endocervical stroma so that most of the neoplastic glands undermine the normal endocervical glands (Fig. 29A). In some of these cases, most of the invasive tumor is in the endocervical stroma rather than in the myometrium. The pattern of invasion may take the form of widespread singly disposed glands with little or no stromal response, resembling the diffusely infiltrating or adenoma malignum pattern of myoinvasion that is seen in the corpus. The more superficial neoplastic glands may mingle with normal endocervical glands. Unfamiliarity with this pattern of cervical involvement can lead to misdiagnosis of a concomitant primary endocervical adenocarcinoma, especially when the more superficial neoplastic glands are mistaken for endocervical adenocarcinoma in situ. Additional sections that show continuity between the neoplastic glands in the cervix and those in the corpus can facilitate the correct diagnosis. As discussed previously, the different immunoprofiles of the two tumors would obviously suggest separate primaries. Also, because the neoplastic glands within the endocervical stroma in these cases are endometrioid (see Fig. 29B), the cervical tumor, if primary, would be an endometrioid carcinoma. Although the frequency of endometrioid carcinomas of the cervix has varied in the literature, they are uncomAdvances in Anatomic Pathology, Vol. 9, No. 3, May, 2002
FIG. 28. Endometrioid carcinoma that has spread directly to involve the endocervical mucosa (left) but does not infiltrate the endocervical stroma.
mon to rare in our experience, as noted earlier. This observation is highlighted by the findings in a recently published study of cervical adenocarcinomas from the Brigham and Womens Hospital and the Massachusetts General Hospital in which only 7% of the tumors were endometrioid (94). Certainly, in cases of a putative primary endometrioid carcinoma of the cervix, extension from an endometrial primary should always be considered. An additional problem with this pattern of invasion is that the glands can be mistaken for eutopic endocervical glands showing tuboendometrioid metaplasia or even mesonephric glands. Appreciation of sometimes subtle architectural arrangements indicative of an infiltrating process and cytologic abnormalities is crucial in this differential diagnosis. MATURATION OF METASTATIC ENDOMETRIOID CARCINOMA The phenomenon just considered is illustrative of the potential for neoplastic endometrioid glands to mature
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FIG. 29. Endometrioid carcinoma that has burrowed within the endocervical stroma. (A) Normal endocervical glands are seen at the top. Note the lack of any significant stromal reaction. Such glands can be misinterpreted as benign. (B) High-power view from case similar to that depicted in A showing low-grade malignant nuclear features. Note mitotic figure.
when they spread. This may be seen at distant sites as well as locally within the uterus. For example, metastatic endometrioid carcinoma in lymph nodes can potentially be confused with mllerian inclusion glands. Features favoring a diagnosis of carcinoma include the absence of capsular involvement and ciliated cells lining the glands, because these are both features typical of inclusion glands. Also, the presence, however focal, of more than mild atypicality and mitotic activity within the glandular lining cells would obviously favor a malignant diagnosis. It should be noted that a lymph node might contain both benign and carcinomatous glands, an appearance that raises the possibility of an independent endometrioid carcinoma arising from the inclusion glands. GRADING The prognostic importance of grading endometrial adenocarcinomas has been recognized for many years. The
1988 FIGO/ISGP grading system for endometrioid adenocarcinomas (95) [with suggested modifications by Zaino et al. (96) in 1995] is by pattern and nuclear features. Tumors that are less than 5% solid are grade 1, those that are 5% to 50% solid are grade 2, and those that are greater than 50% solid are grade 3; the assessment of the solid growth is based only on the glandular component and not on any squamous component that might be present. The presence of grade 3 nuclear features (i.e., marked nuclear pleomorphism, coarse chromatin, prominent nucleoli) in most neoplastic cells in architecturally grade 1 or 2 tumors increases their grade by one (see Fig. 3) (96). It should be noted that a majority of endometrioid carcinomas are architecturally grade 1. Assessment of whether the nuclear features are grade 3, thereby warranting an upgrade of the tumor, is somewhat subjective. Subsequent modifications to the FIGO grading scheme have been suggested but not formally adopted. Takeshima et al. (97) found that architectural grade 1 or
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2 tumors with more than 25% grade 3 nuclei had a behavior similar to those with more than 50% grade 3 nuclei. Taylor et al. (98) have proposed a two-tiered grading system based on the FIGO system in which lowgrade tumors have 20% or less nonsquamous solid areas, whereas high-grade tumors have more than 20% nonsquamous solid areas. They found that this system was less cumbersome, had less interobserver variation, and had the same or better prognostic significance than the three-grade system. Recently, Lax et al. (81) have also proposed a binary architectural grading system for endometrioid carcinomas which they found to have superior reproducibility compared with the FIGO system and identified subsets of advanced stage tumors with favorable and unfavorable prognoses. In this system, a tumor was classified as high grade if at least two of the following three criteria were present: more than 50% solid growth (without distinction of squamous from nonsquamous epithelium), a diffusely infiltrative rather than expansile growth pattern, and tumor cell necrosis. For tumors confined to the endometrium, only criteria 1 and 3 are evaluated; if both are present, the tumors are considered to be of high grade. This system stratified patients in three prognostic groups: patients with stage Ia or Ib low-grade tumors had a 100% 5-year survival rate, patients with higher stage (stage Ic and IIIV) low-grade tumors and those with high-grade tumors confined to the myometrium (stage Ib and Ic) had a 5-year survival rate of 67% to 76%, and patients with advanced stage high-grade tumors had a 26% 5-year survival rate. OTHER PATHOLOGIC PROGNOSTIC FACTORS Prognostic factors for endometrial adenocarcinomas, including those of the endometrioid type, that should be included in the pathology report have been reviewed in detail elsewhere (99,100). In addition to histologic subtype and grade, they include the presence and depth of myometrial invasion and the presence or absence of involvement of the following: lymphovascular spaces (101), the uterine serosa, the cervix (as discussed previously), the parametrium (102), the adnexa, and other submitted tissues such as lymph nodes. Extensive lymphovascular space invasion was more likely to be associated with lymph node spread than focal lymphovascular space invasion in one study (103). The presence of perivascular lymphocytic infiltrates (Fig. 30) has also been shown to be an independent adverse prognostic marker in some studies (104,105) but was not as good a prognosticator as lymphovascular space invasion in another series (106).
FIG. 30. Perivascular aggregates of lymphocytes associated with myoinvasive endometrioid carcinoma (not shown).
In contrast, another study (80) found that perivascular lymphocytes and a tumor-host inflammatory response were in fact associated with a prolonged recurrence-free interval. Coexistent endometrial hyperplasia is a favorable prognostic factor (1721) but is probably explained by the generally lower grade of hyperplasia-related tumors compared with those that are associated with atrophy (26). DNA aneuploidy has been found to be an independent adverse prognostic factor in a number of studies (104,107,108). CARCINOMAS ARISING IN THE LOWER UTERINE SEGMENT From 3% to 6% of endometrial adenocarcinomas arise in the lower uterine segment (isthmus) (109111). In one study, the proportion of tumors in this site rose to 18% if only endometrial carcinomas in women less than 50 years of age were considered (111); conversely, almost 75% of carcinomas of the lower uterine segment in the
ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS same study occurred in women less than 50 years of age. Overall, these studies have found that tumors in the lower uterine segment are more likely to be of high stage, poorly differentiated (high-grade endometrioid carcinomas, often with squamous differentiation, and, less commonly, serous or clear cell carcinomas), and deeply invasive; consequently, they have a worse prognosis than tumors arising elsewhere in the corpus. In contrast to the foregoing, Phelan et al. (112) studied 98 pathologic stage I endometrial adenocarcinomas (histologic subtypes not specified) and found that 42% of them involved the lower uterine segment. No differences in clinicopathologic features were noted between those that did and did not involve the lower uterine segment. CARCINOMAS ARISING IN POLYPS Carcinomas may arise within endometrial polyps (Fig. 31). Criteria for this diagnosis proposed by Ferris and Dockerty (113) and modified by Salm (114) are that the carcinoma must be limited to a portion of the polyp and
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the endometrium surrounding the base of the polyp must be benign. Peterson and Novak (115) found only four carcinomas in a review of 1,100 patients with endometrial polyps; similarly, Salm (114) found six in his review of approximately 1,100 polyps, representing a frequency of 0.55%. More recent studies have found carcinoma in 1.3% (116), 1.5% (117), and 3.2% (118) of polyps studied. In many of the well-documented cases, the carcinoma in the polyp is associated with a similar tumor elsewhere in the corpus (114,116), although the carcinoma is confined to the polyp in some cases (119). In our experience, the former is more common, and the tumor often involves both sites as one contiguous mass. The frequency of the various histologic subtypes of carcinomas arising in polyps seems similar to that of those arising in the endometrium in general, with endometrioid carcinomas being the most common, followed by serous, clear cell, and mucinous carcinomas and only rarely by other cancers, including MMMTs (114,119,120). CARCINOMAS ARISING IN ADENOMYOMAS Because atypicality is a definitional feature of atypical polypoid adenomyomas (APAs) (121,122) and at least some APAs seem to be related to hyperestrinism (123), it is not surprising that an endometrioid adenocarcinoma can rarely arise within an APA. Longacre et al. (124) found foci architecturally resembling well-differentiated adenocarcinoma confined to the APA in 45% of their cases; in none of their cases was there evidence of adenocarcinoma elsewhere in the endometrium. This subset of APAs was designated APAs of low malignant potential, because approximately 15% of them invaded the superficial myometrium in contrast to an absence of invasion in the usual APAs in the same study. More convincing evidence of the malignant potential of APAs is provided by reports of well-differentiated myoinvasive endometrioid adenocarcinoma that has abutted, and may have originated from, the APA (125127). Indeed, in one study currently available only in abstract form (127), 6 of 15 APAs were associated with an endometrioid adenocarcinoma in the same uterus, three of which were myoinvasive; two of the latter seemed to arise from the APA. Although clearly rare, endometrioid carcinomas may also arise within adenomyomas of usual type (128). Kay et al. (129) have reported such a case, and we have recently seen another example. CARCINOMAS ARISING IN SEROSAL ENDOMETRIOSIS
FIG. 31. Endometrioid carcinoma has arisen and replaced approximately two thirds of a senile cystic polyp.
Because endometriosis is common on the uterine serosa and endometrioid carcinoma is the most common
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P. B. CLEMENT AND R. H. YOUNG pregnant women (135). Conservative hormonal management may be successful in young women with endometrioid carcinoma. In contrast, Duska et al. (130) have found that women with endometrial carcinoma who are 40 years old or younger and who are not obese (low body mass index) are more likely to have high-stage disease and a tumor with unfavorable histology such as serous or clear cell carcinoma. ASSOCIATION WITH OVARIAN ENDOMETRIOID CARCINOMA Approximately 5% of endometrioid carcinomas of the corpus are associated with a similar ovarian tumor (136,137). Our criteria for determining whether the tumors are separate primaries or are metastatic are presented in detail elsewhere (138), although this distinction may be difficult in some cases. The tumors are most often independent primaries, because tumor is usually confined to the two sites, and the prognosis is generally that of two stage I tumors (136,139141). In a recent Gynecologic Oncology Group study (137) of 74 cases of simultaneously detected endometrial and ovarian carcinomas, 91% of the uterine tumors and 88% of the ovarian tumors were endometrioid; 88% of the patients had endometrioid carcinoma in both sites. Analyzing the total series of cases, of the 69% of the women who had disease confined to the two sites (all histologic types), the recurrence rate was 10% in contrast to 27% in those with metastases outside the uterus and ovary. The histologic grade also distinguished groups of patients with different probabilities of recurrence at 5 years: 8% for those patients with only grade 1 tumors at both sites and 22.4% for those with a higher grade tumor in either the endometrium or ovary. PERITONEAL KERATIN GRANULOMAS Peritoneal granulomas can form in response to implants of keratin derived from endometrial carcinomas with squamous differentiation (142,143). In some cases, the granulomas are grossly visible at the time of intraoperative or pathologic examination. The granulomas consist of laminated deposits of keratin, sometimes with ghost squamous cells, surrounded by foreign-body giant cells and fibrous tissue (Fig. 33). Follow-up data on these patients suggest that the granulomas have no prognostic significance, although they should be thoroughly sampled by the gynecologist and carefully examined microscopically to exclude the presence of viable tumor. Rarely, large masses of exfoliated keratin are unassociated with a granulomatous reaction, although there may
tumor to arise in endometriosis, it is perhaps surprising that there are no reports in the literature, to our knowledge, of endometrioid carcinomas arising from uterine serosal endometriosis. The fact that this phenomenon occurs, albeit rarely, is documented by a recent case seen by us and illustrated in Figure 32. CARCINOMAS IN YOUNG WOMEN Endometrioid adenocarcinomas occasionally occur in women younger than 40 years of age (130), and it has been estimated that tumors in this age group account for approximately 3% of endometrial carcinomas (131,132). Most of these tumors occur in the fourth decade, but they are occasionally seen in the second and third decades (133,134). Most such tumors are estrogen-related, lowstage, well-differentiated endometrioid carcinomas, often arising in women who are anovulatory (e.g., those with the polycystic ovary syndrome), nulliparous, obese, or combinations thereof. Rare tumors have arisen in
FIG. 32. Endometrioid carcinoma on uterine serosa that was associated with serosal endometriosis and is assumed to have arisen from it.
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verse prognostic features, whereas other studies have found an increase in the frequency of high-grade and/or myoinvasive endometrioid carcinomas, serous carcinomas, and clear cell carcinomas (148,149). Some of the tamoxifen-related carcinomas have arisen within endometrial polyps, lesions that are also increased in frequency in tamoxifen-treated women. Cohen et al. (150) found that endometrial polyps in tamoxifen-treated women are more likely to harbor a carcinoma than polyps from untreated women. Additionally, Silva et al. (149) have postulated that the high frequency of serous and clear cell adenocarcinomas in their study of tamoxifen-treated patients may be a result of the fact that these tumors more often arise from polyps than does endometrioid carcinoma. Currently, there seems to be no consensus as to whether tamoxifen-induced endometrial carcinomas have the usual subtype distribution of carcinomas in untreated women (151) or whether they contain a larger proportion of tumors with a poor prognosis (152). BENIGN MIMICS OF ENDOMETRIOID CARCINOMA The primary purpose of this review has been to focus on the morphology of endometrioid carcinoma rather than on its differential diagnosis, but some remarks on the latter have been made when appropriate. A few additional remarks are indicated, however, on some of the various benign mimics of endometrial carcinoma (Table 5). Many of these lesions are more likely to result in the misdiagnosis of a nonendometrioid carcinoma of the corpus and thus are covered in our upcoming review, which focuses on those tumors (10). Nevertheless, for the sake of completeness, we list all mimics of endometrial carcinoma in Table 5 but comment here only on the first 10 entities. In Table 5, the benign lesion and variant of endometrial carcinoma with which it is most commonly confused are matched, but there is some overlap. For example, papillary proliferations are sometimes misdiagnosed as endometrioid carcinoma and sometimes as serous carcinoma. Much of the interest in this area dates from 1980 when the seminal contribution of Hendrickson and Kempson (153) on the endometrial epithelial metaplasias was published. Only a few of the lesions listed in Table 5 are metaplasias, because we have only listed those metaplasias and other lesions that cause diagnostic difficulty in our experience. For example, we have not listed eosinophilic metaplasia, because the mere presence of cells with abundant eosinophilic cytoplasm within an otherwise unremarkable background should not be problematic. The occurrence of eosinophilic metaplasia in an
FIG. 33. Peritoneal keratin granuloma. Aggregates of keratin are associated with foreign body giant cells. No viable glandular epithelial cells are evident.
be a brisk nonspecific inflammatory response. It should be noted that the number of patients with long-term follow-up is still small. TAMOXIFEN-ASSOCIATED ENDOMETRIAL CARCINOMAS Numerous studies over the past decade have found that tamoxifen, a drug widely used in the adjuvant therapy of breast carcinoma, can have an estrogenic effect on the endometrium and that chronic tamoxifen therapy may be associated with the development of a variety of endometrial lesions, including endometrial adenocarcinoma (144147). Many but not all studies have found that the cumulative dose and duration of tamoxifen treatment affect the relative risk of endometrial carcinoma. Most of the endometrial adenocarcinomas arising in tamoxifen-treated women have been well-differentiated endometrioid adenocarcinomas that lack ad-
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P. B. CLEMENT AND R. H. YOUNG diagnosis of a normal, hyperplastic, or carcinomatous endometrium rather than the nature of the cytoplasm or various other associated findings that may be present. A possible exception to the foregoing is the presence of abundant bland mucinous epithelium in an endometrial curettage specimen, a finding that should raise the possibility of a well-differentiated endometrial mucinous carcinoma. A number of findings related to artifactual disruption of normal or even atrophic endometrium can be confused with endometrioid carcinoma. One of these curettagerelated artifacts occurs when strips of endometrial surface epithelium fragmented during curettage of an atrophic endometrium can appear papillary (Fig. 34), potentially suggesting a papillary carcinoma. The bland cytology and dense atrophic endometrial stroma are diagnostic aids. Similarly, curettage-related fragmentation and compaction of normal proliferative glands can sometimes be confused with hyperplasia or even welldifferentiated carcinoma (Fig. 35). The phenomenon
TABLE 5. Benign endometrial lesions or processes that may cause misdiagnosis of endometrial carcinoma
Variant(s) of endometrial carcinoma potentially mimicked Endometrioid Endometrioid Endometrioid Endometrioid Endometrioid Endometrioid Endometrioid Endometrioid or squamous cell Endometrioid Endometrioid Villoglandular endometrioid or serous Mucinous Mucinous Serous Serous or clear cell
Benign entity Artifactual (curette-induced) Pseudopapillarity of atrophic endometrium Compaction of normal endometrial glands Telescoping* Menstrual-associated collapse with glandular crowding and regeneration Intravascular menstrual endometrium Adenomyosis with atrophic stroma Intravascular adenomyosis Florid squamous metaplasia Atypical polypoid adenomyoma Radiation atypia Polyps with epithelial proliferations Papillary proliferation
Mucinous metaplasia Mucinous metaplasia Syncytial change (papillary syncytial metaplasia) Hobnail cells, after curettage, infarct-associated, intrauterine deviceassociated Arias-Stella reaction Clear cell change of pregnancy Compact endometrial stromal cells with menses or as component of atrophic endometrium Florid inflammatory reaction (lymphoma-like lesion) Malakoplakia Decidua Mesothelial cells Histiocytic nodules Intermediate trophoblast Cytotrophoblast and syncytiotrophoblast
Serous or clear cell Clear cell Small cell
Undifferentiated Undifferentiated Undifferentiated or signet-ring cell Undifferentiated Undifferentiated Squamous cell or undifferentiated Undifferentiated or giant cell
* Telescoping causes confusion primarily (perhaps exclusively) with hyperplasia (see text). Similar changes in fragments of endocervical polyps procured during performance of an endometrial curettage or biopsy may also be problematic as may cervical microglandular hyperplasia or even prominent packed aggregates of endocervical glands with or without squamous metaplasia.
otherwise normal or hyperplastic endometrium or in an endometrioid carcinoma illustrates that whether an alteration is metaplasia or another type of benign lesion, consideration of the background is important, indeed, sometimes crucial in the overall interpretation. What is generally important is whether the architectural and other cytologic features of an endometrial specimen merit a
FIG. 34. Vigorous curettage of an atrophic endometrium has resulted in a pseudopapillary arrangement that may be confused with villoglandular endometrioid carcinoma.
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tation rests on identifying the glandular component as lacking the criteria required for a diagnosis of carcinoma. The APA (121,122) definitionally contains atypical glands and smooth muscle, the appearance of which, especially in a curettage specimen, can be mistaken for myoinvasive endometrioid adenocarcinoma. The correct diagnosis rests on the absence of overtly malignant features in the glands and appreciation of the fact that the smooth muscle of the APA is more cellular and disorganized than that of normal myometrium. Moreover, if myoinvasive carcinoma were present in such a specimen, one would also expect to see fragments of carcinoma lying free and unassociated with smooth muscle. Radiation-induced atypia in benign glands can potentially be misinterpreted as endometrioid carcinoma. The presence of architecturally normal glands lined by epithelial cells with nuclei that vary from bizarre to relatively normal, an absence of mitotic figures, the presence of radiation-type stromal fibroblasts in some cases, and,
FIG. 35. Artifactual compaction of normal proliferative glands that may be confused with hyperplasia or even well-differentiated carcinoma.
aptly referred to as telescoping should not realistically suggest carcinoma but is included for the sake of completeness in Table 5 as another curettage-induced phenomenon. We have certainly seen it raise the possibility of hyperplasia, but the background endometrium is almost invariably normal and there is no cytologic atypia. The stromal breakdown associated with menstruation often results in glandular crowding, regenerative epithelial atypia, and syncytial change (154), a combination of findings that can sometimes be misdiagnosed as carcinoma. Similarly, menstrual endometrium can be found in vascular spaces, and this is occasionally a striking phenomenon (Fig. 36) (155). Indeed, we have seen one case in which this finding was misinterpreted as an endometrial adenocarcinoma with extensive myometrial invasion with prominent vascular invasion. The presence of adenomyotic foci in blood vessels can also cause diagnostic difficulty (156), but awareness of this phenomenon, the presence of intravascular adenomyotic stroma, and the usually conspicuous adenomyosis in the adjacent myometrium facilitate the diagnosis. Metaplastic squamous epithelium of morular type, which characterizes the so-called adenoacanthoma, may also be seen in atypical hyperplasia (157) and rarely in an otherwise unremarkable endometrium. Correct interpre-
FIG. 36. Menstrual endometrium within myometrial blood vessels from a case that was thought to represent intravascular carcinoma.
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P. B. CLEMENT AND R. H. YOUNG ciliated cell, squamous, and hobnail cell metaplasia. Awareness that this lesion tends to occur within polyps and recognition of its characteristically bland cytologic features should facilitate its recognition. It should be noted that this lesion can also occur in the endometrium in the absence of, or at a distance from, polyps. Finally, we have seen cases of benign glands deep within the myometrium, a finding also described by Cullen (3). If this finding were striking, it could be misinterpreted as a minimal deviation pattern of endometrioid adenocarcinoma as discussed earlier. We believe that this finding likely represents atrophic adenomyosis in which the adenomyotic stroma has disappeared in most cases. This interpretation is favored by the finding in otherwise similar cases of thin rims of atrophic adenomyotic stroma around some of the glands as illustrated by Cullen (his Fig. 246) (3). More superficial glands unassociated with any evidence of adenomyosis may be a reflection of the common irregular junction between the basal endometrium and myometrium. METASTATIC CARCINOMAS THAT MAY MIMIC ENDOMETRIOID CARCINOMA Excluding metastatic endometrioid carcinoma from the ovary, the only metastatic carcinoma that can pose some diagnostic difficulty with any measurable frequency is metastatic colonic carcinoma, because as in the ovary, these tumors often have a pseudoendometrioid appearance. Morphologic features that would favor this diagnosis compared with that of primary endometrioid carcinoma include a degree of myometrial involvement exceeding that in the endometrium, unusually prominent lymphatic invasion, high-grade nuclear features in a tumor that is architecturally well differentiated, numerous mitotic figures, and a CK7-negative/CK20-positive immunoprofile. REFERENCES
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Revisión Carcinoma de Endometrio

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Advances in Anatomic Pathology Vol. 9, No. 3, pp. 145184 2002 Lippincott Williams & Wilkins, Inc.

Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002

ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS

TABLE 1. Endometrioid carcinomas of the uterine corpus

Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002

Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002

ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS

FIG. 6. Endometrioid carcinoma with prominent stromal foamy histiocytes.

Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002

Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002

ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS

FIG. 8. Villoglandular endometrioid carcinoma invading the myometrium.

Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002

Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002

Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002

P. B. CLEMENT AND R. H. YOUNG

ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS

ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS

FIG. 15. ies.

Endometrioid carcinoma with occasional psammoma bod-

FIG. 16. plasia.

Endometrioid carcinoma with striking stromal osteoid meta-

Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002

Endometrioid carcinoma with a desmoplastic stroma.

ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS

Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002

P. B. CLEMENT AND R. H. YOUNG

ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS

P. B. CLEMENT AND R. H. YOUNG

Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002

ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS

Serous or clear cell Clear cell Small cell

ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS

Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002

Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002

ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS

Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002

P. B. CLEMENT AND R. H. YOUNG

Advances in Anatomic Pathology, Vol. 9, No. 3, May, 2002

ENDOMETRIOID CARCINOMA OF THE UTERINE CORPUS

114. 115. 116. 117.

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P. B. CLEMENT AND R. H. YOUNG

144. 145. 146. 147.

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