Performance Characteristics of Endometrial Sampling in Diagnosis of Endometrial Carcinoma.

Outpatient endometrial biopsy can give false-negative results, with a 0.9% reported posttest probability for endometrial carcinoma (EC) after a negative result. Our objective was to determine if there has been any improvement in the performance characteristics of endometrial biopsy over the last 15 yr. All hysterectomy specimens with a diagnosis of EC or atypical hyperplasia (AH), reported between May 2011 and May 2015, were identified and cross-referenced for any negative endometrial sampling results during the 5 yr before hysterectomy. Negative endometrial samples were defined as either benign findings or insufficient/nondiagnostic, excluding those diagnosed as AH or EC and those for which follow-up sampling was recommended because of atypia. Of 1677 hysterectomy specimens showing AH or EC there were previous negative biopsies in 172: 116 benign and 56 insufficient/nondiagnostic. Over the same period 22,875 negative endometrial biopsy specimens were reported in our region. The posttest probability of having EC or AH in the hysterectomy specimen, given a negative endometrial biopsy result, was 0.74%. In a subset of 90 cases in which a negative biopsy was followed by a diagnosis of AH or EC in a hysterectomy specimen, the slides were independently reviewed. There were no cases where a diagnosis of carcinoma was missed. In 12 samples atypia or possible atypia was identified, and the level of agreement with the original diagnosis was excellent κ=0.83±0.05. In a prospective comparison of examination of 3 levels from each block versus a single slide in 319 cases, the routine preparation of additional slides did not yield clinically significant information. Although there has been evolution in the diagnostic criteria for AH and for recognition of morphologically subtle forms of AH or EC, our results demonstrate a significant lack of sensitivity of outpatient endometrial sampling in the diagnosis of endometrial malignancy/premalignancy. The sensitivity problems are mainly attributable to failure to sample abnormal endometrium. Independent review of slides or examination of additional levels did little to increase the diagnostic yield.

Endometrial Carcinomas With Clear Cells: A Study of a Heterogeneous Group of Tumors Including Interobserver Variability, Mutation Analysis, and Immunohistochemistry With HNF-1ß.

Endometrial clear cell carcinoma (CC) is an uncommon tumor and often carries a poor prognosis. It has histologic features that overlap with other endometrial carcinomas and is frequently misclassified. Accurate classification is crucial, however, to improve treatment options. The objectives of this study were (1) to assess diagnostic interobserver variability among 5 gynecologic pathologists for tumors originally diagnosed as CC or with a component of CC (n=44); (2) to determine the utility of immunohistochemical markers estrogen receptor and HNF-1ß; and (3) to detect mutations in select genes. Clinical data and morphologic features were also recorded. Agreement among reviewers was only moderate: only 46% of the original CC remained classified as such. After reclassification, estrogen receptor was positive in 8% of CC, 67% of endometrioid carcinomas (EC), and 47% of serous carcinomas (SC). Sensitivities of HNF-1ß in CC, SC, and EC were 62%, 27%, and 17%, respectively, whereas specificity for CC versus EC or SC was 78%. Mutations in PIK3CA, PIK3R1, PTEN, KRAS, and NRAS were detected in 41% of 37 cases that had adequate material for study. At least 1 mutation was identified in 33% of CC, 67% of EC, and 33% of SC. This group of patients had poor outcomes: 72% of the patients with follow-up information had died of disease. In summary, this study suggests that the current pool of CC is a heterogeneous group of tumors from the morphologic, immunophenotypic, and molecular point of views and that only a percentage of them represent true CC.

Recurrent intestinal mucinous borderline tumors of the ovary: a report of 5 cases causing problems in diagnosis, including distinction from mucinous carcinoma.

Intestinal mucinous borderline tumors (IMBTs) of the ovary are generally associated with a highly favorable outcome and rarely recur. We describe 5 cases of IMBT initially treated by cystectomy or by salpingo-oophorectomy that was likely incomplete, with subsequent recurrences. Three cases were received in consultation, and in each of these, the clinical and intraoperative findings were worrisome for mucinous carcinoma, and diagnostic difficulty was encountered by the referring pathologist. The patient age ranged from 28 to 69 (median 53) yrs. All tumors were clinically Stage I at presentation; in at least 3 cases, extensive adhesiolysis was required during their removal. A pathologic diagnosis of IMBT was made in 4 cases; the remaining tumor was inadequately sampled (3 blocks from a 7.5-cm tumor showed predominantly benign to focally borderline mucinous epithelium). A total of 8 recurrences, all as IMBT, developed at mean follow-up of 26 (range, 6-102) mo; 6 of these occurred within ≤2 yr. In 4 cases, removal of recurrent tumor required an extensive operation because of bowel and/or vaginal involvement. Residual ovarian stroma was identified in all recurrences. There was no evidence of invasive mucinous carcinoma, pseudomyxoma peritonei, or a primary tumor elsewhere (including appendix) in any of the cases. Our findings indicate that patients with IMBTs who undergo cystectomy or oophorectomy requiring adhesiolysis are at increased risk of recurrence, which may occur early, be multiple, and potentially require extensive resection if sites such as bowel or vagina are involved. Recurrences of IMBT that develop in this setting likely represent regrowth of incompletely resected IMBT, or arise within residual ovarian tissue. This is the first detailed clinicopathologic study of such cases.

Selected topics in peritoneal pathology.

This essay considers selected peritoneal lesions many of which were the subject of studies coauthored by Dr Robert E. Scully. His article on multilocular peritoneal inclusion cysts has largely led to these lesions being considered non-neoplastic, eschewing the term cystic mesothelioma. These cysts are often associated with reactive mural mesothelial proliferations that can potentially lead to a misdiagnosis of mesothelioma. Clinical findings, such as a common association with endometriosis or prior operations, can prompt consideration of a reactive lesion. Mesothelial hyperplasia may be difficult to distinguish, when florid, from mesothelioma but a variety of gross and microscopic features will aid their recognition. Nodular peritoneal aggregates of histiocytes (sometimes admixed with mesothelial cells) may occasionally be a striking finding that can be misdiagnosed as a metastasis if the patient has a known neoplasm. Appreciation of their bland nuclear features and histiocytic nature, confirmed by immunohistochemical markers, facilitate the diagnosis. Various forms of peritonitis are briefly considered including sclerosing peritonitis, a process sometimes associated with luteinized thecomas (thecomatosis) of the ovaries, an entity first appreciated by Dr Scully. Mesotheliomas are briefly reviewed emphasizing the caution that should be used in applying the designation "well-differentiated papillary mesothelioma." Many interpret the latter as benign, but multifocal lesions must be thoroughly examined histologically because of potential overlapping features with malignant mesothelioma. The morphologic spectrum of malignant mesothelioma and its usually straightforward distinction from müllerian neoplasms is considered, as is its occasional presentation as a dominant ovarian mass. The spectrum of low-grade serous peritoneal neoplasms including the "psammocarcinoma" is reviewed. Finally, various benign müllerian lesions, particularly endometriosis and endosalpingiosis, may be conspicuous in peritoneal specimens and sometimes are grossly striking. The usual presence of benign endometrioid epithelium and stroma should facilitate the correct diagnosis of endometriosis, but in cases in which the stroma is atrophic or the sole component (stromal endometriosis), diagnostic problems may arise.

Reproducibility of histological cell type in high-grade endometrial carcinoma.

Subclassification of endometrial carcinoma according to histological type shows variable interobserver agreement. The aim of this study was to assess specifically the interobserver agreement of histological type in high-grade endometrial carcinomas, recorded by gynecological pathologists from five academic centers across Canada. In a secondary aim, the agreement of consensus diagnosis with immunohistochemical marker combinations was assessed including six routine (TP53, CDKN2A (p16), ER, PGR, Ki67, and VIM) and six experimental immunohistochemical markers (PTEN, ARID1A, CTNNB1, IGF2BP3, HNF1B, and TFF3). The paired interobserver agreement ranged from κ 0.50 to 0.63 (median 0.58) and the intraobserver agreement from κ 0.49 to 0.67 (median 0.61). Consensus about histological type based on morphological assessment was reached in 72% of high-grade endometrial carcinomas. A seven-marker immunohistochemical panel differentiated FIGO grade 3 endometrioid from serous carcinoma with a 100% concordance rate compared with the consensus diagnosis. More practically, a three-marker panel including TP53, ER, and CDKN2A (p16) can aid in the differential diagnosis of FIGO grade 3 endometrioid from endometrial serous carcinoma. Our study demonstrates that the inter- and intraobserver reproducibility of histological type based on morphology alone are mostly moderate. Ancillary techniques such as immunohistochemical marker panels are likely needed to improve diagnostic reproducibility of histological types within high-grade endometrial carcinomas.

Mutation of FOXL2 in granulosa-cell tumors of the ovary.

BACKGROUND: Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The pathogenesis of these tumors is unknown. Moreover, their histopathological diagnosis can be challenging, and there is no curative treatment beyond surgery. METHODS: We analyzed four adult-type GCTs using whole-transcriptome paired-end RNA sequencing. We identified putative GCT-specific mutations that were present in at least three of these samples but were absent from the transcriptomes of 11 epithelial ovarian tumors, published human genomes, and databases of single-nucleotide polymorphisms. We confirmed these variants by direct sequencing of complementary DNA and genomic DNA. We then analyzed additional tumors and matched normal genomic DNA, using a combination of direct sequencing, analyses of restriction-fragment-length polymorphisms, and TaqMan assays. RESULTS: All four index GCTs had a missense point mutation, 402C-->G (C134W), in FOXL2, a gene encoding a transcription factor known to be critical for granulosa-cell development. The FOXL2 mutation was present in 86 of 89 additional adult-type GCTs (97%), in 3 of 14 thecomas (21%), and in 1 of 10 juvenile-type GCTs (10%). The mutation was absent in 49 SCSTs of other types and in 329 unrelated ovarian or breast tumors. CONCLUSIONS: Whole-transcriptome sequencing of four GCTs identified a single, recurrent somatic mutation (402C-->G) in FOXL2 that was present in almost all morphologically identified adult-type GCTs. Mutant FOXL2 is a potential driver in the pathogenesis of adult-type GCTs.

DICER1 and FOXL2 Mutation Status Correlates With Clinicopathologic Features in Ovarian Sertoli-Leydig Cell Tumors.

Sertoli-Leydig cell tumors (SLCTs) are rare ovarian sex cord-stromal neoplasms. The only known recurrent genetic abnormality is DICER1 mutation, with rare mutations reported in FOXL2. We set out to establish a molecular classifier using DICER1 and FOXL2 somatic mutation status and clinicopathologic features in 42 SLCTs. Five tumors (12%) were well differentiated, 31 (74%) moderately differentiated, and 6 (14%) poorly differentiated. Eight (19%) had heterologous elements, and 2 (5%) showed retiform differentiation; all 10 were moderately differentiated. DICER1 RNase IIIb domain mutations were identified in 18/41 (44%; 17 moderately, 1 poorly differentiated), including all cases with retiform or heterologous elements. FOXL2 c.402C>G (p.C134W) mutation was identified in 8/42 (19%) tumors (5 moderately, 3 poorly differentiated). DICER1 and FOXL2 mutations were mutually exclusive. Median age for the cohort was 47 years (range, 15 to 90 y). Patients with DICER1 mutations were younger (median, 24.5 y; range, 15 to 62 y) than patients with FOXL2 mutation (median, 79.5 y; range, 51 to 90 y) (P<0.0001). Nine of 10 tumors with retiform or heterologous elements occurred in premenopausal patients (median, 26.5 y; range, 15 to 57 y). Patients with tumors that were wild type for DICER1 and FOXL2 (15/42, 37%) had an intermediate age (median, 51 y; range, 17 to 74 y). All tumors were FOXL2 positive by immunohistochemistry. Patients with FOXL2 mutation trended toward presenting more often with abnormal bleeding (P=0.13); DICER1-mutant patients trended toward having more androgenic symptoms (P=0.22). Our data suggest at least 3 molecular subtypes of SLCT with distinct clinicopathologic features: DICER1 mutant (younger, more androgenic symptoms, moderately/poorly differentiated, retiform or heterologous elements), FOXL2 mutant (postmenopausal, abnormal bleeding, moderately/poorly differentiated, no retiform or heterologous elements), and DICER1/FOXL2 wild type (intermediate age, no retiform or heterologous elements, including all well-differentiated tumors).

Primary endometrioid adenocarcinoma of the vagina: a clinicopathologic study of 18 cases.

Vaginal adenocarcinoma is the second most common primary cancer of the vagina, yet there has been very little study of most subtypes other than clear cell carcinoma. We reviewed 18 cases of primary vaginal endometrioid adenocarcinoma, in our experience the second most common subtype. The patients ranged from 45 to 81 years of age (mean 60). Most presented with vaginal bleeding, and had had a prior hysterectomy. Five had a history of unopposed estrogen therapy but none had a history of intrauterine diethylstilbestrol exposure. The tumors were at the vaginal apex in 10 cases, in the posterior wall in 3, the lateral wall in 3, and the anterior wall in 1. On microscopic examination, each of the tumors had a pure or predominant component of typical endometrioid adenocarcinoma. There was squamous metaplasia in 4 cases, mucinous metaplasia in 4, and prominent nonvillous papillae in 2. The tumors were grade 1 of 3 in 4 cases, grade 2 in 13, and grade 3 in 1. Eleven cases were FIGO stage I, 5 stage II, and 2 stage IV. Vaginal endometriosis was identified in 14 cases, and is important in indicating a primary vaginal tumor, rather than secondary spread from the endometrium. Other subtypes of adenocarcinoma (such as serous when the tumor has a papillary pattern) and atypical forms of endometriosis, including polypoid endometriosis, are the most common other differential diagnostic considerations. The prognosis seems to be good in low-stage patients, with 11 patients alive and well and 2 alive with recurrent disease.

Cellular fibromas of the ovary: a study of 75 cases including 40 mitotically active tumors emphasizing their distinction from fibrosarcoma.

Cellular fibroblastic tumors of the ovary are currently classified as either cellular fibroma (CF) or fibrosarcoma. The former are characterized by bland nuclei, 3 or fewer mitotic figures per 10 high-power fields (MFs/10 HPFs), and a low malignant potential, whereas fibrosarcomas usually have severe nuclear atypia, > or = 4 MFs/10 HPFs, and an aggressive clinical course. The prognosis of cellular fibromatous tumors with > or = 4 MFs/10 HPFs and low-grade cytology is not established and it is the purpose of this study to investigate that aspect. It has been our anecdotal experience that otherwise typical CFs with > or = 4 MFs/10 HPFs usually have a benign clinical course, suggesting that such tumors should be regarded as "mitotically active cellular fibroma" (MACF) rather than fibrosarcoma. Seventy-five cellular fibromatous neoplasms were analyzed to determine their clinicopathologic features and the appropriateness of "MACF" as a designation for otherwise typical CFs with > or = 4 MFs/10 HPFs. The mean age of patients with CF (n = 35, 0 to 3 MFs/10 HPFs) and MACF (n = 40, > or = 4 MFs/10 HPFs) was 51 and 41 years, respectively. Patients most commonly presented with symptoms related to a pelvic mass. All tumors were unilateral. The mean tumor size of CFs was 8.0 cm and 9.4 cm for MACFs. The majority of the tumors were solid; approximately one-third of them had a cystic component. Ovarian surface adhesions, involvement of the ovarian surface, or both, was present in 6% of CFs and 10% of MACFs. Eleven percent of CFs and 13% of MACFs were associated with extraovarian involvement. All tumors consisted of cellular, intersecting bundles of spindle cells with bland nuclear features. The mean highest mitotic count for MACFs was 6.7 MFs/10 HPFs (range 4 to 19 MFs/10 HPFs). Follow-up of 3 months to 12 years (mean 4.75 y) was available in 18 of the 40 patients with MACFs and was uneventful in all cases. We conclude that cellular fibromatous neoplasms with bland cytology and elevated mitotic counts are associated with favorable patient outcome and should be diagnosed as MACF rather than fibrosarcoma, which usually have moderate to severe atypia and elevated mitotic rates. As prior observations have shown that even typical CFs can occasionally recur locally, particularly if they are associated with rupture or adherence, long-term follow-up for patients with CFs and MACFs is appropriate.

Endometrioid carcinomas of the uterine corpus with sex cord-like formations, hyalinization, and other unusual morphologic features: a report of 31 cases of a neoplasm that may be confused with carcinosarcoma and other uterine neoplasms.

We describe a series of unusual endometrioid carcinomas (ECs) of the uterine corpus characterized in significant part by cords of epithelioid cells, spindle cells, and a hyalinized stroma that sometimes formed osteoid. These features, particularly when prominent, produced an appearance strikingly different from that of conventional EC, sometimes resulting in problems in differential diagnosis, especially with a malignant mullerian mixed tumor (carcinosarcoma). The 31 patients ranged in age from 25 to 83 years (mean, 52 years). The proportion within each stage were as follows: stage Ia, 9.7%, stage Ib, 45.2%, stage Ic, 9.7%, stage IIb, 16.1%, stage IIIc 3.2%, and stage IV, 3.2%. In 4 patients (12.9%), staging information was not available. On microscopic examination, typical EC, which accounted for 10% to 90% of the tumor, was admixed in 90% of cases with cords of epithelioid or spindle cells within a hyalinized stroma. In 3 cases, the tumor contained cords of cells without a hyalinized stroma. Areas with a diffuse growth of fusiform cells suggesting endometrial stromal cells were also occasionally seen in minor amounts. Seventy percent of the tumors exhibited squamous differentiation, and in 50% of the tumors there was a background of endometrial hyperplasia. Two thirds of the tumors were grade 2 and the remainder were grade 1. Vascular space invasion was identified in seven tumors. On immunohistochemical analysis, the typical EC component was strongly positive for keratin, whereas the keratin staining was more focal and variable in the epithelial cells in the cords. Muscle markers (desmin, actin), CD10, and inhibin were negative in the latter. Overexpression of p53 was found in only 1 case. Eighty-three percent of the patients were alive with no evidence of disease on follow-up (range, 2-115 months; mean, 34.4 months). The clinical features, including a typically low stage and generally good prognosis, and histologic findings are different from those of malignant mullerian mixed tumors that are characterized by both high-grade carcinomatous and sarcomatous components and an aggressive clinical course. Confusion with other neoplasms, particularly those with sex cord-like growth, such as uterine tumors resembling ovarian sex cord tumors and epithelioid smooth muscle tumors, may also arise. We refer to tumors with the features described herein as "corded and hyalinized endometrioid carcinomas," a designation that reflects their two most striking and consistent features. Corded and hyalinized endometrioid carcinomas are yet another example of the protean phenotype of endometrioid adenocarcinomas of the female genital tract that has been appreciated only in the last two decades.

Malignant peritoneal mesothelioma in women: a study of 75 cases with emphasis on their morphologic spectrum and differential diagnosis.

Seventy-five malignant mesotheliomas of the peritoneum in women were reviewed to highlight their morphologic spectrum. The patients ranged from 17 to 92 (mean, 47.4) years of age. The clinical presentation was usually abdominal or pelvic pain, abdominal swelling (sometimes due to ascites), or a pelvic mass. On microscopic examination, the majority of the tumors had only an epithelial morphology, but 4 were biphasic and 1 was sarcomatoid. The most common epithelial patterns were tubular and papillary (which often coexisted), but 5 tumors were purely diffuse; 2 had cells with abundant glassy eosinophilic cytoplasm (so-called deciduoid mesothelioma). The cells in the tubular and papillary patterns were generally cuboidal with scant to moderate amounts of eosinophilic cytoplasm. Nuclear atypia was usually only mild, although a minority of cases had moderate or even, occasionally, severe atypia. Many tumors had foci that, viewed in isolation, resembled so-called well-differentiated papillary mesothelioma, and accordingly that diagnosis should be made cautiously. Unusual features were lymphoid follicles (13 cases), striking myxoid stroma (5 cases), prominent foamy histiocytes (5 cases), and a striking vascular proliferation (1 case). The varied morphology of peritoneal malignant mesotheliomas may raise a broad differential diagnosis, but in most cases the resemblance to other tumors is limited. Histochemistry, immunohistochemistry, and electron microscopy may provide important aid, particularly when tissue is limited, but should be needed only occasionally.

Endometrial endometrioid adenocarcinoma with a deceptive pattern of spread to the uterine cervix: a manifestation of stage IIb endometrial carcinoma liable to be misinterpreted as an independent carcinoma or a benign lesion.

The prognosis of endometrial endometrioid adenocarcinoma is determined in part by stage; endocervical stromal involvement (stage IIB) imparts a worsened prognosis. We describe a deceptive pattern of stage IIB disease that mimics a primary endocervical glandular proliferation and may lead to understaging of endometrial endometrioid adenocarcinoma. Fifteen cases of endometrial endometrioid adenocarcinoma with a peculiar pattern of cervical involvement were identified from our consultation files. All cases were referred in consultation because of doubt about the nature of the cervical process and its relation to the corpus tumor; in a few instances, the cervical proliferation was considered possibly benign and in one case was misinterpreted as mesonephric hyperplasia. The patients ranged from 49 to 84 years in age (mean age 64.9 years). There was usually a grossly evident endometrial tumor. The cervix was unremarkable grossly in at least 11 patients. The cervical tumors were composed of variably shaped, often tubular glands with little or no stromal response and mainly invaded as widely spaced glands that often appeared deceptively benign. In 14 cases luminal secretions, mainly eosinophilic, were identified, often leading to consideration of a mesonephric lesion. Ten of the endometrial tumors were grade 1, four grade 2, and one grade 3. One was noninvasive, nine superficially invasive, and five deeply invasive. In four cases myoinvasion had, at least in part, a diffusely infiltrative pattern. The tumors in the cervix showed no in situ component and no definite surface involvement. Continuity with the corpus tumor could be demonstrated in 12 cases. Ten of the cervical tumors invaded more deeply than the endometrial tumor, four invaded to a similar depth, and only one was more superficial than its endometrial counterpart. The cervical and corpus tumors had a similar immunoprofile in nine cases: all were vimentin positive, eight estrogen positive and one negative, four carcinoembryonic antigen negative, and five with focal apical or rare cytoplasmic staining. This immunoprofile in conjunction with routine morphologic similarity between the two tumors and the usual documented continuity between them indicate that the cervical process represents spread from the endometrial endometrioid adenocarcinoma. It is important for both therapeutic and prognostic reasons that the cervical abnormality is not misinterpreted as a benign or malignant primary endocervical glandular process.

Endometrial stromal nodules and endometrial stromal tumors with limited infiltration: a clinicopathologic study of 50 cases.

Experience with endometrial stromal nodules (ESNs) is limited, and no series has been published since the frequent misdiagnosis of highly cellular leiomyomas as ESNs was highlighted. Additionally, although the entirely well-circumscribed margin of most ESNs readily allows a separation from endometrial stromal sarcomas with their typical permeative invasion, some tumors have greater irregularity of their margin than allowable for an ESN following the guidelines of Tavassoli and Norris, but without the typical, and usually extensive, infiltration of endometrial stromal sarcomas. These have been diagnosed by us descriptively as endometrial stromal tumors with limited infiltration. Three cases of this type and 47 ESNs that occurred in patients from 31 to 86 years (mean 53 years) were analyzed. The tumors were typically fleshy and at least in part yellow and ranged from 1.2 to 22 cm (mean 7.1 cm). Seven tumors had one to six focal margin irregularities; in four tumors these did not extend >3 mm beyond the main border of the tumor and were up to three in number. The other three (endometrial stromal tumors with limited infiltration) had four to six irregularities extending up to 9 mm beyond the main border of the tumor. Most neoplasms were densely cellular, but nine were hypocellular with areas that were fibrous, hyalinized, myxoid, edematous, or combinations thereof. The tumor cells almost always had scant cytoplasm, but in one tumor many cells had abundant eosinophilic cytoplasm. There was minimal cytologic atypia. Forty-four tumors had mitotic rates of up to 5 per 10 high power fields, but six had higher rates. Typical arterioles, some of which had hyalinized walls in nine cases, were numerous in all 50 tumors but were conspicuous on low-power examination in only 22. Larger, sometimes thick-walled vessels were seen in 37 tumors but were much less conspicuous than in highly cellular leiomyomas and were often present near the margin of the tumor. The cleft-like spaces of highly cellular leiomyomas were not a feature of these tumors. Twenty-three tumors showed variable degrees of smooth muscle differentiation and sex cord-like differentiation occurred in 12. Cysts were present in 17 tumors and infarct-type necrosis in 34, the latter sometimes causing initial concern for a malignant neoplasm. Follow-up information, available for 32 patients, including five patients whose tumor had some margin irregularity, ranged up to 214 months (mean 43.5 months). All patients were alive with no recurrence. Follow-up information was unfortunately not available for the two tumors with the greatest degree of infiltration. The major conclusions of our study are as follows: ESNs are characteristically soft and yellow; thorough sampling of their margin is mandatory; smooth muscle metaplasia is common and irregular interdigitation of stromal neoplasia with metaplastic smooth muscle may erroneously suggest myometrial infiltration; although typically densely cellular about 20% of ESNs are hypocellular and often fibrous; cellular neoplasms are often punctuated by hyaline plaques; sex cord-like differentiation, broad zones of necrosis and rarely epithelioid cells may complicate the microscopic appearance; typical arterioles are an important microscopic finding but are not always striking, particularly on low-power evaluation; the tumors may have a component of large blood vessels more typical of highly cellular leiomyomas, but they are not as conspicuous as in the latter and the clefts that are frequent in highly cellular leiomyomas are not a feature of ESNs.

Polypoid endometriosis: a clinicopathologic analysis of 24 cases and a review of the literature.

We describe 24 cases of polypoid endometriosis, most of which were referred because of problems in differential diagnosis, particularly distinction from a low-grade müllerian neoplasm. The patients were 23 to 78 years (mean 52.5 years) of age. Seven patients were on unopposed estrogen, four on combined estrogen-progestin therapy, and one patient had a synchronous ovarian thecoma. The most common clinical presentations were a pelvic mass, vaginal polypoid masses, and large bowel obstruction. In some cases, the intraoperative findings suggested a neoplasm. Sites of involvement in order of frequency included colon, ovary, uterine serosa, cervical and/or vaginal mucosa, ureter, fallopian tube, omentum, bladder, paraurethral and paravaginal soft tissue, and retroperitoneum. Multiple sites were involved in seven cases. Five cases occurred within ovarian or extraovarian endometriotic cysts. The lesions ranged up to 14 cm in size and formed polypoid, pink, gray or tan, masses. On microscopic examination, the polypoid masses were composed of an admixture of endometriotic glands and stroma. A variety of glandular architectural patterns were observed, sometimes in combination, most commonly cystic and noncystic simple hyperplasia, but also simple or complex hyperplasia with atypia, disordered proliferative, and cystic atrophy. Various types of epithelial metaplasia (tubal, mucinous, squamous, papillary syncytial metaplasia) were common. Hemorrhage, fibrosis, prominent thick-walled blood vessels, hemosiderin-laden histiocytes, and decidual change were also present in some cases. Eighteen cases were associated with usual (nonpolypoid) endometriosis. In one case, polypoid endometriosis merged with a mucinous borderline tumor of endocervical-type. In all but two cases, polypoid endometriosis lacked periglandular stromal hypercellularity, stromal atypia, and intraglandular stromal papillae, helping distinguish it from adenosarcoma. Focal intraglandular stromal papillae were noted in two cases with focal mild periglandular stromal hypercellularity in one of them, but no stromal atypia was present in either case. Follow-up data in 17 patients indicated that 15 patients were alive without evidence of residual disease, 1 was alive with residual endometriosis, and 1 died of other causes. In conclusion, polypoid endometriosis is a rare manifestation of endometriosis that may be mistaken for a neoplasm on clinical, intraoperative, or pathologic assessment. Some cases may be attributable to exogenous hormones or hyperestrinism and, like conventional endometriosis, some may evolve into a premalignant or, rarely, a neoplastic lesion. The main lesion in the differential is a müllerian (mesodermal) adenosarcoma.

An immunohistochemical analysis of endometrial stromal and smooth muscle tumors of the uterus: a study of 54 cases emphasizing the importance of using a panel because of overlap in immunoreactivity for individual antibodies.

The expression of desmin, h-caldesmon, calponin, CD10, CD34, CD99, inhibin, and keratin (AE1/3-Cam 5.2) was studied in 10 conventional leiomyomas, 9 highly cellular leiomyomas, 9 epithelioid smooth muscle tumors, 9 leiomyosarcomas, 10 endometrial stromal tumors (4 with smooth muscle metaplasia), and 7 uterine tumors resembling ovarian sex cord tumors (UTROSCTs). c-kit expression was tested in 10 endometrial stromal tumors, 7 UTROSCTs, and 9 leiomyosarcomas. Desmin was positive in almost all smooth muscle tumors except those of epithelioid type, which were positive in only about half of the cases. It also stained areas of smooth muscle differentiation in endometrial stromal tumors and five of seven UTROSCTs. h-caldesmon was positive in almost all nonepithelioid smooth muscle tumors and in areas of smooth muscle differentiation in endometrial stromal tumors; it was positive in only about half of the epithelioid smooth muscle tumors and negative in all UTROSCTs. Calponin was positive in most tumor types. CD10 was positive in nine of 10 endometrial stromal tumors and five of seven UTROSCTs, although very focally in the latter group. It was also expressed, however, in almost all leiomyosarcomas, almost 50% of highly cellular leiomyomas, and rarely in the other smooth muscle tumors. CD34 was negative in the tested tumors with rare exceptions. CD99 and inhibin were positive in four of seven and one of seven UTROSCTs. Keratin positivity was found in most (five of seven) UTROSCTs and occasionally in smooth muscle tumors (seven of 37). c-kit was negative in all endometrial stromal tumors, UTROSCTs, and leiomyosarcomas. The major conclusions of this study are as follows: 1) Pure endometrial stromal tumors are usually desmin negative. 2) In contrast to some previous studies, CD10 expression was often seen in smooth muscle tumors, including most leiomyosarcomas and almost half of highly cellular leiomyomas. As a result, a panel of CD10, h-caldesmon, and desmin should be used and will distinguish endometrial stromal tumors from highly cellular leiomyomas in most cases. 3) In contrast to a previous study, no significant differences in immunoreactivity were seen between h-caldesmon and desmin in tumors with smooth muscle differentiation. 4) The absence of h-caldesmon in UTROSCTs helps separate them from epithelioid smooth muscle tumors. 5) UTROSCTs may express epithelial, stromal, and smooth muscle markers, suggesting divergent differentiation. 6) Our study shows less frequent inhibin expression in the sex cord-like elements of the UTROSCTs than in other studies. 7) c-kit may help distinguish metastatic endometrial stromal tumors of the uterus (c-kit negative) from gastrointestinal stromal tumors (c-kit positive). 8) CD34, CD99, and keratin have no or minimal role in this area, but keratin positivity in smooth muscle tumors should not lead to their confusion with epithelial tumors.

Mesodermal (müllerian) adenosarcoma of the ovary: a clinicopathologic analysis of 40 cases and a review of the literature.

Forty cases of mesodermal adenosarcoma of the ovary occurred in women 30-84 years of age (mean 54 years). Abdominal discomfort and distension were the usual complaints. All the patients were treated with an oophorectomy, which was accompanied by a hysterectomy in 85%, a contralateral oophorectomy in 65%, and nonsurgical therapy in 28%. Tumor rupture occurred at or before the operation in 67% of the cases. Twenty-six tumors were stage I, 11 stage II, and 3 stage III. The tumors were unilateral in 97.5% of the cases and 5.5-50 cm (mean 14 cm) in greatest dimension; most of the tumors were predominantly solid but contained numerous small cysts. Microscopic examination revealed sarcomatous overgrowth in 12 tumors. Sex cord-like elements were present in six tumors (including four with sarcomatous overgrowth) and heterologous elements in five (including two with sarcomatous overgrowth). The highest mitotic index of the sarcomatous component was 1-25 (mean 6) mitotic figures per 10 high power fields. Only 6 of 26 women (23%) who were followed postoperatively for > or=5 years were free of tumor. In the other 20 patients recurrent tumor appeared at 0.4-6.6 years (mean 2.6 years) after operation as pure sarcoma (low grade or high grade) or adenosarcoma (with or without sarcomatous overgrowth). Eight women had additional recurrences, and four women had blood-borne metastases. One patient was alive at 15.7 years after the excision of pulmonary metastases. The 5-, 10-, and 15-year survival rates were 64%, 46%, and 30%, respectively. Age <53 years, tumor rupture, a high grade, and the presence of high-grade sarcomatous overgrowth appeared to be associated with recurrence or extraovarian spread. Ovarian adenosarcomas have a worse prognosis than uterine adenosarcomas, presumably because of the greater ease of peritoneal spread. Many of the tumors caused problems in differential diagnosis.

Primary intestinal-type glandular lesions of the vagina: clinical, pathologic, and immunohistochemical features of 14 cases ranging from benign polyp to adenoma to adenocarcinoma.

Primary intestinal-type glandular lesions of the vagina are rare. We report a series of 14 lesions, including 1 intestinal-type polyp without neoplastic features, 3 adenomas (2 with high-grade dysplasia), and 10 adenocarcinomas. Patients ranged in age from 20 to 86 years (mean 60 y) and presented with vaginal bleeding or a mass. No history of diethylstilbestrol exposure, adenosis, or endometriosis was elicited in any patient. The lesions were mostly polypoid, small (0.8 to 2.0 cm), and located in the posterior (6 cases) and lower (7 cases) vagina. One carcinoma metastasized to a para-aortic lymph node; the others were confined to the vagina. The neoplasms exhibited histologic features identical to those seen in primary large intestinal tumors, including variable numbers of goblet cells and in 1 case neuroendocrine cells. Five of the adenocarcinomas contained areas consistent with a precursor adenoma. In 3 cases, a benign urothelium-lined duct was adjacent to the lesion, and in 2 patients benign intestinal-type epithelium was present; no other potential benign precursor lesions were seen. Immunohistochemical analysis was performed on 6 cases; the tumors were positive for CDX-2 (6/6), CK20 (5/6), CEA (5/5), CK7 (4/6), and CA-125 (2/4) and were negative for ER (0/6) and p16 (0/2). Clinical outcome data were available in 3 patients with adenocarcinomas; 1 died of disease in <1 year, and 2 were alive with no evidence of disease at 2 and 7 years. The pertinent literature is reviewed, and the potential origin and differential diagnosis of these lesions are discussed.

Papillary proliferation of the endometrium: a clinicopathologic study of 59 cases of simple and complex papillae without cytologic atypia.

Papillary proliferation of the endometrium (PPE) without cytologic atypia is uncommon and has only been studied in detail by Lehman and Hart in 2001. On histologic examination, PPE ranges from simple papillae with fibrovascular cores, often involving the surface of endometrial polyps, to complex intracystic proliferations; some consider the latter to be analogous to nonatypical complex hyperplasia. To further characterize PPE, with emphasis on the risk of and features associated with concurrent or subsequent neoplasia, the clinicopathologic features of 59 cases without cytologic atypia were studied. The cases were classified into 2 groups according to the degree of architectural complexity and extent of proliferation. Group 1 consisted of those with localized simple papillae. Simple papillae were defined as those with short, predominantly nonbranching stalks; those with occasional secondary branches and/or detached papillae were also included in this group. Localized proliferations were those with 1 or 2 foci involving the surface or the subjacent glands of polyps or nonpolypoid endometrium. Group 2 consisted of those with complex papillae and/or those with diffuse and crowded intracystic papillae. Complex papillae were those with either short or long stalks, with frequent secondary and complex branches. Diffuse proliferation was defined as presence of 3 or more foci within a specimen or involvement of >50% of the endometrial polyp by simple or complex PPE. Any coexistent or subsequent hyperplasia of conventional type (World Health Organization classification) or adenocarcinoma was recorded. The age of patients ranged from 23 to 82 years (median, 53 y); 36 (61%) were postmenopausal. The majority presented with abnormal vaginal bleeding. Sixteen patients (27%) were receiving hormonal preparations including 5 who were treated with a progestogen for preexisting endometrial hyperplasia or low-grade endometrioid adenocarcinoma. The histologic diagnosis of PPE was made in 49 biopsies and in 10 hysterectomy specimens. Thirty-six cases (61%) were classified as group 1 and 23 (39%) as group 2. In 47 cases (80%), there was a coexisting endometrial polyp, 39 (66%) of which were involved by the PPE. Fifty-three cases (90%) had coexisting epithelial metaplastic changes, 41 (77%) of which were involved by the PPE. The most common type of metaplasia was mucinous (41 of 59 cases, or 69%). Follow-up information was known for 46 patients (78%). Coexistent or subsequent nonatypical and atypical hyperplasia was found in 8 (17%) and 6 cases (13%), respectively. In 6 of the 46 cases (13%), a low-grade endometrioid adenocarcinoma was present either in the original specimen or during follow-up. In contrast to group 1 PPE, those with group 2 features were significantly associated with concurrent or subsequent premalignant lesions (nonatypical and atypical hyperplasia) or carcinoma (P<0.0001). This study indicates that localized and architecturally simple PPEs confined to a completely removed polyp are usually associated with a benign outcome and may be appropriately labeled as "benign papillary proliferation of the endometrium." Lesions with architecturally complex papillae, especially when extensive, have an increased risk of concurrent or subsequent endometrial hyperplasia and carcinoma and should probably be regarded as analogous to atypical complex hyperplasia, and the term "complex papillary hyperplasia" is appropriate. As the distinction between simple and complex PPE may be difficult in small endometrial aspirational samples, consideration for curettage should be given to ascertain whether the lesion has been completely removed.