Endometrial carcinoma risk among women diagnosed with endometrial hyperplasia: the 34-year experience in a large health plan.

Classifying endometrial hyperplasia (EH) according to the severity of glandular crowding (simple hyperplasia (SH) vs complex hyperplasia (CH)) and nuclear atypia (simple atypical hyperplasia (SAH) vs complex atypical hyperplasia (CAH)) should predict subsequent endometrial carcinoma risk, but data on progression are lacking. Our nested case-control study of EH progression included 138 cases, who were diagnosed with EH and then with carcinoma (1970-2003) at least 1 year (median, 6.5 years) later, and 241 controls, who were individually matched on age, date, and follow-up duration and counter-matched on EH classification. After centralised pathology panel and medical record review, we generated rate ratios (RRs) and 95% confidence intervals (CIs), adjusted for treatment and repeat biopsies. With disordered proliferative endometrium (DPEM) as the referent, AH significantly increased carcinoma risk (RR=14, 95% CI, 5-38). Risk was highest 1-5 years after AH (RR=48, 95% CI, 8-294), but remained elevated 5 or more years after AH (RR=3.5, 95% CI, 1.0-9.6). Progression risks for SH (RR=2.0, 95% CI, 0.9-4.5) and CH (RR=2.8, 95% CI, 1.0-7.9) were substantially lower and only slightly higher than the progression risk for DPEM. The higher progression risks for AH could foster management guidelines based on markedly different progression risks for atypical vs non-atypical EH.

Uterine myxoid leiomyosarcoma with widespread metastases in a cat.

A 10-year-old domestic shorthair cat was spayed to remove bilateral ovarian masses and an enlarged uterus. Both ovaries were effaced by large, irregular, firm, glistening, white cystic masses filled with clear viscous fluid. The uterine lumen was filled with copious amounts of clear viscous fluid, and the uterus contained multiple, firm, glistening, white nodules. Histologic examination revealed an invasive spindle cell neoplasm with features of malignancy, and extensive hypocellular areas containing an alcian blue-positive myxoid matrix. Tumor cells expressed caldesmon, alpha-smooth muscle actin, and estrogen receptor but were negative for desmin. The animal was euthanized 1 month later because of suspected local tumor recurrence. At necropsy, the abdominal cavity contained 120 ml of mucoid ascites; multiple tumor nodules were present in the abdominal and thoracic cavities. The clinical behavior and gross, microscopic, and immunohistochemical findings established a diagnosis of myxoid leiomyosarcoma.

Molecular genetic analysis of appendiceal mucinous adenomas in identical twins, including one with pseudomyxoma peritonei.

Pseudomyxoma peritonei (PMP) is a clinical syndrome characterized by mucinous ascites and peritoneal lesions composed of histologically bland to low-grade adenomatous mucinous epithelium within pools of extracellular mucin, often with an associated mucinous adenoma of the appendix. There is evidence that the peritoneal lesions in PMP are clonally derived from the associated appendiceal adenoma. Little is known about the molecular genetic alterations or hereditary factors involved in the development of appendiceal mucinous tumors and PMP. We report the only known example of appendiceal mucinous adenomas in identical twin brothers, one of whom developed PMP. We analyzed the status of the K-RAS and APC genes in these tumors using digital polymerase chain reaction and digital single nucleotide polymorphism (SNP) assay. Identical K-RAS mutations were detected in the appendiceal adenoma and peritoneal tumor from the twin with PMP, whereas the adenoma from the other twin harbored a different mutation. Digital SNP analysis demonstrated loss of heterozygosity of APC only in the adenoma from the twin without PMP but not from the appendiceal or peritoneal tumors of the twin with PMP. The adjacent normal tissue in each case retained both APC alleles. The K-RAS mutational analysis supports the view that PMP is clonally derived from the associated appendiceal mucinous adenoma. The lack of loss of heterozygosity of APC in the adenoma and peritoneal tumor from the twin with PMP suggests that loss of heterozygosity of APC is not necessarily involved in the development of all appendiceal adenomas or PMP. The different types of mutations in K-RAS and the different allelic status of the APC locus in the tumors from both twins suggest that mutation in K-RAS and loss of heterozygosity of APC occurs somatically in adenomas and is independent of the identical genetic background of the twins.

Patients with pseudomyxoma peritonei associated with disseminated peritoneal adenomucinosis have a significantly more favorable prognosis than patients with peritoneal mucinous carcinomatosis.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a poorly understood condition characterized by disseminated intraperitoneal mucinous tumors, often with mucinous ascites. The term PMP has been applied historically as a pathologic diagnostic term to both benign and malignant mucinous neoplasms that produce abundant extracellular mucin, resulting in a variable and poorly predictable prognosis. A recent study reported a pathologic classification that separated patients into prognostically distinct groups, but the follow-up was relatively short. METHODS: Long-term follow-up data were analyzed for a previously reported series of 109 patients with PMP to examine the prognostic utility of a pathologic classification system that divided patients into three groups: disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and peritoneal mucinous carcinomatosis with intermediate or discordant features (PMCA-I/D). Patients whose tumors were classified 25 DPAM (n = 65 patients) had disease that was characterized by histologically bland to low-grade adenomatous mucinous epithelium associated with abundant extracellular mucin and fibrosis, often with an identifiable appendiceal mucinous adenoma that was the source of the peritoneal lesions. Patients whose tumors were classified 25 PMCA (n = 30 patients) had disease that was characterized by peritoneal lesions that displayed the cytologic and architectural features of mucinous carcinoma associated with extracellular mucin, often with an identifiable invasive mucinous adenocarcinoma of the gastrointestinal tract. Patients whose tumors were classified 25 PMCA-I (n = 11 patients) had peritoneal lesions that combined the features of DPAM and PMCA derived from well differentiated mucinous adenocarcinomas associated with adenomas. Patients whose tumors were classified 25 PMCA-D (n = 3 patients) had markedly atypical appendiceal adenomas associated with peritoneal lesions similar to PMCA. RESULTS: Patients with DPAM had 5-year and 10-year survival rates of 75% and 68%, respectively (mean follow-up, 96 months; median follow-up, 104 months). Patients with PMCA and PMCA-I/D had a significantly worse prognosis, with 5-year and 10-year survival rates, respectively, of 50% and 21% for PMCA-I/D (mean follow-up, 58 months; median follow-up, 51 months) and 14% and 3% for PMCA (mean follow-up, 27 months; median follow-up, 16 months; P = 0.0001). CONCLUSIONS: The term PMP should be used only as a clinical descriptor for patients who have the syndrome of mucinous ascites accompanied by a characteristic distribution of peritoneal mucinous tumors with the pathologic features of DPAM. DPAM should be used as a pathologic diagnostic term for patients with the bland peritoneal mucinous tumors associated with ruptured appendiceal mucinous adenomas and PMP. These patients should not be diagnosed with carcinoma, because they have disease that is distinct pathologically and prognostically from PMCA.

Glial implants in gliomatosis peritonei arise from normal tissue, not from the associated teratoma.

Metaplasia of subcoelomic mesenchyme has been implicated, but not proven, in the pathogenesis of common gynecological diseases such as endometriosis and rarer entities such as leiomyomatosis peritonealis disseminata and gliomatosis peritonei (GP). GP is associated with ovarian teratomas and is characterized by numerous peritoneal and omental implants composed of glial tissue. Two theories to explain the origin of GP have been proposed. In one, glial implants arise from the teratoma, whereas in the other, pluripotent Müllerian stem cells in the peritoneum or subjacent mesenchyme undergo glial metaplasia. To address the origin of GP, we exploited a unique characteristic of many ovarian teratomas: they often contain a duplicated set of maternal chromosomes and are thus homozygous at polymorphic microsatellite (MS) loci. In contrast, DNA from matched normal or metaplastic tissue (containing genetic material of both maternal and paternal origin) is expected to show heterozygosity at many of these same MS loci. DNA samples extracted from paraffin-embedded normal tissue, ovarian teratoma and three individual laser-dissected glial implants were studied in two cases of GP. In one case, all three implants and normal tissue showed heterozygosity at each of three MS loci on different chromosomes, whereas the teratoma showed homozygosity at the same MS loci. Similar results were observed in the second case. Our findings indicate that glial implants in GP often arise from cells within the peritoneum, presumably pluripotent Müllerian stem cells, and not from the associated ovarian teratoma. This finding has important implications for more common gynecological entities with debatable pathogenesis, such as endometriosis, by definitively demonstrating the metaplastic potential of stem cells within the peritoneal cavity.

Morphology and DNA content analysis in the evaluation of first trimester placentas for partial hydatidiform mole (PHM).

Partial hydatidiform moles (PHM) have defined villous abnormalities and are usually triploid. Their diagnosis often can be made by morphology alone, without confirmation of ploidy, but considerable interobserver variability exists. Other genetic abnormalities such as trisomy can result in placentas with abnormal villous morphology (AVM) similar to that seen in PHMs, leading to diagnostic confusion. Twenty-three cases originally diagnosed as either PHM or AVM were independently reviewed by 3 pathologists. The consensus diagnosis was PHM in 14 cases and AVM in 9. Cases with AVM showed insufficient features for an unequivocal diagnosis of PHM. DNA content was determined on paraffin-embedded tissue by fluorescence in situ hybridization (fsSH) using a chromosome 1 centromeric probe and by image cytometry (IC). Thirteen of 14 cases (93%) classified as PHM were triploid by both FISH and IC. Seven cases of AVM were diploid by FISH and IC, and 1 was triploid by FISH and IC. One of the 9 cases of AVM was determined to be trisomy 18 by karyotyping. This good correlation of consensus diagnosis with ploidy data was much greater than that obtained based on original diagnoses. Comparative genomic hybridization performed on 6 cases of AVM showed gain of chromosome 21 in 1 case and loss of X in another. PHMs displayed at least 3 of the following histologic features: 2 discrete populations of villi, circumferential mild trophoblastic hyperplasia, trophoblastic inclusions, prominent scalloping of villi, cistern formation. Nontriploid AVMs displayed at most 2 of the diagnostic features of PHM. Placentas with genetic abnormalities other than triploidy can display morphologic changes suggestive of PHM and can be misinterpreted as such by routine light microscopy. Stringent application of morphologic criteria improves the correlation of the diagnosis of PHM with triploidy.

A binary architectural grading system for uterine endometrial endometrioid carcinoma has superior reproducibility compared with FIGO grading and identifies subsets of advance-stage tumors with favorable and unfavorable prognosis.

The International Federation of Gynecology and Obstetrics (FIGO) grading of uterine endometrial endometrioid carcinoma requires evaluation of histologic features that can be difficult to assess, including recognition of small amounts of solid growth, distinction of squamous from nonsquamous solid growth, and assessment of degree of nuclear atypia. The authors describe a novel, binary architectural grading system that uses low-magnification assessment of amount of solid growth, pattern of invasion, and presence of necrosis to divide endometrioid carcinomas into low- and high-grade tumors. The authors analyzed its performance for predicting prognosis and with respect to intra- and interobserver reproducibility. A total of 141 endometrioid carcinomas from hysterectomy specimens were graded according to the FIGO system, nuclear grading, and the binary architectural system. A tumor was classified as high grade if at least two of the following three criteria were present: (1) more than 50% solid growth (without distinction of squamous from nonsquamous epithelium); (2) a diffusely infiltrative, rather than expansive, growth pattern; and (3) tumor cell necrosis. For tumors that were confined to the endometrium, only percent solid growth and necrosis were evaluated, and those with both solid growth of more than 50% and necrosis were considered high grade. All tumors were graded independently by three pathologists on two separate occasions. Both inter- and intraobserver agreement using the binary grading system (kappa = 0.65 and 0.79) were superior compared with FIGO (kappa = 0.55 and 0.67) and nuclear grading (kappa = 0.22 and 0.41). The binary grading system stratified patients into three distinct prognostic groups. Patients with stage I low-grade tumors with invasion confined to the inner half of the myometrium (stages IA and IB) had a 100% 5-year survival rate. Patients with low-grade tumors that invaded beyond the outer half of the myometrium (stage IC and stages II-IV) and those with high-grade tumors with invasion confined to the myometrium (stages IB and IC) had a 5-year survival rate of 67% to 76%. In striking contrast to patients with advance-stage low-grade tumors, patients with advance-stage high-grade tumors had a 26% 5-year survival rate. This binary grading system has advantages over FIGO and nuclear grading that permit greater interobserver and intraobserver reproducibility and should be tested in other studies of endometrial endometrioid carcinomas to validate its reproducibility and use for segregating patients into different prognostic groups.

Atypical glandular cells of undetermined significance (AGUS): cytopathologic features, histopathologic results, and human papillomavirus DNA detection.

We intensively reviewed 137 smears initially classified as atypical glandular cells of undetermined significance (AGUS) to refine cytological criteria for evaluating these cases, evaluate histological outcomes, and assess the value of human papillomavirus (HPV) DNA testing in management. Consenting, nonpregnant study participants were identified from a cohort of 46,009 women receiving routine Pap smear screening in a managed care setting. Colposcopy was performed on all women, and at least one histological sample was obtained from each. Review diagnoses were assigned to smears and biopsy specimens by two separate panels of pathologists. DNA testing for cancer-associated HPV types was performed on rinses of cytological samplers after a smear and thin-layer slide had been made. On review, 47 (34%) smears were reclassified as negative, 44 (32%) as AGUS, 30 (22%) as atypical squamous cells of undetermined significance (ASCUS), and 16 (12%) as squamous intraepithelial lesions (SIL). The 19 smears interpreted as high-grade intraepithelial lesions on review included 13 high-grade SIL (HSIL), two HSIL with AGUS, favor neoplastic (endocervical adenocarcinoma in situ [AIS]), and four AGUS, favor neoplastic (AIS). Review histological diagnoses were negative in 105 (77%), squamous or glandular atypia in four (3%), low-grade SIL (LSIL) in nine (7%), HSIL in 12 (9%), AIS in five (4%, including two with concurrent HSIL), and endometrial carcinoma in one (1%). HPV testing identified 11 (92%) of 12 women with histologically confirmed HSIL and all five with AIS (100%). A high-grade intraepithelial lesion or carcinoma is detected in approximately 14% of women with community-based diagnoses of AGUS who are referred for immediate evaluation. Use of refined cytological criteria and HPV DNA testing may permit improved management of women with AGUS.

Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors: atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive, and metastatic carcinomas.

Histologic criteria for the distinction of ovarian mucinous borderline tumors (MBTs) from invasive mucinous carcinomas (MUCCAs) and the definitions of intraepithelial (noninvasive) carcinoma and microinvasion are controversial. Accurate assessment of the behavior of these tumors has been obscured by inclusion of cases of pseudomyxoma peritonei (PMP), an entity of extraovarian origin, and misclassification of the ovarian tumors in PMP and metastatic mucinous carcinomas (METCAs) as either advanced-stage MBTs or primary ovarian MUCCAs. One hundred thirty-six intestinal-type ovarian mucinous tumors without PMP were evaluated for the presence of stromal invasion, marked cytologic atypia, epithelial stratification of more than three cell layers, and necrosis. Criteria for the diagnosis of MBT, MBT with intraepithelial carcinoma, MBT with microinvasion (MIBT), MUCCA, and METCA were established and correlated with behavior. Twenty-three (59%) of 39 patients whose tumors had stromal invasion of more than 5 mm died of disease. Stromal invasion of more than 5 mm was the sole feature that correlated with a poor prognosis. In the absence of this feature, marked cytologic atypia, epithelial stratification of more than three layers, microinvasion (<5 mm), or necrosis did not have an adverse effect on survival. Tumors were classified as MBT (n = 65; 48%) based on absence of stromal invasion, regardless of degree of cytologic atypia or epithelial stratification; of these, 28 (43%) qualified as intraepithelial carcinoma based on epithelial stratification of more than three cell layers or marked cytologic atypia. Tumors with stromal invasion of less than 5 mm were classified as MIBT (n = 8; 6%). Tumors with stromal invasion of more than 5 mm were classified as MUCCA (n = 24; 18%). Tumors with a nodular pattern of stromal invasion, morphology inconsistent with ovarian origin, or a primary site elsewhere were classified as METCA (n = 35; 26%). Four tumors could not be definitively classified. Of the 86 cases with follow-up (median, 33 months) all MBTs (n = 44) and MIBTs (n = 6) were stage I, with 5-year survival rates of 100%. MUCCAs (n = 17) that were stage I had a 5-year survival rate of 91%; all patients with advanced-stage MUCCA died of disease. Five-year survival rate for METCAs (n = 19) was 11%. METCAs were more common than MUCCAs but can mimic MUCCAs and MBTs clinically and histologically. In the absence of a primary site elsewhere, METCA should be strongly suspected when there is bilateral surface involvement and a characteristic nodular pattern of invasion. It is important to recognize this pattern because 5-year survival rate for METCA (11%) was substantially less than that of MUCCA (all stages, 51%) and MBT (100%). Because all MBTs, regardless of degree of atypia or stratification, were stage I and benign, we prefer to designate them as atypical proliferative mucinous tumors. Marked cytologic atypia, epithelial stratification of more than three layers, and microinvasion (<5 mm) had no effect on the behavior of MBT. Noninvasive mucinous tumors with marked cytologic atypia or excessive epithelial stratification can be interpreted as atypical proliferative tumors with intraepithelial carcinoma and those with microinvasion can be designated as atypical proliferative tumors with microinvasion; these tumors appear to represent transitional stages in ovarian mucinous carcinogenesis.

Molecular genetic evidence supporting the clonality and appendiceal origin of Pseudomyxoma peritonei in women.

Pseudomyxoma peritonei (PMP) is a poorly understood condition characterized by mucinous ascites and multifocal peritoneal mucinous tumors. Women with PMP often have mucinous tumors involving both the appendix and the ovaries. Several previous histopathological and immunohistochemical studies of PMP have suggested that most, if not all, cases of PMP in women are derived from mucinous adenomas of the appendix rather than from primary ovarian tumors. A few studies of the molecular genetics of PMP have been recently reported. However, these studies analyzed only a small number of cases and some included a heterogeneous group of mucinous tumors, including both benign and malignant appendiceal and ovarian tumors. We analyzed K-ras mutations and allelic losses of chromosomes 18q, 17p, 5q, and 6q in a substantial number of morphologically uniform cases of PMP with synchronous ovarian and appendiceal tumors as well as in appendiceal mucinous adenomas (MAs) and ovarian mucinous tumors of low malignant potential (MLMPs) unassociated with PMP. Each of the 16 PMP cases (100%) analyzed demonstrated identical K-ras mutations in the appendiceal adenoma and corresponding synchronous ovarian tumor. K-ras mutations were identified in 11 of 16 (69%) appendiceal MAs unassociated with PMP and in 12 of 16 (75%) ovarian MLMPs unassociated with PMP. Two PMP cases showed identical allelic losses in the matched ovarian and appendiceal tumors. A discordant pattern of allelic loss between the ovarian and appendiceal tumors at one or two of the loci tested was observed in six PMP cases. In all but one instance, LOH was observed in the ovarian tumor, whereas both alleles were retained in the matched appendiceal lesion, suggesting tumor progression in a secondary (metastatic) site. Our findings strongly support the conclusion that mucinous tumors involving the appendix and ovaries in women with PMP are clonal and derived from a single site, most likely the appendix.

Atypical immature metaplasia (AIM) of the cervix: is it related to high-grade squamous intraepithelial lesion (HSIL)?

Atypical immature metaplasia (AIM) is a poorly characterized cervical lesion with uncertain biological and clinical significance. AIM shares some, but not all, morphological features of squamous intraepithelial lesions (SILs). SILs are characterized by human papillomavirus (HPV) positivity and increased cellular proliferation, but these features have not been fully evaluated in AIM. Genomic DNA was extracted from 27 microdissected cervical biopsy specimens diagnosed as AIM. HPV DNA was detected by polymerase chain reaction (PCR), using two different sets of L1 gene consensus primers. HPV types were identified by sequence analysis of PCR products and comparison with published HPV sequences. The cell proliferation index was assessed by immunohistochemical staining for Ki-67 (MIB-1) antigen and expressed as the percentage of Ki-67-positive cells. Comparison groups included normal cervix (n = 10) and low-grade (LSILs, n = 19) and high-grade squamous intraepithelial lesions (HSILs, n = 11). Intermediate- or high-risk HPV DNA was detected in 67% (18 of 27) of AIM cases. Low-risk HPV DNA was not detected in any of the specimens. The Ki-67 index in AIM (mean, 33.0 +/- 20.3; median, 29) was comparable to that of LSILs (mean, 21.4 +/- 4.6; median, 21) and was significantly higher than that of normal cervix (mean, 11.0 +/- 2.1; median, 11) (P< .01) and lower than that of HSILs (mean, 60.4 +/- 13.2; median, 60) (P < .01). Of the cases with available follow-up, HPV-positive AIMs were significantly more likely to have a concurrent or subsequent diagnosis of typical HSIL (12 of 15, 80%) than HPV-negative AIMs (one of six, 45%) (P = .014). The wide range of Ki-67 indices and variable HPV status in AIM suggest that AIM represents a heterogeneous group of lesions including bona fide HSILs (high-risk HPV-positive, high Ki-67 index), antecedents (precursors?) of HSILs (high-risk HPV-positive, low to moderate Ki-67 index), and benign reactive conditions (HPV-negative, variable Ki-67 index). HPV testing may be useful in the assessment of atypical epithelial proliferations of the cervix for which a diagnosis of AIM is considered.

Comparison of estrogen and progesterone receptor, Ki-67, and p53 immunoreactivity in uterine endometrioid carcinoma and endometrioid carcinoma with squamous, mucinous, secretory, and ciliated cell differentiation.

An analysis of 77 uterine endometrioid carcinomas was performed to compare pure endometrioid carcinomas and endometrioid carcinomas with various types of cellular differentiation for the expression of estrogen (ER) and progesterone (PR) receptors, p53, and Ki-67 and to correlate these findings with clinicopathologic features. Forty-three pure endometrioid carcinomas and 34 endometrioid carcinomas displaying additional types of cellular differentiation in at least 10% of the tumor (16 squamous, 11 mucinous, four ciliated cell, and three secretory) were analyzed. In 8 of the 16 tumors with squamous differentiation, the squamous component was histologically benign (low grade), and in eight tumors it was histologically malignant (high grade). In tumors showing various types of cellular differentiation except those with a high-grade squamous component, comparison of the endometrioid glandular component with the squamous, mucinous, secretory, and ciliated cell components showed that ER/PR, Ki-67, and p53 expression were generally higher in the glandular component compared with the various differentiated components. These findings parallel the changes that occur in the endometrium in the secretory phase of the menstrual cycle and, therefore, suggest that the differentiated components have undergone terminal differentiation. In contrast, in endometrioid carcinomas with a high-grade squamous component, Ki-67 and p53 expression were the same in the glandular and squamous components suggesting that squamous epithelium in these tumors represented another pathway of cellular differentiation but not one that was terminally differentiated. Endometrioid carcinomas with a high-grade squamous component had significantly higher grade (P = .002), stage (P < .001), cellular proliferation index (P = .0005), and worse outcome (P = .0009) compared with tumors with the other types of cellular differentiation, including those with a low-grade squamous component and pure low-grade endometrioid carcinomas. In addition, carcinomas with a high-grade squamous component occurred in older women and were more frequently associated with atrophic endometrium and less replacement hormone therapy, but the differences were not statistically significant. In conclusion, endometrioid carcinomas with various types of cellular differentiation can be broadly divided into two groups. Tumors with mucinous, secretory, and ciliated cell differentiation and those with a low-grade squamous component are similar to pure low-grade endometrioid carcinomas in that most have high ER and PR expression, low cellular proliferation indices, low p53 immunoreactivity, and good prognosis. In contrast, endometrioid carcinomas with a high-grade squamous component lack expression of ER and PR, have high cellular proliferation indices, often express p53, and have a prognosis similar to poorly differentiated endometrioid carcinomas.

Reproducibility of the diagnosis of endometrial hyperplasia, atypical hyperplasia, and well-differentiated carcinoma.

Many studies have attempted to identify histologic features that aid in the distinction of atypical hyperplasia (AH) from hyperplasia without atypia and well-differentiated endometrioid carcinoma, but few have evaluated the reproducibility of these diagnoses. Five pathologists independently reviewed 100 endometrial biopsy and curettage specimens chosen to represent the entire spectrum of proliferative lesions of the endometrium, including proliferative endometrium (PEM), hyperplasia without atypia, AH, and well-differentiated endometrioid carcinoma. Slides were reviewed twice for diagnosis, with an intervening evaluation of a checklist of histologic features. Intraobserver and interobserver agreement were assessed using the kappa statistic. Intraobserver kappa values ranged from 0.67 to 0.89 (76% to 89% agreement). Interobserver kappa values by diagnostic category were: proliferative endometrium: 0.86; hyperplasia without atypia: 0.60; AH: 0.47; well-differentiated endometrioid carcinoma: 0.83; with a kappa value of 0.69 for all cases combined. Associations between the selected histologic features and the given diagnoses for each pathologist were analyzed using multiple logistic regressions to identify features that were useful for distinguishing among diagnostic categories. Histologic features determined by univariable and multivariable analyses that were found to be most associated with distinguishing diagnostic categories were: proliferative endometrium versus hyperplasia without atypia: gland crowding (univariable, multivariable), and gland branching (univariable); hyperplasia without atypia versus AH: presence of nucleoli (univariable, multivariable), nuclear enlargement (univariable), vesicular chromatin change (univariable), nuclear pleomorphism (univariable), chromatin irregularities (univariable), and loss of polarity (univariable); hyperplasia without atypia versus carcinoma: glandular confluence/complex cribriform pattern (univariable, multivariable), stromal alteration (univariable, multivariable), and necrosis (univariable). In summary, interobserver agreement was good but was lowest for AH. Only the presence of nucleoli was strongly associated with distinction of AH from hyperplasia without atypia. Individual pathologists use additional features to diagnose atypia, but these features are not consistently associated with that diagnosis. Cribriform architectural pattern and stromal alteration were associated with the distinction of well-differentiated endometrioid carcinoma from AH.

Clear cell carcinoma of the endometrium is characterized by a distinctive profile of p53, Ki-67, estrogen, and progesterone receptor expression.

This study was designed to analyze certain clinicopathological features and the profile of p53, Ki-67, estrogen (ER), and progesterone (PR) receptor expression of clear cell carcinoma of the endometrium and to determine whether the pathogenesis of clear cell carcinoma can be accommodated by a dualistic model of endometrial carcinogenesis. In this model, endometrioid carcinoma develops from endometrial hyperplasia under unopposed estrogenic stimulation, and serous carcinoma develops in atrophic endometrium from a putative precursor lesion designated endometrial intraepithelial carcinoma (EIC). Twenty-one clear cell carcinomas of the endometrium were analyzed and compared with 77 endometrioid carcinomas of all grades and 30 serous carcinomas. Clear cell carcinomas showed a distinctive immunoprofile characterized by immunonegativity for ER and PR, low immunoreactivity for p53, and a high Ki-67 proliferation index. ER, PR, and Ki-67 expression were similar to serous carcinoma, but p53 expression was significantly lower in clear cell carcinoma (P < .05). ER and PR expression were significantly lower, and the Ki-67 proliferation index was significantly higher in clear cell carcinoma compared with endometrioid carcinomas (P < .05). p53 expression tended to be higher in clear cell carcinoma compared with endometrioid carcinoma, but the difference was not statistically significant. In contrast to endometrioid carcinoma, clear cell carcinoma was rarely associated with endometrial hyperplasia and serous carcinoma was not. Subdividing clear cell carcinoma morphologically into one that resembled serous carcinoma (clear cell carcinoma with serous features) and another that did not (typical clear cell carcinoma) showed that clear cell carcinoma with serous features had a higher Ki-67 proliferation index than typical clear cell carcinoma, although expression of ER, PR, and p53 were similar. Clear cell carcinoma with serous features was associated with EIC in 50% and was not associated with endometrial hyperplasia. In contrast, typical clear cell carcinoma was associated with endometrial hyperplasia in 40% and was not associated with EIC. In summary, this study provides evidence that clear cell carcinoma of the endometrium, like serous carcinoma, is estrogen independent and shows a high Ki-67 proliferation index. In contrast to serous carcinoma, strong p53 expression occurred less frequently in clear cell carcinoma and predominantly in clear cell carcinoma with serous features. The findings suggest that the molecular events that underlie the development of clear cell carcinoma differ from those of endometrioid and serous carcinoma.

The morphologic spectrum of ovarian metastases of appendiceal adenocarcinomas: a clinicopathologic and immunohistochemical analysis of tumors often misinterpreted as primary ovarian tumors or metastatic tumors from other gastrointestinal sites.

Twenty cases of ovarian metastases derived from appendiceal adenocarcinomas were analyzed. The most common presentation was a pelvic mass. The appendiceal and ovarian tumors were diagnosed concurrently in 15 cases; in the remaining five, the ovarian tumors were diagnosed before the appendiceal tumor. The appendiceal adenocarcinomas demonstrated four morphologic patterns: 1) signet ring cell type, with or without glandular or goblet cell differentiation (14 cases); 2) mixed signet ring cell and intestinal type (two cases); 3) intestinal type (two cases); and 4) typical colorectal type (two cases). The ovarian tumors were bilateral in 16 cases and were histologically similar to the associated appendiceal tumor in each case. Ovarian metastases that demonstrate signet ring cell, glandular, and goblet cell differentiation mimic metastases from gastric adenocarcinoma. Those that are derived from well-differentiated mucinous appendiceal adenocarcinomas mimic primary ovarian mucinous tumors and metastases from the pancreas and biliary tract. Metastases of appendiceal adenocarcinomas of colorectal type simulate both metastatic colorectal carcinoma and primary ovarian endometrioid carcinomas. The appendiceal and ovarian tumors were immunophenotypically identical in each case. Approximately 50% of the appendiceal and ovarian tumors were positive for cytokeratin 7 (CK 7), and all were positive for cytokeratin 20 (CK 20). CK 20 positivity of the ovarian tumors is consistent with gastrointestinal origin; CK 7 positivity does not confirm ovarian origin, because appendiceal carcinomas are positive in 50% of cases. Metastatic appendiceal adenocarcinoma should be considered in the differential diagnosis of mucinous ovarian tumors with signet ring cell, goblet cell, or intestinal type differentiation, especially when these tumors are associated with extraovarian disease and are bilateral.

DCC genetic alterations and expression in endometrial carcinoma.

DCC (Deleted in Colorectal Carcinoma) is a candidate tumor suppressor gene located on the long arm of chromosome 18. DCC was initially identified and cloned during a search for the target gene located in a region of 18q that demonstrated loss of heterozygosity (LOH) in 70 to 80% of colorectal cancers. More recently, the region of 18q harboring the DCC gene has been shown to undergo LOH in approximately 14 to 30% of endometrial carcinomas. These findings suggest that DCC may be a target of LOH in at least some endometrial carcinomas and, therefore, may have a role in the pathogenesis of this common malignancy of the female genital tract. To address this possibility, we analyzed 26 cases of endometrioid endometrial carcinoma for DCC LOH and alterations in an AT microsatellite repeat located in an intron of the DCC gene. LOH was detected in one case (4%). Allelic shifts at the DCC AT repeat were detected in five (19%) additional cases. We also evaluated DCC protein expression by immunohistochemical analysis in normal, hyperplastic, and neoplastic endometrial tissues. Three proliferative and five secretory endometria and one simple endometrial hyperplasia demonstrated staining for DCC. Four of the 26 endometrioid endometrial carcinomas for which frozen tissue was available, including at least one from each histologic grade, and a case of endometrioid carcinoma confined to the endometrium completely lacked detectable staining for DCC. Although DCC LOH was infrequent in endometrial carcinomas, alterations of the gene (LOH or AT repeat alterations) were not uncommon (23% of our cases). In addition, DCC was expressed in normal endometrial tissue, whereas expression was lost in all of the five endometrial carcinomas. The combination of the genetic alterations and loss of DCC protein expression suggests that inactivation of the DCC gene may play a role in the pathogenesis of endometrial carcinoma.

Immunohistochemical evidence supporting the appendiceal origin of pseudomyxoma peritonei in women.

Women with pseudomyxoma peritonei (PMP), characterized by multifocal mucinous implants (disseminated peritoneal adenomucinosis), often have synchronous appendiceal and ovarian mucinous tumors. There has been considerable debate as to whether the ovarian tumors are secondary to the appendiceal tumor or are independent primary ovarian tumors; the latter are usually classified as mucinous tumors of low malignant potential (MLMP). It has been reported that cytokeratins (CK) 7, 18, and 20, carcinoembryonic antigen (CEA), and human alveolar macrophage 56 (HAM-56) are useful markers for distinguishing primary ovarian neoplasms from metastases of intestinal origin. Nearly all primary ovarian MLMP tumors and mucinous carcinomas are positive for CK 7, 18, and 20, CEA, and HAM-56, whereas most colorectal adenocarcinomas are negative for both CK 7 and HAM-56 and positive for CK 20 and CEA. Thirteen appendiceal and 14 ovarian mucinous tumors from 14 cases of PMP and 11 primary ovarian MLMP tumors were studied immunohistochemically for expression of CK 7, 18, and 20, monoclonal and polyclonal CEA (mCEA and pCEA), and HAM-56. Of 14 cases of PMP, 10 (71.4%) had identical staining patterns for all antibodies in both the appendiceal and ovarian tumors. For eight of these, the pattern of immunoreactivity was characterized by negative reactions for CK 7 and HAM-56 and positive reactions for CK 18 and 20, mCEA, and pCEA. One additional case for which only the ovarian tumor could be stained had the same pattern. The remaining two cases were also positive for CK 18 and 20 and CEA, but in addition were positive for CK 7. Two cases were discordant only for CK 7 and one case was discordant for both CK 7 and HAM-56. All 11 MLMP tumors were positive for CK 7 and 18, and pCEA. Eight (72.7%) of 11 were positive for HAM-56, mCEA, and CK 20. There was a statistically significant difference in the frequency of immunoreactivity for CK 7 (p = 0.0005) and HAM-56 (p = 0.0002) between the ovarian mucinous tumors in PMP and the MLMP tumors, with the ovarian tumors in PMP tending to be negative for CK 7 and HAM-56, similar to the appendiceal adenomas. Most ovarian mucinous tumors in PMP demonstrate a pattern of immunoreactivity with CK 7, 18, and 20, CEA, and HAM-56 that is identical to the associated appendiceal adenoma and distinct from primary ovarian MLMP tumors, consistent with the interpretation that these ovarian tumors are secondary to the appendiceal tumor.

Pseudomyxoma peritonei: new concepts in diagnosis, origin, nomenclature, and relationship to mucinous borderline (low malignant potential) tumors of the ovary.

For many years the clinical syndrome of PMP has been enigmatic. Based on recent studies reevaluating the condition, tumors previously designated PMP can now be viewed as two pathologically and prognostically distinct disease processes. Disseminated peritoneal adenomucinosis is characterized by copious mucinous ascites (the classical clinical syndrome of PMP) and histologically bland peritoneal mucinous tumors. The condition can be attributed to a ruptured appendiceal mucinous adenoma in the vast majority of cases. It has an indolent clinical course when surgically treated but may recur over months to years. Peritoneal mucinous carcinomatosis is characterized by abundant peritoneal mucinous tumor, similar to the clinical presentation of adenomucinosis. However, microscopically, the peritoneal tumors have the architectural and cytologic features of carcinoma, are derived from gastrointestinal mucinous adenocarcinomas, and are associated with a significantly worse prognosis than cases of adenomucinosis. A third group of tumors displays intermediate or discordant histologic features but manifests a clinical course very similar to cases of pure peritoneal carcinomatosis. Women often have concomitant ovarian mucinous tumors that suggest primary ovarian neoplasia. Morphologic, immunohistochemical, and molecular studies support the interpretation that the ovarian tumors are secondary and that adenomucinosis is of appendiceal origin in women as well as men. The recognition that the ovarian tumors in nearly all of the cases of DPAM and mucinous carcinomatosis are secondary seriously calls into question the existence of a borderline group of ovarian mucinous tumors. Therefore, primary ovarian mucinous tumors should be classified as either benign or malignant. Tumors exhibiting the features currently interpreted as borderline should be included in the benign group and designated atypical proliferative mucinous tumors.