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Context.— There has long been debate about whether and when there may be a shortage of pathologists in the United States. One way to assess this is to survey the hiring experiences of pathology practices. A 2018 survey revealed a strong demand for pathologists, with expectations of continued strength. This study updates that prior analysis using data from a 2021 survey of pathology practice leaders. Objective.— To assess the US pathologist job market and examine implications. Design.— We analyzed data from the 2021 College of American Pathologists Practice Leader Survey. This survey queried practice leaders, including regarding the hiring of pathologists, the level of experience being sought, success in filling positions, and expectations for hiring in the next 3 years. Results.— Among the 375 surveyed practice leaders (about one-third of all US pathology practices), 282 provided information about pathologist hiring in 2021. A total of 157 of these 282 practices (55.7%) sought to hire at least 1 pathologist in 2021, up from 116 of 256 practices (45.3%) in 2017; the mean number of pathologists hired per practice also increased. In 2021, a total of 175 of 385 positions (45.5%) were to fill new positions, compared with 95 of 249 positions (38.2%) in 2017. Most practice leaders were comfortable hiring pathologists with less than 2 years of posttraining experience. Practice leaders anticipated continued strong demand for hiring pathologists during the next 3 years. Conclusions.— Our analysis confirms that the demand in pathologist hiring is strong and much increased from 2017. We believe, in combination with other job market indicators, that demand may outstrip the supply of pathologists, which is limited by the number of trainees and has remained constant during the past 20 years.

There has been little rigorous assessment of burnout among pathologists and pathology trainees. Given this relative dearth of relevant literature on pathologist burnout, this report aims to raise awareness of the issue among those working in and around this specialty. Our results are based on a survey given in conjunction with the American Board of Pathology's (ABPath) biennial Continuing Certification (CC) reporting of activities required of diplomates to maintain certification. The survey was voluntary, open to all diplomates participating in CC, and conducted over two consecutive years (2019 and 2020), with alternate years comprising different sets of diplomates. The data are based on 1256 respondents (820 from 2019 to 436 from 2020). The three highest aggregate reported rates of burnout (reported as experienced nearly all of the time, most of the time, or part of the time) occurred when respondents were in their first year of residency training (41.1%) and when they were in (47.6%) and beyond (46.6%) their first three years of practice. We considered this high-low-high, or U-shaped distribution in recollected burnout over time among pathologists a notable finding and investigated its distribution among respondents. Conversely at every point in their training and practice, from half to three-quarters of respondents reported never or infrequently experiencing burnout. This study represents the largest pathologist cohort survey to date about pathologists' burnout. Importantly, especially for those considering pathology as a career, these data are on the low end of the distribution of burnout among specialties for those in practice.

Context.— Disagreement exists within the pathology community about the status of the job market for pathologists. Although many agree that jobs in pathology were harder to come by earlier this decade, recent evidence suggests improvement is occurring. Objective.— To assess the state of the job market for pathologists. Design.— We analyzed data from the 2018 College of American Pathologists Practice Leader Survey. This survey contains data from 253 practice leaders on practices' hiring (and retrenchments) in 2017, the skills and level of experience being sought, success in filling those positions, and expectations for hiring in the next 3 years. Results.— Among the surveyed practice leaders, 115 (45.5%) sought to hire at least 1 pathologist in 2017, and together tried to fill 246 full-time equivalent positions that year, of which 93.5 full-time equivalents (38%) were newly created. This hiring was not limited to larger, academic-based practices, but also occurred among smaller practices and practices based in nonacademic hospitals, independent laboratories, and other settings. Although some practices retrenched (60 full-time equivalents in 2017), the net increase was a healthy 187 full-time equivalents. Practices most frequently sought pathologists who had at least 2 years of experience, but the level of experience identified with the “optimal” candidate varied by desired areas of subspecialty expertise. Practice leaders also reported expected growth in hiring, with the number of positions they hope to fill in the next 3 years exceeding those vacated by retirement. Conclusions.— Our findings support the proposition that the demand for pathologists is strong, at least at the current time.

OBJECTIVE Polycarbonate urethane (PCU) is a new biomaterial, and its mechanical properties can be tailored to match that of vaginal tissue. We aimed to determine whether vaginal host immune and extracellular matrix responses differ after PCU versus lightweight polypropylene (PP) mesh implantation. METHODS Hysterectomy and ovariectomy were performed on 24 Sprague-Dawley rats. Animals were divided into 3 groups: (1) PCU vaginal mesh, (2) PP vaginal mesh, and (3) sham controls. Vagina-mesh complexes or vaginas (controls) were excised 90 days after surgery. We quantified responses by comparing: (1) histomorphologic scoring of hematoxylin and eosin- and Masson trichrome-stained slides, (2) macrophage subsets (immunolabeling), (3) pro-inflammatory and anti-inflammatory cytokines (Luminex panel), (4) matrix metalloproteinase (MMP)-2 and -9 using an enzyme-linked immunosorbent assay, and (5) type I/III collagen using picrosirius red staining. RESULTS There was no difference in histomorphologic score between PCU and PP (P = 0.211). Although the histomorphologic response was low surrounding all mesh fibers, groups with PCU and PP mesh had a higher histomorphologic score than the control group (P < 0.005 and P < 0.002, respectively). There were no differences between groups in terms of macrophage subsets, pro-inflammatory cytokines, anti-inflammatory cytokines, MMP-2 and MMP-9, or collagen ratio. CONCLUSIONS Polycarbonate urethane, an elastomer with material properties similar to those of vaginal tissue, elicits minimal host inflammatory responses in a rat model. Because its implantation does not elicit more inflammation than currently used lightweight PP, using PCU for prolapse mesh warrants further investigation with larger animal models.

OBJECTIVES We sought to determine whether vaginal host immune cellular and extracellular matrix responses are altered in a rat sacrocolpopexy model when lightweight polypropylene mesh is attached on tension versus without tension. METHODS We performed hysterectomy and ovariectomy in 32 Sprague-Dawley rats. Animals were assigned to 4 groups (n = 8/group): (1) controls with sham operation only (control), (2) mesh sutured only on the vagina (vaginal mesh), (3) sacrocolpopexy without tension, and (4) sacrocolpopexy with tension. Ninety days later, we excised vagina-mesh complexes. A histomorphologic scoring system of hematoxylin/eosin and Masson trichrome stained slides was used to assess host inflammatory responses. The cellular inflammatory response was further quantified using (1) identification of M1 and M2 macrophage subsets and (2) quantification of proinflammatory and anti-inflammatory cytokines. The extracellular matrix response was evaluated by measuring (1) matrix metalloproteinase-2 and matrix metalloproteinase-9 levels and (2) type I/III collagen. RESULTS Histomorphological tissue responses were greater in all groups with mesh compared with sham controls. Both sacrocolpopexy groups had similar scores, but each group scored significantly higher than the vaginal mesh group. Among the 4 groups, there were no statistically significant differences in M1 or M2 macrophage subsets, proinflammatory or anti-inflammatory cytokines, or extracellular matrix remodeling responses. CONCLUSIONS Attachment of prolapse mesh resulted in an increased histologic inflammatory response independent of tension. Other markers of cellular inflammation and extracellular matrix remodeling showed no differences among experimental groups. Tension on lightweight polypropylene mesh did not significantly alter the host response in this rat sacrocolpopexy model.

Importance There is currently no national organization that publishes its data that serves as the authoritative source of the pathologist workforce in the US. Accurate physician numbers are needed to plan for future health care service requirements. Objective To assess the accuracy of current pathologist workforce estimates in the US by examining why divergency appears in different published resources. Design, Setting, and Participants This study examined the American Board of Pathology classification for pathologist primary specialty and subspecialties and analyzed previously published reports from the following data sources: the Association of American Medical Colleges (AAMC), the Accreditation Council for Graduate Medical Education (ACGME), a 2013 College of American Pathologists (CAP) report, a commercially available version of the American Medical Assoication (AMA) Physician Masterfile, and an unpublished data summary from June 10, 2019. Main Outcomes and Measures Number of physicians classified as pathologists. Results The most recent AAMC data from 2017 (published in 2018) reported 12 839 physicians practicing “anatomic/clinical pathology,” which is a subset of the whole. In comparison, the current AMA Physician Masterfile, which is not available publicly, listed 21 292 active pathologists in June 2019. The AMA Physician Masterfile includes all pathologists in 15 subspecialized training areas as identified by the ACGME. By contrast, AAMC’s data, which derive from the AMA Physician Masterfile data, only count physicians primarily associated with 3 general categories of pathologists and 1 subspecialty category (ie, chemical pathology). Thus, the AAMC pathology workforce estimate does not include those whose principal work is in 11 subspecialty areas, such as blood banking or transfusion medicine, cytopathology, hematopathology, or microbiology. An additional discrepancy relates to the ACGME residency (specialties) and fellowship (subspecialties) training programs in which pathologists with training in dermatopathology appear as dermatologists and pathologists with training in molecular genetic pathology appear as medical geneticists. Conclusions and Relevance This analysis found that most sources reported only select categories of the pathologist workforce rather than the complete workforce. The discordant nature of reporting may pertain to other medical specialties that have undergone increased subspecialization during the past 2 decades (eg, surgery and medicine). Reconsideration of the methods for determining the pathologist workforce and for all workforces in medicine appears to be needed.

The role of tissue interactions was explored to determine whether epithelial differentiation within the developing human reproductive tract is induced and specified by mesenchyme in tissue recombinants composed of mouse vaginal mesenchyme + human uterine tubal epithelium (mVgM+hTubE). The tissue recombinants were grown in DES-treated ovariectomized athymic mice. After 2 to 4 weeks of in vivo growth, several vaginal specific features were expressed in the human tubal epithelium. The mesenchyme-induced effects included morphological change as well as expression of several immunohistochemical markers. Although the mesenchyme-induced shift in vaginal differentiation in the human tubal epithelium was not complete, the partial induction of vaginal markers in human tubal epithelium verifies the importance of mesenchymal-epithelial interactions in development of the human female reproductive tract. In a separate experiment, DES-induction of uterine epithelial progesterone receptor (PGR) and estrogen receptor 1 (ESR1) was explored in tissue recombinants composed of wild-type or Esr1KO mouse uterine mesenchyme + human fetal uterine epithelium (wt UtM+hUtE and Esr1KO UtM+hUtE). The rationale of this experiment was to determine whether DES-induction of PGR and ESR1 is mediated directly via epithelial ESR1 or indirectly (paracrine mechanism) via mesenchymal ESR1. DES-induction of uterine epithelial ESR1 and PGR in Esr1KO UtM+hUtE tissue recombinants (devoid of mesenchymal ESR1) formally eliminates the paracrine mechanism and demonstrates that DES induction of human uterine epithelial ESR1 and PGR is directly mediated via epithelial ESR1.

Context.— Papillary immature metaplasia (PIM) is a known papillary cervical lesion associated with low-risk human papillomavirus (LR-HPV). Objective.— To evaluate additional clinicopathologic features and the HPV genotypes of PIM and discuss the presumptive cell of origin. Design.— A total of 26 PIM cases were evaluated by p16INK4a, cytokeratin (CK) 7, and CK17 immunohistochemical stainings. Human papillomavirus genotyping was performed, by using HPV DNA Chip, HPV polymerase chain reaction (PCR), and real-time PCR. Results.— Histologically, PIM forms either a papillary mass (n = 21 of 26, 81%) or a slightly elevated/flat plaque (n = 5, 19%). All cases contain variable amounts of mucinous epithelia within the lesions. Koilocytosis was identified in 15 of the 26 cases (58%). Sixteen cases (61%) were associated with LR-HPV (types 6, 11, or 42), but 3 cases (12%) with high-risk (HR) HPV (16, 16/18, and 33), 2 cases (8%) with mixed LR- and HR-HPV (6/16 and 11/58), while 2 cases (8%) were negative, but p16INK4a immunostaining showed nonblock positivity in all cases. Eight (31%) had high-grade squamous intraepithelial lesion (HSIL) in the adjacent mucosa, 4 (50%) of which showed direct continuity. Identical HPV subtypes were confirmed in separately microdissected cases from PIM and adjacent HSIL. Most lesions (n = 24, 92%) expressed CK17 (reserve cell marker) in a bottom-heavy pattern and CK7 (squamocolumnar junction [SCJ] marker) in a top-heavy pattern, while most cases of low-grade squamous intraepithelial lesion (LSIL) were negative for both markers. Conclusions.— Our results suggest that PIM is a distinct subset of LSIL showing a productive HPV infection, but PIM involves the transformation zone and is proximal to SCJ, while LSIL is mostly from ectocervix or distal to the SCJ.

Human female reproductive tract development rests mostly upon hematoxilyn and eosin stained sections despite recent advances on molecular mechanisms in mouse studies. We report application of immunohistochemical methods to explore the ontogeny of epithelial and mesenchymal differentiation markers (keratins, homobox proteins, steroid receptors), transcription factors and signaling molecules (TP63 and RUNX1) during human female reproductive tract development. Keratins 6, 7, 8, 10, 14 and 19 (KRT6, KRT7, KRT8, KRT10, KRT14, KRT19) were expressed in a temporally and spatially dynamic fashion. The undifferentiated Müllerian duct and uterovaginal canal, lined by simple columnar epithelia, expressed KRT7, KRT8 and KRT19. Glandular derivatives of the Müllerian duct (uterine tube, uterine corpus and endocervix) maintained expression of these keratins, while tissues that undergo stratified squamous differentiation (exocervix and vagina) expressed KRT6, KRT14 and KRT10 during development in an age-dependent fashion. TP63 and RUNX1 were expressed prior to KRT14, as these two transcription factors are known to be upstream from KRT14 in developing Müllerian epithelium. In the vagina, KRT10, a marker of terminal differentiation, appeared after endogenous estrogens transformed the epithelium to a thick glycogenated squamous epithelium. Uroplakin, a protein unique to urothelium, was expressed only in the bladder, urethra and vaginal introitus, but not in the female reproductive tract itself. Mesenchymal differentiation was examined through immunostaining for HOXA11 (expressed in uterine mesenchyme) and ISL1 (expressed in vaginal mesenchyme). A detailed ontogeny of estrogen receptor alpha (ESR1), progesterone receptor (PGR) and the androgen receptor (AR) provides the mechanistic underpinning for the teratogenicity of estrogens, progestins and androgens on female reproductive tract development. Immunohistochemical analysis of differentiation markers and signaling molecules advance our understanding of normal development of the human female reproductive tract. These observations demonstrate remarkable similarities in mouse and human female reproductive tract development, but also highlight some key differences.

We present a detailed review of the embryonic and fetal development of the human female reproductive tract utilizing specimens from the 5th through the 22nd gestational week. Hematoxylin and eosin (H&E) as well as immunohistochemical stains were used to study the development of the human uterine tube, endometrium, myometrium, uterine cervix and vagina. Our study revisits and updates the classical reports of Koff (1933) and Bulmer (1957) and presents new data on development of human vaginal epithelium. Koff proposed that the upper 4/5ths of the vagina is derived from Müllerian epithelium and the lower 1/5th derived from urogenital sinus epithelium, while Bulmer proposed that vaginal epithelium derives solely from urogenital sinus epithelium. These conclusions were based entirely upon H&E stained sections. A central player in human vaginal epithelial development is the solid vaginal plate, which arises from the uterovaginal canal (fused Müllerian ducts) cranially and squamous epithelium of urogenital sinus caudally. Since Müllerian and urogenital sinus epithelium cannot be unequivocally identified in H&E stained sections, we used immunostaining for PAX2 (reactive with Müllerian epithelium) and FOXA1 (reactive with urogenital sinus epithelium). By this technique, the PAX2/FOXA1 boundary was located at the extreme caudal aspect of the vaginal plate at 12 weeks. During the ensuing weeks, the PAX2/FOXA1 boundary progressively extended cranially such that by 21 weeks the entire vaginal epithelium was FOXA1-reactive and PAX2-negative. This observation supports Bulmer's proposal that human vaginal epithelium derives solely from urogenital sinus epithelium. Clearly, the development of the human vagina is far more complex than previously envisioned and appears to be distinctly different in many respects from mouse vaginal development.

Strumae ovarii are neoplasms composed of normal-appearing thyroid tissue that occur within the ovary and rarely spread to extraovarian sites. A unique case of struma ovarii with widespread dissemination detected 48 years after removal of a pelvic dermoid provided the opportunity to reexamine the molecular nature of this form of neoplasm. One tumor, from the heart, consisting of benign thyroid tissue was found to have whole-genome homozygosity. Another tumor from the right mandible composed of malignant-appearing thyroid tissue showed whole-genome homozygosity and a deletion of 7p, presumably the second hit that transformed it into a cancerous tumor. Specimens from 2 other cases of extraovarian struma confined to the abdomen and 8 of 9 cases of intraovarian struma showed genome-wide segmental homozygosity. These findings confirm errors in meiosis as the origin of struma ovarii. The histological and molecular findings further demonstrate that even when outside the ovary, strumae ovarii can behave nonaggressively until they receive a second hit, thereafter behaving like cancer.

The study of male and female reproductive tract development requires expertise in two separate disciplines, developmental biology and endocrinology. For ease of experimentation and economy, the mouse has been used extensively as a model for human development and pathogenesis, and for the most part similarities in developmental processes and hormone action provide ample justification for the relevance of mouse models for human reproductive tract development. Indeed, there are many examples describing the phenotype of human genetic disorders that have a reasonably comparable phenotype in mice, attesting to the congruence between mouse and human development. However, anatomic, developmental and endocrinologic differences exist between mice and humans that (1) must be appreciated and (2) considered with caution when extrapolating information between all animal models and humans. It is critical that the investigator be aware of both the similarities and differences in organogenesis and hormone action within male and female reproductive tracts so as to focus on those features of mouse models with clear relevance to human development/pathology. This review, written by a team with extensive expertise in the anatomy, developmental biology and endocrinology of both mouse and human urogenital tracts, focusses upon the significant human/mouse differences, and when appropriate voices a cautionary note regarding extrapolation of mouse models for understanding development of human male and female reproductive tracts.

This article presents findings from a 4-year series of surveys of new-in-practice pathologists, and a survey of physician employers of new pathologists, assessing how pathology graduate medical education prepares its graduates for practice. Using the methodology described in our previous study, we develop evidence for the importance of residency training for various practice areas, comparing findings over different practice settings, sizes, and lengths of time in practice. The principal findings are (1) while new-in-practice pathologists and their employers report residency generally prepared them well for practice, some areas—billing and coding, laboratory management, molecular pathology, and pathology informatics—consistently were identified as being important in practice but inadequately prepared for in residency; (2) other areas—autopsy pathology, and subspecialized apheresis and blood donor center blood banking services—consistently were identified as relatively unimportant in practice and excessively prepared for in residency; (3) the notion of a single comprehensive model for categorical training in residency is challenged by the disparity between broad general practice in some settings and narrower subspecialty practice in others; and (4) the need for preparation in some areas evolves during practice, raising questions about the appropriate mode and circumstance for training in these areas. The implications of these findings range from rebalancing the emphasis among practice areas in residency, to reconsidering the structure of graduate medical education in pathology to meet present and evolving future practice needs.

Few medical specialties engage in ongoing, organized data collection to assess how graduate medical education in their disciplines align with practice. Pathology educators, the American Board of Pathology, and major pathology organizations undertook an evidence-based, empirical assessment of what all pathologists need to learn in categorical residency. Two challenges were known when we commenced and we encountered 2 others during the project; all were ultimately satisfactorily addressed. Initial challenges were (1) ensuring broad representation of the new-in-practice pathologist experience and (2) adjusting for the effect on this experience of subspecialty fellowship(s) occurring between residency and practice. Additional challenges were (3) needing to assess and quantify degree and extent of subspecialization in different practice settings and (4) measuring changing practice responsibilities with increasing time in practice. We instituted annual surveys of pathologists who are relatively new (

Development of the human female reproductive tract is reviewed from the ambisexual stage to advanced development of the uterine tube, uterine corpus, uterine cervix and vagina at 22 weeks. Historically this topic has been under-represented in the literature, and for the most part is based upon hematoxylin and eosin stained sections. Recent immunohistochemical studies for PAX2 (reactive with Müllerian epithelium) and FOXA1 (reactive with urogenital sinus epithelium and its known pelvic derivatives) shed light on an age-old debate on the derivation of vaginal epithelium supporting the idea that human vaginal epithelium derives solely from urogenital sinus epithelium. Aside for the vagina, most of the female reproductive tract is derived from the Müllerian ducts, which fuse in the midline to form the uterovaginal canal, the precursor of uterine corpus and uterine cervix an important player in vaginal development as well. Epithelial and mesenchymal differentiation markers are described during human female reproductive tract development (keratins, homeobox proteins (HOXA11 and ISL1), steroid receptors (estrogen receptor alpha and progesterone receptor), transcription factors and signaling molecules (TP63 and RUNX1), which are expressed in a temporally and spatially dynamic fashion. The utility of xenografts and epithelial-mesenchymal tissue recombination studies are reviewed.

In the Diethylstilbestrol [DES] Combined Cohort Follow-up, the age- and calendar-year specific standardized incidence ratio [SIR] for clear cell adenocarcinoma [CCA] was 27.6 (95% confidence interval [CI] 7.51-70.6) for the exposed women. The SIR for breast cancer was 1.17 (95% CI 1.01-1.36) and the hazard ratio [HR] adjusted for birth year and cohort for comparison with the unexposed was 1.05 (95% CI 0.79-1.41). The SIR for pancreatic cancer was 2.43 (95% CI 1.21-4.34) and the adjusted HR for comparison with unexposed women was 7.16 (95% CI 0.84-61.5). There was little evidence of excess risk for other sites. There appeared to be a deficit in risk for endometrial cancer among the exposed (SIR 0.61; 95% CI 0.35-0.98), and an excess in the unexposed (SIR 1.55; 95% CI 0.95-2.40); the adjusted HR was 0.45 (95% CI 0.22-0.93) for the internal comparison. There was no overall excess cancer risk in exposed women compared with general population rates (1.06; 95% CI 0.95-1.17) or with unexposed participants (adjusted HR 1.03; 95% CI 0.84-1.25). These data do not support the suggestion that there is a diathesis of cancers in DES exposed female offspring The excess risk of breast and pancreatic cancers that we observed is concerning and warrants continued follow-up and mechanistic investigation. Environ. Mol. Mutagen. 60:395-403, 2019. Published 2017. This article is a US Government work and is in the public domain in the USA.

Mucinous adenocarcinoma is one of the least common histologic types of endometrial carcinoma, comprising less than 10% (range 1–9%) of these tumors (Fujiwara and Longacre in Am J Surg Pathol 35:537–544, 2011 [1]; Ross et al. in Am J Surg Pathol 7:715–729, 1983 [2], Melhem and Tobon in Int J Gynecol Pathol 6:347–355, 1987 [3]).While focal mucinous differentiation is a common finding in usual endometrioid endometrial adenocarcinoma (Ross et al. in Am J Surg Pathol 7:715–729, 1983 [2]), mucinous endometrial adenocarcinoma is diagnosed when more than 50% of the tumor cells contain intracytoplasmic mucin (Zaino et al. in Tumours of the uterine corpus. WHO press, Geneva [4]). The diagnosis of endometrial adenocarcinoma in general is based on a combination of cytologic and architectural criteria. For mucinous adenocarcinoma, however, the usual diagnostic criteria cannot always be applied uniformly as cytologic atypia is rarely more than minimal to moderate, and architectural complexity is often the only diagnostic clue. Moreover, rare cases of mucinous adenocarcinoma are histologically similar to non-neoplastic endocervical epithelium or adenocarcinoma of cervical origin. For these reasons, establishing a diagnosis of mucinous adenocarcinoma sometimes poses a diagnostic challenge (Vang and Tavassoli in Int J Surg Pathol 11:261–270, 2003 [5]), requiring immunohistochemical and molecular genetic tests as useful adjuncts. The discussion that follows summarizes the clinical, histopathologic, and molecular genetic characteristics, and the possible precursors of endometrial mucinous adenocarcinoma.

This retrospective observational study on faculty development analyzes the Duke University Pathology Department’s 18-year experience with a structured mentoring program involving 51 junior faculty members. The majority had MD degrees only (55%). The percentage of young women faculty hires before 1998 was 25%, increasing to 72% after 2005. Diversity also broadened from 9% with varied heritages before 1998 to 37% since then. The mentoring process pivoted on an annual review process. The reviews generally helped candidates focus much earlier, identified impediments they individually felt, and provided new avenues to gain a national reputation for academic excellence. National committee membership effectively helped gain national exposure. Thirty-eight percent of the mentees served on College of American Pathologists (CAP) committees, exponential multiples of any other national society. Some used CAP resources to develop major programs, some becoming nationally and internationally recognized for their academic activities. Several faculty gained national recognition as thought leaders for publishing about work initiated to serve administrative needs in the Department. The review process identified the need for more protected time for research, issues with time constraints, and avoiding exploitation when collaborating with other departments. This review identified a rigorous faculty mentoring and review process that included annual career counseling, goal-oriented academic careers, monitored advancement to promotion, higher salaries, and national recognition. All contributed to high faculty satisfaction and low faculty turnover. We conclude that a rigorous annual faculty review program and its natural sequence, promotion, can greatly foster faculty satisfaction.

In utero diethylstilbestrol (DES) exposure is a risk factor for rare development of vaginal and cervical cancer and may potentially be a risk factor for breast cancer. Mammography use in this population is relatively unknown; therefore, this study aims to determine if in utero DES exposure is associated with the frequency of mammography screening examinations while considering demographic and clinical factors.Using combined DES cohort questionnaire data, self-reported mammography screening over the past 5 years (2001-2006) was analyzed in women aged ≥45 years. Binary logistic regression assessed if DES exposure was associated with mammography use after adjustment for benign breast disease (BBD), previous cancer diagnosis, and whether insurance access influenced screening use.Overall, the frequency of mammography examinations was similar for both DES-exposed and unexposed women. DES-exposed (n=2986) and unexposed women (n=1397) over the age of 44 reported receiving ≥3 mammography examinations in the past 5 years (73.8% and 74.0%, respectively). After adjustment, DES exposure was not associated with ≥3 mammograms in the past 5 years compared to ≤2 examinations (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.86-1.17), p=0.99).In utero DES exposure was not associated with mammography use, nor was health insurance status or a BBD or cancer diagnosis. Because of the potential elevated risk for breast cancer in women exposed prenatally to DES, continued monitoring of standard mammography recommendations is recommended for this group, which is predominantly over the age of 45.

Before 1971, several million women were exposed in utero to diethylstilbestrol (DES) given to their mothers to prevent pregnancy complications. Several adverse outcomes have been linked to such exposure, but their cumulative effects are not well understood.We combined data from three studies initiated in the 1970s with continued long-term follow-up of 4653 women exposed in utero to DES and 1927 unexposed controls. We assessed the risks of 12 adverse outcomes linked to DES exposure, including cumulative risks to 45 years of age for reproductive outcomes and to 55 years of age for other outcomes, and their relationships to the baseline presence or absence of vaginal epithelial changes, which are correlated with a higher dose of, and earlier exposure to, DES in utero.Cumulative risks in women exposed to DES, as compared with those not exposed, were as follows: for infertility, 33.3% vs. 15.5% (hazard ratio, 2.37; 95% confidence interval [CI], 2.05 to 2.75); spontaneous abortion, 50.3% vs. 38.6% (hazard ratio, 1.64; 95% CI, 1.42 to 1.88); preterm delivery, 53.3% vs. 17.8% (hazard ratio, 4.68; 95% CI, 3.74 to 5.86); loss of second-trimester pregnancy, 16.4% vs. 1.7% (hazard ratio, 3.77; 95% CI, 2.56 to 5.54); ectopic pregnancy, 14.6% vs. 2.9% (hazard ratio, 3.72; 95% CI, 2.58 to 5.38); preeclampsia, 26.4% vs. 13.7% (hazard ratio 1.42; 95% CI, 1.07 to 1.89); stillbirth, 8.9% vs. 2.6% (hazard ratio, 2.45; 95% CI, 1.33 to 4.54); early menopause, 5.1% vs. 1.7% (hazard ratio, 2.35; 95% CI, 1.67 to 3.31); grade 2 or higher cervical intraepithelial neoplasia, 6.9% vs. 3.4% (hazard ratio, 2.28; 95% CI, 1.59 to 3.27); and breast cancer at 40 years of age or older, 3.9% vs. 2.2% (hazard ratio, 1.82; 95% CI, 1.04 to 3.18). For most outcomes, the risks among exposed women were higher for those with vaginal epithelial changes than for those without such changes.In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes. (Funded by the National Cancer Institute.).

Kim K-R, Choi J, Hwang J-E, Baik Y-A, Shim J Y, Kim Y M & Robboy S J (2010) Histopathology57, 587–596 Endocervical-like (Mullerian) mucinous borderline tumours of the ovary are frequently associated with the KRAS mutation Aims: Clinicopathological aspects of the endocervical-like mucinous borderline tumour of the ovary (EMBT), including higher frequencies of bilaterality, endometriosis and hormone receptor reactivity, and often admixtures of various Mullerian-type epithelia, closely resembles endometrioid tumour more than mucinous borderline tumour of the intestinal type (IMBT). Thus, the aims of this study were to determine whether EMBT is really a subtype of mucinous borderline tumours, as shown in the current classification system, and to determine the best classification for EMBT. Methods and results: The clinicopathological and immunohistochemical features of 17 EMBTs were analysed, including oestrogen receptor (ER), progesterone receptor (PR), PTEN, cytokeratins (CK) 7 and 20, and β-catenin. Additionally, mutational analyses of the KRAS (exon 1) and PTEN genes (all nine exons) were performed in all cases, and the results were compared with literature findings for IMBT and endometrioid tumours. Twelve patients (71%) were confirmed histologically to have endometriosis in one or both ovaries. In seven cases, gradual transitions from endometriotic foci to the EMBT were identified. Immunohistochemically, all cases were reactive for ER and PR, with no nuclear expression of β-catenin. CK7 positivity was strong in all patients, whereas there was no reactivity for CK20. PTEN reactivity was diffuse in the nuclei of epithelial and underlying stromal cells. Sixty-nine per cent showed KRAS mutations in exon 1 and codon 12, but no PTEN mutation was identified in any of the nine exons. Conclusion: Our study suggests that EMBT has features of both mucinous and endometrioid tumours and is an additional tumour type arising in endometriosis. While clinicopathological features of EMBTs are closer to endometrioid tumours, they still have molecular characteristics closer to IMBTs.

The Duke experience with 56 vulvar Paget disease patients was analyzed emphasizing pathologic features and controversial issues. Nearly all patients were Caucasian, and their mean age was 69 years. The average length of follow-up was 5.6 years. For each case, the following histologic features were evaluated and their association with disease course was examined: pseudo-invasion, adnexal involvement, signet-ring cells, cytologic atypia, glands formation, epidermal acantholysis, parakeratosis, hyperkeratosis, and chronic inflammation. The recurrence rate after surgical management was 32%, with epidermal acantholysis being the only statistically significant risk factor. Stromal invasion occurred in 10 patients (18%), and was not a statistically significant adverse prognostic indicator, although the single patient who died of the disease had the deepest stromal invasion. Recurrence was more common after resections with positive surgical margins, but this correlation was not statistically significant. Intraoperative frozen section analysis of the margins did not reduce recurrence rate, nor was it useful in attaining permanent free margins. The Paget cells were consistently reactive with cytokeratin-7 and carcinoembryonic antigen and unreactive with S-100 protein, HMB-45, and Mart-1. In addition, the tumor cells were usually positive for mucin stains. This profile helps distinguish vulvar Paget disease from its mimics, Pagetoid squamous cell carcinoma and malignant melanoma.

Struma ovarii that display extraovarian spread or later recurrence is exceedingly rare. Among 88 patients with "malignant" struma ovarii followed for prolonged periods, several features helped to predict the adverse clinical course. Adhesions (graded 2 to 4+), peritoneal fluid (or =1 L) or ovarian serosal rent were worrisome features, occurring in 74% of 27 biologically malignant tumors but only 10% of 61 clinically benign tumors. The size of the strumal component rather than the overall size of the ovarian teratoma also had some predictive value. Tumors with a strumal componentor =6 cm recurred rarely (7%), whereas 33% of the consult and 88% of the literature casesor =12 cm were clinically malignant. Except for a papillary pattern or poorly differentiated cancer, no microscopic feature reliably predicted the clinical outcome, including those typically associated with malignancy in primary thyroid tumors. Among the consult cases, 7% with histologic follicular adenomas and 29% with papillary carcinomas were clinically malignant. Unequivocal vascular invasion was rare, precluding assessment of its effect. Optically clear nuclei, when extensive, were useful to diagnose papillary carcinoma, but were present nevertheless in smaller numbers in both macrofollicular and microfollicular adenomas. Eight tumors confined initially to the ovary (stage 1) recurred. Papillary carcinomas recurred earlier (average 4 y) than follicular adenomatous neoplasms (average 11 y, range: 1-29 y). Overall, the survival rate for all patients was 89% at 10 years and 84% at 25 years, indicating the need for routine long-term follow-up.

To determine if women exposed in utero to diethylstilbestrol (DES) are more likely than unexposed women to receive recommended or additional breast cancer screening examinations.1994 Diethylstilbestrol-Adenosis (DESAD) cohort data are used to assess the degree of recommended compliance of breast cancer screenings found in 3140 DES-exposed and 826 unexposed women. Participants were enrolled at four sites: Houston, Boston, Rochester, and Los Angeles. Logistic regression modeling was used to analyze mailed questionnaire data that included reported frequency over the preceding 5 years (1990-1994) of breast-self examinations (BSEs), clinical breast examinations (CBEs), and mammograms.DES-exposed women exceeded annual recommendations for CBEs (aOR 2.20, 95% CI, 1.04-4.67) among women without a history of benign breast disease (BBD) compared with unexposed women. There were no other statistically significant differences between exposed and unexposed women who reported performing BSEs, CBEs (40 years of age), and mammographies, regardless of BBD history.The majority of DES-exposed women receive breast cancer screenings at least at recommended intervals, but over two thirds do not perform monthly BSEs. Future efforts should be focused on further educating this and other at-risk populations through mailed reminders and during patient consultations on the benefits of screening examinations.

Histologic distinction between complete hydatidiform moles and nonmolar abortuses in early pregnancy is often extremely difficult. This study details the chronologic changes that occur in normal placenta, especially in the villous stroma during gestational weeks 4 to 12 and compares the findings in 63 normal placentas and 73 early complete moles. Over time, the chorionic villi in normal placenta showed gradual but recognizable alterations, from basophilic/hypocellular and nonvascular stroma to basophilic/cellular stroma containing angiogenic cell cords (immature blood vessels), and then to loose, edematous/reticular stroma with mature blood vessels containing vascular lumina and hematopoietic components. A basophilic stroma, which was frequently seen in early complete moles, was a constant feature of chorionic villi younger than week 7 in normal placenta, but had disappeared after week 8, except in the newly branched sprouts. Trophoblastic proliferation was virtually unrecognizable in 59% of early complete moles, whereas circumferential trophoblastic sprouts during weeks 4 to 6 of normal placenta can be mistaken as that of complete moles. Few or no mature blood vessels and excessive stromal karyorrhexis are characteristic features of early complete moles, even in the absence of trophoblastic proliferation, but they are occasionally found in normal placenta younger than week 7. Although many features of normal and molar placenta were similar during the earliest weeks (5 to 6) including basophilic stroma, angiogenic cell cords (immature blood vessels), and often circumferential trophoblastic sprouts and proliferation, already by that time early moles showed significantly greater percentages of stromal cells undergoing karyorrhexis and apoptosis compared with normal placenta (37.6% vs. 5.4%). These results indicate the histologic features do exist early on in pregnancy to differentiate normal from molar pregnancy. Further, it points out that complete hydatidiform mole in addition to being disease of trophoblastic proliferation is also associated with defects in vasculogenesis and maturation of villous stromal constituents.

Uterine leiomyomas (fibroids) are benign tumors that are prevalent in women of reproductive age. Research suggests that activated receptor tyrosine kinases (RTKs) play an important role in the enhanced proliferation observed in fibroids. In this study, a phospho-RTK array technique was used to detect RTK activity in leiomyomas compared with myometrial tissue. We found that fifteen out of seventeen RTKs evaluated in this study were highly expressed (P0.02-0.03) in the leiomyomas, and included the IGF-I/IGF-IR, EGF/EGFR, FGF/FGF-R, HGF/HGF-R, and PDGF/PDGF-R gene families. Due to the higher protein levels of IGF-IR observed in leiomyomas by us in earlier studies, we decided to focus on the activation of the IGF-IR, its downstream effectors, and MAPKp44/42 to confirm our earlier findings; and validate the significance of the increased IGF-IR phosphorylation observed by RTK array analysis in this study. We used immunolocalization, western blot, or immunoprecipitation studies and confirmed that leiomyomas overexpressed IGF-IRbeta and phosphorylated IGF-IRbeta. Additionally, we showed that the downstream effectors, Shc, Grb2, and MAPKp44/42 (P0.02-0.001) were also overexpressed and involved in IGF-IR signaling in these tumors, while IRS-I, PI3K, and AKT were not. In vitro studies showed that IGF-I (100 ng/mL) increased the proliferation of uterine leiomyoma cells (UtLM) (P0.0001), and that phosphorylated IGF-IRbeta, Shc, and MAPKp44/42 were also overexpressed in IGF-I-treated UtLM cells (P0.05), similar to the tissue findings. A neutralizing antibody against the IGF-IRbeta blocked these effects. These data indicate that overexpression of RTKs and, in particular, activation of the IGF-IR signaling pathway through Shc/Grb2/MAPK are important in mediating uterine leiomyoma growth. These data may provide new anti-tumor targets for noninvasive treatment of fibroids.

To assess whether preeclampsia risk is elevated in pregnancies of diethylstilbestrol (DES)-exposed daughters.This study used data from the National Cancer Institute DES Combined Cohorts Follow-up Study. A total of 285 preeclampsia cases (210 exposed and 75 unexposed) occurred in 7,313 live births (4,759 DES exposed and 2,554 unexposed). Poisson regression analysis estimated relative risks and 95% confidence intervals (CI) for preeclampsia adjusted for age at the index pregnancy, parity, education, smoking, body mass index, year of diagnosis, and cohort.In utero DES exposure was associated with nearly a 50% elevation in preeclampsia risk. Adjustment for preeclampsia risk factors attenuated the relative risk slightly (1.42, 95% CI 1.04-1.94). The excess risk with DES was concentrated among women who developed preeclampsia in their first pregnancies (relative risk 1.81, 95% CI 1.17-2.79), who were exposed before 15 weeks of gestation (relative risk 1.57, 95% CI 1.11-2.23), and who were treated with magnesium sulfate (relative risk 2.10, 95% CI 0.82-5.42). Among DES-exposed women who had a prior hysterosalpingogram, preeclampsia prevalence was higher in those with uterine abnormalities (12.4%) than in those without (7.7%).These data suggest that in utero exposure to DES is associated with a slightly elevated risk of preeclampsia, and that one possible biological mechanism involves uterine abnormalities.

Endometrial "hyperplasia," as currently diagnosed, includes the changes caused by an abnormal hormonal state and those caused by a separate category of monoclonal premalignant disease. The appearance of the disease in these 2 functional categories is discontinuous, permitting more specific diagnosis of the condition using the terms "benign endometrial hyperplasia" and "endometrial intraepithelial neoplasia" (EIN), respectively. Benign endometrial hyperplasia involves the entire endometrial compartment and, with protracted estrogen exposure, shows the progressive development of cysts, remodeled glands, vascular thrombi, and stromal microinfarcts. They are best construed as a sequence of changes whereby the appearance at any single time point is uniquely dependent on the preceding combination and the duration of hormonal exposures. In contrast, the premalignant clone of an EIN lesion is characteristically offset from the background endometrium by its altered cytology and crowded architecture. The use of an internal standard for cytology assessment, combined with the distinctive topography of a clonal process, enables the diagnosis of EIN lesions with a long-term cancer risk 45-fold greater than that of their benign endometrial hyperplasia counterparts. The resolution of hormonal and premalignant subsets of traditional "endometrial hyperplasias" is possible using redefined diagnostic criteria, enabling patient therapy to be appropriately matched with the underlying disease mechanisms.

Continuing new insights into the biology of sexual development and advances in chromosome analysis have led to early identification and prompt treatment of the intersexual patient, the results of which facilitate a more normal life for affected individuals. Based on these advances, a classification of abnormal sexual development has been developed and refined that correlates the gonadal and genital anatomy with the chromosomal findings and specific genetic or metabolic defects. In a shift from a classification anchored on whether the intersex revolves about a specific gene or whole chromosomal abnormality, the current classification is organised by broader categories into which the intersexual disorders are divided into 'abnormalities of genital differentiation', due largely to the abnormal production or sensitivity of a single hormone, or 'abnormalities in sex determination', due to abnormal gonadal differentiation, usually testicular, with or without chromosomal aberration. The current classification is an integrated approach to this complex group of disorders and is organised according to the manner by which patients present as well as on the pathophysiological basis of the defect. The classification also groups patients who are at high risk for development of gonadal neoplasia.

Summary: This is the first report of a silent corticotroph cell pituitary adenoma arising in a struma ovarii. The patient, a 79-year-old woman, was found to have an asymptomatic left-sided adnexal mass confirmed by vaginal sonography to be a complex cystic and solid tumor. Pathological anlysis demonstrated an 8-cm partially cystic struma ovarii in which there was a focus of predominantly basophilic adenohypophyseal cells arranged in a diffuse pattern, adjacent to mature neural tissue containing numerous Herring bodies. The epithelial lining cells of the colloid-filled small and cystic follicles were immunoreactive for thyroglobulin. The pituitary cells were predominantly immunoreactive for adrenocorticotropic hormone, in addition to synaptophysin.

Cytology is an effective method for assessing benign endometrium and for discovering premalignant and malignant endometrial states. In addition, it is useful for diagnosing non-neoplastic abnormalities of the endometrium. This overview compares endometrial cytology to endometrial histology for a variety of benign, abnormal non-neoplastic, and neoplastic conditions; and, discusses both diagnostic criteria and pitfalls in the assessment of endometrial brushings specimens. It also makes an attempt to estimate levels of confidence in endometrial cytodiagnosis. When endometrial brushing is used in conjunction with other diagnostic techniques such as ultrasonography/sonohysterography or hysteroscopy, cytology becomes a sensitive case finding technique that shows good patient acceptance (because of a significant decrease in procedure-associated pain) and high diagnostic yield.

Effective physician workforce management requires that the various organizations comprising the House of Medicine be able to assess their current and future workforce supply. This information has direct relevance to funding of graduate medical education. We describe a dynamic modeling tool that examines how individual factors and practice variables can be used to measure and forecast the supply and demand for existing and new physician services. The system we describe, while built to analyze the pathologist workforce, is sufficiently broad and robust for use in any medical specialty. Our design provides a computer-based software model populated with data from surveys and best estimates by specialty experts about current and new activities in the scope of practice. The model describes the steps needed and data required for analysis of supply and demand. Our modeling tool allows educators and policy makers, in addition to physician specialty organizations, to assess how various factors may affect demand (and supply) of current and emerging services. Examples of factors evaluated include types of professional services (3 categories with 16 subcategories), service locations, elements related to the Patient Protection and Affordable Care Act, new technologies, aging population, and changing roles in capitated, value-based, and team-based systems of care. The model also helps identify where physicians in a given specialty will likely need to assume new roles, develop new expertise, and become more efficient in practice to accommodate new value-based payment models.

Women in the 1940s-1960s were prescribed diethylstilbestrol (DES), a nonsteroidal estrogen, to prevent miscarriages, but the practice was terminated after it was discovered that the daughters so exposed in utero were at increased risk for developing clear cell adenocarcinoma (CCA) of the vagina or cervix at early ages. Pap smear screening is one of the principal methods used to identify tumor development and is necessary in this group of women to maintain their health. Currently, little is known about the factors associated with nonutilization of this screening tool in this high-risk population of women.National cohort data from the National Cancer Institute (NCI) DES Combined Cohort Follow-up Study during 1994, 1997, 2001, and 2006 were used to determine which factors were associated with Pap smear screening nonutilization in 2006 among DES-exposed and unexposed women. Self-reported questionnaire data from 2,861 DES-exposed and 1,027 unexposed women were analyzed using binary logistic regression models.DES exposure, not having a previous gynecologic dysplasia diagnosis, lack of insurance, originating cohort, increasing age, and previous screening behavior were all factors associated with not reporting a Pap smear examination in the 2006 questionnaire, although college education reduced nonutilization.Understanding which factors are associated with not acquiring a screening exam can help clinicians better identify which DES-exposed women are at risk for nonutilization and possibly tailor their standard of care to aid in the early detection of cervical and vaginal adenocarcinomas in this high-risk group.

The pathogenetic mechanism underlying the hydropic change in complete hydatidiform moles (CHMs) is poorly understood. A growing body of data suggests that pericytes play a role in vascular maturation. Since maturation of villous stromal vessels in CHMs is markedly impaired at early stages, we postulated that a defect in pericytes around stromal vessels in chorionic villi might cause vascular immaturity and subsequent hydropic change. To investigate this, we examined several markers of pericytes, namely, α-smooth muscle actin (α-SMA), platelet-derived growth factor receptor-β (PDGFR-β), and desmin, in 61 normally developing placentas and 41 CHMs with gestational ages of 4–12 weeks. The ultrastructure of villous stromal vessels was also examined. Mature blood vessels from normal placentas show patent vascular lumens and formed hematopoietic components in the villous stroma. α-SMA and PDGFR-β expression in the villous stroma gradually increased and extended from the chorionic plate to peripheral villous branches. The labeled cells formed a reticular network in the villous stroma and, after week 7, encircled villous stromal vessels. In comparison, α-SMA and PDGFR-β expression in the villous stroma and stromal vessels of CHMs was significantly lower (p

Exploring whether the positive association between birth weight and breast cancer risk differs by other breast cancer risk factors may help inform speculation about biological mechanism. In these data, high birth weight was associated with breast cancer risk in younger and in more educated women, but was not associated overall.

p63 is the identity switch for uterine/vaginal epithelial cell fate, and disruption of p63 expression by diethylstilbestrol (DES) induces cervical/vaginal adenosis in mice. In this article, we report the expression patterns of p63 isoforms (TA, DeltaN, alpha, beta and gamma) in mice, focusing on the reproductive tract. We also present the reproductive tract phenotype of female p63-/- mice. Finally, to better evaluate the potential role of p63 in human development of DES-induced cervical/vaginal adenosis, we describe the ontogeny of p63 in human female fetuses. In adult mice, the DeltaN isoforms of p63 were expressed only in squamous/basal/myoepithelial cells of epithelial tissues, while TA isoforms of p63 were highly expressed in germ cells of the ovary and testis. In fetal mice, the DeltaN and alpha forms of p63 were expressed in the cloacal and urogenital sinus epithelia. In the female p63-/- mice, the sinus vagina developed, but p63-/- sinus vaginal epithelium failed to undergo squamous differentiation confirming an essential role of p63 in squamous epithelial differentiation. Although TAp63 was highly expressed in developing primordial germ cells/oocytes, p63-/- ovaries and oocytes developed normally. The ontogeny of p63 in female reproductive organs was essentially identical in mouse and human. In the human fetus at the susceptible stage for DES-induced cervical/vaginal adenosis, most cervical/vaginal epithelial cells were columnar and negative for p63. Therefore, inhibition of p63 expression by DES should change the cell fate of human Müllerian duct epithelial cells and cause cervical/vaginal adenosis as previously demonstrated in mouse.

Most cervical high-grade squamous intraepithelial lesions (HSILs) persist, but approximately one third regress (ie, no HSIL in follow-up biopsies). To identify factors related to histologic proven persistence or regression. Twenty-eight small histologic (marker) biopsies with adequate follow-up were analyzed for human papillomavirus (HPV) genotypes and different immunoquantitative proliferation, cell cycle regulation, and differentiation markers. All cases had a biopsy-interval between the marker and first follow-up biopsy of at least 100 days (median, 8.2 months; range, 3.4-22.5 months). Follow-up was classified as regression or persistence. All lesions were high-risk (hr) HPV and p16 positive, 63% for HPV-16 or HPV-16 mixed with other hr genotypes, while 37% had other hrHPV types. The marker biopsies of the persistent HSILs had lower p53 and retinoblastoma protein (pRb) detected in the deep half of the epithelium (P = 0.001 and 0.02, respectively) than nonpersistent HSILs. The degree of positivity of p16, Ki-67, cyclin D1, lesion extent, positivity of the resection margins, and patient age were all unrelated to persistence or regression. Lesions with HPV-16 or mixed-16 genotypes had a significantly lower percentage of pRb (P = 0.02), p53 (P = 0.02), and cyclin D (P = 0.04) positive nuclei in the deep epithelial layers. In agreement with this, type-16 positive HSILs had a lower regression percentage than those with other HPV types, but the difference was not significant. HSILs with combined negativity/low positivity for p53 and pRb protein in small histologic biopsies are highly likely to persist, contrasting those in which one of these cell cycle regulators is strongly positive (p53 > 15%; pRb > 40%).

Diethylstilbestrol (DES) is a synthetic estrogen that was widely prescribed to pregnant women before 1971. DES increases the risk of breast cancer in women who took the drug and the risk of reproductive tract abnormalities in their offspring. Dutch investigators have reported a 20-fold increase in risk of hypospadias among sons of women who were exposed to DES in utero. We assessed this relation in data from an ongoing study of DES-exposed persons.Several U.S. cohorts of women with documented exposure in utero to DES have been followed by mailed questionnaires since the 1970s. Comparison subjects are unexposed women of the same ages. In 1997, participants were asked about congenital abnormalities in their children. We calculated prevalence odds ratios for the risk of hypospadias in sons of exposed mothers relative to sons of unexposed mothers using generalized estimating equations to adjust for multiple sons per mother and controlling for maternal age at the son's birth.We obtained data from 3916 exposed and 1746 unexposed women. These women reported a total of 13 liveborn sons with hypospadias (10 exposed, 3 unexposed). The prevalence odds ratio for risk of hypospadias among the exposed was 1.7 (95% confidence interval = 0.4-6.8).Our findings do not support a greatly increased risk of hypospadias among the sons of women exposed to DES in utero, as has been previously reported.

Objective To investigate the association between prenatal diethylstilbestrol (DES) exposure and risk of benign gynecologic tumors. Methods We conducted a collaborative follow-up study of women with and without documented intrauterine exposure to DES. We compared the incidence of self-reported ovarian cysts, paraovarian cysts, and uterine leiomyomata confirmed by medical record in DES-exposed and unexposed women. Results A total of 85 cases of uterine leiomyomata and 168 cases of ovarian or paraovarian cysts were confirmed histologically. After adjustment for age, no association was found between prenatal DES exposure and ovarian cysts or uterine leiomyomata. Prenatal DES exposure was positively associated with paraovarian cysts. Conclusion The present results do not support the hypothesis that prenatal DES exposure increases risk of uterine leiomyomata or ovarian cysts. Prenatal DES exposure was associated with an increased risk of paraovarian cysts, but detection bias cannot be ruled out as an explanation of this finding.

Carcinosarcoma of the uterus has been poorly characterized on cervicovaginal (Pap) smears, and we examine whether they effectively screen for carcinosarcoma and whether an abnormal Pap smear result has any clinical importance. Twenty-five patients with histologically confirmed carcinosarcoma had a conventional Pap smear shortly before diagnosis. Eleven smears (44%) originally were read as abnormal (malignant or atypical), and 4 additional cases were read as abnormal on retrospective review (15/25 [60%]). All malignant elements were epithelial, and 2 cases (8%) had atypical spindle cells, but no diagnostic sarcoma. Cervical involvement was the only histologic parameter correlating with an abnormal Pap smear result (P = .04). Univariate analysis found stage III or IV disease was an adverse prognostic sign compared with stage I or II disease (mean survival, 8 vs 36 months, respectively; P = .001), and multivariate analysis indicated that an abnormal Pap smear result correlated with worse survival (P = .023). The conventional Pap smear is insensitive (60%) for detecting carcinosarcoma, but when the result is abnormal, the Pap is an important stage-independent adverse prognosticator. Carcinosarcoma, earlier known as malignant mixed mesodermal/mullerian tumor, is an uncommon uterine tumor that occurs principally in older women. The tumor typically appears grossly as a large intrauterine mass that often fills and expands the endometrial cavity and histologically discloses a mixture of malignant epithelial and mesenchymal elements. These tumors usually are associated with a poor prognosis. Our study had 3 aims: (1) test whether the routine Papanicolaou (Pap) smear effectively screens for the detection of carcinosarcoma, (2) search for consistent findings to recognize carcinosarcoma on Pap smears, and (3) examine whether the finding of an abnormal smear has independent clinical significance.