To develop diagnostic criteria for chronic endometritis and compare the prevalence of chronic endometritis between women with recurrent pregnancy loss (RPL) and controls.
Cohort study.
Single ...academic fertility center.
Women with unexplained RPL (two or more pregnancy losses) and prospectively recruited controls without a history of RPL or infertility.
Endometrial samples were stained with hematoxylin and eosin and CD138. A pathologist blinded to patient history recorded the number of plasma cells per 10 high-power fields (HPFs). In addition, the presence or absence of endometrial stromal changes was documented.
Prevalence of chronic endometritis.
Endometrial samples from 50 women with unexplained RPL and 26 controls were evaluated. When chronic endometritis was defined as the presence of one or more plasma cells per 10 HPFs, 31% of controls and 56% of women with RPL met the criterion. When both endometrial stromal changes and plasma cells were required for a diagnosis of chronic endometritis, no controls and 30% of women with RPL met the criteria.
Although rare plasma cells were found in biopsy samples from controls, the presence of both plasma cells and endometrial stromal changes was limited to the RPL cohort. We propose that chronic endometritis be defined as the presence of one or more plasma cells per 10 HPFs in the setting of endometrial stromal changes. With the use of these strict diagnostic criteria, women with RPL have a significantly higher rate of chronic endometritis, supporting an association between chronic endometritis and RPL.
Redefiniendo la endometritis crónica: la importancia de los cambios estromales endometriales.
Desarrollar criterios diagnósticos para la endometritis crónica y comparar la prevalencia de endometritis crónica entre mujeres con pérdida recurrente de embarazo (PRE) y controles.
Estudio de cohorte.
Centro académico único de fertilidad.
Mujeres con PRE inexplicada (pérdida de dos o más embarazos) y controles reclutados prospectivamente sin historia de PRE o infertilidad.
Las muestras endometriales fueron teñidas con hematoxilina eosina y marcadas para CD 138. El patólogo desconociendo la historia clínica de la paciente, realizó el recuento del número de células plasmáticas por 10 campos de gran aumento (CGA). Además, se documentó la presencia o ausencia de cambios estromales endometriales.
Prevalencia de endometritis crónica.
Se evaluaron las muestras endometriales de 50 mujeres con PRE inexplicada y de 26 controles. Al definir la endometritis crónica como la presencia de una o más células plasmáticas por 10 CGA, en el 31% de los controles y en el 56% de las mujeres con PRE se encontraron criterios para su diagnóstico. Cuando para el diagnóstico de endometritis crónica se requirió tanto la presencia de células plasmáticas como los cambios en el estroma endometrial, ningún control y sólo el 30% de las mujeres con PRE cumplieron los criterios.
A pesar de que raramente se hallaron células plasmáticas en las biopsias de los controles, la presencia tanto de células plasmáticas como de cambios estromales endometriales se limitó a la cohorte de mujeres con PRE. Proponemos que la endometritis crónica sea definida como la presencia de una o más células plasmáticas por cada 10 CGA en el contexto de los cambios estromales endometriales. Con el uso de estos criterios diagnósticos estrictos las mujeres con PRE tienen una tasa significativamente más alta de endometritis crónica, apoyando la asociación entre endometritis crónica y PRE.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The endocrine system dynamically controls tissue differentiation and homeostasis, but has not been studied using dynamic tissue culture paradigms. Here we show that a microfluidic system supports ...murine ovarian follicles to produce the human 28-day menstrual cycle hormone profile, which controls human female reproductive tract and peripheral tissue dynamics in single, dual and multiple unit microfluidic platforms (Solo-MFP, Duet-MFP and Quintet-MPF, respectively). These systems simulate the in vivo female reproductive tract and the endocrine loops between organ modules for the ovary, fallopian tube, uterus, cervix and liver, with a sustained circulating flow between all tissues. The reproductive tract tissues and peripheral organs integrated into a microfluidic platform, termed EVATAR, represents a powerful new in vitro tool that allows organ-organ integration of hormonal signalling as a phenocopy of menstrual cycle and pregnancy-like endocrine loops and has great potential to be used in drug discovery and toxicology studies.
Cervical intraepithelial neoplasia (CIN) 2 is an equivocal diagnosis, with p16 immunohistochemical positivity currently recommended for diagnostic confirmation. Biomarkers characteristic of ...squamocolumnar junction cells were recently found to be positive in almost all CIN 2 and CIN 3. CIN 1 lesions which express squamocolumnar junction markers (in particular cytokeratin 7 CK7) are associated with a higher rate of subsequent high-grade squamous intraepithelial lesion, suggesting that CK7 may be a useful prognostic biomarker for CIN 1. We sought to determine the utility of CK7 as a prognostic biomarker in the setting of morphologic CIN 2, and to compare this to the utility of p16 in this setting. We performed CK7 immunohistochemical on 116 cases originally diagnosed as CIN 2. Of these, 68.1% were p16 and 90.5% were CK7. A total of 19.5% of patients had a subsequent diagnosis of CIN 3 on biopsy or excision; the index CIN 2 lesion was CK7 in all of these cases (sensitivity 100%) and p16 in all but 1 (21/22; sensitivity 95.5%). The specificity of p16 (37.4%) and CK7 (8.0%) for predicting subsequent CIN 3 were significantly different (P<0.001). While p16 expression was significantly associated with subsequent CIN 3 (P=0.002), CK7 expression was not (P=0.202). We conclude that CK7, unlike p16, is not useful as a prognostic biomarker in CIN 2. While it is still promising as a prognostic marker in CIN 1, additional studies are needed to determine optimal staining/interpretation criteria.
Context.--Pathology resident education has a steep learning curve. Specimen sampling (grossing) is a procedural task, and procedural fields add video materials to their curricula to familiarize ...trainees with procedure(s), reduce errors, and improve patient care. Our team applied this strategy to develop original in-house sampling videos for our program. Objectives.--To evaluate the effect of in-house sampling videos on resident sampling confidence. Design.--Sampling videos covering all major organ systems (AMOS) were created for our postgraduate year 1 (PGY1) trainees. Videos were hosted on a Northwestern cloud server for on-demand access. Trainees completed 3 surveys (0, 6, 12 months) evaluating sampling confidence comparing those who used in-house videos as an educational supplement with those who did not use the videos. Results.--Sampling confidence significantly improved at 6 and 12 months (P < .001) across AMOS and PGY levels. When compared with those who did not use in-house sampling videos, trainees who supplemented their education with in-house sampling videos had significantly higher confidence ratings across AMOS and PGY levels at the start of the study (P < .001) and at 6 months (P = .004). Sampling confidence significantly improved for PGY1 trainees at 6 and 12 months (P < .001); for PGY2 and PGY3 trainees, confidence significantly improved at 6 months (P < .001). When evaluated by organ-specific analyses, sampling and teaching confidence improved across all organ systems and, except for the gastrointestinal system, reached significance at 12 months for all PGY levels. Conclusions.--Sampling videos, when used as a supplement to the existing curriculum, significantly improved trainee confidence. doi: 10.5858/arpa.2022-0153-OA
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Most endometrial cancers are detected early and have a good prognosis, while some endometrial cancers are highly invasive, metastasize early, and respond suboptimally to therapy. Currently, ...appropriate model systems to study the aggressive nature of these tumors are lacking. The objective of this study was to establish a mouse xenograft model of endometrial tumors derived from patients in order to study the biological aggressive characteristics that underlie invasion and metastasis.
Endometrial tumor tissue fragments (1.5 mm × 1.5 mm) from patients undergoing surgery, were transplanted under the renal capsule of NOD scid gamma mice. After 6-8 weeks, tumors were excised and serially transplanted into additional mice for propagation. Immunohistochemical analysis of the tumors was done for various tumor markers.
Four cases of different subtypes of endometrial cancer were grown and propagated in mice. Three of the four tumor cases invaded into the kidneys and to adjacent organs. While all tumors exhibited minimal to no staining for estrogen receptor α, progesterone receptor staining was observed for tumor grafts. In addition, levels and localization of E-cadherin, cytokeratin and vimentin varied depending on subtype. Finally, all tumor xenografts stained positively for urokinase plasminogen activator while 3 tumor xenografts, which showed invasive characteristics, stained positively for urokinase plasminogen activator receptor.
Endometrial tumors transplanted under the renal capsule exhibit growth, invasion and local spread. These tumors can be propagated and used to study aggressive endometrial cancer.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The incidence of anal cancer in the United States is on the rise in high-risk populations. The anal Papanicolaou test (APT) is advocated as a screening tool, in addition to digital rectal examination ...and high-resolution anoscopy.
To review our experience and the current literature to create, in cooperation with clinicians, a standardized screening and treatment algorithm given our large volume of APTs.
All APTs collected between January 2013 and June 2015 were reviewed and correlated with follow-up/concurrent biopsy diagnoses, and clinical and social history. In total, 1417 APTs were performed on 1185 patients and APT results were as follows: 17.4% (247 of 1417) unsatisfactory; 27.9% (395 of 1417) negative; 19.5% (276 of 1417) atypical squamous cells of undetermined significance (ASC-US); 24.1% (342 of 1417) low-grade squamous intraepithelial lesion (LSIL); 3.6% (51 of 1417) atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (HSIL) (ASC-H); and 7.5% (106 of 1417) HSIL. In total 376 cases (26.5%) had concurrent/follow-up biopsy. Review of all unsatisfactory cases with squamous intraepithelial lesion (SIL) on biopsy showed LSIL in 19.2% (5 of 26). Anal Papanicolaou test with cytologic abnormality (ASC-US+) had an 83.8% (315 of 376) rate of biopsy-proven disease, and sensitivity was higher (92%) for high-grade anal intraepithelial neoplasia or worse (AIN2+). Overall detection of AIN2+ using ASC-US+ showed specificity of 26%, negative predictive value of 92%, and positive predictive value of 26%.
Anal cytology has a high abnormal rate (54.7%) and sensitivity but poor correlation with histologic grade. High unsatisfactory rate indicates need for improvement in sampling with 68.4% of cases having SIL on biopsy. Multidisciplinary effort led to improvements in sampling, cytologic interpretation, and development of a standardized management algorithm.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
The pathogenesis of serous ovarian tumors has been extensively investigated, with a dualistic model dividing these cancers into 2 groups. Type I tumors, including low-grade serous carcinoma, is ...characteristic for concurrent presence of borderline tumors, less atypical cytology, relatively indolent biologic behavior, and molecular aberrations related to the MAPK pathway with chromosomal stability. Meanwhile, type II tumors, such as high-grade serous carcinoma, are notable for no significant association with borderline tumors, higher grade cytology, more aggressive biologic behavior, and TP53 mutations along with chromosomal instability. We describe a case of morphologic low-grade serous carcinoma with focally increased cytologic atypia arising in serous borderline tumors involving both ovaries, which demonstrated highly aggressive behavior despite several years of surgical and chemotherapeutic management. Each recurrent specimen contained more uniform higher grade morphology than what was seen in the original specimen. Immunohistochemical and molecular studies in both the original tumor and the most recent recurrence demonstrate identical mutations in the MAPK genes, but with additional mutations in the latter, notably an acquisition of a variant of possible clinical significance in the SMARCA4 gene, which is associated with dedifferentiation and aggressive biologic behavior. This case challenges our current and still evolving understanding of the pathogenesis, biologic behavior, and expected clinical outcome of low-grade serous ovarian carcinomas. It also underscores the need for further investigation into this complicated tumor.
In 2012, the College of American Pathologists and American Society for Colposcopy and Cervical Pathology published the “LAST” recommendations for histopathology reporting of human papilloma ...virus–related squamous lesions of the lower anogenital tract, including the use of a 2-tier nomenclature (low-grade squamous intraepithelial lesion/high-grade squamous intraepithelial lesion LSIL/HSIL) and expanded use of the biomarker p16 to classify equivocal lesions as either precancer (HSIL) or low-grade lesions (LSIL)/non-human papilloma virus changes. We aimed to determine (1) the frequency with which the poorly reproducible diagnosis of intermediate-grade (-IN 2) lesion in the lower anogenital tract would be downgraded on the basis of p16 results, and (2) whether p16 status was predictive of subsequent higher-grade lesions. A total of 200 specimens diagnosed as an intermediate-grade (-IN 2) lesion of the cervix (168), vagina (2), vulva (2), and anus (28) were reviewed and immunostained for p16. Slides were independently reviewed by 2 pathologists, with discrepant p16 interpretations adjudicated by a third pathologist. Of the 200 cases, 32% were negative for p16. Among the 166 patients with subsequent pathology (including 131 excisions), 26.2% of p16-positive cases versus 4.4% of p16-negative cases were associated with a subsequent diagnosis of HSIL (-IN 3) or worse (P=0.002). Reproducibility of the biopsy diagnosis was fair, with no significant difference with the addition of p16 or using 2 versus 3 tiers. In 11.5% of cases, there was discordance in p16 interpretation (κ 0.735, good agreement). The results indicate that using the Lower Anogenital Squamous Terminology recommendations would result in approximately one third of equivocal (-IN 2) diagnoses being downgraded to LSIL over 1 year in a busy academic practice. The significant association of p16 expression with a higher risk for HSIL on a subsequent specimen suggests that use of p16 to adjudicate equivocal (-IN 2) diagnoses in lower anogenital tract specimens as either LSIL or HSIL would likely predict lesion grade more accurately and avoid unnecessary excisional procedures.
The majority of vulvar intraepithelial neoplasia (VIN) is high-grade and is related to high-risk human papillomavirus (HRHPV) (most commonly HPV 16). It is considered to be the precursor of ...HRHPV-related vulvar squamous cell carcinoma. Vulvar condyloma acuminatum is low-risk HPV (LRHPV)-related (most commonly types 6 and 11) and has virtually no risk of neoplastic progression. While infection with multiple LRHPV and HRHPV types has been reported for cervical squamous intraepithelial lesions, coexisting vulvar condyloma and adjacent high-grade VIN have not been well characterized. Eleven cases of concurrent condyloma acuminatum and adjacent flat high-grade VIN and 3 cases of high-grade VIN with prominent condylomatous architecture were analyzed using immunohistochemical analysis of p16 expression, in situ hybridization (ISH) for HPV detection HPV 6/11, HPV 16, HPV 18, and HPV wide spectrum (types 6, 11, 16, 18, 31, 33, 35, 45, 51, 52) probes, and HPV typing by a polymerase chain reaction (PCR)-based method (in select cases). All patients had underlying immunosuppressive conditions (human immunodeficiency virus infection or posttransplant therapy). Among the 11 cases of concurrent high-grade VIN and condyloma, the lesions were directly adjacent to one another in 5 cases (with 2 of these demonstrating an intimate admixture of lesions), and in 6 cases the lesions were found in separate tissue sections from the same specimen. Diffuse/strong p16 expression was seen in all high-grade VIN lesions, whereas patchy/weak staining was found in all condylomata. All condylomata contained HPV 6 or 11 as detected by ISH. HRHPV was detected in all of the accompanying high-grade VIN lesions. Ten contained HPV 16 (9 by ISH, 1 by PCR), with the remaining case containing multiple HPV types by PCR. All condylomatous high-grade VIN lesions demonstrated diffuse/strong p16 expression and had evidence of HRHPV (1 with HPV 16 by ISH, 1 with HPV 18 by ISH, and 1 with multiple HPV types by PCR), with no detection of HPV 6 or 11 by ISH. The restriction of LRHPV to condylomatous components and HRHPV to high-grade VIN components of adjacent lesions suggests these are independent lesions caused by different HPV types. Diffuse p16 expression can highlight small foci of high-grade VIN, which may be overlooked in more abundant condylomatous tissue from immunosuppressed patients. The presence of only HRHPV in those VIN lesions with high-grade cytologic features but prominent condylomatous architecture supports their classification as forms of pure high-grade VIN and distinguishes them from condyloma acuminatum.
Squamous cell carcinomas of the lower anogenital tract that are related to human papillomavirus (HPV) infection represent a significant disease burden worldwide. The diagnosis and management of their ...noninvasive precursors has been the subject of extensive study and debate over several decades, accompanied by an evolving understanding of HPV biology. Recent new consensus recommendations for the pathologic diagnosis of these precursor lesions were published in 2012, the result of the Lower Anogenital Squamous Terminology project cosponsored by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Most salient among the new guidelines are the recommendation to switch to a 2-tiered nomenclature (high-grade squamous intraepithelial lesion and low-grade squamous intraepithelial lesion) rather than the traditional 3-tiered “intraepithelial neoplasia” terminology, and the recommendation to expand use of the immunohistochemical marker p16 to distinguish between low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion/intraepithelial neoplasia 2. The goals of the project were to align diagnostic terminology with our knowledge of HPV biology, increase reproducibility, consolidate diverse systems of nomenclature, and ultimately better determine a patient’s true cancer risk. The clinical guidelines for screening and management of cervical intraepithelial neoplasia have also been recently updated, most notably with a lengthening of screening intervals. In this review, we focus on the new guidelines put forth for pathologic diagnosis of HPV-related anogenital neoplasia, with discussion of the evidence behind them and their potential implications. We also provide an update on relevant biomarkers, clinical recommendations, and the newest developments relating to cervical neoplasia.
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