Pathology and Pathogenesis of Adenomyosis

AbstractAdenomyosis represents a unique pathophysiological condition in which normal-appearing endometrial mucosa resides within myometrium and is thus protected from menstrual shedding. The resulting ectopic presence of endometrial tissue composed of glands and stroma is thought to affect normal contractile function and peristalsis of uterine smooth muscle, causing menometrorrhagia, infertility, and adverse obstetric outcomes. Since the first description of adenomyosis more than 150 years ago, pathologists have studied this lesion by examining tissue specimens, and have proposed multiple explanations to account for its pathogenesis. However, as compared with endometriosis, progress of adenomyosis research has been, at best, incremental mainly due to the lack of standardized protocols in sampling tissue and a lack of consensus diagnostic criteria in pathology practice. Despite these limitations, recent advances in revealing the detailed anatomy and biology of eutopic endometrium offer an unprecedented opportunity to study this common but relatively understudied disorder. Here, we briefly summarize the pathological aspects of adenomyosis from an historical background, and discuss conventional morphology and recent tissue-based molecular studies with a special emphasis on elucidating its tissue of origin from a pathologist's perspective. We also discuss unmet needs in pathology studies that would be important for advancing adenomyosis research.

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Modulation of Striated Muscle Function is Reflected by Thick Filament Structure.

Microscopy and Microanalysis ◽

10.1017/s1431927600032876 ◽

2000 ◽

Vol 6 (S2) ◽

pp. 76-77

Author(s):

Rhea J.C. Levine ◽

Irina Kulakovskaya ◽

H. Lee Sweeney ◽

Saul Winegrad ◽

Zhaohui Yang

Keyword(s):

Structural Changes ◽

Striated Muscle ◽

Contractile Function ◽

Thick Filament ◽

Calcium Sensitivity ◽

Thin Filaments ◽

Calcium Dependent ◽

Regulation Of Activity ◽

Myosin Binding ◽

Tissue Specimens

In mammalian skeletal and cardiac muscles, regulation of activity occurs when calcium binds to troponin on thin filaments, which ultimately results in exposure of myosin-binding sites on actin. However, modulation of contractile function, affecting such parameters as calcium sensitivity, the rate of rise of tension, the expression of maximum tension and/or the rate of onset of relaxation, is also calcium dependent. It is, in part, a property of the thick filament itself and its component myosin and/or accessory proteins. Among these are phosphorylation of myosin regulatory light chains or light chain 2 (RLCs; LC2) and in cardiac, but not skeletal fibers, phosphorylation of myosin-binding protein C (MyBP-C).Gentle methods of separating thick filaments from small tissue specimens, subjected to various experimental protocols designed to explore the functional parameters of such modulatory activities, allow examination of any accompanying structural changes.

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Uterine smooth muscle tumour of uncertain malignant potential and in vitro fertilization treatment in an infertile patient

SAGE Open Medical Case Reports ◽

10.1177/2050313x211012516 ◽

2021 ◽

Vol 9 ◽

pp. 2050313X2110125

Author(s):

Triantafyllidou Olga ◽

Kastora Stavroula Lila ◽

Georgios Kounidas ◽

Papazian Maria ◽

Vlahos Nikolaos

Keyword(s):

Smooth Muscle ◽

In Vitro Fertilization ◽

Malignant Potential ◽

Obstetric Outcomes ◽

Uncertain Malignant Potential ◽

Vitro Fertilization ◽

Uterine Smooth Muscle ◽

First Case ◽

Fertility Sparing

The term smooth uterine muscle of uncertain malignant potential (STUMP) indicates a group of uterine smooth muscle tumours that cannot be diagnosed unequivocally as malignant but does not fulfil the criteria for leiomyoma, or its variants. In this case, we present a woman treated for infertility who presented with an asymptomatic cervical mass, diagnosed as STUMP after three cycles of controlled ovarian stimulation. We reviewed the literature with particular emphasis on the effects of STUMP upon fertility, up-to-date guidance regarding the management of patients’ wishing fertility-sparing approaches and obstetric outcomes. To the best of our knowledge, this is the first case report of STUMP in a patient that has undergone multiple in vitro fertilization treatments as well as the first to provide a putative biological basis for the efficacy of gonadotropin-releasing hormone agonists, in this patient group.

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Lgr5 Does Not Vary Throughout the Menstrual Cycle in Endometriotic Human Eutopic Endometrium

International Journal of Molecular Sciences ◽

10.3390/ijms20010022 ◽

2018 ◽

Vol 20 (1) ◽

pp. 22

Author(s):

Júlia Vallvé-Juanico ◽

Cristian Barón ◽

Elena Suárez-Salvador ◽

Josep Castellví ◽

Agustín Ballesteros ◽

...

Keyword(s):

Menstrual Cycle ◽

Inflammatory Marker ◽

Obstetric Outcomes ◽

Deep Infiltrating Endometriosis ◽

Eutopic Endometrium ◽

Cell Percentage ◽

Inflammatory Phenotype ◽

Lgr5 Expression ◽

G Protein Coupled

Endometriosis is characterized by the abnormal presence of endometrium outside of the uterus, resulting in pelvic pain and infertility. The leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) has been postulated to be a marker of stem cells in the endometrium. However, LGR5+ cells have a macrophage-like phenotype in this tissue, so it is unclear what role LGR5+ cells actually play in the endometrium. Macrophages serve an important function in the endometrium to maintain fertility, while LGR5+ cells generally have a role in tumor progression and are involved in invasion in some cancers. We sought to determine whether LGR5+ cells vary across the menstrual cycle in women with endometriosis and whether there are implications for LGR5 in the aggressiveness of endometriosis and reproductive outcomes. We performed immunofluorescence, flow cytometry, and primary culture in vitro experiments on eutopic and ectopic endometrium from healthy and endometriosis patients and observed that neither LGR5+ cells nor LGR5 expression varied throughout the cycle. Interestingly, we observed that LGR5+ cell percentage overexpressing CD163 (anti-inflammatory marker) was higher in healthy endometrium, suggesting that in endometriosis, endometrium presents a more pro-inflammatory phenotype that likely leads to poor obstetric outcomes. We also observed higher levels of LGR5+ cells in ectopic lesions compared to eutopic endometrium and specifically in deep infiltrating endometriosis, indicating that LGR5 could be involved in progression and aggressiveness of the disease.

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Prospective study of a 10-gene molecular assay to predict tissue of origin in patients with carcinoma of unknown primary (CUP)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.21096 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 21096-21096

Author(s):

G. R. Varadhachary ◽

D. Talantov ◽

T. Jatkoe ◽

A. Rashid ◽

R. Lenzi ◽

...

Keyword(s):

Prospective Study ◽

Metastatic Carcinoma ◽

Unknown Primary ◽

Cancer Type ◽

Carcinoma Of Unknown Primary ◽

Carcinoma Tissue ◽

Gene Assay ◽

Tissue Of Origin ◽

Tissue Specimens ◽

Pathological Assessment

21096 Background: Carcinoma of unknown primary (CUP) where metastatic disease presents without an identifiable primary represents ∼ 3–5% of all cancers. Identifying the origin of the primary tumor in CUP pts can facilitate rational choice of therapeutic regimens. Veridex developed an optimized set of 10 gene markers for a quantitative reverse transcriptase polymerase chain reaction (qRTPCR) assay, and demonstrated high accuracy in predicting the tissue of origin with formalin-fixed, paraffin-embedded (FFPE) metastatic carcinoma samples (J Mol Diagn 2006, 8: 320–9). In this study, the 10-gene assay was prospectively evaluated in CUP pts. Methods: We collected FFPE biopsy tissue specimens from consenting CUP pts at MD Anderson. Eligibile pts met our definition for CUP with adenocarcinoma or poorly differentiated carcinoma. Samples were obtained prior to treatment. 51 pts have been enrolled so far and 11 were ineligible [insufficient samples].Of the 40 pts, qRTPCR assay has been performed on 33 pts. Data on 27/33 is available. A statistical model was used to determine the probability that the metastatic carcinoma tissue assayed originated from 1 of the following 7 categories: lung, pancreas, colon, breast, prostate, ovarian, and other. Subsequently, prediction of the primary by qRTPCR was independently compared with metastatic pattern spread, tumor pathological features, and results of clinical and pathology diagnostic workups. Results: Assay results on 27 prospectively collected CUP patient biopsy specimens are available. In total, CUP tissue of origin prediction by the assay correlated with clinical and pathological assessment in 21 out of 27 evaluated pts (78 %). The most common cancer type predicted by the assay was colon cancer, which correlated with predominantly intra-abdominal metastatic spread in this pt cohort. Conclusions: This prospective study demonstrated the feasibility of conducting gene analysis to predict metastatic carcinoma tissue of origin in FFPE tissue specimens derived from CUP patients. Overall distribution of various primary cancer types as predicted by the assay was consistent with the historical distribution reported for CUP. Assay prediction was concordant with clinical and pathological assessment in 78 % CUP pts. No significant financial relationships to disclose.

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Estrogen degrades Scribble in endometrial epithelial cells through E3 ubiquitin ligase HECW1 in the development of diffuse adenomyosis

Biology of Reproduction ◽

10.1093/biolre/ioz194 ◽

2019 ◽

Author(s):

Zhixing Jin ◽

Haiou Liu ◽

Congjian Xu

Keyword(s):

Epithelial Cells ◽

3D Culture ◽

Expression Level ◽

Eutopic Endometrium ◽

Estrogen Production ◽

Tissue Specimens ◽

Endometrial Epithelial Cells

Abstract Despite its prevalence and the severity of symptoms, little is known about the pathogenesis and etiology of adenomyosis. In previous studies, the protein expression level of the polarity protein Scribble in the eutopic endometrium of patients with adenomyosis was found to be significantly decreased; however, little is known about its regulatory mechanism. In consideration of the important role of supraphysiologic estrogen production in the endometrium in the development of adenomyosis, we analyzed the effect and mechanism of estrogen on the expression of Scribble in vivo and in vitro. Firstly, we found Scribble was down-regulated in eutopic endometrium and negatively related with aromatase P450 in Tamoxifen-induced adenomyosis. Then, we established a 3D culture of primary endometrial epithelial cells and used found that estrogen could disrupt apical-basal polarity of endometrial glandular epithelial cells. Based on the following experiments and GEO datasets screening, we found estrogen regulates the expression level of Scribble by HECW1 through ubiquitination of Scribble protein. At last, we verified the expression of Scribble, HECW1 and aromatase P450 in eutopic endometrium of human and mouse specimens and found the expression of HECW1 and aromatase P450 was significantly increased, while the expression of Scribble was significantly downregulated. Furthermore, a positive correlation was found between HECW1 and aromatase P450, while a negative correlation was found between HECW1 and Scribble in human clinical tissue specimens. Therefore, our research may provide a new understanding of the pathogenesis of adenomyosis.

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Myocardial ischemia: lack of coronary blood flow, myocardial oxygen supply-demand imbalance, or what?

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00139.2019 ◽

2019 ◽

Vol 316 (6) ◽

pp. H1439-H1446 ◽

Cited By ~ 11

Author(s):

Gerd Heusch

Keyword(s):

Blood Flow ◽

Myocardial Ischemia ◽

Myocardial Blood Flow ◽

Coronary Blood Flow ◽

Oxygen Supply ◽

Contractile Function ◽

Historical Background ◽

Prevailing Paradigm ◽

And Function ◽

Myocardial Oxygen Supply

This opinionated article reviews current concepts of myocardial ischemia. Specifically, the historical background is briefly presented. Then, the prevailing paradigm of myocardial oxygen-supply-demand imbalance is criticized since demand is a virtual parameter that cannot be measured and data on measurements of myocardial blood flow and contractile function rather support matching between flow and function. Finally, a concept of myocardial ischemia that focusses on the reduction of coronary blood flow to below 8–10 µl/g per beat with consequences for myocardial electrical, metabolic, contractile and morphological features is advocated.

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Ultrastructural Studies on Genital Infection with the Chlamydial Agent of Guinea Pig Inclusion Conjunctivitis

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100079267 ◽

1977 ◽

Vol 35 ◽

pp. 352-353

Author(s):

B. L. Soloff ◽

A. L. Barron ◽

H. J. White ◽

R. G. Rank

Keyword(s):

Guinea Pig ◽

Sexual Contact ◽

Chlamydia Psittaci ◽

Genital Infection ◽

Major Site ◽

Ultrastructural Studies ◽

Tissue Specimens ◽

Guinea Pig Model ◽

Adequate Tissue ◽

Genital Tissue

Chlamydial organisms (specifically C. trachomatis) have been implicated as a frequent cause of genital infection in the human (1). Study of the histo- pathological aspects of such infections has been impeded because of difficulties in obtaining adequate tissue specimens and the lack of a suitable experimental host. In 1964, Murray (2) isolated the causative agent of guinea pig inclusion conjunctivitis which possesses similarities to human inclusion conjunctivitis. This guinea pig organism was found to be a member of the Chlamydia psittaci subgroup and was designated as the Gp-ic agent. Male guinea pigs have been successfully infected with Gp-ic by intraurethral inoculation. Transmission of the infection to the female by sexual contact has been demonstrated (3). We are not aware of any ultrastructural studies to date concerning the development of this agent in genital tissue.Studies in our laboratory have established that, in our guinea pig model, the cervix is the major site of injection.

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Electron Microscopic Examination of a Transplantable Rat Mammary Carcinoma

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100099842 ◽

1968 ◽

Vol 26 ◽

pp. 20-21

Author(s):

S. Shirahama ◽

G. C. Engle ◽

R. M. Dutcher

Keyword(s):

Electron Microscope ◽

Osmium Tetroxide ◽

Electron Microscopic Examination ◽

Undifferentiated Carcinoma ◽

Uranyl Acetate ◽

Sprague Dawley ◽

Electron Microscopic ◽

North West ◽

X Irradiation ◽

Tissue Specimens

A transplantable carcinoma was established in North West Sprague Dawley (NWSD) rats by use of X-irradiation by Engle and Spencer. The tumor was passaged through 63 generations over a period of 32 months. The original tumor, an adenocarcinoma, changed into an undifferentiated carcinoma following the 19th transplant. The tumor grew well in NWSD rats of either sex at various ages. It was invariably fatal, causing death of the host within 15 to 35 days following transplantation.Tumor, thymus, spleen, and plasma from 7 rats receiving transplants of tumor at 3 to 9 weeks of age were examined with an electron microscope at intervals of 8, 15, 22 and 30 days after transplantation. Four normal control rats of the same age were also examined. The tissues were fixed in glutaraldehyde, postfixed in osmium tetroxide and embedded in Epon. The plasma was separated from heparanized blood and processed as previously described for the tissue specimens. Sections were stained with uranyl acetate followed by lead citrate and examined with an RCA EMU-3G electron microscope.

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