Materiały źródłowe

• #1 Endometrial Cancer Treatment (PDQ®) – NCI

  https://www.cancer.gov/types/uterine/hp/endometrial-treatment-pdq

  Cancer of the endometrium is the most common gynecologic malignancy in the United States and accounts for 7% of all cancers in women. Most cases are diagnosed at an early stage and are amenable to treatment with surgery alone. […] However, patients with pathological features predictive of a high rate of relapse and patients with extrauterine spread at diagnosis have a high rate of relapse despite adjuvant therapy. The most common cause of death in patients with endometrial cancer is cardiovascular disease because of related metabolic risk factors. […] Factors that lead to an excess of estrogen, including obesity and anovulation, lead to an increase in the deposition of the endometrial lining. These changes may lead to endometrial hyperplasia and, in some cases, endometrial cancer. […] Prolonged, unopposed estrogen exposure has been associated with an increased risk of endometrial cancer.

• #2 Uterine Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/258148-overview

  Fibroblast growth factor receptor 2 (FGFR2) is a tyrosine kinase receptor involved in many biological processes. Mutations in FGFR2 have been reported in up to 10-12% of endometrial carcinomas. Inhibition of FGFR2 could be a therapeutic target in endometrial carcinoma. Gatius et al suggest that FGFR2 has a dual role in the endometrium, inhibiting cell proliferation in normal endometria during the menstrual cycle but acting as an oncogene in endometrial carcinoma. […] Endometrial cancers are divided into 2 classes, each with differing pathophysiology and prognosis. […] More than 80% of endometrial carcinomas are type I and are due to unopposed estrogen stimulation, resulting in a low-grade histology. It is often found in association with atypical endometrial hyperplasia, which is thought to be a precursor lesion. Type II endometrial cancers are thought to be estrogen independent, occurring in older women, with high-grade histologies such as uterine papillary serous or clear cell.

• #3 Endometrial Cancer – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK525981/

  Endometrial cancer is a malignancy originating within the epithelial lining of the uterus. […] The condition has historically been classified into type 1 and type 2 endometrial cancer based on histological characteristics. However, results from recent studies have begun classifying endometrial cancers according to a current molecular subgrouping system. […] The most significant risk factors associated with endometrial cancer development include those that increase long-term exposure to unopposed estrogen (eg, obesity and exogenous estrogen). […] Present consensus holds that the pathogenesis of most low-grade endometrial carcinomas begins with uninterrupted endometrial proliferation, hormonally stimulated by endogenous or exogenous estrogen unopposed by progesterone or progestins, progressing through states of simple to complex forms of endometrial hyperplasia.

• #4 Endometrial Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9421940/

  Four molecular subgroup of EC defined by mutation burden and copy number alterations have been categorized in a study of 373 cases of EC by the TCGA. Most ECs have near diploid tumors or focal copy number alterations. Moreover, the mutational burden of most ECs reflects that of most solid tumors, with ~2-3 somatic mutations per megabase sequenced. […] In this study, one subgroup was defined by widespread genomic alterations and extensive amplifications and deletions and was termed the copy number high (CNH) group. The CNH group contained most high-grade, aggressive cancers, and included all uterine serous carcinomas and ~25% of the high-grade endometrioid tumors. The clinical outcome of this subgroup was poor. Most of these tumors had pathogenetic mutations in TP53. These tumors also have frequent somatic mutations in PIK3CA, and mutations in FBXW7 and PPP2R1A, which are unique to CNH tumors.

• #5 Endometrial Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9421940/

  Endometrial cancer (EC) is a malignancy of the inner epithelial lining of the uterus, with an increasing incidence and disease-associated mortality, worldwide. EC comprises distinct histological subtypes and molecular phenotypes. Historically, EC was categorized as Type I (association with unopposed estrogen stimulation, comprising low-grade cells that are more common and have a favorable prognosis) or Type II (not estrogen driven, comprising high-grade cells that are less common and have an unfavorable prognosis). Type I ECs are primarily composed of grade I or grade II endometrioid adenocarcinomas, whereas Type II ECs include grade III endometrioid adenocarcinomas, serous clear cell, undifferentiated and carcinosarcomas. […] EC is often a hormone-sensitive disease thought to commonly arise in the context of excessive estrogenic stimulation of the endometrial lining of the uterus. This estrogenic stimulation leads to mitogenic stimulation, and ultimately, malignant transformation of the endometrial glandular epithelium, and accounts for the development of the more common and lower grade endometrioid ECs. Risk factors for hyperestrogenism include obesity, hormone therapy (such as tamoxifen), ovarian cortical hyperplasia (hyperthecosis), polycystic ovarian syndrome, and hormone-producing tumors. Other histological subtypes of EC, including serous, clear cell, undifferentiated carcinoma and carcinosarcoma, are not as commonly associated with hyperestrogenism.

• #6 Uterine Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/258148-overview

  Fibroblast growth factor receptor 2 (FGFR2) is a tyrosine kinase receptor involved in many biological processes. Mutations in FGFR2 have been reported in up to 10-12% of endometrial carcinomas. Inhibition of FGFR2 could be a therapeutic target in endometrial carcinoma. Gatius et al suggest that FGFR2 has a dual role in the endometrium, inhibiting cell proliferation in normal endometria during the menstrual cycle but acting as an oncogene in endometrial carcinoma. […] Endometrial cancers are divided into 2 classes, each with differing pathophysiology and prognosis. […] More than 80% of endometrial carcinomas are type I and are due to unopposed estrogen stimulation, resulting in a low-grade histology. It is often found in association with atypical endometrial hyperplasia, which is thought to be a precursor lesion. Type II endometrial cancers are thought to be estrogen independent, occurring in older women, with high-grade histologies such as uterine papillary serous or clear cell.

• #7 Endometrial Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9421940/

  Endometrial cancer (EC) is a malignancy of the inner epithelial lining of the uterus, with an increasing incidence and disease-associated mortality, worldwide. EC comprises distinct histological subtypes and molecular phenotypes. Historically, EC was categorized as Type I (association with unopposed estrogen stimulation, comprising low-grade cells that are more common and have a favorable prognosis) or Type II (not estrogen driven, comprising high-grade cells that are less common and have an unfavorable prognosis). Type I ECs are primarily composed of grade I or grade II endometrioid adenocarcinomas, whereas Type II ECs include grade III endometrioid adenocarcinomas, serous clear cell, undifferentiated and carcinosarcomas. […] EC is often a hormone-sensitive disease thought to commonly arise in the context of excessive estrogenic stimulation of the endometrial lining of the uterus. This estrogenic stimulation leads to mitogenic stimulation, and ultimately, malignant transformation of the endometrial glandular epithelium, and accounts for the development of the more common and lower grade endometrioid ECs. Risk factors for hyperestrogenism include obesity, hormone therapy (such as tamoxifen), ovarian cortical hyperplasia (hyperthecosis), polycystic ovarian syndrome, and hormone-producing tumors. Other histological subtypes of EC, including serous, clear cell, undifferentiated carcinoma and carcinosarcoma, are not as commonly associated with hyperestrogenism.

• #8 Theories of Endometrial Carcinogenesis: A Multidisciplinary Approach | Modern Pathology

  https://www.nature.com/articles/3880051

  Type 2 tumors are unrelated to these features, behave aggressively, and lack the progesterone responsiveness of type 1 tumors. […] Histopathologic support for an alternative pathway of endometrial carcinogenesis unrelated to hormone imbalances is derived largely from clinicopathologic studies of serous carcinoma. […] The recognition that AH and endometrioid carcinoma express both estrogen and progesterone receptors is consistent with the status of AH as a precursor lesion and suggests that progesterone therapy may permit the reversal of these lesions in young women seeking to retain fertility. […] EIC is characterized by the replacement of benign surface endometrium and underlying glands by cells with anaplastic nuclei resembling serous carcinoma. […] The development of endometrial hyperplasia and endometrioid carcinoma (type 1 tumors) in women with irregular or anovulatory cycles suggests that prolonged periods without endometrial sloughing may be important in the development of fixed endometrial lesions.

• #9 Endometrial Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9421940/

  Four molecular subgroup of EC defined by mutation burden and copy number alterations have been categorized in a study of 373 cases of EC by the TCGA. Most ECs have near diploid tumors or focal copy number alterations. Moreover, the mutational burden of most ECs reflects that of most solid tumors, with ~2-3 somatic mutations per megabase sequenced. […] In this study, one subgroup was defined by widespread genomic alterations and extensive amplifications and deletions and was termed the copy number high (CNH) group. The CNH group contained most high-grade, aggressive cancers, and included all uterine serous carcinomas and ~25% of the high-grade endometrioid tumors. The clinical outcome of this subgroup was poor. Most of these tumors had pathogenetic mutations in TP53. These tumors also have frequent somatic mutations in PIK3CA, and mutations in FBXW7 and PPP2R1A, which are unique to CNH tumors.

• #10 Endometrial Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9421940/

  Four molecular subgroup of EC defined by mutation burden and copy number alterations have been categorized in a study of 373 cases of EC by the TCGA. Most ECs have near diploid tumors or focal copy number alterations. Moreover, the mutational burden of most ECs reflects that of most solid tumors, with ~2-3 somatic mutations per megabase sequenced. […] In this study, one subgroup was defined by widespread genomic alterations and extensive amplifications and deletions and was termed the copy number high (CNH) group. The CNH group contained most high-grade, aggressive cancers, and included all uterine serous carcinomas and ~25% of the high-grade endometrioid tumors. The clinical outcome of this subgroup was poor. Most of these tumors had pathogenetic mutations in TP53. These tumors also have frequent somatic mutations in PIK3CA, and mutations in FBXW7 and PPP2R1A, which are unique to CNH tumors.

• #11 Endometrial Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9421940/

  Another subgroup of EC was tumors with microsatellite instability (MSI). These tumors have mismatch repair defects and a tumor mutational burden that is ~10-fold greater than that of a general mutational background. These tumors have mutations in many genes owing to their generally high mutation burden, therefore, it can be difficult to differentiate passenger from driver mutations. PTEN, ARID1A, PIK3CA, PIK3R1 and RPL22 are all commonly mutated in the MSI subgroup of EC. Moreover, mutations or epigenetic silencing of MLH1, MSH2, MSH6, PMS2, and less commonly EPCAM, are often responsible for MSI. […] The identification of the molecular subgroups has rapidly changed the way ECs are stratified and treated. Several groups have taken these initial findings from TCGA and extrapolated them for better application to clinical practice. One approach – known as ProMisE (proactive molecular risk classifier for EC) – uses IHC to identify mismatch repair proteins and p53, and sequences the POLE exonuclease domain. ProMisE has identified four molecular subtypes of EC that are analogous but not identical to the four genomic subtypes described in TCGA study: MMRd, DNA POLE (corresponding to the ultramutated (POLE mutated) subtype), p53abn (which demonstrates aberrant p53 immunohistochemical staining and corresponds to the CNH subtype) and p53wt (which corresponds to the CNL subtype). Cases lacking enough information to classify are designated NSMP.

• #12 Endometrial Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9421940/

  Another subgroup of EC was tumors with microsatellite instability (MSI). These tumors have mismatch repair defects and a tumor mutational burden that is ~10-fold greater than that of a general mutational background. These tumors have mutations in many genes owing to their generally high mutation burden, therefore, it can be difficult to differentiate passenger from driver mutations. PTEN, ARID1A, PIK3CA, PIK3R1 and RPL22 are all commonly mutated in the MSI subgroup of EC. Moreover, mutations or epigenetic silencing of MLH1, MSH2, MSH6, PMS2, and less commonly EPCAM, are often responsible for MSI. […] The identification of the molecular subgroups has rapidly changed the way ECs are stratified and treated. Several groups have taken these initial findings from TCGA and extrapolated them for better application to clinical practice. One approach – known as ProMisE (proactive molecular risk classifier for EC) – uses IHC to identify mismatch repair proteins and p53, and sequences the POLE exonuclease domain. ProMisE has identified four molecular subtypes of EC that are analogous but not identical to the four genomic subtypes described in TCGA study: MMRd, DNA POLE (corresponding to the ultramutated (POLE mutated) subtype), p53abn (which demonstrates aberrant p53 immunohistochemical staining and corresponds to the CNH subtype) and p53wt (which corresponds to the CNL subtype). Cases lacking enough information to classify are designated NSMP.

• #13 Endometrial Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9421940/

  Another subgroup of EC was tumors with microsatellite instability (MSI). These tumors have mismatch repair defects and a tumor mutational burden that is ~10-fold greater than that of a general mutational background. These tumors have mutations in many genes owing to their generally high mutation burden, therefore, it can be difficult to differentiate passenger from driver mutations. PTEN, ARID1A, PIK3CA, PIK3R1 and RPL22 are all commonly mutated in the MSI subgroup of EC. Moreover, mutations or epigenetic silencing of MLH1, MSH2, MSH6, PMS2, and less commonly EPCAM, are often responsible for MSI. […] The identification of the molecular subgroups has rapidly changed the way ECs are stratified and treated. Several groups have taken these initial findings from TCGA and extrapolated them for better application to clinical practice. One approach – known as ProMisE (proactive molecular risk classifier for EC) – uses IHC to identify mismatch repair proteins and p53, and sequences the POLE exonuclease domain. ProMisE has identified four molecular subtypes of EC that are analogous but not identical to the four genomic subtypes described in TCGA study: MMRd, DNA POLE (corresponding to the ultramutated (POLE mutated) subtype), p53abn (which demonstrates aberrant p53 immunohistochemical staining and corresponds to the CNH subtype) and p53wt (which corresponds to the CNL subtype). Cases lacking enough information to classify are designated NSMP.

• #14 Endometrial Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9421940/

  Another subgroup of EC was tumors with microsatellite instability (MSI). These tumors have mismatch repair defects and a tumor mutational burden that is ~10-fold greater than that of a general mutational background. These tumors have mutations in many genes owing to their generally high mutation burden, therefore, it can be difficult to differentiate passenger from driver mutations. PTEN, ARID1A, PIK3CA, PIK3R1 and RPL22 are all commonly mutated in the MSI subgroup of EC. Moreover, mutations or epigenetic silencing of MLH1, MSH2, MSH6, PMS2, and less commonly EPCAM, are often responsible for MSI. […] The identification of the molecular subgroups has rapidly changed the way ECs are stratified and treated. Several groups have taken these initial findings from TCGA and extrapolated them for better application to clinical practice. One approach – known as ProMisE (proactive molecular risk classifier for EC) – uses IHC to identify mismatch repair proteins and p53, and sequences the POLE exonuclease domain. ProMisE has identified four molecular subtypes of EC that are analogous but not identical to the four genomic subtypes described in TCGA study: MMRd, DNA POLE (corresponding to the ultramutated (POLE mutated) subtype), p53abn (which demonstrates aberrant p53 immunohistochemical staining and corresponds to the CNH subtype) and p53wt (which corresponds to the CNL subtype). Cases lacking enough information to classify are designated NSMP.

• #15 Endometrial Cancer – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK525981/

  Endometrial cancer is a malignancy originating within the epithelial lining of the uterus. […] The condition has historically been classified into type 1 and type 2 endometrial cancer based on histological characteristics. However, results from recent studies have begun classifying endometrial cancers according to a current molecular subgrouping system. […] The most significant risk factors associated with endometrial cancer development include those that increase long-term exposure to unopposed estrogen (eg, obesity and exogenous estrogen). […] Present consensus holds that the pathogenesis of most low-grade endometrial carcinomas begins with uninterrupted endometrial proliferation, hormonally stimulated by endogenous or exogenous estrogen unopposed by progesterone or progestins, progressing through states of simple to complex forms of endometrial hyperplasia.

• #16 Endometrial Cancer in Reproductive-Aged Females: Etiology and Pathogenesis

  https://www.mdpi.com/2227-9059/12/4/886

  Endometrial cancer is the most common gynecologic malignancy in developed countries, and the incidence is rising in premenopausal females. Type I EC is more common than Type II EC (80% vs. 20%) and is associated with a hyperestrogenic state. Estrogen unopposed by progesterone is considered to be the main driving factor in the pathogenesis of EC. […] Studies have consistently demonstrated that premenopausal women with a hyperestrogenic state are at an increased risk of developing EC. The hypothesis of the unopposed estrogen effect causing endometrial hyperplasia and neoplasia has been described since the 1970s. The unopposed estrogen hypothesis, first described by Key et al. (1988), is a widely accepted theory stating that women with high circulating levels of endogenous estrogen unopposed by progesterone run an increased risk of developing EC. […] Hyperestrogenic states, or increased estrogen exposure, have been proven to be the main driver in the development of Type I EC.

• #17 Endometrial Cancer | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/21102

  Present consensus holds that the pathogenesis of most low-grade endometrial carcinomas begins with uninterrupted endometrial proliferation, hormonally stimulated by endogenous or exogenous estrogen unopposed by progesterone or progestins, progressing through states of simple to complex forms of endometrial hyperplasia. […] Arising in this milieu, histologically recognizable atypical premalignant lesions, defined as endometrial intraepithelial neoplasia (EIN), formerly termed atypical endometrial hyperplasia, may transform into endometrioid carcinoma, characterized by stromal and myometrial invasion, PTEN mutations, and often KRAS2 mutations, microsatellite instability caused by mismatch repair deficiencies (MMRd) found in Lynch syndrome, and near-diploid karyotype. […] Because of this underlying pathologic mechanism, endometrial cancer is more frequently categorized by molecular subgroups based on mutation burden and copy number alterations rather than histological findings.

• #18 Womb (uterus) cancer | NHS inform

  https://www.nhsinform.scot/illnesses-and-conditions/cancer/cancer-types-in-adults/womb-uterus-cancer/

  Cancer begins with a change (mutation) in the structure of the DNA in cells, which can affect how they grow. This means cells grow and reproduce uncontrollably, producing a lump of tissue called a tumour. […] Its not clear exactly what causes womb cancer, but certain things can increase your risk of developing the condition. […] A hormone imbalance is one of the most important risks for womb cancer. Specifically, your risk is increased if you have high levels of a hormone called oestrogen in your body. […] The risk of developing womb cancer is linked to the body’s exposure to oestrogen. Oestrogen is one of the hormones that regulate the reproductive system. […] After the menopause, the body stops producing progesterone. However, there are still small amounts of oestrogen being produced. This unopposed oestrogen causes the cells of the endometrium to divide, which can increase the risk of womb cancer.

• #19 Endometrial cancer: Pathophysiology, diagnosis and management – IJCAAP

  https://www.ijcap.in/html-article/18885

  The ovaries release the two principal female hormones, oestrogen and progesterone; any alterations in the balance between these two hormones affect the health of the endometrium similar to irregular ovulation patterns, a disease in which your body produces more oestrogen than progesterone might elevate the chances of developing endometrial cancer. The risk of endometrial cancer is raised with the use of only estrogen hormones after menopause. […] Long-term oestrogen exposure without progestin opposition is a significant predictor for type I EC. Both endogenous and exogenous oestrogen exposure are possible. Hormone replacement therapy is one form of exogenous oestrogen exposure. Obesity, estrogen-producing tumors, and persistent anovulation are all risk factors for endogenous oestrogen exposure.

• #20 Uterine (Endometrial) Cancer – UChicago Medicine

  https://www.uchicagomedicine.org/cancer/types-treatments/uterine-cancer

  Obesity is an important risk factor for uterine cancer that can be modified. Extra stored fat in a body increases estrogen levels, causes inflammation and can promote cancer development. […] Most common endometrial endometrioid cancers are estrogen dependent. […] Women who are 50 pounds overweight are 10 times more likely to develop endometrial cancer. […] Managing weight through appropriate diet and increasing physical activity can potentially decrease risk for this cancer.

• #21 Endometrial cancer: Pathophysiology, diagnosis and management – IJCAAP

  https://www.ijcap.in/html-article/18885

  Obesity is the primary risk factor for endometrial hyperplasia developing into malignant cancer. Obesity results in excessive peripheral conversion of androgens to estrone in adipose cells; this extra oestrogen promotes endometrial lining growth and frequently results in carcinogenesis. Moreover, prolonged anovulation is more prevalent in obese premenopausal women, which is also a major contributing factor for overexposure of estrogen. […] Tamoxifen therapy has been linked to an increased likelihood of developing EC even while it considerably lowers the risk of breast cancer and breast cancer recurrence. Tamoxifen is a selective oestrogen receptor modulator (SERM), which acts as an oestrogen antagonist in breast tissues but as an agonist in bone and endometrial tissues. Based on the majority of research, tamoxifen-using women had a 2-3 fold greater risk of developing EC than the general population.

• #22 Endometrial Cancer – Life Extension

  https://www.lifeextension.com/protocols/cancer/uterine-endometrial-cancer?srsltid=AfmBOooQviI0wmZJQLdJEndJ7hPEAWL5kCyUngKr5O85FWlJbGlmEQln

  It is important to recognize that the levels of estrogen and progesterone need to be balanced against each other. In fact, unopposed conventional estrogen replacement therapy increases the risk of endometrial cancer by up to 70-fold, but adding progesterone reduces risk to equal that of the population in general. […] The development of endometrial cancer is not only caused by unopposed estrogen therapy, but also by endogenous estrogens (estrogens produced by the body). A number of studies have shown that fat stores can generate estrogen precursors that are able to drive endometrial hyperplasia and carcinoma. Some studies have shown that as many as 40% of endometrial cancer cases may be attributable to obesity. […] Polycystic ovary syndrome (PCOS), a hormonal-metabolic disorder, has been shown to promote endometrial cancer development; it is associated with about a 5-fold increased risk on average across several studies.

• #23 Womb (uterus) cancer | NHS inform

  https://www.nhsinform.scot/illnesses-and-conditions/cancer/cancer-types-in-adults/womb-uterus-cancer/

  Women and anyone with a womb who are treated with tamoxifen (a hormone treatment for breast cancer) can be at an increased risk of developing womb cancer. […] Women and anyone with a womb with diabetes are twice as likely to develop womb cancer as those without the condition. […] Women and anyone with a womb with polycystic ovarian syndrome (PCOS) are at a higher risk of developing womb cancer, as they have high levels of oestrogen in their bodies. […] Endometrial hyperplasia is when the lining of the womb becomes thicker. It may be increase risk of developing womb cancer.

• #24 Endometrial cancer: Pathophysiology, diagnosis and management – IJCAAP

  https://www.ijcap.in/html-article/18885

  Genetic mutations associated to molecular signalling pathways plays important role in the aetiology of EC. This molecular pathways are hampered by circumstances including suppression of cell proliferation, apoptosis, elevation of telomere reverse transcription, and DNA synthesis abnormalities. Genetic Alteration in the phosphate and tensin homolog (PTEN), Catenin beta-1 (CTNNB1), Kirsten rat sarcoma (KRAS) viral oncogene homolog, AT-rich interaction domain 1A (ARID1A),and mismatch repair (MMR) molecular pathways have a substantial impact on ECs. […] Hyperinsulinism is linked to diabetes mellitus or PCOS and plays a significant role in the development of cancer, as it amplifies mitotic activity in the glands and stroma by boosting IGF-1 activity. Excess insulin increases blood free testosterone levels by reducing the formation of the liver sex hormone-binding globulin (SHBG), enhances the production of androgens driven by LH and IGF-I, and increases serum IGF-I bioactivity by suppressing the development of IGF-binding proteins. Women with EC also have insulin binding sites expressed in their endometrial stroma. It follows that excessive insulin signalling can cause endometrial alterations that are pro-proliferative, pro-survival, and inflammatory changes similar to those caused by unopposed oestrogen.

• #25 Endometrial Cancer – Life Extension

  https://www.lifeextension.com/protocols/cancer/uterine-endometrial-cancer?srsltid=AfmBOooQviI0wmZJQLdJEndJ7hPEAWL5kCyUngKr5O85FWlJbGlmEQln

  It is important to recognize that the levels of estrogen and progesterone need to be balanced against each other. In fact, unopposed conventional estrogen replacement therapy increases the risk of endometrial cancer by up to 70-fold, but adding progesterone reduces risk to equal that of the population in general. […] The development of endometrial cancer is not only caused by unopposed estrogen therapy, but also by endogenous estrogens (estrogens produced by the body). A number of studies have shown that fat stores can generate estrogen precursors that are able to drive endometrial hyperplasia and carcinoma. Some studies have shown that as many as 40% of endometrial cancer cases may be attributable to obesity. […] Polycystic ovary syndrome (PCOS), a hormonal-metabolic disorder, has been shown to promote endometrial cancer development; it is associated with about a 5-fold increased risk on average across several studies.

• #26 Endometrial Cancer – Life Extension

  https://www.lifeextension.com/protocols/cancer/uterine-endometrial-cancer?srsltid=AfmBOooQviI0wmZJQLdJEndJ7hPEAWL5kCyUngKr5O85FWlJbGlmEQln

  Tamoxifen treatment has been shown to be associated with a 2- to 3-fold higher risk of developing endometrial cancer, and the risk increases with duration of treatment. […] Diabetes mellitus and hyperinsulinemia (elevated insulin levels) have been shown in many studies to be associated with endometrial cancer. […] Endometrial cancer appears to be especially influenced by dietary and lifestyle factors. A variety of factors related to diet and lifestyle can increase the chances of developing endometrial cancer; chief among them is the consumption of foods high in animal fats and sugars whereas diets high in vegetables and fruits (especially those high in lutein) have lower risk. […] Given that inflammation plays a major role in tumor initiation, omega-3 fatty acids have gained considerable attention in the context of cancer prevention and treatment. Indeed, evidence suggests a higher dietary ratio of omega-3s to omega-6s is associated with a lower risk of endometrial cancer.

• #27 Womb (uterus) cancer | NHS inform

  https://www.nhsinform.scot/illnesses-and-conditions/cancer/cancer-types-in-adults/womb-uterus-cancer/

  Women and anyone with a womb who are treated with tamoxifen (a hormone treatment for breast cancer) can be at an increased risk of developing womb cancer. […] Women and anyone with a womb with diabetes are twice as likely to develop womb cancer as those without the condition. […] Women and anyone with a womb with polycystic ovarian syndrome (PCOS) are at a higher risk of developing womb cancer, as they have high levels of oestrogen in their bodies. […] Endometrial hyperplasia is when the lining of the womb becomes thicker. It may be increase risk of developing womb cancer.

• #28 Endometrial Cancer | Nutrition Guide for Clinicians

  https://nutritionguide.pcrm.org/nutritionguide/view/Nutrition_Guide_for_Clinicians/1342025/all/Endometrial_Cancer

  Early menarche, late menopause, and nulliparity (especially when due to anovulation) may increase the risk for endometrial cancer. […] Estrogen therapy without progestin significantly increases the risk of endometrial cancer. […] Women with hypertension and diabetes (particularly type 2) have an increased risk for endometrial cancer, which may reflect the presence of common risk factors such as obesity. […] Women who have a 1st-degree relative with endometrial cancer are at increased risk of developing endometrial cancer. […] Contraceptive pills containing progestin reduce the risk of endometrial cancer by about 50%. […] Regular physical activity is associated with a 20-30% reduction in risk. […] The risk for uterine cancers appears to be associated with greater intakes of foods found in Western diets (animal products, refined carbohydrates).

• #29 Endometrial Cancer | Nutrition Guide for Clinicians

  https://nutritionguide.pcrm.org/nutritionguide/view/Nutrition_Guide_for_Clinicians/1342025/all/Endometrial_Cancer

  Early menarche, late menopause, and nulliparity (especially when due to anovulation) may increase the risk for endometrial cancer. […] Estrogen therapy without progestin significantly increases the risk of endometrial cancer. […] Women with hypertension and diabetes (particularly type 2) have an increased risk for endometrial cancer, which may reflect the presence of common risk factors such as obesity. […] Women who have a 1st-degree relative with endometrial cancer are at increased risk of developing endometrial cancer. […] Contraceptive pills containing progestin reduce the risk of endometrial cancer by about 50%. […] Regular physical activity is associated with a 20-30% reduction in risk. […] The risk for uterine cancers appears to be associated with greater intakes of foods found in Western diets (animal products, refined carbohydrates).

• #30 Womb (uterus) cancer | NHS inform

  https://www.nhsinform.scot/illnesses-and-conditions/cancer/cancer-types-in-adults/womb-uterus-cancer/

  Cancer begins with a change (mutation) in the structure of the DNA in cells, which can affect how they grow. This means cells grow and reproduce uncontrollably, producing a lump of tissue called a tumour. […] Its not clear exactly what causes womb cancer, but certain things can increase your risk of developing the condition. […] A hormone imbalance is one of the most important risks for womb cancer. Specifically, your risk is increased if you have high levels of a hormone called oestrogen in your body. […] The risk of developing womb cancer is linked to the body’s exposure to oestrogen. Oestrogen is one of the hormones that regulate the reproductive system. […] After the menopause, the body stops producing progesterone. However, there are still small amounts of oestrogen being produced. This unopposed oestrogen causes the cells of the endometrium to divide, which can increase the risk of womb cancer.

• #31 Endometrial cancer – Wikipedia

  https://en.wikipedia.org/wiki/Endometrial_cancer

  The p53 pathway can either be suppressed or highly activated in endometrial cancer. When a mutant version of p53 is overexpressed, the cancer tends to be particularly aggressive. […] Development of an endometrial hyperplasia (overgrowth of endometrial cells) is a significant risk factor because hyperplasias can and often do develop into adenocarcinoma, though cancer can develop without the presence of a hyperplasia. Within ten years, 80-30% of atypical endometrial hyperplasias develop into cancer, whereas 13% of non-atypical hyperplasias do so.

• #32 LearnOncology

  https://www.learnoncology.ca/modules/endometrial-cancer

  Endometrial hyperplasia is characterized by a proliferation of endometrial glands that results in a greater gland to stroma ratio than would be seen in normal endometrial tissue. It is characterized by proliferation of endometrial glands that almost always results from chronic estrogen stimulation unopposed by progesterone. The hyperplasia may be non-neoplastic or neoplastic, however neoplastic hyperplasia is a precursor to the most common form of endometrial carcinoma so the presence of either type of hyperplasia is notable. […] The World Health Organizations classification system for endometrial hyperplasia is based on the architecture of the glands and stroma, and level of nuclear atypia. Nuclear atypia is defined as the presence of nuclear enlargement where the chromatin may be arranged in a clump pattern or be evenly dispersed. These two dimensions yield four categories, seen below with more information. For comparison, normal endometrium exhibits no crowding of glands in the stroma thus is said to have less than 50% gland:stroma ratio.

• #33 Uterine Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/258148-overview

  Endometrioid adenocarcinoma of the endometrium, the most common histology, is usually preceded by adenomatous hyperplasia with atypia. If left untreated, simple and complex endometrial hyperplasia with atypia progress to adenocarcinoma in 8% and 29% of cases, respectively. Without atypia, simple and complex hyperplasia progress to cancer in only 1% and 3% of cases, respectively. […] Less histologic differentiation is associated with a higher incidence of deep myometrial invasion and lymph node metastases. Subsequently, the depth of myometrial invasion and presence of tumor in the lymph nodes is directly related to recurrence rates and 5-year survival rates. […] PTEN mutation is thought to be an early event in low-grade endometrial cancers and is found in 55% of hyperplasia and 85% of cancers, whereas it is not found in benign endometrium.

• #34 Endometrial cancer pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Endometrial_cancer_pathophysiology

  Development of endometrial cancer is the result of multiple genetic mutations. Genes involved in the pathogenesis of endometrial cancer include TP53, KRAS, and PTEN. The pathophysiology of endometrial cancer depends on the histological subtype. […] Endometrial cancer forms when there are errors in normal endometrial cell growth. […] Development of an endometrial hyperplasia (overgrowth of endometrial cells) is a significant risk factor because hyperplasia can and often do develop into adenocarcinoma, though cancer can develop without the presence of a hyperplasia. Within ten years, 830% of atypical endometrial hyperplasias develop into cancer, whereas 13% of non-atypical hyperplasias do so. […] Mutations in the KRAS gene can cause endometrial hyperplasia and therefore type I endometrial cancer. Endometrial hyperplasia typically occurs after the age of 40. Endometrial glandular dysplasia occurs with an overexpression of TP53, and develops into a serous carcinoma (type II endometrial cancer).

• #35 LearnOncology

  https://www.learnoncology.ca/modules/endometrial-cancer

  Endometrial hyperplasia is characterized by a proliferation of endometrial glands that results in a greater gland to stroma ratio than would be seen in normal endometrial tissue. It is characterized by proliferation of endometrial glands that almost always results from chronic estrogen stimulation unopposed by progesterone. The hyperplasia may be non-neoplastic or neoplastic, however neoplastic hyperplasia is a precursor to the most common form of endometrial carcinoma so the presence of either type of hyperplasia is notable. […] The World Health Organizations classification system for endometrial hyperplasia is based on the architecture of the glands and stroma, and level of nuclear atypia. Nuclear atypia is defined as the presence of nuclear enlargement where the chromatin may be arranged in a clump pattern or be evenly dispersed. These two dimensions yield four categories, seen below with more information. For comparison, normal endometrium exhibits no crowding of glands in the stroma thus is said to have less than 50% gland:stroma ratio.

• #36 Endometrial cancer: a genetic point of view – Bianco – Translational Cancer Research

  https://tcr.amegroups.org/article/view/46888/html

  Endometrial cancer has a heterogeneous pathophysiology, encompassing many histological types, microscopical features, pathogenesis, behaviors, and prognosis. […] Endometrial carcinomas have distinguishing molecular features. The most frequently mutated genes in endometrioid carcinomas are PTEN (77%), PIK3CA (53%), PIK3R1 (37%), CTNNB1 (36%), ARID1A (35%), K-RAS (24%), CTCF (20%), RPL22 (12%), TP53 (11%), FGFR2 (11%), and ARID5B (11%). […] Endometrial cancer presents more mutations than any other tumor type studied thus far in the PI3K/AKT pathway by TCGA. […] The RAS-RAF-MEK-ERK pathway plays a central role in regulation of cell proliferation, cell survival, and differentiation, is activated by KRAS mutations in endometrioid carcinoma, and can co-occur with alterations in PTEN, PIK3CA, and/or PIK3R1.

• #37 Endometrial cancer: a genetic point of view – Bianco – Translational Cancer Research

  https://tcr.amegroups.org/article/view/46888/html

  Endometrial cancer has a heterogeneous pathophysiology, encompassing many histological types, microscopical features, pathogenesis, behaviors, and prognosis. […] Endometrial carcinomas have distinguishing molecular features. The most frequently mutated genes in endometrioid carcinomas are PTEN (77%), PIK3CA (53%), PIK3R1 (37%), CTNNB1 (36%), ARID1A (35%), K-RAS (24%), CTCF (20%), RPL22 (12%), TP53 (11%), FGFR2 (11%), and ARID5B (11%). […] Endometrial cancer presents more mutations than any other tumor type studied thus far in the PI3K/AKT pathway by TCGA. […] The RAS-RAF-MEK-ERK pathway plays a central role in regulation of cell proliferation, cell survival, and differentiation, is activated by KRAS mutations in endometrioid carcinoma, and can co-occur with alterations in PTEN, PIK3CA, and/or PIK3R1.

• #38 Theories of Endometrial Carcinogenesis: A Multidisciplinary Approach | Modern Pathology

  https://www.nature.com/articles/3880051

  The identification of MI in AH associated with endometrioid carcinomas, but not in AH without associated carcinoma, suggests that mismatch repair defects may occur in the transition between the two lesions. […] In summary, molecular evidence, though not abundant or entirely consistent between studies, supports the existence of a dualistic model of endometrial carcinogenesis. Endometrioid (type 1) carcinomas are associated with mutations in ras, PTEN, and MI, whereas serous (type 2) carcinomas are associated with p53 mutations. […] The nearly universal detection of p53 mutations in serous carcinoma and its precursor, EIC, including examples of EIC without associated invasion, suggests that p53 mutation may represent the molecular signature of serous carcinoma and possibly define the entity in combination with morphology.

• #39 Endometrial cancer – Wikipedia

  https://en.wikipedia.org/wiki/Endometrial_cancer

  Endometrial cancer is a cancer that arises from the endometrium (the lining of the uterus or womb). It is the result of the abnormal growth of cells that can invade or spread to other parts of the body. […] Endometrial cancer forms when there are errors in normal endometrial cell growth. Usually, when cells grow old or get damaged, they die, and new cells take their place. Cancer starts when new cells form unneeded, and old or damaged cells do not die as they should. The buildup of extra cells often forms a mass of tissue called a growth or tumor. These abnormal cancer cells have many genetic abnormalities that cause them to grow excessively. […] In 10-20% of endometrial cancers, mostly Grade 3 (the highest histologic grade), mutations are found in a tumor suppressor gene, commonly p53 or PTEN. In 20% of endometrial hyperplasias and 50% of endometrioid cancers, PTEN has a loss-of-function mutation or a null mutation, making it less effective or completely ineffective. Loss of PTEN function leads to up-regulation of the PI3k/Akt/mTOR pathway, which causes cell growth.

• #40 Uterine Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/258148-overview

  Endometrioid adenocarcinoma of the endometrium, the most common histology, is usually preceded by adenomatous hyperplasia with atypia. If left untreated, simple and complex endometrial hyperplasia with atypia progress to adenocarcinoma in 8% and 29% of cases, respectively. Without atypia, simple and complex hyperplasia progress to cancer in only 1% and 3% of cases, respectively. […] Less histologic differentiation is associated with a higher incidence of deep myometrial invasion and lymph node metastases. Subsequently, the depth of myometrial invasion and presence of tumor in the lymph nodes is directly related to recurrence rates and 5-year survival rates. […] PTEN mutation is thought to be an early event in low-grade endometrial cancers and is found in 55% of hyperplasia and 85% of cancers, whereas it is not found in benign endometrium.

• #41 Endometrial cancer pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Endometrial_cancer_pathophysiology

  Development of endometrial cancer is the result of multiple genetic mutations. Genes involved in the pathogenesis of endometrial cancer include TP53, KRAS, and PTEN. The pathophysiology of endometrial cancer depends on the histological subtype. […] Endometrial cancer forms when there are errors in normal endometrial cell growth. […] Development of an endometrial hyperplasia (overgrowth of endometrial cells) is a significant risk factor because hyperplasia can and often do develop into adenocarcinoma, though cancer can develop without the presence of a hyperplasia. Within ten years, 830% of atypical endometrial hyperplasias develop into cancer, whereas 13% of non-atypical hyperplasias do so. […] Mutations in the KRAS gene can cause endometrial hyperplasia and therefore type I endometrial cancer. Endometrial hyperplasia typically occurs after the age of 40. Endometrial glandular dysplasia occurs with an overexpression of TP53, and develops into a serous carcinoma (type II endometrial cancer).

• #42 Endometrial Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9421940/

  Another subgroup of EC was tumors with microsatellite instability (MSI). These tumors have mismatch repair defects and a tumor mutational burden that is ~10-fold greater than that of a general mutational background. These tumors have mutations in many genes owing to their generally high mutation burden, therefore, it can be difficult to differentiate passenger from driver mutations. PTEN, ARID1A, PIK3CA, PIK3R1 and RPL22 are all commonly mutated in the MSI subgroup of EC. Moreover, mutations or epigenetic silencing of MLH1, MSH2, MSH6, PMS2, and less commonly EPCAM, are often responsible for MSI. […] The identification of the molecular subgroups has rapidly changed the way ECs are stratified and treated. Several groups have taken these initial findings from TCGA and extrapolated them for better application to clinical practice. One approach – known as ProMisE (proactive molecular risk classifier for EC) – uses IHC to identify mismatch repair proteins and p53, and sequences the POLE exonuclease domain. ProMisE has identified four molecular subtypes of EC that are analogous but not identical to the four genomic subtypes described in TCGA study: MMRd, DNA POLE (corresponding to the ultramutated (POLE mutated) subtype), p53abn (which demonstrates aberrant p53 immunohistochemical staining and corresponds to the CNH subtype) and p53wt (which corresponds to the CNL subtype). Cases lacking enough information to classify are designated NSMP.

• #43 Endometrial Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9421940/

  Another subgroup of EC was tumors with microsatellite instability (MSI). These tumors have mismatch repair defects and a tumor mutational burden that is ~10-fold greater than that of a general mutational background. These tumors have mutations in many genes owing to their generally high mutation burden, therefore, it can be difficult to differentiate passenger from driver mutations. PTEN, ARID1A, PIK3CA, PIK3R1 and RPL22 are all commonly mutated in the MSI subgroup of EC. Moreover, mutations or epigenetic silencing of MLH1, MSH2, MSH6, PMS2, and less commonly EPCAM, are often responsible for MSI. […] The identification of the molecular subgroups has rapidly changed the way ECs are stratified and treated. Several groups have taken these initial findings from TCGA and extrapolated them for better application to clinical practice. One approach – known as ProMisE (proactive molecular risk classifier for EC) – uses IHC to identify mismatch repair proteins and p53, and sequences the POLE exonuclease domain. ProMisE has identified four molecular subtypes of EC that are analogous but not identical to the four genomic subtypes described in TCGA study: MMRd, DNA POLE (corresponding to the ultramutated (POLE mutated) subtype), p53abn (which demonstrates aberrant p53 immunohistochemical staining and corresponds to the CNH subtype) and p53wt (which corresponds to the CNL subtype). Cases lacking enough information to classify are designated NSMP.

• #44 Uterine Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/258148-overview

  Fibroblast growth factor receptor 2 (FGFR2) is a tyrosine kinase receptor involved in many biological processes. Mutations in FGFR2 have been reported in up to 10-12% of endometrial carcinomas. Inhibition of FGFR2 could be a therapeutic target in endometrial carcinoma. Gatius et al suggest that FGFR2 has a dual role in the endometrium, inhibiting cell proliferation in normal endometria during the menstrual cycle but acting as an oncogene in endometrial carcinoma. […] Endometrial cancers are divided into 2 classes, each with differing pathophysiology and prognosis. […] More than 80% of endometrial carcinomas are type I and are due to unopposed estrogen stimulation, resulting in a low-grade histology. It is often found in association with atypical endometrial hyperplasia, which is thought to be a precursor lesion. Type II endometrial cancers are thought to be estrogen independent, occurring in older women, with high-grade histologies such as uterine papillary serous or clear cell.

• #45 Endometrial Cancer | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/21102

  The pathogenesis of non-endometrioid endometrial adenocarcinoma is related to genetic and somatic mutations and not necessarily hormonal factors. […] In low-grade endometrioid cancers, the most commonly occurring endometrial cancer type, malignant endometrial transformation results from mitogenic stimulation of EIN precursor lesions secondary to estrogenic stimulation. […] In contrast to low-grade endometrioid carcinomas, aggressive endometrial serous carcinomas, and clear cell carcinomas typically arise in atrophic, resting, or weakly proliferative endometrium through genetic mutations and epigenetic changes. […] Identical TP53 mutations have been found in foci of benign-appearing endometrium (or „p53 signatures”) endometrial glandular dysplasia and associated serous endometrial intraepithelial carcinoma and invasive endometrial serous carcinomas, giving credence to a concept of endometrial serous carcinogenesis with accumulation of TP53 mutations recognized first as p53 signatures, progressing to endometrial glandular dysplasia, to endometrial intraepithelial carcinoma, and ultimately to endometrial serous carcinomas.

• #46 Theories of Endometrial Carcinogenesis: A Multidisciplinary Approach | Modern Pathology

  https://www.nature.com/articles/3880051

  The identification of MI in AH associated with endometrioid carcinomas, but not in AH without associated carcinoma, suggests that mismatch repair defects may occur in the transition between the two lesions. […] In summary, molecular evidence, though not abundant or entirely consistent between studies, supports the existence of a dualistic model of endometrial carcinogenesis. Endometrioid (type 1) carcinomas are associated with mutations in ras, PTEN, and MI, whereas serous (type 2) carcinomas are associated with p53 mutations. […] The nearly universal detection of p53 mutations in serous carcinoma and its precursor, EIC, including examples of EIC without associated invasion, suggests that p53 mutation may represent the molecular signature of serous carcinoma and possibly define the entity in combination with morphology.

• #47 Endometrial Cancer | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/21102

  The pathogenesis of non-endometrioid endometrial adenocarcinoma is related to genetic and somatic mutations and not necessarily hormonal factors. […] In low-grade endometrioid cancers, the most commonly occurring endometrial cancer type, malignant endometrial transformation results from mitogenic stimulation of EIN precursor lesions secondary to estrogenic stimulation. […] In contrast to low-grade endometrioid carcinomas, aggressive endometrial serous carcinomas, and clear cell carcinomas typically arise in atrophic, resting, or weakly proliferative endometrium through genetic mutations and epigenetic changes. […] Identical TP53 mutations have been found in foci of benign-appearing endometrium (or „p53 signatures”) endometrial glandular dysplasia and associated serous endometrial intraepithelial carcinoma and invasive endometrial serous carcinomas, giving credence to a concept of endometrial serous carcinogenesis with accumulation of TP53 mutations recognized first as p53 signatures, progressing to endometrial glandular dysplasia, to endometrial intraepithelial carcinoma, and ultimately to endometrial serous carcinomas.

• #48 Uterine Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/258148-overview

  Approximately 15-20% of endometrial cancers are type II cancers with papillary serous or clear cell histologies. Papillary serous histology represents 5-10% and clear cell histology represents less than 5% of endometrial cancers. They are considered high grade with poor prognosis. They have a propensity for early nodal or upper abdominal spread even with minimal or no myometrial invasion. The p53 mutation is more common in high-grade tumors, and ERBB-2 (HER-2/neu) mutation is common in type II cancers. […] Carcinosarcomas or malignant mixed mllerian tumors (MMMT) are typically comprised of a high grade epithelial carcinoma and stromal sarcoma. The sarcomatous portion of the tumor may exhibit an endometrial stromal sarcoma (ESS) pattern, if differentiated. […] The histopathologic diagnosis of uterine sarcomas can be unclear until the time of definitive surgery. Diagnosis of leiomyosarcoma is dependent on the number of mitoses and the degree of cellular atypia. The diagnosis of leiomyosarcoma versus leiomyoma and leiomyoma with high mitotic activity or uncertain malignant potential is based on the metastatic potential of the tumor.

• #49 Endometrial cancer: a genetic point of view – Bianco – Translational Cancer Research

  https://tcr.amegroups.org/article/view/46888/html

  The consequence of epigenetic silencing caused by promoter hypermethylation of MLH1 leads to MSI in sporadic endometrioid carcinomas. […] Somatic mutations in PPP2R1A, FBXW7, SPOP, CHD4, and TAF1 are also involved in the serous carcinoma pathogenesis. […] Endometrial cancer risk may be influenced by common low-penetrance variants, such as single nucleotide variants (SNVs), in genes involved in cell survival, estrogen metabolism, and transcriptional control. […] The activation of cannabinoid receptor type 1 (CB1R), a G-protein coupled receptor present in the central nervous system and peripheral tissues such as the ovaries and uterus, can regulate cell proliferation, differentiation, and death. […] The cannabinoid receptor type 2 (CB2R) is expressed the most in endometrial cancer biopsies and has a potential role in the control of cancer cell growth through the regulation of mitochondrial function and cell apoptosis.

• #50 Endometrial Cancer – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK525981/

  The molecular etiologies of high-grade endometrioid and clear cell endometrial carcinomas lack the definition achieved by research on the pathogenesis of endometrial low-grade endometrioid carcinomas and endometrial serous carcinomas. […] Immunologic mechanisms also contribute to malignant endometrial transformation.

• #51 Endometrial cancer: a genetic point of view – Bianco – Translational Cancer Research

  https://tcr.amegroups.org/article/view/46888/html

  The consequence of epigenetic silencing caused by promoter hypermethylation of MLH1 leads to MSI in sporadic endometrioid carcinomas. […] Somatic mutations in PPP2R1A, FBXW7, SPOP, CHD4, and TAF1 are also involved in the serous carcinoma pathogenesis. […] Endometrial cancer risk may be influenced by common low-penetrance variants, such as single nucleotide variants (SNVs), in genes involved in cell survival, estrogen metabolism, and transcriptional control. […] The activation of cannabinoid receptor type 1 (CB1R), a G-protein coupled receptor present in the central nervous system and peripheral tissues such as the ovaries and uterus, can regulate cell proliferation, differentiation, and death. […] The cannabinoid receptor type 2 (CB2R) is expressed the most in endometrial cancer biopsies and has a potential role in the control of cancer cell growth through the regulation of mitochondrial function and cell apoptosis.

• #52 Endometrial Cancer – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK525981/

  Because of this underlying pathologic mechanism, endometrial cancer is more frequently categorized by molecular subgroups based on mutation burden and copy number alterations rather than histological findings. […] The pathogenesis of non-endometrioid endometrial adenocarcinoma is related to genetic and somatic mutations and not necessarily hormonal factors. […] In low-grade endometrioid cancers, the most commonly occurring endometrial cancer type, malignant endometrial transformation results from mitogenic stimulation of EIN precursor lesions secondary to estrogenic stimulation. […] In contrast to low-grade endometrioid carcinomas, aggressive endometrial serous carcinomas, and clear cell carcinomas typically arise in atrophic, resting, or weakly proliferative endometrium through genetic mutations and epigenetic changes.

• #53 Theories of Endometrial Carcinogenesis: A Multidisciplinary Approach | Modern Pathology

  https://www.nature.com/articles/3880051

  Historical observations have suggested that endometrial carcinomas vary in histopathologic appearance and clinical features. […] Specifically, studies suggest that the most common type of endometrial carcinoma, endometrioid adenocarcinoma, develops from endometrial hyperplasia in the setting of excess estrogen exposure and usually pursues an indolent clinical course. In contrast, a minority of endometrial carcinomas, best represented by serous carcinoma, do not seem to be related to estrogenic risk factors or elevated serum hormone levels, and these tumors seem to develop from atrophic rather than hyperplastic epithelium. […] We have proposed that serous carcinomas develop from endometrial intraepithelial carcinoma, a lesion representing malignant transformation of the endometrial surface epithelium.

• #54 Endometrial Cancer – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK525981/

  Because of this underlying pathologic mechanism, endometrial cancer is more frequently categorized by molecular subgroups based on mutation burden and copy number alterations rather than histological findings. […] The pathogenesis of non-endometrioid endometrial adenocarcinoma is related to genetic and somatic mutations and not necessarily hormonal factors. […] In low-grade endometrioid cancers, the most commonly occurring endometrial cancer type, malignant endometrial transformation results from mitogenic stimulation of EIN precursor lesions secondary to estrogenic stimulation. […] In contrast to low-grade endometrioid carcinomas, aggressive endometrial serous carcinomas, and clear cell carcinomas typically arise in atrophic, resting, or weakly proliferative endometrium through genetic mutations and epigenetic changes.

• #55 Endometrial Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9421940/

  Endometrioid ECs develop through malignant transformation of the precursor lesions atypical endometrial hyperplasia (AEH) also known as endometrial intraepithelial neoplasia. AEH often contains somatic PTEN mutations; loss of PTEN is necessary for the development of AEH but is insufficient for progression to invasive carcinoma. ARID1A has a critical role in the transition of precursor AEH lesions to invasive endometrioid carcinomas, and inactivation of TGFB also contributes to the progression of AEH to invasive carcinoma. […] The less common and more aggressive uterine serous carcinomas and the rarer uterine clear cell carcinomas are likely manifestations of increased genotoxic stress that is directly mediated through mutational and epigenetic activation of endometrial precursor cells. These EC subtypes often arise from precursor lesions such as serous endometrial intraepithelial carcinoma (SEIC). SEIC precursor lesions are thought to contain initiating TP53 mutations, as evidenced by abnormal immunohistochemistry staining of p53 and some reports of identifiable somatic TP53 mutations in SEIC precursor lesions and invasive disease.

• #56 Theories of Endometrial Carcinogenesis: A Multidisciplinary Approach | Modern Pathology

  https://www.nature.com/articles/3880051

  Historical observations have suggested that endometrial carcinomas vary in histopathologic appearance and clinical features. […] Specifically, studies suggest that the most common type of endometrial carcinoma, endometrioid adenocarcinoma, develops from endometrial hyperplasia in the setting of excess estrogen exposure and usually pursues an indolent clinical course. In contrast, a minority of endometrial carcinomas, best represented by serous carcinoma, do not seem to be related to estrogenic risk factors or elevated serum hormone levels, and these tumors seem to develop from atrophic rather than hyperplastic epithelium. […] We have proposed that serous carcinomas develop from endometrial intraepithelial carcinoma, a lesion representing malignant transformation of the endometrial surface epithelium.

• #57 Endometrial Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9421940/

  Endometrioid ECs develop through malignant transformation of the precursor lesions atypical endometrial hyperplasia (AEH) also known as endometrial intraepithelial neoplasia. AEH often contains somatic PTEN mutations; loss of PTEN is necessary for the development of AEH but is insufficient for progression to invasive carcinoma. ARID1A has a critical role in the transition of precursor AEH lesions to invasive endometrioid carcinomas, and inactivation of TGFB also contributes to the progression of AEH to invasive carcinoma. […] The less common and more aggressive uterine serous carcinomas and the rarer uterine clear cell carcinomas are likely manifestations of increased genotoxic stress that is directly mediated through mutational and epigenetic activation of endometrial precursor cells. These EC subtypes often arise from precursor lesions such as serous endometrial intraepithelial carcinoma (SEIC). SEIC precursor lesions are thought to contain initiating TP53 mutations, as evidenced by abnormal immunohistochemistry staining of p53 and some reports of identifiable somatic TP53 mutations in SEIC precursor lesions and invasive disease.

• #58 Endometrial Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9421940/

  Endometrioid ECs develop through malignant transformation of the precursor lesions atypical endometrial hyperplasia (AEH) also known as endometrial intraepithelial neoplasia. AEH often contains somatic PTEN mutations; loss of PTEN is necessary for the development of AEH but is insufficient for progression to invasive carcinoma. ARID1A has a critical role in the transition of precursor AEH lesions to invasive endometrioid carcinomas, and inactivation of TGFB also contributes to the progression of AEH to invasive carcinoma. […] The less common and more aggressive uterine serous carcinomas and the rarer uterine clear cell carcinomas are likely manifestations of increased genotoxic stress that is directly mediated through mutational and epigenetic activation of endometrial precursor cells. These EC subtypes often arise from precursor lesions such as serous endometrial intraepithelial carcinoma (SEIC). SEIC precursor lesions are thought to contain initiating TP53 mutations, as evidenced by abnormal immunohistochemistry staining of p53 and some reports of identifiable somatic TP53 mutations in SEIC precursor lesions and invasive disease.

• #59 Endometrial Cancer – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK525981/

  The molecular etiologies of high-grade endometrioid and clear cell endometrial carcinomas lack the definition achieved by research on the pathogenesis of endometrial low-grade endometrioid carcinomas and endometrial serous carcinomas. […] Immunologic mechanisms also contribute to malignant endometrial transformation.

• #60 Endometrial Cancer | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/21102

  The molecular etiologies of high-grade endometrioid and clear cell endometrial carcinomas lack the definition achieved by research on the pathogenesis of endometrial low-grade endometrioid carcinomas and endometrial serous carcinomas. […] Immunologic mechanisms also contribute to malignant endometrial transformation. While the immune system is normally protective against pathogenic changes, study results have identified immunologic factors that promote progression from EIN to endometrial cancer, including tumor-associated macrophages, fibroblasts, and myofibroblasts.

• #61 Endometrial Cancer – Gynecology and Obstetrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/gynecology-and-obstetrics/gynecologic-tumors/endometrial-cancer

  The higher (more undifferentiated) the grade of the tumor, the greater the likelihood of deep myometrial invasion, pelvic or para-aortic lymph node metastases, or extrauterine spread. […] Determining the molecular subtype, if feasible, adds valuable information to the standard clinicopathological risk factors to classify patients with endometrial cancer into risk groups, predict prognosis, and guide treatment recommendations. […] Uterine papillary serous carcinomas (10%), clear cell carcinomas (carcinosarcomas). […] The combination of chemotherapy and immunotherapy has shown synergistic effects in endometrial cancer treatment. In a phase III global randomized double-blind placebo-controlled trial, dostarlimab plus carboplatinpaclitaxel compared with placebo plus carboplatinpaclitaxel significantly increased progression-free survival (PFS) among patients with advanced (stage III or IV) or recurrent endometrial cancer.

• #62 Endometrial Cancer – Gynecology and Obstetrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/gynecology-and-obstetrics/gynecologic-tumors/endometrial-cancer

  Overall survival (OS) at 24 months was 71.3% with dostarlimab and 56.0% with placebo (hazard ratio for mortality, 0.64). Subgroup analysis showed a substantial benefit in patients with high microsatellite instability/mismatch repair-deficient tumors (PFS at 24 months was 61.4% in the dostarlimab group versus 15.7% in the placebo group; hazard ratio for progression or death, 0.28).

• #63 Uterine Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/258148-overview

  Endometrial cancer may originate in a small area (eg, within an endometrial polyp) or in a diffuse multifocal pattern. Early tumor growth is characterized by an exophytic and spreading pattern. This growth is characterized by friability and spontaneous bleeding, even at early stages. Later tumor growth is characterized by myometrial invasion and growth toward the cervix. […] Four routes of spread occur beyond the uterus: Direct/local spread accounts for most local extension beyond the uterus. Lymphatic spread accounts for spread to pelvic, para-aortic, and, rarely, inguinal lymph nodes. Hematologic spread is responsible for metastases to the lungs, liver, bone, and brain (rare). Peritoneal/transtubal spread results in intraperitoneal implants, particularly with uterine papillary serous carcinoma (UPSC), similar to the pattern observed in ovarian cancer.

• #64 Uterine Cancer

  https://www.csh.org.tw/dr.tcj/educartion/f/web/Uterine%20Cancer/index.htm

  Endometrial cancer may originate in a small area (eg, within an endometrial polyp) or a diffuse multifocal pattern. […] Early tumor growth is characterized by an exophytic and spreading pattern. […] As noted in the next section, this growth is characterized by friability and spontaneous bleeding, even at early stages. […] Later tumor growth is characterized by myometrial invasion and growth toward the cervix. […] There are 4 routes of spread beyond the uterus: Direct/local – Accounts for the majority of local extension beyond the uterus; Lymphatic – Accounting for spread to pelvic, para-aortic, and, rarely, inguinal lymph nodes; Hematologic – Responsible for metastases to the lungs, liver, bone, brain (rare); Peritoneal/transtubal – Intraperitoneal implants, particularly with uterine papillary serous carcinoma, similar to the pattern seen in ovarian cancer.

• #65 Uterine Cancer

  https://www.csh.org.tw/dr.tcj/educartion/f/web/Uterine%20Cancer/index.htm

  Endometrial cancer may originate in a small area (eg, within an endometrial polyp) or a diffuse multifocal pattern. […] Early tumor growth is characterized by an exophytic and spreading pattern. […] As noted in the next section, this growth is characterized by friability and spontaneous bleeding, even at early stages. […] Later tumor growth is characterized by myometrial invasion and growth toward the cervix. […] There are 4 routes of spread beyond the uterus: Direct/local – Accounts for the majority of local extension beyond the uterus; Lymphatic – Accounting for spread to pelvic, para-aortic, and, rarely, inguinal lymph nodes; Hematologic – Responsible for metastases to the lungs, liver, bone, brain (rare); Peritoneal/transtubal – Intraperitoneal implants, particularly with uterine papillary serous carcinoma, similar to the pattern seen in ovarian cancer.

• #66 Uterine Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/258148-overview

  Endometrioid adenocarcinoma of the endometrium, the most common histology, is usually preceded by adenomatous hyperplasia with atypia. If left untreated, simple and complex endometrial hyperplasia with atypia progress to adenocarcinoma in 8% and 29% of cases, respectively. Without atypia, simple and complex hyperplasia progress to cancer in only 1% and 3% of cases, respectively. […] Less histologic differentiation is associated with a higher incidence of deep myometrial invasion and lymph node metastases. Subsequently, the depth of myometrial invasion and presence of tumor in the lymph nodes is directly related to recurrence rates and 5-year survival rates. […] PTEN mutation is thought to be an early event in low-grade endometrial cancers and is found in 55% of hyperplasia and 85% of cancers, whereas it is not found in benign endometrium.

• #67 Uterine Cancer

  https://www.csh.org.tw/dr.tcj/educartion/f/web/Uterine%20Cancer/index.htm

  The differentiation of endometrial cancers is one of the most important prognostic factors. […] Less histologic differentiation is associated with higher incidence of deep (one half) myometrial invasion and lymph node metastases. […] Subsequently, the depth of myometrial invasion and presence of tumor in the lymph nodes is directly related to recurrence rates and 5-year survival. […] Carcinosarcomas or homologous mixed mllerian tumors (MMT) typically have an endometrioid carcinoma, usually a higher grade, and an undifferentiated spindle cell sarcoma. […] The sarcomatous portion of the tumor may exhibit an ESS pattern, if differentiated. […] MMTs are characterized by early extrauterine spread and lymph node metastases. […] Endometrial stromal sarcomas (ESS) can be divided into 2 categories: low-grade (LGESS) and high-grade (HGESS) ESS.

• #68 Endometrial Cancer Treatment (PDQ®) – NCI

  https://www.cancer.gov/types/uterine/hp/endometrial-treatment-pdq

  Involvement of the capillary-lymphatic space on histopathological examination correlates with extrauterine and nodal spread of tumor. […] When possible, progesterone and estrogen receptor statuses, assessed either by biochemical or immunohistochemical methods, are included in the evaluation of patients with stage I and stage II cancer. […] Other factors predictive of poor prognosis include a high S-phase fraction, aneuploidy, PTEN loss-of-function variant, PIK3CA variant, TP53 variant, and oncogene expression.

• #69 Endometrial cancer: Pathophysiology, diagnosis and management – IJCAAP

  https://www.ijcap.in/html-article/18885

  The majority of postmenopausal women who are diagnosed with EC are 60 years of age or older. Almost 85% of cases developing after the age of 50 and only 5% before the age of 40, the highest age-specific incidence occurs between the ages of 75 and 79. […] The metabolic syndrome raises the risk of diabetes, heart disease, stroke, and other chronic disease conditions. Hypertension, increased triglycerides, reduced HDL cholesterol, obesity, and hyperglycemia are major contributing factors to all possible causes of the metabolic syndrome. Epidemiologically, type 2 diabetes and hypertension have been linked to an increased risk of EC; however, the associated obesity is the hidden cause. […] The majority of ECs are triggered by sporadic mutations; however, only around 5% of EC instances are due to genetic alterations. Lynch syndrome and Cowden syndrome are examples of genetic predispositions that result in EC.

• #70 Endometrial Cancer – Gynecology and Obstetrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/gynecology-and-obstetrics/gynecologic-tumors/endometrial-cancer

  Endometrial cancer is usually preceded by endometrial hyperplasia. Endometrial carcinoma is commonly classified into 2 types. […] Most endometrial cancers are caused by sporadic mutations. However, in approximately 5% of patients, inherited mutations cause endometrial cancer; endometrial cancer due to inherited mutations tends to occur at a younger age and is often diagnosed 10 to 20 years earlier than sporadic cancer. About half of cases that involve heredity occur in families with Lynch syndrome (hereditary nonpolyposis colorectal cancer (HNPCC]). Patients who have Lynch syndrome have a high risk of developing other cancers (eg, colorectal cancer, ovarian cancer). […] Endometrial cancer may spread as follows: From the surface of the uterine cavity to the cervical canal, Through the myometrium to the serosa and into the peritoneal cavity, Via the lumen of the fallopian tube to the ovary, broad ligament, and peritoneal surfaces, Via the bloodstream, leading to distant metastases, Via the lymphatics.

• #71 Endometrial Cancer – Gynecology and Obstetrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/gynecology-and-obstetrics/gynecologic-tumors/endometrial-cancer

  Endometrial cancer is usually preceded by endometrial hyperplasia. Endometrial carcinoma is commonly classified into 2 types. […] Most endometrial cancers are caused by sporadic mutations. However, in approximately 5% of patients, inherited mutations cause endometrial cancer; endometrial cancer due to inherited mutations tends to occur at a younger age and is often diagnosed 10 to 20 years earlier than sporadic cancer. About half of cases that involve heredity occur in families with Lynch syndrome (hereditary nonpolyposis colorectal cancer (HNPCC]). Patients who have Lynch syndrome have a high risk of developing other cancers (eg, colorectal cancer, ovarian cancer). […] Endometrial cancer may spread as follows: From the surface of the uterine cavity to the cervical canal, Through the myometrium to the serosa and into the peritoneal cavity, Via the lumen of the fallopian tube to the ovary, broad ligament, and peritoneal surfaces, Via the bloodstream, leading to distant metastases, Via the lymphatics.

• #72 Endometrial Carcinoma: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/254083-overview

  The most widely used anticancer drug is tamoxifen, and this drug has been suggested by some studies to cause an increased incidence of adenocarcinoma of the endometrium. […] In contrast to tamoxifen, increasing data indicate that the use of combination oral contraceptives (OCs) decreases the risk of developing endometrial cancer. […] Some associated medical conditions have been found to increase the incidence of endometrial cancer. […] Data suggest that women who have had breast cancer have a 2- to 3-fold increased risk of subsequently developing endometrial cancer. […] Women who have hereditary nonpolyposis colon cancer (HNPCC) appear to have a markedly increased risk for developing endometrial cancer. […] The first type occurs in women who fall into the classic category. These women are obese and have hyperlipidemia, signs of hyperestrogenism, uterine bleeding, infertility, and late onset of menopause.

• #73 Uterine cancer | Causes, Symptoms & Treatments | Cancer Council

  https://www.cancer.org.au/cancer-information/types-of-cancer/uterine-cancer

  Cancer of the uterus occurs when abnormal cells develop in the uterus and begin growing out of control. […] There are two main types of uterine cancer. Endometrial cancers begin in the lining of the uterus (endometrium) and account for about 95% of all cases; and uterine sarcomas, which develop in the muscle tissue (myometrium), and is a rarer form of uterine cancer. […] Some factors that can increase your risk of uterine cancer include: being postmenopausal, or reaching menopause (after age 55); a thickened wall lining (endometrial hyperplasia); never having children; starting periods early (before age 12); having high blood pressure or diabetes; being overweight or obese; family history of ovarian, uterine, or bowel cancer; having a genetic condition such as Cowden syndrome or Lynch syndrome; previous ovarian tumours, or polycystic ovary syndrome; using oestrogen only hormone replacement therapy or fertility treatment; previous radiation therapy to the pelvis; taking tamoxifen to treat breast cancer (the benefits of treating breast cancer usually outweigh the risk of uterine cancer – (talk to your doctor if you are concerned).

• #74 Endometrial Cancer – Life Extension

  https://www.lifeextension.com/protocols/cancer/uterine-endometrial-cancer?srsltid=AfmBOooQviI0wmZJQLdJEndJ7hPEAWL5kCyUngKr5O85FWlJbGlmEQln

  Tamoxifen treatment has been shown to be associated with a 2- to 3-fold higher risk of developing endometrial cancer, and the risk increases with duration of treatment. […] Diabetes mellitus and hyperinsulinemia (elevated insulin levels) have been shown in many studies to be associated with endometrial cancer. […] Endometrial cancer appears to be especially influenced by dietary and lifestyle factors. A variety of factors related to diet and lifestyle can increase the chances of developing endometrial cancer; chief among them is the consumption of foods high in animal fats and sugars whereas diets high in vegetables and fruits (especially those high in lutein) have lower risk. […] Given that inflammation plays a major role in tumor initiation, omega-3 fatty acids have gained considerable attention in the context of cancer prevention and treatment. Indeed, evidence suggests a higher dietary ratio of omega-3s to omega-6s is associated with a lower risk of endometrial cancer.

• #75 Endometrial Cancer | Nutrition Guide for Clinicians

  https://nutritionguide.pcrm.org/nutritionguide/view/Nutrition_Guide_for_Clinicians/1342025/all/Endometrial_Cancer

  Early menarche, late menopause, and nulliparity (especially when due to anovulation) may increase the risk for endometrial cancer. […] Estrogen therapy without progestin significantly increases the risk of endometrial cancer. […] Women with hypertension and diabetes (particularly type 2) have an increased risk for endometrial cancer, which may reflect the presence of common risk factors such as obesity. […] Women who have a 1st-degree relative with endometrial cancer are at increased risk of developing endometrial cancer. […] Contraceptive pills containing progestin reduce the risk of endometrial cancer by about 50%. […] Regular physical activity is associated with a 20-30% reduction in risk. […] The risk for uterine cancers appears to be associated with greater intakes of foods found in Western diets (animal products, refined carbohydrates).

• #76 Endometrial Cancer | Nutrition Guide for Clinicians

  https://nutritionguide.pcrm.org/nutritionguide/view/Nutrition_Guide_for_Clinicians/1342025/all/Endometrial_Cancer

  A 2015 meta-analysis showed that a high soy intake is associated with a nearly 20% lower endometrial cancer risk. […] The Iowa Womens Health Study found a 78% greater risk for endometrial cancer in women who consumed the most sugar-sweetened beverages, compared with those who consumed the lowest amount. […] Women who consume the most coffee were found to have a 20% lower risk for endometrial cancer when compared with those who consumed the lowest amount. […] There appears to be a J-shaped relationship between ethanol consumption and risk for endometrial cancer. […] Limiting high-energy-dense foods and high salt (or foods high in sodium), exercising regularly, and maintaining a healthy weight may reduce cancer risk.

• #77 Endometrial Cancer – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK525981/

  Endometrial cancer is a malignancy originating within the epithelial lining of the uterus. […] The condition has historically been classified into type 1 and type 2 endometrial cancer based on histological characteristics. However, results from recent studies have begun classifying endometrial cancers according to a current molecular subgrouping system. […] The most significant risk factors associated with endometrial cancer development include those that increase long-term exposure to unopposed estrogen (eg, obesity and exogenous estrogen). […] Present consensus holds that the pathogenesis of most low-grade endometrial carcinomas begins with uninterrupted endometrial proliferation, hormonally stimulated by endogenous or exogenous estrogen unopposed by progesterone or progestins, progressing through states of simple to complex forms of endometrial hyperplasia.

• #78 Endometrial Cancer | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/21102

  Present consensus holds that the pathogenesis of most low-grade endometrial carcinomas begins with uninterrupted endometrial proliferation, hormonally stimulated by endogenous or exogenous estrogen unopposed by progesterone or progestins, progressing through states of simple to complex forms of endometrial hyperplasia. […] Arising in this milieu, histologically recognizable atypical premalignant lesions, defined as endometrial intraepithelial neoplasia (EIN), formerly termed atypical endometrial hyperplasia, may transform into endometrioid carcinoma, characterized by stromal and myometrial invasion, PTEN mutations, and often KRAS2 mutations, microsatellite instability caused by mismatch repair deficiencies (MMRd) found in Lynch syndrome, and near-diploid karyotype. […] Because of this underlying pathologic mechanism, endometrial cancer is more frequently categorized by molecular subgroups based on mutation burden and copy number alterations rather than histological findings.

• #79 Endometrial Cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9421940/

  Another subgroup of EC was tumors with microsatellite instability (MSI). These tumors have mismatch repair defects and a tumor mutational burden that is ~10-fold greater than that of a general mutational background. These tumors have mutations in many genes owing to their generally high mutation burden, therefore, it can be difficult to differentiate passenger from driver mutations. PTEN, ARID1A, PIK3CA, PIK3R1 and RPL22 are all commonly mutated in the MSI subgroup of EC. Moreover, mutations or epigenetic silencing of MLH1, MSH2, MSH6, PMS2, and less commonly EPCAM, are often responsible for MSI. […] The identification of the molecular subgroups has rapidly changed the way ECs are stratified and treated. Several groups have taken these initial findings from TCGA and extrapolated them for better application to clinical practice. One approach – known as ProMisE (proactive molecular risk classifier for EC) – uses IHC to identify mismatch repair proteins and p53, and sequences the POLE exonuclease domain. ProMisE has identified four molecular subtypes of EC that are analogous but not identical to the four genomic subtypes described in TCGA study: MMRd, DNA POLE (corresponding to the ultramutated (POLE mutated) subtype), p53abn (which demonstrates aberrant p53 immunohistochemical staining and corresponds to the CNH subtype) and p53wt (which corresponds to the CNL subtype). Cases lacking enough information to classify are designated NSMP.

• #80 Endometrial Cancer – Gynecology and Obstetrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/gynecology-and-obstetrics/gynecologic-tumors/endometrial-cancer

  The higher (more undifferentiated) the grade of the tumor, the greater the likelihood of deep myometrial invasion, pelvic or para-aortic lymph node metastases, or extrauterine spread. […] Determining the molecular subtype, if feasible, adds valuable information to the standard clinicopathological risk factors to classify patients with endometrial cancer into risk groups, predict prognosis, and guide treatment recommendations. […] Uterine papillary serous carcinomas (10%), clear cell carcinomas (carcinosarcomas). […] The combination of chemotherapy and immunotherapy has shown synergistic effects in endometrial cancer treatment. In a phase III global randomized double-blind placebo-controlled trial, dostarlimab plus carboplatinpaclitaxel compared with placebo plus carboplatinpaclitaxel significantly increased progression-free survival (PFS) among patients with advanced (stage III or IV) or recurrent endometrial cancer.

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