Endometrial Hyperplasia and Endometrial Cancer

Overview

Definition

Endometrial hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation (EH) is a state of excessive proliferation of endometrial cells, resulting in an increased gland-to-stroma ratio.

Endometrial carcinoma (EC) refers to excessive proliferation of endometrial cells that are capable of invading surrounding tissues and metastasizing to distant sites.

Epidemiology

• Endometrial cancer is the most common gynecologic cancer in the developed world ( cervical cancer Cervical cancer Cervical cancer, or invasive cervical carcinoma (ICC), is the 3rd most common cancer in women in the world, with > 50% of the cases being fatal. In the United States, ICC is the 13th most common cancer and the cause of < 3% of all cancer deaths due to the slow progression of precursor lesions and, more importantly, effective cancer screening. Cervical Cancer is most common in developing countries).
• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency:
  • EH: 133 per 100,000 woman-years
  • EC: 25 per 100,000 woman-years
• Lifetime risk of EC in U.S. women: approximately 2%
• Both are most common in perimenopausal or early postmenopausal individuals.
• Peak age at diagnosis:
  • EH: 50–54 years
  • EC: 55–70 years
  • Both are rare at < 40 years.
• Ethnicity/race discrepancies:
  • Higher risk of developing EC overall: White women
  • Higher risk of developing type 2 Type 2 Spinal Muscular Atrophy EC: Black women
  • Higher risk of mortality Mortality All deaths reported in a given population. Measures of Health Status from EC: Black women

Classification, Staging, and Grading

Histologic classification of endometrial hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation

There are 2 primary classification systems for endometrial hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation:

• 2014 World Health Organization (WHO)
• Endometrial intraepithelial neoplasia (EIN) classification system

Histologic classification of endometrial cancer

Classification of EC is according to its histologic subtype. Low-grade endometrioid adenocarcinoma is known as type 1 Type 1 Spinal Muscular Atrophy and all others are type 2 Type 2 Spinal Muscular Atrophy. 

• Type 1 Type 1 Spinal Muscular Atrophy cancers: 
  • Include only grades 1 and 2 endometrioid adenocarcinoma
  • Make up 80% of ECs 
  • Have generally favorable outcomes
  • Estrogen-dependent cancers typically derived from EIN
• Type 2 Type 2 Spinal Muscular Atrophy cancers: 
  • Include histologic types:
    • Grade 3 endometrioid adenocarcinoma
    • Serous carcinoma (approximately 10%)
    • Clear cell carcinoma (< 5%)
    • Undifferentiated carcinoma
    • Mixed carcinoma
  • Much more aggressive with poor outcomes 
  • Not estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy dependent
  • Typically exhibit p53 and other genetic mutations Genetic Mutations Carcinogenesis

Grading Grading Methods which attempt to express in replicable terms the level of cell differentiation in neoplasms as increasing anaplasia correlates with the aggressiveness of the neoplasm. Grading, Staging, and Metastasis endometrial carcinoma

The grade describes the amount of solid glandular growth. Endometrial cancer is classified into 1 of 3 grades.

Staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis endometrial carcinoma

The stage describes the extent of tumor Tumor Inflammation spread. Staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis takes into account the size of the tumor Tumor Inflammation, extent of local invasion, lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node involvement, and metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis. There are 4 major stages in EC. Disease is staged based on the “highest” findings. For example, a tumor Tumor Inflammation confined to the cervix Cervix The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Externally, the cervix is lined by stratified squamous cells; however, the cervical canal is lined by columnar epithelium. Uterus, Cervix, and Fallopian Tubes: Anatomy but with positive lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy is classified as stage III. Similarly, direct tumor Tumor Inflammation invasion into the bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess mucosa is stage IV regardless of lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node involvement.

Etiology and Pathophysiology

Etiology

• Benign Benign Fibroadenoma endometrial hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation: chronic estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy exposure that is unopposed by progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones.
• EIN and EC: 
  • Genetic mutations Genetic Mutations Carcinogenesis leading to unrestricted cellular proliferation
  • In many cases, prolonged unopposed estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy exposure also contributes.

Risk factors

Most of the risk factors for both EH and EC include anything that increases unopposed estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy exposure.

• Obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity: Adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or “brite” adipose tissue, which is a transitional form. Adipose Tissue: Histology converts androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens to estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy.
• Polycystic ovary syndrome ( PCOS PCOS Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women, affecting nearly 5%-10% of women in the age group. It is characterized by hyperandrogenism, chronic anovulation leading to oligomenorrhea (or amenorrhea), and metabolic dysfunction. Polycystic Ovarian Syndrome): a condition of chronic anovulation Anovulation Suspension or cessation of ovulation in animals or humans with follicle-containing ovaries (ovarian follicle). Depending on the etiology, ovulation may be induced with appropriate therapy. Polycystic Ovarian Syndrome → ↓ opposing progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones
• Nulliparity
• Early menarche Menarche The first menstrual cycle marked by the initiation of menstruation. Menstrual Cycle/late menopause Menopause Menopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause: more menstrual cycles = ↑ estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy exposure
• Postmenopausal hormone replacement therapy Hormone Replacement Therapy Hormone replacement therapy (HRT) is used to treat symptoms associated with female menopause and in combination to suppress ovulation. Risks and side effects include uterine bleeding, predisposition to cancer, breast tenderness, hyperpigmentation, migraine headaches, hypertension, bloating, and mood changes. Noncontraceptive Estrogen and Progestins ( HRT HRT Hormone replacement therapy (HRT) is used to treat symptoms associated with female menopause and in combination to suppress ovulation. Risks and side effects include uterine bleeding, predisposition to cancer, breast tenderness, hyperpigmentation, migraine headaches, hypertension, bloating, and mood changes. Noncontraceptive Estrogen and Progestins) without adequate progestins Progestins Compounds that interact with progesterone receptors in target tissues to bring about the effects similar to those of progesterone. Primary actions of progestins, including natural and synthetic steroids, are on the uterus and the mammary gland in preparation for and in maintenance of pregnancy. Hormonal Contraceptives
• Tamoxifen Tamoxifen One of the selective estrogen receptor modulators with tissue-specific activities. Tamoxifen acts as an anti-estrogen (inhibiting agent) in the mammary tissue, but as an estrogen (stimulating agent) in cholesterol metabolism, bone density, and cell proliferation in the endometrium. Antiestrogens: estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy antagonist in breast, but has estrogenic activity in endometrium Endometrium The mucous membrane lining of the uterine cavity that is hormonally responsive during the menstrual cycle and pregnancy. The endometrium undergoes cyclic changes that characterize menstruation. After successful fertilization, it serves to sustain the developing embryo. Embryoblast and Trophoblast Development
• Estrogen-secreting ovarian tumors (e.g., granulosa cell Granulosa cell Supporting cells for the developing female gamete in the ovary. They are derived from the coelomic epithelial cells of the gonadal ridge. Granulosa cells form a single layer around the oocyte in the primordial ovarian follicle and advance to form a multilayered cumulus oophorus surrounding the ovum in the graafian follicle. The major functions of granulosa cells include the production of steroids and LH receptors. Puberty tumors)
• Lynch syndrome Lynch syndrome Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome: 
  • Also known as hereditary nonpolyposis colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy cancer ( HNPCC HNPCC Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome)
  • Carries up to a 60% lifetime risk of EC

Protective factors

The following factors decrease the risk of EH/EC:

• Use of combination oral contraceptives
• Cigarette smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases

Pathogenesis of benign Benign Fibroadenoma endometrial hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation

• Estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy naturally stimulates proliferation of endometrial tissue Endometrial tissue The mucous membrane lining of the uterine cavity that is hormonally responsive during the menstrual cycle and pregnancy. The endometrium undergoes cyclic changes that characterize menstruation. After successful fertilization, it serves to sustain the developing embryo. Endometriosis
• Progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones (produced by the corpus luteum Corpus Luteum The yellow body derived from the ruptured ovarian follicle after ovulation. The process of corpus luteum formation, luteinization, is regulated by luteinizing hormone. Ovaries: Anatomy only after ovulation Ovulation The discharge of an ovum from a rupturing follicle in the ovary. Menstrual Cycle) counteracts estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy/has a protective effect on the endometrium Endometrium The mucous membrane lining of the uterine cavity that is hormonally responsive during the menstrual cycle and pregnancy. The endometrium undergoes cyclic changes that characterize menstruation. After successful fertilization, it serves to sustain the developing embryo. Embryoblast and Trophoblast Development
• Excess estrogenic stimulation → diffuse hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation throughout the cavity
• Altering the hormonal milieu (e.g., treating with progestins Progestins Compounds that interact with progesterone receptors in target tissues to bring about the effects similar to those of progesterone. Primary actions of progestins, including natural and synthetic steroids, are on the uterus and the mammary gland in preparation for and in maintenance of pregnancy. Hormonal Contraceptives and/or removing estrogenic stimulation) can lead to resolution of hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation.

Pathogenesis of endometrial intraepithelial neoplasia and endometrial carcinoma

• Genetic mutations Genetic Mutations Carcinogenesis lead to:
  • Uncontrolled proliferation starting from a single location
  • Absence of programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death
• Classic mutations include:
  • PTEN: tumor Tumor Inflammation suppressor (common in type 1 Type 1 Spinal Muscular Atrophy EC)
  • p53: tumor Tumor Inflammation suppressor 
    • Present in > 90% of type 2 Type 2 Spinal Muscular Atrophy ECs
    • Worse outcomes associated with p53 mutations
  • POLE gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics: involved in DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication and repair
  • Lynch syndrome Lynch syndrome Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome mutations ( DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure mismatch repair Mismatch repair A DNA repair pathway involved in correction of errors introduced during DNA replication when an incorrect base, which cannot form hydrogen bonds with the corresponding base in the parent strand, is incorporated into the daughter strand. Exonucleases recognize the base pair mismatch and cause a segment of polynucleotide chain to be excised from the daughter strand, thereby removing the mismatched base. Lynch syndrome genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure)
• Progression of disease (in order):
  • Uncontrolled endometrial proliferation → EIN → EC 
  • Direct extension Extension Examination of the Upper Limbs into the myometrium and adjacent structures 
  • Invasion into lymphatic capillaries Lymphatic capillaries Lymphatic Drainage System: Anatomy 
  • Metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis to regional lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy:
    • Pelvic lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy
    • Para-aortic lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy
  • Distant metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis via lymphatic and hematologic spread

Clinical Presentation

About ¾ of women diagnosed with EC are postmenopausal. The classic presentation is a 60-something-year-old obese woman with postmenopausal bleeding. 

• Abnormal uterine bleeding Abnormal Uterine Bleeding Abnormal uterine bleeding is the medical term for abnormalities in the frequency, volume, duration, and regularity of the menstrual cycle. Abnormal uterine bleeding is classified using the acronym PALM-COEIN, with PALM representing the structural causes and COEIN indicating the non-structural causes. Abnormal Uterine Bleeding (most common presenting symptom):
  • Postmenopausal bleeding 
  • Abnormal menstrual cycles in premenopausal individuals
• Vaginal discharge (clear or white) in postmenopausal women
• Abdominal or pelvic pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways/pressure
• Dyspareunia Dyspareunia Recurrent genital pain occurring during, before, or after sexual intercourse in either the male or the female. Primary Ovarian Insufficiency ( pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways during intercourse)
• Urinary symptoms:
  • Dysuria Dysuria Painful urination. It is often associated with infections of the lower urinary tract. Urinary Tract Infections (UTIs)
  • Difficulty urinating
• Unintentional weight loss Weight loss Decrease in existing body weight. Bariatric Surgery
• EH/EC may 1st be noted as an incidental finding:
  • Endometrial cells on a routine screening Screening Preoperative Care Papanicolaou (Pap) smear
  • Thickened endometrial lining on pelvic imaging done for other indications in a postmenopausal woman
  • Identified on specimen from a hysterectomy done for other indications (e.g., fibroids Fibroids A benign tumor derived from smooth muscle tissue, also known as a fibroid tumor. They rarely occur outside of the uterus and the gastrointestinal tract but can occur in the skin and subcutaneous tissue, probably arising from the smooth muscle of small blood vessels in these tissues. Infertility)

Diagnosis

Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is required for definitive diagnosis of EH and EC. The pelvic exam is usually normal. All women who present with abnormal bleeding (especially postmenopausal bleeding) should be assessed with pelvic ultrasonography and/or biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma.

Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma

• Gold standard for diagnosing both EH and EC
• Methods:
  • In-office biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma with an endometrial pipelle (most reliable when ≥ 50% of the cavity is affected → may miss focal lesions)
  • Surgical biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma with dilation and curettage Curettage A scraping, usually of the interior of a cavity or tract, for removal of new growth or other abnormal tissue, or to obtain material for tissue diagnosis. It is performed with a curet (curette), a spoon-shaped instrument designed for that purpose. Benign Bone Tumors (D&C)
• Histologic findings:
  • Back-to-back glands with no intervening stroma
  • Glands have smooth, luminal contour
  • May see cribriform patterns (gland within a gland)

Imaging

• Methods:
  • Transvaginal pelvic ultrasound: imaging method of choice
  • Saline-infusion sonography Saline-Infusion Sonography Congenital Malformations of the Female Reproductive System ( SIS SIS Infertility): 
    • Saline is injected into the uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Uterus, Cervix, and Fallopian Tubes: Anatomy while real-time sonography Sonography The visualization of deep structures of the body by recording the reflections or echoes of ultrasonic pulses directed into the tissues. Use of ultrasound for imaging or diagnostic purposes employs frequencies ranging from 1. 6 to 10 megahertz. Diagnostic Procedures in Gynecology is performed.
    • Distends the cavity to allow assessment of intrauterine pathology
    • Can differentiate diffusely thickened endometrium Endometrium The mucous membrane lining of the uterine cavity that is hormonally responsive during the menstrual cycle and pregnancy. The endometrium undergoes cyclic changes that characterize menstruation. After successful fertilization, it serves to sustain the developing embryo. Embryoblast and Trophoblast Development (a concern for EH/EC) from endometrial polyp
  • Pelvic MRI: may be indicated if ultrasound is unclear or to assess extent of disease.
  • Chest radiography: to look for metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis
• Findings worrisome for EH/EC:
  • Endometrial thickness ≥ 5 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma in a postmenopausal woman
  • Heterogeneity of the endometrium Endometrium The mucous membrane lining of the uterine cavity that is hormonally responsive during the menstrual cycle and pregnancy. The endometrium undergoes cyclic changes that characterize menstruation. After successful fertilization, it serves to sustain the developing embryo. Embryoblast and Trophoblast Development
  • Loss of a distinct border between the endometrium Endometrium The mucous membrane lining of the uterine cavity that is hormonally responsive during the menstrual cycle and pregnancy. The endometrium undergoes cyclic changes that characterize menstruation. After successful fertilization, it serves to sustain the developing embryo. Embryoblast and Trophoblast Development and myometrium
  • Cystic Cystic Fibrocystic Change lesions in the endometrium Endometrium The mucous membrane lining of the uterine cavity that is hormonally responsive during the menstrual cycle and pregnancy. The endometrium undergoes cyclic changes that characterize menstruation. After successful fertilization, it serves to sustain the developing embryo. Embryoblast and Trophoblast Development

Other assessments

• Pelvic exam: 
  • Typically normal
  • Findings in more advanced disease:
    • Diffusely enlarged uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Uterus, Cervix, and Fallopian Tubes: Anatomy
    • Fixed (nonmobile) pelvic structures
• Pap smear Pap smear Cytological preparation of cells collected from a mucosal surface and stained with Papanicolaou stain. Cervical Cancer Screening (should be up to date)
• CA-125 CA-125 A carbohydrate antigen that occurs in tumors of the ovary as well as in breast, kidney, and gastrointestinal tract tumors and normal tissue. While it is tumor-associated, it is not tumor-specific and may have a protective function against particles and infectious agents at mucosal surfaces. Serum Tumor Markers: 
  • Serologic tumor Tumor Inflammation marker sometimes tracked in individuals with type 2 Type 2 Spinal Muscular Atrophy EC
  • Can be used to follow response to treatment and in posttreatment surveillance Surveillance Developmental Milestones and Normal Growth

Management

Management for benign Benign Fibroadenoma endometrial hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation ( hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation without atypia Atypia Fibrocystic Change)

• Observation (instead of progestin therapy) may be considered in premenopausal women with:
  • Normal weight
  • Known inciting factor removed (e.g., anovulatory woman has now become ovulatory)
• Medical management: 
  • Candidates:
    • Premenopausal women (1st-line)
    • Can be considered in postmenopausal women
  • Because benign Benign Fibroadenoma EH is an estrogen-driven process, treatment is typically with progestin therapy (which naturally opposes the effects of estrogens). 
  • Progestin therapy options include:
    • Levonorgestrel Levonorgestrel A synthetic progestational hormone with actions similar to those of progesterone and about twice as potent as its racemic or (+-)-isomer (norgestrel). It is used for contraception, control of menstrual disorders, and treatment of endometriosis. Hormonal Contraceptives intrauterine device (IUD) (1st-line)
    • Oral progestin therapy: megestrol acetate Megestrol acetate Megestrol acetate is a progestogen with actions and uses similar to those of the progestogens in general. It also has anti-androgenic properties. It is given by mouth in the palliative treatment or as an adjunct to other therapy in endometrial carcinoma and in breast cancer. Noncontraceptive Estrogen and Progestins, medroxyprogesterone
    • Combined oral contraceptives pills (for women who also desire contraception)
• Surgical management:
  • Hysterectomy (definitive treatment)
  • Reasonable in postmenopausal women

Management for endometrial intraepithelial neoplasia ( atypical hyperplasia Atypical Hyperplasia Benign Breast Conditions)

• Hysterectomy: preferred treatment in all individuals
• Progestin therapy can be an alternative in women who:
  • Desire future fertility
  • Are at high risk for surgical complications Surgical complications Surgical complications are conditions, disorders, or adverse events that occur following surgical procedures. The most common general surgical complications include bleeding, infections, injury to the surrounding organs, venous thromboembolic events, and complications from anesthesia. Surgical Complications

Management for endometrial carcinoma

Management is primarily surgical, with potential for adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy. Management of advanced disease is highly individualized.

• Surgical management:
  • Indicated in women who are able to undergo an operation
  • Procedure: 
    • Hysterectomy with a bilateral salpingo-oophorectomy
    • Possible lymphadenectomy of the pelvic and para-aortic nodes (higher stage/grade)
  • Surgery is often curative in low-risk disease (defined as type 1 Type 1 Spinal Muscular Atrophy EC confined to the endometrium Endometrium The mucous membrane lining of the uterine cavity that is hormonally responsive during the menstrual cycle and pregnancy. The endometrium undergoes cyclic changes that characterize menstruation. After successful fertilization, it serves to sustain the developing embryo. Embryoblast and Trophoblast Development).
  • Individuals with locally advanced or metastatic cancer may have cytoreductive or palliative surgery.
• Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy:
  • Often prescribed for individuals with intermediate- or high-risk disease
  • Types:
    • Vaginal brachytherapy (lower toxicity Toxicity Dosage Calculation)
    • Pelvic radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy (↑ toxicity Toxicity Dosage Calculation, including long-term bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess and bowel complications)
• Chemotherapy Chemotherapy Osteosarcoma:
  • May be indicated in high-risk disease
  • If used, regimen includes:
    • Carboplatin Carboplatin An organoplatinum compound that possesses antineoplastic activity. Alkylating Agents and Platinum
    • Paclitaxel Paclitaxel A cyclodecane isolated from the bark of the pacific yew tree, taxus brevifolia. It stabilizes microtubules in their polymerized form leading to cell death. Microtubule and Topoisomerase Inhibitors
• Hormone therapy ( progestins Progestins Compounds that interact with progesterone receptors in target tissues to bring about the effects similar to those of progesterone. Primary actions of progestins, including natural and synthetic steroids, are on the uterus and the mammary gland in preparation for and in maintenance of pregnancy. Hormonal Contraceptives): may be considered in some cases
• Long-term surveillance Surveillance Developmental Milestones and Normal Growth:
  • Regular Regular Insulin pelvic exams
  • Can consider following CA-125 CA-125 A carbohydrate antigen that occurs in tumors of the ovary as well as in breast, kidney, and gastrointestinal tract tumors and normal tissue. While it is tumor-associated, it is not tumor-specific and may have a protective function against particles and infectious agents at mucosal surfaces. Serum Tumor Markers levels
  • Imaging for any suspicion of recurrence:
    • PET PET An imaging technique that combines a positron-emission tomography (PET) scanner and a ct X ray scanner. This establishes a precise anatomic localization in the same session. Nuclear Imaging/CT (preferred)
    • MRI

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

• Risk of progression from EH → EC:
  • Benign Benign Fibroadenoma EH: < 10% progress to EC within 20 years
  • EIN ( hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation with atypia Atypia Fibrocystic Change): 15%–40% will progress to EC within 20 years 
• EC prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas by type:
  • Type 1 Type 1 Spinal Muscular Atrophy:
    • Bleeds early in the course of disease → postmenopausal bleeding is an “obvious” symptom → women present and are diagnosed early (often stage 1 Stage 1 Trypanosoma brucei/African trypanosomiasis)
    • Carries a good prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas
    • Surgery is often curative 
  • Type 2 Type 2 Spinal Muscular Atrophy disease acts more like ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer: 
    • Generally presents at a higher stage
    • Worse prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas
    • Higher rates of recurrence
• 5-year survival rates based on EC stage:
  • Stage I: approximately 80%–90%
  • Stage II: approximately 80%
  • Stage III: approximately 50%–65% 
  • Stage IV: approximately 20%

Differential Diagnosis

• Adenomyosis Adenomyosis Adenomyosis is a benign uterine condition characterized by the presence of ectopic endometrial glands and stroma within the myometrium. Adenomyosis is a common condition, affecting 20%-35% of women, and typically presents with heavy menstrual bleeding and dysmenorrhea. Adenomyosis: very common benign Benign Fibroadenoma uterine condition characterized by the presence of ectopic endometrial glands and stroma within the myometrium. Adenomyosis Adenomyosis Adenomyosis is a benign uterine condition characterized by the presence of ectopic endometrial glands and stroma within the myometrium. Adenomyosis is a common condition, affecting 20%-35% of women, and typically presents with heavy menstrual bleeding and dysmenorrhea. Adenomyosis typically presents with heavy menstrual bleeding Heavy menstrual bleeding Excessive menstrual blood loss (objectively defined as > 80 mL blood loss/cycle). Can be based on heavy flow, as determined by the patient Abnormal Uterine Bleeding and dysmenorrhea. Diagnosis is either clinical or assisted with pelvic imaging, usually transvaginal ultrasonography or, occasionally, MRI. Management is based on the woman’s preference regarding future childbearing and may include hysterectomy, other surgical options, or medical hormonal suppression Suppression Defense Mechanisms with progestins Progestins Compounds that interact with progesterone receptors in target tissues to bring about the effects similar to those of progesterone. Primary actions of progestins, including natural and synthetic steroids, are on the uterus and the mammary gland in preparation for and in maintenance of pregnancy. Hormonal Contraceptives.
• Endometrial atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation:  benign Benign Fibroadenoma condition in which the endometrial lining becomes thin and atrophic because of prolonged states of low estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy. With little to no fluid in the cavity, friction may lead to micro-erosions and a subsequent inflammatory reaction that typically presents with postmenopausal light bleeding or spotting. Endometrial atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation is diagnosed on ultrasonography (which shows a thin endometrial lining) in the setting of a negative endometrial biopsy Endometrial Biopsy Diagnostic Procedures in Gynecology. No treatment is required.
• Endometrial or cervical polyps: pedunculated or sessile projections of the endometrium Endometrium The mucous membrane lining of the uterine cavity that is hormonally responsive during the menstrual cycle and pregnancy. The endometrium undergoes cyclic changes that characterize menstruation. After successful fertilization, it serves to sustain the developing embryo. Embryoblast and Trophoblast Development that result from overgrowth of endometrial glands and stroma around a central vascular stalk. Although these polyps are usually benign Benign Fibroadenoma, they can be malignant, particularly in postmenopausal women. Endometrial or cervical polyps present with abnormal uterine or postmenopausal bleeding, though many are asymptomatic. Endometrial polyps Endometrial polyps Endometrial polyps are pedunculated or sessile projections of the endometrium that result from overgrowth of endometrial glands and stroma around a central vascular stalk. Endometrial polyps are a few millimeters to a few centimeters in size, can occur anywhere within the uterine cavity, and, while usually benign, can be malignant, particularly in postmenopausal women. Endometrial Polyps are best diagnosed with saline-infusion sonography Saline-Infusion Sonography Congenital Malformations of the Female Reproductive System ( SIS SIS Infertility) and are usually treated with hysteroscopic resection. 
• Leiomyomas ( uterine fibroids Uterine Fibroids Gynecological Imaging): common, benign Benign Fibroadenoma tumors arising from smooth muscle cells in the uterine myometrium. Leiomyomas typically present with abnormal bleeding, pelvic pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, and/or bulk symptoms. Fibroids Fibroids A benign tumor derived from smooth muscle tissue, also known as a fibroid tumor. They rarely occur outside of the uterus and the gastrointestinal tract but can occur in the skin and subcutaneous tissue, probably arising from the smooth muscle of small blood vessels in these tissues. Infertility are identified as a hypoechoic Hypoechoic A structure that produces a low-amplitude echo (darker grays) Ultrasound (Sonography), well-circumscribed, round mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast on pelvic ultrasonography. Leiomyomas of the vaginal wall are also possible, though extremely rare. 
• Leiomyosarcoma Leiomyosarcoma Uterine leiomyomas (or uterine fibroids) are benign tumors arising from smooth muscle cells in the uterine myometrium. Leiomyosarcomas, however, are malignant tumors, arising de novo (not from fibroids). Uterine Leiomyoma and Leiomyosarcoma: rare, malignant tumors of uterine smooth muscle that arise de novo (i.e., not from the malignant transformation Transformation Change brought about to an organism’s genetic composition by unidirectional transfer (transfection; transduction, genetic; conjugation, genetic, etc.) and incorporation of foreign DNA into prokaryotic or eukaryotic cells by recombination of part or all of that DNA into the cell’s genome. Bacteriology of fibroids Fibroids A benign tumor derived from smooth muscle tissue, also known as a fibroid tumor. They rarely occur outside of the uterus and the gastrointestinal tract but can occur in the skin and subcutaneous tissue, probably arising from the smooth muscle of small blood vessels in these tissues. Infertility). They present similarly to benign Benign Fibroadenoma leiomyomas (with abnormal bleeding, pelvic pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, and bulk symptoms), making diagnosis difficult. They are usually diagnosed on post-operative hysterectomy specimens done for suspected fibroids Fibroids A benign tumor derived from smooth muscle tissue, also known as a fibroid tumor. They rarely occur outside of the uterus and the gastrointestinal tract but can occur in the skin and subcutaneous tissue, probably arising from the smooth muscle of small blood vessels in these tissues. Infertility. Management involves surgical excision (if not already done) and possibly adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination chemotherapy Chemotherapy Osteosarcoma.
• Cervical cancer Cervical cancer Cervical cancer, or invasive cervical carcinoma (ICC), is the 3rd most common cancer in women in the world, with > 50% of the cases being fatal. In the United States, ICC is the 13th most common cancer and the cause of < 3% of all cancer deaths due to the slow progression of precursor lesions and, more importantly, effective cancer screening. Cervical Cancer: invasive cancer of the cervix Cervix The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Externally, the cervix is lined by stratified squamous cells; however, the cervical canal is lined by columnar epithelium. Uterus, Cervix, and Fallopian Tubes: Anatomy (and the most common gynecologic cancer worldwide). There are 2 major histologic types of cervical cancer Cervical cancer Cervical cancer, or invasive cervical carcinoma (ICC), is the 3rd most common cancer in women in the world, with > 50% of the cases being fatal. In the United States, ICC is the 13th most common cancer and the cause of < 3% of all cancer deaths due to the slow progression of precursor lesions and, more importantly, effective cancer screening. Cervical Cancer: SCC and adenocarcinoma, the vast majority of which are caused by high-risk HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomavirus (HPV) infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease. Early cervical neoplasia is asymptomatic, though more advanced disease may present with abnormal bleeding (especially bleeding on contact). Diagnosis is made by Pap testing with cytology, HPV testing HPV testing Cervical Cancer Screening, and biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma.