Female Reproductive System Pathology

• Pathology of the female reproductive system.
• Instructional objectives include the diseases of the vulva, comparing and contrasting diseases of the vagina, and distinguishing the pathologies of the cervix.
• Inventory of common uterine pathologies will be covered, along with analysis of ovarian pathology symptoms and consequences.
• Analysis of ectopic pregnancy including its causes and common sites is included, along with differentiating pregnancy-related diseases and breast diseases.

Vulvitis

• Reactive inflammation in response to exogenous stimulus.
• Stimuli may be irritants, allergens, or infectious agents.
• HPV, HSV, N. gonorrhea, chlamydia, and Treponema pallidum are sexually transmitted causes.
• Candida is a non-sexually transmitted cause.
• Bartholin's cyst is a complication involving obstruction of secretory ducts leading to blockage and painful dilation.

Nonneoplastic Epithelial Disorders of the Vulva

Lichen Sclerosis

• Characterized by thinning and hardening of the epidermis.
• Presents a zone of acellular, homogenized dermal fibrosis.
• Shows a band-like mononuclear inflammatory cell infiltrate.
• Increases risk for developing squamous cell carcinoma.

Lichen Simplex Chronicus

• Characterized by epithelial thickening (hyperplasia) and hyperkeratosis.
• Associated with pruritus.

Other Vulvar Pathology

Carcinoma of the Vulva

• Can be HPV related, though this presentation is less common.
• Vulvar intraepithelial neoplasia (VIN) is considered pre-cancerous and may progress to invasive carcinoma.
• Risk factors include smoking and immunodeficiency.
• Non-HPV related carcinoma presents as differentiated vulvar intraepithelial neoplasia (dVIN).
• Characterized by cytologic atypia in the basal layer and abnormal keratinization, potentially leading to differentiated keratinized squamous cell carcinoma.
• Risk factors include older age and history reactive epithelial changes like lichen sclerosis.
• May present with Leukoplakia, where 25% of cases are pigmented.

Paget's Disease of the Vulva

• Characterized by intraepidermal proliferation of epithelial cells.
• Can be extramammary, usually in the vulva and without carcinoma association. Alternatively, it can be found in the breast, where it is almost always associated with underlying carcinoma.
• Manifests clinically as a red, scaly, crusted plaque.

Vaginitis

• Characterized by vaginal discharge (leukorrhea).
• Caused by bacterial, fungal, or parasitic pathogens.

Frequent Offenders

• Candida albicans presents as a curdy white discharge, indicating a predisposing influence or superinfection.
• Trichomonas vaginalis causes a copious gray-green discharge and is sexually transmitted which can be identified with microscopy due to the flagellated protozoa.

Malignant Neoplasms of the Vagina

• Squamous Cell Carcinoma is uncommon, typically affecting women over 60, and is often associated with vaginal epithelial neoplasia and HPV.
• Clear Cell Adenocarcinoma involves vaginal adenosis (red, granular foci lined by mucus-secreting or ciliated columnar epithelium) and is a precursor to clear cell carcinoma and rare and usually occurs secondary to in utero diethylstilbestrol exposure.
• Sarcoma Botryoides, also known as embryonal rhabdomyosarcoma, is rare, manifesting as polypoid masses and occurs most often in infants and children under 5, and uncommonly seen in young women.

Causes of Vaginal Bleeding

Premenarchal

• These instances are common with FB, but always consider sexual abuse.
• Precocious puberty may also be a factor in these situations.

Reproductive

• Pregnancy is the most common factor during the reproductive period.
• First, second, and third trimester bleeds should be considered with abnormal uterine bleeding.

Postmenopausal

• Vaginal atrophy and intercourse are the most common causes, but endometrial cancer should be tested as well.

Next-Step Differential

Premenarchal

• If FB (Foreign Body) is suspected, a pelvic exam is needed and may require anesthesia.
• For Sexual Abuse, reporting is required by law if suspected.
• Central precocious puberty is often related to the hypothalamic-pituitary-gonadal axis, while peripheral can be attributed to sex hormones, adrenal glands, or germ cell tumors.

Reproductive

• Vaginal bleeding during pregnancy will be addressed separately.
• Consider PALM COIEN: polyp endometrial polyp, adenomyosis endometrial glands, leiomyoma “fibroid” malignancy reproductive cancer, Ovulation Dsyfxn FSH:LH imbalance, consider asking about IUD for Exclusion.

Postmenopausal

• A good history and physical exam are necessary.
• Documented counseling on Endometrial Cancer needs to be performed.

Vaginal Atrophy

• Common in elderly patients and secondary to falling estrogen levels after menopause.
• Vaginal atrophy is associated with pale, dry, and shiny vulvar tissue and involves a loss of adipose tissue in the labia major and labia minora.
• The prepuce and clitoris are often pale and reduced in size, while examination shows that the introitus may be narrowed and friable.
• In vaginal atrophy, the vaginal walls lack rugae and may be pale and/or erythematous.

First Trimester Vaginal Bleeding

• Causes can be ectopic pregnancy or spontaneous abortion. Both events require further attention.

Second / Third Trimester Vaginal Bleeding

• These scenarios could be indicative of abruption where premature separation of the placenta from the endometrium is the primary concern. Patients can experience painful vaginal bleeding without contractions.
• Patients may experience Previa where vessels get torn resulting in painless vaginal bleeding in early labor.
• In uterine rupture, the uterus can rip causing sudden new and extreme pain in loss of fetal station.

Abruption Additional Information

• Separation of the placenta from the uterine wall after 20 weeks but before delivery.
• Maternal HTN, Abd trauma, Smoking (nearly doubles the risk), Substance abuse (esp. cocaine), Age over 40 yo, and Sudden uterine decompression are all risks.

Cervicitis

• Usually associated with purulent discharge, such as leukorrhea.
• Infections are difficult to determine secondary presence of normal flora and other microbiota.
• Cervicitis falls into two classes, infectious and non-infectious.
• Infections usually all STD.
• Chlamydia, Neisseria gonorrhea and Trichomonas Vaginalis can all be factors.
• HSV can be particularly serious because of potential maternal fetal transmission and systemic HSV infections in the newborn
• Typically treated for GC.

Cervical Neoplasia

• HPV is the causative agent for most cervical dysplasias and cancers. Transformation Zone involves a squamocolumnar junction that undergoes eversion at puberty.
  • Exposes the columnar cells of the endocervix then leading to squamous metaplasia which is a normal process.
  • Risk Factors involve HPV infection, multiple sex partners, the male partner having multiple previous partners, high-risk HPV strains (16,18,31,33), cigarette smoking, and immunodeficiency also play a role.
  • High-Risk HPV strains are 16, 18, 31 and 33. E6 and E7 viral oncoproteins of high-risk variants inhibit p53 & RB (tumor suppressors). HPV vaccine has been proven effective against types associated with carcinoma.
  • Pap testing is good for detection of SIL and carcinoma.

Carcinogenesis (HPV-related)

• Begins with precancerous epithelial change. SIL (Squamous Intraepithelial Lesion) precedes cancer by years to decades Peak incidence of SIL is 30 years old Peak incidence of invasive carcinoma is 45 years old

LSIL (low grade)

• Formerly termed CIN I.
• Not treated as a pre-malignant lesion since it does not progress directly to carcinoma, and only a small % progress to HSIL.

HSIL (high grade)

• Formerly termed CIN II & III.
• Demonstrates proliferation, arrested epithelial maturation, and a decrease in viral replication
• HSIL is considered high risk for progression to carcinoma.

Endometritis

• Inflammation of the endometrium and an established component of Pelvic Inflammatory Disease (PID).
• Has two common types:
  • In acute endometritis, we see neutrophilic infiltrate.
  • In chronic, we see lymphoplasmacytic infiltrate in the stromal layer. PID is frequently caused by N. gonorrhea or C. trachomatis. There are potential risk of infertility and ectopic pregnancy due to scarring of the fallopian tubes.

Pelvic Inflammatory Disease

• Most common: N. Gonorrhoeae or C. Trachomatis.
• Results in Neutrophilic infiltrate in the superficial endometrium Lymphoplasmacytic infiltrate in the stromal layer. Other causes Retained products of conception, a foreign body in the Gl tract Symptoms of include: Fever, Abdominal pain, Menstrual abnormalities

Other Causes

• Potential factors are retained products of conception foreign body (IUD), and ascending infection of GI tract flora.
• Symptoms of endometritis include fever, abdominal pain, and menstrual abnormalities.
• There is potential risk of infertility and ectopic pregnancy due to scarring of the fallopian tubes.

Nonneoplastic Disorders of the Endometrium

Adenomyosis

• Characterized by growth of endometrium into the myometrium.
• Often seen with uterine enlargement.
• Extensive growth may be seen with menorrhagia, dysmenorrhea and pelvic pain.

Endometriosis

• Endometrial glands and stroma located outside of the uterus.
• Tissue is displaced and abnormal.
• Can lead to cyclic bleeding, dysmenorrhea and pelvic pain.

Hypotheses of Endometrial Dispersion

• Regurgitation Theory where menstrual backflow through the fallopian tubes leads to implantation are most favored.
• Benign Metastasis Theory explains that tissue can spread to distant sites from the original site of infection or trauma.
• Extrauterine stem/progenitor cell theory where circulating stem cells from the bone marrow turn into endometrial tissue

Proliferative Lesions

Endometrial Hyperplasia

• Proliferative Response due to Unopposed Endogenous or Exogenous Estrogens,
• Risk Factors include anovulatory cycles, polycystic ovary syndrome, tumors producing estrogen, obesity, counter balancing with progestin.
• The risks can be eliminated by classified based on cell type

Endometrial Carcinoma

• A number of cancer types relating two different carcinomas:
• Endometrioid- associated with estrogen excess and endometrial hyperplasia.
  • Mutations in DNA mismatch repair genes and the tumor suppressor PTEN.
• Serous - Older women
• Risk factors associated with Endometrial Atrophy and Serous Endometrial Intraepithelial Carcinoma (SEIC). -Manifests more with extrauterine extension which can present more intensely.

Other Uterine Abnormalities

• These disorders include Endometrial Polyps which are defined as Small Sessile Lesions that can commonly occur around the time of menopause and be a source of uterine bleeding.
• Another factor that influences uterine health in Leiomyoma. Also referred as fibroids, firm tumors that arise from the myometrium in Estrogen and are more common in pre-menopausal women. Leiomyosarcoma is a tumor in arising of mesenchymal cells from myometrial cells.

Disease of the Ovary

Salpingitis

• This is Inflammation of the Fallopian Tubes from Infections results from PID, usually by Gonorrhoea or Chlamydia. In other cases there is some infection by the staph, strep that spreads to other areas.
• These have the symptoms such as Fever ,Lower Abdominal/Pelvic Pain /Masses that lead to infection.

Polycystic Ovarian Syndrome (PCOS)

• A Complex Endocrine System Disorder Characterized by androgenism , Menstrual Abnormalities, PCOS
• Symptoms after Menarche in Teenages/young Adults,
• Oligomenorrhea, Hirsutism, Infertility and Obesity

Polycystic Ovarian Syndrome

• GnRH is released from the ovary instead of to the uterus. LH will go up and FSH down which contributes hirsutism and acne.

Ovarian Tumors

• Epithelium: Most common malignant type (90%); more common over 40; primarily serous, mucinous, or endometroid.
• Sex cord-Stromal Cells may differentiate toward granulosa, Sertoli, Leydig, or ovarian stromal cell type Depending on the differentiation, they may produce estrogens or androgens.
• Germ cells: Mostly cystic teratomas Most common ovarian tumor in young women; the vast majority are benign. They may differentiate toward oogonia (dysgerminoma), primitive embryonal tissue (embryonal), yolk sac (endodermal sinus tumor), placental tissue (choriocarcinoma), or multiple tissue types (teratoma).

Physiological Changes During Pregnancy: Cardiovascular System

• A decrease in Systemic Vascular Resistance (SVR) Mean Arterial Pressure = Cardiac Output x Systemic Vascular Resistance.
• Progesterone causes smooth muscles to dilate leading to the decrease.

Compensatory mechanisms

• Placental growth: new vessels mean small vessel diameter, causing decreased SVR which then the placenta plateaus at 2.
• Renin/ang/aldo system kicks in further compensate for falling SVR and increases heart rate
• This will drop around 7-20mmHg.

Concerns

There is Increased Fluid from fluid retention so watch out with increased blood volume since venous return is less and may effect kidney function

Cardiovascular Effects

• Note the key changes during pregnancy*
• Systemic vascular resistance goes DOWN.
• Heart rate goes UP(a little as well).
• Blood volume goes UP.
• Stroke volume goes UP.
• Cardiac output gradually goes UP.
• Blood pressure falls to 26 weeks, then nearly returns to baseline.

Potential symptoms

Fluid retention can cause : Daytime Pedal Edema, frequent urination, kidney function decrease.

Pregnancy and Blood Composition

• Increased Volume compensates for falling vascular resistance that then increase fluid retention to help increase blood flow.

• The liver makes more clotting factors that affect how the body makes protein. Estrogens regulate gene transcription in the liver which is regulated in in epithelial cells.

Pathogen of Pregnancy: Cardiovascular

Mean Arterial Pressure = Cardiac Output x Systemic Vascular Resistance Progesterone. Progesterone can stimulate the smooth muscle of the dilator resulting in a decrease in Systemic Vascular Resistance.

Pathogen of Pregnancy: Hematologic

Hematologic: Hemoglobin

Hemoglobin and normal blood volume with an increase of Blood Volume during Pregnancy but watch out for abnormal count below 10.5

• The bodies system have hypercoagulability due to the high estrogen.

Other Pathogen of Pregnancy

Other Changes: Urinary

Creatinine is increased with increased renal prefusion / GFR as well as glycosuria. An increased urine level can effect ascending system infection.

Other Changes: GI

Constipation due to progesterone is dilater decreased transit time. Counsel on dietary fiber and Stool softener to prevent discomfort.

• Gallbladder can cause formation of new stones as well can worsen.

Other Changes: Breast

Mammary Glands can proliferate and cause pain . A more detailed exam is needed to check for abnormalities that can indicate tumor

• The increased hormone and bodily changes result in Hyperpigmentation - Also referred to as "mask of pregnancy" and Etilogy unknown linea alba.

Weight Gain affects amniotic fluid and placenta affects the stores. For those who are underweight, gain more. Underweight is the goal standard to watch. With an increase rate 1Lb per weight total from 29-40Lbs for every woman.

Pregnancy

• Where fertilization combines Spermatozoa inside a Uterine Tube and must combine.

Fertilization

Spermatozoa enter uterine tube (fallopian tube), recognise oocyte and fuses with plasma membrane by injecting itself.

Implantation

• Trophoblast gives off the cytotrophobast, another Synctiotrophoblast that then eats its way into the Uterine. Where the entire of the Endometrical mass is taken, thus causing inflammation and mass.

• 12-13 Days- Hypoblast becomes sac (Blue) that ends the devlopment, the epiblast (green) causes Amonitic that causes the cell devlop.

• Extraembryonic mesoderm (red) causes colligen that converges in other factors.

Placental Development

Structures continue to develop, chorion and chorionic villi then can barrier, provide circulation connecting stalk.