Chapter 19; Female Genital System and Breast

Cervix; Cervicitis;

inflammation of the cervix is very common and associates with Purulent vaginal discharge, Subclassified into; (1) Infectious Cervicitis- Mostly by STD, C. trachomatis is the most common infection - ex; Nabothian Cyst (2) Noninfectious Cervicitis.

Breast Benign Epithelial Lesions; (1) Nonproliferative Disease

nonproliferative =lesions contain single layers of epithelial cells - most common nonproliferative breast lesions- simple cysts lined by a layer of luminal cells that often undergo apocrine metaplasia. ( - Apocrine secretion- may calcify and be detected by mammography. Consists of 3 morphologic changes; (1) Cysts (2) Fibrocystic changes- (most common lesion change) when the cyst is rupture=> Chronic Inflammation=> Fibrosis - Palpable Nodularity of the breast. (3) Adenosis- (change in the structure of the lobules)

Ovaries; Tumors; (3) Mucinous Tumors; Clinical Features

# The prognosis of mucinous cystadenocarcinoma is somewhat better than that of its serous counterpart. # Mutations in KRAS are detected in approximately 50% of ovarian mucinous carcinomas, however this does not help distinguish them from metastatic GI tumors.

Ovaries; Polycystic Ovarian Syndrome (Stein-Leventhal syndrome)

# complex endocrine disorder which characterized by; - hyperandrogenism, menstrual abnormalities, polycystic ovaries, chronic anovulation, and decreased fertility. # Occur in- menarche which present with; - oligomenorrhea - hirsutism - infertility - sometimes with obesity. Morphology; - ovaries- very large, white outer cortex. - Histologic- thickened, fibrotic ovarian capsule overlying innumerable cystic follicles lined by granulosa cells with a hyperplastic luteinized theca interna. - Absence of corpora lutea in the ovary.

Breast Carcinoma; Clinical Features; Targeted Treatment of breast cancer

## Patient with ER positive are more chances to survive # ER positive with estrogen treatment usually become resistant to the treatment.

Vagina; Vaginitis; 2 most common infections

(1) Candida albicans; - Candidal (monilial) Vaginitis- characterized by white discharge and is often symptomatic due to predisposing factors or superinfection (from other strain) (2) Trichomonas vaginalis - Trichomonas vaginalis- STD and produces a watery green discharge. - Active infection stems from SDT of a new strain.

Vulva; Tumors; Includes?

(1) Condylomas. (2) Carcinoma of the vulva. (3) Extramammary Paget disease.

Proliferative lesions of the endometrium and Myometrium; Includes?

(1) Endometrial Hyperplasia. (2) Endometrial Carcinoma. (3) Endometrial Polyp. (4) Leiomyoma. (5) Leiomyosarcoma

Cervix; Neoplasia of the cervix; Mechanism of HPV to develop Squamous intraepithelial lesions

(1) HPV uses host cell DNA polymerases to replicate its genome and produce virions. (2) E6 and E7 Proteins inhibits P53 and RB, (but still not enough to develops invasive carcinoma), and contribute to transformation by; - integration always disrupts an HPV gene that negatively regulates E6 and E7, which leads to their increased expression. - sometimes HPV integrates near a host cell oncogene such as MYC, leading to its overexpression as well. (3) By any diverse factors such as immune and hormonal status and coinfection with other STD agents are play a role to favor the acquisition of somatically acquired mutations that involve both oncogenes and tumor suppressor genes.

Proliferative lesions of the endometrium and Myometrium; (1) Endometrial Hyperplasia; Classification

(1) Hyperplasia without atypia- carries low risk for develop carcinoma. (2) Hyperplasia with Atypia- Also called EIN (Endometrial intraepithelial neoplasia), carry high risk to develops carcinoma. - Treated with Hysterectomy right after discover. - PTEN inactivation- its a tumor suppressor gene which freq found in hyperplasia with atypia.

Cervix; Squamous Intraepithelial Lesion (SIL,CIL); Morphology

(1) LSIL- characterized by; # Dysplastic change- in the lower third of the squamous epithelial. # Koilocytotic Change- in the superficial layers of the epithelium. (2) HSIL (CIN 2)- characterized by; # Dysplasia- extends to the middle third of the epithelium in the form of; - variation in cell and nuclear size - heterogeneity of nuclear chromatin - presence of mitoses. # koilocytotic changes- Still in the superficial layer. (3) HSIL (CIN3)- Characterized by; # Almost complete loss of differentiation, and greater variation in cell and nuclear size, chromatin heterogeneity, abnormal mitoses= changes that affect all layers of the epithelium. # Koilocytotic change- absent.

Vulva; Vulvitis; Nonneoplastic Epithelial Disorders; Includes

(1) Lichen Sclerosus (2) Lichen simplex Chronicus ## Both may coexist in person in different part of the body.

Breast; Structure

(1) Lobule- Functional Unit of the breast, which supported by the intralobular stroma. (2) Inner Luminal Epithelial Cells- Produce milk during lactation. (3) Myoepithelial cells- located basally, have contractile function to aid in mil ejection and to support the basement membrane. (4) The Duct- Conduct the milk to reach the nipple. (5) Interlobular stroma- determine the size of the breast, increase during puberty.

Breast Carcinoma; Division into 4 groups

(1) Luminal A- The majority are lower-grade ER-positive cancers that are HER2 negative. (2) Luminal B- The majority are higher-grade ER-positive cancers that may be HER2 positive (3) HER2-Enriched- The majority overexpress HER2 and do not express ER (4) Basal Like- The majority by gene expression profiling resemble basally located myoepithelial cells and are ER-negative, HER2-negative

Ovaries; Tumors; (3) Mucinous Tumors; Differ from serous tumors by?

(1) Neoplastic epithelium consists of mucin-secreting cells (2) less likely to be malignant. - 10% of mucinous tumors are malignant, 10% are borderline, and 80% are benign.

Cervix; Squamous Intraepithelial Lesion (SIL, Cervical Intraepithelial Lesion); The best detected test and other treatments

(1) Pap smear- the best method - cells are scraped from the transformation zone and examined microscopically. (2) HPV DNA test in cervical scraping (only recommending for 30+) - not so useful under 30 bc most of the infected girls at age of 20 undergo immune clearance of the virus and will never progress into SIL (process that occur for many years) (3) HPV vaccination

Clinical Presentations of Breast Disease; (5) Palpable Masses

(1) Proliferations of stromal cells or epithelial cells and detected when they are 2 to 3 cm in size - ~95% are benign. - Are round to oval and to have circumscribed borders. (2) Malignant tumors- usually invade across tissue planes and have irregular borders.

Vulva; Tumors; (2) Carcinoma of the vulva; Morphology; For both

# Are both commonly manifest as areas of leukoplakia, which will transform into; - exophytic Tumor - ulcerative endophytic Tumors. # The lesions pigmented owing to the presence of melanin. # Are both tend to remain confined to their site of origin for few years=> invade and spread to the first regional lymph node.

Ovaries; Tumors; Teratomas; Clinical Features

# CA-125 - elevated in 75% to 90% of women with epithelial ovarian cancer. - usefulness as a screening test in asymptomatic postmenopausal women is limited. - Greatest value in monitoring response to therapy.

Vulva; Vulvitis; Nonneoplastic Epithelial Disorders; (2) Lichen simplex Chronicus

# Chronic condition Characterized by; - Epithelial thickening particularly in the Stratum Granulosum. - Hyperkeratosis - Increase mitotic activity without atypia. # The nonspecific changes are cause by chronic irritation caused by pruritus related to an underlying inflammatory dermatitis. # appear as area of leukoplakia. # Leukocytes infiltrations. # It's not increase risk of cancer, but involves in the margins of vulvar cancer.

Ovaries; Tumors; Teratomas; Immature Malignant Teratomas

# Clinical detection being 18 years - solid on cut section, and contain areas of necrosis # Microscopic examination - presence of immature elements or minimally differentiated cartilage, bone, muscle, nerve, or other tissues.

Vulva; Tumors; (1) Condylomas.

# Condyloma is a warty lesion of the vulva, Divided into 2 forms; (1) Condylomata lata- flat and small elevated lesions that occur in secondary syphilis. (2) Condylomata acuminata- Papillary or flat warty lesions - occur anywhere on the anogenital surface, as single or multiple lesions. - Cellular feature- koilocytosis, perinuclear cytoplasmic vacuolization and a wrinkled nuclear contour. - 90% are positive for HPV subtypes 6 and 11. (not serious) - Not progress to cancer (usually)

Uterus; Endometriosis; Special Features and Treatment

# Endometrial Tissue not only misplaced but also abnormal; (1) Increase level of inflammatory mediators (PGE2). - Inflammation result from the recruitment and activation of macrophages by factor made by Endometrial stroma cells. (2) Endometrial Stroma cells also make Aromatase- Local Production of Estrogen. ### All this factors enhance the survival and persistence of the endometrial tissue. # Treatment- COX-2 inhibitors and Aromatase inhibitors

Breast Carcinoma; Pathogenesis; Hormonal;

# Estrogen stimulate the production of growth factors which promotes tumor development through paracrine and autocrine mechanism. # Estrogen receptors also regulates other genes which important for tumor development. # Hormonal Influence has important role of transforming Precursors of lesions=> Malignancy.

Cervix; Neoplasia of the cervix; Pathogenesis

# HPV has high tropism toward immature squamous cells of the transformation zone. - They cause SILs (Squamous intraepithelial lesions) which is precursors from which the invasive cervical carcinomas develops. # HPV detected in all cases of; - Cervical intraepithelial neoplasms.(CIN) - Cervical Carcinomas.

Uterus; Endometritis; Overview and pathogenesis

# Inflammation of the endometrium is classified as; (1) Acute (2) Chronic # Endometritis is a component of pelvic inflammatory disease and result of N. gonorrhoeae or C. trachomatis infection. On histological examination; - Superficial endometrium- neutrophilic infiltrate - Stromal lymphoplasmacytic infiltrate. # Tuberculosis- Causes granulomatous endometritis with associated tuberculous salpingitis and peritonitis. # Endometritis can result of- retained products of conception subsequent to miscarriage or delivery or the presence of a foreign body such as an intrauterine device.

Cervix; Invasive Carcinoma; Morphology

# Invasive carcinoma develops in the Transformation zone. - Range from foci stromal invasion=> grossly Exophytic Tumor. # Microscopically; - Consist of tongues and nests of squamous cells that produce a desmoplastic stromal response. - Rare neuroendocrine tumors- resemble small cell carcinoma of the lung # Grading- based on the differentiation; - MInimal Differentiation. - Well differentiated tumors that elaborate Keratin pearls. # Barrel Cervix- Palpable, Created by tumors that encircle the cervix and penetrate the underlying stroma.

Vulva; Vulvitis; Nonneoplastic Epithelial Disorders; (1) Lichen Sclerosus

# Lichen sclerosus is characterized by; - thinning of the epidermis - disappearance of rete pegs - zone of acellular - homogenized - Dermal fibrosis - bandlike mononuclear inflammatory cell infiltrate. # Its Appear as- Leukoplakia (thick, white) # when the entire vulva is affected=> atrophic labia=> vaginal orifice is constricted # occur mostly in Postmenopausal and prepubertal women.

Vulva; Tumors; (3) Extramammary Paget disease; Morphology

# Manifests as- red, crusted plaque that mimic the appearance of an inflammatory dermatitis. # Histological- large tumor cells with abundant pale granular cytoplasm and cytoplasmic vacuoles infiltrate the epidermis, singly and in groups. # Mucin is present

Vulva; Vulvitis

# Most common caused by reactive inflammation by exogenous factors= irritant or an allergen - Contact irritant eczematous dermatitis- manifest as well-defined erythematous weeping and crusting papules and plaque. - Allergic dermatitis- similar clinical appearance and result from allergy to exogenous products. # Can also caused by infections as HPV, HSV-1 or HSV-2 and more # Bartholin gland excretory ducts obstruction- important complication of vulvitis, result in painful dilation of the glands (Bartholin cyst) and abscess formation.

Breast Carcinoma; Morphology; invasive (infiltrative) Carcinoma; Inflammatory Carcinoma

# Patient with swollen erythematous breast without palpable mass. # Inflamed Appearance- due to diffusely infiltrates and obstructs dermal lymphatic spaces (** BUT true Inflammation is absent!!!) # Poorly Differentiates, Highly Metastasized. # About half express ER and 40% to 60% overexpress HER2.

Vulva; Tumors; (3) Extramammary Paget disease; Clinical Features

# Persist for years without evidence of invasion. BUT; # When there is an associated tumor involving=> Paget cells invade locally. # Prognosis is poor.

Proliferative lesions of the endometrium and Myometrium; (4) Leiomyoma Morphology

# Sharply circumscribed, Whorled cut surface white masses. # Multiple tumors that scattered within the uterus. # can be embedded into; - Intramural- Myometrium. - Submucosal- beneath the endometrium. - Subserosal. # Parasitic Leiomyomas- the tumor extended to the surrounding organs from which it receive blood. # Histological Examination- bundles of SMC mimicking normal myometrium.

Breast Carcinoma; Clinical Features; Factors that influence the outcome; (3) Tumor Stage; types

# Stage 0- CIS, survival rate more than 95%. # Stage I- women with smaller cancers and nodes either free of carcinoma or with only very small micrometastases - Survival is ~86% at 10 years. # Stage 2- can be bc large tumor size (T) or up to 3 regional lymph node(M). - Survival is 71%. # Stage 3- Locally advanced cancers large size, involvement of skin or chest wall, or by four or more positive nodes. Only ~54% of patients survive 10 years. # Stage 4- Distant metastasis and survival is very poor

Uterus; Endometriosis; 4 hypotheses that explain the origin of this disease

(1) Regurgitation Theory- Menstrual backflow through the fallopian tube=> implantation. (2) Benign Metastases Theory- endometrial tissue from the uterus can spread via the blood and lymph vessels. (3) Metaplastic Theory- Endometrial Differentiation of coelomic epithelium as the source. (4) Extrauterine Stem/ Progenitor cell Theory- circulating stem/progenitor cells from the bone marrow differentiate into endometrial tissue.

Ovaries; Tumors; (1) Multipotent surface (coelomic) Epithelium Tumors; Risk Factors of Ovarian Cancer

(1) nulliparity (2) family history- BRCA1,2 (5-10%) - Higher with BRCA1. (3) germline mutation *** Oral contraceptive reduce the risk!

Ovaries; Tumors; (2) Serous Tumors; Clinical Features

- Borderline tumors- 100% survival. - BRCA1/2- better prognosis

Breast Stromal Neoplasm; Overview

2 Types of stroma in the breast; (1) Intralobular- divided into 2 tumors which derived from the same driver mutation A. Benign Fibroadenoma. B. Phyllodes Tumor- rarely pursue a malignant Course. (2) Interlobular; A. Hemangioma- Benign B. Angiosarcoma- Malignant

Breast Carcinoma; Pathogenesis; Overview

3 Distinct pathway which each one arise from other driver mutation.

Breast Carcinoma; Pathogenesis; Genetic

3 main genomes which can lead to cancer; (1) BRCA1,2- are tumor suppressor genes, encode protein which required for DNA repair. - BRCA1- strong association with Triple negative cancer ("Basal Like" cancer) and usually inactivated by methylation in 50% of the cases (mutation). - BRCA2- Primarily associated with Luminal A Cancers. (2) TP53- associated with HER2 enriched. (3) PTEN- is important negative regulator of PI3K-AKT pathway. - Strongly associates with Luminal B.

Ovaries; Tumors; Overview

3 possible cells can be affected; (1) Multipotent surface (coelomic) Epithelium. (90%) (mostly arise from the fibria of the fallopian tube) (2) Totipotent Germ Cells. (3) Sex Cord stromal cells.

Vulva; Tumors; (2) Carcinoma of the vulva.

90% are squamous cell carcinoma (the others adenocarcinoma or basal), which have 2 forms that differ in there pathogenesis; (1) High risk HPV strain (16 type)- less common and occur in middle age women, particularly in cigarette smokers. - Vulvar Intraepithelial Neoplasm (VIN)- precancerous change in the epithelial which process into Atypia=> Carcinoma in situ. - Carcinoma development is not inevitable and only occur after many years. (2) In long history of Reactive Epithelial Changes- (ex; Lichen sclerosus) occur in older women. - Differentiated Vulvar Intraepithelial Neoplasms (dVIN)- precancerous lesion, characterised by cytologic atypia confined to the basal layer and abnormal keratinization. - if Untreated=> give rise to HPV negative Squamous cell carcinoma.

Breast Carcinoma; Morphology; invasive (infiltrative) Carcinoma; Grading

All types of invasive breast carcinoma are assigned a grade from 1 (low-grade) to 3 (high-grade) based on nuclear pleomorphism, tubule formation, and proliferation. (1) Low-grade; # Nuclei- like normal cells nuclei. # Well-defined tubules and may be difficult to distinguish from benign lesions. (2) High-grade; # Nuclei are enlarged and have irregular nuclear contours. # Lose this capacity and invade as solid sheets or single cells. Proliferation (mitotic figures counting); # HER2-positive and triple-negative carcinomas- highly proliferative # ER-positive cancers- wide range of proliferation.

Uterus; Endometriosis; Clinical Features;

Almost all cases feature severe dysmenorrhea and pelvic pain resulting from intrapelvic bleeding and intraabdominal adhesions. # Extensive Scarring Of the fallopian tube and ovaries- Produces discomfort in the lower abdomen and eventual sterility. # Rectal wall involvement- may produce pain on defecation. # Uterine or bladder serosa involvement- cause dyspareunia (painful intercourse) and dysuria

Proliferative lesions of the endometrium and Myometrium; (5) Leiomyosarcoma

Arise de novo from mesenchymal cells of the myometrium; Characterized by; = Soft Hemorrhagic necrotic masses. = Cytologic Atypia. = Mitotic Activity. ( increase in mitotic activity can seen in benign tumors= ALL 3 FORMS HAVE TO EXITS.)

Uterus; Abnormal Uterine Bleeding;

Abnormal Uterine bleeding include; menorrhagia, metrorrhagia or postmenopausal bleeding. - Common cause includes; varies depending on the age of the patient. # Dysfunctional Uterine Bleeding- abnormal bleeding from the uterus in the absence of lesion. - Anovulation- most common cause which result from hormonal imbalance in the period of menarche and Premenopausal. - Endocrine disorders, ovarian lesions and generalized metabolic disturbances also cause anovulation.

Ovaries; Tumors; (2) Serous Tumors; Morphology; Malignant:

Adenocarcinomas often have nodular irregularities on their surface. # Papillary projections which protrude into the cystic cavities. # In high-grade carcinoma- the cells are markedly atypical, the papillary formations are usually complex and multilayered. # spread throughout the peritoneal cavity and to regional lymph nodes, including periaortic lymph nodes.

Breast Benign Epithelial Lesions; (2) Proliferative Disease without Atypia

All Associates with epithelial cells Proliferations Includes; (1) epithelial hyperplasia. (2) Sclerosing adenosis. (3) complex sclerosing lesion. (4) Papilloma.

Uterus; Endometritis; Clinical Manifestation

All forms of endometritis manifest with; - fever - abdominal pain - menstrual abnormalities. - increased risk of infertility and ectopic pregnancy due to damage and scarring of the fallopian tubes.

Ovaries; Tumors; (1) Multipotent surface (coelomic) Epithelium Tumors; Clinical Features

All surface epithelial tumors are initially asymptomatic until they become large enough to cause local pressure symptoms (e.g., pain, gastrointestinal complaints, urinary frequency).

Proliferative lesions of the endometrium and Myometrium; (2) Endometrial carcinoma; Pathogenesis; (1) Endometrioid

Arise in the setting of endometrial hyperplasia - similar histological to normal endometrial glands. # Risk Factors; (1) obesity, (2) diabetes, (3) hypertension, (4) infertility, and (5) exposure to unopposed estrogen. ** Which all lead to increase estrogenic stimulation of the endometrium # Mutational involvement; (1) Cowden Syndrome- PTEN germline mutation. (2) Lynch Syndrome- Alterations in DNA mismatch repair genes.

Breast Benign Epithelial Lesions; Overview

Benign Changes divided into 3 groups; (1) Nonproliferative Disease- Not associates with breast cancer. (2) Proliferative Disease without Atypia- includes polyclonal Hyperplasias that associates, which associates with slightly increase risk of breast cancer. (3) Proliferative disease with Atypia- Monoclonal Precancers that are associates with increase risk of breast cancer in both breasts. - 17% develops breast cancer.

Ovaries; Tumors; (2) Serous Tumors; Morphology; Borderline:

Borderline tumors exhibit less cytologic atypia and typically no stromal invasion. - seed the peritoneum, but fortunately, the tumor implants usually are "noninvasive."

Diseases of Pregnancy; Gestational Trophoblastic Diseases; Complete and Partial hydatidiform moles

Both types result from abnormal fertilization with an excess of paternal genetic material. - elevation of hCG in the maternal blood and absence of fetal heart sounds. - early monitoring of pregnancies by ultrasound has lowered the gestational age at detection. - most common before the age of 20 and after the age of 40 years

Breast Carcinoma; Morphology; Noninvasive (in Situ) Carcinoma; Paget Disease Of the nipple

Cause by Extension of DCIS up to the lactiferous duct and into the contiguous skin of the nipple. - Producing unilateral Crusting excudate over the nippleand areolar skin.

Cervix; Neoplasia of the cervix; Overview

Cervix cancers are epithelial origin and mostly caused by HPV. # Transformation zone- area where the columnar epithelium of the endocervix meets the squamous epithelium of the ectocervix. - showing the transition from mature glycogenated squamous epithelium=> immature metaplastic squamous cells, to columnar endocervical glandular epithelium. - Tumors mostly arise in this zone because the cells in this area are constantly changing and dividing.

Ovaries; Tumors; Teratomas; Specialized Teratomas

Composed entirely of specialized tissue. # The most common example is struma ovarii; - composed entirely of mature thyroid tissue=> produce hyperthyroidism

Breast Carcinoma; Morphology; invasive (infiltrative) Carcinoma; Invasive Lobular Carcinoma;

Consists of infiltrating cells that are morphologically similar to the tumor cells seen in LCIS # The Cells- invade stroma individually=> "Single File" form # Divided into 2 Manifests; (1) Palpable masses or mammographic densities. (2) Invasion without desmoplastic Proliferation. # Unique metastatic pattern- spread to CSF, serosal surfaces, GI, ovary, uterus, and bone marrow. # Almost always ER+.

Uterus; Endometriosis; Overview

Define by the presence of endometrial Glands and Stroma in a location outside of the uterus. # It's Multifocal and involves pelvic structure, and less frequently the peritoneal cavity or periumbilical tissue.

Diseases of Pregnancy; Ectopic Pregnancy; Overview

Defined as implantation of a fertilized ovum in any site other than the uterus. - 50% slowed passage results from chronic inflammation and scarring in the oviduct. - Tubal Pregnancy (90%)- mostly due to Chronic salpingitis with scarring - Ovarian pregnancies- result from rare instances in which the ovum is fertilized just as the follicle ruptures. - Gestation within the abdominal cavity- occurs when the fertilized egg drops out of the fimbriated end.

Breast Carcinoma; Morphology; Noninvasive (in Situ) Carcinoma; DCIS

Ductal carcinoma in situ (DCIS)- Distorts lobules into ductlike spaces. # Histologic Changes Types including; - Solid. - Comboid- characterized by extensive central necrosis, which produces toothpaste like necrotic tissue that extrudes from transected ducts on application of gentle pressure. - Cribriform - Papillary - Micropapillary. - "Clinging" # Nuclear appearance- can be bland and monotonous (low nuclear grade) to pleomorphic (high nuclear grade). # Calcification of the derbies necrotic areas. (seen in mammography) # Good prognosis (97% survival), if not treated=> Invasive.

Breast Carcinoma; Clinical Features; Factors that influence the outcome; (3) Tumor Stage; Metastasis of ER, HER2 and triple negative

ER +- bone HER2 and triple negative- brain and viscera.

Breast Carcinoma; Morphology; invasive (infiltrative) Carcinoma; Tubular Carcinoma;

ER-positive/HER2- negative cancer # Detected on mammography as a small irregular mass. # The Tumors arranged in tubules and have low-grade nuclei. # Lymph node metastases are rare # prognosis is excellent.

Breast Carcinoma; Morphology; invasive (infiltrative) Carcinoma; Mucinous (colloid) carcinoma

ER-positive/HER2- negative tumor # Produces abundant amounts of extracellular mucin. # Are soft and gelatinous because of the presence of mucin pools that create an expansile circumscribed mass.

Cervix; Endocervical Polyp;

Endocervical polyps are benign polypoid masses seen protruding from the endocervical mucosa - smooth surface, epithelium containing mucinous secretions and lined the endocervical canal with mucus-secreting columnar cells. # Superimposed chronic inflammation- lead to squamous metaplasia of the overlying epithelium and ulcerations. - These lesions may bleed, but they have no malignant potential.

Ovaries; Tumors; Endometrioid Tumors;

Endometrioid tumors develop in association with endometriosis and may be solid or cystic. - Usually malignant # Microscopically- characterized by formation of tubular glands (similar to endometrium) within the lining of cystic spaces. # 30% have a concomitant endometrial carcinoma. # mutations in the PTEN tumor suppressor gene as well as mutations in other genes that upregulate PI3K-AKT signaling.

Uterus; Endometriosis; Morphology

Endometriosis typically consists of functioning endometrium, which undergoes cyclic bleeding. # Gross Appearance- Red brown nodules due to the collection of the blood in these aberrant foci. # Individual lesions Bind to form large masses. # Chocolate Cysts- occur when the ovaries involved, result in lesion which form large, blood filled Brown cysts. # With time; organization of the blood=> widespread fibrosis occurs=> adhesions among pelvic structures=> sealing of the tubal fimbriated ends=> distortion of the fallopian tubes and ovaries.

Breast Carcinoma; Clinical Features; Factors that influence the outcome; (1) Biological Type.

Evaluated by combination of Morphology, Grad and proliferation, HER2 and ER; (1) Proliferation- Evaluated by the number of mitotic figures. - is shown the responsiveness to chemotherapy. - Rapid growth cancer cells are more sensitive to agent that damage DNA or interfere with cell division. (2) Expression of PR or ER- predict response to antiestrogen or antiprogesterone therapy. - No targeted therapy available for triple negative. (3) Overexpression of HER2- Target therapy which blocking antibodies or mall molecular inhibitors of HER2 in combination of chemotherapy achieved more than 60% response.

Proliferative lesions of the endometrium and Myometrium; (1) Endometrial Hyperplasia; Causes of endometrial hyperplasia:

Excess of estrogen relative to progestin - Common cause of estrogen excess is obesity also- anovulation, prolonged administration of estrogenic steroids without counterbalancing progestin, and estrogen-producing ovarian lesions.

Clinical Presentations of Breast Disease; (6) Gynecomastia.

Only common breast symptom in males. - increase in both stroma and epithelial cells resulting from an imbalance between estrogens.

Vagina; Malignant Neoplasms; Squamous cell Carcinoma

Extremely uncommon cancer in 60+ womens. # VAIN is the precursor lesion that always associates with HPV infection. # Invasive squamous cell carcinoma of the vagina is associated with the presence of HPV DNA in more than 50% of the cases.

Ovaries; Follicle and Luteal Cysts;

Follicle and luteal cysts are common ovarian cysts. - They are considered variants of normal physiology. # Originate from unruptured Graafian follicles or from follicles that rupture and immediately seal. # Morphology; - Filled with clear serous fluid. - Initially Lined by granulosa lining cells or luteal cells=> fluid accumulates=> increase pressure=> atrophy of these cells. Clinical Features; - Large- produce palpable masses and pelvic pain. - Rupture- produce intraperitoneal bleeding and peritoneal symptoms (acute abdomen).

Ovaries; Tumors; Teratomas;

Germ cells neoplasm which 90% Are benign cystic appearance. # arise in the first 2 decades of life= younger the person, the greater the likelihood of malignancy.

Breast Carcinoma; Pathogenesis; Genetic; Common clinically important driver mutation

HER2 is a receptor tyrosine kinase that promotes cell proliferation and opposes apoptosis by stimulating the RAS- and PI3K-AKT signaling pathways. - Cancers that overexpress HER2 are pathogenically distinct and highly proliferative.

Cervix; Neoplasia of the cervix; Types of HPV

HPV 1,2,4,7- Cause benign squamous papillomas (warts). HPV 6,11- Low risk HPV, cause Condyloma, low malignant potential. HPV 16,18- High risk HPV, cause SIL of the cervix and anogenital region..

Cervix; Squamous Intraepithelial Lesion (SIL, Cervical Intraepithelial Lesion); Overview

HPV related Carcinogenesis begin with SIL which usually takes years to develop a cancer, SIL divided into; (1) LSIL (Low grade)= CIN1 - Associates with productive HPV infection and doesn't progress directly to invasive carcinoma. - Often regress but only small percentage progress to HSIL. - 10 times more common (2) HSIL (high grade)= CIN-2 and CIN3 - Increase proliferation, arrested epithelial maturation, lower levels of viral replication. - High risk to develop carcinoma.

Proliferative lesions of the endometrium and Myometrium; (2) Endometrial carcinoma; Morphology; (2) Serous Carcinoma

High grade tumor which Grow in small tufts and papillae with marked cytologic atypia. # Form glands- Create confusion with endometrioid carcinoma. - serous carcinomas exhibit much greater cytologic atypia. # Immunohistochemistry- P53 in serous carcinoma.

Proliferative lesions of the endometrium and Myometrium; (2) Endometrial carcinoma; Clinical Features

Manifest with; (1) Irregular or postmenopausal Bleeding. (2) With progression- the uterus enlarges and may become affixed to surrounding structures as the cancer infiltrates surrounding tissues. - slow to metastasize.

Vagina; Malignant Neoplasms; Clear Cell Adenocarcinoma;

In 1970, clear cell adenocarcinoma was identified in a cluster of young women whose mothers took diethylstilbestrol (prevent threatened abortion). # Small glandular or microcystic inclusions in the vaginal mucosa. (1/3 of infected womens). # Vaginal adenosis- Precursors of lesions, benign lesions, which give rise to this carcinoma.

Breast Benign Epithelial Lesions; (2) Proliferative Disease with Atypia

Includes; (1) Atypical lobular hyperplasia (ALH)- closely resembles lobular carcinoma in situ (LCIS) with limitations. (2) Atypical ductal hyperplasia (ADH)- closely resembles ductal carcinoma in situ (DCIS) with limitations. - The cells are uniform in appearance and form sharply marginated spaces or rigid bridges.

Breast Carcinoma; Clinical Features; Factors that influence the outcome; Overview

Includes; (1) Biological Type. (2) RNA expression Profiling. (3) Tumor Stage.

Breast Carcinoma; Epidemiology And risk Factors; Age and gender

Increase in incidence after age of 30. 75% are older than 50

Diseases of Pregnancy; Placental inflammations and Infections; 2 pattern of infections transmission

Infections reach the placenta by; (1) Ascension through the birth canal- Most common. - Caused by- Mycoplasma, Candida, and bacteria of the vaginal flora. - associated with premature rupture of the fetal membranes. - Acute Chorioamnionitis- shown neutrophilic infiltration associated with edema and congestion. - Funisitis- Acute vasculitis of the umbilical cord caused by infection extension beyond the membranes. (2) Hematogenous (transplacental) spread- less common. - villitis-placental villi are the most frequently affected structures. - infections can affect the fetus and give rise to the "TORCH" complex (toxoplasmosis, other infections, rubella, cytomegalovirus infection, herpes). - also caused by Syphilis, tuberculosis, listeriosis and other viruses.

Clinical Presentations of Breast Disease; (2) Inflammation

Inflammation causes Edematous and erythematous breast. -Rare, and often caused by infection- most commonly by staph.Aureus=> Lead to formation of Lactational Abscesses=> if not treated can lead to Fistula opening onto the skin. - occur usually in lactation and breastfeeding. - Inflammatory breast carcinoma.

Diseases of Pregnancy; Gestational Trophoblastic Diseases; Invasive Mole

Invasive moles are complete moles that are locally invasive but lack the metastatic potential of choriocarcinoma. - retains hydropic villi=> penetrate the uterine wall=> causing rupture and sometimes life-threatening hemorrhage. # Microscopic examination; - Epithelium of the villi shows atypical changes - proliferation of both trophoblast and syncytiotrophoblast.

Breast Carcinoma; Morphology; invasive (infiltrative) Carcinoma; Invasive Ductal Carcinoma

Is Term used for all carcinomas which cannot be subclassified (includes 80# of the cancers). # usually associates with DCIS. # Most grow as tubules ("ductal" carcinoma) and stimulate a reactive desmoplastic stromal proliferation which replaces normal breast fat. (shown densities in mammograph) # The reactive Desmoplastic Stromal proliferation=> Palpable irregular mass. # 60% associates with ER +, 20% HER2 +, 15% ER, HER2 -

Proliferative lesions of the endometrium and Myometrium; (2) Endometrial carcinoma; Overview and classifications

Is the most common freq cancer occur in female genitalia. - Appear in the age 55- 65. - Divided into 2 histological patterns; (1) Endometrioid (80%) (2) Serous Carcinoma (20%)

Breast Carcinoma; Clinical Features; Factors that influence the outcome; (3) Tumor Stage; Features

It is based on features of the; (1) Primary tumor (T)- T1-T4 (size) - T4- represent as inflammatory carcinoma, have ulceration of the skin, deep muscle of the chest wall. (2) Involvement of regional lymph nodes (N)- Majority of the cancers first metastasize to regional nodes. - lymphatic drainage goes to 1 or 2 sentinel lymph node of the axilla. - Diagnosed by Sentinel node biopsy. (3) Presence of distant metastases (M)

Proliferative lesions of the endometrium and Myometrium; (3) Endometrial Polyp; Overview

Key feature of this polyp- Produce abnormal uterine bleeding. - Common in any age but mostly in menopause. - Large polyp- Project from the endometrial mucosa into the uterine cavity. - composed of endometrium resembling the basalis (the deep layer) with small muscular arteries. - Stromal cells- monoclonal.

Breast Carcinoma; Morphology; Noninvasive (in Situ) Carcinoma; LCIS

LCIS Has uniform Appearance, which Usually Expands and involved lobules. # The cell- Monomorphic- have bland, Round nuclei, and are found in loosely cohesive clusters within the lobules. # Very rarely associates with calcification (and that's way detected incidental). # 1/3 develops invasive. # LCIS is both a marker of an increased risk of carcinoma in both breasts and a direct precursor of some cancers.

Ovaries; Tumors; (3) Mucinous Tumors; Morphology; overview and how to differentiate from Krukenberg tumor?

Large multicystic, Mucin Producing epithelial cells # Sign of malignancy- Serosal Penetration and solid areas of growth, pilling up of lining cells, Atypia, Stromal Invasion. # Differentiate from Krukenberg tumor- Are less likely to be bilateral. # Pseudomyxoma Peritonei- stable implantation of mucinous tumor cells in the peritoneum (after rupture of the tumor) with production of copies amounts of mucins.

Ovaries; Tumors; (2) Serous Tumors; Morphology; Benign

Large, spherical to ovoid, cystic structure tumor with 25% is bilateral. - Contain a single layer of columnar epithelial cells that line the cyst or cysts. - Psammoma bodies are common in the tips of papillae.

Clinical Presentations of Breast Disease; (4) Lumpiness

Lumps or Diffuse nodularity throughout the breast- usually result of Normal granular tissue.

Ovaries; Tumors; (1) Multipotent surface (coelomic) Epithelium Tumors; Overview and classifications

Majority of ovarian tumors arise from the; - Fallopian tube- fimbriated end. (most common) - Epithelial cyst in the cortex- Derived from displaced ovarian surface epithelium or the lining of fallopian tube. # Benign lesions; (1) Cystadenoma- Cystic. (2) Cystadenofibroma- cystic with stromal components. # Borderline Tumors- intermediate category, are benign which can recur or prognos into malignant. # Malignant Lesions; (1) Cystadenocarcinoma- Cystic. (2) Carcinoma- Solid.

Breast Carcinoma; Epidemiology And risk Factors; Race/ Ethnicity

Majority of women are European descent, largly bc higher incidence of ER positive Cancers

Ovaries; Tumors; Teratomas; Benign (Mature) Cystic Teratomas;

Marked by the presence of mature tissues derived from all 3 germ cell layers # Dermoid cysts- cysts lined by epidermis peaked with adnexal extensions. # Abdominal Radiograph- shown foci of calcification produce by toothlike structures within the tumor. # Cut section- sebaceous secretion and dermal hair. # Clinical Features; - infertility and are prone to undergo torsion of the ovary. - limbic encephalitis- develop in women with teratomas containing mature neural tissue. (rare) - Squamous cell carcinoma transformation (1%)

Proliferative lesions of the endometrium and Myometrium; (4) Leiomyoma Overview

Most common Benign tumor in females that arise from the SMC in the myometrium - Clinically referred to- Fibroids (firmness) - Estrogen and oral contraceptive increase the risk. - Patients are asymptomatics or with menorrhagia with or without metrorrhagia. Mutational changes; (1) Chromosomal abnormalities- Rearrangements of Chromosomes 6=>12. (2) Mutation in the MED12 gene (70%).

Breast Carcinoma; Overview

Most common malignancy in women. - Almost always Adenocarcinoma, and divided into 3 groups; (1) ER Positive (HER2 negative)- (60%) its Estrogen receptors expression. (2) HER2 Positive (ER Positive or negative)- (20%) Human epidermal growth factor receptors. (3) Triple Negative- (ER, PR, HER2 negative)- (20%)

Ovaries; Tumors; (2) Serous Tumors; Overview and subdivisions

Most common of the ovarian epithelial tumors overall, greatest fraction of malignant ovarian tumors. - 60% are benign, 15% are borderline, and 25% are malignant. Includes 2 types; (1) Low Grade- arise from mutation of genes encode for signaling Proteins (KRAS) (2) High Grade- arise in the fimbriated end of the fallopian tube via serous tubal intraepithelial carcinoma, rather than ovarian coelomic epithelium. - TP53 mutated in 95% of the cases. - NF1, RB, BRCA1,2 also sometimes.

Clinical Presentations of Breast Disease; Overview

Most symptoms of breast lesions are benign Cancer women are 45% with symptoms. The symptoms are; (1) Pain. (2) Inflammation (3) Nipple Discharge. (4) Lumpiness. (5) Palpable Masses. (6) Gynecomastia.

Ovaries; Tumors; Brenner Tumor;

Mostly benign, Unilateral ovarian Solid tumor consisting of abundant stroma containing nests of transitional-type epithelium. # Nests- cystic and lined by columnar mucus-secreting cells. # The tumor arise from; (1) Surface epithelium. (2) Urogenital epithelium trapped within the germinal ridge.

Vulva; Tumors; (2) Carcinoma of the vulva; Morphology; HPV-positive tumors

Multifocal and warty and tend to be poorly differentiated squamous cell carcinomas

Clinical Presentations of Breast Disease; (3) Nipple Discharge

Nipple Discharge normal in small quantities. - Papillomas in the large ducts- Most common benign lesions are cause nipple discharge. - Malignancy sign- Unilateral, spontaneous, Bloody discharge.

Diseases of Pregnancy; Ectopic Pregnancy; Morphology; Tubal pregnancy

Normal in the start but then= Invading placenta eventually burrows through the wall of the fallopian tube, causing; (1) intratubal hematoma (hematosalpinx) (2) intraperitoneal hemorrhage (3) or both

Vulva; Tumors; (3) Extramammary Paget disease; Overview

Paget disease is an intraepidermal proliferation of epithelial cells that can occur in the skin of the vulva or nipple of the breast - not like breast carcinoma, only minority associates with underlying tumor. - Vulvar Paget cells arise from epidermal Progenitor cells.

Clinical Presentations of Breast Disease; (1) Pain

Pain (mastalgia/ Mastodynia) - Period Related- due to cyclic edema and swelling. - Localized in specific area- caused by ruptured cyst or Fat necrosis. - Painful masses- are usually benign, 10% of cancers are cause pain.

Fallopian Tube; Serous Tubal Intraepithelial Carcinoma (STIC)

Precursor lesion that is often found in the fallopian tubes of women who have been diagnosed with high-grade serous ovarian carcinoma. - "tubal hypothesis"- adenocarcinoma of the fallopian tube is the site of origin for many high grade serous carcinoma which arise in the ovary bc the fimbriated end is initially associated with the ovary. - STIC- adenocarcinoma BC it arises from glandular cells in the fallopian tubes.=> Potential to form invasive adenocarcinoma. # Mutation- TP53 Covered 90% of the cases.

Differences between progenitor cells to stem cells

Progenitor cells and stem cells are both types of cells that have the ability to differentiate into various types of cells in the body. However, there are some key differences between the two: - Developmental potential: Stem cells have the ability to differentiate into any type of cell in the body, while progenitor cells can only differentiate into specific cell types. - Self-renewal: Stem cells have the ability to self-renew, meaning they can make identical copies of themselves, whereas progenitor cells have limited self-renewal potential. - Location in the body: Stem cells are typically found in specific locations in the body, such as bone marrow or embryonic tissue, while progenitor cells are found in various tissues and organs throughout the body.

Breast Carcinoma; Morphology; invasive (infiltrative) Carcinoma; Carcinomas with Medullary Features

Special Type of Triple Negative Cancer (5% of all cancers) # Develops as round masses which resemble benign tumor # Consist of sheets of large anaplastic cells. # associates with T cells infiltrations. # Good Prognosis. # Seen in womens with BRCA1 Mutations.

Uterus; Adenomyosis;

Refer to presence of endometrial tissue in the myometrium. # The endometrial tissue induce hypertrophy of the myometrium=> Enlarged globular uterus with a thickened uterine wall. # Extensive Adenomyosis- produce; - Menorrhagia- heavy or prolonged menstrual bleeding. - Dysmenorrhea- menstrual cramps. - Pelvic Pain- particularly prior to menstruation. - Coexist with Endometriosis.

Diseases of Pregnancy; Gestational Trophoblastic Diseases; Overview

Refers to an abnormal proliferation of fetal trophoblast cells Which characterized by Elevation of HcG Hormone level. Divided into 2 categories; (1) Molar lesions; - Partial hydatidiform moles - Complete hydatidiform moles - Invasive hydatidiform moles (2) Nonmolar lesions- consists of choriocarcinoma and other more uncommon types of trophoblast-derived malignancies

Diseases of Pregnancy; Ectopic Pregnancy; Clinical Features

Rupture of an ectopic pregnancy is a medical emergency that, if left untreated, may result in intense abdominal pain and signs of an acute abdomen, often followed by shock - Until the rupture, the pregnancy undistinguished from normal pregnancy.

Cervix; Squamous Intraepithelial Lesion (SIL,CIL); Clinical Features

SIL is asymptomatic and only discovered in Pep smear. - the result followed by colposcopy- acetic acid is used to highlight the lesions. - HSIL- Treated with Con Biopsy= surgical excision.

Fallopian Tube; Inflammation

Salpingitis- almost always occur by infection. (specially STD) - Part of PID. - Strep and Staph- penetrate the wall of the tubes=> give rise to blood borne infections that seed to distans sites. # Sign and Symptoms; (1) fever (2) lower abdominal or pelvic pain and pelvic masses- result of distention of the tubes with either exudate or inflammatory. (3) Tuboovarian abscess- Adherence of the inflamed tube to the ovary and adjacent ligamentous tissues. - Result in adhesions between the ovary and the tube when the inflammation is subside. - Permanent sterility- damage or obstruction of the tubal lumina.

Vagina; Malignant Neoplasms; Sarcoma Botryoides;

Sarcoma botryoides (embryonal rhabdomyosarcoma) # rare form of primary vaginal cancer that manifests as soft polypoid masses. # It usually is encountered in infants and children under 5 age. # Can also be found in urinary bladder and bile duct.

Vulva; Vulvitis; Nonneoplastic Epithelial Disorders; (1) Lichen Sclerosus; Clinical Features

Symptoms includes- itching, pain, and discomfort. ** increase the risk of developing skin cancer

Uterus; Structure

The corpus of the uterus is composed of the; - endometrium. - glands and stroma - myometrium.

Cervix; Invasive Carcinoma; Overview

The most common Cervix carcinoma is squamous cell carcinoma (75%) (Adenocarcinoma 20%, Small cell neuroendocrine carcinoma (5%). # All this types are associated with HPV infection. # SIL is the precursor and will increase the risk to differentiate by; - Smoking cigarettes. - HIV.

Vulva; Vulvitis; Nonneoplastic Epithelial Disorders; (1) Lichen Sclerosus; Pathogenesis

The disease is benign but 5% symptomatic women develops HPV negative squamous cell carcinoma. uncertain, but suggested autoimmune etiology; (1) activated T cells in the subepithelial inflammatory infiltrate (2) increased frequency of autoimmune disorders.

Breast Stromal Neoplasm; Morphology; Intralobular Stroma;

The lesions Are "Biphasic" consist of both stromal cells and epithelial cells. - The neoplastic proliferation of specialized lobular fibroblasts stimulates reactive proliferation of lobular epithelial cells. (1) Fibroadenoma- the tumor mass has circumscribed borders and low cellularity. (2) Phyllodes tumors- the stromal cells tend to outgrow the epithelial cells=> bulbous nodules of proliferating stromal cells that are covered by epithelium. - Have the characteristic "phyllodes" growth pattern - In high-grade- epithelium may be small or absent, producing a sarcomatous appearance. - 2% of phyllodes tumors metastasize to distant sites.

Breast Stromal Neoplasm; Morphology; Interlobular Stroma;

The lesions are Monophasic (only mesenchymal cells) - Induce Benign soft tissue tumors found elsewhere in the body (Hemangioma, lipoma). - Angiosarcoma- the only malignant derived tumor, arise in the breast, usually unknown reason but can induced after local radiotherapy.

Breast Carcinoma; Morphology; Overview And classification

The most common location of tumors within the breast is in the upper outer quadrant (50%), - 4% of women with breast cancer have bilateral tumors. Classification- Are classified morphology whenever they penetrate the basement membrane (invasive) or not (noninvasive); (1) Noninvasive; - Ductal carcinoma in situ (DCIS) - Lobular carcinoma in situ (2) Invasive - Invasive ductal carcinoma. (70% to 80%) - Invasive lobular carcinoma (~10% to 15%) - Carcinoma with medullary features (5%) - Mucinous carcinoma (colloid carcinoma)(~5% ) - Tubular carcinoma (~5%) - Other types

Vulva; Tumors; (3) Extramammary Paget disease; distinguishing Paget disease from vulvar melanoma by?

The presence of mucin, as detected by periodic acid-Schiff (PAS) staining, is useful in distinguishing Paget disease from vulvar melanoma, which lacks mucin.

Vulva; overview and structural components

The vulva is the external female genitalia and includes the; # hair-bearing skin (labia majora) # mucosa (labia minora). - Disorders of the vulva most frequently are inflammatory, rendering them more uncomfortable than serious. - Malignant tumors of the vulva, although life-threatening, are rare.

Vulva; Tumors; (2) Carcinoma of the vulva; Morphology; HPV-negative tumors

Unifocal and typically are well-differentiated keratinizing squamous cell carcinomas.

Breast Carcinoma; Clinical Features; screened and unscreened populations

Unscreened population- cancer are detected as palpable masses, usually are almost invasive, and are 2-3cm size, at least 50% already spread to the regional lymph node. Older Screened Population- 60% are detected before the symptoms, 20% are in situ, - Interval Cancers- cancers that appear suddenly bw screening intervals, are highly proliferative and are at high stage.

Cervix; Invasive Carcinoma; Clinical Features

Usually occur in women with unchecked SIL which progress into Invasive carcinoma. # Symptoms; - Vaginal Bleeding. - Leukorrhea. - Dyspareunia- Pain during sex. - Dysuria. # Treatment; - Hysterectomy- Removal of the uterus. - Lymph node dissection.

Vagina; Vaginitis; Overview

Vaginitis is a common and usually transient condition associated with vaginal discharge (Leukorrhea) # Bacteria and other infections implicated as causative organism which become pathogenic due to certain factors like diabetes, antibiotic therapy...

Proliferative lesions of the endometrium and Myometrium; (2) Endometrial carcinoma; Pathogenesis; (2) Serous Carcinoma

all Caes associates with TP53 mutation. - preceded by a lesion called serous endometrial intraepithelial carcinoma (SEIC) in which TP53 mutations are often detected

Breast Carcinoma; Clinical Features; Factors that influence the outcome; (2) RNA expression Profiling.

clinical value of these assays is their ability to identify patients with slow-growing, antiestrogen-responsive cancers who can be spared the toxicity of chemotherapy.

Proliferative lesions of the endometrium and Myometrium; (2) Endometrial carcinoma; Morphology; (1) Endometrioid

closely resemble normal endometrium and may be exophytic or infiltrative. # Histologic types (1 f the 3); - mucinous - tubal (ciliated) - squamous differentiation. # Lymphovascular invasion- infiltrate the myometrium and can enter vascular spaces # metastasize- regional lymph nodes. # Graded- 1 to 3, based on the degree of differentiation.

Clinical Presentations of Breast Disease; mammographic screening

is a process of using a special x-ray of glands, fat and blood vessels under the skin of the breast to identify any variations from the normal or healthy tissue.