Female Reproductive Pathology

Question 1

Condyloma Acuminata

Answer 1

-Vulva-Neoplasia
-Large anogenital warts, usually multiple
-Due to HPV 6,11
-Papillary and elevated or flat and rugose (wrinkled/creased)
-Key histologic feature: koilocytosis (angular nuclei with perinuclear clearing)
-Not precancerous

Question 2

Leukoplakia

Answer 2

-Vulva-Neoplasia
-Precancerous, white patch that shows vulvar intraepithelial neoplasia (VIN, grade I, II, or III); can progress to vulval carcinoma (some cases associated with HPV)

Question 3

Extramammary Paget Disease

Answer 3

-Vulva-Neoplasia
-Red, scaly crusted plaque that may remain confined to the epithelium for years
-Intrepidermal proliferation of epithelial cells. Usually no subepithelial tumor, but Paget cells may invade (usually within 2-5yrs of presentation)

Question 4

Cervix - Inflammatory Disease

Answer 4

-Cervicitis is extremely common manifesting as mucopurulent to purulent vaginal discharge (leukorrhea)
-Infectious vs. non-infectious distinction may be difficult
-C. trachomatis - 40% of infectious cervicitis

Question 5

Cervical Carcinoma

Answer 5

-Most tumors of the cervix are from epithelium and are caused by oncogenic strains of HPV

Question 6

What are the risk factors of Cervical Carcinoma?

Answer 6

-Persistent HPV infection with high-risk HPV (HRHPV) subtypes (most important risk factor)
-Early age at first intercourse
-Multiple sexual partners
-A male partner with history of multiple partners
-Smoking
-Immunodeficiency

Question 7

Describe the transformation zone in relation to Cervical Carcinoma

Answer 7

-Cervical cancer is caused by HRHPV which are tropic for the immature squamous cells of the transformation zone
-The transformation zone is the squamocolumnar junction of the endocervix (columnar mucus-secreting epithelium) and the exocervix (stratified squamous epithelium)
-The transformation zone moves (everts) from the endocervix at birth to the exocervix in young adults
-The everted columnar cells eventually undergo metaplasia into immature squamous cells, forming the transformation zone in mature adults

Question 8

Cervix - HPV infection

Answer 8

-Most HPV infections are transient and eliminated within months by the host immune response
-“Low risk” types (i.e. 6,11) remain as free episomal viral DNA and cause benign lesions (i.e. condyloma)
-Persistent HPV infections with HRHPV types (i.e. 16,18) –> viral integration –> production of viral oncoprotein E6 (inhibits p53) and E7 (leads to inhibition of RB) –> neoplasia

Question 9

T/F: HPV infection alone is insufficient to cause cancer

Answer 9

TRUE

Question 10

Cervical Carcinoma - Precursors

Answer 10

-Cervical carcinoma evolves from an asymptomatic precancerous lesion that appears many years before invasive carcinoma (Ex: peak ages: precursor = 30yrs; invasive carcinoma = 45yrs)
-Previous 3 tier system (cervical intraepithelial lesion (CIN) I, II, III) replaced with 2 tier system:
-Squamous intraepithelial lesion (SIL) divided into:
1. Low-grade SIL (LSIL)- does not progress directly to carcinoma. Most regress; 10% progress to HSIL
2. High-grade SIL (HSIL)- “high risk” to progress to carcinoma (10% over 10 yrs)…so the majority don’t

Question 11

Cervical Cancer - Screening

Answer 11

-Early detection of SIL (cancer prevention): performed with Papanicolaou (Pap) test/smear (cytologic exam)
-Pap test is the most successful cancer-screening test ever developed
-Screening guidlines (UPSTF 2018):
*21-65 yrs: Pap test every 3 yrars
*30-65 yrs: Can add HPV co-test or just HRHPV test every 5 years (no HPV test for <30yrs)
*>65 yrs: Stop Pap smears unless never been screened or if high risk lesions are present

Question 12

Describe what happens if there is an abnormal Pap smear while screening for cervical cancer?

Answer 12

-Abnormal Pap smear results are followed by biopsy/curettage during colposcopy
-Application of dilute acetic acid makes affected area appear whiter to help guide biopsy

Question 13

How are HSIL and persistent LSIL treated?

Answer 13

With surgical excision (cone biopsy

Question 14

Describe HPV testing for cervical cancer

Answer 14

-HPV will be contracted by most sexually active females at some point so HPV DNA testing by PCR not a great screening took in young patients. Used only if >30yrs
-If HPV negative (by PCR), very low risk of harboring SIL
-Only reliable way to monitor disease is frequent exams, Pap smears and biopsies (can’t predict exactly which lesions will progress)

Question 15

Cervical Carcinoma

Answer 15

-May be invisible or exophytic
-Requires HPV infection AND mutations in tumor suppressor and oncogenes
-Surgery, radiation and chemotherapy may all be used depending on stage
-Prognosis depends on clinical stage. Even with positive nodes, ~50% 5 yr survival

Question 16

List the types of Cervical Carcinoma

Answer 16

-Squamous cell carcinoma (75%)
-Adenocarcinomas (20%) - on the rise
-Small cell neuroendocrine carcinomas (5%)

Question 17

Cervical Cancer - Prevention

Answer 17

-HPV vaccination recommended for boys and girls 11-12yrs
-Gardasil 9 vaccine available in United States protects against HPV 6,11 (preventing genital warts) and high-risk types (16,18, 31, 33, 45, 52, 58)

Question 18

List the Uterine Diseases

Answer 18

-Endometritis
-Adenomyosis
-Endometriosis
-Bleeding and hyperplasia
-Tumors

Question 19

Endometritis

Answer 19

-Inflammation of the endometrium
-May be seen as part of pelvic inflammatory disease
-May be associated with retained products of conception (miscarriage/delivery) or a foreign body (IUD) which act as a focus for infection
-Acute (PMNs) or chronic (lymphocytes) often due to N. gonorrhoeae or C. trachomatis
-Symptoms: fever, abdominal pain, menstrual irregularities, infertility, ectopic pregnancy

Question 20

Adenomyosis

Answer 20

-Growth of basal layer of endometrium into myometrium
-Uterine wall is thickened, uterus enlarged
-If prominent, may produce symptoms of menorrhagia, dysmenorrhea, pelvic pain
-Basal glands do not undergo cyclic bleeding

Question 21

Endometriosis

Answer 21

-Endometrial glands and stroma outside the uterus
-10% of reproductive age females; ~50% of infertile women

Question 22

What is the pathogenesis of Endometriosis

Answer 22

Regurgitation theory - menstrual backflow through fallopian tubes with implantation

Question 23

What is the clinical presentation of Endometriosis

Answer 23

-Dysmenorrhea, pelvic pain, pelvic mass filled with degenerating blood (chocolate cyst)
-Frequently multifocal involving pelvic tissues or peritoneum

Question 24

Leiomyoma (fibroids)

Answer 24

-Uterine tumor
-Most common benign tumor in females typically >30yrs
-Frequently occur as multiple tumors
-Regress after menopause
-May increase in size during pregnancy
-May cause vaginal bleeding
-Rare transformation, even with multiple lesions
-May cause difficulties with becoming pregnant

Question 25

Leiomyosarcoma

Answer 25

-Uterine tumor -Malignant tumor of smooth muscle -Solitary lesions arise de-novo, NOT from preexisting leiomyoma -Recurrence and metastasis (often to the lung) are common with poor prognosis

Question 26

Endometrial Carcinoma

Answer 26

-Most common female genital tract cancer, 55-65yrs -Estrogen excess --> endometrial hyperplasia which can then lead to carcinoma -Majority of cases present in perimenopausal women with estrogen excess -Causes of estrogen excess (risk factors): obesity, prolonged estrogen replacement therapy, estrogen-secreting ovarian tumors -Clinical: marked leukorrhea and irregular bleeding - very concerning sign in postmenopausal woman -Prognosis depends on stage of disease

Question 27

Follicle and Luteal Cysts

Answer 27

-Extremely common -Usually small (<1.5cm), develop just below surface -Large cysts may be palpable/painful; rupture causes intraperitoneal bleeding

Question 28

Polycystic Ovarian Syndrome

Answer 28

-Excess production of mostly androgens by multiple cystic follicles in ovaries -Hirsutism (male hair pattern), oligomenorrhea, infertility, enlarged ovaries with small subcortical cysts

Question 29

Ovarian Cancer

Answer 29

-Risk factors: nulliparity, low parity, family history, BRCA-1 mutation (30% risk) -Surface epithelial tumors (most common) *serous or mucinous *unilateral or bilateral -Germ Cell Tumors - teratoma is most common in this group (typically benign)

Question 30

Ovarian Cancer - Detection

Answer 30

-Usually limited symptoms until widespread. May cause abdominal pain, swelling (if large) or ascites related to seeding of the peritoneal cavity -CA-125: *elevated in a high percentage of epithelial cancer patients, but undetectable in about half of cancers limited to ovary (low sensitivity) *Present in benign conditions and nonovarian cancers (low specificity) *Greatest value = monitoring response to therapy

Question 31

Ectopic Pregnancy

Answer 31

Implantation of fertilized ovum in any site other than uterus -90% in the fallopian tube often caused by scarring of the oviduct -May only be discovered upon rupture which causes intense abdominal pain and sign of acute abdomen (pain, nausea, vomiting). Prompt surgery is necessary

Question 32

Preeclampsia

Answer 32

Edema, proteinuria, hypertension in 2nd, 3rd trimesters

Question 33

Eclampsia

Answer 33

-Preeclampsia symptoms and seizure development -Can be fatal is disseminated intravascular coagulation develops

Question 34

What is the pathogenesis of Preeclampsia and Eclampsia

Answer 34

Spiral arteries remain abnormally narrow --> maternal/placental ischemia, endothelial cell dysfunction --> hypertension, hypercoagulability and possible DIC

Question 35

Spontaneous Abortion

Answer 35

-Miscarriage at <20 weeks gestation (usually 1st trimester) -Occurs in 1/4 of pregnancies -Vaginal bleeding, cramping -Most often due to chromosomal anomalies

Question 36

Sudden Infant Death Syndrome (SIDS)

Answer 36

-Death of a healthy infant (1mo to 1yr) without obvious cause -Infants usually die during sleep -Risk factors: sleeping on stomach, cigarette smoke exposure, prematurity