Gianani Ovarian cancer

Question 1

Adnexal masses

Answer 1

• enlarged structure, usually originating in the ovaries, fallopian tubes, or uterus, that can be palpated on bimanual pelvic exam or seen on radiographic imaging.
• often an incidental finding

Evaluation

• bimanual pelvic exam has low sensitivity for detecting adnexal masses; moderate ability to distinguish benign from malignant masses.
• urine pregnancy test in all women of reproductive age.
• Transvaginal ultrasound - imaging modality of choice for asymptomatic women with pelvic masses
• Obtain cancer antigen 125 (CA-125) in postmenopausal patients with abnormal ultrasound and in premenopausal women with clinical and imaging findings suspicious for malignancy

Management
- observation or surgery (menopausal status, desire to preserve fertility?)

If suspected malignancy:

• refer to a gynecologic oncologist, especially if high-risk features
• perform hysterectomy with bilateral salpingo-oophorectomy and staging procedures unless patient wishes to preserve ability to bear children, in which case, conservative surgery (unilateral salpingo-oophorectomy or ovarian cystectomy) may be an option (staging should still be performed)

If mass is likely benign:
- patients can be followed without intervention regardless of menopausal status for unilocular cysts sized ≤ 10 cm in diameter (almost always benign) (Weak recommendation)
- consider expectant management with observation and repeat imaging for patients with an ultrasound suggesting benign disease or for cases in which morphology is uncertain and there is a strong reason to avoid surgery
- Consider surgical intervention for masses with intermediate risk of malignancy or unclear diagnosis:
- Cystectomy is the generally preferred option for benign masses in premenopausal women; unilateral or bilateral salpingo-oophorectomy are options if ovarian tissue cannot be saved.
- Cystectomy, unilateral or bilateral salpingo-oophorectomy, or hysterectomy are options in postmenopausal women.
- If adnexal mass during pregnancy:
observation generally appropriate

• surgical removal of persistent masses in the second trimester is common despite a lack of evidence to support routine need

Question 2

OVARIAN CANCER

Answer 2

• leading cause of death from gynecologic malignancy,
• most in women aged 60-64 years
• 90% of primary ovarian tumors are epithelial carcinomas, further grouped histologically into 8 subtypes.
• Nonepithelial ovarian cancers include germ cell tumors and sex cord-stromal tumors.
• no reliable screening tests
• symptoms of ovarian cancer often do not present until advanced stages of disease. When present, often include gastrointestinal complaints such as bloating, early satiety, and abdominal and/or pelvic pain.
• Overall survival is estimated at < 50% at 5 years, but survival rates vary by disease stage.

Question 3

Ovarian Cancer risk factors

Answer 3

Age (epithelial cancer)
Family History (First degree relative with ovarian cancer triples risk of disease.
Long period of continuous ovulation (Nulliparity, Early menarche, Late Menopause)

Question 4

Epithelial Tumors of the ovary- type of epithelium

Answer 4

serous- mostly benign. usually bilateral when malignant (30%)

mucinous- less likely bilateral (15% malignant)

endometrioid- tubular glands usually malignant

Question 5

Pseudo-myxoma peritonei.

Answer 5

marked by extensive mucinous ascites, cystic epithelial implants on the peritoneal surfaces, adhesions, and frequent involvement of the ovaries.

if extensive, may result in intestinal obstruction and death.

often appendiceal in origin

Question 6

germ cell tumor summary

Answer 6

15-20% of ovarian tumors
majority are mature cystic teratomas (dermoid cysts) in women of reproductive age

remainder occur in young women and children; then often malignant

immature distinguished from mature teratomas by presence of immature elements, most often consisting of primitive neuroepithelium.

Germ cell tumors show various lines of differentiation toward oogonia (dysgerminoma), extraembryonic yolk sac (yolk sac tumors), plaenta (choriocarcinoma) or multiple germ layers (teratoma)

Question 7

Sertoli-Leydig cell tumors

Answer 7

often functional and commonly produce masculinization or defeminization, few estrogenic effects.

characteristic golden-yellow appearance

Question 8

Granulosa cell tumors.

Answer 8

might produce large amount of estrogens and might behave like low-grade malignancies.

Question 9

sex-cord stromal tumor summary

Answer 9

granulosa cell tumors- most common. indolent. often hormonally active, associated with endometrial hyperplasia/ cancer

fibromas- relatively common benign tumors composed of fibroblasts. Predominantly unilateral and generally hormonally inactive

Pure thecomas- rare, may be hormonaly active

setroli-leydig cell tumors- commonly present with masculinization and less than 5% recur or metastasize

Question 10

Metastatic tumors of the ovary.

Answer 10

commonly of mullerian origin: uterus, fallopian tube, contralateral ovary, pelvic perioneum.

extramullerian tumors metastatic to ovary- carcinoms of the breast and GI tract, incl. colon, stomach, biliary tract, and pancreas. Also rare pseudomyxoma peritonei, from appendiceal tumors. Clasic metastatic GI carcinoma involving the ovaries- Krukenberg tumor, characterized by bilateral metastases composed of mucin-producing, signet-ring cancer cells, most often of gastric origin

Question 11

Non-neoplastic and functional cysts of the ovary

Answer 11

Follicle and luteal cyst.
Polycistic ovaries and stromal hyperthecosis.
Endometriotic ovarian cyst.

Question 12

Cystic follicles

Answer 12

are very common in the ovary. They originate from unruptured follicles or in follicles that have ruptured and immediately sealed.

Question 13

Luteal cysts

Answer 13

present in the normal ovaries of women of reproductive age. These cysts are lined by a rim of bright yellow tissue containing luteinized granulosa cells. They occasionally rupture and cause a peritoneal reaction. Sometimes the combination of old hemorrhage and fibrosis may make their distinction from endometriotic cysts difficult.

Question 14

Endometriotic ovarian cyst.

Answer 14

Present in 60% of women with endometriosis
Only 1% of women with endometriosis has the disease present only in the ovaries
Can cause severe pain

Question 15

Pathology of the fallopian tube.

Answer 15

Infections (Gonococcus, Chlamidia, Tuberculosis).
Ectopic Pregnancy.
Tumors of the fallopian tube are rare. Benign tumors include adenomatoid tumors.
-Primary adenocarcinoma of the fallopian tube
— came to medical attention for abnormal discharge, bleeding or neoplastic cells in the PAP smear.

Question 16

HPV as a carcinogen

Answer 16

• depends on the viral proteins E6 and E7, which interfere with the activity of tumor suppressor proteins that regulate cell growth and survival.
• Although HPV infects immature squamous cells, viral replication occurs in maturing squamous cells.
• Normally, these more mature cells are arrested in the G1 phase of the cell cycle, but they continue to actively progress through the cell cycle when infected with HPV, which uses the host cell DNA synthesis machinery to replicate its own genome.

Question 17

Susceptibility of different type of squamous cells to HPV infection.

Answer 17

HPVs infect:

• immature basal cells of the squamous epithelium in areas of epithelial breaks, or
• immature metaplastic squamous cells present at the squamocolumnar junction.
• requires damage to the surface epithelium, which allows the virus access to the immature cells in the basal layer of the epithelium.

The cervix, - relatively large areas of immature squamous metaplastic epithelium- particularly vulnerable to HPV infection (as compared to, for example, vulvar skin and mucosa that are covered by mature squamous cells.)

Question 18

E6 and E7 HPV proteins

Answer 18

The E6 protein –> degradation of p53, also stimulates the expression of TERT, (the catalytic subunit of telomerase)

The E7 protein–> speeding cells through the G1-S cell cycle checkpoint. It binds to the RB protein and displaces the E2F transcription factors that are normally sequestered by RB, promoting progression through the cell cycle

Question 19

Cervix Microanatomy

Answer 19

• external vaginal portio (ectocervix) and
• endocervical canal.

ectocervix is visible on vaginal examination, covered by a mature squamous epithelium that is continuous with the vaginal wall. The squamous epithelium converges centrally at a small opening termed the external os that leads to the endocervical canal.

• endocervix is lined by columnar, mucus-secreting epithelium. The point where the squamous and columnar epithelium meet is referred to as the squamocolumnar junction.
• position of the junction is variable, changes with age and hormonal influence; moves upwards into the endocervical canal with time.
• The replacement of the glandular epithelium by advancing squamous epithelium = squamous metaplasia.
• area of the cervix where the columnar epithelium abuts the squamous epithelium = “transformation zone.”
• unique epithelial environment of the cervix renders it highly susceptible to infections with HPV, the main cause of cervical cancer. Immature squamous metaplastic epithelial cells in the transformation zone are most susceptible to HPV infection–> this is where cervical precursor lesions and cancers develop.

Question 20

Diseases of the cervix

Answer 20

Inflammation: Acute and Chronic Cervicitis.
Endocervical polyps.
Neoplastic and pre-neoplastic diseases of the cervix.

Question 21

Endocervical polyp

Answer 21

composed of a dense fibrous stroma covered with endocervical columnar epithelium.

Question 22

Acute and Chronic Cervicitis- vaginal environment

Answer 22

Lactobacilli produce lactic acid –> vaginal pH below 4.5, suppressing the growth of other saprophytic and pathogenic organisms. In addition, at low pH, lactobacilli produce bacteriotoxic hydrogen peroxide (H2O2).

If the pH becomes alkaline due to bleeding, sexual intercourse, or vaginal douching, H2O2 production by lactobacilli decreases. Antibiotic therapy that suppress lactobacilli can also cause the pH to rise.

• the altered vaginal environment promotes the overgrowth of other microorganisms, which may result in cervicitis or vaginitis.
• Infections by gonococci, chlamydiae, mycoplasmas, and HSV may produce significant acute or chronic cervicitis
• Marked cervical inflammation produces reparative and reactive changes of the epithelium and shedding of atypical-appearing squamous cells

Question 23

Cervical Carcinoma

Answer 23

• average age: 45 years.
• Squamous cell carcinoma- most common
• The second most common tumor type is adenocarcinoma, - from a precursor lesion called adenocarcinoma in situ.

Adenosquamous and neuroendocrine carcinomas are rare cervical tumors that account for the remaining 5% of cases.

All caused by high-risk HPVs.
-progression time from in situ to invasive adenosquamous and neuroen­docrine carcinomas is shorter than in squamous cell carcinoma, and patients with these tumors often present with advanced disease and have a less favorable prognosis.

Question 24

Adenocarcinoma of the Cervix

Answer 24

characterized by proliferation of glandular epithelium composed of malignant endocervical cells with large, hyperchromatic nuclei and relatively mucin-depleted cytoplasm, resulting in a dark appearance of the glands, as compared to the normal endocervical epithelium. Adenosquamous carcinoma is composed of intermixed malignant glandular and squamous epithelium. Neuroendocrine cervical carcinoma has an appearance similar to small cell carcinoma of the lung , but differs in being positive for high risk HPVs.

Question 25

Squamous Cell Carcinoma of the Cervix

Answer 25

composed of nests and tongues of malignant squamous epi­thelium, either keratinizing or nonkeratinizing, which invade the underlying cervical.

Question 26

staging of cercival carcinoma

Answer 26

Stage O- carcinoma in situ
stage I- confined to cervix
Stage II- extends beyond the cervix but not to the pelvic wall. Involves the vagina but not the lower third.
III- to the pelvic wall. No cancer-free space between the tumor and the pelvic wall. involves the lower third of the vagina
Stage IV- beyond the true pelvis or has involved the mucosa of hte bladder or rectum. Also includes cancers with metastatic dissemination

Question 27

HPV testing

Answer 27

Testing for the presence of HPV DNA in the cervical scrape is a molecular method of cervical cancer screening. HPV testing has a higher sensitivity but lower specificity, as compared to Pap test.
HPV DNA testing may be added to cervical cytology for screening in women aged 30 years or older.
HPV testing of women younger than 30 is not recommended because of the high incidence of infection, and thus the particularly low specificity of HPV test results in this age group

Question 28

HPV Vaccination

Answer 28

A new aspect of cervical cancer prevention is vaccination against high-risk oncogenic HPVs, which is now recommended for all girls and boys by age 11 to 12 years, as well as young men and women up to age 26 years.

Question 29

Step-wise approach to management of pre-neoplastic Cervical Lesions.

Answer 29

Recommendations for the frequency of Pap screening vary, but in general the first smear should be at age 21 years or within 3 years of onset of sexual activity, and thereafter every 3 years.
After age 30, women who have had normal cytology results and are negative for HPV may be screened every 5 years. Women with a normal cytology result, but test positive for high-risk HPV DNA, should have cervical cytology repeated every 6 to 12 months.

Question 30

Cervical Cancer Screening and Prevention

Answer 30

As is well known, cytologic cancer screening has significantly reduced mortality from cervical cancer. In countries where such screening is not widely practiced, cervical cancer continue to exact a high toll.
Abnormal cells from cancer or precursor lesion can be detected on cytologic examination. Using a spatula or brush, the transformation zone of the cervix is circumferentially scraped and the cells are smeared or spun down onto a slide.
Following fixation and staining with the Papanicolaou method, the smears are screened microscopically by eye or (increasingly) with automated image analysis systems

Question 31

cervical cancer summary

Answer 31

Cervical low-grade squamous intraepithelial lesions (LSILs) are productive HPV infections that usually regress spontaneously, but occasionally progress to high-grade squamous intraepithelial lesions (HSILs).
HSILs are characterized by progressive deregulation of the cell cycle and increasing cellular atypia. HSILs may progress to invasive carcinoma.
Almost all cervical precursor lesions and cervical carcinomas are caused by high-risk HPV types, most commonly HPV-16 and HPV-8