Gynecologic and Obstetric Disorders
Juliana G. Szakacs
INTRODUCTIONThe 11th edition is updated to include the latest recommendations for cervical cancer screening and diagnostic testing for diseases of the female genital tract, including abnormalities related to menstruation. New genetic tests for the prenatal screening of heritable disorders are becoming available (see also Chapter 12). Please see the ebook version for the figures referenced in this chapter.
GYNECOLOGIC DISORDERSCANCER OF THE BREAST
□ Definition
Cancer of the breast is a malignancy arising from the breast epithelium (carcinoma) and/or stroma (sarcoma).
□ Clinical Presentation
Breast cancer is the most common malignancy in women and a leading cause of cancer death. Risk factors include increased age and female gender, white
race, preexisting benign proliferative breast disease, dense breast tissue on mammography, use of HRT, postmenopausal obesity, family history of breast or ovarian cancer, exposure to ionizing radiation, and environmental factors. The patient may present with a mass, but most will present with mammographic abnormalities.
race, preexisting benign proliferative breast disease, dense breast tissue on mammography, use of HRT, postmenopausal obesity, family history of breast or ovarian cancer, exposure to ionizing radiation, and environmental factors. The patient may present with a mass, but most will present with mammographic abnormalities.
□ Laboratory Findings
The diagnosis of breast cancer is made on mammographic and/or ultrasound findings followed by biopsy and histologic evaluation. Patients with a familial history of breast or ovarian cancer may be screened for BRCA1 and BRCA2; however, <10% of all breast cancers are associated with genetic mutations (see Chapter 12). Additional syndromes associated with an increase in breast cancer include Li-Fraumeni and Cowden syndromes, which are associated with mutations in the TP53 and PTEN genes, respectively.
The histologic types of breast carcinoma include infiltrating ductal carcinoma (see eBook Figure 10-1C), infiltrating lobular (see eBook Figure 10-2D) carcinoma, and mixed ductal/lobular carcinoma. In addition, there are sarcomas and mixed tumors, phyllodes tumor (see eBook Figure 10-3C).
Molecular subtypes include luminal subtypes A and B (the majority of ER-positive breast cancers), HER2-enriched (often negative for ER and PR), and basal subtypes (triple negative) (see eBook Figures 10-1 to 10-3).
At the time of diagnosis, immunohistochemical staining is performed on the tumor to determine estrogen (ER) and progesterone (PR) receptor expression for prognosis and human epidermal growth factor 2 (HER2) receptors to determine if the patient will respond to Herceptin. Grading is based on architecture, nuclear morphology, and the number of mitoses using a system such as the Scarff-Bloom-Richardson grading system. Staging is based on the tumor-node-metastasis (TNM) system from the American Joint Committee on Cancer and the International Union for Cancer Control.
CANCER OF THE CERVIX
□ Definition
Squamous cell carcinoma of the cervix is one of the most frequent neoplasms that affects a woman’s reproductive system (see eBook Figure 10-4A). Cervical squamous cell carcinoma is the result of infection with high-risk strains of the human papillomavirus (hrHPV), especially (but not exclusively) the oncogenic types 16 and 18. Persistent viral infection transforms the epithelial cells that undergo a progression of changes in the cervix particularly at the squamocolumnar junction, which can be identified on Pap testing and on biopsy. The progression from acute infection to dysplasia to invasive carcinoma may take 3-7 years. Regular screening for high-risk HPV and by Pap testing has decreased the incidence of this cancer worldwide. HPV vaccination should decrease the incidence further in coming years. Adenocarcinoma of the cervix is also caused by HPV transformation of the endocervical cells but is less common than SCC and is not easily detected by Pap testing (see eBook Figure 10-4B).
□ Clinical Presentation
Cervical carcinoma is usually seen in women in their 40s and 50s but may occur as early as the mid-20s if there is a history of early sexual activity and multiple partners. It is more likely in patients who have never been screened or who have not had a Pap or HPV test in the previous 5 years. Patients may be asymptomatic or present with abnormal or postcoital bleeding or vaginal discharge that may be watery, mucoid, or purulent and malodorous. The presence of pelvic or lower back pain suggests advanced disease. Suspicion should be high in the presence of an abnormal Pap test.
□ Laboratory Findings
Pap testing may be performed by conventional smear or liquid methodology (SurePath liquid-based Pap test and ThinPrep Pap test). Cytology is reported in the Bethesda system as negative, atypical squamous cells (ASCUS), low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), squamous cell carcinoma, and atypical glandular cells (AGUS) (see eBook Figure 10-5A-E). A statement on the adequacy of the cellularity for testing is also made.
The U.S. Preventive Services Task Force (USPSTF) recommends screening for cervical cancer with cytology (smear or liquid-based) and high-risk HPV DNA testing as follows:
No screening for women younger than 21 years.
Cytology alone every 3 years should be performed for women aged 21-29 years.
hrHPV alone or hrHPV and cytology cotesting performed every 5 years for women aged 30-65 years or cytology alone every 3 years.
For women with three negative cytology tests or two negative hrHPV or cotesting screens within the past 10 years, no further screening is necessary after age 65 years.
Women with a history of treated CIN 2, CIN 3, or adenocarcinoma in situ should continue routine age-based screening for at least 20 years, even if this extends beyond age 65.
For women who have undergone hysterectomy with removal of the cervix for indications other than CIN 2, CIN 3, or adenocarcinoma in situ in the previous 20 years, no screening is necessary.
For women vaccinated against HPV, follow age-specific recommendations similar to unvaccinated women.
The hrHPV platform used (ISH, PCR, or hybrid capture) does not significantly influence the outcome of screening.
hrHPV testing alone or cotesting results in a higher false-positive rate than does cytology alone, but more CIN2+ lesions were detected.
Women at high risk for cervical cancer (history of cervical cancer, DES exposure, HIV, immunocompromised) may need more frequent screening.
Follow-up of screening tests is as follows:
ASCUS Pap only test for HPV or repeat cytology in 1 year
ASCUS Pap and negative hrHPV rescreen in 3 years
ASCUS Pap and positive hrHPV send for colposcopy
Negative cytology and positive hrHPV repeat cotesting in 12 months or test for HPV 16/18:
Referral of patients for colposcopic examination and biopsy should be performed for patients with positive HPV 16 or 18 and any cytology results higher than LSIL or any patient with AGUS. Patients should undergo biopsy of any visualized cervical lesions and endocervical curettage if no lesions are apparent (see eBook Figures 10-6 and 10-7). For patients with abnormal Pap tests (ASCUS and HSIL), positive hrHPV test and negative biopsy additional tissue diagnosis should be attempted with conization (loop electrocautery excision).
For women diagnosed with invasive squamous cell carcinoma of the cervix, imaging studies (CT or MRI) are recommended to evaluate possible involvement of adjacent organs or metastases.
Testing options:
Many laboratories now offer reflex testing for hrHPV from the liquid Pap vial based on the ACOG recommendations, making it easier for the clinician. In addition, PCR testing for GC, Chlamydia, and Trichomonas may also be performed on the same liquid Pap vial.
Limitations of the Pap test:
False-negative results in approximately 5-10% of cases.
Unsatisfactory cellularity occurs when fewer than 5,000 well-visualized, well-preserved squamous cells in a liquid-based Pap, and 8,000 cells on a conventional smear are obtained.
Sampling problems occur in up to 10% of samples collected; these have integrity issues and are considered unsatisfactory due to the presence of blood or mucous, inflammation, insufficient cells, or problems with the slide preparation. Malignant cells may not be present if the smear is repeated too soon after a previous abnormal smear.
The Pap test was designed to screen for squamous tumors. Other tumor types are less readily diagnosed (e.g., adenocarcinoma, lymphoma, and sarcoma).
Human error in interpreting difficult cells; <3% of preventable cervical cancers are due to misread smears.
Limitations of the HPV test:
Primary hrHPV testing has not been evaluated by long-term studies.
Primary hrHPV testing results in increased numbers of colposcopies per high-grade lesion identified (i.e., an increased false-positive rate over cotesting or cytology alone).
Other tests FDA approved for cotesting include Hybrid Capture 2, Cervista HPV HR test, and Aptima mRNA test, and additional tests may be available at local labs but have not been adequately validated for FDA approval.
HPV tests identify most but not all of the hrHPV types.
Suggested Readings
Nayar R, Wilbur DC, eds. The Bethesda System for Reporting Cervical Cytology, 3rd ed. New York: Springer Science and Business Media, LLC; 2014.
US Preventive Services Task Force. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;320(7):686.
CANCER OF THE ENDOMETRIUM
□ Definition
Endometrial carcinoma is the most common invasive gynecologic cancer in North America (cervical carcinoma is most common worldwide). There are two types recognized. Type 1 is estrogen or tamoxifen related, is usually a low-grade endometrioid type, and is preceded by endometrial intraepithelial neoplasia. Type 2 is unrelated to estrogen or tamoxifen, is usually a higher-grade papillary serous or mixed type, and is associated with p53 mutations without a preceding in situ component. The progression of type 2 disease is usually rapid, and the prognosis is poor.
□ Clinical Presentation
Patients with endometrial carcinoma present with a history of abnormal vaginal bleeding, especially if postmenopausal. Cancer of the endometrium is associated with excessive estrogen exposure (endogenous or exogenous), PTEN mutations, obesity, nulliparity, diabetes, and hypertension. Concurrent ovarian carcinoma may occur in 10-20%. Patients with Lynch and Cowden syndromes are at increased risk for endometrial carcinoma.
□ Laboratory Findings
The diagnosis of endometrial carcinoma is made on endometrial biopsy or curettage (positive in 95% of patients) and rarely is identified on Pap test (see eBook Figure 10-8). A negative Pap test does not rule out carcinoma. The tumor is graded and staged according to the International Federation of Gynecology and Obstetrics (FIGO)/TNM system. Blood tests may show anemia if bleeding is chronic or severe, but otherwise are noncontributory.
CANCER OF THE OVARY
EPITHELIAL OVARIAN CARCINOMA
□ Definition
Cancer of the ovary may derive from the epithelium (95% of cases) or from the stromal supporting cells or germ cells. This section will deal with the epithelial carcinomas arising from the surface of the ovary that are contiguous with the peritoneum and include low-grade serous carcinomas, serous tumors of low malignant potential, high-grade serous carcinomas, mucinous carcinoma, endometrioid carcinomas, clear cell tumors, Brenner (transitional cell) tumors, and undifferentiated carcinomas.
□ Clinical Presentation
Patients may present with either acute symptoms such as bowel obstruction or pleural effusion or subacute symptoms such as adnexal mass, pain, bloating,
urinary frequency, or early satiety. Patients with a positive family history of breast or ovarian cancer or who have BRCA1 or BRCA2 mutations or Lynch syndrome may be at increased risk (see Hereditary and Genetic Diseases, Chapter 12). Patients at high risk for ovarian carcinoma may benefit from screening with transvaginal ultrasound and CA-125.
urinary frequency, or early satiety. Patients with a positive family history of breast or ovarian cancer or who have BRCA1 or BRCA2 mutations or Lynch syndrome may be at increased risk (see Hereditary and Genetic Diseases, Chapter 12). Patients at high risk for ovarian carcinoma may benefit from screening with transvaginal ultrasound and CA-125.
□ Laboratory Findings
The diagnosis of ovarian cancer is made on histologic examination of tissue or cytology of peritoneal or pleural fluid if present (see eBook Figure 10-9). Rarely, abnormal glandular cells may be seen on Pap test, which on further workup are found to originate from the ovary.
Imaging is the most important tool for identifying an adnexal mass. Surgical excision of the intact mass with intraoperative frozen section diagnosis is performed whenever possible as transabdominal FNA or biopsy of ovarian tumors has been shown to increase the risk of seeding the malignant cells into the peritoneum by rupture or incision of the mass.
Screening tests for ovarian carcinoma have been sought to aid in finding these patients before symptoms occur. These include the following:
CA-125 is elevated in approximately 50% of patients with early-stage disease and in >80% of patients with advanced disease. It may also be elevated in normal women and in patients with endometriosis, leiomyoma, cirrhosis, PID, or other malignancies. Following serial CA-125 levels over time may be more beneficial as a screening tool.
Human epididymis protein 4 (HE4) is helpful in diagnosing recurrent or progressive disease or in the evaluation of a suspicious adnexal mass.
Carcinoembryonic antigen (CEA) is nonspecific. Levels may be elevated in malignancies (particularly mucinous carcinomas) of the ovary, GI tract, breast, pancreas, thyroid, and lung. It is also elevated in patients who smoke or who have mucinous cystadenoma, cholecystitis, cirrhosis, pancreatitis, pneumonia, and diverticulitis and IFD.
CA 19-9 is a mucin protein that may be elevated in ovarian cancer but is also positive in gastric, pancreatic and gallbladder cancers. It may be used to follow recurrence in a patient with known CA 19-9-positive ovarian cancer.
OVA1 is a panel that includes five serum biomarkers to assess the likelihood of malignancy in patients with an adnexal mass. Two markers are up-regulated (CA-125 II, beta-2 microglobulin) and three down-regulated (transferrin, transthyretin, apolipoprotein A1). An algorithm determines the patient’s risk for ovarian cancer. OVA1 is commercially available through Quest Diagnostics.
Suggested Reading
Crum CP, Nucci M, Lee KR. Diagnostic Gynecologic and Obstetric Pathology, 3rd ed. Philadelphia, PA: W. B. Saunders Co.; 2011.
OVARIAN GERM CELL TUMORS
□ Definition
Ovarian germ cell neoplasms originate from the germ cells of the ovary and constitute 5% of the malignant ovarian neoplasms. These tumors may be malignant or benign and include teratomas (mature, dermoid, and immature), dysgerminomas, endodermal sinus (yolk sac) tumors, embryonal carcinomas, and nongestational choriocarcinoma (see eBook Figure 10-10).
□ Clinical Presentation
Patients presenting with ovarian germ cell neoplasms are usually between 10 and 30 years of age. They are more frequent in Asian/Pacific Islander and Hispanic women than in Caucasians. Presenting symptoms include effects of hCG production by the tumor (precocious puberty, abnormal vaginal bleeding), abdominal enlargement, ascites, or abdominal pain (including acute abdomen due to torsion).
□ Laboratory Findings
The definitive diagnosis requires histologic evaluation at the time of surgical excision. A presumptive diagnosis may be made with an adnexal mass on pelvic imaging (CT, MRI, or ultrasound) and elevation of an associated tumor marker. Tumor markers are also used to monitor patients post surgical resection for recurrence. These include the following:
hCG is increased in embryonal cell carcinomas, ovarian choriocarcinomas, mixed germ cell tumors, and some dysgerminomas.
AFP is increased in endodermal sinus tumors, embryonal cell carcinomas, mixed germ cell tumors, and some immature teratomas.
Lactate dehydrogenase (LDH) is increased in dysgerminomas.
Suggested Reading
Crum CP, Nucci M, Lee KR. Diagnostic Gynecologic and Obstetric Pathology, 3rd ed. Philadelphia, PA: W. B. Saunders Co.; 2011.
OVARIAN SEX CORD-STROMAL NEOPLASMS
□ Definition
Ovarian sex cord-stromal neoplasms are benign or malignant tumors that arise from the cells supporting the oocytes, including ovarian hormone-producing cells. These are rare tumors constituting <2% of all ovarian cancers. These include fibromas, thecomas, granulosa cell tumors, Sertoli or Sertoli-Leydig cell tumors, and gynandroblastoma.
□ Clinical Presentation
Patients with sex cord tumors present with abdominal distention, bloating, pain or pelvic symptoms, and a finding of adnexal mass on imaging. They also may exhibit hormonal manifestations including signs of estrogen excess
(precocious puberty, abnormal uterine bleeding) or androgen excess (virilization). The risk for sex cord tumors may be decreased in current or past smokers, in women who have taken oral contraceptive pills, and in multiparous women and increased in nonwhite women with obesity or who have a family history of breast or ovarian cancer but are not associated with the BRCA mutation. Mutations in FOXL2 have been seen in granulosa cell tumors, and mutations in DICER1 are associated with Sertoli-Leydig cell tumors.
(precocious puberty, abnormal uterine bleeding) or androgen excess (virilization). The risk for sex cord tumors may be decreased in current or past smokers, in women who have taken oral contraceptive pills, and in multiparous women and increased in nonwhite women with obesity or who have a family history of breast or ovarian cancer but are not associated with the BRCA mutation. Mutations in FOXL2 have been seen in granulosa cell tumors, and mutations in DICER1 are associated with Sertoli-Leydig cell tumors.
□ Laboratory Findings
The diagnosis of sex cord-stromal tumor is made on tissue evaluation at the time of surgery (see eBook Figure 10-11). For any suspected ovarian malignancy, a complete oophorectomy must be performed to prevent potential spread of neoplastic cells. Presumptive diagnosis may be made in a patient with hormonal changes, an adnexal mass on imaging (transpelvic ultrasound), or bimanual exam and elevation of an associated tumor marker. These include the following:
AFP is seen in embryonal carcinoma and polyembryoma and may be seen in immature teratoma, endodermal sinus tumors, mixed germ cell tumors, and Sertoli-Leydig cell tumors.
hCG is seen in embryonal carcinoma, choriocarcinoma, and polyembryoma and may be seen in mixed germ cell tumors and dysgerminoma.
LDH is seen in dysgerminoma and endodermal sinus tumors and may be seen in embryonal carcinoma, choriocarcinoma, immature teratoma, and mixed germ cell tumors.
Inhibin is seen in granulosa cell tumors where both inhibin A and inhibin B should be ordered, and it may be seen in Sertoli-Leydig cell tumors and gonadoblastoma.
Estradiol may be seen in granulosa cell tumors, Sertoli-Leydig cell tumors, gynandroblastoma, immature teratoma, embryonal carcinoma, and dysgerminoma.
Testosterone is elevated when virilization is present in Sertoli-Leydig cell tumors and may also be seen in granulosa cell tumors and gynandroblastoma.
Androstenedione may be seen in gynandroblastoma and Sertoli-Leydig cell tumors.
DHEA may be seen in immature teratoma, gonadoblastoma, and Sertoli-Leydig cell tumors.
Müllerian-inhibiting substance (MIS) appears to be a more specific tumor marker for granulosa cell tumors but is not yet available for clinical use.
Genetic testing is not helpful at this time.
Suggested Reading
Crum CP, Nucci M, Lee KR. Diagnostic Gynecologic and Obstetric Pathology, 3rd ed. Philadelphia, PA: W. B. Saunders Co.; 2011.
PELVIC INFLAMMATORY DISEASE*
□ Definition
Pelvic inflammatory disease (PID) refers to infection of the upper genital tract of women. It may include the endometrium, myometrium, parametrium, uterine tubes, and ovaries. Other pelvic and abdominal organs may be secondarily infected (e.g., peritonitis, perihepatitis). Primary infection of the vagina or cervix serves as the source of pelvic inflammation/infection.
PID is most commonly caused as a complication of infection with sexually transmitted or bacterial vaginosis (BV)-associated pathogens (85%). The remaining cases are caused by other gastrointestinal or respiratory tract pathogens that have colonized the vaginal tract.
Factors for increased risk for PID include risk factors associated with sexually transmitted infection (STI): age <25 years and young age at onset of sexual activity; new or multiple sex partners, especially partners with STI symptoms; unprotected sexual activity; and history of STI. Additional factors may include intrauterine device (IUD) use, douching, and BV.
□ Who Should Be Suspected?
Clinical features:
Diagnosis should be strongly considered in women presenting with abdominal pain if physical examination reveals cervical or adnexal tenderness. Patient typically present with acute onset of pelvic organ tenderness and evidence of lower genital tract inflammation. Clinical presentation depends on the primary sites and severity of infection.
▼ Pelvic organ tenderness is due to infection in any of upper genital tract organs, including the uterus, ovaries, and fallopian tubes.
▼ Signs of lower genital tract inflammation include vaginal discharge, dysuria, cervical tenderness, cervical friability, dyspareunia or postcoital bleeding, etc.
▼ Fever or other systemic symptoms are not typical.
▼ Peritonitis or upper abdominal tenderness suggests more extensive spread, like perihepatitis.
▼ Subclinical PIC may occur as a complication of lower genital infection with Neisseria gonorrhoeae or Chlamydia trachomatis.
□ Laboratory Findings
See Chapter 3 for details about specific laboratory testing.
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