The Washington Manual of Oncology, 3 Ed.

Uterine, Cervical, Vulvar, and Vaginal Cancers

Lindsay M. Kuroki • Pratibha S. Binder • David G. Mutch

 I. UTERINE NEOPLASIA

1. Premalignant disease of the endometrium
2. Background. Endometrial hyperplasia is a spectrum of proliferative disorders primarily of the endometrial glands, and to a lesser extent, the stroma. In the normal menstrual cycle, estrogen stimulation leads to growth and proliferation of the endometrium, whereas progesterone leads to predecidual changes and inhibition of endometrial proliferation. In the absence of progesterone, unopposed estrogen can lead to a spectrum of endometrial abnormalities varying from simple endometrial hyperplasia to endometrial malignancies. This often results from chronic anovulation (polycystic ovarian syndrome and perimenopause), obesity (high peripheral estrogen production), estrogen-producing ovarian neoplasms (granulosa cell tumor), exogenous estrogen administration (hormone replacement therapy), and the use of selective estrogen receptor modulators (SERMs) like tamoxifen that has estrogen-like properties on the endometrium.
3. Presentation. The majority of patients with endometrial hyperplasia remain asymptomatic and therefore these precursor lesions can go unrecognized for years. Some patients are diagnosed due to symptoms of abnormal or postmenopausal bleeding. Other patients may be diagnosed due to incidental abnormal findings on an ultrasound ordered for other reasons or abnormal endometrial cells noted on Papanicolaou (Pap) test. Normal menstrual cycles occur every 28 days (range 21 to 35 days) with a normal duration of 2 to 7 days and an average blood loss of less than 80 mL. Bleeding outside of these ranges or any postmenopausal bleeding should be evaluated. Any age group can be affected, but one should be especially concerned with abnormal bleeding in patients aged 35 years and older. Obesity, a history of anovulatory cycles, use of tamoxifen, and use of exogenous estrogens without concurrent progestational agents are known risk factors.
4. Workup and staging. Typically, the diagnosis can be made with an office endometrial (pipelle) biopsy. If this is nondiagnostic or technically not feasible, a dilation and curettage (D&C), with or without hysteroscopy can be performed to obtain more tissue for accurate histologic diagnosis. The International Society of Gynecological Pathologists classifies endometrial hyperplasia into four distinct categories based on a 1994 classification system looking at architectural structure and cytologic features: simple and complex hyperplasia, both with and without atypia.
5. Therapy and prognosis
6. Simple or complex hyperplasia without atypia. Treatment is usually conservative and depends on the fertility desires of the patient. The risk of developing malignancy over a 13- to 15-year untreated period is 1% for simple and 3% for complex hyperplasia (Table 24-1).

 i. Patients desiring pregnancy. Treatment consists of inducing withdrawal bleed followed by ovulation induction with clomiphene citrate. Withdrawal bleed can be achieved with medroxyprogesterone acetate (Provera), 10 mg PO per day for 5 to 10 days (after a negative pregnancy test) followed by ovulation induction with clomiphene citrate, 50 mg PO on day 5 of bleeding to continue for a total of 5 days. If patient does not menstruate within a month, this cycle of treatment can be repeated with higher doses of clomiphene citrate after pregnancy test is negative.

 ii. Patients not considering pregnancy. Management usually consists of oral, intramuscular, or intrauterine progestins followed by repeat biopsy after 3 to 6 months. Accepted regimens include medroxyprogesterone 10 mg PO for 7 to 13 days/month, depot medroxyprogesterone 150 mg IM every month, oral contraceptive pills, and levonorgestrel intrauterine device (IUD). Regression of hyperplasia occurs in up to 92% of patients treated with levonorgestrel IUD.

TABLE 24-1

Comparison of Follow-up of Patients with Simple and Complex Hyperplasia and Simple and Complex Atypical Hyperplasia (170 Patients)

1. Simple or complex hyperplasia with atypia. Twenty-three percent of untreated atypical hyperplasia progress to endometrial cancer (8% for simple atypical and 29% for complex atypical hyperplasia) over 11 years. More importantly, there is a 13% to 43% rate of concurrent endometrial cancer with atypical hyperplasia. In a Gynecologic Oncology Group (GOG 167) prospective cohort study of women with atypical endometrial hyperplasia, the rate of concurrent endometrial cancer was 43% for analyzed specimens, with 31% of these demonstrating myometrial invasion, and 11% invading the outer 50% of the myometrium (Cancer2006;106:812). Due to these findings, patients with atypical hyperplasia should undergo D&C with or without hysteroscopy to rule out the presence of invasive cancer in the unsampled endometrium.

 i. Patients desiring pregnancy. Progestational agents including megestrol acetate 80 to 160 mg/day and levonorgestrel IUD have been used for treatment. The goal of therapy is complete regression of disease and reversion to normal endometrium followed by ovulation induction or assisted reproductive techniques for pregnancy. Repeat sampling with biopsy or D&C is recommended after 3 months of therapy.

 ii. Patients not considering pregnancy. Medical treatment: Regression is up to 90% with progestational agents including oral medroxyprogesterone (40 mg PO per day) and megestrol acetate (160 to 320 mg PO per day in divided doses) as well as levonorgestrel IUD (Obstetric Gynecol 2012;120:1160). Repeat biopsy or D&C to check for persistence or progression is recommended every 3 to 6 months till regression.Surgical treatment: Extrafascial hysterectomy with gross inspection and frozen section of the endometrium for evidence of endometrial cancer.

5. Complications are rare and minor, usually related to surgical complications of D&C including risk of anesthesia, infection, hemorrhage, and uterine perforation. An underlying concern is inappropriate surgical management due to misdiagnosed cancer.
6. Follow-up. Medically managed patients should be resampled at regular intervals (3 to 12 months) until regression of endometrial pathology. Those with normal histology can then either be taken off therapy or be cycled with progestational agents and should undergo periodic endometrial sampling. Follow-up interval for patients after hysterectomy is not well-established, but annual examinations should be adequate.
7. Current focus. The current focus is on determining molecular markers that predict progression to endometrial cancer and important prognostic factors in fertility-sparing medical management.
8. Endometrial cancer
9. Background. Endometrial cancer is the most common gynecologic malignancy in the United States with a rising incidence over the last 5 years. There were approximately 49,560 new cases and 8,190 deaths due to endometrial cancer in 2013 (CA Cancer J Clin 2013;63:11). Five-year survival for localized disease is 96%, whereas relative survival for all stages is approximately 82%. There are two morphologically and molecularly distinct histologic subtypes: type I and type II. Risk factors for type I endometrial cancer include unopposed exogenous estrogenic stimulation (estrogens or tamoxifen), chronic anovulation, obesity, diabetes mellitus, nulliparity, and late age of menopause (older than 52 years). Type II histology tends to be more sporadic and is not associated with clinical and physical factors mentioned above.
10. Presentation. More than 90% of patients are first seen with abnormal uterine bleeding. Patients with any postmenopausal bleeding or discharge deserve evaluation. Patients with abnormal pre- or perimenopausal bleeding, especially those with history of anovulatory cycles, older than 35 years, or morbidly obese warrant evaluation as well. Pap tests with atypical glandular cells of undetermined significance (AGUS) in patients of any age should be evaluated with a colposcopy, endocervical curettage, and endometrial biopsy. Pap test with endometrial cells on a postmenopausal patient should also be evaluated.

TABLE 24-2

FIGO Surgical Staging and Grade of Endometrial Cancer, 2009

Stage	Description
IA	Tumor limited to uterus, no or less than half myometrial invasion
IB	Tumor limited to uterus, equal to or more than half myometrial invasion
II	Cervical stromal invasion
IIIA	Uterine serosal and/or adnexal involvement
IIIB	Vaginal metastasis and/or parametrial involvement
IIIC1	Positive pelvic lymph nodes
IIIC2	Positive para-aortic lymph nodes (with or without pelvic nodes)
IVA	Bladder and/or bowel/rectal mucosal invasion
IVB	Distant metastases including intra-abdominal and/or inguinal lymph nodes
Grade	Description
1	Less than 5% of tumor is solid sheets of undifferentiated neoplastic cells
2	6%–50% of tumor is solid sheets of undifferentiated neoplastic cells
3	>50% of tumor is solid sheets of undifferentiated neoplastic cells

Cytology is mentioned separately and does not change stage.

FIGO, International Federation of Gynecology and Obstetrics.

3. Workup and staging. An office endometrial biopsy (pipelle) is an extremely sensitive method of obtaining a tissue diagnosis. A meta-analysis of 39 studies involving 7,914 women demonstrated a detection rate for endometrial cancer of 91% and 99.6% in pre- and postmenopausal women, respectively (Cancer 2000;89:1765). Patients with a nondiagnostic office biopsy, persistent bleeding abnormality despite a normal office biopsy, or those unable to undergo an office biopsy should undergo a fractional D&C, with or without hysteroscopy. All patients should be screened for other malignancies as appropriate for age and family history (Pap test, ultrasound, mammogram, and colorectal cancer screening). Cystoscopy, proctoscopy, and radiologic imaging may be necessary, as clinically indicated, if advanced stage is suspected. Surgical staging of endometrial carcinoma was adopted by the International Federation of Gynecologists and Obstetricians (FIGO) in 1988 and then revised in 2009 (Table 24-2). All patients who are medically able should first undergo surgical exploration with appropriate staging. Extrafascial hysterectomy with bilateral salpingo-oophorectomy, collection of peritoneal cytology, pelvic and para-aortic lymph node dissection, and biopsy of any suspicious areas are necessary for staging, except in small well-differentiated tumors without myometrial invasion. Omentectomy or omental biopsy is also indicated for high grade tumors and type II histology.
4. Therapy and prognosis. The first step of treatment is hysterectomy and surgical staging (abdominal, laparoscopic, or robotic). Total laparoscopic staging is being performed with increasing frequency for suspected early-stage endometrial cancer, and lymph node count and survival appear similar when compared to laparotomy. Hysterectomy removes primary tumor and intraoperative findings like size of tumor, myometrial invasion, and grade can help estimate risk or lymph node involvement and need for adjuvant therapy. Removal of adnexa is important due to the risk of metastasis to the ovary, synchronous ovarian cancers, and risk of future recurrence or primary cancer in the ovary. Lymphadenectomy is somewhat more controversial. Lymph node status is prognostically important and is essential in the decision of postoperative adjuvant therapy. But since there are rare but substantial risks and complications associated with the procedure, the benefit of lymphadenectomy is controversial in patients with low risk of positive nodes, high risk of morbid complication, and in patients that will receive adjuvant therapy due to other findings. Historically, radiation therapy (RT) had been the preferred choice of adjuvant therapy for patients with high risk of recurrence. However, the role of chemotherapy in all stages of endometrial cancer is evolving. While low risk stage I disease can be treated with surgery alone, adjuvant treatment for other stages is variable and includes vaginal brachytherapy (VB), external beam pelvic radiation therapy (EBRT), and chemotherapy (Table 24-3).

TABLE 24-3

Treatment of Endometrial Cancer

Condition	Possible adjuvant therapies to consider
Stage IA or IB and grade 1 or 2	No further therapy or vaginal brachytherapy
Stage I and II with HIR	Vaginal brachytherapy vs. pelvic RT
	Vaginal brachytherapy with chemotherapy (currently under investigation, GOG 249)
Stage IIIA (serosal and/or adnexal involvement)	Systemic chemotherapy vs. Pelvic RT and VB or combination
Stage IIIB (vaginal involvement)	Systemic chemotherapy vs. Pelvic RT and VB or combination
Stage IIIC (microscopic nodal involvement)	Systemic chemotherapy vs. Pelvic RT with extended-field radiation to para-aortic region (if indicated) and systemic chemotherapy
Stage IIIC (macroscopic nodal), stage IV, and recurrent disease (extrapelvic)	Palliative RT vs. systemic chemotherapy vs. hormonal therapy vs. targeted therapies or combinations
Recurrent disease (pelvic)	Radiotherapy in the patient without earlier RT vs. possible surgical resection (exenteration) vs. chemotherapy or combinations
High intermediate risk	Risk factors:
Any age with three risk factors	1. Moderately to poorly differentiated tumor
Age>50 with two risk factors	2. Lymph vascular space invasion
Age>70 with one risk factor	3. Outer ⅓ myometrial invasion

RT, radiation therapy; VB, vaginal cuff brachytherapy; HIR, high–intermediate risk.

1. Early stage. Results from GOG 33 and GOG 99 helped define a high intermediate risk (HIR) category for patients with Stage I or II disease with a higher risk of recurrence (Gynecol Oncol 2004;92:744). GOG 99 and PORTEC-1 showed that EBRT compared to no adjuvant treatment decreased local recurrence in patients with HIR stage I or II disease, but survival benefit was not significant. PORTEC-2 compared EBRT to VB and showed both were comparable in local recurrence rate. Therefore, adjuvant radiation treatment is recommended based on HIR criteria and patient desires of further treatment to decrease risk of recurrence or treatment when recurrence occurs. The pooled data from two randomized controlled trials showed a significant decrease in progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) for HIR stage I and II patients treated with combination chemotherapy and pelvic RT compared to pelvic RT alone. Currently there are two randomized trials comparing concurrent chemoradiation followed by adjuvant chemotherapy (PORTEC-3) or VB followed by chemotherapy (GOG 249) to pelvic RT alone in the treatment of HIR early-stage endometrial cancer.
2. Advanced stage. Cytotoxic chemotherapy for advanced stage endometrial cancer includes the following agents (response rate): cisplatin (20% to 35%), carboplatin (30%), doxorubicin (Adriamycin; 20% to 35%), epirubicin (25%) and paclitaxel. The combination of doxorubicin (60 mg/m²) plus cisplatin (50 mg/m²) every 3 weeks showed an improved response rate of 42%, progression-free interval of 6 months, and median OS of 9 months in a randomized trial by the GOG (J Clin Oncol 2004;22:3902). Combination of doxorubicin (60 mg/m² × 7 cycles) and cisplatin (50 mg/m² × 8 cycles) (AC) was superior to whole abdominal radiation (WAI, 30 Gy in 20 fractions with a 15-Gy boost) in a phase III trial of 202 randomized patients with stage III/IV endometrial cancer optimally debulked to ≤2 cm of residual disease with PFS of 50% versus 38% and OS 55% versus 42%, respectively (J Clin Oncol 2006;24:36). In 2004, a GOG trial demonstrated improved survival in patients with advanced or recurrent endometrial cancer treated with TAP (paclitaxel, doxorubicin, cisplatin) as compared to cisplatin and doxorubicin alone, although with increased toxicity (J Clin Oncol 2004;22:2159). A phase III trial comparing TAP and PT (carboplatin/paclitaxel) is currently underway and preliminary results show that PT is non-inferior to TAP and has a more favorable toxicity profile. In GOG 184, patients with stage III/IV endometrial cancer were treated with pelvic RT followed by AC versus TAP. There was no patient outcome benefit by adding paclitaxel but the study showed that combination radiation and chemotherapy was a feasible treatment option with acceptable toxicity.

 Treatment with chemotherapy, RT, and/or hormone therapy is acceptable in patients where surgical staging and debulking is not a medically feasible option. Hormone therapy is also often used for patients with advanced/recurrent disease who test positive for estrogen and progesterone receptors. Response rate with either medroxyprogesterone acetate, 200 mg daily, or megestrol acetate, 160 mg daily, is approximately 20%.

5. Complications. Complications of staging surgery include pain, hemorrhage, infection, and damage to surrounding structure including bowel, bladder, and blood vessels. Lymphocysts and lymphedema of the lower extremities are rare complications of lymphadenectomy. Immediate toxicities from chemotherapy include hematologic, GI, and infectious complications. Immediate and late effects of radiation are usually related to bowel and bladder dysfunction. Concurrent treatment with chemotherapy and radiation therapy is currently under investigation, and the toxicities of combination treatment remain a major concern.
6. Follow-up. Typically patients are evaluated with physical examination, Pap test, and pelvic examination every 3 months for the first year, every 3 to 4 months for the second year, every 6 months for third to fifth year, and then at 6 to 12 month intervals thereafter.
7. Current focus. Current efforts are directed toward elucidating molecular markers that are prognostic and important in understanding endometrial cancer tumorigenesis New advances focused on the etiologic heterogeneity and defects in molecular pathways has lead to better histologic classification and the identification of potential therapies targeting defects in these pathways. Therapies targeting aberrations P13K/AKT/mTOR pathways, tyrosine kinase pathways, and angiogenesis are being studied in preclinical and phase II trials. While single-agent treatment with these drugs have not shown promising results, combination treatment with currently used chemotherapy regimens are being evaluated. Improved prognosis in endometrial cancer patients being treated with metformin has been observed in retrospective studies. Research to identify the pathways associating metformin use with improved endometrial cancer prognosis is underway.
8. Sarcomas
9. Background. These are uncommon tumors arising from the mesenchymal components of the uterus and comprise of 3% to 8% of uterine tumors. The GOG has broadly classified them based on histology: (1) Non-epithelial neoplasms including endometrial stromal sarcoma (ESS), leiomyosarcoma (LMS), and smooth muscle tumor of uncertain malignant potential (STUMP) and (2) Mixed epithelial–nonepithelial tumors including adenosarcoma and carcinosarcoma. Homologous types contain sarcomatous components that are unique to uterine tissue, whereas heterologous types produce stromal components that are not native to the uterus.

TABLE 24-4

FIGO Surgical Staging of Uterine Sarcomas, 2009

Stage	Description
LMS
IA	Tumor limited to the uterus, <5cm
IB	Tumor limited to the uterus, >5cm
IIA	Adnexal involvement
IIB	Tumor extends to extra-uterine pelvic tissue
IIIA	Tumor invades abdominal tissue, one site
IIIB	Tumor invades abdominal tissue, > one site
IIIC	Metastasis to pelvic and/or para-aortic lymph nodes
IVA	Tumor invades bladder and/or bowel mucosa
IVB	Distant metastases
Endometrial stromal sarcoma/adenosarcoma
IA	Tumor limited to endometrium/endocervix, no myometrial invasion
IB	Less than or equal to half myometrial invasion
IC	More than half myometrial invasion
IIA	Adnexal involvement
IIB	Tumor extends to extra-uterine pelvic tissue
IIIA	Tumor invades abdominal tissue, one site
IIIB	Tumor invades abdominal tissue, > one site
IIIC	Metastasis to pelvic and/or para-aortic lymph nodes
IVA	Tumor invades bladder and/or bowel mucosa
IVB	Distant metastases

FIGO, International Federation of Gynecology and Obstetrics.

2. Presentation varies depending on type of tumor. Carcinosarcomas usually present with postmenopausal bleeding, while ESS and LMS can present as abnormal bleeding, rapidly enlarging pelvic pain or pelvic pressure and pain. Uterine sarcomas are often incidental diagnoses on hysterectomy specimens, and reoperation for complete surgical staging is usually not recommended.
3. Workup and staging. Workup is similar to endometrial cancer and involves endometrial biopsy or core biopsy of any masses protruding through the cervix. Pelvic imaging can be performed to delineate the size and origin of protruding masses. Staging for LMS and ESS is summarized in Table 24-4, As more is discovered about the biology and activity of these rare cancers, uterine carcinosarcomas may be considered more closely related to poorly differentiated endometrial carcinomas, and therefore they are staged using the 2009 FIGO staging for endometrial cancer (Table 24-2). Patients should be treated primarily with surgical exploration with appropriate staging, as primary radiotherapy and chemotherapy have very disappointing results.
4. Therapy and prognosis. Although each histologic subtype of sarcoma behaves differently, in general, survival is poor, with more than half the number of patients dying of their disease. For stage I and II disease, adjuvant RT often improves local recurrences but has little impact on long-term survival. Cytotoxic chemotherapy may have a role in the adjuvant setting. Hormonal therapy with high dose progestin therapy (megestrol acetate, 240 to 360 mg p.o. daily) has shown activity against endometrial stromal sarcomas, especially those that are low grade. Advanced stage (III/IV) and recurrent disease have been treated with radiotherapy with minimal success. Chemotherapy is most often used in this setting since phase II trials have shown tolerable toxicities and improved response compared to historical data. Single agent doxorubicin (60 mg/m² IV q3 weeks) or ifosfamide (1.2 to 1.5 g/m² IV q.d. × 4 to 5 days) have shown activity against LMS with approximate response rates of 25% and 20%, respectively. Combination gemcitabine (900 mg/m²IV on day 1 and 8, q3 weeks) and docetaxel (75 mg/m² IV q3 weeks) showed favorable response rates for completely resected stage I–IV disease as well as advanced and recurrent disease (Gynecol Oncol2009;112:563). For carcinosarcomas, ifosfamide plus MESNA, with or without cisplatin, showed response rates of 30% to 50% in patients with advanced, persistent, or recurrent disease (Gynecol Oncol2000;79:147). The combination therapy produced higher response rates but greater toxicity and no survival advantage over single-agent ifosfamide (GOG117). This combination chemotherapy regimen had similar patient outcomes as WAI for stage I–IV disease in a phase III GOG trial (GOG 150). Survival in advanced disease patients was improved by the addition of paclitaxel (135 mg/m² IV q3 weeks up to 8 cycles to ifosfamide). A phase II trial also showed acceptable response rates with paclitaxel and carboplatin in the treatment of carcinosarcoma patients with advanced disease (J Clin Oncol 2010;28:2727). Surgical resection of recurrent sarcoma and chemotherapy has shown to be beneficial in other soft tissue sarcomas, and may provide a survival advantage in uterine sarcomas as well.
5. Current focus. Recent chemotherapy trials for advanced or recurrent LMS have included doxorubicin, 40 mg/m², mitomycin, 8 mg/m², and cisplatin, 60 mg/m² q3 weeks; liposomal doxorubicin (Doxil), 50 mg/m²IV q4 weeks; and paclitaxel, 175 mg/m² i.v. over a 3-hour period q3 weeks. Further studies are underway to establish the use of paclitaxel and carboplatin in the treatment of advanced carcinosarcoma. Determining risk factors, prognostic factors, and the tumorigenesis for uterine sarcomas is also a focus for current research.
6. Gestational trophoblastic disease (GTD)
7. Background. Abnormal growth of the human trophoblast is called GTD. GTD encompasses a spectrum of abnormalities of trophoblastic tissue including classic (complete) hydatidiform moles, partial hydatidiform moles, invasive hydatidiform moles, choriocarcinoma, and placental site trophoblastic tumors. The most common abnormality, the hydatidiform mole, has two pathologic varieties—complete and partial mole. Complete moles are the most common subtype of GTD and typically occur as a result of dispermy, with both chromosomes paternal in origin resulting from fertilization of an empty ovum (46,XX). Partial moles are the result of fertilization of a normal egg by two sperms (69,XXY), resulting in an abnormal pregnancy with fetal parts usually identifiable. The reported incidence of mole varies widely throughout the world, with 1:1,500 pregnancies affected in the United States. Invasive mole is a pathologic diagnosis of a benign tumor that invades the uterine myometrium or on occasion metastasizes. The incidence is estimated at 1:15,000 pregnancies. Choriocarcinoma is a malignant tumor that has a propensity for early metastasis and an aggressive course, arising in 1:40,000 pregnancies. Fifty percent of choriocarcinomas develop after a molar gestation, 25% after a term pregnancy, and 25% after an abortion or an ectopic pregnancy. Placental-site trophoblastic tumor is the rarest variant, arising from the intermediate trophoblast, and is relatively chemotherapy resistant. The tumors often secrete human placental lactogen (HPL), which can be used as a tumor marker. GTD is more common in extremes of reproductive age (teenagers and women, aged 40 to 50 years).
8. Presentation. Most cases of malignant/persistent GTD are seen after a hydatidiform mole. Hydatidiform moles usually present with vaginal bleeding and a positive pregnancy test. Nearly all hydatidiform moles are now diagnosed by ultrasound examination, demonstrating the “snowstorm” appearance of the vesicle-filled intrauterine cavity. Occasionally, patients will have symptoms of preeclampsia, hyperthyroidism, and/or severe hyperemesis. Physical examination demonstrates uterine size larger than estimated gestational dates, bilateral ovarian enlargement (due to thecal lutein cysts), and usually an absence of fetal heart sounds or fetal parts. GTD can also occur after a normal pregnancy, abortion (spontaneous or induced), or ectopic pregnancy, and the diagnosis is often easily missed in these patients. Presentation is the same in these patients, although the delay in diagnosis may lead to widely metastatic disease.
9. Workup and staging. After diagnosis of a molar pregnancy (usually by ultrasound), the patient should undergo chest radiograph (CXR; if positive, a metastatic workup should follow; see later), blood type and cross-matching, and serum quantitative β-human chorionic gonadotropin (HCG) evaluation. Mainstay of treatment is an ultrasound-guided suction D&C followed by sharp curettage. Intravenous oxytocin, 20 to 40 units/L or other uterotonic agents should be used shortly after the beginning of the procedure and continued for several hours to avoid excessive bleeding. Patients with Rh-negative blood should receive Rh immune globulin (RhoGAM), as indicated to prevent isoimmunization in future pregnancies. Patients are followed up after surgery with quantitative pregnancy tests (β-HCG) weekly until normal and then monthly for 1 year. Eighty percent of moles will resolve with D&C alone. Persistent gestational trophoblastic neoplasia (GTN) is diagnosed with any of the following conditions (note that histologic verification is not required): (a) after evacuation of a hydatidiform mole, the HCG level does not decrease appropriately (plateau or two consecutive weeks with an increasing titer), (b) metastatic disease is discovered, or (c) pathologic diagnosis of choriocarcinoma or placental-site trophoblastic tumor. Once the diagnosis of persistent GTN is made, a further metastatic workup should include a complete history and physical examination and computed tomography (CT) of the chest, abdomen, pelvis, and possibly head, if indicated. A pelvic ultrasound should also be performed to rule out an early pregnancy in patients with inadequate contraception. Complete blood count (CBC) and metabolic panel (hepatic and renal) are also indicated. An anatomic staging system (FIGO, 1992) does exist but is seldom clinically used. Prognosis and subsequent therapy are usually based on the World Health Organization (WHO) scoring system or the National Institutes of Health (NIH) system used by most U.S. trophoblastic disease centers (Table 24-5).
10. Therapy and prognosis. Therapy is directed by the NIH class or the WHO score. Prognosis is generally excellent, and the key is to limit toxicity of the therapy as much as possible. Therapy should be started immediately, as delays can be devastating. The primary therapy of malignant GTD is chemotherapy. Surgery is used to decrease the amount of chemotherapy required for remission or to remove resistant foci of disease. Treatment of nonmetastatic GTN includes hysterectomy for those no longer desiring fertility and for all with placental site trophoblastic tumors. Chemotherapy is recommended for all patients, even if hysterectomy is performed, and is usually given as a single agent. Table 24-6 summarizes the chemotherapeutic regimens used to treat GTN. Low risk metastatic GTN is treated primarily with single-agent chemotherapy; both methotrexate and actinomycin D should be used individually before resorting to multi-agent chemotherapy. Single-agent actinomycin D IV q 14 days was found to have superior complete response rates than methotrexate IM weekly (GOG 174); however, all patients were eventually cured after switching to alternative single-agent or multi-agent regimens (J Clin Oncol 2011;29(7):825) High risk metastatic disease is treated with multi-agent chemotherapy with the addition of radiation if a brain metastasis is present and surgery to remove resistant foci in the uterus or chest, as needed. All patients receiving chemotherapy should be evaluated with appropriate laboratory studies (CBC, hepatic, and/or renal panel) for the specific regimens plus a serum rrrrrrrr-HCG every cycle. Treatment should continue until three consecutive normal HCG levels are obtained. At least two courses should be given after the first normal HCG.

TABLE 24-5

Prognostic Classification of Gestational Trophoblastic Neoplasia

1. Nonmetastatic disease

 II. Metastatic disease

 A. Low risk/good prognosis GTN

 1. Short duration since last pregnancy event (<4 mo)

 2. Low pretreatment HCG (<40,000 mIU/mL serum)

 3. No brain or liver metastasis

 4. No prior chemotherapy

 5. Pregnancy event is not a term delivery

 B. High risk/poor prognosis GTN

 1. Long duration since last pregnancy event (>4 mo)

 2. High pretreatment HCG (>40,000 mIU/mL serum)

 3. Brain or liver metastasis

 4. Prior chemotherapy failure

 5. Antecedent term pregnancy

NIH, National Institutes of Health; HCG, human chorionic gonadotropin.

TABLE 24-6

Chemotherapeutic Regimens for Persistent GTN

Nonmetastatic and low risk metastatic GTN

Methotrexate, 30–50 mg/m² IM q wk (preferred method)

Methotrexate, 0.4 mg/kg IV/IM qd × 5 days, repeat every 2 weeks

Methotrexate, 1–1.5 mg/kg IM days (1, 3, 5, 7) + folinic acid, 0.1–0.15 mg/kg IM days (2, 4, 6, 8), repeat every 15–18 days

Actinomycin D, 10–13 μg/kg IV/day × 5 days, repeat every 14 days

Actinomycin D, 1.25 mg/m² IV q14 days (superior to weekly methotrexate in GOG 174)

Etoposide, 200 mg/m²/day PO × 5 days q14 days

High risk metastatic GTN: EMA-CO regimen

EMA-CO regimen

Day 1, etoposide, 100 mg/m² IV (over 30 min); actinomycin D, 0.35 mg IV push; methotrexate 100 mg/m² IV push, then 200 mg/m² IV infusion over 12 h

Day 2, etoposide, 100 mg/m² IV over 30 min; actinomycin D, 0.35-mg IV push; folinic acid, 15 mg PO, IM or IV q12 h × 4 doses

Day 8, vincristine, 1 mg/m² IV plus cyclophosphamide, 600 mg/m² IV

Repeat entire cycle every 2 weeks. Patients with CNS metastasis should also receive radiation therapy and intrathecal methotrexate (12.5 mg on day 8) (Gynecol Oncol 1989;31:439).

Triple Agent (MAC) regimen

Day 1–5, methotrexate, 15 mg IM; actinomycin D 0.5 mg IV; cyclophosphamide 3 mg/kg IV

Repeat cycle every 15 days.

CNS, central nervous system.

5. Complications. Complications are related mainly to the specific chemotherapeutic regimen used. Single-agent therapy is normally well-tolerated with minimal side effects. Any suspicious metastatic sites should not be biopsied due to risk of hemorrhage.
6. Follow-up. Patients should be monitored with serum HCG monthly for 1 year. Contraception is needed for a minimum of 6 months, but 12 months is preferred. If pregnancy should develop, an early ultrasound should be performed to document an intrauterine pregnancy.
7. Current focus. Chemotherapy for low-risk GTN is currently being studied by the GOG 275 in a randomized manner with multiday methotrexate regimen versus pulsed dactinomycin (1.25 mg/m² IV push q14 days). The predictive value of modeled HCG residual production is also being validated in patients treated in GOG 174.
8. UTERINE CERVIX NEOPLASIA
9. Preinvasive lesions of the cervix
10. Background. More than 2.5 million women in the United States have Pap test abnormalities with more than 200,000 new cases of dysplasia diagnosed annually. Human Papilloma Virus (HPV) has been detected in more than 90% of preinvasive and invasive carcinomas, and there is strong evidence that HPV is the etiologic factor in the vast majority of dysplasias and cervical cancers. HPV subtypes 16, 18, 45, and 56 are considered high risk (HR HPV); 31, 33, 35, 51, 52, and 58 are of intermediate risk; and 6, 11, 42, 43, and 44 are of low risk for progression to cancer. Other risk factors for the development of cervical dysplasia include smoking, multiple sexual partners, low socioeconomic status, young age at coitarche, presence of HR HPV, or immunodeficiency.
11. Presentation. Preinvasive lesions of the cervix are often asymptomatic, but can reliably be detected with cytology or biopsy. Median age is approximately 28 years and risk factors are often present.
12. Screening. The goal of screening programs is to identify women with preinvasive disease and manage them appropriately so as to decrease the incidence and mortality rate from cervical cancer. It is estimated that approximately 4 million women per year will have an abnormal Pap result in the United States. Communities that implement cervical cancer screening programs reduce deaths from cervix cancer by approximately 90%, making it one of the most successful cancer screening programs. Unfortunately, most women in whom cervical cancer develops have not been adequately screened. The American Cancer Society and the American College of Obstetrics and Gynecology recommend that annual cervical cytology screening (Pap test) and pelvic examination be initiated at age 21 regardless of onset of sexual activity. Exceptions to this are women with a history of cervical intraepithelial neoplasia (CIN) 2 or greater, diethylstilbestrol (DES) exposure, or who are immunocompromised. In 2012, the American Society for Colposcopy and Cervical Pathology (ASCCP) together with its partner organizations revised the consensus guidelines to reflect improved understanding of: (1) the natural history of HPV infection and cervical cancer precursors; and (2) future pregnancy implications of treatment for CIN among younger women. On the basis of these new guidelines, women aged 21 to 29 years should undergo Pap screening every 3 years. Because of the high prevalence of HPV in this age group, HPV testing should not be used for either co-testing or as a stand-alone test due to potential harm (e.g., psychosocial impact, discomfort from additional diagnostic/therapeutic procedures, and even longer term increased risk of pregnancy complications due to excision procedures). The preferred recommendation for women aged 30 to 64 years is cytology with HPV co-testing every 5 years. Alternatively, cytology alone every 3 years is acceptable.
13. Terminology. In 1988, the Bethesda system for the reporting of cervicovaginal cytologic results was developed in an effort to simplify and bring uniformity to the reporting of cytology results. This was revised in 1991 and 2001 for clearer terminology and larger application. Specimens are now specifically described in regard to specimen adequacy (“satisfactory” or “unsatisfactory”), presence of the transformation zone (“present” or “absent”), and evaluation of epithelial cell histology (“negative for intraepithelial lesion or malignancy” or abnormal) (Table 24-7). More recently in 2012, the Lower Anogenital Squamous Terminology (LAST) project incorporated changes in their classification terminology to reflect HPV-associated squamous lesions of the anogenital tract. Specifically, CIN2 is stratified based on p16 immunostaining—specimens that are p16-negative are referred to as low grade squamous intraepithelial lesions (LSILs) and those that are p16-positive are considered high grade squamous intraepithelial lesions (HSILs).
14. Workup. Colposcopy is performed in specific circumstances for further evaluation of an abnormal Pap result. It is performed with a colposcope that allows magnification of the cervix, which is treated with a 4% acetic acid solution. Colposcopic characteristics of dysplasia include acetowhite changes, punctuations, and abnormal vascularity (mosaicism). Biopsies are performed of abnormal areas, and a histologic diagnosis is made (normal, inflammation, or CIN 1, 2, or 3). Endocervical curettage (ECC) is part of most routine colposcopic examinations, especially those with high grade cytologic abnormalities or if no ectocervical abnormalities are appreciated on colposcopy. The following is a highly simplified approach to managing the abnormal Pap test based on ASCCP guidelines and will not apply to all situations. For atypical squamous cells of undetermined significance (ASCUS), HR HPV DNA testing is at least 80% effective in detecting CIN 2 or 3 and therefore HPV testing is commonly performed. Patients aged 25 and older with ASCUS who are HR HPV–positive should undergo colposcopy, whereas ASCUS HR HPV-negative patients may undergo screening again in 1 year. If the result is ASCUS or worse, colposcopy is recommended; if the result is negative, cytology testing at 3-year intervals is recommended. Atypical squamous cells that cannot exclude HSIL (ASC-H) represent approximately 15% of ASCUS Pap results with a much higher predictive value for detecting CIN 2 to 3. These patients as well as those with LGSIL and HGSIL cytology results need colposcopic examination. However, HR HPV testing is not indicated for ASC-H, LGSIL, and HGSIL cytology since the test is almost always positive and management decisions are not affected (i.e., colposcopy is needed for these groups regardless of HPV results). “Screen and treat” protocols are often implemented if there is a concern for noncompliance with follow-up and is acceptable for women with HSIL cytology. For women with all subcategories of AGC and AIS except atypical endometrial cells, colposcopy with ECC is recommended regardless of HPV result. Endometrial sampling should be performed in conjunction with colposcopy and ECC in women 35 years of age and older because they may be at risk for endometrial hyperplasia/carcinoma. Women with AGC not otherwise specified in whom CIN2+ is not identified, co-testing at 12 and 24 months is recommended. For women with AGC “favor neoplasia” or endocervical AIS cytology, if invasive disease is not identified during colposcopic workup, an excisional procedure is recommended. In addition to these diagnoses, a diagnostic cervical conization may also be necessary in the following situations: (1) inadequate colposcopy, (2) ECC results are positive for CIN3, (3) there is a high grade lesion on Pap test not accounted for by colposcopy, or (4) a biopsy suggesting microinvasion. Cervical conizations are also sometimes therapeutic procedures depending on the extent of dysplasia or histologic abnormality.

TABLE 24-7

Bethesda System of Categorizing Epithelial Cell Abnormalities, 2001

Squamous cell

Atypical squamous cells (ASC)

 Of undetermined significance (ASCUS)

 Cannot exclude high grade squamous intraepithelial lesions (ASC-H)

Low grade squamous intraepithelial lesions (LGSIL)

 Encompassing moderate and severe dysplasia, carcinoma in situ, CIN 2, and CIN 3

 Squamous cell carcinoma

High grade squamous intraepithelial lesions (HGSIL)

 Encompassing moderate and severe dysplasia, carcinoma in situ, CIN 2, and CIN 3

 Squamous cell carcinoma

Glandular cell

 Atypical glandular cells (AGS)

(Specify endocervical, endometrial, or not otherwise specified)

 Endocervical adenocarcinoma in situ (AIS)

 Adenocarcinoma

CIN, cervical intraepithelial neoplasia.

6. Therapy and prognosis. Treatment of CIN is dependent on biopsy results. However, choice of therapy should take into consideration the patient’s age, desire for subsequent fertility, and physician experience. No therapy is 100% effective and the risk and benefits should be thoroughly discussed. For CIN 1 preceded by ASCUS or LGSIL cytology, HPV 16/18 and persistent HPV can safely be monitored with co-testing at 12 months. If both the HPV test and cytology are negative, then age-appropriate retesting 3 years later is recommended. After two consecutive negative Pap tests, routine screening guidelines may be resumed. More than 60% of these abnormalities will spontaneously resolve. Repeated colposcopy should be performed if high grade lesions (≥ ASC or HPV-positive) are present on Pap test. CIN2 remains the consensus threshold for treatment in the United States except in special circumstances (i.e., young women aged 21 to 24 with a histologic diagnosis of CIN2,3 not otherwise specified, and pregnant women, etc.). Treatment options (and their respective failure rates) for CIN include: electrocautery (2.7%), cryosurgery (8.7%), laser (5.6%), cold coagulation (6.8%), loop electrosurgical excisional procedure (LEEP) (4.3%), “cold” knife conization (CKC) (4%), and hysterectomy. LEEPs have gained widespread acceptance and use due to the fact that they are well-tolerated outpatient procedures that have diagnostic and therapeutic effects. For CIN2 lesions, it appears that 40% to 58% will regress if left untreated, while 22% progress to CIN3, and 5% progress to invasive cancer. The estimated spontaneous regression rate for CIN3 is 32% to 47%, with up to 40% progressing to invasive cancer if untreated. Management of AIS, however, remains controversial as many assumptions used to justify conservative management for CIN2 and 3 do not apply. For example, determination of depth of invasion is more obscure due to the extension of AIS into the endocervical canal. Furthermore, AIS can be multifocal and discontinuous. Therefore, negative margins on a specimen do not provide assurance of complete resection. Therefore, total hysterectomy remains the treatment of choice in women who have completed childbearing. Alternatively, women who desire fertility should be counseled that observation is an option, although it carries a less than 10% risk of persistent AIS. Should a patient forego conservative management, if the margins of the specimen are positive or ECC at time of excision contains CIN or AIS, re-excision is preferred.
7. Complications. Complications following an excisional procedure occur in about 1% to 2% of patients. Acute complications include bleeding, infection of the cervix or uterus, anesthesia risk, and injury to surrounding organs such as vaginal sidewall, bladder, and bowel. However, given that the majority of patients are of childbearing age, the more concerning issues to patients are long-term complications related to the integrity of the cervix and its impact on future pregnancy outcomes. Cervical stenosis after a LEEP has been reported between 4.3% and 7.7%. Not only does this impair complete examination of the transformation zone of the cervix, but it also occludes access to the uterine cavity leading to a hematometra or pyometra. In pregnancy, cervical scarring/stenosis may also inhibit the cervix from dilating normally during labor. Other obstetric complications following a LEEP, although controversial, include: increased risk for spontaneous abortion especially in women with a shorter time interval from LEEP to pregnancy, second trimester pregnancy loss, preterm premature rupture of membranes, and preterm delivery.
8. Follow-up. In general, women undergoing observation for CIN1-2 should have Pap tests every 6 months with repeat colposcopy for ASC or worse until 24 months, and then return to routine screening. Unfortunately, many women do not follow up promptly after abnormal cervical cytology. In a retrospective study of over 8,571 women with abnormal cervical cytology, 18.5% were lost to follow-up including 8% of those with HSIL. Follow-up rates were higher for those patients with higher degree of cytologic abnormality (OR 1.29, 95% CI 1.17 to 1.42), older patients (OR 1.03, 95% CI 1.02 to 1.030), and those receiving index Pap test at a larger health care facility (OR 1.13, 95% CI 1.01 to 1.27). For women with CIN1, if disease persists for 2 years, either continued follow-up or treatment is acceptable. For women treated for CIN2-3, co-testing at 12 months and 24 months is recommended. If both co-tests are negative, then retesting in 3 years is recommended, but if any test is abnormal then colposcopy with ECC is recommended. If CIN2 or 3 is identified at the margin of an excisional procedure or in an ECC sample obtained immediately after the procedure, follow-up with cytology and ECC is preferred 4 to 6 months after treatment. Alternatively, repeating the excisional procedure is also acceptable.
9. Current focus. New advances in HPV molecular testing are being developed and integrated into diagnostic and preventative strategies. Two HPV vaccines have been approved in the United States for administration to women aged 9 to 26 years. In June 2006, the U.S. Food and Drug Administration (FDA) approved Gardasil (Merck) as a quadrivalent prophylactic vaccine targeted against HPV subtypes 16/18 (responsible for 70% of cervical cancers worldwide) and 6/11 (responsible for 90% of genital warts). This recombinant vaccine is a mixture of virus-like particles derived from the L1 capsid proteins of the HPV types it is targeted against. It is administered IM in three doses at 0, 2, and 6 months. In 2007, a bivalent prophylactic vaccine, Cervarix also became available in the United States. Since their respective debuts, several randomized controlled trials (RCTs) have established their safety profiles and reported efficacy rates that nearly reach 100% against target HPV types when administered prior to HPV exposure. The Future II Study Group performed a combined analysis of four RCTs to assess the effect of prophylactic HPV vaccination on CIN2/3 and AIS (Lancet 2007;369:1861). In an intention-to-treat analysis, they noted an 18% reduction (95% CI 7 to 29) in the overall rate of CIN2/3 or AIS due to any HPV type compared to placebo. The Costa Rica Vaccine Trial was a community-based double-blind randomized controlled phase 3 trial of 7,466 women aged 18 to 25 years, who were randomized to receive either a bivalent HPV vaccine or hepatitis A vaccination (J Infect Dis 2013;208:385). CIN2+ cases were not significantly different between study groups, and similarly, the proportion of LEEPs done in all HPV-vaccinated women was 5% versus 5.7% in the placebo group with a relative reduction rate of 11.3% (p=0.24, 95% CI: −8.91, 27.8). However, in a subgroup analysis assessing patients who had no evidence of prior HPV exposure, the vaccinated group had a 45.6% rate reduction in LEEPs compared to the controls (p=0.08, 95% CI: −9.34, 73.90).
10. Cervical cancer: Invasive disease
11. Background. Cervix cancer is the third most common gynecologic malignancy in the United States, with approximately 15,000 new cases and 5,000 deaths per year. Worldwide, it is the second leading cause of death from cancer among women with approximately 200,000 deaths annually. Areas of the world that have implemented screening and treatment programs for preinvasive cervical lesions have decreased the mortality by approximately 90%. HPV infection has been well-established as the underlying etiology for the development of cancer with 70% of cases attributed to HPV genotypes 16 and 18.
12. Presentation. The majority of patients with cervical cancer present between ages 45 and 55 years with abnormal vaginal bleeding or discharge, which is often serosanguinous and foul smelling. Late symptoms or indicators of more advanced disease include flank or leg pain, dysuria, hematuria, rectal bleeding, obstipation, and lower extremity edema. Invasive cancer detected by Pap test is much less common. Visually, cervical cancer lesions are exophytic (most common), endophytic, or ulcerative. They are usually very vascular and bleed easily. Biopsies should be performed on all lesions with pathologic confirmation of disease before initiation of therapy.
13. Workup and staging. Women with biopsies suggesting microinvasive cervical cancer without a gross lesion on the cervix should undergo a large cone biopsy to fully evaluate depth of invasion. FIGO staging of cervical cancer is clinical and is determined mainly by physical examination, CXR, intravenous pyelography (IVP), cystoscopy, proctosigmoidoscopy, and results of cone biopsy (if necessary). CT, magnetic resonance imaging (MRI), lymphangiography, and positron emission tomography (PET) scans are used to guide treatment, but should not be used to change the stage. Table 24-8 summarizes FIGO staging of cervix cancer.

TABLE 24-8

FIGO Staging of Cervix Cancer

Stage	Description
0	Carcinoma in situ, intraepithelial carcinoma
I	The carcinoma is confined to the cervix
IA	Microscopic disease. All visible lesions are stage IB.
IA1	Invasion of stroma ≤3 mm in depth, and ≤7 mm width
IA2	Invasion of stroma >3 mm and ≤5 mm in depth, and ≤7 mm width
IB	Visible lesion confined to the cervix
IB1	Visible lesion(s) ≤4 cm
IB2	Visible lesion(s) >4 cm
II	The carcinoma extends beyond the cervix, but does not extend to the distal 1/3 vagina or pelvic sidewall
IIA	Upper 2/3 of vagina, but no obvious parametrial involvement
IIA1	Clinically visible lesion ≤4 cm
IIA2	Clinically visible lesion >4 cm
IIB	Obvious parametrial involvement, but not extending to the sidewall
III	The carcinoma involves the lower 1/3 of the vagina or extension to the pelvic sidewall. All cases of hydronephrosis or nonfunctioning kidney are included, unless they are known to be due to other causes
IIIA	Involvement of the lower 1/3 vagina, but not out to the pelvic sidewall
IIIB	Extension to the pelvic wall and/or hydronephrosis or nonfunctional kidney
IV	The carcinoma has extended beyond the true pelvis
IVA	Involvement of the mucosa of the bladder or rectum
IVB	Distant metastases

FIGO, International Federation of Gynecology and Obstetrics.

4. Therapy and prognosis. In general, all cancers of the cervix can be treated with RT. Specifics of therapy as well as the surgical alternative are as follows: Stage IA1 may be treated with extrafascial hysterectomy or cervical CKC alone in a patient who strongly desires to preserve her fertility. If lymphovascular space invasion (LVSI) is present then modified radical or radical hysterectomy with lymphadenectomy (LND) or pelvic RT and implants is indicated. The risk of lymph node metastasis is very rare (0.2%) and prognosis is excellent with very few deaths due to disease. Patients with stage IA2, IB1, and IIA can be treated with either radical hysterectomy/trachelectomy with pelvic lymphadenectomy or RT; both have similar efficacies. Although controversial, lesions larger than 4 cm (stage 1B2) should be managed with primary radiotherapy except when on a study protocol or if a contraindication to RT exists (e.g., adnexal mass, inflammatory bowel disease, or earlier RT). Surgically managed patients with positive margins, positive lymph nodes, or other high risk factors should be offered adjuvant chemoradiation. Radiosensitivity can be enhanced by cisplatin through the formation of DNA-platinum adducts. Other high risk factors include LVSI plus one of the following: (1) deep one-third penetration of tumor; (2) middle-third penetration and clinical tumor larger than 2 cm; (3) superficial penetration and larger than 5 cm tumor; or (4) tumor larger than 4 cm and middle or deep one-third invasion in the absence of LVSI. Stage IB2, IIB–IVA lesions are treated primarily with RT usually with whole pelvis radiation (5,040 cGy) given as 180- to 200-cGy daily fractions with one to three brachytherapy applications. Patients should be given weekly cisplatin chemotherapy (40 mg/m² IV) as a radiation-sensitizing agent. A CBC with differential, basic metabolic panel (electrolytes and renal panel), and magnesium levels are usually obtained weekly prior to administration of chemotherapy. Stage IVB is usually treated with palliative doses of radiation to minimize symptoms of pain or vaginal bleeding. Chemotherapy in this setting does not have a significant impact on survival. Recurrent disease is treated on the basis of site of recurrence and previous therapies. Surgical resection (e.g., pelvic exenteration) is often attempted if the disease is central and not extending to the sidewall, as this offers the best chance of cure (50%). Radiation is another option if recurrent disease is outside a previously irradiated area. Alternatively, chemotherapy can also be used although the optimal regimen remains unclear. Single-agent cisplatin (50 to 70 mg/m² IV every 3 weeks) has reported response rates of 20% to 30% and is currently the standard with which other agents/combinations are compared. Five-year survival by stage is as follows: IB, 85% to 90%; IIA, 73%; IIB, 65% to 68%; III, 35% to 44%; and IV, 15%. Adenocarcinoma of the cervix is treated in a similar manner as squamous cell carcinoma. Other histologic variants (small cell: neuroendocrine, carcinoid, oat cell; verrucous carcinoma; sarcoma; lymphoma; and melanoma) are very rare and are beyond the scope of this text (see Suggested Readings).
5. Complications. Surgical complications of radical hysterectomy are prolonged bladder dysfunction (4%), fistula formation (1% to 2%), lymphocyst requiring drainage (2% to 3%), pulmonary embolism (fewer than 1%), and operative mortality (fewer than 1%). Complications of RT can be acute or chronic and vary depending on volume, fractionation, and total dose or irradiation. The normal tissue of the cervix and uterus can tolerate high doses of 20,000 to 30,000 cGy in about 2 weeks. However, ovarian ablation occurs with radiation doses of approximately 25 Gy. Other sensitive pelvic organs include the sigmoid, rectosigmoid, and rectum. Fortunately, precise delivery of radiation to target tissues with intensity-modulated radiation therapy reduces damage to surrounding organs. Nonetheless, acute complications of RT are inflammatory and include cystitis, hematuria, proctitis with tenesmus and diarrhea, as well as enteritis with nausea. Chronic RT complications result from obliterative endarteritis that leads to fibrosis and necrosis of normal tissues. They include, but are not limited to, serious small and large bowel injury (3% to 4%) including bowel obstruction, chronic diarrhea, fecal incontinence, and fistula formation; ureteral or urethral stricture, decreased bladder capacity, hematuria, and urinary fistula formation (2%). Sexual dysfunction is common in up to 60% of women and may include vaginal stenosis, shortening of the vagina, dyspareunia, and decreased orgasm.
6. Follow-up. More than one-third of treated patients will have disease recurrence and 80% of them will recur within 2 years of therapy completion. Patients should be seen every 3 months for the first year, every 3 to 4 months for the second year, every 6 months for third to fifth year, and then at 6- to 12-month intervals. Screening CXR, CT, or PET may be useful in evaluating symptomatic or high risk patients. We recommend considering PET at 3, 9, 15, 21 months and then annually for 5 years. During the office visit special attention should be paid to weight loss, abdominal pain, leg pain, and lower extremity edema. Examination should include a complete physical examination including palpation of supraclavicular and inguinal lymph nodes, a bimanual pelvic exam, a Pap test, and rectovaginal exam. The presence of nodularity of the cervix, vagina, or rectum should prompt biopsies.
7. Current focus. Multiple chemotherapeutic agents and combinations including cisplatin, carboplatin, liposomal doxorubicin, bevacizumab, topotecan, ifosfamide, and paclitaxel have been investigated for advanced stage, recurrent, or progressive disease, as these patients typically do very poorly. More recently there have been advances using targeted, biologic therapy with bevacizumab. In a four-armed, phase III trial, GOG 240 randomized 452 women with recurrent or metastatic cervical cancer to one of two chemotherapy regimens alone or combined with 15 mg/kg of bevacizumab. The chemotherapy regiments were (1) cisplatin (50 mg/m²) plus paclitaxel (135 to 175 mg/m²); and (2) topotecan (0.75 mg/m² days 1 to 3) plus paclitaxel (175 mg/m² day 1). At median follow-up of 20.8 months, OS with bevacizumab plus chemotherapy was 17 months versus 13.3 months with chemotherapy alone (HR = 0.71, 95% CI 0.54 to 0.94, p = 0.0035). PFS was 8.2 months for those who received bevacizumab versus 5.9 months for those who received chemotherapy alone (ClinicalTrials.gov identifier: NCT00803062).

 III. VULVAR CANCER

1. Background. Vulvar cancer is the fourth most common gynecologic malignancy with fewer than 3,000 cases diagnosed annually in the United States. Classically, vulvar cancer has been a disease of elderly women, with peak incidence occurring between ages 65 and 75 years, but there appears to be a bimodal age distribution. There is an increasing incidence of younger patients presenting with early-stage vulvar cancer, which often arises from HPV-related preinvasive disease (e.g., chronic vulvar dystrophies such as lichen sclerosis) and is associated with a history of tobacco use. Although not well-understood, other etiologic factors include environmental/industrial toxins, chronic irritants, and chronic infections. Knowledge of the anatomy of the vulva with special attention to the lymphatic drainage is vital to understanding disease progression.
2. Presentation. The vast majority of patients are first seen with complaints of vulvar pruritus or a mass on the vulvar, primarily arising from the labia majora. Other common symptoms of vulvar cancer include pain (23%), bleeding (14%), ulceration (14%), dysuria (10%), discharge (8%), and presence of a groin mass (2.5%). Significant delay up to 16 months following onset of symptoms has been reported.
3. Workup and staging. Biopsy must be done on all suspicious lesions of the vulva, including lumps, ulcers, pigmented areas, and any existing vulvar lesion that displays changes in elevation, color, surface, or sensation; even if a patient is asymptomatic. There are a wide variety of appearances of vulvar cancers: raised, ulcerative, exophytic, white, red, and pigmented. Application of 4% acetic acid solution or toluidine blue to the vulva can help define the extent of some lesions. Colposcopy is only rarely helpful. Biopsy is performed under local anesthesia using a 3- to 5-mm Keyes punch biopsy to sample the worst-appearing areas. Hemostasis is obtained with direct pressure, silver nitrate, or suture ligature. More than 90% of vulvar cancers are squamous cell carcinomas, and the other cell types (melanoma, extramammary Paget’s disease, basal cell carcinoma, adenocarcinoma, verrucous carcinoma, and sarcoma) are all very rare.
4. Therapy and prognosis. The trend for surgical management of vulvar cancer has become more conservative over the last decade. Classically, resection included the labiocrural fold bilaterally over the mons veneris and across the posterior fourchette with complete removal of the subcutaneous tissue with coverage by flaps or skin grafts. Current treatment for invasive vulvar cancer is a radical vulvectomy (down to the level of the underlying deep perineal fascia and the pubic periosteum) with bilateral groin node dissection (usually through separate skin incisions). Two exceptions to this recommendation are the following: (1) biopsy results that demonstrate less than 1 mm of invasion, in which case, a radical excision with at least 1 cm margin should be performed. If the final pathology confirms only microinvasion, the groin lymph nodes need not be sampled; and (2) invasive lesions (larger than 1 mm) that are less than 2 cm in diameter and more than 2 cm from the midline may be staged with ipsilateral groin node dissection alone. FIGO staging is summarized in Table 24-9. Surgical resection in patients with pathologically negative groin nodes is curative in more than 90% of patients. More than half of all patients with positive groin nodes will die of their disease. Currently it is recommended that patients with two or more positive groin nodes undergo inguinal and pelvic irradiation after primary surgery.
5. Complications. Radical vulvectomy with inguinofemoral lymphadenectomy, although less invasive than prior techniques in the past, is still associated with increased risks of wound breakdown (15% to 20%), infection, and lymphocyst formation. Fortunately, diligent surgical technique and the use of closed suction drain(s) in the groin sites help reduce the risk of postoperative complications. These drains are typically removed when output is <25 mL per day. Inguinal cellulitis, lower extremity lymphangitis, and lymphedema are later sequelae and are related to the extent of groin therapy (e.g., high risk women include those who undergo superficial and deep lymphadenectomy and groin irradiation).

TABLE 24-9

FIGO Staging of Vulvar Cancer

Stage	Description
0	Carcinoma in situ, intraepithelial carcinoma
I	Tumor is confined to the vulva/perineum
IA	Lesion ≤2 cm in size with stromal invasion ≤1 mm*, no nodal metastasis
IA1	Lesion >2 cm in size with stromal invasion >1 mm, no nodal metastasis
IA2	Measured invasion of stroma >3 mm and ≤5 mm in depth, and ≤7 mm width
II	Tumor of any size with extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus)
III	Tumor of any size with or without extension to adjacent perineal structures (1/3 lower urethra, 1/3 lower vagina, anus) with positive inguinofemoral lymph nodes
IIIA(i)	With 1 lymph node metastasis (≥5 mm), or
IIIA(ii)	1–2 lymph node metastasis(es) (<5 mm)
IIIB(i)	With ≥2 lymph node metastases (≥5 mm), or
IIIB(ii)	≥3 lymph node metastases (<5 mm)
IIIC	With positive nodes with extracapsular spread
IV	Tumor invades other regional (2/3 upper urethra, 2/3 upper vagina), or distant structures
IVAi	Tumor invades upper urethra and/or vaginal mucosa, bladder mucosa, rectal mucosa, or fixed to pelvic bone, or
IVAii	Fixed or ulcerated inguinofemoral lymph nodes

FIGO, International Federation of Gynecology and Obstetrics.

^*Depth of invasion is defined as the measurement of the tumor from the epithelial–stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion.

1. Follow-up. Most recurrences (70% to 80%) occur in the first 2 years after initial surgery. Patients should be examined every 3 months for the first year, every 4 months for the second year, every 6 months for third to fifth year, and then at 6- to 12-month intervals. During this period biopsies should be liberally performed on any suspected lesion(s). Sexual dysfunction and disfiguring body image are common concerns of patients after treatment completion and should be addressed during follow-up visits.
2. Current focus. Chemoradiation in the neoadjuvant setting has potential to produce high rates of surgical respectability without the morbidity and mortality associated with pelvic exenteration. However, significant heterogeneity in the chemotherapy regimens exists. GOG 101 investigated the use of neoadjuvant chemoradiation (4,760 cGy to the primary and lymph nodes, with concurrent cisplatin/5-FU) for patients with locally advanced vulvar carcinoma (Int JRadiat Oncol Biol Phys 2000;48:1007). Forty-two of 46 patients (91%) completed the chemoradiation per protocol and of these, 38 patients (83%) had resectable disease. Nineteen (50%) experienced recurrence or progression, and 12 of the 38 patients (32%) who underwent surgery were alive and disease-free with a median follow-up of 78 months. With regards to primary treatment for patients with locally advanced vulvar cancer not amendable to resection, the optimal chemotherapy regimen is under current investigation. Specific agents include 5-FU, mitomycin-C, bleomycin, and cisplatin. GOG 205 was a phase II trial of 58 eligible patients investigating the role of primary chemoradiation using RT 5 days per week in 1.8 Gy fractions to a total dose of 57.6 Gy combined with weekly cisplatin 40 mg/m² IV (Gynecol Oncol2012;124:529). Twenty-nine women (64%) achieved a clinical response and of this cohort, 22 (75%) continued to have no evidence of disease after 24 months median follow-up.

 IV. VAGINAL CANCER

1. Background. Vaginal cancers are very rare, accounting for only 1% to 2% of gynecologic malignancies. Squamous cell carcinomas, the most common primary tumors, are most often located on the anterior wall of the upper third of the vagina and are usually multifocal. The specific etiology is unclear, but as with cervical cancer the presence of HPV16 has been associated with up to two-thirds of all new cases of vaginal cancer. Other risk factors include multiple lifetime sexual partners, early age at coitarche, smoking, DES exposure, and prior cervical dysplasia or cervical or anogenital cancer.
2. Presentation. Vaginal bleeding, either spontaneous or after coitus, and vaginal discharge are the most common presenting symptoms. Patients may also present with an abnormal Pap test, pelvic pain, dyspareunia, and/or bowel and bladder complaints. Urinary symptoms are common because often vaginal lesions are close to the vesicle neck resulting in bladder compression at an early stage. However, approximately 5% to 10% of women have no symptoms and the disease is suspected on physical examination.
3. Workup and staging. Definitive diagnosis is made by biopsy. A patient with an abnormal Pap test who has previously undergone hysterectomy or in whom evaluation of the cervix showed no disease should undergo colposcopy of the vagina with biopsies. In a study of 269 patients with metastatic vaginal cancer, 84% were from genital sites (the majority cervical and endometrial cancer) and the remaining were from the gastrointestinal tract or breast. Staging of vaginal cancer (Table 24-10) is similar to that of cervix cancer in that it is a clinical staging system. Stage 0 or vaginal intraepithelial neoplasia (VAIN) is a preinvasive disease and is graded in a manner similar to that of CIN, from I to III. Patients with invasive disease should be evaluated with a complete history and physical examination with special attention to supraclavicular and inguinal lymph nodes. CXR and IVP are indicated as part of staging. Location and tumor size will dictate the necessity of cystoscopy and proctosigmoidoscopy to complete staging. Alternatively, one may consider a CT or MRI.
4. Therapy and prognosis. Squamous cell carcinoma of the vagina is by far the most common primary vaginal cancer and stage-based treatment is as follows: Stage 0 (intraepithelial disease) lesions have an unclear malignant potential and usually only VAIN III lesions are treated. Often they are multifocal so the method of treatment should be tailored to the patient’s presentation. Simple surgical excision and/or ablation (laser vaporization, cryotherapy) are most often used. However, topical treatments are reasonable alternatives—imiquimod applied three times per week for approximately 8 weeks and topical 5-fluorouracil (5-FU) 5 g intravaginally at nighttime for 5 days repeated every 2 to 3 months. 5-FU is generally not as well-tolerated as a topical imiquimod due to significant irritation and burning. All invasive lesions (stage I to IV) can be treated with some form of RT. However, surgical management is an option for lesions 0.5 cm or less, particularly in the upper vagina. Lesions that are thicker than 0.5 cm should undergo radical hysterectomy, upper vaginectomy, and bilateral pelvic lymphadenectomy. For those who have had a prior hysterectomy, pelvic external-beam radiotherapy and interstitial implants are commonly used. Lesions of the lower one-third of the vagina, although staged similarly to upper vaginal lesions, clinically behave more like vulvar carcinomas. Therefore, bilateral inguinal–femoral lymphadenectomy is recommended. Patients may also receive RT tailored to specific lesion(s). Options include brachytherapy alone (tandem and ovoids, intracavitary vaginal cylinder, or interstitial implants) or in conjunction with external-beam radiation to treat pelvic and/or inguinal lymph nodes. Stage II to IVlesions are usually treated first with external-beam radiation (5,000 to 6,000 cGy) to treat the pelvic lymph nodes and to shrink the primary tumor, allowing easier application of brachytherapy with interstitial needles. Actuarial disease-free 10-year survival in patients treated with definitive irradiation by stage at our institution is as follows: I, 75%; II, 49%; III, 32%; and IV, 10%. Most study participants received interstitial or intracavitary therapy or both; however, the addition of external-beam irradiation did not significantly improve survival or tumor control. Clear cell adenocarcinomas, melanomas, rhabdomyosarcomas,and endodermal sinus tumors are rare tumors of the vagina and are beyond the scope of this text—refer to Suggested Readings.

TABLE 24-10

FIGO Staging of Vaginal Cancer

Stage	Characteristics
0	Carcinoma in situ (intraepithelial carcinoma)
I	Carcinoma is limited to the vaginal mucosa
II	Carcinoma has involved the subvaginal tissue, but has not extended into the pelvic wall
III	Carcinoma has extended into the pelvic wall
IV	Carcinoma extension with involvement of the mucosa of the bladder or rectum or extension beyond the true pelvis
IVA	Spread to adjacent organs or direct extension beyond the true pelvis
IVB	Spread to distant organs

FIGO, International Federation of Gynecology and Obstetrics.

1. Complications. Major complications of therapy (primarily radiation) are seen in 10%- to 15% of patients and are directly related to the dose of radiation. Vaginal stenosis, fistulas (large or small bowel, bladder, and ureteral), bowel and ureteral obstruction, and bowel perforation are not uncommon.
2. Follow-up. Patients are usually seen every 3 to 6 months for the first 2 years after therapy and then annually. Patient should be evaluated with pelvic examination and Pap test. Vaginal colposcopy and biopsy are indicated for any suspicious lesion(s). As in vulvar cancer, sexual dysfunction and disfiguring body image are common concerns of patients after treatment completion and should be addressed during follow-up visits. Recurrences can be treated successfully with pelvic exenteration.
3. Current focus. Due to comparable epidemiologic and histologic findings between carcinoma of the cervix and vagina, the two cancers are often treated in a similar manner. To this end, our institution was interested in studying the utility and effectiveness of PET scan to detect primary tumor and lymph node metastases in patients with vaginal cancer. We performed a prospective registry study of 23 consecutive patients with clinical stage II to IVa. Of the 21 patients with an intact primary tumor, 9 (43%) were visualized by CT versus 100% by whole-body FDG-PET. PET scan was also superior to CT for detecting enlarged groin nodes (4 vs. 3) and both groin and pelvic lymph nodes (2 vs. 1) (Int J Radiat Oncol Biol Phys 2005;62:733).