PROLOG: Gynecologic Oncology and Critical Care, Eighth Edition (Assessment & Critique)

By American College of Obstetricians and Gynecologists

The 2021 OB/GYN Coding Manual: Components of Correct Procedural Coding is now available. Coding errors can delay payment, lead to increased denials, and even federal penalties. Ensure that your practice is coding accurately and getting reimbursed efficiently—purchase this essential resource today!ACOG's OB/GYN Coding Manual is the primary billing and coding resource for obstetricians, gynecologists, and their staff. The 2021 expanded edition incorporates instruction from our Procedural Coding for Obstetricians and Gynecologists booklet and includes new sections on Evaluation and Management, Telehealth, and COVID-19.The coding material, which is organized by systems, offers 2021 updates that can be used for billing, preauthorization requirements, appeals, and more. The Appendices include printable tables for the quick reference of the coding guidelines in this manual.The manual follows established CPT guidelines and includes Medicare guideline information for accurately reporting medical procedures. It represents the expert opinions of ACOG staff and members of the ACOG Committee on Health Economics and Coding (CHEC) about the specific services included (or not included) in each ob-gyn procedure code listed.Text and guidance are based on the following:The CPT code vignettes and relative value units (RVUs)Definitions of the global surgical packageBundling rules for global surgical packagesExceptions to the global package bundling rulesCPT's global obstetric packageOrder the 2021 OB/GYN Coding Manual today.

• Language: English
• Publisher: ACOG
• Release date: Apr 26, 2021
• ISBN: 9781948258302

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1

Borderline ovarian tumor

A 20-year-old nulliparous patient underwent a right ovarian cystectomy for management of a 5-cm ovarian cyst. Final pathology shows a serous borderline ovarian tumor, and she is referred to you for management. The operative report reveals no other pelvic or abdominal lesions. The best next step in the management of this patient is

* (A) active surveillance

(B) bilateral salpingectomy

(C) chemotherapy

(D) hysterectomy and bilateral salpingo-oophorectomy

The 2014 World Health Organization (WHO) Classification of Tumours of the Female Genital Organs recommends use of the term borderline ovarian tumor instead of low malignant potential tumor. According to WHO, atypical proliferative tumor is an acceptable synonym for borderline ovarian tumor. The annual incidence of borderline ovarian tumors is less than 5 in 100,000 women. More than 50% of these tumors are serous, and 40% are mucinous histology. Cell types such as clear cell, Brenner, seromucinous, and endometrioid are rarer.

Typically, serous borderline ovarian tumors present as cysts without surface excrescences, and one third occur bilaterally. Serous borderline ovarian tumors include all of the following typical histologic features:

prominent stratification of secretory columnar and ciliated cells

branching papillary architecture

edematous or hyalinized fibrous stroma without stromal invasion

mild or moderate nuclear atypia

hyperchromasia

luminal tufting of detached cells

KRAS mutations are found in one third of serous borderline ovarian tumors. BRAF mutations also are found in approximately one third of these tumor types. These mutations rarely are observed in the same tumor.

Compared with the more common high-grade invasive ovarian cancer, borderline ovarian tumors present in younger women are more likely to be diagnosed at an early stage, are confined to one ovary in 75% of cases, and are associated with a far more favorable prognosis. Although many cases of high-grade serous cancer are believed to arise from the fallopian tube, the origin of serous borderline ovarian tumors appears to be from the ovarian epithelium (Appendix B offers an explanation about this terminology.). Five-year survival rates for patients with stage 1 disease exceed 95%, and the 10-year survival rate is greater than 70%. For patients with advanced disease, 5-year overall survival rate is 65–87%.

For patients who do not desire fertility preservation, primary treatment of borderline ovarian tumors includes bilateral salpingo-oophorectomy and debulking of metastases when present. It is not clear whether hysterectomy enhances prognosis, although it is sensible to perform hysterectomy in patients with endometrioid histology because synchronous endometrial lesions have been reported in some patients. Although omentectomy, peritoneal biopsies, and lymph node dissections are recommended frequently, it is not clear that systematic lymphadenectomy is warranted.

Because patients with serous borderline ovarian tumors have excellent prognoses after surgery alone, chemotherapy is not indicated. There also is no role for postoperative radiation therapy for localized borderline ovarian tumor. For patients with recurrent disease, surgical exploration and cytoreduction are recommended. Considerations for adjunctive postoperative treatment are the same as for primary disease.

In this patient, bilateral salpingectomy is not recommended because the procedure would render her infertile; further, it would be unlikely to improve her outcome because the primary tumor most likely did not originate in her fallopian tubes. Although it is reasonable to discuss hysterectomy and removal of the tubes and residual ovarian tissue with patients who have completed childbearing, it is premature to perform this procedure in this patient who is only age 20 years.

Removal of the right tube and ovary may be considered. The described patient underwent a cystectomy because the preoperative prediction for malignancy was low. In this situation, it would be acceptable to continue surveillance or undergo surgery to remove the right ovary. Because of the relatively high frequency of serous borderline ovarian tumors in reproductive-aged women, there is considerable interest in fertility-preserving treatment options. A subanalysis of the Retrospective Multicenter Outcome Survey in Borderline Ovarian Tumors (referred to as ROBOT), a multi-institutional retrospective review of 950 women with borderline ovarian tumors, by the Arbeitsgemeinschaft Gynaekologische Onkologie (referred to as AGO), found that approximately one third of patients were potentially fertile at the time of presentation. Among patients with reproductive potential (the median age was 31 years), 70% had serous tumors, 25% had peritoneal implants, and 53% had fertility-preserving surgery. In this series, 105 potentially fertile women (38%) were treated with unilateral or bilateral ovarian cystectomy, and in 32 women, the primarily affected ovary was retained. Overall, in the ROBOT study, malignant transformation was less frequent in younger patients, which likely contributed to a favorable prognosis even after recurrence in patients with reproductive potential. Multivariate analysis found that both metastatic disease at presentation and fertility-preserving surgery were associated with worse progression-free survival.

Recurrent disease was more frequent in patients who had conservative surgery, most often occurring in the ovaries; however, all recurrences were borderline. Of patients with retained ovarian tissue, 49% had recurrences, and most recurrences were in the contralateral ovary. Patients who were treated with cystectomy had a higher rate of recurrent disease (hazard ratio 5.7) compared with oophorectomy. There were no instances of malignant transformation among potentially fertile patients with recurrent disease in ovarian tissue. Based on these latter issues, it is important to include the option to remove the residual right ovary as a part of counseling.

The most appropriate recommendation for this patient is active surveillance, which includes clinical follow-up and imaging (most commonly with transvaginal ultrasonography of the ovaries). Long-term follow-up may be particularly important in patients with borderline ovarian tumors given the relatively high proportion of late recurrences.

du Bois A, Ewald-Riegler N, de Gregorio N, Reuss A, Mahner S, Fotopoulou C, et al. Borderline tumours of the ovary: a cohort study of the Arbeitsgmeinschaft Gynakologische Onkologie (AGO) Study Group. Arbeitsgmeinschaft Gynakologische Onkologie (AGO) Study Group. Eur J Cancer 2013;49:1905–14. doi: 10.1016/j.ejca.2013.01.035 Harter P, Gershenson D, Lhomme C, Lecuru F, Ledermann J, Provencher DM, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for ovarian tumors of low malignant potential (borderline ovarian tumors). Int J Gynecol Cancer 2014;24(9 suppl 3):S5–8. doi: 10.1097/IGC.0000000000000282

Trillsch F, Mahner S, Vettorazzi E, Woelber L, Reuss A, Baumann K, et al. Surgical staging and prognosis in serous borderline ovarian tumours (BOT): a subanalysis of the AGO ROBOT study. Br J Cancer 2015;112:660–6. doi: 10.1038/bjc.2014.648

* Indicates correct answer.

Note: See Appendix A for a table of normal values for laboratory tests. See Appendix B for an explanation of ovarian cancer terminology in this edition.

2

Complete mole

A 35-year-old woman, gravida 5, presents with amenorrhea for the past 2 months. Urine pregnancy test is positive. Serum β-human chorionic gonadotropin (hCG) concentration is 120,000 mIU/mL. On examination, her uterus is enlarged to 10 cm. Ultrasonography is shown in Figure 2-1. Suction dilation and evacuation is performed. Other than pathology, this patient’s most significant risk factor for development of gestational trophoblastic neoplasia is

(A) uterine size

* (B) β-hCG concentration

(C) gravidity

(D) patient age

FIGURE 2-1. Described patient’s ultrasonography. (Used with permission of Leslie Clark, MD.)

Hydatidiform moles, also referred to as molar pregnancies, are a rare cellular proliferation of trophoblastic cells. They can be categorized as either partial or complete moles. Both are considered premalignant conditions because they may develop into gestational trophoblastic neoplasia.

Complete moles are characterized by trophoblastic proliferation of the cytotrophoblasts and syncytiotrophoblasts with coincident findings of diffuse hydropic villi that result in the characteristic snowstorm pattern seen on ultrasound imaging, as shown in Figure 2-1. Complete moles lack fetal and embryo development and are mostly 46,XX resulting from a single sperm fertilizing an empty ovum. These patients tend to present with higher β-hCG concentrations (ie, greater than 100,000 mIU/mL) and gestational trophoblastic neoplasia-associated symptoms, such as hyperthyroidism and hyperemesis. Conversely, partial moles are characterized by focal swelling of the villi and the presence of a fetus or embryo. They are genetically triploid (ie, 69,XXY; 69,XYY; and 69XXX) as a result of fertilization of a normal ovum by two sperm. Key differences between these two entities are shown in Table 2-1. Distinguishing complete moles from partial moles may be difficult by pathology alone. Immunohistochemical expression of the cell cycle inhibitor p57 (also referred to as CDKN1C) protein differentiates complete moles from partial moles. Cell cycle inhibitor p57 is a paternally imprinted and maternally expressed gene and therefore this protein is not present in complete moles.

After uterine evacuation, patients with a partial molar or complete molar pregnancies require additional β-hCG concentration monitoring because of the risk of developing gestational trophoblastic neoplasia. Even when hysterectomy is performed, the risk of postmolar gestational trophoblastic neoplasia developing is 3–5% after surgery; therefore, weekly β-hCG measurements are indicated until values normalize. After three normal test results, testing can be performed every 1–3 months for 6 months to ensure postmolar gestational trophoblastic neoplasia does not develop.

The biggest risk factor for developing gestational trophoblastic neoplasia is the presence of a complete molar pregnancy in the antecedent pregnancy. Complete molar pregnancies account for 50% of gestational trophoblastic neoplasia cases, and 15–20% of patients with a complete mole will develop gestational trophoblastic neoplasia. Additionally, complete moles have a 2–3% absolute risk of developing choriocarcinoma, which is more than 2,000-fold higher than the risk of other antecedent pregnancies. Partial moles develop postmolar gestational trophoblastic neoplasia in 1–5% of cases with no reported cases of choriocarcinoma but still warrant monitoring. Other risk factors for developing postmolar gestational trophoblastic neoplasia are the presence of theca lutein cysts greater than 6 cm, β-hCG concentration greater than 100,000 mIU/mL, large uterine size, and age older than 40 years. In this patient who has a β-hCG concentration of 120,000 mIU/mL, is younger than 40 years, and has a minimally enlarged uterus, her greatest risk factor for the development of gestational trophoblastic neoplasia is her elevated β-hCG concentration. Gravidity does not affect the risk of developing gestational trophoblastic neoplasia.

TABLE 2-1. Feature of Complete and Partial Hydatidiform Moles

Republished with permission from See HT, Freedman RS, Kudelka AP, Kavanagh JJ. Gestational trophoblastic disease. In: Eifel PJ, Gershenson DM, Kavanagh JJ, Silva EG, editors. Gynecologic cancer. Springer-Verlag; 2006. p. 226–43; permission conveyed through Copyright Clearance Center, Inc.

Altieri A, Franceschi S, Ferlay J, Smith J, La Vecchia C. Epidemiology and aetiology of gestational trophoblastic diseases. Lancet Oncol 2003;4:670–8. doi: 10.1016/s1470-2045(03)01245-2

Lurain JR. Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. Am J Obstet Gynecol 2010;203:531–9. doi: 10.1016/j.ajog.2010.06.073

See HT, Freedman RS, Kudelka AP, Kavanagh JJ. Gestational trophoblastic disease. In: Eifel PJ, Gershenson DM, Kavanagh JJ, Silva EG, editors. Gynecologic cancer. Springer-Verlag; 2006. p. 226–43.

* Indicates correct answer.

Note: See Appendix A for a table of normal values for laboratory tests. See Appendix B for an explanation of ovarian cancer terminology in this edition.

3

Endometrial cancer

A 69-year-old woman has received a diagnosis of serous uterine cancer after undergoing endometrial biopsy. At presentation, she has symptoms of early satiety, bloating, and abdominal discomfort. She has a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 32 and is a surgical candidate. The most appropriate next step in evaluation is

* (A) computed tomography (CT)

(B) magnetic resonance imaging (MRI)

(C) ultrasonography

(D) positron emission tomography (PET)–CT

Uterine cancer remains the most common gynecologic malignancy in developed countries. Adenocarcinoma of the endometrium is the most common histologic type of endometrial cancer. Endometrial cancer has been traditionally classified into two subtypes, based on clinicopathologic features. Type 1 tumors account for approximately 80% of cases and include endometrioid cancer and grade 1 or grade 2 histology. Type 1 endometrial cancer is associated with a favorable prognosis. These types of cancer often occur because of overexposure to endogenous estrogen, which is seen in cases involving patients with obesity or in patients who are taking unopposed exogeneous estrogen. Complex atypical hyperplasia may be an antecedent or concurrent neoplasia. Hysteroscopy with dilation and curettage would be appropriate to evaluate patients with diagnoses of complex atypical hyperplasia by endometrial biopsy because it could rule out or confirm a concomitant endometrial cancer. Because this patient already has received a diagnosis of serous endometrial cancer, further sampling by hysteroscopy plus dilation and curettage is not indicated.

In contrast, type 2 tumors, including endometrioid cancer with grade 3 histology, as well as serous, clear cell, mucinous, transitional cell, carcinosarcoma, and undifferentiated carcinoma of the uterus, behave more aggressively. Although they account for only 10–20% of all cases of endometrial cancer, they are responsible for 40% of endometrial cancer-related deaths.

Approximately 50–70% of patients with serous uterine cancer present with advanced-stage disease (ie, International Federation of Gynecology and Obstetrics [FIGO] stage III and stage IV). Compared with endometrioid uterine cancer, serous carcinoma has a higher likelihood of showing lymphovascular space involvement and intraperitoneal and extra-abdominal extension. An estimated 60–70% of patients with diagnoses of uterine serous carcinoma have extrauterine disease at the time of initial presentation. Similarly, the risk of lymph nodal metastasis is higher in patients with serous carcinoma than in those with endometrioid cancer. Tumor features, such as histologic grade and depth of myometrial invasion, are not predictive of risk of extrauterine spread in serous cancer, whereas these features can predict risk in endometrioid cancer. A study of 50 patients with pure or mixed uterine serous endometrial cancer revealed that 72% of patients had surgically staged extrauterine disease, or lymph nodal metastases. Lymph node metastases were noted in 36% of patients who did not have myometrial invasion and in 50% of patients with only inner one-half myometrial invasion. The presence of intraperitoneal disease extension did not correlate with increasing depth of myometrial invasion.

Given the risk of extrauterine disease in patients with serous carcinoma, preoperative CT of the abdomen and pelvis is indicated in these patients, such as the described patient, to rule out metastatic disease. This scan may lead to a recommendation for laparotomy and debulking surgery rather than minimally invasive staging surgery. If extensive disease or extra-abdominal disease is found, administering chemotherapy before surgery is another treatment option.

Several studies have evaluated the role and accuracy of PET–CT using the radiolabeled glucose analogue fludeoxyglucose F 18 in the preoperative evaluation of women with high-grade endometrial cancer, including those of serous histology. Positron emission tomography–CT can be used in the presurgical evaluation of patients with serous uterine cancer to assess the presence of extrauterine disease and for operative planning; however, this option is not cost effective as a first-step imaging study. Computed tomography alone is adequate for this patient and therefore is the preferred imaging study.

Magnetic resonance imaging would be an appropriate imaging modality to consider for evaluation of myometrial invasion, as well as involvement of the parametrial tissue. However, given the serous histology of the tumor in this case, the more relevant imaging study should evaluate the presence of extrauterine and distant metastases, including chest metastases; therefore, an MRI would not be the preferred radiologic study. Ultrasonography is an excellent study for pelvic disease and for ovarian and uterine evaluation but does not provide information about the nodal areas and outside of the pelvis.

del Carmen MG, Birrer M, Schorge JO. Uterine papillary serous cancer: a review of the literature. Gynecol Oncol 2012;127:651–61. doi: 10.1016/j.ygyno.2012.09.012

Endometrial cancer. Practice Bulletin No. 149. American College of Obstetricians and Gynecologists. Obstet Gynecol 2015;125:1006–26. doi: 10.1097/01.AOG.0000462977.61229.de

Gee MS, Atri M, Bandos AI, Mannel RS, Gold MA, Lee SI. Identification of distant metastatic disease in uterine cervical and endometrial cancers with FDG PET/CT: analysis from the ACRIN 6671/GOG 0233 Multicenter Trial. Radiology 2018;287:176–84. doi: 10.1148/radiol.2017170963

Goff BA, Kato D, Schmidt RA, Ek M, Ferry JA, Muntz HG, et al. Uterine papillary serous carcinoma: patterns of metastatic spread. Gynecol Oncol 1994;54:264–8. doi: S0090-8258(84)71208-X

Han SS, Lee SH, Kim DH, Kim JW, Park NH, Kang SB, et al. Evaluation of preoperative criteria used to predict lymph node metastasis in endometrial cancer. Acta Obstet Gynecol Scand 2010;89:168–74. doi: 10.3109/00016340903370114

Signorelli M, Guerra L, Buda A, Picchio M, Mangili G, Dell’Anna T, et al. Role of the integrated FDG PET/CT in the surgical management of patients with high risk clinical early stage endometrial cancer: detection of pelvic nodal metastases. Gynecol Oncol 2009;115:231–5. doi: 10.1016/j.ygyno.2009.07.020

* Indicates correct answer.

Note: See Appendix A for a table of normal values for laboratory tests. See Appendix B for an explanation of ovarian cancer terminology in this edition.

4

Instrumental Activities of Daily Living score in an older patient

A 78-year-old woman with metastatic high-grade serous ovarian cancer presents for initial treatment with carboplatin and paclitaxel chemotherapy. Her Instrumental Activities of Daily Living (IADL) score is two standard deviations below the mean for her age. Compared with a patient with a normal IADL score, this patient is more likely to experience

(A) decline in quality of life

(B) further decreased IADL score

* (C) inability to complete prescribed chemotherapy

(D) reduced social activity

Elderly women who undergo chemotherapy for ovarian cancer with carboplatin and paclitaxel have greater risks of toxicity from chemotherapy than younger women. Results from toxicity may include several domains, such as accelerated bone marrow suppression, increased fatigue, decreased quality of life, and inability to complete all planned cycles of chemotherapy. Risk factors for inability to complete treatment include chronologic and physiologic age.

A geriatric assessment includes a measurement of functional status, comorbidities, psychological status, social support, nutritional status, and cognition. The IADL scale gauges self-care skills that allow independent functioning, such as bathing, dressing, preparing meals, and taking prescribed medications (Box 4-1). Assessing the IADL scale for their patients over time allows physicians to determine the global effects of their treatments.

Another way to evaluate tolerance for prescribed therapies is patient-reported outcomes, which evaluate quality of life in an elderly population and are collected directly from the patient. One such tool is the Functional Assessment of Cancer Therapy–Ovary (referred to as the FACT-O; https://www.facit.org/FACITOrg/Questionnaires), a multidimensional patient-reported outcome that comprises four well-being subscales: 1) physical, 2) social, 3) emotional, and 4) functional. Within each subscale, patients respond to their well-being assessment on a scale of 0 to 4 (not at all through very much).

A large prospective trial performed by the Gynecologic Oncology Group specifically evaluated the outcomes of elderly women (ie, older than 70 years) who underwent chemotherapy for treatment of ovarian cancer. Instrumental Activities of Daily Living scores were found to be no worse during chemotherapy than before treatment. This finding is important because maintenance of IADL scores is essential for allowing women to preserve independent function.

Additional domains examined by the Gynecologic Oncology Group included quality of life and social activities during cancer chemotherapy. In both areas, elderly women who were receiving treatment did not suffer. Scores on the FACT-O improved over time, as did patient-reported outcome scores for social activity. This finding was independent of which type of chemotherapy the women received.

Although quality of life, ability to perform instrumental activities of daily living, and social activity remained stable or improved, the completion rate of chemotherapy for elderly women was significantly less in women who started treatment with a lower IADL score. In these women (such as the described patient), the completion of four cycles of chemotherapy without more than a 7-day delay or dose reduction was found to be significantly associated with lower IADL scores.

BOX 4-1

The Lawton Instrumental Activities of Daily Living Scale

Scoring: For each category, circle the item description that most closely resembles the patient’s highest functional level (either 0 or 1).

Lawton MP, Brody EM. Assessment of older people: Self-maintaining and instrumental activities of daily living. The Gerontologist, 9(3), 179–186. Copyright © The Gerontological Society of America. Reproduced [Adapted] by permission of the publisher.

Basen-Engquist K, Bodurka-Bevers D, Fitzgerald MA, Webster K, Cella D, Hu S, et al. Reliability and validity of the functional assessment of cancer therapy-ovarian. J Clin Oncol 2001;19:1809–17. doi: 10.1200/JCO.2001.19.6.1809

FACIT Measurement System. Questionnaires. Accessed January 29, 2020. https://www.facit.org/FACITOrg/Questionnaires

Mohile SG, Dale W, Somerfield MR, Schonberg MA, Boyd CM, Burhenn PS, et al. Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology. J Clin Oncol 2018;36:2326–47. doi: 10.1200/JCO.2018.78.8687

Tortorella L, Vizzielli G, Fusco D, Cho WC, Bernabei R, Scambia G, et al. Ovarian cancer management in the oldest old: improving outcomes and tailoring treatments. Aging Dis 2017;8:677–84. doi: 10.14336/AD.2017.0607

von Gruenigen VE, Huang HQ, Beumer JH, Lankes HA, Tew W, Herzog T, et al. Chemotherapy completion in elderly women with ovarian, primary peritoneal or fallopian tube cancer—an NRG oncology/Gynecologic Oncology Group study. Gynecol Oncol 2017;144:459–67. doi: S0090-8258(16)31602-X

Yao T, DeJong SR, McGree ME, Weaver AL, Cliby WA, Kumar A. Frailty in ovarian cancer identified the need for increased postoperative care requirements following cytoreductive surgery. Gynecol Oncol 2019;153:68–73. doi: S0090-8258(18)31539-7

* Indicates correct answer.

Note: See Appendix A for a table of normal values for laboratory tests. See Appendix B for an explanation of ovarian cancer terminology in this edition.

5

Adenocarcinoma in situ

A 32-year-old nulligravid woman who desires future fertility recently had cervical cytology that demonstrated atypical glandular cells favor neoplasia. Colposcopic examination identified an area of acetowhite epithelium, which was biopsied. Final histology demonstrates cervical intraepithelial neoplasia (CIN) 3 with glandular involvement. Loop electrosurgical excision procedure (LEEP) is performed with final pathology confirming CIN 3 and adenocarcinoma in situ (AIS). The margins are positive for AIS. The best next step in management is

* (A) cold-knife conization

(B) colposcopy with endocervical sampling in 4–6 months

(C) hysterectomy

(D) radical hysterectomy

Cervical adenocarcinoma in situ is the precursor to invasive adenocarcinoma of the cervix. The incidence of AIS has been steadily increasing. Similar to squamous dysplasia, AIS is associated with human papillomavirus infection (HPV). Adenocarcinoma in situ is associated most commonly with HPV-16 (57%), but HPV-18 is associated more commonly with AIS than squamous carcinoma in situ (38% versus 5%). Adenocarcinoma in situ presents significant clinical challenges because this premalignant lesion often is not detected with routine cervical cytology screening and commonly occurs in reproductive-aged women (the estimated average age is 36 years). This lesion can be high in the endocervical canal, limiting detection, and is multifocal and discontinuous (skip lesions). Obtaining negative margins from an excisional procedure does not provide certainty that the disease has been excised completely. These challenges support the rationale for simple (nonradical) hysterectomy as the recommended definitive therapy. For women who want to maintain fertility (such as the described patient) or who desire a more conservative approach, cold-knife cervical conization can be an alternative approach to hysterectomy. A cold-knife cervical conization will confirm diagnosis, assess the extent of disease, and determine whether invasive adenocarcinoma is present. There are conflicting data regarding rates of recurrence and residual disease in women who have had a cold-knife cervical conization for management. Figure 5-1 shows an algorithm for managing AIS.

Although cold-knife conization and LEEP are effective excisional modalities, cold-knife conization is preferred because performing LEEP can result in charred margins, which are difficult to interpret, and may produce a fragmented specimen. However, a recent retrospective population-based cohort study of 338 women with AIS who were managed either with cold-knife conization or LEEP reported similar rates of persistence or recurrence regardless of the type of excisional procedure.

Margin status is the most significant predictor for residual and recurrent disease, making interpretation of margins essential for counseling and management. A meta-analysis of 1,278 patients with AIS clearly illustrated the significance of margin status, demonstrating that when the excisional margins were negative, the likelihood for recurrence was 2.6% compared with an approximately 19% recurrence rate when the margins were positive. One particular challenge regarding management of AIS is the risk of skip lesions, which may account for an estimated 20% risk of residual disease even when negative margins are identified. In contrast, the risk of residual disease with AIS is markedly higher, at 52%, when the margins are positive on the initial excisional procedure. More important, the risk of an invasive adenocarcinoma was associated more commonly with positive margins (5%) compared with negative margins (less than 1%). Ultimately, if childbearing is not desired and cold-knife cervical conization demonstrates negative margins, a simple hysterectomy is recommended for definitive treatment of AIS.

Figure 5-1. Summary of adenocarcinoma in situ management recommendations. Abbreviations: HPV, human papillomavirus. *Cold-knife conization or loop electrosurgical excision procedure acceptable provided an adequate specimen can be obtained: 1) intact, nonfragmented (top-hat serial endocervical excisions unacceptable); 2) length of specimen must be at least 10 mm. †ASCCP Risk-Based Management Consensus guidelines are available at https://journals.lww.com/jlgtd/FullText/2020/04000/2019_ASCCP_Risk_Based_Management_Consensus.3.aspx. (Modified from Teoh D, Musa F, Salani R, Huh W, Jimenez E. Diagnosis and management of adenocarcinoma in situ: a Society of Gynecologic Oncology evidence-based review and recommendations. Obstet Gynecol 2020;135:869–78. doi: 10.1097/AOG.0000000000003761)

For women who desire fertility, a more conservative approach can be used. If the cervical cone margins are negative, a surveillance strategy can be initiated, although there are limited data supporting a universally accepted recommendation for surveillance. Many experts recommend co-testing with cervical cytology and HPV testing combined with an endocervical sampling every 6 months for 2–3 years and then annually until definitive therapy (ie, hysterectomy). Because there is evidence of an increased risk of recurrence in the first 3 years after excision, close surveillance for 3 years is warranted. Furthermore, the addition of HPV co-testing is supported by a robust 90% sensitivity for recurrence and persistence compared with 60% for cervical cytology alone. After childbearing has been completed, a hysterectomy should be considered regardless of the interval of time from diagnosis.

The described patient desires future fertility; therefore, hysterectomy is not warranted. Because of the positive margins on her initial LEEP, a re-excision with a cold-knife conization is the best next step in her treatment. Surveillance with co-testing and endocervical sampling can be employed as a strategy after re-excision and confirmation of negative margins. A radical hysterectomy is rarely necessary unless positive margins persist after multiple excisions and there is a high suspicion for an invasive adenocarcinoma.

Cleveland AA, Gargano JW, Park IU, Griffin MR, Niccolai LM, et al. Cervical adenocarcinoma in situ: Human papillomavirus types and incidence trends in five states, 2008–2015. Int J Cancer. 2020 Feb 1;146(3):810–818. doi: 10.1002/ijc.32340

Management of abnormal cervical cancer screening test results and cervical cancer precursors. Practice Bulletin No. 140. American College of Obstetricians and Gynecologists. Obstet Gynecol 2013;122:1338–67. doi: 10.1097/01.AOG.0000438960.31355.9e

Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. 2012 ASCCP Consensus Guidelines Conference. Obstet Gynecol 2013;121:829–46. doi: 10.1097/AOG.0b013e3182883a34

Munro A, Leung Y, Spilsbury K, Stewart CJ, Semmens J, Codde J, et al. Comparison of cold knife cone biopsy and loop electrosurgical excision procedure in the management of cervical adenocarcinoma in situ: what is the gold standard? Gynecol Oncol 2015;137:258–63. doi: 10.1016/j.ygyno.2015.02.024

Salani R, Puri I, Bristow RE. Adenocarcinoma in situ of the uterine cervix: a metaanalysis of 1278 patients evaluating the predictive value of conization margin status. Am J Obstet Gynecol 2009;200:182.e1–5. doi: 10.1016/j.ajog.2008.09.012

Teoh D, Musa F, Salani R, Huh W, Jimenez E. Diagnosis and management of adenocarcinoma in situ: a Society of Gynecologic Oncology evidence-based review and recommendations. Obstet Gynecol 2020; 135:869–78. doi: 10.1097/AOG.0000000000003761

* Indicates correct answer.

Note: See Appendix A for a table of normal values for laboratory tests. See Appendix B for an explanation of ovarian cancer terminology in this edition.

6

High-risk gestational trophoblastic disease

A 29-year-old patient underwent dilation and curettage for a complete molar pregnancy. Her initial serum β-human chorionic gonadotropin (hCG) concentration was 212,000 mIU/mL. Two months later, she has three serum β-hCG values: 88,000 mIU/mL, 87,000 mIU/mL, and 113,000 mIU/mL over a 2-week period. Pelvic ultrasonography shows a 4-cm intrauterine mass. Computed tomography (CT) reveals five metastatic lesions in the lungs, each measuring between 1 cm and 3 cm, and one 2-cm lesion in the spleen. Magnetic resonance imaging of the brain is unremarkable. The best next step in this patient’s management is

* (A) multiagent chemotherapy

(B) hysterectomy

(C) image-guided biopsy

(D) methotrexate with leucovorin rescue

(E) actinomycin D

High-risk gestational trophoblastic neoplasia is defined as either 1) International Federation of Gynecology and Obstetrics (FIGO) stage IV disease or 2) stage II or III disease with a World Health Organization (WHO) prognostic score of 7 points or more (Appendix C). In contrast, a WHO score of 6 or less defines low-risk category in which only 30% of patients with gestational trophoblastic neoplasia will become resistant to single-agent chemotherapy and subsequently require combination chemotherapy. Low-risk patients have a survival rate that approaches 100%.

Patients with a WHO score of 7 or more are considered a high-risk group, and treatment with multiagent chemotherapy is recommended because the risk of resistance to single-agent chemotherapy is high. The overall survival rate of this high-risk group is approximately 85%. Because gestational trophoblastic neoplasia can progress rapidly and poor outcomes are associated with delays in treatment, it is crucial to rapidly and accurately calculate the WHO prognostic score for every patient with gestational trophoblastic neoplasia so treatment can be initiated promptly. The described patient has stage IV gestational trophoblastic neoplasia based on splenic metastasis and has a WHO prognostic score of 8 points (0 points for age younger than 40 years; 0 points for incident pregnancy of a complete mole; 0 points for 2 months from index pregnancy; 4 points for pretreatment serum β-hCG of 100,000 IU/mL or greater; 1 point for the patient’s largest tumor measuring 4 cm; 2 points for six metastatic lesions; and 1 point for splenic metastasis). Appendix C lists the FIGO staging and WHO scoring system for gestational trophoblastic neoplasia.

Patients with high-risk disease should receive a multiagent chemotherapy. The regimen consists of etoposide, methotrexate, and actinomycin D (EMA), administered on days 1–2, and cyclophosphamide plus oncovin/vincristine (CO), given on day 8. This regimen is referred to as EMA-CO. Treatment is repeated every 14 days. Common adverse effects include alopecia, nausea, vomiting, bone marrow suppression (manifesting as anemia, neutropenia, and thrombocytopenia), and stomatitis. Other less common but more severe toxicities are the increased risk of acute myelogenous leukemia (for cumulative etoposide doses greater than 2,000 mg/m²) and hemorrhagic cystitis (caused by cyclophosphamide). Although there have not been randomized-controlled trials demonstrating the superiority of EMA-CO to other multiagent combinations, this regimen is relatively well tolerated and effective. Patients are treated until their serum β-hCG concentrations normalize and for at least two additional cycles of consolidative therapy after normalization of β-hCG concentrations. After completion of treatment, the serum β-hCG concentration is monitored monthly for 12 months. Throughout the treatment and surveillance periods, every effort should be made to prevent pregnancy. A new pregnancy complicates the interpretation of serum β-hCG concentration. Oral contraception is the preferred treatment because the pills suppress secretion of the luteinizing hormone and follicle-stimulating hormone from the pituitary gland, thereby reducing the interference with serum β-hCG measurements in the lower ranges.

Hysterectomy is offered to patients who have gestational trophoblastic neoplasia confined to the uterus and do not desire future childbearing. Patients with chemotherapy-resistant local disease also are candidates for hysterectomy. Because this patient has extrauterine sites of disease, hysterectomy at this time would not improve her prognosis and would delay chemotherapy, which is the potential curative treatment.

Image-guided biopsies are undertaken when a clinical diagnosis is uncertain. However, biopsy of postmolar gestational trophoblastic neoplasia is not recommended because it may cause profuse bleeding. The described patient’s lesions, as seen on CT, can be considered meta-static disease with a high degree of certainty. Scheduling the biopsy and the subsequent interpretation take valuable time, delaying treatment with the potentially life-saving chemotherapy.

Positron emission tomography–CT can be a helpful tool for diagnosing metastatic disease and monitoring treatment response to anticancer therapies. However, these scans are more expensive than traditional CT. Further, this patient’s CT has been able to identify numerous areas of concern for metastatic disease. Ordering a PET–CT is not cost-effective and would not alter her therapy.

As previously discussed, stage I gestational trophoblastic neoplasia or stage II/III gestational trophoblastic neoplasia with a low-risk WHO prognostic score (ie, less than 7 points) can be treated with single-agent chemotherapy. There are multiple regimens using either methotrexate or actinomycin D. Leucovorin, which is folinic acid, is used to overcome some of the toxicity related to methotrexate. Because this patient has a high-risk gestational trophoblastic neoplasia, she is at high risk of resistance to single-agent therapy and should immediately initiate multiagent chemotherapy with EMA-CO.

Alifrangis C, Agarwal R, Short D, Fisher RA, Sebire NJ, Harvey R, et al. EMA/CO for high-risk gestational trophoblastic neoplasia: good outcomes with induction low-dose etoposide-cisplatin and genetic analysis. J Clin Oncol 2013;31:280–6. doi: 10.1200/JCO.2012.43.1817

Eysbouts YK, Massuger, LF, IntHout J, Lok CA, Sweep, FC, Ottevanger PB. The added value of hysterectomy in the management of gestational trophoblastic neoplasia. Gynecol Oncol 2017;145:536–42. doi: S0090-8258(17)30234-2

National Comprehensive Cancer Network. Gestational trophoblastic neoplasia. Version 1.2020 NCCN Clinical Practice Guidelines in Oncology. NCCN; 2020. Accessed March 16, 2020. https://www.nccn.org/professionals/physician_gls/pdf/gtn.pdf

Ngan HY, Seckl MJ, Berkowitz RS, Xiang Y, Golfier F, Sekharan PK, et al. Update on the diagnosis and management of gestational trophoblastic disease. Int J Gynaecol Obstet 2018;143(suppl 2):79–85. doi: 10.1002/ijgo.12615

* Indicates correct answer.

Note: See Appendix A for a table of normal values for laboratory tests. See Appendix B for an explanation of ovarian cancer terminology in this edition.

7

Human papillomavirus primary screening

Your clinic has recently switched to primary human papillomavirus (HPV) testing for patients aged 30 years and older. The laboratory informs you that one of your patients has tested positive for high-risk, non-16/18 HPV. This patient has no history of abnormal cervical cytology or positive HPV tests. The best next step in management for this patient is

* (A) cervical cytology

(B) colposcopy

(C) loop electrosurgical excisional procedure (LEEP)

(D) repeat HPV test

In 2016, the U.S. Food and Drug Administration approved the first primary HPV screening test, and in 2018, the U.S. Preventive Services Task Force’s cervical cancer screening guidelines added the option for primary HPV screening every 5 years. These guidelines retained the screening options of cytology alone every 3 years and cervical cytology plus HPV co-testing every 5 years.

The randomized controlled Addressing the Need for Advanced HPV Diagnostics (referred to as ATHENA) trial, comparing cytology alone with primary HPV testing or co-testing, showed primary HPV testing was 39% more sensitive for detection of cervical intraepithelial neoplasia (CIN) 3+ compared with cytology alone; however, primary HPV testing was 16% less specific. Notably, geno-typing for HPV-16 or HPV-18 had a positive predictive value for CIN 3+ of 10.2% in the setting of normal cervical cytology. Co-testing did not significantly improve screening sensitivity compared with primary HPV testing.

The ATHENA trial also evaluated 10 triage strategies for cervical cancer screening management. These strategies included three screening options (cytology alone, primary HPV testing, and co-testing) followed by geno-typing triage, atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion cytology triage, or some combination of these three testing options. Genotyping of positive high-risk HPV tests with referral to colposcopy for positive HPV-16 or HPV-18 genotypes has a high sensitivity for CIN 3+. Specificity of a positive high-risk HPV test also can be increased with reflex cytology with referral to colposcopy if cytology shows atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion.

For the described patient who has a positive high-risk, non-16/18 HPV test, the best next step is reflex cervical cytology. If cervical cytology is abnormal, or if she had a diagnosis of HPV-16 or HPV-18, colposcopy would be recommended. Even in the setting of HPV-16 or HPV-18 genotyping, the addition of reflex cytology before colposcopy is preferred by the American Society for Colposcopy and Cervical Pathology Risk-Based Management Guidelines, because those reflex cytology results direct risk-based colposcopy (Table 7-1). Immediate colposcopy after a positive HPV test is not recommended without genotyping or cytology, or both, unless neither genotyping nor reflex cytology is feasible. Direct referral to colposcopy without additional testing would diagnose almost all cases of CIN 3+ (sensitivity 90%), but such testing also would result in a false-positive rate of 38%, which means that one third of colposcopies would be unnecessary and carry increased cost, inconvenience, and unnecessary interventions.

Similarly, an excisional procedure for a positive HPV test without additional evaluation would result in over-treatment for most patients because the independent immediate risk of CIN 3+ in the setting of an HPV-16-positive test (the highest risk HPV genotype) is less than 15%. However, a reflex high-grade squamous intraepithelial lesion cytology result (but not genotyping alone) after a positive HPV test provides the option of excision without intervening colposcopy when risk of CIN 3+ is sufficiently high, per the American Society for Colposcopy and Cervical Pathology’s Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors. Repeat HPV testing is an appropriate surveillance strategy after initial workup of a positive HPV test but is not appropriate without first performing reflex cervical cytology or genotyping for HPV-16 and HPV-18.

TABLE 7-1. Risk-Based Colposcopy Standards*

Abbreviations: ACG, atypical clustered glands; AIS, adenocarcinoma in situ; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesion.

*Data from Wentzensen N, et al. ASCCP Colposcopy Standards: Risk-Based Colposcopy Practice. J Low Genit Tract Dis 2017;21:230–4.

†ASCCP minimal colposcopic reporting standards:

Squamocolumnar junction visibility (fully visualized or not fully visualized)

Acetowhitening (yes or no)

Lesion(s) present (yes or no; acetowhite or other)

Colposcopic impression (normal or benign; low-grade; high-grade; cancer)

‡Insufficient evidence for or against nontarget biopsies in this population.

§Endocervical sampling can be done with a curette or a brush

Modified from Teoh D, Musa F, Salani R, Huh W, Jimenez E. Diagnosis and management of adenocarcinoma in situ: a Society of Gynecologic Oncology evidence-based review and recommendations. Obstet Gynecol 2020;135:869–78. doi: 10.1097/AOG.0000000000003761

In April 2020, the American Society for Colposcopy and Cervical Pathology’s Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors were released. They represent a consensus of 20 professional organizations and patient advocates. These guidelines rely on individual assessment of risk, considering past and current cervical cancer screening test results. These guidelines use technology (eg, smartphone applications or websites) that allow rapid evidence-based updates (https://www.asccp.org/guidelines).

Castle PE, Stoler MH, Wright TC Jr, Sharma A, Wright TL, Behrens CM. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study. Lancet Oncol 2011;12:880–90. doi: 10.1016/S1470-2045(11)70188-7

Cheung LC, Egemen D, Chen X, Katki HA, Demarco M, Wiser AL, et al. 2019 ASCCP risk-based management consensus guidelines: methods for risk estimation, recommended management, and validation. J Low Genit Tract Dis 2020;24:90–101. doi: 10.1097/LGT.0000000000000528

Cox JT, Castle PE, Behrens CM, Sharma A, Wright TC Jr, Cuzick J. Comparison of cervical cancer screening strategies incorporating different combinations of cytology, HPV testing, and genotyping for HPV 16/18: results from the ATHENA HPV study. Am J Obstet Gynecol 2013;208:184.e1–11. doi: 10.1016/j.ajog.2012.11.020

Huh WK, Ault KA, Chelmow D, Davey DD, Goulart RA, Garcia FA, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Gynecol Oncol 2015;136:178–82. doi: 10.1016/j.ygyno.2014.12.022

Melnikow J, Henderson JT, Burda BU, Senger CA, Durbin S, Weyrich MS. Screening for cervical cancer with high-risk human papilloma-virus testing: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA 2018;320:687–705. doi: 10.1001/jama.2018.10400

Perkins RB, Guido RS, Castle PE, Chelmow D, Einstein MH, Garcia F, et al. 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors. 2019 ASCCP Risk-Based Management Consensus Guidelines Committee. J Low Genit Tract Dis 2020;24:102–31. doi: 10.1097/LGT.0000000000000525

Teoh D, Musa F, Salani R, Huh W, Jimenez E. Diagnosis and management of adenocarcinoma in situ: a Society of Gynecologic Oncology evidence-based review and recommendations. Obstet Gynecol. 2020 Apr;135(4):869–878. doi: 10.1097/AOG.0000000000003761

Wright TC Jr, Stoler MH, Behrens CM, Apple R, Derion T, Wright TL. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol 2012;206:46.e1–11. doi: 10.1016/j.ajog.2011.07.024

* Indicates correct answer.

Note: See Appendix A for a table of normal values for laboratory tests. See Appendix B for an explanation of ovarian cancer terminology in this edition.

8

Vulvar cancer

You perform a modified radical vulvectomy and inguinal node dissection for stage II squamous cancer of the vulva (as classified by the International Federation of Gynecology and Obstetrics) on a fit 50-year-old woman. The primary tumor involves the posterior labium majus, perineal body, and anal mucosa, and it impinges on the anal sphincter. Final pathology shows microscopic involvement at the anal margin. No metastatic disease is detected, and the lymph nodes are not involved. The best next step in the treatment of this patient is

(A) chemotherapy

(B) observation

* (C) radiation

(D) re-resection

Vulvar cancer is relatively rare and accounts for less than 1% of cancer diagnoses in women in the United States. More than 95% of primary vulvar cancer diagnoses are squamous cell: the second most common type of vulvar cancer is melanoma. Primary adenocarcinoma, sarcoma, and basal cell neoplasms occur less commonly.

The prognosis for vulvar cancer generally is favorable. According to the International Federation of Gynecology and Obstetrics, the 5-year survival rate for patients with stage I disease is 79%. Five-year survival rates for patients with stages II, III, and IV disease are 59%, 43%, and 13%, respectively.

Vulvar cancer primarily is treated and staged surgically. Superficially invasive (ie, less than 1 mm) tumors are well managed with wide local excision. Deeper and larger tumors are treated more aggressively. Patients who have tumors confined to the vulva with stromal invasion that is greater than 1 mm are managed with modified radical vulvectomy and inguinal node assessment. Sentinel node dissection has been shown to be a reliable substitute for inguinal lymphadenectomy and is associated with far lower morbidity. Treatment with primary chemoradiation is recommended for patients with large tumors, those whose tumors have obviously spread to involve more than the lower vagina, urethra, or anus, or those in whom an adequate resection cannot be achieved without sacrificing continence.

Chemotherapy has a role as a radiosensitizer in the primary management of bulky unresectable vulvar cancer. In addition, systemic treatment with a variety of agents, including cisplatin, 5-fluorouracil, paclitaxel, vinorelbine, and mitomycin-C, has been used for treatment of recurrence and for palliation. Response rates are low. There has been interest in newer biologics, such as gefitinib and erlotinib, that target the epidermal growth factor receptor; however, additional studies are needed to define a possible role in the management of vulvar cancer before it can be recommended for patients such as the one described.

Observation alone is associated with a high risk of recurrence. Several studies have shown that recurrence risk is related to margin status. Although close observation might spare some patients treatment-related morbidity, the high likelihood of regrowth with an involved margin and the higher morbidity associated with treatment of recurrent disease points to a recommendation for additional treatment when margins are positive.

Resection for close, or positive, margins is a good option for patients in whom additional surgery in the midline would not cause incontinence or when the patient’s margin in question is lateral or anterior. In this patient with a microscopically involved anal margin up to the sphincter, re-resection to achieve an adequate margin would necessitate anal resection, thereby risking incontinence and the need for colostomy. Therefore, re-resection in her should be avoided when there are other therapeutic alternatives.

The National Comprehensive Cancer Network guidelines advise radiation for postoperative management of a patient with stage II disease and a positive margin. The risk of significant morbidity associated with extensive resection of the anal sphincter indicates a strong preference for avoiding surgical management. In patients with locally advanced disease, radiation therapy is highly effective. In a series of 38 patients treated at the University of Pittsburgh, there were no reported instances of serious or life-threatening gastrointestinal or genitourinary toxici-ties. A lower dose of radiation to sterilize a positive margin will be