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Gynecology_Novak. 378. Long HJ, Pfeiﬂe DM, Wieand HS, et al. Phase II evaluation of carboplatin in advanced endometrial carcinoma. J Natl Cancer Inst 1988;80:276–278. 385. Miller DS, Blessing JA, Lentz SS, et al. A phase II trial of topotecan in patients with advanced, persistent, or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Gyneocol Oncol 2002;87:247–251. 386. Wadler S, Levy DE, Lincoln ST, et al. Topotecan is an active agent in first line treatment of metastatic or recurrent endometrial carcinoma. Eastern Oncology Cooperative Group Study E3E93. J Clin Oncol 2003;21:2110–2114. 387. Aapro MS, van Wijk FH, Bolis G, et al. Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomized study by the EORTC Gynecologic Cancer Group. Ann Oncol 2003;14:441–448. 388.


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Gynecology_Novak. 388. Edmonson JH, Krook JE, Hilton JF, et al. Randomized phase II studies of cisplatin and a combination of a cyclophosphamidedoxorubicin-cisplatin (CAP) in patients with progestin-refractory advanced endometrial carcinoma. Gynecol Oncol 1987;28:20– 24. 389. Burke TW, Stringer CA, Morris M, et al. Prospective treatment of advanced or recurrent endometrioid carcinoma with cisplatin, doxorubicin, and cyclophosphamide. Gynecol Oncol 1991;40:264– 267. 390. Dimopoulos MP, Papadimitriou CA, Georgoulias V, et al. Paclitaxel and cisplatin in advanced or recurrent carcinoma of the endometrium: long-term results of a phase II multicenter study. Gynecol Oncol 2000;78:52–57. 391. Creasman WT, Odicino F, Maisonneuve P, et al. Carcinoma of 418. Hauptman S, Nadjari B, Kraus J, et al. Uterine tumor resembling ovarian sex-cord tumor: a case report and review of the literature. Virchows Arch 2001;439:97–101. 419.


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Gynecology_Novak. Hauptman S, Nadjari B, Kraus J, et al. Uterine tumor resembling ovarian sex-cord tumor: a case report and review of the literature. Virchows Arch 2001;439:97–101. 419. Taylor HB, Norris HJ. Mesenchymal tumors of the uterus. IV. Diagnosis and prognosis of leiomyosarcoma. Arch Pathol 1966;82:40–44. 420. Gudgeon DH. Leiomyosarcoma of the uterus. Obstet Gynecol 1968;32:96–100. 421. Silverberg SG. Leiomyosarcoma of the uterus: a clinicopathologic study. ObstetGynecol 1971;38:613–628. 422. Christopherson WM, Williamson EO, Gray LA. Leiomyosarcoma of the uterus.Cancer 1972;29:1512–1517. 423. Gallup DG, Cordray DR. Leiomyosarcoma of the uterus: case reports and a review. Obstet Gynecol Surv 1979;34:300–312. 424. Vardi JR, Tovell HMM. Leiomyosarcoma of the uterus: clinicopathologic study. Obstet Gynecol 1980;56:428–434. 425. Van Dinh T, Woodruff JD. Leiomyosarcoma of the uterus. Am J Obstet Gynecol 1982;144:817–823. 426.


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Gynecology_Novak. 425. Van Dinh T, Woodruff JD. Leiomyosarcoma of the uterus. Am J Obstet Gynecol 1982;144:817–823. 426. Berchuck A, Rubin SC, Hoskins WJ, et al. Treatment of uterine leiomyosarcoma. Obstet Gynecol 1988;71:845–850. 427. Leibsohn S, d’Ablaing G, Mishell DR, et al. Leiomyosarcoma in a series of hysterectomies performed for presumed uterine leiomyomas. Am J Obstet Gynecol 1990;162:968–976. 428. Giuntoli RL 2nd, Metzinger DS, DiMarco CS, et al. Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy. Gynecol Oncol 2003;89:460–469. 429. Dinh TA, Oliva EA, Fuller AF Jr, et al. The treatment of uterine leiomyosarcoma: results from a 10-year experience (1990–1999) at the Massachusetts General Hospital. Gynecol Oncol 2004;92: 648–652. 430. Bell SW, Kempson RL, Hendrickson MR. Problematic uterine smooth muscle neoplasms: a clinicopathologic study of 213 cases. Am J Surg Pathol 1994;18:535–558. 431.


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Gynecology_Novak. 430. Bell SW, Kempson RL, Hendrickson MR. Problematic uterine smooth muscle neoplasms: a clinicopathologic study of 213 cases. Am J Surg Pathol 1994;18:535–558. 431. King ME, Dickersin GR, Scully RE. Myxoid leiomyosarcoma of the uterus: a report of six cases. Am J Surg Pathol 1982;6:589–598. 432. Kurman RJ, Norris HJ. Mesenchymal tumors of the uterus. VI. Epithelioid smooth muscle tumors including leiomyoblastoma and clear cell leiomyoma: a clinical and pathologic analysis of 26 cases. Cancer 1976;37:1853–1865. 433. Prayson RA, Goldblum JR, Hart WR. Epithelioid smooth muscle tumors of the uterus: a clinicopathologic study of 18 patients. Am J Surg Pathol 1997;21:383–391. 434. Norris HJ, Parmley T. Mesenchymal tumors of the uterus. V. Intravenous leiomyomatosis: a clinical and pathologic study. Cancer 1975;36:2164–2178. 435. Scharfenberg JC, Geary WL. Intravenous leiomyomatosis. Obstet Gynecol 1974;43:909–914. 436.


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Gynecology_Novak. 435. Scharfenberg JC, Geary WL. Intravenous leiomyomatosis. Obstet Gynecol 1974;43:909–914. 436. Evans AT III, Symmonds RE, Gaffey TA. Recurrent pelvic intravenous leiomyomatosis.Obstet Gynecol 1981;57:260–264. 437. Clement PB, Young RH, Scully RE. Intravenous leiomyomatosis of the uterus: a clinicopathologic analysis of 16 cases with unusual histologic features. Am J Surg Pathol 1988;12:932–945. 438. Abell MR, Littler ER. Benign metastasizing uterine leiomyoma: multiple lymph node metastases. Cancer 1975;36:2206–2213. 439. Banner AS, Carrington CB, Emory WB, et al. Efficacy of oophorectomy in lymph-angioleiomyomatosis and benign metastasizing leiomyoma. N Engl J Med 1981;305:204–209. 440. Tavassoli FA, Norris HJ. Peritoneal leiomyomatosis (leiomyomatosis peritoneal disseminata): a clinicopathologic study of 20 cases with ultrastructural observations. Int J Gynecol Pathol 1982;1: 59–74. 441. Norris HJ, Roth E, Taylor HB. Mesenchymal tumors of the uterus.


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Gynecology_Novak. 441. Norris HJ, Roth E, Taylor HB. Mesenchymal tumors of the uterus. II. A clinical and pathologic study of 31 mixed mesodermal tumors. Obstet Gynecol 1966;28:57–63. 442. Norris HJ, Taylor HB. Mesenchymal tumors of the uterus. III. A clinical pathologic study of 31 carcinosarcomas. Cancer 1966;19:1459–1465. 443. Silverberg SG, Major FJ, Blessing JA, et al. Carcinosarcoma (malignant mixed mesodermal tumor) of the uterus: a Gynecologic Oncology Group pathologic study of 203 cases. Int J Gynecol Pathol 1990;9:1–19. 444. Inthasorn P, Carter J, Valmadre S, et al. Analysis of clinicopathologic factors in malignant mixed mullerian tumors of the uterine corpus. Int J Gynecol Cancer 2002;12:348–353. 445. DiSaia PJ, Castro JR, Rutledge FN. Mixed mesodermal sarcoma of the uterus. AJR Am J Roentgenol 1973;117:632–636. 446.


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Gynecology_Novak. 445. DiSaia PJ, Castro JR, Rutledge FN. Mixed mesodermal sarcoma of the uterus. AJR Am J Roentgenol 1973;117:632–636. 446. Yamada SD, Burger RA, Brewster WR, et al. Pathologic variables and adjuvant therapy as predictors of recurrence and survival for patients with surgically evaluated carcinoma of the uterus. Cancer 2000;88:2782–2786. 447. Macasaet MA, Waxman M. Fruchter RG, et al. Prognostic factors in malignant mesodermal (mullerian) mixed tumors of the uterus. Gynecol Oncol 1985;20:32–42. 448. DiSaia PJ, Morrow CP, Boronow R, et al. Endometrial sarcoma: lymphatic spread pattern. Am J Obstet Gynecol 1978;130:104–105. 449. Geszler G, Szpak CA, Harris RE, et al. Prognostic value of peritoneal washings in patients with malignant mixed mullerian tumors of the uterus. Am J Obstet Gynecol 1986;155:83–89. 450. Clement PB, Scully RE. Mullerian adenosarcoma of the uterus: a clinico-pathologic analysis of 100 cases with a review of the literature. Hum Pathol 1990;21:363–381.


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Gynecology_Novak. 450. Clement PB, Scully RE. Mullerian adenosarcoma of the uterus: a clinico-pathologic analysis of 100 cases with a review of the literature. Hum Pathol 1990;21:363–381. 451. Kaku T, Silverberg SG, Major FJ. Adenosarcoma of the uterus: a Gynecologic Oncology Group study of 31 cases. Int J Gynecol Pathol 1992;11:75–88. 452. Salazar OM, Bonfiglio TA, Patten SF, et al. Uterine sarcomas: analysis of failures with special emphasis on the use of adjuvant radiation therapy. Cancer 1978;42:1161–1170. 453. Spanos WJ, Peters LJ, Oswald MJ. Patterns of recurrence in malignant mixed mullerian tumors of the uterus. Cancer 1986;57:155–159. 454. Vongtama V, Karlen JR, Piver MS, et al. Treatment results and prognostic factors in stage I and II sarcomas of the corpus uteri. AJR Am J Roentgenol 1976;126:139–147. 455. Leitao MM, Brennan MF, Hensley M, et al. Surgical resection of pulmonary and extrapulmonary recurrences of uterine leiomyosarcoma. Gynecol Oncol 2002;87:287–294. 456.


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Gynecology_Novak. 455. Leitao MM, Brennan MF, Hensley M, et al. Surgical resection of pulmonary and extrapulmonary recurrences of uterine leiomyosarcoma. Gynecol Oncol 2002;87:287–294. 456. Belgrad R, Elbadawi N, Rubin P. Uterine sarcomas. Radiology 1975;114:181–188. 457. Salazar OM, Bonfiglio TA, Patten SF, et al. Uterine sarcomas: natural history, treatment, and prognosis. Cancer 1978;42:1152–1160. 458. Perez CA, Askin F, Baglan RJ, et al. Effects of irradiation on mixed mullerian tumors of the uterus. Cancer 1979;43:1274–1284. 459. Hornback NB, Omura G, Major FJ. Observations on the use of adjuvant radiation therapy in patients with stage I and II uterine sarcoma. Int J Radiat Oncol Biol Phys 1986;12:2127–2130. 460. Knocke TH, Kucera H, Dotﬂer D, et al. Results of postoperative radiotherapy in the treatment of sarcoma of the corpus uteri. Cancer 1998;83:1972–1979. 461.


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Gynecology_Novak. 460. Knocke TH, Kucera H, Dotﬂer D, et al. Results of postoperative radiotherapy in the treatment of sarcoma of the corpus uteri. Cancer 1998;83:1972–1979. 461. Molpus KL, Redlin-Frazier S, Reed G, et al. Postoperative pelvic irradiation in early stage uterine mixed mullerian tumors. Eur J Gynecol Oncol 1998;19:541–546. 462. Le T. Adjuvant pelvic radiotherapy for uterine carcinosarcoma in a high-risk population. Eur J Surg Oncol 2001;27:282–285. 463. Livi L, Paiar F, Shah N, et al. Uterine sarcoma: twenty-seven years experience. Int J Radiat Oncol Biol Phys 2003;57:1366–1373. 464. Menczer J, Levy T, Piuva B, et al. A comparison between different postoperative treatment modalities of uterine carcinosarcoma. Gynecol Oncol 2005;97:166–170. 465.


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Gynecology_Novak. 464. Menczer J, Levy T, Piuva B, et al. A comparison between different postoperative treatment modalities of uterine carcinosarcoma. Gynecol Oncol 2005;97:166–170. 465. Reed NS, Mangioni C, Malmstrom H, et al. Phase III randomized study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: an EORTC Gynaecological Cancer Group study (protocol 55874). Int J Gynecol Cancer 2003;13:4. 466. Wolfson AH, Brady MF, Rocereto TF, et al. Gynecologic Oncology Group randomized trial of whole abdominal irradiation (WAI) vs cisplatin-ifosfamide+mesna (CIM) in optimally debulked stage I-IV carcinosarcoma (CS) of the uterus. J Clin Oncol 2006;24: 5001. 467. Kanjeekal S, Chambers A, Fung MF, et al. Systemic therapy for advanced uterine sarcoma: a systemic review of the literature. Gynecol Oncol 2005;97:624–637. 468.


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Gynecology_Novak. 467. Kanjeekal S, Chambers A, Fung MF, et al. Systemic therapy for advanced uterine sarcoma: a systemic review of the literature. Gynecol Oncol 2005;97:624–637. 468. Omura GA, Blessing JA, Major F, et al. A randomized study of adriamycin with and without triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer 1983;52:626–632. 469. Sutton G, Blessing J, Barrett R, et al. Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus: a Gynecology Oncology Group study. Am J Obstet Gynecol 1992;166:556–559. 470. Thigpen JT, Blessing JA, Beecham J, et al. Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent uterine sarcomas: a Gynecologic Oncology Group study. J Clin Oncol 1991;9:1962. 471. Gershenson DM, Kavanagh JJ, Copeland LJ, et al. Cisplatin therapy for a disseminated mixed mesodermal sarcoma of the uterus. J Clin Oncol 1987;5:618–621. 472.


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Gynecology_Novak. 471. Gershenson DM, Kavanagh JJ, Copeland LJ, et al. Cisplatin therapy for a disseminated mixed mesodermal sarcoma of the uterus. J Clin Oncol 1987;5:618–621. 472. Sutton GP, Blessing JA, Rosenshein N, et al. Phase II trial of ifosfamide and mesna in mixed mesodermal tumors of the uterus: a Gynecologic Oncology Group Study. Am J Obstet Gynecol 1989;161:309– 312. 473. Curtin JP, Blessing JA, Soper JT, et al. Paclitaxel in the treatment of carcinosarcoma of the uterus: a Gynecologic Oncology Group Study. Gynecol Oncol 2001;83:268–270. 474. Sutton G, Blessing JA, Ball H. Phase II trial of paclitaxel in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol 1999;74:346–349. 475. Look KY, Sandler A, Blessing JA, et al. Phase II trial of gemcitabine as second-line chemotherapy of uterine leiomyosarcoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004;92:644– 647. 476.


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Gynecology_Novak. Look KY, Sandler A, Blessing JA, et al. Phase II trial of gemcitabine as second-line chemotherapy of uterine leiomyosarcoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004;92:644– 647. 476. Sutton G, Blessing J, Hanjani P, et al. Phase II evaluation of liposomal doxorubicin (Doxil) in recurrent or advanced leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol 2005;96:749–752. 477. Gottlieb JA, Baker LH, O’Bryan RM, et al. Adriamycin used alone and in combination for soft tissue and bony sarcomas. Cancer Chemother Rep (Part 3) 1975;6:271–282. 478. Blum RH, Corson JM, Wilson RE, et al. Successful treatment of metastatic sarcomas with cyclophosphamide, Adriamycin, and DTIC (CAD). Cancer 1980;46:1722–1726. 479. Piver MS, DeEulis TG, Lele SB, et al. Cyclophosphamide, vincristine, adriamycin, and dimethyltriazenoimidazole carboxamide (CYVADIC) for sarcomas of the female genital tract. Gynecol Oncol 1981;14:319–323. 480.


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Gynecology_Novak. 480. Pearl ML, Inagami M, McCauley DL, et al. Mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) chemotherapy for gynecologic sarcomas. Int J Gynecol Cancer 2002;12:745–748. 481. Hensley ML, Maki R, Venkatraman E, et al. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma. J Clin Oncol 2002;20:2824–2831. 482. Nordal RN, Kjørstad KE, Stenwig AE, et al. Leiomyosarcoma (LMS) and endometrial stromal sarcoma (ESS) of the uterus: a survey of patients treated in the Norwegian Radium Hospital 1976–1985. Int J Gynecol Cancer 1993;3:110–115. 483. Berchuck A, Rubin SC, Hoskins WJ, et al. Treatment of endometrial stromal tumors. Gynecol Oncol 1990;36:60–65. 484. Sutton G, Brunetto VL, Kilgore L, et al. A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol 2000;79:47–53. 485.


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Gynecology_Novak. 485. Homesley HD, Filiaci V, Markman M, et al. Gynecologic Oncology Group. Phase III trial of ifosfamide versus ifosfamide plus paclitaxel as first-line treatment of advanced or recurrent uterine carcinosarcoma (mixed mesodermal tumors): a Gynecologic Oncology Group study. J Clin Oncol 2007;25:526–531. 486. Toyoshima M, Akahira J, Matsunaga G, et al. Clinical experiences with combination paclitaxel and carboplatin therapy for advanced or recurrent carcinosarcoma for the uterus. Gynecol Oncol 2004;94:774–778. 487. Omura GA, Blessing JA, Major F, et al. A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group study. J Clin Oncol 1985;3:1240–1245. Caela Miller John C. Elkas Human papillomavirus (HPV) infection is the causal agent of cervical cancer. Screening programs are effective at decreasing the incidence of cervical cancer. Vaccines also help decrease the incidence of cervical cancer.


Gynecology_Novak

Gynecology_Novak. Screening programs are effective at decreasing the incidence of cervical cancer. Vaccines also help decrease the incidence of cervical cancer. The most common histologic type of cervical cancer is squamous, and the relative and absolute incidence of adenocarcinoma is increasing; both histologies are caused by HPV infection. Cervical cancer is clinically staged, although modern radiographic modalities such as computed tomography, magnetic resonance imaging, ultrasound, or positron emission tomography may be beneficial for individual treatment planning. Treatment of cervical cancer is based on stage of disease. Early stage disease (stages I to IIA) can be treated with either radical surgery or radiation therapy. Advanced stage disease (stages IIB to IV) is best treated with chemoradiation.


Gynecology_Novak

Gynecology_Novak. Vaginal cancer is a rare disease with many similarities to cervical cancer. Radiation therapy is the mainstay of treatment for most patients; however, select patients may be treated with radical surgery.


Gynecology_Novak

Gynecology_Novak. Cervical cancer ranks as the third most common gynecologic neoplasm in the United States, behind cancer of the corpus and ovary, mainly as a result of the effectiveness of screening programs. Worldwide, cervical carcinoma continues to be a significant health care problem. In developing countries, where health care resources are limited, cervical carcinoma is the second most frequent cause of cancer death in women. Because cervical cancer is preventable, it is imperative that gynecologists and other primary health care providers to women be familiar with vaccination programs, screening techniques, diagnostic procedures, and risk factors for cervical cancer and management of preinvasive disease. Vaginal cancer is a rare tumor that shares an epidemiology and risk factor profile that is similar to cervical cancer.


Gynecology_Novak

Gynecology_Novak. Invasive cancer of the cervix is considered a preventable disease because it has a long preinvasive state, cervical cytology screening programs are currently available, and the treatment of preinvasive lesions is effective. In spite of the preventable nature of this disease, 12,710 new cases of invasive cervical cancer resulting in 4290 deaths were anticipated in the United States in 2011 (1). Nationally, the lifetime probability of developing cervical cancer is 1:128. Although screening programs in the United States are well established, it is estimated that 30% of cervical cancer cases will occur in women who have never had a Papanicolaou (Pap) test. In developing countries, this percentage approaches 60% (2). Nevertheless, the worldwide incidence of invasive disease is decreasing, and cervical cancer is being diagnosed earlier, leading to better survival rates (1,3). The mean age for cervical cancer in the United States is 47 years, and the distribution of cases is bimodal, with


Gynecology_Novak

Gynecology_Novak. cervical cancer is being diagnosed earlier, leading to better survival rates (1,3). The mean age for cervical cancer in the United States is 47 years, and the distribution of cases is bimodal, with peaks at 35 to 39 years and 60 to 64 years of age (1).


Gynecology_Novak

Gynecology_Novak. There are numerous risk factors for cervical cancer: young age at first intercourse (younger than 16 years), multiple sexual partners, cigarette smoking, race, high parity, low socioeconomic status, and chronic immune suppression. The relationship to oral contraceptive use was debated. Some investigators proposed that use of oral contraceptives might increase the incidence of cervical glandular abnormalities; however, this hypothesis was not consistently supported (4,5). Many of these risk factors are linked to sexual activity and exposure to sexually transmitted diseases. Infection with the herpes virus was thought to be the initiating event in cervical cancer; however, infection with human papillomavirus (HPV) was determined to be the causal agent in the development of cervical cancer, with herpes virus and Chlamydia trachomatis likely acting as cofactors. The role of human immunodeficiency virus (HIV) in cervical cancer is mediated through immune suppression (4). The Centers for


Gynecology_Novak

Gynecology_Novak. with herpes virus and Chlamydia trachomatis likely acting as cofactors. The role of human immunodeficiency virus (HIV) in cervical cancer is mediated through immune suppression (4). The Centers for Disease Control and Prevention described cervical cancer as an acquired immune deficiency syndrome (AIDS)–defining illness in patients infected with HIV (6).


Gynecology_Novak

Gynecology_Novak. The initiating event in cervical dysplasia and carcinogenesis is infection with HPV. HPV infection was detected in up to 99% of women with squamous cervical carcinoma. HPV is the causative agent in both squamous and adenocarcinoma of the cervix, but the respective tumors may have different carcinogenic pathways (7). There are more than 100 different types of HPV, more than 30 of which can affect the lower genital tract. There are 14 high-risk HPV subtypes; two of the high-risk subtypes, 16 and 18, are found in up to 62% of cervical carcinomas. The mechanism by which HPV affects cellular growth and differentiation is through the interaction of viral E6 and E7 proteins with tumor suppressor genes p53 and Rb, respectively. Inhibition of p53 prevents cell cycle arrest and cellular apoptosis, which normally occurs when damaged DNA is present, whereas inhibition of Rb disrupts transcription factor E2F, resulting in unregulated cellular proliferation (8). Both steps are essential for the


Gynecology_Novak

Gynecology_Novak. which normally occurs when damaged DNA is present, whereas inhibition of Rb disrupts transcription factor E2F, resulting in unregulated cellular proliferation (8). Both steps are essential for the malignant transformation of cervical epithelial cells. Two HPV vaccines, the quadrivalent Gardasil and the bivalent Cervarix, are approved by the U.S. Food and Drug Administration (FDA) and protect against subtypes 16 and 18. After 3 years, the efficacy of Gardasil was 99% for preventing cervical intraepithelial neoplasia grades 2 and 3 caused by HPV 16 or 18 in females who were not previously infected with either HPV 16 or 18 before vaccination; however, efficacy was only 44% in those who were infected prior to vaccination (9). Because the quadrivalent and bivalent HPV vaccines both protect only against certain types of HPV, vaccinated women need to continue to receive Pap test screening according to guidelines.


Gynecology_Novak

Gynecology_Novak. Evaluation Vaginal bleeding is the most common symptom occurring in patients with cancer of the cervix. Most often, this is postcoital bleeding, but it may occur as irregular or postmenopausal bleeding. Patients with advanced disease may present with a malodorous vaginal discharge, weight loss, or obstructive uropathy. In asymptomatic women, cervical cancer is most commonly identified through evaluation of abnormal cytologic screening tests. The false-negative rate for Pap tests in the presence of invasive cancer is up to 50%, so a negative Pap test should never be relied on in a symptomatic patient (10). Initially, all women suspected of having cervical cancer should have a general physical examination performed to include evaluation of the supraclavicular, axillary, and inguinofemoral lymph Figure 36.1 Gross appearance of cervical cancer on examination.


Gynecology_Novak

Gynecology_Novak. Figure 36.1 Gross appearance of cervical cancer on examination. Colposcopic Findings of Invasion nodes to exclude the presence of metastatic disease. On pelvic examination, a speculum is inserted into the vagina, and the cervix is inspected for suspicious areas (Fig. 36.1). The vaginal fornices also should be closely inspected. With invasive cancer, the cervix is usually firm and expanded, and these features should be confirmed by digital examination. Rectal examination is important to help establish cervical consistency and size, particularly in patients with endocervical carcinomas. Rectal examination is the only way to determine cervical size if the vaginal fornices have been obliterated by menopausal changes or by the extension of disease. Parametrial extension of disease is best determined by the finding of nodularity beyond the cervix on rectal examination.


Gynecology_Novak

Gynecology_Novak. When obvious tumor growth is present, a cervical biopsy is usually sufficient for diagnosis. If gross disease is not present, a colposcopic examination with cervical biopsies and endocervical curettage is warranted. If the diagnosis cannot be established conclusively with colposcopy and directed biopsies, which may be the case with adenocarcinoma, cervical conization may be necessary.


Gynecology_Novak

Gynecology_Novak. Colposcopic examination is mandatory for patients with suspected early invasive cancer based on cervical cytology and a grossly normal-appearing cervix. Colposcopic findings that suggest invasion are (i) abnormal blood vessels, (ii) irregular surface contour with loss of surface epithelium, and (iii) color tone change. Colposcopically directed biopsies may permit the diagnosis of frank invasion and thus avoid the need for diagnostic cone biopsy, allowing treatment to be administered without delay. If there is debate about the depth of invasion based on the cervical biopsies, and if the clinical stage may be upstaged to stage IA2 or IB1, the patient should undergo a conization. In the presence of a large cervical biopsy specimen showing invasion greater than 3 mm, or two biopsy specimens separated by 7 mm showing invasive cervical carcinoma, therapy should proceed without delay, and the patient could undergo radical surgery or radiation therapy.


Gynecology_Novak

Gynecology_Novak. Abnormal Blood Vessels Abnormal vessels may be looped, branched, or reticular. Abnormal looped vessels are the most common colposcopic finding and arise from the punctated and mosaic vessels present in cervical intraepithelial neoplasia (CIN). As the neoplastic growth process proceeds and the need for oxygen and nutrition increases, angiogenesis occurs as a result of tumor and local tissue production of vascular endothelial growth factor (VEGF),


Gynecology_Novak

Gynecology_Novak. Histologic Appearance of Invasion platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and other cytokines, resulting in the proliferation of blood vessels and neovascularization. Punctate vessels push out over the surface of the epithelium in an erratic fashion, producing the looped, corkscrew, or J-shaped pattern of abnormal vessels characteristic of invasive disease. Abnormal blood vessels arise from the cervical stroma and are pushed to the surface as the underlying cancer invades. The normally branching cervical stromal vessels are best observed over nabothian cysts. In this area, the branches are generally at acute angles, with the caliber of vessels becoming smaller after branching, much like the arborization of a tree. The abnormal branching blood vessels seen with cancer tend to form obtuse or right angles, with the caliber sometimes enlarging after branching. Sharp turns, dilations, and luminal narrowing also characterize these vessels. The surface


Gynecology_Novak

Gynecology_Novak. seen with cancer tend to form obtuse or right angles, with the caliber sometimes enlarging after branching. Sharp turns, dilations, and luminal narrowing also characterize these vessels. The surface epithelium may be lost in these areas, leading to irregular surface contour and friability.


Gynecology_Novak

Gynecology_Novak. Abnormal reticular vessels represent the terminal capillaries of the cervical epithelium. Normal capillaries are best seen in postmenopausal women with atrophic epithelium. When cancer involves this epithelium, the surface is eroded, and the capillary network is exposed. These vessels are very fine and short and appear as small comma-shaped vessels without an organized pattern. They are not specific to invasive cancer; atrophic cervicitis may also have this appearance. Irregular Surface Contour Abnormal surface patterns are observed as tumor growth proceeds. The surface epithelium ulcerates as the cells lose intercellular cohesiveness secondary to loss of desmosomes. Irregular contour may occur as a result of papillary characteristics of the lesion. This finding can be confused with a benign HPV papillary growth on the cervix. For that reason, biopsies should be performed on all papillary cervical growths to avoid missing invasive disease.


Gynecology_Novak

Gynecology_Novak. Color Tone Color tone may change as a result of increasing vascularity, surface epithelial necrosis, and in some cases, production of keratin. The color tone is yellow-orange rather than the expected pink of intact squamous epithelium or the red of the endocervical epithelium. Adenocarcinoma Adenocarcinoma of the cervix does not have a specific colposcopic appearance. All of the aforementioned blood vessels may be seen in these lesions. Because adenocarcinomas tend to develop within the endocervix, endocervical curettage is required as part of the colposcopic examination, and traditional screening methods are less reliable (10).


Gynecology_Novak

Gynecology_Novak. Cervical conization is required to assess correctly the depth and the linear extent of involvement when microinvasion is suspected. Early invasion is characterized by a protrusion of malignant cells from the stromal–epithelial junction. This focus consists of cells that appear better differentiated than the adjacent noninvasive cells and have abundant pink-staining cytoplasm, hyperchromatic nuclei, and small-to medium-sized nucleoli (11). These early invasive lesions form tonguelike processes without measurable volume and are classified as International Federation of Gynecology and Obstetrics (FIGO) stage IA1. With further progression, more tonguelike processes and isolated malignant cells appear in the stroma, followed by a proliferation of fibroblasts (desmoplasia) and a bandlike infiltration of chronic inﬂammatory cells (Fig. 36.2). With increasing depth of invasion, lesions occur at multiple sites, and the growth becomes measurable by depth and linear extent. Lesions that are less


Gynecology_Novak

Gynecology_Novak. of chronic inﬂammatory cells (Fig. 36.2). With increasing depth of invasion, lesions occur at multiple sites, and the growth becomes measurable by depth and linear extent. Lesions that are less than 3 mm in depth are classified as FIGO stage IA1. Lesions that are 3 to 5 mm or more in depth and up to 7 mm in linear extent are classified as FIGO stage IA2 (12). As the depth of stromal invasion increases, so does the risk of capillary lymphatic space involvement. Dilated capillaries, lymphatic spaces, and foreign-body multinucleated giant cells containing keratin debris are often seen in the stroma.


Gynecology_Novak

Gynecology_Novak. The depth of invasion should be measured with a micrometer from the base of the epithelium to the deepest point of invasion. Depth of invasion is a significant predictor for the development of pelvic lymph node metastasis and tumor recurrence. Although lesions that have invaded 3 mm or less rarely metastasize, patients in whom lesions invade between 3 to 5 mm have positive pelvic lymph nodes in 3% to 8% of cases (13). The significance of the cutoff at 3 mm is not identified completely; it was postulated that small capillary–lymphatic spaces at this level are incapable of facilitating the transport of malignant cells. Uneven shrinkage of tissue by fixative often creates space between the tumor nests and the surrounding fibrous stroma, simulating vascular lymphatic invasion (Fig. 36.2). Therefore, suspected vascular–lymphatic involvement


Gynecology_Novak

Gynecology_Novak. Figure 36.2 Microinvasive squamous carcinoma. Multiple irregular tonguelike processes and isolated nests of malignant cells are seen, some surrounded by clear spaces, simulating capillary lymphatic invasion. This is an artifact caused by tissue shrinkage. The depth of stromal invasion is measured from the basement membrane of the overlying cervical intraepithelial neoplasia (CIN). In this case, it is 1.2 mm. with invasion of less than 3 mm should be interpreted with care. A lack of endothelial lining indicates that the space is a fixation artifact rather than true vascular invasion.


Gynecology_Novak

Gynecology_Novak. Staging Cervical cancer is a clinically staged disease. The FIGO staging system is the standard and is applicable to all histologic types of cervical cancer. The FIGO staging system is presented in Table 36.1 and Figure 36.3. The staging procedures allowed by FIGO are listed in Table 36.2. When there is doubt concerning the stage to which a cancer should be allocated, the earlier stage should be selected. After a clinical stage is assigned and treatment is initiated, the stage must not be changed because of subsequent findings by either extended clinical staging or surgical staging. The upstaging of patients during treatment will produce an erroneous perception of improvement in the results of treatment of low-stage disease. Following is a breakdown of the incidence of cervical cancer by stage at diagnosis: 38%, stage I; 32%, stage II; 26%, stage III; and 4%, stage IV (3,13,14).


Gynecology_Novak

Gynecology_Novak. Various investigators used lymphangiography, computed tomography (CT), ultrasonography, magnetic resonance imaging (MRI), and positron emission tomography (PET) in an attempt to improve the accuracy of clinical staging (15–25). These modalities suffer from poor sensitivity and high false-negative rates. Evaluation of the para-aortic lymph nodes with lymphangiography is associated with a false-positive rate of 20% to 40% and a false-negative rate of 10% to 20% (15–17). Overall, lymphangiography has a sensitivity of 79% and specificity of 73% (20). CT has poor sensitivity (34%) but excellent specificity (97%) (21). The accuracy of CT scanning is 80% to 85%; the false-negative rate is 10% to 15%, and the false-positive rate is 20% to 25% (16–18). Ultrasound has a high false-negative rate (30%), low sensitivity (19%), but high specificity (99%) (19). Early data showed that MRI results were comparable to those of CT scanning, a finding confirmed on meta-analysis (21,22). However, a


Gynecology_Novak

Gynecology_Novak. (30%), low sensitivity (19%), but high specificity (99%) (19). Early data showed that MRI results were comparable to those of CT scanning, a finding confirmed on meta-analysis (21,22). However, a systematic review comparing CT scan with MRI showed that MRI is significantly more sensitive with


Gynecology_Novak

Gynecology_Novak. Table 36.1 FIGO Staging of Carcinoma of the Cervix Uteri (2008) Stage I The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded) IA Invasive carcinoma which can be diagnosed only by microscopy, with deepest invasion ≤5mmand largest extension ≤7mm IA1 Measured stromal invasion of ≤3.0 mm in depth and extension of ≤7.0 mm IA2 Measured stromal invasion of >3.0 mm and not >5.0 mm with an extension of not >7.0 mm IB Clinically visible lesions limited to the cervix uteri or pre-clinical cancers greater than stage IAa IB1 Clinically visible lesion ≤4.0 cm in greatest dimension IB2 Clinically visible lesion >4.0 cm in greatest dimension Stage II Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina IIA Without parametrial invasion IIA1 Clinically visible lesion ≤4.0 cm in greatest dimension IIA2 Clinically visible lesion >4 cm in greatest dimension


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Gynecology_Novak. IIA Without parametrial invasion IIA1 Clinically visible lesion ≤4.0 cm in greatest dimension IIA2 Clinically visible lesion >4 cm in greatest dimension Stage III The tumor extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or non-functioning kidneyb IIIA Tumor involves lower third of the vagina, with no extension to the pelvic wall IIIB Extension to the pelvic wall and/or hydronephrosis or non-functioning kidney Stage IV The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to Stage IV IVA Spread of the growth to adjacent organs IVB Spread to distant organs FIGO Committee on Gynecologic Oncology. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int Cynecol Obst 2009;105:103–104.


Gynecology_Novak

Gynecology_Novak. FIGO Committee on Gynecologic Oncology. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int Cynecol Obst 2009;105:103–104. aAll macroscopically visible lesions, even those with superficial invasion, are allotted to stage IB carcinomas. Invasion is limited to a measured stroma invasion with a maximal depth of 5.0 mm and a horizontal extension greater than 7.0 mm. Dept of invasion should not be greater than 5 mm taken from the base of the epithelium of the original tissue squamous or glandular. The depth of invasion should always be reported in millimeters, even those cases with “early minimal stromal invasion” (∼1 mm). The involvement of vascular/lymphatic spaces should not change stage allotment. bOn rectal examination, there is no cancer-free space between the tumor and the pelvic wall. All cases with hydronephrosis or non-functioning kidney are included, unless they are known to be due to another cause.


Gynecology_Novak

Gynecology_Novak. equivalent specificity. Additionally, MRI has excellent sensitivity on T2-weighted images for the detection of parametrial disease (23). As a result, MRI is the preferred study to evaluate tumor size, lymph node metastasis, and local tumor extension. PET scans are increasingly being utilized either alone or in conjunction with CT or MRI to detect metastatic disease; however, large prospective data series are limited. Early studies suggest that PET may be more useful than other techniques for the detection of abdominal and extrapelvic disease, with comparable or better sensitivity (76% to 100%) and specificity (94%) (24,25). In addition, PET scans may be better predictors of treatment outcome. Although early studies show promise for the use of PET scans in evaluating cervical cancer, the sensitivity for detecting metastatic disease less than 1 cm in size appears to be limited (26).


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Gynecology_Novak. When abnormalities are noted on CT, MRI, or PET, radiographic-guided fine-needle aspirations (FNA) can be performed to confirm metastatic disease and individualize treatment planning. Because these tests are not available equally throughout the world and the interpretation of results can be variable, these studies are not used for staging. They may be useful in individual treatment planning.


Gynecology_Novak

Gynecology_Novak. The clinical staging system developed by FIGO is based on the belief that cervical cancer is a local disease until rather late in its course. The accuracy of clinical staging is limited, and surgical evaluation, although not practical or feasible in all patients, can more accurately identify metastatic disease. Surgical staging is advocated by providers who believe that surgical information details the extent of disease, allowing the treatment to be tailored to the individual (27). However, other providers believe that surgical staging should be limited to patients who are enrolled in clinical trials. These beliefs are based on the lack of randomized controlled studies demonstrating a survival benefit in patients who had surgical staging. Figure 36.3 Carcinoma of the cervix uteri: staging cervical cancer (primary tumor and metastases). (From Benedet JL, Odicino F, Maisonneuve P, et al. Carcinoma of the cervix. J Epidemiol Biostat 2001;6:5–44, with permission.)


Gynecology_Novak

Gynecology_Novak. Squamous Cell Carcinoma Invasive squamous cell carcinoma is the most common variety of invasive cancer in the cervix. Histologically, variants of squamous cell carcinoma include large cell keratinizing, large cell nonkeratinizing, and small cell types (28). Large cell keratinizing tumors consist of tumor cells forming irregular infiltrative nests with laminated keratin pearls in the center. Large cell nonkeratinizing carcinomas reveal individual cell keratinization but do not form keratin pearls (Fig. 36.4). The category of small cell carcinoma includes poorly differentiated squamous cell carcinoma and small cell anaplastic carcinoma. If possible, these two tumors should be differentiated. The former contains cells that have small-to medium-sized nuclei and more abundant cytoplasm than those of the latter. The designation of small cell anaplastic


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Gynecology_Novak. Table 36.2 Staging Procedures a Allowed by the International Federation of Gynecology and Obstetrics (FIGO). bInformation that is not allowed by FIGO to change the clinical stage. carcinoma should be reserved for lesions resembling oat cell carcinoma of the lung. Small cell anaplastic carcinoma infiltrates diffusely and consists of tumor cells that have scanty cytoplasm, round to oval small nuclei, coarsely granular chromatin, and high mitotic activity. The nucleoli are absent or small. Immunohistochemistry or electron microscopy can differentiate the small cell neuroendocrine tumors. Patients with the large cell type of carcinoma, with or without keratinization, have a better prognosis than those with the small cell variant. Small cell anaplastic carcinomas behave more aggressively than poorly differentiated squamous carcinomas that contain small cells. Infiltration of parametrial tissue and pelvic lymph node metastasis affect the prognosis.


Gynecology_Novak

Gynecology_Novak. Other less common variants of squamous carcinoma include verrucous carcinoma and papillary (transitional) carcinoma. Verrucous carcinomas may resemble giant condyloma acuminatum, are locally invasive, and rarely metastasize. Papillary carcinomas histologically resemble transitional cells of the bladder and may have more typical squamous cell invasion at the base of the lesion. Papillary carcinomas behave and are treated in a manner similar to traditional squamous cell cancers, except that late recurrences were noted.


Gynecology_Novak

Gynecology_Novak. Adenocarcinoma There is an increasing number of cervical adenocarcinomas reported in women in their 20s and 30s. Although the total number of cases of adenocarcinoma is relatively stable, this disease is appearing more frequently in young women, especially as the number of cases of invasive squamous cell carcinoma decreases. Older reports indicated that 5% of all cervical cancers were adenocarcinomas, whereas newer reports show a proportion as high as 18.5% to 27% (29–31). Much of this proportional increase is related to a decreasing incidence Figure 36.4 Invasive squamous cell carcinoma, large cell nonkeratinizing type. Tumor cells tive of squamous differentiation. of squamous carcinoma secondary to screening programs (which are less accurate at identifying preinvasion adenocarcinoma), greater exposure to oral contraceptives, and a greater exposure to HPV (4,5).


Gynecology_Novak

Gynecology_Novak. Adenocarcinoma in situ (AIS) is believed to be the precursor of invasive adenocarcinoma, and it is not surprising that the two often coexist (32). In addition to AIS, intraepithelial or invasive squamous neoplasia occurs in 30% to 50% of cervical adenocarcinomas (33). A squamous intraepithelial lesion may be observed colposcopically on the ectocervix, and the coexistent adenocarcinoma often is higher in the cervical canal. Patients with AIS who are treated with conization should undergo close clinical follow-up.