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Gynecology_Novak. to correlate with prognosis; patients whose lesions have a volume less than 100 mm3 have an excellent prognosis (184). Additional prognostic factors are the patient’s age, AJCC stage, presence of multifocal or satellite lesions, tumor ulceration, central tumor location, histologic growth pattern, lymph–vascular space involvement, and aneuploidy (158,162–164,194–197).


Gynecology_Novak

Gynecology_Novak. Epidemiology Primary carcinoma of the Bartholin gland is a rare form of vulvar cancer, which accounts for about 2% to 7% of vulvar malignancies (198). Because of its rarity, individual experience with the tumor is limited, and recommendations for management must be based on the review of small published series. Only about 300 cases are reported (46,198,199). Bartholin gland carcinoma is five times more common in postmenopausal than in premenopausal women (200). Histopathology The bilateral Bartholin glands are greater vestibular glands situated posterolaterally in the vulva. Their main duct is lined with stratified squamous epithelium, which changes to transitional epithelium as the terminal ducts are reached. Because tumors may arise from the gland or the duct, a variety of histologic types occur, including adenocarcinomas, squamous carcinomas, and, rarely, transitional cell, adenosquamous, and adenoid cystic carcinomas.


Gynecology_Novak

Gynecology_Novak. Classification of a vulvar tumor as a Bartholin gland carcinoma typically required that it fulfill Honan’s criteria, which are as follows: 1. The tumor is in the correct anatomic position. 2. The tumor is located deep in the labium majus. 3. The overlying skin is intact. 4. There is some recognizable normal gland present. Strict adherence to these criteria results in underdiagnosis of some cases. Large tumors may ulcerate through the overlying skin and obliterate the residual normal gland. Although transition between normal and malignant tissue is the best criterion, some cases will be diagnosed on the basis of their histologic characteristics and anatomic location. Table 38.9 Survival of Patients with Bartholin Gland Carcinoma


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Gynecology_Novak. Table 38.9 Survival of Patients with Bartholin Gland Carcinoma FIGO, International Federation of Gynecology and Obstetrics; NED, no evidence of disease; F/U, follow-up. a Median follow-up in each study was at least 5 years. bTotal >100% because some patients with recurrence remained NED. From references 46, 200, 201, 205. Signs and Symptoms The most common initial symptom of Bartholin gland carcinoma is a vulvar mass or perineal pain. About 10% of patients have a history of inﬂammation of the Bartholin gland, and malignancies may be mistaken for benign cysts or abscesses. Delay of diagnosis is common, particularly for premenopausal patients. The differential diagnosis of any pararectovaginal neoplasm should include cloacogenic carcinoma and secondary neoplasm (199).


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Gynecology_Novak. Treatment Traditionally, treatment was radical vulvectomy with bilateral groin and pelvic node dissection (201). There seems to be no indication for dissection of the pelvic nodes in the absence of positive groin nodes, and good results were reported with hemivulvectomy or radical local excision for the primary tumor (199). Because these lesions are deep in the vulva, extensive dissection is required in the ischiorectal fossa; surgical margins are often close. Postoperative radiation to the vulva decreased the likelihood of local recurrence from 27% (6 of 22 patients) to 7% (1 of 14 patients) (199). If the ipsilateral groin nodes are positive, bilateral groin and pelvic irradiation may decrease regional recurrence. If the tumor is fixed to the inferior pubic ramus or involves adjacent structures, such as the anal sphincter or rectum, preoperative radiation and chemotherapy is preferable to avoid ultraradical surgery. A recent report of 10 consecutive patients with primary Bartholin


Gynecology_Novak

Gynecology_Novak. such as the anal sphincter or rectum, preoperative radiation and chemotherapy is preferable to avoid ultraradical surgery. A recent report of 10 consecutive patients with primary Bartholin gland carcinoma suggests that treatment with radiation or chemoradiation using teletherapy combined with a boost to the primary site or regional nodes and/or interstitial brachytherapy may offer an effective alternative to surgery with 3-and 5-year survival rates of 72% and 66%, respectively (202).


Gynecology_Novak

Gynecology_Novak. Prognosis Because of the deep location of the gland, disease tends to be more advanced than squamous carcinomas at the time of diagnosis but, stage for stage, the prognosis is similar. Five-year disease-free survival rates by stage are summarized in Table 38.9. Adenoid Cystic Carcinoma of the Bartholin Gland The adenoid cystic variety accounts for 15% of Bartholin gland carcinomas. A review of 62 cases reported in the literature demonstrates that adenoid cystic carcinoma of the Bartholin gland is a slow growing tumor characterized by perineural infiltration and a marked propensity for local relapse preceding distant recurrences by years. It is less likely to metastasize to lymph nodes and carries a somewhat better prognosis (Fig. 38.8) (203– 205). The slowly progressive nature of these tumors and the tendency for late recurrences is reﬂected in the disparity between progression-free interval and overall survival (204).


Gynecology_Novak

Gynecology_Novak. Adenocarcinomas of the vulva usually arise in a Bartholin gland or occur in association with Paget disease. They may arise rarely from the skin appendages, paraurethral glands, minor vestibular glands, aberrant breast tissue, endometriosis, or a misplaced cloacal remnant (206). Figure 38.8 Adenoid cystic tumor of the Bartholin gland. Basaloid cells form cribriform, sievelike spaces containing mucinous material. The hyaline stroma is another distinct feature of this tumor.


Gynecology_Novak

Gynecology_Novak. Figure 38.8 Adenoid cystic tumor of the Bartholin gland. Basaloid cells form cribriform, sievelike spaces containing mucinous material. The hyaline stroma is another distinct feature of this tumor. A particularly aggressive type of carcinoma is the adenosquamous carcinoma. This tumor has a number of synonyms, including cylindroma, pseudoglandular squamous cell carcinoma, adenoid squamous cell carcinoma, and adenoacanthoma of the sweat gland of Lever. The tumor has a propensity for perineural invasion, early lymph node metastasis, and local recurrence. One study noted a crude 5-year survival rate of 5.5% (1 of 18) for adenosquamous carcinoma of the vulva, compared with 62.3% (48 of 77) for patients with squamous cell carcinoma (207). Treatment should be radical vulvectomy and bilateral groin dissection. Postoperative radiation therapy may be appropriate.


Gynecology_Novak

Gynecology_Novak. Basal Cell Carcinoma Basal cell carcinomas represent about 2% of vulvar cancers. As with other basal cell carcinomas, vulvar lesions commonly appear as a “rodent ulcer” with rolled edges, although nodules and macules are other morphologic varieties that occur. Most lesions are smaller than 2 cm in diameter and are usually situated on the anterior labia majora. Giant lesions occasionally occur (208). Basal cell carcinoma usually affects postmenopausal white women and is locally aggressive. Symptoms are frequently present for a prolonged period and most often include pruritus, soreness, and irritation (209). It is diagnosed by biopsy, and radical local excision is adequate treatment (210). Metastasis to regional lymph nodes is reported but is rare (211–213). The local recurrence rate is about 10% to 20% (209,214). Basal cell carcinoma of the vulva is associated with a high incidence of antecedent or concomitant malignancies elsewhere (209). In a series of 28 women with vulvar basal cell


Gynecology_Novak

Gynecology_Novak. 10% to 20% (209,214). Basal cell carcinoma of the vulva is associated with a high incidence of antecedent or concomitant malignancies elsewhere (209). In a series of 28 women with vulvar basal cell carcinoma, 10 patients had other basal cell carcinomas, and 10 patients suffered from other primary malignancies (209).


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Gynecology_Novak. About 3% to 5% of basal cell carcinomas contain a malignant squamous component, the so-called basosquamous carcinoma. These lesions are more aggressive and should be treated as squamous carcinomas (213). Another subtype of basal cell carcinoma is the adenoid basal cell carcinoma, which must be differentiated from the more aggressive adenoid cystic carcinoma arising in a Bartholin gland or the skin (213). Figure 38.9 Verrucous carcinoma of the vulva. Note the exophytic hyperkeratotic papillary fronds and endophytic bulky rete pegs with smooth borders.


Gynecology_Novak

Gynecology_Novak. Figure 38.9 Verrucous carcinoma of the vulva. Note the exophytic hyperkeratotic papillary fronds and endophytic bulky rete pegs with smooth borders. Verrucous Carcinoma Verrucous carcinoma is a variant of squamous cell carcinoma and has distinctive clinical and pathologic characteristics (215). Although most commonly found in the oral cavity, verrucous lesions may be found on any moist membrane composed of squamous epithelium (216). In the female genital tract, these lesions may develop on the cervix, vulva, and vagina. The cause of the lesion in the female genital tract is not fully understood, but associated HPV-6 and HPV-11 were found in some studies, whereas others find it to have no association with HPV infection (217,218). Some studies found as many as one-third of the cases to have coexisting squamous carcinoma of the vulva, underscoring the importance of careful histopathologic assessment of these tumors (219).


Gynecology_Novak

Gynecology_Novak. Grossly, the tumors have a cauliﬂowerlike appearance; microscopically, they contain multiple papillary fronds that lack the central connective tissue core that characterizes condylomata acuminata (Fig. 38.9). The gross and microscopic features of a verrucous carcinoma are very similar to those of the giant condyloma of Buschke-Loewenstein, and they probably represent the same disease entity (206). Adequate biopsy from the base of the lesion is required to differentiate a verrucous carcinoma from a benign condyloma acuminatum or a squamous cell carcinoma with a verrucous growth pattern.


Gynecology_Novak

Gynecology_Novak. Verrucous carcinomas usually occur in postmenopausal women, and they are slow-growing but locally destructive lesions. Even bone may be invaded. Metastasis to regional lymph nodes is rare but was reported (220). Radical local excision is the basic treatment, although any palpably suspicious groin nodes should be evaluated with fine-needle aspiration cytology or excisional biopsy. Usually, enlarged nodes will be caused by inﬂammatory hypertrophy (221). If the nodes contain metastases, radical vulvectomy and bilateral inguinal-femoral lymphadenectomy are indicated.


Gynecology_Novak

Gynecology_Novak. Several small studies failed to document any therapeutic advantage with radiation therapy (221). There is concern that radiation may induce anaplastic transformation with subsequent regional and distant metastasis (222). One study reported a corrected 5-year survival rate of 94% for 17 patients treated with surgery alone, compared with 42% for 7 patients treated with surgery and radiation (221). The latter patients had more advanced disease. If there is a recurrence, further surgical excision is the treatment of choice, which occasionally may necessitate some type of exenteration. Sarcomas represent 1.5% of vulvar malignancies and constitute a heterogenous group of tumors (223). Leiomyosarcomas are the most common, and other histologic types include fibrosarcomas, neurofibrosarcomas, liposarcomas, rhabdomyosarcomas, angiosarcomas, epithelioid sarcomas, and malignant schwannomas.


Gynecology_Novak

Gynecology_Novak. Leiomyosarcomas usually appear as enlarging, often painful masses, usually in the labium majus. Smooth muscle tumors of the vulva that show at least three of the following four criteria should be regarded as sarcomas: (i) diameter greater than 5 cm, (ii) infiltrating margins, (iii) 5 or more mitotic figures per 10 high-power fields, (iv) moderate-to-severe cytological atypia (224). The absence of one, or even all, of these features does not guarantee against recurrence (225). Lymphatic metastases are uncommon, and radical local excision is the usual treatment.


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Gynecology_Novak. Epithelioid sarcomas characteristically develop in the soft tissues of the extremities of young adults but rarely may occur on the vulva. In a description of two cases and review of three other reports, the authors concluded that these tumors might mimic a Bartholin cyst, leading to inadequate initial treatment (226). They believed that vulvar epithelioid sarcomas behave more aggressively than their extragenital counterparts, with four of the five patients dying of metastatic disease. They suggested that early recognition and wide excision should improve the prognosis.


Gynecology_Novak

Gynecology_Novak. Rhabdomyosarcomas are the most common soft tissue sarcomas in childhood, and 20% involve the pelvis or genitourinary tract (227). Dramatic gains were made in the treatment of these tumors during the past 20 years. Previously, radical pelvic surgery was the standard approach, but results were poor. A multimodal approach evolved, and survival rates improved significantly, with a corresponding decrease in morbidity. In a report of the experience of the Intergroup Rhabdomyosarcoma Study I and II (1972 to 1984) with primary tumors of the female genital tract, nine patients aged 1 to 19 years had primary vulvar tumors, and these tumors were often regarded as a form of Bartholin gland infection before biopsy (228). They were all managed with chemotherapy (vincristine,or actinomycin D and cyclophosphamide and doxorubicin), with or without radiotherapy. Wide local excision of the tumor, with or without inguinal-femoral lymphadenectomy, was carried out before or after the chemotherapy. Seven of


Gynecology_Novak

Gynecology_Novak. and doxorubicin), with or without radiotherapy. Wide local excision of the tumor, with or without inguinal-femoral lymphadenectomy, was carried out before or after the chemotherapy. Seven of the nine patients were free of disease 4 or more years from diagnosis, one patient was free of disease when lost to follow-up at 5 years, and one patient was alive with disease.


Gynecology_Novak

Gynecology_Novak. In addition to the previously mentioned tumors, a number of malignancies more commonly seen in other areas of the body may rarely occur as isolated vulvar tumors. Lymphomas The genital tract may be involved primarily by malignant lymphomas but, more commonly, involvement is a manifestation of systemic disease. In the lower genital tract, the cervix is most often involved, followed by the vulva and the vagina (229). Most patients are in their third to sixth decades of life, and about three-fourths of the cases involve diffuse large cell or histiocytic non-Hodgkin’s lymphomas. The remainder are nodular or Burkitt’s lymphomas. Treatment is by surgical excision followed by chemotherapy and radiation or both, and the overall 5-year survival rate is about 70% (229). Metastatic Tumors of the Vulva


Gynecology_Novak

Gynecology_Novak. Metastatic Tumors of the Vulva Eight percent of vulvar tumors are metastatic. The most common primary site is the cervix, followed by the endometrium, kidney, and urethra. Most patients in whom vulvar metastases develop have advanced primary tumors when diagnosed, and in about one-fourth of the patients, the primary lesion and the vulvar metastasis are diagnosed simultaneously (235). 1. Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011. CA Cancer J Clin 2011;61:212–236. http://cacancerjournal.org 2. US Cancer Statistics Working Group. United States cancer statistics. Available online at: http://apps.nccd.cdc.gov/uscs/ 3. Judson PL, Habermann EB, Baxter NN, et al. Trends in the incidence of invasive and in situ vulvar carcinoma. Obstet Gynecol 2006;107:1018–1022. 4.


Gynecology_Novak

Gynecology_Novak. Judson PL, Habermann EB, Baxter NN, et al. Trends in the incidence of invasive and in situ vulvar carcinoma. Obstet Gynecol 2006;107:1018–1022. 4. Joura EA, Losch A, Haider-Angeler MG, et al. Trends in vulvar neoplasia. Increasing incidence of vulvar intraepithelial neoplasia and squamous cell carcinoma of the vulva in young women. J Reprod Med 2000;45:613–615. 5. Jones RW, Baranyai J, Stables S. Trends in squamous cell carcinoma of the vulva: the inﬂuence of vulvar intraepithelial neoplasia. Obstet Gynecol 1997;90:448–452. 6. Taussig FJ. Cancer of the vulva: an analysis of 155 cases. Am J Obstet Gynecol 1940;40:764–778. 7. Way S. Carcinoma of the vulva. Am J Obstet Gynecol 1960;79:692– 697. 8. Madsen BS, Jensen HL, van den Brule AJ, et al. Risk factors for invasive squamous cell carcinoma of the vulva and vagina— population-based case-control study in Denmark. Int J Cancer 2008;122:2827—2834. 9. Ansink A. Vulvar squamous cell carcinoma. Semin Dermatol 1996;15:51–59. 10.


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Gynecology_Novak. 9. Ansink A. Vulvar squamous cell carcinoma. Semin Dermatol 1996;15:51–59. 10. van Seters M, van Beurden M, de Craen AJ. Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients. Gynecol Oncol 2005;97:645–651. 11. Hording U, Junge J, Poulsen H, et al. Vulvar intraepithelial neoplasia III: a viral disease of undetermined progressive potential. Gynecol Oncol 1995;56:276–279. 12. Modesitt SC, Waters AB, Walton L, et al. Vulvar intraepithelial neoplasia III: occult cancer and the impact of margin status on recurrence. Obstet Gynecol 1998;92:962–966. 13. Trimble CL, Hildesheim A, Brinton LA, et al. Heterogeneous etiology of squamous carcinoma of the vulva. Obstet Gynecol 1996;87:59–64. 14.


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Gynecology_Novak. 13. Trimble CL, Hildesheim A, Brinton LA, et al. Heterogeneous etiology of squamous carcinoma of the vulva. Obstet Gynecol 1996;87:59–64. 14. Insinga RP, Liaw KL, Johnson LG, et al. A systematic review of the prevalence and attribution of human papillomavirus types among cervical, vaginal, and vulvar precancers and cancers in the United States. Cancer Epidemiol Biomarkers Prev 2008;17:1611–1622. 15. Brinton LA, Nasco PC, Mallin K, et al. Case-control study of cancer of the vulva. Obstet Gynecol 1990;75:859–866. 16. Kurman RJ, Toki T, Schiffman MH. Basaloid and warty carcinomas of the vulva: distinctive types of squamous cell carcinoma frequently associated with human papillomaviruses. Am J Surg Pathol 1993;17:133–145. 17. Vilmer C, Cavelier-Balloy B, Nogues C, et al. Analysis of alterations adjacent to invasive vulvar carcinoma and their relationship with the associated carcinoma: a study of 67 cases. Eur J Gynaecol Oncol 1998;19:25–31. 18.


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Gynecology_Novak. 18. Cooper SM, Gao XH, Powell JJ, et al. Does treatment of vulvar lichen sclerosus inﬂuence its prognosis? Arch Dermatol 2004;140:702–706. 19. Renaud-Vilmer C, Cavelier-Balloy B, Porcher R, et al. Vulvar lichen sclerosus: effect of long-term topical application of a potent steroid on the course of the disease. Arch Dermatol 2004;140:709– 712. 20. Bradford J, Fischer G. Long-term management of vulval lichen sclerosus in adult women. Aust N Z J Obstet Gynaecol 2010;50:148– 152. 21. Carlson JA, Ambros R, Malfetano J, et al. Vulvar lichen sclerosus and squamous cell carcinoma: a cohort, case control, and investigational study with historical perspective; implications for chronic inﬂammation and sclerosis in the development of neoplasia. Hum Pathol 1998;29:932–948. 22. Tate JE, Mutter GL, Boynton KA, et al. Monoclonal origin of vulvar intraepithelial neoplasia and some vulvar hyperplasias. Am J Pathol 1997;150:315–322. 23.


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Gynecology_Novak. 22. Tate JE, Mutter GL, Boynton KA, et al. Monoclonal origin of vulvar intraepithelial neoplasia and some vulvar hyperplasias. Am J Pathol 1997;150:315–322. 23. Raspollini MR, Asirelli G, Moncini D, et al. A comparative analysis of lichen sclerosus of the vulva and lichen sclerosus that evolves to vulvar squamous cell carcinoma. Am J Obstet Gynecol 2007;197:592.e1–e5. 24. Franklin EW, Rutledge FD. Epidemiology of epidermoid carcinoma of the vulva. Obstet Gynecol 1972;39:165–172. 25. Green TH Jr, Ulfelder H, Meigs JV. Epidermoid carcinoma of the vulva: an analysis of 238 cases. Parts I and II. Am J Obstet Gynecol 1958;73:834–864. 26. Woodruff JD. Early invasive carcinoma of the vulva. Clin Oncol 1982;1:349. 27. Binder SW, Huang I, Fu YS, et al. Risk factors for the development of lymph node metastasis in vulvar squamous cell carcinoma. Gynecol Oncol 1990;37:9–16. 28.


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Gynecology_Novak. 27. Binder SW, Huang I, Fu YS, et al. Risk factors for the development of lymph node metastasis in vulvar squamous cell carcinoma. Gynecol Oncol 1990;37:9–16. 28. Boyce J, Fruchter RG, Kasambilides E, et al. Prognostic factors in carcinoma of the vulva. Gynecol Oncol 1985;20:364– 377. 29. Donaldson ES, Powell DE, Hanson MB, et al. Prognostic parameters in invasive vulvar cancer. Gynecol Oncol 1981;11:184–190. 30. Buscema J, Woodruff JD. Progressive histobiologic alterations in the development of vulvar cancer. Am J Obstet Gynecol 1980;138:146–150. 31. Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2009;105:103–104. 32. Rutledge F, Smith JP, Franklin EW. Carcinoma of the vulva. Am J Obstet Gynecol 1970;106:1117–1130. 33. Podratz KC, Symmonds RE, Taylor WF, et al. Carcinoma of the vulva: analysis of treatment and survival. Obstet Gynecol 1983;61:63–74. 34.


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Gynecology_Novak. 33. Podratz KC, Symmonds RE, Taylor WF, et al. Carcinoma of the vulva: analysis of treatment and survival. Obstet Gynecol 1983;61:63–74. 34. Cavanagh D, Fiorica JV, Hoffman MS, et al. Invasive carcinoma of the vulva: changing trends in surgical management. Am J Obstet Gynecol 1990;163:1007–1115. 35. Sturgeon SR, Curtis RE, Johnson K, et al. Second primary cancers after vulvar and vaginal cancers. Am J Obstet Gynecol 1996;174:929– 933. 36. Hacker NF, Van der Velden J. Conservative management of early vulvar cancer. Cancer 1993;71:1673–1677. 37. DiSaia PJ, Creasman WT, Rich WM. An alternative approach to early cancer of the vulva. Am J Obstet Gynecol 1979;133:825–832. 38. Hacker NF, Nieberg RK, Berek JS, et al. Superficially invasive vulvar cancer with nodal metastases. Gynecol Oncol 1983;15:65– 77. 39. Chu J, Tamimi HK, Figge DC. Femoral node metastases with negative superficial inguinal nodes in early vulvar cancer. Am J Obstet Gynecol 1981;140:337–339. 40.


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Gynecology_Novak. 39. Chu J, Tamimi HK, Figge DC. Femoral node metastases with negative superficial inguinal nodes in early vulvar cancer. Am J Obstet Gynecol 1981;140:337–339. 40. Podczaski E, Sexton M, Kaminski P, et al. Recurrent carcinoma of the vulva after conservative treatment for “microinvasive” disease. Gynecol Oncol 1990;39:65–68. 41. Stehman FB, Bundy BN, Dvoretsky PM, et al. Early stage I carcinoma of the vulva treated with ipsilateral superficial inguinal lymphadenectomy and modified radical hemivulvectomy: a prospective study of the Gynecologic Oncology Group. Obstet Gynecol 1992;79:490–497. 42. Gordinier ME, Malpica A, Burke TW, et al. Groin recurrence in patients with vulvar cancer with negative nodes on superficial inguinal lymphadenectomy. Gynecol Oncol 2003;90:625–628. 43. Levenback C, Burke TW, Morris M, et al. Potential applications of intraoperative lymphatic mapping in vulvar cancer. Gynecol Oncol 1995;59:216–220. 44.


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Gynecology_Novak. 43. Levenback C, Burke TW, Morris M, et al. Potential applications of intraoperative lymphatic mapping in vulvar cancer. Gynecol Oncol 1995;59:216–220. 44. Rob L, Robova H, Pluta M, et al. Further data on sentinel lymph node mapping in vulvar cancer by blue dye and radiocolloid Tc99. Int J Gynecol Cancer 2007;17:147–153. 45. Curry SL, Wharton JT, Rutledge F. Positive lymph nodes in vulvar squamous carcinoma. Gynecol Oncol 1980;9:63–67. 46. Leuchter RS, Hacker NF, Voet RL, et al. Primary carcinoma of the Bartholin gland: a report of 14 cases and a review of the literature. Obstet Gynecol 1982;60:361–368. 47. Piver MS, Xynos FP. Pelvic lymphadenectomy in women with carcinoma of the clitoris. Obstet Gynecol 1977;49:592–595. 48. Gonzalez Bosquet J, Magrina JF, Magtibay PM, et al. Patterns of inguinal groin metastases in squamous cell carcinoma of the vulva. Gynecol Oncol 2007;105:742–746. 49.


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Gynecology_Novak. 48. Gonzalez Bosquet J, Magrina JF, Magtibay PM, et al. Patterns of inguinal groin metastases in squamous cell carcinoma of the vulva. Gynecol Oncol 2007;105:742–746. 49. Burke TW, Levenback C, Coleman RL, et al. Surgical therapy of T1 and T2 vulvar carcinoma: further experience with radical wide excision and selective inguinal lymphadenectomy. Gynecol Oncol 1995;57:215–220. 50. Burrell MO, Franklin EW III, Campion MJ, et al. The modified radical vulvectomy with groin dissection: an eight-year experience. Am J Obstet Gynecol 1988;159:715–722. 51. Collins CG, Lee FY, Roman-Lopez JJ. Invasive carcinoma of the vulva with lymph node metastases. Am J Obstet Gynecol 1971;109:446–452. 52. Morley GW. Infiltrative carcinoma of the vulva: results of surgical treatment. Am J Obstet Gynecol 1976;124:874–888. 53. Krupp PJ, Bohm JW. Lymph gland metastases in invasive squamous cell cancer of the vulva. Am J Obstet Gynecol 1978;130:943–952. 54.


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Gynecology_Novak. 53. Krupp PJ, Bohm JW. Lymph gland metastases in invasive squamous cell cancer of the vulva. Am J Obstet Gynecol 1978;130:943–952. 54. Keys H. Gynecologic Oncology Group randomized trials of combined technique therapy of vulvar cancer. Cancer 1993;71:1691– 1696. 55. Benedet JL, Turko M, Fairey RN, et al. Squamous carcinoma of the vulva: results of treatment, 1938 to 1976. Am J Obstet Gynecol 1979;134:201–207. 56. Iversen T, Aalders JG, Christensen A, et al. Squamous cell carcinoma of the vulva: a review of 424 patients, 1956–1974. Gynecol Oncol 1980;9:271–279. 57. Hacker NF, Berek JS, Lagasse LD, et al. Management of regional lymph nodes and their prognostic inﬂuence in vulvar cancer. Obstet Gynecol 1983;61:408–412. 58. Monaghan JM, Hammond IG. Pelvic node dissection in the treatment of vulvar carcinoma—is it necessary? BJOG 1984;91:270–274. 59.


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Gynecology_Novak. 58. Monaghan JM, Hammond IG. Pelvic node dissection in the treatment of vulvar carcinoma—is it necessary? BJOG 1984;91:270–274. 59. Hopkins MP, Reid CG, Vettrano I, et al. Squamous cell carcinoma of the vulva: prognostic factors inﬂuencing survival. Gynecol Oncol 1991;43:113–117. 60. Homesley HD, Bundy BN, Sedlis A, et al. Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes. Obstet Gynecol 1986;68:733–740. 61. Hacker NF. Vulvar cancer. In: Berek JS, Hacker NF, eds. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:536–575. 62. Hacker NF. Revised FIGO staging for carcinoma of the vulva. Int J Gynaecol Obstet 2009;105:105–106. 63. van der Steen S, de Nieuwenhof HP, Massuger L, et al. New FIGO staging system of vulvar cancer indeed provides a better reﬂection of prognosis. Gynecol Oncol 2010;119:520–525. 64.


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Gynecology_Novak. 63. van der Steen S, de Nieuwenhof HP, Massuger L, et al. New FIGO staging system of vulvar cancer indeed provides a better reﬂection of prognosis. Gynecol Oncol 2010;119:520–525. 64. Hopkins MP, Reid GC, Johnston CM, et al. A comparison of staging systems for squamous cell carcinoma of the vulva. Gynecol Oncol 1992;47:34–37. 65. Raspagliesi F, Hanozet F, Ditto A, et al. Clinical and pathological prognostic factors in squamous cell carcinoma of the vulva. Gynecol Oncol 2006;102:333–337. 66. Lataifeh I, Nascimento MC, Nicklin JL, et al. Patterns of recurrence and disease-free survival in advanced squamous cell carcinoma of the vulva. Gynecol Oncol 2004;95:701–705. 67. Fons G, Hyde SE, Buist MR, et al. Prognostic value of bilateral positive nodes in squamous cell cancer of the vulva. Int J Gynecol Cancer 2009;19:1276–1280. 68. College of American Pathologists. Protocol for the examination of specimens from patients with carcinoma of the vulva. October 2009.


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Gynecology_Novak. 68. College of American Pathologists. Protocol for the examination of specimens from patients with carcinoma of the vulva. October 2009. Available online at: http://www.cap.org/apps/docs/committees/ ca ncer/cancerrotocols/2009/Vulva9protocol.pdf 69. Beller U, Quinn MA, Benedet JL, et al. 26th annual report on the results of treatment in gynecological cancer: carcinoma of the vulva. Int J Gynecol Obstet 2006;95:S7–S27. 70. Paladini D, Cross P, Lopes A, et al. Prognostic significance of lymph node variables in squamous cell carcinoma of the vulva. Cancer 1994;74:2491–2496. 71. Homesley HD, Bundy BN, Sedlis A, et al. Assessment of current International Federation of Gynecology and Obstetrics staging of vulvar carcinoma relative to prognostic factors for survival (a Gynecologic Oncology Group study). Am J Obstet Gynecol 1991;164:997– 1003. 72.


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Gynecology_Novak. 205. Yang SY, Lee JW, Kim WS, Jung et al. Adenoid cystic carcinoma of the Bartholin’s gland: report of two cases and review of the literature. Gynecol Oncol 2006;100:422–425. 206. Fu YS, Reagan JW. Benign and malignant epithelial tumors of the vulva. In: Fu YS, Reagan JW, eds. Pathology of the uterine cervix, vagina, and vulva. Philadelphia, PA: WB Saunders, 1989:138– 192. 207. Underwood JW, Adcock LL, Okagaki T. Adenosquamous carcinoma of skin appendages (adenoid squamous cell carcinoma, pseudoglandular squamous cell carcinoma, adenoacanthoma of sweat gland of Lever) of the vulva: a clinical and ultrastructural study. Cancer 1978;42:1851–1858. 208. Dudzinski MR, Askin FB, Fowler WC. Giant basal cell carcinoma of the vulva. Obstet Gynecol 1984;63:57S–60S. 209. Benedet JL, Miller DM, Ehlen TG, et al. Basal cell carcinoma of the vulva: clinical features and treatment results in 28 patients. Obstet Gynecol 1997;90:765–768. 210.


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Gynecology_Novak. 209. Benedet JL, Miller DM, Ehlen TG, et al. Basal cell carcinoma of the vulva: clinical features and treatment results in 28 patients. Obstet Gynecol 1997;90:765–768. 210. de Giorgi V, Salvini C, Massi D, et al. Vulvar basal cell carcinoma: retrospective study and review of literature. Gynecol Oncol 2005;97:192–194. 211. Jimenez HT, Fenoglio CM, Richart RM. Vulvar basal cell carcinoma with metastasis: a case report. Am J Obstet Gynecol 1975;121:285–286. 212. Sworn MJ, Hammond GT, Buchanan R. Metastatic basal cell carcinoma of the vulva: a case report. Br J Obstet Gynaecol 1979;86:332–334. 213. Hoffman MS, Roberts WS, Ruffolo EH. Basal cell carcinoma of the vulva with inguinal lymph node metastases. Gynecol Oncol 1988;29:113–119. 214. Palladino VS, Duffy JL, Bures GJ. Basal cell carcinoma of the vulva. Cancer 1969;24:460–470. 215. Isaacs JH. Verrucous carcinoma of the female genital tract. Gynecol Oncol 1976;4:259–269. 216.


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Gynecology_Novak. Palladino VS, Duffy JL, Bures GJ. Basal cell carcinoma of the vulva. Cancer 1969;24:460–470. 215. Isaacs JH. Verrucous carcinoma of the female genital tract. Gynecol Oncol 1976;4:259–269. 216. Partridge EE, Murad R, Shingleton HM, et al. Verrucous lesions of the female genitalia. II. Verrucous carcinoma. Am J Obstet Gynecol 1980;137:419–424. 217. Kondi-Paphitis A, Deligeorgi-Politi H, Liapis A, et al. Human papillomavirus in verrucous carcinoma of the vulva: an immunopathological study of three cases. Eur J Gynecol Obstet 1998; 19:319–320. 218. Gualco M, Bonin S, Foglia G, et al. Morphologic and biologic studies on ten cases of verrucous carcinoma of the vulva supporting the theory of a discrete clinicopathologic entity. Int J Gynecol Cancer 2003;13:317–324. 219. Haidopoulos D, Diakomanolis E, Rodolakis A, et al. Coexistence of verrucous and squamous carcinoma of the vulva. Aust N Z J Obstet Gynaecol 2005;45:60–63. 220.


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Gynecology_Novak. 219. Haidopoulos D, Diakomanolis E, Rodolakis A, et al. Coexistence of verrucous and squamous carcinoma of the vulva. Aust N Z J Obstet Gynaecol 2005;45:60–63. 220. Gallousis S. Verrucous carcinoma: report of three vulvar cases and a review of the literature. Obstet Gynecol 1972;40:502–507. 221. Japaze H, Van Dinh TV, Woodruff JD. Verrucous carcinoma of the vulva: study of 24 cases. Obstet Gynecol 1982;60:462–466. 222. Demian SDE, Bushkin FL, Echevarria RA. Perineural invasion and anaplastic transformation of verrucous carcinoma. Cancer 1973;32:395–401. 223. Ulutin HC, Zellars RC, Frassica D. Soft tissue sarcoma of the vulva: a clinical study. Int J Gynecol Cancer 2003;13:528–531. 224. Nielsen GP, Rosenberg AE, Koerner FC, et al. Smooth-muscle tumors of the vulva: a clinicopathological study of 25 cases and review of the literature. Am J Surg Pathol 1996;20:779–793. 225. Tavassoli FA, Norris HJ. Smooth muscle tumors of the vulva. Obstet Gynecol 1979;53:213–217. 226.


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Gynecology_Novak. 225. Tavassoli FA, Norris HJ. Smooth muscle tumors of the vulva. Obstet Gynecol 1979;53:213–217. 226. Ulbright TM, Brokaw SA, Stehman FB, et al. Epithelioid sarcoma of the vulva. Cancer 1983;52:1462–1469. 227. Bell J, Averette H, Davis J, et al. Genital rhabdomyosarcoma: current management and review of the literature. Obstet Gynecol Surv 1986;41:257–263. 228. Hays DM, Shimada H, Raney RB Jr, et al. Clinical staging and treatment results in rhabdomyosarcoma of the female genital tract among children and adolescents. Cancer 1988;61:1893–1903. 229. Harris NL, Scully RE. Malignant lymphoma and granulocytic sarcoma of the uterus and vagina. Cancer 1984;53:2530–2545. 230. Dudley AG, Young RH, Lawrence WD, et al. Endodermal sinus tumor of the vulva in an infant. Obstet Gynecol 1983;61:76S–79S. 231. Bottles K, Lacy CG, Goldberg J, et al. Merkel cell carcinoma of the vulva. Obstet Gynecol 1984;63:61S–65S. 232.


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Gynecology_Novak. 231. Bottles K, Lacy CG, Goldberg J, et al. Merkel cell carcinoma of the vulva. Obstet Gynecol 1984;63:61S–65S. 232. Husseinzadeh N, Wesseler T, Newman N, et al. Neuroendocrine (Merkel cell) carcinoma of the vulva. Gynecol Oncol 1988;29:105– 112. 233. Khoury-Collado F, Elliott KS, Lee YC, et al. Merkel cell carcinoma of the Bartholin’s gland. Gynecol Oncol 2005;97:928–931. 234. Bock JE, Andreasson B, Thorn A, et al. Dermatofibromasarcoma protuberans of the vulva. Gynecol Oncol 1985;20:129–135. 235. Dehner LP. Metastatic and secondary tumors of the vulva. Obstet Gynecol 1973;42:47–57. Ross S. Berkowitz Donald P. Goldstein Complete molar pregnancies are generally diploid and all chromosomes are of paternal origin. Partial molar pregnancies are triploid and the extra set of chromosomes is paternal. Complete moles are diagnosed earlier in pregnancy and less frequently present with the classic signs and symptoms.


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Gynecology_Novak. Complete moles are diagnosed earlier in pregnancy and less frequently present with the classic signs and symptoms. Single-agent chemotherapy achieves a high remission rate in nonmetastatic and low-risk metastatic gestational trophoblastic neoplasia. After achieving remission with chemotherapy, patients with gestational trophoblastic neoplasia can anticipate normal reproduction in the future.


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Gynecology_Novak. Gestational trophoblastic disease (GTD) is the term used to describe the heterogeneous group of interrelated lesions that arise from abnormal proliferation of placental trophoblasts. GTD lesions are histologically distinct and can be benign or malignant. Benign lesions consist of hydatidiform moles, complete and partial, whereas malignant lesions consist of invasive mole, placental-site trophoblastic tumor (PSTT), and choriocarcinoma. This subset of malignant lesions that have varying propensities for local invasion and metastasis is referred to as gestational trophoblastic neoplasia (GTN). GTNs are among the rare human tumors that can be cured even in the presence of widespread dissemination (1,2). Although GTNs commonly follow a molar pregnancy, they can occur after any gestational event, including induced or spontaneous abortion, ectopic pregnancy, or term pregnancy.


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Gynecology_Novak. Epidemiology Estimates of the incidence of molar pregnancy vary dramatically in different regions of the world. For example, the incidence of molar pregnancy in Japan (2:1,000 pregnancies) is reported to be about threefold higher than the incidence in Europe or North America (about 0.6 to 1.1 per 1,000 pregnancies) (3). In Taiwan, 1 in 125 pregnancies are molar, while in the Table 39.1 Features of Complete and Partial Hydatidiform Moles United States the incidence is 1 in 1,500 live births. The incidences of complete and partial hydatidiform mole in Ireland were investigated by reviewing all products of conception from first-and second-trimester abortions (4). Based on a thorough pathologic review, the incidence of complete and partial hydatidiform mole was 1:1,945 and 1:695 pregnancies, respectively.


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Gynecology_Novak. While variations in the worldwide incidence of molar pregnancy may result in part from reporting population-based versus hospital-based data, a number of studies suggest that the high incidence in some populations can be attributed to socioeconomic and nutritional factors. The decreasing incidence of molar pregnancy in South Korea is attributed to a more Western diet and improved standard of living (5). Case-control studies from Italy and the United States show that the rate of complete mole increases with decreasing consumption of dietary carotene (vitamin A precursor) and animal fat (6,7). Maternal age and reproductive history inﬂuence the rate of molar pregnancy. Women older than 40 years have a 5-to 10-fold greater risk of having a complete mole, while one in three pregnancies in women older than 50 years results in a molar gestation (8,9). These findings suggest that ova from older women may be more susceptible to abnormal fertilization, resulting in a complete hydatidiform mole.


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Gynecology_Novak. Limited information is available concerning risk factors for partial molar pregnancy. The epidemiologic characteristics of complete and partial mole appear to differ significantly (8–11). The risk for partial mole is associated with the use of oral contraceptives and a history of irregular menstruation, but not with dietary factors (10). Nor does there appear to be an association between maternal age and the risk for partial mole. Pathology and Hydatidiform moles may be categorized as either complete or partial moles on the basis of gross Cytogenetics morphology, histopathology, and karyotype (Table 39.1).


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Gynecology_Novak. Pathology and Hydatidiform moles may be categorized as either complete or partial moles on the basis of gross Cytogenetics morphology, histopathology, and karyotype (Table 39.1). Complete hydatidiform moles exhibit characteristic swelling and trophoblastic hyperplasia (Fig. 39.1). They usually have a 46,XX karyotype, but about 10% have a 46,XY karyotype (12,13). The molar chromosomes are entirely of paternal origin, with mitochondrial DNA of maternal origin (Fig. 39.2) (14). Complete moles usually arise from an ovum fertilized by a haploid sperm, which duplicates its own chromosomes. The ovum nucleus may be absent or inactivated (15). Partial Hydatidiform Mole Partial hydatidiform mole is characterized by the following pathologic features (16) (Fig. 39.3): 1. Chorionic villi of varying size with focal hydatidiform swelling, cavitation, and trophoblastic hyperplasia 2. 3. 4.


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Gynecology_Novak. Chorionic villi of varying size with focal hydatidiform swelling, cavitation, and trophoblastic hyperplasia 2. 3. 4. Partial moles have a triploid karyotype (69 chromosomes); the extra haploid set of chromosomes usually is derived from the father (Fig. 39.4) (17). It is possible that nontriploid partial moles do not exist (18). When a fetus is present in conjunction with a partial mole, it Figure 39.1 Photomicrograph of complete mole demonstrating enlarged villous with central cavitation and surrounding trophoblastic hyperplasia. Figure 39.2 The karyotype of complete hydatidiform mole.


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Gynecology_Novak. Figure 39.2 The karyotype of complete hydatidiform mole. Figure 39.3 Photomicrograph of partial mole showing marked disparity in villous size, trophoblastic inclusions (center), and mild trophoblastic hyperplasia. (From Berkowitz RS, Goldstein OP. Gestational trophoblastic diseases. In: Ryan KJ, BerkowitzR, Barbieri R, eds. Kistner’s gynecology principles and practice, 5th ed. Chicago: Year Book Medical Publishers, 1990:433, with permission.) generally exhibits the stigmata of triploidy, including growth retardation and multiple congenital malformations such as syndactyly and hydrocephaly (Fig. 39.5).


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Gynecology_Novak. When molar pregnancy is diagnosed early in the first trimester, the pathologist can have difficulty distinguishing complete hydatidiform mole from partial hydatidiform mole or hydropic abortions because of smaller villi, less trophoblastic hyperplasia, more primitive villous stroma, and less global necrosis (19,20). Accurate diagnosis can be facilitated through the use of ﬂow cytometry to determine ploidy (i.e., diploid vs. triploid moles) (21) and through assessment of biomarkers of paternally imprinted and maternally expressed gene products (22). Biomarkers that take advantage of imprinted genes to distinguish complete mole and hydropic abortions from other gestations are identified. Because complete moles generally have no maternal chromosomes, paternally imprinted gene products normally expressed only by maternal chromosomes, should be absent. In complete moles, the nuclei of the villous stroma and cytotrophoblastic cells do not express p57, whereas all other gestations, including


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Gynecology_Novak. expressed only by maternal chromosomes, should be absent. In complete moles, the nuclei of the villous stroma and cytotrophoblastic cells do not express p57, whereas all other gestations, including partial moles, are characterized by nuclear immunostaining in these cells. Thus, a complete mole is diploid and negative for p57, a hydropic abortion is diploid (sometimes triploid) and positive for p57, and a partial mole is triploid and positive for p57.


Gynecology_Novak

Gynecology_Novak. Evaluation of families with recurrent molar pregnancy suggests that dysregulation of normal parental imprinting of genes, with loss of maternally transcribed genes, is likely to contribute to the pathogenesis of molar pregnancy. Familial recurrent hydatidiform mole, is a rare occurrence, characterized by recurrent complete hydatidiform mole of biparental origin, rather than the more usual androgenetic origin (23). Genetic mapping shows that in most families the gene responsible is located in a 1.1 Mb region on chromosome 19q13.4. Mutations in the gene result in dysregulation of imprinting in the female germ line with abnormal development of both embryonic and extraembryonic tissue. Figure 39.4 The karyotype of partial hydatidiform mole.


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Gynecology_Novak. Figure 39.4 The karyotype of partial hydatidiform mole. Clinical Features Patients with complete molar pregnancy are diagnosed increasingly earlier in pregnancy and treated before they develop the classic clinical signs and symptoms. This is the result of many changes in clinical practice, such as the frequent use of human chorionic gonadotropin (hCG) measurement and transvaginal ultrasonography in early pregnancy for women with vaginal staining and for determining the gestational dates in asymptomatic women. The following is a description of the classic and current clinical features of complete molar pregnancy (24,25). Vaginal Bleeding Vaginal bleeding is the most common symptom causing patients to


Gynecology_Novak

Gynecology_Novak. Vaginal Bleeding Vaginal bleeding is the most common symptom causing patients to Mole seek treatment for complete molar pregnancy. It had been reported to occur in 97% of cases, whereas currently it is reported to occur in 84% of patients. Molar tissues may separate from the decidua and disrupt maternal vessels, and large volumes of retained blood may distend the endometrial cavity. Because vaginal bleeding may be considerable and prolonged, one-half of these patients had anemia (hemoglobin <10 g/100 mL). Anemia is present in only 5% of patients. Excessive Uterine Size Excessive uterine enlargement relative to gestational age is one of the classic signs of a complete mole, although it was present in only about half of patients.


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Gynecology_Novak. Excessive Uterine Size Excessive uterine enlargement relative to gestational age is one of the classic signs of a complete mole, although it was present in only about half of patients. Currently, excessive uterine size occurs in only 28% of patients. The endometrial cavity may be expanded by both chorionic tissue and retained blood. Excessive uterine size is generally associated with markedly elevated levels of hCG, because uterine enlargement results in part from trophoblastic overgrowth. Preeclampsia Preeclampsia was observed in 27% of patients with a complete hydatidiform mole. Preeclampsia is now reported in only 1 of 74 patients with complete mole at the initial visit. Although preeclampsia is associated with hypertension, proteinuria, and hyperreﬂexia, Figure 39.5 Photomicrograph of a fetal hand demonstrating syndactyly. The fetus had a triploid karyotype, and the chorionic tissues were a partial mole.


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Gynecology_Novak. Figure 39.5 Photomicrograph of a fetal hand demonstrating syndactyly. The fetus had a triploid karyotype, and the chorionic tissues were a partial mole. eclamptic convulsions rarely occur. Preeclampsia develops almost exclusively in patients with excessive uterine size and markedly elevated hCG levels. Hydatidiform mole should be considered whenever preeclampsia develops early in pregnancy. Hyperemesis Gravidarum Hyperemesis requiring antiemetic or intravenous replacement therapy occurred in one-fourth of women with a complete mole, particularly those with excessive uterine size and markedly elevated hCG levels. Severe electrolyte disturbances may develop and require treatment with parenteral ﬂuids. Currently, only 8% of patients have hyperemesis.


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Gynecology_Novak. Hyperthyroidism Clinically evident hyperthyroidism was observed in 7% of patients with a complete molar gestation. These women may have tachycardia, warm skin, and tremor, and the diagnosis can be confirmed by detection of elevated serum levels of free thyroxine (T4) and tri-iodothyronine (T3). Clinical evidence of hyperthyroidism with complete mole is rare. Anesthesia or surgery may precipitate thyroid storm. Thus, if hyperthyroidism is suspected before the induction of anesthesia for molar evacuation, β-adrenergic blocking agents should be administered. Thyroid storm may be manifested by hyperthermia, delirium, convulsions, tachycardia, high-output heart failure, or cardiovascular collapse. Administration of β-adrenergic blocking agents prevents or rapidly reverses many of the metabolic and cardiovascular complications of thyroid storm. After molar evacuation, thyroid function test results rapidly return to normal.


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Gynecology_Novak. Hyperthyroidism develops almost exclusively in patients with very high hCG levels. Some investigators suggest that hCG is the thyroid stimulator in women with molar pregnancy because positive correlations between serum hCG levels and total T4 or T3 concentrations were observed. However, in one study in which thyroid function was measured in 47 patients with a complete mole, no significant correlation was found between serum hCG levels and serum values of free T4 index or free T3 index (26). Although some investigators speculated about a separate chorionic thyrotropin, this substance is not yet isolated.


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Gynecology_Novak. Trophoblastic Embolization Respiratory distress rarely occurs in patients with a complete mole. It is usually diagnosed in patients with excessive uterine size and markedly elevated hCG levels. These patients may have chest pain, dyspnea, tachypnea, and tachycardia and may experience severe respiratory distress during and after molar evacuation. Auscultation of the chest usually reveals diffuse rales, and chest radiographic evaluation may show bilateral pulmonary infiltrates. Respiratory distress usually resolves within 72 hours with cardiopulmonary support. In some circumstances, patients may require mechanical ventilation. Respiratory insufficiency may result from trophoblastic embolization and the cardiopulmonary complications of thyroid storm, preeclampsia, and massive ﬂuid replacement.


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Gynecology_Novak. Theca Lutein Ovarian Cysts Prominent theca lutein ovarian cysts (6 cm in diameter) develop in about one-half of patients with a complete mole (27). Theca lutein ovarian cysts result from high serum hCG levels, which cause ovarian hyperstimulation (28). Because the uterus may be excessively enlarged, theca lutein cysts can be difficult to palpate during physical examination; however, ultrasonography can accurately document their presence and size. After molar evacuation, theca lutein cysts normally regress spontaneously within 2 to 4 months. Prominent theca lutein cysts may cause symptoms of marked pelvic pressure, and they can be decompressed by laparoscopic or ultrasonographically directed aspiration. If acute pelvic pain develops, laparoscopy should be performed to assess possible cystic torsion or rupture.


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Gynecology_Novak. Partial Hydatidiform Mole Patients with partial hydatidiform mole usually do not have the dramatic clinical features characteristic of complete molar pregnancy. These patients have the signs and symptoms of incomplete or missed abortion, and partial mole is diagnosed after histologic review of the tissue obtained by curettage (29). In a survey of 81 patients with a partial mole, the main initial sign was vaginal bleeding, which occurred in 59 patients (72.8%) (30). Excessive uterine enlargement and preeclampsia were present in three patients (3.7%) and two patients (2.5%), respectively. No patient had theca lutein ovarian cysts, hyperemesis, or hyperthyroidism. The initial clinical diagnosis was an incomplete or missed abortion in 74 patients (91.3%) and hydatidiform mole in five patients (6.2%). Pre-evacuation hCG levels were measured in 30 patients and were higher than 100,000 mIU/mL in two patients (6.6%).


Gynecology_Novak

Gynecology_Novak. In this review, patients with any one of these signs were considered at high risk for developing postmolar tumor. After molar evacuation, local uterine invasion occurred in 31%, and metastases developed in 8.8% of the 352 high-risk patients. For the 506 low-risk patients, local invasion was found in only 3.4%, and metastases developed in 0.6%. Older patients are at increased risk of developing postmolar GTN. One study reported that persistent tumor developed after a complete molar pregnancy in 37% of women older than 40 years (27), whereas in another study this finding occurred in 60% of women older than 50 years (31). Partial Hydatidiform Mole Persistent tumor, usually nonmetastatic, develops in approximately 2% to 4% of patients with a partial mole, and chemotherapy is required to achieve remission (32). Patients who develop persistent disease have no distinguishing clinical or pathologic characteristics (33).


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Gynecology_Novak. Diagnosis Ultrasonography is a reliable and sensitive technique for the diagnosis of complete molar pregnancy. Because the chorionic villi exhibit diffuse hydropic swelling, complete moles produce a characteristic vesicular ultrasonographic pattern as soon as in the first trimester (Fig. 39.6). Ultrasonography may contribute to the diagnosis of partial molar pregnancy by demonstrating focal cystic spaces in the placental tissues and an increase in the transverse diameter of the gestational sac (34). When these criteria are present, the positive predictive value for partial mole is 90%. Figure 39.6 Ultrasonogram of a uterus showing a typical pattern of a complete hydatidiform mole. Note the characteristic vesicular ultrasonographic pattern.


Gynecology_Novak

Gynecology_Novak. Figure 39.6 Ultrasonogram of a uterus showing a typical pattern of a complete hydatidiform mole. Note the characteristic vesicular ultrasonographic pattern. Treatment When molar pregnancy is diagnosed, the patient should be evaluated for the presence of associated medical complications, including preeclampsia, hyperthyroidism, electrolyte imbalance, and anemia. After the patient’s condition is stabilized, a decision must be made concerning the most appropriate method of evacuation. Suction Curettage Suction curettage is the preferred method of evacuation, regardless of uterine size, for patients who desire to preserve fertility (32). It involves the following steps: 1. Oxytocin infusion—This procedure is begun before the induction of anesthesia. 2.


Gynecology_Novak

Gynecology_Novak. Oxytocin infusion—This procedure is begun before the induction of anesthesia. 2. Cervical dilation—As the cervix is being dilated, uterine bleeding often increases. Retained blood in the endometrial cavity may be expelled during cervical dilation. Active uterine bleeding should not deter the prompt completion of cervical dilation. 3. Suction curettage—Within a few minutes of commencing suction curettage, uterine size may decrease dramatically, and the bleeding will be well controlled. The use of a 12-mm cannula is strongly advised to facilitate evacuation. If the uterus is larger than 14 weeks of gestation, one hand should be placed on top of the fundus, and the uterus should be massaged to stimulate uterine contraction and reduce the risk of perforation. 4. Sharp curettage—When suction evacuation is believed to be complete, gentle sharp curettage is performed to remove any residual molar tissue.


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Gynecology_Novak. 4. Sharp curettage—When suction evacuation is believed to be complete, gentle sharp curettage is performed to remove any residual molar tissue. Because trophoblast cells express RhD factor, patients who are Rh negative should receive Rh immune globulin at the time of evacuation. Hysterectomy If the patient desires surgical sterilization, a hysterectomy may be performed with the mole in situ. The ovaries may be preserved at the time of surgery, even in the presence of prominent theca lutein cysts. Large ovarian cysts may be decompressed by aspiration. Hysterectomy does not prevent metastasis; patients still require follow-up with assessment of hCG levels. The use of prophylactic chemotherapy at the time of molar evacuation is controversial. The debate concerns the wisdom of exposing all patients to potentially toxic treatment when only about 20% are at risk of developing persistent tumor.


Gynecology_Novak

Gynecology_Novak. In a study of 247 patients with complete molar pregnancy who prophylactically received a single course of actinomycin D (ActD) at the time of evacuation, local uterine invasion developed in 10 patients (4%), and no patients experienced metastasis (35). All 10 patients with local invasion achieved remission after one additional course of chemotherapy. Prophylactic chemotherapy, prevented metastasis and reduced the incidence and morbidity of local uterine invasion. In two prospective randomized studies of prophylactic chemotherapy in patients with a complete mole, a significant decrease in persistent tumor was detected in patients with high-risk mole who received prophylactic chemotherapy (47% and 50% vs. 14%) (36–38). Prophylaxis may be particularly useful in the management of high-risk complete molar pregnancy, especially when hCG assessments for follow-up are unavailable or unreliable.


Gynecology_Novak

Gynecology_Novak. After molar evacuation, patients should be monitored with weekly determinations of β-subunit hCG levels until these levels are normal for 3 consecutive weeks, followed by monthly determinations until the levels are normal for 6 consecutive months (39). The average time to achieve the first normal hCG level after evacuation is about 9 weeks (40). After achieving nondetectable serum hCG levels, the risk of developing GTN approaches zero (41–43). If these findings are confirmed, it is possible that postmolar hCG surveillance could be safely abbreviated. devices should not be inserted until the patient achieves a normal hCG level. If the patient does not desire surgical sterilization, either oral contraceptives or barrier methods should be used.


Gynecology_Novak

Gynecology_Novak. devices should not be inserted until the patient achieves a normal hCG level. If the patient does not desire surgical sterilization, either oral contraceptives or barrier methods should be used. Increased incidence of postmolar persistent tumor was reported among patients who used oral contraceptives before gonadotropin remission (44). However, data from a prospective trial and other centers indicate that oral contraceptive use does not increase the risk of postmolar trophoblastic disease (45–47). It appears that oral contraceptives may be used safely after molar evacuation during the entire interval of hormonal follow-up. Pulmonary At the time of diagnosis, lung involvement is visible by chest radiography in 80% of patients with metastatic GTN. Patients with pulmonary metastasis may have chest pain, cough, hemoptysis, dyspnea, or an asymptomatic lesion visible by chest radiography. Respiratory symptoms may be acute or chronic, persisting over many months.


Gynecology_Novak

Gynecology_Novak. GTN may produce four principal pulmonary patterns: 1. 2. 3. 4. An embolic pattern caused by pulmonary arterial occlusion. Table 39.2 Staging of Gestational Trophoblastic Tumorsb Because respiratory symptoms and radiographic findings may be dramatic, the patient may be thought to have a primary pulmonary disease. Some patients with extensive pulmonary involvement have minimal, if any, gynecologic symptoms because the reproductive organs may be free of trophoblastic tumor. The diagnosis of GTN may be confirmed only after thoracotomy is performed, particularly in patients with a nonmolar antecedent pregnancy. Pulmonary hypertension may develop in patients with GTN secondary to pulmonary arterial occlusion by trophoblastic emboli. The development of early respiratory failure requiring intubation is associated with a poor clinical outcome (49).


Gynecology_Novak

Gynecology_Novak. Central Nervous System Metastatic trophoblastic disease involves the brain in 10% of patients. Cerebral involvement is seen in patients with advanced disease; virtually all patients with brain metastasis have concurrent pulmonary or vaginal involvement or both. Because cerebral lesions frequently hemorrhage spontaneously, most patients develop acute focal neurologic deficits (50,51). Staging An anatomic staging system for GTN was adopted by the International Federation of Gynecology and Obstetrics (FIGO) (Table 39.2). It is hoped that this staging system will encourage the objective comparison of data from various centers (52). Stage I: Patients have persistently elevated hCG levels and tumor confined to the uterine corpus. Stage II: Patients have metastases to the genital tract.


Gynecology_Novak

Gynecology_Novak. Stage I: Patients have persistently elevated hCG levels and tumor confined to the uterine corpus. Stage II: Patients have metastases to the genital tract. Stage III: Patients have pulmonary metastases with or without uterine, vaginal, or pelvic involvement. The diagnosis is based on a rising hCG level in the presence of pulmonary lesions viewed by chest radiography. Stage IV: Patients have advanced disease and involvement of the brain, liver, kidneys, or gastrointestinal tract. These patients are in the highest risk category because they are most likely to be resistant to chemotherapy. Choriocarcinoma is usually present, and the disease commonly follows a nonmolar pregnancy.


Gynecology_Novak

Gynecology_Novak. Prognostic Scoring System In addition to anatomic staging, it is important to consider other variables to predict the likelihood of drug resistance and to assist in selecting appropriate chemotherapy (53). A prognostic scoring system proposed by the World Health Organization reliably predicts the potential for resistance to chemotherapy (Table 39.3). Table 39.3 Scoring System Based on Prognostic Factorsa a The total score for a patient is obtained by adding the individual scores for each prognostic factor. Total score: <7, low risk; ≥7, high risk.


Gynecology_Novak

Gynecology_Novak. When the prognostic score is higher than 6, the patient is categorized as high risk and requires multimodal therapy, which includes intensive combination chemotherapy, and may also include surgery and radiation to achieve remission. Patients with stage I disease usually have a low-risk score, and those with stage IV disease have a high-risk score. The distinction between low and high risk applies mainly to patients with stage II or III disease. Diagnostic Evaluation Optimal management of persistent GTN requires a thorough assessment of the extent of the disease before the initiation of treatment. All patients with persistent GTN should undergo a careful pretreatment evaluation, including the following: 1. 2. Measurement of the serum hCG level 3. Hepatic, thyroid, and renal function tests 4. Determination of baseline peripheral white blood cell and platelet counts The metastatic workup should include the following: 1. 2. Ultrasonography or CT scan of the abdomen and pelvis 3.


Gynecology_Novak

Gynecology_Novak. Determination of baseline peripheral white blood cell and platelet counts The metastatic workup should include the following: 1. 2. Ultrasonography or CT scan of the abdomen and pelvis 3. CT or magnetic resonance imaging (MRI) scan of the head When the pelvic examination and chest radiographic findings are negative, metastatic involvement of other sites is uncommon. Liver ultrasonography and CT or MRI scanning will disclose most hepatic metastases in patients with abnormal liver function tests. CT or MRI scan of the head facilitates the early diagnosis of asymptomatic cerebral lesions. Chest CT scans may detect micrometastases not visible on chest radiography. Chest CT will demonstrate pulmonary micrometastases in about 40% of patients with presumed nonmetastatic disease (54).


Gynecology_Novak

Gynecology_Novak. In patients with choriocarcinoma or metastatic disease, hCG levels may be measured in the cerebrospinal ﬂuid (CSF) to exclude cerebral involvement if the results of CT scanning of the brain are normal. The ratio of plasma-to-CSF hCG tends to be lower than 60 in the presence of cerebral metastases (55). A single plasma-to-CSF hCG ratio may be misleading, because rapid changes in plasma hCG levels may not be reﬂected promptly in the CSF (56). Table 39.4 Protocol for Treatment of GTN aLocal resection optional. Pelvic ultrasonography appears to be useful in detecting extensive trophoblastic uterine involvement and may aid in identifying sites of resistant uterine tumor (57). Because ultrasonography can accurately and noninvasively detect extensive uterine tumor, it may help identify patients who would benefit from hysterectomy. Hysterectomy is performed in all patients with stage I placental-site trophoblastic tumor.


Gynecology_Novak

Gynecology_Novak. Hysterectomy is performed in all patients with stage I placental-site trophoblastic tumor. Because placental-site tumors are resistant to chemotherapy, hysterectomy for presumed nonmetastatic disease is the only curative treatment. Patients with metastatic placental site trophoblastic tumor may still achieve remission, but their tumors are less responsive to chemotherapy (59). Single-agent chemotherapy is the preferred treatment in patients with stage I disease who desire to retain fertility (60). At the NETDC from July 1965 through June 2008, primary single-agent chemotherapy was administered to 561 patients with stage I GTN and 434 patients (77.4%) attained complete remission. The remaining 127 patients with resistant disease subsequently achieved remission after combination chemotherapy or surgical intervention.


Gynecology_Novak

Gynecology_Novak. When a patient’s disease is resistant to single-agent chemotherapy and she desires to preserve fertility, combination chemotherapy should be administered. If the patient’s disease is resistant to single-agent and combination chemotherapy and she wants to retain fertility, local uterine resection may be considered. When local resection is planned, a preoperative ultrasonography, MRI, or arteriography may help to define the site of the resistant tumor. Low-risk disease treated with primary single-agent chemotherapy has a high (approximately 80%) rate of remission in contrast to high-risk disease that usually does not achieve remission with single-agent treatment and requires treatment with primary intensive combination chemotherapy.


Gynecology_Novak

Gynecology_Novak. Vaginal metastases may bleed profusely because they are highly vascular and friable. When bleeding is substantial, it may be controlled by packing the vagina or by wide local excision. Infrequently, arteriographic embolization of the hypogastric arteries may be required to control hemorrhage from vaginal metastases (61). At the NETDC from July 1965 through June 2008, of the 139 patients with low-risk stages II or III disease, 114 (82%) attained complete remission with single-agent chemotherapy. The remaining 25 (18%) patients who had disease resistant to single-agent treatment subsequently achieved remission with combination chemotherapy.


Gynecology_Novak

Gynecology_Novak. Thoracotomy Thoracotomy has a limited but important role in the management of pulmonary metastases. If a patient has a persistent viable pulmonary metastasis following intensive chemotherapy, thoracotomy may be indicated to excise the resistant focus. A thorough metastatic workup should be performed before surgery is undertaken to exclude other sites of persistent disease. It is important to realize that fibrotic pulmonary nodules may persist indefinitely on chest radiography, even after complete gonadotropin remission is attained. In patients undergoing thoracotomy for resistant disease, chemotherapy should be administered postoperatively to treat potential occult sites of micrometastasis. Hysterectomy may be required in patients with metastatic disease to control uterine hemorrhage or sepsis. In patients with extensive uterine tumor, hysterectomy may substantially reduce the trophoblastic tumor burden and limit the need for multiple courses of chemotherapy (62).


Gynecology_Novak

Gynecology_Novak. All patients with low-risk GTN (stages I through III) should undergo follow-up with: 1. Weekly measurement of hCG levels until they are normal for 3 consecutive weeks. 2. Monthly measurement of hCG values until levels are normal for 12 consecutive months. 3. Effective contraception during the entire interval of hormonal follow-up.


Gynecology_Novak

Gynecology_Novak. All patients with high-risk GTN (stages II–IV) should be treated with primary intensive combination chemotherapy and the selective use of radiation therapy and surgery. Between July 1965 and June 2008, of the 103 patients with high-risk GTN stages II–IV treated at the NETDC, 83 (80.5%) achieved complete remission. Before 1975, when single agent therapy was used primarily to treat patients with stage IV GTN, only 6 of 20 patients (30%) attained complete remission. Since 1975, 17 of 21 patients (80.9%) achieved remission. This improvement in survival resulted from the use of multimodal therapy, including primary combination chemotherapy in conjunction with radiation and surgical treatment. Patients with stage IV disease are at the greatest risk of developing rapidly progressive and unresponsive tumors despite intensive multimodal therapy. They should be referred to centers with special expertise in the management of trophoblastic disease.


Gynecology_Novak

Gynecology_Novak. The management of resistant hepatic metastasis is particularly difficult (63). If a patient becomes resistant to systemic chemotherapy, hepatic arterial infusion of chemotherapy may induce complete remission in selected cases. Hepatic resection may be required to control acute bleeding or to excise a focus of resistant tumor. New techniques of arterial embolization may reduce the need for surgical intervention. At the NETDC, cerebral metastases are treated with either whole-brain radiation (3,000 cGy in 10 fractions) or stereotactic radiosurgery in conjunction with combination chemotherapy. Because irradiation may be hemostatic and tumoricidal, the risk of spontaneous cerebral hemorrhage may be lessened by the concurrent use of combination chemotherapy and brain irradiation. Excellent remission rates (86%) were reported in patients with cranial metastases treated with intensive intravenous combination chemotherapy and intrathecal methotrexate (MTX) (64).


Gynecology_Novak

Gynecology_Novak. Craniotomy Craniotomy may be required to provide acute decompression or to control bleeding. It should be performed to manage life-threatening complications so that the patient ultimately will be cured with chemotherapy. In a study of six patients (65), the use of craniotomy to control bleeding resulted in complete remission in three patients. Infrequently, cerebral metastases that are resistant to chemotherapy may be amenable to local resection (66). Patients with cerebral metastases who achieve sustained remission generally have no residual neurologic deficits. Patients with stage IV disease should receive follow-up with: 1. Weekly determination of hCG levels until they are normal for 3 consecutive weeks. 2. Monthly determination of hCG levels until they are normal for 24 consecutive months. These patients require prolonged gonadotropin follow-up because they are at increased risk of late recurrence.


Gynecology_Novak

Gynecology_Novak. Monthly determination of hCG levels until they are normal for 24 consecutive months. These patients require prolonged gonadotropin follow-up because they are at increased risk of late recurrence. An algorithm for the management of persistent GTN is presented in Figure 39.7.


Gynecology_Novak

Gynecology_Novak. These patients require prolonged gonadotropin follow-up because they are at increased risk of late recurrence. An algorithm for the management of persistent GTN is presented in Figure 39.7. GTN Choriocarcinoma Mole Evacuation and weekly hCG levels ↓ hCG levels ↑ or plateau of hCG levels Careful follow-up and contraception Distant metastasis Uterine disease Pelvic metastasis Lung metastasis Stage IVStage I Stage II Stage III Combination chemotherapy ± surgery ± RT Single drug chemotherapy or hysterectomy Calculate risk Low High ResistantFollow-up Metastatic work-up Figure 39.7 Management of gestational trophoblastic tumor. GTN, gestational trophoblastic neoplasia; hCG, human chorionic gonadotropin; RT, radiotherapy. (From Berkowitz RS, Goldstein DP. Gestational trophoblastic neoplasia. In: Berek JS, Hacker NF. Berek and Hacker’s Gynecologic Oncology, 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010;607, with permission.) 1473


Gynecology_Novak

Gynecology_Novak. Technique of Single-Agent Treatment patients were randomized to receive either biweekly ActD 1.25mg/m2 intravenous (IV) bolus or weekly MTX 30 mg/m2 intramuscular (IM). The remission rate was 58% in the MTX arm and 73% in the ActD arm. These results suggest that ActD is superior to the weekly MTX regimen in treating low-risk GTN. Before recommending pulse ActD as the primary modality in the treatment of patients with low-risk GTN, it is important to be aware of the potential for significant toxicity of this regimen compared to those receiving MTX. All patients with low-risk disease in this study ultimately achieved remission, regardless of their initial response. Regarding the true comparative effectiveness of these agents, it would be prudent to compare the biweekly ActD regimen to the more commonly used 5-day or 8-day MTX regimens, which offer a high initial remission rate with minimal toxicity.