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Squamous cell carcinoma of the vulva in pregnancy
GYNECOLOGlC
ONCOLOGY
41, 74-77 (1991)
CASE REPORT Squamous Cell Carcinoma of the Vulva in Pregnancy DAVID H. MOORE, M.D.,* *Division
of Gynecologic North Carolina
Oncology, Department 27599; and tDivision
WESLEY C. FOWLER, JR., M.D.,* AND LESLIE A. WALTON, M.D.* of Obstetrics of Gynecologic
and Gynecology, The University Oncology, The Johns Hopkins
JOHN L. CURRIE, M.D.,? of North Hospital,
Carolina Baltimore,
at Chapel Maryland
Hill, Chapel 21218
Hill,
Received July 30, 1990
Two womenpresentingwith invasive squamouscell cancer of the vulva during pregnancy are reported. The first patient was successfullytreated by radical vulvectomy 2 weeksafter cesarean sectiondelivery; the secondpatient died of disseminatedcancer despiteradical vulvectomy and postoperativeradiation therapy. In the secondcasethe diagnosiswasnot established until 3 months after delivery. Only 12 casesof invasive squamouscell vulvar cancer during pregnancyhave beenpreviously reported. Liberal useof punch biopsyfor any suspicious vulvar lesionsismandatory to enhancethe potential for early diagnosisand successfultreatment. 0 1991 Academic Press, Inc.
Approximately 4000 new cases of invasive squamous cell carcinoma of the vulva are diagnosed each year in the United States. The disease occurs most commonly during the sixth decade of life although 15% of vulvar cancers develop in women less than 40 years of age [1,2]. The coexistence of this disease and pregnancy would appear inevitable; nevertheless, a comprehensive review of the English literature yielded only 12 previously reported cases [3,4]. We report two cases of invasive squamous cell cancer of the vulva during pregnancy to emphasize the diagnostic and therapeutic problems facing the obstetrician/ gynecologist in the management of this rare disease. CASE 1 KS is a 24-year-old nulligravid white female who presented to a local emergency department complaining of a 9-week history of progressive swelling and tenderness on her vulva. A periclitoral “abscess” was incised and drained, followed by 1 week of oral cephalexin and erythromycin antibiotic therapy. Because of her obvious gravid state without antecedent prenatal care she was immedi-
ately referred to an obstetric clinic. Two weeks later an ultrasound examination revealed a singleton fetus of 31 weeks gestational age. Cervical cytology was negative. The clitoral lesion was still present and biopsied, revealing a moderately differentiated squamous cell carcinoma. She subsequently was referred to the Division of Gynecologic Oncology at the University of North Carolina. Physical examination revealed a 3.5 x 5.0-cm raised lesion overlying the clitoris and upper left labium majus and a l.O-cm verrucous lesion of the lower right labium majus (Fig. 1). Inguinal lymph nodes were palpable but not suspicious for metastatic cancer. The clinical diagnosis was stage II squamous cell carcinoma of the vulva. Amniocentesis was performed and study of the amniotic fluid revealed an L:S ratio >2.0 with the presence of phosphatidyl glycerol. Two days later, at approximately 36 weeks gestational age, the patient was delivered by cesarean section of a 2670-g female infant with Apgar scores of 8 and 9 at 1 and 5 min, respectively. Intraoperative cystoscopy showed no urethral or bladder involvement. Internal and external iliac lymph node samples were obtained. Because of the possible need for pelvic radiotherapy following definitive surgery, a right oophoropexy to the right paracolic gutter was performed. All node specimens were negative for metastatic disease. Both mother and infant were discharged on the fifth postoperative day. On postpartum day 14 the patient underwent radical vulvectomy with bilateral inguinal and femoral lymph node dissection and vulvar reconstruction with tensor fascia lata myocutaneous flaps. Inguinal lymph nodes were free of metastatic disease; VIN-III was present at the periurethral surgical margin, but all other margins were negative. Her postoperative course was complicated by
74 0090-8258/91 $1.50 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.
75
CASE REPORTS
A preoperative chest X ray, intravenous pyelogram, and barium enema were negative and computed tomography of the abdomen revealed no pelvic adenopathy. The clinical diagnosis was stage III squamous cell carcinoma of the vulva. She underwent radical vulvectomy with bilateral inguinal and femoral lymph node dissection and vulvar reconstruction with tensor fascia lata myocutaneous flaps. Surgical margins were negative, but six left groin and nine right groin nodes contained metastatic carcinoma. She received 5000 cGy pelvic and groin irradiation. Therapy was complicated by superficial wound breakdown. Sixteen months later she presented with low back pain. A bone scan revealed metastases to the lumbar vertebrae, and computed tomography showed periaortic lymphadenopathy. She received palliative radiation therapy and expired 27 months after the date of initial diagnosis. DISCUSSION
FIG. 1. Ulcerative lesion of clitoris and upper left labium majus in case 1.
necrosis of the distal flaps, requiring surgical debridement. Sixteen months after diagnosis the patient remains without evidence of recurrent disease. CASE 2 EC is a 35year-old G9P& black female who presented during the second trimester of pregnancy with symptoms of vaginal itching and burning and was noted to have a vulvar lesion. She received symptomatic treatment; the lesion was not biopsied. Three months following a term spontaneous vaginal delivery she presented to the Division of Gynecologic Oncology at the University of North Carolina with complaints of vaginal itching, a tender “knot” in her left groin, and a “sore” on her vulva. Physical examination was pertinent for a 0.8 x l.O-cm lesion of the right labium majus (Fig. 2) and a 4.0 x 6.0cm mass of matted lymph nodes in the left groin. Punch biopsy of the vulvar lesion and needle aspiration cytology of the groin nodes were both conclusive for moderately differentiated squamous cell carcinoma.
In 1974 Barclay reviewed thirty previously reported cases of invasive vulvar cancer associated with pregnancy [3]. Sixteen of these thirty women were treated for vulvar cancer at least 6 months prior to becoming pregnant. Fourteen patients were diagnosed with invasive vulvar cancer during pregnancy, and nine of these women had vulvar cancer of squamous cell histology. One patient underwent radiation therapy followed by a cesarean section delivery and bilateral tubal ligation. Eight women underwent vulvectomy prior to either vaginal delivery (three patients) or cesarean section delivery (two patients), or 2 weeks after vaginal delivery (three patients). Abdominal deliveries were performed for suspected placental abruption and vulvar scarring. All patients in this series were alive and without evidence of recurrent vulvar cancer through extended follow-up, although one patient received radiation therapy for a subsequent stage II cervical cancer. In 1977 Lutz et al. described five additional cases of vulvar cancer occurring during pregnancy [4]. One patient had an in situ lesion and another patient had Bartholin’s gland adenocarcinoma. Details concerning lesion size, stage of disease, or mode of treatment were not provided although only the patient with in situ carcinoma survived her cancer. An extensive literature review, including a computer search, disclosed no additional cases of invasive squamous cell vulvar carcinoma occurring during pregnancy. These 2 cases appear to be the 13th and 14th reported cases. Problem issues of accurate diagnosis, staging, and treatment are compounded by the unborn fetus. Considering the paucity of reported cases, data upon which to formulate a rational management plan applicable to most patients are unavailable.
76
MOORE
ET AL.
FIG. 2. The ulcerative lesion in case 2 is located on the lower third of the right labium majus, pinpointed with the hemostat on the Iradical vulvectomy specimen.
While a causative agent for lower genital tract cancer has never been identified, risk factors for the development of vulvar neoplasia resemble those associated with squamous cervical cancers. Additionally, syphylis, herpes genitalis, and chronic granulomatous diseases (e.g., lymphogranuloma venereum) are of possible etiologic significance [5]. Recently, much attention has been focused on the close association between human papillomavirus (HPV) and lower genital tract neoplasia. Many women with vulvar neoplasia have evidence for the presence of HPV by various methods of DNA analysis such as in situ hybridization or Southern blot [6,7]. Viral types 16, 18, and 31 seem to be associated with higher degrees of dysplasia or invasive cancer [B]. Indications for the treatment of low-grade dysplasias or condylomata during pregnancy are uncertain. Following delivery, condylomata often regress in size and become less vascular, reducing the morbidity of treatment. Although treatment of condyloma accuminata during pregnancy remains controversial, it is extremely important to document the size and extent of lesions and to biopsy any atypical or rapidly growing lesions to exclude the presence of an invasive process. Treatment of vulvar cancer coexistent with pregnancy must be highly individualized, with attention to several parameters such as stage, lesion size and location, and gestational age. Radical surgical treatment is the mainstay of therapy during the first two trimesters [9]. Surgical morbidity is proportional to genital vascularity, which increases throughout pregnancy. Barclay [3] reported no
immediate adverse results in any patient receiving antenatal treatment, although one patient eventually required cesarean section delivery for vulvar scarring. Monaghan and Lindeque [9] advocated treatment at any time up to 36 weeks gestation, after which delay into the puerperium was advised. With increasing gestational age there is greater likelihood of thrombotic complications secondary to increased levels of fibrinogen, increased activity of serum coagulation factors (except Factors XI and XIII), and decreased activity of antithrombin III and antifactor Xa [lo]. In the puerperium the incidence of thromboembolic complications is increased three- to fourfold over that in pregnancy [lo]. Postpartum hypercoagulability rapidly reverts to the normal state during the first week after delivery [ll]. Radical surgery should be deferred until after this time interval. Radical vulvectomy has long been the procedure of choice for invasive squamous cell cancer of the vulva and techniques for pelvic reconstruction can reduce the morbidity and disfigurement associated with this operation [ 121. Successful treatment utilizing less radical procedures is possible in early stage disease [13]. Lesion size and location and lymph node status are important factors in selecting patients for less radical procedures. Selecting an appropriate mode of delivery must also be individualized. Following radical vulvectomy women can successfully deliver by the vaginal route and some clinicians propose that cesarean section should be considered only for obstetric indications [3,9]. Large lesions on the vulva are subject to possible laceration and hemorrhage
CASE REPORTS
with vaginal birth, precipitating our decision to proceed with operative delivery in the first case. Lymphatic tumor embolization facilitated by vaginal delivery is of hypothetical concern, Squamous cell cancer of the vulva occurring during pregnancy is rare. It is impossible to establish clinical management protocols through the experience of any one individual or institution. Meticulous attention to vulvar lesions with liberal use of punch biopsy will expedite diagnosis and treatment planning. REFERENCES 1. Zaino, R. J. Carcinoma of the vulva, urethra, and Bartholin’s glands, in Pathology ofthe vulva and vagina (E. J. Wilkinson, Ed.), Churchill/Livingstone, New York, pp. 119-153 (1987). 2. Henson, D., and Tarone, R. An epidemiologic study of cancer of the cervix, vagina, and vulva based on the Third National Cancer Survey in the United States, Am. J. Obstet. GynecoZ. 129, 525-532 (1977). 3. Barclay, D. L. Surgery of the vulva, perineum and vagina in pregnancy, in Surgical disease in pregnancy (H. R. K. Barber, Ed.), Saunders, Philadelphia, pp. 310-342 (1974). 4. Lutz, M. H., Underwood, P. B., Rozier, J. C., and Putney, F. W. Genital malignancy in pregnancy, Am. J. Obstet. Gynecol. 129, 536-542 (1977).
77
5. DiSaia, P. J., and Creasman, W. T. Clinical gynecologic oncology, 3rd ed., M&by, St. Louis (1989). 6. Carson, L. F., Twiggs, L. B., Okagaki, T., Clark, B. A., Ostrow, R. S., and Faras, A. J. Human papillomavirus DNA in adenosquamous carcinoma and squamous cell carcinoma of the vulva, Obstet. Gynecol. 72, 63-67 (1988). 7. Spitzer, M., Krumholz, B. A., and Seltzer, V. L. The multicentric nature of disease related to human papillomavirus infection of the female lower genital tract, Obstet. Gynecol. 73, 303-307 (1989). 8. Reid, R., Greenberg, M., Jenson, A. B., Husain, M., Willett, J., Daoud, Y., Temple, G., Stanhope, C. R., Sherman, A. I., Phibbs, G. D., and Lorincz, A. T. Sexually transmitted papillomaviral infections. I. The anatomic distribution and pathologic grade of neoplastic lesions associated with different viral types, Am. J. Obstet. Gynecol. 156, 212-222 (1987). 9. Monaghan, J. M., and Lindeque, G. Commentary: Vulvar carcinoma in pregnancy, Br. J. Obstet. Gynecof. 93, 785-786 (1986). 10. Hathaway, W. E., and Bonnar, J. Perinatal coagulation, Grune & Stratton, New York (1978). 11. Von Kaulla, E., Droegemueller, W., Aoki, N., and Von Kaulla, K. N. Effect of estrogens on postpartum hypercoagulability and antithrombin III activity, Am. J. Obstet. Gynecol. ll3, 920-926 (1972). 12. Chafe, W., Fowler, W. C., Walton, L. A., and Currie, J. L. Radical vulvectomy with use of tensor fascia lata myocutaneous flap, Am. J. Obstet. Gynecol. 145, 207-213 (1983). 13. Hoffman, M. S., Roberts W. S., Lapolla J. P., and Cavanaugh, D. Recent modifications in the treatment of invasive squamous cell carcinoma of the vulva, Obstet. Gynecol. Surv. 44,227-233 (1989).
ONCOLOGY
41, 74-77 (1991)
CASE REPORT Squamous Cell Carcinoma of the Vulva in Pregnancy DAVID H. MOORE, M.D.,* *Division
of Gynecologic North Carolina
Oncology, Department 27599; and tDivision
WESLEY C. FOWLER, JR., M.D.,* AND LESLIE A. WALTON, M.D.* of Obstetrics of Gynecologic
and Gynecology, The University Oncology, The Johns Hopkins
JOHN L. CURRIE, M.D.,? of North Hospital,
Carolina Baltimore,
at Chapel Maryland
Hill, Chapel 21218
Hill,
Received July 30, 1990
Two womenpresentingwith invasive squamouscell cancer of the vulva during pregnancy are reported. The first patient was successfullytreated by radical vulvectomy 2 weeksafter cesarean sectiondelivery; the secondpatient died of disseminatedcancer despiteradical vulvectomy and postoperativeradiation therapy. In the secondcasethe diagnosiswasnot established until 3 months after delivery. Only 12 casesof invasive squamouscell vulvar cancer during pregnancyhave beenpreviously reported. Liberal useof punch biopsyfor any suspicious vulvar lesionsismandatory to enhancethe potential for early diagnosisand successfultreatment. 0 1991 Academic Press, Inc.
Approximately 4000 new cases of invasive squamous cell carcinoma of the vulva are diagnosed each year in the United States. The disease occurs most commonly during the sixth decade of life although 15% of vulvar cancers develop in women less than 40 years of age [1,2]. The coexistence of this disease and pregnancy would appear inevitable; nevertheless, a comprehensive review of the English literature yielded only 12 previously reported cases [3,4]. We report two cases of invasive squamous cell cancer of the vulva during pregnancy to emphasize the diagnostic and therapeutic problems facing the obstetrician/ gynecologist in the management of this rare disease. CASE 1 KS is a 24-year-old nulligravid white female who presented to a local emergency department complaining of a 9-week history of progressive swelling and tenderness on her vulva. A periclitoral “abscess” was incised and drained, followed by 1 week of oral cephalexin and erythromycin antibiotic therapy. Because of her obvious gravid state without antecedent prenatal care she was immedi-
ately referred to an obstetric clinic. Two weeks later an ultrasound examination revealed a singleton fetus of 31 weeks gestational age. Cervical cytology was negative. The clitoral lesion was still present and biopsied, revealing a moderately differentiated squamous cell carcinoma. She subsequently was referred to the Division of Gynecologic Oncology at the University of North Carolina. Physical examination revealed a 3.5 x 5.0-cm raised lesion overlying the clitoris and upper left labium majus and a l.O-cm verrucous lesion of the lower right labium majus (Fig. 1). Inguinal lymph nodes were palpable but not suspicious for metastatic cancer. The clinical diagnosis was stage II squamous cell carcinoma of the vulva. Amniocentesis was performed and study of the amniotic fluid revealed an L:S ratio >2.0 with the presence of phosphatidyl glycerol. Two days later, at approximately 36 weeks gestational age, the patient was delivered by cesarean section of a 2670-g female infant with Apgar scores of 8 and 9 at 1 and 5 min, respectively. Intraoperative cystoscopy showed no urethral or bladder involvement. Internal and external iliac lymph node samples were obtained. Because of the possible need for pelvic radiotherapy following definitive surgery, a right oophoropexy to the right paracolic gutter was performed. All node specimens were negative for metastatic disease. Both mother and infant were discharged on the fifth postoperative day. On postpartum day 14 the patient underwent radical vulvectomy with bilateral inguinal and femoral lymph node dissection and vulvar reconstruction with tensor fascia lata myocutaneous flaps. Inguinal lymph nodes were free of metastatic disease; VIN-III was present at the periurethral surgical margin, but all other margins were negative. Her postoperative course was complicated by
74 0090-8258/91 $1.50 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.
75
CASE REPORTS
A preoperative chest X ray, intravenous pyelogram, and barium enema were negative and computed tomography of the abdomen revealed no pelvic adenopathy. The clinical diagnosis was stage III squamous cell carcinoma of the vulva. She underwent radical vulvectomy with bilateral inguinal and femoral lymph node dissection and vulvar reconstruction with tensor fascia lata myocutaneous flaps. Surgical margins were negative, but six left groin and nine right groin nodes contained metastatic carcinoma. She received 5000 cGy pelvic and groin irradiation. Therapy was complicated by superficial wound breakdown. Sixteen months later she presented with low back pain. A bone scan revealed metastases to the lumbar vertebrae, and computed tomography showed periaortic lymphadenopathy. She received palliative radiation therapy and expired 27 months after the date of initial diagnosis. DISCUSSION
FIG. 1. Ulcerative lesion of clitoris and upper left labium majus in case 1.
necrosis of the distal flaps, requiring surgical debridement. Sixteen months after diagnosis the patient remains without evidence of recurrent disease. CASE 2 EC is a 35year-old G9P& black female who presented during the second trimester of pregnancy with symptoms of vaginal itching and burning and was noted to have a vulvar lesion. She received symptomatic treatment; the lesion was not biopsied. Three months following a term spontaneous vaginal delivery she presented to the Division of Gynecologic Oncology at the University of North Carolina with complaints of vaginal itching, a tender “knot” in her left groin, and a “sore” on her vulva. Physical examination was pertinent for a 0.8 x l.O-cm lesion of the right labium majus (Fig. 2) and a 4.0 x 6.0cm mass of matted lymph nodes in the left groin. Punch biopsy of the vulvar lesion and needle aspiration cytology of the groin nodes were both conclusive for moderately differentiated squamous cell carcinoma.
In 1974 Barclay reviewed thirty previously reported cases of invasive vulvar cancer associated with pregnancy [3]. Sixteen of these thirty women were treated for vulvar cancer at least 6 months prior to becoming pregnant. Fourteen patients were diagnosed with invasive vulvar cancer during pregnancy, and nine of these women had vulvar cancer of squamous cell histology. One patient underwent radiation therapy followed by a cesarean section delivery and bilateral tubal ligation. Eight women underwent vulvectomy prior to either vaginal delivery (three patients) or cesarean section delivery (two patients), or 2 weeks after vaginal delivery (three patients). Abdominal deliveries were performed for suspected placental abruption and vulvar scarring. All patients in this series were alive and without evidence of recurrent vulvar cancer through extended follow-up, although one patient received radiation therapy for a subsequent stage II cervical cancer. In 1977 Lutz et al. described five additional cases of vulvar cancer occurring during pregnancy [4]. One patient had an in situ lesion and another patient had Bartholin’s gland adenocarcinoma. Details concerning lesion size, stage of disease, or mode of treatment were not provided although only the patient with in situ carcinoma survived her cancer. An extensive literature review, including a computer search, disclosed no additional cases of invasive squamous cell vulvar carcinoma occurring during pregnancy. These 2 cases appear to be the 13th and 14th reported cases. Problem issues of accurate diagnosis, staging, and treatment are compounded by the unborn fetus. Considering the paucity of reported cases, data upon which to formulate a rational management plan applicable to most patients are unavailable.
76
MOORE
ET AL.
FIG. 2. The ulcerative lesion in case 2 is located on the lower third of the right labium majus, pinpointed with the hemostat on the Iradical vulvectomy specimen.
While a causative agent for lower genital tract cancer has never been identified, risk factors for the development of vulvar neoplasia resemble those associated with squamous cervical cancers. Additionally, syphylis, herpes genitalis, and chronic granulomatous diseases (e.g., lymphogranuloma venereum) are of possible etiologic significance [5]. Recently, much attention has been focused on the close association between human papillomavirus (HPV) and lower genital tract neoplasia. Many women with vulvar neoplasia have evidence for the presence of HPV by various methods of DNA analysis such as in situ hybridization or Southern blot [6,7]. Viral types 16, 18, and 31 seem to be associated with higher degrees of dysplasia or invasive cancer [B]. Indications for the treatment of low-grade dysplasias or condylomata during pregnancy are uncertain. Following delivery, condylomata often regress in size and become less vascular, reducing the morbidity of treatment. Although treatment of condyloma accuminata during pregnancy remains controversial, it is extremely important to document the size and extent of lesions and to biopsy any atypical or rapidly growing lesions to exclude the presence of an invasive process. Treatment of vulvar cancer coexistent with pregnancy must be highly individualized, with attention to several parameters such as stage, lesion size and location, and gestational age. Radical surgical treatment is the mainstay of therapy during the first two trimesters [9]. Surgical morbidity is proportional to genital vascularity, which increases throughout pregnancy. Barclay [3] reported no
immediate adverse results in any patient receiving antenatal treatment, although one patient eventually required cesarean section delivery for vulvar scarring. Monaghan and Lindeque [9] advocated treatment at any time up to 36 weeks gestation, after which delay into the puerperium was advised. With increasing gestational age there is greater likelihood of thrombotic complications secondary to increased levels of fibrinogen, increased activity of serum coagulation factors (except Factors XI and XIII), and decreased activity of antithrombin III and antifactor Xa [lo]. In the puerperium the incidence of thromboembolic complications is increased three- to fourfold over that in pregnancy [lo]. Postpartum hypercoagulability rapidly reverts to the normal state during the first week after delivery [ll]. Radical surgery should be deferred until after this time interval. Radical vulvectomy has long been the procedure of choice for invasive squamous cell cancer of the vulva and techniques for pelvic reconstruction can reduce the morbidity and disfigurement associated with this operation [ 121. Successful treatment utilizing less radical procedures is possible in early stage disease [13]. Lesion size and location and lymph node status are important factors in selecting patients for less radical procedures. Selecting an appropriate mode of delivery must also be individualized. Following radical vulvectomy women can successfully deliver by the vaginal route and some clinicians propose that cesarean section should be considered only for obstetric indications [3,9]. Large lesions on the vulva are subject to possible laceration and hemorrhage
CASE REPORTS
with vaginal birth, precipitating our decision to proceed with operative delivery in the first case. Lymphatic tumor embolization facilitated by vaginal delivery is of hypothetical concern, Squamous cell cancer of the vulva occurring during pregnancy is rare. It is impossible to establish clinical management protocols through the experience of any one individual or institution. Meticulous attention to vulvar lesions with liberal use of punch biopsy will expedite diagnosis and treatment planning. REFERENCES 1. Zaino, R. J. Carcinoma of the vulva, urethra, and Bartholin’s glands, in Pathology ofthe vulva and vagina (E. J. Wilkinson, Ed.), Churchill/Livingstone, New York, pp. 119-153 (1987). 2. Henson, D., and Tarone, R. An epidemiologic study of cancer of the cervix, vagina, and vulva based on the Third National Cancer Survey in the United States, Am. J. Obstet. GynecoZ. 129, 525-532 (1977). 3. Barclay, D. L. Surgery of the vulva, perineum and vagina in pregnancy, in Surgical disease in pregnancy (H. R. K. Barber, Ed.), Saunders, Philadelphia, pp. 310-342 (1974). 4. Lutz, M. H., Underwood, P. B., Rozier, J. C., and Putney, F. W. Genital malignancy in pregnancy, Am. J. Obstet. Gynecol. 129, 536-542 (1977).
77
5. DiSaia, P. J., and Creasman, W. T. Clinical gynecologic oncology, 3rd ed., M&by, St. Louis (1989). 6. Carson, L. F., Twiggs, L. B., Okagaki, T., Clark, B. A., Ostrow, R. S., and Faras, A. J. Human papillomavirus DNA in adenosquamous carcinoma and squamous cell carcinoma of the vulva, Obstet. Gynecol. 72, 63-67 (1988). 7. Spitzer, M., Krumholz, B. A., and Seltzer, V. L. The multicentric nature of disease related to human papillomavirus infection of the female lower genital tract, Obstet. Gynecol. 73, 303-307 (1989). 8. Reid, R., Greenberg, M., Jenson, A. B., Husain, M., Willett, J., Daoud, Y., Temple, G., Stanhope, C. R., Sherman, A. I., Phibbs, G. D., and Lorincz, A. T. Sexually transmitted papillomaviral infections. I. The anatomic distribution and pathologic grade of neoplastic lesions associated with different viral types, Am. J. Obstet. Gynecol. 156, 212-222 (1987). 9. Monaghan, J. M., and Lindeque, G. Commentary: Vulvar carcinoma in pregnancy, Br. J. Obstet. Gynecof. 93, 785-786 (1986). 10. Hathaway, W. E., and Bonnar, J. Perinatal coagulation, Grune & Stratton, New York (1978). 11. Von Kaulla, E., Droegemueller, W., Aoki, N., and Von Kaulla, K. N. Effect of estrogens on postpartum hypercoagulability and antithrombin III activity, Am. J. Obstet. Gynecol. ll3, 920-926 (1972). 12. Chafe, W., Fowler, W. C., Walton, L. A., and Currie, J. L. Radical vulvectomy with use of tensor fascia lata myocutaneous flap, Am. J. Obstet. Gynecol. 145, 207-213 (1983). 13. Hoffman, M. S., Roberts W. S., Lapolla J. P., and Cavanaugh, D. Recent modifications in the treatment of invasive squamous cell carcinoma of the vulva, Obstet. Gynecol. Surv. 44,227-233 (1989).