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European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Review
Feto-maternal outcome of pregnancy complicated by vulvar cancer: a systematic review of literature Koji Matsuo a,c, * , Stephanie A. Whitman b , Erin A. Blake d, Charlotte L. Conturie b , Marcia A. Ciccone b , Carrie E. Jung b , Tsuyoshi Takiuchi e, Masato Nishimura f a
Division of Gynecology Oncology, Los Angeles County Medical Center, University of Southern California, Los Angeles, CA, USA Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, Los Angeles, CA, USA c Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA d Department of Obstetrics and Gynecology, University of Colorado, Denver, CO, USA e Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan f Department of Obstetrics and Gynecology, Tokushima University, Tokushima, Japan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 30 December 2013 Received in revised form 26 March 2014 Accepted 8 April 2014
Vulvar cancer is an extremely rare complication during pregnancy, and its effect on pregnancy and survival is not well understood. A systematic literature review was conducted in order to examine the fetal and maternal outcomes and optimal management of pregnancy complicated by vulvar cancer. PubMed/MEDLINE were used to identify case reports with searching keywords “pregnancy” and “vulvar cancer” between January 1955 and February 2014 that identified 36 cases for analysis. Mean age was 30.7. The most common presenting symptom and gestational age were vulvar mass/swelling (75.0%) and the second trimester of pregnancy (54.8%), respectively. Vulvar biopsy at the time of initial presentation to care during pregnancy was performed in only 46.7% of cases. Among delayed cases for biopsy, mean duration of delay was 12.8 weeks and the majority had a delay for more than 8 weeks (62.5%). The majority of vulvar cancer was squamous histology (47.2%) and stage I disease (60.0%). Vulvectomy and inguinal–femoral lymphadenectomy were performed in 97.1% and 63.9%, respectively. Abdominal delivery was recorded in 46.2% of cases. Live birth and full term delivery rates were 96.3% and 74.0%, respectively. For survival analysis, delay in diagnosis and advanced stage disease were commonly associated with decreased disease-free survival (5-year rate, delay in diagnosis >8 versus 8 weeks, 0% versus 69.1%, hazard ratio (HR) 7.86, 95% confidence interval (CI) 2.03–30.6, p = 0.001; and stage III–IV versus stage I–II, 0% versus 59.8%, HR 3.35, 95% CI 1.16–9.68, p = 0.011) and overall survival (5-year rate, delay in diagnosis >8 versus 8 weeks, 0% versus 67.1%, hazard ratio (HR) 14.8, 95% CI 1.77–124, p = 0.001; and stage III–IV versus stage I–II, 0% versus 86.4%, HR 8.22, 95% CI 2.06–33.2, p < 0.001). In conclusion, while the majority of cases resulted in good pregnancy outcomes, diagnosis of vulvar cancer during pregnancy is frequently delayed. Since delayed diagnosis is a significant prognosticator of decreased survival outcomes, early recognition is integral in the management of pregnancy complicated by vulvar cancer. ã 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Vulvar cancer Pregnancy Review
Contents Introduction . . . . . . . . . . . . . . . Materials and methods . . . . . . Source and study selection Clinical information . . . . . Definitions . . . . . . . . . . . . . Statistical analysis . . . . . . .
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* Corresponding author at: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, 2020 Zonal Avenue, IRD520 Los Angeles, CA, 90033, USA. Tel.: +1 323 226 3416; fax: +1 323 226 3427. E-mail address: [email protected] (K. Matsuo). http://dx.doi.org/10.1016/j.ejogrb.2014.04.017 0301-2115/ ã 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Matsuo K, et al. Feto-maternal outcome of pregnancy complicated by vulvar cancer: a systematic review of literature. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.04.017
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Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical demographics . . . . . . . . . . . . . . . . . . . . . Diagnosis of vulvar cancer during pregnancy . . Management of vulvar cancer during pregnancy Pregnancy outcome . . . . . . . . . . . . . . . . . . . . . . . Survival outcome . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction Vulvar cancer is a rare type of gynecologic malignancy with only an estimated 4700 new cases in 2013 in the United States, which accounts for an incidence rate of 3.6 per 100,000 persons [1,2]. Vulvar cancer grows locally at the female external genitalia, and diagnosis is usually made based on biopsy of the vulvar mass [3]. Surgical approach with selective inguinal lymphadenectomy and postoperative radiotherapy is a mainstay of the management of vulvar cancer, and recurrence of the disease often localizes in the vulvar or nodal chain [4]. Vulvar cancer diagnosed during pregnancy is an extremely uncommon clinical entity due to its rare incidence and the fact that it is typically a disease of the elderly [5]. Approximately 1–2 in 1000 women are affected by cancer during pregnancy [6]. When pregnancy and cancer co-exist within a mother, (i) effects of pregnancy on cancer and (ii) effects of cancer on mother and fetus are the important considerations. (i) Pregnancy is characterized by its unique gestational changes in physiologic status such as excess circulating blood volume, endogenous sex and growth hormones, and immunosuppressive status [7]. There is a possibility that the increased production of growth factors from the placenta may stimulate cancer to grow and progress, thus potentially endangering the mother. The physiologic weakened maternal immune system during pregnancy, which allows the fetus to grow in-utero, may also enable tumor growth. (ii) Effects of cancer on pregnancy may include mechanical compression of the uterus by the tumor, tumoral blocking of delivery route, cancer-related inflammatory cytokine production, or cancer metastatic to the fetal–placental units. Therefore, the management of pregnancy complicated by cancer needs a multidisciplinary approach to simultaneously consider the three distinct but interactive entities: mother, fetus, and malignancy. To date, due to its rare incidence, the feto-maternal outcomes and optimal management of pregnancy complicated by vulvar cancer remains understudied. Although the recent consensus opinion suggests that standard surgical treatment is a choice of management for vulvar cancer during pregnancy [8], important clinical questions in this setting remain in various aspects such as the process of diagnosis and cancer treatment with fetus in-situ, and the timing/route of delivery. Here, we conducted a systematic review of literature to outline the characteristics of pregnancy complicated by vulvar cancer. Materials and methods Source and study selection A systematic literature search was conducted by using PubMed/MEDLINE with entry keywords, “pregnancy” and “vulvar cancer” limited to english between January 1955 and February 2014 using methods similar to our previous works [7]. Inclusion criteria were case reports or case series describing pregnant women diagnosed as vulvar cancer during pregnancy or
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immediate postpartum period with detailed descriptions of maternal, fetal, oncologic characteristics and survival outcomes. References of each examined article were evaluated by two authors independently and cited references that met inclusion criteria were also included in the analysis. Exclusion criteria were review articles, suboptimal description, or cases when vulvar cancer was diagnosed prior to the reported pregnancy. (i) Patient demographics and symptoms/diagnosis of vulvar cancer, (ii) treatment patterns for vulvar cancer, (iii) pregnancy and neonatal outcomes, and (iv) oncologic outcomes were abstracted from the case description. Clinical information (i) Patient demographics included year and area of publication, age at cancer diagnosis, race, parity, smoking habitus, and history of human papilloma virus (HPV) infection, genital condyloma, and vulvar dysplasia. In addition, detail history for presenting gestational age and symptom for vulvar cancer, gestational age at vulvar biopsy for cancer diagnosis, location/size of vulvar mass, and imaging modality were abstracted from the records. (ii) Treatment patterns for vulvar cancer were recorded such as surgery for primary vulvar site and regional lymph nodes, radiotherapy (timing and location), and chemotherapy. Postoperative complications for vulvar/inguinal surgery were also examined. (iii) Neonatal outcomes collected were delivery age, route of delivery, birth weight, and complication. (iv) Oncologic outcomes evaluated in our study included histological subtypes of vulvar cancer, location of lymph node metastasis, cancer stage, and survival outcome such as disease-free survival (DFS) and overall survival (OS). Amongst recurrent cases, location of recurrence was abstracted. Definitions In our study, gestational age was grouped in an ordinal fashion: the 1st trimester (8 weeks Mass size 5 cm >5 cm Stage I–II III–IV
Overall survival
5-year (%)
HR (95%CI)
69.1% 0%
1 7.86 (2.03–30.6)
43.8% 0%
1 5.42 (1.65–17.8)
59.8% 0%
1 3.35 (1.16–9.68)
p-value
5-year (%)
HR (95%CI)
67.1% 0%
1 14.8 (1.77–124)
86.4% 0%
1 8.22 (2.06–33.2)
0.001
p-value 0.001
0.002
8 weeks (p = 0.001, Fig. S2B) and stage III– IV disease (p < 0.001, Fig. S2C) were the significant prognosticators associated with decreased OS. Among tested variables, delay in vulvar biopsy >8 weeks showed the largest magnitude of significance for both DFS and OS (Table 5). Delay in initiation of vulvar cancer treatment after diagnostic biopsy was not associated with survival outcomes (4 versus 8 weeks (p = 0.001, Fig. 2B), vulvar mass >5 cm (p = 0.002, Fig. 2C), and stage III–IV disease (p = 0.011, Fig. 2D) were statistically significantly
There were 36 cases of reported pregnancy complicated by vulvar cancer met our inclusion criteria over a half century of the study period; thus highlighting the extreme rarity of this clinical entity. Salient findings of our results are that the diagnosis of vulvar cancer during pregnancy is often delayed, which is notable since the timing of diagnosis is a significant prognosticator of
Fig. 3. Schema for management proposal for vulvar lesions during pregnancy. Algorithm for evaluation and management of vulvar lesion during pregnancy is shown based on our study results.
Please cite this article in press as: Matsuo K, et al. Feto-maternal outcome of pregnancy complicated by vulvar cancer: a systematic review of literature. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.04.017
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adverse survival outcomes. Based on our findings, we propose a management recommendation for vulvar lesions during pregnancy as shown in Fig. 3. Our results showed that more than half of cases (53.3%) did not undergo biopsy of vulvar mass at the time of initial presentation to care during pregnancy. The majority of these cases had a time interval of more than 8 weeks between the initial medical visit and the vulvar biopsy (62.5%). The reason for the delay was mainly due to the low suspicion for malignancy (70%); however, a considerable portion of delayed cases was also related to patient noncompliance (30%). It may be speculated that physicians may have (i) a low index of suspicion for vulvar malignancy in this young population (mean age 30.7) given that vulvar cancer is commonly seen in age of 60–70 [5], and (ii) a hesitancy to recommend invasive intervention such as biopsy during pregnancy due to physiologic changes during gestation such as increased circulating blood flow to vulva that may cause excess bleeding secondary to biopsy. However, delay in diagnosis is not rare in vulvar cancer even in the general population [38]. In an analysis of 102 vulvar cancer patients, approximately one third of vulvar cancer patients had multiple office visits for their symptoms prior to the diagnosis [39]. Because delay in vulvar biopsy was significantly associated with decreased survival outcome, as demonstrated in our study (Table 5), a biopsy for histological diagnosis is strongly recommended for any suspicious mass in the vulva even during pregnancy (Fig 3). Our results showed that the 5-year OS rate for all cases was 61.3% (Fig. S2A). In non-pregnant population, 5-year OS rate in 269 stage I–IV vulvar cancer patients was reported as 66.0% [40]. When cancer stage is stratified in pregnancy-related cases, our results showed that 5-year OS rates for stage I–II and stage III–IV being 86.4% and 0%, respectively. In non-pregnant population, 5-year OS rates for vulvar cancer were 78.5–86.4% for stage I, 58.8–72.0% for stage II, 43.2–59% for stage III, and 13.0% for stage IV, respectively [5,40]. While our study is limited in sample size, it is at least suggested that survival outcomes of patients in whom early-stage vulvar cancer was diagnosed during pregnancy is comparable to non-pregnant vulvar cancer patients. This reproduces the notion by others suggesting that the pregnant state does not alter the course of vulvar cancer prognosis when compared to non-pregnant population [8]. In addition, our analysis showed that tumor size is an important prognostic indicator for vulvar cancer diagnosed during pregnancy (Table 5). This gives the reproducibility of the importance of tumor size for vulvar cancer management even in pregnant population. In other types of gynecologic cancer related to pregnancy, ovarian cancer complicated pregnancy is related to a significantly high risk of fetal and maternal complications. For instance, approximately 40% of pregnancy complicated by ovarian sex-cord stromal tumor is related to serious adverse events to mother and/ or fetus during pregnancy with maternal hemoperitoneum or shock being the most common complication [7]. On the other hand, cervical cancer seems not to impact on maternal outcomes and expectant management for pregnancy is suggested [41]. Because cervical cancer and vulvar cancer share characteristics such as being of mainly squamous histology related to HPV occur in ano-gential area, the management of pregnancy complicated by vulvar cancer can be similar to the one of pregnancy complicated by cervical cancer, i.e., expectant management of pregnancy to increase the chance of fetal maturity. This implies that vulvar surgery can be done during pregnancy with fetus in-situ. Our results showed that vulvar surgery during pregnancy with fetus insitu did not increase risk of preterm delivery or postoperative surgical site complication. Further prospective study will be warranted to evaluate the optimal management of vulvar cancer during pregnancy.
7
Route of delivery is an independent prognosticator in cervical cancer during pregnancy, and vaginal delivery is known to significantly increase the risk of recurrence when compared to abdominal delivery [42]. It is speculated that possible dissemination of tumor cells caused by mechanical dilation of the cervix during labor may attribute to the increased risk of recurrence [42]. Similar concern may exist in vulvar cancer-complicated pregnancy, and vaginal delivery may cause tumor cells dissemination as mechanical dilation of delivery route. However, in our analysis, vaginal delivery did not increase a risk of recurrence when compared to abdominal delivery. However, the exact indication for abdominal versus vaginal delivery was not clearly documented in the record and there may be a possible confounder existent in the analysis. Vulvar cancer surgery is well known to be associated with significantly high risk of postoperative complication. In recent systematic review of literature, rates for surgical site infection, wound dehiscence, lymphocyst, and lymphedema are reported as 21.3–35.4%, 17–39%, 11.0–40.0%, and 14.0–48.8%, respectively [43]. In our study of the pregnant population, postoperative complication rate was relatively lower than those reported for nonpregnant population (3.1–13.0%, Table 3). It may be that the young age of our study population is a protective factor for postoperative complication [44]. In addition, physiologic changes related to gestation, especially excess estrogen during pregnancy, may enhance the wound healing process [45]. Strength of the study is that this is one of the first studies reviewing outcomes of pregnancy complicated by vulvar cancer in relation to both obstetrics and oncologic aspects. A weakness of the study is that this is a retrospective study that may miss potential confounders. For instance, the exact gestational age and time interval were not always described in the literature. Possible limitation is that the sample size is relatively small despite a long study period because of this considerably rare pregnancy complication. Another limitation is that there may be a publication bias, and pregnancies with vulvar cancer which ended in uncomplicated outcomes may not be published. In summary, although vulvar cancer during pregnancy is generally associated with relatively good pregnancy outcomes, the diagnosis is frequently delayed, which resulted in significantly decreased survival outcome of the mother. In this setting, any suspicious mass in the vulvar needs to be carefully examined and prompt biopsy should be considered. Funding support None. Disclosure There is no conflict of interest for the study in all authors. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. ejogrb.2014.04.017. References [1] Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin 2013;63:11–30. [2] Olsen J, Jorgensen TR, Kofoed K, Larsen HK. Incidence and cost of anal, penile, vaginal and vulvar cancer in Denmark. BMC Public Health 2012;12:1082. [3] Dittmer C, Fischer D, Diedrich K, Thill M. Diagnosis and treatment options of vulvar cancer: a review. Arch Gynecol Obstet 2012;285:183–93. [4] Baiocchi G, Rocha RM. Vulvar cancer surgery. Curr Opin Obstet Gynecol 2014;26:9–17.
Please cite this article in press as: Matsuo K, et al. Feto-maternal outcome of pregnancy complicated by vulvar cancer: a systematic review of literature. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.04.017
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[26] Nolan RP. Primary nonpigmented sarcoma of the vulva, with report of a case complicating pregnancy. Am J Obstet Gynecol 1957;73:134–40. [27] De Bruine TL. Cancer of the vulva & pregnancy. Gynaecologia 1958;146 (2):152–6. [28] Collins CG, Barclay DL. Cancer of the vulva, and cancer of the vagina in pregnancy. Clin Obstet Gynecol 1963;30:927–42. [29] Cavanagh D, Hernandez-Roman P. Carcinoma of the vulva complicated by pregnancy. A case report with discussion. J Fla Med Assoc 1965;52:564–6. [30] Di Gilio AR, Cormio G, Resta L, et al. Rapid growth of myxoid leiomyosarcoma of the vulva during pregnancy: a case report. Int J Gynecol Cancer 2004;14:172–5. [31] Ogunleye D, Lewin SN, Huettner P, Herzog TJ. Recurrent vulvar carcinoma in pregnancy. Gynecol Oncol 2004;95:400–1. [32] Ghosh T, Banfield PJ. Carcinoma of the vulva in pregnancy. J Obstet Gynaecol 2004;24:702–3. [33] Keskin N, Iyibozkurt AC, Topuz S, Salihoglu Y, Bengisu E, Berkman S. Invasive squamous carcinoma of the vulva in women aged less than 40 years: report of two cases and a third case diagnosed during pregnancy. Eur J Gynaecol Oncol 2008;29:399–401. [34] Rai H, Odunsi K, Kesterson J, Morrison C, Chan A, Mhawech-Fauceglia P. Epithelioid sarcoma of the vulva in a 17-year-old pregnant woman. Appl Immunohistochem Mol Morphol 2009;17:270–3. [35] Dyduch G, Jach R, Huras H, et al. Recurrent vulvar melanoma in 35-year-old pregnant women. J Low Genit Tract Dis 2013;17:223–5. [36] Nijman TA, Schutter EM, Amant F. Sentinel node procedure in vulvar carcinoma during pregnancy: a case report. Gynecol Oncol Case Rep 2012;2:63–4. [37] Kyriazi MA, Carvounis EE, Kitsou M, et al. Myoepithelial carcinoma of the vulva mimicking bartholin gland abscess in a pregnant woman: case report and review of literature. Int J Gynecol Pathol 2014;29:501–4. [38] Diaz ES, Aoyama C, Baquing MA, et al. Predictors of residual carcinoma or carcinoma-in situ at hysterectomy following cervical conization with positive margins. Gynecol Oncol 2013. [39] Jones RW, Joura EA. Analyzing prior clinical events at presentation in 102 women with vulvar carcinoma. Evidence of diagnostic delays. J Reprod Med 1999;44:766–8. [40] van der Steen S, de Nieuwenhof HP, Massuger L, Bulten J, de Hullu JA. New FIGO staging system of vulvar cancer indeed provides a better reflection of prognosis. Gynecol Oncol 2010;119:520–5. [41] Morice P, Uzan C, Uzan S. Cancer in pregnancy: a challenging conflict of interest. Lancet 2012;379:495–6. [42] Sood AK, Sorosky JI, Mayr N, Anderson B, Buller RE, Niebyl J. Cervical cancer diagnosed shortly after pregnancy: prognostic variables and delivery routes. Obstet Gynecol 2000;95:832–8. [43] Wills A, Obermair A. A review of complications associated with the surgical treatment of vulvar cancer. Gynecol Oncol 2013;131:467–79. [44] Hinten F, van den Einden LC, Hendriks JC, et al. Risk factors for short- and longterm complications after groin surgery in vulvar cancer. Br J Cancer 2011;105:1279–87. [45] Ashcroft GS, Ashworth JJ. Potential role of estrogens in wound healing. Am J Clin Dermatol 2003;4:737–43.
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European Journal of Obstetrics & Gynecology and Reproductive Biology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Review
Feto-maternal outcome of pregnancy complicated by vulvar cancer: a systematic review of literature Koji Matsuo a,c, * , Stephanie A. Whitman b , Erin A. Blake d, Charlotte L. Conturie b , Marcia A. Ciccone b , Carrie E. Jung b , Tsuyoshi Takiuchi e, Masato Nishimura f a
Division of Gynecology Oncology, Los Angeles County Medical Center, University of Southern California, Los Angeles, CA, USA Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, Los Angeles, CA, USA c Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA d Department of Obstetrics and Gynecology, University of Colorado, Denver, CO, USA e Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan f Department of Obstetrics and Gynecology, Tokushima University, Tokushima, Japan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 30 December 2013 Received in revised form 26 March 2014 Accepted 8 April 2014
Vulvar cancer is an extremely rare complication during pregnancy, and its effect on pregnancy and survival is not well understood. A systematic literature review was conducted in order to examine the fetal and maternal outcomes and optimal management of pregnancy complicated by vulvar cancer. PubMed/MEDLINE were used to identify case reports with searching keywords “pregnancy” and “vulvar cancer” between January 1955 and February 2014 that identified 36 cases for analysis. Mean age was 30.7. The most common presenting symptom and gestational age were vulvar mass/swelling (75.0%) and the second trimester of pregnancy (54.8%), respectively. Vulvar biopsy at the time of initial presentation to care during pregnancy was performed in only 46.7% of cases. Among delayed cases for biopsy, mean duration of delay was 12.8 weeks and the majority had a delay for more than 8 weeks (62.5%). The majority of vulvar cancer was squamous histology (47.2%) and stage I disease (60.0%). Vulvectomy and inguinal–femoral lymphadenectomy were performed in 97.1% and 63.9%, respectively. Abdominal delivery was recorded in 46.2% of cases. Live birth and full term delivery rates were 96.3% and 74.0%, respectively. For survival analysis, delay in diagnosis and advanced stage disease were commonly associated with decreased disease-free survival (5-year rate, delay in diagnosis >8 versus 8 weeks, 0% versus 69.1%, hazard ratio (HR) 7.86, 95% confidence interval (CI) 2.03–30.6, p = 0.001; and stage III–IV versus stage I–II, 0% versus 59.8%, HR 3.35, 95% CI 1.16–9.68, p = 0.011) and overall survival (5-year rate, delay in diagnosis >8 versus 8 weeks, 0% versus 67.1%, hazard ratio (HR) 14.8, 95% CI 1.77–124, p = 0.001; and stage III–IV versus stage I–II, 0% versus 86.4%, HR 8.22, 95% CI 2.06–33.2, p < 0.001). In conclusion, while the majority of cases resulted in good pregnancy outcomes, diagnosis of vulvar cancer during pregnancy is frequently delayed. Since delayed diagnosis is a significant prognosticator of decreased survival outcomes, early recognition is integral in the management of pregnancy complicated by vulvar cancer. ã 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Vulvar cancer Pregnancy Review
Contents Introduction . . . . . . . . . . . . . . . Materials and methods . . . . . . Source and study selection Clinical information . . . . . Definitions . . . . . . . . . . . . . Statistical analysis . . . . . . .
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* Corresponding author at: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, 2020 Zonal Avenue, IRD520 Los Angeles, CA, 90033, USA. Tel.: +1 323 226 3416; fax: +1 323 226 3427. E-mail address: [email protected] (K. Matsuo). http://dx.doi.org/10.1016/j.ejogrb.2014.04.017 0301-2115/ ã 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Matsuo K, et al. Feto-maternal outcome of pregnancy complicated by vulvar cancer: a systematic review of literature. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.04.017
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Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical demographics . . . . . . . . . . . . . . . . . . . . . Diagnosis of vulvar cancer during pregnancy . . Management of vulvar cancer during pregnancy Pregnancy outcome . . . . . . . . . . . . . . . . . . . . . . . Survival outcome . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction Vulvar cancer is a rare type of gynecologic malignancy with only an estimated 4700 new cases in 2013 in the United States, which accounts for an incidence rate of 3.6 per 100,000 persons [1,2]. Vulvar cancer grows locally at the female external genitalia, and diagnosis is usually made based on biopsy of the vulvar mass [3]. Surgical approach with selective inguinal lymphadenectomy and postoperative radiotherapy is a mainstay of the management of vulvar cancer, and recurrence of the disease often localizes in the vulvar or nodal chain [4]. Vulvar cancer diagnosed during pregnancy is an extremely uncommon clinical entity due to its rare incidence and the fact that it is typically a disease of the elderly [5]. Approximately 1–2 in 1000 women are affected by cancer during pregnancy [6]. When pregnancy and cancer co-exist within a mother, (i) effects of pregnancy on cancer and (ii) effects of cancer on mother and fetus are the important considerations. (i) Pregnancy is characterized by its unique gestational changes in physiologic status such as excess circulating blood volume, endogenous sex and growth hormones, and immunosuppressive status [7]. There is a possibility that the increased production of growth factors from the placenta may stimulate cancer to grow and progress, thus potentially endangering the mother. The physiologic weakened maternal immune system during pregnancy, which allows the fetus to grow in-utero, may also enable tumor growth. (ii) Effects of cancer on pregnancy may include mechanical compression of the uterus by the tumor, tumoral blocking of delivery route, cancer-related inflammatory cytokine production, or cancer metastatic to the fetal–placental units. Therefore, the management of pregnancy complicated by cancer needs a multidisciplinary approach to simultaneously consider the three distinct but interactive entities: mother, fetus, and malignancy. To date, due to its rare incidence, the feto-maternal outcomes and optimal management of pregnancy complicated by vulvar cancer remains understudied. Although the recent consensus opinion suggests that standard surgical treatment is a choice of management for vulvar cancer during pregnancy [8], important clinical questions in this setting remain in various aspects such as the process of diagnosis and cancer treatment with fetus in-situ, and the timing/route of delivery. Here, we conducted a systematic review of literature to outline the characteristics of pregnancy complicated by vulvar cancer. Materials and methods Source and study selection A systematic literature search was conducted by using PubMed/MEDLINE with entry keywords, “pregnancy” and “vulvar cancer” limited to english between January 1955 and February 2014 using methods similar to our previous works [7]. Inclusion criteria were case reports or case series describing pregnant women diagnosed as vulvar cancer during pregnancy or
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immediate postpartum period with detailed descriptions of maternal, fetal, oncologic characteristics and survival outcomes. References of each examined article were evaluated by two authors independently and cited references that met inclusion criteria were also included in the analysis. Exclusion criteria were review articles, suboptimal description, or cases when vulvar cancer was diagnosed prior to the reported pregnancy. (i) Patient demographics and symptoms/diagnosis of vulvar cancer, (ii) treatment patterns for vulvar cancer, (iii) pregnancy and neonatal outcomes, and (iv) oncologic outcomes were abstracted from the case description. Clinical information (i) Patient demographics included year and area of publication, age at cancer diagnosis, race, parity, smoking habitus, and history of human papilloma virus (HPV) infection, genital condyloma, and vulvar dysplasia. In addition, detail history for presenting gestational age and symptom for vulvar cancer, gestational age at vulvar biopsy for cancer diagnosis, location/size of vulvar mass, and imaging modality were abstracted from the records. (ii) Treatment patterns for vulvar cancer were recorded such as surgery for primary vulvar site and regional lymph nodes, radiotherapy (timing and location), and chemotherapy. Postoperative complications for vulvar/inguinal surgery were also examined. (iii) Neonatal outcomes collected were delivery age, route of delivery, birth weight, and complication. (iv) Oncologic outcomes evaluated in our study included histological subtypes of vulvar cancer, location of lymph node metastasis, cancer stage, and survival outcome such as disease-free survival (DFS) and overall survival (OS). Amongst recurrent cases, location of recurrence was abstracted. Definitions In our study, gestational age was grouped in an ordinal fashion: the 1st trimester (8 weeks Mass size 5 cm >5 cm Stage I–II III–IV
Overall survival
5-year (%)
HR (95%CI)
69.1% 0%
1 7.86 (2.03–30.6)
43.8% 0%
1 5.42 (1.65–17.8)
59.8% 0%
1 3.35 (1.16–9.68)
p-value
5-year (%)
HR (95%CI)
67.1% 0%
1 14.8 (1.77–124)
86.4% 0%
1 8.22 (2.06–33.2)
0.001
p-value 0.001
0.002
8 weeks (p = 0.001, Fig. S2B) and stage III– IV disease (p < 0.001, Fig. S2C) were the significant prognosticators associated with decreased OS. Among tested variables, delay in vulvar biopsy >8 weeks showed the largest magnitude of significance for both DFS and OS (Table 5). Delay in initiation of vulvar cancer treatment after diagnostic biopsy was not associated with survival outcomes (4 versus 8 weeks (p = 0.001, Fig. 2B), vulvar mass >5 cm (p = 0.002, Fig. 2C), and stage III–IV disease (p = 0.011, Fig. 2D) were statistically significantly
There were 36 cases of reported pregnancy complicated by vulvar cancer met our inclusion criteria over a half century of the study period; thus highlighting the extreme rarity of this clinical entity. Salient findings of our results are that the diagnosis of vulvar cancer during pregnancy is often delayed, which is notable since the timing of diagnosis is a significant prognosticator of
Fig. 3. Schema for management proposal for vulvar lesions during pregnancy. Algorithm for evaluation and management of vulvar lesion during pregnancy is shown based on our study results.
Please cite this article in press as: Matsuo K, et al. Feto-maternal outcome of pregnancy complicated by vulvar cancer: a systematic review of literature. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.04.017
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adverse survival outcomes. Based on our findings, we propose a management recommendation for vulvar lesions during pregnancy as shown in Fig. 3. Our results showed that more than half of cases (53.3%) did not undergo biopsy of vulvar mass at the time of initial presentation to care during pregnancy. The majority of these cases had a time interval of more than 8 weeks between the initial medical visit and the vulvar biopsy (62.5%). The reason for the delay was mainly due to the low suspicion for malignancy (70%); however, a considerable portion of delayed cases was also related to patient noncompliance (30%). It may be speculated that physicians may have (i) a low index of suspicion for vulvar malignancy in this young population (mean age 30.7) given that vulvar cancer is commonly seen in age of 60–70 [5], and (ii) a hesitancy to recommend invasive intervention such as biopsy during pregnancy due to physiologic changes during gestation such as increased circulating blood flow to vulva that may cause excess bleeding secondary to biopsy. However, delay in diagnosis is not rare in vulvar cancer even in the general population [38]. In an analysis of 102 vulvar cancer patients, approximately one third of vulvar cancer patients had multiple office visits for their symptoms prior to the diagnosis [39]. Because delay in vulvar biopsy was significantly associated with decreased survival outcome, as demonstrated in our study (Table 5), a biopsy for histological diagnosis is strongly recommended for any suspicious mass in the vulva even during pregnancy (Fig 3). Our results showed that the 5-year OS rate for all cases was 61.3% (Fig. S2A). In non-pregnant population, 5-year OS rate in 269 stage I–IV vulvar cancer patients was reported as 66.0% [40]. When cancer stage is stratified in pregnancy-related cases, our results showed that 5-year OS rates for stage I–II and stage III–IV being 86.4% and 0%, respectively. In non-pregnant population, 5-year OS rates for vulvar cancer were 78.5–86.4% for stage I, 58.8–72.0% for stage II, 43.2–59% for stage III, and 13.0% for stage IV, respectively [5,40]. While our study is limited in sample size, it is at least suggested that survival outcomes of patients in whom early-stage vulvar cancer was diagnosed during pregnancy is comparable to non-pregnant vulvar cancer patients. This reproduces the notion by others suggesting that the pregnant state does not alter the course of vulvar cancer prognosis when compared to non-pregnant population [8]. In addition, our analysis showed that tumor size is an important prognostic indicator for vulvar cancer diagnosed during pregnancy (Table 5). This gives the reproducibility of the importance of tumor size for vulvar cancer management even in pregnant population. In other types of gynecologic cancer related to pregnancy, ovarian cancer complicated pregnancy is related to a significantly high risk of fetal and maternal complications. For instance, approximately 40% of pregnancy complicated by ovarian sex-cord stromal tumor is related to serious adverse events to mother and/ or fetus during pregnancy with maternal hemoperitoneum or shock being the most common complication [7]. On the other hand, cervical cancer seems not to impact on maternal outcomes and expectant management for pregnancy is suggested [41]. Because cervical cancer and vulvar cancer share characteristics such as being of mainly squamous histology related to HPV occur in ano-gential area, the management of pregnancy complicated by vulvar cancer can be similar to the one of pregnancy complicated by cervical cancer, i.e., expectant management of pregnancy to increase the chance of fetal maturity. This implies that vulvar surgery can be done during pregnancy with fetus in-situ. Our results showed that vulvar surgery during pregnancy with fetus insitu did not increase risk of preterm delivery or postoperative surgical site complication. Further prospective study will be warranted to evaluate the optimal management of vulvar cancer during pregnancy.
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Route of delivery is an independent prognosticator in cervical cancer during pregnancy, and vaginal delivery is known to significantly increase the risk of recurrence when compared to abdominal delivery [42]. It is speculated that possible dissemination of tumor cells caused by mechanical dilation of the cervix during labor may attribute to the increased risk of recurrence [42]. Similar concern may exist in vulvar cancer-complicated pregnancy, and vaginal delivery may cause tumor cells dissemination as mechanical dilation of delivery route. However, in our analysis, vaginal delivery did not increase a risk of recurrence when compared to abdominal delivery. However, the exact indication for abdominal versus vaginal delivery was not clearly documented in the record and there may be a possible confounder existent in the analysis. Vulvar cancer surgery is well known to be associated with significantly high risk of postoperative complication. In recent systematic review of literature, rates for surgical site infection, wound dehiscence, lymphocyst, and lymphedema are reported as 21.3–35.4%, 17–39%, 11.0–40.0%, and 14.0–48.8%, respectively [43]. In our study of the pregnant population, postoperative complication rate was relatively lower than those reported for nonpregnant population (3.1–13.0%, Table 3). It may be that the young age of our study population is a protective factor for postoperative complication [44]. In addition, physiologic changes related to gestation, especially excess estrogen during pregnancy, may enhance the wound healing process [45]. Strength of the study is that this is one of the first studies reviewing outcomes of pregnancy complicated by vulvar cancer in relation to both obstetrics and oncologic aspects. A weakness of the study is that this is a retrospective study that may miss potential confounders. For instance, the exact gestational age and time interval were not always described in the literature. Possible limitation is that the sample size is relatively small despite a long study period because of this considerably rare pregnancy complication. Another limitation is that there may be a publication bias, and pregnancies with vulvar cancer which ended in uncomplicated outcomes may not be published. In summary, although vulvar cancer during pregnancy is generally associated with relatively good pregnancy outcomes, the diagnosis is frequently delayed, which resulted in significantly decreased survival outcome of the mother. In this setting, any suspicious mass in the vulvar needs to be carefully examined and prompt biopsy should be considered. Funding support None. Disclosure There is no conflict of interest for the study in all authors. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. ejogrb.2014.04.017. References [1] Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin 2013;63:11–30. [2] Olsen J, Jorgensen TR, Kofoed K, Larsen HK. Incidence and cost of anal, penile, vaginal and vulvar cancer in Denmark. BMC Public Health 2012;12:1082. [3] Dittmer C, Fischer D, Diedrich K, Thill M. Diagnosis and treatment options of vulvar cancer: a review. Arch Gynecol Obstet 2012;285:183–93. [4] Baiocchi G, Rocha RM. Vulvar cancer surgery. Curr Opin Obstet Gynecol 2014;26:9–17.
Please cite this article in press as: Matsuo K, et al. Feto-maternal outcome of pregnancy complicated by vulvar cancer: a systematic review of literature. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.04.017
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