How Can We Treat Vulvar Carcinoma in Pregnancy? A Systematic Review of the Literature

Simple Summary Vulvar squamous cell carcinoma (VSCC) is the most frequent malignant vulvar tumor, with a peak incidence in the 7–8th decades of life. However, VSCCs can also occur in young women. This unfortunate event is even rarer and more worrisome in pregnant women, being hard to manage for gynecologists, oncologists, and radiotherapists. Very few cases have been reported and we felt the need for an updated review on this topic. Thus, we performed a systematic literature review of VSCCs diagnosed during pregnancy, discussing the clinic-pathologic features, the implications in pregnancy outcomes, and the effects of such a diagnosis in the management of mothers and their babies. Abstract According to our systematic literature review (PRISMA guidelines), only 37 vulvar squamous cell carcinomas (VSCCs) were diagnosed during pregnancy (age range: 17–41 years). The tumor size range was 0.3–15 cm. The treatment was performed after (14/37, 38%), before (10/37, 27%), or before-and-after delivery (11/37, 30%). We found that 21/37 (57%) cases were stage I, 2 II (5%), 11 III (30%), and 3 IVB (8%). HPV-related features (condylomas/warts; HPV infection; high-grade squamous intraepithelial lesion) were reported in 11/37 (30%) cases. We also found that 9/37 (24%) patients had inflammatory conditions (lichen sclerosus/planus, psoriasis, chronic dermatitis). The time-to-recurrence/progression (12/37, 32%) ranged from 0 to 36 (mean 9) months. Eight women died of disease (22%) 2.5–48 months after diagnosis, 2 (5%) were alive with disease, and 23 (62%) were disease-free at the end of follow-up. Pregnant patients must be followed-up. Even if they are small, newly arising vulvar lesions should be biopsied, especially in women with risk factors (HPV, dermatosis, etc.). The treatment of VSCCs diagnosed in late third trimester might be delayed until postpartum. Elective cesarean section may prevent vulvar wound dehiscence. In the few reported cases, pregnancy/fetal outcomes seemed to not be affected by invasive treatments during pregnancy. However, clinicians must be careful; larger cohorts should define the best treatment. Definite guidelines are lacking, so a multidisciplinary approach and discussion with patients are mandatory.


Introduction
Vulvar squamous cell carcinoma (VSCC) is the most frequent malignant vulvar tumor [1,2]. VSCC accounted for <1% of all female cancer cases worldwide in 2018 (estimated 44,000 new cases) [1]. As per the "Surveillance, Epidemiology, and End Results Program" (SEER) database of the United States National Cancer Institute, VSCC represented the 0.3% (n: 6120) of all new cancer cases and the 0.2% (n: 1350) of all cancer deaths in 2020 [3]. In higher-income Countries, the estimated 5-year survival rate is 50-70%, with 15,000 cancer deaths/year worldwide [1]. Globally, cancer has been estimated to complicate 1:1000 pregnancies [4]. The birth-rate for women >30 years of age has been increasing while the incidence of many malignancies starts to raise during the 4th decade of life [4]. The peak incidence of VSCC is in the 7th (for Human Papillomavirus (HPV)-related VSCCs) or 8th decades of life (for HPVindependent VSCCs) [1]. However, VSCCs can also occur in young women, especially in the setting of HPV-independent VSCCs associated with lichen sclerosus or planus [1,4,5]. This unfortunate event is even rarer and more worrisome in pregnant patients, being hard to manage for gynecologists, oncologists, and radiotherapists [6]. However, very few cases have been reported. As such, we felt the need of an updated review on this topic. So, we performed a systematic literature review of VSCCs diagnosed during pregnancy, discussing the clinic-pathologic features, the implications in pregnancy outcomes, and the effects of such a diagnosis in management of mothers and their babies.  We identified 528 articles on Pubmed (https://pubmed.ncbi.nlm.nih.gov (accessed on 5 December 2020)), 518 articles on Scopus (https://www.scopus.com/home.uri (accessed on 5 December 2020)), and 106 articles on Web of Science (https://login.webofknowledge. com (accessed on 5 December 2020)) databases. After duplicates exclusion, 782 records underwent first-step screening of titles and abstracts. Of these, 37 full texts were considered for eligibility, and after reading them, 7 articles were excluded for being unfit according to the inclusion criteria or because they presented scant or aggregated data: details of some additional cases excluded from our review [7][8][9][10] are presented as Supplementary Materials. Thirty studies were finally included in the review, for a total of 37 patients diagnosed with VSCC during pregnancy .

Clinical Presentation
According to the time of discovery of the vulvar lesions, the patients can be grouped into:

2.
Pre-conceptional evidence of a vulvar lesion (4/37 cases, 11%). The vulvar lesion was evident 1 [15], some [17], 12 [28], and 15 months [25] before conception, respectively. However, the diagnosis of VSCC was made during the 1st trimester (1 case: 2nd month) [28] or even during the 2nd trimester of pregnancy (3 cases: 19 GW [17]; 16 GW [25]; 5th month [15]). A tumor was diagnosed as a condyloma 6 months before conception, while subsequent biopsy at 29 GW revealed a VSCC [25]: this discrepancy may be due to misdiagnosis of the first biopsy or malignant transformation during pregnancy. Another VSCC was diagnosed during the 5th month of pregnancy in the site where a small itchy lesion of unknown diagnosis had been excised 1 month before conception [15]. In the remaining 2 cases, it was unclear if the lesion was underestimated by clinicians or not presented to the gynecologists' attention [17,28].
In most cases, it was unclear if the vulvar lesion was first identified by patients or clinicians. Additional symptoms or pregnancy complications (see Section 2.18.) may have led the patients to seek clinical evaluation.

Pap Smear
A woman (1/5, 20%) who underwent a Pap smear at presentation received a diagnosis of "Atypical squamous cells of undetermined significance" (ASCUS)/"Atypical glandular cells" (AGC) [27]. Her previous Pap tests were negative, but she had condylomas affecting the entire vulva at presentation, and biopsies also revealed high-grade squamous intraepithelial lesions (H-SIL) of cervix and anus. The remaining 4/5 cases resulted negative [21,28,31,35]. Another patient had a history of VCs and cervical dysplasia treated with cryosurgery at age 22 years (7 years before presentation) [29]: cervical cytology samples were not taken at presentation, as for 3 women which never had abnormal Pap smears in their history [18,20,24].

4.
Misdiagnosis/underestimation by clinicians/patients (4/14 cases, 29%). Clinicians prescribed typical ointments and antibiotics for a vulvar lesion noted during the 3rd month of pregnancy: the correct diagnosis was made after delivery [14]. A lesion that was evident during the 2nd trimester of pregnancy was not biopsied until 3 months after spontaneous vaginal delivery [31]. In 1 case, it took to the clinicians 5 weeks (33-38 GW) to understand the tumor nature of the vulvar lesion and perform a vulvar biopsy: the diagnosis was low-grade squamous intraepithelial lesion (L-SIL; vulvar intraepithelial neoplasia, VIN1) + H-SIL (VIN2). An elective CS was performed at 38 GW; unfortunately, the patient and her family were non-compliant: the lesion grew and extended in the meanwhile [26]. A woman presented at 16 GW with a vulvar lesion and she was referred to the nearby district hospital for further investigations; however, she defaulted and presented instead during labor at term [32].

Chemotherapy
As one patient did not undergo surgery for advanced stage disease at presentation, chemotherapy (carboplatin-vinorelbine) was started at 18 GW: as to local disease progression, chemoradiation was administered 9 days after delivery (cetuximab + cisplatin; then only cetuximab for radiotherapy-induced pancytopenia). Five months after diagnosis, the patient died due to pulmonary metastases [13]. Another patient underwent adjuvant chemoradiation (3 courses of vincristin 1 mg/m 2 and cisplatin 50 mg/m 2 ) for a stage 3 VSCC at least 21 days postpartum: no evidence of disease was found 7 months after diagnosis [21]. No chemotherapy was administered to the remaining 35 patients.
Radiotherapy was performed in 2 women who did not undergo surgery for locally advanced VSCC [13,20]. In the first case [13], chemoradiation was administered after delivery (and few courses of prenatal neoadjuvant chemotherapy): radiation treatment details were not provided. The woman died 5 months after diagnosis for metastatic disease.
In the second case [20], after CS, the patient underwent palliative radiotherapy (50 Gy in 25 fractions) achieving only partial response: the woman died of disease progression 11 months after diagnosis [20].

HPV Status and Cancer Precursors
HPV testing with hybrid capture technique (Digene, Gaithersburg, MD, USA) was tested only in 1 VSCC, resulting positive for high-risk HPV-subtypes (16,18,31,33,35,45,51,52,56) [27]. Conversely, a VSCC was recently reported as HPV-independent [11]. It is difficult to clearly determine if the remaining cases were HPV-associated or not (VSCC, NOS) [1]. Immunohistochemical examination (also including p53 and p16 immunomarkers) or molecular analysis were not performed in any of the reported VSCCs or SIL/VIN. In none of the cases treatment was guided by the HPV status of the tumor.
Despite an evaluation of the HPV status is lacking in most VSCCs, HPV-related lesions (condylomas/warts; HPV infection; genital H-SIL) were globally reported in 11/37 (30%) cases at presentation or in previous history (Table 2) [18,21,[23][24][25][27][28][29]31,36,40]. These lesions may represent an indirect sign of a HPV-associated VSCC, despite they are not specific (especially if the HPV infection was present only in patient's history). Moreover, morphologic evaluation shows limitations in predicting the HPV status of precursor lesions and it cannot be always reliable; however, immunohistochemistry was not performed in any cases (see Discussion). Finally, H-SIL was also associated with inflammatory conditions in 2 cases [18,23].
No HPV-independent VIN (differentiated VIN) was clearly described, despite a vulvar leukoplakia due to hypertrophic lichen planus and hyperplastic vulvar dystrophy without atypia or signs of HPV-infection was reported [22]. One patient was treated with topical corticosteroids from 5 to 12 GW (3 weeks before presentation) for recurrent vulvar psoriasis [13]. Finally, a patient complained of progressive vulvar itching for 17 years: vulvar hyperplasia and chronic dermatitis were found on a biopsy performed 2 years before presentation [14].
Two out of 14 (14%) cases were classified as new metachronous vulvar primaries, both diagnosed during pregnancy: the interval of time from excision of the first lesion to the subsequent tumor was 7 [24] and 11 weeks [23], respectively.

Discussion
Pregnancy is characterized by excess of circulating blood volume, secretion of sex-/growth-hormones, and immunosuppressive status: all these physiologic changes could favor cancer growth or progression . To our review, their potential effect on VSCCs was not investigated by experimental studies as the reported cases were all clinic-pathologic case reports/small series. The effects of cancer on pregnancy may include mechanical uterine compression, tumor blocking of delivery route, cancer-related inflammatory cytokine production, or metastases to fetus or placenta [42]: none of them was reported or investigated by the articles included in our series.
As per the 2021 guidelines of the United States National Comprehensive Cancer Network (NCCN-g) [43], the best treatment of early-stage VSCC is represented by radical local excision (with 1-cm grossly free margins) and unilateral or bilateral inguinofemoral lymphadenectomy (IF-LND) (or SLN biopsy in selected patients). Simple partial vulvectomy should be performed for pT1a tumors with ≤1 mm of stromal invasion: in these cases, IF-LND or SLN biopsy can be omitted if LNs are clinically negative, as the risk of lymphatic spread is <1% [43]. Conversely, radical partial vulvectomy with IF-LND (preceded or not by SLN biopsy) is reserved for more invasive (stage IB-II) VSCCs, as to the >8% risk of lymphatic involvement [43]. Groin treatment should be performed for tumors > pT1a also according to the European Society of Gynecological Oncology (ESGO-g) [44].
For the NCCN-g, women with unifocal VSCC of <4 cm, without suspicious groin nodes on clinical/imaging examination, are "candidates" for SLN biopsy [43]; this procedure is also "recommended" by the ESGO-g [44]. Conversely, larger or multifocal VSCCs require IF-LND by separate incisions [43,44]. SLN procedure should be performed prior to the VSCC excision to avoid disrupting the lymphatic network between the primary tumor and the SLN: if SLN is not found (method failure), IF-LND should be performed [43,44].
Minor differences may be found between NCCN-g and ESGO-g. To the ESGO-g, ipsilateral IF-LND should be performed when a metastasis of any size is found in the SLN [44]. Conversely, to the NCCN-g, IF-LND can be omitted if a single positive SLN reveals a ≤2 mm metastasis and in this case the patients undergo external beam radiation therapy ± chemotherapy [43].
Despite a < 3% risk of contralateral metastases, a unilateral IF-LND or SLN biopsy is appropriate for unifocal lateral tumors <4 cm, located ≥2 cm (NCCN-g) or >1 cm (ESGOg) from the vulvar midline and in the setting of clinically reactive inguinofemoral LNs: if metastatic LNs are found, resection or radiation therapy of the contralateral groin is recommended by the NCCN-g, while contralateral IF-LND may be performed according to the ESGO-g [43,44]. If the tumor is closer to the vulvar midline, the abovementioned procedures should be bilateral [43,44].
The optimal management of the groin for bulky, proven metastatic LNs is unclear (IF-LND vs. the removal of isolated positive LN) especially for unresectable or pT3 VSCCs (NCCN-g/ESGO-g): lymphadenectomy for stage III-IV disease is individualized (NCCN-g) [43,44].
Unfortunately, despite these indications, there are no clearly reported guidelines concerning the treatment of VSCCs diagnosed during pregnancy [5,6]. As such, a mul-tidisciplinary approach is mandatory: mother, fetus and malignancy are distinct but interactive entities.
Surgery can be performed before and/or after delivery [5]. When surgery can be allowed, the treatment of patients diagnosed in the late third trimester might be delayed until postpartum.
In patients with recent vulvar scarring or following plastic reconstruction surgery, or in case of large VSCCs at increased risk of bleeding during vaginal birth, CS should be favored [5]. An elective CS can be performed to prevent vulvar wound dehiscence after vulvar surgery for VSCC, but vaginal delivery cannot be excluded as an option especially in case of small, well-healed vulvar wounds or maybe in case of a small VSCC [5]. Dissemination of tumor cells caused by mechanical dilation of vulva during labor is hypothetically possible, but there is no clear evidence that vaginal delivery may increase the risk of VSCC recurrence: as only 37 patients were reported, larger series are required.
Despite possible risks on pregnancy outcomes and fetal mortality/morbidity, some patients of our series underwent invasive treatment during pregnancy, including extensive lymphadenectomy, SLN resection, radiotherapy, or chemotherapy. In the reported cases, all these types of treatment seemed not to significantly affect the pregnancy/fetal outcomes, as the mothers of the only reported stillborn [36] and resuscitated baby [22] were not treated during pregnancy. The reported treatment complications were usually local (lymphoceles, wound breakdown, abscess/mycosis, hematomas), fortunately without significant impact on the babies. However, the possibility of the development of a systemic infection can not be completely avoided. As to the increased gestational vulvar blood flow (especially in the third trimester), surgery may result in higher blood loss, which can delay the postpartum treatment of cases diagnosed after 36 GW: judicious electrocautery can reduce the blood loss [5].
As per the NCCN-g, SLN biopsy results in decreased postoperative morbidity than IF-LND, which is associated with wound complication (20-40%) or lymphedema (30-70%) [43]: as per our review, the 4 patients who undergo SLN procedure did not have complications, but few cases were tested to allow significant considerations. Fetal exposure to locally injected 99m Tc (0.25 mCi, T1/2: 6 h) can be reduced by short treatment protocols, performing this procedure 2 h after injection using the lowest possible dose [5]. Systemic exposure to 99m Tc seems insignificant, as the isotope is captured in the SLN which is going to be removed. Both lymphoscintigraphy/SPECT (Single Photon Emission Computed Tomography) and Blue dye (for possible anaphylaxis) should be omitted during pregnancy [5]. SLN resection was performed during pregnancy in 2 cases [12,17]: in 1 case, 99m Tc (dosages of 10.73 and 10.15 and 11.07 and 9.9 MBq on 4 sites of injection) was used to identify SLN by scintigraphy [17]. In another case, isosulfan blue was used postpartum to identify bilateral SLN declining 99m Tc for patient's concern about possible radioactive exposure while breast-feeding [18].
During pregnancy, radiotherapy and chemotherapy are contraindicated. Very few patients of our series were treated, apparently without significant effects on pregnancy/fetal outcomes. During this period, if feasible, it's better to achieve the surgical therapy best fitted with the patients' characteristics. When indicated, adjuvant radiotherapy should start soon: to allow delivery, delay of radiotherapy by 6-8 weeks is within safety limits [5,6]. Anyway, data on the efficacy/side effects of adjuvant radiotherapy are scant as to the rarity of VSCCs diagnosed during pregnancy; there are no clearly reported guidelines [6]. Neoadjuvant chemotherapy to reduce tumor size for locally advanced disease remains experimental [5,6].
The search for easily available and cost-effective surrogate markers for molecular analysis/HPV tests have shifted to alternative methods such as immunohistochemistry [1,45,46]. Immunohistochemical block-type p16-positivity (strong, diffuse and continuous in basal layers with variable extension to the superficial layers) is a reliable (although imperfect) surrogate marker of HPV-associated VSCCs: viral oncoproteins E6-E7 cause p53/RB1 degradation leading to p16-overexpression [1,45]. Conversely, p16 is usually negative or non-block in HPV-independent VSCCs [1].
The p16/p53 expression profile seems to have prognostic implications, helping the identification of HPV-related VSCCs, which show a more favorable outcome. Moreover, recent findings suggested that HPV-negative/p53 wild-type VSCCs may have an intermediate prognosis between HPV-positive/p53 wild-type VSCCs and HPV-negative/ p53-mutated VSCCs (worse outcome): larger studies are needed [48]. Unfortunately, immunohistochemical examination (also including p53 and p16 immunomarkers) was not performed in any of the VSCCs of our series. NOTCH1/2, HRAS, or PIK3CA activating mutations were frequently reported in VSCCs [1], but none of the cases included in our review was tested.
Evidence of precursor lesions (HPV-associated SIL; HPV-independent VIN/differentiated VIN; inflammatory conditions) may help the correct diagnosis [1]. While HPV-independent tumors comprise the majority of VSCCs, HPV-independent VIN forms only a small minority (2-3.5%) of all solitary VIN/SIL diagnoses. HPV-negative precursors may be clinically more subtle (less likely to be symptomatic and biopsied) or more difficult to be recognized on histological examination by pathologists; another option is that they may progress quickly to VSCCs (which can replace the precursor areas) [49].
However, morphologic evaluation shows limitations in predicting the HPV status of precursor lesions: histologically ambiguous lesions were described [1,45,[49][50][51][52]. Some HPV-negative VINs showed a basaloid histologic pattern similar to that of HPVassociated H-SILs [50]. Conversely, Rakislova et al. identified differentiated VIN-like and lichen sclerosus-like lesions associated with HPV-related VSCCs [51]. Moreover, Watkins et al. found that HPV-associated H-SIL with superimposed lichen simplex chronicus may mimic HPV-independent VIN (differentiated VIN) with possible abnormal basal p53 expression [52]. In our series, the evaluation of the precursor lesions was morphological, with potential diagnostic pitfalls: immunohistochemistry was not performed in any cases.
For pathologists, the diagnosis is usually straightforward in typical cases despite it's sometimes impossible to establish tumor origin in small biopsies not showing in situ areas. In carcinomas with squamous differentiation (endometrial, urothelial, etc.), a typical nonsquamous component is usually present. Verrucous or warty (condylomatous) carcinomas may be misinterpreted as benign or non-invasive carcinomas. In fact, stromal invasion may be challenging to identify in superficially invasive tumors or biopsy material [1]. Desmoplasia, irregularly shaped nests (sometimes disconnected from the surface), loss of polarity and cytoplasmic eosinophilia of invasive cells favor invasion [1]. Four vulvar lesions were evident in pre-conceptional period (1-15 months before presentation): one was diagnosed as a condyloma 6 months before conception, while subsequent biopsy at 29 GW revealed a VSCC [25]. Another patient received a diagnosis of a L-SIL/H-SIL ("VIN1-2") during pregnancy: as she and her family were non-compliant, it took time to obtain a new biopsy, revealing VSCC [26].
Most VSCCs are asymptomatic, sometimes unrecognizable by obese or pregnant patients with reduced mobility and dilated abdomen: 5/37 (13%) cases were identified during delivery. Some women experienced pruritus, burning sensation, pain, or bleeding, especially in association with vulvar dermatoses.
Patients and clinicians must not underestimate the emergence of new vulvar lesions during pregnancy, especially in women with risk factors (HPV infection, vulvar dermatosis, etc.). New lesions, even if small, should be biopsied and patients must be followed-up.
Unfortunately, VSCC recurrence rates are globally high (12-37%) (32% in our series) [1]. HPV-associated VSCCs have better progression-free survival; other predictive recurrence factors include non-radical resection or tumor-free margins <3 mm, tumor size, lymphovascular or perineural invasion: it was not possible to clearly stratify VSCCs of our series according to these frequently unreported parameters.

Materials and Methods
A systematic literature review was performed according to the PRISMA guidelines [64], searching in multiple databases as previously described [61,62,65]. The study aimed to answer the following PICOS (Population, Intervention, Comparison, Outcomes) questions 1.
Population: patients with a diagnosis of VSCC during pregnancy; 2.
Intervention: any type of treatment, including surgery, chemotherapy, radiotherapy, or observational treatment; 3.
Outcomes: (1) patient's status at last follow-up: no evidence of disease, alive with disease, dead of disease; (2) pregnancy outcome: healthy baby; stillborn.
Study design: retrospective observational study (case series, case reports). Eligibility/inclusion criteria: studies describing patients with a diagnosis of VSCC during pregnancy; review articles were excluded.
Information sources and search strategy: we searched for (pregnancy OR pregnancyassociated OR pregnant OR gravid OR abortus OR abortion) AND (vulva OR vulvar) AND (carcinoma OR carcinomas OR adenocarcinoma OR adenocarcinomas OR cancer OR carcinosarcoma OR carcinosarcomas OR "malignant mixed mullerian") in Pubmed (all fields) (https://pubmed.ncbi.nlm.nih.gov/ (accessed on 5 December 2020)), Web of Science (Topic/Title) (https://login.webofknowledge.com (accessed on 5 December 2020)) and Scopus (Title/Abstract/Keywords) (https://www.scopus.com/home.uri (accessed on 5 December 2020)) databases. No limitations or additional filters were set. Relevant articles were obtained in full-text format and screened for additional references. The bibliographic research ended on 30 January 2021.
Study selection: 2 independent reviewers (Andrea Palicelli, Vincenzo Dario Mandato) selected the studies using a 2-steps screening method. In the first step, the screening of titles and abstracts was performed to verify eligibility/inclusion criteria and exclude irrelevant studies. In the 2nd step, full texts of relevant articles were screened by the 2 reviewers to: (1) verify study eligibility and inclusion criteria and (2) avoid duplications of the included cases. Two other authors (Magda Zanelli, Laura Ardighieri) performed a manual search of reference lists to search for additional relevant publications. Loredana De Marco checked the data extracted.
The objective of the systematic review was as follows: (1) to update and summarize the literature concerning VSCCs diagnosed in pregnancy; (2) to report any information regarding clinic-pathological features, treatment strategies, and patients' outcomes.
Data collection process/data items: data collection was study-related (authors and year of study publication) and case-related (patient age, clinical history/presentation, tumor gross and histological features, tumor stage at presentation, treatment, follow-up, and outcomes).
Statistical analysis: the collected data were reported as continuous or categorical variables. Categorical variables were summarized by frequency and percentage; continuous variables were summarized by ranges and mean and median values where appropriate. Time-to-recurrence was the time from primary treatment to disease recurrence. The survival status was the time from primary treatment to the last follow-up.

Conclusions
In conclusion, VSCCs are exceedingly rare during pregnancy. Patients and clinicians must not underestimate the arising of new vulvar lesions, especially in pregnant women with risk factors (HPV infection, vulvar dermatosis, etc.): even if they are small, they should be biopsied, and the patients must be followed-up.
When surgery is allowed, treatment of patients diagnosed in the late 3rd trimester might be delayed until postpartum. An elective CS can be performed to prevent vulvar wound dehiscence, but vaginal delivery is an option especially in case of small, wellhealed vulvar wounds after vulvar surgery for VSCC. Despite possible risks on pregnancy outcomes and fetal mortality-morbidity, some patients of our series underwent invasive treatment during pregnancy: in the few reported cases, the pregnancy/fetal outcomes seemed not affected by invasive treatments. However, clinicians must be careful: larger cohorts should define the best therapy approach for this rare and unfortunate condition. In the absence of definite guidelines, multidisciplinary approach and discussion with patients are mandatory to tailor therapy according to the tumor, pregnancy, and patient characteristics.
The molecular features and HPV status of VSCCs may be relevant in the future to diagnose and treat VSCC in pregnant women.