Successful Management of HPV-Associated Vulvar Cancer During Pregnancy: A Case Report and Treatment Approach

Introduction

Cancer during pregnancy is challenging because both mother and fetus must be considered in any treatment plan. We must always consider the patient’s preferences, not forgetting the impact of treatment on the developing fetus [1,2].

Cancer in pregnancy is rare, with 1 occurrence in every 1000 pregnancies. The most common cancers found in pregnant women are breast and cervical cancers, leukemia, melanoma, and lymphoma [3]. Vulvar cancer is a disease that most often affects the elderly, with a median age at time of diagnosis of 68 years old [4]. The incidence of vulvar cancer is increasing, while relative survival seems to be declining. Squamous cell carcinoma (SCC) accounts for over 90% of all vulvar cancer cases and is most often preceded by dysplastic changes. Melanoma is the second most common type of vulvar cancer. In addition, basal cell carcinoma (BCC) and extra-mammary Paget’s disease (EMPD) are unique diagnostic challenges [4–6]. The final diagnosis is made based on results of the histopathological examination, but additional laboratory and imaging tests need to be performed [5].

Vulvar squamous cell carcinomas (VSCC) can be classified as human papilloma virus (HPV)-associated or HPV-independent and are usually preceded by non-invasive vulvar intraepithelial neoplasia (VIN). HPV-associated VSCC presents more frequently in young women than HPV-independent tumors. Due to its association with HPV infection, the incidence of vulvar cancer is increasing in young women; however, during pregnancy is still extremely rare [6,8]. Fifty-nine percent of patients present a disease localized in the vulva, 30% with a spread to regional lymph nodes, and 6% with distant metastases. Over 5 years, the overall survival rate is 71% [7]. Surgical excision is the standard therapy. Adjuvant radiation and chemotherapy can be recommended depending on the histopathology and extent of the disease [5].

There have been only 40 HPV-associated and HPV-independent VSCC cases described in the literature [8]. Here, we present the case of a 36-year-old pregnant woman at 23 weeks of pregnancy, diagnosed with HPV-associated VSCC, Federation of Gynecology and Obstetrics (FIGO) stage IB, which means the tumor size was more than 2 cm or stromal invasion was more than 1 mm, but it is still confined to the vulva. VSCC can be classified according to FIGO between IA and IVB. IVB is the most advanced clinical condition, with distant metastases [9]. Our patient underwent standard therapy and gave birth by cesarean section at 38 weeks of pregnancy because of orthopedic indications. No recurrence has been observed for 9 years. However, because vulvar cancer in pregnancy is extremely rare, it is important to sensitize clinicians to the possibility of such a diagnosis and to pay attention to the possibility of providing effective, safe treatment for the fetus during pregnancy. It is essential to remember that some pregnancy physiological effects, such as excess of circulating blood volume, secretion of sex-/growth-hormones, and immunosuppressive status, can favor cancer growth or progression [10].

Case Report

A 36-year-old pregnant woman at 23 weeks of pregnancy was admitted to the Gynecological and Obstetric Hospital at the Department of Surgical Gynecology (Poznań, Poland) in 2014 due to a vulvar tumor. In the gynecological examination, an exophytic lesion with a diameter of 1.5 cm was shown within the left labia minora. The lesion size in the physical examination was measured together with the reaction around it. In examination using a vaginal speculum, there was no outflow of amniotic fluid or normal discharge. Patient’s latest cervical smear, taken 4 months before pregnancy for cervical cancer screening, showed no abnormalities. She was not tested for HPV at that time, and was not vaccinated against HPV. The size of the uterus corresponds to the week of pregnancy. The vaginal part formed and was directed to the sacrum without dilation.

The ultrasound examination found the position of the fetus was variable and measured: BPD=4.7 cm; HC=17.8 cm; AC=16.4 cm; FL=3.4 cm; FHR=155/min. The patient did not consent to additional diagnostic imaging tests due to being in the 23rd week of pregnancy. She was HIV-negative. Surgical removal of the vulvar tumor was performed, including a margin of 1.5 cm of healthy tissue covering the larger and smaller labia on the left side. In histopathological examination, HPV 16-associated VSCC was diagnosed as FIGO stage IB (Figures 1–4). The size of the tumor was 0.5 cm with a depth of invasion 0.3 cm. The Medical Council recommended a sentinel node biopsy due to the significant risk of lymph node metastases, but the patient did not agree to this procedure. Because she did not consent to a sentinel node biopsy, the Radiology Department performed an ultrasound of the lymph nodes. A gynecological check-up showed proper wound healing. The patient gave birth to a baby at 38 weeks of pregnancy by cesarean section due to orthopedic indications. After giving birth, she received no treatment for her previous cancer because she did not consent to a lymph node biopsy. No recurrence has been observed to January 2023. Due to the very long time without recurrence, it can be assumed that the patient’s decision was correct. We would most likely not find neoplastic cells in the sentinel node biopsy. However, it was a severe moral dilemma for the medical team. Due to the patient’s lack of consent, we could not fully comply with the recommended diagnostic and therapeutic standards. The patient is under the supervision of the Oncology Clinic once a year.

Discussion

We presented a case of HPV 16-associated VSCC in a pregnant woman. This type of vulvar cancer often occurs in young people, but, interestingly, it is practically unobserved during pregnancy. As this is a unique case, we discuss prevention, diagnosis, and treatment during pregnancy, and prognosis.

Vulvar cancer is a rare malignant tumor of the female reproductive system, accounting for 1% of all cancers in women and 4% of all gynecological cancers. It is most common in women aged 60–80 years [8]. It should be emphasized that there are also known cases of this cancer in women of childbearing potential, including pregnant women, but these are extremely rare. It is noteworthy that despite its rarity in pregnant patients, it is in this group of women that it is diagnosed at an early stage. It can be assumed that this is because pregnant women tend to undergo regular obstetric examinations [8]. The most common histopathological type in pregnant patients is VSCC [12]. Risk factors for vulvar cancer are HPV infection, other sexually transmitted diseases (eg, HIV co-infection), low socioeconomic status, smoking, immunodeficiency, and lichen sclerosis, which is known to be the leading risk factor for HPV-independent VSCC [11,13]. As part of primary prophylaxis, HPV vaccination is available, the effectiveness of which is tested through long-term analyses carried out, among others, by The Cancer Registry of Norway, which showed a favorable prognosis for reducing the incidence of vulvar cancer among vaccinated women [14]. Currently, there are no screening studies for vulvar cancer that would be part of secondary prevention. Doctors should encourage women to undergo regular gynecological examinations. This allows for early detection of signs and changes in the structure of the vulva, suggesting the presence of cancer and qualifying patients for biopsy [15]. Tertiary prophylaxis includes the treatment of precancerous lesions, among which 2 subtypes are distinguished for HPV-dependent cancer: high-grade squamous intraepithelial lesions (HSIL) and HPV-independent differentiated variant (dVIN) [16].

The basis for the diagnosis is the result of a histopathological examination of material taken during biopsy of the lesion suspected of cancerous growth [5]. Vulvar cancer treatment in pregnant patients is not fundamentally different from that of other women [12,17]. The standard treatment is radical lesion excision, and lymphadenectomy if the cancer is invasive [17,18]. During pregnancy, surgery is best performed between 15 and 20 weeks of gestation due to the size of the uterus and fetus, and it also gives a chance for the wound to heal by the time of delivery [8]. Depending on the histopathological type of vulvar cancer, radiation therapy and chemotherapy may also be used after surgical treatment. Still, we should consider that radiation treatment cannot be given during pregnancy [5]. However, it is important to choose the therapy in such a way as to minimize the negative impact of treatment on the fetus [18,19]. In the case of a cancer diagnosis in the first trimester, 44% of gynecologists recommend termination of pregnancy, and 37% of doctors do not start chemotherapy when the cancer is diagnosed in the third trimester of pregnancy [20,21].

The recurrence rate of vulvar cancer is 37% after 5 years [5]. The prognosis in patients with lymph node metastases is not always poor, but better survival rates without disease progression were shown in those who received adjuvant radiotherapy. Patients with 1 positive node without extracapsular spread tend to have a good prognosis, even without additional treatment [20].

A relatively small number of similar cases are described in the literature [10]. Le Lecointre et al drew attention to the difficult decisions related to treatment of vulvar cancer in pregnant women, in particular due to the possible harmful effects of chemotherapy and radiotherapy on the fetus [22]. Ogunleye et al [2004] described a similar stage of a case diagnosed at 18 weeks of gestation. As in the case described above, the patient underwent only surgical treatment, but due to the larger infiltration, she also required a second surgery after delivery [23]. Many of the described case reports describe lesions removed after birth of the child [10,24]. This may be because most cases are diagnosed in the second and third trimester of pregnancy [10].

It may be safer for the fetus to withhold treatment until the pregnancy is complete, but surgery is possible and effective during pregnancy as well.

Conclusions

Vulvar cancer is a condition that primarily affects the elderly; however, due to the increase in HPV infection it is tending to also occur in younger patients. SCC accounts for over 90% of all vulvar cancer cases and is most often preceded by dysplastic changes. The VSCCs can be classified as HPV-associated and HPV-independent, and are usually preceded by non-invasive VIN. Despite the increase in morbidity in young women, vulvar cancer in pregnancy is still sporadic – there are 40 cases described in the literature. Known risk factors for vulvar cancer include HPV infection, other sexually transmitted diseases, low socioeconomic status, smoking, and immunodeficiency. As part of primary prophylaxis, HPV vaccination is available. During pregnancy, surgery is best performed between 15 and 20 weeks of gestation due to the size of the uterus and fetus. Depending on the histopathological type and sentinel lymph node status, chemotherapy may also be used after surgical treatment, even during pregnancy, but radiation cannot be given during pregnancy. The prognosis in patients with lymph node metastases is not always poor. Making any decisions regarding therapeutic methods during pregnancy involve ethical, moral, and clinical challenges, and there are concerns about the impact of the applied therapy on the developing fetus.