Discussion
VGPA of the uterine cervix is a rare subtype of cervical adenocarcinoma that accounts for 3.7–4.8% of all cervical AC (1,8). Compared with other malignant cervical tumors, VGPA tends to occur in younger women, particularly those of reproductive age. Young and Scully (1) first reported 13 cases of VGPA with an average age of only 33 years old. The etiology of VGA remains unknown. Certain studies (3,4) suggest a role for HPV infection in the pathogenesis of VGPA. Jones et al (3) reported a study in which 15 (62.5%) out of 24 VGPA patients were taking OCP, with a duration of use (when known) ranging between 5 and 20 years; OCPs were considered to be associated with VGPA. In the present study, the median age of the 7 patients was 36.1 years, with a range of 29–42 years. None of the patients had a history of OCP use, but each case was positive for HPV infection. This test result indicates that HPV infection is more likely to be the cause of VGPA. The clinical manifestation of VGPA is similar to other types of cervical cancer with regard to abnormal vaginal bleeding, contact bleeding or abnormal vaginal secretion (1).
The final diagnosis of VGPA depends on pathological confirmation. As Young and Scully (1) reported that conservative treatment is feasible for VGPA, an accurate pre-operative diagnosis allows the opportunity for a number of VGPA-affected women to preserve their fertility. The main feature of VGPA is its villoglandular architecture. Each papilla in the villoglandular structures has a central pedicle that ranges in size and shape from short and thick to long and thin. The central pedicle contains a number of inflammatory cells (Fig. 1). The villoglandular structures are composed of stratified glandular cells, with mild to moderate nuclear atypia, and mitotic figures, with little or no budding from the villoglandular structures (9). A study by Macdonald et al (10) advised following the more recent changes in the definition of a villoglandular tumor rather than continuing to conform to a limited and conservative definition stating the presence of only villoglandular components, with no standard adenomatous or squamous features and no high-grade nuclear abnormalities.
Among the 11 cases initially selected in the present study, only 54.5% (6/11) had the same pre-operative and post-operative diagnosis. Similarly, in a study by Korach et al (6), data were reviewed from the outpatient files of 12 patients who had been diagnosed with VGPA. The final pathology results confirmed a diagnosis of VGPA in only 9 of the patients. Of these 9, only 2 had been correctly pre-operatively diagnosed, while in 3, a benign or pre-malignant initial biopsy result had been determined, and in the remaining 4 patients, an invasive malignant tumor had been diagnosed, consequently necessitating a hysterectomy. The 3 non-VGPA patients were diagnosed with invasive cervical adenocarcinoma on the final histological report. Following integration of the data from the literature review and the results of the present study cases, it may be concluded that pre-treatment punch biopsy diagnosis has a low rate of diagnostic accuracy when compared with the final histological report. This may be attributed to two reasons: Firstly, forming an accurate pre-operative pathological diagnosis is difficult for VGPA. In 30% of cases, VGPA is associated with other types of invasive cancer (1,11–14), which may have a significant impact on its prognosis. It is therefore important to remember that ordinary adenocarcinomas, including deeply invasive tumors, may have a papillary component and that VGPA should only be diagnosed in those lesions that are exclusively grade 1 and unassociated with an underlying conventional adenocarcinoma component. Secondly, the scope of a biopsy is limited, as it is unable to determine whether the entire tumor contains other invasive adenocarcinoma tissues or not. In addition, it is not easy to get to the basement membrane while taking a biopsy, so infiltration cannot be completely ruled out. Therefore, an excision or cone biopsy is occasionally required to establish a VGPA diagnosis when a punch biopsy is not sufficient.
Yamazawa et al (15) suggested that the recommendation of no further treatment may be acceptable for patients who require fertility preservation if the tumor is superficial with no involvement of the vascular space, or if the cone margins exhibit no residual disease. To date, only 6 cases of pregnancy associated with VGPA of the cervix have been reported (Table II). In 3 of these cases, successful conception was achieved following a conservative treatment for VGPA (6,12,14). The 3 remaining cases were diagnosed during the pregnancy (16–18). Nonetheless, the management of cervical VGPA is considered to be a significant challenge. To date, >150 cases of VGA of the cervix have been reported in the English literature, with 12 cases of recurrence and 8 mortalities (Table III) (3,6,19–21). In the clinical analysis of background data, the patients who experienced a poor outcome were closely associated with an advanced FIGO stage and LN metastasis. Of the mortalities, 5 patients had VGPA of stage IIB or greater. LN metastasis was reported in 5 patients, with 3 of these cases developing recurrence (2 patients succumbed to recurrence). As the current follow-up time of VGPA is short, a lack of data is available on the 5-year survival rate.
In the present study, the 7 patients with VGPA had no fertility requirements and exhibited a clinical stage of between IB1-IIA1; therefore, all the patients underwent a radical hysterectomy with or without adjuvant therapy. The follow-up time ranged from 7–57 months, with an average time of 28 months. All patients were alive with no evidence of recurrence at the time of writing this study.
In conclusion, VGPA usually occurs in females of reproductive age. Reproductive and endocrine treatment options are factors that must be considered in the treatment of affected patients, while the proposed conservative treatment for these women allows maintenance of fertility in patients who are young and wish to have children. However, as the number of studies reporting cases of VGPA remains small, and as all are retrospective analyses with a short follow-up time, more prospective randomized controlled trials are required to confirm the prognosis of the disease. Therefore, while choosing treatment options for patients with VGPA, data for disease stage, fertility requirements, follow-up conditions, and the presence of vascular and lymphatic metastasis should be integrated, which for a range of aspects, would aid in prudent decision-making.