The relationship between vaginal cavernous hemangiomas and late pregnancy. A case report and a review of the literature

Summary The occurrence of cavernous hemangiomas in the vagina is very rare. A 34-year-old woman at 33 weeks’ gestation was admitted with a large reddish mass of approximately 5 cm in diameter in the vagina, with bleeding and a sensation of discomfort with walking. The vaginal mass was excised to confirm the pathological diagnosis. Histopathological analysis showed various dilated vessels lined by increased endothelial cells, and the final diagnosis was vaginal cavernous hemangioma. The immunohistochemical analysis showed positive expressions of vascular endothelial growth factor (VEGF), estrogen receptor (ER), and progesterone receptor (PgR) in perivascular stromal cells around the hemangioma. Additionally, the authors reviewed the relationship between genital hemangiomas and pregnancy from the literature. In the female genital tract, six (75%) of eight vaginal hemangiomas were associated with pregnancy, in particular, late pregnancy, in addition to the present case, and eight (32%) of 25 cervical hemangiomas were seen in late pregnancy. Taken together, the hormonal status in late pregnancy may affect the formation of vaginal hemangiomas.


Introduction
The occurrence of hemangiomas in the female genital tract, particularly in the vagina, is very rare [1].In this article, the case of a 34-year-old woman (gravida 2, para 1) who presented at 33 gestational weeks with a vaginal cavernous hemangioma is presented.There have been several previous case studies that reported the rapid proliferation and complete resolution of female genital hemangiomas related to pregnancy [2,3].However, the relationship between hemangioma and pregnancy is not clear.It is presumed that a characteristic feature (e.g.hormonal status) of pregnancy affects the formation of vaginal hemangiomas.This report focuses on not only the relationship between pregnancy and vaginal hemangioma, but also on the expressions of hormonal receptors in vaginal hemangiomas.

Materials and Methods
An asymptomatic 34-year-old woman (gravida 2, para 1) visited the antenatal clinic for routine follow-up at 18 weeks' gestation.She was treated with an episiotomy during the previous delivery.Clinical examination showed no apparent lesions in both the cervix and vagina.At 33 weeks' gestation, she complained of vaginal bleeding and a sensation of discomfort with walking and was referred to thus institution.Clinical examination showed a large reddish mass, approximately 5 cm in diameter, with bleeding, originating from the vaginal wall and protruding from the introitus (Figure 1A).Pelvic MRI showed a thickened vaginal mass with heterogeneous and a slightly high intensity on T2-weighted images (T2WI), the same intensity as soft tissue on T1-weighted images (T1WI) with further enhancement (Figure 1B).Hematoma, hemangioma, and malignant tumor were considered in the differential diagnosis.On excision, the vaginal mass was found to be a hemangioma.Seven weeks later, she gave birth safety to a baby (baby's weight: 3130 grams) through the vaginal tract.The patient provided her informed consent for the publication of this case.
Previous reports of the two hemangiomas, both vaginal and cervical hemangiomas, were identified, and the relationship between hemangioma and pregnancy or oral contraceptive use, which contained both synthetic estrogen and progesterone, was examined.

Results
The vaginal mass was located superficially on the posterior wall mucosa.It could be clearly distinguished from the healthy vaginal wall and was completely resected (Figure 2A).Histopathological analysis showed a polypoid lesion with various dilated vessels which had increased endothe-   lial cells which expressed CD34 and ERG but not D2-40 (Figures 2B, 3A-3E).Ki-67 expression was clearly found in the endothelial cells (Figure 3G) and a mitotic feature was also seen in the ERG-positive vascular endothelial cell (Figure 3F).The final diagnosis was not vaginal varix malformation but vaginal cavernous hemangioma.
Immunohistochemical analysis showed positive expressions of both ER and PgR in perivascular stromal cells around the hemangioma, but no expressions in vascular endothelial cells (Figures 3I, 3J).On the other hand, ER and PgR expressions were not found in the skin hemangioma (not shown).Additionally, hCG expression was not found but VEGF expression was noted in the perivascular stromal cells around the hemangioma.(Figures 3H, 3K).
Seven vaginal hemangiomas have been reported to date (Table 1) [1,[4][5][6][7].Six cases (75%) were associated with pregnancy, in particular, late pregnancy, in addition to the present case.On the other hand, about 60 cervical hemangiomas have been reported in the literature [2,, and the relationships between hemangioma and pregnancy or oral contraceptive use were examined (Table 2).
Eight (32%) of 25 cervical hemangiomas and four (25%) of 16 cervical hemangiomas were found to be related to pregnancy or oral contraceptive use, respectively.All five cervical hemangioma cases that were related to pregnancy (excluding one case because the gestational weeks were not reported) were seen in late pregnancy (26-38 weeks), the same as in vaginal hemangioma cases.

Discussion
A cavernous hemangioma is a benign vascular tumor that rarely involves the female genital tract, especially the vagina [1].In the female genital tract, a dilated vascular structure is sometime noted in the cases of hemangioma, vascular or lymphatic malformation and varix, but the gross findings of those diseases are similar to each other and a differential diagnosis is too difficult.The hemangioma is thought to gradually increasing over time and the pathological feature shows various dilated vessels with increased endothelial cells, which have tumorous potential.It is considered that hemangioma formation is due to injury or con-genital malformation, but the pathogenesis remains unclear.In the present case, there were no conditions, such as trauma and infections, during pregnancy, and no obvious lesions of the vagina and cervix were seen until 18 gestational weeks.However, an episiotomy was performed at the previous delivery, at the same place as the vaginal hemangioma.Yu et al. recently also mentioned that the vaginal hemangioma in terminal pregnancy was observed at the previous episiotomy [7].Therefore, the previous episiotomy may have affected the formation of the vaginal hemangioma in late pregnancy.Second, according to the previous studies, estrogen plays an important role in hemangioma formation in vivo [22], and estrogen promotes the proliferation of hemangioma in vitro [30,31].Reggiani Bonetti et al. reported the presence of estrogen receptors in both endothelial cells and stromal cells of cervical hemangiomas on immunohistochemical analysis [22].Sun et al. previously reported that direct angiogenetic factors, VEGF, matrix metalloproteinase-9 (MMP-9), and nitric oxide (NO), or indirect angiogenetic factors, basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF), and transforming growth factor (TGF), can contribute to the angiogenesis of hemangiomas through estrogen [31].In addition, Duyka et al. mentioned that progesterone also promotes the expansion of vascular malformations [32].In the present case, immunohistochemical analysis showed positive expressions of ER, PgR, and VEGF of the stromal tissue around the hemangioma in pregnancy.Taken together, estrogen and/or progesterone may promote angiogenesis of hemangiomas through the secretion of VEGF in pregnancy.Third, from the literature, six (75%) of eight vaginal hemangiomas and eight (32%) of 25 cervical hemangiomas were associated with pregnancy.Moreover, all vaginal and cervical hemangiomas related to pregnancy were diagnosed in late pregnancy (26-40 gestational weeks).Additionally, four (25%) of 16 cervical hemangiomas were found to be related to oral contraceptive use.Regarding hormonal status in pregnancy, both serum estradiol and progesterone are increased approximately 150 times and 12 times, respectively, in late pregnancy compared to non-pregnancy [33].Outside of the female genital area, several hemangiomas were reported in nasal [34], oral [35], and spinal cord sites [36] during pregnancy.Cardoso et al. reported that over 50% of hemangiomatous lesions were found in the third trimester [35].These reports were consistent with the present result that almost all vaginal hemangiomas were seen in late pregnancy.In summary, the hormonal status in late pregnancy and previous episiotomy may affect the formation of vaginal hemangiomas.However, in the present study, it was not possible to elucidate the mechanisms of vaginal hemangioma formation in pregnancy because only one hemangioma case that occurred during pregnancy was analyzed, and VEGF was the only angiogenic marker used.Further studies are necessary to understand the mechanism of female genital hemangiomas in pregnancy.

Conclusion
The formation of hemangiomas in the female genital area is associated with late pregnancy and the hormonal status in pregnancy, and previous episiotomy may promote angiogenesis of hemangiomas.

Figure 2 .
Figure 2. -(A) Resected specimen.A hematoma-like mass (36×18×14 mm 3 ) originates from the vaginal wall.The healthy vaginal wall is seen in the peripheral zone.(B) Histopathological findings.Proliferation of the various dilated vessels and hemorrhage in the stroma are identified in the polypoid lesion (left: HE stain, right: Elastic van Gieson stain).Bars, 1 mm.

Figure 3 .
Figure 3. -Pathological and immunohistochemical findings.(A, B) HE stain.The congestion and hemorrhage are noted in the hemangioma and the increased endothelial cells are seen in the dilated vessels.(C-E, G) The increased vascular endothelial cells are positive for CD34, ERG, and Ki-67 but negative for D2-40.(F) A mitotic feature is seen in the ERG-positive endothelial cell (arrow).(H-K) The endothelial cells are negative for ER and PgR but the perivascular stromal cells are positive for ER, PgR, and VEGF but negative for hCG.White bars, 500 µm and black bars, 50 µm.

Table 1 .
-Eight cases of vaginal hemangioma in the literature.
NA: not available.