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Prognostic Factors Influencing Decisions About Surgical Treatment of Villoglandular Adenocarcinoma of the Uterine Cervix

Kim, Ha-Jeong MD*; Sung, Ji-Hee MD; Lee, Eunjung MD; Ahn, Soomin MD; Song, Sang Yong MD, PhD; Choi, Chel Hun MD; Kim, Tae-Joong MD; Kim, Byoung-Gie MD, PhD; Bae, Duk-Soo MD, PhD; Lee, Jeong-Won MD, PhD

International Journal of Gynecological Cancer: September 2014 - Volume 24 - Issue 7 - p 1299–1305
doi: 10.1097/IGC.0000000000000197
Cervical Cancer

Objective The objectives of this study were to analyze the clinicopathologic features of villoglandular adenocarcinoma (VGA) of the uterine cervix, a variant of cervical adenocarcinoma with good prognosis, and to discuss the association of human papillomavirus (HPV) infection with VGA.

Methods A retrospective review of medical records was performed to identify the patients with VGA between 1999 and 2007 at the Samsung Medical Center.

Results Fifteen patients were identified among 171 women diagnosed with adenocarcinoma of the cervix. The median age was 40 years (range, 32–72 years). Four patients were treated by cone biopsy and 10 patients by hysterectomy with or without pelvic lymphadenectomy. Five patients had invasion of more than half of the depth of tumor in the cervix. Lymphovascular space invasion was present in 2 patients, one of whom also had lymph node metastases. Three recurrences were identified during the median follow-up of 64 months (range, 9–149 months). An HPV test was positive in 6 of 7 patients. Of the 6 patients with HPV infection, 2 were positive for HPV type 18, one for HPV type 6, and the remaining 3 were positive for 1 or more types of high-risk HPV.

Conclusions Although VGA has been reported to have a favorable prognosis, we observed recurrences in those patients with close margins by the tumor, lymph node metastasis, or advanced stage. Human papillomavirus DNA, mostly HPV types 16 and 18, was associated with VGA. Further studies are warranted on prognostic factors and the pathogenetic role of HPV infections.

*Department of Obstetrics and Gynecology, Institute of Wonkwang Medical Science, College of Medicine, Wonkwang University, Iksan; Departments of †Obstetrics and Gynecology and ‡Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

H.-J.K. and J.-H.S. equally contributed to this article.

Address correspondence and reprint requests to Jeong-Won Lee, MD, PhD, Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea. E-mail:

This study was supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea, Ministry of Education, Republic of Korea (2013R1A1A2013612).

The authors declare no conflicts of interest.

Received March 13, 2014

Received in revised form May 8, 2014

Accepted May 8, 2014

Adenocarcinoma (AC) of the uterine cervix has increased in young women over the last several decades, whereas the incidence of cervical squamous cell carcinoma (SCC) has decreased.1–4 As a result, the incidence of AC of the cervix has risen from 5% to more than 20%.3,5 Adenocarcinoma has a poorer prognosis with high rates of lymph node (LN) involvement, distant metastases, and worse survival compared with SCC.6–9 These cancers may behave differently both clinically and histologically than their more common squamous counterparts.

Villoglandular adenocarcinoma (VGA) of the uterine cervix, a rare subtype of cervical AC, was first reported in 1989.10 Compared with the common types of cervical AC, VGA tends to occur in young women and has a favorable prognosis.11,12 Histologically, VGA is characterized by an exophytic proliferation with long and slender papillary structures and a mild to moderate cellular atypia.13 Villoglandular adenocarcinoma has been associated with superficial invasion, rare lymphovascular invasion, and infrequent LN affection, leading some surgeons to conduct conservative surgery, such as cone biopsy.11,14–17 However, more aggressive cases including death have been reported.11,18,19 Because of the rarity of these tumors, existing data for VGA are limited to evaluations of the natural history and optimal treatment of VGA.

In this study, we reviewed the clinical and pathologic features on 15 patients with VGA and investigated the risk factors for clinical outcomes.

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We retrospectively reviewed electronic medical records to find patients with primary AC of cervical cancer between November 1999 and September 2007 at the Samsung Medical Center of Sungkyunkwan University School of Medicine, Seoul, Korea. Of these, patients with a pathologic diagnosis of VGA were identified and included in this study. An approval was given by the institutional review board of our institution. Slides from each patient were reexamined to confirm the diagnosis. Two expert pathologists (S.M.A. and S.Y.S.) reviewed the pathologic slides without previous knowledge of the clinical outcomes. We excluded patients with other types of AC and those who had only foci of villoglandular patterns. Finally, 15 patients (8.8%) were identified of 171 women diagnosed with AC of the cervix. Demographic information, pathology, and treatment of the disease were collected from the medical records. The clinical profiles included patient age, International Federation of Gynecology and Obstetrics (FIGO) stage, human papillomavirus (HPV) infection, surgical procedure, types of adjuvant therapy, and survival. Size and depth of tumor, lymphovascular space invasion (LVSI), LN metastasis, and tumor invasion of resection margin and parametrium were pathologically investigated.

In 7 cases, HPV testing was performed at the time of diagnosis using a Hybrid Capture 2 (HC2) or an HPV DNA microarray (DNA Chip). Hybrid Capture 2 is a nucleic acid hybridization assay designed for the aggregate detection of 13 high-risk (HR) HPV types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) using a mixture of RNA probes with signal amplification.20,21 Cervical specimens were collected in Specimen Transport Medium (STM; Digene, Bremen, Germany) and tested for HC2. Fifty microliters of each STM specimen was separated for real-time HR and sequencing analysis. Hybrid Capture 2 was performed according to the manufacturer’s instructions, and results with a relative-light-units–cutoff ratio greater than 1.00 were interpreted as positive. DNA Chip is a polymerase chain reaction–based DNA microarray system and an HPV genotyping method for 15 HR HPV types (HPV 6, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, and 68) and 9 low-risk (LR) HPV types (HPV 6, 11, 34, 40, 42, 43, 44, 54, and 70).18 Polymerase chain reaction–based HPV DNA microarray was performed and interpreted according to the manufacturer’s instructions.

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During the study period, VGA was diagnosed in 15 patients (8.8%). The median age of the patients was 40 years, with a range of 32 to 72 years. A biopsy was performed on 7 patients because of abnormal cervical smears. Six patients presented with abnormal vaginal bleeding. In the remaining 2, the clinical presentation was unknown. The FIGO stage of disease was IA1 in 3 patients, IB1 in 11, and IIIC in 1 patient. Four patients were treated by cone biopsy, 2 by hysterectomy with or without pelvic lymphadenectomy, and 8 patients by radical hysterectomy with pelvic lymphadenectomy. One patient with stage IIIC was treated by concurrent chemoradiation therapy. Four of these 15 patients underwent adjuvant therapy. Three patients received external beam radiation because of stromal invasion of more than half of the cervix and LVSI (patients 7, 9, and 13). Another patient (patient 11) received postoperative chemoradiation because of positive pelvic LNs.

The median follow-up period was 64 months (range, 9.37–149.23 months). No patient died of disease occurrence during this time. At the time of review, 12 patients (80%) were alive with no evidence of recurrent disease, and 3 patients showed disease recurrence. Among the 3 patients with recurrent disease, one was alive with recurrent disease.

The details of the patients with recurrent disease were as follows: The first patient (patient 5) presented with stage IB1 and received conization. The tumor showed a minimal stromal invasion to a depth of 3 mm. The margins of excision were uninvolved but were close by the tumor. The patient developed a disease recurrence in the cervix 25 months after diagnosis, underwent a radical hysterectomy, and was alive for 62 months during follow-up. The second patient (patient 11) presented with stage IB2 with metastasis to the pelvic LN and LVSI and underwent postoperative chemoradiation therapy. A disease recurrence was developed in the left supraclavicular LN, left neck LN, and lung 19 months after diagnosis, and the disease persisted after chemotherapy. The third patient (patient 15) presented with a locally advanced-stage disease (stage IIIC). The patient underwent a concurrent chemoradiation therapy, but the tumor recurred in the cervix and rectum 48 months after the initial diagnosis. A hysterectomy with anterior resection of the rectum was performed and adjuvant chemotherapy was administered, and the patient was alive during 6 months of follow-up. The details of the clinical characteristics are shown in Table 1.



Table 2 shows the details of the histopathologic features. All of the biopsy specimens showed a villoglandular pattern (Fig. 1). Villoglandular adenocarcinoma ranged between 3 × 2 and 53 × 42 mm. The depth of invasion exceeded half of cervical thickness in 5 patients. Lymphovascular space invasion was present in 2 patients (patients 9 and 11), and also LN metastases were observed in patient 11.





Table 3 shows the HPV test results of patients with VGA. Of 7 patients with HPV test with HC2 or DNA Chip, 6 were positive for an HPV infection. Of these 6 patients, 2 were positive for HPV type 18, 1 patient was positive for HPV type 6, and the remaining 3 were positive for HR HPV including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68.



Of 171 patients, 15 patients had VGA, and 156 patients did not have VGA. In the comparison of clinicopathologic findings between the 2 groups (Table 4), there were no differences except for median age and FIGO stage. The median age was about 6 years younger in VGA patients than in AC patients, which is statistically significant (P = 0.027). The FIGO stage was significantly different between the 2 groups. Most VGA patients presented an early-stage disease (FIGO stage I, 14/15 [93.3%]). Infections with any HR HPV type were identified in 58.2% of the AC group; 12.7% of the AC group were positive for HVP type 18, 9.1% were positive for HPV type 16, 3.6% were positive for HPV type 33, and the remaining 32.7% were positive for multiple HPV types including HPV types 16 and 18. No statistically significant differences were found regarding HPV infection between the 2 groups.



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We reviewed 15 patients with VGA who were diagnosed and treated at a single institution. Villoglandular adenocarcinoma occurred in relatively younger patients and had a favorable prognosis than common types of cervical AC. Also, VGA could be correlated to HR types of HPV infections. Three recurrences were identified and had more than 1 of the HR factors for recurrence: close margin by the tumor, LN metastasis, and advanced clinical stage.

Villoglandular adenocarcinoma of the uterine cervix has only recently been recognized as a distinct histological entity.10 It is a rare type that accounts for approximately 4% of ACs.11,19 In the international literature, approximately 150 cases have been described in recent years. In our institution, AC of the uterine cervix accounted for 10.4% (171/1648 cases) of all invasive cervical cancers between 1999 and 2007, and 15 (8.8%) of 171 patients with AC were diagnosed as VGA.

Villoglandular adenocarcinoma occurs in relatively younger patients than SCC. In the earlier series, patients’ ages ranged between 22 and 65 years, and the average age was 37 to 45 years.12,14,22,23 Although patient ages ranged widely (32–72 years), our result was similar to the reported median age of 40 years.

Villoglandular adenocarcinoma has been associated with superficial invasion, rare lymphovascular invasion, and infrequent LN affection, leading some surgeons to conduct less radical surgeries, such as conization.11,14–17 In the present study, more than half of the patients had FIGO stage IB1 (11/15, 73.3%), and 3 patients showed early cervical cancer with microscopic lesions (IA1). Moreover, of 11 patients with stage IB1 disease, 2 were treated by cervical conization (conservative treatment). One patient (patient 5) had a known pathologic risk factor (close by the tumor) and had a recurrence in the cervix after conization. The other patient (patient 12) underwent polypectomy of the uterine cervix followed by conization. The 1-cm resected polyp was pathologically diagnosed as VGA. The tumor was purely exophytic without invasion of the underlying stroma and LVSI. The patient underwent conization also. No cancer cells were identified in the resected specimens. No evidence of disease was revealed during the 18 months’ follow-up of the patient.

So far, more than 140 cases of VGA of the cervix have been reported, with 9 recurrences (6.25%) and 8 deaths (Table 5). In the clinical background analysis, those patients had more than 1 risk factor for recurrent disease. The survival of patients with early-stage cervical cancer depends on the presence or absence of several pathologic findings.24 Among several prognostic variables, pelvic LN metastasis, parametrial invasion, and positive or close vaginal margins of resection are considered HR factors for recurrence of early-stage cervical cancer (IA2-IIA).24 Moreover, most important prognostic factors for survival are clinical stage and LN status.25–27 It is noteworthy that the 3 recurrent patients in this series had HR factors for recurrence: close margin by the tumor in 1 patient, LN metastasis in another, and advanced clinical stage in the third. The decision to treat VGA conservatively should be instituted after careful review of the histopathologic findings.



The etiology of VGA is still unknown. A few studies have suggested that HPV infection was involved in the pathogenesis of VGA. In 2000, a case of VGA positive for HPV type 18 was reported.19 In a series of 12 cases of VGA, HPV types 18 (58%) and 16 (42%) were closely associated with VGA.28 Although the latter study was small, the authors suggested that HPV infection may be more prevalent in VGA than in other types of AC.29 In the study for the HPV prevalence in cervical carcinoma in Korean women, the 5 cases of VGA were positive for HPV 16.30 Recently, a molecular analysis by polymerase chain reaction amplification of tumor DNA showed a strong positive signal for HPV-DNA, similar to other previous reports.31 In our series, the prevalence of HPV infection associated with VGA was 71.4% (5/7 cases). Two cases were positive for HPV type 18, and the others were positive for multiple HPV types including HPV type 16 or 18. Human papillomavirus type 18 is the more predominant type in cervical AC in contrast to HPV type 16, which is more predominant in cervical SCC.32–34 However, the pathogenetic role of HPV infection in cervical AC remains still unclear.

The current study has the following limitations. First, the retrospective design is its major limitation. Second, the number of patients was small because of the rarity of these tumors. Third, HPV testing was not considered beforehand for all cases. In addition, there was a diverse method of HPV test due to long-term follow-up study.

In conclusion, we observed that VGA may appear in younger patients and have a favorable prognosis compared with the common AC of the cervix. For selected cases, a conservative surgical approach (cervical conization) is considered feasible. However, much caution is needed in managing patients with VGA, encountering the recurrences in patients with known pathologic risk factors. Before conservative therapy is considered, careful evaluation must be made for the presence of poor prognostic features, such as LVSI and LN metastasis. Also, we reported several cases of HPV-positive VGA, and so we suggest that there is a correlation between HPV infection and VGA. Villoglandular adenocarcinoma is a rare disease with few reports in the literature only. A large multicenter prospective study will be required to determine the proper treatment for the disease and to clarify the correct association between HPV infection and development of VGA.

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1. Sasieni P, Adams J. Changing rates of adenocarcinoma and adenosquamous carcinoma of the cervix in England. Lancet. 2001; 357: 1490–1493.
2. Smith HO, Tiffany MF, Qualls CR, et al. The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States—a 24-year population-based study. Gynecol Oncol. 2000; 78: 97–105.
3. Wang SS, Sherman ME, Hildesheim A, et al. Cervical adenocarcinoma and squamous cell carcinoma incidence trends among white women and black women in the United States for 1976–2000. Cancer. 2004; 100: 1035–1044.
4. Bray F, Carstensen B, Moller H, et al. Incidence trends of adenocarcinoma of the cervix in 13 European countries. Cancer Epidemiol Biomarkers Prev. 2005; 14: 2191–2199.
5. Galic V, Herzog TJ, Lewin SN, et al. Prognostic significance of adenocarcinoma histology in women with cervical cancer. Gynecol Oncol. 2012; 125: 287–291.
6. Yang J, Shikata N, Mizuoka H, et al. Colon carcinogenesis in shrews by intrarectal infusion of N-methyl-N-nitrosourea. Cancer Lett. 1996; 110: 105–112.
7. Eifel PJ, Burke TW, Morris M, et al. Adenocarcinoma as an independent risk factor for disease recurrence in patients with stage IB cervical carcinoma. Gynecol Oncol. 1995; 59: 38–44.
8. Park JY, Kim DY, Kim JH, et al. Outcomes after radical hysterectomy in patients with early-stage adenocarcinoma of uterine cervix. Br J Cancer. 2010; 102: 1692–1698.
9. Lee YY, Choi CH, Kim TJ, et al. A comparison of pure adenocarcinoma and squamous cell carcinoma of the cervix after radical hysterectomy in stage IB-IIA. Gynecol Oncol. 2011; 120: 439–443.
10. Young RH, Scully RE. Villoglandular papillary adenocarcinoma of the uterine cervix. A clinicopathologic analysis of 13 cases. Cancer. 1989; 63: 1773–1779.
11. Kaku T, Kamura T, Shigematsu T, et al. Adenocarcinoma of the uterine cervix with predominantly villogladular papillary growth pattern. Gynecol Oncol. 1997; 64: 147–152.
12. Utsugi K, Shimizu Y, Akiyama F, et al. Clinicopathologic features of villoglandular papillary adenocarcinoma of the uterine cervix. Gynecol Oncol. 2004; 92: 64–70.
13. Khunamornpong S, Siriaunkgul S, Suprasert P. Well-differentiated villoglandular adenocarcinoma of the uterine cervix: cytomorphologic observation of five cases. Diagn Cytopathol. 2002; 26: 10–14.
14. Jones MW, Silverberg SG, Kurman RJ. Well-differentiated villoglandular adenocarcinoma of the uterine cervix: a clinicopathological study of 24 cases. Int J Gynecol Pathol. 1993; 12: 1–7.
15. Macdonald RD, Kirwan J, Hayat K, et al. Villoglandular adenocarcinoma of the cervix: clarity is needed on the histological definition for this difficult diagnosis. Gynecol Oncol. 2006; 100: 192–194.
16. Costa MJ, McIlnay KR, Trelford J. Cervical carcinoma with glandular differentiation: histological evaluation predicts disease recurrence in clinical stage I or II patients. Hum Pathol. 1995; 26: 829–837.
17. Ballo MS, Silverberg SG, Sidawy MK. Cytologic features of well-differentiated villoglandular adenocarcinoma of the cervix. Acta Cytol. 1996; 40: 536–540.
18. Choi YD, Jung WW, Nam JH, et al. Detection of HPV genotypes in cervical lesions by the HPV DNA Chip and sequencing. Gynecol Oncol. 2005; 98: 369–375.
19. Yamazawa K, Matsui H, Seki K, et al. Human papillomavirus-positive well-differentiated villoglandular adenocarcinoma of the uterine cervix: a case report and review of the literature. Gynecol Oncol. 2000; 77: 473–477.
20. Lorincz AT. Hybrid Capture method for detection of human papillomavirus DNA in clinical specimens: a tool for clinical management of equivocal Pap smears and for population screening. J Obstet Gynaecol Res. 1996; 22: 629–636.
21. Poljak M, Brencic A, Seme K, et al. Comparative evaluation of first- and second-generation digene hybrid capture assays for detection of human papillomaviruses associated with high or intermediate risk for cervical cancer. J Clin Microbiol. 1999; 37: 796–797.
22. Khunamornpong S, Maleemonkol S, Siriaunkgul S, et al. Well-Differentiated villoglandular adenocarcinoma of the uterine cervix: a report of 15 cases including two with lymph node metastasis. J Med Assoc Thai. 2001; 84: 882–888.
23. Lataifeh IM, Al-Hussaini M, Uzan C, et al. Villoglandular papillary adenocarcinoma of the cervix: a series of 28 cases including two with lymph node metastasis. Int J Gynecol Cancer. 2013; 23: 900–905.
24. Berek JS, Novak E. Berek & Novak’s Gynecology. 15th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.
25. Baalbergen A, Ewing-Graham PC, Hop WC, et al. Prognostic factors in adenocarcinoma of the uterine cervix. Gynecol Oncol. 2004; 92: 262–267.
26. Kim MK, Jo H, Kong HJ, et al. Postoperative nomogram predicting risk of recurrence after radical hysterectomy for early-stage cervical cancer. Int J Gynecol Cancer. 2010; 20: 1581–1586.
27. Biewenga P, van der Velden J, Mol BW, et al. Prognostic model for survival in patients with early stage cervical cancer. Cancer. 2011; 117: 768–776.
28. Jones MW, Kounelis S, Papadaki H, et al. Well-differentiated villoglandular adenocarcinoma of the uterine cervix: oncogene/tumor suppressor gene alterations and human papillomavirus genotyping. Int J Gynecol Pathol. 2000; 19: 110–117.
29. Duggan MA, McGregor SE, Benoit JL, et al. The human papillomavirus status of invasive cervical adenocarcinoma: a clinicopathological and outcome analysis. Hum Pathol. 1995; 26: 319–325.
30. An HJ, Kim KR, Kim IS, et al. Prevalence of human papillomavirus DNA in various histological subtypes of cervical adenocarcinoma: a population-based study. Mod Pathol. 2005; 18: 528–534.
31. Giordano G, D’Adda T, Gnetti L, et al. Villoglandular adenocarcinoma of the cervix: two new cases with morphological and molecular study. Int J Gynecol Pathol. 2007; 26: 199–204.
32. Bosch FX, Manos MM, Munoz N, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International Biological Study on Cervical Cancer (IBSCC) Study Group. J Natl Cancer Inst. 1995; 87: 796–802.
33. Iwasawa A, Nieminen P, Lehtinen M, et al. Human papillomavirus DNA in uterine cervix squamous cell carcinoma and adenocarcinoma detected by polymerase chain reaction. Cancer. 1996; 77: 2275–2279.
34. Lizano M, Berumen J, Guido MC, et al. Association between human papillomavirus type 18 variants and histopathology of cervical cancer. J Natl Cancer Inst. 1997; 89: 1227–1231.

Villoglandular adenocarcinoma; Uterine cervix; Risk factor for recurrence; HPV infection

© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.