In addition, a meta-analysis of 8 studies demonstrated that patients with ASC had a higher risk of recurrence than those with AC (recurrence HR, 1.43; 95% CI, 1.05–1.95; I2 = 19.4%; Table 2. Sensitivity analyses were performed to evaluate the robustness of the death HR results. The poor prognosis of ASC compared with AC remained significant when any 1 study was removed from the analysis (Supplementary Figure 1, available at http://links.lww.com/IGC/A196).
This meta-analysis showed significantly increased HRs for recurrence and death in patients with ASC compared with those with AC. There was no substantial heterogeneity between studies included in the meta-analysis.
The prognostic significance of ASC histologic diagnosis has been limited by its inclusion as a subtype of AC in many of the studies that evaluate prognosis and outcomes of cervical cancer.39,40 Because Cherry et al41 first reported the poor prognosis of ASC compared with pure AC, a number of studies have evaluated the prognostic significance of ASC. However, the prognostic significance of ASC histologic diagnosis has not yet been determined owing largely to the comparative rarity of this disease. The incidence of ASC is around 6% in uterine cervical cancer,37 which results in difficulties in identifying a sufficient number of cases when considering single institutions.
After a systematic review, we identified 17 relevant articles that compared the outcomes of ASC and AC from 1975 to 2013. The summary estimates of this meta-analysis provide the interesting result of poorer outcomes for patients with ASC in recurrence and death, although most individual studies failed to show a significant difference between the 2 histologic subtypes. This suggests that ASC may be a different disease entity from AC.
Mechanisms related to the poor outcomes of ASC have not yet been extensively evaluated. One potential mechanism may be attributed to the high-risk factors frequently observed in ASC. It is worth noting that a poorer tumor grade and higher prevalence of lymphovascular space invasion (LVSI) have been found more often in ASC than in AC.12,27,28 ,37 However, whether the poor prognosis of ASC remains significant after adjusting for these high-risk factors cannot be determined in this meta-analysis because most of the eligible studies presented univariate HRs from survival curves.
The study patients with ASC had a higher HR than those with AC, especially in early-stage disease. Radical surgery was the treatment of choice for most patients with early-stage cervical cancers. Considering the poor outcomes of ASC, even in early-stage disease, we propose more aggressive guidelines for adjuvant therapy in future clinical trials.
To the best of our knowledge, this is the first meta-analysis to evaluate the prognostic significance of ASC in cervical cancer. However, our study has several potential limitations; these are as follows: first, approximately one third of patient data comes from a single study using the SEER database; second, the performance of adjuvant treatment and type of primary treatment had not been standardized in the studies included in our analysis; third, although most of the studies included in the meta-analysis were conducted before concurrent chemoradiation (CCRT) was accepted as a standard treatment, the prognostic significance of ASC in patients with early-stage cervical cancer treated with radical hysterectomy and CCRT is yet to be determined; and lastly, the interpretation of the literature might be confounded by a failure of investigators to adopt uniform criteria for diagnosis of ASC.
According to the World Health Organization classification, the definition of ASC is composed of a mixture of malignant glandular and squamous epithelium. So, the histologic diagnosis elements are scattered mucin-producing atypical cells in otherwise looking SCC. If the SCC is very poorly differentiated, the glandular elements are identified only by the use of mucin stains. Adenosquamous carcinoma should be distinguished from endometrioid AC with squamous differentiation of the cervix. In ASC, the epithelial component is mostly endocervical type, which is mucin-secreting cells, whereas endometrial cells have no or little intracellular mucin production.42 In addition, glassy cell carcinoma has been recognized as a poorly differentiated form of ASC with an aggressive course and a poor prognosis.43,44 Individual cells have abundant eosinophilic, granular, ground-glass cytoplasm, large round to oval nuclei, and prominent nucleoli. Although glassy cell carcinoma has been classified as a variant of ASC according to World Health Organization classification, most previous studies did not clarify the inclusion of glassy cell carcinoma to ASC. Future studies should endeavor to be specific regarding the exact inclusion criteria being used.
In conclusion, we found that patients with early-stage ASC of the cervix may have worse survival outcomes than those with AC. The current management for ASC is virtually the same as that for AC or SCC. As such, the findings of this study suggest that a new strategy is warranted for the treatment of ASC. Further large-scale studies using multicenter databases or national cancer registries are required to confirm our results. Importantly, only a limited number of studies have been performed using data from after CCRT was accepted as a standard treatment option, meaning that the prognostic significance of ASC should be determined in using data from the CCRT era.
1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011; 61: 69–90.
2. 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.
3. Bray F, Carstensen B, Møller H, et al. Incidence trends of adenocarcinoma of the cervix in 13 European countries. Cancer Epidemiol Biomarkers Prev. 2005; 14: 2191–2199.
4. Sasieni P, Castanon A, Cuzick J. Screening and adenocarcinoma of the cervix. Int J Cancer. 2009; 125: 525–529.
5. Castellsagué X, Díaz M, de Sanjosé S, et al. Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors: implications for screening and prevention. J Natl Cancer Inst. 2006; 98: 303–315.
7. Kato T, Watari H, Takeda M, et al. Multivariate prognostic analysis of adenocarcinoma of the uterine cervix treated with radical hysterectomy and systematic lymphadenectomy. J Gynecol Oncol. 2013; 24: 222–228.
8. 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.
9. 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.
10. Nakanishi T, Ishikawa H, Suzuki Y, et al. A comparison of prognoses of pathologic stage Ib adenocarcinoma and squamous cell carcinoma of the uterine cervix. Gynecol Oncol. 2000; 79: 289–293.
11. Landoni F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet. 1997; 350: 535–540.
12. Farley JH, Hickey KW, Carlson JW, et al. Adenosquamous histology predicts a poor outcome for patients with advanced-stage, but not early-stage, cervical carcinoma. Cancer. 2003; 97: 2196–2202.
13. Gallup DG, Harper RH, Stock RJ. Poor prognosis in patients with adenosquamous cell carcinoma of the cervix. Obstet Gynecol. 1985; 65: 416–422.
14. Lea JS, Coleman RL, Garner EO, et al. Adenosquamous histology predicts poor outcome in low-risk stage IB1 cervical adenocarcinoma. Gynecol Oncol. 2003; 91: 558–562.
15. Look KY, Brunetto VL, Clarke-Pearson DL, et al. An analysis of cell type in patients with surgically staged stage IB carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 1996; 63: 304–311.
16. Korhonen MO. Adenocarcinoma of the uterine cervix. Prognosis and prognostic significance of histology. Cancer. 1984; 53: 1760–1763.
17. Hopkins MP, Schmidt RW, Roberts JA, et al. Gland cell carcinoma (adenocarcinoma) of the cervix. Obstet Gynecol. 1988; 72: 789–795.
18. Kilgore LC, Soong SJ, Gore H, et al. Analysis of prognostic features in adenocarcinoma of the cervix. Gynecol Oncol. 1988; 31: 137–153.
19. Angel C, DuBeshter B, Lin JY. Clinical presentation and management of stage I cervical adenocarcinoma: a 25 year experience. Gynecol Oncol. 1992; 44: 71–78.
20. Harrison TA, Sevin BU, Koechli O, et al. Adenosquamous carcinoma of the cervix: prognosis in early stage disease treated by radical hysterectomy. Gynecol Oncol. 1993; 50: 310–315.
21. Helm CW, Kinney WK, Keeney G, et al. A matched study of surgically treated stage IB adenosquamous carcinoma and adenocarcinoma of the uterine cervix. Int J Gynecol Cancer. 1993; 3: 245–249.
22. Shingleton HM, Bell MC, Fremgen A, et al. Is there really a difference in survival of women with squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma of the cervix? Cancer. 1995; 76: 1948–1955.
23. Yasuda S, Kojima A, Maeno Y, et al. Poor prognosis of patients with stage Ib1 adenosquamous cell carcinoma of the uterine cervix with pelvic lymphnode metastasis. Kobe J Med Sci. 2006; 52: 9–15.
24. dos Reis R, Frumovitz M, Milam MR, et al. Adenosquamous carcinoma versus adenocarcinoma in early-stage cervical cancer patients undergoing radical hysterectomy: an outcomes analysis. Gynecol Oncol. 2007; 107: 458–463.
25. Meng YH, Li S, Hu T, et al. Clinical analysis of 132 cases of cervical adenosquamous carcinoma and cervical adenocarcinoma. Chin J Cancer. 2010; 29: 15–19.
26. Rudtanasudjatum K, Charoenkwan K, Khunamornpong S, et al. Impact of histology on prognosis of patients with early-stage cervical cancer treated with radical surgery. Int J Gynaecol Obstet. 2011; 115: 183–187.
27. Chen JL, Cheng JC, Kuo SH, et al. Outcome analysis of cervical adenosquamous carcinoma compared with adenocarcinoma. Acta Obstet Gynecol Scand. 2012; 91: 1158–1166.
28. Mabuchi S, Okazawa M, Kinose Y, et al. Comparison of the prognoses of FIGO stage I to stage II adenosquamous carcinoma and adenocarcinoma of the uterine cervix treated with radical hysterectomy. Int J Gynecol Cancer. 2012; 22: 1389–1397.
29. Tierney JF, Stewart LA, Ghersi D, et al. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007; 8: 16.
30. Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med. 1997; 127: 820–826.
31. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21: 1539–1558.
32. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315: 629–634.
33. Pekin T, Kavak Z, Yildizhan B, et al. Prognosis and treatment of primary adenocarcinoma and adenosquamous cell carcinoma of the uterine cervix. Eur J Gynaecol Oncol. 2001; 22: 160–163.
34. Flores-Luna L, Salazar-Martinez E, Escudero-De los Rios P, et al. Prognostic factors related to cervical cancer survival in Mexican women. Int J Gynaecol Obstet. 2001; 75: 33–42.
35. 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.
0. For the complete list of references, please contact Jae-Weon Kim, MD. Email: firstname.lastname@example.org.