ADENOCARCINOMA OF THE CERVIX    DiSaia: Clinical Gynecologic Oncology, 6th ed., 2002

Approximately 85%–90% of cervical cancers are squamous cell, and most of the remaining 10%–15% are adenocarcinomas. There appears to be an increase in the frequency of cervical adenocarcinomas, but this may be a result of the decrease in the incidence of invasive squamous cell lesions. Adenocarcinoma arises from the endocervical mucous-producing gland cells; and because of its origin within the cervix, it may be present for a considerable time before it becomes clinically evident. These lesions are characteristically bulky neoplasms that expand the cervical canal and create the so-called barrel-shaped lesions of the cervix. The spread pattern of these lesions is similar to that of squamous cell cancer, with direct extension accompanied by metastases to regional pelvic nodes as the primary routes of dissemination. Local recurrence is more common in these lesions, and this has resulted in the commonly held belief that they are more radioresistant than are their squamous counterpart. It seems more likely, however, that the bulky, expansive nature of these endocervical lesions, rather than a differential in radiosensitivity, accounts for the local recurrence. This problem has led many oncologists to advocate combined radiotherapy and surgery for optimal control of the central lesion.

Although debated as an entity, the term microinvasive adenocarcinoma of the cervix is appearing more frequently in the literature. Authors are reporting their experience using the 1994 FIGO definition of stage Ia cervical cancer. Kaku and associates reported 30 patients who had <5 mm invasion (21 with <3 mm), but 15 had horizontal spread >7 mm. None of the patients with <3 mm stromal invasion recurred. Östör and colleagues, in the largest and most extensive review, identified 77 women with <5 mm invasion. None of the 48 who had pelvic node dissection or the 23 in whom 1 or both adnexa were removed had metastasis. Twenty patients did have >7 mm horizontal spread, and LSI was present in only 7; 4, however, had <3 mm invasion. None of the 24 hysterectomy specimens showed residual disease if conization margins were free. There were two recurrences, but both were in women with >7 mm horizontal spread. Schorze and associates reported 21 patients with stage Ia1 adenocarcinoma of the cervix. None of the patients had LSI. No lymph node metastasis was noted in 16 patients, and none of the 21 patients experienced a recurrence.

Two debatable issues continue with regard to adenocarcinoma of the cervix. Does this cell type carry a worse prognosis than squamous or adenosquamous cell types? For early stage disease, which therapy (radical surgery or radiation) is superior or is there a place for combined treatment? Most studies suggest no difference in survival when adenocarcinomas are compared to squamous carcinomas after correction for stage. The 1998 FIGO Annual Report, which reported >10,000 squamous carcinomas and 1138 adenocarcinomas using multivariant analysis, noted no difference in survival in stage I cancers.

In a study by Chen and associates of 302 adenocarcinomas, it was noted that in early stages, multivariant analysis noted better survival in patients treated with radical surgery compared with those treated with radiation therapy.

Kjorstad and Bond investigated the metastatic potential and patterns of dissemination in 150 patients with stage Ib adenocarcinoma of the cervix treated from 1956–1977. All cases were treated with a combination of intracavitary radium followed by radical hysterectomy with pelvic lymph node dissection. The incidence of pelvic metastases and distant recurrences and the survival rates were the same as those given in previously published reports for squamous cell carcinoma treated in the same manner. In one respect, the adenocarcinomas showed a significant difference from the squamous cell cancers. The incidence of residual tumor in the hysterectomy specimens after intracavitary treatment was much higher (30% vs 11%). Kjorstad and Bond considered that this was a strong argument for surgical treatment of patients with early stages of adenocarcinoma of the cervix.

Berek and colleagues reported on 100 patients with primary adenocarcinoma of the uterine cervix. Of 48 stage I patients, 13 were treated with radical surgery, 16 with radiation alone, and 19 with combination therapy. Analysis of stage I patients by Berek and colleagues showed no significant difference in survival compared with those treated with radical surgery or combination therapy. However, both of these groups had >5-year survival (P > .05) than those treated with radiation alone. A higher tumor grade was associated with poorer survival for each stage regardless of treatment. More complications were associated with radiation therapy than with radical therapy. Radiation therapy alone did not appear to be sufficient therapy for patients with stage I or stage II disease.

Moberg and colleagues reported on 251 patients at Radiumhemmet in Stockholm with adenocarcinoma of the uterine cervix. The 5-year survival rate was compared with that in the total of cervical epithelial malignancies, and the rate was lower in the adenocarcinoma cases, with respective crude 5-year survival rates of 84%, 50%, and 9% in stages I, II, and III. Combined treatment consisting of two intracavitary radium treatments with an interval of 3 weeks followed by a radical hysterectomy with pelvic lymphadenectomy done within 3 months gave improved 5-year survival in a nonrandomized series. Prempree and colleagues also suggested combined therapy for stage II lesions or for those >4 cm.

A large series of 367 cases of adenocarcinoma of the cervix was reported by Eifel and associates. Their conclusions were that the central control of adenocarcinomas with radiation therapy is comparable to that achieved for squamous cell carcinomas of comparable bulk. They found no evidence that combined treatment (radiation therapy plus hysterectomy) improved local regional control or survival. In their study, radiation therapy alone was as effective a treatment for most patients with stage I disease. They noted, as others have, that patients with bulky stage I (>6 cm), stage II, or stage III disease, particularly with poorly differentiated lesions or evidence of nodal spread, had a very high rate of extrapelvic disease spread.

Eifel reported the results of 160 patients with adenocarcinoma of the cervix. Of those patients, 84 were treated with radiation therapy alone; 20 were treated with external and intracavitary radiation followed by hysterectomy; and 56 were treated with radical hysterectomy. Survival was strongly correlated with tumor size and grade. There was a 90% survival rate for lesions <3 cm. After 5 years, 45% of the patients treated with radical hysterectomy had a recurrence. These recurrences were strongly correlated with lymph/vascular space invasion and poorly differentiated lesions, as well as larger tumor size.

Chen and associates from Taiwan reviewed 3678 cases of cervical cancer treated between 1977 and 1994 of which 302 (8.5%) were adenocarcinoma. A higher proportion of cases with adenocarcinoma were of the lower stages and in the younger patient even within a given stage. Survival was better in all stages in patients with squamous compared with adenocarcinoma (81% vs 76% in stage I, P = .0039). When surgery was primary therapy, there was no difference in survival in stage I (83% vs 80.3% survival of squamous and adenocarcinoma, respectively). Survival with radiation therapy noted 71% vs 49%, respectively (P = .0039), in stage I. Survival decreased as age increased within a given stage.

The Anderson group compared 1538 patients with squamous cell carcinoma with 229 adenocarcinoma patients, all stage IB who were treated with radiation. In patients with ≥4 cm tumors, multivariant analysis confirmed that those patients with adenocarcinoma had a significantly poorer survival than did those with squamous carcinoma (59% vs 73%). In a study by the GOG, 813 stage Ia2 and Ib cancers were evaluated. All were treated with radical hysterectomy. There were 645 squamous, 104 adenocarcinoma, and 64 adenosquamous cancers. Radiation was given postoperatively to 16% squamous, 13% adenocarcinomas, and 20% of adenosquamous patients. After adjusting for multiple risk factors, survival was worst for adenosquamous cancer compared with squamous and adenocarcinoma (71.8%, 82.1%, 88%, respectively). A similar finding was noted in a study from Taiwan in which 134 stage IB or II cervical adenocarcinomas or adenosquamous cancers were compared with 757 similarly staged squamous carcinomas treated with radical hysterectomy. The overall survival was 72.2% for the former compared with 81.2% for the squamous cancers. The histology was an independent prognostic factor for recurrence-free survival and overall survival.
Adenocarcinoma of uterine cervix -- prognostic significance of clinicopathologic parameters.

Nola M,  Croat Med J. 2005 Jun;46(3):397-403.

Department of Pathology, Zagreb Croatia

The 5-year survival for this group of patients was 75%. The following parameters proved to be statistically significant in a univariate analysis: clinical stage (P=0.042), architectural grade (P=0.009), and nuclear grade (P=0.002). In the multivariate analysis, the nuclear grade (P=0.007) turned out to be the only statistically significant parameter. According to the nuclear grade, the five-year survival was 80% in the prognostically favorable and only 30% in the unfavorable group of patients. CONCLUSION: Our data showed that in patients with adenocarcinoma of the uterine cervix the nuclear grade, clinical stage, and architectural grade of the tumor represent the most important prognostic parameters. The analysis of DNA ploidy and proliferative activity had no prognostic significance.

Stage I adenocarcinoma of the cervix: does lesion size affect treatment options and prognosis?

Silver DF,  Am J Clin Oncol. 1998 Oct;21(5):431-5.

Department of Gynecologic Oncology, The Roswell Park Cancer Institute, Buffalo

A retrospective analysis of 93 patients with International Federation of Gynecology and Obstetrics stage I adenocarcinoma of the cervix was performed to determine the significance of tumor size, patient age, tumor grade, lymph node status, and primary treatment modality as prognostic variables of 5-year survival and 5-year progression-free survival (PFS). Multivariate analysis demonstrated that patient age and tumor grade were significant variables prognostic of survival (p < 0.01 and p = 0.01, respectively). Tumor size was a significant (p < 0.01) prognostic variable of PFS in a multivariate model that included tumor size and patient age. An important advantage in survival and PFS for patients with lesions smaller than 3 cm compared with those patients with lesions 3 cm or more was observed (92% vs. 76% and 89% vs. 67%, respectively). Among surgically treated patients, survival and PFS among patients with lesions smaller than 3 cm were significantly improved compared with patients with tumors 3 cm or more (97% vs. 77% [p = 0.03] and 90% vs. 69% [p = 0.03], respectively). Significant improvement in survival and PFS was observed among patients with lesions smaller than 3 cm who were treated with surgery compared with those who received radiation therapy (97% vs. 77% [p = 0.03] and 90% vs. 77% [p = 0.048], respectively).

Adenocarcinoma of the uterine cervix. Prognosis and patterns of failure in 367 cases.

Eifel PJ,  Cancer. 1990 Jun 1;65(11):2507-14.

Division of Radiotherapy, University of Texas M. D. Anderson Cancer Center, Houston.

Between 1965 and 1985, 367 patients received initial treatment for adenocarcinoma of the uterine cervix at the M. D. Anderson Cancer Center (MDACC). Of the 334 patients treated with curative intent, 223 had International Federation of Gynecology and Obstetrics (FIGO) Stage I, 60 had Stage II, and 51 had Stage III/IV disease. The 5-year and 10-year relapse-free survival (RFS) rates for all patients treated for Stage I disease were 73% and 70%, respectively. RFS was strongly correlated with initial bulk of disease (P = 0.002), although locoregional control (LRC) was good in all groups: 91 patients with a normal-sized cervix (tumor less than 3 cm) had a 5-year RFS rate of 88% and an actuarial LRC rate of 94%; 102 patients with lesions 3 to 5.9 cm in diameter had an RFS rate of 64% and an LRC rate of 82%; and 22 patients with bulky lesions greater than 6 cm in diameter had a comparable LRC rate of 81%, but an RFS rate of only 45%. Decreased RFS also was strongly correlated with positive lymphangiogram (LAG) results (P = 0.02) and poorly differentiated lesions (P = 0.0014). When initial primary tumor size was taken into account, there was no significant difference in RFS or LRC between patients treated with radiation (RT) alone or RT plus extrafascial hysterectomy (R + S). The 5-year and 10-year RFS rates of 60 patients who received curative therapy for Stage II disease were 32% and 25%, respectively, with an LRC rate of 62% at 5 years. Patients with bulky Stage II disease did particularly poorly, with a 5-year RFS rate of 15%. Decreased RFS was correlated with positive LAG results and poorly differentiated tumors. Most Stage II patients whose disease relapsed died with distant metastases (73%). Forty-eight patients with Stage III/IV disease treated with curative intent had a 5-year survival rate of 31% and a 5-year pelvic disease control rate of 52%. In summary, patients with small volume Stage IB lesions have excellent LRC and survival with RT alone. RT achieves good LRC of bulkier Stage I lesions, but survival decreases with increasing primary tumor size. R + S holds no apparent advantage over RT alone. Patients with more advanced disease have a high rate of relapse with frequent distant metastasis. In particular, the survival of patients with FIGO Stage II disease is much lower than what we have observed after treatment of comparable stage squamous carcinoma.

Histologic subtype has minor importance for overall survival in patients with adenocarcinoma of the uterine cervix: a population-based study of prognostic factors in 505 patients with nonsquamous cell carcinomas of the cervix.

Alfsen GC, Cancer. 2001 Nov 1;92(9):2471-83.

Department of Pathology, The Norwegian Radium Hospital, N-0310 Oslo, Norway.

BACKGROUND: The incidence of adenocarcinoma of the uterine cervix is increasing. For better prognostic information, the authors studied all nonsquamous cell carcinomas (non-SCCs) in the Norwegian population over a total of 15 years. METHODS: All non-SCCs from three 5-year periods (1966-1970, 1976-1980, and 1986-1990) were reviewed and classified according to the World Health Organization classification system, and histopathologic and clinical parameters were registered. Tissue blocks were available from all patients. RESULTS: Of 505 patients, 417 had tumors classified as adenocarcinoma, and 88 had tumors classified as other non-SCC. The mean ages were 53 years and 52 years for patients with adenocarcinoma and non-SCC, respectively. Sixty-two percent of the staged patients had clinical Stage I disease according to the classification system of the International Federation of Gynecology and Obstetrics (FIGO). In univariate analyses, histology, architectural and nuclear grade, extension to the vagina or corpus uteri, tumor length (> 20 mm) or tumor volume (> 3000 mm(3)), infiltration depth (in thirds of the cervical wall), thickness of the remaining wall (< 3 mm), vascular invasion, lymph node metastases, treatment, and patient age were significant variables in patients with FIGO Stage I disease. Variables with no significance in patients with Stage I disease were number of mitoses, state of resection margins, infiltration to ectocervix, tumor thickness, lymphoid reaction, earlier or concomitant cervical intraepithelial neoplasia, stump carcinoma, DNA ploidy or DNA index, or time period. Multivariate analyses of patients with FIGO Stage I disease identified small cell carcinoma, corpus infiltration, vascular invasion, and positive lymph nodes as independent prognostic factors.   CONCLUSIONS: Small cell carcinoma was the only histologic subgroup of independent importance for prognosis in patients with non-SCC of the uterine cervix. No significant difference between major subtypes of adenocarcinoma favored a simplified classification. Extension to the corpus in patients with early-stage disease was of independent significance and should be acknowledged in planning treatment.

Is there really a difference in survival of women with squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma of the cervix?

Shingleton HM,  Cancer. 1995 Nov 15;76(10 Suppl):1948-55.

Emory University, Atlanta, Georgia, USA.

The authors' aim was to assess whether there is a difference in biologic behavior and survival in comparing adenocarcinoma (AdCA), squamous cell carcinoma (SCC), and adenosquamous carcinoma (Ad/SC) of the cervix. METHODS. Cancer registrars at 703 hospitals submitted anonymous data on 11,157 patients with cervical cancer diagnosed and/or treated in 1984 and 1990 for a Patient Care Evaluation Study of the American College of Surgeons. Among these patients, 9351 (83.8%) had SCC; 1405 (12.6%), AdCA; and 401 (3.6%), Ad/SC cancers. There were no significant changes in percentages of the different histologic types between the study years 1984 and 1990, nor was the patient distribution different regarding age, race/ethnicity, and socioeconomic background for each histologic group. Furthermore, the distribution of patients who had had a hysterectomy did not change between 1984 and 1990. RESULTS. A larger percent of patients with SCC (63.8%) than those with Ad/SC (59.8%) or AdCA (50.2%) had tumors larger than 3 cm at greatest dimension. Early stage patients (IA, IB, IIA) often were treated by hysterectomy alone (45.5%) or combined with radiation (21.1%). The remaining patients (21.9%) received radiation alone. Of the patients with clinical stage I disease, 7.6% of Ad/CA patients, 15.5% of Ad/SC patients and 12.6% of SCC patients had positive nodes. Although patients with SCC had higher survival rates for all four clinical stages (I-IV), the differences were only significant for Stage II patients. Patients with clinical stage IB SCC and AdCA treated by surgery alone were found to have significantly better survival rates (93.1% and 94.6% at 5 years, respectively) than women treated by either radiation alone or a combination of surgery and radiation (P < 0.001, both histologic comparisons). For women with Ad/SC tumors, however, the 5-year survival rate was 87.3% for those receiving combined treatment compared with those receiving surgery alone (69.2%) or radiation alone (79.2%). However, these survival curves were not significantly different (P = 0.496). One hundred six patients with positive nodes were available for analysis. The 5-year survival rate of patients with SCC and positive nodes was 76.1%. Surprisingly, patients with Ad/SC and positive nodes had the highest 5-year survival rate (85.7%), whereas, women with AdCA and positive nodes had a sharply reduced 5-year survival rate (33.3%). The curves were significantly different (P < 0.01). For patients with clinical stage I, the risk factors for age, tumor size, nodal status, histologic features, and treatment were analyzed with Cox's multivariate regression. In this analysis, subset IB, greater tumor size, age 80 or older, and positive nodal status were each independently significant for poorer survival. Patients who were treated by surgery alone had a significantly better survival than patients who had other types of treatment or no treatment. Histologic characteristics had no significant effect on survival. In the analysis of patients with pathologic stage I disease, those with SCC had significantly poorer survival and those with Ad/SC had significantly better survival than patients with Ad/CA. Positive nodes had no significant independent effect on survival. In another analysis, tissue type was not found to be an important factor in recurrence time. CONCLUSIONS: 1. Ad/CA and Ad/SC tumors were found to represent 12.6% and 3.6%, respectively, of a large series (N = 11,157) of cervical cancers diagnosed in 1984 and 1990 and reported to the Commission on Cancer of the American College of Surgeons. 2. Two thirds of women with early clinical stage disease (IA, IB, IIA) had hysterectomy as all or part of their primary therapy. 3. No significant differences were found in 5-year survival among the three tissue types in any clinical stage except American Joint Committee on Cancer stage II.

Obesity as a potential risk factor for adenocarcinomas and squamous cell carcinomas of the uterine cervix
James V. Lacey Jr
Cancer 2003;98:814-21.

Hormonal factors may play a more prominent role in cervical adenocarcinoma than squamous cell carcinoma. The authors evaluated whether obesity, which can influence hormone levels, was associated with adenocarcinoma and squamous cell carcinoma. This case-control study included 124 patients with adenocarcinoma, 139 matched patients with squamous cell carcinoma, and 307 matched community control participants. All participants completed interviews and provided cervicovaginal samples for human papillomavirus (HPV) testing.

Height, weight, BMI, and WHR were positively associated with adenocarcinoma. BMI 30 kg/m2 (vs. BMI < 25 kg/m2; OR, 2.1 and 95% CI, 1.1-3.8) and WHR in the highest tertile (vs. the lowest tertile; OR, 1.8 and 95% CI, 0.97-3.3) were associated with adenocarcinoma. Neither height nor weight was found to be associated with squamous cell carcinoma, and associations for BMI 30 kg/m2 (OR, 1.6) and WHR in the highest tertile (OR, 1.6) were weaker and were not statistically significant. Analyses using only HPV positive controls showed similar associations. The data were adjusted for and stratified by screening, but higher BMI and WHR were associated with higher disease stage at diagnosis, even among recently and frequently screened patients with adenocarcinoma. Thus, residual confounding by screening could not be excluded as an explanation for the associations.

Obesity and body fat distribution were associated more strongly with adenocarcinoma than with squamous cell carcinoma. Although questions about screening remain, obesity may have a particular influence on the risk of glandular cervical carcinoma.

The Rising Incidence of Adenocarcinoma Relative to Squamous Cell Carcinoma of the Uterine Cervix in the United States—A 24-Year Population-Based Study

Harriet O. Smith M.D.Gynecologic Oncology  Volume 78, Issue 2 , August 2000, Pages 97-105

The aim of this study was to compare the age adjusted incidence and survival for invasive adenocarcinoma and squamous cell carcinoma of the uterine cervix using population-based data. The SEER database was used to identify all cases of cervical cancer registered between 1973 and 1996.

Results. The age-adjusted incidence rates per 100,000 for all invasive cervical cancers decreased by 36.9% over 24 years [12.35 (1973–1977) vs 7.79 (1993–1996)]. Similarly, the ag


e-adjusted incidence rates for squamous cell carcinoma declined by 41.9% [9.45 (1973–1977) vs 5.49 (1993–1996)]. In contrast, the age-adjusted incidence rates for adenocarcinoma increased by 29.1% [1.34 (1973–1977) vs 1.73 (1993–1996)]. The proportion of adenocarcinoma increased 107.4% relative to all cervical cancer, 95.2% relative to squamous cell carcinoma, and 49.3% relative to the population of women at risk [10.8% vs 22.4% (P < 0.001), 12.4% vs 24.0% (P < 0.001), and 1.40 vs 2.09 per 100,000 women (P < 0.001), respectively]. Observed survival rates for adenocarcinoma vs squamous cell carcinoma were poorer for regional (P = 0.04), but not localized or distant disease.

Conclusions. Over the past 24 years, the incidence of all cervical cancer and squamous cell carcinoma has continued to decline. However, the proportion of adenocarcinoma relative to squamous cell carcinoma and to all cervical cancers has doubled, and the rate of adenocarcinoma per population at risk has also increased. These results suggest that current screening practices in the United States are insufficient to detect a significant proportion of adenocarcinoma precursor lesions.