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Adenocarcinoma of the uterine cervix
GYNECOLOGIC
13, 335-344 (1982)
ONCOLOGY
Adenocarcinoma of the Uterine Cervix’ K. TAMIMI, M. D., AND DAVID C. FIGGE, M. D. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of HISHAM
Washington School of Medicine, Seattle, Washington 98195 Received July 28, 1981
Adenocarcinoma of the cervix represented 12.7% of all cervical carcinomas seen at the University of Washington. The mean age of 66 patients with adenocarinoma of the cervix was not significantly different from the mean age of those with squamous cell carcinoma and was 43.6 (range 15-83). Seventy-six percent of the patients were assigned to Stage I disease. Stage II disease was diagnosed in 15% and Stages III-IV represented 9%. The pathologic diagnosis included adenocarcinoma in 50 patients, adenosquamous carcinoma in 9, clear cell carcinoma in 5, and adenoid cystic carcinoma in 2. The survival rate was directly related to the stage of disease and to the presence or absence of lymph node metastasis. The recurrence rate was significantly higher in adenocarcinoma of the cervix with node metastasis when compared with a similar group of patients with squamous cell carcinoma.
INTRODUCTION The incidence of adenocarcinoma of the uterine cervix is frequently quoted as 5% of all cervical carcinomas [l-3]. Tasker and Collins [4] reported an increasing incidence of adenocarcinoma relative to squamous cell carcinoma of the cervix in Ontario, Canada. Adenocarcinoma represented 5.9% of all cervical malignancies in the period 1953-1967 and 9.5% in the period 1967-1972. Similar observations were made by other investigators [5]. Recent reports have suggested that adenocarcinoma of the cervix is perhaps related to the use of oral contraceptives [5]. It has been suggested that adenocarcinoma of the cervix is biologically different from squamous cell carcinoma, less sensitive to radiation therapy, and has a poorer prognosis. The accepted treatment of adenocarcinoma of the cervix is controversial. The modalities suggested have been radiation therapy alone, radical surgery alone, or a combination of radiation therapy and surgery, It is the purpose of this paper to present our experience in the treatment of adenocarcinoma of the cervix. ’ Presented at the 9th Annual Meeting of the Western Association of Gynecologic Oncologists, Napa, Calif., May 27-30, 1981. 335 0090-8258/82/030335-10$01.00/O Copyright 0 1982 by Academic Press. Inc. All rights of reproduction in any form reserved.
336
TAMIMI
AND
FIGGE
MATERIALS AND METHODS Between 1963 and 1979, a total of 66 patients with the diagnosis of adenocarcinoma of the cervix were treated at the University Hospital, University of Washington. Patients with adenocarcinoma in situ or endometrial carcinoma with extension to the cervix have been excluded from this study. The hospital records, pathology material, and radiation records were examined. The total of 529 patients with cervical cancer were seen in our institution between 1963 and 1979. The incidence of adenocarcinoma of the cervix was 12.7% as illustrated in Fig. 1. This incidence of adenocarcinoma was examined separately in different periods. In the cases diagnosed prior to 1970, the incidence of adenocarcinoma of the cervix was 7.7%, while the incidence of adenocarcinoma of the cervix in the periods 1970-1974 and 1975-1979 was 13.4 and 15.5%, respectively. The relative annual incidence of adenocarcinoma of the cervix during the last 10 years remained relatively constant. The age range was 15-83 years. The mean age was 43.6. The largest number of patients was in the 30-39 category. Forty-eight percent were under the age of 40 and 66% of the patients were premenopausal. The racial distribution did not differ from general patterns of hospital admission. The reproductive history was available for 60 patients. The results are outlined in Table 1. One patient was pregnant at the time of diagnosis. A positive history of oral contraceptive usage was obtained in 16 of 32 patients who were under the age of 40 at the time of diagnosis. The majority of patients had Stage I disease by the FIG0 staging system. The distribution of patients among the various stages is outlined in Table 2. The main complaint was abnormal vaginal bleeding as shown in Table 3. Vaginal discharge was the only complaint in 18% of the patients and 20% had no symptoms. These were originally suspected because of abnormal vaginal cytology or during routine pelvic examination. They were all found to have Stage I disease, except for one patient with Stage II-A disease. The histologic patterns of adenocarcinoma of the cervix are shown in Table 4. Four major patterns were identified: pure adenocarcinoma of the cervix, adenosquamous carcinoma, clear cell adenocarcinoma, and adenoid cystic carAdenocarcinoma
Squamous
1970-74:
1963-69:
20%
0'
20%
40%
60%
80%
100%
FIG. 1. Relative incidence of adenocarcinoma of the cervix. Numbers in parentheses indicate
patients with adenocarcinoma.
ADENOCARCINOMA
OF THE
TABLE
UTERINE
CERVIX
1
PARITY IN 60 PATIENTS WITH ADENOCARCINOMA THE CERVIX
Parity
No. of patients
Percentage
13 9 14 10 14
22 15 23 17 23
Nulliparous Para 1 Para 2 Para 3 Para > 3
TABLE 2 DISTRIBUTION
Stage
OF STAGES
No. of patients
Percentage
II III IV
50 10 4 2
76 15 6 3
Total
66
loo
I
TABLE 3 S~MpT0hfs
Percentage
Symptoms
No. of patients
None Bleeding Discharge Other
13 35 12 6
20 53 18 9
Total
66
loo
TABLE 4 HISTOLOGY
No. of patients
Percentage
Adenocarcinoma Well diff. Mod. diff. Poorly diff.
50 27 12 11
77
Adenosquamous Clear cell Adenoid cystic
9 5 2
13 7 3
66
100
Total
OF
337
338
TAMIMI
AND
FIGGE
cinema. No attempt was made to subclassify adenocarcinoma into various histological subtypes (i.e., endocervical, endometrioid, etc.) [6]. However, we considered the degree of differentiation in our analysis. This was classified into three subgroups: well differentiated, moderately differentiated, and poorly differentiated. Six patients had squamous cell carcinoma in situ of the cervix, coexistent with adenocarcinoma of the cervix. One patient had separate invasive squamous cell carcinoma at a different location in the cervix. Vaginal cytology was positive in 33 patients (50%). The management plan for adenocarcinoma of the cervix was rather uniform. Patients with early stages were treated by radical hysterectomy and bilateral pelvic lymphadenectomy. Advanced stages were treated by radiation therapy. A subset of patients was recognized to have a barrel-shaped cervical lesion and these were treated by a combination of radiation therapy (external radiation therapy to 5000 rad to the pelvic fields and one intracavitary implant) and simple hysterectomy. The two patients with Stage IV disease were treated palliatively. Radical hysterectomy was employed in selected patients with Stage II-A disease. The remainder of patients in Stage II and III were treated primarily by radiation therapy. RESULTS
Stage I Table 5 illustrates the treatment modalities employed in Stage I. The majority of patients were treated by radical hysterectomy and bilateral pelvic lymphadenectomy. The survival of patients is illustrated in Table 6. The survival figures do not reflect the traditionally accepted 5-year survival. The duration of followup range was 16-180 months with a mean of 58.3 months. Although the best survival results were achieved in the group treated by radical hysterectomy and bilateral pelvic lymphadenectomy and the worst results were seen in the group treated by radiation therapy only, the difference in survival is not statistically significant. The method of diagnosis seems to influence the survival rate and probably reflects the tumor size. Twenty-six patients had the diagnosis of adenocarcinoma established by a cervical cone biopsy or after simple hysterectomy for indications other than cancer (I-B occult). The survival rate was 81% in this group. The TABLE 5 STAGEI: TYPE OFTREATMENT No. of patients
Percentage
Radical hyst. + node dissection” Planned pre-op RT + TAH RT only Hyst. + post-op
34 8 6 2
68 16 12 4
Total
50
100
’ Includes two patients in whom previous radiation therapy was considered inadequate.
ADENOCARCINOMA
OF THE
UTERINE
339
CERVIX
TABLE 6 STAGE I: RESULTS OF TREATMENT
No. or patients
NED
(%I
Radical hyst. + nodes Planned pre-op RT + hyst. RT only Hyst. + post-op RT
34 8 6 2
26 5 2 1
(76.5) (62.5) (33.0) (50.0)
Total
50
34
(68)
DOD
(%I
8 3 4 I
(23.5) (37.5) (66.0) (50.0)
16
(32)
remaining 24 patients had a diagnosis established by a cervical biopsy or endocervical curettage with a survival rate of 58% (Table 7). The influence of the grade of tumor and histologic type on survival is illustrated in Table 8. The trend of improved survival rates with well-differentiated adenocarcinoma is evident. The small numbers in the other groups do not allow us to make any conclusion relative to their statistical significance. The outcome of patients with adenosquamous carcinoma is similar to those with poorly differentiated adenocarcinoma. The most significant prognostic factor was the presence of pelvic node metastasis and the presence of tumor in capillary-like spaces on the hysterectomy specimen, as shown in Table 9. The difference in survival rates is statistically significant (P < 0.001). It is important also to point out that one of the two patients with no evidence of disease had a pelvic side wall recurrence 5 years following radical hysterectomy. She was treated by radiation therapy and currently is without evidence of disease 18 months following the recurrence. The other patient has been followed for only 16 months. Two patients had capillary-like space involvement only and both are dead of disease. The overall incidence of positive pelvic node metastases in Stage I as derived from the radical hysterectomy group and the group who underwent exploration following radiation therapy was 18%, and the incidence of positive nodes and capillary-like space involvement was 22%. The incidence of node metastasis in the group of patients that required a cone biopsy for diagnosis was 9% (2/22), although among the rest of the patients this figure reached 32% (9/28). Sites of recurrence relative to the initial treatment are illustrated in Table 10. TABLE 7 STAGE I: METHOD OF DIAGNOSIS vs SURVIVAL
No. of patients
NED (So)
Cone Biopsy or hyst. Cervical biopsy, ECC
21 24
81 58
Total
50
340
TAMIMI
AND
FIGGE
TABLE 8 STAGE I: SURVIVAL RELATED TO HISTOLOGY AND DEGREE OF DIFFERENTIATION
No. of patients
NED
Adenocarcinoma Well diff. Mod. diff. Poorly diff.
40 22 12 6
27 17 7 3
Adenosquamous Clear cell Adenoid cystic
6 2 2
3 2 2
DOD
(%) (32.5) (231
(50)
13 5 5 3
(50) (100) (1W
3 0 0
(%I (67.5) (771
(58)
(42) (50) (501
TABLE 9 STAGE I: SURVIVAL FOLLOWINGRADICAL HYSTERECTOMY+ NODE DISSECTION
No. of patients
NED
(%)
DOD
cm
‘26 8
24 2
(92) (23
2 6
(75)
Negative nodes Positive nodes or C.L. space involvement
@I*
* P
TABLE 10 STAGE I: SITES OF RECURRENCEFOLLOWINGTHERAPY
Planned RT + hyst.
RT only
318
416
112
26
37.5
66
50
Site Vagina Pelvis Distant
3 3 3
1 1 1
0 2 2
1 0 0
5 6 6
Status following Recurrence NED DOD
1 8
0 3
0 4
0 1
1 16
Radical hyst No. Recurrence/ No. treated Percentage recurrence
9134
Hyst. + post-op RT
Total 17
ADENOCARCINOMA
OF THE
UTERINE
CERVIX
341
The diagnosis of recurrence was established in 17 patients (34%). The highest incidence of recurrence was seen in the group of patients treated by radiation therapy only, and the lowest incidence was in the gruop of patients treated by radical hysterectomy and node dissection. Among the patients treated only by radiation therapy, 4 out of 6 developed recurrence. Two patients had distant metastases and the other 2 developed a pelvic recurrence. The sites of recurrence in the radical hysterectomy group were equally represented. Three patients had vaginal recurrence, 3 patients had pelvic recurrence, and 3 patients had distant metastases. Except for 1 patient, all patients who developed recurrence are dead of disease despite varying treatment modalities that included total pelvic exenteration. Distant metastatic sites included liver (3 patients), brain (1 patient), lungs (1 patient), and bone (1 patient). The inveral between the initial treatment and recurrence was slightly longer in those with distant metastases (mean of 24 months) than in the group of patients who developed vaginal or pelvic recurrence (mean of 19 months). Four patients with positive pelvic nodes received 5000 rad radiation therapy to the pelvis following the radical hysterectomy; 1 patient is alive with no evidence of disease after 16 months. The remaining three patients have died of recurrent disease (pelvis, 1 patient; vulva, 1 patient; liver, 1 patient). Stage ZZ
Ten patients were diagnosed as having Stage II adenocarcinoma of the cervix. They were equally divided between Stage II-A and Stage II-B. Radical hysterectomy was employed in the treatment of 2 patients with Stage II-A and both were alive with no evidence of disease for 5 and 13 years. One patient was treated with planned preoperative radiation therapy and conservative hysterectomy and is without evidence of disease 9 years later. Six patients were treated by radiation therapy only. Three of these are dead of disease. The vagina was the site of recurrence in one and the other two recurrences were first detected in the supraclavicular nodes. One patient with Stage II-A was treated by postoperative radiation therapy following conservative hysterectomy and is alive and without evidence of disease for 3 years. All patients with Stage II-A disease are alive without evidence of disease for a period of follow-up of 18-132 months and a mean of 87.4 months. Only 2 out of 5 patients with Stage II-B disease are alive without evidence of disease for 13 years. Stage ZZZand IV
Only one out of four patients with Stage III disease is alive without evidence of disease for 16 months following radiation therapy and conservative hysterectomy. The two patients with Stage IV disease were treated palliatively and both expired shortly after admission. Survival rates according to stage are shown in the Table 11. Complications
of Therapy
Major complications of therapy were examined in relation to the type of treatment. A total of 8 patients had major complications for an incidence of 12%. Among those treated by radical surgery, two types of major complications were
342
TAMIMI
AND
FIGGE
TABLE 11 SURVIVAL
ACCORDING TO STAGE
No. of patients
NED
(%I
DOD
(%)
I
50
10 4 2
34 7 1 0
(68)
II III IV
(0)
16 3 3 2
(32) (30) (75) (100)
42
(63)
24
(36)
Stage
Total
(70)
(25)
encountered: ureterovaginal fistula (2 patients) and wound dehiscence (1 patient). Both fistulae were managed successfully by placement of ureteral stints and neither patient required major operative procedure to correct ureterovaginal fistula. The complications encountered in the radiation therapy group were: rectovaginal fistula (1 patient), enterouterine fistula (1 patient), and severe radiation cystitis (1 patient). All 3 patients required major operative procedure and multiple hospital admissions in the course of management of these complications. Two types of complications were seen in the group of patients treated by a combination of radiation therapy and surgery. These were a lymphocyst (1 patient) that required operative correction, and a ureterovaginal fistula (one patient) that required transuretero ureterostomy. DISCUSSION The incidence of 12.7% of adenocarcinoma of the cervix and the increasing incidence in the 1970s is consistent with recent reports in the literature. The finding that in the 1974-1979 period adenocarcinoma represented 15.1% of all cervical carcinomas is higher than any previous report. There is no readily available explanation. The patterns of referral to this institution could have influenced these results. Young patients that are good surgical candidates comprised the majority of patients in Stage I disease. Berkowitz ef al. [7] reported that 26% of their patients with cervical cancer under the age of 35 had adenocarcinoma. The mean age of 43.6 years is lower than previously reported in similar series. That 48% of patients were under the age of 40 is indicative of the proclivity of adenocarcinoma to occur in young age groups. The DES-related clear cell adenocarcinoma is not a major factor in this apparent increasing incidence. Five cases of clear cell adenocarcinoma of the cervix were encountered. A positive history of exposure to DES in utero was obtained in 3 patients. It is evident that the rising relative incidence of adenocarcinoma of the cervix cannot be attributed to clear cell adenocarcinoma of the cervix related to DES exposure in utero. The role of exogenous hormones is uncertain. Gallup and Abel1 [5] alluded to the possible role of oral contraceptives following their observation that 5 patients in their series were 32 years of age or less, and all had been receiving oral contraceptives for varying periods of time. Our findings relevant to the role of oral contraceptives are inconclusive. Sixteen of 32 patients under the age of
ADENOCARCINOMA
OF THE
UTERINE
CERVIX
343
40 were on oral contraceptives prior to the diagnosis of adenocarcinoma. The majority of these patients used oral contraceptives for more than 4 years. Although no definite statement can be made as to the relationship between adenocarcinoma of the cervix and oral contraceptives, further studies are necessary to clarify this issue, especially the role of prolonged use of oral contraceptives. The apparent increasing incidence of adenocarcinoma of the cervix may be relative rather than absolute. Limited and out-patient measures directed toward eradication of squamous cervical intraepithelial neoplasia are successful in eliminating precursors of invasive squamous cell carcinoma of the cervix while the endocervical epithelium is retained. The finding of 6 patients in our series with squamous cell carcinoma in situ of the cervix is evidence that both types of epithelium can independently and simultaneously undergo a neoplastic change. A similar observation was made by Grundsell et al. [8]. The incidence of lymph node metastasis and capillary-like space involvement in Stage I adenocarinoma was 22%. The impact of lymphatic spread on survival is significant. Of the 8 patients who underwent radical hysterectomy and pelvic lymphadenectomy and found to have positive nodes or CL-space involvement, 2 are alive without evidence of disease (25%), 1 is alive with no evidence of disease following radiation therapy for pelvic side wall recurrence 5 years after radical hysterectomy, and the other patient has only been followed for 16 months following initial treatment. The current materials and previous data published [9] from our institution indicate differences in biological behavior between adenocarcinoma and squamous cell carcinoma of the cervix, especially when lymph nodes are involved. The recurrence and the survival rates in the group of patients with positive pelvic nodes are dissimilar and imply a worse prognosis when seen in patients with adenocarcinoma. Furthermore, the interval between the treatment and detection of recurrence is longer in the group with adenocarcinoma. The increased incidence of distant metastases (brain, liver, and bone) in the group with adenocarcinoma is at variance with the observations in patients with squamous cell carcinoma and is in agreement with Kagan et al. (10). Radical hysterectomy and pelvic lymphadenectomy is an appropriate treatment for early stages of adenocarcinoma of the cervix (Stages I-II-A). The survival rates are similar to those previously reported. The morbidity is acceptable. Furthermore, radical surgery permits the identification of a group that is at extremely high risk for recurrence. Adjunctive therapy in the form of postoperative radiation, chemotherapy, and hormonal therapy based on estrogen and progesterone receptor content, deserves a trial among those patients with positive lymph nodes and/or capillary-like space involvement. REFERENCES 1. Mikuta, J. J., and Celebre, J. A. Adenocarcinoma of the cervix, Obstet. Gynecol. 33, 753-756 (1969). 2. Peete, C. H., Carter, F. B., Cherny, W. B., et al. Follow-up of patients with adenocarcinoma
of the cervix and cervical stump, Amer. J. Obstet. Gynecol. 93, 343-356 (1965). 3. Rutledge, F. N., Galakatos, A. E., Wharton, J. T., and Smith, J. P. Adenocarcinoma of the uterine cervix, Amer. J. Obstef. Gynecol. 122, 236-245 (1975).
344
TAMIMI
AND
FIGGE
4. Tasker, J. T., and Collins, J. A. Adenocarcinoma of the uterine cervix, Amer. J. Obster. Gynecol. 118, 344-358 (1974).
5. Gallup, D. G., and Abell, M. R. Invasive adenocarcinoma of the uterine cervix, Obster. Gynecol. 49, 596-603 (1976). 6. Hurt, W. G., Silverberg, S. G., Frable, W. J., et al. Adenocarcinoma of the cervix: Histopathologic and clinical features, Amer. J. Obster. Gynecol. 129, 304-314 (1977). 7. Berkowitz, R. S., Ehrmann, R. L., Lavizzo-Mourey, R., et al. Invasive cervical carcinoma in young women, Gynecol. Oncol. 8, 311-316 (1979). 8. Grundsell, H., Henrikson, H., Johnsson, J. E., and Trope, C. Prognosis of adenocarcinoma of the uterine cervix, Gynecol. Oncol. 8, 204-208 (1979). 9. Figge, D. C., and Tamimi, H. K. Patterns of recurrence of carcinoma following radical hysterectomy, Amer. J. Obstet. Gynecol. 140, 213-220 (1981). 10. Kagan, A. R., Nussbaum, H., Chan, P. Y. M., et al. Adenocarcinoma of the uterine cervix, Amer. J. Obstet. Gynecol. 117, 464-468 (1973).
13, 335-344 (1982)
ONCOLOGY
Adenocarcinoma of the Uterine Cervix’ K. TAMIMI, M. D., AND DAVID C. FIGGE, M. D. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of HISHAM
Washington School of Medicine, Seattle, Washington 98195 Received July 28, 1981
Adenocarcinoma of the cervix represented 12.7% of all cervical carcinomas seen at the University of Washington. The mean age of 66 patients with adenocarinoma of the cervix was not significantly different from the mean age of those with squamous cell carcinoma and was 43.6 (range 15-83). Seventy-six percent of the patients were assigned to Stage I disease. Stage II disease was diagnosed in 15% and Stages III-IV represented 9%. The pathologic diagnosis included adenocarcinoma in 50 patients, adenosquamous carcinoma in 9, clear cell carcinoma in 5, and adenoid cystic carcinoma in 2. The survival rate was directly related to the stage of disease and to the presence or absence of lymph node metastasis. The recurrence rate was significantly higher in adenocarcinoma of the cervix with node metastasis when compared with a similar group of patients with squamous cell carcinoma.
INTRODUCTION The incidence of adenocarcinoma of the uterine cervix is frequently quoted as 5% of all cervical carcinomas [l-3]. Tasker and Collins [4] reported an increasing incidence of adenocarcinoma relative to squamous cell carcinoma of the cervix in Ontario, Canada. Adenocarcinoma represented 5.9% of all cervical malignancies in the period 1953-1967 and 9.5% in the period 1967-1972. Similar observations were made by other investigators [5]. Recent reports have suggested that adenocarcinoma of the cervix is perhaps related to the use of oral contraceptives [5]. It has been suggested that adenocarcinoma of the cervix is biologically different from squamous cell carcinoma, less sensitive to radiation therapy, and has a poorer prognosis. The accepted treatment of adenocarcinoma of the cervix is controversial. The modalities suggested have been radiation therapy alone, radical surgery alone, or a combination of radiation therapy and surgery, It is the purpose of this paper to present our experience in the treatment of adenocarcinoma of the cervix. ’ Presented at the 9th Annual Meeting of the Western Association of Gynecologic Oncologists, Napa, Calif., May 27-30, 1981. 335 0090-8258/82/030335-10$01.00/O Copyright 0 1982 by Academic Press. Inc. All rights of reproduction in any form reserved.
336
TAMIMI
AND
FIGGE
MATERIALS AND METHODS Between 1963 and 1979, a total of 66 patients with the diagnosis of adenocarcinoma of the cervix were treated at the University Hospital, University of Washington. Patients with adenocarcinoma in situ or endometrial carcinoma with extension to the cervix have been excluded from this study. The hospital records, pathology material, and radiation records were examined. The total of 529 patients with cervical cancer were seen in our institution between 1963 and 1979. The incidence of adenocarcinoma of the cervix was 12.7% as illustrated in Fig. 1. This incidence of adenocarcinoma was examined separately in different periods. In the cases diagnosed prior to 1970, the incidence of adenocarcinoma of the cervix was 7.7%, while the incidence of adenocarcinoma of the cervix in the periods 1970-1974 and 1975-1979 was 13.4 and 15.5%, respectively. The relative annual incidence of adenocarcinoma of the cervix during the last 10 years remained relatively constant. The age range was 15-83 years. The mean age was 43.6. The largest number of patients was in the 30-39 category. Forty-eight percent were under the age of 40 and 66% of the patients were premenopausal. The racial distribution did not differ from general patterns of hospital admission. The reproductive history was available for 60 patients. The results are outlined in Table 1. One patient was pregnant at the time of diagnosis. A positive history of oral contraceptive usage was obtained in 16 of 32 patients who were under the age of 40 at the time of diagnosis. The majority of patients had Stage I disease by the FIG0 staging system. The distribution of patients among the various stages is outlined in Table 2. The main complaint was abnormal vaginal bleeding as shown in Table 3. Vaginal discharge was the only complaint in 18% of the patients and 20% had no symptoms. These were originally suspected because of abnormal vaginal cytology or during routine pelvic examination. They were all found to have Stage I disease, except for one patient with Stage II-A disease. The histologic patterns of adenocarcinoma of the cervix are shown in Table 4. Four major patterns were identified: pure adenocarcinoma of the cervix, adenosquamous carcinoma, clear cell adenocarcinoma, and adenoid cystic carAdenocarcinoma
Squamous
1970-74:
1963-69:
20%
0'
20%
40%
60%
80%
100%
FIG. 1. Relative incidence of adenocarcinoma of the cervix. Numbers in parentheses indicate
patients with adenocarcinoma.
ADENOCARCINOMA
OF THE
TABLE
UTERINE
CERVIX
1
PARITY IN 60 PATIENTS WITH ADENOCARCINOMA THE CERVIX
Parity
No. of patients
Percentage
13 9 14 10 14
22 15 23 17 23
Nulliparous Para 1 Para 2 Para 3 Para > 3
TABLE 2 DISTRIBUTION
Stage
OF STAGES
No. of patients
Percentage
II III IV
50 10 4 2
76 15 6 3
Total
66
loo
I
TABLE 3 S~MpT0hfs
Percentage
Symptoms
No. of patients
None Bleeding Discharge Other
13 35 12 6
20 53 18 9
Total
66
loo
TABLE 4 HISTOLOGY
No. of patients
Percentage
Adenocarcinoma Well diff. Mod. diff. Poorly diff.
50 27 12 11
77
Adenosquamous Clear cell Adenoid cystic
9 5 2
13 7 3
66
100
Total
OF
337
338
TAMIMI
AND
FIGGE
cinema. No attempt was made to subclassify adenocarcinoma into various histological subtypes (i.e., endocervical, endometrioid, etc.) [6]. However, we considered the degree of differentiation in our analysis. This was classified into three subgroups: well differentiated, moderately differentiated, and poorly differentiated. Six patients had squamous cell carcinoma in situ of the cervix, coexistent with adenocarcinoma of the cervix. One patient had separate invasive squamous cell carcinoma at a different location in the cervix. Vaginal cytology was positive in 33 patients (50%). The management plan for adenocarcinoma of the cervix was rather uniform. Patients with early stages were treated by radical hysterectomy and bilateral pelvic lymphadenectomy. Advanced stages were treated by radiation therapy. A subset of patients was recognized to have a barrel-shaped cervical lesion and these were treated by a combination of radiation therapy (external radiation therapy to 5000 rad to the pelvic fields and one intracavitary implant) and simple hysterectomy. The two patients with Stage IV disease were treated palliatively. Radical hysterectomy was employed in selected patients with Stage II-A disease. The remainder of patients in Stage II and III were treated primarily by radiation therapy. RESULTS
Stage I Table 5 illustrates the treatment modalities employed in Stage I. The majority of patients were treated by radical hysterectomy and bilateral pelvic lymphadenectomy. The survival of patients is illustrated in Table 6. The survival figures do not reflect the traditionally accepted 5-year survival. The duration of followup range was 16-180 months with a mean of 58.3 months. Although the best survival results were achieved in the group treated by radical hysterectomy and bilateral pelvic lymphadenectomy and the worst results were seen in the group treated by radiation therapy only, the difference in survival is not statistically significant. The method of diagnosis seems to influence the survival rate and probably reflects the tumor size. Twenty-six patients had the diagnosis of adenocarcinoma established by a cervical cone biopsy or after simple hysterectomy for indications other than cancer (I-B occult). The survival rate was 81% in this group. The TABLE 5 STAGEI: TYPE OFTREATMENT No. of patients
Percentage
Radical hyst. + node dissection” Planned pre-op RT + TAH RT only Hyst. + post-op
34 8 6 2
68 16 12 4
Total
50
100
’ Includes two patients in whom previous radiation therapy was considered inadequate.
ADENOCARCINOMA
OF THE
UTERINE
339
CERVIX
TABLE 6 STAGE I: RESULTS OF TREATMENT
No. or patients
NED
(%I
Radical hyst. + nodes Planned pre-op RT + hyst. RT only Hyst. + post-op RT
34 8 6 2
26 5 2 1
(76.5) (62.5) (33.0) (50.0)
Total
50
34
(68)
DOD
(%I
8 3 4 I
(23.5) (37.5) (66.0) (50.0)
16
(32)
remaining 24 patients had a diagnosis established by a cervical biopsy or endocervical curettage with a survival rate of 58% (Table 7). The influence of the grade of tumor and histologic type on survival is illustrated in Table 8. The trend of improved survival rates with well-differentiated adenocarcinoma is evident. The small numbers in the other groups do not allow us to make any conclusion relative to their statistical significance. The outcome of patients with adenosquamous carcinoma is similar to those with poorly differentiated adenocarcinoma. The most significant prognostic factor was the presence of pelvic node metastasis and the presence of tumor in capillary-like spaces on the hysterectomy specimen, as shown in Table 9. The difference in survival rates is statistically significant (P < 0.001). It is important also to point out that one of the two patients with no evidence of disease had a pelvic side wall recurrence 5 years following radical hysterectomy. She was treated by radiation therapy and currently is without evidence of disease 18 months following the recurrence. The other patient has been followed for only 16 months. Two patients had capillary-like space involvement only and both are dead of disease. The overall incidence of positive pelvic node metastases in Stage I as derived from the radical hysterectomy group and the group who underwent exploration following radiation therapy was 18%, and the incidence of positive nodes and capillary-like space involvement was 22%. The incidence of node metastasis in the group of patients that required a cone biopsy for diagnosis was 9% (2/22), although among the rest of the patients this figure reached 32% (9/28). Sites of recurrence relative to the initial treatment are illustrated in Table 10. TABLE 7 STAGE I: METHOD OF DIAGNOSIS vs SURVIVAL
No. of patients
NED (So)
Cone Biopsy or hyst. Cervical biopsy, ECC
21 24
81 58
Total
50
340
TAMIMI
AND
FIGGE
TABLE 8 STAGE I: SURVIVAL RELATED TO HISTOLOGY AND DEGREE OF DIFFERENTIATION
No. of patients
NED
Adenocarcinoma Well diff. Mod. diff. Poorly diff.
40 22 12 6
27 17 7 3
Adenosquamous Clear cell Adenoid cystic
6 2 2
3 2 2
DOD
(%) (32.5) (231
(50)
13 5 5 3
(50) (100) (1W
3 0 0
(%I (67.5) (771
(58)
(42) (50) (501
TABLE 9 STAGE I: SURVIVAL FOLLOWINGRADICAL HYSTERECTOMY+ NODE DISSECTION
No. of patients
NED
(%)
DOD
cm
‘26 8
24 2
(92) (23
2 6
(75)
Negative nodes Positive nodes or C.L. space involvement
@I*
* P
TABLE 10 STAGE I: SITES OF RECURRENCEFOLLOWINGTHERAPY
Planned RT + hyst.
RT only
318
416
112
26
37.5
66
50
Site Vagina Pelvis Distant
3 3 3
1 1 1
0 2 2
1 0 0
5 6 6
Status following Recurrence NED DOD
1 8
0 3
0 4
0 1
1 16
Radical hyst No. Recurrence/ No. treated Percentage recurrence
9134
Hyst. + post-op RT
Total 17
ADENOCARCINOMA
OF THE
UTERINE
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The diagnosis of recurrence was established in 17 patients (34%). The highest incidence of recurrence was seen in the group of patients treated by radiation therapy only, and the lowest incidence was in the gruop of patients treated by radical hysterectomy and node dissection. Among the patients treated only by radiation therapy, 4 out of 6 developed recurrence. Two patients had distant metastases and the other 2 developed a pelvic recurrence. The sites of recurrence in the radical hysterectomy group were equally represented. Three patients had vaginal recurrence, 3 patients had pelvic recurrence, and 3 patients had distant metastases. Except for 1 patient, all patients who developed recurrence are dead of disease despite varying treatment modalities that included total pelvic exenteration. Distant metastatic sites included liver (3 patients), brain (1 patient), lungs (1 patient), and bone (1 patient). The inveral between the initial treatment and recurrence was slightly longer in those with distant metastases (mean of 24 months) than in the group of patients who developed vaginal or pelvic recurrence (mean of 19 months). Four patients with positive pelvic nodes received 5000 rad radiation therapy to the pelvis following the radical hysterectomy; 1 patient is alive with no evidence of disease after 16 months. The remaining three patients have died of recurrent disease (pelvis, 1 patient; vulva, 1 patient; liver, 1 patient). Stage ZZ
Ten patients were diagnosed as having Stage II adenocarcinoma of the cervix. They were equally divided between Stage II-A and Stage II-B. Radical hysterectomy was employed in the treatment of 2 patients with Stage II-A and both were alive with no evidence of disease for 5 and 13 years. One patient was treated with planned preoperative radiation therapy and conservative hysterectomy and is without evidence of disease 9 years later. Six patients were treated by radiation therapy only. Three of these are dead of disease. The vagina was the site of recurrence in one and the other two recurrences were first detected in the supraclavicular nodes. One patient with Stage II-A was treated by postoperative radiation therapy following conservative hysterectomy and is alive and without evidence of disease for 3 years. All patients with Stage II-A disease are alive without evidence of disease for a period of follow-up of 18-132 months and a mean of 87.4 months. Only 2 out of 5 patients with Stage II-B disease are alive without evidence of disease for 13 years. Stage ZZZand IV
Only one out of four patients with Stage III disease is alive without evidence of disease for 16 months following radiation therapy and conservative hysterectomy. The two patients with Stage IV disease were treated palliatively and both expired shortly after admission. Survival rates according to stage are shown in the Table 11. Complications
of Therapy
Major complications of therapy were examined in relation to the type of treatment. A total of 8 patients had major complications for an incidence of 12%. Among those treated by radical surgery, two types of major complications were
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TAMIMI
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TABLE 11 SURVIVAL
ACCORDING TO STAGE
No. of patients
NED
(%I
DOD
(%)
I
50
10 4 2
34 7 1 0
(68)
II III IV
(0)
16 3 3 2
(32) (30) (75) (100)
42
(63)
24
(36)
Stage
Total
(70)
(25)
encountered: ureterovaginal fistula (2 patients) and wound dehiscence (1 patient). Both fistulae were managed successfully by placement of ureteral stints and neither patient required major operative procedure to correct ureterovaginal fistula. The complications encountered in the radiation therapy group were: rectovaginal fistula (1 patient), enterouterine fistula (1 patient), and severe radiation cystitis (1 patient). All 3 patients required major operative procedure and multiple hospital admissions in the course of management of these complications. Two types of complications were seen in the group of patients treated by a combination of radiation therapy and surgery. These were a lymphocyst (1 patient) that required operative correction, and a ureterovaginal fistula (one patient) that required transuretero ureterostomy. DISCUSSION The incidence of 12.7% of adenocarcinoma of the cervix and the increasing incidence in the 1970s is consistent with recent reports in the literature. The finding that in the 1974-1979 period adenocarcinoma represented 15.1% of all cervical carcinomas is higher than any previous report. There is no readily available explanation. The patterns of referral to this institution could have influenced these results. Young patients that are good surgical candidates comprised the majority of patients in Stage I disease. Berkowitz ef al. [7] reported that 26% of their patients with cervical cancer under the age of 35 had adenocarcinoma. The mean age of 43.6 years is lower than previously reported in similar series. That 48% of patients were under the age of 40 is indicative of the proclivity of adenocarcinoma to occur in young age groups. The DES-related clear cell adenocarcinoma is not a major factor in this apparent increasing incidence. Five cases of clear cell adenocarcinoma of the cervix were encountered. A positive history of exposure to DES in utero was obtained in 3 patients. It is evident that the rising relative incidence of adenocarcinoma of the cervix cannot be attributed to clear cell adenocarcinoma of the cervix related to DES exposure in utero. The role of exogenous hormones is uncertain. Gallup and Abel1 [5] alluded to the possible role of oral contraceptives following their observation that 5 patients in their series were 32 years of age or less, and all had been receiving oral contraceptives for varying periods of time. Our findings relevant to the role of oral contraceptives are inconclusive. Sixteen of 32 patients under the age of
ADENOCARCINOMA
OF THE
UTERINE
CERVIX
343
40 were on oral contraceptives prior to the diagnosis of adenocarcinoma. The majority of these patients used oral contraceptives for more than 4 years. Although no definite statement can be made as to the relationship between adenocarcinoma of the cervix and oral contraceptives, further studies are necessary to clarify this issue, especially the role of prolonged use of oral contraceptives. The apparent increasing incidence of adenocarcinoma of the cervix may be relative rather than absolute. Limited and out-patient measures directed toward eradication of squamous cervical intraepithelial neoplasia are successful in eliminating precursors of invasive squamous cell carcinoma of the cervix while the endocervical epithelium is retained. The finding of 6 patients in our series with squamous cell carcinoma in situ of the cervix is evidence that both types of epithelium can independently and simultaneously undergo a neoplastic change. A similar observation was made by Grundsell et al. [8]. The incidence of lymph node metastasis and capillary-like space involvement in Stage I adenocarinoma was 22%. The impact of lymphatic spread on survival is significant. Of the 8 patients who underwent radical hysterectomy and pelvic lymphadenectomy and found to have positive nodes or CL-space involvement, 2 are alive without evidence of disease (25%), 1 is alive with no evidence of disease following radiation therapy for pelvic side wall recurrence 5 years after radical hysterectomy, and the other patient has only been followed for 16 months following initial treatment. The current materials and previous data published [9] from our institution indicate differences in biological behavior between adenocarcinoma and squamous cell carcinoma of the cervix, especially when lymph nodes are involved. The recurrence and the survival rates in the group of patients with positive pelvic nodes are dissimilar and imply a worse prognosis when seen in patients with adenocarcinoma. Furthermore, the interval between the treatment and detection of recurrence is longer in the group with adenocarcinoma. The increased incidence of distant metastases (brain, liver, and bone) in the group with adenocarcinoma is at variance with the observations in patients with squamous cell carcinoma and is in agreement with Kagan et al. (10). Radical hysterectomy and pelvic lymphadenectomy is an appropriate treatment for early stages of adenocarcinoma of the cervix (Stages I-II-A). The survival rates are similar to those previously reported. The morbidity is acceptable. Furthermore, radical surgery permits the identification of a group that is at extremely high risk for recurrence. Adjunctive therapy in the form of postoperative radiation, chemotherapy, and hormonal therapy based on estrogen and progesterone receptor content, deserves a trial among those patients with positive lymph nodes and/or capillary-like space involvement. REFERENCES 1. Mikuta, J. J., and Celebre, J. A. Adenocarcinoma of the cervix, Obstet. Gynecol. 33, 753-756 (1969). 2. Peete, C. H., Carter, F. B., Cherny, W. B., et al. Follow-up of patients with adenocarcinoma
of the cervix and cervical stump, Amer. J. Obstet. Gynecol. 93, 343-356 (1965). 3. Rutledge, F. N., Galakatos, A. E., Wharton, J. T., and Smith, J. P. Adenocarcinoma of the uterine cervix, Amer. J. Obstef. Gynecol. 122, 236-245 (1975).
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4. Tasker, J. T., and Collins, J. A. Adenocarcinoma of the uterine cervix, Amer. J. Obster. Gynecol. 118, 344-358 (1974).
5. Gallup, D. G., and Abell, M. R. Invasive adenocarcinoma of the uterine cervix, Obster. Gynecol. 49, 596-603 (1976). 6. Hurt, W. G., Silverberg, S. G., Frable, W. J., et al. Adenocarcinoma of the cervix: Histopathologic and clinical features, Amer. J. Obster. Gynecol. 129, 304-314 (1977). 7. Berkowitz, R. S., Ehrmann, R. L., Lavizzo-Mourey, R., et al. Invasive cervical carcinoma in young women, Gynecol. Oncol. 8, 311-316 (1979). 8. Grundsell, H., Henrikson, H., Johnsson, J. E., and Trope, C. Prognosis of adenocarcinoma of the uterine cervix, Gynecol. Oncol. 8, 204-208 (1979). 9. Figge, D. C., and Tamimi, H. K. Patterns of recurrence of carcinoma following radical hysterectomy, Amer. J. Obstet. Gynecol. 140, 213-220 (1981). 10. Kagan, A. R., Nussbaum, H., Chan, P. Y. M., et al. Adenocarcinoma of the uterine cervix, Amer. J. Obstet. Gynecol. 117, 464-468 (1973).