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Early squamous cell carcinoma of the uterine cervix II. Clinical results of a cooperative study in the management of 419 patients with early stromal invasion and microcarcinoma
GYNECOLOGIC
ONCOLOGY
6, 31-50 (1978)
Early Squamous
Cell Carcinoma
of the Uterine
Cervix
II. Clinical Results of a Cooperative Study in the Management of 419 Patients with Early Stromal Invasion and Microcarcinoma
K. J. LOHE,* E. BuRGHARDT,t H. G. HILLEMANNS,§ C. KAUFMANN,$ K. G. OBER,** AND J. ZANDER* *First Department Munich, Munich, Graz, KJniversity
of Obstetrics and Gynecology and School of Midwives, University of and TDepartments of Obstetrics and Gynecology, University of Graz, of Freiburg, Freiburg, $University of Cologne, Cologne, and **University of Erlangen, Erlangen, West Germany
Received March IO, 1977 Clinical studies and therapeutic modalities in 285 patients with early stromal invasion and 134 patients with microcarcinoma collected from six different university hospital departments of gynecology are presented as a contribution to the controversial problem concerning the proper treatment of early cervical cancer. In all six departments, clinical investigation and histologic studies are carried out in a comparable manner. Of the patients, 72% with early stromal invasion and 41% with microcarcinoma were treated with conization or with abdominal, respectively vaginal hysterectomy only, i.e., not with the usual radical cancer therapy. After long-term follow-up, no paiient with early stromal invasion has died: in three patients who died from microcarcinoma, a causal relationship seems to have existed between the fatal cause and microcarcinoma. Our own results and comparable data reported in the literature allow the conclusion that in patients with early stromal invasion or microcarcinoma, a restricted cancer therapy may be possible, just as in patients with carcinoma in situ. If intraluminal tumor invasion is demonstrated in the diagnostic biopsy, an additional lymphadenectomy is advisable. A radical extirpation of parametrial tissues is in no case necessary.
Various opinions exist about how to treat early squamous cancer of the uterine cervix. Views on treatment range from rather conservative methods to radical ones. Thus, it is still a matter of discussion as to which therapy will finally offer a maximum number of advantages to the patients. In the controversy on the problem of early cervical cancer, we shall try to answer the question of which type of management will finally guarantee a “minimal, effective, and safe treatment” [26]. 1. PATIENT MATERIAL
In order to obtain significant results, it was necessary to collect as extensive and well suited a patient material as possible. Therefore, we extended our investigation from the beginning to the departments of gynecology at the Universities of Erlangen, Freiburg, Graz, Heidelberg, and Cologne. All these hospitals have, for 31 0090-8258/78/0061-0031$01.00/0 Copyright @ 1978 by Academic Press, Inc. All rights of reproduction in any form reserved.
32
LOHE
ETAL.
many years, been concerned with the problem of cervical cancer. They all have a pathology laboratory of their own which, by means of special methods of tissue preparation, guarantees a thorough and reliable routine diagnosis. At the same time, it allows scientific problems to be solved. Methods of tissue processing are very similar at all clinics mentioned and correspond to the histologic technique described in the preceding study [321. At these six departments of gynecology, the authors of this paper examined all available histologic tissue slides from patients with early squamous cancer of the cervix and reevaluated the diagnosis of early stromal invasion or microcarcinoma according to the definitions given in the preceding paper [32]. Of 419 patients with early cervical cancer, 285 patients with early stromal invasion (ESI) and 134 patients with microcarcinoma (MC) were selected as being suited for the present investigation. Table 1 gives the number of cases for each clinic. 2. AGE OF PATIENTS
The age distribution of the 419 patients with early cervical cancer is shown in Fig. 1 in groupings by 5-year intervals. The youngest patient with either ES1 or MC is 23 years old. The oldest patient with ES1 is 69 years old and with MC is 7 I years old. Both lesions are most frequently found in patients around the age of 40. Of the patients, 71% with EST (202) and 70% with MC (94) are in their 30s or 40s. ES1 (7%) and MC (3%) are rarely observed before the age of 30. The average age of the 285 patients with ES1 is 43.9 k 1.1 years and of the 134 patients with MC is 44.6 + 1.6 years. 3. SYMPTOMS
AND SIGNS
(VAGINAL
DISCHARGE,
BLEEDING,
AND PAIN)
Examining the frequency of typical gynecological signs and symptoms-vaginal discharge, bleeding, and pain-in our 419 patients suffering from early cervical cancer, we found that 130 out of the 285 patients with ES1 (46%) and 76 out of the 134 patients with MC (57%) complained of one or more of these symptoms. In other words, at the time of the examination, more than 50% of the patients with ES1 and almost 50% of the patients with MC were free of any symptoms and signs. Of the 285 patients with ESI, I6 (6%) had a white-yellowish discharge and 29
DISTRIBUTION
TABLE 1 OF THE PATIENTS WITH EARLY STROMAL INVASION MICROCARCINOMA IN THE DIFFERENT CLINICS
Clinic
ES1
MC
Total
Erlangen Freiburg Graz Heidelberg Cologne Munich
2s 60 99 IO 88 3
17 22 33 8 52 2
42 82 132 18 140 5
285
134
419
Total
’
AND
Percentage 10 20 32 4 33 1 100
MANAGEMENT
OF EARLY
CERVICAL
33
CARCINOMA
medium
ESI age:43,9y.?l,l
m
MC
medium
age:44,6y.tl.6
(n-265)
(n-,34)
40
30
20
10 c t25
26-30
FIG. 1. The distribution microcarcinoma by age.
31-35
36-40
41-45
46-50
of 285 patients with
51-55
56-60
61-65
BB-vyears
early stromal invasion and 134 patients with
(10%) had a red-brownish discharge. Of the 134 patients with MC, 14 had a white-yellowish discharge (10%) and 26 had a red-brownish discharge (19%). Fifty-seven of the 285 patients with ES1 (20%) and 34 of the 134 patients with MC (25%) complained of anomalies of uterine bleeding in the form of spotting or menstruation-like or heavier bleeding, respectively. Taking the so-called contact bleeding, which is known to be an important diagnostic criterion for clinical cervical carcinoma, as a special type of hemorrhage of its own, one finds that 31 (11%) of the 285 patients with ES1 and 18 (13%) of the 134 patients with MC mentioned this important symptom. Twenty-six (9%) of the 285 patients with ES1 and 9 (7%) of the 134 patients with MC complained of various pains in the region of the abdomen. This symptom is thus of no value in the diagnosis of early cervical cancer. In the pertinent literature, abnormal bleeding is also reported to be the main symptom of early cervical cancer [8, 15, 19, 20, 271. Specific symptoms for early lesions do not exist. Besides bleeding anomalies, contact bleeding and redbrownish discharge may, within certain limits, point to early cervical cancer. 4. DlAGNOSTlC METHODS: MACROSCOPIC AND COLPOSCOPIC EVALUATION OF THE PORT10 AND CYTOLOGY
As expected, the macroscopic examination of the surface of the portio offers no reliable means for the detection of early cervical cancer. Only in 50 (18%) of the 285 patients with ES1 and in 38 (28%) of the 134 patients with MC did the macroscopic evaluation of the portio suggest the possibility of a malignant lesion necessitating further diagnostic procedures. Colposcopy is a more reliable method for the detection of early cervical cancer. Breaking down the colposcopic findings obtained from our 251 colposcopied patients with ES1 and our 113 colposcopied patients with MC into negative,
34
LOHE
ETAL.
suspicious, and positive colposcopic findings according to Kern’s classification [ 141, 188 out of the 25 1 patients with ES1 (75%) and 83 out of the 113 patients with MC (73%) showed suspicious or positive colposcopic findings. One-fourth of all colposcopied patients, however, had a normal portio colposcopically. Intracervitally located atypical epithelium cannot be detected by colposcopic examination. Thus, we later found by microscopic examination that 33% of the individual foci with ES1 and 34% of the individual foci with MC were located within the cervix. As compared to colposcopy, cytology assures a considerably higher degree of accuracy and significance. For 262 of the 276 cytologically examined patients with ES1 (95%), the presence of a malignant squamous cell lesion at the cervix could be predicted on the basis of suspicious and positive cytologic findings. Other authors [2, 15, 18, 19, 27, 301 report similar results of correct cytologic diagnosis ranging from 82 to 100% for patients with ESI. The same applies to patients with microcarcinoma. In our 129 patients with MC, cytologic accuracy was 92% (118 out ofa 129 patients). Fidler and Boyd [81 report an accuracy figure of 90%. For certain clinical situations, it is important to know that very often cytology will help diagnose cancerous invasion also in the case of early carcinoma of the cervix. After cytologic examination, we suspected invasion in 86% of our patients with ES1 and in 80% of our patients with MC. Of 31 histologically verified microinvasions, Ng.et al. [24] with the help of cytology correctly diagnosed 27 (87%) and stated: “Objectively it is possible to recognize microinvasion in cellular samples.” Of all the usual diagnostic methods apt to detect an early lesion, cytology, therefore, is the most important. Colposcopy allows us to localize exactly suspicious epithelial areas of the cervix and to sample them. With the naked eye, however, early lesions cannot be detected. 5. MICROSCOPIC
DIAGNOSIS: “EARLY STROMAL OR “MICROCARCINOMA”
INVASION”
A diagnosis of “early stromal invasion” or “microcarcinoma” was made for each of the 419 patients with early cancer of the cervix on a tissue specimen which guaranteed reliable diagnostic statements. The types of tissue samples obtained at the time of the pretherapeutic study and during the definitive therapy are summarized in Fig. 2. The “small” tissue samples- biopsy and curettage of the cervix and the portio-from 20% of the patients with ES1 and from 34% of the patients with MC are represented at the top half of the figure and the “large” tissue samples-ring biopsy, conization, and amputation of the portio, cervical stump, and uterus-from 80% of the patients with ES1 and 66% of the patients with MC are represented at the bottom half of the figure. In all cases of small biopsies in which category fall all extramural cases with a pretherapeutic histologic diagnosis, the subsequent histologic examination of the uterus followed. Thus, the whole lesion of the cervix could be clearly assessed in each case. The material selected for this investigation includes no case in which the diagnosis of early carcinoma was based on a small biopsy alone. Also, in three-quarters of the cases of the large tissue samples, it was possible to examine the uterus histologically. Further growth of cancer beyond the stage of
MANAGEMENT
OF
EARLY
128 ~:...:..::..::..:,..::..:~
CERVICAL
K s
191 3 3 2aE I %
100
a0
60
40
..::..::...y.:~.:: ..,,. , 54 I
PA
6B
1
CERV-ST 9
35
CARCINOMA
a 3
I
11 I 20
20
uterus
m 40
1 60
g&y; I
I
a0
100
x
FIG. 2. The composition of the different types of biopsies in 419 patients (285 ESI, left; 134 MC, right) in whom a diagnosis of early stromal invasion and microcarinoma was made. In the upper box are the “small” biopsies and in the lower box are the “large” biopsies. Each type of biopsy (black columns) shows the corresponding number of uteri later removed and studied in their entirety (dotted columns). ausw, extramural diagnosed cases: pe, biopsy; abr, curettage: absch, curettage of the portio; RB, ring biopsy; KS, conization; PA, amputation of the cervix: CERV-ST, cervical stump; 4, no biopsy before hysterectomy.
microcarcinoma could thus be excluded. In the remaining cases, the large biopsy had already shown the total spread of the cancer infiltration. From 45 patients with ES1 and MC, respectively, no tissue samples were taken before hysterectomy. The diagnosis of a beginning carcinoma was first made by histologic examination of the uterus. These cases rank with the large tissue samples. 6. THERAPY
The therapy given to the 419 patients with beginning cervical cancer ranges from conization to radical operation with subsequent radiation treatment (Fig. 3). With the conization of 66 of the 285 patients with ES1 (23%) and 16 of the 134 patients with MC (12%), a very restricted method of treatment was chosen. Thirteen of the 66 conizated patients with ES1 (20%) and 9 of the 16 conizated patients with MC (56%) were given radiation treatment postoperatively (radium and/or X ray and telecobalt). Vaginal hysterectomy was the preferred therapy in the majority of cases. One hundred eighteen of the 285 patients with ES1 (42%) and 37 of the 134 patients with MC (28%) were treated by this method. In three patients suffering from ES1 (3%) and in three patients suffering from MC (8%), the operation was followed by radiation. In the case of 39 patients with ES1 (14%) and 15 patients with MC (1 I%), abdominal hysterectomy was performed. Postoperative radiation treatment became necessary in two cases of ES1 (5%) and in one case of MC (7%).
36
LOHE
ETAL.
42 %
FIG. 3. The different treatments applied at the six clinics in 285 patients with early stromal invasion (top) and 134 patients with microcarcinoma (bottom): cases with postoperative radiation therapy are indicated by black columns. KS, conization; Vag, vaginal hysterectomy; Abd, abdominal hysterectomy; SA, vaginal radical operation according to the method of Schauta-Amreich; TeLi, radical operation according to the method of Te Linde; Wth, radical operation according to the method of Wertheim-Meigs.
Summing up the patients with conization and abdominal or vaginal hysterectomy, we find that 205 of the 285 patients with ES1 (72%) and 55 of the 134 patients with MC (41%) were given minimal or restricted cancer treatment. A treatment more in line with the usual cancer therapy was given to 62 of the 285 patients with ES1 (2 1%) and to 66 of the 134 patients with MC (49%) if we add together the radical operations according to the methods of Schauta-Amreich, Te Linde, and Wertheim-Meigs. From these patients, 9 with ES1 (15%) and 20 with MC (30%) were subsequently radiated. Among the radical methods of therapy given to patients with ESI, the vaginal radical operation according to the method of Schauta-Amreich predominates with 11% (32/285). It was almost exclusively performed at Graz, Austria. Of the patients, 8% (24/285) underwent an abdominal radical operation mostly according to the method of Wertheim-Meigs with pelvic lymphadenectomy and 2% (6/285) underwent the restricted radical operation according to the method of Te Linde. Among the radical methods of therapy applied to the patients with MC, the abdominal radical operation according to the method of Wertheim-Meigs comes first with 27% (36/134). The vaginal radical operation according to the method of Schauta-Amreich, due to its frequent performance at Graz, follows with 21% (27/134). The abdominal method according to Te Linde was performed in 1% (3/134) of the cases. In 29 patients with ES1 and 37 patients with MC, the operation included the removal of the regional lymph nodes. Diagnostic study of every single lymph node revealed no case of metastatic spread of the tumor. During 219 hysterectomies due to ESI, in 23 cases (11%) one and in 74 cases
MANAGEMENT
OF
EARLY
CERVICAL
CARCINOMA
37
(34%) both adnexa were removed. In 14 (12%) of the 118 hysterectomized patients with MC one and in 45 (38%) of these patients both adnexa were extirpated. Even in the case of radical operations, castration is not necessarily part of the cancer therapy. Histological examination of the extirpated adnexa in no case showed metastatic cancer. 7. CLINICAL
PROGRESS
AFTER
TERMINATION
OF TREATMENT
A. Follow-up time. The time interval between the beginning of therapy and the last time the patient is seen or the death of the patient is called follow-up time. Longer follow-up times allow more conclusive evidence and increase the reliability of the survival rate. Figure 4 shows that in more than half of our cases (59% of the patients with ES1 and 69% of the patients with MC), follow-up time was longer than 5 years and in almost one-fourth of all cases (22% of the patients with ES1 and 26% of the patients with MC), follow-up time exceeded 10 years. il B. Further fare of the patients. As we know from checking into the further fate of the 419 patients with early cervical cancer (Table 2), 267 of the 285 patients with ES1 (94%) and 123 of the 134 patients with MC (92%) are alive and well. Among
30
20
10
10
“.
* 5 y.‘66,7% a10 y.= 26,2%
FIG. 4. The follow-up time in 419 patients (285 ESI, top; 134 MC, bottom) with early stromal invasion and microcarcinoma. Dotted, up to 5 years; solid black, 5 to 10 years; crosses, more than IO years.
38
LOHE
ETAL.
TABLE 2 FURTHER FATEOF THE~I~PATIENTS WITH EARLY CERVICAL CANCER (EARLY STROMAL INVASION AND MICROCARCINOMA) Further fate of patients
ES1 (285) (No./%)
MC (134) (No./%)
Early cancer (4 19) (No./%)
Alive and well “Further growth” Recurrence Lost to follow-up Dead By early cancer By other causes
267193.7 210.7 411.4 612. I
123191.8 110.7 312.2 413.0
390193.1 310.7 711.7 1012.4
312.2 413.0
1613.8
1214.2
310.7
these are two patients with ES1 and one patient with MC who had to be treated a second time within the first 6 months after primary treatment because the incompletely removed atypical cervical lesion had grown back again. Among these there are, moreover, four patients with ES1 who 1, 8,9, and 13 years, respectively, after primary treatment had a local tumor recurrence and were then successfully treated. According to our definition, we speak of tumor recurrency when atypic cell findings appear anew more than 6 months after the conclusion of the primary treatment. Changes observed before this time are referred to as “a further growth” of the original tumor. Six patients with ES1 and four patients with MC are missing. The last report, mostly several years after treatment, showed unremarkable gynecological findings. Most of the missing patients had moved to unknown addresses. In the course of time, 12 patients with ES1 and 7 patients with MC died (Table 3). Except for three cases with MC, death was not connected with the early cervical cancer. The progress of the disease of these three patients with MC is described in detail below. First case: Department of Gynecology, University of Cologne, Hist. Nos. 300 and 340158. H. Berta. A 46-year-old patient came to the hospital with hypermenorrhea. The cervix was colposcopically suspicious and cytologically Pap. V on two occasions. A conization was performed with fractionated curettage. A microcarcinoma (5 x 4 x 3 mm) and, at the cone edges, a carcinoma in siru were removed. An extended abdominal hysterectomy was performed according to the method of Wertheim with extirpation of both adnexa and no lymphadenectomy. The tissue samples obtained at operation revealed a carcinoma in situ, which was, however, not totally resected at the vaginal resection border. There was a postoperative application of 1200 mgeh of radium intravaginally. First of all, the patient was lost to follow-up. Further searching disclosed that, almost 4 years after the first treatment, the patient had been admitted to a small local hospital because of cachexia. According to the hospital director, the patient had died of peritoneal carcinomatosis, the primary tumor being unknown. No autopsy was carried out. Under critical assessment of the case it becomes evident that due to the lack of histological verification of a tumor recurrence, the cause of death remains uncertain. Kaufmann et al. [33] have already described this case and expressed their doubts about a connection between the tumor recurrence and the microcarcinoma. Although it is impossible to exclude the existence of a malignant tumor of another kind, this case, with reservation, is regarded as recurrent microcarcinoma with subsequent death.
(47) (47) (39) (63) (55) (48) (51)
ES1 (52) ES1 (56) ES1 (50) ES1 (53) ES1 (35) ES1 (61) ES1 (36) MC (49) MC (46)
ES1 ES1 ES1 ES1 ES1 MC MC
MC (33) MC (46) MC (64)
Type of early cancer (age of patient in years)
THE CAUSES
3
-
-
1 month 3 years 4 4 5 6 7 5 IO
1 year I 3 6 9 I I
(2) Patients died of other malignant tumors Pelvic tumor Pelvic tumor
(3) Patients died of other causes
2 years 4 7
CERVIX
INVASION
(1) Patients died of early cervical cancer Recurrent tumor, pelvic wall Peritoneal carcinomatosis -
EARLY STROMAL OF THE UTERINE
TABLE
Survival time
IN 12 PATIENTS WITH MICROCARCINOMA
Gynecologic finding
OF DEATH
AND IN
MC MC MC
Cause of death
WITH
Cerebral vascular accident Car accident Cerebral vascular accident Acute heart failure Car accident “Old age” Car accident Diabetes: cerebral vascular accident Pneumonia after gallbladder surgery
Sarcoma of the femur Adenocarcinoma (?) Breast carcinoma Liver carcinoma Breast carcinoma Brain tumor Carcinoma of the fallopian tube
7 PATIENTS
40
LOHE
ETAL.
Second case: Department of Gynecology, University of Cologne, Hist. Nos. 1131 and 1245158. V. Ruth. A 33-year-old patient with no complaints went for a routine checkup. The portio was colposcopically suspicious and cytologically Pap. IV and 11. A conization was performed and a microcarcinoma (8 x 9 x 3 mm) was totally removed. An extended vaginal radical operation according to the method of Schauta was performed without extirpation of the adnexa. During the operation, no enlarged lymph nodes were palpable in the pelvis. The tissue obtained at the operation showed no proof of atypical epithelium. Sixteen months after the first diagnosis, a resistance at the right pelvic wall was palpated. Despite intensive radiation therapy (conventionally, 4000 R/O.D. and, additionally, 1600 R with cavity X-ray tube as well as 7400 R/O.D. with cobalt-60 5 months later), the patient died 2 years after the beginning of therapy. No autopsy was carried out. Under critical assessment, a recurrent microcarcinoma seems to have been the most likely cause of death. But here, too, no histological verification or autopsy was made. This case has already been described by Ober and Huhn [34], by Zinser er al. [35], and by Kaufmann el al. [331. None of these authors questions microcarcinoma as the ultimate cause of death. Nevertheless, a different primary tumor is, at least theoretically, not impossible. However, with reservation, the case is considered as microcarcinoma recurrence with subsequent death. Third case: Department of Gynecology, University of Cologne, Hist. No. 1431158. M. Margarete. A 64-year-old patient came for an examination because of a brownish discharge. The portio was colposcopically normal and cytologically Pap. IV on two occasions. An abdominal hysterectomy was performed with removal of both adnexa. In the tissue obtained at operation, a totally removed microcarcinoma (4 x 3 x 3 mm) was diagnosed. Gynecological checkups in the course of the next 5.5 years gave no evidence of a recurrence. The patient was then lost to follow-up. Thorough investigation revealed that 1.75 year after this date, the patient had been admitted to a local hospital. She was in poor health with tumor metastases in the skull, lungs, pelvic bones, and femur and she received drug therapy. Gynecological examination showed a smooth vaginal stump with no retrovaginal infiltration. Death occurred 7.5 years after primary treatment. No autopsy was performed. Under critical evaluation, we must say that in this case also recurrence was not ascertained histologically or by autopsy. Theoretically, a primary tumor of another kind may have been the possible cause of death. Here too, the case as a microcarcinoma recurrence with subsequent death is made with reservation.
Therefore, none of the 285 patients with ES1 died of this disease, while among the 134 patients treated because of MC, three cases of death caused by this cancer are reported. It must be pointed out, however, that due to the lack of histologic confirmation and autopsy in all three cases, a definite correlation between MC and cause of death could neither be proven nor ruled out. The listing of the patients as “having died of MC” is based merely on historical evidence. Accordingly, we have a 2.2% maximum lethality due to microcarcinoma. C. Survival rate. Table 4 gives the so-called survival rate of the 419 treated patients with early squamous cancer of the cervix including all patients lost to follow-up or deceased. The 5-year survival rate for the patients suffering from ES1 is 95% and for those suffering from MC is 94%. The lo-year survival rate is 86 and 85%, respectively. Thus, the survival rate for our patients with early cervical cancer is, on the average, 10% higher than that for our patients with Stage IB cervical cancer. 8. DISCUSSION AND CONCLUSIONS
For the purpose of comparing and discussing the results of cases collected from six university hospital departments of gynecology with those reported in the
MANAGEMENT
OF
THE SURVIVAL RATES OF CELL CARCINOMA
Survival rates Total 5 years IO years
EARLY
CERVICAL
41
CARCINOMA
TABLE 4 419 PATIENTS
WITH OF THE UTERINE
EARLY SQUAMOUS CERVIX
ES1
MC
Early cancer
[No. WI
[No. (%)I
[No. (%)I
267 of 285 (93.7) 167 of 176 (94.9) 63 of 73 (86.3)
123 of 134 (91.8) 92 of 98 (93.9) 35 of 41 (85.4)
390 of 419 (93.1) 259 of 274 (94.5) 98 of 114 (85.9)
literature, especially in view of therapy and prognosis, we tried to apply our definition and classification of cases of ES1 and MC to the published cases. Publications dealing with the observation of less than 20 individual cases and all cases of “microcarcinoma” not corresponding to our definition of early cervical cancer are not considered in our discussion. Beginning with the histologic tumor definition, three fairly comparable groups could be set up: (I) 895 observations reported in the literature largely corresponding to our definition of ES1 (Table 5); (2) 435 observations reported in the literature largely corresponding to our definition of MC (Table 6): and (3) 1159 cases of early cervical cancer reported in the literature which, by our definition, do not allow a clear separation into ES1 and MC or the survival rates of which are not broken down according to these two tumor forms (Table 7). (1) In the 895 published cases of ES1 as well as in our 285 own cases, radical operation was performed with about equal frequency (17% of the 895 cases compared with 22% of our own cases). The survival rate of all patients with ES1 is, with only a few exceptions, higher than 95%. The lower figures reported by Dilworth and Maxwell [7] (90.5%), Thompson [27] (82%), and Ng and Reagan [23] (82%) and our own rate of 94% are due to the high number of patients deceased in the meantime or lost in the follow-up period. Out of the 895 patients, 13 had a tumor recurrence (1.5%) which, in the case of four patients (0.4%), caused subsequent death. Of our own 285 patients, none died of ESI. Four patients are considered to be recurrences (1.4%). Of the four patients who had ES1 and had died of this disease [ 151, two had been given primary treatment with radium, one had been given combined radium-Xray therapy, and one had been treated with simple hysterectomy. In all these cases, tumor recurrence was palpated within the pelvis. In three cases, metastatic disease beyond the small pelvis had occurred and, in three cases, recurrence had developed after more than 5 years. Kolstadt [15], however, stresses that in the case of one deceased patient, the correct diagnosis should have been Stage IB carcinoma rather than microcarcinema and that in another patient, a metastasizing cancer of the vulva which had been operated 8 years before the ES1 was detected might have been the cause of death. Since Kolstadt fails to give details of the methods of histologic examination, we cannot help doubting the reliability of the histologic diagnosis of ES1 in the other two cases also.
Total Percentage
Latour et al. [ 171 (1957) Dilworth and Maxwell [7] (1962) Christopherson and Parker [5] (1964) Ullery et al. [30] (1965) Green [lo] (1966) Margulis et al. [19] (1967) Thompson [27] (1968) Kottmeier [16] (1969) Ng et al. [24] (1969) Kolstadt [ 151 ( 1969) Boyes et al. [3] (1970) Marcuse [18] (1971) Boutselis et al. [2] (1971) Total Percentage Own results Total Percentage
Reference (year)
TABLE
5
97 Rb 22 KS, 20 Kb 18 KS, 1 Kb, 1 Ut 3 Kb, 24 KS, 1 Ut 40Ks, 12Ut 22 KS, 4 Kb ? KS, ? Kb ? KS, ? Kb 59 KS, 5 Kb, 2 Ut ? KS, ? Kb ? KS, ? Kb ? KS, ? Ut 45 KS
49 Kb, 197 KS, 39 Ut
285 100 1180 100
Type of biopsy”
97 42 20 28 52 26 49 79 66 164 205 22 45 895 100
Number of cases
AND THEIR
285 PATIENTS
15u5 53.311.8 459158 38.914.9
127 10.8
26l19132 1157/15/16l-307153 34.315.9
27121 12l8/I/15l1 I/-
Hysterectomy +/- radb (No.)
WITH
128/85 10.917.2
5319 18.613.2
1Ol-120 2/3l3123 75176 8.418.5
4l49l-
3l--I9 -I1 l/23
Radical operation +/- radb (No.)
Type of therapy
RESULTS IN 895 PATIENTS IN OUR OWN SERIES
53 18.6
74 8.3
-
7 21 1
-
4 3 1 37
Rb-KS-Pa” (No.)
TYPES OF DIAGNOSTIC BIOPSIES AND OF THERAPEUTIC PROCEDURES EARLY STROMAL INVASION IN THE LITERATURE AND IN
323 27.3
13 4.5
42 18 10 3 11 -79 30 86 25 3 3 310 34.6
Radb (No.1
s 5 G .“:
Therapeutic
4 0.3
-
-
4 0.4
-
412.4
-
-
-
-
Dead from recurrent tumor (No./%)
results
4.2 34 2.9
12
222.5
3/1.8 112.2
-316.1 212.5 619.I
l/1.0 419.5 115.0 113.6
Dead from other causes (No./%)
93.7 1124 95.3
267
857 95.8
157 205 22 44
52 26 40 77 54
96 38 19 27
Alive and well (No.1
95.3
93.7
95.8
95.7 100.0 100.0 97.8
100.0 100.0 81.6 97.5 81.8
99.0 90.5 95.0 96.4
Survival rateC (%)
94.9
? 93.5 ? 95.5
?? ? 97.5 95.8
‘I. . 85.7 ? 7
5-year survival rate (%I
’ Abbreviations used: Kb, punch biopsy; Rb, ring biopsy; KS, conization; Pa, amputated portio; Ut, uterus. b Rad, radiation therapy (radium, X ray, or telecobalt or combined radiation therapy). ’ Survival rate = number of patients alive and well minus the number of patients lost to follow-up or dead from their tumor or from other causes.
17 1.4
1.4
2.1 18 1.5
Total Percentage
4
131.5
412.4 411.9 112.2
213.0
217.7 -
6
-
17 >lI 7 30
17
-6112.2 6/9.1
7 10 14 8 21
-
Own results Total Percentage
-
9 IO 6 >5
121.1
(N:.?%)
Recurrence (No./%)
Total Percentage
Latour et a/. [17] (1957) Dilworth and Maxwell [7] (1962) Christopherson and Parker [5] (1964) UUery et al. [30] (1%5) Green [IO] (1966) Mar&s et al. [I91 (1967) Thompson [27] (1968) Kottmeier [ 161 (1969) Ng et al. [24] (1969) Kolstadt [I51 (1969) Boyes ef al. [3] (1970) Marcuse [18] (1971) Boutselis et al. (21 (1971)
Reference (year)
Lost to follow-
Longest followup time (years)
5
8
F Fi
E z ?
2 0
F
%
5
F 2 s? 3
17
8 >I1 27
‘-’ See Table 5, footnotes a-c. d 41 hysterectomies or radical hysterectomies
Total Percentage
Own results Total Percentage
Kottmeier [ 161 (1969) Boyes et al. [3] (1970) Mestwerdt and Wespi [20] (1973) Total Percentage
Reference (year)
(no further distinction
10 1.8
4 3.0
613.5 6 1.4
(N::%)
possible).
27 4.7
3 2.2
18/8.8 613.5 24 5.5
Re currence (No./%)
Therapeutic Dead from recurrent tumor (No./%)
Longest followup time Wears)
Lost to follow-
35 6.2
569 100
17 3.0
3 2.2
1115.4 311.7 14 3.2
7 5.2
Total Percentage
36 Kb, 71 KS, 27 Ut
134 100
6.5
27 28
1
Own results Total Percentage
?Ks, ?Kb
-
Rb-KS-Pa” (No.)
100
174 435
Mestwerdt and Wespi [20] (1973) Total
?Ks, ?Kb ?Ks, ?Kb
Type of biopsy”
Percentage
57 204
Number of cases
Kottmeier [ 161 (1969) Boyes et al. 131 (1970)
Reference (year)
6 WITH
9 1.5
4 3.0
I/1.8 412.3 5 1.1
533 93.7
123 91.8
56 193 161 410 94.3
93.7
91.8
98.2 94.6 92.5 94.3
46l20 4814 35.8/3.0 34.3114.9 _-____________ 4] _------__--__87/20 136123 23.914.0 !_5_:3’3.5 _____________ 7.2 ___________ results Dead from Alive other and Survival causes well rateC (No./%) (96) (No.1
-- / A--7i9 _______ 41 d _______________ l88/41/!!!!9 _______ 4* _____________ .I!!‘20.214.3 _____________ 9.4 __-_________ B_!!-
Type of therapy Hysterectomy Radical operation +/- rad” (No.) +/- radb (No.)
PROCEDURES AND THEIR RESULTS IN 435 PATIENTS AND IN 134 PATIENTS IN OUR OWN SERIES
TABLE
TYPES OF DIAGNOSTIC BIOPSIES AND OF THERAPEUTIC MICROCARCINOMA IN THE LITERATURE
93.9
98.2 93.5 92.3
S-year survival rate (%)
227 39.9
9 6.7
50.2
143 18 218
57
Radb (No.)
0’ 3 q $
%
MANAGEMENT
OF
EARLY
CERVICAL
CARCINOMA
45
(2) In 435 patients with MC found in the literature and in our 134 patients with MC, radical therapy was also performed with about equal frequency (50% of the 435 patients and 4% of our own 134 patients). Radiation therapy was, however, definitely the preferred treatment in the 435 patients of the control group. The survival rates of all 569 patients with MC are above 90%. They range from 92% (our group) to 98% [ 161. The survival rate of our patients is biased by the high number of patients lost to follow-up or deceased. Out of the 435 patients with MC, 24 (5.5%) were later affected by a tumor recurrence; of these, eventually 14 (3%) died (Boyes et al. [3], 11 deceased patients; Mestwerdt and Wespi [20], 3 deceased patients). Out of our 134 patients with MC, 3 patients had a tumor recurrence. These three patients later died, apparently of this tumor. Critical analysis of the 14 patients who died of microcarcinoma [3, 201 shows that tumor size and microcarcinoma by our definition can only be compared restrictively. By occult invasive carcinoma, Boyes et al. [3] mean a lesion where there is frank invasion by confluent masses of neoplastic cells resulting in a measurable tumor from several millimeters to 1.5 cm or more in size. Only in one of the 11 deceased patients did the invasive lesion measure less than 5 mm in size. In the other cases, the lesion was greater than 5 mm. The three cases of Mestwerdt and Wespi [20] also lack a reliable definition of the size of the microcarcinoma. Only the maximum invasion depth of 5 mm is stated. Of the 14 patients who died of MC, 9 succumbed during the first 5 years after primary treatment and 5 died later [3, 201. Eight patients were primarily radiated, one patient had a vagina1 radical operation, and five patients had an abdominal or vaginal hysterectomy. For the radiated patient treated by Mestwerdt and Wespi 1201, death due to carcinoma could not be proven with certainty (radiation fistula?). (3) Almost all of the 1159 patients with ES1 and/or MC reported in the literature had been operated (92% of the patients). Radical operation was the most frequent surgical treatment given to 51% of the patients, of whom 8% were subsequently radiated. For almost every single group of the 1159 patients, the survival rate amounts to over 90%. The mean survival rate of all 1159 patients as a whole is 96%. In the course of time, 16 patients (I .4%) were affected by a tumor recurrence; of these, at least five patients (0.4%) died of their disease. Artner and Holzner [II do not give details on whether their six patients died of either a primary or a recurrent tumor. Of the five patients who died of early cervical cancer, one died of a vaginal recurrence after hysterectomy [13], one died of metastases of unknown localization 6 years after vaginal hysterectomy [22], one died of a cervical recurrence 4 years after cervical amputation [4], one died of a pelvic recurrence and diffuse metastases 5 years after cervical amputation and abdominal radical operation with lymphadenectomy [4], and one died of a recurrence of unknown localization 4 years after the vaginal radical operation with pre- and postoperative radiation [2 1I. Holtorff [13], however, adds that in the case of one deceased patient, the correct diagnosis should have been macrocarcinoma rather than microcarcinoma.
Total Perc(mtage
Hel,& [II] (1961) HoltortT [13] (1962) Way [31] (1964) Prz$bora [25] (1965) Uhl&ann I291 (1966) Coppleson and Reid [6] (1967) Roman and Latour [26] (1967) Musr+y ef al. [22] (1969) Foushee et al. [91 (1969) MO&r et al. [21] (1970) Brand1 et al. [4] (1970) Artnw and Holzner [I] ( 1971)6 Tscharf [28] (1972)
Reference (year)
1159 100
27
126
85
104
29
91 175 91
54 74 64
?
? KS, ? Kb, ? Ut ? KS 74 Kb ? Op. prep. ? ? ? KS, ? Ut ? KS, ? cervix 104 KS 53 KS, 32 Pa ? 14 KS, 12 Kb, I Ut
76
Type of biopsy
163
Number of cases
7
35 3.0
2
13 (5x+Ini) -
349185 30.117.3
2l-
-l-
1315 3/-
A-
76142 4ll-
5
1
414
31/-
-
-l61/-
6 2
34l84134
WITH
503l90 43.417.8
34l1216 54l7l24126 60/3/49l29l27158 64l126l14l-
Radical operation +/- radb (No.)
Type of therapy Hysterectomy +/- radb (No.)
2 4
Rb-KS-Pa” (No.)
PROCEDURES AND THEIR RESULTS IN 1159 PATIENTS MICROCARCINOMA IN THE LITERATURE
TABLE
TYPES OF DIAGNOSTIC BIOPSIES AND OF THERAPEUTIC EARLY STROMAL INVASION AND/OR
4
1
9
5
97 8.4
-
-
49
-
-
6 23
Radb (No.)
&
9
H m
212.6 311.8 314.0 213.1 412.2 212.1 312.8 414.7
IO 14 I6 8 15 9 17 30 21 I4 12 >5 5
Held [ij] (1961) Holtorff[l3] (1962) Way [3t] (1964) Przybora [25] (1965) Uhlmann [29] (1966) Coppleson and Reid [6] (1967) Roman and Latour [26] (1967) Mussey er a/. 1221 (1969) Foushee et al. [9] (1969) Mosler et al. [2l] (1970) Brand1 dt al. [43 (1970)
Artner and Holzner [I] (1971)d Tscharf 1281 (1972)
results
110.6 818.7 211.9 212.3
Dead from other causes (No./%) 74 I58 54 71 62 91 I71 80 29 98 77
Alive and well (No.) 97.3 96.9 100.0 95.9 96.8 100.0 97.7 87.9 100.0 94.2 90.5
Survival rateC (%)
23 1.9
-
IO 0.9
-
5 0.4
-
I3 I.1
II09 95.7
27
95.7
100.0
94.6 92.2 100.0 100.0 94.3 100.0 97.0 93.4 100.0 94.2
S-year survival rate (%)
a-c See Table 5, footnotes a-c. d In the cases of Artner and Holzner [I] (1971) no separation is possible between patients with a recurrent tumor and patients dead from a recurrent tumor and between patients lost to follow-up and patients dead from other causes.
Total Percentage
110.6 -
l/I.0 l/O.9 212.3 .__..__.________ 614.7_________
412.4 l/O.5 212. I l/O.9 212.3
Recurrence (No./%)
Therapeutic Dead from recurrent tumor (No./%)
___________________________ j/2.3________________________________ II7 92.8
(NAY%)
Reference War)
;:,yr;“.’ up time wears)
Lost to follow-
48
LOHE
ET AL.
In the case history described by Mussey et al. [22] (“no invasion greater than 5 mm was seen in numerous sections of the lesion which involved the cervix circumferentially”), the cervical lesion, too, might have been more than microcarcinoma by our definition. Neither Brand1 et al. [4] nor Mosler et al. [213 give any information or reliable details on tumor size in their patients who died of cancer. If we examine the prognosis of all therapeutic procedures taken together, we come to the conclusion that the risk of dying of ES1 is rather small. Out of our 285 patients none and out of the 895 cases reported in the literature at the most four patients (0.4%) died from their cancer. On the other hand, the risk of dying of MC seems to be higher. This statement is supported by the fact that 14 of the 435 patients with MC reported in the literature (3%) died of cancer as well as 3 of our 134 patients (2%), even if a causal association between MC and death is not definitely proven. Although more than 75% of our patients with l’s1 and more than 50% of our patients with MC were given a restricted cancer therapy, 5-year survival rates of 94.9 and 93.%, respectively, were obtained. The corresponding figure for the almost exclusively radically treated patients in our clinic with Stage IB carcinoma is considerably lower in fact, only 85%. On the other hand, our investigation has shown that even the so-called “extended cancer management” applied to early cervical cancer does not guarantee a 100% cure. At least 14 of the total of 26 cancer deaths in our patient material and in the nearly 2500 cases reported in the literature occurred after radical treatment. Moreover, the role of the pelvic lymph nodes in early cervical carcinoma remains uncertain. The fact that in the treatment of at least 12 of the 26 patients having died of this cancer the regional lymph nodes of the pelvic wall were not resected could lead us to think that these lymph nodes should routinely be removed or radiated. This view is, however, contradicted by the cancer deaths of at least 10 of the patients with lymph node treatment and by the very low frequency of metastatic lymph node involvement in early cervical cancer. The large number of patients cured of early cervical cancer after restricted treatment indicates that in most cases total extirpation of the tumor by either ring biopsy, conization, amputation of the cervix, or simple hysterectomy will be a sufficient therapy. The decisive criterion for a successful treatment is the total elimination of the tumor from the cervix. Morphologic tumor characteristics may be of importance for prognosis. The tissue specimens of the three MCs from our deceased patients show in each case an intensely dissociating tumor growth with lymphatic invasion. Therefore, for the moment, one should take these morphologic characteristics into consideration when choosing therapy. Metastases in lymph nodes of the pelvic wall are rare. Tumor metastases in the parametrial tissues or in the ovary where neither observed in our patient material nor reported in the literature. Operative removal of the parametrial tissues then becomes unnecessary and, thus, the most severe postoperative complications, such as ureteric lesions, can be avoided. From our investigations, we conclude that for patients suffering from the different forms of early cervical cancer as defined herein, the therapeutic concepts
MANAGEMENT
OF
EARLY
CERVICAL
CARCINOMA
49
described below seem to be justified and suited to the severity of the disease. (I) To cure early stromal invasion as well as carcinoma in situ, a total elimination of the lesion by conization or simple hysterectomy is sufficient. Further therapeutic steps are not necessary. (2) Microcarcinoma, due to the higher risk involved as compared to early stromal invasion, calls for a more extensive therapy according to the morphologic criteria of the primary tumor. In the majority of cases, a simple hysterectomy is sufficient. If proof is given that the microcarcinoma was totally removed with the conization, further operative measures, in general, may become unnecessary. If tumor invasion in lymph or blood vessels is diagnosed before the operation, additional lymphadenectomy is advisable. However, the authors, except for Burghardt, assert that radical removal of the parametrial tissues is unnecessary. (3) If the lesion has affected the vaginal wall, a corresponding cuff of the vagina must be removed. (4) The final success of the treatment depends on a long-term and regular follow-up of the patients. The reported data show that, due to the good therapeutic results, early stromal invasion and microcarcinoma according to our definition take a very special place, indeed, in cervical cancer therapy.
REFERENCES I. Artner, J., and Holzner, Zschr.
Geburtsh.
H. Zur Frage der beginnenden Stromainvasion
Gyniikol.
175, 209-217
des Zervixkarzinoms,
(1971).
2. Boutselis, J. G., Ullery, J. C., and Charme, L. Diagnosis and management of stage IA (microinvasive) carcinoma of the cervix, Amer. J. Obstet. Gynecol. 110, 984-989 (1971). 3. Boyes, D. A., Worth, A. J., and Fidler, H. K. The results of treatment of 4389 cases of pre-clinical cervical squamous carcinoma, .I. Obster. Gynaecol. Bit. Commonw. 77, 769-780 (1970). 4. Brandl, K., Georgiades, E., and Kraus, U. Die Bedeutung der Portioamputation und Konisation als diagnostische und therapeutische Massnahme nach suspekter oder positiver Routineuntersuchung der Portio vaginalis uteri, Zschr. Geburfsh. Gyndkol. 172, 113-130 (1970). 5. Christopherson, W. M., and Parker, J. E. Microinvasive carcinoma of the uterine cervix, Cancer 17, 1123-I 131 (1964). 6. Coppleson, M., and Reid, B. Preclinical carcinoma of the cervix uteri. Its nature, origin and management, Pergamon press, Oxford (1967). 7. Dilworth, E. E., and Maxwell, G. E. Superficially invasive carcinoma and carcinomain situ of the uterine cervix, Amer. J. O&et. Gynecol. 84, 83-88 (1962). 8. Fidler, H. K., and Boyd, J. R. Occult invasive squamous carcinoma of the cervix, Cancer 12, 764-771 (1960). 9. Foushee, J. H. S., Greiss, F. C., and Lock, F. R. Stage IA squamous cell carcinoma of the uterine cervix, Amer. J. Obstet. Gynecol. 105, 46-58 (1969). 10. Green, G. H. The significance of cervical carcinoma in situ, Amer. J. Obstet. Gynecol. 94, 1009-1022 (1966). 11. Held, E. Wann und wie operieren wir Collumcarcinome?, Gynaecologia 151, 89-94 (1961). 12. Hillemanns, H. G. Das Cervixcarcinom, Gymikologe 1, 150-166 (1%9). 13. Holtorff, J. Zur Therapie des Mikrokarzinoms am Collum uteri, Geburtsh. Frauenheilk. 22, 1097-I 101 (1962). 14. Kern, G. Carcinoma in situ. Vorstadium des Gebirmutterhalskrebses, Springer, Berlin (1964). 15. Kolstadt, P. Carcinoma of the cervix stage IA. Diagnosis and treatment, Amer. J. Obstet. Gynecol. 104, 1015-1022 (1969).
50
LOHE
ET AL.
16. Kottmeier, H. L. Erfahrungen des Radiumhemmet. Stockholm, mit der Behandhmg des Oberflkhencarcinoms und des friihinvasiven darcinoms der Cervix, Arch. Gyniikol. 207, 332-342 (1%9). 17. Latour, J. P. A., Brown, L. B., and Turnbull, L. A. Preclinical carcinoma of the cervix,Amer. J. Obstet. Gynecol. 74, 354-360 (1957). 18. Marcuse, P. M. Incipient microinvasive carcinoma of the uterine cervix. Morphology and clinical data of 22 cases, Obstet. Gynecol. 37, 360-367 (1971). 19. Margulis, R. R., Ely, C. W., and Ladd, J. E. Diagnosis and management of stage IA (microinvasive) carcinoma of the cervix, Obstet. Gynecol. 29, 529-538 (1967). 20. Mestwerdt, G., and Wespi, H. J. Atlas der Kolposkopie, Fischer, Stuttgart, 4th ed. (1973). 21. Mosler, W., Kaiser, P., and Randow, H. Die abgestufte Behandlung der Vor- und Fni’hstadien des Zervixkarzinoms, Deut. Gesundheitsw. 25, 2222-2225 (1970). 22. Mussey, E., Soule, E. H., and Welch, J. S. Microinvasive carcinoma of the cervix. Late results of operative treatment in 91 cases, Amer. J. Obstet. Gynecol. 104, 738-744 (1969). 23. Ng, A. B. P., and Reagan, J. W. Microinvasive carcinoma of the uterine cervix, Amer. J. Clin. Pathol. 52, 51 l-529 (1%9). 24. Ng, A. B. P., Reagan, J. W., and Lindner, E. A. The cellular manifestations of microinvasive squamous cell carcinoma of the uterine cervix, Acta Cytol. 16, 5-13 (1972). 25. Przybora, L. A. Incipient invasion of cervical cancer: Morphological aspects of carcinogenesis in 74 cases, Gynaecologia (Basel) 160, 69-86 (1965). 26. Roman, T. N., and Latour, J. P. A. The effect of early diagnosis on survival statistics in carcinoma of the uterine cervix, Amer. J. Obstet. Gynecol. 97, 739-749 (1%7). 27. Thompson, W. R. Microinvasive carcinoma of the uterine cervix, J. Arkansas Med. Sot. 65, 139-144 (1968). 28. Tscharf, H. Zur Behandlung der Frithstadien des Zervixkarzinoms, drztl. Prax. 24, 4608 (1972). 29. Uhlmann, G. Therapie und Heilungsergebnisse bei Frilhkarzinomen des Collum uteri, Geburtsh. Frauenheifk. 26, 775-780 (1966). 30. Ullery, J. C., Boutselis, J. G., and Botschner, A. C. Microinvasive carcinoma of the cervix, Obstet. Gynecol. 26, 866-875 (1965). 31. Way, S. Microinvasive carcinoma of the cervix, Acta Cytol. 8, 14-15 (1964). 32. Lohe, K. J. Early squamous cell carcinoma of the uterine cervix. I. Definition and histology, Gynecol. Oncol. 6, lo-30 (1978). 33. Kaufmann, C., Ober, K. G., and Huhn, F. 0. Das beginnende Karzinom der Cervix uteri (sog. Mikrokarzinom). Ein Erfahrungsbericht zur Prognose und Therapie an Hand von 130 Beobachtungen, Geburtsh Frauenheilk. 25, 112-13 1 (1965). 34. Ober, K. G., and Huhn, F. 0. Arch. Gyniikol. 197, 262-290 (1962). 35. Zinser, H. K., Meissner, H., and Bdtzelen, H. P., Diagnostische und therapeutische Betrachtungen an 403 Fnj’hfallen, Geburtsh. Frauenheilk. 23, 321-342 (1%3).
ONCOLOGY
6, 31-50 (1978)
Early Squamous
Cell Carcinoma
of the Uterine
Cervix
II. Clinical Results of a Cooperative Study in the Management of 419 Patients with Early Stromal Invasion and Microcarcinoma
K. J. LOHE,* E. BuRGHARDT,t H. G. HILLEMANNS,§ C. KAUFMANN,$ K. G. OBER,** AND J. ZANDER* *First Department Munich, Munich, Graz, KJniversity
of Obstetrics and Gynecology and School of Midwives, University of and TDepartments of Obstetrics and Gynecology, University of Graz, of Freiburg, Freiburg, $University of Cologne, Cologne, and **University of Erlangen, Erlangen, West Germany
Received March IO, 1977 Clinical studies and therapeutic modalities in 285 patients with early stromal invasion and 134 patients with microcarcinoma collected from six different university hospital departments of gynecology are presented as a contribution to the controversial problem concerning the proper treatment of early cervical cancer. In all six departments, clinical investigation and histologic studies are carried out in a comparable manner. Of the patients, 72% with early stromal invasion and 41% with microcarcinoma were treated with conization or with abdominal, respectively vaginal hysterectomy only, i.e., not with the usual radical cancer therapy. After long-term follow-up, no paiient with early stromal invasion has died: in three patients who died from microcarcinoma, a causal relationship seems to have existed between the fatal cause and microcarcinoma. Our own results and comparable data reported in the literature allow the conclusion that in patients with early stromal invasion or microcarcinoma, a restricted cancer therapy may be possible, just as in patients with carcinoma in situ. If intraluminal tumor invasion is demonstrated in the diagnostic biopsy, an additional lymphadenectomy is advisable. A radical extirpation of parametrial tissues is in no case necessary.
Various opinions exist about how to treat early squamous cancer of the uterine cervix. Views on treatment range from rather conservative methods to radical ones. Thus, it is still a matter of discussion as to which therapy will finally offer a maximum number of advantages to the patients. In the controversy on the problem of early cervical cancer, we shall try to answer the question of which type of management will finally guarantee a “minimal, effective, and safe treatment” [26]. 1. PATIENT MATERIAL
In order to obtain significant results, it was necessary to collect as extensive and well suited a patient material as possible. Therefore, we extended our investigation from the beginning to the departments of gynecology at the Universities of Erlangen, Freiburg, Graz, Heidelberg, and Cologne. All these hospitals have, for 31 0090-8258/78/0061-0031$01.00/0 Copyright @ 1978 by Academic Press, Inc. All rights of reproduction in any form reserved.
32
LOHE
ETAL.
many years, been concerned with the problem of cervical cancer. They all have a pathology laboratory of their own which, by means of special methods of tissue preparation, guarantees a thorough and reliable routine diagnosis. At the same time, it allows scientific problems to be solved. Methods of tissue processing are very similar at all clinics mentioned and correspond to the histologic technique described in the preceding study [321. At these six departments of gynecology, the authors of this paper examined all available histologic tissue slides from patients with early squamous cancer of the cervix and reevaluated the diagnosis of early stromal invasion or microcarcinoma according to the definitions given in the preceding paper [32]. Of 419 patients with early cervical cancer, 285 patients with early stromal invasion (ESI) and 134 patients with microcarcinoma (MC) were selected as being suited for the present investigation. Table 1 gives the number of cases for each clinic. 2. AGE OF PATIENTS
The age distribution of the 419 patients with early cervical cancer is shown in Fig. 1 in groupings by 5-year intervals. The youngest patient with either ES1 or MC is 23 years old. The oldest patient with ES1 is 69 years old and with MC is 7 I years old. Both lesions are most frequently found in patients around the age of 40. Of the patients, 71% with EST (202) and 70% with MC (94) are in their 30s or 40s. ES1 (7%) and MC (3%) are rarely observed before the age of 30. The average age of the 285 patients with ES1 is 43.9 k 1.1 years and of the 134 patients with MC is 44.6 + 1.6 years. 3. SYMPTOMS
AND SIGNS
(VAGINAL
DISCHARGE,
BLEEDING,
AND PAIN)
Examining the frequency of typical gynecological signs and symptoms-vaginal discharge, bleeding, and pain-in our 419 patients suffering from early cervical cancer, we found that 130 out of the 285 patients with ES1 (46%) and 76 out of the 134 patients with MC (57%) complained of one or more of these symptoms. In other words, at the time of the examination, more than 50% of the patients with ES1 and almost 50% of the patients with MC were free of any symptoms and signs. Of the 285 patients with ESI, I6 (6%) had a white-yellowish discharge and 29
DISTRIBUTION
TABLE 1 OF THE PATIENTS WITH EARLY STROMAL INVASION MICROCARCINOMA IN THE DIFFERENT CLINICS
Clinic
ES1
MC
Total
Erlangen Freiburg Graz Heidelberg Cologne Munich
2s 60 99 IO 88 3
17 22 33 8 52 2
42 82 132 18 140 5
285
134
419
Total
’
AND
Percentage 10 20 32 4 33 1 100
MANAGEMENT
OF EARLY
CERVICAL
33
CARCINOMA
medium
ESI age:43,9y.?l,l
m
MC
medium
age:44,6y.tl.6
(n-265)
(n-,34)
40
30
20
10 c t25
26-30
FIG. 1. The distribution microcarcinoma by age.
31-35
36-40
41-45
46-50
of 285 patients with
51-55
56-60
61-65
BB-vyears
early stromal invasion and 134 patients with
(10%) had a red-brownish discharge. Of the 134 patients with MC, 14 had a white-yellowish discharge (10%) and 26 had a red-brownish discharge (19%). Fifty-seven of the 285 patients with ES1 (20%) and 34 of the 134 patients with MC (25%) complained of anomalies of uterine bleeding in the form of spotting or menstruation-like or heavier bleeding, respectively. Taking the so-called contact bleeding, which is known to be an important diagnostic criterion for clinical cervical carcinoma, as a special type of hemorrhage of its own, one finds that 31 (11%) of the 285 patients with ES1 and 18 (13%) of the 134 patients with MC mentioned this important symptom. Twenty-six (9%) of the 285 patients with ES1 and 9 (7%) of the 134 patients with MC complained of various pains in the region of the abdomen. This symptom is thus of no value in the diagnosis of early cervical cancer. In the pertinent literature, abnormal bleeding is also reported to be the main symptom of early cervical cancer [8, 15, 19, 20, 271. Specific symptoms for early lesions do not exist. Besides bleeding anomalies, contact bleeding and redbrownish discharge may, within certain limits, point to early cervical cancer. 4. DlAGNOSTlC METHODS: MACROSCOPIC AND COLPOSCOPIC EVALUATION OF THE PORT10 AND CYTOLOGY
As expected, the macroscopic examination of the surface of the portio offers no reliable means for the detection of early cervical cancer. Only in 50 (18%) of the 285 patients with ES1 and in 38 (28%) of the 134 patients with MC did the macroscopic evaluation of the portio suggest the possibility of a malignant lesion necessitating further diagnostic procedures. Colposcopy is a more reliable method for the detection of early cervical cancer. Breaking down the colposcopic findings obtained from our 251 colposcopied patients with ES1 and our 113 colposcopied patients with MC into negative,
34
LOHE
ETAL.
suspicious, and positive colposcopic findings according to Kern’s classification [ 141, 188 out of the 25 1 patients with ES1 (75%) and 83 out of the 113 patients with MC (73%) showed suspicious or positive colposcopic findings. One-fourth of all colposcopied patients, however, had a normal portio colposcopically. Intracervitally located atypical epithelium cannot be detected by colposcopic examination. Thus, we later found by microscopic examination that 33% of the individual foci with ES1 and 34% of the individual foci with MC were located within the cervix. As compared to colposcopy, cytology assures a considerably higher degree of accuracy and significance. For 262 of the 276 cytologically examined patients with ES1 (95%), the presence of a malignant squamous cell lesion at the cervix could be predicted on the basis of suspicious and positive cytologic findings. Other authors [2, 15, 18, 19, 27, 301 report similar results of correct cytologic diagnosis ranging from 82 to 100% for patients with ESI. The same applies to patients with microcarcinoma. In our 129 patients with MC, cytologic accuracy was 92% (118 out ofa 129 patients). Fidler and Boyd [81 report an accuracy figure of 90%. For certain clinical situations, it is important to know that very often cytology will help diagnose cancerous invasion also in the case of early carcinoma of the cervix. After cytologic examination, we suspected invasion in 86% of our patients with ES1 and in 80% of our patients with MC. Of 31 histologically verified microinvasions, Ng.et al. [24] with the help of cytology correctly diagnosed 27 (87%) and stated: “Objectively it is possible to recognize microinvasion in cellular samples.” Of all the usual diagnostic methods apt to detect an early lesion, cytology, therefore, is the most important. Colposcopy allows us to localize exactly suspicious epithelial areas of the cervix and to sample them. With the naked eye, however, early lesions cannot be detected. 5. MICROSCOPIC
DIAGNOSIS: “EARLY STROMAL OR “MICROCARCINOMA”
INVASION”
A diagnosis of “early stromal invasion” or “microcarcinoma” was made for each of the 419 patients with early cancer of the cervix on a tissue specimen which guaranteed reliable diagnostic statements. The types of tissue samples obtained at the time of the pretherapeutic study and during the definitive therapy are summarized in Fig. 2. The “small” tissue samples- biopsy and curettage of the cervix and the portio-from 20% of the patients with ES1 and from 34% of the patients with MC are represented at the top half of the figure and the “large” tissue samples-ring biopsy, conization, and amputation of the portio, cervical stump, and uterus-from 80% of the patients with ES1 and 66% of the patients with MC are represented at the bottom half of the figure. In all cases of small biopsies in which category fall all extramural cases with a pretherapeutic histologic diagnosis, the subsequent histologic examination of the uterus followed. Thus, the whole lesion of the cervix could be clearly assessed in each case. The material selected for this investigation includes no case in which the diagnosis of early carcinoma was based on a small biopsy alone. Also, in three-quarters of the cases of the large tissue samples, it was possible to examine the uterus histologically. Further growth of cancer beyond the stage of
MANAGEMENT
OF
EARLY
128 ~:...:..::..::..:,..::..:~
CERVICAL
K s
191 3 3 2aE I %
100
a0
60
40
..::..::...y.:~.:: ..,,. , 54 I
PA
6B
1
CERV-ST 9
35
CARCINOMA
a 3
I
11 I 20
20
uterus
m 40
1 60
g&y; I
I
a0
100
x
FIG. 2. The composition of the different types of biopsies in 419 patients (285 ESI, left; 134 MC, right) in whom a diagnosis of early stromal invasion and microcarinoma was made. In the upper box are the “small” biopsies and in the lower box are the “large” biopsies. Each type of biopsy (black columns) shows the corresponding number of uteri later removed and studied in their entirety (dotted columns). ausw, extramural diagnosed cases: pe, biopsy; abr, curettage: absch, curettage of the portio; RB, ring biopsy; KS, conization; PA, amputation of the cervix: CERV-ST, cervical stump; 4, no biopsy before hysterectomy.
microcarcinoma could thus be excluded. In the remaining cases, the large biopsy had already shown the total spread of the cancer infiltration. From 45 patients with ES1 and MC, respectively, no tissue samples were taken before hysterectomy. The diagnosis of a beginning carcinoma was first made by histologic examination of the uterus. These cases rank with the large tissue samples. 6. THERAPY
The therapy given to the 419 patients with beginning cervical cancer ranges from conization to radical operation with subsequent radiation treatment (Fig. 3). With the conization of 66 of the 285 patients with ES1 (23%) and 16 of the 134 patients with MC (12%), a very restricted method of treatment was chosen. Thirteen of the 66 conizated patients with ES1 (20%) and 9 of the 16 conizated patients with MC (56%) were given radiation treatment postoperatively (radium and/or X ray and telecobalt). Vaginal hysterectomy was the preferred therapy in the majority of cases. One hundred eighteen of the 285 patients with ES1 (42%) and 37 of the 134 patients with MC (28%) were treated by this method. In three patients suffering from ES1 (3%) and in three patients suffering from MC (8%), the operation was followed by radiation. In the case of 39 patients with ES1 (14%) and 15 patients with MC (1 I%), abdominal hysterectomy was performed. Postoperative radiation treatment became necessary in two cases of ES1 (5%) and in one case of MC (7%).
36
LOHE
ETAL.
42 %
FIG. 3. The different treatments applied at the six clinics in 285 patients with early stromal invasion (top) and 134 patients with microcarcinoma (bottom): cases with postoperative radiation therapy are indicated by black columns. KS, conization; Vag, vaginal hysterectomy; Abd, abdominal hysterectomy; SA, vaginal radical operation according to the method of Schauta-Amreich; TeLi, radical operation according to the method of Te Linde; Wth, radical operation according to the method of Wertheim-Meigs.
Summing up the patients with conization and abdominal or vaginal hysterectomy, we find that 205 of the 285 patients with ES1 (72%) and 55 of the 134 patients with MC (41%) were given minimal or restricted cancer treatment. A treatment more in line with the usual cancer therapy was given to 62 of the 285 patients with ES1 (2 1%) and to 66 of the 134 patients with MC (49%) if we add together the radical operations according to the methods of Schauta-Amreich, Te Linde, and Wertheim-Meigs. From these patients, 9 with ES1 (15%) and 20 with MC (30%) were subsequently radiated. Among the radical methods of therapy given to patients with ESI, the vaginal radical operation according to the method of Schauta-Amreich predominates with 11% (32/285). It was almost exclusively performed at Graz, Austria. Of the patients, 8% (24/285) underwent an abdominal radical operation mostly according to the method of Wertheim-Meigs with pelvic lymphadenectomy and 2% (6/285) underwent the restricted radical operation according to the method of Te Linde. Among the radical methods of therapy applied to the patients with MC, the abdominal radical operation according to the method of Wertheim-Meigs comes first with 27% (36/134). The vaginal radical operation according to the method of Schauta-Amreich, due to its frequent performance at Graz, follows with 21% (27/134). The abdominal method according to Te Linde was performed in 1% (3/134) of the cases. In 29 patients with ES1 and 37 patients with MC, the operation included the removal of the regional lymph nodes. Diagnostic study of every single lymph node revealed no case of metastatic spread of the tumor. During 219 hysterectomies due to ESI, in 23 cases (11%) one and in 74 cases
MANAGEMENT
OF
EARLY
CERVICAL
CARCINOMA
37
(34%) both adnexa were removed. In 14 (12%) of the 118 hysterectomized patients with MC one and in 45 (38%) of these patients both adnexa were extirpated. Even in the case of radical operations, castration is not necessarily part of the cancer therapy. Histological examination of the extirpated adnexa in no case showed metastatic cancer. 7. CLINICAL
PROGRESS
AFTER
TERMINATION
OF TREATMENT
A. Follow-up time. The time interval between the beginning of therapy and the last time the patient is seen or the death of the patient is called follow-up time. Longer follow-up times allow more conclusive evidence and increase the reliability of the survival rate. Figure 4 shows that in more than half of our cases (59% of the patients with ES1 and 69% of the patients with MC), follow-up time was longer than 5 years and in almost one-fourth of all cases (22% of the patients with ES1 and 26% of the patients with MC), follow-up time exceeded 10 years. il B. Further fare of the patients. As we know from checking into the further fate of the 419 patients with early cervical cancer (Table 2), 267 of the 285 patients with ES1 (94%) and 123 of the 134 patients with MC (92%) are alive and well. Among
30
20
10
10
“.
* 5 y.‘66,7% a10 y.= 26,2%
FIG. 4. The follow-up time in 419 patients (285 ESI, top; 134 MC, bottom) with early stromal invasion and microcarcinoma. Dotted, up to 5 years; solid black, 5 to 10 years; crosses, more than IO years.
38
LOHE
ETAL.
TABLE 2 FURTHER FATEOF THE~I~PATIENTS WITH EARLY CERVICAL CANCER (EARLY STROMAL INVASION AND MICROCARCINOMA) Further fate of patients
ES1 (285) (No./%)
MC (134) (No./%)
Early cancer (4 19) (No./%)
Alive and well “Further growth” Recurrence Lost to follow-up Dead By early cancer By other causes
267193.7 210.7 411.4 612. I
123191.8 110.7 312.2 413.0
390193.1 310.7 711.7 1012.4
312.2 413.0
1613.8
1214.2
310.7
these are two patients with ES1 and one patient with MC who had to be treated a second time within the first 6 months after primary treatment because the incompletely removed atypical cervical lesion had grown back again. Among these there are, moreover, four patients with ES1 who 1, 8,9, and 13 years, respectively, after primary treatment had a local tumor recurrence and were then successfully treated. According to our definition, we speak of tumor recurrency when atypic cell findings appear anew more than 6 months after the conclusion of the primary treatment. Changes observed before this time are referred to as “a further growth” of the original tumor. Six patients with ES1 and four patients with MC are missing. The last report, mostly several years after treatment, showed unremarkable gynecological findings. Most of the missing patients had moved to unknown addresses. In the course of time, 12 patients with ES1 and 7 patients with MC died (Table 3). Except for three cases with MC, death was not connected with the early cervical cancer. The progress of the disease of these three patients with MC is described in detail below. First case: Department of Gynecology, University of Cologne, Hist. Nos. 300 and 340158. H. Berta. A 46-year-old patient came to the hospital with hypermenorrhea. The cervix was colposcopically suspicious and cytologically Pap. V on two occasions. A conization was performed with fractionated curettage. A microcarcinoma (5 x 4 x 3 mm) and, at the cone edges, a carcinoma in siru were removed. An extended abdominal hysterectomy was performed according to the method of Wertheim with extirpation of both adnexa and no lymphadenectomy. The tissue samples obtained at operation revealed a carcinoma in situ, which was, however, not totally resected at the vaginal resection border. There was a postoperative application of 1200 mgeh of radium intravaginally. First of all, the patient was lost to follow-up. Further searching disclosed that, almost 4 years after the first treatment, the patient had been admitted to a small local hospital because of cachexia. According to the hospital director, the patient had died of peritoneal carcinomatosis, the primary tumor being unknown. No autopsy was carried out. Under critical assessment of the case it becomes evident that due to the lack of histological verification of a tumor recurrence, the cause of death remains uncertain. Kaufmann et al. [33] have already described this case and expressed their doubts about a connection between the tumor recurrence and the microcarcinoma. Although it is impossible to exclude the existence of a malignant tumor of another kind, this case, with reservation, is regarded as recurrent microcarcinoma with subsequent death.
(47) (47) (39) (63) (55) (48) (51)
ES1 (52) ES1 (56) ES1 (50) ES1 (53) ES1 (35) ES1 (61) ES1 (36) MC (49) MC (46)
ES1 ES1 ES1 ES1 ES1 MC MC
MC (33) MC (46) MC (64)
Type of early cancer (age of patient in years)
THE CAUSES
3
-
-
1 month 3 years 4 4 5 6 7 5 IO
1 year I 3 6 9 I I
(2) Patients died of other malignant tumors Pelvic tumor Pelvic tumor
(3) Patients died of other causes
2 years 4 7
CERVIX
INVASION
(1) Patients died of early cervical cancer Recurrent tumor, pelvic wall Peritoneal carcinomatosis -
EARLY STROMAL OF THE UTERINE
TABLE
Survival time
IN 12 PATIENTS WITH MICROCARCINOMA
Gynecologic finding
OF DEATH
AND IN
MC MC MC
Cause of death
WITH
Cerebral vascular accident Car accident Cerebral vascular accident Acute heart failure Car accident “Old age” Car accident Diabetes: cerebral vascular accident Pneumonia after gallbladder surgery
Sarcoma of the femur Adenocarcinoma (?) Breast carcinoma Liver carcinoma Breast carcinoma Brain tumor Carcinoma of the fallopian tube
7 PATIENTS
40
LOHE
ETAL.
Second case: Department of Gynecology, University of Cologne, Hist. Nos. 1131 and 1245158. V. Ruth. A 33-year-old patient with no complaints went for a routine checkup. The portio was colposcopically suspicious and cytologically Pap. IV and 11. A conization was performed and a microcarcinoma (8 x 9 x 3 mm) was totally removed. An extended vaginal radical operation according to the method of Schauta was performed without extirpation of the adnexa. During the operation, no enlarged lymph nodes were palpable in the pelvis. The tissue obtained at the operation showed no proof of atypical epithelium. Sixteen months after the first diagnosis, a resistance at the right pelvic wall was palpated. Despite intensive radiation therapy (conventionally, 4000 R/O.D. and, additionally, 1600 R with cavity X-ray tube as well as 7400 R/O.D. with cobalt-60 5 months later), the patient died 2 years after the beginning of therapy. No autopsy was carried out. Under critical assessment, a recurrent microcarcinoma seems to have been the most likely cause of death. But here, too, no histological verification or autopsy was made. This case has already been described by Ober and Huhn [34], by Zinser er al. [35], and by Kaufmann el al. [331. None of these authors questions microcarcinoma as the ultimate cause of death. Nevertheless, a different primary tumor is, at least theoretically, not impossible. However, with reservation, the case is considered as microcarcinoma recurrence with subsequent death. Third case: Department of Gynecology, University of Cologne, Hist. No. 1431158. M. Margarete. A 64-year-old patient came for an examination because of a brownish discharge. The portio was colposcopically normal and cytologically Pap. IV on two occasions. An abdominal hysterectomy was performed with removal of both adnexa. In the tissue obtained at operation, a totally removed microcarcinoma (4 x 3 x 3 mm) was diagnosed. Gynecological checkups in the course of the next 5.5 years gave no evidence of a recurrence. The patient was then lost to follow-up. Thorough investigation revealed that 1.75 year after this date, the patient had been admitted to a local hospital. She was in poor health with tumor metastases in the skull, lungs, pelvic bones, and femur and she received drug therapy. Gynecological examination showed a smooth vaginal stump with no retrovaginal infiltration. Death occurred 7.5 years after primary treatment. No autopsy was performed. Under critical evaluation, we must say that in this case also recurrence was not ascertained histologically or by autopsy. Theoretically, a primary tumor of another kind may have been the possible cause of death. Here too, the case as a microcarcinoma recurrence with subsequent death is made with reservation.
Therefore, none of the 285 patients with ES1 died of this disease, while among the 134 patients treated because of MC, three cases of death caused by this cancer are reported. It must be pointed out, however, that due to the lack of histologic confirmation and autopsy in all three cases, a definite correlation between MC and cause of death could neither be proven nor ruled out. The listing of the patients as “having died of MC” is based merely on historical evidence. Accordingly, we have a 2.2% maximum lethality due to microcarcinoma. C. Survival rate. Table 4 gives the so-called survival rate of the 419 treated patients with early squamous cancer of the cervix including all patients lost to follow-up or deceased. The 5-year survival rate for the patients suffering from ES1 is 95% and for those suffering from MC is 94%. The lo-year survival rate is 86 and 85%, respectively. Thus, the survival rate for our patients with early cervical cancer is, on the average, 10% higher than that for our patients with Stage IB cervical cancer. 8. DISCUSSION AND CONCLUSIONS
For the purpose of comparing and discussing the results of cases collected from six university hospital departments of gynecology with those reported in the
MANAGEMENT
OF
THE SURVIVAL RATES OF CELL CARCINOMA
Survival rates Total 5 years IO years
EARLY
CERVICAL
41
CARCINOMA
TABLE 4 419 PATIENTS
WITH OF THE UTERINE
EARLY SQUAMOUS CERVIX
ES1
MC
Early cancer
[No. WI
[No. (%)I
[No. (%)I
267 of 285 (93.7) 167 of 176 (94.9) 63 of 73 (86.3)
123 of 134 (91.8) 92 of 98 (93.9) 35 of 41 (85.4)
390 of 419 (93.1) 259 of 274 (94.5) 98 of 114 (85.9)
literature, especially in view of therapy and prognosis, we tried to apply our definition and classification of cases of ES1 and MC to the published cases. Publications dealing with the observation of less than 20 individual cases and all cases of “microcarcinoma” not corresponding to our definition of early cervical cancer are not considered in our discussion. Beginning with the histologic tumor definition, three fairly comparable groups could be set up: (I) 895 observations reported in the literature largely corresponding to our definition of ES1 (Table 5); (2) 435 observations reported in the literature largely corresponding to our definition of MC (Table 6): and (3) 1159 cases of early cervical cancer reported in the literature which, by our definition, do not allow a clear separation into ES1 and MC or the survival rates of which are not broken down according to these two tumor forms (Table 7). (1) In the 895 published cases of ES1 as well as in our 285 own cases, radical operation was performed with about equal frequency (17% of the 895 cases compared with 22% of our own cases). The survival rate of all patients with ES1 is, with only a few exceptions, higher than 95%. The lower figures reported by Dilworth and Maxwell [7] (90.5%), Thompson [27] (82%), and Ng and Reagan [23] (82%) and our own rate of 94% are due to the high number of patients deceased in the meantime or lost in the follow-up period. Out of the 895 patients, 13 had a tumor recurrence (1.5%) which, in the case of four patients (0.4%), caused subsequent death. Of our own 285 patients, none died of ESI. Four patients are considered to be recurrences (1.4%). Of the four patients who had ES1 and had died of this disease [ 151, two had been given primary treatment with radium, one had been given combined radium-Xray therapy, and one had been treated with simple hysterectomy. In all these cases, tumor recurrence was palpated within the pelvis. In three cases, metastatic disease beyond the small pelvis had occurred and, in three cases, recurrence had developed after more than 5 years. Kolstadt [15], however, stresses that in the case of one deceased patient, the correct diagnosis should have been Stage IB carcinoma rather than microcarcinema and that in another patient, a metastasizing cancer of the vulva which had been operated 8 years before the ES1 was detected might have been the cause of death. Since Kolstadt fails to give details of the methods of histologic examination, we cannot help doubting the reliability of the histologic diagnosis of ES1 in the other two cases also.
Total Percentage
Latour et al. [ 171 (1957) Dilworth and Maxwell [7] (1962) Christopherson and Parker [5] (1964) Ullery et al. [30] (1965) Green [lo] (1966) Margulis et al. [19] (1967) Thompson [27] (1968) Kottmeier [16] (1969) Ng et al. [24] (1969) Kolstadt [ 151 ( 1969) Boyes et al. [3] (1970) Marcuse [18] (1971) Boutselis et al. [2] (1971) Total Percentage Own results Total Percentage
Reference (year)
TABLE
5
97 Rb 22 KS, 20 Kb 18 KS, 1 Kb, 1 Ut 3 Kb, 24 KS, 1 Ut 40Ks, 12Ut 22 KS, 4 Kb ? KS, ? Kb ? KS, ? Kb 59 KS, 5 Kb, 2 Ut ? KS, ? Kb ? KS, ? Kb ? KS, ? Ut 45 KS
49 Kb, 197 KS, 39 Ut
285 100 1180 100
Type of biopsy”
97 42 20 28 52 26 49 79 66 164 205 22 45 895 100
Number of cases
AND THEIR
285 PATIENTS
15u5 53.311.8 459158 38.914.9
127 10.8
26l19132 1157/15/16l-307153 34.315.9
27121 12l8/I/15l1 I/-
Hysterectomy +/- radb (No.)
WITH
128/85 10.917.2
5319 18.613.2
1Ol-120 2/3l3123 75176 8.418.5
4l49l-
3l--I9 -I1 l/23
Radical operation +/- radb (No.)
Type of therapy
RESULTS IN 895 PATIENTS IN OUR OWN SERIES
53 18.6
74 8.3
-
7 21 1
-
4 3 1 37
Rb-KS-Pa” (No.)
TYPES OF DIAGNOSTIC BIOPSIES AND OF THERAPEUTIC PROCEDURES EARLY STROMAL INVASION IN THE LITERATURE AND IN
323 27.3
13 4.5
42 18 10 3 11 -79 30 86 25 3 3 310 34.6
Radb (No.1
s 5 G .“:
Therapeutic
4 0.3
-
-
4 0.4
-
412.4
-
-
-
-
Dead from recurrent tumor (No./%)
results
4.2 34 2.9
12
222.5
3/1.8 112.2
-316.1 212.5 619.I
l/1.0 419.5 115.0 113.6
Dead from other causes (No./%)
93.7 1124 95.3
267
857 95.8
157 205 22 44
52 26 40 77 54
96 38 19 27
Alive and well (No.1
95.3
93.7
95.8
95.7 100.0 100.0 97.8
100.0 100.0 81.6 97.5 81.8
99.0 90.5 95.0 96.4
Survival rateC (%)
94.9
? 93.5 ? 95.5
?? ? 97.5 95.8
‘I. . 85.7 ? 7
5-year survival rate (%I
’ Abbreviations used: Kb, punch biopsy; Rb, ring biopsy; KS, conization; Pa, amputated portio; Ut, uterus. b Rad, radiation therapy (radium, X ray, or telecobalt or combined radiation therapy). ’ Survival rate = number of patients alive and well minus the number of patients lost to follow-up or dead from their tumor or from other causes.
17 1.4
1.4
2.1 18 1.5
Total Percentage
4
131.5
412.4 411.9 112.2
213.0
217.7 -
6
-
17 >lI 7 30
17
-6112.2 6/9.1
7 10 14 8 21
-
Own results Total Percentage
-
9 IO 6 >5
121.1
(N:.?%)
Recurrence (No./%)
Total Percentage
Latour et a/. [17] (1957) Dilworth and Maxwell [7] (1962) Christopherson and Parker [5] (1964) UUery et al. [30] (1%5) Green [IO] (1966) Mar&s et al. [I91 (1967) Thompson [27] (1968) Kottmeier [ 161 (1969) Ng et al. [24] (1969) Kolstadt [I51 (1969) Boyes ef al. [3] (1970) Marcuse [18] (1971) Boutselis et al. (21 (1971)
Reference (year)
Lost to follow-
Longest followup time (years)
5
8
F Fi
E z ?
2 0
F
%
5
F 2 s? 3
17
8 >I1 27
‘-’ See Table 5, footnotes a-c. d 41 hysterectomies or radical hysterectomies
Total Percentage
Own results Total Percentage
Kottmeier [ 161 (1969) Boyes et al. [3] (1970) Mestwerdt and Wespi [20] (1973) Total Percentage
Reference (year)
(no further distinction
10 1.8
4 3.0
613.5 6 1.4
(N::%)
possible).
27 4.7
3 2.2
18/8.8 613.5 24 5.5
Re currence (No./%)
Therapeutic Dead from recurrent tumor (No./%)
Longest followup time Wears)
Lost to follow-
35 6.2
569 100
17 3.0
3 2.2
1115.4 311.7 14 3.2
7 5.2
Total Percentage
36 Kb, 71 KS, 27 Ut
134 100
6.5
27 28
1
Own results Total Percentage
?Ks, ?Kb
-
Rb-KS-Pa” (No.)
100
174 435
Mestwerdt and Wespi [20] (1973) Total
?Ks, ?Kb ?Ks, ?Kb
Type of biopsy”
Percentage
57 204
Number of cases
Kottmeier [ 161 (1969) Boyes et al. 131 (1970)
Reference (year)
6 WITH
9 1.5
4 3.0
I/1.8 412.3 5 1.1
533 93.7
123 91.8
56 193 161 410 94.3
93.7
91.8
98.2 94.6 92.5 94.3
46l20 4814 35.8/3.0 34.3114.9 _-____________ 4] _------__--__87/20 136123 23.914.0 !_5_:3’3.5 _____________ 7.2 ___________ results Dead from Alive other and Survival causes well rateC (No./%) (96) (No.1
-- / A--7i9 _______ 41 d _______________ l88/41/!!!!9 _______ 4* _____________ .I!!‘20.214.3 _____________ 9.4 __-_________ B_!!-
Type of therapy Hysterectomy Radical operation +/- rad” (No.) +/- radb (No.)
PROCEDURES AND THEIR RESULTS IN 435 PATIENTS AND IN 134 PATIENTS IN OUR OWN SERIES
TABLE
TYPES OF DIAGNOSTIC BIOPSIES AND OF THERAPEUTIC MICROCARCINOMA IN THE LITERATURE
93.9
98.2 93.5 92.3
S-year survival rate (%)
227 39.9
9 6.7
50.2
143 18 218
57
Radb (No.)
0’ 3 q $
%
MANAGEMENT
OF
EARLY
CERVICAL
CARCINOMA
45
(2) In 435 patients with MC found in the literature and in our 134 patients with MC, radical therapy was also performed with about equal frequency (50% of the 435 patients and 4% of our own 134 patients). Radiation therapy was, however, definitely the preferred treatment in the 435 patients of the control group. The survival rates of all 569 patients with MC are above 90%. They range from 92% (our group) to 98% [ 161. The survival rate of our patients is biased by the high number of patients lost to follow-up or deceased. Out of the 435 patients with MC, 24 (5.5%) were later affected by a tumor recurrence; of these, eventually 14 (3%) died (Boyes et al. [3], 11 deceased patients; Mestwerdt and Wespi [20], 3 deceased patients). Out of our 134 patients with MC, 3 patients had a tumor recurrence. These three patients later died, apparently of this tumor. Critical analysis of the 14 patients who died of microcarcinoma [3, 201 shows that tumor size and microcarcinoma by our definition can only be compared restrictively. By occult invasive carcinoma, Boyes et al. [3] mean a lesion where there is frank invasion by confluent masses of neoplastic cells resulting in a measurable tumor from several millimeters to 1.5 cm or more in size. Only in one of the 11 deceased patients did the invasive lesion measure less than 5 mm in size. In the other cases, the lesion was greater than 5 mm. The three cases of Mestwerdt and Wespi [20] also lack a reliable definition of the size of the microcarcinoma. Only the maximum invasion depth of 5 mm is stated. Of the 14 patients who died of MC, 9 succumbed during the first 5 years after primary treatment and 5 died later [3, 201. Eight patients were primarily radiated, one patient had a vagina1 radical operation, and five patients had an abdominal or vaginal hysterectomy. For the radiated patient treated by Mestwerdt and Wespi 1201, death due to carcinoma could not be proven with certainty (radiation fistula?). (3) Almost all of the 1159 patients with ES1 and/or MC reported in the literature had been operated (92% of the patients). Radical operation was the most frequent surgical treatment given to 51% of the patients, of whom 8% were subsequently radiated. For almost every single group of the 1159 patients, the survival rate amounts to over 90%. The mean survival rate of all 1159 patients as a whole is 96%. In the course of time, 16 patients (I .4%) were affected by a tumor recurrence; of these, at least five patients (0.4%) died of their disease. Artner and Holzner [II do not give details on whether their six patients died of either a primary or a recurrent tumor. Of the five patients who died of early cervical cancer, one died of a vaginal recurrence after hysterectomy [13], one died of metastases of unknown localization 6 years after vaginal hysterectomy [22], one died of a cervical recurrence 4 years after cervical amputation [4], one died of a pelvic recurrence and diffuse metastases 5 years after cervical amputation and abdominal radical operation with lymphadenectomy [4], and one died of a recurrence of unknown localization 4 years after the vaginal radical operation with pre- and postoperative radiation [2 1I. Holtorff [13], however, adds that in the case of one deceased patient, the correct diagnosis should have been macrocarcinoma rather than microcarcinoma.
Total Perc(mtage
Hel,& [II] (1961) HoltortT [13] (1962) Way [31] (1964) Prz$bora [25] (1965) Uhl&ann I291 (1966) Coppleson and Reid [6] (1967) Roman and Latour [26] (1967) Musr+y ef al. [22] (1969) Foushee et al. [91 (1969) MO&r et al. [21] (1970) Brand1 et al. [4] (1970) Artnw and Holzner [I] ( 1971)6 Tscharf [28] (1972)
Reference (year)
1159 100
27
126
85
104
29
91 175 91
54 74 64
?
? KS, ? Kb, ? Ut ? KS 74 Kb ? Op. prep. ? ? ? KS, ? Ut ? KS, ? cervix 104 KS 53 KS, 32 Pa ? 14 KS, 12 Kb, I Ut
76
Type of biopsy
163
Number of cases
7
35 3.0
2
13 (5x+Ini) -
349185 30.117.3
2l-
-l-
1315 3/-
A-
76142 4ll-
5
1
414
31/-
-
-l61/-
6 2
34l84134
WITH
503l90 43.417.8
34l1216 54l7l24126 60/3/49l29l27158 64l126l14l-
Radical operation +/- radb (No.)
Type of therapy Hysterectomy +/- radb (No.)
2 4
Rb-KS-Pa” (No.)
PROCEDURES AND THEIR RESULTS IN 1159 PATIENTS MICROCARCINOMA IN THE LITERATURE
TABLE
TYPES OF DIAGNOSTIC BIOPSIES AND OF THERAPEUTIC EARLY STROMAL INVASION AND/OR
4
1
9
5
97 8.4
-
-
49
-
-
6 23
Radb (No.)
&
9
H m
212.6 311.8 314.0 213.1 412.2 212.1 312.8 414.7
IO 14 I6 8 15 9 17 30 21 I4 12 >5 5
Held [ij] (1961) Holtorff[l3] (1962) Way [3t] (1964) Przybora [25] (1965) Uhlmann [29] (1966) Coppleson and Reid [6] (1967) Roman and Latour [26] (1967) Mussey er a/. 1221 (1969) Foushee et al. [9] (1969) Mosler et al. [2l] (1970) Brand1 dt al. [43 (1970)
Artner and Holzner [I] (1971)d Tscharf 1281 (1972)
results
110.6 818.7 211.9 212.3
Dead from other causes (No./%) 74 I58 54 71 62 91 I71 80 29 98 77
Alive and well (No.) 97.3 96.9 100.0 95.9 96.8 100.0 97.7 87.9 100.0 94.2 90.5
Survival rateC (%)
23 1.9
-
IO 0.9
-
5 0.4
-
I3 I.1
II09 95.7
27
95.7
100.0
94.6 92.2 100.0 100.0 94.3 100.0 97.0 93.4 100.0 94.2
S-year survival rate (%)
a-c See Table 5, footnotes a-c. d In the cases of Artner and Holzner [I] (1971) no separation is possible between patients with a recurrent tumor and patients dead from a recurrent tumor and between patients lost to follow-up and patients dead from other causes.
Total Percentage
110.6 -
l/I.0 l/O.9 212.3 .__..__.________ 614.7_________
412.4 l/O.5 212. I l/O.9 212.3
Recurrence (No./%)
Therapeutic Dead from recurrent tumor (No./%)
___________________________ j/2.3________________________________ II7 92.8
(NAY%)
Reference War)
;:,yr;“.’ up time wears)
Lost to follow-
48
LOHE
ET AL.
In the case history described by Mussey et al. [22] (“no invasion greater than 5 mm was seen in numerous sections of the lesion which involved the cervix circumferentially”), the cervical lesion, too, might have been more than microcarcinoma by our definition. Neither Brand1 et al. [4] nor Mosler et al. [213 give any information or reliable details on tumor size in their patients who died of cancer. If we examine the prognosis of all therapeutic procedures taken together, we come to the conclusion that the risk of dying of ES1 is rather small. Out of our 285 patients none and out of the 895 cases reported in the literature at the most four patients (0.4%) died from their cancer. On the other hand, the risk of dying of MC seems to be higher. This statement is supported by the fact that 14 of the 435 patients with MC reported in the literature (3%) died of cancer as well as 3 of our 134 patients (2%), even if a causal association between MC and death is not definitely proven. Although more than 75% of our patients with l’s1 and more than 50% of our patients with MC were given a restricted cancer therapy, 5-year survival rates of 94.9 and 93.%, respectively, were obtained. The corresponding figure for the almost exclusively radically treated patients in our clinic with Stage IB carcinoma is considerably lower in fact, only 85%. On the other hand, our investigation has shown that even the so-called “extended cancer management” applied to early cervical cancer does not guarantee a 100% cure. At least 14 of the total of 26 cancer deaths in our patient material and in the nearly 2500 cases reported in the literature occurred after radical treatment. Moreover, the role of the pelvic lymph nodes in early cervical carcinoma remains uncertain. The fact that in the treatment of at least 12 of the 26 patients having died of this cancer the regional lymph nodes of the pelvic wall were not resected could lead us to think that these lymph nodes should routinely be removed or radiated. This view is, however, contradicted by the cancer deaths of at least 10 of the patients with lymph node treatment and by the very low frequency of metastatic lymph node involvement in early cervical cancer. The large number of patients cured of early cervical cancer after restricted treatment indicates that in most cases total extirpation of the tumor by either ring biopsy, conization, amputation of the cervix, or simple hysterectomy will be a sufficient therapy. The decisive criterion for a successful treatment is the total elimination of the tumor from the cervix. Morphologic tumor characteristics may be of importance for prognosis. The tissue specimens of the three MCs from our deceased patients show in each case an intensely dissociating tumor growth with lymphatic invasion. Therefore, for the moment, one should take these morphologic characteristics into consideration when choosing therapy. Metastases in lymph nodes of the pelvic wall are rare. Tumor metastases in the parametrial tissues or in the ovary where neither observed in our patient material nor reported in the literature. Operative removal of the parametrial tissues then becomes unnecessary and, thus, the most severe postoperative complications, such as ureteric lesions, can be avoided. From our investigations, we conclude that for patients suffering from the different forms of early cervical cancer as defined herein, the therapeutic concepts
MANAGEMENT
OF
EARLY
CERVICAL
CARCINOMA
49
described below seem to be justified and suited to the severity of the disease. (I) To cure early stromal invasion as well as carcinoma in situ, a total elimination of the lesion by conization or simple hysterectomy is sufficient. Further therapeutic steps are not necessary. (2) Microcarcinoma, due to the higher risk involved as compared to early stromal invasion, calls for a more extensive therapy according to the morphologic criteria of the primary tumor. In the majority of cases, a simple hysterectomy is sufficient. If proof is given that the microcarcinoma was totally removed with the conization, further operative measures, in general, may become unnecessary. If tumor invasion in lymph or blood vessels is diagnosed before the operation, additional lymphadenectomy is advisable. However, the authors, except for Burghardt, assert that radical removal of the parametrial tissues is unnecessary. (3) If the lesion has affected the vaginal wall, a corresponding cuff of the vagina must be removed. (4) The final success of the treatment depends on a long-term and regular follow-up of the patients. The reported data show that, due to the good therapeutic results, early stromal invasion and microcarcinoma according to our definition take a very special place, indeed, in cervical cancer therapy.
REFERENCES I. Artner, J., and Holzner, Zschr.
Geburtsh.
H. Zur Frage der beginnenden Stromainvasion
Gyniikol.
175, 209-217
des Zervixkarzinoms,
(1971).
2. Boutselis, J. G., Ullery, J. C., and Charme, L. Diagnosis and management of stage IA (microinvasive) carcinoma of the cervix, Amer. J. Obstet. Gynecol. 110, 984-989 (1971). 3. Boyes, D. A., Worth, A. J., and Fidler, H. K. The results of treatment of 4389 cases of pre-clinical cervical squamous carcinoma, .I. Obster. Gynaecol. Bit. Commonw. 77, 769-780 (1970). 4. Brandl, K., Georgiades, E., and Kraus, U. Die Bedeutung der Portioamputation und Konisation als diagnostische und therapeutische Massnahme nach suspekter oder positiver Routineuntersuchung der Portio vaginalis uteri, Zschr. Geburfsh. Gyndkol. 172, 113-130 (1970). 5. Christopherson, W. M., and Parker, J. E. Microinvasive carcinoma of the uterine cervix, Cancer 17, 1123-I 131 (1964). 6. Coppleson, M., and Reid, B. Preclinical carcinoma of the cervix uteri. Its nature, origin and management, Pergamon press, Oxford (1967). 7. Dilworth, E. E., and Maxwell, G. E. Superficially invasive carcinoma and carcinomain situ of the uterine cervix, Amer. J. O&et. Gynecol. 84, 83-88 (1962). 8. Fidler, H. K., and Boyd, J. R. Occult invasive squamous carcinoma of the cervix, Cancer 12, 764-771 (1960). 9. Foushee, J. H. S., Greiss, F. C., and Lock, F. R. Stage IA squamous cell carcinoma of the uterine cervix, Amer. J. Obstet. Gynecol. 105, 46-58 (1969). 10. Green, G. H. The significance of cervical carcinoma in situ, Amer. J. Obstet. Gynecol. 94, 1009-1022 (1966). 11. Held, E. Wann und wie operieren wir Collumcarcinome?, Gynaecologia 151, 89-94 (1961). 12. Hillemanns, H. G. Das Cervixcarcinom, Gymikologe 1, 150-166 (1%9). 13. Holtorff, J. Zur Therapie des Mikrokarzinoms am Collum uteri, Geburtsh. Frauenheilk. 22, 1097-I 101 (1962). 14. Kern, G. Carcinoma in situ. Vorstadium des Gebirmutterhalskrebses, Springer, Berlin (1964). 15. Kolstadt, P. Carcinoma of the cervix stage IA. Diagnosis and treatment, Amer. J. Obstet. Gynecol. 104, 1015-1022 (1969).
50
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16. Kottmeier, H. L. Erfahrungen des Radiumhemmet. Stockholm, mit der Behandhmg des Oberflkhencarcinoms und des friihinvasiven darcinoms der Cervix, Arch. Gyniikol. 207, 332-342 (1%9). 17. Latour, J. P. A., Brown, L. B., and Turnbull, L. A. Preclinical carcinoma of the cervix,Amer. J. Obstet. Gynecol. 74, 354-360 (1957). 18. Marcuse, P. M. Incipient microinvasive carcinoma of the uterine cervix. Morphology and clinical data of 22 cases, Obstet. Gynecol. 37, 360-367 (1971). 19. Margulis, R. R., Ely, C. W., and Ladd, J. E. Diagnosis and management of stage IA (microinvasive) carcinoma of the cervix, Obstet. Gynecol. 29, 529-538 (1967). 20. Mestwerdt, G., and Wespi, H. J. Atlas der Kolposkopie, Fischer, Stuttgart, 4th ed. (1973). 21. Mosler, W., Kaiser, P., and Randow, H. Die abgestufte Behandlung der Vor- und Fni’hstadien des Zervixkarzinoms, Deut. Gesundheitsw. 25, 2222-2225 (1970). 22. Mussey, E., Soule, E. H., and Welch, J. S. Microinvasive carcinoma of the cervix. Late results of operative treatment in 91 cases, Amer. J. Obstet. Gynecol. 104, 738-744 (1969). 23. Ng, A. B. P., and Reagan, J. W. Microinvasive carcinoma of the uterine cervix, Amer. J. Clin. Pathol. 52, 51 l-529 (1%9). 24. Ng, A. B. P., Reagan, J. W., and Lindner, E. A. The cellular manifestations of microinvasive squamous cell carcinoma of the uterine cervix, Acta Cytol. 16, 5-13 (1972). 25. Przybora, L. A. Incipient invasion of cervical cancer: Morphological aspects of carcinogenesis in 74 cases, Gynaecologia (Basel) 160, 69-86 (1965). 26. Roman, T. N., and Latour, J. P. A. The effect of early diagnosis on survival statistics in carcinoma of the uterine cervix, Amer. J. Obstet. Gynecol. 97, 739-749 (1%7). 27. Thompson, W. R. Microinvasive carcinoma of the uterine cervix, J. Arkansas Med. Sot. 65, 139-144 (1968). 28. Tscharf, H. Zur Behandlung der Frithstadien des Zervixkarzinoms, drztl. Prax. 24, 4608 (1972). 29. Uhlmann, G. Therapie und Heilungsergebnisse bei Frilhkarzinomen des Collum uteri, Geburtsh. Frauenheifk. 26, 775-780 (1966). 30. Ullery, J. C., Boutselis, J. G., and Botschner, A. C. Microinvasive carcinoma of the cervix, Obstet. Gynecol. 26, 866-875 (1965). 31. Way, S. Microinvasive carcinoma of the cervix, Acta Cytol. 8, 14-15 (1964). 32. Lohe, K. J. Early squamous cell carcinoma of the uterine cervix. I. Definition and histology, Gynecol. Oncol. 6, lo-30 (1978). 33. Kaufmann, C., Ober, K. G., and Huhn, F. 0. Das beginnende Karzinom der Cervix uteri (sog. Mikrokarzinom). Ein Erfahrungsbericht zur Prognose und Therapie an Hand von 130 Beobachtungen, Geburtsh Frauenheilk. 25, 112-13 1 (1965). 34. Ober, K. G., and Huhn, F. 0. Arch. Gyniikol. 197, 262-290 (1962). 35. Zinser, H. K., Meissner, H., and Bdtzelen, H. P., Diagnostische und therapeutische Betrachtungen an 403 Fnj’hfallen, Geburtsh. Frauenheilk. 23, 321-342 (1%3).