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Histological criteria for the prognosis in patients with operated squamous cell carcinoma of the cervix
GYNECOLOGIC
ONCOLOGY
13, 184-194 (1982)
Histological Criteria for the Prognosis in Patients with Operated Squamous Cell Carcinoma of the Cervix J. BALTZER, K. J. LOHE, W. K&CKE,
AND
J. ZANDER
1. Frauenklinik der Universitiit Miinchen, 8000 Munich 2, Maistrasse 11, and Institut fir Medizinische Datenverarbeitung, Statistik und Biomathematik der Universitiit Miinchen, 8000 Munich 70, Marchioninistrasse 15, West Germany
Received June 29. 1981 Histological criteria for the prognosis were examined in 718 surgical specimens with squamous cell carcinoma of the cervix which were subjected to uniform histological workup. In the distinction between the invasion front and the tumor center the tumor grading in the region of the invasion front had particular prognostic significance. A very pronounced dissociative tumor growth also had an influence on the 5-year survival rates. The poorest prognosis was registered with patients in whom an invasion of the carcinoma into blood vessels could be observed. Taking into account the inflammatory stroma reaction in the center of the tumor and at the invasion front, more favorable recovery results could be registered with a heavy inflammatory infiltration in the region of the invasion front. The increase in tumor volume lead to a deterioriation of the recovery rates. These poorer recovery rates were due to the increase of the macrometastases, whereas tumor cell embolization into lymph nodes did not significantly influence the recovery results.
The recovery rates of patients with operated squamous cell carcinoma of the cervix depend not only on the histologically documented extent of the carcinoma, but also on other tumor parameters. Gusberg et al. [15] pointed out virulence indices in cancer of the cervix. The significance of qualitative and quantitative tumor parameters will be examined below. PATIENTS AND METHODS From the material of a cooperative study of 1092patients with operated cervical carcinoma at four university departments of gynecology and obstetrics [Cologne (Professor C. Kaufmann), Erlangen (Professor K. G. Ober), Heidelberg (Professor J. Zander), Mtinchen I (Professor J. Zander)] surgical specimens from 718 patients with squamous cell carcinoma of the cervix were evaluated [48]. In all patients the extended abdominal uterine extirpation with obligatory lymphadenectomy according to Mackenroth-Latzko-Meigs had been previously performed. The surgical specimen was uniformly examined histologically according to the methods specified by Schneppenheim et al. [33], Matuschka [26] and Lohe et al. [20]. Large surface sections were prepared from all tissue blocks and stained with iron-hematoxylin (Weigert) and eosin. All histological slides were seriously examined once more by one and the same investigator on the basis 184 0090-8258/82/020184-l1$01.00/O Copyright All rights
0 1982 by Academic Press, Inc. of reproduction in any form reserved.
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of a prepared characteristics catalog. Tumor maturity, growth form of the carcinoma, tumor invasion into blood and lymph vessels, as well as extent of the reactive stromal inflammation were evaluated. Tumor maturity was divided into well-, moderately, and poorly differentiated carcinomas. However, differences in the same tumor made the tumor grading more difficult. In order to enable better evaluation the center and the invasion front of the carcinoma were evaluated separately. The irregularity of contour of the tumor growth was registered as “dissociating tumor growth.” For all tumors the extent of dissociative tumor growth was registered by recording an intense, mild, or absent tumor dissociation. To evaluate the reactive stromal inflammation in the tumor region, a distinction among heavy, mild, and absent lymphoplasmacellular infiltration of the stroma was made for every visual field. In order to enable a more exact evaluation, the tumor center and the invasion front were also evaluated separately here. The tumor volume was determined from the height, width, and length of the tumor as a measure of the size of the carcinoma. It was assumed on the basis of earlier random sample calculations by our study group [5] that the growth of the carcinoma in the cervix most likely corresponds to an ellipsoid. In the evaluation of the metastatic spreading of the tumor to the lymph nodes, a distinction was made among metastasis-free lymph nodes, tumor cell embolisms, and micro- and macrometastases [3]. All individual data were transferred to punched cards. The data were processed statistically with the SAVOD dialog system for interactive processing and evaluation of mass medical data [36]. All data are significant at the 1% level. RESULTS In 718 surgical specimens, evaluation of the tumor center revealed a welldifferentiated carcinoma in 16.6%, a moderately differentiated carcinoma in 56.7%, and a poorly differentiated carcinoma in 26.7%. In the region of the invasion front, the percentage of well-differentiated carcinomas amounted to 4.6%; of moderately differentiated carcinomas, 43.3%; and of poorly differentiated carcinomas, 52.1% (Fig. 1). 56.7
603
poorly
m m
moderately
well
tumor centre invasion front
FIG. 1. Separate determination of the degree of tumor maturation for the tumor center and invasion front.
186
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ET AL.
The poorly differentiated carcinomas in the tumor center could also be recognized at the invasion front with the same degree of maturation in 90.1%. In carcinomas with a moderately differentiated tumor center the same degree of maturation was present at the invasion front in more than half of the cases (52.3%), whereas in 43.8% a poorly differentiated carcinoma and in 3.9% a welldifferentiated tumor portion could be found. The carcinomas which were well differentiated in the tumor center displayed the same degree of maturation at the invasion front in only 12.6% of the cases. In the majority of the cases (Fig. 2), however, moderately differentiated (68.1%) and poorly differentiated (19.3%) tumor portions were present. The tendency toward increasing immaturity of the carcinoma in the direction of the invasion front becomes clear on this comparison. To determine the prognostic importance of the different tumor grading the 5-year survival rates were calculated. For patients with poorly differentiated carcinomas in the regions of the tumor center, the 5-year survival rate was 71.6%, and in patients with welldifferentiated carcinomas, 85.6%. In women with poorly differentiated carcinomas in the region of the invasion front the 5-year survival rate was 72.3%, and in women with well-differentiated carcinomas, 96%. The best 5-year survival rates were found in patients with well-differentiated carcinomas at the invasion front and the poorest 5-year survival rates in patients with poorly differentiated tumor portions in the center of the carcinoma (Fig. 3). An intensely dissociating tumor growth was present in one-quarter of the carcinomas (24.3%). More than half of the cases (51.5%) displayed only a mild tumor dissociation. In one-quarter (24.2%) a dissociating tumor growth was not to be observed (Fig. 4). The 5-year survival rate was 86.4% for patients without tumor dissociation, 81% for those with mild tumor dissociation, and 66.2% for those with intense tumor dissociation (Fig. 5). Under close examination of the tumor sections, a tumor invasion of lymphatics (lymphangiosis carcinomatosa) was recorded in more than half of the cases (56.8%). A tumor invasion into blood vessels was present in 9.6% of the cases. The prognostic significance of the tumor invasion into lymphatic and blood vessels is revealed by comparison of the 5-year survival rates. Of the patients with demonstrated lymphangiosis carcinomatosa 31.2% died. With a tumor invasion into blood vessels the percentage of patients who died rose to 70.2% (Fig. 6).
In the evaluation of the reactive stromal inflammation it became evident that the proportion of carcinomas with heavy inflammatory reaction at the invasion front was markedly greater (37.7%) than that in the center of the tumor (31.5%). lNVA!SlON
FIG 2.
Agreement
FRONT
of the tumor grading between tumor center and invasion
front.
SQUAMOUS
CELL
tumorcentre
invasion
90
187
CARCINOMA front
65.6
64
70 50 Fir, 8 dp
10
differentlatl
differentiated Oalive
I
deceased
FIG. 3. Prognostic significance of tumor maturation. Tumor center and invasion front were considered separately. (S-year survival rates).
60
1
51.5
absent
intensely
mild
FIG. 4. Extent of the dissociative tumor growth.
absent
nallve
meld I
Intensely deceased
FIG. 5. Prognostic significance of dissociative tumor growth. U-year survival rates).
188
BALTZER lymph
ET AL. blood
vessels
I.1
93 I
absm
1.8 .2 L-
vessels
3
29.6 17
li
absent prt?SWt I deceased
present
Oak FIG. 6.
Prognostic significance of tumor invasion into blood and lymphatic vessels. (S-year survival rates).
The proportion of tumors lacking an inflammatory stroma reaction was 18.4% in the center of the tumor and 13.6% at the invasion front (Fig. 7). Determination of the 5-year survival rates made it evident that in tumors with heavy inflammatory stromal reaction in the region of the center of the tumor only 13.1% of the patients had died and only 12.2% of the patients with a heavy inflammatory stromal reaction in the region of the invasion front had died. On the other hand with absent inflammatory stromal reaction in the center of the tumor the percentage of the patients who had died was 39.4%. This percentage rose to 44.4% when there was a lack of stromal reaction at the invasion front (Fig. 8). In 595 carcinomas the tumor volume could be calculated from the individual data. The prognostic significance of the tumor volume is shown in Fig. 9, where the 5-year survival rates of the patients are plotted against the individual tumor volumes (Fig. 9). With a tumor volume of 500 to 1500 mm’, the 5-year survival rate of the patients was 84.2%. With volumes of 6500 to 10,000 mm3 the 5-year survival rate fell to 75% and at volumes of over 20,000 mm3, to 59.5%. The different forms of lymph node metastases are also of prognostic significance. In patients with a lack of metastatic spread into the regional lymph nodes,
60 -1
40h: t! ‘i;
20-
ap
absent
m I3 FIG. 7.
front.
mild
heavy
tumor centre invasion front
Extent of the inflammatory stroma reaction in the center of the tumor and at the invasion
SQUAMOUS
CELL
189
CARCINOMA
7i !3
55.6 n
absent 0
mild
hf =v
I” I lild
absent
alive
-
2.7
deceased
FIG. 8. Prognostic significance of the inflammatory stroma reaction. Center of the tumor and invasion front were considered separately. (Syear survival rates).
loo-
?505F
//-//‘
2 6
d/
__---8
lomo1499
FIG.
15003499
35006499
ssoo9999
1000019999
20000- mm.3 94000
---deceased
alive
9. Prognostic significance of the tumor volume measured. (S-year survival rates).
NO META.
FIG.
Ml
TUM MICRO-MACROCELL META META. EMEIOLI
10. Prognostic significance of the lymph node metastases. (S-year survival rates).
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ET AL.
the 5-year survival rate was 88.4%. The 5-year survival rate of women who only had tumor cell embolism in the lymph nodes was 82.5%. With a demonstration of micrometastases the 5-year survival rate fell to 62.1% and with macrometastases, 54% (Fig. 10). DISCUSSION For histological classification of squamous cell carcinomas of the cervix numerous classifications have been suggested. Schottltinder and Kermauner [34] distinguished among mature, moderately mature, and immature carcinomas. The grading of Broders [6, 71 is based on four degrees of different cell differentiation. Further classifications have been communicated by Martzloff [24,25], Lauterwein [ 191,and Schiiller [35]. The studies by Stiiper [39,40] are based on a classification of Pendl comprising 16 single criteria. Glucksmann et al. 1131distinguished between anaplastic and differentiated squamous cell carcinomas. Reagan et al. [32] and Wentz et al. [44-471 have subdivided the squamous cell carcinomas into keratinizing, nonkeratinizing, large cell, and parvocellular carcinomas. The inaccuracy of such a histological classification of the carcinomas on the basis of a small tissue biopsy from the tumor was already pointed out by Martzloff [25]. In his investigations the tumor maturity in the tissue biopsy did not correspond with the degree of maturity of the tumor demonstrated in the surgical specimens in one-third of the cases. The present investigation is based on a classification into well-, moderately, and poorly differentiated carcinomas. This grading was not performed on one tissue biopsy, but always on the entire tumor. Because of the different degrees of tumor maturation, the evaluation was always performed separately for the center and the invasion front of the carcinoma. In this separate evaluation, differences between the tumor center and the invasion front become evident. Whereas mostly well- and moderately differentiated carcinomas were present in the center of the carcinoma, mainly poorly differentiated carcinoma portions were demonstrated at the invasion front. The prognostic significance of this grading separated according to tumor center and invasion front can be demonstrated from the different recovery rates of the patients. Patients with poorly differentiated carcinomas in the center of the tumor or at the invasion front had S-year survival rates of about 72% in each case. Better survival rates of almost 86% were registered in patients with mainly well-differentiated tumor portions in the center of the carcinoma. Patients with well-differentiated carcinoma portions in the region of the invasion front had the best 5-year survival rates (96%). According to Fink and Denk [lo] and Ng and Atkin [28], a better prognosis is to be expected in patients with mature carcinomas. According to Wentz and Reagan [44], Kraus [181, and Van Nagell et al. [41], parvocellular carcinomas are regarded as prognostically unfavorable. Beecham et al. [4] did not find any grading-dependent differences in prognoses for patients who were operated on. Indeed, according to Sidhu ef al. 1381poorer recovery rates were observed in patients with mature carcinomas. According to Morley and Seski [27], however, patients with mature carcinomas had better recovery rates. In the evaluation of the tumor dissociation, the majority of the carcinomas investigated only displayed
SQUAMOUS CELL CARCINOMA
191
a slight degree of dissociative growth. This indicates that in the majority of the cases the squamous cell carcinoma of the cervix grows as a closed tissue. For this growth form of the carcinoma the 5-year survival rates of the operated patients was 86.4%, whereas the 5-year survival rate for patients with a pronounced dissociative tumor growth fell to 66.2%. The significance of the recovery results of a tumor invasion into lymphatic and blood vessels has been pointed out by Akazaki [2], Cherry [8a] and Glucksmann, Parsons et al. [30], Friedell and Parsons [ll], Friedell er al. [ 121, and Van Nagell et al. [42]. Ferenczy [9] reported the frequency of a lymphogenic spread as 25 to 50% for clinical stages Ib and II. In the tumors of the present study, an invasion of the carcinoma in lymphatic vessels was also detected in more than half of the cases. On the other hand, a tumor invasion into blood vessels could only be demonstrated in 9.6% of the cases. This percentage is below that reported by Ober [29], Ferenczy [9], and Kindermann and Jabusch [17]. These authors observed a tumor invasion into blood vessels in 29.4% of the cases. The lower percentage of tumor invasion into blood vessels in the present study may possibly be explained by the fact that small vessels could not be identified since special stains were not available for evaluation. The especially unfavorable prognosis of a tumor invasion into blood vessels communicated in the literature also became evident in the patients we investigated. Whereas 3 1.2% of the patients with demonstrated lymphangiosis carcinomatosa had died, this percentage rose to 70.2% with demonstration of a tumor invasion into blood vessels. Varying prognoses in the absence of heavy inflammatory stroma reactions in the vicinity of the carcinoma have been pointed out by Schtiller [35], Sidhu et al. [38], Abel1 [ 11, and others. With a heavy inflammatory reaction in the center of the tumor and at the invasion front (86.9 and 87.8%, respectively), better 5year survival rates were observed than with absent inflammatory reaction. The 5-year survival rate in the absence of an inflammatory reaction in the tumor center was 60.6%. With an absent inflammatory reaction at the invasion front, the 5-year survival rate even fell to 55.6%. Similar observations were also communicated by Inkuchi et al. [16] for operated gastric carcinoma. Data on tumor measurement in the literature mainly relate to the limitation and size determination of very small carcinomas [21]. Communications on measurements on larger tumors have rarely been made in the literature [8, 14, 29a, 31, 37, 411. In most cases, data on the kind of histological workup of the surgical specimens evaluated or data on the method of measurement are not available from these communications. The surgical specimens of the present study were especially suitable for tumor measurements, since the uniform surgical technique and the identical histological workup of the surgical specimens enabled the measurement of defined parameters. However, measurement errors can be caused by alterations in the size of the tissue fragments, which are also due to the operation, the spreading of the preparation, the fixation, or the embedding of the tissue material. Despite these possibilities of error, which take effect in all measurements, and despite the mathematical inaccuracy of the measurement, the present tumormetric studies
192
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ET AL.
nevertheless appear suitable for determing carcinoma size. Lohe [21] has pointed out the prognostic significance of tumor volume in very small carcinomas. The measurements on macrocarcinomas also make evident that the 5-year survival rate for patients falls with increasing tumor volume. Whereas the 5-year survival rate of these patients was 84.2% with a tumor volume of 500 to 1500 mm3, the S-year survival rate fell to 75% with a tumor volume of 6500 to 10,000 mm3, and to 59.5% with a volume over 20,000 mm3. The linkage between the increase in size of the carcinoma and the frequency of metastases is to be regarded as a possible cause for the deterioration in the recovery results with increasing tumor volume. However, these correlations could only be demonstrated for micrometastases and macrometastases, whereas the frequency of the tumor cell embolizations remained largely unchanged [3]. These various forms of metastases have a different prognostic significance. Whereas women with tumor cell embolization displayed a 5-year survival rate of 82.5%, the S-year survival rate in patients with demonstrated micrometastases was 62.1% and fell to 54% in macrometastases; so far similar observations are not available in the literature. ACKNOWLEDGMENTS This cooperative study has been promoted by the support and kind collaboration of Professor C. Kaufmannt, M.D. (Cologne), and Professor K. G. Ober, M.D. (Erlangen). This study was performed with financial support from the Deutsche Forschungsgemeinschaft Bonn-Bad Godesberg Ba 599/l.
REFERENCES 1. Abell, M. R. Invasive carcinoma of the uterine cervix, in The uterus (H. J. Norris, A. J. Hertig, and M. R. Abell, Eds.), Williams & Wilkins, Baltimore (1973). 2. Akazaki, K. Some problems in the pathologic histology of carcinoma of cervix uteri with special consideration on its relationship to prognosis, Gann 44, 401-418 (1953). 3. Baltzer, J. and Kopcke, W. Tumor size and lymph node metastases in squamous cell carcinoma of the uterine cervix, Arch. Gynecol. 227, 271-278 (1979). 4. Beecham, J. B., Halvorsen, T., and Kolbenstvedt, A. Histologic classification lymphnode metastasis, and patient survival in stage Ib cervical carcinoma. An analysis of 24.5 uniformly treated cases, Gynecol. Oncol. 6, 95-105 (1978). 5. Braunig, G., Lohe, K. J., Baltzer, J., and Zander, J. Tumormetrische Untersuchungen beim Zervixkarzinom, Arch. Gyniikol. 214, 105 (1973). 6. Broders, A. C. Carcinoma. Grading and practical application, Arch. Pathol. 2, 376-381 (1926). 7. Broders, A. C. Practical points on the microscopic grading of carcinoma, N. Y. St. J. Med. 32, 667-671 (1932). 8. Brunschwig, A. Surgical treatment of stage I, cancer of the cervix, Cancer (Phil.) 13, 34-36 (1960). 8a. Cherry, C. P., and Glucksmann, A. Lymphatic embolism and lymphnode metastasis in cancers of vulva and uterine cervix, Cancer 8, 564-575 (1955). 9. Ferenczy, A. Carcinoma and other malignant tumors of the cervix, in Pathology of the female genital tract (A. Blaustein, Ed.), Springer, New York (1977). 10. Fink, F. M., and Denk, M. Cervical carcinoma: Relationship between histology and survival following radiation therapy, Obstet. Gynecol. 35, 393-443 (1970). 11. Friedell, G. H., and Parsons, L. Blood vessel invasion in cancer of the cervix, Cancer 15, 1269-1274 (1962). 12. Friedell, G. H., Steiner, G., and Kistner, R. W. Prognostic value of blood vessel invasion in cervical cancer, Obstet. Gynecol. 29, 855-857 (1967). 13. Glucksmann, A., Cherry, C. P., Dearing, R., and Way, St. Observation on lymphnode involvement in carcinoma of the cervix, J. Obsrer. Gynecol. Brir. Emp. 60, 368-378 (1953).
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14. Graham, R. M., and Graham, J. B. Factors in prognosis in cancer of the uterine cervix. Desquamation of malignant cells, Cancer (Phil.) 3, 15-19 (1960). 15. Gusberg, S. B., Yannopoulos, K., and Cohen, C. J. Virulence indices and lymph nodes in cancer of the cervix, Amer. J. Roentgen. Rad. Ther. Nucl. Med. 111, 213-277 (1971). 16. Inkuchi, K., Inutsuka, S., Furusawa, M., Soejima, K., and Ikeda, T. Stromal reaction around tumor and metastasis and prognosis after curative gastrectomy for carcinoma of the stomach, Cancer 20, 1924-1929 (1967). 17. Kindermann, G., and Jabusch, H. P. The spread of squamous cell carcinoma of the uterine cervix into the blood vessels, Arch. Gyniikol. 212, 1-8 (1972). 18. Kraus, F. T. Gynecologic pathology, Mosby, St. Louis (1967). 19. Lauterwein, C. Die Morphologie des Kollumkarzinoms und ihre Bedeutung fur die Prognose und Therapie, Z. Geburtsh, Gyniikol. 128, 17-106 (1947). 20. Lohe, K. J., Baltzer, J., and Zander, J. Histologische Diagnose und individuelle Krebsbehandlung in der Gynakologie, 118, 1373-1378 (1976). 21. Lohe, K. J. Early squamous cell carcinoma of the uterine cervix. 1. Definition and histology, Gynecol. Oncol. 6, IO-30 (1978). 22. Lohe, K. J., Burghardt, E., Hillemanns, H. G., Kaufmann, C., Ober, K. G., and Zander, J. 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, Gynecol. Oncol. 6, 31-50 (1978). 23. Lohe, K. J. Early squamous cell carcinoma of the uterine cervix. III. Frequency of lymphnode metastasis, Gynecol. Oncol. 6, 51-59 (1978). 24. Martzloff, K. H. Carcinoma of the cervix uteri: A pathologic and clinical study with particular reference to the relative malignancy of the neoplastic process as indicated by the predominant cell type of cancer cell, Bull. Johns Hopkins Hosp. 34, 141-155 (1923). 25. Martzloff, K. H. Epidermoid carcinoma of cervix uteri. A histologic study to determine the resemblance between biopsy specimens and the parent tumor obtained by radical panhysterectomy, Amer. J. Obstet. Gynecol. 16, 578-594 (1928). 26. Matuschka, M. Unsere histologische Technik zur Aufarbeitung von Konisationen, ganzen Uteri und Uteri mit anhangenden Parametrien, Geburtsh. Frauenheilk. 22, 498-505 (1962). 27. Morley, G. W., and Seski, J. C. Radical pelvic surgery versus radiation therapy for stage I carcinoma of the cervix (Exclusive of microinvasion), Amer. J. Obstet. Gynecol. 126, 785-798 (1976). 28. Ng, A. B. P., and Atkin, N. B. Histological cell type and DNA value in the prognosis of squamous cell cancer of uterine cervix, &it. J. Cancer 28, 322-331 (1973). 29. Ober, K. G. Metastasierung aus gynakologischer Sicht. Krebsforschung, Krebsbekampfung, Band 6, 219-237 (1967). 29a. Ober, K. G., and Huhn, F. 0. Die Ausbreitung des Cervixkrebses auf die Parametrien und die Lymphknoten der Beckenwand, Arch. Gynlikol. 197, 262-290 (1962). 30. Parsons, L., Cesare, F., and Friedell, G. H. Primary and surgical treatment of invasive cancer of the cervix, Surg. Gynecol. Obstet. 109, 279-286 (1959). 31. Piver, M. St., and Chung, W. S. Prognostic significance of cervical lesion size and pelvic node metastasis in cervical carcinoma, Obstet. Gynecol. 46, 507-510 (1975). 32. Reagan, J. W., Hamonic, M. J., and Wentz, W. B. Analytical study of cells in cervical squamous cell cancer, Lab. Invest. 6, 241-250 (1957). 33. Schneppenheim, P., Hamper], H., Kaufmann, C., and Ober, K. G. Die Beziehungen des Schleimepithels zum Plattenepithel an der Cervix uteri im Lebenslauf der Frau, Arch. Gyniikol. 190, 303-345 (1958). 34. Schottlaender, J., and Kermauner, F. Zur Kenntnis des Uteruskarzinoms, Karger, Berlin (1912). 35. Schtiller, E. Histologischer Typ und Bestrahlungsheilbarkeit des Carcinoma colli uteri, Strahlentherapie 85, 321-330 (1951). 36. Selbmann, H. K., Raab, A., and Savod, Q. Bentitzerhandbuch. Technischer Bericht 3, ISB Munchen (1976). 37. Senapad, S. Lymphnode invasion in unterine cervical cancer stage I with relation to the size of the primary lesion, J. Med. Assoc. Thai. 59, 399-402 (1976). 38. Sidhu, A. S., Koss, L. G., and Barber, K. R. K. Relation of histologic factors to the response
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of stage I epidermoid carcinoma of the cervix to surgical treatment, Obster. Gynecol. 35, 329-338 (1970). 39. Stiiper, P. Uber Beziehungen zwischen histologischer Struktur und Heilung der Kollumkarzinome. 1. Mitteilung. Untersuchungen tiber die histologische Klassifizierung nach Pendl, Srrahlentherapie 92, 89-107 (1953). 40. Stiiper, P. Uber Beziehungen zwischen histologischer Struktur und Heilung der Kollumkarzinome. 2. Mitteilung. Untersuchungen nach Reifegraden und ahnlichen Einteilungen, Srrahlentherapie
92, 219-236 (1953).
41. Van Nagell, J. R., Donaldson, E. S., Parker, J. C., Van Dyke, A. H., and Wood, E. G. The prognostic significance of cell type and lesion size in patients with cervical cancer treated by radical surgery, Gynecol. Oncol. 5, 142-151 (1977). 42. Van Nagell, J. R., Donaldson, E. S., Parker, J. C., Van Dyke, A. H., and Wood, E. G. The prognostic significance of pelvic lymphnode morphology in carcinoma of the uterine cervix, Cancer 39, 2624-2632 (1977). 43. Van Nagell, J. R., Donaldson, E. S., Wood, E. G., Maruyama, Y., and Utley, J. Small cell cancer of the uterine cervix, Cancer 40, 2243-2249 (1977). 44. Wentz, W. B., and Reagan, J. W. Survival in cervical cancer with respect to cell type, Cancer 12, 384-388 (1959). 45. Wentz, W. B. Histological grade and survival in cervical cancer, Obstet. Gynecol. 18, 412-416 (1961). 46. Wentz, W. B., and Lewis, G. C. Correlation of histologic morphology and survival in cervical cancer following radiation therapy, Obstef. Gynecol. 26, 228-232 (1965). 47. Wentz, W. B., and Jaffe, R. M. Squamous cell carcinoma of the cervix with higher uterine involvement, Obster. Gynecol. 28, 271-272 (1966). 48. Zander, J., Baltzer, J., Lohe, K. J., Ober, K. G., Kaufmann, C. Carcinoma of the cervix: an attempt to individualize treatment, Amer. J. Obster. Gynec. 139, 752-759 (1981).
ONCOLOGY
13, 184-194 (1982)
Histological Criteria for the Prognosis in Patients with Operated Squamous Cell Carcinoma of the Cervix J. BALTZER, K. J. LOHE, W. K&CKE,
AND
J. ZANDER
1. Frauenklinik der Universitiit Miinchen, 8000 Munich 2, Maistrasse 11, and Institut fir Medizinische Datenverarbeitung, Statistik und Biomathematik der Universitiit Miinchen, 8000 Munich 70, Marchioninistrasse 15, West Germany
Received June 29. 1981 Histological criteria for the prognosis were examined in 718 surgical specimens with squamous cell carcinoma of the cervix which were subjected to uniform histological workup. In the distinction between the invasion front and the tumor center the tumor grading in the region of the invasion front had particular prognostic significance. A very pronounced dissociative tumor growth also had an influence on the 5-year survival rates. The poorest prognosis was registered with patients in whom an invasion of the carcinoma into blood vessels could be observed. Taking into account the inflammatory stroma reaction in the center of the tumor and at the invasion front, more favorable recovery results could be registered with a heavy inflammatory infiltration in the region of the invasion front. The increase in tumor volume lead to a deterioriation of the recovery rates. These poorer recovery rates were due to the increase of the macrometastases, whereas tumor cell embolization into lymph nodes did not significantly influence the recovery results.
The recovery rates of patients with operated squamous cell carcinoma of the cervix depend not only on the histologically documented extent of the carcinoma, but also on other tumor parameters. Gusberg et al. [15] pointed out virulence indices in cancer of the cervix. The significance of qualitative and quantitative tumor parameters will be examined below. PATIENTS AND METHODS From the material of a cooperative study of 1092patients with operated cervical carcinoma at four university departments of gynecology and obstetrics [Cologne (Professor C. Kaufmann), Erlangen (Professor K. G. Ober), Heidelberg (Professor J. Zander), Mtinchen I (Professor J. Zander)] surgical specimens from 718 patients with squamous cell carcinoma of the cervix were evaluated [48]. In all patients the extended abdominal uterine extirpation with obligatory lymphadenectomy according to Mackenroth-Latzko-Meigs had been previously performed. The surgical specimen was uniformly examined histologically according to the methods specified by Schneppenheim et al. [33], Matuschka [26] and Lohe et al. [20]. Large surface sections were prepared from all tissue blocks and stained with iron-hematoxylin (Weigert) and eosin. All histological slides were seriously examined once more by one and the same investigator on the basis 184 0090-8258/82/020184-l1$01.00/O Copyright All rights
0 1982 by Academic Press, Inc. of reproduction in any form reserved.
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CELL
CARCINOMA
185
of a prepared characteristics catalog. Tumor maturity, growth form of the carcinoma, tumor invasion into blood and lymph vessels, as well as extent of the reactive stromal inflammation were evaluated. Tumor maturity was divided into well-, moderately, and poorly differentiated carcinomas. However, differences in the same tumor made the tumor grading more difficult. In order to enable better evaluation the center and the invasion front of the carcinoma were evaluated separately. The irregularity of contour of the tumor growth was registered as “dissociating tumor growth.” For all tumors the extent of dissociative tumor growth was registered by recording an intense, mild, or absent tumor dissociation. To evaluate the reactive stromal inflammation in the tumor region, a distinction among heavy, mild, and absent lymphoplasmacellular infiltration of the stroma was made for every visual field. In order to enable a more exact evaluation, the tumor center and the invasion front were also evaluated separately here. The tumor volume was determined from the height, width, and length of the tumor as a measure of the size of the carcinoma. It was assumed on the basis of earlier random sample calculations by our study group [5] that the growth of the carcinoma in the cervix most likely corresponds to an ellipsoid. In the evaluation of the metastatic spreading of the tumor to the lymph nodes, a distinction was made among metastasis-free lymph nodes, tumor cell embolisms, and micro- and macrometastases [3]. All individual data were transferred to punched cards. The data were processed statistically with the SAVOD dialog system for interactive processing and evaluation of mass medical data [36]. All data are significant at the 1% level. RESULTS In 718 surgical specimens, evaluation of the tumor center revealed a welldifferentiated carcinoma in 16.6%, a moderately differentiated carcinoma in 56.7%, and a poorly differentiated carcinoma in 26.7%. In the region of the invasion front, the percentage of well-differentiated carcinomas amounted to 4.6%; of moderately differentiated carcinomas, 43.3%; and of poorly differentiated carcinomas, 52.1% (Fig. 1). 56.7
603
poorly
m m
moderately
well
tumor centre invasion front
FIG. 1. Separate determination of the degree of tumor maturation for the tumor center and invasion front.
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ET AL.
The poorly differentiated carcinomas in the tumor center could also be recognized at the invasion front with the same degree of maturation in 90.1%. In carcinomas with a moderately differentiated tumor center the same degree of maturation was present at the invasion front in more than half of the cases (52.3%), whereas in 43.8% a poorly differentiated carcinoma and in 3.9% a welldifferentiated tumor portion could be found. The carcinomas which were well differentiated in the tumor center displayed the same degree of maturation at the invasion front in only 12.6% of the cases. In the majority of the cases (Fig. 2), however, moderately differentiated (68.1%) and poorly differentiated (19.3%) tumor portions were present. The tendency toward increasing immaturity of the carcinoma in the direction of the invasion front becomes clear on this comparison. To determine the prognostic importance of the different tumor grading the 5-year survival rates were calculated. For patients with poorly differentiated carcinomas in the regions of the tumor center, the 5-year survival rate was 71.6%, and in patients with welldifferentiated carcinomas, 85.6%. In women with poorly differentiated carcinomas in the region of the invasion front the 5-year survival rate was 72.3%, and in women with well-differentiated carcinomas, 96%. The best 5-year survival rates were found in patients with well-differentiated carcinomas at the invasion front and the poorest 5-year survival rates in patients with poorly differentiated tumor portions in the center of the carcinoma (Fig. 3). An intensely dissociating tumor growth was present in one-quarter of the carcinomas (24.3%). More than half of the cases (51.5%) displayed only a mild tumor dissociation. In one-quarter (24.2%) a dissociating tumor growth was not to be observed (Fig. 4). The 5-year survival rate was 86.4% for patients without tumor dissociation, 81% for those with mild tumor dissociation, and 66.2% for those with intense tumor dissociation (Fig. 5). Under close examination of the tumor sections, a tumor invasion of lymphatics (lymphangiosis carcinomatosa) was recorded in more than half of the cases (56.8%). A tumor invasion into blood vessels was present in 9.6% of the cases. The prognostic significance of the tumor invasion into lymphatic and blood vessels is revealed by comparison of the 5-year survival rates. Of the patients with demonstrated lymphangiosis carcinomatosa 31.2% died. With a tumor invasion into blood vessels the percentage of patients who died rose to 70.2% (Fig. 6).
In the evaluation of the reactive stromal inflammation it became evident that the proportion of carcinomas with heavy inflammatory reaction at the invasion front was markedly greater (37.7%) than that in the center of the tumor (31.5%). lNVA!SlON
FIG 2.
Agreement
FRONT
of the tumor grading between tumor center and invasion
front.
SQUAMOUS
CELL
tumorcentre
invasion
90
187
CARCINOMA front
65.6
64
70 50 Fir, 8 dp
10
differentlatl
differentiated Oalive
I
deceased
FIG. 3. Prognostic significance of tumor maturation. Tumor center and invasion front were considered separately. (S-year survival rates).
60
1
51.5
absent
intensely
mild
FIG. 4. Extent of the dissociative tumor growth.
absent
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FIG. 5. Prognostic significance of dissociative tumor growth. U-year survival rates).
188
BALTZER lymph
ET AL. blood
vessels
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1.8 .2 L-
vessels
3
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li
absent prt?SWt I deceased
present
Oak FIG. 6.
Prognostic significance of tumor invasion into blood and lymphatic vessels. (S-year survival rates).
The proportion of tumors lacking an inflammatory stroma reaction was 18.4% in the center of the tumor and 13.6% at the invasion front (Fig. 7). Determination of the 5-year survival rates made it evident that in tumors with heavy inflammatory stromal reaction in the region of the center of the tumor only 13.1% of the patients had died and only 12.2% of the patients with a heavy inflammatory stromal reaction in the region of the invasion front had died. On the other hand with absent inflammatory stromal reaction in the center of the tumor the percentage of the patients who had died was 39.4%. This percentage rose to 44.4% when there was a lack of stromal reaction at the invasion front (Fig. 8). In 595 carcinomas the tumor volume could be calculated from the individual data. The prognostic significance of the tumor volume is shown in Fig. 9, where the 5-year survival rates of the patients are plotted against the individual tumor volumes (Fig. 9). With a tumor volume of 500 to 1500 mm’, the 5-year survival rate of the patients was 84.2%. With volumes of 6500 to 10,000 mm3 the 5-year survival rate fell to 75% and at volumes of over 20,000 mm3, to 59.5%. The different forms of lymph node metastases are also of prognostic significance. In patients with a lack of metastatic spread into the regional lymph nodes,
60 -1
40h: t! ‘i;
20-
ap
absent
m I3 FIG. 7.
front.
mild
heavy
tumor centre invasion front
Extent of the inflammatory stroma reaction in the center of the tumor and at the invasion
SQUAMOUS
CELL
189
CARCINOMA
7i !3
55.6 n
absent 0
mild
hf =v
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-
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FIG. 8. Prognostic significance of the inflammatory stroma reaction. Center of the tumor and invasion front were considered separately. (Syear survival rates).
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9. Prognostic significance of the tumor volume measured. (S-year survival rates).
NO META.
FIG.
Ml
TUM MICRO-MACROCELL META META. EMEIOLI
10. Prognostic significance of the lymph node metastases. (S-year survival rates).
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the 5-year survival rate was 88.4%. The 5-year survival rate of women who only had tumor cell embolism in the lymph nodes was 82.5%. With a demonstration of micrometastases the 5-year survival rate fell to 62.1% and with macrometastases, 54% (Fig. 10). DISCUSSION For histological classification of squamous cell carcinomas of the cervix numerous classifications have been suggested. Schottltinder and Kermauner [34] distinguished among mature, moderately mature, and immature carcinomas. The grading of Broders [6, 71 is based on four degrees of different cell differentiation. Further classifications have been communicated by Martzloff [24,25], Lauterwein [ 191,and Schiiller [35]. The studies by Stiiper [39,40] are based on a classification of Pendl comprising 16 single criteria. Glucksmann et al. 1131distinguished between anaplastic and differentiated squamous cell carcinomas. Reagan et al. [32] and Wentz et al. [44-471 have subdivided the squamous cell carcinomas into keratinizing, nonkeratinizing, large cell, and parvocellular carcinomas. The inaccuracy of such a histological classification of the carcinomas on the basis of a small tissue biopsy from the tumor was already pointed out by Martzloff [25]. In his investigations the tumor maturity in the tissue biopsy did not correspond with the degree of maturity of the tumor demonstrated in the surgical specimens in one-third of the cases. The present investigation is based on a classification into well-, moderately, and poorly differentiated carcinomas. This grading was not performed on one tissue biopsy, but always on the entire tumor. Because of the different degrees of tumor maturation, the evaluation was always performed separately for the center and the invasion front of the carcinoma. In this separate evaluation, differences between the tumor center and the invasion front become evident. Whereas mostly well- and moderately differentiated carcinomas were present in the center of the carcinoma, mainly poorly differentiated carcinoma portions were demonstrated at the invasion front. The prognostic significance of this grading separated according to tumor center and invasion front can be demonstrated from the different recovery rates of the patients. Patients with poorly differentiated carcinomas in the center of the tumor or at the invasion front had S-year survival rates of about 72% in each case. Better survival rates of almost 86% were registered in patients with mainly well-differentiated tumor portions in the center of the carcinoma. Patients with well-differentiated carcinoma portions in the region of the invasion front had the best 5-year survival rates (96%). According to Fink and Denk [lo] and Ng and Atkin [28], a better prognosis is to be expected in patients with mature carcinomas. According to Wentz and Reagan [44], Kraus [181, and Van Nagell et al. [41], parvocellular carcinomas are regarded as prognostically unfavorable. Beecham et al. [4] did not find any grading-dependent differences in prognoses for patients who were operated on. Indeed, according to Sidhu ef al. 1381poorer recovery rates were observed in patients with mature carcinomas. According to Morley and Seski [27], however, patients with mature carcinomas had better recovery rates. In the evaluation of the tumor dissociation, the majority of the carcinomas investigated only displayed
SQUAMOUS CELL CARCINOMA
191
a slight degree of dissociative growth. This indicates that in the majority of the cases the squamous cell carcinoma of the cervix grows as a closed tissue. For this growth form of the carcinoma the 5-year survival rates of the operated patients was 86.4%, whereas the 5-year survival rate for patients with a pronounced dissociative tumor growth fell to 66.2%. The significance of the recovery results of a tumor invasion into lymphatic and blood vessels has been pointed out by Akazaki [2], Cherry [8a] and Glucksmann, Parsons et al. [30], Friedell and Parsons [ll], Friedell er al. [ 121, and Van Nagell et al. [42]. Ferenczy [9] reported the frequency of a lymphogenic spread as 25 to 50% for clinical stages Ib and II. In the tumors of the present study, an invasion of the carcinoma in lymphatic vessels was also detected in more than half of the cases. On the other hand, a tumor invasion into blood vessels could only be demonstrated in 9.6% of the cases. This percentage is below that reported by Ober [29], Ferenczy [9], and Kindermann and Jabusch [17]. These authors observed a tumor invasion into blood vessels in 29.4% of the cases. The lower percentage of tumor invasion into blood vessels in the present study may possibly be explained by the fact that small vessels could not be identified since special stains were not available for evaluation. The especially unfavorable prognosis of a tumor invasion into blood vessels communicated in the literature also became evident in the patients we investigated. Whereas 3 1.2% of the patients with demonstrated lymphangiosis carcinomatosa had died, this percentage rose to 70.2% with demonstration of a tumor invasion into blood vessels. Varying prognoses in the absence of heavy inflammatory stroma reactions in the vicinity of the carcinoma have been pointed out by Schtiller [35], Sidhu et al. [38], Abel1 [ 11, and others. With a heavy inflammatory reaction in the center of the tumor and at the invasion front (86.9 and 87.8%, respectively), better 5year survival rates were observed than with absent inflammatory reaction. The 5-year survival rate in the absence of an inflammatory reaction in the tumor center was 60.6%. With an absent inflammatory reaction at the invasion front, the 5-year survival rate even fell to 55.6%. Similar observations were also communicated by Inkuchi et al. [16] for operated gastric carcinoma. Data on tumor measurement in the literature mainly relate to the limitation and size determination of very small carcinomas [21]. Communications on measurements on larger tumors have rarely been made in the literature [8, 14, 29a, 31, 37, 411. In most cases, data on the kind of histological workup of the surgical specimens evaluated or data on the method of measurement are not available from these communications. The surgical specimens of the present study were especially suitable for tumor measurements, since the uniform surgical technique and the identical histological workup of the surgical specimens enabled the measurement of defined parameters. However, measurement errors can be caused by alterations in the size of the tissue fragments, which are also due to the operation, the spreading of the preparation, the fixation, or the embedding of the tissue material. Despite these possibilities of error, which take effect in all measurements, and despite the mathematical inaccuracy of the measurement, the present tumormetric studies
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nevertheless appear suitable for determing carcinoma size. Lohe [21] has pointed out the prognostic significance of tumor volume in very small carcinomas. The measurements on macrocarcinomas also make evident that the 5-year survival rate for patients falls with increasing tumor volume. Whereas the 5-year survival rate of these patients was 84.2% with a tumor volume of 500 to 1500 mm3, the S-year survival rate fell to 75% with a tumor volume of 6500 to 10,000 mm3, and to 59.5% with a volume over 20,000 mm3. The linkage between the increase in size of the carcinoma and the frequency of metastases is to be regarded as a possible cause for the deterioration in the recovery results with increasing tumor volume. However, these correlations could only be demonstrated for micrometastases and macrometastases, whereas the frequency of the tumor cell embolizations remained largely unchanged [3]. These various forms of metastases have a different prognostic significance. Whereas women with tumor cell embolization displayed a 5-year survival rate of 82.5%, the S-year survival rate in patients with demonstrated micrometastases was 62.1% and fell to 54% in macrometastases; so far similar observations are not available in the literature. ACKNOWLEDGMENTS This cooperative study has been promoted by the support and kind collaboration of Professor C. Kaufmannt, M.D. (Cologne), and Professor K. G. Ober, M.D. (Erlangen). This study was performed with financial support from the Deutsche Forschungsgemeinschaft Bonn-Bad Godesberg Ba 599/l.
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92, 219-236 (1953).
41. Van Nagell, J. R., Donaldson, E. S., Parker, J. C., Van Dyke, A. H., and Wood, E. G. The prognostic significance of cell type and lesion size in patients with cervical cancer treated by radical surgery, Gynecol. Oncol. 5, 142-151 (1977). 42. Van Nagell, J. R., Donaldson, E. S., Parker, J. C., Van Dyke, A. H., and Wood, E. G. The prognostic significance of pelvic lymphnode morphology in carcinoma of the uterine cervix, Cancer 39, 2624-2632 (1977). 43. Van Nagell, J. R., Donaldson, E. S., Wood, E. G., Maruyama, Y., and Utley, J. Small cell cancer of the uterine cervix, Cancer 40, 2243-2249 (1977). 44. Wentz, W. B., and Reagan, J. W. Survival in cervical cancer with respect to cell type, Cancer 12, 384-388 (1959). 45. Wentz, W. B. Histological grade and survival in cervical cancer, Obstet. Gynecol. 18, 412-416 (1961). 46. Wentz, W. B., and Lewis, G. C. Correlation of histologic morphology and survival in cervical cancer following radiation therapy, Obstef. Gynecol. 26, 228-232 (1965). 47. Wentz, W. B., and Jaffe, R. M. Squamous cell carcinoma of the cervix with higher uterine involvement, Obster. Gynecol. 28, 271-272 (1966). 48. Zander, J., Baltzer, J., Lohe, K. J., Ober, K. G., Kaufmann, C. Carcinoma of the cervix: an attempt to individualize treatment, Amer. J. Obster. Gynec. 139, 752-759 (1981).