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Histologic classification, lymph node metastases, and patient survival in stage IB cervical carcinoma
GYNECOLOGIC
ONCOLOGY
6, 9% 105 (1978)
Histologic Classification, Lymph Node Metastases, Patient Survival in Stage IB Cervical Carcinoma
and
An Analysis of 245 Uniformly Treated Cases JACKSONB. BEECHAM, M.D., TORE HALVORSEN, M.D., ANDALF KOLBENSTVEDT, M.D. Departments
of Gynecology,
Pathology,
and Radiology, Oslo, Norway I
The Norwegian
Radium
Hospital,
Received May 3 I, 1977 The role which histologic grading plays in the prognosis of cervical carcinoma is controversial. The basis for subdividing these lesions into small cell carcinomas and keratin- or nonkeratin-producing large cell carcinomas has usually been the assumption, though never statistically supported, that the small cell carcinomas are more aggressive. We tested this hypothesis by studying 245 FIG0 Stage IB cases uniformly treated between 1970 and 1973. To evaluate prognosis, we selected two parameters: lymph node metastases and crude 2-year survival rate. Our data show that there is no statistically significant difference in either of these parameters to suggest that these malignancies behave differently in respect to keratinization or cellular size. Preliminary results suggest that patients in whom the cancer and cervical stroma have a characteristically well-demarcated interface may have improved short-term survival rates.
INTRODUCTION
The variety of growth patterns in cervical carcinoma has intrigued investigators for many years. More recently, such cellular and morphologic characteristics as keratinization, cellular size, and degree of differentiation have been invoked as affecting the overall survival in this disease. Large cell epithelial carcinomas, particularly those with keratin formation, have frequently been depicted as less aggressive than the nonkeratinizing, anaplastic carcinomas, which typically form sheets of small malignant cells. However, the effects that any histologic pattern may have upon prognosis remain statistically unsubstantiated, due to lack of uniformity either in pathologic criteria, study design, treatment methods, or follow-up. To reduce the effect of such variables, we chose to study the initial biopsy specimens from 245 consecutively treated cases of FIG0 Stage IB cervical carcinoma, using lymph node metastases and tumor-free survival rate as indicators of the importance which different histologic growth patterns might have upon the biologic activity in this malignancy. I Address.requests for reprints, to Per Icolstad, Department of Gynecology, Norwegian Hospital, Oslo 3, Norway.
Radium
95 0090-8258/78/0061-0095$01.00/0 Copyright @ 1978 by Academic Press, Inc. All rights of reproduction in any form reserved.
96
BEECHAM,
HALVORSEN,
MATERIALS
AND
KOLBENSTVEDT
AND METHODS
Specimens from approximately 8000-9000 malignancies pass through the Department of Pathology of the Norwegian Radium Hospital annually. Of these, about 350 are cases of invasive carcinoma of the cervix treated in the Department of Gynecology. This represents 90% of all cervix cancers treated in Norway. From this material, we selected 245 consecutively and identically treated patients with Stage IB lesions. Each received two 5-day radium courses, according to a modified Paris method [I]. Radical hysterectomy and pelvic lymphadenectomy followed the radium application 6 weeks later. Lymphangiogram comparison films at the time of surgery helped to assure a thorough dissection from the aorta to the inguinal ligaments [23. Those women who had one or more metastatic lymph nodes received postoperative radiation therapy consisting of a tumor dose to the total pelvis of 4000 rad. The preoperative radium irradiation added approximately 1000 rad to the lymph node areas. A pathologist and a gynecologist together reviewed all the primary biopsies. In those patients who had multiple specimens, we selected the one which most clearly reflected any predominating histologic features. A lymphangiographer and a pathologist together studied all lymph nodes removed. Step-sectioning techniques, frequently revealing micrometastases, demonstrated a 25% incidence of lymph node spread. We then divided all patients into four histologic groups: those with adenocarcinemas, large cell keratinizing carcinomas, nonkeratinizing large cell carcinomas, and small cell carcinomas. Special stains were used when necessary to identify glandular malignant patterns. To classify the epithelial malignancies, we used the criteria initially proposed by Wentz and Reagen [3] and currently accepted by the World Health Organization [4]. According to these sources, the large cell keratinizing carcinoma has a characteristic formation of epithelial pearls and frequently cornified strata of superficial keratinization. The mitotic index is low, and consequently the microscopic appearance is one of a well-differentiated epidermoid lesion (Fig. 1 and 2). The nonkeratinizing large cell carcinoma is usually less differentiated. While isolated cell keratinization exists, there is no epithelial pearl formation and the mitotic index is moderately high. This group frequently demonstrates large areas of pale pleomorphic cells varying in size (Fig. 3 and 4). By contrast, the small cell carcinomas possess sheets of uniformly small basophilic cells (Fig. 5 and 6). Their nuclear:cytoplasmic ratio and mitotic index are high, conveying a generally anaplastic appearance. In the course of our work, we developed a number of impressions concerning the morphologic appearances of carcinomas of the cervix which were not covered by the Wentz and Reagen classification. We finally identified 13 different histologic patterns. The predominant pattern was a mixed one. Many of the other patterns contained only a few cases. Only one of the 13 groups subsequently demonstrated any clinical relevance: It was characterized by a sharp, welldemarcated interface between the cervical tissue and the advancing epithelial growth, giving a ribbon and band appearance to the tissues (Fig, 7 and 8).
STAGE IB CERVICAL
FIGS. 1 and 2. Keratinizing
CARCINOMA
large cell carcinoma. 1, x 190; 2, x750.
97
98
BEECHAM,
HALVORSEN,
FIGS. 3 and 4. Nonkeratinizing
AND
KOLBENSTVEDT
large cell carcinoma. 3, x 190; 4, x750.
STAGE
FIGS.
IB CERVICAL
CARCINOMA
5 AND 6. Small cell carcinoma. 5, x 190; 6, x750.
99
BEECHAM,
HALVORSEN,
AND KOLBENSTVEDT
FIGS. 7 AND 8. The one clinically relevant histologic pattern of carcinoma is characterized by a sharp, well-demarcated interface between the cervical tissue and the advancing epithelial growth. This gives a ribbon and band appearance to the tissues. 7 and 8, x 190.
STAGE
IB
CERVICAL
101
CARCINOMA
Two hundred and fifty-five patients were available for study on the basis of their FIG0 stage and uniform treatment. We eliminated 10 patients. In five, the biopsy interpretations fell outside our selected categories. Two were adenosquamous collision carcinomas, two were possibly not primary cervical lesions, and one could only be diagnosed as a poorly differentiated malignant tumor. Five additional patients were lost to follow-up, four of whom had left Norway during this study. Thus, 245 patients formed the basis for our analyses. Because 90% of recurrences in carcinoma of the cervix develop within 2 years [5], we felt that this time interval was a reasonable point at which to initially study survival figures. We had follow-up information on 98% of the patients. In most instances, our information was based upon a history, physical examination, and cytology specimen. In 10% of the cases, follow-up was by letter from the patient. We assumed that the number of occult recurrences here would be negligible. RESULTS
The predominant histologic pattern was the large cell, nonkeratinizing carcinoma, which occurred in 57% of patients. Small cell carcinomas were the least common, appearing in 6% of cases. Table 1 summarizes the frequency with which the four histologic groups occurred. Sixty-one patients, or 25%, had lymph node metastases. As Table 2 shows, the relative frequency with which cervical cancer metastasizes is not significantly altered by histologic appearance.
TABLE
FREQUENCY
1
OF OCCURRENCE
Number of cases
Group Large cell keratinizing carcinomas Large cell nonkeratinizing carcinomas Small cell carcinomas Adenocarcinomas
54 139 15 37
22 51 6 15
245
100
Number/total number in group
Percentage
13154 351139 4115 9137
25 25 27 24
6 1I245
25
All cases TABLE LYMPH
Group Large cell keratinizing carcinomas Large cell nonkeratinizing carcinomas Small cell carcinomas Adenocarcinomas All cases
NODE
Percentage
2 METASTASES
102
BEECHAM,
HALVORSEN,
AND KOLBENSTVEDT
Keratinization did not affect the frequency with which the large cell carcinomas developed regional spread: The incidence in both was 25%. In addition, we found keratinization to be a widely occurring phenomenon. It appeared to a lesser degree in many of the malignancies subsequently placed in the nonkeratinizing group, and cornified epithelial pearls were even seen in the midst of small cell tumor areas (Fig. 9). [In about 17%, the metastatic cell type did not correspond to the predominating cell type of the primary tumor. The change in cell type did not suggest a specific pattern toward less-differentiated carcinomatous cells.] The overall 2-year tumor-free survival rate representing crude, uncorrected figures was 87%. Table 3 compares this survival rate with histology. Only small cell carcinomas’show any suggestion of a lower survival rate than the overall group: The number of small cell cases, however, precludes any statistical inferences. When we searched for cases containing any small cell areas, whether predominant or not, 23 cases (9%) were found. The 2-year tumor-free survival rate for this group was 87%, identical to the series as a whole. Within our own classification system of 13 different groupings, only one appeared to have any clinical relevance. One-third of the patients (83 of 245) demonstrated a preponderance of the ribbon and band pattern (Fig. 7 and 8) while two-thirds did not. As Table 4 illustrates, there is a slightly lower incidence of lymph node metastases in patients who possess this ribbon and band pattern. The difference is not statistically significant, however. When 2-year survival rates are studied, a more demonstrative trend appears (Table 5). Of the patients with the ribbon and band pattern, 94% were free of disease at 2 years, compared to 84% of the remaining patients.
FIG. 9. Cornified epithelial pearls in the midst of small cell tumor areas. X 150.
STAGE
IB CERVICAL TABLE
~-YEAR
TUMOR-FREE
103
CARCINOMA
3 SURVIVAL
RATE
Number/total number in group
Group Large cell keratinizing carcinomas Large cell nonkeratinizing carcinomas Small cell carcinomas Adenocarcinomas All cases TABLE RIBBON
AND BAND
47154 1231139 12/15 32137
87 88 80 86
2 141245
87
4 PATTERN
GROUP
Number/total number in group
Group Patients exhibiting ribbon and band pattern All others Lymph node metastases, ribbon and band pattern Lymph node metastases, all others TABLE ~-YEAR
TUMOR-FREE
2-Year tumor-free survival
Percentage
831245 1621245 I8/83 431162
Percentage 34 66 22 27
5 SURVIVAL
RATE
Number/total number in group
Ribbon and band pattern All others
78183 1361162
Percentage 94 84
The stromal component of the biopsies varied considerably, and we found it difficult to grade the lymphocytic reaction in areas adjacent to the tumor cells. DISCUSSION
The question of whether the cellular characteristics of cervical carcinoma might influence treatment outcome has intrigued and perplexed investigators for at least 50 years. Broders’ work [6] classifying epithelial carcinomas was a pioneering effort, while Martzloff was among the first to provide in depth analysis of carcinomas of the cervix [7,8]. More recently, the classification originally proposed by Wentz and Reagen [3] has achieved attention. This has led to assertions by these authors and others that the small cell carcinoma is more aggressive and thus should be treated differently than its large cell counterparts [9-131. Several contributors have pointed out, however, that there is no statistically significant data which support these claims [14-171.
104
BEECHAM,
HALVORSEN,
AND
KOLBENSTVEDT
Our data show that in a uniformly treated and carefully followed series of cases of the size presented here, the following facts emerge. First, lymph node metastases appear to be unaffected by any predominant histologic growth pattern. Second, at a 2-year follow-up, when at least 90% of cervical cancers will have recurred, there is no statistically different rate of tumor-free survival among large cell carcinomas, small cell carcinomas, or adenocarcinomas. We also found that in those cases characterized by an orderly and welldemarcated interface between the cervix stroma and the advancing tumor, which we labeled the ribbon and band pattern, there was a high (94%) incidence of tumor-free survival at 2 years; the rate of lymph node metastases was not significantly different, however. Aside from the numerical data, there were equally important pathologic impressions which emerged from our work. To us, any classification system which invokes a differentiation between keratinized large cancer cells, nonkeratinized cells, and small cells is extremely difficult to use. There is a paucity of objective criteria available in the literature. Morphometric qualifications for “small” and “large” cells do not exist, for example, Keratinization, which is in fact ubiquitous, does not seem to us to represent a reliable criterion upon which to classify this disease. In addition, there is the nature of the histologic material itself. As Martzloff pointed out 50 years ago [9], there is frequent discordance between the first specimen and others subsequently removed from the malignancy. Seen in this light, biopsies may represent merely a random sample of a biologic event. Finally, since different histologic types exist within the same lesion, characterization of this lesion by predominant growth patterns may not represent a valid scientific method. We found, for example, 13 different microscopic appearances of carcinoma of the cervix. Such a variability is not surprising, of course, since it is seen in many other malignancies. However, to disregard other growth patterns as subordinate seems artificial, particularly if it is the variability, rather than the consistency, of cervical cancer growth which is truly characteristic. Therefore, as a result of our numerical data and microscopic experience, we believe that histologic grading has no demonstrable relationship to the frequency of lymph node metastases and, as yet, no clinically significant relevance to survival. Scientific methods more subtle than light microscopy, perhaps in the realm of cellular biology or immunology, are required before we have more meaningful answers to the question of malignant growth and spread in cancer of the cervix. REFERENCES 1. Bergsjq, P., and Kristiansen, P. Treatment method and dose distribution in radiotherapy of carcinoma of the cervix, Acta Radiol. 7, 181-192, (1968). 2. Kolbenstvedt, A., and Kolstad, P. Pelvic lymph dissection under preoperative lymphangiographic control, Gynecol. OncoL 2, 39-59 (1974). 3. Wentz, W. B., and Reagen, J. W. Survival in cervical cancer with respeci to celi type, Cancer 12, 384-388 (1959). 4. Cytology of the female genital tract, in International histological c/ussiJication oftumors. Number 8. (G. Riotton and W. M. Christopherson, Eds.), World Health Organization, Geneva, pp. 1-41 (1973).
STAGE
IB CERVICAL
CARCINOMA
105
5. Jampolis, S., Andras, E. J., and Fletcher, Cl. H. Analysis of sites and causes of failures of irradiation in invasive squamous cell carcinoma of the intact uterine cervix, Radiology 115, 681-685 (1975). 6. Broders, A. C. Carcinoma-grading and practical applications, Arch. Pathol. 2, 376-381 (1926). 7. Martzloff, K. H. Relative malignancy of cancer of the cervix uteri as indicated by the predominant cancer cell type, Bull. Johns Hopkins Hosp. 34, 141-149, 184-195 (1923). 8. Ma&off, K. H. Epidermoid carcinoma of the cervix uteri. A histologic study to determine the resemblance between biopsy specimens and the parent tumor obtained by radical panhysterectomy, Amer. J. Ohstet. Gynecol. 16, 578-593 (1928). 9. Wentz, W. B., and Lewis, G. C. Correlation of histologic morphology and survival in cervical cancer following radiation therapy, Ohsret. Gynecol. 26, 228-232 (1965). IO. Sidhu, G. S., Koss, L. Cl., and Barber, H. R. K. Relation of histologic factors to response of stage I epidermoid carcinoma of the cervix to surgical treatment: Analysis of I I5 patients, Obster. Gynecol. 35, 329-338 (1970). I I. Finck, F. M., and Denk, M. Cervical carcinoma: Relationship between histology and survival following radiation therapy, Ohsret. Gynecol. 35, 339-343 (1970). 12. Swan, D. S., and Roddick, J. W. A clinical-pathological correlation of cell type classification for cervical cancer, Amer. J. Obstet. Gynecol. 116, 666-670 (1973). 13. Ng, A. P. B., and Atkin, N. B. Histological cell type and DNA value in the prognosis of squamous cell cancer of the uterine cervix, Brit. J. Cancer 28, 322-33 I (1973). 14. Novak, E. R., and Woodruff, J. D. Gynecologic and obstetrical pathology, Saunders, Philadelphia, p. 124 (1974). 15. Field, C. A., Dockerty, M., and Symmonds, R. E. Small cell cancer of the cervix, Amer. J. Obster. Gynecol. 88, 47-451 (1964). 16. Linell, F., and Monsson, B. The prognostic value of histologic grading of carcinoma of the cervix uteri. A study of 388 cases treated with radium and roentgen therapy, Acta Radio/. 38,219-238 (1952). 17. Gunderson, L. L., Weems, W. S., Hebertson, R. M., and Plenk, H. P. Correlation of histopathology with clinical results following radiation therapy for carcinoma of the cervix, Amer. J. Roentgenol. 120, 74-87 (1974).
ONCOLOGY
6, 9% 105 (1978)
Histologic Classification, Lymph Node Metastases, Patient Survival in Stage IB Cervical Carcinoma
and
An Analysis of 245 Uniformly Treated Cases JACKSONB. BEECHAM, M.D., TORE HALVORSEN, M.D., ANDALF KOLBENSTVEDT, M.D. Departments
of Gynecology,
Pathology,
and Radiology, Oslo, Norway I
The Norwegian
Radium
Hospital,
Received May 3 I, 1977 The role which histologic grading plays in the prognosis of cervical carcinoma is controversial. The basis for subdividing these lesions into small cell carcinomas and keratin- or nonkeratin-producing large cell carcinomas has usually been the assumption, though never statistically supported, that the small cell carcinomas are more aggressive. We tested this hypothesis by studying 245 FIG0 Stage IB cases uniformly treated between 1970 and 1973. To evaluate prognosis, we selected two parameters: lymph node metastases and crude 2-year survival rate. Our data show that there is no statistically significant difference in either of these parameters to suggest that these malignancies behave differently in respect to keratinization or cellular size. Preliminary results suggest that patients in whom the cancer and cervical stroma have a characteristically well-demarcated interface may have improved short-term survival rates.
INTRODUCTION
The variety of growth patterns in cervical carcinoma has intrigued investigators for many years. More recently, such cellular and morphologic characteristics as keratinization, cellular size, and degree of differentiation have been invoked as affecting the overall survival in this disease. Large cell epithelial carcinomas, particularly those with keratin formation, have frequently been depicted as less aggressive than the nonkeratinizing, anaplastic carcinomas, which typically form sheets of small malignant cells. However, the effects that any histologic pattern may have upon prognosis remain statistically unsubstantiated, due to lack of uniformity either in pathologic criteria, study design, treatment methods, or follow-up. To reduce the effect of such variables, we chose to study the initial biopsy specimens from 245 consecutively treated cases of FIG0 Stage IB cervical carcinoma, using lymph node metastases and tumor-free survival rate as indicators of the importance which different histologic growth patterns might have upon the biologic activity in this malignancy. I Address.requests for reprints, to Per Icolstad, Department of Gynecology, Norwegian Hospital, Oslo 3, Norway.
Radium
95 0090-8258/78/0061-0095$01.00/0 Copyright @ 1978 by Academic Press, Inc. All rights of reproduction in any form reserved.
96
BEECHAM,
HALVORSEN,
MATERIALS
AND
KOLBENSTVEDT
AND METHODS
Specimens from approximately 8000-9000 malignancies pass through the Department of Pathology of the Norwegian Radium Hospital annually. Of these, about 350 are cases of invasive carcinoma of the cervix treated in the Department of Gynecology. This represents 90% of all cervix cancers treated in Norway. From this material, we selected 245 consecutively and identically treated patients with Stage IB lesions. Each received two 5-day radium courses, according to a modified Paris method [I]. Radical hysterectomy and pelvic lymphadenectomy followed the radium application 6 weeks later. Lymphangiogram comparison films at the time of surgery helped to assure a thorough dissection from the aorta to the inguinal ligaments [23. Those women who had one or more metastatic lymph nodes received postoperative radiation therapy consisting of a tumor dose to the total pelvis of 4000 rad. The preoperative radium irradiation added approximately 1000 rad to the lymph node areas. A pathologist and a gynecologist together reviewed all the primary biopsies. In those patients who had multiple specimens, we selected the one which most clearly reflected any predominating histologic features. A lymphangiographer and a pathologist together studied all lymph nodes removed. Step-sectioning techniques, frequently revealing micrometastases, demonstrated a 25% incidence of lymph node spread. We then divided all patients into four histologic groups: those with adenocarcinemas, large cell keratinizing carcinomas, nonkeratinizing large cell carcinomas, and small cell carcinomas. Special stains were used when necessary to identify glandular malignant patterns. To classify the epithelial malignancies, we used the criteria initially proposed by Wentz and Reagen [3] and currently accepted by the World Health Organization [4]. According to these sources, the large cell keratinizing carcinoma has a characteristic formation of epithelial pearls and frequently cornified strata of superficial keratinization. The mitotic index is low, and consequently the microscopic appearance is one of a well-differentiated epidermoid lesion (Fig. 1 and 2). The nonkeratinizing large cell carcinoma is usually less differentiated. While isolated cell keratinization exists, there is no epithelial pearl formation and the mitotic index is moderately high. This group frequently demonstrates large areas of pale pleomorphic cells varying in size (Fig. 3 and 4). By contrast, the small cell carcinomas possess sheets of uniformly small basophilic cells (Fig. 5 and 6). Their nuclear:cytoplasmic ratio and mitotic index are high, conveying a generally anaplastic appearance. In the course of our work, we developed a number of impressions concerning the morphologic appearances of carcinomas of the cervix which were not covered by the Wentz and Reagen classification. We finally identified 13 different histologic patterns. The predominant pattern was a mixed one. Many of the other patterns contained only a few cases. Only one of the 13 groups subsequently demonstrated any clinical relevance: It was characterized by a sharp, welldemarcated interface between the cervical tissue and the advancing epithelial growth, giving a ribbon and band appearance to the tissues (Fig, 7 and 8).
STAGE IB CERVICAL
FIGS. 1 and 2. Keratinizing
CARCINOMA
large cell carcinoma. 1, x 190; 2, x750.
97
98
BEECHAM,
HALVORSEN,
FIGS. 3 and 4. Nonkeratinizing
AND
KOLBENSTVEDT
large cell carcinoma. 3, x 190; 4, x750.
STAGE
FIGS.
IB CERVICAL
CARCINOMA
5 AND 6. Small cell carcinoma. 5, x 190; 6, x750.
99
BEECHAM,
HALVORSEN,
AND KOLBENSTVEDT
FIGS. 7 AND 8. The one clinically relevant histologic pattern of carcinoma is characterized by a sharp, well-demarcated interface between the cervical tissue and the advancing epithelial growth. This gives a ribbon and band appearance to the tissues. 7 and 8, x 190.
STAGE
IB
CERVICAL
101
CARCINOMA
Two hundred and fifty-five patients were available for study on the basis of their FIG0 stage and uniform treatment. We eliminated 10 patients. In five, the biopsy interpretations fell outside our selected categories. Two were adenosquamous collision carcinomas, two were possibly not primary cervical lesions, and one could only be diagnosed as a poorly differentiated malignant tumor. Five additional patients were lost to follow-up, four of whom had left Norway during this study. Thus, 245 patients formed the basis for our analyses. Because 90% of recurrences in carcinoma of the cervix develop within 2 years [5], we felt that this time interval was a reasonable point at which to initially study survival figures. We had follow-up information on 98% of the patients. In most instances, our information was based upon a history, physical examination, and cytology specimen. In 10% of the cases, follow-up was by letter from the patient. We assumed that the number of occult recurrences here would be negligible. RESULTS
The predominant histologic pattern was the large cell, nonkeratinizing carcinoma, which occurred in 57% of patients. Small cell carcinomas were the least common, appearing in 6% of cases. Table 1 summarizes the frequency with which the four histologic groups occurred. Sixty-one patients, or 25%, had lymph node metastases. As Table 2 shows, the relative frequency with which cervical cancer metastasizes is not significantly altered by histologic appearance.
TABLE
FREQUENCY
1
OF OCCURRENCE
Number of cases
Group Large cell keratinizing carcinomas Large cell nonkeratinizing carcinomas Small cell carcinomas Adenocarcinomas
54 139 15 37
22 51 6 15
245
100
Number/total number in group
Percentage
13154 351139 4115 9137
25 25 27 24
6 1I245
25
All cases TABLE LYMPH
Group Large cell keratinizing carcinomas Large cell nonkeratinizing carcinomas Small cell carcinomas Adenocarcinomas All cases
NODE
Percentage
2 METASTASES
102
BEECHAM,
HALVORSEN,
AND KOLBENSTVEDT
Keratinization did not affect the frequency with which the large cell carcinomas developed regional spread: The incidence in both was 25%. In addition, we found keratinization to be a widely occurring phenomenon. It appeared to a lesser degree in many of the malignancies subsequently placed in the nonkeratinizing group, and cornified epithelial pearls were even seen in the midst of small cell tumor areas (Fig. 9). [In about 17%, the metastatic cell type did not correspond to the predominating cell type of the primary tumor. The change in cell type did not suggest a specific pattern toward less-differentiated carcinomatous cells.] The overall 2-year tumor-free survival rate representing crude, uncorrected figures was 87%. Table 3 compares this survival rate with histology. Only small cell carcinomas’show any suggestion of a lower survival rate than the overall group: The number of small cell cases, however, precludes any statistical inferences. When we searched for cases containing any small cell areas, whether predominant or not, 23 cases (9%) were found. The 2-year tumor-free survival rate for this group was 87%, identical to the series as a whole. Within our own classification system of 13 different groupings, only one appeared to have any clinical relevance. One-third of the patients (83 of 245) demonstrated a preponderance of the ribbon and band pattern (Fig. 7 and 8) while two-thirds did not. As Table 4 illustrates, there is a slightly lower incidence of lymph node metastases in patients who possess this ribbon and band pattern. The difference is not statistically significant, however. When 2-year survival rates are studied, a more demonstrative trend appears (Table 5). Of the patients with the ribbon and band pattern, 94% were free of disease at 2 years, compared to 84% of the remaining patients.
FIG. 9. Cornified epithelial pearls in the midst of small cell tumor areas. X 150.
STAGE
IB CERVICAL TABLE
~-YEAR
TUMOR-FREE
103
CARCINOMA
3 SURVIVAL
RATE
Number/total number in group
Group Large cell keratinizing carcinomas Large cell nonkeratinizing carcinomas Small cell carcinomas Adenocarcinomas All cases TABLE RIBBON
AND BAND
47154 1231139 12/15 32137
87 88 80 86
2 141245
87
4 PATTERN
GROUP
Number/total number in group
Group Patients exhibiting ribbon and band pattern All others Lymph node metastases, ribbon and band pattern Lymph node metastases, all others TABLE ~-YEAR
TUMOR-FREE
2-Year tumor-free survival
Percentage
831245 1621245 I8/83 431162
Percentage 34 66 22 27
5 SURVIVAL
RATE
Number/total number in group
Ribbon and band pattern All others
78183 1361162
Percentage 94 84
The stromal component of the biopsies varied considerably, and we found it difficult to grade the lymphocytic reaction in areas adjacent to the tumor cells. DISCUSSION
The question of whether the cellular characteristics of cervical carcinoma might influence treatment outcome has intrigued and perplexed investigators for at least 50 years. Broders’ work [6] classifying epithelial carcinomas was a pioneering effort, while Martzloff was among the first to provide in depth analysis of carcinomas of the cervix [7,8]. More recently, the classification originally proposed by Wentz and Reagen [3] has achieved attention. This has led to assertions by these authors and others that the small cell carcinoma is more aggressive and thus should be treated differently than its large cell counterparts [9-131. Several contributors have pointed out, however, that there is no statistically significant data which support these claims [14-171.
104
BEECHAM,
HALVORSEN,
AND
KOLBENSTVEDT
Our data show that in a uniformly treated and carefully followed series of cases of the size presented here, the following facts emerge. First, lymph node metastases appear to be unaffected by any predominant histologic growth pattern. Second, at a 2-year follow-up, when at least 90% of cervical cancers will have recurred, there is no statistically different rate of tumor-free survival among large cell carcinomas, small cell carcinomas, or adenocarcinomas. We also found that in those cases characterized by an orderly and welldemarcated interface between the cervix stroma and the advancing tumor, which we labeled the ribbon and band pattern, there was a high (94%) incidence of tumor-free survival at 2 years; the rate of lymph node metastases was not significantly different, however. Aside from the numerical data, there were equally important pathologic impressions which emerged from our work. To us, any classification system which invokes a differentiation between keratinized large cancer cells, nonkeratinized cells, and small cells is extremely difficult to use. There is a paucity of objective criteria available in the literature. Morphometric qualifications for “small” and “large” cells do not exist, for example, Keratinization, which is in fact ubiquitous, does not seem to us to represent a reliable criterion upon which to classify this disease. In addition, there is the nature of the histologic material itself. As Martzloff pointed out 50 years ago [9], there is frequent discordance between the first specimen and others subsequently removed from the malignancy. Seen in this light, biopsies may represent merely a random sample of a biologic event. Finally, since different histologic types exist within the same lesion, characterization of this lesion by predominant growth patterns may not represent a valid scientific method. We found, for example, 13 different microscopic appearances of carcinoma of the cervix. Such a variability is not surprising, of course, since it is seen in many other malignancies. However, to disregard other growth patterns as subordinate seems artificial, particularly if it is the variability, rather than the consistency, of cervical cancer growth which is truly characteristic. Therefore, as a result of our numerical data and microscopic experience, we believe that histologic grading has no demonstrable relationship to the frequency of lymph node metastases and, as yet, no clinically significant relevance to survival. Scientific methods more subtle than light microscopy, perhaps in the realm of cellular biology or immunology, are required before we have more meaningful answers to the question of malignant growth and spread in cancer of the cervix. REFERENCES 1. Bergsjq, P., and Kristiansen, P. Treatment method and dose distribution in radiotherapy of carcinoma of the cervix, Acta Radiol. 7, 181-192, (1968). 2. Kolbenstvedt, A., and Kolstad, P. Pelvic lymph dissection under preoperative lymphangiographic control, Gynecol. OncoL 2, 39-59 (1974). 3. Wentz, W. B., and Reagen, J. W. Survival in cervical cancer with respeci to celi type, Cancer 12, 384-388 (1959). 4. Cytology of the female genital tract, in International histological c/ussiJication oftumors. Number 8. (G. Riotton and W. M. Christopherson, Eds.), World Health Organization, Geneva, pp. 1-41 (1973).
STAGE
IB CERVICAL
CARCINOMA
105
5. Jampolis, S., Andras, E. J., and Fletcher, Cl. H. Analysis of sites and causes of failures of irradiation in invasive squamous cell carcinoma of the intact uterine cervix, Radiology 115, 681-685 (1975). 6. Broders, A. C. Carcinoma-grading and practical applications, Arch. Pathol. 2, 376-381 (1926). 7. Martzloff, K. H. Relative malignancy of cancer of the cervix uteri as indicated by the predominant cancer cell type, Bull. Johns Hopkins Hosp. 34, 141-149, 184-195 (1923). 8. Ma&off, K. H. Epidermoid carcinoma of the cervix uteri. A histologic study to determine the resemblance between biopsy specimens and the parent tumor obtained by radical panhysterectomy, Amer. J. Ohstet. Gynecol. 16, 578-593 (1928). 9. Wentz, W. B., and Lewis, G. C. Correlation of histologic morphology and survival in cervical cancer following radiation therapy, Ohsret. Gynecol. 26, 228-232 (1965). IO. Sidhu, G. S., Koss, L. Cl., and Barber, H. R. K. Relation of histologic factors to response of stage I epidermoid carcinoma of the cervix to surgical treatment: Analysis of I I5 patients, Obster. Gynecol. 35, 329-338 (1970). I I. Finck, F. M., and Denk, M. Cervical carcinoma: Relationship between histology and survival following radiation therapy, Ohsret. Gynecol. 35, 339-343 (1970). 12. Swan, D. S., and Roddick, J. W. A clinical-pathological correlation of cell type classification for cervical cancer, Amer. J. Obstet. Gynecol. 116, 666-670 (1973). 13. Ng, A. P. B., and Atkin, N. B. Histological cell type and DNA value in the prognosis of squamous cell cancer of the uterine cervix, Brit. J. Cancer 28, 322-33 I (1973). 14. Novak, E. R., and Woodruff, J. D. Gynecologic and obstetrical pathology, Saunders, Philadelphia, p. 124 (1974). 15. Field, C. A., Dockerty, M., and Symmonds, R. E. Small cell cancer of the cervix, Amer. J. Obster. Gynecol. 88, 47-451 (1964). 16. Linell, F., and Monsson, B. The prognostic value of histologic grading of carcinoma of the cervix uteri. A study of 388 cases treated with radium and roentgen therapy, Acta Radio/. 38,219-238 (1952). 17. Gunderson, L. L., Weems, W. S., Hebertson, R. M., and Plenk, H. P. Correlation of histopathology with clinical results following radiation therapy for carcinoma of the cervix, Amer. J. Roentgenol. 120, 74-87 (1974).