THE SIGNIFICANCE OF CELL TYPE IN CERVICAL CANCER'

Transcription

1 THE SIGNIFICANCE OF CELL TYPE IN CERVICAL CANCER' DANIEL G. MORTON, M.D. Assistant Professor of Obstetrics and Gynecology, University of California Medical School, San Francisco Among the factors which have been investigated in an attempt to expla n the differences in the curability of cervical cancer is the type of cell making up the growth. Whether or not growths composed of different types of cells actually react differently to treatment, either irradiation or operation, is unknown, but many have entertained the opinion that such is the case. If they are right, the determination of cell type becomes of great importance. There is a growing doubt that differences in cell type bear a relation to the degree of radiation sensitivity, but the opinion that they are related to curability by operation still prevails. This latter opinion would appear to rest on rather flimsy evidence. Logic certainly tells us that cure by operation should depend entirely upon whether or not all the cancer present is removed, without reference to the type of cell composing it. It is my purpose, however, to present a brief rksumi! of investigations of the cell type in a series of cases for which five-year results were available. Cervical carcinomas may be divided into the squamous or epidermoid, which make up 90 to 95 per cent of the cases, and the cylindrical-cell or adenocarcinomas, which constitute the remainder. While the latter were formerly considered more resistant to treatment than the squamous-cell growths, the majority of authorities now consider that such is not the case. It is usually not possible to differentiate the two forms either by clinical examination or by their response to radiation. Since the number of cervical adenocarcinomas is quite small, few studies on the significance of variations in the cell type have been attempted. Norris' (6) recent article, in which he reports the details of 43 cases, summarizes the results of others. Such growths have been divided into ripe, mid-ripe, and unripe forms, into highly differentiated and undifferentiated forms, and into adenoma malignum, intermediate, and true adenocarcinoma forms, but attempts to correlate these various forms with curability have remained unconvincing. This may possibly be due to the fact that such deductions have of necessity been made from small numbers of cases. Norris believes that those growths with a high mitosis content are the most malignant and the most sensitive to radiation, and inclines to the belief that adenoma malignum carries a better prognosis than the true adenocarcinoma. He believes, too, that adenocarcinomas of the cervix as a group are no less sensitive to radiation than are squamous-cell cancers. Because of the small number I have not attempted to study our cases of cervical adenocarcinoma, but have confined my attention entirely to growths made up of squamous cells. 1 Read before the Sixth Annual Meeting of the Pacific Coast Society of Obstetrics and Gynecology, San Francisco, Nov. 4, This study was made possible by a grant from the Cancer Research Fund of the University of California. 362

2 SIGNIFICANCE OF CELL TYPE IN CERVICAL CANCER 363 For many years efforts have been made to divide squamous-cell growths according to the degree of differentiation of the predominant cells, with the idea that the least differentiated were the most rapidly growing, the most malignant, and incidentally the most susceptible to radiation. Schottlaender and Kermauner (8) recognized three types : the unripe, midripe, and ripe. Broders (1) has divided squamous cancers in general into Grades 1, 2, 3, and 4, in the order of decreasing differentiation and ascending malignancy. Martzloff (4) has classified them as spinal-, spindle-, and transitional-cell, and has attempted to correlate curability with cell type. Since we have followed Martzloff s classification, we will review briefly his criteria. He compared the component cells of the spinal-cell type with those seen in the upper or more superficial layers of the normal squamous lining of the vaginal portion of the cervix. Here under high magnification numerous intercellular bridges or spines may be seen, hence the designation spinal-cell. These cells Martzloff regarded as the most highly differentiated, the most A. B. C. FIG. 1. A. SPINAL-CELL ZONE. B. TRANSITIONAL-CELL ZONE. C. SPINDLE-CELL ZONE slowly growing, and the most resistant to radiation. The zone marked A in the microscopic section reproduced in Fig. 1 shows this type of cell. The component cells of the spindle-cell type Martzloff compared with the basal cells of the vaginal lining of the cervix (Fig. 1, C). These cells he regarded as the least differentiated, the most rapidly growing, and the most susceptible to radiation. The component cells of the transitional-cell type he compared with those seen in the middle layers of the vaginal lining of the cervix (Fig. 1, B). Cancers composed of these cells he regarded as standing midway between the other two in all respects. Examples of the three varieties are illustrated in Figs. 2, 3, and 4. Martzloff s study was based upon 356 cases (excluding adenocarcinomas), all of which were operated upon. He found the incidence of the various cell types to be as follows: Spinal-cell... 14% Transitional-cell y0 Spindle-cell % These percentages I have calculated, to exclude the adenocarcinomas.

3 3 64 DANIEL G. MORTON The microscopic sections of all of our five-year cases, with the exception of those classified as Stage IV, have been studied and the tumors grouped according to Martzloff s plan. The advanced cases have been omitted because we wished to analyze only those in which there was some hope of cure. It was necessary to omit a few others, also, because the slides had been lost or because the cells were too degenerate to permit classification. With these FIG. 2. SPINAL-CELL CARCINOMA eliminations, 160 cases remained for consideration. The results of classification are as follows: Spinal-cell cases (16.2%) Transitional-cell cases (60.0%) Spindle-cell cases (23.8%) In accordance with Martzloff s plan the diagnoses were based upon the predominant cell. In some instances the greatest difficulty was experienced in deciding whether the growth should be classified as transitional or spindle, or transitional or spinal. In a few cases I found myself reversing a previous decision, a fact which constrains me to regard the value of such classifications as questionable. Anyone who has attempted cellular divisions of this kind must have had a similar experience. There are other factors which reflect upon the validity of such divisions. Undoubtedly the predominant cells of any given cervical carcinoma may vary in their appear,ance from the predominant cells in other cases, yet these variations are sometimes more apparent than real. The thickness of the section and plane in which it is cut may alter the appearance of the cells. In a number of growths classified as predominantly spindle-cell, for example, the cells of adjacent normal cervical glands,

4 FIG. 3. SPINDLE-CELL CARCINOMA FIG. 4. TRANSITIONAL-CELL CARCINOMA 365

5 ~ _ 3 66 DANIEL G. MORTON and even of the normal squamous lining, appeared much more elongated and spindle-shaped than usual. This finding can only be interpreted as being due to the manner in which the tissue was cut, and suggests that the cancer cells owed their spindle appearance to the same factor. Another disturbing fact is that the picture often varies totally from one field to another, thus making it difficult to select a predominant cell type. In the third place, sections from the removed tumor often fail to check with those obtained at biopsy, as Martzloff himself has reported. This may mean that the appearance of the cells has changed with time or that there is so much variation in different parts of the tumor that consistent findings are not possible. In either case classification by cell type becomes useless. Finally, in three recent reports in which the same (though different from Martzloff s) classification was used, the incidence of the different cell types differs widely (Table I), showing graphically, and to my mind convincingly, that the division of squamous growths of the cervix into various cell types is not on a sound basis. TAHLE I : Classification of Squamous-cell Carcinoma on Basis of Cell Type, Showing Wide Variation.-..~ ~~ ~-- Author Cell Type Ripe Midripe Unripe Hausding (2) (240 cases) % 35% Norris (7) (118 cases) % l6.2yo Healy (3) (537 cases) yo 15.2% (2.9% Ad.) If, for the sake of argument, we suppose that definite cell types do exist, what evidence is available that they can be correlated with curability? So far as curability by operation is concerned Martzloff (5) reported the interesting results presented in Table 11. He compared his figures with corresponding figures obtained by Broders, assuming that Broders Grades 2, 3, and 4 corresponded with his spinal-, transitional-, and spindle-cell types respectively. TABLE 11: Curability and Cell Type -.-- Martzlofl Spinal-cell % cured Transitional-cell % cured Spindle-cell % cured I Broders Grade 2,... Grade Grade , cured 21.5% cured 9.527& cured The results obtained in the various groups agree closely and seem to show that the results of operation in patients with spindle-cell growths were very poor, while those obtained with transitional and spinal-cell growths were progressively much better. I am not aware of any other figures which show such a definite correlation. As Norris (7) has pointed out, so many other factors enter into the question of curability that it hardly seems possible to consider a single one and have it mean anything. The most important factor of all is the size and shape of the neoplasm. Other pertinent factors are the blood supply of the tumor, the type of vessels, their location, the condition of the

6 SIGNIFICANCE OF CELL TYPE IN CERVICAL CANCER 3 67 patient, the dose and method of radiation if that form of treatment is used. To take an extreme example, it is not possible to compare the curability of a Stage IV spindle-cell growth with a Stage I spinal-cell growth. If the comparison is to man anything, a.11 conditions except the cell type should be identical or nearly so. Neither Norris, Hausding, nor Healy believes that cell type, as determined today, can be correlated with radiosensitivity, although the last author is inclined to believe that degree of malignancy and cell type are related. A recent report by Healy shows that about the same percentage of cures was obtained in the various cell types (all treated by radiation) at the Memorial Hospital in New Pork (Table 111). T.~BLE 111: Percentage of Cures in Ripe, Midripe, and Unripe Types, Memorial Hospital Ripe: 26 cases.... Midripe: 88 cases..... Unripe: 20 cases oj, cured 25.0%o cured 24.3% cured Our own results support the findings of these authors. Table IV shows that the incidence of the various cell types in the group of patients cured for ' more than five years did not differ significantly from the incidence among those who were not cured. TABLE IV: Classification of Cured and Uncured Cases by Cell Type Cell Type Five-year Cures Uncured Spinal-cell (15.0%) Transitional-cell (56.676) Spindle-cell (28.4 yo) Arranging our material to show the percentage of cures for the various cell types (Table V) we obtain results similar to those of Healy: i.e., about the same percentage of cures was obtained in each group. The somewhat high figure for the spindle-cell growths is due to the unduly high percentage of Stage I cases in this group. TABLE V: Percentage of Cures in Author's Series - _ ~ Spinal-cell... 9 (34.64,) Transitional-cell (35.476) Spindle-cell (44.7 yo) * ~ ~~ * An unduly high percentage of Stage I spindle-cell types. One further comparison was made in which all of the cases were of the same stage of advancement, i.c. Stage 111, and all were treated by radiation alone. In one group are the patients who have remained cured for more than five years, in the other those who died in less than a year after treatment. These groups were chosen with the idea that if differences exist in the reaction of the various cell types to treatment they should be evident in two groups

7 _I 368 DANIEL G. MORTON showing such contrasting responses. Table VI shows the number of cases and the percentage incidence of the various cell types for these two groups of patients. The small number of cases detracts from the value of the comparison, but with the cases available, no significant differences were discovered. - TAHLE VI : Classification of Stage Cases Died in Less Cell Type Five-year Cures Than a Year (18 cases) (58 cases) Spinal-cell (11.0%) 14 (24.1%) Transitional-cell (72.3%) 32 (55.1%j Spindle-cell... 3 (16.6%) 12 (20.8%) Both Norris and Hausding believe that rich mitosis content spells increased radiosensitivity ; both found that they had obtained a greater percentage of cures in those patients with mitosis-rich growths. An attempt has been made to arrange our material on this basis, and the results are set forth in Tables VII and VIII. The cases are divided into two groups, those with only a few mitoses and those with a great many. No actual mitosis count was made, but a large number of high power fields were examined in each section and an estimate of mitosis richness or poorness made, I was unable to confirm the findings of Norris and Hausding. The figures, which speak for themselves, show no consistent results. Tmx I VII : Classijiration of Material Acrording I to Mitoses 1 -- Stage 111 Stage 111 Dying I ~ ~ ~ Cured ~ Cured e in Less Than 5 Years 1 Year I :;Ets I Not 31.1% % 1 40% % Few mitoses Tu /, 72.5m0 Many mitoses TABLE VI I I : Relation of Mitoses 10 &res Incidence Few mitoses (68.9y0,) Many mitoses (31.1%) Cases Cured for Five Years 49 (44.9%j * 11 (22.670) * An unduly high percentage of Stage I cases. It would seem that the same objections to a correlation of this kind should apply as were brought to the correlation of curability and cell type, Le., it takes into consideration only one of many factors which determine response to treatment. SUMMARY AND DISCUSSION The division of squamous-cell carcinomas of the cervix uteri on the basis of cell type is difficult as the appearance of the cells depends upon a number

8 SIGNIFICANCE OF CELL TYPE IN CERVICAL CANCER 3 69 of different factors. The manner in which the section is cut, the fact that the picture may vary widely in different portions of the growth and even in adjacent microscopic fields, the fact that the cells may change in appearance with the passage of time, all influence the choice of a predominant cell type. That some growths are composed, on the whole, of more highly differentiated cells than others cannot be denied, but it is highly questionable whether reliable divisions can be made with the methods at our disposal. This contention is convincingly supported by the marked variation in the figures reported by three recent investigators, all using the same classification. Even if reliable divisions were possible it would not be logical to correlate the factor cell type with degree of malignancy, nor with radiosensitivity, nor with curability expressed in terms of five-year cures, because of the multitude of other factors involved in the determination of these conditions. Some of these other factors are rather indefinite, such as the general condition of the patient, the age of the patient, her reactionary powers to treatment, the blood supply in the region of the growth, the presence or absence of infection, etc. Other factors, such as the size, form, and gross extent of the growth are quite definite and far more pertinent than cell type, so much more so that all other factors are completely overshadowed. These contentions appear to be borne out by the investigations of others and by a consideration of our own material, in which no definite differences in the response to treatment could be discovered in the various cell types. Our own material shows the same lack of consistent findings in a consideration of mitosis content as an index of malignancy and radiosensitivity. This was not unexpected in the light of what has been said in regard to cell type; the same argument applies. Since the determination of cell type and mitosis content is very uncertain at best, and since it is not sound reasoning to correlate such individual factors with curability even if they themselves be accurate, we do not believe that cell type or mitosis content are of much significance in the determination of prognosis. BIBLIOGRAPHY 1. BRODERS, H. C.: J. A. M. A. 74: 656, 1920; Ann. Surg. 73: 141, HAUSDING, H.: Strahlentherapie 55: 387, HEALY, W. P., AND FRAZELL, E. L.: Am. J. Obst. & Gynec. 34: 593, MARTZLOFF, K. H.: Bull. Johns Hopkins Hosp. 34: 141, MARTZLOFF, K. H.: Bull. Johns Hopkins Hosp. 40: 160, NORRIS, C. C.: Am. J. Cancer 27: 653, NORRIS, C. C.: Am. J. Roentgenol. 33: 332, SCHOTTLAENDER, J., AND KERMAUNER, F. : Zur Kenntnis des Uteruskarzinoms, S. Karger, Berlin, 1912.