THE JOURNAL CANCER · without cornification, a round-cell and a spindle-cell type. In Germany, ... and keratinisation. The recognition of anaplasia, according to Ewing (1930), is

THE AMERICAN JOURNAL OF CANCER

A Continuation of The Journal of Cancer Research

VOLUME XXIII JANUARY, 1935 NUMBER 1

THE HISTOLOGICAL CLL4SSIFICATION O F CANCERS O F T H E UTERINE CERVIX AND THE RELATION BETWEEN THE

RADIUM TREATMENT GROWTH STRUCTURE AND THE RESULTS O F

H. CHAMBERS

Pathologist t o the Marie Curie Hospi tal; Full-time Invest igator f o r the Medical Research Coullail

The value of histological grading as a means of determining prognosis and estimating the radiosensitivity of malignant tumours is still uncertain. The subject has attracted wide attention since Broders (1922) showed, in squamous cancer, that the success of surgical treatment was closely related to the type of growth and the degree of cell activity. I n cancer of the cervix particularly, the marked differences which occur in structure have led to many attempts to trace a relationship between the histological type and the clinical progress of the disease.

The number of five-year cures reported by Broders (1922) for the most differentiated type of squamous cancer of the cervix treated by surgery was 53.33 per cent as compared with only 9.57 per cent for the most rapidly growing and least differentiated tumours. The corresponding figures given by Martzloff (1927) were 63.6 per cent and 14.01 per cent. After radiotherapy Healy and Cutler (1928) found an equally important but different relationship, more cures being obtained with the anaplastic, rapidly growing tumours than with the highly differentiated and more slowly growing forms of cancer. Adenocar- cinomata Regaud for many years has considered should be treated preferably by surgery because of their insensitivity to radiation.

Apart from the need of a large number of cases treated by a uniform method and followed for a sufficient time, a study of the subject is complicated by the difficulties inherent in the problem of classifying cancer growths into separate and clearly defined groups and by the fact that no method of grading has as yet been generally adopted or accepted as satisfactory.

1

2 H. CHAMBERS

Broders (1922) classified all squamous carcinomata, wherever aris- ing, into four groups depending upon the extent of differentiation. I n Group 1, three quarters of the cells were differentiated; in Group 2, a half; in Group 3, a quarter, and in the fourth group there was no differentiation at all. In a study of 269 cases of cervical cancer, all were placed in groups 2, 3, and 4; none were graded in Group 1. These cases had been treated at the Mayo Clinic by surgery.

Martzloff ’s extensive investigations (1923, 1927) were done on 387 cases of cancer of the cervix, most of which had been operated upon. He described three main groups of squamous carcinomata. A spinal- cell type which corresponded to the cells of the upper layers of the

TABLE I: Cancer of the Cervix: Incidence of Histological Tupes in Reported Series

Author and Method of Treatment

Broders (1922), Surgery

Martrloff (1923,1927) Surgery

Healy and Cutler (1928), Radio- therapy

Schmitz and Hueper (1927), Radiotherapy

The Marie Curie Clinic, Radiotherapy

Histological Type

Type 2, half differentiated Type 3, quarter differentiated Type 4, not differentiated

Spinal Transitional Fat spindle

Adult Plexiform Anaplastio

Spinous, with cornification ’ Spinous, without cornification Round-cell Spindle-cell

Grade 1 Grades 2 & 3 Grade 4

Number of

Cases

23 153 93

50 259 47

35 123 42

6!} 106 49

68 283 99

Incidence

8.54% 56.87% 34.57%

15.5% 66.8% 12.0%

17 % 62% 21%

31%

47% 21.7%

15.1% 62.9% 22.2%

normal stratum mucosum, a transitional-cell type corresponding to the cells of the deeper layers of the cervix epithelium, and a fat spindle- cell type corresponding to the basal or germinating layer. The charac- ter of the predominating cell defined the type, though most forms showed admixtures with the other varieties of cells. The extent of the mixture determined the recognition of eight sub-groups. Martzloff was not prepared to claim that any type of cancer was derived from any particular layer of the normal epithelium and he avoided the term basal-cell cancer for this reason. He took no account of the general configuration of the growth and considered it of little importance. hIartzloff’s method of grading has been very generally adopted, among others by Pemberton (1926), Kimbrough and Norris (1927), and re- cently by Maliphant (1933).

I n a study of 200 cases of cancer of the cervix treated by radiation,

CANCERS O F THE UTERINE CERVIX 3

Healy and Cutler (1928) accepted the degree of anaplasia as the basis for classification but defined only three groups : adult, plexiform, and anaplastic. Healy considered that these three groups corresponded fairly closely to Martzloff’s three types, and the percentage incidence was practically the same (see Table I). Schmitz and Hueper (1930). distinguish four groups of squamous cancer: a spinous type with and without cornification, a round-cell and a spindle-cell type. In Germany, following the early work of Schottlaender and Kermauner (1912), it has been customary to group the cases as “ripe,” “mid-ripe,” and ‘ I unripe. ”

The investigation which forms the subject of this paper has been carried out on the cases of cancer of the cervix treated at the Marie Curie Clinic since it began work in 1925. It has been a matter of routine to confirm the clinical diagnosis by a microscopic examination of tissue obtained from every case treated f o r malignant disease. For this enquiry the sections were first systematically examined and classified into their various histological groups whenever the structure was sufficiently characteristic and when there was enough material. The case records were afterwards studied to find if any special clinical features could be correlated with the particular histological types. The investigation was done more particularly from the point of view of finding evidence to show to what extent, if any, the response of malignant tumours to radiation varies with their histological structure, and also of finding whether there was any evidence to support the prevalent idea that certain histological types are insensitive to radiation.

THE MATERIAL At the present time, when cancer of the cervix is being treated al-

most exclusively by radiotherapy and not by surgical removal, the tissue available f o r histological study is necessarily limited. As extensive curetting is not considered advisable, the tissue sent f o r microscopic examination is usually quite small; it is often heavily infected with bacteria and inflamed, and may be largely necrotic.

Although the diagnosis of malignant disease is usually a matter of no difficulty, many of the sections have to be set aside as unsuitable for histological grading. But it is possible, with careful selection, to classify most of the tumours into different grades. Though it may be seriously questioned whether the tissue is really a fair sample of the general growth structure, this is the only material available at the present time for studying the problem of histological grading in relation to radiosensitivity and its clinical application, and we have there- fore attempted to make use of it. I n this connection Martzloff (1928), in order to study the value of biopsy material, examined 70 specimens of uterine cancer removed by operation and compared the findings with those from the tissue removed f o r diagnosis from the same cases. He concluded that in a third of the cases the examination of biopsy material would fail to indicate correctly the predominating cell type. I n our

4 H. CHAMBERS

material, though the conditions are not strictly comparable, almost the same proportion of the cases have had to be set aside as unsuitable for grading, namely 228 in a total of 678.

METHOD OF GEADING It is generally accepted that the main basis of any system of Frading

should be the degree of differentiation, defining as fa r as possible the comparative degree of cell activity. I n malignant tumours a t most sites it is possible to trace a gradual transition from highly differentiated and more slowly growing forms to completely undifferentiated and rapidly growing varieties. But in separating these kinds it is important to remember that the rate of growth of tumour cells may vary considerably at different places in the individual case, and cell activity is not always a safe guide in determining prognosis. A feature of some of the more slowly growing and highly differentiated tumours, e.g. those of Grade 1, is their special tendency to permeate the tissues and give rise to embolic metastases.

I n squamous cancer the recognition of differentiation depends upon the development of the characters of the mature epithelial cell and the presence of squames, cell pearls, and keratinisation. The recognition of anaplasia, according to Ewing (1930), is not a simple matter; it depends for the most part upon the presence of hyperchromatism and loss of polarity and of numerous mitoses ; the cells as a rule no longer show any squamous characters.

Differentiated squamous tumours differ from the anaplastic growths mainly in the fact that in the former a large proportion of the cells no longer propagate their type, whereas in the latter most of the cells at some time or other are in a state of division. This feature of the squamous carcinomata is of special importance in radiotherapy, for it is generally conceded that there is some truth in the law of Bergoni6 and Tribondeau that rapidly growing cells are more easily affected by radiation than cells which are no longer dividing.

A method of histological grading such as Martzloff '8, which uses the shape and type of the cell as the only basis for classification, is not altogether satisfactory. The difficulties are evident in the variety of names which have been used for describing the different growths (see Table I).

Martzloff 's fat spindle-cell type includes most of the anaplastic growths, but there are many tumours of this kind formed of round and embryonic cells which have no spindle characters. There is also a type of cancer of the cervix, not anaplastic, composed of thin spindle cell8 deeply staining like the cells of the basal germinating layer; these growths are often fibrotic with much intervening tissue. I n Martzloff's classification no account is taken of the general configuration ; he thinks it is not of importance as an indicator of potential malignancy. But to us it seems a mistake to ignore this striking feature of the structure, There is a large group of cancers of the cervix which form a stratified

CANCERS OF T R E UTERINE CERVIX 5

epithelium resembling more or less closely the normal mucosa of the cervix and vagina, and this formation is in itself an indication of some degree of differentiation. In the most clearly defined growths of this kind the structure suggests a continuous layer formation of epithelium which has been thrown into innumerable folds and creases. Growing

Fra. 1.

FIQ. 2.

GRADE 1, ADULT TYPE OF SQUANOUS CARCINOMA. x 105

GRADE 2, SPINDLE TYPE OF SQUAMOUS CARCINOMA. x 105

on the surface these tumours have a papillomatous structure, but when invading they still retain the same general formation. When sectioned the structure suggests a mass of thick-walled tubes cut in all directions, many being without a lumen. There is, as a rule, little intervening tissue.

In our method of grading, the formation of a stratified epithelium has been accepted as the main basis for including cases in Grade 3.

6 H. CHAMBER8

Four chief groups of squamous carcinomata have been defined on the basis of cell differentiation and general architecture. In Grade 1, all the typical cases of the adult common type of squamous carcinoqla have been included (Fig. 1).

In this form the growth invades in cell columns of varying size, often

FIGS. 3 AND 4. GRADE 3, DIFFERENTIATED TYPES OF SQUAMOUS CARCINOMA. X 95

FIG. 5. GRADE 3, TRANSITIONAL TYPE OF SQUAMOUS CARCINOMA. X 105

in single strands of cells, but the habit of forming a stratified epithelium is practically lost. Iceratinisation sometimes occurs, but is not common in cervical growths. Squames, cell pearls, and basal cells are a feature of the structure. This type of cancer is easy to recognise and all observers place these growths in Grade 1; 15 to 20 per cent of all cases of cancer of the cervix are of this kind.

Grade 2 includes the tumours composed of thin spindle cells resembling those of the basal germinating layers (Fig. 2) .


Grade 3 includes all cases in which there is a clear tendency to form a stratified epithelium, and contains four sub-groups, according to the decreasing extent of differentiation. In the sub-group ‘ ‘ keratinised, ’’ the surface layers of the epithelium are transformed into sheets of keratinised squames, which may be in whorls. Regaud and Gricouroff

FIG. 6. GRADE 3, ANAPLASTIC TYPE OF SQUAMOUS CARCINOMA. X 105

FIG. 7. GRADE 4A, ANAPLASTIC TYPE OF SQUAMOUS CARCINOMA. x 105

(1931) describe this type as having peripheral as well as central keratinisation and state that it is met with in 8 per cent of cervical cancers.

In the sub-group “differentiated,” most of the cells furthest from the basal layer are transformed into squames but without keratinisation. In other cases the cells of this region are large and vacuolated but evidently not dividing o r only very occasionally. A basal-cell layer can usually be distinguished (Figs. 3 and 4).

8 H. CHAMBERS

In the sub-group “transitional, ” the architecture of the epithelium is most like that of the normal mucous membrane of the cervix and vagina. The basal-cell layer is distinct, and the gradual change from transitional to spinal cells can usually be made out (Fig. 5 ) .

In the sub-group “anaplastic,” although there is still a formation of stratified epithelium, the cells have lost their squamous characters

68 40

TABLE 11: Cancer of the Cewix: Histological Grading and Percentage Incidence, Marie Curie Clinic (Squamous carcinoma, 678 cases: graded 450, ungraded 228. Adenocarcinoma, 50 cases)

I I

15.01 % 8.9%

Histological Type

Squamous Carcinoma Grade 1, Adult Grade 2, Spindle Grade 3

Keratinised Differentiated Transitional Anaplastic

Total Grade 4

Anaplastic A Anaplastic B

Total

Number of Cases Incidence in 1 450 Cases

10 30

164 39

243

57 42 99

54.0%

TABLE 111: Cancer of Cervix: Histological Grading and Age Incidence (Squamous carcinoma, 678 cases: graded 450, ungraded 228. Adenocarcinoma 50 cases)

Squamous Carcinoma Grade 1,Adult ...................... 0 0 3 4 4 11 9 10 11 8 4 4 0 0 Grade2, Spindle.. . . . . . . . . . . . . . . . . . . 0 0 0 1 4 6 3 5 8 9 4 0 0 0 Grade 3

Keratinised. ...................... 0 0 0 0 3 1 1 2 2 0 1 0 0 0 Differentiated.. . . . . . . . . . . . . . . . . . . . 0 0 0 0 2 1 7 7 1 6 3 1 1 1 Transitional.. . . . . . . . . . . . . . . . . . . . . 0 0 0 4 7 23 23 35 26 31 8 4 3 0 Anaplastic.. . . . . . . . . . . . . . . . . . . . . . . 0 0 2 0 0 2 7 8 13 3 1 3 0 0

AnaplasticA . . . . . . . . . . . . . . . . . . . . . . 0 0 3 5 7 5 6 13 9 2 6 1 0 0 AnaplasticB . . . . . . . . . . . . . . . . . . . . . . 0 0 1 6 7 6 5 7 4 3 2 1 0 0

Adenocarcinoma . . . . . . . . . . . . . . . . . . . . . . . 2 0 0 1 1 9 9 9 9 5 5 0 0 0

Grade 4

and are deeply staining; mitoses can usually be found in all the layers of the epithelium (Fig. 6).

Grade 4 includes all the anaplastic growths which show no formation of stratified epithelium. I n these the tumour cells have no squamous characters and are apparently in active growth. They are round or fat spindle in shape, with deeply staining nuclei, and mitoses are common. In this grade two sub-groups have been made, depending upon the general configuration. In Grade 4A, the growth is arranged in alveolar


masses with a fair amount of intervening tissue (Fig. 7). I n Grade 4B, the tissue is a solid mass of cells with little intervening tissue, and simulates a sarcoma.

Table I1 shows the general incidence of the different forms of cancer of the cervix. For the purpose of comparison with the results of other observers, the incidence figures are repeated in Table I, grades 2 and 3

Gnnoe4 Aha- -+- -+-

t r * l $ 2 6 t . 3 0 . 3 1 t 3 5 . 3 6 & 4 0 . $ 1 ~ ~ ~ t ~ Q S t t o J S 36660 61665 66b70.71b7S 769%. 8i

q y i q m m d A& Pwck-

FIQ. 8. AGE INCIDENCE OF SQUAMOUS CARCINOMA

being added together. I n view of the fact that the method of grading was carried out independently of previous work and that a relatively large number of the sections had to be set aside as unsuitable for classification, the close similarity of the final results with those of Martzloff, and of Healy and Cutler, is significant. It seems to indicate that there are two types of growth easy to recognise, namely the adult and the anaplastic. If all the others are grouped together, three groups can be defined, and the percentage incidence of these three is fairly constant when sufficiently large numbers of cases are considered.

THE AGE INCIDENCE I n Table I11 is shown the number of cases occurring in successive

quinquennial age periods in relation to the various histological grades. The graphs in Fig. 8 show the percentage incidence at different age periods. Each group shows the well known influence of the menopause, with a marked increase in the number of cases between the ages of forty and sixty. There is very little difference between the various histological grades except for Grade 4; in this there is some indication that the anaplastic growths are commoner in younger women. The graph rises and falls some years before the others.

10 H. CHAMBERS

DURATION OF SYMPTOMS The duration of symptoms before treatment in relation to the his-

tological grades is shown in Table IV. The length of time the patients have had symptoms before applying for treatment cannot be determined with certainty, since the clinical record depends upon the individual patient. There seems to be no particular relation between the duration of symptoms and the type of growth. The patients either complain of symptoms in the first six months or they wait until about a year has elapsed ; comparatively few have symptoms lasting between six months and a year. The explanation is not evident. The duration of symptoms seems to have no relation to the clinical stage of the disease; many cases in the most advanced stage had symptoms lasting less than two months, and some of the least advanced had the longest duration of symptoms.

TABLE 1V: Cancer oj the Cervix: Histological Grading and Duration of Symptoms before Treatment (Squamous carcinoma, 678 cases: graded 450, ungraded 228. Adenocarcinoma, 49 cases)

Duration of Symptoms r n A A O A $1 d + in Months m M I A ~ ~ ~ ~ ? A A & A ~ %

* A m ~~

Squamous Carcinoma Grade 1, Adult.. . . . . . . . . . . . . . . . . . 15 4 8 3 12 1 1 4 0 2 9 5 4 Grade2, Spindle.. . . . . . . . . . . . . . . . 11 3 4 3 8 0 2 1 0 0 3 5 0 Grade 3

Keratinised.. . . . . . . . . . . . . . . . . . . 2 2 0 0 0 1 0 0 0 0 2 2 1 Differentiated . . . . . . . . . . . . . . . . . . 4 4 4 3 5 3 0 3 2 0 1 1 0 Transitional.. . . . . . . . . . . . . . . . . . 31 31 15 9 17 6 8 3 3 3 16 20 6 Anaplastic.. . . . . . . . . . . . . . . . . . . . 8 1 1 4 3 6 0 1 1 2 4 2 4

Anaplastic A. . . . . . . . . . . . . . . . . . . 11 13 5 1 9 2 5 0 1 1 3 4 2 AnaplasticB . . . . . . . . . . . . . . . . . . . 8 5 3 4 3 1 1 5 0 0 3 9 0

TOTAL, Squamous Carcinoma.. . . . . 90 63 40 27 57 20 17 17 7 6 41 48 17 Adenocarcinoma .................... 5 7 9 3 4 2 1 4 1 1 2 8 2

Grade 4

-

THE CLINICAL TYPE Table V shows the number of cases occurring in each grade accord-

ing to the description of the clinical condition and in relation to the clinical stage of the disease (League of Nations classification). The nodular group includes a larger proportion of the early cases ; ulcera- tion and crater formation are found in larger proportion in the more advanced cases. The cauliflower growths are chiefly in Grade 3, differentiated, and in Grade 4B, but every histological type is represented in each clinical variety.

RADIOSENSITIVITY AND THE RESULTS OF TREATMENT Our knowledge of radiosensitivity is based partly on experimental

investigations which have been made on the reactions of normal and


malignant tissues to measured doses of x-rays or the radiations from radium, and partly on the histological and clinical examination of malignant growths treated by radiation. Regaud's extensive investigations in both these directions have led to the development of the technique which has been used with such increasing success at the Institut du Radium, in Paris. Although it is generally acknowledged that normal tissues possess greater resistance and powers of recovery after exposure to radiation than many kinds of malignant cells, there is much difference of opinion as to the comparative radiosensitivity of tumours of different histological types. The subject can be studied by tracing the clinical response of a large number of cases to radiation treatment, but it is necessary that the cases should have been treated by a fairly uniform method and by a technique which will cause the disappearance of the growths in a reasonable percentage of cases. The method of radiation used and the dose applied are of primary importance, for the

TABLE V: Squamous Carcinoma (Total Cases 331): Histological Grading and Clinical T y p e

Nodu- Infil- Ulcer- Fungat- Cadi- Endo- Pyo- lar trating ating Crater ing flower cervical metra

Grade1,Adult.. . . . . . . . . . . . . 12 31 20 5 13 3 7 4 Grade 2, Spindle.. . . . . . . . . . . . 18 19 11 4 9 1 5 1

Keratinised . . . . . . . . . . . . . . . 4 2 2 0 2 0 0 0 Differentiated., . . . . . . . . . . . 6 11 7 0 4 6 2 4 Transitional.. . . . . . . . . . . . . 39 57 39 11 30 3 11 8 haplast ic . . . . . . . . . . . . . . . 7 11 2 1 6 1 2 1

haplastic A . . . . . . . . . . . . . 9 18 15 7 14 1 1 1 AnaplasticB.. . . . . . . . . . . . . 5 12 12 1 17 6 0 0

Grade 3

Grade 4

TOTAL. . . . . . . . . . . . . . . . . . 100 161 108 29 95 21 28 19

differences between the responses of cells of varying histological types to radiation tend to disappear as the dose is increased towards the limit '

which can cause the death of any living tissue. The treatment used at the Marie Curie Clinic (1926, 1929) has been

a modification of the method introduced by Forssell. I n general, the principle of the method has not changed since the clinic began work in 1925 and, with few exceptions, the cases have been treated without sup- plementary x-rays, and radium has not been used interstitially. The modifications which we made in the Stockholm technique were mainly due to physical and anatomical considerations, with a view t o improving the distribution of the radium. I n developing the technique we were not consciously concerned with the problems of radiosensitivity, and no modification of dosage has been made on account of the histological structure. It has been the rule to follow the diagnosis of malignancy with a full course of treatment in all cases where this was not contra- indicated for other reasons. The chief object of the treatment has been the direct application to the malignant cells of a dose of radiation large

12 H. CHAMBERS

Stage 4 No

local cure cure

enough to cause them to disappear, and in order that this dose shall reach as deeply as possible, the typical treatment has been planned to give the largest dose of radiation which could be supported without causing irreparable damage to the normal structures. The distribution of the radium has been arranged to give as wide and deep a field of radiation to the primary site as the anatomical conditions would permit from a surface application of radium to the uterine cavity and vaginal vault. Although the method succeeds in treating carcinoma cells

Per cent of local curea

Total Local cases cures

TABLE VI: Cancer of the Cervix.

(Squamous carcinoma, 281 cases.

Results (Local Cures) According to the Histological Grade and

Cases treated more than two Stage of the Disease

years ago) Adenocarcinoma, 37 cases.

8

i

Squamous carcinoma Grade 1, Adult Grade 2, Spindle Grade 3



Grade 4

Adenocarcinoma

27 17 (63.0%)

126 93 (73.8%)

Stage 1

No L O ~ % l local cure cure

1 0 2 0

0 0 0 0 7 0 3 0

1 0 3 0 1 1

Stage 2

No local

cure cure

6 1 7 1

2 2 3 1

21 3 5 0

4 0 3 1

11 0

Stage 3

No Local local cure cure

21 11 12 4

2 1 10 5 43 18

7 4

13 7 11 8 15 8

44 29 (65.9%) 29 21 (72.4%)

1 i] 1 55 37 (67.3%) 0 1 37 27 (72.9%)

within a definite distance of the surface to which the radium is applied, it fails to treat more deeply seated growth cells or metastases in the pelvic glands. For this reason the results of treatment are very de- pendent upon the clinical stage of the disease when the case is first treated. For this reason, also, when considering the response to treatment of growths of different histological types, the disappearance of the growth at the site treated is of more value than the ultimate result; a comparatively large number of the patients who die have extension to the pelvic glands o r metastases and no local recurrence. Until radio- logical technique is sufficiently advanced to treat successfully deep- seated growths and pelvic deposits, these complications must affect the final figures and survival rate,

This enquiry has been made to find out in how many cases the treatment has caused the growth to disappear at the primary site, taking into account the histological type. All cases have been excluded in which it was impossible to place the growth in its histological grade and also all cases where the treatment was not completed. Most of the cases excluded for this reason were in clinical stages 3 and 4 (League of Na- tions classification) and were given only one or two applications of radium; as a rule, the treatment was discontinued because of general


0 3 0 3

contraindications. The results without these deductions are given in the general statistics (Annual Report, British Empire Cancer Cam- paign, 1934), and show a survival rate of 33.48 per cent in a total of 215 cases treated five to six years ago. The cases in Table V I have been under observation for at least two years since treatment and some as long as eight years. The period of two years has been chosen because it gives the largest number of cases. The cases have been counted as locally cured when there has been no return of local symptoms and

TABLE VII: Cancer of the Cervix: Results according to the Histological Grade and. Stage of the Disease (Squamous carcinoma, total cases 222. Adenocarcinoma, total cases 31. Cases treated from

three to eight years ago. L = living. D = dead)

completed

Stage 1 2 3 4

30 13 (43.3%) 0 1 4 4 27 14 (51.8%) 0 0 2 1

-

-

Stage 1 L D

22 6 (27.3%)

109 58 (53.2%)

Squamous carcinoma Grade I, Adult Grade 2, Spindle Grade 3



Grade 4

Adenocarcinoma

0 0 3 0

0 0 4 9

1 0 2 0

0 0 0 0 5 0 3 0

0 0 1 0 1 1

when no growth has been examination.

Stage 2 L D

2 1 6 2

2 1 2 1

14 7 5 0

2 1 1 2 7 3

Stage 3 L D

10 13 6 8

I I I Cases Per cent living excluded,

Stage 1 Total treatment L D cases Living 1 not

3 7 6 8

10 8 /j 34

16 (41.2%)1 0 0 1 2 0 1 31 18 (58.1%) 0 1 2 2

found in the uterus o r vagina on pelvic

Table VI shows the results obtained in relation to the various histological grades and clinical stage of the disease. Table V I I gives thd actual condition of the same patients in December 1933 but includes only those cases which have been under observation over three years.

The importance of the clinical stage of the disease is very evident. Of 90 patients in the early operable and borderline groups (League of Nations method of classification stages 1 and a ) , SO are apparently free of local disease two or more years after treatment, that is 88.8 per cent. In the more advanced groups-3 and 4 6 3 . 1 per cent only are locally cured, that is 144 in a total of 228 cases. There is comparatively little difference between the various histological grades, the best results being obtained in the Grade 3 transitional, and in the adenocarcinomata.

In attempting to determine the significance of these results in relation to the problem of radiosensitivity, it may be questioned whether a treatment designed to give the largest possible dose of radiation to a particular site, with the object of treating successfully the least sensi- tive growths, can be used for detecting differences of sensitivity. It would be reasonable to expect less variation under these conditions

14 H. CHAMBERS

between growths of different histological types than would be obtained if smaller doses were used. I n this connection it is a relevant fact that we have used almost twice the amount of radium Regaud uses, but the exposure is halved. With our treatment in the great majority of cases a growth limited to the cervix is cured irrespective of its histological type, At the same time the normal tissues are not permanently damaged; there are as yet no data to show to what extent the ovaries are permanently injured.

If the more advanced cases are considered separately, those of stage 3, there is still not more than a 15 per cent difference between the

' various histological types, and this is also evident when the results are considered as a whole.

The results may be compared with the findings of Russ and Scott (1926) in the case of mammalian animal tumours exposed to measured doses of x-rays. The variation in the amount of radiation required to produce a lethal effect on tumour cells of different types outside the body did not vary more than 20 or at most 30 per cent.

CONCLUSIONS (1) The biopsy material from 728 cases of cancer of the cervix has

been examined and 500 cases have been histologically graded; 228 were unsuitable f o r classification.

(2 ) The method of grading has been based on the extent of diff eren- tiation and degree of cell activity, but the general architecture of the growth has also been taken into account.

(3) The relationship of the age incidence, duration of the symptoms, and clinical type of the growth, with the histological structure has been considered.

(4) The results of treatment have been recorded with special reference to the local cure of the cancer at the primary site in relation to the histological type; the survival rate has also been recorded of the same cases under observation for more than three years.

(5) The highest percentage of local cures has been obtained in the transitional type of squamous cancer Grade 3, 73.8 per cent, and in the adenocarcinomata, 72.9 per cent, but none of the histological grades show a difference of more than 15 per cent in either local cure or in the number of three-year survivors.

(6) There is no evidence in this material that the adenoearcinomata are insensitive t o radiation.

EEFERENCES BRODERS, A. C. : Epithelioma of genito-urinary organs, Ann. Surg. 75: 574604, 1922. EWING, J.: Radiosensitivity of carcinomas of tongue, Bull. Memorial Hosp., N. Y. 2:

HEALY, W. P., AND CUTLER, M.: Relation between structure and prognosis in cervical

KIMBROUGH, R. A., JR., AND NORRIB, c. c. : Factors influencing end-results in carcinoma

98-104, 1930.

carcinoma under radiation treatment, Am. J. Obst. & Gynec. 16 : 15-28, 1928.

of cervix after irradiation, Am. J. Obst. & Gynec. 13: 279-287, 1927.

CANCERS OF T H E UTERINE CERVIX 15

MALIPHANT, R. G. : Histological classification of cancers of the uterine cervix and relation between cellular structure and prognosis after radium treatment, J. Obst. & Gynaec. Brit. Emp. 40: 444-459, 1933.

Marie Curie Hospital: The Radium Treatment of Cancer of the Uterus, H. K. Lmis and Co., London, 1926 and 1929. Report for 1933, British Empire Cancer Cam- paign, Annual Report, 1934.

MARTZLOFF, K. H.: Carcinoma of the cervix uteri; pathological and clinical study with particular reference to relative malignancy of neoplastic process as indicated by predominant type of cancer cell, Bull. Johns Hopkins Hosp. 34: 141-149, 184-195, 1923.

Carcinoma of cervix uteri; its operative prognosis ; clinical and pathological study to ascertain prognosis following operation for extirpation of malignant process, Bull. Johns Hopkins Hosp. 40: 160-192, 1927.

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THE JOURNAL CANCER · without cornification, a round-cell and a spindle-cell type. In Germany, ... and keratinisation. The recognition of anaplasia, according to Ewing (1930), is