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Thorax (1965), 20, 298. Histology of lung cancer in relation to prognosis K. P. GOLDMAN' From Sully Hospital, Sully, Glamorgan The differences in microscopic appearance which characterize the main histological types of lung cancer suggest associated differences in biological behaviour. For example, their growth rates might be expected to increase as the degree of cell differentiation decreases, in which case the least differentiated tumours would be the most malignant. One method of assessing the relative behaviour of different types of tumour is by studying the survival rates of untreated patients in whom they occur. However, among untreated patients with lung cancer the course of the disease is so short that survival differences between the histological types are small. A more useful index of relative biological behaviour is provided by comparative survival rates after treatment. Many papers have been written about this, mainly on the relation between tumour histology and survival after surgery, and these have been reviewed by Bignall (1958). From the data included in this review, and from other more recent publications, several apparent associations emerge. Squamous-cell carcinoma has been found by most authors to confer the best prognosis, both for surgically treated patients (McDonald, McBurney, Carlisle, and Patton, 1951; Gifford and Waddington, 1957; Ochsner, Ochsner, H'Doubler, and Blalock, 1960; Shinton, 1963; Taylor, Shinton, and Waterhouse, 1963) and for those not treated surgically (Lea, 1952 Ballantyne, Clagett, and McDonald, 1957 Whitwell, 1961). The prognosis associated with adenocarcinoma of the lung is less certain, largely because too few cases have been available for study. Some authors report survival rates similar to those for squamous-cell carcinoma (Kirklin, McDonald, Clagett, Moersch, and Gage, 1955; Bignall and Moon, 1955; Cleland, 1958; Spjut, Roper, and Butcher, 1961 ; Siddons, 1962); others record rates lower than for squamous or undifferentiated tumours (McDonald et al., 1951; Gifford and Waddington, 1957; Ochsner et al., 1960), whereas 1 Present address: Brompton Hospital, London, S.W.3 in one surgical series adenocarcinoma was found to confer the best prognosis of all types (Barrett, Day, O'Rourke, Chapman, Sadeghi, Perry, and Tuttle, 1963). Survival rates after surgery for undifferentiated carcinoma are reported to be lower than for squamous-cell or adenocarcinoma (Kirklin et al., 1955; Bignall and Moon, 1955; Cleland, 1958; Spjut et al., 1961; Barrett et al., 1963). Oat-cell carcinoma, previously included with undifferenti- ated tumours, in more recent series has been classified separately and appears to confer the worst prognosis of all cell types (Kirklin et al., 1955; Rienhoff, King, and Dana, 1958 ; Nicholson, Fox, and Bryce, 1957; Reid and Carr, 1961; Whitwell, 1961; Siddons, 1962; Shinton, 1963; Sensenig, Rossi, and Ehrenhaft, 1963). In contrast to these studies, a small number of authors have found no significant correlation between tumour histology and prognosis (Overholt and Bougas, 1956; Ederer and Mersheimer, 1962). The variation of results in some of these papers may be due to differences in the definition of histological types. This source of error is inevitable while pathologists fail to agree on a uniform system of classification. The purpose of the present paper is to support a system of histo- logical classification which is shown to be related to the survival of patients, although the criteria of definition of cell types differ from those most widely in use. 6 CASE MATERIAL AND METHODS OF STUDY A retrospective survey was undertaken of all patients who attended Sully Hospital during the period 1 January 1954 to 1 October 1960, and who were thought to have primary carcinoma of the lung. Cases in which the diagnosis, on review, seemed doubtful were excluded. The material was analysed by age, sex, tumour histology, method of treatment, and survival. The histological classification of tumours was performed by one pathologist (Dr. R. M. E. Seal) and was not specially reviewed for this study. Classification was according to the predominant cell type. Tumours consisting mainly of well-differentiated cells 298 Histology of lung cancer in relation to prognosis 299 All patients Male Female Under 40 40-49 50-59 60-69 Over 70 TABLE I HISTOLOGICAL TYPE OF TUMOUR ACCORDING TO AGE AND SEX OF PATIENT Squamous-cell No. % 224 37 3 219 39-3 5 114 1 71 19 29-7 106 414 85 35 7 13 44-8 Undifferentiated No. % | 173 28-8 163 29-3 10 22-7 3 21 4 19 29-7 71 27-7 71 29-8 9 31-0 Oat-cell No. % 135 22 5 112 201 23 52 3 10 714 19 29-7 51 19 9 53 22-3 2 6-9 Adenocarcinoma No. % 42 7-0 38 6-8 4 9.1 00 5 7-8 16 6-2 19 8-0 2 6-9 Unclassified No. % 27 4 5 25 4-5 2 4-5 00 2 3-1 12 4-7 10 4-2 3 10 3 Unknown No. 145 133 12 2 14 58 57 14 were classed as squamous-cell carcinoma or adenocarcinoma, according to their characteristic features. Tumours consisting mainly or wholly of undifferentiated cells, which lacked specific characteristics, were grouped together as undifferentiated carcinoma; these included tumours which contained areas suggesting differentiation and which had been classified by the pathologist as poorly differentiated squamous-cell carcinoma or poorly differentiated adenocarcinoma. Tumours consisting of small cells with scanty cytoplasm and hyperchromatic nuclei were classed as oat-cell carcinoma. There were some tumours which could not be placed into one of these four categories, often because of inadequate pathological material, and these were termed unclassified; they included a small number of mixed pathology. Bronchiolar carcinoma was excluded from the series. A histological or cytological report was obtained on 601 cases or 81% of the total. The sources of pathology were resected tumours in 250 cases, biopsies taken at exploratory thoracotomy in 112, biopsy specimens and sputum in 186 inoperable cases, and 57 necropsy specimens. The commonest tumour was squamous-cell carcinoma (37-3 %) and the least common was adenocarcinoma (7-0%). The frequency of the histological types is analysed according to age and sex in Table 1. Of special interest is the high proportion of oat-cell tumours among women and younger patients and the preponderance of squamouscell tumours among men and older patients. Survival was measured up to 1 October 1960, so that all patients were followed for at least two years. Survival rates were analysed according to tumour histology and method of treatment, but deaths from lung cancer were not distinguished from the small number of deaths from other causes. The follow-up was completed on all 746 patients in the series. RESULTS The numbers of patients with each type of tumour that was operable and resectable are given in Table II. In the three largest groups the rates of pulmonary resection were highest for squamouscell (45-5%) and undifferentiated carcinoma (47-4%) and lowest for oat-cell carcinoma (2 6%). TABLE II OPERABILITY IN RELATION TO HISTOLOGICAL TYPE OF TUMOUR TTyupmeouuorf TTootaal All cases Squamous-cell Undifferentiated Oat-cell Adeno- carcinoma 746 224 173 135 42 Clinically Submitted Inoperable* Thhorrcaotomy No. % No. % 379 50 8 367 49-2 89 39 7 135 60-3 58 33-5 115 66-5 65 48*2 70 51 8 9 214 33 78-6 Pulmonary Resection No. % 250 33 5 102 45 5 82 47.4 40 29*6 26 61-9 * Includes patients who refused operation Of the patients with oat-cell carcinoma on whom thoracotomies were performed, only 57 1 % were found to have resectable growths, a much lower proportion than for the other types of tumour. The survival rates of patients treated by pulmonary resection are given in Table III. Deaths within four weeks of operation have been excluded, as they are unlikely to have been influenced by the tumour histology. It is seen that the two years' and five years' survival rates differ considerably according to the histology. The highest rates are recorded for squamous-cell carcinoma, intermediate rates for undifferentiated carcinoma, and the lowest for oat-cell and adenocarcinoma. Of special interest is the comparatively high five years' survival rate after resection for TABLE III SURVIVAL AFTER SURGICAL RESECTION ACCORDING TO HISTOLOGICAL TYPE OF TUMOUR, EXCLUDING 'OPERATIVE' DEATHS Type of Tumour Two Years* At Risk Survivors SurVvi'aval Five Years At Risk Survivors Surv(i0v/a)l Squamous-cell 95 52 54*7 41 17 415 Undifferentiated 71 32 45 1 33 4 12-1 Oat-cell 33 8 24-2 19 1 5.3 Adenocarcinoma 21 4 19*0 7 0 00 All cases 220 96 43-6 100 22 22-0 * Two-year follow-up on patients resected during 1954-60. Fiveyear follow-up on patients resected during 1954-57 300 K. P. Goldman squamous-cell carcinoma, namely 415 o compared with only 53% for oat-cell carcinoma. The survival of patients not treated surgically is given for the first two years after diagnosis (Table IV). This includes patients who were found to have unresectable tumours at thoracotomy, those treated by radiotherapy or chemotherapy, and the remainder who received no specific treatment. The same trend is evident as for the surgical series, namely the highest survival rates associated with squamous-cell tumours and the lowest with oat-cell tumours. However, the correlation of survival with histology, although pronounced at six months and one year, is much less so at two years. Thus for squamous-cell, undifferentiated, and oat-cell carcinoma the six months' survival rates were 38%, 300%, and 1500, respectively, whereas the two years' rates were 2-5%, 2-2%, and l-1 0/ respectively. The numbers of adeno- carcinoma were too few for the associated survival rates to be reliable. TABLE IV SURVIVAL OF PATIENTS NOT TREATED SURGICALLY, RELATED TO HISTOLOGICAL TYPE OF TUMOUR Survival 5 Type of Tumour TotalSix Months- One Year No. % No. % Squamous-cell Undifferentiated Oat-cell Adenocarcinoma Unclassified or unknown 122 91 95 16 166 46 37-7 20 16-4 27 29 7 6 6-6 14 14-7 11 4 25-0 1 6-3 45 49 0 20 24 5 All cases 490 136 27-8 48 9-8 Two Years No. % 3 25 2 22 1 Il 1 6-3 3 56 10 2-0 I From the time of diagnosis The combined experience of all patients in whom the tumour histology was known, whatever the method of treatment, is given in Figure 1. This summarizes the data relating prognosis to tumour histology which is detailed in Tables IT, 11, and IV. Per cent of cases 100- All classified cell types 100%. (574 cases) Resectability 100%.(250 cases) 2 Year Survivors (surgical a non- surgical) 1007. (102 cases) 5 Yecr Survivors (all surgical) 1007.(22 cases) _-- 90- 8o- 777.3 70- 6054.9 50- 40324 30 20- IIla.1 10- 0- M-L m Squamous Cell Carcinoma Oat Cell Carcinoma Lj;jI Undifferentiated Carcinoma flAdenocarcinoma FIG. 1. Resectability and survival rates of 746 patients with lung cancer, related to histology. DISCUSSION 'In addition to the fundamental histogenetic classification by which tumours are grouped solely according to the kinds of tissue from which they spring and of which they consist, it is also necessary to have a further grouping, biologically less fundamental but of great practical value, according to their behaviour and clinical progress' (Willis, 1960). In this paper a system of histological classification of lung cancer has been followed which it was thought would serve the second purpose and provide information about the relative clinical behaviour of different types of tumour. The growth rate of normal tissues appears to vary inversely with cell differentiation. Thus mitoses are rarely observed in highly differentiated tissues, such as neurones or muscle, whereas in continuously proliferating tissues like the skin or bone marrow, mitotic activity is largely confined to zones of undifferentiated cells. It seems reasonable to suppose that the growth rate and cell differentiation of tumours are also inversely related. For survival studies it seemed best therefore to group Histology of Ilung cancer in relation to prognosis 301 together all predominantly undifferentiated tumours) ranging between 29 % (Deal and Belcher, tumours irrespective of their apparent origin. 1963) and 0% (Paulson, 1957), with a wide scatter This differs from current pathological practice, between these two extremes. Although the patho- for lung cancer is generally typed according logical definition of this group varies greatly to the most differentiated tissue. For example, according to different authors, there is overall according to Kreyberg (1961), 'If anywhere agreement that the prognosis associated with in a tumour a definitely specific differentiation undifferentiated carcinoma is worse than that for is found, however limited, this finding decides squamous-cell carcinoma. the type, undifferentiated areas being disregarded'. The finding of other authors that oat-cell It seemed to the author that this results in the carcinoma is associated with a relatively poor grouping together of tumours which may be of prognosis has been confirmed, both for surgical common origin but probably differ in their clinical and non-surgical patients. The proportion of behaviour. patients with this tumour who were submitted to The analysis of survival in 746 patients with thoracotomy was small (52%), which might partly cancer of the lung which has been presented shows reflect the reluctance of surgeons to operate on the best prognosis to be associated with squamous- this type of case. However, at thoracotomy nearly cell carcinoma. The high rates of resectability and half of these patients were found to have unresect- of survival after surgical treatment are in accord able growths, a much higher proportion than in with the findings of most other investigators. Of the other histological groups. particular interest is the high survival rate after Oat-cell carcinoma, as distinct from undiffer- surgery, namely 37-8% at five years, or 41g5% entiated or anaplastic carcinoma, has only been excluding operative deaths. This figure is similar recognized in the last few years. It is now regarded to that reported by Cleland (1958), who found as a pathological entity, and some of these a 42% survival for this group, but most other tumours show signs of differentiation such as authors have recorded lower rates. Thus Taylor tubular or rosette formation (Azzopardi, 1959; and colleagues (1963) reviewed the results of Walter and Pryce, 1960). Only four patients in this surgery in their own and 11 other series and found series with oat-cell carcinoma survived for three the five years' survival rates for patients with years or more; the histology was reviewed, and in squamous-cell carcinoma were all below 40% and three of them there was rosette formation and mostly below 30%. It seems likely that the survival palisading of cells suggesting differentiation. It rates associated with this type of tumour were would be interesting to determine, by means of a especially favourable in the present series because larger investigation, whether these characteristics only well-differentiated tumours were included. are significantly associated with an improved The prognosis associated with adenocarcinoma prognosis. remains undetermined because of its relative The poor outlook of patients with oat-cell infrequency. In the present study there were only carcinoma after surgery has raised the question 42 classified cases, of which a high proportion whether this is a better method of treatment than were treated surgically (62 %). This probably radiotherapy. If treatment is to be determined by reflects the difficulties of obtaining the histology the tumour histology it is important that it should except at thoracotomy, for most of these tumours be reported with accuracy. However, a broncho- are peripheral and beyond the range of the scopic biopsy specimen is not always satisfactory bronchoscope. The survival experience of this and may suggest a different histology from that small group of patients suggests a prognosis after of the main part of the growth. Several investi- surgery inferior to that associated with squamous- gators have compared the histological reports on cell carcinoma. bronchial biopsies with subsequent reports on the The survival rates of patients with undifferenti- resected tumours. Reid and Carr (1961) found ated carcinoma were found to be intermediate agreement between the two sets of reports in most between those of patients with squamous-cell and cases of oat-cell carcinoma but in a small propor- oat-cell tumours. A high proportion of the patients tion of other types of lung cancer. In similar had resectable tumours (47-4%) and their two studies, Siddons (1962) recorded agreement years' survival rate after resection was relatively between the reports in 93% of cases, and Taylor high (45-1 %), but at five years the rate had fallen and colleagues in 90%. However, Deal and to 12-1%, which is well below the figure for Belcher (1963) found that in only two-thirds of squamous carcinoma. Other investigators have the cases of oat-cell and undifferentiated recorded five years' survival rates after surgery carcinoma was the report on the bronchial biopsy for undifferentiated carcinoma (excluding oat-cell the same as that on the operation specimen. It 302 K. P. Goldman seems therefore that a bronchial biopsy provides information about tumour histology with only moderate accuracy, so that the choice of method of treatment should not be based on this information alone. The association between histology and prognosis in cancer of the lung is not necessarily causative, for there may be other factors which vary with the histology and which influence survival. For example, the age of patients varies between the histological groups, in particular between those with oat-cell and squamous-cell carcinoma. Possibly this difference in age structure determines the difference in survival rates, although as yet no simple relation has been demonstrated between prognosis and age (Bignall, 1958). To test this hypothesis, the survival of patients with each type of tumour would have to be analysed by age, an investigation which, to attain significance, would require a much larger series of cases than the present one. SUMMARY The experience of 746 patients with lung cancer has been related to tumour histology. The survival rates in both surgical and non-surgical cases indicate that squamous-cell carcinoma is associated with the best prognosis, oat-cell carcinoma with the worst prognosis, and undifferentiated carcinoma with a prognosis intermediate between these two. In the small proportion of cases of adenocarcinoma the survival rates after surgery were comparatively low. The criteria of definition of cell types are discussed in relation to the association between histology and prognosis. For clinical use it is suggested that the labels 'squamous-cell carcinoma' and 'adenocarcinoma' be confined to well-differentiated tumours and that poorly differentiated tumours are best grouped together. Oat-cell carcinoma is a distinct clinical and pathological group which includes tumours with varying degrees of cell differentiation. There is a suggestion that the prognosis associated with these tumours may vary with this differentiation. I wish to thank Dr. L. R. West for his encouragement and help with this work. I am also grateful to Dr. R. M. E. Seal for valuable discussions on the pathology of lung cancer and to Mr. C. E. Rossiter, of the Pneumoconiosis Research Unit, Llandough, for statistical advice. Permission to publish was granted by Dr. H. M. Foreman, Physician Superintendent of Sully Hospital. Miss G. Smith kindly undertook much secretarial work in connexion with the follow-up of patients. REFERENCES Azzopardi, Bact., 7J8., G. (1959). 513. Oat cell carcinoma of the bronchus. J. Path. Ballantyne, A. J., Clagett, 0. T., and McDonald, J. R. (1957). Vascular Barrett, R. J., invasion in Day, J. C., Ob'rRoonucrhkoeg,enPi.c carcinoma. Thorax, V., Chapman, P. T., 12, 294. Sadeghi, H., Perry, R. W., and Tuttle, W. M. (1963). Primary carcinoma of the lung. Experience with 1,312 patients. J. thorac. cardiovasc. Surg., 46,292. Bignall, J. R. (1958). In Carcinoma of the Lung. Ed. J. R. Bignall, pp. 174, 181. 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