Histopathologic classification of small cell lung cancer. Changing concepts and terminology.

Considerable attention has been devoted to the diagnosis of small cell lung carcinoma (SCLC) and its subtypes. In the literature contradictory opinions have been published concerning the clinical implications of subtyping, largely because of the different criteria used by different pathologists. This article is a consensus report by the Pathology Committee of the International Association for the Study of Lung Cancer. The following classification of SCLC is recommended: (1) Small cell carcinoma. This subtype includes most of the tumors previously included in the oat cell and intermediate subtypes. More than 90% of untreated SCLC fall into this category. (2) Mixed small cell/large cell carcinoma. This subtype, which may be associated with a poor prognosis and response to therapy, contains a spectrum of cell types ranging from typical SCLC to larger cells having prominent nucleoli and resembling large cell carcinoma. (3) Combined small cell carcinomas. Typical SCLC elements are intimately admixed with areas of differentiated squamous cell or adenocarcinoma. This simplified classification of SCLC will facilitate uniformity in the diagnosis and further our understanding of the clinical significance of the rarer SCLC with variant morphologies.

Cerebrospinal fluid cytology diagnosis of meningeal carcinomatosis in patients with small-cell carcinoma of the lung. A study of interobserver and intraobserver variability.

The interobserver and intraobserver variation in the cytologic diagnosis of malignancy was determined in 62 cerebrospinal fluid (CSF) specimens from 46 patients with small-cell carcinoma of the lung. In all patients, lumbar puncture was carried out because of suspected central nervous system metastases. Forty CSF specimens from 26 patients with meningeal carcinomatosis and thus with a high probability of a positive CSF cytology were mixed with 22 specimens from 20 patients without meningeal carcinomatosis. The slides were evaluated blindly by two observers, one of whom evaluated all specimens on two separate occasions; only positive, negative and suspicious conclusions were permitted. The consistency of the intraobserver and interobserver conclusions on the initial CSF specimen in each case was 87%. In 13% of the initial CSF specimens in each case, a suspicious conclusion was reached in one of the three evaluations. For all 62 CSFs, the intraobserver and interobserver disagreement was 2% and 3%, respectively. In the first and second evaluations by the one observer and the single evaluation by the other, 17 (65%), 15 (58%) and 12 (46%), respectively, of the 26 "high probability" patients were found to have malignant cells in the CSF. CSF cytology was negative in all 20 patients without meningeal carcinomatosis. Of 10 patients with autopsy-proven meningeal carcinomatosis, 40% were not diagnosed while alive. Multiple CSFs from repeated lumbar punctures increased the number of positive evaluations by 30%. At least 60% of those patients with a suspicious CSF cytology did in fact have meningeal carcinomatosis. On the other hand, 30% of the patients with a positive lumbar puncture had a subsequent negative one.

Behavior of mild cervical dysplasia during long-term follow-up.

Five hundred and fifty-five women with cervical cytologically diagnosed mild cervical dysplasia were followed by cytology without major treatment. Biopsies were performed in 14% resulting in no significant influence on the outcome of the studied material. Regression to normal occurred in 62% (follow-up 39 months), progression to severe dysplasia/carcinoma in situ/invasive carcinoma in 16% (invasive carcinoma: two patients), and persistence of dysplasia in 22%. Life table analysis calculated the risk of progression of mild dysplasia to be 250 to 800/100,000 women/year. A comparison with the incidence of carcinoma in situ, four of 100,000 women/year, illustrates the yearly risk for a woman with mild dysplasia as 560 times greater than for a woman without cervical dysplasia to develop severe dysplasia/carcinoma in situ/invasive carcinoma.

Endometrial carcinoma diagnosed by the Gynoscann method.

A simple method for screening of the endometrium is a desirable complement to the gynecological examination. Between February and June, 1984, 94 patients underwent cytological sampling by the Gynoscann method immediately before dilatation and curettage at the Department of Gynecological Oncology, Radiumhemmet, and at the Department of Obstetrics and Gynecology, Karolinska Hospital, Stockholm. Ninety-six per cent of the cytological samples were adequate for cytological diagnosis and the same proportion of the curettage specimens for histology. The correlation between cytology and histology was correct in 84% of the cases. Among the 26 cases of endometrial carcinoma, 21 (80%) were correctly diagnosed by cytology. There were no false-positive diagnoses for carcinoma. Atypical hyperplastic endometrium was found in 2 cases by curettage and was correctly correlated with cytology in one case. The sensitivity for endometrial carcinoma was 81% and the specificity 100%. Our conclusion is that the Gynoscann method is safe, easy to use and has proved reliable for the diagnosis of endometrial carcinoma. Further evaluation with larger series giving the cytopathologists increased experience is needed before optimal sensitivity can be achieved.

Reversibility of 20-methylcholanthrene-induced bronchial cell atypia in dogs.

The sequence of cellular alterations in the bronchial epithelium of individual dogs was studied by means of combined morphologic and cytochemical techniques during a period of exposure to 20-methylcholanthrene (20-MC) and during a subsequent period without treatment. In agreement with earlier observations, 20-MC was found to induce progressive cellular changes which in four of seven dogs resulted in the occurrence of cells morphologically diagnosed as cancer cells. When the 20-MC treatment was stopped these cellular alterations were found to regress in three of the four dogs. Only in one dog did the advanced cellular atypia persist and cause the death of the animal. The results indicate that cells exhibiting cytomorphologic and cytochemical characteristics of cancer cells may reflect reversible lesions which regress on withdrawal of the carcinogen.

Behavior of moderate cervical dysplasia during long-term follow-up.

Eight hundred ninety-four women with cytologically diagnosed moderate cervical dysplasia were followed by cytology without major treatment. The results were regression in 54% (follow-up 78 months), progression in 30%, and persistence in 16%. Biopsies were performed in 54%. Results in patients without biopsies were regression in 50%, progression in 35%, and persistence in 15%, implying a statistically significant difference between biopsied and nonbiopsied lesions. Fewer lesions progressed in patients age 51 or older than in younger patients, the progression time also being significantly longer. The cytology periodically returned to normal for more than 12 months in 3.8% of patients with persisting moderate dysplasia. Life table analysis indicated the risk of progression of moderate dysplasia to be 5 to 9/100 women/year. A comparison with the incidence of carcinoma in situ, 4/100,000 women/year, illustrates the yearly progression risk for a cervix with moderate dysplasia as 2000 times greater than for a woman without cervical dysplasia.

Reversibility of bronchial cell atypia.

Various degrees of cellular atypia were induced in the bronchial epithelium of dogs by means of repeated submucous 20-methylcholanthrene injections. Thereafter, the 20-methylcholanthrene treatment was stopped, and the outcome of the bronchial cell atypias in individual dogs was studied using cytomorphological and cytochemical methods. The results suggest that the various degrees of 20-methylcholanthrene-induced cellular atypias, including those cytologically interpreted as malignant, may reflect reversible cellular alterations which disappear after removal of the carcinogen. Similar observations were made in a group of cigarette smokers who, after malignant-appearing cells were observed in the sputum material, stopped smoking or significantly reduced their cigarette consumption.

Retrospective DNA analyses in cervical dysplasia as related to neoplastic progression or regression.

Intracellular DNA distribution was measured in cells from two groups of patients with moderate cervical dysplasia. One group consisted of patients who subsequently developed carcinoma in situ; the other consisted of patients whose lesions regressed to normality. Papanicolaou-stained slides were examined cytologically, and dysplastic cells were located. The slides were then destained and restained by means of the Feulgen DNA staining method, after which they were analyzed in a microspectrophotometer. The DNA distribution pattern of both groups was different from that of normal cells and exhibited the same characteristics observed earlier in premalignant cervical cellular atypias. There was no significant difference between the two groups. The results indicate that quantitative DNA determinations in cytomorphologically equivalent dysplastic cervical cells do not offer additional means of predicting the outcome of the lesions.

Cytomorphological grading and Feulgen DNA-analysis of metaplastic and neoplastic bronchial cells.

Quantitative determinations of nuclear DNA were made on squamous metaplastic and neoplastic cells from sputum cytology specimens. The cellular material was processed by destaining diagnostic smears, restaining by the Feulgen method and relocating the cells for measurement. Adventitious leucocytes were used as internal controls. There was good correlation between increasing degree of aneuploidy as judged from DNA values, and increasing degree of morphologic nuclear atypia. The data indicate a progressive aberration from normality of nuclear DNA content in squamous metaplastic and neoplastic cells exhibiting a progressive degree of atypia. This implies that squamous bronchial carcinoma is preceded by sequential changes of the cellular composition which may be recorded by both quantitative DNA analysis and cytology.

[X-ray negative pulmonary carcinoma with positive sputum cytology (author's transl)]. / Primär röntgennegativer Lungenkrebs bei positiver Sputumzytologie.

The repeated finding of malignant or suspicious cells in the sputum of an apparently normal person must not be ignored. Immediate and intensive attempts should be made to localize the carcinoma. Sometimes, in the presence of a central tumour an early diagnosis can be made radiologically. With peripheral tumours and early diagnosis is more likely. The most successful method for the early localisation of an occult bronchial carcinoma is fibre optic bronchoscopy, with selective bronchial aspiration. Consistent finding of malignant cells in the secretions from a lobar bronchus, provided contamination can be excluded, justifies surgery such as a lobectomy. Delay in instituting treatment while waiting for radiological or bronchoscopic confirmation reduces the chance of successful surgery because of the possibility of metastases or the development of cardiological or respiratory complications.

Clinically occult lung cancer with positive sputum cytology and primarily negative radiological findings.

Five patients with early clinically occult squamous cell carcinoma of the bronchus were reviewed with respect to previous sputum cytological examinations and clinical investigations. In one patient, selective bronchial washings demonstrated the site of the tumour and the patient was successfully operated. In the remaining four patients the interval between cytological diagnosis and radiological, bronchoscopical and/or histological demonstration of the tumour varied between 2 months and 9 years. It seems possible that the duration of bronchogenic carcinoma in situ may be of similar magnitude as that of carcinoma in situ of the cervix (10-15 years). The considerably higher frequency of early stromal invasion after semi-serial sectioning of carcinoma in situ of the bronchus compared with carcinoma in situ of the cervix is emphasized. The results stress that a diagnostic delay of several years is not acceptable, as the possibility of successful treatment will be greatly diminished in such cases.

Is there a changing epidemiology of premalignant lesions of the cervix? Results of cytologic screening of pregnant women.

The selection of women approached for cytologic screening is based on previous studies on age distribution and prevalence and consequent considerations on the risk of developing invasive carcinoma. In order to check if this is appropriate the results of the screening of pregnant women being selected irrespective of their age has been studied for two periods, 1961-64 and 1972. The frequency of lesions was remarkably high among the teenagers of both periods. A significant increase in the incidence of lesions was noted for the period 1972. This increase is most evident in the ages 21 to 30. A shift to more severe lesions was found among the teenagers and in the groups between 31 and 40. In conclusion more effort should be made with respect to cytologic screening of young women, particularly when pregnant. The increased frequency of cytologic atypias among women between 21 and 30 should focus the attention to the possibility that the epidemiology or premalignant lesions of the uterine cervix is changing.