Statistical evaluation of the prognostic value of nuclear DNA content in papillary, follicular, and medullary thyroid tumors.
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Publications and source records attributed to G Auer.
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Histological specimens from 80 invasive breast carcinomas comprising typical cases of 16 ductal, nine papillary, 14 comedo, 13 colloid (mucous), 15 lobular, and 13 medullary carcinomas were examined with respect to nuclear DNA and estrogen receptor content. In agreement with previous studies, ductal carcinomas were found to exhibit different types of nuclear DNA distribution patterns, i.e., tumors with DNA values in the normal diploid or tetraploid regions indicative of good prognosis (euploid tumors) or those with values exceeding the normal tetraploid region indicative of poor prognosis (aneuploid tumors). The majority of the papillary and colloid tumors were euploid, while comedocarcinomas in general had aneuploid profiles. These findings are in agreement with expected survival within these patient groups. In lobular breast carcinomas, the correlation between the DNA distribution patterns and expected patient survival was less obvious; and in medullary carcinomas where the vast majority of the tumors showed aneuploid DNA profiles, the correlation to expected patient survival was low. Thus, lobular carcinoma in general seems to have a worse prognosis than is expected from nuclear DNA analysis, whereas medullary carcinomas in general seem to carry a better prognosis than indicated from DNA measurements. In agreement with earlier reports there was a good correlation between nuclear DNA content of the tumor cells and cytosol estrogen receptor values, i.e., euploid tumors in general exhibited relatively high receptor levels, whereas aneuploid tumors had low or unmeasurable estrogen receptor levels.
The nuclear DNA content in tumor cells from invasive ductal breast carcinomas was analyzed in 26 patients who survived more than 10 years and in 23 patients who died within 2 years after operation. The DNA content of individual tumor cells was measured in sections from the originally paraffin-embedded specimens. In short-term survivors, a large proportion of cells with very high DNA values was found in all tumors except one. Only two patients of the long-term survivors had tumors that exhibited such high DNA values. Prognostic information obtained by DNA analysis compared with histologic malignancy grading showed that the specificity using DNA analysis was distinctly higher. The data thus suggest that analysis of DNA content of tumor cells in breast adenocarcinomas can be a useful supplement to histologic malignancy grading to obtain prognostic guidance in individual patients.
A new sampling method for uterine cervical cancer detection is described. In this method, sampling of cytologic material is done by using a pulse wash instrument. Liquid jets with a diameter of 0.2 mm at a speed of 20 m/s create a successful rinsing effect of cervical epithelial cells due to the high kinetic energy produced. Because cells are suspended in the flushing liquid it is possible to collect material for additional cytochemical, immunocytochemical, and microbiologic diagnostic techniques in addition to a conventional smear technique. Compared to a conventional Papanicolaou smear technique performed in 75 women at two cervical atypia clinics at the Karolinska Hospital, the pulse wash technique is suggested to result in a more representative cellular sample, thus offering a method to decrease false negative diagnoses in uterine cervical cancer detection.
Nuclear DNA content was studied in cytologic preparations obtained from 50 patients aged 35 or less with primary mammary carcinoma. As many as 90% of the tumors were aneuploid, i.e., exhibited DNA profile types III and IV. The cytologic diagnosis was confirmed by histologic examination in 46 patients. The majority of these tumors, 83%, were invasive ductal carcinomas, while medullary carcinomas constituted 13% of the surgical material. As judged from their DNA profiles, most mammary carcinomas in this age group would be tumors of high malignancy potential. This does not seem, however, to influence the prognosis of young women with breast cancer as much as would be expected, possibly because of a better-functioning immune surveillance system in this age group.
Specimens from 17 invasive primary breast adenocarcinomas that showed distinct areas of different histologic appearance were examined with respects to nuclear DNA content of the tumor cells. DNA in individual tumor cells was measured in sections from the original paraffin-embedded specimens. DNA distribution patterns obtained from the histologically different areas in the same tumor were compared. In 15 cases these patterns were very similar, whereas in two cases the patterns were found to be different. The results suggest that, in spite of histological variations, breast carcinoma often show similar nuclear DNA content throughout the entire tumor. Since nuclear DNA content in breast tumors has been shown to be correlated to prognosis, our observations suggest that the differences in structural pattern occasionally seen in mammary adenocarcinoma do not necessarily reflect a dedifferentiation towards more malignant tumor populations.
Twenty primary mammary carcinomas and their corresponding axillary lymphnode metastases were studied. The DNA-content of individual tumor cells was measured in sections from the original paraffin embedded specimens. Comparison between the DNA-patterns obtained from the primary tumor and the corresponding metastases showed very close agreement in all but one case. Both euploid and aneuploid tumors were represented. In spite of having lymphnode metastases at operation, 8 patients survived more than 10 years after operation. All of these patients had euploid tumors, in contrast to 11 patients who died within 2 years, in whom all but one of the tumors showed aneuploid DNA-patterns. The results suggest that tumor progression in terms of lymphnode metastases is usually not associated with major changes in tumor nuclear DNA-content.
Modern immunohistochemical and DNA cytochemical analyses of gastro-intestinal carcinoids have yielded results that have increased our knowledge of the biological properties and the histogenesis of these theoretically and practically so fascinating kinds of neoplasm. Carcinoids in different anatomical localisations were found to show marked differences with regard to their neurohormone peptide immunoreactivity pattern and their ability to evoke clinical signs and symptoms of hormone overproduction. This can be of great help to the practising pathologist when he tries to predict the anatomical site of an unknown primary tumour from the results of this histopathological assessment of a metastatic nodule of a carcinoid. The DNA distribution pattern in the nuclei of carcinoid tumour cells is a tool in the histopathological assessment of the neoplasm that seems to be of some value in predicting the subsequent clinical course of the disease. This conclusion is based on the results of a pilot study of 8 cases of ileal carcinoids with liver and lymph node metastases. It was found that 4 cases with a rapidly progressive fatal disease had a higher proportion on non-diploid tumour cell nuclei than 4 cases still alive and at full work 5 years after the diagnosis of liver metastases. However, the number of aneuploid tumour cell nuclei was negligible in both groups.
The anti-nuclear cross reactivity of the monoclonal anti-actin antibodies M 372/809 was studied in some detail. The reactivity against a number of nuclear constituents was examined in the ELISA test and the capacities of these constituents to block the M 372/809 anti-nuclear and anti-actin reactions were evaluated in indirect immunofluorescence tests against tissue sections and monolayer cultures of fibroblasts and Vero cells. The repetitive polynucleotides polyinosinic and polyguanylic acid and their deoxyanalogues, actin and vimentin, were found to have the antigenic epitope. The epitope was covered or otherwise inactivated in the presence of polycytidylic acid. Using the M 372/809 antibodies as a reagent, carcinoma cell nuclei were found commonly to have an affinity for polyinosinic and polyguanylic acid. This was seldom noted with non-neoplastic cells.
The prognostic value of nuclear DNA content in follicular thyroid tumours was studied in 65 patients. Forty-six (20 with follicular carcinoma and 26 with follicular adenoma) were alive at least 10 years after diagnosis, and 19 had died of follicular thyroid carcinoma 2 months to 13 years after diagnosis. DNA was measured in morphologically identified single tumour cells either on material from fine-needle aspiration biopsy or on histologic sections from the primary tumours. Metastases or locally recurrent tumour were also examined in ten cases. The tumours from the surviving patients had cells with DNA content comparable to that in normal cells, whereas the tumours from the nonsurvivors showed higher DNA values. Primary tumours had essentially the same DNA content as metastases or local recurrence in eight of the ten studied cases. The data suggest that DNA measurement in follicular thyroid tumours offers a valuable addition to standard clinical and microscopic analysis.
The potentiality of DNA analysis to complement morphologic evaluation in classifying serous ovarian tumors as adenoma, borderline malignancy, or invasive adenocarcinoma was investigated in a series of 54 tumors. The DNA analyses were performed on histologic tumor sections. The primary diagnoses were borderline tumor in 24 cases and invasive adenocarcinoma in 30 (World Health Organization classification). When the specimens were reviewed, 17 of the 54 tumors were reclassified, after which the series consisted of 9 adenomas, 24 borderline tumors, and 21 invasive adenocarcinomas. Rising histologic malignancy grade was associated with increasing numbers of cells showing high DNA content. The DNA levels in the adenomas thus were within the diploid range of a normal cell population. They were somewhat higher in the borderline tumors and were highest in the invasive adenocarcinomas. Though no clear-cut intergroup demarcation was discernible, there was a subgroup of adenocarcinomas with greatly elevated DNA levels, indicating high biologic malignancy. The observations suggested that DNA analyses can complement histologic malignancy grading and can be useful for the recognition or highly malignant tumors among invasive adenocarcinomas.
Thirty-two children with gastroesophageal reflux were operated by different techniques which included Nissen's fundoplication in 14 patients. Twenty-one patients could be reexamined, eighteen of whom were without complaints. Being familiar with different operative techniques provides the opportunity to decide from case to case which one to choose.
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Forty-two so-called interval cancers of the breast were studied. The mammograms were reviewed and the tumors were classified as 14 'unrecognized', 9 'observer error', 1 'technical error' and 18 'true' interval cancers. By using a scoring system based upon histologic differentiation, axillary nodal status, estrogen receptor level, and nuclear DNA content, eight ductal carcinomas with high malignancy potential were identified. All of these tumors belonged to the group 'true' interval cancer. The data indicate that the mammographic subgroup 'true' interval cancer identifies the highly malignant tumors. However, even this strictly selected subgroup is heterogeneous since it also includes some tumors with low malignancy potential.
The prognostic significance of DNA content in medullary thyroid carcinoma was studied retrospectively in 16 patients. Five patients died within 3 years of medullary thyroid carcinoma and 11 patients survived for at least 10 years. Clinical data and tumour morphology were studied. DNA measurements on tumour cells in histologic sections were performed with slide cytophotometric technique. The tumours of the survivors had in all but two cases a DNA content comparable to that of normal cells, whereas the tumours of the non-survivors and two of the survivors had higher DNA content. The results indicate that DNA measurements in medullary thyroid carcinoma might be of use in addition to clinical and morphologic data and that further studies are warranted.
Antibodies of the hybridoma clone M 372/809 react with a nuclear antigen in growing cells. Using immunofluorometry and microspectrophotometry, the antigen was found to accumulate to a maximum coincident with the marked early increase in nuclear protein contents. The following DNA increase appeared when the intensity of the reaction with M 372/809 antibodies was decreasing. The antigen increase was inhibited by alpha-amanitin. It may therefore be associated with transcription early in the cell cycle.
Nuclear DNA values were determined in 40 primary papillary thyroid carcinomas, as well as in 52 corresponding local recurrences and metastases were observed either at the time of diagnosis or up to 20 years later. The patient population consisted of 34 survivors and 6 nonsurvivors. In survivors, both the primary tumors and their recurrences and metastases exhibited a majority of cells with DNA values within the normal diploid region, whereas nonsurvivors showed increased and scattered DNA values. In all cases, the primary tumors and the corresponding recurrences and metastases showed similar DNA distribution patterns even if many years had passed between the detection of the primary tumor and the metastases. The results indicate that in papillary thyroid carcinomas, the DNA distribution patterns in the primary tumor and the corresponding recurrences or metastases are generally similar throughout the entire period of disease.
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.