Undifferentiated Cancers Research Articles

Human squamous cell lung cancers express increased epidermal growth factor receptors.

Epidermal growth factor (EGF) promotes the growth of cultured benign and malignant cells. Recent studies have demonstrated that the amount of EGF receptor is elevated in squamous cell carcinoma cells in tissue culture when compared with normal epidermal cells. This study demonstrates that elevated levels of EGF receptor are detected in biopsy specimens of human squamous cell carcinomas of the lung with a murine monoclonal antibody, EGF-R1, which binds specifically to the receptor. The increased receptor ranged from 2.5- to 5-fold that of normal skin. These findings have been observed in 11 of 11 squamous carcinomas and two of two epidermoid head and neck cancers. Seven of eight adenocarcinomas, two of two small cell, and four of eight undifferentiated lung cancers had negligible amounts of EGF receptor. The EGF receptor antibody did not bind significantly to normal lung tissues and 35 nonepidermoid tumors. Therefore, EGF receptor may be an excellent marker for epidermoid malignancies.

Histological subtypes of bronchial carcinoma and their biological behavior

The WHO classification of pulmonary tumors, Geneva 1981, is used to describe the biological and morphological characteristics of the various types of bronchial tumors. The differences in frequency are noted for clinical biopsy material and autopsy statistics for squamous-epithelium cancers and small-cell bronchial carcinomas. The latter are incorrectly seen as undifferentiated cancers. Their particular hormonal activity and leading role among the hormone-producing lung tumors is emphasized. Their relationship to the carcinoids is also discussed briefly. The causes of the relatively common adrenal metastases are listed. The biological-morphological characteristics of the adeno- and bronchiolo-alveolar cancers, as well as of the giant-cell carcinomas, are mentioned.

Lung cancer in young persons

Lung cancer in patients under 40 years old is rare. Among 718 patients with lung cancer, 5% or 35 patients were younger than 40. All but one were heavy smokers. Twelve young patients who had operations survived 41.7 (SD 46.3) months: they included six who had resections of Stage 3 disease and who survived 19.2 (SD 16.0) months. The other six young patients treated operatively were free of nodal metastasis N0); all survived more than 3 years and three of them are apparently cured. The 23 young patients who were not treated operatively survived for 5.6 (SD 3.1) months. The 5 year survival rate of these young operated patients was not different from that of 201 operated patients over 40 years of age. Young nonoperated patients survived for a significantly shorter time (p less than 0.0001) than did the older patients who also received only chemotherapy and/or radiation as a treatment. In young patients adenocarcinomas predominated (48.6%), and the incidence of small cell undifferentiated cancers was high (28.6%). These significant differences as compared to the control group did not explain the short survival time of the young patients treated nonsurgically. We conclude that lung cancer in young persons is virulent and that diagnosis is frequently delayed. Therapy, in selected patients, should include aggressive resection, sometimes despite advanced local disease. This group of patients justifies innovative, intensive efforts at more prompt diagnosis and experimental multimodal therapy.

Relation between time-dose and local control of operable breast cancer treated by tumorectomy and radiotherapy or by radical radiotherapy alone.

67 patients with tumors 3 cm or less and with negative axilla, who had lumpectomy and radiotherapy, and 122 patients with larger tumors or clinically positive axilla, who had radical radiotherapy without prior lumpectomy, were evaluated at five years to determine the optimum dose for local control. 7000 rad in seven to eight weeks controlled 85% of lumpectomy cases, whereas 8000 rad in 81/2 weeks were required to control two-thirds of cases treated by radical irradiation alone. Subclinical (N0, N1a) and clinical disease (N1b) in the axilla was controlled, in a very high percentage, when 6000 and 7000 rad were delivered, respectively. Dose response curves were obtained for clinical disease in the breast and axilla. No such response was elicited for subclinical disease. Undifferentiated cancers had higher recurrence rates than well differentiated tumors. Radiation fibrosis in lumpectomy cases was insignificant, whereas 10% of radically irradiated patients had fibrosis of the breast.

EFFECT OF TSH ON cAMP AND cGMP LEVELS IN THYROID CANCERS, ADENOMAS AND NORMAL HUMAN THYROID TISSUE

ABSTRACT The effect of TSH (50 mU/ml) alone or in combination with theophylline (10 mm) on the cAMP level in human thyroid tissue after a 10 min incubation has been studied in 8 normal tissues, 7 adenomas and 10 thyroid cancers (8 differentiated and 1 anaplastic). Our results have shown the lack of responsiveness to TSH in the 2 anaplastic carcinomas studied, as well as in 4 cases among the 8 differentiated cancers studied. In thyroid adenomas, on the contrary, the cAMP increase in response to TSH was close to that observed in normal tissues. In these adenomas, the mean basal cAMP level (0.43 ± 0.07 pmol/mg tissue) was not statistically different from that in normal tissues (0.36 ± 0.06), while in thyroid cancers the mean basal cAMP level (0.93 ± 0.26) was significantly greater than that in normal tissues (P < 0.05). The cGMP level was measured in the same conditions in 7 normal thyroid tissues and 8 thyroid cancers (7 differentiated and 1 anaplastic). The mean basal cGMP level in these cancers (9 ± 1 fmol/mg tissue) was not statistically different from that in normal tissues (12 ± 2). In response to TSH, no increase of cGMP level was observed in cancers, or in the normal tissues. The disorders of hormone synthesis previously seen in human thyroid cancers did not appear related to a decreased cAMP content, but might be due to a lack of responsiveness to TSH in undifferentiated cancers and in some cases of differentiated carcinomas.

Long-term intermittent adjuvant chemotherapy for primary, resected lung cancer

Adjuvant chemotherapy for lung cancer has previously been unsuccessful in improving the results of pulmonary resections. During a 12 year period, we tested long-term intermittent chemotherapy (LTIC) with mitomycin C and chromomycin A3 adjuvant to resections. LTIC was begun before the operations and the first course was completed postoperatively. Additional courses of 4 weeks each were scheduled at 3 month intervals during the first postoperative year and at 6 month intervals during the next 2 years. LTIC was defined as three or more full courses, and short-term chemotherapy (STC) was defined as a single course of adjuvant treatment. Resections for cancer in 425 patients over a 22 year period included 117 operations during a 10 year control period in which LTIC was not used and 308 during the LTIC test period. Results from adjuvant LTIC in 85 patients were compared with lesser adjuvant chemotherapy in 155 synchronously treated patients who included 77 STC recipients. Further comparison was made between LTIC and asynchronously treated, comparable control subjects. Although there were side effects and occasional deaths from chemotherapy, they did not alter the operative mortality rate. The over-all 5 year survival rate of the adjuvant LTIC patients was 50.9 per cent, as compared to 22.6 per cent in the asynchronous control subjects (p less than 0.01). For patients who were given LTIC adjuvant to palliative resections the 5 year survival rate was 35.6 per cent, as compared to 4.3 per cent for STC patients or 5.2 per cent for asychronous control subjects (p less than 0.01). Strikingly promising results were obtained from adjuvant LTIC in 10 of 33 patients with undifferentiated cancers. We conclude that LTIC prolonged life among lung cancer patients who were not cured by resection alone. Dual-agent LTIC is safe, apparently beneficial, and worthy of further clinical trials in a research setting.

The anatomical precursor of colorectal carcinoma

The very common hyperplastic polyp is not a neoplasm and is unrelated to either adenoma or carcinoma. Adenomas, which are only one-tenth as common, may occur grossly as adenomatous polyps or papillary adenomas. Be they large or small, pedunculated, sessile, or flat, they are true neoplasms—non-invasive and thought of as benign. Depending on size, and probably related to a sessile mode of growth, in adenomas one may readily observe intramucosal carcinoma and/or „early” invasive cancer. On the other hand, although microscopic examination has been performed on many thousands of minute mucosal lesions (e.g. 5 mm or less), „early” cancer, defined as intramucosal carcinoma with or without microinvasion, does not seem to occur unassociated with adenoma. Since colorectal carcinoma is so common, one should easily find many examples of „early” cancer as defined above if the majority of ordinary adenocarcinomas arose directly from normal crypts of Lieberkuhn. (Of course the unusual anaplastic undifferentiated colonic cancers or carcinomas arising in ulcerative colitis remain in an area of unknown morphogenesis). The apparent non-existence of small foci of intramucosal carcinoma, with or without micro-invasion, in normal mucosa, and their frequency in adenomas, are two fundamental pathologic facts. They seem to disprove the proposition that cancer cells ordinarily arise de novo from the normal cells of the crypt of Lieberkuhn without the interposition of a stage in the neoplastic process that we recognize as adenoma.

The Diverse Effects of Histopathology on Manifestations and Outcome of Lung Cancer

The manifestations and outcome of lung cancer in 449 patients have been correlated with the new WHO histologic classifications. The six main histologic groupings were: well-differentiated epidermoid, poorly-differentiated epidermoid, well-differentiated adenocarcinoma, poorly-differentiated adenocarcinoma, large cell undifferentiated, and small cell undifferentiated. The biologic behavior of the well-differentiated and poorly-differentiated groups seemed relatively similar for epidermoid carcinomas, but was substantially different for adenocarcinomas. Adenocarcinomas occurred most commonly among women, and were most likely to be detected either while asymptomatic or after manifest metastasis. Epidermoid carcinomas were most likely to present with a bronchoscopically visible mass, with the “primary” symptom of cough or hemoptysis, and with positive tests for sputum cytology. The mean age at diagnostic detection was similar in all six histologic subgroups, but the mean duration of pretherapeutic symptoms was longer in the epidermoid group than in the others. The epidermoid cancers had the lowest rates of pretherapeutic metastasis, the highest rates of operability and resectability, and the highest overall survival rates. The lowest rates of operability, resectability, and overall survival were in small cell undifferentiated cancers and in poorly-differentiated adenocarcinomas. A striking finding among inoperable patients was that six-month survival rates depended much more on symptom-anatomic stage than on histologic type. The manifestations and outcome of lung cancer in 449 patients have been correlated with the new WHO histologic classifications. The six main histologic groupings were: well-differentiated epidermoid, poorly-differentiated epidermoid, well-differentiated adenocarcinoma, poorly-differentiated adenocarcinoma, large cell undifferentiated, and small cell undifferentiated. The biologic behavior of the well-differentiated and poorly-differentiated groups seemed relatively similar for epidermoid carcinomas, but was substantially different for adenocarcinomas. Adenocarcinomas occurred most commonly among women, and were most likely to be detected either while asymptomatic or after manifest metastasis. Epidermoid carcinomas were most likely to present with a bronchoscopically visible mass, with the “primary” symptom of cough or hemoptysis, and with positive tests for sputum cytology. The mean age at diagnostic detection was similar in all six histologic subgroups, but the mean duration of pretherapeutic symptoms was longer in the epidermoid group than in the others. The epidermoid cancers had the lowest rates of pretherapeutic metastasis, the highest rates of operability and resectability, and the highest overall survival rates. The lowest rates of operability, resectability, and overall survival were in small cell undifferentiated cancers and in poorly-differentiated adenocarcinomas. A striking finding among inoperable patients was that six-month survival rates depended much more on symptom-anatomic stage than on histologic type.

The interpretation of abnormal sexchromatin incidence in human breast tumors on the basis of DNA measurements

1. (1) Sexchromatin incidence and DNA content of Feulgen stained impression prints from 20 normal mammary glands, 8 benign tumors and 60 breast carcinomas were determined numerically and histophotometrically. Benign tumors have approximately the same rate as normal tissue (over 70% sexchromatin positive, over 90% near diploid nuclei). Twenty-two carcinomas with high sexchromatin counts (52%) still contain 79% near diploid nuclei. In cancer with low counts of positive nuclei (10–30%) 54% nuclei are in the diploid, 46% in the tetraploid range. Negative tumors and tumors with high incidence of nuclei with two or more sexbodies contain about 15% near diploid, 60% near tetraploid and 25% high ploid nuclei. Thus the loss of nuclei with one sexbody correlates positively with the loss of diploidy. 2. (2) While in normal tissue and in benign tumors positive and negative nuclei have the same DNA content, the negative nuclei in sexchromatin positive carcinomas show a tendency to hyperdiploidy. Neoplasms, containing negative as well as nuclei with more than one sexbody, show high DNA contents, which may be different for the two types of nuclei. This indicates, that such a tumor is composed of different stemlines. 3. (3) From 80 patients with carcinomas differing in sexchromatin incidence, who had no hormonal treatment, 62·5% with positive tumors survived 5 years, compared to 27·5% with negative tumors. The mean survival time is significantly higher for sexchromatin positive cancer than for cancer with abnormal sexchromatin picture in the group of tumors with lymphnode metastasis at operation. This difference is highly significant if only histologically undifferentiated cancers are considered. Therefore, the loss of nuclei with one sexbody is regarded as a sign of dedifferentiation which enhances the malignancy of breast carcinoma.

Giant cell carcinoma of the lung: Anatomic and clinical correlation

Four additional cases of giant cell carcinoma of the lung are presented. This variety, first so designated and described by Nash and Stout in 1958, is consistent in its lack of differentiation and numerous bizarre pleomorphic giant cells. Histologically, the tumor may be distinguished from other large cell undifferentiated lung cancers, sarcomas and choriocarcinomas. The tumor is highly malignant, averaging seventeen weeks from onset of symptoms to death. A hemolytic process was usually found in all cases in which evidence of such was sought. Its mechanism is obscure but an autoimmune type is possible.

�ber das Vorkommen von Mikrocarcinomen in cirrhotischen Lebern

To select small solitary primary cancers of the liver, which have developed on the ground of a cirrhose, we cut all the cirrhotic livers that had been autopsied in our institute, after having been fixated in 10% formaldehyde, into 5 mm slices. In 54 cirrhotic livers we found in 5 (9%) fully developed carcinomas on the ground of the cirrhose, and 7 (13%) solitary small carcinomatic nodules. Histologically seen the sometimes only 5 mm diameter nodules showed all forms of the classic fully developed liver carcinoma. There were hepatocellular cancers as well as tubulary forms with fibrotic stroma (say cholangiocellulary type) and some other completely undifferentiated cancers. The nodules showed histologically all charakteristics of genuine cancer tissue. However the question whether in all these cases we can also see them as biologically efficient tumours, which we can count to the cancers that have developed on the ground of a cirrhose, remains. The problems on diagnosing initial carcinomas are mentioned and at the same time parallels to superficial cancer of the portio uteri and to the latent cancer of the prostate gland of elderly men are drawn up. This report is supposed to turn the attention toward the appearance of similiar microcarcinomas in other parts of the body.