David Schottenfeld

Chronic inflammation: A common and important factor in the pathogenesis of neoplasia

A causal link between chronic inflammation and carcinogenesis is explored by reviewing illustrative examples of specific cancers and causal agents and mechanisms. The causal agents or pathologic conditions include microbial agents, gastroesophageal reflux, chronic cholecystitis and cholelithiasis, inflammatory bowel disease, and specific agents that cause chronic obstructive or diffuse interstitial lung disease. The proportion of total cancer deaths attributable to infectious agents is estimated to be about 20% to 25% in developing countries and 7% to 10% in more industrialized countries. Recurrent or persistent inflammation may induce, promote, or influence susceptibility to carcinogenesis by causing DNA damage, inciting tissue reparative proliferation, and/or creating a stromal “soil” that is enriched with cytokines and growth factors. Future research on the complex cascade of cellular and humoral factors participating in the chronic inflammatory process will further understanding of the pathogenesis of various cancers and potentially provide a rationale for targeted chemopreventive interventions.

Colposcopy For The Diagnosis of Squamous Intraepithelial Lesions: A Meta-Analysis

Objective To quantify by meta-analysis the performance of colposcopy to set a standard against which new technologies can be compared. Data Sources MEDLINE was searched for articles on colposcopy for diagnosis of squamous intraepithelial lesions (SIL). The search selected articles from 1960 to 1996 combining the key word “colposcopy” with key words “diagnosis,” “positive predictive value,” “negative predictive value,” “likelihood ratio,” and “receiver operating characteristic (ROC) curve.” Methods of Study Selection Articles were selected if the authors studied a population of patients with abnormal screening Papanicolaou smears and presented raw data showing for each cervical lesion type the number of patients judged positive and negative by colposcopic impression versus the standard of colposcopic biopsy results. Nine of 86 studies met these criteria. Tabulation, Integration, and Results Biopsies had been categorized as normal, atypia, cervical intraepithelial neoplasia (CIN) I, CIN II, CIN III, carcinoma in situ, and invasive cancer; we recalculated performance measures using the Bethesda system. Overall sensitivity, specificity, likelihood ratios, ROC curves, and the corresponding areas under the curves were calculated. The average weighted sensitivity of diagnostic colposcopy for the threshold normal compared with all cervix abnormalities (atypia, low-grade SIL, high-grade SIL, cancer) was 96% and the average weighted specificity 48%. For the threshold normal cervix and low-grade SIL compared with high-grade SIL and cancer, average weighted sensitivity was 85% and average weighted specificity 69%. Likelihood ratios generated small but important changes in probability for distinguishing normal cervix and low-grade SIL from high-grade SIL and cancer. Areas under the ROC curve were 0.80 for the threshold normal cervix compared with all abnormalities and 0.82 for the threshold normal cervix and low-grade SIL compared with high-grade SIL and cancer. Conclusion Colposcopy compares favorably with other medical diagnostic tests in terms of sensitivity, specificity, and area under the ROC curve. New diagnostic methods for the cervix can be compared with colposcopy using these quantified values.

Residual mammary carcinoma following simulated partial mastectomy.

Treatment of mammary carcinoma by partial mastectomy rather than by total mastectomy and axillary dissection may diminish the chances of long‐term cure by risking incomplete removal of all local carcinoma at the initial operation. This study was undertaken to determine by pathologic examination how often carcinoma might remain in the breast and axilla after partial mastectomy. The operation was simulated in 203 mastectomy specimens after operations for unilateral invasive carcinoma. In so far as could be determined on gross examination, the entire primary lesion was included in the quadrant which was excised in the simulated procedure. Among 100 women with primary lesions less than 2 cm in diameter, 26% had carcinoma in the breast which remained after simulated partial mastectomy. Six percent of them also had axillary node metastases. An additional 30% only had axillary node metastases. When the primary lesion was more than 2 cm in diameter, 38% of patients had carcinoma in the breast after simulated partial mastectomy, of whom 29% also had axillary metastases. After simulated partial mastectomy, carcinoma was found in 80% of breasts from patients with lesions in the subareolar area, in contrast with 25–35% of patients with a primary carcinoma in one of the four quadrants. None of the 9 patients with medullary and colloid carcinomas that measured under 2 cm had axillary metastases or carcinoma in the breast outside of the primary quadrant. The findings suggested that a familial history of breast carcinoma or a large primary lesion may be associated more often with multifocal disease, but factors such as age at diagnosis, axillary status, and the mammogram report did not have significant predictive value for distinguishing between patients who did or did not have carcinoma in breast tissue after the primary had been removed by a simulated partial mastectomy.

Male breast cancer: a clinicopathologic study of 97 cases.

From 1949 through 1976, 97 men have been treated at Memorial Hospital for primary operable breast cancer. Seven per cent had intraductal carcinoma. Of the patients with invasive carcinoma 30% were pathologic stage I, 54% stage II, and 16% stage III. Fourty-six per cent had pathologically negative axillary lymph nodes. The most common type of tumor was infiltrating duct carcinoma. Fourty per cent of the patients had microscopic gynecomastia. None of the eight patients with intraductal or intracystic carcinoma died of cancer. Survival of the entire group of men with invasive carcinoma was 40% after ten years. The ten-year survival for men with negative nodes was 79%, for men with positive nodes 11%. Comparison with a series of 304 women with breast cancer operated on at Memorial Hospital in 1960 revealed no difference with regard to incidence of positive axillary lymph nodes or stage of disease. There was, however, a significantly lower survival rate for men. This poorer prognosis was limited to those men with pathologically positive axillary nodes.

Risk of Localized and Widespread Endometrial Cancer in Relation to Recent and Discontinued Use of Conjugated Estrogens

In a case-control study of the risk of adenocarcinoma of the endometrium in relation to conjugated-estrogen use, we found that 31 per cent of 425 women with endometrial cancer and 15 per cent of 792 controls reported having used conjugated estrogens; the rate-ratio estimate was 3.5 with a 95 per cent confidence interval of 2.6 to 4.7. For use that lasted at least one year, the rate-ratio estimate for Stage I or II cancer was 5.2 (95 per cent confidence interval, 3.7 to 7.2), and for Stages III and IV combined it was 3.1 (1.5 to 6.4). Among women who had used estrogen for at least one year and then discontinued it, the risk of endometrial cancer remained significantly elevated even after estrogen-free intervals of over 10 years. The findings suggest that long-term use of conjugated estrogen increases the risk of both localized and widespread endometrial cancer. The data also suggest that women who have taken conjugated estrogen for one or more years remain at increased risk for at least 10 years after they discontinue use. Such women should be considered for long-term gynecologic surveillance.

Cigarette smoking and the risk of endometrial cancer

Because of evidence of reduced estrogen excretion in the urine of women who smoke cigarettes and evidence linking estrogen levels to the risk of cancer of the female reproductive system, we evaluated the risk of endometrial cancer in relation to cigarette use in a hospital-based case-control study of 510 women with endometrial cancer (cases) and 727 women with other cancers (controls). The rate-ratio estimate (relative risk) for current smokers as compared with women who had never smoked was 0.7 (95 per cent confidence interval, 0.5 to 1.0), and for former smokers the estimate was 0.9 (0.6 to 1.2). For women currently smoking 25 or more cigarettes per day, the rate-ratio estimate was 0.5 (0.3 to 0.8). The effect of current smoking of at least 25 cigarettes per day appeared to be confined to postmenopausal women, among whom the estimate was 0.5 (0.2 to 0.9). Among premenopausal women the estimate was 0.9 (0.4 to 2.2), but the difference between these two estimates could have been due to chance. The data suggest that women who smoke heavily may have a lower risk of endometrial cancer than nonsmokers. The present findings do not have direct public health importance since cigarettes, overall, have serious deleterious effects. However, if these results are confirmed, elucidation of the underlying mechanisms whereby smoking reduces the risk would be of interest and might be useful in the development of strategies for preventing endometrial cancer.

Pneumocystis carinii Pneumonia: A Cluster of Eleven Cases

An unusual cluster of 11 patients with Pneumocystis carinii pneumonia occurred in a 3-month period at Memorial Hospital, New York. Ten of the 11 patients had lymphoma or leukemia. In 7 patients, corticosteroid therapy was decreased or stopped shortly before pneumocystis pneumonia was diagnosed. The pediatric patients had extensive contact in the outpatient department, and three of them had roomed together, suggesting the possibility of man to man transmission. Tree of 4 adult patients with Hodgkins disease and pneumocystis pneumonia had the same physician. This physician had an indirect immunofluorescent titer of 1:16, as did an infectious disease resident involved in the care of 6 patients. Three of 9 patients tested showed indirect immunofluorescent titers of 1:16 or above, with rising or falling titers on serial specimens. Although definitive evidence of communicability was not established, patients with suspected or proved pneumocystis pneumonia are now isolated in this hospital.

Noninvasive breast carcinoma: frequency of unsuspected invasion and implications for treatment.

One hundred twenty-nine biopsies from 121 patients with a frozen or paraffin section diagnosis of noninvasive breast carcinoma were studied. Eight women had bilateral noninvasive carcinoma. Seven biopsies reported as intraductal on frozen section contained invasive carcinoma on paraffin section. Of the remaining 122 biopsies proven to have noninvasive carcinoma on paraffin section, 39 (34%) were reported at frozen section and as noninvasive carcinoma, 24 (20%) as atypical and 59 (48%) as benign. Intraductal carcinoma (IDC) was identified more often at frozen section (45%) than was lobular carcinoma in situ (19%). Among 41 patients who had bilateral carcinoma with invasive disease in one breast, 76% of contralateral noninvasive carcinoma was LCIS. After excisional biopsy, carcinoma was found in 56% of 103 mastectomy specimens, including invasive carcinoma in 6% of breasts with IDC and 4% with LCIS. Residual noninvasive carcinoma was usually of the same type found at biopsy (90% IDC and 88% LCIS) and involved quadrants other than the biopsy site in 33% with IDC and in 80% with LCIS. When the frozen or paraffin section diagnosis of a generous excisional biopsy was noninvasive breast carcinoma, there was a substantial risk that foci of the same type of noninvasive carcinoma were also present in other quadrants. However, occult foci of invasive carcinoma were quite infrequent and the risk of axillary metastases was very low. Adequate treatment for noninvasive carcinoma requires elimination of all residual foci of noninvasive disease. At present this can best be accomplished by total mastectomy if the operation is properly performed. To insure removal of the axillary extension of the breast and for staging, in continuity dissection of the lowest axillary lymph nodes is also prudent.

Adverse effect of pregnancy on melanoma. A reappraisal

The influence of pregnancy on the prognosis of cutaneous melanoma in women of childbearing age was examined in a retrospective review of 251 surgically treated cases. There was no statistical difference in survival at five years, free of disease, for Stage I melanoma between nulliparous, parous nonpregnant, and pregnant women. For Stage II melanoma, however, a significantly lower survival rate was observed for pregnant patients (29%) and parous women who had experienced activation of the lesion in a previous pregnancy (22%), as compared with that of nulliparous patients (55%) and other patients in the parous group (51%); p < 0.05. This discrepancy in survival, together with the observed higher frequencies of Stage II cases, melanomas occurring on the trunk, and symptoms such as bleeding, ulceration, irritation, and elevation of the lesion, strongly suggest an adverse influence of pregnancy on women with Stage II melanoma.

The role of alcohol and tobacco in multiple primary cancers of the upper digestive system, larynx and lung: a prospective study.

Abstract A five year prospective study was conducted on 733 patients admitted to Memorial Sloan-Kettering Cancer Center with a single primary epidermoid carcinoma of the oral cavity, pharynx or larynx, diagnosed between 1965 and 1968. The survival in women at five years following diagnosis of the index cancer was significantly better than in men. The average annual incidence for second primary carcinomas of the respiratory and upper digestive systems was 18.2 per 1000 in men and 15.4 per 1000 in women. The women were distinguished from the men by their less intensive exposure to tobacco and alcohol previous to the index cancer. The risk of developing a second primary cancer was enhanced significantly by more intensive, combined exposures to tobacco and alcohol prior to the index cancer. Within the first five years after the clinical presentation of the index cancer, the development of any new neoplastic process previously initiated in the exposed tissues was unaffected by altered smoking and drinking habits after the index cancer. Of the 433 deaths occurring at five years in the study population, two-thirds were attributed to metastases or the complications of treatment of a single or multiple primary cancer of the oral cavity, pharynx or larynx, 1.5% to a new primary cancer of the lung or esophagus and 1.4% to a new primary cancer of an organ outside of the respiratory and upper digestive tracts. The significant excesses in cancer mortality in men and women were particularly evident between 45–64 years of age and were distributed throughout all levels of exposure to tobacco and alcohol. The underlying cause in 30.7% was due to diseases other than cancer. Future follow-up will enable us to determine the risk of new primary cancers and intercurrent nonneoplastic diseases in patients who continue to smoke and/or drink, and whether these risks, as suggested by our retrospective study, are enhanced as a result of previous radiation therapy.