Negative regulation of UCP2 by TGFß signaling characterizes low and intermediate-grade primary breast cancer.

The histological manifestation of growth-regulating and differentiation-inducing signals in cancer cells is considered as a key component for clinical outcome prediction and commonly defined as tumor differentiation grade. However, the molecular and functional framework underlying this clinical parameter remains poorly understood. Our correlative data display a significant association (P>0.001) between mitochondrial uncoupling protein 2 (UCP2) and tumor grade in primary breast cancer (n=234). Through mechanistic analyses, we show a synergistic link between UCP2 and established cellular pathways in conferring grade-associated functional phenotypes. Here, the application of well to moderately differentiated primary tumor cell lines has enabled direct observation of SMAD recruitment to the UCP2 promoter underlying repression of gene transcription. In contrast, poorly differentiated tumor cells, known to be TGFß resistant, displayed aberrant UCP2 regulation, and consequently, gene overexpression, which reduced mitochondrial calcium and facilitated the maintenance of mitochondrial membrane potential, thereby significantly decreasing oxidative stress and inhibiting cell death. Conversely, UCP2 silencing in such cells rapidly led to the induction of apoptosis and cell differentiation, concurrent with reduced cell survival and proliferation, confirming gene-specific effects. Demonstration of a biologically driven role for UCP2 dysregulation in promoting multiple characteristics of tumor aggressiveness strongly endorses assessment of gene expression at clinical presentation to augment therapeutic decision-making and improve patient outcome through personalized targeting approaches.

Protocol for the pathologic examination and tissue processing of the mammographically directed breast biopsy.

Achieving the maximum yield of breast cancers detected by mammography has required certain changes in tissue handling and examination of the mammographically directed breast biopsy. This new radiographic technique, increased use of breast-conserving surgical approaches for the treatment of breast cancer, more enlightened and demanding patients, and increasing medical-legal exposure have all contributed to changes in the way surgical pathologists should process and sample breast biopsy specimens.

Impact of mammographic screening on the size and the relative frequency of invasion in breast cancers seen in a community hospital from 1975-1988.

At CPMC routine mammographic screening was introduced in late 1975. The total volume of breast cancers, other than outside consultations, seen in the department increased from 71 in 1975 to 164 by 1988, an increase of 230%. This expansion in volume was due largely to surgical removal of mammographically detected occult, in situ duct and relatively small invasive duct carcinomas. In 1974, prior to routine mammographic screening, in situ carcinomas represented only 4% of all breast cancers seen in the Department of Pathology at CPMC. However, after the introduction of mammographic screening, the proportion of in situ cancers increased steadily. By 1988, 45% of all breast cancers seen in our hospital were found by mammography. While data on the size distribution of invasive breast cancers are not available at our hospital prior to 1976, an appreciable effect of mammography is still evident when the numbers of relatively small invasive cancers detected in 1976 are compared with those detected in 1988. Invasive breast cancers 10 mm in diameter or less represented only 6% of all cancers in our series in 1976, but 33% in 1988. These findings confirm observations made by Gibbs on the pathology of breast cancers found in mammographically screened and unscreened populations. The detection of increasing numbers of relatively small invasive duct carcinomas produced an overall reduction in the average diameters of invasive cancers seen at CPMC. The average dropped from 30 mm in 1975 to a low of 14.8 mm in 1987. Mammography did not appear to be effective in the early detection of invasive lobular cancers and had no impact on reducing their size. The implications of early discovery of in situ duct and relatively small invasive duct carcinomas are for improved patient survival through: (1) preventing progression of in situ duct to invasive duct cancers, and (2) the removal of invasive duct cancers before reaching a size where there is a high risk of metastasis.

Processing the small invasive carcinoma detected in the mammographically directed breast biopsy.

During the next few years pathologists can expect to be called upon with increasing frequency to extract data on a number of cell cycle, biochemical, and genetic features of breast cancers as a routine part of the specimen examination. Obtaining this information without compromising the histologic diagnosis or losing morphologic-based prognostic information is challenging, particularly with small invasive breast cancers, but is a service pathologists should be able to provide.

Significance of DNA content and proliferative rate of the invasive carcinoma found in the mammographically directed breast biopsy.

During the last few years considerable effort has been made to find genetic and biochemical markers that could be used to predict the behavior of cancers with greater accuracy than that obtained by histologic grading or the assessment of other established morphologic features. Because there is considerable evidence that malignant neoplasms have cytogenetic abnormalities, and because atypical features of the nucleus such as pleomorphism and hyperchromasia are known to be prognostically unfavorable findings, quantitative analysis of nuclear DNA was a prime candidate for evaluation. Also, the rate at which malignant tumor cells replicate, and the fraction of tumor cells participating in the proliferative process, are of considerable interest to oncologists for use in assessing patient prognosis and for guiding decisions on the use of various endocrine and cytotoxic agents for adjuvant endocrine and chemotherapy.

Ultrastructural and morphometric features of poorly differentiated and undifferentiated lung tumors.

Initial results are reported from a study of lung carcinomas and carcinoid tumors performed with electron microscopy and morphometric analysis of electron micrographs. The ultrastructural findings are being used to define the range of ultrastructures of the different tumor categories diagnosed by light microscopy using the revised World Health Organization classification. Morphometric data reveal a considerable degree of overlap in cell and nuclear size among different lung tumor types.

The ultrastructure and immunocytochemistry of renal cell carcinoma.

The spectrum of ultrastructural features of a series of primary renal cell adenocarcinomas, including clear cell, granular, oncocytic, and sarcomatoid types, and a group of metastatic renal cell adeno-carcinomas has been studied. The contributions of electron microscopy and immunocytochemistry as adjuncts to light microscopy and histochemistry in the differential diagnosis of metastatic renal cell adenocarcinoma in various anatomic locations are reviewed.

Comparison of T-antigen expression in normal, premalignant, and malignant human colonic tissue using lectin and antibody immunohistochemistry.

The Thomsen-Friedenreich antigen has been implicated as a cancer-associated antigen in some human organs including the colon. Most previous studies of Thomsen-Friedenreich antigen expression in the colon used peanut agglutinin (PNA) to identify the immunodeterminant in tissues. However, evidence from other organs suggests that anti-T antibodies have specificities which differ from those of peanut lectin. To elucidate the nature of the T-immunodeterminant in colonic mucosa, we compared staining by PNA to that of a polyclonal (PAb) and monoclonal (MAb) anti-T antibody. PNA demonstrated the best sensitivity (91%) in cancer tissues but the lowest specificity (68%) in normal mucosa. Staining with MAb was only 76% sensitive but 100% specific. Sensitivity and specificity of PAb were intermediate between PNA and MAb. MAb stained fewer adenomatous polyps than either PNA or PAb, but staining appeared to correlate with premalignant features of the polyps. PNA-binding sites were more prevalent than either PAb or MAb in hyperplastic polyps. Cell cytoplasm was stained by both antibodies more often than by PNA. The majority of fetal colonic specimens stained with all three reagents suggesting that Thomsen-Friedenreich antigen may be an oncodevelopmental antigen in human colon. Differences in staining patterns in some tissues may be due to different antigenic specificities among PNA, PAb, and MAb.

Cancer and aging--pathology.

The results of research in the areas of cytogenetics, molecular biology and cancer epidemiology have recently come together to provide insights into possible mechanisms whereby the aging process may be related to without being directly responsible for carcinogenesis. While the mechanism(s) of age-associated neoplasia have not been determined, current evidence suggests that: (1) Cancer does not appear to be the inevitable consequence of aging, that is a preprogrammed genetic time bomb ticking away just waiting to go off. (2) Cancer is an age-related disease that may arise in a hereditary form--usually in children, and in a sporadic form--usually in adults. (3) Chromosomal abnormalities associated with certain forms of cancer tend to be tumor specific and appear to be related to the activities of oncogenes. Age-related factors may mediate or modulate tumor production and progression, possibly through the conversion of proto-oncogenes to oncogenes.

Patients with polymyositis and dermatomyositis who undergo plasmapheresis therapy. Pathologic findings.

Muscle biopsy specimens were studied in 20 of 26 patients who had polymyositis or dermatomyositis prior to treatment with plasmapheresis and immunosuppressive therapy. Morphologic findings from biopsy specimens were similar among patients with polymyositis and dermatomyositis, except that perifascicular atrophy was a prominent feature in patients with dermatomyositis and inconspicuous or absent in patients with polymyositis; immunofluorescent staining of muscle for immunoglobulins and/or complement was noted more frequently for patients with dermatomyositis than those with polymyositis. Patients judged clinically to have highly active disease had the most severe changes, which consisted of muscle necrosis, regeneration, phagocytosis, and inflammation; those with mild and moderately active disease were indistinguishable pathologically. No correlation between duration of disease and degree of pathologic alteration was found. Six of seven patients with both pretreatment and posttreatment biopsies showed marked improvement in the extent of pathologic alteration, and a statistically significant reduction in the degree of muscle atrophy following treatment.

Tumors of the pilosebaceous unit induced in the rat by the intravenous administration of 7,12-dimethylbenz(A)anthracene.

Six of 70 female Sprague-Dawley rats given a single intravenous injection of 7,12-dimethylbenz[a]anthracene (DMBA) developed 7 pilosebaceous tumors. Two of the tumors showed differentiation toward the upper portion of the pilosebaceous unit while 5 showed differentiation toward the lower portion. Each tumor was examined histochemically for the presence of inner root sheath keratin of the hair follicle using the carbamido diacetyl reaction for citrulline and for hair shaft keratin using boiling ninhydrin reagent. The 2 tumors of the upper portion of the pilosebaceous unit were sebaceous adenomas which were accompained by a keratinizing epithelim like that of the sebaceous gland duct and upper pilosebaceous canal. Histochemically, the keratin was not like that of hair shaft nor inner root sheath. The 5 tumors showing differentiation toward components of the lower pilosebaceous unit were trichoepitheliomas. They were composed of structures which, to varying degrees, recapitulated the organization of the normal hair follicle. Within these follicular structures, both inner root sheath and hair shaft type keratins were found. The occurrence of skin tumors after the intravenous administration of DMBA was unexpected since it is uncommon for skin tumors to be produced by the systematic administration of chemical carcinogens and they have never been described after the oral administration of DMBA. That the route of administration may influence tumor production with this carcinogen is suggested by the fact that the only other reported tumors, which were squamous carcinomas, also followed intravenous injection of DMBA.