Apoptosis and the regulation of cell numbers in normal and neoplastic tissues: an overview.

Interstitial cells in the scars of human myocardial infarctions of different postinfarction times (6 hours to 17 years old) were characterized by antibodies to alpha-smooth muscle actin (ASMA), vimentin, and desmin Basal lamina deposition was studied with antibodies to the basal lamina protein type IV collagen Nonvascular spindle-shaped cells expressing ASMA were present within 4 to 6 days after infarction These cells co-expressed vimentin but no desmin and showed discontinuous basal lamina deposition In electron microscopy these cells showed features characteristic of myofibroblasts The spindle-shaped cells persisted for a long period of time and could even be identified 17 years postinfarction In transmural infarctions they were orientated parallel to the endocardium and epicardium In nontransmural patchy infarctions they showed an orientation adjacent to the cardiomyocytes and appeared to be less dense than in the transmural infarctions In conclusion, myofibroblasts expressing ASMA persist within human myocardial scars and show a preferential alignment that may be the result of the continuous mechanical stress caused by the ongoing contraction and relaxation of the surrounding viable myocardium

The alpha-smooth muscle actin-positive cells in healing human myocardial scars.

Increasingly more coherent data on the molecular characteristics of benign breast lesions and breast cancer precursors have led to the delineation of new multistep pathways of breast cancer progression through genotypic-phenotypic correlations. It has become apparent that oestrogen receptor (ER)-positive and -negative breast lesions are fundamentally distinct diseases. Within the ER-positive group, histological grade is strongly associated with the number and complexity of genetic abnormalities in breast cancer cells. Genomic analyses of high-grade ER-positive breast cancers have revealed that a substantial proportion of these tumours harbour the characteristic genetic aberrations found in low-grade ER-positive disease, suggesting that at least a subgroup of high-grade ER-positive breast cancers may originate from low-grade lesions. The ER-negative group is more complex and heterogeneous, comprising distinct molecular entities, including basal-like, HER2 and molecular apocrine lesions. Importantly, the type and pattern of genetic aberrations found in ER-negative cancers differ from those of ER-positive disease. Here, we review the available molecular data on breast cancer risk indicator and precursor lesions, the putative mechanisms of progression from in situ to invasive disease, and propose a revised model of breast cancer evolution based on the molecular characteristics of distinct subtypes of in situ and invasive breast cancers.

Breast cancer precursors revisited: molecular features and progression pathways.

Background Radial scars are benign breast lesions of uncertain clinical significance. In particular, it is not known whether these lesions alter the risk of breast cancer in women with benign breast disease. We conducted a case–control study of women who had benign breast lesions with or without radial scars. Methods We reviewed benign breast-biopsy specimens from 1396 women enrolled in the Nurses' Health Study, including 255 women in whom breast cancer subsequently developed and 1141 women without subsequent breast cancer (controls). The controls were matched to the women with subsequent breast cancer according to age and the year when the benign lesion was identified. The median follow-up after biopsy of the benign lesions was 12 years. Results Radial scars were identified in biopsy specimens from 99 women (7.1 percent). Most biopsy specimens with radial scars had only one radial scar (60.6 percent), and they tended to be incidental microscopical findings (median size, 4.0 mm). The women with radial sca...

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Radial scars in benign breast-biopsy specimens and the risk of breast cancer

Epithelial hyperplasia of the breast carries an increased likelihood of carcinoma development, with most lesions best understood as markers of higher risk. The indication of increased cancer risk for more worrisome or complex histologic patterns has been supported in many studies. About 25% of women who underwent biopsies in the premammographic era had well-developed hyperplastic changes associated with an elevated risk of 1.5 to 2.0 times that of the general population when age and length of time of follow-up were considered. Somewhat fewer than 5% of women had specific patterns of atypical hyperplasia (AH) that approached the criteria of carcinoma in situ (CIS). These women with AH had a risk of cancer four to five times that of the general population, or about one half the risk associated with microscopic CIS. Only ductal CIS should be considered without question to be an intrinsic precancerous lesion because of its regular association with recurrence at the site of its initial diagnosis. Further studies indicated an appreciable interaction between AH and other nonanatomic risk factors, particularly a family history of breast cancer. Also, lower dosage estrogen replacement after menopause does not affect risk in any histologically defined group. The atypical hyperplastic lesions are more common in women undergoing biopsies on the indication of mammographic calcifications than because of palpable masses. The primary therapeutic implications of these premalignant lesions are intensified breast cancer surveillance and screening for these patients.

Anatomic markers of human premalignancy and risk of breast cancer.

From a study of tissue from 34 cancerous breasts and 34 benign breasts the nature and occurrence of radial scars has been assessed. The frequency of detection was influenced more by the amount of tissue assessed and by the diligence of search than by any association with cancer. Bilaterality and multifocality were features in cancerous and benign breasts and a similar range of scar histological appearance was apparent in both types. The histological features of 103 radial scars were tabulated to compare the association of characteristics within individual scars, and the information used to formulate modes of development and progression. The 'early' stage appeared to correlate with central chronic inflammatory response, many spindle cells and minor fibroelastotic distortion of parenchyma; the 'late' stage showed few spindle cells and dominant fibroelastosis with considerable distortion and separation of parenchymal elements. No support was found for the concept that the lesion is premalignant. Rather it belongs to the spectrum of sclerosing alterations affecting the breast parenchyma which ranges from physiological through to clearly pathological changes. Position in the spectrum depends upon the extent and degree of change.

Radial scars of benign and malignant breasts: comparative features and significance.

Radial scars from 38 cases, comprising 12 associated with cancer and 26 with benign lesions, have been examined by electron microscopy. One-third of the lesions, regarded as being at an early stage of development, showed abundant spindle cells, which displayed the ultrastructural characteristics of myofibroblasts. These included many profiles of endoplasmic reticulum, prominent myofilaments and a close association with collagen and elastic fibres. The remaining ‘mature’ radial scars showed relatively few myofibroblasts, sparsely distributed in the stroma. The stromal cells associated with the ‘early’ lesions were seen in close proximity to degenerating parenchymal struclures, which frequently showed loss of basal lamina. Obliteration of the central parenchymal component appeared to be a prominent feature of radial scar formation. The ultrastructural appearances are consistent with a progressive development of the lesion, associated with sporadic myofibroblast activity.

Myofibroblast activity of radial scars

Immunocytochemistry with monoclonal antibody Y13-259 demonstrated p21 ras in paraffin sections of breast tissue from 171 women: 85 with invasive breast carcinoma, 14 with non-invasive carcinoma and 72 with benign changes only. Many different tissue elements contributed to ras expression. Semiquantitative assessment showed that intensity of immunostaining in the normal epithelium of large ducts, small extralobular ducts and terminal duct lobular units (TDLU) was usually exceeded by that of myoepithelial cells. Vascular smooth muscle and apocrine epithelium also stained strongly, but the flat epithelial cells lining cysts did not express detectable p21 ras. There was a progressive increase from normal epithelium through epithelial hyperplasia of usual type and atypical hyperplasia to carcinoma in situ, without further increase in invasive carcinoma. Expression in carcinomas was inversely related to oestrogen receptor content but independent of the prognosis-associated variables of size, histological type, vascular invasion or lymph node metastasis.

Ras p21 in breast tissue: associations with pathology and cellular localisation.

In this study breast tissue from 114 patients has been examined ultrastructurally for dense core granules (DCG). The tissue included examples of normal 'resting', pregnant and lactating breast plus various benign and malignant lesions. DCG were observed in low numbers in the apical cytoplasm in a proportion of the examples of 'resting' and pregnant breast tissue but were absent in the lactating patients. The incidence appeared to relate to hormonal changes. They were present in 50 per cent of the benign lesions examined. DCG were also observed in a high proportion of the ductal, lobular and tubular carcinomas examined and were associated with luminal differentiation. In the mucoid carcinomas over half the tumours possessed some DCG with large numbers of DCG present within certain of the malignant cells in two cases. It is possible that the granules could be related to mucin secretion. Therefore, in normal, benign and malignant (with the exception of mucoid carcinoma) breast tissue the presence of DCG would appear to be related to hormonal changes and represent prelactational differentiation rather than providing evidence of neuroendocrine differentiation. We emphasize the need for a comprehensive knowledge of the normal morphological variations within a tissue before attempting to interpret its tumours.

Distribution of dense core granules in normal, benign and malignant breast tissue

Specific immunostaining of p21 ras protein by the well-characterized pan-ras antibody Y13-259 is achieved in paraffin sections of human and animal tissues fixed in periodate-lysine-paraformaldehyde-dichromate (PLPD). Intensity of staining is as good as in cryostat sections, with superior histological detail. Localization to plasma membrane is demonstrated in rodent cells genetically manipulated to express abundant p21 ras (the FHO5T1 cell line), both in preparations suspended in agar after culture in vitro and in those growing as tumour in vivo. Strong positive staining is observed in neoplasms of human breast and colon, tissues in which there is independent evidence of elevated ras gene expression. The superior morphology afforded by this technique allows clear characterization of p21 ras expression in small premalignant lesions for which other methods of detection of oncogene expression are not appropriate.

T. J. Anderson

Papers

Radial scars of benign and malignant breasts: comparative features and significance.

Myofibroblast activity of radial scars

Ras p21 in breast tissue: associations with pathology and cellular localisation.

Distribution of dense core granules in normal, benign and malignant breast tissue

Optimal preservation of p21 ras immunoreactivity and morphology in paraffin-embedded tissue.