Biomedical subjects

B S Shoker

Publications and source records attributed to B S Shoker.

10 recordsLinked to original sources

PubMed2003

Angiogenesis and invasive recurrence in ductal carcinoma in situ of the breast.

The development of an invasive recurrence following treatment for ductal carcinoma in situ (DCIS) converts a non-fatal disease to one associated with mortality. To date, no pathological or molecular features have been found to predict for the type of recurrence. Previous studies have suggested that in DCIS angiogenesis may be an important factor in determining the transformation from in situ to invasive carcinoma. We looked at 355 cases of DCIS and found that 32 had subsequently developed recurrent disease. In these 32 cases and in matched controls, periductal vascular density was determined using morphometry and anti-endothelial antibodies, von Willebrand factor (vWF) and CD34. Vascular density was related to the risk of both invasive and in situ recurrence. Normal lobules at least 2 mm away were used as controls. Differences in the phenotype of individual blood vessels was detected by performing dual staining immunofluorescence on selected cases. The microvessel density (MVD), as detected with the CD34 antibody, was higher around foci of DCIS than around normal breast lobules (P=0.001). Furthermore, it was significantly higher in cases of DCIS that recurred (P<0.0001). The findings with the vWF antibody were less clear cut and suggested a trend in decreasing MVD with increasingly aggressive disease. Dual immunofluorescence staining shows that the increase in MVD seen around DCIS is due to an increase in CD34+/vWF-blood vessels. An increase in CD34+/vWF-of blood vessels may be able to predict cases of DCIS that are at a high risk of developing a recurrence.

Aged↗

PubMed2003

Thymidine phosphorylase expression and stromal vascularity in ductal carcinoma in situ of the breast.

AIMS: Periductal angiogenesis in ductal carcinoma in situ is associated with an increased risk of subsequently developing a recurrence. This study aimed to (1) identify the relation between periductal and stromal vascularity and recurrence and (2) determine whether thymidine phosphorylase (TP) is associated with angiogenesis or recurrence in ductal carcinoma in situ (DCIS). METHODS: Twenty cases of DCIS that did not subsequently recur, 20 that developed a subsequent in situ recurrence, and 12 that developed a subsequent invasive recurrence were investigated. Periductal and stromal (hotspot) microvessel density were determined quantitatively using antibodies to CD34 and von Willebrandt factor (vWF). TP expression by DCIS was assessed semiquantitatively using the H score method. RESULTS: Stromal and periductal microvessel density assessed by anti-vWF gave similar mean values, and showed a strong positive correlation. When angiogenesis was assessed with anti-CD34 this association was lost. Not only were the mean values for both types of microvessel density higher than those obtained with anti-vWF, but the periductal microvessel density was significantly greater than the stromal microvessel density. TP expression was associated with stromal microvessel density assessed with anti-vWF, but not with anti-CD34. TP expression was not related to recurrence. No significant difference was identified in TP expression or stromal vascularity in DCIS between cases that recurred as DCIS and those that recurred as invasive carcinoma. CONCLUSIONS: Recurrent in situ or invasive disease after excision of DCIS does not appear to be related to stromal microvessel density or to TP expression by DCIS cells.

Adult↗

PubMed2002

Vascular density and phenotype around ductal carcinoma in situ (DCIS) of the breast.

Up to 50% of recurrences of ductal carcinoma in situ of the breast are associated with invasive carcinoma but no pathological or molecular features have yet been found to predict for the development of invasive disease. For a tumour to invade, it requires the formation of new blood vessels. Previous studies have described a vascular rim around ducts involved by ductal carcinoma in situ, raising the possibility that the characteristics of periductal vascularisation may be important in determining transformation from in situ to invasive disease. Periductal vascular density and phenotype were determined using morphometry and a panel of anti-endothelial antibodies (von Willebrand factor, CD31, CD141 and CD34) and related to the presence of invasive carcinoma and other histological features. Compared to normal lobules, pure ductal carcinoma in situ exhibited a greater density of CD34+ and CD31+ vessels but a decrease in those that were immunopositive for vWF, indicating a difference in phenotype and in density. Ductal carcinoma in situ associated with invasive carcinoma showed a profile of vascular immunostaining similar to that of pure ductal carcinoma in situ but there were significantly greater numbers of CD34+ and CD141+ vessels and fewer staining for vWF. There was a significant negative correlation between vascular density and both the cross-sectional areas of the ducts involved and the extent of the necrosis of the tumour they contained. A correlation between vascular density and nuclear grade was also noted, being highest in the intermediate grade. The greater density of CD34+ and CD141+ vessels around ductal carcinoma in situ associated with invasive carcinoma could reflect a greater predisposition to invade but a direct effect of co-existent invasive carcinoma cannot entirely be ruled out in the present study. The relationship between vascular density, grade, duct size and nuclear grade suggests that periductal angiogenesis increases with tumour growth rate but is unable to keep pace with the most rapidly growing lesions.

Antigens, CD34↗

PubMed2001

Immunodetectable cyclin D(1)is associated with oestrogen receptor but not Ki67 in normal, cancerous and precancerous breast lesions.

Cyclin D1 is associated with cell cycle regulation and has more recently been shown to stimulate the transcriptional functions of the oestrogen receptor (ER). Furthermore, in normal breast there is a negative association between expression of ER and the proliferation marker Ki67 indicating that either ER positive cells are non-dividing or that the receptor is down-regulated as cells enter cycle. This important relationship breaks down in many ER-positive cancers and precancerous breast lesions where the receptor is often detected on proliferating cells. The aims of the present study were to determine the interplay between ER, Ki67 and cyclin D(1)in individual cells within the spectrum of human breast lesions ranging from normal to invasive carcinoma by using dual staining immunofluorescence. We found that in normal breast there was a strong positive association between ER and cyclin D(1)expression. In contrast there was a strong negative association between cyclin D(1)and Ki67 expression. Similar findings were seen for the other precancerous and cancerous breast lesions. Thus immunodetectable cyclin D(1)within individual cells does not appear to be associated with cell cycle progression in the benign or malignant breast but instead may have important interactions with ER.

Antibodies, Monoclonal↗

PubMed2001

Subgroups of non-atypical hyperplasia of breast defined by proliferation of oestrogen receptor-positive cells.

In normal breast, there is a negative association between expression of oestrogen receptor (ER) and the proliferation marker Ki67, indicating that ER-positive (ER+) cells do not divide, or that the receptor is down-regulated when they do so. However, dual staining has been found in carcinomas and precancerous lesions, indicating that abnormal regulation of ER could be important in breast tumourigenesis. ER expression in relationship to cell proliferation was studied in 241 foci of hyperplasia of usual type (HUT), a lesion associated with a 1.5 to 2-fold increase in risk of developing breast cancer. Dual label immunofluorescence was employed, using the antibodies 1D5 and Ki67. Two hundred and thirteen foci of HUT contained ER+ cells, which were distributed singly or contiguously and increased with age. Most foci resembled normal breast, but 51 contained dual labelled cells, which did not increase with age. Some of these foci exhibited few, scattered ER+ cells with greater proliferation rates than the ER-negative (ER-) cells, whereas others contained many, contiguous ER+ cells, whose rate of proliferation was less than that of the ER- cells. The latter picture is similar to that which has previously been reported in atypical ductal hyperplasia and ductal carcinoma in situ. The first type of HUT may evolve into the second. The proportion of Ki67+ cells that was ER+ was similar in both types, suggesting a homeostatic mechanism that slows the proliferation of ER+ cells as they become confluent. Overriding this inhibition may be crucial in further progression. Non-atypical hyperplasia is thus heterogeneous in ER expression and proliferation and a significant proportion exhibit abnormal regulation of ER. These findings could have implications for pathological diagnosis, risk assessment, and prophylactic hormonal therapy.

Adult↗

PubMed2000

Abnormal regulation of the oestrogen receptor in benign breast lesions.

BACKGROUND: In normal breast tissue the oestrogen receptor (ER) and the proliferation associated antigen Ki67 are negatively associated, indicating that ER+ cells are non-dividing, or that the receptor is downregulated as cells enter cycle. This relation is completely or partially lost in many ER+ breast cancers and in in situ proliferations associated with an increased cancer risk, where coexpression of the two markers is often found. AIMS: To determine whether similar changes can be identified in other risk associated breast lesions. PATIENTS/METHODS: Paraffin wax blocks from 12 cases of lactational change, 21 apocrine metaplasias, 22 duct ectasias, 20 sclerosing adenosis, 20 fibroadenomas, 19 phyllodes tumours, 20 radial scars, 21 papillomas (15 solitary and six multiple), 15 gynaecomastias, and nine postmortem male breast tissues were retrieved. Immunohistochemistry was used to determine the expression of ER and dual labelling immunofluorescence was used to detect cells expressing both ER and Ki67. RESULTS: Increased numbers of ER+ cells were seen in sclerosing adenosis, radial scars, papillomas, fibroadenomas, and phyllodes tumours but not in apocrine cysts (where no ER+ cells were detected) or duct ectasia (where normal numbers were found). As in the normal breast, the proportion of ER+ cells increased with age in all lesions with the exception of fibroadenomas. Coexpression of ER and Ki67 was found in an increased proportion of cells of all risk associated lesions studied. ER+ cells were less likely to be dividing than ER- cells in all cases, although this was significant only for sclerosing adenosis. The data on sclerosing adenosis, radial scars, papillomas, and fibroadenomas are comparable with those reported previously in hyperplasia of usual type, whereas those in duct ectasia are similar to those of the normal breast. The findings in all lesions, however, differed from those in ductal carcinoma in situ, where proportions of ER+ and ER+/Ki67+ cells are higher and the relation between ER+ cell numbers and age is lost. Thus, the nature and degree of dysregulation of ER in benign breast lesions is broadly in accordance with the degree of risk of developing breast cancer with which they are associated. In gynaecomastia, the proportions of ER+ and ER+/Ki67+ cells were comparable with those seen in benign female breast lesions, but changes with age were not observed. However, the changes in gynaecomastia were similar to those seen in normal male breast. CONCLUSION: These findings are in keeping with the contention that the dissociation of ER and Ki67 expression is a very early change in the pathway to many breast cancers. However, this change might only have preneoplastic importance in the hormonal milieu of the female breast.

Adult↗

PubMed1999

Oestrogen receptor expression in the normal and pre-cancerous breast.

As oestrogen is associated with most of the epidemiological risk factors for breast cancer, the number and distribution of oestrogen receptor positive (ER+) cells could have a bearing on the development of the disease. ER+ cells were thus studied in the normal breast and in the spectrum of in situ proliferations which range from non-atypical hyperplasia to in situ carcinoma and are associated with different levels of risk for developing breast cancer. In the normal pre-menopausal breast, ER+ cells comprised the minority and were distributed singly, being surrounded by oestrogen receptor negative (ER-) cells. ER+ cells showed a statistically significant increase with age, reaching a plateau after the menopause, and the increase was associated with a tendency for positive cells to become contiguous in patches of variable size. A small proportion of lobules showing involutional change comprised over 90 per cent ER+ cells. The significance of this feature is not clear but no evidence was found that it was pre-cancerous. The percentage of ER+ cells was slightly increased in hyperplasia of usual type (non-atypical hyperplasia, HUT) and the relationship to age was maintained. The staining pattern was variable; in some lesions ER+ cells were surrounded by ER- cells whereas in others there were contiguous groups of positive cells sometimes accounting for more than 90 per cent of cells in the lesion. In contrast, all cases of atypical ductal hyperplasia (ADH), lobular in situ neoplasia (LIN) and ductal carcinoma in situ (DCIS) exhibited positivity of contiguous cells accounting for the majority in the lesions. Furthermore, the relationship between ER+ cell numbers and age was lost in these lesions, indicating autonomy of ER expression or of proliferation of cells expressing the receptor. It is hypothesized that this dysregulation of receptor expression or of ER+ cell numbers at the ADH stage may be the precursor of abnormal expression of cyclins and other cell cycle control proteins which have been shown first to appear in DCIS.

Adult↗

PubMed1999

Estrogen receptor-positive proliferating cells in the normal and precancerous breast.

Recently it has been shown that epithelial cell expression of the estrogen receptor (ER) and that of the proliferation-associated marker Ki-67 are almost mutually exclusive in the normal premenopausal human breast but that coexpression frequently occurs in estrogen receptor-positive (ER+) breast cancers. This coexpression may indicate disordered expression of ER in the cell cycle or failure to suppress division of ER+ cells and could be important in neoplastic transformation. The purpose of this study was to determine whether in situ proliferations known to be associated with different levels of risk for developing breast cancer contain these coexpressing cells and, if so, the stage at which they occur. We found that ER+ proliferating cells were rare in premenopausal lobules but increased with age in the normal breast. There was no difference in nonlesional tissue between cancerous and noncancerous breasts. The percentage of dual-expressing cells was significantly increased, however, in all of the in situ proliferations and correlated positively with the level of risk of developing breast cancer. We suggest that development of at least some human breast cancers is associated with increasing failure to down-regulate ER as cells enter the cycle or to suppress division of ER+ cells. The mechanism may involve the loss of a tumor suppressor gene.

Breast↗

PubMed1999

DCIS grading schemes and clinical implications.

The frequency with which ductal carcinoma in situ (DCIS) is detected has increased greatly since the introduction of mammographic screening. The number of treatment options has also increased and mastectomy has been extensively replaced by local excision with or without radiotherapy. DCIS is generally unicentric, as evidenced by the rarity with which it is bilateral and the location of recurrences at the site of previous surgery. Complete excision is thus curative but assessing adequacy of excision is beset with significant technical problems and consequently margin involvement does not correlate very well with the presence of residual disease in the breast or the development of clinical recurrence. Lesion size is related to recurrence but is also often difficult to measure. At the histological level, DCIS is a heterogeneous group of proliferations varying in cytological and architectural features, some of which are related to clinical outcome. The traditional method of classification was by growth pattern but was found to lack reproducibility and prognostic power. As a consequence, several new classifications have been proposed in recent years. Some have been assessed more rigorously than others in terms of the consistency with which they can be applied and their ability to predict clinical outcome. There is strong evidence, however, that nuclear grade is the best predictor of recurrence and the time scale over which it is likely to occur although presently it can be determined with only fair to moderate consistency. Necrosis is also a useful feature when used in combination with nuclear grade, but specifically recognizing a comedo pattern appears to have little clinical value and is associated with significant diagnostic inconsistency. No histological features to date have been found to predict the development of invasive disease. Histological assessment alone is insufficient to determine how patients with DCIS should be managed, which should also take account pathological assessment of excision margins and lesion size as well as radiological and clinical features.

Breast Neoplasms↗

PubMed1996

Crohn's disease, calculi and cancer: a report of two cases.

We describe two patients with long-standing Crohn's disease in which small bowel obstruction occurred secondary to a combination of small bowel enteroliths and stricture formation. In both patients some of the strictures were infiltrated by small bowel adenocarcinoma.

Adenocarcinoma↗