p53 antigen loss in stored paraffin slides.
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Biomarkers, Tumor↗
Biomedical subjects
S J Schnitt
Publications and source records attributed to S J Schnitt.
Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer.
Solid tumors must induce a vascular stroma to grow beyond a minimal size, and the intensity of the angiogenic response has been correlated with prognosis in breast cancer patients. Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a secreted protein that has been implicated in tumor-associated angiogenesis. Vascular permeability factor directly stimulates endothelial cell growth and also increases microvascular permeability, leading to the extravasation of plasma proteins, which alter the extracellular matrix in a manner that promotes angiogenesis. To determine whether VPF has a role in breast cancer, we used in situ hybridization to study VPF mRNA expression in normal breast tissue (13 specimens), comedo-type ductal carcinoma in situ (DCIS) (four specimens), infiltrating ductal carcinoma (12 specimens), infiltrating lobular carcinoma (two specimens), metastatic ductal carcinoma (three specimens) and metastatic lobular carcinoma (one specimen). Vascular permeability factor mRNA was expressed at a low level by normal duct epithelium but was expressed at high levels in tumor cells in all cases of comedo-type DCIS, infiltrating ductal carcinoma, and metastatic ductal carcinoma. In contrast, VPF mRNA was not expressed at high levels in infiltrating lobular carcinoma. We also used in situ hybridization to study the expression of two recently described endothelial cell surface VPF receptors, flt-1 and kdr. Vascular permeability factor receptor mRNA was strongly expressed in endothelial cells of small vessels adjacent to malignant tumor cells in DCIS, infiltrating ductal carcinoma, and metastatic ductal carcinoma. In contrast, no definite labeling for receptor mRNA was detected in infiltrating lobular carcinoma or nonmalignant breast tissue. The intense expression of VPF mRNA by breast carcinoma cells and of VPF receptor mRNA by endothelial cells of adjacent small blood vessels provides strong evidence linking VPF expression to the angiogenesis associated with comedo-type DCIS, infiltrating ductal, and metastatic ductal breast carcinoma.
Breast Neoplasms↗
The relationship between microscopic margins of resection and the risk of local recurrence in patients with breast cancer treated with breast-conserving surgery and radiation therapy.
BACKGROUND: The relationships among the involvement of tumor at the final margins of resection, the presence of an extensive intraductal component (EIC), and the risk of local recurrence are important considerations in patients treated with conservative surgery and radiation therapy for early stage breast cancer but have not been defined adequately. METHODS: Between 1982 and 1985, 885 patients were treated for clinical Stage I or II invasive breast cancer. The study population was limited to 181 patients with an infiltrating ductal carcinoma who received a radiation dose to the surgical site of 60 Gy or greater, whose final microscopic margins of resection were evaluable, and who had at least 5 years of follow-up. A positive margin was defined as tumor present at the inked margin of resection, a close margin as tumor within 1 mm of the inked margin, and a negative margin as no tumor within 1 mm of the inked margin. A focally positive margin was defined as tumor at the margin in three or fewer low-power fields. In 157 patients (87%), the tumor was evaluable for the presence or absence of an EIC. The median follow-up was 86 months. RESULTS: In 12 of 181 patients (7%), a recurrence developed at or near the primary site (true recurrence/marginal miss [TR/MM]) within 5 years. The 5-year rate of TR/MM (with 95% confidence intervals) among patients with negative, close, focally positive, and more than focally positive margins was 0% (0-4%), 4% (0-20%), 6% (1-17%) and 21% (10-37%), respectively. Patients with positive margins also were more likely to have a distant failure within 5 years (14%, 8%, 25%, and 32% in the four groups, respectively). However, patients with positive margins more often had positive axillary lymph nodes than patients with negative or close margins (59% vs. 38%, P < 0.02). The 5-year rate of TR/MM was 20% for patients with an EIC-positive tumor and 7% for patients with an EIC-negative tumor. However, among the 127 patients with an EIC-negative tumor, the 5-year rate of TR/MM was less than 10% in all margin groups. Among the 30 patients with an EIC-positive tumor, the 5-year rate of TR/MM was 0% when margins were negative or close but 50% when margins were more than focally positive. CONCLUSIONS: These results provide support for the use of breast-conserving surgery and breast irradiation in all patients with uninvolved margins, whether the tumor is EIC-positive or EIC-negative. This study suggests that breast-conserving therapy (including a radiation boost to the primary site) also may be a reasonable option for some patients with an EIC-negative tumor and margin involvement.
Breast↗
Microvessel density and distribution in ductal carcinoma in situ of the breast.
BACKGROUND: Prior studies have suggested that microvessel density is an important prognostic factor in invasive breast cancer. However, the extent and distribution of microvessels in association with ductal carcinoma in situ (DCIS) have not been well defined. PURPOSE: Our goal was to determine the density and distribution of stromal microvessels in DCIS and to investigate the relationships among microvessel density, histopathologic features, HER2/neu oncogene expression, and tumor proliferation rate. METHODS: Of 61 consecutive cases of DCIS identified from hospital pathology reports, 55 cases were evaluated. Breast biopsy specimens had been preserved in paraffin blocks for each DCIS case. Histologic sections of formalin-fixed, paraffin-embedded tissue were stained with hematoxylin-eosin and immunostained for factor VIII-related antigen, the HER2/neu oncoprotein, and the proliferative-associated antigen detected by the Ki-S1 antibody. Factor VIII-stained sections from each case were independently examined by two pathologists and overall tumor-associated stromal microvessel density was scored semiquantitatively on a 1+ to 3+ scale by each observer. Quantitative microvessel counts of DCIS-associated stromal microvessel density were performed. The presence or absence of a cuff of microvessels in immediate apposition to the basement membrane of involved spaces was also evaluated. RESULTS: A variable number of microvessels were found to be present in a diffuse pattern surrounding spaces involved with DCIS. Semiquantitative microvessel scores were 2+ in the majority of cases (53%); 22% of cases were 1+, and 25% were 3+. Quantitative microvessel counts ranged from 17 to 80 vessels per 100x field (0.45 mm2), with a mean +/- SD of 42.9 +/- 16.6. Comedo-type lesions were significantly (P = .004) more often associated with 3+ microvessel density than non-comedo-type lesions by semiquantitative assessment. As determined by both semiquantitative and quantitative analysis, respectively, the presence of prominent microvessel density was significantly associated with marked stromal desmoplasia (P = .05 and P = .04), HER2/neu expression (P = .03 and P = .0002), and high Ki-S1 proliferation index (P = .05 and P = .01). Vascular cuffing around involved spaces was identified in 21 of the 55 cases (38%) and was not significantly associated with histologic features, HER2/neu expression, or Ki-S1 proliferation index. CONCLUSIONS: DCIS of the breast is characterized by two patterns of stromal microvessels. The first pattern is a diffuse increase in stromal microvessels surrounding involved spaces. This pattern is particularly prominent in comedo-type lesions with marked stromal desmoplasia. The second pattern is microvessel cuffing of involved spaces that is present in only a minority of cases and appears unrelated to histologic features evaluated, including DCIS subtype.
Breast Neoplasms↗
Histologic analysis of directional coronary atherectomy samples. A review of findings and their clinical relevance.
Histologic analysis of atherectomy samples from > 400 patients who received directional coronary atherectomy at 3 separate institutions disclosed 2 major categories of tissue: atherosclerotic plaque (with or without thrombus) and intimal proliferation (hyperplasia, with or without thrombus). The predominant tissue type in atherectomy samples from native, primary, or de novo coronary artery stenoses was atherosclerotic plaque. The predominant tissue type in atherectomy samples from restenosis lesions (prior balloon angioplasty, atherectomy, or both) was intimal proliferation with variable amounts of atherosclerotic plaques (with or without thrombus). Deep vessel wall components (media, adventitia) were identified at varying frequencies. The clinical relevance of atherectomy tissue is reviewed.
Atherectomy, Coronary↗
Chest wall recurrence of ductal carcinoma in situ of the breast after mastectomy.
BACKGROUND: Optimal management of ductal carcinoma in situ (DCIS) of the breast is a problem that is occurring with greater frequency, mostly because of the increasing use of mammographic screening. The traditional role of mastectomy for DCIS has been challenged by breast-conserving procedures. Regardless of the method of treatment used, local control with complete tumor eradication is the major goal in the management of DCIS. METHODS AND RESULTS: A patient is reported in whom DCIS recurred in residual breast tissue in the chest wall several years after mastectomy. CONCLUSIONS: Chest wall recurrence of DCIS within residual breast tissue probably is caused by failure of tumor excision, new primary tumor, or both. This observation underscores that (1) mastectomy may not result in complete removal of breast tissue, and (2) this residual breast tissue may be the substrate for "chest wall recurrences" in some patients with breast cancer.
Adult↗
The increasing prevalence of benign proliferative breast lesions in Japanese women.
BACKGROUND: Although the increasing incidence of breast cancer in Japan has been well-documented, the possibility that there also has been an increase in the frequency of benign proliferative breast disease in Japanese women has not been previously studied. METHODS: The authors compared the histologic findings in a series of 266 consecutive benign breast biopsy specimens from 1974 to 1975 (Group I) to those in a series of 266 similar biopsy specimens accessioned at the same institution in Japan one decade later (i.e., 1984 to 1985; Group II). The extent of sampling was similar in both groups. The specimens were categorized as showing nonproliferative lesions, proliferative lesions without atypia, or atypical hyperplasia using the criteria of Dupont and Page. RESULTS: Proliferative lesions without atypia were significantly more common in biopsy specimens from Group II than those from Group I (16.2% versus 9%; P = 0.01). Although atypical hyperplasias were twice as common in Group II as in Group I, these lesions were uncommon in both groups (2% in Group II versus 1% in Group I, p = NS). The differences in pathologic findings between the two groups were most evident in younger women. For patients younger than 40 years of age, the prevalence of proliferative lesions (with or without atypia) was 18% for Group II and 6% for Group I (P = 0.003). For patients 40 years of age or older, proliferative lesions were seen in 17% of patients in Group II and 13% in Group I (P value, not significant). CONCLUSIONS: The frequency of benign proliferative breast lesions in Japanese women, particularly among women younger than 40 years of age, is increasing. These observations are consistent with the results of previous studies in North America that have demonstrated a relationship between benign proliferative breast lesions and the development of breast cancer.
Adolescent↗
Frequency and consequences of intimal hyperplasia in specimens retrieved by directional atherectomy of native primary coronary artery stenoses and subsequent restenoses.
Although intimal hyperplasia is a frequent occurrence after arterial interventional procedures, the overall frequency and significance of intimal hyperplasia in primary coronary lesions has not been previously addressed. The incidence of intimal hyperplasia was therefore examined using standard light microscopy in specimens obtained from native coronary arteries of patients undergoing directional coronary atherectomy. The associated clinical history, angiographic results and clinical outcomes were also tabulated. Intimal hyperplasia was identified in 51 of 55 patients (93%) treated with directional coronary atherectomy for restenosis after a prior intervention. These restenosis lesions had less acute gain in lumen diameter after directional coronary atherectomy, a smaller late lumen diameter, more severe late stenosis (p < 0.04), and tended to have more restenosis defined as late stenosis > or = 50% (restenosis rate 40% for prior restenosis vs 26% for primary lesions). Surprisingly, however, intimal hyperplasia was also identified in 45 of 102 (44%) primary stenoses. Primary lesions (n = 45) with intimal hyperplasia were more likely to occur in younger patients and in the left anterior descending artery than were either primary lesions without intimal hyperplasia (n = 57) or prior restenosis lesions. There were otherwise no differences in the baseline characteristics, angiographic findings or clinical outcome of primary lesions with or without intimal hyperplasia (restenosis rate 28 and 24%, respectively). The event-free survival (72% at 12 months) was similar in all 3 groups. Thus, even though intimal hyperplasia is an almost universal finding in restenosis lesions, intimal hyperplasia is not specific for restenosis since histologically identical hyperplasia may be found in nearly half of primary coronary artery stenoses.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Benign breast disease. Resolved and unresolved issues.
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Breast↗
Clinical and histologic aspects of proliferative and non-proliferative benign breast disease.
It has been known for years that benign breast disease is correlated with an increased risk for the development of breast cancer. Over the years, there have been many studies linking histological changes in benign breast biopsies and subsequent risk of breast cancer. In many of these reports, there was no attempt to standardize criteria and often the patient population under study was relatively small. Over the past decade, three large groups have agreed to use the same definition of benign changes and a unified set of criteria for the diagnosis of these lesions. The results from these three groups [Nashville, Nurses Health Study (NHS), and the Breast Cancer Detection Demonstration Project (BCDDP)] are strikingly similar. All three studies reported that if the biopsy revealed proliferative disease without atypia, the subsequent risk was approximately 1.5x. If the biopsy revealed atypical hyperplasia (AH), the risk was approximately 4.5x. If the patients with AH had a family history of breast cancer, their subsequent risk approached that of patients with in situ carcinoma (approximately 8-10x). In addition to family history, menopausal status seemed to play a role. In patients with AH, the breast cancer risk was much higher in pre- than post-menopausal patients. While the classification scheme proposed by Page and co-workers is useful in assigning different levels of risk to women with benign breast disease, it has not been universally accepted. Our major short-term goal should be to encourage pathologists to apply these criteria in a reproducible manner in their daily practice.(ABSTRACT TRUNCATED AT 250 WORDS)
Breast Diseases↗
Myocardial fibrin deposition in experimental viral myocarditis that progresses to dilated cardiomyopathy.
Myocardial fibrosis is a characteristic late feature in cases of viral myocarditis that progress to dilated cardiomyopathy. However, the pathogenesis of the myocardial fibrosis in such cases is unknown. Prior studies have shown that in healing wounds and tumor stroma generation, interstitial fibrin deposition precedes the development of fibrosis. Therefore, interstitial fibrin deposition in the myocardium was investigated in a murine model of myocarditis in which dilated cardiomyopathy develops. Inbred male C3H/He mice inoculated with coxsackievirus B3 were killed 0, 3, 7, 14, 21, 30, and 60 days after infection. Paraffin sections of hearts were stained with hematoxylin-eosin, Masson's trichrome stain, and antibodies to fibrinogen/fibrin by use of an immunoperoxidase technique. Pretreatment of all mice with anticoagulants and antifibrinolytics 5 minutes before death was used to prevent artifactual fibrin deposition and fibrinolysis during tissue manipulation. Tissue fixation in formalin supplemented with acetic acid served to extract non-cross-linked fibrin, fibrinogen, and fibrinogen and fibrin degradation products, thus ensuring that clotted and cross-linked fibrin was the major immunoreactant. Myocardial fibrin deposition and fibrosis were each quantitated by computer-assisted image analysis. Myocardial fibrin deposition first appeared on day 3, was maximal on day 14, and disappeared by day 30. Conversely, myocardial fibrosis was not detectable until day 14 and was maximal at day 60. Thus, as in healing wounds and developing tumor stroma, fibrin deposition preceded fibrosis in this murine model of myocarditis that progresses to dilated cardiomyopathy.
Animals↗
Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer.
PURPOSE: The prognosis and factors that influence prognosis following salvage mastectomy in patients with recurrence in the treated breast after conservative surgery (CS) and radiation therapy (RT) were investigated. MATERIALS AND METHODS: A total of 1,593 patients with stage I or II invasive breast cancer were treated following gross total excision of the tumor at the Joint Center for Radiation Therapy (JCRT) between 1968 and 1985. One hundred sixty-six of the 1,593 (10%) had subsequent recurrence in the breast. Of these, 123 had salvage mastectomy and constitute the study population. The recurrent tumor was predominantly invasive in 99 patients, noninvasive in 14, and focally invasive in 10. Following mastectomy, chemotherapy or hormonal therapy was administered to 29 patients. The median follow-up time was 39 months after salvage mastectomy. RESULTS: The 5-year actuarial rate of further local or distant relapse for the entire group was 41%. None of the 24 patients with focally invasive or noninvasive tumors had a subsequent relapse. In comparison, the 5-year actuarial rate of further relapse in the 99 patients with a predominantly invasive recurrence was 52% (P = .001). The method of detection of the recurrence, the age of the patient at initial diagnosis, the disease-free interval, and the location of the recurrence in the breast were not found to have a statistically significant association with the risk of further relapse. CONCLUSION: We conclude that the histology of the recurrent tumor is an important prognostic factor for the risk of further relapse. Patients with purely noninvasive or focally invasive tumors have an excellent prognosis following salvage mastectomy. In contrast, patients with predominantly invasive tumors are at substantial risk for further relapse.
Adult↗
Contralateral breast cancer: clinical characteristics and impact on prognosis.
PURPOSE: To determine the characteristics of patients with unilateral breast cancer who subsequently develop contralateral breast cancer (CBC), to assess their prognosis relative to patients who do not develop a CBC, and to assess the feasibility of using conservative surgery (CS) and radiotherapy (RT) to treat CBC. MATERIALS AND METHODS: Of 1,624 women treated with CS and RT for unilateral stage I or II breast cancer at the Joint Center for Radiation Therapy, 77 developed an invasive CBC. Sixty-two CBCs were treated with CS and RT. The median follow-up duration was 95 months from the time of initial breast cancer diagnosis, and 63 months from CBC diagnosis. RESULTS: The cumulative actuarial rate of CBC was 7.0% at 10 years, and the annual incidence rate for CBC was relatively constant. Young age predicted for CBC. When age was analyzed by decade the relative risk (RR) for older patients compared with younger patients was 0.79 (95% confidence interval [CI], 0.62 to 1.01). The presence of lobular carcinoma in situ (LCIS), higher tumor stage, and lack of adjuvant systemic therapy also predicted for CBC with borderline significance. Multivariate analyses showed that CBC was associated with a statistically significant greater likelihood of local recurrence (LR) or distant recurrence (RR, 1.68; 95% CI, 1.03 to 2.71), and distant-only recurrence (RR, 2.17; 95% CI, 1.28 to 3.69). Among assessable patients treated with bilateral RT, 28 of 31 ipsilateral and 11 of 11 contralateral breasts had an excellent or good overall cosmetic outcome at 5 years, and treatment-related complications were minimal. CONCLUSION: We conclude that (1) young age is associated with a greater likelihood of CBC, (2) patients who develop a CBC have a greater subsequent risk of distant relapse as compared with patients without CBC, and (3) it is feasible to deliver sequential nonoverlapping bilateral RT without compromising the cosmetic outcome or increasing complications.
Adult↗
Mammary ducts in the areola: implications for patients undergoing reconstructive surgery of the breast.
The use of selective excision of the nipple with preservation of the areola ("nipple coring") has been advocated for patients undergoing subcutaneous or total glandular mastectomy. This is based on the assumption that all the mammary ducts in the nipple-areola complex are located in the nipple and that the areola is devoid of mammary ductal tissue. To investigate this issue, we performed nipple coring on eight consecutive mastectomy specimens, excised the areolas, and submitted them in their entirety for histologic examination. Mammary ducts identical in appearance to extralobular ducts in the breast parenchyma were identified in the dermis of the areola in all eight cases. These ducts were present throughout the areola, including the most peripheral aspects. We conclude that mammary ducts are a normal component of the areolar dermis and that nipple coring does not result in the removal of all mammary ductal tissue from the nipple-areola complex. This observation should be taken into consideration by reconstructive surgeons considering preservation of the areola in patients undergoing subcutaneous or total glandular mastectomy.
Adult↗
What to do about mammographically detected ductal carcinoma in situ?
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Breast Neoplasms↗
Long-term results of directional coronary atherectomy: predictors of restenosis.
OBJECTIVES: This study was performed to obtain better understanding of the long-term clinical efficacy of directional coronary atherectomy. BACKGROUND: Although this procedure yields favorable acute results, its acceptance has been limited by the perception that late results (that is, freedom from restenosis) are no better than those of conventional angioplasty. METHODS: A total of 225 atherectomies performed in 190 patients between August 1988 and July 1991 were examined. Minimal lumen diameter of the treated segments was measured on angiograms obtained before, after and 6 months after intervention. RESULTS: Although most lesions (97%) had one or more characteristics predictive of unfavorable short- or long-term results after conventional angioplasty, atherectomy was successful in 205 lesions (91%) with a mean residual stenosis of 7 +/- 16%. After subsequent balloon angioplasty in 16 unsuccessful atherectomy attempts, procedural success was 98%. There were no deaths or Q wave myocardial infarctions, and one patient (0.5%) underwent emergency bypass surgery. Six-month angiographic follow-up was obtained in 77% of the eligible patients. The overall angiographic restenosis rate was 32%. Predictors of a lower restenosis rate included a postprocedure lumen diameter > 3 mm (24% vs. 39%, p = 0.047), serum cholesterol < or = 200 mg/dl (18% vs. 40%, p = 0.018) and recent myocardial infarction (16% vs. 37%, p = 0.034). Life-table analysis showed a 2% mortality rate and a 26% incidence of other events (myocardial infarction, repeat revascularization) within the 1st year. The annual 5% mortality rate and 7% incidence of other events during years 2 and 3 were related in large part to the existence or progression of disease at other locations. CONCLUSIONS: Six-month angiographic follow-up of patients who underwent directional coronary atherectomy during the 1st 3 years of our experience shows an overall restenosis rate of 32%, with lower rates in patients with a postatherectomy lumen diameter > or = 3 mm, cholesterol level < or = 200 mg/dl or a recent myocardial infarction. Few if any events relating to the site of atherectomy developed after the 1st year of follow-up.
Atherectomy, Coronary↗
Acute and long-term outcome of narrowed saphenous venous grafts treated by endoluminal stenting and directional atherectomy.
Angioplasty of the narrowed saphenous vein bypass grafts remains a difficult challenge. Over a 37-month period at this institution, 119 of 176 interventions (68%) on saphenous vein grafts (average age 8.3 years from bypass surgery to graft intervention) were performed using either directional coronary atherectomy (n = 35) or Palmaz-Schatz intracoronary stents (n = 84), representing 37% of all stents and 15% of all atherectomies during the study period, respectively. Of the 57 saphenous vein graft lesions treated with conventional balloon angioplasty during this period, 49 (86%) had 1 or more contraindications to stenting or directional atherectomy (thrombus, total occlusion, reference vessel less than 3 mm in diameter). The acute success rate was 99% for stents (1 failure to dilate) and 94% for directional atherectomy (2 failures to cross the lesion with the atherectomy device). Lumen diameter increased from 0.9 to 3.6 mm (reference vessel 3.6) for stents, and from 0.9 to 3.5 mm (reference 3.8) for atherectomy (for all comparisons, p = not significant), with no major complications (abrupt or subabrupt closure, emergent coronary bypass surgery, death, or Q-wave myocardial infarctions). During the same time period 50 of 57 vein grafts (88%) rejected for stenting or atherectomy were dilated successfully by conventional balloon angioplasty, with 3 patients (5%) requiring emergent coronary bypass surgery. Angiographic follow-up was available for 50 of 64 eligible patients (78%).(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Estrogen receptor immunohistochemistry in carcinoma in situ of the breast.
Although estrogen receptor (ER) content and its clinical significance have been extensively evaluated in invasive breast cancer, ER expression in carcinoma in situ (CIS) of the breast and its correlates are less well understood. Thus, using an indirect immunoperoxidase technique and paraffin-embedded tissue, the authors studied ER expression in 100 breast tumors containing CIS with or without invasive carcinoma. The percentages of positive and of strongly positive nuclei were compared among histologic categories of CIS and between CIS and invasive carcinoma. The relationships between histologic features of CIS (cell size, nuclear pleomorphism, necrosis, extent of CIS) the patient's age, and the ER status of CIS also were evaluated. ER expression in pure CIS was compared with that of CIS with adjacent invasive carcinoma. Significant differences were observed between comedo CIS, which was frequently ER negative, and non-comedo and lobular CIS, which usually were positive. A predominance of large cells, independently from other features, was the best morphologic predictor of ER negative status in CIS. ER in CIS correlated with ER in invasive carcinoma in 98% of cases (r2 = 0.677). CIS without invasive carcinoma was more frequently ER weak or negative than CIS associated with invasive carcinoma. There was no difference in the overall percentage of nuclear staining in CIS of women of premenopausal versus postmenopausal age; however, a higher proportion of strongly positive cells occurred in the postmenopausal group. The authors conclude that the ER expression in CIS correlates with pathologic features of differentiation and is similar to that of invasive carcinoma.
Adult↗