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Background: Angiogenesis is a critical factor in the progression of solid tumors, including cervical cancers. The mechanisms responsible for angiogenesis in cervical neoplasia, however, are not well defined.Purpose: Our goal was to determine the relationship between angiogenesis and the expression of the angiogenic cytokine vascular permeability factor (VPF), also known as vascular endothelial growth factor, and its receptors in cervical neoplasia.Methods: Sixty-six cervical biopsy specimens were evaluated; among these, 16 samples were designated as benign, 17 as low-grade squamous intraepithelial lesions, 18 as high-grade squamous intraepithelial lesions, and 15 as invasive squamous cell carcinomas. Histologic sections immunostained for factor VIII-related antigen were evaluated quantitatively for microvessel density and for the presence of epithelial-stromal vascular cuffing. Sections were also evaluated for VPF messenger RNA (mRNA) expression by in situ hybridization.Results: VPF mRNA expression, epithelial-stromal vascular cuffing, and microvessel density counts were significantly increased in invasive carcinoma and in high-grade intraepithelial lesions as compared with low-grade intraepithelial lesions and benign squamous epithelium. Vascular cuffing and increased microvessel density counts were also significantly associated with increased VPF mRNA expression.Conclusions: These observations suggest that VPF is an important angiogenic factor in cervical neoplasia. [ABSTRACT FROM AUTHOR]

Context.—: Laboratories performing predictive marker testing for breast carcinoma are encouraged to compare patient results to published benchmarks., Objective.—: To collect expression rates for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) in invasive breast carcinoma from multiple laboratories., Design.—: Participants submitted data from up to 50 primary cases during the study period. Participants reported ER, PgR, and HER2 results in addition to demographic and histologic information. Participants also provided annual institution-level expression rates., Results.—: A total of 21 institutions submitted data for 687 cases. Aggregate positivity rates for ER and PgR were 85.6% and 75.1%, respectively. Receptor positivity rates were higher in well-differentiated (grade 1) tumors (ER, 97.4%; PgR, 88.0%) compared with moderately differentiated (grade 2) tumors (ER, 92.4%; PgR, 84.0%) and poorly differentiated (grade 3) tumors (ER, 61.8%; PgR, 48.0%). Expression rates were higher in postmenopausal women (ER, 87.2%) than premenopausal women (ER, 79.6%) and higher in lobular carcinomas (ER, 98.7%; PgR, 85.3%) than ductal carcinomas (ER, 84.1%; PgR, 74.5%). The aggregate HER2 positivity (score 3+) rate was 9.0%. The aggregate HER2 equivocal (score 2+) rate was 14.5%. Of 81 equivocal (score 2+) cases, 70 (86.4%) were nonamplified., Conclusions.—: The data from this study provide multi-institutional benchmark data to assist laboratories performing periodic comparisons as part of a quality management program. Overall expression rates were generally similar to those of other published reports, with the exception of the ER-negative and HER2-positive rates, both of which were somewhat lower., (© 2024 College of American Pathologists.)

Context.—: Knowledge of laboratory staff turnover rates are important to laboratory medical directors and hospital administrators who are responsible for ensuring adequate staffing of their clinical laboratories. The current turnover rates for laboratory employees are unknown., Objective.—: To determine the 3-year average employee turnover rates for clinical laboratory staff and to survey the types of institutional human resource practices that may be associated with lower turnover rates., Design.—: We collected data from participating laboratories spanning a 3-year period of 2015-2017, which included the number of full-time equivalent (FTE) staff members that their laboratories employed in several personnel and departmental categories, and the number of laboratory staff FTEs who vacated each of those categories that institutions intended to refill. We calculated the 3-year average turnover rates for all laboratory employees, for several personnel categories, and for major laboratory departmental categories, and assessed the potential associations between 3-year average all laboratory staff turnover rates with institutional human resource practices., Results.—: A total of 23 (20 US and 3 international) participating institutions were included in the analysis. Among the 21 participants providing adequate turnover data, the median of the 3-year average turnover rate for all laboratory staff was 16.2%. Among personnel categories, ancillary staff had the lowest median (11.1% among 21 institutions) and phlebotomist staff had the highest median (24.9% among 20 institutions) of the 3-year average turnover rates. Among laboratory departments, microbiology had the lowest median (7.8% among 18 institutions) and anatomic pathology had the highest median (14.3% among 14 institutions) of the 3-year average turnover rates. Laboratories that developed and communicated clear career paths to their employees and that funded external laboratory continuing education activities had significantly lower 3-year average turnover rates than laboratories that did not implement these strategies., Conclusions.—: Laboratory staff turnover rates among institutions varied widely. Two human resource practices were associated with lower laboratory staff turnover rates.

Introduction: Bilateral reduction mammoplasty is one of the most common plastic surgery procedures performed in the U.S. This study examines the incidence, management, and prognosis of incidental breast cancer identified in reduction specimens from a large cohort of reduction mammoplasty patients., Methods: Breast pathology reports were retrospectively reviewed for evidence of incidental cancers in bilateral reduction mammoplasty specimens from five institutions between 1990 and 2017., Results: A total of 4804 women met the inclusion criteria of this study; incidental cancer was identified in 45 breasts of 39 (0.8%) patients. Six patients (15%) had bilateral cancer. Overall, the maximum diagnosis by breast was 16 invasive cancers and 29 ductal carcinomas in situs. Thirty-three patients had unilateral cancer, 15 (45.5%) of which had high-risk lesions in the contralateral breast. Twenty-one patients underwent mastectomy (12 bilateral and nine unilateral), residual cancer was found in 10 in 25 (40%) therapeutic mastectomies. Seven patients did not undergo mastectomy received breast radiation. The median follow-up was 92 months. No local recurrences were observed in the patients undergoing mastectomy or radiation. Three of 11 (27%) patients who did not undergo mastectomy or radiation developed a local recurrence. The overall survival rate was 87.2% and disease-free survival was 82.1%., Conclusions: Patients undergoing reduction mammoplasty for macromastia have a small but definite risk of incidental breast cancer. The high rate of bilateral cancer, contralateral high-risk lesions, and residual disease at mastectomy mandates thorough pathologic evaluation and careful follow-up of these patients. Mastectomy or breast radiation is recommended for local control given the high likelihood of local recurrence without either.

Purpose: Atypical ductal hyperplasia (ADH) significantly increases the risk of breast cancer in women. However, little is known about the implications of ADH in men., Methods: Review of 932 males with breast pathology was performed to identify cases of ADH. Patients were excluded if ADH was upgraded to cancer on excision, or if they had contralateral breast cancer. Cases were reviewed to determine whether any male with ADH developed breast cancer., Results: Nineteen males were diagnosed with ADH from June 2003 to September 2018. All had gynecomastia. Surgical procedure was mastectomy in 8 patients and excision/reduction in 11. One patient had their nipple areola complex removed, and 1 required a free nipple graft. Median patient age at ADH diagnosis was 25 years (range 18-72 years). Of the 14 patients with bilateral gynecomastia, 10 had bilateral ADH and 4 had unilateral. Five cases of ADH were described as severe, bordering on ductal carcinoma in situ. No patient reported a family history of breast cancer. No patient took tamoxifen. At a mean follow-up of 75 months (range 4-185 months), no patient developed breast cancer., Conclusion: Our study is the first to provide follow-up information for males with ADH. With 6 years of mean follow-up, no male in our series has developed breast cancer. This suggests that either ADH in men does not pose the same risk as ADH in women or that surgical excision of symptomatic gynecomastia in men effectively reduces the risk of breast cancer.

Purpose: A recent comparison of the prognostic accuracy of Breast Cancer Index (BCI) and the Recurrence Score (RS) showed that BCI was more precise than RS. BCI identified a subset of RS low and intermediate risk patients with clinically relevant elevated rates of distant recurrences (DR). The current study analyzed the correlation of BCI and RS risk classification to clinical and pathological parameters and further examined the re-categorization between the two risk group indices in a multi-institutional cohort of hormone receptor positive (HR+) breast cancer patients., Methods: 560 women with HR+, lymph node-negative breast cancer who underwent testing with RS as part of their routine clinical care were included in the final analysis. Individual risk was assessed using predefined categories of RS and BCI (Low, Intermediate and High, respectively). Correlations between BCI, RS, and standard clinical-pathological prognostic factors were examined, and re-categorization of risk groups between BCI and RS was analyzed., Results: An overall significant association between histological tumor grade and RS or BCI was observed with high-grade tumors more prevalent among RS and BCI high-risk patients. The invasive ductal carcinoma histologic subtype was associated with 98% and 93% of high-risk RS and BCI cases, respectively. The invasive lobular subtype accounted for 0% and 6% of high-risk RS and BCI cases, respectively. A poor agreement between the two biomarker risk group indices was demonstrated with more than 51% of the total cohort stratified differently between BCI and RS. As compared with RS, BCI stratified fewer patients into the intermediate-risk group (29% vs. 39%, BCI and RS, respectively) and more patients into the high-risk group (19% vs. 7%, BCI and RS, respectively). Subsets of both RS low- and intermediate-risk patients were identified by BCI as high risk., Conclusions: In this clinical series, BCI and RS risk groups demonstrated a significant association with histological tumor grade. BCI showed a modest correlation with tumor size and no correlation with age, while RS showed no correlation with tumor size or age. Compared with RS, BCI classifies fewer intermediate risk patients, identifies subsets of low and intermediate RS risk patients as high-risk, and provides distinct individualized risk assessment for patients with early-stage breast cancer.

Context Patients choosing to retain the nipple when undergoing therapeutic or prophylactic mastectomy are at risk for cancers arising at that site. Objective To identify cases of invasive carcinoma arising within the nipple and to investigate their clinical, imaging, biologic, and staging features. Design Carcinomas were identified by prospective review of surgical and consult cases at 4 hospitals. Results The 24 patients identified presented with symptoms related to the nipple. Mammography did not detect the cancer in most cases. Ten patients (42%) had skin changes from ductal carcinoma in situ involving nipple skin (Paget disease), with small foci of invasion into the dermis, and 6 of those 10 carcinomas (60%) stained positive for human epidermal growth factor receptor 2 (HER2). The remaining 14 patients (58%) presented with a nipple mass or with skin changes. These were larger invasive carcinomas of both ductal and lobular types. Only 2 of those 14 carcinomas (14%) were HER2 + . Three of 15 patients (20%) undergoing lymph node biopsy had a single metastasis. No patients have had recurrent disease. Conclusions Rare, invasive, primary nipple carcinomas typically present as subtle nipple thickening or an exudative crust on the skin. Imaging studies are often nonrevealing. A variety of histologic and biologic types of carcinomas occur, similar to cancers arising deeper in the breast. Although the carcinomas invaded into the dermis, some with skin ulceration, the likelihood of lymph node metastasis was no higher than carcinomas of similar sizes. Patients who choose to preserve their nipple(s) should be aware of the possibility of breast cancer arising at that site and to bring any observed changes to the attention of their health care providers.

Context: - The College of American Pathologists (CAP) developed protocols for reporting pathologic characteristics of breast cancer specimens, including margin status. The Society of Surgical Oncology (SSO) and the American Society for Radiation Oncology (ASTRO) published treatment guidelines regarding margins in patients with invasive cancer; and SSO, ASTRO, and the American Society of Clinical Oncology (ASCO) recently published guidelines for patients with ductal carcinoma in situ., Objective: - To assess current practices among pathologists with regard to the processing/reporting of breast specimens, assess compliance with CAP cancer protocols, and assess alignment with SSO/ASTRO and SSO/ASTRO/ASCO guidelines., Design: - A survey concerning breast specimen processing/reporting was distributed to pathologists enrolled in the CAP Performance Improvement Program in Surgical Pathology., Results: - Ninety-four percent (716 of 764 respondents) and 91% (699 of 769 respondents) define positive margins as "tumor on ink" for invasive cancer and ductal carcinoma in situ, respectively, in compliance with CAP cancer protocols and with SSO/ASTRO and SSO/ASTRO/ASCO guidelines. Of 791 respondents who provided details regarding methods for margin evaluation, 608 (77%) exclusively examine perpendicular margins, facilitating guideline compliance. However, 183 of 791 respondents (23%) examine en face margins in at least a subset of specimens, which may preclude guideline compliance in some cases. When separate cavity (shave) margins are examined, while 517 of 586 respondents (88%) ink these specimens, 69 of 586 (12%) do not, and this may also preclude guideline compliance in some cases., Conclusions: - A substantial proportion of survey participants report margin status for breast cancer specimens in a manner consistent with CAP cancer protocols, and in alignment with SSO/ASTRO and SSO/ASTRO/ASCO guidelines. However, there are opportunities for some laboratories to modify procedures in order to facilitate more complete adherence to guidelines.

Context: - In 2008, the Joint Commission (JC) implemented a standard mandating formal monitoring of physician professional performance as part of the process of granting and maintaining practice privileges., Objective: - To create a pathology-specific management tool to aid pathologists in constructing a professional practice-monitoring program, thereby meeting the JC mandate., Design: - A total of 105 College of American Pathologists (CAP)-defined metrics were created. Metrics were based on the job descriptions of pathologists' duties in the laboratory, and metric development was aided by experience from the Q-Probes and Q-Tracks programs. The program was offered in a Web-based format, allowing secure data entry, customization of metrics, and central data collection for future benchmarking., Results: - The program was live for 3 years, with 347 pathologists subscribed from 61 practices (median, 4 per institution; range, 1-35). Subscribers used 93 of the CAP-defined metrics and created 109 custom metrics. The median number of CAP-defined metrics used per pathologist was 5 (range, 1-43), and the median custom-defined metrics per pathologist was 2 (range, 1-5). Most frequently, 1 to 3 metrics were monitored (42.7%), with 20% each following 4 to 6 metrics, 5 to 9 metrics, or greater than 10 metrics. Anatomic pathology metrics were used more commonly than clinical pathology metrics. Owing to low registration, the program was discontinued in 2016., Conclusions: - Through careful vetting of metrics it was possible to develop a pathologist-specific management tool to address the JC mandate. While this initial product failed, valuable metrics were developed and implementation knowledge was gained that may be used to address new regulatory requirements for emerging value-based payment systems.

Context: -A review of amended pathology reports provides valuable information regarding defects in the surgical pathology process., Objective: -To review amended breast pathology reports with emphasis placed on interpretative errors and their mechanisms of detection., Design: -All amended pathology reports for breast surgical specimens for a 5-year period at a large academic medical center were retrospectively identified and classified based on an established taxonomy., Results: -Of 12 228 breast pathology reports, 122 amended reports were identified. Most (88 cases; 72%) amendments were due to noninterpretative errors, including 58 report defects, 12 misidentifications, and 3 specimen defects. A few (34 cases; 27.9%) were classified as misinterpretations, including 14 major diagnostic changes (11.5% of all amendments). Among major changes, there were cases of missed microinvasion or small foci of invasion, missed micrometastasis, atypical ductal hyperplasia overcalled as ductal carcinoma in situ, ductal carcinoma in situ involving sclerosing adenosis mistaken for invasive carcinoma, lymphoma mistaken for invasive carcinoma, and amyloidosis misdiagnosed as fat necrosis. Nine major changes were detected at interpretation of receptor studies and were not associated with clinical consequences. Three cases were associated with clinical consequences, and of note, the same pathologist interpreted the corresponding receptor studies., Conclusions: -Review of amended reports was a useful method for identifying error frequencies, types, and methods of detection. Any time that a case is revisited for ancillary studies or other reasons, it is an opportunity for the surgical pathologist to reconsider one's own or another's diagnosis.

Purpose: Extracting information from electronic medical record is a time-consuming and expensive process when done manually. Rule-based and machine learning techniques are two approaches to solving this problem. In this study, we trained a machine learning model on pathology reports to extract pertinent tumor characteristics, which enabled us to create a large database of attribute searchable pathology reports. This database can be used to identify cohorts of patients with characteristics of interest., Methods: We collected a total of 91,505 breast pathology reports from three Partners hospitals: Massachusetts General Hospital, Brigham and Women's Hospital, and Newton-Wellesley Hospital, covering the period from 1978 to 2016. We trained our system with annotations from two datasets, consisting of 6295 and 10,841 manually annotated reports. The system extracts 20 separate categories of information, including atypia types and various tumor characteristics such as receptors. We also report a learning curve analysis to show how much annotation our model needs to perform reasonably., Results: The model accuracy was tested on 500 reports that did not overlap with the training set. The model achieved accuracy of 90% for correctly parsing all carcinoma and atypia categories for a given patient. The average accuracy for individual categories was 97%. Using this classifier, we created a database of 91,505 parsed pathology reports., Conclusions: Our learning curve analysis shows that the model can achieve reasonable results even when trained on a few annotations. We developed a user-friendly interface to the database that allows physicians to easily identify patients with target characteristics and export the matching cohort. This model has the potential to reduce the effort required for analyzing large amounts of data from medical records, and to minimize the cost and time required to glean scientific insight from these data.

Background: The risk of breast cancer in young women diagnosed with atypical hyperplasia and (LCIS) is not well defined. The objectives were to evaluate outcomes and to help determine guidelines for follow-up in this population., Methods: A retrospective review of women under age 35 diagnosed with ADH, ALH, LCIS, and severe ADH from 1987 to 2010 was performed. Patient characteristics, pathology and follow-up were determined from chart review., Results: We identified 58 young women with atypical breast lesions. Median age at diagnosis was 31 years (range 19-34). 34 patients had ADH, 11 had ALH, 8 had LCIS, and 5 had severe ADH. 7 (12%) patients developed breast cancer. The median follow-up was 86 months (range 1-298). Median time to cancer diagnosis was 90 months (range 37-231). 4 cancers were on the same side, 3 were contralateral. 4 were IDC, 1 was ILC, and 2 were DCIS. Cancer was detected by screening mammogram in 4 patients, 2 by clinical exam, and 1 unknown. In the entire cohort, 26 (45%) patients had screening mammograms as part of their follow up, 12 patients had only clinical follow up, and 20 had no additional follow up. 13 patients required subsequent biopsies., Conclusion: Young women with atypical breast lesions are at a markedly increased risk for developing breast cancer and should be followed closely. Based on our findings, we recommend close clinical follow-up, MRI starting at age 25 through age 29, and screening mammograms for those over 30 in this high-risk group of patients.

Women with atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), lobular carcinoma in situ (LCIS), and severe ADH are at increased risk of breast cancer, but a systematic quantification of this risk and the efficacy of chemoprevention in the clinical setting is still lacking. The objective of this study is to evaluate a woman's risk of breast cancer based on atypia type and to determine the effect of chemoprevention in decreasing this risk. Review of 76,333 breast pathology reports from three institutions within Partners Healthcare System, Boston, from 1987 to 2010 using natural language processing was carried out. This approach identified 2,938 women diagnosed with atypical breast lesions. The main outcome of this study is breast cancer occurrence. Of the 2,938 patients with atypical breast lesions, 1,658 were documented to have received no chemoprevention, and 184/1,658 (11.1 %) developed breast cancer at a mean follow-up of 68 months. Estimated 10-year cancer risks were 17.3 % with ADH, 20.7 % with ALH, 23.7 % with LCIS, and 26.0 % with severe ADH. In a subset of patients treated from 1999 on (the chemoprevention era), those who received no chemoprevention had an estimated 10-year breast cancer risk of 21.3 %, whereas those treated with chemoprevention had a 10-year risk of 7.5 % (p < 0.001). Chemoprevention use significantly reduced breast cancer risk for all atypia types (p < 0.05). The risk of breast cancer with atypical breast lesions is substantial. Physicians should counsel patients with ADH, ALH, LCIS, and severe ADH about the benefit of chemoprevention in decreasing their breast cancer risk.

Purpose: Increased microvessel density (MVD), a reflection of tumor angiogenesis, is associated with diminished relapse-free and overall survival (OS) in several subsets of breast cancer patients. However, the utility of this assay in node-positive patients treated with adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF) has not been well studied., Patients and Methods: Immunostaining for factor VIII-related antigen was performed on tissue sections from a subset of node-positive patients who received one of three dose/schedule regimens of CAF during participation in Cancer and Leukemia Group B protocol 8541. Sections from 577 cancers exhibited acceptable tumor and immunostaining quality and were included in the study. Each section was examined quantitatively for MVD as well as non-quantitatively by scoring the presence or absence of a prominent vascular pattern., Results: MVD counts were not associated with relapse-free or OS in univariate analysis. The presence of a prominent plexiform vascular pattern was correlated with decreased OS (P =.0085) in univariate analysis, but this pattern was not an independent prognostic indicator of survival in multivariate analysis. No apparent clinically important interactions between measures of angiogenesis, other prognostic factors, administration of tamoxifen, and chemotherapy dose were observed., Conclusion: Assessment of angiogenesis does not provide useful information regarding prognosis in node-positive breast cancer patients treated with adjuvant CAF, nor do these measures predict which patients will benefit from dose intensification or addition of tamoxifen.

Background: Microvessel density (MVD) is a measure of the extent of new blood vessel growth or angiogenesis, which is required for tumor progression. Increased MVD in primary breast cancers appears to adversely affect disease-free survival and overall survival in patients with breast cancer. However, the clinical implications of angiogenesis in breast cancer metastases have not been well studied. The purpose of this study was to compare intratumoral MVD in primary breast cancer tissues with MVD in axillary lymph node metastases and to evaluate the relationships among primary- and metastatic-tumor MVD, disease-free survival, and overall survival in patients with lymph node-positive, stage II breast cancer who were treated with adjuvant chemotherapy in Cancer and Leukemia Group B Protocol 8082., Methods: Immunostaining for factor VIII-related antigen was performed on tissue sections from 47 primary tumors and 91 axillary lymph nodes containing metastases from 110 patients with lymph node-positive breast cancer. Sections were examined for the presence or absence of focal areas of relatively intense neovascularization (vascular hot spots), and a quantitative assessment of intratumoral MVD was performed., Results: The presence of vascular hot spots in axillary lymph node metastases, but not primary breast cancers, was associated with statistically significantly decreased disease-free survival (P =.006) and overall survival (P =.004) by univariate analysis. Similarly, increased MVD in metastases, but not in primary tumors, was statistically significantly associated with diminished overall survival in these patients (P =.02). In multivariate analysis, the number of positive axillary lymph nodes and the presence of vascular hot spots in axillary lymph node metastases predicted decreased disease-free survival (P =.0001 and.02, respectively) and overall survival (P =.0001 and.007, respectively). All P values were two-sided., Conclusion: This pilot study suggests that assessing neovascularization in axillary lymph node metastases may provide clinically useful information regarding survival in patients with primary breast cancer.

The generation of vascular stroma is essential for solid tumor growth and involves stimulatory and inhibiting factors as well as stromal components that regulate functions such as cellular adhesion, migration, and gene expression. In an effort to obtain a more integrated understanding of vascular stroma formation in breast carcinoma, we examined expression of the angiogenic factor vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF); the VPF/VEGF receptors flt-1 and KDR; thrombospondin-1, which has been reported to inhibit angiogenesis; and the stromal components collagen type I, total fibronectin, ED-A+ fibronectin, versican, and decorin by mRNA in situ hybridization on frozen sections of 113 blocks of breast tissue from 68 patients including 28 sections of breast tissue without malignancy, 18 with in situ carcinomas, 56 with invasive carcinomas, and 8 with metastatic carcinomas. A characteristic expression profile emerged that was remarkably similar in invasive carcinoma, carcinoma in situ, and metastatic carcinoma, with the following characteristics: strong tumor cell expression of VPF/VEGF; strong endothelial cell expression of VPF/VEGF receptors; strong expression of thrombospondin-1 by stromal cells and occasionally by tumor cells; and strong stromal cell expression of collagen type I, total fibronectin, ED-A+ fibronectin, versican, and decorin. The formation of vascular stroma preceded invasion, raising the possibility that tumor cells invade not into normal breast stroma but rather into a richly vascular stroma that they have induced. Similarly, tumor cells at sites of metastasis appear to induce the vascular stroma in which they grow. We conclude that a distinct pattern of mRNA expression characterizes the generation of vascular stroma in breast cancer and that the formation of vascular stroma may play a role not only in growth of the primary tumor but also in invasion and metastasis.

The formation of vascular stroma plays an important role in the pathophysiology of malignancy. We describe the use of in situ hybridization in our laboratory as a tool to study the role of vascular permeability factor/vascular endothelial growth factor in the angiogenesis associated with malignancy.

Increased microvessel density has been described in squamous cell carcinoma of the head and neck and is related to patient prognosis. The factors responsible for the angiogenesis have not been identified. Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a multifunctional angiogenic cytokine expressed at high levels in many tumors. We examined 16 cases of squamous cell carcinoma, 10 cases of high-grade squamous dysplasia, and 19 cases of normal, reactive, or mildly dysplastic squamous mucosa by in situ hybridization for expression of VPF/VEGF and VPF/VEGF receptor mRNA. Strong expression of VPF/VEGF mRNA was seen in 12 of 16 squamous cell carcinomas and in 5 of 10 high-grade squamous dysplasias. In contrast, no cases of normal, reactive, or mild dysplastic squamous epithelium showed strong expression of VPF/VEGF mRNA. Furthermore, strong expression of VPF/VEGF receptor mRNA was seen in 5 of 9 cases of squamous cell carcinoma and 3 of 6 cases of high-grade squamous dysplasia but in only 2 of 14 cases of normal, reactive, or mild dysplastic squamous epithelium. Thus, expression of VPF/VEGF and its receptors is markedly increased in high-grade squamous dysplasia and invasive squamous cell carcinoma of the oral cavity and larynx and may play an important role in the angiogenesis associated with these lesions.

Background: Prior studies have indicated that ductal carcinoma in situ (DCIS) lesions are capable of inducing a vascular stroma. However, the mechanisms responsible for angiogenesis in DCIS currently are not defined. The goal of this study was to determine the relationship between the expression of the angiogenic cytokine vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), and angiogenesis in patients with DCIS., Methods: Forty-six breast biopsies with DCIS were characterized with regard to histologic features on hematoxylin and eosin stained sections, and microvessel density and distribution using sections immunostained for factor VIII-related antigen. In addition, in situ hybridization was performed on formalin fixed, paraffin embedded sections using 35S labeled riboprobes specific for VPF/VEGF., Results: VPF/VEGF expression by tumor cells in DCIS was greater than that observed in adjacent benign ductal or lobular epithelial cells in 96% of the evaluable cases. Moreover, the degree of VPF/VEGF mRNA expression was significantly associated with the degree of angiogenesis in these lesions. Among 22 cases with strong VPF/VEGF mRNA expression, the median microvessel count was 100 +/- 30.6 vessels/field. In contrast, among 24 cases with low level VPF/VEGF mRNA expression, the median microvessel count was 71 +/- 48.6 vessels/field (P = 0.04). In addition, high grade DCIS lesions more commonly were associated with strong VPF/VEGF mRNA expression than low grade lesions, but the results were not statistically significant., Conclusions: These findings suggest that VPF/VEGF is an important angiogenic factor in patients with DCIS.

Background: The presence of tumor at the inked margins (IMs) of breast specimens is associated with an increased risk of local recurrence after breast-conserving therapy for invasive breast carcinoma and ductal carcinoma in situ (DCIS). Given the importance of margin status, some have advocated the use of shaved margins (SMs) as a means of conducting a more complete examination of the specimen margins than could be done with sections taken perpendicular to the IMs. However, it is not known whether these two methods of margin assessment provide comparable information., Methods: To address this issue, the authors studied 22 consecutive breast reexcision specimens (10 DCIS, 6 infiltrating ductal carcinomas, and 6 infiltrating lobular carcinomas) in which the specimen surfaces were inked, the margins were shaved, and tumor was present in at least one of the SM sections. A total of 199 SMs were examined. The SMs were originally embedded in a way that permitted histologic sections to be cut opposite the inked surface. Sections of SM stained with hematoxylin and eosin (H & E) were reviewed and scored for the presence and extent (number of low-power fields) of cancer. The remaining tissue from the SM was then removed from the blocks, cut perpendicular to the IM, and reembedded to permit visualization of tumor in relation to the IM. Sections were then cut from two different levels of each reembedded block and stained with H & E. An SM was considered positive if tumor was present anywhere on the section. An IM was considered positive when tumor extended to the inked surface., Results: Although all 22 excisions had at least 1 positive SM, tumor was present at an IM in only 12 specimens (55%). Among 69 positive SMs, the corresponding IM was positive in only 42 (61%). The likelihood of a positive IM increased with the number of low-power fields of involvement by invasive carcinoma or DCIS on the SM, as follows: 19% with 1 low power-field, 67% with 2 low-power fields, and 97% with > or = 3 low-power fields (all P < 0.02). When the SM was negative, the corresponding IM was negative in 98% of cases., Conclusions: Many patients with positive SMs do not have positive IMs. A positive SM more reliably predicts a positive IM when tumor involves > or = 3 low-power fields of the SM. The authors conclude that the clinical implications of a positive SM may not be the same as those of a positive IM. Clinical outcome studies are needed to define further the implications of positive SMs. [See editorial counterpoint on pages 1453-8 and reply to counterpoint on pages 1459-60, this issue.]

Background: Solid tumors, including endometrial carcinomas, must induce a vascular stroma to grow beyond a minimal size. The mechanisms responsible for angiogenesis in endometrial carcinoma, however, are not well defined. Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a multifunctional cytokine that is an important regulator of tumor angiogenesis. We evaluated VPF/VEGF mRNA and protein expression, as well as VPF/VEGF receptor mRNA expression, in endometrial carcinoma., Methods: Fourteen examples of endometrial carcinoma were evaluated by in situ hybridization; in 7 cases, benign atrophic endometrium from the same patient was also examined. Histologic sections were subjected to in situ hybridization using 35S-labeled riboprobes specific for VPF/VEGF and, in a subset of cases, riboprobes specific for the VPF/VEGF receptors flt-1 and KDR. In addition, ten examples of endometrial carcinoma were evaluated for VPE/VEGF protein expression by immunohistochemistry., Results: All 14 examples of endometrial carcinoma studied by in situ hybridization exhibited focal strong VPF/VEGF mRNA expression by tumor cells. In addition, the endothelial cells of surrounding microvessels strongly expressed flt-1 and KDR mRNAs in all ten cases examined. In contrast, no strong expression of VPF/VEGF, flt-1, or KDR mRNA was observed in the seven examples of benign atrophic endometrium studied. All ten cases of endometrial carcinoma studied by immunohistochemistry exhibited strong VPF/VEGF protein expression by tumor cells., Conclusions: These observations suggest that VPF/VEGF is an important angiogenic factor in endometrial carcinoma.

Purpose: The optimal treatment of ductal carcinoma in situ is controversial. Traditionally, women with this disease have been treated with mastectomy with excellent results, but recently the need for such extensive surgery has been questioned. Long-term data on the use of conservative surgery and radiation therapy for treatment are limited. A retrospective analysis was performed to assess treatment outcome and prognostic factors for patients with ductal carcinoma in situ treated with conservative surgery and radiotherapy., Patients and Methods: From 1976 to 1990, 76 women with ductal carcinoma in situ were treated with conservative surgery followed by radiation therapy. The median age at diagnosis was 48 years. Seventeen patients had a positive family history of breast cancer in a first-degree (n=8) or second-degree (n=9) relative. Median follow-up interval was 74 months for the 71 survivors. In 54 patients, the carcinoma was detected by mammography alone; in 13 patients, by mammography and physical examination; and in 4 patients, by physical examination with a normal mammogram; and in 5 patients, by physical examination alone without mammography. Fifty patients had re-excision after initial biopsy. Final margins were positive in 11, close in 11, negative in 34, and unknown in 20. The median volume of excised tissue was 60 cm3. The axilla was surgically staged in 30 patients (39%) and all were negative. The whole breast was irradiated to a dose of 45 to 50 Gy in all patients. Seventy-two patients also received a boost to the primary site. The median total radiation dose to the primary site was 61 Gy (range, 46 to 71)., Results: Seven patients had a recurrence in the treated breast at 16, 18, 41, 63, 72, 83, and 104 months after treatment. The 5- and 10-year actuarial rates of local recurrence were 4% and 15%, respectively. Six of seven recurrences occurred in the vicinity of the original lesion. Four local recurrences were invasive, and three were ductal carcinoma in situ. Two patients developed a contralateral invasive carcinoma. The 5- and 10-year cause-specific survival rates were 100% and 96%, respectively. The 10-year actuarial rate of local recurrence was 25% in the group with a total excision volume less than 60 cm3, as compared with 0% in those with 60 cm3 or more excised (P=0.04). In patients with a positive family history, the 10-year actuarial rate of local recurrence was 37%, as compared with 9% in patients with a negative family history (P=0.008). Of the 17 patients with a positive family history, four developed either an ipsilateral or contralateral invasive breast cancer, whereas 1 of the 58 patients without a family history developed a subsequent invasive breast cancer (P=0.008)., Conclusion: These results suggest that patients with ductal carcinoma in situ treated with conservative surgery and radiotherapy (including a boost to the primary site) appear to benefit from wide, rather than limited, resection. These results also suggest that family history may be an important prognostic factor for progression of disease.

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.

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.