The male rectus diastasis: a different concept?

PURPOSE: More interest in the treatment of rectus diastasis has been evoked lately. Following the postpartum females from a great distance, the middle-aged males living with obesity are the second most common group of rectus diastasis patients. Although gender differences are considered frequently in regard to cosmetic appearance and symptoms, it is less obvious in classifications and subsequent treatment strategies. Is a unisex approach of rectus diastasis still applicable? The lack of a firm answer warrants this review of the current literature. METHODS: An explorative free-text multi-database bibliographic search (Pubmed/CENTRAL/EMBASE/PEDro/Scholar) was performed with the focus on the rectus diastasis in males. Anticipating the limited references, the design was a non-systematic review. All studies, regardless of study type, language or time period, describing etiology, symptoms, classification and/or treatment options were eligible for inclusion. From the articles retrieved out of this search, additional references were identified by a manual search among the cited references. RESULTS: The multi-database search resulted in a total of 7633 records. Based on the title and abstract 95 records were full text assessed for eligibility. Eleven studies were identified as relevant, six by cross-reference and another four by hand-search were added to provide an insight in gender-specific aspects in rectus diastase. Hereditary causes are differences in collagen-like composition of types and concomitant abdominal aneurysm as well as gender differences in the linea alba architecture. Acquired etiology is distributed into both absolute pressure by visceral obesity and relative pressure caused by weight lifting or improper exercises. Furthermore, the impact of muscle thickness and age are considered as influencers of biomechanics. Gender differences can also play a role in symptoms of body image and core stability. It is known that there are anatomical differences between male and female persons; more transverse fibers are found in infra-umbilical region in women. In classifications the awareness of male rectus diastasis is limited, treatment outcome studies are scarce on males. CONCLUSION: An overview of male-specific aspects of rectus diastasis is provided, underlining that key aspects surrounding rectus diastasis in males differ from females. Although males are the minority of rectus diastasis patients, we recommend that the male rectus diastasis as a concept should be specifically acknowledged in classifications systems and study outcome reporting to evaluate this subgroup more accurately in the future.

META Score: An International Consensus Scoring System on Mesh-Tissue Adhesions.

BACKGROUND: Currently, the lack of consensus on postoperative mesh-tissue adhesion scoring leads to incomparable scientific results. The aim of this study was to develop an adhesion score recognized by experts in the field of hernia surgery. METHODS: Authors of three or more previously published articles on both mesh-tissue adhesion scores and postoperative adhesions were marked as experts. They were queried on seven items using a modified Delphi method. The items concerned the utility of adhesion scoring models, the appropriateness of macroscopic and microscopic variables, the range and use of composite scores or subscores, adhesion-related complications and follow-up length. This study comprised two questionnaire-based rounds and one consensus meeting. RESULTS: The first round was completed by 23 experts (82%), the second round by 18 experts (64%). Of those 18 experts, ten were able to participate in the final consensus meeting and all approved the final proposal. From a total of 158 items, consensus was reached on 90 items. The amount of mesh surface covered with adhesions, tenacity and thickness of adhesions and organ involvement was concluded to be a minimal set of variables to be communicated separately in each future study on mesh adhesions. CONCLUSION: The MEsh Tissue Adhesion scoring system is the first consensus-based scoring system with a wide backing of renowned experts and can be used to assess mesh-related adhesions. By including this minimal set of variables in future research interstudy comparability and objectivity can be increased and eventually linked to clinically relevant outcomes.

Meta-analysis of postoperative pain using non-sutured or sutured single-layer open mesh repair for inguinal hernia.

Background: Chronic postoperative pain occurs in up to 21·7 per cent of patients undergoing open inguinal hernia repair. Several mesh fixation techniques using glue or self-gripping meshes have been developed to reduce postoperative pain. The aim of this meta-analysis was to evaluate RCTs comparing adhesional/self-gripping and sutured single-layer open mesh fixations in the repair of inguinal herniation, with postoperative pain as endpoint. Methods: PubMed, Embase and Cochrane CENTRAL databases were searched systematically for RCTs according to the PRISMA guidelines; the study was registered at PROSPERO (CRD42017056373). Different fixation methods were analysed. The primary outcome, chronic pain, was defined as a postoperative visual analogue scale (VAS) score of at least 3 at 12 months. Secondary outcomes were mean VAS score at 1 week and at 1 month after surgery. Results: Twenty-three studies including 5190 patients were included in the meta-analysis. Adhesional (self-adhering or glued) or self-gripping fixation methods were associated with a significantly lower VAS score at 1 week (mean difference -0·49, 95 per cent c.i. -0·81 to -0·17; P = 0·003) and at 1 month (mean difference -0·31, -0·58 to -0·04; P = 0·02) after surgery than suture fixation, but the incidence of chronic pain after 12 months was similar in the two groups (odds ratio 0·70, 95 per cent c.i. 0·30 to 1·66). Differences in recurrences and complications between groups did not reach statistical significance. Conclusion: There was no difference in the incidence of chronic pain 12 months after different mesh repair fixation techniques despite significant reductions in short-term postoperative pain favouring a non-sutured technique. There were no differences in recurrence rates or in rates of other complications at 1 year.

Complications and recurrence rates of patients with Ehlers-Danlos syndrome undergoing ventral hernioplasty: a case series.

PURPOSE: Ventral hernia repair is one of the most frequently performed surgical procedures, though recurrences are common. Recurrence can be caused by impaired collagen formation or maturation; hence, patients with Ehlers-Danlos syndrome (EDS) are potentially at increased risk for hernia recurrence. EDS causes altered collagen metabolism, though little is known about the influence of EDS on ventral hernioplasty outcomes. This study aims to analyze these patients to report complication rates, recurrence rates, and, if possible, to give recommendations for surgical intervention. METHODS: A retrospective analysis between January 2000 and January 2017 was performed in a university hospital Belgium (UZ Ghent). Data on baseline characteristics, primary surgery, and hernias were extracted from patients' medical charts. Noted endpoints were postoperative complications and recurrences. RESULTS: Fourteen patients (50% males) were included. Ten (71%) had an incisional hernia and four (29%) had a primary ventral hernia. Median age was 45 years (IQR 37.75-52.75), median BMI was 24.82 (IQR 22.43-26.87). Four patients (29%) smoked, one patient (7.1%) had diabetes mellitus, and five patients (36%) had an aneurysm of the abdominal aorta. All patients underwent elective open hernioplasty with mesh reinforcement. Three patients (21%) had a postoperative complication (two infections, one seroma). Recurrence rate was 7.1% (one patient). CONCLUSIONS: This series describes 14 patients with a median follow-up of 50 months and a recurrence rate of 7.1%. The low recurrence rate could be explained by the use of large meshes that reinforce the entire midline to compensate for the reduced collagen strength in EDS patients.

A modified Chevrel technique for ventral hernia repair: long-term results of a single centre cohort.

PURPOSE: To evaluate the short- and long-term results after a modified Chevrel technique for midline incisional hernia repair, regarding surgical technique, hospital stay, wound complications, recurrence rate, and postoperative quality of life. These results will be compared to the literature derived reference values regarding the original and modified Chevrel techniques. METHODS: In this large retrospective, single surgeon, single centre cohort all modified Chevrel hernia repairs between 2000 and 2012 were identified. Results were obtained by reviewing patients' medical charts. Postoperative quality of life was measured using the Carolina Comfort Scale. A multi-database literature search was conducted to compare the results of our series to the literature based reference values. RESULTS: One hundred and fifty-five patients (84 male, 71 female) were included. Eighty patients (52%) had a large incisional hernia (width ≥ 10 cm) according the definition of the European Hernia Society. Fourteen patients (9%) underwent a concomitant procedure. Median length-of-stay was 5 days. Within 30 days postoperative 36 patients (23.2%) had 39 postoperative complications of which 30 were mild (CDC I-II), and nine severe (CDC III-IV). Thirty-one surgical site occurrences were observed in thirty patients (19.4%) of which the majority were seroma (16 patients 10.3%). There was no hernia-related mortality during follow-up. Recurrence rate was 1.8% after a median follow-up of 52 months (12-128 months). Postoperative quality of life was rated excellent. CONCLUSIONS: The modified Chevrel technique for midline ventral hernias results in a moderate complication rate, low recurrence rate and high rated postoperative quality of life.

Patient-reported outcomes (PROs) after total extraperitoneal hernia repair (TEP).

BACKGROUND: Patient-reported outcomes (PROs) such as quality of life (QoL), patient satisfaction, and work impairment, are arguably the most important outcomes of any medical treatment. In 2011, Staerkle and Villiger developed the Core Outcome Measurements Index (COMI) to standardise PROs and PRO measurement for inguinal hernia patients, in an attempt to increase inter-study comparability. The aim of this study is to prospectively evaluate the short- and long-term postoperative QoL, function, patient well-being, pain, and social/work disability, after total extraperitoneal (TEP) inguinal hernia repair and to provide the first clinical experience with the COMI-hernia questionnaire. METHODS: Between January 2013 and December 2014, all patients ≥18 years that were scheduled for elective uni- or bilateral TEP in a regional hospital were approached to participate in this study. Measurements were taken preoperatively, and 6 weeks and 1 year postoperatively. RESULTS: One hundred and twenty patients (113 men, 7 women), mean age 59 years (SD ±12), completed the follow-up of 1 year. Ninety-seven percent of the population reported that the operation improved their complaints. QoL, function, well-being, and pain all improved after 6 weeks and 1 year after surgery. Patients experienced more social and work-related limitations 6 weeks after surgery compared to baseline measurements, though this improved to normal 1 year postoperatively. The incidence of chronic pain was 14% (VAS ≥ 2), which had a negative impact on the patients' sense of well-being. CONCLUSION: Patients recovered well after TEP repair with a good quality of life and fast restore of function. Patient well-being was lower than expected due to a 14% incidence of chronic pain. The COMI-hernia scale provided reasonable insight into the patients' experience, though it was difficult to interpret for both patient and physician.

How to perform the endoscopically assisted components separation technique (ECST) for large ventral hernia repair.

BACKGROUND: The components separation technique (CST) is frequently used for reconstructing large ventral hernias. Unfortunately, it is associated with a high wound complication rate up to 50 %, caused by large wound surface and inherent trauma to abdominal skin vascularization. An endoscopically assisted modification of the original technique (ECST) spares skin vascularization and reduces wound surface, supposedly reducing wound complications. This study accurately describes ECST step by step with detailed illustrations and report the results of a 27 patient cohort. METHODS: Since September 2012 patients with midline hernias without previous subcutaneous dissection and a maximum diameter of approximately 10-15 cm underwent ECST in an expert centre for abdominal wall reconstructions. Prospective data was gathered during inpatient care and 3-6 monthly follow-up. RESULTS: Twenty-seven patients (17 male/10 female) with median age of 60 years (range 35-77), average BMI 27 (SD ±2) kg/m(2) and median ASA classification 2 (range 1-3) underwent ECST. Two patients were excluded due to bilateral conversion to conventional CST and finding of peritoneal metastases. Median defect size was 116 ± 48 cm(2). Median length of stay was 5 days (range 3-15). Wound complication rate was 11 %. Recurrence rate was 29 % after a median follow-up of 13 months. CONCLUSIONS: Endoscopically assisted modification of the original technique can be used for reconstructing large and complex ventral hernias up to 15 cm in diameter. The results of this small sized cohort study showed that ECST is feasible in patients with a uro-, or enterostomy and suggest that ECST reduces wound complication rate when compared to CST.

Negative pressure wound therapy versus standard wound care on quality of life: a systematic review.

OBJECTIVE: Negative pressure wound therapy (NPWT) is a widely accepted treatment modality for open or infected wounds. Premature ending of NPWT occasionally occurs due to negative effects on the quality of life (QoL), however, the actual impact on QoL is unknown. The aim of this review is to analyse the effect of NPWT versus standard wound care (SWC) on QoL when used for the treatment of open or infected wounds. METHOD: A systematic literature search in a range of databases (PubMed, CINAHL, Medline, Web of Science, Science Direct Freedom Collection, SwetsWise, PSYCArticles and Infrotrac Custom Journals) using the following search terms; 'standard wound care', 'wound dressing', 'dressing', 'treatment', OR 'negative pressure wound therapy [MESH]', OR 'vacuum assisted closure' AND 'quality of life [MESH]', 'patient-satisfaction', OR 'experiences' was performed. Methodological quality was assessed using the methodological index for non-randomised studies (MINORS) checklist. RESULTS: There were 42 studies identified, five matched the inclusion criteria: two randomised clinical trials (RCTs), one clinical comparative study, one exploratory prospective cohort study and one quasi experimental pilot study. Median MINORS-score was 75% (58%-96%). There were seven different questionnaires used to measure QoL or a subsidiary outcome. QoL in the NPWT group was lower in the first week, though no difference in QoL was observed thereafter. CONCLUSION: This systematic review observed that QoL improved at the end of therapy independent of which therapy was used. NPWT led to a lower QoL during the first week of treatment, possible due to aniexty, after which a similar or better QoL was reported when compared with SWC. It could be suggested that NPWT might be associated with increased anxiety. DECLARATION OF INTEREST: All authors of this publication have received no financial support or have personal interests conflicting with the objectivity of this manuscript.

The effects of low-intensity pulsed ultrasound and pulsed electromagnetic fields bone growth stimulation in acute fractures: a systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: The aim of this systematic review and meta-analysis was to evaluate the best currently available evidence from randomized controlled trials comparing pulsed electromagnetic fields (PEMF) or low-intensity pulsed ultrasound (LIPUS) bone growth stimulation with placebo for acute fractures. MATERIALS AND METHODS: We performed a systematic literature search of the medical literature from 1980 to 2013 for randomized clinical trials concerning acute fractures in adults treated with PEMF or LIPUS. Two reviewers independently determined the strength of the included studies by assessing the risk of bias according to the criteria in the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Seven hundred and thirty-seven patients from 13 trials were included. Pooled results from 13 trials reporting proportion of nonunion showed no significant difference between PEMF or LIPUS and control. With regard to time to radiological union, we found heterogeneous results that significantly favoured PEMF or LIPUS bone growth stimulation only in non-operatively treated fractures or fractures of the upper limb. Furthermore, we found significant results that suggest that the use of PEMF or LIPUS in acute diaphyseal fractures may accelerate the time to clinical union. CONCLUSIONS: Current evidence from randomized trials is insufficient to conclude a benefit of PEMF or LIPUS bone growth stimulation in reducing the incidence of nonunions when used for treatment in acute fractures. However, our systematic review and meta-analysis suggest that PEMF or LIPUS can be beneficial in the treatment of acute fractures regarding time to radiological and clinical union. PEMF and LIPUS significantly shorten time to radiological union for acute fractures undergoing non-operative treatment and acute fractures of the upper limb. Furthermore, PEMF or LIPUS bone growth stimulation accelerates the time to clinical union for acute diaphyseal fractures.

Risk biomarker assessment for breast cancer progression: replication precision of nuclear morphometry.

Nuclear morphometry is a method for quantitative measurement of histopathologic changes in the appearance of stained cell nuclei. Numerous studies have indicated that these assessments may provide clinically relevant information related to the degree of progression and malignant potential of breast neoplasia. Nuclear features are derived from computerized analysis of digitized microscope images, and a quantitative Feulgen stain for DNA was used. Features analyzed included: (1) DNA content; (2) nuclear size and shape; and (3) texture features, describing spatial features of chromatin distribution. In this study replicated measurements are described on a series of 54 breast carcinoma specimens of differing pathologic grades. Duplicate measurements were performed using two serial sections, which were processed and analyzed separately. The value of a single feature measurement, the nuclear area profile, was shown to be the strongest indicator of progression. A quantitative nuclear grade was derived and shown to be strongly correlated with not only the pathologic nuclear grade, but also with tubule formation, mitotic grade, and with the overall histopathologic grade. Analysis of replication precision showed that the standard methods of the histopathology laboratory, if practiced in a uniform manner, are sufficient to ensure reproducibility of these assessments. We argue that nuclear morphometry provides a standardized and reproducible framework for quantitative pathologic assessments.

Prognostic value of morphometry in patients with normal breast tissue or usual ductal hyperplasia of the breast.

Women with usual ductal hyperplasia have a relative risk of 1.6-1.9 of subsequent breast cancer development. This slightly increased risk is generally not considered sufficiently high to justify (chemo)preventive therapy. It is therefore important to identify high-risk ductal hyperplastic lesions that would benefit from such a treatment. Nuclear morphometric features have been shown in previous work to be useful for objectively describing morphologic features associated with high risk in (pre)invasive breast lesions. The aim of this study was to evaluate whether such morphometric features can also predict subsequent invasive cancer development in patients with the common pattern of usual ductal hyperplasia or a normal breast biopsy. The present case-control study included 423 women with normal breast biopsies (n = 89) or biopsies containing usual ductal hyperplasia (n = 334). Of these 423 women, 132 developed invasive breast cancer during follow-up (mean 16.7 +/- 7.0 years). On the original hematoxylin and eosin-stained sections, nuclear morphometry was performed with a digitizing video overlay system, and mitotic and apoptotic indices were assessed. Patients with mean nuclear feature values for area, perimeter, diameter or longest axis above the 75th percentile had 1.6-1.7 times the breast cancer risk of women with mean nuclear feature values below this value. Pairwise combinations of these features yielded slightly higher cancer risks for the fourth quartile patients, with the highest risk (1.9) for patients with SD of nuclear area and perimeter values above the 75th percentile. The number of apoptotic or mitotic cells had no prognostic value for patients with apparently normal tissue or usual ductal hyperplasia. Our results give a first indication that normal breast tissue or usual ductal hyperplasia harbor nuclear morphologic changes that, when assessed by morphometry, may be used to predict breast cancer development. It is worthwhile studying this further in independent groups of patients with long-term follow-up.

Similarity in expression of cell cycle proteins between in situ and invasive ductal breast lesions of same differentiation grade.

There is increasing evidence that there are different progression routes leading to invasive breast cancer, depending on histology and differentiation grade. The aim of this study was to determine alterations in the expression of proteins involved in proliferation and apoptosis in non-invasive and invasive ductal breast lesions. Immunohistochemistry was performed on 106 usual ductal hyperplasias (UDH), 61 DCIS lesions and 53 invasive ductal breast carcinomas. Increased proliferation (Ki67), overexpression of cyclin D1, HER-2/neu, p21 and p53, and decreased expression of bcl-2 and p27 could already be found in UDH. Significant differences between UDH and DCIS lesions were found for only one protein when UDH was compared with well-differentiated DCIS (p27), for three proteins when compared with intermediately differentiated DCIS (p21, cyclin D1, Ki-67), and for all proteins when compared with poorly-differentiated DCIS. Comparing DCIS with invasive lesions of same differentiation grade, proliferation was elevated in the invasive lesions. Altered expression of the other proteins was in general only slightly increased in the invasive lesion compared with DCIS. The number of proteins with altered expression per lesion was highest in poorly-differentiated lesions and was comparable between DCIS and invasive cancer of the same differentiation grade. In conclusion, the biggest changes in expression of these proliferation and apoptosis related proteins appear to occur during the transition from hyperplasia to DCIS; they probably play a minor role in the transition from DCIS to invasive breast lesion of same differentiation grade. Well-differentiated in situ and invasive breast lesions share many of the aberrations in expression of these proteins, as do poorly-differentiated in situ and invasive lesions. However, there are many differences between the well and poorly-differentiated lesions. This further supports the existence of different progression routes leading to breast cancer.

Ductal invasive G2 and G3 carcinomas of the breast are the end stages of at least two different lines of genetic evolution.

Ductal invasive grade (G) 2 and G3 carcinomas represent the majority of invasive breast cancers. Previous morphological and cytogenetic studies have provided evidence that ductal invasive G2 carcinoma may originate from at least two different genetic pathways. The aim of this study was to evaluate further the heterogeneity of G2 breast cancer in comparison with G3 cancers by cytogenetic and quantitative analysis. To this end, 35 cases of ductal invasive G2 and 42 cases of ductal invasive G3 carcinomas were investigated by means of comparative genomic hybridization (CGH) and these findings were correlated with DNA ploidy status, mitotic activity index (MAI), mean nuclear area (MNA), volume per lumen (VPL), and clinico-pathological parameters. The findings of this study demonstrate that ductal invasive G2 carcinomas, in contrast to ductal invasive G3 carcinomas, have to be interpreted as the morphological end stage resulting from two different cytogenetic and morphological pathways; the loss of 16q material is the cytogenetic key event in the evolution of a subgroup of this entity. By correlating genetic alterations with DNA ploidy status, an extended morphology-based cytogenetic progression model is presented, with early and late genetic alterations in the pathogenesis of breast cancer. The correlation with MAI gives rise to the hypothesis that these different genetic pathways significantly differ in their proliferation rate. Further studies will be required to elucidate which genes contribute to an altered proliferation rate in these subgroups and to the associated prognosis.

Histopathology of fibroadenoma of the breast.

The aim of this study was to make a thorough inventory of the histologic features of epithelium and stroma within and adjacent to breast fibroadenomas in 396 cases. Breast fibroadenomas seemed to display a wide spectrum of proliferative and nonproliferative histologic changes. Hyperplasia (excluding mild hyperplasia) within the fibroadenoma was found in 32.3% of cases. Carcinoma in situ (CIS; 5 ductal, 3 lobular) was found in 8 fibroadenomas (2.0%) removed from 6 patients, the youngest of whom was 40 years of age. In 3 cases CIS was not confined to the fibroadenoma, but also involved the adjacent parenchyma. No invasive carcinoma was present within this series. Complex histologic features were seen in 40.4% of cases, mostly in relatively older patients (mean age, 35.4 years). Hyperplasia in adjacent tissue was found in 8.8% of cases, usually in older patients (mean age, 45.5 years). Known risk-elevating lesions in and around breast fibroadenomas occur frequently and mostly in patients older than 35 years. These findings may have consequences for the clinical management of a subgroup of patients with fibroadenoma.

Nuclear cytometric changes in breast carcinogenesis.

Breast cancer is thought to originate through progressively aberrant precursor lesions, paralleled by increasing morphological changes. The aim of this study was to quantify nuclear features by image cytometry in invasive breast cancer and its early (hyperplasia) and late (ductal carcinoma in situ) precursor lesions, in order to objectively describe nuclear changes in the spectrum of proliferative intraductal and invasive breast lesions. Image cytometry was performed on tissue sections of 20 samples of normal breast tissue, 71 of usual ductal hyperplasia (UDH), nine of atypical ductal hyperplasia (ADH), and 11 of well-differentiated and 13 of poorly differentiated ductal carcinoma in situ (DCIS) lesions. The invasive breast carcinomas consisted of 19 well-differentiated and 24 poorly differentiated lesions. Through the spectrum from normal breast tissue to invasive carcinoma, progressive changes in many nuclear features were measured. Significant differences were found between nuclei of florid ductal hyperplasia compared with mild and moderate ductal hyperplastic lesions, suggesting that florid ductal hyperplasia may be a more advanced lesion than assumed and may contain cancer precursor cells. No differences were found between ADH and well-differentiated DCIS, suggesting that these lesions are closely related. Feature values of well-differentiated DCIS were comparable to values found in well-differentiated invasive carcinoma and the same applied to poorly differentiated DCIS and invasive lesions. These results support the hypothesis that breast cancer develops through different routes of progression, one leading to well-differentiated invasive cancer through well-differentiated DCIS, and one leading to poorly differentiated invasive cancer through poorly differentiated DCIS. In conclusion, image cytometry reveals progressive changes in nuclear morphological and subvisual chromatin distribution features in the spectrum from intraductal proliferations to invasive breast cancer. This provides evidence for a progression from usual to atypical ductal hyperplasia and then to invasive cancer, through different routes for well-differentiated and poorly differentiated lesions.

Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis.

BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates gene expression in critical pathways involved in tumor growth and metastases. In this report, we investigated whether the level of HIF-1 alpha is increased during carcinogenesis in breast tissue and is associated with other tumor biomarkers. METHODS: Paraffin-embedded clinical specimens from five pathologic stages of breast tumorigenesis and from normal breast tissue were used. HIF-1 alpha protein and the biomarkers vascular endothelial growth factor (VEGF), HER-2/neu, p53, Ki-67, and estrogen receptor (ER) were identified immunohistochemically, and microvessel density (a measure of angiogenesis) was determined. Associations among levels of HIF-1 alpha and these biomarkers were tested statistically. All statistical tests are two-sided. RESULTS: The frequency of HIF-1 alpha-positive cells in a specimen increased with the specimen's pathologic stage (P<.001, chi(2) test for trend) as follows: normal breast tissue (0 specimens with > or = 1% HIF-1 alpha-positive cells in 10 specimens tested), ductal hyperplastic lesions (0 in 10), well-differentiated ductal carcinomas in situ (DCIS) (11 in 20), well-differentiated invasive breast cancers (12 in 20), poorly differentiated DCIS (17 in 20), and poorly differentiated invasive carcinomas (20 in 20). Increased levels of HIF-1 alpha were statistically significantly associated with high proliferation and increased expression of VEGF and ER proteins. In DCIS lesions, increased levels of HIF-1 alpha were statistically significantly associated with increased microvessel density. HIF-1alpha showed a borderline association with HER-2/neu but no association with p53. CONCLUSIONS: The level of HIF-1 alpha increases as the pathologic stage increases and is higher in poorly differentiated lesions than in the corresponding type of well-differentiated lesions. Increased levels of HIF-1 alpha are associated with increased proliferation and increased expression of ER and VEGF. Thus, increased levels of HIF-1 alpha are potentially associated with more aggressive tumors.

Correlation of morphologic and cytogenetic parameters of genetic instability with chromosomal alterations in in situ carcinomas of the breast.

Classification of preinvasive breast disease could be better founded using biologic markers, thereby increasing reproducibility. We studied 57 breast ductal and lobular in situ carcinomas by means of comparative genomic hybridization and correlated these findings with quantitative features such as the mean nuclear area, mitotic index (MI), apoptotic index (AI), and the presence or absence of necrosis. Loss of 8p and gains of 8q and 6q were associated, respectively, with a significantly higher MI and AI, whereas loss of 16q was associated with a lower MI and AI. A significantly higher number of alterations per case were seen in tumors with gains of 6q, 8q, and 17q and tumors with loss of 13q. Loss of 16q and gain of 17q correlated with the absence or presence of necrosis, respectively. Our data clearly demonstrate that distinct cytogenetic changes correlate with phenotypic changes, proliferation, and apoptosis. These data may be used to refine existing classification schemes.