Is tissue inhibitor of metalloproteinase-1 a new prognosticator for breast cancer? An analysis of 266 cases.

Overexpression of tissue inhibitor of metalloproteinase-1 at either the messenger RNA or protein level has been related to a poorer prognosis in breast cancer. We investigated the role of tissue inhibitor of metalloproteinase-1 tissue expression, which was evaluated by immunohistochemistry staining of paraffin-embedded samples, as a possible prognostic indicator in breast cancer. The study included 266 patients treated by primary surgery. Tumors were scored tissue inhibitor of metalloproteinase-1 positive when at least 10% of the cells showed moderate or strong staining. Staining was observed in 76 (28.6%) patients; by multivariate analysis, factors independently associated with tissue inhibitor of metalloproteinase-1 positivity included more than 9 metastatic axillary nodes, high Mib-1 expression, and positivity for plasminogen activator inhibitor and CD44. With a median follow-up of 125 months, tissue inhibitor of metalloproteinase-1 expression showed a significant prognostic role in disease-free and overall survival by univariate analysis. Multivariate analysis confirmed an independent negative prognostic impact of tissue inhibitor of metalloproteinase-1 on overall but not disease-free together with high values of Mib-1. The number of involved axillary nodes, and triple negativity were independent predictors of either poorer disease-free or overall survival. In our study, tissue inhibitor of metalloproteinase-1 expression was significantly related to markers of tumor aggressiveness and was a powerful indicator of poorer prognosis, with a difference in 10-year disease-free and overall survival of 14% and 28%, respectively, between tissue inhibitor of metalloproteinase-1-negative and tissue inhibitor of metalloproteinase-1-positive cases. Expression of tissue inhibitor of metalloproteinase-1 also was an independent prognostic factor in node-positive cases, indicating a possible role of tissue inhibitor of metalloproteinase-1 as a marker of reduced chemosensitivity. Thus, tissue inhibitor of metalloproteinase-1 may have a role in clinical practice as a prognostic and predictive factor and a possible target for future therapies.

Treatment of peritoneal carcinomatosis with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: state of the art and future developments.

Peritoneal carcinomatosis (PC) had long been regarded as a terminal disease, characterized by a very poor survival and worth treating with palliative therapy. A new strategy combining maximal surgery (cytoreductive surgery, CRS), with maximal regional chemotherapy (hyperthermic intraperitoneal chemotherapy, HIPEC), has been proposed to treat PC, resulting in long-term survival rates in selected patients. The emerging trend is to view localised peritoneal carcinomatosis, in the absence of other metastases, as a regional metastatic disease that is amenable to locoregional therapy. In spite of the need for more high quality studies, many international experts now agree that the use of this new strategy is a gold standard for treating selected patients with PC with the intent of curing. The best results are achieved in patients with limited disease who have completed macroscopic tumor removal. To offer a comprehensive review, we summarized the present status and possible future progress of this treatment modality, in particular outlining its rationale, current practice and general outcome.

Safety and potential benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in peritoneal carcinomatosis from primary or recurrent ovarian cancer.

OBJECTIVES: To analyze the outcomes of cytoreductive surgery and HIPEC in patients with peritoneal carcinomatosis from ovarian cancer. METHODS: Fifty-three patients with peritoneal carcinomatosis from primary (45 cases) and recurrent (8 cases) ovarian cancer were previously treated by systemic chemotherapy with platinum and taxanes and then submitted to surgical cytoreduction and HIPEC (cisplatin and mitomycin-C) with a closed abdomen technique. The median follow-up period was 27 months (range: 3-107). RESULTS: At the end of operation a complete cytoreduction (CCR-0) was obtained in 37 patients (70%). Major morbidity occurred in 12 patients (23%); reoperation was necessary in 2 patients (4%), and no postoperative mortality was observed. Overall 5-year survival probability was 55%; it was 71% in CCR-0, 44% in CCR-1, and none in patients with CCR-2 or CCR-3 residual tumor (log-rank test: P = 0.017). The cumulative risk of recurrence in 37 CCR-0 cases was 54% at 5 years from operation. CONCLUSIONS: The results of our study indicate the feasibility and the potential benefit of a protocol including systemic chemotherapy, surgical cytoreduction and HIPEC in patients with peritoneal carcinomatosis from ovarian cancer. A phase III trial to compare this approach with conventional treatment is needed.

Impact of age-related comorbidity on results of colorectal cancer surgery.

AIM: To analyze the correlation between preexisting comorbidity and other clinicopathological features, short-term surgical outcome and long-term survival in elderly patients with colorectal cancer (CRC). METHODS: According to age, 403 patients operated on for CRC in our department were divided into group A (< 70 years old) and group B (> or = 70 years old) and analyzed statistically. RESULTS: Rectal localization prevailed in group A (31.6% vs 19.7%, P = 0.027), whereas the percentage of R0 resections was 77% in the two groups. Comorbidity rate was 46.2% and 69.1% for group A and B, respectively (P < 0.001), with a huge difference as regards cardiovascular diseases. Overall, postoperative morbidity was 16.9% and 20.8% in group A and B, respectively (P = 0.367), whereas mortality was limited to group B (4.5%, P = 0.001). In both groups, patients who suffered from postoperative complications had a higher overall comorbidity rate, with preexisting cardiovascular diseases prevailing in group B (P = 0.003). Overall 5-year survival rate was significantly better for group A (75.2% vs 55%, P = 0.006), whereas no significant difference was observed considering disease-specific survival (76.3% vs 76.9%, P = 0.674). CONCLUSION: In spite of an increase in postoperative mortality and a lower overall long-term survival for patients aged > or = 70 years old, it should be considered that, even in the elderly group, a significant number of patients is alive 5 years after CRC resection.

Correlation of microsatellite instability at multiple loci with long-term survival in advanced gastric carcinoma.

HYPOTHESIS: Microsatellite instability (MSI) correlates with clinicopathologic characteristics and long-term prognosis in patients having gastric carcinoma. DESIGN: Analysis of prospectively collected data and biologic material. SETTING: Tertiary University Hospital, Policlinico "Le Scotte," Siena, Italy. PATIENTS: Two hundred fifty patients with gastric carcinoma. MAIN OUTCOME MEASURES: Five mononucleotide repeats (BAT-26, BAT-25, NR-24, NR-21, and NR-27) were analyzed in these patients. RESULTS: An MSI phenotype was identified in 63 patients (25.2%) and correlated with specific clinicopathologic characteristics. Favorable prognosis was confirmed for patients with an MSI phenotype in univariate (P < .001) and multivariate (P = .05) analyses. Significant differences in clinicopathologic characteristics and long-term prognoses were observed among patients with microsatellite-stable tumors, tumors having instability at 2 to 4 markers, and tumors having instability at all 5 markers (MSI/5). The MSI/5 phenotype was associated with older age (P < .001), female sex (P = .001), antral tumor location (P = .04), intestinal histotype (P = .003), and less infiltration of the serosa (P = .006); lymph node involvement was rare (P < .001) and was limited to few (median, 3) metastatic lymph nodes (P = .001). Long-term survival of patients with the MSI/5 phenotype is favorable and was confirmed in multivariate analysis (relative risk vs patients with stable tumors, 0.32; 95% confidence interval, 0.16-0.63; P = .002). CONCLUSIONS: Compared with stable tumors, MSI tumors have distinct clinicopathologic features and are associated with a better prognosis. Patients with the MSI/5 phenotype have a very good prognosis.

Different pathological features and prognosis in gastric cancer patients coming from high-risk and low-risk areas of Italy.

OBJECTIVE: To compare clinicopathological features and long-term outcome in gastric cancer patients coming from high-risk and low-risk areas of Italy. SUMMARY BACKGROUND DATA: Better survival rates have been reported from countries with higher incidence of gastric cancer. METHODS: Data regarding 829 patients coming from Tuscany (group A) and 143 patients coming from Southern Italy (group B) were analyzed. Mean follow-up time was 56 +/- 57 months; it was 85 +/- 63 months in surviving patients or not tumor-related deaths. Prognostic factors were investigated by multivariate analysis with Cox proportional hazard model after verifying the assumption of proportionality of the risk associated with covariates. RESULTS: Lauren diffuse-mixed histotype, younger age, extended lymphadenectomy, and advanced stages were more common in group B. Gastric cancer-related 10-year survival probability was 48% in group A versus 29% in group B (log-rank test: P < 0.001). By multivariate analysis, geographic area was confirmed as a significant prognostic factor (hazard ratio for group B vs. group A: 1.52, 95% confidence interval: 1.12-2.06, P = 0.006). The influence of this factor on long-term survival was independent from other clinical, surgical, and pathologic factors, and was notable in neoplasms involving the serosa (10-year survival probability: 15% in group A vs. 3% in group B, log-rank test: P = 0.005). CONCLUSIONS: Patients coming from low-risk area of Italy showed distinct pathologic features, more advanced stage, and worse prognosis when compared with patients coming from high-risk area. These findings may be indicative of different tumor biology, and may contribute to partly explain worldwide geographic variability in prognosis reported in different series.

CA19-9 serum levels in obstructive jaundice: clinical value in benign and malignant conditions.

BACKGROUND: Obstructive jaundice is frequently associated with false CA19-9 elevation in benign conditions. The diagnostic accuracy of this tumor marker was evaluated in the present longitudinal study. METHODS: In 128 patients admitted for obstructive jaundice (87 with pancreato-biliary malignancy and 41 benign disease) serum CA19-9 was measured. Statistical analysis of marker levels obtained before and after endoscopic biliary drainage was performed in 60 patients. RESULTS: Elevated CA19-9 levels (>37 U/mL) were found in 61% of benign cases and 86% of malignancies. After biliary drainage, decrease of serum CA19-9 was observed in 19 of 38 malignant cases and in almost all benign cases (Wilcoxon matched pairs test: P = .207 and P <.001, respectively). Receiver operating characteristic (ROC) analysis identified a cut-off value of 90 U/mL to be associated with improved diagnostic accuracy after biliary drainage (sensitivity 61%, specificity 95%). CONCLUSIONS: In the presence of successfully drained obstructive jaundice, CA19-9 serum levels that remain unchanged or measure more than 90 U/mL are strongly indicative of a malignant cause of obstruction. However, the real clinical utility of this marker remains controversial.

CDH1 C-160A promoter polymorphism and gastric cancer risk.

The objective of this study was to find out whether C-160A single nucleotide polymorphism of the promoter region of the E-cadherin gene might be a potential genetic marker for identifying individuals at risk for gastric cancer (GC). To test this hypothesis, 412 GC patients and 408 controls were analyzed statistically. A PCR-restriction fragment length polymorphism assay was adopted for C-160A single nucleotide polymorphism detection. No statistical differences were found among CC, CA, and AA genotypes and the risk of GC, even stratifying according to age, sex, and area of residence. Similarly, genotype was not associated with intestinal or diffuse histotypes, or with cardia or noncardia carcinomas. In conclusion, the C-160A polymorphism is not associated with GC risk in the Italian population.

[Surgical treatment of gastric cancer]. / Il trattamento chirurgico del carcinoma gastrico.

Despite the decrease in incidence observed during the last decades, gastric adenocarcinoma remains the fourth most common cancer in the world and the second leading cause of cancer-related death. Radical surgical resection is the best treatment option, though the role of extended and super-extended lymphadenectomy remains debatable. This review examines the different issues related to the surgical treatment of early and advanced gastric adenocarcinoma as well as the most recent strategies for the treatment and prevention of peritoneal carcinomatosis.

Treatment of the intraabdominal abscesses through percutaneous ultrasound-guided drainage in oncological patients: Clinical and microbiological data.

AIM OF THE STUDY: Oncological patients are particularly prone to the onset of septic complications such as abdominal abscesses. The aim of our study was to analyze clinical and microbiological data in a population of oncological patients, submitted to percutaneous ultrasound-guided drainage (PUD) for postoperative abdominal abscesses. PATIENTS AND METHODS: Data from 24 patients operated on for neoplastic pathologies and treated with PUD for abdominal abscesses during the postoperative period were reviewed. In all cases cultural examination with antibiogram was performed. RESULTS: In 5 out of 24 patients (20.8%), the abdominal abscesses appeared after the discharge, with a mean hospital stay of 34.2 +/- 24.9 days. In six out of 24 patients (25%) there were multiple abscesses localizations. The cultural examination was positive in 23 patients and negative only in one patient. Abscesses localized only in the upper abdominal regions had a significant prevalence of monomicrobial cultural examinations (57.1%) with respect to the results for abscesses placed in the lower abdominal regions, that were polymicrobial in 88.8% of cases (p = 0.027). An antibiogram demonstrated a stronger activity of beta-lactamines, chinolones, and glycopeptides with respect to aminogycosides, cephalosporins, and metronidazole. CONCLUSIONS: In oncological patients, the planning of the empiric antibiotic therapy should be based on the anatomotopographic localization of the abdominal abscess and on the typology of the operation performed giving preference to beta-lactamines, chinolones and glycopeptides.

Updates on abdominal desmoid tumors.

Desmoid tumor is a monoclonal, fibroblastic proliferation arising in musculoaponeurotic structures. This connective tissue hyperplasia infiltrates locally, recurs frequently after resection but does not metastasize. Abdominal desmoid occurs sporadically, in association with some familial syndromes and often represents a clinical dilemma for surgeons. The enigmatic biology and anatomical location of abdominal desmoids make treatment recommendations difficult. This distinct pathological entity is reviewed with a specific focus on aetiology and management.

Primary osteosarcoma of the kidney with retroperitoneal hemorrhage. Case report and review of the literature.

Primary osteosarcoma of the kidney is a very rare neoplasm with a very poor prognosis and unclear histogenesis. Only 20 cases have been reported in the literature. It has a strong tendency to recur locally and spread to distant sites. We present the clinical case of a 79-year-old man affected by a primary osteosarcoma of the kidney presenting with substantial retroperitoneal tumor hemorrhage. Laparotomy revealed a massive retroperitoneal hematoma due to a bleeding large stony renal mass with multiple bizarre calcifications. The diagnosis of primary renal osteosarcoma was made on the basis of hematoxylin-eosin staining and confirmed by electron microscopy. Hematoma drainage and radical nephrectomy were performed. To our knowledge this is the first case of bleeding renal osteosarcoma reported in the literature. The most important clinical findings, the pathogenesis and the treatment modalities of this rare neoplasm are discussed.

Postoperative complications and functional results after subtotal gastrectomy with Billroth II reconstruction for primary gastric cancer.

Subtotal gastrectomy is considered the preferred treatment for gastric cancer with antral location. The aim of this study was to assess the incidence of early postoperative complications and late functional results in patients who underwent subtotal gastrectomy with Billroth II reconstruction for primary gastric adenocarcinoma. The results of 310 patients were analyzed with regard to postoperative complications and death rates. Functional results as they relate to the gastric resection were evaluated in 195 disease-free patients. Of the 310 patients, 77 developed postoperative general and surgical complications (24.8%) and 13 consequently died (in-hospital mortality: 4.2%). Although infrequent (6 cases, 1.9%), anastomotic leak was the most serious complication (4 cases died during the postoperative phase). Considering functional results, weight loss continued for the first trimester after surgery, after which it stabilized. Loss of appetite was rarely observed; early after the operation the majority of patients were consuming a normal diet and regularly consumed less than five meals per day (83.6%). Dumping syndrome was uncommon and usually resolved within one year (12.3% at three months, 9.5% after one year, 5.2% after two years). On the other hand, postprandial abdominal fullness was frequently observed (43.1% at three months, 36.1% after one year, 21.3% after three years, and 16.5% after five years). Billroth II reconstruction after subtotal gastrectomy is associated with a limited risk of anastomotic complications. Anastomotic leak, although infrequent, is a life-threatening complaint and requires prompt recognition and aggressive surgical treatment. The incidence of late complications was low and the majority of patients recovered from them within one year after surgery, although the occurrence of postprandial abdominal fullness was not completely irrelevant.

Complications after extended (D2) and superextended (D3) lymphadenectomy for gastric cancer: analysis of potential risk factors.

BACKGROUND: Very few studies from Western centers have compared D2 and D3 dissection in the surgical treatment of gastric cancer. The aim of the prospective observational study reported here was to analyze the postoperative outcome and potential risk factors for complications following D2 and D3 lymphadenectomy. METHODS: A total of 330 consecutive patients, of which 251 submitted to D2 lymphadenectomy and 79 were treated by D3 lymphadenectomy, were enrolled in the study. Twenty potential risk factors for morbidity and mortality were studied by means of univariate and multivariate analysis. RESULTS: Overall morbidity and mortality rates were 34% (111 patients) and 4% (14 patients), respectively. Abdominal abscess, anastomotic leakage, pleuropulmonary diseases and pancreatitis were the most commonly observed complications. No differences in morbidity, surgical morbidity, mortality rates and mean hospital stay between D2 and D3 lymphadenectomy were found. Multivariate analysis revealed that American Society of Anesthesiologists' (ASA) class II/III versus class I, perioperative blood transfusions, and low albumin serum levels were independent predictors of postoperative complications. Age, surgical radicality (R1/R2 vs. R0) and low albumin serum levels independently predicted mortality. Mortality rate was .5% in the 203 patients aged 75 years or younger who underwent curative surgery. Most of deaths were observed in patients older than 75 years with low albumin serum levels or treated by non-curative surgery. CONCLUSIONS: D2 lymphadenectomy represents a feasible procedure associated to acceptable morbidity and mortality rates. In specialized centers, D3 lymphadenectomy may be performed without increasing the risk of postoperative complications and associated deaths in carefully selected patients. These techniques should be avoided in subgroups of patients with a high risk of postoperative mortality.

High incidence of familial gastric cancer in Tuscany, a region in Italy.

OBJECTIVES: Only 1% of diffuse gastric cancers occur in families with autosomal dominant gastric cancer susceptibility. Germline mutations in the E-cadherin gene account for the hereditary diffuse gastric cancer (HDGC) syndrome. We studied a large cohort of gastric cancer patients from Tuscany, a region in Italy, to evaluate the presence of familial clustering of gastric cancer. METHODS: 238 pedigrees were retrospectively studied by structured interviews. All probands with diagnosed gastric cancer were contacted in-person or by phone and tumor types were assessed in first- and second-degree relatives. Familial aggregation was investigated in order to search for families with suspected HDGC. RESULTS: Familial aggregation for gastric cancer was observed in 79 of 238 cases (33.2%). Among these, there were 64 families (81%) with one gastric cancer other than the proband, 10 families with two gastric cancers (12.7%) and 5 families with three gastric cancers (6.3%). Fourteen families fulfilled the HDGC clinical criteria, one of them presenting with a pathogenic germline mutation in the E-cadherin gene (7.1%). CONCLUSIONS: The prevalence of familial HDGC appears extremely high. Since only one pathogenic germline mutation was noted in a family fulfilling the HDGC clinical criteria, factors other than E-cadherin gene mutations may contribute to the familial clustering of HDGC.

Treatment of peritoneal carcinomatosis by cytoreductive surgery and intraperitoneal hyperthermic chemoperfusion (IHCP): postoperative outcome and risk factors for morbidity.

BACKGROUND: Cytoreductive surgery with limited or extended peritonectomy associated with intraperitoneal hyperthermic chemoperfusion (IHCP) has been proposed for treatment of peritoneal carcinomatosis (PC) from abdominal neoplasms. METHODS: Fifty-nine patients with PC from abdominal neoplasms underwent 61 treatments using this technique from January 2000 to August 2005. Surgical debulking, completed by partial or total peritonectomy, was performed in most cases. In 16 patients with positive peritoneal cytology without macroscopic peritoneal disease, IHCP was performed in order to prevent peritoneal recurrence. IHCP was carried out throughout the abdominopelvic cavity for 60 minutes using a closed abdomen technique. Intra-abdominal temperature ranged between 41 degrees C and 43 degrees C; mitomycin C (25 mg/mq) and cisplatin (100 mg/mq) were the anticancer drugs generally used, and they were administered with a flow rate of 700-800 ml/minute. RESULTS: Mean hospital stay was 13 +/- 7 (range 7-49) days. Postoperative complications occurred in 27 patients (44.3%); of these, major morbidity was observed in 17 (27.9%). The most frequent complications were wound infection (9 cases), grade 2 or greater hematological toxicity (5 cases), intestinal fistula (5 cases), and pleural effusion requiring drainage (5 cases). Reoperation was necessary in 5 patients (8.2%). One patient with multiorgan failure died in the postoperative period (mortality rate: 1.6%). Multivariate analysis of several variables identified completeness of cancer resection (CCR-2/3 vs. CCR-0/1, relative risk: 9.27) and age (relative risk: 1.06 per year) as independent predictors of postoperative morbidity. Preliminary follow-up data indicate that survival probability may be high in patients with ovarian or colorectal cancer and low in patients with gastric cancer. CONCLUSIONS: IHCP combined with cytoreductive surgery involves a high risk of morbidity, but postoperative complications could be resolved favorably in most cases with correct patient selection and adequate postoperative care. Tumor residual and advanced age significantly increase the risk of morbidity after this procedure.

[Empiric antibiotic therapy in the treatment of postoperative abdominal abscesses. Clinical and microbiological data]. / Antibioticoterapia empirica nel trattamento degli ascessi addominali postoperatori. Dati clinici e microbiologici.

Abdominal abscesses arising postoperatively constitute a serious problem, particularly in the field of oncological surgery. The aim of our study was to interpret clinical and microbiological data relating to a population of oncological patients, undergoing ultrasound-guided drainage for postoperative abdominal abscesses, so as to be able to better plan empiric antibiotic therapy. We therefore retrospectively analysed the data of 24 patients operated on for neoplastic pathologies and treated with ultrasound-guided percutaneous drainage for abdominal abscesses during the postoperative period. Microbiological and clinical data showed that abscesses located in the lower abdominal regions almost always present a polymicrobial growth, though abscesses in the upper regions are more frequent. Moreover, the antibiotic assay results prompted us to consider the use of beta-lactamines, quinolones and glycopeptides more favourably, in view of their greater efficacy against the microbes tested. Thus, the planning of empiric antibiotic therapy should be based above all on the anatomical-topographic location of the abdominal abscess and on the type of operation performed, with thorough assessment of the use of the above-mentioned antibiotics.

Perforated gastric carcinoma: a report of 10 cases and review of the literature.

BACKGROUND: Perforation is a rare complication of gastric carcinoma, accounting for less than 1% of all gastric cancer cases. The aim of the present study is to evaluate the prognostic value of perforation and to point out the surgical treatment options. METHODS: A total of 10 patients with perforated gastric carcinoma were retrospectively reviewed among 2564 consecutive cases of gastric cancer operated in three Centers belonging to the Italian Research Group for Gastric Cancer. The clinicopathological features including tumor stage and survival were analyzed and compared to literature data. RESULTS: Incidence rate was 0.39%. All patients underwent emergency surgery, being performed gastrectomy in 6 patients (mortality 17%) and repair surgery in 4 patients (mortality 75%). The survival of patients was related to the stage of the disease, with 2 long-survival cases. CONCLUSION: Perforation usually occurs in advanced stages of gastric cancer; nevertheless surgeons should not be always discouraged from a radical treatment of perforated gastric cancer, since perforation even occurs in early stages and seems not to be a negative prognostic factor itself. When possible, emergency gastrectomy should be performed, leaving repair surgery for unresectable tumors. A two-stage treatment is a good treatment option for frail patients with resectable tumors.

Bcl-2 expression correlates with lymphovascular invasion and long-term prognosis in breast cancer.

Alterations in the mechanisms of apoptosis are responsible not only for the progression of breast cancer, but for different responses to treatment as well. Among the genes regulators of apoptosis, the tumor suppressor gene p53 and the bcl-2 gene have raised interest for their possible role as predictors of response to therapy and markers of prognosis. The purpose of our study was to prospectively analyze the prognostic value of the expression of p53 and bcl-2 genes in a series of 235 consecutive patients operated on for breast cancer at the Department of General Surgery and Surgical Oncology of the University of Siena, Italy.p53 and bcl-2 expression were evaluated by immunohistochemistry, their association with conventional clinicopathological factors was analyzed by univariate analysis and their prognostic impact was evaluated by multivariate analysis.p53 and bcl-2 were detected respectively in 15.7 and 75.7% of cases, and resulted significantly related to presence of estrogen receptors for p53 over-expression and presence of peritumor lymphovascular invasion (LVI) for bcl-2 expression. With a median follow-up of 79 months, an independent negative prognostic impact on disease free and overall survival was observed for presence of LVI, absence of bcl-2 expression and number of involved axillary lymphnodes. The expression of bcl-2 improved the prognosis of LVI positive tumors up to values similar to LVI negative cases, while its absence associated to presence of LVI resulted in a poor outcome with only 28% of patients alive at 8 years. These data may indicate that expression of bcl-2 is a marker of breast cancers with reduced capability of distant colonization, even in presence of LVI, and may be particularly useful in the clinical setting, allowing to identify a subset of patients with an high risk of relapse.