Positive predictive value for malignancy on surgical excision of breast lesions of uncertain malignant potential (B3) diagnosed by stereotactic vacuum-assisted needle core biopsy (VANCB): a large multi-institutional study in Italy.

Percutaneous core biopsy (CB) has been introduced to increase the ability of accurately diagnosing breast malignancies without the need of resorting to surgery. Compared to conventional automated 14 gauge needle core biopsy (NCB), vacuum-assisted needle core biopsy (VANCB) allows obtaining larger specimens and has recognized advantages particularly when the radiological pattern is represented by microcalcifications. Regardless of technical improvements, a small percentage of percutaneous CBs performed to detect breast lesions are still classified, according to European and UK guidelines, in the borderline B3 category, including a group of heterogeneous lesions with uncertain malignant potential. We aimed to assess the prevalence and positive predictive values (PPV) on surgical excision (SE) of B3 category (overall and by sub-categories) in a large series of non-palpable breast lesions assessed through VANCB, also comparison with published data on CB. Overall, 26,165 consecutive stereotactic VANCB were identified in 22 Italian centres: 3107 (11.9%) were classified as B3, of which 1644 (54.2%) proceeded to SE to establish a definitive histological diagnosis of breast pathology. Due to a high proportion of microcalcifications as main radiological pattern, the overall PPV was 21.2% (range 10.6%-27.3% for different B3 subtypes), somewhat lower than the average value (24.5%) from published studies (range 9.9%-35.1%). Our study, to date the largest series of B3 with definitive histological assessment on SE, suggests that B3 lesions should be referred for SE even if VANCB is more accurate than NCB in the diagnostic process of non-palpable, sonographically invisible breast lesions.

Characterisation of carotid atherosclerotic plaque: comparison between magnetic resonance imaging and histology.

PURPOSE: The aim of this study was to identify and characterise by magnetic resonance imaging (MRI) carotid plaque constituents such as lipid-rich necrotic core, intraplaque haemorrhage and calcification in patients treated with carotid endarterectomy (CEA) using histological evaluation as the reference standard. MATERIALS AND METHODS: Nineteen patients (13 men and six women) scheduled for CEA between March and August 2004 were imaged on a 1.5-T scanner (Magnetom Symphony, Siemens, Erlangen, Germany). The protocol included four types of sequences [T1, T2, proton density (PD) and three-dimensional time of flight (3D-TOF)]. Images were reviewed for integrity of the fibrous cap, presence of lipid-rich necrotic core, intraplaque haemorrhage and calcification. Signal intensity was assessed relative to the adjacent sternocleidomastoid muscle. Four cross-sections for each lesion were compared with the corresponding histological specimens and independently reviewed by two radiologists and one pathologist. RESULTS: MRI detected lipid-rich necrotic core with a sensitivity and specificity of 91.6% and 95.0%, respectively, whereas it defined intraplaque haemorrhage alone with a sensitivity and specificity of 91.6% and 100%, respectively. Calcification was recognised with a sensitivity and specificity of 80% and 93.7%, respectively. CONCLUSIONS: MRI is able to identify signs of carotid plaque instability with a high sensitivity and specificity. Therefore, it may be useful in evaluating and guiding the treatment of haemodynamically nonsignificant stenoses with a potential embolic risk and, in the future, to assess coronary plaque.

Peritoneal cytology does not increase the prognostic information provided by TNM in gastric cancer.

BACKGROUND: This study aimed at verifying whether peritoneal cytology could improve the prognostic information provided by TNM staging in gastric cancer patients. METHOD: The presence of free peritoneal tumor cells was investigated in 168 patients who underwent curative resection for gastric cancer from January 1992 to July 2002 in Verona, Italy. The influence of peritoneal cytology on survival was evaluated by a Cox regression model, controlling for potential confounders. RESULTS: Twenty-three patients (14%) had positive peritoneal cytology. Patients with positive lavage were more likely to present serosal infiltration (100 vs. 46%) and nodal metastases (91 vs. 67%; P < 0.001). Positive lavage was associated with a very poor prognosis: 3-year survival was only 9% (95% CI 2-27%) when peritoneal cancer cells had been detected, whereas survival reached 50% (95% CI 42-59%) in patients with a negative cytology. In multivariate survival analysis, peritoneal cytology was an independent predictor of mortality when controlling for sex, age, site, histology, and nodal metastases, but not when adjusting also for depth of tumor invasion (RR of positive versus negative = 1.2, 95% CI 0.7-2.0). Similarly, the influence of peritoneal cytology on survival was no longer significant when univariate analysis was restricted to T3/T4 patients (RR = 1.5, 0.9-2.5). CONCLUSIONS: Positive peritoneal cytology was a marker of poor prognosis in gastric cancer patients. Nevertheless, peritoneal lavage did not increase the prognostic information already provided by the TNM staging system in this Italian series.

[Breast calcifications with percutaneous vacuum-assisted biopsy diagnosis of malignancy or atypical hyerplasia: correlations with surgical findings]. / Calcificazioni mammarie con diagnosi di malignità o iperplasia atipica su biopsia percutanea vacuum-assisted: correlazioni dopo escissione chirurgica.

Percutaneous, stereotactic, vacuum-assisted biopsy has become a widely used alternative to open surgical biopsy for the initial diagnosis of breast calcifications. We retrospectively assessed the accuracy of the technique in the diagnoses of malignancy and atypical hyperplasia by correlation with the findings of the subsequent surgical excision. We studied 330 consecutive cases of breast calcifications, 216 (65.5%) of which were determined to be benign and 114 (34.5%) to be malignant or atypical at vacuum-assisted biopsy using an 11 gauge instrument. Of the latter 93 were available for comparison with the subsequent surgery, the specific diagnoses as revealed by percutaneous biopsy were as follows: 11 cases of atypical ductal hyperplasia (ADN), 67 cases of ductal carcinoma in situ (DCIS), 6 infiltrating ductal carcinomas (IFDC), 2 cases of atypical lobular hyperplasia and 7 of lobular carcinoma in situ (LCIS). At histological analysis after surgical excision, 3 (27%) of 11 cases previously diagnosed as ADH and 6 (9%) of 67 cases diagnosed as DCIS were shown to actually be higher grade lesions (DCIS/IFDC and IFDC, respectively). Of the 7 lesions diagnosed at vacuum-assisted biopsy as LCIS, surgery and histological analysis showed one infiltrating globular carcinoma and two DCIS. A total of 21 lesions (4 ADH, 14 DCIS, 1 IFDC, 2 LCIS) were completely removed at percutaneous biopsy; the remaining cases were found totally concordant. These data Indicate a substantial accuracy of the percutaneous biopsy: some lesions (particularly those thought to be ADH and DCIS) can be underestimated for sampling error.

Leiomyosarcoma of the bladder fourteen years after cyclophosphamide therapy for retinoblastoma.

We report a case of bladder leiomyosarcoma which occurred in a 22-year-old female who had been treated with cyclophosphamide for a period of 68 months for retinoblastoma diagnosed at 18 months postpartum. Partial cystectomy was performed. Forty-two months after the operation she is tumor-free.

Comparative study of clinical, pathological and biological characteristics of symptomatic versus asymptomatic breast cancers.

BACKGROUND: It is well known that mammographic screening reduces breast cancer mortality. One possible explanation for this effect is that screening makes it possible to detect smaller breast cancers with fewer involved nodes, but another hypothesis is that some screening-detected tumors are in a pathologically and biologically different phase of evolution from those that are detected clinically. The aim of the present study was to compare the biological, pathological and clinical characteristics of symptomatic vs. asymptomatic breast cancers. PATIENTS AND METHODS: The study considers a series of 1916 consecutive patients who underwent surgery for stage I and II infiltrating breast cancer at Verona hospitals after having undergone ultrasound and mammography (at least one of which was positive). They were divided into two groups on the basis of why they decided to undergo the imaging examinations: group A refers to the 1247 patients with a palpable lump, and group B to the 616 who were asymptomatic. RESULTS: The patients in group A were older, and had larger tumors and a higher percentage of positive nodes than those in group B; they also had significantly higher grade tumors, higher Ki-67 levels, and a higher percentage of ER and PgR negative and c-erbB-2 positive tumors (all of the P-values were significant). A logistic regression analysis adjusted for tumor diameter and age showed a reduction in the significance of each of the considered variables, but all of them remained significantly associated with the modality of diagnosis except ER, PgR and c-erbB-2. CONCLUSIONS: Our results suggest that asymptomatic tumors are biologically different from their clinically presenting counterparts, thus confirming the hypothesis that progression towards greater malignancy may occur during the natural history of breast cancer.

Epithelioid and spindle-celled leiomyosarcoma of the heart. Report of 2 cases and review of the literature.

BACKGROUND: Primary cardiac leiomyosarcomas are rare. Isolated reported cases and small series generally describe spindle-celled, high-grade tumors with poor short-term survival; however, the pathologic features of many of these tumors are incompletely documented. The authors report in detail the clinicopathologic features of 2 relatively low-grade epithelioid and spindle-celled primary cardiac leiomyosarcomas. METHODS: Cases 1 and 2 were studied using standard histochemical and immunohistochemical techniques, and case 1 was examined by electron microscopy. The literature was reviewed with regard to primary cardiac leiomyosarcomas. RESULTS: Both tumors showed epithelioid and spindle-celled areas. The tumor in case 1 was low grade, and the tumor in case 2 was predominately low grade with a high-grade focus. A review of 28 reported cases revealed a wide age range (mean, 43 years), equal male-to-female ratio, and a predilection for the left atrium (48%). Follow-up of reported cases with fewer than 5 mitoses per 10 high-power fields showed a mean survival of 22 months compared with a 9-month mean survival for all others. CONCLUSIONS: Short-term follow-up of reported cases of high-grade cardiac leiomyosarcoma suggests a poor prognosis. Long-term follow-up in our case 2, along with follow-up of reported cases that were histologically similar to our cases, suggests that cardiac leiomyosarcomas with low-grade features or mixed low- and high-grade features also have a poor overall long-term survival, with a high rate of local recurrence and systemic spread.

bcl-2 but not p53 expression is associated with resistance to chemotherapy in advanced breast cancer.

Programmed cell death is an important determinant of the response to chemotherapy. Among the factors controlling this process, a significant role is played by bcl-2 and p53, the expression of which, together with estrogen receptor content and tumor proliferative activity, was investigated by means of immunohistochemistry in 55 advanced breast cancer patients (median age, 60 years; range, 25-71 years). Analysis of bcl-2 expression identified two groups of patients with a significant difference in response rate. A total of 17 patients (31%) responded to chemotherapy (5 had a complete response and 12 had a partial response): 14 of 32 (44%) bcl-2-negative patients (< 40% stained cells) and only 3 of 23 (13%) bcl-2-positive patients (> or = 40% of stained cells; P = 0.019 by Fisher's exact test). The two groups were well balanced in terms of age, performance status, disease-free survival, menopausal status, and type of chemotherapy. bcl-2-negative tumors showed a tendency toward a higher p53 expression and proliferation rate, whereas an excess of bone as the dominant disease site was evident among the bcl-2-positive ones. However, the only variable to result significantly different between the two groups was estrogen receptor expression (P = 0.004). A multivariate logistic regression model showed that bcl-2 maintained its power of discriminating two groups with a different probability of responding to chemotherapy, although the greatest contribution was given by dominant disease site and type of chemotherapy. In conclusion, the results of this study suggest a possible role for bcl-2 in predicting resistance to chemotherapy.

Prognostic significance of estrogen receptors in 405 primary breast cancers: a comparison of immunohistochemical and biochemical methods.

Over the last few years, estrogen receptor determination by means of immunohistochemistry has been extensively used. The aim of this study was to compare this technique with estrogen receptor determination by means of dextran-coated charcoal, and to evaluate whether one of the two methods is more predictive of prognosis. Estrogen receptors were determined by means of both the dextran-coated charcoal method and immunohistochemistry in 405 patients with primary breast cancer; age, pathological tumor size, nodal status, and progesteron receptors by dextran-coated charcoal method were also recorded. The disease-free and overall survival probabilities were estimated using the product-limit method; Cox's proportional hazard model was used to evaluate the prognostic role of estrogen receptors as determined by the two methods. There appears to be a close association between estrogen receptor determination by the two methods (81.5% of concordant results) and their prognostic role was similar, even when the patients were divided into different groups (on the basis of their estrogen receptor status) and adjustments for the effect of other prognostic variables were taken into account. Our study shows that the two methods can be used indifferently to evaluate estrogen receptor status as a prognostic factor in breast cancer patients.

Ki-67 immunostaining in 322 primary breast cancers: associations with clinical and pathological variables and prognosis.

Cell-proliferation markers are very important in the clinical management of cancer patients, and the identification of Ki-67 (a monoclonal antibody that recognizes proliferating cells) can make it easier to define the level of proliferative activity. This study investigated the associations between the Ki-67 levels measured by means of immunohistochemistry, and other clinical and pathological variables and prognosis in 322 breast-cancer patients. A significant association was found (p < 0.001) between Ki-67 values and tumor size, nodal status, estrogen and progesterone receptor status; multivariate analysis showed that Ki-67 levels were associated with disease-free and overall survival, thus confirming that it is an independent prognostic variable. Various statistical approaches were used in an attempt to establish the best cut-off point for dividing patients into groups at high or low risk of relapse but, in this series, we could find no evidence leading to a single "best" cut-off point. We conclude that the quantitative level of Ki-67 could be used as a prognostic factor in breast-cancer patients.

Bone marrow micrometastases in 109 breast cancer patients: correlations with clinical and pathological features and prognosis.

BACKGROUND: The presence in bone marrow of cells which react with monoclonal antibodies against tumor-associated antigens has been proposed over the last few years as a new prognostic factor in breast cancer patients. PATIENTS AND METHODS: Bone marrow aspirates were obtained from 109 stage I and II breast cancer patients during or 2-4 weeks after primary surgery. The samples were processed for leukocyte separation on a Ficoll-Hypaque gradient and then used to prepare cytospin slides for immunocytochemical analysis. The slides were stained with a pool of monoclonal antibodies (MoAbs) which recognize tumor associated antigens, using the alkaline phosphatase anti-alkaline phosphatase method. The median follow-up was 36 months (range 15-62): 22 patients relapsed and 7 died. RESULTS: Thirty-four of the 109 patients (31.1%) had MoAb positive bone marrow cells. The bone marrow was positive in 28/74 (37.9%) patients who had the aspirate taken during surgery and in 6/35 (17.1%) who had it taken after surgery (p = 0.055). No association was found between bone marrow positivity and tumour size, nodal status, menopausal status, estrogen receptor positivity or the proliferative index. No association was found between bone marrow and prognosis: the log-rank test was 0.291 (p > 0.5) for OS and 0.023 for DFS; the hazard ratio (positive vs negative) was 1.51 for OS (95% CI: 0.33-6.86) and 0.93 for DFS (95% CI: 0.35-2.45). CONCLUSIONS: In our series, bone marrow positivity did not correlate with prognostic parameters or prognosis. Of interest is the relative excess of positivity when the bone marrow was obtained during surgery.

Tumor proliferative activity and response to first-line chemotherapy in advanced breast carcinoma.

The relationship between tumor proliferative activity and response to first-line chemotherapy and survival was investigated in 76 advanced breast cancer patients. Proliferative activity was determined by means of Ki-67 immunohistologic staining on primary tumors (55 patients) or at the relapse site (21 patients), and was classified as low ( < or = 25% of stained cells) or high ( > 25% of stained cells). The usual WHO response criteria were used. The median duration of follow-up was 18 months (range 3-58). Forty-seven patients (62%) had tumors with low, and 29 (38%) had tumors with a high rate of proliferative activity. The two groups were well balanced in terms of important variables such as disease-free survival, performance status, age, menopausal status, and the type of first-line chemotherapy (anthracycline-based regimens versus cyclophosphamide-methotrexate-5-fluorouracil). The estrogen receptor (ER) content, measured by means of immunohistochemical assay, was markedly different in the two groups, with 27/47 tumors with low proliferative activity (57%) and 6/29 with high-proliferative activity (21%) being ER positive ( > or = 45% of stained cells) (p = 0.003). Moreover, a significant difference in the metastatic pattern was also evident, with a higher incidence of bone and a lower incidence of soft tissue metastases in the group of patients with tumors with low proliferative activity (p = 0.004). Overall, 10/47 responses (21%: PR = 7, and CR = 3) were observed in the group with a low rate of proliferative activity, versus 14/29 (48%: PR = 9, and CR = 5) in the group with highly proliferative tumors, the difference being statistically significant (p = 0.03). When a multivariate analysis was performed, the only factor that retained independent prognostic significance was the predominant site of disease, particularly soft tissues (p = 0.003). Despite the difference in response rate, when survival analysis was performed according to the Kaplan-Meier method, no significant difference was observed in the two groups, but when the analysis was limited to responsive patients, the median survival observed in those with a low and those with a high rate of proliferation was 35 and 19 months respectively (p = 0.02). The same results were obtained when multivariate survival analysis was carried out using Cox's regression model. These data suggest that there is a link between tumor proliferative activity and response to chemotherapy in advanced breast cancer, and may indicate the need to use more intensive treatments in selected patients with highly proliferative tumors.

Estrogen receptors in 699 primary breast cancers: a comparison of immunohistochemical and biochemical methods.

BACKGROUND: Over the last few years, estrogen receptor (ER) determination by immunohistochemistry (ER-ICA) has been extensively used, but it still remains to be established whether this method can replace the standard biochemical technique using dextran-coated charcoal (ERDCC). PATIENTS AND METHODS: ER were determined by both the dextran-coated charcoal (DCC) method and immunohistochemistry (ICA) in 699 patients with primary breast cancer; other parameters (age, pathological T-pT- and nodal status -pN-, progesterone receptors by DCC, proliferative index by ICA) were also recorded. The 'best' cut-off for ERICA was evaluated by means of Receiver Operating Characteristics (R.O.C.) analysis; logistic regression analysis was used to find adequate 'weights' for stain intensity. RESULTS AND CONCLUSIONS: A significant correlation was found between the two methods (p < 0.001). R.O.C. analysis revealed that the 'best' cut-off for the ERICA score was 45% (sensitivity 0.810, specificity 0.804). Logistic regression analysis showed that an ERICA score which also considers staining intensity does not add any useful information concerning ER content in breast cancers.

Expression of proliferating cell nuclear antigen, Ki-67 antigen, estrogen receptor protein, and tumor suppressor p53 gene in cytologic samples of breast cancer: an immunochemical study with clinical, pathobiological, and histologic correlations.

Sixty-six unselected breast cancers were analyzed in cytologic smears and histologic sections for the expression of Ki-67, proliferating cell nuclear antigen (PCNA), estrogen receptor protein (ERP), and p53 protein using a standard immunochemical method. The results, expressed as both positive cases and labelling index (LI), were compared with clinical and pathobiological variables. Ki-67 and PCNA immunostaining was seen in all cases, whereas ERP was detectable in 46/63 cases and p53 protein in 20/66 cases. The expression of these markers was generally lower in cytology than in histology, though the differences were not statistically significant. PCNA-LI and Ki-67-LI were closely correlated (P < 0.001), the mean PCNA:Ki-67 ratio being 0.92 +/- 0.57. Occasional discrepancies, however, were found. PCNA and Ki-67 expression was associated with an increase in histologic grade and a decrease in ERP content of tumors, whereas p53 was statistically associated with no clinical or pathobiological variables. The data suggest that proliferative activity and oncogene overexpression may be reliably evaluated in breast cancer by FNA cytology, though PCNA is not a suitable indicator for cell proliferation. The results do not resolve the issue as to whether immunostaining for p53 protein constitutes a dedifferentiation product of the tumor, or is a fundamental aspect of the malignant progression. Survival studies in a larger series of tumors are thus needed to elucidate this point.

False-positive immunostaining of normal epithelia and carcinomas with ascites fluid preparations of antimelanoma monoclonal antibody HMB45.

HMB45 is a melanoma-specific monoclonal antibody that has found widespread use in diagnostic pathology. Recent reports, however, have suggested that this antibody may cross-react with a small number of carcinomas and other epithelial cells. The authors tested the hypothesis that these latter reports represent examples of false-positive immunostaining by comparing the immunostaining on breast, salivary gland, and lung tumors with the following: (1) a commercial ascites preparation of this monoclonal antibody; (2) a protein A-purified antibody preparation derived from ascites fluid; and (3) supernatant fluid obtained from the hybridoma cell line. The authors found that all examples of nonmelanoma immunostaining in the carcinomas tested were eliminated with the nonascites fluid preparations, whereas strong immunostaining of melanomas was retained. The authors conclude that contaminated commercial ascites fluid preparations of HMB45 may account for most, if not all, of the reports of nonmelanoma immunostaining with HMB45.

[Epithelial splenic cysts]. / Cisti splenica epiteliale.

The authors describe a case of an epithelial cyst of the spleen treated successfully by splenectomy. Diagnostic techniques and the principles adopted in treatment this rare disease are discussed.