Axillary dissection in patients with preoperative positive nodal cytology: Genuine need or overtreatment?

Recent studies demonstrated the possibility to avoid axillary dissection (ALND) in selected patients with one or two metastatic nodes. Otherwise, patients with positive nodal ultrasound-guided fine-needle aspiration cytology (US-FNAC) currently undergo ALDN. The aim of this study is to quantify the nodal burden in patients with positive US-FNAC treated with ALND and to evaluate if clinical or pathological characteristics associated with low nodal involvement can be identified. This is a multicentric retrospective study involving 297 patients who underwent ALND because of a positive preoperative US-FNAC. A total of 157 patients showed bulky axillary lymph nodes at diagnosis, and 70% of them had three or more metastatic nodes. One hundred and forty patients had a clinically negative axilla and in 50% of them, 4 or more metastatic nodes were found with axillary dissection. Overall, the median number of metastatic nodes was 5. Favorable pathological characteristics of tumors were found in patients with only one or two metastatic nodes: smaller primary tumor, a lower proportion of grade 3, invasive lobular carcinomas and a higher proportion of low-Ki67 tumors. In the group of patients with clinically negative axilla and potentially meeting ACOSOG Z0011 criteria, 22 (31%) showed less than three metastatic axillary nodes. A preoperative positive axillary FNAC is associated with a metastatic nodal burden significantly higher than in patients with positive sentinel lymph node biopsy (SLNB). Nevertheless, about 30% of patients with cN0 axilla, positive axillary FNAC performed because of suspicious nodes on imaging, T1-2 primary tumor and breast-conserving surgery showed less than three metastatic axillary nodes, thus meeting ACOSOG Z0011 trial's criteria and therefore would be eligible for skipping ALND according to current guidelines.

Gene status in HER2 equivocal breast carcinomas: impact of distinct recommendations and contribution of a polymerase chain reaction-based method.

BACKGROUND: The primary objectives of this study on carcinomas with equivocal HER2 expression were to assess the impact of distinct recommendations with regard to identifying patients eligible for anti-HER2 agents by fluorescence in situ hybridization (FISH) and to elucidate whether multiplex ligation-dependent probe amplification (MLPA) may be of support in assessing HER2 gene status. METHODS: A cohort of 957 immunohistochemistry-evaluated HER2-equivocal cases was analyzed by dual-color FISH. The results were assessed according to U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines and American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) 2007 and 2013 guidelines for dual- and single-signal in situ hybridization (ISH) assays. A subgroup of 112 cases was subjected to MLPA. RESULTS: HER2 amplification varied from 15% (ASCO/CAP 2007 HER2/CEP17 ratio) to 29.5% (FDA/EMA HER2 copy number). According to the ASCO/CAP 2013 interpretation of the dual-signal HER2 assay, ISH-positive carcinomas accounted for 19.7%. In contrast with the ASCO/CAP 2007 ratio, this approach labeled as positive all 32 cases (3.34%) with a HER2/CEP17 ratio <2 and an average HER2 copy number ≥6.0 signals per cell. In contrast, only one case showing a HER2 copy number <4 but a ratio ≥2 was diagnosed as positive. MLPA data correlated poorly with FISH results because of the presence of heterogeneous HER2 amplification in 33.9% of all amplified carcinomas; however, MLPA ruled out HER2 amplification in 75% of ISH-evaluated HER2-equivocal carcinomas. CONCLUSION: The ASCO/CAP 2013 guidelines seem to improve the identification of HER2-positive carcinomas. Polymerase chain reaction-based methods such as MLPA can be of help, provided that heterogeneous amplification has been ruled out by ISH.

Liquid-based cytology of the breast: pitfalls unrecognized before specific liquid-based cytology training - proposal for a modification of the diagnostic criteria.

OBJECTIVES: To describe the pitfalls encountered in switching over from conventional smears (CSm) to liquid-based cytology (LBC). To explore modifications of our usual diagnostic criteria. STUDY DESIGN: 190 ThinPrep breast samples with paired biopsies were retrospectively evaluated by two breast cytopathologists experienced only in CSm. They were again studied after LBC training. The diagnostic performances were compared. In additional calculations we included those C4/suspicious samples containing 70% high-grade nuclei and up to 30% nonmalignant cells in the C5/positive category, simulating that they harbored a malignant one-cell population. We prospectively validated this modification of our diagnostic criteria. RESULTS: Training resulted in higher complete sensitivity: 94 versus 86% (p value 0.003) and lower false negative ratio: 4 versus 12% (p value 0.003). Training generated higher complete sensitivity than collaboration without training: 94 versus 89% (p value 0.008). In the simulation, the modified criteria increased absolute sensitivity to 74% with a 0.6% false positive rate. In the validation series, they generated up to 91% absolute sensitivity, 12% suspicious rate and no false negative and false positive diagnoses. CONCLUSION: Training in breast LBC may increase diagnostic performance. Samples containing 70% high-grade nuclei or more can be categorized as malignant.

A multicenter, randomized trial of prophylactic fluconazole in preterm neonates.

BACKGROUND: Invasive candida infections are a major cause of morbidity and mortality in preterm infants. We performed a multicenter, randomized, double-blind, placebo-controlled trial of fluconazole for the prevention of fungal colonization and infection in very-low-birth-weight neonates. METHODS: During a 15-month period, all neonates weighing less than 1500 g at birth from eight tertiary Italian neonatal intensive care units (322 infants) were randomly assigned to receive either fluconazole (at a dose of either 6 mg or 3 mg per kilogram of body weight) or placebo from birth until day 30 of life (day 45 for neonates weighing <1000 g at birth). We performed weekly surveillance cultures and systematic fungal susceptibility testing. RESULTS: Among infants receiving fluconazole, fungal colonization occurred in 9.8% in the 6-mg group and 7.7% in the 3-mg group, as compared with 29.2% in the placebo group (P<0.001 for both fluconazole groups vs. the placebo group). The incidence of invasive fungal infection was 2.7% in the 6-mg group and 3.8% in the 3-mg group, as compared with 13.2% in the placebo group (P=0.005 for the 6-mg group and P=0.02 for the 3-mg group vs. the placebo group). The use of fluconazole did not modify the relationship between colonization and the subsequent development of invasive fungal infection. Overall mortality was similar among groups, as was the incidence of cholestasis. No evidence for the emergence of resistant candida species was observed, but the study did not have substantial power to detect such an effect. CONCLUSIONS: Prophylactic fluconazole reduces the incidence of colonization and invasive candida infection in neonates weighing less than 1500 g at birth. The benefit of treating candida colonization is unclear. (Current Controlled Trials number, ISRCTN85753869 [controlled-trials.com]).

Androgen receptor expression is a significant prognostic factor in estrogen receptor positive breast cancers.

The purpose of this article is to evaluate the prognostic value of androgen receptor (AR) expression in patients with estrogen receptor (ER)-positive breast cancer, treated with endocrine therapy, with or without the addition of chemotherapy. A consecutive series of 953 patients with ER-positive breast cancer, treated between 1998 and 2003, was selected. Repeated immunohistochemistry confirmed the expression of ER in the tumor of 938 patients. AR expression was measured by immunohistochemistry. The Kaplan-Meier method, logrank test and multivariate Cox models were used to explore the impact of AR expression on time to relapse (TTR) and disease specific survival (DSS) in all patients and in subgroups treated with chemo-endocrine therapy or endocrine therapy alone. AR immunoreactivity was assessable in 859 tumors and positive in 609 (70.9%). AR expression was a significant marker of good prognosis for TTR (P = 0.001) and DSS (P < 0.001). This effect was particularly evident in the group of patients receiving chemo-endocrine therapy (TTR (P = 0.015) and DSS (P < 0.001)). Cox models confirmed AR as an independent variable for both TTR (P = 0.003, HR 0.444, 95%CI 0.258-0.765) and DSS (P < 0.001, HR 0.135, 95%CI 0.054-0.337). Thus, we focused on ER-positive luminal B breast cancer that may be selected for chemotherapy because of their more aggressive immunophenotype. In this subset AR expression identified a group of patients with better prognosis for TTR (P = 0.017, HR 0.521, 95%CI 0.306-0.888) and DSS (P = 0.001, HR 0.276, 95% CI 0.130-0.588). AR expression is an independent prognostic factor of better outcome in patients with ER-positive breast cancers.

The circadian gene NPAS2 is a novel prognostic biomarker for breast cancer.

Mounting evidence suggests that neuronal PAS domain protein 2 (NPAS2) and other circadian genes are involved in tumorigenesis and tumor growth, possibly through their control of cancer-related biologic pathways. A missense polymorphism in NPAS2 (Ala394Thr) has been shown to be associated with risk of human tumors including breast cancer. The current study further examined the prognostic significance of NPAS2 in breast cancer by genotyping the Ala394Thr polymorphism and measuring NPAS2 expression. DNA extracted from 348 breast cancer tissue samples was analyzed for NPAS2 genotype using the TaqMan allelic discrimination assay. Of these, 287 also had total RNA available for use in real-time PCR assays to determine NPAS2 expression. NPAS2 genotypes and expression levels were analyzed for associations with prognostic outcomes, as well as correlations with clinical characteristics. A high level of NPAS2 expression was strongly associated with improved disease free survival (AHR = 0.43, 95% CI: 0.21-0.86, P trend = 0.022) and overall survival (AHR = 0.42, 95% CI: 0.19-0.96, P trend = 0.036). In addition, there was a borderline, but nonsignificant association between the NPAS2 genotype corresponding to Thr394Thr and disease free survival (AHR = 1.82, 95% CI: 0.96-3.46). The Ala/Ala, Ala/Thr, and Thr/Thr genotypes were also differentially distributed by tumor severity, as measured by TNM classification (chi (2) (6df, N = 344) = 14.96, P = 0.020). These findings provide the first evidence suggesting prognostic significance of the circadian gene NPAS2 in breast cancer.

Micropapillary ductal carcinoma in situ of the breast: an inter-institutional study.

The clinical significance of micropapillary growth pattern in ductal carcinoma in situ is controversial and the impact of nuclear grading in terms of recurrence of this lesion is yet to be clarified. Our aim was to evaluate, on a series of micropapillary in situ carcinomas, the histological features correlated with recurrence and whether the micropapillary subtype had a different behavior from other non-micropapillary ductal carcinoma in situ. We collected 55 cases of micropapillary in situ carcinomas from four institutions. All cases were reviewed for nuclear grade, extent, necrosis, microinvasion and tested for estrogen and progesterone receptors, Ki67, HER2, EGFR and p53 expression. Clinical data, type of surgery and follow up were obtained for all patients. Our results showed that the nuclear grade is crucial in determining the biology of micropapillary carcinoma in situ, so that the high nuclear grade micropapillary ductal carcinoma in situ more frequently overexpressed HER2, showed higher proliferation index, displayed necrosis and microinvasion and was more extensive than low/intermediate nuclear grade. Logistic regression analysis confirmed the high nuclear grade (Odds ratio: 6.86; CI: 1.40-33.57) as the only parameter associated with elevated risk of local recurrence after breast-conserving surgery. However, the recurrence rate of 19 micropapillary carcinoma in situ, which were part of a cohort of 338 consecutive ductal carcinoma in situ, was significantly higher (log-rank test, P-value=0.019) than that of non-micropapillary, independently of the nuclear grade. In conclusion, although nuclear grade may significantly influence the biological behavior of micropapillary ductal carcinoma in situ, micropapillary growth pattern per se represents a risk factor for local recurrence after breast-conserving surgery.

Role of Magnetic Resonance Imaging in the Evaluation of Breast Cancer Response to Neoadjuvant Chemotherapy.

BACKGROUND/AIM: The aim of the study was to evaluate whether residual tumor assessment by magnetic resonance imaging (MRI) after neoadjuvant chemotherapy (NACT) is fundamental for a successive surgical strategy. PATIENTS AND METHODS: We collected 55 MRIs performed after NACT. RESULTS: Pathological response rate was 20%. MRI's sensitivity, specificity, PPV and NPV were 50%, 88%, 54% and 86%, respectively. We observed a high variability between the different subgroups, with high number of false positives in luminal A/B tumors. Triple negative and HER2+ tumors had almost the same specificity and sensitivity (81% and 50%). Nevertheless, in the HER2+ group, PPV was greater than that in the triple negative group (71% and 33% respectively) and the NPV of the triple negative group was greater than that of the HER2+ one (90% and 64%, respectively). Statistical analysis showed a weak but significant correlation between MRI and pathological assessment of residual tumor dimension. CONCLUSION: The present study, confirms literature data about MRI accuracy in diagnosing HER2+ and triple negative tumors, but suggests caution in case of luminal tumors' evaluation.

High miR-21 expression in breast cancer associated with poor disease-free survival in early stage disease and high TGF-beta1.

MicroRNA-21 (miR-21) is considered an onco-microRNA given its abilities to suppress the actions of several tumor suppressor genes and to promote tumor cell growth, invasion and metastasis. Recently, transforming growth factor-beta (TGF-beta) is found to up-regulate the expression of miR-21, and elevated miR-21 expression is seen frequently in breast cancer. To evaluate the effect of miR-21 on disease progression and its association with TGF-beta, we analyzed miR-21 expression in breast cancer. Fresh tumor samples were collected during surgery from 344 patients diagnosed with primary breast cancer. The expression of miR-21 in tumor samples was measured with a TaqMan microRNA assay using U6 as reference. Levels of miR-21 expression by disease stage, tumor grade, histology, hormone receptor status and lymph node involvement were compared. Cox proportional hazards regression analysis was performed to assess the association of miR-21 expression with disease-free and overall survival. The study results showed that the expression of miR-21 was detected in all tumor samples with substantial variation. High miR-21 expression was associated with features of aggressive disease, including high tumor grade, negative hormone receptor status, and ductal carcinoma. High miR-21 was also positively correlated with TGF-beta1. No associations were found between patient survival and miR-21 expression among all patients, but high miR-21 was associated with poor disease-free survival in early stage patients (HR = 2.08, 95% CI: 1.08-4.00) despite no value for prognosis. The study supports the notion that miR-21 is an onco-microRNA for breast cancer. Elevated miR-21 expression may facilitate tumor progression, and TGF-beta may up-regulate its expression.

Peptide concentrations and mRNA expression of IGF-I, IGF-II and IGFBP-3 in breast cancer and their associations with disease characteristics.

PURPOSE: To measure peptide concentrations and mRNA expression of the IGF Family in breast cancer and to examine their associations with the disease features. EXPERIMENTAL DESIGN: Fresh tumor samples were collected from 348 patients who underwent surgery for breast cancer. Tissue levels of mRNA and peptide of IGF-I, IGF-II, and IGFBP-3 were analyzed with real-time RT-PCR and ELISA, respectively. Cox proportional hazards regression model was used to examine the associations of IGF markers with patient survival. RESULTS: Age was inversely associated with IGF-I, IGF-II and IGFBP-3 at both mRNA and peptide levels. Small tumors, early TNM stages, or low grades were associated with high mRNA expression of IGFs and IGFBP-3. Hormone receptors were positively correlated with IGF-I and IGF-II expression. Survival analysis showed that patients with high expression of one of the IGF-I transcripts, IGF-IA, had lower risk of disease recurrence (HR = 0.47, 95%CI: 0.27-0.81) and death (HR = 0.35, 95%CI: 0.18-0.70) compared to those with low expression. High IGFBP-3 expression was also inversely associated with reduced risk of death (HR = 0.47, 95%CI: 0.23-0.95). Similar associations, however, were not observed when tissue levels of IGF-I peptide or IGFBP-3 protein were analyzed. High IGF-II peptide was related to increased risk of relapse (HR = 1.91, 95%CI: 1.12-3.27). CONCLUSION: Our findings of high mRNA expression of IGFs and IGFBP-3 being associated with less aggressive tumors and favorable prognosis were consistent with previous observations, but were not supported by the measurement of tissue levels of IGF-I peptide and IGFBP-3 protein, suggesting that IGF mRNA expression and tissue levels of IGF peptides are regulated by different mechanisms and assessing these molecules in tumor tissue may have different implications.

Axillary Dissection vs. no Axillary Dissection in Breast Cancer Patients With Positive Sentinel Lymph Node: A Single Institution Experience.

BACKGROUND/AIM: Axillary surgery of breast cancer patients is undergoing a paradigm shift, as axillary lymph node dissection's (ALND) usefulness is being questioned in the treatment of patients with tumor-positive sentinel lymph node biopsy (SLNB). The aim of this study was to investigate the overall survival (OS) and relapse-free survival (RFS) of patients with positive SLNB treated with ALND or not. PATIENTS AND METHODS: We investigated 617 consecutive patients with cN0 operable breast cancer with positive SLNB undergoing mastectomy or conservative surgery. A total of 406 patients underwent ALND and 211 were managed expectantly. RESULTS: No significant difference in OS and RFS was found between the two groups. The incidence of loco-regional recurrence in the SLNB-only group and the ALND group was low and not significant. CONCLUSION: The type of breast cancer surgery and the omission of ALND does not improve OS or RSF rate in cases with metastatic SLN.

Routine use of fluconazole prophylaxis in a neonatal intensive care unit does not select natively fluconazole-resistant Candida subspecies.

BACKGROUND: We have previously demonstrated efficacy against fungal colonization and infection of fluconazole prophylaxis that was routinely administered since 2001 in our ICU for preterm infants <1500 g at birth (VLBW). With prolonged use, concerns exist for the emergence of acquired fungal resistance and of Candida subspecies that are natively fluconazole-resistant (NFR), mostly Candida glabrata and Candida krusei. METHODS: We evaluated retrospectively all clinical and surveillance fungal isolates obtained from VLBW infants in our NICU during a 10-year period (1997-2006). Each fungal isolate was speciated, infants colonized or infected with NFR-Candida spp were identified and the incidence rates of colonization and infection by these fungal species were calculated. A comparison was made of the 6-year (2001-2006) prophylaxis period with the 4-year (1997-2000) preprophylaxis period. RESULTS: Overall, colonization by NFR-Candida spp ranged between 2.8% and 6.6% of VLBW infants yearly admitted, without any increasing trend during the study period. There were 18 of 434 (4.1%) neonates colonized by these species. Five episodes of systemic fungal infections caused by NFR-Candida spp occurred (incidence rate, 1.1%). No significant differences were detected when compared with the preprophylaxis period, when 11 of 295 infants (3.7%) were colonized by NFR-Candida spp and 4 episodes of infection occurred (1.4%) (P = 0.84 and 0.76, respectively). CONCLUSIONS: Fluconazole prophylaxis administered to VLBW neonates in 4- to 6-week courses after birth does not lead to the emergence of natively fluconazole-resistant Candida spp.

Fluorescent in situ hybridization as a screening test for HER2 amplification in G2 and G3 breast cancers of lobular and ductal histotype and metastases.

The aim of the present study was to evaluate the effectiveness of fluorescence in situ hybridisation (FISH), as a screening test, in moderately- (G2) or poorly- (G3) differentiated breast cancers of the ductal (IDC) and lobular (ILC) histotypes and distant metastases. HER2 FISH was performed on 486 G2 and 477 G3 both of IDC and ILC histotypes and in 241 metastases. A significant difference in the HER2 amplification was observed between G2 (14.8%) and G3 (31.9%), with no difference according to the histotype. However, the rate of amplification increased to 36% in the G2/hormone receptor-negative cases as compared to 10.6% in the G2/receptor-positive cases (p<0.0001). HER2 was amplified in 17% of metastases with some differences depending on the location. These data suggest that the HER2 FISH analysis may be an effective screening test in breast cancer metastases and G3 tumors, irrespective of the hormone receptor status or presence of lymphovascular invasion.

Is Sialyl Lewis x antigen expression a prognostic factor in patients with breast cancer?

Sialyl Lewis x (sLex) carbohydrate antigen acts as an adhesion molecule expressed on the surface of cancer cells and is the most important ligand of the selectins present on endothelial cells. sLex expression was correlated to the metastatic potential of breast cancer. The aim of the present work was to evaluate the prognostic value of sLex in a series of breast carcinomas with long-term follow-up. A total of 127 consecutive patients with primary breast cancer were enrolled and followed for a median of 140 months. Tumor grade, mitotic index, histotype, vascular invasion, and tumor extension and sLex were recorded and used in multivariate analysis. sLex antigen was expressed in 37 specimens (21%). Survival was similar for sLex-positive and sLex-negative tumors (62% vs 60%) for overall survival and for disease-free survival (59% vs 56%). Expression of sLex antigen in breast cancer is not associated with breast cancer survival.

p130Cas as a new regulator of mammary epithelial cell proliferation, survival, and HER2-neu oncogene-dependent breast tumorigenesis.

To investigate the mechanisms through which p130Cas adaptor protein is linked to tumorigenesis, we generated mouse mammary tumor virus (MMTV)-p130Cas mice overexpressing p130Cas in the mammary gland. MMTVp130Cas transgenic mice are characterized by extensive mammary epithelial hyperplasia during development and pregnancy and by delayed involution at the end of lactation. These phenotypes are associated with activation of Src kinase, extracellular signal-regulated kinase 1/2, mitogen-activated protein kinase, and Akt pathways, leading to an increased rate of proliferation and a decreased apoptosis. A double-transgenic line derived from crossing MMTV-p130Cas with MMTV-HER2-Neu mice expressing the activated form of the HER2-Neu oncogene develops multifocal mammary tumors with a significantly shorter latency than the HER2-Neu parental strain alone. Mammary epithelial cells isolated from tumors of double-transgenic mice display increased tyrosine phosphorylation, c-Src, and Akt activation compared with cells derived from HER2-Neu tumors. In addition, p130Cas down-regulation by RNA interference increases apoptosis in HER2-Neu-expressing cells, indicating that p130Cas regulates cell survival. Consistently with the double-transgenic mice model, p130Cas is overexpressed in a significant subset of human breast cancers and high levels of p130Cas in association with HER2 expression correlate with elevated proliferation. These findings provide evidences for a role of p130Cas as a positive regulator of both proliferation and survival in normal and transformed mammary epithelial cells. Its overexpression contributes to HER2-Neu-induced breast tumorigenesis, thus identifying this protein as a putative target for clinical therapy.

Sentinel lymph node biopsy and non-sentinel node involvement in special type breast carcinomas with a good prognosis.

This study aimed at identifying factors related to sentinel lymph node (SLN) involvement in patients with tubular, cribriform, mucinous or papillary breast carcinoma and those related to non-SLN metastases if an SLN was positive. Multivariate analyses involved logistic and stepwise regressions. The SLNs harboured metastases in 85 of 572 cases, 78 of whom underwent axillary dissection; 19 presented non-SLN positive disease. Lack of lymphovascular invasion, a tumour size < or = 10 mm and a single SLN removed were the factors predicting an SLN metastasis rate <10%, and patients with these features could be candidates for no surgical axillary staging. A positive SLN proportion of < or = 50% and no lymphovascular invasion were associated with a <10% rate of non-SLN invasion; patients with a positive SLN and these features could be candidates for the omission of completion axillary dissection. The opposite presentation of these factors would mandate SLN biopsy and axillary dissection, respectively.

Sentinel lymph node biopsy in staging small (up to 15 mm) breast carcinomas. Results from a European multi-institutional study.

Sentinel lymph node (SLN) biopsy has become the preferred method for the nodal staging of early breast cancer, but controversy exists regarding its universal use and consequences in small tumors. 2929 cases of breast carcinomas not larger than 15 mm and staged with SLN biopsy with or without axillary dissection were collected from the authors' institutions. The pathology of the SLNs included multilevel hematoxylin and eosin (HE) staining. Cytokeratin immunohistochemistry (IHC) was commonly used for cases negative with HE staining. Variables influencing SLN involvement and non-SLN involvement were studied with logistic regression. Factors that influenced SLN involvement included tumor size, multifocality, grade and age. Small tumors up to 4 mm (including in situ and microinvasive carcinomas) seem to have SLN involvement in less than 10%. Non-SLN metastases were associated with tumor grade, the ratio of involved SLNs and SLN involvement type. Isolated tumor cells were not likely to be associated with further nodal load, whereas micrometastases had some subsets with low risk of non-SLN involvement and subsets with higher proportion of further nodal spread. In situ and microinvasive carcinomas have a very low risk of SLN involvement, therefore, these tumors might not need SLN biopsy for staging, and this may be the approach used for very small invasive carcinomas. If an SLN is involved, isolated tumor cells are rarely if ever associated with non-SLN metastases, and subsets of micrometastatic SLN involvement may be approached similarly. With macrometastases the risk of non-SLN involvement increases, and further axillary treatment should be generally indicated.

The impact of malignant nipple discharge cytology (NDc) in surgical management of breast cancer patients.

BACKGROUND: The role of nipple discharge cytology (NDc) in the surgical management of breast cancer patients is unclear. We aimed: (i) to evaluate the effect of malignant NDc on the surgical approach to the nipple-areola complex, and (ii) to verify the association between malignant NDc and nipple malignancy. METHODS: We retrospectively analyzed a case series of 139 patients with NDc who underwent breast surgery. The clinical and histological findings, types of surgery with emphasis on nipple-areola complex amputation, immunohistochemical phenotypes of the carcinomas and measurements of the tumor-nipple distance were recorded. Additionally, in patients who showed HER2-positive lesions on definitive surgery, we evaluated the HER2 immunocytochemistry of the NDc smears. RESULTS: Thirty-two malignant and 107 benign/borderline NDc diagnoses were identified. All 32 malignant-NDc cases were histologically confirmed as malignant. Thirty borderline/benign-NDc cases were histologically diagnosed as malignant (sensitivity 58%). The majority of the patients with malignant NDc were treated with nipple-areola complex amputations in both the mastectomy and conservative surgery groups (P<0.001, χ251.77). Nipple involvement was strongly associated with HER2-positive ductal carcinoma in-situ (P<0.001, χ211.98). HER2 immunocytochemistry on the NDc revealed a 100% correlation with the immunocytochemistry performed on the surgical tissues. CONCLUSIONS: Malignant NDc influenced surgical management. The association of malignant NDc with nipple involvement is highly related to ductal carcinoma in-situ with HER2 overexpression. In case of HER2 positive NDc, nipple-areola complex involvement is more likely than in HER2 negative cases.

Misalignment of lung vessels: diagnostic role of conventional histology and immunohistochemistry.

Misalignment of lung vessels represents a rare congenital anomaly that may cause respiratory failure in the newborn. It is characterized by abnormal position of pulmonary veins and venules that lie adjacent to arteries and bronchi, and it is usually associated with a decreased number of alveolar capillaries (i.e., alveolar capillary dysplasia), although these two conditions have been separately described. Awareness of this anomaly is required by pathologists because it can be easily overlooked on lung biopsy or autopsy, and because definite diagnosis relies on histology. We report the case of a newborn male baby who developed respiratory distress 18 h after an uncomplicated delivery. The patient died on the 7th day, after high frequency oscillatory ventilation, nitric oxide inhalation and extracorporeal membrane oxygenation were unsuccessful. On autopsy, histology and immunohistochemistry demonstrated diffuse changes, fulfilling diagnostic criteria of misalignment of lung vessels and of alveolar capillary dysplasia in both lungs, with muscularization of very peripheral pulmonary arteries and a prominent interstitial and periadventitial fibrosis. Diffuse distribution of vessel misalignment could explain the rapid onset of respiratory failure, and the presence of diffuse fibrosis might have contributed to irreversible respiratory dysfunction by impairment of lung parenchyma extensibility.