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Size (the "T" in the TNM System) of invasive breast carcinoma is a proven independent prognostic factor; however, its accurate determination can be challenging. The purpose of this review is to discuss the complexities inherent in determining "T"-including those encountered in the clinical measurement ("cT", ie, physical and radiologic assessment) as well as pathologic determination (pT) of invasive breast carcinomas. Pathologic estimation of tumor size, macroscopic, as well as microscopic, can be problematic due to the complexity of multiple situations, seeming confusion regarding staging guidelines, and interobserver variation in interpretation. Additional problematic scenarios in determination of "T" include those incurred in excisions performed after the performance of needle core biopsies, and in cases wherein there are multiple foci of invasive carcinoma, as well as in carcinomas status post-neoadjuvant chemotherapy. It can also be difficult to determine "T" in certain types of invasive carcinoma, particularly those of the lobular type. In this communication, some of the complexities and challenges in determing "T" are discussed, and modest suggestions are offered to assist in optimizing such assessments.

Due to the proximity of the skin, subcutis, and axilla to the breast, the possibility of a "breast mass" actually representing a dermatologic lesion should be considered, particularly if the proliferation does not look characteristically "mammary" in appearance. Even more underappreciated is the scenario of a dermatologic proliferation morphologically masquerading as a breast tumor. The pathologist can fall prey to this pitfall if he/she is led to believe that the location of the tumor is the breast proper. The aim of this review is to provide an overview of dermatologic mimickers of breast lesions and helpful ways to discern between them when possible.

AIMS: There are scant data on the correlation of maximum tumor dimension (MTD) in needle core biopsy (NCB) and in subsequent excisional biopsy (EXB) with various pre-NCB imaging studies (VIS)-especially in the context of screen-detected invasive carcinoma (SIC). METHODS AND RESULTS: Retrospectively studied were consecutive (2012-2013) non-palpable, SIC diagnosed on NCB with subsequent EXB. Data on MTD on VIS (either mammogram, or ultrasound, or MRI), NCB and EXC were analyzed. Mean MTD on VIS was 12.5mm (range: 0-45 mm). Mean MTD on NCB was 6.7 mm (range: 1-15 mm). Mean residual MTD on EXB was 12.9 mm (range: 0-40 mm). Mean number of NCB performed per SIC was 5 (range: 1-13). Overall, 81% of all NCB were involved by SIC. The difference between MTD at EXC and VIS was statistically not significant (p>0.05). Spearman correlation coefficient for MTD on VIS and EXC was r=0.8718 (p<0.0001) showing a significant correlation. The mean tissue volume procured on NCB-calculated by using Aperio whole slide scanning and NIH Image J image analysis was 95.5mm(3) (range: 4.3-887.5mm(3), median: 23 mm(3)). A Bland-Altman plot showed that MTD of >/= 7 mm on EXB is a useful cut-off point predictive of (any) increase in MTD at EXB. Six of the 13 patients with MTD< 7mm on EXB showed a decrease in size; while no patient with MTD on EXB that was >/= 7 mm showed any decrease in size. (Fisher's exact test, P=0.001, two-tailed). Overall 88% (44 out of 50 patients) of SIC showed no decrease in MTD on EXB, with an increase by >/= 4 mm in size (sufficient to upstage "T") in MTD of >/= 7mm on EXB in 75.6% (28 of 37 patients with MTD of >/= 7 mm on EXB). 20.8% of SIC (5 of 24 patients) that were < 7 mm on NCB (with a mean combined Nottingham grade score of 5 {r: 4-6} showed decrease in MTD at EXB. CONCLUSIONS: In this pilot study of SIC, (i) MTD on VIS was predictive of MTD on EXB, (ii) MTD of >/= 7 mm on NCB was predictive of an increased MTD on EXB in most cases, with potential for "upstaging" tumors, and (iii) MTD of < 7 mm on NCB was predictive of decreased MTD on EXB in 20.8% of (mostly grade I) SIC. Procured tissue volume on NCB contributed to decrease in MTD on EXB in small, low-grade carcinomas.

Although Paget disease of the nipple (PDN) is a well-established clinical and pathological neoplastic process, invasive PDN (IPDN) is a relatively newly described disease. The latter entity is characterized by invasive carcinoma that is localized to the nipple and is associated with PDN as well as with either intraductal and/or invasive carcinoma in the underlying breast. To our knowledge, only 17 cases of IPDN, all node negative, have been reported. Here, we report the case of a 68-year-old woman with invasive Paget disease of the left nipple. The patient had a history of intraductal carcinoma, treated by lumpectomy alone. She presented 6 years later with "eczematous" lesion of the ipsilateral nipple, a punch biopsy of which showed a superficially IPDN as well as conventional PDN. The subsequently performed wide excision of the nipple, areola, and underlying breast tissue showed the invasive carcinoma to span 0.6 cm. Then, 3 months later, the patient presented with ipsilateral palpable axillary lymphadenopathy. Axillary dissection revealed metastatic carcinoma in 7 of 19 lymph nodes. This case of IPDN not only represents the deepest extent of invasion reported thus far but also the only one known to be node positive.

UNLABELLED: Phyllodes tumors (PT) are rare fibroepithelial breast tumors representing less than 1 % of all breast malignancies. These tumors are unpredictable and fast growing with a high local recurrence rate, making this disease challenging to treat. Previous literature focused on surgical resection, and breast reconstruction following a mastectomy in patients with PT is rarely addressed. We report a case of a recurrent malignant PT treated with a nipple-sparing mastectomy followed by immediate single-stage silicone implant breast reconstruction. While PT is a rare breast malignancy that presents challenges with both surgical resection and reconstruction, we demonstrate that nipple-sparing mastectomy with immediate implant breast reconstruction with AlloMax is curative and can offer an appealing cosmetic option. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Sprouting of angiogenic perivascular cells is thought to be highly dependent upon autocrine and paracrine growth factor stimulation. Accordingly, we report that corneal angiogenesis induced by ectopic FGF implantation is strongly impaired in NG2/CSPG4 proteoglycan (PG) null mice known to harbour a putative deficit in pericyte proliferation/mobilization. Conversely, no significant differences were seen between wild type and knockout corneas when VEGF was used as an angiocrine factor. Perturbed responsiveness of NG2-deficient pericytes to paracrine and autocrine stimulation by several FGFs could be confirmed in cells isolated from NG2 null mice, while proliferation induced by other growth factors was equivalent in wild type and knockout cells. Identical results were obtained after siRNA-mediated knock-down of NG2 in human smooth muscle-like cell lines, as also demonstrated by the decreased levels of FGF receptor phosphorylation detected in these NG2 deprived cells. Binding assays with recombinant proteins and molecular interactions examined on live cells asserted that FGF-2 bound to NG2 in a glycosaminoglycan-independent, core protein-mediated manner and that the PG was alone capable of retaining FGF-2 on the cell membrane for subsequent receptor presentation. The use of dominant-negative mutant cells, engineered by combined transduction of NG2 deletion constructs and siRNA knock-down of the endogenous PG, allowed us to establish that the FGF co-receptor activity of NG2 is entirely mediated by its extracellular portion. In fact, forced overexpression of the NG2 ectodomain in human smooth muscle-like cells increased their FGF-2-induced mitosis and compensated for low levels of FGF receptor surface expression, in a manner equivalent to that produced by overexpression of the full-length NG2. Upon FGF binding, the cytoplasmic domain of NG2 is phosphorylated, but there is no evidence that this event elicits signal transductions that could bypass the FGFR-mediated ones. Pull-down experiments, protein-protein binding assays and flow cytometry FRET coherently revealed an elective ligand-independent association of NG2 with FGFR1 and FGFR3. The NG2 cooperation with these receptors was also corroborated functionally by the outcome of FGF-2 treatments of cells engineered to express diverse NG2/FGFR combinations. Comprehensively, the findings suggest that perivascular NG2 may serve as a dual modulator of the availability/accessibility of FGF at the cell membrane, as well as the resulting FGFR transducing activity.

AIMS: Quantitative image analysis of histopathology slides is becoming an important technology in diagnostic pathology. To this end, it is essential to combine a robust image analysis software with the most commonly used immunohistochemical staining methods. In this investigation, we describe a practical application of NIH ImageJ software for quantitative vascular image analysis for diaminobenzene chromogen-based CD34 immunostain in breast cancer. CD34 immunostain is in a unique position to identify lymphangiogenesis and angiogenesis simultaneously in a given tumor tissue. This investigation aims at establishing a practical quantitative vascular image analysis solution for diagnostic pathologists by using ImageJ, and CD34 immunostain. METHODS AND RESULTS: Tissue microarray slides containing breast cancer tissue were immunostained for CD34 for simultaneous identification of lymphatic endothelial cells (LEC) and blood vessel endothelial cells (BEC). Digital images were analyzed using NIH ImageJ software. A CD34 score was quantified for each tissue core as a percentage (CD34-positive area/area of tissue core). The mean CD34 scores were 0.24%, 0.40%, 1.30%, 2.33%, 2.64%, and 3.44% for normal breast tissue, in stage IIA, IIB, IIIA, IIIB, and IIIC breast cancer tissue cores, respectively (p<0.0001). The mean CD34 scores were 0.70% and 2.21% for lymph node-negative and lymph node-positive breast cancer patients, respectively (p<0.0001). CONCLUSIONS: ImageJ software seems to be an attractive quantitative image analysis tool for diagnostic pathology for immunohistochemistry-based applications because of its capabilities, availability, and ease of use with most image formats. Our results show the feasibility, versatility, and ease of use of ImageJ and CD34 immunohistochemistry for vascular image analysis in breast pathology. Given the prospects of novel lymphatic and vascular endothelium-targeting therapeutics in breast oncology, the practical analysis of combined LEC and BEC density described in this report could enable diagnostic pathologists to apply quantitative vascular image analysis easily in their pathology practice and translational research.

The walls of angiogenic blood vessel capillaries are composed of two principal cell types, blood vessel endothelial cells (BEC) and pericytes (PC), whereas the walls of lymphatic capillaries are composed of lymphatic endothelial cells (LEC). In this investigation we describe a practical application of NIH ImageJ software for quantitative image analysis for pericytes and endothelial cells in prostate cancer. We used a tissue microarray that contained 49 tissue cores (normal prostate tissue or prostatic carcinomas with Gleason scores of 6 through 10). These prostate cancer samples represented AJCC prognostic stages II, III, and IV. Slides were immunostained with anti-PDGFR-beta antibody for identification of PC, and quantified as microvascular pericyte density (MVPD); they were also immunostained with anti-CD34 antibody for identification of LEC and BEC simultaneously, and quantified as microvascular endothelial density (MVED). CD31 and D2-40 immunostains were used to quantify BEC and lymphatic endothelial cells, respectively. Our results showed higher MVPD and MVED in prostate cancers with higher Gleason scores and higher stages, suggesting the prognostic utility of vascular image analysis in prostate pathology. This investigation demonstrates the feasibility, versatility, and ease of use of ImageJ software and pericyte-specific and endothelial-specific immunohistochemistry for quantitative image analysis in prostate pathology.