Solid Papillary Carcinoma and Encapsulated Papillary Carcinoma of the Breast: Clinical-Pathologic Features and Basement Membrane Studies of 50 Cases.

INTRODUCTION: Solid papillary carcinoma (SPC) and encapsulated papillary carcinoma (EPC) of the breast are usually considered in situ lesions due to favorable prognosis, despite the variable presence of myoepithelial cells. We aimed to describe clinical-pathologic features including basement membrane (BM) studies in these tumors. METHODS: Patients diagnosed with SPC and EPC in 2000-2019 were retrospectively identified. Microscopic slides and clinical history were reviewed. Immunohistochemical stains for BM and myoepithelial markers were performed. RESULTS: Of 23 SPCs and 27 EPCs, there were 5/23 (21.7%) pure SPCs and 9/27 (33.3%) pure EPCs, while 4/23 (17.4%) and 12/27 (44.5%) were associated with ductal carcinoma in situ (DCIS), and 6/23 (26.1%) and 6/27 (22.2%) with invasive carcinoma, respectively; 8/23 (34.8%) SPCs were considered invasive. The median tumor size was 1.7 cm (range 0.1-16). All tumors were positive for hormone receptors and negative for HER2. Myoepithelial cells were absent in 20 tumors (40%) and focally present in 30 (60%). Collagen IV and laminin were negative in most invasive lesions, but they were expressed in 21/21 (100%) and 18/21 (85.7%) of EPCs without invasion, and 16/17 (94.1%) and 10/17 (58.8%) SPCs, including invasive SPCs, respectively. Lymph node involvement was identified in 3/26 (11.5%) patients, including micrometastasis in 1 EPC associated with DCIS, macrometastasis in 1 EPC associated with invasive carcinoma, and isolated tumor cells in 1 invasive SPC. Of 31 patients with outcome data (median follow-up 35 months, range 1-85), 2 (6.5%; 1 SPC, 1 EPC) developed local recurrence, both associated with invasive carcinoma. No distant recurrences or deaths were observed. CONCLUSIONS: Our study confirms favorable prognosis of SPCs and EPCs, with 2 local recurrences occurring in the presence of invasion. SPCs are more commonly associated with invasive carcinoma or considered invasive compared to EPCs (60.9 vs. 22.2%). The presence of BM material and lack of lymph node involvement in most cases indicates that the majority of these tumors may represent in situ lesions; however, some may behave as low-grade invasive malignancy with metastatic potential even in the absence of conventional invasion.

A Survey of Breast Pathologists' Practice in Staging Multiple Foci of Invasive Carcinoma.

BACKGROUND: The American Joint Committee on Cancer (AJCC) staging system is the reference standard for describing the extent of neoplastic disease on the basis of the size of primary tumor (T), and the presence of regional lymph node (N) involvement and distant metastasis (M). Multiple foci of invasive breast carcinoma may pose staging challenges to the reporting pathologist. We set out to evaluate the practice of local breast pathologists with regard to staging of multiple foci of invasive carcinoma. PATIENTS AND METHODS: Breast pathologists were surveyed at a Community of Interest in Breast Pathology meeting. The live voting survey contained 6 case-based scenarios of multiple foci of invasive mammary carcinoma of the same or different histologic type and with unilateral or bilateral involvement. A supporting illustration was provided for each case. RESULTS: There was poor interobserver agreement with no consensus reached among the respondents in any of the cases. Staging choices varied from staging tumors together irrespective of histology or procedure type to staging tumors of the same histologic type together, or staging each tumor focus separately. Confusion was particularly evident when tumor foci with different histologic types were present. CONCLUSION: Inconsistencies exist in the reporting of AJCC pathologic TNM stage for multiple foci of invasive carcinoma. The results serve as a reminder that education and strict adherence to the AJCC guidelines is essential for establishing standard practice in order to provide accurate cancer staging and ensure optimal clinical management.

HER2 fluorescent in situ hybridization signal degradation: a 10-year retrospective study.

CONTEXT: Fluorescence in situ hybridization (FISH) analysis is recommended for invasive breast carcinomas with equivocal (2+) immunohistochemical expression of human epidermal growth factor receptor 2 (HER2). However, existing guidelines for the retention and storage requirements for HER2 FISH slides vary widely among countries and laboratories. OBJECTIVE: To determine the degradation rate of HER2 FISH signals, and the optimal retention time and storage conditions for HER2 FISH slides. DESIGN: Dual-probe HER2 FISH slides from March 2009 to June 2019 were retrieved from the archive to assess the presence, intensity and quantity of the green chromosome enumeration probe 17 (CEP 17) and orange HER2 signals. Per the institutional policy, FISH slides are placed in slide boxes and stored in - 80 °C freezers for up to 4 years, whereas older slides are stored at room temperature. RESULTS: After excluding HER2 FISH slides that were deemed uninterpretable due to technical issues, a total of 6255 slides were assessed. Slides from 2009 to 2014 were stored at room temperature, while slides from 2015 to 2019 were stored in - 80 °C freezers. Slides stored in freezers showed retention of both the green and the orange signals. Slide stored at room temperature demonstrated significant decrease in the signal retention rate and the loss of signal did not progress in a linear fashion. The CEP17 signal was quenched much faster than the HER2 signal. CONCLUSION: Our study is the first to demonstrate HER2 FISH signal degradation with time and slide storage conditions. Storing HER2 FISH slides in a -80 °C freezer allows for retention of both HER2 and CEP17 signals. At room temperature, the signals start to degrade with CEP17 signals lost at a faster rate. The results of the study may be used in official guidelines for storage conditions and retention time for HER2 FISH slides.

Cystic neutrophilic granulomatous mastitis: an update.

Cystic neutrophilic granulomatous mastitis (CNGM) is a rare subtype of granulomatous mastitis with a highly distinct histological pattern often associated with Corynebacterium species. CNGM is characterised by suppurative lipogranulomas that are composed of central lipid vacuoles rimmed by neutrophils and an outer cuff of epithelioid histiocytes. Some of the lipid vacuoles may contain sparse, rod-shaped, gram-positive bacilli that can be easily missed or dismissed. The surrounding mixed inflammatory infiltrate contains Langhans-type giant cells, lymphocytes and neutrophils. CNGM occurs in reproductive age women with a history of pregnancy and typically presents as a palpable mass that can be painful. CNGM has many mimickers, most significantly breast carcinoma. In many cases, CNGM has significant pathological and clinical overlap with other forms of granulomatous mastitis. Given the association with Corynebacterium species, early diagnosis of CNGM is essential in offering patients the most appropriate treatment. Prolonged antibiotic therapy specifically directed to corynebacteria is required, sometimes even beyond resolution of clinical symptoms. This comprehensive review of the existing literature on CNGM describes clinical-pathological features, microbiological findings, challenges associated with the microscopic differential diagnosis, clinical implications of this diagnosis and emerging treatment options. Morphological criteria and suggested comments to convey the degree of diagnostic certainty are also proposed for standard pathology reporting.

Expression-Based Cell Lineage Analysis in Drosophila Through a Course-Based Research Experience for Early Undergraduates.

A variety of genetic techniques have been devised to determine cell lineage relationships during tissue development. Some of these systems monitor cell lineages spatially and/or temporally without regard to gene expression by the cells, whereas others correlate gene expression with the lineage under study. The GAL4 Technique for Real-time and Clonal Expression (G-TRACE) system allows for rapid, fluorescent protein-based visualization of both current and past GAL4 expression patterns and is therefore amenable to genome-wide expression-based lineage screens. Here we describe the results from such a screen, performed by undergraduate students of the University of California, Los Angeles (UCLA) Undergraduate Research Consortium for Functional Genomics (URCFG) and high school summer scholars as part of a discovery-based education program. The results of the screen, which reveal novel expression-based lineage patterns within the brain, the imaginal disc epithelia, and the hematopoietic lymph gland, have been compiled into the G-TRACE Expression Database (GED), an online resource for use by the Drosophila research community. The impact of this discovery-based research experience on student learning gains was assessed independently and shown to be greater than that of similar programs conducted elsewhere. Furthermore, students participating in the URCFG showed considerably higher STEM retention rates than UCLA STEM students that did not participate in the URCFG, as well as STEM students nationwide.

The Transplant Index: A Novel Method to Predict Adult Liver Transplant Waitlist Outcomes.

BACKGROUND: The field of transplantation is shifting outcome priorities from 1-year survival to more comprehensive metrics including transplant rate and waitlist mortality. Identifying disenfranchised candidates (high waitlist death risk, low transplantation chance) can be a focus to improve outcomes. METHODS: Given the waitlist outcomes (continued waiting, death, and transplantation), we aimed to identify factors predicting the likelihood candidates would undergo transplant or death by performing multivariate competing risk analyses of 121 198 candidates in the United Network for Organ Sharing database. We incorporated these probabilities (likelihood of transplantation and waitlist death) into the Transplant Index (TI) to identify disenfranchised candidates (high likelihood of death, low likelihood of transplantation). RESULTS: Half of the patients had low incidences of death and transplantation within 90 days (TI-inactive). The remaining were stratified into 10 groups within a predictive index, the TI. Low TI groups (TI 10, 20, 30) had 90-day transplant rates of 50.8%, 41.6%, and 39.8% respectively, and their respective 90-day death rates were 22.8%, 15.1%, and 10.9%. High TI groups (TI 80, 90, >90) had 90-day transplantation rates of 53.7%, 64.3%, and 73.9%, respectively, and 90-day death rates of 5.9%, 6.5%, and 6.7% respectively. As TI increased, the likelihood of transplantation increased and that of death decreased. Low-TI groups represent the disenfranchised candidates. CONCLUSIONS: The TI identifies disenfranchised candidates on the adult liver transplant waitlist. This is the subgroup that would benefit the most from efforts to increase access to transplantation.

A galling disease? Dieulafoy's lesion of the gallbladder.

INTRODUCTION: Dieulafoy's lesion is a rare vascular anomaly characterized by an abnormally large and tortuous submucosal arteriole leading to an area of mucosal defect with minimal inflammation. It is most often seen in the stomach but could occur anywhere along the gastrointestinal tract. Only five cases of gallbladder Dieulafoy's lesion have been published so far. PRESENTATION OF CASE: We report a case of Dieulafoy's lesion in the gallbladder in a 44 year-old patient who presented with calculous cholecystitis. DISCUSSION: The clinical, radiologic and histologic findings are discussed in light of the existing literature on Dieulafoy's lesions of the gallbladder. CONCLUSION: Gallbladder Dieulafoy's lesion has potentially serious complications and emergency surgery is often required. Due to the rarity of the entity, the diagnosis is often not considered.

Lymphoepithelial cyst of the pancreas and elevated cyst fluid carcinoembryonic antigen: a diagnostic challenge.

CONTEXT: Pancreatic lymphoepithelial cysts are rare, benign cysts which can present diagnostic difficulties. Non-invasive imaging alone is unreliable in distinguishing between benign and malignant cysts. Endoscopic ultrasound (EUS) and fine needle aspiration (FNA) with analysis of cyst fluid is more reliable, but invasive. In addition, tumor markers such as carcinoembryonic antigen (CEA) can be grossly elevated in cyst fluid of benign cysts. CASE REPORT: We present the case of a 67 year old man with an incidental finding of a pancreatic cyst. EUS and FNA-guided aspiration of cyst fluid was performed. Fluid CEA was grossly elevated and resectional surgery was performed. On histological examination the diagnosis was confirmed as lymphoepithelial cyst of the pancreas. CONCLUSION: Tumor markers such as CEA can be elevated in the cyst fluid of benign pancreatic conditions such as lymphoepithelial cyst. Although the diagnosis is challenging preoperatively, if a systematic algorithm is followed, these conditions can be managed safely and efficiently.

Neuropilin-1 and neuropilin-2 expression in the adenoma-carcinoma sequence of colorectal cancer.

AIMS: Neuropilin-1 (NRP1) and neuropilin-2 (NRP2) are transmembrane glycoproteins which interact with vascular endothelial growth factor (VEGF) to prevent tumour cell apoptosis and regulate angiogenesis. However, the precise role of NRP1 and NRP2 in the adenoma-carcinoma sequence (ACS) of colorectal cancer remains unclear, and we aimed to determine this in surgical specimens comprising the ACS. METHODS AND RESULTS: Histological analysis demonstrated that epithelial NRP1 expression increased significantly across the ACS (P = 0.0007), and correlated with microvessel density (MVD; r = 0.505, P = 0.0003) and weakly with VEGF (r = 0.251, P = 0.001). In contrast, although NRP2 epithelial expression was increased significantly in all carcinomas (P < 0.002), there was no correlation with MVD, VEGF or NRP1. Furthermore, patients showing coexpression of NRP1 and NRP2 had a potentially worse prognosis than those expressing a single neuropilin or neither one. Although vascular expression of NRP1 increased significantly across the ACS (P = 0.0004) and correlated with MVD (r = 0.361, P = 0.0006), NRP2 vascular expression decreased significantly (P = 0.0001) and showed an inverse correlation with MVD (r=-0.506, P = 0.0001), suggesting differential roles for neuropilins in the angiogenic process during colorectal cancer development. CONCLUSIONS: These data suggest that an increase in NRP1 and NRP2 epithelial/tumour expression, as well as in NRP1 vascular expression, may be associated with disease progression in colorectal cancer.

Anti-angiogenic drug discovery: lessons from the past and thoughts for the future.

INTRODUCTION: Since the pioneering work of Judah Folkman, the discovery of bevacizumab has introduced the use of anti-angiogenic agents as a new modality for the treatment of cancer. Currently, hundreds of clinical trials involving anti-angiogenic agents, targeting different elements of the tumour angiogenesis pathway, are underway. However, thus far, the benefits of anti-angiogenic therapy in unselected patient populations are often marginal with harmful side effects. AREAS COVERED: This article presents a detailed discussion of the lessons learnt from the use of bevacizumab and other VEGF pathway inhibitors in the clinical setting. Specifically, this article provides a review of the literature on anti-VEGF agents and other angiogenesis inhibitors used in pre-clinical and clinical trials for cancer treatment. EXPERT OPINION: Future anti-angiogenic drug design centres on multiple protein targets and combinations including: growth factors, hypoxia-inducible factor and tumour endothelial cell markers unique to the tumour vasculature. Furthermore, treatment dosing, scheduling and combination with radiation and chemotherapy require further investigation, as does the potential of treating early disease, and the development of biomarkers which accurately predict response to therapy. These are essential for the future development of these drugs with individualised therapy likely to be the ultimate goal.

Occult breast carcinoma in breast reduction specimens in European women.

Breast reduction is a common surgical procedure performed by plastic and oncoplastic breast surgeons. The authors report on the incidence and management of cancer and atypical hyperplasia in breast reduction specimens from one institution over a 10-year period. All patients who underwent breast reduction surgery at Northern General Hospital, Sheffield were identified from an electronic prospective database. The histopathology reports were analyzed. Case records of all patients with significant abnormalities were retrieved and examined to identify their management and follow-up. Between October 1999 and April 2010, 1,588 patients underwent breast reduction. Nine specimens showed atypical hyperplasia (0.57%). Five cancers were detected (0.31%). Four of the five patients had normal screening mammograms 1-3 years before the reduction operation. Of these cancers, four were invasive (three lobular, one ductal) (0.25%) and one was DCIS (0.06%). A lump was felt macroscopically by the pathologist in two of the four patients with invasive cancer. The patients with DCIS did not undergo further surgery, whereas those with invasive disease underwent mastectomy (three patients) and axillary nodal staging (four patients). None of the patients with normal post-reduction breast imaging had residual cancer on histology. The incidence of occult carcinoma in breast reduction specimens is low. Patients should be counseled with regards to the possible consequences preoperatively.

Selective depletion of mutant p53 by cancer chemopreventive isothiocyanates and their structure-activity relationships.

Isothiocyanates (ITCs) derived from cruciferous vegetables induce apoptosis in cancer cells. We demonstrate that certain naturally occurring ITCs selectively deplete mutant p53 but not the wild-type and do so via a transcription-independent mechanism. Direct p53 binding followed by conformational changes appears to be a mechanism by which mutant p53 is depleted. Structure-activity relationship studies (SARs) using naturally occurring and synthetic ITCs show that depletion is influenced by the ITC side-chain moiety. Furthermore, we show that cells with p53 mutations are more sensitive to cytotoxicity induced by phenethyl isothiocyanate (PEITC) than those with the wild-type protein. 2,2-Diphenylethyl ITC, a synthetic ITC, is one of the most potent depletors of mutant p53 studies and induces apoptosis to the greatest extent in mutant p53 breast cancer cells. Collectively, this study shows that mutant p53 depletion may be an important novel target for cancer chemoprevention and therapy by natural and synthetic ITCs.

T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells.

There has been interest in generating T cells expressing chimeric artificial receptors (CARs) targeting CD19/CD20 antigens to treat B-cell lymphomas. If successful, however, this approach would likely impair humoral immunity because T cells may persist long-term. Most low-grade lymphoma and chronic lymphocytic leukemia (B-CLL) cells express monoclonal immunoglobulins carrying either kappa or lambda light chains. We, therefore, explored whether T lymphocytes could be genetically modified to target the tumor-associated light chain, sparing B lymphocytes expressing the reciprocal light chain, and consequently reduce impairment of humoral immunity. We found that T lymphocytes expressing the anti-kappa light chain CAR showed cytotoxic activity against Igkappa(+) tumor cell lines and B-CLL cells both in vitro and in vivo. We also found that the incorporation of the CD28 endodomain within the CAR enhanced the in vitro and in vivo expansion of transgenic T cells after tumor-associated antigen stimulation. Free Igkappa(+) did not compromise the ability of redirected T lymphocytes to eliminate Igkappa(+) tumors because these free immunoglobulins served to sustain proliferation of CAR-CD28 transgenic T cells. Thus, adoptive transfer of T lymphocytes targeting the appropriate light chain could be a useful immunotherapy approach to treat B-lymphocyte malignancies that clonally express immunoglobulin without entirely compromising humoral immunity.

Botulinum toxin a in the treatment of chromhidrosis.

BACKGROUND: Chromhidrosis is an uncommon disorder characterized by secretion of colored sweat by apocrine glands, typically localized to the face or axilla. The current treatments available for chromhidrosis are time consuming and frequently ineffective. OBJECTIVE: Our purpose is to demonstrate a novel approach to the treatment of apocrine chromhidrosis. METHODS: We report a case of apocrine chromhidrosis successfully treated with botulinum toxin A (BTX-A; Botox). RESULTS: BTX-A therapy successfully controlled facial chromhidrosis, and the effects were visible at 19 weeks post-treatment. The therapeutic benefits may be attributed to its inhibitory effects on cholinergic stimulation, adrenergic stimulation, and substance P release, although further studies are necessary to elucidate the precise mechanism of action. CONCLUSION: This report demonstrates a new therapeutic approach to patients suffering from chromhidrosis.