Pseudoangiomatous Stromal Hyperplasia: Radiologic-Pathologic Correlation.

Pseudoangiomatous stromal hyperplasia (PASH) is a benign mesenchymal proliferative lesion of the breast. PASH is postulated to be hormonally induced and predominantly occurs in premenopausal women and postmenopausal women on menopausal hormone therapy. Clinical presentation varies from screen-detected lesions to palpable masses. Imaging findings of PASH are nonspecific. The most common mammographic findings are an oval or round circumscribed non-calcified mass or developing asymmetry. On US, PASH is often seen as an oval hypoechoic mass that may be circumscribed and can have an echogenic rim, or, when manifest as mammographic asymmetry, US may show a corresponding non-mass focal area of echogenic tissue. Limited studies have investigated the MRI appearance, with PASH most often manifesting as non-mass enhancement, or, less often, as an oval or irregular mass with persistent kinetics. Histopathologically, PASH can be mistaken for a fibroadenoma or phyllodes tumor and has features overlapping low-grade angiosarcoma. Assessment of radiologic-pathologic concordance is particularly important as PASH is often an incidental finding, adjacent to the targeted lesion at histopathology. Surgical excision or repeat core-needle biopsy is necessary for discordant suspicious cases. After a benign, concordant diagnosis of PASH, the patient may resume routine screening.

Breast Angiosarcoma: Imaging Features With Histopathologic Correlation.

Breast angiosarcoma is a rare malignancy of endothelial origin that can be categorized as primary angiosarcoma (PAS) or secondary angiosarcoma (SAS) based on etiology. Primary angiosarcoma typically affects younger women with no known risk factors, whereas SAS of the breast typically develops in older women who have undergone breast cancer treatment. There are two types of SAS, one that develops in the setting of chronic lymphedema and one that develops as a radiation-associated neoplasm after breast-conserving therapy (BCT). Clinically, PAS often presents as a palpable mass that may be rapidly growing, whereas SAS presents with skin changes such as erythematous plaques or nodules or with areas of skin discoloration. Mammographically, the appearance of PAS can be nonspecific and may be obscured by the dense tissue that is characteristic of the young patient population it typically affects. Cases of mammographically occult PAS have been visible at US and MRI. Mammography and US have been found to be less sensitive than MRI for the diagnosis of secondary radiation-associated angiosarcoma. Angiosarcomas, both PAS and SAS, are graded, depending on degree of differentiation, as low, intermediate, or high grade. Endothelial markers such as ERG and CD31 immunohistochemical stains are used to support the diagnosis of angiosarcomas. In this article, we review the clinical presentation, imaging findings, associated histopathology, and treatment of primary and secondary breast angiosarcoma.

A pilot study: Comparison of TRPS1 and GATA3 immunoperoxidase staining using cytologic smears in entities reportedly positive for GATA3.

BACKGROUND: Metastatic breast carcinoma (mBC) is frequently encountered and may be challenging to diagnose as the tumor cells can morphologically resemble carcinomas of other primary origins. An additional challenge is that direct smears are often the only sample type available for immunostaining studies in cytology. Trichorhinophalangeal syndrome GATA-binding type 1 1 (TRPS1) is a highly sensitive marker for BC compared to the commonly used marker GATA3, especially in triple-negative BC (TNBC), in histologic samples. However, its sensitivity and specificity in mBC and other GATA3-positive tumors have not been studied. METHODS: The authors identified the following cytology cases: 37 GATA3-positive mBC cases and 19 available cases that were deemed mBC but were GATA3-negative during the original case workup and five cases of each of eight epithelioid entities known to have high rates of GATA3 positivity and commonly seen in cytology practice. Immunostainings of TRPS1 and GATA3 were performed on the chosen smears following standard protocols. RESULTS: TRPS1 was positive in all 37 GATA3-positive mBC cases and in 18 of the 19 GATA3-negative mBC cases. TRPS1 was negative in all five of the seven frequently GATA3-positive epithelioid entities, with the exception of salivary duct carcinomas where GATA3 was positive in a rate ranging 60%-100% among them. CONCLUSIONS: TRPS1 is as sensitive as GATA3 in GATA3-positive mBC and is more sensitive than GATA3 in TNBC. TRPS1 is negative in most GATA3-positive nonbreast tumors. Thus, the combination of TRPS1 and GATA3 could be used to differentiate breast primary from others in most situations.

Immunohistochemical Markers for Distinguishing Metastatic Breast Carcinoma from Other Common Malignancies: Update and Revisit.

Due to the high prevalence of breast cancer in the female, a metastasis from primary breast cancer is usually considered in the differential diagnosis of metastatic carcinoma in the female patient, even for those without a history of breast cancer, as some breast cancers are first diagnosed as metastases. Immunohistochemical analysis for breast cancer markers is the most common way to determine breast cancer origin besides clinical history and histology. In this review, we (1) summarize the commonly used and the newly identified breast cancer markers, including GCDFP-15, mammaglobin, GATA3, SOX10, and TRPS1; (2) point out the strengths and weaknesses of using these markers for breast cancers with luminal/epithelial or basal/myoepithelial differentiation; and (3) recommend diagnostic panels to differentiate breast carcinoma from carcinoma with similar morphology of other origins.

TRPS1, GATA3, and SOX10 expression in triple-negative breast carcinoma.

A diagnostic dilemma can be encountered when primary triple-negative breast carcinoma (TNBC) without an in situ component or metastatic TNBCs lose the currently used organ-specific marker such as GATA3, raising concerns about metastatic carcinoma from other sites. In the current study, we compared the newly identified breast marker TRPS1 with currently used breast markers GATA3 and SOX10 in whole-tissue sections from 315 cases of various subtypes of TNBC. TRPS1 was highly expressed in 100% of triple-negative primary and metastatic invasive lobular carcinomas, 99% of triple-negative primary and metastatic invasive breast carcinoma of no special type (IBC-NST), and 95% of metaplastic breast carcinomas. In contrast, GATA3 and SOX10 were expressed in 94% and 0% of invasive lobular carcinomas, 63% and 74% of IBC-NST, and 50% and 49% of metaplastic breast carcinomas, respectively. For special-type TNBCs, both TRPS1 and GATA3 were negative in acinic cell carcinomas, most cribriform adenoid cystic carcinomas, and neuroendocrine carcinomas, but positive in secretory carcinomas. Triple-negative apocrine carcinoma was the only subtype of TNBC with positive GATA3 but negative TRPS1. These data indicate that TRPS1 is a highly sensitive marker for TNBCs with positivity not only in GATA3/SOX10-positive TNBCs but also in almost all GATA3/SOX10-negative TNBCs.

Expression of TRPS1 in phyllodes tumor and sarcoma of the breast.

When a sarcomatous neoplasm is identified in the breast, distinguishing metaplastic carcinoma, malignant phyllodes tumor (MPT), and primary sarcoma is a diagnostic challenge, especially on small biopsies, as all these tumors may have overlapping morphological features, thoroughly grossing with histological examination and immunohistochemical staining being the standard approach to aid in classifying these lesions. Recently, we identified a highly sensitive and specific breast carcinoma marker TRPS1 with high expression in metaplastic breast carcinoma. In the current study, we tested TRPS1 in MPTs and primary sarcoma of the breast. We found TRPS1 was highly expressed (95%) within spindle cell, chondro-osseous, and/or liposarcomatous components of MPTs, in all breast primary chondrosarcomas and extraskeletal osteosarcomas, but not in other sarcomas of the breast. In extramammary sarcomas, TRPS1 was expressed in 28% of conventional chondrosarcomas and 56% of osteosarcomas of bone, but rarely in undifferentiated pleomorphic sarcomas (UPSs), liposarcomas, and angiosarcomas. In summary, MPTs may share similar genetic background with metaplastic carcinoma exhibiting TRPS1 expression, and TRPS1 may play a role in chondro-osseous differentiation because of its expression in chondro-osseous sarcomas from both breast and extramammary sites. Our findings suggest TRPS1 may be clinically useful in distinguishing MPT and metaplastic carcinoma from primary breast sarcoma except for tumors with chondro-osseous differentiation.

NDRG1 Expression Is an Independent Prognostic Factor in Inflammatory Breast Cancer.

NDRG1 is widely described as a metastasis suppressor in breast cancer. However, we found that NDRG1 is critical in promoting tumorigenesis and brain metastasis in mouse models of inflammatory breast cancer (IBC), a rare but highly aggressive form of breast cancer. We hypothesized that NDRG1 is a prognostic marker associated with poor outcome in patients with IBC. NDRG1 levels in tissue microarrays from 64 IBC patients were evaluated by immunohistochemical staining with NDRG1 (32 NDRG1-low (≤median), 32 NDRG1-high (>median)). Overall and disease-free survival (OS and DSS) were analyzed with Kaplan-Meier curves and log-rank test. Univariate analysis showed NDRG1 expression, tumor grade, disease stage, estrogen receptor (ER) status, and receipt of adjuvant radiation to be associated with OS and DSS. NDRG1-high patients had poorer 10-year OS and DSS than NDRG1-low patients (OS, 19% vs. 45%, p = 0.0278; DSS, 22% vs. 52%, p = 0.0139). On multivariable analysis, NDRG1 independently predicted OS (hazard ratio (HR) = 2.034, p = 0.0274) and DSS (HR = 2.287, p = 0.0174). NDRG1-high ER-negative tumors had worse outcomes OS, p = 0.0003; DSS, p = 0.0003; and NDRG1-high tumors that received adjuvant radiation treatment had poor outcomes (OS, p = 0.0088; DSS, p = 0.0093). NDRG1 was a significant independent prognostic factor for OS and DSS in IBC patients. Targeting NDRG1 may represent a novel strategy for improving clinical outcomes for patients with IBC.

High frequency of p16 and SOX10 coexpression but not androgen receptor expression in triple-negative breast cancers.

Triple-negative breast cancers (TNBCs) represent approximately 12-17% of all breast cancers and have distinctively aggressive clinical courses. Because routine biomarkers for breast cancer do not apply for TNBCs, it is essential to find novel prognostic markers and potential targets for therapeutic agents. p16 and SOX10 are emerging biomarkers with relatively unexplored expressions in TNBCs. We present an analysis of the expression of p16 and SOX10 in combination with that of androgen receptor (AR) and cytokeratin (CK) 5/6 in TNBCs. In addition, we used tissue microarrays (TMAs) to compare frequencies of p16 and SOX10 between TNBCs and non-TNBCs. Fifty-six TNBC samples with clinical data were stained immunohistochemically with p16, SOX10, AR, and CK5/6. Fifty-four cases (96.4%) were invasive ductal carcinoma, not otherwise specified, and 46 cases (82.1%) were Nottingham histologic grade 3. The majority of TNBC cases were positive for p16 (n = 44; 78.6%) and SOX10 (n = 48; 85.7%). AR was positive in 15 cases (26.8%). CK5/6 was positive in 24 cases (42.9%), which were classified as basal-like breast cancer (BLBC) subtype. The frequencies of p16 and SOX10 expression in BLBC and non-BLBC subtypes did not reveal significant statistical difference in a separate analysis. Using archived TNBC and non-TNBC TMAs, we observed that 56% of TNBC cases were positive for p16 compared with 16% of non-TNBC cases (p-value <0.0001). SOX10 was positive in 80% of TNBC cases compared with 35% of non-TNBC cases (p-value <0.0001). A significant correlation was observed between p16 and SOX10 coexpression in TNBC cases (n = 56/80, p = 0.02) but not in non-TNBC cases (n = 23/348; p = 0.626). In conclusion, p16 and SOX10 are frequently expressed in TNBC, regardless of CK5/6 expression. Furthermore, p16 and SOX10 are often coexpressed in TNBCs compared with non-TNBCs.

Induction of DNMT3B by PGE2 and IL6 at Distant Metastatic Sites Promotes Epigenetic Modification and Breast Cancer Colonization.

Current cancer treatments are largely based on the genetic characterization of primary tumors and are ineffective for metastatic disease. Here we report that DNA methyltransferase 3B (DNMT3B) is induced at distant metastatic sites and mediates epigenetic reprogramming of metastatic tumor cells. Multiomics analysis and spontaneous metastatic mouse models revealed that DNMT3B alters multiple pathways including STAT3, NFκB, PI3K/Akt, ß-catenin, and Notch signaling, which are critical for cancer cell survival, apoptosis, proliferation, invasion, and colonization. PGE2 and IL6 were identified as critical inflammatory mediators in DNMT3B induction. DNMT3B expression levels positively correlated with human metastatic progression. Targeting IL6 or COX-2 reduced DNMT3B induction and improved chemo or PD1 therapy. We propose a novel mechanism linking the metastatic microenvironment with epigenetic alterations that occur at distant sites. These results caution against the "Achilles heel" in cancer therapies based on primary tumor characterization and suggests targeting DNMT3B induction as new option for treating metastatic disease. SIGNIFICANCE: These findings reveal that DNMT3B epigenetically regulates multiple pro-oncogenic signaling pathways via the inflammatory microenvironment at distant sites, cautioning the clinical approach basing current therapies on genetic characterization of primary tumors.

Impact of biomarkers and genetic profiling on breast cancer prognostication: A comparative analysis of the 8th edition of breast cancer staging system.

The 8th edition of the American Joint Committee on Cancer (AJCC) staging guidelines combine traditional TNM system with biomarkers to reflect our current understanding of tumor biology and targeted therapy. In this study, we investigated the impact of the TNM + Biomarkers staging system and the additive value of Oncotype Dx™ genomic profile recurrence score (RS) (TNM + Biomarkers+RS <11) for the staging of breast cancer (BC) using data from two tertiary referral cancer centers. Compared to TNM alone, the TNM + Biomarkers system changed the stage group in 32.7% of BCs (27% downstage, 5.7% upstage). Most (98.3%) of the downstaged BCs were estrogen receptor (ER)+/progesterone receptor (PR)+, whereas 78% of the upstaged BCs were ER-/PR-/human epidermal growth factor receptor 2 (HER2)-. Compared to TNM + Biomarkers staging, the addition of genetic profile data (TNM + Biomarker+RS <11) downstaged only <1% BCs. Our analysis suggests that for T1-T2N0 ER+/HER2- BCs, Oncotype Dx™ RS <11 provides added value as a staging parameter only in a very small group of cases compared to TNM + Biomarkers alone.

Complete Genome Sequences of Nine Enterovirus D68 Strains from Patients of the Lower Hudson Valley, New York, 2016.

Complete genome sequences of nine enterovirus D68 (EV-D68) strains from patients in New York were obtained in 2016 by metagenomic next-generation sequencing. Comparative genomic analysis suggests that a new subclade B3, with ~4.5% nucleotide divergence from subclade B1 strains causing the 2014 outbreak, is circulating in the United States in 2016.

Evaluation of a Real-Time Reverse Transcription-PCR Assay for Detection of Enterovirus D68 in Clinical Samples from an Outbreak in New York State in 2014.

An outbreak of severe respiratory illness associated with enterovirus D68 (EV-D68) infection was reported in mid-August 2014 in the United States. In this study, we evaluated the diagnostic utility of an EV-D68-specific real-time reverse transcription-PCR (rRT-PCR) that was recently developed by the Centers for Disease Control and Prevention in clinical samples. Nasopharyngeal (NP) swab specimens from patients in a recent outbreak of respiratory illness in the lower Hudson Valley, New York State, were collected and examined for the presence of human rhinovirus or enterovirus using the FilmArray Respiratory Panel (RP) assay. Samples positive by RP were assessed using EV-D68 rRT-PCR, and the data were compared to results from sequencing analysis of partial VP1 and 5' untranslated region (5'-UTR) sequences of the EV genome. A total of 285 RP-positive NP specimens (260 from the 2014 outbreak and 25 from 2013) were analyzed by rRT-PCR; EV-D68 was detected in 74 of 285 (26.0%) specimens examined. Data for comparisons between rRT-PCR and sequencing analysis were obtained from 194 NP specimens. EV-D68 detection was confirmed by sequencing analysis in 71 of 74 positive and in 1 of 120 randomly selected negative specimens by rRT-PCR. The EV-D68 rRT-PCR showed diagnostic sensitivity and specificity of 98.6% and 97.5%, respectively. Our data suggest that the EV-D68 rRT-PCR is a reliable assay for detection of EV-D68 in clinical samples and has a potential to be used as a tool for rapid diagnosis and outbreak investigation of EV-D68-associated infections in clinical and public health laboratories.

Lyme disease: a case report of a 17-year-old male with fatal Lyme carditis.

Lyme disease is a systemic infection commonly found in the northeastern, mid-Atlantic, and north-central regions of the United States. Of the many systemic manifestations of Lyme disease, cardiac involvement is uncommon and rarely causes mortality. We describe a case of a 17-year-old adolescent who died unexpectedly after a 3-week viral-like syndrome. Postmortem examination was remarkable for diffuse pancarditis characterized by extensive infiltrates of lymphocytes and focal interstitial fibrosis. In the cardiac tissue, Borrelia burgdorferi was identified via special stains, immunohistochemistry, and polymerase chain reaction. The findings support B. burgdorferi as the causative agent for his fulminant carditis and that the patient suffered fatal Lyme carditis. Usually, Lyme carditis is associated with conduction disturbances and is a treatable condition. Nevertheless, few cases of mortality have been reported in the literature. Here, we report a rare example of fatal Lyme carditis in an unsuspected patient.