Abstract Acinic cell carcinoma of breast is a rare subtype of triple negative breast carcinoma and demonstrates extensive morphologic overlap with acinic cell carcinoma of the salivary gland. In this ...study, we perform a detailed morphologic and immunohistochemical description of two cases of this rare entity, and undertake a comprehensive review of all reported cases of breast acinic cell carcinoma in the English language literature to date. One third of reported cases of breast acinic cell carcinoma have been associated with the presence of a ductal carcinoma not otherwise specified (NOS) component, which is frequently poorly differentiated. Breast acinic cell carcinoma can demonstrate focal morphologic features similar to microglandular adenosis; these areas are frequently negative for collagen IV and laminin on immunohistochemistry. The true relationship between these two entities remains unclear, but we advocate that microglandular adenosis-like areas at the periphery of a breast acinic cell carcinoma should be considered part of the carcinomatous process and re-excised if this process extends to the initial surgical margins.
Purpose
To determine if the histology of a breast malignancy influences the appearance of untreated osseous metastases on FDG PET/CT.
Methods
This retrospective study was performed under IRB waiver. ...Our Hospital Information System was screened for breast cancer patients who presented with osseous metastases, who underwent FDG PET/CT prior to systemic therapy or radiotherapy from 2009 to 2012. Patients with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), or mixed ductal/lobular (MDL) histology were included. Patients with a history of other malignancies were excluded. PET/CT was evaluated, blinded to histology, to classify osseous metastases on a per-patient basis as sclerotic, lytic, mixed lytic/sclerotic, or occult on CT, and to record SUVmax for osseous metastases on PET.
Results
Following screening, 95 patients who met the inclusion criteria (74 IDC, 13 ILC, and 8 MDL) were included. ILC osseous metastases were more commonly sclerotic and demonstrated lower SUVmax than IDC metastases. In all IDC and MDL patients with osseous metastases, at least one was FDG-avid. For ILC, all patients with lytic or mixed osseous metastases demonstrated at least one FDG-avid metastasis; however, in only three of seven patients were sclerotic osseous metastases apparent on FDG PET.
Conclusion
The histologic subtype of breast cancer affects the appearance of untreated osseous metastases on FDG PET/CT. In particular, non-FDG-avid sclerotic osseous metastases were more common in patients with ILC than in patients with IDC. Breast cancer histology should be considered when interpreting non-FDG-avid sclerotic osseous lesions on PET/CT, which may be more suspicious for metastases (rather than benign lesions) in patients with ILC.
Invasive breast cancers constitute a heterogeneous group of lesions. Although the most common types are ductal and lobular, this distinction is not meant to indicate the site of origin within the ...mammary ductal system. The main purpose of the identification of specific types of invasive breast carcinoma is to refine the prediction of likely behavior and response to treatment also offered by the other major prognostic factors, including lymph node stage, histologic grade, tumor size, and lymphovascular invasion.
Alterations in protein-protein interaction networks are at the core of malignant transformation but have yet to be translated into appropriate diagnostic tools. We make use of the kinetic selectivity ...properties of an imaging probe to visualize and measure the epichaperome, a pathologic protein-protein interaction network. We are able to assay and image epichaperome networks in cancer and their engagement by inhibitor in patients' tumors at single-lesion resolution in real time, and demonstrate that quantitative evaluation at the level of individual tumors can be used to optimize dose and schedule selection. We thus provide preclinical and clinical evidence in the use of this theranostic platform for precision medicine targeting of the aberrant properties of protein networks.
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•Pathologic protein networks and their engagement in clinic are monitored by imaging•Real-time tumor pharmacometric data are obtained at the level of individual tumors•Theranostic and clinical assay combined provide quantitative tumor measurements•The platform provides dose and schedule information for epichaperome targeting
Pillarsetty et al. demonstrate the ability to visualize the epichaperome, a pathologic protein-protein interaction network, and to measure inhibitor engagement from mice and patients at single-tumor resolution in real time, which facilitates the optimization of dose and schedule selection.
Purpose
Breast fibroglandular tissue (FGT), as visualized on a mammogram (mammographic density, MD), is one of the strongest known risk factors for breast cancer. FGT is also visible on breast MRI, ...and increased background parenchymal enhancement (BPE) in the FGT has been identified as potentially a major breast cancer risk factor. The aim of this exploratory study was to examine the biologic basis of BPE.
Methods
We examined the unaffected contra-lateral breast of 80 breast cancer patients undergoing a prophylactic mastectomy before any treatment other than surgery of their breast cancer. BPE was classified on the BI-RADS scale (minimal/mild/moderate/marked). Slides were stained for microvessel density (MVD), CD34 (another measure of endothelial density), glandular tissue within the FGT and VEGF. Spearman correlations were used to evaluate the associations between BPE and these pathologic variables.
Results
In pre-menopausal patients, BPE was highly correlated with MVD, CD34 and glandular concentration within the FGT, and the pathologic variables were themselves highly correlated. The expression of VEGF was effectively confined to terminal duct lobular unit (TDLU) epithelium. The same relationships of the four pathologic variables with BPE were seen in post-menopausal patients, but the relationships were much weaker and not statistically significant.
Conclusion
The strong correlation of BPE and MVD together with the high correlation of MVD with glandular concentration seen in pre-menopausal patients indicates that increased breast cancer risk associated with BPE in pre-menopausal women is likely to result from its association with increased concentration of glandular tissue in the FGT. The effective confinement of VEGF expression to the TDLUs shows that the signal for MVD growth arises directly from the glandular tissue. Further studies are needed to understand the basis of BPE in post-menopausal women.
The limited translational value in clinic of analyses performed on 2-D cell cultures has prompted a shift toward the generation of 3-dimensional (3-D) multicellular systems. Here we present a ...spontaneously-forming in vitro cancer spheroid model, referred to as spheroids(MARY-X), that precisely reflects the pathophysiological features commonly found in tumor tissues and the lymphovascular embolus. In addition, we have developed a rapid, inexpensive means to evaluate response following drug treatment where spheroid dissolution indices from brightfield image analyses are used to construct dose-response curves resulting in relevant IC50 values. Using the spheroids(MARY-X) model, we demonstrate the unique ability of a new class of molecules, containing the caged Garcinia xanthone (CGX) motif, to induce spheroidal dissolution and apoptosis at IC50 values of 0.42 +/-0.02 μM for gambogic acid and 0.66 +/-0.02 μM for MAD28. On the other hand, treatment of spheroids(MARY-X) with various currently approved chemotherapeutics of solid and blood-borne cancer types failed to induce any response as indicated by high dissolution indices and subsequent poor IC50 values, such as 7.8 +/-3.1 μM for paclitaxel. Our studies highlight the significance of the spheroids(MARY-X) model in drug screening and underscore the potential of the CGX motif as a promising anticancer pharmacophore.
Systems-level assessments of protein-protein interaction (PPI) network dysfunctions are currently out-of-reach because approaches enabling proteome-wide identification, analysis, and modulation of ...context-specific PPI changes in native (unengineered) cells and tissues are lacking. Herein, we take advantage of chemical binders of maladaptive scaffolding structures termed epichaperomes and develop an epichaperome-based 'omics platform, epichaperomics, to identify PPI alterations in disease. We provide multiple lines of evidence, at both biochemical and functional levels, demonstrating the importance of these probes to identify and study PPI network dysfunctions and provide mechanistically and therapeutically relevant proteome-wide insights. As proof-of-principle, we derive systems-level insight into PPI dysfunctions of cancer cells which enabled the discovery of a context-dependent mechanism by which cancer cells enhance the fitness of mitotic protein networks. Importantly, our systems levels analyses support the use of epichaperome chemical binders as therapeutic strategies aimed at normalizing PPI networks.
Stresses associated with disease may pathologically remodel the proteome by both increasing interaction strength and altering interaction partners, resulting in proteome-wide connectivity ...dysfunctions. Chaperones play an important role in these alterations, but how these changes are executed remains largely unknown. Our study unveils a specific N-glycosylation pattern used by a chaperone, Glucose-regulated protein 94 (GRP94), to alter its conformational fitness and stabilize a state most permissive for stable interactions with proteins at the plasma membrane. This “protein assembly mutation’ remodels protein networks and properties of the cell. We show in cells, human specimens, and mouse xenografts that proteome connectivity is restorable by inhibition of the N-glycosylated GRP94 variant. In summary, we provide biochemical evidence for stressor-induced chaperone-mediated protein mis-assemblies and demonstrate how these alterations are actionable in disease.
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•N-glycosylation transforms a chaperone, GRP94, from a folder into a scaffolding protein•These changes are pathologic in nature as they remodel proteome-wide connectivity•The N-glycosylated GRP94 variant is a small and distinct fraction of the GRP94 pool•Proteome dysfunctions mediated by the N-glycosylated GRP94 variant are actionable
Yan et al. show how N-glycosylation transforms a chaperone from a folding to a scaffolding protein that remodels protein connectivity, with the end result of proteome-wide dysfunction. This specific modification, exploited by cancer cells for enhanced fitness, is an actionable target in disease.
The occurrence of benign epithelial inclusions in lymph nodes is well documented and can sometimes mimic metastatic carcinoma. Benign müllerian inclusions, such as endometriosis and endosalpingiosis, ...are common in pelvic and para-aortic lymph nodes, but their presence in supradiaphragmatic lymph nodes is a rare event. We report our experience with 3 patients found to have endosalpingiosis in axillary sentinel lymph nodes obtained for staging of breast carcinoma. All patients were postmenopausal women, with age ranging between 65 and 75 years. Endosalpingiosis involved a single lymph node in 1 patient, and 2 nodes in each of the other 2; it was present in the lymph node capsule in all the 3 cases, with few glands scattered within the lymph node parenchyma in 2 of the patients. The glands contained ciliated and intercalated peg cells, had no periglandular endometrial-type stroma, and showed no atypia or mitotic activity. The epithelium demonstrated positive nuclear immunoreactivity for WT1 and PAX8, and was devoid of myoepithelium or basement membrane. Endosalpingiosis had been misinterpreted as metastatic carcinoma at another hospital in 1 of the 3 patients, with subsequent dissection of 19 additional benign axillary lymph nodes. We conclude that endosalpingiosis can involve axillary lymph nodes and closely simulate metastatic mammary carcinoma. Morphologic identification of ciliated cells and "peg" cells is most helpful to recognize this benign inclusion, and positive immunoreactivity for WT1 and/or PAX8 can be used to support the diagnosis.
Breast cancer is increasingly treated with neoadjuvant chemotherapy to improve surgical resectability and evaluate tumor response, which is assessed histopathologically. Several histopathologic ...classification systems have been previously described for assessment of treatment response.
To test performance in a side-by-side comparison of several histopathologic classification systems after neoadjuvant chemotherapy with clinical outcome.
Sixty-two patients were enrolled in a randomized trial receiving sequential neoadjuvant chemotherapy with doxorubicin and paclitaxel. Histologic sections from the patients' tumors sampled before (core biopsy) and after treatment (excision or mastectomy) were reviewed. Histologic response was assessed following National Surgical Adjuvant Breast and Bowel Project protocol B18, Miller-Payne grading, Sataloff tumor and nodes, Residual Cancer Burden (RCB), and Residual Disease in Breast and Nodes (RDBN). Pathologic classification results were correlated with survival using Kaplan-Meier and Cox hazards regression with a median follow-up of 93 months.
RDBN was associated with distant disease-free survival by univariate and multivariate analysis (P = .01 and .004, respectively), as were lymph node metastases (P = .02 and .01, respectively). Five patients (8%) had complete pathologic response after neoadjuvant chemotherapy, and none of them relapsed during the study period. Survival was shorter among patients with higher Residual Cancer Burden scores, but the associations were not significant. Miller-Payne grading and Sataloff tumor scores were not correlated with survival.
Evaluation of breast specimens after neoadjuvant chemotherapy by the composite index RDBN correlates with long-term outcome. The residual disease in breast and nodes system is suitable for routinely processed pathology cases. This study confirms the importance of lymph node status after neoadjuvant chemotherapy and favorable outcome in patients with pathologic complete response.
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