The 1000 Mitoses Project: A Consensus-Based International Collaborative Study on Mitotic Figures Classification.

Introduction. The identification of mitotic figures is essential for the diagnosis, grading, and classification of various different tumors. Despite its importance, there is a paucity of literature reporting the consistency in interpreting mitotic figures among pathologists. This study leverages publicly accessible datasets and social media to recruit an international group of pathologists to score an image database of more than 1000 mitotic figures collectively. Materials and Methods. Pathologists were instructed to randomly select a digital slide from The Cancer Genome Atlas (TCGA) datasets and annotate 10-20 mitotic figures within a 2 mm2 area. The first 1010 submitted mitotic figures were used to create an image dataset, with each figure transformed into an individual tile at 40x magnification. The dataset was redistributed to all pathologists to review and determine whether each tile constituted a mitotic figure. Results. Overall pathologists had a median agreement rate of 80.2% (range 42.0%-95.7%). Individual mitotic figure tiles had a median agreement rate of 87.1% and a fair inter-rater agreement across all tiles (kappa = 0.284). Mitotic figures in prometaphase had lower percentage agreement rates compared to other phases of mitosis. Conclusion. This dataset stands as the largest international consensus study for mitotic figures to date and can be utilized as a training set for future studies. The agreement range reflects a spectrum of criteria that pathologists use to decide what constitutes a mitotic figure, which may have potential implications in tumor diagnostics and clinical management.

Metastatic neuroendocrine tumor masquerading as orbital cysticercosis.

Orbital metastases secondary to neuroendocrine tumors are exceedingly rare. We present a unique case of a 30-year-old female initially presenting with fever, chills, periorbital swelling, and painful proptosis. CT orbits revealed two ovoid-shaped ring-enhancing lesions in the right lateral and superior rectus muscles and clear sinuses, atypical for infectious post-septal cellulitis. Further work-up included serologic analysis, auto-immune panel, and MRI. Further imaging showed pseudocystic orbital lesions mimicking orbital cysticercosis. Additionally, given the bilateral nature of the lesions and patient's country of origin, this parasitic process was highly suspected. A course of albendazole and steroids led to resolution of symptoms. With a presentation at age 30, this is by far the youngest case reported in literature to date.

Erratum: Zare, A. et al. RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis. Cancers, 2018, 10, 184.

The authors wish to make the following correction to their paper [...].

RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis.

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that is associated with significantly high mortality. In spite of advances in IBC diagnoses, the prognosis is still poor compared to non-IBC. Due to the aggressive nature of the disease, we hypothesize that elevated levels of inflammatory mediators may drive tumorigenesis and metastasis in IBC patients. Utilizing IBC cell models and patient tumor samples, we can detect elevated NF-κB activity and hyperactivation of non-canonical drivers of NF-κB (nuclear factor kappaB)-directed inflammation such as tyrosine phosphorylated receptor-interacting protein kinase 2 (pY RIPK2), when compared to non-IBC cells or patients. Interestingly, elevated RIPK2 activity levels were present in a majority of pre-chemotherapy samples from IBC patients at the time of diagnosis to suggest that patients at diagnosis had molecular activation of NF-κB via RIPK2, a phenomenon we define as "molecular inflammation". Surprisingly, chemotherapy did cause a significant increase in RIPK2 activity and thus molecular inflammation suggesting that chemotherapy does not resolve the molecular activation of NF-κB via RIPK2. This would impact on the metastatic potential of IBC cells. Indeed, we can demonstrate that RIPK2 activity correlated with advanced tumor, metastasis, and group stage as well as body mass index (BMI) to indicate that RIPK2 might be a useful prognostic marker for IBC and advanced stage breast cancer.

Practical Considerations in Breast Papillary Lesions: A Review of the Literature.

CONTEXT: -Diagnosis of papillary breast lesions, especially in core biopsies, is challenging for most pathologists, and these lesions pose problems for patient management. Distinction between benign, premalignant, and malignant components of papillary lesions is challenging, and the diagnosis of invasion is problematic in lesions that have circumscribed margins. Obtaining a balance between overtreatment and undertreatment of these lesions is also challenging. OBJECTIVES: -To provide a classification and a description of the histologic and immunohistochemical features and the differential diagnosis of papillary breast lesions, to provide an update on the molecular pathology of papillary breast lesions, and to discuss the recommendations for further investigation and management of papillary breast lesions. This review provides a concise description of the histologic and immunohistochemical features of the different papillary lesions of the breast. DATA SOURCES: -The standard pathology text books on breast pathology and literature on papillary breast lesions were reviewed with the assistance of the PubMed database ( http://www.ncbi.nlm.nih.gov/pubmed ). CONCLUSIONS: -Knowledge of the clinical presentation, histology, immunoprofile, and behavior of papillary breast lesions will assist pathologists with the diagnosis and optimal management of patients with papillary breast lesions.

p16 expression: a marker of differentiation between childhood malignant melanomas and Spitz nevi.

BACKGROUND: Childhood malignant melanomas frequently present as nodular melanomas with Spitzoid features. Spitz nevus and Spitzoid melanoma overlap clinically and histopathologically and there have been many attempts to differentiate between them. Spitz nevi differ from melanomas by their immunohistochemical pattern of expression of cell cycle and apoptosis regulators such as the p16 protein. OBJECTIVE: The aim of this study was to evaluate in a childhood population the expression of p16 in nodular malignant melanoma of Spitzoid type, Spitz nevi, and a control group of benign compound melanocytic nevi. METHODS: We performed immunohistochemical studies for expression of p16 in 6 Spitzoid malignant melanomas, 18 Spitz nevi, and 12 compound melanocytic nevi in children younger than 18 years. Statistical analysis was used to compare p16 expression, mitotic count/mm(2), and Ki-67 index of childhood nodular malignant melanomas and Spitz nevi. RESULTS: All the childhood melanoma cases were associated with loss of p16 without any correlation with their Breslow thickness whereas all the Spitz nevi and benign melanocytic nevi had strong positive nuclear and cytoplasmic expression of p16 staining. We found a statistically significant difference in p16 expression, mitotic counts, and Ki-67 index when comparing the Spitzoid melanomas with the Spitz nevi. LIMITATIONS: This study is limited by the small number of malignant melanomas, which are known to be rare in childhood. CONCLUSION: p16 Expression in childhood nodular Spitzoid malignant melanomas and Spitz nevi, in conjunction with clinical and histopathological evaluation, may be a useful tool in differentiating between these two entities.

Lymphangiosarcoma complicating extensive congenital mixed vascular malformations.

Pediatric hepatic angiosarcoma is a very rare malignant vascular tumor. A few cases have shown pediatric hepatic angiosarcoma occurring on a background of preexisting vascular lesions. We report the case of a newborn girl who presented extensive limbs and upper trunk cutaneous mixed vascular malformations at birth. These malformations were associated with thrombocytopenia. Cutaneous biopsies revealed complex vascular malformations with a significant lymphatic component. Compressive body suit therapy led to regression of the limbs' cutaneous vascular malformations. At the age of 9 months, the patient presented multiple heterogeneous hepatosplenic nodules. Aggressive treatment with prednisone, vincristine, and hepatosplenic embolizations resulted in initial improvement of the hepatosplenic lesions for few months, followed by an increase of the lesions with failure of response to treatment despite adding alpha-interferon-2b to treatment. The patient died at the age of 19 months. The autopsy's pathological examination revealed a hepatic-based angiosarcoma with plurimetastatic dissemination to the spleen, lungs, peritoneum, pleura, mesenteric linings as well as the serosa of the stomach and small intestine. Multiple cutaneous and visceral complex capillaro-lymphatico-venous malformations were also identified. We hypothesize that these multiple extensive mixed vascular malformations were associated with chronic lymphedema which probably predisposed to the development of the angiosarcoma in our patient.