A Consensus Diagnosis Utilizing Surface KI-67 Expression as an Ancillary Marker in Low-Grade Dysplasia Helps Identify Patients at High Risk of Progression to High-Grade Dysplasia and Esophaegal Adenocarcinoma.

Esophageal adenocarcinoma (EAC) develops in a step-wise manner, from low-grade dysplasia (LGD) to high-grade dysplasia (HGD), and ultimately to invasive EAC. However, there remains diagnostic uncertainty about LGD and its risk of progression to HGD/EAC. The aim is to investigate the role of Ki-67, immune-histochemical marker of proliferation, surface expression in patients with confirmed LGD, and risk stratify progression to HGD/EAC. A retrospective cohort study was conducted. Patients with confirmed LGD and indefinite for dysplasia (IND), with a mean follow-up of ≥1 year, were included. Pathology specimens were stained for Ki-67 and analyzed for evidence of surface expression. Our results reveal that 29% of patients with confirmed LGD who stained positive with Ki-67 progressed to HGD/EAC as opposed to none (0%) of the patients who stained negative, a statistically significant result (P = 0.003). Similarly, specimens from patients with IND were stained and analyzed revealing a nonsignificant trend toward a higher rate of progression for Ki-67 positive cases versus Ki-67 negative, 30% versus 21%, respectively. Ki-67 expression by itself can identify patients with LGD at a high risk of progression.

Identification of high protein kinase CK2α in HPV(+) oropharyngeal squamous cell carcinoma and correlation with clinical outcomes.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) incidence is rising worldwide, especially human papillomavirus (HPV)-associated disease. Historically, high levels of protein kinase CK2 were linked with poor outcomes in head and neck squamous cell carcinoma (HNSCC), without consideration of HPV status. This retrospective study examined tumor CK2α protein expression levels and related clinical outcomes in a cohort of Veteran OPSCC patient tumors which were determined to be predominantly HPV(+). METHODS: Patients at the Minneapolis VA Health Care System with newly diagnosed primary OPSCC from January 2005 to December 2015 were identified. A total of 119 OPSCC patient tumors were stained for CK2α, p16 and Ki-67 proteins and E6/E7 RNA. CK2α protein levels in tumors and correlations with HPV status and Ki-67 index were assessed. Overall survival (OS) analysis was performed stratified by CK2α protein score and separately by HPV status, followed by Cox regression controlling for smoking status. To strengthen the limited HPV(-) data, survival analysis for HPV(-) HNSCC patients in the publicly available The Cancer Genome Atlas (TCGA) PanCancer RNA-seq dataset was determined for CSNK2A1. RESULTS: The patients in the study population were all male and had a predominant history of tobacco and alcohol use. This cohort comprised 84 HPV(+) and 35 HPV(-) tumors. CK2α levels were higher in HPV(+) tumors compared to HPV(-) tumors. Higher CK2α scores positively correlated with higher Ki-67 index. OS improved with increasing CK2α score and separately OS was significantly better for those with HPV(+) as opposed to HPV(-) OPSCC. Both remained significant after controlling for smoking status. High CSNK2A1 mRNA levels from TCGA data associated with worse patient survival in HPV(-) HNSCC. CONCLUSIONS: High CK2α protein levels are detected in HPV(+) OPSCC tumors and demonstrate an unexpected association with improved survival in a strongly HPV(+) OPSCC cohort. Worse survival outcomes for high CSNK2A1 mRNA levels in HPV(-) HNSCC are consistent with historical data. Given these surprising findings and the rising incidence of HPV(+) OPSCC, further study is needed to understand the biological roles of CK2 in HPV(+) and HPV(-) HNSCC and the potential utility for therapeutic targeting of CK2 in these two disease states.

Surface Ki-67 Expression Improves Reproducibility of Dysplasia Diagnosis in Barrett's Esophagus.

OBJECTIVES: Many studies have shown poor reproducibility among pathologists for diagnosing dysplasia in Barrett's esophagus (BE). Immunohistochemical stains (IHC) are not widely used due to overlapping expression patterns in reactive and dysplastic processes. We hypothesized that markers involved in cell-cycle (cyclin D1, Ki-67, P16), differentiation/cell-cell interaction (ß-catenin, SATB2 CD44, OCT4) and senescence (γH2AX) would produce different results in reactive and dysplastic processes. METHODS: A micrograph album of 40 H&E and matching IHCs depicting optimally oriented lesions were evaluated independently by 3 pathologists. Expression was scored separately in the surface, isthmus, and base regions of the glands. RESULTS: Statistical analysis showed that surface Ki-67 expression showed the largest difference in expression and smallest P value (P < .001) for identifying dysplasia. At a cutoff level of 5% or less, negative predictive value (NPV) was 100%. κ correlation between pathologists improved from substantial to almost perfect (0.70-0.95) using ancillary surface Ki-67. CONCLUSION: A case-control study with glass slides including all diagnostic categories using this parameter confirmed improved κ correlation among pathologists (0.29 vs 0.60), better correlation with outcomes (76% vs 69%), increased odd risks (15.3) for progression in positive cases, and an improvement in sensitivity (88% vs 64%) and NPV (88% vs 73%) compared to histology alone.

Response of Aneurysmal Bone Cyst to Denosumab.

STUDY DESIGN: Case report and literature review. OBJECTIVE: To describe a unique case of large sacral aneurysmal bone cysts (ABCs) treated with denosumab and review the literature on this rare entity. SUMMARY AND BACKGROUND DATA: ABCs are expansile osteolytic lesions that typically contain blood-filled spaces separated by fibrous septa. Standard treatment includes surgical resection or curettage and packing; however, for some spinal lesions, the standard approach is not optimal. One therapeutic strategy is to treat spinal ABC with an agent that targets a pathway that is dysregulated in a disease with similar pathophysiology. The bone destruction in both giant cell tumors of bone and ABCs is mediated by RANK ligand (RANKL) produced by the tumor cells. Denosumab, a human monoclonal antibody to RANKL, is effective in the treatment of giant cell tumors of bone. METHODS: We report a case of a large sacral ABC that responded to denosumab. A 27-year-old male developed increasing back pain. Imaging revealed a lytic lesion in the sacrum with no clear solid component and regions where the cortex was difficult to identify. ABC was diagnosed on biopsy. Surgery or radiation treatment was expected to be associated with serious morbidity; therefore, denosumab was given using the regimen for giant cell tumors of bone (120  mg monthly with a loading dose). RESULTS: The patient's pain gradually resolved after 2 months of treatment. New bone formation with a more clearly defined cortex was evident on computed tomographic scan at 16 weeks and continued to show evidence of improvement at 7 and 12 months. Biopsy at 12 months revealed a hypocellular fibrous stroma with new bone formation and no giant cells. CONCLUSION: We conclude that denosumab can result in symptomatic and radiological improvement in ABC and may be useful in select cases. LEVEL OF EVIDENCE: 5.

Endobronchial ultrasound-guided transbronchial needle aspiration diagnosis of mediastinal lymph node metastasis of mucinous adenocarcinoma: arborizing stromal meshwork fragments as a diagnostic clue.

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) is a reliable and accurate method for the diagnosis of mediastinal metastases in patients with pulmonary and extrathoracic neoplasms. We report the cytopathologic findings of a case of metastatic signet-ring cell carcinoma with abundant extracellular mucin production in the mediastinal lymph nodes of a 41-year-old woman, who presented with nausea, abdominal pain, and weight loss. Imaging studies showed a renal mass, numerous lung nodules, and mediastinal and retroperitoneal lymphadenopathy. EBUS-TBNA of level 4R and 7 lymph nodes showed abundant, thick, "clean" mucus with entrapped ciliated bronchial cells, rare histiocytes, and fragments of cartilage. No neoplastic cells could be identified in Diff-Quik®-stained smears during the rapid on-site evaluation, but rare signet-ring cells were identified in the Papanicolaou-stained smears and cellblock sections. A distinctive feature of the aspirates was the presence of large branching (arborizing), "spidery" stromal fiber meshwork fragments. These stained metachromatically (magenta) with Romanowsky-type stains and cyanophilic to orangeophilic with Papanicolaou stains and showed occasional attached bland spindle cells, but had no capillary lumina or CD31-staining endothelial cells. The tumor cells were strongly and diffusely positive for CEA, CDX2, CK7, CK20, and MUC2, supporting the diagnosis of a metastatic signet-ring cell adenocarcinoma, most likely of gastrointestinal origin. We believe that the presence of the large spidery stromal fiber fragments is a useful clue to the presence of a mucinous neoplasm in EBUS-TBNA and allows the differentiation of the neoplastic mucus from contaminating endobronchial mucus.