Faculty Bibliography

Prompt detection and identification of fungal pathogens at the genus and species level is critical in order to provide timely antifungal therapy. Here, we highlight the vital role of molecular diagnostics in achieving a fast and definitive diagnosis of disseminated blastomycosis in a diabetic patient presenting as a brain mass initially thought to be tumoral in nature. A broad-range PCR amplification and sequencing of the fungal ribosomal RNA genes on brain biopsy tissue obtained during elective craniotomy revealed a final microbial identification of Ajellomyces dermatitidis (telemorph of Blastomyces dermatitidis).

BACKGROUND: The characterization of the molecular alterations in thymic epithelial tumors may lead to a better understanding of tumorigenesis, new therapeutic targets, and biomarkers in these tumors. METHODS: Paired tissue (tumor and matched normal) from 15 thymic carcinomas (TCA) and six B3 thymomas were evaluated by exon capture of 275 cancer-related genes, followed by deep coverage next-generation sequencing, which identifies somatic sequence variants, small insertions and deletions, and copy number alterations involving all exons of the captured genes. RESULTS: Non-silent somatic mutations were identified in 12 of 15 (80%) TCA with a median of one mutation per tumor (range 0-26). Recurrent mutations were identified in tumor suppressor genes TP53 (n = 4), SMAD4 (n = 2), and CYLD (n = 2); and chromatin remodeling genes KDM6A (n = 3), SETD2 (n = 2), MLL3 (n = 2), and MLL2 (n = 2). Tumors with TP53 mutation appeared to exhibit more aggressive behavior. Therefore, the role of P53 was evaluated by immunohistochemistry in an additional ten cases. P53 overexpression correlated with TP53 mutation. These tumors had a higher rate of recurrence and death of disease compared to carcinoma with normal p53 expression (p = 0.02 for disease-free survival and p = 0.05 for overall survival). Among the B3 thymomas, mutations were identified in four of six tumors. Mutations in BCOR (BCL6 co-repressor) were seen in three thymomas and MLL3 (involved in histone methylation) in one tumor. CONCLUSIONS: Next-generation sequencing of cancer genes in thymic epithelial tumors revealed a low frequency of mutation, with different patterns between TCA and B3 thymomas. TP53 and BCOR were the most frequently mutated genes in TCA and B3 thymomas, respectively. Alterations in p53 are associated with worse prognosis in TCA.

AIMS: Cryptogenic organising pneumonia (COP) and acute fibrinous and organising pneumonia (AFOP) are recognised patterns of organising pneumonia (OP), a condition that resembles pneumonia but is not caused by infection. We have recognised granulomatous organising pneumonia (GOP) to be a similar histopathological entity where non-necrotising granulomata are intimately associated with the organising connective tissue. To what degree COP, AFOP and GOP represent distinct clinical and pathological disorders is unknown. This cross-sectional study sought to compare the pathological, clinical, and radiographical features of these OP patterns. METHODS: Surgical lung biopsy specimens were reviewed for consecutive patients referred with OP to a metropolitan cancer centre. Clinical information and CT images were acquired from the hospital electronic medical record to determine the clinical and CT characteristics of each OP pattern. RESULTS: Sixty-one patients (35 men, 26 women), mean age 61.5 years (range 8-85 years), were available for analysis. Of these, 43 patients (70%) had at least one prior cancer; 27 (44%) had received chemotherapy and 18 (30%) had received radiation. Approximately, half (32 patients) had respiratory symptoms, most commonly cough, dyspnoea and/or wheezing. While symptoms and mortality rates were not different among OP groups, AFOP patients more commonly had fever (p=0.04). GOP patients less commonly had received chemotherapy (p=0.03) and were more likely to present as masses/nodules (p=0.04). CONCLUSIONS: AFOP and GOP, a newly described OP form, possess clinical and pathological findings that set it apart from a COP, suggesting an emerging spectrum of OP.

This overview of the 4th edition of the World Health Organization (WHO) Classification of thymic tumors has two aims. First, to comprehensively list the established and new tumor entities and variants that are described in the new WHO Classification of thymic epithelial tumors, germ cell tumors, lymphomas, dendritic cell and myeloid neoplasms, and soft-tissue tumors of the thymus and mediastinum; second, to highlight major differences in the new WHO Classification that result from the progress that has been made since the 3rd edition in 2004 at immunohistochemical, genetic and conceptual levels. Refined diagnostic criteria for type A, AB, B1-B3 thymomas and thymic squamous cell carcinoma are given, and it is hoped that these criteria will improve the reproducibility of the classification and its clinical relevance. The clinical perspective of the classification has been strengthened by involving experts from radiology, thoracic surgery, and oncology; by incorporating state-of-the-art positron emission tomography/computed tomography images; and by depicting prototypic cytological specimens. This makes the thymus section of the new WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart a valuable tool for pathologists, cytologists, and clinicians alike. The impact of the new WHO Classification on therapeutic decisions is exemplified in this overview for thymic epithelial tumors and mediastinal lymphomas, and future perspectives and challenges are discussed.

BACKGROUND: Initial management recommendations of papillary thyroid carcinoma (PTC) are very dependent on preoperative studies designed to evaluate the presence of PTC with aggressive features. The purpose of this study was to evaluate whether diffusion-weighted magnetic resonance imaging (DW-MRI) before surgery can be used as a tool to stratify tumor aggressiveness in patients with PTC. METHODS: In this prospective study, 28 patients with PTC underwent DW-MRI studies on a three Tesla MR scanner prior to thyroidectomy. Due to image quality, 21 patients were finally suitable for further analysis. Apparent diffusion coefficients (ADCs) of normal thyroid tissues and PTCs for 21 patients were calculated. Tumor aggressiveness was defined by surgical histopathology. The Mann-Whitney U test was used to compare the difference in ADCs among groups of normal thyroid tissues and PTCs with and without features of tumor aggressiveness. Receiver operating characteristic (ROC) analysis was performed to assess the discriminative specificity, sensitivity, and accuracy of and determine the cutoff value for the ADC in stratifying PTCs with tumor aggressiveness. RESULTS: There was no significant difference in ADC values between normal thyroid tissues and PTCs. However, ADC values of PTCs with extrathyroidal extension (ETE; 1.53+/-0.25x10(-3) mm2/s) were significantly lower than corresponding values from PTCs without ETE (2.37+/-0.67x10(-3) mm2/s; p<0.005). ADC values identified 3 papillary carcinoma patients with extrathyroidal extension that would have otherwise been candidates for observation based on ultrasound evaluations. The cutoff value of ADC to discriminate PTCs with and without ETE was determined at 1.85x10(-3) mm2/s with a sensitivity of 85%, specificity of 85%, and ROC curve area of 0.85. CONCLUSION: ADC value derived from DW-MRI before surgery has the potential to stratify ETE in patients with PTCs.

Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non-small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti-PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti-PD-1 therapy.

One of the consequences of traumatic injuries is the chance of aseptic pulp necrosis to occur which in time may became infected and give origin to periapical pathosis. Although the apical granulomas and cysts are a common condition, there appearance as an extremely large radiolucent image is a rare finding. Differential diagnosis with other radiographic-like pathologies, such as keratocystic odontogenic tumour or unicystic ameloblastoma, is mandatory. The purpose of this paper is to report a very large radicular cyst caused by a single mandibular incisor traumatized long back, in a 60-year-old male. Medical and clinical histories were obtained, radiographic and cone beam CT examinations performed and an initial incisional biopsy was done. The final decision was to perform a surgical enucleation of a lesion, 51.4 mm in length. The enucleated tissue biopsy analysis was able to render the diagnosis as an inflammatory odontogenic cyst. A 2 year follow-up showed complete bone recovery.

Core biopsies obtained using PET/CT guidance contain bound radiotracer and therefore provide information about tracer uptake in situ. Our goal is to develop a method for Quantitative Autoradiography of Biopsy Specimens (QABS), to use this method to correlate 18F-fluorodeoxyglucose (FDG) tracer uptake in situ with histopathology findings, and to briefly discuss its potential application. METHODS: Twenty seven (27) patients referred for a PET/CT-guided biopsy of FDG-avid primary or metastatic lesions in different locations consented to participate in this institutional review board-approved, HIPAA compliant study. Autoradiography (ARG) of biopsy specimens obtained using five types of needles was performed immediately after extraction. The response of ARG imaging plates was calibrated using dummy specimens with known activity obtained using two core biopsy needle sizes. The calibration curves were used to quantify the activity along biopsy specimens obtained with these two needles and to calculate standardized uptake values, SUVARG. ARG images were correlated with histopathologic findings and fused with PET/CT images demonstrating the position of the biopsy needle within the lesion. Logistic regression analysis was performed to search for SUVARG threshold distinguishing benign from malignant tissue in liver biopsy specimens. Pearson correlation between SUVARG of the whole biopsy specimen and average SUVPET over the voxels intersected by the needle in the fused PET/CT was calculated. RESULTS: Activity concentrations were obtained using ARG for 20 specimens extracted with 18G and 20G needles. The probability for finding malignancy in a specimen is larger than 50% (95 % confidence) if SUVARG is larger than 7.3. For core specimens with preserved shape and orientation and in the absence of motion, ARG, CT and PET images registration with spatial accuracy better than 2 mm is achievable. The correlation coefficient between specimen mean SUVARG and SUVPET was 0.66. CONCLUSION: Performing QABS on core biopsy specimens obtained using PET/CT guidance enables in situ correlation of FDG tracer uptake and histopathology on a millimeter scale. QABS promises to provide useful information for guiding interventional radiology procedures and localized therapies and for in situ high spatial resolution validation of radiopharmaceuticals uptake.

The 2011 International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) lung adenocarcinoma classification emphasizes the prognostic significance of histologic subtypes. However, one limitation of this classification is that the highest percentage of patients ( approximately 40%) is classified as acinar predominant tumors, and these patients display a spectrum of favorable and unfavorable clinical behaviors. We investigated whether the cribriform pattern can further stratify prognosis by histologic subtype. Tumor slides from 1038 patients with stage I lung adenocarcinoma (1995-2009) were reviewed. Tumors were classified according to the IASLC/ATS/ERS classification. The percentage of cribriform pattern was recorded, and the cribriform predominant subtype was considered as a subtype for analysis. The log-rank test was used to analyze the association between histologic variables and recurrence-free probability. The 5-year recurrence-free probability for patients with cribriform predominant tumors (n=46) was 70%. The recurrence-free probability for patients with cribriform predominant tumors was significantly lower than that for patients with acinar (5-year recurrence-free probability, 87%; P=0.002) or papillary predominant tumors (83%; P=0.020) but was comparable to that for patients with micropapillary (P=0.34) or solid predominant tumors (P=0.56). The recurrence-free probability for patients with >/=10% cribriform pattern tumors (n=214) was significantly lower (5-year recurrence-free probability, 73%) than that for patients with <10% cribriform pattern tumors (n=824; 84%; P<0.001). In multivariate analysis, patients with acinar predominant tumors with >/=10% cribriform pattern remained at significantly increased risk of recurrence compared with those with <10% cribriform pattern (P=0.042). Cribriform predominant tumors should be considered a distinct subtype with a high risk of recurrence, and presence (>/=10%) of the cribriform pattern is an independent predictor of recurrence, identifying a poor prognostic subset of acinar predominant tumors. Our findings highlight the important prognostic value of comprehensive histologic subtyping and recording the percentage of each histologic pattern, according to the IASLC/ATS/ERS classification with the addition of the cribriform subtype.