Faculty Bibliography

The advent of targeted therapy in lung cancer has heralded a paradigm shift in the practice of cytopathology with the need for accurately subtyping lung carcinoma, as well as providing adequate material for molecular studies, to help guide clinical and therapeutic decisions. The variety and versatility of cytologic-specimen preparations offer significant advantages to molecular testing; however, they frequently remain underused. Therefore, evaluating the utility and adequacy of cytologic specimens is critical, not only from a lung cancer diagnosis standpoint but also for the myriad ancillary studies that are necessary to provide appropriate clinical management. A large fraction of lung cancers are diagnosed by aspiration or exfoliative cytology specimens, and thus, optimizing strategies to triage and best use the tissue for diagnosis and biomarker studies forms a critical component of lung cancer management. This review focuses on the opportunities and challenges of using cytologic specimens for molecular diagnosis of lung cancer and the role of cytopathology in the molecular era.

PURPOSE: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm, whose biological relationship to small cell lung carcinoma (SCLC) versus non-SCLC (NSCLC) remains unclear, contributing to uncertainty regarding optimal clinical management. To clarify these relationships, we analyzed genomic alterations in LCNEC compared to other major lung carcinoma types. EXPERIMENTAL DESIGN: LCNEC (n=45) tumor/normal pairs underwent targeted next-generation sequencing of 241 cancer genes by MSK-IMPACT platform, and comprehensive histologic, immunohistochemical and clinical analysis. Genomic data were compared to MSK-IMPACT analysis of other lung carcinoma histologies (n=242). RESULTS: Commonly altered genes in LCNEC included TP53 (78%), RB1 (38%), STK11 (33%), KEAP1 (31%) and KRAS (22%). Genomic profiles segregated LCNEC into 2 major and 1 minor subsets: SCLC-like (n=18), characterized by TP53+RB1 co-mutation/loss and other SCLC-type alterations, including MYCL amplification; NSCLC-like (n=25), characterized by the lack of co-altered TP53+RB1 and nearly-universal occurrence of NSCLC-type mutations (STK11, KRAS, KEAP1); and carcinoid-like (n=2), characterized by MEN1 mutations and low mutation burden. SCLC-like and NSCLC-like subsets revealed several clinicopathological differences, including higher proliferative activity in SCLC-like tumors (P<0.0001), and exclusive adenocarcinoma-type differentiation marker expression in NSCLC-like tumors (P=0.005). While exhibiting predominant similarity with lung adenocarcinoma, NSCLC-like LCNEC harbored several distinctive genomic alterations, including more frequent mutations in NOTCH family genes (28%), implicated as key regulators of neuroendocrine differentiation. CONCLUSIONS: LCNEC is a biologically-heterogeneous group of tumors, comprising distinct subsets with genomic signatures of SCLC, NSCLC (predominantly adenocarcinoma), and rarely, highly-proliferative carcinoids. Recognition of these subsets may inform the classification and management of LCNEC patients.

Primary cardiac tumors are a rare set of benign and malignant neoplasms found in the heart or pericardium. We describe a patient presenting with nonspecific symptoms and ultimately diagnosed with primary cardiac non-Hodgkin's lymphoma (PCL). Our patient had extensive tumor in the right ventricle, which extended into the right atrium and right ventricular outflow tract. The tumor also encased the right coronary artery, which manifested as ischemic changes on EKG and cardiac MRI. The patient was treated with chemotherapy and achieved complete remission, with dramatic and full resolution of the mass on repeat echocardiography in nine weeks. More studies are needed to understand the optimal management and prognosis of patients with PCL.

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis, rapid development of resistance to chemotherapy and genetic instability. This study profiles DNA methylation in SCLC, patient-derived xenografts (PDX) and cell lines at single-nucleotide resolution. DNA methylation patterns of primary samples are distinct from those of cell lines, whereas PDX maintain a pattern closely consistent with primary samples. Clustering of DNA methylation and gene expression of primary SCLC revealed distinct disease subtypes among histologically indistinguishable primary patient samples with similar genetic alterations. SCLC is notable for dense clustering of high-level methylation in discrete promoter CpG islands, in a pattern clearly distinct from other lung cancers and strongly correlated with high expression of the E2F target and histone methyltransferase gene EZH2. Pharmacologic inhibition of EZH2 in a SCLC PDX markedly inhibited tumor growth.

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.

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).

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.

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.

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.