Search

Combined ganglioneuroma-schwannoma is an exceedingly rare tumor that has only been described in isolated case reports. We document a 64-year-old man with an incidentally discovered combined ganglioneuroma-schwannoma of the retroperitoneum that was intimately associated with sympathetic ganglia. We highlight the morphological and immunohistochemical findings of this rare tumor, and show evidence of its origin from sympathetic ganglia., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This study investigates CD151, a protein linked to cancer progression, in non-small cell lung cancer (NSCLC) patients without epidermal growth factor receptor (EGFR) mutations. These patients often have limited treatment options. The study used retrospective analysis to examine 157 adenocarcinoma biopsy specimens and 199 patient cases from The Cancer Genome Atlas, correlating CD151 expression with patient survival. Cellular studies revealed that CD151 interacts with EGFR, influencing epidermal growth factor (EGF)-induced cell proliferation and the effectiveness of the EGFR inhibitor, erlotinib. A strong association was found between CD151 expression and EGFR mutation status. High CD151 expression in the absence of EGFR mutations is correlated with poorer survival outcomes. Biological assays showed that CD151 colocalizes and associates with EGFR, playing a crucial role in regulating EGF-induced cell proliferation via the AKT and ERK1/2 pathways. Importantly, CD151 expression was found to influence the anti-proliferative effects of the EGFR tyrosine kinase inhibitor, erlotinib. High CD151 expression, in the absence of EGFR mutations, was associated with poorer survival outcomes. It could serve as a potential prognostic marker and influence cellular responses to EGFR-targeted treatments. This study highlights CD151 as a potential novel target for therapeutic intervention in NSCLC, especially in populations lacking EGFR mutations., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Background: Angiosarcoma is a sarcoma that occurs in a range of tissue types, and only rarely in the salivary glands, showing a predilection for the parotid glands of older patients. Preoperative diagnosis may be challenging, especially on cytology, with significant morphological overlap with high-grade primary salivary gland carcinomas. The molecular alterations of this rare salivary gland neoplasm are also not well-characterized., Methods and Results: We present a case of right submandibular gland swelling in a 73-year-old male. On fine needle aspiration, including immunohistochemical stains on cell block, the tumor was initially diagnosed as poorly differentiated carcinoma. Resection of the submandibular gland revealed epithelioid angiosarcoma. We performed molecular work-up of the tumor, utilizing targeted next-generation sequencing, DNA methylation profiling and fluorescence in-situ hybridization. Histopathologic assessment revealed an infiltrative tumor comprising solid sheets of epithelioid cells. The tumor cells formed haphazardly anastomosing vascular channels with intracytoplasmic lumina containing red blood cells. On immunohistochemistry, the tumor cells were positive for CD31, CD34 and ERG. Approximately 40% of the tumor cells showed nuclear expression of GATA3. A pathogenic TP53 R267W mutation was detected on next-generation sequencing. DNA methylation analysis did not cluster the tumor with any known sarcoma type. Copy number analysis showed possible MYC amplification and CDKN2A losses, although only the latter was confirmed on fluorescence in-situ hybridization., Conclusion: Epithelioid angiosarcoma is an important differential diagnosis to high-grade salivary gland carcinoma. In particular, GATA3 expression may be encountered in both angiosarcoma and high-grade salivary gland carcinomas and cause diagnostic confusion. Identification of TP53 mutations and CDKN2A losses suggest shared oncogenic pathways with soft tissue angiosarcomas, and should be further investigated., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Most thyroid nodules are benign. It is important to determine the likelihood of malignancy in such nodules to avoid unnecessary surgery. The primary objective of this study was to characterize the genetic landscape and the performance of a multigene genomic classifier in fine-needle aspiration (FNA) biopsies of cytologically indeterminate thyroid nodules in a Southeast Asian cohort. The secondary objective was to assess the predictive contribution of clinical characteristics to thyroid malignancy., Methods: This prospective, multicenter, blinded study included 132 patients with 134 nodules. Molecular testing (MT) with ThyroSeq v3 was performed on clinical or ex-vivo FNA samples. Centralized pathology review also was performed., Results: Of 134 nodules, consisting of 61% Bethesda category III, 20% category IV, and 19% category V cytology, and 56% were histologically malignant. ThyroSeq yielded negative results in 37.3% of all FNA samples and in 42% of Bethesda category III-IV cytology nodules. Most positive samples had RAS-like (41.7%), followed by BRAF-like (22.6%), and high-risk (17.9%) alterations. Compared with North American patients, the authors observed a higher proportion of RAS-like mutations, specifically NRAS, in Bethesda categories III and IV and more BRAF-like mutations in Bethesda category III. The test had sensitivity, specificity, negative predictive value, and positive predictive value of 89.6%, 73.7%, 84.0%, and 82.1%, respectively. The risk of malignancy was predicted by positive MT and high-suspicion ultrasound characteristics according to American Thyroid Association criteria., Conclusions: Even in the current Southeast Asian cohort with nodules that had a high pretest cancer probability, MT could lead to potential avoidance of diagnostic surgery in 42% of patients with Bethesda category III-IV nodules. MT positivity was a stronger predictor of malignancy than clinical parameters., (© 2024 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Fine needle aspiration cytology (FNAC) is an accurate, minimally invasive, and cost-effective biopsy method for enlarged lymph nodes. While the role of lymph node FNAC in the diagnosis of infectious or reactive conditions and metastatic malignancy is unquestioned, differing views still exist on its role in the diagnosis of lymphoma. Nevertheless, regardless of the practice setting, pitfalls and potential for error exist, and it is incumbent upon the pathologist to be aware of these pitfalls, as this is the first line of defence against errors., Summary: This discussion will focus on potential interpretational errors, specifically highlighting scenarios leading to false-negative and false-positive diagnosis and errors in tumour classification, with an emphasis on cytomorphology. Potential entities that may fly below the radar of the pathologist - so-called off-radar entities - are also discussed, as a reminder to consider broad differentials in cases with unusual morphologic features. Some reasons for false-negative diagnoses include low-grade lymphomas that mimic a mixed, polymorphous reactive lymphoid population or aspirates with a paucity of lesional cells, through either sampling error or the intrinsic nature of the entity, e.g., nodular lymphocyte predominant Hodgkin lymphoma. Some of the potential causes of false-positive diagnoses that are discussed include viral-associated lymphadenopathy, Kikuchi-Fujimoto lymphadenitis, or benign adnexal lesions mimicking metastatic malignancy. Errors in tumour classification covered include metastatic carcinoma, sarcoma, melanoma, and lymphoma mimicking each other, and Hodgkin lymphoma and its mimics. Finally, less common entities such as follicular dendritic cell sarcoma and others are briefly mentioned, to remind us of conditions that may slip under our diagnostic radar., Key Messages: A systematic review of diagnostic pitfalls and traps is elucidated here, with some tips to avoid these traps. The triple approach to the diagnostic workup is emphasised, which includes rigorous clinicopathologic correlation, attention to cytomorphology, and judicious application of ancillary tests., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Social behaviors such as altruism, where one self-sacrifices for collective benefits, critically influence an organism's survival and responses to the environment. Such behaviors are widely exemplified in nature but have been underexplored in cancer cells which are conventionally seen as selfish competitive players. This multidisciplinary study explores altruism and its mechanism in breast cancer cells and its contribution to chemoresistance., Methods: MicroRNA profiling was performed on circulating tumor cells collected from the blood of treated breast cancer patients. Cancer cell lines ectopically expressing candidate miRNA were used in co-culture experiments and treated with docetaxel. Ecological parameters like relative survival and relative fitness were assessed using flow cytometry. Functional studies and characterization performed in vitro and in vivo include proliferation, iTRAQ-mass spectrometry, RNA sequencing, inhibition by small molecules and antibodies, siRNA knockdown, CRISPR/dCas9 inhibition and fluorescence imaging of promoter reporter-expressing cells. Mathematical modeling based on evolutionary game theory was performed to simulate spatial organization of cancer cells., Results: Opposing cancer processes underlie altruism: an oncogenic process involving secretion of IGFBP2 and CCL28 by the altruists to induce survival benefits in neighboring cells under taxane exposure, and a self-sacrificial tumor suppressive process impeding proliferation of altruists via cell cycle arrest. Both processes are regulated concurrently in the altruists by miR-125b, via differential NF-κB signaling specifically through IKKβ. Altruistic cells persist in the tumor despite their self-sacrifice, as they can regenerate epigenetically from non-altruists via a KLF2/PCAF-mediated mechanism. The altruists maintain a sparse spatial organization by inhibiting surrounding cells from adopting the altruistic fate via a lateral inhibition mechanism involving a GAB1-PI3K-AKT-miR-125b signaling circuit., Conclusions: Our data reveal molecular mechanisms underlying manifestation, persistence and spatial spread of cancer cell altruism. A minor population behave altruistically at a cost to itself producing a collective benefit for the tumor, suggesting tumors to be dynamic social systems governed by the same rules of cooperation in social organisms. Understanding cancer cell altruism may lead to more holistic models of tumor evolution and drug response, as well as therapeutic paradigms that account for social interactions. Cancer cells constitute tractable experimental models for fields beyond oncology, like evolutionary ecology and game theory., (© 2023. The Author(s).)

Background: Adding intraperitoneal paclitaxel (IP-PTX) to paclitaxel/5-fluoropyrimidine has shown promising results in patients with gastric cancer peritoneal metastases (GCPM) but has not been studied with standard-of-care platinum/fluoropyrimidine combinations. Our goal to was evaluate IP-PTX with capecitabine/oxaliplatin (XELOX) in GCPM., Methods: Forty-four patients with GCPM received IP PTX (40 mg/m 2 , Days 1, 8), oral capecitabine (1000 mg/m 2 twice daily, Days 1-14) and intravenous oxaliplatin (100 mg/m 2 , Day 1) in 21-day cycles. Patients with synchronous GCPM underwent conversion surgery if they had good response after chemotherapy, conversion to negative cytology, no extraperitoneal metastasis, and no peritoneal disease during surgery. The primary endpoint was overall survival and secondary endpoints were progression-free survival and safety. Outcomes from the trial were compared against a matched cohort of 39 GCPM patients who received systemic chemotherapy (SC) comprising platinum/fluoropyrimidine., Results: The median OS for the IP and SC groups was 14.6 and 10.6 months (hazard ratio [HR] 0.44; 95% confidence interval [CI], 0.26-0.74; p = 0.002). The median PFS for the IP and SC group was 9.5 and 4.4 months respectively (HR 0.39; 95% CI 0.25-0.66; p < 0.001). Patients in the SC group were younger (IP vs. SC, 61 vs. 56 years, p = 0.021) and had better performance status (ECOG 0, IP vs. SC, 47.7% vs. 76.9%, p = 0.007) compared with the IP cohort. In IP group, conversion surgery was performed in 36.1% (13/36) of patients, with a median OS of 24.2 (95% CI 13.1-35.3) months and 1-year OS of 84.6%., Conclusions: IP PTX with XELOX is a promising treatment option for GCPM patients. In patients with good response, conversion surgery was feasible with favourable outcomes., (© 2022. Society of Surgical Oncology.)

Background: The salivary gland neoplasm of uncertain malignant potential (SUMP) category in the Milan System is diagnostically challenging. This study aims to validate a modified scheme for subcategorizing SUMP in a large multi-institutional cohort., Methods: Retrospective review of salivary gland fine-needle aspirations (FNAs) from 10 institutions were classified based on the Milan System. Cases diagnosed as SUMP with available cytology slides and surgical follow-up were retrieved for review and subcategorized based on a modified scheme as follows: basaloid SUMP (B1: absent/scant nonfibrillary matrix; B2: presence of nonfibrillary/mixed-type matrix), oncocytic/oncocytoid SUMP (O1: with mucinous background; O2: without mucinous background), and SUMP not otherwise specified (NOS)., Results: A total of 742 (7.5%) cases from 9938 consecutive salivary gland FNAs were classified as SUMP. Among them, 525 (70.8%) had surgical follow-up and 329 (62.7%) were available for review. The overall risk of malignancy (ROM) of SUMP was 40.4%. There were 156 cases (47.4%) subcategorized as basaloid SUMP with a ROM of 36.5%, 101 (30.7%) as oncocytic/oncocytoid SUMP with a ROM of 52.5%, and 72 (21.9%) as SUMP NOS with a ROM of 31.9%. The ROM of oncocytic/oncocytoid SUMP was significantly higher than basaloid SUMP (P = .0142) and SUMP NOS (P = .0084). No significant differences in ROM were noted between B1 and B2 (36.7% vs 36.4%, P = 1.0000) and O1 and O2 (65.2% vs 48.7%, P = .2349)., Conclusions: The ROM of oncocytic/oncocytoid SUMP was 52.5% and significantly higher than that of basaloid SUMP (36.5%, P = .0142) and SUMP NOS (31.9%, P = .0084), whereas no significant differences in ROM were noted for cases with different types of extracellular matrix or background material., (© 2022 American Cancer Society.)

The coronavirus COVID-19 pandemic has spurred the rapid development of vaccines, with vaccination programmes already underway in many countries. Regional lymphadenopathy is one of the documented side effects of vaccination. We document the fine needle aspiration cytological findings of an enlarged supraclavicular lymph node in a 34-year-old Asian female following the first dose of the Pfizer-BioNTech COVID-19 mRNA vaccine, which appears to be the first such report in a premorbidly well patient with no known history of malignancy. The cytological findings featured a reactive pattern in keeping with follicular hyperplasia, with prominent germinal centre elements including lymphohistiocytic aggregates and tingible-body macrophages. Despite an increased proportion of larger lymphocytes, the overall pattern was in keeping with a reactive pattern, bearing in mind the temporal and geographic relation to the vaccination injection. In instances of localised lymphadenopathy, particularly in supraclavicular or axillary locations, pathologists should be cognizant of the possibility of post-vaccination reactive lymphadenopathy, and seek clinical and radiological hints favouring a benign process, whilst recognising potential morphological overlaps with lymphoproliferative disorders. Awareness of this diagnostic pitfall is especially important as COVID-19 vaccination coverage is ramped up worldwide, leading to an expected increase in incidence of post-vaccination reactive lymphadenopathy., (© 2021 Wiley Periodicals LLC.)

Moderate hypothermia (32 °C) has been previously shown to ameliorate drug-induced liver injuries in vitro. However, there are concerns regarding its clinical relevance as it remains a challenge to perform selective liver cooling in a non-invasive manner. To reconcile this dilemma, we propose the use of pulsed cooling for regional hypothermic conditioning in liver. This involves intermittent cooling applied in pulses of 15 min each, with a one-hour recovery interval between pulses. Cooling is achieved by applying ice packs to the cutaneous region overlying the liver. Through an in vivo C57BL/6NTac mouse study, we demonstrated the feasibility of attaining localized hypothermia close to the liver while maintaining core body temperature. This has successfully ameliorated acetaminophen-induced liver injury based on the liver function tests, liver histology and total weight change. Collectively, we provide a proof of concept for pulsed external localized cooling as being clinically actionable to perform induced selective hypothermia., (© 2021. The Author(s).)

(1) Background: Accurate preoperative identification of medullary thyroid carcinoma (MTC) is challenging due to a spectrum of cytomorphologic features. However, there is a scarcity of studies describing the cytomorphologic features as seen on fine-needle aspiration (FNA) smears prepared using different staining methods. (2) Methods: We performed a retrospective study on MTC cases with available FNA slides from 13 hospitals distributed across 8 Asia-Pacific countries. The differences in the constitutive cytomorphologic features of MTC with each cytopreparatory method were recorded. A comparative analysis of cytologic characteristics was carried out with appropriate statistical tests. (3) Results: Of a total of 167 MTC samples retrospectively recruited, 148 (88.6%) were interpreted as MTC/suspicious for MTC (S-MTC). The staining methods used were Papanicolaou, hematoxylin-eosin, and Romanowsky stains. Seven out of the eleven cytologic criteria can be readily recognized by all three cytopreparatory methods: high cellularity, cellular pleomorphism, plasmacytoid cells, round cells, dyshesive cells, salt-and-pepper chromatin, and binucleation or multinucleation. An accurate diagnosis was achieved in 125 (84.5%) of the 148 samples whose FNAs exhibited five or more atypical features. Conclusions: The present work is the first study on MTC to compare the morphological differences among the cytologic staining techniques. We investigated the constitutive features and the reliability of diagnostic parameters. A feasible scoring system based upon cytomorphologic data alone is proposed to achieve a high degree of diagnostic accuracy.

We describe a case of ectopic cervical thyroid tissue which was involved by fibrosing Hashimoto's thyroiditis and which mimicked metastatic papillary thyroid carcinoma both on fine needle aspiration cytology and biopsy. The patient underwent total thyroidectomy which revealed fibrosing Hashimoto's thyroiditis, but no carcinoma. The entire thyroidectomy specimen was submitted for histopathological assessment. Even in the resected thyroidectomy specimen, there were cytological changes that were strongly reminiscent of papillary thyroid carcinoma. However, interpreted in the correct clinico-pathological context, these cytological alterations were deemed to be reactive secondary to the fibro-inflammatory process.

Background: The accurate preoperative identification of medullary thyroid carcinoma (MTC) is challenging due to the rarity of tumor and variable cytologic appearance. The Asian experience with diagnosing MTC by fine-needle aspiration (FNA) was scarcely reported., Methods: Cases of MTC with available FNA slides were enrolled from 13 hospitals representing 8 Asia-Pacific countries. Clinicopathological information, including sample preparation technique, staining method, original cytologic diagnosis and review diagnosis were collected., Results: Of a total of 145 MTC cases retrospectively recruited, 99 (68.3%) were initially interpreted as MTC/suspicious for MTC (S-MTC). The distribution of original FNA diagnostic categories was not associated with the staining method or sample preparation technique. The staining methods used were Papanicolaou, hematoxylin-eosin and Romanowsky stains. Liquid-based cytology (LBC) was used only in three countries. After reviewing all cases, the diagnostic rate of MTC/S-MTC increased to 91.7% (133/145). Cases with initially unrecognized MTC had either marked pleomorphism or cytology mimicking papillary carcinoma or follicular neoplasm. Although LBC provided certain benefits, there was no significant difference in diagnostic accuracy between conventional smear and LBC. Immunocytochemistry was available in 38 cases (26.2%), all of which were correctly recognized as MTC., Conclusion: Our report summarizes how MTC is handled in contemporary Asian thyroid FNA practice. Although the detection rate of MTC by cytology alone is less satisfactory, integration with ancillary tests could achieve an excellent performance. The recognition of constitutive cytomorphologic features is needed for each cytopreparatory method, which may result in a lower threshold to initiate further workup for MTC., (© 2020 Wiley Periodicals LLC.)

The Bethesda System for Reporting Thyroid Cytopathology has paved the way for comparisons of the practice of thyroid cytology in many different regions. However, there have been comparatively few studies documenting differences between Asian and non-Asian practice. Here, we aim to compare a few key parameters between the two regions, focusing on the indeterminate category of atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS). We compared its incidence, resection rates (RRs), risk of malignancy (ROM), rate of repeat fine needle aspiration (rFNA), ROMs of cytomorphologic subcategories of nuclear atypia (AUS-N) vs. architectural atypia (AUS-A), and, finally, the incidence of papillary thyroid carcinoma (PTC) vs. follicular neoplasms (FNs) in resected AUS/FLUS cases in Asian and non-Asian regions. Where possible, these metrics were compared with the Singapore experience from a tertiary referral institution. While the incidence of AUS/FLUS was similar in both regions, we found geographical differences in the RRs and ROMs, which may reflect a higher collective threshold for surgery in Asian countries. However, both cohorts showed higher ROMs in the AUS-N subcategory as compared to the AUS-A subcategory, supporting the subclassification of the AUS/FLUS based on the presence of nuclear atypia. We also observed a higher incidence of AUS-N coupled with a higher incidence of PTC in resected AUS/FLUS nodules in Asian cohorts, while AUS-A and follicular-patterned neoplasms featured more prominently in the non-Asian cohorts. These incidences may account for the starkly different molecular approaches that we noted-in Asian (chiefly Korean and Chinese) centers, BRAF mutational analysis was favored, while gene panels and gene expression classifiers were more frequently applied in non-Asian centers (chiefly in the United States of America). Overall, the data from Singapore appears more closely aligned to non-Asian trends, despite its geographical location in Southeast Asia and its predominantly Asian population. We conclude that there is significant heterogeneity in the outcomes of the AUS/FLUS categories between and within regions, which is only partially explained by regional variations, and may also reflect different regional diagnostic and management practices. This highlights the importance of understanding the local context in the interpretation of indeterminate Bethesda categories, rather than adopting a "one-size fits all" approach., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/gs-20-555). The series “Asian and Western Practice in Thyroid Pathology: Similarities and Differences” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2020 Gland Surgery. All rights reserved.)

Background: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) aims to provide a common language for risk stratification and management. We examine the incidence of MSRSGC categories and the corresponding risk of malignancy (ROM) within a tertiary referral centre in Southeast Asia., Methods: Salivary gland fine needle aspirations (FNAs) performed within a 10-year period were classified retrospectively according to the MSRSGC. Cytohistologic correlation was performed. The results were compared with the existing literature, including Asian and Western studies., Results: A total of 1384 salivary gland FNAs were evaluated, 421 with corresponding histology. The category distribution was: nondiagnostic, 28.9%; nonneoplastic, 18.0%; atypia of undetermined significance (AUS), 9.8%; benign neoplasm, 32.9%; salivary gland neoplasm of uncertain malignant potential (SUMP), 5.7%; suspicious for malignancy, 1.6%; and malignant, 3.2%. The ROMs were: nondiagnostic, 10.0%; nonneoplastic, 17.5%; AUS, 29.5%; benign neoplasm, 0.5%; SUMP, 17.1%; suspicious for malignancy, 83.3%; and malignant, 100.0%. Our relatively high nondiagnostic rate likely reflects preanalytical factors, whereas our low malignancy rate may be related to population and health care accessibility. Our nonneoplastic ROM was 17.5% compared with 5% to 10% in the literature, likely due to the relatively small number of excised cases; the ROM for SUMP was 17.1% versus 21% to 44% in the literature, possibly reflecting a significant proportion of benign basaloid neoplasms on histology. Interestingly, all false-negative cases in the nonneoplastic category were lymphoid-rich lesions., Conclusion: This is one of the largest single-institution studies in the existing literature documenting both the incidence and ROMs of MSRSGC categories. We also highlight specific challenges surrounding lymphoid-rich lesions., (© 2020 American Cancer Society.)

c-MET receptors are activated in cancers through genomic events like tyrosine kinase domain mutations, juxtamembrane splicing mutation and amplified copy numbers, which can be inhibited by c-MET small molecule inhibitors. Here, we discover that the most common polymorphism known to affect MET gene (N375S), involving the semaphorin domain, confers exquisite binding affinity for HER2 and enables MET N375S to interact with HER2 in a ligand-independent fashion. The resultant MET N375S /HER2 dimer transduces potent proliferative, pro-invasive and pro-metastatic cues through the HER2 signaling axis to drive aggressive squamous cell carcinomas of the head and neck (HNSCC) and lung (LUSC), and is associated with poor prognosis. Accordingly, HER2 blockers, but not c-MET inhibitors, are paradoxically effective at restraining in vivo and in vitro models expressing MET N375S . These results establish MET N375S as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.

We describe a case of papillary thyroid carcinoma with fibromatosis/fasciitis-like stroma (PTC-FLS) that contained the rare BRAF c.1799&#95;1801delTGA (p.V600&#95;K601delinsE) mutation, which has not previously been reported in this tumour, as well as the CTNNB1 c.133T>C (p.S45P) mutation. We also report the novel observation that spindle cells of the mesenchymal component exhibit diffuse nuclear but not cytoplasmic expression of SOX11, whereas the malignant epithelial cells did not. This suggests that immunoreactivity for SOX11 can be an alternative diagnostic tool for evaluating cases of PTC-FLS where the nuclear expression of β-catenin is ambiguous.

Background: Thyroxine replacement following a hemithyroidectomy is not commonly discussed during consent for the procedure as the risk of hypothyroidism is perceived to be low., Methods: Retrospective review of 901 patients who underwent hemithyroidectomy at a tertiary referral institution during the period January 2000 to December 2015. The main outcome studied was the overall incidence of hypothyroidism and the associated risk factors., Results: Hypothyroidism developed in 123 (13%) patients and 94 patients (10%) required hormone supplementation over a mean follow up of 21 months (range 1-168 months). Preoperative TSH of more than 2.5 was seen in 38 of 123 (31%) of patients. Presence of diffuse thyroiditis was the only independent risk factor on multivariate analysis (P = 0.002) found to be associated with the development of hypothyroidism., Conclusion: After thyroid lobectomy, approximately one in 10 patients requiring thyroid hormone treatment for hypothyroidism. Presence of diffuse thyroiditis is a significant risk factor for hypothyroidism., (© 2018 Wiley Periodicals, Inc.)

While most cancer nanomedicine is designed to eliminate cancer, the nanomaterial per se can lead to the formation of micrometre-sized gaps in the blood vessel endothelial walls. Nanomaterials-induced endothelial leakiness (NanoEL) might favour intravasation of surviving cancer cells into the surrounding vasculature and subsequently extravasation, accelerating metastasis. Here, we show that nanoparticles induce endothelial leakiness through disruption of the VE-cadherin-VE-cadherin homophilic interactions at the adherens junction. We show that intravenously injected titanium dioxide, silica and gold nanoparticles significantly accelerate both intravasation and extravasation of breast cancer cells in animal models, increasing the extent of existing metastasis and promoting the appearance of new metastatic sites. Our results add to the understanding of the behaviour of nanoparticles in complex biological systems. The potential for NanoEL needs to be taken into consideration when designing future nanomedicines, especially nanomedicine to treat cancer.

Objective: BRAF mutation is the commonest mutation seen in papillary thyroid cancer (PTC), but its prevalence and clinical significance vary across countries. We aim to evaluate the prevalence and clinico-pathological correlation of BRAF mutation in PTC patients at our centre., Study Design: Retrospective cohort study of 75 consecutive archival thyroid specimens, whereby BRAF mutation was detected using a polymerase chain reaction (PCR) technique and correlated with clinical and pathological features and outcomes., Setting: Tertiary university hospital in Singapore., Participants: A total of 75 consecutive histologically proven archival thyroid specimens from patients who underwent thyroidectomy for PTC were accrued for this study., Main Outcome Measures: Main outcome is to determine the prevalence of the BRAF mutation in our South-East Asian population. Secondary aim is to correlate the mutational status with adverse pathological features like histological variants, multi-focality, lymphovascular invasion and extra-thyroidal extension, clinical features like demographics, TNM stage, recurrence and survival, as well as treatment details like type of surgery performed and radioiodine doses., Results: BRAF mutation was detected in 56% (42/75) of PTC. All but one BRAF-mutated PTC had the BRAFV600E mutation. BRAF-mutated tumours were associated with an advanced T-stage (P = 0.049) and were more likely to have a central neck dissection (P = 0.036). There was no significant correlation between BRAF mutation status and clinical outcomes., Conclusion: The prevalence of BRAF mutation is 56%. BRAF mutation-positive tumours were associated with locally advanced disease, but not poorer survival., (© 2018 John Wiley & Sons Ltd.)

Importance: Approximately 20% of fine-needle aspirations (FNA) of thyroid nodules have indeterminate cytology, most frequently Bethesda category III or IV. Diagnostic surgeries can be avoided for these patients if the nodules are reliably diagnosed as benign without surgery., Objective: To determine the diagnostic accuracy of a multigene classifier (GC) test (ThyroSeq v3) for cytologically indeterminate thyroid nodules., Design, Setting, and Participants: Prospective, blinded cohort study conducted at 10 medical centers, with 782 patients with 1013 nodules enrolled. Eligibility criteria were met in 256 patients with 286 nodules; central pathology review was performed on 274 nodules., Interventions: A total of 286 FNA samples from thyroid nodules underwent molecular analysis using the multigene GC (ThyroSeq v3)., Main Outcomes and Measures: The primary outcome was diagnostic accuracy of the test for thyroid nodules with Bethesda III and IV cytology. The secondary outcome was prediction of cancer by specific genetic alterations in Bethesda III to V nodules., Results: Of the 286 cytologically indeterminate nodules, 206 (72%) were benign, 69 (24%) malignant, and 11 (4%) noninvasive follicular thyroid neoplasms with papillary-like nuclei (NIFTP). A total of 257 (90%) nodules (154 Bethesda III, 93 Bethesda IV, and 10 Bethesda V) had informative GC analysis, with 61% classified as negative and 39% as positive. In Bethesda III and IV nodules combined, the test demonstrated a 94% (95% CI, 86%-98%) sensitivity and 82% (95% CI, 75%-87%) specificity. With a cancer/NIFTP prevalence of 28%, the negative predictive value (NPV) was 97% (95% CI, 93%-99%) and the positive predictive value (PPV) was 66% (95% CI, 56%-75%). The observed 3% false-negative rate was similar to that of benign cytology, and the missed cancers were all low-risk tumors. Among nodules testing positive, specific groups of genetic alterations had cancer probabilities varying from 59% to 100%., Conclusions and Relevance: In this prospective, blinded, multicenter study, the multigene GC test demonstrated a high sensitivity/NPV and reasonably high specificity/PPV, which may obviate diagnostic surgery in up to 61% of patients with Bethesda III to IV indeterminate nodules, and up to 82% of all benign nodules with indeterminate cytology. Information on specific genetic alterations obtained from FNA may help inform individualized treatment of patients with a positive test result.

Background: Aberrant glycosylation is a hallmark of cancer cells and plays an important role in oncogenesis and cancer progression including metastasis. This study aimed to assess alteration in cellular glycosylation, detected by lectin Helix pomatia agglutinin (HPA) binding, in adrenal cancers and to determine whether such altered glycosylation has prognostic significance., Methods: HPA binding lectin histochemistry was performed on archival paraffin wax-embedded specimens of adrenocortical cancers excised from patients attending two tertiary referral centres. Benign tumours were used as controls. Demographic, histological and survival data were collected and compared between patients with HPA-positive and HPA-negative tumours., Results: Thirty-two patients were treated for adrenal cancer between 2000 and 2016; their median age was 49 (range 23-79) years. Fifteen patients had functioning tumours (14 adrenal Cushing's tumours and 1 Conn's tumour). Mean(s.d.) tumour size was 127·71(49·70) mm. None of 10 control tumours expressed HPA-binding glycoproteins. Invasion was associated with HPA-binding glycoproteins (P = 0·018). Local recurrence or metastatic disease did not significantly differ between HPA-positive and HPA-negative adrenocortical cancers. Overall survival was significantly longer in patients with HPA-negative tumours (median survival not reached versus 22 months in patients with HPA-positive tumours; P = 0·002)., Conclusion: Altered cellular glycosylation detected by lectin HPA is associated with poor survival in patients with adrenocortical cancer.

Background: Although The Bethesda System for Reporting Thyroid Cytopathology has provided clinicians with a standardized classification scheme for the diagnosis of thyroid fine-needle aspiration cytology (FNAC) specimens, the indeterminate categories of Bethesda III (B3)-atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS)-and Bethesda IV (B4)-follicular neoplasm/suspicious for follicular neoplasm (FN/SFN)-continue to pose challenges with regards to ideal diagnostic and therapeutic management. Having previously demonstrated the presence of nuclear atypia as a high-risk subgroup in B3, the objective of this study was to evaluate the malignancy rates in the B4 subgroup with nuclear atypia., Methods: A retrospective review of all thyroid FNACs diagnosed as B4 (FN/SFN) between 2008 and 2015 was conducted at a tertiary referral center in Singapore. Data on patient demographics, sonographic features, and final histological diagnosis were collected. This was compared to data from a previous analysis on all nodules diagnosed as B3 (AUS/FLUS) over a similar period., Results: A total of 137/309 (44.3%) and 88/111 (79.3%) FNACs diagnosed as B3 and B4, respectively, underwent surgical excision yielding final histopathological diagnoses. The malignancy rate of B4 was 31/88 (35.2%) compared to B3, which was 37/137 (27.0%). Subclassification based on the presence of architectural versus nuclear atypia showed significantly higher malignancy rates in B4 nodules with nuclear atypia (21.8% vs. 57.6%; p < 0.01). These findings corroborate previous results within the B3 category (malignancy rate of 14.7% vs. 36.8%; p < 0.01). The only sonographic features predictive of malignancy were the presence of macrocalcifications in B4 compared to irregularity of margins in B3., Conclusion: The presence of nuclear atypia identifies subgroups with significant differential malignancy risks within both the B3 and B4 categories. This supports the notion that subclassification is a useful risk stratification tool that can guide diagnostic and therapeutic management of indeterminate thyroid nodules with heterogenous risk profiles.

Objective: Intraperitoneal chemotherapy (IP ChT) is an emerging modality in the treatment of advanced gastric adenocarcinoma with peritoneal disease. Cytological evaluation of peritoneal fluid specimens from patients undergoing IP ChT is important in clinical management. However, direct intraperitoneal exposure to chemotherapeutic agents induces cytomorphological changes in benign constituents of peritoneal fluid, presenting particular challenges to accurate cytological interpretation. These morphological changes have not been well characterised in the literature. We systematically reviewed the cytomorphological features in immunocytochemically-confirmed positive and negative IP ChT peritoneal fluid samples to elucidate the degree of morphological overlap between malignant and reactive cells., Methods: We reviewed 39 peritoneal fluid samples of patients treated with IP ChT, and scored specific cytomorphological parameters of both benign and malignant cells with the aid of relevant immunocytochemical interrogation., Results: The present findings show a significant degree of morphological overlap between reactive and malignant cells. Abnormal, "exploding" mitotic figures, nuclear membrane irregularities, multi-nucleation and cytoplasmic vacuolation were commonly observed in negative fluid specimens. The most helpful feature that favoured malignant cells was the increased nuclear-to-cytoplasmic ratio. A background inflammatory milieu of eosinophils and/or neutrophils was seen in 45-58% of post IP ChT peritoneal fluid specimens. The presence of pseudoparakeratotic cells, a novel observation in post IP ChT fluid specimens is also described., Conclusions: The extent of reactive cytomorphological anomalies arising from treatment with IP ChT poses unique diagnostic challenges and may prompt a malignant or 'atypical' diagnosis in benign reactive samples., (© 2017 John Wiley & Sons Ltd.)

Background: The Bethesda System for Reporting Thyroid Cytopathology is the most widely used classification system for the reporting of thyroid fine-needle aspiration cytology (FNAC) specimens. However, the "atypical" category ("atypia of undetermined significance" [AUS] or "follicular lesion of undetermined significance" [FLUS]) continues to cause diagnostic and therapeutic dilemmas. The objectives of this study were to describe the differential malignancy rates of FNACs diagnosed as AUS/FLUS based on nuclear or architectural atypia and to assess the significance of demographic and ultrasonographic features in predicting malignancy in this category., Methods: A retrospective review was performed of all thyroid FNACs between 2008 and 2014 that were diagnosed as AUS/FLUS at a tertiary referral center in Singapore. Patient demographics, preoperative ultrasonographic features, and follow-up data were collected and correlated with the final histopathologic diagnosis in resected cases., Results: In total, 309 thyroid nodules were diagnosed as AUS/FLUS, and 137 (44%) were surgically excised. Final histology yielded 37 (27%) malignancies. The malignancy rate for nodules that featured nuclear atypia was significantly higher at 36.8% than the rate for nodules that had only architectural atypia at 14.7% (P < .01). After up to 3 repeat FNACs, 67.1% of cases had a more definitive diagnosis. The only predictive sonographic finding for malignancy was irregular margins (P < .01)., Conclusions: The disparity between malignancy risks within the Bethesda "atypical" category suggests that cytologic (nuclear) atypia is significantly more predictive of malignancy than architectural atypia. This supports the substratification of patients according to risk and a corresponding management approach within this category. A sonographic finding of irregular margins is also predictive for malignancy. Cancer Cytopathol 2017;125:245-256. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Purpose: We aimed to evaluate the imaging features of solid pseudopapillary neoplasm (SPN) of the pancreas with an emphasis on radiologic-pathologic correlation., Methods: Ten patients (all female; mean age, 32 years) with histologic or cytologic diagnosis of SPN encountered between January 2007 and December 2013 were included in this study. Preoperative computed tomography (CT) images were reviewed for location, attenuation, enhancement pattern, margin, shape, size, morphology, presence of capsule and calcification. CT appearances were correlated with histopathologic findings., Results: Tumors in the distal pancreatic body and tail had a tendency to be larger (mean size 12.6 cm vs. 4.0 cm). Six of the nine tumors that were resected had a fibrous pseudocapsule at histology, five of which could be identified on CT scan. Eight lesions had mixed hypoenhancing solid components and cystic areas corresponding to tumor necrosis and hemorrhage. The two smallest lesions were purely solid and nonencapsulated. Varied patterns of calcification were seen in four tumors. Three of the four pancreatic tail tumors invaded the spleen. At a median follow-up of 53 months, there was no evidence of recurrence in the nine patients who underwent surgical resection of the tumor., Conclusion: A mixed solid and cystic pancreatic mass in a young woman is suggestive of SPN. However, smaller lesions may be completely solid. Splenic invasion can occur in pancreatic tail SPNs; however, in this series it did not adversely affect the long-term outcome.

Peritoneal metastasis is common in gastric cancer. It is difficult to treat and carries a poor prognosis. Intraperitoneal (IP) delivery of chemotherapy can attain a higher drug exposure in the peritoneal cavity but with reduced systemic toxicity. Therefore, we hypothesized that IP paclitaxel with systemic chemotherapy would be clinically beneficial for gastric cancer with peritoneal metastases. Patients with unresectable and/or recurrent gastric adenocarcinoma with peritoneal dissemination and/or positive peritoneal washing cytology were recruited. They underwent eight cycles of IP paclitaxel and systemic XELOX. The primary endpoint was 1-year overall survival rate and secondary endpoints were safety, response rate, and peritoneal cytological response. Patients who subsequently had no distant metastases and two consecutive negative peritoneal cytologies underwent conversion gastrectomy if there was no macroscopic evidence of peritoneal disease at diagnostic laparoscopy. Twenty-two patients were enrolled, receiving at least one cycle of IP paclitaxel at the time of reporting (data cutoff-March 11, 2016). The median number of cycles was 7.5. The median overall survival was 18.8 months, and the 1-year survival rate was 72.2%. One patient died of neutropenic sepsis. Of 19 evaluable patients with measurable disease, 7 (36.8%) achieved PR, 8 (42.1%) achieved SD, and 4 (21.1%) experienced PD. Peritoneal cytology turned negative in 11 of 17 (64.7%) patients. Six patients underwent conversion gastrectomy (4 R0, 2 R1) with a median survival of 21.6 months (range = 8.7-29.9 months). XELOX and IP paclitaxel appears to be an effective regimen in gastric cancer with peritoneal metastases. Conversion gastrectomy may be considered in patients with a favorable response.

The tumour-initiating cell (TIC) model accounts for phenotypic and functional heterogeneity among tumour cells. MicroRNAs (miRNAs) are regulatory molecules frequently aberrantly expressed in cancers, and may contribute towards tumour heterogeneity and TIC behaviour. More recent efforts have focused on miRNAs as diagnostic or therapeutic targets. Here, we identified the TIC-specific miRNAs, miR-1246 and miR-1290, as crucial drivers for tumour initiation and cancer progression in human non-small cell lung cancer. The loss of either miRNA impacted the tumour-initiating potential of TICs and their ability to metastasize. Longitudinal analyses of serum miR-1246 and miR-1290 levels across time correlate their circulating levels to the clinical response of lung cancer patients who were receiving ongoing anti-neoplastic therapies. Functionally, direct inhibition of either miRNA with locked nucleic acid administered systemically, can arrest the growth of established patient-derived xenograft tumours, thus indicating that these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets.

Genomic analyses of squamous cell carcinoma (SCC) have yet to yield significant strategies against pathway activation to improve treatment. Platinum-based chemotherapy remains the mainstay of treatment for SCC of different histotypes either as a single-agent or alongside other chemotherapeutic drugs or radiotherapy; however, resistance inevitably emerges, which limits the duration of treatment response. To elucidate mechanisms that mediate resistance to cisplatin, we compared drug-induced perturbations to gene and protein expression between cisplatin-sensitive and -resistant SCC cells, and identified MAPK-ERK pathway upregulation and activation in drug-resistant cells. ERK-induced resistance appeared to be activated by Son of Sevenless (SOS) upstream, and mediated through Bim degradation downstream. Clinically, elevated p-ERK expression was associated with shorter disease-free survival in patients with locally advanced head and neck SCC treated with concurrent chemoradiation. Inhibition of MEK/ERK, but not that of EGFR or RAF, augmented cisplatin sensitivity in vitro and demonstrated efficacy and tolerability in vivo. Collectively, these findings suggest that inhibition of the activated SOS-MAPK-ERK pathway may augment patient responses to cisplatin treatment., (©2015 American Association for Cancer Research.)

The presence of the lupus erythematosus (LE) phenomenon has been generally conceptualized as an in vitro occurrence where numerous damaged cells are present and substantial nucleo-phagocytosis has occurred. In systemic lupus erythematosus (SLE), the positive LE cell phenomenon has been shown to indicate active disease with major organ involvement which potentially warrants prompt and heavy immunosuppressive therapy. We report a 36-year-old woman with a known history of SLE who presented with fever, left knee effusion, polyserositis, pancytopenia, low complement and high anti-dsDNA antibody levels whose immunosuppressive treatment was escalated in view of the clinically and serologically active SLE, accompanied by the presence of LE cells in her inflammatory yet sterile left knee synovial fluid. Within 3 days of immunosuppressant escalation, her ascites worsened. While microscopic examination of the ascitic fluid also revealed LE cells, culture of the ascitic fluid later grew Candida parapsilosis. The patient subsequently responded to the addition of anti-fungal therapy into her augmented immunosuppressive regime. Coexistence of the LE cell phenomenon and infection in SLE patients has hitherto not been described. This case illustrates that infection remains to be meticulously excluded despite the presence of the LE phenomenon in the context of clinically and serologically active SLE., (© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Background: Pilomatricomas are benign skin tumors originating from hair matrix cells in the dermal layer of the skin, especially in the head and neck region. They may mimick malignant lesions on fine-needle aspirate cytology., Methods: This is a case report of a pilomatricoma of the cheek which was initially diagnosed as squamous cell carcinoma on fine-needle aspirate cytology. As part of the staging work-up, a PET/CT scan was performed, revealing a FDG-avid superficial cheek lesion and also an ipsilateral FDG-avid level II cervical lymph node, giving the impression of metastatic squamous cell carcinoma., Results: The cheek lesion, as well as the cervical lymph node was excised. The final histology showed benign pilomatricoma and reactive lymphadenopathy., Conclusion: Pilomatricoma should be considered as an uncommon differential diagnosis for an FDG-avid cutaneous lesion on PET/CT, even in the presence of ipsilateral FDG-avid cervical lymphadenopathy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Aim: The purpose of this study was to determine (1) the diagnostic yield for endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in patients with pancreatic cystic lesions, (2) additional value of EUS-FNA over EUS alone in the diagnosis of pancreatic cysts, and (3) diagnostic sensitivity and specificity of EUS and EUS-FNA in the subset of patients where histopathology of surgical specimens were available., Methods: All patients who underwent EUS examination for the evaluation of pancreatic cystic lesions in six Asian centres were included in the study., Results: Of 298 patients with pancreatic cysts who underwent EUS, 132 (44.3 %) underwent FNA. In the entire cohort, pseudocysts and intraductal papillary mucinous neoplasm (IPMN) were the predominant cystic lesions. The cytologic yield of EUS-FNA was 47 %. On univariate analysis, factors associated with higher cytologic yield included vascular involvement on EUS, presence of solid cystic component, and increased number of needle passes during EUS-FNA. On multivariate analysis, presence of solid cystic components and increased number of needle passes during EUS-FNA were associated with higher diagnostic yield of EUS-FNA. For pancreatic cysts with a solid component, the diagnostic yield of EUS-FNA increased significantly from 44 % with one pass to 78 % with more than one pass (p = 0.016). In the absence of a solid component, the diagnostic yield was 29 % with one pass and was not significantly different from the diagnostic yield of 50 % with more than one pass, p = 0.081., Conclusion: The cytologic yield of EUS-FNA was 47 %. When a solid component was present in the cyst, doing more than one pass during EUS-FNA increased its diagnostic yield.

RUNX3 aberrations play a pivotal role in the oncogenesis of breast, gastric, colon, skin and lung tissues. The aim of this study was to characterize further the expression of RUNX3 in lung cancers. To achieve this, a lung cancer tissue microarray (TMA), frozen lung cancer tissues and lung cell lines were examined for RUNX3 expression by immunohistochemistry, while the TMA was also examined for EGFR and p53 expression. RUNX3 promoter methylation status, and EGFR and KRAS mutation status were also investigated. Inactivation of RUNX3 was observed in 70% of the adenocarcinoma samples, and this was associated with promoter hypermethylation but not biased to EGFR/KRAS mutations. Our results suggest a central role of RUNX3 downregulation in pulmonary adenocarcinoma, which may not be dependent of other established cancer-causing pathways and may have important diagnostic and screening implications.

Objectives: To compare the rejection rates of non-small cell lung cancer (NSCLC) samples obtained by differing sampling methods for testing by Sanger sequencing for epidermal growth factor receptor (EGFR) mutations. To assess the association between unsatisfactory outcomes and the quantity of DNA extracted from cytological versus histological samples., Methods: Six hundred and seventy NSCLC samples referred to our centre from 2008 to 2010 were reviewed as a consequence of sample rejection, presence of EGFR mutations, cytological versus histological sampling methods, DNA quantity and the unsatisfactory genotyping rate., Results: Eighty samples were rejected for testing in similar proportions of histological and cytological samples (11.9% versus 10.9%) usually (n = 75) because the amount of cellular material was judged insufficient in small biopsies or cytology samples. The remaining 590 samples on which EGFR testing was attempted yielded 51 (8.6%) unsatisfactory test outcomes caused by failure of the polymerase chain reaction (PCR) (n = 47 cases), uninterpretable Sanger chromatograms (n = 3 cases) and insufficient DNA extracted for PCR (n = 1 case). The difference in rates of unsatisfactory outcomes between cytological samples (seven of 147 samples or 4.7%) versus tissue samples (44 of 443 samples or 9.9%) was clinically relevant but not statistically significant (Mann-Whitney test; P < 0.081). There was no association between the concentration of DNA extracted and the likelihood of an unsatisfactory analysis; which was similar in all types of sections (large and small) while 0% of 37 cytology slides were unsatisfactory., Conclusions: Utilizing cytology samples for EGFR testing avoids unnecessary patient re-biopsing and yields a clinically superior satisfactory rate to the overall satisfactory rate of tissue biopsies of NSCLC. The quality rather than quantity of DNA extracted may be a more important determinant of a satisfactory result., (© 2012 Blackwell Publishing Ltd.)

We present a patient with a 2-cm spiradenocarcinoma of the left arm resembling low-grade salivary gland basal cell adenocarcinoma. In addition to showing attributes of conventional spiradenoma, the benign component showed prominent areas of cystic change with focal apocrine differentiation, glands with and without mucinous differentiation, clear cell change and focal adenoid cystic carcinoma-like areas. The malignant component was composed of nodules of basaloid cells arranged in sheets with variable tendency to luminal differentiation. The nuclear atypia was low-grade, and the mitotic index was high in the malignant component (to 8/10 high power fields). Immunohistochemically, there was diffuse but variable positivity for cytokeratin 7 in both the benign and malignant components. Epithelial membrane antigen was focally positive, highlighting cells with ductal (luminal) differentiation. Expression of p63 was observed in 50 and 80% of the cells in the benign and malignant components, respectively. Calponin was negative. The proliferative index (MIB-1/Ki-67) was <3% in the benign component and up to 10% in the malignant component. Although the malignant component displayed patchy areas with nuclear p53 immunoreactivity with variable intensity, no mutation in the TP53 gene was identified., (Copyright © 2011 John Wiley & Sons A/S.)

Identification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer therapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Sanger sequencing is one of several reliable methods in use to detect KRAS and BRAF mutations to facilitate clinical patient selection for anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy in unresectable metastatic colorectal adenocarcinoma (CRC). Most analyses are made on pretreatment biopsy or resection specimens. There is a scarcity of published studies on the suitability of cytological samples for KRAS testing in this setting., Methods: DNA extraction was attempted on 11 search-retrieved paired cases of histological resections or excisions of CRC and their corresponding cytological samples (representing metastases) and tested for KRAS mutations in exon 2 and 3, as well as BRAF exon 15 mutations by Sanger sequencing. Only KRAS wild-type cases were subjected to BRAF analysis because this is the setting with true diagnostic value, as these mutations are mutually exclusive., Results: Of the 11 paired cases analysed, only eight histology cases showed satisfactory DNA quality for sequencing. Thus, only eight of the corresponding cytology cases were analysed. Seven of the eight cases tested showed the same KRAS genotype on both the aspirated cytology specimen of metastatic carcinoma and the primary tumour (histological specimen), from which we derive an overall concordance rate of 87.5%. The single discordant case was likely to be a true difference as it was demonstrated again on repeat testing of both samples. No BRAF mutations were detected on the four KRAS wild-type cases., Conclusion: A range of cytological samples are suitable for KRAS and BRAF mutation testing, be it from previously stained preparations or cell blocks. These samples would be highly valuable in cases where cytological samples are the only material available for mutation testing., (© 2010 Blackwell Publishing Ltd.)

The role of human papillomavirus (HPV) in the development of lung and esophageal cancer remains inconclusive, which is in contrast to the established role HPV plays in the development of uterine cervical cancer. One of the reasons for this is the difference among reported HPV infection rates in these cancers. An analysis of 485 lung and esophageal cancers (176 lung squamous cell carcinoma, 128 lung adenocarcinoma, 181 esophageal carcinoma) in eight institutions in Asia (Tokyo, Kochi, Kagoshima, and Okinawa, Japan; Seoul and Daegu, Korea; Changhua, Republic of China (Taiwan); Singapore, Singapore) was carried out in order to clarify infection rates with HPV. Samples were examined in one laboratory of the Department of Pathology, the University of Tokyo, Japan in order to avoid inter-laboratory variation using a combination of polymerase chain reaction and in situ hybridization (ISH). HPV was found in 6.3%, 7%, and 9.4% of patients with lung squamous cell carcinoma, lung adenocarcinoma, and esophageal cancer, respectively. Among the geographic areas surveyed, Kagoshima exhibited a significantly higher prevalence of HPV infection in cases of esophageal carcinoma (24.1%). There was no geographical difference in the infection rates of HPV in lung carcinomas. Subtype-specific ISH was also performed, which identified the high-risk HPV types 16/18 in the majority (75.7%) of the patients with lung and esophageal cancer positive for HPV., (Copyright © 2011 Wiley-Liss, Inc.)

Background: There is emerging evidence that bronchioloalveolar carcinoma (BAC) is the forerunner of peripheral adenocarcinoma lung cancers (ALC). Since advanced stage ALC is often diagnosed on cytology alone, we hypothesized that the incidence of BAC is underreported and that a large proportion of ALC in our population are part of the BAC-adenocarcinoma sequence., Methods: We reviewed the pretreatment computed tomographic (CT) scans of 69 patients with ALC and looked for characteristic features of BAC., Results: The median patient age was 63, and the majority were of Chinese descent (75.4%). Women comprised 43.5% of the patients (30 patients) and never-smokers comprised 47.8% (33 patients). Only 15 patients (21.7%) had surgical specimens. The presence of BAC components was reported in the pathology of 16 patients (23.2%). CT features classically associated with BAC were found in 35 patients (50.7%). These included air bronchograms or bubble-like lucencies in 24 patients (34.8%), ground-glass opacities in 19 (27.5%), consolidation or pneumonic picture in 11 (15.9%), diffuse small or miliary nodules in 10 (14.5%), and the CT angiogram sign in 4 (5.8%)., Conclusions: We found provocative radiologic evidence that a large proportion of our ALC cases arise from BAC. The CT findings are consistent with current understanding of the likely pathogenesis of peripheral ALC., (© Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd.)