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Abstract: Six hundred ninety-five mice received adeno-associated virus (AAV) vectors, mostly via portal vein injection. At necropsy, the livers were inspected for tumors, and tissue sections were prepared for histology. We observed only one tumor, a lipoma, resulting in a tumor frequency of 0.14%. This tumor contained fewer vector genomes per total DNA than the surrounding liver tissue, as shown by quantitative PCR. In another mouse we found a macroscopically visible nodule containing lymphocytes. Immunohistochemistry revealed cells not of monoclonal origin, and they contained fewer AAV genomes than the surrounding hepatocytes. There were no macroscopic tumors in 226 control mice. Upon microscopic examination, lymphocytic infiltrates were found in 5% of livers of both control and vector-treated mice; no transgene expression was seen in those infiltrates in AAV-injected animals. Compared to an average frequency of spontaneous liver tumors in C57BL/6 mice (0–10%), and given the absence of high levels of vector DNA in the observed tumor, we conclude that AAV vectors do not predispose these target animals to the formation of liver tumors. [Copyright &y& Elsevier]

Purpose: Dedifferentiated liposarcoma (DDL) and leiomyosarcoma (LMS) are two common subtypes of soft-tissue sarcoma, a rare group of diseases for which new treatments are needed. Chemotherapy remains the standard option for advanced disease. Targeting cyclin-dependent kinase 4 and 6 (CDK4/6) in DDL and mTOR in LMS is of biologic interest. When combined, the CDK4 inhibitor ribociclib and the mTOR inhibitor everolimus have shown synergistic growth inhibition in multiple tumor models, suggesting that this combination could be beneficial in patients., Patients and Methods: This was a single arm, open label, multicenter phase II study of the combination of ribociclib and everolimus. Patients were enrolled into one of two cohorts: DDL or LMS with intact Rb. The primary endpoint was progression-free rate (PFR) at 16 weeks. Secondary endpoints included progression-free survival (PFS) and overall survival, safety and biomarker analyses., Results: In the DDL cohort, 33.3% [95% confidence interval (CI), 15.6%-55.3%] of patients were progression-free at 16 weeks. Median PFS in this cohort was 15.4 weeks (95% CI, 8-36 weeks) with 2 partial responses. In the LMS cohort the PFR at 16 weeks was 29.2% (95% CI, 12.6%-51.1%). Median PFS in this cohort was 15.7 weeks (95% CI, 7.7-NA). Most common toxicities included fatigue (66.7%), anorexia (43.8%), and hyperglycemia (43.8%). Concordance between Rb testing methodologies was poor., Conclusions: The combination of ribociclib and everolimus demonstrates activity in DDL with prolonged stable disease (≥16 weeks) meeting the primary endpoint. Notably partial responses were observed. The primary endpoint was not reached in the LMS cohort. The combination was well tolerated with expected side effects., (©2023 American Association for Cancer Research.)

Introduction: Endobronchial ultrasound (EBUS)-guided transbronchial needle aspirate (TBNA) is a widely used method of minimally invasive lymph node sampling. The benefit of processing samples by cytologic methods versus "core biopsy" is unclear. It is unknown if safety or diagnostic yield varies by needle gauge., Materials and Methods: Between June 2018 and July 2019, 40 patients (56 lesions) undergoing EBUS TBNA lymph node evaluation were enrolled in this single-center prospective trial. Patients were chosen by permuted block randomization to undergo EBUS TBNA starting with 22-gauge (22g) or 19-gauge (19g) needles. Separate samples were sent for processing by cytologic methods and histopathology. Surgical pathologists and cytopathologists were blinded to needle size. The primary endpoint was diagnostic yield. Secondary endpoints compared specimen adequacy by rapid onsite evaluation (ROSE), sample adequacy for molecular testing, sample quality, and safety., Results: Diagnostic yield for histopathologic examination was 87.5% and 83.9% for 19g and 22g respectively (P = 0.625). There was no significant difference in diagnostic yield by cytologic examination based on needle size. There was no significant difference in slide quality. Molecular adequacy for core-biopsy was 77% and 80% for 22g and 19g needles, respectively. Molecular adequacy for cytology cell block was 77% and 80% for 22g and 19g needles, respectively. There were no significant procedural complications., Conclusion: Both the 22g and 19g EBUS TBNA needles provided a similar diagnostic yield and clinical utility for ancillary testing. Processing techniques by cytologic methods or "core biopsy" showed no significant impact in diagnostic yield or utility of molecular testing., (Copyright © 2021 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Well-differentiated liposarcoma/atypical lipomatous tumor (WDLS/ALT) and dedifferentiated liposarcoma (DDLS) have characteristic supernumerary ring and giant marker chromosomes involving the chromosomal region 12q13-15 which contains MDM2 (12q15), CDK4 (12q14.1), HMGA2 (12q14.3), YEATS4 (12q15), CPM (12q15), and FRS2 (12q15). Detecting MDM2 amplification by fluorescence in situ hybridization (FISH) is considered to be the gold standard for the diagnosis of WDLS/ALT and DDLS. In this study, formalin fixed paraffin embedded clinical specimens (16 liposarcomas and 19 benign lipomatous tumors) were used to detect MDM2 amplification and other chromosomal alterations in WDLS/ALT and DDLS by single nucleotide polymorphism-based chromosome microarray (CMA). All 16 liposarcomas showed MDM2 amplification with a MDM2/cep12 ratio from 2.4 to 8.4 by CMA. Ten (62.5%) of these cases had CDK4/cep12 ratio ≥2.0. All the cases without CDK4 amplification were from the thigh. The MDM2/cep12 ratio of all the benign lipomatous tumors (19/19) was within the normal limits. Twenty-one of the 35 benign lipomatous tumors and liposarcomas were also tested for MDM2 amplification by FISH. All the FISH results were consistent with the CMA results (100%). Along with MDM2 amplification, all 16 liposarcomas (100%) also showed amplification of YEATS4, CPM and FRS2. Only 11 of 16 (69%) cases showed HMGA2 amplification. In conclusion, this study demonstrated that CMA on routine formalin fixed paraffin embedded tissue is a sensitive and specific clinical test for detection of MDM2 gene amplification. Moreover, CMA allows simultaneous detection of genomic changes of interest including CDK4 and others, which provides enriched information for diagnosing lipomatous tumors., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Non-small cell lung cancer (NSCLC) is the most common cancer worldwide. With overall 5-year survival estimated at <17%, it is critical to identify factors that regulate NSCLC disease prognosis. NSCLC is commonly driven by mutations in KRAS and TP53 , with activation of additional kinases such as SRC promoting tumor invasion. In this study, we investigated the role of NEDD9, a SRC activator and scaffolding protein, in NSCLC tumorigenesis. In an inducible model of NSCLC dependent on Kras mutation and Trp53 loss ( KP mice), deletion of Nedd9 ( KPN mice) led to the emergence of larger tumors characterized by accelerated rates of tumor growth and elevated proliferation. Orthotopic injection of KP and KPN tumors into the lungs of Nedd9 -wild-type and -null mice indicated the effect of Nedd9 loss was cell-autonomous. Tumors in KPN mice displayed reduced activation of SRC and AKT, indicating that activation of these pathways did not mediate enhanced growth of KPN tumors. NSCLC tumor growth has been shown to require active autophagy, a process dependent on activation of the kinases LKB1 and AMPK. KPN tumors contained high levels of active LKB1 and AMPK and increased autophagy compared with KP tumors. Treatment with the autophagy inhibitor chloroquine completely eliminated the growth advantage of KPN tumors. These data for the first time identify NEDD9 as a negative regulator of LKB1/AMPK-dependent autophagy during early NSCLC tumor growth. SIGNIFICANCE: This study demonstrates a novel role for the scaffolding protein NEDD9 in regulating LKB1-AMPK signaling in early stage non-small cell lung cancer, suppressing autophagy and tumor growth., (©2021 American Association for Cancer Research.)

Primary tracheobronchial adenoid cystic carcinoma is rare, accounting for less than 1% of all lung tumors. Many adenoid cystic carcinomas have been reported to have a specific chromosome translocation t(6;9)/MYB-NFIB. More recently, t(8;9)/MYBL1-NFIB gene fusion was reported in salivary gland adenoid cystic carcinomas which lacked a t(6;9)/MYB-NFIB. Two prior studies showed t(6;9)/MYB-NFIB in tracheobronchial adenoid cystic carcinoma; however, only rare cases of MYBL1 rearrangement have been reported in this carcinoma. In this study, we used targeted RNA sequencing to investigate fusion genes in tracheobronchial adenoid cystic carcinoma at our institution. Fusions of either MYB or MYBL1 genes were detected in 7 of 7 carcinomas. Three cases had MYB-NFIB, and 3 had MYBL1-NFIB. The remaining case showed a rare MYBL1-RAD51B fusion. These findings suggest that rearrangement involving MYB or MYBL1 is a hallmark of tracheobronchial adenoid cystic carcinoma.

Accurate diagnoses of sarcoma are sometimes challenging on conventional histomorphology and immunophenotype. Many specific genetic aberrations including chromosomal translocations have been identified in various sarcomas, which can be detected by fluorescence in situ hybridization and polymerase chain reaction analysis. Next-generation sequencing-based RNA sequencing can screen multiple sarcoma-specific chromosome translocations/fusion genes in 1 test, which is especially useful for sarcoma without obvious differentiation. In this report, we utilized RNA sequencing on formalin-fixed paraffin-embedded (FFPE) specimens to investigate the possibility of diagnosing sarcomas by identifying disease-specific fusion genes. Targeted RNA sequencing was performed on 6 sarcoma cases. The expected genetic alterations (clear cell sarcoma/EWSR1-ATF1, Ewing sarcoma/EWSR1-FLI1, myxoid liposarcoma/DDIT3-FUS) in four cases were detected and confirmed by secondary tests. Interestingly, three SS18 fusion genes (SS18-SSX2B, SS18-SSX2, and SS18-SSX4) were identified in a synovial sarcoma case. A rare fusion gene (EWSR1-PATZ1) was identified in a morphologically challenging case; which enabled us to establish the diagnosis of low grade glioneural tumor. In conclusion, RNA sequencing on FFPE specimen is a reliable method in establishing the diagnosis of sarcoma in daily practice.

Microphthalmia-associated transcription factor (MiT) family translocation renal cell carcinoma harbors variable gene fusions involving either TFE3 or TFEB genes. Multiple 5' fusion partners for TFE3 have been reported, including ASPSCR1, CLTC, DVL2, LUC7L3, KHSRP, PRCC, PARP14, NONO, SFPQ1, MED15, and RBM10. Each of these fusion genes activates TFE3 transcription which can be detected by immunostaining. Using targeted RNA-sequencing, TFE3 fusion gene partners were identified in 5 cases of TFE3 immunohistochemistry positive translocation renal cell carcinoma. Three cases demonstrated known fusions: ASPSCR1-TFE3, MED15-TFE3 and RBM10-TFE3. However, two cases showed unreported NEAT1-TFE3 and KAT6A-TFE3 fusion transcripts. The NEAT1-TFE3 RCC arose in a 59-year-old male; which demonstrated overlapping morphological features seen in NEAT2(MALAT1)-TFEB t(6;11) renal cell carcinoma, including biphasic alveolar/nested tumor cells with eosinophilic cytoplasm. The KAT6A-TFE3 renal cell carcinoma demonstrated typical morphological features of TFE3/Xp11 renal cell carcinoma including papillae, eosinophilic cytoplasm with focal clearing and abundant psammoma bodies. KAT6A gene fusion was reported in some cases of acute myeloid leukemia, which has not been previously reported in solid tumors. This report highlights the genetic complexity of TFE3 translocation renal cell carcinoma; and RNA-sequencing is a powerful approach for elucidating the underlying genetic alterations.

The World Health Organization Classification of Lung Tumors considers "Spread Through Air Spaces" a form of invasion in lung adenocarcinoma. The recently described spread of free-floating cell clusters during lung specimen sectioning, otherwise known as "Spread Through A Knife Surface," represents an ex vivo artifact. The purpose of this study was to prospectively investigate the presence and frequency of these free-floating tumor cell clusters in surgically resected lung cancer specimens and their possible relation to gross examination procedures. A prospective, multi-institutional study of non-small cell lung cancer resection specimen was undertaken. At prosection the first cut was made with a clean knife; the second cut was made in a parallel plane to the first. Four tissue blocks were taken from upper and lower parts of first and second cuts. Hematoxylin and eosin-stained slides were examined for displaced benign and/or malignant tissue fragments. Forty-four resection specimens were studied. The mean number of tumor clusters for blocks 1 to 4 was 0.36, 1.44, 1.86, and 1.95, respectively, and for benign fragments was 0.11, 0.11, 0.13, and 0.25, respectively. Almost all cell clusters were intra-alveolar. Comparison of tumor cell clusters in block 1 with blocks 2 to 4 was significant with P-values (Friedman test for repeated measures 0.03) 0.031, 0.02, and 0.05, respectively. Overall 93% of the loose tissue fragments could be explained by mechanical forces associated with tissue handling. While the 2015 World Health Organization Classification of Lung Tumors recognizes Spread Through Air Spaces as a form of lung cancer invasion, such is debatable and in many instances likely represents mechanical artifact, including dissemination along the prosecting knife blade.

Background: Head and neck squamous cell carcinoma (HNSCC) is potentially curable, but treatment planning remains a challenge. Oncogenic human papillomavirus (HPV)-positive disease is often associated with a good prognosis compared with HPV-negative disease. However, some HPV-positive HNSCC recurs, often with distant metastases and significant treatment resistance., Methods and Results: We performed p16 immunohistochemistry (IHC), in situ hybridization (ISH) for high-risk HPV, and comprehensive genomic profiling on oropharyngeal HNSCC with basaloid features and particularly aggressive disease course, noting a rare genetic event: a deleting mutation (exons 5-17) of the tumor suppressor and dominant cell cycle regulator retinoblastoma 1 (RB1). Genomic and transcriptomic data available through FoundationOne and The Cancer Genome Atlas (TCGA) were reviewed for additional HNSCC cases with RB1 alterations., Conclusion: RB1 alterations may have important prognostic implications, particularly in the context of high p16 expression, in both HPV-positive and HPV-negative HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck 39: E34-E39, 2017., (© 2016 Wiley Periodicals, Inc.)

Introduction: The current WHO classification of lung cancer states that a diagnosis of SCLC can be reliably made on routine histological and cytological grounds but immunohistochemistry (IHC) may be required, particularly (1) in cases in which histologic features are equivocal and (2) in cases in which the pathologist wants to increase confidence in diagnosis. However, reproducibility studies based on hematoxylin and eosin-stained slides alone for SCLC versus large cell neuroendocrine carcinoma (LCNEC) have shown pairwise κ scores ranging from 0.35 to 0.81. This study examines whether judicious use of IHC improves diagnostic reproducibility for SCLC., Methods: Nineteen lung pathologists studied interactive digital images of 79 tumors, predominantly neuroendocrine lung tumors. Images of resection and biopsy specimens were used to make diagnoses solely on the basis of morphologic features (level 1), morphologic features along with requested IHC staining results (level 2), and all available IHC staining results (level 3)., Results: For the 19 pathologists reading all 79 cases, the rate of agreement for level 1 was 64.7%, and it increased to 73.2% and 77.5% in levels 2 and 3, respectively. With IHC, κ scores for four tumor categories (SCLC, LCNEC, carcinoid tumors, and other) increased in resection samples from 0.43 to 0.60 and in biopsy specimens from 0.43 to 0.64., Conclusions: Diagnosis using hematoxylin and eosin staining alone showeds moderate agreement among pathologists in tumors with neuroendocrine morphology, but agreement improved to good in most cases with the judicious use of IHC, especially in the diagnosis of SCLC. An approach for IHC in the differential diagnosis of SCLC is provided., (Copyright © 2017 International Association for the Study of Lung Cancer. All rights reserved.)

Background: The objective of this study was to identify trends and predictors of the time to treatment initiation (TTI) for patients with head and neck squamous cell carcinoma (HNSCC)., Methods: The National Cancer Database (NCDB) was reviewed for the following head and neck cancer sites: oral tongue, oropharynx, larynx, and hypopharynx. TTI was defined as the number of days from diagnosis to the initiation of definitive treatment and was measured according to covariates. Significant differences in the median TTI across each covariate were measured using the Kruskal-Wallis test, and the Spearman test was used to measure trends within covariates. For multivariate analysis, a zero-inflated, negative, binomial regression model was used to estimate the expected TTI, which was expressed in the predicted number of days; and the Vuong test was used to identify the predictors of TTI., Results: In total, 274,630 patients were included. Between 1998 and 2011, the median TTI for all patients was 26 days, and it increased from 19 days to 30 days (P < .0001). Treatment with chemoradiation (CRT) (P < .0001), treatment at academic facilities (P < .0001), and stage IV disease (P < .0001) were associated with increased TTI. TTI significantly increased for each disease stage (P < .0001), treatment modality (P < .0001), and facility type (P < .0001) over time. In addition, patients became more likely to transition care between facilities after diagnosis for treatment initiation (P < .0001) over time. On multivariate analysis, treatment at academic facilities (33 days), transitioning care (37 days), and receipt of CRT (39 days) predicted for a longer TTI., Conclusions: TTI is rising for patients with HNSCC. Those who have advanced-stage disease, receive treatment with CRT, are treated at academic facilities, and who have a transition in care realized the greatest increases in TTI., (© 2014 American Cancer Society.)

Background: The purpose of this study was to report associations between p16 status, clinicopathologic characteristics, and outcomes for head and neck squamous cell carcinoma of unknown primary (CUP)., Methods: Specimens of squamous cell CUP were reanalyzed. Human papillomavirus (HPV) status was determined by p16 stain. A tissue microarray (TMA) was constructed to evaluate biomarkers potentially prognostic in head and neck squamous cell carcinoma (HNSCC)., Results: A majority of the population (n = 26; 74%) was p16 positive (+). Prognostic factors benefiting survival were p16+ status (p < .0001), absence of macroscopic extracapsular extension (ECE; p = .004), younger age (p = .01), and higher grade (p = 0.007). The prognostic implication of worse overall survival (OS) with macroscopic ECE (p = .009) remained significant when limited to patients who were p16+ (p = .002). Exploratory TMA between unknown primary and controls suggested a biomolecular difference between squamous cell CUP and known-primary cancer., Conclusion: The majority of patients with squamous cell CUP were p16+, indicative of HPV association. P16 staining and ECE seem to be the most prognostic features in squamous cell CUP., (© 2014 Wiley Periodicals, Inc.)

Purpose: This is a retrospective analysis of the impact of moderate dysplasia at the resection margin for early stage cancer of the oral tongue., Materials and Methods: Patients with T1-2N0 oral tongue cancer treated with surgery alone at Fox Chase Cancer Center (FCCC) from 1990 to 2010 were reviewed. Tumor and margin characteristics were abstracted from the pathology report. Overall survival (OS), disease-free survival (DFS) and local control (LC) were calculated using the Kaplan Meier method. Predictors of LC, OS and DFS were analyzed., Results: 126 Patients met the inclusion criteria. Dysplasia was present at the final margin in 36% of the cases (severe: 9%, moderate: 15%, mild: 12%). Median follow-up was 52 months. 3 and 5-year actuarial LC for the entire cohort was 77% and 73%, respectively. Actuarial 5-year LC and DFS were significantly worse for patients with moderate or severe dysplasia at the margin vs. none or mild dysplasia at the margin (49% vs 82%, p=0.005 and 49% vs 80%, p=0.008, respectively); 3-year comparisons were not significant. When analyzed separately, the detrimental local effect of moderate dysplasia at the margin persisted (p=0.02) and the effect of severe dysplasia at the margin was approaching significance (p=0.1). Mild dysplasia at the margin did not significantly impair LC or DFS. Multivariate analysis demonstrated worse LC (HR: 2.99, p=0.006) and DFS (HR: 2.84, p=0.008) associated with severe or moderate dysplasia at the margin., Conclusions: Both severe and moderate dysplasia at the margin appear to be correlated with inferior LC and DFS. Additional therapy may be justified, despite added morbidity., (Copyright © 2013. Published by Elsevier Ltd.)

Histological subtyping of pulmonary adenocarcinoma has recently been updated based on predominant pattern, but data on reproducibility are required for validation. This study first assesses reproducibility in subtyping adenocarcinomas and then assesses further the distinction between invasive and non-invasive (wholly lepidic) pattern of adenocarcinoma, among an international group of pulmonary pathologists. Two ring studies were performed using a micro-photographic image-based method, evaluating selected images of lung adenocarcinoma histologic patterns. In the first study, 26 pathologists reviewed representative images of typical and 'difficult' histologic patterns. A total number of scores for the typical patterns combined (n=94) and the difficult cases (n=21) were 2444 and 546, respectively. The mean kappa score (±s.d.) for the five typical patterns combined and for difficult cases were 0.77±0.07 and 0.38±0.14, respectively. Although 70% of the observers identified 12-65% of typical images as single pattern, highest for solid and least for micropapillary, recognizing the predominant pattern was achieved in 92-100%, of the images except for micropapillary pattern (62%). For the second study on invasion, identified as a key problem area from the first study, 28 pathologists submitted and reviewed 64 images representing typical as well as 'difficult' examples. The kappa for typical and difficult cases was 0.55±0.06 and 0.08±0.02, respectively, with consistent subdivision by the same pathologists into invasive and non-invasive categories, due to differing interpretation of terminology defining invasion. In pulmonary adenocarcinomas with classic morphology, which comprise the majority of cases, there is good reproducibility in identifying a predominant pattern and fair reproducibility distinguishing invasive from in-situ (wholly lepidic) patterns. However, more precise definitions and better education on interpretation of existing terminology are required to improve recognition of purely in-situ disease, this being an area of increasing importance., Competing Interests: Disclosure/conflict of interest The authors declare no conflict of interest.

A subset of gastrointestinal stromal tumors (GISTs) lack gain-of-function mutations in c-KIT and PDGFRalpha. These so-called wild-type (WT) GISTs tend to be less responsive to imatinib-based therapies and have a poor prognosis. We identified amplification of IGF1R in a SNP analysis of GIST and thus studied its potential as a therapeutic target in WT and mutant GIST. Expression of IGF1R and downstream effectors in clinical GIST samples was examined by using immunoblots and immunohistochemistry. The roles of IGF1R signaling in GIST and viability were analyzed by using NVP-AEW541, an inhibitor of IGF1R, alone and in combination with imatinib, or via siRNA silencing of IGF1R. IGF1R was strongly overexpressed, and IGF1R amplification was detected at a significantly higher frequency in WT GISTs, including a pediatric WT GIST, compared with mutant GISTs (P = 0.0173 and P = 0.0163, respectively). Inhibition of IGF1R activity in vitro with NVP-AEW541 or down-regulation of expression with siIGF1R led to cytotoxicity and induced apoptosis in GIST cell lines via AKT and MAPK signaling. Combination of NVP-AEW541 and imatinib in GIST cell lines induced a strong cytotoxicity response. Our results reveal that IGF1R is amplified and the protein is overexpressed in WT and pediatric GISTs. We also demonstrate that the aberrant expression of IGF1R may be associated with oncogenesis in WT GISTs and suggest an alternative and/or complementary therapeutic regimen in the clinical management of all GISTs, especially in a subset of tumors that respond less favorably to imatinib-based therapy.

A ferret model of severe acute respiratory syndrome (SARS)-CoV infection was used to evaluate the efficacy of an adenovirus vaccine. Animals were subjected to heterologous prime-boost using vectors from human serotype 5 and chimpanzee derived adenoviruses (human AdHu5 and chimpanzee AdC7) expressing spike protein followed by intranasal challenge with SARS-CoV. Vaccination led to a substantial reduction in viral load and prevented the severe pneumonia seen in unvaccinated animals. The same prime-boost strategy was effective in rhesus macaques in eliciting SARS-CoV specific immune responses. These data indicate that a heterologous adenovirus-based prime-boost vaccine strategy could safely stimulate strong immunity that may be needed for complete protection against SARS-CoV infection.

Screening for lung cancer produces two groups of lung cancers. Baseline cases include all prevalent cases with the expectation that slower-growing cancers and those that have achieved higher stage will be found in greater frequency. Repeat examination is expected to detect those cancers which have crossed the threshold for detection during the screening interval - 1 year in this study - and these are typically more rapidly growing cancers. The two groups encompass the full spectrum of lung cancers. Comparison of the baseline and annual repeat cases revealed differences in types of lung cancer. There were 202 baseline-detected cancers spanning the spectrum of pulmonary neoplasms with some slowly growing, some rapidly progressive and some at high stage; the 48 annual repeat cancers also included a spectrum of lung cancers but with more of the rapidly growing types, and more closely approximated the clinical spectrum of lung cancers. The NE carcinomas showed this trend best; small-cell carcinomas were under-represented and typical carcinoids were only found in the baseline group. Repeat cancers were found to grow rapidly, were typically smaller, less often multiple and the adenocarcinomas were less often pure BAC and less frequently contained a BAC component when invasive. The baseline adenocarcinomas included most of the BAC's, which is a diagnosis that requires special attention to its WHO definition. AAH was found to be frequently associated with adenocarcinoma, particularly BAC. Both baseline and annual repeat cases had a high percentage of invasive carcinomas with comparably high rates of resectability, high rates of node negativity and consequently a high proportion of cases in low stage.

Introduction: Advances in the pathology and computed tomography (CT) of lung adenocarcinoma and bronchioloalveolar carcinoma (BAC) have demonstrated important new prognostic features that have led to changes in classification and diagnostic criteria., Methods: The literature and a set of cases were reviewed by a pathology/CT review panel of pathologists and radiologists who met during a November 2004 International Association for the Study of Lung Cancer/American Society of Clinical Oncology consensus workshop in New York. The group addressed the question of whether sufficient data exist to modify the 2004 World Health Organization (WHO) classification of adenocarcinoma and BAC to define a "minimally invasive" adenocarcinoma with BAC. The problems of diffuse and/or multicentric BAC and adenocarcinoma were evaluated., Results: The clinical concept of BAC needs to be reevaluated with careful attention to the new 2004 WHO criteria because of the major clinical implications. Existing data indicate that patients with solitary, small, peripheral BAC have a 100% 5-year survival rate. The favorable prognostic impact of the restrictive criteria for BAC is already being detected in major epidemiologic data sets such as the Surveillance Epidemiology and End-Results registry. Most lung adenocarcinomas, including those with a BAC component, are invasive and consist of a mixture of histologic patterns. Therefore, they are best classified as adenocarcinoma, mixed subtype. This applies not only to adenocarcinomas with a solitary nodule presentation but also to tumors with a diffuse/multinodular pattern. The percentage of BAC versus invasive components in lung adenocarcinomas seems to be prognostically important. However, at the present time, a consensus definition of "minimally invasive" BAC with a favorable prognosis was not recommended by the panel, so the 1999/2004 WHO criteria for BAC remain unchanged. In small biopsy specimens or cytology specimens, recognition of a BAC component is possible. However, it is not possible to exclude an invasive component. The diagnosis of BAC requires thorough histologic sampling of the tumor., Conclusion: Advances in understanding of the pathology and CT features of BAC and adenocarcinoma have led to important changes in diagnostic criteria and classification of BAC and adenocarcinoma. These criteria need to be uniformly applied by pathologists, radiologists, clinicians, and researchers. The 2004 WHO classification of adenocarcinoma is readily applicable to research studies, but attention needs to be placed on the relative proportion of the adenocarcinoma subtypes. Other recently recognized prognostic features such as size of scar, size of invasive component, or pattern of invasion also seem to be important. More work is needed to determine the most important prognostic pathologic features in lung adenocarcinoma.