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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 or 19-gauge 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 on-site 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-value 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 22-gauge and 19-gauge needles, respectively. Molecular adequacy for cytology cell block was 77% and 80% for 22-gauge and 19-gauge needles, respectively. There were no significant procedural complications. Conclusion Both the 22-gauge and 19-gauge 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.

Papillary renal neoplasm with reverse polarity (PRNRP) is a newly proposed entity with distinct histology and frequent KRAS mutations. To date, 93 cases of PRNRPs have been reported. In this study, we present 7 new cases of PRNRP and review the literature. Most of the pathologic features in our 7 cases are similar to those previously reported cases. However, all 7 of our cases showed at least partial cystic changes, which was not stressed in prior studies. Single-nucleotide polymorphism-microarray based chromosomal analysis demonstrated no trisomy or other alteration of chromosomes 7 or 17; and no loss or other alteration of chromosome Y was detected in all 7 cases. Next-generation sequencing detected KRAS missense mutations in 4 of 7 cases. No fusion genes were detected. In summary, PRNRP is a small, well-circumscribed often encapsulated and cystic neoplasm with loose papillary formations. Cuboidal tumor cells always have eosinophilic cytoplasm and nuclei located at the pole opposite the basement membrane with a low World Health Organization (WHO)/International Society of Urologic Pathologists (ISUP) nuclear grade. The fibrovascular cores can be hyalinized or edematous. Macrophage aggregates and intracellular hemosiderin are uncommon, and no psammoma bodies or necrosis should be seen. Immunophenotypically, this tumor is always positive for CK7 and GATA3, and negative for CD117 and vimentin. CD10 and AMACR can be positive, but often weakly and focally. PRNRP often has KRAS mutations, however, only 32% of cases have chromosomal abnormalities in chromosomes 7, 17, and Y. No recurrences, metastases, or tumor-related deaths have been reported following complete resection.

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.

Non–small cell lung cancer (NSCLC) is the most common cancer worldwide. With overall 5-year survival estimated at 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.

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.

The companion diagnostic test for checkpoint inhibitor immune therapy is an immunohistochemical test for PD-L1. The test has been shown to be reproducible for expression in tumor cells, but not in immune cells. Immune cells were used in the IMpassion130 trial which showed PD-L1 expression was associated with a better outcome. Two large studies have been done assessing immune cell PD-L1 expression in lung cancer. Here, we reanalyze one of those studies, to show that, even with an easier scoring method, there is still only poor agreement between assays and pathologist for immune cell PD-L1 expression.

Purpose: Most gastrointestinal stromal tumors (GIST) have activating mutations of KIT, PDGFRA, or uncommonly BRAF. Fifteen percent of adult and 85% of pediatric GISTs are wild type (WT), commonly having high expression of IGF-1R and loss of succinate dehydrogenase (SDH) complex function. We tested the efficacy of linsitinib, an oral TKI IGF-1R inhibitor, in patients with WT GIST. Patients and Methods: A multicenter phase II trial of linsitinib was conducted. The primary endpoint was objective response rate. Secondary endpoints were clinical benefit rate: complete response, partial response, and stable disease (SD) ≥ 9 months, and quantitative 2[18F]fluoro-2-deoxy-D-glucose (FDG) metabolic response (MR) at week 8. Serum levels for glucose, insulin, IGF-1R ligand IGF1, and binding proteins were obtained to explore correlations to patient outcomes and FDG-PET results. Results: Twenty patients were accrued in a 6-month period. Grade 3–4 toxicities possibly related to linsitinib were uncommon (8.5%). No objective responses were seen. Clinical benefit rate (CBR) at 9 months was 40%. Intense FDG uptake was observed at baseline, with partial MR of 12% and stable metabolic disease of 65% at week 8; these patients had RECIST 1.1 SD as their best response. Progression-free survival (PFS) and overall survival Kaplan–Meier estimates at 9 months were 52% and 80%, respectively. SDHA/B loss determined by IHC was seen in 35% and 88% of cases, respectively. Conclusions: Linsitinib is well tolerated in patients with WT GIST. Although the 9-month CBR was 40%, and PFS at 9 months was 52%, no objective responses were observed. Rapid accrual to this study demonstrates that clinical trials of experimental agents in selected subtypes of GIST are feasible.

ContextSurgical and pathologic handling of lung physically affects lung tissue. This leads to artifacts that alter the morphologic appearance of pulmonary parenchyma.Objective—To describe and illustrate mechanisms of ex vivo artifacts that may lead to diagnostic pitfalls.DesignIn this study 4 mechanisms of ex vivo artifacts and corresponding diagnostic pitfalls are described and illustrated.Results—The 4 patterns of artifacts are: (1) surgical collapse, due to the removal of air and blood from pulmonary resections; (2) ex vivo contraction of bronchial and bronchiolar smooth muscle; (3) clamping edema of open lung biopsies; and (4) spreading of tissue fragments and individual cells through a knife surface. Morphologic pitfalls include diagnostic patterns of adenocarcinoma, asthma, constrictive bronchiolitis, and lymphedema.ConclusionFour patterns of pulmonary ex vivo artifacts are important to recognize in order to avoid morphologic misinterpretations.

Purpose To estimate the overall survival (OS) impact from increasing time to treatment initiation (TTI) for patients with head and neck squamous cell carcinoma (HNSCC). Methods Using the National Cancer Data Base (NCDB), we examined patients who received curative therapy for the following sites: oral tongue, oropharynx, larynx, and hypopharynx. TTI was the number of days from diagnosis to initiation of curative treatment. The effect of TTI on OS was determined by using Cox regression models (MVA). Recursive partitioning analysis (RPA) identified TTI thresholds via conditional inference trees to estimate the greatest differences in OS on the basis of randomly selected training and validation sets, and repeated this 1,000 times to ensure robustness of TTI thresholds. Results A total of 51,655 patients were included. On MVA, TTI of 61 to 90 days versus less than 30 days (hazard ratio [HR], 1.13; 95% CI, 1.08 to 1.19) independently increased mortality risk. TTI of 67 days appeared as the optimal threshold on the training RPA, statistical significance was confirmed in the validation set (P < .001), and the 67-day TTI was the optimal threshold in 54% of repeated simulations. Overall, 96% of simulations validated two optimal TTI thresholds, with ranges of 46 to 52 days and 62 to 67 days. The median OS for TTI of 46 to 52 days or fewer versus 53 to 67 days versus greater than 67 days was 71.9 months (95% CI, 70.3 to 73.5 months) versus 61 months (95% CI, 57 to 66.1 months) versus 46.6 months (95% CI, 42.8 to 50.7 months), respectively (P < .001). In the most recent year with available data (2011), 25% of patients had TTI of greater than 46 days. Conclusion TTI independently affects survival. One in four patients experienced treatment delay. TTI of greater than 46 to 52 days introduced an increased risk of death that was most consistently detrimental beyond 60 days. Prolonged TTI is currently affecting survival.

The 2015 World Health Organization (WHO) Classification of Tumors of the Lung, Pleura, Thymus and Heart has just been published with numerous important changes from the 2004 WHO classification. The most significant changes in this edition involve (1) use of immunohistochemistry throughout the classification, (2) a new emphasis on genetic studies, in particular, integration of molecular testing to help personalize treatment strategies for advanced lung cancer patients, (3) a new classification for small biopsies and cytology similar to that proposed in the 2011 Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, (4) a completely different approach to lung adenocarcinoma as proposed by the 2011 Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, (5) restricting the diagnosis of large cell carcinoma only to resected tumors that lack any clear morphologic or immunohistochemical differentiation with reclassification of the remaining former large cell carcinoma subtypes into different categories, (6) reclassifying squamous cell carcinomas into keratinizing, nonkeratinizing, and basaloid subtypes with the nonkeratinizing tumors requiring immunohistochemistry proof of squamous differentiation, (7) grouping of neuroendocrine tumors together in one category, (8) adding NUT carcinoma, (9) changing the term sclerosing hemangioma to sclerosing pneumocytoma, (10) changing the name hamartoma to "pulmonary hamartoma," (11) creating a group of PEComatous tumors that include (a) lymphangioleiomyomatosis, (b) PEComa, benign (with clear cell tumor as a variant) and

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.

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.

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

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

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.

Surgical removal and pathologic handling of lung tissue has a compressive effect upon its architecture. The effect of surgical atelectasis on morphology has not been examined in depth, especially with respect to lung adenocarcinomas.To examine the influence of surgical atelectasis on morphologic lepidic growth pattern, mimicking papillary adenocarcinoma pattern.In 2 cases serial sections of resected pulmonary adenocarcinoma were used, as was a 3-dimensional reconstruction. Elastin stains were performed on primary and metastatic adenocarcinomas.Perfusion fixation of another case showed marked morphologic differences of less compressed peripheral lung tissue, emphasizing the preexisting alveolar structure. An elastic stain may help identify true lesional architecture.We demonstrate that microscopic sections of adenocarcinoma in situ in compressed/collapsed tissue may give rise to a pseudopapillary pattern mimicking invasive adenocarcinoma. Accurate appreciation of different tumor architecture in lung adenocarcinoma has important biologic and clinical implications. Pathologists should be aware of the possibility of misclassification of adenocarcinoma pattern due to tissue artifacts caused by lung tissue handling.

The impact of extranodal extension (ENE) of metastatic papillary thyroid carcinoma (PTC) on short- and long-term clinical outcomes, including biochemical testing, has not been reported.This single-institution National Cancer Institute-designated Comprehensive Cancer Center cohort study included patients with macroscopic metastases and excluded patients with gross residual disease after surgery, distant disease, or poorly differentiated papillary carcinoma. A suppressed or stimulated thyroglobulin (Tg)1 ng/mL, without suspicious imaging or anti-thyroglobulin antibodies, after radioactive iodine (RAI) treatment was termed an excellent or "complete biochemical response" (CR).Of 89 subjects included, 60 previously untreated patients underwent total thyroidectomy and therapeutic neck dissection; 29 additional patients underwent a neck dissection for persistence or recurrence after prior surgery and RAI administration. ENE, identified in 29 patients (33%), was associated with T4 classification (p = 0.02) and involvement of a greater number of nodes (median 11 vs. 5, p = 0.03). ENE was associated with a 20% increased risk of nodal persistence necessitating additional surgery (p = 0.02). In a multivariable analysis, ENE, T4 classification, and recurrence/persistence proved to be independent predictors of systemic disease progression (ENE: hazard ratio [HR] 4.3 [95% confidence interval (CI) 1.2-15], p = 0.02; T4 classification: HR 4.2 [CI 1.3-14], p = 0.01; recurrent/persistent status: HR 3.6 [CI 1.1-12], p = 0.035). Nodal or systemic disease progression was rare after a biochemical CR; in contrast, in previously untreated patients, stimulated Tg levels (sTg)50 ng/mL prior to initial RAI administration, heralded the progression of nodal disease, and also predicted the eventual development of systemic disease (p = 0.0001). Of those with a sTg50 ng/mL, over 70% underwent surgery for nodal persistence within five years. The presence of ENE diminished the odds of a biochemical CR (odds ratio 3.5% [CI 1.3-10], p = 0.02), and increased the probability that the sTg levels after surgery will exceed 50 ng/mL (odds ratio 5 [CI 1.2-21], p = 0.03). Following surgery for tumor persistence, 25% of those with ENE were rendered biochemically free of disease.ENE diminishes the probability of a biochemical CR after treatment for regional metastatic PTC, and increases the probability of tumor persistence after initial resection, likely from abundant metastasis. ENE and nodal persistence independently predict eventual systemic disease progression.

A new lung adenocarcinoma classification has been published by the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society. This new classification is needed to provide uniform terminology and diagnostic criteria, most especially for bronchioloalveolar carcinoma. It was developed by an international core panel of experts representing all 3 societies with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons.This summary focuses on the aspects of this classification that address resection specimens. The terms bronchioloalveolar carcinoma and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced, such as adenocarcinoma in situ and minimally invasive adenocarcinoma for small solitary adenocarcinomas with either pure lepidic growth (adenocarcinoma in situ) and predominant lepidic growth with invasion of 5 mm or less (minimally invasive adenocarcinoma...

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

Introduction Stage classification provides a consistent language to describe the anatomic extent of disease and is therefore a critical tool in caring for patients. The Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer developed proposals for revision of the classification of lung cancer for the eighth edition of the tumor, node, and metastasis (TNM) classification, which takes effect in 2017. Methods An international database of 94,708 patients with lung cancer diagnosed in 1999–2010 was assembled. This article describes the process and statistical methods used to refine the lung cancer stage classification. Results Extensive analysis allowed definition of tumor, node, and metastasis categories and stage groupings that demonstrated consistent discrimination overall and within multiple different patient cohorts (e.g., clinical or pathologic stage, R0 or R-any resection status, geographic region). Additional analyses provided evidence of applicability over time, across a spectrum of geographic regions, histologic types, evaluative approaches, and follow-up intervals. Conclusions An extensive analysis has produced stage classification proposals for lung cancer with a robust degree of discriminatory consistency and general applicability. Nevertheless, external validation is encouraged to identify areas of strength and weakness; a sound validation should have discriminatory ability and be based on an independent data set of adequate size and sufficient follow-up with enough patients for each subgroup.

The new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification provides, for the first time, standardized terminology for lung cancer diagnosis in small biopsies and cytology; this was not primarily addressed by previous World Health Organization classifications. Until recently there have been no therapeutic implications to further classification of NSCLC, so little attention has been given to the distinction of adenocarcinoma and squamous cell carcinoma in small tissue samples. This situation has changed dramatically in recent years with the discovery of several therapeutic options that are available only to patients with adenocarcinoma or NSCLC, not otherwise specified, rather than squamous cell carcinoma. This includes recommendation for use of special stains as an aid to diagnosis, particularly in the setting of poorly differentiated tumors that do not show clear differentiation by routine light microscopy. A limited diagnostic workup is recommended to preserve as much tissue for molecular testing as possible. Most tumors can be classified using a single adenocarcinoma marker (eg, thyroid transcription factor 1 or mucin) and a single squamous marker (eg, p40 or p63). Carcinomas lacking clear differentiation by morphology and special stains are classified as NSCLC, not otherwise specified. Not otherwise specified carcinomas that stain with adenocarcinoma markers are classified as NSCLC, favor adenocarcinoma, and tumors that stain only with squamous markers are classified as NSCLC, favor squamous cell carcinoma. The need for every institution to develop a multidisciplinary tissue management strategy to obtain these small specimens and process them, not only for diagnosis but also for molecular testing and evaluation of markers of resistance to therapy, is emphasized.

The Use of Immunohistochemistry Improves the Diagnosis of SCLC. An International Reproducibility Study in a Demanding Set of Cases

Context.—Lung cancer is the leading cause of cancer mortality worldwide. Despite technological, therapeutic, and scientific advances, most patients present with incurable disease and a poor chance of long-term survival. For those with potentially curable disease, lung cancer staging greatly influences therapeutic decisions. Therefore, surgical pathologists determine many facets of lung cancer patient care. Objective.—To present the current lung cancer staging system and examine the importance of mediastinal lymph node sampling, and also to discuss particularly confusing and/or challenging areas in lung cancer staging, including assessment of visceral pleura invasion, bronchial and carinal involvement, and the staging of synchronous carcinomas. Data Sources.—Published current and prior staging manuals from the American Joint Committee on Cancer and the International Union Against Cancer as well as selected articles pertaining to lung cancer staging and diagnosis accessible through PubMed (National Library of Medicine) form the basis of this review. Conclusions.—Proper lung cancer staging requires more than a superficial appreciation of the staging system. Clinically relevant specimen gross examination and histologic review depend on a thorough understanding of the staging guidelines. Common sense is also required when one is confronted with a tumor specimen that defies easy assignment to the TNM staging system.

A 78-year-old African-American woman was diagnosed with rheumatoid arthritis (RA) in 1996 after she presented with a symmetrical polyarthritis of the hands. Over the next 4 years, she was treated with multiple disease-modifying antirheumatic drugs including methotrexate, hydroxychloroquine, gold, and leflunomide, all of which were stopped due to side effects or lack of response. She was started on low-dose prednisone in 1998, and was also maintained on low-dose azathioprine, which had been initiated in June. In October 2000, the patient developed a cervical myelopathy, manifested by ataxia and hyperreflexia. Magnetic resonance imaging of the cervical spine showed compression of the ventral cord by an enhancing epidural soft-tissue mass behind the odontoid, which was thought to be pannus, as well as multilevel spondylosis with cord compression at C5– 6. In December 2000, she underwent cervical spine decompression at the C5–6 level but was left with residual ataxia. In early 2000, the patient had begun to lose weight, and this worsened after her spine surgery; she lost 20 lb between August 1999 and April 2001. Computerized tomography (CT) scan of the chest, abdomen, and pelvis without contrast was normal in April 2001. Magnetic resonance imaging of the abdomen was unremarkable except for thickening of the gastric antrum. Endoscopy was normal. Bone-marrow biopsy showed no evidence of malignancy. Testing for antigliadin antibodies and human immunodeficiency virus (HIV) were negative. In May 2001, the patient was started on infliximab for the likelihood that RA activity was contributing to her weight loss and also because of the myelopathy due to the presence of pannus behind the odontoid process. She received the first three infusions but was lost to follow-up. She presented again in September 2001 with a further weight loss of 10 lb and was admitted for further evaluation. The patient_s prior medical history was significant for hypertension, osteoporosis, and a pancreatic cystic mass which, when aspirated in 1998, had revealed no malignant cells. There also was an allergy to contrast dye. Medications at the time of admission were Premarin 0.625 mg daily (qd), prednisone 5 mg qd, furosemide 20 mg qd, and atenolol 50 mg qd. On physical examination, the patient was cachectic, weighing 66 lb. Blood pressure was 110/80 mmHg, and she was afebrile. Significant findings included: chronic swan neck and boutonniere_s deformities of the hands but no active synovitis; hyperreflexia in the lower extremities with mild left-sided dysmetria; and negative Babinski signs. Abdominal examination revealed mild left upper-quadrant abdominal tenderness without masses. Cardiopulmonary examination was within normal limits, and hemoccult stool test was negative. The initial laboratory investigation demonstrated a leukocyte count of 3.7 10/l (normal 3.4–11.2 10/l) with a normal differential, hemoglobin 9.5 g/dl (normal 12–16 g/dl), and platelet count of 201 10/l (normal 150– 450 10/l). Liver, renal, and thyroid function tests, as well as urinalyses, were normal. Serum albumin was 2.9 g/dl, HSSJ (2007) 3: 119–125 DOI 10.1007/s11420-006-9032-1

Introduction Several matrix metalloproteinases (MMPs) are overexpressed in lung cancer and may serve as potential targets for the development of bioactivable probes for molecular imaging. Objective To characterize and monitor the activity of MMPs during the progression of lung adenocarcinoma. Methods K-rasLSL-G12D mice were imaged serially during the development of adenocarcinomas using fluorescence molecular tomography (FMT) and a probe specific for MMP-2, -3, -9 and -13. Lung tumors were identified using FMT and MRI co-registration, and the probe concentration in each tumor was assessed at each time-point. The expression of Mmp2, -3, -9, -13 was quantified by qRT-PCR using RNA isolated from microdissected tumor cells. Immunohistochemical staining of overexpressed MMPs in animals was assessed on human lung tumors. Results In mice, 7 adenomas and 5 adenocarcinomas showed an increase in fluorescent signal on successive FMT scans, starting between weeks 4 and 8. qRT-PCR assays revealed significant overexpression of only Mmp-13 in mice lung tumors. In human tumors, a high MMP-13 immunostaining index was found in tumor cells from invasive lesions (24/27), but in none of the non-invasive (0/4) (p=0.001). Conclusion MMP-13 is detected in early pulmonary invasive adenocarcinomas and may be a potential target for molecular imaging of lung cancer.

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.

A 28-year-old Hispanic female was transferred to New York Presbyterian Hospital in December for pneumonia, unresponsive to antibiotics. She had been in her usual state of health until the preceding summer, when she developed progressive shortness of breath and a cough. Her cough was initially nonproductive, but she eventually developed blood-tinged green sputum, pleuritic chest pain, and persistent fevers and chills. The patient was admitted to an outside hospital in the fall, but left against medical advice and was readmitted 2 months later. An admission arterial blood gas demonstrated a pH of 7.50, PaCO2 of 43 mm Hg and PaO2 of 68 mm Hg on 28% inspired oxygen. A chest film revealed bilateral lower lobe infiltrates and effusions, and a chest computed tomography (CT) scan showed diffuse bilateral airspace disease. Over the course of her admission, the patient was treated with multiple antibiotics including vancomycin, levofloxacin, meropenem, imipenem, linezolid, and amikacin, without significant response. She was ultimately transferred to our institution for further diagnostic workup and treatment. Review of systems upon transfer was notable for a 20-lb weight loss over 2 months, intermittent nausea and vomiting, and mild frontal headaches. She also described bilateral eye pain and redness occurring over the summer, which had resolved spontaneously. The patient had no history of alopecia, rash, oral ulcers, photosensitivity, myalgias, parasthesias, focal weakness, or Raynaud’s symptoms. She had occasional arthralgias, but no morning stiffness. Her medical history was remarkable for morbid obesity, chronic anemia with sickle cell and thalassemia traits, cholelithiasis, and recurrent upper respiratory infections occurring two to three times per year. She had undergone three previous Caesarian sections and had no history of spontaneous pregnancy loss. The patient was single with two living children and studying to be a medical assistant. She had no history of alcohol, tobacco, or illicit drug use, no pets, and no sick contacts. Her last travel was to Puerto Rico at age 11. A tuberculosis purified protein derivative (PPD) skin test yielded negative results 5 years prior to admission, and a test for human immunodeficiency virus (HIV) was also negative. Her family history was remarkable for parents with diabetes and hypertension, a father with alcohol abuse, and a sister with latent tuberculosis, who reportedly completed treatment with isoniazid. She had no known family history of pulmonary or connective tissue disease, and no known drug allergies. Upon transfer to our institution, her medications were imipenem, linezolid, amikacin, prevacid, lopressor, albuterol and atrovent via nebulizer, subcutaneous heparin, and insulin on a sliding scale. Physical examination revealed an obese Hispanic female in moderate respiratory distress. She was febrile (39.6-C) with a heart rate of 106 beats/min and blood pressure of 127/85 mm Hg. She was tachypneic with a respiratory rate of 20 breaths/min and an oxygen saturation of 96% on a 40% face mask. Her cardiopulmonary exam was notable for a grade II/VI systolic murmur and scattered coarse rales throughout both lung fields. Her abdomen was obese but benign, her extremities were without edema and had strong pulses, her skin was without rashes, and her joints exhibited full range of motion without warmth, synovitis, or effusion. Her neurologic exam was unremarkHSSJ (2006) 2: 191–197 DOI 10.1007/s11420-006-9009-0

International audience; Sixty-five people had a resection of their baseline screen-diagnosed lung cancers in the Early Lung Cancer Action Program. Forty-nine of the carcinomas were solitary, and 42 of these were adenocarcinomas. More than 1 carcinoma was found in 16 patients after pathologic examination of the lobectomy specimen; 15 of the 16 second carcinomas were adenocarcinomas, mixed subtype. Eighteen cases were submitted by local pathologists as Bronchioloalveolar carcinomas but were found to be invasive adenocarcinomas according to the World Health Organization classification by the Pathology Review Panel. Of the 65 resected cases, 57 were N0, 7 were N1, and 1 was N2. Upon careful review of the lobectomy specimens, 49 cases had solitary malignancies, 30 were Stage IA, 13 Stage IB, 3 Stage IIA, 2 Stage IIB, and 1 Stage IIIA on the basis of the American Joint Committee on Cancer/International Union for Cancer Control criteria. In the 16 cases found to have multiple malignancies, 6 had histologically different carcinomas and the remaining 10 had histologically identical malignancies. Eighty-three percent (76/92) of the carcinomas invaded the stroma with destruction of normal lung, and 21% (19/92) also showed either pleural or angiolymphatic invasion, even though 88% (57/65) of the carcinomas were free of lymph node metastases. This report describes the pathologic findings of the resected cases. Histopathologic distinctions among atypical adenomatous hyperplasia, bronchioloalveolar carcinomas, and invasive adenocarcinoma are described in detail.

Despite renewed interest in early detection of lung cancer, the relationship between tumor size and survival remains controversial. The objective of this study was to evaluate the relationship between size and stage in patients with T1 (or = 3.0 cm) non-small cell lung cancer (NSCLC).A retrospective review of a lung cancer database from 1995 to 2003 identified 503 patients with completely resected invasive NSCLC with tumorsor = 3 cm. All clinical and pathologic characteristics were recorded. Univariate associations between nodal status and other prognostic factors were explored by chi2 and t tests. The independent effect of tumor size2 cm vsor = 2 cm on the risk of nodal disease was analyzed using a logistic regression model.Of the 503 patients, 324 patients (64.4%) had stage IA disease, 52 patients (10.3%) had stage IB disease, 37 patients (7.4%) had stage IIA disease, 15 patients (3%) had stage IIB disease, 43 patients (8.6%) had stage IIIA disease, 24 patients (4.8%) had stage IIIB disease, and 8 patients (1.6%) had stage IV disease. One hundred patients (19.9%) had nodal metastases. The mean (+/- SD) tumor size of cases without nodal disease was 1.90 +/- 0.67 cm, compared to 2.18 +/- 0.69 cm for node-positive tumors (p = 0.0003; 95% confidence interval [CI] for mean difference, 0.13 to 0.43). Forty-eight of 308 patients (15.6%) with smaller carcinomas (or = 2.0 cm) compared to 52 of 195 patients (26.7%) with carcinomas2.0 cm had nodal metastases (p = 0.002). Exploratory multivariate analysis revealed that only tumor size (or = 2.0 cm [referent] vs2.0 cm) affected nodal status and thus stage (adjusted odds ratio, 2.0; 95% CI, 1.3 to 3.1; p = 0.002).Primary invasive NSCLC2.0 cm was twice as likely to have nodal metastases than carcinomasor = 2.0 cm. Our results suggest that in lung cancer smaller lesions may represent earlier stage disease. These results also suggest the need for further subclassification by tumor size within the current International Union Against Cancer/American Joint Committee on Cancer stage I, with tumors2 cm in size contained in a separate substage. This refinement may help to better clarify which patients might benefit from novel adjuvant or neoadjuvant therapeutic interventions.

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.

Intranasal inhalation of the severe acute respiratory syndrome coronavirus (SARS CoV) in the immunocompetent mouse strain 129SvEv resulted in infection of conducting airway epithelial cells followed by rapid clearance of virus from the lungs and the development of self-limited bronchiolitis. Animals resistant to the effects of interferons by virtue of a deficiency in Stat1 demonstrated a markedly different course following intranasal inhalation of SARS CoV, one characterized by replication of virus in lungs and progressively worsening pulmonary disease with inflammation of small airways and alveoli and systemic spread of the virus to livers and spleens.

Purpose of review Idiopathic interstitial pneumonias (IIP) represent a complex group of relatively rare entities with similar clinical, vaguely similar radiographic and differing histologic features. The recent international multidisciplinary consensus statement produced by the American Thoracic Society/European Respiratory Society aiming to standardize the classification of IIP recognizes nonspecific interstitial pneumonia (NSIP) as a provisional category. While not representing a single disease, but rather a collection of pathologic processes with similar histomorphology, NSIP has been a great source of confusion for pulmonologists, radiologists, and pathologists. Recent findings Lacking diagnostic clinical or radiographic features, NSIP is an IIP with recognizable and reproducible morphologic patterns different from usual interstitial pneumonia (UIP)-pattern as well as other disease patterns. And while overlap with UIP-pattern can be seen in individuals with multiple biopsy samples, those with either cellular or fibrosing variants of NSIP have a better prognosis than UIP-pattern patients. Summary A morphologic diagnosis of NSIP-pattern alerts the clinician to a wide spectrum of potential clinical possibilities and enables researchers to study both this fibrosing interstitial pneumonia pattern and the more common and deadly UIP-pattern separately. Thus, this provisional category is useful to both clinicians and researchers.

There are few reported cases of primary pulmonary paraganglioma in the pathology literature. Given the historical confusion surrounding bronchial tumors, widespread use of the term "chemodectoma" and classification of these lesions as paraganglioma in an outdated World Health Organization classification of lung tumors, the recognition of tumors arising from paraganglia within the lung has not been accepted by leading authorities. We present a well-documented case of a primary pulmonary paraganglioma with typical morphologic features and a supporting immunohistochemical profile. The 0.9 cm endobronchial tumor was submucosal and composed of nests of ovoid cells with abundant eosinophilic cytoplasm, cytoplasmic vacuoles, round to oval nuclei with speckled chromatin, and occasional conspicuous nucleoli. The nests of cells were surrounded by thin-walled vascular channels and stellate spindle cells. The ovoid cells showed strong diffuse staining for chromogranin A, synaptophysin, and faint staining for S-100; they were negative for cytokeratin AE1/AE3, Cam 5.2, and epithelial membrane antigen. The stellate spindle cells stained intensely positive for S-100 protein. A critical review of reported cases of pulmonary chemodectomas and paragangliomas in the English literature features few, if any, well-documented examples. While this exceedingly rare tumor should be discerned from carcinoid tumor, it remains unknown if primary pulmonary paragangliomas behave aggressively like intra-abdominal extra-adrenal paragangliomas, or in a more indolent manner observed with extra-adrenal paragangliomas in other locations.

Purpose: Preclinical studies suggest that treatment with a selective cyclo-oxygenase-2 (COX-2) inhibitor may augment the antitumor effects of chemotherapy. In this study, patients with non–small-cell lung cancer (NSCLC) were preoperatively treated with celecoxib in combination with chemotherapy. End points were toxicity, response rates, and measurement of intratumoral levels of prostaglandin E2(PGE2).Methods: In this phase II trial, 29 patients with stages IB to IIIA NSCLC were treated with two preoperative cycles of paclitaxel and carboplatin, as well as daily celecoxib, followed by surgical resection. Levels of PGE2in the primary tumors and adjacent normal lung tissue were compared in 17 study patients versus 13 controls, who received preoperative paclitaxel/carboplatin without celecoxib.Results: All patients completed preoperative chemotherapy, and 26 completed preoperative celecoxib. The overall clinical response rate was 65% (48% with partial response; 17% with complete response). Grade 3 or 4 neutropenia was observed in 18 patients (62%). Twenty-eight patients were explored and underwent complete resection of their tumors. There were no complete pathologic responses, but seven patients (24%) had minimal residual microscopic disease. The addition of celecoxib to a regimen of paclitaxel and carboplatin abrogated the marked increase in levels of PGE2detected in primary tumors after treatment with paclitaxel and carboplatin alone.Conclusion: In comparison with historically reported response rates, these data suggest that the addition of a selective COX-2 inhibitor may enhance the response to preoperative paclitaxel and carboplatin in patients with NSCLC. Moreover, treatment with celecoxib 400 mg twice daily was sufficient to normalize the increase in PGE2levels found in NSCLC patients after treatment with paclitaxel and carboplatin. Confirmatory trials are planned.

e13025 Background: A few patients with metastatic cancer survive exceptionally longer than others under the same treatment. We hypothesized that there is a specific biologic signature in genetic profiles of long-term survivors that plays a key role in sensitivity to systemic treatment. Methods: Twenty-six patients with metastatic cancer treated at Fox Chase cancer center with exceptional response were included in the study. Exceptional response was defined as complete response > 1 year or stable disease/partial response > 2 years at any time during the disease course. Archived tumor specimens of 16 patients were sequenced and analyzed using Ambry Genetics 142 gene panel. In addition, genes expressions in tumor tissues from 23 exceptional responders and 23 matched controls (age, sex and tumor type) were analyzed using two NanoString nCounter PanCancer panels (Pathway and Immune Profiling). Results: See Table. Conclusions: Multiple common mutations of NOTCH2, NF1, FANCD2, PIK3CB and EPHA5 were found in tumors that responded exceptionally well to treatments. Additionally, certain genes were significantly over-expressed or under-expressed in these tumors compared to matched controls. Underlying mechanisms that these genetic alterations foster, leading to susceptibility to treatment and prolonged patient survival, should be further studied. [Table: see text]

Background The Early Lung Cancer Action Project (ELCAP) was designed to evaluate the usefulness of annual computed tomography (CT) screening for lung carcinoma. With the baseline results having been reported previously, the focus of the current study was on the early results of the repeat screenings. Methods A cohort of 1000 high-risk individuals was recruited for baseline and annual repeat CT screening. At last follow-up, a total of 1184 annual repeat screenings had been performed. A positive result from the screening test was defined as newly detected, one to six noncalcified pulmonary nodules with interim growth. The diagnostic workup of the individuals was guided by recommendations supplied by the ELCAP investigators to the collaborating clinicians. Results Of the 1184 repeat CT screenings, the test result was positive in 30 (2.5%). In 2 of these 30 cases, the individual died (of an unrelated cause) before diagnostic workup and the nodule(s) resolved in another 12 individuals. In the remaining 16 individuals, the absence of further growth was documented by repeat CT in 8 individuals and further growth was documented in the remaining 8 individuals. All eight individuals with further nodular growth underwent biopsy and malignancy was diagnosed in seven. Six of these seven malignancies were nonsmall cell carcinomas (five of which were Stage IA and one of which was Stage IIIA) and the one small cell carcinoma was found to be of limited stage. The median size dimension of these malignancies was 8 mm. In another two subjects, symptoms prompted the interim diagnosis of lung carcinoma. Neither of these malignancies was nodule-associated but rather were endobronchial; one was a Stage IIB nonsmall cell carcinoma and the other was a small cell carcinoma of limited stage. Conclusions False-positive screening test results are uncommon and usually manageable without biopsy; compared with no screening, such screenings permit diagnosis at substantially earlier and thus more curable stages. Annual repetition of CT screening is sufficient to minimize symptom-prompted interim diagnoses of nodule-associated malignancies.

Evaluation of screening for lung cancer depends on accurate pathologic diagnosis of the disease. The majority of CT-detected malignancies are peripheral adenocarcinomas; therefore, patient specimens include putative precursor lesions such as atypical adenomatous hyperplasia, solitary noninvasive, nonmucinous bronchioloalveolar adenocarcinomas (BAC), and small invasive adenocarcinomas. Although not all cytologists and surgical pathologists are familiar with the current 1999 World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC) classification of lung tumors, the diagnosis of lung cancer is made with a high degree of accuracy. Difficulties in diagnosis most often are related to tumor sampling, the size of the sample, and artifacts. A potential problem of CT screening for lung cancer is the detection, or overdiagnosis, of carcinomas that do not interfere with the life or outcome of the patient. The concept of overdiagnosis should not be confused with a false-positive diagnosis of lung cancer by pathologists as these are exceedingly rare. When they occur, false-positive diagnoses most frequently are in the setting of atypical hyperplasia associated with granulomatous inflammation, fibrous scars, and in reactive atypia after radiation and chemotherapy (Fig. 1) . 4 The WHO/IASLC recently has completed a new proposal for the histologic classification of lung tumors. 34 Two major changes are the addition of atypical adenomatous hyperplasia as a preinvasive lesion and a new definition of BAC that requires the tumor to have a purely lepidic pattern without invasive growth. These lesions are likely to be encountered in surgical specimens from patients who are found to have growing nodules on CT.

Lung tumors with neuroendocrine (NE) morphology constitute only 20% of lung malignancies, yet no other group of lung neoplasms has generated so much interest and conflicting opinions among pathologists over the past several decades. The classification of these tumors has evolved with our understanding of the human NE system. Diverse morphologic patterns, a never-ending variety of immunohistochemical markers demonstrating NE function, and molecular techniques have led to complex classification schemes and confusion among not only clinicians, tumor registries, and patients, but also among the surgical pathologists responsible for reproducible tumor diagnoses. For many years lung tumors with NE morphology were diagnosed as either bronchial carcinoid tumors or small cell carcinomas (SCLC). Since 1972, these lesions have been classified as low-grade, intermediate-grade, and high-grade carcinomas. 10 The recently published 1999 World Health Organization (WHO) Histological Typing of Lung and Pleural Tumors serves as an impetus to review our current understanding of pulmonary NE cells, present the current classification scheme, and explore some of the peculiarities of lung NE tumors. Neuroendocrine cells, also known as Kulchitsky's cells, were first recognized by Feyrter 14 in 1938 and referred to as epithelial clear cells as part of a "diffuse epithelial endocrine system." The ability of these cells to take up and decarboxylate amine precursors including 3,4-dihydroxyphenylalanine (l-dopa) and 5-hydroxytryptophan (serotonin) led to the term amine precursor uptake and decarboxylase cells , which were thought to be neural crest cells. 46 The currently accepted dispersed NE system theory postulates that NE cells in different sites of the body are linked by a common NE phenotype and that these cells originated from pluripotent cells that differentiated locally under the control of unique site or organ factors. These cells are postulated to be of three derivations: (1) neural crest derivatives, such as adrenal medulla, paraganglia, and melanocytes; (2) neural tube and ridge-derived cells, such as epiphyseal, hypophyseal, and hypothalamic cells; and (3) derivatives of the NE programmed ectoblast including the gastroenteropancreatic system and bronchopulmonary tree. 47 Frohlich 16 first described NE cells of the lung in 1949 and he postulated that the solitary and nodular cellular aggregates in the walls of bronchi had a chemoreceptive or neurosecretory function. The nonciliated basally located cylindrical cells with clear cytoplasm are individually scattered throughout the bronchi and bronchioles and when clustered in groups of 4 to 10 cells with neural attachments are known as neuroepithelial bodies . NE cells are not found along the alveolar septa. Serotonin immunoreactive pulmonary NE cells are first seen at 8 weeks of gestation, increase in density through embryonic and fetal life, and peak in density at term suggesting a role in pulmonary morphogenesis and maturation. 12 Pulmonary NE cell hyperplasia is seen in a variety of physiologic and pathologic states. Increased numbers and small clusters of pulmonary NE cells are seen in persons living at high altitude; in children with bronchopulmonary dysplasia, cystic fibrosis, and bronchiectasis; in cigarette smoke–associated adult pulmonary diseases, including lung cancer; and in patients with carcinoid tumors. 19,21,30 Increased concentrations of bombesin-like peptides in bronchoalveolar lavage fluid of cigarette smokers and nonsmokers with diffuse idiopathic NE cell hyperplasia with obliterating small airways disease have also been reported. 1,2,21 In 1954, Feyrter 15 suggested that bronchial carcinoid tumors arose from NE cells, and in the mid-1960s Bensch et al 5 and Gmelich et al 18 first described the ultrastructural appearance of NE cells and related these cells to bronchial carcinoid tumors and SCLC. Many now consider the NE cell to be the cell of origin for most NE tumors of the lung, 4,20 a concept that impacts not only on histogenesis but also on classification. One group of investigators describes dysplastic NE cells in the lungs of patients with pulmonary neoplasms and chronic bronchitis and bronchiectasis, 21 and larger aggregates of NE at least partially outside the confines of airway basement membrane are termed carcinoid tumorlets (Fig. 1). These possible precursor lesions usually are incidental lesions found in normal lung or in patients with lung cancer, carcinoid tumors, pulmonary fibrosis, and granulomatous nodules. 10 Rare lymph node metastases have been reported, sometimes in the setting of multiple tumorlets. 13 Interestingly, one recent study reported that almost one third of patients, predominantly women, with resected peripheral carcinoid tumors also had diffuse NE cell hyperplasia and obliterative bronchiolitis. 40 These findings support the association between tumorlets and carcinoid tumors and raise the possibility that the NE hyperplasia causes obliterative bronchiolitis, and not vice versa as previously believed. 40 Although tumorlets of macroscopic size and carcinoid tumor merge as a pathologic entity, 9,39 an arbitrary 0.5 cm cutoff is used by the WHO to distinguish between these entities. 66 It must be emphasized that despite early speculation that carcinoid tumorlets might represent early or in situ SCLC, 6,48 there is no established clinical or pathologic association between these lesions. The current WHO classification recognizes four distinct tumors with NE morphology among the nine major histologic types of malignant epithelial neoplasms 66 : Squamous cell carcinoma Small cell carcinoma Adenocarcinomas Large cell carcinoma Large cell neuroendocrine carcinoma Adenosquamous carcinoma Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements Carcinoid tumor Typical carcinoid tumor Atypical carcinoid tumor Carcinomas of salivary gland type Unclassified carcinoma Typical carcinoid tumor (TC) is a low-grade carcinoma; atypical carcinoid tumor (AC) is an intermediate-grade carcinoma; SCLC and large cell NE carcinoma (LCNEC) are considered high-grade carcinomas (Table 1). Although consideration was given to a conceptual grouping of tumors with NE morphology, differences in epidemiologic, clinical, and biologic characteristics argue against such a classification (Tables 2 and 3).

Background Exposure to environmental tobacco smoke (ETS) is considered to be a major lung cancer risk factor for never smokers. We investigated the hypothesis that never-smoking women who are exposed to ETS and develop lung cancer are a genetically susceptible population. Methods Archival tumor tissues were analyzed from 106 never-smoking women enrolled in a case-control study of ETS (and other personal and environmental factors) and lung cancer risk. We analyzed germline polymorphisms in genes that have been associated with cancer susceptibility and whose products activate (cytochrome P450 1A1 [CYP1A1]) and detoxify (glutathione S-transferases M1 [GSTM1] and T1 [GSTT1]) chemical carcinogens found in tobacco smoke. Results When compared with never smokers who had no ETS exposure and developed lung cancer (n = 55), never smokers with exposure to ETS who developed lung cancer (n = 51) were more likely to be deficient in GSTM1 activity (i.e., were GSTM1 null) because of a genetic polymorphism in the GSTM1 gene (odds ratio = 2.6; 95% confidence interval = 1.1-6.1). A statistically significant rising trend in risk occurred with increasing ETS exposure (two-sided P =. 02), reaching a more than sixfold excess risk in those exposed to 55 pack-years of ETS (ETS pack-year = ETS produced by an active smoker, within a confined space such as a room, who smokes one pack of cigarettes a day for a year). No evidence was found of associations between GSTT1 deficiency or the CYP1A1 valine variant and lung cancer risk due to ETS exposure. Conclusions A common genetic polymorphism divides the population of never smokers into two groups of approximately equal size, one (homozygous carriers of the GSTM1 null allele) that has a statistically significant greater risk of lung cancer from ETS than the other (heterozygous or homozygous carriers of the wild-type GSTM1 allele).

Forty-one cases of pulmonary dirofilariasis in 39 patients are presented. The patients, all Americans, were between 8 and 80 years old (median, 58 years), including 23 men and 16 women. Twenty-two patients were asymptomatic (56%), and the pulmonary nodule was discovered on chest radiographs during a routine physical examination. Seventeen patients (44%) presented with respiratory symptoms or systemic complaints. Peripheral eosinophilia was noted in only 10% of the patients. Radiographically, most lesions were located in the right lung (76%), with a predilection for the lower lobe. In five patients multifocal nodules were seen. All patients underwent thoracotomy with excisional lung biopsy or lobectomy. Pathologically, all cases featured a histiocyte-rimmed necrotic nodule containing fragments of a partially degenerated Dirofilaria immitis. In addition, adjacent lung parenchyma showed morphological features suggestive of other pulmonary processes such as extrinsic allergic alveolitis and/or pulmonary vasculitis syndromes. Three of the five patients with multiple nodules had solitary dirofilarial nodules and adjacent non-small cell carcinomas. The cases presented herein highlight the variable morphological features seen in human pulmonary dirofilariasis and emphasize the need to consider this diagnosis in all cases of necrotizing granulomas of the lung.