An in-silico analysis reveals further evidence of an aggressive subset of lung carcinoids sharing molecular features of high-grade neuroendocrine neoplasms.

Little is known as to whether there may be any pathogenetic link between pulmonary carcinoids and neuroendocrine carcinomas (NECs). A gene signature we previously found to cluster pulmonary carcinoids, large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), and which encompassed MEN1, MYC, MYCL1, RICTOR, RB1, SDHA, SRC and TP53 mutations or copy number variations (CNVs), was used to reclassify an independent cohort of 54 neuroendocrine neoplasms (NENs) [31 typical carcinoids (TC), 11 atypical carcinoids (AC) and 12 SCLC], by means of transcriptome and mutation data. Unsupervised clustering analysis identified two histology-independent clusters, namely CL1 and CL2, where 17/42 (40.5%) carcinoids and all the SCLC samples fell into the latter. CL2 carcinoids affected survival adversely, were enriched in T to G transversions or T > C/C > T transitions in the context of specific mutational signatures, presented with at least 1.5-fold change (FC) increase of gene mutations including TSC2, SMARCA2, SMARCA4, ERBB4 and PTPRZ1, differed for gene expression and showed epigenetic changes in charge of MYC and MTORC1 pathways, cellular senescence, inflammation, high-plasticity cell state and immune system exhaustion. Similar results were also found in two other independent validation sets comprising 101 lung NENs (24 carcinoids, 21 SCLC and 56 LCNEC) and 30 carcinoids, respectively. We herein confirmed an unexpected sharing of molecular traits along the spectrum of lung NENs, with a subset of genomically distinct aggressive carcinoids sharing molecular features of high-grade neuroendocrine neoplasms.

Recent advances and current controversies in lung neuroendocrine neoplasms✰.

In the lung, neuroendocrine tumors (NETs), namely typical and atypical carcinoids, and neuroendocrine carcinomas (NECs), grouping small cell carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC), make up for distinct tumor entities according to epidemiological, genetic, pathologic and clinical data. The proper classification is essential in clinical practice for diagnosis, prognosis and therapy purposes. Through an extensive literature survey, three perspectives on lung NENs have been revised: i) criteria and terminology on biopsy or cytology samples of primaries or metastases; ii) carcinoids with elevated mitotic counts and/or Ki-67 proliferation rates; iii) relevance of molecular landscape to identify new tumor entities and therapeutic targets. Furthermore, a dispute about lung NEN development has been raised according to emerging molecular models. We herein provide a pathology update on practical topics in the setting of lung NENs according to the current classification (recent advances). We have also reappraised the development of these tumors by modeling risk factors and natural history of disease (recent controversies). Combining recent advances and controversies may help clarify our biological understanding of lung NENs and give practical information for the clinical decision-making process.

SDHx and Non-Chromaffin Tumors: A Mediastinal Germ Cell Tumor Occurring in a Young Man with Germline SDHB Mutation.

Background: Mutations in genes encoding one of the subunits of succinate dehydrogenase (SDH) are involved in pheochromocytoma (PHEO) and paraganglioma (PGL) development. Over the last few years, such mutations have also been associated with non-chromaffin tumors. However, immunohistochemistry (IHC) on the tumor tissue and a study on the loss of heterozygosity (LOH) aimed at demonstrating the pathogenic role of SDHx genes have only been employed in a few cases. Case report: We describe the case of a 19-year-old Caucasian man with a germline SDHB mutation, who presented with acne vulgaris resistant to medical treatment. His follow-up for chromaffin tumors was negative, while hormonal tests revealed suppressed gonadotropins with testosterone in the upper range of normality and elevated ß-human chorionic gonadotropin (ß-hCG). At the whole-body enhanced CT scan, a mediastinal lesion suggestive of a germ cell tumor (GCT) was detected. 18FDG-PET (fluorodeoxyglucose-positron emission tomography) imaging showed low glucose metabolism at the mediastinal site. Surgical removal of the mass was uneventful. Pathology confirmed the diagnosis of GCT consisting of cystic teratoma (95%) and seminoma (5%). IHC for SDHB showed normal protein expression, and genetic analysis of the tumor tissue revealed the absence of SDHB LOH. Normalization of the hormonal tests and acne attenuation were achieved after surgery. Conclusion: We report an incidental association of a germinal SDHB mutation and mediastinal GCT in a young Caucasian man. Our paper highlights the importance of IHC and genetic analysis in confirming the etiologic role of SDHx genes in nonchromaffin tumors, thus excluding incidental associations.

Oxaliplatin-Based Chemotherapy in Advanced Neuroendocrine Tumors: Clinical Outcomes and Preliminary Correlation with Biological Factors.

PURPOSE: The role of chemotherapy in low-/intermediate-grade neuroendocrine tumors (NETs) is still debated. We present the results of an Italian multicenter retrospective study evaluating activity and toxicity of oxaliplatin-based chemotherapy in patients with advanced NETs. METHODS: Clinical records from 5 referral centers were reviewed. Disease control rate (DCR) corresponding to PR + SD (partial response + stable disease) at 6 months, progression-free survival (PFS), overall survival (OS) and toxicity were calculated. Ki67 labeling index, grade of differentiation and excision- repair-cross-complementing group 1 (ERCC-1) were analyzed in tissue tumor samples. RESULTS: Seventy-eight patients entered the study. Primary sites were: pancreas in 46, gastrointestinal in 24, lung in 19 and unknown in 10% of patients. The vast majority were G2 (2010 WHO classification). Eighty-six percent of the patients were metastatic, and 87% were pretreated and progressive to previous therapies. Sixty-five percent of the patients received capecitabine/oxaliplatin (CAPOX), 6% gemcitabine/oxaliplatin (GEMOX), and 29% leucovorin/fluorouracil/oxaliplatin (FOLFOX-6). PR occurred in 26% of the patients, half of them with pancreatic NETs, and SD in 54%. With a median follow-up of 21 months, the median PFS and OS were 8 and 32 months with 70 and 45 events, respectively. The most frequent G3 toxicities were neurological and gastrointestinal. ERCC-1 immunohistochemical overexpression was positive in 4/28 evaluated samples, with no significant correlation with clinical outcome. CONCLUSION: This analysis suggests that oxaliplatin-based chemotherapy can be active with a manageable safety profile in advanced NETs irrespective of the primary sites and tumor grade. The 80% DCR and 8-month PFS could justify a prospective study in NETs with intermediate biological characteristics, especially with pancreatic primary tumors.

Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a cytokine with pleiotropic functions in the immune system. It has been associated with allergic reactions in the skin and lungs but also homeostatic tolerogenic responses in the thymus and gut. OBJECTIVE: In human subjects TSLP is present in 2 isoforms, short and long. Here we wanted to investigate the differential expression of the TSLP isoforms and discern their biological implications under homeostatic or inflammatory conditions. METHODS: We evaluated the expression of TSLPs in tissues from healthy subjects, patients with ulcerative colitis, patients with celiac disease, and patients with atopic dermatitis and on epithelial cells and keratinocytes under steady-state conditions or after stimulation. We then tested the immune activity of TSLP isoforms both in vitro and in vivo. RESULTS: We showed that TSLP isoforms are responsible for 2 opposite immune functions. The short isoform is expressed under steady-state conditions and exerts anti-inflammatory activities by affecting the capacity of PBMCs and dendritic cells to produce inflammatory cytokines. Moreover, the short isoform TSLP ameliorates experimental colitis in mice and prevents endotoxin shock. The long isoform of TSLP is proinflammatory and is only expressed during inflammation. The isoforms are differentially regulated by pathogenic bacteria, such as Salmonella species and adhesive-invasive Escherichia coli. CONCLUSIONS: We have solved the dilemma of TSLP being both homeostatic and inflammatory. The TSLP isoform ratio is altered during several inflammatory disorders, with strong implications in disease treatment and prevention. Indeed, targeting of the long isoform of TSLP at the C-terminal portion, which is common to both isoforms, might lead to unwanted side effects caused by neutralization of the homeostatic short isoform.

What clinicians are asking pathologists when dealing with lung neuroendocrine neoplasms?

Lung neuroendocrine tumors (NET) are currently classified in resection specimens according to four histological categories, namely typical carcinoid (TC), atypical carcinoid (AC), large-cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCC). Diagnostic criteria have remained unchanged in the 2015 WHO classification, which has ratified the wide acceptance and popularity of such terminology in the pathologists׳ and clinicians׳ community. A unifying umbrella of NE morphology and differentiation has been recognized in lung NET, which has pushed to enter an unique box of invasive tumors along with diffuse idiopathic pulmonary NE cell hyperplasia (DIPNECH) as a pre-invasive lesion with a potential toward the development of carcinoids. However, uncertainties remain in the terminology of lung NET upon small samples, where Ki-67 antigen could play some role to avoid misdiagnosing carcinoids as high-grade NE tumors. Epidemiologic, clinical and genetic traits support a biological three-tier over a pathology four-tier model, according to which TC are low malignancy tumors, AC intermediate malignancy tumors and LCNEC/SCC high malignancy tumors with no significant differences in survival among them. Inconsistencies in diagnostic reproducibility, troubles in the therapy of AC and LCNEC, and limitations to histology within the same tumor category argue in favor of a global re-thinking of lung NET where a grading system could play a role. This review outlines three main key questions in the field of lung NET: (A) unbiased diagnoses, (B) the role of Ki-67 and tumor grading, and (C) management of predictive markers. Answers are still inconclusive, thus additional research is required to improve our understanding on lung NET.

Impact of robotic surgery on sexual and urinary functions after fully robotic nerve-sparing total mesorectal excision for rectal cancer.

BACKGROUND: Urinary and sexual dysfunctions are recognized complications of rectal cancer surgery. Their incidence after robotic surgery is as yet unknown. The aim of this study was to prospectively evaluate the impact of robotic surgery for rectal cancer on sexual and urinary functions in male and female patients. METHODS AND PROCEDURES: From April 2008 to December 2010, 74 patients undergoing fully robotic resection for rectal cancer were prospectively included in the study. Urinary and sexual dysfunctions affecting quality of life were assessed with specific self-administered questionnaires in all patients undergoing robotic total mesorectal excision (RTME). Results were calculated with validated scoring systems and statistically analyzed. RESULTS: The analyses of the questionnaires completed by the 74 patients who underwent RTME showed that sexual function and general sexual satisfaction decreased significantly 1 month after intervention: 19.1 ± 8.7 versus 11.9 ± 10.2 (P < 0.05) for erectile function and 6.9 ± 2.4 versus 5.3 ± 2.5 (P < 0.05) for general satisfaction in men; 2.6 ± 3.3 versus 0.8 ± 1.4 (P < 0.05) and 2.4 ± 2.5 versus 0.7 ± 1.6 (P < 0.05) for arousal and general satisfaction, respectively, in women. Subsequently, both parameters increased progressively, and 1 year after surgery, the values were comparable to those measured before surgery. Concerning urinary function, the grade of incontinence measured 1 year after the intervention was unchanged for both sexes. CONCLUSIONS: RTME allows for preservation of urinary and sexual functions. This is probably due to the superior movements of the wristed instruments that facilitate fine dissection, coupled with a stable and magnified view that helps in recognizing the inferior hypogastric plexus.

Factors predicting worse prognosis in patients affected by pT3 N0 colon cancer: long-term results of a monocentric series of 137 radically resected patients in a 5-year period.

BACKGROUND AND PURPOSE: For patients with Stage II colon cancer, the use of adjuvant chemotherapy remains controversial. The purpose of this study was to identify clinical and/or pathological findings related to a worse prognosis in this category of patients. PATIENTS AND METHODS: We retrospectively analyzed the data of consecutive patients, extracted by an institutional Tumour Registry, admitted to an affiliated University Hospital in Milan (European Institute of Oncology) for adenocarcinoma of the colon (all sites), between 2000 and 2005, and having a final pT3 N0 pathology staging after curative surgery. Adjuvant chemotherapy was decided as a result of a medical decision within a multidisciplinary Tumor Board. RESULTS: Data of 137 patients were obtained, with a median follow-up of 77 months (range 6-131). Patients who received chemotherapy were younger than patients who did not. Nine patients out of 137 (6.5 %) died as a consequence of colon cancer recurrence; four of them had received adjuvant chemotherapy. Only histological grade III and mucinous histotype were found to impact on cumulative incidence of colon-related events (p 0.03 and 0.02, respectively); no impact was found on cumulative incidence of colonic neoplasm recurrence-related deaths (p 0.74 and 0.74, respectively). Number of analyzed LNs (lymph nodes) emerged as a factor possibly affecting the cumulative incidence of colon-related events (p 0.09) as well as the cumulative incidence of colonic neoplasm recurrence-related deaths (p 0.10). The risk of events was inversely proportional to the number of dissected LNs, even over 20 up to about 25 LNs. Never-smokers exhibited a lower incidence of colon-related events, although the difference was not statistically significant (p 0.09). All other analyzed variables did not show any impact on survival rate, including age, gender, ASA score, BMI, site of colonic neoplasm, multifocality, perivascular invasion, and use of adjuvant chemotherapy. CONCLUSIONS: Histology grading G3 and mucinous histotype were predictors of worse outcome. Efforts to improve LN evaluation should result in clinically significant improvements in outcome, and also the quality of care for patients with radically resected stage II colon cancer.

Probiotic and postbiotic activity in health and disease: comparison on a novel polarised ex-vivo organ culture model.

BACKGROUND AND AIMS: Probiotics and their metabolic products, here called postbiotics, have been proposed as food supplements for a healthier intestinal homeostasis, but also as therapeutic aids in inflammatory bowel disease (IBD) with, however, very little clinical benefit. This may be due to the lack of reliable preclinical models for testing the efficacy of different strains. METHODS: The activity of three probiotic strains of Lactobacillus (or a postbiotic) was analysed and compared with a pathogenic strain of Salmonella on a novel organ culture system of human healthy and IBD intestinal mucosa developed in our laboratory. The system maintains an apical to basolateral polarity during stimulation due to the presence of a glued cave cylinder. The cylinder is detached at the end of the experiment and the tissue is processed for histology and immunohistochemistry. Cytokines released from the basolateral side are analysed. RESULTS: The model system provides several physiological characteristics typical of a mucosal microenvironment including the presence of an organised mucus layer and an apical to basolateral polarity. Polarised administration of bacteria is critical to control the ensuing immune response as it mimics the physiological entrance of bacteria. The authors show that probiotics are not always beneficial for the healthy host and can also be detrimental in inflamed IBD. This study shows that a potent postbiotic can protect against the inflammatory properties of invasive Salmonella on healthy tissue and also downregulate ongoing inflammatory processes in IBD tissue. CONCLUSIONS: Probiotics can have inflammatory activities in both healthy and IBD tissue. Valid preclinical data on proper model systems should therefore be obtained before specific probiotic strains enter the clinics, especially if administered during acute inflammatory responses. Postbiotics may be a safe alternative for the treatment of patients with IBD in the acute inflammatory phase.

Can we avoid axillary dissection in the micrometastatic sentinel node in breast cancer?

There is considerable interest in foregoing axillary dissection (AD) when the sentinel node (SN) is positive in early breast cancer, particularly when involvement is minimal (micrometastases or isolated tumor cells). To address this issue we analyzed outcomes in patients with a single micrometastatic SN who did not receive AD. We selected 377 consecutive patients treated at the European Institute of Oncology between 1999 and 2007 for invasive breast cancer. Classical and competing risks survival analyses were performed to estimate prognostic factors for axillary recurrence, first events and overall survival. Median age was 53 years (range 26-80); median follow-up was 5 years (range 1-9). Most (91.8%) patients received conservative surgery; 209 (55.4%) had only one SN (range 1-8). Five-year overall survival was 97.3%. There were 10 local events, 2 simultaneous local and axillary events, 6 axillary recurrences and 12 distant events. The cumulative incidence of axillary recurrence was 1.6% (95% CI 0.7-3.3). By multivariable analysis, tumor size and grade were significantly associated with axillary recurrence. The high five-year survival and low cumulative incidence of axillary recurrence in this cohort provide justification for the increasingly common practice of foregoing AD in women with minimal SN involvement, and suggest in particular that AD can safely be avoided in women with small, low-grade tumors. Nevertheless, a subset of patients might be at high risk of developing overt axillary disease and efforts should be made to identify such patients by ancillary analyses of the results of ongoing or recently published clinical trials.

A Subset of Large Cell Neuroendocrine Carcinomas in the Gastroenteropancreatic Tract May Evolve from Pre-existing Well-Differentiated Neuroendocrine Tumors.

In the gastro-entero-pancreatic (GEP) tract, neuroendocrine neoplasms (NENs) include well differentiated neuroendocrine tumors (NETs) and high-grade NE carcinomas (NECs), which are thought to make up separate and mutually exclusive tumor entities. Little is known, however, as to whether there may be any pathogenetic link between them. Clustering analysis of a 10-gene panel generated from a previously reported next-generation sequencing analysis on 48 GEP-NENs with clinical annotations was used in the study. Unsupervised cluster analysis showed three histology-independent clusters, namely, C1, C2, and C3, which accounted for 44% of patients but the entire array of mutations. All but two NECs fell into the clusters, yet with different prevalence rates (p < 0.0001). A model was devised according to which NETs were likely to evolve into NECs upon progression of C3 into C1 and C2, despite different morphology. The median Ki-67 labeling index was 5% in C3 showing better prognosis and 50% in C1 and C2 experiencing worse prognosis, with an impressive intra-tumor heterogeneity of diversely proliferating tumor areas. This study suggests that a subset of large cell NECs in the gastroenteropancreatic tract may evolve from pre-existing well-differentiated NETs.

Clinical implications of lung neuroendocrine neoplasm classification.

INTRODUCTION: Neuroendocrine neoplasms of the lung (Lung NENs) encompass NE tumors (NETs), which are in turn split into typical and atypical carcinoids, and NE carcinomas (NECs), which group together small-cell carcinoma and large-cell NE carcinoma. This classification is the current basis for orienting the daily practice of these patients, with diagnostic, prognostic, and predictive inferences. AREAS COVERED: The clinical implications of lung NEN classification are addressed according to three converging perspectives, which were dissected through an extensive literature overview: (1) how to put intratumor heterogeneity into the context of the current classification; (2) how to contextualize immunohistochemistry markers to improve diagnosis, prognosis, and therapy prediction; and (3) how to use immuno-oncology strategies for life-threatening NECs, which still account for 90% or more of lung NENs. EXPERT OPINION: We provide practical insights to account for intratumor heterogeneity, practice the choice of immunohistochemistry markers, and emphasize once again the added value of immuno-oncology in the setting of personalized medicine of lung NENs.

Morphologic and molecular classification of lung neuroendocrine neoplasms.

Neuroendocrine neoplasms (NENs) of the lung encompass neuroendocrine tumors (NETs) composed of typical (TC) and atypical (AC) carcinoids and full-fledged carcinomas (NECs) inclusive of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). NETs and NECs are thought to represent distinct and separate lesions with neither molecular overlap nor common developmental continuum. Two perspectives were addressed regarding the morphologic and molecular classification of lung NENs: (i) a supervised approach by browsing the traditional classification, the relevant gene alterations, and their clinical implications; and (ii) an unsupervised approach, by reappraising neoplasms according to risk factors and natural history of disease to construct an interpretation model relied on biological data. We herein emphasize lights and shadows of the current classification of lung NENs and provide an alternative outlook on these tumors focused on what we currently know about the biological determinants and the natural history of disease.

Full robotic left colon and rectal cancer resection: technique and early outcome.

OBJECTIVE: The technique for robotic resection of the left colon and anterior resection of the rectum with total mesorectal excision is not well defined. In this study we describe a method that standardizes robot and trocar position, and allows for a complete mobilization of the left colon and the rectum, without repositioning of the surgical cart. Outcome and pathology findings are also reported. METHODS: From January 2007 to May 2008 a total of 55 consecutive patients affected by rectal and left colon cancer were operated on, with full robotic technique, using the Da Vinci robot. Data regarding outcome and pathology reports were prospectively collected in a dedicated database. RESULTS: The following procedures were performed 27 left colectomies, 17 anterior resections, 4 intersphincteric resections, 7 abdominoperineal resections. There were 21 female and 34 male patients with a mean age of 63 +/- 9.9 years. Mean operative time was 290 +/- 69 minutes, ranging from 164 to 487 min., none were converted to open surgery. The median number of lymph nodes harvested was 18.5 +/- 8.3 (range 5-45), and circumferential margin was negative in all cases. Distal margin was 25.15 +/- 12.9 mm (range 6-55) for patients with rectal cancer, and 31.6 +/- 20 mm for all the patients in this series. Anastomotic leak rate was 12.7% (7/55); in all cases conservative treatment was successful. CONCLUSIONS: Full robotic colorectal surgery is a safe and effective technique that exploits the advantages of the Da Vinci robot during the whole intervention, without the need to make use of hybrid operations. Outcome and pathology findings are comparable with those observed in open and laparoscopy procedures.

Gastrointestinal basidiobolomycosis: An emerging mycosis difficult to diagnose but curable. Case report and review of the literature.

BACKGROUND: Gastrointestinal basidiobolomycosis (GIB) is a rare mycosis affecting almost exclusively immunocompetent subjects. METHODS: We describe a case of GIB caused by Basidiobolus ranarum in a 25-year-old Italian immunocompetent man resident in Ireland who presented a 2-month history of epigastric pain. Suspecting colon cancer he underwent a right hemicolectomy subsequently leading to a diagnosis of GIB by means of molecular biology. After surgery a 9-month therapy with itraconazole was employed with a good outcome. A review of medical literature regarding GIB cases published in the period 1964-2017 is presented. RESULTS: One-hundred and two cases of GIB were included in this analysis. The disease was observed predominantly in male gender (74.5%) and children (41.2%). Abdominal pain was the single most common complaint (86.3%) followed by fever (40.2%) and evidence of an abdominal mass (30.4%). Peripheral blood eosinophilia was detected in 85.7% of cases. Most of the patients were diagnosed in Saudi Arabia (37.2%) followed by USA (21.6%) and Iran (20.6%). Surgery plus antifungal therapy was employed in the majority of patients (77.5%). An unfavourable outcome was documented globally in 18.6% of patients. CONCLUSIONS: GIB seems to be an emerging intestinal mycosis among immunocompetent patients living in the Middle East and Arizona.

Ki-67 Evaluation for Clinical Decision in Metastatic Lung Carcinoids: A Proof of Concept.

Accrual of metastatic pulmonary carcinoid patients for therapy is usually relied on clinical and histologic characterization, with no role for the proliferation activity as defined by Ki-67 labelling index (LI). A total of 14 carcinoid patients with tumour primaries (TP) and 19 corresponding tumour metastases (TM) were blindly reviewed by 2 different pathologists for necrosis, mitotic count, and Ki-67 LI. Ki-67 LI outperformed histologic subtyping, mitotic count, and necrosis with good to almost excellent (0.40-0.75) inter-observer agreement. About 10% cut-off Ki-67 LI predicted survival better than histology for TP and TM for both observers. The TM patients survived differently according to diverse treatments (somatostatin analogues [SSAs], analogues plus additional treatments except for platinum; platinum-based chemotherapy) in close correlation with <10%, 10% to 20%, and >20% cut-off thresholds of Ki-67 LI, respectively. There was also a trend for an increase in Ki-67 LI in TM as compared with TP. This is the first proof of concept in which a clinical potential is preliminarily suggested for Ki-67 LI to better stratify pulmonary metastatic carcinoid patients for treatment according to a criterion of histology-independent biological aggressiveness.

Recent advances in the molecular landscape of lung neuroendocrine tumors.

INTRODUCTION: Neuroendocrine tumors of the lung (Lung-NETs) make up a heterogenous family of neoplasms showing neuroendocrine differentiation and encompass carcinoids and neuroendocrine carcinomas. On molecular grounds, they considered two completely distinct and separate tumor groups with no overlap of molecular alterations nor common developmental mechanisms. Areas covered: Two perspectives were evaluated based on an extensive review and rethinking of literature: (1) the current classification as an instrument to obtaining clinical and molecular insights into the context of Lung-NETs; and (2) an alternative and innovative interpretation of these tumors, proposing a tripartite separation into early aggressive primary high-grade neuroendocrine tumors (HGNET), differentiating or secondary HGNET, and indolent NET. Expert opinion: We herein provide an alternative outlook on Lung-NETs, which is a paradigm shift to current pathogenesis models and expands the understanding of these tumors.

Pathologic and molecular features of screening low-dose computed tomography (LDCT)-detected lung cancer: a baseline and 2-year repeat study.

Detailed studies on the pathologic and molecular features of low-dose computed tomography (LDCT)-detected carcinomas and comparison with unscreened tumors are still lacking. We evaluated the histopathologic features of 89 LDCT-detected lung cancers resected between 2004 and 2006. These tumors occurred within a cohort of 5202 volunteers undergoing annual LDCT, aged > or =50 years, and with a minimum 20 pack-year index. In adenocarcinomas, central scar diameter, invasion foci size and K-ras mutations were also assessed. The results were compared with those of 89 consecutive lung carcinomas matched for confounding factors (sex, smoking habit), selected from group of 363 consecutive clinically worked-up lung cancer, surgically resected in the same period and at the same Institution. The tumors were diagnosed in 63 males and 26 females (range 50-79 years), 55 of which diagnosed at the baseline (1.05%) and 34 (including 10 repeat cancers) operated after work-up during the second year (0.72%). LDCT-detected tumors showed high resectability rate (89%), earlier stage (63%) and prevalence of adenocarcinoma nodules (72%), most often of the mixed subtype, in comparison with unscreened tumors. A similar prevalence of K-ras mutations was found in both screened and unscreened adenocarcinomas. Repeat cancers were found in 10 screened patients, and were predominantly stage I adenocarcinomas of mixed subtype exhibiting smaller dimension but greater central scar diameter and stromal invasion size in comparison with the other second-year, slower-growing adenocarcinomas. Multiple tumor nodules were identified in 10 patients exclusively at the baseline, were mostly mixed adenocarcinomas and differed in their K-ras mutation profile. Screening-detected lung cancers shared most of the histologic features of fully malignant tumors, in addition to a similar prevalence of K-ras mutations, despite their earlier detection and less advanced clinical stage. Repeat cancers are potentially aggressive tumors. K-ras mutation analysis supports the impression that multifocal tumors at baseline are separate synchronous primaries.