Surgery for pre- and minimally invasive lung adenocarcinoma.

OBJECTIVE: Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are the pre- and minimally invasive forms of lung adenocarcinoma. We aimed to investigate safety results and survival outcomes following different types of surgical resection in a large sample of patients with AIS/MIA. METHODS: Medical records of patients with lung AIS/MIA who underwent surgery between 2012 and 2017 were retrospectively reviewed. Clinical characteristics, surgical types and complications, recurrence-free survival, and overall survival were investigated. RESULTS: A total of 1644 patients (422 AIS and 1222 MIA) were included. The overall surgical complication rate was significantly lower in patients receiving wedge resection (1.0%), and was comparable between patients undergoing segmentectomy (3.3%) or lobectomy (5.6%). Grade ≥ 3 complications occurred in 0.1% of patients in the wedge resection group, and in a comparable proportion of patients in the segmentectomy group (1.5%) and the lobectomy group (1.5%). There was no lymph node metastasis. The 5-year recurrence-free survival rate was 100%. The 5-year overall survival rate in the entire cohort was 98.8%, and was comparable among the wedge resection group (98.8%), the segmentectomy group (98.2%), and the lobectomy group (99.4%). CONCLUSIONS: Sublobar resection, especially wedge resection without lymph node dissection, may be the preferred surgical procedure for patients with AIS/MIA. If there are no risk factors, postoperative follow-up intervals may be extended. These implications should be validated in further studies.

Pulmonary Adenocarcinomas of Low Malignant Potential: Proposed Criteria to Expand the Spectrum Beyond Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma.

Lung cancer screening has improved mortality among high-risk smokers but has coincidentally detected a fraction of nonprogressive adenocarcinoma historically classified as bronchoalveolar carcinoma (BAC). In the National Lung Screening Trial (NLST) the majority of BAC-comprising 29% of computed tomography-detected stage I lung adenocarcinoma-were considered overdiagnosis after extended follow-up comparison with the control arm. In the current classification, adenocarcinoma in situ and minimally invasive adenocarcinoma have replaced BAC but together comprise only ∼5% of stage I lung adenocarcinoma. Lepidic and subsets of papillary and acinar adenocarcinoma also infrequently recur. We, therefore, propose criteria for low malignant potential (LMP) adenocarcinoma among nonmucinous adenocarcinoma measuring ≤3 cm in total, exhibiting ≥15% lepidic growth, and lacking nonpredominant high-grade patterns (≥10% cribriform, ≥5% micropapillary, ≥5% solid), >1 mitosis per 2 mm2, angiolymphatic or visceral pleural invasion, spread through air spaces or necrosis. We tested these criteria in a multi-institutional cohort of 328 invasive stage I (eighth edition) and in situ adenocarcinomas and observed 16% LMP and 7% adenocarcinoma in situ/minimally invasive adenocarcinoma which together (23%) approximated the frequency of overdiagnosed stage I BAC in the NLST. The LMP group had 100% disease-specific survival. The proposed LMP criteria, incorporating multiple histologic parameters, may be a clinically useful "low-grade" prognostic group. Validation of these criteria in additional retrospective cohorts and prospective screen-detected cohorts should be considered.

An experimental protocol for in situ colorectal liver metastases ablation by radiofrequency toward a standard procedure.

BACKGROUND: Radiofrequency ablation (RF) is already a viable alternative to surgical resection for focal liver tumors treatment. The use of RF ablation in combination with surgery or chemotherapy and the large panel of RF tools need new experimental models to develop new opportunities for this kind of therapy. PURPOSE: The purpose of this study was to identify the optimal RF parameters that will allow in situ colic cancer liver metastases destruction with minimal secondary effects. MATERIALS AND METHODS: The CC531s colic cancer tumor cells were used to induce liver metastases in 30 synergic Wag/Rij rats. When metastases reached at least 1 cm in diameter, RF generator RITA 1500X, and expandable tip RF probe Starburst SDE (Angiodynamics, USA) was used for the RF ablation. The animal survival rate and the RF-induced lesions have been studied, while only the generator delivered power has been modified (90W, 20W, and 10W, respectively). RESULTS: Survival was significantly low in the group with 90W-delivered power RF. Moreover, statistically significant differences were revealed between groups with high and low RF power, regarding the morphological changes of the liver parenchyma and the adjacent organs, without significant difference on the RF therapeutically effect. CONCLUSIONS: In an experimental setting, an increased RF generator power induces important lesions of the abdominal organs with subsequently important mortality rate, without improving the RF therapeutic efficiency.

Risk of persistent or recurrent cervical neoplasia in patients with 'pure' adenocarcinoma-in-situ (AIS) or mixed AIS and high-grade cervical squamous neoplasia (cervical intra-epithelial neoplasia grades 2 and 3 (CIN 2/3)): a population-based study.

OBJECTIVE: To compare outcomes of patients with pure adenocarcinoma-in-situ (AIS) and mixed AIS/CIN 2/3 lesions including the incidence of AIS persistence, recurrence and progression to adenocarcinoma. DESIGN: Retrospective cohort study. SETTING: Statewide population in Western Australia. POPULATION: Women diagnosed with AIS between 2001 and 2012. METHODS: We conducted a retrospective, population-based cohort study. MAIN OUTCOME MEASURES: De-identified linked data were utilised to ascertain the association between patient age at excisional treatment, margin status, lesion type, lesion size, and risk of persistent AIS (defined as the presence of AIS <12 months from treatment), recurrent AIS (≥12 months post-treatment), and adenocarcinoma. RESULTS: 636 patients were eligible for analysis. The mean age was 32.3 years and median follow-up interval was 2.5 years. Within the study cohort, 266 patients (41.8%) had pure AIS and 370 (58.2%) had mixed AIS/CIN 2/3. Overall, 47 patients (7.4%) had AIS persistence/recurrence and 12 (1.9%) had adenocarcinoma. Factors associated with persistence/recurrence were pure AIS (hazard ratio (HR) 2.3; 95%CI 1.28-3.94; P = 0.005), age >30 years (HR 2.1; 95%CI 1.16-3.81; P = 0.015), positive endocervical margins (HR 5.8; 95%CI 3.05-10.92; P = <0.001) and AIS lesions >8 mm (HR 2.5; 95%CI 1.00-6.20; P = 0.049). A histologically positive AIS ectocervical margin was not associated with persistence/recurrence. CONCLUSION: In this study, pure AIS was associated with greater risk of persistence/recurrence than was mixed AIS/CIN 2/3. AIS lesions >8 mm and positive endocervical margins were significant predictors for persistent or recurrent disease. TWEETABLE ABSTRACT: Pure cervical adenocarcinoma-in-situ (AIS) may have greater risk of recurrence than AIS co-existing with CIN 2/3.

Reported Incidence and Survival of Fallopian Tube Carcinomas: A Population-Based Analysis From the North American Association of Central Cancer Registries.

Background: Recognition that serous tubal intraepithelial carcinoma (STIC) may represent the first manifestation of many high-grade cancers that were once considered ovarian primary tumors has led to changes in diagnostic practices that could dramatically increase the reporting of tubal carcinomas in US population-based cancer registries. Further, increased detection of early-stage tubal carcinomas through increased recognition coupled with meticulous pathology processing protocols raises important unanswered questions about the clinical behavior of such lesions, which can only be answered using large data sets. However, rates of tubal carcinomas have not been recently analyzed. Accordingly, we analyzed population-based incidence and survival data for fallopian tube carcinoma in situ (CIS; an imperfect surrogate of STIC), tubal carcinomas, and for comparison, ovarian carcinomas, in the North American Association of Central Cancer Registries (NAACCR) registries. Methods: Total counts, standardized incidence rates, and stage-specific survival were computed using 30 NAACCR registries (1999-2012). Temporal incidence rate patterns were analyzed by joinpoint regression with estimates of annual percentage change (APC). All statistical tests were two-sided. Results: Fallopian tube CIS incidence rates were stable from 1999 to 2002, then increased from 2002 to 2012 (APC = 16.2%, 95% confidence interval [CI] = 10.9% to 21.7%, P < .001). Rates of early- and late-stage tubal carcinomas showed similar patterns, whereas high-grade serous ovarian carcinoma rates were relatively stable. Five-year cause-specific survival was 97.9% (95% CI = 93.7% to 99.3%) for tubal CIS and 83.2% (95% CI = 77.3% to 87.7%) for early-stage high-grade serous tubal carcinoma. Conclusions: Reporting of tubal CIS and tubal carcinoma have increased in recent years, likely reflecting changes in pathology processing of specimens and diagnosis. Developing standardized reporting for tubal neoplasms is needed to enable analysis of outcomes for these comparatively uncommon but increasingly recognized tumors.

Prognostic considerations of the new World Health Organization classification of lung adenocarcinoma.

The 2015 World Health Organization (WHO) lung adenocarcinoma classification divides tumours into categories of indolent pre-invasive, minimally invasive and predominantly lepidic and, by examining predominant patterns of invasion, allows for further stratification into intermediate and high-grade tumours. The impact of the 2015 classification on prognosis was reviewed by a PubMed search for search terms "adenocarcinoma", "lung pathology" and "prognosis" and relevant publications reviewed. These were sorted for data on stage and survival as impacted by histological classification, and survival studies were separated into all stage versus stage 1 studies. Predictive aspects of histological classification were also examined, but molecular correlates were not. The separation of adenocarcinoma in situ and minimally invasive adenocarcinoma from invasive subtypes as distinct prognostic entities and the prognostic significance, for disease specific and overall survival for low- and high-grade categories, are discussed. The impact on stage at presentation including risk of node metastasis by histology is examined, as well as histology in relation to recurrence after surgery. Early data with regard to the value of predominant histology in the prediction of chemotherapy response will also be explored.

Comparing treatment and outcomes of ductal carcinoma in situ among women in Missouri by race.

PURPOSE: To investigate whether treatment (surgery, radiation therapy, and endocrine therapy) contributes to racial disparities in outcomes of ductal carcinoma in situ (DCIS). PATIENTS AND METHODS: The analysis included 8184 non-Hispanic White and 954 non-Hispanic Black women diagnosed with DCIS between 1996 and 2011 and identified in the Missouri Cancer Registry. Logistic regression models were used to estimate odds ratios (ORs) of treatment for race. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) of ipsilateral breast tumor (IBT) and contralateral breast tumor (CBT) for race. RESULTS: There was no significant difference between Black and White women in utilization of mastectomy (OR 1.16; 95 % CI 0.99-1.35) or endocrine therapy (OR 1.19; 95 % CI 0.94-1.51). Despite no significant difference in underutilization of radiation therapy (OR 1.14; 95 % CI 0.92-1.42), Black women had higher odds of radiation delay, defined as at least 8 weeks between surgery and radiation (OR 1.92; 95 % CI 1.55-2.37). Among 9138 patients, 184 had IBTs and 326 had CBTs. Black women had a higher risk of IBTs (HR 1.69; 95 % CI 1.15-2.50) and a comparable risk of CBTs (HR 1.19; 95 % CI 0.84-1.68), which were independent of pathological features and treatment. CONCLUSION: Racial differences in DCIS treatment and outcomes exist in Missouri. This study could not completely explain the higher risk of IBTs in Black women. Future studies should identify differences in timely initiation and completion of treatment, which may contribute to the racial difference in IBTs after DCIS.

Early mortality in lung cancer: French prospective multicentre observational study.

BACKGROUND: Despite the progress seen in the last decade in diagnosis and treatment, lung cancer has still a bad prognosis and a substantial number of patients died within the weeks following diagnosis. The objective of this study was to quantify early mortality in lung cancer, to identify patients who are at high risk of early decease, and to describe their management in a real world. METHODS: Prospective observational study including consecutively all adult patients managed for primary lung cancer histologically or cytologically diagnosed in 2010 in the respiratory medicine department of one of the participating French general hospitals. Patients and cancer characteristics and first therapeutic strategy were collected at diagnosis. Dates of death were obtained from investigators or town council of the patient's birth place. All fatal cases were considered regardless of the cause of the death. Multivariate logistic regression model was used to determine the factors significantly and independently associated with death at 1 and 3 months. RESULTS: Seven thousand fifty-one patients from 104 centres were included in the study. Vital status was obtained for 6,981 patients. Respectively, 678 (9.7%) and 1,621 (23.2%) of the 6,981 patients with available data died within 1 and 3 months following diagnosis. As compared with the other patients, they were significantly older and frailer (based on performance status [PS] and recent weight loss) and more frequently reported stage IV tumour. Overall, 64.5% (1 month) and 42.8% (3 months) of patients had no cancer therapy and less than 1% were included in a therapeutic trial. CONCLUSION: About one in four patients died within 3 months following lung cancer diagnosis. Early mortality mainly involves frail patients with advanced cancer and is associated with lack of cancer therapy. This supports the need for early diagnosis and clinical trials in this population. Reducing early mortality to give supplementary time to patients to organise the future is a major challenge for 21(st) century physicians.

Impact of smoking on outcome of resected lung adenocarcinoma.

OBJECTIVE: Smoking is a well-known causative factor of lung cancer and the association of smoking with adenocarcinoma is considered to be the weakest. We investigated the influence of smoking on postoperative prognosis in patients with lung adenocarcinoma. METHODS: One hundred and eighty-one consecutive patients of resected lung adenocarcinoma were studied retrospectively. The histologic subtype was subdivided into 2 groups: lepidic dominant histologic subtype, including adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant invasive adenocarcinoma versus other subtypes. RESULTS: The 5-year survival of ever smokers was significantly unfavorable than that of never smokers. Similarly, there was also a relationship between the patients' survival and Brinkman index (BI), with unfavorable survival found in patients with greater smoking histories. Based on a multivariable analysis, pN status and BI were significant factors affecting the postoperative prognosis of patients undergoing surgery. However, gender, serum carcinoembryonic antigen (CEA) level, lepidic dominant histologic subtype and pure/mixed ground-glass opacity (GGO) were not prognostic factors although previous reports showed prognostic significance. These factors that we failed to find the prognostic significance were significantly associated with smoking. CONCLUSION: The smoking was significantly predictive of an unfavorable prognosis after surgery for lung adenocarcinoma. It is suggested that smoking is associated with serum CEA level, histologic subtype and GGO, resulting in unfavorable outcome.

The percentage of lepidic growth is an independent prognostic factor in invasive adenocarcinoma of the lung.

BACKGROUND: The literature is inconclusive as to whether the percentage of the lepidic component of an invasive adenocarcinoma (AC) of the lung influences prognosis. We studied a population-based series of selected, resected invasive pulmonary ACs to determine if incremental increases in the lepidic component were an independent, prognostic variable. METHODS: Patients undergoing resection for lung cancer reported to the Cancer Registry of Norway and diagnosed in the period 1993-2002 with a bronchioloalveolar carcinoma (BAC) (old terminology) (adenocarcinoma in situ, AIS in the new terminology) in the lung were selected. A pulmonary pathologist reviewed all sections and estimated the percentage of the lepidic component. Follow-up of survival was to the end of 2013. RESULTS: One hundred thirty-one patients were identified, 102 had AC with lepidic growth. Of these, 44 had AC with a component of lepidic growth less than 50% and seven had AC with 95% lepidic component or more. One of the latter cases was considered to be AIS. In regression analyses, superior survival was associated with a greater lepidic component (p = 0.041). Mucinous tumors had a worse prognosis than non-mucinous (p = 0.012) in regression analyses, as did increasing age and stage. The five-year observed survival was 69.0% for non-mucinous cases and 66.7% for the group with a lepidic component of 80% or greater. CONCLUSION: The percentage of the lepidic component appears to be an independent, significant prognostic factor in a selection of pulmonary AC.

Expression of CLDN1 and CLDN10 in lung adenocarcinoma in situ and invasive lepidic predominant adenocarcinoma.

BACKGROUND: Non-mucinous bronchioloalveolar carcinoma (BAC) is considered the early stage of lung adenocarcinoma and is classified as the lung adenocarcioma in situ (AIS) by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society. This study was designed to investigate the gene expression differences between AIS (formerly non-mucinous BAC) and invasive lepidic predominant adenocarcinoma (LPA, formerly non-mucinous BAC pattern with >5 mm invasion, mixed type adenocarcinoma with BAC features) and to investigate the mechanism of the progression of lung adenocarcinoma in situ to invasive adenocarcinoma. METHODS: Gene expression analysis was performed by using Agilent 4 × 44 K Whole Human Genome Oligo Microarray on 10 fresh frozen tissue samples of AIS and LPA, respectively. Real time RT-PCR was used to validate the differential expression of 13 genes selected by cDNA microarray on fresh frozen tissue samples from 41 patients with lung adenocarcinoma and 4 genes were confirmed. These 4 genes were then validated by western blotting. Immunohistochemical staining for these validated genes was performed on formalin-fixed, paraffin-embedded tissue samples from 81 cases of lung adenocarcinomna. RESULTS: We identified a 13 gene expression signature by comparative analysis of gene expression. Expression of these genes strongly differed between AIS and LPA. Four genes (MMP-2, c-fos, claudin 1 (CLDN1) and claudin 10(CLDN10)) were correlated with the results of microarray and real time RT-PCR analyses for the gene-expression data in samples from 41 patients with lung adenocarcinoma. As confirmed by western blotting, the expression levels of MMP-2 and c-fos were higher in LPA than those in AIS; the expression levels of CLDN1 and CLDN10 in LPA were lower than those in AIS. Immunohistochemical staining for these genes in samples from 81 cases of lung adenocarcinoma demonstrated the expressions of CLDN1 and CLDN10 were correlated with overall survival of patients with lung adenocarcinoma. CONCLUSIONS: CLDN1 and CLDN10 may play important roles in the development of AIS to LPA. Overexpression of CLDN1 and CLDN10 indicates a favorable prognosis for overall survival in some patients with lung adenocarcinoma. Expression of CLDN10 may be regulated by the c-fos pathway.