The survival of patients with non–small-cell lung cancer (NSCLC), even when resectable, remains poor. Several small studies suggest that occult metastases (OMs) in pleura, bone marrow (BM), or lymph nodes (LNs) are present in early-stage NSCLC and are associated with a poor outcome. We investigated the prevalence of OMs in resectable NSCLC and their relationship with survival.
Patients and Methods
Eligible patients had previously untreated, potentially resectable NSCLC. Saline lavage of the pleural space, performed before and after pulmonary resection, was examined cytologically. Rib BM and all histologically negative LNs (N0) were examined for OM, diagnosed by cytokeratin immunohistochemistry (IHC). Survival probabilities were estimated using the Kaplan-Meier method. The log-rank test and Cox proportional hazards regression model were used to compare survival of groups of patients. P < .05 was considered significant.
From July 1999 to March 2004, 1,047 eligible patients (538 men and 509 women; median age, 67.2 years) were entered onto the study, of whom 50% had adenocarcinoma and 66% had stage I NSCLC. Pleural lavage was cytologically positive in only 29 patients. OMs were identified in 66 (8.0%) of 821 BM specimens and 130 (22.4%) of 580 LN specimens. In univariate and multivariable analyses OMs in LN but not BM were associated with significantly worse disease-free survival (hazard ratio [HR], 1.50; P = .031) and overall survival (HR, 1.58; P = .009).
In early-stage NSCLC, LN OMs detected by IHC identify patients with a worse prognosis. Future clinical trials should test the role of IHC in identifying patients for adjuvant therapy.
Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies.
An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach.
The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy compared with squamous cell carcinoma, and (3) potential life-threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized.
This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules.
Lung; Adenocarcinoma; Classification; Histologic; Pathology; Oncology; Pulmonary; Radiology; Computed tomography; Molecular; EGFR; KRAS; EML4-ALK; Gene profiling; Gene amplification; Surgery; Limited resection; Bronchioloalveolar carcinoma; Lepidic; Acinar; Papillary; Micropapillary; Solid; Adenocarcinoma in situ; Minimally invasive adenocarcinoma; Colloid; Mucinous cystadenocarcinoma; Enteric; Fetal; Signet ring; Clear cell; Frozen section; TTF-1; p63
Mounting evidence suggests that tumor-infiltrating immune cells have prognostic value for patients with solid organ malignancies. Our aim was to investigate the prognostic significance of the immune microenvironment in patients with stage I lung adenocarcinoma (ADC).
Patients and Methods
Using tissue microarray and immunohistochemistry, we investigated eight types of tumor-infiltrating immune cells in the tumor nest and tumor-associated stroma as well as tumor expression of five cytokines in a uniform cohort of 956 patients with stage I lung ADC (478 each in training and validation cohorts).
Although a high density of stromal forkhead box P3 (FoxP3) –positive cells was associated with shorter recurrence-free probability (RFP; P = .043), the relative proportion of stromal FoxP3 to CD3 was a stronger predictor of recurrence (5-year RFP, 85% for high v 77% for low ratio; P = .004). High expression of tumor interleukin-12 receptor β2 (IL-12Rβ2) was associated with better outcome (5-year RFP, 90% for high v 80% for low expression; P = .026), whereas high expression of tumor IL-7R was associated with worse outcome (5-year RFP, 76% for high v 86% for low expression; P = .001). In multivariate analysis, these immune markers were independently associated with recurrence. Although IL-7R remained significant for poor overall survival, all the markers remained prognostic for recurrence in patients with stages IA and IB disease as well as for patients with tumors ≤ 2 cm.
Our investigation confirms the biologic and prognostic significance of the tumor immune microenvironment for patients with stage I lung ADC and provides support for its use to stratify clinical outcome and immunotherapeutic interventions.
A number of staging systems have been proposed for malignant pleural mesothelioma (MPM) in the past, but few have utilized a TNM (tumor, node, metastasis) system. The International Association for the Study of Lung Cancer (IASLC) and the International Mesothelioma Interest Group (IMIG) previously developed a TNM-staging system which has been accepted by the International Union Against Cancer (UICC) and the American Joint Commission on Cancer (AJCC). The present study examines this staging system by analysing the updated IASLC database for patients with MPM.
De-identified data from participating centres dated from 1995 to 2009 were submitted to the IASLC Statistical Center. Surgical procedures included those with a curative or palliative intent. Survival was measured from the date of pathologic diagnosis to the most recent contact or death. Endpoints included overall survival and analysis of potential prognostic factors.
Data was available for 3,101 patients from 15 centers, mostly from North America and Europe. After a median follow-up of 15 months, a number of clinicopathological and treatment-related prognostic factors were found to significantly influence overall survival. These included overall tumor stage based on the proposed TNM staging system, T category, N category, tumor histology, gender, age, and type of operation.
The IASLC database represents the largest, multicenter and international database on MPM to date. Analyses demonstrate that the proposed TNM staging system effectively distinguishes the T and N categories, but also highlight areas for potential revision in the future.
Pleural mesothelioma; extrapleural pneumonectomy; pleurectomy; decortication; trimodality therapy; multi-institutional database; survival; staging
This is a step-by-step video demonstration of a left extrapleural pneumonectomy for malignant pleural mesothelioma, including thoracotomy incision, extrapleural mobilization of tumor, resection of diaphragm, mediastinal nodal dissection and division of hilar vessels followed by reconstruction of diaphragm and closure of the thoracotomy.
Extrapleural pneumonectomy (EPP); malignant pleural mesothelioma
Although preoperative chemotherapy (cisplatin-etoposide) and radiation followed by surgery is considered a standard-of-care for superior sulcus (SS) cancers, treatment is rigorous and relapse limits long term survival. S0220 was designed to incorporate an active systemic agent, (docetaxel) as consolidation therapy.
Patients with histologically-proven and radiologically-defined T3-T4, N0-N1, M0 SS NSCLC underwent induction therapy with cisplatin-etoposide, concurrently with thoracic RT 45 Gy. Non-progressing patients underwent surgical resection within 7 weeks. Consolidation consisted of docetaxel every 3 weeks for 3 doses. The accrual goal was 45 eligible patients. The primary objective was feasibility.
Of 46 patients registered, 44 were eligible and assessable; 38 (86%) completed induction, 29 (66%) underwent surgical resection, and 20 (45% of eligible, 69% surgical and 91% of those initiating consolidation therapy) completed consolidation docetaxel; 28/29 (97%) underwent a complete (R0) resection; 2 (7%) died of ARDS. In resected patients, 21/29 (72%) had a pathologic complete or near complete response. Known site of first recurrence was local (2), local-systemic (1) and systemic (10), 7 in the brain only. The 3-year progression-free survival is 56% and 3-year overall survival is 61%.
Although trimodality therapy provides excellent R0 and local control, only 66% of patients underwent surgical resection and only 45% completed the treatment regimen. Even in this subset, distant recurrence continues to be a major problem, particularly brain only relapse. Future strategies to improve treatment outcomes in this patient population must increase the effectiveness of systemic therapy and reduce the incidence of brain only metastases.
Patients who survive one non-small cell lung cancer (NSCLC) are at higher risk of a second malignancy. Capacity to repair damaged DNA may modulate individual susceptibility to develop lung cancer. Therefore, we evaluated constitutive and induced DNA damage, and repair capacity, in patients with multiple NSCLC (cases) and compared the results to those obtained in patients with single NSCLC (controls).
One-hundred and eight cases and 99 controls matched by age, gender and time since diagnosis were studied. DNA damage was assessed on peripheral blood lymphocytes by the comet assay before and after exposing cells to a tobacco-derived carcinogen, using the tail moment (TM), and the tail intensity (TI) as measures to assess baseline damage, induced damage and repair capacity.
Constitutive DNA damage, BPDE-induced damage, and repair after BPDE-induced damage were all significantly higher in cases than in controls. These results were confirmed in regression analyses adjusted for potential confounders.
DNA damage as measured by the comet assay is associated with the development of multiple primary tumors in individuals with NSCLC.
Operative mortality rates are of great interest to surgeons, patients, policy makers, and payers as a universal metric for quality assessment. Thirty-day mortality and discharge mortality have been presumed to capture procedure-related mortality. However, many patients die after the 30-day mark or are transferred to other facilities or to home and die there, leading to the underreporting of surgery-related deaths. We hypothesized that a longer period of observation would address these concerns and provide a more accurate measure of operative mortality.
We performed a retrospective review of prospectively maintained institutional databases of patients undergoing resection for lung cancer, esophageal cancer, and mesothelioma.
From 1999 to 2012, 7646 surgical resections were performed: 6119 for lung cancer, 1258 for esophageal cancer, and 269 for mesothelioma. Among the different cancers and across operations, the additional mortality from day 31 to 90 (1.4% [95% CI, 1.2% to 1.8%]; n=111) was similar to that by day 30 (1.2% [95% CI, 1.0% to 1.5%; n=95), resulting in overall 90-day mortality (2.7% [95% CI, 2.3% to 3.1%; n=206) that was more than double 30-day mortality. Respiratory failure, sepsis, and cardiac events were the leading causes of death after thoracic resection.
Among patients who have undergone surgery for thoracic malignancies, considerable mortality attributable to surgery occurs beyond the first 30 days after surgery, as well as after hospital discharge. As cancer surgery constitutes a large portion of general thoracic surgery, we recommend national databases consider the inclusion of 90-day mortality in their data collection.
Mortality; Outcomes; Thoracic; Lung Cancer; Esophageal Cancer; Mesothelioma
Smokers have a higher risk of developing non-small cell lung cancer (NSCLC) than nonsmokers, but the relative risk of developing second primary lung cancer (SPLC) is unclear. Determining the risk of SPLC in smokers versus nonsmokers after treatment of an initial cancer may help guide recommendations for long-term surveillance.
Patients who underwent resection for stage I adenocarcinoma were identified from a prospectively maintained institutional database. Patients with other histologies, synchronous lesions, or who received neoadjuvant or adjuvant therapy were excluded. SPLC were identified based on Martini criteria.
From 1995 to 2012, 2151 patients underwent resection for stage I adenocarcinoma (308 never-smokers [14%] and 1843 ever-smokers [86%]). Thirty never-smokers (9.9%) and 145 ever-smokers (7.8%) developed SPLC. SPLC was detected by surveillance computed tomography scan in the majority of patients (161; 92%). In total, 87% of never-smokers and 83% of ever-smokers had stage I SPLC. There was no significant difference in the cumulative incidence of SPLC between never-smokers and ever-smokers (p=0.18) in a competing-risks analysis. The cumulative incidence at 10 years was 20.3% for never-smokers and 18.2% for ever-smokers.
Although smokers have a greater risk of developing NSCLC, the risk of developing a second primary cancer after resection of stage I lung cancer is comparable between smokers and never smokers. The majority of these second primary cancers are detectable at a curable stage. Ongoing postoperative surveillance should be recommended for all patients regardless of smoking status.
Metachronous; Lung; Never; Smoking; Recurrences
The IASLC/ATS/ERS has recently proposed a new lung adenocarcinoma classification. We investigated whether nuclear features can stratify prognostic subsets. Slides of 485 stage I lung adenocarcinoma patients were reviewed. We evaluated nuclear diameter, nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, prominence of nucleoli, intranuclear inclusions, mitotic count/10 high-power fields (HPF) or 2.4 mm2, and atypical mitoses. Tumors were classified into histologic subtypes according to the IASLC/ATS/ERS classification and grouped by architectural grade into low (adenocarcinoma in situ, minimally invasive adenocarcinoma or lepidic predominant), intermediate (papillary or acinar), and high (micropapillary or solid). Log-rank tests and Cox regression models evaluated the ability of clinicopathologic factors to predict recurrence-free probability. In univariate analyses, nuclear diameter (p=0.007), nuclear atypia (p=0.006), mitotic count (p<0.001), and atypical mitoses (p<0.001) were significant predictors of recurrence. The recurrence-free probability of patients with high mitotic count (≥5/10HPF: n=175) was the lowest (5-year recurrence-free probability=73%), followed by intermediate (2–4/10HPF: n=106, 80%), and low (0–1/10HPF: n=204, 91%, p<0.001). Combined architectural/mitotic grading system stratified patient outcomes (p<0.001): low grade (low architectural grade with any mitotic count and intermediate architectural grade with low mitotic count: n=201, 5-year recurrence-free probability=92%), intermediate grade (intermediate architectural grade with intermediate-high mitotic counts: n=206, 78%), and high grade (high architectural grade with any mitotic count: n=78, 68%). The advantage of adding mitotic count to architectural grade is in stratifying patients with intermediate architectural grade into two prognostically distinct categories (p=0.001). After adjusting for clinicopathologic factors including sex, stage, pleural/lymphovascular invasion, and necrosis, mitotic count was not an independent predictor of recurrence (p=0.178). However, patients with the high architectural/mitotic grade remained at significantly increased risk of recurrence (high vs. low: p=0.005) after adjusting for clinical factors. We proposed this combined architectural/mitotic grade for lung adenocarcinoma as a practical method that can be applied in routine practice.
lung adenocarcinoma; histologic subtype; architectural grade; mitosis; recurrence
According to the IASLC/ATS/ERS classification, the lepidic predominant pattern consists of 3 subtypes: adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and nonmucinous lepidic predominant invasive adenocarcinoma. We reviewed tumor slides from 1038 patients with stage I lung adenocarcinoma, recording the percentage of each histologic pattern and measuring invasive tumor size. Tumors were classified according to the IASLC/ATS/ERS classification: 2 were AIS, 34 MIA, and 103 lepidic predominant invasive. Cumulative incidence of recurrence (CIR) was used to estimate the probability of recurrence. Patients with AIS and MIA experienced no recurrences. Patients with lepidic predominant invasive tumors had a lower risk of recurrence (5-year CIR, 8%) than non-lepidic predominant tumors (n=899; 19%; P=0.003). Patients with >50% lepidic pattern tumors experienced no recurrences (n=84), those with >10%–50% lepidic pattern tumors had an intermediate risk of recurrence (n=344; 5-year CIR, 12%), and those with ≤10% lepidic pattern tumors had the highest risk (n=610; 22%; P<0.001). CIR was lower for patients with ≤2 cm tumors than for those with >2–3 cm tumors (for both total and invasive tumor size), with the difference more pronounced for invasive tumor size (5-year CIR, 13% vs. 21% [total size; P=0.022] and 12% vs. 27% [invasive size; P<0.001]). Most patients with lepidic predominant adenocarcinoma who experienced a recurrence had potential risk factors, including sublobar resection with close margins (≤0.5 cm; n=2), 20%–30% micropapillary component (n=2), and lymphatic or vascular invasion (n=2). It therefore may be possible to identify lepidic predominant adenocarcinomas that carry a low or high risk of recurrence.
Lung adenocarcinoma; Lepidic; Adenocarcinoma in situ; Minimally invasive adenocarcinoma; Recurrence
The 2011 IASLC/ATS/ERS lung adenocarcinoma classification emphasizes the prognostic significance of histologic subtypes. However, one limitation of this classification is that the highest percentage of patients (~40%) is classified as acinar predominant tumors, and these patients display a spectrum of favorable and unfavorable clinical behaviors. We investigated whether the cribriform pattern can further stratify prognosis by histologic subtype. Tumor slides from 1038 patients with stage I lung adenocarcinoma (1995–2009) were reviewed. Tumors were classified according to the IASLC/ATS/ERS classification. The percentage of cribriform pattern was recorded, and the cribriform predominant subtype was considered as a subtype for analysis. The log-rank test was used to analyze the association between histologic variables and recurrence-free probability. The 5-year recurrence-free probability for patients with cribriform predominant tumors (n=46) wasa 70%. The recurrence-free probability for patients with cribriform predominant tumors was significantly lower than that for patients with acinar (5-year recurrence-free probability, 87%; P=0.002) or papillary predominant tumors (83%; P=0.020) but was comparable to that for patients with micropapillary (P=0.34) or solid predominant tumors (P=0.56). The recurrence-free probability for patients with ≥10% cribriform pattern tumors (n=214) was significantly lower (5-year recurrence-free probability, 73%) than that for patients with <10% cribriform pattern tumors (n=824; 84%; P<0.001). In multivariate analysis, patients with acinar predominant tumors with ≥10% cribriform pattern remained at significantly increased risk of recurrence, compared with those with <10% cribriform pattern (P=0.042). Cribriform predominant tumors should be considered a distinct subtype with a high risk of recurrence, and presence (≥10%) of the cribriform pattern is an independent predictor of recurrence, identifying a poor prognostic subset of acinar predominant tumors. Our findings highlight the important prognostic value of comprehensive histologic subtyping and recording the percentage of each histologic pattern, according to the IASLC/ATS/ERS classification with the addition of the cribriform subtype.
lung adenocarcinoma; cribriform; histologic subtype; recurrence
Limited resection is an increasingly utilized option for treatment of clinical stage IA lung adenocarcinoma (ADC) ≤2 cm (T1aN0M0), yet there are no validated predictive factors for postoperative recurrence. We investigated the prognostic value of preoperative consolidation/tumor (C/T) ratio [on computed tomography (CT) scan] and maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose-positron emission tomography (PET) scan.
We retrospectively reviewed 962 consecutive patients who underwent limited resection for lung cancer at Memorial Sloan-Kettering between 2000 and 2008. Patients with available CT and PET scans were included in the analysis. C/T ratio of 25 % (in accordance with the Japan Clinical Oncology Group 0201) and SUVmax of 2.2 (cohort median) were used as cutoffs. Cumulative incidence of recurrence (CIR) was assessed.
A total of 181 patients met the study inclusion criteria. Patients with a low C/T ratio (n = 15) had a significantly lower 5-year recurrence rate compared with patients with a high C/T ratio (n = 166) (5-year CIR, 0 vs. 33 %; p = 0.015), as did patients with low SUVmax (n = 86) compared with patients with high SUVmax (n = 95; 5-year CIR, 18 vs. 40 %; p = 0.002). Furthermore, within the high C/T ratio group, SUVmax further stratified risk of recurrence [5-year CIR, 22 % (low) vs. 40 % (high); p = 0.018].
With the expected increase in diagnoses of small lung ADC as a result of more widespread use of CT screening, C/T ratio and SUVmax are widely available markers that can be used to stratify the risk of recurrence among cT1aN0M0 patients after limited resection.
Small lung adenocarcinoma; Limited resection; Positron emission tomography; SUVmax; Consolidation/tumor ratio
In an effort to identify molecular markers of tumor aggressiveness
and therapeutic targets in lung adenocarcinoma (ADC), we investigated the
expression of mesothelin (MSLN) in lung ADC, as well as its biological and
In a training and validation set of patients with early-stage
(I–III) lung ADC (n=1209), a tissue
microarray consisting of tumors and normal lung tissue was used to examine
the association between MSLN expression and recurrence-free survival (RFS)
and overall survival (OS). The influence of MSLN overexpression on lung ADC
was investigated in vitro and in vivo by
use of clinically relevant orthotopic and metastatic xenogeneic and
syngeneic mouse models.
MSLN was expressed in 69% of lung ADC tumors, with one in
five patients strongly expressing MSLN and no expression in normal lung
tissue. Increased MSLN expression was associated with reduced OS (HR, 1.78
[95% CI, 1.26–2.50];
P<0.01) and RFS (HR, 1.67 [95% CI,
1.21–2.27]; P<0.01) in multivariate
analyses, even after adjustment for currently known markers of tumor
aggressiveness in lung ADC: male sex, smoking history, increasing stage,
morphologic pattern, visceral pleural invasion, lymphatic or vascular
invasion, and mutation status. In vitro, lung ADC cells
overexpressing MSLN demonstrated increased cell proliferation, migration,
and invasion; in vivo, mice with MSLN(+) tumors
demonstrated decreased survival (P=0.001).
MSLN expression in patients with early-stage lung ADC is associated
with increased risk of recurrence and reduced OS, indicating that MSLN
expression is a molecular marker of tumor aggressiveness and a potential
target for therapy.
Mesothelin; lung adenocarcinoma; prognosis; targeted therapy; non-small cell lung cancer
After definitive treatment of esophageal cancer, patients are at high risk for recurrence. Consistent follow-up is important for detection and treatment of recurrence. The optimal surveillance regimen remains undefined. We investigated posttreatment recurrence patterns and methods of detection in survivors of esophageal cancer.
We retrospectively studied a cohort of patients who had undergone surgical resection for esophageal cancer at our institution between 1996 and 2010. Routine computed tomography (CT) scan and upper endoscopy were performed for surveillance.
In total, 1147 patients with resected esophageal adenocarcinoma or squamous cell carcinoma were included (median follow-up, 46 months). Of these, 723 (63%) had received neoadjuvant therapy before surgery. During follow-up, there were 595 deaths (52%) and 435 recurrences (38%) (distant [55%], locoregional [28%], or both [17%]). Half of recurrences were detected as a result of symptoms (n = 217), 45% by routine chest and abdominal CT scan (n = 194), and 1% by surveillance upper endoscopy (n = 6). The recurrence rate decreased from 27 per 100 person-years in posttreatment year 1 to 4 per 100 person-years in year 6. In the first 2 years, the rate of recurrence was higher among patients who had received neoadjuvant therapy (35 per 100 person-years) than among those who had not (14 per 100 person-years) (p < 0.001).
The incidence of recurrence is high after esophagectomy for cancer. Surveillance endoscopy has limited value for detection of asymptomatic local recurrence. The yield from follow-up scans diminishes significantly after the sixth year; surveillance scans after that point are likely unnecessary.
Esophageal Cancer; Surveillance; Endoscopy
Thymic carcinomas (TC) are considered to be more aggressive than thymomas and carry a worse prognosis. We reviewed our recent experience with the surgical management of thymic tumors and compared the outcomes and patterns of relapse between TC and thymoma.
Single institution retrospective cohort study. Data included patient demographics, stage, treatment, pathologic findings, and postoperative outcomes.
During the period 1995–2006, 120 patients with thymic tumors underwent surgery, including 23 patients with TC and 97 patients with thymoma by the WHO 2004 histologic classification. The overall 5 year survival was significantly different between TC and thymoma (TC 53%, thymoma 89%, p=0.01). Data on relapse was available for 112 patients. The progression-free 5 year survival was also significantly different between TC and thymoma (TC 36%, thymoma 75%, p<0.01). By multivariate analysis, thymic carcinoma and incomplete resection were found to be independent predictors of progression-free survival. Relapses in TC tended to occur earlier, and occurred signficantly more frequently at distant sites than in thymoma (60% vs. 13%, p=0.01).
Patterns of relapse differ significantly between TC and thymoma with lower progression-free survival, earlier onset and more distant relapses in TC. Given the greater propensity for distant failures, the inclusion of systemic therapy in the treatment of TC may take on greater importance. Despite significantly higher rates of distant relapse, good overall survival in TC can be achieved.
We sought to analyze the prognostic significance of the new International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) lung adenocarcinoma (ADC) classification for patients undergoing resection for small (≤2cm) lung ADC and to investigate whether histologic subtyping can predict recurrence after limited resection (LR) vs lobectomy (LO).
Comprehensive histologic subtyping was performed according to the IASLC/ATS/ERS classification on all consecutive patients who underwent LR or LO for small lung ADC between 1995 and 2009 at Memorial Sloan-Kettering Cancer Center. Clinical characteristics and pathologic data were retrospectively evaluated for 734 consecutive patients (LR: 258; LO: 476). Cumulative incidence of recurrence (CIR) was calculated using competing risks analysis and compared across groups using Grey’s test. All statistical tests were two-sided.
Application of IASLC/ATS/ERS lung ADC histologic subtyping to predict recurrence demonstrates that, in the LR group but not in the LO group, micropapillary (MIP) component of 5% or greater was associated with an increased risk of recurrence, compared with MIP component of less than 5% (LR: 5-year CIR = 34.2%, 95% confidence interval [CI] = 23.5% to 49.7% vs 5-year CIR = 12.4%, 95% CI = 6.9% to 22.1%, P < .001; LO: 5-year CIR = 19.1%, 95% CI = 12.0% to 30.5% vs 15-year CIR = 12.9%, 95% CI = 7.6% to 21.9%, P = .13). In the LR group, among patients with tumors with an MIP component of 5% or greater, most recurrences (63.4%) were locoregional; MIP component of 5% or greater was statistically significantly associated with increased risk of local recurrence when the surgical margin was less than 1cm (5-year CIR = 32.0%, 95% CI = 18.6% to 46.0% for MIP ≥ 5% vs 5-year CIR = 7.6%, 95% CI = 2.3% to 15.6% for MIP < 5%; P = .007) but not when surgical margin was 1cm or greater (5-year CIR = 13.0%, 95% CI = 4.1% to 22.1% for MIP ≥ 5% vs 5-year CIR = 3.4%, 95% CI = 0% to 7.7% for MIP < 5%; P = .10).
Application of the IASLC/ATS/ERS classification identifies the presence of an MIP component of 5% or greater as independently associated with the risk of recurrence in patients treated with LR.
The staging system for malignant pleural mesothelioma is controversial. To revise this system, the International Association for the Study of Lung Cancer Staging Committee developed an international database. This report analyzes prognostic variables in a surgical population, which are supplementary to previously published CORE variables (stage, histology, sex, age, and type of procedure).
Supplementary prognostic variables were studied in three scenarios: (1) all data available, that is, patient pathologically staged and other CORE variables available (2) only clinical staging available along with CORE variables, and (3) only age, sex, histology, and laboratory parameters are known. Survival was analyzed by Kaplan–Meier, prognostic factors by log rank and stepwise Cox regression modeling after elimination of nonsignificant variables. p value less than 0.05 was significant.
A total of 2141 patients with best tumor, node, metastasis (TNM) stages (pathologic with/without clinical staging) had nonmissing age, sex, histology, and type of surgical procedure. Three prognostic models were defined. Scenario A (all parameters): best pathologic stage, histology, sex, age, type of surgery, adjuvant treatment, white blood cell count (WBC) (≥15.5 or not), and platelets (≥400 k or not) (n = 550). Scenario B (no surgical staging): clinical stage, histology, sex, age, type of surgery, adjuvant treatment, WBC, hemoglobin (<14.6 or not), and platelets (n = 627). Scenario C (limited data): histology, sex, age, WBC, hemoglobin, and platelets (n = 906).
Refinement of these models could define not only the appropriate patient preoperatively for best outcomes after cytoreductive surgery but also stratify surgically treated patients after clinical and pathologic staging who do or do not receive adjuvant therapy.
Mesothelioma; Surgery; Prognosis; Registry; Staging
Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant pleural mesothelioma in which only staging is prognostic for survival. In this study of epithelioid diffuse malignant pleural mesothelioma, we investigate the prognostic utility of nuclear features. The slides of 232 epithelioid diffuse malignant pleural mesothelioma patients (14 stage I, 54 stage II, 130 stage III, and 34 stage IV) from a single institution were reviewed for the following seven nuclear features: nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, intranuclear inclusions, prominence of nucleoli, mitotic count, and atypical mitoses. MIB-1 immunohistochemistry was performed using tissue microarray, and MIB-1 labeling index was recorded as the percentage of positive tumor cells. Median overall survival of all patients was 16 months and correlated with nuclear atypia (P<0.001), chromatin pattern (P=0.031), prominence of nucleoli (P<0.001), mitotic count (P<0.001), and atypical mitoses (P<0.001) by univariate analysis. Multivariate analysis revealed nuclear atypia (P=0.012) and mitotic count (P<0.001) as independent prognostic factors, and these two factors were utilized to create a three-tier nuclear grade score. The resulting nuclear grade stratified patients into three distinct prognostic groups: grade I (n=107, median overall survival = 28 months), grade II (n=91, 14 months), and grade III (n=34, 5 months). Not only was nuclear grade an independent predictor of overall survival (P<0.001), but it was also a stronger discriminator of survival than all currently available factors. Furthermore, nuclear grade was associated with time to recurrence (P=0.004) in patients who underwent complete surgical resection (n=159). MIB-1 labeling index correlated with mitotic count (P<0.001) and nuclear atypia (P=0.037) and stratified overall survival (P<0.001) and time to recurrence (P=0.048), confirming the prognostic value of the nuclear grade. Nuclear grading in epithelioid mesothelioma provides a simple, practical, and cost-effective prognostic tool that better stratifies clinical outcome and time to recurrence than currently available clinicopathologic factors.
epithelioid mesothelioma; MIB-1; mitosis; nuclear atypia; nuclear grade; survival
We investigated the association between the newly proposed International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification and 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET), and whether the combination of these radiologic and pathologic factors can further prognostically stratify patients with stage I lung adenocarcinoma.
We retrospectively evaluated 222 patients with pathologic stage I lung adenocarcinoma who underwent FDG-PET scanning before undergoing surgical resection between 1999 and 2005. Patients were classified by histologic grade according to the IASLC/ATS/ERS classification (low, intermediate, or high grade) and by maximum standard uptake value (SUVmax) (low <3.0, high ≥3.0). The cumulative incidence of recurrence (CIR) was used to estimate recurrence probabilities.
Patients with high-grade histology had higher risk of recurrence (5-year CIR, 29 % [n = 25]) than those with intermediate-grade (13 % [n = 181]) or low-grade (11 % [n = 16]) histology (p = 0.046). High SUVmax was associated with high-grade histology (p < 0.001) and with increased risk of recurrence compared to low SUVmax (5-year CIR, 21 % [n = 113] vs. 8 % [n = 109]; p = 0.013). Among patients with intermediate-grade histology, those with high SUVmax had higher risk of recurrence than those with low SUVmax (5-year CIR, 19 % [n = 87] vs. 7 % [n = 94]; p = 0.033). SUVmax was associated with recurrence even after adjusting for pathologic stage (p = 0.037).
SUVmax on FDG-PET correlates with the IASLC/ATS/ERS classification and can be used to stratify patients with intermediate-grade histology, the predominant histologic subtype, into two prognostic subsets.
A subset of lung adenocarcinomas appears preferentially sensitive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). EGFR-activating mutations and never smoking are associated with response to TKIs.
To describe the morphology of adenocarcinomas responsive to TKIs, compare it to tumors in nonresponding patients, and correlate findings with EGFR mutations, gene copy number, and protein expression.
Material from 52 EGFR TKI-treated patients was studied: 29 responders and 23 nonresponders. Adenocarcinoma subtypes and morphologic features were defined in histologic and cytologic material. EGFR mutations were detected by sequencing, copy number by chromogenic in situ hybridization, and expression by immunohistochemistry.
Tumors from TKI responders tended to be better-differentiated adenocarcinomas with bronchioloalveolar carcinoma components. Nonresponders showed more heterogeneous morphology, higher grade, and more subtypes, and were more likely to show solid growth. In nonresponders, the only pure bronchioloalveolar carcinoma was mucinous, a subtype known to be negative for EGFR mutations. Using World Health Organization criteria, all tumors in both groups other than pure bronchioloalveolar carcinomas would be classified as adenocarcinomas, mixed subtype, thereby obscuring some of these distinctions. EGFR mutations were significantly more common in responders (22/29 vs 0/23; P < .001). Immunohistochemistry and chromogenic in situ hybridization results were not significantly correlated with EGFR mutations or response to TKIs in this study.
Overall, histologic differences exist between tumors that respond to TKIs and those that do not, although sampling affects classification, and there is significant histologic overlap between the 2 groups. Response is strongly associated with EGFR mutations.
We investigated whether thyroid transcription factor–1 (TTF-1) expression correlates with the IASLC/ATS/ERS classification and whether it stratifies patients with stage I lung adenocarcinoma with respect to recurrence.
Patients with stage I lung adenocarcinoma were classified according to the IASLC/ATS/ERS classification. We constructed tissue microarrays and performed immunostaining for TTF-1; 452 cases were available for analysis. Tumors were dichotomized by intensity of nuclear TTF-1 expression: negative (score 0) or positive (score 1–3). Cumulative incidence of recurrence (CIR) was used to estimate recurrence probabilities.
TTF-1 expression was identified in 92% of all patients, including 100% of patients with minimally invasive or lepidic-predominant adenocarcinoma, 94% of acinar-predominant, 98% of papillary-predominant, 93% of micropapillary-predominant, 86% of solid-predominant, 67% of colloid-predominant, and 47% of invasive-mucinous. The CIR for patients with negative TTF-1 expression (n = 34; 5-year CIR, 40%) was significantly higher than that for patients with positive TTF-1 (n = 418; 5-year CIR, 15%; p < 0.001). Among the intermediate-grade tumors, the CIR for patients with negative TTF-1 expression (n = 16; 5-year CIR, 45%) was significantly higher than that for patients with positive TTF-1 (n = 313, 5-year CIR, 14%; p < 0.001). In multivariate analysis, negative TTF-1 expression significantly correlated with increased risk of recurrence (hazard ratio, 2.55; p = 0.009).
TTF-1 expression is an independent predictor of recurrence, stratifying intermediate-grade tumors into 2 prognostic subsets, and it correlates with the IASLC/ATS/ERS classification.
lung adenocarcinoma; thyroid transcription factor–1; histologic subtype; recurrence
Mesothelin (MSLN) is a tumor-associated antigen, being investigated as a biomarker and therapeutic target in malignant pleural mesothelioma (MPM). The biological function of MSLN overexpression in MPM is unknown. We hypothesized that MSLN may promote tumor invasion in MPM, a tumor characterized primarily by regional aggressiveness and rare distant metastases.
Human and murine MPM cells with MSLN forced expression and shRNA knockdown were examined for proliferation, invasion, and matrix metalloproteinase (MMP) secretion. The influence of MSLN overexpression on MPM cell invasion was assessed in an orthotopic mouse model and in patient samples.
MSLN expression promotes MPM cell invasion and MMP secretion in both human and murine MPM cells. In an orthotopic MPM mouse model characterized by our laboratory, MPM cells with MSLN overexpression preferentially localized to the tumor invading edge, co-localized with MMP-9 expression, and promoted decreased survival without an increase in tumor burden progression. In a tissue microarray from epithelioid MPM patients (n=139, 729 cores), MSLN overexpression correlated with higher MMP-9 expression at individual core level. Among stage III MPM patients (n=72), high MSLN expression was observed in 26% of T2 tumors and 51% of T3 tumors.
Our data provide evidence elucidating a biological role for MSLN as a factor promoting tumor invasion and MMP-9 expression in MSLN-expressing MPM. As regional invasion is the characteristic feature in MSLN-expressing solid cancers (MPM, pancreas, and ovarian), our observations add rationale to studies investigating MSLN as a therapeutic target.
Mesothelin; mesothelioma; matrix metalloproteinase; tumor invasion; locoregional aggressiveness
We have recently proposed to reclassify the pleomorphic subtype of epithelioid malignant pleural mesothelioma (MPM) as non-epithelioid (biphasic/sarcomatoid) histology due to its similarly poor prognosis. We sought to investigate whether preoperative maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) correlates with histologic subtype in MPM.
Clinical data was collected for 78 patients with MPM who underwent preoperative FDG-PET. We retrospectively classified the epithelioid tumors into five subtypes: trabecular, tubulopapillary, micropapillary, solid and pleomorphic. Tumors were categorized by SUVmax into two groups: low (<10.0) and high (≥10.0).
The median overall survival of epithelioid tumors with high-SUVmax (n=12) was significantly shorter (7.1 months) than that of epithelioid tumors with low-SUVmax (n=54, 18.9 months, p<0.001) and comparable to non-epithelioid tumors (n=12, 7.2 months). Epithelioid tumors with pleomorphic subtype (n=9) had marginally higher SUVmax (mean±SD: 10.6±5.9) than epithelioid non-pleomorphic subtype (n=57, 6.5±3.2, p=0.050), and were comparable to that of non-epithelioid tumors (n=12, 9.1±4.8). Among the epithelioid tumors with high-SUVmax (n=12), 50% (n=6) showed pleomorphic subtype. In contrast, among epithelioid tumors with low-SUVmax (n=54), 6% (n=3) showed epithelioid pleomorphic subtypes (p=0.001). A positive correlation between mitotic count and SUVmax was observed (r=0.30, p=0.010).
Pleomorphic subtype of epithelioid MPM showed higher SUVmax than epithelioid non-pleomorphic subtype and was similar to non-epithelioid histology. Preoperative SUVmax on FDG-PET in epithelioid MPM can indicate patients with pleomorphic subtype with poor prognosis, supporting their reclassification as non-epithelioid.
Mesothelioma; Pleural neoplasm; Positron emission tomography; Pleomorphic