The Blueprint (BP) Programmed Death Ligand 1 (PD-L1) Immunohistochemistry Comparability Project is a pivotal academic/professional society and industrial collaboration to assess the feasibility of ...harmonizing the clinical use of five independently developed commercial PD-L1 immunohistochemistry assays. The goal of BP phase 2 (BP2) was to validate the results obtained in BP phase 1 by using real-world clinical lung cancer samples.
BP2 were conducted using 81 lung cancer specimens of various histological and sample types, stained with all five trial-validated PD-L1 assays (22C3, 28-8, SP142, SP263, and 73-10); the slides were evaluated by an international panel of pathologists. BP2 also assessed the reliability of PD-L1 scoring by using digital images, and samples prepared for cytological examination. PD-L1 expression was assessed for percentage (tumor proportional score) of tumor cell (TC) and immune cell areas showing PD-L1 staining, with TCs scored continuously or categorically with the cutoffs used in checkpoint inhibitor trials.
The BP2 results showed highly comparable staining by the 22C3, 28-8 and SP263 assays; less sensitivity with the SP142 assay; and higher sensitivity with the 73-10 assay to detect PD-L1 expression on TCs. Glass slide and digital image scorings were highly concordant (Pearson correlation >0.96). There was very strong reliability among pathologists in TC PD-L1 scoring with all assays (overall intraclass correlation coefficient ICC = 0.86–0.93), poor reliability in IC PD-L1 scoring (overall ICC = 0.18–0.19), and good agreement in assessing PD-L1 status on cytological cell block materials (ICC = 0.78–0.85).
BP2 consolidates the analytical evidence for interchangeability of the 22C3, 28-8, and SP263 assays and lower sensitivity of the SP142 assay for determining tumor proportion score on TCs and demonstrates greater sensitivity of the 73-10 assay compared with that of the other assays.
A grading system for pulmonary adenocarcinoma has not been established. The International Association for the Study of Lung Cancer pathology panel evaluated a set of histologic criteria associated ...with prognosis aimed at establishing a grading system for invasive pulmonary adenocarcinoma.
A multi-institutional study involving multiple cohorts of invasive pulmonary adenocarcinomas was conducted. A cohort of 284 stage I pulmonary adenocarcinomas was used as a training set to identify histologic features associated with patient outcomes (recurrence-free survival RFS and overall survival OS). Receiver operating characteristic curve analysis was used to select the best model, which was validated (n = 212) and tested (n = 300, including stage I–III) in independent cohorts. Reproducibility of the model was assessed using kappa statistics.
The best model (area under the receiver operating characteristic curve AUC = 0.749 for RFS and 0.787 for OS) was composed of a combination of predominant plus high-grade histologic pattern with a cutoff of 20% for the latter. The model consists of the following: grade 1, lepidic predominant tumor; grade 2, acinar or papillary predominant tumor, both with no or less than 20% of high-grade patterns; and grade 3, any tumor with 20% or more of high-grade patterns (solid, micropapillary, or complex gland). Similar results were seen in the validation (AUC = 0.732 for RFS and 0.787 for OS) and test cohorts (AUC = 0.690 for RFS and 0.743 for OS), confirming the predictive value of the model. Interobserver reproducibility revealed good agreement (k = 0.617).
A grading system based on the predominant and high-grade patterns is practical and prognostic for invasive pulmonary adenocarcinoma.
Currently, there is no established guidance on how to process and evaluate resected lung cancer specimens after neoadjuvant therapy in the setting of clinical trials and clinical practice. There is ...also a lack of precise definitions on the degree of pathologic response, including major pathologic response or complete pathologic response. For other cancers such as osteosarcoma and colorectal, breast, and esophageal carcinomas, there have been multiple studies investigating pathologic assessment of the effects of neoadjuvant therapy, including some detailed recommendations on how to handle these specimens. A comprehensive mapping approach to gross and histologic processing of osteosarcomas after induction therapy has been used for over 40 years.
The purpose of this article is to outline detailed recommendations on how to process lung cancer resection specimens and to define pathologic response, including major pathologic response or complete pathologic response after neoadjuvant therapy. A standardized approach is recommended to assess the percentages of (1) viable tumor, (2) necrosis, and (3) stroma (including inflammation and fibrosis) with a total adding up to 100%. This is recommended for all systemic therapies, including chemotherapy, chemoradiation, molecular-targeted therapy, immunotherapy, or any future novel therapies yet to be discovered, whether administered alone or in combination. Specific issues may differ for certain therapies such as immunotherapy, but the grossing process should be similar, and the histologic evaluation should contain these basic elements. Standard pathologic response assessment should allow for comparisons between different therapies and correlations with disease-free survival and overall survival in ongoing and future trials. The International Association for the Study of Lung Cancer has an effort to collect such data from existing and future clinical trials. These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as suggestion for good clinical practice outside of clinical trials, to improve consistency of pathologic assessment of treatment response.
The recent development of immune checkpoint inhibitors (ICIs) has led to promising advances in the treatment of patients with NSCLC and SCLC with advanced or metastatic disease. Most ICIs target ...programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) axis with the aim of restoring antitumor immunity. Multiple clinical trials for ICIs have evaluated a predictive value of PD-L1 protein expression in tumor cells and tumor-infiltrating immune cells (ICs) by immunohistochemistry (IHC), for which different assays with specific IHC platforms were applied. Of those, some PD-L1 IHC assays have been validated for the prescription of the corresponding agent for first- or second-line treatment. However, not all laboratories are equipped with the dedicated platforms, and many laboratories have set up in-house or laboratory-developed tests that are more affordable than the generally expensive clinical trial–validated assays. Although PD-L1 IHC test is now deployed in most pathology laboratories, its appropriate implementation and interpretation are critical as a predictive biomarker and can be challenging owing to the multiple antibody clones and platforms or assays available and given the typically small size of samples provided. Because many articles have been published since the issue of the IASLC Atlas of PD-L1 Immunohistochemistry Testing in Lung Cancer, this review by the IASLC Pathology Committee provides updates on the indications of ICIs for lung cancer in 2019 and discusses important considerations on preanalytical, analytical, and postanalytical aspects of PD-L1 IHC testing, including specimen type, validation of assays, external quality assurance, and training.
Immune checkpoint inhibitor (ICI) therapies have revolutionized the management of patients with NSCLC and have led to unprecedented improvements in response rates and survival in a subset of patients ...with this fatal disease. However, the available therapies work only for a minority of patients, are associated with substantial societal cost, and may lead to considerable immune-related adverse events. Therefore, patient selection must be optimized through the use of relevant biomarkers. Programmed death-ligand 1 protein expression by immunohistochemistry is widely used today for the selection of programmed cell death protein 1 inhibitor therapy in patients with NSCLC; however, this approach lacks robust sensitivity and specificity for predicting response. Tumor mutation burden (TMB), or the number of somatic mutations derived from next-generation sequencing techniques, has been widely explored as an alternative or complementary biomarker for response to ICIs. In theory, a higher TMB increases the probability of tumor neoantigen production and therefore, the likelihood of immune recognition and tumor cell killing. Although TMB alone is a simplistic surrogate of this complex interplay, it is a quantitative variable that can be relatively readily measured using currently available sequencing techniques. A large number of clinical trials and retrospective analyses, employing both tumor and blood-based sequencing tools, have evaluated the performance of TMB as a predictive biomarker, and in many cases reveal a correlation between high TMB and ICI response rates and progression-free survival. Many challenges remain before the implementation of TMB as a biomarker in clinical practice. These include the following: (1) identification of therapies whose response is best informed by TMB status; (2) robust definition of a predictive TMB cut point; (3) acceptable sequencing panel size and design; and (4) the need for robust technical and informatic rigor to generate precise and accurate TMB measurements across different laboratories. Finally, effective prediction of response to ICI therapy will likely require integration of TMB with a host of other potential biomarkers, including tumor genomic driver alterations, tumor-immune milieu, and other features of the host immune system. This perspective piece will review the current clinical evidence for TMB as a biomarker and address the technical sequencing considerations and ongoing challenges in the use of TMB in routine practice.
The epithelial‐mesenchymal transition (EMT) is critical for induction of invasiveness and metastasis of human cancers. In this study we investigated the expression profiles of the EMT markers, the ...relationship between EMT markers and patient/tumor/viral factors, and the interplay between major EMT regulators in human hepatocellular carcinoma (HCC). Reduced E‐cadherin and nonmembranous β‐catenin expression, the hallmarks of EMT, were shown in 60.2% and 51.5% of primary HCC samples, respectively. Overexpression of Snail, Twist, or Slug, the major regulators of EMT, was identified in 56.9%, 43.1%, and 51.4% of primary HCCs, respectively. Statistical analysis determined that Snail and Twist, but not Slug, are major EMT inducers in HCC: overexpression of Snail and/or Twist correlated with down‐regulation of E‐cadherin, nonmembranous expression of β‐catenin, and a worse prognosis. In contrast, there were no such significant differences in samples that overexpressed Slug. Coexpression of Snail and Twist correlated with the worst prognosis of HCC. Hepatitis C‐associated HCC was significantly correlated with Twist overexpression. HCC cell lines with increased Snail and Twist expression (e.g., Mahlavu) exhibited a greater capacity for invasiveness/metastasis than cells with low endogenous Twist/Snail expression (e.g., Huh‐7). Overexpression of Snail or/and Twist in Huh‐7 induced EMT and invasiveness/metastasis, whereas knockdown of Twist or Snail in Mahlavu reversed EMT and inhibited invasiveness/metastasis. Twist and Snail were independently regulated, but exerted an additive inhibitory effect to suppress E‐cadherin transcription. Conclusion: Our study provides a comprehensive profile of EMT markers in HCC, and the independent and collaborative effects of Snail and Twist on HCC metastasis were confirmed through different assays. (HEPATOLOGY 2009.)
This study investigated the pattern of recurrence of lung adenocarcinoma and the predictive value of histologic classification in resected lung adenocarcinoma using the new International Association ...for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification system.
Histologic classification of 573 patients undergoing resection for lung adenocarcinoma was determined according to the IASLC/ATS/ERS classification system, and the percentage of each histologic component (lepidic, acinar, papillary, micropapillary, and solid) was recorded. The pattern of recurrence of those components and their predictive value were investigated.
The predominant histologic pattern was significantly associated with sex (P < .01), invasive tumor size (P < .01), T status (P < .01), N status (P < .01), TNM stage (P < .01), and visceral pleural invasion (P < .01). The percentage of recurrence was significantly higher in micropapillary- and solid-predominant adenocarcinomas (P < .01). Micropapillary- and solid-predominant adenocarcinomas had a significantly higher possibility of developing initial extrathoracic-only recurrence than other types (P < .01). The predominant pattern group (micropapillary or solid v lepidic, acinar, or papillary) was a significant prognostic factor in overall survival (OS; P < .01), probability of freedom from recurrence (P < .01), and disease-specific survival (P < .01) in multivariable analysis. For patients receiving adjuvant chemotherapy, solid-predominant adenocarcinoma was a significant predictor for poor OS (P = .04).
In lung adenocarcinoma, the IASLC/ATS/ERS classification system has significant prognostic and predictive value regarding death and recurrence. Solid-predominant adenocarcinoma was also a significant predictor in patients undergoing adjuvant chemotherapy. Prognostic and predictive information is important for stratifying patients for aggressive adjuvant chemoradiotherapy.
Background
Adenocarcinoma is the most common type of lung cancer, and pre-operative biopsy plays an important role to determine its major subtypes. As proposed by the International Association for ...the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) in 2011, the predominant histological subtype of adenocarcinoma is an indicator of outcomes and recurrence rate. However, the value of CT-guided core biopsy in predicting the predominant subtype and detecting the presence of an aggressive subtype of adenocarcinoma, peripheral sub-solid nodule, has less been discussed.
Methods
We retrospectively reviewed 318 consecutive peripheral sub-solid nodules that underwent percutaneous CT-guided lung biopsy and surgical resection, between October 2015 and December 2018 and were diagnosed as adenocarcinoma with histological subtype. The subtyping results from biopsy and surgical pathology were compared to evaluate the concordance rate.
Results
The overall concordance rate between biopsy and surgical pathology in determining the predominant histological subtype was 64%. Better concordance was found in small tumors (≤ 2 cm), in predicting either predominant histology (
χ
2
= 7.091,
P
= 0.008) or high grade adenocarcinoma, micropapillary and/or solid subtype, MIP-SOL (
χ
2
= 22.301,
P
< 0.001). The analysis of ground glass opacity (GGO) component (C/T ratio) obtained significantly higher accuracy in the pure GGO group than in the other two groups in predicting predominant histology or high grade adenocarcinoma (
χ
2
= 17.560,
P
< 0.001 and
χ
2
= 61.938,
P
< 0.001, respectively).
Conclusions
CT-guided core biopsies provide additional value in predicting the histological subtype of lung adenocarcinoma after surgical resection, especially in small tumors (≤ 2 cm) or an initially pure GGO group.
OBJECTIVE:This study investigated the prognostic value of the new International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) ...lung adenocarcinoma classification in resected stage I lung adenocarcinoma.
METHODS:Histological classification of 283 patients undergoing surgical resection for stage I lung adenocarcinoma was determined according to the IASLC/ATS/ERS classification after comprehensive histological subtyping with recording of the percentage of each histological component (lepidic, acinar, papillary, micropapillary, and solid) in 5% increments. Their impact on overall survival, recurrence, and postrecurrence survival was investigated.
RESULTS:The 5-year overall survival and recurrence-free rates were 81.6% and 76.9%, respectively. During follow-up, 57 (20.1%) patients developed recurrence. The 2-year postrecurrence survival rate was 72.3%. The solid predominant group is associated with significant more male sex, higher smoking exposure, larger tumor size, and more poorly differentiated histological grade. Lepidic predominant group had significantly better overall survival (P = 0.002). Micropapillary and solid predominant groups had significantly lower probability of freedom from recurrence (P = 0.004). Older age (P = 0.039), visceral pleural invasion to the surface (PL2) (P = 0.009), and high grade (micropapillary/solid predominant) of the new classification (P = 0.028) were predictors of recurrence in multivariate analysis. The solid predominant group tends to have significantly worse postrecurrence survival (P = 0.074).
CONCLUSIONS:The new adenocarcinoma classification has significant impact on death and recurrence in stage I lung adenocarcinoma. Patients with PL2 and micropapillary/solid predominant pattern have significant higher risk for recurrence. This information is important for patient stratification for aggressive adjuvant chemoradiation therapy.
Immunotherapy including immune checkpoint inhibitors (ICIs) has become the backbone of treatment for most lung cancers with advanced or metastatic disease. In addition, they have increasingly been ...used for early stage tumors in neoadjuvant and adjuvant settings. Unfortunately, however, only a subset of patients experiences meaningful response to ICIs. Although programmed death-ligand 1 (PD-L1) protein expression by immunohistochemistry (IHC) has played a role as the principal predictive biomarker for immunotherapy, its performance may not be optimal, and it suffers multiple practical issues with different companion diagnostic assays approved. Similarly, tumor mutational burden (TMB) has multiple technical issues as a predictive biomarker for ICIs. Now, ongoing research on tumor- and host immune-specific factors has identified immunotherapy biomarkers that may provide better response and prognosis prediction, in particular in a multimodal approach. This review by the International Association for the Study of Lung Cancer Pathology Committee provides an overview of various immunotherapy biomarkers, including updated data on PD-L1 IHC and TMB, and assessments of neoantigens, genetic and epigenetic signatures, immune microenvironment by IHC and transcriptomics, and microbiome and pathologic response to neoadjuvant immunotherapies. The aim of this review is to underline the efficacy of new individual or combined predictive biomarkers beyond PD-L1 IHC and TMB.
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