Jimmy Ruiz, MD
Assistant Professor of Medicine,
Hematology and Oncology
Assistant Director of Cancer Health Equity
Wake Forest Baptist Medical Center –
Comprehensive Cancer Center
Non-small cell lung cancer (NSCLC) is no longer a single disease, but a constellation of cancer types pathologically classified by histology. Hence, a fundamental first step in diagnosis is the retrieval of adequate tissue for histological classification. Greater effort is required from pathologists to, whenever possible, avoid the diagnosis of carcinoma not otherwise specified (NOS).
With the majority of patients with NSCLC presenting with advanced disease, minimally invasive small volume biopsies are increasingly utilized for diagnosis. The fine-needle aspirate (FNA) is the most routinely utilized biopsy approach, and while sufficient for cancer diagnosis, the amount of cellular material from FNAs can be sparse. This is often cited as the limiting factor to the correct classification of NSCLC histology, a problem further compounded by the poor cellular differentiation characteristic of advanced-stage disease. Together, these limitations contribute to errors in NSCLC classification and interobserver disagreement among pathologists.
Despite the advancements in the identification of driver mutations and actionable targeted drugs like the ALK-inhibitor crizotinib and the EGFR-inhibitor erlotinib, chemotherapy remains standard care for the majority of patients with metastatic NSCLC. However, in recent years, NSCLC classification by histology has become essential for the optimal selection of treatment:
There is confirmed differential efficacy of pemetrexed favoring overall survival in patients with advanced NSCLC with adenocarcinoma (AC) histology and less favorable therapeutic efficacy in tumors of squamous cell carcinoma (SCC) histology.
The VEGF-inhibitor bevacizumab is approved for first-line treatment in patients with non- SCC histology. Bevacizumab has been shown to contribute to improved response rates when added to standard therapy, but has a significant increase in pulmonary hemorrhage in SCC histology, which may be fatal.
Efficacy studies of frontline tyrosine kinase inhibitors have shown that AC—but not SCC—histology can predict response to treatment. Most recently, a randomized trial in advanced NSCLC using nab-paclitaxel suggests a differential response rate favoring the drug’s use in patients with SCC histology.
Thus, histological diagnosis in NSCLC has become a major determinant of drug efficacy and prevention of undue toxicity to patients.
Additional immunohistochemical (IHC) stains can aid in the classification of NSCLC. However, numerous tissue assays can significantly deplete the amount of tissue available for additional molecular testing. Testing for emerging predictive genomic biomarkers such as ROS1
, and PIK3CA
, in addition to standard ALK
testing, will only compound the issue of obtaining sufficient tissue from small volume biopsies.
Paramount to ensuring the retrieval of adequate tissue for comprehensive diagnosis of NSCLC is close collaboration and communication among all providers involved in the diagnosis, classification, and treatment of patients. At our institution, we have developed an algorithm that standardizes the retrieval of adequate tissue and the effective pathological processing of specimens for both histology and molecular characterization. Yet, there remain cases where the complete characterization of NSCLC is not possible due to the sparsity of viable tissue samples. This problem has been a central concern, motivating the development of diagnostic technologies that can accurately measure multiple biomarkers in minimal tissue specimens.