Subclassification of Non-small Cell Lung Carcinomas Lacking Morphologic Differentiation on Biopsy Specimens

Abstract

The availability of targeted therapies has created a need for precise subtyping of non-small cell lung carcinomas (NSCLCs). The aim of this study was to assess the utility of immunohistochemical markers in subtyping poorly differentiated NSCLC and to compare the results of immunohistochemical staining on biopsies with the corresponding resections. Thirty-nine cases of NSCLC that could not be further classified on biopsy and had subsequent resection specimens were identified. Classification of the tumor was based on the resection specimen using the World Health Organization criteria. All biopsies and resections were stained with CK7, TTF-1, napsin A (novel aspartic proteinase of the pepsin family), p63, CK5/6, and 34βE12. The specimens included 20 adenocarcinomas (ACs), 15 squamous cell carcinomas (SCCs), and 4 large-cell carcinomas (LCCs). TTF-1 was positive in biopsies from 16 of 20 ACs, 2 of 4 LCCs, and none of the SCCs. p63 was positive in all 15 SCCs, 2 of 20 ACs (both were also positive for TTF-1 and napsin A), and none of the LCCs. CK5/6 was positive in 11 of 15 SCCs (all p63 positive) but none of the ACs or LCCs. Napsin A stained 11 of 19 ACs (all TTF-1 positive) but none of the other tumors. Staining for CK7 was present in 19 of 19 ACs and 9 of 15 SCCs. 34βE12 stained both SCCs (15 of 15) and ACs (12 of 20). The combination of TTF-1, napsin A, p63, and CK5/6 allowed an accurate classification of 30 of39 (77%) cases. Of 232 pairs of slides (biopsy and resection) stained with immunohistochemical markers, 12 (5%) showed discrepancies in immunohistochemical staining between biopsies and their corresponding resections. Immunohistochemical staining using a combination of TTF-1, napsin A, p63, and CK5/6 allows subclassification of poorly differentiated NSCLCs on small lung biopsies in most cases. Discrepancies in immunohistochemical staining between biopsies and resections are uncommon.

Role of Immunohistochemistry in The Subtyping of Non Small Cell Lung Carcinoma on True Cut Lung Biopsies

“…CK5 negative staining together with TTF-1 negativity and P63 diffuse positivity will be enough to support diagnosis of squamous cell carcinoma. We found CK5 is positive in 12(15%) cases (Fig-2A) unlike the studies done by Burnnstrom et al [20] (1%) and Kargi et al [23] (20%) whereas Zhao et al [21] and Mukopadhyay S et al [26] did not show CK5 positivity in adenocarcinoma. The reason for this could be that 30% of pulmonary adenocarcinoma can show focal variable immunostaining for CK5.…”

“…[23] In present study, TTF-1 is positive in 60 adenocarcinoma cases (75%) (Fig-1C) which is higher when compared to the studies done by Kargi et al (40%) [23] , Sainz et al (63%) [24] and in agreement with Modi et al [14] (74%), Bishop JA et al (73%). [25] Higher percentage of positivity has been reported by Mukopadhyay S et al (80%) [26] , Zhao et al (80%) [21] , Gurda et al (84.5%) [18] , Sterlacci et al (83.5%) [19] Yaman et al [27] (85%), Burnnstrom et al [20] (92%) and Xuxy et al (94.59%). [22] The reason for above variability in positivity for TTF-1 could be because TTF-1 will be more positive in better differentiated adenocarcinoma.…”

Primary lung cancer with metastasis to the ipsilateral breast-a case report

“…This marker is used for squamous differentiation, it rarely stains adenocarcinoma. 44 This was not expressed in our case. Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein, its function is a membrane receptor for the epidermal growth factor family.…”

Diagnosis and Predictive Molecular Analysis of Non–Small-Cell Lung Cancer in the Africa-Middle East Region: Challenges and Strategies for Improvement

“…It is important to interpret the IHC tests according to validated levels of staining [16]; for example, squamous predictive markers generally require strong, diffuse staining for accurate diagnosis. Studies evaluating IHC markers have demonstrated that a marker panel comprising TTF-1, p63, CK5/6 and CK7 is the most robust compromise for NSCLC subtyping, particularly when tissue is limited [15,18,19]. Immunophenotyping of NSCLC should therefore be limited to between 2 and 4 markers [13].…”

“…Immunophenotyping of NSCLC should therefore be limited to between 2 and 4 markers [13]. Moreover, Napsin A is not thought to yield additional information beyond that provided by TTF-1, [13] but may be useful when TTF-1 staining is equivocal [18]. Accurate determination of NSCLC subtype is important in the selection of treatment for patients with NSCLC.…”