Early KRAS oncogenic driver mutations in nonmucinous tissue of congenital pulmonary airway malformations as an indicator of potential malignant behavior

Sergei M Hermelijn,Janina L Wolf,T Dorine Den Toom,René M.H Wijnen,Robbert J Rottier,J Marco Schnater,Jan H Von Der Thüsen

doi:10.1016/j.humpath.2020.07.015

Sergei M Hermelijn, Janina L Wolf + Show 5 more

Open Access

https://doi.org/10.1016/j.humpath.2020.07.015

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Journal: Human Pathology	Publication Date: Jul 16, 2020
Citations: 22	License type: cc-by

Affiliation: Erasmus MC

Abstract

The potential for malignant degeneration is the most common reason for some practitioners to resect asymptomatic congenital pulmonary airway malformations (CPAMs). We aimed to investigate the potential of various immunohistochemical (IHC) and genomic biomarkers to predict the presence of mucinous proliferations (MPs) in CPAM. Archival CPAM tissue samples were re-assessed and underwent IHC analysis using a panel of differentiating markers (TTF1/CDX2/CC10/MUC2/MUC5AC/p16/p53/DICER1). In each sample, intensity of IHC staining was assessed separately in normal lung tissue, CPAM, and MPtissue, using a semiquantitative approach. Likewise, next-generation targeted sequencing of known adult lung driver mutations, including KRAS/BRAF/EGFR/ERBB2, was performed in all samples with MP and in control samples of CPAM tissue without MP. We analyzed samples of 25 CPAM type 1 and 25 CPAM type 2 and found MPs in 11 samples. They were all characterized by strong MUC5AC expression, and all carried a KRAS mutation in the MP and adjacent nonmucinous CPAM tissue, whereas the surrounding normal lung tissue was negative. By contrast, in less than half (5 out of 12) control samples lacking MP, the CPAM tissue also carried a KRAS mutation. KRAS mutations in nonmucinous CPAM tissue may identify lesions with a potential for malignant degeneration and may guide histopathological assessment and patient follow-up.

Highlights

Congenital pulmonary airway malformation (CPAM), formerly known as congenital cystic adenomatoid malformation, is the most common congenital lung abnormality (CLA), comprising up to 30% of all CLA [1]
We used a panel of IHC markers (TTF1/CDX2/CC10/ MUC2/MUC5AC/p16/p53/DICER1), which are used in routine diagnostics of lung malignancies, as well as markers we considered useful in distinguishing between CPAM types and abnormalities (Table 2)
We found no difference in CPAM type when basing the classification on either cyst size or cell type, and our final pathology diagnosis based on both resulted in 25 (50%) samples with CPAM type 1 and 25 (50%) with CPAM type 2

Summary

Introduction

Congenital pulmonary airway malformation (CPAM), formerly known as congenital cystic adenomatoid malformation, is the most common congenital lung abnormality (CLA), comprising up to 30% of all CLA [1]. Advances in prenatal ultrasound are leading to an increase in the incidence which suggests this abnormality is more common than originally thought [2]. In recent years, an increasing amount of evidence suggesting malignant degeneration has been found in CPAM, and the conservative management of these lesions is debated [3e5]. The current classification by Stocker is criticized because of the large overlap of lesions, their concurrent occurrence, and the inconsistent use of definitions. The exact pathogenesis remains unknown, and the potential of malignant degeneration has been described in certain subtypes, no definitive evidence has been found for this. The inconsistent use of the classification raises the question whether the malignant potential is only confined to certain subtypes

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