Clinicopathological correlation of p40/TTF1 co-expression in NSCLC and review of related literature

TL;DR

This study investigates the rare co-expression of TTF1 and p40 in NSCLC, analyzing its clinicopathological features, molecular profile, and potential implications for prognosis and treatment, supported by a detailed case report and literature review.

Contribution

It provides the first detailed molecular and ultrastructural analysis of TTF1/p40 co-expressing NSCLC and reviews related literature to understand its clinical significance.

Findings

Co-expression of TTF1 and p40 is associated with aggressive tumor features.

STK11/LKB1 and NF1 co-mutations were identified, linked to poor prognosis.

p40/TTF1 co-expression may represent a distinct NSCLC variant.

Abstract

TTF1 and {\Delta}Np63/p40 have been used to differentiate ADC and SQC in hypofractionated NSCLC because of their sensitivity and specificity. There are few cases where TTF1 and {\Delta}Np63/p40 are expressed together in the same tumour cells, and little is known about the clinicopathological features, treatment and prognosis of such cases. We investigated the electron microscopic features, immunohistochemical expression and molecular variation of a case of TTF1/p40 co-expressing NSCLC and reviewed and summarised the relevant literature. Our patient was a 58-year-old male with a CT showing a left-sided lung occupancy. As in all other cases reported in the literature, the tumour showed a solid growth pattern with polygonal cells, eosinophilic cytoplasm and clearly visible nuclear fission. Immunohistochemistry showed positive for TTF-1, p40, CK5/6, CK7, P63 and p53, and negative for NapsinA and ALK. Electron microscopy showed tumour cells characterised by bidirectional differentiation of adenocytes and squamous cells, consistent with previous reports. Second-generation sequencing suggested co-mutation of STK11/LKB1 and NF1 genes in this case. Mutations in STK11/LKB1 and NF1 genes have been found in ADC and SQC and are often associated with drug resistance and poor prognosis, but STK11/NF1 co-mutation has not been reported and more cases are needed to reveal the association. p40/TTF1 co-expression in NSCLC may be an under-recognised variant of NSCLC The origin may be a double positive stem cell-like basal cell located in the distal airway, with rapid clinical progression and poor prognosis.