NUT midline carcinoma: An unknown therapeutic territory

We read with great interest the article titled "NUT-midline carcinoma of the lung with rare BRD3-NUTM1 fusion," published in the Cancer Research, Statistics and Treatment journal by Jha et al.1 We appreciate Jha et al.1 for the thorough and meticulous case presentation and for including molecular studies like next-generation sequencing (NGS). The article also describes the data on nuclear protein in testis (NUT) carcinoma in the Indian context, its rarity, pathogenesis, treatment options, and prognosis. However, other areas of NUT carcinoma need further discussion and investigation. In the article, Jha et al.1 described that hematoxylin and eosin staining showed NUT-midline carcinoma. However, on histopathology, the tumor cells were diffuse and strongly positive for both P40 and NUT. Why could it not be a squamous cell carcinoma? What are the micromorphological features of NUT carcinoma cells that require further investigation to confirm the diagnosis? Microscopically, the findings can range from completely undifferentiated carcinoma to the squamous differentiation.2,3 Undifferentiated or poorly differentiated carcinoma in the body's midline area, particularly in the head and neck or thorax, should raise the suspicion of NUT carcinoma.3 However, the point of doing immunohistochemistry (IHC) in every case of the head-and-neck or thorax area with poorly differentiated or undifferentiated carcinoma should be debated in a multidisciplinary tumor board. Another important question is when to raise the suspicion of NUT carcinoma in no midline areas of the body. Furthermore, NGS is a powerful tool to identify gene fusions and other genetic abnormalities.1 Gene fusion of nuclear protein in testes gene 1 (NUTM1) with bromodomain gene (BRD 3/4) plays a significant role in the pathogenesis of NUT carcinoma and becomes a potential therapeutic target. NGS should be done in every case of NUT carcinoma to find out any therapeutic targets where there is no definite therapeutic option. As per this article by Jha et al.,1 the programmed cell death ligand 1 (PDL1) expression varied from 0-80% and the expression was associated with an increased responsiveness to chemotherapy and radiotherapy. PDL1 expression should be tested not only for the responsiveness of the chemoradiotherapy but also for immune checkpoint inhibitors. Therapeutic options: Histone deacetylase inhibitors and bromodomain inhibitors have shown improved results in early clinical trials, which needs further investigation to know the therapeutic efficacy.4,5 Anlotinib hydrochloride, a novel multitarget tyrosine kinase inhibitor has shown promising results when used along with radiotherapy.6 Further investigations are needed to know the therapeutic efficacy of other multitarget tyrosine kinase inhibitors in the treatment of NUT carcinoma. Myelicytomatosis oncogene (MYC) promotes the proliferation and undifferentiation in NUT carcinoma. Inhibiting the phosphoinositide 3 kinase (PI3K) signaling pathway might benefit by inhibiting MYC activity by suppressing MYC gene transcription or by downregulating apoptosis of MYC-dependent NUT carcinoma cells.7 To conclude, Jha et al.1 have made a significant contribution to the literature on the investigation, diagnosis, and treatment of NUT carcinoma. However, areas which require further research are scenarios where there is a high chance of diagnosing NUT carcinoma, identifying the different targetable cellular pathways, and optimal sequencing of the available therapeutic options for the management of NUT carcinoma. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.