Authors’ reply to Das et al.

We thank Das et al.[1] for the invaluable insights on our molecular tumor board article, "NUT-midline carcinoma of the lung with rare BRD3–NUTM1 fusion."[2] Das et al.[1] highlighted the immunohistochemical (IHC) phenotypes of nuclear protein in testis (NUT) carcinoma. In our case presentation, IHC positivity of NUT confirmed the histopathologic diagnosis of NUT midline carcinoma of the lung. NUT expression is a hallmark of NUT carcinoma.[3,4] P40 is highly sensitive and specific for squamous cell carcinoma. However, its presence alone does not conclusively confirm squamous cell carcinoma (SCC), like other cancers, may also express P40. In the case described, the tumor cells were positive for both P40 and NUT. While P40 positivity might suggest squamous differentiation, the concomitant strong positivity for NUT is more indicative of NUT carcinoma over squamous cell carcinoma as the final diagnosis. Typically, NUT carcinomas usually occur in the midline structures of the body such as the head, neck, and mediastinum; however, they can also manifest in the non-midline areas. Recognition of NUT carcinoma in the non-midline areas is crucial for timely diagnosis and treatment. The authors' insight is quite compelling in emphasizing the distinctive features of the primary histomorphological examination to identify NUT carcinomas. They also highlighted how identification is more common when it occurs in the non-midline regions. The main histopathologic indications of NUT carcinoma are undifferentiated or poorly differentiated histology and atypical nuclear morphology. In addition, high mitotic index, diffuse growth pattern, elevated Ki-67 proliferation index, and absence of squamous differentiation markers (e.g. CK5/6, p63) in cases with squamous differentiation give strong attestation of NUT carcinoma.[3,5] Similarly, a conjecture of NUT carcinoma should be raised in non-midline regions when there are atypical clinical presentations, rapid tumor growth, characteristic histologic features, young age of onset, failure to respond to standard treatments, or evidence of metastasis. The confirmation of NUT carcinoma is reinforced by IHC staining and positivity for NUT protein, or next-generation sequencing (NGS). We strongly concur with the use of NGS, as it confirms the presence of NUT fusion and opens an avenue for the discovery of new therapeutic targets, deepening our understanding of the complex and aggressive biology exhibited by these tumors. However, NUT carcinoma poses a significant clinical challenge due to its status as an orphan disease, lacking established treatment protocols, and typically presenting a bleak prognosis. Das et al.[1] have provided a holistic overview of therapeutic options for these aggressive cancers. The available sparse information also indicates these tumors may be amenable to treatment with immune checkpoint inhibitors, warranting further investigation.[6] To summarize, an accurate diagnosis of NUT carcinoma requires a comprehensive evaluation by a multidisciplinary team, including pathologists who could employ clinicopathologic correlation for the advanced interpretation of the cases. NUT carcinoma remains a unique challenge in the landscape of solid cancers, with limited treatment options and a generally dismal outlook, making the search for effective therapies for the management of this rare and aggressive cancer more important than ever before. Financial support and sponsorship Nil. Conflicts of interest Kumar Prabhash is a member of the editorial board of Cancer Research, Statistics and Treatment. As such, he may have had access to information and/or participated in decisions that could be perceived as influencing the publication of this manuscript. However, he recused himself from the peer review, editorial, and decision-making process for this manuscript, to ensure that the content is objective and unbiased.