NUT Carcinoma-An Underdiagnosed Malignancy

Abstract

NUT carcinoma (NC) is a rare and highly aggressive malignancy with a dismal prognosis and a median survival of 6-9 months only. Although very few cases of NC are reported each year, the true prevalence is estimated to be much higher, with NC potentially widely underdiagnosed due to the lack of awareness. NC primarily occurs in midline structures including thorax, head, and neck; however, other sites such as pancreas and kidney are also affected, albeit at lower frequencies. NC is characterized by a single translocation involving the NUTM1 (NUT midline carcinoma family member 1) gene and different partner genes. The resulting fusion proteins initiate tumorigenesis through a mechanism involving BET (bromo-domain and extra-terminal motif) proteins such as Bromodomain-containing protein 4 (BRD4) and inordinate acetylation of chromatin, leading to the dysregulation of growth and differentiation genes. While no clinical characteristics are specific for NC, some histologic features can be indicative; therefore, patients with these tumor characteristics should be routinely tested for NUTM1. The diagnosis of NC using immunohistochemistry with a highly specific antibody is straightforward. There are currently no standard-of-care treatment options for patients with NC. However, novel therapies specifically addressing the unique tumorigenic mechanism are under investigation, including BET inhibitors. This review aims to raise awareness of this underdiagnosed cancer entity and provide all patients the opportunity to be properly diagnosed and referred to a clinical study.

Keywords: BET inhibitor; BRD4; NUT carcinoma; NUT rearrangement; NUTM1.

Figure 1

Structured literature search for NC case reports. A structured literature search for published cases of NC was performed on January 20, 2022. Of 336 cases retrieved, 125 were discarded as irrelevant upon the analysis of abstracts. Upon further review of the remaining articles, 12 additional publications were identified. All 223 articles were reviewed in detail; 48 were discarded because they were irrelevant on closer review, did not provide sufficient information on patient data, or contained duplicate cases. The remaining 175 articles provided data on 310 unique cases of NC.

Figure 2

Country of origin of NC cases that were identified in structured literature search. For 306 of the 310 identified cases, the country of origin was available. About half of these presented in the United States, whereas other countries such as Germany were underrepresented relative to the overall population size, suggesting that NC is underdiagnosed.

Figure 3

A model for tumor development in NC through oncogenic mega-domain formation. In healthy cells, BRD complexes including transcription activation factors and mediator complex subunits serve as transcriptional facilitators. These complexes comprise NSD3 and ZNF532. In NC cells, a single translocation creates a NUTM1 fusion protein, in most cases with BRD4 or BRD3 as the fusion partner. The bromo-domains of the BRD proteins tether NUTM1 to acetylated chromatin. NUTM1, in turn, recruits the histone acetyl transferase EP300, thereby increasing the acetylation of the surrounding chromatin. In a feed-forward mechanism, more NUT-fusion protein complexes bind to the additional acetylation sites and the increased acetylation expands, creating acetylated mega-domains in which proliferation genes are transcribed. (23, 25).

Figure 4

Diagnosis of NC based on histopathological features and IHC to NUTM1 (antibody clone C52B1 by Cell Signaling Technology, Danvers, MA, USA) (adapted from French et al., 2018, and reprinted with permission). (A) NCs typically show a monomorphic appearance with round cells. The white arrowhead indicates a cell with “fried-egg” appearance. (B) In certain areas, altered cells may appear more frequently. (C) In some but not all NC tumor samples, focal squamous differentiation can be observed. (D) A common feature is the (sometimes prominent) infiltration by neutrophilic cells. (E) Non-NC tumor tissue does not show any staining of NUTM1. (F) Nuclei in NC tumor tissue show diffuse staining with a typically speckled appearance. A positive staining for NUTM1 in more than 50% of nuclei in a tumor sample is diagnostic for NC. NUT Carcinoma: Clinicopathologic features, pathogenesis, and treatment, Christopher A. French. Copyright © 2018 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd. Reproduced with permission of John Wiley & Sons Ltd.

Figure 5

Recommended algorithm to ensure that a diagnosis of NC is considered in appropriate patients. NUT carcinoma should be considered in every patient presenting with undifferentiated or poorly differentiated squamous carcinoma with monomorphic cells, regardless of the presence of the foci of squamous differentiation. NCs are often characterized by aggressive growth and often, although not always, originate from midline structures. Viral etiology has not been associated with NC, and glandular differentiation is not common; therefore, both can be used to exclude NC. For the diagnosis of NC, it is sufficient to demonstrate the expression of NUTM1 in tumor tissue using IHC to NUTM1. Additional approaches can be chosen to validate the diagnosis or to identify the fusion partner of NUTM1.