Differentiated Papillary NUT Carcinoma: An Unexpected, Deceptively Bland Presentation of a Sinonasal Carcinoma

Over the past decade, the spectrum of malignant tumors of the head and neck has expanded, with many entities characterized by distinct molecular alterations. For example, carcinomas comprise conventional squamous cell carcinomas, NUT carcinomas, DEK::AFF2 carcinomas, EBV- and HPV-associated carcinomas, undifferentiated as well as SWI/SNF complex deficient sinonasal carcinomas, highlighting the variety of different morphologies and molecular pathogeneses [1]. However, morphological overlap between different entities should be considered during the process of histopathological diagnosis. Here we report the case of a 32-year-old male patient, who presented with a non-healing lesion of the upper alveolar ridge after tooth extraction, leading to an oro-antral fistula. The histological features of the initial biopsy appeared deceptively bland, prompting the differential diagnosis of reactive inflammatory changes. However, an external histopathological consultation accompanied by molecular work-up with the detection of a NSD3::NUTM1 fusion, yielded the unexpected diagnosis of a sinonasal NUT carcinoma originating from the maxillary sinus.

The histological and clinical features of the current case represent a highly unusual constellation. Typical NUT carcinoma is characterized by a more undifferentiated monomorphic morphology with small squamous islets and abrupt keratinization. These features were not present in our case. Nevertheless, the molecular profile, the NUT::NSD3 gene fusion, has been recurrently described in NUT carcinomas and confirms the diagnosis, especially in association with a squamous phenotype. Accordingly, this case can be regarded as part of the spectrum of NUT carcinomas and emphasizes the importance of considering this differential diagnosis in mature and well-differentiated squamous cell carcinoma. Such atypical features as well as the lack of awareness of this entity suggest an under-diagnosis and -reporting of NUT carcinomas [6]. The partly prominent squamous epithelial differentiation and the growth pattern are highly unusual and to the best of our knowledge have not been described in NUT carcinomas. In this regard, NUT carcinomas are characterized by translocation-associated fusion oncoproteins that interfere with cell differentiation and cell growth. The majority of NUT-fusions involves BRD4 (bromodomain containing protein 4), leading to an epigenetically induced block of cell differentiation and promotion of cellular growth. NSD3 encodes a histone lysine methyltransferase that binds the extraterminal domain of BRD. In cases harboring the NUT::NSD3 fusion, this alteration probably leads to similar functional oncogenic consequences. However, as presented in this case, the level of interference with cell differentiation might be different in NUT::NSD3 fusion than in NUT::BRD4 fusion [7]. This could explain why NUT::NSD3 fusion positive carcinomas outside the thorax appear to have a significantly better prognosis than their NUT::BRD4 positive counterparts [8]. An additional diagnostic challenge are the reactive, inflammatory squamous epithelial changes, which can be prominent after an intervention such as a tooth extraction. The relatively young patient age and the unusual morphology led to the consideration of an HPV-associated carcinoma, which could not be substantiated, as immunohistochemistry for p16 and molecular analysis for HPV DNA were negative. A carcinoma with DEK::AFF2 gene fusion was considered as the primary differential diagnosis on morphologic grounds. These carcinomas have recently been described and exhibit similar morphologic features to the current case [3, 4]. Importantly, this case presented significant morphological overlap with other head and neck carcinomas. The NUT::NSD3 gene fusion has recently been described in a subset of thyroid carcinomas without classical features, so that there is a rationale for NUT immunohistochemistry and/or molecular testing in unusual cases. In particular, there is increasing evidence that NUT gene fusions can occur in tumors with different underlying cell types (other than squamoid-like cells), such as thyroid follicle cells. Additional data are needed for accurate classification of these increasingly detected neoplasms [9, 10]. The concept of tumoral-mucosal fusion as a potential pitfall of processes underlying the surface mucosa is recognized in minor salivary gland neoplasia [11]. However, the observation that the majority of bland squamous cells in the mucosa were NUT IHC positive in our case, suggests that maturation may be involved. This case further demonstrates that highly sensitive and specific NUT immunohistochemistry is useful in identifying cases with unusual morphology, thus enabling accurate classification.

Future studies on larger numbers of cases are needed for comparing the biological behavior and other features of “differentiated NUT carcinoma” with the classical type.