1. Broad differential application of immunomarkers
Differential Diagnosis
Immunohistochemical markers are crucial to the diagnosis of this entity. The main differential diagnosis is with neuroendocrine carcinoma and the solid form of adenoid cystic carcinoma. Positive epithelial markers exclude lymphoma, melanoma, and primitive neuroectodermal tumour (PNET). Nasopharyngeal carcinoma and oropharyngeal carcinoma associated with high-risk HPV are also included in the differential diagnosis. These entities can be morphologically indistinguishable, so that clinical and radiographic correlation is essential for the diagnosis.
NUT Carcinoma
This rare entity is defined as poorly differentiated carcinoma that expresses the nuclear protein in testis (NUT) gene [17–19]. The diagnosis requires a high degree of suspicion by clinicians and pathologists especially in midline locations, which are a hallmark of the tumour. NUT carcinoma commonly affects young patients but can occur at any age [20]. The most common sites of origin are the nose and paranasal sinuses, but other sites may be affected. Tumours present as a rapidly growing mass with non-specific signs and symptoms [21]. Histologically, the lesion displays undifferentiated/poorly differentiated carcinoma cells similar to those affecting other sites. Diagnosis is based on the detection of rearrangements of the NUT gene (NUTM1). In the majority of tumours, the NUTM1 gene on chromosome 15q14 is fused with BRD4 genes. Less commonly, the NUT1 gene is fused with other partners including the BRD3 and WHSC1L1 genes. The prognosis of patients with this entity is generally poor [22–24].
Neuroendocrine Carcinomas
Tumours of neuroendocrine derivation comprise a spectrum of histomorphologic entities that include well-differentiated neuroendocrine carcinoma (typical carcinoid), moderately differentiated neuroendocrine carcinoma, atypical carcinoid, and poorly differentiated neuroendocrine carcinoma (small and large cell) [25]. These entities are rarely observed in the sinonasal and skull base, and not infrequently lead to differential diagnostic difficulties, which can be resolved by an appropriate use of immunohistochemical studies (Table 1, 2).
Well and Moderately Differentiated (Typical and Atypical Carcinoid)
Histologically, carcinoid tumours are composed of organoid structures, including cell nests, glandular structures, and cords of monotonous basaloid cells with a clear or granular cytoplasm [26]. Atypical carcinoid lesions also exhibit these organised features, but there is evidence of mitotic activity, cellular pleomorphism, and necrosis.
Table 2. Ancillary markers in the differentiation of malignant small cell tumours of the skull base
Poorly Differentiated (Small and Large Cell)
Large and small cell carcinomas are generally composed of undifferentiated cells with a high nuclear to cytoplasmic ratio, high mitotic index, and necrosis.
Differential Diagnosis
The differential diagnosis of these tumours depends on their state of differentiation. For carcinoid and atypical carcinoids it may include adenocarcinoma and pituitary adenoma [27–31]. For small cell neuroendocrine carcinoma, a list of small undifferentiated tumours of different lineages should be included in the differential diagnosis. Immunohistochemical, molecular as well as histomorphologic characteristics should be integrated [32, 33].
Teratocarcinosarcoma
This is a rare skull base and sinonasal tract malignant tumour composed of high-grade carcinomatous, sarcomatous, and immature neural elements [34, 35]. Benign and malignant germ cell elements may also be present. The most frequent sites are the ethmoid, maxillary sinus, and nasal cavity in elderly male patients. The carcinomatous component can be either squamous, adeno, or neuroendocrine, and the sarcomatous can be cartilaginous, bony, or skeletal muscle in nature. Neural elements may contain primitive rosettes with neurofibrillary features [36].
Differential Diagnosis
Especially on limited diagnostic material, the differential diagnosis with sarcomatoid carcinoma and hybrid epithelial and mesenchymal neoplasms may be challenging. Immunohistochemical evaluation of lineage markers including neuroendocrine, p63, and OCT3/4 can be used to highlight the corresponding components.
Sinonasal Adenocarcinomas
There is a spectrum of primary adenocarcinomas originates from either the respiratory epithelium or the underlying seromucinous glands of the sinonasal region (Table 3) [37, 38]. Tumours of respiratory epithelial derivation are frequently located in the nasal cavity and the ethmoid sinus, while those arising from the subepithelial glands frequently affect the nasal cavity and maxillary sinus [39–43]. Grossly, tumours are ill-defined, infiltrative, light tan, and soft [43].
Intestinal-Type Adenocarcinoma
Intestinal-type adenocarcinoma is typically encountered in the sinonasal tract, and its differentiation features are similar to those of adenocarcinomas affecting the intestinal tract. These tumours arise in patients with a history of exposure to hard woods, leather, and certain chemical manufacturing [37–39], and specifically develop in the ethmoid and nasal cavity. Histologically, intestinal-type adenocarcinoma mimics colonic and gastric adenocarcinomas and show significant mucinous and signet-ring features. Seromucinous adenocarcinoma is typically low-grade, with back to back
