diagnosis mandates knowledge, experience, judicial use of lineage and genetic markers, and close interactions between surgeons and pathologists. This pathology paper presents a concise review of the tumours more commonly encountered in the anterior skull base region and their differential diagnosis for practitioners.
Epithelial-Derived Tumours
The majority of epithelium-derived tumours affecting different anatomic sites of the skull base region are malignant. In general, sinonasal carcinomas encompass different types and commonly affect the maxillary sinus (60%), nasal cavity (22%), ethmoid sinus (15%) and, less frequently, the frontal and sphenoid sinuses (3%). Carcinomas arise either de novo from squamous epithelium, squamous metaplasia of respiratory epithelium, or rarely preexisting squamous papillomas, especially the inverted form. The majority of these malignancies are squamous carcinomas and, less commonly, adenocarcinomas and neuroendocrine carcinomas.
Malignant Tumours
Conventional Squamous Carcinoma
Squamous carcinoma typically occurs in elderly individuals in their 6th and 7th decades with a tendency for male gender (M:F 2:1) [1–3]. The most common sites are the maxillary sinus, nasal cavity, and ethmoid, frontal, and sphenoid sinus. Grossly, squamous carcinomas are typical ulcerated and indurate with exophytic features; sinus tumours are bulky and composed of friable light tan tumour tissues [4]. Histologically, tumours typically display squamous differentiation and are graded as well, moderately, or poorly differentiated. Tumours originating from the nasal cavity are generally well differentiated. Tumours of the paranasal sinuses and skull base are commonly non-keratinising carcinomas of intermediate to poor differentiation. Poorly differentiated carcinomas are also called Schneiderian carcinoma and may originate from preexisting inverted papillomas [5, 6]. Rarely, tumours may exhibit spindle cell features and mimic sarcoma or spindle cell melanoma.
Differential Diagnosis
Squamous carcinoma may occasionally pose a diagnostic challenge on small biopsy specimens with sialometaplasia, pseudoepitheliomatous hyperplasia, and Schneiderian papilloma with squamous metaplasia. The common primary lesion to be differentiated in early assessment is inverted papilloma, where a transitional-like squamous proliferation in an inward growth is the typical feature of a lesion frequently observed in the sinonasal tract.
Nasopharyngeal Carcinoma
The histopathologic characteristics of these tumours vary according to the World Health Organisation (WHO) classification [1]. Nasopharyngeal carcinoma is classified into keratinising and non-keratinising phenotypes and corresponds to WHO type I and II/III grades [1]. Pathogenesis is strongly linked to Epstein-Barr virus (EBV) infection and has an ethnic and geographic distribution [7, 8]. Keratinising type (WHO I) is characterised by squamous differentiation showing keratinisation. Non-keratinising types (WHO II and III) are composed of sheets of undifferentiated malignant epithelial cells intimately intermingled with a chronic inflammatory infiltrate which is commonly EBV positive in endemic regions. In situ hybridisation for EBV-encoded RNA is routinely used to identify EBV uniformly in all tumour cells. Serology for EBV-encoded RNA is currently used for follow-up [9, 10].
Sinonasal Undifferentiated Carcinoma
The diagnosis of sinonasal undifferentiated carcinoma is made after the exclusion of morphologically recognised squamous- and glandular-derived carcinomas [11, 12]. Tumours are characterised by primitive malignant epithelial cells with high mitotic figures and cellular necrosis and no squamous or glandular differentiation [13, 14]. Patients are typically elderly males who present with an advanced stage disease. Tumours most commonly originate from the nasal cavity and ethmoid [15, 16]. Grossly, tumours are typically light tan and soft, infiltrative and ill-defined. Histologically, the lesion is composed of sheets of undifferentiated cells with a low nuclear-cytoplasmic ratio, prominent nucleoli, and reticular and clear nuclei with a high mitotic rate and necrosis [15]. Lymphocytic infiltrate may be present associated with epithelial tumour cells, similar to what is observed in nasopharyngeal and human papillomavirus (HPV)-associated oropharyngeal carcinoma [16].
Table 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