Table 4. Genetic rearrangements of potential clinical significance in skull base malignancies
Pleomorphic Adenoma
Pleomorphic adenoma may develop from minor salivary glands of the sinonasal epithelium, prevalently in the nasal cavity. Involvement of the anterior skull base has been observed, especially in recurrent tumours [48]. The tumour has a similar macroscopic appearance to those of major glands; association with carcinoma should always be excluded by careful analysis of the entire specimen [49, 50].
Soft Tissue Tumours: Malignant Tumours
Malignant soft tissue tumours of the skull base are varied and may not infrequently lead to diagnostic and management challenges. Familiarity and proper use of lineage and molecular testing are critical to their diagnosis (Table 4).
Fibrosarcoma
This is the most frequent mesenchymal malignancy of the sinonasal tract, which more commonly affects the maxillary sinus, nasal cavity, and ethmoid. Grossly, the tumour presents as light-tan and fleshy with a smooth surface with soft-to-firm consistency [51–53]. Histologically, the tumour typically forms sweeping spindle cell interlacing bundles extending to surrounding tissue cells with moderate to low mitotic activity.
Differential Diagnosis
A number of benign and malignant spindle cell tumours which encompass desmoid fibromatosis, sinonasal hemangiopericytoma, solitary fibrous tumours, leiomyosarcoma, and epithelioid haemangioendothelioma must be differentiated from this entity. Distinction between fibrosarcoma and desmoid fibromatosis at this location is based on the sparse cellularity and the fibrotic stroma, while differential diagnosis with leiomyosarcoma is based on the detection of smooth muscle features by immunohistochemistry [54–57].
Rhabdomyosarcoma
Rhabdomyosarcoma is a rare form of sarcoma with skeletal muscle differentiation [58–63]. There are three main histological subtypes that include embryonal, alveolar, and pleomorphic variants. The most commonly encountered subtype in the sinonasal site is the embryonal form, which mainly affects the paediatric age. In adults, the alveolar subtype is more common than the embryonal form. Histopathologically, immunohistochemical markers are crucial to detect primitive skeletal muscle differentiation. Genetically, only the alveolar subtype harbours fusion genes (PAX3-FOXO1 and PAX7-FOXO1) [64–66].
Differential Diagnosis
The embryonal subtype should be differentiated from small cell tumours, olfactory neuroblastoma, small cell neuroendocrine carcinoma, and sinonasal melanoma. As aberrant keratin and neuroendocrine markers (synaptophysin/chromogranin) may occur in the alveolar subtype, immunohistochemical assessment for muscle markers (desmin/myogenin) is critical to this diagnosis.
Synovial Sarcoma
Synovial sarcoma may involve the skull base region as extension from oropharynx or adjacent structures [67]. The tumour affects young patients with a median of 25 years and a male predominance. A specific chromosomal translocation t(X;18)(p11;q11) that leads to the formation of the SS18-SSX fusion gene has been described in a subset of patients [68–70]. Histologically, synovial sarcoma may present as a pure spindle cell variant (monophasic) or biphasic when both spindle and epithelial components are present. The epithelioid component is typically formed of cuboidal or columnar epithelial cells forming cords, nests, and pseudoglandular spaces intermingled with a spindle cell proliferation. Although morphology is the cornerstone for diagnosis, ancillary markers, including keratin and epithelial membrane markers, can be used. In situ or PCR-based hybridisation for the t(X;18)(p11.2; q11;2) translocations may be of help, if positive [71, 72].
Differential Diagnosis
Spindle cell tumours including spindle cell carcinoma, fibrosarcoma, melanoma, and metastatic carcinoma to the base of skull are entities that may cause an initial diagnostic challenge, especially on small biopsy samples. The combined clinicopathologic and immunohistochemical marker features should be integrated in the diagnosis of this entity.
Angiosarcoma
Angiosarcoma of the skull base is exceedingly rare, and diagnosis is based on the identification of abnormal vascular proliferation and the invasive nature of tumour. Immunohistochemical positivity for ERG (nuclear expression) and CD31 confirms the vascular origin of the lesion. These markers will also be expressed by the vascular component of angiofibroma and haemangiopericytoma, although the associated stromal components will not stain [73–77].
Chondrosarcoma
Chondrosarcoma commonly develops from the nasal septum or nasoethmoidal complex, but may present as an extension from a maxillary primary. The tumour presents in different age groups, with the mesenchymal phenotype mainly affecting patients in the 2nd and 3rd decades of life [78]. The most common presenting symptoms are craniofacial bone expansion and pain, as well as nasal obstruction and orbital content displacement. Grossly, these tumours manifest translucent and cartilaginous features with scattered calcifications. Myxomatous areas with lobulation are commonly seen. The histologic spectrum seen in these tumours ranges from benign-appearing hyaline cartilaginous lesions to highly cellular malignant spindle cell sarcoma [79–