Mixed Olfactory Neuroblastoma and Adenocarcinoma with In Situ Neuroendocrine Hyperplasia

A 66-year-old right-handed female presented to the Emergency Department after her first generalised tonic–clonic seizure that had started while she was sitting watching television. Four months prior to this, the patient had experienced a single absence-like seizure episode described as a short period of staring without being able to speak. There was also a nine-month history of mild early morning headaches and intermittent anosmia. Her past medical history included choriocarcinoma in remission, coeliac disease, hiatus hernia, osteopaenia and allergic rhinitis. Examination of the head, neck and neurological system was normal. Full blood count, coagulation, liver function, urea and electrolytes were within normal ranges, except for a moderate hyponatraemia (122 mmol/L), low serum osmolality (263 mOsm/kg) and low urine osmolality (134 mOsm/kg), consistent with a syndrome of inappropriate antidiuretic hormone secretion (SIADH).

MRI scan of the head revealed a cystic mass extending from the left nasal cavity into the anterior cranial fossa, associated with vasogenic oedema at the base of both frontal lobes (Fig.  1). There was minor midline shift to the right and minimal effacement of the anterior horn of the left lateral ventricle, but no evidence of hydrocephalus or haemorrhage. The patient was given dexamethasone for reversal of cerebral oedema and levetiracetam for seizure prophylaxis. Computed tomography (CT) scan of the thorax, abdomen and pelvis showed no evidence of disseminated malignancy (modified Kadish stage C, Dulguerov stage T4N0M0, Biller stage T3N0M0). The case was discussed in the neuro-oncology multi-disciplinary team meeting, and the decision was taken to offer an endoscopic-guided anterior skull base biopsy.

Histopathological analysis of the biopsy specimen showed respiratory epithelium with in situ neuroendocrine cell hyperplasia, which was in the form of cell nests composed of small cells containing uniform nuclei and small nucleoli, with interspersed fibrillary neuropil-like material (Fig.  2a, b). The cells stained with chromogranin and synaptophysin, and the neuropil-like material was positive for neurofilament (Fig.  2c–f). No neuroblastoma or neuroendocrine carcinoma were noted in the biopsy. The patient was offered radical resection by an image-guided bicoronal craniotomy and transnasal endoscopic approach. The lateral borders of tumour were dissected to the skull base and anterior and posterior bony borders were drilled down, before repair was made using a right nasoseptal flap. Tumour resection was then completed intracranially.

The specimens surgically resected from the left sinonasal cavity and from inside the anterior cranial fossa revealed a distinctly biphasic tumour, comprising an epithelial component of atypical cuboidal and ciliated columnar cells, and a neuroendocrine component of primitive-appearing small cells with scant cytoplasm and speckled nuclear chromatin (Fig.  3a–d).

The epithelial component was prominent within the sinonasal cavity, and formed glands, cords, cribriform structures and ill-defined sheets. The neuroendocrine component comprising small cells was interspersed with the glandular element. In the intracranial specimen, ill-defined and anastomosing sheets of both components were present. Brain tissue was identified and it is likely that cells with moderately abundant eosinophilic cytoplasm represented native neuronal cells rather than ganglionic differentiation within the tumour. No focal necrosis was seen, however, apoptotic nuclear fragments were present amongst tumour cells. There were, on average, two mitoses per ten high power fields.

Immunohistochemical analysis of the epithelial component showed strong cytokeratin CAM 5.2, AE1/AE3 and CK positivity (Fig.  4a). The small neuroendocrine cells showed patchy and variable intensity perinuclear staining at least focally. Epithelial membrane antigen stained the epithelial component and there was a diffuse, dot-like staining of the neuroendocrine cells. CD56, chromogranin, synaptophysin and calretinin stained the neuroendocrine cells but not the epithelial component (Fig.  4b–d). On S100 staining, there was a focal peripheral staining of some tumour groups in the intracranial component in a manner similar to that observed with sustentacular cells in ONB (Fig.  4e). There was no staining with p63 (Fig.  4f). The proliferation fraction was variable but low overall, and estimated to be less than 10%.

In summary, this was a biphasic tumour with epithelial and neuroendocrine components. Sinonasal teratocarcinosarcoma is a rare tumour that can arise in this site and shows a combination of epithelial, mesenchymal and neuroepithelial elements. This entity was not considered in the differential diagnosis due to the lack of heterologous epithelial elements including squamous cells and of a mesenchymal component with rhabdomyoblastic, cartilaginous, osteoblastic, smooth muscle or adipocytic differentiation [ 17]. Based on the morphology and immunophenotype, the following diagnoses were considered: combined neuroendocrine carcinoma and adenocarcinoma, ONB with divergent glandular differentiation, and mixed ONB and adenocarcinoma. The diagnosis of ONB was favoured over a neuroendocrine carcinoma due to the presence of neuropil-like material, S100 positive sustentacular cells focally within the tumour, positivity of the neuroendocrine component for calretinin and negativity for p63, location of the lesion arising out of the left olfactory groove, and the presence of neuroendocrine hyperplasia. The last feature has been described in ONB [ 18]. The distinction between co-incident adenocarcinoma and divergent glandular differentiation, both of which have been described in cases of ONB, was made on the basis of significant cellular atypia, ciliated cells, and irregular CK staining in the glandular component. Following these considerations, a final diagnosis of mixed ONB and adenocarcinoma was made.

The patient went on to receive adjuvant chemotherapy and radiotherapy. Post-treatment MRI head and whole-body positron emission tomography (PET)-CT showed no evidence of metastasis. However, 9 months after treatment, a soft mobile mass measuring 2 cm in the left neck level IIb/III was identified. Ultrasound of the neck revealed bilateral level IIb-IV nodes. Fine needle aspiration of the palpable left node was performed, which was highly cellular and contained malignant cells arranged both in groups and as a dispersed population. Some cells showed high nuclear-to-cytoplasmic ratio, whilst others contained moderate amounts of pale blue cytoplasm. In places the nuclei had speckled chromatin and showed evidence of moulding. Mucoid material with scattered macrophages and lymphoid cells were present in the background. This cytomorphology was considered consistent with metastatic spread of the primary tumour.

The patient underwent bilateral modified radical neck dissection and node clearance with a temporary tracheostomy for 1 year. Histological examination confirmed metastatic adenocarcinoma with occasional small areas of solid growth suggestive of neuroendocrine differentiation in 20 of 115 nodes. The patient received adjuvant radiotherapy for 6 weeks. Six month post-treatment whole-body PET-CT has shown no evidence of recurrent disease.