Nasopharyngeal tumor developing in a 36‐year‐old man following radiation for a childhood meningioma

Clinical History and Imaging

A 36‐year‐old man presented with a large nasal tumor following a long history of multiple meningiomas. At the age of 13, the patient underwent surgical resection and received a single course of radiation therapy for a left optic meningioma. He did well until age 33, when he was found to have multiple meningiomas in three new locations: falcine (Figure 1a), right petroclival, and right anterior foramen magnum. These were surgically resected but no additional radiation was administered. Three years later, the patient presented with nasal symptoms, headaches, and seizures. Imaging studies revealed a large mass with intracranial and nasopharyngeal components measuring 4.1 × 5.4 × 6.8 cm in greatest dimensions and causing right frontal lobe compression (Figure 1b,c). A systemic workup, including PET CT, for other malignancies was unremarkable. A two‐stage surgical resection was performed. The mass was initially biopsied by transsphenoidal endoscopic approach and then partially resected by bifrontal craniotomy, frontal sinus obliteration, en bloc ethmoidectomy, and nasal cavity resection.

Figure 1.

Microscopic Pathology

Pathologic examination revealed a high‐grade malignant neoplasm that appeared primitive. Architecturally, the tumor consisted of patternless sheets of tumor cells interrupted by abundant glandular, trabecular, and rosette‐like arrangements (Figure 1d). The latter mostly resembled Flexner–Wintersteiner rosettes as they exhibited central canals, while scattered ones mimicked Homer Wright rosettes (Figures 1e and 1f). Occasional lumina with mucinous‐like material were observed. A finely vacuolated, neurophil‐like background was evident on close examination. The neoplastic cells showed a variable degree of pleomorphism, with hyperchromatic nuclei and coarse salt and pepper chromatin and small nucleoli. Mitotic figures were readily identified and apoptotic bodies were abundant (Figure 1g). Extensive hemorrhage and necrosis was present. Periodic acid Schiff (PAS) stain showed the epithelial tumor cells with PAS‐rich contents. Immunohistochemical stains were performed and showed immunoreactivity for AE1/AE3 in many of the tumor cells, particularly in the areas showing glandular differentiation (Figures 1h and 1i). Chromogranin showed faint diffuse immunoreactivity, while synaptophysin was focally immunoreactive (Figure 1j). NeuN immunohistochemical stain elicited a striking pattern of immunoreactivity with abundant intense vesicular staining in an apical fashion in most of the epithelial areas (Figure 1k). CD99, GFAP, SALL4, and WT1 were not immunoreactive. INI1 was expressed by the neoplastic cells. Genetic analysis revealed no rearrangement of the EWSR1 gene. What is your diagnosis?

Diagnosis

Olfactory neuroepithelioma.

Discussion

This unusual and very large extra‐axial tumor appeared to be arising in the nasopharyngeal region with extension through the cribriform plate and into the frontal lobes. The anatomical location, as well as the histologic and immunohistochemical resemblance to the primitive neuroectoderm, raised the possibility of olfactory neuroblastoma. The prominent epithelial features briefly prompted consideration for metastatic carcinoma but clinical workup for systemic disease was negative and the tumor looked decidedly neural, albeit primitive. Furthermore, the epithelioid areas demonstrated striking similarities to the embryonal tumor medulloepithelioma. In essence, this tumor appeared to be an olfactory neuroblastoma with prominent epithelial differentiation. A final diagnosis of olfactory neuroepithelioma was rendered.

Olfactory neuroepithelioma is a term that was proposed to describe a rare high‐grade neoplasm with striking divergent epithelial and neuroendocrine/neuroblastic differentiation 4. The epithelial component is represented by variably sized, back‐to‐back glandular‐like spaces with pale mucinous material. Flexner‐type rosettes and trabecular and cord‐like arrangements might also be present. The neuroblastic component is similar to a more conventional olfactory neuroblastoma/esthesioneuroblastoma though with considerably more mitoses and apoptosis 2, 3. The sheets of high‐grade, hyperchromatic small cells are interrupted by scattered and somewhat inconspicuous Homer Wright rosettes. The glandular‐like areas react with epithelial markers (keratin and EMA) but also variably stain with neuroendocrine markers. They also show striking NeuN immunoreactivity in an apical and vesicular cytoplasmic fashion, similar to what is seen in the vomeronasal sensory epithelium. These observations point to olfactory epithelial differentiation.

At issue here is the possible relationship between the past history of meningiomas and radiation therapy in the area. To our knowledge, this is the first reported case of radiation‐induced olfactory neuroepithelioma. The amount of radiation needed to cause mutations is not necessarily very high, as tumors occur even after low doses of radiation (as low as 3–5 GY). Although epidemiological evidence cites sarcomas and meningiomas as the most frequent tumors to develop following radiation, there have also been consistent reports of low‐ and high‐grade gliomas in previously irradiated regions.

The treatment modalities reported in the literature were highly variable and consisted of various combinations of surgery, radiotherapy, and chemotherapy 1. Olfactory neuroblastoma showed best survival results when the patients were treated with surgery and radiotherapy. Six months following the second surgery in the index patient, the tumor was found to have progressed with intracranial, intraorbital, and leptomeningeal extensions. There was also involvement of the glabella and nasal bone, including the nasal dorsum. Following surgery, the patient was given palliative chemotherapy and few cycles of radiation therapy. Follow up MRI one year after his second surgery showed excellent response. The patient is still alive and doing well. In conclusion, this is a highly unusual neoplasm that is morphologically unique and site specific. It should be thought of as a morphologic variant of olfactory neuroblastoma. Whether one applies the “olfactory neuroepithelioma” terminology is of less consequence as long as it is classified as a primitive neuroectodermal tumor of the nasopharyngeal region. Awareness of the general classification of this tumor could thwart confusion with metastatic carcinomas and possibly spare the patient from an unnecessary workup.