2026 年 13 巻 p. 223-228
Classification of neuroendocrine tumors in the paranasal sinuses is difficult, and the management of olfactory neuroblastoma with epithelial differentiation remains unclear. Recently, a group of tumors that exhibit neuroectodermal differentiation while maintaining distinct epithelial characteristics has been proposed as olfactory carcinoma, with reports indicating that these tumors have distinct clinical features and a worse prognosis than olfactory neuroblastoma. Here, we present a rare case in which an initial biopsy from the nasal cavity yielded a diagnosis of cylindrical cell papilloma, but surgical resection via combined transnasal endoscopic and transcranial approaches ultimately revealed a diagnosis of olfactory carcinoma. An accurate diagnosis is of the utmost importance for paranasal sinus tumors because it significantly impacts the treatment strategies and prognosis. In cases of olfactory carcinoma, sampling the glandular structure only may result in a misdiagnosis of papillary epithelial neoplasm. Therefore, sufficient tissue samples must be collected, and the entire tumor must be evaluated.
Sinonasal neuroendocrine tumors are classified into epithelial-derived neuroendocrine carcinoma and sinonasal undifferentiated carcinoma, as well as neuroectodermal-derived olfactory neuroblastoma (ONB).1) However, the diagnosis of these tumors remains challenging because of their rarity, nonspecific clinical findings, and overlapping histological features.2) ONB, a neuroectodermal malignant tumor arising from the basal cells of the olfactory epithelium, was first reported by Berger et al.3) in 1924. ONB accounts for 2%-3% of paranasal sinus tumors and has an incidence rate of 0.4 cases per million people. Neuroectodermal tumors are defined by the presence of primitive cells that replicate developing neural tissue, with frequent production of a neurofibrillary matrix and rosette formation.4) On immunohistochemical staining, ONB shows positivity for the neuroendocrine markers synaptophysin, chromogranin, and INSM1. In addition, ONB cells can differentiate into melanocytic, myogenic, or ganglionic lineages.5) In particular, ONB exhibits varying degrees of epithelial differentiation, a unique characteristic distinct from peripheral neuroblastomas in other regions. Histological epithelial differentiation may take the form of a well-formed gland or, rarely, squamous pearls.6) Although ONB is typically keratin-negative, up to one-third of cases show localized staining for cytokeratin.5) Other reported names include olfactory neuroepithelioma, mixed ONB and carcinoma, or ONB with divergent epithelial differentiation.7-9) It remains unclear whether the epithelial differentiation pattern should be considered an ONB variant or a separate entity.
Recently, the term olfactory carcinoma (OC) has been proposed for a group of paranasal neuroendocrine tumors. Contrary to the traditional epithelial/nervous system dichotomy, these tumors show neuroectodermal differentiation and have histological similarities to ONB, suggestive of an olfactory nerve origin, while also exhibiting clear epithelial characteristics, such as widespread cytokeratin positivity and abundant gland formation.6)
We report a rare case in which a biopsy specimen obtained from the nasal cavity was initially diagnosed as cylindrical cell papilloma, but the final diagnosis was OC.
A 53-year-old woman presented with a 1-year history of decreased motivation and irritability, as well as a 6-month history of olfactory dysfunction and headaches. A neurological examination revealed olfactory dysfunction, higher brain dysfunction, and mild motor impairment in the left lower limb. Computed tomography (CT) and magnetic resonance imaging examinations revealed a large neoplastic lesion extending from the anterior skull base to the right ethmoid sinus and nasal cavity (Figure 1A-E). Edema was noted in both frontal lobes. Bone defects were observed in the anterior cranial fossa and sinus cavity, but the cellular structure of the right ethmoid sinus was preserved. There was no evidence of orbital invasion. CT examinations of the chest, abdomen, and pelvis showed no evidence of primary malignant tumors or lymph node enlargement. Histological examination of a nasal biopsy revealed papillary proliferation of tall columnar epithelial-like tumor cells with nuclear pseudostratification, suggesting a diagnosis of cylindrical cell papilloma. This preoperative diagnosis from the nasal biopsy was consistent with the radiographic findings. The tumor infiltrated the anterior cranial base and showed lateral expansion. Because resection was considered difficult using the transnasal endoscopic approach alone, the combined transnasal endoscopic and transcranial approaches were employed simultaneously. After complete resection of the tumor, multi-layered skull base reconstruction surgery was performed using the fascia of the thigh, the cranial periosteal flap, and the nasal septal flap (Figure 1F).10) The patient received adjuvant radiotherapy for 6 weeks (60 Gy/30 Fr). During the year following discharge, no signs of recurrence were observed.
A preoperative computed tomography bone window image illustrates the bone defects in the anterior skull base and the sinus cavities (A). Preoperative magnetic resonance imaging examinations revealed a large neoplastic lesion extending from the anterior skull base to the nasal cavity (B: diffusion-weighted image, C: T2-weighted image, D: coronal contrast-enhanced T1-weighted image, and E: sagittal contrast-enhanced T1-weighted image). A postoperative sagittal contrast-enhanced T1-weighted image demonstrates complete tumor removal (F).
The entire specimen, extracted via a transcranial approach, consisted of tumor tissue. The epithelial structure of the capsule was not clearly visible. The tumor parenchyma was composed of nuclear chromatin-rich tumor cells with a high N/C ratio that exhibited dense cord-like patterns as well as epithelial-like arrangements forming glands and Flexner-Wintersteiner rosette-like structures (Figure 2A and B). These epithelial-like cells were positive for keratin CAM5.2 (Figure 2C) and partially positive for CK7 and EMA. Between the cord-like structures, clusters of cells with oval to short spindle-shaped nuclei and a fine fibrous matrix were positive for synaptophysin (Figure 2D), calretinin, and SSTR2. CK20, MUC2, and neurofilament were negative throughout the specimen. INSM1 staining was not performed in this case. A few S100-positive cells were observed around the epithelial-like nests and were considered sustentacular cells. Based on these findings, the tumor was judged to be ONB (Hyams grade III) with epithelial differentiation. The tumor resected from the nasal cavity contained tall columnar epithelial cells with oval-shaped nuclei (Figure 3A). These epithelial cells were diffusely positive for CAM5.2 and negative for CK20, CDX2, and MUC2 (Figure 3B). The synaptophysin-positive cell clusters with oval-to-short, spindle-shaped nuclei observed in the intracranial tumor were nearly absent in the nasal cavity tumor (Figure 3C). The Ki-67 labeling index in the hotspot exceeded 20%. Based solely on the histology of the nasal cavity tumor, the most likely diagnosis was non-intestinal-type paranasal sinus adenocarcinoma. Although the entire intracranial tumor tissue was examined, no transition from paranasal sinus adenocarcinoma to ONB was detected, nor was any coexistence of the 2 tumors identified. Based on the clinical findings and the assumption that the intracranial and nasal cavity tumors represented parts of the same lesion, the tumor was diagnosed as ONB with malignant epithelial components and therefore classified as OC.
The intracranial tumor consisted of cuboidal or polygonal tumor cells with a high N/C ratio arranged in cord-like, rosette-like, or glandular patterns (A, B: H&E). These epithelial-like cells were CAM5.2-positive (C). Cell clusters with round nuclei and a fine fibrous matrix interposed between the cord-like structures were synaptophysin-positive (D). Scale bar, 100 μm (A, C, and D) and 50 μm (B).
H&E: hematoxylin and eosin
The tumor resected from the nasal cavity showed tall columnar epithelium with oval-shaped nuclei proliferating in papillary or glandular patterns (A: H&E). These cells were diffusely positive for CAM5.2 (B) and negative for Synaptophysin (C). Scale bar, 100 μm.
H&E: hematoxylin and eosin
Paranasal sinus tumors are rare, and their histological diversity makes diagnosis difficult. Discrepancies between preoperative and postoperative diagnoses have been reported to occur in up to 21% of cases.11) One contributing factor is that small, fragmented specimens obtained by biopsy may not fully capture the histological characteristics of the tumor, potentially leading to an inaccurate diagnosis. In our case, the tumor was diagnosed as papilloma based on a preoperative biopsy, but after resection, it was diagnosed as OC. For paranasal sinus tumors, an accurate diagnosis is of the utmost importance because it significantly impacts the treatment plans and prognosis. In OC, if only glandular structures are sampled, the tumor may be diagnosed as a papillary epithelial neoplasm. Therefore, it is necessary to collect sufficient specimens and evaluate the entire tumor.
OC is defined as a paranasal sinus tumor that exhibits neuroectodermal components similar to ONB, extensive cytokeratin positivity, and abundant glandular formation, which represent clear epithelial characteristics.6) The specific criteria are (1) histological similarities to ONB, (2) immunohistochemical expression of at least one neuroendocrine-specific marker, including synaptophysin, chromogranin, or INSM1, and (3) epithelial differentiation in the form of either non-focal (>10%) cytokeratin positivity or overt glandular or squamous elements, as observed in the present case. However, it is difficult to clearly classify OC as ONB or other neuroendocrine carcinomas based solely on morphological and immunohistochemical features. Molecular characteristics, such as Wnt pathway mutations and ARID1A inactivation, may be useful for differential diagnosis in the future.12)
From a clinical perspective, it is important to compare OC and ONB. In a previously reported series of 53 OC cases, the median age of the patients was 47 years, with 40% aged <40 years, and the male-to-female ratio was 3.4:1.6) ONB shows equal incidence rates in both sexes and is distributed almost uniformly across all age groups, except for a peak among people in their sixties.1) More than half of the OC cases were diagnosed at Kadish-Morita stage C, with progression beyond the paranasal sinuses. Based on the Hyams classification criteria, the majority of cases were grade 3 (52%) or grade 4 (38%), indicating high malignancy. Multimodal therapy, including surgery and external-beam radiation therapy, was performed in 92% of cases, with additional chemotherapy in 56%. However, the disease showed rapid progression, with half of the patients experiencing recurrence at a median of 8 months, 20% developing distant metastases, and 28% dying from the disease. In ONB, the combination of surgical resection and radiation therapy is generally considered the optimal treatment.13) The 5-year survival rate ranged from 60% to 82%, and the 10-year survival rate ranged from 40% to 63%.14) In summary, OC is considered to occur at a younger age than ONB, affects more males, and has a worse prognosis.
In the present case, a mass effect associated with intracranial progression was observed. Thus, based on the preoperative diagnosis of papilloma, surgical resection via the combined transnasal endoscopic and transcranial approaches was performed, with radiation therapy considered if necessary. Even when a preoperative biopsy diagnosis reveals a malignant tumor, such as OC, ONB, or adenocarcinoma, the treatment strategy generally remains surgical resection with adjuvant radiotherapy. However, depending on the preoperative diagnosis, neoadjuvant therapy or particle therapy should also be considered. Regarding the approach, while en bloc resection is not possible with transnasal endoscopic surgery, this approach yields tumorological outcomes (progression-free survival rate and overall survival rate) equivalent to those of combined cranial and endoscopic resection in appropriate patients with paranasal sinus tumors.15) For lesions that can be resected endoscopically, endoscopic treatment alone can be applied. However, the present case exhibited lateral progression beyond the orbital periosteum and adhesion to the brain parenchyma; therefore, simultaneous transnasal endoscopic and transcranial approaches were selected to achieve safe tumor removal and reliable anterior skull base reconstruction.10) Given the established efficacy of postoperative local radiotherapy for ONB, it was also administered in this case.16)
It has been reported that ONB with epithelial differentiation can occur not only spontaneously but also as a response to chemotherapy or radiation therapy.17) The poor prognosis of OC may be due to the limited effectiveness of radiation therapy for the epithelial component, particularly the glandular structure. Because the preoperative diagnosis was papilloma, chemotherapy was not performed. There have been cases in which preoperative chemotherapy was effective for OC, and since induction chemotherapy is supported for ONB when the disease is advanced at onset, induction chemotherapy may also be considered for OC.6)
In the present case, the patient was diagnosed with ONB based on the intracranial lesion and non-intestinal adenocarcinoma in the nasal cavity tissue, leading to a comprehensive diagnosis of OC. According to the 2019 World Health Organization Classification of Tumors, tumors in which neuroendocrine and non-neuroendocrine components each account for at least 30% of the tumor volume are defined as mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN).18) Although most cases occur in the gastrointestinal tract and pancreas, rare cases have been reported in the nasal cavity and paranasal sinuses.19) OC may also be included within the concept of MiNEN.5) The pathogenesis of MiNEN remains unclear. The "common progenitor cell theory," which suggests that MiNEN arises from the proliferation of a single precursor cell with distinct differentiation patterns, is currently favored over the "collision theory," which posits that MiNEN results from the combined proliferation of 2 distinct tumor clones.20) It is believed that, in most cases, highly proliferative neuroendocrine tumor cells appear through the differentiation of adenocarcinoma cells.21) These cells then aggregate and proliferate in the deep-infiltrating portion of the preceding adenocarcinoma, forming an adenocarcinoma-neuroendocrine neoplasm. Therefore, the pattern of adenocarcinoma in the superficial part of the lesion and neuroendocrine tumor in the deep part is common. In our case, the presence of non-intestinal-type adenocarcinoma in the paranasal sinuses and ONB in the cranium is consistent with this theory. Notably, the nasal cavity tumor was almost entirely composed of non-neuroendocrine cells, resulting in a characteristic biphasic pattern in which the intranasal and intracranial lesions were entirely distinct. Attwood et al.22) also reported that lesions with more prominent epithelial components were observed in the paranasal sinuses, forming glands, cords, cribriform structures, and ill-defined sheets, with a combination of epithelial and neuroendocrine components within the cranial cavity. A nasal cavity biopsy may potentially misdiagnose OC as an epithelial neoplasm.
ONB can exhibit diverse differentiation, and in cases like the present one, it may lead to a diagnosis of OC with clear epithelial characteristics, such as widespread cytokeratin positivity and abundant glandular formation. Compared with ONB, OC has a different clinical course, and because of its poor prognosis, accurate diagnosis and multidisciplinary treatment are crucial. Active resection is necessary to evaluate the entire tumor.
The authors thank Alison Sherwin, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
All authors have no conflict of interest.
Informed consent was obtained from the patient for the publication of this case report and the accompanying images.
