Abbreviations
NB — neuroblastoma
ChSA — chiasmal-sellar area
MRI — magnetic resonance imaging
CT — computed tomography
CNS — central nervous system
LI — labeling index
TFD — total focal dose
SFD — single focal dose
TCS — transcranial surgery
TNS — transnasal surgery
RT — radiotherapy
ChT — chemotherapy
Olfactory neuroblastoma (esthesioneuroblastoma) is a rare malignancy (about 1300 cases have been described since 1924 [1]). This tumor is characterized by invasive growth and distant metastases [2]. Women/men ratio with this disease is 1.7:1, mean age of patients — 40 years (range 1.4—57 years) [3]. Esthesioneuroblastoma grows from stem cells of olfactory epithelium [4]. In the initial stages, the tumor usually occurs in the upper parts of nasal cavity and can infiltrate sinuses [5, 6]. In this case, neoplasm is manifested by shortness of breath and nosebleeds. Invasion of anterior cranial fossa, orbit and ChSA is followed by hyposmia, headache, visual and oculomotor disturbances [7, 8].
Primary neuroblastoma of CNS is also described. These tumors are extremely rare, account for less than 1% of all primary tumors of CNS and usually occur in supratentorial paraventricular region [9, 10]. Primary sellar neuroblastomas are even less common (currently only 11 cases are presented in the literature [11— 19] (Table 1).
It is still difficult to reliably judge about pathogenesis and optimal treatment strategy in patients with primary sellar neuroblastomas due to small number of observations. We report a 29-year-old man with primary sellar neuroblastoma who underwent successful complex treatment.
Case report
A 29-year-old man admitted to the Burdenko Neurosurgery Center on February 11, 2018 with complaints of impaired vision and diplopia. These symptoms occurred 2 months ago. MRI revealed endo-infra-supra-latero (D-S)-retrocellular isointense tumor on T1- and T2-weighted images with bilateral invasion of cavernous sinuses and heterogeneous contrast enhancement (Fig. 1).
Considering clinical and X-ray data, endoscopic endonasal transsphenoidal resection of tumor was performed on February 12, 2018. The bottom of sella turcica was destructed by a tumor. The last one was followed by invasion of sphenoid sinus. We resected only endo- and infracellular parts of the tumor due to advanced blood supply and dense consistency of the neoplasm. It was intraoperatively found that the tumor was not connected with olfactory bulbs and ethmoid cells. Therefore, true origin of the tumor was unclear. Postoperative period was uneventful.
Histological examination — pituitary adenoma with nuclear polymorphism and perivascular structures. Considering partial resection of tumor, radiotherapy was recommended. However, the patient refused additional treatment for personal reasons.
Control MRI of the brain in 3 months after surgery revealed significant tumor enlargement compared with preoperative MRI (Fig. 2).
Clinical symptoms included diabetes insipidus and blindness in the left eye. Considering this situation, redo endoscopic endonasal surgery was performed on May 29, 2018. The bottom of sella turcica is destroyed by a tumor. Dense tumor was characterized by intensive bleeding. It was almost impossible to remove the tumor by conventional sucker that required the use of ultrasound destructor. This method was effective for resection of almost entire endo-infra-suprasellar part of the tumor. However, resection of lateral segments was not performed due to high risk of damage to the vascular-nervous structures of cavernous sinuses (Fig. 3).
Histological examination revealed the fragments of malignant low-grade tumor consisting of relatively monomorphic rounded cells with hyperchromic nuclei and numerous mitoses. In some areas, the tumor was characterized by alveolar structure and small number of perivascular structures. There was variable distribution of cellular density that influenced histological picture. Zones of dense arrangement of small cells with unclear cytoplasm prevailed. In the other areas, less dense arrangement of larger cells with optically empty cytoplasm was observed. Immunohistochemical study revealed significant expression of synaptophysin by tumor cells, membrane expression of CD 56 and CD 99, and S 100 expression in stromal cells. In addition, negative expression of epithelial, melanotic, lymphocytic markers and hormones of pituitary adenoma was determined. Labeling index (LI) Ki-67 was 40—50%. Specimen from the first operation was repeatedly examined and immunohistochemical study was conducted. As a result, negative expression of S-100 and Ki-67 up to 20—30% were detected.
In general, morphological picture is not specific and can correspond to several forms of lesion. In particular, pituitary adenoma could be suspected after the first operation considering predominant histiostructural component with relatively low cellular density and pseudo-alveolar structure.
However, this diagnosis is not confirmed by clinical data (aggressive course of tumor with fast relapse), morphological data after the second operation (significantly increased cellular density, number of mitoses, severity of cellular and nuclear atypia) and immunophenotypic features (high proliferative activity in tumor tissue, expression of CD 56 involved into the processes of adhesion and development of nerve cells and CD 99 regulating early stages of maturation of neuroectodermal cells not typical for pituitary adenoma). It is worth noting that some studies demonstrate the possibility of CD56expression in pituitary adenomas. However, CD56 is detected during immunohistochemical examination only in 50% of cases [20]. Additional conclusion is also confirmed by the absence of expression of hormonal factors.
Another possible diagnosis is neuroendocrine carcinoma. From histological and histogenetic positions, neuroendocrine carcinoma may be confirmed by positive expression of synaptophysin that phenotypically manifests tumoral neuronal component. However, this diagnosis is unlikely considering the lack of expression of cytokeratins (markers of epithelial histogenetic component) and positive expression of CD99.
Lymphoproliferative and melanotic tumors are important variants of differential diagnosis of tumor with morphological properties of malignant low-grade process. In our case, these variants were excluded due to the lack of expression of the most important markers (CD45, CD20, CD79A, CD138, Melan-A, HMB-45) in tumor cells.
Considering immunophenotypic features and morphological characteristics, differential diagnosis included other two neoplasms (Ewing's sarcoma and sellar neuroblastoma). Both tumors have neuroectodermal histogenesis and characterized by expression of synaptophysin. Moreover, membrane expression of CD99, as in our case, is typical for Ewing’s sarcoma and is not typical for neuroblastoma. On the contrary, CD56 expression is determined in neuroblastomas and is not typical for Ewing’s sarcoma. S-100 expression in stromal cells is also somewhat more characteristic for neuroblastoma. Molecular-genetic examination was conducted to determine quantitative changes in the N-Myc gene and clarify the diagnosis. This gene is amplified in some cases of neuroblastoma. However, fluorescence hybridization in situ revealed a balanced profile of the N-Myc gene. Fluorescence hybridization in situ did not reveal translocations characteristic for Ewing's sarcoma.
It should be noted that sellar neuroblastoma and Ewing's sarcoma are partially characterized by similar histogenetic trajectories of development that largely determines their phenotypic similarity. Therefore, overlapping clinical signs may be observed that does not allow us to unambiguously clarify specific lesion in certain clinical case. Nevertheless, summarized morphological, immunohistochemical, molecular-genetic and clinical data are valuable to suppose sellar neuroblastoma in this case (Fig. 4).
Considering the results of histological examination, irradiation of the bed of excised tumor and residual tumor (Novalis Tx linear accelerator, Varian) was performed in dynamic fractionation mode (SFD 1.8—2.2 Gy, TFD 60 Gy). Irradiation was followed by 4 courses of chemotherapy with temozolomide 400 mg/day orally with 28-day interval between the courses.
Follow-up examination with MRI of the brain in 7 months after complex treatment revealed decrease of residual tumor and no continued growth (Fig. 5).
Discussion
Primary origin of esthesioneuroblastoma outside the lamina cribrosa (i.e. area without olfactory epithelium) is extremely rare [21]. The causes of development of these tumors in atypical areas are unclear. To date, there are several theories for explaining this process [11, 22, 23]. In our case, the tumor was characterized by sellar localization that is extremely rare per se. Therefore, pathogenesis of tumor origin in this area is unclear. There are several hypotheses about the origin of neuroblastoma in chiasmal-sellar region. So, Lach et al. [11] suggested that appearance of tumor within sella turcica is associated with transformation of pituitary epithelium into neuronal cells. The last one may be associated with localization of prolactin-immunopositive granules in neural cells. In addition, transformation of pituitary epithelium into neuronal cells is discussed in patients with coexisting neuronal choristoma or gangliocytoma with pituitary adenoma [24, 25].
In our case, infra-endo-supra-latero (D-S) retrocellular growth of tumor was diagnosed. It is quite difficult to determine the area of initial growth. Possible variants were mucous membrane of sphenoid sinus, spread to sella turcica and sinus from supradiaphragmatic space or primary sellar neuroblastoma. Any of these options correlates with above-described theories.
Differential diagnosis of atypically located neuroblastomas is a difficult task. Solution of this issue is necessary for scheduling an adequate comprehensive treatment. The disease should be differentiated with other sinonasal malignancies, meningiomas, chordomas, pituitary adenomas and nasopharyngeal carcinomas [26]. Undoubtedly, morphological examination is the main evidence-based method. However, the diagnosis may be preoperatively suspected considering destruction of surrounding structures (especially bone), direction of spread (neuroblastoma is characterized by invasion of ethmoid bone, superior olfactory recess) and clinical features [1, 7, 8, 12].
The rarity of sellar neuroblastomas determines an empirical approach to their treatment. Neuroblastomas are traditionally regarded as chemoresistant tumors. Thus, surgical treatment followed by irradiation is preferred for these neoplasms [27—29]. Some authors recommend craniospinal irradiation due to high risk (about 40% in one of the series [10]) of metastasis along spinal cord meninges [30].
Considering damage to the central nervous system, some authors recommend adjuvant chemotherapy in patients after subtotal resection of tumor [9]. Moreover, some authors even equate primary neuroblastomas of CNS with medulloblastomas. Thus, their treatment should be carried out according to the same principles [31, 32].
Conclusion
The possibility of development of neuroblastoma in chiasmal-sellar region expands differential diagnosis. However, preoperative capabilities of differential diagnosis are extremely limited.
The authors declare no conflicts of interest.