Primary intracranial neuroendocrine tumor: two case reports

NET originates from amine precursor uptaking and decarboxylation cells (APUD cells), which are called diffuse neuroendocrine system [1‐3]. the intracranial origin is lower than 0.74 % [4]. To the best of our knowledge, this is the first case of primary intracranial NET with Cushing syndrome which is immuno-negative for ACTH. Malignancy is divided into three levels according to the Ki-67-labeling index, with 1~3 % low level, 3~20 % middle level, and up to 20 % high level. The first patient had a rapid progress because of the high proliferation. The second neoplasm developed slowly because the Ki-67 was lower than 1 %. Patients with NET commonly present with no specific clinical features, including focal neurological deficit and intracranial hypertension. Functional tumors secreting one or more hormones would result in some endocrinal symptoms. Non-functional tumors may affect the pituitary function and lead to hypopituitarism, like the first case. In our reported case, lesions invaded into the right cavernous sinus, suprasellar region, and nasal cavity leading to focal deficit such as bilateral exorbitism, left decreased vision, and CSF leak. On imaging, there is also no specificity. Bone erosion on CT scans, hypointensity on T1WI, hyperintensity on T2WI, and homogeneous enhancement are generous characteristics. Whole-body fluorodeoxyglucose-positron emission tomography (FDG-PET) would reveal primary lesions and metastasis. Recent researches suggested somatostatin receptors (SSTR) expressing on the surface of tumor cells could integrate with somatostatin analogue. According to this, SPECT scans with isotope-labeled somatostatin may be a possible way [5]. Biochemical measurement mainly focuses on hormone levels. Some literatures identified CgA that may become a tumor marker because it increased to 70–90 % among patients [6]. In the two present cases, the specimens are positive for CgA. Pathological diagnosis is the golden standard. The neoplasm is comprised of different size cells with uniform nuclei, scant cytoplasm, nidulant, and basophil granulocytes. Irregular mitosis presents based on the degree of differentiation [7]. CgA and Syn are selected as common immunohistochemical items sensitively and nonspecifically [8]. On the basis of recent literatures, peptide hormones and bioamine are no longer recommended to be tested immunohistochemically, because no correlation is confirmed between hormones and clinical presentations and the level of hormones also cannot give us valuable prognosis [9]. For the first case, immunohistochemical analysis of specimen was negative for all the hormones. On electron micrographs, intracytoplasmic neuroendocrine granules with compact cores show high electron density and have much value of differential diagnosis. For the second case, the tumor may have originated 6 years ago, but Cushing syndrome presented in only 2 months. Then, by following the postoperative condition for 1.5 years because of the residual fraction in nasal cavity, the patient has not presented hypercortisolism. The reason may be that NEGs were occasionally observed and not enough to cause the typical Cushing syndrome in a short period.

Diagnosis of NET depends on the pathological characteristics. Immunohistochemistry is one significant differential approach to neuroendocrine ingredients, epithelial ingredients, and neuropeptides. For NET in the sellar region, it should be necessary to discriminate it from esthesioneuroblastoma. Klimstra [7] thought esthesioneuroblastoma was comprised of neuroblasts with uniform circular nuclei and longitudinal cerebromedullary tubes in dendrites. NET comes from epithelium, lacking of neural ingredients. Depending on radiological findings of the second communicating case, most of the tumors situated intracranially in physiological canals in the skull base limited the tumor growth, resulting in minority extending outside the cranial via these canals.

Ectopic secretion of active ACTH or ACTH analogues from the non-pituitary tumors causes ectopic ACTH syndrome, resulting in the presences of Cushing syndrome [10]. Overt and occult lesions both account for ectopic secretion. However, the second immunohistochemistry was negative for ACTH. The main reasons may be as follows. (1) Ectopic tumors may excrete ACTH or ACTH analogue, and the simplex ACTH antibody is insufficient of covering the entirety. (2) Some lesions can produce ACTH and corticotrophin-releasing hormone (CRH) simultaneously [11]. Moreover, Mubarak et al. [6] reported three cases of ectopic CRH tumors with hypercortisolemia, and they also discussed that postoperative ACTH level immediately dropped to normality if the tumor produced ACTH, by contrast, it gradually decreased if the tumor produced CRH. This patient’s postoperative ACTH level was normal after 16 days. Imaging examinations, including CT, MRI, and FDG-PET, are used to identify the tumor sources, check the pituitary, and distinguish it from Cushing disease. It is also necessary to evaluate the biochemical indicator, including electrolytes, glucose, and hormones. Some special tests can be performed when diagnosis is difficult, for example, high-dose dexamethasone test, CRH stimulation test, and inferior petrosal sinus sampling (IPSS) [12].

The key point of diagnosis is how to differentiate between ectopic ACTH syndrome and Cushing disease. The ACTH level of overt ectopic lesion is distinctly higher than that of Cushing disease, but it is approximately the same as Cushing disease in occult lesion. In accordance with recent researches, the standard is that serum cortisol is shown to be 14 % higher than the base after CRH-releasing test is carried out 15 and 30 min later [13]. The other key point is to localize the tumor source. If sellar MRI shows normality, multisite radiological scans are considered, such as the head and neck, the chest, the abdomen, or the pelvis. We found no lesions in other parts of the second patient, and the endocrinal malfunction was related to the anterior skull base tumor.

The optimal treatment of NET is surgical resection of hormone-secreting lesion. Peng et al. [14] reported a case of cervical lymph node metastasis after primary intracranial NET being removed 2 years later. If so, primary lesions resection and lymph nodes dissection are both needed. We chose single transsphenoid and subfrontal approaches for the two cases. Because the majority of the first lesion is located in the sellar and suprasellar regions, vascular supply was not relatively rich. For some bulky vessels showed on the second MRI and the main components of the second tumor located in the anterior cranial base, we chose subfrontal approach, and meanwhile, skull base reconstruction was performed during surgery.

Patients receiving comprehensive treatment, including extended resection of tumor and completion of chemo-radiotherapy, are expected to have longer tumor-free lives than those patients receiving single surgery [10, 15]. Poorly differentiated cells are sensitive to radiation. The first patient with high level of Ki-67 index died of extensive metastasis and had no chance to receive radiotherapy. The second NET with low proliferation was recommended to take a follow-up examination. SSTR2 and SSTR5 on the surface of NET cells can integrate with somatostatin analogue. Some doctors used isotope-labeled drugs, such as ⁹⁰Y-DOTA-octreotide (OCT), ¹¹¹In-DTPA-OCT, and ¹³¹I-DTPA-OCT, to complete the inner irradiation [5]. Because of epithelial origin, drugs, such as adriamycin, 5-fluorouracil, and cisplatin, are chosen for epithelial neoplasm. Few reports described primary intracranial NET, so chemotherapy still needs researches to demonstrate its therapeutic efficiency.