Abstract Neuroendocrine tumors are commonly found in the gastrointestinal, liver, pancreas, lung and other organs. With the development of otorhinolaryngology-head and neck surgery and the improvement of diagnosis and treatment level, the understanding of neuroendocrine tumors in the head and neck has further advanced and gained gradual attention. Keywords: head and neck, neuroendocrine tumor, nasal neuroendocrine tumor
Neuroendocrine tumors (amineprecursor uptake and decarboxylation, APUD) are a group of neoplastic organisms that can take up amine precursors and decarboxylate them to produce related products, which are characterized by organ-like growth pattern and silver-loving cells in histopathology. These tumors can occur in the gastrointestinal tracts, but they can also be found in the gastrointestinal tracts. These tumors can occur in many places such as the gastrointestinal tract, liver, pancreas, lung, skin, throat, thyroid and sinuses. With the development of medicine, the level of diagnosis and treatment of these tumors has been improved, and the treatment methods include surgery, radiotherapy, chemotherapy, endocrine therapy, etc. Zhang Mei, Department of Two Gland Surgery, Shandong Qianfo Mountain Hospital
The clinical manifestations of neuroendocrine tumors in head and neck are various, and their treatment and prognosis are different, so it is important to diagnose correctly. Immunohistochemical examination plays a major role in this diagnosis and differential diagnosis. The former is mainly used for frozen section and the latter for paraffin section. The relevant indexes can be classified into three categories: ① Markers to distinguish epithelial tumors, soft tissue tumors and lymphomas, and markers for epithelial tumors are: epithelialmembrane antigen (EMA), carcinembryonic antigen (EMA), carcinomatous antigen (EMA), carcinomatous antigen (EMA), and carcinomatous antigen (EMA). CAM5.2; connective tissue tumor markers; waveform proteins; lymphoma markers include: multiple B and T cell antibodies, leukocyte common antigen (LCA). (ii) Neuroendocrine markers: neuron specificenolase (NSE), S-100 protein, synaptophysin, glial fibrilaryacidic protein (GFAP), chromogranin, protein gene product 9.5, Leu7, etc. (Table 1). (iii) Neuropeptide markers (Table 2). There are no antibodies to distinguish benign and malignant tumors, so the diagnosis still depends on histological examination.
Table 1 Immunohistochemical markers of some neuroendocrine tumors
Antibodies
Paraganglioma
Atypical carcinoid tumor
Small cell neuroendocrine carcinoma
Olfactory cell carcinoma
Melanoma
CAM5.2
–
+
+
±
+ ±
EMA
–
+
+
–
–
CEA
–
+
+
–
–
Chromogranin
+
+
+
+
–
NSE
+
+
+
+
+
S-100 protein
+
–
–
+
+
GFAP
+
–
–
– –
– –
Calcitonin
–
+
+
±
–
Table 2 Neuropeptides associated with laryngeal neuroendocrine tumors
Typical carcinoid tumors
Vasomotor intestinal peptide
5-Hydroxychromes
Small cell neuroendocrine carcinoma
Growth inhibitory hormone
beta-endorphin
Atypical carcinoid tumor
Han frog skin pigment
Adrenocorticotropic hormone
Calcitonin
Frogellin
Calcitonin gene-related peptide
beta-endorphin
Gastrin-releasing peptide
Calcitonin
Neuropeptide Y
Calcitonin gene-related peptide
Neurohypocretin
Gastrin-releasing polypeptide
5-Hydroxychromes
Glucagon
Growth inhibitory hormone
Human chorionic gonadotropin
Paraganglioma
Insulin
Calcitonin gene-related peptide
Neuropeptide Y
Methionine enkephalin
Neurohypocretin
Neuropeptide Y
5-Hydroxytryptophan
5-Hydroxytryptophan
Growth inhibitory hormone
Growth inhibitory hormone
Substance P
Substance P
[Pathology and staging of nasal neuroendocrine tumors] Silva [1] classified nasal neuroendocrine tumors into two subtypes: neuroblastoma with/without manifestations of olfactory nerve differentiation and nasal neuroendocrine carcinoma. The histogenesis of olfactory neuroblastoma has been suggested to be neurogenic, while others have suggested a neuroendocrine pathogenesis based on immunohistochemical, ultrastructural, and oncogene studies. Histological examination revealed a lobulated arrangement of tumor cells, with neuronal cells and neurogenic fiber masses separated by a vascular and fiber-rich stroma, and a rosette structure surrounded by columnar cells. Cytogenetically it was shown that chromosome 8 is trisomic and the reciprocal translocation of chromosomes 11 and 22, t(11,22)(q24,q12) [2,3], Szymas [4] et al. applied a molecular cytogenetic method, comparative genomic hybridization (CGH), which also demonstrated the presence of chromosome 8 trisomic phenotype, t(11,22)(q24,q12 ) presence is highly supportive of olfactory neuroblastoma as a peripheral primary neuroectodermal tumor (pPNET) [5], but the MIC-2 gene expressed in most pPNETs is not found in olfactory neuroblastoma.Papdaki [6] et al. concluded that P53 gene variants are not closely related to the initial development and progression of olfactory neuroblastoma, while in some of its recurrent tumor cell subpopulations Overexpression of the P53 gene occurs in certain cell subpopulations of their recurrent tumors, and immunostaining for P53 protein in specimens is mild-moderate positive, so overexpression of the P53 gene may be associated with the high ease of recurrence and aggressiveness of certain olfactory neuroblastomas.
[Clinical staging, grading and prognosis] Kadish [7] divided olfactory neuroblastoma into 3 stages, stage A, where the mass is confined to the nasal cavity; stage B, where the mass develops into the sinuses; stage C, where the mass further develops into the orbit, skull base, intracranial, cervical lymph nodes or distant metastases. morita et al. classified cervical lymph nodes or distant metastases as stage D. Hyams grading was proposed based on the lobulated structure of tumor tissue, cytolytic phase, nuclear pleomorphism, wreath-like structure and tumor necrosis: tumors with high differentiation were classified as grades I and II, and those with low differentiation as grades III and IV. However, their prognostic conversion could not be effectively judged based on staging/grading, and Morita and Foote et al. considered pathological grading as the only reliable factor affecting prognosis, while Polin levine et al [8] from the University of Virginia reported no statistical difference in the survival rate of patients with pathology grade II and III tumors respectively; 6 of 9 Hyams grade II cases were stage B and 3 were stage C. 75% responded to adjuvant therapy, 89% were recurrence free and there were no cases of death due to tumor; 1 of 10 Hyams III cases was stage B and 9 were stage C, Among the 10 Hyams III cases, 1 case was stage B, 9 cases were stage C, 62.5% responded to adjuvant therapy, 50% were recurrence-free, and 2 cases died of tumor. Dulguerov, Calcaterra, and Goldsweig and Sundaresan suggested that the extent of tumor resection during surgery is the most important prognostic factor.
[Nasal neuroendocrine carcinoma] Nasal neuroendocrine carcinoma may also originate from the same neuroepithelium as olfactory neuroblasts, but is relatively poorly differentiated histologically. Immunohistochemistry: NSE (+), synaptophysin (+), chromogranin mostly (+), occasionally neurofilament protein (+), Leu (+). It is now thought that undifferentiated carcinoma of the sinus and small cell carcinoma reported in some literature may belong to this category.Min [9] suggested that olfactory neuroblastoma exhibits consistent round nucleated cells in dendrites containing many dense granules of about 150-350 nm in diameter and longitudinally arranged neural tubes, with occasional synaptic connections.Neuroendocrine carcinoma consists of small round cells lacking cytoplasm arranged closely together and lacking adult Neuroendocrine carcinoma consists of small round cells lacking cytoplasm and closely arranged, lacking neural cell-like manifestations, but with epithelial-like manifestations. The major difference between Cytokeratin(+) and olfactory neuroblastoma is the absence of supporting cells in nasal neuroendocrine carcinoma.
Small cell carcinoma of the sinuses is very rare and its incidence is not counted. Koss [10] suggested that it originates from the tissue of the minor salivary glands and the first reported case (Ray chowdhuri, 1965) was a female who died of frontal lobe abscess, meningitis and small cell carcinoma of the frontal septal sinus was found at autopsy. Due to the rarity of the case and lack of recognition, when the patient showed early symptoms such as blood in the sputum, or when cancer cells were found, physicians often focused on the lungs and neglected detailed examination of the upper respiratory tract until symptoms such as nasal congestion, blood in the nasal discharge, and changes in vision occurred, when the lesion was discovered. At this time, its scope is relatively large, although its pathology is similar to that of small cell carcinoma of the lung; with densely stained nuclei, little cytoplasm, and reticulate, cord-like arrangement of cells. However, supratentorial cell carcinoma has the characteristics of not easy to metastasize early and not easy to metastasize widely, but tends to recur locally. Therefore, treatment is surgical resection, radiation therapy, and chemotherapy is feasible for some patients [11, 13].
[Treatment options for olfactory neuroblastoma] Polin levine of the University of Virginia reviewed 34 patients treated from 1976 to 1994 and concluded that since the development of craniofacial surgery and with the development of radiotherapy and chemotherapy, the survival rate of patients with olfactory neuroblastoma has increased from 37.5% to 82%. Currently treated Kaclish a and B stage patients have a high survival rate, Spaulding et al. advocated preoperative radiotherapy (50 Gy) plus craniofacial surgery with better treatment results, but Elkon et al. argued that there are more debates on the combined treatment versus separate treatment options; Levine, spaulding et al. proposed preoperative and postoperative adjuvant chemotherapy along with preoperative radiotherapy plus craniofacial surgery, (with (Evidence suggests that olfactory neuroblastoma is also sensitive to chemotherapy and is mostly effective after one course of treatment, which can be improved with high-dose chemotherapy plus autologous bone marrow transplantation). As the number of chemotherapy cases increases and new chemotherapy regimens are proposed, the best chemotherapy regimen may be determined and adopted in the future. Analysis of tumor response to preoperative radiotherapy revealed that: 2/3 of patients had a 20% or more reduction in their range and nearly 1/2 of patients had a 50% or more reduction in their range, and patients who responded well to preoperative radiotherapy had a higher disease-free survival rate than those who did not respond. However, adjuvant therapy alone cannot completely treat the disease, and adjuvant therapy can reduce stage C lesions to stage B, facilitating complete surgical resection. In addition, even if adjuvant therapy results in complete regression of intracranial lesions, exploratory surgery should be performed and the bone plate at the anterior skull base where tumor cells may be latent should be removed.
The diagnosis of neuroendocrine tumors in the neck includes laryngeal tumors, small cell neuroendocrine carcinoma, paraganglioma (the first two originate from epithelial tissue, while paraganglioma originates from neural tissue) and Merkel cell carcinoma, etc. The diagnosis of these tumors can be made by using the characteristics of growth inhibitory receptors and performing growth inhibitory receptor scintigraphy (scintigraphy), i.e., using the isotope 111 to label growth inhibitory receptors. The results are consistent with the results of MRI and other examinations, and have high sensitivity, specificity, and can detect small lesions and metastases that are not easily identified by MRI, and can show masses up to 5 mm in diameter. In addition growth inhibitors and their mimetics, such as Octreotide, can be used in the treatment of neuroendocrine tumors in the neck and have an inhibitory effect on the growth of the tumor itself, in addition to the endocrine system, probably Octreotide binds to receptors that have a role in regulating signaling and cell growth, and the therapeutic response is related to the dose used and to the subtype of the growth inhibitor receptor [16]. The reported cases showed no signs of continued tumor growth during treatment, and MRI showed partial replacement of the lesion by scarring, which is an effective treatment for patients who cannot be surgically removed and have recurrence after surgery, and the side effects can be manifested as fatty stools and diarrhea because it partially affects the absorption of bile sweat acid and produces fat malabsorption.
Pathologically, laryngeal atypical carcinoid tumor is a moderately differentiated neuroendocrine tumor: the cells are arranged into a network and ribbon-like structure, which can show organoid and pseudoglandular patterns, the cells are polygonal, the cytoplasm is eosinophilic stained, mitotic phase cells are common, and mucus can be seen. Some specimens have amyloid deposits in the stroma (similar to medullary thyroid carcinoma). Immunohistochemistry: EMA (+), CEM (+), keratin (+), sometimes calcitonin (+), and also peptides such as growth inhibitor, 5-hydroxytryptamine, and ACTH. It must be differentiated from paraganglioma and medullary thyroid carcinoma: the prognosis of paraganglioma is better than that of carcinoid tumor and medullary thyroid carcinoma; the prognosis of paraganglioma is better than that of carcinoid tumor, so the differential diagnosis is important: keratin (-), EMA (-), CEA (-), calcitonin (-); medullary thyroid carcinoma is similar to carcinoid tumor in terms of light microscopy and histochemistry, and needs to be combined with clinical and imaging examination of the thyroid gland It needs to be differentiated by clinical and thyroid imaging examinations. The current treatment of atypical carcinoid tumors is based on extended resection such as radiotherapy and chemotherapy, but the results are not good; Milroy reported a case with metastatic and recurrent lesions treated by extended resection and survived for a long time [17, 18].
With the further understanding of head and neck neuroendocrine tumors and the emergence of new technical means, their diagnosis and treatment will continue to improve.
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