Primary neuroendocrine tumor (NET) is mainly composed of neuroendocrine cells, and many organ systems can produce such cancer . NET is divided into three categories based on mitosis count, Ki-67 labeling index, and presence or absence of necrosis, including G1, G2, and G3, corresponding to low-level, intermediate-level, and high-level, respectively . Among them, primary atypical mediastinal neuroendocrine tumors are only reported in very few documents [2, 3, 5-7]. We have summarized them in the Table. At the same time, atypical carcinoids usually have obvious aggressive clinical results, and about 20-30% of patients present with local recurrence or distant metastasis . This aggressive behavior is closely related to its histological grading, and the histological grading itself is directly proportional to the degree of differentiation .
In several previous case reports, the primary NET of the anterior mediastinum is highly aggressive and malignant [2, 3, 5-7]. There are significant differences in clinical manifestations of low-grade and intermediate-grade neuroendocrine tumors with high-grade neuroendocrine carcinoma. The first two often occur in young patients (average age 50 years) without obvious gender orientation or smoking history, while high-grade NET mainly occurs in elderly male patients (average age 65 years) and heavy smokers. However, in our case, the patient is only 45 years old and he is a heavy smoker. Common clinical manifestations include chest pain or chest tightness, difficulty breathing, coughing, sweating, superior vena cava obstruction, hoarseness, fainting, or difficulty swallowing. The occurrence of these symptoms may be due to invasion of important tissue structures in the adjacent thoracic cavity or related to the tumor's production of hormones or cytokines. However, the most terrible clinical manifestations during the perioperative period are tracheal compression, sitting breathing or wheezing, which indicates a significant increase in the risk of airway complications. In addition, syncope symptoms or pericardial effusion can increase the risk of cardiovascular complications.
Radiological diagnosis is usually difficult in the process of clinical diagnosis and treatment with non-specific imaging manifestation in NET. Contrast-enhanced CT scan is the preferred imaging method for this disease . It can accurately show the location, size, density and shape of the tumor. This technology can also clearly show the relationship between the tumor and the surrounding environment, such as the relationship between the tumor and the pericardium, large blood vessels, and chest wall . The NET that originated in the mediastinum appears as irregular soft tissue masses on enhanced CT, with uneven enhancement, and sometimes partial calcification or infringement of surrounding normal structures [6, 7]. A few case reports show that the MR signal is low on the T1-weighted image and high on the T2-weighted image [2, 5].
Atypical and typical carcinoids have similar immunohistochemistry factors. However, high mitotic counts, nucleus polymorphisms, hyperpigmentation, disordered cell arrangement and focal necrosis are more common in atypical carcinoids [5-7]. In our case, the immunohistochemistry results revealed CgA, CD56, Syn, CK19, PCK and GLUT-1 staining was strong positive. But thymus-associated epithelial cell indicators P63 were negative. SSTR2, TdT and CD5 were also negative, and Ki67 index was about 20%-30% in lymphocytes and plasma cells.
The differential diagnosis of NET includes adenocarcinoma, small cell carcinoma (SCC) and thymic neuroendocrine SCC. The exclusion of adenocarcinoma is mainly due to the presence of dense neurosecretory granules in the lesion and no bronchial tissue in the tumor . Considering SSC, the cytoplasm of tumor cells in our case is larger than usually seen in SCC. In addition, the presence of nucleoli and a Ki67 proliferation index of 10% to 20% can also rule out the diagnosis of SCC [2, 5]. In addition, in our case, thymus markers such as P63 and CD5 were negative in immunohistochemistry.
Complete surgical resection is strongly recommended for localized primary NET, according to the newest version of the National Comprehensive Cancer Network (NCCN) guidelines . Surgical resection includes complete removal of the tumor and removal of the surrounding fat tissue, as well as selective removal of lymph nodes. For tumors that are not completely resected, postoperative adjuvant chemotherapy or radiotherapy is recommended. However, no large-scale randomized controlled clinical trials have confirmed the effectiveness of this method so far. For unresectable cases with distant metastases, complete surgical resection of the primary and metastatic foci is still the first choice . Once the patient is unable to undergo surgery, systemic treatment is recommended. Currently, the most commonly used drug is temozolomide . In our case, we did the surgery through mid-sternal thoracotomy with superior vena cava formation, left common carotid artery resection and artificial blood vessel replacement, left upper lobe wedge resection, left phrenic nerve resection, left vagus nerve resection and partial pericardectomy.
In conclusion, NETs are very rare epithelial neoplasms. They usually present as a large mass with an infiltrative nature located in the mediastinum. Early and accurate diagnosis are very important, and surgery remains the mainstay of treatment . Our findings suggest the difficulty of making a diagnosis before surgery and more cases will need to be reported in order to facilitate the preoperative diagnosis of such a rare tumor.