DISCUSSION
As NETs originate in endocrine organs, they can be found in nearly any location in the body, with most arising in the gastrointestinal tract (e.g., GEP-NETs) and respiratory system. Neuroendocrine cells produce neuroregulators, neuropeptides, or neurotransmitter hormones[3]. The fifth edition 2019 of World Health Organization (WHO)[4] and the 2016 European Neuroendocrine Tumor Society (EUETS)[5] classification of digestive system tumors divides gastric NETs into three types by their differentiation, well-differentiated G-NETs and neuroendocrine carcinomas. However, because few duodenal NETs have been reported, the WHO classifies and grades NETs of the gastrointestinal and hepatopancreatobiliary tracts, including duodenal NETs, by their Ki67 index and mitotic rate. The 2016 EUETS classification lists it as a separate category without classification. The 2020 Chinese Society of Gastroenterology Expert Consensus on the Diagnosis and Treatment of Gastrointestinal Pancreatic Neuroendocrine Tumors was based on the above classification[6], but duodenal NETs were not mentioned. Gastrointestinal NETs can be divided into functional and nonfunctional subtypes according to whether secreted hormones can be detected and by the presence of related endocrine symptoms. Functional tumors are slow growing and their onset is usually caused by the secreted hormones rather than tumor proliferation. In the case of nonfunctional tumors, it is generally believed that hormones are secreted but cannot be detected by existing assays. Nonfunctional tumors tend to be more aggressive and invasive than functional tumors[3]. According to the Surveillance, Epidemiology, and End Results (SEER) database of National Cancer Institute, the incidence of G-NETs has risen rapidly in the United States in the past 40 years, and was 0.62/100000 in 2016[7,8]. A study in Argentina[9] reported that G-NETs and D-NETs accounted for 6.9% and 2.0% of all digestive tract NETs, respectively. The most recent study in Japan[10] reported that D-NETs accounted for approximately 5% of GEP-NETs. Epidemiological studies of G-NETs show that the incidence of D-NETs is increasing in many countries worldwide[9-12].
Multiple primary tumors are a unique phenomenon in medicine and are divided into two categories by their time of onset. Synchronous tumors occur simultaneously and heterochronous tumors occur in chronological order. Warren and Gates[13] conducted autopsies of 1078 cancer patients and found that 40 (3.7%) had either occult or clinically apparent second primary tumors. Some studies have reported a correlation of NETs with an increased risk of developing secondary gastrointestinal malignancies. A study of 58596 patients with NETs found that 4612 (7.9%) developed a second primary malignancy during follow-up. Patients with different types of NETs had different incidences of second primary malignancies. G-NET patients had an increased risk of developing second primary malignancies in the esophagus, small intestine, pancreas, and liver but no such risk was reported for D-NETs[14]. In a study of 459 patients Kamp et al[15] found a correlation between GEP-NETs and a second primary malignancy in which the incidence of a GEP-NET combined with a second primary malignancy (mainly colorectal cancer) was increased. The pathogenesis of secondary cancers associated with D-NETs was not clear but it involved the interaction of genetic, environmental, hormonal, medical, and sex-related factors[16-18].
The clinical features of GEP-NETs combined with a second primary malignant tumor lack specificity. A previous study reported that gastrin and cholecystokinin were associated with NETs and induction of tissue growth and cellular malignant transformation in the gastrointestinal tract, leading to colorectal and gastric cancer[19]. In patients with NETs, the possibility of a hormone hypersecretion syndrome, such as paraneoplastic or carcinoid syndrome, must be strongly considered. Vilallonga et al[20] found that 5 of 2155 patients diagnosed with colorectal cancer presented with paraneoplastic or carcinoid syndrome. This study of NETs did not include carcinoid tumors. However, the clinical manifestations of D-NETs are not specific, and not all tumors have the above manifestations. A retrospective study of 927 patients with duodenal endocrine tumors found that the incidence of carcinoid syndrome was only 3.1%[21], and that the incidence of carcinoid syndrome in duodenal NETs may have been even lower. According to the most recent classification of gastric NETs, types I and III often do not present with paraneoplastic or carcinoid syndrome, which makes their diagnosis more difficult. Our patient was admitted to the hospital with abdominal pain. Except for positive fecal occult blood, there were no obvious abnormalities o tumor markers or blood-test indicators. Because a duodenal NET was not considered before surgery, serum chromogranin A (CgA), neuron-specific enolase, and related hormone levels were not tested. However, preoperative enhanced CT of the abdomen showed an abnormal enhancement sign in the duodenal bulb, and gastroscopy and endoscopic ultrasound revealed a slightly hypoechoic lesion with a wide base in the mucosal layer of the anterior wall of the duodenum. Most NETs are hypervascular, and their obvious enhancement characteristics in the arterial phase have a highly suggestive role in qualitative diagnosis. Many studies and current guidelines indicate that enhanced CT and gastroscopy have reference value for the diagnosis of gastrointestinal NETs[22-25]. The WHO and EUETS criteria and the condition of our patient, it can be classified as a G1 NET. However, the classification criteria for D-NETs combined with a second primary cancer have not yet been explicit conclusions.
Different D-NETs have different treatments, but surgery is still the best method for treat D-NETs. Endoscopic submucosal dissection is a safe and efficacious treatment for duodenal carcinoid tumors that are ≤ 10 mm in diameter and limited to the submucosal layer[5,6,26]. For tumors between 10 mm and 20 mm in diameter, endoscopic or surgical treatment can be chosen, but surgery is performed for suspected tumors > 10 mm or tumors with positive margins after resection. The surgery that is selected (e.g., local resection, gastrectomy, or total gastrectomy) is guided by the pathological characteristics and invasiveness of the tumor[2,5]. A literature review of 44 duodenal small-papilla NETs with an average tumor size of 14.0 mm (range: 2-27 mm) found that most were pathological type G1 tumors (20/22). More than half of the lesions (58.3%; 14/24) that were ≥ 10 mm had lymph node metastasis, and duodenal small-papilla NETs had a higher probability of lymph node metastasis[27]. The results have a reference value for the selection of the treatment method for this type of tumor in the future, such as sentinel lymph node biopsy to determine whether to perform radical tumor resection. At present, tumor resection, chemotherapy, targeted therapy, and radionuclide therapy are the conventional treatment methods for GEP-NETs. For localized tumors, only surgery provides the possibility of complete cure[28,29]. However, lymph node metastasis or distant organ micrometastasis may have occurred during or before surgery. Such tumors are often neuroendocrine carcinomas and the treatment of that type of tumor currently relatively consistent. For localized lesions, treatment by local or radical surgery and adjuvant chemotherapy after surgery are relatively common. However, most patients with neuroendocrine carcinoma have distant metastasis at the time of diagnosis, and the tumor is highly malignant and unresectable. In those cases, chemotherapy is the first choice for treatment. Etoposide + cisplatin (EP) is a chemotherapy regimen for small cell lung cancer and was shown to be effective in 67% of cases[30]. Epirubicin + cyclophosphamide (EC) and irinotecan + cisplatin (IP) can be selected as first-line regimens. Ooxaliplatin + leucovorin + 5-fluorouracil (FOLFOX), irinotecan+calcium folinate + 5-fluorouracil (FOLFIRI), and Capecitabine + temozolomide. (CAPTEM) can be used as second-line chemotherapy regimens. Anti-PD-1 therapy can be considered as a third-line treatment in patients with high MSI (MSI-H), mismatch repair deficiency (d-MMR), and high tumor mutation burden (TMB-H)[6]. In this case, the patient did not have secretory NETs, paraneoplastic symptoms or signs, or any ectopic hormone secretion. She was considered to have a well-differentiated G1-like D-NET, and surgical resection was the first choice of treatment. However, during the operation, laparoscopic exploration showed that the texture of the mass was hard, and no enlarged lymph nodes were found near the abdominal aorta. Combined with the preoperative CT and gastroscopy, it was suggested that this type of mass was possibly malignant. In the absence of a pathological diagnosis, distal gastrectomy + gastrojejunostomy was selected for the mass, and the distal stomach, with a volume of 11.5 cm × 8.5 cm × 1.5 cm was resected. Complete resection of the mass may improve the overall prognosis of the patient.
In patients with NETs positive for somatostatin receptors, subcutaneous or intramuscular administration of somatostatin analogs (octreotide LAR 10, 20, or 30 mg intramuscularly every 4 weeks, or lanreotide 60, 90, or 120 mg subcutaneously every 4 weeks) can relieve the symptoms by blocking hormone release[6,31,32]. In addition to being suitable for patients with neuroendocrine carcinoma, chemotherapy and targeted therapy are not currently used as first-line treatment regimens for NETs. In radiological and serological studies, more than half of the patients achieved partial remission (PR) with combined use of cisplatin and etoposide, streptozocin and doxorubicin or 5-fluorouracil[33-35]. Targeted chemotherapeutic drugs (e.g., everolimus or sunitinib) have been used in some studies to improve progression-free survival (PFS), Continuous administration of 37.5 mg daily improved the PFS, overall survival, and objective response rates in patients with advanced NETs. Everolimus was significantly correlated with a median PFS of more than 6.4 mon longer than placebo[36-41]. Isolated liver metastases can be improved with radiofrequency ablation or hepatic artery embolization, or by combining hepatic artery embolization with hepatic artery chemotherapy perfusion[42]. The internal radiation therapy chosen for neuroendocrine liver metastases can be given by injection of radioactive microspheres directly into the hepatic artery. The available isotopes for radiotherapy include yttrium-90, lutetium-177-labeled analogs, and iodine-131-meta-iodobenzylguanidine[43-45].
With the advent of aggressive surgical intervention and second-line treatment with long-acting somatostatin agonists and targeted drugs, the prognosis and long-term survival of patients with NETs have improved. Studies have shown that in the case of malignant tumors, the 5-year survival rate can be as high as 77% to 95% following radical resection of the primary tumor and adjuvant therapy[46,47]. For localized and well-differentiated tumors treated by complete surgical resection, the 5-year survival rate of G-NETs is as high as 90%. Radical resection of the primary tumor, absence of liver metastasis, metachronous liver metastasis, and active treatment of liver metastasis are all favorable factors and improve prognosis[48,49]. However, nearly all patients diagnosed with metastatic gastric neuroendocrine cancer have a recurrence within 7 years of follow-up. Recurrence is difficult to avoid even after a complete cure[49], indicating its refractory characteristics.
In the follow-up of NETs, early studies found that octreotide CT or octreotide SPE-CT scans have an important role in detecting the recurrence of NETs[50,51]. Frilling et al[50] found that 19 of 35 patients with NETs (54.2%) had extrahepatic tumors that were not detected by other imaging techniques, such as CT, MRI, or ultrasound. Octreo-SPECT/CT imaging can be used to detect and locate suspected NETs before their diagnosis[52,53], and can be used to follow-up and detect tumor recurrence after diagnosis or treatment. In this case, the patient was considered to have an early stage duodenal NET, and only CT and laboratory tests were used for follow-up.
Surgery is the most effective treatment for local early-stage colon cancer (stages I and II). Chemotherapy is the standard treatment for patients with locally advanced stage III and IV cancers after radical surgery. For some stage II colon cancer patients, systemic treatment with surgery is based on risk factors and MSI gene status. Commonly used drugs include capecitabine, 5-fluorouracil, irinotecan, and oxaliplatin. Biologics, including bevacizumab, cetuximab, panitumumab, regorafenib, and afatinib are important for the treatment of metastatic colon cancer. Genetic analysis of tumor patients is increasingly used role to guide the selection of treatment plans. The use of radiotherapy is currently limited to palliation of selected metastatic sites (e.g., bone or brain metastases)[44,54-57].
All patients with synchronous colorectal cancer and D-NETs undergo extensive evaluation and clinical monitoring during hospitalization and follow-up to detect disease progression or recurrence. In current practice, patients are followed-up every 3-6 months in the first 3 years and every 6-12 months thereafter. Each follow-up visit includes routine laboratory tests, tumor markers (CEA, CA 19-9, CA 12-5, CgA, and 5-hydroxyindoleacetic acid), gastrointestinal endoscopy, abdominal ultrasound, lymph node ultrasound, chest radiography, and CT or PET/PET-CT scan. Octreotide CT or octreotide SPE-CT scan is also useful to detect recurrence of NETs. In clinical practice, serum CgA is the most commonly used tumor marker for NETs. It can assist in diagnosis, assessment of tumor burden, in treatment, and is helpful for follow-up[55,56,58,59]. We believe that early diagnosis, comprehensive preoperative examination, careful intraoperative exploration, radical resection and regular postoperative monitoring can increase survival time. The treatment strategy depends on many factors, such as the surgical approach, the patient’s general condition, tumor grade, extent of disease, and the response to treatment. It should be analyzed in combination with the individual patient’s status[60,61].
The appearance of synchronous primary tumors is of interest to surgeons and oncologists and the entire medical field. When such a phenomenon is encountered, questions invariably arise regarding common genetic pathways in the pathogenesis of these tumors. With the increasing incidence of multiple primary tumors, clinicians should be vigilant to the possibility of their occurrence. This case involved several interesting aspects of clinical care. First, few cases of synchronous D-NETs occurring with colon adenocarcinoma have been reported. Second, there are no proven diagnostic criteria, treatment approaches, or follow-up guidelines for patients with synchronous D-NETs and a second primary malignancy. Therefore, our experience may help to inform the diagnosis and management of such patients. We also highlight the advantages of HALS, which allows direct palpation of the mass and assessment of its size, texture, and mobility, as well as the surrounding lymph nodes. This assists surgeons in choosing surgical procedures. In addition, the surgical incision is small and postoperative recovery is fast. It also avoids the need for large surgical incisions, incision infections, and fat liquefaction after traditional open surgery. In the setting of synchronous primary tumors as in this patient, the impact of synchronous cancers on overall prognosis must always be considered when planning patient care. Finally, patients who present with multiple primary tumors are a unique opportunity to study the complex etiology of cancer.
