Ileal neuroendocrine tumor: diagnosis by endoscopic capsule

The diagnosis of neuroendocrine tumors of the small intestine is usually challenging. They are infrequent, and the clinical course is insidious with nonspecific manifestations. Routine endoscopic and abdominal imaging studies are more often unremarkable. Therefore, distant metastases are frequently detected at the time of diagnosis. The tumor markers chromogranin A, synaptophysin, and neuron-specific enolase, and capsule endoscopy, and device-assisted enteroscopy are useful resources to establish a diagnosis. The aim was to present a case of neuroendocrine tumor of small intestine diagnosed with base in findings of the capsule endoscopy and further open surgery.


Introduction
Neuroendocrine tumors (NETs) origin in enterochromaffin cells of the gastrointestinal (GI) tract, and small intestinal NETs (SI-NETs) arise from the submucosal crypts (Ahmed, 2020). Even with a slow growth, they usually have metastases at the time of diagnosis (Deguelte et al., 2020;Folkestad et al., 2020, Levy et al., 2020. There is a genetic influence in their etiology associated with deleting of the tumor suppressor gene PLCβ3 that causes uncontrolled growth of the neuroendocrine cells (Kamei et al., 2020).
The diagnosis depends on laboratory, radiology, endoscopy, and histopathology. We report the case of a patient with episodes of obscure intestinal hemorrhage. Being uncommon, with nonspecific symptoms, SINETs cause diagnostic pitfalls, but images by capsule endoscopy (CE) and enteroscopy allow early diagnosis (Kim et al., 2020;Perez-Cuadrado-Robles et al., 2020;Rondonotti et al., 2020;Vasilakakis et al., 2020;Yoo et al., 2020). Intestinal bleeding of unknown origin is a common symptom of adenocarcinoma and gastrointestinal stromal tumors (GISTs), which may propitiate diagnostic challenges or misdiagnosis with NETs (Yoo et al., 2020).
Currently, both the CE and the device-assisted enteroscopy have been employed in several medical centers and can optimize the timely diagnosis and treatment of the SI-NETs. The images of the SI-lumen obtained by swallowing a small digital camera, and the associated enteroscopy can take tissue samples and also perform local interventions.
ARS MEDICA Revista de Ciencias Médicas Volumen 46 número 1 año 2021 Gomes et al. A 54-year-old woman came to the hospital complaining of   intestinal bleeding with clots starting one day ago, without abdominal pain, nausea, vomiting, or general weakness.

Case report
Routine laboratory tests did not show any changes, except for hemoglobin 8.8 g/dL (in the previous month: 12.3 g/dL).
Episodes of intermittent gastrointestinal bleeding occurred about two years ago, some with hemodynamic instability but without etiological clarification. There was a personal history of arterial hypertension, diabetes mellitus, dyslipidemia, hypothyroidism, and two cesarean sections. She denied smoking, alcohol drinking, and use of drugs. The initial investigation included upper digestive endoscopy, angiotomography , enterotomography , and colonoscopy, which revealed no changes. Therefore, he underwent CE (Figure 1 (Folkestad et al., 2020). An initial concern was about GI adenocarcinoma or GIST Yoo et al., 2020).
Besides, metastases from melanoma, lung cancer, breast cancer, cervical cancer, sarcoma, and colon cancer are more common than primary tumors . Because the upper digestive endoscopy, angiotomography, abdominal tomography, and colonoscopy of control did not show any change, we performed the CE, utilized since 2001 to visualize the small bowel and its mucosa by high-quality images. Currently, it is a standard method with a higher diagnostic accuracy and sensitivity than other radiologic tools, allowing earlier diagnosis and treatment of tumors (Rodrigues et al., 2017). With good diagnostic resolution and as the first-line therapeutic procedure for small intestine diseases DAE depends on CE's previous evaluations (Pérez-Cuadrado-Martínez et al., 2020). This useful noninvasive initial approach for small-bowel tumors allows the exam of the entire small bowel, aids in determining the extent of tumor involvement and monitors the response to treatment and can help the decision on the initial approach route for a DAE procedure.
Besides, CE can have a better diagnostic yield than other routine imaging modalities to detect of smaller jejunoileal polyps (Kim et al., 2020). The concern about CE was related to eventual difficulty of distinguishing submucosal lesions from innocent bulges. However, the criteria and scores proved to be accurate to distinguish these changes, such as the smooth, protruding lesion index on CE score -SPICE (Rodrigues et al., 2017). Another possible concern is the difficulty of CE to measure with needed accuracy the lesion size.
The 3D CE device has a similar performance as the conventional CE, with tools of reconstruction and size measurement, optimizing the characterization of the small subepithelial tumors. Thirty one patients, 20 males and a mean age of 44.5 years, underwent the procedure for visualization of the small bowel; completion rate was 77.4%, and the detection rate was 64.5%. Subepithelial tumor diagnosis is the main promising of the 3D CE (Nam et al., 2020).
With the known site of an intestinal lesion, the histopathological study of tumor samples showed CgA, SYP, and AE1 /AE3 positive, establishing the final SI-NET diagnosis. After a careful revision of the small bowel diseases small bowel diseases excised tumor with the loco-regional lymph nodes, the patient underwent an enlargement of the surgical margin and lymphadenectomy. NETs were considered rare; however, with the advancement and availability of new diagnostic modalities such as the endoscopic capsule, an increasing number of this neoplasia has been diagnosed (Ahmed, 2020;Deguelte et al., 2020;Folkestad et al., 2020;Levy et al., 2020).
The majority of NETs are found in the GI and bronchopulmonary locations (Ahmed, 2020). The small intestine is not the most frequent area of NETs but is the most common primary site giving origin to distant metastases (Ahmed, 2020;Deguelte et al., 2020). The majority of tumors are non-functioning and usual manifestations are abdominal pain, partial intestinal obstruction, and hemorrhage (Ahmed, 2020;Deguelte et al., 2020;Folkestad et al., 2020;Kamei et al., 2020). In accordance with the WHO, the well-differentiated NETs are classified by Ki-67 index (%) and mitotic index/10 HPF, as grade 1 (< 3% and < 2); grade 2 (3-20% and 2-20); and grade 3 (> 20% and > 20). The poorly differentiated are grade 3, small cell type, and large cell type, while mixed NETs have at least 30% of other components as acinar or squamous cell carcinoma (Ahmed, 2020). The SINETs have a higher incidence than the small bowel adenocarcinomas, being the most frequent primary small bowel malignancy, representing 25% of the GI-NETs (Ahmed, 2020). The annual incidence of jejunoileal NETs is from 1 to 2 per 100000 persons-years, and over 60% are in the terminal ileum and up to 60 cm of the ileocecal valve (Ahmed, 2020;Deguelte et al., 2020;Folkestad et al., 2020;Kamei et al., 2020). The mean age at diagnosis is in the 6th and 7th decades, without gender difference (Ahmed, 2020).
Promisors in monitoring the disease are circulating tumor cells or tumor transcripts . The estimated detection rate of small-bowel tumors by capsule is from 2% to 9%, and capsule retention is rare (up to 2.6% of cases), more often in intestinal obstruction (Levy et al., 2020). Folkestad et al., reviewed data of 186 patients with SI-NETs and median age of 68 years, 54.3% men, and most of them underwent surgery for curative purposes or to prolong overall survival. Their median overall survival was 9.7 years, and 36 of 120 (30%) patients presented recurrence of disease after a median follow-up time of 5.5 years (Folkestad et al., 2020). Nine of 23 (39.1%) patients with SI-NET had other synchronous abdominal cancer. Tumor stage, carcinoid heart disease, synchronous cancer, preoperatively known SI-NET, elective surgery, curative surgery, and age were all associated with survival (Folkestad et al., 2020). The first treatment option is tumor resection with regional lymphadenectomy (Ahmed, 2020;Deguelte et al., 2020;Folkestad et al., 2020;Kamei et al., 2020); chemotherapy does not improve well-differentiated jejunoileal NETs, while capecitabine and temozolomide are utilized to treat metastatic poorly differentiated tumors (Ahmed, 2020;Deguelte et al., 2020;Folkestad et al., 2020;Kamei et al., 2020). The 5-year survival rate drops from 60% to 18% in the presence of liver metastases, and these implants can be managed with octreotide, transarterial embolization, radiotherapy with yttrium 90-or 177-lutetium-DOTA-lanreotide, TACE, and radiofrequency (Ahmed, 2020; Deguelte ARS MEDICA Revista de Ciencias Médicas Volumen 46 número 1 año 2021 Gomes et al. et al., 2020). NETs in advanced phases may have an increase in estimated survival time if submitted to cytoreductive surgery in association with multidisciplinary management (Deguelte et al., 2020;Kamei et al., 2020). Although with the inherent weaknesses of a single case study, the authors believe that this report may enhance the knowledge about novel diagnostic modalities.

Conclusion
NETs are currently growing in number in daily practice, mainly due the best knowledge about the biological mechanisms of these tumors and advanced resources for diagnosing this condition. SI-NETs should be among the possible causes of an occult digestive bleeding, and the use of the CE has been of great value to establish the diagnosis.
Competing interests: The authors declare that they have no competing interests Source of support: Nil