NETs are relatively rare tumors and located most commonly in the gastrointestinal tract (55%) and bronchopulmonary system (30%) according to a report from the SEER database [5]. Within the gastrointestinal tract, the rectum is the second most common site (20%) after the small intestine [6], and rectal NETs are estimated to occur at a rate of 0.14 to 0.76/100,000 cases [7, 8]. They are typically nonfunctioning and asymptomatic, and thus extremely difficult to diagnose. Recently, however, due to the widespread implementation of colonoscopy as a screening tool, the rate of detection of colorectal NETs is increasing [9, 10]. Most cases of rectal NETs (80–88%) are localized, whereas the remaining NETs (12–20%) are diagnosed with regional lymph node spread and/or distant metastases (21% G1, 30% G2, and 50% neuroendocrine carcinomas [NECs]) [11].
In our case, the patient had no symptoms, and multiple liver tumors were incidentally discovered by abdominal ultrasonography. A CT and a colonoscopy for systemic examination resulted in an accurate diagnosis, and a CT-guided biopsy (CTGB) of the liver and rectum confirmed a NETG2. The liver biopsy was significant in considering whether the liver tumors were metastases of the NET or of the simultaneously discovered colon cancer. The Octreoscan showed an abnormal uptake in multiple organs including the pancreas, and it was difficult to determine the primary site. Finally, clinically, we considered the primary site to be the rectum in terms of the multiplicity of the pancreatic tumors, MRI image pattern concordance between the liver and the pancreatic tumors, and the bulky lymphadenopathy around the rectum. However, we could not unconditionally rule out the possibility of synchronous tumors of the rectal NET and a pancreatic neuroendocrine tumor (P-NET) with either liver metastases of the NET or rectal and liver metastases of the P-NET. According to Yao et al., in patients with an advanced, progressive, nonfunctional GI-NET, treatment with everolimus was associated with statistically significant and clinically meaningful prolongation of progression-free survival (PFS) [12]. Thus, we immediately started the patient on 10 mg per day of everolimus after the surgery.
This case emphasizes that for synchronous cancer, if the cancer can impede continued systemic therapy, we should consider surgical resection before systemic therapy for the NET regardless of the difference in prognosis between the synchronous tumors. Of course, palliative or cytoreductive surgery for the NET should be considered at the same time, regardless of whether it is a primary or metastatic lesion. This is even more true if the NET involves local symptoms. However, in patients diagnosed with a NET with distant metastasis, early systemic therapy is extremely important. We should take not only the patient’s general condition, but also their condition after surgery into consideration in determining the indications for surgery or surgical procedures.
Generally, GI-NETs often show hematogenous metastases, and the most frequent sites of distant spread are the liver, bones, and peritoneal cavity [13,14,15,16]. According to some reports, the tumor size, depth of invasion, and lymph node involvement are all significant predictors of malignant behavior in rectal NETs [17]. Tumors smaller than 1 cm are rarely metastatic, with only 3.7% of rectal NETs that are 0.5 cm or smaller being metastatic at the time of diagnosis; rates of metastatic disease increase to 13.2% in tumors 0.5 to 1.0 cm in size, and to 26–28% in tumors 1 to 2 cm in size [18]. Up to 70% of tumors larger than 2 cm may be metastatic [14, 19]. In addition, many previous studies have reported that the presence of muscularis propria or lymphovascular invasion in a rectal NET is a strong risk factor for metastasis [20,21,22]. In our case, the tumor size was 45 mm and both CT and MRI indicated tumor invasion of the muscularis propria. Therefore, we concluded that these are the reasons why multiple organ metastases developed, despite the rectal NET being well-differentiated (G2). This also supported the diagnosis of a rectal primary NET. Interestingly, the pancreas is extremely rare as a distant metastasis site of a NET [23, 24].
It has been reported in some of the English literature that NETs are associated with synchronous or metachronous secondary primary malignancies (SPMs): rates of SPMs are up to 55% in NETs [25], and Tichansky et al. reported that 8% of patients with colorectal carcinoid also had synchronous cancer [26]. Additionally, Winn et al. reported that in synchronous colon adenocarcinomas with a gastrointestinal carcinoid tumor, the most common location was the sigmoid colon [2]. There are several hypotheses to explain the relationship between NETs and SPMs, including the field-effect theory, the stem cell theory, the neuropeptides theory, the genetic defect hypothesis, and the immunodeficiency theory [25, 27,28,29,30,31,32,33]. When we found that our patient had a simultaneous sigmoid colon cancer, the rectal NET was already well-developed and had multiple organ metastases at the time of diagnosis. To the best of our knowledge, no cases of synchronous colorectal cancer and a GI-NET with distant metastasis have been reported. As the GI-NET may coexist with SPMs, the diagnosis of a GI-NET must be extensively evaluated for SPMs during the workup and follow-up periods. We recommend performing a CT and upper and lower endoscopies.
