An Unusual Cause of Mesenteric Ischemia of the Small Intestine: Jejunal Neuroendocrine Tumor
Article information
Abstract
Small intestinal neuroendocrine tumors are rare gastrointestinal malignancies (< 0.5% of all cancers). Complications at presentation include bleeding, abdominal pain, and bowel obstruction; small bowel ischemia and bowel necrosis are rare. A 63-year-old patient was referred from a rural hospital to Acute Care Surgery with bowel obstruction, and arrived in septic shock. He was resuscitated, diagnosed with mesenteric ischemia, and underwent an exploratory laparotomy which identified an internal hernia (which was released), and small bowel ischemia and necrosis which were resected. The incidence of acute mesenteric ischemia < 0.2% of all acute surgical admissions. Nonocclusive mesenteric ischemia accounts for 20% of all etiologies and was evident in this case. The superior mesenteric artery pulse was clinically palpable and there were no signs intraoperatively of venous stasis at the root of the mesentery. Pathology confirmed multiple small bowel mesentery neuroendocrine tumor nodules. Surgical resection remains the mainstay of treatment.
Introduction
Neoplasms affecting the small intestine are exceedingly rare representing 0.4% of all cancers and 2% of gastrointestinal (GI) malignancies [1]. The global incidence of neoplasms affecting the small intestine ranges between 0.3 and 2.0 per 100,000 per year and has been increasing significantly in recent years. A systematic review of the management and outcomes for small intestinal neuroendocrine tumors with involvement of the superior mesenteric vessels in the United States reported a 4-fold increase over the past fifty years [1]. Neuroendocrine tumors constitute 40% of malignant small intestinal tumors and, although rare, represent the most common small bowel malignancy. Small intestinal neuroendocrine tumors (SI-NETs) arise from neuroendocrine cells lining the bowel (which secrete digestive enzymes and serotonin) and originate in the ileum (70%), duodenum (22%), and jejunum (10%) [1]. Jejunoileal neuroendocrine tumors (JI-NETs) rarely secrete hormones and are asymptomatic; bleeding and obstruction occurs at a later stage. Patients typically present with abdominal pain associated with bowel obstruction [1,2]. Jejunal tumors are capable of metastasizing before reaching a primary size of 1 cm, and all lesions over 1 cm metastasize, typically, to the liver or mesenteric lymph nodes [3]. Tumor-induced intestinal ischemia leading to necrosis is a rare complication of JI-NETs [4,5]. Relatively few studies of SI-NET-induced intestinal ischemic necrosis have been reported in the literature [6]. The pathophysiology has not been clearly elucidated but several theories implicate occlusion of the mesenteric vasculature.
Case Report
A 63-year-old male patient was referred from a rural hospital to the Acute Care Surgery service with bowel obstruction. Upon admission he was in septic shock. He was hypovolemic and pyrexial. In the Emergency Room, he was resuscitated with intravenous fluids and antibiotics. He had profound metabolic acidosis (pH of 7.1) and an arterial blood gas base deficit of −7 mmol/L. His white cell count was 18.8 × 109/L and his lactate 10.2 mmol/L. His phosphorus level was 1.51 mmol/L. His delta neutrophil index was 79.1%. Clinically his abdomen was rigid with guarding and rebound tenderness. He was subsequently transferred to the Intensive Care Unit to continue his physiological resuscitation. A computerized tomography (CT) scan showed bowel obstruction and a radiological diagnosis of mesenteric ischemia was made (Figures 1A and 1B). The patient responded to fluid resuscitation but did require inotropic support. He did not remember his significant medical history. He complained of abdominal pain that had begun the day before. He did not recall a history of food phobia. He signed an informed consent for an exploratory laparotomy and was taken to the Operating Room as part of his ongoing physiological resuscitation. Intraoperatively a diagnostic laparoscopy was performed to visualize the small bowel and gauge the possibility of the etiology being an internal hernia that could be released with minimal effort. Small bowel ischemia and necrosis were observed during the diagnostic laparoscopy and an open laparotomy was performed. He had 30 cm of dead bowel located in the middle of the jejunum (Figure 2). There was no internal hernia. The necrotic bowel was resected. The rest of the small bowel was normal with no signs of ischemia. Clinically, the superior mesenteric pulse, at its origin, could be palpated. He had no signs of venous stasis at the root of the mesentery. He remained clinically stable, so a side-to-side stapled anastomosis of the jejunum was performed. His resuscitation continued in the Surgical Intensive Care Unit. He made an uneventful recovery. He was subsequently lost to follow up, despite numerous attempts to contact him. Pathology confirmed a small bowel mesentery neuroendocrine tumor (Figures 3A and 3B). He had multiple neuroendocrine metastatic nodules, dotted all over the mesentery of the resected specimen (Figures 4A and 4B).
Computerized tomography scan (A) coronal; and (B) axial view showing the ischemic bowel (green arrows).
Necrotic small bowel, mid jejunum at laparotomy.
(A) External; and (B) internal view of a neuroendocrine tumor (blue arrow) in the resected specimen.
Gross pathology specimens showing (A) neuroendocrine tumors in the mucosa (orange arrow); and (B) jejunal mesentery (blue arrow).
Discussion
SI-NETs are slow-growing tumors, characterized by their capacity to secrete bioactive amines and peptides. Their clinical presentation is a rare phenomenon [7]. JI-NETs differ from those occurring in other sites of the GI tract. They present at an advanced stage of disease with metastases to the mesentery or liver [1]. The mean age of diagnosis for JI-NETs is the 6th or 7th decade of life with no sex predilection [8]. The 5-year overall survival for JI-NETs is approximately 60%, with a median survival of approximately 7 years [2]. Factors affecting prognosis include: (1) tumour, node, metastasis stage; (2) World Health Organization grade; (3) tumor multifocality; (4) vascular invasion; (5) mesenteric tumor deposits; and (6) completeness of mesenteric tumor resection [2]. Metastases to the mesentery occur in high frequency with SI-NETs. JI-NETs are generally greater than 2 cm in size, and multiple tumors occur in ≤ 40% of cases. In 70% of JI-NETs muscularis propria with metastasis has invaded the regional lymph nodes, and 50% of patients may have hepatic metastasis at diagnosis [8]. In our patient, the jejunal neuroendocrine tumor had metastasized to the mesentery, with multiple tumor deposits. His CT scan did not show any obvious liver metastasis. Increasing numbers of mesenteric deposits are associated with poor prognosis, conferring an 8-fold risk of disease-specific death compared with a single deposit [9]. Morphological features of deposits do not present a prognostic impact [9]. Mesenteric fibrosis (MF) manifests in 50% of cases, which can impinge on the mesenteric vasculature leading to mesenteric ischemia in about 10% of cases [8]. Patients with mesenteric fibrosis may be completely asymptomatic or present with abdominal pain, intestinal obstruction, GI bleeding, and decreased urinary output [8]. In the case of GI bleeding, endoscopy of the GI tract and CT scans are the standard imaging modalities. In mesenteric ischemia, the standard approach is CT angiography [5]. The CT scan raised a suspicion of mesenteric ischemia in our patient who initially presented with intestinal obstruction. An exploratory laparoscopy revealed small bowel ischemia and necrosis. The treatment for JI-NET remains surgical resection of the affected intestinal segment. This represents the only curative option [3,5]. Surgical resection of the primary tumor and regional metastases is associated with improved overall survival and symptomatic control [1].
A small subset of JI-NETs lead to tumor-induced intestinal ischemia, with the resected surgical specimen displaying intestinal ischemic necrosis [2]. The pathophysiology remains nebulous despite several theories. These include fibrous proliferation involving contracture of the mesentery; tumor mass constricting blood vessels; hyperplasia of elastic tissue within the intima and adventitia of surrounding blood vessels, which may or may not involve thrombosis [6]. In 1960, Moertel [10] reported a series of 209 intestinal carcinoid tumors. There were 4 patients (2%) where intestinal necrosis was involved, and was attributed to mechanical occlusion of the vascular supply in the mesenteric root by a fibrotic reaction associated with large nodal metastases [7]. Anthony et al [11] reported 10 autopsy cases of ileal carcinoid tumors, where 4 of the 10 cases led to small intestine necrosis through obliterative elastic sclerosis of the mesenteric vessels. In 2 of the 10 cases, showing mesenteric ischemia a thick mantle of adventitial elastic tissue encasing the involved arteries and veins was reported, where sclerosis had resulted in narrowing of the vessels leading to ischemia. It was noted that the vascular lesion may be attributed to the local influence of a product from the tumor [8]. Murray-Lyon et al [12] suggested that a combination of restricted blood flow due to the presence of tumor tissue and the characteristic fibrotic reaction at the root of the mesentery resulting in thrombosis, underlies the pathophysiology of intestinal ischemia. In his articles, elastic sclerosis was present in the vessels, yet luminal obstruction was minimal and thus considered insignificant [4]. Mesenteric venous thrombosis has been reported in patients with neuroendocrine tumors and the etiology encompasses venous stasis via direct vessel encasement, or cytokine response leading to fibrosis [9]. Mesenteric venous thrombosis can rapidly progress to intestinal ischemia, with a mortality range of 10%–20% [13]. Qizilbash et al [14] suggested that the etiology of ischemia resulted from tumor inducing vascular fibroblast cells producing excess elastic tissue, as opposed to the influence of a humoral agent, as postulated by Anthony et al [11]. Cell types such as mesenchymal cells, mast cells, and smooth muscle have all been implicated in the cellular induction of elastin production [4]. The pathogenesis of tumor-induced intestinal ischemia remains to be clearly elucidated. Sworn et al [15] has suggested a multifactorial etiology based on the mechanisms mentioned [4]. JI-NET-induced intestinal ischemic necrosis is associated with early mortality [12], with Landau et al [2] reporting a 4.3-fold increased risk of death with the presence of intestinal ischemic necrosis. JI-NETs have features that may uniquely contribute to intestinal ischemic necrosis: (1) they spread to the mesentery, forming bulky masses close to the mesenteric vasculature; and (2) they can induce excessive stromal fibrosis via secretion of growth factors, causing distortion of the mesentery and occlusion of blood vessels [2]. MF surrounding a mesenteric mass is a hallmark of SI-NETs, with the potential to induce intestinal obstruction, edema, and ischemia. MF is associated with a decreased 5-year survival, although it did not remain a significantly negative prognostic factor when corrected for other factors such as age and tumor aggressiveness [11]. In SI-NETs, MF is an abnormal repair process initiated by a complex network of autocrine and paracrine mediators produced from tumor cells and the tumor microenvironment. The tumor microenvironment consists of a network of endothelial and inflammatory cells and mesenchymal stroma elements with fibroblasts. The interactions amongst the network leads to tumor growth and development of fibrosis, possibly via epigenetic changes in tumor cells [3]. JI-NETs may induce ischemic necrosis through mesenteric vascular elastosis, which is frequently associated with JI-NETs. In our patient, the superior mesenteric pulse was palpable and venous stasis was absent at the root of the mesentery. This suggested that the arterial and venous branches of the mesenteric vasculature were likely compromised, but not the actual superior mesenteric artery or vein. We postulated that metastasis to the mesentery resulting in fibrosis and blood vessel occlusion led to the intestinal ischemic necrosis observed in our patient. Most mesenteric ischemia includes vessel occlusion at the origin of the superior mesenteric vessels. As clinicians we should be cognizant of the other possible etiologies as was demonstrated in this case report.
Notes
Author Contributions
Proof of concept, primary surgeon and proof reading: YP. Original literature search, writing of the article and references: AD.
Conflicts of Interest
The authors have no conflicts of interest to declare.
Funding
The authors did not receive any financial support in the writing and research of this article.
Ethical Statement
All ethical standards for publishing were adhered to and written consent was obtained for publication of the pictures used in this article.
Data Availability
All relevant data are included in this manuscript.