Gastrinoma: A Small Tumor with Big Symptoms

Gastrinoma is rare gastrin secreting tumor and can be challenging to diagnose in the absence of typical clinical features. Surgical resection remains the mainstay of treatment and can be curative, but the clinical presentation can compromise complete resection especially if the disease has already metastasized. We present here a 77-year-old lady with abdominal pain and secretory diarrhea. Gastrinoma was diagnosed in a stepwise approach of investigations and then surgically removed. Following surgery, the patient got prescribed octreotide for complete resolution of symptoms. Conservative treatment is only recommended for patients unsuitable for surgery, with widespread metastasis and on patients’ own choice. Gastrinoma: A Small Tumor with Big Symptoms.


Introduction
Gastrinomas are functional neuroendocrine tumors (NET) with excessive pathological secretion of a peptide hormone called Gastrin usually produced by gastric G-cells. These tumors are thought to originate from endodermal pluripotent cells. Gastrin is a physiological stimulus of the stomach parietal cells to produce gastric acid. Gastrinoma cells retain their functional ability to produce and secrete hormone but partially or completely lose their negative feedback inhibition function leading to unwanted and excessive volumes of gastric acid production, atypical stomach and intestinal ulceration and occasionally perforations often termed as Zollinger-Ellison syndrome (ZES). Gastrinoma is a rare NET with 0.1-15 cases per million individuals worldwide [1]. Gastrinoma may be sporadic or associated with multiple endocrine neoplasia type-1 (MEN-1). All patients with a Gastrinoma should be screened for MEN 1. Due to nonspecific symptoms Gastrinomas are usually diagnosed late. Typical symptoms include abdominal pain, secretory diarrhea, esophagitis, and hypercalcemia (4). Serum gastrin level is of great significance for initial screening, while diagnosis requires stepwise approach with help of imaging studies and is confirmed on pathological and immunohistochemical analysis. Surgical management remains the only curative treatment for a Gastrinoma (5). We report here a case of a 77-year-old lady diagnosed with a Gastrinoma. She underwent surgical resection with significant improvement in symptoms. After surgery, she was prescribed octreotides for further control of symptoms.

Case Report
A 77-year-old lady was referred to our Endocrinology clinic from Gastroenterology clinic for assessment of her stomach related symptoms. She had recently moved to England with a significant past medical history of stomach-related symptoms over the previous 10 years. She had been suffering from gradually worsening bouts of watery diarrhoea and vomiting for the previous ten years with a weight loss of 6 stones. The frequency and severity of her symptoms gradually got worse and was occasionally associated with abdominal pain, flushing, severe retching, and heartburns.
Omeprazole and Ranitidine partially improved her symptoms, but the severity of residual symptoms kept getting worse over time. She had undergone a laparotomy for perforated anterior jejunal wall three years ago. During these ten years, she underwent extensive workup for her symptoms. Multiple upper GI endoscopies showed gastritis and duodenitis, biopsy confirmed oesophageal gastric Note: TSH, Thyroid stimulating hormone; FT4, free T4; 5 HIAA,

5-hydroxyindoleacetic acid; tTG, Tissue transglutaminase
Her history was strongly suggestive of gastric acid hypersecretion that is usually secondary to excessive gastrin production. Our clinical suspicion was further strengthened by high serum gastrin level and confirmed on the secretin stimulation test ( Table 2). Once the diagnostic biochemical work-up confirmed gastrin hypersecretion we completed cross-sectional and functional imaging studies including a 68Ga-DOTATATE PET scan, an octreotide scan and endoscopic ultrasound to localize the tumor to assess the possibility of its resection. These imaging studies  (Table 3) and daily injectable octreotide followed by long-acting octreotide was prescribed with complete resolution of symptoms.

Investigations Before surgery(Off PPI) One month after surgery(on PPI) Two months after surgery(on PPI)
Gastrin ( have also been described in other areas, including lymph nodes, biliary tree, ovaries, kidneys, heart, gallbladder, omentum and liver. In advanced cases, liver is the most common site for metastasis. The duodenal and pancreatic Gastrinomas behave similarly clinically [6]. Most Gastrinomas are sporadic in origin but in 20-30% of cases these may be associated with Multiple Endocrine Neoplasia-type 1 (MEN1) [4].
Majority of patients with sporadic Gastrinomas are men between the ages of 30 and 50 years. Our patient presented at a relatively older age. A Review of literature revealed that was relatively one of the few cases of Gatsrinomas which were diagnosed in old age. they have excellent sensitivity and specificity for NETs [11,12].
Somatostatin receptor studies have a sensitivity of 40-60% for duodenal Gastrinomas and 60-100% for pancreatic Gastrinomas [11][12][13]. It has a reported false positive rate of 0-12% but is higher in MEN1/ZES patients because of the multiple endocrine tumors these patients develop. With improvements in imaging, the role of biopsy or cytology in diagnosing ZES, particularly in patients with advanced disease or typical presenting symptoms, is less clear.
All ZES patients must be screened for MEN1 syndrome initially and re-evaluated with time [4,14]. The presence of MEN1/ZES needs family counseling as well as the need to search for other endocrinopathies. MEN syndrome is associated with many functional and nonfunctional NETs and the presence of these tumors has a major impact on the clinical management approach to the Gastrinoma itself. Our patient had a normal parathyroid hormone level (PTH) and blood calcium levels and was subsequently diagnosed with sporadic Gastrinoma. In addition, chromogranin A has been used as a tumor marker for NETs, with a sensitivity of 59% and a specificity of 100% [15]. In our case chromogranin A was raised before resection that dropped to normal range after resection of the lesion. Treatment of a Gastrinoma aims towards control of symptoms by controlling hormone excess and its surgical resection.
Without effective medical treatment, gastric acid hypersecretion can cause severe complications including bleeding, penetrating stomach and intestinal ulcers and fatal outcomes [16,17]. Initially, only total gastrectomy adequately controlled the profound acid hypersecretion. However, with the availability of proton pump inhibitors [18][19][20][21][22], medical control of acid hypersecretion, both acutely and long-term, is possible in the majority of patients.  [17,23,24] have demonstrated that surgical resection extends overall-and diseaserelated survival and also decreases the subsequent development of liver metastases, which are the main determinant of longterm survival in these patients [25][26][27][28]. Although the majority of Gastrinomas grow slowly 50-60% are malignant and have already metastasized at diagnosis [29]. A metastatic malignant Gastrinoma has 5-year survival rate of 20-38% [29]. If tumor has metastasized then control of symptoms is only achieved with medical therapies.
In our case, there was no distant metastasis and tumor was localized to head of pancreas. It was surgically resected and postoperative imaging (Figure 2) confirmed the complete removal of lesion. Gastric hypersecretion may be controlled effectively using PPIs and H2-blockers. However, somatostatins, such as octreotide, have also been used to inhibit the hypersecretion of gastric acid [23]. A routine use has not been established and randomized trials are required. Chemotherapy may be administered for patients with widespread metastasis and those unfit for surgery. The first-line treatment is combined therapy with streptozotocin and 5-fluorouracil or doxorubicin [26].

1.
Our patient presented with a sporadic Gastrinoma at a relatively older age and we suggest clinicians should always suspect atypical presentations of any disease.

2.
Clinicians should always think out of the box to diagnosed uncommon conditions if standard therapies fail to achieve the expected outcomes.