This is a unique case of a patient who was found to have two extremely primary malignancies synchronously, i.e., an ampullary adenocarcinoma arising from a high-grade dysplastic TVAoA with a high-grade ileal GIST. Based on a literature review and to the best of our knowledge, this is the first report of this synchronicity. Primary ampullary tumors are extremely rare, with an incidence of four cases per million population, which is approximately 0.0004%. Distal duodenal polyps are uncommon and have a preponderance of occurring around the ampulla of Vater. Duodenal polyps are found in 4.6% of patients referred for upper endoscopy[2]. Duodenal polyps occur more frequently in the ampulla than in the distal duodenum. Because of the widespread use of upper endoscopy, the incidence of ampullary tumors has been increasing.

Adenomas are the most common ampullary tumors. AoAs can occur as sporadic in a familial inheritance pattern, such as in the setting of FAPS. Two essential points prompted us to write this case report. Firstly, when an AoA is found on upper endoscopy, patients should be sent for screening and periodic surveillance colonoscopy for FAPS. Secondly, AoAs are premalignant lesions can progress to an ampullary adenocarcinoma, which should be identified early for appropriate management and improved outcome. An AoA in the setting of FAPS has a high risk for progression to an ampullary adenocarcinoma. Compared with non-FAPS patients, these patients have an approximately 124-fold increased risk of progression[3]. The diagnosis of an AoA is usually incidental. However, some patients present with obstructive symptoms, such as painless jaundice associated with weight loss, which occurred in our patient due to CBD obstruction[3]. This results in pancreatitis due to pancreatic duct obstruction[3]. When there are constitutional symptoms such as weight loss, an in-depth work-up is needed to evaluate the potential malignant transformation of an AoA. Endoscopic forceps biopsy is only diagnostic in 64% of cases. Diagnostic accuracy is greater when histopathological studies are performed on surgical specimens. Therefore, a final diagnosis should only be made when surgical pathology is available[3,4].

Ampullary carcinoma is the 2^nd most common periampullary regional cancer and metastasizes locally in the abdomen and to the liver. Distant metastasis is less common, but there are case reports describing skeletal and brain metastases[1]. Carcinoma of the ampulla of Vater is a rare tumor accounting for approximately 0.2% of all gastrointestinal malignancies, with an estimated incidence of < 6 cases per million people per year[1]. AoAs and adenocarcinomas originate from the glandular epithelium of the AoV[5]. The cell of origin of these cancers is the epithelial covering of the distal parts of the CBD, pancreatic duct, and periampullary duodenum. Histological subtypes that are common are mucinous, signet ring cell, neuroendocrine, and undifferentiated carcinomas.

A study by Seifert et al[6] revealed that 30% of ampullary adenomas progressed to ampullary adenocarcinomas, which were found during surgery or on follow-up. It also showed that 41.2% of surgically resected ampullary adenocarcinoma patients had residual well-differentiated adenomatous tissue[6].

The next step after diagnosis is established is staging. The usual imaging modalities are CT of the chest, abdomen, and pelvis, MRCP, endoscopic ultrasound, and endoscopic intraductal ultrasound. If there is any biliary tree abnormality in the CT or MRCP, then ERCP plays an important role. ERCP can be diagnostic for determining the extent of the spread of the tumor followed by sphincterotomy and stent placement to facilitate pancreaticobiliary drainage[3].

Incidental and small adenomas may not need any treatment, but high-grade dysplastic tubulovillous adenomas require definitive treatment due to the potential risk of progression to an adenocarcinoma[5].

Management of an ampullary adenocarcinoma:

The patient had a broad-based adenoma in the ampulla, and ampullectomy could have been performed robotically, but it would have been performed for a longer time, and we were concerned about negative margins. On the other hand, a robotic Whipple procedure is possible, but the patient did not agree to that procedure.

In regards to the ileal GIST, minimally invasive surgical resection and robotic resection are available options, although rupture of the tumor may be a potential complication. We have done many of these procedures and have never had a rupture at our facility; in fact, robotic articulation does help to maneuver the tumor without traumatizing it. Therefore, we can perform both ampullectomy, duodenal polyp excision and GIST with minimally invasive surgery either robotically or laparoscopically; some at our facility prefer robotic procedures because of the ease of anastomosis and articulation of the robot. With the Whipple procedure, we can obtain clear margins, but duodenal/ampullary lesions are more challenging because of the risk of positive margins.

An overview of the management of ampullary adenomas and ampullary carcinomas is described in Table 3.

GISTs are rare tumors comprising 3% of gastrointestinal tumors but are the most common mesenchymal tumors of the GI tract[4]. The most common sites are the stomach (60%) and small bowel (30%)[2,3]. These are sporadic tumors, unlike ampullary adenomas. Some studies report that the incidence significantly varies from 0.4 to 2.0 cases per 100000 per year, with a slight male preponderance and a median age of 60-65 years[7-9].

GISTs are malignant mesenchymal tumors whose cell of origin is the myenteric interstitial cells of Cajal; they are also known as pacemaker cells of the GI tract and are found in the proximal muscles surrounding the intermuscular plexus of the GI tract. They are soft tissue sarcomas of the GI tract, but they differ in genetics, pathogenesis, clinical presentation, and management[4].

Most GISTs have universal expression of c-KIT/CD117. DOG-1 is another novel marker and can be seen in c-kit-negative cases. The mitotic rate can predict the risk of recurrence.

In 1998, a breakthrough was achieved when the tyrosine kinase receptor mutation c-kit was identified[10]. The most common mutations in GISTs are located in c-KIT exon 11 in approximately 65% of cases and exon 9 in approximately 10%. GISTs with exon 11 mutations are more sensitive to the tyrosine kinase inhibitor imatinib than those with exon 9 mutations.

Platelet-derived growth factor alpha (PDGFRA) mutations account for approximately 5%-10% of cases. Mutations are located on exons 12, 14, and 18. It is important to identify the D842 V2V mutation in exon 18, as this mutation confers resistance to imatinib. Avapritinib is the preferred treatment for GISTs with this mutation[4].

Other rare GIST mutations are BRAF and NTRK gene rearrangements, which carry therapeutic implications. Histopathological diagnosis depends upon morphological and immunochemical analysis of the tumor. Immunochemistry is usually positive for CD117(KIT) and/or DOG-1 in 95% of patients. Five percent of GISTs are negative for CD117 and/or DOG-1[8].

Mutational analysis of GISTs is important, as it has good predictive value for sensitivity to targeted therapy, as noted previously, and prognosis. The European Society for Medical Oncology practice guidelines recommend testing for mutations as a part of the diagnostic workup for all high-risk GISTs. GISTs negative for KIT/PDGFRA require subsequent immunochemical testing for succinate dehydrogenase complex subunit-B.

Management of GISTs includes multidisciplinary consultation with pathologists, radiologists, surgeons, medical oncologists, and gastroenterologists, etc., to achieve better outcomes.

Standard management of a localized GIST is complete surgical resection or excision without dissection of clinically negative lymph nodes. The goal is to excise the tumor with negative margins. Tumors greater than 2 cm in size should be biopsied and surgically resected. If less than 2 cm in size, surveillance via endoscopic ultrasound can be performed. However, if lesions are suspicious, then they should be surgically resected. Small GISTs located in the upper and lower GI tract can be resected endoscopically by a surgeon who has endoscopic expertise.

Systemic therapy is performed as a neoadjuvant or adjuvant based on tumor size and other characteristics and is the main strategy for the management of advanced/metastatic disease (Tables 4 and 5).

The first-line treatment for KIT exon-9-mutated GISTs is imatinib (800 mg daily), whereas avapritinib (300 mg daily) is the first-line treatment for GISTs with PDGFRA exon 18 D842 V2V mutation[8]. The imatinib dose can be escalated from 400 mg to 800 mg when there is disease progression. Second-line therapy with sunitinib (50 mg daily) is recommended when there is intolerance to imatinib or progressive disease. Regorafenib (160 mg daily) is generally the third-line therapy for patients unresponsive to imatinib and sunitinib. Ripretinib (150 mg daily) is approved in patients who have received prior treatment with three or more kinase inhibitors, including imatinib.

National Comprehensive Cancer Network guidelines recommend follow-up with history and physical and imaging studies every 3 to 6 mo for the first 5 years and then annually after complete resection of GISTs. Relapse to the liver and peritoneum can occur, but distant metastasis to bone and other sites is rare.

The coexistence of the malignancies described in this case is extremely rare, and to our knowledge, this is the first reported case in the literature. Mazur and Clark[10] first published the term GIST in 1983; initially, we considered GISTs as neoplasms of smooth muscle cells and called them gastrointestinal smooth muscle tumors[10]. There have been case reports in the literature reporting GISTs occurring with other histologically diverse parallel primary malignancies. There have been reported occurrences of GISTs of the gastric antrum with colorectal adenocarcinomas[11] and duodenal GISTs with rectal adenocarcinomas[12]. There has been increasing evidence of coexistent, contemporaneous GISTs with other neoplasms of the breast, digestive tract, liver and urogenital system[7,13,14].