Epidemiology and presentation

GP accounts for 6 to 9% of duodenal gastrointestinal neuroendocrine tumors (NET) and ranks as the third most frequent histopathologic type after gastrinomas and somatostatinomas [6, 7]. The exact embryologic origin of GPs remains unclear, but endodermal and ectodermal sources are postulated [8–10].

In a literature survey done by Okubo et al. [11], patients with GP had a mean age of 52.3 (range 15 to 84 years of age), with a slight male predominance (male to female gender ratio 114:76), and a mean tumor size of around 2.5 cm. GP is most commonly found in the duodenum (90%), and its clinical presentation varies from an asymptomatic course to one or more presenting gastrointestinal symptoms [11, 12]. In a systematic review of 263 cases with GP, the most common presentations of GP were gastrointestinal bleeding (48%) and abdominal pain (45%), followed by anemia (20%), and less commonly nausea (7%), weight loss (5.5%), and jaundice (5%) [13]. While lymph node involvement was reported in up to 12% of cases, rare complications such as intestinal obstruction, bile duct obstruction, and liver metastasis (1.1%) can also occur [13, 14].

Pathology, histology, and immunochemistry

GP tumors usually present as single solid well-demarcated lesions that could be polypoid, pedunculated, or sessile, ranging in size from 5.5 to 100 mm [11, 15]. The mass has a gray to white, yellowish appearance, commonly with an overlying mucosal ulcer with bleeding [1]. It is typically centered in the submucosal layer and infiltrates the mucosal and/or muscularis propria layer in more than 50% of cases [11]. As a result, superficial biopsies may not confirm a diagnosis, and deeper sampling is often necessary. The depth of tumor invasion beyond the sphincter of Odi or the submucosal layer has been associated with an increased risk of lymph node metastasis [13].

Histological features of GP show three cell types:

• Epithelioid cells, arranged in a Zellballen (nested) pattern resembling paraganglioma.

• Spindle cells, with schwann cell differentiation, are arranged in streams surrounding the epithelioid nests.

• Ganglion or ganglion-like cells are scattered throughout or merged with spindle cells in fascicular clusters resembling ganglioneuroma [16, 17].

In cases with lymph node metastasis, the metastasized tumor has variable cell types, most commonly made up of epithelioid cells only (46.7%) [1]. Each of the three cell types has characteristic immunohistochemical staining, and in our case, S100 was positive in ganglion and spindle cells [1]. Okubo et al. [13] report that each of the three cell types have unique immunohistochemical profile, with the most common ones being: CD56 (100%), S-100 protein (96%), and CD56 protein (95.2%) in the epithelioid cells, spindle cells, and ganglion-like cells, respectively. Some of the other immunoreactivity markers used are synaptophysin, neuron-specific enolase, progesterone receptor, chromogranin A, pancreatic polypeptide, somatostatin, chromogranin, and cytokeratins [13]. The histological or immunohistochemical differences between tumors with or without lymph node metastasis remain unclear.

GPs are rare and difficult to differentiate from other periampullary neoplasms, including NETs. Immunohistochemical expression of progesterone and pancreatic polypeptide receptors is useful in differentiating GPs from G1 NETs [13]. Biopsy specimens might not contain all 3 characteristic cell types, and definitive diagnosis could be challenging with a low rate of diagnostic biopsies before surgical resection of around 11% [11, 13].

Differential diagnosis and diagnostic pitfalls

It is important to have a broad differential diagnosis in suspected GP cases. The differential diagnosis would include GISTs, NETs, smooth muscle tumors, adenocarcinoma, and ganglioneuromas [1, 7]. A common pitfall is misdiagnosis as NET G1 when only the epithelioid component is sampled, particularly in superficial biopsies that fail to capture the ganglion-like and spindle cell components [13]. Superficial biopsies may not confirm the diagnosis, and deeper sampling is often necessary since GP is typically centered in the submucosal layer. When tissue is limited, immunohistochemistry on the biopsy specimens is essential for definitive diagnosis, as the triphasic morphology may not be fully appreciated in small samples [13, 17].

The most critical differential diagnosis is NET G1 (carcinoid tumor), as GP is often misdiagnosed as NET G1, which carries a poorer prognosis [13]. Okubo et al. [18] report that up to 40% of duodenal lesions initially diagnosed as NET G1 may actually be GP. The key distinguishing features are that GP exhibits the characteristic triphasic morphology with ganglion-like and spindle cell components, whereas NET G1 shows a more uniform neuroendocrine cell population.

Management

Periampullary GP should be considered as a tumor with malignant potential. Factors that could be associated with lymph node metastasis include size (> 2 cm), younger age, female gender, a high mitotic index, nuclear polymorphism, and tumors invading the submucosal layer or causing biliary obstruction [1].

The optimal treatment of periampullary GPs has not been clarified, and treatment options vary [5]. Endoscopic resection is the treatment of choice for most of the duodenal GPs. En bloc resection with negative margins for a pedunculated lesion is possible. In the published literature, endoscopic techniques successfully removing these lesions have been described. Palomino-Martínez et al. [19] report a case of GP adjacent to the ampulla of Vater that was treated with an endoscopic ampullectomy, with successful resection and confirmed negative margins on histopathology. Similarly, Manglekar et al. [20] discuss the case of a 70-year-old female who was found to have a GP in the second part of the duodenum. It was treated with endoscopic submucosal dissection (ESD), and en bloc resection was achieved. Moreover, pancreaticoduodenectomy is recommended for GPs with possible malignancy, submucosal invasion, or pancreatic GP [5]. Localized excision may be used in cases where endoscopic removal is not possible or cannot achieve negative margins [21]. Wong et al. [22] report the case of a patient who received postoperative adjuvant radiation therapy after pylorus-preserving pancreaticoduodenectomy for periampullary paraganglioma with nodal metastases. Utilization of chemotherapy for the management of this disease has not been standardized [23].

A metastatic workup is recommended at the time of diagnosis of GPs with imaging of the chest, abdomen, and pelvis.

One published case reports tumor recurrence 11 years after surgical intervention [24]. Aside from lymph node metastasis, factors affecting tumor recurrence remain unclear, and subsequently, surveillance imaging has not been standardized, but is recommended given the knowledge gap.