Neuroendocrine neoplasms (NENs) are the most common tumor of the appendix, and are identified in approximately 0.16–2.3 % of all appendectomy specimens [1,2]. The majority of these tumors are discovered incidentally during the surgical treatment of appendicitis or other concurrent intraabdominal diseases. Three histological subtypes have been identified based on their neuroendocrine cell lineage: enterochromaffin (EC) cell neuroendocrine tumors (NETs), L-cell NETs, and tubular NETs [2]. Diagnosis is based on histological features and immuonhistochemical stains for neuroendocrine markers. However, the pathogenesis of appendiceal NETs remains unclear.

Appendiceal NENs are graded according to the same 2019 WHO classification criteria as other gastrointestinal (GI) neuroendocrine tumors. Based on mitotic count and Ki-67 proliferation index, they are divided into well-differentiated NETs (grades 1 to 3) and poorly-differentiated neuroendocrine carcinomas (NECs) [3]. Appendiceal NETs are comprised of mostly grade 1 tumors, while grade 2, especially grade 3 NETs and NECs, are extremely rare [1,4]. In contrast to other GI NETs, arising from the stomach, small intestine, rectum and pancreas, appendiceal NETs behave indolently and follow a very favorable clinical course [5].

There are unique anatomic and histological characteristics that make the diagnosis of appendiceal NETs challenging. Foremost, NETs that occur in this small luminal organ seldom exceed a diameter of 1 cm [6]. These incidental small foci are easily exhausted in subsequent histologic sections. Additionally, the appendiceal lamina propria and muscularis propria contains prominent ganglion cells, which are positive for neuroendocrine markers resulting in a highly nonspecific background and presenting a particular diagnostic pitfall [7]. Furthermore, the most commonly used chromogranin antibody in routine practice targets chromogranin A. Unlike synaptophysin, chromogranin is frequently negative in a subset of NETs, notably the L cell NETs [8]. Given the often-limited tumor tissue availability, selection of the most sensitive and specific neuroendocrine marker is imperative.

A small cluster growth pattern of the tumor cells has been found in our study. Such morphological pattern is not readily classifiable under the existing classical subtypes. This specific pattern of appendiceal NET has been inadequately characterized in the literature. This study aims to investigate the diagnostic challenges associated with the small cluster appendiceal NET variant, including its clinicopathologic attributes and immumohistochemical and hormonal profile.