Appendiceal carcinomas occur in adults with a mean age at onset of 55–65 years for primary tumors and 38 years for malignant tumors (1,2). First described by Gagne et al (2,4) in 1969, goblet cell carcinoids (GCCs) exhibit mixed neuroendocrine differentiation and intestinal-type goblet cell morphology; for this reason, they are described as an entity separate from carcinoids and mucinous adenocarcinomas. The incidence of GCC is ~1.2 cases for every million individuals per year among Caucasian women and it is less common among children (2–5). Metastasis has been documented in 8–20% of the cases, with 5-year survival rates ranging from 55 to 80% (6,7).

The diagnosis of GCC is confirmed by pathological examination based on consensus guidelines. Currently, a variety of different classification systems for the nomenclature, grading and staging of neuroendocrine tumors (NETs) are available in an attempt to segregate groups by prognostic value, management and survival (8–13). The 2010 World Health Organization (WHO) tumor classification (8) considered GCCs as a subgroup of mixed adenoneuroendocrine carcinomas (MANECs). The tumor-node-metastasis (TNM) classification of malignant tumors by the Union for International Cancer Control, the American Joint Committee on Cancer and the European Neuroendocrine Tumor Society (ENETS), consider GCCs to be adenocarcinomas (5,9). However, their complexity is such that GCCs were not included in the 2016 ENETS consensus guidelines for Neuroendocrine Neoplasms of the Appendix. Another diagnostic classification for GCC was proposed by Tang et al (10), based on the TNM classification for appendiceal adenocarcinomas, and has been proven useful for predicting clinical behavior and prognosis. In the Tang classification, tumors are subclassified into group A (typical GCC), group B (adenocarcinoma ex-GCC) and group C (adenocarcinoma ex-GCC; poorly differentiated). Additionally, several pathological markers and clinical findings are used to determine prognosis and the course of action for NETs, including origin, stage, grade, tumor size (<2 or >2 cm), histological differentiation (well- or poorly differentiated), invasion of muscularis propria, histopathological examination (hematoxylin and eosin, chromogranin A, synaptophysin and CD56), assessment of mitotic index (mitoses per high-power field), Ki-67 index (<2, >2 and >30%), biological behavior (benign, low-grade and high-grade), lymphovascular invasion and metastasis (10,14). In parallel, a general classification has been established for midgut, hindgut and foregut NETs based on Ki-67 index, including grades 1 (≤2%), 2 (3–20%) and 3 (>20%), as described by Rindi et al (15). In addition, in a recent study by Yozu et al (12), a new grading system was proposed, based on the classification of GCCs as adenocarcinomas, similar to colorectal adenocarcinoma. This complex grading system represents a challenge for the pathologist in routine practice.

Upon diagnosis, surgical management by right hemicolectomy is recommended as the standard surgical approach by the North American Neuroendocrine Tumor Society (NANETS) consensus guidelines if the tumor invasion is at the base of the appendix, for tumors sized >2 cm, and/or if there is evidence of mesoappendiceal or lymphovascular infiltration with lymph node involvement and for intermediate or high-grade tumors (13). Postoperatively, adjuvant chemotherapy includes regimens with or without debulking followed by chemotherapy similar to that for the treatment of adenocarcinoma of the colon (7,10,13). We herein report the cases of two GCC patients with varied clinical presentation who underwent right hemicolectomy, and provide a literature review of similar clinical cases.

Appendiceal carcinomas are found incidentally during surgery in cases of acute appendicitis, representing 1% of appendectomies (2). Appendiceal cancer presents with significant morphological diversity and is further classified into carcinoid (NET), mucinous cystadenocarcinoma, adenocarcinoma, GCC and signet ring cell tumors (2,3). Due to the fact that GCCs are discovered incidentally during routine appendectomy, there is a lack of a standardized classification system and discrepancies regarding specific reliable markers, such as Ki-67; this may lead to misdiagnosis and suboptimal treatment and surgical approaches (i.e., hemicolectomy or multivisceral resection). A literature review of GCCs revealed a constant steady increase in the number of GCC cases over the past decade, evidenced by an increase in case series reports, possibly due to improved detection methods and clinicians' awareness (Table II). The aim of the present case report was to emphasize the lack of a standardized classification system and reliable markers for adequate prognosis, management and/or treatment.

For clinicians, it is a challenging task to develop an evidence-based treatment plan. In addition, there remains the question of whether a right hemicolectomy should have been performed in Case 2. Although surgery in this case is recommended by both NANETS and ENETS (5,13), the extent of surgical resection with appendectomy versus right hemicolectomy is debated. Recent evidence suggests limited or no benefit of right hemicolectomy, primarily in patients with low-grade and/or limited disease burden (20). In another study, Lamarca et al (21) assessed the effects of right hemicolectomy on disease-free survival. The results suggested a higher risk of relapse in patients who underwent right hemicolectomy vs. those receiving appendectomy alone. Despite these results, the authors concluded that appendectomy alone is only justifiable in patients with Tang class A, stage I/II tumours that are unable to undergo surgery due to comorbidities. A meta-analysis by Varisco et al (22) including 100 patients with GCC also failed to identify a significant benefit of hemicolectomy relative to appendectomy.

The marker Ki-67, used to measure cell proliferation, is a widely used marker for NET grading and staging (23,24). Additionally, Ki-67 has exhibited a positive correlation with known prognostic factors (tumor size and metastatic status) and has been extensively investigated in pancreatic and gastrointestinal NETs (25,26); however, no studies have yet provided sufficient evidence for GCCs. Currently, prognosis based on the pathological gradient is mostly dependent on the Ki-67 proliferative index, despite its dynamic change over time (21). A recent study by Liu et al (27) examined the role of Ki-67 as a prognostic factor for GCC. That study, which included 12 patients with GCC, revealed no prognostic significance for GCC. The fact that NETs comprise a heterogeneous group of tumors renders the interpretation of the Ki-67 index for GCC unreliable without an adequate researched cut-off value, which is currently set between 20 and 30% for digestive tract NETs (10,14). In the present case report, Case 1 had a Ki-67 index of 25%, whereas Case 2 had a Ki-67 index of 15%. Both patients underwent right hemicolectomy based on the guidelines; however, surgical intervention should be based on tumor size, invasiveness and careful evaluation of the morphological characteristics of GCC in addition to the Ki-67 index. An important morphological characteristic in GCC reflecting prognosis and survival is the adenocarcinoma component, which may be classified into signet ring-cell and non-signet ring-cell types (28,29). Based on the results reported by Taggart et al (28), the amount of the carcinomatous component should be included in the diagnosis of GCC, since it is associated with the clinical characteristics and stage. Consequently, a consensus guideline assessing the value of the new staging classification is of paramount importance, since there is a 40% risk of morbidity with right hemicolectomy in elderly patients with respiratory and cardiovascular complications (cardiac arrest, pneumonia, pulmonary embolism) (7). Finally, an update of the current 2008 guidelines (7) should consider the following recommendations on the section for GCC of the appendix: i) Tumor marker use (MNF-116, chromogranin A, synaptophysin, keratin-20, CDX-2, CD56, CEA and Ki-67) along with the current staging system (7,20); ii) addition of a Ki-67 cut-off point of >25% in cases treated with right hemicolectomy; and iii) in the early stages, when the tumor is confined to the mucosa and defined as carcinoma in situ, appendectomy alone is adequate, regardless of the Ki-67 value (Tang class A, stage I/II tumors). However, in more advanced stages, when submucosa involvement and possibly lymphatic spread have occurred, prognosis should be revised along with other markers (i.e., Ki-67) to determine whether right hemicolectomy should be performed. To conclude, the overall survival for patients with GCCs varies according to the different references, classifications or staging criteria used. Hence, there is a need for standardization of the classification system to ensure optimal clinical management and outcome predictions.