Appendiceal Goblet Cell Adenocarcinoma (AGCA) is an exceptionally rare tumor originating in the appendix. This malignancy is unique because its cells possess features of both epithelial (glandular) cells, like those in a traditional adenocarcinoma, and neuroendocrine cells. Due to this unusual cellular makeup, AGCA is classified between conventional adenocarcinoma and a neuroendocrine tumor (NET). Its rarity often leads to delayed or incidental diagnosis. The tumor’s aggressive nature and tendency to spread throughout the abdominal cavity necessitate specialized, multidisciplinary treatment strategies.
Defining Appendiceal Goblet Cell Adenocarcinoma
AGCA arises from the secretory cells lining the appendix, specifically the goblet cells, which produce mucus. The defining characteristic of this tumor is its mixed morphology, exhibiting both mucin-secreting (glandular) and neuroendocrine differentiation.
The World Health Organization (WHO) formally adopted the term Appendiceal Goblet Cell Adenocarcinoma in 2019. Historically, it was called “goblet cell carcinoid” or “adenocarcinoid” due to its neuroendocrine component and initial belief that it behaved more indolently. The current nomenclature highlights the tumor’s capacity for aggressive spread and metastasis, differentiating it from less aggressive neuroendocrine tumors of the appendix.
Pathologists grade AGCA based on the percentage of high-grade adenocarcinomatous components within the tumor. Low-grade AGCA shows more tubular or clustered growth patterns, while high-grade disease contains more aggressive, single-cell, or confluent growth patterns. This grading is an important prognostic factor, acknowledging that even tumors with classic “goblet cell” features can lead to poor outcomes if high-grade components are present.
How AGCA Presents and is Discovered
The symptoms associated with AGCA are often vague or entirely absent in the early stages of the disease. The tumor is most commonly discovered incidentally during surgery performed for a presumed case of acute appendicitis. An acutely inflamed appendix, often caused by the tumor obstructing the appendiceal lumen, is the initial presentation in many patients.
For those whose tumor is not found incidentally, common symptoms include chronic abdominal pain, a palpable abdominal mass, or distension. The tumor has a strong propensity to spread to the lining of the abdominal cavity, a process known as peritoneal metastasis. This spread is often accompanied by the production of a jelly-like substance called mucin, which can accumulate in the abdomen, resulting in a condition called pseudomyxoma peritonei (PMP).
Due to the thin wall of the appendix, the tumor can easily breach the appendiceal wall, leading to spillage of tumor cells into the peritoneal cavity. Peritoneal involvement is observed in a high percentage of cases at the time of diagnosis, sometimes reaching 77%. The discovery of peritoneal spread, ascites, or gynecological involvement may also be the first indication of the disease.
Diagnostic Pathway and Staging
The definitive diagnosis of AGCA is made after a histopathological review of the surgically removed appendix specimen. Pathologists identify the mixed cell population and the presence of both mucinous and neuroendocrine features to confirm the diagnosis. Accurate grading, based on the WHO three-tiered system, is performed at this stage to determine the tumor’s malignant aggressiveness.
The staging for AGCA follows the American Joint Committee on Cancer (AJCC) TNM system, similar to that used for colorectal adenocarcinoma. This system assesses the depth of tumor invasion into the appendix wall (T), involvement of regional lymph nodes (N), and the presence of distant metastasis (M). Both the anatomical stage (TNM) and the tumor grade are considered the most significant factors in predicting a patient’s long-term outlook.
Imaging studies, computed tomography (CT) scans and magnetic resonance imaging (MRI), are used to assess the extent of the disease and detect metastasis. While CT images can sometimes mimic typical appendicitis, they are important for evaluating the abdomen and pelvis for peritoneal spread and measuring the Peritoneal Cancer Index (PCI). The PCI is a scoring system used to quantify the burden of disease within the peritoneal cavity, which directly informs surgical planning.
Blood tests measuring tumor markers such as Carcinoembryonic Antigen (CEA) and Cancer Antigen 125 (CA-125) are often performed during the diagnostic process. Although these markers are not specific enough for initial diagnosis, an elevated level may suggest the presence of a tumor or advanced disease. These markers are useful for establishing a baseline value against which the patient’s response to treatment and potential recurrence can be monitored.
Treatment Strategies
The primary treatment strategy for localized AGCA is surgical resection. For almost all patients, the recommended procedure is a right hemicolectomy, which involves removing the appendix, the right side of the colon, and associated lymph nodes. This surgery is necessary due to the tumor’s high risk of spreading to regional lymph nodes and the possibility of residual disease at the base of the appendix.
For patients with peritoneal metastasis, a specialized procedure combining Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is the standard of care. CRS is an operation performed by specialized surgeons, aiming to remove all visible tumor implants and affected organs from the abdominal cavity. This often involves multiple peritonectomy procedures to strip the diseased lining from the abdominal wall and organs.
Immediately following the cytoreduction, the abdomen is bathed in a heated chemotherapy solution, typically containing agents like mitomycin-C or oxaliplatin, for approximately 90 minutes. HIPEC is designed to kill any remaining microscopic cancer cells that were not visible or removable during the surgery. The heat enhances the penetration and efficacy of the chemotherapy, allowing for a high local drug concentration while limiting systemic side effects.
Systemic chemotherapy is often used in the adjuvant setting (after curative surgery) for high-risk, node-positive, or advanced-stage disease, or as palliative treatment for widespread metastatic disease. Chemotherapy regimens commonly include 5-fluorouracil (5-FU) based combinations like FOLFOX (5-FU and oxaliplatin) or FOLFIRI (5-FU and irinotecan).
Long-Term Outlook and Surveillance
The long-term outlook for AGCA is highly variable and depends on the tumor’s grade and stage at the time of diagnosis. Patients with low-grade, localized disease that is completely removed have a much more favorable prognosis. Conversely, patients diagnosed with high-grade or metastatic disease, especially with extensive peritoneal involvement, face a less favorable outcome.
Five-year overall survival rates for patients with Stage IV metastatic disease range significantly, often falling between 18% and 30%. The most important prognostic factor following surgery is the achievement of a complete cytoreduction, meaning no visible tumor remains after the CRS procedure. Patients who achieve this surgical goal experience markedly improved survival rates compared to those with residual disease.
Post-treatment surveillance is structured to detect any recurrence early, as AGCA often recurs in the peritoneal cavity. This follow-up includes regular physical examinations and monitoring of tumor marker levels, such as CEA and CA-125, which can indicate disease progression if they begin to rise. Interval imaging with CT scans of the chest, abdomen, and pelvis is performed typically every six months for the first two to three years, then annually thereafter.
Due to the tumor’s rarity and complex management, care is best delivered by a specialized, multidisciplinary team at a center with expertise in appendiceal and peritoneal surface malignancies. The specialized nature of the surgery makes surveillance a necessary component of long-term care.