Resident Program - Case of the Month

Discussion

Low-grade appendiceal goblet cell adenocarcinoma (LG-GCAC) (formerly typical goblet cell carcinoid) is a mixed endocrine-exocrine neoplasm almost exclusively seen in the appendix. Although rare overall, it nonetheless accounts for 14% of appendiceal cancers (1). Males and females are affected equally, most often between the ages of 40 and 60 years (2). This tumor is important to recognize because it has a distinct behavior that is more aggressive than well-differentiated neuroendocrine (classic carcinoid) tumors and less aggressive than other appendiceal invasive adenocarcinomas.

LG-GCAC frequently presents with clinical findings of appendicitis and is often diagnosed incidentally during appendectomy or ileocecal resection (3). The diagnosis is thus discovered at the time of histopathologic examination. The pathogenesis of LG-GCAC remains to be completely elucidated. It is generally believed that it derives from the pluripotent stem cells at the base of crypts – which can undergo both mucinous and neuroendocrine differentiation (3).

On histologic sections, LG-GCAC usually infiltrates the appendiceal wall circumferentially (Figure 1). Tumor cells grow from the base of the crypts into lamina propria (Figure 2), through muscularis propria and into subserosa, without significant disruption of the appendiceal wall (Figure 1). Although the tumor shows infiltrative growth, desmoplasia is not usually seen in LG-GCAC (2). Morphologically, LG-GCACs are characterized by small tubules or clusters of cells with goblet morphology (e.g., small nucleus compressed by a large cytoplasmic mucin vacuole). Tumor clusters are typically solid and do not demonstrate lumina. In LG-GCAC, individual neoplastic goblet cells may occasionally be seen but are not the predominant pattern (Figure 3). Occasionally, small extracellular mucin pools may be present. Nuclear atypia is usually minimal, and mitoses are infrequent. Generally, focal synaptophysin (Figure 5) or chromogranin A staining is seen in tumor cells, underscoring its neuroendocrine or “carcinoid” lineage, but immunopositivity for these stains are not required for the diagnosis. In contrast, CDX2 is diffusely positive (Figure 4), supporting gastrointestinal origin.

According to the recently published 5^th edition of the World Health Organization Classification of Tumours series – Digestive System Tumours (2), the grade of the appendiceal goblet cell adenocarcinoma is determined by the percentage of high-grade histologic features (e.g., tumor cells infiltrating mostly as single mucinous or non-mucinous cells, complex anastomosing tubules, cribriform nests, single file growth, sheets or large aggregates of goblet or signet ring cells). Grade 1 (low-grade) tumors are defined as consisting of <25% high-grade features, grade 2 (intermediate-grade) tumors 25-50% high-grade features, and grade 3 tumors >50% high-grade features - with the remainder of the tumor demonstrating low-grade histologic features (as described above). High-grade histologic features may also include the presence of stromal desmoplasia, nuclear hyperchromasia, nuclear pleomorphism, high N:C ratios, frequent mitoses, atypical mitotic figures, and necrosis. While perineural invasion is common in both low- and high-grade tumors, lymphovascular invasion is more frequent in high-grade tumors (2).

The differential diagnosis for LG-GCAC includes conventional adenocarcinoma of the appendix, signet-ring cell carcinoma, and well-differentiated neuroendocrine tumor (formerly termed carcinoid). Signet-ring cell carcinoma shows diffuse infiltrative growth of dyscohesive signet ring cells with high-grade cytological features. It is distinguished from high-grade GCAC by the absence of a recognizable LG-GCAC component (2). LG-GCAC is histologically distinct from well-differentiated neuroendocrine tumor which is composed of round, uniform cells with “salt and pepper” chromatin, arranged in moderately sized solid nests, cords, and ribbons. Immunohistochemical staining for neuroendocrine markers such as synaptophysin and chromogranin A shows diffuse strong cytoplasmic positivity throughout the tumor, in contrast to the rare scattered immunopositive foci seen in LG-GCAC.

LG-GCAC tends to invade deeply into the appendiceal wall and penetrate the serosa, with occasional involvement of regional lymph nodes and peritoneum (2). In females, metastases to the ovary are common, where they present as Krukenberg tumors (4). Management of LG-GCAC is not standardized due to the rarity of the disease and lack of expert consensus. For tumors in early stages, simple appendectomy with lifelong surveillance is generally considered adequate, while right hemicolectomy with adjuvant chemotherapy is recommended for advanced tumors (1,3).

References

1. Zhang K, Meyerson C, Kassardjian A, et al. Goblet Cell Carcinoid/Carcinoma: An Update. Adv Anat Pathol.2019 Mar;26(2):75-83.
2. WHO Classification of Tumors. Digestive System Tumors. 5th edition 2019:149-151.
3. Shenoy S. Goblet cell carcinoids of the appendix: Tumor biology, mutations and management strategies. World J Gastrointest Surg. 2016;8(10):660–9.
4. Hristov AC, Young RH, Vang R, et al. Ovarian metastases of appendiceal tumors with goblet cell carcinoidlike and signet ring cell patterns: a report of 30 cases. Am J Surg Pathol. 2007;31(10):1502-1511.