Introduction
Although villous adenomas (VAs) are an uncommon subtype of colonic adenomas, they are clinically important due to their tendency to grow large, produce copious mucus, and induce fluid and electrolyte disturbances (1,2). This mucinous and electrolyte-rich secretory activity is thought to be driven by elevated levels of prostaglandins, especially prostaglandin E2 (PGE2), which can stimulate intracellular cAMP and promote fluid secretion (3,4). Despite this established mechanism, direct comparative analyses of PGE2 and its related enzymatic pathways between VAs and other adenoma subtypes remain limited.
VAs account for approximately 5 to 15% of all colonic adenomas and are predominantly located in the rectosigmoid colon (1,2). The reported incidence of coexistent carcinoma in VAs is high. When these tumors reach a substantial size, they may produce excessive mucin, leading to electrolyte disturbances, renal dysfunction, and, in some cases, neuropsychiatric symptoms (2,5). In certain cases, VAs can secrete large amounts of mucus, resulting in dehydration and severe electrolyte imbalance, a condition referred to as Electrolyte Depletion Syndrome (EDS). Originally documented by McKittrick and Wheelock in 1954(6), this condition, commonly referred to as McKittrick-Wheelock Syndrome, is typified by potassium-rich, tumor-derived mucus. The pathogenesis is believed to involve upregulated PGE2 production with consequent increases in intracellular cAMP, both contributing to the exaggerated secretory response (3,4). Reports of symptomatic improvement with indomethacin, a PGE2 synthesis inhibitor, suggest its potential usefulness as a temporary bridging therapy prior to definitive resection (4,7). Moreover, clinical case reports have described the characteristic features of McKittrick-Wheelock Syndrome associated with VAs, emphasizing the importance of early recognition and appropriate management (8).
This study aims to characterize the differential expression of PGE2, COX-1, and COX-2 in villous vs. tubular adenomas (TAs), with the goal of elucidating their roles in mucin hypersecretion and identifying potential therapeutic implications.
Discussion
In this study, we observed that VAs exhibited substantially higher expression of PGE2 and COX-2 compared to TAs, while COX-1 expression showed no notable differences. Association analyses further revealed that in VAs, PGE2 expression showed a weak-to-moderate association with COX-1 and a weak association with COX-2, whereas such associations were not observed in TAs. These findings suggest a distinct upregulation of the PGE2 signaling pathway in VAs, potentially contributing to their unique biological and clinical characteristics (9,10). Previous reviews have reported that VAs tend to occur more frequently in the distal colon, which is consistent with our findings (2). Case-based literature often describes VAs as large lesions associated with marked clinical manifestations, such as electrolyte disturbances seen in McKittrick-Wheelock syndrome (2). In contrast, many VAs in our cohort were incidentally detected and did not present with overt symptoms, which likely explains their comparatively smaller size despite still being significantly larger than TAs. In our institutional experience, larger VAs showed a tendency to develop electrolyte derangements (data not shown), supporting the notion that lesion size may contribute to the likelihood of clinically significant secretory activity.
The pivotal role of the PGE2 signaling axis in colorectal tumorigenesis and progression has been well documented (9,10). PGE2, primarily produced via COX-2-mediated catalysis, promotes colorectal carcinogenesis by enhancing cell proliferation, angiogenesis, and immune evasion (9-11). Our findings of elevated PGE2 and COX-2 expression in VAs align with this understanding, suggesting that VAs may represent lesions with a more aggressive molecular phenotype compared to TAs. In contrast, the absence of significant associations in TAs indicates that PGE2 signaling is less active in these lesions, consistent with their generally lower malignant potential (1).
Previous studies have also indicated that COX-1 may participate in PGE2 biosynthesis and colorectal neoplasia, particularly in the early stages of adenoma development (12). This is further supported by evidence showing that combined COX-1 and COX-2 activity is elevated in non-neoplastic colonic mucosa from patients with colorectal neoplasia (13). These data suggest that COX-1, traditionally considered a constitutive enzyme, may play a complementary role alongside COX-2 in the biology of VAs. Although COX-1 is classically regarded as a constitutive isoform, emerging evidence suggests that its functional contribution may be selectively amplified in pre-neoplastic and neoplastic contexts without a corresponding increase in protein abundance. In intestinal tumorigenesis models, COX-1-derived PGE2 production has been shown to drive the early phase of polyp initiation before COX-2 induction (14). In our study, COX-1 expression levels were comparable between TAs and VAs; however, a significant association with PGE2 was observed only in VAs. This may reflect the villous architecture, characterized by a large surface area, high secretory activity, and rapid epithelial turnover, facilitating more efficient coupling between constitutively expressed COX-1 and downstream prostanoid synthesis.
Clinically, our findings underscore the importance of early colonoscopic evaluation and timely intervention in patients with suspected EDS. VAs are well recognized as the principal cause of EDS due to their copious secretion of potassium- and chloride-rich mucus, driven in part by PGE2-mediated mechanisms (3,4,8). The markedly elevated PGE2 and COX-2 expression observed in our VA cohort reinforces the mechanistic link between PGE2 overproduction and the secretory diarrhea and electrolyte imbalance characteristic of EDS (4,8). Although VAs are typically managed with endoscopic or surgical resection (1,7), our findings highlight the need for prompt recognition and early treatment in patients presenting with secretory diarrhea, dehydration, or electrolyte disturbances suggestive of EDS. Short-term COX inhibition has been reported to ameliorate PGE2-driven secretory symptoms and may serve as a bridging measure before definitive resection.
The use of COX-2 selective inhibitors or NSAIDs could also be considered as temporary supportive therapy to mitigate secretory symptoms by suppressing PGE2 synthesis (15), although this must be balanced against the known gastrointestinal and cardiovascular risks associated with long-term COX-2 inhibition (16,17).
Beyond these immediate implications, understanding the distinct PGE2 signaling patterns in VAs may provide insights into early tumorigenic processes, as VAs represent an intermediate stage between benign adenomas and malignant transformation (9,10). Advances in digital pathology (18) and molecular profiling, including liquid biopsy (19), may further enhance the precision of VA characterization in future studies.
This study has several limitations. First, the retrospective single-center design and small sample size limit the generalizability of our findings. The number of evaluable VAs was constrained by the availability of well-preserved archival tissue, reducing statistical power, particularly for subgroup and association analyses, and likely contributing to some nonsignificant results. Second, the 10% positivity cutoff for immunohistochemistry is not universally standardized and remains an empirical threshold, although interobserver agreement was high. Third, we evaluated only PGE2, COX-1, and COX-2 expression and did not assess downstream pathways or additional regulatory molecules, limiting mechanistic interpretation. Finally, the lack of multicenter validation and functional assays underscores the need for further studies to confirm and expand upon these findings.
In conclusion, this study demonstrates that VAs exhibit marked activation of the PGE2 signaling pathway, driven by increased COX-2 expression and strengthened functional coupling with COX-1. This coordinated upregulation provides a mechanistic explanation for both the secretory phenotype and the development of EDS in affected patients. These findings underscore the importance of early recognition and timely intervention for suspected EDS and suggest that short-term modulation of PGE2 synthesis may serve as a potential perioperative strategy to alleviate severe secretory symptoms prior to definitive resection.