REPORT CASE ARTICLE

INTRODUCTION

Hyperplastic cholecystosis is a pathological entity of the gallbladder that includes two main forms: cholesterolosis and gallbladder adenomyomatosis (GAM) <sup>1 ➤
1. Parolini F, Indolfi G, Magne MG, Salemme M, Cheli M, Boroni G, et al. Adenomyomatosis of the gallbladder in childhood: A systematic review of the literature and an additional case report. World J Clin Pediatr. 2016;5(2):223–7. doi: 10.5409/wjcp.v5.i2.223</sup> . The latter, considered an acquired degenerative condition, is characterized by proliferation of the mucosal epithelium with deep invagination into the muscular layer, forming Rokitansky-Aschoff sinuses <sup>2 ➤
2. Zarate YA, Bosanko KA, Jarasvaraparn C, Vengoechea J, McDonough EM. Description of the first case of adenomyomatosis of the gallbladder in an infant. Case Rep Pediatr. 2014;2014:248369. doi: 10.1155/2014/248369 3 ➤
3. Pellino G, Sciaudone G, Candilio G, Perna G, Santoriello A, Canonico S, et al. Stepwise approach and surgery for gallbladder adenomyomatosis: a mini-review. Hepatobiliary Pancreat Dis Int HBPD INT. 2013;12(2):136–42. doi: 10.1016/s1499-3872(13)60022-3</sup> . Its prevalence ranges from 1% to 9% in cholecystectomy specimens and is typically an incidental finding in patients operated on for other reasons, such as symptomatic cholelithiasis or cholecystitis <sup>4 ➤
4. Kim JH, Jeong IH, Han JH, Kim JH, Hwang JC, Yoo BM, et al. Clinical/pathological analysis of gallbladder adenomyomatosis; type and pathogenesis. Hepatogastroenterology. 2010;57(99–100):420–5. 5 ➤
5. Nishimura A, Shirai Y, Hatakeyama K. Segmental adenomyomatosis of the gallbladder predisposes to cholecystolithiasis. J Hepatobiliary Pancreat Surg. 2004;11(5):342–7. doi: 10.1007/s00534-004-0911-x</sup> . Although mostly asymptomatic, it can cause pain in the right upper quadrant, which is clinically indistinguishable from biliary colic <sup>6 ➤
6. Lee K-F, Hung EHY, Leung HHW, Lai PBS. A narrative review of gallbladder adenomyomatosis: what we need to know. Ann Transl Med. 2020;8(23):1600. doi: 10.21037/atm-20-4897</sup> . Laboratory tests are usually normal, and there are no specific serological markers for its detection <sup>3 ➤
3. Pellino G, Sciaudone G, Candilio G, Perna G, Santoriello A, Canonico S, et al. Stepwise approach and surgery for gallbladder adenomyomatosis: a mini-review. Hepatobiliary Pancreat Dis Int HBPD INT. 2013;12(2):136–42. doi: 10.1016/s1499-3872(13)60022-3</sup> . While traditionally not considered a premalignant lesion <sup>7 ➤
7. Henson DE, Schwartz AM, Nsouli H, Albores-Saavedra J. Carcinomas of the pancreas, gallbladder, extrahepatic bile ducts, and ampulla of vater share a field for carcinogenesis: a population-based study. Arch Pathol Lab Med. 2009;133(1):67–71. doi: 10.5858/133.1.67</sup> , some authors have suggested a possible role as a precursor of gallbladder cancer, particularly in the segmental type <sup>8 ➤
8. Aldridge MC, Gruffaz F, Castaing D, Bismuth H. Adenomyomatosis of the gallbladder. A premalignant lesion? Surgery. 1991;109(1):107–10. 9 ➤
9. Akçam M, Buyukyavuz I, Çiriş M, Eriş N. Adenomyomatosis of the gallbladder resembling honeycomb in a child. Eur J Pediatr. 2008;167(9):1079–81. doi: 10.1007/s00431-007-0623-8 10 ➤
10. Nabatame N, Shirai Y, Nishimura A, Yokoyama N, Wakai T, Hatakeyama K. High risk of gallbladder carcinoma in elderly patients with segmental adenomyomatosis of the gallbladder. J Exp Clin Cancer Res CR. 2004;23(4):593–8.</sup> .

Historically, GAM has been referred to by various names before being systematized by Jutras in 1960 <sup>11 ➤
11. Jutras JA. Hyperplastic cholecystoses; Hickey lecture, 1960. Am J Roentgenol Radium Ther Nucl Med. 1960;83:795–827.</sup> . Its etiology remains uncertain, although it has been linked to conditions that favor gallstone formation, such as biliary tract anomalies, inflammatory bowel disease, and obesity <sup>12 ➤
12. Yoshimitsu K, Honda H, Aibe H, Shinozaki K, Kuroiwa T, Irie H, et al. Radiologic Diagnosis of Adenomyomatosis of the Gallbladder: Comparative Study Among MRI, Helical CT, and Transabdominal US. J Comput Assist Tomogr. 2001;25(6):843.</sup> . Three morphological patterns have been described: segmental, fundal, and diffuse <sup>13 ➤
13. Stunell H, Buckley O, Geoghegan T, O’Brien J, Ward E, Torreggiani W. Imaging of adenomyomatosis of the gall bladder. J Med Imaging Radiat Oncol. 2008;52(2):109–17. doi: 10.1111/j.1440-1673.2008.01926.x</sup> , with the fundal type being one of the most frequent. Imaging studies may suggest the diagnosis, but in most cases it is confirmed postoperatively through histopathological examination of the gallbladder specimen.

Although GAM is often an incidental finding, its presentation may clinically mimic more serious conditions, including neoplastic lesions <sup>5 ➤
5. Nishimura A, Shirai Y, Hatakeyama K. Segmental adenomyomatosis of the gallbladder predisposes to cholecystolithiasis. J Hepatobiliary Pancreat Surg. 2004;11(5):342–7. doi: 10.1007/s00534-004-0911-x 10 ➤
10. Nabatame N, Shirai Y, Nishimura A, Yokoyama N, Wakai T, Hatakeyama K. High risk of gallbladder carcinoma in elderly patients with segmental adenomyomatosis of the gallbladder. J Exp Clin Cancer Res CR. 2004;23(4):593–8.</sup> . This becomes particularly relevant when atypical histological features, such as dysplasia, are identified, as they may suggest oncogenic risk, as reported in some studies <sup>8 ➤
8. Aldridge MC, Gruffaz F, Castaing D, Bismuth H. Adenomyomatosis of the gallbladder. A premalignant lesion? Surgery. 1991;109(1):107–10. 9 ➤
9. Akçam M, Buyukyavuz I, Çiriş M, Eriş N. Adenomyomatosis of the gallbladder resembling honeycomb in a child. Eur J Pediatr. 2008;167(9):1079–81. doi: 10.1007/s00431-007-0623-8</sup> .

In this context, the cases presented are clinically relevant, as all were initially diagnosed as cholecystitis or cholelithiasis, with no prior suspicion of GAM. The incidental histological finding, along with the identification of dysplasia in one case, underscores the importance of considering this entity in the preoperative differential diagnosis of gallbladder disease <sup>3 ➤
3. Pellino G, Sciaudone G, Candilio G, Perna G, Santoriello A, Canonico S, et al. Stepwise approach and surgery for gallbladder adenomyomatosis: a mini-review. Hepatobiliary Pancreat Dis Int HBPD INT. 2013;12(2):136–42. doi: 10.1016/s1499-3872(13)60022-3</sup> .

Este reporte tiene como objetivo describir una serie de siete casos de adenomiomatosis vesicular, resaltando su presentación clínica, hallazgos anatomopatológicos y el potencial diagnóstico diferencial con neoplasia vesicular.

CASE DESCRIPTION

We present seven cases corresponding to specimens evaluated during routine work in the Department of Pathology. In all cases, GAM was an incidental finding, identified exclusively during histopathological analysis

All patients presented with right upper quadrant pain. No symptoms beyond the typical pattern were reported. Both clinical evaluation and ultrasonography led to an initial diagnosis of cholecystitis or cholelithiasis. No additional imaging studies were performed. Preoperative laboratory tests did not show relevant abnormalities. There were no significant elevations in leukocyte count, liver enzymes, or bilirubin levels. Surgical treatment was scheduled and carried out in all patients.

The seven cases corresponded to six women and one man, all adults; two were under 50 years of age and five were older. In all cases, GAM was identified only through histopathological examination. The patients underwent cholecystectomy for typical gallbladder symptoms, with no prior detection or suspicion of GAM. The table summarizes the main clinical, morphological, and histological characteristics of the evaluated cases.

All lesions were located in the gallbladder fundus, with focal wall thickening ranging from 2 mm to 12 mm. The largest lesion measured 22 × 15 mm and the smallest 4 × 4 mm. The final diagnosis was chronic cholecystitis in all seven cases, cholelithiasis in three cases, and cholesterolosis in four cases. Only two cases presented all three diagnoses, with one of them showing a focus of dysplasia (Case 1). The histopathological finding in all seven cases matched the classical description of GAM, that is, simple columnar epithelium forming multiple invaginations interspersed with hypertrophic smooth muscle bundles (Figure). In the gross image of Case 3, a lesion is seen in the gallbladder fundus, with adjacent cavity-like structures within the wall thickness (Figure). In Case 1, a single focus of glandular dysplasia was identified, located within the muscularis propria, with no evidence of invasion (Figure). It is clearly visible in the lower left quadrant of the microphotograph due to architectural disorganization and more intense staining compared to the epithelium in the lower right quadrant (Figure). In another microphotograph of the same case, the dysplastic focus is observed in the central lower part, beneath the muscularis propria, alongside epithelial projections to the left and right (Figure). The dysplastic focus shows both low-grade and high-grade dysplasia, alternating with patches of normal epithelium (Figure). The lesion is surrounded by isolated lymphocytes and mild fibrosis, similar to adjacent epithelial projections. In other words, the epithelial change is unlikely to be related to inflammatory injury. Multiple sections of the gallbladder were studied, and no other dysplastic foci were found.

Case 1 required additional histopathological evaluation after a focus of epithelial dysplasia was identified (Figure). New tissue samples from the gallbladder were obtained to rule out the presence of additional foci of dysplasia or adenocarcinoma. The initial finding of a single isolated dysplastic focus was confirmed, and the surgical margin was free of lesions.

All patients had a favorable postoperative course following cholecystectomy, with complete resolution of their clinical symptoms. In the case with focal dysplasia, no further studies have been conducted to date. The described lesion is not associated with any known serological markers or elevated laboratory values.

Figure
Representative macroscopic and histopathological findings from the analyzed cases. A) Microphotograph of Case 1 showing, in the lower left quadrant, a focus of glandular dysplasia identifiable by architectural distortion and more intense staining compared to the epithelium in the lower right quadrant. Dysplastic glandular focus located within the thickness of the muscularis propria, without evidence of invasion. (40×, H-E). B) Macroscopic image of Case 3, showing a lesion located in the gallbladder fundus with cavity-like appearance within the wall thickness. C) Microphotograph of Case 4, showing invagination of the hyperplastic epithelium in various forms, alternating with hypertrophic bundles of the muscular layer. (40×, H-E). D) Microphotograph of Case 1, displaying a single focus of glandular dysplasia located in the central lower area, beneath the muscularis propria. Epithelial projections can be seen on both the right and left sides. (40×, H-E). E) Microphotograph of Case 1 demonstrating both low-grade and high-grade dysplasia, alternating with patches of normal epithelium. (400×, H-E).

A

B

C

D

E

DISCUSSION

Various definitions of GAM can be found in the literature. In this review, we consider GAM to be an acquired degenerative disease, characterized by diffuse or localized proliferation of the mucosal epithelium, which deeply invaginates and extends into the thickness of the gallbladder muscular layer <sup>7 ➤
7. Henson DE, Schwartz AM, Nsouli H, Albores-Saavedra J. Carcinomas of the pancreas, gallbladder, extrahepatic bile ducts, and ampulla of vater share a field for carcinogenesis: a population-based study. Arch Pathol Lab Med. 2009;133(1):67–71. doi: 10.5858/133.1.67 14 ➤
14. Joshi JK, Kirk L. Adenomyomatosis. En: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 [cited 2024 Nov 30]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK482244/</sup> . Characteristically, the muscular layer is hypertrophic.

It has been proposed that GAM could represent a precancerous lesion <sup>9 ➤
9. Akçam M, Buyukyavuz I, Çiriş M, Eriş N. Adenomyomatosis of the gallbladder resembling honeycomb in a child. Eur J Pediatr. 2008;167(9):1079–81. doi: 10.1007/s00431-007-0623-8</sup> ; however, this remains controversial, as it would imply that gallbladder adenocarcinoma may develop from this entity. Among the seven cases reported here, one presented a microscopic epithelial focus with both low- and high-grade dysplasia. In our view, it is more likely that this dysplastic focus is not directly related to the GAM itself.

In Case 1, in addition to the classic features of GAM, a definite focus of dysplasia was found alongside other transmural epithelial projections without dysplasia, all located in the subserosa, external to the hypertrophic muscularis propria (Figure 4). Dysplasia refers to a set of architectural and cytological alterations affecting epithelial tissue. It is considered a precancerous lesion that may progress from low-grade dysplasia to high-grade dysplasia, carcinoma in situ, and ultimately, invasive adenocarcinoma.

Bile has an emulsifying function and is produced by hepatocytes. It is a solution that contains, among other substances, bile acids (salts), cholesterol, pigments, various metabolites, and chemical elements. In the gallbladder, bile is not only stored temporarily but also becomes dehydrated, resulting in a proportionally higher concentration of its components. These components, theoretically, could cause progressive epithelial damage. GAM may increase epithelial exposure to the substances contained in bile, as accumulation in the deep crypts prolongs contact time. Cholecystitis and cholelithiasis may further add injurious factors to this context <sup>15 ➤
15. Pilgrim CHC, Groeschl RT, Christians KK, Gamblin TC. Modern perspectives on factors predisposing to the development of gallbladder cancer. HPB. 2013;15(11):839–44. doi: 10.1111/hpb.12046</sup> .

The presence of dysplasia in the gallbladder epithelium should be considered a multifactorial phenomenon that may evolve into gallbladder adenocarcinoma—a malignancy with a very poor prognosis and a short survival period after diagnosis. The causal relationship between GAM and gallbladder adenocarcinoma remains controversial and unproven, except for their occasional coexistence

Cases of GAM associated with gallbladder adenocarcinoma have been described in the literature; however, to the best of our knowledge, this is the first case reporting both low- and high-grade dysplasia within the characteristic context of GAM.

We believe the clinical relevance of this report lies in the fact that GAM is a little-known entity, yet it affects up to 8% of adult patients. Its presence should be thoroughly evaluated, whether or not it is associated with other gallbladder diseases. This is especially important considering that adenocarcinomas have been reported to coexist predominantly with macroscopic segmental-type GAM <sup>12 ➤
12. Yoshimitsu K, Honda H, Aibe H, Shinozaki K, Kuroiwa T, Irie H, et al. Radiologic Diagnosis of Adenomyomatosis of the Gallbladder: Comparative Study Among MRI, Helical CT, and Transabdominal US. J Comput Assist Tomogr. 2001;25(6):843.</sup> .

Furthermore, recognizing this entity is important for pathologists, who must carefully examine all cholecystectomy specimens both macroscopically and microscopically, searching for GAM or dysplasia. Intraoperative pathological examination may also be helpful in certain cases.

For radiologists, GAM has clinical relevance as its preoperative diagnosis depends almost exclusively on imaging studies.

For surgeons, recognizing this disease and its potential relationship with dysplasia and cancer is also important, as the gallbladder is often sectioned or fragmented during surgery, which can irreparably distort its anatomy. In many cases—especially during laparoscopic cholecystectomies—the gallbladder is removed in multiple fragments, posing additional challenges for subsequent pathological evaluation. Finally, we must remember the poor prognosis of gallbladder cancer, which begins with dysplasia that typically progresses over several years.

CONCLUSION

The presence of dysplasia in the context of gallbladder adenomyomatosis reinforces the need for thorough histopathological examination of this entity, given its potential significance in the development of gallbladder neoplasms.