Brazilian Journal of Medical and Biological Research (2018) 51(6): e7411, http://dx.doi.org/10.

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ISSN 1414-431X Overview
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Pathogenesis of gallbladder adenomyomatosis and

its relationship with early-stage gallbladder
carcinoma: an overview
Liwei Pang1, Yan Zhang1, Yuwen Wang2 and Jing Kong1
1
Department of Biliary and Minimally Invasive Surgery, China Medical University Shengjing Hospital Shenyang, Liaoning, China
2
Department of Surgery, The Sixth People’s Hospital of Shenyang, Liaoning, China

Abstract

The exact pathogenesis of gallbladder adenomyomatosis is still lacking and some controversies over its diagnosis and treat-
ment exist. Originally recognized as a precancerous lesion, adenomyomatosis is currently recognized by recent studies as a
benign alteration of the gallbladder that is often associated with cholecystitis and cholecystolithiasis. Gallbladder carcinoma is
an extremely malignant disease with a 5-year survival rate of less than 5%. Therefore, it is important to diagnose, differentiate,
and confirm the relationship between adenomyomatosis and early-stage gallbladder carcinoma. However, the early clinical
symptoms of adenomyomatosis are extremely similar to those of gallbladder stones and cholecystitis, increasing the difficulty
to identify and treat this disease. This article summarizes the research progress on gallbladder adenomyomatosis, aiming to improve
the understanding of the pathogenesis of adenomyomatosis and further provide insight for its clinical diagnosis and treatment.

Key words: Gallbladder adenomyomatosis; Carcinoma; Rokitansky-Aschoff sinuses; Review

Introduction
Gallbladder adenomyomatosis (GA) is a disease char- However, the exact mechanism of GA is not fully under-
acterized by epithelial proliferation and hypertrophy of the stood and its relationship with early-stage GC remains
muscles of the gallbladder wall (1) with an outpouching of unclear. Thus, we aimed to investigate the pathogenesis
the mucosa into or through the thickened muscular layer, of GA and its relationship with early-stage GC.
i.e., the Rokitansky-Aschoff sinuses (RAS) (2). Aldridge
et al. first reported that GA was a precancerous lesion (3). Types of Gallbladder Adenomyomatosis
Afterwards, several articles suggested that gallbladder
cancer originated from adenomyomatosis and the seg- GA has three morphological types according to the
mental-type adenomyomatosis had a higher incidence localization in the gallbladder wall (9): i) fundal (localized)
rate (4,5). Recently, scholars in China and abroad have type, ii) segmental type, and iii) diffuse type (10). The fundal
suggested that adenomyomatosis in the initial stage was (localized) type presents with local thickening, is the most
unrelated with gallbladder carcinoma in that it was only common type and is localized on the fundus of the gall-
proliferation and found in 2.8–5% of all cholecystectomies bladder. The segmental type is often found in the body of
in China and in 2–5% worldwide (5–7). However, gall- gallbladder, the lesion is annular and separates the two
bladder carcinoma (GC) is one of the most lethal carcino- compartments of the gallbladder. The diffuse type presents
mas and its treatment continues to be challenging (8). The with thickening in the unsmooth gallbladder wall (6,11).
outcome of GA is poor, and its overall 5-year survival rate
is less than 5% (8). Pathogenesis of Gallbladder
The early symptoms of GC and GA are usually non- Adenomyomatosis
specific and the patients only present right upper quad-
rant abdominal pain. Unfortunately, GC and GA are often Narrowing of the distal choledoch, neurogenic dysfunc-
associated with gallstones and cholecystitis, which can tion, neuromuscular hyperactivity from abnormal nerve
justify the importance to clarify whether adenomyomatosis structure, etc. are attributed to restricted bile excretion and
has malignant potential or not. increased pressure in the gallbladder, followed by an

Correspondence: Jing Kong: <[email protected]>

Received December 24, 2017 | Accepted March 13, 2018

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Pathogenesis of gallbladder adenomyomatosis 2/5

outpouching of the mucosa into or through the thickened Thus, there is insufficient evidence to prove that GA is a
muscular layer, which is called the Rokitansky-Aschoff precancerous lesion from the perspective of genes.
sinuses (RAS) (12). The hyperplasia of the mucosa and
muscle layer of the gallbladder results in wall thicken- Others
ing, decreasing in size, and rising pressure, which can Jacobs et al. (27) proposed that GA was related with
be revealed on cholecystography, especially after fat cholecystocele. Kainuma et al. (14) reported a case of
saturation. gallbladder adenomyomatosis with pancreaticobiliary mal-
junction and GA was believed to result from chronic stimu-
Insufficiency of gallbladder bud in embryonic period lation as an outcome of pancreatic juice reflux. Seok
Some researchers consider that GA may be associated et al. (28) mentioned that heterotopic pancreas of the gall-
with the insufficiency of gallbladder bud in the embryonic bladder was associated with segmental GA, demonstrat-
period (13,14). Recently, the first case of GA in an infant ing that an ectopic pancreas in the gallbladder may be a
was reported (15). Another report has also shown the occur- risk factor for developing gallbladder cancer. Bedirli et al.
rence of GA in childhood (16), however, there was insuf- (29) proposed that Mirizzi syndrome was a result of chronic
ficient evidence to confirm the disease. inflammation caused by adenomyomatosis.

Gallstones and cholecystitis Imaging Diagnosis of GA and Carcinoma

The long-term stimulation of gallstones and chole- and their Relationship
cystitis leads to epithelial proliferation and hypertrophy of
the muscles of the gallbladder wall. Besides, this stimula- Gallbladder cancer is one of the most lethal cancers,
tion also results in the narrowing of distal choledoch and surgical treatment is challenging, and the 5-year survival
chronic infection (especially by Helicobacter pylori) (17), rate is 5–15% (20). Most early-stage gallbladder carcino-
which inhibits gallbladder activity and increase gallbladder mas remain asymptomatic, similar to GA, making it difficult
intramural pressure. As biliary stasis occurs in the segmental to distinguish between them. However, the widespread
type, the co-existence with cholelithiasis is the highest at use of laparoscopic cholecystectomy shows that there is
88.9%, which has been reported to be 47.4% in the fundal an increase in the number of patients found with incidentally
and diffuse types (18). Taking into consideration that gall- discovered gallbladder cancer (IGBC). Thus, can GA be a
stones and chronic infection (especially by Salmonella precancerous lesion of gallbladder cancer?
typhi) are high-risk factors for GC, some scholars suggest In 1991, Aldridge et al. first pointed out that GA was a
that GA should be considered a precancerous lesion of precancerous lesion (3). After that, Ootani et al. (19) found
GC (18–20). However, we believe that adenomyomatosis that 6.4% of 188 segmental type GA were gallbladder
itself cannot cause cancer and that GA and cholecystitis carcinoma while about 3.1% developed to be malignant
should be seen as carcinogenic factors. without causing adenomyomatosis, after analyzing 279
specimens. Nabatame et al. (4) also reported rates of
Hormones 6.6% (22/334) and 4.3% (181/4226) for the above condi-
Females are more predisposed than males to gall- tions. Recently, Nishimura et al. (18) suggested that adeno-
bladder diseases, including gallstones, GA, and even GC. myomatosis was a precancerous lesion. Kai et al. (30)
GA is frequently found in women over 60 years old and speculated that gross appearance of GA precedes carcino-
estrogen plays an important role. Estrogen can not only genesis. According to these opinions, segmental type GA
increase the rate-limiting enzyme in cholesterol synthesis has a higher risk of developing into gallbladder cancer
and HMG CoA reductase activity but also increase to some extent. Other types of GA, including fundal
cholesterol in the gallbladder, which inhibits the contractile and diffuse types, do not show a strong association with
activity of the gallbladder. Moreover, estrogen induces malignancies of the gallbladder.
the growth of cholesterol crystals and precipitate stones, However, some scholars believe that adenomyo-
and thus may even cause GC (20,21). matosis is unrelated to gallbladder carcinoma and they
reached such a conclusion by comparing the expression
Genes of EGFR, P53, survivin, Rb, and cyclinD1 of GA to that of
It is known that Ki67, P53 (11,22), EGFR (23), survivin, gallbladder cancer (7,25,31). None of the 113 GA patients
and PCNA are related to gallbladder cancer (24). Aldridge among 4704 consecutive patients developed cancer (11).
et al. (3), Ootani et al. (19), and Nishimura et al. (18) Based on histology, adenomyomatosis is an epithelial pro-
agree that GA is a precancerous lesion. However, Chinese liferation and hypertrophy of the muscles of the wall while
scholars (7,25) find that there is no difference between the early-stage gallbladder cancer presents cell dysplasia
expression of Ki67, P53, EGFR, survivin, and PCNA in GA (32,33). Therefore, we cannot be certain that gallbladder
and in chronic cholecystitis. In addition, an article (26) has adenomyomatosis is a precancerous lesion.
reported that DNA in the mucosa of GA is similar to that in Although GA is a benign epithelial proliferation, other
normal mucosa, suggesting that GA contains no oncogene. factors secondary to GA, such as stones, cholecystitis

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Pathogenesis of gallbladder adenomyomatosis 3/5

among others may lead to cancer and dysplastic changes. imaging findings of GA, and concluded that US represents
Because the relationship between GA and GC is not clear the imaging modality of choice for diagnosing GA and MRI
determines that the differentiation between early-stage is used for unclear cases after US. We believe that HRUS
GC and GA be difficult. Ultrasound (US) is the exam of is the best choice to distinguish GA from early-stage wall-
first choice for diagnosing gallbladder disease, but this thickening-type GC.
method has low accuracy and depends largely on the
operator’s skills. The observed features of GA on US are: Conclusions
a) tiny anechoic cystic spaces (i.e. Rokitansky-Aschoff
sinuses); b) focal or diffuse gallbladder wall thickening; GA cannot be regarded as a precancerous lesion
c) intramural echogenic foci; and d) twinkling artifact (also based on available evidence. GA is a benign epithelial
called comet-tail), which is one of the major differential proliferation while stones and cholecystitis secondary
diagnoses between GA and GC (34–37). As for GC, the to GA may lead to dysplastic changes and cancer.
US has low accuracy, reaching 22% accuracy in early Most patients with GA do not have typical symptoms
stages (35), and it cannot distinguish between GC and and usually present chronic cholecystitis and vague abdom-
chronic cholecystitis (16). As for computed tomography inal pain, which complement histological examination
(CT), a characteristic of GA is a rosary sign, showing of cholecystectomy specimens (40–43). The increasing
mucosal epithelium with intramural diverticula (31,33,36) gallbladder intramural pressure may indicate that gall-
and indicates a suspicion of cancer after US. On magnetic bladder decompression delays the adenomyomatosis
resonance imaging (MRI), RAS present with small, progress. Although we have contributed to a further
rounded, high signal intensity foci, called ‘‘pearl necklace understanding of the causes of GA, its current pathogen-
sign’’ (38), especially after fat saturation. The most accurate esis is still not fully understood. With the development
examination is high-resolution ultrasound (HRUS), which of imaging technology, the detection rate of RAS can
can help distinguish GA from early-stage wall-thickening- improve and increase the diagnostic rate of GA before
type GC. The findings on HRUS are the definite presence operation. However, due to limited imaging equipment
of intramural cysts (RAS), intramural echogenic spots, and and technical difficulties, the possibility of misdiagnosis is
cholesterol deposits in the RAS (36). As for the receiver large.
operating characteristic (ROC) curve (Az), a report (35) At present, the main treatment for GA is surgery, but
showed that HRUS had high Az values (greater than 0.90) it is very important to screen patients and make clear
for differentiating GA from early-stage, wall-thickening-type the operation indications, taking the complications after
GC through symmetrical wall thickening, intramural cystic cholecystectomy into consideration. As for asymptomatic
spaces, intramural echogenic foci, and twinkling artefacts, GA, a conservative treatment is recommended with US
which were significantly associated with GA. However, exams twice a year. The fundal type GA can be treated by
irregular thickening of the outer wall, focal innermost partial laparoscopic cholecystectomy. The segmental and
hyperechoic layer (IHL) discontinuity, IHL thickening greater diffuse type should undergo a total laparoscopic chole-
than 1mm, loss of multilayer pattern in the gallbladder wall, cystectomy. Females over 60 years of age who present
and intralesional vascularity were significantly associated gallbladder stones and segmental type GA should undergo
with GC. In recent years, Bonatt et al. (39) summarized surgery (4,44–46).

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