Abstract
Gallbladder cancer is a malignant tumor with high mortality. Early diagnosis is significance to improve the prognosis of patients. Gallbladder adenoma is recognized as a kind of precancerous disease, for the past few years, contrast-enhanced ultrasound was used in the diagnosis of biliary tumors. This case is about gallbladder papillary adenoma with carcinogenesis. There is rare literature on the contrast-enhanced ultrasound manifestations of this type of disease. We hope that this report can help improve the recognition of contrast-enhanced ultrasound features and improve the accuracy of early diagnosis of gallbladder cancer.
Background
Gallbladder cancer is a malignant tumors in the biliary system with high mortality. The incidence of gallbladder cancer ranks sixth among malignant tumors in the digestive system. There are about 528,000 new cases of gallbladder cancer in China every year. Because the incidence of gallbladder carcinoma is relatively insidious and there is no characteristic clinical manifestation, it is often found that the disease is in advanced stage [1–3], and the survival time of patients is shorter [4, 5]. Gallbladder adenoma is one of the intramucosal tumors of the gallbladder. According to the pathological type, it can be divided into tubular adenoma, papillary adenoma and tubular papillary adenoma [6]. Although gallbladder adenoma is a common benign neoplasm, however, in the 1980s, it has been proved that it is closely related to gallbladder cancer [7, 8]. In recent years, some studies have pointed out that the incidence of in situ cancer about gallbladder adenoma is as high as 27%[9]. Therefore, early detection of gallbladder cancer and screening of early carcinogenesis of gallbladder adenoma can provide early treatment for patients to a certain extent, thereby improving prognosis and prolonging survival.
Case presentation
On July 6, 2018, a 73-year-old Chinese woman underwent ultrasound examination in the local area and found a space-occupying lesion of the gallbladder. She had no special symptoms or signs. The diagnosis of gallbladder cancer was considered in both MR and CT examinations of upper abdomen. PET/CT examination also showed that the wall of gallbladder bottom was irregularly thickened and showed mass-like changes with multiple calcification. The maximum SUV values of early and delayed 1.5 hours were 4.1 and 6.4 respectively, the retention index was 56.1%, and the average CT value was 68.5 Hu (Fig. 1); the diagnosis was “gallbladder malignant tumor is possible”. Laboratory tests showed that the patient was a carrier of hepatitis B virus, but the tumor markers including alpha-fetoprotein, carbohydrate antigen 19-9, carbohydrate antigen 125 and carbohydrate antigen 242 were negative.
The wall of the gallbladder bottom is irregularly thickened with mass-like changes, accompanied by multiple calcifications. Focus (arrow) suggests local concentration of fluorodeoxyglucose in the gallbladder.
An experienced ultrasound doctor performed the scanning for the patient who had fasted for more than 10 h with a Aplio 500 ultrasound system (Canon Healthcare, Japan; PVT-375BT,1–6 MHz). Conventional ultrasound showed irregular thickening of the gallbladder wall at the bottom and body of the gallbladder. The thickest part was 27 mm. Patchy strong echo masses were seen in the gallbladder wall. Color Doppler ultrasonography showed linear blood flow in the lesion (Fig. 2). Contrast-enhanced ultrasound (CEUS) were carried out with a low mechanical index (MI <0.2) in regards to the EFSUMB guidelines [17]. The patient received an intravenous 2.4 mL bolus injection of SonoVue (SF6, Bracco, Milan, Italy), followed by a flush of 5 mL saline. A timer was activated after injection. Perfusion of the lesion and adjacent liver parenchyma were continuously recorded on the hard disk for 5 minutes. CEUS showed that the gallbladder wall began to increase unevenly at 18 s, peaked at 28 s, the gallbladder wall mucosal line was interrupted, the serosal line was well continuous (Fig. 3), 39 s showed iso-echo, 76 s showed slightly hypoecho, portal and delayed phases showed slightly hypoechoic changes, and some areas of gallbladder wall has never been enhanced (Fig. 4). CEUS diagnosis of inflammatory lesions is more likely than gallbladder adenocarcinoma.
Conventional ultrasonography showed gallbladder lesions (arrow): irregular thickening of gallbladder wall and patchy hyperechoic masses.
Contrast-enhanced ultrasonography of gallbladder lesions (arrow) in arterial phase: uneven enhancement of gallbladder wall, unclear display of gallbladder intima line at peak, discontinuity of mucosal line and good continuity of serosal line.
Contrast-enhanced ultrasonography of gallbladder lesions(arrow) in portal vein and delayed phase: The contrast agent of gallbladder wall disappeared, showing hypoechoic changes, and part of gallbladder wall was not enhanced.
The patient underwent cholecystectomy plus adjacent segment hepatectomy and gastrohepatic ligament lymphadenectomy in regards to the NCCN guidelines [18]. Gross pathology showed smooth serosa, cauliflower-like mass in gallbladder, slightly fish-like in section, necrosis and fragility on surface. Considered as “papillary adenoma with severe atypical hyperplasia of glandular epithelium, canceration (papillary adenocarcinoma, grade I-II), infiltration of cancer tissue into the subserous layer of gallbladder wall”. There were 6 lymph nodes in 5 groups, and no metastasis was found.
Because the early clinical manifestations of gallbladder cancer and gallbladder adenoma disease are not specific, the common clinical symptoms include right upper abdominal pain and anorexia, which are similar to cholecystitis, so early detection mostly depends on imaging examination. Conventional ultrasound is the most common screening method for diseases. It is convenient, non-radiation and inexpensive. It is sensitive to detect space-occupying lesions in the gallbladder. It can detect lesions with a diameter about 2 mm. Advanced gallbladder cancer can also show gallbladder enlargement, irregular solid mass in the gallbladder cavity, gallbladder wall thickening, blurred structure, etc. [10], but for early carcinogensis is often easy to miss diagnosis. CT scan can be used for gallbladder tomography, which is helpful to detect gallbladder cancer. The enhancement scan can show obvious enhancement of the tumors. However, small lesions are difficult to find. In addition, the CT manifestations of gallbladder cancer are sometimes similar to those of benign gallbladder diseases such as adenomyosis of gallbladder, xanthogranulomatous cholecystitis and so on. It is easy to cause misdiagnosis [11]. MR diffusion-weighted imaging can obtain better carcinogensis information by restricting the diffusion of water molecules, but it is more expensive, difficult for patients to cooperate, and easy to form respiratory artifacts. PET/CT is commonly used in the diagnosis of tumors. Studies have found that the critical value of SUVmax for distinguishing benign and malignant occupancies of gallbladder is 3.65 [12]. However, studies have shown that there is no significant difference between different TNM stages of gallbladder cancer [13], which is not helpful for early detection of carcinogenesis, and it is not suitable for early screening of gallbladder cancer.
CEUS has unique advantages in early diagnosis of gallbladder cancer. It not only has the advantages of convenience and non-radiation of conventional ultrasound, but also can depicting the tumor’s mirco-vascularization [19]. The use of CEUS improves the gallbladder tumor diagnostic accuracy of conventional ultrasound according to the EFSUMB guidelines [20], and has high clinical value in differential diagnosis of space-occupying lesions of gallbladder, which also with high sensitivity and specificity for detection of gallbladder cancer [14]. Study by Negrão De Figueiredo G et al. shows that CEUS displayed a better feasibility and diagnostic accuracy than MRI [21]. Gallbladder adenoma on CEUS showed “rapid enhancement, synchronous decline” and eccentricity enhancement at peak, which was related to the distribution of nutrient vessels of gallbladder adenoma, and was an important feature in differentiating gallbladder adenoma from cholesterol polyp [15]. In addition, gallbladder adenoma showed continuous gallbladder wall structure, narrow base, smooth edge, and overall enhancement was lower than that of gallbladder cancer nodules. After carcinogenesis, the lesion can show “fast-in and fast-out”, usually washout within 35 s [20]. At the peak, the enhancement pattern is diffuse and inhomogeneous enhancement. Although the imaging features are similar to cholangiocarcinoma (CCC), CCC usually washout less than 60 s [22], and most of the masses of early stage CCC are mainly located in the liver, which can be differentiated from gallbladder tumor. The common structure of gallbladder wall is interrupted. The basal part of the lesion is wider and the edge is irregular. The continuity of gallbladder wall structure is a highly specific CEUS feature for differentiating carcinogenesis [15, 16]. However, there is rare literature on whether there are differences in CEUS appearances of different pathological types of gallbladder adenomas after carcinogensis.
Conventional ultrasound showed irregular thickening of gallbladder wall. Color Doppler ultrasonography showed linear blood flow in the lesion. Because the lesion is large and almost full of gallbladder, the diagnosis of gallbladder adenoma is not considered too much. CEUS showed irregular thickening of gallbladder wall, rapid and uneven enhancement of arterial phase, wash-out of portal vein and delayed phase, discontinuity of gallbladder wall mucosal line. Although it was consistent with the manifestations of gallbladder malignant tumors, but because of its good serosal line continuity, the diagnosis of inflammatory lesions was preferred. Finally, the pathological findings after operation showed that gallbladder papillary adenoma with canceration infiltrated into the subserous layer locally. The pathological findings were also consistent with the ultrasonographic findings: malignant features could be seen in ultrasound and CEUS, the mucosal layer of gallbladder wall was interrupted continually, and the serosal layer was complete continuity.
This case of gallbladder papillary adenoma with carcinogenesis is typical in both conventional ultrasonography and CEUS. Although the lesion is large in size, it still does not break through the serosa layer of gallbladder pathologically. It belongs to the early lesion. By summarizing and analyzing the routine ultrasonography and contrast-enhanced imaging manifestations of this case, we can popularize its ultrasonographic features to clinical doctors, so as to help them learn and master its diagnostic points better and improve the diagnostic accuracy.
Funding
This study was supported by Fujian Province for Health and Science Research Project (2019-ZQNB-39 to Hai-xia Yuan) and a program from Xiamen Science and Technology Plan (3502Z20184002 to Hai-xia Yuan).