Abstract
Background: Bile duct adenomas (BDA) may be precursor lesions of small duct-type, including mass-forming type intrahepatic cholangiocarcinoma (ICC). Case Report: A 68-year-old woman was transferred to our facility for the treatment of a liver tumor, possibly metastasized from a pancreatic neuroendocrine tumor. Finally, two liver tumors were resected and histopathologically diagnosed as “BDA” and “ICC with a BDA-like component”. In the BDA-like component, the MUC6 positive rate was notably lower and the Ki-67 positive rate was higher than the other BDAs and ICC component, respectively. The doubling time of the tumor volume in BDA was very long but was shortened (1,510 and 719 days). Distinct enlargement of the tumor and appearance of enhancement through diagnostic imaging was useful in diagnosing the transformation from a BDA to an ICC. Conclusion: An “adenoma-carcinoma sequence” may exist in the transformation process from a BDA to an ICC.
- Bile duct adenoma
- intrahepatic cholangiocarcinoma
- liver metastasis
- pancreatic neuroendocrine tumor
Pancreatic neuroendocrine tumors (pNET) are rare with an annual incidence of less than one case per 100,000 individuals; however, the rate of occurrence of the disease is increasing worldwide (1). The prognosis of a pNET depends on clinicopathological factors, including tumor size, proliferative index, and differentiation (2, 3). Surgical resection of the tumor is the only way to accomplish a cure for primary and metastatic pNETs. In patients with pNETs, the liver is the most common site of metastasis, with a frequency of approximately 28%-77% (4). Everolimus is a targeted drug that can improve progression-free survival in patients with advanced pNET and can cause interstitial pneumonia as a rare but severe adverse event (5). Liver metastases caused from pNET are known as hypervascular tumors in the arterial phase, and half of them were observed to be hypovascular in the portal venous phase through diagnostic imaging (6).
Bile duct adenoma (BDA) is incidentally observed during surgery or autopsy as a subcapsular liver tumor, ranging from 1 to 20 mm in diameter (7). Histopathologically, BDA is an isolated intrahepatic lesion consisting of many small homogeneous ducts with benign cuboidal cells and a narrow lumen (8). The concept of precursor lesions of large duct-type intrahepatic cholangiocarcinoma (ICC) is similar to the general concept of “adenoma-carcinoma sequence” in gastrointestinal tract cancer; however, peripheral small duct-type ICC may have a different histologic phenotype, which is the non-mucinous type, and shows homology or transitions to hepatocellular carcinoma (8). Nakanuma et al. reported a new subtype of ICC with a predominant “ductal plate malformation” pattern (9). Recently, it has been published that BDAs may be precursor lesions of small duct-type ICC that included mass-forming ICC (10). The incidence of BDA was significantly correlated with advanced age and the presence of von Meyenburg complexes. In fact, transitional areas can exist from BDA to ICC in the same tumor (11).
BDAs are incidentally detected through radiological imaging mainly in chronically diseased or cirrhotic livers and present as single subcapsular or superficial lesions of the liver without capsule formation along with being <2 cm in size (12, 13). In previous reports on diagnostic imaging, BDAs generally show arterial phase hyperenhancement and delayed or prolonged enhancement due to the fibrous stroma components in the tumors (12). In contrast, small mass-forming-type ICC (<3 cm) show arterial phase hyperenhancement with washout or peripheral rim sign in the portal to venous phase (12, 14).
Herein, we present a case with ICC and multiple metachronous BDAs successfully treated with hepatectomy. The patient previously underwent systemic medical therapy with Everolimus for liver metastasis caused from pNET. Based on detailed histopathological examination, we can clearly demonstrate the “adenoma-carcinoma sequence” in the peripheral small duct-type ICC.
Case Report
A 68-year-old female patient was transferred to our hospital for the treatment of a liver tumor. Two and a half years ago, she underwent subtotal stomach preserving pancreaticoduodenectomy for pNET and partial liver resection for an unknown liver tumor at the referral hospital. The pancreatic tumor, 1.5 cm in diameter, showed perceptible hypervascularity in the arterial phase with a continuous enhanced effect. In contrast, the liver tumor was an unclear hypovascular tumor. The postoperative histopathology findings showed pNET (gastrinoma, stage IA) and BDA. Preoperative level of serum gastrin before stimulation was 770 pg/ml (normal range < 200 pg/ml). One and a half years after the surgery, a hypervascular liver tumor that mimicked pNET was detected in segment 8 and was subsequently diagnosed as metachronous liver metastasis of pNET without tumor biopsy. Administration of Everolimus was started but was discontinued after 3 months due to interstitial pneumonia. She was referred to our hospital for the treatment of the gradually growing liver tumor. The etiology included both hepatitis B surface antigen (−) and hepatitis C (HCV) antibody (+); however, HCV ribonucleic acid was not detected. The Child-Pugh score was 6 points. She had a low serum albumin level of 3.26 g/dl (normal range=4.1-5.1 g/dl) and an elevated 15-minute indocyanine green retention rate of 27.0% (normal range ≤10%). Total bilirubin, transaminase and prothrombin activity, and platelet count levels were all within normal limits. As for tumor markers, serum levels of alpha-fetoprotein, carbohydrate antigen 19-9, and neuron-specific enolase were within normal limits. Carcinoembryonic antigen (CEA) levels were elevated at 12.8 ng/ml (normal range ≤5 ng/ml) but also elevated at 14.5 ng/ml before the first operation. Contrast-enhanced computed tomography showed an early deep-stained tumor with a diameter of 22 mm in segment 8, which showed the same degree of enhancement as the liver parenchyma in the late phase. Gadolinium dethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced (EOB) magnetic resonance imaging (MRI) showed mild hyperintensity on T2-weighted imaging, a high signal on diffusion-weighted imaging, and a low signal on the hepatobiliary phase (Figure 1A-E). Based on the clinical course, preoperative diagnosis of this tumor was liver metastasis caused by pNET. The tumor in segment 3 was slightly enhanced in the arterial phase and showed prolonged enhancement (Figure 1F-J). Higher signal on diffusion-weighted imaging was shown in the former than that in the latter. The tumor was suspected to be BDA. Segmentectomy of segment 8 and partial resection of the segment 3 tumor was performed. Postoperative histopathological results revealed poorly-differentiated ICC for an S8 lesion and BDA for an S3 lesion.
Serial MRI images demonstrated that the S8 tumor was definitely enlarging, whereas the S3 tumor remained stable in size (Figure 2). The tumor diameters were measured via MRI in the axial hepatobiliary phase (slice thickness: 4 mm) by radiologists with 15 years of experience. The doubling time of the tumor volume (TVDT) was investigated according to the previous papers (15-17). DT was 198 and 194 days for the S8 tumor and 1,510 and 719 days for the S3 tumor during the first and second periods, respectively.
Results of the detailed histopathological examination and immunohistochemistry profiling are summarized in Figure 3 and Table I. BDA1 was a liver tumor that was removed during surgery for pNET. The tumor showed mild atypical cells that proliferated in a cord-like or tubular shape (Figure 3A). The Ki-67 positive rate was <1%, and the MUC6 positive rate was 100% (Figure 3B and C). BDA2 was a resected lesion in segment 3. The tumor also showed a cord-like or tubular proliferation pattern (Figure 3D), and the Ki-67 and MUC6 positive rates were similar to those of BDA1 (Figure 3E and F). A small amount of BDA-like component (approximately 5%), with weak atypia, was observed in the ICC lesion (Figure 3G). The Ki-67 positive rate was low; however, the MUC6 positive rate was evidently lower than that of BDA1 and BDA2 (Figure 3H and I). ICC showed a glandular, cribriform, and solid growth pattern, with a high degree of fibrosis and infiltration of inflammatory cells (Figure 3J). The Ki-67 positive rate was relatively high, whereas the MUC6 positive rate was extremely low (Figure 3K and L).
The patient was discharged on postoperative day 11 from our hospital and is doing well without any recurrence 9 months after the second operation.
Discussion
The patient was transferred to our hospital for a hepatectomy due to a strongly suspicious liver metastasis in segment 8 caused by pNET. Although the patient had already been treated with Everolimus, the tumor showed progression. The primary pNET had been diagnosed as gastrinoma; however, serum gastrin levels were unfortunately not measured during the postoperative observation period. Although the tumor showed an enhancement pattern like that of liver metastasis from pNET by diagnostic imaging (6, 12), a tumor biopsy using a fine needle may be required before chemotherapy. However, percutaneous tumor biopsy or cytology is not recommended for highly malignant liver tumors, including ICC, because of increased risk of intraabdominal tumor seeding (18). Considering the implications of diagnostic treatment, a curative liver resection was performed.
At the time of pancreaticoduodenectomy, a small liver tumor was detected intraoperatively on the liver surface and was enucleated. The histopathological diagnosis was BDA. Fortunately, the other liver tumors in segments 8 and 3 could be followed-up through diagnostic imaging for 22 months. Finally, two tumors were resected, and the former was diagnosed as ICC, whereas the latter was diagnosed as BDA. In the previous papers, median TVDT of mass-forming ICC, HCC, and colorectal liver metastases (CRLM) was 70 days (range=14.5-512.9 days), 79.8 days (range=13.5-355.6 days), and 71.4 days (95% confidence interval=62.8-79.9), respectively (15-17). For our patient, all maximal tumor diameters were measured using the hepatobiliary images of EOB-MRI because of their clear tumor border. Actual TVDT was relatively long (198 and 194 days) for ICC and very long for BDA (1,510 and 719 days). Appearance of early enhancement was one of the signs of transformation from BDA to ICC (12). Upon reviewing the diagnostic images, the degree of early enhancement gradually increased in the tumor decisively diagnosed as ICC.
The ICC lesion contained less BDA-like tumor cells with low atypia (Figure 3G) in the patient. Furthermore, the BDA-like tumor component generally showed immunohistochemistry profiles similar to the IHC phenotype of BDA, in particular MUC6 and Ki67 (Figure 3H and 3I) (19). In a previous paper, it was demonstrated that the ICC lesion contained BDA-like components similar to our patient (11). Recent studies demonstrated that BDA is considered a true tumor with several genetic abnormalities, such as BRAF V600E mutation (20). Furthermore, if some genetic abnormalities of ARID1A, p53, or PBRM1 are added to a BDA, it may transform into small duct-type ICC (10). These findings suggest that the BDA may have transformed into ICC in our patient.
In conclusion, our patient may have demonstrated the “adenoma-carcinoma sequence” to a mass-forming ICC (peripheral small duct-type ICC) derived from BDA. Monitoring of TVDT is strongly recommended during the follow-up period of BDA. Detailed histopathological and genetic examination of the transformation of BDA to ICC is warranted.
Acknowledgements
Department of Community Network Pathology is supported with an unrestricted grant from the Chemo-Sero-Therapeutic Research Institute (KAKETSUKEN).
Footnotes
Authors’ Contributions
Manuscript writing: Oda E, Beppu T. Substantial contributions to conception: Yamamura K, Yuki H, Motohara T, Miyamaoto H. Technical supports and interpretation: Beppu T, Yamamura K, Hara Y, Matsumura K, Akahoshi S, Kinoshita K, Matsumura F. Histopathological diagnosis: Onishi K, Komohara Y.
Conflicts of Interest
All Authors have no conflicts of interest to declare in relation to this article.
- Received August 23, 2021.
- Revision received September 2, 2021.
- Accepted September 3, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.