Von Meyenburg Complexes Research Articles

Hepatic Cysts: Reappraisal of the Classification, Terminology, Differential Diagnosis, and Clinicopathologic Characteristics in 258 Cases.

The literature on liver cysts is highly conflicting, mostly owing to definitional variations. Two hundred and fifty-eight ≥1cm cysts evaluated pathologically using updated criteria were classifiable as: I. Ductal plate malformation related (63%); that is, cystic bile duct hamartoma or not otherwise specified-type benign biliary cyst (35 with polycystic liver disease). These were female predominant (F/M=2.4), large (10cm), often multifocal with degenerative/inflammatory changes and frequently misclassified as "hepatobiliary cystadenoma." II. Neoplastic (13%); 27 (10.5%) had ovarian-type stroma (OTS) and qualified as mucinous cystic neoplasm (MCN) per World Health Organization (WHO). These were female, solitary, mean age 52, mean size 11cm, and 2 were associated with carcinoma (1 in situ and 1 microinvasive). There were 3 intraductal papillary neoplasms, 1 intraductal oncocytic papillary neoplasm, 1 cystic cholangiocarcinoma, and 2 cystic metastasis. III. Infectious/inflammatory (12%). These included 23 hydatid cysts (including 2 Echinococcus alveolaris both misdiagnosed preoperatively as cancer), nonspecific inflammatory cysts (abscesses, inflammatory cysts: 3.4%). IV. Congenital (7%). Mostly small (<3cm); choledochal cyst (5%), foregut cyst (2%). V. Miscellaneous (4%). In conclusion, hepatic cysts occur predominantly in women (3/1), are mostly (90%) non-neoplastic, and seldom (<2%) malignant. Cystic bile duct hamartomas and their relative not otherwise specified-type benign biliary cysts are frequently multifocal and often misdiagnosed as "cystadenoma/carcinoma." Defined by OTS, MCNs (the true "hepatobiliary cystadenoma/carcinoma") are solitary, constitute only 10.5% of hepatic cysts, and have a significantly different profile than the impression in the literature in that essentially all are perimenopausal females, and rarely associated with carcinoma (7%). Since MCNs can only be diagnosed by demonstration of OTS through complete microscopic examination, it is advisable to avoid the term "cystadenoma/cystadenocarcinoma" solely based on radiologic examination, and the following simplified terminology would be preferable in preoperative evaluation to avoid conflicts with the final pathologic diagnosis: (1) noncomplex (favor benign), (2) complex (in 3 subsets, as favor benign, cannot rule out malignancy, or favor malignancy), (3) malignant features.

The Ductal Plate From the Inside Out: An Illustrated Review of Fibropolycystic Liver Disease

Fibropolycystic liver disease is a continuum of disorders that result from insults to the ductal plate at different stages of development and are often associated with each other. Caroli's syndrome, polycystic liver disease, biliary hamartomas, and congenital hepatic fibrosis are included in this complex spectrum that also shows frequent association with renal anomalies, such as polycystic kidney disease and medullary sponge kidney. Choledochal cysts are a controversial point in this topic since they have long been considered part of this spectrum due to morphological similarities, but studies have shown different pathogenesis. This article's purpose is to review these abnormalities through a multimodality radiological perspective offering correlation with its key embryological aspects. Knowing these numerous anomalies and their possible associations may ease an accurate diagnosis and prompt management.

Biliary Duct Hamartomas: A Systematic Review.

Biliary duct hamartomas are benign intrahepatic bile duct lesions. Despite being primarily incidental findings on imaging, these lesions can provide a diagnostic conundrum due to their shared characteristics with malignant tumors. The goal of this systematic review is to offer a thorough clinical profile of biliary duct hamartomas.There were 139 cases of biliary duct hamartomas identified in a structured systematic review of the literature. Patient demographics, clinical presentation, significant laboratory and imaging data, diagnostic modalities, treatment choices, and outcomes were all studied and reported.Biliary duct hamartomas present with mild symptoms and laboratory abnormalities, and while being visible on imaging, the results are non-specific and may require biopsy in case of red flag signs such as weight loss and a progressive increase in the size of the lesion. Furthermore, there are currently no published guidelines for the treatment of biliary duct hamartomas, and many people have had surgery despite the clinically benign nature of these abnormalities. As per the findings of the study, individuals who exhibit signs of malignancy should be investigated further. Eyeballing for red flag symptoms, followed by a specialized imaging scan and invasive treatment, is the three-step approach to biliary duct hamartomas. Since our recommendations include a shift in strategy and do not contradict existing rules, there are likely to be few roadblocks to improvement; the key barriers being technological equipment and image quality.In this study, we intended to pave the way for future research in the field. In our opinion, the next decade will bring a better understanding of the characteristics of biliary hamartomas, disease symptoms, and better recognition of any suspicious features. These indications will aid in reducing the number of unneeded surgical or invasive operations. Finally, the findings of these future studies will allow the medical community to improve and provide the best care possible.

Liver progenitor cells may construct cysts having heterogeneous gene expression of liver-enriched transcription factors in mice with conditional knockout of the Hhex gene

The deletion of the Hhex (Hematopoietically expressed homeobox) gene causes agenesis of the liver and polycystic liver disease depending on its timing. The present study was undertaken to determine the role of the Hhex gene in not only signaling cascades to cyst and abnormal bile duct formation but also the liver progenitor contribution to cystic development. Liver-specific Hhex knockout mice (Alb-Cre/HhexloxP/loxP) in adult stages were used. Wild-type and conditional knockout (cKO) livers were immunohistologically compared for cell growth, and gene expression of liver functions, biliary markers and cystic markers. In Hhex cKO livers, cyst formation and dilated intrahepatic bile ducts were noted, which resembled the histology of the von Meyenburg complex. Ki67 immunohistochemistry showed that the growth activity in bile ducts and cysts of cKO livers was elevated compared with that of wild-type livers. There were far fewer liver progenitor cells or bile ductule cells around portal veins of cKO livers than in wild-type livers. Several liver-enriched transcription factors, including Foxa1 and Foxa2, were heterogeneously expressed in bile ducts and cysts of cKO livers whereas their expression in wild-type bile ducts was comparatively homogeneous. PC1 and PC2 immunohistochemistry revealed their up-regulation in cysts of cKO livers. These data indicate that Hhex is not only required for proper bile duct morphogenesis, but is also involved in cyst formation through promoted cell growth. Liver progenitor cells may form cysts. Unbalanced expression of liver-enriched transcription factors might be involved in cyst formation. Hhex cKO mice may be a good animal model for hepatic cystic diseases.

Chronic inflammatory demyelinating polyneuropathy with anti-contactin-associated protein 1 antibody and bile duct hamartomas in the\xa0liver: a case report

BackgroundAutoantibodies targeting node of Ranvier proteins are rarely reported in China.Case presentationWe present the case of a 66-year-old Chinese man who concomitantly developed chronic inflammatory demyelinating polyneuropathy with anti-contactin-associated protein 1 antibody and bile duct hamartomas in liver, which are rarely reported in China. The man presented with chronic progressive sensory and motor symptoms, bilateral periphery facial paralysis, and protein–cell dissociation of cerebrospinal fluid. Nerve conduction study indicated demyelinating neuropathy. Enhanced magnetic resonance imaging of the liver showed diffuse intrahepatic lesions, which were considered as bile duct hamartomas in the liver. He was suspected as having chronic inflammatory demyelinating polyneuropathy and treated with intravenous immunoglobulin and prednisone. However, his condition got worse. One month later, he was diagnosed with chronic inflammatory demyelinating polyneuropathy associated with anti-contactin-associated protein 1 antibody. He received high-dose methylprednisolone, followed by standard plasma exchange and rituximab therapy. His sensory and motor manifestations were significantly improved at 1 year of follow-up.ConclusionsThis case reminds clinicians to be aware of antiparanodal antibodies, which are associated with specific phenotypes and therapeutic response.

Polycystic liver disease

Polycystic liver disease (PLD) includes three entities in adults : biliary hamartomas which develop as a result of ductal plate malformation, autosomal dominant polycystic liver disease (ADPLD) and autosomal dominant polycystic kidney disease (ADPKD) which occur in the setting of genetic disorders. Hamartomas are asymptomatic and benign. PLD are marked by a steady growth of cysts over time, clinically silent in the majority of cases. Symptomatic forms mainly affect women due to the influence of estrogens on the growth of cysts therefore estrogen treatments are contraindicated in this setting. Diagnosis is based on imaging. Complications are rare but must be identified early in order to offer appropriate care in an expert center.

A Case of Multicystic Biliary Hamartoma Treated with Left Medial Sectionectomy

A Case of Multicystic Biliary Hamartoma Treated with Left Medial Sectionectomy

S2779 Multiple Biliary Hamartomas: A Lesser Known Differential for Cystic Lesions of the Liver

S2779 Multiple Biliary Hamartomas: A Lesser Known Differential for Cystic Lesions of the Liver

Notch‐Hes1 signaling activation in Caroli disease and polycystic liver disease

The Notch signaling pathway plays a key role in the morphogenesis of the biliary tree, but its involvement in cystic biliary diseases, such as Caroli disease (CD) and polycystic liver disease (PLD), has yet to be determined. Immunostaining was performed using liver sections of CD and PLD, and the results were compared with those of congenital hepatic fibrosis (CHF) and von Meyenburg complex (VMC). The expression of Notch receptor 1 (Notch1) was increased in the nuclei of biliary epithelial cells in all cases of CD and PLD, whereas it remained at a low level in CHF and VMC. In addition, Notch2 and Notch3 were preferably expressed in the nuclei of biliary epithelial cells of PLD. Accordingly, the Notch effector Hes1 was highly expressed in biliary epithelial cells of CD and PLD, and the cell proliferative activity was significantly higher in CD and PLD. The expression of the Notch ligand Delta-like 1 was significantly increased in biliary epithelial cells of CD and PLD, which may be causally associated with the nuclear overexpression of Notch1 and Hes1. These results indicate that aberrant activation of the Notch-Hes1 signaling pathway may be responsible for the progression of biliary cystogenesis in CD and PLD.

Ductal Plate Malformations in Captive Snakes

Ductal plate malformations are abnormalities in the liver that arise from inappropriate or incomplete remodeling of the embryologic ductal plate. Various types of ductal plate malformations are reported in the human and veterinary literature, most commonly affecting domestic mammalian species but also fish. We investigated the occurrence and described the histopathologic features of ductal plate malformations in captive snakes. Malformations were identified in 18 snakes: 10 colubrids, 6 vipers, and 2 boids. There was no sex predilection, and the mean age was 17 years. The majority of lesions were incidental with most snakes having one or more comorbidities, most commonly neoplasia or systemic inflammation, that resulted in natural death or euthanasia. Ductal plate malformations in all livers were broadly characterized by a well-demarcated nodule of irregular bile ducts embedded within a varying amount of fibrous stroma. Malformations were further categorized based on the amount of fibrous stroma and dilation of the bile ducts as von Meyenburg complexes, cystic liver disease, and/or an intermediate hybrid subtype representative of cysts arising within von Meyenburg complexes. Histochemical and immunohistochemical staining, including Gomori's trichome and pan-cytokeratin, respectively, were applied on select cases to confirm histologic features. Malignant transformation was not identified within this population.

MR imaging features of multiple biliary hamartomas (Von Meyenburg Complex): A pictorial review and differential diagnosis.

Biliary hamartomas (BHs) are rare malformative cystic/cystic-like lesions of the liver affecting the biliary tree, named after Hanns von Meyenburg who described them for the first time and still known with this eponym to this day. They usually lack clinical symptoms, and abnormalities in liver function tests are unusual; thus, it is typically an incidental finding of liver imaging. Despite being benign lesions, BHs can pose clinical challenges; the first one is differential diagnosis with other more relevant pathological conditions. Therefore, knowledge of MR imaging findings of BHs is helpful for a prompt and correct diagnosis, avoiding unnecessary invasive procedures and/or an excessive number of radiological investigations. This pictorial review is aimed to depict the most typical MR imaging features of multiple biliary hamartomas (von Meyenburg Complex), in order to familiarize the diagnosis and facilitate the differentiation from other hepato-biliary cystic diseases.

Von Meyenburg Complexes Associated with Polycystic Kidney Disease and The Endocystic Mural Nodule Sign: A Case Report

Von Meyenburg Complexes Associated with Polycystic Kidney Disease and The Endocystic Mural Nodule Sign: A Case Report

Spontaneous cystic artery bleed presenting as hemoperitoneum and possible gallbladder cancer

Presenter: Karolin Ginting MD | The Jewish Hospital Background: Hemoperitoneum secondary to spontaneous rupture of cystic artery is extremely rare. When present, it is usually due to malignancy or ruptured pseudoaneurysm. Prompt intervention to control the hemorrhage and multidisciplinary evaluation for etiology is essential. Methods: We report a rare case of hemoperitoneum secondary to spontaneous rupture of cystic artery. The patient initially presented with acute onset abdominal pain. Imaging performed in the emergency department revealed large right upper quadrant hematoma with active extravasation, hemoperitoneum, and gallbladder mass. He underwent emergent embolization of the cystic artery. Follow-up work-up to elucidate the cause of bleeding included magnetic resonance cholangiopancreatography (MRCP), esophagogastroduodenoscopy (EGD) and endoscopic ultrasound (EUS) with biopsy. This showed a large gallstone, as well as possible solid tumor in the lumen of the gallbladder versus hematoma. Patient was discharged home with plans to follow up with us (surgical oncologist). However, three weeks later patient re-presented with acute onset abdominal pain and leukocytosis. Repeat imaging showed near resolution of right upper quadrant hematoma, extensive thickening of the gallbladder wall, pericholecystic stranding and omental masses. The patient consented for cholecystectomy, possible liver resection and lymphadenectomy. Results: Patient underwent diagnostic laparoscopy without any obvious evidence of metastatic disease. Frozen pathology on a small liver nodule came back as bile duct hamartoma. There were omental adhesions to gallbladder and on release of adhesions, a perforated gallbladder was noted. Three stones in right upper quadrant were initially noted but later on elevating the omentum, numerous gallstones throughout the omentum and lower pelvis were found. This explained the findings on the CT scan which were concerning for carcinomatosis. Robotic platform immensely helped to avoid conversion to open procedure. Indocyanine green (ICG) firefly imaging was used to identify cystic duct and common bile duct. Additionally, firefly imaging delineated the plane between gallbladder and liver bed. The gallbladder was removed and sent to pathology for review, which was grossly negative for cancer. All noted stones were meticulously retrieved and extracted from the abdominal cavity. The patient's postoperative course was unremarkable, and he was discharged home the next day. Final pathology showed chronic cholecystitis with bile duct hamartomas. Conclusion: Initial non-operative management of hemoperitoneum secondary to cystic artery rupture via emergent angioembolization is feasible. This is a temporary step to allow complete workup for malignancy and operative planning for interval cholecystectomy. Robotic surgery platform is very useful for difficult gallbladder procedures.

Application Value of Two-Dimensional Ultrasound Combined with Contrast-Enhanced Ultrasound for the Diagnosis of Multiple Bile Duct Hamartomas: A Case Report

Application Value of Two-Dimensional Ultrasound Combined with Contrast-Enhanced Ultrasound for the Diagnosis of Multiple Bile Duct Hamartomas: A Case Report

Utility and Limitations of Albumin mRNA In Situ Hybridization Detection in the Diagnosis of Hepatobiliary Lesions and Metastatic Carcinoma to the Liver.

Albumin messenger RNA (mRNA) in situ hybridization is a sensitive and specific biomarker for hepatocellular carcinoma (HCC). Intrahepatic cholangiocarcinoma (ICC) shows variable sensitivity, whereas extrahepatic cholangiocarcinoma (ECC) and metastatic carcinoma are generally negative. We studied the clinical utility and limitations of albumin mRNA detection in a cohort of HCCs, ICCs, ECCs, bile duct adenomas, bile duct hamartomas, and metastatic carcinomas to the liver; and investigated the variability in sensitivity observed for this biomarker in ICCs. We identified 122 cases of hepatobiliary lesions and metastatic carcinomas. Albumin mRNA detection was performed using RNAscope run on formalin-fixed, paraffin-embedded tissue sections. ICCs were categorized according to the classification proposed by Hayashi and colleagues into the small duct, large duct, and indeterminate subtypes. Albumin mRNA was detected in all 17 HCCs and focally in 6/8 (75%) of bile duct adenomas. All 28 nonhepatic carcinomas, 13 bile duct hamartomas, and 9 ECCs were negative. Albumin mRNA was found in 38/47 (80.9%) of ICC with 35/37 (94.6%) in the small duct subtype, 2/3 (66.7%) in the indeterminate subtype, and 1/7 (14.3%) of the large duct subtype (P<0.003). Albumin mRNA detection is a sensitive and specific biomarker for HCCs. It is highly sensitive and moderately specific in the diagnosis of ICC with small gland morphology, but not ICCs with large duct morphology and in metastatic carcinoma. The variability in the sensitivity of albumin mRNA expression in ICCs may depend on the subtypes of ICC.

S2529 Autosomal Recessive Polycystic Kidney Disease Manifesting as Portal Hypertension

INTRODUCTION: Autosomal recessive polycystic kidney disease (ARPKD) is a rare condition affecting 1 in 20,000 children. The liver is always involved with early fibrosis. The severity and progression of symptoms is variable with some patients not developing symptoms until adolescence or later. Here, we present a rare presentation of ARPKD with splenomegaly and pancytopenia. CASE DESCRIPTION/METHODS: A 22 year-old female with no significant medical history was referred for possible cirrhosis. She was in her usual state of health until developing back pain and fevers. Labs revealed a new pancytopenia with white blood cell 1.2K, hemoglobin 5.7 and platelets 42K. CT showed massive splenomegaly (26 cm), possible cirrhosis, portal hypertension and dilated biliary ducts. AST, ALT, total bilirubin, and alkaline phosphatase were within normal limits. Creatinine was 1.9. Bone marrow biopsy was non-diagnostic. She was seen by Nephrology and thought to have polycystic kidney disease. She reported intermittent left upper quadrant pain. She otherwise denied leg swelling, overt gastrointestinal bleeding, jaundice, nausea or vomiting, alcohol or IV drug use, tattoos, or family history of liver disease. Liver biopsy revealed multiple bile duct hamartomas (von Meyenberg complexes) and focal bridging fibrosis, likely congenital hepatic fibrosis. Upper endoscopy revealed esophageal varices requiring band ligation. Genetic testing confirmed a diagnosis of ARPKD. She was deferred for liver/kidney transplantation due to preserved liver synthetic function and stable renal function not requiring dialysis (GFR 36–39). Given her pancytopenia and persistent symptoms from splenomegaly, partial angio-embolization of the splenic artery was performed. Her cell counts normalized within days to weeks post-procedure. She continues to follow with Hepatology with surveillance endoscopies, doing well with normal spleen size on imaging (Figure 1). DISCUSSION: Congenital hepatic fibrosis can occur alone, but more commonly accompanies a genetic renal disorder, such as in ARPKD. Clinical concerns include portal hypertension and cholangitis from dilated bile ducts. Unlike cirrhosis, hepatocellular function is preserved. Partial splenic artery embolization is a relatively safe procedure for managing portal hypertension. It can help prevent or treat variceal bleeding, hepatic encephalopathy, and improve cell counts. For those who fail medical or less invasive management, transplantation should be considered.Figure 1

Bile duct adenoma may be a precursor lesion of small duct type intrahepatic cholangiocarcinoma.

Precursor lesions of small duct type intrahepatic cholangiocarcinoma (small duct iCCA) have not been clarified so far. We hypothesised that precursor lesions may be frequently distributed in the background liver of small duct iCCA. We determined by histology the presence of bile duct adenomas and von Meyenburg complexes as candidate precursor lesions in the background liver of small duct iCCA, with other primary liver carcinomas as control. Subjects included 28 patients with small duct iCCA, 29 with large duct iCCAs, 60 with combined hepatocellular-cholangiocarcinoma (Comb) and 40 with hepatocellular carcinoma (HCC). The prevalence of bile duct adenomas in the background liver was significantly higher in small duct iCCA (35.7%) compared to other primary liver carcinomas (Comb, 4.9%; 10%, HCC) (P<0.01). The prevalence of bile duct adenomas was significantly associated with the presence of von Meyenburg complexes and ductal plate malformation-like patterns in small duct iCCAs and Combs. Von Meyenburg complexes were detected in 11 small duct iCCA (39.3%), five large duct iCCAs (17.2%), 10 Comb (16.4%) and 13 HCC (33.3%), respectively (P>0.05). Small duct iCCAs showed altered expression of ARID1A (46.4%), p53 (39.3%), PBRM1 (14.3%), IMP3 (85.7%) and EZH2 (82.1%), whereas these markers were negative in bile duct adenomas. Bile duct adenomas may be precursor lesions of small duct iCCAs. Alteration of ARID1A, p53 or PBRM1 may be involved in the carcinogenesis of small duct iCCAs.

Multiple biliary hamartomas \u201cvon Meyenberg complexes\u201d in a newborn: a unique observation

BackgroundBiliary hamartomas are rare benign bile duct malformations consisting of multiple collections of localized duct-like structures that are lined by biliary epithelium and embedded in a fibrous stroma. In general, these malformations are asymptomatic and are usually detected incidentally during imaging, surgical exploration, or autopsy. Previously, the definitive diagnosis of these lesions was possible only with liver biopsy. The use of advanced imaging modalities made it possible to establish the diagnosis when undoubtful imaging findings are evident.Case presentationWe present a 25-day-old male newborn who was referred to our institution with jaundice, abdominal distension, and abdominal U/S that revealed hepatomegaly and involvement of both lobes of the liver with diffuse cystic lesions of variable sizes and echogenicity without a diagnostic suggestion. We discuss the details of imaging findings that enabled to establish the diagnosis of multiple biliary hamartomas and brief the patient’s status on follow-up.ConclusionUp to our best knowledge, the diagnosis of multiple biliary hamartomas has not been previously reported among newborns, making this report an extremely rare if not a unique observation.

Die unklare Leberraumforderung

Unknown liver lesions represent a common clinical challenge, for example in the context of routine ultrasound examinations of primary care physicians. There are different data on the prevalence of primary liver lesions in the literature. As such, a forensic autopsy series described focal liver lesions in about 50 % of all examined men between 35 and 69 years of age with an increasing incidence for older people. In the diagnostic work-up of unclear liver lesions, a careful distinction between lesions that occur in asymptomatic and healthy individuals and are benign in over 95 % of cases, and lesion found in patients with pre-existing malignant, inflammatory or cirrhotic disease must be made. The main goal in the diagnosis of unclear liver lesions is to prove the benignity of the lesion and to exclude a malignant cause as reliably as possible. In case of benign lesions, an attempt should be made to achieve an exact classification. The most common benign focal liver lesions include liver cysts, focal fatty liver deposition or sparing, haemangiomas, focal calcifications, focal nodular hyperplasia (FNH), nodular regenerative hyperplasia, biliary hamartomas (von-Meyenburg complexes) and hepatocellular adenomas. Abscesses, inflammatory infiltrations or pseudotumors as well as sites of extramedullary haematopoiesis are observed much less frequently. Among the most frequent malignant focal liver lesions are metastases of other tumor entities such as colorectal cancer or pancreatic adenocarcinoma as well as hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCA). Other entities such as hepatic lymphomas or mesenchymal malignant neoplasia are extremely rare.

Synchronous occurrence of hepatocellular carcinoma and multiple biliary hamartomas mimicking hepatocellular carcinoma with multiple intra-hepatic metastases

Synchronous occurrence of hepatocellular carcinoma and multiple biliary hamartomas mimicking hepatocellular carcinoma with multiple intra-hepatic metastases