Autosomal dominant polycystic liver disease in a family without polycystic kidney disease associated with a novel missense protein kinase C substrate 80K-H mutation

Polycystic liver disease (PLD) is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. PLD can manifest itself in patients with severe autosomal dominant polycystic kidney disease (ADPKD). Isolated autosomal dominant polycystic liver disease (ADPLD) is genetically distinct from PLD associated with ADPKD, although it may have similar pathogenesis and clinical manifestations. Recently, mutations in two causative genes for ADPLD, independently from ADPKD, have been identified. We report here a family (a mother and her daughter) with a severe form of ADPLD not associated with ADPKD produced by a novel missense protein kinase C substrate 80K-H (PRKCSH) mutation (R281W). This mutation causes a severe phenotype, since the two affected subjects manifested signs of portal hypertension. Doppler sonography, computed tomography (CT) and magnetic resonance (MR) imaging are effective in documenting the underlying lesions in a non-invasive way.     

Multiple cysts in the liver autosomal dominant polycystic liver disease

A 45-year-old woman was admitted because of abdominal pain and a feeling of fullness. Ultrasound and CT scan of the abdomen showed a massively enlarged liver with hundreds of cysts and displacement of the right kidney. There were no cysts in the kidneys. Because several members of her family also had multiple cysts in the liver, the diagnosis of autosomal dominant polycystic liver disease (PCLD) was made. Genetic analysis demonstrated a protein kinase C substrate 80 K-H (PR KCSH) gene mutation (1338-2A>G) and confirmed the clinical diagnosis. A brief review of the genetics and possible treatments is given.     

<Emphasis Type="Italic">PRKCSH</Emphasis> Genetic Mutation Was Not Found in Taiwanese Patients with Polycystic Liver Disease

Polycystic liver disease (PCLD) without polycystic kidney is infrequent in clinical setting. Family clustering is found in patients with PCLD, and it is inherited in an autosomal dominant fashion. Through positional cloning in North America and Europe (mostly in Dutch and Finnish descents), mutations in PRKCSH gene on chromosome 19 were found to be responsible for the disease. We investigated the prevalence of liver cysts and PCLD in Taiwan and investigated whether the PRKCSH mutations exist in Taiwanese. The prevalence of liver cysts is only 0.17% in people under 30 years old and increased gradually to 14.29% in people between 55 and 60 years old and 14.19% in people over 65 years old. PCLD was not found in people under 40 years old. The prevalence is 0.15% between 40 and 45 years old, and increased to 1.37% between 55 and 60 years old, 1.21% between 60 and 65 years old, and 0.99% over 65 years old. There is only one polymorphism (deletion of one GAG repeat in exon 11) found, and the genotype and allele frequency were the same in Taiwanese patients and controls. No mutation, even polymorphism reported in the literature, was found in the 20 cases of PCLD. Our results suggest that PRKCSH gene is not a major genetic cause of PCLD and there may be at least another locus responsible for the disease in Taiwan.     

Evaluation of hepatic cystic lesions

Hepatic cysts are increasingly found as a mere coincidence on abdominal imaging techniques, such as ultrasonography (USG), computed tomography (CT) and magnetic resonance imaging (MRI). These cysts often present a diagnostic challenge. Therefore, we performed a review of the recent literature and developed an evidence-based diagnostic algorithm to guide clinicians in characterising these lesions. Simple cysts are the most common cystic liver disease, and diagnosis is based on typical USG characteristics. Serodiagnostic tests and microbubble contrast-enhanced ultrasound (CEUS) are invaluable in differentiating complicated cysts, echinococcosis and cystadenoma/cystadenocarcinoma when USG, CT and MRI show ambiguous findings. Therefore, serodiagnostic tests and CEUS reduce the need for invasive procedures. Polycystic liver disease (PLD) is arbitrarily defined as the presence of > 20 liver cysts and can present as two distinct genetic disorders: autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (PCLD). Although genetic testing for ADPKD and PCLD is possible, it is rarely performed because it does not affect the therapeutic management of PLD. USG screening of the liver and both kidneys combined with extensive family history taking are the cornerstone of diagnostic decision making in PLD. In conclusion, an amalgamation of these recent advances results in a diagnostic algorithm that facilitates evidence-based clinical decision making.     

Surgical management of polycystic liver disease

Adult polycystic liver disease (PCLD) is an autosomal dominant condition commonly associated with autosomal dominant polycystic kidney disease (ADPKD). However in the last decade, it has been recognized that there is a distinct form of autosomal dominant PCLD that arises without concomitant ADPKD. Early knowledge of the pathogenesis was gained from the study of hepatic cysts in patients with ADPKD. Bile duct overgrowth after embryogenesis results in cystic hepatic dilatations that are known as biliary microhamartomas or von Meyenburg complexes. Further dilatation arises from cellular proliferation and fluid secretion into these cysts. There is a variable, broad spectrum of manifestations of PCLD. Although PCLD is most often asymptomatic, massive hepatomegaly can lead to disabling symptoms of abdominal pain, early satiety, persistent nausea, dyspnea, ascites, biliary obstruction, and lower body edema. Complications of PCLD include cyst rupture and cyst infection. Also, there are associated medical problems, especially intracranial aneurysms and valvular heart disease, which clinicians need to be aware of and evaluate in patients with PCLD. In asymptomatic patients, no treatment is indicated for PCLD. In the symptomatic patient, surgical therapy is the mainstay of treatment tailored to the extent of disease for each patient. Management options include cyst aspiration and sclerosis, open or laparoscopic fenestration, liver resection with fenestration, and liver transplantation. The surgical literature discussing treatment of PCLD, including techniques, outcomes, and complication rates, are summarized in this review.     

Cystic liver diseases. Genetics and cell biology

In 50% of cases, polycystic liver disease is associated with autosomal dominant polycystic kidney disease, which is caused by mutations in the PKD1 and PKD2 genes that encode polycystin-1 and -2, respectively. These proteins form a polycystin-1/2 complex on the plasma membrane, including that localized on the surface of primary cilia, where they act as mechanosensors. Polycystin-1 acts as a (mechano)receptor of environmental signals, and polycystin-2 as a calcium channel mediating intracellular transduction. Isolated autosomal dominant polycystic liver disease is caused by mutations in PRKCSH that encodes hepatocystin, a protein of the endoplasmic reticulum, which may participate in the N-glycosylation and maturation of proteins addressed to the cell surface. Congenital hepatic fibrosis whether it is accompanied by bile duct dilatations (Caroli's syndrome) or not, may be associated with autosomal recessive polycystic kidney disease, which is caused by mutations in PKHD1 that encodes fibrocystin, a protein of primary cilia. Genetic defects in fibrocystin cause ciliary dysfunction, presently considered as a major pathogenic event in cystogenesis. Excessive cell proliferation, a hallmark of cystic biliary epithelium, occurs in combination with deregulation of the epidermal growth factor (EGF) and probably also estrogen receptors. EGF receptor antagonists inhibit kidney and liver cyst development in animal models, and are currently under investigation in phase I and II clinical trials in patients with autosomal dominant polycystic kidney disease.     

Management of polycystic liver disease

The adult forms of polycystic liver disease are characterized by autosomal dominant inheritance and numerous hepatic cysts, with or without renal involvement. Mutations in two distinct genes predispose to renal and liver cysts (PKD1 and PKD2), and mutations in two different genes yield isolated liver cysts (PRKCSH and SEC63). Mutations at certain loci of PKD1 may predispose to more severe renal cystic disease or cerebral aneurysms. Risk factors for severe hepatic cystic disease include aging, female sex, pregnancy, use of exogenous female steroid hormones, degree of renal cystic disease, or severity of renal dysfunction (in patients with mutations in PKD1 or PKD2). Although liver failure or complications of advanced liver disease is rare, some patients develop massive hepatic cystic disease and become clinically symptomatic. There is no effective medical therapy. Treatment options include cyst aspiration and sclerosis, open or laparoscopic cyst fenestration, hepatic resection, and liver transplantation.     

Polycystic liver: clinical characteristics of patients with isolated polycystic liver disease compared with patients with polycystic liver and autosomal dominant polycystic kidney disease

Aim: The goal of this study was to compare the clinical features of patients with isolated polycystic liver disease (PCLD) with those of patients with polycystic liver and autosomal dominant polycystic kidney disease (ADPKD). Methods: Cases were identified from clinical records at the University of Colorado Hospital in Denver (USA) and at the Radboud University Hospital in Nijmegen (the Netherlands) by ICD‐10 codes. To be included in this analysis, patients had to have an initial diagnosis of PCLD within six years of presentation to our clinics. Medical records were reviewed for demographic information, medical history, physical examination, symptoms, complications, laboratory and imaging results, therapy and outcomes. Results: Out of a total of 94, 53 patients met our criteria for entering this study, 19 with PCLD and 34 with ADPKD. The mean time interval from diagnosis of PCLD to presentation in our clinics was 1.21 years for PCLD and 2.76 years for ADPKD (P=NS). PCLD was associated with female gender in both PCLD and ADPKD. Patients with PCLD had greater numbers (P=0.031), and larger sizes of liver cysts (P=0.0051), but had less associated morbidities than patients with ADPKD. Liver cyst decompressions were performed more frequently in PCLD patients (57.9 vs. 23.5%, P=0.012). However, serious hepatic complications, sufficient to require consideration of liver transplantation, were more frequent in patients with ADPKD (0/19 vs. 6/34, P<0.0001). Conclusions: Although PCLD in patients with PCLD is characterized by larger and greater number of hepatic cysts, the clinical course is relatively benign compared with ADPKD.     

Successful living donor liver transplantation for polycystic liver in a patient with autosomal-dominant polycystic kidney disease

Orthotopic liver transplantation has been recommended for patients with disabling polycystic liver disease (PCLD). Because of the shortage of cadaveric donors, living donor liver transplantation (LDLT) has been developed as an alternative. We describe the case of a woman with PCLD as an extrarenal manifestation of autosomal-dominant polycystic kidney disease (ADPKD) who was successfully palliated by LDLT. The patient was a 48-year-old woman with abdominal distention. Computed tomography showed a massively enlarged liver containing innumerable cysts, as well as bilateral kidney cysts. Hepatic and renal functions were well preserved. Genetic analysis of the family did not exclude linkage to the PKD1 locus. Two and a half years after the first examination, the patient reported severely disabling symptoms caused by the PCLD. Living donor liver transplantation was performed using a right-lobe graft. The recipient and donor were both well 8 months after the transplantation. The excised liver weighed 7.4 kg, and the histopathology revealed multiple cysts and von Meyenburg complexes in the portal areas.     

It's not all in the cilium, but on the road to it: genetic interaction network in polycystic kidney and liver diseases and how trafficking and quality control matter

Autosomal dominant polycystic liver disease results from mutations in PRKCSH or SEC63. The respective gene products, glucosidase IIb and SEC63p, function in protein translocation and quality control pathways in the endoplasmic reticulum. Here we show that glucosidase IIb and Sec63p are required in mice for adequate expression of a functional complex of the polycystic kidney disease gene products, polycystin-1 and polycystin-2. We find that polycystin-1 is the rate-limiting component of this complex and that there is a dose–response relationship between cystic dilation and levels of functional polycystin-1 following mutation of Prkcsh or Sec63.Reduced expression of polycystin-1 also serves to sensitize the kidney to cyst formation resulting from mutations in Pkhd1, the recessive polycystic kidney disease gene. Finally, we show that proteasome inhibition increases steady-state levels of polycystin-1 in cells lacking glucosidase IIb and that treatment with a proteasome inhibit or reduces cystic disease in orthologous gene models of human autosomal dominant polycystic liver.     

Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis

Polycystic livers are seen in the rare inherited disorder isolated polycystic liver disease (PCLD) and are recognized as the most common extrarenal manifestation in autosomal dominant polycystic kidney disease. Hepatic cystogenesis is characterized by progressive proliferation of cholangiocytes, ultimately causing hepatomegaly. Genetically, polycystic liver disease is a heterogeneous disorder with incomplete penetrance and caused by mutations in PRKCSH, SEC63, PKD1, or PKD2. Genome-wide SNP typing and Sanger sequencing revealed no pathogenic variants in hitherto genes in an extended PCLD family. We performed whole-exome sequencing of DNA samples from two members. A heterozygous variant c.3562C > T located at a highly conserved amino acid position (p.R1188W) in the low density lipoprotein receptor-related protein 5 (LRP5) gene segregated with the disease (logarithm of odds score, 4.62) but was not observed in more than 1,000 unaffected individuals. Screening of LRP5 in a PCLD cohort identified three additional mutations in three unrelated families with polycystic livers (p.V454M, p.R1529S, and p.D1551N), again all undetected in controls. All variants were predicted to be damaging with profound structural effects on LRP5 protein domains. Liver cyst tissue and normal hepatic tissue samples from patients and controls showed abundant LRP5 expression by immunohistochemistry. Functional activity analyses indicated that mutant LRP5 led to reduced wingless signal activation. In conclusion, we demonstrate that germ-line LRP5 missense mutations are associated with hepatic cystogenesis. The findings presented in this study link the pathophysiology of PCLD to deregulation of the canonical wingless signaling pathway.Polycystic liver diseases (PLD) consist of a group of inherited disorders characterized by abnormal proliferation and differentiation of the bile duct epithelium (1). Ductal plate malformation results in development of multiple fluid-filled cysts spread throughout the liver parenchyma. Progressive hepatic cystogenesis and cyst growth cause hepatomegaly and symptoms such as abdominal distension and pain, pyrosis, anorexia, and dyspnea.Congenital PLD are clinically heterogeneous, and two major types can be distinguished. Autosomal dominant polycystic kidney disease (ADPKD) is a potentially lethal condition afflicting about 1:400–1:1,000 persons in the United States (2). Patients may develop end-stage renal disease resulting from polycystic kidneys, and 83% have the simultaneous presence of multiple hepatic cysts (3). Formal diagnostic criteria for ADPKD include age, number of renal cysts for each kidney, and family history of renal disease (4, 5). Isolated polycystic liver disease (PCLD) shares the phenotype of a polycystic liver but is distinct from ADPKD because renal disease is absent (6). Some patients may, however, have sporadic renal cysts. Diagnosis of PCLD is made by a family history consistent with autosomal dominant inheritance and the presence of at least one (<40 y) or more than three (>40 y) hepatic cysts (7).The natural course of PCLD and ADPKD depends on a spectrum of factors that include age, sex, anticonceptives, pregnancy, and mutation(s) (8–10). Classical linkage analysis has identified four genes that underlie both inherited disorders. Mutations in polycystic kidney disease 1 or 2 (PKD1 or PKD2) genes (NM_601313 and {"type":"entrez-nucleotide","attrs":{"text":"NM_173910","term_id":"27806890","term_text":"NM_173910"}}NM_173910, respectively), which encode polycystin-1 and polycystin-2, are responsible for almost all ADPKD cases (11–13). Both proteins are located in the cilium and are important in renal tubular cell morphogenesis and signaling functions, including the wingless (Wnt) signaling pathway (β-catenin pathway). Mutations in protein kinase C substrate 80K-H (PRKCSH) and Saccharomyces cerevisiae homolog 63 (SEC63) are linked to PCLD ({"type":"entrez-nucleotide","attrs":{"text":"NM_002743.2","term_id":"48255888","term_text":"NM_002743.2"}}NM_002743.2 and {"type":"entrez-nucleotide","attrs":{"text":"NM_007214.4","term_id":"189491764","term_text":"NM_007214.4"}}NM_007214.4, respectively), and both gene products are located to the endoplasmic reticulum and are involved in processing and folding of glycosylated proteins (14–16). In addition, the canonical Wnt signaling may be deregulated by the interaction partner nucleoredoxin of the Sec63 protein during oxidative stress (17). In contrast to ADPKD, only 25% of PCLD cases can be explained by mutations in already known genes (18), indicating that mutations in several other as yet unidentified genes are involved in this disease. We hypothesized that another PCLD gene is involved in an extended PCLD family negative for the known disease genes and performed whole-exome sequencing. This unique approach has proven to be successful for the identification of the genetic cause of other Mendelian disorders (19–21).     

Recurrent renal cell carcinoma leading to a misdiagnosis of polycystic liver disease: A case report

BACKGROUND Polycystic liver disease(PCLD) with a large cystic volume deteriorates the quality of life of patients through substantial effects on the adjacent organs,recurrent cyst infections, cyst rupture, and hemorrhage. Surgical or radiological intervention is usually needed to alleviate these symptoms. We report a rare case of the cystic metastasis of renal cell carcinoma(RCC), which was misdiagnosed as PCLD, as a result of the clinical and radiological similarity between these disorders.CASE SUMMARY A 74-year-old female who had undergone nephrectomy for papillary-type RCC(PRCC) was suffering from abdominal pain and the recurrent intracystic hemorrhage of multiple cysts in the liver. Imaging studies and aspiration cytology of the cysts showed no evidence of malignancy. With a diagnosis of autosomal dominant polycystic liver disease, the patient received hepatectomy for the purpose of mass reduction and infectious cyst removal. Surgery was performed without complications, and the patient was discharged on postoperative day 14. Postoperatively, the pathology revealed a diagnosis of recurrent PRCC with cystic formation.CONCLUSION This case demonstrates the importance of excluding the cystic metastasis of a cancer when liver cysts are observed.     

Polycystic disease caused by deficiency in xylosyltransferase 2, an initiating enzyme of glycosaminoglycan biosynthesis

The basic biochemical mechanisms underlying many heritable human polycystic diseases are unknown despite evidence that most cases are caused by mutations in members of several protein families, the most prominent being the polycystin gene family, whose products are found on the primary cilia, or due to mutations in posttranslational processing and transport. Inherited polycystic kidney disease, the most prevalent polycystic disease, currently affects approximately 500,000 people in the United States. Decreases in proteoglycans (PGs) have been found in tissues and cultured cells from patients who suffer from autosomal dominant polycystic kidney disease, and this PG decrease has been hypothesized to be responsible for cystogenesis. This is possible because alterations in PG concentrations would be predicted to disrupt many homeostatic mechanisms of growth, development, and metabolism. To test this hypothesis, we have generated mice lacking xylosyltransferase 2 (XylT2), an enzyme involved in PG biosynthesis. Here we show that inactivation of XylT2 results in a substantial reduction in PGs and a phenotype characteristic of many aspects of polycystic liver and kidney disease, including biliary epithelial cysts, renal tubule dilation, organ fibrosis, and basement membrane abnormalities. Our findings demonstrate that alterations in PG concentrations can occur due to loss of XylT2, and that reduced PGs can induce cyst development.     

Advances in management of polycystic liver disease

The focus of this review is polycystic liver disease, a genetic disorder characterized by multiple macroscopic liver cysts that initially bud from biliary epithelium but subsequently lack communication with the biliary tree. There are two main clinical presentations: polycystic liver associated with autosomal dominant polycystic kidney disease and isolated polycystic liver disease. Both of these forms of polycystic liver disease exhibit an autosomal dominant pattern of inheritance. Clinical manifestations of polycystic liver disease are related to either mass effect of the volume of hepatic cysts or to complications arising within the cysts. Polycystic liver disease rarely progresses to hepatic failure or clinical complications of portal hypertension. Management is directed at counseling patients and families, treating complications and reducing cyst load by surgical techniques: cyst fenestration, hepatic resection or, rarely, hepatic transplantation. Recent research suggests that blockade of cyst secretion or inhibition of epithelial cells might be useful in halting progression of disease – these observations are discussed in this review.     

Patients with isolated polycystic liver disease referred to liver centres: clinical characterization of 137 cases

Background and aim: Isolated polycystic liver disease (PCLD) is characterized by the presence of multiple cysts in the liver in the absence of polycystic kidneys. The clinical profile of PCLD is poorly defined and we set up a study for the clinical characteristics of PCLD. Methods: We collected clinical data on 188 PCLD patients (defined as >10 liver cysts) from five tertiary referral centres, and 137 patients were selected for the purpose of this study. We performed molecular analysis of the PCLD associated genes PRKCSH and SEC63 in 91 patients. Results: A total of 118 (86%) patients were female. The majority of patients (88%) had >20 cysts. The median age at diagnosis was 47 years (range 23–84). 37 (41%) patients carried a mutation. Clinical symptoms at presentation were present in 111 (84%) patients. γ‐glutamyl transferase was elevated to 1.4 times upper limit of normal (interquartile range 1.0–2.7). The presence of a mutation and female gender predicted a more severe course: female patients were 9 years younger at the time of diagnosis (47 years; range 23–84) and 91% had symptoms (P<0.01); likewise, mutation carriers were younger at presentation (39 years; range 35–48) and 95% of this cohort had symptoms (P<0.01). During follow‐up [median 8.2 years (range 0–35)], 10% of untreated and 51% of treated patients developed complications. Mortality in this cohort was 8%, but only 2% died of PCLD‐related causes. 58% of patients were treated a median of 2 years (range 0–25) after diagnosis. Conclusion: Symptomatic PCLD patients are mainly females. Females and mutation carriers were younger at diagnosis and had a more severe course of disease.     

A case of successful management of portosystemic shunt with autosomal dominant polycystic kidney disease by balloon-occluded retrograde transvenous obliteration and partial splenic embolization

We describe a patient with autosomal dominant polycystic kidney disease who was successfully managed for severe abdominal distension, impaired liver function and a portosystemic shunt by interventional therapies. The patient's intra-hepatic portal vein was compressed and narrowed by multiple liver cysts, which resulted in a decrease of the portal blood flow and portal hypertension due to a huge gastro-renal shunt These haemodynamic changes were assumed to contribute to insufficient protein synthesis in the liver. Therefore, we first repeatedly performed minocycline hydrochloride instillations to treat the multiple liver cysts. Then, we conducted a partial splenic embolization to prevent elevation of the portal vein pressure prior to balloon-occluded retrograde transvenous obliteration which was performed to increase the portal blood flow. The portal blood flow markedly increased, and protein synthesis in the liver also recovered and the clinical symptoms improved. The patient has been monitored for more than two years up to the present and her liver function parameters have remained within the normal range. Renal insufficiency is known to be a major prognostic factor in autosomal dominant polycystic kidney disease. In some cases, however, liver involvement with multiple cysts may result in a fatal outcome. In such cases, interventional therapies, as provided to this patient, should be considered.     

Polycystic liver diseases

Polycystic liver diseases (PCLDs) are genetic disorders with heterogeneous etiologies and a range of phenotypic presentations. PCLD exhibits both autosomal or recessive dominant pattern of inheritance and is characterized by the progressive development of multiple cysts, isolated or associated with polycystic kidney disease, that appear more extensive in women. Cholangiocytes have primary cilia, functionally important organelles (act as mechanosensors) that are involved in both normal developmental and pathological processes. The absence of polycystin-1, 2, and fibrocystin/polyductin, normally localized to primary cilia, represent a potential mechanism leading to cyst formation, associated with increased cell proliferation and apoptosis, enhanced fluid secretion, abnormal cell–matrix interactions, and alterations in cell polarity. Proliferative and secretive activities of cystic epithelium can be regulated by estrogens either directly or by synergizing growth factors including nerve growth factor, IGF1, FSH and VEGF.The abnormalities of primary cilia and the sensitivity to proliferative effects of estrogens and different growth factors in PCLD cystic epithelium provide the morpho-functional basis for future treatment targets, based on the possible modulation of the formation and progression of hepatic cysts.     

Liver cysts in patients with autosomal dominant polycystic kidney disease

Liver cysts were found in 46 (29 per cent) of 158 patients over 10 years of age with documented autosomal dominant-type polycystic kidney disease (PKD) from 62 unrelated families. Hepatic cysts were not found in any patient at risk for PKD in whom renal cysts were not detected. The prevalence of liver cysts increased with advancing age and with declining rate of glomerular filtration. Results of clinical and laboratory studies indicate that polycystic liver disease in patients with autosomal dominant-type PKD is a benign condition, rarely, if ever, causing impaired liver function or portal hypertension.     

Polycystic liver disease without autosomal dominant polycystic kidney disease

Polycystic liver disease is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. The natural history and clinical manifestations of polycystic liver disease are based on the disease as it manifests in patients with autosomal dominant polycystic kidney disease (ADPKD). The occurrence of polycystic liver disease independently from polycystic kidney disease has been known for a long time. More recently, a gene for autosomal dominant polycystic liver disease has been identified on chromosome 19p 13.2-13.1. Isolated polycystic liver disease is underdiagnosed and genetically distinct from polycystic liver disease associated with ADPKD but with similar pathogenesis and clinical manifestations. We report here two men with polycystic liver disease no associated with ADPKD. Ultrasound and computed tomography imaging were effective in documenting the underlying lesions non-invasively.