Hepatoblastoma in a child with a paternally-inherited ABCC8 mutation and mosaic paternal uniparental disomy 11p causing focal congenital hyperinsulinism

Hepatoblastoma is a tumour of early childhood occurring in association with genetic syndromes including Beckwith–Wiedemann Syndrome (BWS) which results from dominance of paternally-inherited genes on chromosome 11p15. We report a child without clinical BWS, neonatally diagnosed with focal congenital hyperinsulinism resulting from a paternally-inherited recessively-acting mutation of ABCC8 and pancreatic paternal uniparental disomy (UPD) for chromosome 11p15, who subsequently developed hepatoblastoma. Genetic testing showed UPD 11p15 in the pancreas and liver but not systemically, allowing the expression of mutated ABCC8 in both tissues. Infants with large or multifocal forms of focal congenital hyperinsulinism may be at risk of BWS-like tumours due to mosaic UPD despite negative whole-blood and buccal DNA testing and tumour surveillance should be considered for this minority.     

Beckwith-Wiedemann syndrome and uniparental disomy 11p: fine mapping of the recombination breakpoints and evaluation of several techniques

Beckwith-Wiedemann syndrome (BWS) is a phenotypically and genotypically heterogeneous overgrowth syndrome characterized by somatic overgrowth, macroglossia and abdominal wall defects. Other usual findings are hemihyperplasia, embryonal tumours, adrenocortical cytomegaly, ear anomalies, visceromegaly, renal abnormalities, neonatal hypoglycaemia, cleft palate, polydactyly and a positive family history. BWS is a complex, multigenic disorder associated, in up to 90% of patients, with alteration in the expression or function of one or more genes in the 11p15.5 imprinted gene cluster. There are several molecular anomalies associated with BWS and the large proportion of cases, about 85%, is sporadic and karyotypically normal. One of the major categories of BWS molecular alteration (10-20% of cases) is represented by mosaic paternal uniparental disomy (pUPD), namely patients with two paternally derived copies of chromosome 11p15 and no maternal contribution for that. In these patients, in addition to the effects of IGF2 overexpression, a decreased level of the maternally expressed gene CDKN1C may contribute to the BWS phenotype. In this paper, we reviewed a series of nine patients with BWS because of pUPD using several methods with the aim to evaluate the percentage of mosaicism, the methylation status at both loci, the extension of the pUPD at the short arm and the breakpoints of recombination. Fine mapping of mitotic recombination breakpoints by single-nucleotide polymorphism-array in individuals with UPD and fine estimation of epigenetic defects will provide a basis for understanding the aetiology of BWS, allowing more accurate prognostic predictions and facilitating management and surveillance of individuals with this disorder.     

Benign hepatic lesions and orally administered contraceptives. A report of seven cases and a critical analysis of the literature.

A consecutive series of 12 benign hepatic lesions in women consisted of six cases of focal nodular hyperplasia and six cases of liver cell adenoma. Five of the six women with liver cell adenoma and two of the six with focal nodular hyperplasia had taken orally active contraceptive hormones. These few cases reflect a similar impression gained from a critical analysis of the literature, namely, that focal nodular hyperplasia may be unrelated to the oral administration of contraceptive hormones, whereas the increase in liver cell adenoma reported in recent years is probably related to such therapy. Two women with liver cell adenomas were asymptomatic six and four years after incomplete resection of the tumor. These are the longest intervals thus far reported for uncomplicated survival in incompletely resected liver cell adenoma.     

Transferrin receptor expression in benign tumours and in hepatoblastoma of the liver

To further investigate the possible usefulness of antitransferrin receptor staining in the differential diagnosis between benign and malignant primary liver tumours, we examined the transferrin receptor expression in ten cases of focal nodular hyperplasia, six of nodular regenerative hyperplasia, two adenomas and six hepatoblastomas. In focal nodular hyperplasia, the ductular structures were always positive and the parenchymal cells displayed three staining patterns of moderate intensity. In nodular regenerative hyperplasia there was scattered, relatively weak transferrin receptor staining. The tumour cells in the adenomas were only weakly positive. Three hepatoblastomas showed an intense staining of tumour cells; one was weakly positive and two were negative. A high intensity of transferrin receptor staining, as previously described in hepatocellular carcinomas, was only observed in the hepatoblastomas. This gives further credence to the usefulness of strong transferrin receptor expression in evaluating the malignant nature of tumour foci in liver biopsies.     

Autosomal recessive cystinuria caused by genome‐wide paternal uniparental isodisomy in a patient with Beckwith–Wiedemann syndrome

Approximately 20% of Beckwith–Wiedemann syndrome (BWS) cases are caused by mosaic paternal uniparental disomy of chromosome 11 (pUPD11). Although pUPD11 is usually limited to the short arm of chromosome 11, a small minority of BWS cases show genome‐wide mosaic pUPD (GWpUPD). These patients show variable clinical features depending on mosaic ratio, imprinting status of other chromosomes, and paternally inherited recessive mutations. To date, there have been no reports of a mosaic GWpUPD patient with an autosomal recessive disease caused by a paternally inherited recessive mutation. Here, we describe a patient concurrently showing the clinical features of BWS and autosomal recessive cystinuria. Genetic analyses revealed that the patient has mosaic GWpUPD and an inherited paternal homozygous mutation in SLC7A9. This is the first report indicating that a paternally inherited recessive mutation can cause an autosomal recessive disease in cases of GWpUPD mosaicism. Investigation into recessive mutations and the dysregulation of imprinting domains is critical in understanding precise clinical conditions of patients with mosaic GWpUPD.     

Non-neoplastic nodular lesions in the liver

The classical nomenclature and categorization of neoplastic and non-neoplastic nodular lesions of the liver are being revised due to the tremendous volume of information recently published on this issue. The diagnostic histopathology of non-neoplastic nodular (tumor-like) lesions of the liver that are recognizable in biopsied, surgically resected and autop sied livers is reviewed using current terminology. Generally, such nodules are infrequent and even rare in routine liver specimens. Non-neoplastic nodules include focal nodular hyperplasia, nodular regenerative hyperplasia, compensatory hyperplasia of the liver, pseudonodule of the liver demonstrable by angiography, partial nodular transformation, focal fatty change, nodular hepatic area shown by modified angiography, cirrhotic large regenerative nodule with variable atypia, anoxic pseudolobular necrosis, intrahepatic bile duct adenoma, biliary and mesenchymal hamartoma, and mesenchymal nodular lesions such as inflammatory pseu-dotumor and pseudolymphoma, pseudolipoma, peliosis hepatis, solitary necrotic nodule, and so on. Some of these develop preferentially in non-cirrhotic or cirrhotic livers, while others occur with similar prevalence in cirrhotic and non-cirrhotic livers. Some occur multiply or diffusely and others singly. As to the pathogenesis of these nodules, it is speculated that hyperplasia due to disturbed intrahepatic circulation or hormonal imbalance, preneoplastic characteristics, abnormal metabolic disturbance, hamartoma or focal necrobiotic processes, and infection have a role. Knowledge and awareness of these non-neoplastic nodular lesions are necessary for precise diagnosis and differentiation of these nodular lesions from neoplastic hepatic nodules.     

Focal nodular hyperplasia with calcification and ossification

We describe a 33-year-old woman with Crohn's disease, who presented with recurrent episodes of small bowel obstruction. A solitary liver lesion was discovered incidentally by abdominal ultrasound. Pathological examination of the resected specimen revealed features typical of focal nodular hyperplasia together with uncommon findings including calcification, ossification and fibrous obliteration of blood-filled "cysts", changes more commonly associated with regression in hepatic haemangiomas. This report strengthens the favoured hypothesis that a vascular malformation underlies the pathogenesis of focal nodular hyperplasia.     

Methylation analysis in tongue tissue of BWS patients identifies the (EPI)genetic cause in 3 patients with normal methylation levels in blood

The Beckwith–Wiedemann syndrome is caused by disturbed imprinting of genes at 11p15.5. Routine diagnostic testing for Beckwith–Wiedemann syndrome (BWS) includes methylation analysis of the imprinting centers ICR1 and ICR2 in DNA extracted from lymphocytes. In approximately 15% of BWS patients the diagnosis cannot be molecularly confirmed. In this study we determined the methylation status in resected tongue tissue of 11 BWS patients and compared this to the genetic defects found by routine diagnostic screening of blood lymphocytes. In all three patients with normal methylation levels in blood, aberrant methylation patterns were found in tongue tissue. In two patients a UPD was detected and the third case had hypermethylation of ICR1. This result shows that tissue specific mosaic (epi)genetic changes, not present in blood, is the underlying defect in at least a subset of BWS patients without a molecular diagnosis after standard genetic testing.     

皮质醇增多症——216例手术切除肾上腺的病理分析

目的 探讨皮质醇增多症的肾上腺改变特点以及形态与功能的关系。方法 收集２１６例皮质醇增多症患者手术切除的肾上腺标本,其中肾上腺皮质增生１６０例,肾上腺腺瘤５０例,肾上腺腺癌６例。用测微尺测量肾上腺皮质厚度,研究皮质厚度、重量与皮质醇增多症程度之间的关系,肾上腺形态改变特点,总结形态与功能的联系。结果 皮质醇增多症中以肾上腺皮质增生为最常见,其次为腺瘤,而腺癌则很少见。肾上腺皮质增生时皮质增厚,重量增加,并依轻、中、高度增生的顺序其皮质厚度及重量的均值逐渐增大,其中致密细胞所占比例及细胞肥大出现的频率也增多。复发标本中,增生程度大多高于原发标本,其致密细胞所占比例也比原发标本高。肾上腺腺瘤中致密细胞所占比例亦较高。肾上腺腺瘤和腺癌在大小、重量上有明显差别,前者最大者直径８ｃｍ,最重１０５ｇ,而腺癌大小直径为９．５     

Carcinoid tumors of the thymus and Cushing's syndrome: Clinicopathologic features and current best evidence regarding the cell of origin of these unusual neoplasms

It is uncertain whether thymic neuroendocrine tumors (NET) associated with Cushing's syndrome (CS) produce corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH) and whether the thymus contains ACTH and/or CRH cells that could originate NET.The clinicopathologic features of 5 typical (TC) and 6 atypical carcinoids (ATC), 10 additional non-neoplastic thymi, 6 adrenal glands with bilateral nodular hyperplasia and 8 adrenal cortical adenomas were reviewed. Representative slides were immunostained for ACTH and CRH. Four (36.4%) of the 11 patients had CS. The incidence of Masaoka stage IV was higher (p < 0.0001) in patients with ATC than TC. Only 2 (18.1%) of the 11 patients were alive at follow-up. Ten NET were CRH immunoreactive and 6 were ACTH immunoreactive. Thymic NET with CS exhibited stronger immunoreactivity for ACTH and CRH than those without CS. Non-neoplastic thymi exhibited scattered ACTH and CRH immunoreactive cells. Normal adrenal cortex and glands with bilateral nodular hyperplasia showed diffuse CRH immunoreactivity while adrenal adenomas showed no or only focal CRH immunoreactivity. Literature review showed no association between thymic NET and adrenal adenomas.The thymus contains CRH and ACTH immunoreactive cells that are probably the origin of thymic NET. Neoplasms associated with CS exhibit strong immunoreactivity for both hormones, suggesting that CRH probably plays a role in the pathogenesis of CS. As adrenals with bilateral nodular hyperplasia exhibit diffuse CRH immunoreactivity and adrenal cortical adenomas either lack this finding or show few immunoreactive cells, this marker may be useful to distinguish these lesions.     

Hamartomas and malformations of the liver

Hamartomas and malformations of the liver are rare and can lead to diagnostic challenges. Most present as mass lesions that can mimic true neoplasms of the liver on imaging and sometimes on histology, one example being focal nodular hyperplasia. The primary cell type in the hamartomas and malformations can be biliary, vascular, or hepatic. Biliary lesions include bile duct hamartomas and simple liver cysts. Other cystic malformations include the ciliated hepatic foregut cysts and mesothelial cysts. Vascular malformations include telangiectasias, arteriovenous malformations, and hereditary lymphedema. Malformations composed primarily of hepatocytes include accessory lobes and focal nodular hyperplasia. All of these entities are discussed, with a focus on the diagnostic histological findings.     

Hepatic stellate cells are activated around central scars of focal nodular hyperplasia of the liver--a potential mechanism of central scar formation

Focal nodular hyperplasia of the liver is typically accompanied by a central scar, but cases that lack the central scar are occasionally encountered. This study was performed to clarify the mechanism of the central scar formation in focal nodular hyperplasia. Immunohistochemical analysis was performed for liver sections of focal nodular hyperplasia with and without a central scar. For comparison, liver specimens of focal nodular hyperplasia-like nodules and nodular regenerative hyperplasia were used. Immunostaining showed that activated hepatic stellate cells, as determined by alpha-smooth muscle actin expression, were invariably observed in all cases of focal nodular hyperplasia with a central scar, whereas focal nodular hyperplasia without a central scar and nodular regenerative hyperplasia lacked hepatic stellate cell activation. Hepatic stellate cell activation in focal nodular hyperplasia with a central scar was accompanied by the expression of 8-hydroxy-2'-deoxyguanosine and inducible nitric oxide synthase in the liver. Expression of 8-hydroxy-2'-deoxyguanosine and inducible nitric oxide synthase was rarely seen in focal nodular hyperplasia without a central scar, focal nodular hyperplasia-like nodules, or nodular regenerative hyperplasia. Overexpression of vascular endothelial growth factor was also observed in focal nodular hyperplasia with a central scar. These results suggest that the central part of focal nodular hyperplasia suffers from hyperoxic conditions due to arterial hyperperfusion; and the resultant oxidative stress may activate hepatic stellate cells, leading to central scar formation. In addition, vascular endothelial growth factor may contribute to the proliferation of abnormal vessels as an angiogenic inducer.     

Mosaic paternal haploidy in a patient with pancreatoblastoma and Beckwith–Wiedemann spectrum

Pancreatoblastoma is a rare type of pancreatic cancer in children. Here, we describe a case in which Beckwith‐Wiedemann syndrome (BWS) was first suspected because of placental mesenchymal dysplasia. Although the baby did not show the stigmata characteristic of BWS or abnormal peripheral blood methylation, she developed a massive pancreatoblastoma 2 months later. She survived after partial excision of the tumor and chemotherapy. The methylation pattern of the pancreatoblastoma tissue was typical of BWS. Single nucleotide polymorphism (SNP) array analyzes revealed that the pancreatoblastoma tissue had genome‐wide loss of maternal alleles. Peripheral blood and nontumor pancreatic tissue showed normal biparental genomic contribution. Interphase fluorescence in situ hybridization analysis with centromeric probes for chromosomes 2 and 11 revealed haploid pancreatoblastoma cells, whereas the placental mesenchymal dysplasia tissue and nontumor pancreas tissue showed diploidy. SNP genotype analysis suggested the presence of mosaicism with the pancreatoblastoma tissue having a different paternal haplotype than that of the peripheral blood and nontumor pancreatic tissue. We report for the first time mosaic paternal haploidy associated with pancreatoblastoma. Babies with placental mesenchymal dysplasia, even those without a definitive diagnosis of BWS, need to be closely followed for the occurrence of embryonic tumors.     

A mixed hamartoma of the liver: light and electron microscopy

The gross, microscopic, and ultrastructural features of a mixed liver hamartoma occurring in a three month old infant are reported. The differentiation from two solid liver masses, focal nodular hyperplasia and liver cell adenoma is emphasized. Mesenchymal hamartomas, though usually cystic rather than solid masses, share the histologic feature of fibroductular tissue with mixed liver hamartomas and focal nodular hyperplasia. Only the mixed liver hamartoma has extremely broad fields of ductules and an embryonic type of hepatocyte at the ultrastructural level. These and other hepatic lesions show morphologic evidence of transformation of liver cells into biliary epithelial cells in association with vascular connective tissue.     

Androgenetic chimerism as an etiology for Beckwith–Wiedemann syndrome: diagnosis and management

PurposeBeckwith–Wiedemann syndrome (BWS) is a human genomic imprinting disorder characterized by lateralized overgrowth, macroglossia, abdominal wall defects, congenital hyperinsulinism, and predisposition to embryonal tumors. One of the molecular etiologies underlying BWS is paternal uniparental isodisomy of chromosome 11p15.5 (pUPD11). About 8% of pUPD11 cases are due to genome-wide paternal uniparental isodisomy (GWpUPD). About 30 cases of live-born patients with GWpUPD have been described, most of whom were mosaic and female. We present male patients with BWS due to GWpUPD, elucidate the underlying mechanism, and make recommendations for management.MethodsThree male patients with GWpUPD underwent clinical and molecular evaluation by single-nucleotide polymorphism (SNP) microarrays in different tissues. Previously published cases of GWpUPD were reviewed.ResultsSNP microarray demonstrated a GWpUPD cell population with sex chromosomes XX and biparental cell population with sex chromosomes XY, consistent with dispermic androgenetic chimerism.ConclusionSNP microarray is necessary to distinguish GWpUPD cases and the underlying mechanisms. The percentage of GWpUPD cell population within a specific tissue type correlated with the amount of tissue dysplasia. Males with BWS due to GWpUPD are important to distinguish from other molecular etiologies because the mechanism indicates risk for germ cell tumors and autosomal recessive diseases in addition to other BWS features.     

Focal hyperplastic hepatocellular nodules in hepatic venous outflow obstruction: a clinicopathological study of four patients and 24 nodules

AIMS: In hepatic venous outflow obstruction (Budd-Chiari syndrome), focal hepatocellular nodules are occasionally discovered showing variable morphology. These could be interpreted either as neoplastic (adenoma), regenerative (large regenerative nodule) or reactive to abnormal vasculature (focal nodular hyperplasia). The aim of this study was to investigate their histogenesis and to determine their morphological characteristics in order to provide diagnostic criteria. MATERIAL AND METHODS: Twenty-four hepatocellular nodules were studied, which were found in three explanted livers and in one additional autopsied liver from four patients with Budd-Chiari syndrome. As controls, we employed three explanted livers without nodules from patients who also suffered from Budd-Chiari syndrome. We attempted to classify the nodules morphologically as either adenoma-like, large regenerative nodule or focal nodular hyperplasia-like, using criteria from the literature. RESULTS: Out of the four cases, we observed two nodules in each of two livers, five in the third one and up to 15 in the remaining one. The size of the nodules ranged from 4 to 25 mm. Eleven nodules could be categorized as large regenerative nodules (two of them with a central scar), seven as focal nodular hyperplasia-like and six as adenoma-like. Some large regenerative nodules showed proliferated arteries with muscular hyperplasia similar to that seen in focal nodular hyperplasia. In the individual livers we could find nodules of various categories. Patchy or diffuse monoacinar regeneration was seen in most cases (six out of seven cases) in the macroscopically non-nodular liver parenchyma. In addition, thrombotic obstruction of portal vein branches was present in all except one of the nodular cases, but in none of the controls. Thus, it appears that portal venous obstructions are frequently, but not invariably associated with the development of nodules. CONCLUSIONS: The hepatocellular nodules seen in livers from patients with Budd-Chiari syndrome share morphological characteristics with large regenerative nodules, focal nodular hyperplasia and hepatocellular adenomas. Their multiplicity, the existence of mixed lesions, the frequent hepatocellular regenerative background as well as the frequently associated portal venous obstructions suggest that these nodules are regenerative in nature and conditioned by an uneven blood perfusion throughout the liver. In their differential diagnosis, the clinicopathological context in which they occur is of paramount importance and should allow recognition that those resembling adenomas may not be true neoplasms.     

Focal nodular hyperplasia of the liver: An electron microscopic study of the vascular lesions

Localized myointimal proliferation with narrowing of blood vessels is frequently seen associated with focal nodular hyperplasia of the liver. The apparent increase in the incidence of focal nodular hyperplasia in women may be associated with the oral use of contraceptive medications, and it has been suggested that the nodules could be areas of focal cirrhosis following liver infarction. A light and electron microscopic study was undertaken to try to determine the pathogenesis of the vascular abnormalities. The observation of intravascular coagulation, recurrent endothelial damage, and myointimal proliferation about bifurcations suggests that the changes could be produced by repeated platelet-fibrin aggregate embolic injury.     

Adrenal myelolipomas composed with adrenal nodular hyperplasia in the same gland

Adrenal myelolipoma is a benign neoplasm composed of an admixture of hemopoietic elements and mature adipose tissue. The incidence of adrenal myelolipoma is reported as between 4% and 5% of adrenal incidentaloma. The association of an adrenal myelolipoma and adrenal nodular hyperplasia or adrenal adenoma is rare. Four cases of adrenal myelolipomas in the material of 702 incidentally discovered adrenal lesions treated in our center are presented in this paper (in a group of 294 operated patients). Two myelolipomas have been reported as isolated adrenal masses and two - in association with adrenocortical nodular hyperplasia.     

P-450c17mRNA在原发性醛固酮增多症肾上腺皮质腺瘤及增生组织中的表达及意义

为探讨细胞色素P-450 c17 -羟化酶(P-450 c17 )mRNA 在原发性醛固酮增多症(原醛)肾上腺皮质腺瘤（APA）及增生组织中的表达及其意义，采用 Northern Blot 法对7 例APA 组织，3 例结节样增生组织，7 例正常肾上腺组织，1 例腹壁骨骼肌组织P-450 c17 mRNA 的表达水平进行检测。结果显示P-450 c17 mRNA 在原醛APA组织与正常肾上腺组织中的表达有显著性差异P<0.05。P-450 c17 mRNA 在原醛肾上腺皮质增生组织与正常肾上腺组织中的表达、在原醛APA 组织与原醛肾上腺皮质增生组织中的表达相似。提示P-450 c17 mRNA 在APA 组织中的表达降低很可能是原醛APA 组织分泌过多醛固酮(ALD)的分子生物学原因。     

Focal nodular hyperplasia of the liver, benign hepatomas, oral contraceptives and other drugs affecting the liver.

Due to the claim of an association between focal nodular hyperplasia of the liver, benign hepatomas and oral contraceptives, the files in the departments of pathology at the university hospitals in Lund and Malm? were examined for these two diagnoses made since 1945 and 1957, respectively. 26 cases of focal nodular hyperplasia of the liver and 7 benign hepatomas were found, 18 and 2, respectively, in women. Since 1963, the year before oral contraceptives were introduced in Sweden, focal nodular hyperplasia has been diagnosed in 8 women in the reproductive period of life; 4 of these had taken oral contraceptives. The 4 diagnoses were established in 1972-1974. At most, 25 per cent of Swedish females between the ages of 15 and 44 years have been on oral contraceptives. The Swedish series of 28 patients with focal nodular hyperplasia comprised 3 epileptics and 3 diabetics. At least two of the epileptics had been treated with barbiturates and/or hydantoins. The prevalence of drug-treated epilepsy in Sweden is 0.4-0.5 per cent, and of diabetes about 2 per cent. The possible aetiological role of drugs provoking an increase of the smooth-surfaced endoplasmic reticulum of the liver and proliferation of vascular fibrous tissue in a part of the liver which preveiously may have been damaged by vascular disturbances or trauma, is considered. No relationship between benign hepatomas and drugs was found. The observations support the notion that oral contraceptives may be of aetiological importance in the development of focal nodular hyperplasia of the liver, although the material is too small for epidemiological and statistical analysis.