Biopsy-proven Hepatocellular Carcinoma in a 53-year-old Woman With Arginase Deficiency.

Arginase 1 deficiency, the least common urea cycle disorder, commonly presents with childhood-onset spastic paraplegia, progressive neurologic impairment, epilepsy, and developmental delay or regression. Biopsy-proven cirrhosis and hepatocellular carcinoma diagnosed via clinical and imaging studies (but without biopsy confirmation) have been previously reported. We report, herein, a case of a 53-year-old woman with arginase 1 deficiency who developed symptoms of "abdominal bloating." Imaging studies (ultrasound and magnetic resonance imaging) demonstrated 2 dominant hepatic masses, measuring 5.9 cm and 5.7 cm in greatest dimensions and located in hepatic segments 5 and 6, respectively. Core biopsies of the lesions demonstrated well-differentiated hepatocellular carcinoma. Immunohistochemistry performed on the segment 5 lesion was negative for arginase 1. This report represents, to the best of our knowledge, the first case of biopsy-proven hepatocellular carcinoma in an individual with arginase 1 deficiency.

Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation.

BACKGROUND. Orthotopic liver transplant (OLT) is the primary therapy for end-stage liver disease and acute liver failure. However, ischemia/reperfusion injury (IRI) can severely compromise allograft survival. To understand the evolution of immune responses underlying OLT-IRI, we evaluated longitudinal cytokine expression profiles from adult OLT recipients before transplant through 1 month after transplant. METHODS. We measured the expression of 38 cytokines, chemokines, and growth factors in preoperative and postoperative recipient circulating systemic blood (before transplant and 1 day, 1 week, and 1 month after transplant) and intraoperative portal blood (before and after reperfusion) of 53 OLT patients and analyzed this expression in relation to biopsy-proven IRI (n = 26 IRI+; 27 IRI-), clinical liver function tests early (days 1-7) after transplant, and expression of genes encoding cytokine receptors in biopsies of donor allograft taken before and after reperfusion. RESULTS. Bilirubin and arginine transaminase levels early after transplant correlated with IRI. Fourteen cytokines were significantly increased in the systemic and/or portal blood of IRI+ recipients that shifted from innate to adaptive-immune responses over time. Additionally, expression of cognate receptors for 10 of these cytokines was detected in donor organ biopsies by RNAseq. CONCLUSION. These results provide a mechanistic roadmap of the early immunological events both before and after IRI and suggest several candidates for patient stratification, monitoring, and treatment. FUNDING. Ruth L. Kirschstein National Research Service Award T32CA009120, Keck Foundation award 986722, and a Quantitative & Computational Biosciences Collaboratory Postdoctoral Fellowship.

Gadoxetate Disodium-Enhanced MRI to Differentiate Dysplastic Nodules and Grade of Hepatocellular Carcinoma: Correlation With Histopathology.

OBJECTIVE: The objective of our study was to determine quantitative differences to differentiate low-grade from high-grade dysplastic nodules (DNs) and low-grade from high-grade hepatocellular carcinomas (HCCs) using gadoxetate disodium-enhanced MRI. MATERIALS AND METHODS: A retrospective study of 149 hepatic nodules in 127 consecutive patients who underwent gadoxetic acid-enhanced MRI was performed. MRI signal intensities (SIs) of the representative lesion ROI and of ROIs in liver parenchyma adjacent to the lesion were measured on unenhanced T1-weighted imaging and on dynamic contrast-enhanced MRI in the arterial, portal venous, delayed, and hepatobiliary phases. The relative SI of the lesion was calculated for each phase as the relative intensity ratio as follows: [mass SI / liver SI]. RESULTS: Of the 149 liver lesions, nine (6.0%) were low-grade DNs, 21 (14.1%) were high-grade DNs, 83 (55.7%) were low-grade HCCs, and 36 (24.2%) were high-grade HCCs. The optimal cutoffs for differentiating low-grade DNs from high-grade DNs and HCCs were an unenhanced to arterial SI of ≥ 0 or a relative SI on T2-weighted imaging of ≤ 1.5, with a positive predictive value (PPV) of 99.2% and accuracy of 88.6%. The optimal cutoffs for differentiating low-grade HCCs from high-grade HCCs were a relative hepatobiliary SI of ≤ 0.5 or a relative T2 SI of ≥ 1.5, with a PPV of 81.0% and an accuracy of 60.5%. CONCLUSION: Gadoxetate disodium-enhanced MRI allows quantitative differentiation of low-grade DNs from high-grade DNs and HCCs, but significant overlap was seen between low-grade HCCs and high-grade HCCs.

Splenic hamartomas in Alagille syndrome: case report and literature review.

Alagille syndrome is a rare autosomal dominant disorder with characteristic findings of paucity of intrahepatic bile ducts, congenital heart disease, and vertebral, ocular, and renal abnormalities. We present a unique autopsy case of an 18-year-old female with Alagille syndrome and splenic hamartomas. Autopsy findings included growth restriction, Tetralogy of Fallot, paucity of intrahepatic bile ducts, end-stage renal disease with mesangiolipidosis, and splenomegaly with two well-circumscribed, splenic tumors. Histologic findings of the splenic tumors revealed disorganized vascular channels lined by cells without cytologic atypia. Immunohistochemical analysis demonstrated CD8(+)CD31(+) endothelial cells, consistent with splenic hamartomas. In summary, Alagille syndrome is a rare genetic disorder characterized by JAG1 mutations and disrupted Notch signaling. Review of the literature highlights the importance of Notch signaling in vascular development and disorders. However, to our knowledge this is the first description of splenic hamartomas in Alagille syndrome.

Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features.

Hepatocellular carcinomas exhibit heterogeneous morphologies by routine light microscopy. Although some morphologies represent insignificant variations in growth patterns, others may represent unrecognized subtypes of hepatocellular carcinoma. Identification of these subtypes could lead to separation of hepatocellular carcinomas into discrete groups with unique underlying genetic changes, prognosis, or therapeutic responses. In order to identify potential subtypes, two pathologists independently screened a cohort of 219 unselected hepatocellular carcinoma resection specimens and divided cases into potential subtypes. One of these promising candidate subtypes was further evaluated using histological and molecular techniques. This subtype was characterized by a unique and consistent set of histological features: smooth chromophobic cytoplasm, abrupt focal nuclear anaplasia (small clusters of tumor cells with marked nuclear anaplasia in a background of tumor cells with bland nuclear cytology), and scattered microscopic pseudocysts--we designate this variant as 'chromophobe hepatocellular carcinoma with abrupt anaplasia'. Thirteen cases were identified (6% of all hepatocellular carcinomas), including 6 men and 7 women with an average age of 61 years. Six cases occurred in cirrhotic livers. Serum AFP was elevated in 6 out of 10 cases. There were a variety of underlying liver diseases, but cases were enrichment for chronic hepatitis B, P=0.006. Interestingly, at the molecular level, this variant was strongly associated with the alternative lengthening of telomere (ALT) phenotype by telomere FISH. ALT is a telomerase-independent mechanism of telomere maintenance and is found in approximately 8% of unselected hepatocellular carcinomas. In contrast, 11/12 (92%) of the cases of chromophobe hepatocellular carcinoma with abrupt anaplasia were ALT-positive. In summary, we propose that chromophobe hepatocellular carcinoma with abrupt anaplasia represents a new subtype of hepatocellular carcinoma with unique morphological and molecular features.

Hepatitis C-associated cryoglobulinemic glomerulonephritis with crystalline deposits.

Infection with hepatitis C virus has been associated with a number of extrahepatic manifestations, including kidney disease. Of the glomerular pathologic states described with hepatitis C virus infection, cryoglobulinemic glomerulonephritis is the most prevalent. On kidney biopsy, cryoglobulinemic glomerulonephritis has a variable appearance, with a membranoproliferative pattern of injury as the most common light microscopic finding. Ultrastructurally, curved and paired microtubules are the most characteristic finding, but these also can be variable. We present a case of cryoglobulinemic glomerulonephritis with distinct and highly unusual ultrastructural findings.

Irreversible electroporation in porcine liver: acute computed tomography appearance of ablation zone with histopathologic correlation.

OBJECTIVE: The objective of this study was to define acute computed tomography (CT) characteristics of ablation zone created by irreversible electroporation (IRE) in porcine liver, with histopathologic correlation. METHODS: Twenty-three IRE ablation zones were created in 4 Yorkshire pig livers percutaneously under image guidance. A prototype generator was used (Ethicon Endo-surgery, Cincinnati, Ohio). Variable spacing of paired electrodes between 1 and 2.0 cm was used. Contrast-enhanced multiphasic CT scans were obtained. Pigs were killed after 5 to 6 hours for gross pathology sectioning with routine and vital histological stains. Computed tomography images were analyzed using 3-dimensional software, and ablation zone size measured on CT was correlated with pathologically determined size. RESULTS: Nineteen of 19 ablation zones created with up to 1.5-cm spacing showed fusion between individual ablation zones generated by each electrode. Ablation zones were isodense precontrast and hypodense to liver postcontrast, with best delineation in the portal phase. Nine of these had nondistorted circumferential margins on both CT and gross pathology suitable for correlation, and among these, size measurements on CT were closely correlated with pathologically determined ablation zone size. Most importantly, on the delayed venous phase, there is internal enhancement within the ablation zone itself, except for small perielectrode zones that remained hypodense. On histopathology, IRE ablation zones showed preserved microvasculature with congestion of sinusoids, except for small perielectrode zones where coagulative changes were suggested. CONCLUSION: Portal phase contrast-enhanced CT scans correlate well with liver IRE ablation size and shape on histopathology.

Assessment of hepatic steatosis by transplant surgeon and expert pathologist: a prospective, double-blind evaluation of 201 donor livers.

An accurate clinical assessment of hepatic steatosis before transplantation is critical for successful outcomes after liver transplantation, especially if a pathologist is not available at the time of procurement. This prospective study investigated the surgeon's accuracy in predicting hepatic steatosis and organ quality in 201 adult donor livers. A steatosis assessment by a blinded expert pathologist served as the reference gold standard. The surgeon's steatosis estimate correlated more strongly with large-droplet macrovesicular steatosis [ld-MaS; nonparametric Spearman correlation coefficient (rS ) = 0.504] versus small-droplet macrovesicular steatosis (sd-MaS; rS = 0.398). True microvesicular steatosis was present in only 2 donors (1%). Liver texture criteria (yellowness, absence of scratch marks, and round edges) were mainly associated with ld-MaS (variance = 0.619) and were less associated with sd-MaS (variance = 0.264). The prediction of ≥30% ld-MaS versus <30% ld-MaS was excellent when liver texture criteria were used (accuracy = 86.2%), but it was less accurate when the surgeon's direct estimation of the steatosis percentage was used (accuracy = 75.5%). The surgeon's quality grading correlated with the degree of ld-MaS and the surgeon's steatosis estimate as well as the incidence of poor initial function and primary nonfunction. In conclusion, the precise estimation of steatosis remains challenging even in experienced hands. Liver texture characteristics are more helpful in identifying macrosteatotic organs than the surgeon's actual perception of steatosis. These findings are especially important when histological assessment is not available at the donor's hospital.

Histopathology of de novo autoimmune hepatitis.

De novo autoimmune hepatitis (DAIH) is a well-recognized complication of pediatric liver transplantation (LT). The diagnosis is largely based on elevated liver function test results and the development of autoimmune antibodies. The histology of DAIH was first described in 1998. We present detailed histological data from the largest series to date of pretreatment and posttreatment biopsy samples from pediatric LT patients with DAIH. The histological evaluation included first an assessment of the predominant pattern of injury (hepatitis, rejection, or bile duct obstruction). Then, the necroinflammatory activity (interface, lobular, and perivenular), plasma cell density, rejection activity index, and fibrosis were scored. Seventy of 685 pediatric patients (10.2%) who underwent LT developed DAIH according to clinical and biopsy findings. Fifty-one pretreatment biopsy samples and 38 posttreatment biopsy samples were available for a retrospective review. The predominant pattern of injury (hepatitis, rejection, or bile duct obstruction) was determined, and biopsy samples were scored for the necroinflammatory activity (interface, lobular, and perivenular), plasma cell density, rejection activity index, and fibrosis. The most common pattern of injury was lobular hepatitis, which was frequently unaccompanied by interface necroinflammatory activity or prominent plasma cell infiltrates. Seven of the 51 cases had features strongly suggestive of acute rejection. Posttreatment biopsy samples showed a reduction in the degree of necroinflammatory activity and plasma cell infiltrates. In most patients, the degree of fibrosis was stable or had regressed. Because the histological features of DAIH are variable and nonspecific, a high index of suspicion and correlation with autoimmune antibodies are necessary to establish the diagnosis. In the majority of patients with DAIH, treatment appears to yield good clinical outcomes and histological improvements.

Regulated hepatic reperfusion mitigates ischemia-reperfusion injury and improves survival after prolonged liver warm ischemia: a pilot study on a novel concept of organ resuscitation in a large animal model.

BACKGROUND: Ischemia-reperfusion injury (IRI) can occur during hepatic surgery and transplantation. IRI causes hepatic mitochondrial and microcirculatory impairment, resulting in acute liver dysfunction and failure. We proposed a novel strategy of regulated hepatic reperfusion (RHR) to reverse the cellular metabolic deficit that incurred during organ ischemia by using a substrate-enriched, oxygen-saturated, and leukocyte-depleted perfusate delivered under regulated reperfusion pressure, temperature, and pH. We investigate the use of RHR in mitigating IRI after a prolonged period of warm ischemia. METHODS: Using a 2-hour liver warm ischemia swine model, 2 methods of liver reperfusion were compared. The control group (n = 6) received conventional reperfusion with unmodified portal venous blood under unregulated reperfusion pressure, temperature, and pH. The experimental group (n = 6) received RHR. We analyzed the effects of RHR on post-reperfusion hemodynamic changes, liver function, and 7-day animal survival. RESULTS: RHR resulted in 100% survival compared with 50% in the control group (p = 0.05). Post-reperfusion syndrome was not observed in the RHR group, but it occurred in 83% of the control group. RHR resulted in a lesser degree of change from baseline serum alanine aminotransferase levels, aspartate aminotransferase, and lactate dehydrogenase after reperfusion compared with the control group. Histopathologic evaluation showed minimal ischemic changes in the RHR group, whereas a considerable degree of coagulative hepatocellular necrosis was observed in the control group. CONCLUSIONS: Regulated hepatic reperfusion mitigates IRI, facilitates liver function recovery, and improves survival after a prolonged period of hepatic warm ischemia. This novel strategy has potential applicability to clinical hepatic surgery and liver transplantation when marginal grafts are used.

Interleukin-22: implications for liver ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion injury (IRI) is common in general surgery and organ transplantation, and in the case of liver, it triggers proinflammatory innate immune cascade and hepatic necrosis, leading to increased incidence of early and late organ rejection. Interleukin (IL)-22, an inducible cytokine of T-cell origin and a member of the IL-10 superfamily, acts on target tissues through IL-22 receptor (IL-22R1). METHODS: Partial hepatic warm ischemia was induced in C57Bl/6 wild-type (WT) and type 1 interferon receptor-deficient (KO) mice for 90 min followed by 6 to 24 hr of reperfusion. WT mice were treated at 30 min before the ischemia insult with recombinant IL-22 or anti-IL-22 neutralizing antibody; phosphate-buffered saline and IgG served as respective controls. RESULTS: IL-22 was detected at 24 hr but not 6 hr of liver IRI. The expression of IL-22R1 was increased by 6 hr of reperfusion in WT but not type 1 interferon receptor KO mice that were protected from IRI. Treatment of WT mice with recombinant IL-22 decreased serum aspartate aminotransferase levels, ameliorated cardinal histological features of IR damage (Suzuki's score) and diminished leukocyte sequestration, along with the expression of IL-22R1 and pro-inflammatory cytokines. IL-22 antibody did not appreciably affect IRI but increased IL-22R1 transcription in the liver. Administration of IL-22 protein exerted hepatoprotection by STAT3 activation. CONCLUSIONS: This is the first report investigating immune modulation by T-cell-derived IL-22 in liver injury caused by warm ischemia and reperfusion. Treatment with IL-22 protein may represent a novel therapeutic strategy to prevent liver IRI in transplant recipients.

Expression of glypican-3 in undifferentiated embryonal sarcoma and mesenchymal hamartoma of the liver.

Glypican-3 (GPC3) is an oncofetal protein that has been demonstrated to be a useful diagnostic immunomarker for hepatocellular carcinoma and hepatoblastoma. Its expression in mesenchymal tumors of the liver, particularly undifferentiated embryonal sarcoma (UES) and mesenchymal hamartoma (MH), has not been investigated. In this study, a total of 24 UESs and 18 MHs were immunohistochemically stained for GPC3 expression. The results showed cytoplasmic staining for GPC3 in 14 (58%) UESs, of which 6 exhibited diffuse immunoreactivity and the remaining 8 showed focal positivity. The patients with GPC3-positive UES tended to be younger (mean 18 years; median 11 years) than those with GPC3-negative tumors (mean 39.4 years; median 27 years), although the difference did not reach statistical significance (P = .06). Eight MHs also exhibited GPC3 immunoreactivity (44%; 4 diffuse and 4 focal). Positive staining in all 8 cases was primarily seen in entrapped nonlesional hepatocytes with a canalicular and cytoplasmic staining pattern. In only 4 cases (22%) was GPC3 immunoreactivity also observed in the mesenchymal component. The patients with positive staining also tended to be younger (mean 2.6 years; median 1.1 years) compared with those with negative staining (mean 16.3 years; median 4.5 years), but the difference was not statistically significant (P = .15). Our data demonstrate that GPC3 is expressed in a subset of UES and MH of the liver. Caution should thus be exercised when evaluating a GPC3-expressing hepatic neoplasm, particularly on a needle biopsy when the differential diagnosis includes poorly differentiated hepatocellular carcinoma or hepatoblastoma.

Total parenteral nutrition therapy and liver injury: a histopathologic study with clinical correlation.

Total parenteral nutrition (TPN) therapy is a well-recognized cause of liver injury. The histologic changes attributed to TPN in the literature vary widely. In this study, we describe the histopathologic changes associated with TPN therapy and relate these changes to various clinical parameters. We conducted a retrospective study of 89 patients who underwent biopsy or liver transplantation while on TPN. We report that (1) ductopenia, a previously unreported finding, is seen in a significant number of patients on TPN. It is more frequently seen in patients with low stage of fibrosis and may have an inverse relationship with the length of therapy; (2) Perivenular fibrosis is a feature frequently seen in patients with high-stage portal fibrosis. In fact, we find the combination of portal and perivenular fibrosis to be a characteristic of TPN injury; (3) Infants are more susceptible to TPN-related hepatocellular injury, are more likely to develop fibrosis, and progress to high-stage fibrosis more rapidly than older children and adults; (4) Cholestasis, although more common in infants, is the most common pathologic finding in all age groups; (5) Steatosis is more commonly seen in older children and adults than in infants; (6) Progression to fibrosis in infants may be dependent on the length of therapy and the underlying disease for which TPN is administered; and (7) Clinical markers of liver injury (eg, elevated liver enzymes) do not predict the degree of hepatocellular injury or fibrosis, and therefore, serial biopsies may be indicated for patients on TPN therapy.

Apolipoprotein A1 and C-terminal fragment of α-1 antichymotrypsin are candidate plasma biomarkers associated with acute renal allograft rejection.

BACKGROUND: Current diagnostic methods of renal allograft rejection are neither sensitive nor specific. Needle biopsies are invasive and associated with patient morbidity. Thus, it is desirable to develop noninvasive tests to predict and diagnose rejection. METHODS: Using a case-control approach, surface-enhanced laser desorption/ionization time-of-flight mass spectrometry was used to identify plasma proteins associated with renal allograft rejection. From each rejection patient (n=16), two plasma samples (one near the biopsy date and the other at a time postbiopsy) were compared. Biopsy-confirmed nonrejection patients (n=48) were further analyzed as controls. Antibody-based quantitative enzyme-linked immunosorbent assay was performed to validate candidate biomarker apolipoprotein A1 (Apo A1) in a subset of the original and a second cohort of biopsy-confirmed rejection (n=40) and nonrejection (n=70) patients. RESULTS: Twenty-two proteins/peptides showed significant differences between rejection and postrejection samples. Peptides 5191 Da and 4467 Da detected rejection with 100% sensitivity and 94% specificity. The 4467 Da peptide was identified as the C-terminal fragment of α-1 antichymotrypsin and a 28 kDa protein was determined as Apo A1. Both protein levels were significantly lower at rejection compared with postrejection. Protein levels of nonrejection patients were similar to the postrejection samples. Apo A1 enzyme-linked immunosorbent assay results showed significantly lower Apo A1 levels (P=0.001 for the original and P=4.14E-11 for the second cohort) at the time of rejection compared with nonrejection which coincides with the SELDI findings. CONCLUSIONS: Together α-1 antichymotrypsin, Apo A1, and the unidentified 5191 Da peptide provide a plasma molecular profile, and this is associated with acute cellular renal allograft rejection.

Type I interferon pathway mediates renal ischemia/reperfusion injury.

BACKGROUND: Ischemia/reperfusion (I/R) injury is a common cause of acute renal failure after kidney transplantation. This study was designed to analyze the role of type I interferon (IFN) signaling downstream of Toll-like receptor 2/Toll-like receptor 4 activation in the mechanism of I/R-triggered kidney damage. METHODS: Local warm ischemia was induced in groups wild-type (WT) and type I IFN receptor (IFNAR)-/- mice (C57BL/6) by clamping both kidney pedicles for 45 min. Mice were killed at 5/24/72 hr after reperfusion for serum and kidney sampling. RESULTS: At 5 hr, serum creatinine and blood urea nitrogen levels were markedly reduced in IFNAR-/- mice as compared with WT. By 24 hr after reperfusion, both serum creatinine/blood urea nitrogen in WT increased further, whereas those in IFNAR-/- mice remained comparable with sham controls. Histological analyses showed significantly higher percentage of tubules in the outer medulla displaying cell necrosis, loss of the brush border, cast formation and tubular dilatation in WT mice, as compared with IFNAR-/-. Immunohistology revealed increased neutrophil and macrophage infiltration in the outer medulla in WT mice. The expression of proinflammatory tumor necrosis factor-α, interleukin-1, interleukin-6, and CXCL-2 was markedly reduced selectively in IFNAR-/- mice. Finally, terminal deoxynucleotide transferase-mediated dUTP nick-end labeling analysis showed significantly decreased frequency of apoptotic tubular epithelial cells in IFNAR-deficient mice, as compared with WT. CONCLUSION: This is the first report, which documents the key role of type I IFN signaling in the mechanism of kidney I/R injury. Type I IFN may thus serve as a novel target for the therapy against renal I/R injury.

Predictive index for tumor recurrence after liver transplantation for locally advanced intrahepatic and hilar cholangiocarcinoma.

BACKGROUND: Current criteria for orthotopic liver transplantation (OLT) for cholangiocarcinoma (CCA) remain restricted to early stage and small hilar tumors, excluding patients with locally advanced intrahepatic and hilar CCA for potential cure. The present study was undertaken to define a prognostic scoring system for risk stratification of patients with intrahepatic and hilar CCA who might benefit from OLT and to allow expansion of current OLT criteria. STUDY DESIGN: We conducted a retrospective review of 40 patients who underwent OLT for locally advanced intrahepatic and hilar CCA at our center between February 1985 and June 2010. Median follow-up was 3 years. Independent risk factors for tumor recurrence after OLT were identified using the Cox model and were assigned risk score points. Points were summed and assigned to predictive index categories: 0 to 3 for low risk, 4 to 7 for intermediate risk, and 8 to 15 for high risk. RESULTS: Seven multivariate factors predictive for tumor recurrence included multifocal tumor, perineural invasion, infiltrative growth pattern, lack of neoadjuvant and adjuvant therapy, history of primary sclerosing cholangitis, hilar tumors, and lymphovascular invasion. The 5-year tumor recurrence-free patient survival was significantly higher in low-risk (78%) compared with intermediate- (19%) and high-risk (0%) groups (p < 0.001); survival benefit was also seen in intermediate- compared with high-risk groups. CONCLUSIONS: This model was highly predictive of long-term outcomes after OLT for locally advanced intrahepatic and hilar CCA and can be applied clinically for risk stratification of patients considered for OLT. Long-term disease recurrence-free survival was excellent in low-risk and acceptable in intermediate-risk groups, justifying the expansion of liver transplant criteria for treatment of this challenging malignancy.

CT and MRI improve detection of hepatocellular carcinoma, compared with ultrasound alone, in patients with cirrhosis.

BACKGROUND & AIMS: In patients with cirrhosis, hepatocellular carcinoma (HCC) is detected by ultrasound (US), computed tomography (CT), or magnetic resonance imaging (MRI); US is recommended for screening and surveillance. We performed a retrospective analysis of the abilities of these cross-sectional imaging modalities to detect HCC. METHODS: We analyzed data from 638 consecutive adult patients with cirrhosis who received liver transplants within 6 months of imaging at a tertiary care institution. Imaging reports and serum alpha-fetoprotein levels were compared with results from pathology analysis of explants as the reference standard. Sensitivities of US, CT, and MRI were calculated overall and in defined size categories. False-positive imaging results and patient-based specificities were evaluated. RESULTS: Of the 638 patients, 225 (35%) had HCC, confirmed by pathology analysis of liver explants. In 23 cases, the lesions were infiltrative or extensively multifocal. In the remaining 202 explants (337 numerable, discrete nodules), respective lesion-based sensitivities of US, CT, and MRI were 46%, 65%, and 72% overall and 21%, 40%, and 47% for small (<2 cm) HCC. The sensitivity of US increased with the availability of CT or MRI data (P = .049); sensitivity values were 62% and 85% for lesions 2-4 and ≥ 4 cm, respectively. Patient-based specificities of US, CT, and MRI were 96%, 96%, and 87%, respectively. CONCLUSIONS: US, CT, and MRI did not detect small HCC lesions with high levels of sensitivity, although CT and MRI provide substantial improvements over unenhanced US in patients with cirrhosis who received liver transplants.

Diffuse cirrhosis-like hepatocellular carcinoma: a clinically and radiographically undetected variant mimicking cirrhosis.

A rare variant of hepatocellular carcinoma (HCC) is encountered that produces small cirrhosis-like nodules diffusely throughout the liver (CL-HCC), instead of a larger evident mass. This pattern remains undetected as carcinoma clinically and radiographically and is unexpectedly discovered after liver transplantation in the explanted native liver. We studied 10 such cases (9 males and 1 female, age 35 to 80 y) from 4 medical centers. The pretransplant clinical, laboratory, and radiographical studies were reviewed to determine the cause and stage of liver disease, alpha-fetoprotein (AFP) levels, and detectability of a mass on imaging. All 10 cases had underlying cirrhosis of varying etiology [3 hepatitis C virus (HCV), 3 alcoholic hepatitis, 1 hepatitis B virus, 1 autoimmune, and 2 mixed HCV/alcoholic hepatitis and hemochromatosis/HCV] and underwent orthotopic liver transplantation with no preoperative clinical suspicion of HCC. Ultrasound and/or dynamic imaging showed cirrhosis and no definite HCC. AFP levels were only mildly elevated in only 3 of 10 cases (144, 150, and 252 ng/mL). Grossly, there were innumerable (from about 20 to >1000) small CL-HCC nodules (0.2 to 0.6 cm) scattered among cirrhotic nodules. Histologically, these were well or moderately differentiated HCC, often with pseudoglandular pattern, perinodular sclerotic rims, cholestasis, frequent Mallory bodies, and small vessel invasion. In addition to the usual HCC immunophenotype, CL-HCC showed frequent ubiquitin and cytoplasmic and membranous CD10 positivity, relatively low Ki-67 proliferative index and absence of AFP immunohistochemically. CL-HCC warrants recognition as a unique HCC variant that evades pretransplant detection despite massive tumor burden, mimics cirrhotic nodules, and shows some uncommon pathologic and immunophenotypical characteristics.