2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Human monoclonal antibody MBL-HCV1 delays HCV viral rebound following liver transplantation: a randomized controlled study.

Rapid allograft infection complicates liver transplantation (LT) in patients with hepatitis C virus (HCV). Pegylated interferon-α and ribavirin therapy after LT has significant toxicity and limited efficacy. The effect of a human monoclonal antibody targeting the HCV E2 glycoprotein (MBL-HCV1) on viral clearance was examined in a randomized, double-blind, placebo-controlled pilot study in patients infected with HCV genotype 1a undergoing LT. Subjects received 11 infusions of 50 mg/kg MBL-HCV1 (n=6) or placebo (n=5) intravenously with three infusions on day of transplant, a single infusion on days 1 through 7 and one infusion on day 14 after LT. MBL-HCV1 was well-tolerated and reduced viral load for a period ranging from 7 to 28 days. Median change in viral load (log10 IU/mL) from baseline was significantly greater (p=0.02) for the antibody-treated group (range -3.07 to -3.34) compared to placebo group (range -0.331 to -1.01) on days 3 through 6 posttransplant. MBL-HCV1 treatment significantly delayed median time to viral rebound compared to placebo treatment (18.7 days vs. 2.4 days, p<0.001). As with other HCV monotherapies, antibody-treated subjects had resistance-associated variants at the time of viral rebound. A combination study of MBL-HCV1 with a direct-acting antiviral is underway.

Successful algorithm for selective liver biopsy in the right hepatic lobe live donor (RHLD).

Routine versus selective predonation liver biopsy (LBx) remains controversial for assuring the safety of right hepatic lobe live donor (RHLD). Between December 1999 and March 2007, 403 potential RHLD were evaluated; 142 donated. Indications for selective LBx were: abnormal liver function tests or imaging studies, body mass index (BMI) >28, history of substance abuse or family history of immune mediated liver disease. All donors had a LBx at the time of surgery. Of 403 potential RLD, 149(36.9%) were accepted as donors, 25(6.3%) had their recipient receive a deceased donor graft, 94(23.4%) were rejected, 52(12.9%) stopped the evaluation process, 76(18.8%) withdrew from the process and 7(1.7%) are currently completing evaluation. Eighty-seven (21.5%) met criteria and were biopsied. Seventy-three (83.9%) had either normal (n = 24) or macrosteatosis <10% (n = 49); 51 of these donated. Abnormal LBx eliminated 15 potential donors. No significant abnormalities were found in donation biopsies of donors not meeting algorithm criteria. Three of 87 (3.4%) had complications requiring overnight admission (2 for pain, 1 for bleeding; transfusion not required). Use of this algorithm resulted in 78% of potential donors avoiding biopsy and potential complications. No significant liver pathology was identified in donors not meeting criteria for evaluation LBx. Routine predonation LBx is unnecessary in potential RHLD.

Improved survival after live donor adult liver transplantation (LDALT) using right lobe grafts: program experience and lessons learned.

We present our program experience with 85 live donor adult liver transplantation (LDALT) procedures using right lobe grafts with five simultaneous live donor kidney transplants using different donors performed over a 6-year period. After an "early" 2-year experience of 25 LDALT procedures, program improvements in donor and recipient selection, preoperative imaging, donor and recipient surgical technique and immunosuppressive management significantly reduced operative mortality (16% vs. 3.3%, p = 0.038) and improved patient and graft 1-year survival in recipients during our "later" experience with the next 60 cases (January 2001 and March 2005; patient survival: early 70.8% vs. later 92.7%, p = 0.028; graft survival: Early 64% vs. later 91.1%, p = 0.019, respectively). Overall patient and graft survival were 82% and 80%. There was a trend for less postoperative complications (major and minor) with program experience (early 88% vs. later 66.7%; p = 0.054) but overall morbidity remained at 73.8%. Biliary complications (cholangitis, disruption, leak or stricture) were not influenced by program experience (early 32% vs. later 38%). Liver volume adjusted to 100% of standard liver volume (SLV) within 1 month post-transplant. Despite a high rate of morbidity after LDALT, excellent patient and graft survival can be achieved with program experience.

Histological recurrence and progression of hepatitis C after orthotopic liver transplantation: influence of immunosuppressive regimens.

Post-orthotopic liver transplantation (OLT) recurrence of hepatitis C is virtually universal, but histological progression of disease is not. This study examines long-term clinical and liver histological features at and after OLT to elucidate factors predictive of hepatitis C recurrence and progression after OLT. A blinded retrospective review of clinical, serological, and histopathologic features of 65 patients who underwent OLT for hepatitis C and Non A Non B hepatitis was conducted. Histological findings of recurrent hepatitis C and progression (fibrosis, >or= grade 2 by last follow-up) were correlated with clinical parameters. Histological recurrence of hepatitis C was seen in 43 of 65 patients, with progression in 19 patients. Histological findings in the native liver and post-OLT biopsy specimen at the time of recurrence showed no correlation with hepatitis C recurrence and progression. Patients treated with azathioprine (AZA)-containing immunosuppressive regimens experienced less recurrence (6 of 17 v 37 of 48 patients; P < .005) and progression (1 of 17 v 18 of 48 patients; P = .014) than those without AZA as part of their immunosuppressive regimen. No difference was seen between patients treated with cyclosporine versus those administered FK506 (P > .05). Histological recurrence of hepatitis C after OLT is seen in 66% of patients with progressive disease and 29% of all patients. The grade of inflammation in the native liver at the time of OLT and time of recurrence is not predictive of progression. AZA-containing regimens reduce histological recurrence and progression of hepatitis C in post-OLT patients.

Atypical ductal hyperplasia in stereotactic breast biopsies: enhanced accuracy of diagnosis with the mammotome.

There is little literature assessing the incidence of subsequent carcinoma in patients diagnosed with atypical ductal hyperplasia (ADH) by mammotome. We reviewed 216 stereotactic mammotome biopsies (SMBs) and compared the results to the 121 automated tru-cut biopsies (ATC) performed at our breast care center from June 1994 to July 1998. The median age in the mammotome series was 57 years, compared to 56 years in the ATC group. An increase in biopsies for microcalcifications (49% versus 41%) was noted in the SMB series. This was accompanied by an increase in the number of cases with a diagnosis of pure ductal carcinoma in situ (DCIS) (10% versus 4%). Compared to the tru-cut, in which 38% (3 of 8) of the cases diagnosed as atypical hyperplasia (AH) showed DCIS and/or invasive carcinoma on open biopsy, none of the cases diagnosed as AH on mammotome revealed carcinoma on open biopsy. ADH is more accurately diagnosed with SMB than by the ATC method and may not be an indication for subsequent open biopsy.

Adult-to-adult live donor liver transplantation: a short-term clinicopathologic study.

With the success of pediatric live donor liver transplantation (LDLT) and the continued shortage of cadaveric donors, adult-to-adult LDLT has been performed at some centers, including ours. We performed a detailed histologic review of all liver specimens obtained from 9 adult recipients at and after LDLT and correlated these findings with the patients' course and outcome. Five patients had histologic evidence of biliary tract pathology; 3 of 5 required surgical or radiologic intervention. The other 2 had clinically insignificant biliary disease. Diffuse hepatocytic hemorrhagic necrosis secondary to massive portal blood flow after portal venous revascularization resulted in graft failure and retransplantation in a single patient with severe preoperative portal hypertension. Two perioperative deaths were caused by sepsis and multiorgan failure (day 25) and generalized thrombosis related to factor V Leiden (day 6). The preoperative diagnosis, presence of portal vein thrombosis in the native liver, postoperative cholangiopathy, and subcapsular hemorrhagic necrosis in donor liver wedge biopsies did not affect the short-term outcome. In conclusion, biliary tract pathology is common after adult-to-adult LDLT but does not negatively affect graft or patient survival. Infrequent but catastrophic vascular complications related to portal hemodynamics or thrombosis can result in graft loss and/or patient death.

Histologic recurrence-free outcome after orthotopic liver transplantation for chronic hepatitis B.

Recurrent hepatitis B (HB) following orthotopic liver transplantation (OLT) for chronic disease is common. However, an unpredictable minority of patients follow a recurrence-free course. Clinical, virologic, and pathologic data from patients surviving longer than 60 days (n=24) with pathologically confirmed nonrecurrence of HB following OLT for chronic HB were reviewed to identify factors associated with nonrecurrence of HB. Nine of 24 patients had no histologic and immunohistologic evidence of recurrent HB. In addition to pre-OLT hepatitis B e antigen (HBeAg) negativity, coexisting delta and anti-HB therapy/prophylaxis, other acquired viral infections and their therapy, and severe acute rejection due to noncompliance were considered the possible protective factors against HB recurrence in these 9 patients. Histologic and, particularly immunopathologic, evaluation of liver biopsies must be utilized in definitively diagnosing recurrence of HB.

Livers from patients with apolipoprotein A-I amyloidosis are not suitable as "domino" donors.

Orthotopic liver transplantation, by eliminating the major site of amyloidogenic protein synthesis, is currently the only definitive treatment of most hereditary amyloidoses. Because of the minimal parenchymal involvement, the explanted livers from familial amyloidotic polyneuropathy (FAP) patients have been transplanted into non-FAP patients in a "domino" fashion. The aim of this study was to evaluate the extent of amyloid deposits in explanted livers from two patients with apolipoprotein A-I amyloidosis, with the Arg26 mutation, to determine their suitability as domino donors. A detailed histologic review of the explanted livers from two patients was performed and assessed for the extent of amyloid deposition by routine and Congo red stains. Both patients had identical histopathologic features. The liver parenchymal involvement was strikingly severe. Large patches of amyloid separated hepatic cords, with accentuation around the central veins. All portal triads were consistently and markedly involved with amorphous eosinophilic deposits within the connective tissue compressing the bile ducts and vascular structures. Hilar vessels had patchy deposits. No involvement of hilar nerve branches was seen. The hepatic parenchyma is extensively involved in hereditary Apolipoprotein A-I amyloidosis, with the Arg26 mutation. These livers, removed at orthotopic liver transplantation, are not suitable for domino donation.

Steatosis in donor and transplant liver biopsies.

The purpose of this study was to identify the significance and clinical correlation of steatosis in donor and posttransplantation liver biopsies. One hundred twenty-six liver biopsies with fatty change from 86 liver transplant patients were reviewed. Micro- and macro-steatosis were graded semiquantitatively and correlated with clinical and other pathologic parameters. Fifty-one donor biopsy specimens, from 50 patients, had combinations of micro- (predominantly) and macro-steatosis. One of 2 patients with high-grade micro- and macro-steatosis required a retransplantation on the third day. Three early deaths were not related to graft dysfunction. In 36 patients, steatosis developed after transplantation. In 13 of 36, steatosis was seen in the early postoperative period with a background of severe ischemic injury, 6 of whom died within 45 days posttransplantation. Other causes of steatosis developing after liver transplantation included hepatitis C (n = 12), alcoholic steatohepatitis (n = 3), diabetes mellitus or obesity (n = 7) and poor nutrition (n = 2). The presence of steatosis in 1 patient's donor and all posttransplantation biopsy specimens remained unexplained. In conclusion, (1) microsteatosis in donor liver biopsy specimens has no effect on graft function; (2) ischemic injury with development of steatosis in the early posttransplantation period may be associated with poor clinical outcome; and (3) steatosis in the posttransplantation period is uncommon and usually related to recurrent or acquired hepatitis C.

Liver transplantation for autoimmune hepatitis: a long-term pathologic study.

Autoimmune hepatitis (AIH) after liver transplantation (LT) may recur and is difficult to diagnose. Our aims were to define the histopathology of and factors related to AIH recurrence. Fourteen of 475 patients received LT for AIH; 2 died perioperatively. Liver specimens (native and post-LT biopsies) from 12 other patients were reviewed and correlated with pre- and post-LT clinical course and outcome. Recurrent AIH was seen in 5 of 12 patients, 35 to 280 days post-LT as lobular hepatitis with acidophil bodies and lymphoplasmacytic infiltrate. Portal/interface hepatitis was seen with disease progression and 2 of 5 patients developed cirrhosis. Of 7 nonrecurrent patients, 1 had acquired hepatitis C with lobular/portal hepatitis and none developed cirrhosis. Histology suggestive of overlap syndrome was seen in 3 of 12 native livers with no effect on post-LT course or pathology. High-grade necroinflammation was present in native livers at LT in 5 of 5 cases with recurrent AIH and in 1 of 7 without recurrence (P <.01). Pre-LT disease duration, donor/recipient gender distribution, HLA studies, and rejection episodes did not correlate with AIH recurrence. We conclude that (1) recurrent AIH is not uncommon and was seen in 42% of patients with lymphoplasmacytic lobular, portal, and interface hepatitis; (2) acidophil bodies with lymphoplasmacytic cells are seen in early recurrent AIH; (3) recurrent AIH appears at variable time periods post-LT, and the progression is slow; and (4) high-grade inflammation in native liver at LT is a strong predictor of recurrent AIH.

Immunocytochemical staining of Kupffer and endothelial cells in fine needle aspiration cytology of hepatocellular carcinoma.

OBJECTIVE: To evaluate the significance of the presence of Kupffer and endothelial cells in distinguishing hepatocellular carcinoma (HCC) and adenocarcinoma (AC) on cytologic smears. STUDY DESIGN: Fine needle aspiration biopsies (FNABs) from 43 cases, 21 HCC and 22 AC (8 primary and 14 metastatic), were immunostained for Factor VIII and vimentin as markers for endothelial cells and Kupffer cells, respectively. Cytologic diagnosis was verified by histologic and/or clinical follow-up. RESULTS: Eighteen of the 21 cases (86%) of HCC and 11 (5 primary and 6 metastatic) of 22 cases (50%) of AC showed positive immunostaining for Factor VIII (P = .02). Vimentin immunostaining was positive in 55% of HCCs and 41% of ACs (P = .74). Forty-five percent of cases of HCC showed immunostaining for both Factor VIII and vimentin, while 22% of cases of AC showed immunostaining for both Factor VIII and vimentin (P = .18). CONCLUSION: Immunocytochemical identification of endothelial cells using Factor VIII may have important diagnostic value in separating HCC from adenocarcinomas in liver FNABs. The presence of Kupffer cells labeled with vimentin has no diagnostic significance in FNAB of these tumors.

Orthotopic liver transplantation for familial amyloidotic polyneuropathy: a pathological study.

Familial amyloidotic polyneuropathy (FAP), a hereditary form of systemic amyloidosis with clinically significant neuropathy and cardiomyopathy, is caused by a genetic defect of the transthyretin gene, which is mostly synthesized in the liver. Orthotopic liver transplantation (OLT) is thought to eliminate the amyloidogenic protein and currently is the only definitive treatment for this disorder. The aim of this study was to define the distribution and extent of amyloid deposition in tissues from these patients and evaluate the suitability of the resected FAP livers for transplantation into non-FAP patients. Surgical specimens from 14 patients removed at the time of OLT and autopsy tissues from 3 of the 14 were examined histologically using hematoxylin and eosin and Congo red-stained sections. The extent of amyloid deposits was evaluated, semiquantitatively graded from negative to marked, and correlated with clinical course and patient outcome. Amyloid deposits were consistently seen in hilar and vagus nerves. Liver lobular involvement was minimal in 1 and absent in the other 13 cases, with portal arterial amyloid deposits seen in 7 cases. At autopsy, extensive amyloid deposition in the heart was seen in all 3 cases with involvement of the conduction system. The extent of amyloid deposition at OLT did not correlate with the duration of symptoms before OLT or patient outcome after OLT. In conclusion, liver parenchymal involvement in FAP is minimal, and these explants are suitable for grafting in non-FAP patients. The recipients of such grafts must be carefully observed for the development of any amyloid-related disease, particularly cardiomyopathy. Of the tissues removed at OLT, the histopathologic confirmation of FAP is most consistently made by the examination of hilar and vagus nerves.

Recurrent hepatitis B, hepatitis C, and combined hepatitis B and C in liver allografts: a comparative pathological study.

Although recurrence of viral hepatitis in liver transplants is common, data comparing recurrent hepatitis B (HB), hepatitis C (HC), and co-existing dual hepatitis B and C (HB&C) are sparse. Posttransplantation liver biopsies, along with molecular, serological, immunohistochemical, and clinical data from 27 patients with pretransplantation diagnosis of chronic viral hepatitis, were reviewed. The patients were placed into 4 groups: Group I, with pretransplantation HB (n = 8); group II, with pretransplantation HC (n = 10); group III with pretransplantation HC and anti-HB surface or core antibody (n = 4); and group IV, with pretransplantation HB&C (n = 5). The histopathologic findings and patient outcome were compared in the 4 groups. A high rate of recurrence of viral hepatitis was seen for all 4 groups: Group I = 100%, group II = 90%, Group III = 100%, and group IV = 80%, with the mean (median) recurrence time of 308 (224), 82 (52), 61 (64), and 125 (70) days, respectively. The number of deaths (their median survival times) were: group I = 4 (374 days), group II = 4 (794 days), group III = 1 (1,143 days), and group IV = 5 (448 days). The earliest histological findings of lobular injury was the presence of acidophil bodies and Kupffer cell hyperplasia, the latter being more prominent in recurrent HC cases. Recurrent HB presented in 2 forms: early (before 150 days) with poor survival and with either severe necroinflammatory histology or with features of fibrosing cholestatic hepatitis, and delayed (after 150 days), with mild necro-inflammatory activity and prolonged survival. HC with or without anti-HB antibodies had early recurrence, but the course was slowly progressive. Patients with HB&C had recurrence of both viruses; however, the course was dictated by HB virus.

Sarcoidosis with selective involvement of a second liver allograft: report of a case and review of the literature.

A case of sarcoidosis recurrent in a patient's second liver allograft is described. There was no granulomatous disease seen in the patient's first liver allograft. After the second orthotopic liver transplantation (OLT), the patient was successfully treated for acute rejection, aspergillus infection, and cytomegalovirus viremia. Approximately 2 months after the second OLT, the patient was treated with long-term interferon-alpha for recurrent hepatitis C. Five years after the operation, he experienced liver failure secondary to recurrent hepatitis and underwent a third OLT. This is only the second reported case of sarcoidosis recurrent in the liver parenchyma of a transplanted organ and the first in which interferon-alpha might have played a role.

Nodular lymphoid lesion of the liver: an immune-mediated disorder mimicking low-grade malignant lymphoma.

Three cases of unusual lymphoid infiltrate forming nodular macroscopic masses in the liver were studied in the authors' surgical pathology laboratory. These lesions posed difficulty in diagnosis, and their differentiation from low-grade lymphoma was not possible on histopathologic evaluation alone. The liver masses were analyzed histologically and immunohistochemically as well as for clonal immunoglobulin heavy chain (IgH) and T-cell receptor gamma (TCR-gamma) gene rearrangements. The lesions were seen as solitary grossly distinct firm nodules in all three patients, measuring 0.4, 0.7, and 1.5 cm, respectively, in their greatest dimensions. Two were found in livers removed because of end-stage primary biliary cirrhosis at the time of orthotopic liver transplantation, and the third was an incidental finding during laparotomy. Microscopically, these were nodules composed of small lymphocytes, plasma cells, and immunoblasts, with varying degrees of admixed acute inflammatory cells and scattered lymphoid follicles. By immunohistochemistry and molecular studies, these were found to be reactive lymphoid proliferations. All patients are alive and well at 2, 4, and 13 years, respectively. It is concluded that these cases represent a unique type of nodular lymphoid lesion, which is probably an immune-mediated benign reactive hyperplasia. It constitutes an entity by itself and must be distinguished from low-grade lymphoma. For a definitive diagnosis, immunohistochemistry and molecular studies are required.

Fibrosis/cirrhosis after orthotopic liver transplantation.

The causes and pathologic changes leading to fibrosis and cirrhosis after orthotopic liver transplantation (OLT) are not fully defined. The computerized pathology files were searched for cases of fibrosis/cirrhosis after OLT. Of 493 grafts from 435 patients, 35 grafts from 32 patients of posttransplantation liver fibrosis/cirrhosis were identified and retrieved (7%). Detailed histopathologic examinations of all post-OLT liver biopsy specimens were performed in conjunction with clinical, virologic, serologic, and molecular diagnostics information. Two cases with subcapsular septa and fibrous tissue close to hilum were excluded as false positives. Fibrosis/cirrhosis was confirmed in the remaining 33 grafts. In 20, the underlying cause was recurrent viral hepatitis, including eight with hepatitis C, 10 with hepatitis B, and two with combined hepatitis C and B. Another two with pretransplantation chronic hepatitis B developed cirrhosis without detectable virologic markers after OLT; these were biliary type secondary to obstruction in one, and chronic changes due to severe graft ischemia in one. Three patients acquired hepatitis C after OLT, with molecular confirmation available in two. In five patients, the underlying causes were Budd-Chiari syndrome and autoimmune hepatitis, recurrent autoimmune hepatitis, recurrent primary biliary cirrhosis, alcohol-induced liver disease, and recurrent bile duct carcinoma. Three cases had centrilobular fibrosis but without bridging septa or cirrhosis as a result of chronic rejection. It was concluded that (1) Cirrhosis after OLT is uncommon (7%). (2) Chronic rejection does not lead to cirrhosis, but it may result in centrilobular fibrosis. (3) In most (70%) cases, cirrhosis after OLT is attributed to recurrent or acquired viral hepatitis.

Inflammatory myofibroblastic tumor of the pancreaticobiliary region: morphologic and immunocytochemical study of three cases.

Inflammatory myofibroblastic tumor (IMT) is a rare tumor of the pancreaticobiliary region. The etiology and biologic behavior of IMTs at this site are unknown. We present three patients with IMT of the pancreaticobiliary region, each with long-term follow-up. In all three cases a second tumor developed. Grossly these tumors mimicked a malignant process. Microscopically, all were composed of an admixture of spindle cells and chronic inflammatory cells, including plasma cells, lymphocytes, eosinophils, and macrophages. The spindle cells stained positively for smooth muscle actin and vimentin but were negative for S-100, cytokeratin, CD35, and latent membrane protein. Results of in situ hybridization with EBER probes were negative in all cases. In addition to carcinoma, the differential diagnosis of these tumors includes follicular dendritic cell tumor and inflammatory fibrosarcoma. The importance of extensive pathologic examination to prevent misdiagnosis and the need for long-term follow-up are emphasized. This subset of IMT does not appear to be related to Epstein-Barr virus.

Allelic deletion and mutation of the von Hippel-Lindau (VHL) tumor suppressor gene in pancreatic microcystic adenomas.

An association between pancreatic microcystic (serous) adenomas (MCAs) and von Hippel-Lindau (VHL) disease has been suggested. However, genetic alterations of the VHL gene in MCAs of the pancreas have never been reported. In this study, we performed genetic analysis of 12 pancreatic MCAs. In 2 cases, VHL disease was documented clinically, and 10 cases were sporadic. For LOH analysis, tumor and normal pancreatic cells were procured from formalin-fixed, paraffin-embedded material using tissue microdissection. After DNA extraction, the samples were amplified by polymerase chain reaction using the polymorphic markers D3S2452, D3S1110, D3S192, and D3S656. In addition, the sporadic tumors were analyzed for VHL gene mutations using probes 3b/10b and K55/K56. Both MCAs associated with VHL disease showed LOH with at least one of the microsatellite markers tested. Among the 10 sporadic cases, 7 tumors showed LOH at the VHL gene locus. A somatic VHL gene mutation on exon 2 was documented in one sporadic case. The study provides the first direct genetic evidence for the role of the VHL gene in MCA tumorigenesis. Furthermore, VHL gene alterations may be detected in both VHL-associated and sporadic pancreatic MCAs.