The Evolution of Earned, Transparent, and Quantifiable Faculty Salary Compensation: The Johns Hopkins Pathology Experience.

Faculty value equitable and transparent policies for determining salaries and expect their compensation to compare favorably to the marketplace. Academic institutions use compensation to recruit and retain talented faculty as well as to reward accomplishment. Institutions are therefore working to decrease salary disparities that appear arbitrary or reflect long-standing biases and to identify metrics for merit-based remuneration. Ours is a large academic pathology department with 97 tenure-track faculty. Faculty salaries are comprised of 3 parts (A + B + C). Part A is determined by the type of appointment and years at rank; part B recognizes defined administrative, educational, or clinical roles; and part C is a bonus to reward and incentivize activities that forward the missions of the department and medical school. A policy for part C allocations was first codified and approved by department faculty in 1993. It rewarded performance using a semiquantitative scale, based on subjective evaluations of the department director (chair) in consultation with deputy directors (vice chairs) and division directors. Faculty could not directly calculate their part C, and distributions data were not widely disclosed. Over the last 2 years (2015-2017), we have implemented a more objective formula for quantifying an earned part C, which is primarily designed to recognize scholarship in the form of research productivity, educational excellence, and clinical quality improvement. Here, we share our experience with this approach, reviewing part C calculations as made for individual faculty members, providing a global view of the resulting allocations, and considering how the process and outcomes reflect our values.

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.

Practice patterns in cervical cancer screening and human papillomavirus testing.

The use of human papillomavirus DNA testing plus Papanicolaou (Pap) testing (cotesting) for cervical cancer screening in women 30 years and older has been recommended since 2006. However, few studies have detailed the adoption of such cotesting in clinical practice. We examined the trends in monthly percentage of Pap tests ordered as cotests in our laboratory over a 2.5-year period and used joinpoint regression to identify periods in which there was a change in the average monthly proportion of cotests. Cotesting of patients 30 years and older increased from 15.9% in January 2008 to 39.4% in June 2010. In patients aged 18 to 29 years, cotesting initially increased, but showed a downward trend in the last 14 months of the study, ending at 7.7% in June 2010. Our study highlights increased adoption of age-appropriate cotesting as well as the persistence of age-inappropriate cotesting.

Neonatal cholestasis as initial manifestation of type 2 Gaucher disease: a continuum in the spectrum of early onset Gaucher disease.

Gaucher disease type 2 [OMIM #230800] is a rare lysosomal storage disorder with usual onset between 3 and 6 months of age leading to progressive neurodegeneration and death within the first 2 years of life. Rarely it may lack the characteristic symptom-free period and initially manifest prenatally or in the neonatal period. The early course of neonatal onset classic type 2 variants is not well known, and reports of early histological changes in the liver of type 2 Gaucher disease patients are scarce. We describe a patient who presented in the immediate postnatal period with cholestasis without hepatomegaly associated with hepatocellular giant-cell transformation on liver biopsy, thrombocytopenia, and failure to thrive. This was initially thought to represent neonatal giant-cell hepatitis and the correct diagnosis was not made until the age of 6 months. Hepatocellular giant transformation has not been described in the classic acute neuronopathic form of GD. However, it has been reported in congenital GD with nonimmune hydrops and neonatal hepatitis, an example of perinatal lethal Gaucher disease (PLGD), which sometimes is regarded as an entity separate from GD type 2. Our case illustrates that neonatal cholestasis may be part of a spectrum of manifestations which spans a continuum between the PLGD and classic type 2 GD. Giant cells are a nonspecific finding but may reflect the presence of a systemic inflammatory process that recently has been implicated in the brain stem degeneration associated with acute neuronopathic GD.

Trends of human papillomavirus testing in cervical cancer screening at a large academic cytology laboratory.

OBJECTIVE: To estimate time trends of actual provider use of human papillomavirus (HPV) testing in cervical cancer screening by using laboratory and administrative data from the Johns Hopkins Hospital Division of Cytopathology in Baltimore, Maryland. METHODS: In this ecologic trend study, we analyzed 178,510 Pap specimen records and 12,221 HPV tests among 85,048 patients from 2001 to 2007. Monthly frequencies and proportions of HPV reflex testing and HPV cotesting with Pap (stratified by patient ages 30 and older and 18-29 years) were calculated. Time trends of monthly HPV testing proportions were analyzed using joinpoint regression methods. RESULTS: From April 2002, when the American Society for Colposcopy and Cervical Pathology added HPV reflex testing to its guidelines, to December 2007, the monthly the proportion of reflex testing was 95.8%. From February 2004, when the society added HPV cotesting with Pap among women aged 30 years or older to its guidelines, to December 2007, the overall proportion HPV cotesting with Pap among patients aged 30 years or older was 7.8% (compared with 4.9% among patients 18-29 years [P<.01]). The highest proportion of HPV cotesting among women aged 30 years or older, 15%, was observed in September 2006, and the trend later plateaued around 13%. The monthly proportions of HPV reflex testing and cotesting with Pap changed significantly over time. CONCLUSION: These data reveal that a small percentage of women aged 30 years or older received HPV cotesting with Pap, thus identifying a significant opportunity for providers to improve patient care in cervical cancer prevention. LEVEL OF EVIDENCE: III.

New-onset autoimmune hepatitis in young patients with preexisting liver disease.

Autoimmune hepatitis (AIH) is thought to be a primary liver disease, occurring in the absence of any known etiology. We present three unusual cases of new-onset AIH in young female patients with longstanding preexisting liver disease (Alagille's syndrome, cystic fibrosis liver disease and sickle cell hepatopathy). All patients developed an insidious onset of abdominal pain, fatigue, jaundice and hepatitis after many years of their primary diagnosis and had negative serology for hepatitis A, B, C, cytomegalovirus and Epstein-Barr virus. The occurrence of AIH in these patients may be due to a complex interaction between the underlying liver disease, chronic medication use and genetic predisposition resulting in altered immunoregulatory mechanisms.

Immunostaining of plasma cells in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by inflammatory destruction of the intrahepatic bile ducts. The differential diagnosis for PBC often includes autoimmune hepatitis (AIH). Both diseases can show prominent plasma cells and other overlapping histologic features. It is interesting that both diseases can involve elevated levels of serum immunoglobulins, with IgM elevations typical of PBC and IgG elevations typical of AIH. We investigated whether this difference could be useful histologically by immunostaining plasma cells in liver biopsy specimens for IgG and IgM. We examined 56 cases: 18 of PBC and 38 of AIH. In PBC, plasma cells in the portal tracts were predominantly IgM+, whereas in AIH, plasma cells were predominately IgG+ (P < .0001). Immunostaining for IgM and IgG can be helpful in differentiating PBC from AIH.

Hepatitis in common variable immunodeficiency.

Common variable immunodeficiency is an important form of primary immunodeficiency disease. The most recognized histologic manifestation of common variable immunodeficiency is a paucity of plasma cells in gut biopsies. However, chronic inflammation can affect other organs including the liver. This study was designed to characterize the histologic findings in liver biopsies of individuals with common variable immunodeficiency. Thirteen liver biopsies from 10 patients were identified. The most common indication for biopsy was elevated liver enzymes, hepatomegaly, and/or splenomegaly. The biopsies typically showed mild portal and mild-to-moderate lobular chronic inflammation with minimal or absent interface activity. Plasma cells were absent in all cases. The biopsy specimens showed no fibrosis (n = 5) or mild portal fibrosis (n = 5). In 2 patients with follow-up biopsies, no fibrosis progression was identified. Four individuals showed small numbers of scattered portal and/or lobular granulomas, 3 of whom had diagnoses of coexistent sarcoidosis. Overall, the inflammatory changes in the biopsies were reminiscent of those seen in individuals with chronic inflammation of the gut, which can lead to translocation of intestinal luminal antigens to the liver and a mild hepatitis. Subsequent review of concurrent intestinal biopsies available in 7 individuals showed intestinal inflammation in 5 of 7 cases. In conclusion, liver biopsies in individuals with common variable immunodeficiency show mild portal and lobular inflammation with no or mild portal fibrosis. The etiology of the common variable immunodeficiency hepatitis remains unclear but, in some cases, may be secondary to mucosal inflammation in the gastrointestinal tract.

Malignant transformation of hepatic adenomas.

Hepatic adenomas are benign neoplasms of the liver that occur in several well-defined clinical settings, but principally that of excess hormone exposure. They have a small but poorly characterized risk of malignant degeneration. The clinical presentation and pathological findings were reviewed for all hepatic adenomas resected between January 1, 2003 and July 1, 2006. Immunohistochemistry for p53, beta-catenin and alpha-fetoprotein (AFP) were performed on those cases with malignant transformation and exon 3 of beta-catenin was amplified and sequenced. A total of 17 hepatic adenomas were resected and 3 showed malignant transformation. All three cases were in women with an age range of 23-33 years. The clinical presentations were vague abdominal pain. Histologically, the malignant transformation occurred within otherwise typical hepatic adenomas. Two of three cases showed patchy atypia throughout the hepatic adenoma. The hepatocellular carcinoma arose as distinct nodules directly within the adenomas, effectively ruling out synchronous lesions. The hepatocellular carcinomas were unifocal in two cases and multifocal in one case with the greatest dimensions of the hepatocellular carcinoma being 2.5, 2.2, and 1 cm. Immunostains for AFP and beta-catenin were negative in both the hepatic adenomas and areas of hepatocellular carcinoma. p53 immunostaining was positive within the areas of malignant transformation in one case. No mutations or deletions were seen in exon 3 of the beta-catenin gene for either the adenomas or the carcinoma. In conclusion, two of the cases that developed hepatocellular carcinomas showed cytological atypia in the background adenoma. The hepatocellular carcinomas arose as distinct nodules within the adenomas. No common molecular pathway of hepatocellular carcinogenesis was observed by examining AFP, beta-catenin, and p53 immunostains and no beta-catenin mutations or deletions were found.

Histology of symptomatic acute hepatitis C infection in immunocompetent adults.

Acute hepatitis C in immunocompetent individuals is rarely symptomatic and rarely biopsied. Thus, the histologic descriptions of acute hepatitis C remain limited. The histology of 5 cases of acute hepatitis C in adults were studied by selecting cases from the consult and surgical pathology files of a single institution. The 5 individuals, 3 males and 2 females, had an average age at biopsy of 50+/-17 years. They presented with jaundice and other nonspecific abdominal symptoms. The time interval from clinical presentation to biopsy ranged from 2 to 18 weeks. The average alanine aminotransferase/aspartate aminotransferase/alkaline phosphatase at the time of biopsy was 308/73/85 U/L. The average total bilirubin was 5.2 mg/dL. Each individual had a single liver biopsy. The histologic findings of the 2 cases biopsied in close temporal proximity to the initial clinical presentation showed similar histologic findings of mixed portal infiltrates with lymphocytes and neutrophils along with bile ductular proliferation that raised the possibility of down stream biliary tract disease. The lobules showed canalicular cholestasis and mild to moderate inflammation. In the third and fourth case, obtained 8 weeks after presentation, the biopsies showed mild to moderate portal and lobular lymphocytic inflammation, findings that were also present in the last case, obtained 18 weeks after presentation. In conclusion, early after acute hepatitis C viral infection, biopsies can have a cholestatic pattern whereas later biopsies tend to show mild nonspecific portal and lobular lymphocytic inflammation. Proper histologic diagnosis can be aided by an awareness of the various histologic findings, which vary depending on the time interval from clinical symptoms to biopsy.

Impact of surgical delay on long-term cancer control for clinically localized prostate cancer.

PURPOSE: Radical retropubic prostatectomy (RRP) as definitive management for clinically localized prostate cancer is commonly performed within months of diagnosis. Despite patient anxiety there is little evidence to suggest that a delay of several months from diagnosis to RRP is associated with a worse cancer control rate. However, a recent study cast doubt on the safety of such a delay with respect to cancer control. Therefore, in a contemporary series we determined long-term cancer control in men who underwent RRP for clinically localized prostate cancer with some treated early and others treated after a longer delay. MATERIALS AND METHODS: We analyzed data on 926 men who underwent RRP between January 1989 and December 1994. Age, preoperative serum prostate specific antigen (PSA), biopsy Gleason score, clinical and pathological stage, and biochemical recurrence were compared between 162 men who underwent RRP 60 days or less from biopsy and 764 who underwent RRP after a greater delay. Disease-free (PSA less than 0.2 ng/ml) survival rates were compared using Kaplan-Meier analysis. Pathological staging was compared using logistic regression. RESULTS: The different groups were well matched for age, serum PSA, pathological stage and followup. However, significantly more men who underwent RRP between 121 and 150 days, and 151 days or greater had T1c disease (48% and 57% vs 35%, p<0.04 and <0.0001, respectively). In addition, significantly more men operated on at 151 days or greater had biopsy Gleason scores 2 to 6 (86% vs 65%, p<0.0001) and significantly fewer had Gleason score 7 disease (13% vs 30%, p<0.002). Men who underwent RRP after 60 or less days had 5 and 10-year biochemical disease-free survival rates comparable to those in men who underwent RRP after 61 to 90, 91 to 120 and 121 to 150 days after diagnosis (82% and 78%, 86% and 78%, 86% and 75%, and 86% and 82%, respectively). Those operated on at 151 days or greater had significantly greater 5 and 10-year biochemical disease-free survival rates (89% and 87%, p<0.04). However, when patients were stratified into different subgroups based on clinical stage, serum PSA and biopsy Gleason score a delay of 150 days or greater no longer impacted differently on long-term cancer control rates. CONCLUSIONS: Delays of up to several months from prostate cancer diagnosis to RRP do not appear to impact long-term biochemical cancer control rates. Therefore, patients can be reassured that there is no immediate urgency to perform RRP after prostate cancer diagnosis, especially in those with T1c disease and biopsy Gleason scores less than 7.

Diffuse lymphoplasmacytic chronic cholecystitis is highly specific for extrahepatic biliary tract disease but does not distinguish between primary and secondary sclerosing cholangiopathy.

Previous studies of gallbladder pathology in primary sclerosing cholangitis (PSC) have suggested that a distinctive histologic triad ("diffuse lymphoplasmacytic acalculous cholecystitis," composed of diffuse, mucosal-based, dense lymphoplasmacytic infiltrates) is commonly present in gallbladders of patients with PSC and is relatively specific for that disease. However, prior control populations have included only patients with cholecystitis/cholelithiasis and hepatitis, and have not evaluated patients with non-PSC-associated extrahepatic biliary tract disease. We recently observed cases of diffuse lymphoplasmacytic chronic cholecystitis in a subset of patients with biliary tract disease associated with lymphoplasmacytic sclerosing pancreatitis and among patients undergoing Whipple resection for pancreatic head malignancy, suggesting that diffuse lymphoplasmacytic chronic cholecystitis is not specific for PSC. We studied 20 gallbladders from patients with obstructive jaundice due to malignancies of the pancreatic head, duodenum, or ampulla and 5 gallbladders from patients with choledocholithiasis, and compared them with 20 gallbladders from patients with PSC and 20 gallbladders with cholelithiasis. The following histologic features were evaluated: degree of mucosal and deep inflammation, lymphoid nodules, epithelial metaplasia, muscular hypertrophy, Rokitansky-Aschoff sinuses, fibrosis, and cholesterolosis. Gallbladders in malignancy-associated obstructive jaundice were nearly identical to gallbladders in PSC with respect to scores for mucosal inflammation, lymphoid nodules, and frequency of diffuse lymphoplasmacytic chronic cholecystitis (60% vs. 50%, respectively). PSC gallbladders, however, were significantly more likely to contain focal or extensive epithelial metaplasia (P = 0.01). The cholelithiasis control group was characterized by lack of significant mucosal inflammation in the majority of cases (95%) and frequent Rokitansky-Aschoff sinuses, fibrosis, and muscular hypertrophy. Gallbladders in the choledocholithiasis group showed overlapping histologic features with PSC/malignancy-associated obstructive jaundice and cholelithiasis. These results suggest that a pattern of diffuse lymphoplasmacytic chronic cholecystitis is highly specific for extrahepatic biliary tract disease but does not distinguish between primary and secondary cholangiopathies.

Lymphoplasmacytic chronic cholecystitis and biliary tract disease in patients with lymphoplasmacytic sclerosing pancreatitis.

Lymphoplasmacytic sclerosing pancreatitis (LPSP) represents a distinctive form of chronic pancreatitis characterized by diffuse fibroinflammatory infiltrates that can involve both the pancreatic ducts and acinar parenchyma. Several cases of inflammatory infiltrates within the gallbladder have been reported in association with LPSP, but the spectrum of gallbladder pathology in patients with LPSP has not been systematically reviewed. Many patients with LPSP have distal CBD fibrosis, strictures, and inflammation, features that overlap somewhat with primary sclerosing cholangitis (PSC). In PSC, a pattern of gallbladder pathology termed "diffuse acalculous lymphoplasmacytic chronic cholecystitis" has been previously described as showing a triad of diffuse, mucosal-based, plasma cell-rich inflammatory infiltrates. We studied 20 gallbladders from patients with LPSP and compared them with 20 gallbladders in PSC, 20 gallbladders with chronic cholelithiasis, and 10 gallbladders from patients with benign (non-LPSP) pancreatic disease. The following features were evaluated: degree and composition of mucosal inflammation and deep (mural) inflammation, lymphoid nodules, metaplasia, dysplasia/neoplasia, fibrosis, muscular hypertrophy, Rokitansky-Aschoff sinuses, and cholesterolosis. The majority (60%) of gallbladders in LPSP contained moderate or marked inflammatory infiltrates and lymphoid nodules, frequencies similar to PSC but significantly higher than in chronic cholelithiasis and benign non-LPSP pancreatic disease. LPSP gallbladders received the highest scores for deep inflammation of all groups, and 35% of LPSP gallbladders showed transmural chronic cholecystitis. Overall, "diffuse lymphoplasmacytic chronic cholecystitis" was present in 50% of PSC cases and 25% of LPSP cases, but in only 5% of chronic cholelithiasis and none of non-LPSP benign pancreatic disease. Mucosal inflammation in LPSP gallbladders correlated significantly with the presence of inflammation in the extrapancreatic portion of the CBD. These findings suggest that inflammatory pathology of the gallbladder is frequently associated with LPSP and that it is part of the spectrum of biliary tract disease in these patients, rather than a simple reflection of the pancreatitis itself.

Eosinophilic pancreatitis and increased eosinophils in the pancreas.

Prominent eosinophilic infiltrates are an unusual finding in the pancreas. Eosinophilic pancreatitis is one rare etiology of pancreatic eosinophilia, but other described causes of eosinophilic infiltrates have also included pancreatic allograft rejection, pancreatic pseudocyst, lymphoplasmacytic sclerosing pancreatitis (LPSP), inflammatory myofibroblastic tumor, and histiocytosis X. In this study we describe the clinicopathologic features of three new cases of eosinophilic pancreatitis and conduct a retrospective 18-year institutional review of the myriad disease processes associated with pancreatic eosinophilia. In the files of the Johns Hopkins Hospital, <1% of all pancreatic specimens had been noted to show increased numbers of eosinophils. Eosinophilic pancreatitis itself was a rare etiology for pancreatic eosinophilia, with only one in-house case over the 18-year study period and two additional referral cases. Other disease processes associated with prominent eosinophilic infiltrates were more common and included pancreatic allograft rejection (14 cases), LPSP (5 of 24 total LPSP cases evaluated), inflammatory myofibroblastic tumor (4 cases), and systemic mastocytosis (1 case). Patients with eosinophilic pancreatitis showed two distinct histologic patterns: 1) a diffuse periductal, acinar, and septal eosinophilic infiltrate with eosinophilic phlebitis and arteritis; and 2) localized intense eosinophilic infiltrates associated with pseudocyst formation. All three patients with eosinophilic pancreatitis had peripheral eosinophilia, and all had multiorgan involvement. One patient with LPSP also had marked peripheral eosinophilia, and 5 of 24 LPSP cases demonstrated prominent eosinophilic infiltrates in the gallbladder, biliary tree, and/or duodenum. Notably, not all of these patients with LPSP with prominent eosinophils in other organs had increased eosinophils in the pancreas itself. These results emphasize the infrequent nature of pancreatic eosinophilia and its multiple potential disease associations. True eosinophilic pancreatitis, although a fascinating clinicopathologic entity, is one of the rarest causes of pancreatic eosinophilia.

Pancreaticoduodenectomy (Whipple resections) in patients without malignancy: are they all 'chronic pancreatitis'?

Pancreaticoduodenectomy (Whipple resection) has evolved into a safe procedure in major high-volume medical centers for the treatment of pancreatic adenocarcinoma and refractory chronic pancreatitis. However, some Whipple resections performed for a clinical suspicion of malignancy reveal only benign disease on pathologic examination. We evaluated the frequency of such Whipple resections without tumor in a large series of pancreaticoduodenectomies and classified the diverse pancreatic and biliary tract diseases present in these specimens. Of 442 Whipple resections performed during 1999-2001, 47 (10.6%) were negative for neoplastic disease and, in 40 cases, had been performed for a clinical suspicion of malignancy. Most Whipple resections revealed benign pancreatic disease, including 8 (17%) alcohol-associated chronic pancreatitis, 4 (8.5%) gallstone-associated pancreatitis, 1 (2.1%) pancreas divisum, 6 (12.8%) "ordinary" chronic pancreatitis of unknown etiology, and 11 (23.4%) lymphoplasmacytic sclerosing pancreatitis. In particular, patients with lymphoplasmacytic sclerosing pancreatitis were all thought to harbor malignancy, whereas only 13 of 19 (68.4%) of Whipple resections showing histologically "ordinary" forms of chronic pancreatitis were performed for a clinical suspicion of malignancy. Benign biliary tract disease, including three cases of primary sclerosing cholangitis, two cases of choledocholithiasis-associated chronic biliary tract disease, and four fibroinflammatory strictures isolated to the intrapancreatic common bile duct, was a common etiology for clinically suspicious Whipple resections (22.5% of cases). Pancreatic intraepithelial neoplasia (PanIN) was a common finding among all pancreata, whether involved by pancreatitis or histologically normal. Overall, PanIN 1A/1B was present in 68.1%, PanIN 2 in 40.4%, and PanIN 3 in just 2.1%. These findings indicate that "benign but clinically suspicious" Whipple resections are relatively common in high-volume centers (9.2%) and reveal a diverse group of clinicopathologically distinctive pancreatic and biliary tract disease.

Microsatellite instability in intraductal papillary neoplasms of the biliary tract.

Intraductal papillary neoplasms of the biliary tree are unusual lesions characterized by solitary or diffuse growth along the intra- and/or extrahepatic biliary tract. Biliary papillary neoplasms bear some clinicopathologic similarity to intraductal papillary mucinous neoplasms of the pancreas. Like intraductal papillary mucinous neoplasms of the pancreas, biliary papillary neoplasms can be purely intraductal lesions or can give rise to invasive adenocarcinomas. We recently studied the genetic alterations present in a series of biliary papillary neoplasms and noted the presence of allelic shifts in some biliary tumors during allelic loss assays on chromosomes 5q and 18q. This suggested that microsatellite instability might play a role in the molecular pathogenesis of biliary papillary neoplasms. Genomic DNA was extracted from 17 intraductal papillary neoplasms, 6 associated invasive cholangiocarcinomas, and corresponding normal tissues, and microsatellite instability testing was performed using the 5 microsatellite loci recommended by the 1997 National Cancer Institute-sponsored consensus conference (D2S123, D5S346, D17S250, Bat-25, and Bat-26). High-level microsatellite instability was considered to be present when at least two of five microsatellite loci showed allelic shifts, and low-level microsatellite instability, when only one locus was shifted, as per the National Cancer Institute criteria. We also determined the methylation status of the DNA mismatch repair gene hMLH1 by bisulfite treatment of genomic DNA, followed by methylation-specific PCR. High-level microsatellite instability was present in 2 of 17 (11.8%) biliary papillary neoplasms, including 1 case of purely intraductal tumor and 1 case with both intraductal and invasive cholangiocarcinoma components. In both cases there was extensive microsatellite instability, with allelic shifts in five of five and four of five microsatellite markers, respectively. Low-level microsatellite instability was present in 6 of 17 (35.3%) biliary papillary neoplasms, including 2 cases of purely intraductal tumor and 4 cases with both intraductal and invasive cholangiocarcinoma components. Interestingly, the pattern of allelic shifts was frequently not identical between the intraductal and invasive cholangiocarcinoma components; although the same microsatellite markers were shifted, alleles of differing lengths were generated in the intraductal and invasive components of the neoplasms with high-level microsatellite instability and of two neoplasms with low-level microsatellite instability. None of the biliary papillary neoplasms (0 of 10 cases with adequate DNA for evaluation) showed methylation of hMLH1. These results indicate that microsatellite instability is a relatively frequent event in papillary neoplasms of the biliary tree but is not associated with hMLH1 promoter hypermethylation. The finding that alleles of differing lengths were frequently generated between the intraductal and invasive components of those tumors with microsatellite instability suggests that there is significant genetic heterogeneity within these neoplasms.

Hepatitic variant of graft-versus-host disease after donor lymphocyte infusion.

Graft-versus-host disease (GVHD) of the liver is characterized by bile duct damage and portal lymphocytic infiltrate. We report acute hepatitislike presentation of GVHD after donor lymphocyte infusion (DLI). Between April 1998 and September 2001, 73 patients received 94 DLI treatments. Liver GVHD developed after DLI in 22 (30%) patients whose median age was 43 years (range, 21 to 61 years). Onset of liver dysfunction was at 35 days (range, 11 to 406 days) after DLI. Fifteen patients underwent liver biopsy, and the diagnosis of liver GVHD was confirmed in 13 (87%) patients. After viral hepatitis and recent drug exposure were excluded, 11 (50%) patients were given a diagnosis of a hepatitic variant of GVHD based on histologic evidence of lobular hepatitis (n = 5), elevation of maximum serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level more than 10 times the upper normal limit (n = 9), or both. There was a significant difference in maximum ALT (P =.002) and AST (P =.01) level between the hepatitic-variant and classical GVHD groups. GVHD progressed in 14 (64%) patients, and 10 patients died after a median follow-up of 221 days (range, 31-1284 days). These observations suggest that GVHD that occurs after DLI may have distinct clinical features. Hepatitic-variant GVHD should be considered in the differential diagnosis in DLI recipients with unexplained hepatitis.

Outcome of orthotopic liver transplantation in patients with hepatitis C.

Recurrence of chronic hepatitis C (HCV) after orthotopic liver transplantation (OLT) is universal. The published studies suggest that the short-term outcome is good in these patients, but the long-term prognosis remains unclear. The purpose of this study was to evaluate the outcome of patients with HCV undergoing OLT in a single center and to analyze the risk factors associated with poor outcome. In this retrospective study, we evaluated the outcome of 58 OLT patients with proven HCV who underwent OLT between February 1990 and April 1997 at our institution. The median follow-up time was 36.9 months. Recurrent posttransplant HCV hepatitis was confirmed by liver biochemistry, histology, and persistent HCV RNA in the serum. The patient and graft survival of patients with HCV was compared to that of 42 primary biliary cirrhosis (PBC) and 41 primary sclerosing cholangitis (PSC) patients transplanted during the same period. Following OLT, biochemical evidence of recurrent HCV hepatitis was absent in 46%. Forty percent of patients had recurrent HCV hepatitis and 14% had clinical evidence of recurrent HCV. Thirty-one patients were on cyclosporine, 22 patients on tacrolimus, and 5 patients had cyclosporine switched to tacrolimus or vice versa. The recurrence rate of HCV chronic hepatitis was similar in patients who had cyclosporine (35.5%) or tacrolimus (45.5%) based immunosuppression. Eleven patients (19%) died and five patients (8.6%) were retransplanted for chronic rejection (two), mismatch (one), or primary graft nonfunction (two). The cumulative patient survival rates of one, three, and five years were 94.8%, 84.1%, and 62.2%, respectively. The severity of liver disease progressed with time; 8% of patients developed cirrhosis within two years. The survival rate did not show any relation between HCV recurrence and the type of immunosuppression. In conclusion, although the survival of patients with HCV was not statistically significant compared to those with PBC or PSC, there was a trend towards a lower five-year survival in HCV.