Friday, November 22, 2019

HPHS Journal Watch: September/October 2019

Journal of Pathology

Genomic landscape of lymphoepithelioma-like hepatocellular carcinoma.
Chan AW, Zhang Z, Chong CC, et al. J Pathol. 2019 Oct;249(2):166-172.

Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is a distinct variant of HCC, characterized by dense tumor-infiltrating lymphocytes (TILs) and better clinical outcomes. The authors studied the genomic landscape of 12 LEL-HCC using whole-exome sequencing, and further underpinned those genetic alterations related to an immune active microenvironment by comparing findings to 15 classic HCC (c-HCC) that were sequenced in parallel. They found similar mutational burden between LEL-HCC and c-HCC. Interestingly, somatic nucleotide variation incidences of specific genes (CTNNB1, AXIN1, NOTCH1, and NOTCH2) were significantly higher in c-HCC than LEL-HCC, suggesting a plausible link between activated Wnt/β-catenin and Notch signaling pathways and immune avoidance. LEL-HCC had a higher frequency of positive PDL-1 protein expression than c-HCC (66.7% vs 6.6%). Marked focal amplification of chromosome 11q13.3 was prevalent in LEL-HCC. Using The Cancer Genome Atlas dataset, they further established oncogenes expressed from chromosome 11q13.3 (CCND1, FGF19, and FGF4) to be strongly associated with the immune checkpoint signature (CD274, PDCD1, BTLA, CTLA4, HAVCR2, IDO1, and LAG3). Their results illustrate the somatic landscape of LEL-HCC, and highlight molecular alterations that could be exploited in combinatory therapy with checkpoint inhibitors in targeting HCC.


Keratin 19-expressing hepatocellular carcinoma and small-duct type intrahepatic cholangiocarcinoma show a similar postoperative clinical course but have distinct genetic features.
Akita M, Ajiki T, Fukumoto T, Itoh T, Zen Y. 2019 Sep;75(3):385-393.

The authors compared clinicopathological and genetic features between keratin 19 (K19)-expressing hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Consecutive cases of HCC (n = 430) were classified into K19+ and K19- using immunohistochemistry. ICCA cases were also separated into small-(S-iCCA; n = 36) and large-duct types (n = 22) based on recently proposed criteria, with the former being used in the present study. Mutational hot-spots in TERT, CTNNB1, KRAS and IDH1 were sequenced. Twenty-six cases (6%) of HCC expressed K19. K19+ HCC was more strongly associated with chronic hepatitis B than K19- HCC and S-iCCA (46% versus 17% and 6%; both P < 0.001). Lymph node metastasis was observed in K19+ HCC (8%) and S-iCCA (22%), but was exceptional in K19- HCC (1%). K19+ HCC had TERT promoter mutations less frequently than K19- HCC (31% versus 59%; P = 0.022), and lacked alterations in KRAS and IDH1. CTNNB1 mutations were similarly observed in K19+ and K19- HCC (23% and 19%, respectively), but rare in S-iCCA (3%). The postoperative survival curve of K19+ HCC was almost identical to that of S-iCCA in the first 5 years (approximately 50% at 5 years), and significantly worse than that of K19- HCC (P = 0.040). Extrahepatic recurrence was more common in K19+ HCC (50%) and S-iCCA (35%) than in K19- HCC (15%) (P = 0.001). The authors conclude that although K19+ HCC and S-iCCA showed similar biological behaviors, they did not share any driver gene mutations, suggesting the possible involvement of epigenetic alterations in the iCCA-like features of K19+ HCC.

American Journal of Surgical Pathology

Prognostic Value of Poorly Differentiated Clusters in Liver Metastatic Lesions of Colorectal Carcinoma.
Yonemura K, Kajiwara Y, Ao T, Mochizuki S, Shinto E, Okamoto K, Hase K, Ueno H. Am J Surg Pathol. 2019 Oct;43(10):1341-1348.

Poorly differentiated clusters (PDC) have been shown in multiple studies to be a prognostic marker in colorectal carcinoma (CRC). Most previous studies, however, have been based on the primary tumor and not metastases. This retrospective study aimed to determine the prognostic impact of PDC in colorectal liver metastases (CRLM) and compare them to their respective primary tumor in 204 patients. PDC was graded as G1 (<5 clusters), G2 (5-9 clusters), and G3 (³10 clusters). PDC grade G2/G3 in CRLM was found to be an independent prognostic factor of overall and recurrence free survival on multivariate analysis. PDC grade in CRLM also correlated to PDC grade in their respective primary sites. In summary, PDC may be an important prognostic marker in CRLM.

The Pathologic and Genetic Characteristics of the Intestinal Subtype of Intraductal Papillary Neoplasms of the Bile Duct.
Nakanuma Y, Kakuda Y, Fukumura Y, Sugino T, Uesaka K, Serizawa M, Terada T, Ohnishi Y. Am J Surg Pathol. 2019 Sep;43(9):1212-1220.

This study characterized histologic findings in 34, and genetic mutations in 21, cases of intestinal subtype intraductal papillary neoplasm of the bile duct (iIPNB). Intrahepatic iIPNBs tended to show a villous-papillary pattern, MUC5AC expression, and mutations in KRAS and GNAS. Meanwhile, extrahepatic iIPNBs more often showed a papillary pattern, CD10 expression, and mutations in TP53 and PIK3CA. Predominant high-grade dysplasia and/or presence of architectural complexity were more common in extrahepatic iIPNBs. Awareness of these differences may aid in diagnosis and are suggestive of differences in tumor biology between intrahepatic and extra hepatic iIPNBs.

Tumor Budding in Intrahepatic Cholangiocarcinoma: A Predictor of Postsurgery Outcomes.
Tanaka M, Yamauchi N, Ushiku T, Shibahara J, Hayashi A, Misumi K, Yasunaga Y, Morikawa T, Kokudo T, Arita J, Sakamoto Y, Hasegawa K, Fukayama M. Am J Surg Pathol. 2019 Sep;43(9):1180-1190.

This retrospective study evaluated 107 intrahepatic cholangiocarcinomas (ICC) and compared them to 54 perihilar cholangiocarcinomas (PCC) and 40 extrahepatic cholangiocarcinomas (ECC) to determine the prognostic significance of tumor budding (TB). TB was performed in whole tumor areas and graded as low (0-4 buds), intermediate (5-9 buds), and high (³10 buds). ICC was also subtyped as type 1 (hilar) and type 2 (peripheral). Univariate and multivariate analysis showed intermediate and high TB to be a negative prognostic factor for recurrence-free and overall survival in ICC and PCC, but not ECC. With regards to ICC subtypes, TB was a statistically significant prognostic factor in type 2 but not in type 1. In summary, TB may be an important prognostic marker in ICC and PCC.

Modern pathology

Immunohistochemical and molecular features of cholangiolocellular carcinoma are similar to well-differentiated intrahepatic cholangiocarcinoma.
Balitzer D, Joseph NM, Ferrell L, Shafizadeh N, Jain D, Zhang X, Yeh M, di Tommaso L, Kakar S. Mod Pathol. 2019 Oct; 32(10): 1486-1494.

Cholangiolocellular carcinoma is characterized by low grade cytologic atypia, and anastomosing cords and glands resembling cholangioles or canals of Hering. Capture-based next generation sequencing targeting the coding regions of 479 cancer genes and select introns was performed on 17 cases (5 cholangiolocellular carcinomas, 7 intrahepatic cholangiocarcinomas, 5 mixed cholangiolocellular-intrahepatic cholangiocarcinomas) along with immunohistochemistry for CK19, SALL4, CD56, CD117, and EMA. CK19 and EMA were positive in all cases; both luminal and cytoplasmic EMA was seen in 3/5 cholangiolocellular carcinoma and 3/6 intrahepatic cholangiocarcinomas. CD117 and SALL4 were negative in all cases. CD56 was positive in 2/5 cholangiolocellular carcinoma, 4/6 intrahepatic cholangiocarcinoma and 2/5 mixed cases. Mutations typical of intrahepatic cholangiocarcinoma (IDH1/2, PBRM1, FGFR2) were present in 90% of cases with cholangiolocellular carcinoma component. The genomic profile (IDH1/2 mutations, FGFR2 fusions, chromatin-remodeling gene mutations such as ARID1APBRM1) and copy number alterations were similar in cholangiolocellular carcinoma, intrahepatic cholangiocarcinoma and mixed cholangiolocellular-intrahepatic cholangiocarcinoma. In all mixed cases, the immunohistochemistry results, mutational profile and copy number alterations in both components were similar. The authors conclude that cholangiolocellular carcinoma should be categorized as a histologic subtype of well-differentiated intrahepatic cholangiocarcinoma, and should not be considered a distinct entity, or a variant of combined hepatocellular-cholangiocarcinoma unless a distinct hepatocellular component is also present.

Journal of Gastroenterology and Hepatology

Non‐invasive structure–function assessment of the liver by 2D time‐harmonic elastography and the dynamic Liver MAximum capacity (LiMAx) test.
Heucke N, Wuensch T, Mohr J, et al. J Gastroenterol Hepatol. 2019 Sep; 34(9): 1611-1619.

The aim of this study was the combined measurement of liver function by the 13C‐methacetin Liver MAximum capacity (LiMAx) test and tissue‐structure related stiffness by 2D time‐harmonic elastography for the assessment of liver disease progression. LiMAx test and time‐harmonic elastography, serological scores fibrosis 4 index and aspartate aminotransferase to platelet ratio index were used in patients with chronic liver diseases (n = 75) and healthy control subjects (n = 22). LiMAx values correlated negatively with liver stiffness (r = −0.747), aminotransferase to platelet ratio index (r = −0.604), and fibrosis 4 (r = −0.573). Median (interquartile range) LiMAx values decreased with fibrosis progression from 395 μg/kg/h (371–460 μg/kg/h) in participants with no fibrosis to 173 μg/kg/h (126–309 μg/kg/h) in patients with severe fibrosis. Median liver stiffness increased progressively with the stage of fibrosis from no fibrosis (1.56 m/s [1.52–1.63 m/s]) to moderate fibrosis (1.60 m/s [1.54–1.67 m/s]) to severe fibrosis 1.85 m/s [1.76–1.92 m/s]). The authors conclude that structural changes in the liver correlate with a functional decline of the organ.

Clinical Gastroenterology and Hepatology

Health-related Quality of Life in Nonalcoholic Fatty Liver Disease Associates With Hepatic Inflammation.
Huber Y, Boyle M, Hallsworth K, Tiniakos D, Straub BK, Labenz C, Ruckes C, Galle PR, Romero-Gómez M, Anstee QM, Schattenberg JM; EPoS Consortium Investigators. Clin Gastroenterol Hepatol. 2019 Sep; 17(10):2085-2092.

Chronic liver disease has negative effects on health-related quality of life (HRQL). The authors collected data from 304 patients with histologically defined NAFLD that were enrolled prospectively into the European NAFLD Registry that included subjects from Germany, the United Kingdom, and Spain. They observed a substantial burden of symptoms in patients. In addition to increased age, female sex, and the presence of diabetes, detection of lobular inflammation in biopsies correlated with lower health-related quality of life (HRQL).

Human Pathology

Fine-needle aspiration of the liver: a 10-year single institution retrospective review.
McHugh KE, Policarpio-Nicolas MLC, Reynolds JP. Hum Pathol. 2019 Oct; 92:25-31.

Fine-needle aspiration (FNA) of liver masses is a minimally invasive means of evaluation, with diagnostic accuracy of over 85%. The authors conducted a 10-year retrospective review of a single institution's cytopathology experience with the diagnosis of liver lesions. Associated concurrent and subsequent surgical pathology and cytopathology cases were identified. All FNA cases were organized into four diagnostic categories: positive for malignancy, atypical, negative for malignancy, and non-diagnostic. 713 hepatic FNAs were categorized as follows: positive for malignancy 467 (65.5%), atypical 49 (6.9%), negative 171 (24.0%) and non-diagnostic 26 (3.6%). Based on the review, diagnostic performance of hepatic FNA shows a sensitivity of 93.4% and specificity of 96.7%. Read more to learn the specifics of both diagnostic performance and the frequency with which various diagnostic entities present as hepatic lesions.

Distinct histomorphological features are associated with IDH1 mutation in intrahepatic cholangiocarcinoma.
Wang T, Drill E, Vakiani E, Pak LM, Boerner T, Askan G, Schvartzman JM, Simpson AL, Jarnagin WR, Sigel CS. Hum Pathol. 2019 Sep; 91:19-25.

Mutations in IDH1 (mIDH1) define a molecular subclass of intrahepatic cholangiocarcinoma (ICC) and IDH-targeted therapies are in development. Characterizing mIDH1 ICC histomorphology is of clinical interest for efficient identification. Resected ICCs with targeted next-generation sequencing were selected. By slide review, blinded to IDH status, data were collected for histology type, mucin production, necrosis, fibrosis, cytoplasm cell shape, and architectural pattern. Parameters were compared between mIDH1and IDH wild-type controls. In the examined cohort (113 ICC: 29 mIDH1 and 84 IDH wild-type), all IDH1-mutant tumors were of small duct-type histology, thus analysis was limited to 101 small duct-type tumors. The authors conclude that mIDH1 ICCs are more likely to have plump cuboidal/polygonal shape (P = .014) and geographic-type fibrosis (P = .005); however, IDH1 mutation is not associated with a distinct architectural pattern.

The expression of gastrointestinal differentiation markers in extrahepatic cholangiocarcinoma: clinicopathological significance based on tumor location.
Ishida K, Osakabe M, Eizuka M, Tai S, Sugimoto R, Fujita Y, Katagiri H, Takahara T, Uesugi N, Nitta H, Sasaki A, Sugai T. Hum Pathol. 2019 Oct; 92:91-100.

The authors aimed to clarify the role of gastrointestinal differentiation marker expression in extrahepatic CCA based on tumor location. MUC2, MUC5AC, MUC6, CD10, CDX-2, and CK 20 immunohistochemical expression was examined in perihilar (n=30) and distal (n=54) CCAs. Through semi-quantitative scoring and hierarchical clustering, perihilar and distal CCAs were stratified into two subgroups.


Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation.
Hamesch K, et al. Gastroenterology. 2019 Sep; 157(3):705-719.

The authors assessed the liver disease burden and associated features in adults with the severe alpha-1 antitrypsin deficiency (AATD). A variety of demographic parameters, comorbidities, lung- and liver-related health, and blood samples were collected. Liver fibrosis was assessed non-invasively via AST/platelet ratio index, HepaScore, and via transient elastography. Liver steatosis was determined via transient elastography. The authors found evidence of liver steatosis, impaired lipid secretion, and factors associated with significant liver fibrosis in adults carriers versus controls.

Journal of Hepatology

Molecular and histological correlations in liver cancer.
Calderaro J, Ziol M, Paradis V, Zucman-Rossi, J. Journal of Hepatology 2019. Sep 71(3); 616–630.

This article reviews the most recent data regarding hepatocellular carcinoma (HCC), a highly diverse cancer, focusing on its molecular and histological characteristics.  Employing high-throughput sequencing and gene expression profiling, novel distinct transcriptomic subclasses and several recurrent genetic alterations are characterized.  Numerous HCC subtypes with distinct histological features are discussed.  HCC phenotype seems parallel to certain gene mutations, tumor subgroups and/or oncogenic pathways. For instance, well-differentiated, CTNNB1-mutated HCCs exhibit a homogeneous subtype characterized by cholestasis, microtrabecular and pseudoglandular architectural patterns; another non-proliferative subtype shows a gene expression pattern similar to that of mature hepatocytes and displays a steatohepatitic phenotype. In contrast, proliferative HCCs are most often poorly differentiated and possess progenitor features. A new morphological variant of proliferative HCC referred to as ‘‘macrotrabecular-massive”, is linked with angiogenesis activation and poor prognosis. This article discusses a compilation of novel information that will potentially lead to improved precision medicine for this highly aggressive malignancy.

American Journal of Clinical Pathology

Recurrent Idiopathic Liver Allograft Failure.
Schiano TD, Florman S, Fiel MI. Am J Clin Pathol. 2019 Aug 1; 152(3): 369-376.

This article better characterizes clinical and histopathological features of antibody-mediated rejection (AMR) as a major contributing factor of recurrent idiopathic liver allograft failure, highlighting the need for pathologists and transplant physicians to recognize the varied histopathological features of AMR necessary for allograft-saving timely medical interventions.

American Journal of Gastroenterology

Histologic Findings of Advanced Fibrosis and Cirrhosis in Patients With Nonalcoholic Fatty Liver Disease Who Have Normal Aminotransferase Levels.
Gawrieh S, Wilson LA, Cummings OW, Clark JM, Loomba R, Hameed B, Abdelmalek MF, Dasarathy S, Neuschwander-Tetri BA, Kowdley K, Kleiner D. Am J Gastroenterol. 2019 Oct 1; 114(10):1626-35.

This paper studied 534 adults with biopsy-proven NAFLD and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <40U/L within 3 months of their liver biopsy. The authors found that the prevalence of NASH F2-F3 and cirrhosis was 19% and 7%, respectively. The main risk factors for NASH F2-3 were type 2 diabetes, white race, lower low-density lipoprotein, lower platelet count, higher AST/ALT ratio, higher serum triglycerides, and hypertension. The conclusion was that patients with these risk factors are more likely to have significant fibrosis in their liver biopsy.

Combined Hepatocellular Cholangiocarcinoma: A Population-Based Retrospective Study.
Ramai D, Ofosu A, Lai JK, Reddy M, Adler DG. Am Journal Gastroenterol. 2019 Sep 1; 114(9):1496-501.

In this study the overall incidence of combined hepatocellular cholangiocarcinoma (CHC) between 2004 and 2014 was 0.05 per 100,000 per year. Incidence increased with age, with the highest incidence in men occurring between 60 and 64 years and 75–79 years for women. Women had a higher incidence of CHC. Most tumors were poorly differentiated while the most common stage at presentation was stage 4.  This paper adds to our knowledge, but in the absence of histological review the conclusions must be considered provisional.

Prepared by:
Nafis Shafizadeh MD (Editor); Southern California Permanente Medical Group
Daniela Allende MD; Cleveland Clinic
Vishal Chandan MBBS; University of California Irvine
Robert Goldin MD; Imperial College, London
Bella Goyal MD; California Pacific Pathology Medical Group
Grace Guzman MD; University of Illinois
Mojgan Hosseini MD; University of California San Diego
Heather Stevenson-Lerner MD PhD; University of Texas
Eric Yee MD; University of Arkansas

Monday, November 18, 2019

President's Message October 2019

Dear Friends and Fellow Hepatophiles,

We are approaching the  end of the year and requests for renewal of membership will be going out soon.  If you are interested in joining one of the HPHS committees, please indicate your preference with your renewal.  The new committee appointments are typically discussed by the Executive committee before the USCAP annual meeting.

The society is gearing up for the USCAP meeting next year.  The line-up for the Companion  Society meeting is final and preparations for the Hans Popper reception are underway.  The HPHS education committee will soon send an invitation for submission of accepted abstracts for the Trainee award.  Look out for the Abstract Award and other USCAP-related announcements, which will be sent by email, and also posted on the website and Twitter.

Several other changes are also in the works.  The Website committee has been working diligently on a new and updated website, which is expected to go live early next year.  The Executive committee has been reviewing the Bylaws and Standard Operating Procedures.  Updates to these documents will be finalized and presented to the membership at the HPHS at USCAP.

I urge all members to actively participate in the society’s endeavors by volunteering for a committee, contributing to case of the month, sharing ideas for member surveys, and sending your feedback.


Sanjay Kakar, MD
President, Hans Popper Hepatopathology Society

Interesting Case October 2019

Case contributed by:
Bailey Hutchison, M.D. and Joseph Misdraji, M.D.
Massachusetts General Hospital Department of Pathology, Boston, MA

Clinical History 
A 52-year-old female with a history of ankylosing spondylitis on immunosuppression presented with a 15-pound weight loss, fatigue, and night sweats over 4 months. Three years prior, she had undergone open heart mitral valve annuloplasty for rheumatic mitral valve stenosis. Laboratory investigation revealed pancytopenia, alkaline phosphatase of 1,070 U/mL, AST of 115 U/L and ALT of 51 U/L.  Anti-smooth muscle antibody was positive. Angiotensin converting enzyme was 151 U/L (ULN 67 U/L). An MRI demonstrated splenomegaly.  A viral hepatitis panel and tuberculosis screen prior to the initiation of immunosuppressive therapy had been negative. Liver and bone marrow biopsies were performed.

Pathologic Findings 
Figure 1:  Low power view of the liver biopsy shows marked sinusoidal congestion and steatosis.
Figure 1

Figure 2: Medium power view of the liver biopsy shows a granuloma (upper right) with a background of marked sinusoidal congestion with hepatic plate attenuation and steatosis.
Figure 2

Figure 3: High power view of the liver biopsy shows small non-necrotizing loose granuloma in a background of sinusoidal congestion and steatosis.
Figure 3

Figure 4: High power view of the bone marrow biopsy shows a small granuloma.
Figure 4
Disseminated non-tuberculous mycobacterial infection following cardiac surgery.

Infection by non-tuberculous mycobacteria has been associated with contamination of medical instruments and potable water supplies in hospitals and other healthcare settings. Mycobacterium chimaera is the most widely known example, with numerous cases associated with contaminated heater-cooler water units used in cardiac surgery. Infection by or outbreaks of M. abscessus have also been reported, although the association with cardiac surgery is less clear than with M. chimaera.

M. chimaera is a species of the Mycobacterium avium complex which became notorious in 2015 when Sax and colleagues in Zurich reported 6 patients who had prosthetic valve endocarditis or vascular graft infections due to M. chimaera. An investigation pointed to contaminated heater-cooler water units used in open-heart surgery. It is believed that contamination occurred during the manufacturing process and during surgery, M. chimaera became aerosolized by the rear cooling fan and contaminated the surgical field.  Since the original report, numerous cases have been reported. Because the latency period before symptomatic infection can be as long as 5 years (median 18 months), there is concern that the outbreak is not over. The most common clinical presentations of M. chimaera infection are cardiac manifestations (endocarditis, vascular graft infection, and mycotic aneurysm) or wound infections (mediastinitis and sternal wound infection), and most patients have prosthetic material that serves as a nidus for infection. Granulomatous disease that mimics sarcoidosis has been described, and patients are not infrequently inappropriately treated with immunosuppression for sarcoidosis or a presumed autoimmune disorder. In patients infected with M. chimaera, liver function tests typically show a biliary pattern of injury, with prominent alkaline phosphatase elevation and only mildly elevated aminotransferases.

The histologic features in the liver have been described in a small number of cases and include small ill-formed collections of histiocytes in sinusoids together with changes of venous outflow obstruction (e.g., sinusoidal dilation, congestion, and hepatic plate atrophy). Well-formed granulomas and giant cells are  absent in reported cases.  AFB stain is insensitive but PCR from tissue extracts can be positive. Culture remains the gold standard for diagnosis, and M. chimaera can be isolated from blood, urine, and affected body tissues.

In this case, despite the suspicion for M. chimaera, the organism was never able to be cultured. Instead, M. abscessus was cultured from an axillary lymph node. The patient was treated for disseminated mycobacterial infection for 18 months and her symptoms resolved. She underwent explant of the mitral valve annuloplasty ring with mitral valve replacement using homograft.  A follow-up liver biopsy later showed mild cardiac-type fibrosis with resolution of granulomas.

1.       Sax H, Bloemberg G, Hasse B, et al. Prolonged outbreak of Mycobacterium chimaera infection after open-chest heart surgery. Clin Infect Diseases. 2015;61:67-75
2.       Kothavade RJ, Dhurat RS, Mishra SN, Kothavade UR. Clinical and laboratory aspects of the diagnosis and management of cutaneous and subcutaneous infections caused by rapidly growing mycobacteria. Eur J Clin Microbiol Infect Dis 2013;32:161-188.
3.       Shafizadeh N, Hale G, Bhatnagar J, Alshak N, Nomura, J. Mycobacterium chimaera hepatitis:  a new disease entity. Am J Surg Pathol 2019;43(2):244-250.
4.       Schreiber PW, Hasse B, Sax H. Mycobacterium chimaera infections after cardiac surgery-lessons learned. Clin Microbiol Infect 2008;24 (11):1117-1118.
5.       Scriven JE, Scobie A, Verlander NQ, Houston A, Collyns T, Cajic V, et al. Mycobacterium chimaera infection following cardiac surgery in the United Kingdom: clinical features and outcome of the first 30 cases. Clin Microbiol Infect 2018;24:1164-70.
6.       Stammers AH, Riley JB. The heater cooler as a source of infection from nontuberculous mycobacteria. JECT 2016;48:55-59.
7.       Baker AW, Lewis SS, Alexander BD, et al. Two-phase hospital-associated outbreak of Mycobacterium abscessus: Investigation and mitigation. CID 2017;64:902-911.

Friday, September 27, 2019

HPHS Journal Watch: July/August 2019


Improvements in Histologic Features and Diagnosis Associated With Improvement in Fibrosis in Nonalcoholic Steatohepatitis: Results From the Nonalcoholic Steatohepatitis Clinical Research Network Treatment Trials.
Brunt EM, Kleiner DE, Wilson LA, et al. Hepatology. 2019 Aug;70(2):522-531.

This is a retrospective study focusing on outcomes from Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with NASH Trial (PIVENS) and Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial (FLINT) and analyzing baseline and final biopsies. This study sought associations between observed improvements in fibrosis with improvement in specific histologic features, nonalcoholic fatty liver disease activity score (NAS) ≥2, diagnostic category, and primary histologically based outcomes of two adult NASH treatment trials. In PIVENS 221/240 subjects had baseline and 96-week biopsies, and in FLINT 200/283 subjects had baseline and 72-week biopsies. Fibrosis improvement was seen in a greater total number of PIVENS (38%) treated subjects (pioglitazone 44%, vitamin E 41%) compared to FLINT total (29%) treated subjects and less likely in placebo subjects in both studies. Controlling for treatment group, fibrosis improvement was associated most strongly with resolution of NASH (PIVENS, odds ratio [OR], 3.9; 95% confidence interval [CI] 2.0-7.6; P < 0.001; FLINT, OR, 8.0; 95% CI 3.1-20.9; P < 0.001), and improved NAS by ≥2 (PIVENS, OR, 2.4; 95% CI 1.3-4.3; P = 0.003; FLINT, OR, 4.2; 95% CI 2.1-8.3; P < 0.001). Improved fibrosis was associated with improved steatosis, ballooning, Mallory-Denk bodies, and portal, but not lobular, inflammation. These findings support a strong link between histologic resolution of steatohepatitis with improvement in fibrosis in NASH.

Phenobarbital-Induced Liver Injury With Nodal Angiomatosis.
Cheng LT, Yeh MM, Lu CC. Hepatology. 2019 Jul;70(1):437-439.

This is a case report on an 18 year old presenting with fever, atypical lymphocytosis, and lymphadenopathy due to phenobarbital induced injury. The authors found approximately 90 and 41 cases of phenobarbital-induced liver injury reported in LiverTox and VigiBase, respectively. In their case, RUCAM scores for phenobarbital were 8 corresponding to “probable” status after excluding other etiologies. Histologic findings in the liver included interface hepatitis with inflammatory infiltrates in the portal area extending into the hepatic lobule. Foci of hepatocytic lytic necrosis, hepatocytic swelling, cholestasis, and acidophil bodies were observed. Although similar, autoimmune hepatitis was excluded based on clinical presentation and resolution of liver enzymes without steroids. Bone marrow revealed normal cellularity without abnormal blasts or malignant cells. Histological examination of the axillary lymph nodes showed a proliferation of small blood vessels in the sinus lined by hyperplastic endothelial cells, compatible with nodal angiomatosis. Bacillary angiomatosis and Kaposi sarcoma were reasonably excluded based on the absence of bacteria, neutrophils, Warthin-Starry staining, and malignant cells from nodal biopsy and negative serum tests.

American Journal of Surgical Pathology

Macrotrabecular Hepatocellular Carcinoma: An Aggressive Subtype of Hepatocellular Carcinoma.
Jeon Y, Benedict M, Taddei T, Jain D, Zhang X. Am J Surg Pathol. 2019 Jul;43(7):943-948.

The macrotrabecular (MT) subtype of hepatocellular carcinoma (MT-HCC) has recently been shown to have specific molecular alterations and a worse prognosis. Previous studies have defined MT-HCC as neoplasms with trabeculae >6 cells thick that comprise >50% of the tumor. The purpose of this study was to determine the significance of lesser proportions of a MT component. This retrospective study compared 41 HCCs with a MT component to 105 conventional HCCs (CV-HCC). HCCs with 10-29% MT component showed similar clinicopathologic features to CV-HCC. Meanwhile, HCCs with ³30% MT component more commonly showed the following characteristics compared to CV-HCC: tended to be larger; seen in non-cirrhotic livers; present in patients with chronic viral hepatitis B; contained anaplastic tumor cells; displayed microvascular invasion; had higher pathologic stage; were of higher histologic grade; associated with higher AFP levels. Patients that had HCCs with ³30% MT component had a decreased overall and recurrence-free survival. This study confirms prognostic findings from previous studies and the authors propose a lower cutoff for MT pattern requirement (³30% rather than >50% MT component) for diagnosis of MT-HCC.

Clinical Gastroenterology and Hepatology
Primary Gastrointestinal Stromal Tumor of the Liver
Hu HJ, Fu YY, Li FY. Clin Gastroenterol Hepatol. 2019 August;17(9):e106.

A 79-year-old woman presented with epigastric discomfort.  A mass was excised from the liver and additional studies including immunohistochemical stains (GIST1 and CD34) confirmed the presence of a gastrointestinal stromal tumor (GIST).  A primary from another site was not identified and the tumor was diagnosed as a primary hepatic GIST.

Modern pathology

Detection of DNA damage response in nonalcoholic fatty liver disease via p53-binding protein 1 nuclear expression.
Akazawa Y, Nakashima R, Matsuda K, et al. Modern Pathology. 2019 Jul;32(7):997-1007.

Nonalcoholic fatty liver disease is a major liver disease that leads to cirrhosis and/or hepatocellular carcinoma in a subset of patients.  The authors investigated nuclear 53BP1-positive foci formation as an indicator of DNA double-strand breaks in human nonalcoholic fatty liver disease tissues by immunofluorescence microscopy in 52 liver tissue samples, including 43 nonalcoholic fatty liver disease samples and 9 controls. They showed that the number of abnormal 53BP1-positive foci in hepatocytes (defined as three or more discrete nuclear foci and/or large foci greater than 1 μM) was significantly increased in nonalcoholic fatty liver disease compared to controls, both in nonalcoholic fatty liver and nonalcoholic steatohepatitis patients (p < 0.01). Analysis of 53BP1 expression might be a feasible technique to estimate genomic instability in nonalcoholic fatty liver disease.

Journal of Gastroenterology and Hepatology 

Screening for non‐alcoholic fatty liver disease in patients with type 2 diabetes mellitus using transient elastography.
Lai LL, Wan Yusoff WN, Vethakkan SR, et al. Gastroenterol Hepatol. 2019 Aug;34(8):1396-1403.

This paper studies the prevalence of NALFD and advanced fibrosis among T2DM patients. The study includes 557 patients (mean age 61.4 ± 10.8 years, male 40.6%). Of the 171 patients with liver stiffness measurement ≥ 8 kPa, 71 patients underwent liver biopsy. The majority had non-alcoholic steatohepatitis (83.1%) and ≥ F1 fibrosis (87.3%) while advanced fibrosis was seen in 36.6%. The prevalence of NAFLD and advanced fibrosis based on transient elastography was 72.4% and 21.0%, respectively. On multivariate analysis, independent factors associated with NAFLD were central obesity (OR 4.856, 95% confidence interval [CI] 2.749-8.577, P = 0.006), serum triglyceride (OR 1.585, 95% CI 1.056-2.381, P = 0.026), and alanine aminotransferase levels (OR 1.047, 95% CI 1.025-1.070, P < 0.001) while advanced fibrosis was associated with serum high-density lipoprotein cholesterol (OR 0.355, 95% CI 0.126-0.997, P = 0.049), alanine aminotransferase (OR 1.023, 95% CI 1.009-1.037, P = 0.001), γ-glutamyltransferase (OR 1.005, 95% CI 1.001-1.008, P = 0.017), and platelet levels (OR 0.995, 95% CI 0.992-0.999, P = 0.010). Seventy-one patients underwent liver biopsy.

Journal of Hepatology

Wilson’s disease: Fatal when overlooked, curable when diagnosed.
Ferenci P, Ott P. J Hepatol. 2019 Jul;71(1):222-224.

A snapshot summary of the highlights of Wilson’s disease (WD) could be found in the July issue. Briefly, WD is an autosomal recessive disorder caused by mutations in the ATP7B gene. Hepatic ATP7B protein regulates the whole body content of copper by mediating its excretion into bile or irreversible incorporation into ceruloplasmin. Liver histology is non-specific and may include the whole spectrum of liver pathology. Steatosis is a common finding in non-cirrhotic patients where it may resemble non-alcoholic steatohepatitis. Most often a range of tests including measurements related to copper metabolism (serum copper, ceruloplasmin, urinary copper excretion, hepatic copper content) and molecular genetic testing are needed to diagnose or exclude WD. Life-long treatment with copper-chelators (D-penicillamine triethylenetetramine, tetrathiomolybdate) or zinc is needed.

Glycolytic activation of peritumoral monocytes fosters immune privilege via the PFKFB3-PD-L1 axis in human hepatocellular carcinoma.
Chen DP, Ning WR, Jiang ZZ, et al. J. Hepatol. 2019. Aug;71(2), 333–343.

Programmed cell death 1 ligand 1 (PD-L1) expressed on antigen-presenting cells, rather than tumor cells, has been described to carry a key role in checkpoint blockade therapy.  Understanding of mechanisms that control the manifestation of PD-L1 on tumor-infiltrating monocytes/macrophages will usher development of new PD-L1 blockade schemes with high specificity and efficiency. The current study shows a novel mechanism by which metabolic switching links immune activation responses to immune tolerance in the tumor milieu, recognizing possible targets for upcoming immune-based anticancer therapies.

PD-L1 expression on antigen-presenting cells (APCs) is vital for T cell impairment, and PD-L1-expressing dendritic cells and macrophages may therapeutically predict the clinical efficacy of PD-L1/PD-1 blockade. The authors state that the current study provides proof that cellular glycolysis arbitrates the stimulation of monocytes by tumor microenvironmental signals, which lead to the induction of PD-L1 expression on these cells and consequent autologous CD8+ T cell suppression in peritumoral tissues of human HCC. Notably, a key glycolytic enzyme, PFKFB3, has been identified as an important mediator regulating PD-L1 expression on peritumoral monocytes by activation of the NF-jB signaling pathway.

American Journal of Clinical Pathology 

Albumin In Situ Hybridization Can Be Positive in Adenocarcinomas and Other Tumors From Diverse Sites.
Nasir A, Lehrke HD, Mounajjed T, et al. Am J Clin Pathol. 2019 Jul 5;152(2):190-199.

The authors evaluated 221 tumors for albumin mRNA. Albumin mRNA was detected in all hepatocellular carcinomas (HCCs) and 81% of intrahepatic cholangiocarcinomas. Carcinomas of lung (20%), gallbladder (39%), and breast (18%) origin showed expression. Yolk sac tumor (25%) and acinar cell carcinoma (29%) also showed expression. The authors discuss the potential diagnostic pitfalls of albumin ISH.


British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis.
Chapman MH, Thorburn D, Hirschfield GM, et al. Gut. 2019 Aug;68(8):1356-1378.

When assessing the role of liver biopsy, the authors (quoting Am J Gastroenterol 2003;98:1155) are consistent with other recent guidelines (including, e.g., AASLD) that the newer imaging techniques have reduced the need for a liver biopsy. They suggest that there is a role when there is a clinical suspicion of IgG4-SC, PSC overlap/variant syndromes and for diagnosis of small duct PSC, and that biopsy may also help in otherwise unexplained cholestasis.

They provide a useful review of the range of pathological changes seen in PSC (Gut 1980; 21:870) but point out that onion skin fibrosis is rarely seen in a liver biopsy and that the biopsy usually only shows the generic features of chronic cholestasis. The way in which PSC can be staged histologically is also described (Hepatology 1981;1:632), although this is rarely done in practice. Overall, they recommend that liver biopsy is normally reserved for possible small duct PSC, assessment of suspected possible overlap variants, or instances where the diagnosis is unclear. They assess this as strong recommendation supported by moderate quality evidence.

Also included is a useful review of IgG4-related sclerosing cholangitis which emphasizes the role of biopsy and the diagnostic criteria. They point out that while FNA cytology is useful to exclude malignancy it cannot be relied upon to make the diagnosis of IgG4-RD. On the other hand, the safety and ease whereby biopsies of the major papilla can be taken makes this a useful site to obtain tissue from.

American Journal of Gastroenterology

Gastrointestinal Manifestations of Rheumatological Diseases.
Krӧner PT, Tolaymat OA, Bowman AW, et al. Am J of Gastroenterology. 2019 Sep;114(9):1441-54.

This is a useful review which, understandably, focuses on the gut involvement in these diseases, but hepato-biliary involvement is also covered.

Human Pathology

Evaluation of histologic changes in the livers of patients with early and late hepatic artery thrombosis.
Lee M, Agostini-Vulaj D, Gonzalez RS. Hum Pathol. 2019 Aug;90:8-13.

Hepatic artery thrombosis (HAT) following orthotopic liver transplant (OLT) is a common vascular postoperative complication that can occur early (<30 days since OLT) or late (>30 days since OLT). This study investigated the histopathologic features in biopsy and resection specimens of early and late HAT. 94 cases (25 biopsies and 69 explanted hepatectomies) from 69 patients were studied.  Common histologic findings in HAT included lobular necrosis, portal inflammation, ductular reaction, lobular cholestasis, and bile-tinged macrophages. Lobular necrosis was more common in early HAT and ductular reaction and bile in veins were more common in late HAT.  This study reports on the spectrum of findings and highlights potential diagnostic pitfalls.


Transferrin receptor 1 overexpression is associated with tumour de-differentiation and acts as a potential prognostic indicator of hepatocellular carcinoma.
Adachi M, Kai K, Yamaji K, Ide T, Noshiro, Kawaguchi, Aishima S. Histopathology. 2019 Jul;75(1):63-73.

The aim of this study is to clarify the role of iron regulatory protein in the progression of hepatocellular carcinoma (HCC) and patient outcome. The authors investigated the mRNA level of iron metabolism-related genes, including hepcidin, ferroportin 1 (FPN-1) and transferrin receptor (TFR)-1/2 in 210 cases of HCC. TFR-1/2 protein expression was then evaluated in surgical specimens from 210 cases using immunohistochemistry, and also compared the clinicopathological factors with TFR-1/2 expression. The mRNA expression levels of TFR-1 were significantly increased in HCC tissues compared with adjacent non-cancerous tissues (P = 0.0013), but there were no differences in other genes. High expression of TFR-1 in HCC was associated with the absence of alcohol abuse (P = 0.0467), liver cirrhosis (P < 0.0001), higher alpha-fetoprotein (AFP; P < 0.0001), smaller tumour size (P = 0.0022), poor histological differentiation (P < 0.0001) and morphological features (P < 0.0001). In contrast, high expression of TFR-2 in HCC was associated with lower AFP (P < 0.0001), well-differentiated histological grade (P < 0.0001) and morphological features (P = 0.0010). Multivariate analysis for both overall survival and recurrence-free survival indicated that high TFR-1 expression was a significant prognostic factor for poor outcome. The authors conclude that an inverse correlation of TFR-1 and TFR-2 expression in AFP and tumour differentiation. TFR-1 overexpression suggests a higher risk of recurrence and death in HCC patients following liver resection.

Prepared by:
Nafis Shafizadeh MD (Editor); Southern California Permanente Medical Group
Daniela Allende MD; Cleveland Clinic
Vishal Chandan MBBS; University of California Irvine
Robert Goldin MD; Imperial College, London
Bella Goyal MD; California Pacific Pathology Medical Group
Grace Guzman MD; University of Illinois
Mojgan Hosseini MD; University of California San Diego
Heather Stevenson-Lerner MD PhD; University of Texas
Eric Yee MD; University of Arkansas