3/28/2017
A LIVER TUMOR WITH
AN IDENTITY CRISIS
Stephen M. Lagana MD
Assistant Professor of Pathology
Columbia University Medical Center
New York, NY USA
[email protected]
Disclosure of Relevant
Financial Relationships
USCAP requires that all planners (Education Committee) in a position to
influence or control the content of CME disclose any relevant financial
relationship WITH COMMERCIAL INTERESTS which they or their
spouse/partner have, or have had, within the past 12 months, which relates
to
the content of this educational activity and creates a conflict of interest.
I have no relevant financial disclosures
Thomas Starzl, MD. Died on March 3, 2017
CASE HISTORY
• Elderly female
• ETOH user, but not known to have cirrhosis
• Abdominal fullness
• LFT normal
• 4-5 lesions in the liver with 5.7cm dominant nodule
• PET CT otherwise normal
• Biopsy obtained
1
3/28/2017
Differential Diagnosis, take 1
• Obviously malignant
Histological features of HCC and ChCa (or Met PBAdca)
Features that favor HCC
Features that favor ChCa
• Obviously carcinoma
• Not obviously primary or secondary
• Cells quite pink
• IHC markers of common sites of metastasis negative
• TTF1
• CDX2
• PAX8
• GATA3
• Somewhat trabecular
• No definite gland
formation
• No definite mucin
• Extensively fibrotic tumor
stroma
• Wouldn’t swear that there
are no glands
• No bile identified
production
• Main considerations:
• HCC
• Intrahepatic cholangiocarcinoma (ChCa)
• Metastatic pancreatobiliary adenocarcinoma
2
3/28/2017
3
3/28/2017
Conclusion
Preserved portal tract (different case)
• Scirrhous variant of hepatocellular carcinoma
• Rare
• Cords and nests of neoplastic cells in dense fibrous stroma
{Matsuura 2005}
• Cells have hepatoid morphology
• Must NOT have mucin production
• Mucin is a feature of adenocarcinoma, not HCC
• Seems to have similar clinical features and prognosis as
traditional HCC
• Distinction from traditional HCC probably not relevant for
clinical care (as of today)
• Distinction from ChCa and metastatic disease critical
Ancillary testing
Immunohistochemistry
{Krings 2013}
• General theme-expresses markers of hepatic and biliary
differentiation
• Need some HCC marker; would not make dx without at
least 1 convincing marker
• Must not produce mucin (should be proven)
• Newer markers such as albumin ISH and bile salt export
pump not yet investigated
GPC3 and ARG
combined for 100%
sensitivity
• In my experience, these have both been positive in 2 of 2 cases
{Lagana 2012}
Differential Diagnosis, deeper dive
• Combined HCC-ChCa
• Should have biphasic morphology
• Populations should stain distinctively
• Combined hepatocellular-cholangiocarcinoma with stem cell
Newer markers in liver tumors
• Bile Salt Export Pump
• Present exclusively in hepatocytes at the bile canaliculus
• Main driver of bile salt efflux from hepatocyte
• Genetic lack of BSEP causes PFIC2
features, intermediate cell type
• According to WHO 2010, the cells are “small, oval-shaped, with
hyperchromatic nuclei and scant cytoplasm”
• Scirrhous HCC cells look like HCC
• Scirrhous HCC does not express much C-KIT or CD56 {Krings 2013}
• Fibrolamellar HCC
• Very different patient population (kids, young adults), no cirrhosis
• Recent discovery of a chimeric kinase due to a deletion on Ch.19
resulting in DNAJB1-PRKACA transcript {Honeyman 2014}
• Detectable by PCR, FISH, and mRNA ISH {Graham 2015}
4
3/28/2017
Additional studies on BSEP
{Nguyen 2015}
BSEP was diluted to 1:200 vs. 1:100 and incubation was 15m
compared to 32m
Low grade HCC, BSEP
High grade HCC
High grade HCC, BSEP
{Lagana 2015}
{Fujikura 2016}
Conclusions regarding BSEP
In-situ hybridization for albumin
• Seems to be most specific marker for HCC
• Due to lack of expression in other cell types/carcinomas, do not
need canalicular pattern to consider positive
• Targets mRNA for albumin
• Though usually canalicular
• Sensitivity is good overall, but drops with worsening
differentiation
• Need to optimize in your lab
• Useful as part of a panel
• Commercially available kit which runs on automated platform
• Positive
• HCC, excellent sensitivity (92 of 93 HCC) {Shahid 2015}
• Intrahepatic cholangiocarcinoma
• Highly sensitive {Ferrone 2016}
• Less highly sensitive {Avadhani, USCAP 2017, #1657}, {Lehrke, USCAP 2017, #1680}
• Bile duct adenomas {Moy 2016}
• Hepatoblastoma, fibrolamellar HCC {Koehne de Gonzalez USCAP 2016,
#1667}
• Negative
• Most other cancers (including PDAC, Distal CBD, Klatskin) {Ferrone 2016}
• Pitfalls
• Pancreatic acinar carcinoma {Askan 2016}
• Occasional adca of diverse sites {Lehrke, USCAP 2017, #1680}
Albumin ISH in ChCa
Conclusions regarding albumin ISH
• Excellent sensitivity for HCC
• Probably good sensitivity for intrahepatic ChCa
• ? kit, other factors
• This multispecificity means cannot help differentiate HCC
from ChCa
• Cannot discriminate BDA vs. ChCa
• Evolving understanding of pitfalls
5
3/28/2017
Approach to PD liver tumors
Steve’s Preferred Approach
(based on literature, experience,
and the quirks of our lab).
*Combining steps perfectly reasonable
Albumin ISH
HCC stains
10&20)
CK (pan), CK8/18, LMWCK, CK5, CK7, CK19, CK20, S100, HMB45, CD45, CKIT. Let’s assume some CK positivity
TTF1, GATA3, PAX8, NKX3.1, CDX2. Let’s assume not obviously metastatic
Positivity favors HCC or IH‐ChCa. PDAC, Klatskin generally negative
Mucin
IH‐ChCa
1st line
Any
Arginase, GPC3, BSEP
• Need to build a base of experience with these tests
• If limited tumor, get 20 serial blanks with occasional H&E (Bl
Carcinoma
Exclude metastasis
• Careful H&E assessment, consideration of clinical hx
• Keep the basics in mind (mucin, bile)
• Keep the pitfalls in mind
• Let the amount of tumor determine your work-up
• No silver bullets
• Cost of ancillary testing in pathology is a rounding error in cancer
care
PD Tumor 2nd
line
HepPar, CD10, pCEA, AFP
HCC
Any If all HCC markers ‐, but albumin
+, consider IH‐ChCa. However, if 7/19 and mucin negative, consider “undifferentiated carcinoma, favor primary.” If albumin – and HCC markers negative, consider “PD/undiff
carcinoma, favor secondary” and give ddx based on remainder of markers/histology.
Consider variants. If fibrotic and expresses biliary CK, consider
scirrhous HCC. If pediatric, consider FL‐HCC
R/O combined HCC/Cholangio
If lacks classic histo of HCC & ChCa, consider stem cell markers
References
1.
Askan G, Deshpande V, Klimstra DS, Adsay V, Sigel C, Shia J, et al. Expression of Markers of Hepatocellular Differentiation in Pancreatic Acinar Cell Neoplasms: A Potential Diagnostic Pitfall. Am J Clin Pathol. 2016;146(2):163‐9.
2.
Ferrone CR, Ting DT, Shahid M, Konstantinidis IT, Sabbatino F, Goyal L, et al. The Ability to Diagnose Intrahepatic Cholangiocarcinoma Definitively Using Novel Branched DNA‐Enhanced Albumin RNA In Situ Hybridization Technology. Ann Surg Oncol. 2016;23(1):290‐6.
3.
Fujikura K, Yamasaki T, Otani K, Kanzawa M, Fukumoto T, Ku Y, et al. BSEP and MDR3: Useful Immunohistochemical Markers to Discriminate Hepatocellular Carcinomas From Intrahepatic Cholangiocarcinomas and Hepatoid Carcinomas. Am J Surg Pathol. 2016;40(5):689‐96.
4.
Graham RP, Jin L, Knutson DL, Kloft‐Nelson SM, Greipp PT, Waldburger N, et al. DNAJB1‐PRKACA is specific for fibrolamellar
carcinoma. Mod Pathol. 2015;28(6):822‐9.
5.
Honeyman JN, Simon EP, Robine N, Chiaroni‐Clarke R, Darcy DG, Lim, II, et al. Detection of a recurrent DNAJB1‐PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science. 2014;343(6174):1010‐4.
6.
Jensen K, Krusenstjerna‐Hafstrom R, Lohse J, Petersen KH, Derand H. A novel quantitative immunohistochemistry method for precise protein measurements directly in formalin‐fixed, paraffin‐embedded specimens: analytical performance measuring HER2. Mod
Pathol. 2017;30(2):180‐93.
7.
Krings G, Ramachandran R, Jain D, Wu TT, Yeh MM, Torbenson M, et al. Immunohistochemical pitfalls and the importance of glypican 3 and arginase in the diagnosis of scirrhous hepatocellular carcinoma. Mod Pathol. 2013;26(6):782‐91.
8.
Lagana SM, Moreira RK, Remotti HE, Bao F. Glutamine synthetase, heat shock protein‐70, and glypican‐3 in intrahepatic cholangiocarcinoma and tumors metastatic to liver. Appl Immunohistochem Mol Morphol. 2013;21(3):254‐7.
9.
Lagana SM, Salomao M, Remotti HE, Knisely AS, Moreira RK. Bile salt export pump: a sensitive and specific immunohistochemical marker of hepatocellular carcinoma. Histopathology. 2015;66(4):598‐602.
10.
Matsuura S, Aishima S, Taguchi K, Asayama Y, Terashi T, Honda H, et al. 'Scirrhous' type hepatocellular carcinomas: a special reference to expression of cytokeratin 7 and hepatocyte paraffin 1. Histopathology. 2005;47(4):382‐90.
11.
Moy AP, Arora K, Deshpande V. Albumin expression distinguishes bile duct adenomas from metastatic adenocarcinoma. Histopathology. 2016;69(3):423‐30.
12.
Nguyen T, Phillips D, Jain D, Torbenson M, Wu TT, Yeh MM, et al. Comparison of 5 Immunohistochemical Markers of Hepatocellular Differentiation for the Diagnosis of Hepatocellular Carcinoma. Arch Pathol Lab Med. 2015;139(8):1028‐34.
13.
Shahid M, Mubeen A, Tse J, Kakar S, Bateman AC, Borger D, et al. Branched chain in situ hybridization for albumin as a marker of hepatocellular differentiation: evaluation of manual and automated in situ hybridization platforms. Am J Surg Pathol. 2015;39(1):25‐34.
6