Immunohistochemical Typing of Adenocarcinomas of the Pancreatobiliary System Improves Diagnosis and Prognostic Stratification.
OBJECTIVE
Adenocarcinomas of the pancreatobiliary system are currently classified by their primary anatomical location. In particular, the pathological diagnosis of intrahepatic cholangiocarcinoma is still considered as a diagnosis of exclusion of metastatic adenocarcinoma. Periampullary cancers have been previously classified according to the histological type of differentiation (pancreatobiliary, intestinal), but overlapping morphological features hinder their differential diagnosis. We performed an integrative immunohistochemical analysis of pancreato-biliary tumors to improve their diagnosis and prediction of outcome.


METHODS
This was a retrospective observational cohort study on patients with adenocarcinoma of the pancreatobiliary system who underwent diagnostic core needle biopsy or surgical resection at a tertiary referral center. 409 tumor samples were analyzed with up to 27 conventional antibodies used in diagnostic pathology. Immunohistochemical scoring system was the percentage of stained tumor cells. Bioinformatic analysis, internal validation, and survival analysis were performed.


RESULTS
Hierarchical clustering and differential expression analysis identified three immunohistochemical tumor types (extrahepatic pancreatobiliary, intestinal, and intrahepatic cholangiocarcinoma) and the discriminant markers between them. Among patients who underwent surgical resection of their primary tumor with curative intent, the intestinal type showed an adjusted hazard ratio of 0.19 for overall survival (95% confidence interval 0.05-0.72; p value = 0.014) compared to the extrahepatic pancreatobiliary type.


CONCLUSIONS
Integrative immunohistochemical classification of adenocarcinomas of the pancreatobiliary system results in a characteristic immunohistochemical profile for intrahepatic cholangiocarcinoma and intestinal type adenocarcinoma, which helps in distinguishing them from metastatic and pancreatobiliary type adenocarcinoma, respectively. A diagnostic immunohistochemical panel and additional extended panels of discriminant markers are proposed as guidance for their pathological diagnosis.
Department of Laboratory Medicine (LABMED) Division of Pathology, Karolinska Institute, Stockholm, Sweden.|Department of Clinical Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden.
Carlos
http://orcid.org/0000-0001-6863-5959
C
Fernández Moro
Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden.
Alejandro
A
Fernandez-Woodbridge
Department of Clinical Science Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.|Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.
Melroy
M
Alistair D'souza
School of Electronic Engineering and Computer Science, Queen Mary University of London, London, United Kingdom.
Qianni
Q
Zhang
Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden.
Benedek
B
Bozoky
Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institute, Stockholm, Sweden.
Senthil Vasan
SV
Kandaswamy
Service of Pathology, Ospedale Fatebenefratelli "S. Giovanni Calibita", Rome, Italy.
Piera
P
Catalano
Department of Clinical Science Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.
Rainer
R
Heuchel
Department of Clinical Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden.
Sonia
S
Shtembari
Department of Clinical Science Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.|Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.
Marco
M
Del Chiaro
Department of Laboratory Medicine (LABMED) Division of Pathology, Karolinska Institute, Stockholm, Sweden.|Department of Clinical Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden.
Olof
O
Danielsson
Department of Laboratory Medicine (LABMED) Division of Pathology, Karolinska Institute, Stockholm, Sweden.|Department of Clinical Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden.
Mikael
M
Björnstedt
Department of Clinical Science Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.|Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.
J Matthias
JM
Löhr
Department of Clinical Science Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.|Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.
Bengt
B
Isaksson
Department of Clinical Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden.
Caroline
C
Verbeke
Department of Clinical Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden.
Béla
B
Bozóky
D000230:Adenocarcinoma / Q000175:diagnosis* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001661:Biliary Tract Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000175:diagnosis / Q000378:metabolism; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods* / Q000706:statistics & numerical data; D007414:Intestinal Neoplasms / Q000175:diagnosis / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D025341:Principal Component Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D012189:Retrospective Studies; D012680:Sensitivity and Specificity
D014408:Biomarkers, Tumor