Dataset Information

Hybrid model integrating immunohistochemistry and expression profiling for the classification of carcinomas of unknown primary site.

ABSTRACT: Identification of the site of origin for 'malignancy with unknown primary' remains a challenge for modern pathology. Correct diagnosis is critical to defining the most beneficial treatment for the patient. Standard pathological approaches combine morphology and immunohistochemical (IHC) studies to first subclassify cytokeratin-positive carcinomas into adenocarcinoma, squamous cell carcinoma, neuroendocrine carcinoma, and urothelial carcinoma. Subsequently, organ-specific IHC-markers, if available, are used to assign the tumor's primary site of origin. Previous gene expression classifiers have shown promise in tumor classification but cannot readily be integrated into standard practice because they ignore the algorithmic hierarchy used by pathologists. Here we present a novel hybrid approach integrating a hierarchy of gene expression classifiers into the algorithmic method used with IHC. In this method, a tumor is initially assigned to one of the carcinoma subclasses by the top tier classifier. Dependent on initial classification, one of three second-tier classifiers assign primary site resulting in both carcinoma subtype and primary site classification. First tier classifier accuracies were 89%, 88%, and 75% for cross-validation, independent, and institutional independent test sets, respectively. Second tier accuracies were 87%, 90%, and 87% for adenocarcinoma, squamous, and neuroendocrine carcinoma respectively. Therefore, we can successfully separate the four main subtypes of carcinoma and subsequently assign primary site by incorporation of gene expression-based classifiers into the standard algorithmic pathology approach.

SUBMITTER: Centeno BA

PROVIDER: S-EPMC2893632 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Hybrid model integrating immunohistochemistry and expression profiling for the classification of carcinomas of unknown primary site.

Centeno Barbara A BA Bloom Gregory G Chen Dung-Tsa DT Chen Zhihua Z Gruidl Mike M Nasir Aejaz A Yeatman Timothy Y TY

The Journal of molecular diagnostics : JMD 20100617 4

Identification of the site of origin for 'malignancy with unknown primary' remains a challenge for modern pathology. Correct diagnosis is critical to defining the most beneficial treatment for the patient. Standard pathological approaches combine morphology and immunohistochemical (IHC) studies to first subclassify cytokeratin-positive carcinomas into adenocarcinoma, squamous cell carcinoma, neuroendocrine carcinoma, and urothelial carcinoma. Subsequently, organ-specific IHC-markers, if availabl ...[more]

PMID: 20558571

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Project description:BackgroundCarcinoma of unknown primary origin (CUP) accounts for 2%-5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm.Materials and methodsCentrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture-based FoundationOne CDx assay (mean coverage, >600×). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed death-ligand 1 (PD-L1) positivity were determined.ResultsA total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabase of DNA; 34 patients (11.6%) had a TMB ≥16 mutations per megabase. Three patients (1%) had high MSI, and 42 (14%) displayed high PD-L1 expression (tumor proportion score ≥50%). gLOH could be assessed in 199 of 303 specimens; 19.6% had a score of >16%.ConclusionsThirty-two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD-L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP-informed treatment. Clinical trial identification number. NCT03498521 IMPLICATIONS FOR PRACTICE: The findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, such as programmed death-ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling-informed treatment.

Dataset Information

Hybrid model integrating immunohistochemistry and expression profiling for the classification of carcinomas of unknown primary site.

Publications

Hybrid model integrating immunohistochemistry and expression profiling for the classification of carcinomas of unknown primary site.

Similar Datasets

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