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Elfving, H., Thurfjell, V., Mattsson, J. S., Backman, M., Strell, C. & Micke, P. (2024). Tumor Heterogeneity Confounds Lymphocyte Metrics in Diagnostic Lung Cancer Biopsies. Archives of Pathology & Laboratory Medicine, 148(1), e18-e24
Open this publication in new window or tab >>Tumor Heterogeneity Confounds Lymphocyte Metrics in Diagnostic Lung Cancer Biopsies
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2024 (English)In: Archives of Pathology & Laboratory Medicine, ISSN 0003-9985, E-ISSN 1543-2165, Vol. 148, no 1, p. e18-e24Article in journal (Refereed) Published
Abstract [en]

Context.—The immune microenvironment is involved in fundamental aspects of tumorigenesis, and immune scores are now being developed for clinical diagnostics. Objective.—To evaluate how well small diagnostic biopsies and tissue microarrays (TMAs) reflect immune cell infiltration compared to the whole tumor slide, in tissue from patients with non–small cell lung cancer. Design.—A TMA was constructed comprising tissue from surgical resection specimens of 58 patients with non–small cell lung cancer, with available preoperative biopsy material. Whole sections, biopsies, and TMA were stained for the pan-T lymphocyte marker CD3 to determine densities of tumor-infiltrating lymphocytes. Immune cell infiltration was assessed semiquantitatively as well as objectively with a microscopic grid count. For 19 of the cases, RNA sequencing data were available. Results.—The semiquantitative comparison of immune cell infiltration between the whole section and the biopsy displayed fair agreement (intraclass correlation coefficient [ICC], 0.29; P ¼ .01; CI, 0.03–0.51). In contrast, the TMA showed substantial agreement compared with the whole slide (ICC, 0.64; P , .001; CI, 0.39–0.79). The grid-based method did not enhance the agreement between the different tissue materials. The comparison of CD3 RNA sequencing data with CD3 cell annotations confirmed the poor representativity of biopsies as well as the stronger correlation for the TMA cores. Conclusions.—Although overall lymphocyte infiltration is relatively well represented on TMAs, the representativity in diagnostic lung cancer biopsies is poor. This finding challenges the concept of using biopsies to establish immune scores as prognostic or predictive biomarkers for diagnostic applications.

Place, publisher, year, edition, pages
Archives of Pathology and Laboratory Medicine, 2024
Keywords
lung cancer, immunotherapy, checkpoint inhibitors, tumor microenvironment, prognosis, PD-L1, lymphocytes
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-517148 (URN)10.5858/arpa.2022-0327-oa (DOI)001137617500012 ()
Available from: 2023-12-04 Created: 2023-12-04 Last updated: 2024-02-21Bibliographically approved
Mezheyeuski, A., Backman, M., Mattsson, J. S., Martin-Bernabe, A., Larsson, C., Hrynchyk, I., . . . Sjöblom, T. (2023). An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancers. EBioMedicine, 88, Article ID 104452.
Open this publication in new window or tab >>An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancers
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2023 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 88, article id 104452Article in journal (Refereed) Published
Abstract [en]

Background: Cancer immunity is based on the interaction of a multitude of cells in the spatial context of the tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve the accuracy in predicting disease progression.

Methods: Through a multiplex in situ analysis we evaluated 15 immune cell classes in 1481 tumour samples. Single-cell and bulk RNAseq data sets were used for functional analysis and validation of prognostic and predictive associations.

Findings: By combining the prognostic information of anti-tumoural CD8+ lymphocytes and tumour supportive CD68+CD163+ macrophages in colorectal cancer we generated a signature of immune activation (SIA). The prognostic impact of SIA was independent of conventional parameters and comparable with the state-of-art immune score. The SIA was also associated with patient survival in oesophageal adenocarcinoma, bladder cancer, lung adenocarcinoma and melanoma, but not in endometrial, ovarian and squamous cell lung carcinoma. We identified CD68+CD163+ macrophages as the major producers of complement C1q, which could serve as a surrogate marker of this macrophage subset. Consequently, the RNA-based version of SIA (ratio of CD8A to C1QA) was predictive for survival in independent RNAseq data sets from these six cancer types. Finally, the CD8A/C1QA mRNA ratio was also predictive for the response to checkpoint inhibitor therapy.

Interpretation: Our findings extend current concepts to procure prognostic information from the tumour immune microenvironment and provide an immune activation signature with high clinical potential in common human cancer types.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Tumour immunology, Macrophages, Immunoscore
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-501100 (URN)10.1016/j.ebiom.2023.104452 (DOI)000963637000001 ()36724681 (PubMedID)
Funder
Swedish Cancer Society, CAN 2018/772Swedish Cancer Society, CAN 2019/447Swedish Cancer Society, CAN 2018/816Region UppsalaInsamlingsstiftelsen Lions Cancerforskningsfond Mellansverige Uppsala-ÖrebroErik, Karin och Gösta Selanders FoundationP.O. Zetterling Foundation
Available from: 2023-05-03 Created: 2023-05-03 Last updated: 2023-05-03Bibliographically approved
Hikmet Noraddin, F., Rassy, M., Backman, M., Méar, L., Mattsson, J. S., Djureinovic, D., . . . Lindskog, C. (2023). Expression of cancer-testis antigens in the immune microenvironment of non-small cell lung cancer. Molecular Oncology, 17(12), 2603-2617
Open this publication in new window or tab >>Expression of cancer-testis antigens in the immune microenvironment of non-small cell lung cancer
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2023 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 17, no 12, p. 2603-2617Article in journal (Refereed) Published
Abstract [en]

The antigenic repertoire of tumors is critical for successful anti-cancer immune response and the efficacy of immunotherapy. Cancer-testis antigens (CTAs) are targets of humoral and cellular immune reactions. We aimed to characterize CTA expression in non-small cell lung cancer (NSCLC) in the context of the immune microenvironment. Of 90 CTAs validated by RNA sequencing, eight CTAs (DPEP3, EZHIP, MAGEA4, MAGEB2, MAGEC2, PAGE1, PRAME, and TKTL1) were selected for immunohistochemical profiling in cancer tissues from 328 NSCLC patients. CTA expression was compared with immune cell densities in the tumor environment and with genomic, transcriptomic, and clinical data. Most NSCLC cases (79%) expressed at least one of the analyzed CTAs, and CTA protein expression correlated generally with RNA expression. CTA profiles were associated with immune profiles: high MAGEA4 expression was related to M2 macrophages (CD163) and regulatory T cells (FOXP3), low MAGEA4 was associated with T cells (CD3), and high EZHIP was associated with plasma cell infiltration (adj. P-value < 0.05). None of the CTAs correlated with clinical outcomes. The current study provides a comprehensive evaluation of CTAs and suggests that their association with immune cells may indicate in situ immunogenic effects. The findings support the rationale to harness CTAs as targets for immunotherapy.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
cancer-testis antigens, immune phenotype, immune-oncology, non-small cell lung cancer
National Category
Cancer and Oncology Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-522496 (URN)10.1002/1878-0261.13474 (DOI)001020469000001 ()37341056 (PubMedID)
Funder
Swedish Cancer Society, 21 1790Knut and Alice Wallenberg Foundation, 2015.0344Sjöberg Foundation
Available from: 2024-02-07 Created: 2024-02-07 Last updated: 2024-02-07Bibliographically approved
Pellinen, T., Paavolainen, L., Martín-Bernabé, A., Papatella Araujo, R., Strell, C., Mezheyeuski, A., . . . Östman, A. (2023). Fibroblast subsets in non-small cell lung cancer: Associations with survival, mutations, and immune features. Journal of the National Cancer Institute, 115(1), 71-82
Open this publication in new window or tab >>Fibroblast subsets in non-small cell lung cancer: Associations with survival, mutations, and immune features
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2023 (English)In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 115, no 1, p. 71-82Article in journal (Refereed) Published
Abstract [en]

Background

Cancer-associated fibroblasts (CAFs) are molecularly heterogeneous mesenchymal cells that interact with malignant cells and immune cells and confer anti- and protumorigenic functions. Prior in situ profiling studies of human CAFs have largely relied on scoring single markers, thus presenting a limited view of their molecular complexity. Our objective was to study the complex spatial tumor microenvironment of non-small cell lung cancer (NSCLC) with multiple CAF biomarkers, identify novel CAF subsets, and explore their associations with patient outcome.

Methods

Multiplex fluorescence immunohistochemistry was employed to spatially profile the CAF landscape in 2 population-based NSCLC cohorts (n = 636) using antibodies against 4 fibroblast markers: platelet-derived growth factor receptor-alpha (PDGFRA) and -beta (PDGFRB), fibroblast activation protein (FAP), and alpha-smooth muscle actin (αSMA). The CAF subsets were analyzed for their correlations with mutations, immune characteristics, and clinical variables as well as overall survival.

Results

Two CAF subsets, CAF7 (PDGFRA-/PDGFRB+/FAP+/αSMA+) and CAF13 (PDGFRA+/PDGFRB+/FAP-/αSMA+), showed statistically significant but opposite associations with tumor histology, driver mutations (tumor protein p53 [TP53] and epidermal growth factor receptor [EGFR]), immune features (programmed death-ligand 1 and CD163), and prognosis. In patients with early stage tumors (pathological tumor-node-metastasis IA-IB), CAF7 and CAF13 acted as independent prognostic factors.

Conclusions

Multimarker-defined CAF subsets were identified through high-content spatial profiling. The robust associations of CAFs with driver mutations, immune features, and outcome suggest CAFs as essential factors in NSCLC progression and warrant further studies to explore their potential as biomarkers or therapeutic targets. This study also highlights multiplex fluorescence immunohistochemistry–based CAF profiling as a powerful tool for the discovery of clinically relevant CAF subsets.

Place, publisher, year, edition, pages
Oxford University Press, 2023
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-492026 (URN)10.1093/jnci/djac178 (DOI)000867162300001 ()36083003 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilInsamlingsstiftelsen Lions Cancerforskningsfond Mellansverige Uppsala-ÖrebroSjöberg Foundation
Available from: 2022-12-30 Created: 2022-12-30 Last updated: 2023-04-18Bibliographically approved
Tsakonas, G., Koulouris, A., Kazmierczak, D., Botling, J., Ortiz-Villalon, C., Nord, H., . . . Ekman, S. (2023). Matched Analyses of Brain Metastases versus Primary Non-Small Cell Lung Cancer Reveal a Unique microRNA Signature. International Journal of Molecular Sciences, 24(1), Article ID 193.
Open this publication in new window or tab >>Matched Analyses of Brain Metastases versus Primary Non-Small Cell Lung Cancer Reveal a Unique microRNA Signature
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2023 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, no 1, article id 193Article in journal (Refereed) Published
Abstract [en]

Distant spreading of tumor cells to the central nervous system in non-small cell lung cancer (NSCLC) occurs frequently and poses major clinical issues due to limited treatment options. RNAs displaying differential expression in brain metastasis versus primary NSCLC may explain distant tumor growth and may potentially be used as therapeutic targets. In this study, we conducted systematic microRNA expression profiling from tissue biopsies of primary NSCLC and brain metastases from 25 patients. RNA analysis was performed using the nCounter Human v3 miRNA Expression Assay, NanoString technologies, followed by differential expression analysis and in silico target gene pathway analysis. We uncovered a panel of 11 microRNAs with differential expression and excellent diagnostic performance in brain metastasis versus primary NSCLC. Five microRNAs were upregulated in brain metastasis (miR-129-2-3p, miR-124-3p, miR-219a-2-3p, miR-219a-5p, and miR-9-5p) and six microRNAs were downregulated in brain metastasis (miR-142-3p, miR-150-5p, miR-199b-5p, miR-199a-3p, miR-199b-5p, and miR-199a-5p). The differentially expressed microRNAs were predicted to converge on distinct target gene networks originating from five to twelve core target genes. In conclusion, we uncovered a unique microRNA profile linked to two target gene networks. Our results highlight the potential of specific microRNAs as biomarkers for brain metastasis in NSCLC and indicate plausible mechanistic connections.

Place, publisher, year, edition, pages
MDPI, 2023
Keywords
non-small cell lung cancer, brain metastasis, microRNA
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-495351 (URN)10.3390/ijms24010193 (DOI)000908716700001 ()36613642 (PubMedID)
Available from: 2023-01-30 Created: 2023-01-30 Last updated: 2023-01-30Bibliographically approved
Gerdtsson, A. S., Knulst, M., Botling, J., Mezheyeuski, A., Micke, P. & Ek, S. (2023). Phenotypic characterization of spatial immune infiltration niches in non-small cell lung cancer. Oncoimmunology, 12(1), Article ID 2206725.
Open this publication in new window or tab >>Phenotypic characterization of spatial immune infiltration niches in non-small cell lung cancer
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2023 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 12, no 1, article id 2206725Article in journal (Refereed) Published
Abstract [en]

The immune microenvironment of non-small cell lung cancer (NSCLC) is heterogeneous, which impedes the prediction of response to immune checkpoint inhibitors. We have mapped the expression of 49 proteins to spatial immune niches in 33 NSCLC tumors and report key differences in phenotype and function associated with the spatial context of immune infiltration. Tumor-infiltrating leukocytes (TIL), identified in 42% of tumors, had a similar proportion of lymphocyte antigens compared to stromal leukocytes (SL) but displayed significantly higher levels of functional, mainly immune suppressive, markers including PD-L1, PD-L2, CTLA-4, B7-H3, OX40L, and IDO1. In contrast, SL expressed higher levels of the targetable T-cell activation marker CD27, which increased with a longer distance to the tumor. Correlation analysis confirmed that metabolic-driven immune regulatory mechanisms, including ARG1 and IDO1, are present in the TIL. Tertiary lymphoid structures (TLS) were identified in 30% of patients. They displayed less variation in the expression profile and with significantly higher levels of pan lymphocyte and activation markers, dendritic cells, and antigen presentation compared to other immune niches. TLS also had higher CTLA-4 expression than non-structured SL, which may indicate immune dysfunction. Neither the presence of TIL nor TLS was associated with improved clinical outcomes. The apparent discrimination in functional profiles of distinct immune niches, independent of the overall level of leukocytes, illustrates the importance of spatial profiling to deconvolute how the immune microenvironment can dictate a therapeutic response and to identify biomarkers in the context of immunomodulatory treatment.

Place, publisher, year, edition, pages
Taylor & Francis, 2023
Keywords
NSCLC, immune infiltration, tertiary lymphoid structures, tumor-infiltrating leukocytes, spatial omics
National Category
Cancer and Oncology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-502194 (URN)10.1080/2162402X.2023.2206725 (DOI)000975993900001 ()37139184 (PubMedID)
Available from: 2023-05-24 Created: 2023-05-24 Last updated: 2023-05-24Bibliographically approved
Backman, M., Strell, C., Lindberg, A., Mattsson, J. S. M., Elfving, H., Brunnström, H., . . . Micke, P. (2023). Spatial immunophenotyping of the tumour microenvironment in non-small cell lung cancer. European Journal of Cancer, 185, 40-52
Open this publication in new window or tab >>Spatial immunophenotyping of the tumour microenvironment in non-small cell lung cancer
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2023 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 185, p. 40-52Article in journal (Refereed) Published
Abstract [en]

Introduction: Immune cells in the tumour microenvironment are associated with prognosis and response to therapy. We aimed to comprehensively characterise the spatial im-mune phenotypes in the mutational and clinicopathological background of non-small cell lung cancer (NSCLC).

Methods: We established a multiplexed fluorescence imaging pipeline to spatially quantify 13 immune cell subsets in 359 NSCLC cases: CD4 effector cells (CD4-Eff), CD4 regulatory cells (CD4-Treg), CD8 effector cells (CD8-Eff), CD8 regulatory cells (CD8-Treg), B-cells, natural killer cells, natural killer T-cells, M1 macrophages (M1), CD163 thorn myeloid cells (CD163), M2 macrophages (M2), immature dendritic cells (iDCs), mature dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs).

Results: CD4-Eff cells, CD8-Eff cells and M1 macrophages were the most abundant immune cells invading the tumour cell compartment and indicated a patient group with a favourable prognosis in the cluster analysis. Likewise, single densities of lymphocytic subsets (CD4-Eff, CD4-Treg, CD8-Treg, B-cells and pDCs) were independently associated with longer survival. However, when these immune cells were located close to CD8-Treg cells, the favourable impact was attenuated. In the multivariable Cox regression model, including cell densities and distances, the densities of M1 and CD163 cells and distances between cells (CD8-Treg-B-cells, CD8-Eff-cancer cells and B-cells-CD4-Treg) demonstrated positive prognostic impact, whereas short M2-M1 distances were prognostically unfavourable.

Conclusion: We present a unique spatial profile of the in situ immune cell landscape in NSCLC as a publicly available data set. Cell densities and cell distances contribute independently to prognostic information on clinical outcomes, suggesting that spatial information is crucial for diagnostic use.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Immune cell infiltration, Multiplex imaging, Checkpoint therapy, Tumour microenvironment, Lung cancer, NSCLC
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-502648 (URN)10.1016/j.ejca.2023.02.012 (DOI)000959970600001 ()36963351 (PubMedID)
Funder
Swedish Cancer SocietySjöberg FoundationInsamlingsstiftelsen Lions Cancerforskningsfond Mellansverige Uppsala-ÖrebroErik, Karin och Gösta Selanders Foundation
Note

De två sista författarna delar sistaförfattarskapet

Available from: 2023-05-31 Created: 2023-05-31 Last updated: 2024-03-06Bibliographically approved
Harryvan, T., Hawinkels, L., Östman, A., ten Dijke, P., Strell, C., Hornsveld, M., . . . Kop, M. (2022). A Novel Pancreatic Cancer Mini-tumor Model to Study Desmoplasia and Myofibroblastic Cancer-Associated Fibroblast Differentiation. Gastro Hep Advances, 1(4), 678-681
Open this publication in new window or tab >>A Novel Pancreatic Cancer Mini-tumor Model to Study Desmoplasia and Myofibroblastic Cancer-Associated Fibroblast Differentiation
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2022 (English)In: Gastro Hep Advances, ISSN 2772-5723, Vol. 1, no 4, p. 678-681Article in journal (Refereed) Published
Place, publisher, year, edition, pages
ElsevierElsevier BV, 2022
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-492449 (URN)10.1016/j.gastha.2022.04.019 (DOI)35937541 (PubMedID)
Available from: 2023-01-04 Created: 2023-01-04 Last updated: 2024-01-15Bibliographically approved
Thurfjell, V., Micke, P., Yu, H., Krupar, R., Svensson, M. A., Brunnström, H., . . . Mattsson, J. S. (2022). Comparison of ROS1-rearrangement detection methods in a cohort of surgically resected non-small cell lung carcinomas.. Translational lung cancer research, 11(12), 2477-2494
Open this publication in new window or tab >>Comparison of ROS1-rearrangement detection methods in a cohort of surgically resected non-small cell lung carcinomas.
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2022 (English)In: Translational lung cancer research, ISSN 2218-6751, Vol. 11, no 12, p. 2477-2494Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) harboring a ROS proto-oncogene 1 (ROS1)-rearrangement respond to treatment with ROS1 inhibitors. To distinguish these rare cases, screening with immunohistochemistry (IHC) for ROS1 protein expression has been suggested. However, the reliability of such an assay and the comparability of the antibody clones has been debated. Therefore we evaluated the diagnostic performance of current detection strategies for ROS1-rearrangement in two NSCLC-patient cohorts.

METHODS: Resected tissue samples, retrospectively collected from consecutive NSCLC-patients surgically treated at Uppsala University Hospital were incorporated into tissue microarrays [all n=676, adenocarcinomas (AC) n=401, squamous cell carcinomas (SCC) n=213, other NSCLC n=62]. ROS1-rearrangements were detected using fluorescence in situ hybridization (FISH) (Abbott Molecular; ZytoVision). In parallel, ROS1 protein expression was detected using IHC with three antibody clones (D4D6, SP384, EPMGHR2) and accuracy, sensitivity, and specificity were determined. Gene expression microarray data (Affymetrix) and RNA-sequencing data were available for a subset of patients. NanoString analyses were performed for samples with positive or ambiguous results (n=21).

RESULTS: Using FISH, 2/630 (0.3% all NSCLC; 0.5% non-squamous NSCLC) cases were positive for ROS1 fusion. Additionally, nine cases demonstrated ambiguous FISH results. Using IHC, ROS1 protein expression was detected in 24/665 (3.6% all NSCLC; 5.1% non-squamous NSCLC) cases with clone D4D6, in 18/639 (2.8% all NSCLC; 3.9% non-squamous NSCLC) cases with clone SP384, and in 1/593 (0.2% all NSCLC; 0.3% non-squamous NSCLC) case with clone EPMGHR2. Elevated RNA-levels were seen in 19/369 (5.1%) cases (Affymetrix and RNA-sequencing combined). The overlap of positive results between the assays was poor. Only one of the FISH-positive cases was positive with all antibodies and demonstrated high RNA-expression. This rearrangement was confirmed in the NanoString-assay and also in the RNA-sequencing data. Other cases with high protein/RNA-expression or ambiguous FISH were negative in the NanoString-assay.

CONCLUSIONS: The occurrence of ROS1 fusions is low in our cohorts. The IHC assays detected the fusions, but the accuracy varied depending on the clone. The presumably false-positive and uncertain FISH results questions this method for detection of ROS1-rearrangements. Thus, when IHC is used for screening, transcript-based assays are preferable for validation in clinical diagnostics.

Place, publisher, year, edition, pages
AME Publishing Company, 2022
Keywords
Crizotinib, ROS proto-oncogene 1 (ROS1), fusion gene detection, molecular pathology, targeted therapy
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-495327 (URN)10.21037/tlcr-22-504 (DOI)000894803800001 ()36636421 (PubMedID)
Available from: 2023-01-26 Created: 2023-01-26 Last updated: 2023-04-21Bibliographically approved
Ericson Lindquist, K., Ciornei, C., Westbom-Fremer, S., Gudinaviciene, I., Ehinger, A., Mylona, N., . . . Brunnström, H. (2022). Difficulties in diagnostics of lung tumours in biopsies: an interpathologist concordance study evaluating the international diagnostic guidelines. Journal of Clinical Pathology, 75(5), 302-309
Open this publication in new window or tab >>Difficulties in diagnostics of lung tumours in biopsies: an interpathologist concordance study evaluating the international diagnostic guidelines
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2022 (English)In: Journal of Clinical Pathology, ISSN 0021-9746, E-ISSN 1472-4146, Vol. 75, no 5, p. 302-309Article in journal (Refereed) Published
Abstract [en]

AIMS: Accurate and reliable diagnosis is essential for lung cancer treatment. The study aim was to investigate interpathologist diagnostic concordance for pulmonary tumours according to WHO diagnostic criteria.

METHODS: Fifty-two unselected lung and bronchial biopsies were diagnosed by a thoracic pathologist based on a broad spectrum of immunohistochemical (IHC) stainings, molecular data and clinical/radiological information. Slides stained with H&E, thyroid transcription factor-1 (TTF-1) clone SPT24 and p40 were scanned and provided digitally to 20 pathologists unaware of reference diagnoses. The pathologists independently diagnosed the cases and stated if further diagnostic markers were deemed necessary.

RESULTS: In 31 (60%) of the cases, ≥80% of the pathologists agreed with each other and with the reference diagnosis. Lower agreement was seen in non-small cell neuroendocrine tumours and in squamous cell carcinoma with diffuse TTF-1 positivity. Agreement with the reference diagnosis ranged from 26 to 45 (50%-87%) for the individual pathologists. The pathologists requested additional IHC staining in 15-44 (29%-85%) of the 52 cases. In nearly half (17 of 36) of the malignant cases, one or more pathologist advocated for a different final diagnosis than the reference without need of additional IHC markers, potentially leading to different clinical treatment.

CONCLUSIONS: Interpathologist diagnostic agreement is moderate for small unselected bronchial and lung biopsies based on a minimal panel of markers. Neuroendocrine morphology is sometimes missed and TTF-1 clone SPT24 should be interpreted with caution. Our results suggest an intensified education need for thoracic pathologists and a more generous use of diagnostic IHC markers.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2022
Keywords
diagnosis, immunohistochemistry, lung neoplasms
National Category
Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-465260 (URN)10.1136/jclinpath-2020-207257 (DOI)000727496600001 ()33547095 (PubMedID)
Available from: 2022-01-17 Created: 2022-01-17 Last updated: 2023-07-17Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-1210-5961

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