{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T08:23:30Z","timestamp":1788337410175,"version":"build-2803163510"},"reference-count":32,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Animals"],"abstract":"<jats:p>DNA mismatch repair (MMR) proteins have been investigated as biomarkers in human oncology, but their role in canine PPCs has not been characterized. Immunohistochemistry for MCK, TTF-1, MSH2, and MSH6 was performed and evaluated in relation to clinicopathological parameters. Affected dogs had a median age of 10.6 years. Histologically, 16 tumors were classified as adenocarcinoma and one as adenosquamous carcinoma, with papillary architecture predominating. MCK and TTF-1 immunoreactivity was detected in all cases, supporting epithelial and pulmonary differentiation when considered with histopathological and available clinical findings. Absent MSH2 immunoreactivity was observed in 17.6% of cases, whereas absent MSH6 immunoreactivity was observed in 11.8%. MSH2 expression showed a significant inverse association with tumor volume (p = 0.006), whereas no significant associations were identified between MSH6 expression and the evaluated clinicopathological parameters. As only MSH2 and MSH6 were assessed and no microsatellite instability or molecular analyses were performed, the observed abnormalities cannot be interpreted as definitive evidence of functional MMR deficiency. These findings provide preliminary data on MSH2 and MSH6 expression in canine PPCs and support further investigation using comprehensive MMR assessment and molecular approaches.<\/jats:p>","DOI":"10.3390\/ani16172726","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T07:53:11Z","timestamp":1788335591000},"page":"2726","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunohistochemical Expression of MSH2 and MSH6 Mismatch Repair Proteins and Their Pathological Correlations in Canine Primary Pulmonary Carcinoma"],"prefix":"10.3390","volume":"16","author":[{"given":"Alexandra","family":"Morar","sequence":"first","affiliation":[{"name":"Department of Veterinary Pathology, Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, 400372 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0455-1366","authenticated-orcid":false,"given":"Corina","family":"Toma","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathology, Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, 400372 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8268-288X","authenticated-orcid":false,"given":"Drago\u0219","family":"Hodor","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathology, Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, 400372 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0000-9737","authenticated-orcid":false,"given":"Claudiu","family":"Gal","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathology, Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, 400372 Cluj-Napoca, Romania"},{"name":"Department of Veterinary Pathology, Synevovet, Industriilor 25, 077040 Chiajna, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5968-0459","authenticated-orcid":false,"given":"Ibrahima Mamadou","family":"Sall","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathology, Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, 400372 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8987-6038","authenticated-orcid":false,"given":"Marian","family":"Taulescu","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathology, Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, 400372 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Cornel","family":"C\u0103toi","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathology, Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, 400372 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.2460\/javma.1997.211.11.1422","article-title":"Evaluation of Prognostic Factors for Dogs with Primary Lung Tumors: 67 Cases (1985\u20131992)","volume":"211","author":"McNiel","year":"1997","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"106","DOI":"10.2460\/javma.1989.195.01.106","article-title":"Classification of Primary Lung Tumors in Dogs: 210 Cases (1975\u20131985)","volume":"195","author":"Ogilvie","year":"1989","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_3","first-page":"1628","article-title":"Primary Pulmonary Neoplasms in the Dog: A Review of 29 Cases","volume":"147","author":"Brodey","year":"1965","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1093\/carcin\/19.6.959","article-title":"Rapid Detection of K-Ras Gene Mutations in Canine Lung Cancer Using Single-Strand Conformational Polymorphism Analysis","volume":"19","author":"Griffey","year":"1998","journal-title":"Carcinogenesis"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wilson, D.W. (2016). Tumors of the Respiratory Tract. Tumors in Domestic Animals, John Wiley & Sons.","DOI":"10.1002\/9781119181200.ch12"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"109","DOI":"10.2460\/javma.1989.195.01.109","article-title":"Prognostic Factors for Tumor Remission and Survival in Dogs after Surgery for Primary Lung Tumor: 76 Cases (1975\u20131985)","volume":"195","author":"Ogilvie","year":"1989","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_7","first-page":"53","article-title":"Structural, Molecular and Cellular Functions of MSH2 and MSH6 during DNA Mismatch Repair, Damage Signaling and Other Noncanonical Activities","volume":"743","author":"Edelbrock","year":"2013","journal-title":"Mutat. Res.\/Fundam. Mol. Mech. Mutagen."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.7150\/ijbs.71714","article-title":"The Role of DNA Mismatch Repair in Immunotherapy of Human Cancer","volume":"18","author":"He","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_9","unstructured":"Scarpa, A., Cataldo, I., and Salvatore, L. (2016). Microsatellite Instability-Defective DNA Mismatch Repair: ESMO Biomarker Factsheet, European Society for Medical Oncology (ESMO)."},{"key":"ref_10","unstructured":"Kohlmann, W., and Gruber, S.B. (1993). Lynch Syndrome. GeneReviews 1993\u20132018, University of Washington."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Liu, Y., Ye, S., Liu, Z., Chen, Z., and Liang, X. (2026). Lynch Syndrome as a Spectrum of Four Distinct Genetic Disorders: Toward Genotype-Guided Precision Management in the NGS Era. Cancers, 18.","DOI":"10.3390\/cancers18030506"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1549416","DOI":"10.3389\/or.2025.1549416","article-title":"A Brief Review of Lynch Syndrome: Understanding the Dual Cancer Risk between Endometrial and Colorectal Cancer","volume":"19","author":"Pallatt","year":"2025","journal-title":"Oncol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.jtho.2023.10.004","article-title":"Microsatellite Instability and Mismatch Repair Deficiency Define a Distinct Subset of Lung Cancers Characterized by Smoking Exposure, High Tumor Mutational Burden, and Recurrent Somatic MLH1 Inactivation","volume":"19","author":"Yang","year":"2024","journal-title":"J. Thorac. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Yanagawa, N., Yamada, N., Sugimoto, R., Osakabe, M., Uesugi, N., Shiono, S., Endoh, M., Ogata, S., Saito, H., and Maemondo, M. (2021). The Frequency of DNA Mismatch Repair Deficiency Is Very Low in Surgically Resected Lung Carcinoma. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.752005"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s00428-015-1892-7","article-title":"Microsatellite Instability in Pulmonary Adenocarcinomas: A Comprehensive Study of 480 Cases","volume":"468","author":"Warth","year":"2016","journal-title":"Virchows Arch."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1177\/03009858211022704","article-title":"Mismatch Repair Deficiency in Canine Neoplasms","volume":"58","author":"Inanaga","year":"2021","journal-title":"Vet. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e013623","DOI":"10.1136\/jitc-2025-013623","article-title":"Caninized PD-1 Monoclonal Antibody in Oral Malignant Melanoma: Efficacy and Exploratory Biomarker Analysis","volume":"14","author":"Igase","year":"2026","journal-title":"J. Immunother. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Mazzone, E., and Aresu, L. (2024). Comprehensive Analysis of Microsatellite Instability in Canine Cancers: Implications for Comparative Oncology and Personalized Veterinary Medicine. Animals, 14.","DOI":"10.20944\/preprints202407.0300.v1"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1177\/03009858211013712","article-title":"International Guidelines for Veterinary Tumor Pathology: A Call to Action","volume":"58","author":"Meuten","year":"2021","journal-title":"Vet. Pathol."},{"key":"ref_20","first-page":"138","article-title":"Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue","volume":"8","author":"Remmele","year":"1987","journal-title":"Pathologe"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic Local Alignment Search Tool","volume":"215","author":"Altschul","year":"1990","journal-title":"J. Mol. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"MSB201175","DOI":"10.1038\/msb.2011.75","article-title":"Fast, Scalable Generation of High-quality Protein Multiple Sequence Alignments Using Clustal Omega","volume":"7","author":"Sievers","year":"2011","journal-title":"Mol. Syst. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1007\/BF00300234","article-title":"Determination of Subcutaneous Tumor Size in Athymic (Nude) Mice","volume":"24","author":"Tomayko","year":"1989","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"234","DOI":"10.2460\/javma.20.12.0698","article-title":"Distribution of Histopathologic Types of Primary Pulmonary Neoplasia in Dogs and Outcome of Affected Dogs: 340 Cases (2010\u20132019)","volume":"260","author":"McPhetridge","year":"2022","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1111\/j.1740-8261.2010.01759.x","article-title":"Computed Tomographic Appearance of Primary Lung Tumors in Dogs","volume":"52","author":"Marolf","year":"2011","journal-title":"Vet. Radiol. Ultrasound"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Louie, N., Hung, D., Mosca, A., Almendros, A., and Giuliano, A. (2026). Survival Analysis of Different Treatment Modalities and Associated Outcomes for Canine Primary Pulmonary Carcinoma. Front. Vet. Sci., 13.","DOI":"10.3389\/fvets.2026.1683766"},{"key":"ref_27","unstructured":"Maxie, M.G. (2016). Respiratory System, Jubb, Kennedy, and Palmer\u2019s Pathology of Domestic Animals, Elsevier."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1354\/vp.42-3-315","article-title":"Usefulness of Thyroid Transcription Factor-1 Immunohistochemical Staining in the Differential Diagnosis of Primary Pulmonary Tumors of Dogs","volume":"42","author":"Miller","year":"2005","journal-title":"Vet. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4479","DOI":"10.1002\/cam4.4832","article-title":"Simple IHC Reveals Complex MMR Alternations than PCR Assays: Validation by LCM and Next-generation Sequencing","volume":"11","author":"Amemiya","year":"2022","journal-title":"Cancer Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1158\/2159-8290.CD-18-0150","article-title":"The Clinical Impact of the Genomic Landscape of Mismatch Repair\u2013Deficient Cancers","volume":"8","author":"Germano","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1038\/s41379-019-0414-6","article-title":"Retained Mismatch Repair Protein Expression Occurs in Approximately 6% of Microsatellite Instability-High Cancers and Is Associated with Missense Mutations in Mismatch Repair Genes","volume":"33","author":"Hechtman","year":"2020","journal-title":"Mod. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5866","DOI":"10.1158\/1078-0432.CCR-19-1145","article-title":"Identification of Recurrent Activating HER2 Mutations in Primary Canine Pulmonary Adenocarcinoma","volume":"25","author":"Lorch","year":"2019","journal-title":"Clin. Cancer Res."}],"container-title":["Animals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2615\/16\/17\/2726\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T08:05:21Z","timestamp":1788336321000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2615\/16\/17\/2726"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,2]]},"references-count":32,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ani16172726"],"URL":"https:\/\/doi.org\/10.3390\/ani16172726","relation":{},"ISSN":["2076-2615"],"issn-type":[{"value":"2076-2615","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,2]]}}}