Correlation of clinical, pathologic, and genetic parameters with intratumoral immune milieu in mucinous adenocarcinoma of the colon.
Humans
DNA Mismatch Repair
B7-H1 Antigen
/ genetics
MutS Homolog 2 Protein
/ genetics
Mismatch Repair Endonuclease PMS2
/ genetics
Proto-Oncogene Proteins B-raf
/ genetics
Adenocarcinoma, Mucinous
/ genetics
Colonic Neoplasms
/ pathology
Biomarkers
Forkhead Transcription Factors
Mucins
Colorectal Neoplasms
/ pathology
Biomarkers, Tumor
/ genetics
Journal
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
ISSN: 1530-0285
Titre abrégé: Mod Pathol
Pays: United States
ID NLM: 8806605
Informations de publication
Date de publication:
11 2022
11 2022
Historique:
received:
16
06
2021
accepted:
21
04
2022
revised:
20
04
2022
pubmed:
20
5
2022
medline:
28
10
2022
entrez:
19
5
2022
Statut:
ppublish
Résumé
Mucinous adenocarcinoma (MAD), the most common subtype of colonic adenocarcinoma (CA), requires >50% intratumoral mucin. There is limited data regarding the impact of MAD on key lymphocyte subsets and therapeutically critical immune elements. In this study we address: (1) the definition of MAD, (2) grading of MAD, and (3) the impact of MAD and extracellular mucin on intratumoral immune milieu. Estimation of the percentage of intratumoral mucin was performed by two pathologists. Tissue microarrays were stained for immune markers including CD8, CD163, PD-L1, FoxP3, β2 microglobulin, HLA class I, and HLA class II. Immunohistochemistry for BRAF V600E was performed. MMR status was determined on immunohistochemistry for MSH2, MSH6, MLH1, PMS2. Manual and automated HALO platforms were used for quantification. The 903 CAs included 62 (6.9%) MAD and 841 CA with ≤ 50% mucin. We identified 225 CAs with mucinous differentiation, defined by ≥10% mucin. On univariate analysis neither cut point, 50% (p = 0.08) and 10% (p = 0.08) mucin, correlated with disease-specific survival (DSS). There were no differences in key clinical, histological and molecular features between MAD and CA with mucinous differentiation. On univariate analysis of patients with MAD, tumor grade correlated with DSS (p = 0.0001) while MMR status did not (p = 0.86). There was no statistically significant difference in CD8 (P = 0.17) and CD163 (P = 0.05) positive immune cells between MAD and conventional CA. However, deficient (d) MMR MADs showed fewer CD8 (P = 0.0001), CD163 (P = 0.0001) and PD-L1 (P = 0.003) positive immune cells compared to proficient (p)MMR MADs, a finding also seen with at 10% mucin cut point. Although MAD does not impact DSS, this study raises the possibility that the immune milieu of dMMR MADs and tumors with > =10% mucin may differ from pMMR MADs and tumors with <10% mucin, a finding that may impact immune-oncology based therapeutics.
Identifiants
pubmed: 35590108
doi: 10.1038/s41379-022-01095-7
pii: S0893-3952(22)00239-3
doi:
Substances chimiques
B7-H1 Antigen
0
MutS Homolog 2 Protein
EC 3.6.1.3
Mismatch Repair Endonuclease PMS2
EC 3.6.1.3
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Biomarkers
0
Forkhead Transcription Factors
0
Mucins
0
Biomarkers, Tumor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1723-1731Informations de copyright
© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.
Références
Kanemitsu, Y., Kato, T., Hirai, T., Yasui, K., Morimoto, T., Shimizu, Y. et al. Survival after curative resection for mucinous adenocarcinoma of the colorectum. Dis. Colon Rectum 46, 160–167 (2003).
Park, J. S., Huh, J. W., Park, Y. A., Cho, Y. B., Yun, S. H., Kim, H. C. et al. Prognostic comparison between mucinous and nonmucinous adenocarcinoma in colorectal cancer. Medicine 94, e658 (2015).
Verhulst, J., Ferdinande, L., Demetter, P. Ceelen, W. Mucinous subtype as prognostic factor in colorectal cancer: a systematic review and meta-analysis. J. Clin. Pathol. 65, 381–388 (2012).
Catalano, V., Loupakis, F., Graziano, F., Bisonni, R., Torresi, U., Vincenzi, B. et al. Prognosis of mucinous histology for patients with radically resected stage II and III colon cancer. Ann. Oncol. 23, 135–141 (2012).
Kang, H., O’Connell, J. B., Maggard, M. A., Sack, J. & Ko, C. Y. A 10-year outcomes evaluation of mucinous and signet-ring cell carcinoma of the colon and rectum. Dis. Colon Rectum 48, 1161–1168 (2005).
Negri, F. V., Wotherspoon, A., Cunningham, D., Norman, A. R., Chong, G. & Ross, P. J. Mucinous histology predicts for reduced fluorouracil responsiveness and survival in advanced colorectal cancer. Ann. Oncol. 16, 1305–1310 (2005).
Catalano, V., Loupakis, F., Graziano, F., Torresi, U., Bisonni, R., Mari, D. et al. Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy. Br. J. Cancer 100, 881–887 (2009).
Mekenkamp, L. J., Heesterbeek, K. J., Koopman, M., Tol, J., Teerenstra, S., Venderbosch, S. et al. Mucinous adenocarcinomas: poor prognosis in metastatic colorectal cancer. Eur. J. Cancer 48, 501–509 (2012).
Gonzalez, R. S., Cates, J. M. M. & Washington, K. Associations among histological characteristics and patient outcomes in colorectal carcinoma with a mucinous component. Histopathology 74, 406-414 (2019).
Andrici, J., Farzin, M., Sioson, L., Clarkson, A., Watson, N., Toon, C. W. et al. Mismatch repair deficiency as a prognostic factor in mucinous colorectal cancer. Mod. Pathol. 29, 266–274 (2016).
Board, W. C. o. T. E. WHO classification of tumours of the digestive system. 5th ed edn (International Agency for Research on Cancer, Lyon, 2019).
Yoon, Y. S., Kim, J., Hong, S. M., Lee, J. L., Kim, C. W., Park, I. J. et al. Clinical implications of mucinous components correlated with microsatellite instability in patients with colorectal cancer. Colorectal Dis. 17, O161–167 (2015).
Jung, S. H., Kim, S. H. & Kim, J. H. Prognostic impact of microsatellite instability in colorectal cancer presenting with mucinous, signet-ring, and poorly differentiated cells. Ann. Coloproctol. 32, 58–65 (2016).
Leopoldo, S., Lorena, B., Cinzia, A., Gabriella, D. C., Angela Luciana, B., Renato, C. et al. Two subtypes of mucinous adenocarcinoma of the colorectum: clinicopathological and genetic features. Ann. Surg. Oncol. 15, 1429–1439 (2008).
Greenson, J. K., Bonner, J. D., Ben-Yzhak, O., Cohen, H. I., Miselevich, I., Resnick, M. B. et al. Phenotype of microsatellite unstable colorectal carcinomas: well-differentiated and focally mucinous tumors and the absence of dirty necrosis correlate with microsatellite instability. Am. J. Surg. Pathol. 27, 563–570 (2003).
Williams, D. S., Mouradov, D., Newman, M. R., Amini, E., Nickless, D. K., Fang, C. G. et al. Tumour infiltrating lymphocyte status is superior to histological grade, DNA mismatch repair and BRAF mutation for prognosis of colorectal adenocarcinomas with mucinous differentiation. Mod. Pathol. 33, 1420–1432 (2020).
Hartman, D. J., Frank, M., Seigh, L., Choudry, H., Pingpank, J., Holtzman, M. et al. Automated Quantitation of CD8-positive T Cells Predicts Prognosis in Colonic Adenocarcinoma With Mucinous, Signet Ring Cell, or Medullary Differentiation Independent of Mismatch Repair Protein Status. Am. J. Surg. Pathol. 44, 991–1001 (2020).
Ganesh, K., Stadler, Z. K., Cercek, A., Mendelsohn, R. B., Shia, J., Segal, N. H. et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat. Rev. Gastroenterol. Hepatol. 16, 361-375 (2019).
Le, D. T., Uram, J. N., Wang, H., Bartlett, B. R., Kemberling, H., Eyring, A. D. et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
Le, D. T., Durham, J. N., Smith, K. N., Wang, H., Bartlett, B. R., Aulakh, L. K. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).
Routhier, C. A., Mochel, M. C., Lynch, K., Dias-Santagata, D., Louis, D. N. & Hoang, M. P. Comparison of 2 monoclonal antibodies for immunohistochemical detection of BRAF V600E mutation in malignant melanoma, pulmonary carcinoma, gastrointestinal carcinoma, thyroid carcinoma, and gliomas. Hum. Pathol. 44, 2563–2570 (2013).
Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pages, C. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).
Galon, J., Fridman, W. H. & Pages, F. The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res. 67, 1883–1886 (2007).
Kim, S. H., Shin, S. J., Lee, K. Y., Kim, H., Kim, T. I., Kang, D. R. et al. Prognostic value of mucinous histology depends on microsatellite instability status in patients with stage III colon cancer treated with adjuvant FOLFOX chemotherapy: a retrospective cohort study. Ann. Surg. Oncol. 20, 3407–3413 (2013).
Kazama, Y., Watanabe, T., Kanazawa, T., Kazama, S., Tada, T., Tanaka, J. et al. Mucinous colorectal cancers with chromosomal instability: a biologically distinct and aggressive subtype. Diagn. Mol. Pathol. 15, 30–34 (2006).
Inamura, K., Yamauchi, M., Nishihara, R., Kim, S. A., Mima, K., Sukawa, Y. et al. Prognostic significance and molecular features of signet-ring cell and mucinous components in colorectal carcinoma. Ann. Surg. Oncol. 22, 1226–1235 (2015).
Langner, C., Harbaum, L., Pollheimer, M. J., Kornprat, P., Lindtner, R. A., Schlemmer, A. et al. Mucinous differentiation in colorectal cancer--indicator of poor prognosis? Histopathology 60, 1060–1072 (2012).
Ogino, S., Brahmandam, M., Cantor, M., Namgyal, C., Kawasaki, T., Kirkner, G. et al. Distinct molecular features of colorectal carcinoma with signet ring cell component and colorectal carcinoma with mucinous component. Mod. Pathol. 19, 59–68 (2006).
Kazama, Y., Watanabe, T., Kanazawa, T., Tada, T., Tanaka, J. & Nagawa, H. Mucinous carcinomas of the colon and rectum show higher rates of microsatellite instability and lower rates of chromosomal instability: a study matched for T classification and tumor location. Cancer 103, 2023–2029 (2005).
Kufe, D. W. Mucins in cancer: function, prognosis and therapy. Nat. Rev. Cancer 9, 874–885 (2009).
Bhatia, R., Gautam, S. K., Cannon, A., Thompson, C., Hall, B. R., Aithal, A. et al. Cancer-associated mucins: role in immune modulation and metastasis. Cancer Metastasis Rev. 38, 223–236 (2019).
Van der Sluis, M., De Koning, B. A., De Bruijn, A. C., Velcich, A., Meijerink, J. P., Van Goudoever, J. B. et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131, 117–129 (2006).
Kleinovink, J. W., Marijt, K. A., Schoonderwoerd, M. J. A., van Hall, T., Ossendorp, F. & Fransen, M. F. PD-L1 expression on malignant cells is no prerequisite for checkpoint therapy. Oncoimmunology 6, e1294299 (2017).
Lau, J., Cheung, J., Navarro, A., Lianoglou, S., Haley, B., Totpal, K. et al. Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice. Nat. Commun. 8, 14572 (2017).
Tang, H., Liang, Y., Anders, R. A., Taube, J. M., Qiu, X., Mulgaonkar, A. et al. PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression. J. Clin. Investig. 128, 580–588 (2018).