CD8+ Lymphocyte Intratumoral Infiltration As a Stage-independent Predictor of Merkel Cell Carcinoma Survival: a Population-based Study

Overview

Journal Am J Clin Pathol

Publisher Oxford University Press

Specialty Pathology

Date 2014 Sep 21

PMID 25239411

Citations 54

Authors

Kelly G Paulson

Jayasri G Iyer

William T Simonson

Astrid Blom

Renee M Thibodeau

Miranda Schmidt

Stephanie Pietromonaco

Monica Sokil

E Margaret Warton

Maryam M Asgari

Paul Nghiem

Affiliations

Soon will be listed here.

Abstract

Objectives: Intratumoral CD8+ lymphocytes (IT-CD8s) have shown promise as a prognostic indicator for Merkel cell carcinoma (MCC). We tested whether IT-CD8s predict survival among a population-based MCC cohort.

Methods: One hundred thirty-seven MCC cases that had not previously been analyzed for IT-CD8s were studied.

Results: Three-year MCC-specific survival rates were 56%, 72%, and 100% for patients with absent (n = 46), low (n = 85), and moderate or strong (n = 6) IT-CD8s, respectively. Increased IT-CD8s were associated with improved MCC-specific survival in a multivariate competing risk-regression analysis including stage, age, and sex (hazard ratio [HR] = 0.5; 95% confidence interval [CI] = 0.3-0.9). Although a similar trend was observed for overall survival, statistical significance was not reached (HR = 0.8; 95% CI = 0.6-1.0), likely because of the high rate of non-MCC deaths among older patients.

Conclusions: This study of prospectively captured MCC cases supports the concept that cellular immunity is important in MCC outcome and that CD8+ lymphocyte infiltration adds prognostic information to conventional staging.

Citing Articles

Development of a Multiplex Immunofluorescence Assay for Tumor Microenvironment Studies of Human and Murine Merkel Cell Carcinoma.

Sun L, Verhaegen M, McGue J, Olivei A, Dlugosz A, Frankel T Lab Invest. 2024; 104(10):102128.

PMID: 39182611 PMC: 11502254. DOI: 10.1016/j.labinv.2024.102128.

Merkel cell carcinoma: updates in tumor biology, emerging therapies, and preclinical models.

Pedersen E, Verhaegen M, Joseph M, Harms K, Harms P Front Oncol. 2024; 14:1413793.

PMID: 39136002 PMC: 11317257. DOI: 10.3389/fonc.2024.1413793.

Merkel Cell Carcinoma.

Strong J, Hallaert P, Brownell I Hematol Oncol Clin North Am. 2024; 38(5):1133-1147.

PMID: 39060119 PMC: 11423797. DOI: 10.1016/j.hoc.2024.05.013.

Merkel Cell Carcinoma: Integrating Epidemiology, Immunology, and Therapeutic Updates.

Becker J, Stang A, Schrama D, Ugurel S Am J Clin Dermatol. 2024; 25(4):541-557.

PMID: 38649621 PMC: 11193695. DOI: 10.1007/s40257-024-00858-z.

T antigen-specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma.

Hansen U, Church C, Carnaz Simoes A, Frej M, Bentzen A, Tvingsholm S J Clin Invest. 2024; 134(8).

PMID: 38618958 PMC: 11014655. DOI: 10.1172/JCI177082.

References

Houben R, Shuda M, Weinkam R, Schrama D, Feng H, Chang Y . Merkel cell polyomavirus-infected Merkel cell carcinoma cells require expression of viral T antigens. J Virol. 2010; 84(14):7064-72. PMC: 2898224. DOI: 10.1128/JVI.02400-09. View

de Jong R, Leffers N, Boezen H, ten Hoor K, van der Zee A, Hollema H . Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer. Gynecol Oncol. 2009; 114(1):105-10. DOI: 10.1016/j.ygyno.2009.03.022. View

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C . Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006; 313(5795):1960-4. DOI: 10.1126/science.1129139. View

Denkert C, Loibl S, Noske A, Roller M, Muller B, Komor M . Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2009; 28(1):105-13. DOI: 10.1200/JCO.2009.23.7370. View

Andea A, Coit D, Amin B, Busam K . Merkel cell carcinoma: histologic features and prognosis. Cancer. 2008; 113(9):2549-58. DOI: 10.1002/cncr.23874. View

Schumacher K, Haensch W, Roefzaad C, Schlag P . Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res. 2001; 61(10):3932-6. View

Seo A, Lee H, Kim E, Kim H, Jang M, Lee H . Tumour-infiltrating CD8+ lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. Br J Cancer. 2013; 109(10):2705-13. PMC: 3833219. DOI: 10.1038/bjc.2013.634. View

Galon J, Pages F, Marincola F, Thurin M, Trinchieri G, Fox B . The immune score as a new possible approach for the classification of cancer. J Transl Med. 2012; 10:1. PMC: 3269368. DOI: 10.1186/1479-5876-10-1. View

Heath M, Jaimes N, Lemos B, Mostaghimi A, Wang L, Penas P . Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol. 2008; 58(3):375-81. PMC: 2335370. DOI: 10.1016/j.jaad.2007.11.020. View

10.

Albores-Saavedra J, Batich K, Chable-Montero F, Sagy N, Schwartz A, Henson D . Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol. 2009; 37(1):20-7. DOI: 10.1111/j.1600-0560.2009.01370.x. View

11.

Penn I, First M . Merkel's cell carcinoma in organ recipients: report of 41 cases. Transplantation. 1999; 68(11):1717-21. DOI: 10.1097/00007890-199912150-00015. View

12.

Shuda M, Arora R, Kwun H, Feng H, Sarid R, Fernandez-Figueras M . Human Merkel cell polyomavirus infection I. MCV T antigen expression in Merkel cell carcinoma, lymphoid tissues and lymphoid tumors. Int J Cancer. 2009; 125(6):1243-9. PMC: 6388400. DOI: 10.1002/ijc.24510. View

13.

Matkowski R, Gisterek I, Halon A, Lacko A, Szewczyk K, Staszek U . The prognostic role of tumor-infiltrating CD4 and CD8 T lymphocytes in breast cancer. Anticancer Res. 2009; 29(7):2445-51. View

14.

Feng H, Shuda M, Chang Y, Moore P . Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008; 319(5866):1096-100. PMC: 2740911. DOI: 10.1126/science.1152586. View

15.

Engels E, Frisch M, Goedert J, Biggar R, Miller R . Merkel cell carcinoma and HIV infection. Lancet. 2002; 359(9305):497-8. DOI: 10.1016/S0140-6736(02)07668-7. View

16.

Paulson K, Iyer J, Tegeder A, Thibodeau R, Schelter J, Koba S . Transcriptome-wide studies of merkel cell carcinoma and validation of intratumoral CD8+ lymphocyte invasion as an independent predictor of survival. J Clin Oncol. 2011; 29(12):1539-46. PMC: 3082974. DOI: 10.1200/JCO.2010.30.6308. View

17.

Gao Q, Qiu S, Fan J, Zhou J, Wang X, Xiao Y . Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007; 25(18):2586-93. DOI: 10.1200/JCO.2006.09.4565. View

18.

Sato E, Olson S, Ahn J, Bundy B, Nishikawa H, Qian F . Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A. 2005; 102(51):18538-43. PMC: 1311741. DOI: 10.1073/pnas.0509182102. View

19.

Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G, Meatchi T . Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol. 2011; 29(6):610-8. DOI: 10.1200/JCO.2010.30.5425. View

20.

Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R . Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005; 353(25):2654-66. DOI: 10.1056/NEJMoa051424. View