胸腺腫瘤為一生長於前縱膈腔之少見腫瘤，根據腫瘤組織型態可分為胸腺瘤與胸腺癌。胸腺腫瘤多無症狀，少部分胸腺瘤可因出現附腫瘤性神經症候群而早期發現。手術完整切除為治癒胸腺腫瘤之唯一機會，然即便完整切除，不論胸腺瘤或胸腺癌均有復發可能，且復發時間可能長達數年後；而對於無法完整切除之胸腺腫瘤，現階段之藥物治療，放射線治療，甚至臨床試驗，效果均有限。對於胸腺腫瘤預後因子，雖文獻均有報告，然對手術後影響復發之臨床因素，以及影響整體存活之分子生物學因子，尚無完整研究。此外，現階段並無獨立可靠的分子生物學標記。胸腺腫瘤的個人化醫療目前處於發展起步。本院為台灣南部國立醫學中心，創院至今累積不少胸腺腫瘤治療經驗，故在此整理術後患者臨床資料以分析影響術後復發原因，並以手術檢體進一步分析影響胸腺腫瘤之分子生物學因子，期望在即將到來的免疫治療世代，對於未能手術的患者，能有改善存活的契機。

Thymic epithelial tumors (TETs) are rare tumors arising from the thymus in the anterior mediastinum, and histologically classified into thymoma and thymic carcinoma. Most of the tumors are indolent, although some patients with thymic epithelial tumors could be cormorbid with paraneoplastic syndrome and make early detection possible. Complete resection remains the only opportunity of cure, but recurrence is often the scenario and may occur many years later. For patients not amenable of radical resection, the outcomes are not satisfactory despite the application of multi-modality treatment including chemotherapy, radiotherapy, and some ongoing clinical trials. Prognosticators for thymic epithelial tumors have been reported, but investigation on the clinical and molecular prognosticators for recurrence and survival was not conclusive. Besides, there is lack of independent and reliable molecular markers. The field of personalized medicine for thymic malignancies is in the early stages of development. As a national medical center in southern Taiwan, we have accumulated a substantial number of patients undergoing surgery for thymic epithelial tumors, and therefore retrospectively analyze the clinical prognosticators for recurrence and survival. Furthermore, the surgical specimen will be analyzed to investigate the molecular prognosticators for recurrence and survival, hopefully improving the treatment outcomes of non-surgical patients in the era of immunotherapy.

1. Venuta F, Anile M, Diso D, et al. Thymoma and thymic carcinoma. Eur J Cardiothorac Surg. 2010;37(1):13-25.
2. Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg. 2003;76(3):878-884; discussion 884-875.
3. Wright CD, Wain JC, Wong DR, et al. Predictors of recurrence in thymic tumors: importance of invasion, World Health Organization histology, and size. J Thorac Cardiovasc Surg. 2005;130(5):1413-1421.
4. Okumura M, Shiono H, Inoue M, et al. Outcome of surgical treatment for recurrent thymic epithelial tumors with reference to world health organization histologic classification system. J Surg Oncol. 2007;95(1):40-44.
5. Thomas A, Rajan A, Berman A, et al. Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial. Lancet Oncol. 2015;16(2):177-186.
6. Marulli G, Margaritora S, Lucchi M, et al. Surgical treatment of recurrent thymoma: is it worthwhile?dagger. Eur J Cardiothorac Surg. 2016;49(1):327-332.
7. Kirzinger L, Boy S, Marienhagen J, et al. Octreotide LAR and Prednisone as Neoadjuvant Treatment in Patients with Primary or Locally Recurrent Unresectable Thymic Tumors: A Phase II Study. PLoS One. 2016;11(12):e0168215.
8. Korst RJ, Bezjak A, Blackmon S, et al. Neoadjuvant chemoradiotherapy for locally advanced thymic tumors: a phase II, multi-institutional clinical trial. J Thorac Cardiovasc Surg. 2014;147(1):36-44, 46 e31.
9. Huang J, Rizk NP, Travis WD, et al. Comparison of patterns of relapse in thymic carcinoma and thymoma. J Thorac Cardiovasc Surg. 2009;138(1):26-31.
10. Hamaji M, Allen MS, Cassivi SD, et al. The role of surgical management in recurrent thymic tumors. Ann Thorac Surg. 2012;94(1):247-254; discussion 254.
11. Strobel P, Bauer A, Puppe B, et al. Tumor recurrence and survival in patients treated for thymomas and thymic squamous cell carcinomas: a retrospective analysis. J Clin Oncol. 2004;22(8):1501-1509.
12. Detterbeck FC, Parsons AM. Thymic tumors. Ann Thorac Surg. 2004;77(5):1860-1869.
13. Tseng YL, Wang ST, Wu MH, Lin MY, Lai WW, Cheng FF. Thymic carcinoma: involvement of great vessels indicates poor prognosis. Ann Thorac Surg. 2003;76(4):1041-1045.
14. Marchevsky AM, Walts AE. PD-L1, PD-1, CD4, and CD8 expression in neoplastic and nonneoplastic thymus. Hum Pathol. 2017;60:16-23.
15. Spranger S, Spaapen RM, Zha Y, et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013;5(200):200ra116.
16. Ferdinande L, Decaestecker C, Verset L, et al. Clinicopathological significance of indoleamine 2,3-dioxygenase 1 expression in colorectal cancer. Br J Cancer. 2012;106(1):141-147.
17. Okamoto A, Nikaido T, Ochiai K, et al. Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin Cancer Res. 2005;11(16):6030-6039.
18. Pan K, Wang H, Chen MS, et al. Expression and prognosis role of indoleamine 2,3-dioxygenase in hepatocellular carcinoma. J Cancer Res Clin Oncol. 2008;134(11):1247-1253.
19. Ninomiya S, Hara T, Tsurumi H, et al. Indoleamine 2,3-dioxygenase in tumor tissue indicates prognosis in patients with diffuse large B-cell lymphoma treated with R-CHOP. Ann Hematol. 2011;90(4):409-416.
20. Patil PA, Blakely AM, Lombardo KA, et al. Expression of PD-L1, indoleamine 2,3-dioxygenase and the immune microenvironment in gastric adenocarcinoma. Histopathology. 2018.
21. Haritos AA, Caldarella J, Horecker BL. Simultaneous isolation and determination of prothymosin alpha, parathymosin alpha, thymosin beta 4, and thymosin beta 10. Anal Biochem. 1985;144(2):436-440.
22. Clinton M, Graeve L, el-Dorry H, Rodriguez-Boulan E, Horecker BL. Evidence for nuclear targeting of prothymosin and parathymosin synthesized in situ. Proc Natl Acad Sci U S A. 1991;88(15):6608-6612.
23. Bianco NR, Montano MM. Regulation of prothymosin alpha by estrogen receptor alpha: molecular mechanisms and relevance in estrogen-mediated breast cell growth. Oncogene. 2002;21(34):5233-5244.
24. Vareli K, Tsolas O, Frangou-Lazaridis M. Regulation of prothymosin alpha during the cell cycle. Eur J Biochem. 1996;238(3):799-806.
25. Wu CL, Shiau AL, Lin CS. Prothymosin alpha promotes cell proliferation in NIH3T3 cells. Life Sci. 1997;61(21):2091-2101.
26. Jiang X, Kim HE, Shu H, et al. Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway. Science. 2003;299(5604):223-226.
27. Jou YC, Tung CL, Tsai YS, et al. Prognostic relevance of prothymosin-alpha expression in human upper urinary tract transitional cell carcinoma. Urology. 2009;74(4):951-957.
28. Tripathi SC, Matta A, Kaur J, et al. Overexpression of prothymosin alpha predicts poor disease outcome in head and neck cancer. PLoS One. 2011;6(5):e19213.
29. Zhang M, Cui F, Lu S, et al. Increased expression of prothymosin-alpha, independently or combined with TP53, correlates with poor prognosis in colorectal cancer. Int J Clin Exp Pathol. 2014;7(8):4867-4876.
30. Chen K, Xiong L, Yang Z, Huang S, Zeng R, Miao X. Prothymosin-alpha and parathymosin expression predicts poor prognosis in squamous and adenosquamous carcinomas of the gallbladder. Oncol Lett. 2018;15(4):4485-4494.
31. Skopeliti M, Iconomidou VA, Derhovanessian E, et al. Prothymosin alpha immunoactive carboxyl-terminal peptide TKKQKTDEDD stimulates lymphocyte reactions, induces dendritic cell maturation and adopts a beta-sheet conformation in a sequence-specific manner. Mol Immunol. 2009;46(5):784-792.
32. Ha SY, Song DH, Hwang SH, Cho SY, Park CK. Expression of prothymosin alpha predicts early recurrence and poor prognosis of hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2015;14(2):171-177.
33. Lai WW, Wu MH, Chou NS, Lin MY. Surgery for malignant involvement of the superior vena cava. J Formos Med Assoc. 1992;91(10):991-995.
34. Tsuchida Y, Therasse P. Response evaluation criteria in solid tumors (RECIST): new guidelines. Medical and pediatric oncology. 2001;37(1):1-3.
35. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European journal of cancer. 2009;45(2):228-247.
36. Huang J, Detterbeck FC, Wang Z, Loehrer PJ, Sr. Standard outcome measures for thymic malignancies. J Thorac Oncol. 2010;5(12):2017-2023.
37. Venuta F, Rendina EA, Anile M, de Giacomo T, Vitolo D, Coloni GF. Thymoma and thymic carcinoma. General thoracic and cardiovascular surgery. 2012;60(1):1-12.
38. Okereke IC, Kesler KA, Freeman RK, et al. Thymic carcinoma: outcomes after surgical resection. Ann Thorac Surg. 2012;93(5):1668-1672; discussion 1672-1663.
39. Kim DJ, Yang WI, Choi SS, Kim KD, Chung KY. Prognostic and clinical relevance of the World Health Organization schema for the classification of thymic epithelial tumors: a clinicopathologic study of 108 patients and literature review. Chest. 2005;127(3):755-761.
40. Weksler B, Dhupar R, Parikh V, Nason KS, Pennathur A, Ferson PF. Thymic carcinoma: a multivariate analysis of factors predictive of survival in 290 patients. Ann Thorac Surg. 2013;95(1):299-303.
41. Cardillo G, Carleo F, Giunti R, et al. Predictors of survival in patients with locally advanced thymoma and thymic carcinoma (Masaoka stages III and IVa). Eur J Cardiothorac Surg. 2010;37(4):819-823.
42. Kang MW, Lee ES, Jo J, et al. Stage III thymic epithelial neoplasms are not homogeneous with regard to clinical, pathological, and prognostic features. J Thorac Oncol. 2009;4(12):1561-1567.
43. Margaritora S, Cesario A, Cusumano G, et al. Thirty-five-year follow-up analysis of clinical and pathologic outcomes of thymoma surgery. Ann Thorac Surg. 2010;89(1):245-252; discussion 252.
44. Mao ZF, Mo XA, Qin C, Lai YR, Hackett ML. Incidence of thymoma in myasthenia gravis: a systematic review. Journal of clinical neurology. 2012;8(3):161-169.
45. Hosaka Y, Tsuchida M, Toyabe S, Umezu H, Eimoto T, Hayashi J. Masaoka stage and histologic grade predict prognosis in patients with thymic carcinoma. Ann Thorac Surg. 2010;89(3):912-917.
46. Blumberg D, Burt ME, Bains MS, et al. Thymic carcinoma: current staging does not predict prognosis. J Thorac Cardiovasc Surg. 1998;115(2):303-308; discussion 308-309.
47. Bae MK, Byun CS, Lee CY, et al. Clinical outcomes and prognosis of recurrent thymoma management. J Thorac Oncol. 2012;7(8):1304-1314.
48. Weissferdt A, Fujimoto J, Kalhor N, et al. Expression of PD-1 and PD-L1 in thymic epithelial neoplasms. Mod Pathol. 2017.
49. Katsuya Y, Fujita Y, Horinouchi H, Ohe Y, Watanabe S, Tsuta K. Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma. Lung Cancer. 2015;88(2):154-159.
50. Padda SK, Riess JW, Schwartz EJ, et al. Diffuse high intensity PD-L1 staining in thymic epithelial tumors. J Thorac Oncol. 2015;10(3):500-508.
51. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800.
52. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454.
53. Yokoyama S, Miyoshi H, Nishi T, et al. Clinicopathologic and Prognostic Implications of Programmed Death Ligand 1 Expression in Thymoma. Ann Thorac Surg. 2016;101(4):1361-1369.
54. Yokoyama S, Miyoshi H, Nakashima K, et al. Prognostic Value of Programmed Death Ligand 1 and Programmed Death 1 Expression in Thymic Carcinoma. Clin Cancer Res. 2016;22(18):4727-4734.
55. Katz JB, Muller AJ, Prendergast GC. Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev. 2008;222:206-221.
56. Schalper KA, Carvajal-Hausdorf D, McLaughlin J, et al. Differential Expression and Significance of PD-L1, IDO-1, and B7-H4 in Human Lung Cancer. Clin Cancer Res. 2017;23(2):370-378.
57. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011;331(6024):1565-1570.
58. Shang B, Liu Y, Jiang SJ, Liu Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep. 2015;5:15179.
59. Qian F, Qingping Y, Linquan W, et al. High tumor-infiltrating FoxP3(+) T cells predict poor survival in estrogen receptor-positive breast cancer: A meta-analysis. Eur J Surg Oncol. 2017;43(7):1258-1264.
60. West NR, Kost SE, Martin SD, et al. Tumour-infiltrating FOXP3(+) lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer. Br J Cancer. 2013;108(1):155-162.
61. Nardone V, Botta C, Caraglia M, et al. Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse. Cancer Biol Ther. 2016;17(11):1213-1220.
62. Li Z, Dong P, Ren M, et al. PD-L1 Expression Is Associated with Tumor FOXP3(+) Regulatory T-Cell Infiltration of Breast Cancer and Poor Prognosis of Patient. J Cancer. 2016;7(7):784-793.
63. Ryan M, Crow J, Kahmke R, Fisher SR, Su Z, Lee WT. FoxP3 and indoleamine 2,3-dioxygenase immunoreactivity in sentinel nodes from melanoma patients. Am J Otolaryngol. 2014;35(6):689-694.
64. Ryu HS, Park YS, Park HJ, et al. Expression of indoleamine 2,3-dioxygenase and infiltration of FOXP3+ regulatory T cells are associated with aggressive features of papillary thyroid microcarcinoma. Thyroid. 2014;24(8):1232-1240.
65. Nakamura T, Shima T, Saeki A, et al. Expression of indoleamine 2, 3-dioxygenase and the recruitment of Foxp3-expressing regulatory T cells in the development and progression of uterine cervical cancer. Cancer Sci. 2007;98(6):874-881.
66. Kim WY, Jeon YK, Kim TM, et al. Increased quantity of tumor-infiltrating FOXP3-positive regulatory T cells is an independent predictor for improved clinical outcome in extranodal NK/T-cell lymphoma. Ann Oncol. 2009;20(10):1688-1696.
67. Song JJ, Zhao SJ, Fang J, et al. Foxp3 overexpression in tumor cells predicts poor survival in oral squamous cell carcinoma. BMC Cancer. 2016;16:530.
68. Salama P, Phillips M, Grieu F, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol. 2009;27(2):186-192.
69. Mahmoud SM, Paish EC, Powe DG, et al. An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer. Breast Cancer Res Treat. 2011;127(1):99-108.
70. Mahmoud SM, Paish EC, Powe DG, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29(15):1949-1955.
71. Fisher DT, Chen Q, Appenheimer MM, et al. Hurdles to lymphocyte trafficking in the tumor microenvironment: implications for effective immunotherapy. Immunol Invest. 2006;35(3-4):251-277.
72. Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007;7(9):678-689.
73. Blatner NR, Bonertz A, Beckhove P, et al. In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction. Proc Natl Acad Sci U S A. 2010;107(14):6430-6435.
74. DeNardo DG, Johansson M, Coussens LM. Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Rev. 2008;27(1):11-18.
75. Sharma MD, Shinde R, McGaha TL, et al. The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment. Sci Adv. 2015;1(10):e1500845.
76. Tseng YL, Chang JM, Lai WW, et al. Behind and Beyond the Masaoka Staging: A 25-Year Follow-up Study of Tumor Recurrence in Completely Resected Thymic Epithelial Tumors in a Single Institution. Medicine (Baltimore). 2015;94(52):e2278.
77. Yen YT, Lai WW, Chang KW, et al. Factors predicting recurrence and postrecurrence survival in completely resected thymic carcinoma. Ann Thorac Surg. 2014;97(4):1169-1175.
78. Friedrich K, Dolznig H, Han X, Moriggl R. Steering of carcinoma progression by the YIN/YANG interaction of STAT1/STAT3. Biosci Trends. 2017;11(1):1-8.
79. Meissl K, Macho-Maschler S, Muller M, Strobl B. The good and the bad faces of STAT1 in solid tumours. Cytokine. 2017;89:12-20.
80. Zhang HF, Lai R. STAT3 in Cancer-Friend or Foe? Cancers (Basel). 2014;6(3):1408-1440.