The prognosis and disease course of medullary thyroid carcinoma (MTC) can vary widely among patients. Effective risk stratification is important for ensuring timely treatment and personalized follow-up. Biomarkers can enhance risk stratification and guide the development of targeted anticancer therapies and imaging techniques. While numerous studies have explored various immunohistochemical biomarkers in MTC, an overview is still lacking. This study aimed to provide a comprehensive overview of immunohistochemical biomarkers and their role in the prognosis of MTC patients, with a primary focus on overall survival (OS).
Methods:
This review was preregistered in PROSPERO (CRD42023469437). A systematic search was performed using the online medical databases Embase, MEDLINE (Ovid), and Cochrane. Quality was assessed using an adapted scoring system based on the REMARK criteria and the Quality in Prognosis Studies tool. The primary outcome was OS. Secondary outcomes included other types of survival and associations with clinicopathological risk factors and recurrence.
Results:
Of 2992 studies, 108 were included, investigating 170 unique biomarkers and with sample sizes ranging from 11 to 327 participants. The majority (72%) were reported in only one article. A minority of studies were rated as high quality (28%). Markers of proliferation Ki-67 (Ki-67) and programmed cell death-ligand 1 (PD-L1) were significantly associated with OS (hazard ratio [HR]: 6.67, confidence interval [CI]: 1.43–31.18 and HR: 3.34, CI: 1.18–9.51).
Conclusions:
Our systematic review provides a comprehensive synthesis of the literature on immunohistochemical biomarkers in MTC and highlights the need for high-quality validation studies. Our meta-analysis confirms the prognostic value of Ki-67, although with varying certainty due to large differences in study quality. Furthermore, we describe the association of PD-L1 positivity with poorer OS, increased recurrence, and more aggressive clinicopathological features, which supports the rationale for further investigating the potential of anti-PD-1/PD-L1 immunotherapy for advanced MTC.
MaoY, XingM. Recent incidences and differential trends of thyroid cancer in the USA. Endocr Relat Cancer, 2016; 23(4):313–322.
2.
LimH, DevesaSS, SosaJA, et al.Trends in thyroid cancer incidence and mortality in the United States, 1974–2013. JAMA, 2017; 317(13):1338–1348.
3.
ModiglianiE, CohenR, CamposJM, et al.Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: Results in 899 patients. The GETC Study Group. Groupe d’etude des tumeurs a calcitonine. Clin Endocrinol (Oxf), 1998; 48(3):265–273.
4.
RomanS, LinR, SosaJA. Prognosis of medullary thyroid carcinoma: Demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer, 2006; 107(9):2134–2142.
5.
RandleRW, BalentineCJ, LeversonGE, et al.Trends in the presentation, treatment, and survival of patients with medullary thyroid cancer over the past 30 years. Surgery, 2017; 161(1):137–146.
6.
VuongHG, OdateT, NgoHTT, et al.Clinical significance of RET and RAS mutations in sporadic medullary thyroid carcinoma: A meta-analysis. Endocr Relat Cancer, 2018; 25(6):633–641.
7.
WongK, ChengL, FornerS, et al.Long-term clinical outcomes of patients with medullary thyroid cancer: A single institution, tertiary referral centre experience. Clin Oncol (R Coll Radiol), 2025; 37:103686.
8.
AdamMA, ThomasS, RomanSA, et al.Rethinking the current american joint committee on cancer TNM staging system for medullary thyroid cancer. JAMA Surg, 2017; 152(9):869–876.
9.
XuB, FuchsTL, AhmadiS, et al.International medullary thyroid carcinoma grading system: A validated grading system for medullary thyroid carcinoma. J Clin Oncol, 2022; 40(1):96–104.
10.
NiJ, ZhangX, LiuY, et al.A comparison of the predictive value of International Medullary Thyroid Carcinoma Grading System (IMTCGS) with that of other risk factors in a Chinese Medullary Thyroid Carcinoma Cohort. Clin Endocrinol (Oxf), 2025; 102(5):589–599.
11.
PreteA, TorregrossaL, GambaleC, et al.The usefulness of the international grading system in the management of sporadic medullary thyroid carcinoma. Thyroid, 2025; 35(4):387–396.
12.
WusimanD, GuoL, LiL, et al.Clinicopathological and prognostic significance of PD-L1 and TIM-3 expression in medullary thyroid carcinoma: A retrospective immunohistochemistry study. J Endocrinol Invest, 2024; 47(1):91–100.
13.
LubinDJ, BehrmanDB, GoyalS, et al.Independent validation of the international grading system for medullary thyroid carcinoma: A single institution experience. Mod Pathol, 2023; 36(9):100235.
14.
KarkheiranB, JahanbinB, ShahverdiG, et al.Evaluation of PD-L1 antigen expression using immunohistochemistry technique in medullary thyroid carcinoma samples. Int J Physiol Pathophysiol Pharmacol, 2023; 15(1):12–20.
15.
WilliamsMD, MaJ, GrubbsEG, et al.ATF4 loss of heterozygosity is associated with poor overall survival in medullary thyroid carcinoma. Am J Cancer Res, 2021; 11(6):3227–3239.
16.
IngenwerthM, BrandenburgT, Fuhrer-SakelD, et al.DLL3 (delta-like protein 3) expression correlates with stromal desmoplasia and lymph node metastases in medullary thyroid carcinomas. Endocr Connect, 2021; 10(3):283–289.
17.
BikasA, JensenK, PatelA, et al.Cytochrome C Oxidase Subunit 4 (COX4): A potential therapeutic target for the treatment of medullary thyroid cancer. Cancers (Basel), 2020; 12(9):2548.
18.
YangX, LiuG, LiW, et al.Silencing of zinc finger protein 703 inhibits medullary thyroid carcinoma cell proliferation in vitro and in vivo. Oncol Lett, 2020; 19(1):943–951.
19.
Hincza-NowakK, KowalikA, WalczykA, et al.CD276 as a candidate target for immunotherapy in medullary thyroid cancer. Int J Mol Sci, 2023; 24(12).
20.
Vazquez-LorenteH, DunderovicDM, TaticSB, et al.Matrix Metalloproteinases 2 and 9 and their tissue inhibitors in the diagnostics of medullary thyroid carcinoma. Appl Immunohistochem Mol Morphol, 2023; 31(2):121–127.
21.
BaiY, GuoT, NiuD, et al.Clinical significance and interrelations of PD-L1 expression, Ki-67 index, and molecular alterations in sporadic medullary thyroid carcinoma from a Chinese population. Virchows Arch, 2022; 481(6):903–911.
22.
GuP, LingB, MaW, et al.Indoleamine 2,3-dioxygenase 2 immunohistochemical expression in medullary thyroid carcinoma: Implications in prognosis and immunomodulatory effects. BMC Cancer, 2022; 22(1):1116.
23.
CelepliP, BigatI, KarabulutS, et al.Evaluation of Lipocalin-2 and Twist expression in thyroid cancers and its relationship with epithelial mesenchymal transition. Ann Diagn Pathol, 2022; 59:151973.
24.
KemalY, ÇalişkanS, GunS, et al.PD-L1 expression in medullary thyroid carcinoma and its association with clinicopathological findings. Turk Patoloji Derg, 2022; 38(2):106–113.
25.
NiuY, WangW, JiangX, et al.High expression of HHLA2 predicts poor prognosis in medullary thyroid carcinoma. Jpn J Clin Oncol, 2022; 52(7):759–765.
26.
RuanX, YiJ, HuL, et al.Reduced MHC class II expression in medullary thyroid cancer identifies patients with poor prognosis. Endocr Relat Cancer, 2022; 29(2):87–98.
27.
Bagheri-YarmandR, DaduR, YeL, et al.ONC201 shows potent anticancer activity against medullary thyroid cancer via transcriptional inhibition of RET, VEGFR2, and IGFBP2. Mol Cancer Ther, 2021; 20(4):665–675.
28.
VissioE, MalettaF, FissoreJ, et al.External validation of three available grading systems for medullary thyroid carcinoma in a single institution cohort. Endocr Pathol, 2022; 33(3):359–370.
29.
ShiX, LiCW, TanLC, et al.Immune Co-inhibitory receptors PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT in medullary thyroid cancers: A large cohort study. J Clin Endocrinol Metab, 2021; 106(1):120–132.
30.
Cordero-BarrealA, CaleirasE, Lopez de MaturanaE, et al.CD133 expression in medullary thyroid cancer cells identifies patients with poor prognosis. J Clin Endocrinol Metab, 2020; 105(11):dgaa527.
31.
VargasCVF, CeolinL, ScheffelRS, et al.The tissue expression pattern of CA 19.9 is associated with oncological features in medullary thyroid carcinoma. Endocrine, 2020; 70(3):544–551.
32.
MissaouiN, ChouaibiS, LimamS, et al.Signification of forkhead box A1 (FOXA1) expression in thyroid cancers. J Egypt Natl Canc Inst, 2019; 31(1):11.
33.
ShiX, YuPC, LeiBW, et al.Association between programmed Death-Ligand 1 expression and clinicopathological characteristics, structural recurrence, and biochemical recurrence/persistent disease in medullary thyroid carcinoma. Thyroid, 2019; 29(9):1269–1278.
34.
SagliettiC, La RosaS, SykiotisGP, et al.Expression of Prox1 in medullary thyroid carcinoma is associated with chromogranin A and calcitonin expression and with Ki67 proliferative index, but not with prognosis. Endocr Pathol, 2019; 30(2):138–145.
35.
BiY, RenX, BaiX, et al.PD-1/PD-L1 expressions in medullary thyroid carcinoma: Clinicopathologic and prognostic analysis of Chinese population. Eur J Surg Oncol, 2019; 45(3):353–358.
36.
de VriesLH, LodewijkL, WillemsSM, et al.SSTR2A expression in medullary thyroid carcinoma is correlated with longer survival. Endocrine, 2018; 62(3):639–647.
37.
LodewijkL, WillemsSM, DreijerinkKMA, et al.The theranostic target prostate-specific membrane antigen is expressed in medullary thyroid cancer. Hum Pathol, 2018; 81:245–254.
38.
ZhanS, LiJ, WangT, et al.Quantitative proteomics analysis of sporadic medullary thyroid cancer reveals FN1 as a potential novel candidate prognostic biomarker. Oncologist, 2018; 23(12):1415–1425.
39.
WernerTA, ForsterCM, DizdarL, et al.CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma. Br J Cancer, 2017; 117(12):1837–1845.
40.
ValenciagaA, GrubbsEG, PorterK, et al.Reduced retinoblastoma protein expression is associated with decreased patient survival in medullary thyroid cancer. Thyroid, 2017; 27(12):1523–1533.
41.
KendlerDB, AraujoMLJr, AlencarR, et al.Somatostatin receptor subtype 1 might be a predictor of better response to therapy in medullary thyroid carcinoma. Endocrine, 2017; 58(3):474–480.
42.
MourraN, BennisM, BoellePY, et al.Clusterin expression in medullary thyroid carcinoma is inversely correlated with the presence of lymph node metastases. Hum Pathol, 2017; 64:37–43.
43.
LodewijkL, van DiestP, van der GroepP, et al.Expression of HIF-1alpha in medullary thyroid cancer identifies a subgroup with poor prognosis. Oncotarget, 2017; 8(17):28650–28659.
44.
Bagheri-YarmandR, WilliamsMD, GrubbsEG, et al.ATF4 targets RET for degradation and is a candidate tumor suppressor gene in medullary thyroid cancer. J Clin Endocrinol Metab, 2017; 102(3):933–941.
45.
PezzaniR, BertazzaL, CavedonE, et al.Novel prognostic factors associated with cell cycle control in sporadic medullary thyroid cancer patients. Int J Endocrinol, 2019; 2019:9421079.
46.
CappagliV, PotesCS, FerreiraLB, et al.Calcitonin receptor expression in medullary thyroid carcinoma. PeerJ, 2017; 5:e3778.
47.
HeracM, NiederleB, RadererM, et al.Expression of somatostatin receptor 2A in medullary thyroid carcinoma is associated with lymph node metastasis. Apmis, 2016; 124(10):839–845.
48.
SteinerF, Hauser-KronbergerC, RendlG, et al.Expression of Tenascin C, EGFR, E-Cadherin, and TTF-1 in medullary thyroid carcinoma and the correlation with RET mutation status. Int J Mol Sci, 2016; 17(7):1093.
49.
WernerTA, Tamkan-OlcekY, DizdarL, et al.Survivin and XIAP: Two valuable biomarkers in medullary thyroid carcinoma. Br J Cancer, 2016; 114(4):427–434.
50.
FerreiraLB, EloyC, PestanaA, et al.Osteopontin expression is correlated with differentiation and good prognosis in medullary thyroid carcinoma. Eur J Endocrinol, 2016; 174(4):551–561.
51.
BiY, MengY, WuH, et al.Expression of the potential cancer stem cell markers CD133 and CD44 in medullary thyroid carcinoma: A ten-year follow-up and prognostic analysis. J Surg Oncol, 2016; 113(2):144–151.
52.
GurgulE, KasprzakA, BlaszczykA, et al.Ghrelin and obestatin in thyroid gland—immunohistochemical expression in nodular goiter, papillary and medullary cancer. Folia Histochem Cytobiol, 2015; 53(1):19–25.
53.
MilmanS, ArnoldJL, PriceM, et al.Medullary thyroid cancer that stains negative for Ca 19-9 has decreased metastatic potential. Endocr Pract, 2015; 21(6):590–594.
54.
KaraarslanS, Nur YurumF, Ebru PalaE, et al.The relationship of melanocytic differentiation with prognostic markers in medullary thyroid carcinomas. Pathol Res Pract, 2015; 211(5):356–360.
55.
PennelliG, GaluppiniF, BarolloS, et al.The PDCD4/miR-21 pathway in medullary thyroid carcinoma. Hum Pathol, 2015; 46(1):50–57.
56.
FanYL, LiXQ. Expression of leptin and its receptor in thyroid carcinoma: Distinctive prognostic significance in different subtypes. Clin Endocrinol (Oxf), 2015; 83(2):261–267.
57.
LyraJ, VinagreJ, BatistaR, et al.mTOR activation in medullary thyroid carcinoma with RAS mutation. Eur J Endocrinol, 2014; 171(5):633–640.
58.
WajnerSM, CappC, BrasilBA, et al.Reduced tissue inhibitor of metalloproteinase-2 expression is associated with advanced medullary thyroid carcinoma. Oncol Lett, 2014; 7(3):731–737.
59.
ErovicBM, KimD, CassolC, et al.Prognostic and predictive markers in medullary thyroid carcinoma. Endocr Pathol, 2012; 23(4):232–242.
60.
TamburrinoA, MolinoloAA, SalernoP, et al.Activation of the mTOR pathway in primary medullary thyroid carcinoma and lymph node metastases. Clin Cancer Res, 2012; 18(13):3532–3540.
61.
KoperekO, BergnerO, PichlhoferB, et al.Expression of hypoxia-associated proteins in sporadic medullary thyroid cancer is associated with desmoplastic stroma reaction and lymph node metastasis and may indicate somatic mutations in the VHL gene. J Pathol, 2011; 225(1):63–72.
62.
MianC, PennelliG, BarolloS, et al.Combined RET and Ki-67 assessment in sporadic medullary thyroid carcinoma: A useful tool for patient risk stratification. Eur J Endocrinol, 2011; 164(6):971–976.
63.
CappC, WajnerSM, SiqueiraDR, et al.Increased expression of vascular endothelial growth factor and its receptors, VEGFR-1 and VEGFR-2, in medullary thyroid carcinoma. Thyroid, 2010; 20(8):863–871.
64.
RiosA, RodriguezJM, AcostaJM, et al.Prognostic value of histological and immunohistochemical characteristics for predicting the recurrence of medullary thyroid carcinoma. Ann Surg Oncol, 2010; 17(9):2444–2451.
65.
TaiebD, GiusianoS, SebagF, et al.Tumor protein p53-induced nuclear protein (TP53INP1) expression in medullary thyroid carcinoma: A molecular guide to the optimal extent of surgery? World j Surg, 2010; 34(4):830–835.
66.
Rodriguez-AntonaC, PallaresJ, Montero-CondeC, et al.Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis. Endocr Relat Cancer, 2010; 17(1):7–16.
67.
CavalheiroBG, JunqueiraCR, BrandaoLG. Expression of membrane type 1 matrix metalloproteinase in medullary thyroid carcinoma: Prognostic implications. Head Neck, 2010; 32(1):58–67.
68.
CavalheiroBG, JunqueiraCR, BrandaoLG. Ratio of metalloproteinase 2 to tissue inhibitor of metalloproteinase 2 in medullary thyroid carcinoma. Arch Otolaryngol Head Neck Surg, 2009; 135(8):812–817.
69.
CavalheiroBG, JunqueiraCR, BrandaoLG. Expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 2 (TIMP-2) in medullary thyroid carcinoma: Prognostic implications. Thyroid, 2008; 18(8):865–871.
70.
ChoMA, LeeMK, NamKH, et al.Expression and role of estrogen receptor alpha and beta in medullary thyroid carcinoma: Different roles in cancer growth and apoptosis. J Endocrinol, 2007; 195(2):255–263.
71.
KoperekO, ScheubaC, PuriC, et al.Molecular characterization of the desmoplastic tumor stroma in medullary thyroid carcinoma. Int J Oncol, 2007; 31(1):59–67.
72.
RuggeriRM, SciacchitanoS, VitarelliE, et al.Immunoexpression of multidrug-resistance protein 2 and cyclooxygenase 2 in medullary thyroid carcinomas. Arch Pathol Lab Med, 2006; 130(7):1014–1019.
73.
ItoY, YoshidaH, NakamuraY, et al.Expression of Jun activation domain-binding protein 1 and p27 (Kip1) in thyroid medullary carcinoma. Pathology, 2005; 37(3):216–219.
74.
ItoY, NakamuraY, YoshidaH, et al.Polo-like kinase 1 expression in medullary carcinoma of the thyroid: Its relationship with clinicopathological features. Pathobiology, 2005; 72(4):186–190.
75.
ItoY, YoshidaH, MotooY, et al.Expression of p8 protein in medullary thyroid carcinoma. Anticancer Res, 2005; 25(5):3419–3423.
76.
ItoY, YoshidaH, TomodaC, et al.Expression of cdc25B and cdc25A in medullary thyroid carcinoma: Cdc25B expression level predicts a poor prognosis. Cancer Lett, 2005; 229(2):291–297.
77.
MustafaT, KlonischT, Hombach-KlonischS, et al.Expression of CD97 and CD55 in human medullary thyroid carcinomas. Int J Oncol, 2004; 24(2):285–294.
78.
TisellLE, OdenA, MuthA, et al.The Ki67 index a prognostic marker in medullary thyroid carcinoma. Br J Cancer, 2003; 89(11):2093–2097.
79.
FaggianoA, TalbotM, LacroixL, et al.Differential expression of galectin-3 in medullary thyroid carcinoma and C-cell hyperplasia. Clin Endocrinol (Oxf), 2002; 57(6):813–819.
80.
PapottiM, KumarU, VolanteM, et al.Immunohistochemical detection of somatostatin receptor types 1-5 in medullary carcinoma of the thyroid. Clin Endocrinol (Oxf), 2001; 54(5):641–649.
81.
CvejicD, SavinS, GolubovicS, et al.Galectin-3 and carcinoembryonic antigen expression in medullary thyroid carcinoma: Possible relation to tumour progression. Histopathology, 2000; 37(6):530–535.
82.
ScopsiL, SampietroG, BoracchiP, et al.Argyrophilia and chromogranin A and B immunostaining in patients with sporadic medullary thyroid carcinoma. A critical appraisal of their prognostic utility. J Pathol, 1998; 184(4):414–419.
83.
WangW, JohanssonHE, BergholmUI, et al.Expression of c-Myc, TGF-alpha and EGF-receptor in sporadic medullary thyroid carcinoma. Acta Oncol, 1997; 36(4):407–411.
84.
BasoloF, PollinaL, PaciniF, et al.Expression of the Mr 67,000 laminin receptor is an adverse prognostic indicator in human thyroid cancer: An immunohistochemical study. Clin Cancer Res, 1996; 2(10):1777–1780.
85.
ScopsiL, SampietroG, BoracchiP, et al.Multivariate analysis of prognostic factors in sporadic medullary carcinoma of the thyroid. A retrospective study of 109 consecutive patients. Cancer, 1996; 78(10):2173–2183.
86.
DottoriniME, AssiA, SironiM, et al.Multivariate analysis of patients with medullary thyroid carcinoma. Prognostic significance and impact on treatment of clinical and pathologic variables. Cancer, 1996; 77(8):1556–1565.
87.
MizukamiY, NonomuraA, MichigishiT, et al.Medullary thyroid carcinoma experienced at Kanazawa University Hospital. J Surg Oncol, 1996; 61(1):27–33.
88.
WangW, JohanssonH, BergholmU, et al.Apoptosis and expression of the proto-oncogenes bcl-2 and p53 and the proliferation factor Ki-67 in human medullary thyroid carcinoma. Endocr Pathol, 1996; 7(1):37–45.
89.
VialeG, RoncalliM, GrimeliusL, et al.Prognostic value of bcl-2 immunoreactivity in medullary thyroid carcinoma. Hum Pathol, 1995; 26(9):945–950.
90.
HolmR, HoieJ, KaalhusO, et al.Immunohistochemical detection of nm23/NDP kinase and cathepsin D in medullary carcinomas of the thyroid gland. Virchows Arch, 1995; 427(3):289–294.
91.
VierbuchenM, SchroderS, LarenaA, et al.Native and sialic acid masked Lewis(a) antigen reactivity in medullary thyroid carcinoma. Distinct tumour-associated and prognostic relevant antigens. Virchows Arch, 1994; 424(2):205–211.
92.
RoncalliM, VialeG, GrimeliusL, et al.Prognostic value of N-myc immunoreactivity in medullary thyroid carcinoma. Cancer, 1994; 74(1):134–141.
93.
LangleF, SolimanT, NeuholdN, et al.CD15 (LeuM1) immunoreactivity: Prognostic factor for sporadic and hereditary medullary thyroid cancer? World j Surg, 1994; 18(4):583–587.
94.
SkopelitouA, KorkolopoulouP, PapanikolaouA, et al.Proliferating cell nuclear antigen (PCNA) in medullary thyroid carcinoma. J Cancer Res Clin Oncol, 1993; 119(7):379–381.
95.
NeuholdN, LangleF, GnantM, et al.Relationship of CD15 immunoreactivity and prognosis in sporadic medullary thyroid carcinoma. J Cancer Res Clin Oncol, 1992; 118(8):629–634.
96.
PaciniF, BasoloF, EliseiR, et al.Medullary thyroid cancer. An immunohistochemical and humoral study using six separate antigens. Am J Clin Pathol, 1991; 95(3):300–308.
97.
ScopsiL, FerrariC, PilottiS, et al.Immunocytochemical localization and identification of prosomatostatin gene products in medullary carcinoma of human thyroid gland. Hum Pathol, 1990; 21(8):820–830.
98.
PaciniF, EliseiR, AnelliS, et al.Somatostatin in medullary thyroid cancer. In vitro and in vivo studies. Cancer, 1989; 63(6):1189–1195.
99.
SchroderS, SchwarzW, RehpenningW, et al.Leu-M1 immunoreactivity and prognosis in medullary carcinomas of the thyroid gland. J Cancer Res Clin Oncol, 1988; 114(3):291–296.
100.
FuchsTL, NassourAJ, GloverA, et al.A proposed grading scheme for medullary thyroid carcinoma based on proliferative activity (Ki-67 and Mitotic Count) and coagulative necrosis. Am J Surg Pathol, 2020; 44(10):1419–1428.
101.
SchroderS, BockerW, BaischH, et al.Prognostic factors in medullary thyroid carcinomas. Survival in relation to age, sex, stage, histology, immunocytochemistry, and DNA content. Cancer, 1988; 61(4):806–816.
102.
SaadMF, OrdonezNG, GuidoJJ, et al.The prognostic value of calcitonin immunostaining in medullary carcinoma of the thyroid. J Clin Endocrinol Metab, 1984; 59(5):850–856.
103.
CvejicD, SavinS, PaunovicI, et al.Immunohistochemical localization of matrix metalloproteinase-2 (MMP-2) in medullary thyroid carcinoma. Arch Oncol, 2000; 8(3):95–97.
104.
CvejićD, SavinS, PetrovićI, et al.Galectin-3 expression in medullary thyroid carcinoma in relation to tumor progression. Arch Oncol, 2003; 11(2):71–74.
105.
AraujoAN, CamachoCP, MendesTB, et al.Comprehensive assessment of copy number alterations uncovers recurrent AIFM3 and DLK1 copy gain in medullary thyroid carcinoma. Cancers (Basel), 2021; 13(2):218.
106.
NahmJH, KimHM, KooJS. Glycolysis-related protein expression in thyroid cancer. Tumour Biol, 2017; 39(3):1010428317695922.
107.
SunWY, KimHM, JungWH, et al.Expression of serine/glycine metabolism-related proteins is different according to the thyroid cancer subtype. J Transl Med, 2016; 14(1):168.
108.
KimHM, KimES, KooJS. Expression of autophagy-related proteins in different types of thyroid cancer. Int J Mol Sci, 2017; 18(3):540.
109.
MeloDH, MamedeRCM, NederL, et al.Expression of cancer/testis antigens MAGE-A, MAGE-C1, GAGE and CTAG1B in benign and malignant thyroid diseases. Oncol Lett, 2017; 14(6):6485–6496.
110.
PapottiM, OliveroM, VolanteM, et al.Expression of Hepatocyte Growth Factor (HGF) and its Receptor (MET) in medullary carcinoma of the thyroid. Endocr Pathol, 2000; 11(1):19–30.
111.
PollinaL, PaciniF, FontaniniG, et al.bcl-2, p53 and proliferating cell nuclear antigen expression is related to the degree of differentiation in thyroid carcinomas. Br J Cancer, 1996; 73(2):139–143.
112.
KawabataW, SuzukiT, MoriyaT, et al.Estrogen receptors (alpha and beta) and 17beta-hydroxysteroid dehydrogenase type 1 and 2 in thyroid disorders: Possible in situ estrogen synthesis and actions. Mod Pathol, 2003; 16(5):437–444.
113.
JagerEC, van HemelBM, RutgersB, et al.Validation of the international medullary thyroid cancer grading system and identification of EZH2 as a prognostic and potential therapeutic marker in medullary thyroid cancer. Cancers (Basel), 2025; 17(5):737.
114.
ZhangQ, HuY, ChenX, et al.Preoperative prediction of Ki-67 expression in medullary thyroid carcinoma based on ultrasonographic features: A 10-year retrospective study. Eur J Radiol, 2025; 188:112134.
115.
XuB, BaineMK, JungbluthA, et al.Detection of SEZ6, a therapeutic target, in medullary thyroid carcinoma. J Clin Endocrinol Metab, 2025; 110(7):2041–2046.
116.
WangZ, GuoF, FuG, et al.Predictive and prognostic value of aurora kinase A combined with tumor-infiltrating lymphocytes in medullary thyroid carcinoma. Front Oncol, 2024; 14:1379420.
117.
de VriesLH, LodewijkL, PijnappelEW, et al.Expression of integrin alphavbeta3 in medullary thyroid carcinoma. Future Oncol, 2024; 20(27):2015–2022.
118.
Ruz-CaracuelI, Caniego-CasasT, Alonso-GordoaT, et al.Transcriptomic differences in medullary thyroid carcinoma according to grade. Endocr Pathol, 2024; 35(3):207–218.
119.
BelleraCA, PenelN, OualiM, et al.Guidelines for time-to-event end point definitions in sarcomas and gastrointestinal stromal tumors (GIST) trials: Results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)dagger. Ann Oncol, 2015; 26(5):865–872.
120.
BelleraCA, PulidoM, GourgouS, et al.Protocol of the definition for the assessment of time-to-event endpoints in CANcer trials (DATECAN) project: Formal consensus method for the development of guidelines for standardised time-to-event endpoints’ definitions in cancer clinical trials. Eur J Cancer, 2013; 49(4):769–781.
121.
BonnetainF, BonsingB, ConroyT, et al.Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials). Eur J Cancer, 2014; 50(17):2983–2993.
122.
Gourgou-BourgadeS, CameronD, PoortmansP, et al.Guidelines for time-to-event end point definitions in breast cancer trials: Results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials). Ann Oncol, 2015; 26(12):2505–2506.
LindseySC, GanlyI, PalmerF, et al.Response to initial therapy predicts clinical outcomes in medullary thyroid cancer. Thyroid, 2015; 25(2):242–249.
125.
RindiG, KlimstraDS, Abedi-ArdekaniB, et al.A common classification framework for neuroendocrine neoplasms: An International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol, 2018; 31(12):1770–1786.
126.
PanDH, WenDY, LuoYH, et al.The diagnostic and prognostic values of Ki-67/MIB-1 expression in thyroid cancer: A meta-analysis with 6,051 cases. Onco Targets Ther, 2017; 10:3261–3276.
127.
ZouW, WolchokJD, ChenL. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med, 2016; 8(328):328rv4.
128.
Di MolfettaS, DottoA, FanciulliG, et al.Immune checkpoint inhibitors: New weapons against medullary thyroid cancer? Front Endocrinol (Lausanne), 2021; 12:667784.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
