Journal of Cancer Research and Practice 4 (2017) 95e99

Contents lists available at ScienceDirect

Journal of Cancer Research and Practice

journal homepage: http://www.journals.elsevier.com/journal-of-cancer-
research-and-practice

Original Article

Characteristics of lymphocyte-infiltrating papillary thyroid cancer

Chi-Yu Kuo a, Tsang-Pai Liu a, b, c, Po-Sheng Yang a, b, Shih-Ping Cheng a, b, *
a
Department of Surgery, MacKay Memorial Hospital, Taipei, Taiwan
b
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
c
Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Background: The tumor-promoting or tumor-suppressing role of tumor-associated lymphocytes remains
Received 26 January 2017 a subject of debate. We examined thyroid cancer data from The Cancer Genome Atlas in an attempt to
Received in revised form define the relationship between lymphocyte infiltrates and clinical and molecular presentations.
10 March 2017
Methods: Patient characteristics and transcriptome profiling were compared between groups dichoto-
Accepted 17 March 2017
Available online 18 March 2017
mized by the percentage of tumor-infiltrating lymphocytes of the primary tumor. Differentially
expressed genes were subjected to functional enrichment analyses.
Results: In 52% of the tumors, there was no lymphocyte infiltration. Papillary thyroid cancer with infil-
Keywords:
Lymphocyte
trating lymphocytes was associated with classical histologic features, multifocality, and lymph node
Papillary thyroid cancer metastasis. Patients with lymphocyte-infiltrating cancer had a longer overall survival duration (log-rank
Survival P ¼ 0.018). A total of 3151 differentially expressed genes were identified. Pathways related to immune
Immune response were upregulated, where the expression of several thyroid-related genes was downregulated.
Differentiation Conclusion: Papillary thyroid cancer with tumor-infiltrating lymphocytes is associated with an upregu-
lation of immune response and cytokine production, along with a trend which suggests an overall
survival benefit.
© 2017 Taiwan Oncology Society. Production and hosting by Elsevier B.V. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction
Since Rudolf Virchow identified leukocytes in tumor tissues in
1863, inflammation has been intimately implicated in cancer
development and progression. The presence of an inflammatory
infiltrate in tumor tissue may represent inflammatory conditions
preceding the development of malignancy. Studies have shown
that an inflammatory milieu could contribute to proliferation and
survival of malignant cells, sabotage adaptive immunity, and
stimulate angiogenesis and metastasis.1 On the other hand, in-
flammatory infiltrates may represent the host response to the tu-
mor. Heterogeneous immune infiltrates have been shown in
diverse tissue types and may portend an improved prognosis.2
Different types of tumor-associated inflammatory cells have
been identified in thyroid cancer.3 These consist of cells of the
innate immune system (mainly macrophages, mast cells, and
neutrophils) as well as cells associated with an adaptive immune
* Corresponding author. Department of Surgery, MacKay Memorial Hospital, 92,
Chung-Shan North Road, Section 2, Taipei, 10449, Taiwan.
E-mail address: surg.mmh@gmail.com (S.-P. Cheng).
Peer review under responsibility of Taiwan Oncology Society.
response (T and B cells). In general, innate immune cells are more
likely to have tumor-promoting properties.4 Previously, we have
found that thyroid cancer patients in the higher tertile of
neutrophil-to-lymphocyte ratio had a significantly larger tumor
size and a high recurrence risk.5 In contrast, the role of adaptive
immune cells is still a matter of debate. Several studies have shown
that patients whose tumors are not infiltrated by lymphocytes
present a high recurrence rate, suggesting that the presence of
lymphocytes in the thyroid tumor microenvironment indicates a
favorable prognosis.6 On the contrary, other researchers reported
that thyroid cancer with tumor-associated lymphocytes exhibited
higher disease stage and increased incidence of invasion and lymph
node metastasis.7 Furthermore, the enrichment of CD8þ lympho-
cytes has been associated with disease recurrence.8
Lymphocytic infiltrates in thyroid cancer may suggest a back-
ground of chronic lymphocytic thyroiditis. Thyroiditis is charac-
terized by a cellular immune response with dense lymphocytic
infiltration of the thyroid gland, as well as by a humoral immune
response leading to the production of autoantibodies against thy-
roid antigens. Recently, a meta-analysis investigated the correlation
between papillary thyroid cancer and histologically proven Hashi-
moto's thyroiditis.9 The results revealed that thyroiditis was more

http://dx.doi.org/10.1016/j.jcrpr.2017.03.003
2311-3006/© 2017 Taiwan Oncology Society. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.
org/licenses/by-nc-nd/4.0/).
96 C.-Y. Kuo et al. / Journal of Cancer Research and Practice 4 (2017) 95e99

frequently observed in papillary thyroid cancer than in benign
thyroid diseases, and cancer patients with thyroiditis had a longer
duration of recurrence-free survival. This seemingly paradoxical
phenomenon deserves further investigation, because it may pro-
vide insight into the immune dysregulation involved in both dis-
orders. In the present study, we examined the data of The Cancer
Genome Atlas (TCGA) project in an attempt to define the relation-
ship between lymphocyte infiltrates and clinical and molecular
presentations.
2. Materials and methods
Patient characteristics and preprocessed gene expression data of
patients with papillary thyroid cancer were downloaded from
Genomic Data Commons (https://gdc.cancer.gov/) in August 2016.10
The mRNA expression profile was obtained by Illumina HiSeq 2000
RNA sequencing version 2 level 3 data, and expressed as RNA-Seq
by Expectation Maximization (RSEM) values.11,12 The information
on new tumor event, disease status, and patient mortality was
updated to incorporate the latest follow-up. Patients who had
missing transcriptome profiling or who lacked tumor-infiltrating
lymphocyte data were excluded from the analysis. Finally, a total
of 497 patients were included in the study.
The percentage of tumor-infiltrating lymphocytes of the pri-
mary tumor was significantly skewed, ranging from 0 to 30% (mean
1.5%, median 0%). There were no tumor-infiltrating lymphocytes in
257 (52%) of the cases. We used the X-tile software (Yale University,
New Haven, CT, USA) to determine an optimal cut-off point.13,14 For
categorical variables, the chi-square test, Fisher's exact test, or the
Cochran-Armitage trend test was used to determine the difference
between groups.15 For continuous variables, unpaired two-tailed
Student's t-test was performed.16 Overall survival and recurrence-
free survival were compared using Kaplan-Meier curves and log-
rank tests. The level of statistical significance was chosen as
P < 0.05.
To identify transcriptome changes in association with lympho-
cyte infiltration, the gene expression profile of the tumors with
tumor-infiltrating lymphocytes less or more frequent than the cut-
off were thoroughly compared. Median RSEM values of all gene
expression data obtained from RNA sequencing were calculated10;
then, genes with a median value of less than 4.1374 (the first
quartile) were excluded to avoid any variation caused by low-level
expressions. The expression levels of remaining genes were
compared one by one between the two groups using Wilcoxon rank
sum tests. Genes with a P value of less than 0.01 (differentially
expressed genes) were subjected to functional enrichment ana-
lyses. Spearman's rank correlation test was used for correlation
studies.17
The Kyoto Encyclopedia of Genes and Genomes (KEGG) anno-
tation of differentially expressed genes was analyzed using Web-
based Gene Set Analysis Toolkit (WebGestalt, http://www.
webgestalt.org/) and the Database for Annotation, Visualization
and Integration Discovery (DAVID, https://david.ncifcrf.gov/).18 In
WebGestalt, the minimum number of genes for enrichment was set
at 5, and the significance analysis was performed using the hy-
pergeometric test with the significance level set at P ¼ 0.01. In
DAVID, the parameters were set to their default values.
3. Results
In the present study, nearly one-half of the tumors were absent
for lymphocyte infiltration. The cut-off of lymphocyte infiltration
was determined at 1%. In total, 258 (52%) patients had tumor-
infiltrating lymphocytes less than 1%, while 239 (48%) patients
had tumor-infiltrating lymphocytes greater than or equal to 1%. The
characteristics of the two groups are listed in Table 1. Papillary
thyroid cancer with infiltrating lymphocytes 1% was associated
with classical histologic features, multifocality, and lymph node
metastasis. However, there was no difference in TNM stage or the
frequency of BRAF mutation between the two groups. As shown in
Fig. 1, papillary thyroid cancer with infiltrating lymphocytes 1%
was associated with a better overall survival (log-rank P ¼ 0.018),
but there was no difference in recurrence-free survival (log-rank
P ¼ 0.851). Histological subtype did not influence overall survival
(log-rank P ¼ 0.419) or recurrence-free survival (log-rank
P ¼ 0.274).
There were 3151 differentially expressed genes identified from
the transcriptome profiling data of 497 patients (Fig. 2). Among

Table 1
Clinicopathological features of 497 patients with papillary thyroid cancer grouped by the percentage of tumor-infiltrating lymphocytes.

Lymphocyte <1% (n ¼ 258) Lymphocyte  1% (n ¼ 239) P value

Histology, n (%) 0.001

Classical 178 (69%) 176 (74%)
Follicular variant 64 (25%) 34 (14%)
Tall cell 15 (6%) 21 (9%)
Others 1 (0%) 8 (3%)
Female, n (%) 191 (74%) 172 (72%) 0.604
Family history, n (%) 15 (6%) 10 (4%) 0.406
Age (years) 48 ± 16 47 ± 16 0.577
Tumor size (cm) 2.9 ± 1.7 2.9 ± 1.7 0.868
Extrathyroidal extension, n (%) 0.339
None 179 (70%) 149 (66%)
Minimal 67 (26%) 66 (29%)
Advanced 9 (4%) 10 (4%)
Multifocality, n (%) 105 (42%) 118 (50%) 0.048
Lymph node metastasis, n (%) 101 (39%) 121 (51%) 0.010
Distant metastasis, n (%) 7 (3%) 1 (0%) 0.070
TNM stage, n (%) 0.933
Stage I 141 (55%) 140 (59%)
Stage II 38 (15%) 14 (6%)
Stage III 53 (21%) 56 (24%)
Stage IV 25 (10%) 28 (12%)
BRAF mutation, n (%) 133 (52%) 119 (50%) 0.695

Data are expressed as number (percentage) or mean ± SD.

Bold-fond numbers indicate statistical significance (P < 0.05).
 C.-Y. Kuo et al. / Journal of Cancer Research and Practice 4 (2017) 95e99 97

Fig. 2. Study flowchart for functional enrichment analysis.

4. Discussion

Chronic lymphocytic thyroiditis is the most common autoim-

mune inflammatory thyroid disease. Interestingly, the prevalence
of chronic lymphocytic thyroiditis has increased over time.19 It is
not uncommon to find thyroid cancer in patients who had a thy-
roidectomy for thyroiditis even when malignancy was not sus-
pected preoperatively.20 However, the association between
Fig. 1. Overall survival (A) and recurrence-free survival (B) of 497 patients with thyroiditis and thyroid cancer remains controversial. We and other
papillary thyroid cancer grouped by the percentage of tumor-infiltrating lymphocytes. groups have shown that lymphocytic thyroiditis is associated with
an increased risk of thyroid cancer.21,22 Still others have argued that
the presence of thyroiditis has a higher frequency of suspicious
cytology by way of fine-needle aspiration cytology, which results in
these differentially expressed genes, 2190 genes were found to be a selection bias.23,24
upregulated in the group with infiltrating lymphocytes 1%. As In this study, we found that papillary thyroid cancer with infil-
shown in Table 2, these genes were enriched in pathways related to trating lymphocytes was associated with a better overall survival.
immune response, hematopoiesis, cytokine production, and cell Our finding is consistent with previous reports, suggesting that
adhesion molecules. We found that several genes of interest differentiated thyroid cancer with coexisting thyroiditis has a bet-
showed upregulated expression, including PDCD1 (Spearman's ter long-term outcome.25,26 We demonstrated a higher frequency
rho ¼ 0.229, P < 0.0001), CTLA4 (rho ¼ 0.328, P < 0.0001), IDO1 of lymph node metastasis in lymphocyte-infiltrating thyroid can-
(rho ¼ 0.246, P < 0.0001), IDO2 (rho ¼ 0.197, P < 0.0001), and cers. Although similar findings have been reported in other
FOXP3 (rho ¼ 0.287, P < 0.0001). There was no difference in
expression of CD274 (PD-L1) between the two groups.
In addition, we found that 961 genes were downregulated in the
Table 2
group with infiltrating lymphocytes 1%. Enriched pathways are Top ten KEGG pathways of upregulated genes associated with tumor-infiltrating
listed in Table 3. Initial TCGA identified several thyroid-related lymphocytes 1% in papillary thyroid cancer.
genes constituting the thyroid differentiation score (TDS).11
Pathway WebGestalt DAVID
Among the 13 mRNA expression levels included in the TDS, three P value P value
were downregulated: DUOX1 (Spearman's rho ¼ 0.177,
Staphylococcus aureus infection 9.12e-23 8.18e-13
P ¼ 0.0001), DUOX2 (rho ¼ 0.179, P ¼ 0.0001), and TG Hematopoietic cell lineage 2.38e-24 6.19e-12
(rho ¼ 0.208, P < 0.0001). Notably, PVRL4 expression was upre- Cytokine-cytokine receptor interaction 7.41e-33 7.45e-12
gulated (rho ¼ 0.130, P ¼ 0.004). The remaining 9 genes in the TDS Cell adhesion molecules (CAMs) 9.68e-25 1.72e-11
showed no significant difference between the two groups, Phagosome 2.16e-26 2.45e-11
Graft-versus-host disease 8.73e-18 3.50e-11
including SLC5A5 (sodium-iodide symporter) and TPO. For other
Allograft rejection 5.23e-19 6.43e-11
thyroid-related genes, TSHR expression was significantly down- Leishmaniasis 4.91e-21 9.44e-11
regulated (rho ¼ 0.176, P ¼ 0.0001). The distributions are depicted Osteoclast differentiation 1.14e-23 1.73e-10
in Fig. 3. Viral myocarditis 3.88e-17 1.37e-09
98 C.-Y. Kuo et al. / Journal of Cancer Research and Practice 4 (2017) 95e99

Table 3 influenced by variations in levels of tumor stroma or lymphocyte

Top ten KEGG pathways of downregulated genes associated with tumor-infiltrating infiltration.11 In a comprehensive study of purity correlated genes,
lymphocytes 1% in papillary thyroid cancer.
only the expression of CTLA4 and CD274 in our analysis was
Pathway WebGestalt DAVID influenced by the tumor purity level.4
P value P value We acknowledge several limitations in this study. Varying de-
Protein processing in endoplasmic reticulum 3.01e-10 1.64e-06 grees of lymphocyte infiltrations or overt thyroiditis resulting in the
Neurotrophin signaling pathway 3.90e-05 1.92e-03 destruction of thyroid follicles is the most common cause of hy-
N-Glycan biosynthesis 1.88e-05 4.11e-03
pothyroidism in iodine-replete countries. Increasing evidence has
Insulin signaling pathway 2.70e-05 5.25e-03
Valine, leucine and isoleucine degradation 3.00e-04 1.33e-02 confirmed the association between higher serum thyrotropin (TSH)
Lysosome 2.70e-05 1.51e-02
Lysine degradation 3.00e-04 1.77e-02
Glycosylphosphatidylinositol(GPI)-anchor biosynthesis 8.00e-04 1.94e-02
Renal cell carcinoma 4.00e-04 2.03e-02
Colorectal cancer 3.00e-04 2.03e-02

studies,7 a meta-analysis suggests that papillary cancer with

coexisting thyroiditis was associated with a lower rate of lymph
node metastasis (P ¼ 0.041).9 The discrepancy may lie in the fact
that prophylactic lymph node dissection is not routinely performed
in differentiated thyroid cancer (9.9% Nx status in the TCGA data). In
the meta-analysis, there was significant statistical heterogeneity
among the studies (P ¼ 0.012). Moreover, we noted that
lymphocyte-infiltrating cancer was more likely to have multifocal
involvement. This is in keeping with the experience of other re-
searchers.9 As for the clonality of multifocal thyroid cancer, an in-
dependent origin of the different tumor has been demonstrated.27
In this regard, our observation may partially be explained by the
active role of inflammation in thyroid tumorigenesis.
Papillary thyroid cancer with lymphocytic infiltrates was asso-
ciated with classical histologic features, but not with the status of
BRAF mutation in our study. BRAF mutation is the most common
genetic alteration in papillary thyroid cancer, and is typically
associated with classical subtype or tall-cell variant.28 Studies have
yielded discrepant results concerning the impact of inflammation
on BRAF mutation in thyroid cancer. Some studies have shown that
papillary thyroid cancer with lymphocytic thyroiditis or with
greater lymphocyte infiltration is more likely to be BRAF wild-
type.29,30 Nonetheless, there are reports that BRAF mutation was
associated with a higher frequency of tumor-associated lympho-
cytes.31 Consistent with our findings, Huang and colleagues found
that tall-cell and classical papillary thyroid cancer possesses more
immune activities under miRNA regulation than the follicular
variant of papillary cancer.32 Our pathway analysis also confirmed
an upregulation of immune response and cytokine production in
lymphocyte-infiltrating thyroid cancer. However, this observation
requires further validation whether an upregulation in these
pathways accounts for a better overall survival in patients with a
lymphocyte-infiltrating thyroid cancer because the expression of
some immunosuppressive molecules including PD-1 (programmed
death 1) and IDO1 (indoleamine 2,3-dioxygenase 1) was also
upregulated.
We observed a downregulation of several thyroid-related genes
such as DUOX1, DUOX2, TG, and TSHR. This may appear counter-
intuitive given that dedifferentiation typically worsens patient
outcomes. However, it is noteworthy that there was no difference in
the expression of SLC5A5 (sodium-iodide symporter), which plays a
central role in radioactive iodine therapy and treatment outcomes.
A previous study suggested that cytokine production in patients
with papillary thyroid cancer and thyroiditis shifted toward Th2
immunity.33 Cytokine profiles may directly or indirectly influence
the expression of thyroid-related genes. It is unlikely that our
observation is influenced by the decreased tumor purity due to a Fig. 3. Expression of several thyroid-related genes versus the percentage of tumor-
higher density of lymphocyte infiltration. The initial TCGA analysis infiltrating lymphocytes. (A) TSHR, Spearman's correlation P ¼ 0.0001; (B) TG,
Spearman's correlation P < 0.0001; (C) SLC5A5, Spearman's correlation P ¼ 0.195.
demonstrated that global expression levels were not strongly
RSEM, RNA-Seq by Expectation Maximization.
 C.-Y. Kuo et al. / Journal of Cancer Research and Practice 4 (2017) 95e99
concentrations and the likelihood of thyroid cancer.34 Treatment
with thyroxine may reduce TSH levels and decrease the occurrence
of thyroid cancer in patients with thyroiditis.35 In this study, the
data of thyroid function was not available. Additionally, tumor-
infiltrating lymphocytes need to be distinguished from “back-
ground” thyroiditis.36 The percentage of lymphocyte infiltration
was based on the regular pathological examination, and pheno-
typical analysis was not performed in this study. The function of
infiltrating lymphocytes may depend on context-sensitive profiling
and may not be universal.
In summary, our analysis revealed that papillary thyroid cancer
with tumor-infiltrating lymphocytes is associated with an upre-
gulation of immune response and cytokine production, along with
a trend for an overall survival benefit.
Conflict of interest
The authors declare no conflicts of interest involved in this
study.
Acknowledgments
This work was supported by a grant (MMH-TW-10504) from
Mackay Memorial Hospital. The funders had no role in study
design, data collection and analysis, decision to publish, or prepa-
ration of the manuscript.
References
1. Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and
treatment effectiveness. Lancet Oncol. 2014;15:e493e503.
2. Iglesia MD, Parker JS, Hoadley KA, Serody JS, Perou CM, Vincent BG. Genomic
analysis of immune cell infiltrates across 11 tumor types. J Natl Cancer Inst.
2016;108:djw144.
3. Pusztaszeri MP, Faquin WC, Sadow PM. Tumor-associated inflammatory cells in
thyroid carcinomas. Surg Pathol Clin. 2014;7:501e514.
4. Li B, Severson E, Pignon JC, et al. Comprehensive analyses of tumor immunity:
implications for cancer immunotherapy. Genome Biol. 2016;17:174.
5. Liu CL, Lee JJ, Liu TP, Chang YC, Hsu YC, Cheng SP. Blood neutrophil-to-
lymphocyte ratio correlates with tumor size in patients with differentiated
thyroid cancer. J Surg Oncol. 2013;107:493e497.
6. Cunha LL, Marcello MA, Ward LS. The role of the inflammatory microenvi-
ronment in thyroid carcinogenesis. Endocr Relat Cancer. 2014;21:R85eR103.
7. French JD, Weber ZJ, Fretwell DL, Said S, Klopper JP, Haugen BR. Tumor-asso-
ciated lymphocytes and increased FoxP3þ regulatory T cell frequency correlate
with more aggressive papillary thyroid cancer. J Clin Endocrinol Metab.
2010;95:2325e2333.
8. Cunha LL, Marcello MA, Nonogaki S, et al. CD8þ tumour-infiltrating lympho-
cytes and COX2 expression may predict relapse in differentiated thyroid can-
cer. Clin Endocrinol (Oxf). 2015;83:246e253.
9. Lee JH, Kim Y, Choi JW, Kim YS. The association between papillary thyroid
carcinoma and histologically proven Hashimoto's thyroiditis: a meta-analysis.
Eur J Endocrinol. 2013;168:343e349.
10. Chien MN, Yang PS, Lee JJ, Wang TY, Hsu YC, Cheng SP. Recurrence-associated
genes in papillary thyroid cancer: an analysis of the Cancer Genome Atlas data.
Surgery. 2017. http://dx.doi.org/10.1016/j.surg.2016.12.039 (in press).
11. Cancer Genome Atlas Research Network. Integrated genomic characterization
of papillary thyroid carcinoma. Cell. 2014;159:676e690.
12. Hsu YC, Liu CL, Yang PS, Tsai CH, Lee JJ, Cheng SP. Interaction of age at diagnosis
with transcriptional profiling in papillary thyroid cancer. World J Surg.
2016;40:2922e2929.
13. Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for
biomarker assessment and outcome-based cut-point optimization. Clin Cancer
99
Res. 2004;10:7252e7259.
14. Cheng SP, Yang PS, Chien MN, Chen MJ, Lee JJ, Liu CL. Aberrant expression of
tumor-associated carbohydrate antigen Globo H in thyroid carcinoma. J Surg
Oncol. 2016;114:853e858.
15. Cheng SP, Liu CL, Chen MJ, et al. CD74 expression and its therapeutic potential
in thyroid carcinoma. Endocr Relat Cancer. 2015;22:179e190.
16. Ho KC, Lee JJ, Liu TP, Yang PS, Cheng SP. Influence of dialysis modalities on
patients undergoing parathyroidectomy for renal hyperparathyroidism. Formos
J Surg. 2015;48:151e156.
17. Cheng SP, Hsu YC, Liu CL, et al. Significance of allelic percentage of BRAF
c.1799T > A (V600E) mutation in papillary thyroid carcinoma. Ann Surg Oncol.
2014;21(Suppl 4):S619eS626.
18. Cheng SP, Chen MJ, Chien MN, Lin CH, Lee JJ, Liu CL. Overexpression of teneurin
transmembrane protein 1 is a potential marker of disease progression in
papillary thyroid carcinoma. Clin Exp Med. 2017. http://dx.doi.org/10.1007/
s10238-016-0445-y (in press).
19. Oh CM, Park S, Lee JY, et al. Increased prevalence of chronic lymphocytic
thyroiditis in Korean patients with papillary thyroid cancer. PLoS One. 2014;9:
e99054.
20. Shih ML, Lee JA, Hsieh CB, et al. Thyroidectomy for Hashimoto's thyroiditis:
complications and associated cancers. Thyroid. 2008;18:729e734.
21. Liu CL, Cheng SP, Lin HW, Lai YL. Risk of thyroid cancer in patients with
thyroiditis: a population-based cohort study. Ann Surg Oncol. 2014;21:
843e849.
22. Farrell E, Heffron C, Murphy M, O'Leary G, Sheahan P. Impact of lymphocytic
thyroiditis on incidence of pathological incidental thyroid carcinoma. Head
Neck. 2017;39:122e127.
23. Jankovic B, Le KT, Hershman JM. Clinical Review: Hashimoto's thyroiditis and
papillary thyroid carcinoma: is there a correlation? J Clin Endocrinol Metab.
2013;98:474e482.
24. Castagna MG, Belardini V, Memmo S, et al. Nodules in autoimmune thyroiditis
are associated with increased risk of thyroid cancer in surgical series but not in
cytological series: evidence for selection bias. J Clin Endocrinol Metab. 2014;99:
3193e3198.
25. Huang BY, Hseuh C, Chao TC, Lin KJ, Lin JD. Well-differentiated thyroid carci-
noma with concomitant Hashimoto's thyroiditis present with less aggressive
clinical stage and low recurrence. Endocr Pathol. 2011;22:144e149.
26. Dvorkin S, Robenshtok E, Hirsch D, Strenov Y, Shimon I, Benbassat CA. Differ-
entiated thyroid cancer is associated with less aggressive disease and better
outcome in patients with coexisting Hashimotos thyroiditis. J Clin Endocrinol
Metab. 2013;98:2409e2414.
27. Giannini R, Ugolini C, Lupi C, et al. The heterogeneous distribution of BRAF
mutation supports the independent clonal origin of distinct tumor foci in
multifocal papillary thyroid carcinoma. J Clin Endocrinol Metab. 2007;92:
3511e3516.
28. Riesco-Eizaguirre G, Santisteban P. Advances in the molecular pathogenesis of
thyroid cancer: lessons from the cancer genome. Eur J Endocrinol. 2016;175:
R203eR217.
29. Smallridge RC, Chindris AM, Asmann YW, et al. RNA sequencing identifies
multiple fusion transcripts, differentially expressed genes, and reduced
expression of immune function genes in BRAF (V600E) mutant vs BRAF wild-
type papillary thyroid carcinoma. J Clin Endocrinol Metab. 2014;99:
E338eE347.
30. Kim SK, Woo JW, Lee JH, et al. Chronic lymphocytic thyroiditis and BRAF V600E
in papillary thyroid carcinoma. Endocr Relat Cancer. 2016;23:27e34.
31. Bastman JJ, Serracino HS, Zhu Y, et al. Tumor-infiltrating T cells and the PD-1
checkpoint pathway in advanced differentiated and anaplastic thyroid can-
cer. J Clin Endocrinol Metab. 2016;101:2863e2873.
32. Huang CT, Oyang YJ, Huang HC, Juan HF. MicroRNA-mediated networks un-
derlie immune response regulation in papillary thyroid carcinoma. Sci Rep.
2014;4:6495.
33. Zivancevic-Simonovic S, Mihaljevic O, Majstorovic I, et al. Cytokine production
in patients with papillary thyroid cancer and associated autoimmune Hashi-
moto thyroiditis. Cancer Immunol Immunother. 2015;64:1011e1019.
34. Nieto H, Boelaert K. Thyroid-stimulating hormone in thyroid cancer: does it
matter? Endocr Relat Cancer. 2016;23:T109eT121.
35. Fiore E, Rago T, Latrofa F, et al. Hashimoto's thyroiditis is associated with
papillary thyroid carcinoma: role of TSH and of treatment with L-thyroxine.
Endocr Relat Cancer. 2011;18:429e437.
36. Ehlers M, Schott M. Hashimoto's thyroiditis and papillary thyroid cancer: are
they immunologically linked? Trends Endocrinol Metab. 2014;25:656e664.