MALATTIE AUTOIMMUNI DELLA TIROIDE

Hashimoto’s Thyroiditis and Thyroid Cancer
Paolo Vitti
Endocrine Unit, Dept of Clinical and Experimental Medicine
University of Pisa
Journal of Clinical Endocrinology and Metabolism, 1965
J Natl Cancer Inst 2005
FEBS LETTERS 1973
JCEM 1993
Endocrinology 1987
JCEM 1995
European J Endocrinol 2001
JCEM 2003
JCEM 1985
Thyroid Autoimmunity and Cancer
Is Hashimoto Thyroiditis associated with PTC ?
Histology

Diagnosis of HT
Clinical criteria

Chronic tissue inflammation may create a favorable environment to
development of cancer

Possible immune response to tumor unrelated to classical HT
Lymphocytic tissue infiltration is associated with PTC
more than with benign nodules
60
50
60
50
P<0.0001
40
P<0.0001
40
Thyroid
Cancer
Benign
nodules
30
30
20
20
10
10
0
0
n=161
n=161
Ott et al., Am Surg, 1987
Thyroid
cancer
Benign
nodules
n=122
n=222
Pisanu et al., Chir Ital, 2003
Clinical diagnosis in 72 patients with PTC with
moderate to severe thyroid lymphocytic
infiltration at histology
40
N. of patients
35
30
25
20
15
10
5
0
Nodular Thyroid
Disease
Hashimoto
Thyroiditis
Graves Disease
Latrofa et al, JCEM 2012
Prevalence of PTC in HT ……. clinics vs pathology
- 1.2 % in 8 FNA studies including 18,023 specimens
- 27.5 % in 8 archival thyroidectomy studies including 9,884 specimens
Conclusion: thyroidectomy studies are subject to selection bias
45
40
35
30
25
20
15
10
5
0
Multinodular Goiter n= 8415
p = NS
p = 0.02
p = NS
Single/isolate Nodule n= 4035
50
All
Females
Males
% of TAb positive
% of TAb positive
TAb prevalence in BNTD vs PTC
40
p = NS
p = NS
All
Females
p = 0.02
30
20
10
0
BNTD
Males
PTC
Fiore et al, JEI 2009
% of histological samples
Thyroid lymphocytic infiltration at histology
in BNTD vs PTC
70
60
50
40
30
BNTD
PTC
20
10
0
MNG
S/I
Fiore et al, JEI 2009
% TAb positive
Prevalence of TAb in BNTD and PTC according to
lymphocytic infiltration at histology
90
80
70
60
50
40
30
20
10
0
BNTD
PTC
MNG
S/I
Fiore et al, JEI 2009
Summary 1
- Moderate to severe lymphocytic infiltration at histology is more
common in PTC than in BNTD
- The correlation between thyroid lymphocytic infiltration and
circulating TAb is present in BNTD, much less in PTC
Summary 2
- PTC is not associated to serum TAb in the whole series of
patients, but only in males with single nodules.
- In this latter group of patients:
- serum TAb are probably related to the presence of the tumor
rather then to autoimmune thyroiditis
- HT is less prevalent and thus not sufficient to overcome the
phenomenon of tumor associated immune reaction
Conclusion
These data suggest that we are dealing with 2 different phenomena
- Coexistence of HT and PTC
- Immune reaction to PTC independent of “classical” HT
Prevalence of PTC according to serum TSH concentrations
20
% of PTC
15
10
TSH
(μU/mL)
OR
95% CI
p value *
0.40-0.59
1.79
1.42-2-23
0.0005
0.60-0.89
2.72
2.24-3.30
<0.0001
0.90-1.30
3.76
3.12-4.53
<0.0001
1.31-3.40
5.32
4.45-6.36
<0.0001
> 3.40
10.36
6.34-16.89
<0.0001
5
0
<0.40
10059
0.40-0.59 0.60-0.89 0.9-1.30 1.31-3.40
4143
5047
4406
4132
>3.40 TSH μU/mL
127
N. of patients
Fiore et al, End Rel Canc 2010
Criteria for the clinical diagnosis
of Hashimoto Thyroiditis
•
High levels of TgAb and TPOAb > 100 U/mL
•
Hypothyroidism
•
Tissue hypoechogenicity at thyroid ultrasound
Fiore et al, End Rel Cancer 2011
Hashimoto
Thyroiditis
Normal
Thyroid
Diffuse
Thyroiditis
Focal
Thyroiditis
Thyroid Ultrasound and Thyroid Function
in the follow-up
100
Euthyroid
Hypothyroid
80
60
40
20
0
HYPOECHOGENICITY
+
(N= 7)
++
(N= 19)
+++
(N= 18)
Marcocci et al, JCEM 1990
HT and PTC: our experience in a
large series of patients submitted to FNA
• Nodular Hashimoto thyroiditis (NHT)
– High levels of both TgAb and TPOAb (>100 U/mL)
– Hypothyroidism (treated or untreated)
– Positive TgAb and/or TPOAb at low level, euthyroidism and diffuse hypoehcoic
“thyroiditis” pattern at thyroid ultrasound.
• Nodular goiter (NG)
– Single or multiple nodules
– Euthyroidism or subclinical hyperthyroidism
– Cold nodules or both cold and “hot” nodules at thyroid scan
– No TgAb and/or TPOAb (TAb-NG) or TAb at low level in the absence of a
“thyroiditis” pattern at thyroid ultrasound (TAb+NG)
Fiore et al, End Rel Cancer 2011
Patients according to the clinical diagnosis and
treatment with L-thyroxine
Untreated
L-T4 treated
Total
NHT
893
638
1531
TAb+NG
2360
1035
3395
TAb-NG
6571
2241
8812
Total
9824
3914
13738
Fiore et al, End Rel Cancer 2011
Frequency of PTC and serum TSH according to
clinical diagnosis in untreated patients
p = 0.002
p <0.0001
p = 0.009
12
4
10
p = ns
6
4
TSH (µU/mL)
PTC (%)
8
p <0.0001
3
p = ns
2
1
2
0
0
Nodular Goiter TAb – (n = 6571)
Nodular Goiter TAb + (n = 2360)
Hashimoto Thyroiditis (n = 893)
Fiore et al, End Rel Cancer 2011
Criteria for diagnosis of HT
in untreated patients
– High levels of both TgAb and TPOAb (>100 U/mL)
n = 681
– Low TAb, hypothyroidism
n = 79
tot = 760
– Low TAb, euthyroidism and diffuse hypoechoic “thyroiditis”
pattern at ultrasound
n = 133
Fiore et al, End Rel Cancer 2011
Frequency of PTC according to TAb levels
and serum TSH in untreated patients
p = 0.004
3,5
p = 0.03
10
3
p = ns
TSH µU/mL
8
PTC (%)
p = <0.0001
2,5
6
p < 0.0001
2
1,5
1
,5
4
N of patients
Negative
Low TAb
6571
2838
High TAb
or hypothyroidism
760
0
Negative
6571
Low TAb
2838
High TAb
or hypothyroidism
760
Fiore et al, End Rel Cancer 2011
Independent predictors of the diagnosis of PTC defined
by binary logistic regression in untreated patients
Variabile
p
TSH
<0.0001
OR
Fiore et al, End Rel Cancer 2011
Independent predictors of the diagnosis of PTC defined
by binary logistic regression in untreated patients
Variabile
p
TSH
<0.0001
Clinical Diagnosis
(HT)
-
OR
Fiore et al, End Rel Cancer 2011
Independent predictors of the diagnosis of PTC defined
by binary logistic regression in untreated patients
Variabile
p
TSH
<0.0001
TPOAb
-
Clinical Diagnosis
(HT)
-
OR
Fiore et al, End Rel Cancer 2011
Independent predictors of the diagnosis of PTC defined
by binary logistic regression in untreated patients
Variabile
p
TSH
<0.0001
TgAb
0.0003
TPOAb
-
Clinical Diagnosis
(HT)
-
OR
Fiore et al, End Rel Cancer 2011
Independent predictors of the diagnosis of PTC defined
by binary logistic regression in untreated patients
Variabile
p
OR
TSH
<0.0001
66.5
TgAb
0.0003
2.0
TPOAb
-
-
Clinical Diagnosis
(HT)
-
-
Fiore et al, End Rel Cancer 2011
Tg epitope recognition by TgAb
D
A
T
g
Serum
TgAb
B
C
TgAbFab
TgAb binding adjusted in
the absence of TgAb-Fab
Epitope recognition evaluated
by inhibition byTgAb-Fab
Fab
+
+
+
Wells coated with
human Tg
Latrofa et al, JCEM 2008
Tg epitope recognition by TgAb
according to thyroid disease
Latrofa et al, JCEM 2008
Tg epitope recognition by TgAb
according to thyroid disease
Latrofa et al, JCEM 2008
Tg epitope recognition by TgAb
according to thyroid disease
Latrofa et al, JCEM 2008
Tg epitope recognition by TgAb
according to thyroid disease
•
The lower inhibition exerted by the monoclonals in nodular
goiter and PTC indicates that in these conditions TgAb are
directed to antigenic sites not comprised among those that
are dominant in autoimmune thyroid diseases, showing a less
restricted epitopic pattern
Latrofa et al, JCEM 2008
TgAb association with PTC
•
TgAb recognize different epitopes of Tg in patients with
PTC alone or PTC associated with HT
•
TgAb may be either the expression of coexistent HT or an
immune reaction to Tg unrelated to HT
•
This may be explained by a different presentation to the
immune system of antigenic sites on Tg caused by the
neoplastic process and the process of goiter development
Latrofa et al, JCEM 2008
Serum TSH and risk of PTC in
nodular Hashimoto Thyroiditis
-
These data stress the point that, besides this association with
TgAb that is likely due to an immune response to the tumor
and not to autoimmune thyroiditis, the clinical parameter
strictly associated with PTC in nodular Hashimoto Thyroiditis
is serum TSH, independently of the autoimmune process
Serum TSH and frequency of PTC according to
clinical diagnosis in L-T4 treated patients
4
p = 0.0035
p < 0.001
2
PTC (%)
TSH (µU/mL)
p < 0.001
3
p < 0.001
12
p < 0.001
8
p = ns
p = 0.07
4
1
0
N of patients
0
2241
1035
638
Nodular Goiter TAb –
Nodular Goiter TAb +
Hashimoto Thyroiditis
N of patients
All
3914
TSH < 0.9 µU/mL
3085
Fiore et al, End Rel Cancer 2011
Normal/ elevated
TSH
Initiation
Progression
BRAF
TSH
RET/PTC
?
Clinically Detectable Cancer
?
Undetectable
Low TSH
L-Thyroxine
Cancer
Thyroid
Autonomy
Fiore & Vitti, JCEM 2012
TSH receptor signaling dependence of
Braf-induced thyroid tumor in mice
BrafV600E Knock-in mice
TSH R KO mice
TSH
invasive thyroid cancer with short latency
BrafV600E Knock-in / TSH R KO
longer latency and less aggressive cancer
Franco et al, PNAS 2011
Hashimoto Thyroiditis and PTC
Conclusions 1
• Different scenario of clinical vs histological HT
• PTC is associated with thyroid lymphocytic infiltration in the
absence of clinical HT
• PTC is associated to circulating TAb only in the subgroup of
patients with low prevalence of clinical HT
• The different pattern of epitope recognition of Tg by TgAb in
HT vs PTC supports the hypothesis that 2 different mechanisms are
involved
Hashimoto Thyroiditis and PTC
Conclusions 2
•
•
•
When strict clinical diagnostic criteria for HT are used an
association with PTC may be found
This association is related to serum TSH level rather than to
thyroiditis per se
L-thyroxine treatment, reducing serum TSH level, also reduces
clinically detectable PTC in patients with nodular HT as well
as in patients with nodular thyroid disease
Calambrone
ETA 2012
Immagini divise
2014
Prevalence of PTC in nodular HT ….. clinics vs pathology
- 4.5 % in 373 patients submitted to FNA, not different
from Graves’ disease (5%) nodular goiter TAb + (4.3%)
or TAb – (5.0%)
- 67.8% of 28 patients submitted to surgery vs 40% in Graves,
36.9% in nodular goiter Tab+ and 37.2% in nodular goiter Tab Conclusion: thyroidectomy studies are subject to selection bias