ORIGINAL

ARTICLE

Age- and Gender-Specific Risk of Thyroid Cancer inPatients with Familial Adenomatous Polyposis
Shinya Uchino,1 Hideki Ishikawa,2,3 Akira Miyauchi,4 Mitsuyoshi Hirokawa,4Shiro Noguchi,1 Mineko Ushiama,5 Teruhiko Yoshida,5 Masahito Michikura,3
Kokichi Sugano,6 Toshiyuki Sakai2
1

Noguchi Thyroid Clinic and Hospital Foundation, Oita, Japan; 2Department of Molecular-Targeting
Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto,
Japan; 3Ishikawa Gastrointestinal Clinic, Osaka, Japan; 4Kuma Hospital, Kobe, Japan; 5Division of
Genetics, National Cancer Center Research Institute, Tokyo, Japan; 6Oncogene Research Unit/Cancer
Prevention Unit, Tochigi Cancer Center, Utsunomiya, Japan

Context: The cribriform-morula variant of papillary thyroid carcinoma (CMV-PTC) is a rare variantof papillary thyroid carcinoma (PTC) and is associated with familial adenomatous polyposis (FAP).
However, the incidence and the nature of CMV-PTC among FAP patients have not been wellcharacterized.
Objective: The aim of this study was to determine the incidence and characteristics of thyroid cancer
screened by neck ultrasonography for FAP patients.
Design, Patients and Intervention: A total of 129 FAP patients were included in this study. Neckultrasonography was performed using a 12.0 MHz transducer probe. Germline APC gene mutation
was examined for by the protein truncation test (PTT) or DNA sequencing methods.
Results: Twenty-one patients (16.3%) had solid nodules, and 24 patients (18.6%) had benign cystic
nodules. In total, PTC was found in 11 patients (16% of the women and 0% of the men), 8 of whichwere CMV-PTC and the rest were classical PTC. In 17 female patients with thyroid nodules, CMV-PTC
occurred in 8 of 9 patients who were 35 years age or younger, but in none of the 8 patients who
were older than 36 (p⫽0.0004 by Fisher’s exact test). The APC germline mutations in 8 patients with
CMV-PTC were present at the 5⬘ side of the profuse type of FAP region (codons 1249 –1330).
Conclusions: The prevalence of CMV-PTC in FAP patients was higher than previously reported andthis type of tumor was found preferentially in younger (under age 35) female patients with FAP
in this cohort.

amilial adenomatous polyposis (FAP) is an autosomal
dominant polyposis syndrome that is characterizedby hundreds of colorectal adenomatous polyps. The majorcausative gene for FAP is the APC gene, which is locatedin the 5q21 region. Individuals with a germline APC genemutation have an almost 100% risk of developing colorectal cancer during their life time. Gastric or duodenal
polyps, desmoid tumors, congenital hypertrophy of retinal pigmentation, and thyroid cancer are other wellknown extracolonic manifestations of FAP. Crail (1) wasF

the first to publish a case report of brain and thyroid carcinomas in a patient with FAP. Since this report, many
papers have further documented this interesting association; however, the histological characteristics of thyroid
cancer in FAP patients were not described until the 1990’s.
Harach et al (2) first described the histological characteristics as a cribriform pattern with solid areas and a spindlecell component. This specific tumor subtype is known as
the cribriform-morula variant of papillary thyroid carcinoma (CMV-PTC).

ISSN Print 0021-972X ISSN Online 1945-7197
Printed in USA
Copyright © 2016 by the Endocrine Society
Received May 5, 2016. Accepted September 8, 2016.

Abbreviations: FAP: familial adenomatous polyposis; CMV-PTC: cribriform-morula variantof papillary thyroid carcinoma; PTC: papillary thyroid carcinoma; H&E: Hematoxylin and
Eosin; FNABC: fine-needle aspiration biopsy cytology; ER: estrogen receptor; PgR: progesterone receptor

doi: 10.1210/jc.2016-2043

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1

2

Papillary Thyroid Cancer in FAP Patients

J Clin Endocrinol MetabIn young female FAP patients, the incidence of thyroid
cancer before age 35 is 160 times higher than in the general
population (3). This figure is based on the clinical incidence of thyroid cancer, ie, cancers that are discovered dueto the presence of clinical symptoms or a palpable necknodule in FAP patients. The prognosis of FAP patients
once depended on colorectal cancer outcomes, but recent
advances in the management of colorectal cancer havesuccessfully improved colorectal cancer survival. Now
that deaths due to colorectal cancer can be prevented, theearly discovery and treatment of the extracolonic manifestations of FAP have becomes increasingly important.
Thyroid carcinoma in FAP patients is thought to berelatively rare; with an approximate rate of 0.4 –1.3%,
according to a retrospective review of large registries (4 –7). However, the results of these studies were based on
retrospective observations, mainly in symptomatic patients. Thyroid cancer in FAP patients is generally indolent
and has few clinical symptoms. Recent progress in highresolution ultrasonographic devices for imaging has madeultrasonography the first choice for detecting thyroid nodules even if the nodules are too small to palpate. The incidence of thyroid cancer in FAP patients may be underestimated in the absence of ultrasonographic screening;
the true incidence of thyroid cancer among FAP patients
therefore unknown. The aim of this study was to use systematic ultrasonographic screening to investigate the incidence of thyroid cancer and its association with APC
gene mutations in FAP patients.

Materials and Methods
Patients
One hundred twenty-nine Japanese patients belonging to 95
families with FAP who treated between May 2008 and October2010 at the Ishikawa Clinic, Osaka, Japan were entered in thisstudy. The patients included 60 males and 69 females. Thirtynine of the patients had undergone colorectal surgery; specifically ileo-anal anastomosis (IAA) in 7 patients, ileo-anal canalTable 1.

anastomosis (IACA) in one patient, ileo-rectal anastomosis(IRA) in 26 patients, right colectomy in two patients, left colectomy in one patient and colostomy in two patients. The remaining 90 patients had not undergone colorectal surgery and were
followed up with periodic colonoscopies, with or without extensive polypectomy. Two female patients had previously undergone thyroidectomy for thyroid cancer at another hospitalprior to this study. Hematoxylin and Eosin (H&E)-stained specimens from these thyroid carcinomas were requested by ourstudy group and examined by Dr. Hirokawa, an expert pathologist. Another 127 patients had not previously undergone thyroid screening.
This study was approved by the ethics committee of Noguchi
Thyroid Clinic and Hospital Foundation, Oita, Japan and Kyoto
Prefectural University of Medicine, Kyoto, Japan. The ethicalreview for protocol performing this study in Ishikawa Clinic andKuma Hospita l was delegated to the review boards in Noguchi
Thyroid Clinic c and Hospital Foundation, and the protocol wasapproved. All patients provided written informed consent forneck ultrasonographic screening. The APC gene was analyzed in
120 patients, who gave written informed consent for the genestudy.

Ultraosonographic thyroid screening
Thyroid ultrasonography was performed using a LOGIQ e
Expert with a 12.0 MHz 12L-RS transducer probe (GE HealthCare Japan Inc. Japan) at the Ishikawa Clinic. An expert ultrasonographer at Kuma Hospital, Osaka, Japan reexamined patients in whom the first ultrasonographic screening had identified a thyroid nodule. For solid thyroid nodules that were larger
than 5 mm in diameter, fine-needle aspiration biopsy cytology(FNABC) was performed. When the thyroid nodule shows entirely cystic and there are no solid components in ultrasonographic imaging, the nodule is diagnosed as cyst. In patients withcystic thyroid nodule(s) (whether single or multiple), FNABC
was deferred, and the patients were observed. When the FNABC
findings were suspicious for malignancy, surgery was recommended. Thyroid operations consisted of total thyroidectomy
with central compartment dissection of the neck and were performed at Kuma Hospital.

Immunohistochemical evaluation
In tumors that were diagnosed as CMV-PTC, immunohistochemical analyses of ␤-catenin, the estrogen receptor (ER), progesterone receptor (PgR) and Ki-67 (MIB1) were also performed

Age of patients and results of neck ultrasonographic screening

Average
MedianRange

Age
Previous thyroid surgery
Solid tumor(s)Solitary
MultipleCyst(s)Solitary
MultipleAll(n ⴝ 129)Men(n ⴝ 60)

Women(n ⴝ 69)

40.0 ⫹/- 15.4
37.0
17– 83
2
21
12
9
24
12
12

41.2 ⫹/- 15.5
38.5
17– 83
0
6
6
0
7
4
3

39.0 ⫹/- 15.3
36.0
17– 83
2
15
6
9
17
8
9

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doi: 10.1210/jc.2016-2043

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using 4-␮m-thick, formalin-fixed, paraffin-embedded tissues.
Immunostaining was performed using the automated Leica
Bond-Max system and Bond Refine detection kit (Leica Microsystems, Wetzlar, Germany) according to the manufacturer’s instructions. The antibodies used were as follows; ␤-catenin (␤catenin1, mouse monoclonal antibody, 1:200 dilution, Dako,
Carpinteria, CA), ER (clone 6F11, mouse monoclonal antibody,
1:400 dilution, Novocastra, Newcastle, UK), PgR (clone
PgR636, mouse monoclonal antibody, 1:200 dilution, DAKO),
and Ki-67 (clone MIB-1, mouse monoclonal antibody, 1:200
dilution, Dako) (8).

Genetic analysis
APC germline mutation was investigated with the protein
truncation (PTT) assay or DNA sequencing from peripheral
blood leukocytes according to a previously published method(9 –11). The PTT assay was performed at Otsuka assay company,
Tokushima, Japan. Dr. T. Yoshida and M. Ushiama, of the Genetics Division of the National Cancer Center Research Institute,Japan performed DNA sequencing.

Statistical analysis
Statistical analyses were performed with the ␹2 test or Fisher’s
exact test, using SAS JMP software version 9 (SAS Institute Inc.).

Results
Ultrasonographic thyroid screening and diagnosis
of PTCThe average age of the 129 patients in the present study
was 40.0 ⫹/- 15.4 years, with a median age of 37 years(range; 17– 83 years old). There were no significant differences in the age of the male and female patients (Table
1). Ultrasonographic screening identified thyroid nodules
in 45 patients (34.9%). Twenty-one patients (16.3%) had
solid nodules (solitary in 12 and multiple in 9), and 24
patients (18.6%) had benign cysts (solitary in 12 and multiple in 12, Table 1). During follow-up, cystic nodule(s)had not enlarged and no thyroid nodule suspected for cancer had been emerged in all patients with cystic nodule(s).
In 6 male patients who had a solitary solid nodule (5–22mm in diameter on ultrasonography), cytology was benign; these patients were closely followed and did not receive therapy (Table 2 and Figure 1A). None of the maleTable 2. Association of neck ultrasonography withcytological/histological diagnosis
Diagnosis of

NumberBenigntypicalCMV-

NeckUltrasonography
Solid tumor(s)Solitary (Men)
Multiple (Men)Solitary (Women)
Multiple (Women)ofPatients
21
6
0
6
9

Tumor

PTC

PTC

12
6
0
3
3

3
0
0
2
1

6
0
0
1
5

3

patients had multiple solid nodules.
In 6 female patients who had a solitary solid nodule(7– 46 mm in diameter on ultrasonography), PTC was diagnosed by FNABC in 3 patients (classical PTC in 2 and
CMV-PTC in one). In one 24-year-old patient with classical PTC (Patient A in Table 3), the nodule was 7 mm indiameter and was located in the isthmus; this patient underwent total thyroidectomy with central compartment
dissection. Microscopic lymph node metastases were present (2/6). Patient B is a 36-year-old with a 6-mm classical
PTC; the patient refused surgery and is presently underclose observation. Patient J, aged 32 years, had an 8-mm
CMV-PTC; this patient also opted to not have surgery andis being observed as well.
In 9 female patients with multiple solid nodules (6 –30
mm in diameter according to ultrasonography), PTC wasdiagnosed cytologically in 6 patients; classical PTC was
found in 1 patient, and CMV-PTC was diagnosed in 5
patients (Figure 1B, 1C and 1D). One 47-year-old patientwith classical PTC (Patient C) had multiple cancers in theleft lobe, with a maximum tumor diameter of 10 mm. Thispatient underwent total thyroidectomy with central compartment dissection. Microscopic lymph node metastases
were absent (0/13). Five patients aged 18, 22, 25, 27 and35 years (Patients D, G, H, I and K, respectively), had
CMV-PTC and underwent total thyroidectomy with central compartment dissection. The maximum tumor diameters were 7, 5, 32, 12 and 10 mm, respectively. None ofthese patients had invasion outside the thyroid gland or
lymph node metastases (0/0, 0/12, 0/4, 0/5, and 0/7, respectively). Immunohistochemistry for ␤-catenin, estrogen receptor and progesterone receptor was positive in all
CMV-PTCs (Figure 1E and 1F) and negative in all classical
PTCs. The tumor cells of CMV-PTCs demonstrated nuclear and cytoplasmic expression of ␤-catenin, strong nuclear positivity for estrogen receptor and strong nuclear
positivity for PgR. The MIB-1 labeling index was also
positive in all CMV-PTCs (5%–10% in 4 patients and
0%–5% in 1). The 2 female patients who had undergone
previous thyroid surgery had CMV-PTC upon further
pathologic examination (Patients E and F).
In total, PTC was found in 11 patients (16% of females); 8 of these nodules were CMV-PTC. In 17 female
patients with solid thyroid nodules, including 2 patients
who had previous thyroid surgery (aged 37.9 ⫾ 16.3
years, range 18 –79 years), CMV-PTC was found in 8 of 9
patients aged 35 years or younger, and in none of the 8patients who were older than 36 years (P ⫽ .0004 by
Fisher’s exact test). The average age of the patients with
CMV-PTC was 24.8 ⫹/- 6.2 years old.

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4

Papillary Thyroid Cancer in FAP Patients

J Clin Endocrinol Metabwith CMV-PTC had mutations at region A (codons 2– 479) in 4 patients,
region B (codons 348 –758) in 1 patient, and region C (codons 658 –
1283) in 3 patients. Patients withclassical PTC had mutations at region A in 1 patient, region C in 1
patient and deletion at the APC locus
in 1 patient. DNA sequencing
showed APC germline mutations atcodons 159 (n ⫽ 2), 161, 302, 689,
964, 1068, and 1157, Table 3).

Discussion
The risk of developing thyroid cancer has been known to be muchhigher in FAP patients than in thenormal population but previous
studies have reported that the incidence of thyroid cancer among FAP
patients was only approximately
1%. Plail et al (3), in an analysis of
998 FAP patients from the FAP registry at St. Mark’s Hospital in London, reported a 160-fold increased
risk of developing a thyroid carcinoma before the age of 35 years in
FAP patients compared to the norFigure 1. Ultrasonographic, Cytopathological and Histopathological Findings of Thyroid Nodules
mal population. Of special note isin FAP Patients. A, Ultrasonography shows an iso- to low echoic solid nodule in a 63-year-oldman. The nodule was located in the left lobe, with a maximum diameter of 11 mm. FNABC
that thyroid cancer was first reshowed a benign nodule, and the patient is now being followed. Mass: thyroid nodule, CCA:
ported being very common incommon carotid artery. B, Ultrasonography shows an iso- to low echoic solid nodule withyounger patients, especially before
multiple small cystic changes in patient H. The nodule was located in the left lobe, with a
the age of 35. However, the incimaximum diameter of 30 mm. FNABC showed CMV-PTC, and total thyroidectomy was
performed. C, The photograph shows the cytopathologic findings of CMV-PTC in patient H
dence of thyroid cancer in Plail’s re(x40). The tumor cells show hypercellularity, a cribriform pattern, morules, peculiar nuclear
port was only 0.7% (7/998). Many
clearing and the absence of colloid in the background. The findings are typical for CMV-PTC. D,
other studies have also observed that
The photograph shows the histopathology of hematoxylin-eosin-stained CMV-PTC in patient H(x10). The cribriform pattern without colloid content, formed by the carcinoma cells, is a special
the incidence of differentiated thyfeature of the tumor. E, Immunohistochemical staining for ␤-catenin demonstrates nuclear android carcinoma in FAP patients is becytoplasmic accumulation due to an APC germline mutation in patient I (x40). F,
tween 0.4 –1.3% (4 –7, 12). HowImmunohistochemical staining for the estrogen receptor in patient I (x40). Strong nuclear
accumulation is noted in the tumor cells.
ever, these data were retrospective
reviews of registry data that deAssociation between PTC development andpended on the presence of clinical symptoms (such as neckmutationsswelling) for diagnosis, and did not perform systematic
PTT and/or DNA sequencing was performed in 120 thyroid screening tests. Because most FAP patients diepatients. A PTT assay was performed in 100 patients and from colorectal cancer and the prognosis of thyroid cancer
DNA was sequenced in 32 patients. Both PTT and se- is favorable, little attention has been paid to detecting ocquencing were performed in 12 patients. Table 4 summa- cult thyroid nodules in FAP patients (13).
rizes the results of the PTT and sequencing analyses. The
Some investigators have recommended careful palpasites of the mutations were divided into regions A-F of the tion of the thyroid gland and cervical lymph nodes, espeAPC gene based on the PTT assay. Ninety-one of the 120 cially in young women, to screen FAP patients for thyroid(75.8%) patients had APC germline mutations. Patients nodules (3). Recent advances in high-resolution ultra-

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5

FAP. In this series, 72 (38%) had thyroid nodules, 5 (2.6%) had PTC, andonly one had CMV-PTC. In their retrospective review of 664 FAP patients in a registry, 14 (2.1%) were
found to have thyroid cancer. Elevenof the 14 were female. Although theincidence of thyroid cancer was
slightly higher than previous estimates, these figures are much lower
than our observation that PTC occurred in 16% of female FAP patients. One of the main reasons forthe different incidence rates may be
the criteria for performing FNABC.
Jarrar et al performed FNABC for
nodules that were larger than 10 mm
in diameter. In contrast, we performed FNABC for solid nodules
that were larger than 5 mm. In fact,
the maximum tumor diameter in 7 of
the 9 newly diagnosed PTC in ourstudy was less than or equal to 10
mm. Another reason for the discrepancy may have been due to the difficulties of diagnosing CMV-PTC in
cytological specimens. The cytological findings of CMV-PTC show unusual features, and expertise isneeded to diagnose this disease (8).
CMV-PTC is an extremely rare variant of papillary thyroid carcinoma,
representing approximately 0.16%
Figure 2. Incidence of Thyroid Cancer by Age and Sex in FAP Patients. A, Incidence of papillaryof all thyroid malignancies (16).
thyroid cancer (both classical type and CMVPTC) by age and sex. Straight line denotes female
Therefore, it is comparatively diffiand a dotted line denotes male. B, Incidence of CMVPTC by age and sex. Straight line denotes
female and a dotted line denotes male.
cult, even for experienced cytologists, to diagnose CMV-PTC in cysonography have enabled the detection of small, nonpaltological specimens because of its rarity.
pable thyroid nodules and can distinguish benign from
With respect to genetic abnormalities in patients withmalignant nodules by the combined use of FNABC. CurCMV-PTC, Cetta et al (17) reported that 21 of 24 APC
rently, thyroid ultrasonography is routinely used for pagermline mutations were found in exon 18, the distributients with palpable nodules as well as for patients withouttion of these mutations was associated with the CHRPE
clinical symptoms. In a retrospective chart review of theHigh-Risk Gastrointestinal Cancer Clinic, Herraiz et al region (congenital hypertrophy of the retinal pigment ep(14) reported that PTC was diagnosed in 6 of 51 (12%) ithelium, ie, codons 463–1387). Truta et al (18) reported
FAP patients. CMV-PTC was found in five female pa- that germline mutations were predominantly found proxtients, and classical PTC was found in one female patient. imally to the mutation cluster region (codons 1286 –In this series, ultrasonography was used in 28 of 51 pa- 1514). In this study, only 4 of 8 (50%) mutations weretients, and detected thyroid nodules in 22 (79%) patients located in the CHRPE area and no mutations were found
who had at least one ultrasonographic screening. PTC was in the mutation cluster region. In fact, the other 4 mutafound in 2 (7%) patients who underwent ultrasonogra- tions were located in the 5⬘ side from the CHRPE region.
phy. Recently, Jarrar et al (15) also performed ultrasono- All mutations were located in the 5⬘ side of the region
graphic screening for thyroid cancer in 192 patients with specific for profuse type of FAP (codons 1249 –1330) (19,The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 09 November 2016. at 00:49 For personal use only. No other uses without permission. . All rights reserved.

6

Papillary Thyroid Cancer in FAP Patients

Table 3.

J Clin Endocrinol Metab

Details of FAP patients with papillary thyroid carcinoma
Histology or

Solitaryor

Operation

Tumor

No.

Age

Sex

Cytology of PTC

Procedure

Multiple

A
B
C
D

24
36
47
18

F
F
F
F

Classical
Classical
Classical
Cribriform variant

Total Tx
not performed
Total Tx
Total Txsolitary
solitary
multiple
multiple

Diameter
(mm)
7
6
10
7

E
F
G
H
I
J
K

19
20
22
25
27
32
35

F
F
F
F
F
F
F

Cribriform variant
Cribriform variant
Cribriform variant
Cribriform variant
Cribriform variant
Cribriform variant
Cribriform variant

op. before
op. before
Total Tx
Total Tx
Total Tx
not performed
Total Txsolitary
solitary
multiple
multiple
multipleslolitary
multiple

NA
NA
10
32
12
8
10

APC Germline
LN
metastasis
2/6

Mutationc.3593C⬎G, p.S1198X
c.508 9del2GA
Deletion at APC locus
codon964⬃966
TTAAATAGT⬎AAGT
c.476dupAc.2065 2066del1GC
c.477C⬎A, p.Y159X
c.481C⬎T, p.Q161X
c.3469G⬎T, p.E1157X
c.3202 3205del4TCAA
c904C⬎T, p.R302X(TGA)

0/13
0/0
none
none
0/12
0/4
0/5
0/7

Total Tx; total thyroidectomy, NA; not assessed.

Table 4.

Association of thyroid tumor with APC germline mutation
Women

Region of APC Mutation(codons) or Deletion
RegionA (2– 479)
RegionB (348 –758)
RegionC (658 –1283)
RegionD (1099 –1700)
Region E-F (1547–2843)
Region, unspecified
Deletion at the APC locus
No mutation
Not examined

Total Number
of Patietns
33
17
28
4
0
7
2
29
9

Number ofPatients
21
11
20
3
0
5
1
6
2

Men

Cyst

Benign TumorClassical PTC

CMV-PTC

Number of Patients

Cyst

Benign TumorClassical PTC

CMV-PTC

7
2
6
0
0
0
0
2
0

3
0
2
0
0
0
0
1
0

1
0
1
0
0
0
1
0
0

4
1
3
0
0
0
0
0
0

12
6
8
1
0
2
1
23
7

0
0
0
0
0
0
0
6
1

1
0
0
0
0
0
1
2
2

0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0

20). We previously reported a case of 25-year-old woman
with FAP-associated CMV-PTC who carried a germline
mutation within the mutation cluster region (21). Six ofthe patient’s 12 tumors contained APC somatic mutations
that were concentrated in codons 308 –935. Several papers also have described germline and somatic APC mutations in FAP-associated CMVPTC (22, 23). Five of 8
germline mutations found in this study were withincodons 308 –935, and the remaining 3 were outside fromthis area. Further examinations for somatic mutations inthese tumors could resolve this question. Furthermore, we
found nuclear and cytoplasmic accumulation of ␤-cateninin the tumor cells of CMV-PTC; ␤-catenin may accumulate because of the loss of the ␤-catenin binding site(codons 1020 –1169) of the APC protein (which is truncated due to the 5⬘ side of the mutation) and the inabilityof ␤-catenin to bind to the APC protein. As a result, degradation of ␤-catenin cannot proceed, and ␤-catenin accumulates in the cell nucleus and cytoplasm. From ourresults of immunohistochemistry, we speculate that abnormal expression of ß-catenin, estrogen receptor andprogesterone receptor is associated with the developmentof CMV-PTCs of patients with abnormal structure of APC
protein.
It is well known that CMV-PTC is found in younger
female FAP patients, especially in those younger than 35

years old. In this paper, systematic ultrasonographic
screening confirmed the absence of CMV-PTC in all male
FAP patients and female FAP patients who were over 35
years. It is difficult to determine why this phenomenon
occurs in CMV-PTC. ER␣ was immunoreactive in the nucleus of CMV-PTC cases, unlike classical PTC. The different expression pattern of ER␣ may be the key to thefemale preponderance of this disease. Furthermore, CMVPTC may spontaneously regress after the age of 35 years
in women. There have been many reports of spontaneoustumor regression, including neuroblastoma, lymphoma,
and others (24 –28). Although the exact mechanism of
spontaneous regression remains a mystery, various mechanisms have been proposed. Neuroblastoma is the bestknown example of spontaneous regression of a tumor.
Neuroblastomas expressing TrkA (tropomyosin receptor
kinase A) are biologically favorable and prone to spontaneous regression of differentiation (29). TrkA plays animportant role in the regulation of growth, differentiationand programmed cell death of neurons in the peripheral
and central nervous systems. Interestingly, rearrangementof the TrkA gene is also found in some PTCs and is thoughtto activate the RAF-MEK-ERK pathway (30). The expression of TrkA may help explain this phenomenon in
CMV-PTC.
In conclusion, the rate of CMV-PTC found in FAP pa-

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doi: 10.1210/jc.2016-2043

tients by ultrasonographic screening was higher than previously reported. Careful follow-up without thyroid surgery may put into a strategy for these asymptomatic female
FAP patients whose thyroid nodules are suspected for
CMV-PTC.

Acknowledgments
Address all correspondence and requests for reprints to: Corresponding author to whom reprint requests should be addressed:
Shinya Uchino, Noguchi Thyroid Clinic and Hospital Foundation, 7–52, Aoyama machi, Beppu, Oita, Japan. Tel; ⫹81–97721–2151,
Fax;⫹81–977-21–9711,
E-mail:uchino@noguchi-med.or.jp.
This work was supported by Grant Support: This study was
supported, in part, by Grants-in-Aid for Cancer Research and for
the Third Term Comprehensive Control Research for Cancerfrom the Ministry of Health, Labor, and Welfare, Japan, as well
as by the National Cancer Center Research and Development
Fund (21bunshi-9-, 23-A-2 and 23-A-7), and Practical Research
for Innovative Cancer Control of Health and Labor Sciences
Research Expenses, a Commission of the Ministry of Health,
Labor and Welfare, Japan.
Disclosure of Potential Conflicts of Interest: No potential
conflicts of interest were disclosed.

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