Prevalence of Thyroid Cancer in Familial Adenomatous Polyposis
Syndrome and the Role of Screening Ultrasound Examinations
MAITE HERRAIZ,* GIUSEPPE BARBESINO,‡WILLIAM FAQUIN,§GAYUN CHAN–SMUTKO,?DEVANSHI PATEL,?
KRISTEN M. SHANNON,?GILBERT H. DANIELS,‡and DANIEL C. CHUNG*,?
*Gastrointestinal Unit and‡Thyroid Unit, Department of Medicine;§Department of Pathology; and?Center for Cancer Risk Analysis, Massachusetts General Hospital,
Background & Aims: Thyroid carcinoma is an extraint-
estinal manifestation of familial adenomatous polyposis
(FAP) syndrome, but the precise risk is unknown. The
optimal approach for thyroid cancer screening has not been
established. We sought to define the prevalence of thyroid
cancer and the role of screening ultrasound in FAP
patients. Methods: We performed a retrospective chart
review of 51 patients with a proven diagnosis of FAP at a
single tertiary institution. Clinical records, genetic test re-
sults, ultrasound examinations, and histopathology were
reviewed. Results: Papillary thyroid cancer was diagnosed
in 6 female patients (12%). The mean age of thyroid cancer
diagnosis was 33 years, and mean tumor size was 12 mm.
However, all patients had additional malignant foci that
were small (1–9 mm), and none had suspicious features of
malignancy on ultrasound. Of 28 patients who had at least
one screening ultrasound, 22 (79%) had thyroid nodules,
and 2 (7%) had papillary thyroid carcinoma. Of those with
nodules, 68% had multinodular disease. A follow-up ultra-
sound in 12 patients after a mean of 15 months revealed no
changes in either the number or size of nodules.
Conclusions: The 12% prevalence of thyroid cancer in
this series of FAP patients is significantly higher than in
previous reports. Among patients undergoing screening ul-
trasound, 7% had thyroid cancer. Nodular thyroid disease is
very common in FAP. Because small nodules (<9 mm)
might also be malignant, close follow-up with ultrasound
and fine-needle aspiration might be warranted.
multiple intestinal and extraintestinal cancers. Left untreated,
almost all patients will develop colorectal cancer and die by the
age of 40–50 years. The risk of colorectal cancer can be sub-
stantially reduced by endoscopic screening and prophylactic
surgery.1Because prophylactic colectomy has become the stan-
dard of care, the risks of other extracolonic cancers have be-
come more apparent.2,3
Thyroid cancer (TC) is among the extracolonic tumors ob-
served in FAP, and it typically is the cribriform-morular variant
of papillary carcinoma.4In fact, identification of the cribriform-
morular variant of papillary TC should lead to an investigation
for FAP.5The exact prevalence of TC in FAP patients is thought
to be low, and a lifetime risk of 2% has been suggested.6Others
have estimated the relative risk of papillary TC in female polyposis
patients to be 100–160 times higher than in the general popula-
amilial adenomatous polyposis (FAP) syndrome is an au-
tosomal dominant disorder associated with a high risk of
tion.7,8Although the prognosis is generally good, deaths attribut-
able to papillary TC in FAP patients have been reported.4,9,10
Therefore, screening with either neck palpation or ultrasonog-
raphy has been proposed.6,8,9,11,12
During the past decade, thyroid ultrasound (TU) has become
an essential part of the examination for thyroid disease. Because
it is sensitive and noninvasive, high-frequency ultrasound ex-
amination appears to be an ideal screening method for nodular
as well as diffuse thyroid disease. The prevalence of palpable
thyroid nodules in the adult general population is approxi-
mately 5% in women and 1% in men.13,14In contrast, the
prevalence of thyroid nodules detected by high-resolution ul-
trasound ranges from 19%–67% of randomly selected individ-
uals, with higher frequencies in women and the elderly.15Be-
tween 5%–10% of all thyroid nodules are malignant.16
Furthermore, nonpalpable nodules have the same risk of ma-
lignancy as palpable nodules of the same size.17Currently, TU
is routinely used to identify nonpalpable thyroid nodules in
high-risk patients exposed to radiation during childhood and
One important shortcoming of TU is its low specificity for
the diagnosis of cancer. Consequently, it has been suggested
that only nodules larger than 1 cm undergo further evaluation
with fine-needle aspiration (FNA) because of their potential to
become clinically significant cancers.16Papini et al20considered
hypoechoic nodules measuring 8–15 mm with central blood
flow, ill-defined margins, or microcalcifications as suspicious
Screening guidelines for TC in patients with FAP are neither
consistent nor well-established. Some have recommended an-
nual thyroid palpation by physical examination.8,21Screening
with TU has also been proposed, but the frequency of scanning
and potential benefits are unknown. In the current study, we
present the prevalence of TC and our experience with TU in a
well-characterized FAP cohort.
Patients and Methods
We performed a retrospective chart review of patients
referred to the High-Risk Gastrointestinal Cancer Clinic at
Massachusetts General Hospital since 1994 and identified all
Abbreviations used in this paper: C-MV, cribriform-morular variant;
FAP, familial adenomatous polyposis; FNA, fine-needle aspiration; SD,
standard deviation; TC, thyroid cancer; TU, thyroid ultrasound.
© 2007 by the AGA Institute
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2007;5:367–373
patients with a proven diagnosis of FAP. In most cases, the
diagnosis of FAP was confirmed with germline APC gene test-
ing. In those patients who did not undergo genetic testing or
who had an inconclusive genetic test result, the diagnosis was
established by clinical criteria including: diffuse colonic adeno-
matous polyposis; presence of extracolonic manifestations of
FAP including fundic gland polyps, duodenal adenomas, amp-
ullary adenomas, desmoid tumors or osteomas; and family
history of FAP. MYH gene testing was performed in selected
patients without a family history of FAP. APC genetic testing
was performed commercially in Clinical Laboratories Improve-
ment Act–approved laboratories. MYH genetic testing was per-
formed as previously reported.22
Medical records were reviewed to determine age, sex, diagno-
sis of TC, age at FAP diagnosis, age at TC diagnosis, number of
polyps, presence of extracolonic manifestations, family history,
and results of genetic testing. TU and FNA reports were also
reviewed. We have routinely recommended annual screening for
TC, and beginning in 2002, we have specifically recommended
TU for all FAP patients older than 16 years of age in our clinic.
The number, size, and location of nodules, as well as the echo
structure (solid, cystic, or mixed), presence of calcification, and
characteristics of the nodule margins (well-defined or ill-
defined) were recorded. All histologic slides were reviewed by a
thyroid pathologist (W.F.) to assess the number, size, and loca-
tion of all tumor nodules. This study was approved by the
Institutional Review Board of Massachusetts General Hospital.
Fifty-one patients fulfilled clinical and/or genetic crite-
ria for FAP. In 40 patients, the diagnosis was confirmed by the
presence of a deleterious germline mutation in the APC gene. In
the remaining 11 patients who did not have genetic testing or
did not have an identifiable APC mutation, the diagnosis was
based on clinical criteria. Eight patients had a personal history
of diffuse colonic polyposis, 1 or more extracolonic manifesta-
tions related to FAP, and a positive family history of FAP. In 2
patients with diffuse colonic polyposis and extracolonic mani-
festations of FAP but no family history, germline MYH gene
testing was negative for the 2 most common mutations (G382D
and Y165C), suggesting these were de novo cases of FAP with-
out an identifiable APC mutation. The final patient was diag-
nosed with more than 1000 polyps and 2 synchronous colon
cancers (transverse colon, stage II and left colon, stage III) at age
47 years. This patient also had multiple fundic gland polyps,
duodenal and jejunal adenomas, and desmoid tumors. No fam-
ily history was present, and the patient declined genetic testing.
Fifty-one patients were part of 28 kindreds; 32 (63%) were
female, and 19 (37%) were male. In 8 of these kindreds, there
were 2 or more affected family members who were included in
our study. The mean age of our entire population was 40 ? 18
(standard deviation [SD]) years (range, 12–80 years). The mean
age among the women was 40 ? 19 years (range, 12–80 years),
and the mean age of the men was 41 ? 16 years (range, 14–65
Prevalence of Thyroid Cancer in Familial
Papillary thyroid carcinoma was diagnosed in 6 of 51
FAP patients, an overall prevalence of 12%. The clinical features
of these patients are shown in Table 1. All patients with TC were
female, resulting in a prevalence of 19% in women and 0% in
men. Of 28 patients who had a screening ultrasound, 2 (7%) had
papillary thyroid carcinoma. Two pairs of affected patients were
second-degree relatives (with 5 and 10 affected family members
in each kindred). The mean age at diagnosis of FAP was 28 years
(range, 19–48 years), and the mean age of TC diagnosis was 33
years (range, 18–51 years). Two patients (33%) had a diagnosis
of TC before the diagnosis of FAP, and in 1 patient (16%), the
2 diagnoses were made simultaneously. Extracolonic manifes-
tations of FAP were present in 5 patients: fundic gland polyps
(67%), duodenal polyps (50%), ampullary adenomas (33%), and
desmoid tumors (50%). The recognition that the cribriform-
morular variant of papillary TC is associated with FAP led to
the diagnosis of de novo FAP in a young patient (19 years)
without a family history of FAP.
Three of the 6 TC patients (50%) came to attention after they
personally noticed an enlarged nodule in the neck. The remain-
ing 3 were identified by screening, 1 by physical examination
and 2 by TU. A deleterious mutation in the APC gene was
detected in all patients with TC. In one family the protein
truncation test was positive, and mutations were identified by
full gene sequencing in the other patients. None of these germ-
line mutations were located in the mutation cluster region
(codons 1286–1513). The precise locations of the mutations
identified are shown in Table 1.
Table 1. Clinical Features of 6 FAP Patients With TC
Patient ID no.
Age at diagnosis
of FAP (y)
Age at diagnosis
of TC (y)
Family history of
TC and FAP
DA, AA, DT
FGP, DA, DT
FGP, DA, AA
Routine physical exam
Q PTT, segment 2
Q PTT, segment 2
Mean ? SD28 ? 1033 ? 14
DA, duodenal adenoma; AA, ampullary adenoma; DT, desmoid tumor; FGP, fundic gland polyps; PTT, protein truncation test.
aPatients 13 and 20 are second-degree relatives.
bPatients 49 and 91 are second-degree relatives.
368HERRAIZ ET ALCLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 3
Treatment and Long-Term Results
Surgical treatment consisted of total thyroidectomy in
5 patients and subtotal thyroidectomy in 1. Four patients
received postoperative adjuvant therapy with iodine-131. All
patients were treated with levothyroxine, 4 with doses designed
to suppress serum thyroid-stimulating hormone. The mean
follow-up was 68 months (range, 26–186 months). No patient
developed distant metastases or local recurrences, and all are
alive and disease free.
Correlation Between Histopathologic and
The pathologic findings for the 6 cases of TC are sum-
marized in Table 2. Papillary carcinoma was identified in all
cases, with 5 of the 6 cases being the cribriform-morular vari-
ant. Histologic examination of these nodules revealed a combi-
nation of solid areas, squamous morules, and empty cribriform
spaces formed by 2-cell thick bridges of cuboidal epithelial cells
(Figure 1). The nuclei of the epithelial cells were enlarged, oval,
and grooved. The sixth case showed histologic features of con-
ventional papillary TC. All of the tumors were multicentric, and
the thyroid glands contained between 2 and 5 tumor foci. The
mean size of the largest nodule was 12 mm (range, 9–15 mm).
Bilateral disease was confirmed in 4 (67%) patients, and only 1
(16%) had lymph node involvement. None of them displayed
direct extrathyroidal extension.
We analyzed ultrasound characteristics and nodule size to
determine their sensitivity in detecting TC in FAP patients. Five
of our 6 patients had a preoperative TU. Pictorial correlations
between TU and pathologic findings for each TC patient are
depicted in Figure 2. By ultrasound criteria, patient 13 had 1
suspicious nodule (15 mm) located in the lower pole of the
right lobe and 3 more benign-appearing nodules between 3 and
8 mm. Histologically, both the suspicious 15-mm nodule as
well as the benign-appearing 8-mm nodule were malignant
(papillary TC, cribriform-morular variant). Furthermore, there
were 2 more small foci (1 mm and 3 mm) of cribriform-morular
variant TC that were not identified on TU. In patient 20, six
nodules were identified by TU. The largest one (15 mm) was
suspicious by ultrasound criteria and malignant at surgery.
Histologic examination revealed that all 3 benign-appearing
nodules located in the upper pole of the right lobe (6–9 mm)
were also malignant; 1 was the follicular variant of papillary
carcinoma, and 2 were the cribriform-morular variant. One
9-mm nodule was suspicious by ultrasound criteria in patient
68 and proved to be malignant. In addition, a second 2-mm TC
was also found. In patient 71, one 11-mm nodule was consid-
ered suspicious by ultrasound criteria and confirmed by histo-
logic examination. Three were nonsuspicious by ultrasound
and proved to be benign. However, 3 additional microscopic
Table 2. Pathologic Findings, Treatment, and Follow-up of 6 Patients With TC
Patient ID no. Histology
(no. foci of TC)BilateralLymph node Treatment Follow-up (mo)
TT ? I131
TT ? I131
TT ? I131
TT ? I131
6/6 (100%)4/6 (67%)1/6 (16%)
C-MV, cribriform-morular variant; ST, subtotal thyroidectomy; TT, total thyroidectomy.
aPatients 13 and 20 are second-degree relatives.
bPatients 49 and 91 are second-degree relatives.
Figure 1. Cribriform-morular variant of papillary carcinoma. (A) Tumor
consists of empty cribriform spaces adjacent to focal squamous
morules. (B) Cribriform spaces are formed by bridges 1–2 cells wide.
Nuclei of malignant cells are oval, pale, and grooved. (C) Microscopic
cribriform-morular papillary carcinoma. Even small foci of carcinoma,
lar variant of papillary carcinoma (hematoxylin-eosin stain).
March 2007 THYROID CANCER SCREENING IN FAP SYNDROME369
foci of cribriform-morular papillary TC were also discovered
that were not visualized by TU. Patient 91 had an 11-mm
nodule suspicious on TU and malignant at surgery. Two of 6
nodules thought not to be suspicious by ultrasound (3 mm)
were malignant, and 2 additional small foci (1 and 3 mm) not
identified by ultrasound were discovered. In all 5 cases, addi-
tional foci of cancer were identified histologically that were
either not identified by TU or not considered to be suspicious
by ultrasound criteria. These foci were less than 9 mm.
Prevalence of Thyroid Nodules in Familial
Adenomatous Polyposis Patients
Thirty-nine of the 46 FAP patients in our series who
were older than 16 years were offered screening TU. Three
patients were not referred because of their poor clinical condi-
tion, and 4 patients were previously diagnosed with TC. Among
the 39 FAP patients (23 women and 16 men) offered screening,
28 (72%) elected to have the examination. None reported symp-
toms or signs potentially related to thyroid disease, and all were
performed as screening examinations. With respect to uptake,
78% of the women and 63% of the men had the TU performed.
Eighty-three percent of patients 50 years or younger had a
screening ultrasound, in contrast to 53% of patients older than
Two of the 28 (7%; patients 68 and 91) had papillary TC.
Eighteen (64%) were female, and ten (36%) were male. The mean
age of this population was 42 years (range, 21–66 years). A
uniformly homogeneous echo texture was found in 5 subjects
(2 women and 3 men). The mean age of these patients with a
normal ultrasound was 40 years (range, 24–52 years). Ultra-
sound abnormalities were found in 23 subjects (82%), who
included 1 female patient with a diffusely enlarged gland and
22 patients (79%) with nodular thyroid disease. The mean age of
patients with nodular thyroid disease was 44 years (range,
21–66 years). Nineteen of the 22 FAP patients with nodular
thyroid disease had more than 100 colonic adenomas.
Among the 22 patients with nodular disease, 7 (32%) had a
solitary nodule, and 15 (68%) had multiple nodules (mean, 3;
Table 3. Features of Thyroid Nodules in 28 FAP Patients
Undergoing TU Screening Compared With the
FAP patients Historical series34
(n ? 10)
(n ? 18)
(n ? 123)
(n ? 130)
Any thyroid nodule
NOTE. Percentage is shown in parentheses.
Figure 2. Pictorial correlation between histopatho-
with TC who had a TU performed before surgery. (A)
Number, size, and location of nodules identified on
TU. Nodules that displayed sonographic features
suspicious for malignancy are shown in gray. (B)
Number, size, and location of malignant nodules
identified by histopathologic examination.
370HERRAIZ ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 3
range, 2–7 nodules). The largest nodule was ?9 mm in 9
patients (41%) and ?9 mm in 13 patients (59%). The echo
structure of the nodules was solid in 15 patients (68%), solid-
cystic in 4 (18%), and cystic in 3 (14%). Table 3 indicates that the
number and size of nodules in our FAP patients are much
higher than what is observed in the general population, on the
basis of historical series.
FNA was performed without complications in 10 patients
with solid nodules ?9 mm in diameter. Two 10-mm cystic
nodules in young female patients (26 and 29 years old) were not
biopsied. Close follow-up was recommended for a 64-year-old
male patient with a 9-mm solid nodule with significant comor-
bidities. An inadequate sample was obtained in 1 patient. In 2
female patients with 9-mm and 11-mm nodules with well-
defined borders, the samples were suspicious for malignancy.
One of these nodules also displayed microcalcifications. Both
underwent surgery, and papillary TC was confirmed in both
cases. The cytology was benign in the remaining 7 patients.
Follow-up Ultrasound Examinations
Twelve patients had a follow-up ultrasound examina-
tion performed after a mean of 15 months (range, 6–30
months), and there were no changes in either the number or
size of nodules. Four of these patients had a prior negative FNA.
Eight patients had a third ultrasound after a mean of 27
months from the first ultrasound (range, 24–33 months). Of
these 8 patients, one 30-year-old man from a family with 2 cases
of TC had 3 normal TU examinations. Five patients with multi-
nodular disease on the first 2 ultrasounds remained stable. A
single small nodule in a 48-year-old man showed slight enlarge-
ment (from 5 to 6 mm) when compared with the second TU.
One 41-year-old male patient with 2 normal ultrasounds was
found to have 2 bilateral nodules (9 and 19 mm) on the third
examination. FNA demonstrated atypical cells. Total thyroid-
ectomy was performed, and the specimen revealed granuloma-
tous (de Quervain’s) thyroiditis.
It has been estimated that the lifetime risk of papillary
TC is 2% in patients with FAP,6and the prevalence of TC in
different FAP registries has been reported to be 1%–2%.10,23
However, the 12% overall prevalence of TC in our cohort of 51
FAP patients was significantly higher. Although the numbers
are small, the risk in women appears to be greater than in men.
It should be noted that not all of our patients underwent
screening ultrasound, possibly placing the risk even higher.
Overall, our findings suggest that the risk of TC in the FAP
population might be greater than previously appreciated and
highlight the need to define the optimal screening strategy
There are several potential explanations for this observed
increase in the prevalence of TC in our FAP patients. The use of
screening ultrasound might account for increased detection of
subclinical TC. There might also be geographic variations in
risk among different FAP populations. Plail et al8reported 7
TCs among 998 patients in the St Mark’s Hospital Polyposis
Registry in the United Kingdom, and van der Linde et al21
reported 4 TCs among 601 patients from the Dutch FAP reg-
istry. Environmental factors could modulate risk, and recent
estimates suggest that TC rates in the U.S. are significantly
higher than in Europe. In 2001, the age standardized incidence
rate of TC in the United Kingdom was 2.2/100,00024and
2.0/100,000 in the Netherlands,25whereas the rate in the U.S.
was 8.2/100,000.26Furthermore, there has been an unambigu-
ous increase in the incidence of TC during the last 3 decades in
the U.S. Data from the Surveillance Epidemiology End Results
program indicated that the age-adjusted incidence rate of TC
for women was 6.2/100,000 in 1983. In contrast, the rate in-
creased to 13.1/100,000 in 2002.26The increasing incidence of
TC in the U.S. might reflect a true increase in the occurrence
of cancer, an increase in the detection of subclinical disease, or
both.27Those factors that have contributed to an increase in the
incidence of TC in the U.S. general population might have a
disproportionate impact on this susceptible population.
An important feature of our series is that it represents a
well-characterized cohort of patients with a proven diagnosis of
FAP, and most patients have received all of their care at our
institution in a longitudinal manner. Some of the older series
included relatives at-risk without a diagnosis of FAP, and the
nature of the long-term follow-up in these registries was not
specified.6,8Consequently, the risk of TC in these series might
have been underestimated.
The natural history of TC depends on the underlying his-
tology, and the overall 10-year survival rates are 98% for patients
with papillary carcinoma and 92% for those with follicular car-
cinoma.28Papillary microcarcinomas (tumors less than 1 cm) oc-
cur in at least 5% of all individuals not suspected of having
papillary TC at autopsy.29Case series report cancer-related mor-
tality as high as 1% for papillary microcarcinomas.30Presently,
it is not possible to identify which tumors will have an unfa-
vorable prognosis. However, an age ?45 years at diagnosis of
TC is associated with a higher risk for tumor recurrence and
cancer-related mortality.31Multicentricity is another factor pos-
sibly associated with an increased risk of recurrence.30In our
population, 2 of 6 patients were diagnosed with TC at an older
age (49 and 51 years), and all 6 patients had multifocal tumors.
Whether these features might have an impact on the natural
history of TC in FAP requires further investigation in larger
As in other studies, most of the papillary carcinomas in our
series were the cribriform-morular variant. The cribriform-
morular variant is a very rare subtype of papillary thyroid
carcinoma representing approximately 0.16% of all papillary
carcinoma cases.32The overall prognosis of the cribriform-
morular variant of TC is similar to that of conventional papil-
lary carcinoma, with less than 10% of cases demonstrating an
aggressive clinical behavior. Among patients with FAP who have
synchronous TC, up to 92% of these cases have been reported to
exhibit histologic features of the cribriform-morular variant.4
Although not all cribriform-morular variants of papillary car-
cinoma are associated with FAP, a significant proportion is,
such that any patient presenting with this rare carcinoma
should be evaluated for FAP.
Two APC germline mutations were identified that have not
been previously associated with TC (R564X and D1948X). In-
terestingly, the D1948X mutation is located at the 3= end of the
gene (distal to codon 1596), and mutations in this region have
been associated with the attenuated variant of FAP.33The lim-
ited burden of colonic polyps in this kindred (with 10 family
members affected) is consistent with the attenuated version of
the syndrome. Previous reports have not implicated a signifi-
March 2007 THYROID CANCER SCREENING IN FAP SYNDROME371
cant risk for TC in attenuated FAP kindreds, but the presence
of 2 TCs in this family without other recognized risk factors
suggests that patients with attenuated FAP might also be at
higher risk for TC. Further studies in larger attenuated FAP
populations are warranted.
The American Thyroid Association recommends ultrasound-
guided FNA in patients with nodules that are 8–15 mm in size
and have suspicious ultrasonographic findings (ill-defined mar-
gins, hypoechoic echo texture, microcalcifications, or central
blood flow), a history of radiation exposure, or family history of
TC. In our series, the suspicious nodules in patients ultimately
diagnosed with TC were larger than 10 mm in 5 patients (range,
11–15 mm) and 9 mm with microcalcifications in 1 patient.
None of the other nodules displayed ultrasonographic features
of malignancy. On histopathologic examination, however,
many additional malignant foci were identified that were
smaller than 10 mm (range, 1–9 mm). FNA was performed in 10
patients, with solid nodules ?9 mm identified by TU, and 2 of
the 6 TC cases (33%) were discovered through this approach on
the basis of TU screening. Calcifications were present in 3 of
those 10 nodules, but only 1 was malignant. Ill-defined margins
were present in 2 nodules, but in both cases the cytology was
benign. Therefore, neither the presence of calcification nor
the shape of the margins was highly predictive of malignancy
in our series. Thus, it appears that the unusual variant of TC
most often found in FAP patients is not associated with the
typical TU features of sporadic papillary TC. Use of a size
cutoff of 9 mm efficiently detected malignant nodules. How-
ever, many nodules ?1 cm might also be malignant in FAP
The natural history of small thyroid nodules identified by
ultrasound is not well-described. Nodular thyroid disease was
very common in our patients and appears more common than
in the general population.15This feature has not been described
previously in FAP patients. We found 2 tumors among 22
patients with nodular thyroid disease (9%), which is similar to
published reports of malignancy in 5%–10% of thyroid nodules
in the general population. The high prevalence of thyroid nod-
ules in FAP patients complicates the screening process for TC
and highlights the need to develop new molecular strategies
that might identify the subset of FAP patients at higher risk.
Because nodules ?9 mm might also be malignant, periodic
follow-up with TU and FNA should be considered. The natural
history of thyroid nodules in FAP patients is unknown. Within
our relatively short follow-up period, there were no changes in
TU findings in 12 patients who had a second ultrasound ex-
amination after a mean of 15 months. Among the 8 patients
who had a third ultrasound, one developed 2 new suspicious
nodules that ultimately proved to be benign. These findings
suggest a slow rate of nodule development and growth. There-
fore, it is possible that subsequent TU examinations can be
safely performed at intervals greater than 1 year. Larger studies
with longer periods of observation are necessary to determine
the optimal screening protocol and to determine whether such
screening has an impact on TC survival in FAP patients.
1. Heiskanen I, Luostarinen T, Jarvinen HJ. Impact of screening
examinations on survival in familial adenomatous polyposis.
Scand J Gastroenterol 2000;35:1284–1287.
2. Belchetz LA, Berk T, Bapat BV, et al. Changing causes of mortality
in patients with familial adenomatous polyposis. Dis Colon Rec-
3. Nugent KP, Spigelman AD, Phillips RK. Risk of extracolonic can-
cer in familial adenomatous polyposis. Br J Surg 1996;83:1121–
4. Perrier ND, van Heerden JA, Goellner JR, et al. Thyroid cancer in
patients with familial adenomatous polyposis. World J Surg
5. Harach HR, Williams GT, Williams ED. Familial adenomatous
polyposis associated thyroid carcinoma: a distinct type of follic-
ular cell neoplasm. Histopathology 1994;25:549–561.
6. Giardiello FM, Offerhaus GJ, Lee DH, et al. Increased risk of
thyroid and pancreatic carcinoma in familial adenomatous polyp-
osis. Gut 1993;34:1394–1396.
7. Bulow S, Holm NV, Mellemgaard A. Papillary thyroid carcinoma in
Danish patients with familial adenomatous polyposis. Int J Colo-
rectal Dis 1988;3:29–31.
8. Plail RO, Bussey HJ, Glazer G, et al. Adenomatous polyposis: an
association with carcinoma of the thyroid. Br J Surg 1987;74:
9. Bell B, Mazzaferri EL. Familial adenomatous polyposis (Gardner’s
syndrome) and thyroid carcinoma: a case report and review of the
literature. Dig Dis Sci 1993;38:185–190.
10. Bulow C, Bulow S. Is screening for thyroid carcinoma indicated in
familial adenomatous polyposis? the Leeds Castle Polyposis
Group. Int J Colorectal Dis 1997;12:240–242.
11. Cetta F, Montalto G, Gori M, et al. Germline mutations of the APC
gene in patients with familial adenomatous polyposis-associated
thyroid carcinoma: results from a European cooperative study.
J Clin Endocrinol Metab 2000;85:286–292.
12. Cetta F, Olschwang S, Petracci M, et al. Genetic alterations in
thyroid carcinoma associated with familial adenomatous polypo-
sis: clinical implications and suggestions for early detection.
World J Surg 1998;22:1231–1236.
13. Tunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid
disease in a community: the Whickham survey. Clin Endocrinol
14. Vander JB, Gaston EA, Dawber TR. The significance of nontoxic
thyroid nodules: final report of a 15-year study of the incidence of
thyroid malignancy. Ann Intern Med 1968;69:537–540.
15. Tan GH, Gharib H. Thyroid incidentalomas: management ap-
proaches to nonpalpable nodules discovered incidentally on thy-
roid imaging. Ann Intern Med 1997;126:226–231.
16. Cooper DS, Doherty GM, Haugen BR, et al. Management guide-
lines for patients with thyroid nodules and differentiated thyroid
cancer. Thyroid 2006;16:109–142.
17. Hagag P, Strauss S, Weiss M. Role of ultrasound-guided fine-
needle aspiration biopsy in evaluation of nonpalpable thyroid
nodules. Thyroid 1998;8:989–995.
18. Ito M, Yamashita S, Ashizawa K, et al. Childhood thyroid dis-
eases around Chernobyl evaluated by ultrasound examination
and fine needle aspiration cytology. Thyroid 1995;5:365–368.
19. Shafford EA, Kingston JE, Healy JC, et al. Thyroid nodular disease
after radiotherapy to the neck for childhood Hodgkin’s disease.
Br J Cancer 1999;80:808–814.
20. Papini E, Guglielmi R, Bianchini A, et al. Risk of malignancy in
nonpalpable thyroid nodules: predictive value of ultrasound and
color-Doppler features. J Clin Endocrinol Metab 2002;87:1941–
21. van der Linde K, Vasen HF, van Vliet AC. Occurrence of thyroid
carcinoma in Dutch patients with familial adenomatous polypo-
sis: an epidemiological study and report of new cases. Eur J
Gastroenterol Hepatol 1998;10:777–781.
22. Jo WS, Bandipalliam P, Shannon KM, et al. Correlation of polyp
number and family history of colon cancer with germline MYH
mutations. Clin Gastroenterol Hepatol 2005;3:1022–1028.
372 HERRAIZ ET ALCLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 3
23. Truta B, Allen BA, Conrad PG, et al. Genotype and phenotype of Download full-text
patients with both familial adenomatous polyposis and thyroid
carcinoma. Fam Cancer 2003;2:95–99.
24. Cancer Research UK Information Resource Centre. CancerStats.
Available at: http//:info.cancerresearchuk.org/cancerstats, 2004.
Accessed June 9, 2006.
25. Dutch Comprehensive Cancer Centres. Available at: www.
iKCnet.nl, 2003. Accessed June 9, 2006.
26. Ries LAG, Harkins D, Krapcho M, et al. SEER cancer statistics
review, 1975-2003. Available at: http://seer.cancer.gov/csr/
1975_2003/, 2005. Accessed June 9, 2006.
27. Davies L, Welch HG. Increasing incidence of thyroid cancer in the
United States, 1973–2002. JAMA 2006;295:2164–2167.
28. Gilliland FD, Hunt WC, Morris DM, et al. Prognostic factors for
thyroid carcinoma: a population-based study of 15,698 cases
from the Surveillance, Epidemiology and End Results (SEER)
program 1973-1991. Cancer 1997;79:564–573.
29. Kovacs GL, Gonda G, Vadasz G, et al. Epidemiology of thyroid
microcarcinoma found in autopsy series conducted in areas of
different iodine intake. Thyroid 2005;15:152–157.
30. Chow SM, Law SC, Chan JK, et al. Papillary microcarcinoma of
the thyroid: prognostic significance of lymph node metastasis
and multifocality. Cancer 2003;98:31–40.
31. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and
medical therapy on papillary and follicular thyroid cancer. Am J
32. Tomoda C, Miyauchi A, Uruno T, et al. Cribriform-morular variant
of papillary thyroid carcinoma: clue to early detection of familial
adenomatous polyposis-associated colon cancer. World J Surg
33. Hernegger GS, Moore HG, Guillem JG. Attenuated familial adeno-
matous polyposis: an evolving and poorly understood entity. Dis
Colon Rectum 2002;45:127–136.
34. Brander A, Viikinkoski P, Nickels J, et al. Thyroid gland: US
screening in a random adult population. Radiology 1991;181:
Address requests for reprints to: Daniel C. Chung, MD, Gastrointes-
tinal Unit, Department of Medicine, Massachusetts General Hospital,
50 Blossom St, GRJ 825, Boston, Massachusettes 02114. e-mail:
email@example.com; fax: (617) 726-5895.
Supported by a postdoctoral fellowship from the Fundacion Ramon
Areces (Spain) (M.H.).
March 2007 THYROID CANCER SCREENING IN FAP SYNDROME373