similar to the LH&subunit mutation
(Weiss et al. 1992).
References
Dacou-VoutetakisG, Fekquate DM, Drakopou-
10UM, Kourides IA, Dracopoli NC: 1990. Fa-
milial hypothyroidism caused by a nonsense
mutation in the thyroid-stimulatinghormone
subunit gene. Am J Hum Genet 46:988–993.
Dracopoli NC, Rettig WJ, Whitfield GK, et al.:
1986. Assignment of the gene for the ~-sub-
unit of thyroid stimulating hormone to the
short arm of chromosome 1. Proc Natl Acad
Sci USA 83:1822-1826.
Dracopoli NC, Rose E, Whitfield GK, et al.:
1988. Two thyroid hormone regulated gene,
the ~-subunits of nerve growth factor
(NGFB) and thyroid stimulating hormone
(TSHB), are located less than 310 kb apart in
both human and mouse genomes. Genomics
3:161-167.
HayashizakiY, Miyai K, Onishi T,Kumaham Y:
1986.Effects of corticotropin releasingfactor
and growth hormone releasing factor on pi-
tuitary hormone secretion in patients with
congenitalthyrotropinTSH deficiency.Horm
Metab Res 18:842-846.
HayashizakiY, Hiraoka Y, Endo Y, Matsubara
K: 1989.Thyroid stimulatinghormone (TSH)
deficiency caused by a single base substitu-
tion in the CAGYCregion of the TSH-13sub-
unit gene. EMBO J 8:2291–2296.
Hayashizaki X Hiraoka Y, Tatsumi K, et al.:
1990. Deoxyribonucleic acid analysis of five
families with familial inheritedthyroid stim-
ulating hormone deficiency. J Clin Endo-
crinol Metab 71:792–796.
MatthewsCH, Borgato S, Beck-Peccoz P,et al.:
1993. Primary amenorrhea and infertility
due to a mutation in the beta-subunit of fol-
licle-stimulating hormone. AMHC Forum
5:83-86.
Medeiros-Neto G, Herodotou DT, Rajan S, et
al.: 1996. A circulating, biologically inactive
thyrotropincaused by a mutation in the beta
subunit gene. J Clin Invest 97:125CL1255.
Miyai K, Azukizawa M, Kumahara Y: 1971. Fa-
milial isolated thyrotropin deficiency with
cretinism. N Engl J Med 285:1053–1045.
Miyai K, Endo Y, Iijima Y, Kabutomori O, Ha-
yashizaki Y: 1988/. Serum free a thyrotropin
subunit in congenital isolatedthyrotropinde-
ficiency. Endocrinol Jpn 35:517-521.
Miyai KI, HayashizakiY,HiraokaY, et al.: 1988.
Familial hypothyroidism due to thyrotropin
gene abnormality In Imura H, Shizume K,
Yoshida S, eds. Progress in Endocrinology
(Proc of the 8th Intern Congr of Endocrinol).
Excerpta Medica, Amsterdam, New York &
Oxford, vol 1, pp 545-550.
20 @ 1997,ElsevierScienceInc., 1043-2760/97/$17.00
Mori R, SawaiT,Kwoshita E, et al.: 1991.Rapid Shupnik MA, GreenspanSL, Redway EC: 1986.
detectionof a point mutationin thymid-stim- Transcriptional regulation of thyrotropin
ulating hormone p-subunit gene causing iso- subunit gene by thyrotropin releasing hor-
lated thyroid-stimulating hormone defi- mone and dopamine in pituitarycell culture.
ciency. Jpn J Hum Genet 36:313–316. J Biol Chem 261:12,675–12,679.
Okada T, Hirano F, FurukayaM, Sato S: 1980. Weiss J, Axelmd L, Whitcomb RW, Harris PE,
Congenital isolated TSH deficiency: a case Crowley FN, Jameson JL: 1992. Hypogo-
report. Pediatr Clin (in Japanese)43:283–7.
nadism caused by a single amino-acid substi-
Pierce JG, Parsons TF: 1981. Glycoprotein tution in the &subunit of luteinizing hor-
hormones: structureand function. Annu Rev mone. N Engl J Med 316:179-183.
Biochem 50:465495.
Wondisford FE, Magner JA, Weintraub BD:
Sato K, Mano T, SakuraiM, FurukawaY: 1975.
1991. Thymtropin. In Bravennan LE, Utiger
Isolated thyrotropin deficiency-a case with
RD, eds. The Thyroid, 6th ed. Philadelphia,
normal leukocyte function. Clin Endocrinol
JB Lippincott, pp 257-276. TEM
(in Japanese)23:525-529.
Risk Factors for Thyroid Cancer
Yuri E. Nikiforov and James A. Fagin
The potential risk factors for thyroid carcinoma development include
genetic predisposition, exposure to therapeutic or environmental ion-
izing radiation, residence in areas of iodine deficiency or excess, history
of preexisting benign thyroid disease, as well as hormonal and repro-
ductive factors. In this review, we analyze some of the epidemiological
data, as well as the possible molecular mechanisms by which certain
environmental and genetic factors might predispose to thyroid tumor-
igenesis. 01997, Elsevier Science Inc. (Trends Endocrinol Metab 1997;
8:20-25).
Tumors of the thyroid gland vary in their garded as variants of follicular tumors
biological behavior, degree of differenti- but display a greater predisposition to
ation, and prognosis, all of which are local recurrences and may carry a more
closely related to their histological type. serious prognosis. Anaplastic carcino-
Most thyroid tumors originate from the mas are the most aggressive form of thy-
follicular thyroid epitheliums. Papillary roid cancer and are predominantly a tu-
carcinomas are the most common form mor of the elderly. They exhibit a total
of thyroid cancer. They usually have a loss of thyroid-differentiated properties
favorable prognosis, in spite of a propen- and a very rapid-growth rate, and they
sity to spread by lymphatic dissemina- often have widespread metastasis and a
tion throughout the thyroid gland and to bleak outcome. Medulla~ carcinomas
local lymph nodes. Follicular carcino- originate from calcitonin-secreting
mas, in contrast, tend to invade blood
C-cells (parafollicular thyroid cells) and
vessels and give rise to distant me-
are occasionally familial. Their epidemi-
tastasis. Hiirthle cell carcinomas are re-
ology has been recently reviewed in this
journal and will, therefore, not be con-
sidered further. Other primary tumors of
Yuri E. Nikiforov and James A. Fagin are at the thyroid gland are extremely rare and
the Division of Endocrinology and Metabo-
include mostly malignant lymphomas
lism, Universityof Cincinnati College of Med-
icine, Cincinnati, OH 45267, USA. and different variants of sarcomas. In
PIIS1043-276O(96)OO2O4-4 TEA4vol. 8, IV’O. f, 1997
Table 1. Risk factors for thvroid cancer tients with FAPfrequently exhibit loss of
heterozygosity at this locus, consistent
Familial predisposition
a. Familial papilla~ carcinoma: rare, genetics poorly characterized
with a role for APC as a tumor-suppres-
b. Familial adenomatosis polyposis: up to 160-fold increased risk of thyroid sor gene, requiring loss of function of
carcinoma in women under 35 both alleles in order for the recessive
c. Cowden’s disease phenotype to emerge. There is no infor-
d. Multiple endocrine neoplasia type I: associated with thyroid adenomas. mation as to whether thyroid carcino-
Predisposition to malignancy not known mas from patients with FAP also have
2. Ionizing radiation (see Table 2) somatic mutations of the wild-type allele
a. External therapeutic irradiation: best-established and most significant risk of the APC gene, or whether the predis-
factor position to tumorigenesis in the thyroid
b. Environmental irradiation: Hiroshima, Nagasaki, Marshall Islands, is conferred by a “modifier” gene. In this
Chernobyl regard, it is noteworthy that mutations
3. Iodine intake of APC are not prevalent in sporadic thy-
a. Iodine deficiency: follicular carcinoma roid carcinomas (Zeki et al. 1994). Thy-
b. Iodine sufficiency: papillary carcinoma roid lesions are also reported as the most
4. Preexisting benign thyroid disease frequent extracutaneous manifestation
a. Follicular adenoma: predisposition to follicular carcinoma of Cowden’s disease (multiple hamar-
b. Graves’ disease: relative risk for thyroid carcinoma is controversial toma syndrome), being observed in two
c. Chronic lymphocytic thyroiditis: association with thyroid lymphoma thirds of patients; they include benign
5. Hormonal and reproductive factors thyroid lesions (adenomas, goiteq thyro-
a. Biological basis for female predisposition is unknown glossal duct cyst) and follicular thyroid
6. Geographic and ethnic factors
carcinoma. There are case reports de-
7. Diet, drugs: Uncertain influence
scribing the association of thyroid carci-
noma with Peutz-Jeghers syndrome
(Reed et al. 1990) and ataxia-telangiecta-
this review we examine the risk factors with an inherited cancer syndrome is sia (Ohta et al. 1986). In patients with
for thyroid carcinoma development, with familial adenomatous polyposis MEN1, thyroid disease is observed
based primarily on epidemiological ob- (FAP), as well as with Gardner’s syn- mostly as benign lesions (nodular hyper-
servations, and we also discuss the pos- drome, a variant of FAPcharacterized by plasia, goiter, adenoma) and, far more
sible molecular mechanisms by which numerous adenomatous polyps of colon, rarely as a malignancy (DeLellis 1995).
environmental and genetic factors might osteomas, soft tissue lesions, and other The gene-conferring predisposition to
predispose to thyroid tumorigenesis (Ta- extracolonic neoplasms. More than 60 MEN1 is located on chromosome 1lq13
ble 1). cases of thyroid carcinoma have been and is believed to function as a tumor
reported in patients with FAP(Harach et suppressor. Tumors from patients with
al. 1994). These tumors are found mostly MEN1 exhibit frequent loss of heterozy-
● Genetic Predisposition
in patients under the age of 30, with a gosity at this locus, presumably result-
The majority of tumors originating from marked female preponderance (female ing in loss of function of the normal
the foIlicular epitheliumsdo not show a to male ratio of 8:1). Women below 35 alIele (Larsson et al. 1988). Loss of het-
familial occurrence and are not part of years of age with FAP have been esti-
erozygosity at chromosome 1lq13 is
any inherited syndrome. There are scat- mated to have a 160-fold higher risk of
also found in sporadic follicular thyroid
tered reports in the literatureon the famil- thyroid carcinoma than normal individ-
neoplasms, suggesting that the putative
ial occurrence of thyroid carcinoma of fol- uals (Plail et al. 1987). These tumors are
tumor-suppressor gene(s) at this locus
licular cell origin, mainly involvingpapil- characterized by multifocality, and well-
may play a significant role in thyroid
lary carcinomas (Stoffer et al. 1986). demarcated, encapsulated lesions. Al-
though most of them were diagnosed as tumorigenesis (Matsuo et al. 1991, Zede-
Howeve~ familial cases of follicular and
anaplastic carcinomas, as well as of be- papillary carcinomas, they often possess nius et al. 1995).
nign thyroid lesions, have also been de- unusual features, such as areas of crib-
scribed. Familialpapillarycarcinoma was riform and solid and spindle cells within
observed in 3.5% of 226 consecutive pap- the tumors (Harach et al. 1994). Owing ● Ionizing Radiation
illarycarcinoma patients from the United to the relatively high prevalence of thy-
States (Stoffer et al. 1986) and in 3.8V0of roid carcinomas in patients with FAP, A history of exposure to ionizing radia-
383 patients from Iceland (Hrafnkelsson aggressive screening for thyroid diseases tion is the best-established risk factor for
et al. 1989).The sex ratio, age distribution, has been advocated for patients with this differentiated thyroid cancer of follicu-
and histological features of these tumors disorder. predisposition to FAP is con- lar cell origin. The most significant
were largely comparable to those of spo- ferred by germline-inactivating muta- sources of exposure have been after ther-
radic cases. tions of the adenomatous polyposis coli apeutic irradiation and through environ-
The best-recognized association of (APC) gene, which maps to chromosome mental disasters, which are discussed
thyroid cancer of follicular cell origin 5q21. Colorectal neoplasms from pa- separately here.

TEM vol. 8) No. 1, 1997 Q 1997,ElsevierScienceInc., 1043-2760/97/$17.00

PIIS1043-2760(96)O02
O4-4 21
External Therapeutic Irradiation
The association between radiation expo-
sure to the thyroid gland and subsequent
development of thyroid cancer was first
described in 1950 in children who re-
ceived x-ray therapy for an enlarged thy-
mus (Duffy and Fitzgerald 1950). Since
then, numerous reports have docu-
mented increased incidence of thyroid
neoplasms in patients with a history of
prior irradiation for benign diseases of
the head, neck, and thorax. A metaanal-
ysis of 878 cases of thyroid cancer in
children showed that 76V0 of patients
had a history of x-ray therapy to the
head and neck, usually for an enlarged
thymus, tonsils, or adenoids; others had
been treated for hemangiomas, acne, ec-
zema, nevi, and other benign conditions
(Winship and Rosvoll 1970). Most of
these tumors were diagnosed between
1946 and 1959. After 1965, the use of
radiation therapy for the stated benign
conditions was discouraged, and the in-
cidence of childhood thyroid malig-
nancy decreased dramatically. The long-
terrn follow-up of patients subjected to
radiation in childhood demonstrates
that thyroid carcinomas start to develop
s–10 years after exposure, reach a max-
imum in 25–29 years, and the incidence
continues to be higher 40–45 years after
the event (Schneider et al. 1993, Shore et
al. 1993). In a pooled analysis of seven
separate studies, the relative risk (RR) of
thyroid cancer was found to follow a
linear dose dependency in children un-
der the age of 15 years, down to a dose of
0.1 Gy (Ron et al. 1995). For childhood
exposures, the pooled excess RR per Gy
was 7.7. The younger the child at expo-
sure, however, the higher the excess RR.
The most common tumor associated
with radiation exposure is papillary thy-
roid carcinoma. The biological behavior
and overall prognosis of radiation-in-
duced papillary thyroid carcinomas are
comparable to those of papillary carci-
nomas in the population not exposed to
radiation.
Irradiation for benign conditions such
as thymic enlargement and acne has
been abandoned. Radiation therapy,
however, continues to be an important
tool for the treatment of a variety of
malignancies. These patients, especially
those treated at a young age, are also at
high risk for thyroid carcinoma develop-
ment. The RR for thyroid cancer follow-
@ 1997.ElsevierScienceInc., 1043-2760/97/$17.00
22
ing treatment of Wilms tumor (estimat- from ingestion of contaminated food and
ed mean thyroid dose of 3.1 Gy) was 132, water and through inhalationled to inter-
and after treatment of neuroblastoma nal exposure to the thyroid gland, which
(thyroid dose of 6.6 Gy), the RR was 350 was 3–10 times higher in children than in
(Tucker et al. 1991). At the much higher adults, with doses to the thyroid varying
doses used for the treatment of hemato- from O to >1000 cGy. An increased inci-
logical malignancies (that is, 24-31 Gy), dence of thyroid cancer in children from
the RR dropped to 67–81.
the most contaminated areas of Belarus
In light of the role of radiation expo- (that is, the Gomel region) was noted as
sure in the development of thyroid can-
early as 4 years after the accident (Kazak-
cer, several investigators have examined
ov et al. 1992). Between 1991 and 1992,
the possible carcinogenic effects of 1311
the incidence of childhood thyroid cancer
used for either diagnosis or therapy of
in Belarus was 60-fold greater than prior
thyroid abnormalities. Although isolated
to the disaster (Nikiforov and Gnepp
cases of cancer have been reported after
1994). The risk of thyroid carcinoma was
radioiodine therapy, no increased risk of
thyroid cancer has been documented af- inversely correlated with the distance of
ter 1311treatment for hyperthyroidism residence location from the source of ra-
(Helm et al. 1991). Similarly, a recent dioactive contamination. The age at the
comprehensive study indicated that di- time of exposure was an important mod-
agnostic administration of 1311was asso- ulatingfactor: the greatestnumber of chil-
ciated with a slight but nonsignificant dren subsequently developing thyroid
excess risk of thyroid cancer, with the cancer was less than 1 year of age at the
excess cancers probably due to the un- time of the accident, with the number of
derlying thyroid condition and not the cases decreasing with increasing age at
radiation exposure (Hall et al. 1996). exposure (Nikiforov et al. 1996a). Almost
100?4 of these tumors are papillary thy-
Environmental Irradiation roid carcinomas. There has been consid-
Long-term follow-up of survivorsof atom- erable interest in identifying the genetic
ic-bomb exposure to gamma and neutron events associated with these childhood
radiation in Japan in 1945 revealed an thyroid cancers, as they represent an un-
increased risk for thyroid cancer, which precedented paradigm of radiation-in-
was higher in individuals exposed at 30 duced cance~ Radiation is known to in-
years of age or less (Prentice et al. 1982), duce DNA-strand breaks, but the precise
and particularlyin females exposed at less genetic targetsare likelyto vary according
than 19 years of age (Ezaki et al. 1991).A to the cell type. Preliminary studies sug-
linear relationship was found between gest that rearrangementsresulting in the
thyroid cancer incidence and levels of aberrant expression of the intracellular
gamma irradiation to the thyroid gland domain of the ret receptor (that is, ret/PTC
(Prentice et al. 1982). The incidence of rearrangements) are common in post-
thyroid cancer was also increased among Chernobyl papillary thyroid carcinomas
residents of the MarshallIslands exposed (IUugbauer et al. 1995, Fugazzola et al.
to fallout radiation after detonation of a 1995). It is unclear whether ret/PTCrear-
thermonuclear device on the Bikini atoll rangements are due to radiation damage
in 1954 (Conard 1984). The exposure to
or whether they are common to pediatric
the thyroid gland resulted from internal
thyroid cancers regardless of their etiol-
irradiation from absorbed short-lived ra-
ogy. In contrast, these tumors do not ex-
dioiodines (13’1, 1321,1331,‘351) and, to
hibit mutations of ras, indicating that this
some extent, penetratingy radiation. Ap-
protooncogene is not a mediator of radia-
pearance of thyroid carcinomas was noted
tion-induced tumor formation (Nikiforov
10 years after the exposure, with seven
papillary,one follicular, and seven occult et al. 1996b).Furthermore,althoughCher-
thyroid cancers diagnosed among the 250 nobyl-related papillary carcinomas ex-
exposed individualsduring the 34 years of hibit certain histopathological features of
careful monitoring (Cronkite et al. 1995). tumor aggression, they have a very low
As a result of the accident at the Cher- prevalence of mutations of the p53 tumor
nobyl nuclear power plant on April 26, suppressor gene (Nikiforov et al. 1996b).
1986, millions of curies of short-lived ra- The characteristic features of radiation-
dioiodine isotopes were released in the induced thyroid tumors are summarized
fallout. The absorption of radioiodines in Table 2.
PIIS1043-2760(96)O02
O4-4 TEM vol. 8, No. 1, 1997
Table 2. Characteristics of radiation-induced thyroid tumors
1. Latent period of 4–45 years
2. Linear dose–response relationship
3. Strong inverse correlation with age at exposure
4. Histopathology
Benign: adenomatoid nodules
Malignant: papilla~ carcinoma (solid, follicular variants)
5. Genetics (post-Chernobyl tumors): high prevalence of ret/PTC, no t-asor p53
mutations (papillary carcinomas)
● Endemic Goiter,Iodine
Deficiency,and Iodine Excess
A higher incidence of thyroid carcinoma
has been demonstrated in areas of io-
dine deficiency and endemic goiter, par-
ticularly among those living in these re-
gions for 20 years and longer or during
childhood (Belfiore et al. 1987). These
populations are characterized by in-
creased incidence of follicular and ana-
plastic thyroid carcinomas, with a simi-
lar distribution between males and fe-
males. Most anaplastic carcinomas are
found in thyroid glands coexisting with
nodular goiter. In contrast to the higher
prevalence of follicular cancer in iodine-
deficiency areas, the proportion of pap-
illary carcinomas seems to be higher in
regions with excess iodine intake, such
as Iceland, Japan, and the Pacific islands
(Franceschi et al. 1993). In Switzerland
and Paraguay, where severe iodine defi-
ciency was previously common, wide
prophylactic iodinization led to a signif-
icant reduction of follicular and anaplas-
tic tumors, whereas the proportion of
papillary carcinomas appeared to in-
crease (Franceschi et al. 1993). There is,
at present, no understanding of the
mechanisms by which iodine deficiency
or excess promote thyroid tumorigene-
sis, let alone on how they appear to favor
particular histopathological forms of the
disease.
● PreexistingBenign Thyroid
Disease
In addition to ionizing radiation, a previ-
ous history of thyroid adenoma and goiter
are consistentlyrecognized as risk factors
for thyroid carcinoma, based primarilyon
epidemiological data from case-control
studies (Ron et al. 1987, Kolonel et al.
1990, Franceschi et al. 1993). Thyroid
nodules (follicular adenomas) were asso-
ciated with a higher RR (10 to 33) than
TEM vol. 8, No. 1, 1997 Q 1997,ElsevierScienceInc., 1043-2760/97/$17.00
nontoxic goiter (6 to 10). The risk of thy-
roid cancer in patients with preexisting
thyroid nodules was higher during the
first 10years after diagnosis of the benign
lesion, whereas for goiter it was higher 10
years or more after diagnosis (Ron et al.
1987,D’Avanzoet al. 1995).Most previous
studies did not detect a significant differ-
ence in risk for specific histological types
of thyroid carcinomas. Recent observa-
tions based on the latest World Health
Organization(WHO) classification of thy-
roid tumors (which provides clear criteria
to distinguish papillary from follicular
cancer) demonstrate,however,thatpreex-
istence of thyroid nodules, although con-
ferring a greater risk for both types
of differentiated thyroid cancer, deter-
mines a much higher risk for follicular
rather than papillary thyroid carcinoma
(D’Avanzoet al. 1995).
In addition to the epidemiological
data summarized above, the relation-
ship between preexisting benign thyroid
disease and carcinoma is supported by
some pathological and molecular ge-
netic evidence. Morphologically, thyroid
carcinoma can be found to arise within
an adenoma or to develop several years
after a cytologically confirmed diagnosis
of benign adenoma. Somatic mutations
of ras oncogenes appear to be about
equally prevalent in follicular adenomas
and carcinomas and, to a lesser extent,
in papillary carcinomas, suggesting that
they occur early in the process of tumor
formation. Transgenic mice overexpress-
ing mutant ras in thyrocytes, however,
have a relatively low prevalence of thy-
roid adenomas and scant evidence of
progression toward malignancy (Santel-
li et al. 1993). Nevertheless, in most hy-
pothetical schemes of the genetic evolu-
tion of thyroid tumors, adenomas are
depicted as precursor lesions, at least for
follicular carcinomas (Fagin 1994). For
thyroid goiter, the genetic mechanisms
are less evident. Notably, most nodules
PIIS1043-2760(96)O02
in multinodular goiter glands are clonal
(Namba et al. 1990a, Aeschimann et al.
1993), and many harbor mutations of
ras (Namba et al. 1990b).
Whereas thyroid cancer is found more
often in nonfunctioning and hypofunc-
tioning thyroid nodules, autonomously
functioning (“hot”) nodules only rarely
become malignant (Ashcraft and Van
Herle 1981). Hyperfunctioning ade-
nomas are characterized by a high prev-
alence of mutations of the TSH receptor
or of the G,a subunit of the heterotrim-
eric G protein to which it couples, result-
ing in constitutive activation of adenylyl
cyclase and stimulation of growth and
differentiated properties. Interestingly
thyroid carcinomas have a much lower
prevalence of these genetic defects (Mat-
suo et al. 1993, Spambalg et al. 1996,
Russo et al. 1996), which is consistent
with the clinical observation that auton-
omously functioning thyroid nodules do
not usually progress to malignancy.
An association between thyroid carci-
noma and Graves’ disease or lympho-
cytic thyroiditis has been reported.
Other reports, however, including that of
the U.S. Cooperative Thyrotoxicosis
Therapy Follow-up Study (Dobyns et al.
1974), did not confirm the higher risk
for thyroid carcinomas in patients with
these diseases. This issue remains con-
troversial, as a number of studies report
a higher than expected frequency of dif-
ferentiated thyroid carcinomas in pa-
tients with surgically treated Graves’ dis-
ease (Mazzaferri 1990). Patients with
chronic lymphocytic thyroiditis have a
higher risk (up to 67-fold) for develop-
ment of malignant thyroid lymphoma
(Helm et al. 1985). Because this tumor is
exceedingly rare in the general popula-
tion, the overall incidence of thyroid
lymphoma in patients with thyroiditis is
still low and does not justify aggressive
screening strategies.
Anaplasticcarcinomas are usuallydiag-
nosed in patients with a history of a pre-
vious thyroid disorder, such as goiter or
differentiatedfollicular or papillary carci-
nomas (Demeter et al. 1991). Foci of ana-
plastic carcinoma can be found micro-
scopically in surgical or autopsy speci-
mens within areas of well-differentiated
follicular or papillary cancer. The factors
responsible for transformation from well-
differentiated to undifferentiated tumors
are unknown. Mutationsin thep53 tumor-
suppressor gene appear to play an impor-
O4-4 23
tant role in this transition, as they are
found with high prevalence in undifferen-
tiated, but not in well-differentiated thy-
roid cancers (Fagin 1994).
. Hormonal and Reproductive
Factors
The role of hormonal and reproductive
factors in the pathogenesis of thyroid car-
cinoma has long been suspected on the
basis of a higher incidence of cancer in
women than in men. The incidence of thy-
roid cancer is 1.6 times higher in married
versus single females of reproductive age,
as shown by population-based data from
the U.S. Third National Cancer Survey
(Ernster et al. 1979). Moreove~ an in-
creased risk of thyroid carcinoma has
been reported in patientswith breast can-
cer (Ron et al. 1984).Nevertheless,numer-
ous studies have failed to detect a strong
association between specific hormonal
parameters or interventions and thyroid
cancer development. Use of estrogen-con-
taining preparations, including oral con-
traceptives, lactation suppressants, or
postmenopausalestrogens,has been asso-
ciated with a RR for thyroid cancer of
1.4-1.7, particularly of follicular carci-
noma. Other factors resulting in a mar-
ginalincreasein the RR for thyroid cancer
include a history of one or more pregnan-
cies, or of miscarriages (Ron et al. 1987).
Thyroid cancer risk has also been associ-
ated with obesity (Kolonel et al. 1990).
Q GeographicDifferences
and Ethnicity
The incidence of thyroid cancer varies in
differentgeographic areasand among eth-
nic groups. Regions with higher than av-
erage incidence of thyroid cancer include
Iceland, Hawaii, and New Caledonia. In
Hawaii, where the overall age-adjusted
thyroid cancer rates are 8.1 per 100,000
for women and 3.1 per 100,000 for men,
the highest rate for women occurred in
Filipinas(18.2 per 100,000),and for men,
in Chinese(6.3 per 100,000).The analysis
of ethnic patterns of thyroid cancer inci-
dence in other parts of the United States
also showed obvious differences (Spitz et
al. 1988). Compared with white men and
women, Puerto Rican Hispanics and
blacks had significantlylower thyroid can-
cer risk (weighted ratios ranged from 0.5
to 0.7). In contrast, New Mexican His-
panic men and Chinese,Japanese,Hawai-
24 @ 1997,ElsevierScienceInc., 1043-2760/97/$17.00
ian, and Filipino men and women had award. Dr. Fagin is the recipient of an
significantlyhigher rates (weighted ratios Established Investigatorship Award
ranged from 1.56 to 3.17). These differ- from the American Heart Association
ences may be due to local environmental and Bristol Myers-Squibb.
factors, rather than genetic susceptibility
as ethnic-specific rates for these groups
are much higher in the United States as
compared with the same ethnic groups
living in other parts of the world. For the Aeschimann S, Kopp PA, Kimura ET, et aL:
residentsof Hawaii,an increasedrisk was
found to be associated with intakeof sea-
food and dietary iodine (Kolonel et al.
1990).
. Other Factors (Diet and Drugs)
There are conflicting results regarding
the possible relationship between the
consumption of fish and other iodine-
rich products and thyroid carcinoma.
Intake of nutritional goitrogens, which
include vegetables containing cyano-
genic glucosides (most forms of cab-
bage, cauliflower, broccoli, and other
members of the cruciferous family), is
not associated with increased risk of thy-
roid carcinoma and may even be protec-
tive (Ron et al. 1987). There is no epide-
miological evidence of increased risk of
thyroid cancer in smokers.
Broad screening of more than 200
drugs for carcinogenicity revealed that
griseofulvin and senna were associated
with increased risk for thyroid carci-
noma (Friedman and Ury 1983). In an-
other study, spironolactone and regular
use of vitamin D, but not of calcium
supplements, were significantly associ-
ated with thyroid cancer, mostly medul-
lary carcinoma (Ron et al. 1987). In sev-
eral series, patients with parathyroid ad-
enomas consistently demonstrated
higher than expected incidence of non-
medullary thyroid cancers, most often
papillary carcinomas, which are re-
ported in 5%-10.7% of patients with par-
athyroid adenomas (LiVolsi and Feind
1976). Thyroid follicular adenomas and
goiter are also found often in these pa-
tients. This may reflect common tumor-
initiating events leading to both parathy-
roid and thyroid neoplasms, or it may
reflect secondary effects of hypercalce-
mia on follicular cell tumorigenesis.
● Acknowledgments
This work was supported in part by
grant CA 50706 and a University of Cin-
cinnati Cancer Research Challenge
PIIS1043-2760(96)O02
References
1993. Morphological and functional poly-
mo~hism within clonaf thyroid nodules. J
Clin Endocrinol Metab 77:846-851.
AshcraftMW, Van HerleAJ: 1981. Management
of thyroidnoduksIl: scanning techniques,thy-
roid suppressivetherapy,and fine needleaspi-
ration.Head Neck Surgery3:297–322.
Belfiore A, La Rosa GL, Padova G, Sava L,
Ippolito O, VigneriR: 1987. The frequency of
cold thyroid nodofes and thyroid malignan-
cies in patientsfrom an iodine deficient area.
Cancer 60:3096-3102.
Conard RA: 1984. Lateradiation effects in Mar-
shall Islanders exposed to fallout 28 years
ago. In Boice JD Jr, Fraumeni JF Jr, eds.
Radiation Carcinogenesis:Epidemiology and
Bio]ogicaf Significance. New York, Raven
Press, pp 57+5.
CronkiteEP, Bond VP, Conard RA: 1995. Med-
icaf effects of exposure of human beings to
fallout radiation from a thermonuclear ex-
plosion. Stem Cells 13:49-57.
D’AvanzoB, La VecchiaC, FmnceschiS, NegriE,
TakarniniR: 1995. History of thyroid diseases
andsubsequentthyroidcancerrisk.CancerEp
idemiol BiomarkersPrev4:193–199.
DeLellisRA: 1995. Biology of disease: multiple
endocrine neoplasia syndromes revisited.
Lab Invest 72:494-505.
Demeter JG, de Jong SA, Lawrence AM, Pal-
oyan E: 1991. Anaplastic thyroid carcinoma.
Surgery 110:956-963.
Dobyns BM, Sheline GE, Workman JB, et al.:
1974. Malignant and benign neoplasms of
the thyroid in patients treated for
hyperthyroidism:a report of the cooperative
thyrotoxicosis therapyfollow-up study.J Clin
Endocnnol Metab 38:97&998.
Duffy BJ, Fitzgemld PJ: 1950. Cancer of the
thyroid in children: a report of 28 cases. J
Clin Endocrinol Metab 10:12961308.
Ernster VL, Sacks ST, Selvin S, Petrakis NL:
1979. Cancer incidence by marital status:
U.S. Third National Cancer Survey. J Natl
Cancer Inst 63:567-585.
Ezaki H, Takeichi N, Yoshimoto Y: 1991. Thy-
roid cancer: epidemiologicaf study of thyroid
cancer in A-bomb survivors from extended
life span study cohort in Hiroshima. J Radiat
Res 32:193-200.
Fagin JA: 1994. Molecular pathogenesis of hu-
man thyroid neoplasms. Thyroid Today 17:
1–7.
O4-4 TEM vol. 8, No. 1, 1997
Franceschi S, Boyle P, Maisonneuve P, et al.:
1993. The epidemiology of thyroid carci-
noma. Crit Rev Oncog 4:25–52.
Friedman GD, Ury HK: 1983. Screening for
possible drug carcinogenicity: second report
of findings. J Natl Cancer Inst 71:1165–1175.
Fugazzola L, Pilotti S, Pinchera A, et aL: 1995,
Oncogenicrearrangementsof the RETproto-
oncogene in papillary thyroid carcinomas
from children exposed to the Chernobyl nu-
clear accident. Cancer Res 55:5617–5620.
Hall P,MattssonA, Boyce JD,Jr: 1996. Thyroid
cancer after diagnostic administration of io-
dine-131. Radiat Res 145:86-92.
Harach HR, Williams GT, Williams ED: 1994.
Familiaf adenomatous pcdyposis associated
thyroid carcinoma: a distinct type of follicu-
lar cell neoplasm. Histopathology 25:549-
561.
Helm L-E, Blomgren H, Lowhagen T: 1985.
Cancer risks in patients with chronic lym-
phocytic thyroiditis. N Engl J Med 312:601-
604.
Helm L-E, Hall R Wiklund K, et al.: 1991. Can-
cer risk after iodine-131 therapy for hyper-
thyroidism. J Natl Cancer Inst 83:1072–1077.
HrafnkelssonJ, TuliniusH, Jonasson JG, Olafs-
dottir G, Sigvafdason H: 1989. Papillarythy-
roid carcinoma in Iceland. Acta Oncol 28:
785-788.
Kazakov VS, Demidchik EP, Astakhova LN:
1992. Thyroid cancer after Chernobyl. Na-
ture 359:21.
Klugbauer S, Lengfelder E, Demidchik EP,
Rabes HM: 1995. High prevalence of ret re-
arrangement in thyroid tumors of children
from Bekuus after the Chernobylreactor ac-
cident. Oncogene 11:2459–2461.
Kolonel LN, HankinJH, WilkensLR, Fukunaga
FH, Hinds MW: 1990. An epidemiologic
study of thyroid cancer in Hawaii. Cancer
Causes Control 1:223-234.
Larsson C, Skogseid B, Oberg K, NakamuraY:
1988. Multiple endocrine neoplasia type 1
gene maps to chromosome 11 and is lost in
insulinoma. Nature 332:85–87.
LiVolsi VA, Feind CR: 1976. Parathyroid ade-
noma and nonmedullary thyroid cancer.
Cancer 38:1391-1393.
Matsuo K, TangS-H, Fagin JA: 1991. AfIelotype
of human thyroid tumors: loss of chromo-
some 1lq13 sequences in follicular neo-
plasms. MoI Endocnnol 5:1873-1879.
Matsuo K, Friedman E, Gejman PV, Fagin JA:
1993. The thyrotropin receptor (TSH-R) is
TEM vol. 8, NO. 1, 1997 Q 1997,ElsevierScienceInc., 1043-2760/97/$17.00
not an oncogene for thyroid tumors: struc-
tural studies of the TSH-R and the alpha-
subunit of Gs in human thyroid neoplasms. J
Clin Endocrinol Metab 76:1446-1451.
Mazzaferri EL: 1990. Thyroid cancer and
Gravesdisease. J Clin Endocrinol Metab 70:
826829.
Namba H, Matsuo K, Fagin JA: 1990a. C]onal
composition of benign and malignanthuman
thyroid tumors. J Clin Invest 86:12&125.
Namba H, Rubin SA, Fagin JA: 1990b. Point
mutationsof ras oncogenes arean earlyevent
in thyroid tumorigenesis. Mol Endocnnol
4;1474-1479.
Nikiforov Y, Gnepp DR: 1994. Pediatricthyroid
cancer after the Chernobyl disaster: patho-
morphologic study of 84 cases (1991–1992)
from the Republic of Belarus.Cancer74:748-
766.
Nikiforov Y, Gnepp DR, Fagin JA: 1996a. Thy-
roid lesions in children and adolescents after
the Chernobyl disaster: implications for the
study of radiation tumorigenesis. J Clin En-
docrinol Metab 81:9-14.
Nikiforov YE, Nikiforova MN, Gnepp DR, Fa-
gin JA: 1996b. Premfence of mutations of ras
and p53 in benign and mafignant thyroid
tumors from children exposed to radiation
after the Chernobyl nuclear accident. Onco-
gene 13:687-693.
Ohta S, Katsura T, Shimada M, Shima A, Ch-
ishiro H, Matsubara H: 1986. Ataxia-telang-
iectasia with papillary carcinoma of the thy-
roid. Am J PediatrHematol Oncol 8:255–268.
Plail RO, Bussey HJR, Glazer G, Thomson JPS:
1987.Adenomatouspolyposis: an association
with carcinoma of the thyroid. Br J Surg
74:377-380.
Prentice RL, Kato H, Yoshimoto K, Mason M:
1982.Radiation exposure and thyroid cancer
incidence among Hiroshima and Nagasaki
residents. Nad Cancer Inst Monogr 62:207–
212.
Reed MWR, Harris SC, QuayleAR, Talbot CH:
1990. The association between thyroid neo-
plasia and intestinalpolyps. ArmR Coil Surg
Engl 72:357-359.
Ron E, Curtis R, Hoffman DA, Flannery JT:
1984. Multiple primary breast and thyroid
cancer. Br J Cancer 49:87–92.
Ron E, KleinermanRA, Boice JD,Jr,LiVolsiVA,
FlanneryJT, Fraumeni ~, Jr: 1987. A popu-
lation-based case-control study of thyroid
cancer. J Natl Cancer Inst 79:1–12.
PII S1043-2760(96)O02
Ron E, Lubin JH, Shore RE, et aL: 1995. Thy-
roid cancer after exposure to externalirradi-
ation. Radiat Res 141:259–277.
Russo D, Artun F,SchlumbergerM, et aL: 1996.
Activatingmutations of the TSH receptor in
differentiatedthyroid carcinomas. Oncogene
11:1907-1911.
%ntelli G, de Franciscis V, Portefla G, et al.:
1993. Production of transgenicmice express-
ing the Ki-ras oncogene under the control of
a thyroglobulin promoter. Cancer Res 53:
5523-5527.
Schneider AB, Ron E, Lubin J, StovaflM, Gier-
lowski TC: 1993. Dose-responserelationships
forradiation-induced thyroid cancer and thy-
roid nodues: evidence for the prolonged ef-
fects of radiation on the thyroid. J Clin En-
docrinol Metab 77:362-369.
Shore RE, HildrethN, DvoretskyP,AndresenE,
Moseson M, Pastemack B: 1993. Thyroid
cancer among persons given x-ray treatment
in infancy for an enlarged thymus gland. Am
J Epidemiol 137:1068-1080.
Spambafg D, Sharifi N, Elisei R, et aL: 1996.
Structural studies of the TSH receptor and
Gs alpha in human thyroid cancem: lowprev-
alence of mutations predicts infrequent in-
volvement in malignant transformation. J
Clin Endocrin Metab 81:3898-3901.
Spitz MR, Sider JG,Klatz RL, Pollack ES, New-
ell GR: 1988. Ethnic patternsof thyroid can-
cer incidence in the United States, 1973–
1981. Int J Cancer 42:549-553.
Stoffer SS, Van Dyke DL, Vaden Bach J, Szpu-
nar W, Weiss L: 1986. Familiaf papillary car-
cinoma of the thyroid. Am J Med Genet 25:
775-782.
Tucker MA, Jones PHM, Boice JD, JL et aL:
1991. Therapeuticradiation at a young age is
linked to secondary thyroid cancer. Cancer
Res 51:2885-2888.
Winship T, Rosvofl RV: 1970. Thyroid carci-
noma in childhood: final report on a 20 year
study.Clin Proc 26:327–349.
Zedenius J, Wallin G, Svensson A, et aL: 1995.
Aflelotyping of follicular thyroid tumors.
Hum Genet 96:27-32.
Zeki K, Spambalg D, Sharifi N, Gonsky R, Fa-
gin JA: 1994. Mutations of the adenomatous
polyposis coli gene in sporadic thyroid neo-
plasms. J Clin Endocnnol Metab 79:1317-
1321. TEM
O4-4 25