ORIGINAL STUDIES, REVIEWS,
AND SCHOLARLY DIALOG
THYROID CANCER AND NODULES
In Patients with Thyroid Cancer of Follicular Cell Origin,
a Family History of Nonmedullary Thyroid Cancer
in One First-Degree Relative Is Associated
with More Aggressive Disease
Haggi Mazeh, Joy Benavidez, Jennifer L. Poehls, Linda Youngwirth,
Herbert Chen, and Rebecca S. Sippel
Background: About 5% of nonmedullary thyroid cancers (NMTCs) are familial. Most patients with a family
history of thyroid cancer do not meet the definition of familial NMTC (FNMTC; two or more affected family
members). The aim of this study was to determine whether patients with a family history of NMTC, but who do
not meet the definition of FNMTC, have more aggressive disease.
Methods: A database of 1502 thyroidectomies was reviewed and 358 patients with NMTC who did not have a
family history of benign thyroid disease and who underwent thyroidectomy from January 1994 to December
2008 were identified. These included 324 (90%) patients with papillary thyroid carcinoma (PTC), 24 (7%) with
follicular thyroid cancer, and 10 (3%) with anaplastic or Hu ¨rthle cell carcinoma. Among them, those with and
without a family history of NMTC in first-degree relatives were compared. Then patients with only one affected
family member were compared with FNMTC patients.
Results: Thirty-seven (10%) patients had a family history of thyroid cancer, all to of which had PTC. Patients
with a family history of NMTC had a similar tumor size than those without (2–0 vs. 2.1–0cm, p=0.72) but they
were significantly younger (43–3 vs. 49–1 years, p=0.04), and more likely to have multicentricity (48% vs. 22%,
p=0.01), malignant lymph nodes (22% vs. 11%, p=0.02), and local invasion to surrounding tissues (5.4% vs.
0.6%, p=0.007). They also had a higher recurrence rate (24% vs. 12%, p=0.03) than patients without a family
history. Interestingly, patients with only one affected family member were similar to FNMTC patients with
respect to age (44–4 vs. 40–3 years, p=0.4), tumor size (2–0 vs. 1.9–0cm, p=0.65), rate of multicentricity (44%
vs. 52%, p=0.57), malignant lymph nodes (22% vs. 21%, p=0.93), local invasiveness (5.5% vs. 11%, p=0.59), and
disease recurrence (28% vs. 21%, p=0.56).
Conclusion: Patients with NMTC having a family history of thyroid cancer have more aggressive disease,
regardless of whether they meet the current definition of FNMTC regarding number of affected family members.
Therefore, any positive family history should be considered a risk factor for more aggressive thyroid carcinoma.
main categories: medullary thyroid cancer, which arises from
the calcitonin-producing C cells, and nonmedullary thyroid
cancer (NMTC), which originates from follicular cells (3).
Approximately 95% of thyroid cancers are NMTC (4), con-
sisting of four histologic subtypes (papillary, follicular,
Hu ¨rthle cell, and anaplastic thyroid cancers). Papillary thy-
roid carcinoma (PTC) is the most common, comprising 85% of
hyroid cancer is the most common endocrine-related
cancer in the United States (1,2). It is classified into two
the NMTC cases (5). Most of the NMTC occurs sporadically.
However, it has been estimated that 3.5%–6.2% of NMTC are
familial in origin (6,7). Histologically, sporadic and familial
thyroid cancers are indistinguishable.
in 24-year-old identical twins (8). Population studies since then
have shown that the risk of thyroid cancer increases ninefold in
or more first-degree relatives diagnosed with thyroid cancer of
follicular cell origin without another familial syndrome (3).
Section of Endocrine Surgery, Department of Surgery, University of Wisconsin, Madison, Wisconsin.
Volume 22, Number 1, 2012
ª Mary Ann Liebert, Inc.
When there are two people in a family with NMTC, there is a
risk of NMTC increases to >95% when there are three or more
affected family members (10). However, given the stringent
definition of FNMTC, most patients with a positive family his-
tory of thyroid cancer do not meet the definition.
Evidence suggests that FNMTC behaves in an autosomal
dominant manner with incomplete penetrance and variable
expressivity (6,11–13). Several linkage studies have mapped
out various chromosomal regions that may contain FNMTC
susceptibility genes. These include TCO1, MNG1, fPTC/PRN
or PRN1, and NMTC1 (14–18). However, the responsible gene
is yet to be identified. In the absence of a genetic marker,
FNMTC cannot be easily differentiated from sporadic NMTC
and families cannot be screened for a genetic condition.
Previous studies have shown that FNMTC is more ag-
gressive than sporadic NMTC with an increased risk of re-
currence, local invasion, multicentricity, and lymph node
metastases (5). The aim of this study was to determine whe-
ther a positive family history is associated with more ad-
vanced disease and to determine what impact the extent of
family history had on the aggressiveness of disease.
Materials and Methods
We conducted a retrospective review of 1502 patients who
underwent a thyroidectomy between January 1994 and De-
cember 2008. Data were obtained from a prospectively
maintained endocrine surgery database at the University of
Wisconsin. Of the entire cohort, we identified 422 patients
who underwent thyroidectomy for NMTC. We defined
NMTC as any thyroid malignancy of follicular cell origin,
which included papillary, follicular, Hu ¨rthle cell, or ana-
plastic carcinoma. A family history was obtained from all the
patients and a family history was considered positive when
patients had at least one first-degree relative with NMTC.
These data were recorded in the database prospectively.
When a family history was apparent and the affected family
member had undergone thyroid surgery, the tumor histol-
possible. Family history and medical information (demo-
graphics, radiation exposure, additional cancer syndromes:
familial adenomatous polyopsis) were confirmed by a care-
ful review of the electronic health records and by reviewing
endocrinology and endocrine surgery clinic notes. The
presence of a positive or negative family history was docu-
mented, as was the number of affected family members.
disease (multinodular goiter, follicular adenoma, Grave’s dis-
ease, and Hashimoto’s thyroiditis) and compared only those
with a positive family history of NMTC to those without a
positive family history of NMTC or benign thyroid disease.
Patients with a family history of benign thyroid disease may or
may not carry the genetic mutation seen in patients with
Total patients undergoing total thyroidectomy
Patients with NMTC
Family history of benign thyroid disease
(n = 64)
Positive malignant family history
No family history
2 or more family members affected
1 Family member affected
Study flow chart.
4 MAZEH ET AL.
FNMTC. Therefore, these patients were excluded from this
study to ensure the cleanest comparison. Patients were then
We assessed baseline characteristics within our patient pop-
ulation in an attempt to determine whether a positive family
history of NMTC was the key factor in predicting disease ag-
thyroid gland, and the most recent thyroglobulin levels were
obtained from probands with a positive family history of
NMTC and analyzed against those without a family history.
We defined a positive family history as one or more first-
degree relatives affected with NMTC. Aggressive features of
the disease such as multicentricity, local invasion, positive
lymph node metastasis, and disease recurrence were com-
pared to those with no affected family members. We defined
recurrence based on the need for reoperation or a positive
whole-body scan showing metastatic disease.
Since many NMTC patients with a family history do not
meet the definition of FNMTC (two or more affected first-
degree relatives), we also performed a subset analysis to de-
termine the aggressiveness of thyroid cancer in patients with
affected family members (who met the definition of FNMTC).
We performed all statistical analyses using SSPS (version
17). Comparison between the two groups was performed
using the unpaired t-test and Chi-square. The difference be-
tween the two means was considered significant at a p<0.05.
Of the entire cohort of 1502 thyroidectomies, 422 patients
underwent surgery for NMTC. Patients with family history of
benign thyroid disease were excluded (n=64). Study partici-
pants (n=358) included 321 (90%) patients without a family
history of NMTC and 37 (10%) patients with a positive family
history of NMTC (Fig. 1). Most of the patients had surgery for
papillary thyroid cancer (n=324, 90%), but 7% had follicular
thyroid cancer and 3% had anaplastic or Hu ¨rthle cell carci-
noma. All patients with a positive family history of thyroid
cancer were identified to have PTC on final pathology and all
of their affected family members also had PTC. Of those with
a positive family history, 49% (18/37) had only one affected
family member, 27% (10/37) had two affected family mem-
bers, and 24% (9/37) had three or more affected family
After comparing baseline characteristics between our
positive family history and no family history cohorts, we
found no significant difference in gender, nodule size, gland
weight, or the most recent thyroglobulin levels (Table 1).
However, compared with the patients with sporadic disease,
patients with any positive family history were younger and
more likely to demonstrate multicentricity (48% vs. 22%,
p=0.01), malignant lymph nodes (22% vs. 11%, p=0.02), local
invasion to surrounding tissues (5% vs. 0.6%, p=0.007), and
disease recurrence (24% vs. 12%, p=0.03; Table 1).
In the group with a positive family history, subset analysis
revealed no significant difference between patients with only
one affected first-degree relative versus those with two or
more affected first-degree relatives (Table 2). Specifically, the
comparison revealed similarly higher rates of multicentricity
(44% vs. 52%, p=0.57), malignant lymph nodes (22% vs. 21%,
p=0.93), local invasion to surrounding tissues (5.5% vs. 11%,
p=0.59), and disease recurrence (28% vs. 21%, p=0.56) in
two or more affected family members.
Our analysis shows that FNMTC, namely PTC, is more
aggressive than sporadic NMTC as portrayed by younger age
at presentation and increased multicentricity, lymph node
involvement, distant metastases, and recurrence. The pres-
ence of a positive family history was a significant predictor of
aggressiveness. Interestingly, we found that the more ag-
gressive pattern was seen not only in those patients who
currentlymeet thedefinition ofFNMTC(twoormoreaffected
family members) but also in those patients with only one af-
fected family member. This suggests that implementation of
the current definition of FNMTC may omit a significant
number of patients with familial disease.
Most authors agree that FNMTC behaves more aggres-
Table 1. Baseline and Tumor Aggressiveness
Characteristics Between Patients with Any Family
History of Nonmedullary Thyroid Cancer
and Patients Without a Positive Family History
Nodule size (cm)
Gland weight (g)
Recent Tg levels (ng/mL)
Malignant lymph nodes
FH, family history; Tg, thyroglobulin.
Table 2. Baseline and Tumor Aggressiveness
Characteristics Between Patients with One
Affected Family Member and Patients with Two
or More Affected Family Members
Two or more
Nodule size (cm)
Gland weight (g)
Recent Tg levels (ng/mL)
Malignant lymph nodes
AGGRESSIVE DISEASE IDENTIFIED IN ANY FAMILY HISTORY OF NMTC5
be significant (p=0.04) in their FNMTC patients as well as a
dramatically increased occurrence of multicentricity, yet
lymph node metastases and invasion to surrounding tissues
were not significant between sporadic and FNMTC patients
(23). In the Ito study, 7% of FNMTC patients reported three or
more affected family members, whereas our cohort consisted
of 24% (9/37) FNMTC patients among the same category.
This is a large difference in patient background and may ac-
count for the discrepancy between results especially since the
risk for FNMTC increases to >95% when patients present
with three or more affected members (10).
thyroid cancer or other follicular-derived malignancies, all
patients with a positive family history in this study had PTC;
therefore, our results reflect best on patients with a positive
family history of PTC only.
The conflicting results in the literature maybe due to the
inclusion of patients with a family history of two or less af-
fected relatives into analyses, diluting the degree of aggres-
siveness (10,19). However, our study showed that patients
with only one affected family member had a similar degree of
aggressiveness as those who met the definition for FNMTC. A
possible explanation for this finding is thatthese are really not
two different groups. Triponez and colleagues showed that
survival was significantly shorter in index cases who were
diagnosed before the familial predisposition was recognized
(22). Many of the patients with only one affected family
member probably do have familial disease, but it may have
not yet been recognized as such. In a similar regard, we also
chose to eliminate patients with a family history of benign
thyroid disease from our study. Most of the kindreds of
FNMTC also have a high prevalence of benign nodular dis-
ease (18). Therefore, some patients with a family history of
only benign thyroid disease may actually have the unrecog-
nized putative genetic mutation(s) associated with FNMTC.
Thus, it would be impossible to know whether to appropri-
ately allocate these patients to the positive family history
cleanest comparison we excluded patients with a family his-
tory of benign thyroid disease.
It is not clearly understood why patients with a positive
family history behave more aggressively. An inherited pre-
disposition is assumed, supported by reports of vertical
transmission in consecutive generations, horizontal trans-
mission to siblings, an increased percentage of males with
FNMTC compared with sporadic NMTC, and preponderance
of multicentric and recurrent tumors (4,5,21,24,25). Cappe-
zone et al. demonstrated that FNMTC exhibits ‘‘clinical an-
ticipation,’’ with the second generation acquiring the disease
at an earlier age and more advanced disease at presentation,
also supporting genetic susceptibility (20). Other possible
mechanisms explaining the familial association include an
unidentified environmental factor or ascertainment bias—
family membersof a patient withNMTC maybe evaluated for
thyroid disease more frequently than controls (12). Environ-
mental exposure to low-dose radiation may also promote
cancer development in thyroid glands that are already ge-
netically predisposed to malignancy (26,27).
Linkage analyses and other genetic studies have had dif-
ficulty in identifying a genetic marker for FNMTC. A possible
explanation is that FNMTC is not caused by a single gene, but
is rather a heterogenous inherited syndrome with more than
one susceptibility gene (12,28). Pal et al. showed that FNMTC
patients were also at risk of developing other cancers (breast,
kidney, colon, bladder, melanoma, and lymphoma), sug-
gesting that these susceptibility genes may predispose to
other cancers (6). Finding genes involved in FNMTC may
provide information about other cancers as well (25,29).
It has been recommended that patients with FNMTC un-
dergo more aggressive therapy with a total thyroidectomy,
prophylactic central neck dissection, followed by postopera-
tive radioactive iodine therapy (RAI) regardless of tumor size
and lifelong thyroid suppression to reduce disease recurrence
(5). A therapeutic lateral neck dissection should be performed
if positive lymph nodes are identified. RAI remnant ablation
and prophylactic central neck dissection are hotly debated
to better identify patients with more aggressive disease up
front who maybe more likely to benefit from these interven-
tions. Since we currently have no means to genetically screen
at-risk family members, neck ultrasound can play an impor-
tant role in early recognition.
A positive family history should not be the only factor for
using more aggressive therapy but it may tip the scales if the
patient already presents with other high-risk features (presen-
tation at young age, malegender,and lymph nodemetastasis).
These patients should be thoroughly evaluated with an ultra-
sound and fine-needle aspiration of thyroid nodules. A nega-
tive fine needle aspiration (FNA) should not automatically
exclude patients from surgery, since FNA is not as reliable in
FNMTC due to the increased rate of multifocality, bilaterality,
and multiple benign nodules seen in FNMTC patients
(28,30,31). Musholt et al. proposed that the presence of multi-
nodular goiter itself in at least three first- or second-degree
relatives represents a primary criterion for FNMTC (32).
To some the results of this study may seem counter intui-
tive. As patients with a positive family history of thyroid
cancer might be evaluated more frequently, or even poten-
disease would be diagnosed at an earlier stage. This potential
bias should only lessen the differences between our groups,
suggesting that the true difference in aggressiveness maybe
even greater than we have found.
We do not think that the definition of FNMTC should be
changed, but we must acknowledge that the definition is so
stringent that it may not capture all of the FNMTC patients.
Modifying the definition may result in a dilution effect
whereby patients with sporadic disease are erroneously in-
cluded among the true FNMTC patients. Nevertheless, it is
possible that bona fide FNMTC patients may only have one
family member diagnosed at the time of presentation.
Therefore, in the absence of a genetic marker, we think that
any family history of thyroid cancer should be considered
FNMTC is a separate clinical entity that warrants aggres-
sive therapy due to its increased multicentricity, lymph node
metastasis, local invasion, and frequent recurrence. We an-
ticipate that characterizing the responsible gene(s) will clear
the ambiguity surrounding FNMTC diagnosis and provide
insights for optimal therapeutic approaches. Until genetic
testing can clearly identify those with familial disease, we
6MAZEH ET AL.
to identify NMTC patients with a positive family history. This
information can then be used to identify patients who may
have more aggressive disease, are at higher risk for recur-
rence, and therefore, may benefit from more aggressive initial
The authors have no acknowledgements to disclose.
The authors declare that no competing financial interests
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Address correspondence to:
Rebecca S. Sippel, M.D.
Section of Endocrine Surgery
Department of Surgery
University of Wisconsin
600 Highland Ave.
Madison, WI 53792
8 MAZEH ET AL.