An Evidence-based Approach to Familial
Nonmedullary Thyroid Cancer: Screening,
Clinical Management, and Follow-up
Rebecca S. Sippel, MD,
Nadine R. Caron, MD,
Orlo H. Clark, MD
University of California San Francisco Department of Surgery, UCSF Comprehensive Cancer Center at Mount Zion,
z1600 Divisidero Street, Hellman Building, Room C-347, San Francisco, California
Northern Medical Group, University of Northern British Columbia, 3333 University Way, Prince George, British Columbia
V2N 429, Canada
Approximately 5% of nonmedullary thyroid cancers are of familial origin. When two or more family
members are diagnosed with nonmedullary thyroid cancer in the absence of other known asso-
ciated syndromes it is termed familial nonmedullary thyroid cancer (FNMTC). The genetic
inheritance of FNMTC remains unknown, but it is believed to be an autosomal dominant mode of
inheritance with incomplete penetrance and variable expressivity. FNMTC has been shown to be
more aggressive and to have a worse prognosis than sporadic nonmedullary thyroid cancer. For
example, studies have demonstrated that individuals with FNMTC have an increased risk of
multifocal disease, local invasion, and lymph node metastases. These aggressive features appear
to contribute to the higher recurrence rate and decreased disease-free survival seen in FNMTC
patients compared to those with sporadic differentiated thyroid cancer. This article is an overview
of the literature available in the English language discussing FNMTC. Critical questions regarding
the screening, management, and follow-up of these patients are addressed with answers pro-
posed based on the available literature. The quality of the evidence is ranked according to
Sackett’s criteria. Overall, the literature quality is somewhat limited, based on the low prevalence
of FNMTC, the difﬁculty in identifying familial cases, the variable study designs, and limited long-
term follow-up. Conclusions: To date, the optimal clinical approach is yet to be established, but
improved awareness and screening will permit earlier detection, more timely intervention, and
hopefully improved outcomes for patients and their families.
Thyroid cancer is the eighth most common cancer in
the United States, and it is estimated that 30,000 new
cases will be diagnosed in 2006 with 1500 associated
Approximately 95% of thyroid cancers are non-
medullary thyroid cancers (NMTC) that arise from the
thyroid follicular cells.
There are four histologic subtypes
of NMTC: papillary (85%), follicular (11%), Hu
(3%), and anaplastic (1%).
Most NMTC arise sporadi-
cally. However, it is estimated a familial origin is present
in 3.5%–6.2% of patients with NMTC.
The ﬁrst description of familial papillary thyroid can-
cer was in 1955, when Robinson and Orr reported 24-
year-old identical twins with papillary thyroid cancer.
Since then population studies have shown that the risk of
thyroid cancer is increased ﬁve- to ninefold in individuals
with a ﬁrst-degree relative with thyroid cancer.
When there are two people in a family with NMTC the risk
that the patient has a familial syndrome is between 31%
When there are three or more people with
NMTC the risk of a familial syndrome exceeds 95%.
Familial nonmedullary thyroid cancer (FNMTC) is
deﬁned by the diagnosis of two or more ﬁrst-degree rel-
Correspondence to: Orlo H. Clark, MD, e-mail: clarko@surgery.
Ó 2007 by the Socie
Internationale de Chirurgie World J Surg (2007) 31: 924–933
Published Online: 5 April 2007 DOI: 10.1007/s00268-006-0847-1