Management of Papillary Thyroid Cancer
Management of Papillary Thyroid Cancer
Thyroid cancer accounts for more than 90% of all endocrine malignancies
and for more than 50% of all deaths from endocrine cancer. The
incidence of thyroid cancer has been increasing since the 1930s,
most likely because of the practice of therapeutic irradiation
in childhood. The abrupt rise in incidence around 1974 was probably
due to the institution at that time of vigorous examination of
individuals who had had prior neck irradiation .
American Cancer Society statistics for the past 25 years suggest
that the incidence of thyroid cancer has risen slowly since the
mid 1970s. Disease incidence increased from 7,800 cases per year
in 1974 to 12,500 cases per year in 1992, with more than two-thirds
of new cases occurring in women. However, mortality from thyroid
cancer has changed little during this period (Figure 1).
Most patients have localized or regional disease at the time of
diagnosis, and the 5-year survival rate has exceeded 80% since
1960 and 90% since 1970. Therefore, thyroid cancer remains a relatively
modest oncologic concern, accounting for less than 2% of all cancers
since 1974 and for less than 0.5% of all deaths from cancer (Figure
Among patients with thyroid cancer, approximately 60% to 70% have
differentiated, papillary thyroid cancer. This article presents
a broad clinical overview of papillary thyroid cancer and emphasizes
disease features that modify prognosis and affect clinical management.
The risk of radiation-induced thyroid cancer has been well documented;
data on other causes of thyroid cancer are sparse. Prolonged thyroid-stimulating
hormone (TSH) elevation has been implicated as a potential risk
factor, but patients with primary hypothyroidism do not appear
to have an increased risk of papillary thyroid cancer. Thyroid-stimulatory
immunoglobulins present in patients with Graves' disease have
also been implicated. Associations with Hashimoto's thyroiditis,
Graves' disease, and multinodular goiter have been reported. However,
causative relationships between these diseases and papillary thyroid
cancer remain poorly documented.
In a recent epidemiologic review of thyroid cancer in the United
States , important differences in incidence emerged among ethnic
groups. Thyroid cancer was less common in Puerto Rican Hispanics
and blacks than in white persons, but New Mexican Hispanics and
Asian-Americans had higher rates. Genetic susceptibility is unlikely
to account for all the differences. For example, Asians living
in the United States are at higher risk for thyroid cancer than
Asians living in their native countries.
Although papillary thyroid cancer is generally considered a sporadic
disease, it is important to keep in mind that disease clusters
have been reported in kindreds with familial polyposis and Gardner's
syndrome . Reports of familial disease in the absence of either
a hereditary syndrome or neck irradiation increase the likelihood
that genetic predisposition plays a role in pathogenesis. In support
of this thesis, several recent studies have demonstrated complex
structural chromosomal aberrations and cytogenetic abnormalities
of chromosome 10q in association with papillary thyroid cancer
Irradiation in Childhood
During the early decades of the 20th century, low-dose irradiation
(usually < 2.0 Gy) to the head and neck was often used for
the treatment of benign childhood conditions, such as thymic enlargement,
tonsillitis, otitis, hemangiomas, ringworm, and acne. This medical
practice has clearly emerged as an important risk factor for the
development of papillary thyroid cancer and is considered by many
to be responsible for increasing its incidence.
The excess relative risk of thyroid cancer appears to depend on
total radiation dose, fractionation schedule, and patient age
at the time of irradiation . To date, medical use of radioactive
iodine-131 has not been shown to confer a significant risk of
papillary thyroid cancer (Table 1). A persistent concern has been
the carcinogenic potential of radioactive fallout. However, careful
review of available studies reveals methodologic inconsistencies
that may have exaggerated risk estimates .
The time between the irradiation and diagnosis of the thyroid
tumor averages 10 years but may be more than 30 years. In a recent
study, Schneider et al  demonstrated that radiation-induced
thyroid neoplasms are rare in the first 5 to 10 years after treatment
and cluster between 20 and 40 years post-therapy. Women have a
40% higher rate of radiation-induced thyroid cancer than men,
but the slopes of dose-response curves, which reach maximal rates
25 to 29 years after radiation exposure, appear similar for the
Increased awareness of thyroid radiosensitivity, especially in
children, has resulted in the virtual elimination of irradiation
for benign conditions and is generating a reassessment of medical
radiation use. Thus, radiation-related thyroid cancer is expected
to subside as a public health concern in the coming years.
Radiotherapy for Hodgkin's and Non-Hodgkin's Lymphomas
The efficacy of radiotherapy in controlling Hodgkin's and non-Hodgkin's
lymphomas has been instrumental in achieving high cure rates.
Consequently, radiotherapy is likely to continue as an important
component of the therapeutic armamentarium for these cancers.
Because many young cancer survivors can expect a near-normal lifespan
after neck irradiation, it is important to define their particular
risks of thyroid cancer and to design appropriate surveillance
and therapeutic strategies.
Radiation doses to the thyroid of more than 200 cGy, especially
when given at a young age, have been linked to an increased risk
of both benign and malignant thyroid neoplasms . Tucker et
al found a 13-fold increase in the risk of thyroid cancer in this
group , and Hancock et al noted that benign thyroid abnormalities
are even more common . Systematic evaluation of the irradiated
thyroid gland reveals significant pathologic  as well as radiologic
We also have found a heightened risk of thyroid cancer after therapeutic
neck (mantle) irradiation for Hodgkin's disease during childhood
(Table 2). Among 166 patients irradiated at or before age 16 years
and for whom a minimum of 15 years of follow-up is available,
12 have been treated for thyroid cancer to date (unpublished data;
patient population identified through a search of the database
maintained by the Department of Patient Studies at M.D. Anderson).
The presence of papillary thyroid carcinoma in 7% of irradiated
Hodgkin's disease survivors exceeds the prevalence of thyroid
cancer in the general population, and suggests that prior therapeutic
irradiation represents an important risk factor for thyroid cancer.
In our patients, thyroid cancer was found 7 to 19 years after
irradiation by investigation of either palpable thyroid nodules
or ultrasound abnormalities; all have proven to be papillary thyroid
cancers, and all patients remain alive. During the same period
and using the same database, only two cases of thyroid cancer
were diagnosed among 750 adults treated for Hodgkin's disease,
emphasizing the importance of age as a cofactor for the carcinogenic
potential of radiation. Fortunately, patients with radiation-related
papillary thyroid cancer appear to have the same excellent prognosis
as do patients with sporadic disease, even though the former may
have more extensive disease at diagnosis .
Because hyperparathyroidism also may occur with increased frequency
after neck irradiation , it is particularly important to investigate
previously irradiated patients very carefully for parathyroid
dysfunction before thyroid surgery, to avoid the potential need
Papillary thyroid cancer is predominantly a sporadic disease.
Patients typically present with a dominant thyroid mass or enlarged
cervical lymph nodes . Thyroid nodules are relatively common,
but less than 15% of clinically detectable solitary thyroid nodules
are malignant [14,15].
Histologically, many tumors have both papillary and follicular
elements and are referred to as "follicular variants of papillary
carcinoma;" such tumors are classified as papillary lesions
because their clinical behavior resembles that of pure papillary
cancers. In adults, the size of papillary thyroid cancer can vary
considerably, from microscopic cancers to large tumors that may
invade the thyroid capsule and even infiltrate adjacent structures.
Up to 40% of adults present with cervical lymph node metastases;
the figure is much higher in persons younger than 20 years. At
the time of presentation, affected lymph nodes are generally on
the same side as the primary tumor, but bilateral and mediastinal
metastases are encountered in a few patients. Although regional
lymph node invasion is fairly common, there is very little tendency
toward systemic dissemination.
Sites of distant metastases, in order of decreasing frequency,
are the lung, bone, and, rarely, other soft tissues. Older patients
are more likely to present with invasive tumors and have a higher
risk for distant metastases [16,17].