Pediatr Blood Cancer

BRIEF REPORTSurveillance Following Head, Neck, and Chest Radiotherapy:

Thyroid Ultrasound Monitoring for Secondary Thyroid Malignancy

Caitlin Kelly, MD,1* Linda Rivard, RN,2,3 Sharad Salvi, MD,2,3 Ammar Hayani, MD,2,3 William Hopkins, MD,4

Sarah O’Brien, MD, MSc,1,5 Laura Martin, MD,1 and Jason Canner, DO2,3

INTRODUCTION

Children who receive radiotherapy for a primary malignancy

are well known to be at increased risk for secondary malignancy.

In the most recent published data from the Childhood Cancer

Survivor Study (CCSS) there have been 119 pathologically con-

firmed secondary thyroid malignancies in 12,547 five-year survi-

vors who have received radiation treatment [1]. These data

confirmed previously published findings that the rate of secondary

thyroid malignancy is dependent on radiation dose received. At a

dose of 20 Gy they found a relative risk of 14.6-fold. There is a

downturn in the dose–response relationship after 20–25 Gy which

is believed to be due to the high percentage of cell death from

higher radiation doses. Dead cells are unlikely to have subsequent

malignant transformation. Higher incidence of secondary thyroid

cancer was also found to be associated with younger age of

radiation exposure and female sex.

In a study using the CCSS cohort of patients by Veiga et al.

[2], an increased risk of secondary thyroid malignancy was dis-

covered in those who received an alkylating agent in combination

with radiation, but only at radiation doses <20 Gy. This is due to

cell sparing that occurs at lower radiation doses enabling viable

cells to have subsequent malignant transformation.

Secondary thyroid cancer may not be detected for over

10 years after the original diagnosis [1]. Current Children’s On-

cology Group survivorship guidelines for children with prior

radiation exposure to the thyroid gland recommend yearly thyroid

exams palpating for nodules along with yearly thyroid function

blood tests [3]. Studies have shown, however, that physical exam-

ination alone is not adequate to identify nodules, even those that

are larger in size. Schneider et al. [4] found that even a nodule

1.5 cm in size or greater could not be palpated in half of the

patients studied. Thyroid function testing has also been studied to

see if it is useful to distinguish between benign and malignant

nodules. Results have found that neither TSH nor T4 correlate

well with ultrasound findings and thus are not helpful in identify-

ing malignant nodules [5].

As thyroid ultrasound can detect nodules as small as 2–3 mm,

there will be nodules identified that may not have clinical signifi-

cance [4]. Mihailescu et al. [6] found that serial ultrasounds are

able to detect those nodules that are rapidly growing over time

and thus more likely to be malignant. In their study, only 10

patients (cohort of 216 patients) with benign nodular disease on

fine needle aspirate (FNA) had nodules that grew over time. More

so, only 3 of the 10 patients were found to have malignancy on

repeat FNA. Their study suggests that stable findings on serial

ultrasounds is associated with a low-risk for malignancy.

The objective of this study was to determine the frequency and

outcomes of thyroid nodules detected in a single-institution pop-

ulation of long-term pediatric cancer survivors undergoing screen-

ing with thyroid ultrasounds.

PATIENTS AND METHODS

At Hope Children’s Hospital in Oak Lawn, Illinois, we

performed an IRB approved, retrospective chart review of 47

pediatric cancer survivors who received head, neck, or chest

radiotherapy between 1987 and 2007. The thyroid ultrasound

was done as the standard of care within our long-term survivor-

ship clinic. We determined the frequency and results of thyroid

ultrasound screening in this patient population. We specifically

reviewed all pathology reports of those patients who had thyroid

nodules and underwent thyroidectomy.

Children who receive head, neck, or chest radiotherapy forvarious primary malignancies have increased risk for secondarythyroid malignancy. Thyroid nodules are difficult to identify byphysical examination and/or laboratory tests. Thyroid ultrasoundcan detect non-palpable nodules without adverse side effects. Weperformed a retrospective chart review of 36 patients who receivedradiotherapy and underwent thyroid ultrasound. Forty-seven

percent (n ¼ 17) had �1 nodule(s) detected. Seven patients under-went thyroidectomy; four of whom were diagnosed with thyroidmalignancy. Our study suggests routine use of thyroid ultrasound inhigh-risk patients detects subclinical thyroid nodules and potentialthyroid malignancy post-radiotherapy. Pediatr Blood Cancer� 2012 Wiley Periodicals, Inc.

Key words: long-term follow up; pediatric cancer survivors; radiotherapy; secondary malignancy; thyroid nodules; thyroidultrasound

1Division of Pediatric Hematology/Oncology, Nationwide Children’s

Hospital/The Ohio State University, Columbus, Ohio; 2Department of

Hematology/Oncology, Advocate Hope Children’s Hospital, Oak

Lawn, Illinois; 3Pediatric Oncology Survivorship in Transition,

Advocate Hope Children’s Hospital, Oak Lawn, Illinois; 4Department

of Surgery, Advocate Christ Hospital, Oak Lawn, Illinois; 5Center for

Innovation in Pediatric Practice, The Research Institute at Nationwide

Children’s Hospital, Columbus, Ohio

Conflict of interest: Nothing to declare.

This work was presented in poster form at the 23rd American Society

of Pediatric Hematology/Oncology Annual Meeting, Montreal, CA,

April 7–10, 2010.

*Correspondence to: Caitlin Kelly, MD, The Department of Hematol-

ogy/Oncology/BMT Nationwide Children’s Hospital, 700 Children’s

Drive Columbus, OH 43205.

E-mail: caitlin.kelly@nationwidechildrens.org

Received 17 May 2012; Accepted 16 July 2012

� 2012 Wiley Periodicals, Inc.DOI 10.1002/pbc.24285Published online in Wiley Online Library(wileyonlinelibrary.com).

RESULTS

Children in our study received radiation between the ages of

8 months and 18 years (median age 9.9 years), and had a variety

of primary cancers with subsequently varying amounts of radio-

therapy (Table I). The largest population of patients had acute

leukemia (n ¼ 15) of which seven underwent bone marrow trans-

plantation. The remaining primary diseases were: Hodgkin’s lym-

phoma, a mixture of CNS tumors, and solid tumors. Radiation

dosage ranged from 12 to 61.2 Gy. The median follow-up since

original diagnosis was 8 years.

In our cohort of 47 patients who received radiotherapy, 36

(77%) patients had thyroid ultrasounds. Seventeen (47%) of those

children had �1 nodule(s) detected on ultrasound. Seven (41%) of

these patients underwent thyroidectomy (one partial thyroidecto-

my), and four (24%) patients were found to have thyroid malig-

nancy (Table II). Physical exam did not detect any nodules

identified by ultrasound. Median time to develop secondary thy-

roid malignancy was 10 years after treatment. The remaining 10

patients with abnormal ultrasounds continue to receive thyroid

evaluation, including ultrasound, every 6–12 months, to monitor

growth of the nodule(s).

DISCUSSION

As survival from the majority of childhood cancers continues

to improve, treatment-related secondary cancers are likely to

become an increasingly common part of long-term follow up.

In a cohort of childhood cancer survivors in 58 hospitals in

Germany, Austria, and Switzerland, 7.5% of secondary malignan-

cies were thyroid cancer [7]. In our retrospective review, we found

that almost half of post-radiotherapy childhood cancer survivors

who received thyroid ultrasounds had thyroid nodules and that of

TABLE II. Four Cases of Secondary Thyroid Malignancy Detected by Thyroid Ultrasound Screening

Primary malignancy Radiation dose

Thyroid

function

(pre-surgery)

Thyroid

physical

exam

Thyroid

ultrasound results

Timing of

thyroidectomy Biopsy results

Infantile ALL s/p BMT TBI 1200 cGY Euthyroid Normal Enlarging nodule in

right lobe

8 years post-tx Papillary thyroid

cancer

ALL (diagnosed

at 30 months)

Cranial 1800 cGY Euthyroid Normal Multiple nodules

with new nodule

appearance in

<6 months

11 years post-tx Papillary thyroid

cancer

Medulloblastoma

(diagnosed age 8)

Cranialspinal with

posterior Fossa boost

2300 cGY/3200 cGY

Euthyroid Normal Increasing nodule

size over 6-month

time period

8 years post-tx Papillary thyroid

cancer

ALL w/CNS relapse

and secondary

synovial carcinoma

(wrist; original

diagnosis age 2)

TBI 1200 cGY Euthyroid Normal Multiple nodules

>1 cm

13 years post-tx Micropapillary

thyroid cancer

TABLE I. Demographic and Clinical Characteristics of Study Population

Study group (N ¼ 47)

Patient characteristics

Female, n (%) 30 (64%)

Median age of diagnosis (range) 9.9 years (8 months to 18 years)

Time since diagnosis of first tumor (range) 8 years (2–22 years)

Primary cancer

Leukemia 15 (32%)

Hodgkins lymphoma 13 (27.6%)

CNS 8 (17%)

Solid tumors 6 (12.8%)

Non-Hodgkins lymphoma 5 (10.6%)

Radiation field received

Cranial n (%; average dose) 14 (30%; 20.5 Gy)

Cranial-spinal n, (%; average dose) 7 (15%; 28.8 Gy w/average boost 39 Gy)

Mantle n, (%; average dose) 11 (23%; 22.6 Gy)

Lung n (%; average dose) 4 (8.6%; 12 Gy)

Neck n (%; average dose) 3 (6.4%; 45.3 Gy)

Posterior Fossa n (%; average dose) 1 (2%; 45 Gy)

Total body n (%; average dose) 7 (15%; 12.8 Gy)

2 Kelly et al.

Pediatr Blood Cancer DOI 10.1002/pbc

those, 24% had a biopsy proven secondary thyroid malignancy.

Our data are consistent with other case series that demonstrated

malignant nodules are more likely to occur in a euthryoid state

and after a radiation dose �30 Gy [8]. Large prospective studies

are needed to identify the true incidence of thyroid nodules

in survivors and to establish the relationship between thyroid

nodules and future malignancy.

Currently the Children’s Oncology Group guidelines on the

long-term follow up of patients who have received head, neck, or

mantle radiotherapy include yearly physical thyroid examination

and thyroid function blood testing. These patients are at high-risk

for secondary thyroid malignancy and radiation induced papillary

thyroid cancer can be more aggressive than non-radiation induced

papillary thyroid cancer [9]. Additional studies are warranted to

reach a decision on the timing of initiation of ultrasound screen-

ing and frequency of ultrasound screening in survivors. Under-

standing that some irregularities found on ultrasound may pre-

exist radiation exposure a baseline thyroid ultrasound may be

useful. Further studies to identify particular risk factors for thy-

roid nodules have the potential to influence screening guidelines

as well. As an example, a CCSS study of Hodgkin’s lymphoma

survivors found female sex, a radiation dose to the thyroid of

25 Gy and time from radiation of �10 years to be independent

risk factors for thyroid nodules [10].

In a study by Brignardello et al., five cases of papillary carcino-

ma were found (N ¼ 129), of which only two patients had palpable

nodules. Median time to diagnosis of secondary thyroid malignancy

was 13.2 years. Our study also emphasizes the need for long-term

attention to the detection of thyroid nodules as the median time to

develop secondary thyroid malignancies was 10 years.

Our study is limited due to its retrospective nature and lack of

a control population to compare the incidence of thyroid nodules

in the pediatric population. There are no published data on the

natural incidence of thyroid nodules in non-radiation exposed

pediatric patients. Thyroid ultrasounds are generally only per-

formed on pediatric patients who have a palpable nodule and as

mentioned previously, physical exam may not be able to detect

nodules in our high-risk patient population.

Future research is needed to increase the understanding of the

baseline incidence of thyroid nodules in the pediatric population

and to determine the proper utilization of thyroid ultrasound in

screening radiation exposed childhood cancer survivors.

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Pediatric Thyroid Ultrasound Screening Post-Radiotherapy 3

Pediatr Blood Cancer DOI 10.1002/pbc