DISCUSSION Gerald T. Kangelaris, MD, and Lisa A. Orloff, MD

Role of Thyroid Stimulating Immunoglobulin in Rapidly Progressive
Metastatic Thyroid Cancer Following Total Thyroidectomy
Gerald T. Kangelaris, MD, and Lisa A. Orloff, MD
Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, CA
ABSTRACT
DISCUSSION
DISCUSSION (CONTINUED)
Objectives: To present a case of rapidly progressive metastatic papillary thyroid
carcinoma following total thyroidectomy in a patient with Graves’ disease, and
review the relevant literature.
The thyroid-stimulating hormone receptor is a G-protein coupled receptor found
on the surface of thyroid epithelial cells.3 The binding of thyrotropin (TSH)
activates cellular G proteins and the downstream adenylate cyclase / cyclic AMP
signal transduction cascade, resulting in thyroid cellular growth and
development, increased iodide uptake via the synthesis of the sodium-iodide
symporter, and thyroid hormone synthesis and release. Functional TSH
receptors are found on differentiated thyroid cancers, and the belief that
thyrotropin stimulates their iodine trapping function and growth has led to the
common practices of TSH suppression following total thyroidectomy and
withholding exogenous thyroid supplementation prior to radioactive iodine
therapy.4
In contrast, a number of case series have associated WDTC in Graves’ disease
with aggressive behavior.8,9,10 These cancers showed higher than expected rates of
distant metastases, muscle invasion, and nodal metastases. In addition to these
case series, a number of case reports implicate Graves’ disease in the rapid growth
of WDTC, increased aggressiveness of WDTC, and transformation of WDTC to
anaplastic carcinoma.1,11-13
Study Design: Illustrative case report and literature review.
Methods: A 17 year-old woman with incidentally identified papillary thyroid
carcinoma following total thyroidectomy for Graves’ disease experienced rapidly
progressive metastatic disease prior to adjuvant therapy. The literature
pertaining to Graves’ disease and its effect on the incidence and outcomes of
thyroid carcinoma is reviewed, and the potential role of thyroid stimulating
immunoglobulin (TSI) as a thyroid cancer growth factor is discussed.
Results: Total thyroidectomy was notable for oncocytic variant of papillary
thyroid carcinoma without extrathyroidal spread or lymphovascular invasion.
Post-operatively the patient’s TSH was suppressed but TSI remained elevated.
Within four months’ time and before adjuvant radioactive iodine ablation could
be delivered, the patient was clinically and radiographically identified with
diffusely enlarged lateral and central compartment cervical lymphadenopathy,
which was not present preoperatively. Neck dissection yielded 16 positive
nodes in multiple levels and the patient was treated with adjuvant radioactive
iodine. She remains disease-free at 12 months follow-up.
Conclusions: The effect of Graves’ disease in the incidence and outcomes of
well-differentiated thyroid carcinoma remains controversial. Clinicians should
consider thyroid stimulating immunoglobulin as a potential thyroid cancer
growth factor.
INTRODUCTION
Graves’ disease is an autoimmune thyroid disorder in which thyroid stimulating
antibodies (TSI, thyroid stimulating immunoglobulin) bind to and stimulate the
thyroid-stimulating hormone (TSH) receptor causing the phenotypic
hyperthyroidism and resultant characteristic sequelae. Since Filetti and
colleagues1 implicated TSI in the promotion of thyroid cancer development over
20 years ago, debate has continued whether these autoantibodies influence the
frequency and intensify the aggressiveness of thyroid cancer in Graves’
disease. Proponents of this theory generally advocate a molecular basis similar
to the method by which TSH stimulates the growth and function of differentiated
thyroid carcinoma via TSH receptor activation.2
Patient with Graves’ goiter and incidentally-found papillary thyroid
cancer following total thyroidectomy. She developed diffuse and
rapidly growing cervical nodal metastases despite appropriate TSH
suppression, suggesting TSI as a possible tumor growth factor.
Two case control studies support the assertion that Graves’ disease is associated
with increased aggressiveness in WDTC. Belfiore and colleagues14 compared 13
patients with thyroid cancer and Graves’ disease with 137 euthyroid controls.
Despite having similar sized nodules and fewer cases of follicular thyroid cancer
(23.1 versus 37.2 percent), patients with Graves’ disease had statistically significant
greater rates of multicentric histology and distant metastases, and a trend towards
increased frequency of extrathyroidal invasion and nodal metastases. Patients with
Graves’ also had greater rates of redo lymphadenectomy and recurrent and
persistent disease. Two of the 13 Graves’ patients also had clinically evident rapid
growth of metastatic lymphadenopathy within 5 months following total
thyroidectomy. Pellegriti and colleagues15 compared 21 non-occult WDTC in
patients with Graves’ disease with 70 euthyroid controls matched for sex, age,
tumor size, and histology. Graves’ patients showed higher rates of distant
metastases (28.6 vs. 8.5 percent) and persistent disease and cancer-related death
(23.8 vs. 2.9 percent).
Indirect evidence suggests that TSI may promote tumor pathogenesis via
stimulation of the TSH receptor. Malignant thyroid nodules retain TSH receptor
expression16 and tumor metastases can take up I-131 in the presence of TSI even
with suppressed TSH.17 Serum IgG from patients with Graves’ disease increases
intracellular cAMP levels in human follicular thyroid carcinoma cells in vitro and
stimulates DNA synthesis in rat thyroid follicular cells.1 While the half-life of
circulating IgG is typically 7-23 days, TSI may persist years after total
thyroidecotmy.14,18 The rapid recurrence of metastatic thyroid carcinoma years after
total thyroidectomy can occur concomitantly with the development of clinically
evident Graves’ disease, suggesting a non-TSH alterative mechanism of cancer
stimulation.1,13,19
While several studies have examined the prevalence and existence of
aggressive features of differentiated thyroid cancer in Graves’ disease at the
time of cancer treatment, a limited number of case reports have correlated
delayed progression or recurrence of thyroid cancer following total
thyroidectomy. We present a case of an incidental papillary thyroid cancer
identified after total thyroidectomy for Graves’ disease that resulted in diffuse
and rapidly growing metastatic disease months after treatment.
Despite these findings, several studies have found no evidence of increased tumor
aggressiveness in Graves’ disease patients. A multicenter case series of 557
patients with Graves’ disease examined 21 cases of WDTC.20 The authors identified
high rates of nodules, but no aggressive findings on histology or clinical course. A
case control study by Hales and colleagues21 compared 16 patients with Graves’
and WDTC with 110 euthyroid age and sex matched controls. While the Graves
group had statistically significant smaller tumors (0.9 cm vs. 2.3 cm), there were no
differences in invasion, multicentricity on histology, distant metastases, or deaths. A
second case control study by Yano and colleagues22 compared 154 patients with
Graves’ disease and papillary thyroid cancer treated surgically with 176 euthyroid
controls matched for age and tumor size. They found no differences in multicentric
histology, lymph node metastases, or distant metastases. Additionally, among the
group with Graves’ disease, there was no association between levels of TSI and
multifocal histology or lymph node metastases.
CASE PRESENTATION
CONCLUSIONS
A 17-year-old woman presented with a several month history of an enlarging
anterior neck mass associated with a clinical history and laboratory values
consistent with Graves’ disease without ophthalmopathy. Thyroid ultrasound
revealed a massive hypervascular goiter without evidence of nodularity or
cervical lymphadenopathy. The patient was initially managed with methimazole
but developed alternating hypo- and hyperthyroidism that was difficult to control.
Total thyroidectomy was performed September 2008 for symptom control in lieu
of radioactive iodine (I-131) ablation therapy given the massive size of the
goiter. Final pathology was notable for extensive papillary thyroid carcinoma,
oncocytic variant, with negative surgical margins and no lymphovascular
invasion. She was placed on levothyroxine replacement pending I-131 ablation
therapy. The patient remained asymptomatic in the post-operative period.
A routine clinic examination performed December 2008 prior to I-131 ablation
revealed palpable cervical lymphadenopathy. A neck ultrasound and MRI were
notable for new and extensive abnormal-appearing lymphadenopathy within the
central neck and left lateral neck levels II, III, and IV. Laboratory values found
the patient to have suppressed TSH but elevated TSI; serum TSH was 0.03
mIU/L (normal 0.4 to 4.0), free thyroxine was 15 pmol/L (normal 9-24),
thyroglobulin was 55 ng/mL (normal <34) without thyroglobulin antibodies, and
TSI was 299% of normal (normal <125).
One week later the patient underwent a central and left selective neck
dissection encompassing levels II-VI. Final pathology revealed metastatic
papillary thyroid cancer in 16 of 86 lymph nodes, encompassing levels II, III, IV,
and VI, all without evidence of extranodal invasion. The patient ultimately
underwent I-131 therapy with 159 mCi in June 2009; delays occurred because
of patient compliance issues. She has been followed closely since that time
and is clinically and radiographically free of disease with an undetectable
thyroglobulin, although her TSI remains elevated at 297% of normal.
Enlarged goiter in patient with Graves’ disease. Final pathology
revealed extensive papillary thyroid carcinoma, oncocytic variant,
with negative margins and no lymphovascular invasion.
The TSI found in Graves’ disease are immunoglobulins of the IgG1 subclass that
bind to and stimulate the TSH receptor causing the trademark hyperthyroid
clinical findings.3 In 1988, Filetti and colleagues1 first hypothesized that TSI may
behave as a promoter in the pathogenesis of thyroid cancer after demonstrating
in vitro that tumor adenylate cyclase activity responded to serum IgG
preparations from patients with Graves’ disease.
In support of Filetti’s theory, there appears to be an increased incidence of both
thyroid nodules and thyroid cancer among patients with Graves’ disease. 5,6 The
overall incidence of thyroid carcinoma in Graves’ disease is reported to range
from 0 to 9.8%, while that of the general population ranges from 0.5 to 10 per
100,000 in epidemiologic studies and 4.5 to 356 per 1,000 in autopsy
examinations.5
Whether thyroid cancer in Graves’ disease behaves more aggressively remains
controversial. Well-differentiated thyroid carcinoma (WDTC) is a generally
indolent disease, with 30-year cancer-specific mortality rates for papillary and
follicular thyroid cancers without metastases at presentation approximating 6 and
10 percent, respectively.7 Only about 10 percent of differentiated thyroid
carcinomas develop distant metastases or critical invasion of extrathyroidal
structures and cause death.5
We describe the clinical course of a 17 year-old patient with Graves’ disease and
incidentally identified papillary thyroid cancer who experienced markedly aggressive
tumor growth and rapid development of diffuse nodal metastases atypical for welldifferentiated thyroid cancer. While a number of studies have implicated an
increased incidence of thyroid cancer among patients with Graves’ disease, the
evidence that Graves’ disease causes aggressive tumor behavior remains
controversial. Physicians should be aware of the increased risk of malignancy and
be cognizant of the possibility of increased tumor aggressiveness when evaluating,
treating, and monitoring this patient population.
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