<div>Title: Spectrum of Thyroid Disease in a Single Patient: A Case of
Papillary Thyroid Carcinoma in a Patient with Graves Disease and
Hashimoto’s thyroiditis</div><div>Authors: Pooja Patel, DO (email:
poojaapatel15@gmail.com,
Institution: Rutgers University New Jersey Medical School, Department of
Internal Medicine), Janna Prater, MD
(praterja@einstein.edu,
Institution: Einstein Medical Center, Department of Endocrinology),
Zubair Baloch, MD
(baloch@pennmedicine.upenn.edu,
Institution: University of Pennsylvania, Department of Pathology), Jane
V Mayrin, MD (mayrinja@einstein.edu, Institution: Einstein Medical
Center, Department of Endocrinology)</div><div>Data Availability Statement: N/A</div><div>Funding Statement: N/A</div><div>Conflict of Interest: The authors declare that there is no conflict of
interest to be reported.</div><div>Ethics Approval Statement: This study did not include any experiments on
animals or human subjects.</div><div>Patient Consent Statement: Written informed consent was obtained from
the patient to publish this case report.</div><div>Permission to Reproduce Material From Other Sources: N/A</div><div>Clinical Trial Registration: N/A</div><div>Abstract:</div><div>A 65-year-old male with history of Hashimoto’s thyroiditis on
Levothyroxine developed Graves’ disease with ocular symptoms and was
treated with teprotumumab without improvement. Total thyroidectomy was
performed to control hyperthyroidism. Surgical pathology revealed
multifocal papillary thyroid carcinoma. Rarely a spectrum of thyroid
disorders is seen in a single patient.</div><div>Introduction</div><div>Hashimoto’s thyroiditis and Graves’ disease are the most common
autoimmune thyroid disorders. Hashimoto’s thyroiditis is the most common
type of primary hypothyroidism and Graves’ disease is the most common
type of primary hyperthyroidism. The conversion of hyperthyroidism to
hypothyroidism has been reported, but the conversion of hypothyroidism
to hyperthyroidism has been considered a rare phenomenon. [1] In
addition, studies have associated Hashimoto’s thyroiditis with an
increased risk of developing papillary thyroid carcinoma. [2] In
this case report, we present at 65-year-old male who was incidentally
discovered to have papillary thyroid carcinoma following conversion of
Hashimoto’s thyroiditis to Graves’ disease. This case highlights a rare
instance of a single patient presenting with the full spectrum of
thyroid disease: Hashimoto’s thyroiditis, Graves’ disease, and papillary
thyroid carcinoma.</div><div>Case Presentation</div><div>A 65-year-old Caucasian male with past medical history of Hashimoto’s
thyroiditis and GERD presented to the endocrinology office for
evaluation of hyperthyroidism. The patient presented with symptoms of
binocular diplopia (L&gt;R), proptosis, ocular dryness and
erythema. The patient’s main concern was regarding difficulty driving
due to his ocular symptoms. On physical exam, the patient had a
normal-sized thyroid, without palpable nodules and no evidence of bruit
or thrill. Eye exam revealed bilateral proptosis (left greater that
right), conjunctival erythema, limitation of lateral gaze bilaterally,
and lower lid retraction bilaterally. He reported that the diagnosis of
Hashimoto’s thyroiditis was made one year prior and he was started on
thyroid hormone replacement with levothyroxine 150 mcg at that time. The
patient denied any family history of thyroid disorders and any prior
tobacco use. He admitted to rare alcohol consumption.</div><div>The patient was found to have biochemical evidence of hyperthyroidism
including thyroid stimulating hormone (TSH) suppression with a value of
0.03 mIU/L (normal range: 0.5 – 5 mIU/L) and free thyroid hormone (FT4)
value of 1.0 ng/dL (normal range: 0.7-1.9 ng/dL). Due to the findings of
TSH suppression, the patient underwent a taper of levothyroxine 150 mcg
over a period of seven months. After levothyroxine was discontinued, he
remained both clinically and biochemically hyperthyroid. Repeat thyroid
workup revealed TSH &lt;0.01 mIU/L, FT4 0.7, thyroid stimulating
immunoglobulin (TSI) of 349 % (Normal Range: &lt;130%
baseline). Thyroid US revealed a 0.7 cm mixed nodule in the right upper
lobe, 0.7 cm mixed hyperechoic nodule in the right middle lobe and 0.5
cm hyperechoic nodule in the left middle lobe. Based on the presence of
ocular symptoms, physical exam findings, suppressed TSH, and elevated
TSI levels, the diagnosis of Graves’ disease was made. The patient was
started on methimazole 10 mg daily. The dose of methimazole was
decreased over the next few months to 2.5 mg daily to achieve and
maintain biochemical euthyroidism.</div><div>Due to significant diplopia and proptosis, the patient was deemed to be
a good candidate for teprotumumab. However, despite completing seven out
of eight cycles of therapy, he reported no resolution of his visual
symptoms. He was not deemed to be a candidate for radioactive iodine
therapy given his active eye disease. Total thyroidectomy was advised as
a permanent option to control of his hyperthyroidism and with the
expectation that decreasing TSI would lead to improvement of his visual
symptoms in the future or allow him to undergo surgical correction of
his orbitopathy. Final surgical pathology following thyroidectomy
revealed multifocal papillary thyroid carcinoma involving both lobes of
the thyroid and isthmus. Surgical pathology of the thyroid gland
revealed thyroid follicular microcarcinoma (Figures 1 and 2), thyroid
follicular hyperplasia and lymphocytic infiltrates (Figures 3 and 4).
The patient was started on levothyroxine following his thyroidectomy and
remains euthyroid since then.</div><div>Discussion</div><div>Hashimoto’s thyroiditis is the most common type of autoimmune thyroid
disease and type of primary hypothyroidism. Hashimoto’s thyroiditis is
diagnosed with clinical and biochemical evidence of a hypothyroid state.
Diagnosis includes elevated TSH, low FT4, positive autoimmune antibodies
including anti-thyroperoxidase and anti-thyroglobulin antibodies. In
Hashimoto’s thyroiditis, there is lymphocytic infiltration of thyroid
follicular cells, often resulting in fibrosis of the thyroid. [1]
Females are disproportionately more affected than males. [2] There
are certain genetic and environmental factors that increase one’s risk
of developing Hashimoto’s thyroiditis. There is an increased association
among gene loci and Hashimoto’s including HLA-DR3, HLA-DR4, and HLA-DQ.
[3] In addition, excessive iodine intake has been associated with
increased risk of Hashimoto’s thyroiditis. [4] Patients with
Hashimoto’s thyroiditis typically present with a constellation of
symptoms including fatigue, dry skin, constipation, cold intolerance,
weight gain, goiter, and neck pain. [5] Patients are typically
treated with levothyroxine to establish a euthyroid state. [5] In
our case, the patient was diagnosed with Hashimoto’s thyroiditis and
treated with a full weight- based dose of levothyroxine 150 mcg for one
year. He developed clinical and biochemical evidence of hyperthyroidism
and presented to the endocrinology office for further care.</div><div>Graves’ Disease is the most common type of hyperthyroidism, commonly
affecting individuals 30-50 years of age. Similarly to Hashimoto’s
thyroiditis, females are disproportionately more affected by Graves’
disease than males. [6] Graves’ disease is diagnosed with clinical
and biochemical evidence of a hyperthyroid state, such as low to
suppressed TSH, high FT4 and autoimmune antibodies including thyroid
stimulating immunoglobulins (TSIs). There has been a proposed
association between low iodine intake and Graves’ disease. [4] In
Graves’ disease, the immune system produces thyroid stimulating
immunoglobulins that cause the thyroid to produce excessive thyroid
hormone. The clinical manifestations of Graves’ disease vary from person
to person and depend on the severity of the disease. Common symptoms
include weight loss, palpitations, dyspnea, tremor, fatigue, heat
intolerance, and hair loss. Graves’ disease can also manifest with
ocular symptoms including lid lag, lid retraction, diplopia, periorbital
edema, and scleral injection. [6] Graves’ disease can be complicated
by severe ophthalmopathy including corneal breakdown and optic
neuropathy. [7] In our case, the patient presented with symptoms of
severe ophthalmopathy including bilateral proptosis (L&gt;R),
diplopia, erythema and dryness. Graves’ disease can be managed with
anti-thyroid drugs, surgical resection or radioactive iodine therapy.
Anti-thyroid medications include methimazole, carbimazole and
propylthiouracil, which inhibit thyroid hormone production. Radioactive
iodine has also been widely utilized to treat patients with Graves’
disease, but has the adverse side effect profile of worsening Graves’
ophthalmopathy. [8] In this case, the patient was diagnosed with
Graves’ disease due to presence of orbitopathy, suppressed TSH and
positive TSIs. The patient achieved biochemical control of his
hyperthyroidism with methimazole 2.5 mg. Afterwards, total thyroidectomy
was performed to alleviate his ocular symptoms and to enable permanent
control of his hyperthyroidism. Radioactive iodine treatment was not
recommended to prevent worsening ophthalmopathy.</div><div>There have been reported cases of conversion of hyperthyroidism to
hypothyroidism, which seem to be more exceedingly common than the
converse as seen in our patient. [9] The conversion of
hypothyroidism to hyperthyroidism has been considered a rare phenomenon,
but there are an increasing number of cases reported. [9-11] The
exact mechanism of conversion of hypothyroidism to hyperthyroidism is
still under investigation, but there are a few theories that have been
postulated. One theory suggests that an imbalance of thyroid stimulating
and blocking antibodies may contribute to the thyroid state and
subsequent conversion. [12] Another theory suggests that in
genetically susceptible individuals, an environmental trigger may play a
role in conversion from hypothyroidism to hyperthyroidism. [11] In
this case, it is unclear what triggered the conversion of Hashimoto’s
thyroiditis to Graves’ disease. An imbalance of autoimmune thyroid
antibodies may have contributed to the conversion and corresponding
ocular thyrotoxicosis symptoms. Our patient’s conversion from
hypothyroidism to hyperthyroidism within 1 year is the shortest time
interval of conversion reported in current literature. [13]</div><div>In patients with Hashimoto’s thyroiditis, there is a rare cause of a
transient hyperthyroid state, called Hashitoxicosis. Hashitoxicosis
precedes the signs and symptoms of the hypothyroid state associated with
Hashimoto’s thyroiditis and lasts a few weeks to months. It occurs as a
result of the biochemical release of preformed thyroid hormone due to
autoimmune destruction of the thyroid. Patients may present with
biochemical laboratory results and clinical symptoms consistent with a
hyperthyroid state that mimics Grave’s disease. [14] While this
unique phenomenon is a cause of hyperthyroidism, it is an unlikely cause
of the hyperthyroid state in our patient. The patient presented with
biochemical and clinical evidence of hyperthyroidism following his
hypothyroid state. Additionally, the patient’s hyperthyroid state lasted
greater than one year, longer than the typical transient hyperthyroid
phase of Hashitoxicosis. While Hashitoxicosis was on the differential
diagnosis for our patient, it was ultimately ruled out due to time frame
of the patient’s hyperthyroid state.</div><div>Papillary thyroid carcinoma is the most common type of thyroid
malignancy, representing 70-80% of all diagnosed thyroid cancers.
[15] There is some controversy whether there is a relationship
between Hashimoto’s thyroiditis and development of papillary thyroid
carcinoma. Prior research studies suggest that Hashimoto’s thyroiditis
is associated with an increased risk of developing papillary thyroid
carcinoma. [16, 17] A meta-analysis that evaluated
histopathologically proven papillary thyroid carcinoma provides evidence
to suggest that there is a strong association between Hashimoto’s
thyroiditis and papillary thyroid carcinoma compared to other benign
thyroid conditions and thyroid cancers. <sup>[</sup>18] Other
studies found no evidence to support the relationship between
Hashimoto’s thyroiditis and papillary thyroid carcinoma. [19] There
are a few different hypotheses regarding the pathogenesis from
Hashimoto’s thyroiditis to papillary thyroid carcinoma. One hypothesis
suggests that in Hashimoto’s thyroiditis, the chronic inflammatory state
and lymphocytic infiltration results in damage, promoting pathogenesis
of papillary thyroid carcinoma. [20] Another hypothesis suggests
that in Hashimoto’s, the elevated TSH levels stimulate follicular
epithelial cell proliferation and increase the likelihood of malignant
transformation to papillary thyroid carcinoma. [21] A study
investigating biopsy proven co-existing papillary thyroid carcinoma and
Hashimoto’s thyroiditis demonstrated associations including a higher
female predominance, multifocal involvement of the thyroid, no
involvement of extrathyroidal structures, and no lymph node metastasis.
[18]In this case, surgical pathology following total thyroidectomy
revealed papillary thyroid carcinoma with multifocal involvement of the
thyroid gland involving both thyroid lobes and isthmus. The patient
underwent total thyroidectomy for permanent control of hyperthyroidism
and the finding of thyroid malignancy was incidental. Hashimoto’s
thyroiditis may have contributed to an increased risk of developing
papillary thyroid carcinoma. In addition, the patient demonstrated
multifocal involvement of the cancer, no extrathyroidal cancer
involvement, and no lymph node metastasis, consistent with prior
research studies regarding the association of Hashimoto’s thyroiditis
and papillary thyroid carcinoma. Furthermore, Graves’ disease with
thyroid nodular lesions has also been associated with an increased risk
of developing papillary thyroid carcinoma. In this case, thyroid US
demonstrated nodular lesions in the right upper and middle lobes and
left middle lobe of the thyroid. The combination of nodular thyroid
lesions and Graves’ disease may have also increased the patient’s risk
of subsequent development of papillary thyroid carcinoma.</div><div>This case report highlights the need for a high index of suspicion for
Graves’ disease if a patient with a known diagnosis of Hashimoto’s
thyroiditis is presenting with thyrotoxic symptoms, regardless of the
time interval elapsed from initial diagnosis. This patient presented
with symptoms of ocular thyrotoxicosis only one year following treatment
with levothyroxine. This represents the shortest reported time interval
in current literature regarding transformation from hypothyroidism to
hyperthyroidism. In addition, this patient was incidentally diagnosed
with papillary thyroid carcinoma following thyroidectomy, which provides
further evidence to suggest papillary thyroid carcinoma is associated
with Hashimoto’s thyroiditis and Graves’ disease. This case depicts the
unique spectrum of thyroid disease in a single patient: conversion of
hypothyroidism to hyperthyroidism and presence of papillary thyroid
carcinoma, all in the same gland. Future studies investigating this
distinct conversion can provide further insight into the association
between autoimmune thyroid disease and thyroid malignancy</div><div>References:</div><div>1. Ahmed R, A.-S.S., and Akhtar M., <i>Hashimoto’s thyroiditis: a
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303-308.</div><div>21. McLeoid DS, W.K., Carpenter AD, et al., <i>Thyrotropin and
thyroid cancer diagnosis: a systematic review and dose response
meta-analysis.</i> Journal of Clinical Endocrinological Metabolism, 2012.<b>97</b> : p. 2682-2692.</div><div>Author List: Pooja Patel, DO (email:
poojaapatel15@gmail.com,
Institution: Rutgers University New Jersey Medical School, Department of
Internal Medicine), Janna Prater, MD
(praterja@einstein.edu,
Institution: Einstein Medical Center, Department of Endocrinology),
Zubair Baloch, MD
(baloch@pennmedicine.upenn.edu,
Institution: University of Pennsylvania, Department of Pathology), Jane
V Mayrin, MD (mayrinja@einstein.edu, Institution: Einstein Medical
Center, Department of Endocrinology)</div><div>Author Contributions: PP drafted and prepared the original manuscript.
JM and JP obtained patient data and revised manuscript for important
intellectual content from an endocrinology perspective. ZB provided
insight from a histopathological perspective and revised the manuscript
for important intellectual content from a pathology perspective. PP, JM
and JP contributed equally to literature review and revising manuscript
drafts. All authors approved of the final submission and have made
significant contributions to the manuscript.</div><div>Acknowledgements: We would like to acknowledge Lisa, M. Price, MSLIS,
for editorial consulting.</div><div>Conflict of Interest Statement: The authors declare no conflict of
interest.</div>