Abstract
Summary
We report the case of a male patient with papillary thyroid cancer, familial thoracic aortic aneurysm and dissection, and a variation in the MYH11 gene. Because of considerable tumor bulk in the neck that was not resectable, the patient underwent partial resection at age 14 years. Since then, the patient has received only suppressive thyroid hormone therapy. He is now 71 years old, which is 57 years after the initial resection. The patient received care at our institution from July 2009 to August 2019, during which we documented the stability of multiple calcified masses in the neck. Follow-up examinations at another institution from September 2019 to April 2023 also confirmed the stability of the masses. The underlying cause of this unusually long indolent course of the disease is unclear. Whether extensive tumor calcifications or the MYH11 sequence variation contributed to the disease course is also uncertain.
Learning points
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Papillary thyroid cancer with neck metastases may, in some cases, be stable and remain asymptomatic for decades.
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If locoregional stability of papillary thyroid cancer is documented for many years, observation may be preferable to extensive neck surgery in selected cases.
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This is the first report of an MYH11 gene alteration and thoracic aortic aneurysm in a patient with papillary thyroid cancer with indolent neck metastases.
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Future studies of MYH11 gene alterations in thyroid carcinoma are needed.
Background
We report the case of a patient with partially unresectable papillary thyroid cancer that has been treated with only suppressive thyroid hormone therapy for the past 57 years. Multiple calcified masses have persisted without growth in the neck, and the patient has remained asymptomatic. Our findings of a rare indolent course of papillary thyroid cancer suggest that if a prolonged history of stable papillary thyroid masses is documented, aggressive surgical procedures with possible adverse effects and other acute measures may be avoided. To our knowledge, this is the first case report of familial thoracic aortic aneurysm and an MYH11 variation in a patient with papillary thyroid cancer. MYH11 alterations have been reported in other malignant neoplasms; therefore, additional studies on MYH11 alterations and thyroid cancer are warranted.
Case presentation
We report the case of a male patient with marfanoid habitus, familial thoracic aortic aneurysm and dissection, and a sequence variation in the gene encoding myosin heavy chain 11 (MYH11). The patient underwent surgical resection of papillary thyroid cancer at age 14 years in 1966 at another institution. The neck tumor was only partially resectable, yet he has remained asymptomatic with only suppressive thyroid hormone therapy, despite persistent neck metastases. We followed the patient at our institution from July 2009 to August 2019. Follow-up examinations at another institution from September 2019 to April 2023 confirmed a lack of thyroid cancer-related symptoms and evidence of stable disease in imaging studies.
We also performed a systematic review of English language reports on papillary thyroid cancer and its potential association with MYH11 alterations. We searched the following databases for relevant articles: EBM Reviews – Cochrane Central Register of Controlled Trials (April 2023); EBM Reviews – Cochrane Database of Systematic Reviews (2005 to May 23, 2023); Embase (1974 to May 23, 2023); and Ovid MEDLINE® and Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations, Daily and Versions (1946 to May 23, 2023).
The patient was first seen at our institution in July 2009 for evaluation of marfanoid habitus and ascending thoracic aortic aneurysm. He was then referred to endocrinology for evaluation of papillary thyroid cancer. We reviewed his surgical report from 1966, which indicated that the right and left thyroid lobes had firm masses. Extrathyroidal extensions had adhered to the trachea, and only incomplete excision of the right and left thyroid lobes and excision of a pretracheal lymph node were possible. Histopathologic analysis of frozen sections of the resected tissue indicated papillary thyroid cancer. The slides containing the pathologic specimens were discarded and were therefore unavailable for review by our pathologist. The patient was treated with and had continued suppressive thyroid hormone therapy (thyroid extract) for 44 years and had remained asymptomatic for many decades. No further interventions were performed, and radioiodine therapy was not given. Computed tomography (CT) of the neck and chest in 1986 at another institution showed no metastatic thyroid cancer outside of the neck.
Investigation
His first physical examination at our institution indicated physical signs of marfanoid habitus (e.g. tall features and a reduced ratio of the upper to lower body), thyroidectomy scar, and a palpable firm lump in the left lateral neck that was approximately 2.5 cm. While on thyroid extract treatment, his serum thyrotropin level was 0.01 mIU/L, and his serum free thyroxine level was 1.8 ng/dL, which is indicative of excessive thyroid hormone therapy. The results of a thyroglobulin antibody test were negative, and his serum thyroglobulin level was 2.4 ng/mL. Chest CT did not show abnormalities other than ascending thoracic aortic aneurysm. Neck CT showed multiple calcified masses (Fig. 1). Ultrasonography of the thyroid showed multiple lesions in the neck with calcifications. The largest mass in the left thyroid bed was 1.7 cm, and a metastasis in a left lateral lymph node was 2.6 cm in the longest diameter (Fig. 2). We performed fine-needle aspiration biopsy on the lesions in the left thyroid bed and left upper neck, and the pathologic characteristics were consistent with classic papillary thyroid cancer metastases in the left lateral lymph node and recurrent or persistent thyroid cancer in the left thyroid bed (Fig. 3).
Calcified masses in the bilateral thyroid beds. Representative computed tomographic image of the patient 43 years after partial resection is shown. Arrows indicate bilateral calcified papillary thyroid masses.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 1; 10.1530/EDM-23-0088
Ultrasonography of primary thyroid mass and lymph node metastasis. (A) Sagittal image of the left thyroid bed depicting a 1.7 cm mass with calcifications. Arrows indicate prominent shadowing of calcifications within the mass. (B) Sagittal image of a 2.6 cm metastasis in the left neck lymph node with small calcifications. Arrows indicate small nonshadowing calcifications in the lymph node metastasis.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 1; 10.1530/EDM-23-0088
Cytologic characteristics of papillary thyroid cancer lymph node metastasis. Representative photomicrographs of Papanicolaou staining of cytologic smears obtained from fine-needle aspiration biopsy are shown. Group of epithelial cells with enlarged oval nuclei with longitudinal grooves (A) and scattered cytoplasmic intranuclear pseudoinclusions (B, arrow) are evident in a background of lymphocytes.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 1; 10.1530/EDM-23-0088
Genetic consultation for evaluation of thoracic aortic aneurysm and marfanoid habitus was provided. Although some physical signs of a connective tissue disorder were evident, his symptoms did not qualify for diagnosis of classic Marfan syndrome according to the Ghent criteria (1). Subsequent genetic testing for Marfan syndrome (FBN1 and ACTA2) was negative (2), but a sequence variation in the MYH11 gene was suggestive of familial thoracic aortic aneurysm and dissection (3, 4). However, no family history of aortic aneurysm was reported, and first-degree relatives were not available for genetic testing.
Treatment
Observation was suggested during consultation with a head and neck surgeon. Treatment with suppressive thyroxine therapy was continued.
Outcome and follow-up
The patient was followed annually with laboratory tests and ultrasonography, magnetic resonance imaging, and CT of the neck, which indicated no notable changes in the neck lesions. Treatment was switched to levothyroxine suppressive therapy in December 2009. To date, he has remained without thyroid cancer–related symptoms. His last neck ultrasonography assessment at our institution was in 2019 and did not show any progression of the neck lesions from those imaged in August 2009. While under suppressive levothyroxine therapy, his serum thyroglobulin levels were stable (2.2–3.4 ng/mL), thyrotropin level was 0.05 mIU/L, and free thyroxine level was 1.3 ng/dL. During follow-up telephone calls on February 15, 2023, and April 23, 2023, he reported no symptoms from thyroid cancer or any neck discomfort. Ultrasonography of the neck at another institution in 2021 showed no changes in the neck lesions from those in previous images. The patient has remained on the same dose of levothyroxine, and his self-assessment indicated good health at the age of 71 years.
Discussion
Our patient with partially resectable, partially calcified papillary thyroid cancer has had stability of neck metastases and residual thyroid lesions for more than 57 years. Indolent papillary thyroid cancer is common, and 90% of T1aN0M0 papillary thyroid cancers remain stable for more than 10 years of follow-up (5). However, the papillary thyroid cancer in our case differs from typical indolent subclinical thyroid cancers because it was first detected at age 14 years and had extrathyroidal neck metastases and incomplete resection at diagnosis.
Children and adolescents with papillary thyroid cancer usually have excellent survival rates (6). Hay et al. (6) reported findings from a long-term follow-up study (median: 29 years) of 215 patients with papillary thyroid cancer who were 21 years or younger (range: 3–21 years) from 1940 through 2008. The cause-specific mortality rate at age 40 years was only 2%, although 5% of these patients had incomplete resection, 78% had neck lymph node metastases, and 6% had distant metastases (6).
Whether calcification affects the behavior of differentiated thyroid cancer is unknown. Psammomatous calcification may be associated with multifocality and development of neck lymph node metastases (7, 8). Because we did not have the original tissue to evaluate and cytologic assessment was performed only in 2009, whether the coarse calcification of the masses in our case was related to psammoma bodies is unclear. However, the ultrasonographic characteristics of calcification were not typical for psammomatous calcification (9), and no psammoma bodies were noted in the cytologic analysis.
Progression rates of only 5–10% have been reported for patients with asymptomatic papillary microcarcinoma who undergo nonsurgical observation (10, 11, 12). Moreover, some studies have reported that extensive calcification and poor vascularity were strongly correlated with nonprogressive disease in such patients (10, 11). A 10-year active surveillance study reported a 13% progression rate for low-risk T1aN0M0 papillary thyroid cancer (12). In that study, the pattern of calcification did not positively or negatively correlate with progression (12). Another active surveillance study of low-risk T1bN0M0 papillary thyroid cancer showed that high vascularity and weak calcification were associated with a high risk of tumor progression (13). However, others have suggested that thyroid papillary microcarcinomas with ultrasonography-positive calcification have a higher rate of lymph node metastasis (14). The lesions in our patient had low vascularity and dense, coarse calcification. Whether this anatomic pattern explains the long indolent history of the papillary thyroid cancer remains unclear.
The potential association of this unusual course of papillary thyroid cancer with the MYH11 variation is also of interest. In our extensive review, no reports of MYH11 alterations in thyroid cancer were evident, although an association between an MYH9 variation and thyroid cancer aggressiveness was reported (15). MYH11 alterations are reportedly associated with aggressiveness of multiple other malignant neoplasms (16), but we did not identify any studies reporting such an association for follicular cell–derived thyroid cancer. We did identify one case report of a 47-year-old patient with Marfan syndrome who had an aggressive villous-type variant of papillary cancer (17). Two cases of treatment-associated acute myelogenous leukemia with MYH11 variations were also reported after treatment of thyroid cancer with radiotherapy (18) and low-dose radioactive iodine (19). Development of treatment-associated acute myelogenous leukemia with MYH11 alterations after cancer-directed therapies is a known phenomenon (18).
We describe an unusual case of papillary thyroid cancer in a patient with marfanoid habitus, familial thoracic aortic aneurysm and dissection, and an MYH11 variation. His thyroid cancer was initially treated with partial resection, which has remained asymptomatic with persistent calcified metastases for 57 years. The stability of these neck lesions has been documented for 14 years. Whether extensive calcification and low vascularity are markers of such a prolonged indolent course of papillary thyroid cancer is uncertain. Whether the MYH11 sequence variation contributed to this unusual indolent course is also unclear. Future studies of MYH11 alterations in thyroid cancer are needed.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the case study reported.
Funding
This research was funded by a research grant donated by the benefactor Mr D. Goff.
Patient consent
Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient.
Author contribution statement
VF wrote and organized the manuscript. AAS helped with interpretation of pathologic findings and selection of pathologic imaging, in addition to modification and editing of the manuscript. RAL performed the fine-needle aspiration biopsy and interpreted the neck ultrasonography findings. All authors participated in manuscript preparation.
Acknowledgements
Nisha Badders, PhD, ELS, Mayo Clinic, substantively edited the manuscript and provided helpful suggestions. The Scientific Publications staff at Mayo Clinic provided proofreading and administrative and clerical support.
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