Abstract
Summary
A 60-year-old woman presented to our clinic with an acute onset 3 months history of right ankle pain. The patient had a history of poorly differentiated thyroid cancer, which was treated with total thyroidectomy, left lateral neck dissection levels II–V and central neck dissection levels VI–VII followed by postoperative I-131 radioactive iodine (131I) ablation therapy 3.7 GBq 6 months ago. The post-131I WBS showed residual iodine-avid thyroid tissue with no other iodine-avid disease or metastasis. SPECT/CT of the neck and chest showed nonavid bilateral pulmonary nodules, discrete nodal masses in mediastinum and nonavid bone lesions. FDG-PET CT scan showed FDG-avid mediastinal lymph nodes (LN), innumerable non-FDG-avid subcentimetric pulmonary nodules and few FDG-avid lytic lesions in the skeleton. X-ray and MRI of the right ankle showed a well-marginated lytic lesion in the posterior body of calcaneus and 5 × 6 cm soft tissue mass lesion, respectively. The histopathology of the calcaneus mass confirmed a positive immunostaining for thyroid origin which includes thyroglobulin and TTF-1 with PAX-8. Endobronchial mediastinal and bronchial LN biopsy confirmed thyroid cancer metastasis. Gene mutation showed HRAS and GNA13 with a high tumor mutational burden. We describe a rare case of poorly differentiated thyroid cancer in a patient who presented with right ankle pain; we confirmed the cause to be a calcaneus metastasis from the thyroid cancer, with calcaneus being an extremely rare site for bone metastases. Gene mutations points toward treatment with immune checkpoint inhibitors.
Learning points
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Poorly differentiated thyroid carcinoma (PDTC) usually metastasizes to lung and bone but can rarely occur in the calcaneus.
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Patients with distant metastases have significantly worse long-term prognosis.
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Radiotherapy is effective in reducing the metastatic pains as well as reducing the size of the metastasis.
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PAX-8 staining can be used to differentiate thyroid carcinomas from lung adenocarcinomas.
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The importance of searching for gene mutations to decide the treatment of PDTC.
Background
Thyroid cancer is the most common endocrine malignancy, with the majority of cancer being differentiated thyroid cancers (DTC), including papillary thyroid cancer carcinoma (PTC), follicular thyroid carcinoma (FTC) and Hürthle cell cancer (1). Poorly differentiated thyroid cancer (PDTC) accounts for 3–15% of all thyroid carcinomas, and it is an individual form of thyroid carcinoma derived from follicular epithelial cells, ranking between DTC and anaplastic thyroid cancer (ATC) regarding the degree of differentiation and clinical behavior (1).
Bone metastasis occurs in 4–5 % of all thyroid cancers, with PDTC having worse 10-year overall survival reaching 15 % compared to 27% in DTC (2). Bone metastasis occurs mainly to the axial skeleton, especially the spine and the pelvis in thyroid cancer as cancer cells easily reach the red marrow of these bone segments due to high blood flow and drainage of the neck region by Batson’s vertebral venous plexus (3).
To the best of our knowledge, there are no previous reported cases of PDTC metastasizing to the calcaneus.
We report a case of PDTC with bone metastasis to the calcaneus which is an extremely rare site for bone metastases.
Case presentation
A 60-year-old woman presented to our clinic with an acute-onset 3-month history of right ankle pain. The patient had a history of poorly differentiated thyroid cancer that was treated with total thyroidectomy, left lateral neck dissection levels II–V and central neck dissection levels VI–VII, followed by postoperative I-131 radioactive iodine (131I) ablation therapy 3.7 GBq 6 months ago.
The post-131I WBS showed residual iodine-avid thyroid tissue with no other iodine-avid disease or metastasis. SPECT/CT of the neck and chest showed nonavid bilateral pulmonary nodules, discrete nodal masses in mediastinum and nonavid bone lesions. FDG-PET CT scan showed FDG-avid mediastinal lymph nodes, innumerable non-FDG-avid subcentimetric pulmonary nodules and few FDG-avid lytic lesions in the skeleton.
X-ray and MRI of the right ankle showed a well-marginated lytic lesion in the posterior body of calcaneus and 5 × 6 cm soft tissue mass lesion, respectively.
Investigation
Investigations: X-ray of the right ankle showed a well-marginated lytic lesion in the posterior body of calcaneus and MRI of the right ankle revealed an expansile 5 × 6 cm soft tissue mass lesion in the posterior calcaneus with altered signal intensity (Figs. 1 and 2A andB).
X-ray of the right ankle. Well-marginated lytic lesion in the posterior body of calcaneus – likely metastatic. No fracture seen on the X-ray. No dislocations seen. Ankle joint is normal.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 4; 10.1530/EDM-23-0103
MRI of the ankle. (A) SAG T2 STIR – an expansile lesion in the posterior calcaneus with altered signal intensity and associated marrow edema in the rest of the calcaneus bone. (B) Axial T1 – lesion 5 × 6 cm appears hypointense and shows homogeneous postcontrast enhancement. Findings are in keeping with an aggressive bone lesion, with provided clinical information likely suggesting a metastatic deposit.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 4; 10.1530/EDM-23-0103
Off thyroxine, TSH was 66 mIU/L, FT4 2.7 pmol/L, Tg >500 µg/L and Tg antibodies 29 IU/mL (n < 115). On thyroxine suppression, TSH was 0.01 mIU/L, FT4 23 pmol/L and Tg >500 µg/L.
The 131I WBS post the first iodine ablation dose showed iodine-avid residual thyroid tissue in the neck with no avid distant metastasis. SPECT/CT showed bilateral pulmonary nodules and discrete nodal masses in mediastinum, which did not show any iodine avidity (Fig. 3).
WBS 1-131 and SPECT/CT post therapy dose. Posttherapy iodine-131 whole-body scan; anterior and posterior planar images show intense iodine-avid residual thyroid tissue in the neck. No other site of iodine-avid metastases is seen.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 4; 10.1530/EDM-23-0103
FDG-PET CT scan done for further evaluation showed FDG-avid mediastinal lymph nodes (LN), innumerable non-FDG-avid subcentimetric pulmonary nodules and few foci of metabolic activity overlying lytic lesions in the skeleton (Fig. 4A, B and C).
FDG-PET CT scan. (A) Showing multiple FDG-avid mediastinal lymph nodes. (B) FDG-avid osteolytic skeletal metastases. (C) Tiny FDG-negative bilateral lung nodules.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 4; 10.1530/EDM-23-0103
The histopathology of the calcaneus mass confirmed a positive immunostains for thyroid origin which includes thyroglobulin and thyroid transcription factor 1 (TTF-1) with PAX-8 were positive (Fig. 5A, B, C and D).
Histopathology. (A) H&E stain (20×) showing metastatic thyroid carcinoma. The follicular cells organized in trabecular pattern with scattered microfollicles containing scanty colloid material (arrows show the follicles). (B) IHC: Tumoral cells show strong and diffuse nuclear staining for TTF-1. (C) IHC: Tumoral cells show strong and diffuse nuclear staining for PAX-8. (D) IHC: Tumoral cells show strong and diffuse cytoplasmic staining for thyroglobulin.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 4; 10.1530/EDM-23-0103
An endobronchial ultrasound bronchoscopy (EBUS) was utilized to visualize the LN stations, which showed multiple large mediastinal LN, right lower paratracheal LN (4R), a large subcarinal LN station 7 and large right hilar (11R) LN. The left hilar station (11L) was also visualized and was enlarged. Cytology confirmed thyroid cancer metastasis with tumor cells that are diffuse and strongly positive for TTF-1 and CK-7 and thyroglobulin (patchy).
Gene mutation was positive for HRAS and GNA13 with a high tumor mutational burden (10.83 mut/Mb).
Treatment
Thyroxine suppression was continued.
After a Multi-Disciplinary Team (MDT) discussion, and based on symptom assessment, she was planned for palliative radiotherapy to treat the painful right heel and L4 lumbar metastases. The lesion on the posterior end of L4 vertebral body was causing mass effect over cauda equina anteriorly. She was CT simulated in supine position and planned on VMAT to keep the bowel dose at a minimum. She received 20 Gy in five-session radiotherapy to the L4 lumbar spine. Upon receiving the biopsy confirmation of right calcaneus bone lesion, she was planned for palliative 3D conformal radiotherapy. To avoid the left foot from parallel-opposed lateral fields, her right foot was elevated and fixed on an extremity board along with an immobilization thermoplastic mask. She received 21 Gy in three sessions. Her course during radiation remained uneventful and pain reduced significantly (Fig. 6).
Planning and dosimetry data of lumbar L4 (A and B, respectively) and right foot (C and D, respectively). Note the immobilization setup of right foot.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 4; 10.1530/EDM-23-0103
In addition, she is taking monthly intravenous bisphosphonate, i.e. zoledronic acid.
As she has progressive disease with multiple sites of non-iodine-avid distant metastases, we plan to treat her with pembrolizumab as the patient has been confirmed to have a high tumor mutational burden for HRAS.
Outcome and follow-up
During the follow-up of the patient after she received radiotherapy and monthly intravenous bisphosphonate, i.e. zoledronic acid, the right ankle pain disappeared and we planned to treat her with pembrolizumab.
Discussion
This is the first reported case of poorly differentiated thyroid carcinoma metastasis to the calcaneus to our knowledge. PDTC is a rare but clinically highly significant entity as it accounts for a relatively high number of deaths related to thyroid carcinoma (1). Distant metastasis occurs mainly in the lungs and bones and ranges between 36% and 85% (4).
Bone metastasis occurs mainly to the axial skeleton, especially the spine and the pelvis in thyroid cancer (5). There is only one reported case of follicular thyroid cancer metastasizing to the calcaneus 12 years post total thyroidectomy and radioactive iodine treatment (2). The lesion was lytic lesion similar to that of our patient. Immunostaining of the patient with metastatic follicular cancer showed cytokeratin, cytokeratin 7, and thyroglobulin, while the lesion in our patient showed positive immunostaining for thyroglobulin, TTF-1 and PAX-8. Therefore, bone metastasis in DTC and PDTC may occur in unusual places.
Poorly differentiated thyroid cancer has a 10-year overall survival of 15% compared to 40% in other thyroid cancers, making it more aggressive than DTC (5). Early detection of bone metastasis and prevention of skeletal related events (SRE) such as spine fracture are important in improving patient’s quality of life. Patients with bone metastasis can benefit from bone irradiation. External beam radiotherapy (EBRT) is used to locally control the disease and to reduce the incidence of local recurrence with no impact on overall survival, representing a valuable treatment tool in unresectable, incompletely resected tumors and in locoregional recurrence (3). It can similarly benefit bone metastasis with the additional benefit of pain reduction (6).
Our patient has undergone EBRT for her metastatic bone lesion in the L4 lumbar spine and right calcaneus lesions for tumor size reduction and pain relief.
Bisphosphonate therapy is the current standard of care for preventing SRE, including pain, in patients with bone metastasis by inhibiting osteoclast-mediated bone resorption; bisphosphonate therapy also has antitumor effects (7). Treatment with bisphosphonates in patients with thyroid bone metastasis may improve quality of life and SRE (7). The patient was also started on zoledronic acid monthly as a treatment for bone metastasis.
Immunohistochemistry increases the accuracy of diagnosis of tumor by narrowing the differential diagnoses (1). There is no specific immunohistochemical marker for the detection of PDTC yet, but PDTC is immunoreactive for TTF-1, PAX-8 and cytokeratin, confirming that it originates from follicular epithelial cells (1). In addition, the negative expression of calcitonin, chromogranin and carcinoembryonic antigen excludes neuroendocrine tumors, medullary thyroid carcinoma (1). In our patient, the pathology from calcaneus mass was positive for PAX-8 and TTF-1, confirming the diagnosis of metastatic thyroid cancer.
Aggressive thyroid cancer and PDTC may show mutations in tyrosine kinase receptors (RET), in components of the MAPK/PI3K signaling pathway (RAS and BRAF) or chromosomal rearrangements (RET/PTC and NTRK hybrids) allowing TKI treatments to be part of therapeutic options in such tumors (8). The most frequent molecular alteration in PDTC is BRAF mutations which occur in 81% of cases and BRAFV600E mutation occurs in 33% of patients. VGEF overexpression is prevalent in 37% of patients, while RAS mutations occur in 28% of patients. Mutations in the genes in PI3K/AKT/mTOR pathway occur in 11% of patients, while mutations in TP53 occurs in 8–35% of patients (9). Sorafenib and lenvatinib have been approved for radioactive iodine-resistant DTC in patients with RET, c-KIT, VEGFR 1-3 and PDGFR (9). These approved drugs do not require the existence of specific mutation in order to be administered to patients.
As the post 131I WBS showed non-iodine-avid metastatic thyroid cancer, the gene mutation was performed to decide on trial of TKI treatment. Her gene mutation confirmed HRAS and GNA13 mutations with a high tumor mutational burden 10.83 Mut/Mb, which points toward treatment with the immune checkpoint inhibitor pembrolizumab instead of TKI. GNA13 is upregulated in many solid tumors and impacts survival and metastases in these patients.
In one cohort study, pembrolizumab demonstrated durable antitumor activity in a small subset of patients with advanced thyroid cancer (10). In addition, adding pembrolizumab to lenvatinib therapy in patients progressing on lenvatinib therapy can have a favorable outcome. We will consider a trial of pembrolizumab in our patient.
In conclusion, we report a rare case of PTDC with bone metastasis to an unusual location the calcaneus. Treatment with EBRT and bisphosphonates can help to reduce the disease and pain. Immune checkpoint inhibitors should be considered in this patient as she has non-iodine-avid metastatic thyroid cancer, with positive gene HRAS and GNA13 mutations with a high tumor mutational burden (10.83 mut/Mb).
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 did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Written informed consent for publication of the clinical details and clinical images was obtained from the patient’s son.
Author contribution statement
OE and ABK were involved in management of the patient. AJ treated the patient with radioactive iodine. SB provided the images of the patient. YR reported the histopathology of calcaneus mass. SFH treated the patient with radiotherapy. OE and ABK were involved in the literature review and writing of the manuscript.
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