INTRODUCTION
Distant metastases are a leading cause of differentiated thyroid cancer (DTC)-related morbidity and death.[1 - 4
Approximately a third of DTC patients with radioactive iodine (RAI)-avid bone metastasis can achieve a complete bone metastasis response with RAI treatment alone or in combination with bone metastatic focal treatment.[5
The formation of premetastatic lesions acts as a platform for circulating tumor cells to colonize and form metastasis.[6
Is it possible that the radioiodine is concentrated by the micrometastases, even before their expansion into overt metastases?
My hypothesis is based on my experience with a patient of differentiated cancer thyroid who had presented to me for further management that I share below. She was found to have skeletal metastasis on a three mCi diagnostic Iodine-131 whole body scan with single photon emission computed tomography-computed tomography (SPECT-CT).
CASE REPORT
A 33-year-old female patient, a case of differentiated cancer thyroid, who underwent right hemithyroidectomy followed by completion thyroidectomy. She was diagnosed to have follicular variant of papillary thyroid carcinoma with focal capsular invasion on histopathology.
Her stimulated antithyroglobulin antibodies were elevated. Iodine-131 whole-body scan dated September 18, 2021, revealed a significant uptake in the neck (star artifact noted) [Figure 1a ]. There were tracer avid lesions involving the skull (multiple lesions), L3 and L5 vertebrae, left superior pubic ramus, and left ilium. However, there were no corresponding sclerotic/lytic lesions on the SPECT-CT images [Figure 1b -d ].
Figure 1: (a) Iodine-131 whole-body scan dated September 18, 2021, reveals a star artifact in the neck and hot spots involving skull, lumbar region, and pelvis. (b) Iodine-131 SPECT-CT images of lumbar region acquired with the diagnostic iodine-131 whole-body scan reveal hot spots (tracer avid metastatic lesions) corresponding to body of L3 and L5 vertebrae with no corresponding sclerotic or lytic lesion. (c) Iodine-131 SPECT-CT images of the head and neck acquired with the diagnostic iodine-131 whole-body scan reveal tracer avid skeletal metastasis involving the skull with no corresponding sclerotic/lytic lesion. (d) Iodine-131 SPECT-CT images of pelvis acquired with the diagnostic iodine-131 whole-body scan reveal tracer avid skeletal metastasis involving the left pubis with no corresponding sclerotic/lytic lesion. SPECT-CT: Single-photon emission computed tomography-computed tomography
The patient was treated with a high-dose radioiodine therapy (175 mCi). A dose of 200–250 mCi RAI therapy is indicated in patients with skeletal metastasis. However, a lower dose of 175 mCi RAI therapy was administered in view of the star artifact (due to the significant residual functioning thyroid tissue) to prevent radiation thyroiditis. The posttherapy scan confirmed the findings of the pretherapy diagnostic iodine-131 whole-body scan, and there was a new lesion seen involving a right-sided rib [Figures 2a and b ].
Figure 2: (a and b) Iodine-131 whole-body posttherapy scan dated October 8, 2021.It reveals tracer avid lesions corresponding to the lesions seen in pretherapy iodine-131 scan dated Sept ’21. A new lesion is seen involving right-sided rib, confirmed on SPECT-CT images. SPECT-CT: Single-photon emission computed tomography-computed tomography
The patient was followed up after 6 months. This time, the diagnostic iodine-131 whole-body scan dated April 07, 2022, did not reveal any tracer avid functioning thyroid tissue. There was no tracer avid metastasis detected [Figure 3 ].
Figure 3: Iodine-131 whole-body scan dated April 6, 2022, approximately 6 months posthigh-dose radioiodine therapy reveals no tracer avid lesion
Her stimulated Serum Thyroglobulin levels were 2.26 ng/ml in the absence of elevated antithyroglobulin antibodies (dated April 4, 2022). These were repeated from another laboratory, and her stimulated S. Thyroglobulin levels were found to be 1.48 ng/ml in the absence of elevated antithyroglobulin antibodies (dated April 6, 2022).
The patient underwent a whole-body fluorodeoxyglucose positron emission tomography-CT scan to rule out “dedifferentiation,” and it did not reveal any tracer avid lesion. There is no significant metabolically active disease in the body [Figure 4a -c ]. Thus, the patient was confirmed to be cured of thyroid cancer.
Figure 4: (a-c) Whole-body FDG PET scan dated April 7, 2022, reveals no tracer avid lesion in the neck/elsewhere in the body. There is no significant metabolically active disease in the body. FDG: Fluorodeoxyglucose, PET: Positron emission tomography
The patient has been advised yearly follow-up investigations for the next 3 years.
DISCUSSION
Metastasis to the bone is facilitated by the fenestrated structure of the bone marrow sinusoid capillaries, high blood flow in the areas of red marrow, and adhesive molecules on tumor cells that bind to the bone marrow stromal cells such as osteoblasts and osteoclasts as well as bone metastasis.[7 , 8
Bone homeostasis is maintained by the balanced production of osteoblasts and osteoclasts. Disruption of this balance can convert normal niche to metastatic niches. Niches in the bone marrow can be newly induced as a result of tumor-secreted factors or they can be adapted from pre-existing physiological niches such as stem cell niches. Interaction between activated stromal cells and other cells in the premetastatic niche enables the survival of tumor cells. As a next step, micrometastasis is formed by the recruitment of metastatic tumor cells into premetastatic niche. Bone micrometastasis can stay in a stem-like, dormant state before expansion into overt macrometastatic lesions.[9
Occult asymptomatic bone metastasis or early bone metastasis that is visible on a diagnostic iodine-131 whole-body scan, but not on cross-sectional imaging has not been investigated in structured studies with large numbers.
Of the 178 patients studied in a retrospective study from France, 145 were treated with RAI and 46 achieved a complete response to treatment. Of these 46 patients, 56% had bone metastasis without any structural abnormality on cross-sectional imaging.[5
In light of this molecular mechanism of bone metastasis, what the iodine-131 whole-body scans pick up without any sclerotic or lytic lesion on CT scan, is probably the micrometastasis or dormant metastatic cells in the premetastatic niche. Irradiation of these sites by the locally deposited radioiodine kills the metastatic tumor cells in the premetastatic niche. As overt metastases are not formed, we do not see a sclerotic/lytic component on the CT images.
There is no evidence for better efficacy in terms of overall survival of a dosimetric approach compared with an empirical approach for determining the treatment activity for DTC patients with distant metastasis.
In view of the above, can we downsize the empirical radioiodine-therapy dosage in these patients and thus reduce the radiation burden to the patients?
CONCLUSION
We need to study further the category of patients with bone metastasis (and no other organ metastasis) from DTC, but no corresponding sclerotic/lytic lesions on cross-sectional imaging and follow them up for a few years after a complete response to therapy to rule out recurrence. These could be labeled as patients with early bone metastasis. They could form a separate category of patients with a lower indicated radioiodine dosage (rather than the 200–250 mCi RAI therapy dosage required in bone metastasis).
Personalized dosimetric studies have to be carried out on these patients to standardize the RAI therapy dosage for a fixed empirical dose approach.
In this way, the radiation burden to the patient and the nuclear medicine team involved can be reduced further.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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