Incidentally Detected Metachronous Malignancy in Patients of Papillary Carcinoma of Thyroid Posthigh-Dose Radioiodine Therapy

Abstract

Thyroid cancer is one of the most common endocrine cancers. The most common histological subtypes are papillary and follicular variants; these are “differentiated thyroid cancers” and are associated with an excellent prognosis. The exact mechanism of thyroid cancer is not known. Several genetic alterations and environmental factors are found to be associated with this cancer. Patients with differentiated thyroid cancer are treated with postoperative radioactive iodine (RAI) therapy to ablate residual thyroid tissue and metastatic micro-foci. It is thought that after RAI, there is an increased risk of secondary malignancies such as lung, renal, and stomach cancer and lymphomas. However, the risk of secondary malignancy is not clear. They may be associated with genetic syndromes, environmental factors, and radiation exposure. The secondary malignancy may be detected incidentally during follow-up or present with signs and symptoms of that malignancy. There is no direct association between second malignancy and radiation exposure in I-131 therapies. We present a case series of five patients treated with high doses of I-131 for the remnant. The patients developed metachronous malignancies later in life.

Introduction

Thyroid carcinoma is one of the most common malignancies of the endocrine system.[1] The majority belongs to well-differentiated thyroid cancers (papillary carcinoma of the thyroid, follicular cancer, etc.) and are relatively indolent, with a 20-year survival rate of 95%. These are related to long-term survival in a significant number of patients. Therapy options for differentiated thyroid cancer (DTC) have long consisted of total thyroidectomy, levothyroxine suppression therapy, and radioiodine I-131 therapy (RIT). RIT has been proven safe and effective therapy in the short term. However, any radiation exposure increases the stochastic probability of malignancy; owing to its radioactive nature and high biological half-life, it has been contemplated that I-131 exposure might lead to a higher risk for the occurrence of a second malignancy. Numerous cancers are thought to be induced by radiation exposure, based on epidemiologic studies involving environmental, medical, and occupational exposures.[2,3,4,5]

There is no unanimity in the literature regarding the second malignancy after I-131 therapy. A recent large-size study by Kim et al. enrolling 52,103 thyroid cancer patients who have received I-131 therapy showed a statistically significant rise in secondary cancer. These patients had a latent period ranging from months to years from radiation exposure to the development of malignancy. In general second primary malignancies are usually. However, there is also an increased incidence of salivary, kidney, breast, prostate, melanoma, non-Hodgkin lymphoma, leukemia, multiple myeloma, and brain cancer.[6]

However, an epidemiological study done by Piciu et al. stated that patients treated with I-131 therapy for thyroid cancers had no correlation with radioiodine's low and medium activities and the development of the second malignancy. They followed 1990 patients diagnosed with differentiated thyroid carcinoma (DTC) treated with thyroidectomy and adjuvant radioiodine therapy for a median surveillance duration of 182 months (range, 120–516 months). The mean radiation dose from I-131 was 63.2 mCi (2338 MBq), with a range of 30 mCi (1111 MBq) to 90 mCi (3330 MBq).[7]

During the long term, follow-up patients treated with I-131 may present with other primary malignancies. Findings reported in previous studies have confirmed that there are risks of second primary malignancy (SPM) related to radiation dose, age, and latency.[8] There is a lack of evidence and significant bias in demonstrating this relationship.[9] It is hypothesized that the increased risk of SPM may be related to a genetic predisposition or treatment-related complication.

The increased risk of SPM in papillary thyroid cancer (PTC) has been reported in several cancer registries and epidemiologic studies.[10,11,12,13] It is hypothesized that the increased risk of SPM may be related to a genetic predisposition or treatment-related complication. Radioactive iodine therapy (RAI), common adjuvant therapy for the management of PTC, typically the following surgery, has been a target of debate due to side effects such as sialadenitis, taste loss, and, most critically, SPM.

We followed more than 2500 patients registered under the nuclear medicine department from 1992 to 2022. We reviewed the departmental data retrospectively, and five patients were found to develop a SPM.

Patients particulars and history

A 66-year-old female with a history of anterior neck swelling was diagnosed with papillary carcinoma of thyroid. She underwent total thyroidectomy and was treated with 100 mCi of I-131 in October 2014. The patient was on regular follow-up and on tablet thyronorm 175 mcg. After 4 years, in 2018, she developed a lump in the right breast with nipple retraction and was diagnosed with infiltrating ductal carcinoma (IDC) subsequently on tru-cut biopsy of the right breast lump. She underwent breast conservation surgery in April 2018 and was ER/PR+ve and HER2nu−ve on histochemistry [Figure 1].

Figure 1:

(a) I-131 scan showing no abnormal uptake, (b) F¹⁸ FDG PET/CT MIP showing abnormal uptake in the neck region, (c and d) Fused PET/CT images showing F18 FDG avid supra-mediastinal mass (metastasis from Ca right breast) and CT images showing soft tissue density mass, respectively. FDG PET/CT: Fluorodeoxyglucose positron emission tomography/computed tomography, MIP: Maximum intensity projection image

A 60-year-old female presented with neck swelling and was diagnosed with papillary carcinoma thyroid. She underwent a total thyroidectomy in 2007. She was treated with 40 mCi of I131 in 2008. The patient was on follow-up with 100 mcg of thyronorm and presented with left breast swelling in January 2022. Fine-needle aspiration cytology (FNAC) (January 11, 2022). She underwent left modified radical mastectomy, HPE-IDC [Figure 2].

Figure 2:

(a) I-131 scan showing no abnormal uptake, (b) F¹⁸ FDG PET/CT MIP showing abnormal uptake in the left axilla, (c and d) Fused PET/CT images showing F18 FDG avid left axillary mass (residual disease) and CT images showing soft tissue density lesion, respectively. FDG PET/CT: Fluorodeoxyglucose positron emission tomography/computed tomography, MIP: Maximum intensity projection image

A 52-year-old male presented with left neck swelling. He underwent left hemithyroidectomy. HPE-PCT (tall-cell variant). Completion thyroidectomy was done on May 15, 2015. 50 mCi of I-131 was given orally under supervision on July 23, 2015. The patient was advised suppression with 175 mcg of thyronorm and presented with a headache in September 2021. Contrast Enhance MRI- showed solid cystic extra-axial lesion in left temporal lobe which shows post contrast enhancement in solid component suggestive of meningioma Grade I [Figure 3].

Figure 3:

(a) I-131 scan showing no abnormal uptake, (b) F¹⁸ FDG PET/CT MIP showing increased uptake in the brain, (c and d) Fused PET/CT and CT images showing F18 FDG avid lesion soft tissue lesion in the left frontal lobe. FDG PET/CT: Fluorodeoxyglucose positron emission tomography/computed tomography, MIP: Maximum intensity projection image

A 48‐year‐old female patient presented with anterior neck swelling for the past 2 years. She underwent total thyroidectomy with left paratracheal dissection in October 2020. histopathological examination (HPE)‐ suggestive of multifocal PCT. She was treated with 100 mCi of I‐131 on December 28, 2020. Susequently she complained of breast swelling in April 2022. Mammography – left breast – an irregular high‐density mass with partly speculated and partly indistinct margins measuring 28 × 26 × 30 mm is seen in the upper outer quadrant in the middle third of the left breast. Intralesional fine pleomorphic and linear calcifications were also noted. Core biopsy and immunohistochemistry (IHC) – suggestive of IDC Grade II, ER/PR‐Her‐2‐neu: 3 + Ki67 35%–40%. She underwent left breast conservation surgery on May 30, 2022, HPE [Figure 4].

Figure 4:

(a) I-131 scan showing no abnormal uptake, (b) F¹⁸ FDG PET/CT MIP showing abnormal uptake in the upper quadrant of the left breast, (c and d) Fused PET/CT images showing F18 FDG avid lesion in the left breast and CT images showing soft tissue density lesion, respectively. FDG PET/CT: Fluorodeoxyglucose positron emission tomography/computed tomography, MIP: Maximum intensity projection image

A 41-year female presented with anterior neck swelling, diagnosed with papillary carcinoma thyroid. She underwent total thyroidectomy, followed by subsequent radioiodine therapy with 70 mCi of Iodine-131. The patient achieved remission and remained disease-free for 3 years when she developed right neck swelling and dyspnea. Computed tomography revealed severe left pleural effusion left lung mass in October 2019. FNAC from the right cervical swelling and cytopathology of the pleural fluid showed the presence of malignant cells. Biopsy of the cervical lymph node revealed metastatic adenocarcinoma with CK7 and TTF1 positive, and CK20 and thyroglobulin are negative. Mutation for epidermal growth factor receptor was positive. Diagnosis of carcinoma lung was established by combining radiological, histopathology, and IHC finding [Figure 5].

Figure 5:

(a) I-131 scan showing no abnormal uptake, (b) F¹⁸ FDG PET/CT MIP showing extensive metastasis and mediastinal lesions, (c and d) Fused PET/CT images showing F18 FDG avid left pleural thickening and CT images showing left pleural effusion. FDG PET/CT: Fluorodeoxyglucose positron emission tomography/computed tomography, MIP: Maximum intensity projection image

Discussion

Of five patients who developed a SPM in our study, three patients developed breast carcinoma, one patient developed lung cancer, and one developed meningioma. The old studies state that overall hematological malignancies are one of the most common malignancies. All five patients in our study developed solid malignancy, and none developed hematological malignancy. The average I-131 dose to the patient is 72 mCi ranging from 40 mCi to 100 mCi. There is no minimum and maximum amount of radiation that causes second malignancy.

There was an increased incidence of SPM among patients diagnosed with PTC at a younger age. Radiation therapy, including RAI, is known to increase the risk of SPM, especially bone cancer, kidney cancer, hematologic malignancies, and prostate cancer, in multiple studies. This maybe because RAI accumulates in the bone marrow and is excreted through the kidneys. The salivary gland and breast express Na⁺/I⁻ symporter, which promotes selective uptake of RAI.[14,15,16]

Even though the overall incidence rate was lower, patients who did not undergo any RAI still had an increased incidence of SPM. This may be due to the genetic susceptibility of thyroid cancer patients. Studies suggest that the telomerase reverse transcriptase mutation and germline mutations of folliculin are associated with kidney cancer and PTC.[17,18] Mutations of CHEK2 are also associated with an increased risk of kidney, thyroid, prostate, and breast cancers.[19,20,21] In this study, 60% of patients developed breast carcinoma out of the SPM. It maybe due to more uptake of I-131 in the breast due to NaI symporter leading to more radiation exposure to the breast tissue. However, a dose of radiation to the patient does not correlate with developing a second malignancy. This incidence of cancers maybe due to genetic mutations like CHEK 2 inhibitors.

The recent advances in genomic diagnostics may enable tailoring screening strategies for patients with primary thyroid cancer for further risk of SPM. It is demonstrated decreased incidence of colorectal cancer in thyroid cancer survivors who did not undergo radiation therapy. There is evidence that a higher thyroid hormone level induces cell differentiation and mitigates tumor formation in colorectal cancer stem cells.[22] Since thyroid cancer survivors tend to be on TSH suppression therapy, they typically have higher thyroid hormone levels than their counterparts; this may unexpectedly lead to decreased incidence of colorectal cancer.

Thyroid carcinoma are more common in young patients with overalll good prognosis. The carcinogenic risk associated with the therapeutic administration of radioiodine needs to be quantified. Some organs are of particular concern because radioiodine is actively concentrated in the tissue (e.g., the salivary glands) or because they are the therapeutic route of administration (e.g., the digestive tract). Three factors on which radiation dose is delivered to healthy tissue depend on the administered activity, the uptake by the tissue, and the length of time that the isotope resides in the target tissue. Compared with the general population reference rates, an excess of 20%–90% of second cancer incidence after thyroid carcinoma has been observed in most large cohort studies.[23] An excess of second cancer in survivors of first cancer might result from detection and surveillance bias, shared genetic or environmental risk factors, or first cancer treatment.

Conclusion

Few instances of metachronous malignancy are noted after I-131 therapy. A study indicated that high radioiodine activity during thyroid carcinoma treatment probably increases the risk of future leukemia, salivary gland, digestive tract cancer, soft tissue, and bone sarcomas. However, no definitive association is noted. Nevertheless, we did not know the exact shape of the relationship between the activity administered and the risk of second cancer. We did not even know that metachronous malignancy is due to I-131 therapy or genetic mutation with syndromic involvement. Therefore, according to our study, although the risk of malignancy due to I-131 therapy is very low or I-131 therapy is very safe, we should plan radioiodine treatment very judicially and smartly by considering each factor. The risk–benefit ratio should be thoroughly considered before treatment.

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.