Radioactive iodine (131-I RAI) has been used in the treatment of thyroid cancer to eliminate residual thyroid tissue after thyroidectomy and to treat metastatic disease. RAI ablation decreases tumor recurrence, development of distant metastases, and cancer death. Leukemia is a rare complication following exposure to ionizing radiation, and there are very few case reports documenting the occurrence of acute myeloid leukemia (AML), subsequent to RAI therapy.[1,2,3,4,5,6,7,8] In the initial reports, almost all the cases have occurred after a cumulative dosage of more than 800 mCi, in patients more than 50 years of age and with intervals between the dosage of RAI <12 months.[9,10] Here, we present a rare case of AML secondary to RAI therapy.
A 52-year-old female who had complained of fever, headache, fatigue, weight loss, abdominal distention, and pallor, presented to her local physician where on routine investigations, she was found to have severe anemia and thrombocytopenia. In view of her low blood counts, she received a blood transfusion there. The symptoms subsided only to reappear again after 2 months for which she was again transfused with packed red blood cells and platelets. After the reappearance of symptoms despite repeated blood transfusions, she was referred to our institute where on detailed past history she was found to have undergone total thyroidectomy 11 years back in 2011 for FTC. A postoperative RAI uptake scan at that time showed thyroid bed remnant with lymph nodal and skeletal uptake for which she was given RAI therapy. She had received eight cycles of RAI therapy (200 mCi each) for 4 years from 2012 to 2016 making a cumulative RAI dose of 1600 mCi. Following this, she also received palliative RT for L4 spinal metastasis. Her current hematological investigations revealed pancytopenia with a hemoglobin level of 60 g/L, mean corpuscular volume of 98 fL, corrected reticulocyte count of 0.8%, leukocyte count of 1.7 × 109/L, and platelet count of 10 × 109/L. His peripheral smear examination revealed pancytopenia with 8% intermediate-size myeloid blasts showing scant to moderate, sparsely granular cytoplasm without any Auer rods, round nuclear outline, fine chromatin, and one to two nucleoli. Dysplastic (pseudo-Pelger-Huet) neutrophils were also evident. Her routine blood investigations were thus, suggestive of myelodysplastic syndrome (MDS). Subsequently, bone marrow aspiration smears revealed a marked hypercellularity with dysplastic trilineage hematopoiesis and 35% myeloid blasts. Stained tissue sections from bone marrow trephine biopsy revealed a hypercellular marrow for age (average cellularity; 80%) with increased reticulin fibrosis (MF grade 2, World Health Organization [WHO]) and the presence of an increased population of myeloid blasts arranged in loose interstitial clusters and sheets (>50% of marrow nucleated cells) admixed with loosely clustered dysplastic early erythroid progenitors, and presence of dysplastic megakaryocytes (5–6/high power field) showing abnormal nuclear chromatin and small-cell morphology. On immunohistochemistry, the blasts were strongly and diffusely positive for CD 34, CD 117, Human Leukocyte Antigen – DR isotype, and weakly positive for myeloperoxidase, thus confirming the diagnosis of AML with myelodysplasia-related changes (WHO category II) as per the 2017 revised WHO classification (Figure 1a-d). This case highlights the importance of periodic hematological investigations and routine follow-up of patients undergoing RAI therapy, especially who are above 45 years of age as bone marrow recovery is reported to be delayed in the elderly age group.
Leukemia as a second malignancy after treatment of thyroid cancer is rare and was first reported in 1955. Transient leukopenia and thrombocytopenia were observed after RAI administration. Bone marrow recovery after RAI treatment is delayed after 45 years of age.[11,12] Bone marrow suppression after RAI treatment is divided into four grades according to the WHO classification. The fourth grade is bone marrow aplasia and AML. The majority of the cases of leukemia documented in the literature are of acute leukemia, both myeloid and lymphoid,[1,2,3,4,5,6,7,8] followed by chronic myeloid leukemia and rarely chronic lymphocytic leukemia.[13,14,15,16,17] The overall incidence of acute leukemia following RAI therapy, however, is low as documented by Menzel etal. and Chow. Chow in his cohort of 1348 patients did not observe any case of acute leukemia after a mean dose of 3.4 GBq (91.8 mCi) in papillary thyroid carcinoma and 4.14 GBq (111.89 mCi) in FTC. Similarly, de Vathaire etal. in their study followed 1497 patients receiving an average of 7.2 GBq (194.59 mCi) of RAI but found no instances of leukemia. A German cohort studied 107 patients with thyroid carcinoma with bone metastasis. In that study, four patients developed AML. These patients received the maximum dose of RAI (11.1 GBq) within a very short interval and showed high uptake in bone metastasis.
It has been observed that leukemias following RAI therapy usually occur after cumulative doses higher than 800 mCi[6,8] although there have been cases of acute leukemia developing after a dosage of 150 mCi and as low as 22.1 mCi. The exact etiopathogenesis is not well-understood although its clastogenic effects and induction of chromosomal aberration, specifically of chromosome 17, are well documented in the literature.[21,22] It is believed that 131I at any dose could cause sublethal damage to the bone marrow, and individual susceptibility plays an important role in patients developing leukemia after 131I treatment. Thus, it is recommended that the bone marrow should not receive a total dose which exceeding 1000 mCi, and there should be an interval of at least 1 year between the doses. Furthermore, it is important to follow-up with the patient with routine hematological investigations regularly, to early diagnose and treat the disease.
The use of 131I appears to be increasing even for nonmalignant thyroid diseases and its benefits in the treatment of hyperthyroidism and thyroid cancer are proven but these patients require a regular follow-up even after completing the therapy. Although the development of the secondary malignancies can be due to aging or other causes rather than 131I exposure, there is sufficient evidence suggesting the role of RAI therapy in leukemogenesis. Thus, strict follow-up is recommended in such patients, for early detection of MDSs, leukemias, or other hematological disorders.
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 initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
1. Blom PS, Querido A, Leeksma CH. Acute leukaemia following x-ray and radioiodine treatment of thyroid carcinoma Br J Radiol. 1955;28:165–6
2. Alsaud A, Mohamed S, Yassin MA, Ashour A, Obeidat K, Azrieh B. Acute myeloid leukemia after low-dose radioiodine therapy for papillary thyroid carcinoma Case Rep Oncol. 2020;13:207–11
3. Oluwasanjo A, Pathak R, Ukaigwe A, Alese O. Therapy-related acute myeloid leukemia following radioactive iodine treatment for thyroid cancer Cancer Causes Control. 2016;27:143–6
4. Jeong JH, Ahn JY, Park SH, Park MJ, Kim KH, Hong JS. A case of therapy-related acute myeloid leukemia with inv(16)(p13.1q22) after single low-dose iodine-131 treatment for thyroid cancer Korean J Hematol. 2012;47:225–8
5. Roldán Schilling V, Fernández Abellán P, Domínguez Escribano JR, Rivas González C, Mut Barberá E, Calatayud Cendra R. Acute leukemias after treatment with radioiodine for thyroid cancer Haematologica. 1998;83:767–8
6. Richards EM, Marcus RE. Acute promyelocytic leukaemia following radioiodine therapy Clin Lab Haematol. 1993;15:55–8
7. Grudeva-Popova J, Yaneva M, Zisov K, Ananoshtev N. Therapy-related acute promyelocytic leukemia after treatment with radioiodine for thyroid cancer: Case report with literature review J BUON. 2007;12:129–32
8. Laurenti L, Salutari P, Sica S, Piccirillo N, Zini G, Zollino M, et al Acute myeloid leukemia after iodine-131 treatment for thyroid disorders Ann Hematol. 1998;76:271–2
9. Edmonds CJ, Smith T. The long-term hazards of the treatment of thyroid cancer with radioiodine Br J Radiol. 1986;59:45–51
10. Brincker H, Hansen HS, Andersen AP. Induction of leukemia by 131-I treatment of thyroid carcinoma Br J Cancer. 1973;28:232–7
11. Alexander C, Bader JB, Schaefer A, Finke C, Kirsch CM. Intermediate and long-term side effects of high-dose radioiodine therapy for thyroid carcinoma J Nucl Med. 1998;39:1551–4
12. Menzel C, Grünwald F, Schomburg A, Palmedo H, Bender H, Späth G, et al “High-dose” radioiodine therapy in advanced differentiated thyroid carcinoma J Nucl Med. 1996;37:1496–503
13. Walgraeve D, Verhoef G, Stul M, Cassiman JJ, Mecucci C, Van den Berghe H, et al Chronic myelogenous leukemia after treatment with 131-I for thyroid carcinoma. Report of a case and review of the literature Cancer Genet Cytogenet. 1991;55:217–24
14. Shimon I, Kneller A, Olchovsky D. Chronic myeloid leukaemia following 131-I treatment for thyroid carcinoma: A report of two cases and review of the literature Clin Endocrinol (Oxf). 1995;43:651–4
15. Alfiar F, Amato D, Lipton JH. Chronic myeloid leukemia in a woman with papillary carcinoma of the thyroid treated with radioactive iodine Leuk Lymphoma. 1997;27:365–7
16. Pavithran K, Doval DC. Chronic myeloid leukemia in a man with papillary carcinoma of the thyroid treated with radioactive iodine Am J Clin Oncol. 2005;28:216
17. Wang KL, Lin LY, Chen PM, Lin HD. Chronic myeloid leukemia after treatment with 131 for thyroid carcinoma J Chin Med Assoc. 2005;68:230–3
18. Chow SM. Side effects of high-dose radioactive iodine for ablation or treatment of differentiated thyroid carcinoma J Hong Kong Coll Radiol. 2005;8:127–35
19. de Vathaire F, Schlumberger M, Delisle MJ, Francese C, Challeton C, de la Genardiére E, et al Leukaemias and cancers following iodine-131 administration for thyroid cancer Br J Cancer. 1997;75:734–9
20. Petrich T, Widjaja A, Musholt TJ, Hofmann M, Brunkhorst T, Ehrenheim C, et al Outcome after radioiodine therapy in 107 patients with differentiated thyroid carcinoma and initial bone metastases: Side-effects and influence of age Eur J Nucl Med. 2001;28:203–8
21. Lopes Rodrigues C, Corbo R, Proença Martins FP, Barbosa da Fonseca LM, Aranha IP, Gutfilen B. Low dosage of 131iodine effects on chromosomes Yale J Biol Med. 2003;76:109–14
22. Ramírez MJ, Puerto S, Galofré P, Parry EM, Parry JM, Creus A, et al Multicolour FISH detection of radioactive iodine-induced 17cen-p53 chromosomal breakage in buccal cells from therapeutically exposed patients Carcinogenesis. 2000;21:1581–6