Onset of Graves’ Disease and Thyroid Cancer After Chemo and Radiotherapy for Medulloblastoma

1. Abstract

1.1. Introduction: External beam Radiotherapy (RTE) treatment for head and neck cancers is associated to the development of late thyroid sequelae whose risk is persistent for decades.

1.2. Case report: We describe a rare case of a 21 yrs woman treated with RTE plus CHE for medulloblastoma diagnosed when she was fourteen. Five years later, for the onset of primitive hypothyroidism, with negative antibodies and a diffuse hypoechoic pattern at ultrasound, she started Levothyroxine (L-T4) therapy. At the annual control visit a small hypoechoic nodule (4 mm) to the right thyroid lobe has been detected. Eight months later the patient complained a state of thyrotoxicosis, TRab positive, with thyroid-associated orbitopathy. The nodule was increased in size and suspicious as also a lateral neck lymph node (LN). Fine needle aspiration biopsy and thyroglobulin (Tg) measurement on LN confirmed the diagnosis of thyroid carcinoma. After total thyroidectomy and LN dissection, with histological diagnosis of follicular-papillary microcarcinoma with LN metastasis in central and right latero-cervical compartment, the patient underwent 131I treatment. Tg was 62 pg/ml (after LT4 withdrawal) and whole-body scan

showed neck and diffuse bilateral lung uptake.

1.3. Conclusion: We describe a rare case of a patient who developed autoimmune thyroid disease, hypothyroidism and subsequent Graves’ disease with orbitopathy, followed by aggressive thyroid cancer some years later after treatment for medulloblastoma. Only few similar cases were previously described in literature [1]. Thyroid alterations are common during long-term follow-up of patients previously treated with RTE. Therefore a careful long-term follow-up with thyroid morpho-functional screening is indicated.

2. Key words

Thyroid cancer; Thyroid cancer outcome; Thyroid cancer risk factors; Neck irradiation; Childhood cancer survivor; Graves’ orbitopathy

3. Case Report

A 19-year-old young woman accessed our clinic for the onset of primary hypothyroidism. Five years before, at the age of 14 years, she was diagnosed with medulloblastoma and treated with surgery, external radiotherapy (RTE) and chemotherapy (CHE). At first visit in our Thyroid Clinic, thyroid function revealed a condition of hypothyroidism for which therapy with levothyroxine (L-T4) has been started; anti-peroxidase (AbTPO) and anti-thyroglobulin (AbTg) antibodies were negative and thyroid ultrasound showed a finely inhomogeneous pattern. At the annual control neck ultrasound showed a small hypoechoic nodule of 4 mm in size in the nervousness, sweating, palpitations, fine tremors and moderate and active thyroid-associated orbitopathy (lacrimation, diplopia, clinical activity score (CAS) = 3; NOSPECS: eyelid opening 13 mm bilaterally, Hertel 22 mm on the right and 22 mm on left, moderate decrease of ocular motility in upgaze). Thyroid function tests confirmed that the patient was in thyrotoxicosis state: TSH 0.08 μIU/ml (ref.0.35-5.0), FT4 2.14 ng/dl (ref. 0.6- 1.8), FT3 6.21 pg/mL (ref. 2.3-4.2), with positive anti-TSH receptor antibodies (TRab) (17 U/ref. < 0.5). L-T4 has been withdrawn and corticosteroids therapy started for orbitopathy. At ultrasound, the right lobe nodule has been increased, from 4 mm to 9 mm, and presented microcalcifications and irregular margins and furthermore a 9 mm lymph node (LN) with suspicious features was detected in the right lateral-cervical compartment. Ultrasound guided fine needle aspiration biopsy of thyroid nodule was suspected for papillary Thyroid Cancer (TC) and thyroglobulin (Tg) measurement in washout fluid from suspicious LN was positive (>475 ng/ml). The patient underwent total thyroidectomy and LN dissection (central and right latero-cervical compartments) with histological diagnosis of papillary carcinoma of follicular variant (8 mm) in the right lobe without capsule or vascular invasion, thyroiditis in the remaining parenchyma, and central (8/10 with a max diameter of 0.4 cm) and right latero-cervical (5/36 with a max diameter of 1 cm) compartment LN metastases. pT1b pN1b; Stage: I (TNM VIII edition). Whole-body scan after treatment with 100 mCi of 131 - Iodine, after LT4 withdrawal, showed diffuse bilateral neck and lung uptake (Figure 1); Tg was 62 ng/ml with negative AbTg. Figure 1: Whole-body scan (anterior and posterior view) after treatment with 100 mCi of 131Ishowing diffuse bilateral neck and lung uptake Neck ultrasound was negative and CT scan confirmed lung nodular lesions of 3 and 4 mm in size at the upper lobe of the right lung. At the last control visit thyroid, under LT4 treatment, Tg was 3 ng/ ml. Thyroid-associated orbitopathy was inactivated (lacrimation and diplopia disappeared, CAS 2; NOSPECS: eyelid opening 13 mm bilaterally, Hertel 21 mm bilaterally, ocular motility was unchanged). 4. Discussion Thyroid dysfunction is a relatively frequent late-effect of exposure of the thyroid gland to therapeutic doses of external ionizing irradiation for head and neck cancers [2-5]. Radiotherapy is an integral part of management of childhood and adolescence tumors, particularly head and neck malignancies, used either alone or in combination with CHE [6]. Although thyroid is considered to be relatively radio-resistant (but radiosensitive in young age) there is a dose-effect relationship. Direct irradiation of the thyroid gland may produce a broad spectrum of thyroid diseases including hypothyroidism, thyroiditis, Graves’ disease (GD), thyroid-related orbitopathy, thyroid adenoma, multinodular goiter and thyroid carcinoma [7]. The latency interval between radiation exposure and the development of thyroid dysfunction or TC varies greatly ranging from 6 months to 40 years. Subclinical and overt hypothyroidism are the most common finding in populations of irradiated patients who have undergone periodic biochemical screening up to 50%, mostly within 5 years from therapy [2-5, 7-9]. Moreover CHE would sensitize the thyroid gland to radiation and will increase the incidence of hypothyroidism [6].

5. Conclusion

The present case describes a particular and rare clinical condition characterized by the onset, in a patient subjected to previous RTE and CHE of: 1) primitive hypothyroidism, 2)subsequent hyperthyroidism with orbitopathy and 3) TC with aggressive characteristics. The onset of GD in patients undergoing RTE of the neck has a prevalence of about 5% vs hypothyroidism (prevalence up to 30%). The pathogenesis of hyperthyroidism in these patients is not clear but the auto-antigens released by the damaged thyroid tissue could trigger the autoimmune response and lead to the development of TSH anti-receptor antibodies that could be implicated in thyroid carcinogenesis. The role of CHE in the pathogenesis of thyroid alterations is not known and remains to be clarified if it has an additional effect when administered in combination with RTE. This report indicates the need of periodic morpho-functional thyroid evaluation in patientstreated with neck RTE and CHE, particularly during childhood or adolescence.

References

1. Jaber JJ, Thomas FJ, Carfrae MJ, Galati LT. Radiotherapy-associated euthyroid Graves ophthalmopathy following floor-of-mouth surgery: a case report. Ear, nose, & throat journal. 2008; 87(9): 533-6.

2. Hancock SL, McDougall IR, Constine LS. Thyroid abnormalities after therapeutic external radiation. International journal of radiation oncology, biology, physics. 1995; 31(5): 1165-70.

3. Oberfield SE, Allen JC, Pollack J, New MI, Levine LS. Long-term endocrine sequelae after treatment of medulloblastoma: prospective study of growth and thyroid function. The Journal of pediatrics. 1986; 108(2): 219-23.

4. Ogilvy-Stuart AL, Clark DJ, Wallace WH, Gibson BE, Stevens RF, Shalet SM, et al. Endocrine deficit after fractionated total body irradiation. Archives of disease in childhood. 1992; 67(9): 1107-10.

5. Tami TA, Gomez P, Parker GS, Gupta MB, Frassica DA. Thyroid dysfunction after radiation therapy in head and neck cancer patients. American journal of otolaryngology. 1992; 13(6): 357-62.

6. Banipal R, Mahajan MK, Uppal B, John M. Thyroid diseases as a sequelae following treatment of head and neck cancer. Indian journal of cancer. 2011; 48(2): 194-8.

7. Hancock SL, Cox RS, McDougall IR. Thyroid diseases after treatment of Hodgkin’s disease. The New England journal of medicine. 1991; 325(9): 599-605.

8. Grande C. Hypothyroidism following radiotherapy for head and neck cancer: multivariate analysis of risk factors. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 1992; 25(1): 31-6.

9. Thomas BC, Stanhope R, Plowman PN, Leiper AD. Endocrine function following single fraction and fractionated total body irradiation for bone marrow transplantation in childhood. Acta endocrinologica. 1993; 128(6): 508-12.

10. Ron E, Lubin JH, Shore RE, Mabuchi K, Modan B, Pottern LM, et al. Thyroid cancer after exposure to external radiation: a pooled analysis ofseven studies. Radiation research. 1995; 141(3): 259-77.

11. Richardson DB. Exposure to ionizing radiation in adulthood and thyroid cancer incidence. Epidemiology. 2009; 20(2): 181-7.

12. Black P, Straaten A, Gutjahr P. Secondary thyroid carcinoma after treatment for childhood cancer. Medical and pediatric oncology. 1998; 31(2): 91-5.

13. Tell R, Sjodin H, Lundell G, Lewin F, Lewensohn R. Hypothyroidism after external radiotherapy for head and neck cancer. International journal of radiation oncology, biology, physics. 1997; 39(2): 303-8.

14. Turner SL, Tiver KW, Boyages SC. Thyroid dysfunction following radiotherapy for head and neck cancer. International journal of radiation oncology, biology, physics. 1995; 31(2): 279-83.

15. Goldberg RC, Chaikoff IL, et al. Histopathological changes induced in the normal thyroid and other tissues of the rat by internal radiation with various doses of radioactive iodine. Endocrinology. 1950; 46(1): 72-90.

16. Nishiyama K, Tanaka E, Tarui Y, Miyauchi K, Okagawa K. A prospective analysis of subacute thyroid dysfunction after neck irradiation. International journal of radiation oncology, biology, physics. 1996; 34(2): 439-44.

17. Orgiazzi J. Anti-TSH receptor antibodies in clinical practice. Endocrinology and metabolism clinics of North America. 2000; 29(2): 339-55.

18. Takasu N, Matsushita M. Changes of TSH-Stimulation Blocking Antibody (TSBAb) and Thyroid Stimulating Antibody (TSAb) Over 10 Yearsin 34 TSBAb-Positive Patients with Hypothyroidism and in 98 TSAb-Positive Graves’ Patients with Hyperthyroidism: Reevaluation of TSBAb and TSAb in TSH-Receptor-Antibody (TRAb)-Positive Patients. Journal of thyroid research. 2012; 2012: 182176.

Citation:

Vargas-Flores E. Onset of Graves’ Disease and Thyroid Cancer After Chemo and Radiotherapy for Medulloblastoma . Annals of Clinical and Medical Case Reports 2020