J Pediatr Endocr Met 2014; aop
Letter to the Editor Alessandro Mussa*, Patrizia Matarazzo and Andrea Corrias
Papillary thyroid cancer and autoimmune polyglandular syndrome Keywords: papillary thyroid cancer; polyglandular syndrome; thyroid cencer; thyroid nodules. DOI 10.1515/jpem-2014-0268 Received June 23, 2014; accepted July 9, 2014
To the Editor, With great interest, we read the article by Karavanaki et al. (1), who reported on a patient with autoimmune polyglandular syndrome (APS) type II and papillary thyroid carcinoma and highlighted the controversial relationship between thyroid autoimmunity and cancer. We take this opportunity to comment on this debated issue and to describe an overlapping case we have diagnosed and followed recently. In 2005, a 12-year-old boy was admitted at our institution for acute abdominal pain and dehydration; the presence of hyponatremia, hypoglycemia, and hyperkalemia prompted the suspicion of acute mineralocorticoid and glucocorticoid deficiency. Diagnostic tests revealed elevated adrenocorticotropic hormone concentrations ( > 1200 pg/mL) and undetectable serum cortisol levels, confirming a primary adrenal insufficiency of autoimmune origin (serum anti-21-hydroxylase antibody positive titer). Further investigations showed also the coexistence of euthyroid Hashimoto’s thyroiditis; the boy had positive anti-thyroperoxidase ( > 126 U/mL, normal < 40) and anti-human thyroglobulin (888 U/mL, normal < 35) antibody titer and a mildly enlarged thyroid
*Corresponding author: Alessandro Mussa, Division of Pediatric Endocrinology, Department of Pediatrics and Public Health, Regina Margherita Children’s Hospital, University of Turin, Piazza Polonia 94, 10126, Turin, Italy, Phone: +39 0113131985, Fax: +39 0113135217, E-mail: [email protected] Patrizia Matarazzo and Andrea Corrias: Division of Pediatric Endocrinology, Department of Pediatrics and Public Health, Regina Margherita Children’s Hospital, University of Turin, Piazza Polonia 94, 10126, Turin, Italy
with decreased echogenicity and inhomogeneous ultrasound pattern. The diagnosis was consistent with APS type II; the patient was prescribed replacement therapy with oral hydrocortisone and fludrocortisone acetate and followed up quarterly. Of note, the recent patient history was positive for an episode of pharyngitis and one of severe gastroenteritis. Results of the laboratory assays were consistent with a previous streptococcal infection (anti-streptolysin O titer > 500 U/mL) and a recent hepatitis A infection (IgM index 3.14, positive > 1). A few months after the diagnosis of APS type II, the thyroid function switched to hypothyroidism with serum thyroid-stimulating hormone (TSH) level of 11.8 mU/L (0.4–4.4 mU/L) and fT4 level of 9.6 pg/mL (9.8–16.6 pg/mL); levothyroxine treatment was started. The follow-up of this case lasted until the actual age of 20 years; antibodies against transglutaminase, glutamic acid decarboxylase, tyrosine phosphatase-like molecule, gastric parietal cells, and cholinergic receptor were checked yearly and were persistently negative. Results of the twice-yearly clinical evaluation; levels of vitamin B, folate, calcium, phosphorus, parathormone, and glycemia; platelet counts; and liver enzyme dosages have always been normal, and the boy underwent regular growth and pubertal development. At 16 years of age, his annual thyroid ultrasound, which was also part of the follow-up, revealed a hypoechoic nodule at the right thyroid lobe with a maximum diameter of 15 mm, increased intravascular blood flow, and irregular margins. Fine-needle biopsy cytology was consistent with papillary thyroid carcinoma, and the boy underwent total thyroidectomy and central compartment lymph node dissection. Histology confirmed the cytological diagnosis, and the boy was submitted to radioactive iodine treatment. Currently, serum thyroglobulin levels are undetectable and there is no evidence of disease relapse. As yet, there is no clear evidence supporting a correlation between thyroid autoimmunity and papillary thyroid cancer (2). Conflicting reports continue to come forward and controversy exists also as to what would be the etiological relationship between them. Still, it remains
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2 Mussa et al.: Papillary thyroid cancer and autoimmune polyglandular syndrome
unclear whether autoimmune thyroiditis predisposes to papillary thyroid carcinoma development or it represents an incidental histologic finding in cancer cases, or, on the contrary, whether it is the result of a systemic/ localized immune system response against tumoral cells. A hypothetical causal link between thyroid autoimmunity and papillary cancer is in the creation of a favorable setting for malignant transformation; the production of reactive oxygen species by the autoimmune inflammatory response may increase the chances of DNA damage and the likelihood of mutations, eventually leading to cancer development. In contrast, it has also been hypothesized that the autoimmune response may protect against thyroid carcinoma, reflecting a systemic immune aggression counteracting tumor expansion. Likewise, recent studies also suggested a genetic link between thyroiditis and papillary cancer involving the PI3K/AKT pathway and RET/PTC gene rearrangements (2). Also, these two disease entities may be connected by a rise in serum TSH level; transient, overlooked, or mild subclinical hypothyroidism in autoimmune thyroiditis may overstimulate the proliferation and growth of follicular cells. Actually, several studies support the role of TSH as a risk factor for differentiated thyroid cancer in both adults and children (3, 4). Finally, the association between thyroiditis and cancer may be spurious, reflecting a detection bias; ultrasound scan performed for the diagnosis or follow-up of thyroiditis causes a lowering of the detection threshold of asymptomatic thyroid nodules. This bias is likely responsible for the different diagnostic features of isolated and thyroiditis-associated papillary cancer cases that are also observed in childhood (5, 6); obviously, these differences impact cancer prognosis too, which seems different in the two populations (7). Conversely, it should be noted that thyroid nodules > 1 cm in size do have the same likelihood of malignancy, either presenting or not in the context of autoimmune thyroiditis (8). Concluding, for sure most of the studies on the relationship between thyroid autoimmunity and differentiated cancer are spoiled by either selection or detection biases (9). Methodology efforts in research aiming at avoiding these distortions are complex to the point that it appears unlikely that definitive conclusions on this debated issue will be reached shortly. Anyhow, the controversies still persisting in the search for this correlation indicate that, if there is one, thyroid autoimmunity is only responsible for a small increase in cancer risk, probably negligible. This leads to questioning the need to perform a malignancy surveillance by ultrasound in thyroiditis patients, a topic that has been once more
a matter of vivid scientific debate. However, the aforementioned observations concerning the relationship between isolated thyroid autoimmunity and cancer are not immediately translatable to the APS context. Cases of papillary thyroid cancer in patients with APS including thyroiditis may prove interesting with this view, representing disease models with potential clues for scientific research. Besides the patient described by Karavanaki et al. (1) and the case we described, we found in the literature another report suggesting the association between papillary thyroid cancer and APS type II (10). Moreover, it is also worth pointing out that patients with APS type I/II have a nonsignificant increased mortality rate for thyroid cancer, approximately two-fold that expected in healthy subjects (11). With this respect, we fully agree with the authors: an ultrasound-based malignancy surveillance approach in APS type II patients appears prudential and fully justified.
References 1. Karavanaki K, Karayianni C, Vassiliou I, Tzanela M, Sdogou T, et al. Multiple autoimmunity, type 1 diabetes (T1DM), autoimmune thyroiditis and thyroid cancer: is there an association? A case report and literature review. J Pediatr Endocrinol Metab 2014, doi: 10.1515/jpem-2013-0370. 2. Jankovic B, Le KT, Hershman JM. Clinical review: Hashimoto’s thyroiditis and papillary thyroid carcinoma: is there a correlation? J Clin Endocrinol Metab 2013;98:474–82. 3. Mussa A, Salerno MC, Bona G, Wasniewska M, Segni M, et al. Serum thyrotropin concentration in children with isolated thyroid nodules. J Pediatr 2013;163:1465–70. 4. Fiore E, Vitti P. Serum TSH and risk of papillary thyroid cancer in nodular thyroid disease. J Clin Endocrinol Metab 2012;97: 1134–45. 5. Corrias A, Cassio A, Weber G, Mussa A, Wasniewska M, et al. Thyroid nodules and cancer in children and adolescents affected by autoimmune thyroiditis. Arch Pediatr Adolesc Med 2008;162:526–31. 6. Corrias A, Mussa A, Baronio F, Arrigo T, Salerno M, et al. Diagnostic features of thyroid nodules in pediatrics. Arch Pediatr Adolesc Med 2010;164:714–9. 7. Lun Y, Wu X, Xia Q, Han Y, Zhang X, et al. Hashimoto’s thyroiditis as a risk factor of papillary thyroid cancer may improve cancer prognosis. Otolaryngol Head Neck Surg 2013;148:396–402. 8. Corrias A, Mussa A. Thyroid nodules in pediatrics: which ones can be left alone, which ones must be investigated, when and how. J Clin Res Pediatr Endocrinol 2013;5:57–69. 9. Grazia Castagna M, Belardini V, Memmo S, Maino F, Di Santo A, et al. Nodules in autoimmune thyroiditis are associated with increased risk of thyroid cancer in surgical series, but not in cytological series: evidence for selection bias. J Clin Endocrinol Metab 2014:jc20141302.
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Mussa et al.: Papillary thyroid cancer and autoimmune polyglandular syndrome 3
10. Leães CG, Rios MC, Passaglia JP, Pereira-Lima JF, Oliveira Mda C. Autoimmune polyglandular syndrome: an unusual presentation with empty sella, premature ovarian failure, and Hashimoto’s thyroiditis associated with thyroid cancer. Gynecol Endocrinol 2012;28:999–1001.
11. Bensing S, Brandt L, Tabaroj F, Sjöberg O, Nilsson B, et al. Increased death risk and altered cancer incidence pattern in patients with isolated or combined autoimmune primary adrenocortical insufficiency. Clin Endocrinol (Oxf) 2008;69:697–704.
Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/12/15 1:09 PM
Letter to the Editor Alessandro Mussa*, Patrizia Matarazzo and Andrea Corrias
Papillary thyroid cancer and autoimmune polyglandular syndrome Keywords: papillary thyroid cancer; polyglandular syndrome; thyroid cencer; thyroid nodules. DOI 10.1515/jpem-2014-0268 Received June 23, 2014; accepted July 9, 2014
To the Editor, With great interest, we read the article by Karavanaki et al. (1), who reported on a patient with autoimmune polyglandular syndrome (APS) type II and papillary thyroid carcinoma and highlighted the controversial relationship between thyroid autoimmunity and cancer. We take this opportunity to comment on this debated issue and to describe an overlapping case we have diagnosed and followed recently. In 2005, a 12-year-old boy was admitted at our institution for acute abdominal pain and dehydration; the presence of hyponatremia, hypoglycemia, and hyperkalemia prompted the suspicion of acute mineralocorticoid and glucocorticoid deficiency. Diagnostic tests revealed elevated adrenocorticotropic hormone concentrations ( > 1200 pg/mL) and undetectable serum cortisol levels, confirming a primary adrenal insufficiency of autoimmune origin (serum anti-21-hydroxylase antibody positive titer). Further investigations showed also the coexistence of euthyroid Hashimoto’s thyroiditis; the boy had positive anti-thyroperoxidase ( > 126 U/mL, normal < 40) and anti-human thyroglobulin (888 U/mL, normal < 35) antibody titer and a mildly enlarged thyroid
*Corresponding author: Alessandro Mussa, Division of Pediatric Endocrinology, Department of Pediatrics and Public Health, Regina Margherita Children’s Hospital, University of Turin, Piazza Polonia 94, 10126, Turin, Italy, Phone: +39 0113131985, Fax: +39 0113135217, E-mail: [email protected] Patrizia Matarazzo and Andrea Corrias: Division of Pediatric Endocrinology, Department of Pediatrics and Public Health, Regina Margherita Children’s Hospital, University of Turin, Piazza Polonia 94, 10126, Turin, Italy
with decreased echogenicity and inhomogeneous ultrasound pattern. The diagnosis was consistent with APS type II; the patient was prescribed replacement therapy with oral hydrocortisone and fludrocortisone acetate and followed up quarterly. Of note, the recent patient history was positive for an episode of pharyngitis and one of severe gastroenteritis. Results of the laboratory assays were consistent with a previous streptococcal infection (anti-streptolysin O titer > 500 U/mL) and a recent hepatitis A infection (IgM index 3.14, positive > 1). A few months after the diagnosis of APS type II, the thyroid function switched to hypothyroidism with serum thyroid-stimulating hormone (TSH) level of 11.8 mU/L (0.4–4.4 mU/L) and fT4 level of 9.6 pg/mL (9.8–16.6 pg/mL); levothyroxine treatment was started. The follow-up of this case lasted until the actual age of 20 years; antibodies against transglutaminase, glutamic acid decarboxylase, tyrosine phosphatase-like molecule, gastric parietal cells, and cholinergic receptor were checked yearly and were persistently negative. Results of the twice-yearly clinical evaluation; levels of vitamin B, folate, calcium, phosphorus, parathormone, and glycemia; platelet counts; and liver enzyme dosages have always been normal, and the boy underwent regular growth and pubertal development. At 16 years of age, his annual thyroid ultrasound, which was also part of the follow-up, revealed a hypoechoic nodule at the right thyroid lobe with a maximum diameter of 15 mm, increased intravascular blood flow, and irregular margins. Fine-needle biopsy cytology was consistent with papillary thyroid carcinoma, and the boy underwent total thyroidectomy and central compartment lymph node dissection. Histology confirmed the cytological diagnosis, and the boy was submitted to radioactive iodine treatment. Currently, serum thyroglobulin levels are undetectable and there is no evidence of disease relapse. As yet, there is no clear evidence supporting a correlation between thyroid autoimmunity and papillary thyroid cancer (2). Conflicting reports continue to come forward and controversy exists also as to what would be the etiological relationship between them. Still, it remains
Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/12/15 1:09 PM
2 Mussa et al.: Papillary thyroid cancer and autoimmune polyglandular syndrome
unclear whether autoimmune thyroiditis predisposes to papillary thyroid carcinoma development or it represents an incidental histologic finding in cancer cases, or, on the contrary, whether it is the result of a systemic/ localized immune system response against tumoral cells. A hypothetical causal link between thyroid autoimmunity and papillary cancer is in the creation of a favorable setting for malignant transformation; the production of reactive oxygen species by the autoimmune inflammatory response may increase the chances of DNA damage and the likelihood of mutations, eventually leading to cancer development. In contrast, it has also been hypothesized that the autoimmune response may protect against thyroid carcinoma, reflecting a systemic immune aggression counteracting tumor expansion. Likewise, recent studies also suggested a genetic link between thyroiditis and papillary cancer involving the PI3K/AKT pathway and RET/PTC gene rearrangements (2). Also, these two disease entities may be connected by a rise in serum TSH level; transient, overlooked, or mild subclinical hypothyroidism in autoimmune thyroiditis may overstimulate the proliferation and growth of follicular cells. Actually, several studies support the role of TSH as a risk factor for differentiated thyroid cancer in both adults and children (3, 4). Finally, the association between thyroiditis and cancer may be spurious, reflecting a detection bias; ultrasound scan performed for the diagnosis or follow-up of thyroiditis causes a lowering of the detection threshold of asymptomatic thyroid nodules. This bias is likely responsible for the different diagnostic features of isolated and thyroiditis-associated papillary cancer cases that are also observed in childhood (5, 6); obviously, these differences impact cancer prognosis too, which seems different in the two populations (7). Conversely, it should be noted that thyroid nodules > 1 cm in size do have the same likelihood of malignancy, either presenting or not in the context of autoimmune thyroiditis (8). Concluding, for sure most of the studies on the relationship between thyroid autoimmunity and differentiated cancer are spoiled by either selection or detection biases (9). Methodology efforts in research aiming at avoiding these distortions are complex to the point that it appears unlikely that definitive conclusions on this debated issue will be reached shortly. Anyhow, the controversies still persisting in the search for this correlation indicate that, if there is one, thyroid autoimmunity is only responsible for a small increase in cancer risk, probably negligible. This leads to questioning the need to perform a malignancy surveillance by ultrasound in thyroiditis patients, a topic that has been once more
a matter of vivid scientific debate. However, the aforementioned observations concerning the relationship between isolated thyroid autoimmunity and cancer are not immediately translatable to the APS context. Cases of papillary thyroid cancer in patients with APS including thyroiditis may prove interesting with this view, representing disease models with potential clues for scientific research. Besides the patient described by Karavanaki et al. (1) and the case we described, we found in the literature another report suggesting the association between papillary thyroid cancer and APS type II (10). Moreover, it is also worth pointing out that patients with APS type I/II have a nonsignificant increased mortality rate for thyroid cancer, approximately two-fold that expected in healthy subjects (11). With this respect, we fully agree with the authors: an ultrasound-based malignancy surveillance approach in APS type II patients appears prudential and fully justified.
References 1. Karavanaki K, Karayianni C, Vassiliou I, Tzanela M, Sdogou T, et al. Multiple autoimmunity, type 1 diabetes (T1DM), autoimmune thyroiditis and thyroid cancer: is there an association? A case report and literature review. J Pediatr Endocrinol Metab 2014, doi: 10.1515/jpem-2013-0370. 2. Jankovic B, Le KT, Hershman JM. Clinical review: Hashimoto’s thyroiditis and papillary thyroid carcinoma: is there a correlation? J Clin Endocrinol Metab 2013;98:474–82. 3. Mussa A, Salerno MC, Bona G, Wasniewska M, Segni M, et al. Serum thyrotropin concentration in children with isolated thyroid nodules. J Pediatr 2013;163:1465–70. 4. Fiore E, Vitti P. Serum TSH and risk of papillary thyroid cancer in nodular thyroid disease. J Clin Endocrinol Metab 2012;97: 1134–45. 5. Corrias A, Cassio A, Weber G, Mussa A, Wasniewska M, et al. Thyroid nodules and cancer in children and adolescents affected by autoimmune thyroiditis. Arch Pediatr Adolesc Med 2008;162:526–31. 6. Corrias A, Mussa A, Baronio F, Arrigo T, Salerno M, et al. Diagnostic features of thyroid nodules in pediatrics. Arch Pediatr Adolesc Med 2010;164:714–9. 7. Lun Y, Wu X, Xia Q, Han Y, Zhang X, et al. Hashimoto’s thyroiditis as a risk factor of papillary thyroid cancer may improve cancer prognosis. Otolaryngol Head Neck Surg 2013;148:396–402. 8. Corrias A, Mussa A. Thyroid nodules in pediatrics: which ones can be left alone, which ones must be investigated, when and how. J Clin Res Pediatr Endocrinol 2013;5:57–69. 9. Grazia Castagna M, Belardini V, Memmo S, Maino F, Di Santo A, et al. Nodules in autoimmune thyroiditis are associated with increased risk of thyroid cancer in surgical series, but not in cytological series: evidence for selection bias. J Clin Endocrinol Metab 2014:jc20141302.
Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/12/15 1:09 PM
Mussa et al.: Papillary thyroid cancer and autoimmune polyglandular syndrome 3
10. Leães CG, Rios MC, Passaglia JP, Pereira-Lima JF, Oliveira Mda C. Autoimmune polyglandular syndrome: an unusual presentation with empty sella, premature ovarian failure, and Hashimoto’s thyroiditis associated with thyroid cancer. Gynecol Endocrinol 2012;28:999–1001.
11. Bensing S, Brandt L, Tabaroj F, Sjöberg O, Nilsson B, et al. Increased death risk and altered cancer incidence pattern in patients with isolated or combined autoimmune primary adrenocortical insufficiency. Clin Endocrinol (Oxf) 2008;69:697–704.
Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/12/15 1:09 PM
