Surgical Therapy of the Thyroid Papillary Carcinoma in Children: Experience With 56 Patients <16 Years Old

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1 Surgical Therapy of the Thyroid Papillary Carcinoma in Children: Experience With 56 Patients <16 Years Old By Claudio Spinelli, Alessia Bertocchini, Alessandro Antonelli, and Paolo Miccoli Pisa, Italy Background/Purpose: This article is an anatomic, clinical, therapeutic, and prognostic assessment of 56 children 16 years of age or younger, who underwent a surgical operation for thyroid papillary carcinoma from April 1988 to December 2001 in the Department of General Surgery at the University of Pisa. Of these 56 patients, 22 are Belarus children (39%) in whom carcinoma developed after the nuclear accident in Chernobyl in April 1986, whereas 34 (61%) are children with differentiated nonirradiated tumors. The purpose of this work was to compare the group of children who had radiation-induced thyroid carcinoma with the group affected by non radiation-induced carcinoma to evaluate if there are significant clinical, anatomic, and prognostic differences between them and to identify the best surgical strategy to adopt. Results: At the time of clinical presentation, the tumor was limited to the thyroid gland in 28 cases (50%), whereas in the others, in 24 cases (43%) metastases in the neck lymph nodes were present or had infiltrated the extrathyroid tissues as was seen in 4 cases (7%). The surgical operation was a total thyroidectomy in 37 cases (66%), whereas in 19 patients with radiation-induced carcinoma it was a hemithyroidectomy followed by a completion of thyroidectomy in Pisa (34%). The histologic examination showed multifocal sites of papillary adenocarcinoma in the gland in 23% of cases, and both lobes of the thyroid gland were involved with tumor in 23% of patients. The postsurgical follow-up showed a mortality rate of 0% and a recurrence rate of 33.5% (64% radiation-induced carcinoma v 3% non radiation-induced carcinoma; P.0001). At the moment, 8 of 22 cases (36%) with radiation-induced carcinoma are free of disease versus 33 of 34 (97%) with non radiation-induced carcinoma (P.0001). Conclusions: These findings show carcinoma of the thyroid in children has a low risk of mortality but a high risk of recurrence. Children with radiation-induced thyroid carcinoma are more likely to have a recurrence of the disease. Total thyroidectomy for the treatment of both radiationinduced and non radiation-induced carcinomas appears to represent, on the basis of these results, the best therapeutic option. J Pediatr Surg 39: Elsevier Inc. All rights reserved. INDEX WORDS: Childhood papillary thyroid cancer, irradiated thyroid cancer, Chernobyl nuclear accident, total thyroidectomy. THYROID CARCINOMA in children is a rare pathology; it comprises 3% of all tumors in children with an annual incidence of 0.2 to 0.4 per million children. 1,2 In 1998 the annual incidence of thyroid cancer in the United States was about 18,000 new cases, and it results in approximately 1,200 deaths each year. 3 Since the middle of the 1970s a decrease in carcinoma incidence owing to a more limited use of radiation in the therapy of benign pathologies of the head and neck has been observed, whereas since 1990 a 62-fold increase of carcinoma incidence has been recorded in children who live in Belarus, Ukraine and the Briansk territory after the nuclear accident at the Chernobyl nuclear plant. 4-7 In children, papillary thyroid carcinoma (PTC) has an initial clinical presentation and a follow-up different From the Cathedral of Pediatric Surgery, Department of Surgery, University of Pisa, Pisa, Italy. Address reprint requests to Claudio Spinelli, Cattedra Di Chirurgia Pediatrica, Dipartimento Di Chirurgia- Universita Degli Studi Di Pisa, Via Roma, Pisa, Italy Elsevier Inc. All rights reserved /04/ $30.00/0 doi: /j.jpedsurg from that in adults. In adults the PTC presents itself with a tumor localized in the thyroid gland (67%), a mass in the thyroid gland associated with the cervical lymphadenopathy (13%), or only lymphadenopathy (20%). 8 More frequently (90%), at the moment of diagnosis, children have palpable lymph node metastases. Paradoxically, despite these parameters, children have a better prognosis than adults. 1,9,10 In children, thyroid carcinoma manifests itself with a high incidence of cervical lymph node metastases, extrathyroid extent, and metastases, the most common sites of which are the lungs and bones Because of this strange combination of benign prognosis with an aggressive presentation there is not just one choice of treatment. In this work we analyzed the anatomic and clinical presentation as well as therapy and follow-up of 56 young patients 16 years or younger who underwent surgical operations from 1988 to 2001 for thyroid-differentiated carcinoma. MATERIALS AND METHODS In the Department of General Surgery at the University of Studies, Pisa, 56 children 16 years of age or younger with a diagnosis of 1500 Journal of Pediatric Surgery, Vol 39, No 10 (October), 2004: pp

2 THYROID CANCER IN CHILDREN 1501 PTC from April 1988 to December 2001 underwent a surgical operation. Of these 56, 22 (39%) are Belarus children who manifested a thyroid papillary carcinoma after being exposed to ionizing radiation produced from the explosion of the Chernobyl nuclear power plant. Thirty-four (61%) are children who had a thyroid carcinoma but no history of exposure to ionizing radiation. All the children underwent clinical, instrumental, and laboratory examinations. The presurgical examinations carried out were clinical, hematochemical, a complete profile of the thyroid hormones, determinations of the auto-antibodies of the thyroid, an ultrasound scan of the neck, aspiration using a thin needle of the thyroid nodule for a cytologic examination, a laryngoscopy, and a chest radiograph. The De Groot classification 15 was used to determine the stratification of the disease: class 1 tumor limited to the thyroid gland, class 2 metastases in the neck lymph nodes, class 3 tumor invading the thyroid gland, and class 4, distant metastases. Patients with PTC at a low risk of recurrent or persistent disease belong to classes 1 and 2, whereas those of classes 3 and 4 are at a high risk. The children underwent total thyroidectomy or a completion of thyroidectomy after a previous thyroid lobectomy. The time between the first and the second operation was on average 30 months (range, 1 to 6 years). A lymphadenectomy was carried out in patients with evidence of lymph node metastases in the lateral or central compartment regions. A functional modified radical neck dissection was performed to remove all fibrous tissue with lymph nodes, but all motor and sensory nerves as well as the sternocleidomastoid muscle and internal jugular vein were preserved unless invaded by tumor. A postsurgical evaluation was carried out with monitoring of the calcium in the 3 days after the operations, a complete profile of the thyroid hormones, and a laryngoscopy to evaluate recurrent laryngeal nerve function. The follow-up at 5.5 years 41 months was made with laboratory examination: a complete profile of the thyroid hormones (TSH, thyroglobulin), a determination of the autoantibodies of the thyroid (autoantibodies antithyroglobulin), and calcium serum as well as instrumental exams: a thyroid ultrasound scan and a total body scintigraphy. The first follow-up after the surgical treatment was made after about 6 weeks from the operations in a hypothyroid state, using a total body scintigraphy with iodine 131. In the presence of iodium absorbing activity limited to the thyroid bed, a therapeutic dose of about 30 to 50 mci was administered to completely eliminate residual thyroid carcinoma. However, in the case in which the lymph nodes or lungs were involved, a therapeutic dose of about 100 mci was imposed. A total body scintigraphy was repeated after 6 to 12 months from the first, after an appropriate suspension of the thyroid suppression therapy. In the cases in which the disease remained, a new dose of Iodio-radium of about 100 to 150 mci was administered every year. Remission was declared when the patient had a negative total body scintigraphy with immeasurable thyroglobulin levels. When this result was obtained, we began to lengthen the intervals between the scintigraphy examination while continuing to clinically follow-up with the patients and monitoring circulating thyroglobulin. These patients remained off thyroid replacement therapy. Two consecutive negative total body scintigraphies with immeasurable serum thyroglobulin in a hypothyroid state were sufficient evidence of remission to refrain from further routine scintigraphy. The medical therapy consisted of 1-thyroxine to suppress the secretion of endogen TSH and vitamin D and calcium in case of hypocalcemia. A statistical analysis was made on the data comparing the group of the children with radio-induced PTC (RIC) versus non radio-induced PTC (NRIC) using Yates corrected 2 test. RESULTS Of these 56 children, 39 were girls (70%; 14 of 22 RIC versus 25 of 34 NRIC and 17 were boys (30%; 8 of 22 RIC versus 9 of 34 NRIC). The average age at the moment of diagnosis was 11.5 years (9.6 RIC versus 13.4 NRIC) with a range of 4 to 16 years (4 to 14 RIC versus 7 to 16 NRIC). At the moment of diagnosis, 28 patients were in class 1 (50%; 8 of 22 RIC versus 20 of 34 NRIC; P.1712), 24 in class 2 (43%; 12 of 22 RIC versus 12 of 34 NRIC; P.2520), 4 in class 3 (7%; 2 of 22 RIC versus 2 of 34 NRIC), and 0 in class 4 (Table 1). Thirty-seven children (66%) underwent a total thyroidectomy (3 of 22 RIC versus 34 of 34 NRIC), whereas 19 (34%) had a lobectomy followed by a completion of the thyroidectomy (19 of 22 RIC versus 0 of 34 NRIC). Thirty-four (61%) underwent a latero-cervical lymphadenectomy (20 of 22 RIC versus 14 of 34 NRIC; P.0005), of which, 19 cases (56%) were bilateral (3 of 20 RIC versus 6 of 14 NRIC; P.3529), and 15 were monolateral (44%; 7 of 20 RIC versus 8 of 14 NRIC; P.3529); of which, 25 were synchronous tumor (12 of 20 RIC versus 13 of 14 NRIC; P.0814), and 9 were metachronous tumor (8 of 20 RIC versus 1 of 14 NRIC; P.0814; Table 2). Of the 28 cases in class 1, 22 cases (78.5%) underwent Table 1. Clinical and Epidemiologic Data of Children With RIC versus NRIC RIC NRIC P Value* Cases Age (range, 4 to 14) 13.4 (range, 7 to 16) Sex (F/M) 39/17 14/8 25/9 Not significant Histology Papillary 56 Papillary 22 Papillary 34 Multifocal 13 6 (27.3%) 7 (20.6%) Not significant Both lobes 13 6 (27.3%) 7 (20.6%) Not significant Stratification Class (36.4%) 20 (58.8%).1712 Class (54.5%) 12 (35.3%).2520 Class (9.1%) 2 (5.9%) Not significant Class Not significant

3 1502 SPINELLI ET AL Table 2. Surgical Therapy Operation 56 Cases RIC NRIC P Value* Total thyroidectomy 37 (66%) 3 (8%) 34 (92%) Completion of thyroidectomy 19 (34%) 19 (100%) 0 (0%) Latero-cervical lymphadenectomy 34 (61%) 20 (59%) 4 (41%).0005 Bilateral latero-cervical lymphadenectomy 19 (56%) 13 (68%) 6 (32%).3529 Monolateral latero-cervical lymphadenectomy 15 (44%) 7 (47%) 8 (53%).3529 Synchrony latero-cervical lymphadenectomy 25 (73.5%) 12 (48%) 13 (52%).0814 Metachrony latero-cervical lymphadenectomy 9 (26.5%) 8 (89%) 1 (11%).0814 a total thyroidectomy (TT 2 8 RIC versus 20 of 20 NRIC) followed by a second operation of latero-cervical lymphadenectomy in 2 cases (1 of 8 RIC versus 1 of 20 NRIC), the other 6 cases (21.5%) affected by radiation-induced carcinoma underwent, in their own country, a lobectomy (6 of 8 RIC versus 0 of 20 NRIC), and underwent later in Pisa a completion of the thyroidectomy (CT), associated in 5 cases with a latero-cervical lymphadenectomy. Of the 24 cases in class 2, 13 (54%) underwent total thyroidectomy associated with a latero-cervical lymphadenectomy (1 of 12 RIC versus 12 of 12 NRIC), in 2 cases (1 of 12 RIC versus 1 of 12 NRIC), a second surgical operation was necessary owing to residues of neck lymph node metastases. The other 11 cases of class 2 (46%) affected by radiation-induced carcinoma underwent a lobectomy associated with latero-cervical lymphadenectomy in their own country (11 of 12 RIC versus 0 of 12 NRIC), and underwent later in Pisa a completion of thyroidectomy associated in 2 cases with a latero-cervical lymphadenectomy. Of the 4 cases in class 3, 2 (50%) underwent a total thyroidectomy (0 of 2 RIC versus 2 of 2 NRIC), associated in 1 case with a latero-cervical lymphadenectomy, whereas in 2 cases (50%) affected by radiation-induced carcinomas (2 of 2 RIC versus 0 of 2 NRIC, they underwent a lobectomy in their own country followed by a second operation in Pisa, a completion of thyroidectomy associated with a latero-cervical lymphadenectomy. The histologic examination showed a papillary carcinoma in 37 cases of those who underwent a total thyroidectomy (34 NRIC versus 3 RIC). In 19 cases of patients treated with a complete thyroidectomy, a papillary thyroid residual carcinoma in the removed lobe was observed in 3 cases, whereas the lobectomy carried out previously had shown a papillary thyroid cancer in all these patients. In 13 cases (23%) (6 of 22 RIC versus 7 of 34 NRIC), multifocal sites of papillary adenocarcinoma were found throughout the gland; in 13 cases (23%; 6 of 22 RIC versus 7 of 34 NRIC), the carcinoma was seen in both lobes; in 4 cases (7%; 2 of 22 RIC versus 2 of 34 NRIC), the carcinoma presented itself with an extrathyroid infiltration and an invasion of the capsule and vessels. The surgical complications, after the treatment of the 56 children carried out in Pisa, were an acute respiratory insufficiency in 3 cases (5%; 1 of 19 CT versus 2 of 37 TT), which required a temporary tracheotomy, in 4 cases (7%) a permanent hypoparathyroidism (2 of 19 CT versus 2 of 37 TT; P.8755) and in 3 cases (5%) a vocal cord paralysis (2 of 19 CT versus 1 of 37 TT; P.5456; Table 3). In all 56 patients, a follow-up of 5.5 years 41 months was carried out. Currently, of 28 young patients in class 1 26 (93%) are free of disease (6 of 8 RIC versus 20 of 20 NRIC) and 2 (7%) have lung metastases (2 of 8 RIC versus 0 of 20 NRIC) of whom, 1 also has bone metastases (P.1314). Of the 24 cases in class 2, 12 (50%) are currently free of disease (1 of 12 RIC versus 11 of 12 NRIC), 5 (21%) manifest cervical lymph nodal metastases relapses (4 of 12 RIC versus 1 of 12 NRIC) 7 (29%) lung metastases (7 of 12 RIC versus 7 of 12 NRIC), of whom, 5 are associated with cervical lymph nodal metastases relapses (P.0002). Of 4 cases in class 3, 3 (75%) are free of disease (1 of 2 RIC versus 2 of 2 NRIC), and 1 (25%) manifests cervical lymph nodal metastases (1 of 2 RIC versus 0 of 2 NRIC; P.995). On the whole, considering all the children regardless of their initial stratification, 41 (73%) are currently free of disease (8 of 22 RIC versus 33 of 34 NRIC), 1 (2%) manifests cervical lymph nodal metastases (1 of 22 RIC versus 0 of 34 NRIC), 5 (9%) have lymph nodal metastases relapses (4 of 22 RIC versus 1 of 34 NRIC), and 9 Table 3. Postsurgical Complications Cases Completion of Thyroidectomy (19 Cases) Total Thyroidectomy (37 Cases) P Value* Tracheotomy for Acute respiratory insuficience 3 (5.3%) 1 (4.5%) 2 (5.9%) Not significant Permanent hypoparathyroidism 4 (7.1%) 2 (9%) 2 (5.9%).8755 Monolateral vocal cord paralysis 3 (5.3%) 2 (9%) 1 (2.9%).5456

4 THYROID CANCER IN CHILDREN 1503 (16%) have lung metastases (9 of 22 RIC versus 0 of 34 NRIC), of whom, 5 are associated with lymph nodal metastases relapses and 1 with bone metastases (P.0001; Table 4; Fig 1). DISCUSSION The therapeutic strategy of thyroid papillary carcinoma in children is a controversial subject. Experts debate about the most appropriate extent of thyroidectomy, the use of postoperative radioactive iodine ablation, and the need to administer thyroid hormone to suppress the thyroid-stimulating hormone (TSH). 16 The controversy persists because no prospective, randomized, controlled study has evaluated the extent of thyroidectomy, postoperative radioactive iodine therapy, and TSH suppressive therapy. 17 A large multicenter trial with a long follow-up would be required. Generally, 3 surgical approaches have been advocated among experts: thyroid lobectomy or hemithyroidectomy (total removal of one lobe and the isthmus), near-total thyroidectomy (total lobectomy and subtotal resection on the contralateral side to leave 1 g of thyroid tissue), and total thyroidectomy. Some investigators, 13,18,19 believing in the good prognosis of this tumor, consider that the best therapeutic approach is nonextended surgery (thyroid lobectomy or hemithyroidectomy). The most important clinical reasons for carrying out a lobectomy or hemithyroidectomy in children with PTC instead of a thyroidectomy is that the mortality rate does not appear to change significantly in either type of treatment, and the incidence of postoperative complications is minor. Other investigators claim that the safest and most effective primary treatment for thyroid carcinoma in children is total thyroidectomy. Multivariate analysis in large retrospective studies both in children and adults, have reported higher recurrence and mortality rates in those patients who have undergone procedures less than total thyroidectomy. 15,25-27 Fig 1. Postsurgical follow-up. An age inferior to or equal to 16 years and a major surgical extent seem to be directly correlated with the increase in morbidity. 12,13 In particular, from our data we have seen 3 cases (5.3%) of acute respiratory insufficiency that required temporary tracheotomy for bilateral hypomobility of the vocal cords of a transitory type, 3 cases (5.3%) of monolateral paralysis of a vocal cord, and 4 cases (7.5%) of permanent hypoparathyroidism. Complications were significantly higher in the group of children who underwent a completion of thyroidectomy compared with those who underwent only total thyroidectomy (P.5). Recurrent laryngeal nerve injury is particularly high in thyroid surgery in children with a percentage that ranges from 0.5% to 30%. 13,28,29 This complication occurs more often in operations for carcinomas of great extent, in particular, thyroid carcinomas with extrathyroid extent and lymph node metastases. 28 Children are at major risk of both temporary and permanent postoperative hypocalcemy compared with adults. The greater the extent of Table 4. Postsurgical Follow-Up Cases RIC NRIC P Value* Class 1 28 (50%) (75%) Free 20 (100%) Free (25%) Recurrence Class 2 24 (43%) (8.3%) Free 11 (91.7%) Free (91.7%) Recurrence 1 (8.3%) Recurrence Class 3 4 (7%) (50%) Free 2 (100%) Free Not significant (.995) 1 (50%) Recurrence Total (36.4%) Free 33 (97.1%) Free (63.6%) Recurrence 1 (2.9%) Recurrence

5 1504 SPINELLI ET AL surgical excision the higher the risk of hypocalcemia with a percentage that ranges from 8% to 24%. 12,16 Although advocates of lesser procedures contend that the risk of complications is higher after total thyroidectomy, numerous surgeons experienced in performing total thyroidectomy report lower complication rates than the rates reported by some surgeons performing lesser procedures. 30 Total thyroidectomy for thyroid-differentiated carcinoma has some advantages. (1) The thyroglobulin (Tg) dosage is more useful as a marker of relapses when all the thyroid tissue has been removed. After total thyroidectomy, an elevated Tg level ( 3 mg/dl) in patients with PTC indicates either normal residual thyroid tissue or persistent of recurrent thyroid cancer. Using serum Tg levels to follow-up with patients with PTC can reduce the need for frequent radioactive iodine scanning. 31,32 (2) A total thyroidectomy removes all primitive tumor sites and also multiple tumor foci and the potential residual cancer that could remain in the contralateral lobe. In the literature, the multifocality and the presence of cancer in both lobes recurs with high frequency both in pediatric and adult patients, respectively, in 50% to 80% 16,22,33 and 30% to 61%. 13,16,20,34 In our data, in the cases of completion of thyroidectomy, we have observed that 3 of 19 (16%) presented thyroid papillary carcinoma residues in the remaining lobe after lobectomy that had not been diagnosed previously. (3) The removal of all the thyroid gland excludes the possibility of the papillary cancer residues transforming into a nondifferentiated type, anaplastic (1%), which is uniformly lethal. 35,36 (4) There is the possibility of effectively treating thyroid-differentiated cancer metastases with radioactive iodine therapy, as the incidence of distant metastases is high, especially in the lungs in these children. 28,37,38 (5) There is the possibility of finding hidden metastases, especially in the lungs, with total body scintigraphy, which can be carried out only after total thyroidectomy. These are difficult to see with a lung radiography, whereas they are identified easily with a scintigraphy. 1,28 So, without the help of total body scintigraphy in the postsurgical follow-up, these are diagnosed only later so as to require a higher dose of I 131 with a higher risk of collateral effects. 39 In our data, we have a high incidence of lung metastases (9 of 22; 41%) diagnosed with total body scintigraphy, especially in children with RIC. The percentage reaches up to 63.6% if we include the cervical lymph nodes and bone metastases diagnosed with scintigraphy in addition to the lung lesions. The postsurgical follow-up has shown a mortality rate of 0% and a recurrent rate of 33.5% (64% radiation-induced carcinoma versus 3% non radiationinduced carcinoma), thus, underlining a different biological behavior between the induced carcinomas by ionizing radiations versus non radio-induced forms. In the first group, we observed a diagnosis of the disease at a much earlier age in a more advanced stage and a higher recurrence of disease with metastases of the cervical lymph nodes and distant metastases. Although many of these patients present a relapse of the disease, the percentage of global survival is excellent in both groups. It was observed that in 70% of Belarus children with radio-induced thyroid papillary carcinoma present with a mutation of proto-oncogene RET, specific and exclusive for this hystologic type of tumor, PTC (papillary thyroid carcinoma). 40 Such a high percentage has not been found in adult patients in any geographical area. This makes us suppose that the activation of RET is typical of infantile papillary carcinoma or more likely is specifically associated with papillary carcinoma induced by radiation. 41,42 At an experimental level in the transgenic mouse model, we observed that the presence of RET/PTC3 is associated with an aggressive form with a high tendency for metastases of the regional lymph nodes and those at distance (lungs). 42 Probably also the different choice of surgical therapy in both groups of our study may have influenced the prognosis of patients with radiation-induced carcinoma. The radiation-induced papillary carcinoma was treated with a surgical strategy in 2 stages. The first step was lobectomy followed by a completion of thyroidectomy, with an average interval between the 2 surgical operations of 30 months (1 to 6 years), whereas a single-phase, total thyroidectomy from the start was carried out in the non radiation-induced carcinoma patients. 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