Short Communication 379
Diagnose eines papillären Schilddrüsenkarzinoms bei einem Mädchen mit Morbus Basedow Case report
▼
A 13-year-old girl presented to her pediatrician with headaches, tremor and restlessness of some weeks duration. The family had noticed swelling of the neck and protrusion of the eyes. The patient’s past medical history was uneventful. There was no endocrinopathy or malignancy known in the family. The parents migrated from Iraq. Endocrine assessment detected a goiter (WHO 2 °) and exophthalmos. Laboratory analysis revealed overt hyperthyroidism (thyroid-stimulating hormone (TSH) 0.04 mU/l (0.35–5); free thyroxine (fT4) 56.7 pmol/l (10.3–21); free triiodothyronine (fT3) 39.2 pmol/l (2.76–6.45)). Elevated serum TSH receptor antibodies (TRAb) of 2.36 U/l (0–1.5) confirmed the diagnosis of GD. An ultrasound of the thyroid showed a large gland with signs of inflammation and hyperperfusion, but no nodules. A treatment with 15 mg thiamazole daily was started. The management was complicated by constantly high fT3 levels, although increasing doses of thiamazole were administered and times of non-compliance. Thyroxine supplementation was needed after 6 months to normalize fT4 levels. A year later the girl presented with clinical recurrence of GD. As the response to medical treatment was not satisfactory further treatment options were discussed. The progressive goiter and aggravating exophthalmos were the reason to opt for the surgical excision of the thyroid in a high volume center. During thyroidectomy a small thyroid nodule was found in the left lower lobe of the enlarged gland (69 g; right lobe: 7.2 × 4.3 × 2.6 cm; left lobe 7 × 4.2 × 2.5 cm). A papillary thyroid carcinoma measuring 1.8 × 0.8 × 0.8 cm with penetration of the isthmus and the thyroid capsule was diagnosed by histology. Up to 0.1 cm infiltration into the perithyroid soft tissue and lymphatic vessels was detected. The surrounding thyroid tissue showed increased endocrine activity and signs of chronic inflammation in agreement with GD.
To assess tumor stage the patient was referred to our hospital. Sonography revealed enlarged cervical lymph nodes. On Iodine-123 scintigraphy lymph nodes around the trachea and in the left cervical region showed iodine tracer uptake ▶ Fig. 1). No furindicating metastases (● ther evidence of distant metastases was detected. A multidisciplinary team discussed therapy options and recommended cervical lymphadenectomy prior to radioiodine ablative therapy. The patient was started on triiodothyronine. Clinical symptoms of hyperthyroidism occurred before a complete suppression of TSH could be achieved. A systematic cervical lymphadenectomy (K1a, K1b, K3) was performed 3 months after the initial surgery. 5 of 37 excised lymph nodes showed metastases. 3 were found in the central compartment opposite to the primary tumor and 2 in the left upper lateral compartment. The patient developed a superficial wound infection 10 days postoperatively treated with local antiseptic swathes and oral antibiotics. Hypoparathyroidism and laryngeal nerve lesion ▶ Table 1). could be excluded (● 10 days after surgery the patient underwent ablative radioiodine therapy (131I 3.579 GBq) without complications. A post therapy whole body radioiodine scan showed intense iodine uptake pretracheally, in the thyroid bed and along the thyroglossal duct, attributed to thyroid remnants. No signs of further metastases were found. The patient was started on hormone substitution with 137.5 μg thyroxine later adjusted to 150 μg daily. At follow-up 2 months later a radioiodine scan revealed pathological tracer uptake in 2 cervical regions one in the previous left thyroid bed and one lateral of the left carotid artery, correlated to hypodense lesions on sonography. An elevated thyroglobulin level (17.54 ng/ml, TSH > 100 mU/l) substantiated the suspicion of ▶ Table 1). The surgitumor metastases (● cal excision of the two lesions was recommended but the girl and her family
Discussion
▼
We present a case of an adolescent girl with GD and thyroid cancer. A papillary thyroid carcinoma was found unexpectedly following thyroidectomy 12 months after the diagnosis of GD. Ultrasound studies of the thyroid gland had not raised a suspicion of malignancy but a progressing goiter. It remains to be discussed if additional ultrasound of the neck soft tissues and reevaluation of thyroid texture prior to surgery would have identified suspicious lymph nodes or the malignant thyroid nodule in our patient. Ideally total thyroidectomy and lymphadenectomy should be performed at once in patients with thyroid cancer.
Thyroid cancer and Graves’ disease
▼
In patients with GD (including all ages) nonmedullary thyroid cancer can be found in 1.3–13.7 %, exceeding the risk in the general population. No statistic data is available for GD and the associated risk for malignancy in the pediatric population. The prognosis of thyroid cancer in GD patients is interpreted controversially. A study from Japan found longer diseasefree survival and a better prognosis in GD patients with a thyroid carcinoma compared to non-GD’ patients (Kikuchi S et al., Br J Surg 2006; 93: 434–439). Yano et al. (Eur J Endocrinol 2007; 157: 325– 329) found no difference in the outcome. Then again patients with non-occult differentiated thyroid cancer and GD had more advanced tumor stages and a higher risk for distant metastatic disease (Pellegriti G et al., J Clin Endocrinol Metab 2013; 98: 1014–1021). In a Chinese cohort of GD patients, thyroid cancer was diagnosed in 13.7 % often acompanied with lymph node involvement. Young age was the only significant factor predicting metastatic disease. The youngest patient was a 13-year-old girl with metastatic thyroid carcinoma (Ren M et al., World J Surg 2013; 1–8). We suppose that in youths presenting with a thyroid carcinoma in association with GD, an aggressive treatment should be favored.
Gesing J et al. Papillary thyroid carcinoma in … Klin Padiatr 2014; 226: 379–381
Downloaded by: University of Pittsburgh. Copyrighted material.
Papillary Thyroid Carcinoma in an Adolescent Girl with Graves’ Disease
refused to a third surgical approach. Therefore a second course of radioiodine ablation is planned.
Short Communication
a
b
c
Fig. 1 a Planar iodine-123 scintigraphy after thyroidectomy revealed focal iodine uptake in left cervical and paratracheal regions (arrows), subsequently histologically proven as lymph node metastasis. b, c Diagnostic iodine-131 neck and thorax SPECT/CT two months after cervical lymphadenectomy and radioiodine ablation therapy raised suspicion of recurrent left cervical lymph node metastasis.
Table 1 Thyroid function, tumor markers and calcium after diagnosis of thyroid cancer. Date
06/13 06/13 07/13 08/13 09/13 10/13 10/13 11/13 01/14 01/14 01/14 02/14
TSH (mU/l) physiological range target value pre-thyroidectomy post-thyroidectomy
lymphadenectomy radioablative therapy
pre-scintigraphy post-scintigraphy
fT3 (pmol/l)
0.51–4.6 < 0.1 0.035 (0.4–4) 3.15 13.1 4.77 54.4 34.3 > 100 3.44 0.33 > 100 28.1 1.34 (0.51–4-6)
fT4 (pmol/l)
4.42–7.9
12–22
8.69 (2.8–7.7) 1.95 8.82 10.49 < 0.4 < 0.4
14.3 (10.3–24.5) 5.35 2.06 1.48 0.87 0.94
4.99 4.84
21.42 19.13
5.11 (4.42–7.9)
26.07 (12–22)
TG (ng/ml)
TG-Ab
TR-Ab
(U/ml)
(U/l)
Calcium (mmol/l)
1.4–78 8 mm) fine needle aspiration is recommended. Analysis of BRAF V600E mutation can help to identify malignancy in
Gesing J et al. Papillary thyroid carcinoma in … Klin Padiatr 2014; 226: 379–381
unclear cases. In mutation positive cancers lymph node metastases and recurrence is more likely. An Iodine-123 scintigraphy and a whole body MRI may be considered to analyze tumor stage.
Downloaded by: University of Pittsburgh. Copyrighted material.
380
Short Communication 381
Follow-up management
▼
Thyroglobulin should be used as biochemical tumor marker for follow-up. In our patient thyroglobulin remained elevated after thyroidectomy and radioablative therapy indicating tumor metastases ▶ Table 1). In some cases TgAb and TRAb (● can be used as surrogate parameters for tumor persistence or recurrence. High TgAb have been related to tumor recurrence in patients with isolated thyroid cancer and low thyroglobulin levels (Hsieh CJ et al., Thyroid 2014; 24: 488– 493). In patients with GD and thyroid
cancer TRAb were found to indicate relapse of hyperthyroidism and tumor recurrence. TSH suppression should be pursued on the long-term.
▶ Think of a thyroid carcinoma also in pediatric patients with Graves’ disease
Contributor’s Statement Clinicians should bear in mind that a thyroid carcinoma is possible also in a pediatric patient with GD. There is some evidence to suggest a higher prevalence of thyroid carcinomas in patients with GD and that this coincidence might be associated with more aggressive tumors ▶ Table 2) especially in young age. (●
▼
Key points
Conflict of interest: The authors have no conflict of interest to disclose.
▼
▶ Follow your patient with Graves’ disease closely ▶ Perform sonography of the thyroid including neighbouring soft tissues on a regular basis and reevaluate findings prior to surgery
Study concept: W. Kiess Acquisition of data: J. Gesing, A. Keller, T. Lincke Drafting: J. Gesing Analysis and interpretation: T. Lincke, R. Pfaeffle, J. Gesing Revision: R. Pfaeffle, A. Keller, W. Kiess, P. Lamesch, T. Lincke, O. Sabri, H. Christiansen.
J. Gesing, R. Pfaeffle, H. Christiansen, A. Keller, T. Lincke, P. Lamesch, O. Sabri, W. Kiess; Germany
Gesing J et al. Papillary thyroid carcinoma in … Klin Padiatr 2014; 226: 379–381
Downloaded by: University of Pittsburgh. Copyrighted material.
Calcitonin should be measured to exclude medullary thyroid cancer. Therapy consists of thyroidectomy followed by radioablation. Frozen section can be helpful to adapt surgery in case of unknown malignancy and prevent the patient from multistep operative procedures.
Diagnose eines papillären Schilddrüsenkarzinoms bei einem Mädchen mit Morbus Basedow Case report
▼
A 13-year-old girl presented to her pediatrician with headaches, tremor and restlessness of some weeks duration. The family had noticed swelling of the neck and protrusion of the eyes. The patient’s past medical history was uneventful. There was no endocrinopathy or malignancy known in the family. The parents migrated from Iraq. Endocrine assessment detected a goiter (WHO 2 °) and exophthalmos. Laboratory analysis revealed overt hyperthyroidism (thyroid-stimulating hormone (TSH) 0.04 mU/l (0.35–5); free thyroxine (fT4) 56.7 pmol/l (10.3–21); free triiodothyronine (fT3) 39.2 pmol/l (2.76–6.45)). Elevated serum TSH receptor antibodies (TRAb) of 2.36 U/l (0–1.5) confirmed the diagnosis of GD. An ultrasound of the thyroid showed a large gland with signs of inflammation and hyperperfusion, but no nodules. A treatment with 15 mg thiamazole daily was started. The management was complicated by constantly high fT3 levels, although increasing doses of thiamazole were administered and times of non-compliance. Thyroxine supplementation was needed after 6 months to normalize fT4 levels. A year later the girl presented with clinical recurrence of GD. As the response to medical treatment was not satisfactory further treatment options were discussed. The progressive goiter and aggravating exophthalmos were the reason to opt for the surgical excision of the thyroid in a high volume center. During thyroidectomy a small thyroid nodule was found in the left lower lobe of the enlarged gland (69 g; right lobe: 7.2 × 4.3 × 2.6 cm; left lobe 7 × 4.2 × 2.5 cm). A papillary thyroid carcinoma measuring 1.8 × 0.8 × 0.8 cm with penetration of the isthmus and the thyroid capsule was diagnosed by histology. Up to 0.1 cm infiltration into the perithyroid soft tissue and lymphatic vessels was detected. The surrounding thyroid tissue showed increased endocrine activity and signs of chronic inflammation in agreement with GD.
To assess tumor stage the patient was referred to our hospital. Sonography revealed enlarged cervical lymph nodes. On Iodine-123 scintigraphy lymph nodes around the trachea and in the left cervical region showed iodine tracer uptake ▶ Fig. 1). No furindicating metastases (● ther evidence of distant metastases was detected. A multidisciplinary team discussed therapy options and recommended cervical lymphadenectomy prior to radioiodine ablative therapy. The patient was started on triiodothyronine. Clinical symptoms of hyperthyroidism occurred before a complete suppression of TSH could be achieved. A systematic cervical lymphadenectomy (K1a, K1b, K3) was performed 3 months after the initial surgery. 5 of 37 excised lymph nodes showed metastases. 3 were found in the central compartment opposite to the primary tumor and 2 in the left upper lateral compartment. The patient developed a superficial wound infection 10 days postoperatively treated with local antiseptic swathes and oral antibiotics. Hypoparathyroidism and laryngeal nerve lesion ▶ Table 1). could be excluded (● 10 days after surgery the patient underwent ablative radioiodine therapy (131I 3.579 GBq) without complications. A post therapy whole body radioiodine scan showed intense iodine uptake pretracheally, in the thyroid bed and along the thyroglossal duct, attributed to thyroid remnants. No signs of further metastases were found. The patient was started on hormone substitution with 137.5 μg thyroxine later adjusted to 150 μg daily. At follow-up 2 months later a radioiodine scan revealed pathological tracer uptake in 2 cervical regions one in the previous left thyroid bed and one lateral of the left carotid artery, correlated to hypodense lesions on sonography. An elevated thyroglobulin level (17.54 ng/ml, TSH > 100 mU/l) substantiated the suspicion of ▶ Table 1). The surgitumor metastases (● cal excision of the two lesions was recommended but the girl and her family
Discussion
▼
We present a case of an adolescent girl with GD and thyroid cancer. A papillary thyroid carcinoma was found unexpectedly following thyroidectomy 12 months after the diagnosis of GD. Ultrasound studies of the thyroid gland had not raised a suspicion of malignancy but a progressing goiter. It remains to be discussed if additional ultrasound of the neck soft tissues and reevaluation of thyroid texture prior to surgery would have identified suspicious lymph nodes or the malignant thyroid nodule in our patient. Ideally total thyroidectomy and lymphadenectomy should be performed at once in patients with thyroid cancer.
Thyroid cancer and Graves’ disease
▼
In patients with GD (including all ages) nonmedullary thyroid cancer can be found in 1.3–13.7 %, exceeding the risk in the general population. No statistic data is available for GD and the associated risk for malignancy in the pediatric population. The prognosis of thyroid cancer in GD patients is interpreted controversially. A study from Japan found longer diseasefree survival and a better prognosis in GD patients with a thyroid carcinoma compared to non-GD’ patients (Kikuchi S et al., Br J Surg 2006; 93: 434–439). Yano et al. (Eur J Endocrinol 2007; 157: 325– 329) found no difference in the outcome. Then again patients with non-occult differentiated thyroid cancer and GD had more advanced tumor stages and a higher risk for distant metastatic disease (Pellegriti G et al., J Clin Endocrinol Metab 2013; 98: 1014–1021). In a Chinese cohort of GD patients, thyroid cancer was diagnosed in 13.7 % often acompanied with lymph node involvement. Young age was the only significant factor predicting metastatic disease. The youngest patient was a 13-year-old girl with metastatic thyroid carcinoma (Ren M et al., World J Surg 2013; 1–8). We suppose that in youths presenting with a thyroid carcinoma in association with GD, an aggressive treatment should be favored.
Gesing J et al. Papillary thyroid carcinoma in … Klin Padiatr 2014; 226: 379–381
Downloaded by: University of Pittsburgh. Copyrighted material.
Papillary Thyroid Carcinoma in an Adolescent Girl with Graves’ Disease
refused to a third surgical approach. Therefore a second course of radioiodine ablation is planned.
Short Communication
a
b
c
Fig. 1 a Planar iodine-123 scintigraphy after thyroidectomy revealed focal iodine uptake in left cervical and paratracheal regions (arrows), subsequently histologically proven as lymph node metastasis. b, c Diagnostic iodine-131 neck and thorax SPECT/CT two months after cervical lymphadenectomy and radioiodine ablation therapy raised suspicion of recurrent left cervical lymph node metastasis.
Table 1 Thyroid function, tumor markers and calcium after diagnosis of thyroid cancer. Date
06/13 06/13 07/13 08/13 09/13 10/13 10/13 11/13 01/14 01/14 01/14 02/14
TSH (mU/l) physiological range target value pre-thyroidectomy post-thyroidectomy
lymphadenectomy radioablative therapy
pre-scintigraphy post-scintigraphy
fT3 (pmol/l)
0.51–4.6 < 0.1 0.035 (0.4–4) 3.15 13.1 4.77 54.4 34.3 > 100 3.44 0.33 > 100 28.1 1.34 (0.51–4-6)
fT4 (pmol/l)
4.42–7.9
12–22
8.69 (2.8–7.7) 1.95 8.82 10.49 < 0.4 < 0.4
14.3 (10.3–24.5) 5.35 2.06 1.48 0.87 0.94
4.99 4.84
21.42 19.13
5.11 (4.42–7.9)
26.07 (12–22)
TG (ng/ml)
TG-Ab
TR-Ab
(U/ml)
(U/l)
Calcium (mmol/l)
1.4–78 8 mm) fine needle aspiration is recommended. Analysis of BRAF V600E mutation can help to identify malignancy in
Gesing J et al. Papillary thyroid carcinoma in … Klin Padiatr 2014; 226: 379–381
unclear cases. In mutation positive cancers lymph node metastases and recurrence is more likely. An Iodine-123 scintigraphy and a whole body MRI may be considered to analyze tumor stage.
Downloaded by: University of Pittsburgh. Copyrighted material.
380
Short Communication 381
Follow-up management
▼
Thyroglobulin should be used as biochemical tumor marker for follow-up. In our patient thyroglobulin remained elevated after thyroidectomy and radioablative therapy indicating tumor metastases ▶ Table 1). In some cases TgAb and TRAb (● can be used as surrogate parameters for tumor persistence or recurrence. High TgAb have been related to tumor recurrence in patients with isolated thyroid cancer and low thyroglobulin levels (Hsieh CJ et al., Thyroid 2014; 24: 488– 493). In patients with GD and thyroid
cancer TRAb were found to indicate relapse of hyperthyroidism and tumor recurrence. TSH suppression should be pursued on the long-term.
▶ Think of a thyroid carcinoma also in pediatric patients with Graves’ disease
Contributor’s Statement Clinicians should bear in mind that a thyroid carcinoma is possible also in a pediatric patient with GD. There is some evidence to suggest a higher prevalence of thyroid carcinomas in patients with GD and that this coincidence might be associated with more aggressive tumors ▶ Table 2) especially in young age. (●
▼
Key points
Conflict of interest: The authors have no conflict of interest to disclose.
▼
▶ Follow your patient with Graves’ disease closely ▶ Perform sonography of the thyroid including neighbouring soft tissues on a regular basis and reevaluate findings prior to surgery
Study concept: W. Kiess Acquisition of data: J. Gesing, A. Keller, T. Lincke Drafting: J. Gesing Analysis and interpretation: T. Lincke, R. Pfaeffle, J. Gesing Revision: R. Pfaeffle, A. Keller, W. Kiess, P. Lamesch, T. Lincke, O. Sabri, H. Christiansen.
J. Gesing, R. Pfaeffle, H. Christiansen, A. Keller, T. Lincke, P. Lamesch, O. Sabri, W. Kiess; Germany
Gesing J et al. Papillary thyroid carcinoma in … Klin Padiatr 2014; 226: 379–381
Downloaded by: University of Pittsburgh. Copyrighted material.
Calcitonin should be measured to exclude medullary thyroid cancer. Therapy consists of thyroidectomy followed by radioablation. Frozen section can be helpful to adapt surgery in case of unknown malignancy and prevent the patient from multistep operative procedures.
