Abstract
Purpose: To investigate clinical characteristics and surgical treatment of multifocal papillary thyroid carcinoma. Methods: A total of 648 patients diagnosed with papillary thyroid carcinoma were enrolled, 168 with multifocal papillary thyroid carcinoma. Clinicopathological factors including gender, age at diagnosis, family history of thyroid tumor, multiplicity and bilaterality of tumor, extra-thyroidal extension, lymph node involvement and other factors were statistically compared. Results: The incidence of multifocal papillary thyroid carcinoma was 25.9% and 117 presented with bilateral thyroid gland lesions. In multifocal group, patients had a higher ratio of male subjects, family history of thyroidal tumor, neck lymph node metastasis and extra-thyroidal extension by B-ultrasound. Solitary papillary thyroid carcinoma tended to be with a higher rate of benign goiters. In multifocal group, males with neck lymphadenectasis, ≥ 3 tumor masses or bilaterality of tumors tended to present with larger tumors, a higher incidence of neck lymph node metastasis and extra-thyroidal extension. 164 cases completed the follow-up, 5 died, 1 suspected with lung metastasis and still survived, 6 underwent repeated surgery due to lymph node recurrence at 3-41 months postoperatively and 2 surgically treated with recurrent gland tumor. Overall 1-, 2-, 5-, and 10-year survival rate was 98.2%, 97.4%, 96.5% and 96.5%, respectively. Conclusion: Multifocal papillary thyroid carcinoma is more malignant and highly differentiated than solitary lesions. Total thyroidectomy combined with neck dissection of central compartment could be utilized as standard treatment. Lateral nodular dissection should be considered for the patients with lymph node metastasis.
Keywords: Thyroid tumors, thyroidectomy, neck lymph node dissection, papillary carcinoma
Introduction
Thyroidal cancer is the most common endocrine-related malignant tumor. Multifocal papillary thyroid carcinoma is equally relatively common in clinical practice [1,2]. This study retrospectively evaluated the clinical data of 648 patients who were pathologically diagnosed with papillary thyroid carcinoma and underwent surgery in our hospital for the first time from January 2000 to December 2011 (168 of whom showing multifocal papillary thyroid carcinoma), aiming to investigate the clinical characteristics and surgical approach in treatment of multifocal papillary thyroid carcinoma.
Materials and methods
General data
Among 168 patients with multifocal papillary thyroid carcinoma, 49 (29.2%) were male and 119 (70.8%) were female, aged 42 ± 4.1 years (range from 14 to 78 years). A total of 114 patients (67.9%) presented with neck masses as the primary symptom. Physical examination revealed 38 cases (22.6%) with neck masses, 6 (3.6%) neck lymph node enlargement, 1 (0.6%) hoarseness and nine (3.9%) with alternative symptoms. Upon admission, physical examination indicated palpable lymph node enlargement in 18 cases. Prior to surgery, 156 patients underwent B-ultrasound of the thyroid gland, 71 (45.5%) among whom presenting with neck lymph node enlargement and 101 (64.7%) showing signs of calcified lymph nodular lesions. In total, 137 patients received thyroid function test, identifying that the serum level of thyroid stimulating hormone (TSH) was higher than normal value in 12 cases. Preoperative examination detected distal metastasis involving lung, bone and adrenal in 2 patients.
Subsequent follow-up
The follow-up was conducted in the patterns of paying a visit, making telephone calls or the most recent outpatient visit and medical records. The death of patients or the time of final follow-up was regarded as the endpoint of the follow up. The follow-up was concluded until December 31, 2012.
Statistical analysis
SPSS 14.0 statistical software package was used for data processing. Chin-square or F tests were utilized for group comparison. Kaplan-Meier method was employed for survival estimates. Log-rank test was used to compare survivals among groups. α = 0.05 was considered as statistical significance.
Results
Surgical approach
In total, 107 patients underwent partial or total resection of the affected gland lobe plus isthmus plus contralateral side, 37 thyroidectomy, 11 bilateral subtotal thyroidectomy, 12 excision of the affected gland lobe with/without isthmus and 1 receiving subtotal resection on the affected side. A total of 84 patients underwent neck lymph node dissection including 52 receiving unilateral dissection, 5 bilateral dissection and 27 VI area dissection alone. Six patients were treated with palliative excision, manifested as neck trachea, esophagus, recurrent laryngeal nerve and carotid sheath widely surrounded by tumors and two patients were complicated with tumor thrombosis in internal jugular vein. Two cases presented with distal metastasis involving lung, bone and adrenal. Six patients received partial excision of the affected gland lobe plus isthmus plus contralateral side, 1 had thyroidal lobectomy, 2 bilateral subtotal thyroidectomy, 3 palliative neck nodular dissection and 1 VI zone dissection.
Surgical observations and pathological examination
In this study, 22 patients had lesions located on the left side (13 cases with 2 lesions and 9 cases with ≥ 3 lesions), 24 right side (15 with 2 lesions and 9 with ≥ 3 lesions), 5 isthmus side (4 with 2 lesions and 1 with ≥ 3 lesions) and 117 bilateral sides (67 with 2 lesions and 50 with ≥ 3 lesions). The tumor with a maximum diameter of ≤ 1 cm was defined as small carcinoma. A total of 66 patients (39.3%) had non-small carcinoma, 68 (40.5%) simple small carcinoma and 34 (20.2%) small carcinoma complicated with non-small carcinoma (20.2%). A total of 99 patients (58.9%) had 2 lesions and 69 (41.1%) ≥ 3 lesions with the maximal number of 13 lesions. In total, 69 resected samples had benign thyroid disease including 44 (26.2%) nodular Goiter, 4 (2.4%) thyroid adenoma, 12 (7.1%) Hashimoto’s thyroiditis, 5 (3.0%) nodular Goiter complicated with thyroid adenoma, 3 (1.8%) hyperthyroidism and 1 (0.6%) hyperthyroidism complicated with thyroid adenoma. Fifty nine cases (35.1%) were accompanied with neck lymph nodular metastasis including 55 (32.7%) unilateral and 4 (2.4%) bilateral metastasis. Nineteen (11.3%) presented with extra-thyroidal involvement (recurrent laryngeal nerve, trachea, esophagus, jugular vein or surrounding muscles, etc).
Comparison of clinicopathological factors between multifocal and solitary groups
Compared with patients with solitary lesion, those in the multifocal group were characterized with a higher ratio of clinicopathological factors including male (P = 0.004), a family history of malignant thyroid tumors (P = 0.031), neck lymph node enlargement detected by physical examination (P = 0.000) and B-ultrasound (P = 0.001), nodular calcified lesions (P = 0.001), neck nodular metastasis (P = 0.008) and extra-thyroidal involvement (P = 0.001), etc.
The incidence of patients complicated with benign thyroid disease in the solitary group was significantly higher than that in the multifocal group (P = 0.000). No statistical significance was observed between two groups in terms of age (P = 0.235), TSH level (P = 0.114) and maximum diameter of a tumor (P = 0.180), etc, as illustrated in Table 1.
Table 1.
Comparison of clinicopathological characteristics between multifocal and solitary groups (n)
| Parameters | Multifocal group (n = 168) | Solitary group (n = 480) | χ2 or F valuea | P value |
|---|---|---|---|---|
| Gender | ||||
| Male | 49 | 89 | 8.382 | 0.004 |
| Female | 119 | 391 | ||
| Mean age (year) | 42.2 ± 12.2 | 43.5 ± 12.7 | 1.190 | 0.235 |
| Family history of malignant tumor | ||||
| Yes | 8 | 7 | 4.634 | 0.031 |
| No | 160 | 471 | ||
| Neck lymph nodular enlargement by physical examinationb | ||||
| Yes | 18 | 14 | 16.344 | 0.000 |
| No | 148 | 464 | ||
| TSH level elevation | ||||
| Yes | 12 | 19 | 2.500 | 0.114 |
| No | 125 | 360 | ||
| Lymph nodular enlargement by B-ultrasound | ||||
| Yes | 71 | 139 | 11.531 | 0.001 |
| No | 85 | 232 | ||
| Nodular calcified lesions | ||||
| Yes | 101 | 223 | 11.544 | 0.001 |
| No | 55 | 232 | ||
| Maximum diameter of a tumor (mm) | 17.3 ± 13.0 | 15.7 ± 12.7 | 1.343 | 0.180 |
| Complicated with benign thyroidal diseasesb | ||||
| Yes | 69 | 287 | 17.616 | 0.000 |
| No | 99 | 193 | ||
| Neck lymph nodular metastasis | ||||
| Yes | 59 | 118 | 6.958 | 0.008 |
| No | 109 | 362 | ||
| Extra-thyroidal involvement | ||||
| Yes | 19 | 20 | 11.225 | 0.001 |
| No | 149 | 460 | ||
Denotes mean age and maximum diameter of a tumor (F value), χ2 for other parameters;
denotes thyroid.
Comparison of clinicopathological factors of multifocal papillary thyroid carcinoma
Male patients with neck lymph node enlargement, bilateral tumors and ≥ 3 lesions were incline to relatively high degree of malignancy and were characterized with a relatively high incidence of large tumors, neck lymph node metastasis or extra-thyroidal involvement. Those complicated with benign thyroid diseases presented with a relatively low degree of malignant multifocal papillary thyroid carcinoma (Table 2). Patients with a family history of thyroid cancer had a relatively younger age of onset (31.0 ± 10.7 vs 42.7 ± 12.0, χ2 = 7.338, P = 0.007). Neck lymph node metastasis was not correlated with the maximum diameter of a tumor (F = 2.043, P = 0.157).
Table 2.
Comparison of clinicopathological characteristics in patients with multifocal papillary thyroid carcinoma
| Parameters | Multifocal small carcinoma (n) | Maximum diameter of a tumor (mm) | Neck lymph nodular metastasis (n) | Extra-thyroidal involvement (n) | |||
|---|---|---|---|---|---|---|---|
|
|
|
||||||
| Yes | No | Yes | No | Yes | No | ||
| Gender | |||||||
| Male | 21 | 28 | 23.4 ± 17.8 | 22 | 27 | 11 | 38 |
| Female | 81 | 38 | 14.7 ± 9.4 | 37 | 82 | 8 | 111 |
| χ2 | 9.248 | 16.730 | 2.903 | 8.558 | |||
| P value | 0.002 | 0.000 | 0.088 | 0.003 | |||
| Family history of thyroid cancer | |||||||
| Yes | 4 | 4 | 16.9 ± 9.0 | 5 | 3 | 1 | 7 |
| No | 98 | 62 | 17.3 ± 13.2 | 54 | 106 | 18 | 142 |
| χ2 | 0.404 | 0.008 | 2.764 | 0.012 | |||
| P value | 0.525 | 0.931 | 0.096 | 0.931 | |||
| Neck lymph nodular enlargement by physical examination | |||||||
| Yes | 1 | 17 | 25.9 ± 11.5 | 15 | 3 | 6 | 12 |
| No | 100 | 48 | 16.3 ± 12.9 | 44 | 104 | 12 | 136 |
| χ2 | 25.904 | 8.868 | 20.128 | 10.563 | |||
| P value | 0.000 | 0.004 | 0.000 | 0.001 | |||
| Lymph nodular enlargement by B-ultrasound | |||||||
| Yes | 38 | 33 | 19.1 ± 11.6 | 38 | 33 | 12 | 59 |
| No | 58 | 27 | 15.4 ± 11.8 | 16 | 69 | 4 | 81 |
| χ2 | 3.539 | 1.948 | 20.578 | 6.251 | |||
| P value | 0.060 | 0.146 | 0.000 | 0.012 | |||
| Nodular calcified lesions by B-ultrasound | |||||||
| Yes | 62 | 39 | 16.8 ± 11.9 | 38 | 63 | 11 | 90 |
| No | 34 | 21 | 17.5 ± 11.8 | 16 | 39 | 5 | 50 |
| χ2 | 0.003 | 0.434 | 1.146 | 0.125 | |||
| P value | 0.958 | 0.649 | 0.284 | 0.723 | |||
| Complicated with benign thyroidal diseases | |||||||
| Yes | 52 | 17 | 13.2 ± 8.6 | 14 | 55 | 0 | 69 |
| No | 50 | 49 | 20.3 ± 14.9 | 45 | 54 | 19 | 80 |
| χ2 | 10.533 | 12.407 | 11.301 | 14.931 | |||
| P value | 0.001 | 0.001 | 0.001 | 0.000 | |||
| Tumor sites | |||||||
| Unilateral | 34 | 17 | 14.1 ± 12.0 | 13 | 38 | 1 | 50 |
| Bilateral | 68 | 49 | 18.6 ± 13.3 | 46 | 71 | 18 | 99 |
| χ2 | 1.085 | 4.130 | 2.980 | 6.381 | |||
| P value | 0.297 | 0.044 | 0.084 | 0.012 | |||
| Number of tumors | |||||||
| 2 lesions | 66 | 33 | 16.3 ± 12.1 | 26 | 73 | 8 | 91 |
| ≥ 3 lesions | 36 | 33 | 18.7 ± 14.3 | 33 | 36 | 11 | 58 |
| χ2 | 3.581 | 1.281 | 8.298 | 2.505 | |||
| P value | 0.058 | 0.259 | 0.004 | 0.113 | |||
Clinical prognosis
All patients received adjuvant thyroxine or levothyrocine therapies postoperatively and 22 were treated with 131I. In total, 164 patients (97.6%) were followed up. The mean follow-up duration was 46 months (range: 2-127 months). Among 6 cases receiving palliative excision, 5 patients died from apnea (n = 3), systemic metastasis complicated with failure (n = 1) and unknown causes (n = 1) at postoperative 2, 3, 6, 24 and 30 months. One was lost contact during follow up. Among the 159 patients, one case was suspected with pulmonary metastasis detected by chest CT scans and still survived for 16 months. During postoperative 3 to 41 months (median 12 months), 6 patients underwent repeated surgery due to neck lymph node recurrence including 5 bilateral and 1 unilateral carcinoma. Four previously received unilateral neck lymph node dissection. Another 2 patients underwent repeated operation due to the recurrent contralateral remnant adenoma at postoperative 13 and 24 months (gland lobe, isthmus and contralateral subtotal thyroidectomy, unilateral neck lymph dissection or VI area dissection). No patients undergoing radical resection died. The overall 1-, 2-, 5- and 10-year survival rates achieved 98.2%, 97.4%, 96.5% and 96.5%. AJCC staging: 133 were evaluated as stage I, 7 stage II, 14 stage III, 11 stage IV and 3 stage IVc. AJCC staging was correlated with clinical prognosis (χ2 = 168.832, P = 0.000).
Discussion
Multifocal lesion is one of clinical characteristics of papillary thyroid carcinoma with an incidence of 18%-87% [3,4]. In this study, the prevalence of multifocal lesions was 25.9%. In addition, the incidence of bilateral lesions was 69.6%. Multifocal lesions mainly occurred in male subjects with a family history of malignant thyroid tumors. However, the incidence of Goiter, Hashimoto’s thyroiditis or alternative benign diseases in multifocal patients was lower compared with those in solitary lesions (41% vs 60%). These outcomes hinted that the pathogenesis of thyroid diseases probably varies. Multifocal lesions have a higher degree of malignant characteristics, manifested as a higher incidence of neck lymph metastasis and extra-thyroidal infiltration. In patients with multifocal lesions, male subjects with neck lymph nodular enlargement, bilateral tumor involvement and ≥ 3 lesions were more incline to a higher degree of malignancy. The papillary thyroid carcinoma subjects complicated with benign thyroid diseases presented with relatively small tumors and a relatively low incidence of lymph node metastasis. Most of them were primarily diagnosed with benign thyroid diseases, which further validate the results of small thyroid cancer investigations [5-7].
Thyroid cancer can be classified into two phenotypes: “dominant cancer” regarding cancer node as primary symptom and “sporadic cancer” manifested as benign diseases. The dominant cancer has a higher degree of malignancy. Whether multifocal lesions arise from thyroid gland metastasis or multiclonal origins remains controversial. Recent studies demonstrated that partial multifocal papillary thyroid carcinoma is of multiclonal origin [8]. In this clinical trial, the incidence of lymph nodular metastasis was relatively high in patients with non-small cancer, hinting that this event probably arises from thyroid gland metastasis. Nevertheless, Bansal et al [9] found that the percentage of papillary thyroid carcinoma patients with ≥ 3 lesions arising from multiclonal origin was higher, indicating that the number of lesions could not be used to identify its origin.
In this study, the proportion of multifocal papillary thyroid carcinoma subjects involving with bilateral thyroid was added up to 69.6%. Previous studies reported that patients presented with multifocal tumors after unilateral thyroidectomy and underwent total thyroidectomy within half a year. The incidence of contralateral small gland lobe cancer was 69.1%, significantly higher than 26.9% in patients with unilateral solitary lesions [10].
Consequently, it is necessary to perform total thyroidectomy in patients suffering from multifocal papillary thyroid carcinoma. However, only two cases (1.2%) had recurrent thyroid tumors in this study. For patients who did not undergo total thyroidectomy, it is equally a feasible option to excise remnant thyroid when they are suspected with recurrence. It has been recognized that neck lymph node dissection should be performed for patients with lymph node metastasis, whereas it remains debatable whether it should be conduced for those without lymph node metastasis detected by preoperative examination.
The British guidelines of thyroid cancer treatment suggested that multifocal cancer should be surgically treated with total thyroidectomy in combination with central lymph node dissection. Lateral lymph node dissection may be considered when palpable enlarged lymph nodes are detected in clinical settings [11-13]. American guidelines proposed that lymph node dissection should be performed for clinical cases with palpable lymph node enlargement [14]. The findings in this study and Park’s investigation demonstrated that the incidence of lymph node metastasis in multifocal patients is higher compared with that in those with solitary lesions. In recent years, cNO patients without lymph node enlargement underwent conventional central dissection and the incidence of lymph node metastasis ranged from 47.6% to 51.3% [15-19]. We also conducted conventional central lymph node dissection in cNO patients and found the incidence of lymph node metastasis exceeded 30%. Among 6 patients with recurrent lymph node lesions, two cases did not undergo neck lymph node dissection and recurred in VI area at postoperative l0 and 14 months.
Taken together, we recommend the application of conventional central neck lymph node dissection for papillary thyroid carcinoma patients. Lateral lymph node dissection may be considered when enlarged lymph nodes are detected in lateral area. Multifocal lesions possess a higher degree of biological malignancy compared with solitary cases. Total thyroidectomy combined with central lymph node dissection should be regarded as the standard surgery. AJCC grading remains a pivotal prognosis factor of multifocal papillary thyroid carcinoma.
Disclosure of conflict of interest
None.
References
- 1.Gao J, Yu Y, Li X, Zhao J, Zhao C, Zhao J, Liu Y, Li Y, Gao M. Clinical and biological features of familial nonmedullary thyroid carcinoma. Zhonghua Zhong Liu Za Zhi. 2014;36:202–6. [PubMed] [Google Scholar]
- 2.Fridman M, Savva N, Krasko O, Mankovskaya S, Branovan DI, Schmid KW, Demidchik Y. Initial presentation and late results of treatment of post-chernobyl papillary thyroid carcinoma in children and adolescents of belarus. J Clin Endocrinol Metab. 2014;99:2932–41. doi: 10.1210/jc.2013-3131. [DOI] [PubMed] [Google Scholar]
- 3.Singhal S, Sippel RS, Chen H, Schneider DF. Distinguishing classical papillary thyroid microcancers from follicular-variant microcancers. J Surg Res. 2014;190:151–6. doi: 10.1016/j.jss.2014.03.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Ahn HY, Chung YJ, Kim BS, Kang KH, Seok JW, Kim HS, Park SJ, Cho BY. Clinical significance of the BRAF V600E mutation in multifocal papillary thyroid carcinoma in Korea. Surgery. 2014;155:689–95. doi: 10.1016/j.surg.2013.12.025. [DOI] [PubMed] [Google Scholar]
- 5.Kuo SF, Lin SF, Chao TC, Hsueh C, Lin KJ, Lin JD. Prognosis of multifocal papillary thyroid carcinoma. Int J Endocrinol. 2013;2013:809382. doi: 10.1155/2013/809382. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Lubitz CC, Economopoulos KP, Pawlak AC, Lynch K, Dias-Santagata D, Faquin WC, Sadow PM. Hobnail variant of papillary thyroid carcinoma: an institutional case series and molecular profile. Thyroid. 2014;24:958–65. doi: 10.1089/thy.2013.0573. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Iacobone M, Jansson S, Barczyński M, Goretzki P. Multifocal papillary thyroid carcinoma--a consensus report of the European Society of Endocrine Surgeons (ESES) Langenbecks Arch Surg. 2014;399:141–54. doi: 10.1007/s00423-013-1145-7. [DOI] [PubMed] [Google Scholar]
- 8.Frank R, Baloch ZW, Gentile C, Watt CD, LiVolsi VA. Multifocal Fibrosing Thyroiditis and Its Association with Papillary Thyroid Carcinoma Using BRAF Pyrosequencing. Endocr Pathol. 2014;25:236–40. doi: 10.1007/s12022-013-9289-0. [DOI] [PubMed] [Google Scholar]
- 9.Bansal M, Gandhi M, Ferris RL, Nikiforova MN, Yip L, Carty SE, Nikiforov YE. Molecular and histopathologic characteristics of multifocal papillary thyroid carcinoma. Am J Surg Pathol. 2013;37:1586–91. doi: 10.1097/PAS.0b013e318292b780. [DOI] [PubMed] [Google Scholar]
- 10.Bauer AJ. Clinical behavior and genetics of nonsyndromic, familial nonmedullary thyroid cancer. Front Horm Res. 2013;41:141–8. doi: 10.1159/000345674. [DOI] [PubMed] [Google Scholar]
- 11.Kuhn E, Teller L, Piana S, Rosai J, Merino MJ. Different clonal origin of bilateral papillary thyroid carcinoma, with a review of the literature. Endocr Pathol. 2012;23:101–7. doi: 10.1007/s12022-012-9202-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Park JH, Lee YS, Kim BW, Chang HS, Park CS. Skip lateral neck node metastases in papillary thyroid carcinoma. World J Surg. 2012;36:743–7. doi: 10.1007/s00268-012-1476-5. [DOI] [PubMed] [Google Scholar]
- 13.Coca-Pelaz A, Vivanco-Allende B, Alvarez-Marcos C, Suarez-Nieto C. Multifocal papillary thyroid carcinoma associated with primary amyloid goiter. Auris Nasus Larynx. 2012;39:549–51. doi: 10.1016/j.anl.2011.09.003. [DOI] [PubMed] [Google Scholar]
- 14.British Thyroid Association Guidelines for the Management of Thyroid Cancer in Adults. 2002 doi: 10.1097/00006231-200409000-00006. [DOI] [PubMed] [Google Scholar]
- 15.Takada H, Kikumori T, Imai T, Sawaki M, Shibata A, Kiuchi T. Patterns of lymph node metastases in papillary thyroid carcinoma: results from consecutive bilateral cervical lymph node dissection. World J Surg. 2011;35:1560–6. doi: 10.1007/s00268-011-1133-4. [DOI] [PubMed] [Google Scholar]
- 16.Wu AW, Wang MB, Nguyen CT. Surgical practice patterns in the treatment of papillary thyroid microcarcinoma. Arch Otolaryngol Head Neck Surg. 2010;136:1182–90. doi: 10.1001/archoto.2010.193. [DOI] [PubMed] [Google Scholar]
- 17.Polyzos SA, Anastasilakis AD, Iakovou IP, Partsalidou V. Primary hyperparathyroidism and incidental multifocal metastatic papillary thyroid carcinoma in a man. Arq Bras Endocrinol Metabol. 2010;54:578–82. doi: 10.1590/s0004-27302010000600012. [DOI] [PubMed] [Google Scholar]
- 18.Chaychi L, Belbruno K, Golding A, Memoli V. Unusual manifestation of parathyroid carcinoma in the setting of papillary thyroid cancer. Endocr Pract. 2010;16:664–8. doi: 10.4158/EP10061.CR. [DOI] [PubMed] [Google Scholar]
- 19.Lombardi CP, Bellantone R, De Crea C, Paladino NC, Fadda G, Salvatori M, Raffaelli M. Papillary thyroid microcarcinoma: extrathyroidal extension, lymph node metastases, and risk factors for recurrence in a high prevalence of goiter area. World J Surg. 2010;34:1214–21. doi: 10.1007/s00268-009-0375-x. [DOI] [PubMed] [Google Scholar]