Relationship between lymphovascular invasion and clinicopathological features of papillary thyroid carcinoma

  • Atakan Sezer Department of Surgery, Faculty of Medicine, Trakya University, Edirne, Turkey
  • Mehmet Celik Department of Endocrinology, Faculty of Medicine, Trakya University, Edirne, Turkey
  • Buket Yilmaz Bulbul Department of Endocrinology, Faculty of Medicine, Trakya University, Edirne, Turkey
  • Nuray Can Department of Pathology, Faculty of Medicine, Trakya University, Edirne, Turkey
  • Ebru Tastekin Department of Pathology, Faculty of Medicine, Trakya University, Edirne, Turkey
  • Semra Ayturk Department of Endocrinology, Faculty of Medicine, Trakya University, Edirne, Turkey
  • Funda Ustun Department of Nuclear Medicine, Faculty of Medicine, Trakya University, Edirne, Turkey
  • Sibel Guldiken Department of Endocrinology, Faculty of Medicine, Trakya University, Edirne, Turkey
  • Necdet Sut Department of Biostatistics, Faculty of Medicine, Trakya University, Edirne, Turkey
Keywords: Papillary thyroid carcinoma, clinicopathological features, lymphovascular, PTC, LVI, lymphovascular invasion, BRAFV600E mutation

Abstract

Lymphovascular invasion (LVI) is an important prognostic factor in various solid tumors, however, data on the association between LVI and thyroid carcinomas are limited. In this study, we evaluated the relationship between LVI and clinicopathological features of papillary thyroid carcinoma (PTC). Six hundred seventy-eight patients diagnosed with PTC between 2012 and 2015 were included into the study. Patients were classified based on the presence or absence of LVI. Gender, age, ultrasonography (US), tumor size and multifocality, BRAFV600E mutation, perineural and capsular invasion, extrathyroid extension (ETE), nodal metastasis, and recurrences were evaluated, and risk analysis was performed for each parameter. The number of patients with LVI [LVI (+)] was 63, while the number of patients without LVI [LVI (-)] was 615. The female/male ratio was 564/114. LVI was present in 18.4% of male patients and in 7.4 % of female patients. In the age group between 17-25 years LVI was detected in 6/13 patients, and this result was statistically significant compared to other age groups (p = 0.004). Suspicious lymph nodes upon US, perineural or capsular invasion, ETE, tumor size, and nodal metastasis were significantly more frequent in LVI (+) group (p < 0.001). The frequency of BRAFV600E mutation was also significantly higher in LVI (+) group (p < 0.001). Overall, the presence of LVI was associated with gender, tumor size, age, lymph node metastasis, pathological lymph nodes, perineural and capsular invasion, ETE, and BRAFV600E mutation. These results suggest that in PTC patients undergoing thyroidectomy, the presence of LVI should be considered as an indicator of aggressive clinicopathological features and those patients should be followed up carefully for recurrences and metastasis.

Downloads

Download data is not yet available.

Author Biographies

Atakan Sezer, Department of Surgery, Faculty of Medicine, Trakya University, Edirne, Turkey
Department of Surgery
Mehmet Celik, Department of Endocrinology, Faculty of Medicine, Trakya University, Edirne, Turkey
Department of Endocrinology
Buket Yilmaz Bulbul, Department of Endocrinology, Faculty of Medicine, Trakya University, Edirne, Turkey
Department of Endocrinology
Nuray Can, Department of Pathology, Faculty of Medicine, Trakya University, Edirne, Turkey
Department of Pathology
Ebru Tastekin, Department of Pathology, Faculty of Medicine, Trakya University, Edirne, Turkey
Department of Pathology
Semra Ayturk, Department of Endocrinology, Faculty of Medicine, Trakya University, Edirne, Turkey
Department of Endocrinology
Funda Ustun, Department of Nuclear Medicine, Faculty of Medicine, Trakya University, Edirne, Turkey
Department of Nuclear Medicine
Sibel Guldiken, Department of Endocrinology, Faculty of Medicine, Trakya University, Edirne, Turkey
Department of Endocrinology
Necdet Sut, Department of Biostatistics, Faculty of Medicine, Trakya University, Edirne, Turkey
Department of Biostatistics

References

Aschebrook-Kilfoy B, Ward MH, Sabra MM, Devesa SS. Thyroid cancer incidence patterns in the United States by histologic type, 1992–2006. Thyroid 2011;21(2):125-34. https://doi.org/10.1089/thy.2010.0021.

Lang BH, Yih PCL, Shek TWH, Wan KY, Wong KP, Lo CY. Factors affecting the adequacy of lymph node yield in prophylactic unilateral central neck dissection for papillary thyroid carcinoma. J Surg Oncol 2012;106(8):966-71. https://doi.org/10.1002/jso.23201.

American Cancer Society. Cancer Facts & Figures 2016. Atlanta: American Cancer Society; 2016 [cited 2016 November 10]. Available from: https://old.cancer.org/acs/groups/content/@research/documents/document/acspc-047079.pdf.

Cooper D, Doherty G, Haugen B, Kloos R, Lee S, Mandel S, et al. American Thyroid Association (ATA) guidelines task force on thyroid nodules and differentiated thyroid cancer. Revised American thyroid association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19(11):1167-214. https://doi.org/10.1089/thy.2009.0110.

Dralle H, Machens A. Surgical approaches in thyroid cancer and lymph-node metastases. Best Pract Res Clin Endocrinol Metab 2008;22(6):971-87. https://doi.org/10.1016/j.beem.2008.09.018.

Lang BH, Lo CY, Chan WF, Lam KY, Wan KY. Staging systems for papillary thyroid carcinoma: A review and comparison. Ann Surg 2007;245(3):366-78. https://doi.org/10.1097/01.sla.0000250445.92336.2a.

Hay ID. Papillary thyroid carcinoma. Endocrinol Metab Clin North Am 1990;19(3):545-76.

Cady B, Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 1988;104(6):947-53.

Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: Development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 1993;114(6):1050-7.

Byar DP, Green SB, Dor P, Williams ED, Colon J, van Gilse HA, et al. A prognostic index for thyroid carcinoma. A study of the E.O.R.T.C. Thyroid Cancer Cooperative Group. Eur J Cancer 1979;15(8):1033-41.

https://doi.org/10.1016/0014-2964(79)90291-3.

Cady B. Hayes Martin Lecture. Our AMES is true: how an old concept still hits the mark: or, risk group assignment points the arrow to rational therapy selection in differentiated thyroid cancer. Am J Surg 1997;174(5):462-8.

https://doi.org/10.1016/S0002-9610(97)00162-1.

Lang BH, Lo CY, Chan WF, Lam KY, Wan KY. Prognostic factors in papillary and follicular thyroid carcinoma: Their implications for cancer staging. Ann Surg Oncol 2007;14(2):730-8. https://doi.org/10.1245/s10434-006-9207-5.

Duntas L, Grab-Duntas BM. Risk and prognostic factor for differentiated thyroid cancer. Hell J Nucl Med 2006;9(3):156-62.

Santos T, Estêvão R, Antunes L, Certal V, Silva JC, Monteiro E. Clinical and histopathological prognostic factors in locoregional advanced laryngeal cancer. J Laryngol Otol 2016;130(10):948-53. https://doi.org/10.1017/S002221511600880X.

Nathenson MJ, Ravi V, Fleming N, Wang WL, Conley A. Uterine Adenosarcoma: A review. Curr Oncol Rep 2016;18(11):68. https://doi.org/10.1007/s11912-016-0552-7.

Kommoss F, Kommoss F, Grevenkamp F, Bunz A-K, Taran F-A, Fend F, et al. L1CAM: Amending the "low-risk" category in endometrial carcinoma. J Cancer Res Clin Oncol 2016;143(2):255-262.

Al-Sukhni E, Attwood K, Gabriel EM, LeVea CM, Kanehira K, Nurkin SJ. Lymphovascular and perineural invasion are associated with poor prognostic features and outcomes in colorectal cancer: A retrospective cohort study. Int J Surg 2017;37:42-9. https://doi.org/10.1016/j.ijsu.2016.08.528.

Wei YS, Yao DS, Long Y. Evaluation of the association between perineural invasion and clinical and histopathological features of cervical cancer. Mol Clin Oncol 2016;5(3):307-11. https://doi.org/10.3892/mco.2016.941.

Min KW, Kim DH, Son BK, Kim EK, Ahn SB, Kim SH, et al. Invasion depth measured in millimeters is a predictor of survival in patients with distal bile duct cancer: Decision tree approach. World J Surg 2017;41(1):232-40. https://doi.org/10.1007/s00268-016-3687-7.

Barbera L, Gien LT, Sutradhar R, Thomas G, Covens A, Elit L, et al. The added value of pathology review in vulva cancer: Results from a population-based cohort study. Int J Gynecol Pathol 2017;36(2):107-10. DOI: 10.1097/PGP.0000000000000313.

Ieni A, Barresi V, Cardia R, Licata L, Di Bari F, Benvenga S, et al. The micropapillary/hobnail variant of papillary thyroid carcinoma: A review of series described in the literature compared to a series from one southern Italy pathology institution. Rev Endocr Metab Disord 2016 Nov 28. [Epub ahead of print].

https://doi.org/10.1007/s11154-016-9398-4.

Xu B, Wang L, Tuttle RM, Ganly I, Ghossein R. Prognostic impact of extent of vascular invasion in low-grade encapsulated follicular cell-derived thyroid carcinomas: A clinicopathologic study of 276 cases. Hum Pathol 2015;46(12):1789-98. https://doi.org/10.1016/j.humpath.2015.08.015.

Liu L, Chang JW, Jung SN, Park HS, Oh T, Lim YC, et al. Clinical implications of the extent of BRAFV600E alleles in patients with papillary thyroid carcinoma. Oral Oncol 2016;62:72-7. https://doi.org/10.1016/j.oraloncology.2016.10.005.

Walts AE, Mirocha JM, Bose S. Follicular variant of papillary thyroid carcinoma (FVPTC): Histological features, BRAF V600E mutation, and lymph node status. J Cancer Res Clin Oncol 2015;141(10):1749-56.

https://doi.org/10.1007/s00432-015-1939-9.

Pontius LN, Youngwirth LM, Thomas SM, Scheri RP, Roman SA, Sosa JA. Lymphovascular invasion is associated with survival for papillary thyroid cancer. Endocr Relat Cancer 2016;23(7):555-62. https://doi.org/10.1530/ERC-16-0123.

Mete O, Asa SL. Pathological definition and clinical significance of vascular invasion in thyroid carcinomas of follicular epithelial derivation. Mod Pathol 2011;24(12):1545-52. https://doi.org/10.1038/modpathol.2011.119.

Wiltshire JJ, Drake TM, Uttley L, Balasubramanian SP. Systematic review of trends in the incidence rates of thyroid cancer. Thyroid 2016;26(11):1541-52. https://doi.org/10.1089/thy.2016.0100.

Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R, Howlader N, et al. SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. Bethesda, MD: National Cancer Institute; 2009.

Can N, Tastekin E, Ozyilmaz F, Sezer YA, Guldiken S, Sut N, et al. Histopathological evidence of lymph node metastasis in papillary thyroid carcinoma. Endocr Pathol 2015;26(3):218-28. https://doi.org/10.1007/s12022-015-9382-7.

Yildirim E. A model for predicting outcomes in patients with differentiated thyroid cancer and model performance in comparison with other classification systems. J Am Coll Surg 2005;200(3):378-92. https://doi.org/10.1016/j.jamcollsurg.2004.10.031.

Akslen LA. Prognostic importance of histologic grading in papillary thyroid carcinoma. Cancer 1993;72(9):2680-5. https://doi.org/10.1002/1097-0142(19931101)72:9<2680::AID-CNCR2820720926>3.0.CO;2-D.

Sebastian SO, Gonzalez JR, Paricio PP, Perez JS, Flores DP, Madrona AP, et al. Papillary thyroid carcinoma: Prognostic index for survival including the histological variety. Arch Surg 2000;135(3):272-7. https://doi.org/10.1001/archsurg.135.3.272.

Sugitani I, Kasai N, Fujimoto Y, Yanagisawa A. A novel classification system for patients with PTC: Addition of the new variables of large (3 cm or greater) nodal metastases and reclassification during the follow-up period. Surgery 2004;135(2):139-48. https://doi.org/10.1016/S0039-6060(03)00384-2.

Song YJ, Shin SH, Cho JS, Park MH, Yoon JH, Jegal YJ. The role of lymphovascular invasion as a prognostic factor in patients with lymph node-positive operable invasive breast cancer. J Breast Cancer 2011;14(3):198-203. https://doi.org/10.4048/jbc.2011.14.3.198.

Khwaja SS, Ivanovich J, DeWees TA, Ochoa L, Mullen DF, Thomas M, et al. Lymphovascular space invasion and lack of down staging after neoadjuvant chemotherapy are strong predictors of adverse outcome in young women with locally advanced breast cancer. Cancer Med 2016;5(2):230-8. https://doi.org/10.1002/cam4.586.

Gardner RE, Tuttle RM, Burman KD, Haddady S, Truman C, Sparling YH, et al. Prognostic importance of vascular invasion in papillary thyroid carcinoma. Arch Otolaryngol Head Neck Surg 2000;126(3):309-12. https://doi.org/10.1001/archotol.126.3.309.

Falvo L, Catania A, D'Andrea V, Marzullo A, Giustiniani MC, De Antoni E. Prognostic importance of histologic vascular invasion in papillary thyroid carcinoma. Ann Surg 2005;241(4):640-6. https://doi.org/10.1097/01.sla.0000157317.60536.08.

Kim JM, Kim TY, Kim WB, Gong G, Kim SC, Hong SJ, et al. Lymphovascular invasion is associated with lateral cervical lymph node metastasis in papillary thyroid carcinoma. Laryngoscope 2006;116(11):2081-5. https://doi.org/10.1097/01.mlg.0000242118.79647.a9.

Hsieh SH, Chen ST, Hsueh C, Chao TC, Lin JD. Gender-specific variation in the prognosis of papillary thyroid cancer TNM stages II to IV. Int J Endocrinol 2012;2012:379097. DOI: 10.1155/2012/379097.

Haymart MR. Understanding the relationship between age and thyroid cancer. Oncologist 2009;14(3):216-21. https://doi.org/10.1634/theoncologist.2008-0194.

Qu H, Sun Gr, Liu Y, He Qs. Clinical risk factors for central lymph node metastasis in papillary thyroid carcinoma: A systematic review and meta‐analysis. Clin Endocrinol 2015;83(1):124-32. https://doi.org/10.1111/cen.12583.

Kim SY, Kwak JY, Kim EK, Yoon JH, Moon HJ. Association of preoperative US features and recurrence in patients with classic papillary thyroid carcinoma. Radiology 2015;277(2):574-83. https://doi.org/10.1148/radiol.2015142470.

Nam SY, Shin JH, Han BK, Ko EY, Ko ES, Hahn SY, et al. Preoperative ultrasonographic features of papillary thyroid carcinoma predictbiological behavior. J Clin Endocrinol Metab 2013;98(4):1476-82. https://doi.org/10.1210/jc.2012-4072.

Liu L, Chang JW, Jung SN, Park HS, Oh T, Lim YC, et al. Clinical implications of the extent of BRAFV600E alleles in patients with papillary thyroid carcinoma. Oral Oncol 2016;62:72-7. https://doi.org/10.1016/j.oraloncology.2016.10.005.

Kakarmath S, Heller HT, Alexander CA, Cibas ES, Krane JF, Barletta JA, et al. Clinical, sonographic, and pathological characteristics of RAS-positive versus BRAF-positive thyroid carcinoma. J Clin Endocrinol Metab 2016;101(12):4938-44.

https://doi.org/10.1210/jc.2016-2620.

Gambardella C, Tartaglia E, Nunziata A, Izzo G, Siciliano G, Cavallo F, et al. Clinical significance of prophylactic central compartment neck dissection in the treatment of clinically node-negative papillary thyroid cancer patients. World J Surg Oncol 2016;14(1):247. https://doi.org/10.1186/s12957-016-1003-5.

Conzo G, Mauriello C, Docimo G, Gambardella C, Thomas G, Cavallo F, et al. Clinicopathological pattern of lymph node recurrence of papillary thyroid cancer. Implications for surgery. Int J Surg 2014;12 Suppl 1:S194-7. https://doi.org/10.1016/j.ijsu.2014.05.010.

Relationship between lymphovascular invasion and clinicopathological features of papillary thyroid carcinoma
Published
2017-05-20
How to Cite
1.
Sezer A, Celik M, Yilmaz BulbulB, Can N, Tastekin E, Ayturk S, Ustun F, Guldiken S, Sut N. Relationship between lymphovascular invasion and clinicopathological features of papillary thyroid carcinoma. Bosn J of Basic Med Sci [Internet]. 2017May20 [cited 2020Nov.27];17(2):144-51. Available from: https://bjbms.org/ojs/index.php/bjbms/article/view/1924
Section
Translational and Clinical Research

INTRODUCTION

Among the tumors of endocrine system, thyroid carcinoma is the most common malignancy, although only 1% of all cancers are of this type. The majority of thyroid cancers are well-differentiated tumors originating from thyroid follicular cells. The most common type of thyroid cancer is papillary thyroid cancer (PTC), representing 85% of all thyroid cancer cases [1]. According to the data from “Cancer Facts and Figures, 2016”, thyroid cancer was diagnosed in over 64,000 individuals in 2016 in the U.S.A, and the incidence rate increased approximately 5% in the last 10 years [2,3]. Although PTC is a slowly growing tumor and has an excellent prognosis, with expected 5-year survival greater than 98%, histological subtypes of PTC such as columnar cell variant (CCV), tall cell variant (TCV), and diffuse sclerosing variant (DSV) have a relatively worse prognosis [4,5]. Among the most frequently used staging systems for estimating the prognosis and risk of recurrence in thyroid carcinomas are those developed by the Union for International Cancer Control (UICC) and American Joint Commission on Cancer (AJCC) [the TNM Classification of Malignant Tumours (TNM)], European Organization for Research and Treatment of Cancer (EORTC), Mayo Clinic (Age, Grade, Extent, Size or AGES and Metastases, Age, Complete resection, Invasion, Size or MACIS), and Lahey Clinic (Age, Metastases, Extent, Size or AMES) [6]. These systems consistently include clinicopathological parameters, however, factors such as age, gender, tumor type and size, extracapsular extension, lymph nodes, lymphovascular invasion (LVI), and distant metastasis are not all covered by a single staging system [7-13]. Although LVI is a poor prognostic factor for numerous cancers, including laryngeal, uterine, endometrial, colorectal, cervical, bile duct, and vulvar cancer, none of the staging systems include LVI in staging of thyroid carcinomas [14-20]. In a clinical series conducted by Ieni et al. [21], 295 PTC patients (8 of them with a newly described entity - micropapillary/hobnail variant [MPHC]) were evaluated and the authors concluded that the prognosis of MPHC-PTC tumors was better compared to the other groups, possibly due to a lower rate of vascular invasion in this group [21]. In another study conducted by Xu et al. [22], extensive vascular invasion (EVI) was an independent predictor of poor recurrence-free survival in low-grade encapsulated follicular cell–derived thyroid carcinomas (LGEFCs), and patients with EVI may be considered for more aggressive treatment modalities. Data on the association between LVI and clinicopathological features of PTC are limited to small case series, and conflicting results have been reported [23-26]. In this study, we investigated the relationship between the presence of LVI and clinical features and histopathological outcomes of PTC patients.

MATERIALS AND METHODS

Medical reports of patients who were diagnosed with PTC at Faculty of Medicine, Trakya University, and operated between 2010 and 2015, were obtained from the institutional database system. The institutional Ethics Committee approved the study protocol. Patients were classified based on the presence or absence of lymphovascular invasion [LVI (+) or LVI (-)]. Gender, age, preoperative neck and thyroid ultrasonography (US), tumor size and multifocality, BRAFV600E mutation, perineural invasion, capsular invasion, ETE, lymph node metastasis, local recurrences, tumor localization, tumor focality, and the presence of Hashimoto’s thyroiditis were evaluated.

Radiological examination

All patients underwent detailed preoperative neck and thyroid US for determining the presence of nodules and lymph nodes and thyroid and nodule size. Suspicious features indicating a malignant thyroid nodule, such as as microcalcification, irregular margins, ratio of anteroposterior to transverse dimension, presence of central vascularization, absence of halo, and hypoechogenicity were recorded for each nodule. The size, shape, cortex thickness, microcalcification, loss of fatty hyperechoic hilum, echogenicity, and cystic proportion were determined for lymph nodes.

Histopathological evaluation

Sections obtained from formalin-fixed, paraffin-embedded (FFPE) blocks of thyroidectomy specimens were stained with hematoxylin and eosin (H&E) stain and re-evaluated by two pathologists in a blind manner. The presence of LVI was determined if tumor cells were observed in lymphovascular spaces, the cells underlay endothelium of lymphovascular channels, the cells invaded through a vessel wall and endothelium, or thrombus was adherent to intravascular tumor, as described by Mete et al. [26]. The histopathological subtypes of PTC were classified as: classic PTC, follicular variant, oncocytic variant, and aggressive variants (CCV, TCV, and DSV). Tumor size was measured in unifocal tumors as the largest diameter and defined as “Tumor size”. Each nodule for multifocal tumors was measured separately and defined as “Total tumor size”.

BRAF mutation analysis

DNA was isolated from FFPE tissue samples containing at least 30% of tumor cells. Then, DNA purification was performed using nucleic acid isolation kits for FFPE tissues (QIAamp® DNA FFPE Tissue Kit, EZ1® DNA Tissue Kit, PAXgene® Tissue Containers, and PAXgene Tissue DNA Kit, QIAGEN, Hilden, Germany). Following polymerase chain reaction (PCR), pyrosequencing analyses were performed on a PyroMarkQ24 sequencing system (Hilden, Germany) using Seq Primer BRAF 600 or Seq Primer BRAF 464–469 sequencing primers.

Surgical procedure and follow-up

All patients underwent total thyroidectomy. Patients with lymph node metastasis had lymph node dissection. Thyroglobulin values, neck US, whole-body scan, follow-up frequency, and postoperative, radioiodine ablation treatment were organized case specific in accordance with American Thyroid Association Guidelines (ATA) [4].

Statistical analysis

Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 20.0 (IBM Corp, Armonk, NY) and MedCalc version 12.7.7 (MedCalc Software bvba, Ostend, Belgium). Results were expressed as mean ± standard deviation (SD) or numbers and percentages. The Mann-Whitney U test was used for the comparison of numeric independent factors, including age, tumor size (unifocal), and tumor total size (multifocal), between LVI (+) and LVI (-) group. Categorical independent factors were compared using the Chi-squared test. Odds ratios and 95% confidence intervals were calculated using logistic regression analysis. For discriminating between LVI (+) and LVI (-) groups, the cut-off values of tumor size (unifocal) and total tumor size (multifocal) were determined using a receiver operating characteristic (ROC) curve. Next, the area under the curve (AUC), sensitivity, specificity, and positive and negative likelihood ratios were calculated. A p value less than 0.05 was accepted as statistically significant.

RESULTS

We reviewed medical reports from 705 patients diagnosed with PTC between 2010 and 2015. A total of 678 patients were included in the final sample, while 27 patients were excluded due to lost to follow-up. The sample included 564 (83.2%) female and 114 (16.8%) male patients, and the female/male ratio was 4.96. LVI was histologically confirmed in 63/678 (9.3%) patients, while 615/678 (90.7%) patients did not have LVI. Among the female patients, 7.4% had LVI and 18.4% of male patients had LVI. The risk of LVI was 2.80 times greater in the male patients compared to the female patients [95% CI = 1.59-4.95; p < 0.001] (Table 1).

TABLE 1: Relationship between demographic data and risk of LVI in PTC patients

The overall mean age was 49.4 ± 12.3 years (min-max: 17-79 years). The mean age for male and female patients was 52.2 ± 14.2 and 48.9 ± 11.8 years, respectively (p = 0.021). The mean age of male and female patients with LVI was 44.3 ± 16.7 and 44.6 ± 12.2 years, respectively. The risk of LVI was higher in younger patients compared to older patients [for female patients OR = 0.96; 95% CI = 0.94-0.99; p = 0.018; for male patients OR = 0.95; 95% CI; p = 0.019] (Table 1 and Figure 1). When the patients were classified according to the age into two groups (i.e. <45 and >45 years old), the ratio of LVI (+) patients was statistically higher in the <45 years group (OR = 2.20; 95% CI = 1.30-3.72; p = 0.004). A detailed classification of the patients according to the age decades in relation to the risk of LVI is shown in Table 2. The patients in 17-25 years group had the highest rate of LVI compared to the other age groups [p = 0.004] (Table 1).

FIGURE 1: A significantly higher risk of lymphovascular invasion (LVI) was observed in younger papillary thyroid carcinoma patients (<45 years old) compared to the patients with >45 years (OR = 2.20; 95% CI = 1.30-3.72; p = 0.004).
TABLE 2: Frequency of LVI in different age groups of PTC patients

Preoperative neck US revealed pathological lymph nodes in 37/675 patients. The patients with pathological lymph nodes, preoperatively detected with US, had a statistically higher rate of LVI compared to patients without pathological lymph nodes (OR = 16.69; 95% CI = 8.14-34.24; p < 0.001).

The mean tumor size for unifocal tumors was 10.91 ± 12.03 mm (min-max: 0.1-90 mm). The mean tumor size for multifocal tumors was 16.14 ± 15.16 mm (min-max: 0.1-93 mm). The mean unifocal tumor size for patients with LVI was 22.2 ± 14.7 mm and 9.8 ± 11.1 mm in LVI (-) group (p < 0.001). The mean tumor size for multifocal tumors was 28.62 ± 20.3 mm in LVI (+) and 14.82 ± 13.9 mm in LVI (-) group (p < 0.001). The risk of LVI for every 1 mm of the tumor was 1.05 times greater for unifocal tumors (OR = 1.05; 95% CI = 1.02-1.08) and 1.04 times greater for multifocal tumors [OR = 1.04; 95% CI = 1.02-1.05] (Table 3).

TABLE 3: Relationship between tumor size and LVI in PTC patients

To discriminate between LVI (+) and LVI (-) cases, ROC curve analysis was performed. The cut-off point for the size of unifocal tumors was >9.5 mm (92.3% sensitivity, 70.4% specificity, and 84% accuracy), and >13 mm for the size of multifocal tumors [82.5% sensitivity, 61% specificity, and 75% accuracy] (Table 4, Figure 2).

TABLE 4: Likelihood of LVI in PTC patients in relation to the tumor size
FIGURE 2: To discriminate between lymphovascular invasion [LVI (+)] and LVI (-) cases, receiver operating characteristic (ROC) curve analysis was performed. The cut-off point for the size of unifocal tumors was >9.5 mm (92.3% sensitivity, 70.4% specificity, and 84% accuracy), and >13 mm for the size of multifocal tumors (82.5 % sensitivity, 61 % specificity, and 75 % accuracy).

Ninety-three patients out of 453 patients were positive for BRAFV600E mutation [BRAF(+) patients]. Among the BRAF(+) patients, 23 had LVI and 70 did not have LVI (p < 0.001). The frequency of BRAFV600E mutation was 4.40 times higher in patients with LVI compared to the patients without LVI (95% CI = 2.36-8.20) (Table 5).

TABLE 5: Relationship between LVI and histopathological parameters of PTC patients

Perineural invasion was observed in 12/677 patients (1.7%). Among these patients, perineural invasion was observed in 6/62 patients with LVI (9.7%) and in 6/615 patients without LVI [1%] (p < 0.001). The frequency of perineural invasion was 10.87 times higher in patients with LVI compared to the patients without LVI (95% CI = 3.39-34.83) (Table 5).

The number of patients with capsular invasion was 217/678 patients (32%). The risk of capsular invasion was 11.49 times greater in patients with LVI compared to the patients without LVI (OR = 11.49; 95% CI = 5.98-22.09; p < 0.001) (Table 5).

ETE was observed in 136/678 patients (20.05%). A statistically significant difference was observed in the frequency of ETE between LVI (+) and LVI (-) group (OR = 19.16; 95% CI = 10.28-35.70; p < 0.001) (Table 5).

Lymph node metastasis was observed in 62/409 patients (15.15%). Lymph node metastasis was significantly more common in LVI (+) group compared to LVI (-) group, and the risk was 30.61 times greater in LVI (+) group (OR = 30.61; 95% CI = 14.99-62.49; p < 0.001) (Table 5).

Among the 678 patients, only 14 patients (2.1%) had local lymph node recurrences. The frequency of lymph node recurrences was statistically higher in patients with LVI compared to the patients who did not have LVI (p < 0.001).

According to the PTC histopathological subtypes, follicular variant was observed in 53.09% (n = 360/678) cases, oncocytic variant in 14.60% (n = 99/678), classic PTC in 28.76% (n = 195/678), and aggressive variants of PTC in 3.53% (n = 24/678) (Table 5). According to the multivariate analysis of the outcomes of histopathological subtypes, the lowest risk of LVI was observed in the follicular variant compared with the other subtypes. The risk of LVI was 1.70 times greater in the patients with oncocytic variant, 2.73 times greater in the classic PTC, and 7.00 times greater in the patients with aggressive variants of PTC.

No significant differences were observed between LVI (+) and LVI (-) groups in terms of the tumor location, presence of multi- or unifocal tumors, number of tumor foci, and the presence of Hashimoto’s thyroiditis (p > 0.05).

The median follow-up time was 33.54 ± 23.21 months (min-max = 12-160 months). During approximately 3-year median follow-up period, no local lymph node metastasis was observed. Only one patient with distant metastases was detected. Thus, the number of distant metastases was insufficient to conduct a statistical evaluation.

DISCUSSION

In this study, we investigated the correlation between LVI and clinicopathological features of PTC patients. The results showed that the presence of LVI in PTC patients could be considered as a prognostic risk factor of disease worsening, and these patients should be monitored as high-risk PTC patients. The majority of thyroid cancers are PTC [1,27,28]. According to the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, PTC surveys are based on the stage of cancer in combination with the extension of disease. Although patients with a localized PTC have a 99.9% survival rate, PTC patients with distant metastases have poorer life expectancy (55.3%) [28]. The staging systems for PTC differ between several organizations. EORTC thyroid cancer staging system includes age, gender, tumor differentiation, capsule invasion, and metastasis [6]. Similarly, thyroid cancer staging systems of Mayo Clinic, Lahey Clinic, University of Chicago, and UICC/AJCC are based on the information on age, extension of tumor, gender, and completeness of surgery [6, 29-33]. The definition of LVI in thyroid cancer patients was described by Mete et al. [27] and included the following points: the presence of tumor cells in lymphovascular spaces or endothelium of lymphovascular channels, invasion of tumor cells through a vessel wall and endothelium, or the presence of thrombus adherent to intravascular tumor. Although LVI is a poor prognostic factor in different cancers, it is not included into the staging systems for PTC [14-20]. A retrospective analysis of breast cancer patients showed that the presence of LVI in these patients indicates a poor prognosis [34,35]. The impact of LVI on the progression and severity of thyroid cancers is discussed only with limited case series, and conflicting results are reported. The frequency of LVI in thyroid cancer ranges from 2% to 14% and it decreases to 5% among PTC patients [9]. In the studies of Gardner et al. [36] and Falvo et al. [37], LVI was observed in 7.5% and 9.5% of PTC patients, respectively. In another study, LVI was determined in 4.9% of PTC patients (n = 662) [38]. The largest study investigating the association between LVI and PTC was published by Pontius et al. [25]. The authors reported 11.6% incidence of LVI in PTC patients [25]. In the current study, we showed 9.3% rate of LVI among the PTC patients.

The association between gender and the severity of PTC is well investigated. The male gender is considered to be a poor prognostic factor in PTC [39]. Several studies in which the association between LVI and gender was examined showed that the rate of LVI in male patients was higher (8.4% to 10.5%) compared to female patients (4.8% to 9.4%) [25,36-38]. We found that the risk for LVI was 2.80 times greater in the male patients compared to the female patients, and this rate (18.4%) was also higher compared to the rates reported in the literature.

Thyroid cancer staging systems also indicate age as a prognostic factor [40]. A number of studies showed that PTC patients older than 45 years have poor prognosis [2,4,6,9,11,12]. However, several studies also indicated worse prognosis and the presenece of lymph node and distant metastasis in younger PTC patients. For example, in a group of 211 PTC patients, Can et al. [29] documented a significantly higher rate of lymph node metastases and LVI in PTC patients younger than 45 years (p = 0.023). In a meta-analysis of Qu et al. [41] patients younger than 45 years had significantly higher rates of nodal metastasis compared to older patients (50.4% versus 37.6%, p = 0.0005). Our results on the association between the age and LVI in the PTC patients mostly do not correspond with the previous studies. In our sample, patients of both genders, generally younger than 45 years, and aged between 17 and 25 years had a significantly higher rate of LVI.

Preoperative US is one of the most important diagnostic tools, and the treatment may be determined based on US results. US findings that indicate malignant characteristics of PTC include ETE, nodal metastasis, and a higher TNM stage compared to PTC with benign characteristics [42,43]. We showed that the PTC patients with suspicious US results for lymph node metastasis had a significantly higher rate of LVI, which is in agreement with previous studies. Furthermore, we suggest that in PTC patients who underwent thyroidectomy and who have LVI and lymph node metastasis, meticulous scanning of lymph nodes should be performed, if they did not have lymph node dissection. On the other hand, in LVI patients without nodal involvement, the follow-up of disease should focus on local neck metastasis.

Tumor size is another parameter for staging PTC. Larger tumors tend to have more lymph node metastasis, ETE, or distant metastasis. Previous studies showed that the tumor size in LVI patients ranged from 1.59-2.8 cm in diameter [25,37,38]. Our study is the first to investigate the cut-off tumor size for unifocal and multifocal tumors. Moreover, we showed, for the first time, that a 1.05 times greater risk of LVI exist for every 1 mm enlargement of the tumor size. The ROC curve analysis showed >9.5 mm for the umor size in unifocal tumors and >13 mm for the tumor size in multifocal tumors. The tumor sizes observed in our study are the smallest tumor sizes reported in the literature that indicate the presence of LVI.

The BRAF gene mutation is found in approximately 45% of thyroid cancer patients and most studies indicate that the BRAF mutation is a poor prognostic factor in these patients. However, recent studies on the BRAF mutation status in PTC patients showed conflicting results; furthermore, limited data exist on the association between the BRAF mutation and LVI in PTC patients [44,45]. A recent trial demonstrated that among 60 patients with the BRAF mutation, 90% had LVI. In another study, among 71 BRAF(+) PTC patients, 46% had LVI, and the BRAF mutation was found to be a statistically significant risk factor for LVI in these PTC patients [45]. Our study is the largest clinical series investigating the association between the presence of LVI and BRAF mutation in PTC patients. The presence of LVI may be an indicator for the presence of BRAF mutation in PTC patients, likewise, clinicians may perform a mutation analysis in PTC patients with LVI, to plan the follow-up and treatment.

Capsular invasion, ETE, and perineural invasion are considered to be poor prognostic factors in PTC patients and their coexsistence with LVI was noted in several studies [25,29,36-38,41].

Lymph node metastasis is one of the most important factors affecting preoperative treatment strategies in PTC patients. In the case of lymph node metastasis, the type of surgery, extent of dissection, radioiodine therapy, and the radioiodine dose are adjusted in PTC patients. Lymph node dissection is a controversial issue with regard to the survival benefit. Qu et al. [41] conducted a meta-analysis investigating the association between LVI and lymph node metastasis, and showed that LVI was significantly associated with an increased risk of central lymph node metastasis. Our results showed the higher rate of lymph node metastasis (69%) as well as the higher risk of lymph node metastasis (OR = 30.61) in PTC patients with LVI. Poor prognostic factors such as capsular invasion, ETE, perineural invasion, and LVI are more frequently observed in the aggressive subtypes of thyroid carcinoma [46]. For example, Mete et al. [26] reported 2.2% rate of LVI in well-differentiated PTC and 26% in poorly differentiated PTC [26]. Our results also showed that the highest rate of LVI is associated with the aggressive forms of PTC.

In a retrospective study investigating lymph node recurrence in 210 PTC patients, Conzo et al. [47] showed that locoregional lymph node recurrence is more frequent in young male patients and in primary tumors less than 2 cm in size. In addition, lymph node relapse was more frequently associated with follicular variant PTC [47].

The main limitation of our study are imprecise results on local recurrence of PTC and distant metastasis rates, due to the relatively short follow-up period. The presence of LVI in association with poor prognostic factors of thyroid carcinoma should alert clinicians to closely follow-up and re-evaluate the patient. Even in the case of low-risk patients and lack of histopathological data on lymph nodes, clinicians should monitor the patients with LVI for recurrences. Additionally, LVI might be considered as a parameter in the PTC staging systems, and the presence of LVI may help in determining adjuvant therapy strategies (e.g., radioiodine ablation therapy or L-Thyroxine suppression therapy).

DECLARATION OF INTERESTS

The authors declare no conflict of interests.

REFERENCES

  1. , , , (). Thyroid cancer incidence patterns in the United States by histologic type 1992–2006. Thyroid. https://doi.org/10.1089/thy.2010.0021
  2. , , , , , (). Factors affecting the adequacy of lymph node yield in prophylactic unilateral central neck dissection for papillary thyroid carcinoma. J Surg Oncol. https://doi.org/10.1002/jso.23201
  3. , , , , , (). American Thyroid Association (ATA) guidelines task force on thyroid nodules and differentiated thyroid cancer. Revised American thyroid association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. https://doi.org/10.1089/thy.2009.0110
  4. , (). Surgical approaches in thyroid cancer and lymph-node metastases. Best Pract Res Clin Endocrinol Metab. https://doi.org/10.1016/j.beem.2008.09.018
  5. , , , , (). Staging systems for papillary thyroid carcinoma: A review and comparison. Ann Surg. https://doi.org/10.1097/01.sla.0000250445.92336.2a
  6. (). Papillary thyroid carcinoma. Endocrinol Metab Clin North Am.
  7. , (). An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery.
  8. , , , , (). Predicting outcome in papillary thyroid carcinoma: Development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery.
  9. , , , , , (). A prognostic index for thyroid carcinoma. A study of the E.O.R.T.C. Thyroid Cancer Cooperative Group. Eur J Cancer. https://doi.org/10.1016/0014-2964(79)90291-3
  10. (). Hayes Martin Lecture. Our AMES is true: how an old concept still hits the mark: or, risk group assignment points the arrow to rational therapy selection in differentiated thyroid cancer. Am J Surg. https://doi.org/10.1016/S0002-9610(97)00162-1
  11. , , , , (). Prognostic factors in papillary and follicular thyroid carcinoma: Their implications for cancer staging. Ann Surg Oncol. https://doi.org/10.1245/s10434-006-9207-5
  12. , (). Risk and prognostic factor for differentiated thyroid cancer. Hell J Nucl Med.
  13. , , , , , (). Clinical and histopathological prognostic factors in locoregional advanced laryngeal cancer. J Laryngol Otol. https://doi.org/10.1017/S002221511600880X
  14. , , , , (). Uterine Adenosarcoma: A review. Curr Oncol Rep. https://doi.org/10.1007/s11912-016-0552-7
  15. , , , , , (). L1CAM: Amending the “low-risk” category in endometrial carcinoma. J Cancer Res Clin Oncol.
  16. , , , , , (). Lymphovascular and perineural invasion are associated with poor prognostic features and outcomes in colorectal cancer: A retrospective cohort study. Int J Surg. https://doi.org/10.1016/j.ijsu.2016.08.528
  17. , , (). Evaluation of the association between perineural invasion and clinical and histopathological features of cervical cancer. Mol Clin Oncol. https://doi.org/10.3892/mco.2016.941
  18. , , , , , (). Invasion depth measured in millimeters is a predictor of survival in patients with distal bile duct cancer: Decision tree approach. World J Surg. https://doi.org/10.1007/s00268-016-3687-7
  19. , , , , , (). The added value of pathology review in vulva cancer: Results from a population-based cohort study. Int J Gynecol Pathol. DOI: 10.1097/PGP.0000000000000313
  20. , , , , , (). The micropapillary/hobnail variant of papillary thyroid carcinoma: A review of series described in the literature compared to a series from one southern Italy pathology institution. Rev Endocr Metab Disord. Epub ahead of printhttps://doi.org/10.1007/s11154-016-9398-4
  21. , , , , (). Prognostic impact of extent of vascular invasion in low-grade encapsulated follicular cell-derived thyroid carcinomas: A clinicopathologic study of 276 cases. Hum Pathol. https://doi.org/10.1016/j.humpath.2015.08.015
  22. , , , , , (). Clinical implications of the extent of BRAFV600E alleles in patients with papillary thyroid carcinoma. Oral Oncol. https://doi.org/10.1016/j.oraloncology.2016.10.005
  23. , , (). Follicular variant of papillary thyroid carcinoma (FVPTC): Histological features, BRAF V600E mutation, and lymph node status. J Cancer Res Clin Oncol. https://doi.org/10.1007/s00432-015-1939-9
  24. , , , , , (). Lymphovascular invasion is associated with survival for papillary thyroid cancer. Endocr Relat Cancer. https://doi.org/10.1530/ERC-16-0123
  25. , (). Pathological definition and clinical significance of vascular invasion in thyroid carcinomas of follicular epithelial derivation. Mod Pathol. https://doi.org/10.1038/modpathol.2011.119
  26. , , , (). Systematic review of trends in the incidence rates of thyroid cancer. Thyroid. https://doi.org/10.1089/thy.2016.0100
  27. , , , , , (). . SEER Cancer Statistics Review 1975-2006, National Cancer Institute.
  28. , , , , , (). Histopathological evidence of lymph node metastasis in papillary thyroid carcinoma. Endocr Pathol. https://doi.org/10.1007/s12022-015-9382-7
  29. (). A model for predicting outcomes in patients with differentiated thyroid cancer and model performance in comparison with other classification systems. J Am Coll Surg. https://doi.org/10.1016/j.jamcollsurg.2004.10.031
  30. (). Prognostic importance of histologic grading in papillary thyroid carcinoma. Cancer. https://doi.org/10.1002/1097-0142(19931101)72: 9<2680: AID-CNCR2820720926>3.0.CO;2-D
  31. , , , , , (). Papillary thyroid carcinoma: Prognostic index for survival including the histological variety. Arch Surg. https://doi.org/10.1001/archsurg.135.3.272
  32. , , , (). A novel classification system for patients with PTC: Addition of the new variables of large (3 cm or greater) nodal metastases and reclassification during the follow-up period. Surgery. https://doi.org/10.1016/S0039-6060(03)00384-2
  33. , , , , , (). The role of lymphovascular invasion as a prognostic factor in patients with lymph node-positive operable invasive breast cancer. J Breast Cancer. https://doi.org/10.4048/jbc.2011.14.3.198
  34. , , , , , (). Lymphovascular space invasion and lack of down staging after neoadjuvant chemotherapy are strong predictors of adverse outcome in young women with locally advanced breast cancer. Cancer Med. https://doi.org/10.1002/cam4.586
  35. , , , , , (). Prognostic importance of vascular invasion in papillary thyroid carcinoma. Arch Otolaryngol Head Neck Surg. https://doi.org/10.1001/archotol.126.3.309
  36. , , , , , (). Prognostic importance of histologic vascular invasion in papillary thyroid carcinoma. Ann Surg. https://doi.org/10.1097/01.sla.0000157317.60536.08
  37. , , , , , (). Lymphovascular invasion is associated with lateral cervical lymph node metastasis in papillary thyroid carcinoma. Laryngoscope. https://doi.org/10.1097/01.mlg.0000242118.79647.a9
  38. , , , , (). Gender-specific variation in the prognosis of papillary thyroid cancer TNM stages II to IV. Int J Endocrinol. DOI: 10.1155/2012/379097
  39. (). Understanding the relationship between age and thyroid cancer. Oncologist. https://doi.org/10.1634/theoncologist.2008-0194
  40. , , , (). Clinical risk factors for central lymph node metastasis in papillary thyroid carcinoma: A systematic review and meta-analysis. Clin Endocrinol. https://doi.org/10.1111/cen.12583
  41. , , , , (). Association of preoperative US features and recurrence in patients with classic papillary thyroid carcinoma. Radiology. https://doi.org/10.1148/radiol.2015142470
  42. , , , , , (). Preoperative ultrasonographic features of papillary thyroid carcinoma predictbiological behavior. J Clin Endocrinol Metab. https://doi.org/10.1210/jc.2012-4072
  43. , , , , , (). Clinical implications of the extent of BRAFV600E alleles in patients with papillary thyroid carcinoma. Oral Oncol. https://doi.org/10.1016/j.oraloncology.2016.10.005
  44. , , , , , (). Clinical, sonographic, and pathological characteristics of RAS-positive versus BRAF-positive thyroid carcinoma. J Clin Endocrinol Metab. https://doi.org/10.1210/jc.2016-2620
  45. , , , , , (). Clinical significance of prophylactic central compartment neck dissection in the treatment of clinically node-negative papillary thyroid cancer patients. World J Surg Oncol. https://doi.org/10.1186/s12957-016-1003-5
  46. , , , , , (). Clinicopathological pattern of lymph node recurrence of papillary thyroid cancer. Implications for surgery. Int J Surg. https://doi.org/10.1016/j.ijsu.2014.05.010