|Ahead of print
Factors predicting contralateral nodal spread in papillary carcinoma of thyroid
Harish Verma1, Nija Shah2, Prateek Jain2, Kapila Manikantan2, Rajeev Sharan2, Pattatheyil Arun2
1 Department of Surgical Oncology, Tata Medical Center, Kolkata, West Bengal, India
2 Department of Head and Neck Surgery, Tata Medical Center, Kolkata, West Bengal, India
|Date of Submission||28-Jul-2019|
|Date of Decision||18-Jan-2020|
|Date of Acceptance||03-Jun-2020|
|Date of Web Publication||27-Jan-2021|
Department of Head and Neck Surgery, Tata Medical Center, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
Background: Lymph node metastasis (LNM) is evident in about 20–50% of cases at presentation in papillary carcinoma thyroid (PTC). There are no clear recommendations for the need and extent of lateral and central compartment dissection in PTC.
Methods: A total of 83 patients who underwent total thyroidectomy and bilateral selective neck dissection for diagnosed PTC from September 2011 to October 2017 were retrospectively analyzed.
Results: Tumor site was bilobar or involving isthmus in 40 patients. Contralateral LNM was seen in 42 patients. Both radiological (median size 2.6 cm, P = 0.051) and pathological (median size 3.65 cm, P = 0.015) size of tumor, tumor involving isthmus or bilateral lobes (P = 0.006), and lymphovascular invasion (LVI) (P = 0.026) had significant correlation with contralateral LNM.
Conclusion: Size and site of tumor, ipsilateral lateral compartment nodes involvement, and LVI status of tumor significantly increases the probability of contralateral LNM in patients of PTC.
Keywords: Neck dissection, papillary carcinoma thyroid, thyroid cancer, thyroidectomyKey Message Elective contralateral neck dissection is recommended in patients with large size of thyroid tumor, midline / bilateral thyroid nodules and in patients with proven lateral compartment node involvement.
| » Introduction|| |
The incidence of thyroid cancer is showing an increasing trend all across the globe. The incidence has increased by more than 250% in last two decades and by more than 150% in the last decade alone. Papillary thyroid cancer (PTC) is the most common of all thyroid cancer and comprises about 85% of diagnosed cases. Lymph node metastasis (LNM) is evident in 20–50% patients at presentation.,,,, This can increase up to 80% if micrometastases are also considered., The 10-year survival rates from PTC is extremely encouraging at 99% in node-negative patients but decreases to 97% in the presence of lymph node metastasis. With increasing incidence, even a small change in survival is bound to affect a large number of patients.
Lymphatic drainage and consequently nodal metastasis in thyroid cancers follows a specific pattern. Usually, tumor first spreads to the central compartment lymph nodes described as level VI. In the central compartment, ipsilateral paratracheal and pre-tracheal lymph nodes are the first to be involved. Subsequently, the disease spreads to the ipsilateral jugular chain of lymph nodes (levels II, III, IV, and V). Rarely, skip metastasis in the lateral compartment has been found without involvement of central compartment (9.6%)., Later, contralateral paratracheal lymph nodes and jugular lymph nodes get involved. Last, mediastinal nodes are found to harbor PTC metastasis in advanced cases., Lymph node involvement can either be macroscopic or microscopic.
The risk of disease recurrence increases with macroscopic metastasis in lymph nodes, but the effect of microscopic lymph node metastases on recurrence rates and survival is less clear.,,,,, So, there is always a controversy regarding decision making on the extent of neck dissection for PTC.
LNM upstages the tumor and also increases the risk of recurrence for disease. The risk stratification also takes into account the size and number of metastatic lymph nodes and extranodal extension in addition to clinical N1 stage of the disease.
Prophylactic neck dissection may still lower the already lower recurrence rate of PTC but it has to be balanced with the risk of potential complications like spinal accessory nerve injury, major vessel injury, and chyle leak that are less likely to be associated with thyroidectomy alone with or without a central neck dissection. The role of prophylactic contralateral neck dissection when ipsilateral neck nodes are positive is not clear. In this study, we have tried to evaluate clinicopathological factors that may help us in decision making for the need of a lateral neck dissection in a node-negative contralateral neck when the ipsilateral neck is positive.
| » Material and Methods|| |
This is a retrospective study of 393 patients who underwent surgery for PTC in a tertiary care hospital from September 2011 to October 2017. Institutional ethics and review board clearance was obtained for this study. Patient data were retrieved from the hospital database, patient charts, and histopathology reports. Amongst these patients, 83 patients underwent total thyroidectomy with bilateral selective neck dissection from level II-IV with or without level VI (central compartment), preserving internal jugular vein, sternocleidomastoid, and spinal accessory nerve, unless otherwise indicated for local extension. Patients diagnosed with other forms of thyroid carcinoma other than PTC, distant metastasis at presentation, those who underwent hemithyroidectomy, completion thyroidectomy, or single-sided neck dissection were excluded from the study. Patients were also excluded if the PTC was a second primary tumor.
Descriptive and inferential statistics were performed with SPSS 17 (IBM Corp., Chicago, Illinois, USA). Continuous variables were analyzed using regression analysis, categorical variables were analyzed using independent samples t-test. P value of = 0.05 was considered to be statistically significant.
| » Results|| |
There were a total of 83 patients who underwent total thyroidectomy with bilateral selective neck dissection for PTC. A summary of patient demographics and clinico-pathological characteristics for the entire population is presented in [Table 1]. Of the 83 patients, 71% were women. The median patient age at the time of presentation to our institution was 38 years (range 08–70 years). Contralateral LNM showed statistically significant association with the size of tumor obtained by pre-operative radiological imaging (p = 0.051) as well as postoperative pathological 't' size (P = 0.015) and with bilateral or centrally located tumors (P = 0.006). It was also significantly associated with lympho-vascular invasion (LVI) (P = 0.026). Central compartment dissection was performed in all patients as per institutional policy. Histopathologic information from the central compartment could not be retrieved in 9 patients as lymph node stations were not marked separately from the lateral compartment. Among 74 patients where central compartment tissue was labeled separately, 63 (85.1%) patient had central compartment nodal metastasis [Table 2]. Eleven patients had lateral nodal metastasis without involving central compartment nodes. From these 11 patients which did not have metastasis to central compartment nodes, 4 patients had metastasis to contralateral LNM. Thus, in our study, we found 14.8% patients with skip metastases directly involving lateral neck nodes without central neck node involvement.
In the subgroup analysis of patients with a unilateral thyroid tumor [Table 3], we found that 14 of the 43 (32.5%) patients with exclusively unilateral thyroid tumor (median size 4 cm, range 0.4–7.5 cm) had contralateral LNM. Larger tumor size was significantly associated with contralateral LNM (p = 0.001). There was no significant association between the incidence of contralateral LNM with LVI (p = 0.456), perineural invasion (PNI) (p = 0.523), extrathyroid extension (ETE) (p = 0.756), or extranodal extension (ENE) (p = 0.136).
|Table 3: Patient demographics and clinico-pathological features in unilateral thyroid lesions|
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For the subgroup analysis of patients according to the age group, we divided the cases in three subgroups (=15 years, 16-55 years and >55 years). We found that two out four patients in the =15 years age group had contralateral LNM and nine out of fourteen patients in the >55 years age group had contralateral LNM. This difference was not found to be statistically significant (p = 0.530) but this result needs to be interpreted with caution due to the very low number of patients in the analysis.
| » Discussion|| |
PTC is the most common histological type of thyroid carcinoma and seen more commonly in women. Our patient cohort, similarly, comprised of 59 women, constituting 71.1% of all patients. Median age at presentation was 38 years, suggesting it's a relatively young cohort. Complete disease clearance is of paramount importance in these patients to prevent disease recurrence, the role of prophylactic lateral neck dissection in the treatment of PTC is debatable. Although it is generally performed only when node involvement is evident macroscopically by clinical or radiological examination, interpretation of high risk features intra-operatively may be unreliable. Node involvement is currently considered to be indicative of a poor prognosis for local recurrence,,,,, and survival. In a few series, node dissection has resulted in a reduction in local recurrence in patients with nodal metastasis.,, and sometimes has a beneficial effect on survival.
The detection of lymph node involvement in PTC with LNM ranges from 30 to 80%, depending on the modality used., At present, ultrasonography (USG) is the recommended diagnostic tool for the preoperative staging of PTC. High-resolution USG certainly helps with lateral lymphatics but its major limitation is that it lacks sensitivity in diagnosing central compartment lymph node metastasis. Other imaging modalities like computed tomography scan and magnetic resonance imaging have other issues of cost, exposure to radiation, consumption of time, and reliability in identifying nodes as involved with cancer and hence, are not used routinely.
Two large studies, both analyses of the Surveillance, Epidemiology, and End Results (SEER) database, have found that lymph node metastasis is significantly associated with decreased survival in patients of PTC above 45 years of age., In a comprehensive analysis of the National Cancer Data Base (47,902 patients) and SEER (21,855 patients), Adam et al. in 2015 showed a small but significantly increased risk of death for younger patients (<45 years) and in patients with lymph node metastases compared to those without nodes. Also, there was an increase in the risk of mortality when the number of metastatic lymph nodes was more than 6.
In this study, we found that site of the tumor was significantly associated with contralateral LNM, with tumors involving bilateral lobes or isthmus being more likely to cause bilateral LNM. In 1993, Noguchi et al. had analyzed 135 patients, who underwent total thyroidectomy with bilateral neck dissection for PTC and reported similar findings. Differential pattern of lymphatic drainage in the central thyroid, as compared to the peripheral part has been cited as a reason for this.
In this study, both radiological and histopathological size of the tumor was independently associated with the increase in possibility of bilateral/contralateral LNM. In 2000, Oshihama et al. analyzed 1776 patients with PTC and reported association of bilateral/contralateral LNM with male sex, large primary tumor size, bilobar involvement, and ETE. However, our study did not find any correlation with gender or ETE.
In 2002, Machens et al. published a retrospective review on pattern of nodal metastasis in thyroid cancers. In 296 patient of thyroid cancers, they reported significant correlation between the number and rate of nodal metastasis in lateral compartment with more than 5 positive central compartment nodes. In this study, we also found that central compartment nodal involvement was associated with increased chances of contralateral/bilateral LNM though it was not statistically significant (p = 0.067).
In 2017, Kim et al. published a data of more than 10,000 patients and reported that male sex, tumor size >4 cm, bilobar involvement, and bilateral central lymph node metastasis were significantly associated with contralateral LNM. In 1999, Mirallie et al. in their study of 158 patients of PTC had reported vascular invasion (P = 0.02), male sex (P = 0.008), absence of a tumor capsule (P < 0.0001) and perithyroid involvement (P < 0.0001) to be associated with lateral node involvement. But unlike these studies, our study failed to find association between contralateral LNM with age, ETE, and PNI.
Another large study by Wang et al. in 2018 analyzing the SEER database, published that in each T stage, nodal positivity rates were inversely associated with age at diagnosis, which was validated by multivariate logistic regression analysis (p < 0.001). In the present study, we found significant association between the age and contralateral LNM. This could be due to the small number of young (=15 years) patients.
In this study, LVI was also found to be a significant factor for contralateral LNM (P = 0.026). Since LVI can be reported only on postoperative histopathology, it does not assist in planning the need and extent of lateral compartment dissection.
A systematic review published by Attard et al. in 2019, analyzed the 13 articles for skip metastases to lateral cervical LNM. The incidence of skip metastases ranged from 1.6 to 21.8% in different studies with risk factors being the age >45 years, tumor size <5 mm, and tumor located in the upper pole or isthmus of thyroid gland. In this study, we found 14.8% patients with skip metastases which showed lateral neck nodes without central neck node involvement.
Like any other study, this study also has some limitations. This study is limited by its retrospective design. The number of patients analyzed was also small. Survival analysis could not be done in the study because of a small follow-up period.
| » Conclusion|| |
Contralateral lymph node metastasis is seen more commonly when the primary tumor is large, involves both lobes or the isthmus. Central compartment nodal metastasis also predicts the involvement of the contralateral lateral compartments. Prophylactic contralateral neck dissection should be considered when ipsilateral lateral compartment nodes are involved, when the tumor size is large, involving the isthmus, both lobes of the thyroid and when multiple central compartment nodes are present.
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[Table 1], [Table 2], [Table 3]