Cervical lymph node metastasis is a major adverse prognostic factor in patients with PC[20–22].Neck dissection is the best treatment for cervical lymph node metastasis of PC.But for CNO PC, neck dissection is controversial.For patients with CNO, there are few clinical studies on whether neck dissection benefits the prognosis.In our study,we found there was no significant differences between no neck dissection cohort and neck dissection cohort on PFS before PSM(P = 0.34)(Fig. 2A).However,neck dissection cohort had a better PFS than no dissection cohort after PSM(P = 0.025)(Fig. 2B).Because there were significant differences on differentiation(P = 0.003) before PSM ,and the rate of poor differentiation in no neck dissection cohort is larger than that in neck dissection cohort(Table 2).In previous studies, histological grade had a significant difference in prognosis, with poorly differentiated tumors having a worse prognosis[23–25].Differences in the degree of differentiation after PSM were eliminated (Table 3).Furthermore,there were no significant differences between no neck dissection cohort and neck dissection cohort on OS before and after PSM(P = 0.34,0.22)(Fig. 2C D).
In addition,no lymph node metastasis cohort had a better PFS than lymph node metastasis cohort before PSM(P = 0.0053)(Fig. 2A).As Table 4 shown,we found there were significant differences on tumor types and differentiation(P < 0.05),and lymph node metastasis cohort had more high-grade tumor type and poorer differentiation. After PSM,there no significant differences between this two cohort on all data (P > 0.05)(Table 4) ,and there was no significant differences between this two cohorts on PFS(P = 0.37)(Fig. 2B).In addition,there were no significant differences between no lymph node metastasis cohort and lymph node metastasis cohort on OS before and after PSM(P = 0.74,0.88)(Fig. 2C D).
Patients with OLNM and patients with non OLNM can achieve the same prognosis after neck dissection, which explains the necessity of neck dissection.Prophylactic neck dissection is primarily intended to remove occult metastasis lymph node.The reason why the PFS in the neck dissection cohort was better than that in the no neck dissection cohort may be the occult metastasis lymph nodes were not resected. Since OLNM was pathologically obtained after neck dissection, we could not compare the prognostic effects between OLNM and non OLNM in the no dissection cohort.
However, performing neck dissection for all patients may cause additional trauma.It is necessary to screen out patients with high risk factors appropriately. Prophylactic neck lymph node dissection can be performed in high-risk patients.Studies have shown that high tumor grade, external parotid invasion, tumor size ≥ 4 centimeter, and facial nerve invasion are associated with lymph node metastasis[26] .Wang et al. found that the main factors related to lymph node metastasis of PC were nerve invasion, high T stage, and histological type [27].According to a study published by Stodulski et al., the incidence of OLNM was 30% in 66 CNO patients who had undergone neck dissection. In univariate analysis, intra-parotid/periparotid metastasis, external parotid invasion, high T-stage and histology were considered as risk factors for OLNM. Intra-parotid/periparotid metastasis was an independent risk factor in multivariate analyses [28].De Brito Santos et al. found that 17 out of 46 (37%)cN0 patients who underwent neck dissection had OLNM.Multivariate analysis showed that histological types and T3-T4 staging were independent predictors of lymph node metastasis[26].
The UK National Multidisciplinary Guidelines recommend selective neck dissection for cN0 patients with T3-T4 staging or high-grade tumours (squamous cell carcinoma and undifferentiated carcinoma, adenocarcinoma, high-grade mucoepidermoid carcinoma and precancerous pleomorphic adenoma)[2, 4].Yoo et al. reported histological grade was an independent risk factor[29].The World Health Organization has identified 22 different histological types of salivary tumors [30]. This diversity of histology, together with the diversity of associated biological behaviors, leads to a different risk of lymph node metastasis [2, 30, 31]. Histology grade is considered to be a risk factor for lymph node spread in patients with PC.Undifferentiated carcinoma, squamous cell carcinoma, salivary duct carcinoma, non-specific adenocarcinoma, and high-grade mucoepidermoid carcinoma have a greater than 50% risk of OLNM,While in acinar cell carcinoma, secretory carcinoma, adenoid cystic carcinoma and low-grade mucoepidermoid carcinoma, the risk is very low, accounting for about 2–4%[21, 32–35].Compared with low-grade tumors, high-grade parotid tumors are more likely to develop OLNM. In a retrospective study of 90/142 patients with CN0 PC who underwent neck dissection, Klussmann et al. found that the rate of OLNM in patients with high-grade tumors was 49%[36].It has been reported that pleomorphic adenoma has a lymph node metastasis rate as high as 52%[21]. It is important to note that carcinomatous pleomorphic adenomas are often aggressive, but their malignant components may also represent low-grade tumors, such as myoepithelial carcinomas with low cervical metastasis potential. However, in many cases, malignant ingredients are difficult to classify and are usually represented by higher-grade ingredients[37].
Armstrong et al observed that in cN0 PC patients, the risk of developing OLNM was 24% for T4 tumors, 16% for T3 tumors, and 7% for T1-T2 tumors[38].Some authors have also reported that age is a predictor of lymph node metastasis in patients with parotid carcinoma. Age ≥ 60 years reported by Poulsen et al[39], and age ≥ 61 years reported by Klussmann et al., are important risk factors for neck metastasis[36].
Our data shows the OLNM of low grade tumor types accounted for 30%.The OLNM rate of poor differentiation was 50%. The numbers of patients in T3 T4 were lower than T1 T2 in the overall data (Table 1), so it was difficult to compare the differences in OLNM between patients in T1,T2 and T3,T4. Maybe those cause the odd date (T4 OR 0: 468-2.139, P = 1).However, it can be seen that the rate of OLNM in T2 patients is significantly higher than that in T2 patients. .Univariate analysis showed
Tumor Types(low grade malignancy)(OR:-1.103,95%CI:1.008–9.007,P = 0.048), poor differentiation(OR: 0.987,95%CI: 1.371–5.252,P = 0.004) were significantly associated with OLNM of CNO PC.After multivariate analysis,poor differentiation was independent risky factor(OR:0.060,95%CI: 0.247–4.566,P = 0.028).
Although we know the risk factors of OLNM, it is difficult to apply these parameters into the decision-making process. In fact, in most cases, definitive histology and tumor grade cannot be obtained before surgery. In addition, high-risk histological findings associated with OLNM are usually identified only after a thorough pathological examination of the specimen. The diagnostic accuracy of fine needle aspiration cytology for the correct histological type and grade is generally low, with an accuracy of 51–79% in most reported series[7, 8].In some centers with experienced cytopathologists, the accuracy of fine needle aspiration cytology may be higher[40].
In this case, frozen sections can be very useful to at least provide a grade of the malignancy[41].However, the tumor definition of frozen sections has the major disadvantage of not being able to plan the surgery in advance and discuss it at a multidisciplinary meeting.With recent advances in molecular medicine, some molecular markers may be associated with lymph node metastasis in head and neck malignancies, but data on the usefulness of molecular prognostic markers in salivary gland malignancies are still lacking[42, 43].The risk of cN0 OLNM depends on the diagnostic technique of neck staging. Therefore, the clinically negative neck of a few decades ago is very different from the clinically negative neck of today. Advances in diagnostic methods for detecting OLNM have hindered the translation of retrospective findings into current clinical practice[44].