The Incidence of N1 And N2 Metastases in Relation to the Presence/Absence of the Peritumoral Lymphovascular Invasion

The incidence of N1 and N2 metastases in relation to the presence of peritumoral lymphovascular infiltration and tumor grade in bronchial carcinoma still remain insufficiently researched areas that can provide valuable guidance on cancer aggressiveness, disease spread, prognosis and treatment.
Being that each lung lobe has its own lymphatic drainage, metastatic spread of lung cancer by lymphatic route depends on its location. Consequently, understanding the metastatic spread of cancer to regional lymph nodes requires good knowledge of the anatomy of the lymphatic system of each lobe [1-6].
The influence of numerous factors, i.e., the most common types of lung cancer, tumor size as well as the degree of differentiation and stage of the malignant disease on the occurrence of N1 and N2 metastases has been thoroughly investigated. Several studies have shown a statistically significant difference in the occurrence of N1 and N2 metastases in relation to the type and size of the bronchial carcinoma. The relationship between the occurrence of N1 and N2 metastases and the degree of immaturity of the tumor in the bronchial carcinoma remains insufficiently documented [1-6].
A literature review of available medical databases and research articles over the past 10 years was conducted, but the strong association between the presence of N1 and N2 metastases and pathohistological confirmation of peritumoral lymphovascular invasion (a reliable indicator that correlates with the tumor aggressiveness in bronchial carcinoma) was not observed in other studies.

We analyzed data from patients diagnosed with bronchial carcinoma who underwent surgical resection during their hospital stay at the Clinic of Thoracic Surgery, Clinical Center University of Sarajevo from 01.01.2013 to 01.01.2018. In total, this study included 331 patients of all ages, both men and women, diagnosed with bronchial carcinoma using various diagnostic procedures. In these patients, surgical treatment was indicated, and the anatomical resection was performed.

A total of 331 patients diagnosed with bronchial carcinoma underwent surgical resection during their hospital stay at the Clinic of Thoracic Surgery from 01.01.2013 to 01.01.2018. The mean age of the patients was 62.69 ± 7.46.
Histopathological findings in relation to the type of bronchial carcinoma are shown in Table 1.

Table 1:Definitive histopathological diagnoses in relation to the type of bronchial carcinoma.

In our study, the squamous cell carcinoma was the most common type of bronchial carcinoma, found in 54.98% of cases (182 out of 331 patients), followed by adenocarcinoma, which was found in 42.30% of cases (140 out of 331 patients). The least common type of bronchial carcinoma was large cell carcinoma, found in 2.72% of cases (nine out of 331 patents).
The relation between the most common histopathological diagnoses and surgical resections is shown in Figure 1.

Figure 1:The relation between the most common histopathological diagnoses and surgical resections.

Standard lobectomy was the most common surgical resection of both squamous cell carcinoma, i.e., in 54.94% of cases (100 out of 182 patients) and adenocarcinoma, i.e., 66.42% of cases (93 out of 140 patients).
The prevalence of lymph node (N0, N1 and N2) involvement in bronchial carcinoma is shown in Table 2.

Table 2:The prevalence of lymph node involvement in patients diagnosed with bronchial carcinoma.

The most common were cases without the presence of malignant cells in the lymph nodes (N0), i.e., 55.59% of cases (184 out of 331 patients), N1 metastases were present in 39.88% of cases (132 out of 331 patients), and N2 metastases were observed in 4.53% of cases (15 out of 331 patients).
The relation between N0, N1 and N2 metastases and the most common histopathological diagnoses is shown in Table 3.

Table 3: The prevalence of N0, N1 and N2 metastases and their relation to the most common histopathological diagnoses.

More than half of the patients with both squamous cell carcinoma, i.e., 52.75% of cases (96 out of 182 patients) and adenocarcinoma, i.e., 58.57% of cases (82 out of 140 patients) had no lymph node metastases (N0). N1 lymph node involvement (positive ipsilateral hilar lymph nodes) was present in 43.96% of cases with squamous cell carcinoma and in 35.00% of cases with adenocarcinoma. N2 lymph node involvement was present in 3.30% of cases with squamous cell carcinoma and in 6.43% of cases with adenocarcinoma.
The prevalence of the peritumoral lymphovascular invasion and its relation to the lymph node status is shown in Table 4.

Table 4: The prevalence of the peritumoral lymphovascular invasion and its relation to the lymph node status.

*PLVI - peritumoral lymphovascular invasion.

Peritumoral lymphovascular invasion was present in 37.55% of cases (86 out of 229 patients) with N0 disease and in 55.89% of cases (128 out of 229 patients) with N1 disease as well as in 6.55% of cases (15 out of 229 patients) with confirmed N2 disease.
Peritumoral lymphovascular invasion was not present in 96% of cases (98 out of 102 patients) with NO disease, 3.92% of cases (4 out of 102 patients) with N1 disease as well as 0.98% of cases (1 out of 102 patients) with confirmed N2 disease.

Table 5: The frequency of lymph node metastases in relation to the presence of peritumoral lymphovascular invasion.

The frequency of lymph node metastases in relation to the presence of peritumoral lymphovascular invasion is shown in Table 5.
It is possible to calculate the sensitivity, specificity, positive and negative predictive values of the peritumoral lymphovascular infiltration in relation to the presence of lymph node metastases. Their values were obtained as follows: sensitivity (97.27%), specificity (53.26%), positive predictive value (62.447%) and negative predictive value (96.07%). The overall accuracy was 72.8%.

Table 6: The prevalence of N1 lymph node metastases in relation to the presence of peritumoral lymphovascular infiltration.

Data for calculating the relative risk of N1 lymph node metastases in relation to the presence of peritumoral lymphovascular infiltration is shown in Table 6.
The risk of lymph node metastases in patients with peritumoral lymphovascular invasion was calculated as follows:
The risk among patients with PLVI = (a/b) = 128/4 = 31.00.
The risk of lymph node metastases in patients without peritumoral lymphovascular invasion was calculated as follows:
The risk among patients without PLVI = (c/d) = 86/98 = 0.87
We investigated the association between the peritumoral lymphovascular invasion and regional lymph node metastases using Spearman’s rank correlation coefficient. There was a statistically significant correlation between the variables, i.e., ρ = 0.544, n = 331, p < 0.0001. The presence of peritumoral lymphovascular invasion was more often accompanied by the presence of metastases in the corresponding regional lymph nodes.

The presence of N1 disease significantly affects the five-year survival rate, and it has been observed that the same corresponds to the number of involved N1 lymph nodes. The presence of N2 disease is still the subject of much debate, which leads to the fact that most surgeons and oncologists at present opt for a combined approach to N2 NSCLC. It has been shown that patients who have been preoperatively diagnosed with N2 lymphadenopathy do not benefit much from surgical treatment [7-10]. In contrast, patients whose N2 disease is not clearly clinically classified, but diagnosed via surgical treatment or using the histopathological examination, have a better postoperative outcome [11,12].
Lymph nodes in patients diagnosed with bronchial carcinoma who were treated in this study were not proportionally affected by metastatic spread of the disease as seen from the obtained results. The most common were patients without the presence of malignant cells in the lymph nodes (N0), i.e., 55.59% of cases, N1 metastases were present in 39.88% of cases, and N2 metastases in 4.53% of cases of bronchial carcinoma.
Almost similar results have been published in several other literature reports [1-9]. Given the fact that the majority, i.e., 95.47%, of patients who have undergone surgical treatment had N0 and N1 lymph node status, it can be assumed and concluded that there was a relatively good diagnostic assessment of patients as well as clinical determination of the disease stage and selection of patients for surgical treatment.
In more than half of the patients, both in the squamous cell population group, i.e., 52.75% of cases (96 out of 182 patients) as well as in the adenocarcinoma population group, i.e., 58.57% of cases (82 out of 140 patients), no lymph node metastases were present.
In relation to the presence or absence of peritumoral lymphovascular invasion in patients diagnosed with bronchial carcinoma, the following results were obtained:
Peritumoral lymphovascular invasion was present in 72.46% of cases (229 out of 316 patients) with the presence of lymph node metastases in 62.44% of cases [N1 metastases in 89.51% of cases (128 out of 143 patients) and N2 in 10.49% of cases (15 out of 143 patients)].
Based on the available data, sensitivity (97.27%), specificity (53.26%), positive predictive value (62.447%) as well as the negative predictive value (96.07%) were calculated. The overall accuracy was 72.8%. The total relative risk of lymph node metastases in relation to the presence of peritumoral lymphovascular invasion is 35.63, which means that there is a 35.63 times higher chance of developing disease with the lymph node metastasis in the presence of peritumoral lymphovascular invasion compared to when it is not present.
The study unequivocally confirmed that the presence of peritumoral lymphovascular invasion was more often accompanied by the presence of metastases in the corresponding regional lymph nodes. An association between the presence of peritumoral lymphovascular invasion and the frequency of N1 and N2 metastases was observed.
The presence of peritumoral lymphovascular invasion can serve as a good predictor in relation to the assessment of the lymph node status, and indirectly have both prognostic and therapeutic significance for these patients.
However, there are reports in the available literature on other types of malignancies, primarily breast cancer and cervical cancer, in which similar studies (the presence of peritumoral lymphovascular invasion and the lymph node status) have been conducted and have shown an association between the peritumoral lymphovascular invasion and more frequent occurrence of lymph node metastases [7-13].

a) Peritumoral lymphovascular invasion was present in 70.52% of cases (229 out of 331 patients) diagnosed with bronchial carcinoma.
b) Lymph nodes were involved in 70.52% of cases (229 out of 331 patients) with present lymphovascular invasion and in only 3.30% of cases (4 out of 331 patients) in which the lymphovascular invasion was not present.
c) Lymph nodes were not involved in 84% of cases (86 out of 229 patients) with present lymphovascular invasion and in 53.00% of cases (98 out of 102 patients) in which the lymphovascular invasion was not present.
d) In those cases, without lymph node involvement (N0) peritumoral lymphovascular invasion was present in 46.13% of cases (86 out of 244 patients).
e) Peritumoral lymphovascular invasion was present in 53.26% of cases (143 out of 244 patients) with confirmed N1 disease. f) Peritumoral lymphovascular invasion was present in 100% of cases (all 15 patients) with confirmed N2 disease.
g) Regardless of the fact that the presence of the peritumoral lymphovascular invasion was not accompanied by the occurence of N1 and N2 metastases in all patients diagnosed with bronchial carcinoma, it was found that there was a statistically significant difference in metastatic lymph node involvement in relation to the presence of the peritumoral lymphovascular invasion.
h) By calculating the total relative risk, there is almost a 30-fold higher risk of developing metastases in N1 and N2 lymph nodes in the presence of the peritumoral lymphovascular invasion.

The presence or absence of the peritumoral lymphovascular invasion can be used both in predicting and excluding the presence or absence of the lymph node involvement.

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