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Metastatic Lymph Node Ratio: A Promising Parameter and Its Relation with Patient Related Factors in Cases of Primary Organ Malignancy

Background: Metastatic lymph node ratio (MLR) is defined as the ratio of number of positive lymph nodes (LNs) or LNM to total nodes harvested (LNH). Recent studies have suggested that MLR is more accurate in predicting overall survival and recurrence‐free survival rate compared to the number of positive nodes alone. Materials and methods: Total 58 cases of primary organ malignancy were evaluated from June 2018 to June 2019 including Head and neck (HN), Breast, Gastrointestinal tract (GIT) and Genitourinary tract (GUT) malignancy. Age, gender, LNH, LNM, MLR, tumor stage and tumor grade were accessed for each of the cases. Results: Out of total 58, there were 12, 33, 11 and 2 cases each of HN, Breast, GIT and GUT malignancy respectively. M:F ratio was 1:2.2. Maximum cases (39.6%) were seen in the age group of 35-45 years. 186 out of 530 LNs showed metastasis. Mean MLR for lymph node-positive cases were 0.3. Majority of HN malignancy cases (41.6%) were found in T1/T2 stage, breast malignancy cases (42.4%) in T2 stage, GIT malignancy cases (63.6%) in T3 stage, 50% of GUT malignancy cases in T3 and 50% were in T4 stage. Maximum well‐differentiated (10, 83.3%) cases belonged to HN, moderately (15, 45.4%) and poorly differentiated (18, 54.5%) to breast respectively. We found significant association of MLR with tumor stage and tumor grade. (p-value < 0.001) Conclusion: The routine inclusion of MLR in tumor reporting by pathologists may become a prognostic aid for clinicians along with TNM staging system.


INTRODUCTION
The status of regional lymph node metastasis (LNM) has been widely considered as an important prognostic factor to plan subsequent management of patients with primary organ malignancy [1]. Lymph nodes (LNs) draining a tumor may enlarge due to metastasis (LNM) or reactive hyperplasia [2]. One of the most commonly used prognostic factors is the tumor-node-metastasis (TNM) staging system [4]. Although LNM is a simple, convenient, and reliable method for precise staging, the identified number of metastatic LNs depends on the number of dissected LNs. A low number of examined LNs may lead to false understating and subsequent underestimation of cancer spread. This phenomenon is referred to as stage migration.
Metastatic lymph node ratio (MLR) is defined as the ratio of number of positive LNs or LNM to total nodes removed or harvested (LNH) and is used as an important prognostic factor. Recent studies have suggested that MLR is more accurate in predicting overall survival and recurrence-free survival rate compared to the number of positive nodes alone.
There is also disparity regarding the number of LNs to be resected [1]. The number of positive lymph nodes and the total number of dissected lymph nodes are affected by a lymph nodes dissection procedure and confirmed by pathological examination [4].
Some groups have recently proposed the metastatic lymph node ratio (MLR) as an alternative prognostic factor to supplement the limitations of the conventional N staging system, particularly when a limited number of LNs is obtained [3].
The routine inclusion of MLR in tumor reporting by pathologists may become a prognostic aid for clinicians alongside tumor stage and tumor grade [2].

AIMS AND OBJECTIVES
 To evaluate the prevalence of various primary organ malignancy and its metastasis.  To evaluate the distribution of primary organ malignancy as per the age and gender of the patients.  To evaluate total LNH, LNM, and MLR in resected specimens of primary organ malignancy.  To evaluate the cases as per their MLR groups.  To evaluate the relation of MLR with tumor stage and tumor grade.

MATERIALS AND METHODS
We carried out a retrospective observational study. In the current study, we included the cases of primary organ malignancies that came to the hospital over a period from June 2018 to June 2019. Total 58 resection specimens of primary organ malignancy with local LN clearance were included in this study.
Age, gender, LNH, LNM, MLR, tumor stage and tumor grade were accessed for each of the cases. All data were recorded in MS Excel sheet. These data were represented in tabulated as well as graphical formats. We calculated the pvalue as and when required and pvalue of < 0.001 was considered as significant. The statistical analysis was performed using MS Excel and SPSS software.

DISCUSSION
The present study evaluated the data regarding age, gender, LNH, LNM, MLR, tumor stage and tumor grade from primary organ malignancy cases resected with local nodal clearance. LNH, LNM and MLR were studied for correlation with tumor stage and tumor grade.
The peak age group of affected patients in our study was 35-45 years. There was marked female preponderance over males in our study. These findings of our study were comparable with the study done by various other studies [2]. Akagi et al. and Zeng et al. reported male predominance in colorectal and gastric carcinoma, as did Chen et al. in or opharyngeal malignancy [4,6,7]. The male predominance in GIT and HN malignancies may reflect lifestyle related behavior as alcoholism, processed junk food, smoking, and tobacco chewing.
The recommended LNH values are 10, 12, 12, and 40 in breast, GIT, GUT, and HN respectively. Shinde et al. found mean LNH values 23.7, 15.5, 6.6 and 9.9 in HN, Breast, GIT and GUT respectively which were similar to our study. Techniques to further improve the yield of LNH include meticulous dissection during grossing, intratumoral India ink injection during surgery, ex-vivo intra-arterial injection of methylene blue, and chemical fat clearance using acetone and alcohol. Shinde et al. found mean LNM values 0.6, 4.4, 1.4 and 0.9 in HN, Breast, GIT and GUT respectively which were similar to our study [2].
LNH, LNM and LNR cutoff values show organ wise variation, hence need standardization before their usage in cancer staging systems. [1] Serial recuts, use of immunohistochemistry, one step nucleic acid amplification, and polymerase chain reaction can further aid in detecting minute nodal metastases [2].
In present study, majority of HN malignancy cases (41.6%) were found in T1/T2 stage and 83.3% were well differentiated. Majority of breast malignancy cases (42.4%) were found in T2 stage and 54.5% poorly differentiated. Majority of GIT malignancy cases (63.6%) were found in T3 stage and 54.5% were moderately differentiated. 50% of GUT cases were in T3 and 50% were in T4 stage and 50% was well differentiated and 50% were poorly differentiated. Titipungul [11].
We found significant association between MLR with tumor stage and tumor grade (p-value < 0.001), which was comparable to the study done by Saedi et al. [3].
A study done by Chen et al. on HN case reported that patient with higher MLR was shown to have poor survival. [4] LNR and number of positive lymph nodes are important prognostic factors with regard to overall survival for patients with nodepositive breast cancer, but LNR has a more correlated value in breast cancer subtypes [5]. Lee et al. in his published study declared that the MLR was a simple and reproducible prognostic factor that supplemented the limitation of the conventional N staging system and provided more accurate prognostic stratification in advanced gastric cancer [12]. Kwon et al. in his study showed that MLR is one of the main factors in predicting 5 years survivals of patients with gastric cancer [13]. Lymph node (LN) metastasis is one of the most important prognostic factors of gastric cancer [3]. Wright et al. found that higher MLR was associated with higher risk of death in GUT cases [14].

CONCLUSIONS
Previous studies did not define a specific cutoff value for MLR, but patients with a higher MLR were shown to have poor survival. In addition to the AJCC TNM classification system, LNR may be useful in stratifying risk in patients with primary organ malignancy. MLR is more valuable and reliable prognostic factor than total metastatic LN because it removes the effects of total number of resected LNs in determining patient prognosis. The routine inclusion of MLR in tumor reporting by pathologists may become a prognostic aid for clinicians along with TNM staging system. This can predict relapse and survival of cancer patients more closely.