Treatment of Parotid Non-Hodgkin Lymphoma: A Meta-Analysis.

PURPOSE: This meta-analysis aimed to review the published outcomes of parotid non-Hodgkin lymphoma (NHL) pertaining to different treatment modalities.
MATERIALS AND METHODS: A total of 48 journal articles published between 1993 and 2015, comprising 742 cases of parotid NHL, were initially evaluated. In total, 108 patients from 12 studies who had sufficient data for analysis, including age, tumor histopathology, treatment modality, and outcome at final follow-up, were included. Patients were randomly assigned to different categories on the basis of histopathology and treatment modality. Groups were compared using Kaplan-Meier survival curve analysis and the Mann-Whitney U test.
RESULTS: Log-rank tests demonstrated that for early-stage (I and II) parotid NHL of all histopathology variants, radiation therapy significantly improved the survival rate versus chemotherapy ( P = .043), as well as combined treatment with chemotherapy and radiation therapy ( P = .023). For early-stage diffuse large B-cell lymphoma, combined treatment significantly improved survival versus single treatment ( P = .028). No treatment was received by seven patients with early-stage mucosa-associated lymphoid tissue lymphoma after undergoing parotidectomy. When the clinical outcomes of these patients were compared with those of other patients with the same histology who underwent further treatment, no significant differences were noted in survival outcomes.
CONCLUSION: Radiation therapy seems to be a valid treatment of early-stage parotid NHL. However, for diffuse large B-cell lymphoma, survival was higher with combined treatment versus single treatment. For early-stage parotid mucosa-associated lymphoid tissue lymphoma, complete excision of the tumor through superficial parotidectomy may have similar survival outcome.

INTRODUCTION

The head and neck region is a common site for extranodal non-Hodgkin lymphoma (NHL). The prevalence of extranodal NHL is most common in the GI tract, whereas the head and neck region serves as the second most frequent anatomic site of extranodal lymphomas.[1,2] The salivary glands serve as the site for nearly 12% of extranodal lymphomas of the head and neck region, which accounts for 2% to 5% of salivary gland neoplasms. Parotid glands serve as the most common site for salivary gland lymphomas, whereas nearly 20% of salivary gland lymphomas infect the submandibular and minor salivary glands.[1-5] Mucosa-associated lymphoid tissue (MALT) lymphomas are regarded as the most common histologic type of lymphomas affecting the salivary glands. Moreover, follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) are also included among common histologic forms of lymphoma, which most often target the salivary glands.[3-5]

In the case of malignant lymphoma, chemotherapy and/or radiation therapy are performed; however, the selection of treatment modalities is entirely on the basis of parameters including the histologic subtype and stage of lymphoma. The diagnosis of parotid malignant lymphoma is performed by the surgeon, who either obtains a tissue sample through fine-needle aspiration or open surgical biopsy. In the majority of parotid lymphomas cases, patients experience a painless mass resembling benign parotid tumors. For this reason, excisional parotidectomy is recommended for patients with suspected parotid lymphoma, and the diagnosis is entirely on the basis of outcomes of the excisional parotidectomy. This meta-analysis aimed to analyze the literature illustrating the outcomes of parotid NHL treatment and compared the outcomes using different treatment modalities for parotid lymphoma.

MATERIALS AND METHODS

Review Context

A literature review related to diversified treatment procedures for parotid NHL was initiated by searching globally conducted studies, to acquire insight to treatment procedures used for parotid NHL from a broader perspective.

Inclusion and Exclusion Criteria

Studies published between 1993 and 2015 that included three or more patients were included in this meta-analysis. Moreover, studies providing sufficient patient-related data, including age, tumor histopathology, treatment modality, and outcome at final follow-up were considered appropriate for inclusion. Studies reporting single cases were excluded. If multiple research articles were published by a single institution and all of them focused on the same patient population, the most recently conducted studies were included in this meta-analysis to avoid redundancy.

Search Strategy

The literature was searched systematically for studies that were conducted to analyze treatment strategies for parotid NHL. The most relevant articles for this meta-analysis were searched for using terms such as “parotid non-Hodgkin’s lymphoma,” “parotid lymphoma,” and “treatment modalities.” These search terms were separated by using the Boolean operators “OR” and “AND.”

The Medline database was used to search for relevant articles. This database was selected because it can provide access to updated literature on the effectiveness of diversified treatment strategies for parotid NHL. A total of 48 journal articles were retrieved from the Medline database. These retrieved articles comprised approximately 742 cases of parotid NHL. An initial screening of these articles was conducted. Among the retrieved articles, studies that did not provide data regarding the involvement of submandibular or parotid gland tumors were excluded, with the exception of studies highlighting > 85% of the sample population affected with parotid NHL.

After the screening process, 108 patients with parotid NHL from 12 studies were found to be eligible for this study. The studies included in this meta-analysis are listed in Table 1. Patients were further categorized into different groups, on the basis of treatment modalities and histopathology. Clinical outcomes and effectiveness of treatment strategies were compared by using statistical tools, including the Mann-Whitney U test and Kaplan-Meier survival curve. For this meta-analysis, test results with a P value < .05 were considered as significant.

Table 1

Summary of Studies Included in the Current Meta-Analysis

RESULTS

Of the 48 retrieved journal articles,[1-48] 12[4,6-16] were considered to be eligible. These 12 articles met the inclusion criteria and provided sufficient data in 108 patients. Approximately 58% of the participants included in this meta-analysis were female and between 31 and 38 years of age (median age, 59 years). A wide majority of participants included in this study presented with the initial stages of parotid NHL (stage I and II), whereas 23% of participants were diagnosed as having stage III and IV NHL.

The most common histology was MALT lymphoma (48 patients), followed by follicular lymphoma (33 patients). DLBCL was diagnosed in 20 patients, and seven patients were diagnosed as having other less common histology types. Approximately 64% of patients underwent a parotidectomy procedure rather than open surgical biopsy for diagnosis. Nearly one-third of the patients were treated using either chemotherapy or radiation therapy, and 27% received combined chemoradiation therapy. The remaining 12% of patients received neither chemotherapy nor radiation therapy.

Outcomes of log-rank tests revealed that for early-stage parotid NHL (stage I and II) of all histopathology variants, radiation therapy alone significantly improved the survival rate compared with chemotherapy (P = .043; Fig 1). Radiation therapy also significantly improved the survival rate compared with combined treatment with chemotherapy and radiation therapy (P = .023; Fig 2).

Fig 1

Log-rank test showing survival for early stage (I and II) parotid non-Hodgkin lymphoma comparing radiation therapy (RT) with chemotherapy (CH).

Fig 2

Log-rank test showing survival for early-stage (I and II) parotid non-Hodgkin lymphoma comparing radiation therapy (RT) with combined treatment with chemotherapy (CT) and RT.

For the DLBCL variant, combined treatment significantly improved the survival rate compared with single treatment (P = .028; Fig 3). Among the evaluated participants, seven patients with early-stage MALT lymphoma did not receive any treatment after undergoing parotidectomy. When the clinical outcomes of these patients were compared with those of patients who had similar histology and had received further treatment, no significant difference was noted in the survival outcome.

Fig 3

Log-rank test showing survival for diffuse large B-cell lymphoma comparing chemotherapy (CH) to combined CH and radiation therapy (RT).

DISCUSSION

MALT lymphoma of salivary glands has a high recurrence rate and aggressive behavior during an indolent clinical course. The recurrence rate of MALT lymphoma of salivary glands is higher than that of MALT lymphoma of the thyroid and stomach. The 10-year recurrence-free rate of MALT lymphoma of salivary glands is 68%, whereas the 10-year recurrence-free rate of MALT lymphoma of the thyroid and stomach was reported to be 95% and 92%, respectively. Extragastric lymphomas are reported to be more aggressive. The risk for recurrence of head and neck MALT lymphomas is further enhanced when only local therapies are applied for treatment.[13,36]

Parotid lymphomas are considered to be more aggressive than MALT lymphomas, whereas parotid lymphomas are more likely to be of low grade. Patients suspected of having parotid lymphoma demonstrate better prognosis compared with patients suspected of having other types of extranodal lymphomas.[37,38]

Olivier et al[39] conducted a randomized controlled trial consisting of patients with stage I and II parotid NHL, who were categorized into intervention and control groups. The intervention group was treated with radiation therapy, whereas the control group received treatment other than radiation therapy. Patients with parotid NHL who were treated with radiation therapy demonstrated significant improvement in clinical outcomes in terms of local control. On the other hand, there was no significant improvement in overall survival or disease-specific survival between the groups after 10 years of follow up. The current study revealed improved survival rates for patients in the initial stages of parotid NHL, who were treated with radiation therapy, compared with patients receiving either chemotherapy or combined treatment.

A study conducted by Tiplady et al[40] acquired data from the Scotland and New Castle Lymphoma Group registry. Their findings revealed that patients with stage I low-grade diseases (follicular lymphoma and MALT lymphoma) did not experience different clinical outcomes. Patients included in the study were treated using different modalities, whereas some of the patients included in the current study were treated by surgical procedures. However, considering the outcomes of this meta-analysis, seven patients with early-stage MALT lymphoma received no further treatment other than parotidectomy. However, there was no difference in the survival rate of these patients compared with that of patients with a similar histology who received further treatment.

Feinstein et al[41] conducted an analysis of 2,140 patients with parotid lymphoma. Data were acquired from the SEER database, and the findings revealed that patients who were treated with surgical procedures were at a 35% reduced risk of mortality compared with patients who underwent other treatment procedures.

The findings of this meta-analysis revealed that parotid lymphomas behave differently than lymphomas in other organs.[42-46]

In conclusion, the findings of this meta-analysis suggest that radiation therapy is a valid treatment of early-stage parotid NHL, with the exception of the DLBCL variant. Combined treatment significantly improved survival compared with single treatment. For the early-stage parotid MALT lymphoma variant, complete excision of the tumor via superficial parotidectomy may have a similar survival outcome.