Parotid gland lymphoma: Prognostic analysis of 2140 patients

The LaryngoscopeVC 2013 The American Laryngological,Rhinological and Otological Society, Inc.

Parotid Gland Lymphoma: Prognostic Analysis of 2140 Patients

Aaron J. Feinstein, MD, MHS; Maria M. Ciarleglio, PhD; Xiangyu Cong, MS;

Michael D. Otremba, MD; Benjamin L. Judson, MD

Objectives/Hypothesis: Assess the demographic, clinical, and pathologic features of patients with parotid glandlymphoma and their prognostic importance using US population-based data.

Study Design: Retrospective cohort study.Methods: Patients were selected from the Surveillance, Epidemiology, and End Results program database between the

years of 1973 and 2008, and individual characteristics were compared using univariate and multivariate Cox proportionalhazards models. Kaplan-Meier survival curves were constructed and log-rank tests were performed.

Results: We identified 2,140 patients with primary parotid gland lymphoma. Hodgkin lymphoma was found in 3.5% ofpatients. More common were non-Hodgkin lymphoma subtypes: marginal zone B-cell lymphoma, follicular lymphoma, and dif-fuse large B cell lymphoma accounted for 27.9%, 25.8%, and 23.7% of cases, respectively. Survival was decreased withpatient age over 50 years, increasing stage, male gender, non-Hodgkin histology, and status other than married. Of thepatients, 72.0% received some form of surgery, and 136 patients had facial nerve sacrifice during parotidectomy.

Conclusions: Non-Hodgkin lymphoma is the predominant type of lymphoma seen in the parotid gland. Patient andhistologic features determine survival, and surgery is often performed. Facial nerve sacrifice, which is contraindicated giventhe systemic nature of lymphoma and the role of chemotherapy and radiation in its treatment, is reported in 6.4% of patientswith parotid gland lymphoma.

Key Words: Parotid gland, lymphoma, salivary gland neoplasms, Surveillance, Epidemiology and End Results program.Level of Evidence: 2b.

Laryngoscope, 123:1199–1203, 2013

INTRODUCTIONThe head and neck is a frequent site of involvement

for the over 70,000 cases of lymphoma that occur annu-ally in the United States. Approximately 75% oflymphomas present as adenopathy and 25% presentextranodally, with 5% of extranodal lymphomas occur-ring in the major salivary glands.1,2 An estimated 2% ofall salivary gland tumors are lymphomas.3,4 Althoughthere are several single-institution series of parotid lym-phoma, there has not been an analysis of prognosticfeatures using US population-based data. Barnes et al.identified 33 primary parotid lymphomas among 820patients undergoing parotid surgery; there were 18women and 15 men with 73% of patients between 50and 80 years old; 82% of patients had stage I or II dis-ease and all the tumors were subtypes of non-Hodgkin

lymphoma (NHL).5 Tiplady et al. presented 136 cases ofprimary parotid lymphoma where the female to maleratio was 1.3:1 and the median age was 69 years; 72% ofpatients had stage I or II disease and eight cases weredetermined to be Hodgkin lymphoma.6

Looking at all lymphomas, NHL accounts for 89%of new cases, with over 25 different subtypes, the major-ity of which (84%) have a B cell origin.3,7,8 Hodgkinlymphoma represents 11% of cases and typicallypresents as cervical or supraclavicular lymphadenopa-thy. The classic B symptoms of fever, drenching nightsweats, and weight loss occur in less than 20% ofpatients with stage I/II Hodgkin lymphoma and under50% of those with stage III/IV disease; they are founduncommonly in NHL, being present in only 20% ofpatients with stage III/IV diffuse large B cell lymphoma(DLBCL) and rarely in other subtypes.9

The standard of care for lymphoma includes chemo-therapy and/or radiation tailored to the histologic subtypeof disease. Otolaryngologists are usually involved in thediagnostic workup of patients with parotid masses, andare responsible for obtaining adequate tissue for diagno-sis. Fine-needle aspiration (FNA) of lymphoma is subjectto the highest error rate of all FNAs in the head andneck, with a false-negative rate of 32%.10 Although FNAcan definitively diagnose lymphoma in some patients, itis often inadequate, and a tissue biopsy of some sort isfrequently required. Because patients with parotidtumors are typically taken to surgery without a tissuediagnosis following either an FNA or no prior biopsy,

From the Section of Otolaryngology, Department of Surgery (A.J.F.,M.D.O., B.L.J.), Yale University School of Medicine, New Haven; Yale Centerfor Analytical Sciences (M.M.C., X.C.), Yale School of Public Health, NewHaven, Connecticut, U.S.A.

Editor’s Note: This Manuscript was accepted for publicationOctober 30, 2012.

This study used the Surveillance, Epidemiology, and End Resultsdatabase. The interpretation and reporting of these data are the soleresponsibility of the authors.

The authors have no funding, financial relationships, or conflictsof interest to disclose.

Send correspondence to Benjamin L. Judson, MD, MPA, 800Howard Avenue, YPB 425, New Haven, CT 06519-1369.E-mail: [email protected]

DOI: 10.1002/lary.23901

Laryngoscope 123: May 2013 Feinstein et al.: Parotid Gland Lymphoma

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some patients with lymphoma of the salivary gland aretreated with initial surgical excision. In this study weinvestigated patients with parotid gland lymphoma todiscern the important demographic, clinical, surgical, andpathologic factors impacting patient survival.

MATERIALS AND METHODSThis study used the National Cancer Institute’s Surveil-

lance, Epidemiology and End Results (SEER) Programdatabase, which collects information from tumor registries in 15states and covers 28% of the US population. Patient level dataare available for sociodemographic and cancer characteristicsincluding sex, age, and race, as well as tumor stage, histology,and type of operation performed. SEER records the use of radia-tion therapy but does not reliably track administration ofchemotherapy.

We first selected all patients in the SEER-17 registriesdatabase between 1973 and 2008 diagnosed with a primarylymphoma occurring in the major salivary glands. The topogra-phy codes were based on the International Classification ofDiseases for Oncology, 2nd Edition: parotid gland (C.079) andmajor salivary glands (C.080-C.089). This sample was then re-stricted to patients with parotid gland lymphoma. The log-ranktest was used to compare unadjusted demographic and clinicalcharacteristics. Kaplan-Meier survival curves were constructedfor each characteristic of interest, with the log-rank test used totest the equality of survival experiences over the levels of eachvariable. Variables that were significantly associated with sur-vival in the univariate analysis were entered into amultivariate Cox proportional hazards model. Stepwise modelselection was used to determine the final multivariate model.Statistical analyses were performed using SAS version 9.2 (SASInstitute Inc., Cary, NC).

RESULTSWe identified 2,675 patients with primary lym-

phoma of the major salivary glands, and 2,140 patients(80%) had primary lymphoma of the parotid gland.These patients had a mean age of 64.1 6 16.8 years, andthe number of cases increased with age, as expected; the

TABLE I.Summary of Demographic, Clinical, and Pathologic Characteristics

Among 2,140 Patients With Primary Parotid Gland Lymphoma.

Characteristics No. (%) P*

Age, yr 64.1 6 16.8 NA

Age category, yr <.001

0–18 30 (1.4)

18–30 48 (2.2)

30–40 112 (5.2)

40–50 266 (12.4)

50–60 342 (16.0)

60–70 474 (22.1)

70–80 514 (24.0)

>80 354 (16.5)

Sex .024

Male 911 (42.6)

Female 1229 (57.4)

Race .100

White 1837 (85.8)

Black 142 (6.6)

Other 161 (7.5)

Marital status <.001

Married 1194 (55.8)

Single/separated/divorced/widowed

842 (39.3)

Missing 104 (4.9)

Location .086

Midwest 480 (22.4)

Northeast 342 (16.0)

South 171 (8.0)

West 1147 (53.6)

Period <.001

1973–1991 344 (16.1)

1992–1999 456 (21.3)

2000–2008 1340 (62.6)

Stage <.001

I 1065 (49.8)

II 449 (21.0)

III 118 (5.5)

IV 190 (8.9)

Missing 318 (14.9)

Histology <.001

Hodgkin lymphoma 75 (3.5)

Small B lymphocytic lymphoma 75 (3.5)

Diffuse large B-cell lymphoma 507 (23.7)

Follicular lymphoma 553 (25.8)

Marginal zone B-cell lymphoma 598 (27.9)

Other lymphoma 332 (15.5)

B symptom .068

Yes 91 (4.3)

No 1027 (48.0)

Missing 1022 (47.8)

Laterality .904

Right 1002 (46.8)

(Continued)

TABLE I.(Continued).

Characteristics No. (%) P*

Left 1045 (48.8)

Bilateral 50 (2.3)

Missing 43 (2.0)

Surgery .272

Biopsy 235 (11.0)

Parotidectomy 1156 (54.0)

Parotidectomy with facialnerve sacrifice

136 (6.4)

No surgery 595 (27.8)

Missing 18 (0.8)

Radiation .005

Has Radiation 834 (39.0)

No Radiation 1257 (58.7)

Missing 49 (2.3)

*P value from log-rank testNA¼not applicable.


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greatest number of cases occurred in patients aged 70 to80 years (Table I). There was a female predominance,with 57.4% of cases occurring in women. Most patientsin this sample were white (85.8%), with 6.6% blackpatients and 7.5% of another race. The majority ofpatients were married (55.8%). More patients in oursample were diagnosed in later time periods, consistentwith additional state registries beginning to report tothe national SEER program.

Parotid gland lymphoma did not occur more oftenon the left or right side of the body, and was found toarise bilaterally in 50 patients (2.3%). NHL accountedfor nearly all cases; Hodgkin lymphoma was found in3.5% of patients. The most common histologic subtype ofNHL encountered was marginal zone B-cell lymphoma(MALT), with 27.9% of cases. Follicular lymphoma anddiffuse large B cell lymphoma (DLBCL) were also com-mon, representing 25.8% and 23.7%, respectively. Thesmall B lymphocytic lymphoma occurred in 3.5% ofcases, and a wide variety of histologic types accountedfor the remaining 332 cases.

Most patients in this sample presented with stage Idisease (49.8%). Nearly a quarter had stage II disease(21.0%), and stage III and IV were less commonlyencountered. Data on systemic B symptoms and prurituswere frequently missing or unknown; among thepatients with data available, 91.9% (1,027 of 1,118) didnot experience any systemic symptoms.

Surgery was frequently performed for thesepatients, with 71.4% receiving some type of procedure.Of the patients undergoing surgery, 15.4% (235 of 1,527)had an excisional biopsy performed. There were 75.7% ofpatients (1,156 of 1,527) treated with parotidectomy,whereas 8.9% of patients (136 of 1,527) had parotidec-tomy with facial nerve sacrifice. Radiation therapy wasgiven to 834 patients (39.0%). Data on chemotherapy arenot reliably recorded in the SEER database and couldnot be evaluated in this study.

The risk of death increased with age (Fig. 1). Therisk for those over the age of 50 was significantly greaterthan those 0 to 18 years old, with patients age 50 to 60

years having 12.6 times the risk of death as compared topatients aged 0 to 18 years (P ¼ .012) (Table II). Theadjusted hazard ratios (HRs) for patients aged 60 to 70,70 to 80, and over age 80 years as compared to thosebetween 0 to 18 years were 17.3 (P ¼ .005), 31 (P <.001), and 69 (P < .001). Females had a 37% lower riskof death as compared to males (P < .001), and thosepatients who were not married had a 47% greater risk ofdeath as compared to those who were married (P <.001). Patients diagnosed during 2000 to 2008 had a 37%

Fig. 1. Kaplan-Meier survival curve by patient age at presentation.

TABLE II.Results of Cox Proportional Hazard Model.

CharacteristicAdjusted

Hazard Ratio (95% CI) P

Age, yr <.001*

0–18 (reference) 1.00 —

18–30 1.66 (0.15–18.34) .680

30–40 4.79 (0.62–36.83) .132

40–50 7.04 (0.96–51.80) .055

50–60 12.61 (1.73–91.88) .012

60–70 17.25 (2.39–124.57) .005

70–80 31.20 (4.33–224.86) .006

>80 69.03 (9.57–497.84) <.001

Sex <.001*

Male (reference) 1.00 —

Female 0.63 (0.53–0.76) <.001

Marital Status <.001*

Married (reference) 1.00 —

Single/separated/divorced/widowed

1.47 (1.23–1.75) <.001

Period <.001*

1973–1991 (reference) 1.00 —

1992–1999 0.82 (0.63–1.06) .131

2000–2008 0.63 (0.48–0.83) .001

Stage <.001*

I (reference) 1.00 —

II 1.35 (1.11–1.63) .003

III 1.60 (1.13–2.26) .008

IV 1.58 (1.23–2.03) <.001

Histology <.001*

Hodgkin lymphoma(reference)

1.00 —

Small B lymphocyticlymphoma

1.28 (0.98–1.68) .070

Diffuse large B-celllymphoma

1.95 (1.15–3.31) .013

Follicular lymphoma 2.36 (1.84–3.04) <.001

Marginal zone B-celllymphoma

1.27 (0.79–2.02) .323

Other lymphoma 1.86 (1.41–2.47) <.001

Surgery <.001*

No surgery (reference) 1.00 —

Has surgery 0.65 (0.54–0.77) <.001

*Overall type III P value of the variable (over all levels).CI ¼ confidence interval.


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lower risk of death as compared to those from 1973 to1991 (P < .001) (Fig. 2).

The tumor stage did carry prognostic significance;patients with stage IV disease had 1.58 times the risk ofdeath as compared to patients with stage I disease (P <.001). The median survival time was 12.3 years for stageI, 9.1 years for stage II, 8.3 years for stage III, and 8.0years for stage IV. Lymphoma histologic subtype exerteda significant effect on survival, with Hodgkin lymphomademonstrating the longest survival (Fig. 3). Follicularlymphoma carried the highest risk of mortality as com-pared to Hodgkin lymphoma (HR 2.36; P < .001).Patients undergoing surgery were found to have 35%lower risk of death as compared to those not undergoingsurgery (P < .001) (Fig. 4). Use of radiation therapy wasassociated with improved survival, with median survivalfor those receiving radiation of 11.5 years compared to9.0 years for those not receiving radiation (P ¼ .005).

DISCUSSIONWe have identified 2,140 cases of primary lym-

phoma arising in the parotid gland between 1973 and

2008. The risk of death from parotid lymphomaincreases substantially with age and stage of disease,and women have a lower risk of death compared to men.We were interested to find that married patients had animproved survival relative to single, widowed, ordivorced patients; this observation has been noted previ-ously in patients with pancreatic cancer, breast cancer,and those undergoing coronary artery bypass graft sur-gery, although it is not uniformly reported.11–13

Patients with Hodgkin lymphoma had the best sur-vival among this cohort, although Hodgkin was also theleast common form of lymphoma encountered. Hodgkinlymphoma more commonly presents with adenopathy,and although the parotid gland is known to have intra-parotid lymph nodes, primary lymphoma is diagnosedwhen the initial site of disease is the parotid glandregardless of whether the tumor arose from the salivarygland or lymphatic tissue. Prior studies have demon-strated that non-Hodgkin lymphoma predominates inthe salivary glands.4–6,14,15

We were interested to find that patients undergoingsurgery had improved survival relative to patients whodid not have surgery. It is possible that patients notundergoing surgery had significant comorbidities pre-cluding surgery that impacted their survival, but wewere unable to fully assess this question within theSEER database. Radiation was also associated withimproved survival, although like surgery, those selectedto receive treatment may have had fewer comorbiditiesor other favorable prognostic features that factored intheir selection.

The main limitation of this study is the unavailabil-ity of detailed clinical information on these patientswithin the SEER database. The use of chemotherapy isnot accurately recorded, and therefore we could notassess its use in general or whether the type of chemo-therapy administered or its combination with radiationtherapy was consistent with national practice guidelines.Preoperative and intraoperative pathology reports couldnot be examined to better understand surgical indica-tions. Specifically, we are unable to determine whether

Fig. 2. Kaplan-Meier survival curve by era of diagnosis.

Fig. 3. Kaplan-Meier survival curve by tumor histology.

Fig. 4. Kaplan-Meier survival curve by surgery status.


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preoperative FNA or intraoperative frozen sectionresults were available to the surgeons involved in paroti-dectomy procedures, or whether these results wereaccurate relative to final pathology results. However,this study does benefit from the very large sample size,as well as the extensive duration of follow-up.

CONCLUSIONPrimary lymphoma of the parotid gland is an

uncommon tumor that remains an important considera-tion in the evaluation and treatment of parotid lesions.Although FNA can in some cases provide a diagnosis, itis frequently inadequate. Excisional biopsy or parotidec-tomy are often performed to establish a diagnosis.Although facial nerve sacrifice is contraindicated in pa-rotid gland lymphoma because complete surgical excisionis not established as part of the first line treatment oflymphomas, it is still performed. Frozen section identifi-cation of lymphoma prior to nerve sacrifice is importantto avoid causing the patient unnecessary morbidity.

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Parotid gland lymphoma: Prognostic analysis of 2140 patients