Month 2014

Parotid lymphoma: a review of clinical presentation and management Jonathan W. Shum, DDS, MD,a Max Emmerling,b Joshua E. Lubek, DDS, MD,c and Robert A. Ord, DDS, MDd University of Texas Health Science Center at Houston, Houston, TX, USA; University of Maryland School of Dentistry and Greenebaum Cancer Center, Baltimore, MD, USA

Lymphoma of the parotid gland is a relatively rare occurrence among head and neck tumors. Presentation is indistinguishable from other swellings of the parotid gland; therefore, it is important to consider lymphoma in the differential diagnosis when examining parotid swellings. Parotid lymphomas are most likely to be B-cell non-Hodgkin lymphoma of 1 of 3 types, which include follicular, marginal zone, and diffuse large B cell, although other histologic patterns have been described. We present a review of 3 patients with parotid lymphoma who presented to the University of Maryland Medical Center’s Department of Oral and Maxillofacial Surgery with facial swelling. Two patients were diagnosed with follicular lymphoma, whereas the third was diagnosed with marginal zone lymphoma. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;-:e1-e5)

Head and neck tumors occurring within the salivary glands account for 3% of all head and neck malignancies diagnosed in the United States.1 Tumors that occur in the parotid gland compose the significant proportion of all salivary gland head and neck tumors. Of these, the rule of 80s pertains to the likelihood of a parotid lesion being of benign or malignant origin (80% to 20%, respectively). Among parotid tumors, incidence of lymphoma is rare, occurring in only 1% to 4% of patients who present with a parotid tumor.2 Diagnosis of lymphoma is often not considered preoperatively when a new parotid mass is evaluated.3 There is no distinguishing clinical or radiographic feature to provide a definitive diagnosis. Because of this difficulty, patients may undergo unnecessary surgical procedures, such as parotidectomy, which carries associated risk to the facial nerve.4 Treatment of parotid lymphoma is generally nonsurgical and completed with radiation, chemotherapy, or both. We reviewed 3 patients who presented to the Department of Oral and Maxillofacial Surgery with a diagnosis of parotid lymphoma, all of which presented initially with a swelling of the parotid gland. Of these patients, 2 were categorized histologically as having follicular lymphoma, whereas the third was categorized as having marginal zone lymphoma. From these cases, we highlight the clinical presentation, imaging, and

treatment rendered, as well as presenting a brief review of the current literature on the management of parotid lymphomas.

CASE 1 A 53-year-old woman presented for evaluation of a growing 1.5  1.2-cm left parotid mass over the past 3 months. The patient denied any history of fever, night sweats, or significant weight loss. The medical history was significant for Hashimoto thyroiditis and Sjögren syndrome. She reported occasional alcohol intake, 3 glasses of wine per day, but denied any history of tobacco or illicit drug use. A fine-needle aspiration biopsy (FNAB) found monoclonal B-cell lymphoma with scattered atypical lymphoid cells admixed with mature lymphocytes and rare monocytes. The pathologic diagnosis was established via open biopsy, with immunohistochemical stains finding the lymphoid cells to be positive for CD20, CD19, CD22, CD23, and CD52. The Ki67 was estimated at only 10% to 30% of the lesion, consistent with a low-grade marginal zone or MALT (mucosa-associated lymphoid tissue) lymphoma. There was no evidence of adjacent lymph node involvement or additional extranodal sites by positron emission tomographyecomputed tomography (PET-CT) scan, and the cancer was staged at I-AE. At the time of her diagnosis, the patient had a lactose dehydrogenase (LDH) concentration of 155 U/L. The patient was treated with a 30.6 Gy total dose of radiation therapy to the site of the primary tumor. Upon last follow-up, at 5 years after treatment, there was no evidence of recurrence.


Assistant Professor, Department of Oral and Maxillofacial Surgery, University of Texas Health Science Center at Houston. b Dental student, University of Maryland School of Dentistry. c Fellowship Director of Maxillofacial Oncology and Microvascular Reconstruction, Department of Oral and Maxillofacial Surgery; Assistant Professor, University of Maryland, Greenebaum Cancer Center. d Professor and Chairman, Department of Oral and Maxillofacial Surgery, University of Maryland, Greenebaum Cancer Center. Received for publication Sep 15, 2013; accepted for publication Oct 16, 2013. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.10.013

CASE 2 A 53-year-old man presented with a right parotid swelling and a palpable ipsilateral submental lymph node. MRI found a 2.1-cm mass in the superficial lobe of the parotid gland and a 9-mm mass toward the tail of the gland. The patient reported that he had noticed the right side of his face growing progressively larger over the past 4 months. The patient denied any history of fever, night sweats, or significant weight loss. Medical and social history were noncontributory. An FNAB was performed on the parotid mass and found rare groups of moderately atypical epithelial cells present in a background of


ORAL AND MAXILLOFACIAL SURGERY e2 Shum et al. lymphocytes. The patient then underwent open biopsy of the submental lymph node and extracapsular dissection of the right parotid tumor. Immunohistochemical staining was positive for CD20, CD10, and BCL2, with a Ki67 level that ranged between 15% and 60%. The patient was diagnosed with follicular lymphoma, grade 3A. A PET-CT scan found multiple active disease sites in the abdomen, with a maximum standardized uptake value (SUV) of 11.6, indicating stage III-AE disease. At the time of his diagnosis, the patient had an LDH level of 167 U/L. The patient was treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) for 6 cycles, followed by maintenance rituximab for 2 years. An end-of-treatment PET-CT scan found no evidence of relapse.

CASE 3 A 63-year-old man was evaluated for extraction of a fractured tooth. On routine examination of the head and neck, a 7.0  8.0-cm mass in the right preauricular region was noted; the patient had not been aware of it. His medical history was noncontributory, and he had no history of smoking tobacco, drinking alcohol, or using illicit drugs. An FNAB found abundant lymphocytes. Subsequently, a core biopsy was performed that yielded tissue with a population of mediumsized to large atypical lymphoid cells. Immunohistochemical stains were positive for CD10, CD20, BCL2, and BCL6. Open biopsy of the right parotid mass found follicular lymphoma, 75% grade 1 or 2 and 25% grade 3a, with focal areas of confluent large cells. A bone marrow biopsy performed on the left anterior iliac crest did not find marrow involvement, and PET-CT found a SUV of 15 at the parotid site and involvement of level 4 and 5b lymph nodes, consistent with stage II-AE disease. At the time of his diagnosis, the patient had an LDH level of 166 U/L. The patient completed R-CHOP for 3 cycles, followed by radiation therapy to a dose of 36 Gy. PET-CT found interval resolution of the primary tumor and cervical lymph nodes at the completion of this treatment. Upon last follow-up, at 1 year after treatment, there was no evidence of recurrence.

DISCUSSION Lymphoma of the parotid gland is usually a nonHodgkin lymphoma (NHL) of B-cell origin. Although most of these lesions have been described as extranodal NHL, it is possible that some may arise in lymphoid tissue that is associated within the parotid gland.5 The gland parenchyma is often secondarily involved, making the determination of the origin of the lymphoma difficult to discern. Despite this controversy, treatment of these patients is not affected.5 The average age of detection is 61.4 years; generally, the disease does not affect patients under 50 years of age. There is a relative tendency more toward males than females, at a ratio of about 2:1.2,6,7 Of lymphoma histology, follicular, MALT (marginal zone), and diffuse large B-cell lymphoma are the more common in the parotid. Patients with primary parotid lymphoma

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generally present with an asymptomatic enlarging mass of the parotid gland over a period of 4 to 6 months.2 Other symptoms include bilateral parotid swelling, cervical lymphadenopathy, pain, or facial nerve paresis.7,8 Clinical examination of a parotid lymphoma is indistinguishable from a benign or malignant parotid tumor and should always be considered as part of the differential diagnosis. The presence of an underlying autoimmune disorder, such as Sjögren syndrome, is associated with an increased risk of lymphoma, reported to be as high as 44%.9 Additionally, these conditions are associated with an increased incidence of lymphoma within the parotid gland, specifically marginal zone lymphoma.9 Initial evaluation for a parotid mass should include computed tomography (CT) or magnetic resonance imaging (MRI) to determine location, shape, and size. The presence of extraglandular involvement, cervical lymphadenopathy, and the relationship to vital structures are also readily assessed with imaging.10,11 CT and MRI have been described to be equally effective when evaluating for parotid tumor location, margin, and infiltration.12 Loggins and Urquhart3 reported the utility of CT scans in the evaluation of parotid lymphomas and described several trends in the majority of patients with parotid lymphoma, including bilateral parotid involvement, multiple masses, lymphadenopathy, and an ill-defined tumor. The benefits of CT imaging also include increased accessibility, lower cost, and faster results compared with MRI.12 MRI is the preferred imaging modality at our institution, owing to its superior soft tissue contrast.13 Although MRI has the ability to define the internal architecture of complex masses, it is not histologically specific.14 When reviewing an MRI, it is important to accurately differentiate between extraparotid and intraparotid location of the tumor to determine spatial relationship to and involvement of the facial nerve. Radiographic features that may suggest perineural involvement include enlargement or bony erosion of skull base neural foramina, obliteration of perineural fat planes, and nerve enlargement or abnormal contrast enhancement.15,16 Facial nerve involvement by parotid tumors is more commonly associated with salivary gland carcinomas, deep lobe involvement, and tumors larger than 4 cm.17-19 The presence of facial nerve involvement would generally indicate the necessity for total parotidectomy and facial nerve sacrifice; however, in cases of parotid lymphoma, the nerve can generally be spared. MRI of parotid lymphomas may display homogenous enhancement in both T1- and T2-weighted images, with well-defined margins and lobulated surfaces within the parotid gland, as seen in Figure 1.16,20 Additional reviews further corroborate

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Fig. 1. Axial images (from case 3) of a right parotid lymphoma. T2-weighted MRI image (left) versus T1-weighted MRI image (right). Well-defined margins and lobulated surfaces within the parotid gland can be seen.

these findings, suggesting no true pathognomonic features of lymphoma, but indicating that the presence of poor margin definition, infiltration, and multifocal lesions should raise clinical suspicion of the possibility of malignant disease.11,21,22 PET scanning with 18-fluoro-deoxyglucose (FDG/PET) is also frequently used in the management of NHL to define a treatment plan, to determine prognosis, and also to provide a means for surveillance within the posttreatment course. PET has 80% sensitivity and 90% specificity in the identification of malignancy.15 Additionally, findings from prospective studies indicate that PET correlates well with patient survival outcome, with a positive and negative predictive value of 85% across studies.15 Along with the characterization of a parotid mass by imaging studies, an FNAB is routinely obtained. Faced with a parotid mass of unknown etiology, one can rule out a variety of pathologic entities with the completion of an FNAB, particularly in conjunction with flow cytometry and immunophenotyping. FNAB with flow cytometry is an established initial method for diagnosis and classification of lymphoma.23-26 Studies suggest that the sensitivity and specificity for FNAB with flow cytometry are reported to be as high as 95% and 85%, respectively, for the detection of lymphoma.27 Despite the accuracy in identifying the presence of lymphoma, the ability to differentiate the histologic type of lymphoma is less reliable. Tissue biopsy is frequently required to confirm a specific subtype or establish grading of lymphoma.28 Without these readily available tests, patients may be exposed to unnecessary risks associated with surgical procedures. It was reported that 71.4% of patients with parotid lymphoma undergo some form of surgery, 8.9% of which experience parotidectomy with facial nerve sacrifice.28 The prognosis of lymphoma found in the parotid gland will depend on the histology, staging, and risk

factors as noted in the International Prognostic Index (IPI).29 Low-grade or indolent lymphomas are characterized by slow growth and sometimes spontaneous regressions.15 The 2 main histologic types of low-grade lymphoma of the parotid include marginal zone (i.e., MALT) and follicular, with MALT being the most frequent.4,30 Compared with other extranodal locations of NHL, parotid lymphomas are more often of low grade and have a better prognosis.31 High-grade or aggressive lymphomas are characterized by fast growth and a rapidly destructive nature if left untreated. The most common high-grade lymphoma to affect the parotid gland is diffuse large B-cell lymphoma, some cases of which may have transformed from an underlying lowgrade histology. Less common aggressive lymphomas include follicular large B-cell lymphoma and mantle cell lymphoma.15 The overall survival rate for parotid NHL is 75% at 5 years and 60% at 10 years, whereas lymphomas originating from other extranodal sites have a decreased survival of approximately 40%.28,31 Prognosis additionally depends on staging evaluation, which is accomplished via PET-CT and bone marrow biopsy to determine the extent of the disease process. Localized disease has a better prognosis than extensive disease.2 Feinstein et al.28 reviewed 2140 patients from the Surveillance, Epidemiology and End Results (SEER) data and identified prognostic factors associated with parotid lymphoma. Tumor stage carried prognostic significance, as stage IV disease was associated with a 1.58-fold higher risk of death as compared with stage I disease. Median survival time was 12.3 years for stage I, 9.1 years for stage II, 8.3 years for stage III, and 8.0 years for stage IV.28 A brief summary of the Ann Arbor staging is located in Table I.32 Low-grade lymphomas are curable with radiotherapy when localized, but even when they are more extensive, they have a good prognosis, owing to their indolent behavior.


Table I. Ann Arbor staging system32 I II



Modifiers A B


Involvement of 1 lymph node or extranodal organ/site Involvement of 2 or more lymph node regions on the same side of the diaphragm, or localized involvement of an extranodal site/organ and 1 or more lymph node regions on the same side of the diaphragm Involvement of lymph node regions on both sides of the diaphragm, which might be accompanied by localized involvement of an extranodal organ/site or spleen or both; the spleen is regarded as nodal Diffuse or disseminated involvement of 1 or more distant extranodal organs with or without associated lymph node involvement Absence of B symptoms (listed below) Temperature > 38 C, night sweats, and weight loss of greater than 10% of body weight in the 6 months preceding admission are defined as systemic symptoms Involvement of extranodal organ/site Involvement of spleen

Treatment in these cases may vary from a watchful waiting approach when asymptomatic to chemotherapy and radiotherapy.22 Aggressive lymphomas are presumed to have disseminated disease, even when it is not overtly evident on radiologic scans, and are therefore treated with systemic chemotherapy and rituximab (usually R-CHOP). R-CHOP is traditionally given every 21 days for 6 to 8 cycles. Patients are routinely monitored for toxicities such as neutropenia, thrombocytopenia, renal impairment, hepatic impairment, and neurotoxicity.33 Blood work is obtained routinely after each cycle to monitor for toxicity. For most NHL subtypes at extranodal locations, when radiation is indicated, general dose totals range from 24 to 30 Gy for low-grade disease and 30 to 50 Gy for high-grade lymphomas.22,34,35 After the histology and stage are determined, the prognosis can be further specified using the IPI, in which 4 risk groups are delineated based on the presence or absence of clinical features. For aggressive lymphomas, these include age, LDH level, Eastern Cooperative Oncology Group performance status, stage, and the number of implicated extranodal sites.36 For indolent lymphomas, the Follicular Lymphoma International Prognostic Index (FLIPI) considers the following clinical features: age, stage of lymphoma, blood hemoglobin, number of lymph node areas affected, and serum LDH level.37 Furthermore, comorbidity with Sjögren syndrome may confer a worse prognosis, owing to both frequent systemic involvement and a high incidence of aggressive histology in these patients.4 On review of our case series, in case 1, the patient’s marginal zone lymphoma was consistent with her history of Sjögren syndrome, which acts as a significant

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risk factor for parotid lymphoma. Marginal zone lymphoma is of low grade and is also localized. She was appropriately treated with radiotherapy. The lack of distant disease on PET-CT scan also contributes to a good prognosis, reflecting a lower stage of disease. In cases 2 and 3, both patients were diagnosed with follicular lymphoma. Although normally indolent, grade 3 follicular lymphoma exhibits aggressive behavior. Therefore, these patients were treated with systemic chemotherapy, specifically R-CHOP. In case 3, additional sites of involvement were determined via PET-CT scan, indicating a more advanced stage of disease compared with case 2 and therefore a worse prognosis. The patient in case 3 also received radiotherapy as part of his treatment regimen. FLIPI was used to assess the prognosis for the patients in cases 2 and 3, both of whom were rated as being at low risk and given estimated 5-year and 10-year survival rates of 91% and 71%, respectively.37 The majority of patients with primary parotid lymphoma present with an otherwise asymptomatic mass of the parotid gland. All 3 cases in this series presented with an asymptomatic swelling, one of which was discovered as an incidental finding at a dental visit. Symptoms of bilateral parotid swelling have been described but are rare. Other presenting symptoms may include cervical lymphadenopathy, pain, or facial nerve paresis. The presence of an underlying autoimmune disorder may suggest the possibility of a lymphoma, owing to a relatively high frequency of coincidence, as illustrated in case 1. Clinical examination of a parotid lymphoma is indistinguishable from other benign or malignant parotid swellings and should always be part of the differential diagnosis. Imaging may also provide limited information, with characteristics similar to the salivary gland malignant tumors. Case 3 illustrates a large, well-defined, amorphous mass that occupies both superficial and deep lobes of the parotid (see Figure 1). Evaluation with MRI found enhancement in both T1 and T2 windows. With respect to its size, shape, and location, most would assume malignant salivary gland tumor. The finding of lymphocytes on FNAB would suggest the diagnosis of lymphoma, and the histologic pattern is then identified with open biopsy, as performed in the cases described. Treatment can then be tailored to the specific grade and histologic type via chemotherapy, radiotherapy, or both, and prognosis is generally good. Clinical awareness of the aforementioned features will assist in prompt recognition and referral to an oncologist for definitive treatment.

REFERENCES 1. Speight PM, Barrett AW. Salivary gland tumors. Oral Dis. 2002;8(5):229-240.

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Parotid lymphoma: a review of clinical presentation and management.

Lymphoma of the parotid gland is a relatively rare occurrence among head and neck tumors. Presentation is indistinguishable from other swellings of th...
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