Parotid Metastasis of Renal Cell Carcinoma: A Case Report and Review of the Literature

Background: To review the presentation and management of renal cell carcinoma metastatic to the parotid gland. Methods: Case report and review of the literature. Results: There have been 45 cases of renal cell carcinoma metastatic to the parotid gland reported in the English literature. A parotid lesion can be the initial clinical presentation of this malignancy (even before primary site identification). A case of patient with a parotid mass noted 4 years after undergoing a nephrectomy for renal cell carcinoma is presented. Superficial parotidectomy with facial nerve monitoring demonstrated metastatic renal cell carcinoma with negative margins on pathology. Conclusions: Metastatic renal cell carcinoma should be considered in the differential diagnosis a vascular parotid mass in patients have a history of prior diagnosis of renal cell carcinoma. After diagnosis is established, a systemic assessment should be performed given that solitary parotid metastases are uncommon. Due to the limited number of cases reported in the literature, clinical outcomes are difficult to predict.


Background
Malignancies of the parotid gland are relatively uncommon, accounting for only 3-6% of all head and neck cancers and 0.3% of all cancers [1]. Approximately 30% of parotid tumors are malignant and most represent primary salivary gland tumors. Metastatic spread to the parotid is uncommon but should be considered at the time of initial assessment of a parotid mass. The most common primary malignancies associated with metastasis to the parotid are cutaneous neoplasms of the head and neck [2]. However, ductal carcinoma of the breast, rhabdomyosarcoma, small cell carcinoma of the lung, and renal cell carcinoma are also primary tumors that harbor the potential for metastatic spread to the parotid that have been reported [2,3].
Renal cell carcinoma (RCC) is a relatively uncommon cancer with approximately 54,000 new cases and 13,000 deaths noted annually in the United States. It has a 3:2 male predominance and a peak incidence in the 6 th and 7 th decades of life. Though tobacco use, obesity, and hypertension are the only identified risk factor, most cases are sporadic. The classic triad of clinical presentation includes hematuria, pain, and abdominal mass, however greater than 50% of cases are detected incidentally during abdominal imaging for another indication [4].
RCC is well known for its unique potential to metastasize to nearly every organ system in the body. The tumor is highly vascular and thought to metastasize via both hematogenous (via the Batson's plexus) and lymphatic routes [5]. The most common sites for metastasis are the lung, bone, adrenal, liver, brain, and the contralateral kidney [4]. Though not as frequent, metastatic RCC to the head and neck has been identified in the thyroid, salivary glands, skull base, sinuses, pharynx, tonsils, tongue, lip and skin [6]. Metastasis to the parotid gland is very rare. In a study by Bernicker et al of 65 patients with RCC metastasis to the head and neck, none of the patients presented with parotid metastasis [6]. The first case of RCC metastatic to the parotid gland was published by Patey et al in 1965 [7]. Since then there have only been 45 reported cases reported in the English literature [5,39]. Although this entity is uncommon in presentation, this review highlights issues that may assist the head and neck surgeon with a pathologic diagnosis not often encountered cephalad to the clavicles.

Methods
PubMed and MEDLINE were used to search the English literature database (from 1965-2011) using the terms "renal cell carcinoma" and "parotid gland." References from those articles were thoroughly reviewed. Only relevant publications were included. Cases of renal cell carcinoma metastatic to the parotid gland were reviewed with emphasis on patient age, gender, presenting symptoms and duration, time interval since diagnosis of primary cancer, physical exam, diagnostic tests results including fine needle aspiration (FNA), radiologic

Case report
A 71 year-old man was referred for management of a right parotid mass that was first noticed 2 years prior. Over the preceding 12 months the mass had become increasingly tender after being accidentally traumatized. The patient denied any significant change in size of the mass, paresthesia, or facial weakness. There was no associated dysphagia, hoarseness, otalgia, dyspnea, or unexplained weight loss. He had a past medical history significant for hypertension. Of note, the patient had undergone a right nephrectomy 5 years prior for renal cell carcinoma. The patients also had a 50+ pack-year smoking history and denied a family history of renal diagnoses or other cancer syndromes.
On physical exam, there was a non-tender, soft mass in the tail of the right parotid without associated lymphadenopathy. The patient's body-mass index (BMI) was 24.33 and blood pressure was 145/65 during evaluation. Both computed tomography (CT) scan (Figure 1 & 2) and magnetic resonance imaging (MRI) of the neck with contrast had been performed prior and showed an isolated right-sided lobular parotid mass that measured 3.0 x 2.4 x 2.5cm. Of note, the mass demonstrated an intense uptake of contrast. On repeat MRI at the time of evaluation there was noted to be an interval increase of the mass to 3.5 x 3.2 x 3.7 cm. The patient underwent a total parotidectomy with facial nerve preservation. Intraoperative facial nerve 4-channel monitoring was utilized.
On pathologic review, the parotid was noted to harbor a soft, well-encapsulated, orange-tan, homogenous wellcircumscribed lesion with areas of hemorrhage (Figure 3). The tumor appeared to be confined within a thin capsule. The remainder of the specimen demonstrated normal parotid tissue. Histological evaluation demonstrated polygonal to round cells with abundant clear cytoplasm and large nucleoli containing small nucleoli (Figure 2), in a stark contrast to normal parotid tissue (Figure 4). Immunohistochemistry revealed positive staining for vimentin ( Figure 5) and CD10 (Figure 6), which lead to the diagnosis of renal cell carcinoma metastatic to the parotid gland.
Following this diagnosis, the patient underwent full-body imaging which demonstrated 3 small lesions in the pancreas that were stable compared to prior imaging. One year after the surgery, the patient was doing well and remained disease-free.
In 16 of the cases, parotid metastasis was the first sign of the renal primary. Fourteen of the patients had been diagnosed and treated for RCC in prior to parotid metastasis with an interval prior parotid presentation that spanned from 5 months to 19 years. Wayne et al. [9] reported a patient that was diagnosed with RCC of the parotid but no primary tumor was ever identified. In 16 of the cases, the patients were found to have metastatic disease beyond the parotid upon subsequent work-up. Four patients appeared to have isolated parotid disease at the time of their presentation but went on to develop other distant metastatic disease. There were 4 cases of isolated parotid metastasis. Seven reports did not discuss distant metastasis.
Fine needle aspiration was performed in 13 of the reported cases. It was diagnostic in 3, non-diagnostic in 10, and not mentioned in 18 of the published cases. Twenty-eight of the patients underwent excision of the parotid disease. Fifteen patients underwent superficial parotidectomies, 1 underwent a partial parotidectomy, 1 underwent a "deep" parotidectomy, and 5 underwent total parotidectomy. The remaining 6 authors did not detail the extent of the procedure beyond excision of the mass. Three authors elected to perform neck dissections in addition to parotidectomy. 11 authors mentioned the facial nerve with preservation noted in 10 of the cases. In 1 case the inferior portion of the facial nerve required sacrifice for complete resection of the tumor. There were 3 reports of locally recurrent disease after excision. Two patients were not managed with palliative intent with radiotherapy and pain relief. One author did not comment on therapy.

Discussion
Metastasis from RCC to the parotid gland is a rare finding. RCC also poses a particular diagnostic challenge because distant disease can present synchronous with the diagnosis of the primary renal tumor or a metachronous distant presentation may occur many years after therapy for the primary. For greater than 50% of the case presentations reviewed, the parotid lesion was the first sign of renal disease. Review of the cases presented in the literature suggests the most likely presentation is of an asymptomatic, unilateral parotid mass. Associated pain, palpable pulse, bruit, tinnitus, and numbness have been reported but are less common. Somewhat surprisingly, facial nerve weakness is extremely uncommon with only one documented case in the literature [14]. Although most cases of RCC are sporadic, hereditary forms (such as seen with associated with Von Hippel-Lindau disease) have been described and may require screening in high-risk populations. Fine needle aspiration did not yield a diagnosis all but 3 of the cases reviewed. In this scenario, FNA is commonly non-diagnostic and carries a risk of false positive results. Even if a clear cell tumor is identified on FNA, differentiating the cells from a primary parotid tumor often requires immunohistochemical staining by an experienced pathologist. Differential diagnosis of clear cell tumors of the parotid gland includes clear cell variants of pleomorphic adenoma, myoepithelial carcinoma, epithelial-myoepithelial carcinoma, acinic cell carcinoma, adenocarcinoma of the salivary glands, hyalinizing clear cell carcinoma, mucoepidermoid carcinoma, oncocytoma, odontogenic carcinoma, and metastatic disease [13,38]. Clear cells can also result as artifact in slide preparation.
Immunohistochemistry can be used to distinguish RCC from other clear cell carcinomas of the parotid gland. RCC is known to stain positively for CD10 and vimentin, which were the utilized in the diagnosis of our patient [12]. CD10, also known as common acute lymphoblastic leukemia antigen (CALLA) or neprilysin, is a zinc-dependent metalloproteinase enzyme. Vimentin is an intermediate filament. Both are membranous stains that illuminate the cytoplasmic membrane when positive. CEA is more classically positive in clear cell tumors of parotid origin [12].
Appropriate management options for patients with parotid metastases from renal cell carcinoma is best determined by a multidisciplinary team that includes Otolaryngology, Medical Oncology, and Urology. Therapy for primary renal cell carcinoma ranges from radical or partial nephrectomy [4] to cytoreductive therapy (cryoablation and radiofrequency ablation) and is dependent upon the stage, grade and size of the presenting tumor. Isolated parotid metastasis is also ideally managed by local excision with disease-free margins with facial nerve preservation (when possible). Of the 27 cases in the literature that were managed with local excision, 3 experienced local recurrences [16,24,29]. Recurrence occurred following superficial parotidectomies in all 3 cases, with a disease-free interval of 18 months to 4 years. Two of those patients had untreated renal primaries at the time of disease recurrence [24,29].
Prognosis for patients with parotid metastasis from RCC is difficult to predict due to the limited number of cases reported in the literature. The most important prognostic factor for RCC is pathologic stage. Distant metastasis carries a 1-year survival of 50%, 5-year survival of 5 to 30%, and 10-year survival of 0 to 5%. The presentation of an isolated parotid metastasis is favorable to multiple site distant metastatic spread of disease. Metachronous disease presentation suggests a less aggressive presentation [4]. Review of the literature demonstrated that greater than 50% of the patients found to have parotid RCC had other sites of metastasis. This highlights the need for a thorough metastatic work-up and a collaborative team approach for systemic renal cell carcinoma. Metastatic evaluation includes a chest radiograph, abdominal and pelvic CT or MRI, and liver function tests. Bone scan and chest CT can be reserved for patients with elevated alkaline phosphatase and abnormal chest radiographs, respectively [4].

Conclusions
Renal cell carcinoma (RCC) is a neoplasm with a unique metastatic potential to spread to nearly every organ system in the body. While RCC should not be high on the differential for all parotid gland masses, it should be considered when patients have a history of RCC and when FNA identifies a clear cell tumor. A thorough work-up should be performed, as solitary parotid metastases are rare in the literature and other occult sites may coexist. Isolated parotid disease is best managed with complete surgical excision and facial nerve preservation is usually possible.

Competing interests
The Authors declare that they have no competing interests. Author contributions CL was involved in the paper's conception, acquisition of data, drafting and revising of the manuscript. RW was involved in the paper's conception, revising and final approval of the manuscript. Both authors read and approved of the final version of the paper.