Metastatic Renal Cell Carcinoma Presenting as Painful Chewing Successfully Treated with Combined Nivolumab and Sunitinib


Fade Mahmoud, MD, FACP; Al-Ola Abdallah, MD; Konstantinos Arnaoutakis, MD; Issam Makhoul, MD

Perm J 2016 Summer;20(3):15-149 [Full Citation]
E-pub: 06/27/2016


Introduction: Metastatic renal cell carcinoma (RCC) to the head and neck is rare. It is the third-most common cause of distant metastasis to the head and neck, after breast cancer and lung cancer. Several drugs are available to treat metastatic RCC including high-dose interleukin and targeted therapy. Immunotherapy with nivolumab was recently approved by the US Food and Drug Administration (FDA) as a second-line treatment for patients with metastatic RCC.
Case Presentation: We present a case of metastatic RCC in a 71-year-old man with a single complaint of a 1-year history of pain while chewing food. Positron emission tomography-computed tomography showed diffuse metastatic disease. Nivolumab, off-label use before its recent FDA approval, was combined with sunitinib and resulted in an excellent and ongoing response.
Discussion: RCC is the third-most common cause of distant metastasis to the head and neck. The patient described in this case did not have any symptoms commonly seen in RCC, such as painless hematuria, weight loss, anorexia, fatigue, or anemia, despite the bulk of his disease. The other important aspect of this case is the almost complete response of his metastatic disease to the combination of nivolumab and sunitinib that was used off label before the FDA issued the approval. Future clinical trials should look at combining immunotherapy with targeted therapy in metastatic RCC.


Renal cell carcinoma (RCC) is more common in men than in women, with an overall annual incidence of approximately 3.7%.1 The median age of onset is around 64 years.1 Approximately 62,000 new cases and 14,000 deaths caused by RCC occur annually.1 Up to 30% of patients with RCC present with metastatic disease.1 Most patients are asymptomatic until the disease is advanced. The classic triad of flank pain, hematuria, and a palpable abdominal mass is present in only 9% of patients. Several risk factors are thought to play a role in the etiology of RCC; these include smoking, hypertension, obesity, renal cystic disease, use of nonsteroidal anti-inflammatory drugs and other analgesics, chronic hepatitis C infection, and history of kidney stones.2-5

High-dose interleukin (HDIL-2) is the only therapy that provides a potential cure in a minority of patients.6 Several targeted therapies are approved as first-line for those patients who are not fit for HDIL-2.6 The recent advent of immunotherapy with checkpoint inhibitors has brought hope to patients with metastatic renal cell carcinoma. In this case we discuss a unique presentation of metastatic renal cell carcinoma. Also we report an excellent sustained tumor response to combined sunitinib and nivolumab.

Case Presentation

A 71-year-old man presented with pain while chewing, progressively worse, during the last year. He initially saw his dentist, and an oral exam did not reveal any abnormalities. Pain medications were prescribed for use as needed. His symptoms gradually got worse, so he was referred to an otolaryngologist.

Soft tissue neck computed tomography (CT) with contrast revealed a 5-cm intensely enhancing mass with extensive vascular supply in the left masticator space (Figure 1). Fine needle aspiration of the mass showed large cells with clear vesicular cytoplasm. These cells were reactive to paired box gene 8 (PAX8) and pankeratin, whereas the supporting cells were reactive to smooth muscle actin. These findings were suggestive of metastatic renal cell carcinoma (RCC). Full-body positron emission tomography (PET)-CT confirmed the above findings but also revealed masses at the inferior pole of the left kidney, retroperitoneal lymphadenopathy, and bilateral lung nodules (Figure 2A). The differential diagnosis based on the location of the mass included schwannoma, hemangiopericytoma, angiosarcoma, lymphoma, and metastatic carcinoma, particularly lung carcinoma and RCC. Sunitinib, an inhibitor of cellular signaling that targets multiple receptor tyrosine kinases, was initiated at 50 mg orally daily (4 weeks on and 2 weeks off). His pain was controlled with opioids, but we discussed with him palliative radiation therapy to the left masticator space mass in case his pain became resistent to opioids. Follow up PET-CT postsunitinib therapy showed an interval progression of his disease (Figure 2B). Nivolumab, an anti-program death receptor 1 inhibitor, was not approved yet by the US Food and Drug Administration, but we decided to add it to sunitinib, and the combined treatment resulted in almost complete response (Figure 2C). Table 1 illustrates a timeline of his follow-up visits, diagnostic tests, and interventions.

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Surpassed only by breast cancer and lung cancer, RCC is the third-most common cause of distant metastasis to the head and neck.7 Head-and-neck metastasis is the presenting complaint for 7.5% of patients with RCC.8 However, only 1% of patients with RCC have metastasis confined to the head and neck.8 A retrospective chart review of 21 cases of metastasis of RCC to the head and neck found that the most common sites of metastasis were bone (n = 6), skin and subcutaneous tissue (n = 6), and lymph nodes (n = 5).9 A head-and-neck metastasis may occasionally be the presenting sign in a patient with RCC or may follow the primary diagnosis by many years.9 Our patient did not have any symptoms commonly seen in RCC, such as painless hematuria, weight loss, anorexia, fatigue, or anemia, despite the bulk of his disease. It was only pain while chewing food that led to the diagnosis of metastatic RCC. CT scan with contrast is the imaging modality of choice in demonstrating the vascularity and extent of the lesion.7

The pathology revealed cells that are reactive to PAX8 and pankeratin. PAX8 and paired box gene 2 (PAX2) are transcription factors important for fetal development of several organs, including kidney, müllerian organs, brain, and eye. Both are good markers for renal cell tumors. Almost all RCCs are positive for PAX8, which is frequently expressed by lymphoma (100%), nephrogenic adenoma (100%), parathyroid tumors (62%), thyroid tumors (100%), and müllerian organ-derived tumors (92%).10,11 Tumors that may be negative or infrequently positive for PAX2, including chromophobe RCC, oncocytoma, and sarcomatoid RCC, are often positive for PAX8.12

Several drugs are available to treat metastatic RCC. Patients with good Karnofsky performance status (≥ 80%) and intact organ function are treated with high-dose interleukin-2 (HDIL-2) up front. HDIL-2 can induce long-term remissions in approximately 10% of patients.12 This treatment is associated with an approximately 4% mortality rate, so it is extremely important to select patients who are fit for this therapy. Several targeted therapies were approved as first-line for those patients who are not fit for HDIL-2, but treatment is based on risk groups. The Memorial Sloan-Kettering Cancer Center prognostic score stratifies patients with metastatic RCC into poor, intermediate, and favorable risk categories on the basis of the number of adverse clinical and laboratory parameters present.13 Poor prognostic factors include a Karnofsky performance status of less than 80 (80 indicates normal activity with effort and some signs or symptoms of disease), time from diagnosis to treatment less than 12 months, serum lactate dehydrogenase more than 1.5 times the upper limit of normal, corrected serum calcium greater than 10 mg/dL, and hemoglobin less than the lower limit of normal.13 Patients in the favorable-risk group have no poor prognostic factors, those in the intermediate-risk category have 1 or 2 adverse prognostic factors, and patients with poor-risk RCC have more than 2 poor prognostic factors. Patients in the favorable or intermediate risk group are treated with sunitinib, pazopanib, or interferon alpha plus bevacizumab,14-16 whereas the front-line treatment for those in the poor risk group is temsirolimus alone.17 Axitinib and sorafenib has been approved as second-line treatment, for use after other targeted therapy or cytokine therapy has failed.18

Activating the immune system appears to be a promising strategy to treat metastatic RCC. Since 2011, 2 novel classes of immunotherapy drugs have been approved: the cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab and the program death receptor 1 inhibitors pembrolizumab and nivolumab.19 In melanoma the combination of ipilimumab and nivolumab resulted in an objective response rate of 61%.19

In a phase I trial, patients with metastatic RCC received nivolumab in combination with sunitinb (50 mg, 4 weeks on, 2 weeks off) or pazopanib (800 mg daily), until progression/unacceptable toxicity. The starting dosage of nivolumab was 2 mg/kg intravenously every 3 weeks with planned escalation to 5 mg/kg intravenously every 3 weeks. Objective response rate was 52% among patients receiving nivolumab and sutent and 45% among those receiving nivolumab and pazopanib. Almost half the responses occurred by the first assessment, which is week 6 of treatment. The investigators concluded that nivolumab plus sutent or pazopanib showed encouraging antitumor activity and a manageable safety profile in patients with metastatic RCC.20 The decision to add nivolumab (off-label use) in our patient was based on the results of the above phase I trial. Three months later (November 23, 2015), the FDA approved nivolumab on the basis of results of an open label, randomized study that showed an overall survival advantage of nivolumab over everolimus in patients with metastatic RCC who failed antiangiogenic agents.21 Those treated with nivolumab lived an average of 25 months compared with 19.6 months in those treated with Afinitor. Additionally, 21.5% of those treated with nivolumab experienced a complete or partial shrinkage of their tumors, which lasted an average of 23 months, compared with 3.9% of those taking everolimus, lasting an average of 13.7 months.21,22

Our patient appears to be tolerating the combination of nivolumab and sunitinib. His follow-up PET-CT showed improvement in his disease (Table 1).

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Metastatic cancer to the head and neck is rare. Breast cancer, lung cancer, and RCC are the most common causes of distant metastasis to the head and neck. In our case, pain while chewing food was the only presenting symptom of metastatic RCC. Immunotherapy with interleukin-2 or interferon-alpha, biologic, or targeted therapy are all viable options for patients with metastatic RCC. Most recently the FDA approved nivolumab in the second-line setting after patients have failed antiangiogenic agents. Our patient had an almost complete response to combined nivolumab and sunitinib. Further studies should look into the combination of targeted therapy and immunotherapy in the front-line setting among patients with metastatic RCC.

Disclosure Statement

The author(s) have no conflicts of interest to disclose.


Leslie Parker, ELS, provided editorial assistance.

How to Cite this Article

Mahmoud F, Abdallah AO, Arnaoutakis K, Makhoul I. Metastatic renal cell carcinoma presenting as painful chewing successfully treated with combined nivolumab and sunitinib. Perm J 2016 Summer;20(3):15-149. DOI:

1.    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015 Jan-Feb;65(1):5-29. DOI:
    2.    Hunt JD, van der Hel OL, McMillan GP, Boffetta P, Brennan P. Renal cell carcinoma in relation to cigarette smoking: meta-analysis of 24 studies. Int J Cancer 2005 Mar 10;114(1):101-8. DOI:
    3.    Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell carcinoma. Eur Urol 2011 Oct;60(4):615-21. DOI: Erratum in: Eur Urol 2011 Dec;60(6):1317. DOI:
    4.    Cho E, Curhan G, Hankinson SE, et al. Prospective evaluation of analgesic use and risk of renal cell cancer. Arch Intern Med 2011 Sep 12;171(16):1487-93. DOI:
    5.    Gordon SC, Moonka D, Brown KA, et al. Risk for renal cell carcinoma in chronic hepatitis C infection. Cancer Epidemiol Biomarkers Prev 2010 Apr;19(4):1066-73. DOI:
    6.    Klapper JA, Downey SG, Smith FO, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma: a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer 2008 Jul 15;113(2):293-301. DOI:
    7.    Pritchyk KM, Schiff BA, Newkirk KA, Krowiak E, Deeb ZE. Metastatic renal cell carcinoma to the head and neck. Laryngoscope 2002 Sep;112(9):1598-602. DOI:
    8.    Boles R, Cerny J. Head and neck metastases from renal carcinomas. Mich Med 1971 Jul;70(16):616-8.
    9.    Langille G, Taylor SM, Bullock MJ. Metastatic renal cell carcinoma to the head and neck: summary of 21 cases. J Otolaryngol Head Neck Surg 2008 Aug;37(4):515-21.
    10.    Ozcan A, Shen SS, Hamilton C, et al. PAX 8 expression in non-neoplastic tissues, primary tumors, and metastatic tumors: a comprehensive immunohistochemical study. Mod Pathol 2011 Jun;24(6):751-64. DOI:
    11.    Truong LD, Shen SS. Immunohistochemical diagnosis of renal neoplasms. Arch Pathol Lab Med 2011 Jan;135(1):92-109. DOI:
    12.    Gupta R, Balzer B, Picken M, et al. Diagnostic implications of transcription factor Pax 2 protein and transmembrane enzyme complex carbonic anhydrase IX immunoreactivity in adult renal epithelial neoplasms. Am J Surg Pathol 2009 Feb;33(2):241-7. DOI:
    13.    Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999 Aug;17(8):2530-40.
    14.    Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013 Aug 22;369(8):722-31. DOI:
    15.    Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007 Jan 11;356(2):115-24. DOI:
    16.    Escudier B, Pluzanska A, Koralewski P, et al; AVOREN Trial Investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007 Dec 22;370(9605):2103-11. DOI:
    17.    Hudes G, Carducci M, Tomczak P, et al; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007 May 31;356(22):2271-81. DOI:
    18.    Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol 2013 Dec;14(13):1287-94. DOI:
    19.    Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015 May 21;372(21):2006-17. DOI:
    20.    Amin A, Plimack ER, Infante JR, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC). ASCO Annual Meeting Abstracts. J Clinical Oncol 2014 May 20;32(15 Suppl):5010.
    21.    FDA News Release: FDA approves Opdivo to treat advanced form of kidney cancer [Internet]. Silver Spring, MD: US Food and Drug Administration; 2015 Nov 23 [cited 2016 Mar 9]. Available from:
    22.    Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 Investigators. Nivolumab versus Everolimus in advanced renal-cell carcinoma.
N Engl J Med 2015 Nov 5; 373(19):1803-13. DOI:


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