Renal Cell Carcinoma: Delayed Metachronous Metastases to Parotid and Cerebellum Antonia Kolokythas, DDS, MSc,* Scott Weiskopf, DDS,y Manmeet Singh, DO,z and Robert J. Cabay, MD, DDSx Purpose:
The purpose of this report is to describe a rare case of delayed metachronous isolated metastases of renal cell carcinoma (RCC) to the parotid gland and the cerebellum. The metastases occurred more than a decade after treatment of the primary tumor without any other systemic involvement. In addition, the potential differential diagnosis of the parotid mass based on presentation and imaging is discussed.
Materials and Methods:
An 83-year-old man presented for evaluation and treatment of a rapidly growing mass at the right parotid region. He had a history of RCC resection 10 years before this presentation and had no evidence of persistent disease at the primary site. The diagnosis of metastatic RCC was made after fine-needle aspiration biopsy examination of the mass. The patient underwent superficial parotidectomy for resection of the tumor. Approximately 1.5 years later, he complained of loss of balance. Further investigation disclosed a cerebellar mass that at biopsy examination was found to represent RCC. He underwent stereotactic ablation of the mass. He currently remains free of disease at the primary site and the parotid and without further known brain metastases.
Results:
This report presents the 29th case of a solitary parotid mass consistent with metastatic RCC 10 years after successful treatment of the primary RCC. Approximately 1.5 years later, the patient presented with new-onset loss of balance. Further investigation disclosed a mass to the cerebellum consistent with metastatic RCC. This case is unique because the brain involvement occurred extremely late, 11.5 years after successful treatment of primary RCC and 1.5 years after resection of a metastatic RCC to the parotid, and without any evidence of other metastases.
Conclusions: Late distant metastases of RCC are not uncommon and patients require life surveillance follow-up, but such late presentation of metachronous metastases without systemic disease progression is unique. The patterns of metastases of RCC are not clearly defined and this diagnosis should be considered, especially in patients with relevant history. Ó 2015 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 73:1296-1303, 2015
Renal cell carcinoma (RCC) is the most common renal malignancy (approximately 90% of cases) with high metastatic potential. It is among the top 10 most common malignancies for men and women, with a 2:1 male-to-female predilection. The usual age of presentation is the sixth to seventh decade of life. Most of these tumors are incidentally discovered at abdominal imag-
ing and usually carry a better prognosis owing to early-stage disease. Conversely, when patients present with local or systemic symptomatology, metastatic disease is commonly present and this carries a very poor prognosis.1-6 Surgical resection for small solitary lesions has been established as the standard management for RCC, with the goal being adequate
Received from the Department of Oral and Maxillofacial Surgery,
at Chicago, 801 S Paulina Street, Chicago, IL 60612; e-mail:
University of Illinois at Chicago, Chicago, IL.
[email protected]
*Associate Professor, Program Director, Director of Research. yFormer Chief Resident.
Received December 30 2014 Accepted January 20 2015
zSurgical Pathology Fellow, Department of Pathology.
Ó 2015 American Association of Oral and Maxillofacial Surgeons
xAssistant Professor of Clinical Pathology, Department of
0278-2391/15/00072-5
Pathology.
http://dx.doi.org/10.1016/j.joms.2015.01.017
Address correspondence and reprint requests to Dr Kolokythas: Department of Oral and Maxillofacial Surgery, University of Illinois
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cancer control with kidney function preservation when possible. Unfortunately, RCC is known to metastasize and approximately 20% of patients will go on to develop metastatic disease within the first 3 to 5 years after treatment of the primary tumor.1,2,4-6 Common sites of metastases include the lungs, liver, bone, and brain and these patients have an overall poor prognosis. RCC metastasis to the head and neck is usually a late manifestation, with thyroid, skin, skull, and nodal involvement as the most common sites. Involvement of the parotid has been reported most commonly along with widely spread disease, whereas only 28 cases of solitary involvement have been reported thus far.7-22 Most of these cases are late presentations, several years after treatment of the primary tumor. In contrast, brain metastases from RCC are reported early in the course of the disease process, within the first 1 to 2 years, with an incidence up to 17%.23,24 This report describes a rare case of RCC with delayed metachronous metastases to the parotid and later to the cerebellum without systemic involvement that was treated at the authors’ institution. To the authors’ knowledge, there are no reported cases of such pattern of late metachronous metastases of RCC more than a decade after successful treatment of a small solitary tumor and without evidence of systemic disease spread.
Report of Case An 83-year-old man presented to the Department of Oral and Maxillofacial Surgery at the University of Illinois at Chicago with a chief complaint of a mass at the right parotid region of approximately 5 weeks duration. The patient recalled first noticing the mass after a minor blunt trauma to the region after a fall. He denied any pain or paresthesia of the region at that time. After 1 week, the patient saw no resolution and sought care by an ear, nose, and throat surgeon. He was placed on a 1-week course of antibiotic therapy and saw no improvement after the course was completed. At this time, the patient began to notice a mild increase in the size of the lesion and a warm sensation to the region and complained of minor paresthesia to the preauricular area. At this point, he was referred to the authors’ clinic for further evaluation. The patient’s medical history was noteworthy for prostate cancer, treated with brachytherapy in 2000; RCC of the left kidney, treated with surgical excision in 2004; and basal cell carcinoma lesions on the face and back, treated with surgical excision. The patient’s general appearance was normal, except for mild asymmetry of the face owing to the small mass in the right preauricular and parotid region. Clinical examination showed a 1.0- 1.0-cm firm nodule in the right parotid region. The mass was
independent of the overlying skin and nontender to palpation. There was no weakness noted of the facial musculature or other signs of facial nerve involvement. No skin lesions were identified and no cervical lymphadenopathy was noted. Intraoral examination showed no lesions, masses, or other abnormalities. Maximum interincisal opening was normal without any deviation or deflection at opening or closing. Likewise, the temporomandibular joint examination was without abnormal findings. The salivary flow from the parotid gland was noted to be normal. At this point, the patient underwent magnetic resonance imaging (MRI) for further investigation of the nature of the mass. MRI study showed a rounded and enhancing mass within the superficial lobe of the right parotid gland. The mass was measured as 1.3 1.4 1.1 cm in the transverse, anteroposterior, and craniocaudal dimensions, respectively (Figs 1-3). Of note, there also was the suggestion of a hemosiderin ring surrounding the mass. No definite perineural involvement was identified. Ethical approval and patient consent were not required for this article.
Differential Diagnosis The patient presented with a 5-week history of swelling to the right parotid region. Swelling was accompanied by a complaint of warmth in the region and mild enlargement of the mass since the initial presentation. Differential diagnosis based purely on clinical evaluation would include salivary gland tumor (pleomorphic adenoma, mucoepidermoid carcinoma, Warthin tumor [WT]), muscular neoplasm (rhabdomyoma, leiomyoma), or metastatic disease. Benign and malignant lesions should be included in the differential diagnosis with symptoms of paresthesia because this could be explained by a mass effect from the lesion or invasion. Advanced imaging, such as MRI, can further clarify and narrow down the diagnosis. MRI was chosen for this patient over computed tomographic (CT) scan given the higher soft tissue contrast capability. The authors’ differential diagnosis included several salivary gland tumors. Pleomorphic adenoma (PA) is the most common salivary gland tumor. PAs are typically unilateral and are lobulated in nature, leading to the lesion being described as having a ‘‘cluster of grapes’’ appearance.25,26 More than 75% of these lesions are found in the superficial lobe of the parotid gland. The appearance of PAs on MRI is variable because the tumor components (epithelial/myoepithelial vs. mesenchymal) will impact the MRI signal. Typically, however, on T1-weighted MR images, these lesions tend to appear as low signal intensity masses (especially the smaller lesions), but can encompass areas of high signal intensity secondary to cystic or calcific
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FIGURE 1. T1-weighted magnetic resonance image, axial cut, displays the tumor (arrow). Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
changes. On T2-weighted images, the lesion will appear characteristically as a high signal intensity mass with a thin low intensity rim.27-31 WT, or papillary cystadenoma lymphomatosum, is the second most common benign salivary gland lesion. These lesions are typically found in the tail of the parotid and have a 15% incidence of appearing bilaterally.26 The T1-weighted MRI signal of WT is typically low signal intensity, whereas the T2-weighted signal is high or heterogeneous.27,31 The last salivary gland tumor on the differential diagnosis is the mucoepidermoid carcinoma. Mucoepidermoid carcinoma is the most common salivary gland malignancy and more than 50% are found in the parotid gland.26 These lesions have imaging characteristics based largely on histologic grade. The low-grade
and well-differentiated lesions are marginated and heterogenous with an increased T2-weighted MRI signal intensity. This is in contrast to the higher grade lesions that display lower signal intensity on T2weighted images.27,31,32 Based on the MRI findings and location of the lesion, the possibility of a muscular neoplasm was eliminated, whereas the possibility of a metastatic origin tumor remained in the differential diagnosis. Of note, the patient’s most recent (within the past year) laboratory and radiographic surveillances for prostate cancer and RCC were negative. At this point, histopathologic examination of the lesion by fine-needle aspiration (FNA) biopsy examination was deemed necessary. The specimen aspirated from the mass appeared bloody. Air-dried and alcohol-fixed smears were
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FIGURE 2. T1-weighted magnetic resonance image, axial cut with contrast, displays the tumor (arrow). Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
prepared, stained, and microscopically examined, showing isolated and aggregating tumor cells against a background of peripheral blood elements. The tissue fragments harboring the aggregating cells frequently displayed a high level of vascularity. Many tumor cells contained abundant, wispy, vacuolated cytoplasm (Fig 4). These cells also contained generally round, hyperchromatic nuclei with nucleoli of variable prominence (Fig 5). The hematoxylin and eosin–stained histologic sections obtained from the cell block fabricated from the needle rinses were composed largely of tumor cells that contained clear to finely granular, slightly eosinophilic cytoplasm and that displayed various degrees of solid, alveolar, and acinar architecture, set in a network of small, delicate blood vessels. Immunohistochemical studies performed on additional cell block sections showed cytokeratin cocktail (AE1 and AE3), CD10, and RCC marker immunoreactivity in the tumor cells (Fig 6). Overall, the cytopathologic
findings were consistent with metastatic RCC involving the parotid gland. Given the results of the FNA examination, a fullbody positron-emission tomographic CT (PET-CT) scan was completed. Results of the scan showed a small nodular mass within the right parotid with a mild increase of standardized uptake value of 3.3. No other active hypermetabolic or neoplastic process was identified.
Treatment Given the results of the MRI, FNA, and PET-CT examinations and after discussion at the institutional multidisciplinary head and neck tumor board, the decision was made to perform a superficial parotidectomy sparing the facial nerve. The portion of parotid gland that the pathology laboratory received measured 5.8 4.8 2.7 cm. Serial sectioning of the glandular tissue
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FIGURE 3. T2-weighted magnetic resonance image, axial cut, shows the tumor (arrow). Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
showed a well-circumscribed, hemorrhagic mass that measured 1.8 1.1 0.9 cm (Fig 7). The hematoxylin and eosin–stained histologic sections of the mass obtained from this specimen displayed microscopic features that were very similar to those observed in the cell block sections fabricated from the prior FNA of the mass (Fig 8). A final histopathologic diagnosis of metastatic RCC involving the parotid gland was rendered. Postoperatively, the patient had no facial nerve deficits and no other postoperative complications. Adjunct therapy was not deemed necessary after review of the final histopathologic examination and consultation with medical oncology. Periodic clinical examination and yearly PET scans were recommended and planned for surveillance. He remained symptom free from the primary RCC site and the parotidectomy site and free of disease at clinical and radiographic evaluation. Approximately 1.5 years after parotidectomy and during routine follow-up examination, the
patient complained of new-onset dizziness and loss of equilibrium. He was seen by his primary physician and was referred to an ear, nose, and throat surgeon for further evaluation. At radiographic examination with CT scanning for potential middle ear abnormalities, a mass was identified involving the cerebellum. Then, the patient was referred to a neurosurgeon and the mass was investigated by biopsy examination. The biopsy examination showed metastatic RCC and the patient underwent stereotactic radiotherapy of the mass. Whole-body PET scanning showed no other lesions. Surveillance imaging of the brain after stereotactic ablation of the metastatic RCC showed no other brain involvement.
Discussion RCC accounts for approximately 90% of all renal cancers and has high metastatic potential, with 20 to 30%
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FIGURE 4. Fine-needle aspiration specimen preparation shows many tumor cells containing abundant, wispy, vacuolated cytoplasm. Stain, Romanowsky; magnification, 100.
FIGURE 6. Immunohistochemical staining of the fine-needle aspiration specimen showing positivity of tumor cells for renal cell carcinoma marker. Magnification, 200.
Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
of patients diagnosed with metastatic disease at the time of or very soon after treatment of the primary tumor. Overall, these tumors have a very poor prognosis especially when metastases is present.1,2 Common sites of metastases for RCC include the lungs, bone, liver, and brain. Metastases to the head and neck region from RCC are relatively rare. The largest series of RCC metastatic to the head and neck was reported by Bernicker et al33 in 1997 with 65 cases. Patients had cervical lymphadenopathy or involvement of extranodal sites, such as the skin, thyroid, skull, lip, or pharynx, but no parotid involvement. This metastatic pattern could be explained by lymphatic spread of
tumor through the thoracic duct. Alternatively, spread could have occurred through the Batson paraspinal venous plexus, with tumor emboli from the primary site.34,35 Of note, RCC is known to invade the renal vein or the vena cava directly and this is taken into account for staging purposes.3 Secondary tumors of the parotid gland occur infrequently and usually originate from melanoma or squamous cell carcinoma tumors of the head and neck. Among the most commonly metastasizing tumors to the head and neck are neoplasms originating from the urogenital tract, prostate, ovary, and kidneys.15,33-37 Within the head and neck, metastases of RCC to the parotid are even less common, with approximately 28 reported cases thus far in the literature.7-17,19-22,38-40 At rare occasions, metastatic disease has been the initial presenting symptom and the reason the
FIGURE 5. Fine-needle aspiration specimen preparation of tumor cells containing generally round, hyperchromatic nuclei with nucleoli of variable prominence. Stain, Papanicolaou; magnification, 200.
FIGURE 7. Gross image of serially sectioned parotid specimen depicts a well-circumscribed, hemorrhagic mass measuring 1.8 1.1 0.9 cm.
Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
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This report presents the 29th case of a solitary parotid mass consistent with metastatic RCC 10 years after successful treatment of the primary RCC. Approximately 1.5 years later, the patient presented with new-onset loss of balance. Further investigation showed a mass to the cerebellum consistent with metastatic RCC. This case is unique because brain involvement occurred extremely late, 11.5 years after successful treatment of primary RCC and 1.5 years after resection of a metastatic RCC to the parotid, and without any evidence of other metastases. The patterns of metastases of RCC are not clearly defined and this diagnosis should be considered, especially in patients with relevant history. FIGURE 8. Metastatic renal cell carcinoma detected in the superficial parotidectomy specimen. Magnification, 200. Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
primary tumor was identified.8,18,22,41 In all reported cases of metastatic RCC to the parotid gland, the most common presenting symptom was a painless mass with or without facial paralysis and, less often, neurosensory disturbances. In addition, synchronous bilateral parotid metastases from RCC have been reported.17,40 Interestingly, nodal involvement with primary parotid metastases only has never been reported. The high vascularity of RCC and the fact that the kidneys receive the largest percentage of blood volume per mass per minute (approximately 25%) perhaps better support the vascular spread of these tumors, in addition to their tendency for direct vein invasion, as noted earlier.3,15,42,43 The incidence of brain metastases observed in patients with RCC is reported at 3.9 to 24%, with most cases presenting within the first 3 years after treatment of the primary tumor. Rarely, brain metastases have been reported more than 10 years after the initial diagnosis.44 RCC brain metastases are susceptible to spontaneous intracranial hemorrhage because of high tumor vascularity. In addition, these tumors are associated with large amounts of peritumoral edema. As such, presenting symptoms can include confusion, headaches, and, very often, seizures, and these have been reported in up to 98% of patients. Currently routine screening of the central nervous system (CNS) is not undertaken for patients who are diagnosed with RCC and no guidelines exist for CNS imaging for those with metastatic disease. CNS surveillance is not recommended for early-stage localized RCC. In addition, because most patients (up to 90%) with metastatic disease to the brain already have concurrent metastases to other more common sites, CNS surveillance is not supported, unless there is suggested symptomatology.23,45-47
References 1. Ljungberg B, Campbell SC, Choi HY, et al: The epidemiology of renal cell carcinoma. Eur Urol 60:615, 2011 2. Gupta K, Miller JD, Li JZ, et al: Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): A literature review. Cancer Treat Rev 34:193, 2008 3. Rini BI, Campbell SC, Escudier B: Renal cell carcinoma. Lancet 373:1119, 2009 4. Ljungberg B, Cowan NC, Hanbury DC, et al: EAU guidelines on renal cell carcinoma: The 2010 update. Eur Urol 58:398, 2010 5. Escudier B, Kataja V: ESMO Guidelines Working Group: Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(suppl 5):v137, 2010 6. Powles T, Jones R, Chowdhury S, et al: The application of the National Institute of Clinical Excellence guidelines for treatment of metastatic renal cell carcinoma in the United Kingdom: Friend or foe? BJU Int 106:453, 2010 7. Adil G, Murat D, Ayhan O, et al: Renal cell carcinoma metastasis to the parotid gland. BJU Int 83:861, 1999 8. Borghi L, Bianchini E, Ballotta MR, et al: Metastatic renal cell carcinoma presenting as a parotid tumor: A case report. Pathologica 87:168, 1995 9. Coppa GF, Oszczakiewicz M: Parotid gland metastasis from renal carcinoma. Int Surg 75:198, 1990 10. Gangopadhyay K, Abuzeid MO, Martin JM, et al: Metastatic renal cell carcinoma of the parotid gland presenting as a neck mass. Int J Clin Pract 52:196, 1998 11. G€ ogu €¸s C, Kilic¸ O, Tulunay O, et al: Solitary metastasis of renal cell carcinoma to the parotid gland 10 years after radical nephrectomy. Int J Urol 11:894, 2004 12. Gunbay MU, Ceryan K, Kupelioglu AA: Metastatic renal carcinoma to the parotid gland. J Laryngol Otol 103:417, 1989 13. Hosn-Centenero SA, Coll-Anglada M, Pradillos-Garces A, et al: A rare case of renal cell carcinoma metastasis in the parotid gland eleven years after the initial diagnosis. Acta Otorrinolaringol Esp 65:375, 2014 14. Owens RM, Friedman CD, Becker SP: Renal cell carcinoma with metastasis to the parotid gland: Case reports and review of the literature. Head Neck 11:174, 1989 15. Park YW, Hlivko TJ: Parotid gland metastasis from renal cell carcinoma. Laryngoscope 112:453, 2002 16. Pisani P, Angeli G, Krengli M, et al: Renal carcinoma metastasis to the parotid gland. J Laryngol Otol 104:352, 1990 17. Ravi R, Tongaonkar HB, Kulkarni JN, et al: Synchronous bilateral parotid metastases from renal cell carcinoma. A case report. Indian J Cancer 29:40, 1992 18. Sist TC Jr, Marchetta FC, Milley PC: Renal cell carcinoma presenting as a primary parotid gland tumor. Oral Surg Oral Med Oral Pathol 53:499, 1982 19. Spreafico R, Nicoletti G, Ferrario F, et al: Parotid metastasis from renal cell carcinoma: A case report and review of the literature. Acta Otorhinolaryngol Ital 28:266, 2008
KOLOKYTHAS ET AL 20. Sykes TC, Patel A, Archer D, et al: Parotid metastasis from renal cell carcinoma. Br J Urol 76:398, 1995 21. Vara A, Madrigal B, Perez del Rıo MJ, et al: Parotid metastasis from renal clear cell adenocarcinoma. An unusual site for metastasis. Urol Int 61:196, 1998 22. Yanlan C, Liping S, Shaomin C, et al: Metastasis to the parotid region as an initial presentation of renal cell carcinoma: A case report. Oncol Lett 5:997, 2013 23. Shuch B, La Rochelle JC, Klatte T, et al: Brain metastasis from renal cell carcinoma: Presentation, recurrence, and survival. Cancer 113:1641, 2008 24. Harada Y, Nonomura N, Kondo M, et al: Clinical study of brain metastasis of renal cell carcinoma. Eur Urol 36:230, 1999 25. Shah G: MR imaging of salivary glands. Magn Reson Clin North Am 10:631, 2002 26. Carlson EO: Tumors of the parotid gland, in Textbook and Color Atlas of Salivary Gland Pathology Carlson EO (ed) Vol 1. Ames, IA, Wiley-Blackwell, 2008, pp 171–198 27. Madani G, Beale T: Tumors of the salivary glands. Semin Ultrasound CT MR 27:452, 2006 28. Ikeda K, Katoh T, Ha-Kawa SK, et al: The usefulness of MR in establishing the diagnosis of parotid pleomorphic adenoma. AJNR Am J Neuroradiol 17:555, 1996 29. Moonis G, Patel P, Koshkareva Y, et al: Imaging characteristics of recurrent pleomorphic adenoma of the parotid gland. AJNR Am J Neuroradiol 28:1532, 2007 30. Kinoshita T, Ishii K, Naganuma H, et al: MR imaging findings of parotid tumors with pathologic diagnostic clues: A pictorial essay. Clin Imaging 28:93, 2004 31. Jacob P: Diagnostic imaging of salivary gland pathology, in Textbook and Color Atlas of Salivary Gland Pathology Carlson EO (ed) Vol 1. Ames, IA, Wiley-Blackwell, 2008, pp 19–66 32. Lowe LH, Stokes LS, Johnson JE, et al: Swelling at the angle of the mandible: Imaging of the pediatric parotid gland and periparotid region. Radiographics 21:1211, 2001 33. Bernicker E, Khuri FR, Ellerhorst JA, et al: A case series of 65 patients with renal cell cancer presenting with metastases to the head and neck region [abstract]. Am Soc Clin Oncol Proc 16A:1171, 1997 34. Geldof AA: Models for cancer skeletal metastasis: A reappraisal of Batson’s plexus. Anticancer Res 17:1535, 1997
1303 35. Vider M, Maruyama Y, Narvaez R: Significance of the vertebral venous (Batson’s) plexus in metastatic spread in colorectal carcinoma. Cancer 40:67, 1977 36. Hessan H, Strauss M, Sharkey FE: Urogenital tract carcinoma metastatic to the head and neck. Laryngoscope 96:1352, 1986 37. Park YW, Park MH: Vocal cord paralysis from prostatic carcinoma metastasizing to the larynx. Head Neck 15:455, 1993 38. Smits JG, Slootweg PJ: Renal cell carcinoma with metastasis to the submandibular and parotid glands. A case report. J Maxillofac Surg 12:235, 1984 39. Harrison DJ, McLaren K, Tennant W: A clear cell tumour of the parotid. J Laryngol Otol 101:633, 1987 40. Sarangi PP, Hameed B: Bilateral parotid gland metastases from a hypernephroma. J R Coll Surg Edinb 36:128, 1991 41. Melnick SJ, Amazon K, Dembrow V: Metastatic renal cell carcinoma presenting as a parotid tumor: A case report with immunohistochemical findings and a review of the literature. Hum Pathol 20:195, 1989 42. Tosco L, Palazzetti A, Crivellaro S, et al: [Batson’s paravertebral venous plexus and single vertebral metastases from renal cell carcinoma]. Urologia 77(suppl 16):42, 2010 in Italian). 43. D’Agostino G, Bigotti A, Pace G: [Importance of Batson’s plexus in the determination of isolated cerebral metastases]. Tumori 53: 237, 1967 (in Italian) 44. Choi WH, Koh YC, Song SW, et al: Extremely delayed brain metastasis from renal cell carcinoma. Brain Tumor Res Treat 1: 99, 2013 45. Lam JS, Shvarts O, Leppert JT, et al: Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system. J Urol 174:466, 2005 46. Ljungberg B, Alamdari FI, Rasmuson T, et al: Follow-up guidelines for nonmetastatic renal cell carcinoma based on the occurrence of metastases after radical nephrectomy. BJU Int 84:405, 1999 47. Levy DA, Slaton JW, Swanson DA, et al: Stage specific guidelines for surveillance after radical nephrectomy for local renal cell carcinoma. J Urol 159:1163, 1998
The purpose of this report is to describe a rare case of delayed metachronous isolated metastases of renal cell carcinoma (RCC) to the parotid gland and the cerebellum. The metastases occurred more than a decade after treatment of the primary tumor without any other systemic involvement. In addition, the potential differential diagnosis of the parotid mass based on presentation and imaging is discussed.
Materials and Methods:
An 83-year-old man presented for evaluation and treatment of a rapidly growing mass at the right parotid region. He had a history of RCC resection 10 years before this presentation and had no evidence of persistent disease at the primary site. The diagnosis of metastatic RCC was made after fine-needle aspiration biopsy examination of the mass. The patient underwent superficial parotidectomy for resection of the tumor. Approximately 1.5 years later, he complained of loss of balance. Further investigation disclosed a cerebellar mass that at biopsy examination was found to represent RCC. He underwent stereotactic ablation of the mass. He currently remains free of disease at the primary site and the parotid and without further known brain metastases.
Results:
This report presents the 29th case of a solitary parotid mass consistent with metastatic RCC 10 years after successful treatment of the primary RCC. Approximately 1.5 years later, the patient presented with new-onset loss of balance. Further investigation disclosed a mass to the cerebellum consistent with metastatic RCC. This case is unique because the brain involvement occurred extremely late, 11.5 years after successful treatment of primary RCC and 1.5 years after resection of a metastatic RCC to the parotid, and without any evidence of other metastases.
Conclusions: Late distant metastases of RCC are not uncommon and patients require life surveillance follow-up, but such late presentation of metachronous metastases without systemic disease progression is unique. The patterns of metastases of RCC are not clearly defined and this diagnosis should be considered, especially in patients with relevant history. Ó 2015 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 73:1296-1303, 2015
Renal cell carcinoma (RCC) is the most common renal malignancy (approximately 90% of cases) with high metastatic potential. It is among the top 10 most common malignancies for men and women, with a 2:1 male-to-female predilection. The usual age of presentation is the sixth to seventh decade of life. Most of these tumors are incidentally discovered at abdominal imag-
ing and usually carry a better prognosis owing to early-stage disease. Conversely, when patients present with local or systemic symptomatology, metastatic disease is commonly present and this carries a very poor prognosis.1-6 Surgical resection for small solitary lesions has been established as the standard management for RCC, with the goal being adequate
Received from the Department of Oral and Maxillofacial Surgery,
at Chicago, 801 S Paulina Street, Chicago, IL 60612; e-mail:
University of Illinois at Chicago, Chicago, IL.
[email protected]
*Associate Professor, Program Director, Director of Research. yFormer Chief Resident.
Received December 30 2014 Accepted January 20 2015
zSurgical Pathology Fellow, Department of Pathology.
Ó 2015 American Association of Oral and Maxillofacial Surgeons
xAssistant Professor of Clinical Pathology, Department of
0278-2391/15/00072-5
Pathology.
http://dx.doi.org/10.1016/j.joms.2015.01.017
Address correspondence and reprint requests to Dr Kolokythas: Department of Oral and Maxillofacial Surgery, University of Illinois
1296
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cancer control with kidney function preservation when possible. Unfortunately, RCC is known to metastasize and approximately 20% of patients will go on to develop metastatic disease within the first 3 to 5 years after treatment of the primary tumor.1,2,4-6 Common sites of metastases include the lungs, liver, bone, and brain and these patients have an overall poor prognosis. RCC metastasis to the head and neck is usually a late manifestation, with thyroid, skin, skull, and nodal involvement as the most common sites. Involvement of the parotid has been reported most commonly along with widely spread disease, whereas only 28 cases of solitary involvement have been reported thus far.7-22 Most of these cases are late presentations, several years after treatment of the primary tumor. In contrast, brain metastases from RCC are reported early in the course of the disease process, within the first 1 to 2 years, with an incidence up to 17%.23,24 This report describes a rare case of RCC with delayed metachronous metastases to the parotid and later to the cerebellum without systemic involvement that was treated at the authors’ institution. To the authors’ knowledge, there are no reported cases of such pattern of late metachronous metastases of RCC more than a decade after successful treatment of a small solitary tumor and without evidence of systemic disease spread.
Report of Case An 83-year-old man presented to the Department of Oral and Maxillofacial Surgery at the University of Illinois at Chicago with a chief complaint of a mass at the right parotid region of approximately 5 weeks duration. The patient recalled first noticing the mass after a minor blunt trauma to the region after a fall. He denied any pain or paresthesia of the region at that time. After 1 week, the patient saw no resolution and sought care by an ear, nose, and throat surgeon. He was placed on a 1-week course of antibiotic therapy and saw no improvement after the course was completed. At this time, the patient began to notice a mild increase in the size of the lesion and a warm sensation to the region and complained of minor paresthesia to the preauricular area. At this point, he was referred to the authors’ clinic for further evaluation. The patient’s medical history was noteworthy for prostate cancer, treated with brachytherapy in 2000; RCC of the left kidney, treated with surgical excision in 2004; and basal cell carcinoma lesions on the face and back, treated with surgical excision. The patient’s general appearance was normal, except for mild asymmetry of the face owing to the small mass in the right preauricular and parotid region. Clinical examination showed a 1.0- 1.0-cm firm nodule in the right parotid region. The mass was
independent of the overlying skin and nontender to palpation. There was no weakness noted of the facial musculature or other signs of facial nerve involvement. No skin lesions were identified and no cervical lymphadenopathy was noted. Intraoral examination showed no lesions, masses, or other abnormalities. Maximum interincisal opening was normal without any deviation or deflection at opening or closing. Likewise, the temporomandibular joint examination was without abnormal findings. The salivary flow from the parotid gland was noted to be normal. At this point, the patient underwent magnetic resonance imaging (MRI) for further investigation of the nature of the mass. MRI study showed a rounded and enhancing mass within the superficial lobe of the right parotid gland. The mass was measured as 1.3 1.4 1.1 cm in the transverse, anteroposterior, and craniocaudal dimensions, respectively (Figs 1-3). Of note, there also was the suggestion of a hemosiderin ring surrounding the mass. No definite perineural involvement was identified. Ethical approval and patient consent were not required for this article.
Differential Diagnosis The patient presented with a 5-week history of swelling to the right parotid region. Swelling was accompanied by a complaint of warmth in the region and mild enlargement of the mass since the initial presentation. Differential diagnosis based purely on clinical evaluation would include salivary gland tumor (pleomorphic adenoma, mucoepidermoid carcinoma, Warthin tumor [WT]), muscular neoplasm (rhabdomyoma, leiomyoma), or metastatic disease. Benign and malignant lesions should be included in the differential diagnosis with symptoms of paresthesia because this could be explained by a mass effect from the lesion or invasion. Advanced imaging, such as MRI, can further clarify and narrow down the diagnosis. MRI was chosen for this patient over computed tomographic (CT) scan given the higher soft tissue contrast capability. The authors’ differential diagnosis included several salivary gland tumors. Pleomorphic adenoma (PA) is the most common salivary gland tumor. PAs are typically unilateral and are lobulated in nature, leading to the lesion being described as having a ‘‘cluster of grapes’’ appearance.25,26 More than 75% of these lesions are found in the superficial lobe of the parotid gland. The appearance of PAs on MRI is variable because the tumor components (epithelial/myoepithelial vs. mesenchymal) will impact the MRI signal. Typically, however, on T1-weighted MR images, these lesions tend to appear as low signal intensity masses (especially the smaller lesions), but can encompass areas of high signal intensity secondary to cystic or calcific
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FIGURE 1. T1-weighted magnetic resonance image, axial cut, displays the tumor (arrow). Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
changes. On T2-weighted images, the lesion will appear characteristically as a high signal intensity mass with a thin low intensity rim.27-31 WT, or papillary cystadenoma lymphomatosum, is the second most common benign salivary gland lesion. These lesions are typically found in the tail of the parotid and have a 15% incidence of appearing bilaterally.26 The T1-weighted MRI signal of WT is typically low signal intensity, whereas the T2-weighted signal is high or heterogeneous.27,31 The last salivary gland tumor on the differential diagnosis is the mucoepidermoid carcinoma. Mucoepidermoid carcinoma is the most common salivary gland malignancy and more than 50% are found in the parotid gland.26 These lesions have imaging characteristics based largely on histologic grade. The low-grade
and well-differentiated lesions are marginated and heterogenous with an increased T2-weighted MRI signal intensity. This is in contrast to the higher grade lesions that display lower signal intensity on T2weighted images.27,31,32 Based on the MRI findings and location of the lesion, the possibility of a muscular neoplasm was eliminated, whereas the possibility of a metastatic origin tumor remained in the differential diagnosis. Of note, the patient’s most recent (within the past year) laboratory and radiographic surveillances for prostate cancer and RCC were negative. At this point, histopathologic examination of the lesion by fine-needle aspiration (FNA) biopsy examination was deemed necessary. The specimen aspirated from the mass appeared bloody. Air-dried and alcohol-fixed smears were
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FIGURE 2. T1-weighted magnetic resonance image, axial cut with contrast, displays the tumor (arrow). Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
prepared, stained, and microscopically examined, showing isolated and aggregating tumor cells against a background of peripheral blood elements. The tissue fragments harboring the aggregating cells frequently displayed a high level of vascularity. Many tumor cells contained abundant, wispy, vacuolated cytoplasm (Fig 4). These cells also contained generally round, hyperchromatic nuclei with nucleoli of variable prominence (Fig 5). The hematoxylin and eosin–stained histologic sections obtained from the cell block fabricated from the needle rinses were composed largely of tumor cells that contained clear to finely granular, slightly eosinophilic cytoplasm and that displayed various degrees of solid, alveolar, and acinar architecture, set in a network of small, delicate blood vessels. Immunohistochemical studies performed on additional cell block sections showed cytokeratin cocktail (AE1 and AE3), CD10, and RCC marker immunoreactivity in the tumor cells (Fig 6). Overall, the cytopathologic
findings were consistent with metastatic RCC involving the parotid gland. Given the results of the FNA examination, a fullbody positron-emission tomographic CT (PET-CT) scan was completed. Results of the scan showed a small nodular mass within the right parotid with a mild increase of standardized uptake value of 3.3. No other active hypermetabolic or neoplastic process was identified.
Treatment Given the results of the MRI, FNA, and PET-CT examinations and after discussion at the institutional multidisciplinary head and neck tumor board, the decision was made to perform a superficial parotidectomy sparing the facial nerve. The portion of parotid gland that the pathology laboratory received measured 5.8 4.8 2.7 cm. Serial sectioning of the glandular tissue
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FIGURE 3. T2-weighted magnetic resonance image, axial cut, shows the tumor (arrow). Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
showed a well-circumscribed, hemorrhagic mass that measured 1.8 1.1 0.9 cm (Fig 7). The hematoxylin and eosin–stained histologic sections of the mass obtained from this specimen displayed microscopic features that were very similar to those observed in the cell block sections fabricated from the prior FNA of the mass (Fig 8). A final histopathologic diagnosis of metastatic RCC involving the parotid gland was rendered. Postoperatively, the patient had no facial nerve deficits and no other postoperative complications. Adjunct therapy was not deemed necessary after review of the final histopathologic examination and consultation with medical oncology. Periodic clinical examination and yearly PET scans were recommended and planned for surveillance. He remained symptom free from the primary RCC site and the parotidectomy site and free of disease at clinical and radiographic evaluation. Approximately 1.5 years after parotidectomy and during routine follow-up examination, the
patient complained of new-onset dizziness and loss of equilibrium. He was seen by his primary physician and was referred to an ear, nose, and throat surgeon for further evaluation. At radiographic examination with CT scanning for potential middle ear abnormalities, a mass was identified involving the cerebellum. Then, the patient was referred to a neurosurgeon and the mass was investigated by biopsy examination. The biopsy examination showed metastatic RCC and the patient underwent stereotactic radiotherapy of the mass. Whole-body PET scanning showed no other lesions. Surveillance imaging of the brain after stereotactic ablation of the metastatic RCC showed no other brain involvement.
Discussion RCC accounts for approximately 90% of all renal cancers and has high metastatic potential, with 20 to 30%
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FIGURE 4. Fine-needle aspiration specimen preparation shows many tumor cells containing abundant, wispy, vacuolated cytoplasm. Stain, Romanowsky; magnification, 100.
FIGURE 6. Immunohistochemical staining of the fine-needle aspiration specimen showing positivity of tumor cells for renal cell carcinoma marker. Magnification, 200.
Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
of patients diagnosed with metastatic disease at the time of or very soon after treatment of the primary tumor. Overall, these tumors have a very poor prognosis especially when metastases is present.1,2 Common sites of metastases for RCC include the lungs, bone, liver, and brain. Metastases to the head and neck region from RCC are relatively rare. The largest series of RCC metastatic to the head and neck was reported by Bernicker et al33 in 1997 with 65 cases. Patients had cervical lymphadenopathy or involvement of extranodal sites, such as the skin, thyroid, skull, lip, or pharynx, but no parotid involvement. This metastatic pattern could be explained by lymphatic spread of
tumor through the thoracic duct. Alternatively, spread could have occurred through the Batson paraspinal venous plexus, with tumor emboli from the primary site.34,35 Of note, RCC is known to invade the renal vein or the vena cava directly and this is taken into account for staging purposes.3 Secondary tumors of the parotid gland occur infrequently and usually originate from melanoma or squamous cell carcinoma tumors of the head and neck. Among the most commonly metastasizing tumors to the head and neck are neoplasms originating from the urogenital tract, prostate, ovary, and kidneys.15,33-37 Within the head and neck, metastases of RCC to the parotid are even less common, with approximately 28 reported cases thus far in the literature.7-17,19-22,38-40 At rare occasions, metastatic disease has been the initial presenting symptom and the reason the
FIGURE 5. Fine-needle aspiration specimen preparation of tumor cells containing generally round, hyperchromatic nuclei with nucleoli of variable prominence. Stain, Papanicolaou; magnification, 200.
FIGURE 7. Gross image of serially sectioned parotid specimen depicts a well-circumscribed, hemorrhagic mass measuring 1.8 1.1 0.9 cm.
Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
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This report presents the 29th case of a solitary parotid mass consistent with metastatic RCC 10 years after successful treatment of the primary RCC. Approximately 1.5 years later, the patient presented with new-onset loss of balance. Further investigation showed a mass to the cerebellum consistent with metastatic RCC. This case is unique because brain involvement occurred extremely late, 11.5 years after successful treatment of primary RCC and 1.5 years after resection of a metastatic RCC to the parotid, and without any evidence of other metastases. The patterns of metastases of RCC are not clearly defined and this diagnosis should be considered, especially in patients with relevant history. FIGURE 8. Metastatic renal cell carcinoma detected in the superficial parotidectomy specimen. Magnification, 200. Kolokythas et al. Delayed Metastatic Renal Cell Carcinoma. J Oral Maxillofac Surg 2015.
primary tumor was identified.8,18,22,41 In all reported cases of metastatic RCC to the parotid gland, the most common presenting symptom was a painless mass with or without facial paralysis and, less often, neurosensory disturbances. In addition, synchronous bilateral parotid metastases from RCC have been reported.17,40 Interestingly, nodal involvement with primary parotid metastases only has never been reported. The high vascularity of RCC and the fact that the kidneys receive the largest percentage of blood volume per mass per minute (approximately 25%) perhaps better support the vascular spread of these tumors, in addition to their tendency for direct vein invasion, as noted earlier.3,15,42,43 The incidence of brain metastases observed in patients with RCC is reported at 3.9 to 24%, with most cases presenting within the first 3 years after treatment of the primary tumor. Rarely, brain metastases have been reported more than 10 years after the initial diagnosis.44 RCC brain metastases are susceptible to spontaneous intracranial hemorrhage because of high tumor vascularity. In addition, these tumors are associated with large amounts of peritumoral edema. As such, presenting symptoms can include confusion, headaches, and, very often, seizures, and these have been reported in up to 98% of patients. Currently routine screening of the central nervous system (CNS) is not undertaken for patients who are diagnosed with RCC and no guidelines exist for CNS imaging for those with metastatic disease. CNS surveillance is not recommended for early-stage localized RCC. In addition, because most patients (up to 90%) with metastatic disease to the brain already have concurrent metastases to other more common sites, CNS surveillance is not supported, unless there is suggested symptomatology.23,45-47
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