Very Delayed Brain Metastasis from a Clear Cell Renal Cell Carcinoma: Report of Two Cases and a Literature Review

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most prevalent primary kidney cancer. Although its relevant capability to disseminate, long-term brain metastasis is very unusual. The present paper describes two cases of delayed brain metastasis: one occipital that occurred 20 years after a radical nephrectomy, and one thalamic after 11 years. An extensive literature review was also carried out, and only 31 cases of delayed brain metastasis from ccRCC were found. The authors provide an analysis of all 33 cases, focusing on clinical, radiological, and histological features, along with current treatment recommendations.

 

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Resumo

O carcinoma de células renais claras (ccRCC) é o câncer renal primário mais prevalente. Embora tenha uma capacidade relevante de disseminação, a metástase cerebral de longo prazo é muito incomum. O presente artigo descreve dois casos de metástase cerebral tardia: uma occipital, ocorrida 20 anos após uma nefrectomia radical, e uma talâmica após 11 anos. Uma extensa revisão da literatura também foi realizada, e apenas 31 casos de metástase cerebral tardia de ccRCC foram encontrados. Os autores fornecem uma análise de todos os 33 casos, com foco em características clínicas, radiológicas e histológicas, além das recomendações de tratamento atuais.

 

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Keywords

late onset disorders - renal cell carcinoma - case report - brain metastasis

Palavras-chave

doenças de início tardio - carcinoma de células renais - relato de caso - metástase cerebral

Introduction

It is estimated that 73,750 people in the United States will be diagnosed with kidney cancer by 2020. This represents 4.08% of all new cases among the ten most prevalent types of cancers.[1] [2] Renal cell carcinoma (RCC) accounts for 85% of all primary kidney neoplasms, with up to 75% of them being from the clear cell subtype (ccRCC).[1] [3]

This tumor is more common in older men and is highly associated with alterations in the von-Hippel-Lindau (vHL) gene.[2] [3] [4] [5] Other well-established risk factors are smoking, hypertension, and obesity.[6] The latter is probably the reason for the current increasing trend.[7]

High rates of metastasis and relapse are associated with ccRCC,[2] [3] [5] [8] occurring in up to 1/3 of the patients,[3] compared to 12% of all kidney cancers at the time of diagnosis.[7]

The most prevalent locations of ccRCC metastases are the lung, bone, liver, and central nervous system (CNS).[3] Interestingly, up to 6% of patients with brain metastasis have RCC.[9] Intratumoral brain hemorrhage can be found in 46% of these lesions.[10]

The median interval between the diagnosis of RCC and brain metastasis was approximately 17 months.[10] Late metastasis is defined as a recurrence more than 10 years after nephrectomy.[11] To the best of the authors' knowledge, there are only 31 cases reported in the literature.

We herein report two new cases and provide a literature review of all 33 documented patients. The objective is to discuss the localization, clinical presentation, characteristics of the lesion, treatment, and differential diagnosis of delayed ccRCC CNS metastasis.

 

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Materials and Methods

The present report is in accordance with the Case Report (CARE) guidelines.[12]

The terms searched in EMBASE, PubMed, BVS/Bireme, and Cochrane were LATE (or DELAYED), BRAIN, METASTASIS and RENAL CELL CARCINOMA (or HIPERNEFROMA), according to the Medical Subject Headings (MeSH).

In this paper, 17 complete case reports and 5 abstracts in English with proper information were evaluated. There were few articles[13] [14] about all types of renal cell carcinoma metastasis, so some information was not accessible. The methodology is summarized in the flow chart ([Fig. 1]).

Fig. 1 Flowchart of the steps of the review on late-onset brain metastasis from clear cell renal cell carcinoma (ccRCC).

 

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Results

Case Report 1

A 60-year-old man suffered a severe fast-onset headache in January of 2020, without any deficit in the neurological examination. Right radical nephrectomy was conducted 20 years before because of ccRCC, without lymph node or adrenal invasion, with favorable oncological control up to 5 years.

Initial head computed tomography (CT) followed by brain magnetic resonance imaging (MRI) revealed a small, acute, hemorrhagic, left, parieto-occipital lesion ([Fig. 2A, B]). A possible diagnosis was of microarterovenous malformation, but the angiography study showed a hypervascular lesion without early draining.

Fig. 2 Findings from case 1. Pre-operative axial brain magnetic resonance imaging (MRI) scan showing a small left occipital lesion (A) in T1-weighted with contrast and (B) in T2-weighted fluid-attenuated inversion recovery (FLAIR). Histology with hematoxylin and eosin stain at (C) 100x and (D) 400x magnification.

A left occipital craniotomy was performed, with an en bloc total resection. The histologic evaluation showed a vascular lesion among atypical cells with clear cytoplasm and hyperchromatic nuclei, consistent with ccRCC metastasis ([Fig. 2C, D]).

After 4 months of follow-up, the patient is without neurological deficits, under clinical surveillance of the oncological team. No other lesion was identified, and complementary stereotactic radiosurgery (SRS) was performed.

 

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Case Report 2

A 72-year-old man with 1-year of progressive memory impairment showed a right thalamic lesion associated with hydrocephalus in a brain MRI ([Fig. 3]). An endoscopic third ventriculostomy and biopsy performed in September 2019 had an inconclusive diagnosis. In November, an ipsilateral transcortical parietal approach was accomplished through neuronavigation assistance to reach the right ventricular atrium, and a total resection was performed. An urgent reoperation was required due to symptomatic hemorrhage in the resection bed, followed by a prolonged hospital stay with pulmonary and urinary infections. Anatomopathological analyses indicated a hypervascular lesion showing cells with round nuclei and clear cytoplasm, compatible with ccRCC metastasis.

Fig. 3 Findings from case 2. Preoperative axial brain MRI scan showing a right thalamic lesion (A) in T1-weighted with contrast, (B) in T2-weighted FLAIR, and (C) in T2-weighted*. (D) Surgical anatomical specimen.

The patient's previous history exhibited incidental ccRCC with radical nephrectomy in 2008, and a neuroendocrine rectal tumor after a colectomy in 2014. Both had satisfactory oncological monitoring, and neither preoperative survey pointed to local recurrence or other metastases.

6 months after surgery, the patient is recovering from hemiparesis and is saying a few words. No complimentary treatment was proposed yet on behalf of the clinical scenario.

 

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Discussion

There is a relatively high incidence of ccRCC, as well as extensive morbidity and mortality because 12% of patients present with advanced disease at diagnosis[7] and ⅓ may have metastasis during the evolution of follow-up.[3]

The treatment for ccRCC restricted to the kidney is usually radical nephrectomy, and standardized screening policies are up to 5 years, with CNS screening indicated only under clinical suspicion.[15] [16] [17]

Most cases of secondary lesions tend to present in the first 5 years of the disease. Late-onset metastasis is a tumor diagnosed after more than 10 years of nephrectomy. This definition is extensively used, although arbitrarily established.[11] We found 30 cases of CNS late recurrence, including the two described above. All of them are cited in [Table 1], and their analysis is hereafter.

Table 1 Summary of reported cases of delayed CNS metastasis from ccRCC

Author, year	Interval (years)	Age (years), sex	Characteristics	Treatment	Survival/recurrence (months)
Middleton, 1967	14	-, M	Temporal [-]	TR	204/-
Killebrew et al., 1983	13	55, F	Intraventricular [EA]	TR	48/-
Ishikawa et al., 1990	14	46, F	Parietal [C]	TR	28/-
Salvati et al., 1992	13	–	–	TR, RT	–
	17	–	–	TR, RT	–
Ammirati et al., 1993	13	63, F	Cerebellum [C]	TR	27/9
Radley et al., 1993	18	78, M	Temporal [C]	TR	12/-
	15	60, F	Temporal [H]	TR, RT	–
Cervoni et al., 1993	13	61, M	Frontal [S]	TR	49/-
	17	65, F	Frontal [C]	TR	56/-
Karasawa et al., 1994	11	57, M	Frontal [H]	TR	8/-
Kudo et al., 1995	23	76, M	Occipital [S,H]	TR	8/-
Jubelirer, 1996	15	86, F	Frontal [S,H]	Partial	1,5/-
Kuroki et al., 1999	12	86, F	Temp-parietal[S]	TR, RT	–
	15	67, M	Frontal [S] Frontal [H]	TR, RT TR, RT	-/3
Motoyama et al., 2000	15	70, F	Intraventricular [H]	TR	12/-
Roser et al., 2002	19	61, M	Frontal [C]	TR	14/-
Cimatti et al., 2004	13	61, M	Frontal [S]	TR	13/-
	17	65, F	Frontal [C]	TR	58/-
	26	67, M	Temporal [S]	TR, RT	36/-
	12	52, M	Parietal [S] Cerebellum [S]	TR SRS	1/-
Sadatomo et al., 2005	15	77, M	Thalamus [S,H]	Partial,SRS	7/-
Montano et al., 2007	20	65, M	Falx [EA]	TR	4/-
Bademci, 2008	20	68, F	Temporoparietal [EA]	TR	–
Choi et al., 2013	18	76, F	Parietal [EA] 4th ventricle [EA]	Partial SRS	66/-
Aydin et al., 2015	11	72, M	Frontoparietal [H]	TR	–
Kolokythas et al., 2015	11,5	84, M	Cerebellum [-]	Biopsy,SRS	–
Fukushima et al., 2016	22	60, M	Cerebellum [S] Frontal [C] Parietal [S]	TR TR TR	36/-
Doi et al., 2019	11	59, M	Frontal [S,H] Temporal [S,H]	TR, SRS TR, SRS	27/-
	12	73, F	Cerebellum [EA]	TR	14/-
	11,5	61, M	Frontal [EA] Frontal [EA]	TR, SRS TR, SRS	16/-
Present case (1)	20	60, M	Occipital [H]	TR, SRS	4/-
Present case (2)	11	72, M	Thalamus [H]	TR	6/-

Abbreviations: C, cystic; ccRCC, clear cell renal cell carcinoma; CNS, central nervous system; EA, extraaxial; F, female; H, hematoma or hypervascular lesion; M, male; RT, radiotherapy; S, solid; SRS, fractionated stereotactic radiation therapy; TR, total removal; -, no data available.

Between the most accepted theories on why these tumors tend to present their metastasis in such an extended period, the most accepted one is based on the slow growth (i.e., low mitotic index) of ccRCC micrometastasis. Furthermore, it can be influenced by immunologic status.[18] [19]

The risk of late recurrence and higher mortality seems to be associated with age, size, pathologic stage and grade, the absence of adjuvant treatment, and lymph node metastasis. The latter was the only factor that could predict recurrence, according to Miyao et al.[20]

Regarding the presentation site, the literature case series showed a higher frequency in the frontal (34.2%), parietal (17.1%), and temporal lobes (17.1%). This report is the second describing occipital or thalamic metastasis. Other sites were the cerebellum (12.2%), intraventricular (7.3%), and one case in the falx (2.4%). Previously, Postler and Meyermann[21] found no preferable involvement site, though theirs was not a delayed brain metastasis series.

Regarding symptoms, headache was the most prevalent (14 cases, 45.2%), followed by paresis (13 cases, 41.9%), gait disturbance (8 cases, 25.8%), and aphasia (6 cases, 19.4%). Other symptoms described are dizziness, seizure, visual loss, memory impairment, vomiting, confusion, alexia, facial palsy, scalp mass, and loss of consciousness. The symptomology depends on the localization of the mass and its size.

The time-lapse presentation makes diagnosis uncertain. Lesions had hypervascularity or caused excessive bleeding in 14 cases (50%). In that context, an angiographic study is imperative to discard vascular diseases, such as in case 1, in which an arteriovenous malformation was suspected.

In 10 cases (35.7%), the tumor was solid, with a ring-enhancing signal after contrast. Therefore, high-grade gliomas and other metastases should be discarded with an anatomopathological study. In 7 cases (25%), it was extra-axial, which mimics a meningioma. The correct diagnosis in all cases was made just after the histological analyses. In 6 cases (21.4%), it was cystic, like hemangioblastoma. Since vHL syndrome is commonly associated with ccRCC and histological studies can be dubious, markers are helpful to differentiate it.[22]

The chosen therapies for brain metastasis depend on several issues: number of lesions, size, location, neurological symptoms, presence of extracranial secondary lesions, histologic aspect, and previous treatments.[23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34]

Total surgical resection is the first treatment option. In general, for tumors in eloquent areas, patients with low Karnofsky performance status (< 80) or multiple metastases (> 3), biopsy followed by SRS can be performed, achieving 90 to 95% local control in the first year.[35] This same approach could be applied for ccRCC's delayed metastases. However, considering that these tumors are relatively radioresistant, a lower success rate would probably be expected.[36] The same applies to whole-brain radiotherapy, which has a lesser effect, needing higher doses of radiation to control it.[36] Nonetheless, this is the modality of choice for patients with more than ten lesions on the CNS and relatively short life expectancy.[37]

The total removal was made in 22 lesions (55%), and it was associated with radiotherapy (SRS or whole brain) in 12 (30%). Partial resection or biopsy followed by SRS was performed in 3 cases (7.5%). There was one case of only partial resection due to excessive bleeding, and an only-SRS case was performed in a deep lesion. The survival media was 30.22 months, with a median of 14. There was a selection bias, considering that the survival time for patients was up to the study date. A quarter of patients had other metastatic sites, of which 75% were in the lungs. Other places were in the bone, breast, or parotid.

Patients with advanced local disease or metastasis without local surgical control could benefit from adjuvant immunotherapy and molecular-focused treatment with systemic medications acting as vascular endothelial growth factor (VEGF) inhibitors or immunotherapy. Drugs such as nivolumab (anti-PD-1) and ipilimumab (anti-CTLA4) have been gaining space in the treatment of these conditions.[38] Despite this, none of the late-onset reports cited any complementary chemotherapy. Most likely, there is a selection bias regarding the neurosurgical focus of those reports.

 

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Conclusion

Late-onset metastasis is a rare condition with a variable presentation. Because of temporality, it's habitually only defined after histological analysis. The presentation can mimic common diseases such as meningioma, arteriovenous malformation, intraparenchymal hemorrhage, or hemangioblastoma. Hence, an expansive intracranial process in patients with a history of ccRCC resection should be used to analyze the likelihood of delayed metastasis.

 

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Conflict of Interest

The authors have no conflict of interests to declare.

Acknowledgments

The authors would like to thank to the neurosurgical team at Hospital das Clínicas da Universidade Federal de Minas Gerais.

Author's Contributions

GFSQ: data extraction, data synthesis, and writing — original draft; BF: ensured coherence and clarity of the manuscript. All authors contributed to the review of the text and approved the final version of the manuscript.

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Publication History

Received: 08 October 2024

Accepted: 20 March 2025

Article published online:
08 October 2025