Dear Editor,

We recently read with great interest “Clear-cell renal cell carcinoma (RCC) and glioblastoma (GBM) multiforme coexistence: Double primary malignancy, does it have a causal relationship?” by Simanjuntak et al., who describes a case of concurrent RCC and GBM.[ 10 ] We have recently encountered a similar case in our clinical practice. We would like to describe our case of metachronous RCC and GBM, briefly summarize the existing literature regarding RCC and GBM, and comment on points raised by Simanjuntak et al.[ 10 ]

CASE DESCRIPTION

A 61-year-old previously high functioning woman presented with word finding difficulty, memory changes, and difficulty drawing shapes. Prior medical history included RCC treated with nephrectomy 4 years prior. Subsequent magnetic resonance imaging (MRI) revealed a 6.3 × 5.6 × 5.5 cm deep left frontal lesion, with an additional right frontal juxtacortical lesion (0.5 cm maximal diameter), and a third lesion in the right cingulate gyrus (2 cm maximal diameter); all three lesions demonstrated peripheral enhancement [ Figure 1 ]. The patient’s language and memory deficits continued to progress, and the patient developed mobility impairments and right sided hemiparesis. Due to progressive symptoms, cerebral edema, and mass effect, the patient elected to undergo surgical resection of the largest lesion. The preoperative course was complicated by bilateral lower extremity deep vein thromboses, which were treated with an inferior vena cava filter before craniotomy. The patient later underwent an uneventful resection of the largest lesion through a left superior frontal sulcus approach. Intraoperative squash prep pathology demonstrated hypercellularity and extensive necrosis, with no metastatic cancer. The final neuropathological diagnosis returned as GBM, Isocitrate dehydrogenase 1 (IDH1) wild-type, alpha thalassemia/mental retardation syndrome X-linked (ATRX) intact, epidermal growth factor receptor amplified, O6-methylguanine-DNA-methyltransferase (MGMT) nonmethylated. The postoperative course was complicated by a hematoma at the resection site. A repeat craniotomy for hematoma resection was completed, but the patient did not improve neurologically [ Figure 2 ]. A goal of care discussion with the family resulted in a change in code status. The patient died approximately 3-week postoperatively.

Figure 1:

(a) Axial T1-weighted contrast-enhanced magnetic resonance (MR) image obtained 3 weeks before surgery. The lesion measures 4.2 × 4.5 cm. (b and c). Axial T1-weighted contrast enhanced MR image obtained 3 weeks after the MRI in (a). The tumor measured grew to 6.3 × 5.5 cm. All three tumors are visible in (c and d). Coronal T1-weighted contrast-enhanced MR image obtained 3 weeks after the magnetic resonance imaging in (a).

Figure 2:

(a) Axial T1-weighted contrast-enhanced magnetic resonance (MR) image 10 days after surgery. (b) Coronal T1-weighted contrast-enhanced MR image 10 days after surgery.

LITERATURE REVIEW

According to our literature search, our case represents the 132^nd known patient with both RCC and GBM. Simanjuntak et al. have admirably described both their case and Franke et al.’s cases; we refer readers to review Simanjuntak et al. for a complete description of these cases.[ 2 , 10 ] We have subsequently identified two case reports not described by Simanjuntak et al., a recently reported case series/database analysis including 126 cases of RCC followed by GBM, and an investigation of malignancies in long-term survivors (LTS) of GBM that describes one RCC arising in a patient with an existing GBM diagnosis.[ 4 , 8 , 9 , 11 ] A brief overview of all cases is found in Table 1 .

Table 1:

Case descriptions of GBM and RCC in the same patient.

Rugala describes a 56-year-old female who presented for new onset seizures, with subsequent MRI demonstrating a T2 hyperintense lesion with surrounding edema in the right temporal lobe; abdominal computed tomography demonstrated a heterogeneous hypodense lesion in the right kidney. A subsequent craniotomy was performed, followed shortly soon after by nephrectomy. Brain histopathological analysis revealed a neoplasm of glial origin, with immunohistochemistry demonstrating: casein kinase 1 (CK 1) (−), glial fibrillary acidic protein (GFAP) (+), subsequently diagnosed as GBM; the kidney tumor was diagnosed as RCC. Brain radiation and temozolomide were soon initiated. Amazingly, at the time of publication, 7 years later, the patient was reported to be neurologically intact, with follow-up imaging demonstrating only demyelinating changes in the surgical and radiation site; additionally, there was no proof either of relapse or dissemination of RCC.[ 9 ]

COMMENTS

There is no established relationship linking RCC and GBM. Although uncommon, these cancers are not exclusive to one another, and both can occur in the same patient.[ 2 ] Different patterns of coincidental RCC and GBM have been reported, including both synchronous and metachronous presentations.[ 2 , 4 , 8 - 11 ] Although no clear relationship between these two cancers has been elucidated, it has been suggested that they may cooccur due to therapeutic side effects, underlying genetic syndromes, or as an unfortunate coincidence.

GBM and RCC in the same patient may occur metachronously, with the second malignancy possibly occurring due to therapy for the first malignancy.[ 4 , 11 ] Cranial radiation therapy and some pharmacotherapies have been shown to increase the risk of GBM, as demonstrated by Myong and Park’s case (described above).[ 8 , 11 ] However, Zhang et al. were not able to confidently attribute GBM development to any specific therapeutic measure incurred during treatment for RCC, as none of the described patients received cranial radiotherapy, and the pharmacotherapy between patients was inconsistent.[ 11 ] In addition, Kim et al.’s description of an RCC occurring in a patient with existing GBM does not show a relationship between GBM treatment and RCC; the patient received only gross total resection and cranial radiotherapy for GBM, without concurrent temozolomide, making it difficult to link GBM treatment to the development of the RCC.[ 4 ] All malignancies that were attributed to GBM treatment were located in the radiation field.[ 4 ] In addition, temozolomide is classically linked to the development of hematologic malignancies, not RCC.[ 6 ] There is no clearly defined relationship linking the treatment of RCC or GBM to the subsequent development of the other malignancy type.

It has been suggested RCC and GBM may occur in the same patient as part of genetic syndromes, although there is no clear evidence as to which genes, alleles, or mutations are responsible.[ 10 , 11 ] Simanjuntak et al. implicate genetic syndromes, such as Li-Fraumeni syndrome, neurofibromatosis, and VHL, as possibly being involved.[ 10 ] Notably, VHL is an established predisposition to developing RCC, although it does not seem to play a role in GBM. Krieg et al. show that VHL-associated hemangioblastomas display distinct genetic features from GBM, and GBM displays wild-type VHL expression.[ 5 ] Furthermore, in the only identified case of GBM occurring in VHL (described above), Myong and Park posit the GBM was more likely related to prior radiation therapy and an inherited mutation.[ 8 ] Li Fraumeni syndrome, neurofibromatosis and Turcot syndrome are all syndromes that predispose to GBM.[ 1 , 3 , 7 ] However, none of these are linked to the development of RCC. We have been unable to identify a common underlying genetic syndrome linking GBM to RCC.

There are currently no concrete data demonstrating an association between RCC and GBM, and we agree with Simanjuntak et al. that concurrent RCC and GBM likely represents an unfortunate coincidence, although it is possible, there is an underlying relationship between the two. The literature does not indicate that any specific treatment protocol is particularly effective for these patients. Because there is no known underlying mechanism responsible for the cooccurrence of these cancers, we believe that each cancer should be treated as its own entity, in accordance with the respective standards of care.

We agree with Simanjuntak et al. that it is important to document these unusual cases. RCC and GBM in the same patient are likely to be underdiagnosed and underreported.[ 10 ] The true occurrence of both cancers in a single person is likely higher than currently believed and is likely to increase as outcomes continue to improve.[ 11 ] GBM in the setting of RCC is highly likely to be misdiagnosed as metastatic disease, which may profoundly impact the treatment strategy.[ 11 ] Stupp protocol, including surgical resection, should be initiated as soon as possible following the diagnosis of GBM. The rate of surgical resection of metastatic RCC is lower than GBM, suggesting that some presumed RCC metastases are misdiagnosed GBMs that do not undergo surgical resection and Stupp protocol.[ 11 ] We believe, it is important for neurosurgeons to remain cognizant that brain lesions in the presence of systemic cancers are not necessarily brain metastases. Even in the presence of systemic cancers, we believe that GBM should be included as a differential for brain lesions, especially if only one lesion is detected. In conclusion, we commend Simantunjak et al. for an excellent case report describing concurrent RCC and GBM, and we would like to add a description of a similar case to the literature.

Declaration of patient consent

Patient’s consent not required as patient’s identity is not disclosed or compromised.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.

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