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Page 2 of 12 Mansinho et al. J Cancer Metastasis Treat 2021;7:44 https://dx.doi.org/10.20517/2394-4722.2021.88

75% of all cases. ccRCC is characterized by frequent alterations in the Von Hippel-Lindau (VHL) gene,
upregulation of VEGF, activation of the phosphoinositol-3-kinase-Akt-mTOR pathway, and increased
[1]
migration ability and angiogenesis . Among the non-clear cell RCC, papillary RCC is the most prevalent
[2]
(10%-15%), and characterized by MET alterations (Type I) or a panoply of molecular alterations (Type II) .

Evidence suggests that metastasis in RCC is mostly driven by hematogenous dispersion of tumor-derived
microvesicles, which carry CD105-positive RCC cancer stem cells and pro-angiogenic mRNAs . In VHL-
[3]
mutated ccRCC, HIF-regulated CUB-domain-containing protein and MUC1 are considered to be
metastasis drivers, by increasing migration . As in other cancers, the chemokine receptor CXCR4 is also
[4,5]
upregulated in ccRCC and associated with increased metastatic ability .
[6]
Bone can be affected by metastatic disease in virtually any cancer. One pivotal discovery in cancer research
was breast cancer cell tropism to bone, which led to the “seed and soil hypothesis” . Bone metastases (BM),
[7]
also common among patients with RCC, are present in up to one third of patients with metastatic disease
[8]
[Table 1] .
BM can lead to significant morbidity in cancer patients, with progressive autonomy loss and impaired
quality of life (QoL) . In metastatic RCC (mRCC), BM are typically osteolytic, compromising bone
[14]
integrity and eventually leading to skeletal-related events (SREs), including pathologic fractures, impending
fracture requiring surgical intervention, bone pain requiring radiotherapy, spinal cord compression, and
[15]
hypercalcemia . In addition to these devastating complications, BM have a negative impact on the
progression-free survival (PFS) and overall survival (OS) of mRCC patients treated with systemic therapies
[16]
compared to patients without BM . Moreover, development of BM at first-line treatment start resulted in
significantly shorter survival compared with later points in time. Despite several studies reporting that BM
are associated with higher risk of morbidity and shorter survival in mRCC patients, heterogeneity of study
populations has been a critical drawback . Median OS after diagnosis of RCC BM ranges from 12 to 28
[17]
months . Suggested reasons for poor survival outcomes in BM patients include interactions between
[18]
cancer cells and tumor microenvironment, particularly bone microenvironment, with subsequent bone
destruction and rapid tumor growth . A retrospective analysis of 94 patients with RCC and BM suggested
[19]
five prognosis-predictive risk factors in this setting: sarcomatoid differentiation of the primary tumor (P =
0.001), spinal involvement (P = 0.003), extraosseous metastases (P = 0.021), increased alkaline phosphatase
levels (> 1.5 times the upper limit of normal; P = 0.0003), and increased C-reactive protein levels
(> 0.3 mg/dL, P = 0.018) .
[20]

BM are associated with substantial morbidity, mortality, QoL deterioration, and economic burden. A recent
propensity score matching analysis revealed that the presence of BM negatively affects OS outcomes in
mRCC patients treated with first-line tyrosine kinase inhibitors (TKI), particularly in the International
Metastatic Renal Cell Carcinoma Database (IMDC) intermediate-risk group . Treatment toxicity and
[21]
disease progression are expected to have a negative impact on QoL while increasing costs, due to the
associated need for additional treatment, hospitalizations, and other management requirements. Therefore,
correctly identifying patients with BM for preemptive treatment is of utmost importance for minimizing
morbidity and improving patient outcomes and QoL. This review addresses RCC BM pathophysiology, as
well as diagnosis and treatment in the mRCC setting.

BONE METASTASES PATHOPHYSIOLOGY
The metastatic cascade is an intricate and complex process that culminates with cancer cell seeding and
colonization at a distant site of the primary tumor . Bone marrow is a preferential site for seeding of
[22]