1 Introduction
2 Prevalence and risk factors of HCC BM
Tab.1 Reported incidences of HCC BM in various patient cohorts |
Period | Center | Diagnostic approaches | Incidence of BM | Rate of BM in EhMs |
---|---|---|---|---|
1962–1981 [16] | Single | Autopsy | 16.10% (14/87) | N.A. |
1969–1978 [9] | Single | Autopsy | 5.33% (12/225) | 8.33% (12/144) |
1969–1983 [4] | Single | Autopsy | N.A. | 20% |
1978–1987 [11] | Single | BS, radiography, CT, and/or MRI | 4.46% (12/269) | N.A. |
1983–1987 [10] | Single | Plain films, bone scans, or CT | 5.06% (20/395) | N.A. |
1988–1997 [11] | Single | BS, radiography, CT, and/or MRI | 12.87% (52/404) | N.A. |
1988–2012 [4] | Single | Autopsy | N.A. | 32.1% |
1990–2005 [17] | Single | CT, MRI, BS, and/or PET with FDG | 5.63% (56/995) | 37.09% (56/151) |
1990–2006 [18] | Single | Bone X-ray, BS, and CT or MRI | 3.65% (87/2386) | 25.44% (87/342) |
1992–1997 [19] | Single | CT | 10.17% (41/403) | 27.70% (41/148) |
2002–2014 [15] | Single | At least one imaging modality | 23.59% (151/640) | 32.90% (151/459) |
2005–2015 [20] | Single | Symptoms, and CT or MRI | 1.97% (20/1017) | N.A. |
2006–2009 [21] | Single | PET/CT | N.A. | 19.07% (49/257) |
2009–2016 [5] | Single | Radiological images or pathological findings | 9.71% (76/783) | N.A. |
2010–2013 [12] | Multiple | Unknown | N.A. | 22.93% (1008/4396) |
2010–2014 [22] | Multiple | Unknown | 4.29% (1567/36 507) | N.A. |
2010–2015 [13] | Multiple | Unknown | N.A. | 32.47% (1015/3126) |
Note: Bolded information indicates constitutive analyses from the same institutions or database.Abbreviations: BM, bone metastasis; EhMs, extrahepatic metastases; N.A., not available; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; FDG, fluorodeoxyglucose; BS, bone scintigraphy. |
3 Pathology and symptoms
4 Imaging-based diagnostic approaches
4.1 Plain X-ray
Fig.1 Imaging techniques for the diagnosis of HCC BM. (A) X-ray images of metastatic HCC lesions in the right humerus (left image) and in the L1 vertebral body (right image). (B) Anterior and posterior positions of BS for a patient with multiple BM (left panel) and a patient with a bone lesion in the right scapula (right panel). (C) MRI of skeletal HCC lesions in the L1 vertebral body (upper row) and L3 vertebral body (lower row). (D) CT scans of BM in the right humerus (upper row) and the spine (lower row). (E) Whole-body 18F-FDG PET/CT images of BM in the fifth right rib (left panel) and right ilium (right panel). Arrows point to metastatic HCC bone lesions. Abbreviations: CT, computed tomography; BS, bone scintigraphy; MRI, magnetic resonance imaging; PET, positron emission tomography; BM, bone metastasis; LT, left; RT, right; AP, anteroposterior; TS, transverse section; T1WI, T1 weighted image; T2WI, T2 weighted image; STIR, short time inversion recovery; MIP, maximum intensity projection. |
4.2 BS
4.3 MRI
4.4 CT, PET, and PET/CT
5 Prognosis and therapeutic approaches
Tab.2 Prognosis and risk factors for HCC patients with BM |
Period | Treatment | Prognosis | Independent risk factors |
---|---|---|---|
1978–1987 [11] | RT, surgery, ethanol injection, and supportive care | Median OS: 170 days | – |
1981–1997 [48] | Palliative RT | Median OS from the diagnosis of spinal metastasis: 3 months | Responssive RT (complete response, partial response) and good performance status (score < 2) |
1988–1997 [11] | RT, surgery, ethanol injection, and supportive care | Median OS: 227 days | – |
1991–2000 [25] | RT | OS rates at 1 and 2 years of 50% and 20%, respectively, with a median OS of 12 months from the time of HCC diagnosis; OS rates from the occurrence of BM at 1 and 2 years of 15% and 4%, respectively, with the median OS of 5 months | Tumor stage within the liver and the presence of metastases to organs |
1992–2012 [49] | RT | Median OS from diagnosis of spinal metastases: 4.5 months; 1- and 2-year OS rates of 18.1% and 6.3%, respectively | Performance status (ECOG), presence of uncontrolled primary HCC, and presence of extrahepatic metastases |
1993–2013 [14] | Sorafenib, RT, BP and surgery | Median OS from the diagnosis of BM: 7 months | HCC etiology, performance status (ECOG), BM localized to the spine and not receiving any BP treatment |
1997–2007 [44] | RT | Median OS after the diagnosis of BM: 7.4 months; 1-year and 2-year OS rates of 32.4% and 13.2%, respectively | Low KPS, high AFP levels, uncontrolled intrahepatic tumor, and receiving treatment within the past 5 years |
2000–2011 [50] | RT | Median OS: 7.0 months; OS rates at 1 and 2 years of 13.8% and 6.9%, respectively | – |
2000–2018 [45] | Surgery, RT, chemotherapy, and bone-modifying agents | Median OS from the initiation of treatment: 7.4 ± 8.2 months (range 0.3–36 months) for all; 10.46 ± 8.05 months for surgical groups, and 5.19 ± 7.72 months for the conservative treatment groups | Patient’s general condition, the serum albumin level, and bone-modifying agent treatment |
2002–2009 [51] | Irradiation/zoledronic acid | Median OS from the initial date of therapy: 6.0 months (95% CI 0.0–12.7 months) for patients treated with zoledronic acid, and 4.2 months (95% CI 1.2–7.2 months) for patients treated with non-zoledronic acid; cumulative OS rates at 3 months of 74% and 44% and at 6 months of 79% and 37% | – |
2002–2011 [52] | SRS, cRT | Median OS: 3 months in the cRT group and 7 months in the SRS group | Child–Pugh class and KPS |
2002–2014 [15] | Radiation, surgical resection, BPs, and sorafenib | Median OS after the diagnosis of any type of metastasis: 5.6 months (95% CI 4.6–6.9) | AFP levels, Child–Pugh score, and SREs |
2005–2011 [53] | EBRT | Median OS after the first EBRT: 3.8 months | – |
2006–2013 [54] | Surgery, EBRT | Median OS: 261 days (range 22–1359 days) after the diagnosis of metastasis, and 180 days (range 19–1351 days) after the initial operation | Tomita scoring system |
2009–2014 [55] | EBRT | Median OS for the entire cohort: 8.0 months; 1-year and 2-year survival rates of 35.1% and 10.8%, respectively in patients receiving conventional fraction EBRT, and of 38.7% and 15.1%, respectively, in patients receiving hypofraction RT | KPS, TB, and intrahepatic tumor control |
2009–2016 [5] | Sorafenib, sunitinib or lenvatinib RT, zoledronic acid and denosumab | Median OS after the diagnosis of BM: 11.7 months (range 0.2–94.5 months) | Age over 75 years, HCV, and Child–Pugh class B/C |
2010–2014 [22] | Surgery and other N/A | Median OS from the time of diagnosis of HCC: 3.00 months (95% CI 2.77–3.24 months) | Unmarried, uninsured, high primary tumor stage, high regional lymph node (N1), lung metastases, poor tumor differentiated grade, and elevated AFP, without surgery |
2010–2014 [56] | Zoledronic acid, palliative RT, curettage, and wide resection | Median OS after BM diagnosis: 11 months (range 4–52); 1- and 2-year survival rates of 44.2% and 11.6%, respectively | Progression beyond the University of California San Francisco criteria and the treatment of the primary tumors |
2011–2016 [57] | RT | Median OS after RT: 13.6, 4.8, and 2.6 months for the low-, intermediate-, and high-risk groups, respectively | ECOG performance status, controlled primary HCC, and extrahepatic metastases other than bone |
2014–2017 [58] | RT and other N/A | Median OS from the start of the RT for BM: 6.5 months; 1- and 2-year survival rates after diagnosis of BM of 35.5% and 13.5%, respectively | Child–Pugh class A group, increase in AFP beyond 30 ng/mL, and HCC size of more than 5 cm |
Abbreviations: RT, radiotherapy; OS, overall survival time; BM, bone metastases; ECOG, Eastern Cooperative Oncology Group; KPS, Karnofsky performance status; TB, total bilirubin; SRS, stereotactic radiosurgery; cRT, conventional radiation therapy; BP, bisphosphonate. |
Fig.2 Outline of the multidisciplinary treatment options for patients with HCC and BM. Therapeutic strategies for HCC BM should be determined in accordance with the systematic evaluation of each patient’s general condition by a multidisciplinary team. BTAs are recommended to be started at the definite diagnosis of BM. Treatments for primary HCC, BM, and systematic symptoms are the three approaches for controlling disease progression and alleviating cancer-induced bone pain. Abbreviations: BM, bone metastases; BTAs, bone-targeting agents; EBRT, external beam radiotherapy; BPs, bisphosphonates; SRE, skeleton-related events. |
5.1 Prognosis
5.2 RT
5.3 BTAs
5.4 Sorafenib
5.5 Surgery
5.6 TAE
5.7 Multidisciplinary teams and other palliative approaches
6 Advances in basic studies
6.1 Cancer BM cascade
Fig.3 Hypothetical bone metastatic cascade of HCC. On the basis of the academic advances in cancer BM, an integrated metastatic process was proposed for HCC bone lesion formation. (A) The malignant transformation of liver cells and microenvironment predispose HCC cells to metastasis by augmenting their mobility and inducing angiogenesis. HCC cells exploit the arterial bloodstream and vertebral venous system to spread to the bone cavity. The dysregulation and immunosuppressive status of the bone microenvironment benefit the settlement, proliferation, and further metastasis of disseminated tumor cells in the bone. Additionally, signals that induce the osteotropism of cancer cells are predelivered to the bone from the primary tumor site and prepare metastatic niches. Conversely, the bone microenvironment modulates the behavior of tumor cells at the primary site via the secretion of various bioactive substances. (B) The formation of a metastatic lesion in bone. The disseminated tumor cells first home to the bone cavity and adhere to bone stromal cells to settle inside the bone. Bone metastatic tumor cells either remain dormant or directly start to colonize and form micro-metastatic lesions. By interacting with various bone stromal cells, the migrated tumor cells finally thrive inside the bone and expand into a macrometastatic lesion. |
6.2 Uncoupled bone remodeling
Fig.4 Disturbed homeostasis of the bone microenvironment driven by tumor cells. Bone-metastasized tumor cells trigger the imbalances of immune-suppressive/immune-active and osteoclastic/osteoblastic activities to escape from immune elimination and initiate excessive bone reconstruction. Thriving tumor cells, the immune-privileged microenvironment, and uncoupled bone remodeling benefit each other through various bioactive molecules to perpetuate the destructive vicious cycle. Abbreviations: TAMs, tumor associated macrophages; Tregs, regulatory T cells; Th17, CD4+ T helper cells 17; MDSCs, myeloid-derived suppressor cells; DCs, dendritic cells; pDCs, plasmacytoid DCs; TI-DCs, tumor-infiltrating DCs; NK cells, natural killer cells; TIMs, tumor inflammatory macrophages. |
6.3 Immunosuppressive bone microenvironment for tumor cells
6.4 Molecular mechanisms of HCC BM
Tab.3 Biomarkers for the prediction of diagnosis and prognosis of HCC BM |
Gene | Subject | Expression pattern | Biological function/molecular mechanism | Potential application |
---|---|---|---|---|
CTGF [137,139] | Primary tumor | Highly expressed in patients with HCC and BM | – | Risk factor of BM |
IL-11 [137,139] | Primary tumor | Highly expressed in patients with HCC and BM | – | Risk factor of BM |
MMP-1 [137,140] | Peritumor/HCC cell lines | Highly expressed in patients with HCC and BM/in osteotropic cells lines | – | Risk factor of BM |
CXCR4 [139,141] | Primary tumor | Highly expressed in patients with HCC and BM | – | Risk factor of BM |
FRZB [136] | BM | Highly expressed in bone metastatic lesions | – | – |
PNI [142] | BM | High density in bone metastatic lesions | – | – |
RNF219 [134] | Primary tumor/BM/HCC cell lines | Highly expressed in patients with HCC and BM/in bone metastatic lesions/in osteotropic cell lines | Promotes osteoclastogenesis by upregulating LGALS3 in a YAP1/β-catenin complex-dependent manner | Therapeutic target |
LGALS3 [134] | Primary tumor/BM/HCC cell lines | Highly expressed in patients with HCC and BM/in bone metastatic lesions/in osteotropic cell lines | Promotes osteoclastogenesis and aggravate SREs | Therapeutic target |
miR-34a [143] | Serum/primary tumor | Low expression in the serum and in the primary tumor of patients with HCC and BM | Promotes the migration and invasion of HCC cells by upregulating SMAD4 to further activate TGFβ signaling and upregulate its downstream effectors | Risk factor of BM and therapeutic target |
lnc34a [144] | Serum/primary tumor | Highly expressed in the serum and primary tumor of patients and HCC and BM | Suppresses miR-34a expression epigenetically through DNMT3A/PHB2 and HDAC1 and sponging miR-34a | Risk factor of BM |
lncZEB1-AS1 [145] | Primary tumor | Highly expressed in patients with HCC and BM | Promotes the migration and invasion of HCC cells by sponging miR-302b to activate PI3K/AKT signaling and increase EGFR expression | Therapeutic target |
H19 [133] | Primary tumor/BM/HCC cell lines | Highly expressed in patients with HCC and BM/in bone metastatic lesions/in osteotropic cell lines | Promotes the migration and invasion of HCC cells by sponging miR-200b-3p and inducing osteoclastogenesis through the PPP1CA/p38MAPK axis | Therapeutic target |
CCL2 [146] | CAFs | Highly expressed in CAFs in primary site | Promotes the migration of HCC cells by activating hedgehog signaling | Therapeutic target |
CCL5 [146] | CAFs | Highly expressed in CAFs in primary site | Promotes the migration of HCC cells by activating hedgehog signaling | Therapeutic target |
CCL7 [146] | CAFs | Highly expressed in CAFs in primary site | Promotes the invasion of HCC cells by activating TGFβ signaling | Therapeutic target |
CXCL16 [146] | CAFs | Highly expressed in CAFs in primary site | Promotes the invasion of HCC cells by activating TGFβ signaling | Therapeutic target |
MAPK14 [147] | BMECs | Excessive activation in BMECs | Upregulates ADAM17 expression | Therapeutic target |
ADAM17 [147] | BMECs | Highly expressed in BMECs | Promotes the secretion of CX3CL1 | Therapeutic target |
CX3CL1 [147] | HCC/BMECs | Highly expressed in bone metastatic lesions/in BMECs | Promotes the migration and invasion of HCC cells by activating PIK3CA/AKT1 and RHOA/ROCK2 signaling | Therapeutic target |
CX3CL1R [147] | HCC | Highly expressed in bone metastatic lesions | Promotes the migration and invasion of HCC cells by activating PIK3CA/AKT1 and RHOA/ROCK2 signaling | Therapeutic target |
Abbreviations: HCC, hepatocellular carcinoma; BM, bone metastases; CTGF, connective tissue growth factor; IL-11, interleukin-11; MMP-1, matrix metallopeptidase-1; CXCR4, C-X-C motif chemokine receptor 4; FRZB, frizzled-related protein; PNI, perineural density; RNF219, ring finger protein 219; LGALS3, galectin 3; YAP1, Yes1 associated transcriptional regulator; SREs, skeleton-related events; SMAD4, SMAD family member 4; TGFβ, transforming growth factor β; DNMT3A, DNA methyltransferase 3 α; PHB2, prohibitin 2; HDAC1, histone deacetylase 1; lnc, long non-coding RNA; PI3K, phosphatidylinositol 3-kinase; AKT, AKT serine/threonine kinase; EGFR, epidermal growth factor receptor; PPP1CA, protein phosphatase 1 catalytic subunit α; MAPK, mitogen activated kinase-like protein; CCL, chemokine (C-C motif) ligand; CAFs, cancer-associated fibroblasts; CXCL, C-X-C motif chemokine ligand; BMECs, bone marrow endothelial cells; ADAM17, ADAM metallopeptidase domain 17; CX3CL1, C-X3-C motif chemokine ligand 1; CX3CL1R, CX3CL1 receptor; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α; RHOA, ras homolog family member A; ROCK2, Rho associated coiled-coil containing protein kinase 2. |
Fig.5 Molecular mechanism of HCC BM. Elevated expression levels of H19, lnc34a, lncZEB1, and RNF219 in HCC cells contribute to strengthened bone metastatic ability by enhancing the migration, invasion, and metastasis ability of HCC cells and inducing osteolytic activities in bone. CCL2, CCL5, CCL7, and CXCL16 secreted by CAFs in primary sites activate Hh and TGFβ signaling in HCC cells to facilitate their metastatic capacities. High levels of IL11, CTGF, and MMP-1 have been found in primary HCCs with bone lesions and predict bone metastatic events. Various cytokines released from bone remodeling and bone stromal cells, such as BMECs, support the outgrowth of disseminated HCC cells in bone. Abbreviations: CAFs, cancer-associated fibroblasts; BMEC, bone marrow endothelial cells; OC, osteoclasts. |