The histopathology of skeletal metastases

Introduction

The human skeleton is a multifunctional tissue responsible for a variety of functions including biomechanical support, protection of vital organs, strength, and mobility as well as the maintenances of calcium and phosphate homeostasis [ ]. Stephen Paget was the first to describe the complexity of the bone in 1889, when he proposed that tumor cells have a proclivity for certain organs, where they “seed” into a friendly “soil” and eventually grow into metastatic lesions. Bone is one of the most common sites for metastasis in patients with solid tumors arising from breast, prostate, lung, thyroid, and kidney, with over 400,000 individuals in the United States affected annually [ ]. Approximately 70% of patients with advanced prostate or breast cancer and up to 40% of patients with other advanced solid tumors will develop bone metastases over the course of their disease. In addition, more than 50% of advanced prostate cancer cases and 20% of advanced breast cancer cases will have metastatic disease clinically confined to the skeleton [ ]. The development of bone metastasis from a solid tumor is a devastating complication and usually means that their disease has reached the point of being incurable. Patients with bone metastases are at risk for skeletal complications such as intractable bone pain, decreased mobility, and pathologic bone loss associated with fractures, spinal compression, and sequelae related to hypercalcemia [ , ]. Given the prevalence of these malignant diseases, bone metastasis constitutes a major clinical problem with significant implications for health-care resources [ ].

Treatment and prevention of bone metastases

There have been great advancements in the treatment and prevention of metastatic disease of bone in recent years [ ]. Bone-targeting treatment for metastatic disease includes local/regional strategies (orthopedic surgery, radiation therapy) and systemic approaches (inhibitors of bone resorption, anabolic agents, and radiopharmaceuticals) [ ]. The bisphosphonates, a group of pyrophosphate analogue compounds which reduce bone resorption and consequently the incidence of skeletal-related events, have been shown to reduce skeletal morbidity by 30%–50% in multiple myeloma as well as in a wide range of solid tumors. They have been increasingly used to prevent skeletal complications and relieve bone pain [ ]. Other agents such as cathepsin K inhibitors and matrix metalloproteinases inhibitors have also been proposed as therapeutic agents [ ]. More recently, denosumab, a fully humanized anti-RANKL monoclonal antibody that targets molecules involved in osteoclast differentiation and activation, has begun to be used clinically as an antiresorptive agent [ , ]. In addition, strategies that target the skeletal system have shown promise in the adjuvant setting for the prevention of bone metastases [ , ]. Adjuvant bisphosphonates have been shown to reduce the risk of bone metastases in patients with physiologic or iatrogenic menopause, while the data on denosumab are contradictory and await further confirmation [ ].

Nonetheless, such treatment approaches for early-stage disease such as breast cancer can be lengthy and expensive and only a proportion of patients are likely to receive clinical benefit. The development of biomarkers with the ability to predict more accurately which individual patients are at risk for the development of bone metastasis would allow such adjuvant treatment approaches to be targeted to those individuals who would be the most likely to benefit. The application of genomics in the study of cancer biology has shown great promise for uncovering gene signatures involved in the clinical behavior of tumors. These advances should enable the development of new biomarkers to predict risk of progression, including the development of bone metastases [ ].

Biology of bone metastases

Bone is the preferred site of metastasis for a subset of solid tumors, which may be at least partly related to its unique anatomic vascular system, that is, sinusoidal systems of red marrow that are lined by endothelium with large intercellular gaps and “Batson's vertebral venous plexus” that lack venous valves [ ]. Furthermore, bone is a dynamic tissue with a unique microenvironment that undergoes continuous turnover and remodeling to help maintain skeletal integrity and structural support for the body as well as providing a source of ions to support mineral homeostasis. The maintenance of skeletal mass in the face of these conflicting demands requires the coordinated activity of the two principal cell types responsible for bone resorption and formation: the osteoclast and the osteoblast [ ]. The physiologic balance of ongoing bone remodeling cycles that occur throughout the skeleton is both temporally and spatially coupled, involving complex regulatory mechanisms that closely link the activity of these two important cell types. The pathogenesis of bone metastasis appears to reflect cooperative interactions between cancer cells and the bone microenvironment where normal bone cell function is coopted or reprogramed by the tumor. Complex regulatory signaling therefore must exist between metastatic tumor cells and the host bone that interrupt this balance, facilitating the establishment and progression of the tumor within skeletal tissues. Indeed, current evidence suggests that in order for metastatic tumor cells to establish and grow within bone, they must be able to interfere with normal bone cell function, tipping the balance in favor of osteoclast activation and bone resorption [ ].

The mechanisms for bone metastasis are complex, involving many steps which include angiogenesis, invasion, and proliferation in the bone microenvironment. Bone-homing tumor cells overexpress chemokine receptors such as CXCR4, whose ligand CXCL12 is secreted by bone marrow stroma [ ]. Moreover, the bone marrow compartment provides a receptive, favorable, growth factor–enriched environment in which circulating/disseminated tumor cells can survive and colonize [ ]. Tumor cells in the bone microenvironment interact with mesenchymal and hematopoietic progenitors at multiple stages of development by producing a large number of cytokines, disrupting osteoclastic and/or osteoblastic activities, and causing an imbalance of the processes of bone formation and resorption. Marrow-resident tumor cells secrete factors including parathyroid hormone–related peptide, interleukins, and prostaglandins to active osteoblast RANKL release to promote lytic lesions as well as other factors that inhibit osteoblastic differentiation [ ]. This imbalance in turn may facilitate the proliferation of metastatic foci in bone [ , ]. Bone is unique in that it serves as a large repository of immobilized growth factors such as TGF-beta, IGF-I/II, FGF, PDGF, bone morphogenetic proteins, as well as calcium. The activation of osteoclastic bone resorption will release these numerous growth factors into the local bone microenvironment, which can in turn stimulate metastatic tumor cell deposits in a paracrine fashion, promoting tumor progression [ ]. Once released, these growth factors can not only stimulate the local growth of tumor cells but can also circulate and may stimulate remote metastatic tumor growth [ ].

Recent studies also have indicated the potential prognostic clinical significance of finding circulating tumor cells (CTCs) or disseminated tumor cells (DTCs) within the bone marrow of cancer patients [ , ]. There have been an increasing number of studies showing that the presence of tumor cells in these sites is prognostic for recurrence and survival. A recent study showed that EPCAM+, CD44+, CD47+, and MET+ expressed by CTC from breast cancer patients can give rise to bone, lung, and liver metastases and are associated with lower overall survival [ ]. Increased levels of transforming growth factor-beta and chemokine CXCL1 in the plasma have also been implicated in the seeding of CTC to distant sites including skeletal tissues in patients with metastatic breast cancer [ ]. Pierga et al. [ ] have confirmed the prognostic and predictive value of CTC in a large prospective trial for metastatic breast cancer patients being treated with first-line chemotherapy. Epithelial-to-mesenchymal transition (EMT) has also been extensively studied and suggested as one of the mechanisms for metastasis [ ]. EMT can promote cancer progression, convey migratory and invasive properties, induce stem cell–like properties, and contribute to immunosuppression allowing tumor cell evasion of the immune system [ ].

Bone metastases

The primary tumors that affect the bone most frequently are cancers of the breast, prostate, lungs, thyroid, and kidneys [ ]. The affinity for skeletal dissemination displayed by this select group of primary tumors suggests that these diseases share common biological characteristics that allow malignant cells from these tumors to establish and grow in the bone microenvironment [ ]. Skeletal involvement by metastatic disease can be classified as either osteolytic or osteoblastic, based on radiographic findings. This classification, while useful clinically, in fact represents two extremes of a continuum in which dysregulation of the processes of normal bone remodeling has occurred [ ]. While metastatic deposits within the skeleton originating from different primary sites can show varying degrees of lytic and blastic reaction within the affected bone, virtually all tumors cause osteolysis. On one end of this spectrum, tumors such as myeloma and metastases from lung, kidney, and thyroid are usually purely lytic in nature. Metastatic breast cancer to the bone, on the other hand, can be purely lytic or mixed lytic and blastic [ ]. Purely blastic lesions are far less common and are usually seen in metastatic carcinomas from the prostate [ ].