Seed, soil, and spine stereotactic radiosurgery: A unique case of metastatic dissemination

Abstract

A 52 year-old gentleman with metastatic pheochromocytoma received single fraction spine stereotactic radiosurgery (SSRS) to an isolated L3 metastasis. Two years later, he developed widespread osseous metastatic disease involving nearly every vertebral body level with the striking exception of the treated L3 vertebrae. The “seed and soil” hypothesis of metastatic dissemination was developed over a century ago and states that tumors cells (the “seed”) preferentially grow in select host tissue microenvironments (the “soil”). The high-dose radiation delivered by SSRS may have altered the microenvironment “soil” of the treated L3 vertebrae, rendering it inhospitable to the growth of future metastases. With emerging evidence in support of high-dose stereotactic radiation for oligometastatic disease, there will likely be increasing opportunity to observe and understand treatment changes in the tissue microenvironment and how it relates to the potential for metastatic seeding.

Case Presentation

A 52 year-old otherwise healthy gentleman presented with refractory hypertension and heat intolerance. A Computed Tomography (CT) scan revealed a left adrenal mass, and surgical resection confirmed pheochromocytoma. He subsequently was without evidence of disease until five years later when he again developed uncontrolled hypertension. Restaging revealed limited osseous metastatic disease and he underwent palliative fractionated radiation to a symptomatic sacral metastasis followed by systemic treatment with denosumab.

One year following, he was noted to have developed an L3 posterior vertebral body metastasis measuring 1.4cm (Figure 1a). He underwent single fraction spine stereotactic radiosurgery (SSRS) to a dose of 24 Gy encompassing gross disease and 16 Gy to the remaining vertebral body and pedicles (Figure 1b) (No posterior elements were included in the field. While the minimum dose to the at risk bone was approximately 9 Gy, the V98% of the at risk bone was approximately 15 Gy). He continued on denosumab but by two years after SSRS developed widespread osseous metastatic disease involving nearly every vertebral body level with the striking exception of the treated L3 vertebrae (Figure 1c and 1d). Notably, he had progressed in the sacrum within the field of previous fractionated radiotherapy (Figure 2). His osseous disease also included the central skull base and Meckel’s cave bilaterally. He transitioned to hospice and soon after expired.

Figure 1.

A sagittal T1-weighted MRI scan of the spine showing a single metastasis at L3 (panel a). This was treated with single fraction SSRS to a dose of 24 Gy (panel b). Two years later, the patient developed widespread osseous metastatic disease at nearly every vertebral body level other than the previously treated vertebrae (panels c and d).

Figure 2.

A sagittal T2-weighted MRI of the sacrum showing the left-sided metastasis (panel a) treated previously with conventionally-fractionated radiotherapy (33 Gy in 11 fx, panel b). At time of widespread spine progression, T1 with contrast MRI of the sacrum (panel c) suggested progressive disease within the previously treated sacrum.

Discussion

The number of patients living with metastatic cancer in the United States is on the rise, likely due to an aging population and recent advances in systemic therapy (1). Osseous metastases are among the most common sites of spread, with the majority occurring in the vertebral bodies which may cause pain, instability, fracture, and/or neurologic compromise (2). SSRS is an increasingly used non-invasive treatment for vertebral metastases that delivers high-dose conformal radiation to the disease with relative sparing of the adjacent spinal cord or nerve roots (3). In the presented case, the patient developed widespread osseous metastases that involved every vertebral body with the exception of the previously treated (two-years prior) L3 vertebrae. The high-dose radiation delivered by SSRS may have altered the microenvironment and/or vasculature of the treated region, rendering it inhospitable and immune to the growth of future metastases. In stark contrast to the absence of progression within the bone treated previously by SSRS, the patient developed progressive disease in the sacrum within the field treated previously by conventionally fractionated radiation. This suggests that high-dose ablative radiation may affect the microenvironment and/or host vasculature differentially than conventional doses.

The pathophysiology of metastatic disease is incompletely understood, but likely includes angiogenesis of the primary tumor, circulation of tumor cells, the mechanical lodgment of cells in the microvasculature, and migration of cells into surrounding tissue (4). Observing the selective targeting of metastases to specific host organs, Stephen Paget published in 1889 what is now known as the “seed and soil” hypothesis of metastatic disease (5). Noting that breast cancer commonly metastasized to the liver and rarely to the spleen despite similar vascular supply, Paget concluded that tumors cells (the “seed”) preferentially grew in select host tissue microenvironments (the “soil”). Studies over the ensuing century offered a biological explanation for the hypothesis, identifying numerous important interactions between tumor cells and the host microenvironment including those involved with adhesion, angiogenesis, immunogenicity, and the expression of cytokines, chemokines, and growth factors (6). Modification of any of these interactions may impact the relative hospitability of the host “soil”. Stereotactic radiotherapy, moreover, may impact the metastatic potential of the malignant cells (aka the “seed”). While there exist rare clinical examples of the abscopal effect whereby radiation to a local tumor elicits an immune response leading to regression of disease outside the radiation field (7), there is another hypothesis of metastatic potential following radiotherapy described by Judah Folkman and others. Supported by laboratory evidence, this hypothesis suggests that radiotherapy may suppress a tumor’s anti-angiogenic signal and lead to rapid progression of distant disease outside the treatment field (8, 9). While widespread progression occurred two years following stereotactic radiation in this patient and it is unclear if there exists any connection between the radiation treatment and progression, the Folkman hypothesis underlines the potentially complex relationship between radiation treatment effects to both “seed” and “soil”.

Bone is the third most common site of metastatic spread, likely owing not only to a rich supply of blood but to the unique and constant process of resorption and remodeling as mediated by osteoclast and osteoblast activity. This tightly regulated interplay aims to maintain skeletal integrity and involves the expression of numerous hormones and growth factors including interkeulin-1, interleukin-6, insulin-like growth factor, transforming growth factor, and parathyroid hormone. These factors, along with an acidic pH and high extracellular calcium content, have been proposed to make bone a particularly favorable microenvironment for the growth and proliferation of metastatic cancer cells (10).

SSRS is a form of stereotactic body radiotherapy (SBRT) by which advanced treatment delivery techniques (e.g., intensity modulated radiotherapy or IMRT) are combined with precise image guidance and rigid immobilization to deliver a high dose of conformal radiation to the target in one or several treatment sessions. Radiation induces an inflammatory response with recruitment of fibroblasts, proteins, and enzymes, ultimately leading to changes in stromal cell function, fibrosis, and necrosis (11). Moreover, large fraction sizes (>10 Gy such as is delivered by SSRS) have been shown to be particularly damaging to the tumor and tissue microvasculature with a more pro-inflammatory and pro-oxidant response compared to conventionally-fractionated radiation (12). Some having hypothesized that late vertebral body fractures following SSRS are related to these fibrotic and vascular changes within the bone microenvironment (13). To our knowledge, however, the effects of SSRS on the host tissue microenvironment for potential metastatic seeding have not been reported in literature.

One limitation of this case study is the possibility that the fibrotic changes of the treated vertebrae following SSRS make detection of future metastases more challenging. MRI, however, is a well-established method for identifying recurrent or progressive disease within an SSRS field (14). In this case, the MRI of interest was interpreted by a neuroradiologist of whom spine imaging is a large component of their practice. While PET/CT and/or bone scan may have provided valuable functional information, these were not performed in this case.

Here, we report a case of SSRS that appears to have rendered the host tissue microenvironment or “soil” uniquely inhospitable to metastatic seeding. The underlying mechanism is unclear but may be related to stromal and/or vasculature changes in the bone following radiation. With emerging evidence in support of high-dose stereotactic radiation for oligometastatic disease, there will likely be increasing opportunity to observe and understand treatment changes in the tissue microenvironment and how it relates to the potential for metastatic seeding.