Pathways Case Record: Metastasis Through the Lymphatic System
In This Case Study
- A 43-year-old man with pre-diabetes mellitus presented with persistent dry cough and dyspnea. The patient subsequently developed bilateral leg edema and toe discoloration
- Further tests revealed a large right lower pole renal mass, bilateral lung infiltrates with septal thickening and pleural effusions, and diffuse lymphadenopathy. He developed progressively worsening hypoxia and cardiac arrest
- The Pathways Consult Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on the key question of why the patient developed profound pulmonary lymphangitic carcinomatosis
A 43-year-old man with pre-diabetes mellitus presented with persistent dry cough and dyspnea. The patient subsequently developed bilateral leg edema and toe discoloration. Further tests revealed a large right lower pole renal mass, bilateral lung infiltrates with septal thickening and pleural effusions, and diffuse lymphadenopathy. He developed progressively worsening hypoxia and cardiac arrest. Ultimately, retroperitoneal lymph node biopsy led to the diagnosis of epithelial-variant angiomyolipoma and he was treated with intravenous temsirolimus. Evaluation of the biopsy pathology suggested poorly differentiated carcinoma. Despite antibiotics and diuresis, the patient, unfortunately, had refractory hypoxemia and succumbed to his illness.
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The Pathways Consult Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on the key question of why the patient developed profound pulmonary lymphangitic carcinomatosis. Three mechanistic questions were addressed:
- Why might malignant cells travel through the lymphatic system?
- What drives the lymphatic spread of certain tumors?
- What are some properties of his tumor that might have permitted the extensive lymphatic spread?
Background and Diagnosis
Metastasis occurs when the initial tumor gains motility through the destruction of proteins in the surrounding matrix and stroma and subsequently enters the circulation or lymphatic system (Nat Rev Cancer). Tumor cells that survive entry into circulation/lymphatics can then arrest at a secondary site, often initially as occult or dormant micro-metastases. Although lymphatic tumor spread was initially thought to be a passive process, there is growing evidence that active processes contribute to how cancers spread through tissue lymphatics (J Cell Biol).
Lymph may provide a more favorable environment for tumors to spread compared to blood for several reasons. First, the presence of iron and oxygen in the blood can facilitate cell death through ferroptosis (Nature), which can limit the survival of malignant cells in blood but not lymph. Furthermore, metabolomic analyses demonstrated protective mono-unsaturated fatty acids, including oleic acid, in lymph malignant melanoma cells. Thus, lymph appears to protect metastasizing cells from ferroptosis by reducing oxidative stress and thus increasing cell survival during subsequent migration through the blood.
Historically, it was believed that metastatic cells actively invaded pre-existing lymphatic vessels and then traveled to lymph nodes. While this may be the case in some instances, the discovery of lymphangiogenesis downstream of the VEGF-C/VEGFR-3 signaling axis between pre-metastatic cells and lymphatic endothelial cells (LECs) indicates that new lymph vessels may, in fact, grow towards tumors (J Clin Invest). Additionally, this interaction upregulates prostaglandins, which cause dilation of lymph vessels and promote more favorable environments for metastatic cells to migrate towards lymph nodes. Once in lymph nodes, tumor cells can produce more VEGF-C, amplifying lymph channel formation (Cancer Res). Mouse models demonstrated that VEGF-C or VEGFR-3 blockade reduced lymphangiogenesis and metastatic burden, suggesting possible clinical therapeutic strategies (J Natl Cancer Inst). However, further studies are warranted to understand the impact of VEGF-C blockage on other organs, which cancers secrete VEGF-C, what leads to an upregulation of this pathway and where is it upregulated.
In addition to lymphangiogenesis, metastasis can be assisted by chemokine signaling. Chemokines are small, secreted protein molecules that direct cell movement. Multiple cell types, including LECs, can express chemokines that can mediate cell trafficking. The chemokine CCL21 is constitutively expressed by peripheral LECs and binds to its receptor CCR7 in immune cells, producing a chemokine gradient that guides honing to the lymph node. The CXCR4 receptor and CXCL12 ligand pair can act in a similar, perhaps redundant fashion, but this chemokine also participates in neutrophil honing to the lymph node (J Immunol). Malignant tumors have been shown to take advantage of this system by upregulating the receptors and ligands in this pathway to promote migration and invasion (Nature). It is possible that upregulation of these chemokine receptors and/or ligands in our patient may contribute to the expansive malignancy observed. CCR7 expression on tissue sections has been further shown to correlate with lymph nodal metastasis in colorectal cancer (Int J Cancer). The mechanism(s) for the upregulation of these receptors are not well understood but is presumed to involve upregulation by HIF in the setting of relative tumor hypoxia inhibiting von Hippel-Lindau tumor suppressor protein (Nature). Thus, the Pathways Service hypothesized that amplification of lymphangiogenesis (via VEGF-C signaling) or chemokine signaling contributed to the extensive lymphatic metastasis presented in our patient.
Summary and Future Steps
The role of the lymphatic system in metastasis is being actively investigated and may represent a treatment strategy to reduce the spread of certain cancers. Recent evidence provides multiple potential pathways leveraged by tumor cells to travel through the lymphatics and establish in a secondary organ, including 1) protection from ferroptosis, 2) VEGF-C/VEGFR-3 induced lymphangiogenesis and 3) upregulation of chemokines CCR7 and CXCR4. Transcriptional analyses of the primary tumor, nodal metastases, pulmonary metastases, as well as "uninvolved" controls from the organ of origin may provide insight into which pathways are upregulated in extensive lymphatic metastasis from this patient.
Although we are no longer able to explore the underlying pathology contributing to this patient's disease, further investigation into the role of VEGF-C/VEGFR-3 blockade or chemokine signaling blockade (e.g., CCR7 or CXCR4) is warranted. Future studies may provide an actionable target for lymphatic metastasis and benefit many other patients in similar clinical situations.
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