Turning the tide in sentinel lymph nodes

Los Angeles - The sentinel lymph nodes in melanoma patients are subjected to tumor-induced immune suppression, and reversal of such may be the key to preventing or reversing metastases, according to recent study results.

Tumor-induced immune suppression seems to facilitate melanoma metastases by inhibiting the generation of tumor-specific cytotoxic T cells that fight the tumor cells of primary and metastatic melanomas. The reversal of this immune modulation, and the immunologic strengthening of the sentinel lymph nodes, may have positive effects on melanoma management by curbing metastases, one expert speculates.

"In the past, (sentinel) lymph nodes were regarded as potential immunological barriers to cancer spread, but more recently, they have been shown to be partially immune-suppressed. The sentinel lymph node is the most likely site for the earliest stages of regional lymph node metastases and is the lymph node that is most powerfully influenced by tumor-derived factors such as cytokines," says Alistair J. Cochran, M.D., professor in the departments of pathology and laboratory medicine and surgery at David Geffen School of Medicine, University of California, Los Angeles.

Dr. Cochran's study results indicate that cytokine therapy could prevent or reverse the development of lymph node metastases, thereby removing a crucial link in the chain of progression that could ultimately lead to lethal metastases.

He says that the intratumoral or peritumoral administration of immune-stimulating cytokines such as granulocyte/macrophage colony-stimulating factor (GM-CSF) is a potential alternative to classical active or passive systemic immune therapy.

"Intratumoral injections of cytokines would achieve tumor-targeted, locally high concentrations of reagent with reduced systemic toxicity. GM-CSF employed as an adjuvant has reportedly induced regression of tumor in some patients. GM-CSF seems to cause an anti-tumor effect by activating macrophages, T cells and dendritic cells," he says.

Tackling treatment debates

The treatment of melanoma is still a disputed issue.

There are two schools of thought regarding this. The first school is to do lymphatic mapping and dissection of the sentinel lymph node(s) with excision of the primary and immediate complete lymph node dissection if the sentinel node contains tumor.

The second school is to excise the primary tumor and observe the patient for the development of clinically evident lymph node metastases, delaying complete lymph node dissection until the nodes are clinically detectable.

"In the absence of a clearly ideal approach for the management of patients with early stage melanoma, minimally invasive intraoperative lymphatic mapping and sentinel node biopsy have become the standard approach for determining regional lymph node status," Dr. Cochran says. "This procedure can accurately detect clinically occult metastases in the sentinel lymph nodes."

He says that melanoma-specific survival is considerably and significantly higher after immediate complete lymph node dissection (CLND) for clinically undetectable sentinel lymph node metastases than after a delayed CLND for clinically palpable node metastases.

According to Dr. Cochran, identifying the factors that determine the ability of cancers to metastasize, and prevention of such spread, is pivotal in melanoma management.

Proximity and probability

"The sentinel lymph node is the site where potentially autoreactive lymphocytes initially encounter tissue-specific antigens and develop acquired immunity - that is, tolerance or activation.

"The downregulation of immune activity in lymph nodes that are anatomically close to the primary tumor indicates that sentinel lymph nodes are likely to be immune-modulated to a greater extent than are tumor-remote regional lymph nodes," Dr. Cochran says.

He says that sentinel lymph nodes are highly susceptible to modulation by tumor-generated bioactive molecules that downregulate multiple crucial and interlinked lymph node functions.

He observes that nodes located closer to the tumor were more immune-suppressed than were those situated farther away.

"Such downregulation of lymph node cells and their functions precedes the establishment of nodal metastases and might be a prerequisite for the survival and proliferation of tumor cells that are destined to form metastases," he explains.