Physiological Mechanisms that Predispose to the Development of Breast Cancer-Associated Lymphedema

Breast cancer-associated impairments in upper extremity lymphatic function represent one of the most common sets of presentation for the clinical problem of lymphedema.^1–4 Somewhat paradoxically, and counter-intuitively, the work of Stanton et al. has created a framework for understanding this clinical problem, in which the predisposition to this problem resides in a constitutively enhanced lymphatic pump, rather than in one that represents a predilection to inadequate function when obstructive anatomy and function follows breast cancer interventions. Many features of breast cancer-associated lymphedema are not readily explained by regional obstructive phenomenology.^5,6 and, thus, it appears that that there are constitutive, bilateral physiological lymphatic alterations in subjects at increased risk for post-treatment lymphedema, and that these alterations can be identified and quantified prior to any treatment interventions.^5–7

In the current issue of Lymphatic Research and Biology, this group of investigators has further extended their very valuable observations. ⁸ The authors measured the maximum lymphatic pump pressure and the transport rate of ^99mTc-Nanocoll that can be generated by the contractile upper limb lymphatics before and after breast cancer surgery. These studies were accomplished in study subjects who had two subsequent years of clinical follow-up to determine the ultimate lymphedema status following breast cancer interventions. In those subjects who ultimately developed lymphedema, the lymphatic pump pressure was higher and the rate of lymph tracer transport into the forearm was greater. In addition, upon post-operative assessment, impaired forearm tracer transport occurred in those who later developed lymphedema, but not in the subjects that remained free of a subsequent functional deficit.

Thus, these data imply that axillary lymphatic obstruction does not, alone, explain breast cancer-associated lymphedema. While surgical trauma does appear to compromise lymph drainage, the effects of that compromise are enhanced in those who are constitutively predisposed on the basis of high pre-surgical levels of lymphatic pressures and transport. These observations open the door to enhanced pre-treatment screening for lymphedema predisposition and may also, in future, provide a route to successful pre-emptive pharmacological intervention.