In-Transit Melanoma: An Individualized Approach

The majority of locoregional recurrences in melanoma occur in the form of intradermal or subcutaneous local or in-transit metastasis. In-transit melanoma represents contamination of the lymphatic space that, if treated, can result in long-term cure in a subset of patients. The management of in-transit metastases is challenging, since the treatments and extent of disease vary greatly based on the number, depth, location, and distribution of lesions, and on their biological behavior. A number of different treatment options exist, but there is no level 1 evidence to guide clinical decision-making. Herein we present our institutional treatment algorithm, which allows for individualization based on the patient's presentation.

Introduction

The simultaneous push for standardized treatment guidelines and "individualized medicine" may appear contradictory. If we develop evidence-based guidelines to follow as best practice for all patients with a disease, then how can we at the same time be individualizing care? However, personalized medicine does not prohibit the use of guidelines, and as we become more sophisticated, gene expression patterns-as opposed to the current crude gross clinical findings utilized today-will play a more central role in governing the treatment options we pursue. We are beginning to realize that most cancers, including melanoma, do not represent a single disease but rather are a phenotypic representation of a diverse array of underlying genetic changes that likely can be broken down into a few subtypes. Given that there are no randomized trials comparing the different approaches to in-transit melanoma, we have developed guidelines for patients who present with this pattern of disease, and we outline here our institutional preferred treatment decisions based on the extent and type of disease. Clearly we remain at the beginning stages of understanding this complex disease, and we look forward to modifying our algorithm as knowledge in this field advances.

Incidence and Pathophysiology

In-transit metastases develop from regional contamination of the intralymphatic system and occur shortly (mean, 16 months) after definitive treatment of the primary melanoma in 10% of patients.[1] The network of lymphatics draining from the primary tumor to the regional basin is quite robust. The clinical manifestation of an in-transit metastasis occurs when malignant cells present in the lymphatic system multiply to the point that they become palpable or visible at or just below the skin. These isolated lesions may appear indolent and easily treatable. However, such lesions are frequently just the tip of the iceberg, and an individual lesion often represents the most advanced presentation of many subclinical in-transit metastases. This is the reason localized treatment often fails and recurrence remains the rule. In-transit melanoma is associated with aggressive clinical and pathological factors such as increasing age, greater Breslow thickness, ulceration, high tumor mitotic rate, presence of angiolymphatic invasion, positive sentinel lymph nodes (SLNs), and extremity location.[1,2] While SLN metastases are associated with a 24% incidence of subsequent in-transit metastasis, the SLN procedure itself does not increase the incidence of in-transit disease.[2]

These in-transit metastases must be distinguished from a true local recurrence, which often involves the epidermis, representing regrowth of residual primary disease from incomplete resection. Given the recommendations of contemporary guidelines for wide local excision, true local recurrences should be an uncommon event, except in certain settings, such as lentigo maligna of the face. In-transit metastases are associated with a significantly worse prognosis compared with true local recurrence and therefore are classified as stage IIIB or IIIC disease, depending on the status of the regional lymph nodes as defined below (B = negative; C = positive).[3]

Because the definitions used in the literature vary, we want to clarify that we are using the term "in-transit metastasis" to include satellites, microsatellites, and in-transit metastasis. Microsatellites are defined as "any discontinuous nest of intralymphatic metastatic cells > 0.05 mm in diameter that is clearly separated by normal dermis (not fibrosis or inflammation) from the main invasive component of melanoma by a distance of at least 0.3 mm."[3] Satellite and in-transit metastases are cutaneous and/or subcutaneous metastases that occur between the primary melanoma and the first echelon regional lymph nodes, which have arbitrarily been distinguished on the basis of whether they are located within or more than 2 cm from the primary tumor. There does not appear to be a survival difference between patients with satellites and patients with in-transit metastases; the pathogenesis is identical, as is treatment-and the differences in terminology are chiefly of historical interest, since the 2-cm proximity rule has no anatomic or physiologic basis.[4] Prognosis after in-transit recurrence is largely the result of pathological features of the primary melanoma and the presence or absence of synchronous lymph node metastasis, as well as of the disease-free interval prior to recurrence.[5,6] Satellites and in-transit metastases are both considered intralymphatic metastases and are classified as N2c, with 5- and 10-year survivals of 69% and 52%, respectively, which are somewhat better than the 5- and 10-year survivals (59% and 43%, respectively) for stage IIIB patients overall, but still similar enough to make this classification the "closest fit."[3] Patients with both satellites/in-transit metastases and nodal metastases have a worse prognosis than patients who have either satellites/in-transit metastases or nodal metastases alone.[4,7] Consequently, the presence of a satellite or in-transit metastasis in addition to one or more positive lymph nodes is staged as N3.[3,8]

Algorithm

FIGURE 1

Algorithm for the Treatment of In-Transit Melanoma

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