ABSTRACT: 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.
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. 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.
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).
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." 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. 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." 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]
It is understood that patients with in-transit disease are at high risk for further locoregional and distant recurrence. Many potential treatment options exist for this disease, with no accepted "best practice." Patients with this pattern of disease vary greatly in terms of the number, depth, location, and distribution of lesions. With an acknowledgement of these complexities and limitations, we have reviewed the literature and have developed a clinical algorithm (Figure 1) to facilitate the individualization of treatment and to improve patient outcomes. This algorithm will evolve as our understanding of the biology and immunology of melanoma disease progression matures.
Intralymphatic spread is not a single disease entity but rather represents diverse and complex patterns of failure, with patients frequently experiencing multiple treatments; this makes comparing outcomes challenging. For each treatment there is a select group of patients who will have a complete response and long-term survival. Although there is a lack of level I evidence to guide management, there are some consistent principles in the literature that we have used as the basis for our treatment algorithm.
Patients who develop locoregional recurrence should be adequately restaged with positron-emission tomography (PET)–computed tomography (CT), since 10% to 20% of these patients may have simultaneous distant relapse necessitating a change in management.[2,9] However, if the disease is indeed localized, then the simplest technique should be employed first—ie, complete excision and primary closure when possible. There are no evidence-based data to support a particular width of peripheral margins of excision for in-transit metastases, and the wide local excision guidelines for a primary lesion do not apply. A single cutaneous metastasis can be narrowly resected, and we typically utilize a 5-mm gross margin. These individual lesions are, in general, well circumscribed, and negative microscopic margins should be obtained if excision is performed for therapeutic rather than diagnostic purposes. Unfortunately, surgical excision is not always feasible, and in patients with too many lesions to resect, recurrence within a short time period following resection, or numerous recurrences, alternative treatment approaches should be considered as outlined below. A multifocal metastasis within a circumscribed area may be resected en-bloc. Primary closure is preferred; however, lack of redundant skin and lymphedema from previous interventions may necessitate rotation flaps or skin grafting. Skin grafting has the advantage of not impairing lymphatic flow. Rarely, uncontrollable pain, extensive locoregional tumor progression, or ulcerating and fungating lesions exhaust other treatment measures, and palliative amputation may remain the only option. Initial reports of amputation for advanced melanoma were associated with poor outcomes. Recent reports of salvage amputation still report a 36% incidence of stump recurrence, with approximately 20% of patients surviving more than 5 years.[11,12] We employ limb-preserving therapies whenever possible, reserving amputations for cases in which all other measures have been exhausted.
In the absence of prior regional nodal dissection, patients with first-time in-transit recurrences should undergo nodal restaging with SLN biopsy, since up to 50% of patients have synchronous nodal metastasis.[13-16] Prior wide local excision does not appear to adversely impact the ability to detect lymphatic metastases, and SLN biopsy has been found to be accurate in the setting of recurrent melanoma.[14,15] SLN biopsy and subsequent lymphadenectomy for nodal positivity are prognostic, identifying patients with a higher risk of relapse (median disease-free survival of 16 months for node-positive status compared with 36 months when SLNs were negative); the procedure also offers excellent regional control.