Metastatic Melanoma In Regional Lymph Nodes

Once patients develop metastatic melanoma in their regional nodes, prognostic factors based on the primary melanoma contribute very little to the prognostic model. For most solid tumors, including melanoma, the most powerful predictor of survival is the presence or absence of lymph node metastases. The presence of lymph node metastases decreases the 5-year survival of patients approximately 40% compared with those who have no evidence of nodal metastases. Much time, effort, and expense is placed on identifying prognostic factors based on the primary tumor, and not enough emphasis is given to identifying which patients really have signs of micrometastatic disease in their nodal basins. For instance, there are currently 26 prognostic factors (Table 1) for melanoma based on variables from the primary tumor. Yet, in multiple regression analysis performed on many collected populations in the literature, the lymph node status of the patient is the most powerful factor for predicting recurrence and survival. Primary tumor

Table 1 Twenty-six Prognostic Factors for Melanoma Based on the Primary Tumor

Tumor thickness

S phase

Ulceration

DR-1 expression

Clark level

DNA index

Histological type

Heat-shock protein expression

Cell type

HLA-DR staining

Primary site

p53 mutations

Regression

Cell adhesion molecule expression

Mitosis

Proteases expression

Lymphocytic infiltration

Migration-associated molecule expression

Vertical maturation grade

Angiogenesis-related factor expression

Blood vessel invasion

Oncogene expression

Lymphatic space invasion

Estrogen receptor expression

Ploidy

Cytokine; growth factor expression

variables such as Breslow thickness, ulceration, primary site, and gender may add to the prognostic model, but only after nodal status is considered.

Routine histological examination of the regional lymph nodes, which typically involves making one or two sections of the central area of the node and staining with a standard Hematoxylin & Eosin (H&E) method, examines less than 1-5% of the submitted material and may miss micrometastatic disease (Fig. 1). The sensitivity of this examination is finding one abnormal melanoma cell in a background of 10,000 normal lymphocytes. If serial sectioning and immunohis-tochemical staining (Fig. 2) are added, the yield of positive dissections may double and the sensitivity becomes identifying one abnormal melanoma cell in a background of 100,000 normal lymphocytes. Serial sectioning and immunohisto-chemical staining techniques have been available for years, yet have not been incorporated into the everyday practice of the pathologist because of the time and expense involved.

New technology that enables the surgeon to map the cutaneous lymphatic flow from the primary tumor and identify the sentinel node (first-tier node, firstechelon node) in the regional basin could contribute to better nodal staging of the melanoma patient. This procedure, as initially proposed by Morton et al. [3,4],

Lymph Nodes Forearm
Figure 1 H&E photomicrograph of the sentinel lymph node in a patient with a 2.0mm melanoma on the right arm. Metastatic melanoma can invade the sentinel node as single cells (arrows) and with low-volume disease.
Sentinel Lymph Node

Figure 2 Immunohistochemistry staining with the melanoma specific S-100 stain. The metastatic cells will stain brown with the immunoperoxidase technique while the rest of the surrounding lymphocyte does not stain. The routine use of immunohistochemistry will increase the sensitivity of the examination for occult metastases. The figure also illustrates how metastatic melanoma can be a very low-volume disease.

Figure 2 Immunohistochemistry staining with the melanoma specific S-100 stain. The metastatic cells will stain brown with the immunoperoxidase technique while the rest of the surrounding lymphocyte does not stain. The routine use of immunohistochemistry will increase the sensitivity of the examination for occult metastases. The figure also illustrates how metastatic melanoma can be a very low-volume disease.

has shown that the sentinel lymph node is the first site of metastatic disease, and if the sentinel lymph node is negative, then the remainder of the lymph nodes in the basin should also be negative [5,6]. Selective lymphadenectomy also allows for detailed examination of the sentinel node, because it is an examination of one or two nodes. This advance allows the pathologist to serial section the node and use immunohistochemistry to look for micrometastatic disease. Nevertheless, 25% of the histological node negative Stage I and II melanoma patients will recur and die of their disease within 5 years of diagnosis, suggesting that some of these patients have missed nodal micrometastases or these patients suffer from hematogenous metastases. A more sensitive method was needed to accurately identify the presence or absence of metastatic disease in the node.

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