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EDITORIALS |
From the Cutaneous Oncology Program, Lakeland Regional Cancer Center, Lakeland, Florida.
Correspondence: Douglas S. Reintgen, MD, Lakeland Regional Cancer Center, 3525 Lakeland Hills Boulevard, PO Box 91057, Lakeland, FL; Fax: 863-904-1802; E-mail: doug.reintgen{at}lrmc.com
Two papers published in this issue of the Annals of Surgical Oncology involved the emerging field of molecular staging of cancers. For many years investigators have wondered why some patients with melanoma, despite being node negative, recur and die of their disease. Is this due to hematogenous spread from the primary site or perhaps missed micrometastatic disease when the regional basin is sampled? The manuscript by Gradilone and colleagues1 from the University of Rome would suggest that at least some component of these recurrences and deaths are due to missed micrometastatic disease and inaccurate staging in the regional basin. The paper by Ruka et al.,2 from the Skfodouska-Curie Memorial Cancer Center and Institute of Oncology in Poland examined the afferent lymphatic flow into the regional basin after a therapeutic lymph node dissection in patients with melanoma and discovered that some patients shed tumor cells after this operation and those patients are identified to have a worse prognosis. Both groups used the RT-PCR technology, a technology that has the sensitivity of identifying 1 cancer cell in a background of a million normal cells. This sensitivity cannot be matched by routine histology and the human eye under the microscope, which is on the magnitude of being able to identify 1 cancer cell in a background of 10,000 normal lymphocytes.
The field of molecular staging for melanoma got its start in 1991 when Smith et al.3 identified circulating tumor cells with a very sensitive RT-PCR assay for tyrosinase. Tyrosinase is an enzyme that catalyzes the first two steps of the biosynthetic pathway of melanin synthesis. All cells in the body have the gene for tyrosinase but only cells that produce pigment, such as melanocytes and melanoma cells, will express the mRNA for this gene. If this gene product is found in the sentinel lymph node (SLN) or afferent lymphatic flow, that is good evidence that metastatic disease exits. The challenge has been to show clinical correlation. In other words, does finding evidence of metastatic disease with RT-PCR assays portend the patient to have a poorer prognosis.
Heller and colleagues from the University of South Florida were the first to recognize that routine histologic examination of the regional basin can miss micrometastatic disease.4 Using a simple lymph node culture technique, this group showed that malignant melanoma cells could be grown from lymph nodes called histologic negative by the pathologist. This missed micrometastatic disease was found to be clinically relevant in that these patients up-staged with the method had a significantly higher recurrence rate and poorer survival.5 The tissue culture method proved cumbersome and inefficient in that results were not available for a number of weeks. A more sensitive RT-PCR assay was developed for metastatic melanoma in the SLN6 and approximately 40% of the so-called histologic negative patients were found to have evidence of metastatic disease in their regional basin. Again this missed micrometastasis disease, now termed "submicroscopic disease", was found to be clinically important in that patients up-staged with the technique had a significantly worse outcome. In multivariate regression analysis that included known prognostic factors for melanoma, including tumor thickness and ulceration, it was the status of the SLN, either determined by routine histology or the RT-PCR assay that was the most important predictor of recurrence and death.7 This finding has now been supported by 6 different laboratories and one national trial throughout the world,8–16 including the recent publication from the University of Rome group.
The University of Rome group used a multiple marker assay (tyrosinase and MIA (melanoma inhibiting activity)) and showed that in 129 SLNs that were called histologic negative by the pathologist (although 6 SLNs had immunohistochemical evidence of metastatic disease) evidence of metastatic disease was found in 54% of the SLNs with the tyrosinase marker and in 17% of the SLNs with the MIA marker. Most of the recurrences and deaths were in patients up-staged with the more sensitive assays. It seemed from the manuscript that the unit of analysis was lymph nodes and not patients and the manuscript does not list the number of patients analyzed, the number of basins dissected/patient and the number of SLNs removed per basin. It is inferred from the manuscript that perhaps the study had 129 patients and 129 SLNs analyzed or 1 SLN/patient. This would be quite an unusual series since up to a third of the patients with melanoma will have more than one basin dissected due to the primary melanoma being in watershed areas of the body, particularly with trunk or head and neck melanoma. In addition, the mean number of SLNs removed per basin is 1.8 – 2.5 in many series. Nevertheless, this paper adds to the finding that missed micrometastatic disease, disease that is missed by routine pathologic examination, is clinically relevant disease.
The second report from the Poland group examined 93 patients with Stage III melanoma and found that 19.4% of the patients had evidence of tumor cells in the afferent lymphatic drainage entering the regional basin after a therapeutic lymph node dissection. These patients were identified to be a high risk group in that 83% of them recurred compared to a 35% recurrence rate in the patients who had no evidence of intra-lymphatic melanoma cells after therapeutic lymph node dissection (TLND). The interesting finding in this population is that the recurrence were not local-regional as you would expect, but more often systemic. The authors try to tie this finding with circulating melanoma cells and a worse prognosis, and it was surprising that patients with afferent lymphatic tumor cells did not have a higher recurrence rate either locally, in-transit or in the regional basin. The authors hypothesize that the tumor cells in the cut lymphatics are a source or marker of systemic disease and they are probably correct.
The age of molecular staging of cancers is approaching. Within 10 years, routine histology will take a back seat to very sensitive molecular staging assays. Ultrastaging will occur in various compartments of the body, such as primary site margins, afferent lymphatic flow into the regional basin, SLNs, peripheral blood and bone marrow. Patients negative in all these compartments will be considered cured of their disease, or at least closer to being cured of their disease than what we could identify with standard staging methods. Adjuvant therapies will be tailored to only those patients identified to be at high risk for recurrence by these very sensitive assays for occult metastases.
Received for publication September 10, 2004. Accepted for publication September 22, 2004.
REFERENCES
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