INTRODUCTION
Each year in the United States there are about 600,000 cases of skin cancer. This is about one-third of all new cancers in the country. Most of these cancers are basal cell (480,000) or squamous cell (120,000) cancers, which are seldom life threatening. There are about 30,000 new cases of malignant melanoma in the United States and about 6,700 deaths. Unfortunately the incidence of melanoma is increasing about 4% each year. Melanoma is the most common cancer among women who are 25 to 29
years of age. By the year 2,000 an estimated one person out of every 90 will develop melanoma sometime during his or her lifetime. The good news is that deaths from melanoma are increasing far more slowly than new cases. This is due to early detection by patients and physicians alike.
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STAGES OF DISEASE
There have been several different staging systems for melanoma. The simplest includes only three stages: I localized disease, II positive regional lymph nodes, and III distant metastases. Since most staging systems reserve stage IV for the presence of distant metastases, this system is seldom used. Recently, the American Joint Committee on Cancer recommended the following staging system.
Stage I - The tumor is 1.5 mm thick or less without nodal or distant spread. The five-year survival rate is about 90%.
Stage II - The tumor is thicker than 1.5 mm, but less than 4 mm without nodal or distant spread. The five-year survival rate is about 70%.
Stage III - The tumor is thicker than 4 mm or lymph node metastasis is present. The five-year survival rate is about 40%.
Stage IV - Distant metastases are present. The five-year survival rate is less than 10%.
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TYPES OF TREATMENT
Surgery
The Primary Lesion
The treatment of a primary malignant melanoma has always been complete surgical excision. There has been debate about how much surrounding skin and underlying fatty tissue should be removed.
Melanomas are usually excised with an elliptical incision, which is about three times as long as it is wide. If the length of excision is too short, a "dog ear" or elevation is produced at each end of the scar. A 1 cm melanoma excised with 2 cm on each side results in the removal of an area of skin, which is 5 cm wide and 15 cm long. The resulting scar would be almost 6 inches long.
Mohs micrographic surgery removes the melanoma layer by layer until normal tissue is reached. This is less deforming than excision.
The Regional Lymph Nodes
If a patient has lymph nodes which are enlarged with melanoma then most of the regional lymph nodes are removed - both enlarged and normal nodes. Complications do occur frequently, especially in the leg. Complications include swelling of the arm or leg, wound infection and breakdown of the skin. Regional lymph nodes which do not feel enlarged may contain microscopic cancer cells. Many surgeons believe that regional lymph nodes should be removed to test for the presence of these cells. This is called an
elective lymph node dissection (ELND). The complications are listed above. A sentinel node biopsy is the easiest way to t removes just those few lymph nodes most likely to contain melanoma cells which have spread from the primary lesion. These nodes are identified by injecting a colored or radioactive dye near the primary lesion. This new procedure has fewer complications than a complete lymph node dissection.
Radiation
Radiation may help shrink large tumors and relieve pain in advanced disease, but it plays a very small role for most patients with this disease.
Chemotherapy
Chemotherapy with single drugs yields a response or tumor shrinkage in about 20% of patients. Multidrug therapy can increase this response rate to 40% or more. Unfortunately, tumor response rarely translates into improved survival.
Hyperthermia
Isolated regional perfusion has prolonged life for some patients with advanced disease. Only the involved extremity is treated. Tubes are inserted into the artery and vein of the involved arm or leg. A tourniquet is applied and the extremity is placed on heart-lung bypass perfusion machine. The arm or leg is isolated from the rest of the body's circulation. The extremity is perfused with heated blood, which contains a high concentration of a drug. Heat enhances the effectiveness of this treatment.
Immunotherapy
Interferon may provide a small survival advantage for patients with positive lymph nodes. During the 1970's and 1980's BCG was scratched into the melanoma or surrounding skin. Results appeared promising at first, but ultimately there was no increase in survival. Attempts have been made to treat patients with their own white blood cells. These cells have been concentrated from the patient's blood or removed from tumor specimens. The cells are cloned in a lab and stimulated to multiply many times. They are stimulated with a lymphocyte stimulating protein (interleukin-2) and infused back into the patient. The response rate for this treatment is about the same as for chemotherapy. This treatment has greatly increased our understanding of the immune response to cancer. It should not be judged on the basis of its current effectiveness.
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TCC ANALYSIS
Primary Lesion
The debate today focuses upon the width of normal appearing skin which should be removed around the melanoma. Most surgeons agree that thin lesions (less than 0.75 mm) may be excised with a 1 cm margin. Most surgeons now use a wider margin (2 - 3 cm) for thicker lesions. Some studies have demonstrated that patients treated with a narrow margin of excision (less than 2 cm) have a 12% - 13% chance of developing local recurrence. This compares with a 3% chance of local recurrence following a 3 cm excision. Local recurrence may increase to 20% among patients with lesions 4 mm or greater excised with margins of 1 cm or less. Nevertheless, investigators from both Australia and the Netherlands found no increase in local recurrence following excisions of less than 1 cm.,
Fortunately, none of these studies suggests that this increase in local recurrence causes a decrease in survival. There has never been a study, which demonstrates that wide margins improve survival. If aggressive surgery would impair bodily function or leave a disfiguring scar, you may want to consider having a narrow margin of excision. These margins should be checked by a pathologist to be sure that they are free of tumor cells. Mohs micrographic surgery is an excellent choice.
Elective Lymph Node Dissection
A sentinel node biopsy samples those lymph nodes most likely to contain cancer cells without causing great injury to the patient. The popularity of this procedure has decreased the need to debate the pros and cons of a major lymph node dissection.
The purpose of elective lymph node dissection is to remove the tumor cells before they spread to distant organs. Patients with thin lesions (less than 1 mm) are not usually treated with an elective lymph node dissection (ELND), because the chances of tumor spread are low. Patients with thick lesions (thicker than 4 mm) are also not treated with ELND, because the chances are great that the disease has already spread to distant organs. It is too late for this precautionary procedure to be of help.
Today the debate centers upon patients with lesions which are 1 4 mm in thickness. Two scientifically controlled studies have failed to find a benefit for ELND in this group of patients, although the studies may have been too small to show a slight benefit. A 1994 retrospective study from Duke also failed to find a survival benefit for ELND. Alternatively, many surgeons have reported that patients with this disease live longer if their lymph nodes are also removed during the first operation (the removal of the melanoma). Their retrospective studies have exaggerated this benefit, because some patients treated with a delayed lymph node dissection developed large nodal recurrences. They died because of the volume of the recurrent nodal disease was so large. Many of them could have been cured if they had returned to their doctors earlier at the first sign of enlarging lymph nodes. The problem was not failure to remove the lymph nodes at the first operation. The problem was failure to remove them before they enlarged to the point of becoming a source of circulating melanoma cells the cause of tumor spread.
Malignant melanoma is a highly aggressive malignancy that can disseminate from a small primary or regional lymph node. This is unlike breast cancer, which can usually be felt before it spreads. I believe that wide excision alone should be limited to reliable patients, who can be seen by a physician every two to three months, and who can perform regular, effective self examination. Physicians must be prepared to contact those patients who miss their followup visits. Physicians and patients alike must be willing to accept the potential threat to survival of nodal disease. If this strict followup protocol is not followed, the patient should seriously consider having an ELND.
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TREATMENT OPTIONS
Stage I - A primary melanoma which is 1.5 mm thick or less and the regional lymph nodes do not feel enlarged. Authorities agree that thin melanomas (less than 0.75 mm) can be safely excised with a 1 cm (3/8") margin on each side of the melanoma. I believe that 1.5 mm lesions may also be prudently removed with a margin of 1 cm. Some areas of the body have cosmetic significance, e.g., the face, the fingers, toes, genitals, anus, etc. Here a narrow excision with a pathologically negative margin may be appropriate. Mohs micrographic surgery accomplished this goal. Sentinel node biopsy may be prudent for a patient with a lesion which is
1.0 - 2.0 cm. thick Routine elective lymph node dissection (ELND) may benefit this same patient. If ELND is declined, patients must learn careful self examination and be followed by their physicians every two to three months. They must understand that they may be living with a time bomb. Patients unwilling to accept this threat should have an ELND.
Stage II - The melanoma is thicker than 1.5 mm and the regional lymph nodes do not feel enlarged. Local recurrence rates are likely to increase among patients with thick tumors excised with narrow margins, as discussed above. The width of excision is usually a cosmetic decision, which you will balance against the recurrence risks. There is no reliable evidence that narrow margins of excision adversely affect survival. Sentinel node biopsy is prudent for most patients. The role of ELND is discussed above.
Stage III - Enlarged lymph nodes can be felt. The primary lesion should be excised as suggested for Stages I and II. The regional lymph nodes should be removed.
Stage IV - The disease has spread to distant organs. Chemotherapy or immunological therapy.
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MEDICAL RESEARCH
Studies of malignant melanoma fall into two categories: those that like at treatment of the primary lesion, and those that look at treatment of the lymph nodes.
The Primary Lesio
In 1908, Sampson Handley delivered the famous Hunterian Lectures on malignant melanoma to the Royal College of Surgeons of England.(1) By his own admission Handley had never treated a case of primary malignant melanoma. Indeed, he had never seen a case. He based all of his recommendations upon a single autopsy of a patient who had died of disseminated melanoma. Nevertheless, his recommendations became the standard of treatment for most of this century. His lectures are still cited in the surgical literature. Handley suggested excising a one inch circumference of skin and a two-inch margin of subcutaneous tissue around the melanoma. That recommendation was later expanded to five centimeters, and even 15 cm in selected cases.(2),(3) Several investigators supported this trend by reporting premalignant changes in the skin within several centimeters of the primary lesion.(4),(5),(6) As recently as 1990 Morton has recommended margins of 3 cm for melanomas of intermediate thickness.(7)
The World Health Organization (WHO) evaluated the records of 593 patients.(8) They concluded that when lesions were removed with a margin of 2 cm or more, the local recurrence rate was about 5%. If the margin of excision was reduced to 1 or 2 cm, the local recurrence rate increased to about 12%. Surprisingly, the increased rate of local recurrence did not cause a reduction of patient survival.
Schmoeckel(9) from the University of Munich analyzed 585 cases of primary Stage I malignant melanoma seen at the University of Munich. Only three patients (2.9%) treated with margins of greater than 3 cm developed local recurrence, while 36 patients (10%) treated with narrower margins developed locally recurrent disease. The increased rate of local recurrence did not adversely affect survival. Multivariate analysis demonstrated that local recurrence was an indicator of a poor prognosis, but not its cause.
Heenan(10) from the University of Western Australia reported 189 patients with Stage I malignant melanoma; 74 patients had lesions thicker than 1.5 mm, and 71% were treated with a skin graft or flap. He found that margins of excision as narrow as 1 cm did not affect survival and concluded,". . . wide excision as the standard treatment of malignant melanoma is not justified." In 1992, Heenan and colleagues presented additional information on 530 patients.(11) Thirty-five percent had their tumors excised with surgical margins of < 1 cm. Neither local recurrence nor survival was adversely affected by narrow margins of excision.
In 1977, Pitt(12) from Victoria, Australia reviewed the literature on margins of excision for melanoma stated, "There is no evidence in the literature to show that wide excision confers greater protection than narrow excision in the treatment of malignant melanoma. In 1983, Ackerman and Sheiner(13) from the New York University School of Medicine performed a similar review which also included information from the WHO study.(14) They concluded,"In short, surgery for a primary cutaneous malignant melanoma should be no different from surgery for any other malignant neoplasm that is primary in the skin. Excision of additional centimeters of normal skin does not enhance survival . . ."
Elder(15) and colleagues from the University of Pennsylvania studied 105 patients with malignant melanoma and concluded," . . . our data suggest that the extent of local surgery does not influence patient survival." Indeed there are no published studies, which show that narrow margins of excision reduce overall survival.
I have found only two studies, which have suggested this association. In 1983, Aitken et al.(16) concluded that "patients with deeper lesions excised with a margin of less than 2 cm had a significantly greater risk of dying." The following year, they reversed this position.(17) Lehman(18) reported a difference in the five-year survival rates of 42 patients treated with either primary closure (33%) or skin graft (52%). This study was done before Clark's levels or depths of invasion were measured. It is likely that deep nodular lesions were excised primarily, and superficial spreading lesions were treated with a graft.
In 1993, O'Rourke at al. from Queensland, Australia, provided data, which supports conservative surgery for malignant melanoma.(19) They studied 187 patients. Eighty-six lesions were excised with a margin of 1.5 cm or less; one hundred and one lesions were excised with a margin of greater than 1.5 cm. There was no significant difference in the recurrence rates for these two groups. They recommended margins of 1.0 cm to 1.5 cm for stage I disease. In the accompanying editorial, Seigler of Duke University recommends a 2-cm margin.(20) Brown and Goldsmith recommend narrow, pathologically negative margins in cosmetically sensitive areas.(21)
Many studies have demonstrated that patients treated with a narrow margin (less than 1 - 2 cm) have an increased chance of developing local recurrence. If your surgery would leave a disfiguring scar, you will want to consider the evidence, which supports narrow margins of excision. There has never been a paper published which demonstrates that narrow margins of excision reduce survival. There has never been a study, which demonstrates that wide margins improve survival.
The Regional Lymph Nodes
For decades surgeons in the United States have debated the value of removing regional lymph nodes, even if the nodes were not enlarged. This has been called an elective lymph node dissection (ELND). It is well known that 30% to 60% of patients with intermediate level (1.5 - 4.0 mm) lesions have microscopically positive lymph nodes. Some surgeons have wanted to remove these melanoma cells before they spread to distant organs. Some arguments for and against this procedure (ELND) have been well summarized.(22),(23),(24)
It is now agreed that patients with either thin lesions or thick lesions are unlikely to benefit from ELND. Patients with thin lesions (less than 1 mm) are unlikely to have melanoma cells in their regional lymph nodes. Patients with thick (greater than 4.0 mm) lesions are likely to have melanoma cells already spread to distant sites. In either case an ELND has little chance of improving survival. The debate now centers on patients with lesions of intermediate thickness (1 mm to 4.0 mm).
Among the best known studies, which support ELND, are those by Balch and associates. In 1981, they studied 1,786 patients treated between 1955 and 1980 at the University of Alabama in Birmingham (UAB) and the Sydney Melanoma Unit (SMU) in Sydney, Australia. They concluded that ELND benefited patients with lesions between 1.5 and 4.0 mm.(25) They reported a 10-year survival rate of 70% among patients treated with ELND. Patients treated with wide excision alone were less likely to survive 10 years -- 15% at the UAB and 45% at the SMU.
Contrary evidence has come from The World Health Organization (WHO), which conducted a randomized, prospective trial in Europe. The trial studied patients treated by wide excision with or without ELND.(26) These investigators concluded that ELND offers no survival advantage over wide excision alone. They reported a 73% ten-year survival rate among patients with 2.0 to 4.0 mm lesions treated with wide excision with or without ELND. The Mayo Clinic also performed a randomized, prospective trial and reached a similar conclusion.(27)
I believe that this debate hinges on one very important factor. How carefully was each patient followed after surgery? The UAB started a melanoma registry in 1975. Information for their study was obtained from "patient records and by telephone interviews with the patients, their families and their primary physicians."(28) Many UAB patients treated with wide excision alone developed easily palpable nodal disease. Indeed 31% of patients who returned with melanoma in their lymph nodes had five or more positive nodes.(29) The survival of these patients was no greater than that of patients who had palpable nodal disease, when they were first seen at UAB. Thus, the follow-up procedures at the University of Alabama were of no advantage over patient self evaluation and referral.
The SMU began evaluating patients prospectively in 1964. Patients were seen every two to four months during the first two years.(30) I believe that the three fold difference in 10-year survival rates between UAB and SMU (45% vs. 15%) may be due to the extent of nodal disease in the two studies. Patients treated by wide excision alone at the UAB may have had a 15% 10-year survival rate, because they were followed less frequently and developed sizable nodal disease. The tumor burden of extensive nodal disease may have been responsible for some deaths at the UAB that were prevented by an earlier delayed dissection at SMU. Thus, the real issue may not be whether an ELND is needed, but at precisely what level of tumor burden does nodal disease become an added survival risk.
By contrast, patients in the WHO trial were all followed prospectively every one to three months and treated promptly if nodal disease appeared. 22 These patients had a 50% 5-year survival rate. This was equivalent to the survival of patients who had positive lymph nodes after an ELND. In other words, consider those patients with microscopic cancer in their lymph nodes. One group has an ELND. The other group has surgery several months later after the lymph nodes have become barely palpable. The WHO trial concluded that the survival of both groups of patients is the same. This experience differs from that reported by Balch, where nodal disease was allowed to grow -- not to the tumor burden of early disease, but to the readily palpable tumor burden of clinical Stage III disease.
NOTE: The paragraph below was published in 1995 in Making the Right Choice. My predictions have since been verified in a scientific trial.
There may be a few individuals with thin lesions who develop nodal disease and die as a result of the tumor burden of the nodes. Balch found that 24% of his patients with 1.5 - 2.5 mm lesion had pathologically positive lymph nodes. In the WHO trial about 20% of patients had positive nodes. Even among patients with 1.0 - 1.9 mm primary lesions, 14% had positive lymph nodes, regardless of treatment. The 10-year survival rates of these patients were: immediate dissection - 85%, delayed dissection - 66% (p = 0.34). This difference may be real, if the tumor burden of the nodal recurrence exceeded the tumor burden of the primary lesion and the defense threshold of the patient. Some patients who survived their thin primary lesions were unable to survive their nodal disease. I believe the records of individual patients should be reviewed to see if excess deaths occurred among patients with more advanced nodal disease.
It is also possible that in a few other patients melanoma within regional lymph nodes may metastasize to distant organs before it becomes palpable. The WHO trial dealt in averages. There are no tests to identify these patients. There are two studies currently in progress, which address this matter. The NCI Intergroup Melanoma Committee is taking place in the United States and the WHO Melanoma study is in Europe. I suggest that these investigators make an effort to carefully measure the volume of cancer in the lymph nodes. This is difficult to do. But it is important for surgeons to learn the volume of tumor which the average patient can tolerate before the tumor spreads. (See Chapter 3 for an explanation of the battle between the tumor and the patient.) For each patient this tumor volume should be compared to the volume of the primary tumor. Future studies should also include an immunological evaluation of each patient.
In conclusion, some retrospective studies may have exaggerated the benefit of ELND, because some patients treated with delayed dissection developed sizable nodal recurrence. They died because of the volume of the recurrent nodal disease. Malignant melanoma is a highly aggressive malignancy that can disseminate from a small primary or regional lymph node. This is unlike breast cancer, which can usually be felt before it spreads.
1. Handley WS: The pathology of melanotic growths in relation to their operative treatment. Lecture II Lancet 1907; 1: 996-1003.
2. McNeer G, Cantin J: Local failure in the treatment of melanoma. Am J Roentgenol 1967; 99:791-808.
3. Petersen NC, Bodenham DC, Lloyd OC: Malignant melanoma of the skin. Br J Plast Surg 1962; 15:49-116.
4. Wong CK: A study of melanocytes in the normal skin surrounding malignant melanomata. Dermatologica 1970; 141: 215-225.
5. Cochran AJ: Histology and prognosis in malignant melanoma. J Path 1969; 97: 459-468.
6. Olsen G: The malignant melanoma of the skin: new theories based on a study of 500 cases. Acta Chir Scand [Suppl.] 1966; 365: 1-220.
7. Morton DL. Current management of malignant melanoma. Ann Surg 1990; 212: 123-124.
8. Cascinelli N, van der Esch EP, Breslow A, Morabito A, Bufalino R: Stage I malignant melanoma of the skin: the problem of resection margins. Europ J Cancer 1980; 16: 1079-1085.
9. Schmoeckel C, Bockelbrink A, Bockelbrink H, Braun-Falco O: Low- and high-risk malignant melanoma - III. Prognostic significance of the resection margin. Eur J Clin Oncol 1983; 19: 245-249.
10. Heenan PJ, Weeramanthri T, Holman CDJ, Armstrong BK: Surgical treatment and survival from cutaneous malignant melanoma. Aust NZ J Surg 1985; 55: 229-234.
11. Heenan PJ, English DR, Holman CDJ, et al. The effects of surgical treatment on survival and local recurrence of cutaneous malignant melanoma. Cancer 1992; 69:421-6.
12. Pitt TTE: Aspects of surgical treatment for malignant melanoma: The place of biopsy and wide excision. Aust NZ J Surg 1977; 47: 757-766.
13. Ackerman AB, Scheiner AM: How wide and deep is wide and deep enough? Human Path 1983; 14: 743-744.
14. Cascinelli N, van der Esch EP, Breslow A, Morabito A, Bufalino R: Stage I malignant melanoma of the skin: the problem of resection margins. Europ J Cancer 1980; 16: 1079-1085.
15. Elder DE, Guerry D, Heiberger R, LaRossa D et al: Optimal resection margin for cutaneous malignant melanoma. Plast Reconstr Surg 1983; 71: 66-72.
16. Aitken DR, Clausen K: Klein JP, James AG. The extent of primary melanoma excision. A re-evaluation-how wide is wide? Ann Surg 1983; 198: 634-641.
17. Aitken DR, James AG, Carey LC: Local cutaneous recurrence after conservative excision of malignant melanoma. Arch Surg 1984; 119: 643-646.
18. Lehman JA, Cross FS, Richey DG: Clinical study of forty-nine patients with malignant melanoma. Cancer 1966; 19: 611-9.
19. O'Rourke MGE, Altmann CR. Melanoma recurrence after excision is a wide margin justified? Ann Surg 1993; 217:2-5.
20. Seigler HF. Clinicopathologic factors relating to surgical margins for cutaneous melanoma . Ann Surg 1993; 217:1.
21. Brown M, Goldsmith LA. Excision margins for melanoma in awkward places lie the eyelid. JAMA 1993, 269:588-589. (Letter)
22. Balch CM, Milton GW, Cascinelli N, Sim FH. Elective Lymph Node Dissection: Pros and Cons. In: Balch CM, Houghton AN, Milton GW, Sober AJ. Cutaneous Melanoma. Philadelphia: J. B. Lippincott, 1992.
23. McCarthy WH, Shaw HM, Cascinelli N, Santinami N, Belli F. Elective lymph node dissection for melanoma: two perspectives. World J Surg 1992;16:203-213.
24. Sutherland CM, Mather FJ. Prophylactic lymph node dissection for malignant melanoma: What to do while we wait. J Surg Oncol 51:1-4, 1992.
25. Balch CM, Soong S-J, Milton GW, et al. A comparison of prognostic factors and surgical results in 1,786 patients with localized (stage I) melanoma treated in Alabama, USA and New South Wales, Australia. Ann Surg 1982; 196:677-684.
26. Veronesi U, Adamus J, Bandiera DC, et al. Delayed regional lymph node dissection in stage I melanoma of the skin of the lower extremities. Cancer 1982; 49:2420-2430.
27. Sim FH, Taylor WF, Pritchard DJ, Soule EH. Lymphadenectomy in the management of stage I malignant melanoma: a prospective randomized study. Mayo Clin Proc 1986; 61:697-705.
28. Balch CM, Murad TM, Soong S-J, et al. A multifactorial analysis of melanoma: Prognostic histopathological features comparing Clark's and Breslow's methods. Ann Surg 1978; 188:732-742.
29. Balch CM, Soong S-J, Shaw HM, Urist MM, McCarthy WH. Analysis of prognostic factors in 8500 patients with cutaneous melanoma. In: Balch CM, Houghton AN, Milton GW, Sober AJ. Cutaneous Melanoma. Philadelphia: J. B. Lippincott, 1992.
30. McCarthy WH, Shaw HM, Thompson JF, Milton GW. Time and frequency of recurrence of cutaneous stage I malignant melanoma with guidelines for follow-up study. Surg Gynecol Obstet 1988; 166:497-502.
Medical Research since 1995
All of the studies of malignant melanoma fall into two categories: those that like at treatment of the primary lesion, and those that look at treatment of the lymph nodes.
The Primary Lesion
Since 1995, Mohs micrographic surgery has become accepted treatment in several academic medical centers. J.A. Zitelli and colleagues of Shadyside Medical Center in Pittsburgh conducted a prospective study of 535 patients treated for melanoma using the Mohs technique.(1) Eighty-three percent of lesions were successfully excised with a 6 mm margin; a 1.2 cm margin was required to remove 97 percent of all lesions. They achieved 5-year survival rates which were equivalent to patients treated by standard wide-margin surgery. Local recurrences from inadequate excision of the primary tumor were very rare (0.5 percent). The authors recommend Mohs micrographic surgery when narrow margins are desired
S.N. Snow and associates of the Mohs Surgery Clinic in Madison, Wisconsin, treated 179 patients with melanoma from 1981 to 1991.(2) They concluded that the Mohs technique was effective treatment for patients with melanomas of thin and intermediate thickness. For deeper lesions the number of cases was insufficient to evaluate.
By 1998, K. M. Keaton and associates at the M. D. Anderson Cancer Center studied 278 patients with thick melanomas, i.e., deeper than 4 mm.(3) The median tumor thickness for their patients was 6 mm. After a median follow-up of 257 months, the local recurrence rate was 27%. These investigators found that neither local recurrence nor excisional margin significantly affected overall survival. They concluded that a 2 cm margin of excision was adequate for patients with thick lesions (> 4 mm).
D.A. Hudson and associates of the University of Cape Town, South Africa, treated 106 patients with stage I melanoma of the face.(4) Margins of excision ranged from less than 1 cm to greater than 2 cm. Seven patients developed local recurrences, but these were not influenced by the size of the excision margin. The authors concluded that stage I melanoma of the face should be treated with a complete excision, microscopically confirmed by a pathologist. They found that this could be achieved with margins of excisions of less than 1 cm.
Erroneous Conclusions
Many studies have now proven that a narrow margin of excision - and the local recurrence which may follow - does not adversely affect survival. This conflicts with the prevailing paradigm and some investigators are now resorting to faulty research techniques to support their erroneous beliefs.
X. D. Dong and associates of Duke University Medical Center studied 648 patients who developed local recurrence following the removal of the original melanoma.(5) The Duke investigators reported that 48.5% of these patients died within five years of their local recurrence. (They did not compare this mortality rate to that of patients who remained free of local recurrence.) They concluded that this mortality rate was high and that local recurrence caused the melanoma to spread. They suggested that patients may benefit from more aggressive local therapy, e.g., wider margins of excision.
This study is seriously flawed, because there are at least two types of local recurrence. First, cancer cells may have already spread to a distant organ (metastasis), before the original melanoma was removed. As the metastasis grows it may shed additional cancer cells into the blood stream, where they eventually make there way back to the site of surgery. (Experimental research has shown that cancer cells are attracted to tissue, which has been injured by surgery.) This first type of local recurrence has a very bad prognosis, because the cancer has already spread. Modern scans and other tests may not detect the distant metastasis until is almost an inch in size. This may be months after the local recurrence is first seen. Thus, the distant metastasis appears to follow - and thus be caused by - the local recurrence. But, this is incorrect.
The second type of recurrence involves cancer cells left behind in the skin following the removal of the original melanoma. I prefer to call this "local persistence." Local persistence is not a threat to patient survival. Patients who are able to prevent the spread of disease from their original melanoma, are able to prevent the spread of disease from a recurrent - or persistent - melanoma. This is precisely the way breast cancer behaves. Even in the well-known NSABP lumpectomy trial, patients who developed local recurrence were 4.6 times as likely to develop distant metastases as those who remained free of local recurrence. But, the NSABP investigators concluded correctly that local recurrence was the indicator of a poor prognosis, but not its cause.
X. D. Dong and associates of Duke University combined patients with two types of local recurrence in their study. It is not surprising that these patients had a poor prognosis. Many of them already had distant metastases and developed local recurrence from the distant disease. Some of the patients had local persistence and their survival was not affected. But, they were lost in this faulty study. Contrary to the study from Duke, aggressive local therapy has no affect on patient survival.
The Regional Lymph Nodes
Sentinel Lymph Node Biopsy
Sentinel lymph node biopsy is a new technique which removes only those few lymph nodes which are close to the melanoma - those nodes where the melanoma is most likely to spread. Before surgery a dye in injected into the skin around the melanoma. The dye flows into the nearest (sentinel) lymph node(s) and a scan identifies the node(s) in question. The is called lymphatic mapping. A blue colored dye allows the surgeon to see the sentinel lymph node while performing the biopsy. By removing very few lymph nodes the surgeon can determine the status of all the nodes in the region. If cancer cells are found in the sentinel node, the surgeon usually removes most of the remaining regional nodes. This technique causes few effects and can be performed on any patient about whom there is any question of lymph node spread. For most patients it has largely eliminated the decades long debate about the value of elective lymph node dissection in patients with melanoma. Regrettably, there is much we can learn from this debate - lessons that are now ignored.
Surprising New Information about Elective Lymph Node Dissection (ELND)
In 1996, Intergroup Melanoma Trial published the results of a randomized trial of 740 patients with localized melanoma, 1.0 to 4.0 mm thick.(6) Half of the patients received an ELND. The other half was observed. If the lymph nodes enlarged with cancer cells, they were removed. Among the patients to benefit from an ELND were those with very thin lesions, 1.0 - 2.0 mm. This was surprising, because these patients were the least likely to have positive regional lymph nodes. Why did ELND benefit only those patients least likely to have positive lymph nodes? The authors of this study offered no explanation for their surprising results. In 1995, I commented on similar data that had already been published from another study. I also offered an explanation for these paradoxical results.
The Texas Cancer Center believes that all available medical evidence continues to support the increased use of limited surgery for malignant melanoma.
1. Zitelli JA, Brown C, Hanussa BH. Mohs micrographic surgery for the treatment of primary cutaneous melanoma. J Am Acad Dermatol 37:236-45, 1997.
2. Snow SN, Mohs FE, Oriba HA, Dudley CM, Leverson CM, Hetzer M. Cutaneous malignant melanoma treated by Mohs surgery. Review of the treatment of 179 cases from the Mohs Melanoma Registry. Dermatol Surg 23:1055-60, 1997.
3. Heaton KM, Sussman JJ, Gershenwald JE, Lee JF, Reintgen DS, Mansfield PF, Ross MI. Surgical marg and prognostic factors in patients with thick (> 4 mm) primary melanoma. Ann Surg Oncol 5:322-8, 1998.
4. Hudson DA, Krige JE, Grobbelaar AO, Morgan B, Grover R. Melanoma of the face: the safety of narrow excision margins. Scand J Plast Reconstr Surg Hand Surg 32:97-104, 1998.
5. Dong XD, Tyler D, Johnson JL, DeMatos P, Seigler HF. Analysis of prognosis and disease progression after local recurrence of melanoma. Cancer 88:1063-1071, 2000.
6. Balch CM, Soong S--J, Bartolucci AA, et al. Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg 224:255-266, 1996.
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The Texas Cancer Center gratefully welcomes contributions from all those 
