Developments in melanoma management – success and failure

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Emeritus Professor of Surgery
The University of Sydney


Abstract

Melanoma is a high priority cancer in Australia with a lifetime risk of occurrence of 1 in 30. However the incidence rate rise is stabilising and survival now exceeds 90%. The improvements in melanoma survival are mostly based on mostly early diagnosis. The management of melanoma has gone from radical surgery to a conservative individualised approach based on new and better understandings of the biology and behaviour of the malignant melanocyte. Despite many “unknowns” and many earlier inappropriate management approaches, the outlook for melanoma patients has steadily improved over the last 50 years.


Melanoma is known abroad as the Australian cancer. In Australia, its prevalence and community educational programs have given it high priority in the minds of most Australians, even though it now has the best survival (more than 90%) of all major cancers and for the majority of patients who develop melanoma, only relatively minor surgery is curative.

The high profile of melanoma in Australia is mainly due to its association with the perceived lifestyle of the Australian citizens, with sun, sand and surf dominating both local and international views of Australians. However, while it is certainly true that melanoma is very much more common in Australia than anywhere else in the world, its mortality is generally overestimated by the Australian populace. NSW is the largest state in Australia, with approximately five million people and the most recent data on melanoma comes from Cancer Institute NSW, which has recently reviewed melanoma in NSW from 1994 – 2003.1 In 2003 there were 3239 new cases of melanoma and 407 deaths in NSW. The lifetime risks for melanoma were 1 in 24 for males and 1 in 35 for females.

In Australia the incidence of melanoma is between 36.9 to 51.1/105/year for males and 25.9 to 38.1/105/year for females (world standardised rates). Queensland has the highest incidence. These rates are more than three times the US rates for whites (15.4 for males and 11.6 for females per 100,000) and six times the UK rates of 5.8 males and 7.4 females per 100,000.

The dominant feature in Australian melanoma incidence data is a high incidence in older males and this is reflected also in mortality (Figure 1). There is a virtual stabilisation of mortality for patients under the age of 40.

Figure 1: Age standardised incidence and mortality NSW 2004.

The management of melanoma in Australia has been influenced by general worldwide interest in the disease and research both here and elsewhere. In Australia a large emphasis is placed on melanoma prevention by The Cancer Council Australia and the state-based Cancer Councils, non-government foundations, such as the Melanoma Foundation, the Skin Cancer Foundation and clinical melanoma units in every state in Australia and in New Zealand. Australian clinicians and researchers can take credit for many contributions to the increasingly successful management of melanoma. However, there have been many blind pathways during the development of the management of melanoma, with much time and effort spent pursuing pathways which have not led to substantial improvements in outcome.

Primary prevention

Australian skin cancer preventative programs have an enviable reputation throughout the world. No other nation has comparable emphasis on the prevention of melanoma.2 All Australian states have state-specific educational programs and one program, “Slip, Slop, Slap” which originated in Victoria, is used nationally as the basis for national public education programs on the prevention of sunlight damage to the skin.3

A degree of success can be claimed for these programs. From 1984 to 1993 in NSW, melanoma incidence rates increased by 54% in males and 17% in females. From 1994 to 2003 the age standardised incidence rate rose by only 15% in males and 12% in females and mortality rates are now almost stable. (Figure 2) Furthermore much of the incidence rate rise in males can be attributed to the older male population who receive the majority of their skin sun damage prior to the great emphasis on skin cancer prevention that began in the decade 1980–1990. For younger cohorts preventative programs now show a satisfying stabilisation in incidence rates and in mortality (Figure 2). The obvious failure to date of these preventative programs is concentrated particularly on one specific community group, older males. This is unlikely to be changed in the near future because sun damage to the skin is essentially irreversible and for this group the predisposition to skin cancer has been established by earlier sunlight exposure.

Figure 2: Changes in cancer rates and mortality 1994-2003 (NSW)

Causation

The basic premise of melanoma causation is that ultraviolet light damages melanocytes in the skin, particularly those in naevi, causing a transformation to a malignant phenotype. This occurs in the basement membrane of the skin  (in-situ melanoma), which then becomes invasive, cells are released into the surrounding tissue fluid with subsequent invasion of the lymphatics, involvement of the lymph nodes and, with or without lymph node involvement, systemic metastatic disease. Ultraviolet light is known to promote malignant change by a direct mutagenetic effect on DNA, stimulation of growth factors, reduction in cutaneous immunity, promotion of reactive oxygen species which damage DNA and suppress apoptosis and cumulative damage, which selects for a malignant phenotype that has the ability to stimulate blood vessel growth and directly invade blood vessels and lymphatics. Melanoma synthesis, particularly involving pheomelanin, produces by-products, which may of themselves be carcinogenic. Detailed information is now available4 on the metabolic pathways and on the immune-suppressive effect of ultraviolet light on the skin. Many of the metabolic pathways involved in the development of the malignant phenotype are known and the interaction of sunlight with skin cell genetics is under intensive investigation. Particular attention has been placed on the CDKN2A gene and its protein products, p16 and p14ARF. Details of these genetic pathways are reviewed elsewhere in this journal by Graham Mann.

It is clear that ultraviolet light does not cause melanoma. Ultraviolet light is specifically related to susceptibility and predisposition. Figure 3 lists the known predisposing factors for melanoma and these are clearly related to ultraviolet light and genetics, but there are many questions about the interaction of ultraviolet light on genetically susceptible skin. These questions include:

  1. Given the excessive exposure to sunlight by the majority of white skinned Australians, why do so few get melanoma? One in 30 Australians will develop melanoma during their lifetime, whilst 29 others will not.
  2. Australians have on average more than 40 naevi and many Australians have hundreds of naevi, yet on any individual melanoma patient only one, or sometimes two, become malignant.
  3. Melanoma is quite common on areas of the skin not exposed to ultraviolet light and it also occurs on mucosal surfaces where ultraviolet light clearly does not play a role.
  4. Many people have all the risk factors for melanoma but do not get it, while some people with no risk factors do get it.
  5. Young people who get the majority of ultraviolet exposure get far less melanoma than older people who have much less exposure. 
  6. In southern Australia it is the recreational exposure of the affluent classes, which correlates with melanoma incidence, but this dose response relationship disappears in northern Australia where chronic exposure seems to be the predisposing factor.

Some of the anomalies in the ultraviolet story are attributed to the immunosuppressive effect of ultraviolet light on the skin. This could explain the lack of relationship between direct exposure and the development of melanoma, especially the site distribution of the melanoma, but there are many questions still unexplained about this immunosuppressive effect. The relatively low risk for immunosuppressed people and people with AIDS (Figure 3) is difficult to explain. Squamous cell carcinoma incidence is higher in most patients after immunosuppression, while melanoma incidence is only marginally increased. Recent studies have implicated ultraviolet A as a major cause of immunosuppression but this is yet to be generally accepted. The amount of ultraviolet light seems to be important with small doses improving skin immunity while large doses are depressant.

Figure 3: Clinical risk factors for melanoma

Clearly there is a yet undetermined factor involved in causation of melanoma. It is only possible to state that ultraviolet light and genetics play a role in predisposition to melanoma but certainly do not explain its occurrence. Diet, urban pollution, stress, viruses, radio waves and electromagnetic energy have all been suggested as the unknown factor X, but to date none of these has shown to have any significant association with melanoma incidence and mortality. 

Sunscreens are a part of the recommended protection methods against melanoma, but debate on the effectiveness of sunscreens in melanoma protection has filled the literature for the last 10 years.2 A consensus has developed that sunscreens do have a role in melanoma prevention provided they are used appropriately, contain UVA as well as UVB protection and are used as adjuvants to sun avoidance, particularly in the middle of the day (“11 to 3 stay under a tree”).

Genetic susceptibility also has many unanswered questions. It is clear that many genetically susceptible people, eg. redheaded freckled people with light-coloured eyes do not all get melanoma while many people with type 4 skin, brown hair and brown eyes do get melanoma. One interesting anomaly is the fact that the occurrence of melanoma in one twin is virtually never associated with melanoma in the other twin despite identical genes and similar UV exposure. 

Early diagnosis (secondary prevention)

Early diagnosis (secondary prevention) has been an outstanding success story, particularly in Australia. The risk of death from melanoma is dependent on tumour thickness, which is measured by the pathologists as the maximum vertical diameter of the melanoma from the granular cell layer of the skin to the deepest malignant cell excluding infiltration along natural tissue planes such as hair follicles and sebaceous gland ducts. The UICC/AJCC classification of melanoma thickness is now generally accepted worldwide and is as follows:

TIS – In situ melanoma (no invasion)
T1 – Melanoma – 1mm (thickness)
T2 – Melanoma 1.1-2.0mm
T3 – Melanoma 2.1-4.0mm
T4 – Melanoma > 4mm

(The full AJCC/UICC classification can be found in Reference 2)

An important new biological characteristic of melanoma has recently been added to this classification system, surface ulceration. Surface ulceration is not traumatic ulceration but a histopathological finding where the skin surface over the melanoma is no longer evident. The UICC/AJCC classification has been modified with each category having an A or B sub-category. The A category means without ulceration and the B category indicates ulceration. The presence of this ulceration, the mechanism of which is unknown, significantly increases the risk that the melanoma will metastasise. Curiously enough the presence of ulceration of the primary tumour remains an important prognostic criteria, even when the patient already has lymph node involvement.

The largest increase in melanoma rates has occurred in early melanomas (T1). The thickness measurements in Australia have been falling every year since accurate measurement was available in the early 1980s and now the median thickness is around 0.7mm. In NSW, superficial spreading melanoma increased from 5.2/105/year in 1986 to 20.6/105/year in 1988, after which rates ranged from 19-23/105/year in 2002. Rates for nodular melanoma increased much more slowly, from 6.1 to 8/105/year between 1988 to 2003. A substantial peak in melanoma incidence occurred late in 1987 following a dramatic 60 Minutes program entitled “Goodbye Sunshine” (Figure 4). This program was generated by the Melanoma Foundation of the University of Sydney and led to the diagnosis of more than 500 new melanomas in the six months following the program.5 The downside of television footage has been the development of an unrealistic fear of melanoma in the general populace, evidenced by excessive attendance at skin cancer clinics for “mole checks”, even by people with no significant risk factors. The rates for all melanomas increased only marginally over the last 10 years, ie. by 15% in males and by 12% in females. These increases of less than 1.5% per year contrast dramatically with the 5-10% increases per year during the 1980s (Figure 5).

Figure 4: Age standardised incidence rates - NSW (1970-2005) Figure 5: Remoteness variation incidence and mortality

Some epidemiologists have suggested this large incidence increase of very early melanoma is artefactual and is caused by a large number of lesions, diagnosed as melanoma by pathologists, being  “non metastasising melanomas”, ie. melanomas which would not progress and might even regress if they were not excised.6 The most recent NSW data add some credence to this view in that people with little access to skin cancer clinics, dermatologists or major melanoma centres, have a lower incidence of melanoma than those for whom there is easy access for diagnosis of suspect skin lesions (Figure 5). 

The clinical diagnosis of melanoma is based on the A (asymmetry) B (border) C (colour) D (diameter) system developed by the New York School of Medicine.  However early diagnosis of melanoma has been substantially influenced by two recent developments. The first of these is the advent of surface microscopy or dermoscopy, which is detailed in this edition of Cancer Forum by Scott Menzies. Dermoscopy has demonstrated a significant improvement in the rate of diagnosis of early melanoma.7 Recent research7 suggests that automated diagnosis of melanoma on pigmented skin lesions may well be available in the near future.

The second influence on early diagnosis of melanoma has been the advent of skin cancer clinics staffed by general practitioners. Because of convenience, no necessity for referral and bulk billing, these clinics have been enthusiastically endorsed by the general population. This had led to a substantial increase in the number of pigmented lesions excised and has raised considerable difficulty for pathologists to determine what is actually a melanoma, so substantial over-diagnosis is possible. There is no doubt that the differentiation of early melanoma is difficult, even for more experienced pathologists. At the Sydney Melanoma Unit, reclassification of histopathologically diagnosed melanomas as benign and sometimes of dysplastic naevi as melanoma, is not exceptionally rare.

Unfortunately the appropriate clinical trial to answer the question of “non-metastasising melanoma” cannot be done. It is unlikely that any clinician would not excise these doubtful lesions given the consequences of failure to diagnose a potentially lethal lesion and the medico-legal complications of such an event.

Primary melanoma management

The management of primary melanoma has undergone substantial change since the disease was first described by William Norris, an English physician in 1820. Misconceptions about the behaviour of melanoma have led to substantial overtreatment of the disease. In 1857 Norris described an advanced melanoma and advocated extensive local surgery. Following that, in 1907 William Sampson Handley, on the basis of a single autopsy examination of a patient with advanced melanoma, advocated regional dissection and even amputation in selected cases. In 1908, Hogarth Pringle, also a prominent surgeon of that time, also recommended excision of the skin between the primary and the lymph node field (incontinuity dissection). These recommendations were accepted almost up to the present day, with wide local excision, radical node dissection and sometimes incontinuity resection being relatively standard approaches to melanoma up to the mid-1980s. By contrast, current therapy for 85% of patients is a limited local excision and, for only an additional 10% a lymph node; sampling by way of sentinel node biopsy is undertaken. Radical surgery is now confined to patients with locally advanced tumours and proven nodal metastatic disease. It must, of course, be conceded that Norris, Handley and Pringle and the many surgeons who followed their recommendations were dealing with melanoma patients presenting for treatment at a locally advanced stage. Survival in the first few years of the 20th century was around 15%. Survival at the present time in Australia exceeds 90%, clearly indicating the advanced nature of the disease being treated by the surgical pioneers.

The margins of excision of primary melanoma has decreased regularly since the turn of the 20th century, when “dinner plate” excisions measuring at least 5cm in diameter requiring an extensive skin graft were standard practice. At that time it was felt that flap closure, although cosmetically more acceptable, might delay diagnosis of local recurrence and therefore was not recommended, so many patients had large unsightly skin grafts. However, subsequent research has shown that flap closure does not facilitate local recurrence. The necessity for wide excision was based on a high local recurrence rate, evident in early reviews of melanoma management and a hypothesis that melanocytes in the vicinity of a melanoma were unstable and recurrence was due to these melanocytes becoming melanomas following the removal of the clinically visible lesion.9,10,11 In the last 20 years this theory has lost credence.  It is now known that local recurrence is essentially due to “satellitosis”, ie. the tendency of melanomas, as they invade deeper into the dermis, to release cells into the surrounding tissue fluid. These cells invade local lymphatics outside the excision margin. This phenomenon is clearly related to tumour thickness. A further theory has been propounded12,13 that some of the local recurrences are due to metastasisation back to the primary melanoma site from an as yet undeclared systemic metastasis. However this is unlikely to be the cause in very many patients given that more than 50% of patients with local recurrence survive the disease. It is more likely that the systemic disease that does occur in many patients with local recurrence is the result of metastases from the recurrent tumour as it develops.14 Death from metastatic disease in these patients is correlated with tumour thickness of the locally recurrent nodule.

An unexplained fact about locally recurrent melanoma is that it can recur many years after the primary melanoma has been excised, without any evidence of systemic recurrence.

Most recent studies show that the margin of excision is related to local recurrence rates but survival is not influenced. A large recent study15 revealed that the loco-regional recurrence, including nodal recurrence, was related to width of excision but not to survival. This suggests strongly that intransit recurrence and nodal recurrence is due to melanoma cells in lymphatics outside the primary excision margin, which are removed when a wider excision is done but not excised with the narrow excisions.

Intransit recurrence

The development of the recurrence of melanoma between the primary melanoma and the lymph nodes is a difficult and devastating problem for the melanoma patient. Untreated, the disease may progress relentlessly to a situation in which the entire limb can be almost completely replaced by melanoma. This sometimes occurs in the absence of systemic disease.  Standard treatment for this type of recurrence is isolation perfusion, which was pioneered in the US by Krementz almost 50 years ago. It remained the treatment of choice until the last 10 years when a much less aggressive, but almost equally efficacious treatment of isolation infusion was pioneered in Europe and Australia. It is now the method of choice for intransit recurrence. The outcome of this treatment modality is reviewed by John Thompson in this edition of Cancer Forum. Because of the accessibility of the tumour to local therapies, many other techniques have been tried for the treatment of intransit metastases. These include simple surgical excision of the recurrence, injection of cytotoxic into the nodules, cryotherapy for superficial recurrences, injection of immunotherapeutic substances into the nodules, electroporation, a technique utilising electrical energy to open tumour cell pores to increase absorption of cytotoxic agents, local radiotherapy and, of course, amputation. None of these techniques has yet been successful to a level at which they can be recommended in place of isolation infusion. 

Lymph node management

The management of the lymph nodes of patients with melanoma has undergone the same correction of misunderstandings of tumour behaviour as occurred with primary melanoma. Elective lymph node dissection was debated for almost 100 years without conclusive proof of its efficacy and, in many cases, without precise knowledge of the lymphatic drainage pathways. With the advent of good lymphatic mapping (lymphoscintigraphy) it has become apparent that many of the earlier clinical trials of elective lymph node dissection, particularly axillary and neck dissections, were flawed by the selection of inappropriate node fields for excision. The selection of node fields was based on the long admired work of Sappey16, which determined lymphatic pathways by injection of mercury into cadavers. Modern  lymphoscintigraphy, using a radioactive labeled antimony trisulphide, has shown that at least 18% of melanomas on the trunk and many melanomas on the head and neck have lymph node drainage to nodes not predicted by clinical assessment, based on Sappey’s rather dogmatic lines!17

Elective lymph node dissection disappeared when sentinel lymph node biopsy was introduced by Donald Morton in the early 1980s. Sentinel node technique is detailed in this edition of Cancer Forum by John Thompson. However, even sentinel node biopsy, an elegant and technically challenging procedure, has not yet been shown to have survival value, although it is clearly the best prognostic indicator of melanoma behaviour. In this and other trials, the outcome for patients with positive sentinel nodes, which is followed by completion lymph node dissection, is statistically better than the outcome for patients who have dissection for clinically apparent nodal involvement but, this is not a randomly selected group comparison. 

The important question now is to determine which patients with a positive sentinel node should have completion lymphadenectomy. In the recent interim analysis of the Multicenter Selective Lymphadenectomy Trial (MSLTI), less than 20% of patients had nodes other than the sentinel node involved in the completion lymphadenectomy. A new international trial (MSLTII) has been set up to answer this question.

One of the other unanswered questions about malignant melanoma is the significance of reverse transcriptase polymerase chain reaction (RT-PCR) positive lymph nodes. Up to 30% of nodes negative to routine histopathological examination will contain RT-PCR positive cells. This fact mitigates against unqualified acceptance of the previous selective lymph node dissection trials and also of the recent MSLTI trial outcomes. RT-PCR was not included in the MSLTI trial design. However, RT-PCR is included in the MSLTII protocol. The prognosis for RT-PCR positive patients is slightly worse when these cells are detected in their nodes.

No studies to date have confirmed that melanoma cells in lymph nodes are necessarily progressive. It remains possible that, in some people, nodal metastatic disease may be protective and this could explain the lack of survival value for nodal surgery when compared to observation regimens. A clinical trial to assess this possibility is unlikely.

Adjuvant therapy

Immunotherapy of melanoma is reviewed elsewhere in this edition of Cancer Forum by Peter Hersey. The concept that the body’s natural immunity to melanoma can be harnessed to prevent recurrence of locally advanced and nodal melanoma is attractive, as is the view that immunotherapy may be effective even for systemic disease. Unfortunately, to this date adjuvant therapy for thick primary melanomas and nodal disease has been disappointing and for systemic metastatic disease even less satisfactory. The Sydney Melanoma Unit began immunotherapy trials more than 20 years ago using a variety of immune stimulants such as bisdiazobenzadine and gamma globulin coupled with irradiated melanoma cells, and a variety of approaches using Bacillus Calmette-Guérin (BCG). BCG was also used as an adjuvant in a large international adjuvant trial undertaken by the WHO Melanoma Group.  None of these earlier trials had any significant success. Over the last 20 years a large number of immunotherapy and chemotherapy adjuvant trials have been undertaken but, to date no regimen has substantially altered the prognosis for this group of patients. At the present time all adjuvant regimens are only justified in the context of a clinical trial. Similarly, immunotherapy in the presence of established systemic disease has so far been successful only in a small number of individual patients. 

Disseminated melanoma

Therapy for disseminated melanoma is reviewed in this edition of Cancer Forum by Richard Kefford. In summary, the management of disseminated melanoma remains unsatisfactory. Despite a multitude of studies with single agent chemotherapy, multiple agent chemotherapy and biochemotherapy, the outcome for patients with disseminated melanoma remains poor. The best survival for patients with disseminated melanoma occurs where the disease manifestation is a solitary nodule in a single organ or where a small number of metastatic nodules can be resected. In this instance, particularly in the lung, a long-term benefit can be achieved. For this reason most major melanoma centres encourage an aggressive surgical policy and metastatic melanoma is resected where the tumour burden is low. This is often followed by an experimental immunotherapy protocol within the clinical trial setting.
At the present time in the absence of a worthwhile standard therapy for melanoma, most centres encourage patients with disseminated disease to enter clinical trials of new agents.

Conclusion

Despite many journeys down the wrong pathway, the outlook for melanoma patients has improved steadily since the days of Norris, Handley and Pringle. The situation at the present time is moderately satisfactory with 90% of patients presenting with primary melanoma being cured by surgery. This is a 70% improvement since the early 1900s. Most of these patients (80%) will be cured by local surgery only. A further 15% will undergo biopsy of a lymph node, 15% of these will have a positive node and more than 50% of node positive patients will be cured by node dissection. The remaining patients are the major problem for melanoma management worldwide. However, there is a large and increasingly active research effort into finding a cure for disseminated melanoma. With the passage of time these efforts will undoubtedly lead to the desired outcome for most these patients. 

References

1. Cancer in NSW. Incidence and Mortality 2003.  NSW Central Cancer Registry – Cancer Institute NSW 2005.

2. McCarthy WH. The Australian experience in sun protection and screening for melanoma. J Surg Oncol 2004; 86:236-45.

3. Sinclair C, Borland R, Davidson N et al. From slip! slop! slap! to sunsmart: a profile of a health education campaign. Cancer Forum 1994;18:183-7.

4. Thompson JF, Scolyer RA, Kefford RF. Cutaneous melanoma. Lancet 2005;365:687-703.

5. Theobald T, Marks R, Hill D, Dorevitch A. “Goodbye Sunshine”: effects of a television programme about melanoma on beliefs, behaviour and melanoma thickness. J Am Acad Dermatol 1991; 25:717-23.

6. Burton RC, Armstrong BK. Recent incidence trends imply a nonmetastasising form of invasive melanoma. Melanoma Res 1994; 4:107-13.

7. Westerhoff K, McCarthy WH, Menzies SW. Increase in the sensitivity for melanoma diagnosis by primary care physicians using skin surface microscopy.  Br J Dermatol 2000; 143:1016-20.

8 Davis NC, Shaw HM, McCarthy WH. Melanoma: an historical perspective.  In: Textbook of Melanoma. JF Thompson, DL Morton, BBR Kroon (eds). Martin Dunitz, London, 2004.

9. Olsen G. The malignant melanoma of the skin. New theories based on a study of 500 cases. Acta Chir Scand 1966; 365(suppl) 1-222.

10. Wong CK. A study of melanocytes in the normal skin surrounding malignant melanomata. Dermatologica 1970; 141:215-25.

11. Cochran AJ. Studies of the melanocytes of the epidermis adjacent to tumors. J Invest Dermatol 1971; 57:38-43.

12. Heenan PJ, Ghaznawie M.  The pathogenesis of local recurrence of melanoma at the primary excision site. Br J Plast Surg 1999; 52:209-13.

13. Heenan PJ. Local recurrence of melanoma. Pathology 2004; 141:215-25.

14. McCarthy WH. Melanoma: margins for error – another view. ANZ J Surg 2002; 72:304-6.

15. Thomas JM, Newton-Bishop J, A’Hern R et al. Excision margins in high-risk malignant melanoma.  N Engl J Med 2004; 350:757-66.

16. Sappey MPC. Anatomie, physiologie, pathologie des vaisseux lymphatiques considéres chez l’homme et les vertèbres.  A DeLahaye, E Lecrosnier (eds). Paris, 1874.

17. Uren RF, Thompson JF, Howman-Giles RB. Lymphatic Drainage of the Skin and Breast: Locating the Sentinel Nodes. Harwood Academic Publishers, Amsterdam, 1999

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