Current Management of Melanoma

In the last decade, the clinical management of melanoma has become more effective: basic clinical studies, randomized clinical trials, and new drugs have greatly improved the prognosis of patients, both in the initial and in the advanced stage of the disease.

This book offers a wide and up-to-date overview of the multidisciplinary treatment of melanoma. Among the topics discussed, there are the role of sentinel lymph node biopsy and the radical dissection, following the results of international randomized clinical trials, in particular MSLT-II. The last chapters are focused on new medical treatments in adjuvant, neoadjuvant, and metastatic settings.

The volume has been written for all the professionals involved in melanoma treatment, such as general surgeons, surgical oncologists, medical oncologists, dermatologists, radiotherapists, and nuclear medicine physicians.

• Language: English
• Publisher: Springer
• Release date: Oct 15, 2020
• ISBN: 9783030453473

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© Springer Nature Switzerland AG 2021

F. Cafiero, F. De Cian (eds.)Current Management of MelanomaUpdates in Surgeryhttps://doi.org/10.1007/978-3-030-45347-3_1

1. The History of Melanoma: From Incas to the Third Millennium

Ferdinando Cafiero¹  , Matteo Mascherini²   and Pietro Paolo Tavilla³  

(1)

Surgery Unit 1, Department of Surgery, IRCCS Ospedale Policlinico San Martino, Genoa, Italy

(2)

Surgical Clinic Unit 1, Department of Surgery, IRCCS Ospedale Policlinico San Martino, Genoa, Italy

(3)

Plastic and Reconstructive Surgery at Dermatologic Clinic, Department of Specialist Medicine, IRCCS Ospedale Policlinico San Martino, Genoa, Italy

Ferdinando Cafiero (Corresponding author)

Email: [e-mail]

Matteo Mascherini

Email: [e-mail]

Pietro Paolo Tavilla

Email: [e-mail]

Keywords

MelanomaHistory of medicineDonald MortonSentinel lymph nodeWide excision

1.1 From Ancient Times to the Beginning of the Twentieth Century

The first evidence of melanoma belongs to the diffuse melanotic metastases found in the skeletons of pre-Columbian mummies in Peru, radiocarbon dated to the fourth century BC [1].

In 1787, John Hunter, working in London, successfully removed a recurrent melanoma from the jaw of a 35-year-old man. Hunter reported the tumor to be soft and black and labeled it as a cancerous fungous excrescence [2]. The preserved tumor was later diagnosed as a melanoma in 1968, and is still housed in the Hunterian Museum at Lincoln’s Inn Fields in London, UK [3].

René Laennec, the inventor of the stethoscope, was the father of the term mélanose, from the ancient Greek μέλᾱς, μέλαινᾰ, μέλᾰν. During a lecture in Paris in 1804, he used this noun to describe lung metastases [4].

The natural history of the disease was first described by William Norris in 1820. In his Case of fungoid disease he particularized a case of a patient affected by melanoma, from local recurrence to death for metastases. He wrote When removed, it recurred rapidly in the scar; groin nodal metastases preceded the development of multiple subcutaneous lesions, a cough, and death [5]. Norris continued to collect several cases of melanoma and, in his paper published in 1857, he proposed a wide excision to prevent local recurrence. He was also the first to notice the correlation between pale phototype or high number of nevi and incidence of melanoma [6].

In 1840, Samuel Cooper wrote The first lines of the theory and practice of surgery and observed that the advanced stages of melanomas were untreatable, stating the only chance for benefit depends upon the early removal of the disease [7].

In 1851, Fergusson performed the first groin radical dissection for lymph nodal metastases. The surgical intervention was published in The Lancet [8].

In 1853, Sir James Paget described the transition from the radial growth to the vertical growth phase [9], and he identified this process as the breaking point for the development of distant recurrence.

Sir Jonathan Hutchinson made the first description of subungual melanoma (1857) and determined that early amputation is demanded to prevent a high risk of recurrence of disease.

In the second half of nineteenth century, the interest in lymph node recurrence and surgery increased. Based on previous studies and publications, the first site of melanoma metastases seemed to be the locoregional nodal basin. The development of anesthesia helped in the surgical treatment, which could be more invasive than in the past.

In 1892, Herbert Snow, a London surgeon, proposed that all melanoma should be treated by a wide local excision and anticipatory gland excision. Snow stated that it is essential to remove, whenever possible, those lymph glands which first receive the infective protoplasm, and bar its entrance into the blood, before they have undergone increase in bulk and that palpable enlargement of these glands is unfortunately but a late symptom of deposit therein: by the time it occurs there is almost always implication of deeper organs or tissues [10]. On the basis of this concept of anticipation of disease, in the twentieth century some trials tried to compare prophylactic or elective lymph node dissection (ELND) to observational follow-up.

In 1907, William Handley strongly recommended that the wide excision should be of 2 in. (5 cm) laterally and should include 2 in. (5 cm) of subcutaneous layer, to prevent the dissemination of disease through the just discovered lymphatic vessels [11]. This led to a very aggressive approach to treating the primary tumor, which lasted for more than half a century. The trend was similar to breast cancer treatment, in which Halsted advocated radical mastectomy as the best way to prolong survival.

For many years, a wide excision of more than 2 cm, regardless of local stage, with or without prophylactic lymph nodal dissection, was the gold standard for melanoma treatment.

1.2 Recent History

The first isolated limb perfusions (ILP) were performed in the 50s by the North American surgeons Creech and Krementz, for palliation of in-transit disease as an alternative to amputation; after a difficult start due to toxicity of the drugs escaping into the systemic circulation, the surgical technique improved together with patient outcomes.

In the 60s and 70s Wallace Clark and Alexander Breslow proposed a standard scale to assess the prognosis of melanoma based upon the histological examination. Clark based his scale on the level of invasion from epidermis, to dermis and subcutaneous tissue [12]. Breslow stratified melanoma patients considering the total vertical depth of the melanoma from the granular layer of the epidermis to the area of deepest penetration into the skin [13, 14]. In both classifications, the lower the level or depth of invasion, the better the prognosis. With regard to the Clark and Breslow levels, clinicians could select patients for prophylactic lymph node dissection.

According to the relation between local stage and prognosis, Handley’s very wide excision was thought to be excessive and several randomized, prospective trials were performed:

WHO trial: 1 cm vs. 3 cm (Breslow <2 mm)

Intergroup melanoma trial: 2 cm vs. 4 cm (Breslow 1–4 mm)

Swedish trial: 2 cm vs. 5 cm (Breslow 0.8–2 mm)

European trial: 2 vs. 5 cm (Breslow <2 mm)

All these trials confirmed that adequate treatment of primary melanoma is linked to a better overall survival, but narrower margins than those proposed by Handley were equally safe.

1.3 The Present

Following the less-is-more approach, similarly to breast cancer history, lymph node surgery has become more conservative. In 1992, Donald Morton (Fig. 1.1) described the technique of sentinel lymph node biopsy (SLNB) [15]. Using a blue dye and then other markers, surgeons could perform a minimally invasive operation in order to stage patients affected by melanoma and stratify those who could benefit from a radical dissection, also named completion lymph node dissection (CLND). Morton’s sentinel lymph node completely changed clinical practice in melanoma and about 80% of patients affected by melanoma were able to avoid the sequelae of radical dissection. Parallelly, Armando E. Giuliano promoted the SLNB in breast cancer in 1994, to stratify patients who would not benefit from a dissection [16].

../images/485096_1_En_1_Chapter/485096_1_En_1_Fig1_HTML.jpg

Fig. 1.1

Dr. Donald Morton (1934–2014), the pioneer of sentinel lymph node biopsy (by courtesy of John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, CA, USA)

1.4 Conclusion

In less than a 100 years, surgery for melanoma has been revolutionized. More recently, even the treatment of pathologically positive lymph nodes has completely changed. Completion lymph node dissection is now reserved for a limited number of patients. Effective systemic treatment in stage IV patients is used as adjuvant therapy instead of CLND. On the other hand, more patients can now benefit from surgery in advanced stage disease. The next chapters of this book will explain the state of the art of melanoma clinical practice.

Acknowledgments

This chapter is partially inspired by Rebecca VW, Sondak VK, Smalley KS. A brief history of melanoma: from mummies to mutations. Melanoma Res. 2012;22(2):114–22.

References

1.

Urteaga O, Pack G. On the antiquity of melanoma. Cancer. 1966;19(5):607–10.Crossref

2.

Home E. Observations on cancer, case VIII. London: 1805.

3.

Bodenham DC. A study of 650 observed malignant melanomas in the South-West region. Ann R Coll Surg Engl. 1968;43(4):218–39.PubMedPubMedCentral

4.

Laennec RTH. Extrait du Mémoire del M. Laennec sur les mélanoses. Bulletin de l'École de Médecine de Paris. 1806;Seconde Année(II):24–6. (reprinted in: Bulletins de la Faculté de Médecine de Paris, Première Série, Tome Premier. Paris: Imprimerie de Migneret; 1812).

5.

Norris W. Case of fungoid disease. Edinb Med Surg J. 1820;16(65):562–5.PubMedPubMedCentral

6.

Norris W. Eight cases of melanosis with pathological and therapeutical remarks on that disease. London: Longman; 1857.

7.

Cooper S. The first lines of the theory and practice of surgery. London: Longman; 1840.

8.

Fergusson A. Recurrence of a melanotic tumour; removal. Lancet. 1851;57(1449):622.

9.

Paget J. Lectures on surgical pathology. London: Longman, Brown, Green and Longman; 1853. p. 639.

10.

Snow H. On melanotic cancerous disease. Lancet. 1892;140(3607):872–4.Crossref

11.

Handley WS. On the pathology of melanotic growths in relation to their operative treatment. Lancet. 1907;169(4362):927–33.Crossref

12.

Clark WH. A classification of malignant melanoma in man correlated with histogenesis and biologic behavior. In: Montagna W, Hu F, editors. Advances in biology of the skin, the pigmentary system, vol. VIII. London: Pergamon Press; 1967. p. 621–47.

13.

Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970;172(5):902–8.Crossref

14.

Breslow A, Macht SD. Optimal size of resection margin for thin cutaneous melanoma. Surg Gynecol Obstet. 1977;145(5):691–2.PubMed

15.

Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127(4):392–9.Crossref

16.

Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg. 1994;220(3):391–8.Crossref

© Springer Nature Switzerland AG 2021

F. Cafiero, F. De Cian (eds.)Current Management of MelanomaUpdates in Surgeryhttps://doi.org/10.1007/978-3-030-45347-3_2

2. Epidemiology, Prevention and Clinical Diagnosis of Melanoma

Pietro Quaglino¹  , Paolo Fava¹  , Paolo Broganelli¹  , Lorenza Burzi¹  , Elena Marra¹  , Simone Ribero¹   and Maria Teresa Fierro¹  

(1)

Dermatologic Clinic, Department of Medical Sciences, University of Turin, Turin, Italy

Pietro Quaglino (Corresponding author)

Email: [e-mail]

Paolo Fava

Email: [e-mail]

Paolo Broganelli

Email: [e-mail]

Lorenza Burzi

Email: [e-mail]

Elena Marra

Email: [e-mail]

Simone Ribero

Email: [e-mail]

Maria Teresa Fierro

Email: [e-mail]

Keywords

Melanoma epidemiologyMelanoma preventionDermoscopySuperficial spreading melanomaNodular melanoma

2.1 Epidemiology

The worldwide distribution of melanoma is characterized by significantly higher incidence rates in Australia, New Zealand and North America, followed by Northern Europe and, with decreasing values, Southern Europe. Melanoma is rare in Africa, South America, and Asia.

According to the GLOBOCAN report, among 38 specific cancers worldwide, melanoma ranks 23rd for estimated incidence of new cases in 2018, with 287,700 new cases and an age standardized ratio of 3.1 per 100,000 and a slight predominance among males over females (150,700 vs. 137,000). Estimated melanoma deaths in the same year were 60,700, more in males than in females [1]. In Europe a total of 144,200 new estimated cases were evaluated for 2018, figures that make melanoma the sixth most common tumor in Europe after breast, colorectum, lung, prostate and bladder [2].

A significant part of these cases can be attributed to exposure to ultraviolet radiation (UVR). Globally, an estimated 168,000 new melanoma cases worldwide were attributable to excess UVR in 2012. This corresponds to 75.7% of all new melanoma cases, meaning that there would be approximately 151,000 fewer melanoma cases worldwide in the case of correct sun exposure [3].

The incidence rates of melanoma continue to rise in most European countries (primarily Southern and Eastern Europe), whereas in other parts of the world such as Australia, New Zealand, the US, Canada, Israel and Norway, the rates have become fairly stable (US, Canada and Norway) or decreased (Australia, New Zealand). These trends were mainly identified in younger people (25–44 years) whereas a constant increase is found in the generations born before 1950 [4].

As to Italy, according to the AIRTUM 2018 data (available at www.​AIRTUM.​com), there has been a steady increase in the incidence of melanoma since the 90s (values of 5–7/100,000 per year) up to now (20–22/100,000 per year). According to the analysis by age distribution, even if melanoma is more frequent in patients aged more than 50 years, in younger people from 0 to 49 years melanoma represents the second most common tumor in males and the third in females. Moreover, it is the most frequent tumor diagnosed during pregnancy, accounting for 30% of all neoplastic diagnoses in that period [5].

It is important to note, however, that the increase in melanoma has been widely confirmed to be mainly driven by thin melanomas, whereas the incidence of thick melanomas shows only a slow increase. Trends for melanoma in situ show a marked and constant increase, representing today about 40% of all diagnosed cases but not included in cancer registries [6]. Part of the rise in incidence may be explained by improved screening. Early melanoma diagnosis saves lives but there is a stable percentage of melanoma tumors that kill, with very little changes in mortality over time.

2.2 Prevention

It is well known that an incorrect sun exposure with sunburns is one of the main risk factors for melanoma, and therefore primary prevention campaigns for education on correct sun exposure represent a major tool for reducing the rising incidence of melanoma. A systematic review [7] concluded that educational approaches to increasing UV-protective behaviors were effective when implemented in primary schools and in recreational settings, and that insufficient evidence was available when implemented in other settings. However, the literature data are controversial as to the true efficacy of these educational interventions in modifying sun exposure behavior.

The nationwide French and German studies of Sancho-Garnier et al. [8] and Stover et al. [9] demonstrated an early improvement in children’s attitudes whereas other studies failed to confirm these results also in high-risk countries [10]. Modest changes in sun exposure were also reported following an intensive education campaign in the US among adolescents and students [11]. As to Italy, the study SoleSi SoleNo failed to demonstrate any effect in reducing sunburns or improving sun protection behavior of an educational intervention involving children, parents and teachers [12]. Interestingly, a long-term study from Australia reported an early improvement followed by a stabilization and thereafter a decline in sun protection habits in the same cohort [13]. Together, these data suggest that probably the best strategy is represented by continuous educational messages from multiple sources leading to an improvement in sun exposure behavior as a cumulative result of a number of low-intensity interventions.

The impact of skin cancer screening and secondary prevention campaigns on melanoma incidence and mortality is still debated. A recent meta-analysis supported a potential role, even though the strength of the evidence was low and biases could not be ruled out. The data suggest that implementation of skin cancer screening could lead to an increased incidence of in situ and invasive skin cancer, with increasing rates of thin melanoma and decreasing rates of thick melanoma, but a lower incidence of invasive melanoma after cessation of screening. A significant reduction in melanoma mortality was shown by some studies [14]. In 2003, a skin cancer screening campaign based on total body skin examination was launched in the federal state of Schleswig-Holstein, Germany (SCREEN study), leading to a reported 48% decline in melanoma mortality in 2008. In the same year, skin screening was extended to the rest of Germany. The introduction of nationwide skin cancer screening in 2008 has not yet led to any measurable decline in mortality due to melanoma [15].

2.3 Risk Factors

Risk factors are divided into three groups:

Family and genetics

Skin features (nevi, phenotype/phototype—see Table 2.1)

Acquired.

Table 2.1

Fitzpatrick skin type classification

The current Fitzpatrick skin type classification has six types ranging from extremely fair (Type I) to very dark (type VI)

Source: Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol. 1988;124(6):869

The first two are called intrinsic or constitutional, while the third group consists of extrinsic factors (including environmental ones). It is evident that these three groups of risk factors are interrelated, as a greater or lesser sensitivity to potential harmful effects of solar radiation is determined by the endogenous risk factors [16–18] (Fig. 2.1).

../images/485096_1_En_2_Chapter/485096_1_En_2_Fig1_HTML.png

Fig. 2.1

Cutaneous melanoma risk factors

The first two groups of risk factors identify the patients to be referred to dermatological check-ups for the early diagnosis of melanoma (secondary prevention), while the third group identifies risk factors that must be taken into consideration in prevention campaigns for awareness-raising of the population (primary prevention).

Family and genetic risk factors consist of the presence of melanoma cases in the family and the finding of mutations of susceptibility genes for melanoma (such as CDK4 in particular).

The phenotype/phototype identifies the characters of the skin that are related to a different risk of developing melanoma, such as race, cutaneous phenotype (color of the skin, eyes, hair), phototype (which identifies the reactivity of the skin to UVR, the risk of burns and the ability to tan), and the presence of numerous or atypical nevi. The characteristics associated with a greater risk of developing melanoma are represented by the presence of numerous solar lentigines, red or blond hair, poor ability to tan, tendency to sunburn. The number of nevi (and in particular the number of atypical nevi) is an important predisposing factor, regardless of size and distribution. In fact, melanoma arises on a pre-existing acquired or congenital melanocytic nevus in 22% to 57% of cases. Considering the common occurrence of nevi in the general population, and the relatively low incidence of melanoma (although increasing), the estimated possibility that a nevus turns into melanoma is not high (about 1/7000 nevi). However, the number of nevi is a factor associated with an increased risk of developing melanoma even on healthy skin, especially if the size of the moles is >5 mm. The most important extrinsic risk factor is represented by exposure to natural and/or artificial sources of UVR. The onset of melanoma is related to intense but intermittent sun exposure—especially of skin areas not usually exposed to light—and to sunburns, particularly in childhood and adolescence. Only lentigo maligna melanoma would depend on the cumulative dose of UVR. The association between melanoma and use of tanning lamps was examined in a recent meta-analysis that reported a 75% increase in the risk of developing melanoma in subjects aged <35 years who use sun beds [19, 20]. It has also been recently shown that failure to use sun protection factors is a risk factor for the development of melanoma [21].

2.4 Clinical Features and Growth Pattern of Primary Melanoma

Melanoma occurs at a pre-existing acquired or congenital melanocytic nevus or in contiguity with it, in a percentage of cases varying between 20% and 50%. Up to 10–15% of melanoma patients may develop multiple cutaneous melanomas. Melanomas in sites other than the skin may occur in 10% of cases and for the most part they occur at the ocular level (conjunctiva or choroid) or at mucosal level (oral cavity, nasal mucosa, vulva and vagina, anus and anorectal canal, and penis). Melanoma can also occur at the nail level. Primary melanomas originating from the internal organs (esophagus, bronchi, bladder, adrenal glands, leptomeninges) are extremely rare. In a percentage varying from 1% to 12% of cases, the site of onset of melanoma is not recognizable and therefore a diagnosis of melanoma is made from the finding of a metastasis, usually lymph nodal, in the absence of a clinically evident primitive melanoma (the so-called unknown primary melanoma).

The clinical-morphological evolution of cutaneous melanoma can develop through two different modalities (Figs. 2.2 and 2.3; Table 2.2).

../images/485096_1_En_2_Chapter/485096_1_En_2_Fig2_HTML.png

Fig. 2.2

The multifaceted clinical features of melanoma: (a, b)