Authors:

Riccardo A. Audisio

Roger Olofsson Bagge

The first documented case of a secondary melanoma deposit was reported in 1787 by the Scottish surgeon John Hunter (1728–1793), although he never explicitly identified the disease as melanoma. Hunter's original specimen, No. 219, is preserved in the Hunterian Museum of the Royal College of Surgeons of England. The specimen was taken from a 35-year-old man who had a recurrent mass behind the angle of his lower jaw. The lump was excised but recurred locally three years later. The metastasis grew slowly until it was struck with a stick during a drunken brawl, causing it to double in size over the next few weeks. After removing the lump, Hunter reported that “on making a section of it, the original tumor was white in its substance and of a uniform texture; the part formed since the accident was spongy and soft, of a dark black appearance, resembling what is commonly termed a cancerous fungous excrescence” ^[1]. Several years later, in 1968, Bodenham (2) re-examined the same specimen and ^[2] reported that microscopic examination confirmed that the specimen showed “lymphatic tissue infiltrated by very large melanotic sarcoma cells” – presumably a secondary melanoma metastasis with no known primary tumor.

In a lecture presented to the Faculté de Médecine de Paris in 1804, and later published in 1806, the French physician René Laennec (1781–1826) ^[3] first described melanoma as a disease entity, although credit was given to Dupuytren instead. Guillaume Dupuytren ^[4] claimed that he had noted the disease several years before Laennec’s publication and mentioned it in his lectures. He called the condition "cancer noire," or black cancer, although most others at that time, including Laennec, believed melanosis to be an incidental product of degeneration. He observed that melanoma metastases in the mediastinal and hilar lymph nodes were distinct from the more common black bronchial glands, whose colour he recognized as being due to a large quantity of inhaled carbon.

He also described melanomas affecting the liver, lungs, eye, pituitary gland, stomach, and peritoneal surface. Additionally, he observed that melanotic deposits in the lungs did not cause the same hectic fever associated with tuberculosis, a common cause of death at the time. Laennec first used the term "melanosis" in an 1812 issue of the Bulletin de la Faculté de Médecine de Paris. The word is derived from the Greek word for "black." The first case of melanoma described in the English literature was recorded in 1820 by William Norris (1792–1877). He initially referred to it as a “case of fungoid disease,” but he accurately described a patient who died of disseminated melanoma. Norris later declared that this patient was “the first genuine good case of melanoma,” as the following description attests. ^[5]. William Norris was the first to study melanoma in depth. Norris observed that neither surgery nor medical treatments were effective once the melanoma had widely dispersed. To control recurrence, he advocated for a wide excision of the tumor along with the surrounding unaffected skin, believing this approach to be more effective in preventing the tumor's regrowth ^[6].

Still in England, a case report published in 1851 in the Lancet ^[7] describes a 45-year-old woman with secondary melanoma of the groin that occurred 2 years after excision of a dark tumor on the mons veneris. The secondary deposit was excised, “the patient having been rendered insensible by chloroform. The tumour was about the size of an orange and when cut into presented all the characters of melanosis. The patient progressed favourably and was discharged well approximately 6 weeks after the operation.” This is apparently the first published case report involving surgical excision of a metastatic melanoma, although Hunter’s pathology specimen was obtained by surgical excision (1787).

The first documented North American case of melanoma was described by Isaac Parish: in 1837 he reported of a 43-year old widow, who was admitted to Wills Hospital in Philadelphia, PA.

The English surgeon James Paget (1814-1899) has to be mentioned since he was the first to report a relatively “large” series of 25 patients with “melanoid cancer”: 17 women and 8 men, aged between 20 and 60 years. Paget also described what we now refer to as superficial spreading melanoma, using the following words: “The patient is usually aware of a time at which a mole, observed as an unchanging mark from birth or infancy, began to grow. In some instances, the growth is superficial, and the dark spot acquires a larger area and appears slightly raised by some growth beneath it: in other cases, the mole rises and becomes very prominent or nearly pendulous”^[8].

One more British physician deserves mention: William Sampson Handley (1872–1962), whose recommendations formed the basis for melanoma treatment for over 50 years. His approach remained influential until the effectiveness of extensive resection of primary melanomas and lymphadenectomy began to be questioned. Handley recommended and illustrated operations for “melanotic sarcoma of the skin. When malignant melanoma arises in the digits, amputation should be performed at once. The flaps should never be cut so as to include any skin within, at least, one inch of the tumour.”

Nowadays, melanoma is usually detected by skin inspection, but the diagnosis is confirmed with an excisional biopsy and importantly, this fairly minor operation will cure most thin melanomas.

Local anaesthesia is injected into the area to numb it before the excision. The pigmented lesion is then excised, along with a small (typically 2-5 mm) amount of skin around the edges. The wound is usually stitched back together afterward, leaving a small scar. The removed sample is then reviewed with a microscope verify the diagnosis and to guide further treatment. All patients with a confirmed melanoma will then undergo a wide-local excision with a 1-2 cm margin around the scar from the first excision. This is based on the old recommendation from William Handley, to always remove an extra inch of healthy tissue. However, how wide this margin should be, or if it is even necessary at all, can be questioned.

Natale Cascinelli, a surgical oncologist from Milan and President of the WHO Melanoma Programme, investigated on melanoma since the 1970’s, looking into research opportunities ^[9], lymphocyte toxicity ^[10], multiple primary melanomas ^[11], and comparing the outcomes of different regimens ^[12]. In the ‘80s he gained prominence by leading international research projects ^[13] including randomized trials of adjuvant chemotherapy, immunotherapy, or immunochemotherapy on patients with melanoma. He also pioneered regional perfusion in melanoma ^{[14] [15]}. The focus was then moved to study the width of the resection margins ^[16]. A randomized prospective study was therefore set up to assess the efficacy of narrow excision (1 cm margin) for primary melanomas no thicker than 2 mm. Narrow excision was performed in 305 patients, and wide excision (margins of 3 cm or more) was performed in 307 patients. There was no difference between the groups on subsequent development of metastatic disease involving regional nodes (4.6% vs 6.5%) or distant organs (2.3% vs 2.6%). Only three patients had a local recurrence as a first relapse, all had undergone narrow excision, and each had a primary melanoma with a thickness of 1 mm or more. The absence of local recurrence in the group of patients with a primary melanoma thinner than 1 mm and the very low rate of local recurrences indicate that a narrow excision margin is a safe and effective procedure for such patients ^[17]. After this first trial, there has been an additional five trials exploring different excision margins, one from UK (1 vs 3 cm) ^{[18] [19]}, one from the Intergroup Melanoma Surgical Trial in US (2 vs 4 cm) ^{[20] [22]}, one from the French Group of Research on Malignant Melanoma (2 vs 5 cm) ^[23] and two from Swedish Melanoma Study Group (2 vs 5 cm and 2 vs 4cm, respectively) ^[24]. In a recent meta-analysis summarizing these six trials, there was no difference in locoregional recurrences or survival between the wide or more narrow margins investigated ^[25]. Currently there is one ongoing trial, the MelMarT trial, an international effort randomizing 2,998 patients from 176 sites in nine different countries to 1 vs 2 cm margin ^{[26] [27]}. This trial is anticipated to be fully accrued in early 2025, but the first reports on recurrences and survival will then take additional time. The next step will be to question if there is really a role for a wide local excision if the first diagnostic excision was radical. The first trial examining this is currently started in Sweden, the Wise vs Wide trial, that will include approximately 2,500 patients with a thin melanoma and randomize these to a wide local excision of 1 cm or no wide local excision at all ^[28]. This might mark the first step towards the end of a long-standing tradition based on the more than 100-year old notion of Dr Handley that a melanoma should be excised with a 1-inch margin. A notion that might have been correct of that time when all patients presented with more advanced tumours and no other treatments were available.

Bibliography

Rebecca, Vito W, Sondak, Vernon, Smalley, Keiran S. « A Brief History of Melanoma: From Mummies to Mutations », Melanoma Res, 2012 Apr;22(2):114–122.

Sober, A.J., Balch, C.M., Thompson, J.F., Kirkwood, J.M. (2020). A History of Melanoma: From Hunter to Morton. In: Balch, C., et al. Cutaneous Melanoma. Springer, Cham.