Is nail melanoma really rare?

NAIL MELANOMA IS NOT RARE

Non-acral melanomas (NAM) in skin of colour are rare, but do occur. Nail melanomas are the most common melanoma type in dark-skinned individuals and Asians. In terms of absolute numbers, NAM may occur approximately as often as ALMs and NUMs in Caucasians; however, the proportion of NUMs is higher (upto 20–50% of all melanomas) in Africans, African Americans, native Americans and Asians.^[6,7] Nevertheless, it has to be admitted that reports of NUMs from dark-skinned population are uncommon and mostly recent. Specifically, NAMs account for approximately 0.18–8% of cases in Europeans, 10–23% in Asians, with 40% in Japan,^[7] and >25% in African Americans. A 10-year survey of 4 regions in the United Kingdom demonstrated that NUM represented 1.% of melanomas (incidence of 1/million of population per year).^[8] In the German Melanoma Registry, ALMs constitute about 6.5– 8% of all cutaneous melanomas; while NUMs constitute 1.8% (C Garbe, personal communication, 2014). In Japan, 8.3% of all melanomas are NUMs.^[7] There is a clear-cut trend towards more reports on NUM in the literature. This is also evident in India, where altogether only 7 NUMs have been reported over a period of 23 years, all being far-advanced tumours [Figure 1a and b].^[9-12] However, a cautious estimate of one NUM per million population in India would yield an incidence of more than 1400 NUMs.

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Figure 1:

Right middle fingernail of an Indian immigrant to Switzerland with a far-advanced subungual melanoma. (a) Dorsal view. (b) Acral view. Note the massive increase in volume of the nail matrix and bed with a broad split of the nail plate, which is wider proximally than distally. (a) There is both Hutchinson as well as pseudo-Hutchinson sign on the proximal nail fold. (b) The Hutchinson sign is extending beyond the hyponychium.

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A simple calculation shows that rarity is a relative term. NUM in light-skinned Caucasians make up roughly 1.5–2.5% of all melanomas. The total surface of all 20 human nail fields is <1% of the body surface. Most of the nail melanomas are pigmented and derive from the matrix, which makes up about 15–25% of the nail field only. Thus, 1.1–1.9% of melanomas in Caucasians and 6–7% in Japanese, are derived from the nail matrix which itself constitutes roughly 0.2% (or less) of the body surface area. Hence, the nail matrix may be considered a hot spot for melanoma development!

The nail is overrepresented as a localisation for melanomas in light-skinned individuals; and is a preferred localisation for melanomas in Asians and Blacks! As people of colour outnumber light-skinned Caucasians; the absolute number of NUM in the world cannot be low, even though there appears to be an important underreporting.

The claim that NUM are rare is commonly used as an excuse for late diagnosis or misdiagnosis of the reported melanoma. Reports like “A 69-year-old woman with a chronic nail lesion was initially diagnosed as onychomycosis and treated with partial onychectomy without histological evaluation. The lesion persisted and subsequent dermatological evaluation revealed an ulcerated exophytic mass, which was confirmed as an acral nodular melanoma with a Breslow thickness of 7.5 mm.” may be difficult to explain^[13] The included figure in the report shows a pigmented tumour occupying the entire fingertip. It remains enigmatic how such a lesion can be diagnosed as onychomycosis. There are many more similar articles describing a wrong diagnosis of NUM.

NAIL MELANOMA DIAGNOSIS IS USUALLY NOT DIFFICULT

NUM is often diagnosed late, which is the main reason for its poor prognosis. As approximately three-quarters of NUMs of Caucasians are pigmented, their diagnosis is even easier than that of cutaneous melanomas. Brown streaks in the nail are pronounced in Caucasians but are often not taken seriously by the consulting physician [Figure 2]. Periungual pigmentation is not infrequent and indicates a long-standing process. Nevertheless, the melanoma is still very often in situ [Figure 3].

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Figure 2:

The right thumbnail of an 87-year-old man with an extensive subungual melanoma. Note that the longitudinal pigmentation is proximally wider than distally, which is a sign of rapid growth, and that there is a split formation just in front of the cuticle in addition to the round defect from a punch biopsy.

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Figure 3:

Melanoma in-situ of the right thumb nail of a 51-year-old female patient. Note the extensive periungual pigmentation that extends to the ulnar side of the distal phalanx, while the darker melanonychia is on the radial side of the thumbnail. (a) Irregular melanonychia, more pronounced on the radial side of the thumb nail. (b) Extensive periungual pigmentation, more pronounced on the ulnar side of the thumb’s distal phalanx.

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Why are there so many misdiagnoses and often year-long delays of treatment? This is because physicians often do not think of melanoma [Figure 4]! A recently acquired brown streak in the nail of an adult must evoke the suspicion of NUM, and all diagnostic measures necessary to confirm or exclude it should be carried out. It is important to remember that there are no blood and other laboratory tests for diagnosis. It can only be made with a biopsy and histopathology. Thus, awareness regarding NUM is of utmost importance.^[14]

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Figure 4:

Long-standing advanced subungual melanoma of the left big toe in a 48-year-old female patient. There is severe nail dystrophy and periungual pigmentation on the proximal nail fold, extending over the hyponychium onto the tip of the toe.

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The list of initial wrong diagnoses considered in reported cases of NUM is long. It mostly includes benign conditions such as ingrowing toenail [Figure 5], foot ulcer, warts, onychomycosis, bruising and subungual haematoma, foreign body, pyogenic granuloma, poroma, hyperkeratosis, corns and callus, necrosis, paronychia or ganglion, to mention but a few.^[15-19]

The real diagnostic challenge is amelanotic NUM, which usually, but not exclusively, derives from the nail bed. In its earliest stage, it may present with lichenoid features.^[20] As soon as the lesion occupies a significant proportion of the nail bed keratinocytes, onycholysis develops rapidly. It is followed by superficial erosion and ulceration [Figure 6].^[21] Malodorous oozing is the next step in the natural history of amelanotic nail bed melanoma. Long-standing amelanotic nail melanomas often occupy large portions of the distal digit and invade the bone. It is worth noting that amelanotic NUM preferentially occurs on fingers, particularly the thumbs.

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Figure 5:

Amelanotic melanoma misdiagnosed and treated as a wart for many years. The patient had inguinal lymph node metastases at the time of consultation.

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Figure 6:

Subungual amelanotic melanoma of the left thumb in a 62-year-old man. (a) The suspected clinical diagnosis was a subungual fibrokeratoma under an area of onycholysis. (b) After nail avulsion, the differential diagnosis entertained were squamous cell carcinoma and amelanotic melanoma. Histopathology confirmed the diagnosis of an amelanotic nail bed melanoma.

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It is often claimed that it is not possible to determine the nature of the pigment causing longitudinal melanonychia.^[22] This is not true. In longitudinal melanonychia, the pigment is formed in the nail matrix and incorporated in the nail plate; thus, it reaches the free edge of the nail plate. Here, it can be seen with the naked eye and particularly well with end-on onychoscopy, which even permits the assessment and localisation of the melanocyte focus in the distal or proximal matrix. Human melanin is finely granular and easily seen in Fontana-stained sections of a nail clipping; however, the pigmentation may be subtle enough to escape notice in haematoxylin and eosin-stained sections. Even though melanin granules are not big enough to be detected with low- and middle-magnification dermatoscopy, reflectance confocal laser scanning microscopy is able to visualise them. Blood, fungal melanin, microbial pigments and exogenous pigments can be ruled out with naked eye examination as they do not form the characteristic longitudinal brown band composed of fine lines, typical of longitudinal melanonychia. Blood is often seen as a large lake of reddish-brown material not reaching upto the free nail plate margin. It reacts positively with pseudocatalase (peroxidase) reaction, and stains with patent blue.^[23] Fungal melanin is (usually) diffuse. Microbial and exogenous pigments can often be scraped off the surface.

Another diagnostic challenge, particularly faced by physicians trained on Caucasian patients, is recognising NUMs in people of colour. Longitudinal melanonychia in this population is often physiologic and usually starts in early adulthood. It may at first start with a single band that slowly widens and involves more and more nails. The ‘ugly duckling’ sign is useful in this population. Any brown band standing out by its deeper colour, rapid development, associated periungual pigmentation or potential nail dystrophy, like splitting, should be considered suspicious, and examined meticulously by an expert [Figure 1].

NAIL MELANOMA PROGNOSIS

The claim that NUM is a particularly aggressive form of melanoma is not correct. Early NUM, when treated with wide local excision has a very high chance of being cured. It is the late diagnosis that makes the prognosis poor. This is even more pronounced with amelanotic NUM.^[24] Periungual pigmentation is usually a sign of a long-standing lesion. Hyponychial invasion and a Breslow index over 2.5 mm are particularly poor prognostic signs. Interestingly, pigmented subungual melanomas, when extending upto the hyponychium, may leave the nail bed amelanotic, with the pigment forming a frame around the distal nail unit. There are many reports in the literature of a decade(s)-long history of a brown nail before the melanoma diagnosis was made and an adequate treatment was instituted. Various statements like

• “Acral melanoma is a rare and aggressive subtype of melanoma that arises on non-sun-exposed areas such as the soles, palms, and nail beds. It is often diagnosed at advanced stages and carries a poor prognosis.”^[25]

• “Acral lentiginous melanoma is a rare and aggressive subtype of melanoma that commonly affects the palms, soles and nail beds”.^[26]

• “Acral melanoma (AM), also known as acral lentiginous melanoma (ALM), is a rare subtype of melanoma that predominantly occurs on the palms, soles and nail beds”^[27]

are incorrect in three ways. NUM is not rare, it is not more aggressive than other types of melanomas, and most often, does not arise from the nail bed, but the nail matrix.^[5]

It is known that repetitive trauma worsens the prognosis of melanomas. The most frequent localisations of NUM, i.e the thumb and big toe, are those that are often traumatised. In this respect, it is important to note that the 5- and 10-year survival rates of NUMs are even worse than those of melanomas of the palms and soles.^[28,29] An intact immune system plays an important role in the prognosis of melanomas. It may be important that the nail, specifically the matrix, has an immune privilege that suppresses defence responses.^[30]

Very recently, two different subpopulations of melanocytes persisting into adult life have been isolated, based on their preferential anatomical site-specific enrichment during foetal development. The gene expression of the melanocytes allows them to be classified into two subtypes: volar-like (v-mel) and non-volar cutaneous-like (c-mel). V-mel melanocytes are particularly localised in volar skin and are retained in ALM.^[31] Even though the nail melanocytes have not yet been specifically investigated, it is intriguing to hypothesise that different melanocyte subpopulations may explain the peculiar behaviour of NUMs.

NAIL MELANOMA TREATMENT

For NUMs up to 1 mm thickness, there is no significant difference between functional surgery and amputation [Figure 7]. A wide local excision is defined as excision with a 6mm margin around the anatomical borders of the nail unit, and 10mm margin around Hutchinson sign.^[5] Where wide local excision is not enough also amputation is - most probably - not life-saving.^[32,33] Amputation of a thumb in an already metastasising NUM is not indicated.^[5]

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Figure 7:

Early invasive subungual melanoma. Breslow index 0.7 mm. (a) Dorsal view. (b) Eight weeks after wide local excision and healing by secondary intention.

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CONCLUSION

NUM is probably not a rare tumour. It is probably under-detected and under-reported. This is particularly unfortunate as an early diagnosis is important to save patients’ lives.