What are the clinical features of melanoma and how do atypical melanomas present?

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Introduction

Whilst there is evidence that early detection of superficial spreading melanomas has improved, with a corresponding reduction in both median tumor thickness and melanoma mortality from this subtype,[1] a number of studies have also shown an increasing or stable incidence rate of thick melanomas.[2][3][4][5][6][7] Nodular, desmoplastic and acral lentiginous melanomas are often diagnosed when they are much thicker lesions compared to superficial spreading melanoma.[8][9][3][4][6][10] This is in part due to their atypical clinical presentation. Improved diagnostic accuracy of these subtypes can significantly improve mortality from melanoma.

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Classification of melanoma

Melanoma is currently classified into subtypes; superficial spreading (SSM), nodular melanoma (NM), lentigo maligna melanoma (LMM), acral lentiginous (ALM) and desmoplastic melanoma (DM), based on various morphologic and histologic characteristics.[11][12] SSM is the most common subtype accounting for approximately 55-60% of melanoma, and is characterised by a slow radial growth phase (months to years), (with pagetoid spread of atypical melanocytes within the epidermis, followed by invasion into the dermis. LMM accounts for approximately 10-15% of cases in Australia, occurring on sun damaged skin with a slow lentiginous (linear) proliferation of atypical melanocytes along the basal layer of the epidermis, commonly involving hair follicles and sweat ducts, which may be present for years prior to invasion. Acral lentiginous melanomas (which make up only 1-2% of cases in Australia) arise on glabrous skin and also have a prominent lentiginous radial growth component, but appear not to be causally associated with sun exposure. NM accounts for 10-15% of cases and differs from the other main subtypes by being uniformly invasive (early vertical growth) with a lack of epidermal involvement (radial growth) beyond 3 rete ridges. Desmoplastic melanomas account for 1-2% of cases in Australia and are characterized by malignant spindled melanocytes with surrounding fibrous stroma. They can be difficult to diagnose both clinically and on histopathology.

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Clinical presentations of melanoma subtypes

As well as having distinct histopathology, melanoma subtypes differ in their clinical presentation.

Superficial spreading melanoma

SSM is more common in younger patients and tends to occur on the trunk of naevus prone individuals and has a strong relationship with intermittent sun exposure. It presents as an Asymmetrical pigmented lesion with irregular Borders, Colour variation, typically of larger Diameter (the ABCD rule). Macroscopically, it tends to stand out as an ‘ugly duckling’. Common specific dermoscopic features are branched streaks or pseudopods, blue-grey veil, multiple irregular brown dots or globules, regression features, inverse or broadened network and atypical/polymorphous vessels.

Nodular melanoma

Whilst NM account for only 10-15% of melanomas in Australia, they contribute disproportionately to melanoma deaths.[6] In contrast to SSM, NM does not conform to the ABCD rule, but is more often a symmetrical, dome shaped, hypomelanotic lesion. The EFG aide memoire reminds us that they are often Elevated, Firm and Growing.[13] NM may therefore masquerade as basal or squamous cell carcinomas or angiomas. Many NM appear to the patient to be without pigment but closer inspection will reveal light pigmentation in some and focal pigmentation in others. Dermoscopy will show melanin pigment in 90% of NM although 27% in one large series were lightly or focally pigmented and 9.6% were completely amelanotic.[14] Dermoscopic features seen in other subtypes are less common, but, blue-white veil, blue areas, black areas, milky pink areas, atypical vessels, and symmetry of pigment pattern are more commonly identified.[14] NM is more commonly found on severely sun damaged sites such as the head and neck of older individuals and is less commonly associated with large numbers of naevi.[15] NM tend to exhibit more rapid vertical growth compared to SSM and LMM, and are much thicker at diagnosis.[16][4]

Lentigo maligna melanoma

Lentigo Maligna (in-situ disease) may be present for months to years before invasion occurs. These lesions usually present as an asymmetrical pigmented macule which may occasionally be amelanotic (pink). Dermoscopic clues can be subtle, and include asymmetrical perifollicular pigmentation, grey and black dots (annular granular structures) and rhomboidal structures.

LMM (invasive disease) typically occurs on the head and neck of older patients and is associated with other signs of chronic sun exposure, such as solar lentigines, solar keratoses and non-melanoma skin cancer.

Desmoplastic melanoma

Desmoplastic melanoma also typically occurs on chronically sun-damaged skin, typically the head and neck, including the lip, nose and ears. It may arise de novo, or in association with a pre-existing lentigo maligna. It is more often amelanotic, firm or scar like in appearance. Dermoscopy is less useful in diagnosing DM unless features of an associated radial growth phase melanoma are present. It may be misdiagnosed clinically as a dermatofibroma, scar or non-melanoma skin cancer. Recurrence at the site of a previous biopsy diagnosed as benign on histopathology (e.g. as dermatofibroma, neurofibroma, scar) is not an uncommon presentation of DM as the histopathology can be difficult in some cases, particularly with partial biopsy. Review of previous pathology can be helpful where there is clinical suspicion.

Acral lentiginous and subungal melanoma

Acral lentiginous melanoma may arise de novo or from a pre-existing naevus and occurs more commonly on the sole than on the the palm. ALM may also arise from the nail apparatus (subungual melanoma). They may have a prolonged radial growth phase (similar to LMM) before becoming invasive. ALM typically presents with light asymmetric macular pigmentation, which may be patchy and therefore mistaken for a stain or bruise. Over 30% of cases are hypomelanotic.[17] It has a predominant parallel ridge pattern on dermoscopy. Occasionally ALM can be verrucous and, particularly if hypomelanotic, may mimic plantar warts or tinea infection. If pared down, an ALM would not show the typical pinpoint vessels of a wart.

Subungual melanoma typically presents as longtitudinal melanonychia (full length longitudinal brown to black pigment band arising from the nail matrix). This band typically broadens over time and dermoscopically one can observe streaks within the band with variable colour, thickness and spacing. Pigmentation of the proximal or lateral nail fold (Hutchinson’s sign) may be present. Growth of the tumour may cause nail dystrophy and eventual destruction of the nail plate. Subungual haematoma is a common differential diagnosis and may be distinguished by the presence of multiple reddish globules at the periphery of the pigmented area. These will grow out when observed over months. Bleeding within a tumour may occur, however, and the presence of subungal blood can not be used to rule out melanoma.[18] Hypomelanotic subungual melanoma may present as a nail dystrophy and readily be mistaken for nail trauma or infection.

Spitzoid melanoma

Spitzoid melanoma is at the malignant end of the spectrum of melanocytic lesions which includes Spitz naevus and atypical Spitz tumour. The typical benign Spitz naevus occurs in the young (usually <20) presenting as a pink dome-shaped symmetrical papule with a well defined border (10% are pigmented). Atypical Spitz tumour and spitzoid melanoma tend to present as larger lesions, often asymmetrical with more irregular border and surface, and pink to variegated, at any age but usually >10.[19][20] Spitz type lesions are defined by their histomorphology with large epithelioid and/or spindling melanocytes. Pathological assessment of these tumors is challenging and expert histopathological review should be considered prior to definitive surgical management. Partial biopsy is particularly unreliable with Spitz lesions. As yet there are no definitive molecular markers to assist diagnosis but this area is developing.

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Atypical clinical features

Melanoma may not conform to the usual ABCD criteria. They may be symmetric, dome shaped and skin coloured. Any lesion that is Elevated, Firm and Growing over a period of more than one month should raise suspicion for melanoma.

Lack of pigment is significantly associated with poorer diagnostic accuracy.[21] Up to 20% of all melanomas are only partially pigmented (hypomelanotic), with true amelanosis much less common.[22][23] Nodular, desmoplastic and ALM subtypes are more commonly hypomelanotic (over 40% of cases) compared to SSM and LMM subtypes (approximately 10-25% of cases).[15][23][17] Hypomelanotic melanomas may mimic basal cell carcinoma clinically, with a slightly shiny surface and atypical vessels on dermoscopy. Other dermoscopic clues include scar-like depigmentation, inverse network, irregular blue grey dots, blue-white veil and milky pink areas.[22][24] Whilst dermoscopic sensitivity is around 90% for pigmented lesions, it is much lower for predominantly amelanotic lesions.

Tumor thickness is not necessarily related to diagnostic delay.[2][25][26][27] Whilst some melanomas grow slowly over a number of years, others will become thick and life- threatening over weeks to months. More rapid growth has been associated with NM and desmoplastic subtypes as well as amelanosis.[16][28][29][30] These subtypes are more common on chronically sun damaged skin, typically on the head and neck and predominantly in older males.[9]

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Dynamic features of melanomas

Perhaps the most helpful clinical feature of melanomas is that biologically significant melanomas are changing, regardless of their other clinical features. If these changes have been accurately perceived by the patient or there is photographic evidence to demonstrate stability or change, this may be very helpful in determining the right index of suspicion. Radial growth phase melanomas change in size, shape or colour and vertical growth phase melanomas elevation, ulceration and may bleed. A history of the duration of a lesion and any change within it is a minimum requirement for the assessment of any potential skin cancer.

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Evidence summary and recommendations

Evidence summary Level References
NM, ALM and desmoplastic subtypes more commonly present as thick lesions and improved diagnostic accuracy of these is therefore critical. III-2, III-3, IV [10], [6], [9], [7], [4], [3]
Nodular melanomas are associated with more rapid vertical growth compared to superficial spreading melanomas. III-3, IV [28], [16], [29], [30]
Up to 20% of all melanomas are amelanotic or only partially pigmented, with this being more common amongst NM, ALM and desmoplastic subtypes. IV [15], [17], [23]
Amelanosis/hypomelanosis is significantly associated with poorer diagnostic accuracy. III-2, III-3 [21], [22]


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Melanomas are generally distinguished from benign lesions by their history of change and thick melanomas often do not conform to the ‘ABCD’ rule, but are Elevated, Firm and Growing. Therefore, careful history taking is important and any lesion that continues to grow or change in size, shape, colour or elevation over a period of more than one month should be biopsied and assessed histologically or referred for expert opinion.


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Suspicious raised lesions should be excised and not monitored.

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Conclusions

A thorough history of the lesion with regards to change in morphology and/or growth over time is important. As there is a narrow window of opportunity for both patients and doctors to detect rapidly growing lesions whilst they are still thin, an awareness of the ‘atypical’ features of melanoma is critical.

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References

  1. Smithson SL, Pan Y, Mar V. Differing trends in thickness and survival between nodular and non-nodular primary cutaneous melanoma in Victoria, Australia. Med J Aust 2015 Jul 6;203(1):20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26126561.
  2. 2.0 2.1 Baade PD, English DR, Youl PH, McPherson M, Elwood JM, Aitken JF. The relationship between melanoma thickness and time to diagnosis in a large population-based study. Arch Dermatol 2006 Nov;142(11):1422-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17116832.
  3. 3.0 3.1 3.2 Criscione VD, Weinstock MA. Melanoma thickness trends in the United States, 1988-2006. J Invest Dermatol 2010 Mar;130(3):793-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19829301.
  4. 4.0 4.1 4.2 4.3 Demierre MF, Chung C, Miller DR, Geller AC. Early detection of thick melanomas in the United States: beware of the nodular subtype. Arch Dermatol 2005 Jun;141(6):745-50 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15967921.
  5. Lipsker DM, Hedelin G, Heid E, Grosshans EM, Cribier BJ. Striking increase of thin melanomas contrasts with stable incidence of thick melanomas. Arch Dermatol 1999 Dec;135(12):1451-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10606049.
  6. 6.0 6.1 6.2 6.3 Mar V, Roberts H, Wolfe R, English DR, Kelly JW. Nodular melanoma: a distinct clinical entity and the largest contributor to melanoma deaths in Victoria, Australia. J Am Acad Dermatol 2013 Apr;68(4):568-75 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23182058.
  7. 7.0 7.1 Tejera-Vaquerizo A, Mendiola-Fernández M, Fernández-Orland A, Herrera-Ceballos E. Thick melanoma: the problem continues. J Eur Acad Dermatol Venereol 2008 May;22(5):575-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18081751.
  8. Bergenmar M, Ringborg U, Månsson Brahme E, Brandberg Y. Nodular histogenetic type -- the most significant factor for thick melanoma: implications for prevention. Melanoma Res 1998 Oct;8(5):403-11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9835453.
  9. 9.0 9.1 9.2 Chamberlain AJ, Fritschi L, Giles GG, Dowling JP, Kelly JW. Nodular type and older age as the most significant associations of thick melanoma in Victoria, Australia. Arch Dermatol 2002 May;138(5):609-14 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12020221.
  10. 10.0 10.1 Baumert J, Schmidt M, Giehl KA, Volkenandt M, Plewig G, Wendtner C, et al. Time trends in tumour thickness vary in subgroups: analysis of 6475 patients by age, tumour site and melanoma subtype. Melanoma Res 2009 Feb;19(1):24-30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19430403.
  11. LeBoit P, Burg G, Weedon D, Sarasin A. Skin Tumors, Pathology and Genetics. Lyon, France: IARC Press; 2006 [cited 2016 Feb 2] Available from: https://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb6/bb6-cover.pdf.
  12. McGovern VJ, Mihm MC Jr, Bailly C, Booth JC, Clark WH Jr, Cochran AJ, et al. The classification of malignant melanoma and its histologic reporting. Cancer 1973 Dec;32(6):1446-57 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/4757934.
  13. Kelly JW, Chamberlain AJ, Staples MP, McAvoy B. Nodular melanoma. No longer as simple as ABC. Aust Fam Physician 2003 Sep;32(9):706-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14524207.
  14. 14.0 14.1 Menzies SW, Moloney FJ, Byth K, Avramidis M, Argenziano G, Zalaudek I, et al. Dermoscopic evaluation of nodular melanoma. JAMA Dermatol 2013 Jun;149(6):699-709 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23553375.
  15. 15.0 15.1 15.2 Chamberlain AJ, Fritschi L, Kelly JW. Nodular melanoma: patients' perceptions of presenting features and implications for earlier detection. J Am Acad Dermatol 2003 May;48(5):694-701 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12734497.
  16. 16.0 16.1 16.2 Liu W, Dowling JP, Murray WK, McArthur GA, Thompson JF, Wolfe R, et al. Rate of growth in melanomas: characteristics and associations of rapidly growing melanomas. Arch Dermatol 2006 Dec;142(12):1551-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17178980.
  17. 17.0 17.1 17.2 Phan A, Dalle S, Touzet S, Ronger-Savlé S, Balme B, Thomas L. Dermoscopic features of acral lentiginous melanoma in a large series of 110 cases in a white population. Br J Dermatol 2010 Apr;162(4):765-71 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19922528.
  18. Braun RP, Baran R, Le Gal FA, Dalle S, Ronger S, Pandolfi R, et al. Diagnosis and management of nail pigmentations. J Am Acad Dermatol 2007 May;56(5):835-47 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17320240.
  19. Luo S, Sepehr A, Tsao H. Spitz nevi and other Spitzoid lesions part I. Background and diagnoses. J Am Acad Dermatol 2011 Dec;65(6):1073-84 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22082838.
  20. McCormack CJ, Conyers RK, Scolyer RA, Kirkwood J, Speakman D, Wong N, et al. Atypical Spitzoid neoplasms: a review of potential markers of biological behavior including sentinel node biopsy. Melanoma Res 2014 Oct;24(5):437-47 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24892957.
  21. 21.0 21.1 Lin MJ, Mar V, McLean C, Wolfe R, Kelly JW. Diagnostic accuracy of malignant melanoma according to subtype. Australas J Dermatol 2014 Feb;55(1):35-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24283461.
  22. 22.0 22.1 22.2 Menzies SW, Kreusch J, Byth K, Pizzichetta MA, Marghoob A, Braun R, et al. Dermoscopic evaluation of amelanotic and hypomelanotic melanoma. Arch Dermatol 2008 Sep;144(9):1120-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18794455.
  23. 23.0 23.1 23.2 Liu W, D, Murray W, Macarthur G, Wolfe R, Kelly J. Amelanotic primary cutaneous melanoma – clinical associations and dynamic evolution. Australas J Dermatol 2006;47, A1.
  24. Pizzichetta MA, Talamini R, Stanganelli I, Puddu P, Bono R, Argenziano G, et al. Amelanotic/hypomelanotic melanoma: clinical and dermoscopic features. Br J Dermatol 2004 Jun;150(6):1117-24 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15214897.
  25. Betti R, Martino P, Vergani R, Gualandri L, Crosti C. Nodular melanomas: analysis of the casistic and relationship with thick melanomas and diagnostic delay. J Dermatol 2008 Oct;35(10):643-50 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19017043.
  26. Richard MA, Grob JJ, Avril MF, Delaunay M, Gouvernet J, Wolkenstein P, et al. Delays in diagnosis and melanoma prognosis (II): the role of doctors. Int J Cancer 2000 May 20;89(3):280-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10861505.
  27. Richard MA, Grob JJ, Avril MF, Delaunay M, Gouvernet J, Wolkenstein P, et al. Delays in diagnosis and melanoma prognosis (I): the role of patients. Int J Cancer 2000 May 20;89(3):271-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10861504.
  28. 28.0 28.1 Lin MJ, Mar V, McLean C, Kelly JW. An objective measure of growth rate using partial biopsy specimens of melanomas that were initially misdiagnosed. J Am Acad Dermatol 2014 Oct;71(4):691-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24976443.
  29. 29.0 29.1 Martorell-Calatayud A, Nagore E, Botella-Estrada R, Scherer D, Requena C, Serra-Guillén C, et al. Defining fast-growing melanomas: reappraisal of epidemiological, clinical, and histological features. Melanoma Res 2011 Apr;21(2):131-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21183860.
  30. 30.0 30.1 Tejera-Vaquerizo A, Barrera-Vigo MV, López-Navarro N, Herrera-Ceballos E. Growth rate as a prognostic factor in localized invasive cutaneous melanoma. J Eur Acad Dermatol Venereol 2010 Feb;24(2):147-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19627405.

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Appendices