Development of a practical guide for the early recognition for malignant melanoma of the foot and nail unit
© Bristow and de Berker; licensee BioMed Central Ltd. 2010
Received: 7 June 2010
Accepted: 28 September 2010
Published: 28 September 2010
Malignant melanoma is a rare but potentially lethal form of cancer which may arise on the foot. Evidence suggests that due to misdiagnosis and later recognition, foot melanoma has a poorer prognosis than cutaneous melanoma elsewhere.
A panel of experts representing podiatry and dermatologists with a special interest in skin oncology was assembled to review the literature and clinical evidence to develop a clinical guide for the early recognition of plantar and nail unit melanoma.
A systematic review of the literature revealed little high quality data to inform the guide. However a significant number of case reports and series were available for analysis. From these, the salient features were collated and summarised into the guide. Based on these features a new acronym "CUBED" for foot melanoma was drafted and incorporated in the guide.
The use of this guide may help clinicians in their assessment of suspicious lesions on the foot (including the nail unit). Earlier detection of suspicious pedal lesions may facilitate earlier referral for expert assessment and definitive diagnosis. The guide is currently being field tested amongst practitioners.
The incidence of malignant melanoma (MM) continues to rise in the UK and Europe . Despite being an uncommon form of skin cancer it is responsible for the majority of skin cancer deaths . Health education campaigns have increased public awareness of the problem and there is evidence to show that sectors of the population are presenting earlier with their suspicious skin lesions [3–5]. Despite these improvements, mortality and morbidity still remains high, particularly within subsets of the population such as older adults [6, 7], males [8–10], the less affluent  and less well educated [12, 13].
Around 3-15% of all cutaneous MM arise on the foot [14, 15]. However, MM arising on the foot holds a poorer prognosis than melanoma elsewhere [16, 17]. The reasons for this are not certain, but there are several possible explanations. The basic prognostic indicator for melanoma at all sites is the thickness of the tumour as measured under the microscope in millimetres. This is known as the Breslow thickness. The greater the thickness of the tumour, the more likely that the patient will die in the following five years. Thick lesions on the hands and feet have been shown to have a worse prognosis than tumours of a similar thickness elsewhere . Some investigators have attributed this to pedal lesions being more aggressive in nature , though others have disputed this as a statistical anomaly due to the small numbers involved . Other authors have suggested that the Breslow thickness grading in plantar and nail melanoma is often more difficult to determine or inconclusive .
Delay in diagnosis is a further factor, where the length of history of the melanoma has a correlation with Breslow thickness and hence deterioration of prognosis. Foot lesions are often detected by health care practitioners later than lesions elsewhere. A tumour on the face is more likely to result in prompt action by the patient and practitioner than one on the foot. Furthermore, lesions between the toes, beneath the nail or on the sole are further concealed. As a result, delayed presentation results in thicker, more advanced tumours [22–24]. Secondly, foot melanoma, possibly because of its rarity, is frequently misdiagnosed as a more common foot disorder such as tinea pedis [25–29], onychomycosis , warts [31–36], haematoma [25, 37–39], paronychia , ingrowing toe nail [41–43], bacterial infection , ischaemia or necrosis [14, 40], blisters, ganglions, callus , benign tumours [45, 46] and ulceration [47–54]. Misdiagnosis rate for foot lesions have been reported to be between 25%-66% [14, 25, 40] compared with much lower rates of around 12-16% for melanoma in other anatomical locations [27, 55, 56]. This is probably a reflection of the fact that patients do not initially suspect the diagnosis of skin cancer at these sites and therefore consult healthcare professionals other than dermatologists with lesions who may not be so aware of the possibility of a malignant lesion.
The priority of skin cancer has been highlighted by the Government in its strategy to reform Cancer Services in the UK . Through the "SUNSMART" campaign http://www.sunsmart.org.uk, the government aims to increase public awareness of the disease and stress the importance of seeking professional opinion. On the professional side, guidelines issued from the National Institute for Clinical Excellence (NICE) stress the importance of health care professionals being aware of the modified 7-point checklist  for assessment of pigmented skin lesions and where any patient presenting with a skin lesions should be referred to a specialist skin care team . Some guidelines have been published in the UK and Australasia, specifically for medical practitioners for melanoma [60–62] but none are known to exist specifically for lesions arising on the foot. A review of cases in one district , demonstrated a significant number of melanoma cases were seen by foot specialists prior to diagnosis.
The need for greater awareness to permit earlier recognition of foot melanoma amongst health care practitioners has been expressed . In turn this could lead to faster recognition, referral and diagnosis. Authors have commented that the traditional melanoma screening algorithms, the ABCDE system & 7-point checklist may be less effective when applied to the foot [25, 40, 63]. The plantar surface with its thickened epidermis is subject to trauma and hyperkeratotic changes which are not found elsewhere and may disguise critical signs.
In conjunction with the Society of Chiropodists and Podiatrists (Faculty of Podiatric Medicine and General Practice), a panel was convened to draft guidance for its members to raise awareness of the condition. The guide development group consisted of a team consisting of a podiatrist and four dermatologists each with a special interest in skin cancer.
foot OR feet OR "lower extremity" OR acral OR plantar OR nail OR leg OR ankle OR sub-ungual (233864)
Diagn* OR recogn*OR screen* (2518063)
Limits: English Language & Human
Total of combination: 843
Levels of evidence (adapted from )
Level of Evidence
Type of evidence
High quality meta-analyses, or systematic reviews of randomised controlled trials (RCTs).
Well conducted meta-analyses, systematic reviews of RCTs.
Meta-analyses, systematic reviews of RCTs or RCTs with a high risk of bias.
High quality systematic reviews of cohort or case-control studies. High quality cohort or case-control studies with a low risk of confounding bias or chance.
Well conducted case-control or cohort studies with a low risk of confounding bias or chance.
Case-control or cohort studies with a high risk of confounding bias or chance.
Non-analytic studies (case reports, case series).
Expert opinion, formal consensus.
The review of the literature identified a lack of high level evidence to inform the development of a guide. Based on the NICE grading system, a small number of case-control studies were identified examining aetiology, incidence and clinical features (level 2). Most of the published literature pertaining to foot melanoma was ranked at level 3, being predominantly case reports (n = 44), literature reviews/discussions (n = 21) and case series (n = 14) of foot melanoma. On this basis, it was accepted that the paper would be drafted on the strength of the available evidence with informed consensus methods amongst the group to develop guidance.
All case reports and case series were examined by the authors. The hierarchy of evidence places such literature at a low level, just above that of medical opinion. However, case studies have the capacity to report rare diseases or the manifestations of disease which can be a useful learning tool in medical education . The authors reviewed these papers looking for common themes, key messages and learning points. The focus of such papers was often around misdiagnosis, delay and deterioration of the lesion. Based on this data, a new acronym was proposed specific for foot melanoma. An existing ABCDE acronym was included for nail melanoma .
Subsequent to drafting the paper was reviewed by the panel. External reviewers were identified. These included practising podiatrists and chiropodists, a general practitioner, a diabetologist and other specialists involved in foot care. To facilitate a simple and rapid feedback mechanism, participants were electronically e-mailed a copy of the draft guidelines and then asked to respond by an online feedback website. Respondents were asked to comment on the draft including content, readability and clarity of the draft document. Following the consultation, amendments were made and the guidelines have been reviewed and have been submitted for publication.
The development and use of a guide may help clinicians in their assessment of suspicious lesions on the foot (including the nail unit). Earlier detection of suspicious pedal lesions may facilitate earlier referral for expert assessment and definitive diagnosis. The guide has been tested amongst practitioners and has been submitted for publication.
The melanoma working group consisted of:
Ivan Bristow, Lecturer, School of Health Sciences, University of Southampton, UK
David de Berker, Consultant Dermatologist, Bristol Royal Infirmary, Bristol, UK
Katharine Acland, Consultant Dermatologist, St John's Institute of Dermatology, St Thomas' Hospital London, UK
Richard Turner, Consultant Dermatologist, Churchill Hospital, Oxford Radcliffe Hospitals, Oxford, UK
Jonathan Bowling, Dermatologist, Churchill Hospital, Oxford Radcliffe Hospitals, Oxford, UK
The authors would like to thank colleagues who reviewed the drafts and for their detailed feedback including Laurie King and Alistair McInnes.
- Karim-Kos HE, de Vries E, Soerjomataram I, Lemmens V, Siesling S, Coebergh JW: Recent trends of cancer in Europe: A combined approach of incidence, survival and mortality for 17 cancer sites since the 1990s. Eur J Cancer. 2008, 44: 1345-1389. 10.1016/j.ejca.2007.12.015.View ArticlePubMedGoogle Scholar
- UK Skin Cancer mortality statistics. [http://info.cancerresearchuk.org/cancerstats/types/skin/mortality/]
- Buettner P, Leiter U, Eigentler T, Garbe C: Development of prognostic factors and survival in cutaneous melanoma over 25 years. Cancer. 2005, 103: 616-624. 10.1002/cncr.20816.View ArticlePubMedGoogle Scholar
- Harman KE, Fuller LC, Salisbury JR, Higgins EM, du Vivier AW: Trends in the presentation of cutaneous malignant melanoma over three decades at King's College Hospital, London. Clin Exp Dermatol. 2004, 29: 563-566. 10.1111/j.1365-2230.2004.01620.x.View ArticlePubMedGoogle Scholar
- MacKie RM, Hole D: Audit of public education campaign to encourage earlier detection of malignant melanoma. BMJ. 1992, 304: 1012-1015. 10.1136/bmj.304.6833.1012.View ArticlePubMedPubMed CentralGoogle Scholar
- Payette MJ, Katz M, Grant-Kels JM: Melanoma prognostic factors found in the dermatopathology report. Clin Dermatol. 2009, 27: 53-74. 10.1016/j.clindermatol.2008.09.006.View ArticlePubMedGoogle Scholar
- Rex J, Paradelo C, Mangas C, Hilari JM, Fernandez-Figueras MT, Ferrandiz C: Management of primary cutaneous melanoma of the hands and feet: a clinicoprognostic study. Dermatol Surg. 2009, 35: 1505-1513. 10.1111/j.1524-4725.2009.01265.x.View ArticlePubMedGoogle Scholar
- Downing A, Yu XQ, Newton-Bishop J, Forman D: Trends in prognostic factors and survival from cutaneous melanoma in Yorkshire, UK and New South Wales, Australia between 1993 and 2003. Int J Cancer. 2008, 123: 861-866. 10.1002/ijc.23495.View ArticlePubMedGoogle Scholar
- Phan A, Touzet S, Dalle S, Ronger-Savle S, Balme B, Thomas L: Acral lentiginous melanoma: a clinicoprognostic study of 126 cases. Br J Dermatol. 2006, 155: 561-569. 10.1111/j.1365-2133.2006.07368.x.View ArticlePubMedGoogle Scholar
- Swetter SM, Johnson TM, Miller DR, Layton CJ, Brooks KR, Geller AC: Melanoma in Middle-aged and Older Men: A Multi-institutional Survey Study of Factors Related to Tumor Thickness. Arch Dermatol. 2009, 145: 397-404. 10.1001/archdermatol.2008.603.PubMedGoogle Scholar
- Ortiz CA, Goodwin JS, Freeman JL: The effect of socioeconomic factors on incidence, stage at diagnosis and survival of cutaneous melanoma. Med Sci Monit. 2005, 11: RA163-172.PubMedGoogle Scholar
- Baumert J, Plewig G, Volkenandt M, Schmid-Wendtner MH: Factors associated with a high tumour thickness in patients with melanoma. Br J Dermatol. 2007, 156: 938-944. 10.1111/j.1365-2133.2007.07805.x.View ArticlePubMedGoogle Scholar
- Schmid-Wendtner MH, Baumert J, Stange J, Volkenandt M: Delay in the diagnosis of cutaneous melanoma: an analysis of 233 patients. Melanoma Res. 2002, 12: 389-394. 10.1097/00008390-200208000-00012.View ArticlePubMedGoogle Scholar
- Bennett DR, Wasson D, MacArthur JD, McMillen MA: The effect of misdiagnosis and delay in diagnosis on clinical outcome in melanomas of the foot. J Am Coll Surg. 1994, 179: 279-284.PubMedGoogle Scholar
- Soong SJ, Shaw HM, Balch CM, McCarthy WH, Urist MM, Lee JY: Predicting survival and recurrence in localized melanoma: a multivariate approach. World J Surg. 1992, 16: 191-195. 10.1007/BF02071520.View ArticlePubMedGoogle Scholar
- Dwyer PK, Mackie RM, Watt DC, Aitchison TC: Plantar malignant melanoma in a white Caucasian population. Br J Dermatol. 1993, 128: 115-120. 10.1111/j.1365-2133.1993.tb15138.x.View ArticlePubMedGoogle Scholar
- Hsueh E, Lucci A, Qi K, Morton D: Survival of patients with mealnoma of the lower extremity decreases with distance from the trunk. Cancer Causes Control. 1998, 85: 383-388.Google Scholar
- Day CL, Sober AJ, Kopf AW, Lew RA, Mihm MC, Golomb FM, Hennessey P, Harris MN, Gumport SL, Raker JW, et al: A prognostic model for clinical stage I melanoma of the lower extremity. Location on foot as independent risk factor for recurrent disease. Surgery. 1981, 89: 599-603.PubMedGoogle Scholar
- Talley LI, Soong S-j, Harrison RA, McCarthy WH, Urist MM, Balch CM: Clinical Outcomes of Localized Melanoma of the Foot: A Case-Control Study. J Clin Epidemiol. 1998, 51: 853-857. 10.1016/S0895-4356(98)00071-7.View ArticlePubMedGoogle Scholar
- Barnes B, Seigler H, Saxby T, Kocher M, Harrelson J: Melanoma of the foot. J Bone Joint Surg Am. 1994, 76: 892-898.PubMedGoogle Scholar
- Dawber RP, Colver GB: The spectrum of malignant melanoma of the nail apparatus. Semin Dermatol. 1991, 10: 82-87.PubMedGoogle Scholar
- Franke W, Neumann NJ, Ruzicka T, Schulte K: Plantar malignant melanoma - a challenge for early recognition. Melanoma Res. 2000, 10: 571-576. 10.1097/00008390-200012000-00009.View ArticlePubMedGoogle Scholar
- Hemo Y, Gutman M, Klausner JM: Anatomic site of primary melanoma is associated with depth of invasion. Arch Surg. 1999, 134: 148-150. 10.1001/archsurg.134.2.148.View ArticlePubMedGoogle Scholar
- Nagore E, Oliver V, Moreno-Picot S, Fortea JM: Primary cutaneous melanoma in hidden sites is associated with thicker tumours - a study of 829 patients. Eur J Cancer. 2001, 37: 79-82. 10.1016/S0959-8049(00)00370-1.View ArticlePubMedGoogle Scholar
- Bristow I, Acland K: Acral lentiginous melanoma of the foot: a review of 27 cases. J Foot Ankle Res. 2008, 1: 11-10.1186/1757-1146-1-11.View ArticlePubMedPubMed CentralGoogle Scholar
- Dainichi T, Kobayashi C, Fujita S, Shiramizu K, Ishiko T, Kiryu H, Urabe K, Tsuneyoshi M, Furue M: Interdigital amelanotic spindle-cell melanoma mimicking an inflammatory process due to dermatophytosis. J Dermatol. 2007, 34: 716-719. 10.1111/j.1346-8138.2007.00367.x.View ArticlePubMedGoogle Scholar
- Dunkley MP, Morris AM: Cutaneous malignant melanoma: audit of the diagnostic process. Ann R Coll Surg Engl. 1991, 73: 248-252.PubMedPubMed CentralGoogle Scholar
- Serarslan G, Akcaly C, Atik E: Acral lentiginous melanoma misdiagnosed as tinea pedis: a case report. Int J Dermatol. 2004, 43: 37-38. 10.1111/j.1365-4632.2004.02085.x.View ArticlePubMedGoogle Scholar
- Waddington AM, Hogg L: The surgical management of a subungual acral malignant melanoma:a case presentation and review of the literature. Brit J Pod. 2007, 10: 166-170.Google Scholar
- De Giorgi V, Sestini S, Massi D, Panelos J, Papi F, Dini M, Lotti T: Subungual melanoma: a particularly invasive "onychomycosis". J Am Geriatr Soc. 2007, 55: 2094-2096. 10.1111/j.1532-5415.2007.01438.x.View ArticlePubMedGoogle Scholar
- Arroyo MP, Chu DH, Mobini N, Park HS: Verrucous plaque on the foot. J Cutan Pathol. 2004, 31: 271-273. 10.1111/j.0303-6987.2003.00185.x.View ArticlePubMedGoogle Scholar
- De Giorgi V, Massi D: Images in clinical medicine. Plantar melanoma--a false vegetant wart. N Engl J Med. 2006, 355: e13-10.1056/NEJMicm055674.View ArticlePubMedGoogle Scholar
- Knedgen J, Colburn M, Cooke R, Silvani S: Digital occurrence of nodular malignant melanoma. J Am Podiatr Med Assoc. 1997, 87: 178-182.View ArticlePubMedGoogle Scholar
- McBurney EI, Herron CB: Melanoma mimicking plantar wart. J Am Acad Dermatol. 1979, 1: 144-146. 10.1016/S0190-9622(79)70012-0.View ArticlePubMedGoogle Scholar
- Rosen T: Acral lentigious melanoma misdiagnosed as verruca plantaris: a case report. Dermatol Online J. 2006, 12:Google Scholar
- Virgili A, Corazza M: Guess what! Metastatic malignant melanoma of the leg from a warty acral amelanotic malignant melanoma. Eur J Dermatol. 2001, 11: 591-592.PubMedGoogle Scholar
- Fountain JA: Recognition of subungual hematoma as an imitator of subungual melanoma. J Am Acad Dermatol. 1990, 23: 773-774. 10.1016/S0190-9622(08)81099-7.View ArticlePubMedGoogle Scholar
- Hussain W, Desai S, Fitzgerald D: An (un)lucky blow to the nail?. Clin Exp Dermatol. 2009, 34: 446-447. 10.1111/j.1365-2230.2008.02889.x.View ArticlePubMedGoogle Scholar
- Yasuoka , Ueda , Ohgami , Hayashi , Ichihashi : Amelanotic acral lentiginous malignant melanoma. Br J Dermatol. 1999, 141: 370-372. 10.1046/j.1365-2133.1999.03009.x.View ArticlePubMedGoogle Scholar
- Metzger S, Ellwanger U, Stroebel W, Schiebel U, Rassner G, Fierlbeck G: Extent and consequences of physician delay in the diagnosis of acral melanoma. Melanoma Res. 1998, 8: 181-186. 10.1097/00008390-199804000-00014.View ArticlePubMedGoogle Scholar
- Lemont H, Brady J: Amelanotic Melanoma Masquerading as an Ingrown Toenail. J Am Podiatr Med Assoc. 2002, 92: 306-307.View ArticlePubMedGoogle Scholar
- Soon SL, Solomon AR, Papadopoulos D, Murray DR, McAlpine B, Washington CV: Acral lentiginous melanoma mimicking benign disease: the Emory experience. J Am Acad Dermatol. 2003, 48: 183-188. 10.1067/mjd.2003.63.View ArticlePubMedGoogle Scholar
- Winslet M, Tejan J: Subungual amelanotic melanoma: a diagnostic pitfall. Postgrad Med J. 1990, 66: 200-202. 10.1136/pgmj.66.773.200.View ArticlePubMedPubMed CentralGoogle Scholar
- Lemon B, Burns R: Malignant melanoma: A literature review and case presentation. J Foot Ankle Surg. 1998, 37: 48-54. 10.1016/S1067-2516(98)80011-2.View ArticlePubMedGoogle Scholar
- Elmets CA, Ceilley RI: Amelanotic melanoma presenting as a pyogenic granuloma. Cutis. 1980, 25: 164-166. 168PubMedGoogle Scholar
- Thomson CE, Lang S: Clinical review of an atypical malignant melanoma. Brit J Pod Med. 1991, 46: 75-77.Google Scholar
- Bristow I, Metcalfe S: Case report. Acral lentiginous melanoma or diabetic foot ulcer?. Diabetic Foot Journal. 2008, 11: 28-31.Google Scholar
- Gregson CL, Allain TJ: Amelanotic malignant melanoma disguised as a diabetic foot ulcer. Diabet Med. 2004, 21: 924-927. 10.1111/j.1464-5491.2004.01338.x.View ArticlePubMedGoogle Scholar
- Jude E, Dorman S, Kumar S, HBarnett AH: Malignant melanoma masquerading as a diabetic foot ulcer - a case report. Brit J Pod Med. 1997, 52: 35-36.Google Scholar
- Kong MF, Jogia R, Jackson S, Quinn M, McNally P, Davies M: Malignant melanoma presenting as a foot ulcer. Lancet. 2005, 366: 1750-10.1016/S0140-6736(05)67701-X.View ArticlePubMedGoogle Scholar
- Longobardi JJ: A foot "ulcer" resistant to healing. Acral-lentiginous melanoma. Adv Wound Care. 1997, 10: 16-18PubMedGoogle Scholar
- Rogers LC, Armstrong DG, Boulton AJ, Freemont AJ, Malik RA: Malignant melanoma misdiagnosed as a diabetic foot ulcer. Diabetes Care. 2007, 30: 444-445. 10.2337/dc06-2251.View ArticlePubMedGoogle Scholar
- Perks AGB, Miller G, Watson JS: Acral lentignous malignant melanoma in a diabetic foot:a plea for better education. The Foot. 1993, 3: 83-85. 10.1016/0958-2592(93)90067-D.View ArticleGoogle Scholar
- Yesil S, Demir T, Akinci B, Pabuccuoglu U, Ilknur T, Saklamaz A: Amelanotic melanoma misdiagnosed as a diabetic foot ulcer. J Diabetes Complications. 2007, 21: 335-337. 10.1016/j.jdiacomp.2006.05.004.View ArticlePubMedGoogle Scholar
- Krige JE, Isaacs S, Hudson DA, King HS, Strover RM, Johnson CA: Delay in the diagnosis of cutaneous malignant melanoma. A prospective study in 250 patients. Cancer. 1991, 68: 2064-2068. 10.1002/1097-0142(19911101)68:9<2064::AID-CNCR2820680937>3.0.CO;2-3.View ArticlePubMedGoogle Scholar
- Osborne JE, Bourke JF, Graham-Brown RAC, Hutchinson PE: False negative clinical diagnoses of malignant melanoma. Brit J Dermatol. 1999, 140: 902-908. 10.1046/j.1365-2133.1999.02823.x.View ArticleGoogle Scholar
- Department of Health: Cancer Reform Strategy. 2007, Book Cancer Reform Strategy (Editor ed.^eds.). CityGoogle Scholar
- MacKie RM: Clinical recognition of early invasive malignant melanoma. BMJ. 1990, 301: 1005-1006. 10.1136/bmj.301.6759.1005.View ArticlePubMedPubMed CentralGoogle Scholar
- National Institute for Health and Clinical Excellence: Referral guidelines for suspected cancer. Book Referral guidelines for suspected cancer (Editor ed.^eds.). 2005, City: Department of HealthGoogle Scholar
- Bishop JAN, Corrie PG, Hall PN, Evans J, Gore ME, Kirkham N, Roberts DLL, Anstey AV, Barlow RJ, Cox NH: UK guidelines for the management of cutaneous melanoma. Br J Plast Surg. 2002, 55: 46-54. 10.1054/bjps.2001.3745.View ArticlePubMedGoogle Scholar
- Roberts D, Anstey A, Barlow R, Cox N: UK guidelines on the management of cutaneous melanoma. Br J Dermatol. 2002, 146: 7-17. 10.1046/j.1365-2133.2001.04614.x.View ArticlePubMedGoogle Scholar
- Australian Cancer Network Melanoma Guidelines Revision Working Party: Clinical Practice Guidelines for the management of melanoma in Australia and New Zealand. 2008, Wellington: Cancer Council Australia and Australian Cancer Network, Sydney and New Zealand Guidelines GroupGoogle Scholar
- Albreski D, Sloan SB: Melanoma of the feet: misdiagnosed and misunderstood. Clin Dermatol. 2009, 27: 556-563. 10.1016/j.clindermatol.2008.09.014.View ArticlePubMedGoogle Scholar
- Reviewing and grading the evidence. [http://www.nice.org.uk/niceMedia/pdf/GDM_Chapter7_0305.pdf]
- Vandenbroucke JP: In Defense of Case Reports and Case Series. Ann Intern Med. 2001, 134: 330-334.View ArticlePubMedGoogle Scholar
- Levit EK, Kagen MH, Scher RK, Grossman M, Altman E: The ABC rule for clinical detection of subungual melanoma. J Am Acad Dermatol. 2000, 42: 269-274. 10.1016/S0190-9622(00)90137-3.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.