Malignant melanoma, although rare, is a skin cancer with the highest mortality. This report presents a 55-year-old man who had been followed-up for diabetes mellitus for 14 years, and was diagnosed with a malignant melanoma that had developed on the base of a diabetic foot ulcer. The major common characteristic of malignant melanomas misdiagnosed as foot ulcer in the literature was that these cases have a very aggressive course, and metastasize in a short time. Thus, early biopsy is required in painful, pigmented foot ulcers with atypical localization that do not respond to standard treatment in patients with diabetes.
Malignant melanoma misdiagnosed as a diabetic foot ulcer.
Although it accounts for only 4% of skin cancers, 80% of deaths due to skin cancer are attributed to malignant melanoma.1 Until recently, it has been considered a definitively fatal condition. However, owing to the efforts of training and raising awareness, patients who are diagnosed early may be cured with surgical treatment. Delayed diagnosis is still associated with high mortality rates.
Micro- and macrovascular complications due to diabetes mellitus are the major long-term morbidities of this condition. Ulcers of the lower limbs due to peripheral neuropathy, angiopathy, and infections are more frequent than in nondiabetics. The most common conditions causing foot ulcers, other than diabetic complications in diabetes patients, are Charcot Marie Tooth disease, spina bifida, spinal trauma, and Hansen’s disease (leprosy).2
Malignant melanoma is an invasive and metastatic tumor with an increasing frequency and high mortality. More than 33% of all melanomas develop on the lower limbs.3,4 The most common site of involvement of malignant melanomas of the foot is the plantar region.5 Plantar melanomas are still rare in the melanoma population, as only 0.9%–7% have invasive primary cutaneous melanomas located on the plantar region.1,6 There is no significant difference between mean tumor thickness on the plantar surface and that on the leg.7 Five-year survival rates are between 56% and 71%.8 Unsurprisingly, earlier stage and thinner tumors (< 4 mm) have a better prognosis.8 In another study, the survival rates of palmoplantar melanomas were lower compared to other regions.9
Misdiagnosis of palmoplantar melanomas was reported to delay treatment for 12 months, increase tumor thickness, and decrease the 5-year survival rate for up to 68.9%.10 In a study reviewing 53 cases of lower limb melanomas in plantar region, melanoma was misdiagnosed in 11 out of 18 patients (61%).11 Thus, rapid diagnosis and treatment are critical in these patients.
Malignant melanomas are most frequently confused with nonhealing ulcers, warts, blisters, hyperkeratotic lesions, foreign bodies, pyogenic granules, benign nevi, tinea pedis, and onychomycosis.12 Diabetic foot ulcers are not yet included on this list. Plantar ulceration is frequent in diabetic patients because small lesions developing with high pressure or trauma go unnoticed due to diabetic sensorial neuropathy and transform into diabetic foot ulcers with microangiopathic ischemia in time.
A recent large cohort study found that colon, rectum, liver, biliary tract, pancreas, kidney, leukemia, and melanoma are significantly elevated among men with diabetes.13 In 1985, O’Mara et al14 noted a raised risk of melanoma and nonmelanoma skin cancers in women with diabetes. The hypothesized biological mechanisms are related to the effect of insulin and insulin-like growth factors on tumoral cell proliferation.15,16 Additionally, advanced glycation end products (AGE) have been implicated in the growth and migration of human melanoma cells.17 In the same study, AGE were present in beds of human melanoma tumor, where as barely detected in normal skin. However, in Canada, Rousseau et al18 found that diabetes was associated with an increased risk of liver cancer among diabetics with no other types of cancer, including melanoma. A link between cancer and diabetes remains controversial.
Biopsy rates for lesions in the plantar area have increased recently. There are 13 malignant melanoma cases misdiagnosed as diabetic foot ulcers in the literature, and our patient is the 14th case. The characteristics of the all misdiagnosed patients reported in the English literature are summarized in the Table 1. Data on various parameters, such as the duration of diabetes mellitus, history of trauma on the foot, presence of peripheral neuropathy, or ischemia were not available for previous cases; therefore, commenting on the common points of cases is difficult. The possible correlations between the duration of diabetes mellitus, duration of foot ulcers, location of ulcers, development of malignant lesions, age and sex of patients, frequencies of malignancy, and poor/good control of blood glucose levels, will be unraveled as the number of cases in the literature increases.
Kong et al2 suggested that early biopsy was indicated if neuropathy or ischemia was not present, if the ulcer had an atypical localization, if it was painful/pigmented, and did not respond to standard treatment. Excisional biopsy should be performed to allow staging of the malignant melanoma. A significant cause of misdiagnosis is that a dermatologist does not usually examine these patients. All atypical, suspicious ulcers should be consulted with a dermatologist.10
A 55-year-old man who has been followed-up for Type 2 diabetes mellitus for 5 years presented with an ulcer of the right heel. The lesion had started with a skin abrasion 5 months previously, and had enlarged and become a painless ulcer with serous fluid. Extensive debridement, oral antibiotic, and silver-based topical agents were used, but were not successful. Secondary debridement and intravenous antibiotics were started. All of these efforts were not useful to minimize ulcer dimensions and an incisional biopsy was taken from the ulcer base. The histopathological examination showed malignant melanoma cells (stained with HMB-45) with a Breslow depth of 5 mm (Figure 1).
The conditions including peripheral neuropathy, peripheral ischemic disease, and trauma were not detected. Physical examination revealed hepatosplenomegaly, ascites, painful lymph node enlargement in the right inguinal region, and a 6-cm diameter ulcerative lesion of the right heel with small, pigmented areas and an irregular border (Figure 2). Reactive Achilles reflexes, rosy-pink skin color, normal skin temperature, and hair loss were detected on both lower extremities. Direct x-rays did not reveal any evidence of osteomyelitis. Blood glucose levels were high and not regulated and serum HbA1C was 9 mg/dL. A biopsy taken from the right inguinal lymph node revealed metastasis of melanoma, liver, and brain metastases were detected. The patient died within a few weeks.
A patient may have more than one medical condition concurrently. Thus, considering the worst scenario may be life saving.
1. Franke W, Neumann NJ, Ruzicka T, Schulte KW. Plantar malignant melanoma—a challenge for early recognition. Melanoma Res. 2000;10:571-576.
2. Kong MF, Jogia R, Jackson S, Quinn M, Davies M. When to biopsy a foot ulcer? Seven cases of malignant melanoma presenting as foot ulcers. Pract Diabetes Int. 2008;25:5–8.
3. Balch C, Soong S, Shaw H, et al. Changing trends in the clinical and pathological features of melanoma. In: Balch C, Houghton G, Milton G, Sober A, Soong S, eds. Cutaneous Melanoma. Philadelphia, PA: Lippincott Williams & Wilkins; 1992:40–45.
4. Lemon B, Burns R. Malignant melanoma: a literature review and case presentation. J Foot Ankle Surg. 1998;37:48–54.
5. Fortin PT, Freiberg AA, Rees R, Sondak VK, Johnson TM. Malignant melanoma of the food and ankle. J Bone Joint Surg Am. 1995;77:1396–1403.
6. Baumert J, Schmidt M, Giehl KA, et al. Time trends in tumor thickness vary in subgroups: analysis of 6475 patients by age, tumour site and melanoma subtype. Melanoma Res. 2009;19:24–30.
7. Dwyer PK, Mackie RM, Watt DC, Aitchison TC. Plantar malignant melanoma in a white Caucasian population. Br J Dermatol. 1993;128:115–120.
8. Kato T, Suetake T, Tabata N, Takahashi K, Tagami H. Epidemiology and prognosis of plantar melanoma in 62 Japanese patients over a 28-year period. Int J Dermatol. 1999;38:515–519.
9. Hsueh EC, Lucci A, Qi K, Morton DL. Survival of patients with melanoma of the lower extremities decreases with distance from the trunk. Cancer. 1999;85:383–388.
10. Metzger S, Ellwanger U, Stroebel W, Schiebel U, Rassner G, Fierlbeck G. Extend and consequences of physician delay in the diagnosis of acral melanoma. Melanoma Res. 1998;8:181–186.
11. Soon SL, Solomon AR Jr, 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.
12. Bennett DR, Wasson D, MacArthur JD, McMillen MA. The effect of misdiagnosis on clinical outcome in melanomas of the foot. J Am Coll Surg. 1994;179:279–284.
13. Atchison EA, Gridley G, Carreon JD, Leitzmann MF, McGlynn KA. Risk of cancer in a large cohort of U.S. veterans with diabetes. Int J Cancer. 2011;128(3):635–643.
14. O’Mara BA, Byers T, Schoenfeld E. Diabetes mellitus and cancer risk: a multisite case-control study. J Chronic Dis. 1985;38(5):435–441.
15. LeRoith D, Baserga R, Helman L, Roberts CT Jr. Insulin-like growth factors and cancer. Ann Intern Med. 1995;122(1):54–59.
16. Fisher WE, Boros LG, Schirmer WJ. Insulin promotes pancreatic cancer: evidence for endocrine influence on exocrine pancreatic tumors. J Surg Res. 1996;63(1):310–313.
17. Abe R, Shimizu T, Sugawara H, et al. Regulation of human melanoma growth and metastasis by AGE-AGE receptor interactions. J Invest Dermatol. 2004;122(2):461–467.
18. Rousseau MC, Parent ME, Pollak MN, Siemiatycki J. Diabetes mellitus and cancer risk in a population-based case-control study among men from Montreal, Canada. Int J Cancer. 2006;118(8):2105–2109.
19. Bayram I, Ugras S, Reçber D. Diagnosis of diabetic foot amputation for malignant melanoma of the finger. Van Tıp Dergisi. 2002;9(2):63–65. [Article in Turkish]
20. Rogers LC, Armstrong DG, Boulton AJ, Freemont AJ, Malik RA. Malignant melanoma misdiagnosed as a diabetic foot ulcer. Diabetes Care. 2007;30(2):444–445.
21. Gregson CL, Allain TJ. Amelanotic malignant melanoma disguised as a diabetic foot ulcer. Diabet Med. 2004;21(8):924–927.
22. Zelent ME, Neese DJ, Graham RB. Malignant melanoma masquerading as a decubitus heel ulceration. WOUNDS. 2006;18(1):25–28.
23. Yeşil S, Demir T, Akinci B, Pabuccuoglu U, Ilknur T, Saklamaz A. Amelanotic melanoma misdiagnosed as a diabetic foot ulcer. J Diabetes Complications. 2007;21(5):335-337.
24. Bristow I. Case report. Acral lentiginous melanoma or diabetic foot ulcer? Diabetic Foot. 2008;11(1):28–35.
25. Fernando DJ, Rajendra J, Emmerson E. A non-healing foot ulcer in a patient with type 2 diabetes mellitus. Eur J Intern Med. 2006;17(6):452.
26. Torres T, Rosmaninho A, Caetano M, Selores M. Malignant melanoma misdiagnosed as a diabetic foot ulcer. Diabet Med. 2010;27:1302–1303.
Drs. Ata and Arıcan are from the Mersin University Faculty of Medicine, Department of Medical Oncology, Turkey; Dr. Polat is from the Mersin University Faculty of Medicine, Department of Pathology, Turkey; and Dr. Tanrıverdi is from Erciyes University Faculty of Medicine, Department of Endocrinology, Kayseri, Turkey.
Address correspondence to:
Alper Ata, MD
Saglik Arastirma Hastanesi
Tıbbi Onkoloji BD 33000