Journal of Diabetes and Its Complications 21 (2007) 335 – 337
Amelanotic melanoma misdiagnosed as a diabetic foot ulcer Sena YeYila,4, Tevfik Demira, Baris Akincia, Ugur Pabuccuoglub, Turna I˙lknurc, Ali Saklamaza a
Department of Endocrinology and Metabolism, School of Medicine, Dokuz Eylul University, Izmir, Turkey b Department of Pathology, School of Medicine, Dokuz Eylul University, Izmir, Turkey c Department of Dermatology, School of Medicine, Dokuz Eylul University, Izmir, Turkey Received 17 March 2006; accepted 2 May 2006
Abstract Amelanotic melanoma often leads to delayed clinical diagnosis because of its wide range of clinical appearances and lack of pigmentation. Misdiagnosis of amelanotic melanoma is also common, particularly when it is located at the foot. We report here a 71-year-old male patient with a 17-year history of type 2 diabetes mellitus who presented with a small ulcer under his fifth metatarsal head, which was previously misdiagnosed as a diabetic foot ulcer. The patient was treated with local wound care and systemic antibiotics without any improvement of the ulcer. Further investigation of the patient in our clinic revealed plantar amelanotic melanoma. D 2007 Elsevier Inc. All rights reserved. Keywords: Diabetic foot ulcer; Amelanotic melanoma
1. Introduction The differential diagnosis of a foot ulcer may be difficult (Gregson & Allain, 2004). Amelanotic melanoma is a rare type of skin cancer. It exhibits a higher misdiagnosis rate because of its wide range of clinical spectra. Misdiagnosis and delay in diagnosis may lead to poor patient outcome (Soon et al., 2003). We describe here a diabetic patient with plantar amelanotic melanoma, which was misdiagnosed as a diabetic foot ulcer.
2. Case A 71-year-old male patient with a 17-year history of type 2 diabetes mellitus presented to our clinic with
4 Corresponding author. Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Dokuz Eylul University, InciraltV, Izmir 35340, Turkey. Tel.: +90 2324123740; fax: +90 232 2792267. E-mail address:
[email protected] (S. YeYil). 1056-8727/07/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jdiacomp.2006.05.004
atypical hypergranulation and painless ulcer under his left fifth metatarsal head. He was treated with oral antidiabetics, and his diabetes was not well-controlled (HbA1c=8.2%). He did not have significant macrovascular and microvascular complications of diabetes. In 2001, he noticed a small ulcer under his fifth metatarsal head, and the lesion grew larger in time. He insisted that the lesion was due to the trauma of ill-fitting shoes. He was previously admitted by another physician, and the lesion was diagnosed as a diabetic foot ulcer. The ulcer was initially managed with local wound care and systematic antibiotics. However, no healing was noted, and atypical fragile hypergranulation developed on the ulcer base. On clinical examination, there was a 4-cm-diameter ulcer under the left fifth metatarsal head. There was no erythema, warmth, or tenderness on palpation in the area of the foot ulcer (Fig. 1). He had good pedal pulses and no peripheral neuropathy. An X-ray of the foot did not show any osteomyelitis. He went on to have an incisional punch biopsy of his left foot ulcer, which showed the dermis to be diffusely infiltrated by malignant tumor, displaying melan-A positivity. The diagnosis was malignant melanoma (Fig. 2).
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Fig. 1. Foot ulcer under the left fifth metatarsal head of the patient.
Further investigations revealed involvement of inguinal lymph nodes. He was referred to a plastic surgeon, but he refused surgery and subsequent chemotherapy. A few weeks later, he developed a distant metastasis of malignant melanoma. He was then admitted to a hospital and received inguinal radiotherapy and three courses of systemic chemotherapy, including interferon and, later, temozolomide. However, he died after 3 months because of the metastatic disease.
3. Discussion Melanoma is an invasive and metastatic tumor that has displayed an increasing incidence in recent years and has a high mortality rate. It accounts for approximately 4% of all skin cancers, but it is responsible for 79% of all skin-cancerrelated deaths (Franke, Neumann, Ruzicka, & Schulte, 2000). Unusual variants of melanoma, including amelanotic melanoma, constitute less than 5% of all melanomas (Perniciaro, 1997). Amelanotic melanoma may be located on various sites of the body. Franke et al. found that, in their group of 925 melanomas, approximately 7% were located in the plantar region. Given the variety of clinical presentations possible in the absence of significant pigmentation, amelanotic melanoma often presents as an advanced lesion that has been treated unsuccessfully by topical agents, especially in a diabetic patient, as in our case (Gregson & Allain, 2004; Kong et al., 2005). Delay in diagnosis or misdiagnosis of acral melanoma is more frequent than that of melanomas at other localizations. Several retrospective studies indicate the misdiagnosis rate of acral melanoma as 25–36% (Fortin, Freiberg, Rees, Sondak, & Johnson, 1995; Metzger et al., 1998). Lesions may be painless and may go unnoticed by the patients. They are frequently ulcerated and may mimic several lesions such as plantar warts, fungal disorders, hyperkeratotic lesions, and diabetic foot ulcers (Gregson & Allain, 2004; Kong et al., 2005; Serarslan, Akcal, & Atik, 2004).
The association between diabetes and cancer is a complex condition. The relationship between skin cancer incidence/prevalence and diabetes is also unclear. Ragozzino, Melton, Chu, and Palumbo (1982) demonstrated that the risk of having nonmelanoma skin cancer significantly increases following the diagnosis of diabetes mellitus. O’Mara, Byers, and Schoenfeld (1985) noted a positive correlation between diabetes and nonmelanoma skin cancer in females. They did not find any association between type of diabetes treatment and cancer risk. However, Chuang, Lewis, and Spandau (2005) reported a decreased incidence of nonmelanoma skin cancer in patients with type 2 diabetes mellitus who use insulin. Our patient’s diabetes was suboptimally controlled with oral antidiabetics. Recently, Rousseau, Parent, Pollak, and Siemiatycki (2006) showed that, although diabetes was associated with an increased risk of liver cancer among men in Canada, no association between melanoma and diabetes was observed. On the other hand, Bell, Jenkinson, Murrells, Skeet, and Everall (1987) found a statistically significant risk of melanoma among diabetic women, particularly in the postmenopausal age group. Furthermore, a higher prevalence of diabetes mellitus in patients with acral lentiginous melanoma was reported in a study from Singapore (Tan, Chua, Lim, & Goh, 2001). Evidence from population-based studies and clinical trials indicates that hyperglycemic patients experience higher mortality and recurrence rates of coexistent cancer. Growth factors such as insulin-like growth factor and factors associated with hyperglycemia have been proposed in the pathogenesis of cancer development in diabetics. Abe et al.
Fig. 2. Ulcerated tumor tissue composed of pleomorphic malignant cells diffusely infiltrating the dermis (10, hematoxylin and eosin staining).
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(2004) identified a critical role of interactions between advanced glycosylation end products and their receptors (RAGE) in the growth and metastasis of human melanoma. In addition, the relationship between hyperglycemia and immune dysfunction is well-described. Immunosuppression is associated with a 2.5-fold to a 10-fold risk of melanoma (Gregson & Allain, 2004). In our patient, poor glycemic control may have led to the development and progression of the malign condition via both mechanisms. In this particular case, there was a suspected history of trauma due to ill-fitting shoes. Furthermore, the location of the ulcer was very much prone to trauma. The influence of mechanical irritation on a preexisting lesion has been proposed as a major risk factor for the development of malignant melanoma. Franke et al. (2000) reported that 94.4% of plantar melanomas were located at the margins of plantar pressure areas, and 43% of patients had preexisting plantar skin lesions. Malignant melanoma presenting as diabetic foot ulcer is rarely reported. We found three such reports, including a total of seven cases, that present patients with malignant melanoma disguised as diabetic foot ulcer (Gregson & Allain, 2004; Kong et al., 2005). There is no consensus about when the clinician should perform a biopsy for a diabetic foot ulcer. However, some findings are helpful in considering early biopsy. The absence of diabetic neuropathy, peripheral arterial disease, and history of trauma should raise the suspicion of melanoma or other specific lesions (Kong et al., 2005). If the foot ulcer is resistant to therapy, any cause for delayed healing should be identified, such as foreign bodies, severe arterial disease, recurrent trauma, or persistent infection due to resistant microorganisms (Gregson & Allain, 2004). Additionally, dermatology consultation should be done when atypical ulcer is present (Franke et al., 2000). Finally, clinicians should be aware of the risk of misdiagnosis of amelanotic melanoma in diabetic patients. An early biopsy should be considered for all diabetic foot ulcers in the absence of chronic diabetic complications, particularly if the ulcer looks atypical or if hypergranulation tissue is present, as in our case. We suggest that early biopsy is also necessary when there is no identified cause of nonhealing in a diabetic foot ulcer.
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References Abe, R., Shimizu, T., Sugawara, H., Watanabe, H., Nakamura, H., Choei, H., Sasaki, N., Yamagishi, S., Takeuchi, M., & Shimizu, H. (2004). Regulation of human melanoma growth and metastasis by AGE–AGE receptor interactions. Journal of Investigative Dermatology, 122, 461 – 467. Bell, C. M., Jenkinson, C. M., Murrells, T. J., Skeet, R. G., & Everall, J. D. (1987). Aetiological factors in cutaneous malignant melanomas seen at a UK skin clinic. Journal of Epidemiology and Community Health, 41, 306 – 311. Chuang, T. Y., Lewis, D. A., & Spandau, D. F. (2005). Decreased incidence of nonmelanoma skin cancer in patients with type 2 diabetes mellitus using insulin: A pilot study. British Journal of Dermatology, 153, 552 – 557. Fortin, P. T., Freiberg, A. A., Rees, R., Sondak, V. K., & Johnson, T. M. (1995). Malignant melanoma of the foot and ankle. Journal of Bone and Joint Surgery, 77, 1396 – 1403. Franke, W., Neumann, N. J., Ruzicka, T., & Schulte, K. W. (2000). Plantar malignant melanoma—A challenge for early recognition. Melanoma Research, 10, 571 – 576. Gregson, C. L., & Allain, T. J. (2004). Amelanotic malignant melanoma disguised as a diabetic foot ulcer. Diabetic Medicine, 21, 924 – 927. Kong, M. F., Jogia, R., Jackson, S., Quinn, M., McNally, P., & Davies, M. (2005). Malignant melanoma presenting as a foot ulcer. Lancet, 366, 1750. Metzger, S., Ellwanger, U., Stroebel, W., Schiebel, U., Rassner, G., & Fierlbeck, G. (1998). Extent and consequences of physician delay in the diagnosis of acral melanoma. Melanoma Research, 8, 181 – 186. O’Mara, B. A., Byers, T., & Schoenfeld, E. (1985). Diabetes mellitus and cancer risk: A multisite case–control study. Journal of Chronic Diseases, 38, 435 – 441. Perniciaro, C. (1997). Dermatopathologic variants of malignant melanoma. Mayo Clinic Proceedings, 72, 273 – 279. Ragozzino, M., Melton, L. J., Chu, C. P., & Palumbo, P. J. (1982). Subsequent cancer risk in the incidence cohort of Rochester, Minnesota, residents with diabetes mellitus. Journal of Chronic Diseases, 35, 13 – 19. Rousseau, M. C., Parent, M. E., Pollak, M. N., & Siemiatycki, J. (2006). Diabetes mellitus and cancer risk in a population-based case–control study among men from Montreal, Canada. International Journal of Cancer, 118, 2105 – 2109. Serarslan, G., Akcal, C., & Atik, E. (2004). Acral lentiginous melanoma misdiagnosed as Tinea pedis: A case report. International Journal of Dermatology, 43, 37 – 38. Soon, S. L., Solomon, A. R., Jr., Papadopoulos, D., Murray, D. R., McAlpine, B., & Washington, C. V. (2003). Acral lentiginous melanoma mimicking benign disease: The Emory experience. Journal of the American Academy of Dermatology, 48, 183 – 188. Tan, E., Chua, S. H., Lim, J. T., & Goh, C. L. (2001). Malignant melanoma seen in a tertiary dermatological centre, Singapore. Annals of the Academy of Medicine, Singapore, 30, 414 – 418.
