CLINICALLY SPEAKING
Acral Lentiginous Melanoma of the Foot Misdiagnosed as a Traumatic Ulcer A Cautionary Case Priyanka Gumaste, BA* Lauren Penn, MD* Nicole Cohen* Russell Berman, MD† Anna Pavlick, DO‡ David Polsky, MD, PhD* The incidence of cutaneous melanoma is rising faster than that of almost any other cancer in the United States. Acral lentiginous melanoma is a subtype of melanoma that involves the palms, soles, and nail beds. Although it is one of the rarer types of melanoma, it has a poorer prognosis than other more common subtypes. We describe a case of plantar acral melanoma in a 66-year-old woman that was initially misdiagnosed as a traumatic foot ulcer. We highlight this case to emphasize the importance of close observation and biopsy of ulcerative lesions of the foot that have atypical features or are refractory to standard treatment. (J Am Podiatr Med Assoc 105(2): 189-194, 2015)
Melanoma is a malignant tumor composed of pigment-producing cells called melanocytes. It commonly arises in the skin (91.2%) but can affect other pigmented tissues, such as the retina (5.2%) and intestinal mucosa (1.3%).1 The incidence of cutaneous melanoma is rising faster than that of almost any other cancer in the United States. Melanoma has a poor prognosis if detected late. It is estimated that in 2014 there were 76,100 new cases of melanoma diagnosed and 9,710 melanomarelated deaths.2 Cutaneous melanoma is categorized into four main subtypes: superficial spreading, nodular, lentigo maligna, and acral lentiginous, which compose 70%, 15% to 30%, 5% to 10%, and 2% to 10% of cases, respectively.3 Acral lentiginous melanoma (ALM) involves the palms, soles, and nail apparatus. Although the incidence of ALM is similar across racial and ethnic groups, it represents a *The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, NYU Langone Medical Center, New York, NY. †Department of Surgery, New York University School of Medicine, NYU Langone Medical Center, New York, NY. ‡Division of Medical Oncology, Department of Medicine, New York University School of Medicine, NYU Langone Medical Center, New York, NY. Corresponding author: David Polsky, MD, PhD, NYU Langone Medical Center, 522 First Ave, New York, NY 10016. (E-mail: [email protected])
disproportionate percentage of melanomas in darker-skinned patients.4 In the United States, black, Asian, Pacific Islander, and Hispanic individuals compose less than 3% of individuals with superficial spreading melanoma, the most common histologic subtype. Patients with skin of color, however, represent nearly 18% of those diagnosed as having ALM.5 Acral lentiginous melanoma is of particular importance because it is regarded as one of the more aggressive types of melanoma. Although the absolute cause of this finding is unclear, it is believed to result from inherent molecular differences6-8 in these tumors and a delay in diagnosis often caused by initial misdiagnosis.9-13 There are numerous reports of ALM being misdiagnosed as common disorders, such as fungal infections,14 warts,15 and diabetic foot ulcers.16 Herein we present a case of ALM of the foot initially misdiagnosed as a traumatic ulcer.
Case Report A 66-year-old white woman presented to the dermatology clinic in 2008 with a 1-month history of an ulcer on her left heel. She attributed the lesion to trauma while dancing barefoot on a wooden
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Figure 1. A, Nonhealing ulcer on the left heel measuring 4.5 3 5 mm. B, Close-up image of the ulcer and surrounding skin shows central dark red blotches with erythema and two areas of grey-brown pigment peripherally.
floor, and she noticed that it had not been healing. She had one episode of bleeding during the evolution of the lesion, but none since that time. The patient was unsure whether a lesion had been present before the trauma. Her medical history was significant for hypercholesterolemia, thyroid nodules that were being monitored, depression, and two stage I melanomas of her left arm diagnosed in 1981 and 1998. The patient’s family history was also significant for melanoma in a 19-year-old cousin who died of metastatic disease. Her daily medications included simvastatin and imipramine. On physical examination, the patient had blue eyes, red hair, and fair skin. Examination of her left heel revealed a 4.5 3 5-mm clean-based ulcer with slight central scale and a focal area of dark pigmentation that was presumed to be foreign material. No signs of infection were appreciated. Wound care with petroleum jelly and occlusion under a bandage was recommended. At a 4-month follow-up visit, the lesion showed minimal improvement. During the interval, the patient had it debrided twice by an outside podiatric physician, with no improvement. Close-up photographic imaging of the ulcer and surrounding skin showed central dark red blotches with erythema and two areas of grey-brown pigment peripherally (Fig. 1). Intensive wound care with warm soaks, petroleum jelly, and bandages was recommended.
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The patient was also instructed that a biopsy would be necessary if the lesion did not heal in 6 weeks. One week after her visit, the patient called the clinic concerned that the lesion had been worsening, prompting a referral to a dermatologic surgeon that week. A superficial shave biopsy of the pigmented area at the periphery of the ulcer showed melanoma cells. A subsequent excisional biopsy of the ulcer revealed an ulcerated melanoma measuring 3.15 mm thick with up to three mitoses per highpowered field (Fig. 2). There were focal areas of perineural invasion, and immunostaining for D240 confirmed the presence of atypical melanocytes in lymphatic vessels. There was no evidence of regression. The patient was seen by a surgical oncologist (R.B.), who performed a wide local excision with 2cm margins of normal-appearing skin along with intraoperative lymphatic mapping and sentinel lymph node biopsy. The melanoma was excised with clear margins; however, two additional primary melanomas, physically separate from the ulcer, were also noted in the excision specimen: a 0.9-mm ALM and a melanoma in situ. Four sentinel lymph nodes in the popliteal and inguinal regions were negative for metastatic melanoma; however, the subcapsular sinus of one popliteal lymph node was positive for a small focus (0.15 mm) of melanoma cells. There was also a metastatic focus in the
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oped an ipilimumab-induced endocrinopathy and was treated with corticosteroids, with complete resolution of her symptoms. She was slowly tapered off corticosteroids over 8 weeks, and ipilimumab therapy was discontinued. She remains disease free.
Discussion
Figure 2. Histopathologic analysis of the biopsied
lesion. There is a broad and asymmetrical proliferation of enlarged melanocytes arranged as irregular nests and confluent single units at the dermoepidermal junction, nests and single units at all levels of the epidermis, and nests in the papillary and reticular dermis. Melanocytes have enlarged hyperchromatic nuclei with basophilic nucleoli and a moderate amount of pale-staining cytoplasm. The epidermis is hyperplastic, and there is ulceration in the center of the lesion (H&E, x10). lymphatic vessels of the perinodal fat. As a result, her melanoma staging was IIIa. The patient was advised to undergo complete popliteal lymphadenectomy, but she declined additional surgical intervention. She opted for radiation treatment to the popliteal region and the site of the primary melanoma. One year after completing surgery and radiation, she developed three satellite nodules that were excised. She was subsequently enrolled in a melanoma vaccine clinical trial. This study aimed to use the immunogenic cancer/testis antigen NY-ESO-1, which is expressed by numerous cancers, including melanoma, to stimulate a host immune response against cancer cells. She completed this vaccine protocol over a 3-month period and was expectantly observed. The patient was well until 1.5 years later, when she developed multiple in-transit lesions of the left lower extremity. Owing to the number and scattered locations of the nodules, they were considered unresectable. She then underwent isolated limb infusion therapy followed by ipilimumab therapy as part of a clinical research study. She had complete resolution of her disease by week 24 and was given a maintenance dose of ipilimumab every 12 weeks thereafter. She continued maintenance ipilimumab therapy until week 48, when she developed overwhelming fatigue, lethargy, and headaches. The patient devel-
Diagnosing melanoma at an early stage has a profound effect on patient outcomes.17 Stage I disease, which is localized to the skin, has a 5-year survival rate of 98%. This rate decreases dramatically to 62% with regional spread (stage III disease) and 16% with the development of distant metastases to skin, lymph nodes, or visceral organs (stage IV disease).18 There are several factors that are important in the staging of melanoma. The status of the sentinel node is the single most predictive factor for survival and recurrence in nonmetastatic melanoma.19 In the absence of sentinel node biopsy, tumor thickness measured in millimeters, also known as Breslow thickness, is the strongest prognostic indicator.20 Other important factors for staging include mitotic rate, ulceration, and metastatic spread. Acral lentiginous melanoma can be more difficult to diagnose than other types of melanoma. It classically appears as a black-brown macule, patch, or thin plaque with irregular borders on the palms or soles. When ALM involves the nail, it typically presents as a longitudinal band with multiple shades of brown, black, blue, or grey in the nail plate, ie, longitudinal melanonychia. Involvement of the proximal nail fold or hyponichium, termed Hutchinson’s sign, is an indicator of locally advanced disease.21 Diagnosis of ALM can be challenging because traditional diagnostic criteria for melanomas elsewhere in the body based on asymmetry, border irregularity, multiple colors, a diameter of 6 mm or larger, or evolution of any of these features (ABCDE)22 can be difficult to ascertain. Plantar surfaces, in particular, are often traumatized, which can obscure or alter the appearance of an underlying lesion.9 Furthermore, some ALMs of the foot are amelanotic, compounding the problem.23 Many clinicians are reluctant to perform a biopsy on the foot, especially the plantar surface.9 Biopsying acral lesions can be more difficult than in other locations. If performed on the plantar surface, the procedure can cause scarring at the biopsy site, leading to pain with ambulation. Furthermore, many elderly patients have comorbidities such as venous insufficiency, diabetes, and peripheral arterial disease that can complicate a biopsy and postoperative
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care. For these reasons, plantar ALMs are often misdiagnosed as common pedal disorders, such as warts, fungal or bacterial infections, hematomas, ingrown toenails, ischemia or necrosis, blisters, ganglions, calluses, benign tumors, and, in this particular case, ulcers.20 Diagnosis of a melanoma presenting as an ulcer can be challenging because the differential diagnosis for ulcerations on the foot is broad. Common causes of foot ulcers include diabetes, trauma, infection, neuropathy, and vascular insufficiency (Table 1).24 Treatment of ulcers varies based on their underlying etiology. Most ulcers, however, are managed with treatments that retain moisture to expedite wound healing. Occlusive or semiocclusive wound dressings are commonly used to speed reepithelialization, stimulate collagen synthesis, and promote angiogenesis.25 An ulcer that does not heal despite appropriate treatment should spark concern. When evaluating a patient with a nonhealing wound, a thorough history is critical. History should include 1) initial presentation, time course, and response to treatment; 2) history of wounds, including previous diagnoses and response to treatment; 3) family history of chronic wounds or poor wound healing; 4) associated signs and symptoms, such as pain, edema, or neuropathy; 5) systemic conditions that may predispose patients to wound development or poor healing, such as diabetes, human immunodeficiency virus/acquired immunodeficiency syndrome, sickle cell anemia, Raynaud’s syndrome, rheumatologic disease, chemotherapy, anemia, weight loss, viral hepatitis, illicit drug use, transfusions, or neurologic disorders; and 6) thorough medication history.25 A comprehensive history will help reveal the cause of an ulcer, provide prognostic information, and guide therapy. An ulcer with an atypical presentation or one that fails to improve with appropriate treatment should prompt reconsideration of the working diagnosis. To address the diagnostic challenges associated with foot lesions presented previously, Bristow et al23 created the acronym ‘‘CUBED’’ to identify lesions of concern (Table 2). According to this algorithm, when any two features apply, the patient should be referred to a dermatologist. When dealing specifically with ulcers, biopsy should be performed if 1) the ulcer looks suspicious or atypical, 2) there is no evidence of neuropathy or ischemia, 3) the ulcer does not heal despite adherence to treatment for 12 weeks, 4) the ulcer is in an unusual anatomical site, 5) the ulcer is painful, and 6) there
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Table 1. Differential Diagnosis of Foot Ulcersa Venous disease Venous obstruction (DVT, pregnancy, congenital anomalies) Venous reflux (primary varicose veins, previous DVTs, incompetent perforators) Calf muscle pump dysfunction (neuromuscular disease, arthritis) Arterial insufficiency Peripheral artery disease Diabetes mellitus Diabetic neuropathy Trauma/excessive pressure Pressure ulcer Bedridden/elderly Lymphedema Chronic venous disease Obesity Trauma Previous surgery Infectious Staphylococcus aureus b-Hemolytic streptococci Pseudomonas Vasculitis and autoimmune disease Rheumatoid arthritis Systemic lupus erythematosus Scleroderma Thromboangiitis obliterans (Buerger’s disease) Cryoglobulinemia Polyarteritis nodosa Granulomatosis with polyangiitis (Wegener’s) Inflammatory Pyoderma gangrenosum Calciphylaxis Hemodialysis Drug-induced skin necrosis Warfarin Heparin Malignancy Squamous cell carcinoma (Marjolin’s ulcers) Basal cell carcinoma Melanoma Abbreviation: DVT, deep vein thrombosis. Adapted from Fukaya and Margolis.24
a
is pigmentation. In addition, if the etiology of an ulcer is uncertain, it should be biopsied.26 The goal of surgical treatment of melanoma is resection of the lesion with adequate surgical margins. Classically, for melanomas with a Breslow
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Table 2. Features to Identify Acral Lesions Needing Referral: CUBEDa
4.
C ¼ Colored variation in a lesion U ¼ Uncertain diagnosis B ¼ Bleeding lesions on the foot or under the nail E ¼ Enlargement or deterioration of a lesion or ulcer despite therapy
5.
D ¼ Delay in healing of any lesion beyond 2 months a
Adapted from Bristow et al.23
thickness of 1 mm or less, a 1-cm margin is sufficient. If a lesion is 1 mm or greater in thickness, a sentinel lymph node biopsy is also recommended.27 Sentinel node biopsy is often considered for thinner lesions when adverse histologic criteria are present, such as ulceration. One author recommended appropriate surgical excision and biopsy of sentinel lymph nodes in ALM, even in lesions less than 1 mm thick.28 It is, therefore, imperative that these lesions be identified and diagnosed before progressing to advanced stages to preserve limb function.
6.
7.
8.
9. 10. 11.
12.
Conclusions In cases of ALM, delay in diagnosis is the most modifiable prognostic indicator. It is important that melanomas be considered in the differential diagnosis of nonhealing foot ulcers and atypical acral lesions, especially in patients with a personal or family history of melanoma, as was the case with this patient. We highlight this case to emphasize the importance of close observation and biopsy of pedal ulcers that have atypical features or are refractory to standard treatment.
13.
14.
15.
16.
17.
Financial Disclosure: None reported. Conflict of Interest: None reported. 18.
References 1. CHANG AE, KARNELL LH, MENCK HR: American College of Surgeons Commission on Cancer and the American Cancer Society: The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. Cancer 83: 1664, 1998. 2. HOWLADER N, NOONE AM, KRAPCHO M, ET AL (eds): SEER Cancer Statistics Review, 1975–2011. Available at: http:// seer.cancer.gov/csr/1975_2011. Accessed January 22, 2015. 3. AGARWALA SS, KIRKWOOD JM: ‘‘Melanoma: Epidemiology,’’
19.
20.
21.
in Encyclopedia of Cancer, 2nd Ed, edited by RB Joseph, p 153, Academic Press, New York, 2002. BRADFORD PT, GOLDSTEIN AM, MCMASTER ML, ET AL: Acral lentiginous melanoma: incidence and survival patterns in the United States, 1986–2005. Arch Dermatol 145: 427, 2009. WU XC, EIDE MJ, KING J, ET AL: Racial and ethnic variations in incidence and survival of cutaneous melanoma in the United States, 1999–2006. J Am Acad Dermatol 65: S26, 2011. CURTIN JA, FRIDLYAND J, KAGESHITA T, ET AL: Distinct sets of genetic alterations in melanoma. N Engl J Med 353: 2135, 2005. CURTIN JA, BUSAM K, PINKEL D, ET AL: Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24: 4340, 2006. MIRACCO C, SANTOPIETRO R, BIAGIOLI M, ET AL: Different patterns of cell proliferation and death and oncogene expression in cutaneous malignant melanoma. J Cutan Pathol 25: 244, 1998. ALBRESKI D, SLOAN SB: Melanoma of the feet: misdiagnosed and misunderstood. Clin Dermatol 27: 556, 2009. BARNES BC, SEIGLER HF, SAXBY TS, ET AL: Melanoma of the foot. J Bone Joint Surg Am 76: 892, 1994. FRANKE W, NEUMANN NJ, RUZICKA T, ET AL: Plantar malignant melanoma: a challenge for early recognition. Melanoma Res 10: 571, 2000. TALLEY LI, SOONG S, HARRISON RA, ET AL: Clinical outcomes of localized melanoma of the foot: a case-control study. J Clin Epidemiol 51: 853, 1998. DAWBER RP, COLVER GB: The spectrum of malignant melanoma of the nail apparatus. Semin Dermatol 10: 82, 1991. SERARSLAN G, AKCALY C, ATIK E: Acral lentiginous melanoma misdiagnosed as tinea pedis: a case report. Int J Dermatol 43: 37, 2004. ROSEN T: Acral lentiginous melanoma misdiagnosed as verruca plantaris: a case report. Dermatol Online J 12: 3, 2006. HUSSIN P, LOKE SC, NOOR FM, ET AL: Malignant melanoma of the foot in patients with diabetes mellitus: a trap for the unwary. Med J Malaysia 67: 422, 2012. BALCH CM, GERSHENWALD JE, SOONG SJ, ET AL: Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27: 6199, 2009. AMERICAN CANCER SOCIETY: Cancer Facts & Figures, 2011, American Cancer Society, Atlanta, 2011. GERSHENWALD JE, THOMPSON W, MANSFIELD PF, ET AL: Multiinstitutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17: 976, 1999. BRISTOW IR, DE BERKER DA: Development of a practical guide for the early recognition for malignant melanoma of the foot and nail unit. J Foot Ankle Res 3: 22, 2010. PROIETTO G, GIACULLI E, DE BIASIO F, ET AL: Conservative surgical treatment of a thin acral lentiginous melanoma of the thumb with no recurrences: a case report. Dermatol Ther 26: 260, 2013.
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22. ABBASI NR, SHAW HM, RIGEL DS, ET AL: Early diagnosis of cutaneous melanoma: revisiting the ABCD criteria. JAMA 292: 2771, 2004. 23. BRISTOW IR, DE BERKER DA, ACLAND KM, ET AL: Clinical guidelines for the recognition of melanoma of the foot and nail unit. J Foot Ankle Res 3: 25, 2010. 24. FUKAYA E, MARGOLIS DJ: Approach to diagnosing lower extremity ulcers. Dermatologic Ther 26: 181, 2013. 25. FONDER MA, LAZARUS GS, COWAN DA, ET AL: Treating the chronic wound: a practical approach to the care of
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nonhealing wounds and wound care dressings. J Am Acad Dermatol 58: 185, 2008. 26. KONG MF, JOGIA R, JACKSON S, ET AL: When to biopsy a foot ulcer? Seven cases of malignant melanoma presenting as foot ulcers. Pract Diabetes Int 25: 5, 2008. 27. THOMPSON JF, SCOLYER RA, KEFFORD RF: Cutaneous melanoma. Lancet 365: 687, 2005. 28. NAHABEDIAN MY, TUFARO AP, MANSON PN: Sentinel lymph node biopsy for the T1 (thin) melanoma: is it necessary? Ann Plast Surg 50: 601, 2003.
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Acral Lentiginous Melanoma of the Foot Misdiagnosed as a Traumatic Ulcer A Cautionary Case Priyanka Gumaste, BA* Lauren Penn, MD* Nicole Cohen* Russell Berman, MD† Anna Pavlick, DO‡ David Polsky, MD, PhD* The incidence of cutaneous melanoma is rising faster than that of almost any other cancer in the United States. Acral lentiginous melanoma is a subtype of melanoma that involves the palms, soles, and nail beds. Although it is one of the rarer types of melanoma, it has a poorer prognosis than other more common subtypes. We describe a case of plantar acral melanoma in a 66-year-old woman that was initially misdiagnosed as a traumatic foot ulcer. We highlight this case to emphasize the importance of close observation and biopsy of ulcerative lesions of the foot that have atypical features or are refractory to standard treatment. (J Am Podiatr Med Assoc 105(2): 189-194, 2015)
Melanoma is a malignant tumor composed of pigment-producing cells called melanocytes. It commonly arises in the skin (91.2%) but can affect other pigmented tissues, such as the retina (5.2%) and intestinal mucosa (1.3%).1 The incidence of cutaneous melanoma is rising faster than that of almost any other cancer in the United States. Melanoma has a poor prognosis if detected late. It is estimated that in 2014 there were 76,100 new cases of melanoma diagnosed and 9,710 melanomarelated deaths.2 Cutaneous melanoma is categorized into four main subtypes: superficial spreading, nodular, lentigo maligna, and acral lentiginous, which compose 70%, 15% to 30%, 5% to 10%, and 2% to 10% of cases, respectively.3 Acral lentiginous melanoma (ALM) involves the palms, soles, and nail apparatus. Although the incidence of ALM is similar across racial and ethnic groups, it represents a *The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, NYU Langone Medical Center, New York, NY. †Department of Surgery, New York University School of Medicine, NYU Langone Medical Center, New York, NY. ‡Division of Medical Oncology, Department of Medicine, New York University School of Medicine, NYU Langone Medical Center, New York, NY. Corresponding author: David Polsky, MD, PhD, NYU Langone Medical Center, 522 First Ave, New York, NY 10016. (E-mail: [email protected])
disproportionate percentage of melanomas in darker-skinned patients.4 In the United States, black, Asian, Pacific Islander, and Hispanic individuals compose less than 3% of individuals with superficial spreading melanoma, the most common histologic subtype. Patients with skin of color, however, represent nearly 18% of those diagnosed as having ALM.5 Acral lentiginous melanoma is of particular importance because it is regarded as one of the more aggressive types of melanoma. Although the absolute cause of this finding is unclear, it is believed to result from inherent molecular differences6-8 in these tumors and a delay in diagnosis often caused by initial misdiagnosis.9-13 There are numerous reports of ALM being misdiagnosed as common disorders, such as fungal infections,14 warts,15 and diabetic foot ulcers.16 Herein we present a case of ALM of the foot initially misdiagnosed as a traumatic ulcer.
Case Report A 66-year-old white woman presented to the dermatology clinic in 2008 with a 1-month history of an ulcer on her left heel. She attributed the lesion to trauma while dancing barefoot on a wooden
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Figure 1. A, Nonhealing ulcer on the left heel measuring 4.5 3 5 mm. B, Close-up image of the ulcer and surrounding skin shows central dark red blotches with erythema and two areas of grey-brown pigment peripherally.
floor, and she noticed that it had not been healing. She had one episode of bleeding during the evolution of the lesion, but none since that time. The patient was unsure whether a lesion had been present before the trauma. Her medical history was significant for hypercholesterolemia, thyroid nodules that were being monitored, depression, and two stage I melanomas of her left arm diagnosed in 1981 and 1998. The patient’s family history was also significant for melanoma in a 19-year-old cousin who died of metastatic disease. Her daily medications included simvastatin and imipramine. On physical examination, the patient had blue eyes, red hair, and fair skin. Examination of her left heel revealed a 4.5 3 5-mm clean-based ulcer with slight central scale and a focal area of dark pigmentation that was presumed to be foreign material. No signs of infection were appreciated. Wound care with petroleum jelly and occlusion under a bandage was recommended. At a 4-month follow-up visit, the lesion showed minimal improvement. During the interval, the patient had it debrided twice by an outside podiatric physician, with no improvement. Close-up photographic imaging of the ulcer and surrounding skin showed central dark red blotches with erythema and two areas of grey-brown pigment peripherally (Fig. 1). Intensive wound care with warm soaks, petroleum jelly, and bandages was recommended.
190
The patient was also instructed that a biopsy would be necessary if the lesion did not heal in 6 weeks. One week after her visit, the patient called the clinic concerned that the lesion had been worsening, prompting a referral to a dermatologic surgeon that week. A superficial shave biopsy of the pigmented area at the periphery of the ulcer showed melanoma cells. A subsequent excisional biopsy of the ulcer revealed an ulcerated melanoma measuring 3.15 mm thick with up to three mitoses per highpowered field (Fig. 2). There were focal areas of perineural invasion, and immunostaining for D240 confirmed the presence of atypical melanocytes in lymphatic vessels. There was no evidence of regression. The patient was seen by a surgical oncologist (R.B.), who performed a wide local excision with 2cm margins of normal-appearing skin along with intraoperative lymphatic mapping and sentinel lymph node biopsy. The melanoma was excised with clear margins; however, two additional primary melanomas, physically separate from the ulcer, were also noted in the excision specimen: a 0.9-mm ALM and a melanoma in situ. Four sentinel lymph nodes in the popliteal and inguinal regions were negative for metastatic melanoma; however, the subcapsular sinus of one popliteal lymph node was positive for a small focus (0.15 mm) of melanoma cells. There was also a metastatic focus in the
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oped an ipilimumab-induced endocrinopathy and was treated with corticosteroids, with complete resolution of her symptoms. She was slowly tapered off corticosteroids over 8 weeks, and ipilimumab therapy was discontinued. She remains disease free.
Discussion
Figure 2. Histopathologic analysis of the biopsied
lesion. There is a broad and asymmetrical proliferation of enlarged melanocytes arranged as irregular nests and confluent single units at the dermoepidermal junction, nests and single units at all levels of the epidermis, and nests in the papillary and reticular dermis. Melanocytes have enlarged hyperchromatic nuclei with basophilic nucleoli and a moderate amount of pale-staining cytoplasm. The epidermis is hyperplastic, and there is ulceration in the center of the lesion (H&E, x10). lymphatic vessels of the perinodal fat. As a result, her melanoma staging was IIIa. The patient was advised to undergo complete popliteal lymphadenectomy, but she declined additional surgical intervention. She opted for radiation treatment to the popliteal region and the site of the primary melanoma. One year after completing surgery and radiation, she developed three satellite nodules that were excised. She was subsequently enrolled in a melanoma vaccine clinical trial. This study aimed to use the immunogenic cancer/testis antigen NY-ESO-1, which is expressed by numerous cancers, including melanoma, to stimulate a host immune response against cancer cells. She completed this vaccine protocol over a 3-month period and was expectantly observed. The patient was well until 1.5 years later, when she developed multiple in-transit lesions of the left lower extremity. Owing to the number and scattered locations of the nodules, they were considered unresectable. She then underwent isolated limb infusion therapy followed by ipilimumab therapy as part of a clinical research study. She had complete resolution of her disease by week 24 and was given a maintenance dose of ipilimumab every 12 weeks thereafter. She continued maintenance ipilimumab therapy until week 48, when she developed overwhelming fatigue, lethargy, and headaches. The patient devel-
Diagnosing melanoma at an early stage has a profound effect on patient outcomes.17 Stage I disease, which is localized to the skin, has a 5-year survival rate of 98%. This rate decreases dramatically to 62% with regional spread (stage III disease) and 16% with the development of distant metastases to skin, lymph nodes, or visceral organs (stage IV disease).18 There are several factors that are important in the staging of melanoma. The status of the sentinel node is the single most predictive factor for survival and recurrence in nonmetastatic melanoma.19 In the absence of sentinel node biopsy, tumor thickness measured in millimeters, also known as Breslow thickness, is the strongest prognostic indicator.20 Other important factors for staging include mitotic rate, ulceration, and metastatic spread. Acral lentiginous melanoma can be more difficult to diagnose than other types of melanoma. It classically appears as a black-brown macule, patch, or thin plaque with irregular borders on the palms or soles. When ALM involves the nail, it typically presents as a longitudinal band with multiple shades of brown, black, blue, or grey in the nail plate, ie, longitudinal melanonychia. Involvement of the proximal nail fold or hyponichium, termed Hutchinson’s sign, is an indicator of locally advanced disease.21 Diagnosis of ALM can be challenging because traditional diagnostic criteria for melanomas elsewhere in the body based on asymmetry, border irregularity, multiple colors, a diameter of 6 mm or larger, or evolution of any of these features (ABCDE)22 can be difficult to ascertain. Plantar surfaces, in particular, are often traumatized, which can obscure or alter the appearance of an underlying lesion.9 Furthermore, some ALMs of the foot are amelanotic, compounding the problem.23 Many clinicians are reluctant to perform a biopsy on the foot, especially the plantar surface.9 Biopsying acral lesions can be more difficult than in other locations. If performed on the plantar surface, the procedure can cause scarring at the biopsy site, leading to pain with ambulation. Furthermore, many elderly patients have comorbidities such as venous insufficiency, diabetes, and peripheral arterial disease that can complicate a biopsy and postoperative
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care. For these reasons, plantar ALMs are often misdiagnosed as common pedal disorders, such as warts, fungal or bacterial infections, hematomas, ingrown toenails, ischemia or necrosis, blisters, ganglions, calluses, benign tumors, and, in this particular case, ulcers.20 Diagnosis of a melanoma presenting as an ulcer can be challenging because the differential diagnosis for ulcerations on the foot is broad. Common causes of foot ulcers include diabetes, trauma, infection, neuropathy, and vascular insufficiency (Table 1).24 Treatment of ulcers varies based on their underlying etiology. Most ulcers, however, are managed with treatments that retain moisture to expedite wound healing. Occlusive or semiocclusive wound dressings are commonly used to speed reepithelialization, stimulate collagen synthesis, and promote angiogenesis.25 An ulcer that does not heal despite appropriate treatment should spark concern. When evaluating a patient with a nonhealing wound, a thorough history is critical. History should include 1) initial presentation, time course, and response to treatment; 2) history of wounds, including previous diagnoses and response to treatment; 3) family history of chronic wounds or poor wound healing; 4) associated signs and symptoms, such as pain, edema, or neuropathy; 5) systemic conditions that may predispose patients to wound development or poor healing, such as diabetes, human immunodeficiency virus/acquired immunodeficiency syndrome, sickle cell anemia, Raynaud’s syndrome, rheumatologic disease, chemotherapy, anemia, weight loss, viral hepatitis, illicit drug use, transfusions, or neurologic disorders; and 6) thorough medication history.25 A comprehensive history will help reveal the cause of an ulcer, provide prognostic information, and guide therapy. An ulcer with an atypical presentation or one that fails to improve with appropriate treatment should prompt reconsideration of the working diagnosis. To address the diagnostic challenges associated with foot lesions presented previously, Bristow et al23 created the acronym ‘‘CUBED’’ to identify lesions of concern (Table 2). According to this algorithm, when any two features apply, the patient should be referred to a dermatologist. When dealing specifically with ulcers, biopsy should be performed if 1) the ulcer looks suspicious or atypical, 2) there is no evidence of neuropathy or ischemia, 3) the ulcer does not heal despite adherence to treatment for 12 weeks, 4) the ulcer is in an unusual anatomical site, 5) the ulcer is painful, and 6) there
192
Table 1. Differential Diagnosis of Foot Ulcersa Venous disease Venous obstruction (DVT, pregnancy, congenital anomalies) Venous reflux (primary varicose veins, previous DVTs, incompetent perforators) Calf muscle pump dysfunction (neuromuscular disease, arthritis) Arterial insufficiency Peripheral artery disease Diabetes mellitus Diabetic neuropathy Trauma/excessive pressure Pressure ulcer Bedridden/elderly Lymphedema Chronic venous disease Obesity Trauma Previous surgery Infectious Staphylococcus aureus b-Hemolytic streptococci Pseudomonas Vasculitis and autoimmune disease Rheumatoid arthritis Systemic lupus erythematosus Scleroderma Thromboangiitis obliterans (Buerger’s disease) Cryoglobulinemia Polyarteritis nodosa Granulomatosis with polyangiitis (Wegener’s) Inflammatory Pyoderma gangrenosum Calciphylaxis Hemodialysis Drug-induced skin necrosis Warfarin Heparin Malignancy Squamous cell carcinoma (Marjolin’s ulcers) Basal cell carcinoma Melanoma Abbreviation: DVT, deep vein thrombosis. Adapted from Fukaya and Margolis.24
a
is pigmentation. In addition, if the etiology of an ulcer is uncertain, it should be biopsied.26 The goal of surgical treatment of melanoma is resection of the lesion with adequate surgical margins. Classically, for melanomas with a Breslow
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Table 2. Features to Identify Acral Lesions Needing Referral: CUBEDa
4.
C ¼ Colored variation in a lesion U ¼ Uncertain diagnosis B ¼ Bleeding lesions on the foot or under the nail E ¼ Enlargement or deterioration of a lesion or ulcer despite therapy
5.
D ¼ Delay in healing of any lesion beyond 2 months a
Adapted from Bristow et al.23
thickness of 1 mm or less, a 1-cm margin is sufficient. If a lesion is 1 mm or greater in thickness, a sentinel lymph node biopsy is also recommended.27 Sentinel node biopsy is often considered for thinner lesions when adverse histologic criteria are present, such as ulceration. One author recommended appropriate surgical excision and biopsy of sentinel lymph nodes in ALM, even in lesions less than 1 mm thick.28 It is, therefore, imperative that these lesions be identified and diagnosed before progressing to advanced stages to preserve limb function.
6.
7.
8.
9. 10. 11.
12.
Conclusions In cases of ALM, delay in diagnosis is the most modifiable prognostic indicator. It is important that melanomas be considered in the differential diagnosis of nonhealing foot ulcers and atypical acral lesions, especially in patients with a personal or family history of melanoma, as was the case with this patient. We highlight this case to emphasize the importance of close observation and biopsy of pedal ulcers that have atypical features or are refractory to standard treatment.
13.
14.
15.
16.
17.
Financial Disclosure: None reported. Conflict of Interest: None reported. 18.
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