Due to the potentially dire consequences of amelanotic melanoma, early diagnosis is critical. Accordingly, this author reviews the challenges of the differential diagnosis, discusses a variety of insightful case studies and offers a protocol for facilitating more timely biopsies of suspicious lesions.
In days gone by in the podiatric literature, the reporting of melanoma of any type on the lower extremity, particularly the feet, was a relatively uncommon occurrence. In my experience, most of these reports in the podiatric literature were “surprise” diagnoses. More accurately, treatment for some lesion would begin and based on non-response to treatment, someone decided to do a biopsy, yielding the true nature of the lesion as melanoma.
I have been studying melanoma since 1982 and have been speaking about it since 1995. I am still surprised to hear podiatric clinicians tell me that after 40 years of practice, they have never seen a melanoma. At this point, it is not a matter of not seeing it. It is a matter of missing it.
In the lay and professional literature, it is well documented that melanoma has been skyrocketing in incidence over the last half century. If we only include invasive melanoma, the incidence of developing melanoma in someone born today and living a normal lifespan in the United States is 1 in 50.1 In 1930, the incidence was 1 in 1,500. If we include both non-invasive and invasive presentations of melanoma, the incidence is currently 1 in 32.
In 2009, there were 121,840 new cases of melanoma in the United States with 68,720 being invasive and 53,120 were in-situ. (Researchers have recently noted an explosive increase in the incidence of non-melanoma skin cancers as well.2) Melanoma in-situ is defined as being confined to its origin in the epidermis. Invasive melanoma is defined as having extended into the dermis, thus gaining access to the blood vessels and lymphatics, and the ability to metastasize. In 2009, 8,650 deaths were recorded as a result of melanoma.1
Simply stated, melanoma is occurring in your patients and it is occurring in your area of expertise. Indeed, DPMs have an obligation to survey patients’ skin in their area of expertise and licensure for suspect lesions.
As far as melanomas go, about 30 to 35 percent of all lesions occur on the lower extremities.3 If physicians diagnose melanoma at the non-invasive or in-situ stage, it is thought to be completely curable if one excises it at this stage. Once melanoma becomes invasive, the five-year survival rates decrease in direct proportion to the thickness (depth in millimeters) of the lesion. The pathology report will also note other parameters such as Clark’s levels, the presence of mitotic figures and whether there is vessel or lymphatic invasion. There is 10 times more incidence of melanoma in Caucasians than African-Americans.4
Most students and clinicians are well versed in the diagnostic criteria (the ABCDE mnemonic) for pigmented lesions that should give one a high index of suspicion that the lesion might be a melanoma.
Asymmetry. This is defined as a lesion that one is unable to bisect in any way that produces mirror images.
Border irregularity. This is defined as scalloped edges or poor definition as to where the lesion begins or ends.
Color variegation. In early lesions, this refers to varying shades of tan to brown to black. In later stages, this changes to red, white and blue.
Diameter greater than 6 mm. This refers to the fact that most melanomas do not reveal themselves until they are at least 6 mm in the widest dimension.
However, lesion diameter less than 6 mm alone does not rule out melanoma.
Enlargement or elevation. This can be noted by the clinician or related by the patient. In my mind, this by itself is enough to warrant a biopsy.
Therefore, for most melanomas, clinicians will be alerted by the fact that the lesion produces melanin and thereby becomes a different color (usually tan to brown to black) to the surrounding skin. This allows for assessment according to the aforementioned established criteria.
As if this is not difficult enough, there is a variant of melanoma that is deficient in pigment or produces no pigment at all. This is amelanotic melanoma. Specifically because of the lack of pigment, these lesions are commonly diagnosed at later stages and deeper levels, especially on the feet. They are more commonly associated with the nodular subtype of melanoma and represent less than 5 percent of all melanomas. Due to the lack of pigment, we do not have repeatable criteria for diagnosis such as the aforementioned ABCDE mnemonic for pigmented lesions of the skin.
Theoretically, amelanotic presentations can occur in any type of melanoma. There are case reports of amelanotic acral lentiginous melanoma, amelanotic lentigo maligna melanoma and amelanotic superficial spreading melanoma.5-7 In addition to the difficulty of diagnosing these lesions due to the lack of pigment, other misdiagnoses include eczema, edema, Bowen’s disease and actinic keratoses.6 Physicians have also reported nail bed papulosquamous disease and resulting nail plate dystrophy without pigmentation. This includes nail plate striations, thinning, lysis and splinter hemorrhages.5
Other nail unit disturbances include nail bed granulation tissue, loss of the nail plate, furrows in the nail plate and drainage. In my experience, chronic paronychia is by far the most common misdiagnosis of subungual amelanotic melanoma, most commonly the nodular type.
When appearing on skin, amelanotic melanomas typically present as pink, reddish or flesh colored. Due to the lack of the tip-off of pigment, the lesions are commonly not diagnosed until growth occurs and/or the lesions begin to become symptomatic (itching or pain), bleed or are chronically irritated by clothing or footwear.8 For a summary of clinical findings of amelanotic melanoma, see “Key Facts About Amelanotic Melanoma” at right.
Further complicating the diagnosis of amelanotic melanoma, the lesion can also mimic skin ulcerations in which typically long terms of treatment are common before healing occurs or before one seeks an alternative diagnosis. I have had two cases of amelanotic melanoma masquerading as a plantar diabetic foot ulcer and several colleagues have had similar experiences. The hesitancy to biopsy an ulcerated lesion also contributes to diagnosis in later stages.
One interesting reported case of a amelanotic melanoma disguised as a diabetic foot ulcer adds another potentially problematic issue. This is because treatment for complications of diabetes may be immunosuppressive and therefore contribute to the advancing of the cancer.9
In this case, a patient with type 2 diabetes with a longstanding stable right foot ulcer of 15 years underwent treatment with cyclophosphamide and prednisone for nephrotic syndrome over a seven-month period.9 The patient’s foot ulcer had previously received treatment from podiatric, vascular and orthopedic specialists over the years.
Near the conclusion of immunosuppressive therapy that resolved the nephrotic syndrome, the patient’s right leg became edematous and a mass developed in her thigh. Although an initial examination determined the mass to be swollen lymph nodes, a biopsy revealed amelanotic melanoma. This subsequently forced a biopsy of the ulcer, which was amelanotic melanoma all along and apparently allowed to disseminate from the immunosuppressive therapy.
A 74-year-old female presented to the office of a colleague with medial nail fold swelling, granulation tissue and drainage of the right hallux. The physician diagnosed a paronychia and performed a straight back nail avulsion with local anesthesia. After drainage and granulation tissue persisted, and the physician ruled out a retained nail fragment, a biopsy revealed deeply invasive melanoma. The patient received a referral for definitive treatment. The patient underwent positron emission tomography (PET) scanning, which was negative.
After amputation of the hallux to the level of the MPJ and sentinel lymph node biopsy (which was ultimately negative), she received interferon treatment. She succumbed in four years with lung metastases.
A 66-year-old female stated that her nail fell off after wearing a tight shoe (see photo at left). Being diabetic, she received treatment for infection for three weeks. Her DPM recommended biopsy due to non-resolution of granulation tissue in the nail bed but she delayed having a biopsy. After three months, she relented and the physician performed two punch biopsies through the nail bed.
After two punches through the nail bed, the diagnosis was amelanotic nodular melanoma. The patient underwent amputation to the level of the MPJ and sentinel node biopsy. Preoperative PET scanning was negative. The depth of the lesion on microscopic examination was 11 mm and invasive to bone. It is important to note that immediately before losing the nail, the patient noted that the nail’s appearance was exactly like that of the adjacent, normal third toenail.
After undergoing an amputation and negative sentinel node biopsy, the patient had interferon therapy. As of this writing, there is no evidence of disease.
A 70-year-old male patient stated unequivocally that his third toenail lesion occurred on a recent hiking trip three weeks prior and that at the beginning of the trip, the nail unit was identical in appearance to the adjacent clear nail (see photo at right). He attributed the lesion to rubbing from a hiking boot. He then saw his regular DPM, who referred him for a workup of this lesion.
A biopsy eventually revealed a level IV invasive melanoma. The patient was lost to follow-up as care continued at another institution.
A 65-year-old female patient went for her regular pedicure in August 2009 and states she felt a sharp pain in the right hallux when the pedicurist used a certain instrument (see photos at left). She did not bleed. She developed toenail lysis centrally two weeks later and saw a DPM, who assumed infection based on the history. Treatment continued until the patient sought another opinion in late January 2010.
The patient received a referral to me. I performed a biopsy on the initial visit on February 15, 2010. Histology revealed nodular amelanotic melanoma of at least 2.7 mm in depth with many evident mitoses.
The patient then underwent amputation to the level of the MPJ and a sentinel lymph node biopsy. This revealed a very large sentinel node that was positive for melanoma. Subsequent lymph node dissection of the groin revealed more positive nodes, leading to a very grim prognosis.
As of this writing, the patient has severe lymphedema of the right leg due to the complete groin dissection and is getting ready to start chemotherapy.
In 2007, a very active 82-year-old female heard from a pedicurist that she had a wart on her heel and that she should see a podiatrist, which she did immediately. The podiatrist noted a keratotic lesion that resembled a wart but he was suspicious about it. Although the lesion had no pigment suggestive of melanoma and was not ulcerated, he decided that the appearance was not typical of a wart and performed a biopsy. The diagnosis was minimally invasive amelanotic melanoma.
Upon referring the patient to me for definitive care, the treating podiatrist was unable to be more specific about what made him suspicious. The patient underwent wide excision with a skin graft along with sentinel lymph node biopsy (see above photo). Preoperative PET scanning was negative. She started on interferon therapy but discontinued this due to side effects. She soon completed a more personalized course with dosing spaced out to help minimize side effects.
Interestingly, the patient recently underwent a follow-up PET scan (scheduled annually since her surgery) to search for signs of metastatic disease from the original tumor. There was a positive finding in one lower lung lobe, which turned out to be a primary lung malignancy. This was caught early and was totally resectable. As far as melanoma goes, she remains free of any evident disease.
It only takes a brief review of the literature to realize that all forms of melanoma may present with amelanotic variants and may even masquerade as other lesions, even other tumors that do not rise to the level of urgency that melanoma does. This of course contributes to diagnosis at later stages of the disease. An additional complicating factor is that very often the history of the lesions may support another diagnosis such as trauma or foot ulcer. In the other extreme, there may be a rapidly developing process, from days to weeks, culminating in ulceration, bleeding and toenail lysis.
We must be proactive in the early diagnosis of melanoma in all of our patients. (See “A Suggested Protocol For Obtaining Biopsies Of Lesions” at right.) The best way to do this is to set out on any one day and actively screen all patients for skin lesions to the level of the tibial tubercule, whatever the chief concern articulated by the patient. I am virtually certain that very soon, less than a few days even, you will come across lesions that cause some concern or doubt, and must, at a minimum, undergo histologic diagnosis. Whether you do the biopsy yourself or get a dermatology consult, you will be elevating your standard of care and saving lives for sure.
Dr. Markinson is the Chief of Podiatric Medicine and Surgery in the Leni and Peter W. May Department of Orthopedic Surgery of the Mount Sinai School of Medicine in New York City. He is also an instructor in the Department of Dermatological Surgery at the Mount Sinai School of Medicine.
Dr. Markinson is a Fellow of the American Society of Podiatric Dermatology. He is board certified by the American Board of Podiatric Orthopedics and Primary Podiatric Medicine.
1. American Cancer Society. Cancer Facts and Figures, 2009.
2. Rogers H, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 2010;146(3):283-7
3. Cho E, Rosner BA, Colditz GA. Risk factors for melanoma by body site for whites. Cancer Epidemiology, Biomarkers & Prevention 2005; 14(5):1241-1244.
4. American Cancer Society. Cancer Facts and Figures, 2007, pp. 1–56.
5. Andre J, Moulonguet I, Goetmann-Bonvallot S. In situ amelanotic melanoma of the nail unit mimicking lichen planus. Arch Dermatol 2010;146(4):418-21.
6. Kaufmann R, Nikelski K, Weber R, Sterry W. Amelanotic lentigo maligna melanoma. J Am Acad Dermatol 1995;32(2):339-42.
7. Holder JE, Colloby PS, et al. Amelanotic superficial spreading malignant melanoma mimicking Bowen’s disease. Br J Dermatol 1996;134(3):519-21.
8. Berman K. Amelanotic melanoma and subungual melanoma. Available at http://www.healthcentral.com/skin-cancer/c/83/17284/melanoma/ , 2007.
9. Gregson CL, Allain TJ. Amelanotic malignant melanoma disguised as a diabetic foot ulcer. Diabetic Medicine 2004, 21(8):924-927.
10. Swetter S. Malignant melanoma: differential diagnoses and workup. Available at http://emedicine.medscape.com/article/1100753-diagnosis , 2010.