What You Should Know About Malignant Melanoma

In an article published in the New England Journal of Medicine (NEJM) in 2006, the author gives an account of a 53-year-old female patient who received treatment from a podiatrist for a plantar wart for two years. She underwent electrocoagulation therapy without histological examination.
Her lesion grew and she eventually sought the care of the NEJM author, who biopsied the lesion and noticed enlarged inguinal lymph nodes. The biopsy revealed amelanotic melanoma exceeding 6 mm in thickness (Clark’s level IV). Despite excision of the lesion and involved lymph nodes, and interferon therapy, the patient died six months after presenting.1
As podiatric physicians, we often encounter various lesions that occur on the lower extremities. The vast majority of these lesions turn out to be benign. Some examples of benign lesions include skin tags, hyperkeratoses and dermatofibromas. Other benign lesions, such as nevi, present with a pigmented appearance.
Nevi can occur as three typical variants: junctional, compound and dermal/intradermal nevi. Junctional nevi present as flat, nonpalpable, hyperpigmented lesions that occur at the dermoepidermal junction above the basement membrane. Compound nevi are most commonly rounded, raised and hyperpigmented. One may see these lesions at the dermoepidermal junction and also within the dermis. Dermal nevi present as round, raised, flesh-colored or pigmented. They occur entirely within the dermis. We also manage and treat many other typical problems such as verruca and ulcers.
When these typical lesions are resistant to care and become chronic non-healing issues, we need to ask ourselves a key question.
Could this lesion be malignant?
The incidence of malignant melanoma has increased over the last few decades. This increase could be attributed to the increase in biopsies performed by physicians as well as an increase of ultraviolet radiation secondary to atmospheric changes.
Melanoma of the foot accounts for approximately 3 to 15 percent of all cutaneous forms of melanomas and, in 7 percent of these cases, they are located on the plantar surface.2-3 Clark, et al., first classified cutaneous melanomas in 1969 as superficial spreading melanoma, lentigo malignant melanoma and nodular melanoma.4 Reed, et al., subsequently described a fourth subtype, acral lentiginous melanoma, which primarily occurs on the plantar and palmar surfaces.5

Pertinent Insights On Acral Lentiginous Melanoma

Acral lentiginous melanoma (ALM) is most common among people with darker pigmented skin (such as natives of Asia, India, Africa and African-Americans). It is relatively infrequent in the fairer skin populations.6,7 Acral lentiginous melanoma is the most common subtype of melanoma that presents on the plantar surface of the foot.3
Due to its unusual site of occurrence, ALM is often misdiagnosed as a wide variety of conditions. These conditions include verruca, hyperkeratoses, onychomycosis, tinea, blisters, keratoacanthoma, onychocryptosis, crusty lesions, ulcerations, sweat gland conditions, non-healing traumatic wounds, foreign bodies, subungual hematomas and nevi.1,8-14
There are at least two accounts of ALMs that were misdiagnosed as diabetic foot ulcers.12,14 Also bear in mind that acral lentiginous melanoma may present as an amelanotic lesion and may not exhibit the classic signs of malignant melanoma associated with the mnemonic “ABCD” (asymmetry, border, color and diameter).6
Researchers have shown that ALM has a high association with:
• high total body nevus counts;
• nevi on the soles;
• a penetrating injury of the feet or hands; and
• heavy exposure to agricultural chemicals.15
However, it was interesting to note that the same study showed that current cigarette smoking was inversely related to cases of acral melanoma.

Other Findings In The Literature On Misdiagnosed ALM In The Lower Extremity
Soon, et al., reviewed 53 lower extremity melanomas and found that 11 of 18 (61 percent) misdiagnosed melanomas were located on the plantar surface of the foot.11 After histopathological analysis, the study authors determined that all the misdiagnosed lesions were ALM.
Metzger, et al., showed that ALM has a greater delay in diagnosis and is more often misdiagnosed versus other subtypes of melanomas.10 They reported that 17 (52 percent) out of 33 subungual melanomas and 10 (20 percent) out of 50 palmoplantar melanomas were clinically misdiagnosed by physicians. In 23 of the 27 misdiagnosed cases (85 percent), non-dermatologists made the clinical misdiagnosis.
According to this study, misdiagnosis caused a median delay of 12 months in the diagnosis of palmoplantar melanomas and 18 months in the diagnosis of subungual melanomas. They determined this was associated with increased tumor thickness, a more advanced stage at the time of melanoma diagnosis and a lower estimated five-year survival rate.

What The Studies Reveal About Excision And The Use Of Sentinel Lymph Node Biopsies
Excision of the primary lesion is still reportedly the treatment of choice for cutaneous malignant melanoma. There is much debate, however, regarding the extent of the resected margins.
Historically, 5 cm margins were the treatment of choice. However, in a prospective, randomized study, Balch, et al., evaluated patients with melanomas of tumor thickness ranging from 1.0 to 4.0 mm. For one group, surgeons performed 2 cm resections while they performed 4 cm resections for another group.16 They concluded that the 10-year survival rate was not statistically different and the incidence of recurrence was the same for both groups. Lens, et al., also showed no statistical difference in recurrence or survival between patients with melanomas receiving either narrow or wide margin resections.17
Veronesi, et al., also corroborated these findings. They conducted a randomized prospective study of 305 patients who received narrow excision (1 cm margins) for an average tumor thickness of 0.99 mm and also studied 307 patients receiving wide excision (3 cm or more) for an average tumor thickness of 1.02 mm.18 They concluded there was no statistical difference between the two groups in the subsequent development of metatstatic disease, disease-free survival rates and overall survival rates.
Other authors advocate having varying widths of excisional margins dependent upon the stage and depth of the melanoma. For lesions less than 0.76 mm thick, a 1 cm margin is adequate. For any lesion greater than 0.76 mm thick, margins of 3 to 5 cm are recommended.19
After resection, one must consider obtaining a sentinel lymph node (SLN) biopsy. In the past, the practice was that patients with stage 0 melanoma should not undergo lymph node dissection whereas patients with tumor thickness exceeding 4.0 mm should undergo the procedure.19 Recent researchers performed SLN biopsies on 94 patients with melanoma with Breslow’s thickness of > 0.76 mm. Nineteen (20.2 percent) were positive and 75 (79.8 percent) were negative. No positive SLN occurred in malignant melanoma with Breslow’s thickness of < 1.0 mm.20 Researchers have also shown that ulceration of the melanoma lesion is a predictor of a positive SLN.20 More specifically, one study showed that ulceration of > 2 percent of the lesion was more often associated with a positive SLN and ulceration of < 2 percent of the lesion was more often associated with a negative SLN.21

Case Study: When A Patient Presents With A Hyperpigmented Lesion

A 78-year-old female presented to our clinic complaining of a lesion under her right fourth and fifth toes. She thought it was a corn or callus. The lesion had been present for about four months and had become discolored with tenderness to the area. The patient rated the pain as three to four out of 10 on a visual analog scale. The patient denied having any other similar lesions. She also reported having some numbness in her feet. Her spouse urged her to have lesion examined two to three months earlier but she chose not to undergo an examination.
The patient has a history of large cell lung cancer of her left lower lobe with a peribronchial node that was positive for metastases. The lung tumor was stage IIB with subsequent lobe resection in November 1999. Her other past medical history consists of mitral valve prolapse, atrial tachycardia, chronic obstructive pulmonary disease (COPD), emphysema, gastroesophageal reflux disease (GERD), generalized anxiety disorder, vitamin B12 deficiency and osteoporosis. The patient’s past surgeries include appendectomy, tonsillectomy, adenoidectomy and C-section. Her medications included ipratropium bromide and albuterol sulfate (Combivent, Boehringer Ingelheim Pharmaceuticals), fluticasone propionate and salmeterol inhalation powder (Advair Diskus, GlaxoSmithKline), and digoxin (Lanoxin, GlaxoSmithKline). She was also undergoing home oxygen therapy. She reported allergies to macrolide antibiotics and clarithromycin (Biaxin, Abbott Laboratories). The family history was significant for diabetes. She denied tobacco, alcohol and recreational drug use.
In our clinical exam, we noted the patient had a hyperpigmented lesion at the plantar right fourth web space with heterogeneous color and irregular borders. The lesion was slightly greater than 6 mm in diameter at its most narrow dimension and less than 1 cm at its largest dimension. There was no appreciable drainage and no other similar lesions. Her neurovascular status was intact with no gross musculoskeletal deformities.
The patient elected to have a punch biopsy of the lesion. We performed a 5-mm punch biopsy of the central aspect of the lesion in the office and we sent the specimen to dermatopathology.
We irrigated the wound and closed it using two simple interrupted sutures of 5-0 prolene. The pathology report initially showed the type of lesion to be unclassified with layered, migratory and focal, expansile vertical growth. The cell type was a high-grade epithelioid tumor cell with no mitotic growth. No tumor cells were infiltrating the lymphocytes.
According to Breslow’s criteria, the lesion was 1.68 mm and was a superficial level IV lesion as per Clark’s criteria. Upon receiving the pathology report, we immediately discussed the case with oncology and referred it to the melanoma team. After consultations with general and orthopaedic surgery, the patient subsequently consented to surgical resection but she would not consent to a sentinel node biopsy. The orthopaedic surgeon resected the lesion and utilized 2.5 to 3 cm margins. The surgeon amputated toes three through five, and resected the distal one-third of the fourth and fifth metatarsals. The surgeon closed the wound with a skin flap. There were no complications from the operation.
The surgeons sent the amputated sections for pathology and the final diagnosis was ALM demonstrating Breslow’s criteria of 1.32 mm and Clark’s criteria of a superficial level IV lesion. The patient received outpatient follow-up for appropriate wound care. The patient died four months after her surgery from complications secondary to her COPD.
This case demonstrates the importance of checking web spaces on all patients and inquiring about all cutaneous lesions one encounters in the clinical exam. When in doubt, it is always best to biopsy.

In Conclusion
Most of the lower extremity lesions that we encounter — such as skin tags, hyperkeratosis, dermatofibromas and various types of nevi — are benign. However, the incidence of malignant lesions is increasing, partially due to the increased numbers of biopsies being performed and partially due to increased ultraviolet radiation exposure in patients. The various types of malignant lesions include ALM, which the literature has shown is susceptible to misdiagnosis or delayed diagnosis given its unusual location.
The literature and the aforementioned case study illustrate the importance of considering whether a chronic, non-healing lesion could be malignant.
We often base our diagnoses on the patient history but the patient history may not be as helpful in cases of atypical or suspicious lesions. The patient may have a rationale as to why the lesion appears as it does but it may be prudent to disregard this information and place more emphasis on the physical exam and clinical suspicion. In the case of benign, typical appearing lesions such as verrucae, it is our preference to biopsy if the lesion does not respond to three standard treatments or if there is recurrence.
At times, one may see an atypical lesion when examining the patient’s web spaces or plantar feet. In some cases, the patient may not be aware of the lesion’s existence or it may not have been the presenting complaint. It may be helpful to have a mirror available in order to show the lesion to the patient. It is also helpful to have a digital camera available so you can print and file the photo with the patient’s chart.
It is better to over-biopsy than under-biopsy. If all of a clinician’s biopsies turn out to be positive, he or she is likely not biopsying enough lesions and is likely missing important diagnoses.
Given the potentially lethal consequences of malignant lesions, it is vital to take a biopsy whenever there is doubt. The earlier one detects cancerous lesions and facilitates an accurate diagnosis, the better the chances are for a good outcome.

Dr. Lashley is a second-year resident in a three-year residency program that is co-sponsored by the Cleveland Clinic Foundation and the Surgical Hospital of Oklahoma.

Dr. McKee is a Staff Podiatrist and Residency On-Site Coordinator in the Department of Orthopedic Surgery at the Center For the Foot And Ankle at the Cleveland Clinic. He is a Fellow of the American College of Foot and Ankle Surgeons.

References:

1. De Giorgi V. et al. Plantar melanoma- A false vegetant wart. NEJM 355(13): e13, 2006.
2. Soong S, et al. Predicting survival and recurrence in localized melanoma: a multivariate approach. World J Surg 16:191-5, 1992.
3. Franke W, et al. Plantar malignant melanoma- a challenge for early recognition. Melanoma Res 10: 571-76. 2000.
4. Clark W, et al. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res 29:705-27. 1969
5. Reed RJ. Acral lentiginous melanoma. In: New Concepts in Surgical Pathology of the Skin (Hartmann W, Kay S, Reed RJ, eds). New York: John Wiley & Sons, Inc., 1976: 89-90.
6. Dwyer P, et al. Plantar malignant melanoma in a white Caucasian population. Br J Dermatol 128(2):115-20, 1993.
7. Wong T, et al. Acral lentiginous melanoma (including in situ melanoma) arising in association with naevocellular naevi. Melanoma Res 6(3): 241-6. 1996.
8. Rosen T. Acral lentiginous melanoma misdiagnosed as verruca plantaris: A case report. Dermatol Online J 12(4):3, 2006.
9. Serarslan G, et al. Acral lentiginous melanoma misdiagnosed as tinea pedis: a case report. Int J Dermatol 43:37-38, 2004.
10. Metzger S, et al. Extent and consequences of physician delay in the diagnosis of acral melanoma. Melanoma Res 8(2): 181-6, 1998.
11. Soon S, et al. Acral lentiginous melanoma mimicking benign disease: The Emory experience. J Am Acad Dermatol 48(2): 183-8, 2003.
12. Rogers L. et al. Malignant melanoma misdiagnosed as a diabetic foot ulcer. Diabetes Care 30(2): 444-445, 2007.
13. Dalmau J. et al. Acral melanoma simulating warts: Dermoscopic clues to prevent missing a melanoma. Dermatol Surg 32: 1072-78, 2006.
14. Kong M. et al. Malignant melanoma presenting as a foot ulcer. Lancet 366: 1750, 2005.
15. Green A. et al. A case-control study of melanomas of the soles and palms (Australia and Scotland). Cancer Causes Control 10(1): 21-5, 1999.
16. Balch CM, et al. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cmexcision margins for 740 patients with 1–4 mm melanomas. Ann Surg Oncol 8(2); 101-8, 2001.
17. Lens MB, et al. Excision margins in the treatment of primary cutaneous melanoma. A systemic review of randomized controlled trials comparing narrow vs. wide excision. Arch Surg 137(10): 1101-1105, 2002.
18. Veronesi U, et al. Thin stage 1 primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. NEJM 318(18): 1159-1162, 1988.
19. Fortin PT, et al. Malignant melanoma of the foot and ankle. J Bone Jnt Surg Am 77(9): 1396-403. 1995.
20. Cuellar FA, et al. Small cell melanoma and ulceration as predictors of positive sentinel lymph node in malignant melanoma patients. Melanoma Res 14: 277-282, 2004.
21. Grande Sarpa, H, et al. Prognostic significance of extent of ulceration in primary cutaneous melanoma. Am J Surg Path 30(11): 1396-1400. 2006.

Editor’s note: For related articles, see “Identifying Skin Malignancies On The Distal Lower Extremity” in the September 2003 issue of Podiatry Today, “Expert Insights On Diagnosing Pigmented Skin Lesions” in the April 2005 issue and “Soft Tissue Masses: When To Treat, When To Refer” in the May 2006 issue.