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Dermatology Diagnosis

When A Patient Presents With A Non-Healing Blister Of The Great Toe

A 68-year-old male presented complaining of a non-healing blister of his great toe. The blister originated on the medial aspect of his left hallux about six months prior to the patient seeking medical evaluation. The patient attributed the blister to a long hike in the past. This non-painful blister progressed to an ulceration over several months, prompting the patient to seek care. Attempts to offload the area of concern yielded no improvement. 

Aside from a history of daily alcohol use and cervical radiculopathy, the patient had an unremarkable medical history. Physically, the patient appeared to be in good health. A focused bilateral lower extremity exam included findings of palpable pedal pulses, diminished protective sensation and hallux extensus with no other deformities or deficiencies. There was a hypergranular ulceration on the left hallux with macerated borders encompassing the plantar medial digit (see first photo above). There were no acute signs of infection. Plain film radiographs did not reveal any cortical erosions, periosteal reaction or visible osseous tumors. Given that there were no clinical signs of infection, we did not pursue labs or cultures. 

After three weeks of conservative measures, including local wound care and offloading, the ulceration size remained unchanged as did the hypergranular appearance. Given this failure to improve, we performed a punch biopsy of the lesion. 

Pathology results confirmed an ulcerative malignant melanoma with a depth of at least four mm. We subsequently performed a left hallux amputation and there was a subsequent sentinel lymph node biopsy. The final ulceration measurements were 4.5 cm x 3.5 cm with 0.6 cm depth, and there was a positive sentinel inguinal lymph node biopsy. 

A whole body positron emission tomography (PET) scan revealed disease advancement to the lung, mediastinum and liver (see images on page 15). At this time, the patient received a diagnosis of metastatic malignant melanoma (American Joint Committee on Cancer (AJCC) stage pT4N1M1a, BRAF negative). Brain metastasis was detected shortly thereafter. The patient had a short course of palliative systemic immunotherapy with ipilimumab (Yervoy®, Bristol-Myers Squibb) but passed away six months after the initial presentation. 

Key Questions To Consider 

1. When should one biopsy a pedal lesion for diagnosis? 

2. What is the prognosis for ulcerative malignant melanoma in the foot? 

3. What is the treatment for these lesions? 

4. What is the proper follow-up? 

Answering The Key Diagnostic Questions 

1. Clinicians must carry a high index of suspicion with a low threshold for biopsy when treating pedal ulcerations, especially those that fail to improve with proper care. 

2. One determines the prognosis by the stage and advancement of the disease, specifically thickness or depth of the lesion. 

3. Once one has confirmed a malignant melanocytic lesion, the fundamental treatment is local wide excision. Sentinel lymph nodes may require biopsy if the lesion is one mm or greater in depth. Metastatic disease requires immunotherapy and oftentimes radiation. 

4. Lifelong follow-up is essential for anyone with melanoma. Recommended follow-up intervals depend on the stage of the melanoma. 

Essential Biopsy Considerations 

It is paramount that clinicians include melanoma in the differential diagnosis when treating all pedal ulcerations irrespective of medical history as ulcerative melanoma can mimic neuropathic or traumatic lesions. Not only has lesion thickness proven to be a significant influence in melanoma prognosis but primary melanoma of the foot is associated with poorer outcomes in comparison to whole body data, prompting the need for early detection of foot melanoma.1-3 Thus, a high index of suspicion with a low threshold for biopsy is necessary for detection and appropriate treatment of melanoma. 

Invasive malignant melanoma can be visually indistinguishable from neuropathic ulcerations, hence requiring biopsy for diagnosis. A high incidence of misdiagnosis exists for lesions on the lower extremity with a significantly higher mortality and lower disease-free survival rate in patients with misdiagnosed melanoma.4-6 It is imperative to biopsy any suspicious lesions or lesions that fail to improve with proper care. Early, accurate diagnosis can prevent the development of advanced disease and improve overall survival outcomes. 

What The Literature Reveals About The Prognosis Of Malignant Melanoma In The Foot 

One determines prognosis in these cases by the stage and advancement of the disease, specifically thickness or depth of the lesion. The incidence of metastatic disease and five-year mortality increases when lesion/depth is greater than or equal to one mm.7 Physicians have previously used the Breslow Depth and Clark Level classifications for melanoma. Breslow evaluated the depth of the biopsied lesion in millimeters and Clark assessed depth based on the anatomical layer.8 

More recently, the American Joint Committee on Cancer created melanoma staging based on the tumor depth, lymph node involvement and metastasis (TNM), which also allows for prognostic evaluation.9 Stages I and II describe localized disease to the primary site whereas stage III involves regional lymph node metastasis and stage IV is marked by distant metastatic disease. 

The prognosis for primary melanoma of the foot is worse than other anatomic locations of the body.1,3,10 The rationale for poorer outcomes in the foot is thought to be multifactorial. Difficulty performing self-examination of the foot can delay initial presentation for evaluation and misdiagnosis due to melanoma mimicking other common ulcerative lesions can delay diagnosis. Adams and colleagues showed that out of 76 patients with melanoma of the foot, only 56 percent had localized disease in comparison to the 84 percent noted in the National Cancer Institute’s Surveillance, Epidemiology, and End Results program data, showing increased progression of disease in the foot at initial diagnosis.1,11 

Again, this relates to melanoma of the foot mimicking other common ulcerative conditions or these lesions possibly being painless and not easily visualized. A recently proposed theory regarding differences in tumor biology when comparing primary melanoma of the foot to other sun-exposed areas of the body states that a majority of plantar melanomas will not have the BRAF or NRAS mutations commonly associated with melanomas in sun-exposed skin.12 

The five-year survival rate of primary melanoma of the foot and ankle is reportedly as low as 52 percent in comparison to 84 percent when considering whole body data.10 Not only are there significantly worse outcomes in the foot and ankle in comparison to other anatomic locations, but there are also worse outcomes when comparing primary melanoma of the foot to the toe.1 Prognosis significantly declines when there is melanoma localized to the toe with a five-year survival rate of 50 percent.1 Patients with ulcerative malignant melanoma lesions also reportedly have lower survival rates in comparison to patients with non-ulcerative lesions.1 

What You Should Know About Proper Treatment Planning And Follow-Up 

Suspected lesions require biopsy via punch or incision. A superficial shave biopsy has the risk of compromising pathological diagnosis and not encompassing the true depth of the melanoma. Once one has confirmed melanoma, the fundamental treatment is local wide excision if the physician has not obtained this with the initial biopsy. Physicians can determine the margins needed for complete excision of the lesion by assessing the depth of the biopsied lesion. It is important to note that the melanoma may extend beyond visible margins or have satellite lesions. (See “Recommendations For Wide Local Excision Of Cutaneous Melanoma” above.) 

Sentinel lymph nodes, the first lymph nodes to which cancer cells are most likely to spread to from a primary tumor, require biopsy when the thickness of the melanoma is greater than or equal to one mm. 

If the lesion is ulcerative, the clinician must have a high suspicion for regional or metastatic disease.13 Lymph node positivity and bulky nodal disease may further require complete node dissection.14 If the sentinel lymph node is negative, it is unlikely that the cancer has spread via the lymphatics. Metastatic disease requires immunotherapy and often radiation. Most importantly, after any treatment for melanoma, routine dermatologic screening and follow-up are key. 

It is essential to have proper follow-up for patients treated for melanoma to evaluate for recurrence, spread or new primary melanoma. This includes skin and lymph node exams. It is important to emphasize and counsel patients that lifelong follow-up is vital for anyone diagnosed with melanoma. 

Recommended follow up depends on the stage of the melanoma. The follow-up for American Joint Committee on Cancer stages IA to IIA should be every three to 12 months for the first five years followed by annual appointments. Stages IIB through IV require evaluations every three to six months for the first two years, three to 12 months for the next three years and then annually.15 One should consider chest radiographs, computed tomography (CT) and/or positron emission tomography scan every three to 12 months as well as an annual brain MRI for patients whose disease classification is stage IIB and above.15 Providers can discontinue routine imaging once a patient has five years of remission without recurrence. 

In Summary 

This case involved a 68-year-old male who was initially treated for a neuropathic ulceration without improvement, prompting biopsy and diagnosis of invasive malignant melanoma with metastatic progression. This case demonstrates the importance of early diagnosis of melanoma and early biopsy of lesions. A delay in diagnosis can have catastrophic consequences due to disease progression from delayed treatment. 

Melanoma of the foot frequently presents in later stages in comparison to anatomic 

locations elsewhere in the body, making a timely diagnosis even more critical. Treatment algorithms are dependent on the depth of the primary lesion as well as the spread of the disease. Lifelong follow-up evaluations are essential for all patients diagnosed with melanoma.  

Dr. Ramirez is a first-year resident with the San Francisco Bay Foot and Ankle Surgery Residency Program at Kaiser Permanente in Oakland, Calif. 

Dr. Dionisopoulos is a second-year resident with the San Francisco Bay Foot and Ankle Surgery Residency Program at Kaiser Permanente in Oakland, Calif. 

Dr. Williams is a Fellow of the American College of Foot and Ankle Surgeons, and is board-certified by the American Board of Foot and Ankle Surgery. Dr. Williams is an Attending Physician with the San Francisco Bay Foot and Ankle Surgery Residency Program at Kaiser Permanente in Oakland, Calif. 

Dermatology Diagnosis
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By Fernando Ramirez II, DPM, Shontal B. Dionisopoulos, DPM and Mitzi Williams, DPM, FACFAS
References

1. Adams BE, Peng PD, Williams ML. Melanoma of the foot is associated with advanced disease and poorer survival. J Foot Ankle Surg. 2017;57(1):52- 55. 

2. Shaikh WR, Dusza SW, Weinstock MA, Oliveria SA, Geller AC, Halpern AC. Melanoma thickness and survival trends in the United States, 1989- 2009. J Natl Cancer Inst. 2016;108(1):djv294. 

3. 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(2):383–388. 

4. 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(2):183–188. 

5. Lemon B, Burns R. Malignant melanoma: a literature review and case presentation. J Foot Ankle Surg. 1998;37(1):48–54. 

6. Balch C, Soong S, Shaw H, et al. Changing trends in the clinical and pathological features of melanoma. In: C. Balch, G. Houghton, G. Milton, A. Sober, S. Soong, eds. Cutaneous Melanoma. Philadelphia: Lippincott Williams & Wilkins;1992:40-45. 

7. Murali R, Haydu LE, Long GV, Quinn MJ, Saw RP, Shannon K. Clinical and pathologic factors associated with distant metastasis and survival in patients with thin primary cutaneous melanoma. Ann Surg Oncol. 2012;19(6):1782–1789. 

8. Melanoma Research Alliance. Breslow depth and Clark level. Available at: https://www. curemelanoma.org/about-melanoma/melanoma-staging/breslow-depth-and-clark-level/#:~:text=The%20current%20staging%20 system%20adopted,node%2C%20metastasis%20 (TNM). Accessed July 15, 2020. 

9. Melanoma Research Alliance. Understanding melanoma staging. Available at: https://www. curemelanoma.org/about-melanoma/melanoma-staging/understanding-melanoma-staging/ . Accessed July 15, 2020. 

10. Walsh SM, Fisher SG, Sage RA. Survival of patients with primary pedal melanoma. J Foot Ankle Surg. 2003;42(4):193–198. 

11. National Cancer Institute. Cancer Stat Facts: Melanoma of the Skin. Available at: seer.cancer. gov/statfacts/html/melan.html . Accessed July 7, 2020. 

12. Curtin JA, Fridlyand J, Kageshita T. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135–2147. 

13. Garbe C, Ellwanger U, Tronnier M, Brocker EB, Orfanos CE. A critical analysis based on data of the German Central Malignant Melanoma Registry. Cancer. 2002;94(8):2305–2307. 

14. Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017;376(23):2211-2222. 

15. Trotter SC, Sroa N, Winkelmann RR, Olencki T, Bechtel M. A global review of melanoma follow-up guidelines. J Clin Aesthet Dermatol. 2013;6(9):18-26. 

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