Trauma-Induced Melanocyte Implantation Leading to Subcutaneous Melanoma

Melanoma is often challenging to diagnose when it lacks a visible primary cutaneous lesion. In such cases, melanoma of unknown primary (MUP) is often considered.¹ MUP occurs when melanoma metastasizes to sites such as the subcutaneous tissue or lymph nodes without any obvious primary lesion on the skin.¹ This diagnosis carries a favorable prognosis compared with cutaneous metastatic melanoma.¹ This report presents a unique case of melanoma in a 66-year-old male patient, in which the melanoma developed subcutaneously after the traumatic removal of a preexisting epidermal nevus, which could initially suggest MUP but does not meet the criteria for this condition.²

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Case Presentation

A 66-year-old non-Hispanic Caucasian man presented with a slow-growing, nontender lump in his left groin. He denied systemic symptoms such as fever, weight loss, or nausea. His medical history included hypertension, dyslipidemia, and obesity. An ultrasound-guided needle biopsy of the groin lump revealed stage III malignant melanoma. The histopathological analysis confirmed melanoma, with strong S-100, SOX10, and MART-1 staining, indicative of melanoma cells.²

Upon further investigation, the patient reported a history of trauma to a preexisting nevus on his left ankle. Two years earlier, the patient accidentally scraped off the mole with his toenail; the injury site healed but a deep, rock-hard nodule formed in the same area. The patient’s clinical timeline and the biopsy of the subcutaneous nodule suggested that melanoma had developed at the site of the previous trauma. This trauma likely led to the implantation of melanocytes into the subcutaneous tissue, which eventually resulted in malignant melanoma.²

Diagnostic Assessment

Further evaluation of the patient included a PET scan, which showed a 1.4 × 0.9 cm nodule in the left medial ankle with increased standardized uptake value (SUV) and a left inguinal lymph node with even higher SUV, suggesting metastasis. An MRI of the brain revealed no other metastatic lesions. A biopsy from the ankle mass confirmed a nodular malignant melanoma with Breslow depth of 8.9 mm, without any epidermal component, ulceration, or lymphovascular invasion.

The subcutaneous melanoma at the left ankle was surgically excised with wide local excision, and the left inguinal lymph node was also removed, revealing metastatic melanoma. Following this, the patient was staged as III using the American Joint Committee on Cancer 8th edition criteria, with clinical staging of cT0, cN1b, cM0 and pathological staging of pT4a, pN1b, cM0.2 After surgery, the patient underwent adjuvant immunotherapy with pembrolizumab and radiation to the left inguinal area. Despite therapy, metastases were later identified in the lungs, vertebrae, ribs, and liver. The patient began a new treatment regimen with ipilimumab-nivolumab.

Differential Diagnosis and Considerations for MUP

When a patient presents with melanoma without an evident primary lesion, MUP must be considered. MUP is characterized by the presence of melanoma in subcutaneous tissue, lymph nodes, or visceral organs without any identifiable primary site in the skin, eyes, or mucosa. Approximately 2% to 9% of melanoma metastases present as MUP.¹ However, the criteria set forth by Das Gupta et al in 1963 help guide the diagnosis.³ These criteria include exclusion of cases with prior trauma, surgery, or other manipulation of the skin, such as excision or cauterization of nevi.³ Additionally, Das Gupta’s criteria stress the importance of a thorough physical examination, including ophthalmologic and genital exams.³

In this case, the patient’s history of trauma to the nevus on the left ankle suggested that the melanoma originated in the traumatized nevus, rather than being a true case of MUP. The subcutaneous nodule and inguinal lymph node metastasis were likely a consequence of the implantation of melanocytes into the deeper tissues due to trauma. Although PET/CT imaging was helpful in identifying the likely primary site, the patient’s melanoma did not meet Das Gupta’s criteria for MUP because of the traumatic origin of the lesion.³

Prognosis and Survival

The prognosis of MUP patients has been a subject of debate. Some studies suggest that patients with MUP have a better overall survival compared with those with melanoma of a known primary site (MKP).⁴ A meta-analysis by Bae et al found that patients with stage III MUP had significantly better survival rates compared with those with stage III MKP.⁴ This has led to the hypothesis that an immune-mediated regression of the primary tumor may contribute to the development of MUP. However, the results of other studies show that the survival outcomes between MUP and MKP are similar, especially in cases with a limited number of metastatic lymph nodes.⁵ For instance, a study found no significant difference in survival for MUP and MKP patients when only 1 lymph node was involved, but when more than 2 lymph nodes were affected, patients with MUP had poorer survival outcomes.⁵

Treatment and Management of MUP Compared With Cutaneous Metastatic Melanoma

The management of MUP is similar to that of cutaneous metastatic melanoma, with a focus on surgical removal of the primary lesion (if identified) and lymph node dissection. In this case, the patient underwent wide local excision of the subcutaneous melanoma and lymph node dissection.² Following surgery, adjuvant therapies, including immunotherapy and radiation, were employed. Routine and long-term follow-up are essential for patients with MUP, as occult primary lesions may become detectable years after the initial diagnosis.²

Trauma as a Trigger for Melanoma Development

While the case presented does not meet the criteria for MUP, it highlights the potential role of trauma in the development of melanoma. Mechanical trauma to the skin can induce changes in melanocytes that may contribute to melanoma formation. This can be seen in conditions such as tattoo-related melanoma, where the mechanical insertion of pigment into the dermis can induce melanocytic changes that may eventually result in melanoma.⁶ Similarly, dermabrasion and other forms of skin trauma can lead to atypical melanocytic changes that mimic melanoma in situ.⁶ In this patient’s case, the trauma from the accidental scraping of the nevus on the left ankle likely caused melanocyte implantation into the subcutaneous tissue. This form of mechanical trauma is a plausible mechanism for the development of melanoma in the absence of an obvious primary site.

Conclusion

This case illustrates a unique presentation of melanoma that initially appeared to be a case of MUP but was ultimately attributed to trauma to a preexisting nevus. While MUP is a rare and challenging diagnosis, this case highlights the importance of a thorough patient history and clinical examination, as well as the potential role of mechanical trauma in triggering melanoma development. The patient’s management was guided by current melanoma treatment protocols, including surgical excision, immunotherapy, and radiation. Further research into the relationship between trauma and melanoma formation could provide valuable insights into the pathogenesis of melanoma in these unique cases.

Isabella J. Tan is a third-year medical student at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey.

References

1. Scott JF, Gerstenblith MR. Melanoma of unknown primary. In: Scott JF, Gerstenblith MR, eds. Noncutaneous Melanoma. Codon Publications: pg 1-19
2. Workman L, Fang L, Blazevic M, Chen J, Simman R. A case of subcutaneous metastatic malignant melanoma of the left medial ankle: a case report and review of literature. J Med Case Rep. 2024;18(1):647. doi:10.1186/s13256-024-04908-2
3. Das Gupta T, Bowden L, Berg JW. Malignant melanoma
   of unknown primary origin. Surg Gynecol Obstet. 1963;117:341-345
4. Bae JM, Choi YY, Kim DS, et al. Metastatic melanomas of unknown primary show better prognosis than those of known primary: a systematic review and meta-analysis of observational studies. J Am Acad Dermatol. 2015;72(1):59-70. doi:10.1016/j.jaad.2014.09.029
5. Boussios S, Rassy E, Samartzis E, et al. Melanoma of unknown primary: new perspectives for an old story. Crit Rev Oncol Hematol. 2021;158:103208. doi:10.1016/j.critrevonc.2020.103208
6. Kaskel P, Kind P, Sander S, Peter RU, Krähn G. Trauma and melanoma formation: a true association? Br J Dermatol. 2000;143(4):749-753. doi:10.1046/j.1365-2133.2000.03770.x