Discussion

Morphologic basis of the diagnosis

The lesion shows a relatively symmetric dermal proliferation beneath an intact, mildly undulating epidermis. Superficial nests contain conventional rounded nevus cells, with focal melanin pigment and multinucleated forms. The deeper component consists of pale spindle cells arranged in short neuroid bundles and rounded lamellated aggregates resembling Wagner-Meissner corpuscles. This combination supports a diagnosis of melanocytic nevus with neurotization. There is no evidence of junctional proliferation, significant mitotic activity, or necrosis.

Neurotization is a recognized differentiation pattern in melanocytic nevi, characterized by type C spindle cells, fibrillary cytoplasm, neuroid cords, and nevic corpuscles. Misago described a spectrum that includes conventional neurotized nevi, nerve fascicle-like structures, and palisaded arrangements. These patterns can resemble peripheral nerve sheath tumors. The term neurotized nevus refers to this morphologic differentiation and does not indicate a separate neural tumor. [1]

Benign intradermal nevi containing multinucleated giant melanocytes have been reported. Multinucleation alone is not evidence of melanoma; its significance depends on nuclear features, background cytology, architecture, maturation, and mitotic activity. Here, the multinucleated forms appear within an otherwise bland nested proliferation. The term multinucleated nevus cells is appropriate and does not require each giant cell to be classified as Touton-like or osteoclast-like. [2]

Diagnostic approach and differential diagnosis

Begin by reviewing the entire lesion at low power before focusing on the unusual cells. Evaluate circumscription, symmetry, the superficial melanocytic component, and its relation to the deeper neuroid population. Look for a discordant expansile nodule, persistent deep atypia, or mitotic activity. Deeper levels may help clarify an inconspicuous conventional component. A superficial or transected biopsy limits assessment of maturation and the lesion base, so clinical history and previous biopsies should be considered alongside the histology.

1. Neurofibroma and neuroma. Extensive neurotization can obscure the melanocytic nature of a nevus. Conventional nevus-cell nests with a transition into the neuroid component support a nevus diagnosis. S100 is not helpful because both lesions express it. Chen and colleagues compared 49 neurotized nevi with 49 neurofibromas: all nevi showed Melan-A staining in neurotized areas, while all neurofibromas were negative. Neurofilament highlighted scattered elements in both groups. Melan-A is useful when morphology is unclear but must be localized to the lesional cells. Some neurotized areas may lack Melan-A staining, especially in limited samples, so a negative stain does not exclude a neurotized nevus; results should be interpreted alongside the conventional nevus component and the staining distribution. [4]

2. Perineuriomatous melanocytic nevus. This rare pattern may show an abrupt transition from a superficial melanocytic component to deeper bland spindle cells, whorls, and fibromyxoid stroma. Ferreira and colleagues described six cases that could mimic desmoplastic melanoma. In a subsequent series of 100 extensively neurotized nevi, EMA was positive in 61%, and GLUT1 and claudin-1 were positive in all cases, often near corpuscle-like structures. Perineurial-marker expression alone does not confirm a separate perineurioma, and perineurial differentiation is not the same as malignant perineural invasion. The histomorphology here does not indicate this specific subtype. [5,6]

3. Desmoplastic melanoma. Some cases closely resemble neurofibroma or neurotized nevus and may be cytologically subtle. Infiltrative growth, focal atypia, neurotropism, or an atypical junctional component requires careful evaluation. Gerami and colleagues reported 12 neurofibroma-like desmoplastic melanomas, showing that a neural appearance does not guarantee benignity. Neurofilament-positive axons may be trapped in melanoma. Neither the presence of axons nor a negative PRAME stain can outweigh concerning morphology. [7]

Common diagnostic pitfalls

1. Overcalling multinucleation. Large multinucleated cells can be present in benign nevi. Assess the entire lesion and the nuclear features, not just cell size. [2]

2. Mistaking nevic corpuscles for a separate neural neoplasm. Check for conventional melanocytic nests and continuity with the neuroid component. [1,4]

3. Equating immunophenotype with diagnosis. S100 is found in both neural and melanocytic lesions, and perineurial markers may be expressed in neurotized nevi. [4-6]

References

1. Misago N. The relationship between melanocytes and peripheral nerve sheath cells (Part I): melanocytic nevus (excluding so-called "blue nevus") with peripheral nerve sheath differentiation. Am J Dermatopathol. 2000;22(3):217-229.

2. Enos T, Vandergriff T. Intradermal nevus with osteoclast-like giant cell melanocytes. J Cutan Pathol. 2019;46:888-891. doi:10.1111/cup.13519

3. Russo I, Sartor E, Cappellesso R, et al. Cutaneous nevoid melanoma: a retrospective study on clinico-pathological characteristics, with a focus on dermoscopic features and survival analysis. Cancers. 2025;17(1):65. doi:10.3390/cancers17010065

4. Chen Y, Klonowski PW, Lind AC, Lu D. Differentiating neurotized melanocytic nevi from neurofibromas using Melan-A (MART-1) immunohistochemical stain. Arch Pathol Lab Med. 2012;136(7):810-815. doi:10.5858/arpa.2011-0335-OA. PMID: 22742554

5. Ferreira I, Kind P, Van Den Berghe I, et al. Melanocytic naevi with perineurial differentiation: a distinctive variant of neurotised naevi and a diagnostic pitfall with desmoplastic melanoma. Histopathology. 2018;72:679-684. doi:10.1111/his.13418

6. Leblebici C, Mod BN, Cin M, Özcan B. Perineural differentiation in neurotized nevi. Pathol Res Pract. 2024;255:155184. doi:10.1016/j.prp.2024.155184. PMID: 38324967

7. Gerami P, Kim D, Zhang B, et al. Desmoplastic melanomas mimicking neurofibromas. Am J Dermatopathol. 2020;42(12):916-922. doi:10.1097/DAD.000000000000175