Diagnosis -- Pigmented Nodular Malignant Melanoma with Spindled and Epithelioid Cells.


Pigmented nodular malignant melanoma with spindled and epithelioid cells.


Deep penetrating nevus (DPN) is a distinct histological category with a specific genetic signature (included in WHO 2016). It was first reported by Seab and his colleagues in 1989 (1). It is one of the challenging diagnoses because of many similarities and overlapping features between other melanocytic lesions such as plexiform and pigmented Spitz tumors, blue nevi, and pigmented epithelioid melanocytomas (PEM). Also, they lack nevomelanocytic cytologic gradient (2).

Nevertheless, classic DPN should not be misdiagnosed as malignant melanoma (3). DPN is usually asymmetrical, wedge-shaped melanocytic proliferation in which its tip extends to the reticular dermis (4). The tumor cells are spindled and epithelioid melanocytic cells arranged in vertically oriented fascicles exhibiting cytoplasmic melanization. Singly enlarged cells with hyperchromatic nuclei containing cytoplasmic pseudo-intranuclear inclusions are occasionally seen (3).

A certain subset of melanocytic lesions displays DPN features but with enhanced cytologic and architectural atypia that exceeds the conventional DPN features. This subset usually shows areas of infiltrative or nodular expansile growth pattern and a higher incidence of regional lymph node metastasis. This category of melanocytic lesions is known as borderline DPN-like tumors or DPN-like melanoma. They share some criteria of plexiform melanomas which can be an evolution into a more aggressive melanoma type (3).

Our case exhibited morphological features of DPN like melanoma in addition to features of pigmented epithelioid melanocytomas and blue nevi. Preserved BAP1 expression combined with nuclear beta-catenin expression in tumor cells was suggestive of DPN like melanoma diagnosis in our case, however, In such cases, molecular studies are encouraged for better categorization.

DPN is recently characterized by a specific genetic signature, combining mutations of the ?-catenin and MAPK pathways. This is through many combinations of events, frequently combined BRAF V600E and exon 3 CTNNB1 mutations. Yeh et al reported that DPN that arise from common acquired nevus showed activation of MAP kinase pathway of both DPN and common acquired nevus components while CTNNB1 mutation is limited to the DPN component only. Additional oncogenic mutations in DPN-like-melanoma including TERT promoter regions C250Tand C228T, TP53 mutations, and biallelic loss of CDKN2A are recognized in the same study (5).

Targeted DNA/RNA sequencing by Next Generation Sequencing (NGS) was performed in our case, and showed BRAF V600K, CTNNB1 S45F, and TERT promoter region C250T mutations. This genetic signature confirms the diagnosis of DPN-like melanoma.

Our case is a classical DPN-like melanoma case with typical IHC and genetic abnormalities. Usually, such cases show a good prognosis & response to immunotherapy despite the large tumor burden (3).


  1. Seab JA Jr., Graham JH, Helwig EB. Deep penetrating nevus. Am J Surg Pathol 1989; 13:39-44.
  2. Robson A, Morley-Quante M, Hempel H, McKee PH, Calonje E. Deep penetrating naevus: clinicopathological study of 31 cases with further delineation of histological features allowing distinction from other pigmented benign melanocytic lesions and melanoma. Histopathology. 2003; 43:529- 37.
  3. Magro CM, Abraham RM, Guo R, Li S, Wang X, Proper S, Crowson AN, Mihm M. Deep penetrating nevus-like borderline tumors: A unique subset of ambiguous melanocytic tumors with malignant potential and normal cytogenetics. Eur J Dermatol 2014; 24(5): 594-602.
  4. Magro CM, Crowson AN, Mihm MC Jr., et al. The dermal-based borderline melanocytic tumor: a categorical approach. J Am Acad Dermatol 2010; 62:469-79.
  5. Yeh I, Lang UE, Durieux E, Tee MK, Jorapur A, Shain AH, Haddad V, Pissaloux D, Chen X, Cerroni L, Judson RL, LeBoit PE, McCalmont TH, Bastian BC, de la Fouchardière. Combined activation of MAP kinase pathway and ?-catenin signaling cause deep penetrating nevi. Nat Commun 2017; 8:644.

Contributed by Shaymaa Hegazy, MD and Arivarasan Karunamurthy, MD

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