Deep penetrating thoughts about deep penetrating nevi

By Warren R. Heymann, MD
Jan. 14, 2019

What do the terms “intermediate” and “indeterminate” mean to you?

I thought a great deal about this while attending the melanoma symposium at the American Society of Dermatopathology meeting in Chicago (November 2018).

Merriam-Webster defines intermediate as “being or occurring at the middle place, stage, or degree or between extremes” and indeterminate as “not definitely or precisely determined or fixed: vague”.

Every dermatopathologist confronts atypical pigmented lesions, often with Spitzoid histology, that are difficult to classify — which, by definition, makes them indeterminate (hence, terms such as MELTUMP — melanocytic tumors of uncertain malignant potential). The key question, of course, is prognosis, and how to manage these lesions — are lesions of minimal or low risk, intermediate, or high risk to develop melanoma? If lesions were incompletely excised, can they be observed, or is re-excision warranted? If so, what margin should be obtained?

This commentary will focus on the deep penetrating nevus (DPN), which has been classified as an “intermediate/indeterminate” lesion.

DPN is often a worrisome lesion clinically because of its very dark appearance that may have changed quickly. DPN occur most frequently in the first 3 decades of life. Congenital onset has been reported and lesions rarely arise in patients older than 50 years. Females appear to have a slightly higher incidence compared with males. DPN occur on the head and neck in approximately 35% of cases, on the trunk in 25%, and on the upper extremities in 20.5%. Less commonly, DPN occur on the lower extremities, and they have only rarely been described on distal extremities or mucosal surfaces. (1)

Histologically, DPN get your attention, mandating differentiation from other heavily pigmented melanocytic lesions including melanoma (especially animal type), melanosis of partially or completely regressed melanoma, blue nevus, pigmented Spitzoid lesions, recurrent nevus, combined nevus, pigmented spindle cell nevus, epithelioid blue nevus of the Carney complex/pigmented epithelioid melanocytoma, hyperpigmented scar after surgery of melanoma in which there are also melanophages and hyperpigmentation due to minocycline (or other drugs), a tattoo or a hyperpigmented scar.

Histological features that favoring a diagnosis of melanoma include dimension (>6 mm), asymmetry, poor circumscription, irregular confluent nests, confluent lentiginous junctional melanocytic proliferation, lack of maturation with descent in the dermis, suprabasal Pagetoid melanocytes, asymmetrical distribution of melanin pigment, cytological atypia, dermal mitotic figures, asymmetrical dermal lymphocytic infiltrate and necrosis. In contrast, DPN display a benign architectural pattern including an inverted wedge shape with periadnexal involvement. There are nests or fascicles of epithelioid cells with some pleomorphism, nuclear pseudoinclusions, and vacuolated nuclei with smudged nuclear contour admixed with background variable pigmentation and numerous pigment-laden macrophages (2).

According to Strazzula et al: “There is no conclusive evidence that a pure DPN without atypical features has metastatic or malignant potential. Given that biopsy is necessary for diagnosis, many DPN will be removed in their entirety during an excisional biopsy, if performed. If lesions are found to have positive surgical margins, re-excision may not be necessary given the rarity of clinical recurrence. However, any DPN with atypical features or foci concerning for malignant melanoma should be removed in its entirety with appropriate surgical margins.” (1)

Can molecular biology make prognosis more precise?

It has been demonstrated that mutations of the β-catenin and mitogen-activated protein kinase (MAPK) pathways are characteristic of DPN. Mutations of the β-catenin pathway change the phenotype of a common nevus with BRAF mutation into that of DPN, with increased pigmentation, cell volume and nuclear cyclin D1 levels. (3) Telomerase reverse transcriptase (TERT) promoter mutations are commonly found in malignant melanomas but rare in melanocytic nevi. In a recent study of 86 primary melanomas, 72 melanocytic nevi, and 40 diagnostically problematic melanocytic proliferations. TERT promoter mutations demonstrated a positive predictive value of 98.5% and a negative predictive value of 78.9%. (4)

Yeh et al propose that β-catenin and MAPK pathway mutations alone are insufficient to fully transform melanocytes, and that additional mutations such as immortalizing mutations of TERT and loss of CDKN2A are required for DPN to progress to melanoma. Their results identify DPN as an intermediate melanocytic neoplasm, with a progression stage positioned between benign nevus and DPN-like melanoma. (3).

This returns us to the question I originally proposed. Is it justified to call such lesions “intermediate” given the track record of DPN only rarely developing melanoma? Is there a better terminology available, until such time that molecular techniques offer precise prognostication?

There are five diagnostic categories mapping to corresponding clinical management suggestions using the Melanocytic Pathology Assessment Tool & Hierarchy for Diagnosis (MPATH-Dx): 1) nevus /mild atypia (no further treatment required); 2) moderate atypia (narrow but complete re-excision); 3) severe atypia/melanoma in situ (repeat excision with at least 5 mm margins); 4 & 5) T1a melanoma (wide excision) and T1b melanoma (wide excision with additional treatment required). (5) Based on this classification, DPN would be considered as MPATH-Dx 2.

It is easy for dermatopathologists to recommend a re-excision, but that does not translate to ease in the clinic. Imagine yourself as 30-year-old woman just diagnosed with a DPN of the cheek that extended to the base of the specimen. What decision would you make regarding re-excision if the chance of developing melanoma was presented as a very low versus an intermediate risk?

I do not pretend to have the answers — of course, every patient must be dealt with individually. It is not just a matter of semantics — words have important implications. It is incumbent on the dermatopathology community to be as judicious as possible in classification of “indeterminate” lesions to allow clinicians and patients to make the best possible decisions.

Point to remember: Deep penetrating nevi are low risk lesions that will ultimately be prognosticated by molecular methods.

1. Strazzula L, et al. The deep penetrating nevus J Am Acad Dermatol 2014; 71: 1234-40.
2. Aung PP, et al. Differential diagnosis of heavily pigmented melanocytic lesions: challenges and diagnostic approach. J Clin Pathol 2015; 963-70
3. Yeh I, et al. Combined activation of MAP kinase pathway and β-catenin signaling cause deep penetrating nevi. Nat Commun 2017 21;8(1): 644.
4. Thomas NE, et al. Utility of TERT promoter mutations for cutaneous primary melanoma diagnosis. Am J Dermatopathol 2018; Sep 11 [Epub ahead of print}.
5. Zhao G, et al. The utilization of Spitz-related nomenclature in the histological interpretation of cutaneous melanocytic lesions by practicing pathologists: Results from the M-Path study. J Cutan Pathol 2017; 44: 5-14.