The entity ‘mildly dysplastic naevus’ has been removed from the World Health Organisation’s classification of dysplastic naevi. Dysplastic naevi are now to be graded as ‘low grade dysplastic naevus’ (previous moderately dysplastic naevus) or ‘high grade dysplastic naevus’ (previous severely dysplastic naevus).

Current data suggest no further treatment is necessary for lentiginous junctional/compound naevi and dysplastic naevus with low grade dysplasia (previous mildly dysplastic and moderately dysplastic naevi) with clear histologic margins and no pigment evident clinically, unless there was a high level of prebiopsy clinical concern.

Re-excision with a 2-5mm clinical clearance is recommended for high grade dysplastic naevi (previous severely dysplastic naevi) with involved histologic margins.

There is growing evidence that observation may be reasonable for low grade dysplastic naevi (previous moderately dysplastic naevus) if they were excised with clinically clear margins/ no residual clinical pigment is observed, despite histologically involved margins. More data may be required before this is accepted into clinical practice.

There does not appear to be a clear consensus regarding whether high grade dysplastic (previous severely dysplastic) naevi require re-excision, if initially excised with clear margins, albeit less than 2mm.

 

Dysplastic naevus: the controversy since the 1970s

The entity of dysplastic naevus has been shrouded in controversy since first described in the 1970s.¹ This appears to be due to:

1. Interobserver differences between histopathologists in applying the previous three tier grading system for dysplasia
2. Perceived risk of progression to melanoma, and
3. The possibility of benign entities simulating melanoma, all of which contribute to uncertainty and variability in management.^2,3

Dysplastic naevi are benign neoplasms of melanocytes.³ Dysplasia in melanocytes may occur de novo or in association with either congenital dermal naevi or common dermal naevi. It is probable that dysplasia arising in pre-existing naevi results from successive acquisition of genetic abnormalities^.3 Both common naevi and dysplastic naevi demonstrate BRAF or NRAS mutations.³ It was at one time proposed that there is a step-wise model of tumour progression from dysplastic naevi through mild, to moderate, then severe dysplasia, and finally melanoma.⁴ However, there is no evidence that dysplastic naevi are, in fact, common precursors of melanoma.⁴ In actuality, the most common naevus remnant found in association with melanoma is the common acquired naevus.⁴ Given the large number of dysplastic naevi, compared with the comparatively small number of melanomas arising in association with dysplastic naevi, it seems that the rate of progression from dysplastic naevus to melanoma is extremely low.⁴ Dysplastic naevi seen associated with melanomas have an increased incidence of TERT promoter mutations, a common early genetic event in the evolution of melanoma in situ.³ This suggests that some dysplastic naevi are an intermediate entity between benign naevus and melanoma.³ There is a lack of data examining the frequency of similar genetic alterations in non-melanoma associated dysplastic naevi; thus, although the risk of progression is very low, it is suggested that naevi with high grade dysplasia or added genetic events (e.g. TERT promoter mutation) are considered for complete excision.³ It has been suggested that dysplastic naevi represent a marker of increased risk for an individual developing melanoma.⁵ It is difficult to establish the risk of melanoma at a separate site in patients with dysplastic naevi, as the reported incidence of dysplastic naevi in fair-skinned individuals varies widely (between 2% and 50%).⁴ One study has demonstrated that only the diameter of the dysplastic naevus had a significant association with a personal history of melanoma,⁶ whilst another study has shown that individuals with many naevi, whether common or dysplastic, have an increased risk of developing melanoma.⁷ Thus it would seem that two factors are associated with an individual’s risk of developing melanoma: a large number of common or dysplastic naevi (>100) and the larger size of the naevi (>4.4mm).⁶ It is generally agreed that there is low interobserver agreement between pathologists when grading dysplastic naevi, particularly in those lesions exhibiting moderate atypia to early in situ melanoma.^8,9 This leads to uncertainty with regard to management of these lesions, especially if there is margin involvement. In 2017, Wall et al.2 conducted a survey investigating the management of dysplastic naevi by Australian dermatologists. This survey demonstrated that, similarly to comparable studies reported within the USA and Canada, most dermatologists would re-excise a moderately or severely dysplastic naevus with involved margins.² There is, however, variability in Australian dermatologists’ approaches to severely dysplastic naevi (clinically concerning for melanoma) which are completely excised on biopsy, with 44% re-excising with a 5mm margin, and the remainder considering no further treatment necessary.² In addition, whilst between 5-12% of US and Canadian dermatologists re-excise mildly dysplastic naevi involving margins, that rate in Australian dermatologists is 49%.² A consensus statement released by Kim et al.¹⁰ in 2015 identified a critical gap in knowledge with regard to management of dysplastic naevi with involved margins. This consensus statement recommended that mildly to moderately dysplastic naevi with clear histologic margins need no re-excision. If a biopsy report reveals severe dysplasia with positive margins, re-excision to achieve a 2-5mm clinical margin is recommended. The statement suggested that mildly dysplastic naevi with positive histologic margins after biopsy (and no residual pigment) may be observed, and while observation may be a reasonable option for moderately dysplastic naevi with positive histologic margins (and no clinical pigment), more data are required to make a definitive recommendation.¹⁰ A further multi-centre retrospective cohort study in 2018 by Kim et al.¹¹ suggests that close observation is a reasonable management approach for moderately dysplastic naevi with positive histologic margins. No specific recommendations are made regarding a severely dysplastic naevus with clear margins on biopsy.  

WHO redefines melanocytic naevi

The World Health Organisation (WHO) released their new Classification of Skin Tumours in 2018.³ They define dysplastic naevus as ‘a subset of melanocytic naevi that are clinically atypical and characterized histologically by architectural disorder and cytological atypia, always involving their junctional component.¹⁰ Diagnostic criteria for dysplastic naevi traditionally include a division of cytoarchitectural atypia into mild, moderate and severe categories.³ Pathologists often further subdivide these categories into ‘mild to moderate’ and ‘moderate to severe’ to reflect the histological field effect often perceived in these lesions. Lentiginous junctional or compound naevi (previously labelled mildly dysplastic naevi) are not associated with increased melanoma risk/progression to melanoma, and are also common within the population.³ The WHO consensus meeting working group recommends against the continued use of the term ‘mildly dysplastic naevus’ and instead recommends the use of low grade and high grade dysplasia. So, where are we now with these new recommendations regarding the grading of dysplastic naevi, and what are the management implications? It seems that the new WHO recommendations support the view that biopsies of the previously known mildly dysplastic naevi need no further treatment, having removed the entity from their classification. It would appear that there is agreement that dysplastic naevi with high grade dysplasia (previous severely dysplastic naevi) with involved margins requires re-excision to achieve a 2-5mm clinical margin of clearance. However, there appears to be no recommendations or clear consensus regarding whether these high grade dysplastic (previous severely dysplastic) naevi require re-excision, if initially excised with clear margins, albeit less than 2mm. With regard to dysplastic naevi with low grade dysplasia (previous moderately dysplastic naevi), there is a slowly growing body of evidence to suggest that it may be reasonable for these cases to be observed if they were excised with clinically clear margins/no residual clinical pigment is observed, despite histologically involved margins. Given the current variation in clinical management of these lesions, as well as the continued lack of interobserver agreement between histopathologists when diagnosing these lesions, more data may be required before this recommendation is accepted. In conclusion, as the consensus statement by Kim et al.¹⁰ recommends, the decision to re-excise dysplastic naevi should be based on both the clinical and histologic findings. If the prebiopsy level of clinical concern is high, re-excision should be considered if the biopsy reveals positive margins, even if the level of histopathological dysplasia is low. In addition, there may be clinical scenarios warranting re-excision of a mildly, mildly-moderately/moderately dysplastic lesion (now known as lentiginous junctional/compound naevi and dysplastic naevus with low grade dysplasia respectively), including patient preference.¹⁰  

References:

1. Duffy K, Grossman D. The dysplastic nevus: from historical perspective to management in the modern era. J Am Acad Dermatol. 2012;67 (1): 1. E1-18. DOI: 10.1016/j.jaad.2012.03.013
2. Wall N, De’Ambrosis B, Muir J. The management of dysplastic naevi: a survey of Australian dermatologists. Australasian Journal of Dermatology. 2017;58:304-307. DOI: 10.1111/ajd.12720
3. Elder DE, Massi D, Scolyer RA, Willemze R, editors (2018). WHO classification of skin tumours. 4th Ed. Lyon: IARC.
4. Busam KJ, Gerami P, Scolyer RA (2019). Pathology of Melanocytic Tumors. 1st Ed. Philadelphia: Elsevier.
5. Elder DE. Dysplastic naevi: an update. Pathology. 2010;56(1):112-120.
6. Xiong M, Rabkin M, Piepkorn M, Barnhill R, Argenyi Z, et al. Diameter of dysplastic naevi is a more robust bio marker of increased melanoma risk than degree of histologic dysplasia: a case-controlled study. J Am Acad Dermatol. 2014;71(6):12578.e4. DOI: https://doi.org/10.1016/j.jaad.2014.07.030
7. Holly EA, Kelly JW, et al. Number of melanocytic nevi as a major risk factor for malignant melanoma. J Am Acad Dermatol. 1987;17:459-468. DOI: https://doi.org/10.1016/S0190-9622(87)70230-8
8. Hiscox B, Hardin MR, Orengo IF, Rosen T, Mir M, Diwan AH: Recurrence of moderately dysplastic nevi with positive histological margins. J Am Acad Dermatol . 2017;76:527530.  DOI: 10.1016/j.jaad.2016.09.009
9. Stefanato C. The “Dysplastic Nevus” Conundrum: A look back, a peek forward. Dermatopathology. 2018;5:53-57. DOl: https://doi.org/10.1159/000487924 
10. Kim C, Swetter S, Curiel-Lewandrowski C, Grichnik J, Grossman D, et al. Addressing the knowledge gap in clinical recommendations for management and complete excision of clinically atypical nevi/dysplastic nevi. JAMA Dermatol. 2015;151(2):212218. DOI: 10.1001/jamadermatol.2014.2694
11. Kim C, Berry E, Marchetti M, Swetter S, Liam G, et al. Risk of subsequent cutaneous melanoma in moderately dysplastic nevi excisional biopsies but with positive histologic margins. JAMA Dermatology. 2018;154(12):1401-1408 DOI: 10.1001/jamadermatol.2018.3359

  - General Practice Pathology is a regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.  

Cutaneous disorders are among the most common conditions presented to primary care doctors. Many are easily identifiable and may be dealt with effectively without the need for cutaneous biopsy. Nevertheless, in many instances the diagnosis is not obvious on clinical grounds. The rash may display atypical features or may not respond to therapy as predicted. In these cases, and when dealing with cutaneous tumours or worrying pigmented lesions, cutaneous biopsy with histological assessment becomes necessary. The art of cutaneous biopsy is to derive the maximum amount of information from the minimum amount of tissue, causing least discomfort to the patient. This will be achieved if due regard is given to the advantages and shortcomings of the various techniques available for biopsying cutaneous tissue, and if the pathologist is supplied with a good clinical history.

Clinical History

For several reasons, clinical history assists greatly in the interpretation of skin biopsies. Clinicopathological correlation is particularly important in many inflammatory cutaneous disorders. As the histological features can be very similar, clinical notes may help us to arrange a list of provisional diagnoses in order of likelihood. The key features to discuss with regard to cutaneous rashes include:

• duration
• distribution
• description (macular, papular, vasculitic or vesicular)
• drugs or other possible aetiological agents
• provisional clinical diagnosis.

As there is wide variation in the normal microscopic picture from different sites, the area biopsied should also be stated. For biopsies performed to distinguish between squamous cell carcinoma and keratoacanthoma, the rate of growth of the lesion is important. When sending specimens of pigmented lesions, the degree of clinical suspicion should be stated, together with any history of melanoma within the individual or within the individual’s family. Any condition associated with cutaneous disorders, such as systemic lupus erythematosus, pregnancy or bone marrow transplant, should be mentioned in the clinical notes. The clinical history should also include the type of biopsy procedure used (see below) as this determines the way we handle the specimen in the laboratory. For example, the whole of an incisional biopsy will be blocked in order to gain the maximum amount of information, whereas an excisional biopsy will be transversely sectioned in order to fully assess the lateral excision margins in the case of a tumour biopsy.

Excision Biopsy

This is the best technique to use for pigmented lesions and cutaneous tumours. It allows for histological assessment and diagnosis of the lesion, and assessment of surgical excision margins. If appropriate, an orientation suture can be placed at one end of the excision, e.g. the superior end of the specimen, so that if the excision is inadequate, the margin involved can be indicated on an accompanying diagram. Occasionally, excision biopsy is appropriate for inflammatory cutaneous disorders where the condition is characterised by the formation of vesicles. The best chance of removing an intact vesicle (which greatly aids diagnosis) may be through excision.

Incision Biopsy

With incision biopsy, a thin elliptical biopsy is taken radially through the edge of the tumour or through the edge of a macular or annular rash. Incision biopsy is superior to punch biopsy for diagnosing rashes, more tissue is displayed on histological section and scarring is often reduced. A typical incision biopsy is 5-6 mm in length and about 2 mm in width. It should be deep enough to extend into the subcutaneous adipose tissue. The biopsy should run radially from the centre or central areas of the lesion to include approximately 1 mm of normal cutaneous tissue surrounding the lesion.

Punch Biopsy

Punch biopsies are easier to perform and, in general, are more convenient. Nevertheless, they nearly always yield less information than an incision biopsy. For tumours, the biopsy should be taken centrally. For cutaneous eruptions, the biopsy should be taken from an area typical of the rash. In some cases, multiple biopsies may increase the amount of information. In this procedure, it is best not to include normal skin. Punch biopsies come in various sizes. As 2 mm punches often yield inadequate information for diagnosis, a 3 mm punch biopsy is the smallest that should be used.

Shave Biopsy/Curettage

This technique is suitable for superficially-located lesions with plaque-like clinical features, e.g. seborrhoeic keratoses. It is not an appropriate technique for nodular lesions, cutaneous rashes or melanocytic lesions.

General comments concerning cutaneous biopsies

Preparation of the skin surface: Be gentle when cleaning the skin surface prior to biopsy; try not to disturb any overlying scale as the keratin layers sometimes contain diagnostic information (e.g. this is where dermatophytic fungi may be seen). Let any alcohol preparation dry before collecting specimens for immunofluorescence. Local anaesthesia: Only a small amount of local anaesthetic is required for punch biopsy procedures (0.5 mL maximum). Too much local anaesthetic within the tissues can distort the histological appearances and simulate dermal oedema. Marking the lesion: It is often prudent to mark the target area for biopsy with an ink marker, as some lesions can blanch following introduction of local anaesthetic. The erythema in many lesions is due to vascular dilatation occurring as part of the inflammatory disorder. Local anaesthetic can cause vasoconstriction and diminish the erythema clinically. This may result in a poorly targeted biopsy yielding subdiagnostic histology. Depth of biopsy: It is best to continue into the subcutaneous adipose tissue so that the entire dermis is represented on histological section. This helps greatly with the categorisation of many inflammatory skin disorders and also demonstrates the deep border of any cutaneous tumour. When performing a punch biopsy, the biopsy instrument appears to ‘give’ when it penetrates the dermal connective tissue into subcutaneous adipose tissue. A similar sensation will be noticed when dissecting free an incision biopsy. Care with biopsy tissue: All too often, after biopsy tissue has been retrieved from the patient, crush artefact occurs during its transfer into formalin. Crush artefact greatly distorts the histological appearance and repeat biopsy may become necessary. Rather than grasping the biopsy tissue with non-tooth forceps, it should be transferred to the specimen container using needle tips, a skin hook or fine forceps, delicately grasping one edge of the biopsy. Fixative: Ordinary blue, 10% buffered formalin supplied with the specimen jars is suitable for nearly all cutaneous biopsies, except those submitted for microbiological culture or immunofluorescent examination. Labelling: Please label all specimen containers with the patient’s name and details, which should match those stated on the request slip. Unlabelled specimens can still be processed and interpreted if they arrive with labelled paperwork; however, the medico-legal status of any generated report is doubtful. The report will usually be generated with a ‘specimen received unlabelled’ comment attached.

Conclusion

Diagnosing cutaneous conditions can be challenging. The chances of success are improved when the clinician, is armed with a variety of biopsy techniques for use in the correct clinical setting, and when the pathologist is supplied with an adequate clinical history.   - General Practice Pathology is a regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.