By Prof McKee Dysplastic nevus: History - In 1978 At The Royal Society of Medicine in London, I saw my first patient with familial melanoma syndrome. The patient, an adolescent girl had innumerable nevi generated considerable interest at the meeting. I remember her very clearly although sadly I have no follow-up on her progress. This condition had first been described by Wallace Clark (in 1978) in a paper entitled The B-K mole syndrome. The initials coming from the first two patients that he encountered with this condition. He was one of my greatest heroes in Dermatopathology. The condition was later called The Dysplastic Nevus Syndrome and subsequently an alternative nomenclature- Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM) was suggested. Later dysplastic nevus was referred to as Clark's nevus much to the irritation of Wallace Clark. At that time I reported Dermatopathology in the Department of Pathology at St Thomas' Hospital, London. Subsequently I also reported cases at St John's Hospital for Diseases of the Skin. Over the next 20 years a battle was fought between those who accepted the entity and those who would have nothing to do with it arguing that it did not exist. It would take too long to go into the matter in detail. I suppose through a combination of hero-worship of Wallace Clark combined with the intense energy that the publications generated, I had no difficulty taking the concept on board. To me, they were instantly recognizable (and still are) although what to do with them was another matter. In a very UK-like fashion, the recommended policy of grading such nevi was dismissed out of hand and a recommendation for re-excision was rarely given. Mind you, this was in the days of excisional biopsy and so the margins were very rarely affected. When I moved to Boston 1998, I entered the lion's mouth as it were. My daily diet was banal nevi, dysplastic nevi and melanoma in any combination that you can imagine. Frequently very large numbers of clinically atypical nevi crossed my desk and microscope. I must have looked at thousands and thousands of such nevi. There has been much said about the reproducibility of the features of a dysplastic nevus. I have never bought in to this. To me, the features are very clear and provided one follows the rules implicitly, their recognition is not problematical. The table below summarizes their features quite nicely. In Boston, I was under an obligation to grade cytological atypia (not something I had ever done in the UK) and many of the Dermatologists wanted a further treatment recommendation- to re-excise or not and how many mm margin would be appropriate. I don't necessarily believe that this latter is always necessary but "When in Rome"! The interesting thing is that even now, 40 years later the topic can be a source of such animated discussion. Now here is where some of you may be able to help me. I have been trying to find a landmark paper showing distinctive molecular differences between a common melanocytic nevus, a mildly atypical dysplastic nevus, a moderately atypical dysplastic nevus and a severely atypical dysplastic nevus, preferably in a paper that didn't begin with the all too often words"Dysplastic nevi are a source of controversy and diagnostic difficulty. There is significant intra- and inter- observer variation" or the like. All comments are welcome. I am posting a photograph of what I would regard as a very typical dysplastic nevus followed by a banal common melanocytic nevus. Below is a fairly generic tabulation of grading GradingThese lesions are often graded § : Grade Size of nucleus Other features Mild 1x keratinocyte nucleus no nucleoli/very small nucleoli †, slight hyperchromasia Mild cytologic atypia:The nuclei of mildly atypical cells are irregular, hyperchromatic and do not exceed the size of the nuclei of the keratinocytes in the mid prickle cell layer.
Moderate 1-2x keratinocyte nucleus small nucleoli †, irregular nuclear contoursModerate cytologic atypia:Moderate atypia is characterized by nuclei greater than the size of the nuclei of the keratinocytes within the mid prickle cell layer but less then twice their diameter.
Severe >2x keratinocyte nucleus prominent nucleoli †‡Severe cytologic atypia:Severely atypical nuclei are greater than twice the size of the nuclei of the keratinocytes in the mid prickle cell layer. The nuclei may become vesicular with prominent nucleoli with increasing grade.
† The sizes "very small", "small" and "prominent" are not defined; it is suggested that "very small" is visible with the 40x objective, "small" with the 20x objective and "prominent" with the 10x objective. Focal, rare small nucleoli are not significant; they can be seen in benign melanocytic nevi.‡ Prominent nucleoli (alone) is considered enough to call "severe".
Comment: I get occasional questions relating to cytological atypia in nevoid populations, it's grading and significance. The importance very much depends upon the context of the nevus. For example neonatal, acral and genital nevi commonly have cytological atypia, mild pagetoid spread and even one or two dermal mitoses and yet these features are of no clinical significance. Where atypia becomes relevant is in the context of the dysplastic nevus. This is not the time or place to resurrect Ackerman's argument that there is no such thing as a dysplastic nevus. Let us for the moment just accept the entity and agree that it can be recognized both clinically and histologically. I am posting some images to show its features.
It is characterized by a shoulder i.e. the junctional component extends beyond the dermal component. The junctional is both lentiginous and nested and often appears very disorganized. The nevus cells and/or nests are present along the sides as well as the tips of the rate ridges. Bridging of nests between adjacent epidermal ridges is a regular feature. Fine melanin particles are often present (dusty pigmentation). By common practice in the US, the degree of cytological atypia is graded according to the system originally proposed by Wallace Clarke. The nucleus of a banal nevus melanocyte serves as a useful reference point for normality. The nuclei of mildly atypical cells are irregular, hyperchromatic and do not exceed the size of the nuclei of the keratinocytes in the mid prickle cell layer. Moderate atypia is characterized by nuclei greater than the size of the nuclei of the keratinocytes within the mid prickle cell layer but less then twice their diameter. Severely atypical nuclei are greater than twice the size of the nuclei of the keratinocytes in the mid prickle cell layer. The nuclei may become vesicular with prominent nucleoli with increasing grade. Pagetoid spread is never allowed in a dysplastic nevus. Its presence is taken as implying in situ melanoma.
In biopsy material, mild and moderately atypical dysplastic nevi are re-excised to give a 2 mm clear margin. Severely atypical nevi and in situ melanoma in biopsy specimens are re-excised with a 5mm clear margin.
The significance of grading dysplastic nuclei is uncertain and its use varies from country to country. Some don't believe in grading atypic at all while others use a two grade system- mild and severe (lumping mild and moderate together). This latter has to my mind considerable merit as it is often difficult to distinguish between mild and moderate atypia. It should be noted that the grade is made upon the worst nucleus visible.
I don't believe that we fully understand the biological potential of the dysplastic nevus and its progression but for the moment, the use of a grading system means that we are all talking on the same page and the dermatologists know what to do with the patient.
Posted are images to illustrate these points. Shoulder, lentiginous and nested growth pattern with fibroplasia, bridging between rate ridges, banal nevus cells, mild cytological atypia, moderate cytological atypia and severe cytological atypia. Lastly is in situ melanoma with clear pagetoid spread.
Please not not post comments saying that you don't believe in dysplastic nevus. It just perpetuates the distracting discussion that has bedeviled this entity for decades. The overwhelming majority of dermatologists and dermatopathologists that I worked with at Harvard Medical School had no problems what so ever with the system. In fact, if I forgot to give the nevus a grade, their secretary would call very promptly to ensure that I added this to the report!!!Dysplastic nevus :Shoulder (the junctional component extends beyond the dermal component), lentiginous and nested junctional component. There is marked fibroplasia and focal pigment incontinence. The dermal component shows good maturation.
The nevus cells and/or nests are present along the sides as well as the tips of the rate ridges. Fine melanin particles are often present (dusty pigmentation)
Bridging of nests between adjacent epidermal ridges is a regular feature
Banal common melanocytic nevus with junctional nests ( The nucleus of a banal nevus melanocyte serves as a useful reference point for normality ) :
Pagetoid spread is never allowed in a dysplastic nevus. Its presence is taken as implying in situ melanoma.
Treatment: In biopsy material, mild and moderately atypical dysplastic nevi are re-excised to give a 2 mm clear margin. Severely atypical nevi and in situ melanoma in biopsy specimens are re-excised with a 5mm clear margin. More group discussion: https://m.facebook.com/groups/1866953236891815?view=permalink&id=19414092194T Ref: The dysplastic nevus by R. J. Friedman et al.
The Genetic Evolution of Melanoma from Precursor Lesions :https://www.nejm.org/doi/full/10.1056/NEJMoa1502583
Interesting article on molecular pathology of melanoma- an integrated taxonomy of melanocytic neoplasia https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831647/
Additional article on molecular criteria of DN :https://www.jidonline.org/article/S0022-202X(16)32089-9/fulltext