J Cutan Pathol 2013: 40: 993–995 doi: 10.1111/cup.12260 John Wiley & Sons. Printed in Singapore
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Editorial
Believe it or not: a truism or an entrenched paradigm? Keywords: diagnostic concordance, dysplastic nevus, dysplastic nevus syndrome, HRAS-mutated Spitz nevus Whether one is a full-bore dysplasticist who believes without question that melanocytic nevi progress gradually through increasing dysplasia and atypia with eventuation as melanoma at one pole, whether one is a fanatical Ackerman clone who views the histopathologic interpretation and oncogenesis of melanocytic tumors much like a light switch (it’s either on or off, yes or no, melanoma or not) at the other, or whether one falls somewhere between those extremes, dermatopathologists of any stripe can agree that requisition forms bearing a clinical context of rule out dysplasia or rule out atypia are exceedingly common in the laboratory and that a sizable proportion of each diagnostic day is spent deliberating whether given biopsy specimens demonstrate utterly conventional melanocytic nevi, dysplastic/Clark/atypical melanocytic nevi, or melanoma. Furthermore, it must be clear to all that concern for melanocytic nevi being atypical is epidemic and utterly entrenched in the clinical realm, or alternatively the concept is being exploited clinically for remunerative gain, because otherwise such large volumes of biopsies would not enter the dermatopathology laboratory in the first place. What is far less obvious, at least to this observer, is whether the concept has broad validity or not. Furthermore, it remains murky whether patient management in the context of dysplastic nevi, once a biopsy has been procured, examined, and reported upon, is reproducible or whimsical (the latter seems likely). While it is clear that while interobserver agreement in the microscopic diagnosis of dysplastic nevus is occasionally excellent, it is more commonly mediocre.1 – 3 It is also clear that the morphology of dysplastic nevi can be closely mimicked by other melanocytic tumors, including melanoma.4 – 6 With respect to management, a recent review of 100 biopsies has documented that recommendations for reexcision are highly capricious, as like-minded
pathologists are commonly unable to agree whether reexcision is necessary or not, and an individual pathologist does not make consistent recommendations when reevaluating previously interpreted specimens (Brianne Daniels, personal communication). In short, in at least some instances a diagnosis of the type of melanocytic nevus under discussion may not be completed reproducibly, and when that potentially wobbly opinion is coupled in a pathology report with a judgment regarding reexcision, one dermatopathologist may not agree with another and one may not even agree with oneself. Certainly the lack of consistency alluded to in the preceding sentence should be of grave concern to a scientific discipline, at least one that wishes to be taken seriously. Those who report a given melanocytic nevus as being dysplastic, whether done on occasion or as an hourly event, presumably believe that they are rendering a diagnosis that has tightly constrained implications. In other words, to render an outright (or, for that matter, a veiled) diagnosis of dysplastic/Clark nevus is to imply that it represents a melanocytic nevus sui generis rather than a histopathologic reaction pattern that can be seen more broadly. Indeed, there is reason to believe that melanocytic nevi can assume reasonably narrow histomorphology that is triggered by specific molecular underpinnings. HRAS-mutated Spitz nevi, perhaps the prototype of this phenomenon, represent broad, horizontally oriented, and hypercellular desmoplastic Spitz nevi that are easily misinterpreted as melanoma, especially by non-dermatopathologists, because of large size, relatively high cellularity, and the presence of dermal melanocytes in mitosis, constituting a combination that breaks many of the rules used daily for separating benign from malignant.7 Most blue nevi, a subset of which are reasonably microscopically homogeneous, are triggered by activating mutations in the Ras-like domain of GNAQ (or by mutations
993
Editorial in the paralogue GNA11), while deep penetrating nevi, the clinical kinfolk of blue nevi, are genetically unrelated.8 Do all melanocytic nevi (or all categories of melanocytic nevi), defined through precise microscopic work, have specific, narrow, and definable genetic triggers? It seems likely that the answer to this question can be yes, provided that the histopathologic recognition of the melanocytic nevus (or category of melanocytic nevus) is sufficiently constrained. Is it likely that melanocytic nevi termed dysplastic or atypical, as currently diagnosed, have a specific, narrow, and definable genetic trigger? It seems likely that the answer at present is no, considering the heterogeneous and variable qualities associated with melanocytic dysplasia and the documented lack of precise diagnostic reproducibility at this point in time. Some two decades ago, Shapiro put forth an unnoticed (minimally cited) ‘unifying perspective’ regarding dysplastic nevi.9 The manuscript represents an interesting read and is worthy of re-review for both the young student of dermatopathology and the longstanding practitioner alike. Contradictory statements and data regarding dysplastic nevi are catalogued in the work, and the following premise is offered: dysplastic nevi do not exist as a distinct clinicopathologic entity, but the larger concept of dysplastic nevus may hold legitimacy. The first segment of this compound sentence should be considered revolutionary in many quarters. If a dysplastic nevus, as broadly used at present, is not a melanocytic nevus sui generis, should the diagnosis be made at all? Certainly it is troubling to consider that the attributes that guide many dermatopathologists to a diagnosis of dysplastic nevus are shared by growing conventional melanocytic nevi, melanocytic nevi ‘of a special site’, ‘spastic’ (spitzoid dysplastic) nevi, some congenital melanocytic nevi, and melanoma.6,9,10 If data regarding the clinical significance of dysplastic nevi has been skewed by the inclusion of histomorphologically similar non-dysplastic nevi, then conclusions based on such data must be, by definition, suspect. Consider also the possibility that since dysplastic nevus has not yet been defined as a tumor sui generis in the fullest sense of the term, and since the upper end of the spectrum of such nevi exhibits histomorphology overlapping with that of nevoid melanoma, entrenched concepts regarding the incidence and prevalence of melanoma ex melanocytic nevus may be biased. Is it conceivable
that in a world with an expansive view of dysplastic nevi that some examples of melanoma ex melanocytic nevus actually represent melanoma ex melanoma? It is not merely conceivable but highly plausible. The second portion of Shapiro’s premise (the larger concept of dysplastic nevus may hold legitimacy) refers to the ongoing collective observation that it is utterly clear that there is an underlying correlation between melanocytic nevi and melanoma.9 Shapiro suggests that melanocytic nevi with a ‘proliferative junctional component’9 (or, one suspects, a proliferative component in any tissue compartment) pose a risk for the secondary development of melanoma. However, common sense suggests that the precise tabulation of that risk cannot be based upon correlation with an enormous and potentially overused diagnostic category such as dysplastic nevus. It has been known for decades that patients with numerous melanocytic nevi have an increased risk of melanoma, with the secondary tumor occurring either in direct continuity with their melanocytic nevus or developing at a non-contiguous site. With that as a given, it comes as absolutely no surprise that a patient with many melanocytic nevi that have been called dysplastic also has an increased risk of melanoma. What would be earth-shattering would be to learn that a patient group with a precisely-defined subset (call them dysplastic nevi sui generis) of our current morass of dysplastic nevi had not only an increased risk of melanoma, but also that this particular histomorphology was directly associated with a specific molecular aberration. Or to learn that hypermelanotic melanocytic nevi, which are often called dysplastic but probably deserve a different fate, did not signify an increased risk of melanoma. Or to learn whether HRAS-mutated Spitz nevi or angiomatoid Spitz nevi do or do not correlate with lifetime melanoma risk. Basing decisions regarding diagnosis, patient management, and systemic risk upon non-unique or non-distinctive histopathologic parameters will only serve to fuel ongoing controversy regarding the significance of flat melanocytic nevi, a diagnostic grouping that may include tumors non ex suo genere (not of a kind) rather than sui generis. Timothy H. McCalmont, Editor-in-Chief San Francisco, CA, USA
References 1. Pozo L, Naase M, Cerio R, Blanes A, Diaz-Cano SJ. Critical analysis of histologic criteria for grading atypical (dysplastic) melanocytic nevi. Am J Clin Pathol. 2001; 115: 194.
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2. Weinstock MA, Barnhill RL, Rhodes AR, Brodsky GL. Reliability of the histopathologic diagnosis of melanocytic dysplasia. The Dysplastic Nevus Panel. Arch Dermatol. 1997; 133: 953.
3. Meyer LJ, Piepkorn M, Goldgar DE, et al. Interobserver concordance in discriminating clinical atypia of melanocytic nevi, and correlations with histologic atypia. J Am Acad Dermatol. 1996; 34: 618.
Editorial 4. Farrahi F, Egbert BM, Swetter SM. Histologic similarities between lentigo maligna and dysplastic nevus: importance of clinicopathologic distinction. J Cutan Pathol. 2005;32: 405-12. Erratum in. J Cutan Pathol. 2005; 32: 521. 5. Kutzner H, Metzler G, Argenyi Z, et al. Histological and genetic evidence for a variant of superficial spreading melanoma composed
predominantly of large nests. Mod Pathol. 2012; 25: 838. 6. Cook MG, Fallowfield ME. Dysplastic naevi-an alternative view. Histopathology. 1990; 16:29. 7. McCalmont TH, Vemula S, Sands P, Bastian BC. Molecular-microscopical correlation in dermatopathology. J Cutan Pathol. 2011; 38: 324.
8. McCalmont TH. The light bulb. J Cutan Pathol. 2012; 39: 671. 9. Shapiro PE. Making sense of the dysplastic nevus controversy. A unifying perspective. Am J Dermatopathol. 1992; 14: 350. 10. McCalmont TH. A house of cards. J Cutan Pathol. 2012; 39: 739.
995
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Editorial
Believe it or not: a truism or an entrenched paradigm? Keywords: diagnostic concordance, dysplastic nevus, dysplastic nevus syndrome, HRAS-mutated Spitz nevus Whether one is a full-bore dysplasticist who believes without question that melanocytic nevi progress gradually through increasing dysplasia and atypia with eventuation as melanoma at one pole, whether one is a fanatical Ackerman clone who views the histopathologic interpretation and oncogenesis of melanocytic tumors much like a light switch (it’s either on or off, yes or no, melanoma or not) at the other, or whether one falls somewhere between those extremes, dermatopathologists of any stripe can agree that requisition forms bearing a clinical context of rule out dysplasia or rule out atypia are exceedingly common in the laboratory and that a sizable proportion of each diagnostic day is spent deliberating whether given biopsy specimens demonstrate utterly conventional melanocytic nevi, dysplastic/Clark/atypical melanocytic nevi, or melanoma. Furthermore, it must be clear to all that concern for melanocytic nevi being atypical is epidemic and utterly entrenched in the clinical realm, or alternatively the concept is being exploited clinically for remunerative gain, because otherwise such large volumes of biopsies would not enter the dermatopathology laboratory in the first place. What is far less obvious, at least to this observer, is whether the concept has broad validity or not. Furthermore, it remains murky whether patient management in the context of dysplastic nevi, once a biopsy has been procured, examined, and reported upon, is reproducible or whimsical (the latter seems likely). While it is clear that while interobserver agreement in the microscopic diagnosis of dysplastic nevus is occasionally excellent, it is more commonly mediocre.1 – 3 It is also clear that the morphology of dysplastic nevi can be closely mimicked by other melanocytic tumors, including melanoma.4 – 6 With respect to management, a recent review of 100 biopsies has documented that recommendations for reexcision are highly capricious, as like-minded
pathologists are commonly unable to agree whether reexcision is necessary or not, and an individual pathologist does not make consistent recommendations when reevaluating previously interpreted specimens (Brianne Daniels, personal communication). In short, in at least some instances a diagnosis of the type of melanocytic nevus under discussion may not be completed reproducibly, and when that potentially wobbly opinion is coupled in a pathology report with a judgment regarding reexcision, one dermatopathologist may not agree with another and one may not even agree with oneself. Certainly the lack of consistency alluded to in the preceding sentence should be of grave concern to a scientific discipline, at least one that wishes to be taken seriously. Those who report a given melanocytic nevus as being dysplastic, whether done on occasion or as an hourly event, presumably believe that they are rendering a diagnosis that has tightly constrained implications. In other words, to render an outright (or, for that matter, a veiled) diagnosis of dysplastic/Clark nevus is to imply that it represents a melanocytic nevus sui generis rather than a histopathologic reaction pattern that can be seen more broadly. Indeed, there is reason to believe that melanocytic nevi can assume reasonably narrow histomorphology that is triggered by specific molecular underpinnings. HRAS-mutated Spitz nevi, perhaps the prototype of this phenomenon, represent broad, horizontally oriented, and hypercellular desmoplastic Spitz nevi that are easily misinterpreted as melanoma, especially by non-dermatopathologists, because of large size, relatively high cellularity, and the presence of dermal melanocytes in mitosis, constituting a combination that breaks many of the rules used daily for separating benign from malignant.7 Most blue nevi, a subset of which are reasonably microscopically homogeneous, are triggered by activating mutations in the Ras-like domain of GNAQ (or by mutations
993
Editorial in the paralogue GNA11), while deep penetrating nevi, the clinical kinfolk of blue nevi, are genetically unrelated.8 Do all melanocytic nevi (or all categories of melanocytic nevi), defined through precise microscopic work, have specific, narrow, and definable genetic triggers? It seems likely that the answer to this question can be yes, provided that the histopathologic recognition of the melanocytic nevus (or category of melanocytic nevus) is sufficiently constrained. Is it likely that melanocytic nevi termed dysplastic or atypical, as currently diagnosed, have a specific, narrow, and definable genetic trigger? It seems likely that the answer at present is no, considering the heterogeneous and variable qualities associated with melanocytic dysplasia and the documented lack of precise diagnostic reproducibility at this point in time. Some two decades ago, Shapiro put forth an unnoticed (minimally cited) ‘unifying perspective’ regarding dysplastic nevi.9 The manuscript represents an interesting read and is worthy of re-review for both the young student of dermatopathology and the longstanding practitioner alike. Contradictory statements and data regarding dysplastic nevi are catalogued in the work, and the following premise is offered: dysplastic nevi do not exist as a distinct clinicopathologic entity, but the larger concept of dysplastic nevus may hold legitimacy. The first segment of this compound sentence should be considered revolutionary in many quarters. If a dysplastic nevus, as broadly used at present, is not a melanocytic nevus sui generis, should the diagnosis be made at all? Certainly it is troubling to consider that the attributes that guide many dermatopathologists to a diagnosis of dysplastic nevus are shared by growing conventional melanocytic nevi, melanocytic nevi ‘of a special site’, ‘spastic’ (spitzoid dysplastic) nevi, some congenital melanocytic nevi, and melanoma.6,9,10 If data regarding the clinical significance of dysplastic nevi has been skewed by the inclusion of histomorphologically similar non-dysplastic nevi, then conclusions based on such data must be, by definition, suspect. Consider also the possibility that since dysplastic nevus has not yet been defined as a tumor sui generis in the fullest sense of the term, and since the upper end of the spectrum of such nevi exhibits histomorphology overlapping with that of nevoid melanoma, entrenched concepts regarding the incidence and prevalence of melanoma ex melanocytic nevus may be biased. Is it conceivable
that in a world with an expansive view of dysplastic nevi that some examples of melanoma ex melanocytic nevus actually represent melanoma ex melanoma? It is not merely conceivable but highly plausible. The second portion of Shapiro’s premise (the larger concept of dysplastic nevus may hold legitimacy) refers to the ongoing collective observation that it is utterly clear that there is an underlying correlation between melanocytic nevi and melanoma.9 Shapiro suggests that melanocytic nevi with a ‘proliferative junctional component’9 (or, one suspects, a proliferative component in any tissue compartment) pose a risk for the secondary development of melanoma. However, common sense suggests that the precise tabulation of that risk cannot be based upon correlation with an enormous and potentially overused diagnostic category such as dysplastic nevus. It has been known for decades that patients with numerous melanocytic nevi have an increased risk of melanoma, with the secondary tumor occurring either in direct continuity with their melanocytic nevus or developing at a non-contiguous site. With that as a given, it comes as absolutely no surprise that a patient with many melanocytic nevi that have been called dysplastic also has an increased risk of melanoma. What would be earth-shattering would be to learn that a patient group with a precisely-defined subset (call them dysplastic nevi sui generis) of our current morass of dysplastic nevi had not only an increased risk of melanoma, but also that this particular histomorphology was directly associated with a specific molecular aberration. Or to learn that hypermelanotic melanocytic nevi, which are often called dysplastic but probably deserve a different fate, did not signify an increased risk of melanoma. Or to learn whether HRAS-mutated Spitz nevi or angiomatoid Spitz nevi do or do not correlate with lifetime melanoma risk. Basing decisions regarding diagnosis, patient management, and systemic risk upon non-unique or non-distinctive histopathologic parameters will only serve to fuel ongoing controversy regarding the significance of flat melanocytic nevi, a diagnostic grouping that may include tumors non ex suo genere (not of a kind) rather than sui generis. Timothy H. McCalmont, Editor-in-Chief San Francisco, CA, USA
References 1. Pozo L, Naase M, Cerio R, Blanes A, Diaz-Cano SJ. Critical analysis of histologic criteria for grading atypical (dysplastic) melanocytic nevi. Am J Clin Pathol. 2001; 115: 194.
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2. Weinstock MA, Barnhill RL, Rhodes AR, Brodsky GL. Reliability of the histopathologic diagnosis of melanocytic dysplasia. The Dysplastic Nevus Panel. Arch Dermatol. 1997; 133: 953.
3. Meyer LJ, Piepkorn M, Goldgar DE, et al. Interobserver concordance in discriminating clinical atypia of melanocytic nevi, and correlations with histologic atypia. J Am Acad Dermatol. 1996; 34: 618.
Editorial 4. Farrahi F, Egbert BM, Swetter SM. Histologic similarities between lentigo maligna and dysplastic nevus: importance of clinicopathologic distinction. J Cutan Pathol. 2005;32: 405-12. Erratum in. J Cutan Pathol. 2005; 32: 521. 5. Kutzner H, Metzler G, Argenyi Z, et al. Histological and genetic evidence for a variant of superficial spreading melanoma composed
predominantly of large nests. Mod Pathol. 2012; 25: 838. 6. Cook MG, Fallowfield ME. Dysplastic naevi-an alternative view. Histopathology. 1990; 16:29. 7. McCalmont TH, Vemula S, Sands P, Bastian BC. Molecular-microscopical correlation in dermatopathology. J Cutan Pathol. 2011; 38: 324.
8. McCalmont TH. The light bulb. J Cutan Pathol. 2012; 39: 671. 9. Shapiro PE. Making sense of the dysplastic nevus controversy. A unifying perspective. Am J Dermatopathol. 1992; 14: 350. 10. McCalmont TH. A house of cards. J Cutan Pathol. 2012; 39: 739.
995
