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The regenerating naevus
Pathology (- 2015) -(-), pp. 1–5
M E L A N O C Y T I C T U M O U R PAT H O L O G Y
The regenerating naevus RICARDO E. VILAIN1,2,3, STANLEY W. MCCARTHY4,5,6 RICHARD A. SCOLYER4,5,6
AND
1
School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, 2Hunter Cancer Research Alliance (HCRA), Calvary Mater Newcastle, Waratah, 3 Division of Anatomical Pathology, Pathology North (Hunter), New Lambton Heights, 4 Melanoma Institute Australia, North Sydney, 5Sydney Medical School, University of Sydney, Sydney, and 6Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
Summary The re-emergence of a melanocytic proliferation at the site of a previously excised pigmented lesion may not only cause great concern clinically but may also be amongst the most difficult of all melanocytic lesions for pathologists to assess. These lesions can adopt an appearance which may be impossible to confidently distinguish from a regressing or traumatised melanoma on histological grounds alone. For this reason, careful attention must be paid to the clinical context which has given rise to the lesion or a misdiagnosis may occur. In the absence of a corroborating history of prior surgery or trauma to the site, a diagnosis of a regenerating naevus may only be provisional. When considering a diagnosis of regenerating naevus, whenever possible, it is important to review and confirm the benign nature of the precursor lesion. Nevertheless, 50 years of research into this phenomenon has identified certain characteristic clinical features and histological patterns which provide clues both to clinicians and pathologists that will assist them to make the correct diagnosis and avoid over diagnosing as melanoma what is ultimately a benign process. Key words: Diagnosis; pathology; melanoma; persistent naevus; pseudomelanoma; regenerating naevus; recurrent naevus. Received 26 November, accepted 27 November 2015
INTRODUCTION The regenerating naevus is recognised as a potential diagnostic pitfall in melanocyte pathology.1–3 Repigmentation at the site of a partially or completely excised naevus can generate considerable concern for patients as well as clinicians and the presence of a melanocytic proliferation at the site of a previously excised pigmented lesion may cause diagnostic uncertainty for pathologists. These uncommon lesions are particularly prone to pathological misdiagnosis in partial biopsy specimens, especially when they are examined without knowledge of pertinent clinical information, for their histopathological appearance can show considerable overlap with regressing melanomas.
The phenomenon of recurrent naevi has long been recognised,4 but the capacity of trauma to induce junctional melanocyte ‘activation’, and thus regeneration and hyperplasia, was first systematically studied by Cox and Walton.5 They analysed the changes in cellularity between initial biopsies and re-excision specimens and noted that in up to 56% of patients’ re-biopsies, naevi exhibited a degree of junctional melanocyte hyperplasia which exceeded that observed in the original naevus. Although the authors highlighted that an understating of the nature of trauma-induced stimulated junctional activity can help inform subsequent surgical management, it was left to the work of Ackerman and Kornberg6 and Reed and colleagues7 to highlight the capacity for this phenomenon to mimic melanoma. Ackerman and Kornberg documented a series of eight patients with rapidly recurring pigmented lesions following incomplete excision that displayed common histological features which could, if assessed in isolation, lead to misdiagnosis of melanoma for what they proposed was a benign process. Of most concern pathologically was the presence of histological features which overlap with those found in superficial spreading melanoma in situ; a hypercellular proliferation of junctional melanocytes with a greatly variable nested and single cell growth pattern, occasional confluent growth as well as some cytological atypia and, in particular, the presence of pagetoid spread. The latter may be particularly florid within regenerating naevi. They counselled that although there are features which are helpful in avoiding over-diagnosing these lesions as melanoma, namely the presence of sharply circumscribed borders, absence of necrosis, rarity of mitoses, invariable subjacent often scar-like dermal fibrosis and the recognition of dermal naevus remnants, the most important thing to remember was that ‘only accurate review of the original biopsy specimen can confirm with certainty the benign nature of the original neoplasm’. Their observations and advice remain relevant to this day. The label ‘pseudomelanoma’ has been controversial since its inception.8 Although the term alerts the diagnostician to the need for vigilance in avoiding over diagnosing these lesions as melanoma, pseudomelanoma continues to be used to identify non-melanocytic lesions which clinically simulate melanoma.9–12 Regenerating naevus, recurrent naevus and
Print ISSN 0031-3025/Online ISSN 1465-3931 © 2016 Published by Elsevier Ltd on behalf of Royal College of Pathologists of Australasia. DOI: http://dx.doi.org/10.1016/j.pathol.2015.12.009 Please cite this article in press as: Vilain RE, et al., The regenerating naevus, Pathology (2015), http://dx.doi.org/10.1016/j.pathol.2015.12.009
2
Pathology (2015), -(-), -
VILAIN et al.
Table 1
Summary of studies assessing naevus recurrence rates
Study Bong et al.13 Ferrandiz et al.14 Gambichler et al.15 Goodson et al.16 Tallon et al.17
Naevi
Method of removal
Margin involvement
Minimum follow up
Recurrence rate
83 204 77 246
Shave, 100% Shave, 100% Shave, 100% Shave, 60.1% Punch, 27.3% Excision, 16.6% Shave, 12.4% Punch, 9.9% Excision, 74.5% Other, 3.3%
NA 64% 12% 52.0%
12 months 3 months 6 months 24 months
27% 19.6% 13% 2.8%
26.3%
60 months
0.3%a
1035
NA, not assessed. a
Recurrence rate calculated from laboratory database.
persistent naevus are used interchangeably in the literature and, in the authors’ opinion, all represent more appropriate terms than pseudomelanoma, because not all regenerating naevi pose diagnostic difficulty for the pathologist but they are all the result of the benign proliferation of naevocytes at the site of trauma.
CLINICAL FEATURES The incidence of regenerating naevi varies considerably in the literature. Method of excision and thus likelihood of margin involvement, as well as clinical follow up and the method of assessing for the presence of recurrence (i.e., clinical examination alone or histopathological confirmation) has differed between the various studies on the subject and correspondingly the rate of recurrence varies from 0.3% to 27% (Table 1). However, it is apparent that amongst the case series with higher proportions of shave biopsies, the rate of recurrence is higher.13–17 Regenerating naevi display characteristic clinical features (Table 2). They are reported to occur more frequently in females and young patients.18–20 The back is commonly cited as the body region most likely to give rise to a recurrence.1 Some have proposed that this is could be a function of a thicker dermis being more likely to harbour residual naevocytes,20 while others contend this reflects the general distribution of biopsied naevi.21 The reported rate of involvement Table 2
of the margins by naevus cells in the primary excision is typically high.17 Most regenerating naevi arise from common acquired naevi, followed by dysplastic naevi and congenital naevi12 (Table 2). Recurrences in specialised naevi such as Spitz naevus22 or blue naevi23 are considered to be uncommon events but this probably reflects the prevalence of these tumours. Regenerating naevi usually recur rapidly, most commonly within 6 months and almost always within 12 months of the prior biopsy or traumatic event, although we have seen cases of late recurrence of naevi confirmed on review of the prior specimen and subsequent long-term clinical follow-up. The clinical presentation is variable but some recurring patterns have been described. Recurrent naevi typically break the common clinical rules of benignity, displaying asymmetry, irregular borders and variegated colouration. Other common dermoscopic features include radial lines and a centrifugal growth pattern.24–26 Recurrent naevi are characteristically strictly macular lesions,6 but recurrent blue naevi23 and Spitz naevi22 are notable exceptions. In a dermoscopic comparison of 98 recurrent naevi and 62 recurrent melanomas, Blum et al. demonstrated features such as a circular pattern, eccentric hyperpigmentation, chaotic, non-continuous growth and extension beyond the scar were patterns more commonly, but not exclusively, encountered in melanoma.25
Summary of studies assessing the clinical features of recurrent naevi King et al.18 354 cases
Sommer et al.20 205 cases
Park et al.19 175 cases
72% 30 (7–92)
65% ‘most between 25-50 years’ (6–88)
85% ‘most…between 20–30 years’ (3–76)
Female Median age (range) Site Head and neck Chest/Abdomen Back Extremities Precursor naevus Common acquired Congenital Dysplastic Other
6% 20% 57% 16%
10% 15% 49% 24%
26% ‘Trunk’ (54%) – 16%
64% 6% 28% 1%
26% NA 72% 1%
NA NA NA NA
Original naevus with involved margins Median months to recurrence (range)
77% 5 (1–63)
75% ‘most biopsied <6 months’
97% 4.75 (1–216)
NA, not assessed.
Please cite this article in press as: Vilain RE, et al., The regenerating naevus, Pathology (2015), http://dx.doi.org/10.1016/j.pathol.2015.12.009
THE REGENERATING NAEVUS
3
Fig. 1
A trizonal pattern of fibrosis and cellularity is seen in classical regenerating naevi. A heavily pigmented, hyperplastic junctional and superficial melanocytic component (zone 1) cap a central zone of angiofibroplasia (zone 2) while the periphery is populated by the original residual naevocyte population (zone 3).
Fig. 3
HISTOLOGICAL FEATURES
Maturation is not as well developed as is seen within common naevi and their nuclear features are commonly reported to resemble those encountered in the overlying junctional population (Fig. 3).18 The maturation gradient in HMB45 expression seen in common benign naevi is often reproduced in regenerating naevi21 but this is not always the case and retention of HMB45 staining in the deeper dermal part of a regenerating naevus can cause diagnostic concern for melanoma. Similarly to the proliferation rate seen in ordinary naevi, regenerating naevi are expected to show a low mitotic rate and Ki-67 index. Correspondingly, the presence of more than occasional mitoses should prompt the reappraisal of a benign diagnosis and the close search for other atypical features. The epidermal changes present an important clue to the presence of regeneration. Regenerating epidermis typically displays effacement of its normal rete pattern, acanthosis and overlying compact hyperkeratosis (Fig. 4). Nevertheless, the rete ridges can be preserved in as many as 15% of regenerating naevi and thus their presence is not incompatible with a regenerating phenomenon.18 As mentioned above, the dermis should show the features of healing or healed scar tissue; dense fibrosis with horizontally arranged layering, telangiectasia or angiofibroplasia and, in addition, melanophages and chronic inflammatory cells are commonly present (Fig. 5). It is useful to remember that while these features can
When occurring in its classical form, a regenerating naevus is a relatively straightforward diagnosis. The typical appearance at low power is trizonal19 (Fig. 1 and 2A) with the three zones comprising the atypical junctional/superficial dermal melanocytic proliferation (the first zone) within a superficial dermal scar (the second zone) with underlying dermal naevus cells (the third zone). The scarring usually extends deep to the superficially distributed regenerating naevocytes, the latter often showing some mild cytological atypia. At the periphery of the scar, the original residual naevocyte population is commonly encountered. The regenerating melanocytes can be densely pigmented. An epithelioid morphology typically dominates18 (Fig. 3). The cytoplasm can be abundant; the nuclei feature smooth vesicular chromatin and prominent nucleoli (Fig. 3). Atypical cytological features are commonly encountered (Fig. 2B) but, importantly, the degree of severity of the cytological atypia does not equate to that usually seen in invasive melanoma.10 The junctional component is usually a mixture of lentiginous and nested melanocytes, and their arrangement is not uniform or symmetrically distributed. Extension of melanocytes into the upper epidermal layers (pagetoid spread) is frequently encountered18 (Fig. 2B). The dermal naevocytes are most commonly nested and irregularly distributed and not infrequently heavily pigmented.
The junctional and dermal components can share a very similar cytological appearance, particularly of their nuclei. This has been used as evidence by some that the dermal nests in regenerating naevi originate from the junctional component.18,19
Fig. 2 This regenerating melanocytic naevus was excised from the thigh of an 8-year-old girl. (A) The lesion demonstrates the typical trizonal pattern; on the right of the
photomicrograph, a hyperplastic junctional population overlies a scarred dermis. The pre-existing compound naevus can be seen on the left. (B) A high power view reveals a proliferation of atypical melanocytes with extensive upward spread, which can be deceiving for melanoma in situ if assessed in isolation. The review of the initial biopsy confirmed the presence of a banal compound naevus.
Please cite this article in press as: Vilain RE, et al., The regenerating naevus, Pathology (2015), http://dx.doi.org/10.1016/j.pathol.2015.12.009
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Pathology (2015), -(-), -
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This compound regenerating naevus shows a hyperplastic junctional population of melanocytes in a nested and lentiginous growth pattern populating an epidermis which displays signs of repair; effacement of the rete architecture; acanthosis, hypergranulosis and hyperkeratosis. The subjacent scarred dermis contains densely pigmented naevocyte nests.
Fig. 4
overlap considerably with regression (a phenomenon that may occur in both naevi and melanomas), regressing melanomas are more likely to be associated with epidermal thinning than acanthosis. As recommended by King et al., in biopsies where the dermal scarring extends to the margins of the excision, the typical features of a regenerating naevus, particularly when occurring in retiform epidermis, may be indistinguishable from melanoma with regression.18 In these instances, a high index of suspicion and the ability to review the initial excision is the most reliable way to arrive at the correct diagnosis.
RECURRENT SPITZ AND BLUE NAEVI The recurrence of benign specialised naevi such as blue and Spitz naevi are uncommon events.22,23 However, when this occurs they can be particularly challenging lesions to diagnose pathologically because the regeneration of both of these types of naevi can even more closely resemble melanoma. Both regenerating blue and Spitz naevi can manifest nodular lesions, which extend beyond the confines of the scar.22,23,27 Indeed, their recurrences can even appear as as agminated22,28 or satellite lesions,22 thus clinically resembling melanoma. Like melanomas, their time to recurrence is reportedly longer than regenerating common naevi (>32 months for blue naevi23 and approximately 17 months for Spitz naevi22).
Recurrent blue naevi most commonly arise from the incomplete excision of a deep seated fascicular component.23 The recurrent naevocytes can display similar or greater cytological atypia and cellularity than their precursor lesions and the overall architecture can recreate that seen in the initial biopsy or display a ‘phenotypic divergence’ from the original neoplasm. However, frank malignant features such as en masse necrosis, a high mitotic rate and high grade cytological atypia should be taken to represent evidence of a malignant transformation.23 Spitz naevi, on the other hand, have been shown to recur in one of several patterns: (1) a junctional only population exhibiting the same range of features encountered in a typical regenerating naevus, (2) a replica of the original compound lesion with identical cytological and architectural features, (3) a desmoplastic pattern, and (4) an expansile nodular growth pattern which resembles melanoma. The dermal component in all patterns usually displays low mitotic rates and a maturation gradient on HMB45 staining. Furthermore, comparative genomic hybridisation has revealed an absence of large scale chromosomal abnormalities in most cases.22 In view of their rarity and unusual histological features, these uncommon regenerating naevi not only mandate a review of the original lesion but probably also warrant seeking a second opinion from a pathologist experienced in the assessment of melanocytic tumours and, if the clinical circumstances permit, a complete excision of the lesion.
CONCLUSION Because of the difficulty in distinguishing them from melanoma both clinically and pathologically, regenerating naevi can be intimidating lesions to evaluate. A minor portion can show features which overlap considerably with regressing melanoma. There are clues to assist in making the correct diagnosis: a consistent clinical history, a rapid recurrence, a trizonal histopathological pattern that includes scar tissue, low dermal mitotic rate and an overall low degree of cytological atypia which should not exceed that typically encountered in invasive melanoma, are all helpful features. However, for borderline lesions, whenever possible, every effort should be made to review the preceding excision and complete excision is generally advisable. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Address for correspondence: Dr Ricardo E. Vilain, Pathology North Hunter, NSW Health Pathology, John Hunter Hospital, Locked Bag 1, Hunter Region Mail Centre, Newcastle, NSW, 2310, Australia. E-mail: [email protected]
References
Fig. 5 Orderly central fibrosis and angiofibroplasia are near invariable features
in regenerating naevi. In this example, melanophages are also distributed within the scarred dermis.
1. Brenn T. Pitfalls in the evaluation of melanocytic lesions. Histopathology 2012; 60: 690–705. 2. Wick M. Selected benign lesions that may be confused pathologically with cutaneous melanoma. Pathol Case Rev 2015; 20: 82–101. 3. Marsch A, High WA. Medicolegal issues with regard to melanoma and pigmented lesions in dermatopathology. Dermatol Clin 2012; 30: 593–615. v–vi. 4. Schoenfeld RJ, Pinkus H. The recurrence of nevi after incomplete removal. AMA Arch Derm 1958; 78: 30–5. 5. Cox AJ, Walton RG. Pigmented nevi. Induced changes in the junctional component. Calif Med 1966; 104: 32–4.
Please cite this article in press as: Vilain RE, et al., The regenerating naevus, Pathology (2015), http://dx.doi.org/10.1016/j.pathol.2015.12.009
THE REGENERATING NAEVUS
6. Kornberg R, Ackerman AB. Pseudomelanoma: recurrent melanocytic nevus following partial surgical removal. Arch Dermatol 1975; 111: 1588–90. 7. Reed RJ, Ichinose H, Clark WH, Mihm MC. Common and uncommon melanocytic nevi and borderline melanomas. Semin Oncol 1975; 2: 119–47. 8. Reed BW. Pseudomelanoma. Arch Dermatol 1976; 112: 1611–2. 9. Shields CL, Manalac J, Das C, Ferguson K, Shields JA. Choroidal melanoma: clinical features, classification, and top 10 pseudomelanomas. Curr Opin Ophthalmol 2014; 25: 177–85. 10. Means AD, Prieto VG, Reed JA, Shea CR. Pathology of Challenging Melanocytic Neoplasms: Diagnosis and Management. New York: Springer, 2014. 11. Pinkus H, Mehregan AH. A Guide to Dermatohistopathology. New York: Appleton-Century-Crofts, 1981; 591. 12. Fox JC, Reed JA, Shea CR. The recurrent nevus phenomenon: a history of challenge, controversy, and discovery. Arch Pathol Lab Med 2011; 135: 842–6. 13. Bong JL, Perkins W. Shave excision of benign facial melanocytic naevi: a patient’s satisfaction survey. Dermatol Surg 2003; 29: 227–9. 14. Ferrandiz L, Moreno-Ramirez D, Camacho FM. Shave excision of common acquired melanocytic nevi: cosmetic outcome, recurrences, and complications. Dermatol Surg 2005; 31: 1112–5. 15. Gambichler T, Senger E, Rapp S, Alamouti D, Altmeyer P, Hoffmann K. Deep shave excision of macular melanocytic nevi with the razor blade biopsy technique. Dermatol Surg 2000; 26: 662–6. 16. Goodson AG, Florell SR, Boucher KM, Grossman D. Low rates of clinical recurrence after biopsy of benign to moderately dysplastic melanocytic nevi. J Am Acad Dermatol 2010; 62: 591–6. 17. Tallon B, Snow J. Low clinically significant rate of recurrence in benign nevi. Am J Dermatopathol 2012; 34: 706–9.
5
18. King R, Hayzen BA, Page RN, Googe PB, Zeagler D, Mihm MC. Recurrent nevus phenomenon: a clinicopathologic study of 357 cases and histologic comparison with melanoma with regression. Mod Pathol 2009; 22: 611–7. 19. Park HK, Leonard DD, Arrington JH, Lund HZ. Recurrent melanocytic nevi: clinical and histologic review of 175 cases. J Am Acad Dermatol 1987; 17: 285–92. 20. Sommer LL, Barcia SM, Clarke LE, Helm KF. Persistent melanocytic nevi: a review and analysis of 205 cases. J Cutan Pathol 2011; 38: 503–7. 21. Hoang MP, Prieto VG, Burchette JL, Shea CR. Recurrent melanocytic nevus: a histologic and immunohistochemical evaluation. J Cutan Pathol 2001; 28: 400–6. 22. Harvell JD, Bastian BC, LeBoit PE. Persistent (recurrent) Spitz nevi: a histopathologic, immunohistochemical, and molecular pathologic study of 22 cases. Am J Surg Pathol 2002; 26: 654–61. 23. Harvell JD, White WL. Persistent and recurrent blue nevi. Am J Dermatopathol 1999; 21: 506–17. 24. Marghoob AA, Changchien L, DeFazio J, et al. The most common challenges in melanoma diagnosis and how to avoid them. Australas J Dermatol 2009; 50: 1–15. 25. Blum A, Hofmann-Wellenhof R, Marghoob AA, et al. Recurrent melanocytic nevi and melanomas in dermoscopy: results of a multicenter study of the International Dermoscopy Society. JAMA Dermatol 2014; 150: 138–45. 26. Tschandl P. Recurrent nevi: report of three cases with dermatoscopicdermatopathologic correlation. Dermatol Pract Concept 2013; 3: 29–32. 27. Tanaka K, Mihara M, Shimao S, Taniguchi K. The local recurrence of pigmented Spitz nevus after removal. J Dermatol 1990; 17: 575–80. 28. Krasovec M, Gianadda B, Hohl D. Giant recurrence of a multiple agminated Spitz nevus. J Am Acad Dermatol 1995; 33: 386–8.
Please cite this article in press as: Vilain RE, et al., The regenerating naevus, Pathology (2015), http://dx.doi.org/10.1016/j.pathol.2015.12.009
M E L A N O C Y T I C T U M O U R PAT H O L O G Y
The regenerating naevus RICARDO E. VILAIN1,2,3, STANLEY W. MCCARTHY4,5,6 RICHARD A. SCOLYER4,5,6
AND
1
School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, 2Hunter Cancer Research Alliance (HCRA), Calvary Mater Newcastle, Waratah, 3 Division of Anatomical Pathology, Pathology North (Hunter), New Lambton Heights, 4 Melanoma Institute Australia, North Sydney, 5Sydney Medical School, University of Sydney, Sydney, and 6Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
Summary The re-emergence of a melanocytic proliferation at the site of a previously excised pigmented lesion may not only cause great concern clinically but may also be amongst the most difficult of all melanocytic lesions for pathologists to assess. These lesions can adopt an appearance which may be impossible to confidently distinguish from a regressing or traumatised melanoma on histological grounds alone. For this reason, careful attention must be paid to the clinical context which has given rise to the lesion or a misdiagnosis may occur. In the absence of a corroborating history of prior surgery or trauma to the site, a diagnosis of a regenerating naevus may only be provisional. When considering a diagnosis of regenerating naevus, whenever possible, it is important to review and confirm the benign nature of the precursor lesion. Nevertheless, 50 years of research into this phenomenon has identified certain characteristic clinical features and histological patterns which provide clues both to clinicians and pathologists that will assist them to make the correct diagnosis and avoid over diagnosing as melanoma what is ultimately a benign process. Key words: Diagnosis; pathology; melanoma; persistent naevus; pseudomelanoma; regenerating naevus; recurrent naevus. Received 26 November, accepted 27 November 2015
INTRODUCTION The regenerating naevus is recognised as a potential diagnostic pitfall in melanocyte pathology.1–3 Repigmentation at the site of a partially or completely excised naevus can generate considerable concern for patients as well as clinicians and the presence of a melanocytic proliferation at the site of a previously excised pigmented lesion may cause diagnostic uncertainty for pathologists. These uncommon lesions are particularly prone to pathological misdiagnosis in partial biopsy specimens, especially when they are examined without knowledge of pertinent clinical information, for their histopathological appearance can show considerable overlap with regressing melanomas.
The phenomenon of recurrent naevi has long been recognised,4 but the capacity of trauma to induce junctional melanocyte ‘activation’, and thus regeneration and hyperplasia, was first systematically studied by Cox and Walton.5 They analysed the changes in cellularity between initial biopsies and re-excision specimens and noted that in up to 56% of patients’ re-biopsies, naevi exhibited a degree of junctional melanocyte hyperplasia which exceeded that observed in the original naevus. Although the authors highlighted that an understating of the nature of trauma-induced stimulated junctional activity can help inform subsequent surgical management, it was left to the work of Ackerman and Kornberg6 and Reed and colleagues7 to highlight the capacity for this phenomenon to mimic melanoma. Ackerman and Kornberg documented a series of eight patients with rapidly recurring pigmented lesions following incomplete excision that displayed common histological features which could, if assessed in isolation, lead to misdiagnosis of melanoma for what they proposed was a benign process. Of most concern pathologically was the presence of histological features which overlap with those found in superficial spreading melanoma in situ; a hypercellular proliferation of junctional melanocytes with a greatly variable nested and single cell growth pattern, occasional confluent growth as well as some cytological atypia and, in particular, the presence of pagetoid spread. The latter may be particularly florid within regenerating naevi. They counselled that although there are features which are helpful in avoiding over-diagnosing these lesions as melanoma, namely the presence of sharply circumscribed borders, absence of necrosis, rarity of mitoses, invariable subjacent often scar-like dermal fibrosis and the recognition of dermal naevus remnants, the most important thing to remember was that ‘only accurate review of the original biopsy specimen can confirm with certainty the benign nature of the original neoplasm’. Their observations and advice remain relevant to this day. The label ‘pseudomelanoma’ has been controversial since its inception.8 Although the term alerts the diagnostician to the need for vigilance in avoiding over diagnosing these lesions as melanoma, pseudomelanoma continues to be used to identify non-melanocytic lesions which clinically simulate melanoma.9–12 Regenerating naevus, recurrent naevus and
Print ISSN 0031-3025/Online ISSN 1465-3931 © 2016 Published by Elsevier Ltd on behalf of Royal College of Pathologists of Australasia. DOI: http://dx.doi.org/10.1016/j.pathol.2015.12.009 Please cite this article in press as: Vilain RE, et al., The regenerating naevus, Pathology (2015), http://dx.doi.org/10.1016/j.pathol.2015.12.009
2
Pathology (2015), -(-), -
VILAIN et al.
Table 1
Summary of studies assessing naevus recurrence rates
Study Bong et al.13 Ferrandiz et al.14 Gambichler et al.15 Goodson et al.16 Tallon et al.17
Naevi
Method of removal
Margin involvement
Minimum follow up
Recurrence rate
83 204 77 246
Shave, 100% Shave, 100% Shave, 100% Shave, 60.1% Punch, 27.3% Excision, 16.6% Shave, 12.4% Punch, 9.9% Excision, 74.5% Other, 3.3%
NA 64% 12% 52.0%
12 months 3 months 6 months 24 months
27% 19.6% 13% 2.8%
26.3%
60 months
0.3%a
1035
NA, not assessed. a
Recurrence rate calculated from laboratory database.
persistent naevus are used interchangeably in the literature and, in the authors’ opinion, all represent more appropriate terms than pseudomelanoma, because not all regenerating naevi pose diagnostic difficulty for the pathologist but they are all the result of the benign proliferation of naevocytes at the site of trauma.
CLINICAL FEATURES The incidence of regenerating naevi varies considerably in the literature. Method of excision and thus likelihood of margin involvement, as well as clinical follow up and the method of assessing for the presence of recurrence (i.e., clinical examination alone or histopathological confirmation) has differed between the various studies on the subject and correspondingly the rate of recurrence varies from 0.3% to 27% (Table 1). However, it is apparent that amongst the case series with higher proportions of shave biopsies, the rate of recurrence is higher.13–17 Regenerating naevi display characteristic clinical features (Table 2). They are reported to occur more frequently in females and young patients.18–20 The back is commonly cited as the body region most likely to give rise to a recurrence.1 Some have proposed that this is could be a function of a thicker dermis being more likely to harbour residual naevocytes,20 while others contend this reflects the general distribution of biopsied naevi.21 The reported rate of involvement Table 2
of the margins by naevus cells in the primary excision is typically high.17 Most regenerating naevi arise from common acquired naevi, followed by dysplastic naevi and congenital naevi12 (Table 2). Recurrences in specialised naevi such as Spitz naevus22 or blue naevi23 are considered to be uncommon events but this probably reflects the prevalence of these tumours. Regenerating naevi usually recur rapidly, most commonly within 6 months and almost always within 12 months of the prior biopsy or traumatic event, although we have seen cases of late recurrence of naevi confirmed on review of the prior specimen and subsequent long-term clinical follow-up. The clinical presentation is variable but some recurring patterns have been described. Recurrent naevi typically break the common clinical rules of benignity, displaying asymmetry, irregular borders and variegated colouration. Other common dermoscopic features include radial lines and a centrifugal growth pattern.24–26 Recurrent naevi are characteristically strictly macular lesions,6 but recurrent blue naevi23 and Spitz naevi22 are notable exceptions. In a dermoscopic comparison of 98 recurrent naevi and 62 recurrent melanomas, Blum et al. demonstrated features such as a circular pattern, eccentric hyperpigmentation, chaotic, non-continuous growth and extension beyond the scar were patterns more commonly, but not exclusively, encountered in melanoma.25
Summary of studies assessing the clinical features of recurrent naevi King et al.18 354 cases
Sommer et al.20 205 cases
Park et al.19 175 cases
72% 30 (7–92)
65% ‘most between 25-50 years’ (6–88)
85% ‘most…between 20–30 years’ (3–76)
Female Median age (range) Site Head and neck Chest/Abdomen Back Extremities Precursor naevus Common acquired Congenital Dysplastic Other
6% 20% 57% 16%
10% 15% 49% 24%
26% ‘Trunk’ (54%) – 16%
64% 6% 28% 1%
26% NA 72% 1%
NA NA NA NA
Original naevus with involved margins Median months to recurrence (range)
77% 5 (1–63)
75% ‘most biopsied <6 months’
97% 4.75 (1–216)
NA, not assessed.
Please cite this article in press as: Vilain RE, et al., The regenerating naevus, Pathology (2015), http://dx.doi.org/10.1016/j.pathol.2015.12.009
THE REGENERATING NAEVUS
3
Fig. 1
A trizonal pattern of fibrosis and cellularity is seen in classical regenerating naevi. A heavily pigmented, hyperplastic junctional and superficial melanocytic component (zone 1) cap a central zone of angiofibroplasia (zone 2) while the periphery is populated by the original residual naevocyte population (zone 3).
Fig. 3
HISTOLOGICAL FEATURES
Maturation is not as well developed as is seen within common naevi and their nuclear features are commonly reported to resemble those encountered in the overlying junctional population (Fig. 3).18 The maturation gradient in HMB45 expression seen in common benign naevi is often reproduced in regenerating naevi21 but this is not always the case and retention of HMB45 staining in the deeper dermal part of a regenerating naevus can cause diagnostic concern for melanoma. Similarly to the proliferation rate seen in ordinary naevi, regenerating naevi are expected to show a low mitotic rate and Ki-67 index. Correspondingly, the presence of more than occasional mitoses should prompt the reappraisal of a benign diagnosis and the close search for other atypical features. The epidermal changes present an important clue to the presence of regeneration. Regenerating epidermis typically displays effacement of its normal rete pattern, acanthosis and overlying compact hyperkeratosis (Fig. 4). Nevertheless, the rete ridges can be preserved in as many as 15% of regenerating naevi and thus their presence is not incompatible with a regenerating phenomenon.18 As mentioned above, the dermis should show the features of healing or healed scar tissue; dense fibrosis with horizontally arranged layering, telangiectasia or angiofibroplasia and, in addition, melanophages and chronic inflammatory cells are commonly present (Fig. 5). It is useful to remember that while these features can
When occurring in its classical form, a regenerating naevus is a relatively straightforward diagnosis. The typical appearance at low power is trizonal19 (Fig. 1 and 2A) with the three zones comprising the atypical junctional/superficial dermal melanocytic proliferation (the first zone) within a superficial dermal scar (the second zone) with underlying dermal naevus cells (the third zone). The scarring usually extends deep to the superficially distributed regenerating naevocytes, the latter often showing some mild cytological atypia. At the periphery of the scar, the original residual naevocyte population is commonly encountered. The regenerating melanocytes can be densely pigmented. An epithelioid morphology typically dominates18 (Fig. 3). The cytoplasm can be abundant; the nuclei feature smooth vesicular chromatin and prominent nucleoli (Fig. 3). Atypical cytological features are commonly encountered (Fig. 2B) but, importantly, the degree of severity of the cytological atypia does not equate to that usually seen in invasive melanoma.10 The junctional component is usually a mixture of lentiginous and nested melanocytes, and their arrangement is not uniform or symmetrically distributed. Extension of melanocytes into the upper epidermal layers (pagetoid spread) is frequently encountered18 (Fig. 2B). The dermal naevocytes are most commonly nested and irregularly distributed and not infrequently heavily pigmented.
The junctional and dermal components can share a very similar cytological appearance, particularly of their nuclei. This has been used as evidence by some that the dermal nests in regenerating naevi originate from the junctional component.18,19
Fig. 2 This regenerating melanocytic naevus was excised from the thigh of an 8-year-old girl. (A) The lesion demonstrates the typical trizonal pattern; on the right of the
photomicrograph, a hyperplastic junctional population overlies a scarred dermis. The pre-existing compound naevus can be seen on the left. (B) A high power view reveals a proliferation of atypical melanocytes with extensive upward spread, which can be deceiving for melanoma in situ if assessed in isolation. The review of the initial biopsy confirmed the presence of a banal compound naevus.
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Pathology (2015), -(-), -
VILAIN et al.
This compound regenerating naevus shows a hyperplastic junctional population of melanocytes in a nested and lentiginous growth pattern populating an epidermis which displays signs of repair; effacement of the rete architecture; acanthosis, hypergranulosis and hyperkeratosis. The subjacent scarred dermis contains densely pigmented naevocyte nests.
Fig. 4
overlap considerably with regression (a phenomenon that may occur in both naevi and melanomas), regressing melanomas are more likely to be associated with epidermal thinning than acanthosis. As recommended by King et al., in biopsies where the dermal scarring extends to the margins of the excision, the typical features of a regenerating naevus, particularly when occurring in retiform epidermis, may be indistinguishable from melanoma with regression.18 In these instances, a high index of suspicion and the ability to review the initial excision is the most reliable way to arrive at the correct diagnosis.
RECURRENT SPITZ AND BLUE NAEVI The recurrence of benign specialised naevi such as blue and Spitz naevi are uncommon events.22,23 However, when this occurs they can be particularly challenging lesions to diagnose pathologically because the regeneration of both of these types of naevi can even more closely resemble melanoma. Both regenerating blue and Spitz naevi can manifest nodular lesions, which extend beyond the confines of the scar.22,23,27 Indeed, their recurrences can even appear as as agminated22,28 or satellite lesions,22 thus clinically resembling melanoma. Like melanomas, their time to recurrence is reportedly longer than regenerating common naevi (>32 months for blue naevi23 and approximately 17 months for Spitz naevi22).
Recurrent blue naevi most commonly arise from the incomplete excision of a deep seated fascicular component.23 The recurrent naevocytes can display similar or greater cytological atypia and cellularity than their precursor lesions and the overall architecture can recreate that seen in the initial biopsy or display a ‘phenotypic divergence’ from the original neoplasm. However, frank malignant features such as en masse necrosis, a high mitotic rate and high grade cytological atypia should be taken to represent evidence of a malignant transformation.23 Spitz naevi, on the other hand, have been shown to recur in one of several patterns: (1) a junctional only population exhibiting the same range of features encountered in a typical regenerating naevus, (2) a replica of the original compound lesion with identical cytological and architectural features, (3) a desmoplastic pattern, and (4) an expansile nodular growth pattern which resembles melanoma. The dermal component in all patterns usually displays low mitotic rates and a maturation gradient on HMB45 staining. Furthermore, comparative genomic hybridisation has revealed an absence of large scale chromosomal abnormalities in most cases.22 In view of their rarity and unusual histological features, these uncommon regenerating naevi not only mandate a review of the original lesion but probably also warrant seeking a second opinion from a pathologist experienced in the assessment of melanocytic tumours and, if the clinical circumstances permit, a complete excision of the lesion.
CONCLUSION Because of the difficulty in distinguishing them from melanoma both clinically and pathologically, regenerating naevi can be intimidating lesions to evaluate. A minor portion can show features which overlap considerably with regressing melanoma. There are clues to assist in making the correct diagnosis: a consistent clinical history, a rapid recurrence, a trizonal histopathological pattern that includes scar tissue, low dermal mitotic rate and an overall low degree of cytological atypia which should not exceed that typically encountered in invasive melanoma, are all helpful features. However, for borderline lesions, whenever possible, every effort should be made to review the preceding excision and complete excision is generally advisable. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Address for correspondence: Dr Ricardo E. Vilain, Pathology North Hunter, NSW Health Pathology, John Hunter Hospital, Locked Bag 1, Hunter Region Mail Centre, Newcastle, NSW, 2310, Australia. E-mail: [email protected]
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Fig. 5 Orderly central fibrosis and angiofibroplasia are near invariable features
in regenerating naevi. In this example, melanophages are also distributed within the scarred dermis.
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