- Email: [email protected]
Intradermal nevi with atypical nuclei in the elderly: The senescent nevus
DERMATOPATHOLOGY
Intradermal nevi with atypical nuclei in the elderly: The senescent nevus Alan S. Boyd, MD,a,b Sheau-Chiann Chen, PhD,c and Yu Shyr, PhDc Nashville, Tennessee Background: Benign melanocytic nevi removed from elderly patients may demonstrate focal areas with nuclear atypia. Objective: We sought to determine the prevalence of these nevi and their clinical and histologic features. Methods: Intradermal nevi from patients older than 60 years were evaluated for areas of focal nuclear atypia and analyzed for 9 histologic characteristics. The patients’ sex, biopsy sites, and clinical diagnoses were also tabulated. A statistical analysis of the 2 groups was undertaken. Results: In all, 197 specimens from 157 patients were found. Twenty exhibited nuclear atypia (senescent nevi) and 177 did not (benign nevi). Significant differences were found for suggested clinical diagnosis, epithelioid-appearing melanocytes, the number of mast cells, evidence of solar elastosis, the number of intranuclear pseudoinclusions, and the presence of abnormally staining connective tissue. Limitations: This is a single-site, retrospective analysis involving a modest number of specimens. In addition, only a single age group was evaluated and only intradermal nevi were examined. Conclusions: The presence of focal nuclear atypia in benign melanocytic nevi in the elderly is not a rare finding. As these features are likely a result of the age of the lesion and possibly of long-standing ultraviolet light exposure, the term ‘‘senescent’’ nevus is suggested. ( J Am Acad Dermatol http://dx.doi.org/10.1016/ j.jaad.2015.06.013.) Key words: ancient; atypia; elderly; intranuclear pseudoinclusions; nevus; senescent; symplastic.
T
he terms ‘‘ancient’’ and ‘‘symplastic’’ have been applied to benign cutaneous tumors with atypical cellular features suggestive of a malignant process. They have not, however, been used when referring to benign melanocytic nevi exhibiting foci of cells exhibiting atypical nuclei. Neither appellation would be appropriate for these lesions. The designation ‘‘ancient’’ nevus has been applied to melanocytic and cellular blue nevi with both displaying distinct histologic features.1-3 Given that ‘‘symplast’’ implies a multinucleated syncytia and has been invoked to depict an indolent uterine leiomyoma, this name appears unsuitable as well.4 These nevi with atypical nuclei are seen more
commonly in elderly patients and the name ‘‘senescent nevus’’ is suggested. To determine the prevalence of these neoplasms and better characterize their clinical and histologic features, 177 intradermal nevi removed from patients older than 60 years were evaluated.
From the Department of Medicine, Division of Dermatology,a the Department of Pathology,b and the Center for Quantitative Studies,c Vanderbilt University Medical Center. Funding sources: None. Conflicts of interest: None declared. Accepted for publication June 6, 2015. Reprint requests: Alan S. Boyd, MD, Department of Medicine, Division of Dermatology, Vanderbilt University Medical Center,
719 Thompson Ln, Suite 26300, Nashville, TN 37204. E-mail: [email protected]. Published online July 14, 2015. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.06.013
METHODS A computer-generated search of the Vanderbilt University Medical Center Dermatopathology Service was undertaken for all benign intradermal nevi diagnosed in patients older than 60 years during the calendar year 2013. As no definition of ‘‘elderly’’ exists, a cut-off of 60 years was arbitrarily imposed, a position taken by other investigators.5,6 All
1
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specimens were reviewed by a board-certified derand Table II the histologic features of their biopsy matopathologist (A. S. B.) to validate the diagnoses. specimens. Twenty senescent nevi (7%) were found Excluded were any nevi exhibiting inflammation/ (Fig 1). Benign nevi totaled 177 from 157 patients ulceration, blue nevi, Spitz nevi, halo nevi, nevi with (93%). One patient had a senescent nevi and a congenital features, balloon cell nevi, or nevi arising benign nevi. There was a significant difference in in patients with a history of melanoma. ‘‘Collision’’ the clinical diagnoses suggested by the submitting tumors were also excluded. clinicians for senescent versus benign nevi but The nevi were divided into not for the patient sex or sites 2 groups: those with focal of biopsy. Histologically, CAPSULE SUMMARY areas of atypia, defined as senescent nevi were more nuclear enlargement, pleolikely than benign nevi to Benign nevi in elderly patients may morphism, hyperchromasia, exhibit epithelioid features demonstrate focal areas of nuclear multiple nucleoli, enlarged (Fig 2), greater numbers of atypia. nucleoli, a change in nuclemast cells, evidence of solar These nevi demonstrate significantly olar color, binucleation, and/ elastosis, the presence of more mast cells, epithelioid cells, solar or thickened nuclear memintranuclear pseudoincluelastosis, abnormally staining connective branes, and those without. A sions (Fig 3), and areas of tissue, and intranuclear nevus was considered to abnormally staining connecpseudoinclusions. exhibit ‘‘focal atypia’’ if there tive tissue (Fig 4). No signifwas at least 1 medium-power icant differences were noted These features may be a result of the field in which all or nearly all in the 2 groups regarding lesions’ age and/or ultraviolet light the cells visible exhibited pigmented intranuclear exposure; thus, the term ‘‘senescent’’ some or all of the features pseudoinclusions, nevus cell nevus is suggested. noted above. The age and pigment production, the sex of each patient, the site presence of balloon cell of biopsy, and the suggested clinical diagnosis were change, or the presence of telangiectasias. In 3 tabulated. The biopsy stroma was evaluated for the senescent nevi and 10 benign nevi immunohistopresence or absence of solar elastosis, mast cells, chemical stains for proliferative nuclear activity (MiBabnormally staining connective tissue, and telangiec1) (Fig 5) or mitotic activity (pHH3) were performed. tases. The nevus cells were assessed for the presence None were remarkable. In only 1 specimen (a benign or absence of epithelioid features, pigment producnevi) was an isolated mitotic figure noted. tion, balloon cell change, and pigmented intranuclear In the 4 specimens studied by immunohistochempseudoinclusions. The number of intranuclear pseuistry, all the melanocytes stained positive for p16, doinclusions was stratified as 0 = less than 5% of nuclei BAP1, and BRAFV600E. affected, 1 = 5% to 10% of nuclei affected, 2 = 10% to 50% of nuclei affected, and 3 = more than 50% of DISCUSSION nuclei affected. Nevi exhibiting nuclear atypia were Benign intradermal nevi with foci of atypical metermed ‘‘senescent nevi’’ and those without were lanocyte nuclei have not been previously reported. designated ‘‘benign nevi.’’ A comparison was made That these nevi are benign is not in question. All of the clinical and histologic features in both groups. possessed a normal silhouette without nuclear crowdBecause of the epithelioid features noted, 4 ing, pagetoid spread, adnexal colonization, or mitotic randomly selected senescent nevi were stained for activity. The foci of nuclear atypia, depending on their p16, BAP1, and mutant BRAFV600E expression. size, may often only be appreciable using higherpower magnification. The immunohistochemical Statistical analysis staining pattern of melanocytes in senescent nevi Goodness-of-fit test (Fisher exact test) was used to also supports their banality (Fig 6). P16 expression is compare the distribution difference between the 2 associated with cellular senescent melanocytes (megroups with respect to each parameter. Each test was lanocytes irreversibly in proliferative arrest) but not in 2-sided at the .05 level of significance. Analyses were melanoma cells.7 Loss of BAP1 expression is noted in performed in R 3.1.2 (R Foundation for Statistical a cancer susceptibility syndrome that includes the Computing, Vienna, Austria). recently described Wiesner nevus.8 The BAP1 positivity in senescent nevi delineates them from that syndrome. BRAFV600E mutations were noted in each RESULTS of the specimens studied, although the presence of A total of 197 specimens from 156 patients were this mutation in banal melanocytic nevi is well known found. Table I lists the clinical features of the patients d
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Table I. Clinical features of patients and suggested clinical diagnoses Senescent nevi
Sex Male Female Site of biopsy Head and neck Trunk Legs Arms Clinical diagnosis BCC CN/IDN None Melanoma SK DN SCC FEP Cyst NMSC
Benign nevi
65 (42%) 92 (58%) .4499
15 5 0 0
(75%) (25%) (0%) (0%)
84 52 10 11
(54%) (33%) (6%) (7%)
8 5 5 1 1 0 0 0 0 0
(40%) (25%) (25%) (5%) (5%) (0%) (0%) (0%) (0%) (0%)
29 67 25 4 2 18 5 3 2 2
(18%) (43%) (16%) (3%) (1%) (12%) (3%) (2%) (1%) (1%)
Senescent nevi
P value
.4694 9 (45%) 11 (55%)
Table II. Histologic features of biopsy specimens
.096
BCC, Basal cell carcinoma; CN, compound nevus; DN, dysplastic nevus; FEP, fibroepithelial polyp; IDN, intradermal nevus; NMSC, nonmelanoma skin cancer; SCC, squamous cell carcinoma; SK, seborrheic keratosis.
and in some studies exceeds 80% of studied samples.9,10 Busam et al11 recently evaluated 8 cases of Spitzoid melanocytic proliferations exhibiting epithelioid features in part or in whole. None of the melanocytes with an epithelioid phenotype expressed BAP1 suggesting the epithelioid features in senescent nevi are unrelated. The melanocytes in senescent nevi exhibit enlarged nuclei with occasional chromatin clumping, hyperchromasia, prominent pink to purple nucleoli, and asymmetric nuclear outlines. Binucleate forms were present but nuclear crowding, mitotic figures, and necrosis were not. Only rare multinucleated cells were found. At low to medium power it was occasionally possible to appreciate a clear demarcation of these senescent cells and their normal counterparts (Fig 7). The nests of cells in senescent nevi are statistically more likely than benign nevi to exhibit epithelioid features, actinic damage, and intranuclear pseudoinclusions. Interestingly, senescent nevi were also more likely to demonstrate purple to magenta connective tissue that stained positive with an elastin stain but negative with a trichrome stain (Fig 8). These elastic fibers often demonstrated a vertical rather than perpendicular orientation with regard to the epidermis similar to that noted in collagenous and elastotic plaques of the hands. When prominent, these elastic fibers are readily visible at low-power magnification.
Epithelioid features Yes No Solar elastosis Yes No Mast cells Yes No Abnormally staining connective tissue Yes No Pigmented intranuclear pseudoinclusions Yes No Nevus cell pigment production Yes No Balloon cell change Yes No Intranuclear pseudoinclusions 0 1 2 Telangiectasis Yes No
Benign nevi
P value
.0001 17 (85%) 3 (15%)
55 (35%) 102 (65%)
11 (55%) 9 (45%)
38 (24%) 119 (76%)
15 (75%) 5 (25%)
67 (43%) 90 (57%)
.0058
.0060
.0186 8 (40%) 12 (60%)
26 (17%) 131 (83%) .019
7 (35%) 13 (65%)
19 (12%) 138 (88%) .0341
0 (0%) 20 (100%)
26 (17%) 131 (83%)
4 (20%) 16 (80%)
23 (15%) 134 (85%)
.05278
.0723 3 (15%) 15 (75%) 2 (10%)
72 (46%) 71 (45%) 14 (9%)
9 (45%) 11 (55%)
65 (41%) 92 (59%)
.8145
Once the presence of these nevi became appreciated, what to term them required consideration. The adjective ‘‘symplastic’’ has been applied to other cutaneous tumors including trichodiscoma, leiomyoma, glomus tumor, and hemangioma.4,12-14 However, as previously noted, the definition of ‘‘symplast’’ is inappropriate.4 The ‘‘ancient’’ nevus was described in 1993.1 Kerl et al2 later reported on 13 such cases suggesting the term ‘‘pleomorphic melanocytic nevus with degenerative changes.’’ Their patients’ median age was 40 years and most lesions arose on the trunk appearing as pink, red, brown, and bluish papules. Histologically, they were endo-exophytic tumors with 2 melanocyte cell types, one with larger nuclei and the other with small, monomorphous nuclei. Mitotic figures were noted as were degenerative stromal changes including hemorrhage, hemosiderin deposition, hyaline angiopathy, thrombosed vessels, pseudovascular spaces, myxoid changes, and fibrosis. The authors believed
4 Boyd, Chen, and Shyr
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Fig 1. Intradermal nevi in the elderly with atypical nuclei. A, Atypical nevus cells with enlarged, abnormal nuclei. Note some nuclei exhibit multiple intranuclear pseudoinclusions. B, Atypical nevus cells with some nuclei exhibiting almost monster cellelike features. C, Atypical nevus cells, some demonstrating multiple nucleoli. D, Atypical nevus cells. Note the binucleate cells on the left.
Fig 2. Intradermal nevus in the elderly with atypical nuclei. There is a clear demarcation of senescent and banal nevus cells.
Fig 3. Intradermal nevus in the elderly with atypical nuclei. Intranuclear pseudoinclusions in the atypical nuclei of senescent nevus.
the large melanocytes resulted from degenerative changes. After a median follow-up of 9 years there were no recurrences of the tumors or metastatic spread. Cerroni et al3 described 6 cases of blue nevi with similar histologic characteristics terming them ‘‘ancient’’ blue nevi. They believed these features resulted from the vascular changes appreciated. McGovern15 in 1983 depicted what he termed a ‘‘bizarre’’ nevus with enlarged cells and multinucleated or ‘‘monster’’ cells, however no subsequent reports of this nevus have been forthcoming. By
definition, a monster cell exhibits a nucleus 3 times larger than that of a normal cell, features that are not found in a senescent nevi. Perhaps the most common tumor encountered in dermatopathology with degenerative changes and nuclear pleomorphism is that of an ancient schwannoma. Argenyi et al16 reported on 15 cases that demonstrated macrocystic, microcystic, and myxoid degeneration with fibrosis, stromal edema, and xanthomatous changes. In 11 specimens vascular abnormalities including hemorrhage with
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Fig 4. Intradermal nevus in the elderly with atypical nuclei. Abnormally staining connective tissue.
Fig 5. Intradermal nevus in the elderly with atypical nuclei. Mart-1 (red)/MiB-1 (brown) combination stain of the nevus depicted in Fig 2. Note the lack of proliferative nuclear activity exhibited by the melanocytes.
thrombosis, myxomatous alternation, and vessel wall hyalinization were noted. Nuclei exhibited polygonal features, variable pleomorphism, and bubbly chromatin. Mitotic figures were not found. The histologic features of nevi in the elderly have received little attention.5,6,17 Maize and Foster17 analyzed 279 nevi from patients of all ages for architecture, fibrosis, fatty infiltration, mucin deposition, and neural changes. Thirty-six specimens were from patients older than 60 years and 30 of these were intradermal. They noted that stromal fibrosis, fatty infiltration, and mucin deposition were significantly more likely to be present in the intradermal nevi removed from older patients. Piliouras et al6 evaluated 59 nevi in patients from 60 to 89 years of age. They found a decreasing number of total nevus counts with age noting that the decrease in Clark nevi (those with a junctional component of nevus cells) might be secondary to ultraviolet irradiation. Dermoscopic features were described in these nevi but pathologic analysis was not undertaken. Martinka et al5 assessed the histologic features of 215 nevi from patients older than 60 years, 95 (44%) of which were intradermal. They noted 19 biopsy
Boyd, Chen, and Shyr 5
specimens (9%) exhibited dermal cytologic atypia defined as prominent nucleoli, increased nuclear to cytoplasmic ratio, and irregular chromatin pattern. Solar elastosis was present in 101 specimens (47%) with fragmented elastic fibers often present in the adjacent stroma. These fibers were illustrated and are similar to the abnormally staining connective tissue in our patients’ biopsy specimens, however the authors did not histologically confirm them as elastic. Interestingly, they noted such fibers are not present in nevi of younger adults and wrote that they ‘‘represent a normal finding in some senescent nevi in older patients.’’ They also found ‘‘ancient’’ changes as described by Kerl et al1 in 37 biopsy specimens (17%) but did not comment on or depict their features. Massi and LeBoit18 wrote on and illustrated ‘‘nevi with atypical nuclei.’’ Their description and depiction of the nuclear features of these lesions is similar to the senescent nevi described here. The term ‘‘senescent’’ was deduced to be the most appropriate term as it derives from the Latin word ‘‘senescere’’ meaning ‘‘to grow old.’’ In today’s medical literature this concept is applied almost exclusively to oncogene activation-induced proliferation arrest19-21 but not to the histologic changes in long-standing nevi. It is proposed that senescent nevi exhibit these features in part because of the aging of the melanocytes given that some of them have been present for multiple decades. The significant association with the epithelioid morphology in senescent nevi would support this contention as this characteristic is noted in long-standing nevi. It is also possible these features are secondary to cumulative ultraviolet exposure. Patients with a senescent nevi were significantly more likely to demonstrate solar elastosis and abnormally stained connective tissue, changes associated with chronic sun exposure.21 The presence of greater numbers of intranuclear pseudoinclusions in senescent nevi would not be unexpected in nevi with excessive sun damage as Perez and Sanchez22 noted they appear commonly in nevi removed from albino patients with significant solar elastosis. Finally, because there is a significant association between senescent nevi and the presence of abnormally staining connective tissue it is possible the nuclear atypia noted may have arisen secondary to stromal-melanocyte interactions. Hedley et al23 described altered melanocyte morphology when exposed to extracellular matrix proteins in vitro. Carlson et al24 noted nevi arising in association with lichen sclerosus demonstrate ‘‘activated’’ features presumably secondary to changes in the stroma surrounding them.
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Fig 6. Intradermal nevi in the elderly with atypical nuclei. A, Hematoxylin and eosin features of a senescent nevi. BAP1 (B), BRAFV600E (C), and p16 (D) staining of the nuclei.
cohort might solidify the contentions presented and the strength of the statistical associations. In sum, there exists within the cohort of benign intradermal nevi a subset exhibiting focal areas of nuclear atypia. These senescent nevi demonstrate statistically increased amounts of solar elastosis, abnormally staining connective tissue, and nuclear pseudoinclusions. It is important that pathologists recognize senescent nevi to prevent their misinterpretation as anything other than benign. Fig 7. Intradermal nevus in the elderly with atypical nuclei. The melanocytes in the middle of the dermis exhibit the epithelioid features and the nuclear atypia of senescent nevus whereas those elsewhere demonstrate characteristics normally present in intradermal nevus. A delineation between these 2 populations of cells has been made with a white line.
This study has several limitations. First, this was a single-site, respective evaluation. Second, because only biopsy specimens from patients older than 60 years were evaluated it is unknown if similar features are present in other age groups, although if ultraviolet exposure is responsible for the changes noted it seems all but certain they would be present in younger patients. Third, the number of specimens evaluated was modest in number. Using a larger
REFERENCES 1. Kerl H, Soyer HP, Cerroni L, Wolf L. ‘‘Ancient’’ nevusea benign simulator of melanoma. J Cutan Pathol. 1993;20:550. 2. Kerl H, Wolf IG, Kerl K, Cerroni L, Kutrzner H, Argenyi ZB. Ancient melanocytic nevus: a simulator of malignant melanoma. Am J Dermatopathol. 2011;33:127-130. 3. Cerroni L, Borroni RG, Massone C, Kerl H. ‘‘Ancient’’ blue nevi (cellular blue nevi with degenerative stromal changes). Am J Dermatopathology. 2008;30:1-5. 4. Geok S, Goh N, Dayrit JF, Calonje E. Symplastic hemangioma: report of two cases. J Cutan Pathol. 2006;33:735-740. 5. Martinka M, Bruecks AK, Trotter MJ. Histologic spectrum of melanocytic nevi removed from patient [ 60 years of age. J Cut Med Surg. 2007;11:168-173. 6. Piliouras P, Gilmore S, Wurm EM, Soyer HP, Zalaudek I. New insights into nevogenesis: number, distribution and dermoscopic patterns of nevi in the elderly. Austral J Derm. 2011;52: 254-258. 7. Gray-Schopfer VC, Cheong SC, Chong H, et al. Cellular senescent in nevi and immortalization in melanoma: a role for p16? Br J Canc. 2006;95:496-505.
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Fig 8. Intradermal nevi in the elderly with atypical nuclei. A, Abnormally staining connective tissue with adjacent melanocytes with atypical nuclei. B, Elastin stain of the same specimen demonstrating this connective tissue is elastin. 8. Llamas-Velasco M, Perez-Gonzalez CP, Requena L, Kutzner H. Histopathologic clues for the diagnosis of Wiesner nevus. J Am Acad Dermatol. 2014;70:549-554. 9. Poynter JN, Elder JT, Fullen DR, et al. BRAF and NRAS mutations in melanoma and melanocytic nevi. Mel Res. 2006;16:267-273. 10. Kumar R, Angelini S, Snellman E, Hemminki K. BRAF mutations are common somatic events in melanocytic nevi. J Invest Dermatol. 2004;122:342-348. 11. Busam KJ, Sung J, Wisner T, von Deimling A, Jongbluth A. Combined BRAFV600E-positive melanocytic lesions with large epithelioid cells lacking BAP1 expression and conventional nevomelanocytes. Am J Surg Pathol. 2013;378:193-199. 12. Usmani N, Merchant W, Yung A. A case of cutaneous symplastic leiomyomaea rare variant of cutaneous pilar leiomyoma. J Cutan Pathol. 2008;35:329-331. 13. Kamarashev J, French LE, Dummer R, Kerl K. Symplastic glomus tumorea rare but distinct benign histological variant with analogy to other ‘‘ancient’’ benign skin neoplasms. J Cutan Pathol. 2009;36:1099-1102. 14. Battistella M, van Eeckhourt P, Cribier B. Symplastic trichodiscoma: a spindle-cell predominant variant of trichodiscoma with pseudosarcomatous/ancient features. J Cutan Pathol. 2011;33:e81-e83. 15. McGovern VJ. Melanoma. Histological diagnosis and prognosis. New York (NY): Raven Press; 1983. 16. Argenyi ZB, Balogh K, Abraham AA. Degenerative (‘‘ancient’’) changes in benign cutaneous schwannoma. A light
17. 18. 19. 20.
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microscopic, histochemical and immunohistochemical study. J Cutan Pathol. 1993;20:148-153. Maize JC, Foster G. Age-related changes in melanocytic nevi. Clin Exp Dermatol. 1979;4:49-58. Massi G, LeBoit PE. Histologic diagnosis of nevi and melanoma. New York (NY): Springer Heidelberg; 2014. Chandeck C, Mooi WJ. Oncogene-induced cellular senescence. Adv Anat Pathol. 2010;17:42-48. Vredeveld LC, Possik PA, Smit MA, et al. Abrogating of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanogenesis. Gen Develop. 2012;26: 1055-1069. Fung C, Pupo GM, Scolyer RA, Kefford RF, Rizos H. p16(INK) (4a) deficiency promotes DNA hyper-replication and genetic instability in melanocytes. Pig Cell & Mel Res. 2013;26: 236-246. Perez MI, Sanchez JL. Histopathologic evaluation of melanocytic nevi in oculocutaneous albinism. Am J Dermatopathol. 1985;7:23-28. Hedley S, Gawkrodger DJ, Weetman AP, MacNeil S. Investigation of the influence of extracellular matrix proteins on normal human melanocyte morphology and melanogenic activity. Br J Dermatol. 1996;135:888-897. Carlson JA, Mu XC, Slominski A, et al. Melanocytic proliferations associated with lichen sclerosus. Arch Dermatol. 2002; 138:77-87.
Intradermal nevi with atypical nuclei in the elderly: The senescent nevus Alan S. Boyd, MD,a,b Sheau-Chiann Chen, PhD,c and Yu Shyr, PhDc Nashville, Tennessee Background: Benign melanocytic nevi removed from elderly patients may demonstrate focal areas with nuclear atypia. Objective: We sought to determine the prevalence of these nevi and their clinical and histologic features. Methods: Intradermal nevi from patients older than 60 years were evaluated for areas of focal nuclear atypia and analyzed for 9 histologic characteristics. The patients’ sex, biopsy sites, and clinical diagnoses were also tabulated. A statistical analysis of the 2 groups was undertaken. Results: In all, 197 specimens from 157 patients were found. Twenty exhibited nuclear atypia (senescent nevi) and 177 did not (benign nevi). Significant differences were found for suggested clinical diagnosis, epithelioid-appearing melanocytes, the number of mast cells, evidence of solar elastosis, the number of intranuclear pseudoinclusions, and the presence of abnormally staining connective tissue. Limitations: This is a single-site, retrospective analysis involving a modest number of specimens. In addition, only a single age group was evaluated and only intradermal nevi were examined. Conclusions: The presence of focal nuclear atypia in benign melanocytic nevi in the elderly is not a rare finding. As these features are likely a result of the age of the lesion and possibly of long-standing ultraviolet light exposure, the term ‘‘senescent’’ nevus is suggested. ( J Am Acad Dermatol http://dx.doi.org/10.1016/ j.jaad.2015.06.013.) Key words: ancient; atypia; elderly; intranuclear pseudoinclusions; nevus; senescent; symplastic.
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he terms ‘‘ancient’’ and ‘‘symplastic’’ have been applied to benign cutaneous tumors with atypical cellular features suggestive of a malignant process. They have not, however, been used when referring to benign melanocytic nevi exhibiting foci of cells exhibiting atypical nuclei. Neither appellation would be appropriate for these lesions. The designation ‘‘ancient’’ nevus has been applied to melanocytic and cellular blue nevi with both displaying distinct histologic features.1-3 Given that ‘‘symplast’’ implies a multinucleated syncytia and has been invoked to depict an indolent uterine leiomyoma, this name appears unsuitable as well.4 These nevi with atypical nuclei are seen more
commonly in elderly patients and the name ‘‘senescent nevus’’ is suggested. To determine the prevalence of these neoplasms and better characterize their clinical and histologic features, 177 intradermal nevi removed from patients older than 60 years were evaluated.
From the Department of Medicine, Division of Dermatology,a the Department of Pathology,b and the Center for Quantitative Studies,c Vanderbilt University Medical Center. Funding sources: None. Conflicts of interest: None declared. Accepted for publication June 6, 2015. Reprint requests: Alan S. Boyd, MD, Department of Medicine, Division of Dermatology, Vanderbilt University Medical Center,
719 Thompson Ln, Suite 26300, Nashville, TN 37204. E-mail: [email protected]. Published online July 14, 2015. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.06.013
METHODS A computer-generated search of the Vanderbilt University Medical Center Dermatopathology Service was undertaken for all benign intradermal nevi diagnosed in patients older than 60 years during the calendar year 2013. As no definition of ‘‘elderly’’ exists, a cut-off of 60 years was arbitrarily imposed, a position taken by other investigators.5,6 All
1
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2 Boyd, Chen, and Shyr
specimens were reviewed by a board-certified derand Table II the histologic features of their biopsy matopathologist (A. S. B.) to validate the diagnoses. specimens. Twenty senescent nevi (7%) were found Excluded were any nevi exhibiting inflammation/ (Fig 1). Benign nevi totaled 177 from 157 patients ulceration, blue nevi, Spitz nevi, halo nevi, nevi with (93%). One patient had a senescent nevi and a congenital features, balloon cell nevi, or nevi arising benign nevi. There was a significant difference in in patients with a history of melanoma. ‘‘Collision’’ the clinical diagnoses suggested by the submitting tumors were also excluded. clinicians for senescent versus benign nevi but The nevi were divided into not for the patient sex or sites 2 groups: those with focal of biopsy. Histologically, CAPSULE SUMMARY areas of atypia, defined as senescent nevi were more nuclear enlargement, pleolikely than benign nevi to Benign nevi in elderly patients may morphism, hyperchromasia, exhibit epithelioid features demonstrate focal areas of nuclear multiple nucleoli, enlarged (Fig 2), greater numbers of atypia. nucleoli, a change in nuclemast cells, evidence of solar These nevi demonstrate significantly olar color, binucleation, and/ elastosis, the presence of more mast cells, epithelioid cells, solar or thickened nuclear memintranuclear pseudoincluelastosis, abnormally staining connective branes, and those without. A sions (Fig 3), and areas of tissue, and intranuclear nevus was considered to abnormally staining connecpseudoinclusions. exhibit ‘‘focal atypia’’ if there tive tissue (Fig 4). No signifwas at least 1 medium-power icant differences were noted These features may be a result of the field in which all or nearly all in the 2 groups regarding lesions’ age and/or ultraviolet light the cells visible exhibited pigmented intranuclear exposure; thus, the term ‘‘senescent’’ some or all of the features pseudoinclusions, nevus cell nevus is suggested. noted above. The age and pigment production, the sex of each patient, the site presence of balloon cell of biopsy, and the suggested clinical diagnosis were change, or the presence of telangiectasias. In 3 tabulated. The biopsy stroma was evaluated for the senescent nevi and 10 benign nevi immunohistopresence or absence of solar elastosis, mast cells, chemical stains for proliferative nuclear activity (MiBabnormally staining connective tissue, and telangiec1) (Fig 5) or mitotic activity (pHH3) were performed. tases. The nevus cells were assessed for the presence None were remarkable. In only 1 specimen (a benign or absence of epithelioid features, pigment producnevi) was an isolated mitotic figure noted. tion, balloon cell change, and pigmented intranuclear In the 4 specimens studied by immunohistochempseudoinclusions. The number of intranuclear pseuistry, all the melanocytes stained positive for p16, doinclusions was stratified as 0 = less than 5% of nuclei BAP1, and BRAFV600E. affected, 1 = 5% to 10% of nuclei affected, 2 = 10% to 50% of nuclei affected, and 3 = more than 50% of DISCUSSION nuclei affected. Nevi exhibiting nuclear atypia were Benign intradermal nevi with foci of atypical metermed ‘‘senescent nevi’’ and those without were lanocyte nuclei have not been previously reported. designated ‘‘benign nevi.’’ A comparison was made That these nevi are benign is not in question. All of the clinical and histologic features in both groups. possessed a normal silhouette without nuclear crowdBecause of the epithelioid features noted, 4 ing, pagetoid spread, adnexal colonization, or mitotic randomly selected senescent nevi were stained for activity. The foci of nuclear atypia, depending on their p16, BAP1, and mutant BRAFV600E expression. size, may often only be appreciable using higherpower magnification. The immunohistochemical Statistical analysis staining pattern of melanocytes in senescent nevi Goodness-of-fit test (Fisher exact test) was used to also supports their banality (Fig 6). P16 expression is compare the distribution difference between the 2 associated with cellular senescent melanocytes (megroups with respect to each parameter. Each test was lanocytes irreversibly in proliferative arrest) but not in 2-sided at the .05 level of significance. Analyses were melanoma cells.7 Loss of BAP1 expression is noted in performed in R 3.1.2 (R Foundation for Statistical a cancer susceptibility syndrome that includes the Computing, Vienna, Austria). recently described Wiesner nevus.8 The BAP1 positivity in senescent nevi delineates them from that syndrome. BRAFV600E mutations were noted in each RESULTS of the specimens studied, although the presence of A total of 197 specimens from 156 patients were this mutation in banal melanocytic nevi is well known found. Table I lists the clinical features of the patients d
d
d
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Boyd, Chen, and Shyr 3
Table I. Clinical features of patients and suggested clinical diagnoses Senescent nevi
Sex Male Female Site of biopsy Head and neck Trunk Legs Arms Clinical diagnosis BCC CN/IDN None Melanoma SK DN SCC FEP Cyst NMSC
Benign nevi
65 (42%) 92 (58%) .4499
15 5 0 0
(75%) (25%) (0%) (0%)
84 52 10 11
(54%) (33%) (6%) (7%)
8 5 5 1 1 0 0 0 0 0
(40%) (25%) (25%) (5%) (5%) (0%) (0%) (0%) (0%) (0%)
29 67 25 4 2 18 5 3 2 2
(18%) (43%) (16%) (3%) (1%) (12%) (3%) (2%) (1%) (1%)
Senescent nevi
P value
.4694 9 (45%) 11 (55%)
Table II. Histologic features of biopsy specimens
.096
BCC, Basal cell carcinoma; CN, compound nevus; DN, dysplastic nevus; FEP, fibroepithelial polyp; IDN, intradermal nevus; NMSC, nonmelanoma skin cancer; SCC, squamous cell carcinoma; SK, seborrheic keratosis.
and in some studies exceeds 80% of studied samples.9,10 Busam et al11 recently evaluated 8 cases of Spitzoid melanocytic proliferations exhibiting epithelioid features in part or in whole. None of the melanocytes with an epithelioid phenotype expressed BAP1 suggesting the epithelioid features in senescent nevi are unrelated. The melanocytes in senescent nevi exhibit enlarged nuclei with occasional chromatin clumping, hyperchromasia, prominent pink to purple nucleoli, and asymmetric nuclear outlines. Binucleate forms were present but nuclear crowding, mitotic figures, and necrosis were not. Only rare multinucleated cells were found. At low to medium power it was occasionally possible to appreciate a clear demarcation of these senescent cells and their normal counterparts (Fig 7). The nests of cells in senescent nevi are statistically more likely than benign nevi to exhibit epithelioid features, actinic damage, and intranuclear pseudoinclusions. Interestingly, senescent nevi were also more likely to demonstrate purple to magenta connective tissue that stained positive with an elastin stain but negative with a trichrome stain (Fig 8). These elastic fibers often demonstrated a vertical rather than perpendicular orientation with regard to the epidermis similar to that noted in collagenous and elastotic plaques of the hands. When prominent, these elastic fibers are readily visible at low-power magnification.
Epithelioid features Yes No Solar elastosis Yes No Mast cells Yes No Abnormally staining connective tissue Yes No Pigmented intranuclear pseudoinclusions Yes No Nevus cell pigment production Yes No Balloon cell change Yes No Intranuclear pseudoinclusions 0 1 2 Telangiectasis Yes No
Benign nevi
P value
.0001 17 (85%) 3 (15%)
55 (35%) 102 (65%)
11 (55%) 9 (45%)
38 (24%) 119 (76%)
15 (75%) 5 (25%)
67 (43%) 90 (57%)
.0058
.0060
.0186 8 (40%) 12 (60%)
26 (17%) 131 (83%) .019
7 (35%) 13 (65%)
19 (12%) 138 (88%) .0341
0 (0%) 20 (100%)
26 (17%) 131 (83%)
4 (20%) 16 (80%)
23 (15%) 134 (85%)
.05278
.0723 3 (15%) 15 (75%) 2 (10%)
72 (46%) 71 (45%) 14 (9%)
9 (45%) 11 (55%)
65 (41%) 92 (59%)
.8145
Once the presence of these nevi became appreciated, what to term them required consideration. The adjective ‘‘symplastic’’ has been applied to other cutaneous tumors including trichodiscoma, leiomyoma, glomus tumor, and hemangioma.4,12-14 However, as previously noted, the definition of ‘‘symplast’’ is inappropriate.4 The ‘‘ancient’’ nevus was described in 1993.1 Kerl et al2 later reported on 13 such cases suggesting the term ‘‘pleomorphic melanocytic nevus with degenerative changes.’’ Their patients’ median age was 40 years and most lesions arose on the trunk appearing as pink, red, brown, and bluish papules. Histologically, they were endo-exophytic tumors with 2 melanocyte cell types, one with larger nuclei and the other with small, monomorphous nuclei. Mitotic figures were noted as were degenerative stromal changes including hemorrhage, hemosiderin deposition, hyaline angiopathy, thrombosed vessels, pseudovascular spaces, myxoid changes, and fibrosis. The authors believed
4 Boyd, Chen, and Shyr
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Fig 1. Intradermal nevi in the elderly with atypical nuclei. A, Atypical nevus cells with enlarged, abnormal nuclei. Note some nuclei exhibit multiple intranuclear pseudoinclusions. B, Atypical nevus cells with some nuclei exhibiting almost monster cellelike features. C, Atypical nevus cells, some demonstrating multiple nucleoli. D, Atypical nevus cells. Note the binucleate cells on the left.
Fig 2. Intradermal nevus in the elderly with atypical nuclei. There is a clear demarcation of senescent and banal nevus cells.
Fig 3. Intradermal nevus in the elderly with atypical nuclei. Intranuclear pseudoinclusions in the atypical nuclei of senescent nevus.
the large melanocytes resulted from degenerative changes. After a median follow-up of 9 years there were no recurrences of the tumors or metastatic spread. Cerroni et al3 described 6 cases of blue nevi with similar histologic characteristics terming them ‘‘ancient’’ blue nevi. They believed these features resulted from the vascular changes appreciated. McGovern15 in 1983 depicted what he termed a ‘‘bizarre’’ nevus with enlarged cells and multinucleated or ‘‘monster’’ cells, however no subsequent reports of this nevus have been forthcoming. By
definition, a monster cell exhibits a nucleus 3 times larger than that of a normal cell, features that are not found in a senescent nevi. Perhaps the most common tumor encountered in dermatopathology with degenerative changes and nuclear pleomorphism is that of an ancient schwannoma. Argenyi et al16 reported on 15 cases that demonstrated macrocystic, microcystic, and myxoid degeneration with fibrosis, stromal edema, and xanthomatous changes. In 11 specimens vascular abnormalities including hemorrhage with
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Fig 4. Intradermal nevus in the elderly with atypical nuclei. Abnormally staining connective tissue.
Fig 5. Intradermal nevus in the elderly with atypical nuclei. Mart-1 (red)/MiB-1 (brown) combination stain of the nevus depicted in Fig 2. Note the lack of proliferative nuclear activity exhibited by the melanocytes.
thrombosis, myxomatous alternation, and vessel wall hyalinization were noted. Nuclei exhibited polygonal features, variable pleomorphism, and bubbly chromatin. Mitotic figures were not found. The histologic features of nevi in the elderly have received little attention.5,6,17 Maize and Foster17 analyzed 279 nevi from patients of all ages for architecture, fibrosis, fatty infiltration, mucin deposition, and neural changes. Thirty-six specimens were from patients older than 60 years and 30 of these were intradermal. They noted that stromal fibrosis, fatty infiltration, and mucin deposition were significantly more likely to be present in the intradermal nevi removed from older patients. Piliouras et al6 evaluated 59 nevi in patients from 60 to 89 years of age. They found a decreasing number of total nevus counts with age noting that the decrease in Clark nevi (those with a junctional component of nevus cells) might be secondary to ultraviolet irradiation. Dermoscopic features were described in these nevi but pathologic analysis was not undertaken. Martinka et al5 assessed the histologic features of 215 nevi from patients older than 60 years, 95 (44%) of which were intradermal. They noted 19 biopsy
Boyd, Chen, and Shyr 5
specimens (9%) exhibited dermal cytologic atypia defined as prominent nucleoli, increased nuclear to cytoplasmic ratio, and irregular chromatin pattern. Solar elastosis was present in 101 specimens (47%) with fragmented elastic fibers often present in the adjacent stroma. These fibers were illustrated and are similar to the abnormally staining connective tissue in our patients’ biopsy specimens, however the authors did not histologically confirm them as elastic. Interestingly, they noted such fibers are not present in nevi of younger adults and wrote that they ‘‘represent a normal finding in some senescent nevi in older patients.’’ They also found ‘‘ancient’’ changes as described by Kerl et al1 in 37 biopsy specimens (17%) but did not comment on or depict their features. Massi and LeBoit18 wrote on and illustrated ‘‘nevi with atypical nuclei.’’ Their description and depiction of the nuclear features of these lesions is similar to the senescent nevi described here. The term ‘‘senescent’’ was deduced to be the most appropriate term as it derives from the Latin word ‘‘senescere’’ meaning ‘‘to grow old.’’ In today’s medical literature this concept is applied almost exclusively to oncogene activation-induced proliferation arrest19-21 but not to the histologic changes in long-standing nevi. It is proposed that senescent nevi exhibit these features in part because of the aging of the melanocytes given that some of them have been present for multiple decades. The significant association with the epithelioid morphology in senescent nevi would support this contention as this characteristic is noted in long-standing nevi. It is also possible these features are secondary to cumulative ultraviolet exposure. Patients with a senescent nevi were significantly more likely to demonstrate solar elastosis and abnormally stained connective tissue, changes associated with chronic sun exposure.21 The presence of greater numbers of intranuclear pseudoinclusions in senescent nevi would not be unexpected in nevi with excessive sun damage as Perez and Sanchez22 noted they appear commonly in nevi removed from albino patients with significant solar elastosis. Finally, because there is a significant association between senescent nevi and the presence of abnormally staining connective tissue it is possible the nuclear atypia noted may have arisen secondary to stromal-melanocyte interactions. Hedley et al23 described altered melanocyte morphology when exposed to extracellular matrix proteins in vitro. Carlson et al24 noted nevi arising in association with lichen sclerosus demonstrate ‘‘activated’’ features presumably secondary to changes in the stroma surrounding them.
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Fig 6. Intradermal nevi in the elderly with atypical nuclei. A, Hematoxylin and eosin features of a senescent nevi. BAP1 (B), BRAFV600E (C), and p16 (D) staining of the nuclei.
cohort might solidify the contentions presented and the strength of the statistical associations. In sum, there exists within the cohort of benign intradermal nevi a subset exhibiting focal areas of nuclear atypia. These senescent nevi demonstrate statistically increased amounts of solar elastosis, abnormally staining connective tissue, and nuclear pseudoinclusions. It is important that pathologists recognize senescent nevi to prevent their misinterpretation as anything other than benign. Fig 7. Intradermal nevus in the elderly with atypical nuclei. The melanocytes in the middle of the dermis exhibit the epithelioid features and the nuclear atypia of senescent nevus whereas those elsewhere demonstrate characteristics normally present in intradermal nevus. A delineation between these 2 populations of cells has been made with a white line.
This study has several limitations. First, this was a single-site, respective evaluation. Second, because only biopsy specimens from patients older than 60 years were evaluated it is unknown if similar features are present in other age groups, although if ultraviolet exposure is responsible for the changes noted it seems all but certain they would be present in younger patients. Third, the number of specimens evaluated was modest in number. Using a larger
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