Apart from the atypical mole phenotype, development of new melanocytic nevi in older individuals is uncommon and considered worrisome for melanoma. We performed a retrospective case series in a Veterans Affairs population from 1991 to 2013 to characterize blue nevi (BN) by patient age at biopsy, location, self-reported duration, and relation to prior or subsequent development of cutaneous melanoma.
A total of 204 BN were identified in 194 predominantly male patients (90.7%) who had a mean (SD) age of 62.8 (14.4) years. Clinical duration of 10 years or less was reported by 90.3% of patients with available data (32.0%). Histopathologic examination classified 74.0% of BN as common, 1.5% as cellular, and 24.5% as combined type. No malignant BN were identified; however, 18 primary melanomas were diagnosed, most (72.2%) prior to blue nevus biopsy, including 38.9% in situ and 61.1% with mean (SD) Breslow thickness of 1.02 (0.99) mm.
Conclusions and Relevance
The later patient-reported onset of BN suggests a potential alternative mechanism of nevogenesis compared with common acquired nevi and differs from prior reports of BN development in younger adults. The lack of association with melanoma in older individuals suggests that most benign-appearing BN may be safely observed, even in a cohort at higher risk for skin cancer.
Blue nevi (BN) are benign pigmented lesions with rare malignant potential. They are considered a subset of dermal dendritic melanocytic proliferations, which derive their dark blue or bluish black color from the scattering of light by dermal melanin, known as the Tyndall effect.1,2 The melanocytes in BN typically stain positive for Human Melanoma Black-45 (HMB-45), suggesting that BN stem from latent dendritic melanocytes trapped in the dermal layer during their migration from the neural crest to the epidermis.3 There are 3 main histologic subtypes of BN: common (including sclerotic type), combined, and cellular. Common BN generally present as solitary and small (1-5 mm) dark blue macules or dome-shaped papules. Blue nevi are also commonly observed as part of combined nevi, most often in conjunction with a compound or intradermal nevus, and less frequently, with a Spitz or dysplastic nevus. Cellular BN are more likely than common BN to be elevated, larger in size, and have greater malignant potential.1
Patients may report BN as an aesthetic concern because they are often mistaken for cosmetic or traumatic tattoos. For the clinician, the differential diagnosis ranges from benign entities, such as common nevi, tattoo, or postinflammatory pigment alteration, to malignant entities, such as pigmented basal cell carcinoma or melanoma.
Apart from the setting of the atypical mole or dysplastic nevi syndrome, development of new melanocytic nevi after age 50 years is uncommon and raises concern about the diagnosis of cutaneous melanoma. Based on our clinical observation of the increased frequency and later onset of BN in a predominantly elderly population, we sought to characterize BN clinically and histopathologically to elucidate patient-reported age of onset, the relationship to prior, concomitant, or subsequent primary melanoma, and their malignant potential, including the proportion of cases identified as malignant BN or blue nevus–like melanoma.
A retrospective review of BN identified from 1991 to 2013 in the Veterans Affairs Palo Alto Health Care System (VAPAHCS) Pathology Service database was performed, with clinical chart review to determine patient outcome, reported duration of the lesion, and other clinical characteristics. The VAPAHCS electronic medical record did not become widely available until 1997, thereby limiting clinical data annotation for 33 patients. Clinical outcome data were assessed through May 30, 2013. The study was approved by Stanford University and VAPAHCS institutional review boards.
A total of 204 cases of biopsy-proven BN were identified in 194 patients who had a mean (SD) age of 62.8 (14.4) years, with most biopsies being performed to exclude the diagnosis of melanoma based on patient report of short or unknown duration of the lesion. Patients were predominantly male (90.7%) and white, typical of the VAPAHCS population, although race/ethnicity was not noted in all cases. The mean duration of patient follow-up was 9.0 years (range, 0-22 years).
In terms of histologic subtypes, 151 of 204 BN (74.0%) were diagnosed as common, 50 of 204 (24.5%) were diagnosed as combined (BN with intradermal nevus in 84.0% and compound nevus in 16.0%, 2 of which were also noted to be mild to moderately dysplastic), and 3 of 204 (1.5%) as cellular. Most BN were located on the extremities (93 of 204 [45.6%]), followed by the head and neck (64 of 204 [31.3%]), and the back (35 of 204 [17.2%]). Of the 15 BN on the hands, 8 (53.3%) were on the dorsal surface, while only 2 of 9 BN on the feet (22.2%) were located dorsally. For the 64 head and neck BN, 33 (51.6%) were located on the scalp, 16 (25.0%) on the forehead-temple-eyebrow-eyelid region, 6 (9.4%) on the preauricular-cheek region, 3 (4.7%) on the ear, 2 (3.1%) in the oral mucosa, 2 (3.1%) on the neck, and 1 each (1.6%) on the posterior auricular region and conjunctival mucosa. Cellular blue nevi were located on the scalp, upper back, and dorsal hand.
Clinical and histologic features are summarized in Table 1 and representative histopathologic images are shown in the Figure.
A, Blue nevus, sclerotic type with dendritic melanocytes interspersed in dense collagen. B, Combined nevus with nevocellular intradermal nevus and dendritic melanocytes (original magnification ×10 for both).
The estimated duration of the BN prior to biopsy diagnosis was based on patient-reported onset of the lesion. Clinical duration was available for 65 BN in 62 patients, of whom 56 (who had a mean [SD] age of 57.8 [15.9] years) reported acquiring the nevus 10 years or less prior to diagnostic biopsy. Nine patients reported the lesion as being of “new” onset. Only 10 patients reported a recent change in size or symptoms of the lesion prior to biopsy, including 3 from the cohort with reported clinical duration of 10 years or less, 2 from the cohort of duration greater than 10 years, and 5 of unspecified duration.
Eighteen primary melanomas were identified in 16 patients with BN, 7 of 18 (38.9%) of which were melanoma in situ and 11 of 18 (61.1%) were thin invasive melanoma, with a mean (SD) Breslow thickness of 1.02 (0.99) mm. Most melanomas (13 of 18 [72.2%]) were diagnosed prior to BN biopsy (mean, 3.0 years), and 3 of 18 (16.7%) were biopsied at the same time. Melanomas were mainly located on the back (6 of 18 [33.3%]) and arms (6 of 18 [33.3%]), followed by the chest (2 of 18 [11.1%]), and neck, nose, preauricular-cheek region, and trunk, 1 of 18 for each (5.6% per site). These results are summarized in Table 2.
To our knowledge, this study represents the largest BN cohort described according to histopathologic subtype, patient characteristics, estimated duration of lesion and relation to malignant BN as well as to prior, concomitant, or subsequent cutaneous melanoma. Our cohort was composed of predominantly older white men, typical of the VAPAHCS patient demographics. Notably, it highlights the occurrence of benign BN in an older-age demographic markedly different from the younger, female patient population previously described in the literature.
Common BN are reported to arise most frequently in women and younger adults (mean age, 38.6 years).4 They occur most often on the scalp, as well as the dorsal surfaces of hands and feet.3 Cellular BN may be congenital or acquired and have a higher incidence in females (2.2:1) and in adults younger than 40 years, with usual location on the buttocks or scalp.5 Some authors have hypothesized that female hormones may play a role in acquired BN based on this sex and age predilection.6 In our cohort of predominantly older men (mean age, >60 years), we identified that BN were commonly reported to develop later in life in the subset of patients in whom estimated duration of the lesion was possible.
Similar to prior reports, 45.6% of the BN cases in our cohort were located on the extremities (including the dorsal hands and feet) and 16.2% on the scalp, although BN were commonly noted in other regions of the head and neck (31.3%) and on the back (17.2%). Notably, there were 2 cases of BN arising in the oral mucosa and 1 on the conjunctival mucosa, which have rarely been reported in the literature.4
Furthermore, in the subset of patients in whom clinical duration of the lesion was reported, 90.3% noted onset in later adulthood, suggesting a potentially different mechanism of nevogenesis compared with common acquired nevi, most of which develop prior to age 40 years.5 Our findings support the concept that BN are not uncommon in older individuals and, combined with lack of malignant BN in our cohort, suggest that most banal-appearing BN in older individuals can be safely followed with clinical observation rather than biopsied to exclude melanoma. However, this recommendation is contingent on clinical stability of the lesion with no patient report of recent change as well as dermoscopic examination of the lesion, which can aid in the diagnosis of BN.
Blue nevi remain an important entity in the differential diagnosis of melanoma, especially in older patient populations at high risk for skin cancer, such as patients in the VA Healthcare System. In a study assessing VA cancer incidence using 2007 VA Central Cancer Registry data, melanoma was the fifth most common cancer, accounting for 3.4% of cases.7 Melanomas that arise in association with BN, typically referred to as “malignant BN” or “blue nevus–like melanoma,” are most commonly associated with the cellular type and have only been rarely reported to arise from common BN.8,9 Although malignant BN have been characterized as more aggressive in nature than conventional melanoma,10 a recent case series of 23 patients suggests that clinical outcomes were similar when matched with common melanoma subtypes for Breslow thickness and ulceration.11 In a study by Van Raamsdonk et al,12 83% of BN were found to harbor activating somatic mutations in the GNAQ gene that encodes the ras-like domain. Blue nevi do not seem to harbor oncogenic mutations that are commonly found in other nevi or melanoma, including BRAF,13NRAS,14 or c-kit.15 In our cohort with a mean of 9.0 years clinical follow-up, there were no reports of melanoma arising from common, combined (including with dysplastic features), or cellular BN. However, as with other melanocytic lesions, BN should be biopsied in cases with rapid growth or atypical clinical and/or dermoscopic features to exclude malignant transformation.
In our BN cohort, 8.2% of patients were also diagnosed as having in situ or thin cutaneous melanoma, an incidence rate which is higher than that reported by the VA Central Cancer Registry but likely reflects the increased skin cancer risk of patients followed by dermatology. In addition, most melanomas (72.2%) occurred before the BN diagnosis, which limits our ability to draw conclusions regarding the association of BN with subsequent melanoma development, particularly in a population at higher risk based on age, increased lifetime sun exposure, and fair skin phenotype. However, our findings reinforce the concept that BN represent a distinct subtype of melanocytic neoplasms with rare malignant potential.
Our study has several limitations. First, it is difficult to generalize our findings to a broader population because of the relatively homogeneous nature of our VAPAHCS study cohort. However, while the older age distribution does not provide further insight into the incidence of BN in a younger demographic, it does serve to highlight the apparent development of benign BN in individuals older than 50 years. Second, age of onset and/or duration of BN were determined by patient recollection of such, with potential recall bias as patients may have had difficulty remembering when their BN first developed. Incomplete documentation of patient report regarding BN duration in 68.0% of our cases also limits firm conclusions on identifying the precise age at onset of BN.
This large retrospective case series of predominantly older men at high risk for skin cancer suggests that BN may occur later in life than previously reported and that they do not seem to have increased malignant potential based on age, male sex, and prior or subsequent cutaneous melanoma development. Larger, population-based studies are necessary to further characterize the incidence and duration of BN in older individuals as well as their association with malignant BN and subsequent development of cutaneous melanoma. In conjunction with recent genetic studies demonstrating different mutations in BN compared with other nevus subtypes and melanoma, our findings support the concept that benign BN are not uncommonly acquired in older age individuals and that they may be safely clinically followed in the absence of concerning clinical and/or dermoscopic features.
Corresponding Author: Susan M. Swetter, MD, Department of Dermatology, Pigmented Lesion and Melanoma Program, Stanford University Medical Center, 900 Blake Wilbur Dr, W0103, Stanford, CA 94305-5356 (firstname.lastname@example.org).
Accepted for Publication: August 6, 2013.
Published Online: April 30, 2014. doi:10.1001/jamadermatol.2013.7366.
Author Contributions: Dr Cabral had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Cabral, Chen, Swetter.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Cabral, Chen, Swetter.
Critical revision of the manuscript for important intellectual content: All authors.
Administrative, technical, or material support: Cabral.
Study supervision: Swetter.
Conflict of Interest Disclosures: None reported.
Previous Presentation: This study was presented in part as a poster at the American Society for Dermatologic Surgery Annual Meeting; October 4, 2012; Atlanta, Georgia.
Cabral ES, Chen FW, Egbert BM, Swetter SM. Acquired Blue Nevi in Older IndividualsRetrospective Case Series From a Veterans Affairs Population, 1991 to 2013. JAMA Dermatol. 2014;150(8):873-876. doi:10.1001/jamadermatol.2013.7366