Agminated Atypical (Dysplastic) Nevi: Title and subTitle BreakCase Report and Review of the Literature FREE

ATYPICAL MOLES and the atypical mole (dysplastic nevus) syndrome arerecognized as distinct clinical entities.^{1 - 2} Most dermatopathologists also agree on the existence of the histologic entityknown as a dysplastic nevus.^{3 - 4} Clinically, most atypical nevi are solitary lesions that begin to appear aroundpuberty. We describe a patient with the atypical mole syndrome who had multipleagminated atypical nevi that were histologically characterized as dysplasticnevi. Agminated as it pertains to melanocytic neviis defined as a circumscribed grouping of pigmented lesions confined to abody segment. Our patient had approximately 50 nevi clustered in a 5 ×3-cm area of skin on his right arm. Although the existence of agminated melanocyticnevi has been documented,⁵ to our knowledgeagminated atypical (dysplastic) nevi have never been reported in the literature.

A 44-year-old man was referred to the dermatology clinic for evaluationof multiple irregular moles. The patient reported that his nevi developedduring his teenage years. He denied a family history of multiple moles ormelanoma.

On physical examination, the patient had more than 100 melanocytic nevi,and a few of these nevi appeared clinically atypical. The largest nevus, onthe right side of his chest, measured 1 cm in greatest diameter (Figure 1). The patient also had an irregularmelanocytic neoplasm on the right side of his mandible that on subsequentbiopsy proved to be melanoma in situ.

The patient had a cluster of approximately 50 melanocytic nevi on hisright arm, all distributed in an area 5 × 3 cm in diameter (Figure 2 and Figure 3). The patient stated that this cluster of nevi first becameapparent at the age of 15 years. No background café-au-lait pigmentationwas noted clinically or with the aid of a Wood light examination. Dermoscopyrevealed that all the nevi had a "diffuse and patchy" network pattern⁶ (Figure 4A).However, one area was darker (Figure 3)and on dermoscopy had black dots, globules, and structureless areas (Figure 4B). Because this area had nevi thatdiffered from the other surrounding nevi, it was excised.⁷ The histopathologic findings revealed a lentiginous compound melanocytic nevuswith architectural disorder of its intraepidermal component and irregularplacement of nests of variable size and shape, fusion of nests, and asymmetricextension of the junctional component beyond the confines of the intradermalnevus component (Figure 5A). Severalmelanocytes contained abnormally large nuclei, some that were twice the normalsize, and the nuclei had irregular contours. Furthermore, papillary dermalfibroplasia with a sparse lymphohistiocytic infiltrate was present (Figure 5B). In light of the presence of architecturaldisorder and cytologic atypia, a diagnosis of dysplastic nevus was made.

Atypical moles (dysplastic nevi) are acquired pigmented lesions thatdevelop during puberty and continue to develop and change throughout life.Although they may appear anywhere on the body, they primarily develop on thetrunk.

Clinically, atypical nevi share many features of malignant melanoma,including asymmetry, border irregularity, color variability, and a diametergreater than 6 mm.⁸ They can be multiple orsolitary, and can develop in patients with or without a family history ofsimilar lesions.

We describe a patient with the atypical mole syndrome who had an unusualpresentation of multiple, clustered, clinically atypical (dysplastic) nevi.To our knowledge, this is the first reported case of agminated atypical (dysplastic)nevi. In this patient, the diagnosis of atypical (dysplastic) nevi was basedon clinical and histologic features. Clinically, some of the patient's neviwere irregular, demonstrated variegation of color, and were greater than 6mm in diameter. The dermoscopic feature of a patchy network was also consistentwith a diagnosis of dysplastic nevi.⁶ The histologicdiagnosis of the biopsied section was that of a dysplastic nevus or a nevuswith "architectural disorder and cytologic atypia."⁹

A review of the literature revealed that the term agminated has been used to describe several different cutaneous lesions.Pigmented lesions that have been described as agminated include melanocyticnevi,⁵ congenital melanocytic nevi,¹⁰ Spitz nevi,^{11 - 12} nevi spilus,^{13 - 14} blue nevi,^{15 - 16} and multiple lentigines.¹⁷ Other nonpigmented agminated lesions reported inthe literature include xanthogranulomas,¹⁸ angiofibromas,¹⁹ and neurilemomas.²⁰ Historically, atypical (dysplastic) nevi have notbeen reported to occur in an agminated distribution.

Based on this patient's clinical and histologic features, the diagnosisof agminated atypical (dysplastic) nevi, and not any of the other previouslyreported agminated lesions, is most accurate. By definition, congenital melanocytic nevi are melanocytic nevi that are present atbirth or develop shortly after birth. Because our patient's nevi developedduring his teenage years, it is unlikely that they were congenital melanocyticnevi.²¹ In addition, the histopathologic featureswere not consistent with congenital melanocytic nevi.

It is unlikely that the cluster of lesions were Spitz nevi. Althoughmultiple agminated Spitz nevi have been reported,²² the histologic features of Spitz nevi are quite different and demonstrateadmixed spindle and epitheliod cells arranged in irregular nests with occasionalmitotic figures. These features were not seen in this patient's biopsy specimen.In addition, the clinical features of agminated Spitz nevi are also different.Spitz nevi tend to develop in early childhood, predominately occur on theface, and are pink.¹¹ In our patient, the nevidid not develop until puberty, occurred on his arm, and were brown.

The diagnoses of nevus spilus,²³ bluenevi, and lentiginosis can be ruled out based on clinical and histologic features.Unlike our patient, who developed his "agminated atypical moles" at the ageof 15 years, nevus spilus is usually apparent by early infancy or childhood.^{21 ,23} The diagnosis of nevus spilus isalso not consistent with the clinical examination because of the obvious lackof background pigmentation, a feature commonly seen in a nevus spilus. Furthermore,the pathological features of our patient's agminated lesions also failed todemonstrate the background of lentigo, as would be seen in a nevus spilus.The diagnosis of blue nevi was not made because clinically they did not appearas blue or black dome-shaped papules, and histologically they did not demonstratedermal melanocytes grouped in irregular bundles admixed with melanophages.¹⁶ The diagnosis of agminated lentiginosis was not madebecause the histologic features did not demonstrate elongation of the reteridges and hyperplasia of melanocytes.¹⁷

It has been proposed that the atypical mole syndrome has either an autosomaldominant mode of inheritance with incomplete penetrance or a polygenic modeof inheritance.² The specific gene or genesthat predispose to the development of dysplastic nevi and the precipitantsfor the formation of individual melanocytic nevi have not been identified.However, sun exposure has been implicated in the development of melanocyticnevi.²⁴ Furthermore, it has been postulatedthat some atypical melanocytic nevi may develop through loss of heterozygosity(LOH).^{25 - 26} Loss of heterozygosityis the loss of a normal wild-type allele, leading to the expression of a mutantor recessive allele.²⁷ One mechanism for acquiredloss of an allele may be through mutations induced by UV exposure.²⁸ The specific etiology of agminated nevi is not known.Local environmental factors, such as UV radiation, may play a role in thedevelopment of clustered lesions. However, it is also possible that this agminatedpattern may represent LOH, occurring during embryogenesis, as has been postulatedto account for the segmental distribution of lesions such as neurofibromas,porokeratosis, and Becker nevi.²⁷ In our patient,the agminated dysplastic nevi occurred in the presence of the atypical molesyndrome. Other examples of segmental clustering of skin lesions superimposedon a generalized less severe form of the condition may shed light on the pathogenesisin our case. Autosomal dominant skin disorders, such as neurofibromatosis,sometimes occur in a segmental pattern superimposed on a less severe but diffuseform of the same disorder.²⁷ This phenomenonmay be explained by an early postzygotic mutational event giving rise to LOHat the locus responsible for the trait. A person can also have a segmentalmanifestation of a polygenic skin disorder, such as segmental severe psoriasis,superimposed on symmetric involvement of ordinary psoriasis.²⁷ This too can be explained by LOH occurring in a somatic cell during earlyembryogenesis, resulting in either homozygosity or hemizygosity for one ofthe genes predisposing to psoriasis. Future studies of the distribution oflesions in cases of agminated nevi such as ours coupled with genetic analysisof microdissected tissues may shed light on the timing and nature of theseevents.

In conclusion, based on a review of clinical entities occurring in anagminated distribution, we believe that our case is the first report of agminatedatypical (dysplastic) nevi. This is a new, previously undescribed, clinicalvariant of atypical (dysplastic) nevi occurring in a patient with the atypicalmole syndrome and adds to the phenotypic spectrum of this entity. In addition,this case raises the possibility that LOH may play a role in the developmentof some cases of dysplastic nevi or atypical mole syndrome.

Accepted for publication February 26, 2001.

We thank Nathan Ellis, PhD, for reviewing the manuscript and helpingus to better understand the concept of loss of heterozygosity.

Corresponding author and reprints: Ashfaq A. Marghoob, MD, DermatologyService, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York,NY 10021.