Nevus spilus (Speckled Lentiginous Nevus, Naevus Sur Naevus)

Nevus Spilus [Speckled Lentiginous Nevus, Naevus Sur Naevus]

Are You Confident of the Diagnosis?

Characteristic findings on physical examination

A nevus spilus (NS) or speckled lentiginous nevus (SLN) typically presents before the age of 2 as a light brown macule or patch containing smaller, more darkly pigmented macules or papules within the borders (Figure 1). These smaller pigmented aspects may appear after the first background patch is noted. NS is thought by most but not all authors to represent a type of congenital melanocytic nevus.

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Typically a NS is a benign, isolated lesion with limited dimensions. The larger background patch tends to range in size from 2 to 10 cm, though it can reach the size of greater than 20 cm, as seen in giant congenital nevi. The smaller pigmented “speckles” tend to range in size from 1 to 3 mm, and can reach up to 9 mm in diameter.

Microscopically, the two types of clinical features appear very different. The tan-brown background pigmentation exhibits features with lentigo simplex: the epidermis is acanthotic with elongation and hyperpigmentation of the rete ridges and an associated mild increase in the number of single melanocytes along the dermal-epidermal junction. Others have reported the appearance of melanocytic nests in these areas as well.

In contrast, the “speckled areas” within this lentiginous background can exhibit a range of reported histolopathologic appearances: from simple lentigines to ordinary nevi (junctional, compound or intradermal) to blue nevi to Spitz nevi. There have been reported cases of melanoma arising in nevus spilus. Schaffer has likened the speckled lentiginous nevus/nevus spilus to a “…melanocytic garden, and within this garden a variety of lesions can grow, from junctional nevi to blue nevi to melanoma…” No consistent correlation has been made between the clinical setting of the nevus spilus, the anatomic distribution or their histopathologic appearance.

NS can present anywhere on the body. It has even been reported as covering both the upper and lower eyelid in the case of one patient. In certain individuals, NS can cover larger areas of the body, giving a “checkerboard’ pattern.” Certain NS lesions have been described erroneously in the past as having a “zosteriform’ appearance,” even though the distribution of NS is not dermatomal. However, NS lesions may follow lines of Blaschko, particularly if they are linear. When a NS is large and segmental, it may be a sign of one of the following rare congenital disorders: phacomatosis pigmentovascularis type III or phacomatosis spilorosea, phacomatosis pigmentokeratotica, or speckled lentiginous nevus syndrome (SLNS). Phacomatosis pigmentokeratotica is now understood to represent a form of a “Mosaic RASopathy” caused by post-zygomatic mutations in the RAF/RAS/MAPK pathway.

Originally NS was considered a single diagnosis, but has now been split into two separate conditions: nevus spilus maculosus (NSM) and nevus spilus Papulosus (NSP). NSM demonstrates the typical light brown patch with uniformly small, darker brown macules spread evenly throughout in a “polka-dot’ pattern. NSP demonstrates both macules and papules of varying sizes scattered in an uneven pattern, resembling a “star map.”

While NSM lesions tend to have a stable appearance and do not change much throughout life, NSP lesions often present as light tan patches present at birth that then develop dark brown macules and papules as the patient progresses from childhood to adulthood. The macules and papules in NSP can change in size and color as the patient ages as well. Most importantly, NSM is only associated with phakomatosis pigmentovascularis type III (aka phacomatosis spilorosea), whereas NSP is associated with phacomatosis pigmentokeratotica and speckled lentiginous nevus syndrome (SLNS).

Expected results of diagnostic studies

Diagnostic studies are rarely performed on individuals with NS. They are commonly followed clinically, and the majority of them are a clearcut clinical diagnosis that do not require any work-up.

Diagnosis confirmation

Clinically, the differential diagnosis for early NS (which presents as a solitary light brown macule or patch) includes a cafe-au-lait macule, Becker pigmented hairy nevus, agminated lentigines, congenital nevus, and other lentigines. Twenty percent of the general population can have a solitary cafe-au-lait macule, but these will consistently lack the hyperpigmented macules and papules seen in NS. Multiple cafe-au-lait macules should raise suspicion for neurofibromatosis and a cafe-au-lait macule with irregular borders may be seen in the McCune-Albright syndrome. A Becker pigmented hairy nevus may be challenging to differentiate from NS, and may not be evident until the classic hypertrichosis becomes evident in later years.

Perhaps the most challenging to differentiate clinically from NS are agminated lentigines. These lesions are defined as numerous lentigines (small pigmented macules with sharp circumscribed borders), geographically arranged either in a dermatomal distribution, a checkerboard pattern, or a midline cluster pattern, and can be uni- or bilateral. They are ultimately distinguished by having a background of normal skin, as opposed to the hyperpigmented light brown background patch seen in NS. As NS lesions develop their characteristic “speckles,” there are very few pigmented lesions that can mimic their clinical appearance.

Who is at Risk for Developing this Disease?

NS occurs in roughly 2% of the general population. There is no reported gender or racial preference for development of NS.

What is the Cause of the Disease?

Etiology

The etiology of NS is not entirely clear, however, mutations in HRAS have been implicated. It is generally considered to be a congenital nevus, though some authors contend that it can be acquired, due to the fact that it is often not present at birth, and more common in school aged children and adults.

Pathophysiology

The pathogenesis of NS is thought to be a genetic field defect in neural crest melanoblasts, causing aberrant melanocytic proliferation at a specific site in the skin.

Systemic Implications and Complications

In rare cases, malignant degeneration of NS has been reported. The true incidence of progression to melanoma is unknown, however. Risk factors for melanoma arising in a NS are thought to include the presence of a lesion since birth and a lesion greater than 4 cm in diameter. The overall morbidity and mortality associated with malignant transformation of NS reflect that of a melanoma seen in isolation, with depth of invasion being the most important prognostic factor.

As described above, Spitz nevi and blue nevi have been reported in association with both NSP and NSM. Apart from malignant transformation, NSM and NSP can be associated with underlying congenital abnormalities, as mentioned above. These will be discussed below in the Unusual Clinical Scenarios section.

Treatment Options

Treatment options are summarized in Table I.

Table I.

Medical Treatment	Surgical and other Procedures	Physical Modalities
Baseline assessment, photography	Punch excision of “speckled” aspects if they are concerning for representing a melanoma, as with other cutaneous melanocytic lesions	None
Education for patient and family regarding signs of malignant transformation, ABCDE’s	Light ablation with IPL using a 590-nm filter has been used, but would not be recommended by the authors due to potential impact on melanoma detection and inappropriate treatment of a melanoma
Close monitoring
Regular follow up visits with photography of lesion

ABCDE, asymmetry, border, color, diameter, elevation; IPL, intense pulsed light.

Optimal Therapeutic Approach for this Disease

NS is a benign lesion that does not require treatment. Some patients or their parents may be concerned about the cosmetic appearance of the lesion if it is in a cosmetically sensistive area, such as the face. Wide excision may be performed in some cases, but must be balanced against the appearance of a large scar. Laser ablation would not be suggested by the authors due to the fact that laser treatment may make it more difficult to accurately monitor and assess the lesion for change.

If risk factors for transformation to a melanoma are present, such as the lesion being present from birth or the lesion being greater than 4 cm in size, then close monitoring by the patient, the patient’s family, and potentially by a dermatologist is recommended. If the lesion progresses to a melanoma, then the appropriate management is recommended below.

Patient Management

The most appropriate management for NS is a baseline assessment of the lesion, with close clinical monitoring, typically on an annual basis, or more frequently if changing. Baseline photography could assist in accurate monitoring. Education of the family and patient regarding the signs of melanoma, the ABCDE’s (asymmetry, border, color, diameter, elevation), and how to monitor the NS lesion at home is important. It should be made clear that the risk of progression to melanoma is extremely low, but there is a risk and monitoring is still necessary.

If a melanoma has been identified in a NS lesion, the standard recommendation is for wide excision of the entire pigmented patch. Since NS is often present in the pediatric population, and parents may be concerned about a large scar, some parents may decline wide excision. If parents do decline the full wide excision, even after a detailed explanation of the risks of inadequate therapy, then it is recommended that the aspect with the melanoma undergo wide excision followed by punch excision of the remaining ’speckled’ aspects of the lesion.

If a NSP is segmental, then the patient must be evaluated for SLNS and phacomatosis pigmentokeratotica which represent mosaic RASopathies. If a NSM is segmental, then the patient should be evaluated for phacomatosis pigmentovascularis type III, aka phacomatosis spilorosea. These congenital conditions are extremely rare, and are discussed below.

Unusual Clinical Scenarios to Consider in Patient Management

Phacomatosis is an umbrella term referring to malformation syndromes that classically involve the skin, eye, and central nervous system. Ordinary NS lesions are not associated with these disorders. However, large and figurate NS lesions can be associated with phacomatoses. Phacomatosis pigmentovascularis and phacomatosis pigmentokeratotica are syndromic conditions where the NS lesion coexists with either a vascular nevus or an organoid nevus respectively.

SLNS is considered a form of phacomatosis pigmentokeratotica, now termed a mosaic RASopathy. The evaluation for this rarely reported syndrome can be challenging, as the clinical presentation of SLN syndrome is subtle, and the degree to which a patient is affected is variable. It is characterized by a large figurate NSP in association with peripheral nerve and neuromuscular disturbances, as well as skeletal muscle and central nervous system anomalies.

The anomalies include pectoral muscle hypertrophy, leg sensorimotor neuropathy, popliteal nerve palsy, limb asymmetry, hyperhidrosis, dysesthesia, hyperalgesia, scoliosis, and rarely extrapyramidal symptoms. Other noted clincal features include gingival hypertrophy, right bundle branch block, dyslexia, developmental delay, obsessive compulsive disorder, Tourette’s syndrome, and melanoma.

Evaluation and treatment of patients with a suspicion of these conditions should be multidisciplinary and include dermatologic, orthopedic, ophthalmologic and neurologic evaluation. Neurologic imaging is essential, particularly with craniocervical lesions.

NS have also been seen in FACES syndrome (facial features, anorexia, cachexia, and eye and skin anomalies).

What is the Evidence?

Boncoraglio, GB, Parati, EA, Ciceri, E, Rinaldi, R, Capella, GL. “Intracranial cavernoma and speckled lentiginous nevus: extending the spectrum of phakomatosis”. Neurol Sci. vol. 31. 2010. pp. 841-4. (A case report of a patient with a congenital left laterocervical NS associated with an ipsilateral intracranial extraaxial cavernous angioma.)

Cohen, HJ, Minkin, W, Frank, SB. “Nevus spilus”. Arch Dermatol. vol. 102. 1970. pp. 433-7. (An overview of the entity.)

Gulati, G. “Nevus Spilus”. Indian Pediatrics. vol. 42. 2005. pp. 831(A case report of a 4-year-old boy with NS along his left cheek and vermillion lip, with a short review of NS.)

Happle, R. “Speckled lentiginous nevi: no longer one single disorder”. Arch Dermatol. vol. 146. 2010. pp. 204(A brief comment on an article delineating the differences between speckled lentiginous nevi (SLN) and segmental lentiginosis. The author highlights the need to separate SLN into the macular and the papular variants.)

Happle, R. “Speckled lentiginous naevus: which of the two disorders do you mean”. Clin Exp Dermatol. vol. 34. 2008. pp. 133-5. (A short review of the author’s experience with NS and the need to distinguish NSM from NSP.)

Ramolia, P, Treadwell, P, Haggstrom, A. “Speckled lentiginous nevus syndrome associated with musculoskeletal abnormalities”. Ped Dermatol. vol. 26. 2009. pp. 298-301. (A case report of a 9-year-old boy with SLNS, and a brief review of the previous five cases reported in the literature. The article also reviews the varied features of SLNS and its relation to phacomatosis pigementokeratotica. The authors advocate for a multidisciplinary approach for evaluation and treatment of these patients.)

Schaffer, JV, Orlow, SJ, Lazova, R, Bolognia, JL. “Speckled lentiginous nevus: within the spectrum of congenital melanocytic nevi”. Arch Derm. vol. 137. 2001. pp. 172-8. (A review of 10 cases of SLN, making a case that these lesions represent a form of congenital nevus. The risk of progression to melanoma is also described and monitoring and treatment options are reviewed.)

Torchia, D. “More on the speckled lentiginous nevus syndrome”. Dermatology. vol. 221. 2010. pp. 324-5. (A brief review of the reported cases of patients with SLNS and its association with large segmental NSP.)

Vaidya, DC. “Nevus spilus”. Cutis. vol. 80. 2007. pp. 465-8. (A short review article on nevus spilus, illustrating the epidemiology and the clinical and histologic appearance of these lesions, as well as the current opinion that there are two forms of the disorder, NSM and NSP, and the underlying congenital abnormalities seen with these two variants. Monitoring and treatment options are also described.)

Vidaurri-de la Cruz, H, Happle, R. “Two distinct types of speckled lentiginous nevi characterized by macular versus papular speckles”. Dermatology. vol. 212. 2006. pp. 53-8. (A careful review of the 64 cases of NS from 1970-2004, with the conclusion that NS should be divided into NSM and NSP based on differing clinical features, histolopathologic features, and disease associations.)

Sarin, KY, McNiff, JM, Kwok, S, Kim, J, Khavari, PA. “Activating HRAS mutation in nevus spilus”. J Invest Dermatol. vol. 134. 2014 Jun. pp. 1766-8. (A study of 8 nevi spili which all demonstrated point mutations in HRAS, implicating the gene in the development of the tumor.)

Luo, S, Tsao, H. “Epidermal, sebaceous, and melanocytic nevoid proliferations are spectrums of mosaic RASopathies”. J Invest Dermatol. vol. 134. 2014 Oct. pp. 2493-6. (A review of the “Mosaic Rasopathies” – the concept that post-zygotic mutations in the RAF/RAS/MAPK pathway can result in not only keratinocytic and sebaceous epidermal nevi but also certain melanocytic lesions such as nevus spilus.)

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