A man, aged 34 years, presented with an intermittently pruritic lesion on his left mid-back. The lesion had been present for years and was slowly enlarging. The patient desired an elective excision of the lesion to alleviate repeated irritation from clothing. Review of systems was otherwise negative.
The man’s medical and family histories were unremarkable. On physical examination, a 7-mm rubbery, skin-colored papule was appreciated on the left mid-back. The remainder of the examination was within normal limits.
A woman, aged 33 years, presented with what she described as a mole that had been present for more than 10 years. She complained of repetitive trauma and bleeding to the lesion and desired elective excision. The lesion had not been changing in size and/or color, and there was no associated pruritus. Review of symptoms was otherwise negative.
Medical and family histories were unremarkable. Physical examination revealed a 6-mm skin-colored to tan papule on the left lateral thigh. A similar lesion was noted on the trunk.
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Case #1: Neurofibroma
Neurofibromas were first described as fibrous tumors. Verocay later suggested a neuroectodermal origin, which was ultimately confirmed by immunohistochemical and ultrastructural studies.1 In 1882, von Recklinghausen provided the medical community with the first in-depth clinical and pathologic description of the physically devastating condition of neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease. However, it was not until the mid-20th century that Crowe, Schull, and Neel compiled a comprehensive description of the manifestations of NF1 that is still in use today.
The two main categories of neurofibromas are the solitary type and the plexiform type. Both types occur equally in males and females. Solitary cutaneous neurofibromas are relatively common and usually arise around puberty. However, multiple cutaneous neurofibromas, along with other characteristic stigmata to be discussed later, should alert the clinician to the diagnosis of neurofibromatosis. Plexiform-type neurofibromas are probably congenital in origin but do not become physically apparent until age 4 or 5 years. The presence of a plexiform neurofibroma almost always indicates that the patient has NF1.
The exact pathogenesis of solitary neurofibromas is unclear. However, the basic process involves proliferation of the entire neuromesenchyme, which includes Schwann cells, perineural cells, endoneurial fibroblasts, mast cells, and cell types with intermediate features.2 The extent of proliferation of each cell line varies. Hence, the resulting histologic composition and architecture is variable.
Neurofibromas are usually solitary; soft or rubbery; skin-colored to pink, tan, or brown papulonodules that range in size from 0.2 cm to 2 cm. The growths are most commonly seen on the head or trunk and may become pedunculated. Neurofibromas are usually slow-growing and asymptomatic, but some patients complain of pruritus. The “buttonhole sign” (i.e., effortless invagination of the tumor after gentle external pressure) is a characteristic feature.
Plexiform neurofibromas are usually seen on the trunk and proximal extremities and present as tender, firm, dermal, or subcutaneous nodules or masses that may become baggy or pedunculated. Both hyperpigmentation and hypertrichosis may overlie plexiform neurofibromas. Recognition of these lesions is important because they are considered pathognomonic for NF1, and approximately 3% to 15% may transform into malignant peripheral-nerve sheath tumors. The onset of rapid growth or pain in a previously stable plexiform neurofibroma may indicate malignant transformation.
Cutaneous neurofibromas are composed of a well- circumscribed but unencapsulated dermal collection of small nerve fibers and haphazardly arranged slender spindle cells. The spindle cells represent a mixture of Schwann cells, perineural cells, and fibroblasts. The collagenous stroma has varying amounts of mucin and scattered mast cells. Mitotic figures are absent or rare. Plexiform neurofibromas are composed of large, irregularly expanded, twisted nerve fascicles composed of spindle-shaped fibroblasts and Schwann cells in a myxoid matrix.
Solitary neurofibromas may be mistaken for intradermal nevi, compound nevi, soft fibromas, dermatofibromas, and neuromas. Plexiform neurofibromas with overlying hyperpigmentation and hypertrichosis may be mistaken for a congenital melanocytic nevus.
Multiple neurofibromas or a single plexiform neurofibroma warrants further investigation because these may be a clinical manifestation of the systemic disorder NF1. The incidence of NFI is thought to be approximately 1 in 3,000. Although NF1 is an autosomal-dominant disorder, as many as 50% of NF1 patients harbor spontaneous mutations. The NF1 gene is located on chromosome 17q11.2, and mutations lead to inactivation of the GAP-related protein neurofibromin.
One of the functions of neurofibromin is to negatively regulate the proto-oncogene, ras. The ras protein is a G-protein, which like all other G-proteins, requires GTP. GAPs, including neurofibromin, hydrolize GTP to GDP, thereby terminating the ras signal and halting cell-cycle progression, survival, and cytoskeletal reorganization. Thus, neurofibromin has tumor-suppressor properties.
To make the diagnosis of NF1, two or more of the following must be present:
- Six or more café-au-lait macules (>5 mm in prepubertal individuals and >15 mm in postpubetral individuals)
- Two or more neurofibromas of any type or one plexiform neurofibroma
- Freckling in the axillary or inguinal regions (Crowe’s sign)
- Optic gliomas
- Two or more Lisch nodules (iris hamartomas)
- Osseous lesions (sphenoid wing dysplasia or thinning of the long bone cortex)
- A first-degree relative with NF1
Individuals with NF1 may also have neurologic or cardiovascular manifestations. Management of those who are found to have NF1 requires a multidisciplinary approach dictated by the patient’s specific NF1 concerns.
Neurofibromatosis type 2 (NF2) is genetically distinct from NF1 and is characterized by café-au-lait macules, neurofibromas, schwannomas, and a variety of intracranial tumors, including bilateral schwannomas of the acoustic nerves.
Patients should be reassured of the benign nature of solitary neurofibromas. If desired, simple excision is curative. Laser ablation has also been used to eradicate neurofibromas.3,4 Patients who have a plexiform neurofibroma should be periodically followed, and rapid growth or pain within the lesion should merit immediate evaluation to exclude malignant transformation.
In this case, a punch excision was performed per the patient’s request. The remainder of the cutaneous examination did not reveal any characteristic stigmata suggestive of NF1.
Case #: Intradermal nevus
Intradermal, compound, and junctional nevi are classified as common acquired melanocytic nevi. They are also known by the terms “nevocellular nevi,” or more simply put, “moles.” Not much is known about the history of acquired melanocytic nevi. This is largely attributable to the fact that acquired melanocytic nevi are so common that they are considered a normal variant.
Nevi are seen equally in both males and females. The prevalence is related to age, race and genetic and environmental factors. During early childhood, only a few nevi are present. With time, however, nevi slowly increase in number, rapidly develop at the onset of puberty, and then peak between ages 20 and 29 years. Following this peak, the nevi begin to disappear as the individual gets older.
Genetic factors also play a role in the development of melanocytic nevi. Parents with increased numbers of nevi have been shown to have children with a similar affinity. Whites have a greater number of nevi than do darker-skinned individuals. Nevi are also more prevalent in whites and fair-skinned individuals. However, darker-skinned individuals such as African-Americans and Asians have a higher prevalence of melanocytic nevi on the palms, soles, nail bed and conjunctivae than do whites.
Some evidence also points to such environmental influences as UV exposure in the development of nevi.5 Individuals who live in warm and sunny climates tend to have more nevi than do individuals who live in more temperate climates.
Melanocytic nevi originate from melanoblasts, which are cells that arise in the neural crest and migrate to the epidermis. The nevi are thought to represent hamartomas, or benign proliferations of melanocytes that possess some growth advantage over surrounding basilar melanocytes. These slightly altered nevus cells, or melanocytes, go on to produce a junctional nevus within the epidermis.
It is hypothesized that these melanocytes subsequently migrate into the dermis, thereby producing a compound nevus.6 When the melanocytic cells are no longer seen in the epidermis, an intradermal nevus is formed.
Common acquired melanocytic nevi are typically round or ovoid lesions that measure approximately 2 mm to 6 mm in diameter. Benign nevi tend to be symmetric with well-defined borders and regular color variation throughout. Clinically, junctional nevi are medium-to-dark-brown macules.
Under the dermatoscope, one can appreciate that the pigment tends to fade toward the periphery. Compound nevi vary in elevation and tend to be lighter shades of brown. The most common dermatoscopic features are multiple round ovoid globules that resemble a cobblestone pattern. Intradermal nevi are usually more elevated and are either light tan or skin-colored. These lesions show focal globules and/or pale structureless areas and comma vessels under the dermatoscope.
Common acquired melanocytic nevi contain nests of melanocytes in the epidermis (junctional nevi), dermis (intradermal nevi), or both (compound nevi). In the superficial dermis, the cells generally have an epithelioid appearance and contain abundant cytoplasm. These melanocytes contain moderate amounts of melanin. As the cells mature and travel deeper into the dermis, they lose cytoplasm and the cells become smaller, resembling lymphocytes. These melanocytes rarely produce melanin.
Junctional nevi must be distinguished from ephelides, simple lentigines, solar lentigines, café-au-lait macules, and macular seborrheic keratosis. Compound nevi may be differentiated from seborrheic keratoses by their lack of verrucous surface and pseudo-horn cysts. Dermatofibromas may also be mistaken for compound nevi. Neurofibromas and fibroepithelial polyps may be indistinguishable from skin-colored or slightly pigmented and/or pedunculated dermal nevi.
Benign melanocytic nevi are distinguished from atypical nevi and melanoma by their overall symmetry, regular borders, homogenous color, smaller diameter, and stable clinical appearance. However, a significant proportion of patients with melanoma have reported the existence of a longstanding melanocytic nevus at the site of melanoma development. In fact, it is estimated that approximately one-third of melanomas are associated with a prior melanocytic nevus; the other two-thirds are thought to arise de novo. Interestingly, individuals with an increased number of melanocytic nevi are at higher risk of developing melanoma.
Common acquired melanocytic nevi are benign and are not normally excised unless the physician and/or patient has noticed a change in appearance, there is clinical concern for melanoma, for cosmetic reasons, or if the patient complains of repetitive trauma.
A shave biopsy often is performed to remove junctional nevi completely or to remove the protruding portion of compound and intradermal nevi. Since the melanocytic nests are present in the dermis of compound and intradermal nevi, these lesions may return after simple shave excision. A punch excision or simple excision is a better method to assure complete removal but may result in a more noticeable scar.
To address this woman’s complaints of repetitive trauma, punch excision was used to remove her intradermal nevus.
Kerri Robbin, MD, is a resident in the Department of Dermatology at Baylor College of Medicine in Houston.
- Verocay J. Zur kenntnis der Neurofibrome. Beitr Pathol Annat Allg Pathol. 1910;48:1-69.
- Scheithauer BW, Woodruff JM, Erlandson RA. Tumors of the peripheral nervous system. In: Atlas of Tumor Pathology, 3rd series, Fascicle 24. Washington, D.C.: Armed Forces Institute of Pathology; 1999:1-415.
- Kriechbaumer LK, Susani M, Kircher SG, Happak W. Vaporization of cutaneous neurofibromas with an erbium: yttrium-aluminum-garnet laser: a comparative histologic evaluation. Plast Reconstr Surg. 2012;129:602e-604e.
- Kim HJ, Lee KG, Yi SM, et al. Successful treatment of multiple cutaneous neurofibromas using a combination of shave excision and laser photothermocoagulation with a 1,444-nm neodymium-doped yttrium aluminum garnet laser. Dermatol Surg. 2012;38:960-963.
- Karlsson MA, Wahlgren CF, Wiklund K, Rodvall Y. Parental sun- protective regimens and prevalence of common melanocytic naevi among 7-year-old children in Sweden: changes over a 5-year period. Br J Dermatol. 2011;164:830-837.
- Brodell R, Sims DM, Zaim MT. Natural history of melanocytic nevi. Am Fam Physician. 1988;38:93-101.