Blue nevus (Common, Dendritic, Cellular Blue Nevus)
Are You Confident of the Diagnosis?
Blue nevi (BN) are benign melanocytic neoplasms that can be congenital or acquired. On physical examination, they have a characteristic blue-gray color rather than the brown color commonly seen in benign nevi. This blue-gray color is attributed to the deep dermal location of melanin in this entity. Because the pigment is relatively deep, it is susceptible to the Tyndall effect, in which there is selective absorption of the longer wavelengths of light by the dermal pigment, with the reflection off the skin to the eye of the shorter (blue) wavelengths.
BN are typically characterized histologically as either dendritic (common) blue nevi (DBN) or cellular blue nevi (CBN). These two types can often present in the same lesion, and the lesion is normally named based on the more histologically prominent (>50%) cell type. BN are divided into these two forms based on their clinical and histopathologic features as described below. Both DBN and CBN frequently harbor mutations in the Gαq class of G-protein α subunits, Gnaq and Gna11 proteins.
The clinical differential diagnosis for BN in general includes the congenital dermal melanocytoses, such as the Mongolian spot, nevus of Ito, nevus of Ota, nevus fusocaeruleus zygomaticus, acquired dermal melanocytosis of the face and extremities, and dermal melanocyte hamartoma. These are differentiated from BN based on their clinical features, in addition to a lack of cellularity and stromal sclerosis on histology. The differential diagnosis also includes benign nevi, deep penetrating nevus, epithelioid blue nevus and melanoma.
COMMON BLUE NEVI (DENDRITIC BLUE NEVI)
Characteristic findings on physical examination
On clinical examination, DBN (common blue nevus, Jadassohn-Tieche type) are most often well demarcated papules, less than 1cm in diameter, ranging in color from blue to gray, to blue-black to black. They are typically seen on glabrous skin, most often on the face and extremities. There have, however, been rare cases of BN occurring in the subungual portion of the nail unit, the orbit, the conjunctiva, the oral and genital mucosa, the oral cavity, sino-nasal mucosa, bronchus, esophagus, lymph nodes, uterine cervix, endometrium, and prostate.
Expected results of diagnostic studies
The common blue nevus is a proliferation of spindle and dendritic melanocytes centered in the dermis. At scanning magnification, a blue nevus is characterized by a dome-shaped proliferation of pigmented spindle cells forming a nodule in the dermis (
Microscopic images of blue nevi.
The epidermis is uninvolved in common blue nevi; however, peri-appendageal growth is not uncommon. The common blue nevus is composed of a variably dense proliferation of spindle-shaped and dendritic melanocytes with an associated infiltrate of pigment-laden macrophages (“melanophages”) (
Higher power examination reveals spindled cells that typically exhibit slender, long dendritic cytoplasmic processes. These fine cytoplasmic processes contain variable amounts of homogeneous, fine, brown intracytoplasmic melanin pigment. In some cases, this pigment can be so dense as to obscure the nuclear detail. The nuclei in blue nevi are typically elongated or spindle-shaped and hyperchromatic and typically exhibit minimal atypia or pleomorphism (
Maturation in blue nevi is evident at the peripheral and deep aspects of the lesion, where the spindle-shaped cells insinuate themselves singly among the thickened collagen fibers of the reticular dermis (
A sclerosing variant of DBN may resemble desmoplastic melanoma, but can be contrasted based on negligible cytologic atypia and positive staining for HMB-45 and often S-100 in the dendritic cells. Benign nevic cell aggregates are composed of small round to oval cells with round to oval nuclei and scant cytoplasm, devoid of cytologic atypia, and with very little associated pigment.
Common blue nevi can be seen microscopically in association with other benign nevi—typically a congenital pattern nevus. In the typical setting, there is an intimate association of banal nevic cells (compound, junctional or intradermal) associated with fascicles of pigmented spindle/dendritic cells of a blue nevus.
Immunohistochemical studies can be a useful ancillary technique invoked in the diagnosis of blue nevi. Blue nevi are typically strongly and diffusely positive for S100, Melan-A and HMB-45. The uniform positivity for HMB-45 is a particularly helpful feature in the distinction among other melanocytic and from non-melanocytic proliferations (see below).
The microscopic differential diagnosis for common blue nevi includes dermatofibroma, neurofibroma and desmoplastic melanoma.
A dermatofibroma (“benign fibrous histiocytoma”) is a fibrohistiocytic proliferation in the dermis, composed of spindle-shaped dendritic cells, which insinuate themselves among the dermal collagen bundles (“collagen trapping”). The epidermis overlying these exhibits a typical acanthosis with broad-based, elongated rete. However, the lesional cells of a dermatofibroma lack prominent intracytoplasmic pigment, and melanophages are uncommon in dermatofibromas; in addition, immunohistochemical studies of dermatofibromas reveal positivity in the lesional cells for Factor XIIIa, D2-40 and occasionally CD163, but negativity for melanocytic markers.
A neurofibroma is characterized by an intradermal proliferation of spindled cells with minimal overlying epidermal changes. Intracytoplasmic pigment and melanophages are not prominent, and immunohistochemical studies are negative for melanocytic markers HMB-45 and Melan-A.
Finally, desmoplastic melanoma typically occurs in association with an overlying melanoma in situ, lentigo maligna type. In contrast to blue nevi, the dermal proliferation of spindled melanocytes in desmoplastic melanoma typically exhibits cytologic atypia and conspicuous mitotic figures and often is associated with relatively dense lymphoid aggregates scattered within the lesion.
CELLULAR BLUE NEVI
Characteristic findings on physical examination
Clinically, CBN are most commonly located on the scalp, lower back, and buttocks (
Classical location of a cellular blue nevus.
Expected results of diagnostic studies
The cellular blue nevus can present a diagnostic pitfall microscopically and must be distinguished from melanoma. At scanning magnification, the cellular blue nevus exhibits a characteristic silhouette. In the upper portions of the dermis, the typical blue nevus architecture is evident: a broad-based proliferation of pigmented spindle cells forming a plate-like configuration. A narrow, bulbous proliferation of melanocytes projects from this, forming a well-circumscribed protrusion that emanates deeply into the dermis and occasionally the subcutis. This “dumb-bell” architecture is often a characteristic clue to the diagnosis of cellular blue nevus.
Higher-power examination reveals the pigmented spindled and dendritic melanocytes typical of a blue nevus and in addition, more cellular islands of larger spindle-shaped cells with pale to clear cytoplasm containing minimal—if any—pigment and large ovoid nuclei. As in the common blue nevus, melanophages are interspersed among the cells of the cellular blue nevus. However, the presence of pigmented spindle-shaped melanocytes and melanophages abutting aggregates of cells with clear cytoplasm imparts a “biphasic” quality that is the most characteristic pattern of a cellular blue nevus.
Although the dense cellularity of a cellular blue nevus may be worrisome for melanoma, reassuring features include minimal cytologic atypia, rare mitoses (none atypical) and the absence of tumor necrosis or epidermal ulceration. One may see in an atypical CBN isolated mitotic activity or focal necrosis without other features concerning for malignancy such as cell crowding, nuclear atypia, hyperchromasia, or expansile growth. If any of these other features are seen, then an assessment of the risk factors for this tumor must be made by the pathologist and clinician in order to make an adequate management plan.
It should be noted that perineural invasion and intralymphatic tumor are features of CBN and should not be used to distinguish CBN from a melanoma. Lymph node involvement in CBN is very rare and should raise concern. Features concerning for malignancy include tumoral necrosis, cytologic atypia and pleomorphism, and frequent mitoses (>2/mm2). Studies designed to arrive at a consensus of features distinguishing atypical CBN and malignant blue nevus have not produced reliable criteria.
Who is at Risk for Developing this Disease?
DBN are mostly acquired, rarely congenital, and may present at any age, although they are most commonly first noted in the first four decades of life. There is no gender preference for DBN.
CBN may be found at any age (range 6-to-85 years old) and may be present at birth, but are most commonly first noted in adults under 40-years-old. For reasons that are not clear, women are more likely than men to develop a CBN (2.2:1).
What is the Cause of the Disease?
Why a nevus takes on the clinical and microscopic appearance of a blue nevus rather than an "ordinary" nevus is not clear. The spindled nature of the cells in BN has given rise to the notion that they resemble immature melanocytes that migrated from the neural crest to the skin in embryogenesis and were somehow arrested in the dermis. Another possible theory states that these cells could be Schwann cells with a melanocytic differentiation, or a common neural crest cell that exhibits features of both Schwann cells and melanocyte lines.
Systemic Implications and Complications
A solitary BN typically has no systemic implications or complications. Regional lymph node involvement is very rare, though possible. As noted above, blue nevi can occur rarely in mucosal and extracutaneous sites.
Recurrent BN occur with some frequency with incompletely excised primary lesions. These often exhibit degenerative or "ancient change," and can display atypical features not seen in the primary lesion such as pleomorphism and mitotic activity. These recurrent nevi tend to follow a benign course; however, given the histologic features and the chance that recurrence could indicate malignant transformation, re-excision may be indicated in some cases.
There has been debate regarding the term "malignant blue nevus," which indicates a tumor with the features similar to a CBN that metastasized and resulted in patient death. Recently, the term "blue-nevus-like-melanoma" has been proposed as a replacement of this term to indicate that the growth is in fact a form of melanoma. A blue-nevus-like melanoma is often very deep in the skin and a mortality rate as high as 70% has been reported. Rare cases of melanoma arising in a CBN have also been reported. The melanoma cells arising in CBN have a different genetic profile than the surrounding CBN cells, in that they tend to harbor GNA11 mutations and demonstrate loss of BAP1. Melanoma associated with DBN is exceedingly rare.
Rarely, some patients may present with multiple BN, which are mostly DBN (
Bilateral blue nevi. (Courtesy of Bryan Anderson, MD)
|Medical Therapies||Physical Therapies||Surgical Therapies|
Optimal Therapeutic Approach for this Disease
Blue nevi are benign lesions and do not need to be excised if the diagnosis is clear. If there is a question about the diagnosis, an excisional biopsy attempting to remove the entire lesion could be considered. The melanocytes of a blue nevus are often quite deep and a shave biopsy may transect the lesion. Similarly, laser treatment would be unlikely to penetrate deeply enough into the skin to be effective.
Patients who present with a lesion that is clinically suspicious for BN should be counseled that these lesions are benign. In the majority of cases a biopsy will reveal a DBN, CBN, or a lesion with features of both types of BN. If a biopsy were to be performed, a complete excisional biopsy aimed towards establishing clear histologic margins would be recommended to prevent a recurrent nevus phenomenon and later confusion and concern for an evolving malignancy.
If the microscopic features of the biopsy are concerning, with tumoral necrosis, cellular atypia and pleomorphism, the presence of mitoses (>2/mm2), cell crowding, infiltrative growth pattern, expansile growth, or the presence of junctional activity (ie, pagetoid epidermal invasion), then an additional surgical procedure may be indicated. The role of sentinel lymph node biopsy in such a situation has not been clearly defined in patients with these confusing melanocytic lesions.
Unusual Clinical Scenarios to Consider in Patient Management
Amelanotic blue nevus is a rare variant that presents as a more hypopigmented variant and accounts for approximately 3% of all blue nevi. It has a similar age and sex distribution as BN and occurs at any body site. These lesions can be challenging to classify histologically and can be confused easily with a malignant process such as a desmoplastic melanoma. Careful review by an expert dermatopathologist is recommended.
Multiple BN may run in families. However, they may also occur in the setting of LAMB syndrome (Lentigines, Atrial and Mucocutaneous myxomas and multiple Blue nevi), or NAME syndrome (blue Nevi, Atrial myxomas, Myxoid neurofibromas, Ephelides). There is an additional variant of BN called an epithelioid blue nevus (EBN), which occurs in the Carney complex (myxomas, endocrine overactivity, spotty skin pigmentation, and psammomatous melanocytic schwannomas). EBN can also occur as an isolated lesion in children and adults.
What is the Evidence?
Gonzalez-Campora, R, Galera-Davidson, H, Vázquez-Ramírez, FJ, Díaz-Cano, S. "Blue nevus: classical types and new related entities. A differential diagnostic review". Pathol Res Pract. vol. 190. 1994. pp. 627-35.(An overview of the microscopic characteristics of blue nevi.)
Murali, R, McCarthy, SW, Scolyer, RA. "Blue nevi and related lesions: A review highlighting atypical and newly described variants, distinguishing features and diagnostic pitfalls". Adv Anat Pathol. vol. 16. 2009. pp. 365-82.(This article is a thorough review of blue nevi and associated lesions, focusing strongly on the histologic features and immunohistochemical profiles that distinguish these lesions from each other.)
Lee, HY, Na, SY, Son, YM, Kang, HK, Baek, JO, Lee, JR. "A malignant melanoma associated with a blue nevus of the lip". Ann Dermatol. vol. 22. 2010. pp. 119-24.(A case report of a probable blue-nevus-like melanoma that highlights that these lesions can present in unusual mucocutaneous locations as well as extracutaneous locations. The authors also review the controversy regarding the term "malignant blue nevus" and melanoma in association with a blue nevus.)
Zembowicz, A, Phadke, PA. "Blue nevi and variants: An update". Arch Pathol Lab Med. vol. 135. 2011. pp. 327-36.(A review of the histologic and immunohistochemical profiles of blue nevi and similar lesions, with a summary of recent investigations into the mutations and molecular markers present in blue nevi as compared with melanocytic nevi and melanoma.)
Costa, S, Byrne, M, Pissaloux, D, Haddad, V, Paindavoine, S, Thomas, L. "Melanomas Associated With Blue Nevi or Mimicking Cellular Blue Nevi: Clinical, Pathologic, and Molecular Study of 11 Cases Displaying a High Frequency of GNA11 Mutations, BAP1 Expression Loss, and a Predilection for the Scalp". Am J Surg Pathol. vol. 40. 2016 Mar. pp. 368-77.(A study investigating the genetic variations seen in cellular blue nevi and melanoma arising in/associated with blue nevi.)
Copyright © 2017, 2012 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
Sign Up for Free e-newsletters
Psychiatry Advisor Articles
- Triiodothyronine in the Treatment of Bipolar Depression
- Intranasal Oxytocin Reduces Negative Effects, Improves Cognitive Function in Schizophrenia
- E-Cigarettes Associated With More Harms Than Benefits at Population Level
- Examining Rates of Long-Term Opioid Use in Youth With Psychiatric Disorders
- Addressing Racial Disparities in Bipolar Disorder Treatment
- Suicide-Screening Toolkit Can Help Identify Youths at High Risk for Suicide
- Researchers Identify Novel Potential Biomarkers for Autism
- Agoraphobia: An Evolving Understanding of Definitions and Treatment
- Triiodothyronine in the Treatment of Bipolar Depression
- Parental Pressure to Diet Linked With Long-term Harm in Adolescents
- Virtual Reality-Based CBT Reduces Paranoid Ideation, Anxiety in Psychotic Disorders
- Supported Employment vs Transitional Work in Veterans With PTSD
- Comparing Pharmacologic Treatments for Prevention of Rehospitalization in BP
- Preliminary Evidence Suggests Suicidal Thinking Is Self-Reinforcing
- Lower Fluoxetine Efficacy in Elderly Patients With Major Depressive Disorder