Amelanotic melanoma (AM) is a rare form of cutaneous melanoma that lacks melanin. Clinically identifying AM is challenging, as it can resemble other neoplasms or inflammatory conditions of the skin (Stojkovic-Filipovic & Kittler, 2014). Because of a delay in diagnosis, AM often presents at a more advanced stage compared with the classic, pigmented melanoma (Muinonen-Martin et al., 2018). There are four subtypes of cutaneous melanoma, namely, superficial spreading, nodular, lentigo maligna, and acral lentiginous; any subtype of melanoma can be amelanotic (Kaizer-Salk et al., 2018). Approximately 2%-8% of all melanomas are amelanotic, although the actual prevalence may be higher because of underrecognition or misdiagnosis (Koch & Lange, 2000).

PATHOGENESIS

The pathophysiology of AM is related to chronic accumulation of sun damage, similar to pigmented melanoma (Wee et al., 2018). The complete mechanism of amelanosis is still not completely understood. What is known is that AM cells are able to maintain their melanocytic lineage and melanin-forming ability, contradicting previous hypotheses that the cells are de-differentiated or poorly differentiated (Chacon et al., 2020). If this is true, a decrease in tyrosinase or another melanin-forming enzyme activity may be responsible.

A family history is present in 7%-15% of melanomas. A subset of these patients have a germline mutation that predisposes them to melanoma (Toussi et al., 2020). Germline mutations in the melanocortin-1 receptor (MC1R) gene, melanocyte inducing transcription factor, and ARF tumor suppressor have been proposed to play a role. MC1R is a G-protein-coupled receptor for melanocyte-stimulating hormone that controls melanogenesis, which contributes to skin and hair color (Massi et al., 2013). Many patients with AM reportedly carry MC1R connected to red hair color. Melanocyte inducing transcription factor is a melanocytic lineage-specific transcription factor that regulates differentiation, proliferation, and survival of melanocytes. ARF tumor suppressor protein is encoded by the cyclin-dependent kinase inhibitor 2A gene and regulates the cell cycle through inhibiting p53 ubiquitination (Toussi et al., 2020). In one analysis, target mutations for BRAFV600E and proto-oncogene receptor tyrosine kinase were present at a rate of 70.3% and 12.1%, respectively (Massi et al., 2013).

DEMOGRAPHICS

AM is typically seen in older individuals with sun-damaged skin and located in areas of chronic sun exposure (Stojkovic-Filipovic & Kittler, 2014). It has been reported that AM is more common in women, although reports vary on gender predominance (McClain et al., 2012; Thomas et al., 2014).

CLINICAL FEATURES

AM has many nonspecific presentations, which makes diagnosis challenging. It may present clinically as an erythematous macule or patch or as a skin-colored nodule with or without ulceration (Figure 1; Stojkovic-Filipovic & Kittler, 2014). Evolution occurs over weeks to months (Muinonen-Martin et al., 2018). Common locations for melanoma include, but are not limited to, the head, neck, trunk, and lower limbs; however, for AM, there is no preponderance for a specific location on the body (Figure 2; Pampena et al., 2020; Thomas et al., 2014). In acral lesions, there may be pigmented macules in the periphery and change may occur very slowly.

FIGURE 1. Amelanotic melanoma presenting clinically as a pink asymmetrical macule with irregular borders. Photo courtesy of Maral Skelsey, MD, Dermatologic Surgery Center of Washington. Used with permission.

FIGURE 2. Amelanotic melanoma presenting as a pink bland papule on the scalp. Photo courtesy of Sylvana Brickley, MSN, FNP-BC, DCNP. Used with permission.

Nodular and superficial spreading melanomas are the most common subtypes of AM (Paolino et al., 2020). Other subtypes include melanoma in situ, lentigo maligna, desmoplastic, nevoid, lentiginous, spitzoid, and angiomatoid. Nodular melanoma is commonly found in men older than 50 years old and present on the head and neck (Kalkhoran et al., 2010). The age cohort of the nodular subtype is significantly higher than the superficial spreading subtype (Warycha et al., 2008). In addition, the nodular variant tends to be smaller in diameter, presents with regular borders and elevation, and grows faster in comparison with the superficial spreading subtype (Kalkhoran et al., 2010, Stojkovic-Filipovic & Kittler, 2014).

Although the ABCDE criteria is a useful tool to screen for a pigmented melanoma, where classic signs of asymmetry, irregular border, two or more colors, diameter over 6 mm, and evolution are present, these criteria do not adequately apply to amelanotic lesions. For instance, AM tends to be red or skin colored rather than black, blue, or dark brown. The nodular type of AM tends to be more symmetric (Figures 2 and 3). With so much attention focused on irregularities, particularly in shape and color, clinicians may overlook uniform and nonpigmented lesions as reassuring or nonsuspicious (McClain et al., 2012). In addition, AM more commonly presents as a papule as compared with pigmented melanomas (Klebanov et al., 2019). An addition of EFG (elevation, firmness, progressive growth for over 1 month) to the ABCDE criteria has been suggested to provide a more comprehensive assessment such that amelanotic lesions will less likely be missed (Garcia-Lozano et al., 2019). Clinical features alone are not sufficient in correctly diagnosing melanoma, as it is often misdiagnosed as an amelanotic benign melanocytic lesion (Pizzichetta et al., 2004).

FIGURE 3. Amelanotic melanoma presenting clinically as a pink bland papule. Photo courtesy of Maral Skelsey, MD, Dermatologic Surgery Center of Washington. Used with permission.

DERMOSCOPY

Dermoscopy is a noninvasive technique that improves the detection of pigmented and nonpigmented skin lesions compared with the naked eye (Stojkovic-Filipovic & Kittler, 2014). Dermoscopic diagnosis of melanoma has higher sensitivity and specificity in comparison with a clinical diagnosis (Pizzichetta et al., 2004).

AM may show vascular patterns, scar-like depigmentation, and/or ulceration on dermoscopy. Accuracy of the dermoscopic findings relies on the proficiency and technique of the clinician, as applying too much pressure during an examination can distort the vascular appearance (Kaizer-Salk et al., 2018).

AM cannot be definitively diagnosed via dermoscopy, as dotted vessels, hairpin vessels, and milky-red areas have been found in benign lesions like seborrheic keratoses and nevi as well as pigmented melanomas (Pizzichetta et al., 2004). However, awareness of the many and nonspecific features of AM on dermoscopy is still vital for clinicians. On dermoscopy of flat AM, vessels may look like red pinpoint dots, whereas in nodular AM, vessels may appear linear with or without red dots. Nodular lesions are more commonly found than macular lesions. Other terminologies used to describe the vasculature's appearance under dermoscopy are "hairpin," "coils," and "loops" (Stojkovic-Filipovic & Kittler, 2014). Milky-red areas have also been described (Figure 4; Pampena et al., 2020). Despite the nonspecific features of AM on dermoscopy, dotted and linear vessels have been reported to be the most predictive dermatoscopic vascular features, whereas "comma-like" vessels are less associated with AM (Figure 5). In addition, linear vessels have been associated with more advanced diseases. A centrally predominant vascular arrangement on dermatoscopy is more predictive for AM than a linear arrangement. However, nodular AM lacks a specific vascular distribution. Hairpin vessels have also been observed in primary metastatic AM (Kaizer-Salk et al., 2018).

FIGURE 4. Dermoscopy of amelanotic melanoma featuring shiny white lines, milky red areas, and dotted vessels. Photo courtesy of Maral Skelsey, MD, Dermatologic Surgery Center of Washington. Used with permission.

FIGURE 5. Dermoscopy of amelanotic melanoma featuring shiny white lines, dotted vessels, and linear vessels. Photo courtesy of Maral Skelsey, MD, Dermatologic Surgery Center of Washington. Used with permission.

Scar-like depigmentation and shiny white lines are nonspecific dermatoscopic findings of AM. Also seen in Spitz nevi, areas of depigmentation are formed from white reticular lines (Kaizer-Salk et al., 2018). Ulceration is found more often in thicker than thinner AM.

On dermoscopy, nodular and superficial AMs have been characterized by a blue-white veil, structureless areas with the presence of hairpin vessels, dotted vessels, and milky-red areas (Kalkhoran et al., 2010). The presence of these structures may differentiate AM from other amelanotic benign lesions (Pizzichetta et al., 2004). The vascular structures discussed are all more common in nodular than superficial subtypes (Ciudad-Blanco et al., 2014). Typical features of pigmented melanoma, such as atypical and negative pigment networks, radial streaming, pseudopods, irregular blotches, atypical dots, and globules, are absent in AM (Kalkhoran et al., 2010).

DIFFERENTIAL DIAGNOSIS

AM can resemble malignant neoplasms, such as basal cell carcinoma and squamous cell carcinoma (Muinonen-Martin et al., 2018), as well as benign growths, such as nevi, hemangiomas, and seborrheic keratoses (Kaizer-Salk et al., 2018). AM can also mimic inflammatory skin conditions, such as eczema, psoriasis, rosacea, and contact dermatitis (Kaizer-Salk et al., 2018).

HISTOPATHOLOGY

Diagnosis of AM is established through histopathology, which shows nests of large, irregularly shaped and spaced melanocytes, hyperchromatic and pleomorphic nuclei, and pigmented cytoplasms (Silva et al., 2019). Melanoma is known for its diverse histopathological presentation, mimicking Ewing sarcoma, rhabdomyosarcoma, chondrosarcoma, or small cell carcinoma (Shetty et al., 2014). Immunohistochemistry is often required for distinction. AM expresses positive staining for HMB45 and S-100, confirming that it is indeed a melanoma. In general, AM tend to be thicker at the time of presentation (Breslow thickness > 1.0 mm) and has a higher mitotic rate compared with pigmented melanoma, which coincides with a worse prognosis (Paolino et al., 2020).

PROGNOSIS

Prognosis relies on pathologic staging assessed through Breslow tumor thickness, nodal status, and metastasis (Silva et al., 2019). Because of nonspecific clinical appearance that impedes timely diagnosis, AM is typically diagnosed at a late stage, so prognosis is usually worse when compared with pigmented melanoma (Stojkovic-Filipovic & Kittler, 2014). For that same reason, metastasis is seen more frequently with AM (Muinonen-Martin et al. 2018). The mortality rate of metastatic disease is high despite improvements in treatment options. Once the stage has been accounted for, the survival disparity is not significantly different when compared with pigmented melanoma.

TREATMENT

Once the diagnosis is confirmed through histology, a wide local excision of the primary tumor is necessary, which is usually performed by a board-certified dermatologic surgeon, plastic surgeon, or surgical oncologist. Wide local excision of primary tumors is recommended with margins of 0.5 cm for in-situ melanomas, 1 cm for tumors with a thickness of up to 2 mm, and 2 cm for thicker tumors (Michielin et al., 2019). AM with >0.8-mm Breslow depth or <0.8 mm with ulceration requires a sentinel lymph node biopsy for precise staging (Michielin et al., 2019). When elected, sentinel lymph node biopsy should be performed concomitantly with wide local excision whenever possible to minimize morbidity (Gannon et al., 2006). Adjuvant therapies, such as chemotherapy, radiation, and immunotherapy, may be considered by oncology in patients with high-risk primary melanoma or completely resected lymph node metastases (Michielin et al., 2019).

PREVENTION

Sunburn avoidance offers the most protection for preventing future development of a melanoma, especially in Fitzpatrick phototype 1 individuals. Other highly recommended methods of sun protection include application of sunscreen with at least SPF 30+, sun-protective clothing, shade-seeking, and avoidance of sun between the hours of 10 a.m. and 2 p.m. Patients with a previously diagnosed melanoma should be closely followed with full skin examination and physical lymph node examination. One recommended schedule for full skin examination and lymph node examination is every 3 months for 3 years from the original melanoma diagnosis, then every 6 months for up to 5 years after diagnosis, and then every year indefinitely (Rueth et al., 2015).

AM is a rare type of melanoma that may often be overlooked on clinical examination because of its lack of pigment, leading to detection at later stages and subsequent poorer prognosis. There are germline mutations associated with AM, which indicates a hereditary component. Among the most common subtypes of AM includes nodular and superficial spreading. Diagnosis can be completed through a combination of clinical presentation, dermoscopy, and histological analysis. Prognosis is usually poor given the stage at the time of presentation. Being able to recognize and identify AM correctly is crucial to early detection and improved patient survival.

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