A brown macule on the arm and face

Case #1: MelanomaMelanoma is a complex, heterogeneous cancer that is commonly cutaneous in origin.1,2 In 2014, there were an estimated 1.1 million people living with cutaneous melanoma in the United States, with a higher prevalence in men compared with women.3...

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Case #1: Melanoma

Melanoma is a complex, heterogeneous cancer that is commonly cutaneous in origin.^1,2 In 2014, there were an estimated 1.1 million people living with cutaneous melanoma in the United States, with a higher prevalence in men compared with women.³ Signified by the transformation of melanocytes (specialized pigmented cells predominantly found in the basal layer of the epidermis) to tumor cells, primary melanoma has a complex pathogenesis.¹ Genetic and environmental factors, specifically ultraviolet radiation, characterizes the etiology of the disease, as well as highlights risk factors for disease development.^1,4 Notably, the strongest independent risk factors—increased number of common melanocytic nevi, presence of atypical melanocytic nevi, and presence of solar lentigines (SLs)—reflect both genetic susceptibility and environmental exposure.²

Because early recognition is critical to improving survival, several initiatives have been utilized to improve public awareness on the evaluation of pigmented lesions. The ABCDE acronym (Asymmetry, Border irregularity, Color variegation, Diameter, and Evolving lesions) highlights typical features, though not all melanomas present with all 5 characteristics.^1,2 Clinical diagnosis can be augmented by the use of dermoscopy or skin surface microscopy, which increases clinical diagnostic sensitivity.² Skin biopsy, however, remains the standard practice for diagnosing cutaneous melanoma.

It is thought that melanomas progress through 2 phases. The radial growth phase, characterized by horizontal and infiltrative spread of melanocytes, is not considered to have metastatic potential, whereas the vertical growth phase—the presence of dermal nests of large, atypical melanocytes—does have metastatic capacity.^1,2 The 4 major subtypes of cutaneous melanoma, based on the histologic patterns of the early, radial growth phase, include (1) superficial spreading melanoma (SSM), (2) nodular melanoma, (3) lentigo maligna melanoma (LMM), and (4) acral lentiginous melanoma (ALM).²

SSM is the most common subtype of cutaneous melanoma, and is responsible for the highest proportion of fatal melanomas.^2,5 Usually, SSM begins as an asymptomatic macule distinguished by color variations, irregular borders, and a predominant radial growth phase. It is most frequently found on the trunks of men and the legs of women.^2,5 Pagetoid and nested epithelioid cells in the intraepidermal portion typify the histological characteristics of SSM.¹

Nodular melanoma is the second most common subtype of cutaneous melanoma. Lesions tend to be more varied in color, ranging from pink-red to blue-black, and present clinically as firm papules or nodules, commonly associated with ulceration.⁶ Though nodular melanomas can occur at any body site, they tend to have a predilection to sun-exposed areas such as the head and neck. Histologically, nodular melanoma lacks significant intraepidermal tumor cells beyond the edges of the dermal component.^2,6

LMM occurs in chronically sun-damaged skin, commonly on the face, particularly the nose and cheek. LMM presents as a gradually enlarging tumor that is flat and multipigmented.¹ It tends to occur much later in life (most commonly the seventh decade) due to its requisite for cumulative sun exposure.^2,7 Histologically, tumor cells show a lentiginous spread. The presence of a sun-damaged background, demonstrated by epidermal atrophy, solar elastosis, and dermal thinning, distinguishes LMM from the other subtypes.^1,2

ALM is one of the least common subtypes of cutaneous melanoma. Clinically, it presents as an asymmetric, brown to black macule with color variation and irregular borders.¹ ALM typically occurs on hairless areas such as the palms and soles, distinguishing it from the other subtypes. Diffuse lentiginous proliferation of tumor cells along the basal layer characterize early histologic findings.²

A few differential diagnoses (divided into melanocytic and nonmelanocytic) to consider when considering melanoma include SL, atypical nevus, seborrheic keratosis (SK), and pigmented basal cell carcinoma (BCC). Because these cutaneous lesions share many of the same clinical features as melanoma, dermoscopy or skin biopsy are usually needed to aid in diagnosis.^1,2 Dermoscopy is particularly useful in distinguishing melanocytic lesions—characterized by the presence of a pigmented network, streaks, aggregated globules, homogenous blue pigment, or parallel pattern—from nonmelanocytic ones.²

An SL, a melanocytic lesion, presents as a tan or brown macule on sun-exposed areas of the skin. Under the dermoscope, an SL can display diffuse brown pigmentation, fingerprint-like structures, and a fine regular network.² Biopsy results of an SL demonstrate basilar hyperpigmentation of keratinocytes with a possibly mild increase in the number of melanocytes.⁸

An atypical nevus, distinguished by asymmetrical borders, large size, or varied coloration, is a benign melanocytic lesion. Clinically, an atypical nevus may fulfill many of the features highlighted by the ABCDE acronym. Atypical nevi also manifest the histologic atypia seen in melanoma. Though there is significant overlap between the 2, atypical nevi are distinguished by their general stability in size and color.^9,10

SK is characterized by a waxy, “stuck-on,” verrucous-appearing papule or plaque. It is a nonmelanocytic lesion, and thus dermoscopic analysis assists in distinguishing an SK from a melanoma. However, any dark or atypical appearing SK should be biopsied to confirm the diagnosis.²

BCC is a neoplasm of basal keratinocytes with several subtypes, one of which is pigmented BCC. Described as blue, brown, or black papules or nodules with border irregularities and possible color variegation, pigmented BCCs clinically resemble melanomas. Dermoscopy can aid in differentiating the two since pigmented BCCs lack melanocytic features, such as the pigmented network. Biopsy results formally confirm diagnosis.¹¹

If a patient comes into the clinic with a lesion suspected of being melanoma, the patient should be referred to a dermatologist for a skin biopsy. Biopsy results can confirm the diagnosis of melanoma, and can aid in the prognosis and management of the patient.

Due to the possible role of ultraviolet (UV) light, the United States Preventative Services Task Force recommends that primary care physicians counsel patients on sun-protective strategies, including the regular use of sunscreen.^1,2,4 Secondary prevention involves early detection because late stages, characterized by increased thickness and evidence of ulceration, are associated with poorer prognosis.¹ Treatment of melanoma largely revolves around surgical excision with increasing margins for increasing tumor thickness.² Depending on the stage of the melanoma and if metastases, patients may also be treated with chemotherapy and other biologic therapies. Further understanding of the genetic factors underlying disease pathogenesis, including the mitogen-activated protein kinase (MAPK), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and programmed death 1 (PD-1) pathways, has allowed for the development of targeted biologic therapies.¹² Close clinical surveillance of patients after diagnosis of melanoma is imperative, as patients are at risk for local or systemic recurrences and second primary melanomas.² Patients diagnosed with melanoma should have a skin check every 3 months after their diagnosis for 1 to 2 years. If no other concerning lesions arise within the first 2 years of melanoma diagnosis, skin checks can be performed every 6 months.

A biopsy of the lesion on the patient in this vignette was performed, and a diagnosis of SSM was confirmed. Due to the depth of invasion into the dermis, the patient was referred to a surgical oncologist for sentinel node biopsy and treatment. He is now in remission.

Case #2: Solar lentigo

Approximately 90% of the white population older than 60 years have SLs. Though mainly observed in the white population, SLs can also occur in people of other ethnicities.^13,14 Lentigines usually appear later in life on chronic sun-exposed skin. The association with age and sun damage is well reflected in the different names used for SLs, including age spots, lentigo senilis, sun-induced freckles, and sunburn freckles.¹⁴ However, it is important to note that SL can also be seen in younger individuals with extensive UV radiation (UVR) exposure, as well as in young children with certain genetic conditions (specifically xeroderma pigmentosum).¹³

Ranging in color from tan to dark brown to black, SLs are well-circumscribed, round, oval, or irregularly shaped macules that vary from 3 mm to 2 cm in diameter.¹³ As stated above, SLs have a predilection for sun-exposed areas, and are commonly found on the dorsal aspects of hands and forearms, the face, the upper chest, and the back.¹⁵ The pathogenesis of SLs is in line with a history of chronic UVR exposure; in response to UV stress, a cytokine cascade results in fibroblast proliferation, causing epidermal hyperplasia, and an increased production of melanosomes by melanocytes, which are subsequently transferred to neighboring keratinocytes. It is this complex interplay among cytokines, melanocytes, keratinocytes, and fibroblasts that ultimately manifests as an SL.^16,17 Further studies have also highlighted a genetic component (variants in the melanocortin-1 receptor gene and mutations in FGFR3 and PIK3CA) in the pathogenesis of SL.^15,17

Due to their evolving nature and association with sun exposure, further evidence is sometimes needed to confirm the diagnosis, and, more importantly, to rule out cutaneous malignancy. Dermoscopy, or skin surface microscopy, is commonly employed. Dermoscopic evaluation of SL reveals features of a benign, melanocytic lesion: diffuse opaque-brown pigmentation, sharply demarcated borders, fingerprinting, and a reticular network of thin lines.^13,18 A more invasive approach, skin biopsy, is used if uncertainty remains in the diagnosis. Histologic features of SLs show a hyperpigmented basal layer and elongated epidermal ridges, forming a reticulated pattern.¹³ In some cases, there may be an increase in melanocyte number. Other findings include presence of melanophages and mild lymphocytic infiltrate in the superficial dermis.¹³

Several conditions may mimic solar lentigines. Some differential diagnoses to consider include lentigo simplex, macular SK, melanocytic nevus, ephelides, and melanoma.

Lentigo simplex appears clinically similar; lesions are described as being homogenous pigmented macules, ranging from light brown to black, that are well circumscribed with regular borders.¹³ Lentigo simplex lesions, however, tend to be much smaller (usually <5 mm) and can be found anywhere on the skin, including mucous membranes and palmoplantar surfaces.

Clinically, it may be difficult to distinguish macular SK from SL, and many believe these lesions to be on the same continuum. Dermoscopy is particularly helpful because SKs lack melanocytic features, such as a pigmented network, which is found in SLs. In addition, SKs have distinguishing features, such as comedo-like openings and fissures, which are linear, keratin-filled depressions.^18,19 A skin biopsy demonstrating a keratotic surface with horn cysts is consistent with SK.¹³

Melanocytic nevi are well-demarcated, symmetric, round to oval lesions that are not limited to sun-exposed skin. There are three forms of melanocytic nevi: junctional, dermal, and compound. These distinctions are based on the location of melanocytic nests in the epidermis, dermis, or both, respectfully.^13,20 Clinically, junctional nevi are flat, whereas dermal and compound nevi are papular. Dermoscopic evaluation reveals melanocytic findings, such as a globular architecture.^13,20

Ephelides, also commonly known as freckles, are well-demarcated, round, oval, or irregularly shaped lesions found only on sun-exposed areas. In contrast to Sls, ephelides appear in early childhood and usually fade with reduced UVR exposure. Dermoscopic features include uniform pigmentation and moth-eaten edges.¹⁷

Melanoma is a malignant cancer signified by the transformation of melanocytes—specialized pigmented cells predominantly found in the basal layer of the epidermis—to tumor cells. The SSM and LMM subtypes clinically resemble SLs. Melanomas tend to be larger and asymmetrical with irregular pigmentation and color variegation. Biopsy is usually needed and reveals a lentiginous spread of tumor cells with a sun-damaged background, demonstrated by epidermal atrophy, solar elastosis, and dermal thinning.^1,2

SLs are benign lesions, though their presence does indicate chronic UV exposure, a risk factor for the development of cutaneous malignancies. As such, preventative measures to limit sun exposure, such as the regular use of sunscreen and protective clothing, should be encouraged. If patients do want to pursue treatment, laser therapy and cryotherapy are first-line management strategies.²¹

The patient in this vignette was advised that her lesion was benign. Due to her concern, the lesion was biopsied and the diagnosis of SL was confirmed. She was advised that no further treatment was necessary.

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Pooja Reddy, is a medical student at the Baylor College of Medicine, and Christopher Rizk, MD, is a dermatology resident at the Baylor College of Medicine in Houston.

References

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