Acral and Subungual Melanoma

General Comments

Melanocytic lesions of acral skin are at particular risk of being misdiagnosed for a variety of reasons. On the one hand, acral melanoma (AM) may have very subtle histologic features, particularly in the early in situ stage and at its periphery. Such lesions may not be diagnosed as melanoma by the unwary pathologist. Indeed, misdiagnosis and delayed treatment of AM represents a common cause of medicolegal action against dermatologists and pathologists. On the other hand, there is also risk for benign pigmented lesions to be misinterpreted as malignant. Acral nevi may, for example, display some pagetoid spread, a feature that is often associated with melanoma when it occurs at nonacral sites.

A major problem for the diagnostic assessment of acral pigmented lesions is the difficulty in performing biopsies on the plantar or palmer aspects of the hands, the web spaces, or the nail apparatus; this often limits optimal tissue sampling. Pathologists are commonly faced with the challenge of interpreting small biopsies that include only part of an acral pigmented lesion. As a consequence, some of the histologic features that are important for diagnosis (e.g., size, symmetry, circumscription) cannot be assessed. Because the pathologic diagnosis of any melanocytic tumor rests on balancing the presence and degree of a range of architectural and cytologic features as well as features of the host response and correlating this with clinical details, interpreting a partial biopsy of a melanocytic tumor can be particularly challenging at times, such challenges can preclude a definitive diagnosis unless solid evidence is obtained from ancillary studies or until the entire lesion has been examined.

With any partial biopsy, it is important to interpret the biopsy in the context of the clinical findings and particularly to consider whether the biopsy is representative of the lesion. For this reason, in a report of any partial biopsy of a melanocytic tumor, it is often appropriate for pathologists to state that careful clinical-pathologic correlation is necessary; if the pathologic features are not concordant with the clinical appearances, consideration should be given to performing a repeat biopsy.

Site-Specific Microanatomy of Volar Skin and Correlations With Dermoscopy

Special attention must be given to the unique histology of acral skin and the nail apparatus ( Figs. 14.1 and 14.2 ). Familiarity with the distinct microanatomic features will assist pathologists in assessing biopsies from these regions. The volar surfaces of acral skin on the palms and soles contain a thickened stratum corneum that forms dermatoglyphs: sinusoidal parallel patterns of ridges and sulci (furrows). The coiled intraepidermal ducts (acrosyringia) of eccrine glands emerge on the ridges (see Fig. 14.2 ). The epidermal rete pegs directly underlying the ridges are termed the cristae profunda intermediae (CPI), whereas the rete beneath the sulci is termed the cristae profunda limitans (CPL).

The dermatoglyphs are well visualized by dermoscopy, which forms an important part of the clinicopathologic workup of melanocytic lesions on acral skin. Although the two-dimensional technique of dermoscopy does not directly distinguish the slightly raised ridges from furrows by their elevation, it can discriminate ridges from furrows by size (ridges are usually wider than furrows) and the fact that the sweat gland openings are located in the centers of the ridges.

Two important dermoscopic findings suspicious for AM include the parallel ridge pattern, corresponding to melanin granules in the cornified layer over the CPI, and irregular diffuse pigmentation ( Fig. 14.3 ). In contrast, acral melanocytic nevi usually show parallel furrows of lattice-like or fibrillar patterns with pigment columns over the CPL ( Fig. 14.4 ). These pigmentation patterns do not always reflect the distribution of melanocytes. Although AMs show a preferential proliferation of melanocytes in the CPI, acral nevi can show melanocytes in both the CPI and CPL; however, only CPL melanocytes transfer their melanin granules to the upper epidermis in nevi.

Microanatomy of the Nail Apparatus

The nail apparatus is composed of the nail plate, the nail matrix, and the nail folds (see Fig. 14.1 ). The germinal matrix is located on the ventral floor beneath the proximal nail fold; it produces 90% of the nail plate. The proximal two-thirds of the matrix, delimited distally by the cuticle, contain the highest relative concentration of melanocytes. These melanocytes are predominantly dormant and are located suprabasally, between the second and the fourth layers of germinative epithelium. In contrast, the distal matrix contains both active and dormant melanocytes in the two basal layers. Normal nonneoplastic melanocytes are rare in the proximal nail fold and nail bed.

Melanonychia

Melanonychia is the term used to describe brown to black discoloration of the nail unit due to melanin pigment ( Fig. 14.5 ). Longitudinal melanonychia refers to the presence of a pigmented band in the nail plate. Melanonychia can result from melanocyte activation or proliferation. Active melanocytes, usually in the distal matrix, transfer melanosomes through their dendritic processes to differentiating onychocytes, thus producing increased pigmentation of the nail matrix and plate. Melanocytes can be activated by diverse etiologic processes including pregnancy, drugs, and local and systemic diseases. Melanocyte proliferation manifests as increased densitey of melanocytes in the matrix, as seen in lentigines, nevi, and melanomas. The digit involved, age of the patient, width of the band, the number of colors, destructive changes to the nail plate, and the presence or absence of the Hutchinson sign are parameters used by clinicians to assess the probability of a melanoma being the cause of melanonychia.

Dermoscopy is useful for investigating the cause of melanonychia. Dermoscopy of the free edge of the nail plate can determine whether longitudinal melanonychia is present in the ventral nail plate and thus originates from the distal matrix or whether the pigmented band is in the dorsal nail plate and originates in the proximal matrix.

Clinical Findings

As at other sites, AM may manifest as a pigmented or amelanotic lesion. The clinical diagnosis of amelanotic lesions is particularly challenging. Pigmented AMs typically manifest as flat dark macules. Most lesions slowly enlarge, displaying irregular borders. By the time a lesion comes to medical attention and is biopsied, it is often already relatively large. Although a completely flat lesion may be found to be associated with invasive melanoma, invasion is more likely to be found when a papule, nodule, or ulcer develops within a pigmented patch of macule. Most AMs develop de novo, but a minor subset arises in association with a melanocytic nevus.

There are diagnostically useful dermoscopic clues unique to volar skin (see Fig. 14.3 ). An irregular pigmented macule or patch on acral skin with a history of a recently appearing and darkening or peripherally expanding pigmentation in an adult patient, particularly an elderly patient, is very suspicious for melanoma.

The clinical diagnosis of subungual melanomas may be obvious, especially if the periungual acral skin is already involved ( Fig. 14.6 ) or melanonychia is irregular and pigment extends proximally to the cuticle and peripherally or distally to periungual skin (positive Hutchinson's sign) ( Fig. 14.7 ). However, the diagnosis can be very difficult for melanoma in situ in its early evolving stage, when it may present as relatively discrete longitudinal melanonychia or as an amelanotic nail change. For pigmented nail lesions, especially for the assessment of the significance of longitudinal melanonychia, dermoscopy is also of great value. Three main dermoscopic findings favoring melanoma over benign pigmented lesions include brown coloration of the background, the presence of irregular longitudinal lines, and the micro-Hutchinson sign (cuticular pigmentation not visible by naked eye examination).

AM probably has a similar incidence among different ethnicities. AM is the most frequent subtype of melanoma in Asian, African, and Hispanic people due to a low incidence of cutaneous melanoma in nonacral sites. Patients with AM tend to be older than those with superficial spreading melanoma (mean age 63 years). A difference in gender prevalence has not been consistently reported. Eighty percent of AMs affect the foot. These lesions most commonly originate on the heel and least often on the palm. Subungual melanoma comprises 20% to 30% of AMs and is more commonly found in the fingernails as opposed to the toenails; lesions on the thumb and great toe are more frequent than those in other nail units.

Amelanotic melanomas can arise at acral and subungual sites as nodular melanomas and are often associated with diagnostic delay because the possibility of melanoma is not considered clinically.

The etiology of AM remains largely unknown. In contrast to cutaneous melanoma, ultraviolet light exposure and total body nevus counts are not associated with an increased risk of AM. There does appear to be a relationship between (micro) trauma and the development of AM, as evidenced by the preferential involvement of trauma-prone sites: weight-bearing areas of the foot, thumb, and great toe nail units and right-sided versus left-sided fingernails.

Pathologic Findings

Melanoma of Volar Skin (Palmar or Plantar Melanoma)

A predominant lentiginous growth pattern is typical and most commonly found in AMs of volar skin ( Fig. 14.8 ). A pagetoid and nested growth (features of superficial spreading melanoma) may also be found at acral sites ( Fig. 14.9 ), especially in melanomas arising in association with acral melanocytic nevi or at the dorsa of the hands and feet. Some AMs are nodular melanomas with no or only a very small in situ component confined to an area overlying the invasive tumor nodule. Some lesions may display unusual features (e.g., spitzoid, blue nevus–like, sarcomatoid, and others).

In acral lentiginous melanomas there is a (usually broad) proliferation of solitary units of melanocytes along the dermoepidermal junction (see Fig. 14.9 ). The density of melanocytes may be quite variable within a large lesion usually (higher centrally than peripherally). In more cellular areas, nests and/or pagetoid spread may be seen ( Fig. 14.10 ). How many melanocytes are present also depends on the evolution of the neoplasm. During the early evolving stage of an AM in situ, lesional melanocytes are often nonconfluent. A definitive diagnosis may then not be possible on histologic grounds alone unless prominent cytologic atypia is present ( Fig. 14.11 ). As the pathology progresses, there is an increase in cell density, and junctional melanocytes may become confluent. Extension of melanoma in situ into sweat ducts, sometimes all the way down to sweat glands, may occur ( Fig. 14.12 ). A lichenoid lymphocytic infiltrate is found in approximately 50% of cases and can be a helpful diagnostic sign ( Fig. 14.13 ).

The cytology of early evolving lesions of acral lentiginous melanoma can be subtle, with just a slight increase in junctional melanocyte density in spite of a clinical picture strongly suggestive of melanoma. More developed lesions usually display cytologic atypia. Melanocytes are often enlarged. Their nuclei may be hyperchromatic or contain nucleoli. Nests of irregular size, shape, and distribution may be present and become confluent in the late stages of in situ disease. On occasion, particularly elderly patients, an in situ melanoma of acral skin may display a prominent nested (“dysplastic” nevus–like) growth pattern at the dermoepidermal junction ( Fig. 14.14 ).

Melanoma in situ expands radially as an enlarging macule, often for years, before foci of invasion develop. These can be irregular and show skip areas, highlighting the importance of adequate biopsies and pathologic examination of multiple levels from small biopsies. Invasive disease can present with an epithelioid or spindled morphology, including a desmoplastic variant. The invasive tumor may form dense solid aggregates ( Fig. 14.15 ) or invade in a single-cell pattern ( Fig. 14.16 ). In some lesions, particularly in elderly patients and subungual lesions, invasive melanoma may display some nevoid features ( Fig. 14.17 ). Tumors may be pigmented or amelanotic.