Acral lentiginous melanoma (ALM), first described by Reed et al. in 1976, is a histopathologic subtype of cutaneous melanoma (CM) that arises on the palms, soles, or within the nail apparatus 1. Although ALM represents only a small percentage of all CMs in populations predominantly of European descent, it is the most common subtype in most Latin American, African, and Asian countries, where other histopathologic variants are markedly underrepresented 2. The fact that these slow-growing tumors often develop in “hidden” locations and remain clinically subtle during their early stages hinders early clinical detection, likely contributing to their poorer overall prognosis compared to other CM subtypes 2-4. Not only that, but early histopathologic diagnosis of ALM is particularly challenging. In this sense, excisional biopsy—the gold standard for histopathological evaluation of melanocytic neoplasms—is often not performed at the initial assessment of ALM due to the large lesion size at presentation and the anatomic peculiarities of acral skin, which can limit primary closure even for relatively small lesions 3. Consequently, pathologists frequently receive partial samples from slow-growing tumors that, despite their sometimes large size, may still be in situ, with no clear evidence of invasion. Likewise, the diagnosis of early ALM often relies on subtle histopathologic features, particularly a paucicellular proliferation of nearly typical melanocytes along the epidermal basal layer. Therefore, definitive diagnosis must be based on a close correlation of clinical and dermatoscopic findings 5. Otherwise, because these microscopic findings may be insufficient for the pathologist to confidently render a diagnosis of melanoma, misinterpretation of such subtle features may lead to insufficient or inappropriate management under ambiguous diagnostic labels such as “atypical melanosis” 5, 6. As a result, diagnostic delay in this context can lead to more complex reconstructive procedures, increased morbidity, long-term disability, and higher healthcare costs. Furthermore, prognosis in patients progressing to advanced stages (III–IV) may be severely affected by two main factors: (1) the low prevalence of BRAF mutations (approximately 15%–21%) in acral CMs 7, which limits first-line therapeutic options to immunotherapy; and (2) the lower effectiveness of both anti-PD-1 monotherapy and combined anti-CTLA-4/anti-PD-1 therapy in acral CM, with lower response rates, progression-free survival, and overall survival compared with other CM subtypes, probably due to a lower mutational burden 8. Given these challenges, promoting early diagnostic strategies and clarifying certain clinico-dermatoscopic and histopathologic concepts are of utmost importance in the specific management of ALM. The aim of this article is to highlight the need for multidisciplinary collaboration in the diagnosis of very early ALMs, in which histopathologic criteria alone may be insufficient for non-expert pathologists and could lead to misdiagnosis. To this end, we present two illustrative cases of early ALM of the hands, in which multidisciplinary evaluation was essential to reach a final diagnosis, and we review additional diagnostic clues described in the literature that may be useful in similar cases. A 52-year-old woman with skin type IV presented with a slowly but continuously enlarging pigmented lesion, 11 mm in diameter, on the second finger of her right hand, which had been present for at least 2 years (Figure 1A1). Dermatoscopic examination revealed irregular diffuse pigmentation and a parallel ridge pattern (PRP) (Figure 1A2). Histopathologic evaluation of an initial incisional biopsy demonstrated a mild, non-continuous proliferation of melanocytes without atypia, associated with keratinocyte hyperpigmentation and dermal melanophages. Because of clinicopathologic discrepancies and the absence of definitive histopathologic evidence of malignancy, the lesion was completely excised. The excision specimen showed a paucicellular lentiginous proliferation of melanocytes without significant cytologic atypia (Figure 1B–D). HMB-45 immunostaining revealed partial confluence of this proliferation, and “Preferentially Expressed Antigen in Melanoma” (PRAME) staining was positive (Figure 1E–G). Based on the combined clinical, dermatoscopic, histopathologic, and immunohistochemical findings, a final diagnosis of early in situ ALM was established, and wide local excision was performed. A 55-year-old woman, also with skin type IV, presented with a slowly enlarging pigmented lesion, 7 mm in diameter, on her left thumb (Figure 2A1). Dermatoscopy revealed a clear-cut PRP (Figure 2A2), prompting direct excisional biopsy. Hematoxylin and eosin (H p = 0.001) and previous punch biopsy (OR 6.06, 95% CI 1.95, 18.86; p = 0.013) have been associated with diagnostic change 14. From a clinical standpoint, we must start from two key concepts: those acquired acral pigmented lesions that are (1) larger than 7 mm and/or (2) that appear in patients older than 50 years should be interpreted in the first instance as a possible ALM 16. Moreover, the advent of dermatoscopy has been a turning point in the early detection of ALM. The so-called PRP is the cornerstone of dermatoscopic diagnosis of ALM, achieving 99–100% specificity compared to acral nevi 17, 18. Histopathologically, the PRP corresponds to a band-like pigmentation on the ridges of the skin markings, resulting from preferential proliferation of melanocytes along the crista profunda intermedia, located immediately beneath the ridges 19. It is worth noting that this pattern has also been described in single-cell lentiginous melanocytic proliferations previously categorized as AMOF 12, 20, and more rarely in drug-induced pigmentation, subcorneal hemorrhage, or Laugier–Hunziker syndrome 21. However, Saida et al. 18 identified this pattern in only 6 of 609 (1.0%) acral nevi, reinforcing from a clinico-dermatoscopic perspective the view that such incipient lesions represent the earliest histologic stage of ALM. In addition, several ancillary techniques (immunohistochemistry and molecular tests) can aid pathologic diagnosis. A recent single-center cohort study by Zheng et al. 22, analyzing 122 acral specimens, reported a sensitivity of 72.5% and a specificity of 97.4% for PRAME positivity in in situ acral melanomas. When combined PRAME-positive/p16-negative status was used, specificity reached 100%, albeit with lower sensitivity (22.5%). The diagnostic utility of PRAME immunostaining and p16 loss in differentiating acral melanocytic lesions has also been highlighted in previous studies 23, 24. Finally, amplification of cyclin D1 (CCND1), detectable by fluorescence in situ hybridization (FISH), can be detected even at a very early progression phase of ALM 25. In fact, Ogata et al. found FISH positivity in 4/5 (80%) acral lesions analogous to these two cases, that is, showing a “PRP” but histologically characterized by insufficient melanocyte proliferation and atypia to diagnose malignant melanoma using H&E staining 26. Early-stage ALM may display extremely subtle histopathologic features, often limited to mild lentiginous melanocytic hyperplasia without significant cytologic atypia. In such cases, a definitive diagnosis cannot rely solely on histopathologic findings. Instead, a comprehensive evaluation integrating clinical, dermatoscopic, and histopathologic data—supplemented by immunohistochemistry and molecular analyses when available—is essential (Table 1). Multiple or larger incisional biopsies are recommended for large lesions where primary reconstruction after an excisional biopsy would be complex. Because these lesions may exhibit inconspicuous histopathologic changes even when large, observation alone is not recommended, and wide local excision according to clinical guidelines should remain the standard of care. For all these reasons, ambiguous terms such as “AMOF” or “atypical hyperplasia” should be definitively abandoned. Acquired pigmented lesion Irregularly pigmented Size ≥ 7 mm Appearance at ≥ 50 years “Parallel ridge pattern” Irregular diffuse pigmentation BRAAFF checklista (Sometimes subtle) proliferation of melanocytes as non-equidistant single units Absence of nests Clear-cut cellular atypia may be absent Preferential proliferation in the crista profunda intermedia PRAME + Loss of p16 CCND1 amplification The authors have nothing to report. All people designated as authors had participated in the work to take public responsibility in its contents. The authors declare that artificial intelligence has not been used for collecting, analyzing or interpreting the data of this manuscript. This case series was conducted in accordance with the Declaration of Helsinki. Written informed consent has been obtained from the patient for the use of image and publication of his case details. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Álvarez‐Salafranca et al. (Mon,) studied this question.
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