Melanoma pathology: new approaches and classification

Abstract

Cancer is caused by the accumulation of pathogenic alterations of the genome and epigenome that result in permanent changes that disrupt cellular homeostasis. The genes that become corrupted in this process vary among different tumour types, reflecting specific vulnerabilities and dependencies of the cell from which the cancer originated. This also applies to 'melanoma', a cancer that constitutes not one, but multiple diseases that can be separated based on their cell of origin, aetiology, clinical appearance and course, and response to treatment. In this article, we review the current classification of melanoma within distinct evolutionary pathways and the associated genetic alterations. In addition, we review the application of molecular diagnostics to the diagnosis of melanocytic tumours in the context of histopathological assessment.

Figure 1.. Low cumulative sun damage (low-CSD) melanoma arising from a nevus on the back of a 45-year-old man.

The nevus is in the mid-dermis and composed of small melanocytes that mature with descent in the dermis (lower right). The melanoma is composed of large nests of atypical melanocytes with abundant cytoplasmic pigment arrayed in the epidermis and superficial dermis (upper left). Note the minimal amount of solar elastosis in the dermis. Both the nevus and the melanoma harbor a BRAF V600E mutation while the melanoma alone harbors a TERT promoter mutation and copy number gains and losses characteristic of melanoma. This case was previously reported (case 2). Hematoxylin and eosin stained slide digitally imaged at 40x magnification.

Figure 2.. Melanoma in situ arising on skin with high cumulative sun damage (high-CSD).

Note the extent of solar elastosis in the dermis. There is a broad junctional proliferation of melanocytes arrayed predominantly as single cells limited to the lower epidermis (lentiginous growth pattern). Hematoxylin and eosin stained slide digitally imaged at 40x magnification.

Figure 3.. Spitz Melanoma with ALK fusion.

A. Low magnification view demonstrates an asymmetrically distributed compound melanocytic proliferation. Epidermal hyperplasia as is typical of Spitz nevus is present. B. Medium magnification view of the expansile dermal nests. C. High magnification view of melanocytes with expanded cytoplasm, atypical nuclei and mitotic activity. Spitzoid cytomorphology is present. This Spitz melanoma occurred on the thigh of a 23-year-old woman and demonstrated multiple copy number gains and losses including CDK4 amplification, and was previously reported (case 7). Hematoxylin and eosin stained slide digitally imaged at 40x magnification.

Figure 4.. Acral melanoma arising within a broad patch of acral melanoma in situ.

A. Low magnification view demonstrates an ulcerated nodule of invasive melanoma arising within a melanoma in situ. B. Medium magnification view of the adjacent melanoma in situ shows the lentiginous growth pattern, similar to the high-CSD melanoma in situ in Figure 2. Hematoxylin and eosin stained slide digitally imaged at 40x magnification. C. The copy number profile shows the log2 ratio of the tumor genome compared to a normal reference on the y-axis along the genome on the x-axis. A log2 ratio of 0 represents a normal or unaltered copy number state. The acral melanoma depicted here has numerous copy number losses (chromosomal regions with log2ratio <−0.5) and gains (log2ratio>0.5) including focal amplifications of TERT, CDK4 and MDM2 (log2ratio>2).

Figure 5.. Pseudo-melanomatous atypical proliferative nodule arising in a congenital nevus.

A. Low magnification view shows a large nodule arising within a giant congenital nevus on the neck of a 3-year-old boy. B. Medium magnification view of the nodule demonstrates sheets of melanocytes with scant cytoplasm and nuclei with an open chromatin pattern. Pyknotic nuclei are present. Hematoxylin and eosin stained slide digitally imaged at 40x magnification. C. Copy number profile shows gains and losses of whole chromosomes. A notable exception is the copy number change of chromosome 1 which affects only the long chromosomal arm.

Figure 6.. Melanoma arising within a blue nevus on the scalp of a 23-year-old man.

A. Low magnification view demonstrates a partly necrotic and hemorrhagic nodule that extends into the subcutis. The melanoma harbored GNA11 Q209L and SF3B1 R625C mutations. B. Medium magnification view of region outlined in A shows blue nevus on the left, melanoma centrally, and hemorrhage and necrosis on the right. Hematoxylin and eosin stained slide digitally imaged at 40x magnification. C. Copy number profile reveals copy gains and losses, including monosomy 3, characteristic of uveal and blue melanomas.