Pigmented epithelioid melanocytoma is a rare cutaneous melanocytic proliferation considered high-grade melanocytoma in the 2018 WHO Classification of Skin Tumors. Little has been reported about the associated genetic drivers in addition to BRAF and MAP2K1 mutations or PRKCA gene fusions. Here, we present a series of 21 cases of PRKAR1A-inactivated melanocytic tumors in which we could assess the associated genetic background. We identified 9 different driver genes related to the common, Spitz, blue nevi, and PRKC-fused groups. Nine cases were associated with a canonical BRAF p.V600E mutation, a hallmark of the common nevus group. They occurred mainly in young adults. All were combined (biphenotypic) cases with a variable proportion of compound nevus. The pigmented epithelioid melanocytoma component was made of thin fascicules or isolated epithelioid cells covered by a dense hyperpigmented melanophage background and was predominantly located in the upper dermis. One such case was malignant. Six cases were associated with Spitz-related genetic anomalies ranging from HRAS or MAP2K1 mutations to gene fusions involving MAP3K8, MAP3K3, and RET. They occurred mainly in children and young adults. Morphologically, they showed large confluent junctional nests in a hyperplastic epidermis and a fascicular dermal component of spindled and epithelioid melanocytes with a frequent wedged silhouette. Intravascular invasion was observed in 4/6 cases. Five cases were associated with canonical mutations of the blue nevus group with 4 CYSLTR2 p.L129Q and 1 GNAQ p.Q209L mutations. They were removed mainly in adults and showed a frequent junctional component with epidermal hyperplasia. The dermal component showed dense fascicules of spindled and epithelioid melanocytes predominating over melanophages. One case occurred in a PRKCA-fused tumor in an adolescent with classic morphologic features. These results could potentially shift the concept of PRKAR1A-inactivated melanocytoma, changing from a rather unified model to a more complex one, including genetic subgroup variations with clinical and morphologic specificities. The genetic background of PRKAR1A-inactivated melanocytic tumors should be systematically explored to better understand the extent and clinical behavior of these complex lesions.

色素上皮样黑色素细胞瘤是一种罕见的皮肤黑色素细胞增殖，在 2018 年世界卫生组织皮肤肿瘤分类中被认为是高级别黑色素细胞瘤。除了BRAF和MAP2K1突变或PRKCA基因融合之外，有关相关遗传驱动因素的报道很少。在这里，我们提出了一系列 21 个PRKAR1A失活的黑素细胞肿瘤病例，我们可以在其中评估相关的遗传背景。我们鉴定了 9 个与普通、Spitz、蓝痣和PRKC融合组相关的不同驱动基因。9 例病例与典型BRAF p.V600E 突变有关，这是常见痣组的标志。它们主要发生在年轻人中。所有病例均为混合（双表型）病例，具有不同比例的复合痣。色素上皮样黑素细胞瘤成分由薄束或孤立的上皮样细胞组成，被致密的色素沉着过度的黑素噬菌体背景覆盖，主要位于真皮上部。其中一例是恶性的。6 例与 Spitz 相关的遗传异常有关，范围从HRAS或MAP2K1突变到涉及MAP3K8、MAP3K3和RET的基因融合。它们主要发生在儿童和年轻人中。在形态学上，它们在增生的表皮和纺锤形和上皮样黑素细胞的束状真皮成分中显示出大的汇合连接巢，具有频繁的楔形轮廓。4/6 例观察到血管内侵犯。5 例病例与蓝痣组的典型突变相关，其中 4 个CYSLTR2 p.L129Q 突变和 1 个GNAQ p.Q209L 突变。它们主要在成人中被去除，并表现出频繁的表皮增生的连接成分。真皮成分显示出密集的纺锤形和上皮样黑素细胞束，其在噬黑素细胞中占主导地位。一个病例发生在一名青少年的PRKCA融合肿瘤中，具有典型的形态学特征。这些结果可能会改变PRKAR1A失活黑色素细胞瘤的概念，从一个相当统一的模型转变为一个更复杂的模型，包括具有临床和形态学特异性的遗传亚组变异。应系统地探索PRKAR1A失活黑素细胞肿瘤的遗传背景，以更好地了解这些复杂病变的范围和临床行为。