Zembowicz Artur, Knoepp Stewart M, Bei Thalia, Stergiopoulos Sotirios, Eng Charis, Mihm Martin C, Stratakis Constantine A
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Am J Surg Pathol. 2007 Nov;31(11):1764-75. doi: 10.1097/PAS.0b013e318057faa7.
Pigmented epithelioid melanocytoma (PEM) is a recently described entity comprising most cases previously described as "animal-type melanoma" and epithelioid blue nevus (EBN) occurring in patients with the multiple neoplasia syndrome Carney complex (CNC). Mutations of the protein kinase A regulatory subunit type 1alpha (R1alpha) (coded by the PRKAR1A gene) are found in more than half of CNC patients. In this study, we investigated whether PEM and EBN are related at the molecular level, and whether changes in the PRKAR1A gene status and the expression of the R1alpha protein may be involved in the pathogenesis of PEM and other melanocytic lesions. Histologic analysis of hematoxylin and eosin-stained sections and immunohistochemistry (IHC) with R1alpha antibody were performed on 34 sporadic PEMs, 8 CNC-associated PEMs from patients with known PRKAR1A mutations, 297 benign and malignant melanocytic tumors (127 conventional sections of 10 compound nevi, 10 Spitz nevi, 5 deep-penetrating nevi, 5 blue nevi, 6 cellular blue nevi, 2 malignant blue nevi, 3 lentigo maligna, and 86 melanomas of various types); in addition, 170 tissue microarray sections consisting of 35 benign nevi, 60 primary melanomas, and 75 metastatic melanomas, and 5 equine dermal melanomas, were examined. Histologic diagnoses were based on preexisting pathologic reports and were confirmed for this study. DNA studies [loss of heterozygosity (LOH) for the 17q22-24 locus and the PRKAR1A gene sequencing] were performed on 60 melanomas and 7 PEMs. IHC showed that R1alpha was expressed in all but one core from tissue microarrays (169/170), and in all 127 melanocytic lesions evaluated in conventional sections. By contrast, R1alpha was not expressed in the 8 EBN from patients with CNC and PRKAR1A mutations. Expression of R1alpha was lost in 28 of 34 PEMs (82%). R1alpha was expressed in the 5 equine melanomas studied. DNA studies correlated with IHC findings: there were no PRKAR1A mutations in any of the melanomas studied and the rate of LOH for 17q22-24 was less than 7%; 5 of the 7 PEMs showed extensive 17q22-24 LOH but no PRKAR1A mutations. The results support the concept that PEM is a distinct melanocytic tumor occurring in a sporadic setting and in the context of CNC. They also suggest that PEM differs from melanomas in equine melanotic disease, further arguing that the term animal-type melanoma may be a misnomer for this group of lesions. Loss of expression of R1alpha offers a useful diagnostic test that helps to distinguish PEM from lesions that mimic it histologically.
色素性上皮样黑素细胞瘤（PEM）是一种最近被描述的病变，包括大多数以前被描述为“动物型黑素瘤”的病例以及发生于患有多发性肿瘤综合征卡尼综合征（CNC）患者的上皮样蓝痣（EBN）。超过半数的CNC患者存在蛋白激酶A调节亚基1α（R1α）（由PRKAR1A基因编码）的突变。在本研究中，我们调查了PEM和EBN在分子水平上是否相关，以及PRKAR1A基因状态的改变和R1α蛋白的表达是否可能参与PEM和其他黑素细胞性病变的发病机制。对34例散发性PEM、8例来自已知PRKAR1A突变患者的CNC相关PEM、297例良性和恶性黑素细胞性肿瘤（10个复合痣的127个常规切片、10个Spitz痣、5个深部穿透性痣、5个蓝痣、6个细胞性蓝痣、2个恶性蓝痣、3个恶性雀斑样痣以及86个各种类型的黑素瘤）进行苏木精-伊红染色切片的组织学分析以及用R1α抗体进行免疫组织化学（IHC）检测；此外，还检查了由35个良性痣、60个原发性黑素瘤和75个转移性黑素瘤组成的170个组织微阵列切片以及5个马皮肤黑素瘤。组织学诊断基于既往病理报告，并在本研究中得到确认。对60例黑素瘤和7例PEM进行了DNA研究[17q22 - 24位点的杂合性缺失（LOH）和PRKAR1A基因测序]。IHC显示，除组织微阵列的一个核心外（169/170），R1α在所有样本中均有表达，并且在常规切片评估的所有127个黑素细胞性病变中也均有表达。相比之下，来自患有CNC和PRKAR1A突变患者的8个EBN中R1α未表达。34例PEM中有28例（82%）R1α表达缺失。在研究的5个马黑素瘤中R1α有表达。DNA研究与IHC结果相关：在所研究的任何黑素瘤中均未发现PRKAR1A突变，17q22 - 24的LOH率低于7%；7例PEM中有5例显示广泛的17q22 - 24 LOH但无PRKAR1A突变。结果支持PEM是一种散发性以及在CNC背景下发生的独特黑素细胞性肿瘤这一概念。它们还表明PEM与马黑素沉着病中的黑素瘤不同，进一步说明“动物型黑素瘤”这一术语可能是对这组病变的误称。R1α表达缺失提供了一种有用的诊断检测方法，有助于将PEM与组织学上与之相似的病变区分开来。
