Abstract：
BACKGROUND: In the current study, we examined the real-world prevalence of highly pigmented advanced melanomas (HPMel) and the clinicopathologic, genomic, and ICPI biomarker signatures of this class of tumors.
METHODS: Our case archive of clinical melanoma samples for which the ordering physician requested testing for both PD-L1 immunohistochemistry (IHC) and comprehensive genomic profiling (CGP) was screened for HPMel cases, as well as for non-pigmented or lightly pigmented advanced melanoma cases (LPMel).
RESULTS: Of the 1268 consecutive melanoma biopsies in our archive that had been submitted for PD-L1 IHC, 13.0% (165/1268) were HPMel and 87.0% (1103/1268) were LPMel. In the HPMel cohort, we saw a significantly lower tumor mutational burden (TMB, median 8.8 mutations/Mb) than in the LPMel group (11.4 mut/Mb), although there was substantial overlap. In examining characteristic secondary genomic alterations (GA), we found that the frequencies of GA in TERTp, CDKN2A, TP53, and PTEN were significantly lower in the HPMel cases than in LPMel. A higher rate of GA in CTNNB1, APC, PRKAR1A, and KIT was identified in the HPMel cohort compared with LPMel.
CONCLUSIONS: In this study, we quantified the failure rates of melanoma samples for PD-L1 testing due to high melanin pigmentation and showed that CGP can be used in these patients to identify biomarkers that can guide treatment decisions for HPMel patients. Using this practical clinical definition for tumor pigmentation, our results indicate that HPMel are frequent at 13% of melanoma samples, and in general appear molecularly less developed, with a lower TMB and less frequent secondary GA of melanoma progression.
METHODS: Our case archive of clinical melanoma samples for which the ordering physician requested testing for both PD-L1 immunohistochemistry (IHC) and comprehensive genomic profiling (CGP) was screened for HPMel cases, as well as for non-pigmented or lightly pigmented advanced melanoma cases (LPMel).
RESULTS: Of the 1268 consecutive melanoma biopsies in our archive that had been submitted for PD-L1 IHC, 13.0% (165/1268) were HPMel and 87.0% (1103/1268) were LPMel. In the HPMel cohort, we saw a significantly lower tumor mutational burden (TMB, median 8.8 mutations/Mb) than in the LPMel group (11.4 mut/Mb), although there was substantial overlap. In examining characteristic secondary genomic alterations (GA), we found that the frequencies of GA in TERTp, CDKN2A, TP53, and PTEN were significantly lower in the HPMel cases than in LPMel. A higher rate of GA in CTNNB1, APC, PRKAR1A, and KIT was identified in the HPMel cohort compared with LPMel.
CONCLUSIONS: In this study, we quantified the failure rates of melanoma samples for PD-L1 testing due to high melanin pigmentation and showed that CGP can be used in these patients to identify biomarkers that can guide treatment decisions for HPMel patients. Using this practical clinical definition for tumor pigmentation, our results indicate that HPMel are frequent at 13% of melanoma samples, and in general appear molecularly less developed, with a lower TMB and less frequent secondary GA of melanoma progression.
摘要：
背景：在当前的研究中，我们检查了高色素性晚期黑色素瘤（HPMel）的真实世界患病率和临床病理，基因组，和此类肿瘤的ICPI生物标志物特征。
方法：我们的临床黑色素瘤样本档案中，主治医师要求对其进行PD-L1免疫组织化学（IHC）和综合基因组分析（CGP）检测，以筛选HPMel病例，以及非色素沉着或轻度色素沉着的晚期黑色素瘤病例（LPMel）。
结果：在我们的档案中已提交PD-L1IHC的1268例连续黑色素瘤活检中，13.0%(165/1268)为HPMel,87.0%(1103/1268)为LPMel。在HPMel队列中，我们看到肿瘤突变负担显著降低(TMB，中位数8.8突变/Mb）比LPMel组（11.4mut/Mb），尽管存在大量重叠。在检查特征性次级基因组改变(GA)时，我们发现在TERTp中GA的频率，CDKN2A,TP53和PTEN在HPMel病例中明显低于LPMel。在CTNNB1、APC、PRKAR1A,与LPMel相比，HPMel队列中发现了KIT。
结论：在这项研究中，我们量化了由于黑色素沉着较高而导致的黑色素瘤样本PD-L1检测的失败率,并表明CGP可用于这些患者,以鉴定可指导HPMel患者治疗决策的生物标志物.使用肿瘤色素沉着的实际临床定义，我们的结果表明，HPMel在13％的黑色素瘤样本中很常见，一般来说，分子发育较少，具有较低的TMB和较低频率的黑色素瘤进展的继发性GA。
方法：我们的临床黑色素瘤样本档案中，主治医师要求对其进行PD-L1免疫组织化学（IHC）和综合基因组分析（CGP）检测，以筛选HPMel病例，以及非色素沉着或轻度色素沉着的晚期黑色素瘤病例（LPMel）。
结果：在我们的档案中已提交PD-L1IHC的1268例连续黑色素瘤活检中，13.0%(165/1268)为HPMel,87.0%(1103/1268)为LPMel。在HPMel队列中，我们看到肿瘤突变负担显著降低(TMB，中位数8.8突变/Mb）比LPMel组（11.4mut/Mb），尽管存在大量重叠。在检查特征性次级基因组改变(GA)时，我们发现在TERTp中GA的频率，CDKN2A,TP53和PTEN在HPMel病例中明显低于LPMel。在CTNNB1、APC、PRKAR1A,与LPMel相比，HPMel队列中发现了KIT。
结论：在这项研究中，我们量化了由于黑色素沉着较高而导致的黑色素瘤样本PD-L1检测的失败率,并表明CGP可用于这些患者,以鉴定可指导HPMel患者治疗决策的生物标志物.使用肿瘤色素沉着的实际临床定义，我们的结果表明，HPMel在13％的黑色素瘤样本中很常见，一般来说，分子发育较少，具有较低的TMB和较低频率的黑色素瘤进展的继发性GA。
