BRAFV600E immunopositive Melanomas Show Low Frequency of Heterogeneity and Association With Epithelioid Tumor Cells

Verlinden, I.; Hurk, Karin van den; Clarijs, Ruud; Willig, Arjan P.; Stallinga, Cecile M.; Roemen, Guido M.J.M.; Hausen, Axel zur; Speel, Ernst‐Jan M.; Winnepenninckx, Véronique

doi:10.1097/md.0000000000000285

Cited by 15 publications

(16 citation statements)

References 38 publications

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“…Therefore, most cutaneous melanomas have a homogeneous BRAF mutation status within a single tumor. Indeed, several studies have found relatively homogeneous BRAF V600E expression in melanoma [27][28][29][30]. However, some studies, including our previous one, have shown definite intratumor heterogeneity of BRAF V600E [16,31,32].…”

Section: Discussionmentioning

confidence: 66%

Immunohistochemical BRAF V600E Expression and Intratumor BRAF V600E Heterogeneity in Acral Melanoma: Implication in Melanoma-Specific Survival

Ito

Kaku-Ito

Murata

et al. 2020

JCM

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Acral melanoma, a distinct form of cutaneous melanoma originating in the glabrous skin of the palms, soles, and nail beds, has a different genetic background from other subtypes of cutaneous melanoma. The roles of oncogenic BRAF mutations of acral melanoma in pathogenesis and patient outcomes have not been fully elucidated. We retrieved a total of 112 patients with primary acral melanoma and checked their BRAF V600E status using immunohistochemical staining of VE1 antibody. Among these cases, 21 acral melanoma samples (18.8%) showed positive BRAF V600E staining, and of those, 11 samples (9.8%) showed a heterogeneous staining pattern, with a mixture of VE1-positive and VE1-negative cells. BRAF V600E positivity was significantly associated with thicker melanoma (p = 0.0015). There was no significant difference in clinicopathological factors between homogeneous and heterogeneous VE1-positive acral melanoma. Both patients with BRAF V600E-positive acral melanoma and those with heterogeneous BRAF V600E had significantly shorter melanoma-specific survival than those with BRAF V600E-negative melanoma in Kaplan–Meier analysis (p = 0.0283 and p = 0.0065, respectively). These findings provide novel insights into the pathobiology of acral melanoma.

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Section: Discussionmentioning

confidence: 66%

Immunohistochemical BRAF V600E Expression and Intratumor BRAF V600E Heterogeneity in Acral Melanoma: Implication in Melanoma-Specific Survival

Ito

Kaku-Ito

Murata

et al. 2020

JCM

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“…While the finding of 100% concordance may not be replicated in future larger series or in other populations, taken in the context of previous studies our findings add further support to the conclusion that differences in BRAF status between primary and metastatic sites as determined by IHC are significantly less common than discordance as assessed by PCR. [18][19][20][21][22][23][24]37 Our description of a case of apparent PCR discordance which was subsequently shown to be due to a false negative at one site suggests that some of this difference in findings between methods may be due to technical difficulties with obtaining accurate molecular data from small tumor deposits.…”

Section: Discussionmentioning

confidence: 89%

“…It is noteworthy that in previous work on BRAF status discordance between primary and metastatic melanoma, the pooled rate of discordance was lower in studies using IHC to detect mutant protein, compared with those using DNA‐based approaches . Across seven studies using the VE1 anti‐V600E BRAF antibody, the mean discordance was 5.6% . By contrast, the mean discordance was 14% in DNA‐based studies .…”

Section: Introductionmentioning

confidence: 84%

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High concordance of BRAF mutational status in matched primary and metastatic melanoma

et al. 2018

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Background Techniques for the accurate identification of activating mutations of BRAF in metastatic melanoma are of great clinical importance, due to the availability of targeted therapies for these tumors. There is uncertainty regarding the frequency with which BRAF status differs between primary and metastatic sites. Methods Between 2011 and 2016, 219 melanoma cases underwent BRAF testing in our institution. In 53 of these cases, paired primary and metastatic specimens were available for polymerase chain reaction (PCR) and immunohistochemical evaluation. Results Fifty‐two out of 53 cases (98%) showed concordant BRAF status between primary and metastatic site by immunohistochemistry (IHC). In one case, a metastasis and its matched primary were positive by IHC, but the metastasis was negative on PCR. On further investigation, PCR was positive in the primary, and repeat PCR in the metastasis was positive, following macrodissection. Conclusions Our results suggest that discordance of BRAF mutational status between primaries and metastases is a rare occurrence. In one case, IHC provided strong evidence that initial PCR testing had provided a false‐negative result due to low tumor volume. Thus, in cases where tissue is difficult to obtain from a metastasis or unavailable, the primary tumor can be used with confidence.

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“…Tumor heterogeneity refers to the existence of subpopulations of cells with distinct molecular variation within individual tumors (intra-tumor heterogeneity) or between tumors at different sites within a patient (inter-tumor heterogeneity). Previous studies have revealed that melanoma is associated with inter-tumor heterogenous BRAF status in about 4%-25% of patients [17,18]. If wild-type BRAF melanoma cells are exposed to BRAF inhibitors, the melanoma cells may paradoxically activate the MAPK pathway [18], causing adverse effects.…”

Section: Introductionmentioning

confidence: 99%

Intra- and Inter-Tumor BRAF Heterogeneity in Acral Melanoma: An Immunohistochemical Analysis

Ito

Kaku-Ito

Murata

et al. 2019

IJMS

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The current development of BRAF inhibitors has revolutionized the treatment of unresectable melanoma. As the potential heterogeneity of BRAF mutations in melanoma has been reported, accurate detection of BRAF mutations are important. However, the genetic heterogeneity of acral melanoma—a distinct type of melanoma with a unique genetic background—has not fully been investigated. We conducted a retrospective review of our acral melanoma patients. Of the 196 patients with acral melanoma, we retrieved 31 pairs of primary and matched metastatic melanomas. We immunostained the 31 pairs with VE1, a BRAFV600E-mutation-specific monoclonal antibody. Immunohistochemistry with VE1 showed a high degree of sensitivity and specificity for detecting BRAFV600E mutations compared with the real-time polymerase chain reaction method. A total of nine primary (29.0%) and eight metastatic (25.8%) acral melanomas were positive for VE1. In three patients (9.7%), we observed a discordance of VE1 staining between the primary and metastatic lesions. Of note, VE1 immunohistochemical staining revealed a remarkable degree of intra-tumor genetic heterogeneity in acral melanoma. Our study reveals that VE1 immunostaining is a useful ancillary method for detecting BRAFV600E mutations in acral melanoma and allows for a clear visualization of intra- and inter-tumor BRAF heterogeneity.

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BRAFV600E immunopositive Melanomas Show Low Frequency of Heterogeneity and Association With Epithelioid Tumor Cells

Abstract: Supplemental Digital Content is available in the text

Cited by 15 publications

References 38 publications

Immunohistochemical BRAF V600E Expression and Intratumor BRAF V600E Heterogeneity in Acral Melanoma: Implication in Melanoma-Specific Survival

Immunohistochemical BRAF V600E Expression and Intratumor BRAF V600E Heterogeneity in Acral Melanoma: Implication in Melanoma-Specific Survival

High concordance of BRAF mutational status in matched primary and metastatic melanoma

Intra- and Inter-Tumor BRAF Heterogeneity in Acral Melanoma: An Immunohistochemical Analysis

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