Mixed versus pure variants of desmoplastic melanoma: a genetic and immunohistochemical appraisal

Miller, Daniel D.; Emley, Andrew; Yang, Shi; Richards, Joanna E.; Lee, Jung Eun; Deng, April; Hoang, Mai P.; Mahalingam, Meera

doi:10.1038/modpathol.2011.196

Cited by 46 publications

(49 citation statements)

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“…[1][2][3] The BRAFV600E mutation is seen at particularly high rates in primary and metastatic melanoma (20-70%), papillary thyroid carcinoma (40-70%), colorectal carcinoma (5-10%), and in select benign tumors such as melanocytic nevi. 2,[4][5][6][7][8][9][10] Given its prevalence and role in increasing tumor cell proliferation and metastases, BRAFV600E has emerged as an important biomarker for clinicians. In early melanomas, the BRAF mutation status has not been shown to affect overall survival; however, in metastatic melanoma, it has been associated with a poorer survival rate.…”

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confidence: 99%

Immunohistochemistry with a mutation-specific monoclonal antibody as a screening tool for the BRAFV600E mutational status in primary cutaneous malignant melanoma

2013

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The V600E mutation of BRAF has emerged as both an effective biomarker and therapeutic target for select benign and malignant cutaneous and non-cutaneous human tumors and is typically determined using DNAbased techniques that include allele-specific PCR and direct DNA sequencing. Recently however, the development of new antibodies directed against the V600E protein has opened the door for an easier and more efficient strategy for identifying this mutation. Our present aim was to determine the efficacy of one such antibody, anti-B-Raf (V600E), a mouse monoclonal antibody in which the immunogen is a synthetic peptide derived from the internal region of BRAFV600E. A total of 35 cases of primary cutaneous melanoma were evaluated using a combination of DNA-based techniques that included allele-specific PCR and/or direct DNA sequencing and immunohistochemistry. Cases of papillary thyroid carcinomas (n ¼ 5) and colorectal carcinomas (n ¼ 5), known to harbor the BRAFV600E mutation, served as positive controls for the study. DNA analyses revealed that 6 of 35 (17%) cases of the primary cutaneous malignant melanoma possessed the BRAFV600E mutation. For immunohistochemical analyses, cytoplasmic positivity with anti-B-Raf was noted in 7 of 35 (20%) cases of primary melanoma and in all 10 positive controls. Statistical analyses of the data demonstrated that the sensitivity of the immunohistochemistry was 100% and specificity was 97%. Findings from the current study support the potential use of immunohistochemistry as an ancillary screening tool to assess the BRAFV600E mutation status in primary cutaneous melanoma.

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Immunohistochemistry with a mutation-specific monoclonal antibody as a screening tool for the BRAFV600E mutational status in primary cutaneous malignant melanoma

2013

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“…Regarding desmoplastic malignant melanoma a complete absence of BRAF mutations 21 as well as a reduced mutation rate 22 has been reported. Recently, Miller et al 23 have observed a lack of BRAF mutations in pure desmoplastic malignant melanoma compared to a low frequency in the mixed subtype and a trend toward an increased RETp frequency in pure desmoplastic malignant melanoma. Kim et al 24 extended mutation analysis in desmoplastic malignant melanoma to BRAF and KIT reporting wild-type BRAF and KIT in all tumors investigated.…”

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confidence: 99%

“…22 Subclassification of desmoplastic malignant melanoma into pure and mixed type is not only clinically relevant, but also apparently reflects different mutation patterns as well. Miller et al 23 have recently shown that pure desmoplastic malignant melanoma is devoid of BRAF mutations as opposed to mixed desmoplastic malignant melanoma, which did exhibit BRAF mutations albeit at a low level (6% of cases). In addition, absence of BRAF mutations in an investigation including 10 desmoplastic melanomas (not further subclassified) has been reported by another group.…”

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“…25,26 This activation has been linked to the observed neurotropism in desmoplastic melanoma and pancreatic ductal adenocarcinoma among others. Narita et al 25 have described a significantly higher frequency of RETp in desmoplastic melanomas (61%) compared to nondesmoplastic melanomas (31%) analyzing RETp from tumor DNA, but Miller et al 23 have only detected RETp in 33% of pure and in 24% of mixed desmoplastic malignant melanoma. In the light of occasional, somatic, de novo RETp occurrences reported in pancreatic adenocarcinoma, 27 Bar et al 28 have investigated germline DNA for RETp in melanoma patients and found germline RETp in 30% of patients with desmoplastic melanomas, compared to 21% in nondesmoplastic malignant melanoma patients, but this difference was not significant at the investigated sample size.…”

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Mutational dichotomy in desmoplastic malignant melanoma corroborated by multigene panel analysis

et al. 2015

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Desmoplastic malignant melanoma is a distinct melanoma entity histologically subtyped into mixed and pure forms due to significantly reduced lymph node metastases in the pure form. Recent reports investigating common actionable driver mutations have demonstrated a lack of BRAF, NRAS, and KIT mutation in pure desmoplastic melanoma. In search for alternative driver mutations next generation amplicon sequencing for hotspot mutations in 50 genes cardinal to tumorigenesis was performed and in addition the RET G691S polymorphism was investigated. Data from 21 desmoplastic melanomas (12 pure and 9 mixed) were retrieved. Pure desmoplastic melanomas were either devoid of mutations (50%) or displayed mutations in tumor suppressor genes (TP53, CDKN2A, and SMAD4) singularly or in combination with the exception of a PIK3CA double-mutation lacking established biological relevance. Mixed desmoplastic melanomas on the contrary were frequently mutated (89%), and 67% exhibited activating mutations similar to common-type cutaneous malignant melanomas (BRAF, NRAS, FGFR2, and ERBB2). Separate analysis of morphologically heterogeneous tumor areas in four mixed desmoplastic malignant melanomas displayed no difference in mutation status and RET G691 status. GNAQ and GNA11, two oncogenes in BRAF and NRAS wild-type uveal melanomas, were not mutated in our cohort. The RET G691S polymorphism was found in 25% of pure and 38% of mixed desmoplastic melanomas. Apart from RET G691S our findings demonstrate absence of activating driver mutations in pure desmoplastic melanoma beyond previously investigated oncogenes (BRAF, NRAS, and KIT). The findings underline the therapeutic dichotomy of mixed versus pure desmoplastic melanoma with regard to activating mutations primarily of the mitogen-activated protein kinase pathway.

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“…The examples of desmoplastic melanomas, including both mixed and pure types, were based on established morphologic criteria. 9 All cases of synovial sarcomas harbored the SYT-SSX t(X;18) chromosomal translocation, and all cases of clear-cell sarcomas harbored the EWS break apart by fluorescent in situ hybridization (FISH).…”

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confidence: 99%

Growth-associated protein 43 in differentiating peripheral nerve sheath tumors from other non-neural spindle cell neoplasms

Chen

et al. 2014

Modern Pathology

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The malignant peripheral nerve sheath tumor is a relatively uncommon type of soft tissue sarcoma arising from a peripheral nerve or extraneural soft tissues and showing nerve sheath differentiation. The diagnosis of malignant peripheral nerve sheath tumor is one of the most challenging tasks in surgical pathology because of its uncommon type (5-10% soft tissue sarcomas), morphologic resemblance to other spindle cell neoplasms and lack of sensitive and specific immunohistochemical markers. The pathologic diagnosis is more straightforward in the clinical setting of neurofibromatosis-1, but problems are mainly centered on the non-neurofibromatosis-1 malignant peripheral nerve sheath tumors. To date, S100 protein is the most widely applied marker in the case of a suspected malignant peripheral nerve sheath tumor, yet its suboptimal sensitivity and its expression in other spindle cell neoplasms, including spindle cell melanoma, clear-cell sarcoma, leiomyosarcoma and monophasic synovial sarcoma, add to the diagnostic conundrum. Growth-associated protein 43 (GAP43), a membrane-associated phosphoprotein expressed in neuronal growth cones and Schwann cell precursors during neural development and axonal regeneration, was applied to a set of nerve sheath and non-nerve sheath spindle cell neoplasms. The findings in this study indicate that GAP43 is expressed in malignant peripheral nerve sheath tumors (n ¼ 18/21; 86%) and demonstrates a sensitivity superior to S100 protein (n ¼ 13/21; 62%). GAP43 is also positive in neurofibromas (n ¼ 17/18; 94%), schwannomas (n ¼ 11/12; 92%) and desmoplastic melanomas (n ¼ 7/10; 70%). In contrast, it is negative in the non-desmoplastic spindle cell melanomas (n ¼ 20/22; 91%). Of the other non-neural soft tissue sarcomas, GAP43 is non-reactive in most leiomyosarcomas (n ¼ 14/16; 88%) and clear-cell sarcomas (n ¼ 8/8), and only focally positive in monophasic synovial sarcomas (n ¼ 3/7; 43%). GAP43 is seemingly a highly sensitive marker for peripheral nerve sheath tumors and may serve as a useful diagnostic adjunct in the diagnosis of malignant peripheral nerve sheath tumor from other spindle cell neoplasms, including spindle cell melanoma.

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Mixed versus pure variants of desmoplastic melanoma: a genetic and immunohistochemical appraisal

Cited by 46 publications

References 45 publications

Immunohistochemistry with a mutation-specific monoclonal antibody as a screening tool for the BRAFV600E mutational status in primary cutaneous malignant melanoma

Immunohistochemistry with a mutation-specific monoclonal antibody as a screening tool for the BRAFV600E mutational status in primary cutaneous malignant melanoma

Mutational dichotomy in desmoplastic malignant melanoma corroborated by multigene panel analysis

Growth-associated protein 43 in differentiating peripheral nerve sheath tumors from other non-neural spindle cell neoplasms

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