Clinicopathologic and genetic characterization of invasive melanoma with BRAF V600K mutation: A study of 16 cases.

BACKGROUND: The clinicopathologic and genetic features of cutaneous melanoma with a BRAF V600K mutation are not well-known. We aimed to evaluate these characteristics in comparison with those associated with BRAF V600E. METHODS: Real-time polymerase chain reaction (PCR) and/or the MassARRAY® system were used to detect BRAF V600K in 16 invasive melanomas and confirm BRAF V600E in another 60 cases. Immunohistochemistry and panel next-generation sequencing were used to evaluate protein expression and tumor mutation burden, respectively. RESULTS: The median age of melanoma patients harboring the BRAF V600K mutation (72.5 years) was higher than those with the BRAF V600E (58.5 years). The two groups also differed in sex (13/16 [81.3%] male in the V600K group vs. 23/60 [38.3%] in V600E) and in the frequency of scalp involvement (8/16 [50.0%] in V600K vs. 1/60 [1.6%] in V600E). The clinical appearance was similar to a superficial spreading melanoma. Histopathologically, non-nested lentiginous intraepidermal spread and subtle solar elastosis were observed. One patient (1/13, 7.7%) had a pre-existing intradermal nevus. Diffuse PRAME immunoexpression was seen in only one (14.3%) of seven tested cases. Loss of p16 expression was observed in all 12 cases (100%) analyzed. The tumor mutation burden was 8 and 6 mutations/Mb in the two tested cases. CONCLUSIONS: Melanoma carrying the BRAF V600K mutation showed the predominance on the scalp of elderly men, lentiginous intraepidermal growth, subtle solar elastosis, possible existence of intradermal nevus component, frequent loss of p16 immunoexpression, limited immunoreactivity for PRAME, and intermediate tumor mutation burden.

Metanephric adenoma with BRAF V600K mutation and a doubtful radiological imaging: pitfalls in the diagnostic process.

Metanephric adenoma (MA) is an uncommon benign renal tumor whose histomorphological aspect resembles that of Wilms' tumor and papillary renal cell carcinoma. From a diagnostic and therapeutic perspective, recognition of this entity is important as it has a more favorable clinical outcome compared with Wilms' tumor and papillary renal cell carcinoma. MA should not be treated with nephrectomy if the tumor size is small, opting for a conservative treatment. However, the preoperative diagnosis of this disease is extremely challenging. The present study describes a case of this rare disease, showing an ambiguous radiological imaging and that only after a percutaneous biopsy, was defined as a MA and treated with partial nephrectomy. Moreover, the histological diagnosis of this case was partially complicated by the equivocal immunohistochemical analysis showing negativity for BRAF VE1 staining. Only the mutational analysis demonstrated the presence of the BRAF V600K mutation (for the first time described in a case of metanephric adenoma), highlighting the necessity of sequencing in case of MA with negativity for BRAF VE1 clone.

Current Controversies and Challenges on BRAF V600K-Mutant Cutaneous Melanoma.

About 50% of melanomas harbour a BRAF mutation. Of these 50%, 10% have a V600K mutation. Although it is the second most common driver mutation after V600E, no specific studies have been conducted to identify a clinical and therapeutic gold standard for this patient subgroup. We analysed articles, including registrative clinical trials, to identify common clinical and biological traits of the V600K melanoma population, including different adopted therapeutic strategies. Melanoma V600K seems to be more frequent in Caucasian, male and elderly populations with a history of chronic sun damage and exposure. Prognosis is poor and no specific prognostic factor has been identified. Recent findings have underlined how melanoma V600K seems to be less dependent on the ERK/MAPK pathway, with a higher expression of PI3KB and a strong inhibition of multiple antiapoptotic pathways. Both target therapy with BRAF inhibitors + MEK inhibitors and immunotherapy with anti-checkpoint blockades are effective in melanoma V600K, although no sufficient evidence can currently support a formal recommendation for first line treatment choice in IIIC unresectable/IV stage patients. Still, melanoma V600K represents an unmet medical need and a marker of poor prognosis for cutaneous melanoma.

Spontaneous rupture of malignant papillary craniopharyngioma with CSF seeding and metastatic deposits: A case report and literature review.

Introduction: Craniopharyngiomas are benign tumours mainly confined to the cranial cavity in the suprasellar region. Research Question and Case Description: We present a rare case of an aggressive papillary craniopharyngioma with disseminated spinal intradural disease. A 67-year-old woman presented with a 4-month history of headache, visual disturbance, acute confusion and radicular leg pain. Previous history of breast carcinoma (ER â€‹+ â€‹PR â€‹+ â€‹HER2-) was noted. The importance of histological diagnosis prior to treatment of sellar or suprasellar lesions with atypical or aggressive features is explored. Materials and methods: MRI demonstrated a partly solid and partly cystic pituitary mass lesion in the sellar and suprasellar region with chiasmal compression and hypothalamic involvement. The sella was mildly enlarged and there were no calcifications. Whole neuraxis MRI revealed intradural deposits involving the ventricular system, spinal cord and conus. Within a month, the lesion rapidly increased in size. The patient underwent a craniotomy and transventricular resection of the sellar and suprasellar mass. Cranial lesion histology favoured papillary craniopharyngioma, confirmed by BRAF V600 mutation. Lumbar puncture CSF cytology confirmed craniopharyngioma with BRAF mutation and no evidence of metastatic breast cancer. Results: The patient remained confused postoperatively without focal neurological deficit and underwent palliative whole brain radiotherapy. She died 4 months later. A review of the literature identified 29 reports of ruptured craniopharyngioma. Discussion and Conclusion: Ruptured craniopharyngioma presents with a suprasellar mass and drop lesions in the spinal canal, characteristics radiologically indistinguishable from metastatic disease. The importance of histological diagnoses in directing the management of these cases is highlighted.

Primary Melanoma of the Lung Treated with Surgery, Dabrafenib and Trametinib.

This is a case report on a 69-year-old woman who was diagnosed with malignant melanoma presenting in the lung. A complete staging workup was performed by her oncologist, with no skin lesion identified as a primary. CT-guided needle biopsy of the lung nodule was completed, with pathology revealing atypical cells consistent with malignant melanoma. Following full body examination by the cutaneous oncologist, a robotic wedge resection and lymph node dissection accompanied by bronchoscopy were performed. Molecular testing (Caris Life Sciences) of the surgical tumor specimen revealed pathological BRAF DNA mutation in exon 15/p.V600K. The patient was initially treated with nivolumab, then treated with a combination of dabrafenib and trametinib at recurrence.

Biology and treatment of BRAF mutant metastatic melanoma.

BRAF inhibitors were among the first systemic therapies to show clinical benefit in metastatic melanoma. Here, we review the spectrum of BRAF mutations in melanoma, their role in oncogenesis, clinicopathological associations and response to treatment. The differing biology and clinical features of V600E- and V600K-mutated melanoma are outlined. The molecular changes associated with BRAF fusion genes and their response to targeted therapies, as well as the role of immunotherapy in treatment sequencing with targeted therapies are discussed.

Toward a Molecular Classification of Colorectal Cancer: The Role of BRAF.

Different genetic aberrations of BRAF have been reported in various malignancies. BRAF is member of the RAS/RAF/MEK/ERK pathway and constitutive activity of this pathway can lead to increased cellular growth, invasion, and metastasis. The most common activating BRAF mutation in colorectal cancer is the V600E mutation, which is present in 5-15% of all tumors, and up to 80% of tumors with high microsatellite instability (MSI) harbor this mutation. BRAF mutation is associated with proximal location, higher age, female gender, MSI-H, high grade, and mucinous histology, and is a marker of poor prognosis in colorectal cancer. The role of BRAF mutation as a predictive marker in respect of EGFR targeted treatments is controversial. BRAF V600 selective inhibitors have been approved for the treatment of V600 mutation positive metastatic melanoma, but the response rates in colorectal cancer are poor. This might be due to innate resistance mechanisms of colorectal cancers against the treatment solely targeting BRAF. To overcome resistance the combination of treatments, simultaneous inhibition of BRAF and MEK or PI3K/mTOR, might emerge as a successful therapeutic concept.