Melanoma brain metastases
Epidemiology
Cagney et al. identified 26430 patients with brain metastases at diagnosis of cancer. Patients with small cell and non-small cell lung cancer displayed the highest rates of identified brain metastases at diagnosis; among patients presenting with metastatic disease, patients with melanoma (28.2%)lung adenocarcinoma (26.8%), non-small cell lung cancer not otherwise specified/other lung cancer (25.6%), small cell lung cancer (23.5%), squamous cell carcinoma of the lung (15.9%), bronchioloalveolar carcinoma (15.5%), and renal cancer (10.8%) had an incidence proportion of identified brain metastases of >10%. 1).
Autopsy reports show that 75% of melanoma patients die with brain metastases 2)
Melanoma is the third most common diagnosis among patients with brain metastases 3). , after brain metastases of lung cancer and breast cancer.
Parker et al. report the incidence of synchronous brain metastases (sBM), defined as BM identified at the time of primary cancer diagnosis from 2015 to 2019 using National Cancer Institute's (NCI's) Surveillance, Epidemiology, and End Results Program database.
Methods: We identified 1,872,057 patients with malignancies diagnosed between 2015 and 2019 from the SEER 17 Registries database, including 35,986 (1.9%) patients with sBM. Age-adjusted incidence rates were examined using the NCI Joinpoint software. Kaplan-Meier curves and a multivariate Cox regression model were used to investigate survival.
Results: The incidence rate of sBM from 2015 to 2019 was 7.1 persons per 100,000. Lung and bronchus cancers had the highest incidence of sBM (5.18 to 5.64 per 100,000), followed by melanoma (0.30 to 0.34 per 100,000) and breast cancers (0.24 to 0.30 per 100,000) 4).
Diagnosis
Treatment
Case series
Wegner et al queried the NCDB from 2010 to 2015 for patients with melanoma brain metastases treated with immunotherapy and stereotactic radiosurgery (SRS). Receiver operator characteristic (ROC) curve analysis was done to determine a timepoint associated with outcome. Cox regression was used to identify predictors of survival. Propensity matching was done to account for indication bias.
They identified 247 patients meeting the above criteria. The median patient age was 62 years (27-90) and the vast majority were Caucasian (99%). The median SRS dose was 22 Gy (18-24 Gy).The median time to SRS was 39 days (0-344) and the median time to immunotherapy was 56 days (6-454). The ROC analysis revealed 8 days from SRS to immunotherapy as associated with outcome. Fifty-six patients had immunotherapy prior to SRS, 30 patients had immunotherapy within 0-7 days of SRS, and the remaining 161 had immunotherapy greater than 7 days from SRS. Three year survival rates were 21%, 55%, and 35% for those timeframes, respectively (p = 0.0153). Propensity matching of the 0-7 day and > 7 day groups yielded 28 pairs and Kaplan Meier analysis showed 3 year overall survival of 55% and 35%, in favor of immunotherapy within 7 days of SRS (p = 0.0357). Multivariable Cox regression identified lack of extracranial disease, more recent year of treatment, and time from SRS to immunotherapy of 0-7 days as predictors of improved survival.
Conclusions: Immunotherapy within 7 days of SRS shows a possible association with improve outcomes in patients with brain metastases from melanoma 5).
70 patients with metastatic melanoma were treated for brain metastases at a tertiary treatment centre. The median overall survival (OS) for all patients was 10.2 months. 51 patients received localised treatment; 7 resection (median OS 10 months), 11 resection and SRS (median OS 17.3 months) and 33 SRS alone (median OS 17.4 months). For patients treated with SRS those who had <2 cm3 treated had a better median OS (20.5 months) compared to those who had >2 cm3 treated (12 months). 69 Patients received systemic treatment. The median OS of patients who did not have CNS-directed treatment was poor (median OS 1.2 months). Patients treated with first line dual immunotherapy had the best median OS (26.7 months), compared to anti-PD-1 (14.1 months), ipilimumab (14.3 months) and kinase inhibitors (10.9 months). Despite advancements in treatment, the development of brain metastases in melanoma is associated with worse outcomes. A combination of CNS-directed and systemic treatment is important to improve survival. Dual immunotherapy appears to be the most effective systemic treatment and the use of SRS improved outcomes. As metastatic melanoma treatments evolve there need to be an ongoing focus to ensure these strategies adequately treat intracranial disease 6)
Among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval [CI], 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases.
Conclusions: Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058 .) 7).
Robin et al., retrospectively identified all consecutive cases of newly diagnosed melanoma brain metastases (MBM) treated with Gamma Knife radiosurgery at a single institution between 2012 and 2017, and included only patients that initiated CPIs within 8 weeks before or after radiosurgery.
Thirty-eight patients were included with a median follow-up of 31.6 months. Two-year local control was 92%. Median time to out-of-field CNS and extra-CNS progression were 8.4 and 7.9 months, respectively. Median progression-free survival (PFS) was 3.4 months and median overall survival (OS) was not reached (NR). Twenty-five patients (66%) received anti-CTLA4 and 13 patients (34%) received anti-PD-1+/-anti-CTLA4. Compared with anti-CTLA4, patients that received anti-PD-1+/-anti-CTLA4 had significant improvements in time to out-of-field CNS progression (p = 0.049), extra-CNS progression (p = 0.015), and PFS (p = 0.043), with median time to out-of-field CNS progression of NR vs. 3.1 months, median time to extra-CNS progression of NR vs. 4.4 months, and median PFS of 20.3 vs. 2.4 months. Six patients (16%) developed grade ≥ 2 CNS toxicities (grade 2: 3, grade 3: 3, grade 4/5: 0).
Excellent outcomes were observed in patients that initiated CPIs within 8 weeks of undergoing radiosurgery for newly diagnosed MBM. There appears to be an advantage to anti-PD-1 or combination therapy compared to anti-CTLA4 8).
Case reports from the General University Hospital of Alicante
Q11823
50 year old female
History of superficial spreading melanoma surgically treated 6 years before, with a BRESLOW score of 0.9mm, located on the back. Margins were clear, and sentinel nodes were negative—annual follow-up by Dermatology.
Symptoms began with incomplete responses and some behavioral incoherence over the past weekend, worsening throughout the week with the following symptoms:
Bradypsychia. Incoherent speech. Instability in gait with claudication of the right lower limb. Headache with associated vomiting.
Conscious and oriented in person-time, but disoriented in space. Motor aphasia with bradypsychia and inability for repetition.
Strength preserved in upper limbs, but 4/5 strength in both lower limbs. Recent gait instability with an increased base of support.
Radiological Findings:
Hyperdense solid tumor in the left frontal lobe, probably related to the characteristics of the primary melanoma, with intense enhancement and areas of cystic-necrotic appearance. Contralateral extension through the corpus callosum. Perilesional edema in the left frontal lobe and to a lesser extent in the more medial inferior aspect of the right frontal lobe. Mass Effect with partial collapse of the left frontal horn and right lateral ventricle. Presence of two additional nodular lesions in the left frontal pole.
Diagnostic Impression: Multiple brain metastases in the left frontal lobe, with the largest lesion measuring approximately 5 x 4 x 4 cm with contralateral extension and mass effect. Possible primary tumors include the previously treated melanoma in 2018 or a pulmonary origin due to the presence of a lung nodule not detected in previous radiological studies.
Treatment with high-dose dexamethasone (4mg every 6-8 hours) was initiated.
Right lateral decubitus position
Right Frontal Craniotomy
Frontal controlateral unilateral interhemispheric approach
A 67-year-old woman with a medical history of obesity, Arterial hypertension Diabetes mellitus.
Medical treatment with Eprosartan and hydrochlorothiazide combination, Atorvastatin, Fenofibrate, Bisoprolol, Insulin glargine, Aspirin, Metformin + Sitagliptin, Omeprazole, Empagliflozin.
She was find on the floor of her home with Glasgow Coma Scale of 3 points.
Head computed tomography:
Heterogeneous intraaxial tumor in the left frontal lobe, hyperdense on the periphery, with some small hemorrhagic focus and cystic/necrotic central areas, associated with significant surrounding edema; It causes slight obliteration of the frontal horn of the left lateral ventricle. With the finding of a lung mass, it is highly suggestive of hemorrhagic metastasis.
She was able to be extubated on the first day of admission, due to neurological improvement. Given the suspicion of epiletic seizures secondary to metastasis, the patient was treated with Dexamethasone and Levetiracetam.
MRI
Left frontal intraaxial lesion with a maximum diameter of 4.1 cm with significant surrounding vasogenic edema and heterogeneous uptake related to metastases. Another right parasagittal parietal millimeter focus and another dot in the right semioval center, as well as one in the left cerebellar hemisphere and another 2 dubious right frontal dots, all of them related to metastases, can also be seen.
Lymph node biopsy melanoma
Case Report: Management of Metastatic Melanoma with Cerebral Involvement in a 63-year-old Woman
Abstract: This case report presents the clinical management of a 63-year-old woman with a history of type 2 diabetes mellitus, dyslipidemia, benign intramedullary tumor, and hyperthyroidism. She was admitted to the emergency department with a ten-day history of altered behavior, disorientation, incoherent speech, and worsened urinary control. Neurological examination and imaging revealed a cerebral lesion suspicious of metastatic melanoma. The patient underwent a neuronavigation biopsy, confirming the diagnosis. The management included adjuvant treatments tailored to the presence or absence of BRAF mutation. The patient showed favorable post-surgical evolution and was transferred for further evaluation and convalescence.
Introduction: Metastatic melanoma is a highly aggressive malignancy associated with poor prognosis, especially when it involves the central nervous system (CNS). Early detection and appropriate management are crucial for improving patient outcomes. We present the case of a 63-year-old woman with a complex medical history who presented with neurological symptoms suggestive of CNS involvement by metastatic melanoma.
Case Presentation: A 63-year-old woman with a history of type 2 diabetes mellitus, dyslipidemia, benign intramedullary tumor, and hyperthyroidism presented to the emergency department with altered behavior, disorientation, incoherent speech, and urinary incontinence. Her family reported a ten-day history of these symptoms, along with difficulties in performing daily tasks. The patient's cognitive impairment hindered her understanding of her condition.
Clinical Examination: Upon admission, the patient's vital signs were stable. Neurological examination revealed normal cranial nerve functions, except for bilateral extensor plantar reflex. Muscle strength was preserved, except for slightly reduced strength in the right lower limb. No focal neurological deficits were observed. The patient's gait was not assessed due to her condition.
Imaging Findings: A cranial CT scan revealed a 4.3 x 2.5 x 3.7 cm space-occupying lesion in the left frontal lobe, associated with perilesional edema and mass effect on the adjacent structures. A diagnosis of metastatic melanoma vs. other possible pathologies was considered. A subsequent MRI showed a small vascular malformation with hemorrhage adjacent to the falx, as well as other lesions suggestive of metastatic melanoma. PET-CT scans identified probable cerebral and thyroid metastases.
Biopsy and Pathological Findings: The patient underwent a neuronavigation biopsy, and the histopathological examination confirmed the diagnosis of metastatic melanoma. Further investigation included BRAF mutation testing to guide treatment decisions.
Treatment Approach: The patient's case was discussed in the Neurooncology committee, and the treatment plan was tailored based on the presence or absence of the BRAF mutation. In the presence of BRAF mutation, the patient would receive BRAF-MEK blockade therapy. In the absence of BRAF mutation, double immunotherapy would be considered.
Postoperative Evolution: Following the neuronavigation biopsy, the patient showed favorable post-surgical evolution. She had a Glasgow Coma Scale score of 15, tolerated oral intake, and maintained a sitting position. The surgical wound was dry and healthy, and she remained afebrile.
Conclusion: This case report highlights the importance of considering metastatic melanoma in patients with a complex medical history presenting with neurological symptoms. Prompt diagnosis and tailored management, including genetic testing for mutation status, play a crucial role in optimizing treatment outcomes. In this case, neuronavigation biopsy confirmed metastatic melanoma, and the patient's condition improved post-surgery. The ongoing evaluation and treatment will further inform the management of this challenging condition. Continuous monitoring and targeted therapy based on molecular findings are essential for improving the patient's long-term prognosis.