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Clinical case
Brainstem melanomas presenting as a cavernous malformation Mélanomes du tronc cérébral mimant un cavernome A.Y. Lu a , A.R. Patel b , G.A. Kuzmik a , K.-K. Atsina a , R.A. Bronen a,c , P.M. Jabbour d , D.M. Hasan e , A.O. Vortmeyer f , B.G. Welch b , K.R. Bulsara a,∗ a
Department of Neurosurgery, Yale School of Medicine, New Haven CT 06510, United States University of Texas Southwestern Medical Center, Dallas TX 75390, United States c Department of Diagnostic Radiology, Yale University School of Medicine, New Haven CT 06510, United States d Department of Neurosurgery, Thomas Jefferson University and Jefferson Hospital for Neuroscience, Philadelphia PA 19107, United States e Department of Neurosurgery, University of Iowa, Iowa City, IA 52242, United States f Department of Pathology, Yale School of Medicine, New Haven CT 06510, United States b
a r t i c l e
i n f o
Article history: Received 21 November 2013 Received in revised form 16 January 2014 Accepted 19 February 2014 Available online xxx Keywords: Brain stem Melanoma Cavernous malformations of CNS and retina
a b s t r a c t Background. – Melanoma lesions in the brainstem can be difficult to distinguish radiographically and clinically from cavernous malformations. However, the treatment modalities and clinical course of these two diseases differ considerably. We report two cases of melanoma presenting as brainstem hemorrhages. Case description. – A 69-year-old male was found to have a hemorrhagic lesion of the right dorsal midbrain. After a repeat hemorrhage, the lesion was resected and found to be hyperchromatic. Nonetheless, the patient suffered rebleeding and died 3 months later. A 62-year-old female was similarly found to have an acute pontine hemorrhage. After resection of the lesion, she underwent whole-brain radiation therapy but ultimately died 5.5 months later. The histopathology of both lesions was consistent with melanoma. Conclusions. – Melanoma in the brainstem can mimic cavernous malformations. While management of these lesions includes stereotactic radiosurgery, whole-brain radiation, and surgical resection, metastatic brainstem melanoma follows an aggressive clinical course with a poor prognosis. © 2014 Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Tronc cérébral Mélanome Malformations caverneuses du système nerveux central et de la rétine
Contexte. – Les lésions de mélanome localisées au tronc cérébral peuvent être difficiles à distinguer cliniquement et radiologiquement des malformations caverneuses. Toutefois, les modalités de traitement et l’évolution clinique de ces deux maladies sont très différentes. Nous rapportons deux cas de mélanome se présentant comme des hémorragies du tronc cérébral. Descriptions de cas. – Un homme de 69 ans était atteint d’une lésion hémorragique du mésencéphale dorsal. Après un deuxième épisode hémorragique, la lésion a été réséquée et était hyperchromatique. Pourtant le patient a présenté une récidive hémorragique et est décédé 3 mois plus tard. Une femme de 62 ans a présenté une hémorragie pontique aiguë. Après résection de la lésion, elle a subi une radiothérapie pan-cérébrale mais est décédée 5,5 mois plus tard. L’examen histopathologique des deux lésions était compatible avec un mélanome. Conclusions. – Les mélanomes localisés au tronc cérébral peuvent imiter les cavernomes. Alors que le traitement de ces lésions comprend la radiochirurgie stéréotaxique, la radiothérapie du pan-cérébrale et la résection chirurgicale, le mélanome métastatique du tronc cérébral est de mauvais pronostic. © 2014 Elsevier Masson SAS. Tous droits réservés.
Abbreviations: CNS, Central nervous system; CT, Computed tomography; CTA, CT angiogram; MRI, Magnetic resonance imaging; SRS, Stereotactic radiosurgery; WBRT, Whole-brain radiation therapy. ∗ Corresponding author. Yale Department of Neurosurgery, TMP 4 New Haven, CT 06520. E-mail address: [email protected] (K.R. Bulsara). http://dx.doi.org/10.1016/j.neuchi.2014.02.005 0028-3770/© 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Lu AY, et al. Brainstem melanomas presenting as a cavernous malformation. Neurochirurgie (2014), http://dx.doi.org/10.1016/j.neuchi.2014.02.005
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1. Introduction Melanoma represents the third most common type of cancer to metastasize to the brain. Malignant metastases to the brainstem are rare, accounting for only 3–5% of all brain metastases [1]. Given their tendency to hemorrhage, metastatic melanoma lesions of the brainstem may mimic cavernous malformations, which likewise present as focal brainstem hemorrhages [2]. The clinical course of melanoma of the brainstem is decidedly more aggressive than that of cavernomas with a median survival of only four months [3]. Accordingly, melanoma should be considered in the differential diagnosis of brainstem hemorrhages in the appropriate clinical setting. Here, we report two cases of melanoma presenting as brainstem hemorrhages and review the management of these rare lesions. In one patient, no primary lesion was identified, raising the possibility of a primary CNS lesion. 2. Case report 2.1. Case 1 A 69-year-old right-handed male with a previous medical history that included hypertension and prostate cancer presented with acute dizziness and diplopia. On physical examination, his cranial nerve testing was significant for bilateral sixth nerve palsies and upgaze restriction. Pupils were 3 mm on the right and 3.5 mm on the left and reactive. Sensorimotor examination revealed full strength in all extremities but left-sided drift and sensory extinction. Initial head CT revealed a 1.3-cm right dorsal midbrain hemorrhage (Fig. 1A). A CT angiogram (CTA) was negative for vascular lesions, however a magnetic resonance angiogram preformed at this time confirmed a hemorrhagic lesion in the subacute methemoglobin phase that was thought to be a cavernous malformation (Fig. 1B and C). A CT of the chest, abdomen, and pelvis revealed only a known, benign mass of the left kidney. After one week, the patient improved neurologically as the hemorrhage was resolving, and he was discharged. Three months later, the patient presented again with acute loss of consciousness. CTA revealed a marked change in the colliculus lesions, with a 2.6 × 3.4 cm brainstem hemorrhage extending into the inferior left thalamus (Fig. 2). Given the patient’s deteriorating condition and lack of other treatment options, he underwent
Fig. 2. Axial non-contrast CT image showing enlarged 2.1 × 2.6 × 3.4 cm hemorrhage extending into the medial inferior aspect of the thalamus. Image de tomodensitométrie axiale sans contraste montrant une hémorragie s’étendant à la face inférieure interne du thalamus.
microsurgical resection of the hemorrhagic brainstem lesion via a right occipital transtentorial approach. Intraoperatively, the brainstem in the area of the lesion was noted to be darkly discolored. Histopathology showed a well-vascularized tumor with hyperchromatic nuclei and faint eosinophilic cytoplasm (Fig. 3). Immunohistochemistry was positive for S100 and negative for glial fibrillary acidic protein (GFAP), keratin, and cd20. All findings were consistent with a diagnosis of melanoma. Three months after surgery, he suffered a further hemorrhage and was placed on comfort care. No primary site other than the observed lesion was identified, raising the possibility of a primary CNS melanoma.
Fig. 1. A. Axial non-contrast CT image showing a 1.3 cm brainstem hemorrhage. B. Axial gadolinium-enhanced T1-weighted MRI demonstrating a non-enhancing hyperintense lesion centered within the superior colliculus consistent with a subacute hemorrhage from a previously presumed cavernoma. C. Sagittal gadolinium-enhanced T1-weighted MRI showing the lesion in the dorsal midbrain. A. Scanner en coupe axiale sans contraste montrant une hémorragie de 1,3 cm de diamètre dans le tronc cérébral. B. IRM en séquence T1 avec gadolinium montrant un hypersignal centré dans le colliculus supérieur compatible avec une hémorragie subaiguë du cavernome présumé. C. IRM en T1 avec Gadolinium en incidence sagittale montrant la lésion dans le mésencéphale dorsal.
Please cite this article in press as: Lu AY, et al. Brainstem melanomas presenting as a cavernous malformation. Neurochirurgie (2014), http://dx.doi.org/10.1016/j.neuchi.2014.02.005
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Fig. 3. A. Hematoxylin and eosin stain (40 × magnification) showing a well-vascularized tumor with cells arranged in monotonous sheets with hyperchromatic nuclei and faint eosinophilic cytoplasm surrounding focal pleomorphism. B. S100 stain (40 × magnification) showing areas of S100 positivity, consistent with melanoma. A. Coloration à l’hématoxyline et à l’éosine (40×) montrant une tumeur bien vascularisée avec des cellules disposées en feuillets avec des noyaux hyperchromatiques et cytoplasme éosinophile. B. Coloration S100 (40×) montrant les zones de positivité S100, caractéristiques du mélanome.
Fig. 4. A. Axial non-contrast CT image revealing a pontine hemorrhage measuring 2.2 × 1.5 cm. B. Axial gadolinium-enhanced T1-weighted MRI, which shows an enhancing lesion within the pons. C. Sagittal gadolinium-enhanced T1-weighted MRI demonstrating the lesion between acute and subacute hemorrhagic state. A. Scanner sans injection révélant une hémorragie pontique mesurant 2,2 × 1,5 cm. B. IRM en T1 postgadolinium en incidence axiale qui montre une lésion pontique. C. IRM T1 gadolinium sagittale montrant la lésion hémorragique aiguë ou subaiguë.
2.2. Case 2 A 62-year-old right-handed female presented with one week of dizziness and dysphagia. A neurologic examination showed no other cranial nerve deficit, full strength, and intact sensation. Initial imaging studies revealed a 2.2 × 1.5 cm acute pontine hemorrhage with no clearly identifiable underlying mass (Fig. 4). No other intracranial lesions were identified. CT of the chest, abdomen, and pelvis revealed two masses within the right lung. One week after initial presentation, the patient developed dysarthria, a nuclear third and sixth nerve palsies along with right hemiparesis. Additional imaging studies revealed enlargement of the pontine hemorrhage to 3 cm (Fig. 5). The location and multiple hemorrhages suggested the presence of a brainstem cavernous malformation or hemorrhagic metastatic tumor. Based on the progressive clinical decline, a midline suboccipital craniotomy was performed for evacuation of the pontine hematoma. Post-operative MRI demonstrated evacuation of the pontine hematoma with only a small amount of residual hemorrhage. Histopathology from the pontine lesion was consistent with melanoma. Immediate post-operative neurologic examination demonstrated a right third nerve palsy, left facial weakness, and stable antigravity right hemiparesis with some resistance. There was improvement in right lateral gaze with persistent restriction of left lateral gaze. The patient was discharged to an inpatient rehabilitation facility two weeks after surgery. A biopsy of the lung lesions also revealed the diagnosis of melanoma. No definitive skin lesion was identified despite a dermatological evaluation. The patient underwent a single round of whole-brain
Fig. 5. Axial non-contrast CT image revealing an enlarging hematoma (2.8 × 2.1 cm) within the pons. Image axiale de CT sans injection révélant un hématome agrandissement centropontique.
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radiation therapy (WBRT) for treatment of her metastatic disease. She died 5.5 months after initial presentation. 3. Discussion The most frequent occurrence of melanoma in the central nervous system (CNS) is through metastasis. Some series suggest that CNS metastasis occurs at a frequency of greater than 50% [3–6]. Up to 20% of melanoma patients with CNS involvement also have brainstem involvement [6]. Primary melanocytic tumors of the CNS, originating from melanoblasts accompanying the pial sheaths of vascular bundles or from neuroectodermal rest cells during embryogenesis [7], are much more rare and should only be considered primary after a thorough evaluation determines the absence of cutaneous, mucosal (GI) and retinal disease. While melanoma is classically considered a radioresistant lesion, various sources suggest a dose responsive effect [8,9]. Recent literature has focused on the role of stereotactic radiosurgery (SRS) for local management of brainstem metastases. Nonetheless, metastatic melanoma has a median survival of 113 days [3]. Kased et al. and Hatiboglu et al. have characterized outcomes from patients with brainstem metastasis from melanoma. Kased et al. found melanoma to be associated with a “poor brainstem outcome”, which was defined as a complication within the brainstem or treatment failure [10]. Hatiboglu et al. reported an association with shorter local progression-free survival in patients with brainstem melanoma when compared to those with other primary cancers [11]. A newer and increasingly prevalent treatment modality for melanoma metastases to the brain, including the brainstem, is immunotherapy [5]. Ipilimumab is a monoclonal antibody against cytotoxic T lymphocyte antigen-4 (CTLA-4) that has shown a CNS response rate of 16% in a phase II study. Another class of therapeutic with promise is BRAF inhibitors. Many melanomas express a mutated form of the BRAF gene. Dabrafenib and vemurafenib are two inhibitors of mutant BRAF that are currently being evaluated in clinical trials and early results indicate that some patients have shown response [12]. Lambrolizumab (previously known as MK3475) is an anti-programmed death-1 monoclonal antibody that has also shown promise in treating advanced melanoma [13]. The treatment of brainstem melanoma metastasis poses a great challenge for physicians. Obtaining the correct diagnosis remains the foremost challenge for these lesions that may be mistaken for brainstem cavernomas. T1-weighted, T2-weighted, and T2* or susceptibility-weighted sequences are used to assess hemorrhage, age of the hemorrhage, and with the additional help of post-contrast imaging, exclude an underlying mass. CTA and postcontrast imaging can also assess other vascular lesions [14]. While cavernomas typically have a hemosiderin ring, a recent hemorrhage from a cavernoma may be indistinguishable from other acute or early subacute hemorrhagic lesion. It is particularly important to consider other diagnoses when clusters of hemorrhages occur because hemorrhagic metastases may also present in this manner. Once a diagnosis of metastatic brainstem melanoma is confirmed, SRS is a treatment option that may reduce morbidity when
compared to WBRT or open surgery, and should be considered in patients with smaller lesions (< 3 cm) and few melanoma metastases throughout the rest of the brain. While the overall efficacy of SRS with melanoma remains uncertain, recent data suggests there is a benefit [15]. The goal of treatment should be to control local progression as overall survival is more likely influenced by systemic burden of disease. Concomitant immunotherapy should also be considered. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments We would like to thank Dr. Dennis D. Spencer for his input on the clinical management of the patient described in Case 1, and Dr. Ajay Malhotra for his input on how best to diagnose hemorrhage in the brainstem. References [1] Fuentes S, Delsanti C, Metellus P, Peragut JC, Grisoli F, Regis J. Brainstem metastases: management using gamma knife radiosurgery. Neurosurgery 2006;58(1):37–42. [2] Watanabe M, Nakao Y, Yamamoto T, Mori K, Wada R. Intra-axial brainstem malignant melanoma mimicking cavernous angioma–case report. Neurol Med Chir 2008;48(11):519–21. [3] Sampson JH, Carter JH, Friedman AH, Seigler HF. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 1998;88(1):11–20. [4] Amer MH, Al Sarraf M, Baker LH, Vaitkevicius VK. Malignant melanoma and central nervous system metastases: incidence, diagnosis, treatment and survival. Cancer 1978;42(2):660–8. [5] Carlino M, Fogarty G, Long G. Treatment of melanoma brain metastases: a new paradigm. Cancer J 2012;18(2):208–12. [6] de la Monte SM, Moore GW, Hutchins GM. Patterned distribution of metastases from malignant melanoma in humans. Cancer Res 1983;43(7):3427–33. [7] Farrokh D, Fransen P, Faverly D. MR findings of a primary intramedullary malignant melanoma: case report and literature review. AJNR Am J Neuroradiol 2011;22:1864–6. [8] Barranco SC, Romsdahl MM, Humphrey RM. The radiation response of human malignant melanoma cells grown in vitro. Cancer Res 1971;31(6): 830–3. [9] Wadasadawala T, Trivedi S, Gupta T, Epari S, Jalali R. The diagnostic dilemma of primary central nervous system melanoma. J Clin Neurosci 2010;17(8): 1014–7. [10] Kased N, Huang K, Nakamura JL, Sahgal A, Larson DA, McDermott MW, et al. Gamma knife radiosurgery for brainstem metastases: the UCSF experience. J Neurooncol 2008;86(2):195–205. [11] Hatiboglu MA, Chang EL, Suki D, Sawaya R, Wildrick DM, Weinberg JS. Outcomes and prognostic factors for patients with brainstem metastases undergoing stereotactic radiosurgery. Neurosurgery 2011;69(4):796–806. [12] Yoo TW, Park ES, Kwon do H, Kim CJ. Gamma knife radiosurgery for brainstem metastasis. J Korean Neurosurg Soc 2011;50(4):299–303. [13] Hamid O, Robert C, Daud A, Hodi FS, Hwu W, Kefford R, et al. Safety and tumor responses with lambrolizumab (Anti–PD-1) in melanoma. N Engl J Med 2013;369(2):134–44. [14] Kidwell CS, Wintermark M. Imaging of intracranial haemorrhage. Lancet Neurol 2008;7:256–67. [15] Kawabe T, Yamamoto M, Sato Y, Barfod BE, Urakawa Y, Kasuya H, et al. Gamma Knife surgery for patients with brainstem metastases. J Neurosurg 2012;117 Suppl.:23–30.
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Clinical case
Brainstem melanomas presenting as a cavernous malformation Mélanomes du tronc cérébral mimant un cavernome A.Y. Lu a , A.R. Patel b , G.A. Kuzmik a , K.-K. Atsina a , R.A. Bronen a,c , P.M. Jabbour d , D.M. Hasan e , A.O. Vortmeyer f , B.G. Welch b , K.R. Bulsara a,∗ a
Department of Neurosurgery, Yale School of Medicine, New Haven CT 06510, United States University of Texas Southwestern Medical Center, Dallas TX 75390, United States c Department of Diagnostic Radiology, Yale University School of Medicine, New Haven CT 06510, United States d Department of Neurosurgery, Thomas Jefferson University and Jefferson Hospital for Neuroscience, Philadelphia PA 19107, United States e Department of Neurosurgery, University of Iowa, Iowa City, IA 52242, United States f Department of Pathology, Yale School of Medicine, New Haven CT 06510, United States b
a r t i c l e
i n f o
Article history: Received 21 November 2013 Received in revised form 16 January 2014 Accepted 19 February 2014 Available online xxx Keywords: Brain stem Melanoma Cavernous malformations of CNS and retina
a b s t r a c t Background. – Melanoma lesions in the brainstem can be difficult to distinguish radiographically and clinically from cavernous malformations. However, the treatment modalities and clinical course of these two diseases differ considerably. We report two cases of melanoma presenting as brainstem hemorrhages. Case description. – A 69-year-old male was found to have a hemorrhagic lesion of the right dorsal midbrain. After a repeat hemorrhage, the lesion was resected and found to be hyperchromatic. Nonetheless, the patient suffered rebleeding and died 3 months later. A 62-year-old female was similarly found to have an acute pontine hemorrhage. After resection of the lesion, she underwent whole-brain radiation therapy but ultimately died 5.5 months later. The histopathology of both lesions was consistent with melanoma. Conclusions. – Melanoma in the brainstem can mimic cavernous malformations. While management of these lesions includes stereotactic radiosurgery, whole-brain radiation, and surgical resection, metastatic brainstem melanoma follows an aggressive clinical course with a poor prognosis. © 2014 Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Tronc cérébral Mélanome Malformations caverneuses du système nerveux central et de la rétine
Contexte. – Les lésions de mélanome localisées au tronc cérébral peuvent être difficiles à distinguer cliniquement et radiologiquement des malformations caverneuses. Toutefois, les modalités de traitement et l’évolution clinique de ces deux maladies sont très différentes. Nous rapportons deux cas de mélanome se présentant comme des hémorragies du tronc cérébral. Descriptions de cas. – Un homme de 69 ans était atteint d’une lésion hémorragique du mésencéphale dorsal. Après un deuxième épisode hémorragique, la lésion a été réséquée et était hyperchromatique. Pourtant le patient a présenté une récidive hémorragique et est décédé 3 mois plus tard. Une femme de 62 ans a présenté une hémorragie pontique aiguë. Après résection de la lésion, elle a subi une radiothérapie pan-cérébrale mais est décédée 5,5 mois plus tard. L’examen histopathologique des deux lésions était compatible avec un mélanome. Conclusions. – Les mélanomes localisés au tronc cérébral peuvent imiter les cavernomes. Alors que le traitement de ces lésions comprend la radiochirurgie stéréotaxique, la radiothérapie du pan-cérébrale et la résection chirurgicale, le mélanome métastatique du tronc cérébral est de mauvais pronostic. © 2014 Elsevier Masson SAS. Tous droits réservés.
Abbreviations: CNS, Central nervous system; CT, Computed tomography; CTA, CT angiogram; MRI, Magnetic resonance imaging; SRS, Stereotactic radiosurgery; WBRT, Whole-brain radiation therapy. ∗ Corresponding author. Yale Department of Neurosurgery, TMP 4 New Haven, CT 06520. E-mail address: [email protected] (K.R. Bulsara). http://dx.doi.org/10.1016/j.neuchi.2014.02.005 0028-3770/© 2014 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Lu AY, et al. Brainstem melanomas presenting as a cavernous malformation. Neurochirurgie (2014), http://dx.doi.org/10.1016/j.neuchi.2014.02.005
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1. Introduction Melanoma represents the third most common type of cancer to metastasize to the brain. Malignant metastases to the brainstem are rare, accounting for only 3–5% of all brain metastases [1]. Given their tendency to hemorrhage, metastatic melanoma lesions of the brainstem may mimic cavernous malformations, which likewise present as focal brainstem hemorrhages [2]. The clinical course of melanoma of the brainstem is decidedly more aggressive than that of cavernomas with a median survival of only four months [3]. Accordingly, melanoma should be considered in the differential diagnosis of brainstem hemorrhages in the appropriate clinical setting. Here, we report two cases of melanoma presenting as brainstem hemorrhages and review the management of these rare lesions. In one patient, no primary lesion was identified, raising the possibility of a primary CNS lesion. 2. Case report 2.1. Case 1 A 69-year-old right-handed male with a previous medical history that included hypertension and prostate cancer presented with acute dizziness and diplopia. On physical examination, his cranial nerve testing was significant for bilateral sixth nerve palsies and upgaze restriction. Pupils were 3 mm on the right and 3.5 mm on the left and reactive. Sensorimotor examination revealed full strength in all extremities but left-sided drift and sensory extinction. Initial head CT revealed a 1.3-cm right dorsal midbrain hemorrhage (Fig. 1A). A CT angiogram (CTA) was negative for vascular lesions, however a magnetic resonance angiogram preformed at this time confirmed a hemorrhagic lesion in the subacute methemoglobin phase that was thought to be a cavernous malformation (Fig. 1B and C). A CT of the chest, abdomen, and pelvis revealed only a known, benign mass of the left kidney. After one week, the patient improved neurologically as the hemorrhage was resolving, and he was discharged. Three months later, the patient presented again with acute loss of consciousness. CTA revealed a marked change in the colliculus lesions, with a 2.6 × 3.4 cm brainstem hemorrhage extending into the inferior left thalamus (Fig. 2). Given the patient’s deteriorating condition and lack of other treatment options, he underwent
Fig. 2. Axial non-contrast CT image showing enlarged 2.1 × 2.6 × 3.4 cm hemorrhage extending into the medial inferior aspect of the thalamus. Image de tomodensitométrie axiale sans contraste montrant une hémorragie s’étendant à la face inférieure interne du thalamus.
microsurgical resection of the hemorrhagic brainstem lesion via a right occipital transtentorial approach. Intraoperatively, the brainstem in the area of the lesion was noted to be darkly discolored. Histopathology showed a well-vascularized tumor with hyperchromatic nuclei and faint eosinophilic cytoplasm (Fig. 3). Immunohistochemistry was positive for S100 and negative for glial fibrillary acidic protein (GFAP), keratin, and cd20. All findings were consistent with a diagnosis of melanoma. Three months after surgery, he suffered a further hemorrhage and was placed on comfort care. No primary site other than the observed lesion was identified, raising the possibility of a primary CNS melanoma.
Fig. 1. A. Axial non-contrast CT image showing a 1.3 cm brainstem hemorrhage. B. Axial gadolinium-enhanced T1-weighted MRI demonstrating a non-enhancing hyperintense lesion centered within the superior colliculus consistent with a subacute hemorrhage from a previously presumed cavernoma. C. Sagittal gadolinium-enhanced T1-weighted MRI showing the lesion in the dorsal midbrain. A. Scanner en coupe axiale sans contraste montrant une hémorragie de 1,3 cm de diamètre dans le tronc cérébral. B. IRM en séquence T1 avec gadolinium montrant un hypersignal centré dans le colliculus supérieur compatible avec une hémorragie subaiguë du cavernome présumé. C. IRM en T1 avec Gadolinium en incidence sagittale montrant la lésion dans le mésencéphale dorsal.
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Fig. 3. A. Hematoxylin and eosin stain (40 × magnification) showing a well-vascularized tumor with cells arranged in monotonous sheets with hyperchromatic nuclei and faint eosinophilic cytoplasm surrounding focal pleomorphism. B. S100 stain (40 × magnification) showing areas of S100 positivity, consistent with melanoma. A. Coloration à l’hématoxyline et à l’éosine (40×) montrant une tumeur bien vascularisée avec des cellules disposées en feuillets avec des noyaux hyperchromatiques et cytoplasme éosinophile. B. Coloration S100 (40×) montrant les zones de positivité S100, caractéristiques du mélanome.
Fig. 4. A. Axial non-contrast CT image revealing a pontine hemorrhage measuring 2.2 × 1.5 cm. B. Axial gadolinium-enhanced T1-weighted MRI, which shows an enhancing lesion within the pons. C. Sagittal gadolinium-enhanced T1-weighted MRI demonstrating the lesion between acute and subacute hemorrhagic state. A. Scanner sans injection révélant une hémorragie pontique mesurant 2,2 × 1,5 cm. B. IRM en T1 postgadolinium en incidence axiale qui montre une lésion pontique. C. IRM T1 gadolinium sagittale montrant la lésion hémorragique aiguë ou subaiguë.
2.2. Case 2 A 62-year-old right-handed female presented with one week of dizziness and dysphagia. A neurologic examination showed no other cranial nerve deficit, full strength, and intact sensation. Initial imaging studies revealed a 2.2 × 1.5 cm acute pontine hemorrhage with no clearly identifiable underlying mass (Fig. 4). No other intracranial lesions were identified. CT of the chest, abdomen, and pelvis revealed two masses within the right lung. One week after initial presentation, the patient developed dysarthria, a nuclear third and sixth nerve palsies along with right hemiparesis. Additional imaging studies revealed enlargement of the pontine hemorrhage to 3 cm (Fig. 5). The location and multiple hemorrhages suggested the presence of a brainstem cavernous malformation or hemorrhagic metastatic tumor. Based on the progressive clinical decline, a midline suboccipital craniotomy was performed for evacuation of the pontine hematoma. Post-operative MRI demonstrated evacuation of the pontine hematoma with only a small amount of residual hemorrhage. Histopathology from the pontine lesion was consistent with melanoma. Immediate post-operative neurologic examination demonstrated a right third nerve palsy, left facial weakness, and stable antigravity right hemiparesis with some resistance. There was improvement in right lateral gaze with persistent restriction of left lateral gaze. The patient was discharged to an inpatient rehabilitation facility two weeks after surgery. A biopsy of the lung lesions also revealed the diagnosis of melanoma. No definitive skin lesion was identified despite a dermatological evaluation. The patient underwent a single round of whole-brain
Fig. 5. Axial non-contrast CT image revealing an enlarging hematoma (2.8 × 2.1 cm) within the pons. Image axiale de CT sans injection révélant un hématome agrandissement centropontique.
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radiation therapy (WBRT) for treatment of her metastatic disease. She died 5.5 months after initial presentation. 3. Discussion The most frequent occurrence of melanoma in the central nervous system (CNS) is through metastasis. Some series suggest that CNS metastasis occurs at a frequency of greater than 50% [3–6]. Up to 20% of melanoma patients with CNS involvement also have brainstem involvement [6]. Primary melanocytic tumors of the CNS, originating from melanoblasts accompanying the pial sheaths of vascular bundles or from neuroectodermal rest cells during embryogenesis [7], are much more rare and should only be considered primary after a thorough evaluation determines the absence of cutaneous, mucosal (GI) and retinal disease. While melanoma is classically considered a radioresistant lesion, various sources suggest a dose responsive effect [8,9]. Recent literature has focused on the role of stereotactic radiosurgery (SRS) for local management of brainstem metastases. Nonetheless, metastatic melanoma has a median survival of 113 days [3]. Kased et al. and Hatiboglu et al. have characterized outcomes from patients with brainstem metastasis from melanoma. Kased et al. found melanoma to be associated with a “poor brainstem outcome”, which was defined as a complication within the brainstem or treatment failure [10]. Hatiboglu et al. reported an association with shorter local progression-free survival in patients with brainstem melanoma when compared to those with other primary cancers [11]. A newer and increasingly prevalent treatment modality for melanoma metastases to the brain, including the brainstem, is immunotherapy [5]. Ipilimumab is a monoclonal antibody against cytotoxic T lymphocyte antigen-4 (CTLA-4) that has shown a CNS response rate of 16% in a phase II study. Another class of therapeutic with promise is BRAF inhibitors. Many melanomas express a mutated form of the BRAF gene. Dabrafenib and vemurafenib are two inhibitors of mutant BRAF that are currently being evaluated in clinical trials and early results indicate that some patients have shown response [12]. Lambrolizumab (previously known as MK3475) is an anti-programmed death-1 monoclonal antibody that has also shown promise in treating advanced melanoma [13]. The treatment of brainstem melanoma metastasis poses a great challenge for physicians. Obtaining the correct diagnosis remains the foremost challenge for these lesions that may be mistaken for brainstem cavernomas. T1-weighted, T2-weighted, and T2* or susceptibility-weighted sequences are used to assess hemorrhage, age of the hemorrhage, and with the additional help of post-contrast imaging, exclude an underlying mass. CTA and postcontrast imaging can also assess other vascular lesions [14]. While cavernomas typically have a hemosiderin ring, a recent hemorrhage from a cavernoma may be indistinguishable from other acute or early subacute hemorrhagic lesion. It is particularly important to consider other diagnoses when clusters of hemorrhages occur because hemorrhagic metastases may also present in this manner. Once a diagnosis of metastatic brainstem melanoma is confirmed, SRS is a treatment option that may reduce morbidity when
compared to WBRT or open surgery, and should be considered in patients with smaller lesions (< 3 cm) and few melanoma metastases throughout the rest of the brain. While the overall efficacy of SRS with melanoma remains uncertain, recent data suggests there is a benefit [15]. The goal of treatment should be to control local progression as overall survival is more likely influenced by systemic burden of disease. Concomitant immunotherapy should also be considered. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments We would like to thank Dr. Dennis D. Spencer for his input on the clinical management of the patient described in Case 1, and Dr. Ajay Malhotra for his input on how best to diagnose hemorrhage in the brainstem. References [1] Fuentes S, Delsanti C, Metellus P, Peragut JC, Grisoli F, Regis J. Brainstem metastases: management using gamma knife radiosurgery. Neurosurgery 2006;58(1):37–42. [2] Watanabe M, Nakao Y, Yamamoto T, Mori K, Wada R. Intra-axial brainstem malignant melanoma mimicking cavernous angioma–case report. Neurol Med Chir 2008;48(11):519–21. [3] Sampson JH, Carter JH, Friedman AH, Seigler HF. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 1998;88(1):11–20. [4] Amer MH, Al Sarraf M, Baker LH, Vaitkevicius VK. Malignant melanoma and central nervous system metastases: incidence, diagnosis, treatment and survival. Cancer 1978;42(2):660–8. [5] Carlino M, Fogarty G, Long G. Treatment of melanoma brain metastases: a new paradigm. Cancer J 2012;18(2):208–12. [6] de la Monte SM, Moore GW, Hutchins GM. Patterned distribution of metastases from malignant melanoma in humans. Cancer Res 1983;43(7):3427–33. [7] Farrokh D, Fransen P, Faverly D. MR findings of a primary intramedullary malignant melanoma: case report and literature review. AJNR Am J Neuroradiol 2011;22:1864–6. [8] Barranco SC, Romsdahl MM, Humphrey RM. The radiation response of human malignant melanoma cells grown in vitro. Cancer Res 1971;31(6): 830–3. [9] Wadasadawala T, Trivedi S, Gupta T, Epari S, Jalali R. The diagnostic dilemma of primary central nervous system melanoma. J Clin Neurosci 2010;17(8): 1014–7. [10] Kased N, Huang K, Nakamura JL, Sahgal A, Larson DA, McDermott MW, et al. Gamma knife radiosurgery for brainstem metastases: the UCSF experience. J Neurooncol 2008;86(2):195–205. [11] Hatiboglu MA, Chang EL, Suki D, Sawaya R, Wildrick DM, Weinberg JS. Outcomes and prognostic factors for patients with brainstem metastases undergoing stereotactic radiosurgery. Neurosurgery 2011;69(4):796–806. [12] Yoo TW, Park ES, Kwon do H, Kim CJ. Gamma knife radiosurgery for brainstem metastasis. J Korean Neurosurg Soc 2011;50(4):299–303. [13] Hamid O, Robert C, Daud A, Hodi FS, Hwu W, Kefford R, et al. Safety and tumor responses with lambrolizumab (Anti–PD-1) in melanoma. N Engl J Med 2013;369(2):134–44. [14] Kidwell CS, Wintermark M. Imaging of intracranial haemorrhage. Lancet Neurol 2008;7:256–67. [15] Kawabe T, Yamamoto M, Sato Y, Barfod BE, Urakawa Y, Kasuya H, et al. Gamma Knife surgery for patients with brainstem metastases. J Neurosurg 2012;117 Suppl.:23–30.
Please cite this article in press as: Lu AY, et al. Brainstem melanomas presenting as a cavernous malformation. Neurochirurgie (2014), http://dx.doi.org/10.1016/j.neuchi.2014.02.005
