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Microsurgery for the treatment of primary malignant intracranial melanoma: A surgical series and literature review J. Wang, Z.-Z. Guo, Y.-J. Wang*, S.-G. Zhang, D.-G. Xing Department of Neurosurgery, The First Hospital of China Medical University, No 155 Nanjing North Street, Heping Ward, Shenyang 110001, China Accepted 24 November 2013 Available online - - -
Abstracts Background: Primary malignant intracranial melanomas are rare tumors of the central nervous system. These tumors are highly malignant and are associated with poor prognosis. The field of neurosurgery has struggled with the diagnosis and treatment of these tumors. Methods: In this study, we present a surgical series of eight patients with primary malignant intracranial melanomas and retrospectively analyze the clinical features, imaging findings, pathological features and prognoses of these patients. Results: All patients underwent microsurgery. Total and subtotal resection of the tumor was achieved in six and two patients, respectively. Of the eight patients, seven showed improvement while one remained the same at time of discharge. There was no neurosurgical deterioration. Radiotherapy was conducted in six patients after operation. The average follow-up duration was 13.8 months (range ¼ 9e26 months). During the follow-up period, three patients died from this disease. One patient suffered from recurrence at the 16th month and underwent second surgery. The other patients were still alive with no evidence of tumor recurrence. Conclusion: Microsurgery and radiotherapy should be the first line managements for patients with primary malignant intracranial melanomas. Improvements in chemotherapy, immunotherapy and targeted therapies may provide more effective treatments for malignant intracranial melanomas. Ó 2013 Elsevier Ltd. All rights reserved. Keywords: Melanoma; Microsurgery; Radiotherapy; Chemotherapy
Introduction Malignant intracranial melanomas are divided into primary and secondary subtypes, depending on the origin of the tumor. Primary malignant intracranial melanoma is a rare tumor of the central nervous system, while the development of secondary or brain metastatic melanomas is a frequent occurrence in patients with disseminated melanoma. These tumors are highly malignant and are associated with poor prognosis.1e6 The rarity of the primary malignant intracranial melanomas contributes to the high chance of misdiagnosis. The author of this report diagnosed and treated eight patients with primary malignant intracranial melanoma between January 2002 and September 2013. All these patients underwent microsurgery. Pathological examinations confirmed that the resected lesions were * Corresponding author. Tel.: þ86 024 83283132; fax: þ86 024 83283313. E-mail addresses: [email protected], [email protected] (Y.-J. Wang).
consistent with the diagnosis of malignant melanoma. In the current report, the clinical characteristics of these cases and treatment strategies for malignant melanoma were discussed. A review of relevant literature was conducted to explore the therapeutic strategies for this type of rare disease. Materials and methods Selection of patients Our surgical series included 8 patients, who had malignant intracranial melanomas surgically resected at the First Hospital of China Medical University between January 2002 and September 2013. In this series, 6 patients were female and two male. Their ages ranged from 33 to 74 years (median ¼ 55.4 years). The lesions were located in the left frontal lobe in 2 patients, the bottom of the left temporal fossa in 2 (Figs. 1e3), right frontal lobe in 2, posterior brainstem in 1 (Fig. 4), right parietal lobe in 1 (Table 1).
0748-7983/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2013.11.024 Please cite this article in press as: Wang J, et al., Microsurgery for the treatment of primary malignant intracranial melanoma: A surgical series and literature review, Eur J Surg Oncol (2013), http://dx.doi.org/10.1016/j.ejso.2013.11.024
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Figure 1. Pre- and postoperative CT and MRI scans in the patient accompanied by Nevus of Ota. (AeE) CT and MRI scans on 05/16/2009 showing a very small lesion in the tentorium cerebelli area with short T1 and T2 signals. (FeK) MRI scans on 04/20/2010 showing a slow growth of the lesion. (L) CT scans on 07/13/2011 showing a rapid growth of the lesion. (MeS) Postoperative CT scans on 07/21/2011 and enhanced MRI scans on 08/24/2011 showing complete resection of the lesion. (T) CT scans on 12/25/2011 showing the recurrence of the lesion.
Treatments All patients underwent tumor excision by microneurosurgery operations. Surgeries were performed in general anesthesia using the operating microscope and microsurgical instrumentation in all cases. The lesion was approached by a standard pterional craniotomy in one
patient. Frontal and parietal craniotomy was administered in four and one patients, respectively. Subtemporal craniotomy was used in one patient. Suboccipital craniotomy was taken in the remnant one patient. The lesions were found to be soft and gray and black in color, with relatively clear border separating the tumor from the normal brain tissue in 6 patients. These lesions could be removed gently
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Figure 2. Pre- and postoperative CT and MRI scans in the second operation. (A) Preoperative cranial CT showing high-density lesions. (BeG) Preoperative enhanced cranial MRI showing the origin of the lesion in the tentorium cerebelli with short T1 and T2 signals of significant intensification and the “dural tail sign”. (H,I) Large amount of melanin pigmentation were detected in the region covered by branch I and II of the left facial trigeminal nerve, sclera and palate. (J,K) The lesion was observed intraoperatively as having a shiny black color and originated from the tentorium cerebelli, with obvious thickening and complete melanosis of the local dura mater. (L) Postoperative cranial CT showing a clean surgical cavity. (MeT) Postoperative enhanced MRI showing complete resection of the lesion.
without damage to the surrounding tissues. In contrast, in the brainstem melanoma patient, there was no clear border separating the tumor from the pons and then the vast majority of the tumor was resected under the microscope. In the other patient accompanied by Nevus of Ota, large amounts of melanin pigmentation were observed intraoperatively in
the scalp, subcutaneous tissue, periosteum, skull, dura mater, arachnoid and pia mater (especially at the cranial base). The tumor was originated from the dura mater of the middle cranial fossa, with obvious thickening and complete melanosis in the dura mater of the entire middle cranial fossa. Therefore, the largest lesion was resected prior
Please cite this article in press as: Wang J, et al., Microsurgery for the treatment of primary malignant intracranial melanoma: A surgical series and literature review, Eur J Surg Oncol (2013), http://dx.doi.org/10.1016/j.ejso.2013.11.024
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Figure 3. Postoperative pathology at 200. (A) Hematoxylin and eosin (H&E) staining showing large nuclei and clear heteromorphism, with a large amount of melanin pigmentation. (BeD) Immunohistochemistry showing strong positive staining. B, S-100 (þ); C, HMB45 (þ); D, Melan-A (þ).
to electric coagulation in the dura mater of the cranial base and then only subtotal resection of the tumor was achieved in this patient. Radiotherapy was conducted in 6 patients after operation. The other two patients decided to abandon this treatment because of the side effects of radiation therapy. After the surgery, the diagnosis of malignant melanoma was confirmed through postoperative pathological examination and the final diagnosis of primary intracranial melanoma was consistent with the three basic conditions outlined by Willis. Results Clinical manifestations Clinically, symptoms at onset were headache in 3 patients, numbness and weakness in the limbs in 2, partial epilepsy in 1, facial numbness in 1. The tumor was found incidentally in one patient. The average duration of these symptoms was 14 months with the duration ranging from a minimum of 2 weeks to a maximum of 16 months. Karnofsky Performance Status (KPS) ranges from 50 to 100. Detailed clinical presentations are summarized in Table 1.
CT angiography (3D-CTA) scanning to determine the relationship of the tumor to the internal carotid artery, as well as any bony changes, such as erosive and compressive changes. The volume of the tumors varied from 3.3 2.2 2.8 cm to 4.2 5.2 6.0 cm. A cranial magnetic resonance imaging (MRI) scan revealed short T1 and slightly long T2 signals in the lesions overall, though mixed signals were observed in various portions of the lesions. Surgical outcomes An MRI was performed within 72 h of surgery for all patients to confirm whether there was any remnant tumor. Total resection of the tumor was achieved in six patients (Figs. 1 and 2) and subtotal resection of the tumor was achieved in two (Fig. 4). Of the eight patients, seven showed improvement while one remained the same at time of discharge. There was no neurosurgical deterioration. The average follow-up duration was 13.8 months (range ¼ 9e26 months). During the follow-up period, three patients died from this disease (or severe edema secondary to radiotherapy). One patient suffered from recurrence at the 16th month and underwent second surgery. The other patients were still alive with no evidence of tumor recurrence. Pathological results
Radiological findings Before surgery, all patients were evaluated by CTand MRI scans. One patient was also evaluated by three-dimensional
All lesions resected were pathologically examined and the diagnosis of malignant melanoma was confirmed. Light microscopy demonstrated that the tumor cells were
Please cite this article in press as: Wang J, et al., Microsurgery for the treatment of primary malignant intracranial melanoma: A surgical series and literature review, Eur J Surg Oncol (2013), http://dx.doi.org/10.1016/j.ejso.2013.11.024
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Figure 4. Pre- and postoperative MRI scans of the brainstem melanoma. (A) Preoperative enhanced MRI presenting a tumor with significant enhancement in the posterior pons. (B) A cross-section of the tumor displaying an equal T2 signal. (C) A sagittal section of the tumor displaying a short T1 signal. (D) Preoperative enhanced MRI presenting a sagittal section of the malignant brainstem melanoma. (E) Postoperative MRI scan. The T2 signal of the cross-section suggested that the tumor was nearly completely resected. (F) Postoperative MRI scan. The T1 signal of the sagittal section suggested that the tumor was nearly completely resected. (G) Postoperative pathological examination of the melanoma. H&E staining revealed a large amount of pigmentation, 40. (H) Strong, positive immunoreactivity to the melanoma cell-specific monoclonal antibody HMB-45, 100.
distributed in a concentric or slightly one-sided manner. Morphologically, they exhibited a long spindle or polygonal shape. A portion or most cells contained a large amount of melanin, and the nuclei were large and showed signs of mitosis. Immunohistochemistry revealed that all lesions were immunoreactive to antibodies of human melanoma black 45 (HMB45) and melanoma, while six lesions revealed positive immunoreactivity with sangtec100 (S-100). Discussion The epidemiology of intracranial melanoma Primary intracranial melanomas are notably rare. The first identified instance of this tumor was reported by
Virchow in 1859.1 Malignant intracranial melanomas are divided into primary and secondary subtypes, depending on the origin of the tumor. Primary intracranial melanomas are further divided into three categories: diffuse leptomeningeal melanoma (or melanoma fibromatosis), melanoma and primary malignant melanoma.1,2,4 Statistically, the incidence of primary intracranial melanomas in the population is approximately 0.005/100,000. Men are more likely to develop these tumors than women.1,3,5 Malignant intracranial melanomas account for approximately 0.1% of all intracranial tumors.1e4 In addition, primary intracranial melanomas predominantly originate from the leptomeningeal melanocytes. Proliferation of the leptomeningeal melanocytes can produce benign or malignant tumors. These cells are found underneath the brain and the brainstem, inside the ventricles, at the optic chiasm, in the grooves of the
Please cite this article in press as: Wang J, et al., Microsurgery for the treatment of primary malignant intracranial melanoma: A surgical series and literature review, Eur J Surg Oncol (2013), http://dx.doi.org/10.1016/j.ejso.2013.11.024
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Table 1 Clinical summary of 8 patients with primary malignant intracranial melanomas. Patient
Age(yrs)/ sex
Clinical symptoms
Location
Extent of resection
Treatment
Follow-up (mths)
1 2
74/M 52/F
Posterior pons Bottom of the left temporal fossa
Subtotal Total
Neurosurgery, radiotherapy Neurosurgery, radiotherapy
9/Deatha 16/10/Alive
3 4 5
58/F 47/M 33/F
Intermittent headache with nausea and vomiting Sixteen months after receiving intracranial surgery for a malignant melanoma, headache, dizziness and nausea Numbness and weakness in the right limbs Headache, partial epilepsy, intermittent aphasia Intermittent headache, facial numbness of the left side
Total Total Subtotal
Neurosurgery Neurosurgery, radiotherapy Neurosurgery, radiotherapy
22/Deathb 16/Alive 14/Alive
6 7 8
49/F 67/F 63/F
Left frontal lobe Left frontal lobe The bottom of the left temporal fossa, left temporal lobe Right frontal lobe Right parietal lobe Right frontal lobe
Total Total Total
Neurosurgery, radiotherapy Neurosurgery, radiotherapy Neurosurgery
13/Deathc 11/Alive 9/Alive
None Weakness in the left limbs, headache Headache, slow response
a Hydrocephalus caused by the residual tumor and brainstem edema (from radiotherapy) was detected at the 7 months follow-up. However, the patient family refused to take VeP shunt because of the body condition of the patient. Sudden death occurred to the patient 2 months later, although mannitol and dexamethasone was injected for several weeks. b Tumor recurrence was found at the 16th month after surgery. The patient refused to take second operation or radiotherapy because of economic reasons. c Severe brain edema and suspected tumor recurrence was found at the 10th month after radiotherapy. The patient refused to take bony decompression surgery due to the poor prognosis of this disease and economic reasons.
various lobes, in the substantia nigra and in the choroid.1,2,6e8 Furthermore, these intracranial lesions are usually secondary malignant melanomas. In this report, a postoperative systemic examination (including CT scans of chest and abdomen, skin and eye examinations) revealed all cases exhibited no lesions in the other parts of his body and he had no history of melanoma surgery (non-brain). Thus, all patients were diagnosed with primary malignant brainstem melanoma. This diagnosis was also consistent with the three basic conditions for diagnosing primary melanoma as outlined by Willis. These criteria include: (1) no skin or eye melanoma; (2) no history of melanoma surgery in the skin or eyes and (3) no extracranial visceral melanoma metastases. Several scholars believe that only a meticulous autopsy can exclude possible extracranial melanomas.9 Remarkably, two patients in this group were accompanied by nevus of Ota. Nevus of Ota can be complicated with intracranial malignant melanoma, which mainly occurs in patients with intracranial metastases of malignantly transformed nevus of Ota or primary intracranial malignant melanoma. The two patients in the current report demonstrated the latter type of disease, which was even more rare. The clinical features of malignant intracranial melanoma The clinical features of malignant intracranial melanoma are generally atypical. In addition to the focal neurological deficits caused by lesions in different parts of the body, patients can also present with symptoms related to chronically increased intracranial pressure. These symptoms include headache, nausea, vomiting, acutely increased intracranial pressure and epilepsy secondary to lesion hemorrhage.1,10e14 The international literature reveals that the
incidences of the initial clinical symptoms are as follows: intracranial hypertension and hydrocephalus (43.2%); focal neurological deficits (34.6%); intracerebral hemorrhage or subarachnoid hemorrhage (17.3%); and secondary epilepsy (11.1%).1 In general, malignant intracranial melanomas are associated with an acute onset, a short clinical course and high mortality. The prognoses of patients with primary malignant intracranial melanomas are slightly better than those of patients with secondary malignant melanomas. These individuals have been reported to survive for more than 10 years, but the average survival time is still short.1,5 The imaging features of malignant intracranial melanoma Malignant intracranial melanomas may display high (common) or equal/low densities on CT scans. These tumors are enhanced by contrast CT but generally lack specificity. However, MRI scans often reveal features of typical melanoma lesions that are different than those of other intracranial tumors, such as meningioma and glioma. The melanin in melanoma lesions often produce high signal intensities in T1WI, low signal intensities in T2WI and high signal intensities in the FLAIR scans. The degree of enhancement varies.7,10e14 MRI scans of malignant intracranial melanomas reveal features specific to the disease. In typical malignant intracranial melanoma cells, the melanin contains free radicals and unpaired electrons. These molecules can produce superfluous metal ion complexes, which shorten the T1WI and T2WI relaxation times on MRI. Malignant intracranial melanomas are divided into four subtypes according to the melanin content of the tumors and they may show different imaging features on MRI scans. The subtypes include: (1) melanoma, characterized by a high T1WI signal intensity, a low T2WI signal
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intensity and equal or high signal intensity on a proton density-weighted scan; (2) non-melanoma, characterized by low or equal T1WI signal intensity, high or equal T2WI signal intensity and high or equal signal intensity on a proton density-weighted scan; (3) uncertain or mixed, characterized by an MRI signal that is different from those of the melanoma and non-melanoma types and can exhibit a mixed nature; and (4) hemorrhagic lesions, characterized by the different phases of bleeding. The melanoma (Type 1) and hemorrhagic (Type 4) lesions are the most common and account for approximately 70% of malignant intracranial melanomas.1 In this report, all patients presented tumors that were rich with melanoma cells. The imaging features of their lesions were consistent with those of Type 1. Although malignant intracranial melanomas present specific imaging features, the disease remains difficult to diagnose, due to its low incidence, and misdiagnosis is therefore common. As some authors pointed out, primary malignant intracranial melanomas are easily misdiagnosed as meningioma, preoperatively.1,5,8 Two patients in the present report had been misdiagnosed with other tumors prior to surgery. The correct diagnoses were not made until the black lesions that are typical of the disease were discovered during surgery. Thus, sometimes, it is difficult to diagnose malignant intracranial melanomas just based on imagistic findings. We agree that the diagnosis of the disease relies on preoperative, intraoperative and postoperative pathological findings.1,4 The pathological features of malignant intracranial melanoma Pathological diagnosis is the gold standard for diagnosing malignant melanomas. Routine H&E and immunohistochemical staining techniques can help diagnose the majority of malignant melanomas. H&E staining can also reveal the overall morphology of the tumor cells. Under a light microscope, the cells are polygonal or spindleshaped and exhibit signs of mitosis and hyperpigmentation. Immunohistochemical staining of the tumor tissue with a variety of antibodies can diagnose the disease and differentiate it from other diseases. The S-100, melanomaassociated antigen (Melanoma), anti-melanoma antibody HMB-45 and Vimentin (VIM) are highly specific to malignant melanomas.1,2,10 S-100 was the first marker to be associated with the disease. Immunochemistry with the S-100 antibody is highly sensitive (95%) to malignant melanomas. HMB-45 is a newly discovered specific antimelanoma cell antibody that binds to pre-melanosome globulin and reacts with melanoma-specific antigens and incomplete melanoma cells. Therefore, HMB-45 is a valuable, highly sensitive and highly specific tool for pathologically diagnosing hypochromic or amelanotic malignant melanomas in clinical settings. VIM is a mesenchymal tumor marker that plays a complementary role in the diagnosis and the differential diagnosis of malignant
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melanoma when used in concert with other markers. EMA is an epithelial membrane marker. Though EMA is not expressed in malignant melanoma cells, it can be used to identify neuroepithelial tumors such as meningiomas and gliomas. In contrast, glial fibrillary acidic protein (GFAP) and cell keratin (CK) are usually not expressed in meningeal melanomas. These markers are inconsistently expressed in malignant intracranial melanomas and are therefore used only as references.1,2,4,10 In this report, HMB-45 and Melanoma were both highly expressed in the tumors from all patients. S-100 was highly expressed in 6 cased but was not detected in 2 cased, and Vimentin was highly expressed in 5 cases but was not detected in 3 cases. Comprehensive treatment of malignant intracranial melanoma The current treatment of primary and secondary malignant intracranial melanomas does not guarantee an optimistic prognosis. Microsurgery, local radiation therapy (such as SRS), whole-brain radiotherapy (WBRT), chemotherapy, immunotherapy and targeted therapies are currently administered to treat the disease. Combinations of these treatment options are also employed.1,2,4,6,8,10e38 Surgical resection We and most authors agree that whenever possible, complete surgical excision and/or radiotherapy should be the first line managements (standard practice) for patients with primary malignant intracranial melanoma or limited (one to three) brain metastatic melanomas (secondary).1,22e28 The consideration of surgical resection is dependent upon the location and size of the tumor, the number of lesions, the overall state of systemic disease and symptoms of patients at the time of diagnosis. In general, for patients with single primary malignant intracranial melanoma lesion, if the lesion 3 cm in diameter that present with significant mass effects (or peritumorial edema) or CSF obstruction, microsurgical excision should be recommended first and then followed by local radiotherapy (such as SRS) or SRS þ WBRT.1,3,6,9,22,23,25e27,29 The prognoses of the patients that undergo complete resection are better than those of the patients who undergo partial resection.1,22,23 Moreover, the prognoses of patients who undergo microsurgery with SRS and/or WBRT are better than those of patients who undergo either microsurgery or WBRT alone.1,22,24,23 The treatment protocol is different if the primary malignant intracranial melanoma is relatively small (maximum diameter < 3 cm) or is deep in the brain and resection of the tumor will cause significant neurologic sequelae (but the diagnosis has been confirmed by stereotactic biopsy). In these cases, local radiotherapy (SRS or Gamma-knife (GK)) or auxiliary WBRT are indicated.3,6,7,22,25,29e31 For patients with brain metastatic melanomas (secondary), resection is also the first line
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management for patients with a favorable prognosis with limited (one to three) brain metastases, according to National Comprehensive Cancer Network (NCCN) guidelines.23 An overall survival advantage of resection has been shown in several large retrospective studies over best supportive care (6.5e8.7 vs. 1.3e2.1 months).23 And other studies have also shown improved outcomes with surgery when compared with WBRT alone.23,29
performance status and serum LDH values indicate whether patients with advanced intra- and extracranial tumor manifestations are candidates for palliative WBRT or best supportive care.26 Currently, most authors agree that WBRT (alone or in combination with chemotherapy) still remains an option for palliation in patients with multiple brain metastatic melanomas or in whom resection or SRS is not feasible.23
Radiosurgery It is well known that, in contrast to large (>3 cm) lesions, smaller lesions are easily treated via radiosurgery. Radiosurgery, such as stereotactic radiosurgery (SRS) and GK, has emerged as a comparable alterative to resection of brain metastases.23,25,30,31 And in small case series reports, survival following radiosurgery (either SRS or GK) has been quite encouraging.22,23,25,30,31 Stereotactic radiosurgery appears to overcome the inherent radioresistance of brain metastasis from melanoma and, thereby, affords a high rate of local tumor control. Reports from leading centers indicate a favorable benefit to risk profile for radiosurgery in melanoma patients. Local tumor control after radiosurgery generally exceeds 80%, and neurological complications as a result of radiosurgery are infrequent.25 A higher performance status and lower intracranial tumor burden in melanoma patients at the time of radiosurgery are associated with longer survival.25 Therefore, as mentioned above, most authors agree that radiosurgery (such as SRS or GK) should be recommended for deep, smaller (3 cm, total number of lesions 7), or residual lesions (the diagnosis of malignant intracranial melanoma has been confirmed by resection or stereotactic biopsy) with minimal neurologic symptoms, minimal vasogenic edema, and absence of hydrocephalus or midline shift.22,23,30,31
Chemotherapy/immunotherapy/targeted therapies Currently, standard chemotherapy agents used in the treatment of metastatic melanoma have shown limited response rates in the management of brain metastases.23 The lack of efficacy of these drugs results from their inability to penetrate the bloodebrain barrier (BBB) and astrocyte protection against chemotherapy-induced apoptosis through paracrine signaling.23 However, as some authors pointed out, when the tumors grow beyond 1e2 mm in diameter within the brain parenchyma, the BBB becomes structurally and functionally comprised, increasing the permeability.23 Currently, a number of chemotherapy agents for malignant intracranial melanoma have been already in Stage II or Stage III clinical trials and have achieved some success.20e23,33,36,37 Of the chemotherapy agents studied to date, temozolomide and fotemustine appear to have the most intracrainial disease activity.23,33 However, no improvement has been observed in the overall survival.23 Other therapeutic strategies, including immunotherapy-based regimes (such as highdose interleukin-2, autologous tumor-infiltrating lymphocytes or T-cell receptor-transduced lymphocytes, anticytotoxic T-lymphocyte antigen 4 therapy with ipilimumab), have also been utilized in metastatic melanoma patients and active responses (including prolonged the overall survival) were obtained in some cases.19,20,23,32,34e36 In addition, recently discovered mutations in the melanoma genome have led to the development of “targeted therapy”. Thus, many clinical investigators are also exploring the efficacy of gene therapy (targeted therapy) for intracranial malignant melanoma. Of the genetic mutations identified in melanoma cells, a single mutation in BRAF (V600E) has been proved to be existing in about 50e60% of human cutaneous melanomas.21e23,37 Therefore, some researchers are now exploring the application of BRAF inhibitor therapy (e.g, vemurafenib, dabrafenib) in metastatic brain melanoma patients with BRAF V600 mutations, and the preliminary data has been presented at the 2011 ASCO General Meeting.21e23,26,37,38 In conclusion, although current standard treatments with neurosurgery and/or radiotherapy have improved the overall survival of patients with intracranial melanomas, the treatment of malignant intracranial melanomas still remains an on going challenge to neurosurgeons. Improvements in chemotherapy, immunotherapy and targeted therapies may provide more effective treatments for malignant intracranial melanomas.
Whole brain radiotherapy Traditionally, whole brain radiotherapy has been used or considered a useful method to treat brain metastasis.22 And surgery followed by WBRT therapy is a category 1 recommendation by NCCN guidelines for patients with limited brain metastases.22,23 In contrast, many scholars believe that melanoma is insensitive to radiotherapy or radioresistant to the commonly used doses (e.g., 30Gy in 10 fractions over 2 weeks elapsed time).22,24,25 Recent studies have shown that the addition of adjuvant WBRT to resection significantly decreases the local recurrence rate and neurologic complications when compared with surgery alone.23,29 And the combination of WBRT with SRS has been shown to be more effective in prospective studies than either WBRT or SRS alone.14,23,29 However, no improvement in the overall survival was found in either study, and concerns exist over cognitive decline with WBRT.22,23 Therefore, some authors ever ask themselves if WBRT should automatically be added after surgical excision and/SRS.22 Recent studies show that Karnofsky
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Statement All the authors listed in the article made contributions to the study and there are no financial conflicts. This study has been supported by the National Natural Science Foundation of China (No. 31100770).
14.
15.
Conflict of interest statement 16.
None. 17.
Acknowledgments 18.
This study has been supported by the National Natural Science Foundation of China (No. 31100770). We thank all the other staffs of the neurosurgery department of the first hospital of China Medical University for their technical help.
19.
20.
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32.
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randomized controlled multicentre phase III trial. J Neurooncol 2008;87(3):299–307. Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004;363(9422):1665–72. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006;295(21):2483–91. Gogas HJ, Kirkwood JM, Sondak VK. Chemotherapy for metastatic melanoma: time for a change? Cancer 2007;109(3):455–64. Perez DG, Suman VJ, Fitch TR, et al. Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N047A. Cancer 2009;115(1):119–27. Kottschade LA, Suman VJ, Amatruda 3rd T, et al. A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1). Cancer 2011;117(8):1704–10. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8):711–23. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364(26):2517–26. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364(26):2507–16. Shapiro DG, Samlowski WE. Management of melanoma brain metastases in the era of targeted therapy. J Skin Cancer 2011;845863. Gibney GT, Forsyth PA, Sondak VK. Melanoma in the brain: biology and therapeutic options. Melanoma Res 2012;22(3):177–83. Jaiswal S, Vij M, Tungria A, Jaiswal AK, Srivastava AK, Behari S. Primary melanocytic tumors of the central nervous system: a neuroradiological and clinicopathological study of five cases and brief review of literature. Neurol India 2011;59(3):413–9. Ramakrishna N, Margolin KA. Multidisciplinary approach to brain metastasis from melanoma; local therapies for central nervous system metastases. Am Soc Clin Oncol Educ Book 2013; 2013:399–403. Partl R, Richtig E, Avian A, Berghold A, Kapp KS. Karnofsky performance status and lactate dehydrogenase predict the benefit of palliative whole-brain irradiation in patients with advanced intra- and extracranial metastases from malignant melanoma. Int J Radiat Oncol Biol Phys 2012;85(3):662–6. Ewend MG, Morris DE, Carey LA, Ladha AM, Brem S. Guidelines for the initial management of metastatic brain tumors: role of surgery, radiosurgery, and radiation therapy. J Natl Compr Canc Netw 2008; 6(5):505–13. Konstadoulakis MM, Messaris E, Zografos G, Androulakis G, Karakousis C. Prognostic factors in malignant melanoma patients with solitary or multiple brain metastases. Is there a role for surgery? J Neurosurg Sci 2000;44(4):211–8. Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol 2011;29(2):134–41. Alexander III E, Moriarty TM, Davis RB, et al. Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases. J Natl Cancer Inst 1995;87(1):34–40. Flickinger JC, Kondziolka D, Lunsford LD, et al. A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 1994;28(4):797–802. Hong JJ, Rosenberg SA, Dudley ME, et al. Successful treatment of melanoma brain metastases with adoptive cell therapy. Clin Cancer Res 2010;16(19):4892–8.
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33. Agarwala SS, Kirkwood JM, Gore M, et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol 2004;22(11):2101–7. 34. Guirguis LM, Yang JC, White DE, et al. Safety and efficacy of highdose interleukin-2 therapy in patients with brain metastases. J Immunother 2002;25(1):82–7. 35. Powell S, Dudek AZ. Single-institution outcome of high-dose interleukin-2 (HD IL-2) therapy for metastatic melanoma and analysis of favorable response in brain metastases. Anticancer Res 2009;29(10): 4189–93.
36. Di Giacomo AM, Ascierto PA, Fonsatti E, et al. Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an openlabel, single-arm phase 2 trial. Lancet Oncol 2012;13(9):879–86. 37. Kirkwood JM, Bastholt L, Robert C, et al. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res 2012;18(2):555–67. 38. Rochet NM, Dronca RS, Kottschade LA, et al. Melanoma brain metastases and vemurafenib: need for further investigation. Mayo Clin Proc 2012;87(10):976–81.
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Microsurgery for the treatment of primary malignant intracranial melanoma: A surgical series and literature review J. Wang, Z.-Z. Guo, Y.-J. Wang*, S.-G. Zhang, D.-G. Xing Department of Neurosurgery, The First Hospital of China Medical University, No 155 Nanjing North Street, Heping Ward, Shenyang 110001, China Accepted 24 November 2013 Available online - - -
Abstracts Background: Primary malignant intracranial melanomas are rare tumors of the central nervous system. These tumors are highly malignant and are associated with poor prognosis. The field of neurosurgery has struggled with the diagnosis and treatment of these tumors. Methods: In this study, we present a surgical series of eight patients with primary malignant intracranial melanomas and retrospectively analyze the clinical features, imaging findings, pathological features and prognoses of these patients. Results: All patients underwent microsurgery. Total and subtotal resection of the tumor was achieved in six and two patients, respectively. Of the eight patients, seven showed improvement while one remained the same at time of discharge. There was no neurosurgical deterioration. Radiotherapy was conducted in six patients after operation. The average follow-up duration was 13.8 months (range ¼ 9e26 months). During the follow-up period, three patients died from this disease. One patient suffered from recurrence at the 16th month and underwent second surgery. The other patients were still alive with no evidence of tumor recurrence. Conclusion: Microsurgery and radiotherapy should be the first line managements for patients with primary malignant intracranial melanomas. Improvements in chemotherapy, immunotherapy and targeted therapies may provide more effective treatments for malignant intracranial melanomas. Ó 2013 Elsevier Ltd. All rights reserved. Keywords: Melanoma; Microsurgery; Radiotherapy; Chemotherapy
Introduction Malignant intracranial melanomas are divided into primary and secondary subtypes, depending on the origin of the tumor. Primary malignant intracranial melanoma is a rare tumor of the central nervous system, while the development of secondary or brain metastatic melanomas is a frequent occurrence in patients with disseminated melanoma. These tumors are highly malignant and are associated with poor prognosis.1e6 The rarity of the primary malignant intracranial melanomas contributes to the high chance of misdiagnosis. The author of this report diagnosed and treated eight patients with primary malignant intracranial melanoma between January 2002 and September 2013. All these patients underwent microsurgery. Pathological examinations confirmed that the resected lesions were * Corresponding author. Tel.: þ86 024 83283132; fax: þ86 024 83283313. E-mail addresses: [email protected], [email protected] (Y.-J. Wang).
consistent with the diagnosis of malignant melanoma. In the current report, the clinical characteristics of these cases and treatment strategies for malignant melanoma were discussed. A review of relevant literature was conducted to explore the therapeutic strategies for this type of rare disease. Materials and methods Selection of patients Our surgical series included 8 patients, who had malignant intracranial melanomas surgically resected at the First Hospital of China Medical University between January 2002 and September 2013. In this series, 6 patients were female and two male. Their ages ranged from 33 to 74 years (median ¼ 55.4 years). The lesions were located in the left frontal lobe in 2 patients, the bottom of the left temporal fossa in 2 (Figs. 1e3), right frontal lobe in 2, posterior brainstem in 1 (Fig. 4), right parietal lobe in 1 (Table 1).
0748-7983/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2013.11.024 Please cite this article in press as: Wang J, et al., Microsurgery for the treatment of primary malignant intracranial melanoma: A surgical series and literature review, Eur J Surg Oncol (2013), http://dx.doi.org/10.1016/j.ejso.2013.11.024
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Figure 1. Pre- and postoperative CT and MRI scans in the patient accompanied by Nevus of Ota. (AeE) CT and MRI scans on 05/16/2009 showing a very small lesion in the tentorium cerebelli area with short T1 and T2 signals. (FeK) MRI scans on 04/20/2010 showing a slow growth of the lesion. (L) CT scans on 07/13/2011 showing a rapid growth of the lesion. (MeS) Postoperative CT scans on 07/21/2011 and enhanced MRI scans on 08/24/2011 showing complete resection of the lesion. (T) CT scans on 12/25/2011 showing the recurrence of the lesion.
Treatments All patients underwent tumor excision by microneurosurgery operations. Surgeries were performed in general anesthesia using the operating microscope and microsurgical instrumentation in all cases. The lesion was approached by a standard pterional craniotomy in one
patient. Frontal and parietal craniotomy was administered in four and one patients, respectively. Subtemporal craniotomy was used in one patient. Suboccipital craniotomy was taken in the remnant one patient. The lesions were found to be soft and gray and black in color, with relatively clear border separating the tumor from the normal brain tissue in 6 patients. These lesions could be removed gently
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Figure 2. Pre- and postoperative CT and MRI scans in the second operation. (A) Preoperative cranial CT showing high-density lesions. (BeG) Preoperative enhanced cranial MRI showing the origin of the lesion in the tentorium cerebelli with short T1 and T2 signals of significant intensification and the “dural tail sign”. (H,I) Large amount of melanin pigmentation were detected in the region covered by branch I and II of the left facial trigeminal nerve, sclera and palate. (J,K) The lesion was observed intraoperatively as having a shiny black color and originated from the tentorium cerebelli, with obvious thickening and complete melanosis of the local dura mater. (L) Postoperative cranial CT showing a clean surgical cavity. (MeT) Postoperative enhanced MRI showing complete resection of the lesion.
without damage to the surrounding tissues. In contrast, in the brainstem melanoma patient, there was no clear border separating the tumor from the pons and then the vast majority of the tumor was resected under the microscope. In the other patient accompanied by Nevus of Ota, large amounts of melanin pigmentation were observed intraoperatively in
the scalp, subcutaneous tissue, periosteum, skull, dura mater, arachnoid and pia mater (especially at the cranial base). The tumor was originated from the dura mater of the middle cranial fossa, with obvious thickening and complete melanosis in the dura mater of the entire middle cranial fossa. Therefore, the largest lesion was resected prior
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Figure 3. Postoperative pathology at 200. (A) Hematoxylin and eosin (H&E) staining showing large nuclei and clear heteromorphism, with a large amount of melanin pigmentation. (BeD) Immunohistochemistry showing strong positive staining. B, S-100 (þ); C, HMB45 (þ); D, Melan-A (þ).
to electric coagulation in the dura mater of the cranial base and then only subtotal resection of the tumor was achieved in this patient. Radiotherapy was conducted in 6 patients after operation. The other two patients decided to abandon this treatment because of the side effects of radiation therapy. After the surgery, the diagnosis of malignant melanoma was confirmed through postoperative pathological examination and the final diagnosis of primary intracranial melanoma was consistent with the three basic conditions outlined by Willis. Results Clinical manifestations Clinically, symptoms at onset were headache in 3 patients, numbness and weakness in the limbs in 2, partial epilepsy in 1, facial numbness in 1. The tumor was found incidentally in one patient. The average duration of these symptoms was 14 months with the duration ranging from a minimum of 2 weeks to a maximum of 16 months. Karnofsky Performance Status (KPS) ranges from 50 to 100. Detailed clinical presentations are summarized in Table 1.
CT angiography (3D-CTA) scanning to determine the relationship of the tumor to the internal carotid artery, as well as any bony changes, such as erosive and compressive changes. The volume of the tumors varied from 3.3 2.2 2.8 cm to 4.2 5.2 6.0 cm. A cranial magnetic resonance imaging (MRI) scan revealed short T1 and slightly long T2 signals in the lesions overall, though mixed signals were observed in various portions of the lesions. Surgical outcomes An MRI was performed within 72 h of surgery for all patients to confirm whether there was any remnant tumor. Total resection of the tumor was achieved in six patients (Figs. 1 and 2) and subtotal resection of the tumor was achieved in two (Fig. 4). Of the eight patients, seven showed improvement while one remained the same at time of discharge. There was no neurosurgical deterioration. The average follow-up duration was 13.8 months (range ¼ 9e26 months). During the follow-up period, three patients died from this disease (or severe edema secondary to radiotherapy). One patient suffered from recurrence at the 16th month and underwent second surgery. The other patients were still alive with no evidence of tumor recurrence. Pathological results
Radiological findings Before surgery, all patients were evaluated by CTand MRI scans. One patient was also evaluated by three-dimensional
All lesions resected were pathologically examined and the diagnosis of malignant melanoma was confirmed. Light microscopy demonstrated that the tumor cells were
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Figure 4. Pre- and postoperative MRI scans of the brainstem melanoma. (A) Preoperative enhanced MRI presenting a tumor with significant enhancement in the posterior pons. (B) A cross-section of the tumor displaying an equal T2 signal. (C) A sagittal section of the tumor displaying a short T1 signal. (D) Preoperative enhanced MRI presenting a sagittal section of the malignant brainstem melanoma. (E) Postoperative MRI scan. The T2 signal of the cross-section suggested that the tumor was nearly completely resected. (F) Postoperative MRI scan. The T1 signal of the sagittal section suggested that the tumor was nearly completely resected. (G) Postoperative pathological examination of the melanoma. H&E staining revealed a large amount of pigmentation, 40. (H) Strong, positive immunoreactivity to the melanoma cell-specific monoclonal antibody HMB-45, 100.
distributed in a concentric or slightly one-sided manner. Morphologically, they exhibited a long spindle or polygonal shape. A portion or most cells contained a large amount of melanin, and the nuclei were large and showed signs of mitosis. Immunohistochemistry revealed that all lesions were immunoreactive to antibodies of human melanoma black 45 (HMB45) and melanoma, while six lesions revealed positive immunoreactivity with sangtec100 (S-100). Discussion The epidemiology of intracranial melanoma Primary intracranial melanomas are notably rare. The first identified instance of this tumor was reported by
Virchow in 1859.1 Malignant intracranial melanomas are divided into primary and secondary subtypes, depending on the origin of the tumor. Primary intracranial melanomas are further divided into three categories: diffuse leptomeningeal melanoma (or melanoma fibromatosis), melanoma and primary malignant melanoma.1,2,4 Statistically, the incidence of primary intracranial melanomas in the population is approximately 0.005/100,000. Men are more likely to develop these tumors than women.1,3,5 Malignant intracranial melanomas account for approximately 0.1% of all intracranial tumors.1e4 In addition, primary intracranial melanomas predominantly originate from the leptomeningeal melanocytes. Proliferation of the leptomeningeal melanocytes can produce benign or malignant tumors. These cells are found underneath the brain and the brainstem, inside the ventricles, at the optic chiasm, in the grooves of the
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Table 1 Clinical summary of 8 patients with primary malignant intracranial melanomas. Patient
Age(yrs)/ sex
Clinical symptoms
Location
Extent of resection
Treatment
Follow-up (mths)
1 2
74/M 52/F
Posterior pons Bottom of the left temporal fossa
Subtotal Total
Neurosurgery, radiotherapy Neurosurgery, radiotherapy
9/Deatha 16/10/Alive
3 4 5
58/F 47/M 33/F
Intermittent headache with nausea and vomiting Sixteen months after receiving intracranial surgery for a malignant melanoma, headache, dizziness and nausea Numbness and weakness in the right limbs Headache, partial epilepsy, intermittent aphasia Intermittent headache, facial numbness of the left side
Total Total Subtotal
Neurosurgery Neurosurgery, radiotherapy Neurosurgery, radiotherapy
22/Deathb 16/Alive 14/Alive
6 7 8
49/F 67/F 63/F
Left frontal lobe Left frontal lobe The bottom of the left temporal fossa, left temporal lobe Right frontal lobe Right parietal lobe Right frontal lobe
Total Total Total
Neurosurgery, radiotherapy Neurosurgery, radiotherapy Neurosurgery
13/Deathc 11/Alive 9/Alive
None Weakness in the left limbs, headache Headache, slow response
a Hydrocephalus caused by the residual tumor and brainstem edema (from radiotherapy) was detected at the 7 months follow-up. However, the patient family refused to take VeP shunt because of the body condition of the patient. Sudden death occurred to the patient 2 months later, although mannitol and dexamethasone was injected for several weeks. b Tumor recurrence was found at the 16th month after surgery. The patient refused to take second operation or radiotherapy because of economic reasons. c Severe brain edema and suspected tumor recurrence was found at the 10th month after radiotherapy. The patient refused to take bony decompression surgery due to the poor prognosis of this disease and economic reasons.
various lobes, in the substantia nigra and in the choroid.1,2,6e8 Furthermore, these intracranial lesions are usually secondary malignant melanomas. In this report, a postoperative systemic examination (including CT scans of chest and abdomen, skin and eye examinations) revealed all cases exhibited no lesions in the other parts of his body and he had no history of melanoma surgery (non-brain). Thus, all patients were diagnosed with primary malignant brainstem melanoma. This diagnosis was also consistent with the three basic conditions for diagnosing primary melanoma as outlined by Willis. These criteria include: (1) no skin or eye melanoma; (2) no history of melanoma surgery in the skin or eyes and (3) no extracranial visceral melanoma metastases. Several scholars believe that only a meticulous autopsy can exclude possible extracranial melanomas.9 Remarkably, two patients in this group were accompanied by nevus of Ota. Nevus of Ota can be complicated with intracranial malignant melanoma, which mainly occurs in patients with intracranial metastases of malignantly transformed nevus of Ota or primary intracranial malignant melanoma. The two patients in the current report demonstrated the latter type of disease, which was even more rare. The clinical features of malignant intracranial melanoma The clinical features of malignant intracranial melanoma are generally atypical. In addition to the focal neurological deficits caused by lesions in different parts of the body, patients can also present with symptoms related to chronically increased intracranial pressure. These symptoms include headache, nausea, vomiting, acutely increased intracranial pressure and epilepsy secondary to lesion hemorrhage.1,10e14 The international literature reveals that the
incidences of the initial clinical symptoms are as follows: intracranial hypertension and hydrocephalus (43.2%); focal neurological deficits (34.6%); intracerebral hemorrhage or subarachnoid hemorrhage (17.3%); and secondary epilepsy (11.1%).1 In general, malignant intracranial melanomas are associated with an acute onset, a short clinical course and high mortality. The prognoses of patients with primary malignant intracranial melanomas are slightly better than those of patients with secondary malignant melanomas. These individuals have been reported to survive for more than 10 years, but the average survival time is still short.1,5 The imaging features of malignant intracranial melanoma Malignant intracranial melanomas may display high (common) or equal/low densities on CT scans. These tumors are enhanced by contrast CT but generally lack specificity. However, MRI scans often reveal features of typical melanoma lesions that are different than those of other intracranial tumors, such as meningioma and glioma. The melanin in melanoma lesions often produce high signal intensities in T1WI, low signal intensities in T2WI and high signal intensities in the FLAIR scans. The degree of enhancement varies.7,10e14 MRI scans of malignant intracranial melanomas reveal features specific to the disease. In typical malignant intracranial melanoma cells, the melanin contains free radicals and unpaired electrons. These molecules can produce superfluous metal ion complexes, which shorten the T1WI and T2WI relaxation times on MRI. Malignant intracranial melanomas are divided into four subtypes according to the melanin content of the tumors and they may show different imaging features on MRI scans. The subtypes include: (1) melanoma, characterized by a high T1WI signal intensity, a low T2WI signal
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intensity and equal or high signal intensity on a proton density-weighted scan; (2) non-melanoma, characterized by low or equal T1WI signal intensity, high or equal T2WI signal intensity and high or equal signal intensity on a proton density-weighted scan; (3) uncertain or mixed, characterized by an MRI signal that is different from those of the melanoma and non-melanoma types and can exhibit a mixed nature; and (4) hemorrhagic lesions, characterized by the different phases of bleeding. The melanoma (Type 1) and hemorrhagic (Type 4) lesions are the most common and account for approximately 70% of malignant intracranial melanomas.1 In this report, all patients presented tumors that were rich with melanoma cells. The imaging features of their lesions were consistent with those of Type 1. Although malignant intracranial melanomas present specific imaging features, the disease remains difficult to diagnose, due to its low incidence, and misdiagnosis is therefore common. As some authors pointed out, primary malignant intracranial melanomas are easily misdiagnosed as meningioma, preoperatively.1,5,8 Two patients in the present report had been misdiagnosed with other tumors prior to surgery. The correct diagnoses were not made until the black lesions that are typical of the disease were discovered during surgery. Thus, sometimes, it is difficult to diagnose malignant intracranial melanomas just based on imagistic findings. We agree that the diagnosis of the disease relies on preoperative, intraoperative and postoperative pathological findings.1,4 The pathological features of malignant intracranial melanoma Pathological diagnosis is the gold standard for diagnosing malignant melanomas. Routine H&E and immunohistochemical staining techniques can help diagnose the majority of malignant melanomas. H&E staining can also reveal the overall morphology of the tumor cells. Under a light microscope, the cells are polygonal or spindleshaped and exhibit signs of mitosis and hyperpigmentation. Immunohistochemical staining of the tumor tissue with a variety of antibodies can diagnose the disease and differentiate it from other diseases. The S-100, melanomaassociated antigen (Melanoma), anti-melanoma antibody HMB-45 and Vimentin (VIM) are highly specific to malignant melanomas.1,2,10 S-100 was the first marker to be associated with the disease. Immunochemistry with the S-100 antibody is highly sensitive (95%) to malignant melanomas. HMB-45 is a newly discovered specific antimelanoma cell antibody that binds to pre-melanosome globulin and reacts with melanoma-specific antigens and incomplete melanoma cells. Therefore, HMB-45 is a valuable, highly sensitive and highly specific tool for pathologically diagnosing hypochromic or amelanotic malignant melanomas in clinical settings. VIM is a mesenchymal tumor marker that plays a complementary role in the diagnosis and the differential diagnosis of malignant
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melanoma when used in concert with other markers. EMA is an epithelial membrane marker. Though EMA is not expressed in malignant melanoma cells, it can be used to identify neuroepithelial tumors such as meningiomas and gliomas. In contrast, glial fibrillary acidic protein (GFAP) and cell keratin (CK) are usually not expressed in meningeal melanomas. These markers are inconsistently expressed in malignant intracranial melanomas and are therefore used only as references.1,2,4,10 In this report, HMB-45 and Melanoma were both highly expressed in the tumors from all patients. S-100 was highly expressed in 6 cased but was not detected in 2 cased, and Vimentin was highly expressed in 5 cases but was not detected in 3 cases. Comprehensive treatment of malignant intracranial melanoma The current treatment of primary and secondary malignant intracranial melanomas does not guarantee an optimistic prognosis. Microsurgery, local radiation therapy (such as SRS), whole-brain radiotherapy (WBRT), chemotherapy, immunotherapy and targeted therapies are currently administered to treat the disease. Combinations of these treatment options are also employed.1,2,4,6,8,10e38 Surgical resection We and most authors agree that whenever possible, complete surgical excision and/or radiotherapy should be the first line managements (standard practice) for patients with primary malignant intracranial melanoma or limited (one to three) brain metastatic melanomas (secondary).1,22e28 The consideration of surgical resection is dependent upon the location and size of the tumor, the number of lesions, the overall state of systemic disease and symptoms of patients at the time of diagnosis. In general, for patients with single primary malignant intracranial melanoma lesion, if the lesion 3 cm in diameter that present with significant mass effects (or peritumorial edema) or CSF obstruction, microsurgical excision should be recommended first and then followed by local radiotherapy (such as SRS) or SRS þ WBRT.1,3,6,9,22,23,25e27,29 The prognoses of the patients that undergo complete resection are better than those of the patients who undergo partial resection.1,22,23 Moreover, the prognoses of patients who undergo microsurgery with SRS and/or WBRT are better than those of patients who undergo either microsurgery or WBRT alone.1,22,24,23 The treatment protocol is different if the primary malignant intracranial melanoma is relatively small (maximum diameter < 3 cm) or is deep in the brain and resection of the tumor will cause significant neurologic sequelae (but the diagnosis has been confirmed by stereotactic biopsy). In these cases, local radiotherapy (SRS or Gamma-knife (GK)) or auxiliary WBRT are indicated.3,6,7,22,25,29e31 For patients with brain metastatic melanomas (secondary), resection is also the first line
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management for patients with a favorable prognosis with limited (one to three) brain metastases, according to National Comprehensive Cancer Network (NCCN) guidelines.23 An overall survival advantage of resection has been shown in several large retrospective studies over best supportive care (6.5e8.7 vs. 1.3e2.1 months).23 And other studies have also shown improved outcomes with surgery when compared with WBRT alone.23,29
performance status and serum LDH values indicate whether patients with advanced intra- and extracranial tumor manifestations are candidates for palliative WBRT or best supportive care.26 Currently, most authors agree that WBRT (alone or in combination with chemotherapy) still remains an option for palliation in patients with multiple brain metastatic melanomas or in whom resection or SRS is not feasible.23
Radiosurgery It is well known that, in contrast to large (>3 cm) lesions, smaller lesions are easily treated via radiosurgery. Radiosurgery, such as stereotactic radiosurgery (SRS) and GK, has emerged as a comparable alterative to resection of brain metastases.23,25,30,31 And in small case series reports, survival following radiosurgery (either SRS or GK) has been quite encouraging.22,23,25,30,31 Stereotactic radiosurgery appears to overcome the inherent radioresistance of brain metastasis from melanoma and, thereby, affords a high rate of local tumor control. Reports from leading centers indicate a favorable benefit to risk profile for radiosurgery in melanoma patients. Local tumor control after radiosurgery generally exceeds 80%, and neurological complications as a result of radiosurgery are infrequent.25 A higher performance status and lower intracranial tumor burden in melanoma patients at the time of radiosurgery are associated with longer survival.25 Therefore, as mentioned above, most authors agree that radiosurgery (such as SRS or GK) should be recommended for deep, smaller (3 cm, total number of lesions 7), or residual lesions (the diagnosis of malignant intracranial melanoma has been confirmed by resection or stereotactic biopsy) with minimal neurologic symptoms, minimal vasogenic edema, and absence of hydrocephalus or midline shift.22,23,30,31
Chemotherapy/immunotherapy/targeted therapies Currently, standard chemotherapy agents used in the treatment of metastatic melanoma have shown limited response rates in the management of brain metastases.23 The lack of efficacy of these drugs results from their inability to penetrate the bloodebrain barrier (BBB) and astrocyte protection against chemotherapy-induced apoptosis through paracrine signaling.23 However, as some authors pointed out, when the tumors grow beyond 1e2 mm in diameter within the brain parenchyma, the BBB becomes structurally and functionally comprised, increasing the permeability.23 Currently, a number of chemotherapy agents for malignant intracranial melanoma have been already in Stage II or Stage III clinical trials and have achieved some success.20e23,33,36,37 Of the chemotherapy agents studied to date, temozolomide and fotemustine appear to have the most intracrainial disease activity.23,33 However, no improvement has been observed in the overall survival.23 Other therapeutic strategies, including immunotherapy-based regimes (such as highdose interleukin-2, autologous tumor-infiltrating lymphocytes or T-cell receptor-transduced lymphocytes, anticytotoxic T-lymphocyte antigen 4 therapy with ipilimumab), have also been utilized in metastatic melanoma patients and active responses (including prolonged the overall survival) were obtained in some cases.19,20,23,32,34e36 In addition, recently discovered mutations in the melanoma genome have led to the development of “targeted therapy”. Thus, many clinical investigators are also exploring the efficacy of gene therapy (targeted therapy) for intracranial malignant melanoma. Of the genetic mutations identified in melanoma cells, a single mutation in BRAF (V600E) has been proved to be existing in about 50e60% of human cutaneous melanomas.21e23,37 Therefore, some researchers are now exploring the application of BRAF inhibitor therapy (e.g, vemurafenib, dabrafenib) in metastatic brain melanoma patients with BRAF V600 mutations, and the preliminary data has been presented at the 2011 ASCO General Meeting.21e23,26,37,38 In conclusion, although current standard treatments with neurosurgery and/or radiotherapy have improved the overall survival of patients with intracranial melanomas, the treatment of malignant intracranial melanomas still remains an on going challenge to neurosurgeons. Improvements in chemotherapy, immunotherapy and targeted therapies may provide more effective treatments for malignant intracranial melanomas.
Whole brain radiotherapy Traditionally, whole brain radiotherapy has been used or considered a useful method to treat brain metastasis.22 And surgery followed by WBRT therapy is a category 1 recommendation by NCCN guidelines for patients with limited brain metastases.22,23 In contrast, many scholars believe that melanoma is insensitive to radiotherapy or radioresistant to the commonly used doses (e.g., 30Gy in 10 fractions over 2 weeks elapsed time).22,24,25 Recent studies have shown that the addition of adjuvant WBRT to resection significantly decreases the local recurrence rate and neurologic complications when compared with surgery alone.23,29 And the combination of WBRT with SRS has been shown to be more effective in prospective studies than either WBRT or SRS alone.14,23,29 However, no improvement in the overall survival was found in either study, and concerns exist over cognitive decline with WBRT.22,23 Therefore, some authors ever ask themselves if WBRT should automatically be added after surgical excision and/SRS.22 Recent studies show that Karnofsky
Please cite this article in press as: Wang J, et al., Microsurgery for the treatment of primary malignant intracranial melanoma: A surgical series and literature review, Eur J Surg Oncol (2013), http://dx.doi.org/10.1016/j.ejso.2013.11.024
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Statement All the authors listed in the article made contributions to the study and there are no financial conflicts. This study has been supported by the National Natural Science Foundation of China (No. 31100770).
14.
15.
Conflict of interest statement 16.
None. 17.
Acknowledgments 18.
This study has been supported by the National Natural Science Foundation of China (No. 31100770). We thank all the other staffs of the neurosurgery department of the first hospital of China Medical University for their technical help.
19.
20.
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