Metastatic melanoma (Pathological diagnosis: Amelanotic melanoma, metastatic to brain, with unknown primary site)
In this case, a 65 year old man presented with relatively acute onset of weakness on the left side of the body. Although a stroke was initially suspected by the emergency room staff, his presentation of gradual progression, lack of a well-defined sudden onset, and relatively patchy involvement (i.e., significant involvement of his upper extremity out of proportion to the lower extremity without involvement of his face) was quickly recognized as highly atypical for ischemic disease. A non-contrasted CT scan of the head revealed several hyperdense, well-circumscribed lesions of variable sizes, located near the gray-white junction, without a high degree of mass effect on adjacent tissue. The appearance of these lesions suggested hemorrhage, although many of the lesions exhibited small central hypodensities. MRI of the brain in this patient demonstrated the partially increased signal on T1 and decreased signal on T2 suggestive of intracellular methemoglobin, which may be seen in the first few days following acute hemorrhage into a lesion. and typically results in increased signal intensity in both T1 and T2 weighted scans. All of the lesions showed somewhat heterogenous signal, with some areas of increased signal intensity on both T1 and T2 weighted sequences, suggestive of presence of extracellular as well as intracellular methemoglobin, which is usually seen several days after onset of hemorrhage.
The occurrence of multiple hemorrhagic lesions near the gray-white junction in a previously healthy older man without clear risk factors suggesting an alternative cause should always raise concerns for metastatic malignancy. Other potential causes of multiple hemorrhagic brain lesions of similar ages include hemorrhagic embolic infarctions in cases of infective endocarditis, multiple foci of bleeding associated with a hematologic disorder, and (less likely) hematologic spread of vasoinvasive organisms such as Aspergillus spp. Occasionally, tuberculomas in poorly controlled patients may hemorrhage, but simultaneous hemorrhage of multiple sites would be extremely rare. Cerebral vasculitis may also present with multiple hemorrhagic brain lesions, although rarely of identical age. The lesions associated with vasculitides typically involve deep as well as superficial sites, and frequently are accompanied (or dominated by) ischemic lesions corresponding to vascular territories. Other potential causes of well-circumscribed lesions near the gray-white junction or cortical folds, such as cysticercosis, typically form thin-walled cysts enclosing fluid of CSF density, and only rarely show a hemorrhagic component.
Hemorrhage into brain metastases is uncommon, representing less than 10% of cases of intracranial bleeding (Weisberg, 1985). Although theoretically any metastasis can be complicated by intratumoral bleeding, in practice a few tumor types account for a large percentage of hemorrhagic metastases: lung carcinoma (both bronchogenic and small-cell types), melanoma, renal cell carcinoma, and choriocarcinoma. In general, these represent rapidly growing tumors associated with intense neovascularization. In our patient, we initially suspected the possibility of a lung tumor as there was a long history of tobacco use (over 80 pack-years). However, work-up of the chest including chest X-ray, CT scan of the chest, and (later) bronchoscopy with bronchial lavage for cytology were all unremarkable. High-resolution contrast enhanced CT of the abdomen and pelvis did not reveal evidence of renal tumors or occult lymphadenopathy. A thorough skin exam did not reveal any evidence of melanoma, or any suspicious moles. Examination of the oral mucosa and tongue, as well as funduscopic examination for pigmented lesions, was also unremarkable.
Definitive diagnosis in this case was only made following craniotomy with excision biopsy of one of the superficial brain metastases. A poorly differentiated, large-cell tumor was seen on initial analysis, associated with neovascularization and blood-filled lacunae, and foci of reactive inflammatory cells at the tumor borders. Traces of melanin were infrequently seen in cells of hematoxylin and eosin stained sections, but in view of the comparative rarity of this finding, the tumor was classified as amelanotic in nature. Histochemical staining characteristics of the tumor (positive immunoperoxidase staining for cytokeratin and S-100 protein), together with the previous findings, confirmed the diagnosis of melanoma.
Following diagnosis, the patient wished to have only hospice care, rather than further diagnostic or therapeutic interventions. He died 4 weeks after the date of the initial diagnosis. An autopsy was not obtained.
Very few reports selectively describe metastatic melanoma to the brain with unknown primary source (e.g., Nogami et al., 1992). Several retrospective studies analyzing hundreds of patients with brain metastasis of unknown primary origin suggest that bronchogenic carcinoma is the primary source in the majority of cases. Breast cancer and melanoma are less likely sources for brain metastasis as the only manifestation of cancer, since these tumors commonly have systemic manifestations before metastasizing to the brain (Van de Pol, 1996, Hamann et al., 1993, Nguyen et al., 1998). This discussion will thus generally review tumor metastases to the brain with special emphasis on metastatic melanoma, where data are available.
Brain metastases may be single or multiple, with several studies suggesting that multiple metastases occur in as many as three fourths of patients with documented cerebral metastasis (Sze et al., 1990). Brain metastases tend to be more commonly located at terminal "watershed areas" of the arterial circulation, most commonly in the area directly beneath the gray-white junction, where the intracranial vessels tend to rapidly narrow in diameter (Delattre et al., 1988; Hwang et al., 1996). Approximately 80% of brain metastases are located in the cerebral hemispheres, 15% in the cerebellum, and 5% in the brain stem (Delattre et al., 1988), largely paralleling the distribution of cerebral blood flow to these regions. Intacranial metastatic melanoma follows the general pattern of other metastases, with multiple metastases diagnosed in 62% of 101 patients with confirmed metastatic melanoma to the brain (Ginaldi et al., 1980). However, the majority (72%) of cases of metastatic melanoma to the brain had evidence of hemorrhage on non-contrasted CT scans (Ginaldi et al., 1980).
Clinical presentation of brain metastases is similar to that of other space occupying lesions in the brain, with headache and progressive, focal neurologic symptoms and signs. Papilledema is present in less than 25% of patients with brain metastases. Approximately 15% of patients have seizures as the first sign of the metastasis. An additional 5-10% of patients may present with acute neurologic symptoms caused by hemorrhage into or sudden expansion of the metastasis, and 1-2% of patients present with a nonfocal encephalopathy as the only sign of the brain metastasis. It is worth noting that although the majority of cerebral metastases of melanoma have radiographic evidence of hemorrhage, only a portion of these actually present with signs or symptoms suggesting the precipitous expansion of an intracranial mass. Brain metastases may be detected before the primary tumor is diagnosed, however, over 80% of brain metastases are discovered after the diagnosis of systemic cancer has been made.
Intracranial metastases develop in 20-40% of patients with cancer (Posner, 1996). Out of 1,100,000 new cases of brain metastases that occur each year in the United States, metastatic melanoma accounts for over 32,000 new cases (Posner, 1992). In adult populations, the most common sources of brain metastases are the lung (27%), malignant melanoma (22%), and breast cancer (15%). Gastrointestinal tract, and genito-urinary tract cancers are responsible for less than 10% of brain metastases (Cairncross and Posner, 1983). In patients younger than 21 years of age, brain metastases arise most often from sarcomas (e.g., osteogenic sarcoma, rhabdomyosarcoma, and Ewing's sarcoma) and germ cell tumors (Graus et al., 1983; Tasdemiroglu and Patchell, 1997). Brain metastasis of unknown primary origin accounts for 5-11% of all brain metastases (Merchut, 1989). As previously noted, the incidence of tumor types accounting for hemorrhagic metastases clearly differs from the distribution of tumor types accounting for cerebral metastases in general.
The best diagnostic test for brain metastases is contrast-enhanced MRI (Sze et al., 1990; Davis et al., 1991), which is more sensitive than either enhanced CT scanning (including double-dose delayed contrast) or unenhanced MRI in detecting metastatic brain lesions. It is not uncommon for a patient with an apparently single lesion on contrast-enhanced CT to have multiple lesions revealed by contrast-enhanced MRI. Several findings that favor metastases include multiplicity of lesions, location of lesions at the gray-white junction or in the border zone between two major arterial distributions, a rather well demarcated margin of the tumor lesion, and a small tumor nidus with a large amount of associated vasogenic edema. Interpretation of MRI findings may be confounded in some highly melanized lesions by the inherent paramagnetic effects of melanin, which displays a hyperintense signal in relation to the cortex on T1-weighted images, and hypointense signal in relation to the cortex on T2-weighted images (Isiklar et al., 1995). In this regard, unenhanced CT scanning may be helpful to confirm a hemorrhagic component of a suspected metastasis in which the existence of melanin cannot be excluded.
Because of the potential for rapid expansion of both the tumor nidus and associated vasogenic edema, most patients with brain metastases should be started on corticosteroid therapy at diagnosis. It is reported that more than 70% of patients show symptomatic improvement following steroid therapy, with improvement believed to be primarily due to reduction of vasogenic edema surrounding the metastasis. It is also suggested that steroids may reduce complications related to radiation therapy. Routine prophylactic anticonvulsant therapy in unselected patients with brain metastases is not of proven benefit (Glantz et al., 1996), and therefore most physicians begin anticonvulsants only in patients which have developed seizures.
Radiotherapy: Conventional whole brain radiation therapy (WBRT) is the most common treatment for patients with multiple brain metastases. Several studies suggest that WBRT increases the median length of survival by 3-6 months, in relatively unselected patients with brain metastases. Data from large retrospective studies have suggested that more than half of patients treated with whole-brain radiation therapy die ultimately from progressive systemic cancer and not as a direct result of brain metastases (Cairncross and Posner, 1983; Patchell et al., 1986; Posner, 1996). Current recommended doses of WBRT are 3000 to 5000 cGy (Gelber et al., 1981; Kurtz et al., 1981). For patients expected to survive one year or longer, a more prolonged course of radiotherapy with smaller doses per fraction is usually recommended. The role of radiotherapy in management of metastatic melanoma is less remarkable. Although 60-70% of patients receiving WBRT show initial significant neurological improvement, the response is usually of very short duration. Life expectancy of these patients is so short that some have argued that the benefits of treatment are not outweighed by time spent undergoing therapy, and the current recommendation is that each case should be considered individually (Taylor and Gore, 1995).
Surgery: Surgical resection plus postoperative WBRT is the treatment of choice for patients with surgically accessible single brain metastases, including metastatic melanoma (Patchell et al., 1990; Vecht et al., 1993; Posner, 1996), however, the role of surgery in the management of multiple metastases is unclear. One study (Bindal et al., 1993) analyzed patients with multiple metastases who had all tumors resected and compared these with patients with multiple metastases who had some but not all of their brain metastases resected. They found that the group with completely resected multiple metastases did relatively well (median survival, 14 months) and was similar to the group with single resected metastases (median survival, 14 months). The patients who did not have all of their brain tumors removed had significantly less survival, (median survival, six months). Although these studies are quite interesting, they have not been verified in large-scale, randomized prospective trials, and the current practice in most cases is to treat multiple metastases with WBRT alone.
Stereotaxic Radiosurgery: This method delivers intense focal irradiation to a circumscribed area of the brain by using a linear accelerator or multiple Cobalt-60 sources ("Gamma Knife"), causing tissue destruction in the area targeted. Radiosurgery, therefore, is not a replacement for WBRT, but instead could offer a substitute for surgical therapy. Several studies suggested that local control rate for radiosurgery in the treatment of single metastases may be similar to that achieved by conventional surgery (Mehta et al., 1993; Alexander et al., 1995; Auchter et al., 1996; Flickenger et al., 1996). Radiosurgery is a promising treatment for patients with multiple metastases in that it may deliver the benefits of surgical resection without the necessity of multiple craniotomies. A study of 45 patients with metastatic melanoma to the brain who received stereotaxic radiosurgery showed halting of the progression of intracranial disease in 78% of patients, with the overall survival rate of patients who received radiosurgery matching or exceeding those previously reported for surgery and other forms of radiotherapy (Lavine et al., 1999). Clearly, more work needs to be done to prospectively compare this approach with other therapies.
Chemotherapy: The success of chemotherapy in metastatic melanoma to the brain has been limited because of chemo-resistance and poor drug delivery. The newer nitrosurea fotemustine penetrates the blood brain barrier and have shown encouraging results in management of metastatic melanoma to the brain, particularly in combination with WBRT (e.g., Ulrich et al., 1999). However, these regimens are associated with significant bone-marrow suppression, and have not been prospectively evaluated in large-scale studies.
Both single and multiple brain metastases are associated with a poor prognosis, regardless of treatment. Untreated patients have a median survival time of only about four weeks (Cairncross and Posner, 1983), and nearly all untreated patients die as a direct result of the brain tumor. With corticosteroid therapy as the only treatment, the median survival rate is about eight weeks (Chang et al., 1992). WBRT, surgery, and radiosurgery may increase median survival time by as much as 3-6 months and decrease deaths resulting from neurological causes.
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