Case 38-2004 — A 40-Year-Old Man with a Large Tumor of the Skull
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《新英格兰医药杂志》
Dr. Ronald Takvorian (Hematology–Oncology): A 40-year-old man was admitted to this hospital because of a mass of the skull. The patient had been in his usual state of good health until two months before admission, when he noticed a firm, walnut-sized, painless mass on the top of his head. It enlarged slightly during the next couple of months, and he saw his primary care physician. Computed tomographic (CT) and magnetic resonance imaging (MRI) scans showed an intracranial lesion thought to be a meningioma; the patient was referred to a neurosurgeon at this hospital.
The patient had been told previously that he had borderline hypertension, but he was otherwise well and he took no medications. He had no fatigue, weakness, changes in mental or neurologic function, constipation, abdominal pain, or increased urination. He worked full-time as a computer design engineer. He was married with no children. There was no history of cancer in his parents or siblings.
On physical examination, the blood pressure was 145/92 mm Hg. Other vital signs were normal. There was an irregular, soft swelling in the midline of the scalp, but the remainder of the physical examination showed no abnormalities. The results of laboratory studies, including a complete blood count, levels of electrolytes and albumin, tests of liver function and renal function, and urinalysis were within normal ranges.
Repeated CT and MRI scans showed a contrast-enhanced mass, 6.8 by 5.8 by 4.4 cm, involving the dura at the vertex. The mass invaded the superior sagittal sinus and compressed the right motor strip inferiorly and anteriorly. There were multiple collateral vessels around the tumor. The cerebellar tonsils were displaced inferiorly by 9 mm. The mass destroyed the overlying calvarium at the vertex, with involvement of both the inner and outer tables, and extended beyond the calvarium to the subgaleal soft tissues. The total tumor volume was 68 ml.
Three weeks after these imaging studies were obtained, the patient was admitted to the hospital and a bifrontal and biparietal craniotomy was performed. The mass was adherent to the sagittal sinus; therefore, a subtotal resection of the tumor was performed, with duroplasty and cranioplasty.
Differential Diagnosis
Dr. Ara Kassarjian: A topogram of the brain shows a destructive expansile, lytic lesion that involves the inner and outer cortexes of the parietal bone, with focal protuberance in the scalp as a result (Figure 1A). A CT scan of the brain shows a hyperattenuating mass near the vertex, which crosses the midline but is more prominent on the right (Figure 1B). There is apparent remodeling of the inner cortex of the parietal bone. On images showing a more superior position, the mass involves the diploic space and breaches the outer cortex. Images obtained after the intravenous administration of contrast medium show intense enhancement of the mass. The sagittal sinus remains patent.
Figure 1. CT Studies of the Brain at Initial Evaluation.
A topogram from a CT of the brain shows a destructive expansile, lytic lesion that involves the inner and outer cortexes of the parietal bone (Panel A, arrow) with a resulting focal protuberance in the scalp. A non–contrast-enhanced axial CT scan of the brain near the vertex (Panel B) shows a hyperattenuating mass that crosses the midline and causes scalloping (arrows) of the inner cortex of the parietal bones on both sides of the sagittal suture.
An MRI of the brain shows an extra-axial mass near the midline, which involves the parietal bones and has an extracalvarial soft-tissue component (Figure 2). The mass is isointense in relation to gray matter on T1-weighted images that were obtained before the contrast medium was administered, is hypointense on T2-weighted images, and shows intense enhancement after the administration of gadolinium. There is a small associated, tapering, enhanced component that is on the periphery of the mass that probably represents a dural reaction, known as a dural tail. There is no edema in the adjacent brain parenchyma. The mass replaces the normal fatty marrow of the parietal bones; however, there is no surrounding marrow edema. The remainder of the brain as shown on the MRI is normal.
Figure 2. MRI Studies of the Brain.
An axial T2-weighted image of the brain shows a round, hypointense extra-axial mass (Panel A). There is no edema in the adjacent brain parenchyma or in the marrow of the parietal bones. A sagittal T1-weighted image of the brain (Panel B), obtained after the administration of gadolinium, shows an ovoid, densely enhancing extra-axial mass that involves the calvarium and some invasion of the cortex of both the inner and outer tables of the parietal bone. There is a small dural tail (arrow). The sagittal sinus is patent.
In summary, CT and MRI of the brain show an extra-axial mass that breaches the calvarium and extends into the soft tissue of the scalp. The most common extra-axial mass is a meningioma. The hyperattenuation of the lesion as shown by CT and the hypointensity depicted on the T2-weighted MRI sequences are consistent with a highly cellular mass such as a meningioma. In addition, meningiomas typically show intense enhancement and a dural tail. However, a dural tail is not specific for meningioma and may be seen with any lesion that abuts or involves the dura. Hyperostosis of the adjacent calvarium is typical of a meningioma but is observed in only approximately 20 percent of meningiomas. Although atypical and anaplastic meningiomas and hemangiopericytomas may have more aggressive osseous destruction, these lesions often demonstrate more heterogeneous signal intensity on T2-weighted imaging than is seen in this case. The calvarial destruction and transcalvarial extension of the mass apparent in this patient are seen only rarely with meningiomas.1
Although almost any primary osseous neoplasm may involve the calvarium, metastases and multiple myeloma are the two most common malignant calvarial neoplasms in adults.2 Renal and thyroid carcinomas are the two neoplasms typically associated with lytic expansile metastases. Multiple myeloma typically is manifested as multiple lytic lesions.3 However, a plasmacytoma (a tumoral mass of plasma cells), particularly when located in a long or flat bone, may result in an expansile lesion. Unlike many other malignant neoplasms, osseous lesions in myeloma may have well-defined and occasionally slightly sclerotic borders that falsely suggest a nonaggressive lesion.
Pathological Discussion
Dr. Wen Jing: Histologic examination of the resected specimen showed a cellular tumor invading both dura and bone (Figure 3A). Tumor cells lacked cohesion, with eccentric nuclei and abundant cytoplasm; some had a prominent paranuclear hof (Golgi apparatus) (Figure 3B). Scattered mitotic figures were present. The tumor cells were negative for the B-cell antigen CD20 but positive for another B-cell antigen, CD79a. CD20 is usually absent on plasma cells, but CD79a is expressed; this immunophenotype suggests a plasma-cell tumor (Figure 3C). There were cytoplasmic lambda light chains, which were also present in intranuclear inclusions (Dutcher bodies); staining for the presence of kappa light chains was negative (Figure 3D). These findings are diagnostic of plasmacytoma. Microscopical examination of a bone-marrow–biopsy specimen showed no evidence of a plasma-cell myeloma.
Figure 3. Biopsy Specimen of the Dural Tumor.
At low magnification (Panel A), there is a tumor invading bone. At higher magnification (Panel B), the tumor cells have eccentric nuclei and abundant cytoplasm. The tumor cells express cytoplasmic lambda light chains; an intranuclear inclusion containing a light chain is also present (Panel C, arrow). Staining for kappa light chains is negative (Panel D). (The stain used in Panels A and B is hematoxylin and eosin and in Panels C and D immunoperoxidase.)
Plasmacytomas are clonal proliferations of plasma cells that are identical to those of plasma-cell myeloma but have a localized osseous or extraosseous growth pattern.4 Solitary plasmacytoma of bone (osseous plasmacytoma) and extraosseous (extramedullary) plasmacytomas each make up about 5 percent of plasma-cell neoplasms. The most common sites of osseous plasmacytomas are in marrow areas with the most active hematopoiesis, including, in descending order of frequency, the vertebrae, ribs, skull, pelvis, femur, clavicle, and scapula. Approximately 80 percent of extraosseous plasmacytomas occur in the upper respiratory tract, including the oropharynx, nasopharynx, sinuses, and larynx. At 10 years after diagnosis, 55 percent of patients with osseous plasmacytomas have a diagnosis of plasma-cell myeloma, and 10 percent have either local recurrence of the plasmacytoma or another solitary plasmacytoma.5 In contrast, the development of typical plasma-cell myeloma occurrs in only 10 to 30 percent of patients with extraosseous plasmacytoma.5,6
Plasma-cell myeloma is a multifocal tumor characterized by skeletal destruction with osteolytic lesions, pathologic fractures, bone pain, hypercalcemia, anemia, and, typically, generalized bone marrow involvement and a serum monoclonal protein. Plasmacytomas also occur, and rare patients, such as this one, may have multiple plasmacytomas without diffuse marrow involvement. Plasma-cell myeloma is the second most common lymphoid cancer in this country. The diagnosis is based on a combination of pathological, radiologic, and clinical features (Table 1).7 In this patient, the finding of plasmacytoma on biopsy meets a major criterion for the diagnosis, and the finding of multiple lytic bone lesions that occurred later meets a minor criterion; thus, the minimum of one major and one minor criterion has been met, and a diagnosis of multiple myeloma can be made.
Table 1. Diagnostic Criteria for Plasma-Cell Myeloma.
Discussion of Management
Dr. Takvorian: There were no surgical complications in this patient, and he was discharged 72 hours after surgery. A radiographic skeletal survey performed 10 days after he was discharged showed lytic lesions in the distal right femoral metaphysis and the proximal right tibial metaphysis. Additional subtle lucencies were seen in the middle of the left radius and in the left femur. The L5 lumbar region had a sclerotic appearance, with loss of height. An abdominal–pelvic CT scan showed diffuse, minimally enlarged periportal lymph nodes (about 1 cm in greatest diameter) of unclear clinical significance. A thoracic CT scan showed no evidence of hilar or mediastinal lymphadenopathy. A fine-needle aspirate of a posterior cervical lymph node was negative for malignant cells. Tests of liver and renal function and a complete blood count were normal, as were the calcium and phosphorus levels. Results of serum protein studies are shown in Table 2. Five weeks of radiation therapy to the scalp was given at another hospital. Treatment was begun with monthly doses of pamidronate (90 mg, given intravenously).
Table 2. Laboratory-Test Results.
A follow-up radiographic skeletal survey obtained five months after the patient was discharged showed a new lytic bone lesion in the left distal clavicle and a lesion in the right greater trochanter. Six months later, another skeletal survey showed no changes.
I followed the patient in the clinic at three-month intervals, and he received monthly pamidronate infusions and underwent semiannual skeletal radiography. He continued to work full-time as a computer design engineer and had no symptoms. There was no change in his laboratory-test results for the first year; the globulin remained elevated, with an increase in IgA and IgG, but there was no indication of monoclonal paraprotein bands (M component) or of Bence Jones protein. A repeated bone marrow biopsy performed 13 months after the diagnosis showed a minimal increase in plasma cells to 2 percent, but with no evidence of a clonal population. Three months later, the patient noticed pain in his left clavicle where his automobile seat belt touched it. Dr. Kassarjian, could you show us the bone radiographs?
Dr. Kassarjian: A radiograph of the left clavicle shows a lytic expansile lesion of the lateral end of the clavicle that extends to the articular surface (Figure 4). The lesion has a slightly sclerotic, well-defined medial border. The lateral border is less well defined and has a moth-eaten appearance in some regions, whereas the superior cortex is barely visible and may have an associated soft-tissue mass. There is no internal mineralization or fracture. A radiographic skeletal survey showed other similarly well-defined lesions involving the proximal and distal ends of the right femur, the distal left femur, and the proximal right tibia. There was no increase in the size of these lesions as compared with the results of previous studies.
Figure 4. Radiograph of the Left Clavicle.
There is an expansile, lytic lesion of the lateral end of the clavicle that extends to the articular surface. The lesion has a slightly sclerotic, well-defined medial border and an ill-defined, "moth-eaten" lateral margin.
Dr. Takvorian: Nineteen months after the diagnosis, serum protein electrophoresis for the first time showed two M components at very low concentrations (Table 2). The results of other laboratory tests were unchanged. The patient continued to have tenderness of the left clavicle, but the bone lesions had not enlarged on repeated skeletal surveys. I referred him to the bone marrow–transplantation team for a discussion of how transplantation would fit into a treatment plan, and I asked Dr. Richardson to come to our conference today to discuss treatment options for this patient.
Dr. Paul G. Richardson: This otherwise healthy 40-year-old man had an unusual manifestation of multiple myeloma, with multiple osseous plasmacytomas and a relatively oligosecretory biphenotypic tumor, as reflected by the low-concentration M components confirmed on immunofixation to be IgA lambda and IgG lambda. Multiple myeloma has not been a curable disease with currently available therapies, and although the overall median survival with standard treatment is around three years, there is great clinical variability. The decision to treat rests on the evaluation of the patient's symptoms and the risk of rapid progression. Risk factors for rapid disease progression in multiple myeloma are predominantly those that are associated with a high or increasing tumor burden (Table 3).7
This patient has not had a large amount of serum paraprotein, and his elevated IgG and IgA levels were polyclonal and did not reflect the volume of disease. It is important that his serum IgM concentration has remained normal throughout and urine protein electrophoreses have not revealed any Bence Jones proteinuria. Other laboratory-test results, including the albumin level, have remained normal. Despite these reassuring laboratory findings, the large plasmacytoma involving the vertex of his calvarium and the evidence of substantial tumor burden (Durie–Salmon stage 3A, Table 3)7 represented by the multiple bony lesions identified by the initial radiographic skeletal survey have been of considerable concern.
A recent consensus study has shown that beta2-microglobulin and albumin together are the most important predictors of outcome in myeloma (Table 4).8 Although we do not have the former measure in this patient, the normal albumin level was reassuring. Other findings, such as the increased plasma-cell-proliferation fraction and the presence of abnormalities on cytogenetic examination, are indicators of a poor prognosis in myeloma, but they are not yet universally accepted as measures that should routinely determine treatment decisions. Furthermore, this information is not available in this case.
Table 4. Proposed New System for the Staging for Multiple Myeloma.
The patient's initial treatment with radiation therapy, followed by bisphosphonate infusions together with careful observation, was appropriate. Radiation therapy is effective in preventing local recurrence of osseous plasmacytomas. Biphosphonate agents are effective in relieving symptoms of bone pain and reducing the risk of fractures, and when used continuously they may improve overall survival.9 However, a follow-up skeletal survey three months later showed progression of lytic disease with worsening lesions in the left distal clavicle and in the right greater trochanter, in addition to those of the distal left femur and right proximal tibia noted earlier. Subsequent radiographic skeletal surveys showed relative stability of these lesions, but the patient's clinical course had been sufficiently worrisome to both his primary medical oncologist and the patient to prompt discussion of additional therapeutic options, including peripheral-blood stem-cell transplantation.
In my view, two treatment options exist in this case. Whereas the patient has disease progression, as reflected by worsening bone disease and the appearance of a small paraprotein (as shown by serum protein electrophoresis), this progression had not been matched by substantial changes in his hematocrit, symptom status, or renal function. Moreover, his radiographic skeletal survey had shown clear evidence of disease progression three months after the initial staging, but the findings on subsequent skeletal surveys have been stable. Therefore, one approach would be a period of further close observation and frequent follow-up evaluations, along with continued bisphosphonate therapy. Consideration could be given to the use of the potent aminobisphosphonate zolendronic acid, which has been shown to be at least equivalent to pamidronate in terms of efficacy with respect to bone lesion progression, with the convenience of a 15-to-30-minute infusion time as compared with the standard 2-hour infusion required for pamidronate given at the same intervals.10
The other approach would be to begin initial therapy with the goal of moving toward autologous peripheral-blood stem-cell transplantation with melphalan-based conditioning as consolidation therapy, especially if the tumor responds to the initial treatment. Additional strategies after initial therapy could include a double intensification and tandem stem-cell transplantation approach, an autologous stem-cell transplantation followed by nonmyeloablative allogeneic stem-cell transplantation, and a single autologous stem-cell transplantation with a novel biologic approach to follow.
Initial Therapy for Plasma-Cell Myeloma
A number of options exist for initial therapy for this patient, including combination chemotherapy (such as the agents vincristine, doxorubicin, and dexamethasone)11; dexamethasone as a single agent; dexamethasone in combination with thalidomide; or the use of bortezomib, a novel proteasome inhibitor recently approved for use in relapsed, refractory multiple myeloma12 and currently under study as initial therapy in phase 2 trials.13
Combination Chemotherapy
Combination chemotherapy, with vincristine, doxorubicin, and dexamethasone, has been the standard of care for many years. The inconvenience of continuous intravenous administration together with the high rates of complications reported with the use of these drugs, including alopecia, neutropenia, mucositis, peripheral neuropathy, and catheter-related complications such as thrombosis and infection,14 make this combination less than ideal. Most important, alkylator-based initial therapy (especially oral low-dose melphalan) should be avoided to minimize the risks of stem-cell damage.15 Thus, it is worthwhile to consider other options for this patient that have recently become available.
Thalidomide
Thalidomide has been shown to be effective in the treatment of both relapsed and relapsed, refractory multiple myeloma, with an overall response rate of 32 percent among patients who had relapses after stem-cell transplantation.16,17,18,19,20 The mechanisms of action of thalidomide in multiple myeloma are not fully understood but probably include growth arrest during the gap 1, or G1, phase of cell proliferation, disruption of adhesion, and the inhibition of growth-promoting cytokines released from both tumor and bone marrow stroma, together with antiangiogenic effects and anti–tumor-directed immune stimulation.21 The addition of dexamethasone to thalidomide has an additive effect, with response rates of 35 to 60 percent.22 In newly diagnosed or untreated patients such as this man, thalidomide in combination with dexamethasone results in higher response rates than with dexamethasone alone — in the range of 66 percent to 72 percent.23,24
Thalidomide is not without toxic effects. The most important are peripheral neuropathy and deep-vein thrombosis, with the latter having an incidence of between 5 percent and 16 percent, which is significantly higher when thalidomide is combined with dexamethasone and chemotherapy.21,25,26 Thalidomide analogues have also been studied as an option to treat advanced multiple myeloma and have shown activity and more manageable toxic effects as compared with thalidomide, with minimal neuropathy, sedation, thrombosis, and constipation reported.26 On the basis of these promising results, studies in newly diagnosed patients have begun. With appropriate thromboprophylaxis, the combination of thalidomide and dexamethasone would be a reasonable option to pursue in this patient.
Bortezomib
Bortezomib is another option for this patient. Bortezomib is a novel, selective, and reversible inhibitor of the proteasome, a key intracellular structure responsible for the degradation of ubiquinated proteins that has been shown to be especially active against multiple-myeloma cells in vitro and myeloma-associated bone marrow stroma, as well as in a murine model.27,28,29 After a phase 1 study in patients with hematologic cancer suggested activity in a subgroup of patients with relapsed myeloma,30 a large, multicenter phase 2 study of bortezomib in relapsed and refractory disease12 found a response rate of 35 percent and a statistically significant improvement in the time to progression of disease, together with an overall survival advantage as compared with treatment with high-dose dexamethasone.31 Peripheral neuropathy and transient thrombocytopenia were the most common side effects recorded in patients treated with bortezomib.
On the basis of these results, a series of phase 2 studies have explored the role of bortezomib alone, with dexamethasone, or in combination with chemotherapy as primary therapy for multiple myeloma. Response rates of 77 percent, with mild-to-moderate toxic effects, have been reported for bortezomib used alone or with dexamethasone,13 and response rates as high as 92 percent for bortezomib combined with dexamethasone and doxorubicin. The latter treatment was associated with side effects, including neuropathy.32 Participation in such a study would be a very reasonable option for this patient.
Stem-Cell Transplantation
The therapies discussed above do not usually result in long-term disease-free survival when used alone in multiple myeloma, so patients who respond to them are typically advised to proceed to high-dose therapy followed by stem-cell transplantation.33,34 Once responsiveness to initial therapy is confirmed, then stem-cell mobilization (typically using cyclophosphamide and granulocyte colony-stimulating factor) would be recommended. In a younger patient, such as this man, data from randomized trials suggest benefit from double autologous stem-cell transplantation in patients who do not have a complete response after the first intensification.35 Thus, consideration of a double or tandem melphalan-based approach supported by autologous stem-cell transplantation would be reasonable. However, the toxic effects associated with double autologous stem-cell transplantation and their potential impact on the quality of life (as compared with the effects of a single autologous stem-cell transplantation) should also be kept in mind.
HLA typing of the patient and his siblings should be considered, since nonrandomized data have suggested that a single autologous stem-cell transplantation, followed by a nonmyeloablative allogeneic stem-cell transplantation, may be beneficial for patients with matched sibling donors. However, limitations to nonmyeloablative allotransplantation include high rates of chronic graft-versus-host disease that approach 70 percent.36
Most recently, data from randomized trials indicate that low doses of thalidomide have a benefit when given as maintenance therapy after stem-cell transplantation.37 Thus, a single intensification approach with thalidomide as maintenance therapy would be another possibility for this patient at the conclusion of successful initial therapy. Given these options, I would encourage him to participate in a clinical trial comparing these approaches, should he opt for transplantation as part of his treatment.
In terms of prognosis, the median event-free survival has improved to between two and three years, usually for those patients 70 years of age or younger who successfully undergo autologous stem-cell transplantation.33,34 Overall survival is also superior when compared with that associated with standard therapies, with a median survival of approximately five years reported.33 Double autologous stem-cell transplantation in selected subgroups of patients may improve survival even more, but the effect of allogeneic stem-cell transplantation remains to be established.35 The advent of novel, biologically derived agents such as thalidomide, thalidomide analogues, and bortezomib holds promise not only for improving the quality of response, duration of response, and survival, but also for providing therapies that may be more specifically targeted and less toxic, and so improve patient outcomes.38
In this case, I would advise the patient either to continue with a conservative approach to management with bisphosphonate therapy and careful observation, keeping additional systemic treatment in reserve, or to pursue a more intensive approach with initial treatment (ideally protocol-directed) followed by transplantation.
Dr. Takvorian: After this conference, I discussed treatment options with this patient, and he elected not to undergo additional treatment for his myeloma. At that time, monthly zolendronic acid was substituted for pamidronate. Thirty-one months after the diagnosis, increasing pain in the left clavicle led him to agree to a course of radiation therapy that I suggested as an option, although radiographically, the bone lesions were unchanged. Unfortunately, this treatment has had only a minimal effect on his pain, which he now controls with oxycodone and acetaminophen. I have urged him on many occasions recently to begin treatment with one of the regimens described by Dr. Richardson, but he has declined. The beta2-microglobulin level was recently measured and was 1.85 mg per deciliter. Three years after the diagnosis he is still receiving only monthly doses of zolendronic acid.
Anatomical Diagnosis
Plasma-cell myeloma.
Source Information
From the Jerome Lipper Multiple Myeloma Center, Division of Hematologic Oncology, Department of Medicine, Brigham and Women's Hospital and the Dana–Farber Cancer Institute (P.G.R.); the Departments of Radiology (A.K.) and Pathology (W.J.), Massachusetts General Hospital; and the Departments of Medicine (P.G.R.), Radiology (A.K.), and Pathology (W.J.), Harvard Medical School.
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The patient had been told previously that he had borderline hypertension, but he was otherwise well and he took no medications. He had no fatigue, weakness, changes in mental or neurologic function, constipation, abdominal pain, or increased urination. He worked full-time as a computer design engineer. He was married with no children. There was no history of cancer in his parents or siblings.
On physical examination, the blood pressure was 145/92 mm Hg. Other vital signs were normal. There was an irregular, soft swelling in the midline of the scalp, but the remainder of the physical examination showed no abnormalities. The results of laboratory studies, including a complete blood count, levels of electrolytes and albumin, tests of liver function and renal function, and urinalysis were within normal ranges.
Repeated CT and MRI scans showed a contrast-enhanced mass, 6.8 by 5.8 by 4.4 cm, involving the dura at the vertex. The mass invaded the superior sagittal sinus and compressed the right motor strip inferiorly and anteriorly. There were multiple collateral vessels around the tumor. The cerebellar tonsils were displaced inferiorly by 9 mm. The mass destroyed the overlying calvarium at the vertex, with involvement of both the inner and outer tables, and extended beyond the calvarium to the subgaleal soft tissues. The total tumor volume was 68 ml.
Three weeks after these imaging studies were obtained, the patient was admitted to the hospital and a bifrontal and biparietal craniotomy was performed. The mass was adherent to the sagittal sinus; therefore, a subtotal resection of the tumor was performed, with duroplasty and cranioplasty.
Differential Diagnosis
Dr. Ara Kassarjian: A topogram of the brain shows a destructive expansile, lytic lesion that involves the inner and outer cortexes of the parietal bone, with focal protuberance in the scalp as a result (Figure 1A). A CT scan of the brain shows a hyperattenuating mass near the vertex, which crosses the midline but is more prominent on the right (Figure 1B). There is apparent remodeling of the inner cortex of the parietal bone. On images showing a more superior position, the mass involves the diploic space and breaches the outer cortex. Images obtained after the intravenous administration of contrast medium show intense enhancement of the mass. The sagittal sinus remains patent.
Figure 1. CT Studies of the Brain at Initial Evaluation.
A topogram from a CT of the brain shows a destructive expansile, lytic lesion that involves the inner and outer cortexes of the parietal bone (Panel A, arrow) with a resulting focal protuberance in the scalp. A non–contrast-enhanced axial CT scan of the brain near the vertex (Panel B) shows a hyperattenuating mass that crosses the midline and causes scalloping (arrows) of the inner cortex of the parietal bones on both sides of the sagittal suture.
An MRI of the brain shows an extra-axial mass near the midline, which involves the parietal bones and has an extracalvarial soft-tissue component (Figure 2). The mass is isointense in relation to gray matter on T1-weighted images that were obtained before the contrast medium was administered, is hypointense on T2-weighted images, and shows intense enhancement after the administration of gadolinium. There is a small associated, tapering, enhanced component that is on the periphery of the mass that probably represents a dural reaction, known as a dural tail. There is no edema in the adjacent brain parenchyma. The mass replaces the normal fatty marrow of the parietal bones; however, there is no surrounding marrow edema. The remainder of the brain as shown on the MRI is normal.
Figure 2. MRI Studies of the Brain.
An axial T2-weighted image of the brain shows a round, hypointense extra-axial mass (Panel A). There is no edema in the adjacent brain parenchyma or in the marrow of the parietal bones. A sagittal T1-weighted image of the brain (Panel B), obtained after the administration of gadolinium, shows an ovoid, densely enhancing extra-axial mass that involves the calvarium and some invasion of the cortex of both the inner and outer tables of the parietal bone. There is a small dural tail (arrow). The sagittal sinus is patent.
In summary, CT and MRI of the brain show an extra-axial mass that breaches the calvarium and extends into the soft tissue of the scalp. The most common extra-axial mass is a meningioma. The hyperattenuation of the lesion as shown by CT and the hypointensity depicted on the T2-weighted MRI sequences are consistent with a highly cellular mass such as a meningioma. In addition, meningiomas typically show intense enhancement and a dural tail. However, a dural tail is not specific for meningioma and may be seen with any lesion that abuts or involves the dura. Hyperostosis of the adjacent calvarium is typical of a meningioma but is observed in only approximately 20 percent of meningiomas. Although atypical and anaplastic meningiomas and hemangiopericytomas may have more aggressive osseous destruction, these lesions often demonstrate more heterogeneous signal intensity on T2-weighted imaging than is seen in this case. The calvarial destruction and transcalvarial extension of the mass apparent in this patient are seen only rarely with meningiomas.1
Although almost any primary osseous neoplasm may involve the calvarium, metastases and multiple myeloma are the two most common malignant calvarial neoplasms in adults.2 Renal and thyroid carcinomas are the two neoplasms typically associated with lytic expansile metastases. Multiple myeloma typically is manifested as multiple lytic lesions.3 However, a plasmacytoma (a tumoral mass of plasma cells), particularly when located in a long or flat bone, may result in an expansile lesion. Unlike many other malignant neoplasms, osseous lesions in myeloma may have well-defined and occasionally slightly sclerotic borders that falsely suggest a nonaggressive lesion.
Pathological Discussion
Dr. Wen Jing: Histologic examination of the resected specimen showed a cellular tumor invading both dura and bone (Figure 3A). Tumor cells lacked cohesion, with eccentric nuclei and abundant cytoplasm; some had a prominent paranuclear hof (Golgi apparatus) (Figure 3B). Scattered mitotic figures were present. The tumor cells were negative for the B-cell antigen CD20 but positive for another B-cell antigen, CD79a. CD20 is usually absent on plasma cells, but CD79a is expressed; this immunophenotype suggests a plasma-cell tumor (Figure 3C). There were cytoplasmic lambda light chains, which were also present in intranuclear inclusions (Dutcher bodies); staining for the presence of kappa light chains was negative (Figure 3D). These findings are diagnostic of plasmacytoma. Microscopical examination of a bone-marrow–biopsy specimen showed no evidence of a plasma-cell myeloma.
Figure 3. Biopsy Specimen of the Dural Tumor.
At low magnification (Panel A), there is a tumor invading bone. At higher magnification (Panel B), the tumor cells have eccentric nuclei and abundant cytoplasm. The tumor cells express cytoplasmic lambda light chains; an intranuclear inclusion containing a light chain is also present (Panel C, arrow). Staining for kappa light chains is negative (Panel D). (The stain used in Panels A and B is hematoxylin and eosin and in Panels C and D immunoperoxidase.)
Plasmacytomas are clonal proliferations of plasma cells that are identical to those of plasma-cell myeloma but have a localized osseous or extraosseous growth pattern.4 Solitary plasmacytoma of bone (osseous plasmacytoma) and extraosseous (extramedullary) plasmacytomas each make up about 5 percent of plasma-cell neoplasms. The most common sites of osseous plasmacytomas are in marrow areas with the most active hematopoiesis, including, in descending order of frequency, the vertebrae, ribs, skull, pelvis, femur, clavicle, and scapula. Approximately 80 percent of extraosseous plasmacytomas occur in the upper respiratory tract, including the oropharynx, nasopharynx, sinuses, and larynx. At 10 years after diagnosis, 55 percent of patients with osseous plasmacytomas have a diagnosis of plasma-cell myeloma, and 10 percent have either local recurrence of the plasmacytoma or another solitary plasmacytoma.5 In contrast, the development of typical plasma-cell myeloma occurrs in only 10 to 30 percent of patients with extraosseous plasmacytoma.5,6
Plasma-cell myeloma is a multifocal tumor characterized by skeletal destruction with osteolytic lesions, pathologic fractures, bone pain, hypercalcemia, anemia, and, typically, generalized bone marrow involvement and a serum monoclonal protein. Plasmacytomas also occur, and rare patients, such as this one, may have multiple plasmacytomas without diffuse marrow involvement. Plasma-cell myeloma is the second most common lymphoid cancer in this country. The diagnosis is based on a combination of pathological, radiologic, and clinical features (Table 1).7 In this patient, the finding of plasmacytoma on biopsy meets a major criterion for the diagnosis, and the finding of multiple lytic bone lesions that occurred later meets a minor criterion; thus, the minimum of one major and one minor criterion has been met, and a diagnosis of multiple myeloma can be made.
Table 1. Diagnostic Criteria for Plasma-Cell Myeloma.
Discussion of Management
Dr. Takvorian: There were no surgical complications in this patient, and he was discharged 72 hours after surgery. A radiographic skeletal survey performed 10 days after he was discharged showed lytic lesions in the distal right femoral metaphysis and the proximal right tibial metaphysis. Additional subtle lucencies were seen in the middle of the left radius and in the left femur. The L5 lumbar region had a sclerotic appearance, with loss of height. An abdominal–pelvic CT scan showed diffuse, minimally enlarged periportal lymph nodes (about 1 cm in greatest diameter) of unclear clinical significance. A thoracic CT scan showed no evidence of hilar or mediastinal lymphadenopathy. A fine-needle aspirate of a posterior cervical lymph node was negative for malignant cells. Tests of liver and renal function and a complete blood count were normal, as were the calcium and phosphorus levels. Results of serum protein studies are shown in Table 2. Five weeks of radiation therapy to the scalp was given at another hospital. Treatment was begun with monthly doses of pamidronate (90 mg, given intravenously).
Table 2. Laboratory-Test Results.
A follow-up radiographic skeletal survey obtained five months after the patient was discharged showed a new lytic bone lesion in the left distal clavicle and a lesion in the right greater trochanter. Six months later, another skeletal survey showed no changes.
I followed the patient in the clinic at three-month intervals, and he received monthly pamidronate infusions and underwent semiannual skeletal radiography. He continued to work full-time as a computer design engineer and had no symptoms. There was no change in his laboratory-test results for the first year; the globulin remained elevated, with an increase in IgA and IgG, but there was no indication of monoclonal paraprotein bands (M component) or of Bence Jones protein. A repeated bone marrow biopsy performed 13 months after the diagnosis showed a minimal increase in plasma cells to 2 percent, but with no evidence of a clonal population. Three months later, the patient noticed pain in his left clavicle where his automobile seat belt touched it. Dr. Kassarjian, could you show us the bone radiographs?
Dr. Kassarjian: A radiograph of the left clavicle shows a lytic expansile lesion of the lateral end of the clavicle that extends to the articular surface (Figure 4). The lesion has a slightly sclerotic, well-defined medial border. The lateral border is less well defined and has a moth-eaten appearance in some regions, whereas the superior cortex is barely visible and may have an associated soft-tissue mass. There is no internal mineralization or fracture. A radiographic skeletal survey showed other similarly well-defined lesions involving the proximal and distal ends of the right femur, the distal left femur, and the proximal right tibia. There was no increase in the size of these lesions as compared with the results of previous studies.
Figure 4. Radiograph of the Left Clavicle.
There is an expansile, lytic lesion of the lateral end of the clavicle that extends to the articular surface. The lesion has a slightly sclerotic, well-defined medial border and an ill-defined, "moth-eaten" lateral margin.
Dr. Takvorian: Nineteen months after the diagnosis, serum protein electrophoresis for the first time showed two M components at very low concentrations (Table 2). The results of other laboratory tests were unchanged. The patient continued to have tenderness of the left clavicle, but the bone lesions had not enlarged on repeated skeletal surveys. I referred him to the bone marrow–transplantation team for a discussion of how transplantation would fit into a treatment plan, and I asked Dr. Richardson to come to our conference today to discuss treatment options for this patient.
Dr. Paul G. Richardson: This otherwise healthy 40-year-old man had an unusual manifestation of multiple myeloma, with multiple osseous plasmacytomas and a relatively oligosecretory biphenotypic tumor, as reflected by the low-concentration M components confirmed on immunofixation to be IgA lambda and IgG lambda. Multiple myeloma has not been a curable disease with currently available therapies, and although the overall median survival with standard treatment is around three years, there is great clinical variability. The decision to treat rests on the evaluation of the patient's symptoms and the risk of rapid progression. Risk factors for rapid disease progression in multiple myeloma are predominantly those that are associated with a high or increasing tumor burden (Table 3).7
This patient has not had a large amount of serum paraprotein, and his elevated IgG and IgA levels were polyclonal and did not reflect the volume of disease. It is important that his serum IgM concentration has remained normal throughout and urine protein electrophoreses have not revealed any Bence Jones proteinuria. Other laboratory-test results, including the albumin level, have remained normal. Despite these reassuring laboratory findings, the large plasmacytoma involving the vertex of his calvarium and the evidence of substantial tumor burden (Durie–Salmon stage 3A, Table 3)7 represented by the multiple bony lesions identified by the initial radiographic skeletal survey have been of considerable concern.
A recent consensus study has shown that beta2-microglobulin and albumin together are the most important predictors of outcome in myeloma (Table 4).8 Although we do not have the former measure in this patient, the normal albumin level was reassuring. Other findings, such as the increased plasma-cell-proliferation fraction and the presence of abnormalities on cytogenetic examination, are indicators of a poor prognosis in myeloma, but they are not yet universally accepted as measures that should routinely determine treatment decisions. Furthermore, this information is not available in this case.
Table 4. Proposed New System for the Staging for Multiple Myeloma.
The patient's initial treatment with radiation therapy, followed by bisphosphonate infusions together with careful observation, was appropriate. Radiation therapy is effective in preventing local recurrence of osseous plasmacytomas. Biphosphonate agents are effective in relieving symptoms of bone pain and reducing the risk of fractures, and when used continuously they may improve overall survival.9 However, a follow-up skeletal survey three months later showed progression of lytic disease with worsening lesions in the left distal clavicle and in the right greater trochanter, in addition to those of the distal left femur and right proximal tibia noted earlier. Subsequent radiographic skeletal surveys showed relative stability of these lesions, but the patient's clinical course had been sufficiently worrisome to both his primary medical oncologist and the patient to prompt discussion of additional therapeutic options, including peripheral-blood stem-cell transplantation.
In my view, two treatment options exist in this case. Whereas the patient has disease progression, as reflected by worsening bone disease and the appearance of a small paraprotein (as shown by serum protein electrophoresis), this progression had not been matched by substantial changes in his hematocrit, symptom status, or renal function. Moreover, his radiographic skeletal survey had shown clear evidence of disease progression three months after the initial staging, but the findings on subsequent skeletal surveys have been stable. Therefore, one approach would be a period of further close observation and frequent follow-up evaluations, along with continued bisphosphonate therapy. Consideration could be given to the use of the potent aminobisphosphonate zolendronic acid, which has been shown to be at least equivalent to pamidronate in terms of efficacy with respect to bone lesion progression, with the convenience of a 15-to-30-minute infusion time as compared with the standard 2-hour infusion required for pamidronate given at the same intervals.10
The other approach would be to begin initial therapy with the goal of moving toward autologous peripheral-blood stem-cell transplantation with melphalan-based conditioning as consolidation therapy, especially if the tumor responds to the initial treatment. Additional strategies after initial therapy could include a double intensification and tandem stem-cell transplantation approach, an autologous stem-cell transplantation followed by nonmyeloablative allogeneic stem-cell transplantation, and a single autologous stem-cell transplantation with a novel biologic approach to follow.
Initial Therapy for Plasma-Cell Myeloma
A number of options exist for initial therapy for this patient, including combination chemotherapy (such as the agents vincristine, doxorubicin, and dexamethasone)11; dexamethasone as a single agent; dexamethasone in combination with thalidomide; or the use of bortezomib, a novel proteasome inhibitor recently approved for use in relapsed, refractory multiple myeloma12 and currently under study as initial therapy in phase 2 trials.13
Combination Chemotherapy
Combination chemotherapy, with vincristine, doxorubicin, and dexamethasone, has been the standard of care for many years. The inconvenience of continuous intravenous administration together with the high rates of complications reported with the use of these drugs, including alopecia, neutropenia, mucositis, peripheral neuropathy, and catheter-related complications such as thrombosis and infection,14 make this combination less than ideal. Most important, alkylator-based initial therapy (especially oral low-dose melphalan) should be avoided to minimize the risks of stem-cell damage.15 Thus, it is worthwhile to consider other options for this patient that have recently become available.
Thalidomide
Thalidomide has been shown to be effective in the treatment of both relapsed and relapsed, refractory multiple myeloma, with an overall response rate of 32 percent among patients who had relapses after stem-cell transplantation.16,17,18,19,20 The mechanisms of action of thalidomide in multiple myeloma are not fully understood but probably include growth arrest during the gap 1, or G1, phase of cell proliferation, disruption of adhesion, and the inhibition of growth-promoting cytokines released from both tumor and bone marrow stroma, together with antiangiogenic effects and anti–tumor-directed immune stimulation.21 The addition of dexamethasone to thalidomide has an additive effect, with response rates of 35 to 60 percent.22 In newly diagnosed or untreated patients such as this man, thalidomide in combination with dexamethasone results in higher response rates than with dexamethasone alone — in the range of 66 percent to 72 percent.23,24
Thalidomide is not without toxic effects. The most important are peripheral neuropathy and deep-vein thrombosis, with the latter having an incidence of between 5 percent and 16 percent, which is significantly higher when thalidomide is combined with dexamethasone and chemotherapy.21,25,26 Thalidomide analogues have also been studied as an option to treat advanced multiple myeloma and have shown activity and more manageable toxic effects as compared with thalidomide, with minimal neuropathy, sedation, thrombosis, and constipation reported.26 On the basis of these promising results, studies in newly diagnosed patients have begun. With appropriate thromboprophylaxis, the combination of thalidomide and dexamethasone would be a reasonable option to pursue in this patient.
Bortezomib
Bortezomib is another option for this patient. Bortezomib is a novel, selective, and reversible inhibitor of the proteasome, a key intracellular structure responsible for the degradation of ubiquinated proteins that has been shown to be especially active against multiple-myeloma cells in vitro and myeloma-associated bone marrow stroma, as well as in a murine model.27,28,29 After a phase 1 study in patients with hematologic cancer suggested activity in a subgroup of patients with relapsed myeloma,30 a large, multicenter phase 2 study of bortezomib in relapsed and refractory disease12 found a response rate of 35 percent and a statistically significant improvement in the time to progression of disease, together with an overall survival advantage as compared with treatment with high-dose dexamethasone.31 Peripheral neuropathy and transient thrombocytopenia were the most common side effects recorded in patients treated with bortezomib.
On the basis of these results, a series of phase 2 studies have explored the role of bortezomib alone, with dexamethasone, or in combination with chemotherapy as primary therapy for multiple myeloma. Response rates of 77 percent, with mild-to-moderate toxic effects, have been reported for bortezomib used alone or with dexamethasone,13 and response rates as high as 92 percent for bortezomib combined with dexamethasone and doxorubicin. The latter treatment was associated with side effects, including neuropathy.32 Participation in such a study would be a very reasonable option for this patient.
Stem-Cell Transplantation
The therapies discussed above do not usually result in long-term disease-free survival when used alone in multiple myeloma, so patients who respond to them are typically advised to proceed to high-dose therapy followed by stem-cell transplantation.33,34 Once responsiveness to initial therapy is confirmed, then stem-cell mobilization (typically using cyclophosphamide and granulocyte colony-stimulating factor) would be recommended. In a younger patient, such as this man, data from randomized trials suggest benefit from double autologous stem-cell transplantation in patients who do not have a complete response after the first intensification.35 Thus, consideration of a double or tandem melphalan-based approach supported by autologous stem-cell transplantation would be reasonable. However, the toxic effects associated with double autologous stem-cell transplantation and their potential impact on the quality of life (as compared with the effects of a single autologous stem-cell transplantation) should also be kept in mind.
HLA typing of the patient and his siblings should be considered, since nonrandomized data have suggested that a single autologous stem-cell transplantation, followed by a nonmyeloablative allogeneic stem-cell transplantation, may be beneficial for patients with matched sibling donors. However, limitations to nonmyeloablative allotransplantation include high rates of chronic graft-versus-host disease that approach 70 percent.36
Most recently, data from randomized trials indicate that low doses of thalidomide have a benefit when given as maintenance therapy after stem-cell transplantation.37 Thus, a single intensification approach with thalidomide as maintenance therapy would be another possibility for this patient at the conclusion of successful initial therapy. Given these options, I would encourage him to participate in a clinical trial comparing these approaches, should he opt for transplantation as part of his treatment.
In terms of prognosis, the median event-free survival has improved to between two and three years, usually for those patients 70 years of age or younger who successfully undergo autologous stem-cell transplantation.33,34 Overall survival is also superior when compared with that associated with standard therapies, with a median survival of approximately five years reported.33 Double autologous stem-cell transplantation in selected subgroups of patients may improve survival even more, but the effect of allogeneic stem-cell transplantation remains to be established.35 The advent of novel, biologically derived agents such as thalidomide, thalidomide analogues, and bortezomib holds promise not only for improving the quality of response, duration of response, and survival, but also for providing therapies that may be more specifically targeted and less toxic, and so improve patient outcomes.38
In this case, I would advise the patient either to continue with a conservative approach to management with bisphosphonate therapy and careful observation, keeping additional systemic treatment in reserve, or to pursue a more intensive approach with initial treatment (ideally protocol-directed) followed by transplantation.
Dr. Takvorian: After this conference, I discussed treatment options with this patient, and he elected not to undergo additional treatment for his myeloma. At that time, monthly zolendronic acid was substituted for pamidronate. Thirty-one months after the diagnosis, increasing pain in the left clavicle led him to agree to a course of radiation therapy that I suggested as an option, although radiographically, the bone lesions were unchanged. Unfortunately, this treatment has had only a minimal effect on his pain, which he now controls with oxycodone and acetaminophen. I have urged him on many occasions recently to begin treatment with one of the regimens described by Dr. Richardson, but he has declined. The beta2-microglobulin level was recently measured and was 1.85 mg per deciliter. Three years after the diagnosis he is still receiving only monthly doses of zolendronic acid.
Anatomical Diagnosis
Plasma-cell myeloma.
Source Information
From the Jerome Lipper Multiple Myeloma Center, Division of Hematologic Oncology, Department of Medicine, Brigham and Women's Hospital and the Dana–Farber Cancer Institute (P.G.R.); the Departments of Radiology (A.K.) and Pathology (W.J.), Massachusetts General Hospital; and the Departments of Medicine (P.G.R.), Radiology (A.K.), and Pathology (W.J.), Harvard Medical School.
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