Skeletal Metastases of Melanoma: Radiographic,

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1 103 Gerald T. Eon1 2 Wilson S. Wong1 Richard H. Gold1 Larry A. Kaiser3 Received October 1 0, 1 980; accepted after revision January 1 2, Department of Radiological Sciences, UCLA Center for the Health Sciences, Los Angeles, CA Address reprint requests to R. H. Gold 2 Present address: Department of Radiology, Flinders Medical Center, Bedford Park, S. Australia Australia. 3 Division of Surgical Oncology, UCLA Center for the Health Sciences, Los Angeles, CA AJR 137: , July X/81 / $00.00 American Roentgen Ray Society Skeletal Metastases of Melanoma: Radiographic, Scintigraphic, and Clinical Review The radiographic manifestations of I 27 skeletal metastases in 50 patients with melanoma were reviewed and correlated with the scintigraphic findings. Although the features of most of the metastases were nonspecific and appeared similar to those of other osteolytic metastases, several of them had unusual features, including expansion, subarticular location, osteosclerosis, and a thin, sclerotic rim. These features could result in some of the metastases being mistaken for other lesions. The radionuclide bone scans were more sensitive in that they detected the lesions earlier and in greater numbers than the radiographs. Prognosis was poor once skeletal metastasis was diagnosed, the mean survival time being 4.7 months. There have been several published reports of skeletal metastases of malignant melanoma, but only two of them contained a significant number of patients [1, 2]: Stewart and coworkers [1 ] dealt mainly with management while Selby et al. [2] described the radiographic features. Recent advances in the earlier detection and management of melanoma have led to an improved prognosis and a longer disease-free interval [3-5]. The recurrence rate is lower and the survival rate higher in patients treated with adjunctive bacille Calmette-Gu#{233}rin (BCG) immunotherapy [3, 5]. It is thus appropriate to reassess the radiographic features and the progression of osseous metastases. In addition, correlation will be made with the scintigraphic findings, and the relative merits of each imaging method will be discussed. Materials and Methods Abstracts of the charts of all patients with melanoma in the UCLA Tumor Registry from to were reviewed. In addition, a computer search was made of all surgical pathology and autopsy reports of patients with melanoma who also had scintigraphic studies performed from to Of a total of melanoma patients identified by the computer, 1 45 had evidence of skeletal metastases on scintigraphic study, biopsy, or at autopsy. Of these, 50 had radiographic evidence of osseous metastases and form the basis of this investigation. The other 95 patients had either positive radionuclide bone scans in the absence of radiographic evidence of metastasis on their radiographs were unavailable. Most diagnoses were proven by biopsy or autopsy, although not every bone lesion was proved histologically in every patient. The scintignams of the bone were obtained 3-4 hr after an intravenous injection of 1 5 mci (555 MBq) of a9mtc diphosphonate. Views of the skeleton were obtained using a rectilinear scanner, a gamma scintillation camera, or a Phocon scanner. When the gamma scintillation camera was used, both anterior and posterior views were obtained. Additional localized views were obtained as needed. Concurrent radiographs were obtained of any suspicious areas of increased uptake of radionuclide. Full skeletal radiographic surveys were available in most patients. Follow-up films revealing progression of the skeletal metastases were available for 26 patients.

2 104 FON ET AL. AJR:137, July 1981 Results There were 33 males and 1 7 females, years old (mean, 44.5 years). Four patients had a second malignancy other than melanoma, two of which were incidental findings at autopsy and had not metastasized. In the other two patients, the additional malignancy had been detected before the melanoma. In all four cases, the bony lesions were shown histologically to be metastases from the melanoma. The organs that were involved at the initial manifestation of metastatic disease for all patients are shown in table 1: 26 (52%) initially had bone metastases alone or in combination with metastases of other organs; 27 had metastases detected in only one organ at their initial presentation of metastatic disease, and, of these, 1 2 had them in the skeleton. Of seven patients who had metastatic melanoma from an unknown primary site, four had metastases to bone, two of whom were seen with pathologic fractures. The time interval from diagnosis of melanoma to clinical detection of metastatic disease varied from 1 month to 13 years (mean, 42.5 months). Of 30 patients who had regional lymphadenectomy for staging, the time interval from diagnosis to manifestation of metastasis was 50 months for stage I and 1 9 months for stage II disease. Stage I refers to disease localized to the primary site, stage II to the presence of metastases in regional lymph nodes, and stage Ill to disseminated disease. The mean interval between disseminated disease and skeletal metastasis was only 2.7 months. Once the diagnosis of osseous metastasis was made, the mean survival time was only 4.7 months for the 30 patients who were known to have died. The other patients were lost to follow-up. Excluding one patient who had widely disseminated skeletal metastases too numerous to count (fig. 1 ), 1 27 individual osseous lesions were studied. Metastases to the axial skeleton accounted for 80% of the lesions (fig. 2). The ribs were involved by 38% of the metastases. In 29 patients who had solitary osseous metastases, the incidence of occurrence in the ribs was similarly 38%. In the vertebral column, the appendages were less commonly affected than either the bodies or a combination of both. In the long bones, the metastases were usually located symmetrically in the diaphyses, although four (4.3%) lesions TABLE 1 : Organs Involved with Metastatic Disease at Initial Presentation Bone Lung Brain Soft tissues Nodes Liver Intestines Total Organ Single Organ Involvement 12 (44.5) 6 (22.2) 1 (3.7) 5 (1 8.5) 3 (11.1) 0 0 No. Patient s (%) 5ingle and Multiple Organ Involvement (100.0) 76 Fig. 1.-Anteropostenior view of pelvis. Explosive development of numerous metastases 2 months after normal examination Fig. 2.-Skeletal distribution of melanoma metastases. were subarticular (fig. 3A), and three of these were associated with joint effusion (fig. 3B). The vast majority of the lesions were osteolytic with only eight (6.3%) showing either osteosclerosis or a mixture of osteolysis and osteosclerosis (fig. 4A). It is of interest to note that in one case, despite the absence of local therapy, the lesion changed from purely osteolytic to a mixed process over a 6 month period. The margins of the lesions were usually poorly defined, although in one case, a well defined sclerotic rim was found (fig. 3A). Twenty-seven (21 %) lesions in 1 1 patients had a geographic pattern in the bony metastases. The mean survival from the time of diagnosis of osseous metastases in six of these patients who were known to have died was 5.5 months

3 AJR:137, July 1981 SKELETAL METASTASES OF MELANOMA 105!T B Fig. 4.-Three patients with various metastatic configurations. A, Antero- metastasis with interrupted peniosteal new bone response (arrows)., Anposterior view of right ischium. Well circumscribed osteoblastic metastasis tenopostenior view of fifth rib. Osteoblastic metastasis associated with ex- (arrowhead). B, Anteropostenior view of left humerus. Moth-eaten osteolytic pansion of adjacent costochondral junction (arrowheads).

4 106 FON ET AL. AJR:137, July 1981 (table 2). The moth-eaten pattern was found in 73 (57%) lesions in 28 patients, 1 7 of whom died after a mean interval of 4.6 months. The patients with a permeative pattern survived only 3.6 months (table 2). More than one pattern of growth in the skeletal metastases was seen in 1 1 patients. In these patients, the pattern selected for calculation of the survival rate was the one that had the greater number of lesions. In those cases where there were equal numbers of lesions in each pattern, the one which is more aggressive in behavior as described by Lodwick [6] was selected. Typical periosteal reaction was relatively uncommon, being present in 1 2 (9%) lesions (fig. 46) and was characteristically scant, longitudinally linear, and interrupted. An almost equal number (1 3) of lesions were found to be, expansile ; one of these was most unusual in that it involved the costochondral junction (fig. 4C). The expanded cortical margins of these lesions are in fact a reflection of linear periosteal new bone that is slowly and progressively deposited at the periphery of the cortex which has undergone progressive endosteal resorption due to the stimulus of underlying tumor. The skeletal metastases weakened the bone considerably, as pathologic fractures occurred in 74 (58%) sites. While soft-tissue swelling was usually seen in association with the fractures, it was also found in 25 (1 9%) lesions TABLE 2: SurvIval Time and Metastatic Pattern Pattern Lesions N o. (%) Patients Known Dead Mean 5urvival (months) Geographic 27(21) Moth-eaten 73 (57) Permeative 1 4 (1 1 ) Pattern destroyed 1 3 (1 1 ) Total 127(100) without any definite evidence of a fracture, suggesting penetration of the cortex by tumor. Such penetration was not demonstrated on the radiographs, but might perhaps be visible by computed tomography. Follow-up films were obtained in 26 patients 1-9 months (mean, 3.7 months) from the time of initial radiographic evidence of skeletal metastases. Significant progression of the initial lesion and/or new lesions in other parts of the skeleton were seen in 21 (80%) patients. Progression of the initial lesion was manifested by increase in size, further osteolysis, pathologic fracture, or increased soft-tissue swelling. Progression was quite variable but was usually noted within 4-8 weeks (fig. 1 ). There were no instances to suggest regression or improvement of the lesions with the possible exception of the single case where the lesion changed from a purely lytic to a mixed process over a 6 month period. A total of 40 patients had radionuclide bone scans. Ten patients had evidence of skeletal metastases on bone scans on an average of 2.7 months (range, 1-7 months) before any radiographic changes could be detected. The bone scans in these 1 0 patients yielded a total of 24 sites of increased uptake compared with 21 sites disclosed on subsequent films. Five patients, whose films showed a total of eight lesions at initial presentation, had negative bone scans months earlier. The other 25 patients had their bone scans within 1 week of their radiographs. The scans revealed 71 abnormal sites, while the radiographs disclosed a total of 64 sites. There were three patients who had one or more osseous lesion on the films that were silent on the bone scans. In one patient, the bone scan actually showed a photon-deficient lesion (fig. 5). Discussion There is considerable variation in the reported incidence of skeletal metastases from malignant melanoma. In their Fig. 5.-A, Lateral view of sternum. Osteolytic metastases to manubrium (arrowheads). B, Lesion is photon deficient (arrow) on radionuclide bone scan.

5 AJR:137, July 1981 SKELETAL METASTASES OF MELANOMA 107 review of the literature, Wilner and Breckenridge [7] showed that the incidence was 0.85%-18.6%. In our series of 145 patients, the incidence of skeletal metastasis detected by radionuclide bone scans and/or radiographs was 7.8% (1 45 of 1,870 patients). Autopsy studies reveal a much higher incidence, ranging from 35% [8] to 49% [2]. One reason for the failure to detect skeletal metastasis prior to autopsy is the relative insensitivity of both radionuclide bone scans and standard radiographs. Until the onset of cortical destruction, most medullary lesions remain radiographically invisible [9]. Moreover, most skeletal metastases from melanoma progress rapidly within 4-8 weeks once they have become radiographically evident. Hence, the short time interval between radiologic examination and autopsy may preclude identification of some metastases. Although ours was a selective series, 52% (26 of 50) of the patients had osseous lesions, either involving the bone alone or in combination with other organs, as the initial feature of their metastatic disease. Although the radiologic features of most skeletal metastases from melanoma in our series were nonspecific and appeared similar to those of other osteolytic metastases, several unusual features in some of the metastases could have resulted in their being mistaken for other lesions. Fortunately, these features were not common. The subarticular location of four (4.3%) lesions was unusual and could have led to a misdiagnosis of giant cell tumor. Selby et al. [2] specifically reported that this feature was not found in their autopsy series of 33 patients. The proximity of the metastasis to an articular surface resulted in joint effusions in three cases (fig. 3B). Unlike previous investigations [1, 7, 10, 1 1 ], which failed to associate periosteal reaction with melanoma metastasis, periosteal new bone was found in 1 2 (9%) lesions in our series (fig. 4B). Selby and coworkers [2] also detected periosteal reaction in some of their metastases, and, similar to our own analysis, found it to be characteristically minimal, requiring careful examination for identification. Other uncommon features in our series also found infrequently by other observers were expansion of the bone in 1 3 (10%) lesions [7, 1 1 ], a mixed osteolytic and osteoblastic process in eight (6%) lesions [2, 1 1 ], and the presence of a thin, sclerotic rim around one lesion [7, 1 1 ]. Steiner and Mac- Donald [1 1 ] maintained that the presence of a sclerotic rim surrounding one metastatic melanoma lesion in their series was associated with long survival (9 years). However, our patient whose lesion had a sclerotic rim died 1 0 months after the initial diagnosis of the primary melanoma. Although it is tempting to postulate that the presence of osteosclerosis, whether within a lesion or at its margin, and periosteal new bone are related to therapy, we could find no evidence to support this. The patients with these unusual features had the same treatment as the others, consisting of combinations of chemotherapy, immunotherapy (BCG administration and tumor cell vaccine), and, in a few cases, localized hyperthermia. None of the lesions that showed osteosclerosis or periosteal reaction had local direct irradiation. Hypertrophic osteoarthropathy in association with pulmonary metastases from malignant melanoma has been reported [ ], but was not observed in our series. Description and implication of radiographic patterns of bone destruction have been extensively presented by Lodwick [6]. According to him, the rate of growth in primary bone tumors is related to the pattern of destruction, being most rapid in the permeative, intermediate in the motheaten, and least rapid in the geographic pattern. Accordingly, in our series, the survival interval from the time of detection of skeletal metastases to death in those patients with permeative, moth-eaten, and geographic patterns of bone destruction were 3.6, 4.6, and 5.5 months, respectively (table 2). While these survival rates agree with the Lodwick concept [6], it must be realized that there are probably other factors, such as cerebral, hepatic, and pulmonary metastases, that may contribute to the patients deaths. The mean survival time from the diagnosis of skeletal metastases, regardless of the pattern of bony destruction, in our patients was 4.7 months. This is somewhat longer than the 3.5 and 3.6 months previously reported [1, 1 1], and could perhaps be a reflection of the improved prognosis as a result of the recent advances in the earlier detection and management of melanoma [3-5]. However, the prognosis still remains poor, with rapid progression of the osseous lesions once they are diagnosed. Several authors have suggested that radionuclide bone scanning is useful only in symptomatic melanoma patients with stage I or stage II disease and in all patients with stage Ill disease [ ]. According to those authors, the scintigram should not be used as a routine screening test in asymptomatic patients with stage I or II disease as the probability of detecting clinically occult metastases is low [ ]. We did not have the opportunity to compare the scans with the films for each of the different stages of the disease, since most of our patients were either symptomatic or in stage III disease. However, when we compared the scans of these patients with their radiographs, we found the scans more sensitive in that they detected a greater number of lesions and also detected them earlier (mean time interval, 2.7 months) than the films. Sklaroff and Charkes [1 9] found that pain may precede radiographic evidence of bony metastatic disease by several months. The sensitivity of the bone scan makes it a useful tool for both the detection of early metastasis and in the monitoring of response to various treatment methods. On the other hand, the bone scan had a false-negative incidence of 7.5% (three patients) in our series. This may occur when the lesions are growing too rapidly or too slowly to stimulate significant reactive bone production [18]. ACKNOWLEDGMENTS We thank David Allman for photographic assistance and Judy Merit for manuscript preparation. REFERENCES 1. Stewart WR, Gelberman RH, Harnelson JM, Seigler HF. Skeletal metastases of melanoma. J Bone JointSurg [Am] 1 978;6O: Selby HM, Sherman RS, Pack GT. A roentgen study of bone

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