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1 Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
2 Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Correspondence: Address correspondence and reprint requests to: Daniel G. Coit; E-mail: coitd{at}mskcc.org
ABSTRACT
Background: It is common to obtain radiological studies around the time of a positive sentinel lymph node biopsy (SLNB) to exclude patients with distant metastases from completion lymph node dissection. The yield of such a work-up is unknown.
Methods: Patients were identified from a prospectively maintained database. Medical records were reviewed.
Results: Over an 8-year period, 181 patients had a positive SLNB. At least one study (computed tomography or magnetic resonance imaging of the brain; chest x-ray; computed tomography of the thorax, abdomen, or pelvis; positron-emission tomography scan; or bone scan) was obtained around the time of SLNB in 178 patients (98%). Studies were obtained after SLNB in 107 patients (59%). Studies ordered after SLNB resulted in indeterminate findings in 51 patients (48% of those studied). Among patients tested after SLNB, four were found to have metastatic disease (positive rate 3.7%). All of these patients had both a thick melanoma and macrometastasis within the SLN. The number of patients with indeterminate findings would be decreased and the yield of the work-up increased by 4 fold, by restricting the work-up to those with thick melanoma and macrometastasis.
Conclusions: Radiological studies obtained after a positive SLN produce indeterminate findings in about half of the patients and identify distant disease in 3.7%. Restricting work-up to patients with thick melanoma and macrometastasis on SLNB would spare patients from indeterminate findings and increase the yield of the evaluation.
Key Words: Melanoma • Sentinel lymph node • Metastasis • Computed tomography • Positron-emission tomography • Radiology
The use of sentinel lymph node biopsy (SLNB) for staging patients with melanoma has been widely adopted because it provides powerful prognostic information with minor morbidity. Metastatic melanoma in the sentinel lymph node (SLN) predicts a greater risk of recurrence and death from melanoma than can be predicted by primary tumor factors alone.1–4 It remains unproven, however, whether the prognostic information provided by SLNB or the removal of occult metastatic disease in the regional lymph nodes translates into any measurable clinical benefit.5–7
Most patients with a positive SLN undergo radiological studies to evaluate the extent of disease,8,9 though the yield and utility of this approach remains unknown. The rationale for performing an extent of disease (EOD) evaluation for melanoma patients found to have a positive SLN is clear. Patients with a positive SLN are at higher risk to eventually manifest distant metastatic disease than those with a negative SLN.1–4 Perhaps most importantly, completion lymph node dissection (CLND) is unlikely to provide any benefit in the setting of occult distant metastases. Thus, patients can be spared the morbidity of a regional lymphadenectomy if distant disease is detected.
The yield of an EOD evaluation in patients with melanoma and a positive SLN depends on the incidence of occult metastatic disease in these patients as well as on the ability of available tests to detect the disease. The current literature on this subject is hampered in two regards.10–22 First, some of the data predates SLNB. More importantly, to our knowledge, there is no study that specifically examines studies obtained after the lymph node biopsy. By including radiological studies obtained prior to SLNB or elective lymph node dissection (ELND), the true yield of an EOD work-up is underestimated. It is unlikely that patients found to have distant metastasis would be subjected to a procedure on a clinically uninvolved regional lymph node basin, and hence they would not be captured in the study.
The aim of this study was to evaluate the yield of radiological studies employed to detect distant disease in patients with melanoma found to have a positive SLN.
METHODS
Patients
Patients were identified by review of a prospectively maintained institutional database of all melanoma patients who underwent an SLNB at Memorial Sloan-Kettering Cancer Center from January 1, 1998 through December 31, 2005. All patients with metastatic melanoma found on SLNB were included in the study.
Clinicopathological Variables and Statistical Analysis
After institutional review board approval (WA0006-05), medical records were reviewed for pertinent patient and tumor variables as needed to confirm and supplement the data contained in the prospective database. Reports of radiological studies were obtained from the electronic medical record, which contained reports for both internal and external studies over this time period. Radiological studies were included in this analysis if they were obtained either between the time of diagnosis of melanoma and SLNB or between SLNB and CLND or within 6 weeks after SLNB for patients who did not undergo CLND. Radiological studies were classified as positive if there were findings interpreted as representing a distant metastasis that was either confirmed histologically or felt to be sufficiently diagnostic without tissue diagnosis by the treating clinicians as indicated in the medical record. Studies were classified as indeterminate if there were findings reported by the radiologist as possibly due to metastatic melanoma. The remaining studies were classified as negative. Screening radiological studies included computed tomography (CT) or magnetic resonance imaging (MRI) scans of the brain, chest x-rays, CT scans of the thorax, CT scans of the abdomen, CT scans of the pelvis, bone scans, and positron-emission tomography (PET) scans.
Differences in distant metastasis-free survival were evaluated using the log rank test. Correlations between significant variables were identified with chi-square analysis and the two-tailed Fisher’s exact test. SPSS 11.0 statistical software (SPSS, Chicago, IL, USA) was used for analysis. Confidence intervals for proportions were calculated using the adjusted Wald method. P values < .05 were considered significant.
RESULTS
Demographic Information
One hundred eighty-one patients were found to have metastatic melanoma in a sentinel node out of 1519 patients who underwent SLNB for melanoma over an 8-year period at a single institution (12%). The clinical and pathological variables of these patients are shown in Table 1
. The median age was 60 years old, and there was a male predominance (67%). Almost all cases were Clark level IV (74%) or V (19%) with a median tumor Breslow thickness of 3 mm (range 0.75–38 mm). A CLND was performed in 160 of the 181 patients (88%).
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. The most common studies obtained were chest x-rays, body CT scans (thorax, abdomen, and/or pelvis), and PET scans, and these were obtained in 84%, 68%, and 53% of patients studied, respectively. One patient had a chest x-ray only. The remaining 177 patients had additional studies. No patient had a bone scan without a body CT. Three patients had a CT or MRI of the brain without a body CT, but one of these had a PET scan.
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).
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As the purpose of this study was to determine the utility of a staging evaluation performed after a positive SLNB, the remainder of the analysis focuses only on studies obtained between the SLNB and the completion lymphadenectomy (160 patients) or within 6 weeks after the SLNB for patients who did not undergo elective completion lymphadenectomy (21 patients). One hundred seven patients (59%) had at least one study performed after SLNB. Excluding chest x-rays, 92 patients (51%) had some EOD work-up after a positive SLNB. Indeterminate findings were noted in 51 of these patients (48% of those studied) or in 46 patients (50%) if chest x-rays were excluded. Four of 107 patients (3.7%) were found to have occult metastatic disease on studies obtained after SLNB.
There was a bias in patients who had an EOD work-up before versus after a positive SLNB. Of patients with thick melanoma (
4-mm Breslow thickness), only 31 of 71 patients (44%) had not had a body CT scan or a PET scan before SLNB, whereas 89 of 109 patients with thin or intermediate thickness melanoma (82%) were similarly body CT and PET naïve at the time of their positive SLNB (
2 = 28, P < 0.001). Of the SLN (+) patients who were body CT and PET naïve at the time of their SLNB, however, there was no difference in the percentage of patients who had further radiologic studies based on Breslow depth. Among patients who were body CT and PET naïve prior to SLNB, those found to have macrometastasis in the SLN were more likely than those with micrometastasis to undergo subsequent radiologic studies (53/71 (75%) versus 24/49 (49%); 2 = 8.3, P = 0.006).
Additional Invasive Procedures Performed Based on EOD Work-up
Of the five patients with metastatic disease identified by a staging study, three had CT-guided biopsies to obtain histological confirmation. In the additional two patients, metastatic melanoma was diagnosed clinically by the presence of widespread abnormalities on imaging and the concordance of CT scans and PET scans.
Four patients with indeterminate findings on imaging underwent invasive procedures at least in part to exclude the diagnosis of metastatic melanoma. One patient underwent bronchoscopy, mediastinoscopy, and open lung wedge resection demonstrating granulomas possibly due to sarcoidosis. One patient with a melanoma of the trunk underwent negative fine needle and core biopsies of enlarged inguinal lymph nodes. Another patient underwent a nondiagnostic biopsy and then excision of a lytic lesion of the cervical spine that proved to be fibrous dysplasia. The fourth patient had extremity melanoma and multiple enlarged, hypermetabolic lymph nodes in the mediastinum, abdomen, and pelvis. A fine needle aspirate of a retroperitoneal lymph node demonstrated lymphoma. Only in the case with fibrous dysplasia in the cervical spine was the indeterminate imaging obtained after the positive SLNB; in the other three cases, the invasive procedures were performed prior to SLNB.
Three patients (1.7% of those studied) were diagnosed with a second malignancy by staging work-up for melanoma. Two patients were found to have renal cell carcinoma on preoperative CT imaging. One patient (mentioned previously) was found to have lymphoma.
Factors Associated with Metastatic Disease Found on EOD Work-up after Positive SLNB
Features of the five patients found to have distant metastatic melanoma by staging radiological studies obtained around the time of a positive SLNB are shown in Table 3. All of these patients had high-risk features of the primary tumor or SLN metastases. In particular, all patients had tumors 4 mm thick, and all patients had macrometastases in the SLN. Ulceration was present in four cases.
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. Of note, if the body CT scans and PET scans ordered were restricted to patients with thick melanomas, the frequency of positive studies would have been 13% (95% confidence interval 4.4–29%) versus 4.4% (1.4–11%), and 13 versus 44 patients would have had indeterminate results. If these tests were restricted to patients with macrometastases in the SLN, the incidence of positive studies would have been 6.4% (2.1–16%) with 31 patients having indeterminate results. If only patients with both thick melanomas and macrometastases in the SLN had undergone body CT or PET imaging, the frequency of positive studies would have been 16% (5.8–35%), and only 10 patients would have had indeterminate results.
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It is clear that patients with melanoma found to have lymph node metastasis on sentinel lymph node biopsy (SLNB) are at increased risk of developing distant metastases compared to patients with a negative SLNB.1–4 The standard treatment for patients with a positive SLN is to undergo CLND. An EOD evaluation is often performed in order to exclude patients with distant metastasis from CLND. The yield of radiological studies in detecting distant metastasis after positive SLNB has not been previously defined.
While in this study an EOD work-up was performed on almost every patient with a positive SLN, we found significant variation in the array of radiological studies obtained and the timing of these studies (before or after SLNB).
We chose to concentrate on the work-up performed after a positive SLNB, as the work-up obtained at the time of diagnosis of melanoma may have influenced whether an SLNB was performed. Thus by including studies obtained before SLNB in a retrospective analysis including only patients with a positive SLNB, the yield of radiological studies may be underestimated.
We found a bias in the timing at which radiological studies ordered for EOD work-up were obtained. Patients with thick melanoma (4-mm Breslow thickness) were more likely to have a work-up before SLNB than those with intermediate or thin melanoma. In addition, patients with macrometastases found on SLNB who had not previously had body CT scans or PET scans were more likely to undergo a further work-up than those with micrometastases.
Approximately half of patients with a positive SLN who had radiological studies obtained after SLNB were noted to have findings indeterminate for distant metastasis. The percentage of studies with indeterminate findings ranged from 0–41%. The frequency of indeterminate findings on radiologic studies in our study is higher than other recent studies. Similar to prior reports, chest CT scan was the study most commonly associated with indeterminate findings. However, the frequency of indeterminate findings on chest CT has been reported as 19%15 and 14%22 compared to 41% here. Despite the frequency of indeterminate findings in our study, clinical suspicion in this setting led to a subsequent invasive procedure in only one patient not having occult distant metastases.
The yield of radiological studies for true metastatic disease in SLN positive patients was 3.7%. The yield of individual studies ranged 0–4.6%. Metastases were only detected on body CT scans and PET scans. All patients in whom metastatic disease was detected had tumors thicker than 4 mm, and four of five had ulcerated lesions. Furthermore, all patients found to have distant metastases had macrometastases on SLNB. By restricting the EOD work-up to these high risk patients, the yield of true positive findings would have increased 4 fold.
To our knowledge, there is no other study in the literature that specifically addresses the question of the yield of radiological studies ordered after a patient with malignant melanoma is determined to have a positive SLNB. Two recent studies evaluated the yield of CT scans of the thorax, abdomen, and pelvis as well as CT or MRI scans of the brain obtained around the time of a positive SLNB.
The first study was a series of 185 patients seen at the University of California San Fransisco.15 Similar to our findings, CT and MRI scans of the brain, performed in 112 patients, did not detect any distant metastasis. Body CT scans (CT thorax performed in 142 patients and CT abdomen/pelvis performed in 146 patients) detected metastatic disease in a single patient, who despite being staged with a chest x-ray, PET scan, and brain MRI before CLND, had lung metastases detected by CT imaging two months after CLND was performed. This patient, consistent with the characteristics of the patients found to have metastatic disease in our series, had a 4.5-mm Breslow thickness primary tumor with ulceration and macrometastasis in the SLNB.
The M.D. Anderson Cancer Center (MDACC) recently reported the yield of CT and MRI scans in 314 SLN positive patients.22 Five of 270 patients who were studied were found to have distant metastases (1.9%). Individually, CT or MRI of the brain identified metastases in only 2 of 310 studies (0.6%). CT of the thorax identified metastasis in 4 of 243 (1.6%) patients, and abdominopelvic CTs identified metastasis in only 1 of 265 (0.4%). All but one of the five patients found to have distant disease had lung metastases. The remaining patient had an isolated brain metastasis. One patient had lung, brain, and liver metastases. Similar to our results, the finding of distant metastatic disease at the time of a positive SLNB was confined to patients with advanced features of the primary tumor and SLN. All five patients had macrometastatic disease found on SLNB and ulcerated primary tumors. Interestingly, while the group found to have distant metastases had, on the whole, thicker tumors, three of the five had tumors <4 mm thick with one patient having a 1.3-mm Breslow thickness tumor. The reason for the discrepancy between studies with regard to thickness is likely due to the relatively small numbers of patients with distant metastases in both studies. While the authors indicated that the institutional practice at M.D. Anderson is to perform no staging other than serum lactate dehydrogenase level (LDH) and chest x-ray prior to SLNB, no other mention is made of the timing of the radiologic studies. It would seem unlikely that all patients were referred for SLNB without prior imaging, especially among patients with high-risk tumors. The authors do not specifically address this point.
Two large studies address the yield of CT scans in the setting of newly diagnosed stage III melanoma prior to the era of SLNB. These studies from M.D. Anderson Cancer Center12 and from Memorial Sloan-Kettering Cancer Center (MSKCC)13 reported that 8.3% and 5.1% of asymptomatic patients, respectively, had distant disease detected by CT imaging. Most patients in these studies had clinically apparent nodal metastasis, and thus the higher yields reported compared to the present study are not surprising. Only the 21% of patients in the MDACC report who had stage III disease diagnosed by elective lymph node dissection would be comparable to SLN positive patients in the modern era. CT scans of the brain identified skull metastases in 1 of 82 patients (1%) in the MDACC study, and none of the 104 patients in the MSKCC report.
Two retrospective studies17,21 and five prospective studies14,18–20,23 evaluating the utility of PET scan in melanoma address imaging in SLN positive patients. Each study has few patients, but collectively PET scans were performed on 117 patients and identified distant disease in only one (0.8%). An additional patient, 1 of 10 SLN positive patients in the prospective study from our center, had distant disease identified, although in this case it was found by CT scan while the PET scan was negative.20 The comparatively low yield in these studies compared to the present study may reflect the more selective use of PET scans in our series. Ninety-six of the 117 patients (82%) in the above studies were prospective studies in which PET scan was evaluated in a variety of clinical scenarios, often with the primary aim of comparing PET scan to SLNB in detecting regional disease.
The use of bone scans and chest x-rays for the staging of patients with asymptomatic regional lymph node metastases has not been well evaluated. In a study from 1975, bone scan identified asymptomatic bone metastases in 2 of 13 patients (15%) with clinically evident stage III disease and an additional 1 of 35 (2.8%) with clinical stage II disease;10 however, it is unclear whether these patients would have had metastatic disease detected by another modality in an EOD work-up.
The utility of chest x-ray in patients with clinically localized melanoma was evaluated prospectively in a recent study. Although distant disease was not found in any of the 210 patients studied, only 14 patients had a positive SLNB. Indeterminate findings were present on 7.1% of the chest x-rays overall.16 In our study chest x-ray alone did not identify any occult metastases either prior to or after SLNB.
This study, along with other large series evaluating the yield of radiologic studies in patients found to have melanoma metastatic to regional lymph nodes, is limited in that the data have been collected retrospectively. Patients have not been evaluated for metastatic disease in a uniform fashion. Thus, there are inherent biases related to the extent and timing of the work-up of individual patients. Ultimately, decisions about what tests were recommended for each patient were made by the treating physicians. The true yield of an EOD evaluation in patients with a positive SLN would be best determined by prospectively implementing a standardized work-up in patients before and after SLNB. This approach would allow evaluation of the sensitivity of an EOD work-up as related to clinical suspicion of distant metastasis as well as determination of the clinical utility of an EOD work-up on clinical decision making.
In summary, the yield of radiological studies ordered in patients with malignant melanoma after a positive SLNB in detecting distant metastases is 3.7%. Of studies ordered in this clinical setting, body CT scans and PET scans have the highest yield. Patients with thick melanomas (4-mm Breslow thickness) and/or macrometastases in the SLN are more likely to harbor detectable distant metastatic disease than those with intermediate/thin melanoma and/or micrometastasis in the SLN. The yield of an EOD disease work-up can be increased, and the number of indeterminate findings can be decreased by restricting work-up to patients with these features.
Received for publication November 14, 2006. Accepted for publication January 2, 2007.
REFERENCES
This article has been cited by other articles:
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  Z. I. Nowecki, P. Rutkowski, and W. Michej The Survival Benefit to Patients with Positive Sentinel Node Melanoma After Completion Lymph Node Dissection May Be Limited to the Subgroup with a Primary Lesion Breslow Thickness Greater Than 1.0 and Less Than or Equal to 4 mm (pT2-pT3) Ann. Surg. Oncol., August 1, 2008; 15(8): 2223 - 2234. [Abstract] [Full Text] [PDF]
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