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10.1245/ASO.2006.01.016
Annals of Surgical Oncology 13:712-720 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Hepatic Resection for Metastatic Melanoma: Distinct Patterns of Recurrence and Prognosis for Ocular Versus Cutaneous Disease

Timothy M. Pawlik, MD, MPH1, Daria Zorzi, MD1, Eddie K. Abdalla, MD1, Bryan M. Clary, MD3, Jeffrey E. Gershenwald, MD1, Merrick I. Ross, MD1, Thomas A. Aloia, MD1, Steven A. Curley, MD1, Luis H. Camacho, MD, MPH2, Lorenzo Capussotti, MD4, Dominique Elias, MD5 and Jean-Nicolas Vauthey, MD1

1 Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 444, Houston, Texas 77030
2 Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, Texas 77030
3 Department of Surgery, Duke University Medical Center, Trent Drive, Box 3247, Durham, North Carolina 27710
4 Unit of Surgical Oncology, Institute for Research and the Cure of Cancer, Strada Provinciale 142, Km. 3.95, 10060 Candiolo, Italy
5 Department of Surgery, Gustave Roussy Institute, 39 Rue Camille Desmoulins, 94805 Villejuif Cedex, France

Correspondence: Address correspondence and reprint requests to: Jean-Nicolas Vauthey, MD; E-mail: jvauthey{at}mdanderson.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Resection of melanoma metastatic to the liver remains controversial. We evaluated the efficacy of hepatic resection in patients with metastatic ocular and cutaneous melanoma and assessed factors that could affect survival after resection.

Methods: Forty patients with hepatic melanoma metastasis underwent resection at four major hepatobiliary centers. Clinicopathologic factors were evaluated with regard to recurrence and survival by using {chi}2 and log-rank tests.

Results: The primary tumor was ocular in 16 patients and cutaneous in 24. The median disease-free interval from the time of primary tumor treatment to hepatic metastasis was the same for both groups (ocular, 62.9 months; cutaneous, 63.1 months; P = .94). Most patients underwent either an extended hepatic resection (37.5%) or hemihepatectomy (22.5%). Twenty-six patients (65%) received perioperative systemic therapy. Thirty (75.0%) of 40 patients developed tumor recurrence. The median time to recurrence after hepatic resection was 8.3 months (ocular, 8.8 months; cutaneous, 4.7 months; P = .3). Patients with primary ocular melanoma were more likely to experience recurrence within the liver (53.3% vs. 17.4%; P = .015), whereas patients with a cutaneous primary tumor more often developed extrahepatic involvement. The 5-year survival rate for patients with a primary ocular melanoma was 20.5%, whereas there were no 5-year survivors for patients with cutaneous melanoma (P = .03).

Conclusions: Patterns of recurrence and prognosis after resection of hepatic melanoma metastasis differ depending on whether the primary melanoma is ocular or cutaneous. Resection should be performed as part of a multidisciplinary approach, because recurrence is common.

Key Words: Melanoma • Ocular • Cutaneous • Liver • Resection • Outcome


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Melanoma is the fifth most common malignancy among men and the seventh most common malignancy among women in the United States. The incidence of cutaneous melanoma is approximately 55,100 cases per year,1 whereas ocular melanoma occurs at a frequency of 4,000 per year.2 Depending on the clinicopathologic characteristics of the primary tumor, up to one third of patients with melanoma may develop distant metastasis.3,4 A common site for distant metastasis, particularly for ocular melanoma, is the liver. In fact, up to 40% of patients with ocular melanoma have hepatic metastasis present at initial diagnosis, and the liver becomes involved in up to 95% of individuals who develop metastatic disease.5 Although cutaneous melanoma metastasizes to the liver less frequently, it still occurs in 15% to 20% of patients with metastatic disease.6,7

Historically, the median survival of patients with hepatic melanoma metastasis has ranged from 2 to 7 months.6,8–11 Chemotherapy is of limited efficacy against melanoma, with treatment response rates of 10% to 30%.12–15 For this reason, surgical resection is the only potentially curative option for patients with melanoma metastatic to the liver. Some investigators, however, have suggested that resection of hepatic melanoma metastasis is not warranted because of the dismal prognosis. Other investigators have suggested that resection may be appropriate only in patients with an ocular primary tumor, because of the worse clinical course of patients with cutaneous melanoma.6,8 To date, most studies reporting on hepatic metastasis from melanoma have been either case reports16–19 or small case series.20–24 The role of hepatic resection for melanoma metastasis, therefore, remains poorly defined. This study examined a large, multi-institutional experience of hepatic resection for metastatic melanoma. The objective of this study was to evaluate the efficacy of hepatic resection in patients with metastatic ocular versus cutaneous melanoma and to assess additional factors that may affect survival after resection of melanoma metastatic to the liver.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Forty patients with metastatic melanoma involving the liver who were treated with hepatic resection with curative intent between April 1988 and May 2004 were identified from the databases of four major hepatobiliary centers: the University of Texas M. D. Anderson Cancer Center (Houston, TX), Duke University Medical Center (Durham, NC), Gustave Roussy Institute (Villejuif, France), and the Institute for Research and the Cure of Cancer (Candiolo, Italy). Before surgery, all patients were evaluated with a baseline history and physical examination; serum laboratory tests; computed tomography or magnetic resonance imaging scans of the abdomen and pelvis; and a chest radiograph or chest computed tomography.

Data Collection
The following data were collected for each patient: sex; age; anatomical location and histological characteristics of the primary melanoma; details of the initial treatment of the primary melanoma; lymph node status of the primary melanoma; time interval from the initial treatment of the primary melanoma to metastasis; details of any adjuvant treatment of the hepatic metastasis; surgical procedure for the metastatic lesions; intrahepatic tumor number, location, and size; recurrence status; disease-free interval; date of last follow-up; and death date. Data regarding the timing (preoperative vs. postoperative) and the type of systemic therapy were also recorded. Tumor size was defined as the largest diameter of the metastatic lesion. Resection was classified as less than a hemihepatectomy (e.g., segmentectomy or subsegmentectomy), or extended hepatic resection (five or more liver segments). Data were collected and filed in Excel format (Microsoft, Inc., Seattle, WA) and processed with SPSS software (SPSS, Inc., Chicago, IL).

Statistical Analysis
All data are presented as percentages of patients or the median value. Statistical analyses were performed by using {chi}2 tests to test for differences in variables with regard to recurrence and survival. Actuarial survival was calculated by using the Kaplan-Meier method. Differences in survival were examined by using the log-rank test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
The clinical characteristics of the study patients are listed in Table 1Go. Among the 40 patients, 16 patients had a primary ocular melanoma, whereas 24 patients had a primary cutaneous melanoma. There were 24 men and 16 women; the male:female ratio was 1.5:1. The median patient age was 45 years (range, 27–66 years). Although there was no statistical difference in sex distribution (P = .5), patients with a primary cutaneous melanoma were younger than patients with a primary ocular melanoma (median age, 40 vs. 52 years, respectively; P = .005). The median size of the hepatic metastasis was the same in both patient cohorts (ocular, 4.3 cm; cutaneous, 4.2 cm; P = .99). Patients with cutaneous melanoma tended to have multiple metastatic lesions (65.2% vs. 50.0% for ocular), although this did not reach statistical significance (P = .26). Of those patients with multiple tumors, the median number of lesions was the same (n = 3) whether the primary melanoma was ocular or cutaneous. After surgery, the median length of stay was 7.3 days (range, 3–35 days). The perioperative mortality rate was 5.0%.


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  		TABLE 1. Clinical and pathologic features of patients (n = 40)
 
Primary Ocular Melanoma
Treatment of the primary ocular melanoma included radiotherapy (n = 8; 50.0%) and enucleation (n = 8; 50.0%). No patient with an ocular melanoma had evaluation of the regional lymph nodes as part of the initial operative procedure. The median disease-free interval from the treatment of the primary tumor to the time of hepatic metastasis was 62.9 months (range, 2 months to 17 years). The only site of distant metastatic disease for all 16 patients with a primary ocular melanoma was the liver.

Surgical resection of the hepatic metastasis involved an extended hepatic resection (n = 7; 43.8%) or a hemihepatectomy (n = 3; 18.7%) in most patients (n = 10; 62.5%). Only a minority of patients (n = 6; 37.5%) underwent less than a hemihepatectomy. Three patients (18.8%) had radiofrequency ablation performed in conjunction with hepatic resection (two patients had a segmentectomy and one patient had an extended hepatic resection). Two patients (12.5%) had a positive microscopic surgical resection margin. In addition to surgical resection, nine patients (56.3%) received systemic therapy (Table 2Go).


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  		TABLE 2. Details of patients who received systemic therapy (n = 26)
 
Primary Cutaneous Melanoma
All 24 patients with a cutaneous melanoma had a wide local excision of the primary tumor. Twelve patients (50.0%) also had a regional lymphadenectomy. The median number of lymph nodes harvested was 17 (range, 7–27), and the median number of positive nodes was 4 (range, 0–27). The median disease-free interval from the time of wide local excision to the time of hepatic metastasis was 63.1 months (range, 13.6 months to 31 years), which is not different from the disease-free interval of patients with a primary ocular melanoma (P = .94). Unlike patients with ocular melanoma, patients with cutaneous melanoma were more likely to have metachronous or synchronous metastases (ocular, n = 0; cutaneous, n = 8; P = .03). Five patients had metachronous metastases: lung metastasis followed by liver metastasis (n = 4) and parathyroid metastasis followed by liver metastasis (n = 1). The median time between the first site of metastasis and the development of liver metastasis was 27 months (range, 3 months to 14 years). Three patients had synchronous metastases (liver plus small bowel, n = 2; liver plus iliac lymph nodes, n = 1).

Similar to patients with an ocular primary melanoma, most patients with cutaneous melanoma underwent either an extended hepatic resection (n = 8; 33.3%) or a hemihepatectomy (n = 6; 25.0%), whereas 10 patients (41.7%) underwent less than a hemihepatectomy. No patient with cutaneous melanoma had radiofrequency ablation. Only one (4.2%) patient had a positive microscopic surgical resection margin. Seventeen patients (70.8%) received some form of systemic therapy (Table 2Go).

Outcome: Patterns of Recurrence and Survival
Recurrence
With a median follow-up of 22.6 months from the time of hepatic resection, 30 (75.0%) of 40 patients developed a recurrence. The median time to recurrence after hepatic resection was 8.3 months (range, 1–33.5 months). The rate of recurrence was the same for patients with a primary ocular melanoma (n = 12; 75.0%) and cutaneous melanoma (n = 18; 75.0%; P = .9). Patients with a primary ocular melanoma tended to have a longer disease-free survival (8.8 months) than patients with a primary cutaneous melanoma (4.7 months; P = .3; Fig. 1Go).


Figure 1
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  		FIG. 1. Despite similar recurrence rates for patients with a primary ocular melanoma (n = 12; 75.0%) and cutaneous melanoma (n = 18; 75.0%; P = .9), patients with a primary ocular melanoma tended to have a longer disease-free survival (8.8 months) than patients with a primary cutaneous melanoma (4.7 months; P = .3).

 
Among patients who experience disease recurrence (n = 30) after hepatic resection, the liver was the most common site of tumor recurrence (n = 12; 40%). Other sites of recurrence after hepatic resection were lung (n = 8; 26.7%), brain (n = 6; 20.0%), dermis/soft tissue (n = 6; 20.0%), distant lymph nodes (n = 5; 16.7%), bone (n = 2; 6.7%), adrenal gland (n = 2; 6.7%), and viscera (n = 2; 6.7%; Table 3Go). The pattern of recurrence differed according to the primary site of the melanoma. Patients with a primary ocular melanoma were more likely to have recurrence within the liver (ocular, n = 8 [53.3%]; cutaneous, n = 4 [17.4%]; P = .015), whereas patients with a primary cutaneous melanoma more often developed brain metastasis (ocular, n = 1 [12.5%]; cutaneous, n = 5 [21.7%]; P = .04). In fact, patients with a cutaneous melanoma were significantly more likely to have recurrence outside of the liver after resection compared with patients who had an ocular primary melanoma (cutaneous, 24 extrahepatic metastatic sites; ocular, 7 extrahepatic metastatic sites; P = .015; Table 3Go).


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  		TABLE 3. Pattern of recurrence after hepatic resection for melanoma metastasis
 
Several clinicopathologic factors were associated with any recurrence after hepatic resection. Among all patients, those with a history of receiving chemotherapy (P = .13), unilateral liver metastasis (P = .13), and size of hepatic metastasis <5 cm (P = .15) tended to have a decreased chance of recurrence. Other factors, such as the extent of the surgical procedure (P = .4), the number of liver metastases (P = .3), or the pathologic status of the resection margin (P = .4), were not associated with the recurrence risk. Factors affecting recurrence were different according to the primary site of the melanoma. Although no clinicopathologic factors were associated with the recurrence risk in patients with an ocular melanoma (all factors P > .5), several factors were associated with recurrence in patients with a primary cutaneous melanoma. Specifically, patients with unilateral liver metastasis (P = .13) or hepatic metastasis measuring <5 cm (P = .16) tended to have a lower incidence of recurrence after liver resection. Patients with cutaneous melanoma who presented with synchronous metastases (liver plus other site) also had a shorter disease-free survival (2.8 months) compared with patients who presented with either metachronous disease (8.0 months) or solitary liver metastasis (4.3 months; Table 4Go). The clinicopathologic characteristics of the primary cutaneous melanoma (pathologic lymph node status, tumor thickness, presence of ulceration, and Breslow depth) did not affect the risk of recurrence after hepatic resection (all factors P > .5).


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  		TABLE 4. Disease-free and overall survival of patients with cutaneous melanoma (n = 23) based on clinical presentation
 
Survival
Among all patients, the median survival was 28.2 months (range, 4.6–93.7 months), and the 5-year survival rate was 10.9%. Patients with a primary ocular melanoma tended to have a longer median survival (29.4 months) than patients with a primary cutaneous melanoma (23.6 months), although this did not reach statistical significance (P = .2; Fig. 2Go). Patients with a primary ocular melanoma did, however, have a significantly better long-term prognosis than those with primary cutaneous melanoma. The 2-year survival rate was 61.5% for patients with a primary ocular melanoma, compared with 47.7% for patients with a primary cutaneous melanoma (P = .04). Similarly, the 5-year survival rate for patients with a primary ocular melanoma was 20.5%, whereas there were no 5-year survivors for patients with cutaneous melanoma (P = .03). The longest survival duration for a patient with ocular melanoma metastatic to the liver was 93.7 months from the time of liver resection; in comparison, the longest that a patient survived after hepatic resection for cutaneous melanoma metastasis was 45.4 months.


Figure 2
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  		FIG. 2. Patients with a primary ocular melanoma had a slightly longer median survival (29.4 months) compared with patients with a primary cutaneous melanoma (23.6 months); however, patients with a primary ocular melanoma had a significantly better long-term prognosis. Whereas the 5-year survival rate for patients with a primary ocular melanoma was 20.5%, there were no 5-year survivors for patients with a cutaneous primary tumor (P = .03).

 
In general, clinicopathologic factors were not predictive of survival after hepatic resection for melanoma metastasis. Tumor location, size, and number, as well as the pathologic status of the surgical resection margin and the disease-free interval between the time of the primary tumor and liver metastasis, did not predict survival (all factors P > .5). Although a history of having received systemic therapy was also not associated with survival in patients with a primary ocular melanoma (P = .6), prior systemic therapy did predict survival outcome in patients with a cutaneous melanoma. Patients with a primary cutaneous melanoma who received some form of systemic therapy had a longer median survival (28.6 months; 95% confidence interval [CI], 14.3–42.9 months) compared with patients who underwent surgery alone (4.9 months; 95% CI, 1.0–9.8 months; P = .001; Fig. 3Go). In addition, patients who received preoperative systemic therapy tended to have a longer median survival (41.0 months; 95% CI, 22.1–60.0 months) than patients who had systemic therapy in the postoperative setting (23.6 months; 95% CI, 15.0–32.2 months; P = .06).


Figure 3
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  		FIG. 3. A history of exposure to systemic therapy predicted survival in patients with cutaneous melanoma. Patients who received some form of systemic therapy had a longer median survival (28.6 months; 95% confidence interval [CI], 14.3–42.9 months) than patients who underwent surgery alone (4.9 months; 95% CI, 1.0–9.8 months; P = .001).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although the role of metastasectomy in patients with stage IV melanoma is controversial, complete resection of gastrointestinal,25–27 adrenal,28,29 or pulmonary melanoma metastases30–32 has been reported to result in overall survival periods ranging from 24 to 49 months. The role of metastasectomy for melanoma metastatic to the liver, however, remains poorly defined. There have been only a few reports of long-term survival after hepatic resection of melanoma metastasis.18,22,23,33,34 Most of these studies, however, have included patients with either ocular8,12,22 or cutaneous17,19,35 melanoma exclusively or have failed to stratify the patients on the basis of the primary site of the melanoma.36 To our knowledge, this study constitutes the largest report to date that specifically compares patients with ocular versus cutaneous melanoma who underwent hepatic metastasectomy with a curative intent.

Traditionally, ocular and cutaneous melanoma have been thought to differ with regard to natural history, prognosis, and treatment.8,37 The Eastern Cooperative Oncology Group (ECOG) compared the characteristics of a large cohort of patients (n = 713) with either metastatic ocular or cutaneous melanoma.37 As in this study, patients with ocular melanoma tended to be older and had a distinct pattern of metastasis as compared with patients who had cutaneous melanoma.37 Specifically, the ECOG study noted that patients with ocular melanoma were significantly more likely to have isolated liver metastasis. We also confirmed these findings. Of the patients with ocular melanoma, all 16 presented with isolated liver metastasis, and the overwhelming majority of recurrences after hepatic resection were within the liver. In contrast, patients with cutaneous melanoma were more likely to present with extrahepatic synchronous or metachronous disease and more frequently had extrahepatic sites of recurrence (Table 3Go). These data corroborate that metastatic ocular melanoma has a certain tropism for the liver, whereas cutaneous melanoma has a more systemic recurrence pattern. Data from both the ECOG trial and the current study provide compelling evidence that metastatic ocular and cutaneous melanoma behave in distinct biological manners.

Despite an attempt at curative resection, the overwhelming majority (75%) of patients with metastatic melanoma had disease recurrence. Time to recurrence tended to be longer in patients with ocular melanoma than in patients with cutaneous melanoma. Although no unique prognostic factors were associated with disease-free survival in patients with ocular melanoma, patients with cutaneous melanoma tended to fare better if they presented with less hepatic tumor burden (i.e., unilateral liver metastasis or hepatic metastasis measuring <5 cm). In addition, patients with cutaneous melanoma who presented with synchronous metastases (liver plus another site) did particularly poorly, with a median disease-free survival of only 2.8 months. On the basis of these facts, it is our current recommendation that patients with synchronous metastatic disease not undergo hepatic resection, but instead receive systemic therapy. In patients who receive neoadjuvant systemic therapy, only those with a satisfactory response to systemic therapy are believed to be good candidates for surgical resection of residual areas of disease.

Because of the poor results with surgery alone, chemotherapy has been used in an attempt to extend survival.38 Other investigators have noted a differential response to chemotherapy in patients with ocular versus cutaneous melanoma. For example, the ECOG37 noted that the response to chemotherapy was significantly different between patients with ocular versus cutaneous melanoma. In the ECOG study, none of the 51 patients with metastatic ocular melanoma responded to therapy, compared with 74 responders in the cutaneous melanoma group (P = .03).37 Among the subgroup of 218 patients with liver metastases, no patient with an ocular primary tumor responded to therapy, whereas the response rate was 9% for cutaneous primary tumors. Nathan et al.38 reported on the results of patients with ocular or cutaneous melanoma who were treated with cisplatin, dacarbazine, carmustine, and tamoxifen. Of the 16 patients with ocular melanoma who had hepatic metastasis, only 1 (6%) achieved a partial response. In contrast, of the 57 patients with cutaneous melanoma who had liver metastases, 19 (33.3%) achieved an objective response (P = .05). Our data seem to corroborate the previous findings that chemotherapy may have a more substantial role in the treatment of patients with metastatic cutaneous melanoma as compared with ocular melanoma. In this study, chemotherapy was a significant predictor of prolonged survival in patients with cutaneous melanoma, but not in patients with ocular melanoma. Specifically, patients with cutaneous melanoma who were treated with chemotherapy had a >5-fold increase in their median survival as compared with patients who did not receive chemotherapy (Fig. 3Go). Data from this study, however, are difficult to interpret. Given the retrospective nature of the study, it is not possible for us to comment definitively on the ultimate role of chemotherapy. Clearly a selection bias exists when the outcome of patients treated with systemic therapy is compared with that of patients who undergo resection alone, and this selection bias alone could potentially explain the differences encountered in the outcome of these two groups. Future prospective trials will be needed to delineate further the effect and role of chemotherapy in patients with melanoma metastatic to the liver.

In analyzing the entire cohort of patients, patients with metastatic ocular melanoma tended to have a longer overall survival after hepatic metastasectomy. Specifically, the median survival for patients with metastatic ocular melanoma was 29.4 months. Aoyama et al.22 reported a similar overall survival of 27 months in 12 patients who underwent surgical resection of metastatic ocular melanoma. Similar to disease-free survival, no clinicopathologic factor was predictive of survival in patients with ocular melanoma. Although patients with metastatic cutaneous melanoma had a slightly shorter median overall survival (23.6 months), their 2- and 5-year survival rates were significantly shorter. In fact, no patient with metastatic cutaneous melanoma was alive 4 years after hepatic resection. In other studies20,39,40 that have investigated hepatic resection for cutaneous melanoma, the median survival after surgery has been between 10 and 20 months, and long-term survival has been the exception.

A limitation of this study is the lack of a control group. Inclusion of a group of patients with melanoma metastatic to the liver who had not undergone surgical resection would have been informative for comparison purposes. However, the identification of an appropriate comparison group was not feasible. Nonsurgical patients with diffuse metastatic disease are not a proper comparison group, because this group is likely to have more comorbidities and a higher burden of disease. In addition, finding a nonsurgical group that was more comparable to the patients in this study (e.g., a median disease-free period of 60 months and liver-only melanoma metastasis) was not feasible given that this clinical pattern of recurrence is very uncommon. Despite this limitation, this study did suggest that patients with hepatic melanoma metastasis who are highly selected have a longer median survival (28.2 months) than the historical median survival of patients with hepatic melanoma metastasis (2–7 months).6,8–11 Selection of appropriate patients for hepatic resection of metastatic melanoma must be individualized and include an extensive evaluation of the extent of the disease. Metastatic ocular and cutaneous melanomas have important clinical differences that should be considered at the time of treatment. Although most patients experience disease recurrence, resection of melanoma metastatic to the liver may improve disease-free and overall survival in selected patients. We currently recommend that patients with limited metastatic disease who can be rendered surgically free of disease be considered for potential hepatic resection. Resection, however, should be performed as part of a multidisciplinary approach in conjunction with systemic therapy, because this may result in prolonged survival for patients, especially those with cutaneous primary tumors. In the future, multi-institutional prospective studies analyzing prognostic factors in patients with hepatic melanoma metastases will be needed to further define the appropriate role of resection and chemotherapy.

Received for publication January 25, 2005. Accepted for publication October 24, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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