|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 26, No 4 (February 1), 2008: pp. 535-541 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.0285 Improved Survival After Lymphadenectomy for Nodal Metastasis From an Unknown Primary Melanoma
From the Roy E. Coats Research Laboratories and the Sonya Valley Ghidossi Vaccine Laboratory of the John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA Corresponding author: Donald L. Morton, MD, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404; e-mail: mortond{at}jwci.org
Purpose No primary lesion is identified in 10% to 20% of patients presenting with palpable evidence of regional metastatic melanoma. Because the prognostic significance of unknown primary melanoma (MUP) is unclear, we compared clinical outcomes of patients with MUP and known primary melanoma (MKP) with regional nodal metastases. Patients and Methods We reviewed our 13,000-patient prospective melanoma database (1971 through 2005) to identify patients managed with regional lymphadenectomy for palpable nodal metastases from MUP or MKP. Multivariate analysis identified prognostic factors significant for survival. MUP and MKP were then matched by significant covariates. Overall survival (OS) was estimated by Kaplan-Meier method and compared by log-rank analysis.
Results Multivariate analysis of data from 1,571 study patients identified four significant covariates associated with worse prognosis: age Conclusion Lymphadenectomy is effective for nodal metastasis from MUP. The significantly better postoperative survival for MUP versus MKP suggests a strong endogenous immune response against the primary melanoma. Immunologic studies to identify cell-mediated and antibody components of this response may lead to new approaches for determining melanoma prognosis and treatment.
Melanoma of unknown primary (MUP) is an interesting phenomenon that has not been clearly explained. One commonly accepted theory is that an unrecognized primary lesion has undergone spontaneous regression mediated by an endogenous immune response.1 Other explanations have included malignant transformation of an ectopic nodal melanocyte and an unrecognized primary melanoma.1,2 The clinical presentation of MUP with nodal metastasis (American Joint Committee on Cancer stage III) is characterized by palpable lymphadenopathy without an apparent primary melanoma and without evidence of further metastatic disease. Its prognostic significance is unclear3-16; some studies have reported poorer outcomes for MUP compared with known primary melanoma (MKP),3-5 whereas others have reported equivalent or better outcomes2,3,6-10 (Table 1). Small sample size and lack of control for important prognostic variables may have contributed to the survival differences in the reported studies.
The need for clarification of this disparity and for better analysis prompted us to review our experience with MUP. We hypothesized that after controlling for prognostic variables, MUP with nodal metastases would confer a more favorable outcome than MKP with nodal metastases. Confirmation of our hypothesis would support an aggressive approach to management of patients with MUP. Furthermore, if an enhanced immune system is responsible for improved survival in MUP, then the determination of immunologic activity of immune components may have important implications for development of immunotherapeutic approaches to treatment. Herein, we report the largest series of patients with nodal metastases from an unknown primary site of melanoma.
Clinical records for 13,000 melanoma patients registered into a prospective melanoma database from April 1, 1971, to December 31, 2005 (34-year period), were computer-searched to identify patients presenting with palpable metastases in a single lymphatic basin. Our study group comprised the subgroup of 1,571 patients who underwent therapeutic regional lymphadenectomy within 3 months of presentation and who had histopathologically confirmed nodal melanoma without evidence of concurrent skin/soft tissue or distant metastatic disease. The staging work-up to rule out potential metastatic disease included brain and body imaging studies available at the time of diagnosis. In addition, patients with no apparent primary melanoma underwent cutaneous, ophthalmologic, and anogenital examination.
Each patient's age (< 60 or Approval for this retrospective study was obtained from the John Wayne Cancer Institute-Saint John's Health Center joint institutional review board.
Statistics
Of the 1,571 study patients, 262 had MUP and 1,309 had MKP (Table 2). Distribution of age was similar for MUP (range, 16 to 86 years; median, 46 years) and MKP (range, 11 to 89 years; median, 49 years). Both groups had a greater proportion of younger patients and male patients. Almost half (47.7%) of the 1,571 patients had an axillary site of nodal metastasis, and more than half (65.9%) had at least two tumor-involved nodes. General distribution of age, sex, number of tumor-involved nodes, and decade of diagnosis was similar between MUP and MKP groups.
At a median and mean follow-up of 36 and 77 months, respectively (range, 1 to 420 months), for all 1,571 patients, median survival and 5-year rate of OS were 127 months and 55% ± 6%, respectively, for 262 patients with MUP, as compared with 42 months and 44% ± 3%, respectively, for 1,309 patients with MKP (P = .0021; Fig 1A). Of the 1,571 patients, 1,024 patients (65%) died early, with median and mean follow-up periods of 21 months and 39 months, respectively, whereas 547 patients (35%) were alive, with median and mean follow-up periods of 128 months and 148 months, respectively.
Multivariate analysis of the 1,571 patients identified five significant factors: age, sex, nodal tumor burden, decade of diagnosis, and status of primary (MUP or MKP; Table 3). Site of nodal basin was not significant. The marginal significance in the decade of diagnosis (hazard ratio = 0.989) was a reflection of the poorer survival of patients treated during the 1980s and of censoring during the most current decade (2000 to 2005). Greater risk was associated with age  60 years, male sex, increased number of tumor-involved nodes (> one), and MKP. The risk of death was 40% lower in the MUP group than the MKP group (hazard ratio = 1.507; Table 3).
Age, sex, number of tumor-involved nodes, and decade of diagnosis were used for prognostic matching of MUP and MKP patients. Computer matching identified 221 pairs (Table 2): 5-year and 10-year rates of OS for patients with MUP versus patients with MKP were 58% ± 7% versus 40% ± 7%, respectively, and 52% ± 7% versus 36% ± 7%, respectively (P = .0006; Fig 1B). Median OS was also significantly longer in the MUP group than the MKP group (165 months v 34 months; P = .0006). Although DFS differences between patients with MUP and patients with MKP did not reach statistical significance (P = .0661), recurrence tended to occur later in patients with MUP than in patients with MKP (median and 5-year DFS of 34 months and 47% ± 7%, respectively, for patients with MUP v 19 months and 35% ± 7%, respectively, for patients with MKP).
To determine the durability of the survival comparison between MUP and MKP groups, we repeated the matching process after excluding any patients who had not undergone excision of The original 221 pairs were further stratified by nodal tumor burden to evaluate survival. The higher OS among patients with MUP reached significance only when at least two nodes contained tumor. Respective 5-year OS rates for MUP versus MKP were 67% ± 15% versus 51% ± 16% for one positive node (P = .267), 66% ± 10% versus 46% ± 11% for two to three positive nodes (P = .017), and 46% ± 10% versus 28% ± 9% for more than three positive nodes (P = .015; Figs 2A, 2B, and 2C). As would be expected, OS was inversely correlated with the number of tumor-positive nodes.
The effect of adjuvant therapy on outcome for the matched 221 pairs was evaluated. Adjuvant therapy for purposes of this analysis was defined as any medical therapy received after lymphadenectomy. A total of 181 patients with MKP (82%) and 174 patients with MUP (79%) received adjuvant therapy; the distribution of patients was similar (Table 4). Immunotherapy consisted of vaccine (102 patients with MKP v 108 patients with MUP), bacille Calmette-Guerin (53 patients with MKP v 37 patients with MUP), or granulocyte-macrophage colony-stimulating factor (four patients with MKP v one patient with MUP). Outcome for 181 patients with MKP treated with adjuvant therapy was not significantly different than the outcome for 40 patients with MKP treated with surgery alone (5-year OS of 39% ± 4% v 44% ± 8%, respectively; P = .8584). Similarly, the outcome for 174 patients with MUP who received adjuvant therapy was not significantly different than the outcome for 47 patients with MUP who did not receive adjuvant therapy (5-year OS of 55% ± 4% v 72% ± 8%, respectively; P = .1393).
Over the 34-year period, staff at John Wayne Cancer Institute have treated more than 3,000 patients with melanoma metastatic to regional sites, and this analysis of the survival rates and prognostic factors represents the largest such study for MUP with nodal metastasis. This large review of patients with melanoma having clinical evidence of regional node metastasis found a survival benefit for MUP as compared with MKP. This benefit was seen before and after prognostic matching. This finding suggests that most patients with MUP can expect long-term survival after adequate lymphadenectomy. The median duration of follow-up was found to be shorter than expected in our analysis because a large percentage (65%) of deaths occurred early, with a median follow-up of 21 months. Conversely, the patients who were alive or censored had longer follow-up (median of 127 months). There were minimal differences when follow-up periods were compared between MUP and MKP. Chang and Knapper8 reported 5-year survival rates of 46% for patients with MUP as compared with 39% for historical controls. However, the degree of significance was not reported, and the MKP comparison group consisted of patients with both clinical and occult nodal disease, unlike the current analysis. In their study, regional lymphadenectomy within 3 months after diagnosis of MUP was also found to have a survival advantage as compared with delayed lymphadenectomy. In our study, we selected patients who underwent regional lymphadenectomy within 3 months of diagnosis. The National Cancer Data Base study of patients with MUP reported 5-year survival rates of 55% with lymphadenectomy (n = 160) and 27% without lymphadenectomy (n = 40); however, the sample size of the untreated group precluded a statistical comparison.3 This study also reported a somewhat lower OS rate among all patients with stage III MUP as compared with patients with stage III MKP, but this comparison was not controlled for prognostic factors. Other studies2,7 with fewer patients found a significant survival advantage for MUP. The current results are compatible with our prior report of longer survival for MUP versus MKP (46% v 37%, respectively).6 However, this was a nonsignificant survival advantage for MUP as a result of the small sample size. Our current study represents a larger population with longer follow-up and prognostic controls. When we stratified our prognostically matched pairs by nodal tumor burden, OS was invariably better for patients with MUP than for patients with MKP, although this difference reached statistical significance only with involvement of more than one node. Lack of significance in the single positive nodal comparison is likely due to the sample size. Cormier et al7 evaluated survival characteristics of patients with MUP stratified by lymph node burden but did not find statistical significance except in patients with N3 disease. This may have been a function of the sample size and lack of control for other prognostic variables. Our analysis indicates that MUP metastatic to regional lymph nodes is more common in men than in women and more common in patients younger than 60 years. Our data also suggest that MUP is more likely to involve the axillary rather than the inguinal or cervical basin. This finding is consistent with most studies of MUP.2,6-8,11 Our study group's higher rate of multiple- versus single-node involvement differs from other reports.2,6,7 Although male sex and multiple tumor-involved nodes would suggest poorer outcomes, Katz et al12 suggested that either regression or transformation of ectopic nodal melanocytes may account for the higher proportion of male patients with MUP. Men may have a greater tendency to harbor ectopic melanocytes that undergo malignant transformation. However, this does not account for the superior survival found in MUP. Men may be more likely to ignore a primary melanoma until regression and presentation as metastasis. Alternatively, because the distribution of melanoma differs in men and women, men may develop melanoma in a location where regression is more likely. Extremity or truncal location would be supported by the prevalence of axillary nodal involvement in our patients. Our patients’ relatively high nodal burden as compared with other reports might reflect a longer period during which subclinical disease was controlled by the endogenous antimelanoma immune response. The prevalence of younger patients in our MUP group could indicate a stronger immune system. Proposed causes for MUP2,7,13 include failure to recognize a primary lesion during clinical examination, prior removal of the primary lesion during traumatic injury or by excision without pathologic diagnosis, de novo malignant transformation of ectopic nodal melanocyte(s), and spontaneous regression of the primary lesion. The first two possibilities are improbable among patients whose assessment and treatment follow the standard of care. The third possibility stems from the observation of benign nevus cells in lymph nodes,13,14 which may be a result of so-called benign metastasis or differentiation from arrested neural crest cells.15 Shenoy et al15 have shown that melanoma could arise from precursor nevus cells in an axillary lymph node. However, this does not necessarily explain the survival benefit seen in patients with MUP. We believe that the most likely explanation for MUP is immune-induced regression of the primary tumor. Partial regression has been reported in 9% to 46% of primary melanomas; the incidence is lower for complete regression.16 Experimental data on immunologic studies and spontaneous regression in primary melanomas support an endogenous antimelanoma immune response. Mauer et al18 identified a circulating factor that potentiated lymphocytic cytotoxicity in regressing melanoma; since then, increased lymphocytic infiltrates have been demonstrated in regressed melanomas.19 Cellular immune recognition and response to melanoma-associated antigens have been thought to induce spontaneous regression mediated by cytotoxic lymphocytes.20-22 Furthermore, a favorable prognosis has been associated with the presence of tumor-infiltrating lymphocytes in melanoma.23,24 Humoral mechanisms for melanoma tumor destruction also have been proposed. Antibody attachment to melanoma cell membranes has been demonstrated by direct and indirect immunofluorescence.25 Cytotoxic antibodies against cultured melanoma cells have been found in serum of patients with melanoma.26-28 A study comparing the immunologic aspects of MUP and MKP discovered a higher prevalence of antimelanoma antibodies in patients with MUP but no difference in lymphoproliferative activity.29 Endogenous humoral responses to antigens expressed on melanoma cells have been correlated with improved survival in patients with melanoma.30,31 Most likely a combination of cellular and humoral responses is involved. An endogenous immune response against melanoma might also explain the superior postoperative survival in patients with stage III MUP versus stage III MKP. By removing clinically evident tumor, lymphadenectomy may allow the MUP patient's already stimulated immune system to eradicate any residual occult disease. Nonsurgical management of clinically palpable stage III MUP or MKP is associated with worse survival than surgical management,3 possibly because cytoreduction decreases not only tumor load but also the level of immunosuppressants. Reduced immunosuppression might allow enhanced antitumor immune functions, including humoral and cellular cytotoxic responses that eliminate microscopic tumor load.32 Specific immune responses have been correlated with survival after resection of melanoma without adjuvant immunotherapy.31 Further characterization of these immune responses should allow the identification of biomarkers to monitor a patient's response to adjuvant therapy. It is often mistakenly assumed that MUP with palpable nodal disease represents stage IV metastatic melanoma, for which systemic therapy is often favored as the initial treatment rather than surgery. Our data strongly suggest that the initial treatment of MUP with nodal metastasis should be regional lymphadenectomy. The favorable postoperative prognosis of patients undergoing lymphadenectomy for clinically palpable nodal metastasis from MUP indicates the importance of an accurate staging work-up that includes complete imaging to rule out distant disease. Unless the results of this work-up are positive for metastasis beyond the regional basin, patients should undergo therapeutic (and potentially curative) regional lymphadenectomy as the standard of care.
The author(s) indicated no potential conflicts of interest.
Conception and design: Chris C. Lee, Mark B. Faries, Donald L. Morton Financial support: Donald L. Morton Administrative support: Donald L. Morton Collection and assembly of data: Chris C. Lee, Leslie A. Wanek Data analysis and interpretation: Chris C. Lee, Leslie A. Wanek, Donald L. Morton Manuscript writing: Chris C. Lee, Mark B. Faries, Donald L. Morton Final approval of manuscript: Chris C. Lee, Mark B. Faries, Leslie A. Wanek, Donald L. Morton
Supported by Grants No. CA29605 and CA12582 from the National Cancer Institute and by funding from the Wayne and Gladys Valley Foundation (Oakland, CA), the Harold J. McAlister Charitable Foundation (Los Angeles, CA), the Family of Robert Novick (Los Angeles, CA), the Weil Family Fund (Los Angeles, CA), the Wrather Family Foundation (Los Alamos, CA), the Amyx Foundation Inc (Boise, ID), Berton M. Kirshner (Los Angeles, CA), Todd Kirshner (Los Angeles, CA), Mr and Mrs Louis Johnson, (Stanfield, AZ), Heather and Jim Murren (Las Vegas, NV), Mrs Marianne Reis (Lake Forest, CA), and the Wallis Foundation (Los Angeles, CA). Presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
1. Giuliano AE, Cochran AJ, Morton DL: Melanoma from unknown primary site and amelanotic melanoma. Semin Oncol 9:442-447, 1982[Medline] 2. Anbari KK, Schuchter LM, Bucky LP, et al: Melanoma of unknown primary site: Presentation, treatment, and prognosis—A single institution study. University of Pennsylvania Pigmented Lesion Study Group. Cancer 79:1816-1821, 1997[CrossRef][Medline] 3. Chang AE, Karnell LH, Menck HR: The National Cancer Data Base report on cutaneous and noncutaneous melanoma: A summary of 84,836 cases from the past decade—The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 83:1664-1678, 1998[CrossRef][Medline] 4. Milton GW, Shaw HM, McCarthy WH: Occult primary malignant melanoma: Factors influencing survival. Br J Surg 64:805-808, 1977[Medline] 5. Pack GT, Gerber DM, Scharnagel IM: End results in the treatment of malignant melanoma: A report of 1190 cases. Ann Surg 136:905-911, 1952[Medline] 6. Wong JH, Cagle LA, Morton DL: Surgical treatment of lymph nodes with metastatic melanoma from unknown primary site. Arch Surg 122:1380-1383, 1987 7. Cormier JN, Xing Y, Feng L, et al: Metastatic melanoma to lymph nodes in patients with unknown primary sites. Cancer 106:2012-2020, 2006[CrossRef][Medline] 8. Chang P, Knapper WH: Metastatic melanoma of unknown primary. Cancer 49:1106-1111, 1982[CrossRef][Medline] 9. Reintgen DS, McCarty KS, Woodard B, et al: Metastatic malignant melanoma with an unknown primary. Surg Gynecol Obstet 156:335-340, 1983[Medline] 10. Schlagenhauff B, Stroebel W, Ellwanger U, et al: Metastatic melanoma of unknown primary origin shows prognostic similarities to regional metastatic melanoma: Recommendations for initial staging examinations. Cancer 80:60-65, 1997[CrossRef][Medline] 11. Giuliano AE, Moseley HS, Morton DL: Clinical aspects of unknown primary melanoma. Ann Surg 191:98-104, 1980[Medline] 12. Katz KA, Jonasch E, Hodi FS, et al: Melanoma of unknown primary: Experience at Massachusetts General Hospital and Dana-Farber Cancer Institute. Melanoma Res 15:77-82, 2005[CrossRef][Medline] 13. Das Gupta T, Bowden L, Berg JW: Malignant melanoma of unknown primary origin. Surg Gynecol Obstet 117:341-345, 1963[Medline] 14. Ridolfi RL, Rosen PP, Thaler H: Nevus cell aggregates associated with lymph nodes: Estimated frequency and clinical significance. Cancer 39:164-171, 1977[CrossRef][Medline] 15. Shenoy BV, Fort L 3rd, Benjamin SP: Malignant melanoma primary in lymph node: The case of the missing link. Am J Surg Pathol 11:140-146, 1987[CrossRef][Medline] 16. Blessing K, McLaren KM: Histological regression in primary cutaneous melanoma: Recognition, prevalence and significance. Histopathology 20:315-322, 1992[Medline] 17. Baab GH, McBride CM: Malignant melanoma: The patient with an unknown site of primary origin. Arch Surg 110:896-900, 1975 18. Maurer H, McIntyre OR, Rueckert F: Spontaneous regression of malignant melanoma: Pathologic and immunologic study in a ten year survivor. Am J Surg 127:397-403, 1974[CrossRef][Medline] 19. Tefany FJ, Barnetson RS, Halliday GM, et al: Immunocytochemical analysis of the cellular infiltrate in primary regressing and non-regressing malignant melanoma. J Invest Dermatol 97:197-202, 1991[CrossRef][Medline] 20. Saleh FH, Crotty KA, Hersey P, et al: Primary melanoma tumour regression associated with an immune response to the tumour-associated antigen melan-A/MART-1. Int J Cancer 94:551-557, 2001[CrossRef][Medline] 21. Saleh FH, Crotty KA, Hersey P, et al: Autonomous histopathological regression of primary tumours associated with specific immune responses to cancer antigens. J Pathol 200:383-395, 2003[CrossRef][Medline] 22. Zorn E, Hercend T: A MAGE-6-encoded peptide is recognized by expanded lymphocytes infiltrating a spontaneously regressing human primary melanoma lesion. Eur J Immunol 29:602-607, 1999[CrossRef][Medline] 23. Clemente CG, Mihm MC Jr, Bufalino R, et al: Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77:1303-1310, 1996[CrossRef][Medline] 24. Haanen JB, Baars A, Gomez R, et al: Melanoma-specific tumor-infiltrating lymphocytes but not circulating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients. Cancer Immunol Immunother 55:451-458, 2006[CrossRef][Medline] 25. Morton DL, Malmgren RA, Holmes EC, et al: Demonstration of antibodies against human malignant melanoma by immunofluorescence. Surgery 64:233-240, 1968[Medline] 26. Lewis MG, Ikonopisov RL, Nairn RC, et al: Tumour-specific antibodies in human malignant melanoma and their relationship to the extent of the disease. BMJ 3:547-552, 1969 27. Bodurtha AJ, Chee DO, Laucius JF, et al: Clinical and immunological significance of human melanoma cytotoxic antibody. Cancer Res 35:189-193, 1975 28. Canevari S, Fossati G, Della Porta G, et al: Humoral cytotoxicity in melanoma patients and its correlation with the extent and course of the disease. Int J Cancer 16:722-729, 1975[Medline] 29. Giuliano AE, Moseley HS, Irie RF, et al: Immunologic aspects of unknown primary melanoma. Surgery 87:101-105, 1980[Medline] 30. Litvak DA, Gupta RK, Yee R, et al: Endogenous immune response to early- and intermediate-stage melanoma is correlated with outcomes and is independent of locoregional relapse and standard prognostic factors. J Am Coll Surg 198:27-35, 2004[CrossRef][Medline] 31. Hsueh EC, Gupta RK, Yee R, et al: Does endogenous immune response determine the outcome of surgical therapy for metastatic melanoma? Ann Surg Oncol 7:232-238, 2000[CrossRef][Medline] 32. Morton DL, Ollila DW, Hsueh EC, et al: Cytoreductive surgery and adjuvant immunotherapy: A new management paradigm for metastatic melanoma. CA Cancer J Clin 49:101-116, 65, 1999[Abstract] Submitted August 17, 2007; accepted October 19, 2007.
Related Correspondence
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
