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Correlation Between Prognostic Factors and Increasing Age in Melanoma

From the Department of Surgery, Division of Surgical Oncology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky (CC, RCGM, KMM); University of Texas M. D. Anderson Cancer Center, Houston, Texas (MIR); Lakeland Regional Cancer Center, Tampa, Florida (DSR); University of Arkansas, Little Rock, Arkansas (MJE); LDS Hospital, Salt Lake City, Utah (RDN); University of Texas Medical Branch, Galveston, Texas (CC); Advertek Incorporated, Louisville, Kentucky (LJH, AJS); and Department of Statistics, University of Kentucky, Lexington, Kentucky (AJS).

Correspondence: Address correspondence and reprint requests to: Kelly M. McMasters, MD, PhD, University of Louisville, Division of Surgical Oncology, 315 East Broadway, Louisville, KY 40202; Fax: 502-629-3183; E-mail: kelly.mcmasters{at}nortonhealthcare.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1: SUNBELT MELANOMA... REFERENCES

 
Background: Age of patients with melanoma varies directly with mortality and inversely with the presence of sentinel lymph node (SLN) metastasis. To gain further insight into this apparent paradox, we analyzed the relationship between age and other major prognostic factors.

Methods: The Sunbelt Melanoma Trial is a prospective, randomized study with 79 institutions involving SLN biopsy for melanoma. Eligible patients were 18 to 70 years old with melanoma of 1.0-mm Breslow thickness and clinically N0 regional lymph nodes. SLNs were evaluated by serial histological sections and immunohistochemistry for S-100 protein.

Results: A total of 3076 patients were enrolled in the study, with a median follow-up of 19 months. Five age groups were examined: 18 to 30, 31 to 40, 41 to 50, 51 to 60, and 61 to 70 years. Trends between age and several key prognostic factors was identified: as age group increased, so did Breslow thickness (analysis of variance; P < .001), the incidence of ulceration and regression, and the proportion of male patients (each variable: ², P < .001). The incidence of SLN metastasis, however, declined with increasing age (²; P < .001).

Conclusions: As age increases, so does Breslow thickness, the incidence of ulceration and regression, and the proportion of male patients—all poor prognostic factors. However, the frequency of SLN metastasis declines with increasing age. It is not known whether this represents a decreased sensitivity (higher false-negative rate) of the SLN procedure in older patients or a different biological behavior (hematogenous spread) of melanomas in older patients.

Key Words: Melanoma • Sentinel lymph node • Age • Prognostic factors

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1: SUNBELT MELANOMA... REFERENCES

 
It is well established that the mortality rate from melanoma increases directly with age.¹ Although this might be attributed to an increased propensity of older patients to present with thicker, ulcerated melanomas, age has been noted to be an independent adverse prognostic indicator of overall survival among patients with melanoma.^1,2 Overall, the strongest predictor of mortality for patients with melanoma is the status of the regional lymph nodes.¹ It is interesting to note, however, that the incidence of sentinel lymph node (SLN) metastasis varies inversely with age.^3,4 To gain further insight into this apparent paradox, in which the presence of nodal metastasis decreases while mortality increases in older patients, we analyzed the relationship between age and other major prognostic factors.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1: SUNBELT MELANOMA... REFERENCES

 
The Sunbelt Melanoma Trial is an institutional research review board–approved prospective, randomized clinical trial studying SLN biopsy for cutaneous melanoma. A total of 3076 patients from 79 medical centers were enrolled between June 1997 and August 2002. Eligible patients were aged 18 to 70 years with melanoma of 1.0-mm Breslow thickness and clinically uninvolved (N0) regional lymph nodes. Because the Sunbelt Melanoma Trial⁵ randomizes patients to adjuvant interferon alfa-2b therapy, patients older than 70 years were excluded.

All patients underwent wide local excision of the primary melanoma and SLN biopsy with intradermal injection of both ^99mTc-labeled sulfur colloid and 1% isosulfan blue dye around the tumor site. A preoperative lymphoscintigram and intraoperative lymphatic mapping with a gamma probe were used to identify the radioactive SLNs. All blue-stained lymph nodes and all nodes 10% of the highest radioactive node were harvested as SLNs.⁶

Pathologic analyses included hematoxylin and eosin (H&E) staining at multiple levels, with at least five sections per block and two additional sections for immunohistochemistry (IHC) for S-100 protein. In a minority of centers, IHC for HMB-45, MART-1 (melanoma antigen recognized by T cells), or other melanoma markers was also performed. The first 10 cases and all cases of SLN metastasis from every center were reviewed by a central pathology review committee. A positive SLN was defined as metastasis detected by either H&E or IHC.

Statistical comparisons were performed with Pearson’s ² trend test, Fisher’s exact test, or analysis of variance. Multivariate logistic regression for factors predictive of SLN metastasis was performed. Comparison of disease-free survival was performed by the methods of Kaplan and Meier; the log-rank test was used to assess significance. Significance was determined at P < .05. All analyses were performed with SAS software (SAS Institute, Cary, NC). Data from all 3076 patients were included when available (i.e., unknown data were excluded from the analysis).

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1: SUNBELT MELANOMA... REFERENCES

 
The frequency and percentage distribution of the patient population’s clinicopathologic characteristics are listed in Table 1 by five age groups: 18 to 30, 31 to 40, 41 to 50, 51 to 60, and 61 to 70 years. The median follow-up was 19 months. With increasing decades, the proportion of male patients increased (P < .001) from 42% (18–30 years) to 60% (60–70 years). Both Breslow thickness and Clark level significantly increased with increasing age category. For the youngest age group (18–30 years), the mean tumor thickness was 1.96 ± .097 mm (mean ± SEM); however, for the oldest age group (>60 years), the mean thickness was 2.49 ± .83 mm (P < .001; analysis of variance). The presence of ulceration (19%–29%) and evidence of regression (5%–12%) increased with increasing age groups (P < .001; ² trend test). Prognostic variables that were not statistically significant by age group included lymphovascular invasion and a vertical growth phase. Acral lentiginous melanoma was most common in patients older than 60 years (4%) compared with the 18 to 30 age group (.003%; P < .001; ²). The superficial spreading subtype was more prevalent among the younger patients (48% among the 18- to 30-year-old group vs. 35% for the 61- to 70-year-old age group; P < .001; ²). The desmoplastic subtype also increased as age increased (P < .043; ²). Desmoplastic melanoma represented 2% of all the histological subtypes; it is relatively rare among the 18- to 30-year-old age group (.3%) and is more prevalent in the >60-year-old age group (2.9%).

View larger version (17K): [in this window] [in a new window]   FIG. 1. Histopathologic characteristics of melanoma by age. There is a proportional increase with tumor ulceration, tumor regression, the acral lentiginous melanoma subtype, and the desmoplastic melanoma subtype with increasing age. The inverse relationship is shown between age and sentinel lymph node (SLN) metastasis, as well as the superficial spreading melanoma subtype.

Logistic regression was performed to identify factors predictive of SLN metastasis. First, age was entered into the model as a continuous variable, along with sex, Breslow thickness, ulceration, regression, histological subtypes, and number of nodal basins. The odds ratio for age as a continuous variable was .98, with confidence intervals of .97 to .99 (P < .001). Thus, age as a continuous variable proved to be an independent predictor of SLN metastasis. Further analysis by decade of age group was performed in the regression model to elucidate trends by age category (Table 3). The 18- to 30-year age group was significantly predictive of SLN positivity when compared with the 41 to 50, 51 to 60, and over 60 age groups (P = .041, <.001, and <.001, respectively). In this multivariate analysis, male sex, the presence of tumor regression, and the number of nodal basins from which SLNs were harvested were all not significant factors for predicting SLN metastasis. Not unexpectedly, increasing Breslow thickness (2.0–4.0 mm and >4.0 mm vs. <2.0 mm), the presence (vs. absence) of ulceration, and the acral lentiginous melanoma subtype, compared with other histological subtypes, were all predictive of SLN tumor involvement.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1: SUNBELT MELANOMA... REFERENCES

For example, younger women are known to have a more indolent course of disease compared with older patients or younger men of the same age group.^9–11 It has been hypothesized that, because the SLN status is the single most important factor predicting survival,¹² perhaps young women have a lower incidence of SLN metastasis compared with men of the same age.¹³ Indeed, this seems to be true for women 40 years of age (Table 2). Our finding that age is an independent factor predicting the presence of nodal metastasis in women 40 years of age is consistent with the observation of Stidham et al.¹⁰ that the female survival advantage exists independently of tumor thickness. The possibility of hormonal or other sex-specific factors that play a role in modulating the growth and metastatic potential of melanoma cannot be excluded, and further studies are required to explain our findings.

There exists an apparent paradox in that older patients have a lower SLN metastasis rate yet have a decreased overall survival compared with younger patients.^3,4 In a cohort of 263 patients, Statius Muller³ showed that the SLN positivity rate decreased with increasing age from 39% of 18- to 30-year-old patients with positive SLNs to 17% for 71- to 84-year-old patients. The 3-year disease-free survival decreased from 90% for the young age group to 79% for the oldest age group. It is not known whether this observation represents a decreased sensitivity of the SLN procedure (higher rate of false-negative results) in older patients or a different biological behavior of melanomas in older patients.

With longer follow-up, if we find that the proportion of false-negative SLN results (recurrences in regional nodal basins previously determined to be SLN negative) is higher in older patients, this might suggest that the SLN biopsy technique is less accurate in older patients. Given the low false-negative rate seen to date in our current study, this possibility seems less likely. Rather, these data suggest a hypothesis that with increasing age, melanoma may metastasize more frequently via hematogenous spread without concomitant regional nodal involvement. This hypothesis will be evaluated with longer follow-up for patterns of recurrence and overall survival.

An alternative hypothesis that may also explain our findings is that SLN biopsy detects a greater proportion of micrometastasis that may not be clinically significant in younger patients. For example, younger patients may have a generally more competent immune system that may eliminate small micrometastatic deposits before they manifest clinically. To address this issue, we compared the fraction of patients with positive SLNs detected by IHC-only methods and found no significant differences among the age groups (Table 2). Although we do not have complete data on the size of the foci of metastatic disease with the SLNs in this study, tumor burden may be an important factor. For instance, perhaps older patients have a lower incidence of SLN metastases but a greater tumor burden per positive SLNs. Emerging evidence on the importance of the pattern and size of SLN micrometastasis by using micromorphometry analysis^14,15 may prove to be important to the study of age-related effects on nodal metastasis.

Although it has not been established that SLN biopsy improves survival,¹⁶ the staging information¹⁷ gained is invaluable. This will allow us to prospectively evaluate the age-related differences in patterns of recurrence to better define the biological behavior of melanoma with respect to age. As an example, younger patients with positive SLNs may have a propensity to present with late locoregional recurrences, whereas older patients may develop distant metastases. In an intriguing study by Gamel et al.,¹⁸ which used data from the Duke Comprehensive Cancer Center and had a maximum follow-up of 22 years and more than 5300 patients, a parametric statistical analysis was presented that compared high risk and low risk of death from melanoma. For example, a woman with a thin .5-mm nonulcerated melanoma would have a lifetime cure rate of 80% and a median tumor-specific survival of 10 years. This means that half of the deaths from melanoma will occur >10 years after treat-ment. In contrast, a man with an ulcerated 8.0-mm-thick melanoma would have a 16% probability of cure and a median tumor-specific survival of 2.7 years. However, if this patient should survive for 15 years, his conditional probability of cure would increase to 90%. How these prognostic factors interact with patient age in predicting the likelihood of cure remains to be established.

Trends of specific histological variants of melanoma are age related. In other reports, acral lentiginous melanoma and lentigo maligna melanoma both tend to occur in patients around the age of 60 years.^8,19 Our study confirms the increase in acral lentiginous melanoma among older patients; this trend was not seen for the lentigo maligna subtype. The desmoplastic variant is known to be associated with a higher risk of local recurrence and subsequent distant disease.²⁰ This is consistent with our data, which correlates the increasing proportion of the desmoplastic variant with increasing age. With regard to tumor regression, Loggie et al.⁸ found no differences by age. However, our data show that on univariate analysis, tumor regression directly correlates with increasing age (Fig. 1). Although the clinical and prognostic significance of tumor regression in melanoma is controversial,²¹ the presence of extensive regression among thin melanomas may indicate a higher risk for developing either locoregional or distant metastases.²²

Several caveats to this study are noteworthy. Patients with thin melanomas (<1.0 mm) were excluded from this study. Therefore, we cannot comment on the effect of age on the incidence of thin melanomas or the presence of SLN metastasis in such patients.²³ Furthermore, patients older than 70 years were excluded from this study. Accordingly, we cannot determine the relationship of age and prognostic variables in older patients. Finally, a much longer follow-up time will be needed to conclude the prognostic significance of age, positive SLNs, and other predictive factors on overall survival.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1: SUNBELT MELANOMA... REFERENCES

 
These data establish a near-linear relationship between age and several major prognostic factors in melanoma patients. As age increases, so does Breslow thickness, the incidence of ulceration and regression, and the proportion of male patients—all poor prognostic factors. Incongruously, however, the frequency of SLN metastasis declines with increasing age. Further study and longer follow-up will better establish the relationship between age and other prognostic factors in melanoma.

	APPENDIX 1: SUNBELT MELANOMA TRIAL INVESTIGATORS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1: SUNBELT MELANOMA... REFERENCES

 
Stephan Ariyan, MD, Yale University, New Haven, CT; Frederick Aronson, MD, Maine Center for Cancer Care, Scarborough, ME; Michael B. Atkins, MD, Beth Israel Deaconess Medical Center, Boston, MA; Bruce Averbook, MD, Metro Health Medical Center, Cleveland, OH; Paul Baron, MD, Roper Hospital, Charleston, SC; Mansoor H. Beg, MD, North Shore University Hospital, Great Neck, NY; Peter D. Beitsch, MD, Dallas Surgical Group (St. Paul Medical Center), Dallas, TX; John L. Bell, MD, UT Medical Center, Knoxville, TN; Marc Boisvert, MD, Washington Cancer Institute, Washington, DC; Richard A. Bold, MD, UC Davis Cancer Center, Sacramento, CA; Ralph Broadwater, MD, Arkansas Cancer Research Center, Little Rock, AR; Ned Z. Carp, MD, Lankenau Hospital, Wynnewood, PA; A. Lawrence Cervino, MD, Summa Health Systems/Akron, Akron, OH; David Z. J. Chu, MD, City of Hope National Center, Duarte, CA; Rosa Cuenca, MD, East Carolina University, Greenville, NC; Paul S. Dale, MD, Southeastern Surgical Oncologists, Macon, GA; George W, Daneker, MD, Northside Hospital-Atlanta Regional Community Clinical Oncology Program, Atlanta, GA; Scott Davidson, MD, Cancer Center at Providence Hospital, Mobile, AL; Bradley Scott Davidson, MD, Mobile Infirmary Medical Center, Mobile, AL; Marie France Demierre, MD, Boston Medical, Boston, MA; Mukund S. Didolkar, MD, Sinai Hospital of Baltimore, Baltimore, MD; Raza Dilawari, MD, Methodist Hospitals of Memphis (Boston Baskin), Memphis, TN; Larry Dillon, MD, Memorial Hospital Colorado Springs, Colorado Springs, CO; Paul S. Dudrik, MD, UT Medical Center, Knoxville, TN; David Dunning, MD, Northern Virginia Oncology Group, PC, Fairfax, VA; J. Benton Dupont, MD, Baton Rouge General Medical Center, Baton Rouge, LA; Burton L. Eisenberg, MD, Fox Chase Cancer Center, Philadelphia, PA; Robert K. Finley III, MD, Dayton Clinical Oncology Program, Dayton, OH; Thomas G. Frazier, MD, Bryn Mawr Hospital, Bryn Mawr, PA; Michele Gadd, MD, Massachusetts General Hospital, Boston, MA; Charles E. Geyer, Jr., MD, Joe Arrington Cancer Center, Lubbock, TX; W. Larry Gluck, MD, Cancer Centers of the Carolinas, Greenville, SC; James S. Goydos, MD, Cancer Institute of New Jersey, New Brunswick, NJ; Keith Heaton, MD, Park Nicollet Clinic/HealthSystem Minnesota, St. Louis Park, MN; Richard A. Hoefer, Jr., DO, FACS, Oyster Point Surgical Associates, PC, Newport News, VA; Ryan F. Holbrook, MD, Sacred Heart Medical Center/Deaconess Medical Center, Spokane, WA; Lisa Jacobs, MD, University of Missouri Ellis Fischel Cancer Center, Columbia, MO; William Jewell, MD, Kansas University Research Institute, Kansas City, KS; Peter Jochimsen, MD, University of Iowa, Iowa City, IA; Denise L. Johnson, MD, Stanford University Medical Center, Stanford, CA; Richard Keidan, MD, William Beaumont Hospital, Royal Oak, MI; Mark C. Kelley, MD, Vanderbilt University Medical Center, Nashville, TN; V. Suzanne Klimberg, MD, Arkansas Cancer Research Center, Little Rock, AR; Mark Kozloff, MD, Ingalls Hospital, Harvey, IL; William G. Kraybill, MD, Roswell Park Cancer Institute, Buffalo, NY; Joseph A. Kuhn, MD, Baylor University Medical Center, Dallas, TX; Jeffrey E. Lee, MD, M. D. Anderson Cancer Center, Houston, TX; D. Scott Lind, MD, University of Florida College of Medicine, Gainesville, FL; Paul F. Mansfield, MD, M. D. Anderson Cancer Center, Houston, TX; Kelly Marc McMasters, MD, University of Louisville, Louisville, KY; Greg P. Midis, MD, UT Medical Center, Knoxville, TN; Richard C. Montgomery, MD, Lexington Clinic/St. Joseph Hospital, Lexington, KY; Michael Nolen, MD, University of Oklahoma College of Medicine, Tulsa, OK; James H. North, MD, Eisenhower Army Medical Center, Fort Gordon, GA; R. Dirk Noyes, MD, LDS Hospital, Salt Lake City, UT; Thomas Olencki, DO, The Cleveland Clinic Foundation, Cleveland, OH; Steven Pandelidis, MD, York Hospital, York, PA; David B. Pearlstone, MD, Cancer Centers of the Carolinas, Greenville, SC; Roger R. Perry, MD, Sentara Cancer Institute/East Virginia Medical School, Norfolk, VA; E. Phillip Polack, MD, Wheeling Hospital West Virginia, Wheeling, WV; Maurice Rawlings, Jr., MD, Memorial Hospital, Chattanooga, TN; Douglas Reintgen, MD, Moffitt Cancer Center, Tampa, FL; Calvin Ridgeway, MD, Albuquerque Surgical Group, PA, Albuquerque, NM; Lee B. Riley, MD, PhD, St. Luke’s Hospital, Bethlehem, PA; David C. Ritter, MD, Lee Memorial Cancer Center, Naples, FL; Catherine Ronaghan, MD, Joe Arrington Cancer Center, Lubbock, TX; Merrick I. Ross, MD, M. D. Anderson Cancer Center, Houston, TX; Elizabeth Saettler, MD, CancerCare/Manitoba, Winnepeg, Manitoba, Canada; Armando Sardi, MD, St. Agnes Healthcare, Baltimore, MD; Donna Schade, MD, M. D. Anderson Cancer Center Orlando, Orlando, FL; Elin R. Sigurdson, MD, Fox Chase Cancer Center, Philadelphia, PA; David A. Sloan, MD, University of Kentucky, Lexington, KY; Jeffrey Sussman, MD, University of Cincinnati, Cincinnati, OH; Kenneth K. Tanabe, MD, Massachusetts General Hospital, Boston, MA; Peter Tate, MD, Central Baptist Hospital, Lexington, KY; Clifford Thompson, MD, Mima Century Research Associates, Melbourne, FL; Roderick Tompkins, MD, Kings Daughters-Ashland, Ashland, KY; Courtney M. Townsend, Jr., MD, University of Texas Medical Branch-Galveston, Galveston, TX; Douglas Tyler, MD, Duke University Medical Center, Durham, NC; Marshall M. Urist, MD, University of Alabama-Birmingham, Birmingham, AL; Charles N. Verheyden, MD, PhD, Scott and White Memorial Hospital-Texas, Temple, TX; and Richard L. White, Jr., MD, Carolinas Medical Center, Charlotte, NC.

	ACKNOWLEDGMENTS

 
The appendices and acknowledgments are available online in the full-text version at www.annalssurgicaloncology.org. They are not available in the PDF version.

Supported by a grant from Schering Oncology-Biotech and the Center for Advanced Surgical Technologies of Norton Hospital, Louisville, KY. The authors thank Deborah Hulsewede, Debra Williams, Sherri Matthews, and Diana Simpson for their continued dedication to the data management and coordination of this study and Susan Kemper for her expert manuscript preparation. The authors also thank all members of the Sunbelt Melanoma Trial Study Group (Appendix 1) for their continued participation.

	FOOTNOTES

 
Presented at the Society of Surgical Oncology, Los Angeles, California, March 5–9, 2003.

As age increases, the Breslow thickness, the prevalence of ulceration and regression, and the proportion of male patients—all poor prognostic factors—also increase. However, the frequency of sentinel lymph node metastasis declines with increasing age. Trends in prognostic factors and age are explored.

Received for publication April 11, 2003. Accepted for publication October 21, 2003.

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TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS APPENDIX 1: SUNBELT MELANOMA... REFERENCES

 

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				K. M. McMasters Editorial: What Good is Sentinel Lymph Node Biopsy for Melanoma if it does not Improve Survival? Ann. Surg. Oncol., September 1, 2004; 11(9): 810 - 812. [Full Text] [PDF]

				G. W. Carlson Editorial: Age and the Incidence of Sentinel Lymph Node Metastases in Melanoma Ann. Surg. Oncol., March 1, 2004; 11(3): 236 - 237. [Full Text] [PDF]

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