Patients with thick cutaneous melanoma ( 4 mm) pose a challenge. Prognostic Factors in Patients with Thick Cutaneous Melanoma (> 4 mm)

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1 1049 Prognostic Factors in Patients with Thick Cutaneous Melanoma (> 4 mm) Elizabeth Zettersten, M.D. 1 Richard W. Sagebiel, M.D. 1 James R. Miller III, Ph.D. 1,2 Sreedhar Tallapureddy, M.D. 1 Stanley P. L. Leong, M.D. 2 Mohammed Kashani-Sabet, M.D. 1 1 Melanoma Center, Cutaneous Oncology Program, University of California at San Francisco, Comprehensive Cancer Center, San Francisco, California. 2 Department of Surgery, University of California at San Francisco/Mt. Zion Medical Center, San Francisco, California. BACKGROUND. The current study was conducted to examine the role of multiple clinical and histologic factors in the prognostic assessment of patients with thick primary melanoma ( 4 mm, classified as T4). METHODS. A retrospective analysis was performed in 329 patients with T4 cutaneous melanomas who were seen at the University of California at San Francisco Melanoma Center between 1978 and Fourteen histopathologic features were recorded prospectively by a single dermatopathologist. In addition, 9 clinical factors were analyzed. RESULTS. Several histologic factors were found to have a significant impact on the survival of patients with T4 melanoma. On univariate analysis, tumor thickness, ulceration, mitotic rate, microsatellites, vascular involvement, and histogenetic type of the primary tumor all were found to have a significant impact on the overall survival rate. Regional lymph node involvement reduced the overall survival of T4 patients dramatically. The 5-year overall survival of patients with lymph node-negative T4 disease was 61%, compared with 30% for those with lymph node-positive disease. When lymph node status was taken into account, tumor thickness, vascular involvement, and ulceration all remained independent predictors of overall survival on multivariate Cox regression analysis. Neither age, gender, nor anatomic location appeared to affect the recurrence-free or overall survival rates. CONCLUSIONS. Patients with thick primary cutaneous melanomas ( 4 mm) comprise a heterogeneous group. The presence or absence of lymph node involvement, vascular involvement, and ulceration appears to result in significantly divergent overall survival rates in this patient cohort. Consideration of these factors has important implications in the management of patients with T4 melanoma. Cancer 2002;94: American Cancer Society. DOI /cncr KEYWORDS: thick melanoma, ulceration, vascular involvement, risk factors, survival. Presented in part at the 5th World Melanoma Conference, Venice, Italy, February 27 March 3, Address for reprints: Mohammed Kashani-Sabet, M.D., Melanoma Center, University of California at San Francisco Comprehensive Cancer Center, 1600 Divisadero Street, 4th floor, San Francisco, CA 94115; Fax: (415) ; kashanisabet@orca.ucsf.edu Received July 20, 2001; revision received October 12, 2001; accepted November 7, Patients with thick cutaneous melanoma ( 4 mm) pose a challenge to the treating physician because significant controversies exist regarding both the medical and the surgical management of these patients. In 1995, high-dose interferon- -2b (HDI) was approved by the U.S. Food and Drug Administration (FDA) both for thick melanomas (tumors 4 mm in thickness [T4], with no regional lymph node metastasis [N0] and no distant metastasis [M0]; Stage IIB [T4N0M0]), and for metastatic melanoma to the regional lymph nodes (any tumor thickness [T1 4], any metastasis to regional lymph nodes [N1 2], no distant metastasis [M0]; Stage III [T1 4N1 2M0]) (according to the 1992 American Joint Commission on Cancer (AJCC) staging system 1 ). The FDA approval was based on the Eastern Coop American Cancer Society

2 1050 CANCER February 15, 2002 / Volume 94 / Number 4 erative Oncology Group (ECOG) Study E1684, which showed both a significant recurrence-free survival (RFS) and a significant overall survival (OS) advantage in patients treated with HDI, compared with observation only. 2 Only 16 T4 patients were treated with HDI, thereby precluding a complete analysis of the benefit of HDI in this specific patient cohort. The intergroup trial E1690 confirmed a significant RFS advantage but no OS advantage in patients receiving HDI. 3 Most recently, the intergroup trial E1694/S9512/C demonstrated a significant treatment benefit for HDI versus the GM2-KLH/QS-21 vaccine, with a median follow-up period of 16 months. 4 None of these studies stratified T4 patients based on other histopathologic features of the primary tumor such as ulceration, vascular invasion, and microsatellites, which in part may have contributed to some of the varying results observed. To our knowledge to date, the relative impact of such factors on the prognosis of patients with thick melanoma is unclear, and the routine use of HDI in T4 patients remains controversial. In the surgical community, the controversies regarding elective lymph node dissection (ELND) in patients with intermediate-thickness melanomas have been long-standing. Several studies could not justify a therapeutic effect from ELND, 5 7 whereas some demonstrated a survival benefit 8,9 and others demonstrated increased survival only in specific subgroups of patients who had undergone prophylactic regional lymph node dissection. 10 However no randomized studies have been conducted to date analyzing the therapeutic benefit of ELND in patients with T4 disease. The advent of sentinel lymph node (SLN) mapping 11 at major medical centers in the early 1990s revealed that up to 20% of patients with melanomas thicker than mm harbor micrometastases in the regional lymph node basin. A relation between increasing tumor thickness and increasing risk of positive SLN status also has been demonstrated, with thick melanomas having a 34 44% lymph node positivity rate. 12,13 In addition, by focusing on the histopathologic risk factors in the primary tumor such as the presence of ulceration, vascular invasion, microsatellites, and the mitotic rate, a probabilistic approach can be developed to predict the risk of occult micrometastasis to the regional lymph node basin. 14 However, to our knowledge, few studies to date have focused on the role of histopathologic risk factors in patients with thick primary melanoma. The current study attempts to delineate the impact of multiple histopathologic and clinical risk factors, and specifically their interactions, on the survival of a large cohort of patients with T4 melanoma. MATERIALS AND METHODS The records of 336 patients with thick primary melanomas ( 4 mm) seen at the University of California at San Francisco (UCSF) Melanoma Center over the past 29 years were reviewed. The following 14 histopathologic features were analyzed by a single dermatopathologist (R.W.S.): Breslow tumor thickness, Clark level, mitotic rate, histogenetic type, ulceration, vascular involvement, regression, microsatellites, angiogenesis, tumor-infiltrating lymphocytes in the vertical growth phase, desmoplasia, neurotropism, regional lymph node status, and total number of lymph nodes involved after complete lymph node dissection. In addition, 9 clinical factors were analyzed; age, gender, tumor location, the number of primary melanomas, evidence of clinically palpable lymph nodes, site of first recurrence, site of distant metastases, history of nonmelanoma skin cancer, and history of other cancers. Patients with known chronic immunosuppression were excluded from the study in order not to skew the data, including patients with human immunodeficiency virus infection (HIV) (one patient); intravenous drug abusers with unknown HIV status (two patients); and patients treated with long-term immunosuppressive drugs for chronic rheumatoid arthritis, temporal arteritis, and polymyositis (three patients). In addition, one transsexual female who was receiving high-dose estrogen hormone replacement therapy was excluded due to the controversy regarding the influence of high-dose estrogen on melanoma pathogenesis. 15 Three patients who died of other types of metastatic cancer (breast carcinoma, prostate carcinoma, and large cell lung carcinoma, respectively) also were eliminated from the study. Patients with a family history of melanoma (n 11), patients with a past medical history of cancer (mostly nonmelanoma skin cancer) who were considered to be either cured or in disease remission (n 46), patients with multiple primary melanomas (n 19), and pregnant patients (n 2) all were included in the current study. The final number of patients included in the statistical analyses was 329. Univariate statistical analyses were performed using the probability log-rank test. Multivariate analysis was performed with the Cox proportional hazards regression model, with ulceration, vascular involvement, microsatellites, and lymph node status as categoric variables, and tumor thickness and mitotic rate as continuous variables. When indicated, Kaplan Meier survival curves were generated using the twotailed log-rank test. Unless otherwise specifically noted, all P values were two-tailed. P values 0.05 were considered statistically significant.

3 Prognostic Factors in Thick Melanoma/Zettersten et al TABLE 1 Demographic Data of 329 Patients with T4 Melanoma Clinical factors No. of patients Percentage (%) Gender Male Female Age (yrs) Location Head/neck Upper back Lower extremities Upper extremities Chest 24 7 Lower back 12 4 Abdomen 8 3 Other (buttock, vulva, anus) 20 6 Lymph node status Negative Positive Sentinel lymph node biopsy Negative Positive Elective lymph node dissection Negative Positive TABLE 2 Significant OS Differences in T4 (> 4 mm) Melanoma Based on Histopathologic Attributes using Univariate Analysis T4 risk factors No. of patients Median OS (yrs) P value Tumor thickness (mm) Tumor type Desmoplastic Nodular superficial Ulceration Absent Present Vascular involvement Absent Present Microsatellites Absent Present Mitotic rate 5/mm /mm Lymph node status Negative Positive OS: overall survival. RESULTS The median OS of the entire T4 cohort of 329 patients was 4.6 years, with a 5-year OS rate of 46%. Gender, Age, and Location Table 1 shows the demographic factors that were considered in the current study of 329 patients with thick melanoma ( 4 mm, classified as T4). Approximately 67% of the patients were males, and the median age was 57 years. Neither gender nor age were found to affect the RFS or the OS significantly in the current patient cohort. Different anatomic locations of the primary tumor also were documented, and were subdivided into the head and neck region (28%), upper back (20%), lower back (4%), chest (7%), abdomen (3%), upper extremities (13%), lower extremities (19%), and buttocks and mucosa (6%). There were no statistically significant differences with regard to RFS or OS between any of these anatomic sites. Lymph Node Status The lymph node status was documented in 300 patients, 151 of whom (50%) had regional lymph node involvement. Patients without lymph node metastasis (Stage IIB [T4N0M0] disease) had a 5-year OS rate of 61%, whereas patients with regional lymph node metastasis (Stage III [T4N1-2M0] disease) had a 5-year OS rate of only 30%. The median OS survival was 5.7 years for Stage IIB patients versus 2.6 years for Stage III patients, respectively (P ) (Table 2) (Fig. 1). SLN biopsies have been performed at the UCSF Melanoma Center since 1993, and 66 (22%) of the T4 patients included in the current study underwent this procedure at the time of diagnosis, 28 of whom (42%) were found to have at least 1 positive SLN. To date, only 1 patient diagnosed with a negative SLN biopsy (Stage IIB) developed recurrent disease, and due to the relative short follow-up period the median OS in SLNnegative patients had not been reached at the time of last follow-up. The median OS in the SLN-positive group was 3.0 years. The median OS in patients with a positive ELND was 2.3 years, and the median OS in patients with a negative ELND was 7.3 years (P ). Tumor Thickness Each full mm thickness between 4 8 mm was investigated as a cutoff point, and the 8-mm cutoff point was proven to provide additional prognostic significance for OS. The 5-year OS rate was 49% in patients with melanomas between 4 8 mm, and was 33% in patients with melanomas 8 mm. The median OS in these subgroups was 5.0 years and 2.6 years, respectively (P ) (Table 2).

4 1052 CANCER February 15, 2002 / Volume 94 / Number 4 FIGURE 1. Kaplan Meier curve of overall survival based on lymph node status in patients with T4 tumors. Tumor Type Nodular melanoma and superficial spreading melanoma were the most common subtypes (46% and 23%, respectively), followed by desmoplastic melanoma (9%), acral-lentiginous melanoma (4%), and lentigo maligna melanoma (3%). Approximately 11% of the melanomas were unclassified, 1% were classified as spindle cell melanoma, and 3% were classified as mucosal melanomas, including anal (n 5), vulvar (n 2), labial (n 1), and palatal (n 1). Of the 9% of patients diagnosed with desmoplastic melanoma (n 28), 96% (n 27) had neurotropism. Even though the presence of neurotropism has been believed to be a risk factor for early recurrence, 16 the 5-year OS rate in the desmoplastic neurotropic subgroup was 70%. The median OS had not been reached in the desmoplastic neurotropic subgroup at the time of last follow-up, but it exceeded 6.0 years. In contrast, the nondesmoplastic melanoma subgroup had a 5-year OS rate of 44% and a median OS of 3.0 years (P ). There were no significant differences with regard to RFS or OS between the nodular melanoma and the superficial spreading melanoma subgroups; therefore, these two subgroups were combined and compared with the desmoplastic neurotropic melanoma subgroup. The 5-year OS rate of the desmoplastic neurotropic melanoma group was 70%, versus 41% for the combined nodular and superficial spreading melanoma group (P ) (Table 2). The lentigo maligna melanoma subgroup did not appear to have significant survival differences when compared with any of the other histogenetic subgroups. Ulceration The ulceration status was documented in 254 patients, revealing the presence of ulceration in 62% of the primary lesions. The presence of ulceration impacted both the RFS (data not shown) and OS significantly on univariate analysis. The 5-year OS rate in the nonulcerated group was 54% versus 34% in the ulcerated group, with a median OS of 5.2 years versus 2.9 years, respectively (P ) (Table 2) (Fig. 2). Mitotic Rate The mitotic rate was recorded in 266 patients, and ranged from 0 to 25/mm 2, with a median of 6/mm 2. Approximately 71% of the patients were found to have a high mitotic index, defined as 5/mm 2. Univariate analysis demonstrated that the 5-year OS rate of patients with a high mitotic rate was 35% compared with 63% in patients with a low mitotic rate. The median OS was 3.1 years and 5.9 years, respectively (P ) (Table 2). Vascular Involvement Information regarding tumor cell involvement of the dermal vasculature was available for 242 patients. Approximately 64% of the tumors had no vascular invasion, 22% had uncertain invasion (defined as tumor cells found directly adjacent to the vascular endothelium), and 14% had definite vascular invasion (defined

5 Prognostic Factors in Thick Melanoma/Zettersten et al FIGURE 2. Kaplan Meier curve of overall survival based on the presence or absence of ulceration in patients with T4 primary melanoma. as tumor cells present within the vessel lumen). There was a 50% OS rate and a median OS of 5.0 years in the subgroup without any vascular involvement, but only a 17% 5-year OS rate and a median OS of 2.1 years in the subgroup with uncertain vascular invasion (P ). When uncertain vascular invasion was grouped with definite tumor cell invasion and compared with absent vascular involvement, there were significant differences with regard to both the RFS (data not shown) and OS. The 5-year OS rate was 50% in the group lacking vascular involvement and was 25% in the group with combined uncertain plus definite vascular invasion. The median OS was 5.0 years and 2.6 years, respectively (P ) (Table 2) (Fig. 3). Microsatellites The presence or absence of microsatellites was recorded in a total of 237 patients. Microsatellites were noted in 26% of the patients. Both the RFS (data not shown) and the OS were significantly impacted by this feature. The 5-year OS rate in patients without microsatellites was 47%, compared with 26% in patients with microsatellites in their primary tumor, and the median OS was 4.9 years versus 2.6 years, respectively (P ) (Table 2). Clark Level, Regression, and Tumor-Infiltrating Lymphocytes Neither Clark level nor regression of the primary tumor was found to have any significant impact on the RFS or the OS in this patient cohort. Tumor-infiltrating lymphocytes were studied in 200 patients, and the majority (53%) were found to have no tumor-infiltrating lymphocytes in the vertical growth phase. The other tumors had mostly sparsely infiltrating lymphocytes with only a few (7%) reported to have a moderate host response in the vertical growth phase, and only 3 patients (1.5%) were found to have a brisk host response. Cox Regression Analysis By univariate analysis, lymph node status, vascular involvement, ulceration, tumor thickness, mitotic rate, and microsatellites all were found to have significant prognostic value in predicting the OS of patients with T4 disease (Table 2). The relative impact of these prognostic factors then was assessed by performing multivariate Cox regression analysis. When factors in the primary tumor alone were evaluated, only vascular involvement (P 0.005) and tumor thickness (P 0.017) were found to be significant by Cox regression analysis. (Table 3). However, when lymph node status was added to the model, the lymph node status (P ), vascular involvement (P 0.012), tumor thickness (P 0.013), and ulceration (P 0.022) all were proven to be of significance for OS (Table 4). DISCUSSION The reported 10-year survival rate for thick melanomas varies widely, from 23% 68%. 17 In the current study, the most powerful predictive factor for both

6 1054 CANCER February 15, 2002 / Volume 94 / Number 4 FIGURE 3. Kaplan Meier curve of overall survival based on the presence or absence of vascular involvement in patients with T4 primary melanoma. TABLE 3 Histopathologic Risk Factors in the Primary T4 Tumor Impacting OS T4 risk factors Hazard ratio P value a Vascular involvement Tumor thickness Ulceration Mitotic rate Microsatellites OS: overall survival. a P values were determined using Cox regression analysis. TABLE 4 Significant Independent Risk Factors Impacting OS using Cox Regression Analysis T4 risk factors Hazard ratio P value Lymph node status Vascular involvement Tumor thickness Ulceration OS: overall survival. RFS and OS was the lymph node status, a finding confirming multiple previous studies. 18,19 Patients with Stage IIB disease [T4N0M0] had a 5-year OS rate of 61% compared with only 30% in patients with Stage III disease [T4N1-2M0] (P ). Ulceration also has been shown to be an independent risk factor in primary cutaneous melanoma In the 1992 AJCC staging system, all T4 melanomas are grouped together as Stage IIB. 1 Recently, it has been proposed that ulceration should be added to a new AJCC staging system, based on reports that demonstrated that the presence of ulceration reduced the 5-year OS rate in patients with Stage IIB melanoma from 69 48% when ulceration was present. 23,24 In the current study of T4 melanoma, the 5-year OS rate was reduced significantly from 54 34% when ulceration was present in the primary tumor (P ). Several studies have reported ulceration and lymph node status to be powerful predictors of OS in patients with thick melanomas In a study of 131 patients with thick (T4) melanoma, Gershenwald et al. 28 reported that patients with negative SLN biopsies and absent ulceration had a 3-year OS rate of 86%, whereas T4 patients with a positive SLN biopsy and ulceration present had a 3-year OS rate of 57% (P 0.003). The current study of 329 patients with T4 melanoma confirmed, over a longer follow-up period, the interaction between positive lymph node status and ulceration in the prediction of OS. Figure 4 shows a 5-year OS rate of 62% and a median OS of 6.0 years in T4 patients with negative lymph node status and absent ulceration, but a 5-year OS rate of only 18% and a median OS of 1.6 years in patients with both positive lymph node status and ulceration present (P ). Ulceration was found to impact survival significantly in the lymph nodepositive setting, with a median OS of 3.0 years versus 1.6 years (P 0.018) in patients with absent versus

7 Prognostic Factors in Thick Melanoma/Zettersten et al FIGURE 4. Algorithm of the prognostic impact of ulceration on the median overall survival (OS) in patients with T4 primary melanoma with known lymph node (LN) status. invasion in the primary tumor (P 0.057). These results point to the presence of two histopathologic factors in primary T4 melanoma that retain prognostic value even in patients with lymph node-positive disease. Most important, to our knowledge the current study is the first to demonstrate by multivariate analysis that lymph node status, vascular involvement, tumor thickness within the T4 subgroup, and ulceration all are strong independent prognostic factors for OS. The significant impact that high-risk histologic features have on survival highlights the importance of careful histopathologic review and regional lymph node analysis at the time of diagnosis in patients with thick melanoma. The data generated in the current study suggest that histopathologic factors such as ulceration, vascular involvement mitotic rate, and microsatellites should be recorded routinely in pathology reports of thick primary melanomas. Accurate microstaging of this heterogeneous group of T4 patients can help in better assessing the prognosis of individual patients and thereby could facilitate decisions regarding adjuvant therapy with HDI or experimental treatment modalities (e.g., vaccines 35,36 ). Finally, the histopathologic factors found to be significant predictors of OS may be used to stratify patients when conducting adjuvant therapy trials. FIGURE 5. Algorithm of the prognostic impact of vascular involvement on the median overall survival (OS) in patients with T4 primary melanoma with known lymph node (LN) status. present ulceration, respectively, on 1-tailed univariate analysis. However, ulceration in the primary T4 melanoma did not appear to impact the OS to a significant degree in patients with negative regional lymph nodes. Vascular invasion has been described as another strong factor predicting OS, and lack of this feature has been documented in long-term survivors of thick melanomas. 33,34 Figure 5 indicates that lymph node-negative T4 patients without vascular involvement in their primary tumor have a survival advantage over T4 patients with negative lymph nodes but with vascular involvement present, with a median OS of 5.8 years versus 4.0 years, respectively (P 0.038). It is interesting to note that T4 patients with lymph nodepositive disease and vascular involvement present in the primary tumor have only a 13% 5-year OS rate and a median OS of 1.5 years, versus a 33% 5-year OS rate and a median OS of 3.5 years in T4 patients with lymph node-positive disease but with absent vascular REFERENCES 1. Fleming ID, Cooper JS, Henson DE, Hutter RVP, Kennedy BJ, Murphy GP, et al. editors. Malignant melanoma of the skin. In: American Joint Committee on Cancer staging manual. 5th edition. Philadelphia: Lippincott-Raven, 1997: Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alpha-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST J Clin Oncol 1996; 14: Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernsthoff MS, et al. High- and low-dose interferon alpha-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 2000;18: Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernsthoff MS, et al. High-dose interferon alpha-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C J Clin Oncol 2001;19: Silberman AW. Malignant melanoma. Practical considerations concerning prophylactic regional lymph node dissection Ann Surg 1987;206: Veronesi U, Adamus J, Bandiera DC, Brennhovd IO, Caceres E, Cascinelli N, et al. Inefficacy of immediate node dissection in stage I melanoma of the limbs. N Engl J Med 1977; 297:

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