Thick Primary Tumors Research Articles

Melanoma Deaths by Thickness: Most Melanoma Deaths Are Not Attributable to Thin Melanomas

IntroductionPrevious population-based studies have reported that the majority of melanoma mortality is related to patients with thin (≤1 mm Breslow thickness) melanomas. The aim of the present study was to evaluate the relative proportion of melanoma-specific deaths across all stages of melanoma at diagnosis over the past 20 y in the United States. MethodsA review of all cutaneous melanoma cases in the US Surveillance, Epidemiology, and End Results registry from 2004 to 2020 was performed. Breslow thickness was categorized as thin (≤1.0 mm), intermediate (>1-4 mm), or thick (>4 mm). All-cause deaths and melanoma-specific deaths were compared across tumor thickness and stage groups at diagnosis. Survival analysis was performed with nonmelanoma deaths considered as a competing risk to estimate the cumulative incidence of melanoma-specific death. ResultsMost melanoma deaths occurred in patients who initially presented with local disease (53%) compared to regional (36%) or distant (11%) disease (P < 0.001). However, most (66%) of the melanoma-specific deaths in patients who presented with localized disease were in those with intermediate or thick (i.e., Breslow thickness >1.0 mm) primary tumors compared to those with thin melanomas (34%). The cumulative incidence of melanoma-specific death at 10 y in patients with localized thin melanomas at the time of diagnosis was 2.6% (95% confidence intervals 2.5%-2.7%). ConclusionsThe public health burden in terms of melanoma-specific mortality is related to patients with tumors >1 mm Breslow thickness, many of whom have regional and distant metastatic disease at the time of diagnosis, not patients with thin melanomas.

Expression of NGF/proNGF and Their Receptors TrkA, p75NTR and Sortilin in Melanoma.

There is increasing evidence that nerve growth factor (NGF) and its receptors, the neurotrophic receptor tyrosine kinase 1 (NTRK1/TrkA), the common neurotrophin receptor (NGFR/p75NTR) and the membrane receptor sortilin, participate in cancer growth. In melanoma, there have been some reports suggesting that NGF, TrkA and p75NTR are dysregulated, but the expression of the NGF precursor (proNGF) and its membrane receptor sortilin is unknown. In this study, we investigated the expression of NGF, proNGF, TrkA, p75NTR and sortilin by immunohistochemistry in a series of human tissue samples (n = 100), including non-cancerous nevi (n = 20), primary melanomas (n = 40), lymph node metastases (n = 20) and distant metastases (n = 20). Immunostaining was digitally quantified and revealed NGF and proNGF were expressed in all nevi and primary melanomas, and that the level of expression decreased from primary tumors to melanoma metastases (p = 0.0179 and p < 0.0001, respectively). Interestingly, TrkA protein expression was high in nevi and thin primary tumors but was strongly downregulated in thick primary tumors (p < 0.0001) and metastases (p < 0.0001). While p75NTR and sortilin were both expressed in most nevi and melanomas, there was no significant difference in expression between them. Together, these results pointed to a downregulation of NGF/ProNGF and TrkA in melanoma, and thus did not provide evidence to support the use of anti-proNGF/NGF or anti-TrkA therapies in advanced and metastatic forms of melanoma.

Higher rates of regional disease but improved outcomes in pediatric versus adult melanoma

BackgroundMalignant melanoma is rare in the pediatric population and management is largely extrapolated from adult guidelines. Adult data have shown that immediate completion lymph node dissection (CLND) does not improve overall survival in selected patients with clinically node negative, sentinel lymph node-positive disease. Current nodal management in children is unknown. MethodsThe National Cancer Database (NCDB) was queried for patients with melanoma from 2012-2017 and patients categorized as pediatric (≤18 years, n=962) or adult (n=327,987). Factors associated with CLND in children with positive SLNB were evaluated in multivariable analysis. Kaplan-Meier survival analysis was performed. ResultsCompared to adults, children present with thicker primary tumors (T3 or T4 26.5% vs 15.5%, p<0.001), resulting in higher rates of nodal assessment with SLN biopsy or LND (60.2% vs 36.6%, p<0.001) and higher rates of regional nodal disease (35.1% vs 23.4%, p<0.001). Children underwent higher rates of CLND after SLN biopsy (10.4% vs 4.1%) and upfront lymph node dissection (15.2% vs 8.7%). A decreased rate of CLND was noted in 2017 compared to 2012 (odds ratio (OR) 0.16 (p=0.005). CLND was performed more often on multivariable analysis for older pediatric age (>12 years, OR=1.6, p=0.037) and lower extremity primary (OR=0.29, p<0.001). Children with regional nodal disease have improved 3-year overall survival compared to adults (96.5% vs 71.0%, p<0.001). ConclusionsChildren with melanoma have higher rates of nodal disease but better survival than adults. As in adults, there has been a recent increase in close nodal observation rather than CLND for patients with positive SLN. Further study of nodal surveillance for pediatric patients is warranted.

Primary melanoma histologic subtype (HS) impacts melanoma specific survival (MSS) and response to systemic therapy.

9577 Background: Unlike other solid tumors, the impact of primary HS on melanoma survival and response to systemic therapy is not well studied. Nodular melanoma (NM) has a worse prognosis than superficial spreading melanoma (SSM), which is usually attributed to thicker primary tumors. Herein, we examine the hypothesis that HS might have an impact on MSS independent of thickness and that NM and SSM exhibit different mutational landscapes that associate with response to checkpoint inhibitor immunotherapy (IT) and BRAF targeted therapy (TT) in the metastatic setting. Methods: Primary NM and SSM patients prospectively enrolled at NYU (2002 - 2016) were compared to the most recent SEER cohort (1973 - 2012) and analyzed with respect to MSS. Next-Generation Sequencing (NGS) was performed on a subset of matched tumor-germline pairs, allowing a comparison of the mutational landscape between NM and SSM. In the metastatic setting, survival analyses were used to compare outcomes and responses to treatment across HS. Results: The NYU cohort of 1,621 patients with either NM (n = 510) or SSM (n = 1,111) was representative of the analogous SEER cohort (21,339 NM, 97,169 SSM), with NM presenting as thicker, more ulcerated, and later stage (all p &lt; 0.001). Among the NYU cohort, NM was found to have lower rates of TIL (p = 0.047), higher mitotic index (p &lt; 0.001), and higher rates of NRAS mutation (p &lt; 0.001). In multivariate Cox models, NM was a significant predictor of worse MSS, independent of thickness and stage (p = 0.01). NM had a significantly lower mutational burden across the exome (p &lt; 0.001). Some of the most under-mutated genes noted in NM were NOTCH4, BCL2L12 and RPS6KA6 (all p &lt; 0.01). Among patients treated with TT (n = 56), NM remained a significant predictor of worse MSS (p = 0.004). However, there was no difference in response to IT. Conclusions: NM and SSM show divergent mutational patterns which may contribute to their different clinical behaviors and responses to BRAF targeted therapy. More studies are needed to better understand the key molecular and cellular processes driving such differences. Integration of HS data into prospective clinical trial reporting is needed to better assess its impact on response to treatment.

Malignant head and neck melanoma: Part 2: Therapy

Resection margins of melanomas in the head and neck region often have to be adapted according anatomical circumstances. In the case of thicker primary tumors or after complete resection of locoregional lymph node metastases, adjuvant therapy with interferon-α can be performed; in some cases, adjuvant radiotherapy may also be indicated. In the case of inoperable lymph node or distant metastases, systemic treatment is required. Beside well-established mono- or polychemotherapy regimens, newer targeted therapies with BRAF inhibitors (vemurafenib, dabrafenib), mitogenic-activated protein kinase (MEK) inhibitors (trametinib, binimetinib, and cobimetinib), and kinase inhibitors (imatinib, sunitinib, nilotinib, dasatinib) are also available.

High Expression of Wee1 Is Associated with Poor Disease-Free Survival in Malignant Melanoma: Potential for Targeted Therapy

Notoriously resistant malignant melanoma is one of the most increasing forms of cancer worldwide; there is thus a precarious need for new treatment options. The Wee1 kinase is a major regulator of the G2/M checkpoint, and halts the cell cycle by adding a negative phosphorylation on CDK1 (Tyr15). Additionally, Wee1 has a function in safeguarding the genome integrity during DNA synthesis. To assess the role of Wee1 in development and progression of malignant melanoma we examined its expression in a panel of paraffin-embedded patient derived tissue of benign nevi and primary- and metastatic melanomas, as well as in agarose-embedded cultured melanocytes. We found that Wee1 expression increased in the direction of malignancy, and showed a strong, positive correlation with known biomarkers involved in cell cycle regulation: Cyclin A (p<0.0001), Ki67 (p<0.0001), Cyclin D3 (p = 0.001), p21Cip1/WAF1 (p = 0.003), p53 (p = 0.025). Furthermore, high Wee1 expression was associated with thicker primary tumors (p = 0.001), ulceration (p = 0.005) and poor disease-free survival (p = 0.008). Transfections using siWee1 in metastatic melanoma cell lines; WM239WTp53, WM45.1MUTp53 and LOXWTp53, further support our hypothesis of a tumor promoting role of Wee1 in melanomas. Whereas no effect was observed in LOX cells, transfection with siWee1 led to accumulation of cells in G1/S and S phase of the cell cycle in WM239 and WM45.1 cells, respectively. Both latter cell lines displayed DNA damage and induction of apoptosis, in the absence of Wee1, indicating that the effect of silencing Wee1 may not be solely dependent of the p53 status of the cells. Together these results reveal the importance of Wee1 as a prognostic biomarker in melanomas, and indicate a potential role for targeted therapy, alone or in combination with other agents.

Improved survival with elective neck dissection in thick early‐stage oral squamous cell carcinoma

Management of the node-negative neck in T1 to T2 oral squamous cell carcinoma (SCC) remains controversial. The purpose of this study was to determine if elective neck dissection improves outcomes in thick primary tumors since this reflects current practice in most institutions and has not been specifically addressed in the literature. Retrospective analysis comparing elective neck dissection versus observation in 153 patients with T1 to T2 N0 oral SCC ≥4 mm thick. On multivariable analysis, elective neck dissection was a significant predictor of improved regional control (hazard ratio [HR], 0.1; p < .001), disease-specific (HR, 0.1; p < .001), and overall survival (HR, 0.3; p = .001). Regional failure accounted for 22% of disease-related deaths in the elective neck dissection group compared to 92% in the observation arm. Elective neck dissection is associated with a clinically significant survival advantage in thick T1 to T2 oral SCC by reducing the risk of regional failure, and we support its routine application in these patients.

So‐called “malignant blue nevus”

Melanomas that arise in association with or that resemble blue nevi are extremely rare and have been termed "malignant blue nevi." The authors report on a single-institutional clinicopathologic study of "blue nevus-like melanomas" (BNLMs). Twenty-six patients were identified with a "malignant blue nevus" over 29 years at the Sydney Melanoma Unit. Twenty-three patients were included in the current study after pathologic review. Clinical outcomes of those patients were compared with the outcomes in a matched control group of patients with melanoma (matched for age, sex, Breslow thickness, Clark level, ulceration, and anatomic site). The median patient age was 44 years, and men comprised 65% of the patients. The tumors were distributed evenly among skin sites, and their median Breslow thickness was 5.5 mm. After a median follow-up of 36.5 months, there was no difference in survival (P = .702) between patients with BNLM and patients in the control group. BNLMs tended to present at a more advanced stage, with thicker primary tumors, but had a metastatic pattern comparable to and was not more aggressive in behavior than other types of melanoma. The authors concluded that BNLMs should be treated in the same way as any other melanoma variants based on clinical staging and pathologic prognostic indices.

Survival in patients with synchronous versus metachronous lymph node (LN) involvement in stage III melanoma: Is there a difference?

9034 Background: The presence of regional LN metastasis in melanoma patients is a major determinant of outcome. The objective of this analysis was to compare the outcomes of patients with synchronous vs. metachronous LN metastasis. Methods: Medical records for all patients who underwent therapeutic LN dissection (LND) at our institution (1975–2000) were reviewed. Only patients with macroscopic LN metastasis (N1b, N2b, and N3) were included; those with LN metastasis within 12 months of primary tumor diagnosis were defined as synchronous disease (SD) while those with LN metastasis after this period were defined as metachronous disease (MD). Kaplan-Meier survival analyses were performed to compare disease specific survival (DSS) from the time of LN dissection for both groups. Multivariate analyses were performed to identify prognostic factors for DSS. Results: The cohort was comprised of 491 patients: 250 (51%) had SD and 241 (49%) had MD. Median time to LN involvement was 1.7 months in the SD group vs. 2.8 years in the MD group. While the groups were similar with respect to nodal stage and nodal clinical/pathologic features, significant differences with respect to primary tumor and patient characteristics included a higher incidence of younger patients (p=0.03), thick primary tumors (p< 0.001), and tumor ulceration (p=0.002) in the SD group. With a median follow-up of 8.9 years, DSS for the entire cohort was 3.2 years. Median DSS was 2.4 years and 3.7 years for SD vs. MD respectively (p=0.04). Multivariate analyses confirmed that adverse prognostic factors for DSS included SD, male gender, advanced age, extracapsular nodal extension, and higher nodal stage (N2b or N3 versus N1b). Conclusions: Metachronous LN metastasis occurs in a significant number of patients more than 2 years following treatment of their primary tumor. MD is associated with better DSS compared to those who present with SD possibly indicating differences in tumor biology which is not completely explained by primary tumor factors and should be considered in clinical decision making. No significant financial relationships to disclose.

Therapie von Hautmetastasen beim malignen Melanom

Malignant melanoma represents a particular challenge for dermatologists and oncologists because of its high and increasing incidence and the poor prognosis of patients with thick primary tumors (T3, T4). In advanced stages of melanoma, cutaneous and subcutaneous metastases have a special significance, as they markedly affect the patient and may lead to a limitation in quality of life. While topical therapy is possible, there are only limited clinical studies. The location, number, size and distribution of skin metastases, involvement of internal organs, age and general condition should be considered in assessing therapeutic options. Especially with solitary, easily accessible metastases, surgical excision represents the therapy of choice. Ablation using CO(2) laser is an alternative. With extensive metastases in just one extremity, isolated limb perfusion (ILP) with melphalan is an option, while multiple, smaller metastases can be irradiated. Further, several chemotherapeutic agents and immune modulators can be used topically, peri- and intralesionally.

Assessment of the role of sentinel lymph node biopsy for primary cutaneous desmoplastic melanoma

The role of sentinel lymph node biopsy (SLNB) in the treatment of desmoplastic melanoma (DM) remains undefined. The purpose of this study was to evaluate the use of SLNB for DM. In all, 1850 patients with cutaneous melanoma underwent wide local excision and SLNB. Patients with DM were identified and stratified as 'pure' DM or 'mixed' DM (i.e., DM associated with at least one other common histologic subtype). Of the 1850 patients, 65 (3.5%) had DM. Of these, 46 (70.8%) had pure DM and 19 (29.2%) had mixed DM. Patients with pure DM had a median tumor thickness of 3.5 mm and 6.5% were ulcerated. Compared with patients with pure DM, patients with either mixed DM or non-DM (n = 1785) had thinner primary tumors (median, 1.7 mm and 1.5 mm, respectively, each P < 0.001 vs. pure DM) that were more likely to be ulcerated (27.7% and 21.3%, respectively, each P < 0.05 vs. pure DM). Although the incidence of a positive SLN was similar in patients with mixed DM (15.8%) and non-DM (17.5%), patients with pure DM were less likely to have a positive SLN (2.2%) (each P < 0.01 vs. non-DM and mixed DM). At a median follow-up of 2.9 years, no patient with pure DM had recurred. Despite having thicker primary tumors, patients with pure DM have a lower incidence of positive SLNs compared with patients with non-DM. Whereas the treatment approach for patients with mixed DM should be similar to that of other melanoma patients, patients with pure DM are unlikely to have metastatic disease in regional lymph nodes and SLNB may not be warranted.

Biology of Desmoplastic Melanoma: A Case-Control Comparison With Other Melanomas

Previous studies have established that patients with desmoplastic melanoma (DM) have thicker primary tumors. Consequently, comparisons with other forms of melanoma have been strongly biased by differences in Breslow stage. This is the first case-matched control study comparing DM with other forms of melanoma. From a database of 3,202 melanoma patients treated at one institution, 89 patients with DM and 178 case-matched control patients (2:1) were identified by matching for tumor thickness, age, sex, and year of diagnosis. Clinical, pathologic, and outcome information was obtained from chart review. Controls were matched successfully to patients for tumor thickness, age, sex, and year of diagnosis. Presentation with American Joint Committee on Cancer stage III or IV disease is less common in patients with DM compared to case-matched control patients (5% v 21%; P < .001). Re-excisions to obtain clear surgical margins are required more often in patients with DM compared to case-matched control patients (21% v 6%; P < .001). Risk of positive sentinel nodes is lower in patients with DM compared to case-matched control patients (8% v 34%; P = .013). Despite these differences, survival rates of patients with DM are the same as case-matched control patients. Use of case-matched control patients matched for tumor thickness avoids biases introduced by the advanced Breslow stage of DMs. DMs are more locally aggressive than thickness-matched controls, and positive sentinel nodes are limited to patients with thick primary tumors. Importantly, patients with DM have survival rates similar to patients with other melanomas of similar thickness.

A case-control study of desmoplastic melanoma

7529 Background: Previous studies have established that patients with desmoplastic melanoma have thicker primary tumors. Consequently, comparisons between desmoplastic melanoma and other forms of melanoma in these studies have been strongly biased by differences in Breslow stage. This is the first case-matched control study comparing desmoplastic melanoma with other forms of melanoma. Methods: From a database of 3202 melanoma patients treated at one institution, 89 patients with desmoplastic melanoma and 178 case-matched control patients (2:1) were identified by matching for thickness, age, gender, and year of diagnosis. Clinical, pathological, and outcome information were analyzed. Results: The median tumor thickness for all patients in the database is 0.96 mm, whereas the median thickness for desmoplastic melanoma patients is 2.60 mm. As per study design, the median tumor thickness for the 178 case-matched control patients is the same (2.60 mm) as for desmoplastic melanoma patients. Presentation with AJCC stage III or IV disease is less common in desmoplastic melanoma patients compared to case-matched control patients (5% versus 21%, p < 0.001). Re-excisions to obtain clear surgical margins are required more often in desmoplastic melanoma (21% versus 6%; p < 0.001). The risk of positive sentinel nodes is lower in desmoplastic melanoma patients compared to case-matched control patients (8% versus 34%, p = 0.013). Overall survival, cause-specific survival, and disease-free survival in desmoplastic melanoma patients are the same as those in case-matched control patients. Conclusions: Desmoplastic melanoma patients present with thicker primary melanomas than patients with other forms of melanoma. Use of case-matched control patients matched for tumor thickness avoids biases introduced by this observation. Desmoplastic melanomas are more locally aggressive, but have a lower risk of lymph node metastases compared to melanomas in case-matched control patients. The observed 8% rate of positive sentinel nodes in desmoplastic melanoma patients should be factored into decisions concerning sentinel lymph node biopsy. Importantly, desmoplastic melanoma patients have survival rates similar to patients with other melanomas of similar thickness. No significant financial relationships to disclose.

Prognostic implications of thick (>or=4-mm) melanoma in the era of intraoperative lymphatic mapping and sentinel lymphadenectomy.

Lymphatic mapping/sentinel lymphadenectomy (LM/SL) has become a routine part of our treatment algorithm for primary melanoma, yet its role in the management of thick (>or=4-mm) lesions is unknown. One hundred twenty-one patients with thick primaries underwent LM/SL at our institute. Survival curves were constructed from Kaplan-Meier estimates and analyzed by Cox proportional hazards methods. Sixty-three percent of patients were men, median age 54 years. The primary tumor sites were trunk (46%), extremities (32%), and head and neck (21%). Primary thickness ranged from 4 to 15 mm (median, 6.0 mm). Forty-five percent of primary tumors were ulcerated. Thirty-five percent of patients had tumor-positive dissections. Median follow-up was 31 months. The overall 5-year survival was no different (P =.726) for ulcerated and nonulcerated lesions. There was no difference (P =.159) in overall survival after tumor-negative (60% +/- 7%) and tumor-positive (50% +/- 10%) dissections. The 5-year disease-free survival was significantly (P =.012) lower in patients with tumor-positive (34% +/- 9%) than tumor-negative (47% +/- 7%) dissections. Although LM/SL has become a popular technique for staging the regional lymph nodes in early-stage melanoma, our results suggest that sentinel node status is predictive of disease-free survival for thick primary tumors but is not yet reflective of overall survival. The role of LM/SL for patients with thick primary tumors is not clearly defined.

Evaluation of the proliferation marker MIB-1 in the prognosis of cutaneous malignant melanoma.

The proliferation marker MIB-1, which recognizes the Ki-67 antigen, provides independent prognostic information in several tumor types. Its utility in melanoma has been evaluated mostly in studies of thick primary tumors. Its usefulness in thinner lesions has not been assessed adequately. A well characterized cohort of 137 patients diagnosed with primary cutaneous melanoma at the New York University School of Medicine between 1972 and 1982 was studied based on the availability of representative tissues and adequate clinical follow-up. Twenty-one tumors were less than or equal to 1.0 mm thick, 94 were between 1.01 and 4.0 mm thick, and 22 were thicker than 4.0 mm. Tumor cell proliferation was assessed by immunohistochemistry using the monoclonal antibody MIB-1. MIB-1 expression was correlated with baseline clinicopathologic parameters, as well as recurrence (RR), disease-free (DFS), and overall survival (OS) rates. Median follow-up among survivors was 6.5 years (range, 5.6-17.5). High proliferative index, defined as 20% or more of tumor cells showing nuclear immunoreactivity, was observed in 65 of 137 (47.4%) cases. High proliferative index was significantly correlated with increased tumor thickness (P < 0.001) and higher stage (P = 0.03). Trends approaching statistical significance were observed with ulceration of the primary tumor (P = 0.09), male gender (P = 0.06), and shorter DFS (P = 0.12). No significant associations were seen between high proliferative index and RR or OS. In multivariate analyses, tumor thickness was the strongest predictor of clinical outcome. In primary cutaneous melanoma, a high proliferative index is associated with clinicopathologic parameters predictive of worse clinical outcomes. However, it was not an independent predictor of clinical outcome.

MELANOMA: A Multidisciplinary Approach for the General Surgeon

Advances in the understanding of the biology and treatment of melanoma have moved the care of melanoma patients into an increasingly multidisciplinary environment. Surgeons must understand these advances because they will often be responsible for directing the overall care of these patients. Most patients with melanomas more than 1 mm in diameter and no evidence of metastatic disease should be offered SLNB to more accurately stage them and direct decisions about participation in postoperative adjuvant therapy trials. Until the results of the MSLT are known, the effect of SLNB and ELND on outcome remains unknown. SLNs should be analyzed with serial sectioning and immunohistochemistry to avoid missing micro-metastatic disease. Based on the results of the ECOG-1684 trial, the FDA approved IFN-alpha 2b for the adjuvant treatment of melanoma patients with thick primary tumors (> 4 mm) or resected nodal disease. IFN-alpha 2b treatment is expensive and potentially toxic. The data from ECOG-1684 do not support the use of IFN-alpha 2b in patients with node-negative disease. In light of the ECOG-1690 trial results, the role of high-dose IFN-alpha 2b in the management of patients with resected nodal disease is considerably less clear. Any recommendations for treatment with high-dose IFN-alpha 2b should be made only after weighing the costs, side effects, and potential benefits for individual patients. Numerous, less toxic, promising, adjuvant immunotherapeutic strategies have been developed and are being tested in multicenter, prospective, randomized trials. These strategies include GMK, PMCV, and Melacine. If the results of any of these trials show a survival advantage compared with placebo or equivalent survival compared with IFN-alpha 2b, these immunotherapeutic agents will become the adjuvant treatment of choice for patients with resected high-risk melanoma. RT-PCR detection of tyrosinase in SLNs can identify patients with submicroscopic nodal disease who may be at increased risk for recurrence or death from melanoma. An ongoing, prospective, randomized trial will determine whether patients with histologically negative but RT-PCR-positive SLNs will benefit from lymphadenectomy or adjuvant IFN-alpha 2b therapy. RT-PCR can also identify minimal residual disease in peripheral blood and bone marrow from patients with high-risk melanoma, but RT-PCR analysis of peripheral blood and bone marrow is still experimental, and procedural details need to be standardized and prospectively validated in large patient groups before its use can be considered the standard of care.

Prognosis of thick cutaneous melanoma

Background: Ten percent of all patients with melanoma present with thick primary tumors (≥ 4 mm or Clark level V). To determine factors associated with outcomes, we performed a retrospective analysis of 120 patients who had definitive primary treatment of their thick cutaneous melanomas at Memorial Sloan-Kettering Cancer Center between January 1986 and April 1995. Study Design: Data were collected via chart review and patient interview. Association between factors was determined by chi-square analysis. Survival analysis was performed by the method of Kaplan and Meier. Univariate analysis by log-rank testing and multivariate analysis using the Cox regression model were used to identify factors associated with disease-free and overall survival. Results: Median age was 61 years (range 19 to 87 years). There were 80 males and 40 females. Median Breslow thickness was 6 mm (range 1.8 to 25.0 mm). Ninety-three patients (78%) underwent lymphadenectomy (52 elective and 41 therapeutic). Twenty-one percent (11 of 52) of the elective dissections were positive. Median followup was 3.8 years (5.2 years for patients no evident disease and 2.0 years for those dead of disease). Overall survival for the entire group was 62% at 5 years and 43% at 10 years. Age, gender, and anatomic site (axial versus extremity) were not factors predictive of overall survival. Increasing thickness, nodal status at presentation (American Joint Commission on Cancer stage II versus III), and the presence of ulceration were significant predictors of both disease relapse and disease-specific mortality in both univariate and multivariate analyses. There was no difference in postrelapse survival between patients suffering local, nodal, or distant relapse (p = 0.63). Conclusions: Patients presenting with thick cutaneous melanomas are expected to have more than 50% 5-year survival, and they should not be denied the opportunity for aggressive locoregional management. Thickness, positive nodal status, and ulceration are associated with a higher mortality rate. The fact that patients with local or nodal recurrences fare as poorly as those with overt distant metastases implies that the former events are predictors of subclinical systemic disease.

HLA‐DQB1*0301 association with increased cutaneous melanoma risk

Susceptibility to a variety of malignancies has been linked to human leukocyte antigen (HLA) genes, including the HLA class II allele DQB1*0301. To determine whether melanoma risk is associated with HLA class II alleles, molecular oligotyping of HLA class II-DRB1, -DQA1 and -DQB1 genes was performed for 45 patients with melanoma. The DQB1*0301 allele was present in 56% of melanoma patients vs. 27% of 200 local Caucasian controls. This difference was highly significant (Bonferroni's-corrected chi-square p = 0.003, OR = 3.4). No other class II allele tested was present at significantly increased or decreased frequency in melanoma patients. Furthermore, presence of DQB1*0301 in melanoma patients was associated with advanced disease. Melanoma patients carrying the DQB1*0301 allele presented on average with thicker primary tumors (mean 3.7 mm vs. 1.8 mm, 2-tailed p = 0.02) and were more likely to present with regional or distant metastatic disease (stages III-IV, 44% vs. 5%, chi-square p = 0.003), compared to melanoma patients without DQB1*0301. Risk of melanoma incidence or progression may be influenced by DQB1*0301 or a closely linked gene.

Occult tumor cells in the lymph nodes of patients with pathological stage I malignant melanoma. An immunohistological study.

We examined 2,227 lymph nodes from 100 patients with clinical Stage I cutaneous melanoma for the presence of microscopic deposits of tumor. On examination of hematoxylin-and-eosin-stained sections, none had melanoma. Sixteen nodes from 14 patients had melanoma detectable by an antiserum to S-100 protein in a peroxidase-antiperoxidase (PAP) assay. The melanomatous nature of these cells was confirmed by their reaction with the melanoma-directed monoclonal antibody NKl/C3. The incidence of occult nodal metastases was highest in patients with deeply invasive and micrometrically thick primary tumors. The incidence of occult melanoma was not increased where additional serial sections were cut and semiserial sections examined. Pitfalls in the identification of occult melanoma cells (OMC) include S-100 protein-positive interdigitating dendritic cells, capsular nevus cells, a minority of sinus "macrophages," and the Schwann cells of node-associated nerves. Thus, we conclude that the incidence of early melanoma metastases in the regional lymph nodes of patients with clinical Stage I melanoma is greater than has previously been appreciated on the basis of assessment of routine hematoxylin-and-eosin-stained sections. Six of the 14 patients with OMC died of melanoma (41%), as compared to only 18 of 86 patients without OMC (21%; 0.10 greater than P greater than 0.05).

A tumor-associated antigen expressed in melanoma cells with lower malignant potential.

The antigen K-1-2, detectable by a MAb is found in nevi and melanomas. It is associated with melanoma cells of low invasive and metastatic potential as shown by immunoperoxidase studies with cell lines, biopsies and autopsies: K-1-2 occurs in melanoma cell line SK-Mel 25, but not in cell line A-375. A-375 has a higher malignant potential than SK-Mel 25 because, in contrast to SK-Mel 25, it produces plasminogen activator and grows in nude mice. K-1-2 was frequently strongly expressed (greater than or equal to 50% cells positive) in flat (less than 1.5 mm) and less frequently in medium and thick primary tumors. In thick primary melanomas K-1-2 positive cells were confined to the junctional zone or to marginal, flat areas of the tumor. Only rarely does K-1-2 occur in metastases. Strong expression of the K-1-2 antigen was found less often in primary melanomas, which develop early metastases, than in tumors that had not metastasized during an observation period of 18 months. In 5 patients with disseminated metastatic disease, metastases strongly expressing K-1-2 and those negative for this marker or containing only a minor percentage of K-1-2 positive cells were observed simultaneously or at different times. These findings suggest that a change from high malignancy to low malignancy--as observed in animal systems--may also occur in human melanoma.