Localized Melanoma Research Articles

Primary melanoma of the female urethra

We evaluate tumor characteristics, recurrence and survival following surgical treatment for female urethral melanoma.A review of the records of all female patients with primary localized urethral melanoma (11, mean age 68 years) who underwent partial urethrectomy (7) or radical extirpation (4) from 1950 to 1999 was performed to determine disease specific survival and/or tumor characteristics correlating with survival. Clinical and pathological stage, tumor location, nodal status, adjuvant therapy and tumor pathological components including depth, width, necrosis and vascular/lymphatic invasion, were evaluated. Overall disease recurrence, crude and disease specific survival rates were calculated using the Kaplan-Meier method.Malignant melanoma occurred in the distal urethra in all 11 cases with local extension into the vagina (T3) in 7. Mean depth of invasion was 6.1 mm and mean tumor width was 2.0 cm. No vascular/lymphatic invasion or tumor necrosis was seen pathologically. No patient had received adjuvant therapy at the time of initial surgery. There were 7 recurrences (6 of 7 within 1 year postoperatively). Of the 7 cases of partial urethrectomy, urethral recurrence (1 with concurrent lung metastasis) developed in 5 and none had bladder recurrence. Those who underwent radical surgery had recurrence in the pelvis and lungs (1) and inguinal lymph nodes (1). Crude and disease specific survival ± standard error at 3 years was 27 ± 15% and 38 ± 19%, respectively.Primary female urethral melanoma is associated with a rapid and high local recurrence rate (60% at 1 year). Overall and cancer specific survival at 3 years is 27% and 38%, respectively. Local failure may in part be due to inadequate resection.

Who Is to Blame for False-Negative Sentinel Node Biopsies in Melanoma?

No matter how one defines standard of care, sentinel lymph node biopsy (SLNB) has become standard of care for the treatment of clinically localized melanoma.1,2 Given this fact, it is surprising that more attention has not been paid to the issue of false-negative results of sentinel node biopsy. In the current issue of Annals of Surgical Oncology, Scoggins et al. report on the false-negative rate of sentinel node biopsy from a large series of patients entered prospectively into the multi-institutional Sunbelt Melanoma Trial.3 An important starting point for any discussion of this topic is how to define and report the false-negative rate. Some investigators have reported the number of false-negative sentinel node biopsies (generally defined as any first recurrence of melanoma in a lymph node potentially draining the primary tumor) occurring out of all procedures performed. This is an incorrect representation of the false-negative rate and not a relevant number to patients and surgeons. In contrast, a very important number is the ratio of true-negative biopsies to all negative biopsies (false negatives plus true negatives). This is the negative predictive value of the sentinel node biopsy procedure and is of great value to surgeons when they counsel patients after a negative sentinel node biopsy procedure, but it is still not the false-negative rate. The negative predictive value of sentinel node biopsy in large series has been reported between 94 and 98.5% (Table 1), meaning that only 2–6 patients per 100 who are told their nodes are negative are given that information incorrectly. However, the actual definition of the false-negative rate is the ratio of false-negative results to the total number of positive lymph nodes (false negatives plus true positives). This value has been reported in the range 6–21%. Importantly, any method of reporting on the likelihood that a truly positive lymph node will be missed by the sentinel node procedure depends on the a priori likelihood that any lymph nodes are actually involved by melanoma. Put another way, if all the lymph nodes in a patient are uninvolved by tumor, it does not matter which nodes the surgeon removes—the result will be a true negative. The corollary of this, however, is that patients whose melanoma is most likely to have spread to the regional nodes are those most likely to have a false-negative sentinel node biopsy. It also follows that different series of patients undergoing sentinel node biopsy using identical techniques (and with identical accuracy) will report different false-negative rates and negative predictive values if the baseline characteristics of the melanoma patients differ. In addition, because nodal recurrences can take many years to manifest clinically, as the duration of follow-up increases, the false-negative rate and total positive node percentage will increase. In the Sunbelt Melanoma Trial data reported by Scoggins et al., after median follow-up of 61 months, the overall likelihood of a positive lymph node was 19.8% (486/2,451), the negative predictive value of a sentinel node biopsy was 97.0% (1,906/59 + 1,906), and the false-negative rate was 10.8% (59/59 + 486).3 The corresponding values in other contemporary large series of melanoma patients undergoing sentinel node biopsy are shown in Table 1.

Final Version of 2009 AJCC Melanoma Staging and Classification

To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database. The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria. Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm(2)), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level. Using an evidence-based approach, revisions to the AJCC melanoma staging system have been made that reflect our improved understanding of this disease. These revisions will be formally incorporated into the seventh edition (2009) of the AJCC Cancer Staging Manual and implemented by early 2010.

Sentinel lymph node biopsy from the vantage point of an oncologic surgeon

Sentinel lymph node biopsy has greatly influenced the surgical management of clinically localized primary melanoma. Lymphatic mapping and sentinel lymph node biopsy have been used for the selective management of the draining regional lymph node basin of primary cutaneous melanoma. Oncologic surgeons have adopted this procedure to selectively identify occult nodal status in melanoma patients who are at a higher risk of regional metastasis. The current standard of treatment of tumor-positive sentinel lymph node metastasis is immediate completion lymphadenectomy, but considerable debate surrounds the utility of this procedure. This contribution reviews development, technical aspects, selective management of the lymph node basin, and sentinel lymph node biopsy techniques.

Isolated Limb Infusion for Malignant Melanoma: Predictors of Response and Outcome

Isolated limb infusion (ILI) is an alternative to isolated limb perfusion (ILP) for the treatment of unresectable limb melanoma recurrence. The aims of this study were to determine the response rates of unresectable local and/or in-transit melanoma of the upper or lower limb to ILI and to identify factors predictive of survival. A prospective database identified 74 patients (35 male and 39 female) with local and/or in-transit melanoma recurrence without metastatic disease who underwent hyperthermic ILI with melphalan at a single institution between January 1996 and December 2008. Three patients could not be evaluated for response. Median follow-up was 34 months. Of the 74 patients, the majority had N2c disease (57/74, 67%), while 17/74 (33%) patients had N3 disease. Median maximum temperature achieved was 38.1 degrees C and median tourniquet time was 32.5 min. Wieberdink III/IV complications occurred following 7/74 (10%) ILI and were associated with higher limb volumes and higher total melphalan dose. Complete response (CR) was seen following 17/71 (24%) ILI and the partial response rate was 30% (22/71). The median duration of CR was 43 months. Univariable analyses found that limb volume >8.0 l and maximum limb temperature >38.5 degrees C were the only independent factors predictive for a CR following ILI. Multivariate analyses identified CR and positive lymph nodes as the only independent prognostic factors for melanoma-specific survival. Patients who obtain CR have significantly improved survival compared with nonresponders. The challenge remains to improve CR rates and prospectively identify responders.

Melanoma in Pediatric, Adolescent, and Young Adult Patients

The family practitioner, pediatrician, and dermatologist all have potential roles in the primary prevention, diagnosis, and treatment of localized thin melanomas. Surgical and medical oncologists are often involved when controversy arises over the nature of the skin lesion or whether sentinel lymph node (SLN) biopsies and adjuvant therapy are to be contemplated. This overview of melanoma will deal with the primary and nodal pathology, surgery, and medical therapy of melanoma in pediatric, adolescent, and young adult patients--and will raise areas of controversy that are only recently being addressed in databases of cases from this age group.

Sentinel Lymph Node Biopsy in Pediatric and Adolescent Cutaneous Melanoma Patients

The rarity of melanoma in young patients, particularly pediatric ones, has to date precluded any valid comparisons being made between young patients and adults undergoing sentinel lymph node biopsy (SLNB) for intermediate thickness localized melanoma. The present study takes advantage of the large Sydney Melanoma Unit (SMU) database to clarify this issue. Clinical and pathologic data on pediatric and adolescent AJCC Stage I and II cutaneous melanoma patients aged <20 years undergoing SLNB at the SMU between January 1993 and February 2008 were reviewed. SLNB positivity rates and outcomes in these patients were compared with adult SMU patients. In 55 young patients, overall median tumor thickness was 1.7 mm (range, 0.6-5.2 mm) and overall SLNB positivity rate was 14 of 55 (25%), tumors tending to be thicker (median, 2.6 mm), and SLNB positivity rate higher (2 of 6; 33%) in patients aged <10 years. Of the 14 patients, 13 underwent immediate completion lymph node dissection (CLND); 2 patients had non-SLN metastases (15.4%). Only 0.7% of a total of 295 lymph nodes removed at CLND were involved with melanoma. In 14 SLNB-positive patients with follow-up data, 3 (21%) have died from melanoma after a median follow-up of 60 months, compared with 42% of 356 SLNB positive adults. Although the SLNB positivity rate was higher in pediatric and adolescent melanoma patients than in adults (25% vs. 17%, respectively), non-SLN positivity and melanoma-specific death rates were low.

Mood state and melanoma outcome in the Multicenter Selective Lymphadenectomy Trial

9603 Background: Emotional state has been linked to cancer survival, but its influence on the outcome of early melanoma is unclear. The Multicenter Selective Lymphadenectomy Trial (MSLT-I) randomized patients with clinically localized cutaneous melanoma to wide local excision (WEX) plus observation or to WEX plus sentinel lymph node biopsy (SNB). Clinical endpoints included disease-specific and disease-free survival. A substudy of this phase III trial evaluated the impact of mood state on survival, and the impact of recurrence on mood state. Methods: Patients were asked to complete a 65-question form within 6 months of enrollment (baseline) and every 12 months thereafter. This questionnaire measured 6 identifiable mood states (vigor-activity, tension-anxiety, depression, anger-hostility, fatigue-inertia, confusion-bewilderment) of the Profile of Mood States (POMS), a validated mood scale for assessing responses to therapy. Self-reported data from the questionnaires were linked to demographic and clinical variables. Results: Of 2,001 patients accrued to MSLT-I, 1,620 completed the questionnaire at baseline. The baseline distribution of POMS variables was similar in the two treatment arms (data not shown). Patients with more vigor at baseline had a significantly longer disease-free and overall survival ( Table ), even after adjusting for age, tumor thickness, site, and ulceration status (p &lt;0.001). Among 136 patients who completed a questionnaire within 6 months after recurrence, comparison of baseline and post-recurrence responses revealed significant changes in mood state: tension, fatigue and confusion increased, whereas vigor decreased (p = 0.0004, 0.0171, 0.0089, and 0.0028, respectively). Conclusions: Vigor, a measure of energy and optimism, is directly correlated with disease-free and overall survival in early melanoma. The negative impact of recurrence on mood state suggests that SNB as a tool for preventing recurrence might also improve mood state and psychological well-being. Supported by NIH CA29605. [Table: see text] No significant financial relationships to disclose.

Microscopic Satellites Around a Primary Melanoma: Another Piece of the Puzzle in Melanoma Staging

This is an important subject that is applicable to surgical treatments of the primary melanoma and the regional lymph nodes as well as melanoma prognosis and staging. The importance of cancer staging, of course, is to partition patients into risk groups based upon disease-specific survival rates. In turn, the converse of survival rates at 5 or 10 years reflects the incidence of distant microscopic metastases at the time of staging from which a patient would ultimately succumb. With respect to the nodal (N) classification in melanoma, the two most important prognostic features are number of nodal metastases (1 versus 2/ 3 versus C4) and tumor burden (i.e., microscopic or clinically occult versus macroscopic or clinically apparent nodal metastases). The third criterion for defining the N category is the presence or absence of satellites or in transit metastases, regardless of the number of lesions. The clinical presence of satellites around a primary melanoma or of in-transit metastases between the primary melanoma site and the regional lymph node basin represent intralymphatic metastases that portend a relatively poor prognosis. The available data show no substantial difference in survival outcome for these two anatomically defined entities. But what about microscopic satellites? These are defined as any discontinuous nest of intralymphatic metastatic cells [0.05 mm in diameter that are clearly separated by normal dermis (not fibrosis or inflammation) from the main invasive component of melanoma by a distance of at least 0.3 mm. In the past, the definition of microsatellites has varied, and this may account for some of the differences in results regarding their prognostic significance. As a result, the level of evidence regarding the prognostic significance of microsatellites is less robust, but the available data indicates that this is an adverse finding associated with an increased risk of regional recurrences and a decreased disease-free survival rate similar to that of clinically detectable satellites. Whether microsatellites represent an independent predictor of survival outcome is less clear, but at present the preponderance of evidence suggests that this feature represents an adverse prognostic factor for survival. Accordingly, the America Joint Committee on Cancer (AJCC) Melanoma Staging Committee has recommended that this feature of early lymphatic metastases, as defined above, be retained in the category of N2c melanoma. This issue of the Annals of Surgical Oncology includes a valuable contribution to our decade-long work on melanoma staging as regards microsatellites. In this setting, the AJCC Melanoma Staging Database did not have direct data that could be applied to the staging rules for patients with microscopic satellitosis, except that published in the literature, much of which was published years ago. This study by Kimsey and colleagues from Memorial Sloan– Kettering Cancer Center (MSKCC) was made possible by the commitment made through the years by MSKCC surgeons to collect prospective data on their melanoma patients, which now includes almost 4,000 prospectively followed patients. Among these patients was a carefully studied cohort of 38 patients with newly diagnosed, clinically localized melanoma containing microscopic satellitosis. These primary melanomas had very aggressive features, including a median thickness of 5.4 mm and the majority (71%) being ulcerated. The 5-year overall and disease-free survival rates in these patients were 34% and 18%, respectively, and 68% had pathologically involved regional nodal metastases. They clearly constitute a highrisk group of patients for both regional and distant metastases that needs to be accounted for in our staging rules. In the 6th edition of the Cancer Staging Manual, the Melanoma Staging Committee modified its staging criteria Society of Surgical Oncology 2009

Microscopic Satellitosis in Patients with Primary Cutaneous Melanoma: Implications for Nodal Basin Staging

Microscopic satellitosis in melanoma is uncommon. The role of regional basin staging/therapy in patients with this high-risk feature has not been well defined. Patients presenting from 1996 to 2005 with clinically localized melanoma containing microscopic satellitosis were identified from a prospective, single-institution database. Multiple factors were analyzed to determine their predictive value for recurrence. The management of the draining nodal basin was evaluated to determine its impact on recurrence and survival. Thirty-eight patients presented to our institution during this time period with clinically localized melanoma containing microscopic satellitosis. The 5-year overall and disease-free survivals in these patients were 34% and 18%, respectively. Sixty-eight percent had pathologically involved regional nodal metastases. With median follow-up of 21 months, 68% recurred, with a median time to recurrence of 9 months. Lymphovascular invasion (LVI) (p = 0.01), tumor regression (p = 0.04), and positive regional lymph nodes (p = 0.02) were associated with an increased risk of recurrence. Of the 31 patients who underwent sentinel lymph node (SLN) biopsy, 22 had metastasis in the SLN (71%). Fifteen of these patients underwent completion lymphadenectomy (CLND) and seven were observed. There was no difference in disease-free survival (DFS), disease-specific survival (DSS), or overall survival (OS) between these groups (p = 0.42). Pathological lymph node metastases were more prevalent (68%) than in any group previously defined. Regional nodal status predicted recurrence but not nodal recurrence. In SLN-positive patients, CLND did not improve DFS, DSS, or OS, although the number of patients was small. Further studies are needed to determine the utility of regional nodal staging/therapy in these high-risk patients.

Sentinel Lymph Node Biopsy in Melanoma

Sentinel lymph node biopsy (SLNB) for patients with newly diagnosed localized invasive melanoma provides excellent prognostic information and results in improved regional disease control. Prior to the common use of SLNB, regional nodal recurrence was the single most common site of melanoma recurrence, with symptomatic, bulky disease that could be disabling and difficult or impossible to control. With the widespread use of SLNB, regional recurrence of melanoma is much less frequent. Even without clear evidence of improvement in overall survival, the significant and reliable prognostic information and the improved regional control make sentinel node biopsy an important procedure that should be offered routinely to many patients with newly diagnosed melanoma.

Expression of cyclooxygenase‐2 and peroxisome proliferator‐activated receptor gamma during malignant melanoma progression

Cancer chemoprevention using nonsteroidal anti-inflammatory drugs is frequently attributed to cyclooxygenase-2 (COX-2) inhibition, although recent studies suggest that peroxisome proliferator-activated receptor gamma (PPARgamma) may also be involved. While surgical excision remains the treatment mainstay for localized malignant melanoma, certain high-risk patients may benefit from adjunctive chemotherapy. In this study, we compared COX-2 and PPARgamma immunohistological staining in benign nevi, primary melanomas and metastatic melanomas to help predict the effectiveness of compounds targeting these markers. COX-2 and PPARgamma immunohistological staining was performed and reviewed in 99 melanocytic lesions, including 38 benign nevi, 32 primary melanomas and 29 metastatic melanomas. There was a significant increase in both COX-2 and PPARgamma immunostaining in melanomas compared with benign nevi. Metastatic melanomas were more likely to have a higher number of PPARgamma-immunopositive cells. They were also more likely to express COX-2 than primary melanomas. Neither COX-2 nor PPARgamma expression was associated with a specific pathologic subtype. COX-2 and PPARgamma may help modulate the progression of melanocytic precursor lesions to disseminated malignant melanoma. As such, they may serve as candidate substrates for targeted cancer therapies and may be particularly useful as adjuncts to surgery.

O.479 Diagnostic of peripheral vascular reticulum diseases

The sentinel node status is the most important single factor determining overall survival for patients with localized melanoma. Preoperative lymphoscintigraphy (LS) is essential in locating the correct sentinel lymph node (SN) and the reproducibility of the method determines the accuracy of the sentinel node biopsy (SNB). This study aims at determining the reproducibility and accuracy of LS in routine clinical practice after long-term follow-up.One hundred and eight melanoma patients with clinically unpredictable lymphatic drainage were prospectively enrolled to undergo two LS. The first LS was performed to determine the site and number of the lymphatic basins to plan SNB anesthesia and the second preoperative LS was to allow SN localization intra-operatively.Lymphatic drainage was demonstrated in all patients. In 84 of 108 cases, both LSs were concordant in terms of site and number of nodal basins visualized. After a median follow-up of 80 months, no nodal recurrence was observed in the five patients with a decreased number of lymph node basins. In the group with increased number of lymph node basins, one patient developed nodal metastases in the same regional lymph node basin visualized by both LS studies.LS is an accurate and reproducible method to determine the localization of the sentinel node in the day-to-day routine to clinical practice when primary melanoma is also located in body sites with variable lymphatic drainage.

O.480 Discrepancy in flndings after targeted therapy – a case report

The sentinel node status is the most important single factor determining overall survival for patients with localized melanoma. Preoperative lymphoscintigraphy (LS) is essential in locating the correct sentinel lymph node (SN) and the reproducibility of the method determines the accuracy of the sentinel node biopsy (SNB). This study aims at determining the reproducibility and accuracy of LS in routine clinical practice after long-term follow-up.One hundred and eight melanoma patients with clinically unpredictable lymphatic drainage were prospectively enrolled to undergo two LS. The first LS was performed to determine the site and number of the lymphatic basins to plan SNB anesthesia and the second preoperative LS was to allow SN localization intra-operatively.Lymphatic drainage was demonstrated in all patients. In 84 of 108 cases, both LSs were concordant in terms of site and number of nodal basins visualized. After a median follow-up of 80 months, no nodal recurrence was observed in the five patients with a decreased number of lymph node basins. In the group with increased number of lymph node basins, one patient developed nodal metastases in the same regional lymph node basin visualized by both LS studies.LS is an accurate and reproducible method to determine the localization of the sentinel node in the day-to-day routine to clinical practice when primary melanoma is also located in body sites with variable lymphatic drainage.

Angiotropism is an Independent Predictor of Local Recurrence and In-transit Metastasis in Primary Cutaneous Melanoma

The migration of melanoma cells along the external surface of blood vessels (angiotropism) has recently been proposed as a mechanism for melanoma metastasis (termed extravascular migratory metastasis). To determine whether the presence of angiotropism, as seen in the routine hematoxylin and eosin sections of primary cutaneous melanomas (PCMs), predicts the development of local or in-transit melanoma recurrence, 32 patients with a PCM who developed local or in-transit recurrence were matched for Breslow thickness with 59 "control" patients with a PCM who did not. The slides from both groups of patients were analyzed in a "blinded" manner for evidence of angiotropism. Other histologic and clinical variables were also assessed. Angiotropism was found more often in patients who developed local or in-transit recurrence (cases) compared with those patients who did not (controls) (P=0.02). Variables that showed a statistically significant association with angiotropism on univariate analysis were: increasing Breslow thickness (P<0.0001), greater Clark level (P<0.001), increasing mitotic index (P<0.0001), presence of ulceration (P<0.01), and absence of regression (P<0.05). The median disease-free survival was 72 months for patients with angiotropism and 104 months for those without (P=0.02). On multivariate analysis the presence of angiotropism was an independent predictor of decreased disease-free survival (P=0.02). This is the first reported study to identify a statistically significant association between the development of local or in-transit recurrence of PCM and the histologic presence of angiotropism and that angiotropism is an independent predictor of decreased disease-free survival, as far as we are aware. Our findings support the hypothesis that angiotropism represents a pathogenic mechanism for metastasis in patients with PCM.

Management of melanomas of the female genital tract

The significant increase in cutaneous melanomas over the past 30 years has led to studies resulting in advances in their diagnosis, staging, surgical treatment, and adjuvant therapies. Similar approaches have been investigated in patients with far rarer malignant melanomas of the female genital tract. This review will summarize the current state of knowledge on the incidence, causes, presenting symptoms, prognostic factors, therapeutic approaches, and outcomes, site-by-site, for primary melanomas of the vulva, vagina, urethra, ovary, and the uterine cervix. Surgery remains the initial treatment of choice for localized melanomas of the female genital tract, with less radical, organ function preserving resections demonstrating similar control rates compared with more radical surgical approaches in vulva and possibly vaginal melanomas. Radiation therapy may play a role in the treatment of patients with close resection margins, regional nodal metastasis, or unresectable tumors. Sentinel lymph node studies, positron emission tomography and computed tomography scans for staging and evaluation of response, and adjuvant chemo or biochemotherapy warrant further investigation. The results of treatment for female genital tract melanomas remain poor. Although surgery remains the initial treatment of choice for localized disease, adjuvant local-regional, and systemic therapies are needed.

Visualization of Circulating Melanoma Cells in Peripheral Blood of Patients with Primary Uveal Melanoma

In patients with uveal melanoma, tumor cell dissemination and subsequent formation of metastases are confined mainly to the hematogenous route. Here, we sought to isolate circulating melanoma cells in peripheral blood of patients with primary uveal melanoma and clinically localized disease. Blood samples from 52 patients with clinically localized uveal melanoma and from 20 control individuals were prospectively collected before therapy of the primary tumor. Tumor cells expressing the melanoma-associated chondroitin sulfate proteoglycan were enriched by immunomagnetic cell sorting and visualized by immunocytologic staining. Results were compared with clinical data at presentation. In 10 of 52 patients [19%; 95% confidence interval (95% CI), 10-33%], between 1 and 5 circulating melanoma cells were detected in 50 mL peripheral blood. No melanoma-associated chondroitin sulfate proteoglycan-positive cells were detected in any of the 20 controls examined. The presence of tumor cells in peripheral blood was associated with ciliary body invasion [odds ratio (OR), 20.0; 95% CI, 3.0-131.7], advanced local tumor stage (OR, 6.7; 95% CI, 1.8-25.4), and anterior tumor localization (OR, 4.0; 95% CI, 1.2-12.7), all established factors for uveal melanoma progression. Immunomagnetic enrichment enables detection of intact melanoma cells in peripheral blood of patients with clinically localized ocular disease. Visualization and capturing of these cells provide a unique tool for characterizing potentially metastasizing tumor cells from a primary melanoma at an early stage of the disease.

Radiation Therapy as Primary and Adjuvant Treatment for Local and Regional Melanoma

The role of radiation therapy as primary and adjuvant therapy for localized or locally advanced melanoma is controversial. To develop evidence-based guidelines, PubMed was searched using the keywords melanoma AND (radiation OR radiotherapy). These references were reviewed and the relevant articles selected. The articles were then reviewed for further references. Because of the paucity of prospective or randomized trials, no attempt was made to classify the quality of the results. No phase III trials of nodal irradiation for prevention of regional recurrence are available. A phase III trial is being completed by the Tasman Radiation Oncology Group. A phase II trial has been completed by the group. Multiple retrospective series have been published. The available data appear to confirm that nodal radiation therapy is effective in preventing nodal recurrence. No dose response or fraction size response was found. According to generally accepted guidelines, radiation therapy should be offered for patients who have nodes greater than 3 cm, more than 3 involved nodes, or extracapsular extension. For radiation therapy for the treatment of metastatic disease, a phase III trial showed that 50 Gy in 2.5-Gy fractions was as effective as 32 Gy in 8-Gy fractions, with 25% complete remission and 35% partial remission. In contrast, the retrospective studies support that larger fraction sizes, at least 4 Gy, are more effective. Adjuvant nodal irradiation appears to be effective for the prevention of nodal recurrence. Radiation therapy can also be effective for treatment of local disease, if surgery is not an option.

The Complex Relationships Between Sentinel Node Positivity, Patient Age, and Primary Tumor Desmoplasia: Analysis of 2303 Melanoma Patients Treated at a Single Center

Recent studies have shown that younger age is associated with a greater likelihood of positive sentinel node (SN) status in patients with localized melanoma. This is a paradoxical situation because it is well known that younger patients have a far more favorable overall survival rate than older patients. In addition, desmoplastic melanomas are associated with a lower frequency of SN positivity, although this is less well documented. The outcome for 2303 cutaneous melanoma patients undergoing sentinel lymph node biopsy (SLNB) at the Sydney Melanoma Unit between 1993 and 2006 was examined to clarify the role of patient age and desmoplastic histogenetic type on SN positivity. By univariate analysis, patients aged <40 years had a higher SN positivity rate (22.6%) than patients aged > or =40 years (15.4%; P < .004). Features associated with SN positivity were tumor thickness, mitotic rate, ulcerative state, and nondesmoplastic histogenetic type (all P < .001). Patient sex and primary melanoma site were not statistically significantly associated. Multivariate analyses revealed that only tumor thickness, patient age, nondesmoplastic type (all P < .001), and ulceration (P < .026) were independently associated with SN positivity. Key prognostic determinants such as total number of disease-positive nodes (both SNs and non-SNs) and site of first relapse did not vary according to age. Tumor thickness, patient age, desmoplastic histogenetic type, and primary melanoma ulceration were all independently associated with SN status. The factors underlying the paradox of a poorer survival rate in older patients despite a lower incidence of positive SNs remain unclear.

Primary Cutaneous Melanoma with Regression Does not Require a Lower Threshold for Sentinel Lymph Node Biopsy

Histological evidence of primary tumor regression (RG) is observed in 35% or fewer patients with cutaneous melanoma. Some advocate a lower threshold for sentinel lymph node (SLN) biopsy when RG is present. We identified 1,349 patients presenting to our center with clinically localized cutaneous melanoma between 1995 and 2004. Of these, 344 demonstrated histological RG in their primary melanoma. A retrospective analysis of their medical records was performed to obtain clinical and pathological information. The median Breslow depth for the 344 patients with RG was 1.1 mm versus 1.5 mm for 1,005 patients with no regression (NRG) (P < 0.005). SLN biopsy was performed in 64% of patients with RG and 72% without. Positive SLN was more common in those with NRG than in those with RG (18% vs 10%, P = 0.005). Only one RG patient with thin melanoma (</=1 mm, Clark IV) had a positive SLN. When stratified by Breslow depth, patients with RG had lower rates of SLN positivity in all groups (</=1.0mm, >1.0 and </=2.0mm, >2 and </=4 mm, and >4.0 mm). Recurrence was more common in patients with NRG (21% vs 12%; P < 0.005). Both local and systemic recurrence occurred more commonly in patients with NRG (4% vs 1%, P = 0.002 and 8% vs 3%, P < 0.005, respectively) The presence of histological RG in a primary melanoma predicts neither SLN positivity when stratified by Breslow depth nor increased risk of recurrence when compared with melanomas with NRG.