Evaluation of incomplete sentinel node biopsy procedures and sentinel node positivity rates as surgical quality-assurance parameters in melanoma patients.

BACKGROUND: There is little literature describing quality assurance (QA) validation of an individual surgeon's ability to perform sentinel node biopsy (SNB) in melanoma patients. This study aims to evaluate incomplete SNB rates and SNB positivity rates as potential QA parameters. METHODS: An institutional database identified 2,874 patients with primary melanoma who had SNB performed when there was lymphoscintigraphy drainage to a single lymphatic field. Lymphoscintigraphy data were obtained from another database. Lymphoscintigraphy utilized small-particle colloid, allowing visualization of channels entering sentinel nodes on early dynamic scanning. Incomplete SNB was defined as retrieval of fewer sentinel nodes than identified on lymphoscintigraphy. RESULTS: The overall rate of incomplete SNB was 17.7 % (including axilla 7.8 %, neck 23.3 %, and groin 28.8 %). Individual surgeons varied significantly in their proportion of SNBs performed in each region (p < 0.001). The surgeons' overall incomplete SNB rate varied significantly (p < 0.001). The surgeons' incomplete SNB rate in the axilla ranged 3-16 % (p < 0.001), median 6 %; groin 21-41 % (p = 0.002), median 26 %; and neck 19-43 % (p = 0.374), median 22 %. The respective axillary, groin, and neck SNB positivity rate for incomplete SNB patients were 10, 23, and 18 % compared to "complete" SNB patients 14, 19, and 14 %. There were no significant differences between surgeons' SNB positivity rates. CONCLUSIONS: Incomplete SNB rates vary between surgeons in each region. SNB positivity rates do not vary commensurate with the incomplete SNB rates. The ranges described could be used as QA parameters, however because none of these experienced surgeons are outliers, the robustness of these parameters remains unproven.

Proposed quality standards for regional lymph node dissections in patients with melanoma.

OBJECTIVE: The experience of the Sydney Melanoma Unit (SMU) is documented to offer quality assurance (QA) standards and an acceptable range for lymph node yield for regional lymph node dissection (RLND) in melanoma patients. SUMMARY BACKGROUND DATA: Surgery is the most effective treatment for melanoma involving lymph nodes (LN). QA for RLND procedures, including adequacy of surgery and histopathology, is not well developed. The number of LN removed is one auditable measurement, known as a reliable predictor of surgical quality in other tumors. METHODS: Data were retrieved from the SMU prospective database for patients treated from 1993 to 2006. There were 2039 RLND by SMU surgeons and 324 by non-SMU surgeons. The axilla, groin, cervical dissections of < or = 3 levels (CD < or = 3) and cervical dissections > or = 4 levels (CD > or = 4) were assessed. RESULTS: At axillary dissection the mean number of LN resected by SMU surgeons was 21.9 (median 21; range 1-83; 90% of cases > or = 10 LN), groin dissection mean 14.5 LN (median 13; range 1-54; 90% of cases > or = 7 LN), CD < or = 3 dissection mean 19.5 LN (median 18.5; range 1-52; 90% of cases > or = 6 LN) and CD > or = 4 dissection mean 38.9 LN (median 36; range 5-103; 90% of cases > or = 20 LN). SMU surgeons retrieved significantly more LN than non-SMU surgeons for axillary and groin dissections (P < 0.0005). CONCLUSIONS: These data benchmark performance for melanoma RLND. Cases with a low node count (below the 90 percentile) should be assessed critically. Standard RLND operations should have a reproducible mean and predictable distribution of LN retrieved.

Diagnostic accuracy of fine needle biopsy for metastatic melanoma and its implications for patient management.

BACKGROUND: The use of fine needle biopsy (FNB) for the diagnosis of metastatic melanoma can lead to the early removal and treatment of metastases, reduce the frequency of unnecessary surgery, and facilitate the staging of patients enrolled in clinical trials of adjuvant therapies. In this study, the accuracy of FNB for the diagnosis of metastatic melanoma was investigated. METHODS: A retrospective cohort study was performed with 2204 consecutive FNBs performed on 1416 patients known or suspected to have metastatic melanoma. Almost three-quarters (1582) of these FNBs were verified by either histopathologic diagnosis following surgical resection or clinical follow-up. RESULTS: FNB for metastatic melanoma was found to have an overall sensitivity of 92.1% and a specificity of 99.2%, with 69 false-negative and 5 false-positive findings identified. The sensitivity of the procedure was found to be influenced by six factors. The use of immunostains, reporting of the specimen by a cytopathologist who had reported >500 cases, lesions located in the skin and subcutis, and patients with ulcerated primary melanomas were factors associated with a significant improvement in the sensitivity of the test. However, FNBs performed in masses located in lymph nodes of the axilla and FNBs that required more than one needle pass to obtain a sample were far more likely to result in false-negative results. CONCLUSIONS: FNB is a rapid, accurate, and clinically useful technique for the assessment of disease status in patients with suspected metastatic melanoma.

Conditional Survival: An Assessment of the Prognosis of Patients at Time Points After Initial Diagnosis and Treatment of Locoregional Melanoma Metastasis.

Purpose Standard cancer staging and prognostic estimates are determined at the time of the patient's initial disease presentation. Conditional survival is an alternative, dynamic assessment from follow-up time points after the initial disease diagnosis and is based on the condition of survivorship. Estimates of conditional survival can provide critical prognostic information for patients and clinicians, guide subsequent cancer follow-up schedules, and influence decisions regarding treatments. The current study presents conditional survival estimates developed from a cohort of 4,540 patients diagnosed with stage III melanoma treated at a single institution. Methods Patients with stage III disease at first melanoma diagnosis (initial; n = 2,042), or who developed locoregional metastasis as a first recurrence some time after primary diagnosis (recurrent; n = 2,498), were assessed. Conditional melanoma-specific survival (MSS) estimates up to 5 years after diagnosis were adjusted for age, sex, and 8th edition American Joint Committee on Cancer (AJCC) stage. Results Older age at diagnosis of stage III disease conveyed a worse prognosis at each conditional survival time point. Males had significantly worse MSS outcomes for up to 2 years of conditional survival, after which males and females had similar MSS. For patients with AJCC stage IIIB and stage IIIC disease, MSS outcomes were similar to those of patients with stage IIIA disease after 3 and 5 years of survivorship, respectively. Conclusion Adjuvant systemic treatments may have the greatest benefit when administered within the first 2 years of stage III melanoma diagnosis, during which period prognosis is significantly worse for male patients of increasing age and AJCC substage. Conditional survival estimates illustrate improved survival prospects for patients with cancer returning for follow-up and may define a finite period of increased risk after diagnosis.

Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: results of a randomized trial.

PURPOSE: Patients with high-risk melanoma treated by immunotherapy with vaccinia viral lysates were found in phase II studies to have improved survival compared with historical controls. We therefore elected to test this therapy in a phase III study. PATIENTS AND METHODS: A prospective, randomized, multicenter trial to determine whether immunotherapy with a vaccine prepared from vaccinia melanoma cell lysates (VMCL) over a 2-year period after definitive surgery would improve relapse-free survival (RFS) and overall survival (OS) in patients with American Joint Committee on Cancer stage IIB and III melanoma compared with a control group treated only with surgery. RESULTS: A total of 700 patients were randomized: 353 to VMCL and 347 to no immunotherapy. Seventy-seven percent had lymph node (LN) metastases and 66% had clinically detected LN metastases. Analysis on the basis of all eligible, randomized patients (n = 675) found, after a median follow-up period of 8 years, a median OS of 88 months in the control versus 151 months in the treated group (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.64 to 1.02; P =.068 by stratified univariate Cox analysis). At 5 and 10 years, survival rates for control and treated patients were 54.8% v 60.6% and 41% v 53.4%, respectively. Median RFS was 43 months in the control group compared with 83 months in the treated group (HR, 0.86; 95% CI, 0.7 to 1.07; P =.17). RFS at 5 years was 50.9% for the treated group and 46.8% for the control group. There were no selective benefits from the vaccine for particular subsets of patients. CONCLUSION: Immunotherapy with VMCL was not associated with a statistically significant improvement in OS or RFS, with CIs not ruling out important gains from such treatment.

Treatment of metastatic melanoma using electroporation therapy with bleomycin (electrochemotherapy).

Electroporation therapy (EPT) is a novel treatment modality that uses brief, high-intensity, pulsed electrical currents to enhance the uptake of chemotherapeutic agents, vaccines and genes into cells. This technique is potentially useful for patients with secondary and, possibly, some primary tumours. Nineteen patients with metastatic melanoma were enrolled in a phase two, randomized, open-label study comparing intralesional bleomycin+EPT with intralesional bleomycin alone. Of 18 study lesions, 13 (72%) showed a complete response, one (5%) showed a partial response, three (18%) showed no change and one (5%) showed disease progression over a period of greater than 12 weeks. This represents a 78% objective response rate, which was significantly greater than the 32% response rate observed in the 19 patients with tumours treated with intralesional bleomycin alone (chi=7.94, 1 df, P=0.005). An additional 36 lesions, not enrolled in the study, were also treated with bleomycin+EPT. Of the total of 54 lesions treated with bleomycin+EPT, there was a 72% objective response rate. EPT treatment was well tolerated and was performed on an outpatient basis.

Surgical treatment of splenic metastases in patients with melanoma.

BACKGROUND: Surgery is rarely undertaken for metastatic melanoma in the spleen. To identify indications for surgical treatment, results after splenectomy for metastatic melanoma were analyzed. STUDY DESIGN: A retrospective study in which all patients at the Sydney Melanoma Unit recorded as having splenic metastases between January 1990 and May 2001 were identified. For those who underwent surgery, indications for splenectomy, operative complications, and outcomes were documented. RESULTS: Splenectomy was performed in 15 patients, and 98 patients were treated conservatively. Indications for surgery were rupture of the spleen (n = 1), discomfort or pain (n = 7), and the spleen as an apparently solitary site of metastasis (n = 7). All seven symptomatic patients were free of pain after recovery from surgery. Postoperative morbidity occurred in two patients (14%) but there was no mortality. Median overall survival after splenectomy was 11 months, with a survival of 23 months for the subgroup of patients treated for a solitary lesion. Two patients who underwent splenectomy were disease free after more than 2 years of followup. Median overall survival of the conservatively treated patients was 4 months, which was statistically shorter than median survival of the patients who underwent splenectomy (p = 0.02). CONCLUSIONS: Splenectomy can provide good palliation for symptomatic patients with melanoma metastases in the spleen. A selected group of patients with solitary splenic metastases can achieve longterm disease-free survival after splenectomy.

Surgical management of cerebral metastases from melanoma: outcome in 147 patients treated at a single institution over two decades.

OBJECT: The aim of this study was to review the outcome of patients who underwent surgery for treatment of cerebral metastatic melanoma. METHODS: A retrospective analysis was performed in 147 patients with cerebral metastases from melanoma who were treated surgically at a single institution between 1979 and 1999. Almost all patients underwent postoperative wholebrain radiation therapy. The mean patient age was 53 years (range 17-76 years); 69% of patients were male. A single cerebral metastasis was identified in 84% of patients, although 56% had synchronous extracranial metastases. The 30-day postoperative mortality rate was 2% and neurological symptoms resolved or improved in 78% of patients. Recurrence of intracerebral disease was seen in 55% of patients and 26% died of intracerebral metastases. Twenty-four patients underwent reoperation for recurrent cerebral disease. The median survival duration from the time of surgery for all patients was 8.5 months; the 3- and 5-year survival rates were 9% and 5%, respectively. Factors that significantly influenced survival on univariate analysis were the number of cerebral metastases (p = 0.015), a macroscopically complete excision (p < 0.05), and reoperation for recurrence (p = 0.02). The presence of extracranial metastases did not significantly influence survival. On multivariate analysis only the number of cerebral metastases significantly affected survival (p = 0.04). CONCLUSIONS: For the majority of patients with cerebral metastases from melanoma, surgery with adjuvant radiation therapy is a treatment option that improves neurological symptoms and produces minimal morbidity. Long-term survival (> 3 years) most likely occurs in patients with a single cerebral metastasis and no demonstrable extracranial disease. Reoperation for recurrent cerebral disease may be appropriate in selected cases.

The Sydney Melanoma Unit--a multidisciplinary melanoma treatment center.

The undoubted success of the SMU as a specialist multidisciplinary melanoma treatment center has clearly been the result of many factors. Perhaps chief among these was the vision and commitment that led Dr. Milton to establish it in the first place, and the sharing of that vision and commitment by those who were associated with him and by those who joined the SMU later. Another vitally important element, however, has been the continuing sense of unity and purpose fostered by the weekly SMU clinical meetings, which are truly multidisciplinary, in which all staff are encouraged to participate, and at which the desirability of adherence to agreed, evidence-based treatment guidelines is emphasized. A further influential factor has been the SMU's strong commitment to clinical and basic research as a concomitant of high quality clinical care, with stimulation, encouragement, and advice provided at its monthly multidisciplinary research meetings, where all current and proposed clinical and laboratory studies are discussed. As a result of these activities, despite an ever-increasing number of people working within it, the SMU has been able to present to referring doctors, to patients, and to the community a unified commitment to the best possible patient care and to high quality clinical and laboratory research. These groups have responded by recognizing the SMU as the major referral center for melanoma in Australia, as evidenced by the steadily increasing number of patients referred to it for treatment each year. Melanoma is a more pressing health problem in Australia than elsewhere, because it is the third most common cancer in women (after breast cancer and colorectal cancer), and the fourth most common cancer in men (after prostate cancer, colorectal cancer, and lung cancer). Nevertheless the experiences of the SMU as a large multidisciplinary melanoma treatment center are likely to have relevance and application in other countries, where the incidence of melanoma is lower but continues to rise, and may within a few years approach rates currently recorded in Australia.

Early diagnosis of cutaneous melanoma: revisiting the ABCD criteria.

CONTEXT: The incidence of cutaneous melanoma has increased over the past several decades, making its early diagnosis a continuing public health priority. The ABCD (Asymmetry, Border irregularity, Color variegation, Diameter >6 mm) acronym for the appraisal of cutaneous pigmented lesions was devised in 1985 and has been widely adopted but requires reexamination in light of recent data regarding the existence of small-diameter (< or =6 mm) melanomas. EVIDENCE ACQUISITION: Cochrane Library and PubMed searches for the period 1980-2004 were conducted using search terms ABCD and melanoma and small-diameter melanoma. Bibliographies of retrieved articles were also used to identify additional relevant information. EVIDENCE SYNTHESIS: Available data do not support the utility of lowering the diameter criterion of ABCD from the current greater than 6 mm guideline. However, the data support expansion to ABCDE to emphasize the significance of evolving pigmented lesions in the natural history of melanoma. Physicians and patients with nevi should be attentive to changes (evolving) of size, shape, symptoms (itching, tenderness), surface (especially bleeding), and shades of color. CONCLUSIONS: The ABCD criteria for the gross inspection of pigmented skin lesions and early diagnosis of cutaneous melanoma should be expanded to ABCDE (to include "evolving"). No change to the existing diameter criterion is required at this time.

Histopathologic excision margin affects local recurrence rate: analysis of 2681 patients with melanomas < or =2 mm thick.

OBJECTIVE: Prospective trials have shown that 1-cm and 2-cm margins are safe for melanomas <1 mm thick and > or =1 mm thick, respectively. It is unknown whether narrower margins increase the risk of LR or mortality. SUMMARY BACKGROUND DATA: To determine the relationship between histopathologic excision margin, local recurrence (LR) and survival for patients with melanomas < or =2 mm thick. METHODS: Data were extracted from the Sydney Melanoma Unit database for all patients with cutaneous melanoma < or =2 mm thick, diagnosed up to 1996. Patients with positive excision margins or follow-up <12 months were excluded, leaving 2681 for analysis. Outcome measures were LR (recurrence <5 cm from the excision scar), in-transit recurrence, and disease-specific survival. Factors predicting LR and overall survival were tested with Cox proportional hazards analysis. RESULTS: Median follow-up was 83.8 months. LR was identified in 55 patients (median time to recurrence, 37 months). At 120 months, the actuarial LR rate was 2.9%. Five-year survival after LR was 52.8%. In multivariate analysis, only margin of excision and tumor thickness were predictive of LR (both P = 0.003). When all patients with a margin <0.8 cm in fixed tissue (corresponding to a margin of <1 cm in vivo) were excluded from analysis, margin was no longer significant in predicting LR. Thickness, ulceration, and site were predictive of survival, but margin was not (P = 0.49). CONCLUSIONS: Histopathologic margin affects the risk of LR. However, if the in vivo margin is > or =1 cm, it no longer predicts risk of LR. Patient survival is not affected by margin.

Outcome in 846 cutaneous melanoma patients from a single center after a negative sentinel node biopsy.

BACKGROUND: A negative sentinel node biopsy (SNB) implies a good prognosis for melanoma patients. The purpose of this study was to determine the long-term outcome for melanoma patients with a negative SNB. METHODS: Survival and prognostic factors were analyzed for 836 SNB-negative patients. All patients with a node field recurrence were reviewed, and sentinel node (SN) tissue was reexamined. RESULTS: The median tumor thickness was 1.7 mm, and 23.8% were ulcerated. The median follow-up was 42.1 months. Melanoma specific survival at 5 years was 90%, compared with 56% for SN-positive patients (P < .001). On multivariate analysis, only thickness and ulceration retained significance for disease-free and disease-specific survival. Five-year survival for patients with nonulcerated lesions was 94% vs. 78% with ulceration. Eighty-three patients (9.9%) had a recurrence. Twenty-seven patients developed recurrence in the regional node field, and in 22 of these, it was the first recurrence site. Six developed local recurrence, 17 an in-transit metastasis, and 58 distant disease. The false-negative rate was 13.2%. SN slides and tissue blocks were further examined in 18 patients with recurrence in the node field, and metastatic disease was found in 3 of them. CONCLUSIONS: This large, single-center study confirms that patients with a negative SNB have a significantly better prognosis than those with positive SNs. In those with a negative SNB, primary tumor thickness and ulceration are independent predictors of survival. Incorrect pathologic diagnosis contributed to only a minority of the false-negative results in this study.

The Australian experience in sun protection and screening for melanoma.

Australia has the world's highest incidence of skin cancer. Despite excellent prevention and early diagnosis education programs and an increasing percentage of the population with darker and more UV tolerant skins, skin cancer remains a major and expensive community medical problem. However, primary and secondary prevention programs are now showing positive outcomes, especially in melanoma incidence and survival. Primary and secondary prevention programs are conducted by a variety of non-government organizations such as the Australian Cancer Council, which is comprised of state anticancer groups, with some assistance from State and Federal health agencies. Current and future campaigns are becoming focused on specific community groups, noticeably teenagers and the older population. The role of sunscreens as the primary preventative approach has been superceded by sunlight avoidance campaigns. In light of an increasing rate of early diagnosis, a low and falling morbidity of melanoma, improving general practitioner competence in skin cancer diagnosis and proliferation of skin cancer clinics throughout Australia, it is unlikely a national skin cancer screening program will be implemented. Ozone depletion, a sunlight overloaded environment, increased leisure time and an outdoor lifestyle necessitate continued efforts to minimise the cost and morbidity of skin cancer in Australia.

Prognosis for patients with thin cutaneous melanoma: long-term survival data from New South Wales Central Cancer Registry and the Sydney Melanoma Unit.

BACKGROUND: Estimates of long-term survival for patients with thin (< or = 1 mm) primary cutaneous melanomas vary widely. Two separate methods were used to study the survival of patients with melanoma from New South Wales (NSW), Australia, and from the Sydney Melanoma Unit (SMU). METHODS: The NSW Central Cancer Registry (NSWCCR) provided data on all patients who were diagnosed with cutaneous melanomas that measured < or = 1 mm thick between 1983 and 1998, inclusive. Patients with metastases at the time of diagnosis were not included, leaving 18,088 patients for analysis. The SMU data base was analyzed to extract data for all patients with thin melanomas who met the same criteria from 1979 to 1998, inclusive. All patients who had their primary tumors treated definitively elsewhere were excluded, leaving 2746 patients for analysis. Ten-year Kaplan-Meier survival rates were calculated, and significant differences were determined using log-rank analysis. Prognostic factors were evaluated with Cox proportional hazards analysis. RESULTS: The NSWCCR analysis revealed a 10-year survival rate of 96.4%. The 10-year survival rate for patients at SMU was 92.7%. Among the patients at SMU who died, the median time to recurrence was 49.8 months, and the median time to death was 65.9 months. The 10-year survival for patients at SMU who had lesions that measured < or = 0.75 mm was 96.9% compared with 84.3% for patients who had lesions that measured 0.76-1.0 mm. For patients who had ulcerated melanomas measuring < or = 1 mm thick, the 10-year survival rate was 83%, compared with 92.3% for patients who had nonulcerated melanomas. CONCLUSIONS: The results of the current study confirmed the excellent survival rate for patients with thin melanomas. Higher-risk subsets of patients who may warrant consideration for aggressive investigation and treatment are identifiable.

The prognostic importance of tumor mitotic rate confirmed in 1317 patients with primary cutaneous melanoma and long follow-up.

BACKGROUND: The late Dr. Vincent McGovern (1915 to 1983) was an international authority on melanoma pathology and one of the first to suggest that assessment of tumor mitotic rate (TMR) might provide useful prognostic information. Data for a large cohort of patients, now with extended follow-up, whose tumors had been assessed by Dr. McGovern were analyzed to reassess the independent prognostic value of TMR in primary localized, cutaneous melanoma. METHODS: Information was extracted from the Sydney Melanoma Unit database for 1317 patients treated between 1957 and 1982 for whom there was complete clinical information and whose primary lesion pathology, which included tumor thickness, ulcerative state, and TMR, had been assessed by Dr. McGovern. All these assessments were made according to the recommendations of the Eighth International Pigment Cell Conference, held in Sydney in 1972 under the auspices of the International Union Against Cancer. Factors predicting melanoma-specific survival were analyzed with the Cox proportional hazards regression model. RESULTS: Stage, according to the recently revised American Joint Committee on Cancer Staging System (which is based on tumor thickness and ulceration) was the most predictive factor for survival (P<.0001). This was followed by primary lesion site (P<.0001), patient age (P=.0005), and TMR (P=.008). CONCLUSIONS: TMR was confirmed to be an important independent predictor of survival of patients with primary cutaneous melanoma. However, its predictive value was less than it was when assessed according to the 1982 revisions of the 1972 TMR recommendations.

Correlation between preoperative lymphoscintigraphy and metastatic nodal disease sites in 362 patients with cutaneous melanomas of the head and neck.

OBJECTIVE: Lymphoscintigraphy for head and neck melanomas demonstrates a wide variation in lymphatic drainage pathways, and sentinel nodes (SNs) are reported in sites that are not clinically predicted (discordant). To assess the clinical relevance of these discordant node fields, the lymphoscintigrams of patients with head and neck melanomas were analyzed and correlated with the sites of metastatic nodal disease. METHODS: In 362 patients with head and neck melanomas who underwent lymphoscintigraphy, the locations of the SNs were compared with the locations of the primary tumors. The SNs were removed and examined in 136 patients and an elective or therapeutic regional lymph node dissection was performed in 40 patients. RESULTS: Lymphoscintigraphy identified a total of 918 SNs (mean 2.5 per patient). One or more SNs was located in a discordant site in 114 patients (31.5%). Lymph node metastases developed in 16 patients with nonoperated SNs, all underneath the tattoo spots on the skin used to mark the position of the SNs. In 14 patients SN biopsy revealed metastatic melanoma. After a negative SN biopsy procedure 11 patients developed regional lymph node metastases during follow-up. Elective and therapeutic neck dissections demonstrated 10 patients with nodal metastases, all located in predicted node fields. Of the 51 patients with involved lymph nodes, 7 had positive nodes in discordant sites (13.7%). CONCLUSIONS: Metastases from head and neck melanomas can occur in any SN demonstrated by lymphoscintigraphy. SNs in discordant as well as predicted node fields should be removed and examined to optimize the accuracy of staging.