Kerwin Shannon

Determinants of Outcome in Melanoma Patients With Cerebral Metastases

PURPOSE To analyze prognostic factors, effects of treatment, and survival for patients with cerebral metastases from melanoma. PATIENTS AND METHODS All melanoma patients with cerebral metastases treated at the Sydney Melanoma Unit between 1952 and 2000 were identified. From 1985 to 2000, patients were diagnosed and treated using consistent modern techniques and this cohort was analyzed in detail. Multivariate analysis of prognostic factors for survival was performed. RESULTS A total of 1137 patients with cerebral metastases were identified; 686 were treated between 1985 and 2000. For these 686 patients, the median time from primary diagnosis to cerebral metastasis was 3.1 years (range, 0 to 41 years). A total of 646 patients (94%) have died as a result of melanoma. The median survival from the time of diagnosis of cerebral metastasis was 4.1 months (range, 0 to 17.2 years). Treatment was as follows: surgery and postoperative radiotherapy, 158 patients; surgery alone, 47 patients; radiotherapy alone, 236 patients; and supportive care alone, 210 patients. Median survival according to treatment received for these four groups was 8.9, 8.7, 3.4, and 2.1 months, respectively; the differences between surgery and nonsurgery groups were statistically significant. On multivariate analysis, significant factors associated with improved survival were surgical treatment (P <.0001), no concurrent extracerebral metastases (P <.0001), younger age (P =.0007), and longer disease-free interval (P =.036). Prognostic factors analysis confirmed the important influence of patient selection on treatment received. CONCLUSION This large series documents the characteristics of patients who developed cerebral metastases from melanoma. Median survival was dependent on treatment, which in turn was dependent on patient selection.

Experience with 998 cutaneous melanomas of the head and neck over 30 years

Between 1960 and 1990, a total of 998 patients were treated at the Sydney Melanoma Unit for cutaneous melanoma of the head and neck. There were 595 male and 403 female patients, with a median age of 53 years. The most common primary lesion site was the face (47%), followed by the neck (29%), scalp (14%), and ear (10%). Histologic types were as follows: superficial spreading 30%, nodular melanoma 28%, lentigo maligna melanoma 16%, and other 26%. All patients underwent surgical treatment. Primary closure of wounds was achieved in 52% of patients, and excision margins were 2 cm or less in 45%. A total of 152 patients had therapeutic neck dissections, and 234 had elective neck dissections. The overall local recurrence rate was 13%, and this was significantly influenced by increasing tumor thickness and Clark level. The recurrence rate in the neck after neck dissection was 24%, and the rate of parotid recurrences was 14%. Melanoma-specific survival was 77% at 5 years and 66% at 10 years for the entire group. By univariate analysis, survival varied significantly with age, tumor thickness, ulceration, anatomic sub-site, histologically positive nodes, and the presence of distant metastases. A diagnosis of lentigo maligna melanoma and elective lymph node dissection both appeared to improve survival. With multivariate analysis, all of these factors remained significant prognostic factors except elective node dissection, which lost its beneficial influence.

Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial

BACKGROUND The use of radiotherapy after therapeutic lymphadenectomy for patients with melanoma at high risk of further lymph-node field and distant recurrence is controversial. Decisions for radiotherapy in this setting are made on the basis of retrospective, non-randomised studies. We did this randomised trial to assess the effect of adjuvant radiotherapy on lymph-node field control in patients who had undergone therapeutic lymphadenectomy for metastatic melanoma in regional lymph nodes. METHODS This randomised controlled trial included patients from 16 hospitals in Australia, New Zealand, the Netherlands, and Brazil. To be eligible for this trial, patients had to be at high risk of lymph-node field relapse, judged on the basis of number of nodes involved, extranodal spread, and maximum size of involved nodes. After lymphadenectomy, randomisation was done centrally by computer and patients assigned by telephone in a ratio of 1:1 to receive adjuvant radiotherapy of 48 Gy in 20 fractions or observation, with institution, lymph-node field, number of involved nodes, maximum node diameter, and extent of extranodal spread as minimisation factors. Participants, those giving treatment, and those assessing outcomes were not masked to treatment allocation. The primary endpoint was lymph-node field relapse (as a first relapse), analysed for all eligible patients. The study is registered at ClinicalTrials.gov, number NCT00287196. The trial is now closed and follow-up discontinued. FINDINGS 123 patients were randomly allocated to the adjuvant radiotherapy group and 127 to the observation group between March 20, 2002, and Sept 21, 2007. Two patients withdrew consent and 31 had a major eligibility infringement as decided by the independent data monitoring committee, resulting in 217 eligible for the primary analysis (109 in the adjuvant radiotherapy group and 108 in the observation group). Median follow-up was 40 months (IQR 27-55). Risk of lymph-node field relapse was significantly reduced in the adjuvant radiotherapy group compared with the observation group (20 relapses in the radiotherapy group vs 34 in the observation group, hazard ratio [HR] 0·56, 95% CI 0·32-0·98; p=0·041), but no differences were noted for relapse-free survival (70 vs 73 events, HR 0·91, 95% CI 0·65-1·26; p=0·56) or overall survival (59 vs 47 deaths, HR 1·37, 95% CI 0·94-2·01; p=0·12). The most common grade 3 and 4 adverse events were seroma (nine in the radiotherapy group vs 11 in the observation group), radiation dermatitis (19 in the radiotherapy group), and wound infection (three in the radiotherapy group vs seven in the observation group). INTERPRETATION Adjuvant radiotherapy improves lymph-node field control in patients at high risk of lymph-node field relapse after therapeutic lymphadenectomy for metastatic melanoma. Adjuvant radiotherapy should be discussed with patients at high risk of relapse after lymphadenectomy. FUNDING National Health and Medical Research Council of Australia, Cancer Australia, Melanoma Institute Australia, Cancer Council of South Australia.

Outcome in 846 Cutaneous Melanoma Patients From a Single Center After a Negative Sentinel Node Biopsy

BackgroundA 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.MethodsSurvival 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.ResultsThe 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.ConclusionsThis 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.

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.

Implications for Clinical Staging of Metastatic Cutaneous Squamous Carcinoma of the Head and Neck Based on a Multicenter Study of Treatment Outcomes

Cutaneous squamous cell carcinoma (SCC) of the head and neck is a common cancer that has the potential to metastasize to lymph nodes in the parotid gland and neck. Previous studies have highlighted limitations with the current TNM staging system for metastatic skin carcinoma. The aim of this study was to test a new staging system that may provide better discrimination between patient groups.

Alterations in miRNA processing and expression in pleomorphic adenomas of the salivary gland

Genome‐wide microRNA (miRNA) expression profiling of salivary gland pleomorphic adenomas revealed a distinct expression signature consisting largely of upregulated miRNAs compared with matched normal tissue. Microarray data were confirmed by quantitative real time RT‐PCR (q‐RTPCR). Five miRNA genes upregulated in the tumours were found in close proximity to fragile sites and/or cancer associated genomic regions. Interestingly, q‐RTPCR revealed an increase in the expression of components of the miRNA processing machinery (Dicer, Drosha, DGCR8 and p68) in tumours suggesting that the deregulation of miRNA expression may result from increased miRNA biogenesis. Target gene prediction analysis of the altered miRNAs indicated that genes in a number of signalling pathways important in tumourigenesis including WNT, MAPK and JAK‐STAT were overrepresented. Significantly, the oncogene PLAG1 was overexpressed in our cohort and may be potentially regulated by these miRNAs. This is the first study to examine changes in the miRNA milieu in pleomorphic adenoma, the most common salivary gland tumour. This study has demonstrated an upregulation of both miRNAs genes and an upregulation of the miRNA processing machinery. These changes may be potential underlying mechanisms for the development of these benign tumours.

Sentinel lymph node biopsy in patients with thin primary cutaneous melanoma.

ObjectivesTo determine the rate and clinicopathologic factors predictive of sentinel lymph node (SLN) positivity, regional lymph node recurrence, and survival in a large series of patients with thin primary cutaneous melanoma who underwent SLN biopsy (SLNB). Methods:Patients with thin (⩽1 mm) melanomas who underwent SLNB between 1992 and 2009 at Melanoma Institute Australia were identified from the Melanoma Institute Australia database. The association of clinicopathologic features with SLN status, lymph node recurrence, and survival was analyzed. Results:In 432 patients [226 men, 206 women; median age 49.5 years (range: 14.4–85.0 years)], SLNB was positive for metastatic melanoma in 29 (6.7%) patients. No SLN positivity was detected in 37 patients with primary tumor thickness 0.50 mm or less. Breslow thickness (P = 0.012) and presence of lymphovascular invasion (P = 0.018) were the only factors significantly associated with SLN positivity. Regional lymph node recurrence was significantly more common in tumors located in the head/neck region (4/33, 12%) than in extremities (3/245, 1.2%) and trunk (2/154, 1.3%) (P < 0.001). Primary tumor mitotic rate was a significant predictor of melanoma-specific survival (Hazard Ratio [HR] = 1.2, 95% confidence interval: 1.09–1.35, P < 0.001). Conclusions:There is a low but significant rate of SLN positivity in patients with primary melanomas 0.51 to 1.0 mm in thickness. Given its prognostic importance, SLNB should be considered in such patients, particularly if there is lymphatic permeation by melanoma at the primary tumor site. More frequent regional node field recurrences in patients with head/neck primary tumors may be a consequence of complex lymphatic drainage patterns in this region.

Lymph node ratio as an independent prognostic factor in oral squamous cell carcinoma

We aimed to validate the lymph node ratio (LNR) as an independent prognostic factor in oral squamous cell carcinoma (OSCC) and compare its utility with the current nodal staging system.

Outcomes of primary surgical treatment of T1 and T2 carcinomas of the oropharynx

Oropharyngeal cancers represent 10%–15% of all head and neck cancers. At presentation 60%–70% will have advanced‐stage disease with a high incidence of neck metastases. Primary treatment employing radiotherapy, with or without chemotherapy, is widely prescribed. The aim of this study is to analyze the outcome of definitive surgical management of T1–T2 cancers of the oropharynx.