The role of full-thickness scalp resection for management of primary scalp melanoma.

BACKGROUND: Scalp melanoma is aggressive and has a proclivity for regional metastasis. We hypothesize that subperiosteal scalp melanoma resection reduces in-transit/satellite recurrence, when compared with subgaleal resection. METHODS: We identified patients with intermediate to deep, primary scalp melanoma referred to head/neck surgery over an 8-year period. Patients were compared based on scalp resection depth, including subperiosteal (resection to the level of calvarium) and subgaleal (resection including skin, subcutaneous tissue, and galea). The dependent variables were in-transit/satellite recurrence and time to in-transit/satellite recurrence. RESULTS: Among 48 identified patients, the in-transit/satellite recurrence rate was 16.7%. Subgaleal resection patients had higher in-transit/satellite recurrence rates than subperiosteal resection patients (24.0% vs. 8.7%, P=0.155). Among node-negative patients, subgaleal resection had significantly higher in-transit/satellite metastasis rates when compared with subperiosteal resection (26.3% vs. 0%, P=0.047). CONCLUSION: For node-negative, primary scalp melanoma, subperiosteal resection significantly decreases in-transit/satellite recurrence when compared with subgaleal resection. Given our small sample size, further studies are necessary to confirm these results.

Sentinel lymph node biopsy is accurate and prognostic in head and neck melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) has emerged as a widely used staging procedure for cutaneous melanoma. However, debate remains around the accuracy and prognostic implications of SLNB for cutaneous melanoma arising in the head and neck, as previous reports have demonstrated inferior results to those in nonhead and neck regions. Through the largest single-institution series of head and neck melanoma patients, the authors set out to demonstrate that SLNB accuracy and prognostic value in the head and neck region are comparable to other sites. METHODS: A prospectively collected database was queried for cutaneous head and neck melanoma patients who underwent SLNB at the University of Michigan between 1997 and 2007. Primary endpoints included SLNB result, time to recurrence, site of recurrence, and date and cause of death. Multivariate models were constructed for analyses. RESULTS: Three hundred fifty-three patients were identified. A sentinel lymph node was identified in 352 of 353 patients (99.7%). Sixty-nine of the 353 (19.6%) patients had a positive SLNB. Seventeen of 68 patients (25%) undergoing completion lymphadenectomy after a positive SLNB result had at least 1 additional positive nonsentinel lymph node. Patients with local control and a negative SLNB failed regionally in 4.2% of cases. Multivariate analysis revealed positive SLNB status to be the most prognostic clinicopathologic predictor of poor outcome; hazard ratio was 4.23 for SLNB status and recurrence-free survival (P < .0001) and 3.33 for overall survival (P < .0001). CONCLUSIONS: SLNB is accurate and its results are of prognostic importance for head and neck melanoma patients.

Is a level III dissection necessary for a positive sentinel lymph node in melanoma?

BACKGROUND: For melanoma patients with a positive axillary SLN, the extent of ALND remains controversial, with debate over whether a level III dissection is needed. METHODS: We queried our IRB approved prospective database for patients with a positive axillary SLN who had a level I/II dissection only, and compared recurrence and complication rates to the existing literature. RESULTS: Between 1998 and 2008, 270 patients had 285 level I/II ALNDs for a positive SLN. Median number of SLN removed was 2, while the median number of involved SLN was 1 (range 1-4). An average of 18.7 nodes/ALND were removed, with 13% having positive non-SLN. Post-operative complications occurred in 31 patients (11%), primarily cellulitis (8%). After a mean follow-up of 44 months, 14 patients had a regional recurrence in the axillary basin (5%). CONCLUSIONS: The complication rate and regional recurrence rate for patients undergoing a level I/II ALND for a positive SLN are either lower than or on par with reported series of ALND for level I, II, and III dissections, suggesting that in this setting, the level III dissection may be of minimal benefit.

Features predicting sentinel lymph node positivity in Merkel cell carcinoma.

PURPOSE: Merkel cell carcinoma (MCC) is a relatively rare, potentially aggressive cutaneous malignancy. We examined the clinical and histologic features of primary MCC that may correlate with the probability of a positive sentinel lymph node (SLN). METHODS: Ninety-five patients with MCC who underwent SLN biopsy at the University of Michigan were identified. SLN biopsy was performed on 97 primary tumors, and an SLN was identified in 93 instances. These were reviewed for clinical and histologic features and associated SLN positivity. Univariate associations between these characteristics and a positive SLN were tested for by using either the χ(2) or the Fisher's exact test. A backward elimination algorithm was used to help create a best multiple variable model to explain a positive SLN. RESULTS: SLN positivity was significantly associated with the clinical size of the lesion, greatest horizontal histologic dimension, tumor thickness, mitotic rate, and histologic growth pattern. Two competing multivariate models were generated to predict a positive SLN. The histologic growth pattern was present in both models and combined with either tumor thickness or mitotic rate. CONCLUSION: Increasing clinical size, increasing tumor thickness, increasing mitotic rate, and infiltrative tumor growth pattern were significantly associated with a greater likelihood of a positive SLN. By using the growth pattern and tumor thickness model, no subgroup of patients was predicted to have a lower than 15% to 20% likelihood of a positive SLN. This suggests that all patients presenting with MCC without clinical evidence of regional lymph node disease should be considered for SLN biopsy.

Surgical management of primary disease.

Despite advancements in the treatment of melanoma, surgical management remains the cornerstone for treatment and long-term survival. The authors present their surgical approach to the patient with melanoma including evaluation, treatment, and reconstruction. In addition, management of melanoma occurring in difficult anatomic areas and in special patient populations is reviewed.

Is there a benefit to sentinel lymph node biopsy in patients with T4 melanoma?

BACKGROUND: Controversy exists as to whether patients with thick (Breslow depth>4 mm), clinically lymph node-negative melanoma require sentinel lymph node (SLN) biopsy. The authors examined the impact of SLN biopsy on prognosis and outcome in this patient population. METHODS: A review of the authors' institutional review board-approved melanoma database identified 293 patients with T4 melanoma who underwent surgical excision between 1998 and 2007. Patient demographics, histologic features, and outcome were recorded and analyzed. RESULTS: Of 227 T4 patients who had an SLN biopsy, 107 (47%) were positive. The strongest predictors of a positive SLN included angiolymphatic invasion, satellitosis, or ulceration of the primary tumor. Patients with a T4 melanoma and a negative SLN had a significantly better 5-year distant disease-free survival (DDFS) (85.3% vs 47.8%; P<.0001) and overall survival (OS) (80% vs 47%; P<.0001) compared with those with metastases to the SLN. For SLN-positive patients, only angiolymphatic invasion was a significant predictor of DDFS, with a hazard ratio of 2.29 (P=.007). Ulceration was not significant when examining SLN-positive patients but the most significant factor among SLN-negative patients, with a hazard ratio of 5.78 (P=.02). Increasing Breslow thickness and mitotic rate were also significantly associated with poorer outcome. Patients without ulceration or SLN metastases had an extremely good prognosis, with a 5-year OS>90% and a 5-year DDFS of 95%. CONCLUSIONS: Clinically lymph node-negative T4 melanoma cases should be strongly considered for SLN biopsy, regardless of Breslow depth. SLN lymph node status is the most significant prognostic sign among these patients. T4 patients with a negative SLN have an excellent prognosis in the absence of ulceration and should not be considered candidates for adjuvant high-dose interferon.

Prognostic significance of a positive nonsentinel lymph node in cutaneous melanoma.

PURPOSE: Sentinel lymph node (SLN) biopsy provides important prognostic information for patients with cutaneous melanoma. There may be additional prognostic significance to melanoma spreading from the SLN to nonsentinel lymph nodes (NSLN). We examined the implications of a positive NSLN for overall and distant disease-free survival. METHODS: Using a prospectively maintained, Institutional Review Board-approved melanoma database we studied patients who had a cutaneous melanoma, a positive SLN, and a completion lymph node dissection (CLND). Survival was determined using a combination of hospital records and the Social Security Death Index (SSDI). Univariate and multivariate Cox regression analysis was performed to further characterize predictors of overall and distant disease-free survival. Kaplan-Meier analysis was used to generate survival curves. RESULTS: A total of 429 patients with positive SLN biopsies were identified, with at least one positive NSLN identified in 71 (17%). Median follow-up time was 36.8 months. Presence of a positive NSLN was significantly associated with poor outcome, although long-term survival was possible. Presence of ulceration, high mitotic rate, angiolymphatic invasion, total number of positive nodes, and volume of disease>1% in the SLN were significant predictors of survival on univariate analysis, but lost significance on multivariate. Multivariate Cox analysis revealed several predictors of overall survival: increasing age [hazard ratio (HR) 1.04, P<0.01], Breslow depth (HR 1.76, P<0.01), presence of extracapsular extension in the SLN (HR 2.39, P<0.01), and positive NSLN (HR 1.92, P<0.01). CONCLUSION: Among node-positive melanoma patients, presence of a positive NSLN is a highly significant poor prognostic sign, even after considering the total number of positive nodes and volume of disease in the SLN. CLND after a positive SLN provides this important prognostic information.

Do micromorphometric features of metastatic deposits within sentinel nodes predict nonsentinel lymph node involvement in melanoma?

INTRODUCTION: Multiple attempts have been made to identify melanoma patients with a positive sentinel lymph node (SLN) who are unlikely to harbor residual disease in the nonsentinel lymph nodes (NSLN). We examined whether the size and location of the metastases within the SLN may help further stratify the risk of additional positive NSLN. METHODS: A review of our Institutional Review Board (IRB)-approved melanoma database was undertaken to identify all SLN positive patients with SLN micromorphometric features. Univariate logistic regression techniques were used to assess potential significant associations. Decision tree analysis was used to identify which features best predicted patients at low risk for harboring additional disease. RESULTS: The likelihood of finding additional disease on completion lymph node dissection was significantly associated with primary location on the head and neck or lower extremity (P = 0.01), Breslow thickness >4 mm (P = 0.001), the presence of angiolymphatic invasion (P < 0.0001), satellitosis (P = 0.004), extranodal extension (P = 0.0002), three or more positive SLN (P = 0.02) and tumor burden within the SLN >1% surface area (P = 0.004). Sex, age, mitotic rate, ulceration, Clark level, histologic subtype, regression, and number of SLN removed had no association with finding a positive NSLN. Location of the metastases (capsular, subcapsular or parenchymal) showed no correlation with a positive NSLN. Decision tree analysis incorporating size of the metastatic burden within the SLN along with Breslow thickness can identify melanoma patients with a positive SLN who have a very low risk of harboring additional disease with the NSLN. CONCLUSION: Size of the metastatic burden within the SLN, measured as a percentage of the surface area, helps stratify the risk of harboring residual disease in the nonsentinel lymph nodes (NSLN), and may allow for selective completion lymphadenectomy.

The effects of TeleWound management on use of service and financial outcomes.

This study investigated the effects of a TeleWound program on the use of service and financial outcomes among homebound patients with chronic wounds. The TeleWound program consisted of a Web-based transmission of digital photographs together with a clinical protocol. It enabled homebound patients with chronic pressure ulcers to be monitored remotely by a plastic surgeon. Chronic wounds are highly prevalent among chronically ill patients in the United States (U.S.). About 5 million chronically ill patients in the U.S. have chronic wounds, and the aggregate cost of their care exceeds $20 billion annually. Although 25% of home care referrals in the U.S. are for wounds, less than 0.2% of the registered nurses in the U.S. are wound care certified. This implies that the majority of patients with chronic wounds may not be receiving optimal care in their home environments. We hypothesized that TeleWound management would reduce visits to the emergency department (ED), hospitalization, length of stay, and visit acuity. Hence, it would improve financial performance for the hospital. A quasi-experimental design was used. A sample of 19 patients receiving this intervention was observed prospectively for 2 years. This was matched to a historical control group of an additional 19 patients from hospital records. Findings from the study revealed that TeleWound patients had fewer ED visits, fewer hospitalizations, and shorter length of stay, as compared to the control group. Overall, they encumbered lower cost. The results of this clinical study are striking and provide strong encouragement that a single provider can affect positive clinical and financial outcomes using a telemedicine wound care program. TeleWound was found to be a credible modality to manage pressure ulcers at lower cost and possibly better health outcomes. The next step in this process is to integrate the model into daily practice at bellwether medical centers to determine programmatic effectiveness in larger clinical arenas.

The impact of factors beyond Breslow depth on predicting sentinel lymph node positivity in melanoma.

BACKGROUND: In addition to Breslow depth, the authors previously described how increasing mitotic rate and decreasing age predicted sentinel lymph node (SLN) metastases in patients with melanoma. The objectives of the current study were to verify those previous results and to create a prediction model for the better selection of which patients with melanoma should undergo SLN biopsy. METHODS: The authors reviewed 1130 consecutive patients with melanoma in a prospective database who underwent successful SLN biopsy. After eliminating patients aged <16 years and patients who had melanomas that measured <1 mm, 910 remaining patients were reviewed for clinical and pathologic features and positive SLN status. Univariate association of patient and tumor characteristics with positive SLN status was explored by using standard logistic regression techniques, and the best multivariate model that predicted lymph node metastases was constructed by using a backward stepwise-elimination technique. RESULTS: The characteristics that were associated significantly with lymph node metastasis were angiolymphatic invasion, the absence of regression, increasing mitotic rate, satellitosis, ulceration, increasing Breslow depth, decreasing age, and location (trunk or lower extremity compared with upper extremity or head/neck). Previously reported interactions between mitotic rate and age and between Breslow depth and age were confirmed. The best multivariate model included patient age (linear), angiolymphatic invasion, the number of mitoses (linear), the interaction between patient age and the number of mitoses, Breslow depth (linear), the interaction between patient age and Breslow depth, and primary tumor location. CONCLUSIONS: Younger age, increasing mitotic rate (especially in younger patients), increasing Breslow depth (especially in older patients), angiolymphatic invasion, and trunk or lower extremity location of the primary tumor were associated with a greater likelihood of positive SLN status. The current results support the use of factors beyond Breslow depth to determine the risk of positive SLN status in patients with cutaneous melanoma.

Predictors of nonsentinel lymph node positivity in patients with a positive sentinel node for melanoma.

BACKGROUND: Patients found to harbor melanoma micrometastases in the sentinel lymph node (SLN) are recommended to proceed to complete lymph node dissection (CLND), although the majority of patients will have no additional disease identified in the nonsentinel lymph nodes (NSLNs). We sought to assess predictive factors associated with finding positive NSLNs, and identify a subset of patients with low likelihood of finding additional disease on CLND. STUDY DESIGN: We queried our prospective melanoma database for patients from January 1996 to August 2003 with a positive SLN. Univariable logistic regression models were fit for multiple factors and a positive NSLN. To derive a probabilistic model for occurrence of one or more positive NSLN(s), a multivariable logistic model was fit using a stepwise variable selection method. RESULTS: Of 980 patients who underwent SLN biopsy for cutaneous melanoma, 232 (24%) had a positive SLN; 221 (23%) followed by CLND. Of these patients, 34 (15%) had one or more positive NSLN(s). In multivariable analysis, male gender (odds ratio [OR] 3.6 [95% CI 1.33, 9.71]; p = 0.01), Breslow thickness (OR 4.58 [95% CI 1.28, 16.36]; p = 0.019), extranodal extension (OR 3.2 [95% CI 1.0, 10.5]; p = 0.05), and three or more positive sentinel nodes (OR 65.81 [95% CI 5.2, 825.7]; p = 0.001) were all associated with the likelihood of finding additional positive nodes on CLND. Of 47 patients with minimal tumor burden in the SLN, only 1 (2%) had additional disease in the NSLN. CONCLUSIONS: These results provide additional data to plan clinical trials to answer the question of who can safely avoid CLND after a positive SLN. Patients with minimal tumor burden in the SLN might be the most likely group, although defining "minimal tumor burden" must be standardized. Serial sectioning and immunohistochemistry on the NSLN in any "low-risk" group must be performed in a clinical trial to confirm that residual disease is unlikely before avoiding CLND can be recommended.

The use of a bovine collagen construct for reconstruction of full-thickness scalp defects in the elderly patient with cutaneous malignancy.

Full-thickness defects of the scalp following cancer resection are reconstructive challenges when bone is exposed. Local, regional, and/or free tissue transfer have all been described for reconstruction when the pericranium is exposed. We examined the surgical outcomes from 23 patients who underwent placement of bovine collagen constructs. Thereafter, delayed skin grafting was performed. The average age of the patients was 70 years. All patients had one of the following: melanoma (n = 13) squamous cell carcinoma (n = 5), angiosarcoma (n = 2), basal cell carcinoma (n = 1), spindle cell carcinoma (n = 1), or malignant pilar tumor (n = 1). The average defect size was 51 cm, with a range of 9 cm to 169 cm. Average time between bovine construct placement and skin grafting was 30 days. Histologic studies demonstrated persistence of the construct and infiltration of nascent fibroblasts. Six patients had delayed healing due to microabscesses in the constructs. All wounds eventually healed. In the elderly, this is a simple method to treat full-thickness scalp defects.

Reliability of sentinel lymph node mapping with biopsy for head and neck cutaneous melanoma.

OBJECTIVES: To determine (1) the reliability of sentinel lymph node mapping with biopsy (SLNB) in head and neck cutaneous melanoma to accurately stage nodal basins and (2) the safety of SLNB in both the neck and parotid regions. DESIGN: Retrospective cohort study with a median follow-up of 25 months. All patients had a minimum follow-up of 1 year. SETTING: Academic medical center. PATIENTS: Eighty evaluable patients diagnosed as having head and neck cutaneous melanoma and staged using SLNB. INTERVENTIONS: Sentinel lymph nodes were identified using preoperative lymphoscintigraphy and a combination of intraoperative gamma probe and isosulfan blue dye. Patients with a SLN positive for melanoma underwent therapeutic lymphadenectomy followed by an evaluation for adjuvant therapies. Patients with a negative SLNB result were followed up clinically. MAIN OUTCOME MEASURES: Percentage of positive SLNs, regional recurrence in the setting of a negative SLNB result (false-negative rate), and procedure complications. RESULTS: The mean Breslow depth was 2.35 mm. A SLN was identified in 77 (96.3%) of cases, with an average of 2.18 nodes per patient. Of the sentinel nodes identified, 74% were from the neck region. The remaining 26% were from the parotid basin. No facial nerve complications occurred. Of the patients, 14 (18%) were SLN positive for metastatic melanoma. The regional failure rate in the setting of a negative SLNB result was 4.5%. CONCLUSIONS: Sentinel lymph node mapping with biopsy is a reliable technique to diagnose regional spread from head and neck cutaneous melanoma. This procedure can be performed in both neck and parotid nodal basins with safety and accuracy similar to non-head and neck sites.

Role of glutathione redox dysfunction in diabetic wounds.

We propose that diabetic foot ulcers and diabetic mouse wounds have insufficient glutathione to maintain correct cellular redox potential. Therefore, tissue samples from the wound edge of diabetic foot ulcers, diabetic mice wounds and nondiabetic mice wounds were obtained. Levels of glutathione, cysteine, and mixed protein disulfide were determined and topical application of esterified glutathione in carboxymethylcellulose or carboxymethylcellulose alone was applied to the mice wounds. Diabetic foot ulcer mean glutathione levels were 150.6 pmol/mg in the controls and 53.4 pmol/mg at the wound edge (p < 0.05), while mean cysteine levels were 22.3 pmol/mg in the control and 10.5 pmol/mg at the wound edge (p < 0.05). The mixed protein disulfide levels were elevated in the wounds (14.6 pmol/mg), but not in the control (6.9 pmol/mg) (p < 0.05). The glutathione levels were lower in the diabetic mouse wounds (155 pmol/mg) than the nondiabetic mouse wounds (205 pmol/mg) (p=0.04). The diabetic mouse treated with carboxymethylcellulose alone healed slower (19.5 +/- 2.2 days) than the nondiabetic mouse DM (11.5 +/- 0.5 days) (p < 0.001). The diabetic mouse that received topical glutathione healed significantly faster (12.5 +/- 0.8 days) than the carboxymethylcellulose-treated mice (19.5 +/- 2.2 days) (p < 0.001). Glutathione levels in the diabetic mouse (26.0 pmol/mg) were lower than in the nondiabetic mouse (311.7 pmol/mg) (p < 0.05) after glutathione treatment. In the glutathione-treated diabetic mouse, the oxidized glutathione was higher (26.7%) than in the nondiabetic mouse (9.9%) (p=0.05). These data suggest that cellular redox dysfunction and lower glutathione levels are present in diabetic foot ulcers and diabetic mouse wounds.

MAP kinase pathways involving hsp27 regulate fibroblast-mediated wound contraction.

BACKGROUND: Heat shock protein 27 (hsp27) has been shown to modulate actin arrays in a manner dependent on its phosphorylation status. Hsp27 is phosphorylated by mitogen-activated protein kinase-activated protein kinase 2/3, which is regulated by mitogen-activated protein (MAP) kinases. We hypothesize that hsp27 phosphorylation modulates wound contraction. MATERIALS AND METHODS: In these studies, a specific p38 MAP kinase inhibitor, SB203580, and a specific MAPK/extracellular signal-regulated kinase kinase 1,2 inhibitor, PD98059, were used to inhibit kinase activity. The effect of MAP kinase inhibitors was tested using a tissue culture model, the fibroblast-populated collagen lattice (FPCL) contraction assay, and a rat full-thickness skin defect model of wound healing. Hsp27 phosphorylation status was determined by isoelectric focus and Western blot analysis. RESULTS: We show here that hsp27 phosphorylation correlates with FPCL contraction and with contraction in vivo. In the tissue culture model, each inhibitor reduced FPCL contraction and hsp27 phosphorylation. Hsp27 phosphorylation correlated with both p38 and ERK1, 2 activation. Hsp27 was highly phosphorylated in the wound edge during wound healing in a rat in vivo model. The phosphorylation status was highest in the granulation tissue. Treatment with both kinase inhibitors significantly delayed wound contraction in vivo, which correlated with inhibition of hsp27 phosphorylation. CONCLUSIONS: This study demonstrates that ERK and p38 kinase cascades play important roles in wound contraction. Additionally, these data implicate hsp27 as being a key molecule in modulating the effects of these kinases.