Jonathan R. Stretch

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.

Micromorphometric features of positive sentinel lymph nodes predict involvement of nonsentinel nodes in patients with melanoma.

The aim of the present study was to determine whether micromorphometric features of positive sentinel lymph nodes (SLNs) from patients with melanoma are useful for predicting further nodal involvement in completion lymph node dissection (CLND) specimens. Of 986 patients with melanoma undergoing SLN biopsy between March 1992 and February 2001, 175 (17.7%) had at least 1 positive SLN and 140 had subsequent CLND specimens available for review. Further nodal involvement in CLND specimens was present in 24 (17.1%) of 140 patients. Of 8 micromorphometric features of the SLNs that were assessed, the presence of metastases in CLND specimens was correlated significantly with a tumor penetrative depth (maximum distance of melanoma cells from the inner margin of the SLN capsule) of more than 2 mm (P < .05), a deposit size of more than 10 mm2 (P < .01), the presence of melanoma cells in perinodal lymphatic vessels (P < .01), and the effacement of nodal architecture by metastatic melanoma cells (P < .05). Our results indicate that some morphologic features of melanoma metastases in SLNs predict the likelihood of further nodal involvement in CLND specimens.

Sentinel Lymph Node Biopsy in Histologically Ambiguous Melanocytic Tumors With Spitzoid Features (So-Called Atypical Spitzoid Tumors)

BackgroundThe distinction of Spitz nevi from melanomas with spitzoid morphology can be difficult. For lesions with overlapping histopathologic features, it may be impossible to predict their malignant potential with certainty. The current study evaluated the role of sentinel lymph node (SLN) biopsy in patients with such atypical spitzoid tumors.MethodsThe clinical and histopathologic features of 21 patients with atypical spitzoid tumors who underwent SLN biopsy were reviewed and correlated with the presence or absence of metastatic tumor in their corresponding SLNs.ResultsThe atypical histopathologic features that were most frequently present included incomplete maturation (11 patients, 52%), two or more dermal mitoses per square millimeter (13 patients, 62%), and deep dermal mitoses (11 patients, 52%). Six patients (29%) showed SLN metastasis. There were histopathologic differences between tumors with positive SLN when compared with tumors with negative SLN: mean tumor thickness (3.38 mm vs. 2.04 mm), incomplete maturation (83% vs. 40%), median dermal mitotic rate (3.5/mm2 vs. 2/mm2), deep dermal mitoses (83% vs. 47%), and expansile dermal nodules (50% vs. 13%). However, of these, only the difference in mean tumor thickness reached statistical significance (P < .05).ConclusionsSLN biopsy offers a means of assessing the metastatic potential of atypical spitzoid tumors and aids in the management of these patients by selecting patients who may benefit from a regional node field dissection and those in whom the use of adjuvant therapies could be considered.

Whole-genome landscapes of major melanoma subtypes

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.

Subungual Melanoma: A Study of 124 Cases Highlighting Features of Early Lesions, Potential Pitfalls in Diagnosis, and Guidelines for Histologic Reporting

Subungual melanoma (SUM) is an uncommon variant of melanoma that is often difficult to diagnose, both clinically and pathologically. In an attempt to provide pathologic clues to diagnosis, especially in early lesions or small biopsies, and to provide practical advice to pathologists in reporting, the clinicopathologic features of 124 cases of SUM were reviewed, the largest series reported to date. The features of 28 cases of subungual melanoma in situ (MIS), comprising 4 cases of MIS and 24 cases where areas of MIS were present adjacent to dermal-invasive SUMs, were compared with those of a similar number of acral nevi to identify useful distinguishing features. The median age of the patients was 59 years and the most common site was the great toe (24%). Nine percent of cases were AJCC stage 0, 14% were stage I, 41% were stage II, 32% were stage III, and 4% were stage IV at initial diagnosis. The commonest histogenetic subtype was acral lentiginous (66%), followed by nodular (25%) and desmoplastic (7%). The majority of tumors were locally advanced at presentation with 79% being Clark level IV or V. The median Breslow thickness was 3.2 mm. The median mitotic rate was 3 per mm2 and 33% of cases demonstrated primary tumor ulceration. Seven of 29 patients (24%) who underwent a sentinel lymph node biopsy had nodal disease. Multivariate Cox-regression analysis showed higher disease stage to be the only significant predictor of shortened survival. In comparison to acral nevi, MIS more frequently showed lack of circumscription, a prominent lentiginous growth pattern, predominance of single cells over nests, moderate-to-severe cytologic atypia, a dense and haphazard pagetoid intraepidermal spread of melanocytes, and the presence of junctional/subjunctional lymphocytes (“tumor infiltrating lymphocytes”). Tumor infiltrating lymphocytes have not been highlighted previously as a feature of subungual MIS and represent a useful diagnostic clue. Guidelines for the reporting of SUMs are also presented. Knowledge and recognition of the pathologic features of SUMs and the important features that distinguish them from nevi should reduce the frequency of misdiagnosis.

Prognostic factors in cutaneous desmoplastic melanoma: a study of 252 patients.

Desmoplastic melanoma (DM) is a rare subtype of melanoma that is characterized by malignant spindle cells separated by prominent, fibrocollagenous stroma. Primary melanomas either may be entirely desmoplastic or almost entirely desmoplastic (pure DM [pDM]) or may exhibit a desmoplastic component admixed with a nondesmoplastic component (combined DM [cDM]).

A Sentinel Node Biopsy Does Not Increase the Incidence of In-Transit Metastasis in Patients With Primary Cutaneous Melanoma

BackgroundIt has been suggested that performing a sentinel node biopsy (SNB) in patients with cutaneous melanoma increases the incidence of in-transit metastasis (ITM).MethodsITM rates for 2018 patients with primary melanomas ≥1.0 mm thick treated at a single institution between 1991 and 2000 according to 3 protocols were compared: wide local excision (WLE) only (n = 1035), WLE plus SNB (n = 754), and WLE plus elective lymph node dissection (n = 229).ResultsThe incidence of ITM for the three protocols was 4.9%, 3.6%, and 5.7%, respectively (not significant), and as a first site of recurrent disease the incidence was 2.5%, 2.4%, and 4.4%, respectively (not significant). The subset of patients who were node positive after SNB and after elective lymph node dissection also had similar ITM rates (10.8% and 7.1%, respectively; P = .11). On multivariate analysis, primary tumor thickness and patient age predicted ITM as a first recurrence, but type of treatment did not. Patients who underwent WLE only and who had a subsequent therapeutic lymph node dissection (n = 149) had an ITM rate of 24.2%, compared with 10.8% in patients with a tumor-positive sentinel node treated with immediate dissection (n = 102; P = .03).ConclusionsPerforming an SNB in patients with melanoma treated by WLE does not increase the incidence of ITM.

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.

Improving Management and Patient Care in Lentigo Maligna by Mapping With In Vivo Confocal Microscopy

IMPORTANCE Lentigo maligna (LM) is a clinical, pathologic, and therapeutic challenge with a higher risk of local recurrence than other types of melanoma correctly treated and also carries the cosmetically sensitive localization of head and neck. OBJECTIVE To determine whether in vivo reflectance confocal microscopy (RCM) mapping of difficult LM cases might alter patient care and management. DESIGN Analysis of LM and LM melanoma (LMM) in a series of patients with large facial lesions requiring complex reconstructive surgery and/or recurrent or poorly delineated lesions at any body sites were investigated. SETTINGS Two tertiary referral melanoma centers in Sydney, Australia. PARTICIPANTS Thirty-seven patients with LM (including 5 with LMM) were mapped with RCM. Fifteen patients had a recurrent LM, including 9 with multiple prior recurrences. The LM was classified amelanotic in 10 patients, lightly pigmented in 9, and partially pigmented in 18. INTERVENTIONS The RCM images were obtained in 4 radial directions (allowing for anatomic barriers) for LM margin delineation using an RCM LM score previously described by our research team. MAIN OUTCOME MEASURES Differences in the margin of LM as determined by RCM vs dermoscopy vs histopathologic analysis. RESULTS Seventeen of 29 patients (59%) with dermoscopically visible lesions had subclinical (RCM-identified) disease evident more than 5 mm beyond the dermoscopy margin (ie, beyond the excision margin recommended in published guidelines). The RCM mapping changed the management in 27 patients (73%): 11 patients had a major change in their surgical procedure, and 16 were offered radiotherapy or imiquimod treatment as a consequence of the RCM findings. Treatment was surgical in 17 of 37 patients. Surgical excision margins (based on the RCM mapping) were histopathologically involved in only 2 patients, each of whom had an LM lesion larger than 6 cm. CONCLUSIONS AND RELEVANCE In vivo RCM can provide valuable information facilitating optimal patient care management.

Diagnosis of metastatic melanoma by fine-needle biopsy : Analysis of 2,204 cases

Fine-needle biopsy (FNB) has been reported as a rapid, minimally invasive technique for the diagnosis of metastatic melanoma. The diagnostic accuracy of FNB was assessed in a consecutive series of 2,204 FNBs of clinically suspicious lesions from patients with previous primary melanomas treated at the Sydney Melanoma Unit, Sydney, Australia, between January 1992 and December 2002. The sensitivity and specificity of FNB were 96.3% and 98.9%, respectively. There were 5 false-positive cases (0.6%), which were verified as metastatic adenocarcinoma (3 cases) or reactive processes (organizing hematoma and chronic osteomyelitis, 1 each). False-negative diagnoses (6.7% of cases) were associated with a variety of clinicopathologic factors, including difficult-to-access anatomic sites (eg, high axilla or deep inguinal), small lesions, and lesional characteristics such asfibrosis, necrosis, or cystic change. FNB is a highly accurate, rapid, and cost-effective procedure for the diagnosis of metastatic melanoma and should be considered as the initial diagnostic procedure of choice in patients with melanoma with clinically suspected metastases.