Kerry A. Crotty

The Impact of In Vivo Reflectance Confocal Microscopy on the Diagnostic Accuracy of Lentigo Maligna and Equivocal Pigmented and Nonpigmented Macules of the Face.

Limited studies have reported the in vivo reflectance confocal microscopy (RCM) features of lentigo maligna (LM). A total of 64 RCM features were scored retrospectively and blinded to diagnosis in a consecutive series of RCM sampled, clinically equivocal, macules of the face (n=81 LM, n=203 benign macules (BMs)). In addition to describing RCM diagnostic features for LM (univariate), an algorithm was developed (LM score) to distinguish LM from BM. This comprised two major features each scoring +2 points (nonedged papillae and round large pagetoid cells > 20 microm), and four minor features; three scored +1 point each (three or more atypical cells at the dermoepidermal junction in five 0.5 x 0.5 mm(2) fields, follicular localization of atypical cells, and nucleated cells within the dermal papillae), and one (negative) feature scored -1 point (a broadened honeycomb pattern). A LM score of > or = 2 resulted in a sensitivity of 85% and specificity of 76% for the diagnosis of LM (odds ratio (OR) for LM 18.6; 95% confidence interval: 9.3-37.1). The algorithm was equally effective in the diagnosis of amelanotic lesions and showed good interobserver reproducibility (87%). In a test set of 29 LMs and 44 BMs, the OR for LM was 60.7 (confidence interval: 11.9-309) (93% sensitivity, 82% specificity).

A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions

Differentiation between malignant melanomas and benign nevi can sometimes be difficult by conventional histopathology, and additional diagnostic markers may be helpful. This study investigated the immunoreactivity of the cell proliferation marker MIB1-Ki67 in 23 compound nevi, 17 dysplastic nevi, 8 Spitz nevi (SN), and 24 malignant melanomas (MMs) and evaluated its ability in separating benign nevi from MMs. In each lesion, the average number (percentage) of MIB1-positive nuclei (%MIB1-Mean) and the maximal number (percentage) of MIB1-positive nuclei (%MIB1-Max) were determined from each of the superficial, middle, and deep dermal zones of the lesion as well as from the entire lesion. The %MIB1-Max was determined from subjectively selected area(s) of high count. Malignant melanomas had a significantly greater %MIB1-Mean and %MIB1-Max than all benign nevi in all individual zones and in the entire lesion (p < 0.05). Discriminant analysis showed that the %MIB1-Mean and %MIB1-Max counted from the whole lesions had better discriminating abilities than from the individual zones. By using the %MIB1-Mean from all zones, all lesions except 1 SN and 3 MMs could be correctly classified as benign or malignant. When using the %MIB1-Max from all zones, all but 2 SN could be correctly separated as benign or malignant. Thus, MIB1-Ki67 immunoreactivity closely correlates with the benignancy or malignancy of melanocytic lesions and may assist in the differentiation of benign nevi from MMs.

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.

Spitz naevus versus spitzoid melanoma: when and how can they be distinguished?

Summary Spitz naevus is a benign melanocytic lesion that shares many histological features with melanoma. While Spitz naevi characteristically occur in children and young adults and melanomas in the middle‐aged and elderly, either tumour can occur in patients of any age. In many cases, the histopathological diagnosis of Spitz naevus is straightforward, particularly in small lesions displaying many or all of the typical histological features and occurring in young patients. Tumours that deviate from the classic description, however, cause difficulties in diagnosis. In this review, we highlight histopathological features of Spitz naevi and those that may be useful in distinguishing Spitz naevi from melanomas. We find that the presence of good symmetry, Kamino bodies, and uniformity of cell nests or sheets from side‐to‐side favours a Spitz naevus. The presence of abnormal mitoses, a dermal mitotic rate of > 2/mm 2, and mitotic figures within 0.25 mm of the deep border of the lesion favours a melanoma. Immunohistochemical stains for HMB45 and Ki67 sometimes provide additional useful information. Despite this, in some cases it may not be possible to give an unequivocal diagnosis. Recommendations for the reporting of such cases are provided. New techniques have also demonstrated chromosomal, molecular and genetic differences between Spitz naevi and melanomas. This report highlights these new data and speculates on their possible future role in the diagnosis of borderline lesions.

Subungual melanoma of the hand

Subungual melanoma is a rare but well-recognized tumor of the hand. Its management is ill defined and the factors influencing prognosis have not been well described. The clinicopathologic features of a series of 38 patients with subungual melanoma of the hand are reported. The median thickness was 3 mm, and only seven patients presented with pathologic stage I disease (American Joint Committee on Cancer [AJCC] system). Ulceration and lack of pigmentation were the only significant univariate prognostic indicators. There was no significant difference in local recurrence rates among patients whose amputation was carried out proximal or distal to the interphalangeal joint of the thumb or the middle of the middle phalanx in the other fingers. Management of the regional lymph node field based on the use of selective lymphadenectomy is described.

Primary melanoma tumour regression associated with an immune response to the tumour-associated antigen melan-A/MART-1

A prediction of the theory of immunologic surveillance is that tumour antigens can be recognised by cell‐mediated immunity during early development of the primary tumour by formation of tumour antigen‐specific cytotoxic lymphocytes (CTLs) and that such recognition leads to destruction of those tumour cells (tumour regression) with subsequent appearance of tumour antigen‐loss variants. However, this has never been shown in nonviral‐induced experimental animal models of primary malignancy or in human primary cancer. We examined 2 groups of human melanoma patients where primary tumour regression was observed. Twenty‐three patients with multiple (≥3) primary melanoma showed significant histologic regression of their last tumour (median tumour regression 33%) compared to matched tumours from patients with a single primary melanoma (median 0%) (p = 0.008) or compared to their first primary tumour (median 0%) (p = 0.001). This increased regression is consistent with an “immunisation effect” seen in murine tumour transplantation studies where innoculation with ≥3 asynchronous tumours induces transplantation rejection on subsequent challenge. A significant decrease in MART‐1‐positive stained tumour area in the last primary tumour from multiple melanoma subjects (median 8%) vs. matched single melanoma patients (median 79%) (p = 0.004) and in the last vs. first tumour (median 76%) in multiple primary subjects was found (p = 0.008). Metastatic tumours from 17 patients whose primary skin melanomas had completely regressed (occult primary melanoma) also showed significant MART‐1 tumour‐loss variants (median 0% MART‐1‐positive tumour) compared to matched metastatic tumours from patients with nonregressing primary tumours (median 51%) (p = 0.001). A correlation with the presence of peripheral blood MART‐1‐specific CTLs (MHC class I‐restricted IFN‐γ producing T lymphocytes) and MART‐1 tumour antigen‐loss variants was found (p = 0.001). Thus, in 2 groups of human melanoma subjects, we provide evidence of tumour regression associated with Melan A/MART‐1 tumour antigen‐loss variants correlating with formation of specific Melan A/MART‐1 CTLs.

Melanoma histological Breslow thickness predicted by 75-MHz ultrasonography.

Background  Ultrasound at 20 MHz tends to overestimate melanoma Breslow thickness due to lymphocytic infiltration or naevus remnant.

Toxic epidermal necrolysis in acquired immunodeficiency syndrome treated with intravenous gammaglobulin

A 31‐year‐old man with the acquired immunodeficiency syndrome who developed toxic epidermal necrolysis (TEN) was successfully treated with intravenous immunoglobulin. He presented with a widespread, blistering skin rash, extensive mucosal ulceration, high‐grade fever and pancytopaenia. Nevirapine, a non‐nucleoside reverse transcriptase inhibitor, was suspected as the culprit drug, although the patient had been taking this medication for 6 months. The patient also demonstrated an increased number of gamma/delta (γδ) T cells that decreased concomitantly with his clinical improvement. This correlation has not been described in TEN previously and may be of pathophysiological significance.

Analysis of histopathological factors associated with prolonged survival of 10 years or more for patients with thick melanomas (> 5 mm)

Although tumour thickness is the best predictor of melanoma prognosis in patients with localized cutaneous melanoma, prolonged survival occasionally occurs in patients with thick melanomas (> 5 mm). This study examined histological features which were associated with long‐term survival.

Low prevalence of RAS-RAF-activating mutations in Spitz melanocytic nevi compared with other melanocytic lesions.

Abstract:  Melanocytic lesions, including Spitz nevi (SN), common benign nevi (CBN) and cutaneous metastatic melanoma (CMM), were analyzed for activating mutations in NRAS, HRAS and BRAF oncogenes, which induce cellular proliferation via the MAP kinase pathway. One of 22 (4.5%) SN tested showed an HRAS G61L mutation. Another lesion, a ‘halo’ SN, showed a BRAF V600E (T1796A) mutation. BRAF V600E mutations were found in two thirds (20/31) of CBN, while a further 19% (6/31) showed NRAS codon 61 mutations. One third of CMM (10/30) had various BRAF mutations of codon 600, and a further 6% (2/31) showed NRAS codon 61 mutations. Seventeen SN tested for loss of heterozygosity (LOH) at 9p and 10q regions, known to be frequently deleted in melanoma, showed LOH at the 9p loci D9S942 and IFNA. A further lesion was found with low‐level microsatellite instability at one locus, D10S214. The low rate of RAS‐RAF mutations (2/22, 9.1%) observed in SN suggests that these lesions harbor as yet undetected activating mutations in other components of the RAS‐RAF‐MEK‐ERK‐MAPK pathway. Germline DNA from members of 111 multiple‐case melanoma families, representing a range of known (CDKN2A) and unknown predisposing gene defects, was analyzed for germline BRAF mutations, but none was found.