Atypical Melanocytic Neoplasms Research Articles

42391 A 10-Year Review of a Single Academic Institution’s Experience with Atypical Compound Melanocytic Neoplasms

42391 A 10-Year Review of a Single Academic Institution’s Experience with Atypical Compound Melanocytic Neoplasms

PRAME Expression Correlates With Genomic Aberration and Malignant Diagnosis of Spitzoid Melanocytic Neoplasms.

Spitzoid melanocytic neoplasms are a diagnostically challenging class of lesions in dermatopathology. Recently, molecular assays and immunohistochemical markers have been explored as ancillary methods to assist in the diagnostic workup. Specifically, preferentially expressed antigen in melanoma (PRAME) immunohistochemistry is a nuclear stain commonly positive in melanomas, but not in nevi. This study investigates PRAME immunoreactivity (≥75% positive nuclear staining in tumor cells) in a set of 59 spitzoid melanocytic neoplasms with known clinical outcomes. We compared PRAME status with (1) the clinical outcomes, (2) the morphologic diagnoses, and (3) the status of TERT promoter mutation. Regarding clinical outcomes, 3 cases developed metastatic disease, of which 2 expressed diffusely positive PRAME staining. Of the 56 cases that did not show evidence of metastasis, 6 expressed diffusely positive PRAME staining. Morphologically, diffusely positive PRAME staining was seen in 7 of 21 cases (33.3%) diagnosed as melanoma and only 1 benign tumor 1 of 38 (2.6%). There were 4 of 8 cases with a TERT promoter mutation which were diffusely PRAME-positive compared with 4 of 51 cases without TERT promoter mutation ( P = 0.001). Our results show a statistically significant correlation between PRAME expression and the diagnosis, outcome, and TERT promoter mutation status of atypical spitzoid melanocytic neoplasms, suggesting immunohistochemistry for PRAME can help support a suspected diagnosis. However, because of occasional false-positive and negative test results, correlation with the clinical and histologic findings as well as results from other tests is needed for the interpretation of diagnostically challenging spitzoid melanocytic neoplasms.

Characteristics of melanoma in white and nonwhite children, adolescents, and young adults: Analysis of a pediatric melanoma institutional registry, 1995‐2018

To characterize clinical differences among nonwhite/multiethnic vs white children, adolescents, and young adults with melanoma or atypical melanocytic neoplasms, including atypical Spitz tumors. A cohort of 55 patients (< 25years of age) prospectively followed from 1995 to 2018 in the Stanford Pigmented Lesion and Melanoma Program was analyzed for differences in clinical presentation, including skin phototype, race/ethnicity, age, sex, tumor/melanoma characteristics, and outcome. Seventeen patients (9 males and 8 females) were classified as nonwhite (predominantly skin phototype IV) and of Hispanic, Asian, or Black/African American ethnicity, and 38 patients (21 males and 17 females) were classified as white (predominantly phototypes I/II). Ages ranged from 6months to 24years, and median follow-up was 36months (range 1-180months). Melanomas were diagnosed in 87% of whites in our cohort, compared to 65% of nonwhites, with the remainder representing mainly atypical Spitz tumors. Lesions were usually brought to the attention of a health care provider by the patient or family (P<0.05). Compared with whites, nonwhites were more likely to present at a younger mean age (10.9years vs 15.4years, P<0.05) and with pink/clinically amelanotic tumors (59% vs 24%, P=0.02). This long-term prospective institutional study showed clinically relevant differences between nonwhite vs white children, adolescents, and young adults diagnosed with melanoma and atypical melanocytic neoplasms. Nonwhite patients presented at a younger age and had more clinically amelanotic melanocytic tumors. Increased recognition of clinical factors and risk of these tumors in nonwhites could result in earlier diagnosis.

How to Discuss Equivocal Melanocytic Neoplasms with Patients

While fortunately relatively rare, occasionally a dermatologist will biopsy a pigmented lesion, submit it to the dermatopathologist and a diagnosis is rendered that is equivocal for one reason or another. One of the more perplexing cases is when it comes back as “atypical Spitzoid melanocytic neoplasm,” especially when the patient is not a young child. As a clinical dermatologist and dermatopathologist, I have had experience in rendering these diagnoses as well as counseling patients who have received such diagnoses.

A Comprehensive Approach to Pediatric Atypical Melanocytic Neoplasms with Comment on the Role of Sentinel Lymph Node Biopsy.

Pediatric melanoma has been rising in incidence in recent years and its management poses challenges that are frequently exacerbated by diagnostic uncertainty about the benign or malignant nature of many pediatric melanocytic neoplasms. Sentinel lymph node biopsy (SLNB), originally described by Dr. Donald L. Morton, has been incorporated selectively into the management of pediatric atypical melanocytic neoplasms (AMNs), but its value and significance in this scenario have been controversial. Herein, we describe a comprehensive approach to the evaluation and management of pediatric AMNs that involves SLNB as a diagnostic, staging, and potentially therapeutic tool. We also describe our approach to educating patients and their families about the inherent uncertainties involved in diagnosing and predicting the ultimate behavior of pediatric melanocytic lesions. In addition, we stress the importance of long-term follow-up, as well as ongoing research to improve our understanding of the prognostic factors and histopathologic characteristics that may one day allow us to minimize or eliminate entirely this diagnostically uncertain category of skin lesions.

Simulants of Malignant Melanoma.

During the recent period, dermoscopy has yielded improvement in the early disclosure of various atypical melanocytic neoplasms (AMN) of the skin. Beyond this clinical procedure, AMN histopathology remains mandatory for establishing their precise diagnosis. Of note, panels of experts in AMN merely report moderate agreement in various puzzling cases. Divergences in opinion and misdiagnosis are likely increased when histopathological criteria are not fine-tuned and when facing a diversity of AMN types. Furthermore, some AMN have been differently named in the literature including atypical Spitz tumor, metastasizing Spitz tumor, borderline and intermediate melanocytic tumor, malignant Spitz nevus, pigmented epithelioid melanocytoma or animal-type melanoma. Some acronyms have been further suggested such as MELTUMP (after melanocytic tumor of uncertain malignant potential) and STUMP (after Spitzoid melanocytic tumor of uncertain malignant potential). In this review, such AMN at the exclusion of cutaneous malignant melanoma (MM) variants, are grouped under the tentative broad heading skin melanocytoma. Such set of AMN frequently follows an indolent course, although they exhibit atypical and sometimes worrisome patterns or cytological atypia. Rare cases of skin melanocytomas progress to loco regional clusters of lesions (agminate melanocytomas), and even to regional lymph nodes. At times, the distinction between a skin melanocytoma and MM remains puzzling. However, multipronged immunohistochemistry and emerging molecular biology help profiling any malignancy risk if present.

Histomorphologic assessment and interobserver diagnostic reproducibility of atypical spitzoid melanocytic neoplasms with long-term follow-up.

Predicting clinical behavior of atypical Spitz tumors remains problematic. In this study, we assessed interobserver agreement of diagnosis by 13 expert dermatopathologists for atypical Spitz tumors (n=75). We determined which histomorphologic features were most heavily weighted for their diagnostic significance by the experts and also which histomorphologic features had a statistically significant correlation with clinical outcome. There was a low interobserver agreement among the experts in categorizing lesions as malignant versus nonmalignant (κ=0.30). The histomorphologic features that were given the most diagnostic significance by the experts were: consumption of the epidermis, atypical mitoses, high-grade cytologic atypia, and mitotic rate. Conversely, the histomorphologic features that most correlated with disease progression were: frequent mitoses, deep mitoses, asymmetry, high-grade cytologic atypia, and ulceration. The presence and/or pattern of pagetoid spread, consumption of the epidermis, and lymphoid aggregates demonstrated no association with clinical behavior. The results support the assertion that there is a lack of consensus in the assessment of atypical Spitz tumors by expert dermatopathologists. Importantly, many features used to distinguish conventional melanoma from nevi were not useful in predicting the behavior of atypical Spitz tumors. This study may provide some guidance regarding histologic assessment of these enigmatic tumors.

Evidence-Based Clinical Practice Guidelines on the Use of Sentinel Lymph Node Biopsy in Melanoma

Sentinel lymph node biopsy (SLNB) was introduced in 1992 to allow histopathologic evaluation of the "sentinel" node, that is, the first node along the lymphatic drainage pathway from the primary melanoma. This procedure has less risk of complications than a complete lymphadenectomy, and if the sentinel node is uninvolved by tumor the likelihood a complete lymphadenectomy would find metastatic disease in that nodal basin is very low. SLNB is now widely used worldwide in the staging of melanoma as well as breast and Merkel cell carcinomas. SLNB provides safe, reliable staging for patients with clinically node-negative melanomas 1 mm or greater in thickness, with an acceptably low rate of failure in the sentinel node-negative basin. Evidence-based guidelines jointly produced by ASCO and the Society of Surgical Oncology (SSO) recommend SLNB for patients with intermediate-thickness melanomas and also state that SLNB may be recommended for patients with thick melanomas. Major remaining areas of uncertainty include the indications for SLNB in patients with thin melanomas, pediatric patients, and patients with atypical melanocytic neoplasms; the optimal radiotracers and dyes for lymphatic mapping; and the necessity of complete lymphadenectomy in all sentinel node-positive patients.

Cutaneous melanocytomas: a conceptual cluster of atypical and indolent melanocytic neoplasms

In recent years, clinical dermoscopy has yielded improvement in the early disclosure of various atypical melanocytic neoplasms (AMN). Beyond this approach, histopathology of AMN remains mandatory in the establishment of their precise diagnosis and proper management. Of note, panels of expert pathologists in AMN diagnosis report only moderate agreement in a variety of puzzling cases. The risk for divergence in opinion and microscopic misdiagnosis is probably increased when histopathologic criteria are not fine-tuned and when the number of AMN entities is increasing. In addition, some of the AMN have been differently designated in the literature including atypical Spitz tumor, metastasizing Spitz tumor, borderline and intermediate melanocytic tumor, malignant Spitz nevus and pigmented epithelioid melanocytoma or animal-type melanoma. Some acronyms have been further proposed such as MELTUMP (after ‘melanocytic tumor of uncertain malignant potential’) and STUMP (after ‘Spitzoid melanocytic tumor of uncertain ...

Evidence-Based Clinical Practice Guidelines on the Use of Sentinel Lymph Node Biopsy in Melanoma

Sentinel lymph node biopsy (SLNB) was introduced in 1992 to allow histopathologic evaluation of the "sentinel" node, that is, the first node along the lymphatic drainage pathway from the primary melanoma. This procedure has less risk of complications than a complete lymphadenectomy, and if the sentinel node is uninvolved by tumor the likelihood a complete lymphadenectomy would find metastatic disease in that nodal basin is very low. SLNB is now widely used worldwide in the staging of melanoma as well as breast and Merkel cell carcinomas. SLNB provides safe, reliable staging for patients with clinically node-negative melanomas 1 mm or greater in thickness, with an acceptably low rate of failure in the sentinel node-negative basin. Evidence-based guidelines jointly produced by ASCO and the Society of Surgical Oncology (SSO) recommend SLNB for patients with intermediate-thickness melanomas and also state that SLNB may be recommended for patients with thick melanomas. Major remaining areas of uncertainty include the indications for SLNB in patients with thin melanomas, pediatric patients, and patients with atypical melanocytic neoplasms; the optimal radiotracers and dyes for lymphatic mapping; and the necessity of complete lymphadenectomy in all sentinel node-positive patients.

Sentinel node biopsy in atypical melanocytic neoplasms in childhood: a single institution experience in 24 patients

Sentinel lymph node biopsy (SLNB) is a controversial but frequently used adjunct to wide excision of difficult-to-diagnose melanocytic proliferations of childhood. We herein report our institutional experience with SLNB in pediatric patients with these lesions, hereafter referred to as 'atypical melanocytic proliferations'. Our prospectively collected melanoma database was queried for patients ≤21 years of age status post-SLNB for a diagnosis of atypical melanocytic proliferation in which the diagnosis of melanoma ≥1 mm in depth was considered in the differential diagnosis by one or more expert dermatopathologists and for which no diagnostic consensus could be reached. Of 24 patients identified over 17 years, 7 patients (29%) had a positive sentinel lymph node (SLN). Six SLN-positive patients underwent complete lymph node dissection, with one (14%) having additional nodal involvement identified. With a median follow-up of 4.1 years (range < 0.1 to 14.8 years), all patients showed no evidence of disease. Despite a significant rate of identification of melanocytes in SLNs of children with atypical melanocytic proliferations, survival appears favorable and controversy surrounding the significance of nodal involvement remains. Further studies with larger numbers of patients and long-term follow-up are needed before the true prognostic value of SLNB in this setting can be determined.

Tracking and Treating Malignant Melanoma Metastases

Tracking and Treating Malignant Melanoma Metastases

Molecular dermatopathology in malignant melanoma.

At present, immunohistochemistry is taken for granted in the establishment of malignant melanoma (MM) diagnosis. In recent years, molecular diagnosis in dermatopathology has benefited from a vast array of advances in the fields of genomics and proteomics. Sensitive techniques are available for detecting specific DNA and RNA sequences by molecular hybridization. This paper intends to update methods of molecular cytogenetics available as diagnostic adjuncts in the field of MM. Cytogenetics has highlighted the pathogenesis of atypical melanocytic neoplasms with emphasis on the activation of the mitogen-activated protein kinase (MAPK) signalling pathway during the initiation step of the neoplasms. 20 to 40% of MM families have mutations in the tumour suppressor gene p16 or CDKN2A. In addition, somatic mutations in p16, p53, BRAF, and cKIT are present in MM. Genome-wide scan analyses on MM indicate positive associations for genes involved in melanocytic naevi, but MM is likely caused by a variety of common low-penetrance genes. Molecular dermatopathology is expanding, and its use in the assessment of melanocytic neoplasms appears to be promising in the fields of research and diagnosis. Molecular dermatopathology will probably make its way to an increased number of diagnostic laboratories. The expected benefit should improve the patient management. This evolution points to a need for evolution in the training requirements and role of dermatopathologists.

Atypical Spitzoid Melanocytic Neoplasms With Angiotropism: A Potential Mechanism of Locoregional Involvement

Atypical spitzoid melanocytic neoplasms (ASMN) may prove difficult to distinguish microscopically from melanoma, and their biological behavior may be unpredictable. ASMN may result in regional lymph node (LN) metastases and frequent sentinel lymph node (SLN) deposits. Angiotropism and extravascular migratory metastasis may account for locoregional metastases in melanoma and thus may potentially explain such locoregional involvement in ASMN. Nine ASMN with angiotropism from 2006 to 2010 were studied. Angiotropism was defined as melanocytes closely opposed to the external surfaces of microvascular channels without intravasation. There were 5 women and 4 men aged 6-40 (mean 18.7) years with ASMN involving the head and neck (5), the extremities (3), and the trunk (1), and the lesions ranged in diameters from 3.5 to 10 (mean 6.2) mm. Breslow thicknesses ranged from 0.66 to 5.35 (mean 3.21) mm, 5 lesions Clark level IV and 4 level V, and dermal mitotic rates varied from 1 to 5 (mean 2.4) per square millimeter. Despite follow-up of 6 months or less in 4 subjects, 5 patients showed regional tumor spread based on detection of SLN deposits, local recurrence, or clinical satellite and LN metastases. Four of 5 patients (80%) undergoing SLN biopsy showed nodal positivity with 2 SLN deposits of >6 mm. Among 4 patients not having SLN biopsy, 1 patient developed local LN metastases after 2 years. We report for the first time angiotropism in ASMN and suggest that such angiotropism seems to correlate with and may explain regional tumor spread in this neoplastic system.

Age and Breslow Depth Are Associated with a Positive Sentinel Lymph Node in Patients with Cutaneous Melanocytic Tumors of Uncertain Malignant Potential

Atypical melanocytic neoplasms present a therapeutic dilemma. Current consensus is to perform a sentinel lymph node (SLN) biopsy as part of management. However, it is unclear whether this is required in all patients. We present our experience with sentinel lymphadenectomy in these patients and examine the clinical and pathologic variables associated with a positive SLN. A prospectively maintained melanoma database was queried for patients with controversial melanocytic lesions. All patients between January 1997 and January 2009 were included. Demographic and pathologic information was collected and correlated with results of SLN biopsy. Thirty-one patients underwent SLN biopsy. Median patient age was 19 years (range 5 to 59 years) and median tumor Breslow depth was 1.35 mm. Five patients (16%) had a positive SLN. Those with a positive SLN were younger (median 11 vs 23.5 years, p = 0.02) and had a greater Breslow depth (median 1.90 vs 1.09; p = 0.03) than those who were SLN negative. Median follow-up was 16 months for patients with at least 6 months of follow-up time and there have been no recurrences identified. We report an SLN positive rate of 16% in patients with atypical melanocytic tumors. Younger age and greater Breslow depth are associated with having a positive SLN. These results confirm earlier work demonstrating the importance of SLN biopsy in this disease and highlight the need to measure Breslow depth in these lesions so that they can be appropriately stratified as to the need for SLN biopsy.

Utility of Lymph Node Assessment for Atypical Spitzoid Melanocytic Neoplasms

Atypical spitzoid melanocytic neoplasms (ASMN) are cutaneous lesions of uncertain malignant potential, which can be difficult to distinguish from cutaneous melanoma. Sentinel lymph node (SLN) biopsy is a safe and useful prognostic tool for staging melanoma, but its role in staging ASMNs is not established nor is the significance of positive SLNs in these patients known. This study attempts to characterize the significance of nodal disease in ASMN. Patients with ASMNs who presented to the melanoma service from 1992 to 2007 were identified from a prospective database. Histological review was performed by two dermatopathologists. Demographic, treatment, and outcome data were reviewed. A total of 58 patients with ASMNs were treated during the time analyzed; 31 (53%) underwent wide local excision and observation (WLE); 27 underwent wide excision and SLN biopsy. Median age was 24 (range, 6-60) years. Mean Breslow thickness was 2.9 (range, 0.5-10) mm. Median follow-up was 56 (range, 1-160) months. Ten of 58 (17%) patients had nodal metastasis. Four (13%) of 31 patients who underwent WLE developed nodal recurrences, and 6 of 27 (22%) patients had a positive SLN biopsy. Of patients with positive SLNs, none have recurred after undergoing completion lymphadenectomy. One patient presented with synchronous brain metastasis and inguinal lymphadenopathy and died of disease. Nodal status does not seem to convey the same prognosis that it does in standard melanoma. There may be a limited ability for progression within the nodal basin in patients with these lesions. This subset of patients would benefit from genetic data complementing histologic analysis.

Molecular histology on the diagnostic cutting edge between malignant melanomas and cutaneous melanocytomas (Review)

In recent years, the screening accuracy of clinical dermoscopy has increased in the early detection of evolving atypical melanocytic neoplasms. However, the most dramatic cases of human malignant melanomas (MM), i.e. the fast-growing neoplasms, usually escape the classical clinical criteria of MM. As a result, a number of puzzling cases exhibit uncertain clues for MM. Thus, the risk of microscopic misdiagnosis is likely on the rise if the histological criteria are not fine-tuned. This review summarizes a conceptual classification of atypical melanocytic neoplasms grouped under the heading of melanocytomas. Some immunohistochemical markers are tentatively used as discriminators between fast-growing MM and melanocytomas. However, some differences seem to be more statistically significant than clinically useful due to extensive overlap in immunoreactivity from any case to case. A multipronged immunohistological screening is therefore welcome.

First analysis of an international pediatric melanoma and atypical melanocytic neoplasm database

9013 Background: Pediatric melanoma (PM) care has been extrapolated from adult melanoma data. PM and atypical melanocytic neoplasms (AMNs) appear to have different biology. An international database (DB) was developed to clarify their behavior. Methods: IRB approval was obtained at 12 institutions. An SQL-DB was developed for web entry of de-identified demographic and pathologic data for PM and AMN patients (pts) &lt; 21yr through an honest broker system at the University of Pittsburgh. Institutions retained a key of pts entered with assigned numbers for quality assurance and updates. Statistical analysis used Kaplan-Meier survival curves, univariate linear trends and log rank tests. In situ melanoma was excluded from PM survival analysis. Results: 828 pts were registered as of 31 Oct 2008 (ages 11mo-23; median 15yr). 34 pts 21–23yr entered were left in the DB for statistical comparison. Diagnosis years ranged from 1936–2008. 455 pts had complete follow-up. Too few AMN pts had complete follow-up for analysis (18/208). After excluding 32 in situ and 40 with other incomplete data, 365 PM out of 415 total PM were evaluable for OS and 351 for DFS (Stage IV removed). Mean/median age for evaluable PM pts was 16.44/17-yrs (range 1–21yr). 591 pts were age 10–20 while 203 were &lt; 10. Sentinel lymph node (SLN) biopsy showed spread in 30.1 % PM pts (compared to 50% [4/8] of AMN SLN pts). 10-yr PM OS was 80.6%, and pts 0–10 yr had 100% 10-yr OS compared to 69.6% for pts age 10–15 and 79.49% for age 15–20 (p= 0.1473). OS did not differ significantly by gender. Stage predicted OS (p&lt;0.0001). 10-yr OS was 94.13% for Stage I (n=174), 79.62% for stage II (n=67) &amp; 77.14% for stage III (n=75). Thickness affected 10-yr OS: 0–1mm=97% (n=147), 1.1–2mm 70% (n=84), 2.01–4mm 78% (n=71) &amp; &gt;4mm 81% (n=25), p= 0.0099. Survival was similar for pts with PM &gt; 1mm of the several T stage groupings. Ulceration adversely affected OS (p=0.022). Mitosis, defined as present/absent did not alter survival. Nodal metastasis correlated with worse OS (p= 0.170). Conclusions: Stage, thickness, ulceration, and nodal status are significant predictors of OS for PM. Further study will focus on multivariable analysis of PM and AMNs after updating pts, increasing accrual, and cleaning data. No significant financial relationships to disclose.

Highlighting the immunohistochemical profile of melanocytomas (Review)

The histological assessment of atypical melanocytic neoplasms is mandatory to ensure proper diagnosis and treatment. However, for some atypical lesions, expert pathologists report only moderate concordance in the diagnosis. In addition, certain atypical neoplasms have been coined differently in the literature. These designations include among others atypical and metastasizing Spitz tumor, malignant Spitz naevus, borderline and intermediate melanocytic tumor, and melanocytic tumor of uncertain malignant potential (MELTUMP) or Spitzoid melanocytic tumor of uncertain malignant potential (STUMP). These neoplasms are grouped here under the heading melanocytoma. Such melanocytic lesions have a benign outcome but exhibit an atypical and worrisome aspect. Rare individual cases of melanocytomas can progress to locoregional disease (agminate melanocytomas), and even beyond. At times, the distinction between melanocytoma and melanoma is difficult and may even be impossible. However, multipronged immunohistochemistry can help define malignancy risk stratification and therapeutic guidelines.

Ungewöhnliche Formvarianten maligner melanozytärer Tumoren

Benign and malignant melanocytic neoplasms are relatively frequent and show a broad morphological heterogeneity. The spectrum of malignant melanomas comprises the four main types, superficial spreading malignant melanoma, nodular malignant melanoma, lentigo-maligna melanoma and acrolentiginous malignant melanoma. In addition the rare spitzoid malignant melanoma, desmoplastic malignant melanoma as well as some unusual variants of malignant melanoma can be distinguished. The latter include nevoid malignant melanoma, a form of malignant melanoma resembling benign melanocytic nevi, animal type malignant melanoma, an atypical melanocytic neoplasm with numerous melanophages and prominent melanosis resembling an atypical epithelioid blue naevus as well as regressive malignant melanoma, and representing a questionably distinct entity, balloon cell and signet-ring malignant melanomas, melanoma types with degenerative clear cell changes, as well as myxoid and osteogenic malignant melanomas that are characterized by unusual stromal changes.