Dermal Mitotic Rate Research Articles

The Relationship Between Epidermal Mitotic Density, Atypical Mitotic FigureDensity, Breslow Depth, Ulceration, and Dermal Mitotic Rate in Cutaneous Melanoma: A Retrospective Cohort Study.

Prognostic factors for melanoma include Breslow depth (BD), ulceration, and dermal mitotic rate (DMR). No studies have queried the effect of epidermal mitotic density (EMD) or atypical mitotic figure density (AMD) in an outcome-based assessment. Our objective was to determine if there is a relationship between EMD, AMD, BD, DMR, and ulceration and patient outcomes. This was a retrospective cohort study of 185 cases of thick and thin melanomas. Univariate and multivariate cause-specific regression analysis was performed. There was a positive correlation between EMD and BD (P = .0001). The difference between AMD in thick and thin melanomas was statistically significant. For every unit increase in EMD, patients had a 2.8-fold increase in the risk of distant metastasis; however, statistical significance was lost in the multivariate analysis. In adjusted analyses, ulceration, DMR, and BD were associated with outcomes. There were no statistically significant correlations between AMD and outcomes. This study is limited by its small sample size, diminution of the epidermis in some thick melanomas preventing EMD estimates, and reproducibility of mitotic figure counting. EMD and AMD do not seem to have any independent value in multivariate analyses for melanoma. Ulceration, BD, and DMR were significantly associated with outcomes and further solidify these known predictors of prognosis.

Molecular Profiling of Noncoding Mutations Distinguishes Nevoid Melanomas From Mitotically Active Nevi in Pregnancy.

The accurate recognition of subtle melanomas and their distinction from benign mimics is an oft-recurring diagnostic problem, critical for patient management. Melanomas that bear resemblance to benign nevi (so-called nevoid melanomas, NMs) and benign mitotically active nevi in pregnancy (MANP) are 2 lesions particularly prone to error. Molecular data, including analysis of noncoding regions, in MANP and NM are very limited. This study sought to identify differences in clinical, pathologic, and molecular characteristics between MANP and NMs to facilitate correct diagnosis and reduce the risk of overtreatment or undertreatment. Clinicopathologic characteristics of NM (n=18) and MANP (n=30) were evaluated, and mutation data were analyzed using next-generation sequencing for available cases in each group (NM, n=8; MANP, n=12). All MANP showed innocent histopathologic characteristics apart from increased mitotic activity, frequently in both superficial and deep parts of the lesion (median dermal mitotic rate: 2/mm, range: 1 to 7/mm). All cases of NM demonstrated a characteristic nevoid silhouette, subtle atypical architectural and cytologic features, and variable mitoses (median mitotic rate: 3/mm, range: 1 to 5/mm). Median NM tumor thickness was 1.4 mm. Four of 10 NM patients with follow-up had metastatic disease, including 3 patients who developed widespread metastases, with 1 disease-related death. No other recurrences have been identified (follow-up period: 24 to 60 mo). None of the 15 MANP patients with available follow-up had a recurrence. Most NMs harbored hotspot mutations in NRAS (6/8, 75%). Noncoding mutations were significantly more common in NMs than in MANP (median: 4 vs. 0, P=0.0014). Copy number alterations were infrequent but, when present, were seen in NMs (3/8 NMs vs. 0/12 MANP). All NMs but only 1 of 12 MANP had >1 abnormality in the noncoding regions. Similar to conventional common acquired nevi, MANP mostly harbored driver BRAF mutations, while activating NRAS mutations, noncoding mutations, and copy number alterations were rare. NM and MANP have subtle but recognizable distinguishing histopathologic characteristics that are underpinned by molecular differences. Mutation analysis of targeted noncoding mutations may assist in the diagnosis of difficult lesions.

Predictors of sentinel lymph node positivity in thin melanoma using the National Cancer Database

Sentinel lymph node biopsy (SLNB) specimens are often obtained from patients for further staging after these patients have undergone melanoma excision. Limited data regarding predictors of SLNB positivity in thin melanoma are available. We sought to evaluate predictors of SLNB positivity in thin melanoma. Patients with cutaneous melanoma with a Breslow thickness ≤1.00mm who received a SLNB were identified from the National Cancer Database between 2004 and 2014 (n=9186). Predictors of SLNB positivity were analyzed using logistic regression. In a multivariate analysis, patients <60years of age (P<.001) and Breslow thickness >0.8mm(P=.03) were at increased risk for positive sentinel lymph node (SLN). Moreover, on multivariate analysis, the presence of dermal mitoses increased the odds of SLN positivity by 95% (odds ratio [OR] 1.95 [95% confidence interval {CI} 1.53-2.5], P<.001), ulceration by 63% (OR 1.63 [95% CI 1.21-2.18], P<.001), and Clark level IV to V by 48% (OR 1.48 [95% CI 1.19-1.85]). Patients without ulceration but with dermal mitoses had 92% (OR 1.92 [95% CI 1.5-2.48], P<.001) increased SLN positivity. Limited survival data are available. Younger age, a Breslow thickness >0.8mm, the presence of dermal mitoses, ulceration, and Clark level IV to V are positive predictors of positive SLN. While the new American Joint Committee on Cancer system has removed dermal mitotic rate from staging, continued evaluation of dermal mitotic rate could be valuable for guiding surgical decision making about SLNB.

Tumor Thickness and Mitotic Rate Robustly Predict Melanoma-Specific Survival in Patients with Primary Vulvar Melanoma: A Retrospective Review of 100 Cases.

Purpose: Primary vulvar melanoma (PVM) is the second most common vulvar malignancy. Despite their distinct anatomic site and unique molecular-genetic alterations, PVMs are staged according to the American Joint Committee on Cancer (AJCC) guidelines for primary cutaneous melanomas (PCM). However, whether parameters derived for PCM also apply to PVM remain a critical yet largely unexplored clinical question. The objective of this study was to determine the parameters predictive of survival in PVM.Experimental Design: We retrospectively reviewed 100 patients with PVM and determined associations between clinical and histopathologic parameters and disease-specific survival (DSS) and overall survival (OS).Results: Univariate Cox regression analysis demonstrated older age (>56 years), greater tumor thickness, higher dermal mitotic rate, ulceration, lymphovascular invasion, perineural invasion, microscopic satellitosis, and absence of precursor nevus associated with decreased OS. Furthermore, age, midline, and/or multifocal involvement, greater tumor thickness, higher dermal mitotic rate, ulceration, lack of regression, lymphovascular invasion, perineural invasion, and microscopic satellitosis associated with decreased DSS. Multivariate analysis demonstrated tumor thickness, dermal mitotic rate, lymphovascular invasion, microscopic satellitosis, and absence of precursor nevus independently predicted shorter OS. Only tumor thickness and increased dermal mitotic rate (≥2/mm2) independently predicted reduced DSS. In comparison with the AJCC T-category, a novel, bivariate T-category based only on tumor thickness and dermal mitotic rate robustly predicted OS and DSS in our patient cohort.Conclusions: In the largest single institutional study of PVM, we demonstrate a combination of tumor thickness and mitotic rate comprise a simple but robust T-category to direct staging and prognosis. Clin Cancer Res; 23(8); 2093-104. ©2016 AACR.

Atypical Spitz Tumors With 6q23 Deletions

Determining risk assessment for aggressive behavior of atypical Spitz tumors (ASTs) remains a significant challenge for pathologists. Despite the presence of many concerning histological features such as tumor ulceration, expansile growth, dermal mitotic rate, and cytological atypia, the overwhelming majority of these tumors behave in an indolent fashion. Recently, we have noted that using cytogenetics, one can identify ASTs with high likelihood for aggressive behavior allowing for a clinically significant risk assessment. In this retrospective case-controlled study, we examined the clinical and histological features of 24 cases of ASTs that were found to have isolated copy number deletions in 6q23 when studied by probes targeting 6p25, 6q23, Cep6, 11q13, 9p21, and Cep9. Although 6 of 11 patients had a positive sentinel node biopsy, none of the patients developed tumor in a nonsentinel node, palpable adenopathy, in transit metastasis, or distant metastasis. Histopathologically, the tumors showed minimal pagetoid spread (P = 0.004) and trended toward a histological presentation with expansile nodular growth (P = 0.08) and focal ulceration (P = 0.19). Furthermore, we also depict and illustrate the challenges that may occur in accurately identifying 6q23 deletions using fluorescence in situ hybridization in ASTs.

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

The 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. The 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. The 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/mm(2) vs. 2/mm(2)), 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). SLN 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.

Biologic and Prognostic Significance of Dermal Ki67 Expression, Mitoses, and Tumorigenicity in Thin Invasive Cutaneous Melanoma

Tumor cell proliferation is a central feature of melanoma progression. In this study, we characterized three biomarkers of proliferation (Ki67 expression, dermal mitotic rate [MR], and tumorigenicity) in thin (< or = 1.00 mm) primary cutaneous melanomas and examined their association with prognosis. We used immunohistochemistry to determine Ki67 expression using the monoclonal antibody MIB-1 in lesions from a prospective cohort that included 396 patients with thin invasive primary melanomas seen between 1972 and 1991. A multivariate Cox proportional hazards model was used to define independent prognostic factors, and recursive partitioning was used to develop a prognostic tree identifying risk groups. Dermal Ki67 expression was lower than epidermal Ki67 expression in radial growth phase (RGP) melanomas (n = 171), and dermal Ki67 expression and MR were higher in tumorigenic vertical growth phase (VGP) melanomas (n = 193) compared with RGP and nontumorigenic VGP melanomas (n = 42). Dermal Ki67 expression, MR greater than 0, growth phase, thickness, ulceration, tumor-infiltrating lymphocytes, and sex were associated with metastasis at 10 years, however, only dermal Ki67 expression, MR greater than 0, and sex were independent prognostic factors. Two high-risk groups were identified: men and women with dermal MR greater than 0 and dermal Ki67 expression > or = 20% in tumor cells and men with MR greater than 0 and Ki67 expression less than 20%, with 10-year metastasis rates of 39% and 20%, respectively. Proliferation slows as melanoma cells enter the dermis and then increases with the onset of tumorigenic VGP. Ki67 expression and dermal MR provide independent prognostic information that can potentially be used in risk-based management of patients.

Histological expression of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in human primary melanoma

Tumour necrosis factor-related apoptosis ligand (TRAIL) appears to selectively induce apoptosis in a wide range of cultured malignant cells, including melanoma. This study was designed to attempt to clarify the role of TRAIL in the biology of human melanoma. Tissue sections cut from formalin-fixed, paraffin-embedded tissue blocks of 45 primary cutaneous melanomas were tested for expression of TRAIL using immunohistochemistry. The intensity, pattern of staining and percentage of positively stained tumour cells were evaluated in each melanoma. Breslow thickness, ulcerative state, dermal mitotic rate and the presence of tumour infiltrating lymphocytes were measured/determined in each case. Median follow up for the cohort of patients was 10 months (range 1-18). Survival analysis was conducted using the Kaplan-Meier method. The level of expression of TRAIL was compared with the various histological determinants using the two-tailed Fisher's exact test and the chi2-test. Overall and disease-free survival were 72 and 48%, respectively, and did not correlate with TRAIL expression. Among the pathological prognostic determinants, only mitotic rate showed a statistically significant correlation with TRAIL expression using the chi2-test (P=0.04). We conclude that TRAIL expression in melanoma defines a more aggressive/proliferative phenotype, either through selection of apoptotic resistant cells or by secondary induction of other factors enhancing proliferation of more malignant cells. Analysis of a larger group of patients with longer follow-up is required to determine whether TRAIL expression correlates with survival of patients.

Pathology of melanocytic lesions: new, controversial, and clinically important issues.

Patients with primary cutaneous melanocytic lesions rely not only on the knowledge, skills, and experience of their treating clinician but also on the fundamentally important input of their pathologist for accurate diagnosis and appropriate management. Free and precise communication between pathologists and surgeons is important and undoubtedly improves patient care, particularly when managing difficult or complicated cases. To provide both patient and surgeon with the necessary information they require to make the most appropriate decisions, the pathology report should include all pathologic factors that are important in determining the patient's prognosis and management. Use of a synoptic format for pathology reporting of melanomas can facilitate this. Recent studies have established that the dermal mitotic rate of a primary cutaneous melanoma is a major prognostic determinant, and have shown that its assessment and that of other important histopathologic prognostic variables are reproducible between pathologists. Sentinel node (SN) biopsy has provided a minimally invasive procedure that can accurately predict the regional node status of melanoma patients. It is well demonstrated that the use of immunohistochemical stains assists in the detection of melanoma micrometastases in SNs, although it remains unclear which is the optimal pathologic protocol for SN evaluation and whether there is a role for reverse transcriptase polymerase chain reaction (RT-PCR) in SN assessment. False negative SN biopsies may occur as a result of errors in lymphatic mapping or sentinel lymphadenectomy, or because of a deficiency in the process of histopathologic evaluation. Recent studies have shown that the likelihood of non-SN involvement when the SN is positive correlates mostly with the extent of SN involvement, in particular the tumor penetrative depth (defined as the maximum distance of melanoma cells from the inner margin of the SN capsule). It appears that assessment of the micromorphometric features of positive SNs may be useful in predicting which patients have a low probability of having metastatic tumor in non-SNs, and therefore in selecting patients who potentially may be spared a completion lymph node dissection. It is likely that future advances in our understanding of the molecular biology of melanoma will provide new insights into tumor classification, improve diagnostic accuracy and prognostic ability, and lead to the development of more precisely targeted therapies.

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

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/mm2, 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.