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Biomedical subjects

R L Barnhill

Publications and source records attributed to R L Barnhill.

At least 19 recordsLinked to original sources
PubMed2006

Dysplastic naevi with moderate to severe histological dysplasia: a risk factor for melanoma.

BACKGROUND: The risk of malignant melanoma associated with histologically dysplastic naevi (HDN) has not been defined. While clinically atypical naevi appear to confer an independent risk of melanoma, no study has evaluated the extent to which HDN are predictive of melanoma. OBJECTIVES: To estimate the risk of melanoma associated with HDN. Secondarily, the risk associated with number of naevi and large naevi is estimated. METHODS: We enrolled 80 patients with newly diagnosed melanoma along with 80 spousal controls. After obtaining information on melanoma risk factors and performing a complete cutaneous examination, the most clinically atypical naevus was biopsied in both cases and controls. Histological dysplasia was then assessed independently by 13 dermatopathologists (0, no dysplasia; 1, mild dysplasia; 2, moderate dysplasia; 3, severe dysplasia). The dermatopathologists were blinded as to whether the naevi were from melanoma subjects or controls. Multivariate analyses were performed to determine if there was an independent association between the degree of histological dysplasia in naevi and a personal history of melanoma. RESULTS: In persons with naevi receiving an average score of > 1 (i.e. naevi considered to have greater than mild histological dysplasia), there was an increased risk of melanoma [odds ratio (OR) 2.60, 95% confidence interval (CI) 0.99-6.86] which persisted after adjustment for confounders (OR 3.99, 95% CI 1.02-15.71). Very few dermatopathologists reliably graded naevi of subjects with melanoma as being more dysplastic than naevi of control subjects. Among the entire group, the interobserver reliability associated with grading histological dysplasia in naevi was poor (weighted kappa 0.28). CONCLUSIONS: HDN do appear to confer an independent risk of melanoma. However, this result may add more to our biological understanding of melanoma risk than to clinical assessment of risk, because HDN assessed by a single pathologist generally cannot be used to assess risk of melanoma. Future studies should be directed at establishing reproducible, predictive criteria for grading naevi.

Adult↗
PubMed2003

Interobserver reproducibility of ulceration assessment in primary cutaneous melanomas.

In the recently revised melanoma staging system proposed by the American Joint Committee on Cancer (AJCC), ulceration assessment by the pathologist is a pivotal parameter. Patients upstaged because of ulceration might be included in adjuvant trials conducted in AJCC stage II melanoma patients. Therefore, accuracy based on interobserver reproducibility for melanoma ulceration assessment is crucial for proper clinical management. In some cases, it is extremely difficult, even for an experienced pathologist, to distinguish between trauma-induced ulceration, artifact and tumoral ulceration. Whether this difficulty may be resolved by the use of a more precise definition of ulceration has not been evaluated. Therefore, we have proposed a refined definition of melanoma ulceration and we tested whether this definition might improve the interobserver interpretative reproducibility of ulceration in primary cutaneous melanomas. The results of this study support the need for a more precise definition of melanoma ulceration that rules out biopsy trauma or processing artifact and could be incorporated into a standardised pathology worksheet for reporting primary melanomas.

Biopsy↗
PubMed2003

Epidermal hyperplasia overlying human melanoma correlates with tumour depth and angiogenesis.

The aim of this study was to determine whether epidermal hyperplasia overlying cutaneous human melanoma is associated with increased tumour angiogenesis, tumour growth and the potential for metastasis. Forty-two surgical specimens of cutaneous human melanoma of different depths, each containing epidermis present in the tumour-free margin, were analysed by immunohistochemistry for the expression of the pro-angiogenic molecules basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) and the anti-angiogenic molecule interferon-beta (IFN-beta). The epidermis overlying intermediate and thick (1.0-10.0 mm), but not thin (0.5-1.0 mm), melanoma specimens was hyperplastic. Although the expression level of bFGF, VEGF and IL-8 in the epidermis directly overlying the tumour was similar to that in the distant epidermis, the expression of IFN-beta was significantly decreased in keratinocytes overlying intermediate and thick, but not thin, melanomas. The microvessel density was also increased in intermediate and thick specimens. Human melanoma cells were injected subcutaneously into nude mice. The resulting tumours were used to determine the association between overlying epidermal hyperplasia and neoplastic angiogenesis. Similar to human autochthonous melanomas, epidermal hyperplasia was found only over lesions produced by metastatic cells. Although there was no change in the expression of the pro-angiogenic molecules, the expression of IFN-beta was significantly decreased in the hyperplastic epidermis. Conditioned medium collected from cultures of the metastatic cell line induced in vitro proliferation of mouse keratinocytes, whereas conditioned medium collected from cultures of the non-metastatic cell line did not. Collectively, the data demonstrate that metastatic melanoma cells induce keratinocyte proliferation, leading to decreased expression of the negative regulator of angiogenesis, IFN-beta, and hence to increased angiogenesis.

Animals↗
PubMed2001

Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas.

BACKGROUND: The Intergroup Melanoma Surgical Trial began in 1983 to examine the optimal surgical margins of excision for primary melanomas of intermediate thickness (i.e., 1-4 mm). There is now a median 10-year follow-up. METHODS: There were two cohorts entered into a prospective multi-institutional trial: (1) 468 patients with melanomas on the trunk or proximal extremity who randomly received a 2 cm or 4 cm radial excision margin and (2) 272 patients with melanomas on the head, neck, or distal extremities who received a 2 cm radial excision margin. RESULTS: A local recurrence (LR) was associated with a high mortality rate, with a 5-year survival rate of only 9% (as a first relapse) or 11% (anytime) compared with an 86% survival for those patients who did not have a LR (P < .0001). The 10-year survival for all patients with a LR was 5%. The 10-year survival rates were not significantly different when comparing 2 cm vs. 4 cm margins of excision (70% vs. 77%) or comparing the management of the regional lymph nodes (observation vs. elective node dissection). The incidences of LR were the same for patients having a 2 cm vs. 4 cm excision margin regardless of whether the comparisons were made as first relapse (0.4% vs. 0.9%) or at anytime (2.1% vs. 2.6%). When analyzed by anatomic site, the LR rates were 1.1% for melanomas arising on the proximal extremity, 3.1% for the trunk, 5.3% for the distal extremities, and 9.4% for the head and neck. The most profound influence on LR rates was the presence or absence of ulceration; it was 6.6% vs. 1.1% in the randomized group involving the trunk and proximal extremity and was 16.2% vs. 2.1% in the non-randomized group involving the distal extremity and head and neck (P < .001). A multivariate (Cox) regression analysis showed that ulceration was an adverse and independent factor (P = .0001) as was head and neck melanoma site (P = .01), while the remaining factors were not significant (all with P > .12). CONCLUSION: For this group of melanoma patients, a local recurrence is associated with a high mortality rate, a 2-cm margin of excision is safe and ulceration of the primary melanoma is the most significant prognostic factor heralding an increased risk for a local recurrence.

Humans↗
PubMed2001

The biology of melanoma micrometastases.

The biology and significance of micrometastases remain poorly understood. Whether such deposits represent hypothetical "dormant" metastases, simply the earliest metastases recognizable, or both has not been resolved. Attempting to answer the latter question among many others, we carried out studies on the rates of proliferation, and microvessel counts in melanoma micrometastases taken from sentinel lymph nodes as compared to conventional melanoma lymph node macrometastases. We found that these micrometastases were not vascularized and had low (and comparable) rates of both proliferation and apoptosis, suggesting a steady or dormant state. On the other hand, the macrometastases were fully vascularized and more proliferative, i.e., they had rates of proliferation that were significantly higher compared to the micrometastases and rate of apoptosis. How micrometastases develop is also poorly understood. Tumor cells are thought to arrive in lymph nodes and other sites through the blood and lymphatic circulation and to extravasate. However, in addition to the latter explanation, another mechanism may be operable which we have proposed as extravascular migratory metastasis. In studies of metastatic melanoma we have identified melanoma cells positioned on the surface of endothelial cells both by light and electron microscopy. We have also identified ultrastructurally the presence of an amorphous matrix interposed between the latter two cell types that shows immunostaining for laminin and, recently, the beta-2 chain of laminin. Thus, we currently believe that the latter form of "free" laminin may play a role in this proposed mechanism of metastasis and thus in the formation of micrometastases.

Animals↗
PubMed2000

Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial.

BACKGROUND: Ten- to 15-year survival results were analyzed from a prospective multi-institutional randomized surgical trial that involved 740 stages I and II melanoma patients with intermediate thickness melanomas (1.0 to 4.0 mm) and compared elective (immediate) lymph node dissection (ELND) with clinical observation of the lymph nodes as well as prognostic factors that independently predict outcomes. METHODS: Eligible patients were stratified according to tumor thickness, anatomical site, and ulceration, and then prerandomized to either ELND or nodal observation. By using Cox stepwise multivariate regression analysis, the independent predictors of outcome were tumor thickness (P < .001), the presence of tumor ulceration (P < .001), trunk site (P = .003), and patient age more than 60 years (P = .01). RESULTS: Overall 10-year survival was not significantly different for patients who received ELND or nodal observation (77% vs. 73%; P = .12). Among the prospectively stratified subgroups of patients, 10-year survival rates favored those patients with ELND, with a 30% reduction in mortality rate for the 543 patients with nonulcerated melanomas (84% vs. 77%; P = .03), a 30% reduction in mortality rate for the 446 patients with tumor thickness of 1.0 to 2.0 mm (86% vs. 80%; P = .03), and a 27% reduction in mortality rate for 385 patients with limb melanomas (84% vs. 78%; P = .05). Of these subgroups, the presence or absence of ulceration should be the key factor for making treatment recommendations with regard to ELND for patients with intermediate thickness melanomas. CONCLUSIONS: These long-term survival rates from patients treated at 77 institutions demonstrate that ulceration and tumor thickness are dominant predictive factors that should be used in the staging of stages I and II melanomas, and confer a survival advantage for these subgroups of prospectively defined melanoma patients.

Extremities↗
PubMed2000

Signs and symptoms of melanoma in older populations.

We conducted a descriptive study to assess the relationship between increasing age and the reporting of melanoma signs/symptoms in 634 hospital-based and 624 population-based incident cases of melanoma. Multivariate logistic regression was used to evaluate the relationship between older age (> or = 50 years) and the reporting of melanoma signs/symptoms. Older patients were less likely to report itching and change in elevation of their lesions (P < 0.05). Change in color was also less likely to be reported by older patients, although not statistically significant. Ulceration of the lesion was reported significantly more by older patients (P < 0.05). Older individuals may be less likely to report itching and change in elevation/color of their lesions, but more likely to report ulceration, a symptom associated with advanced disease and poor prognosis. Further research is necessary to provide a better understanding of the development of melanoma in older populations so that new strategies can be explored to improve early detection in this age group.

Adult↗
PubMed2000

Histopathological features of flexural melanocytic nevi: a study of 40 cases.

Melanocytic nevi in certain locations such as the genital and acral sites may have atypical histologic features simulating melanoma. We studied the microscopic findings of 40 melanocytic nevi of flexural sites (axilla, umbilicus, inguinal creases, pubis, scrotum and perianal area) to verify if flexural nevi show distinctive features similar to melanocytic nevi of the genital skin. The patients were young (mean age 20 years), the lesions were mostly removed for cosmetic reasons and we are not aware of any deaths or complications related to the removed nevi. We found that 22 (55.5%) out of 40 flexural nevi had "a nested and dyshesive pattern" similar to the melanocytic nevi of genital skin. This pattern was characterized by the confluence of enlarged nests with variation in size, shape and position at the dermo-epidermal junction and by the diminished cohesion of melanocytes. Dermatopathologists should pay attention to the "nested and dyshesive pattern" of flexural nevi that may mimick histologic changes of melanoma.

Adult↗
PubMed2000

Malignant melanoma, dysplastic melanocytic nevi, and Spitz tumors. Histologic classification and characteristics.

The classification and pertinent histopathologic features of cutaneous melanoma, dysplastic melanocytic nevi, and Spitz tumors are presented. A discussion on melanoma emphasizes an objective approach to classification based on histomorphologic features including location in the skin, disposition and frequency of melanocytes, other specific morphologic features, and cell type. Other topics addressed include common and unusual variants of melanoma, the use of immunohistochemistry, and the histopathologic reporting of melanoma.

Adolescent↗
PubMed2000

The histologic diagnosis of melanoma.

The pathologic diagnosis of melanoma is of crucial importance because it provides the patient and his or her attending physician with the knowledge of a potentially life-threatening or an almost curable condition. The histopathologic diagnosis of melanoma is based on the simultaneous or systematic assessment of several well-known histopathologic features. This article discusses the author's approach to the histopathologic diagnosis of melanoma for specific situations.

Adolescent↗
PubMed1999

Spitz tumors in children: a grading system for risk stratification.

OBJECTIVE: To describe a grading system for risk stratification of atypical Spitz tumors in children and adolescents. In some circumstances, unequivocal distinction between Spitz nevus and melanoma is practically impossible. It is likely that these lesions for which we lack specific diagnostic criteria represent a broad histological continuum extending from benign to malignant tumors. Therefore, we propose that Spitz tumors be categorized into low-, intermediate-, or high-risk categories based on the accumulation of abnormal features. DESIGN: Retrospective study. SETTINGS: Institutional practice. PATIENTS: We present 30 cases of atypical Spitz tumors in patients younger than 18 years evaluated for at least 3 years or in whom a metastatic event developed during this period. INTERVENTION: None. MAIN OUTCOME MEASURE: The grading system was formulated after data collection. RESULTS: Among the parameters studied, only diagnosis at age greater than 10 years, diameter of the lesion greater than 10 mm, presence of ulceration, involvement of the subcutaneous fat (level V), and mitotic activity of at least 6/mm2 carried a likelihood ratio greater than 1.50 and were therefore used for the grading system. CONCLUSION: The application of an objective grading system, such as the one described herein for the first time, is the first step in providing useful information for the management of atypical Spitz tumors.

Adolescent↗
PubMed1999

Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome.

The biological nature of Spitz nevi/tumors and their diagnostic distinction from, or relationship to, melanoma remain unresolved issues. In this report, a series of 30 melanocytic lesions removed from 28 patients, including atypical Spitz nevi/tumors and metastasizing Spitzoid tumors/melanomas, were evaluated by a panel of dermatopathologists to evaluate interobserver diagnostic concordance and to assess the prognostic power of histological criteria. For inclusion in the study, each lesion had to display some criteria for the Spitz nevus, and in addition one of the following was required: (1) definitive clinical outcome such as metastasis or death of disease, or (2) long-term follow-up if the patient remained disease free. Each lesion was reviewed independently and blinded as to the clinical data by 10 pathologists, who categorized them as (1) typical Spitz nevus/tumor, (2) atypical Spitz nevus/tumor, (3) melanoma, (4) tumor with unknown biological potential, or (5) other melanocytic lesion. There was limited discussion of criteria before the review. Evaluation of 17 Spitzoid lesions yielded no clear consensus as to diagnosis; in only one case did six or more pathologists agree on a single category, regardless of clinical outcome. Notably, however, some lesions that proved fatal were categorized by most observers as either Spitz nevi or atypical Spitz tumors. Conversely, seven or more pathologists scored 13 lesions as melanoma. These results illustrate (1) substantial diagnostic difficulties posed by many Spitz tumors, especially those with atypical features, even among experts, and (2) the lack of objective criteria for their distinction from melanoma and for gauging their malignant potential. Nevertheless, our observations do suggest that a biological relationship exists between the Spitz nevus/tumor and melanoma.

Adolescent↗
PubMed1999

Patient knowledge, awareness, and delay in seeking medical attention for malignant melanoma.

We investigated the relationship between patient knowledge, awareness, and delay in seeking medical attention for melanoma. The study population was comprised of 255 cases with cutaneous melanoma newly diagnosed during January 15, 1987 to May 15, 1989, who were part of a population-based case control study. Personal interviews were conducted to obtain information on patient's knowledge of melanoma signs and symptoms, skin awareness, delay in seeking medical attention, and related covariates. The adjusted odds ratio for the association between skin awareness and delay was 0.30 (95% confidence interval 0.12-0.71). Odds ratios ranged from 0.43 to 0.81 for knowledge and delay. Awareness of skin changes was associated with a reduced Breslow depth for stage I melanomas. Individuals who are aware of skin changes and abnormalities appear to be less likely to delay seeking medical attention for melanoma. Knowledge of melanoma signs and symptoms may also contribute to a decreased delay in melanoma diagnosis.

Adolescent↗
PubMed1999

Plexiform spitz nevus: an intradermal spitz nevus with plexiform growth pattern.

Two cases of a distinctive variant of Spitz (spindle and epithelioid cell) nevus are described. One lesion developed on the lower leg of a 17-year-old boy and the other lesion on the back of a 52-year-old man. The microscopic appearance was characterized by a plexiform arrangement of bundles and lobules of enlarged spindle to epithelioid melanocytes throughout the superficial and deep dermis. Intraepidermal melanocytic proliferation was unappreciated. Some lobules were circumscribed by a thin rim of compressed fibrous tissue. In both cases a myxoid stroma was present. The cells had abundant eosinophilic cytoplasm with well-defined borders. The nuclei were enlarged, consistently ovoid and vesicular, with small nucleoli. Both cases contained scattered multinucleate giant cells similar to those observed in classical form of Spitz nevi. No melanin pigment was detectable by light microscopy. No mitoses were observed in one case and a rare mitosis was present in the other. Tumor cells were strongly immunoreactive for S-100, but not for HMB-45, desmin, and actin. The differential diagnosis of this distinctive tumor includes desmoplastic/neurotropic melanoma, plexiform spindle cell nevus, cellular blue nevus, plexiform neurofibroma, and cellular neurothekeoma. The designation of "plexiform Spitz nevus" is chosen to emphasize its distinctive plexiform growth pattern.

Adolescent↗
PubMed1999

Ultrastructural and immunohistochemical studies of the periendothelial matrix in human melanoma: evidence for an amorphous matrix containing laminin.

Angiogenesis and the extracellular matrix are fundamental to tumor progression from in situ to invasive and metastatic disease. Laminin, a major glycoprotein integrated into basement membranes, is observed in angiogenesis and tumorigenesis. A recent study described an association between melanoma cells and endothelial cells via an amorphous matrix containing laminin. In the current study, we have examined 45 cases of human primary and metastatic melanomas by electron microscopy for the presence of an amorphous matrix. We observed an amorphous matrix without a clearly delineated lamina or basement membrane in 41 of the 45 melanomas studied. 28 cases with tissue blocks available for study were examined by immunohistochemistry for the expression of laminin and type IV collagen. We observed the presence of an angiocentric matrix containing laminin in 24 of the 28 melanomas studied. Since laminin is involved in tumor migration, the presence of laminin between melanoma cells and small vessels suggests a role for this material in periendothelial tumor migration. However, further study is required to characterize the nature of this material and the mechanisms involved.

Adult↗