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Biomedical subjects

David E Elder

Publications and source records attributed to David E Elder.

At least 37 records · Page 2Linked to original sources
PubMed2004

Induction of melanoma phenotypes in human skin by growth factors and ultraviolet B.

Exposure to UV radiation likely plays a key role in melanoma development, whereas other etiologic agents remain unknown. Here we show that in normal human skin an increased expression of a combination of three growth factors, basic fibroblast growth factor, stem cell factor, and endothelin-3, along with exposure to UVB can transform normal melanocytes into a melanoma phenotype within 4 weeks. Invasion of melanoma lesions was found in skin from newborn donors, whereas melanomas in adult skin were of a noninvasive in situ type only. This suggests that susceptibility of skin to exogenous tumor promoters is dependent on age. This is the first report on human cancer initiation in vivo in which an imbalance of physiological factors combined with an environmental carcinogen can lead to transformation of normal tissue.

Adult↗
PubMed2004

The approach to the patient with a difficult melanocytic lesion.

Although most histological diagnoses are made with relative ease and with great specificity and reproducibility, there is a subset of cases in which a specific and reproducible diagnosis is difficult or even impossible to render. In the melanocytic system, these cases can be divided into two broad categories. The first category, 'superficial atypical melanocytic proliferations of uncertain significance' (SAMPUS), includes predominantly junctional melanocytic proliferations, and melanocytic proliferations that are confined to the epidermis and papillary dermis, without evidence of tumorigenic proliferation or mitotic activity there. The prognosis for cure of these lesions is excellent if they are completely excised. Such lesions may include, for example, dysplastic naevi, Spitz naevi or pigmented spindle cell naevi with a few atypical melanocytes above the dermal-epidermal junction, or with greater than average cytological atypia, or with mitoses, where the differential diagnosis of melanoma in situ is difficult or impossible to rule out. The other category, 'melanocytic tumours of uncertain malignant potential' (MELTUMP), is comprised of melanocytic proliferations that form tumours in the dermis, and are therefore potentially capable of metastasis. Examples of such lesions may include atypical Spitz naevi, deep penetrating naevi, possible naevoid melanomas, or cellular blue naevi, where because of increased mitotic activity or cytologic atypia, a diagnosis of invasive or tumorigenic melanoma cannot be ruled out. In managing such lesions, we follow two main principles. The first is to manage each lesion with therapy designed to be adequate for management of the most significant consideration in the differential diagnosis. The second principle is to make clinicians and patients specifically aware of the diagnostic difficulty in their lesion, so that management can be undertaken on a true informed consent basis.

Diagnosis, Differential↗
PubMed2004

Expression of Melan-A and Ki-67 in desmoplastic melanoma and desmoplastic nevi.

BACKGROUND: Desmoplastic melanoma (DMM) is an uncommon melanoma variant with a distinct morphology, including a prominent spindle cell component with fibrosis, as well as a distinct immunohistochemical profile. Histologically, the spindle cell component of DMM can be confused with sclerotic/desmoplastic nevi, nonpigmented blue nevi, scar, and neural tumors. The histological distinction between sclerotic/desmoplastic/blue nevi and DMM using standard light microscopic techniques can be exceedingly subtle. Therefore, we investigated whether immunohistochemical staining for Melan-A and Ki-67 expression can be used to discriminate these lesions, distinguishing between epithelioid and spindle cell compartments of the lesions. DESIGN: Fifty cases of DMM and 13 cases of sclerotic/desmoplastic/blue nevi were identified. Standard immunohistochemical techniques were used with antibodies towards HMB-45, Melan-A (A103), and Ki-67; 43 of 50 DMM cases were available for staining with Melan-A, 42 of 50 for HMB-45, and 31 of 50 cases were stained with Ki-67. All 13 nevi were stained for Melan-A and 8 for Ki-67. Immunoreactivity to Ki-67 antibody was scored as 0 to 5%, 6 to 10%, 11 to 30%, or greater than 30% positive tumor cells. RESULTS: Only 3 of 43 and 3 of 42 of spindle cell compartments of DMMs were positive for Melan-A and HMB-45, respectively. Focal staining of epithelioid cells in the junctional component or superficial dermis was observed in 33% (14/43). In contrast, 100% of the 13 nevi were strongly positive for Melan-A (P < 0.001). Seventeen melanomas (55%) were 0 to 5% positive for Ki-67, five (16%) fell into the 6 to 10% category, three (10%) were between 11 and 30%, and six (19%) were at least focally greater than 30% positive. All 8 nevi (100%) had less than 5% positive cells for Ki-67 (P = 0.02), with only 2 cases having more than 2% positive cells. CONCLUSION: The sclerotic/desmoplastic and hypopigmented blue nevi were uniformly positive for Melan-A, while the vast majority of DMM were negative in their spindle cell compartments. Melan-A is very useful in distinguishing between DMM and sclerotic nevi. Ki-67 appears to be an inconsistent marker for DMM. However, a high labeling index (over 5%) may be used as a clue in diagnosing DMM.

Antigens, Neoplasm↗
PubMed2004

Cellular nodules in congenital pattern nevi.

BACKGROUND: The diagnosis of 'cellular dermal nodule in melanocytic nevi' is challenging, as it can simulate invasive and tumorigenic melanoma. Because cellular nodules are presumed benign, it is essential to differentiate them from true malignant melanoma arising within a nevus, which portends a poor prognosis. Although presumed benign, to date, no published long-term follow-up studies have proved the benignity of this lesion. METHODS: To better understand the clinical behavior and histological features of these lesions, we present a clinical pathological study of a cohort of 26 cases, for which we obtained clinical follow up by chart review and questionnaires. RESULTS: Clinical follow up was obtained on 16 out of 26 patients (61.5%) and ranged from 12 to 132 months (average 62.3 months). The cellular nodules in congenital pattern nevi, reported here, had an invariably benign clinical course. CONCLUSIONS: Features useful in differentiating cellular nodule from melanoma include: (1) lack of high-grade uniform cellular atypia; (2) lack of necrosis within the nodule; (3) rarity of mitoses; (4) evidence of maturation in the form of blending or transitional forms between the cells in the nodule and the adjacent nevus cells; (5) lack of pagetoid spread into the overlying epidermis; and (6) no destructive expansile growth. The difference between cellular nodule and melanoma arising from nevus can be very subtle, and it is important to emphasize that these lesions must be assessed on an individual case-by-case basis.

Adolescent↗
PubMed2004

Variability in nomenclature used for nevi with architectural disorder and cytologic atypia (microscopically dysplastic nevi) by dermatologists and dermatopathologists.

BACKGROUND: Although a nevus with the microscopic features of a "dysplastic nevus" is commonly seen, the nomenclature used to describe such a lesion has been thought to be inconsistent. A 1992 National Institutes of Health (NIH) Consensus Conference sought to unify nomenclature and suggested that the term "nevus with architectural disorder" be used along with a comment on melanocytic atypia. METHODS: We performed a cross-sectional mail survey to determine preferred terminology as well as the level of adherence to the NIH-recommended nomenclature. All 856 active members of the American Society of Dermatopathology (ASDP) and 1100 (13.0%) of the 8471 active members of the American Academy of Dermatology (AAD) were surveyed. RESULTS: Five hundred and thirty-three ASDP members and 483 AAD members who fulfilled eligibility criteria completed the questionnaire. The term "dysplastic nevus" was favored by the largest number of responders (favored by 39.1% of ASDP members and 62.3% of AAD members), while the 1992 NIH Consensus Conference-recommended terminology was the second most popular term (25.3% of ASDP and 15.1% of AAD members). Dermatopathologists (OR = 1.9, p = 0.0001) and those who had dual training in dermatology and dermatopathology (OR = 1.6, p = 0.02 for ASDP members; OR = 2.3, p = 0.02 for AAD members) were more likely to adhere to the 1992 NIH Consensus Conference nomenclature. CONCLUSIONS: Despite attempts to unify nomenclature for microscopically dysplastic nevi through the NIH Consensus Conference, wide variation in terminology persists.

Consensus Statements as Topic↗
PubMed2004

A practical approach to selected problematic melanocytic lesions.

Pigmented skin lesions are among the most common skin lesions. A majority can be diagnosed with ease; however, a minority of the cases are difficult and have the potential for error with catastrophic consequences for patients and the potential for litigation. Melanoma-related claims are second only to breast biopsy-related claims in surgical pathology. This review tries to highlight the problematic areas and diagnostic pitfalls in melanocytic lesions with emphasis on melanomas that might be underdiagnosed and benign melanocytic lesions that might be overdiagnosed and on practical approaches to deal with these lesions. Scanning power examination only is insufficient to avoid the potential diagnostic pitfalls in melanocytic lesions. We recommend examination of every melanocytic lesion in at least several high-power fields for cytologic atypia and mitotic activity. When dealing with problematic cases, it is important to see the entire lesion to determine whether lateral circumscription, nevoid maturation, and deep mitotic activity are present. Immunohistochemical analysis is useful, but it cannot replace careful examination of H&E-stained sections.

Female↗
PubMed2004

Diet and melanoma in a case-control study.

BACKGROUND: Malignant melanoma has been one of the most rapidly increasing cancers within the United States with few modifiable risk factors. This study investigates risk related to dietary factors, which are potentially modifiable. METHODS: Newly diagnosed patients with melanoma (n = 502) were recruited from pigment lesion clinics and controls (n = 565) were recruited from outpatient clinics. To investigate the relationship between melanoma and dietary factors in this case-control study, study subjects were requested to complete a food frequency questionnaire, which assessed diet over the previous year. Using logistic regression, odds ratios (ORs) for melanoma were computed for nutrient and alcohol intake. RESULTS: Persons in high versus low quintiles of energy-adjusted vitamin D, alpha-carotene, beta-carotene, cryptoxanthin, lutein, and lycopene had significantly reduced risk for melanoma (ORs < or = 0.67), which remained after adjustment for presence of dysplastic nevi, education, and skin response to repeated sun exposure. Addition of micronutrients from supplements did not add an additional reduction in risk. High alcohol consumption was associated with an increased risk for melanoma, which remained after adjustment for confounders [OR (95% confidence interval) in highest versus lowest quintiles, 1.65 (1.09-2.49)]. CONCLUSIONS: Diets consisting of foods rich in vitamin D and carotenoids and low in alcohol may be associated with a reduction in risk for melanoma. These analyses should be repeated in large, prospective studies.

Adult↗
PubMed2003

Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation.

Dysregulated activation of Ras or its downstream effectors such as mitogen-activated protein kinase kinase and ERK has been shown to play a critical role in tumorigenesis of many cancer types. However, in melanoma, activating mutations in Ras are rarely observed and are limited to N-Ras in UV-exposed cells. In this study, we identify constitutively activated ERK in almost all melanoma cell lines and in tumor tissues tested, which is in contrast to normal melanocytes and several early stage radial growth phase melanoma lines where ERK can be activated by serum or growth factors. Constitutive activation of ERK is preceded by phosphorylation of mitogen-activated protein kinase kinase and c-RAF. In all of the melanoma cell lines tested, Ras is constitutively activated without underlying mutations. On the contrary, activating mutations in the kinase domain of BRAF are present in the majority of the cell lines tested. Furthermore, ERK activation can be partially inhibited from the cell surface using inhibitors of fibroblast growth factor and hepatocyte growth factor but not interleukin 8 signaling pathways. These data suggest that melanoma growth, invasion, and metastasis are attributable to constitutively activated ERK apparently mediated by excessive growth factors through autocrine mechanisms and BRAF kinase activation.

Enzyme Activation↗
PubMed2003

Gene expression profiling of melanocytic lesions.

DNA microarrays, microscopic grids of DNA, can be used to assess gene expression within a particular cell or cell population. Since DNA from thousands of genes can be hybridized and analyzed in one experiment, researchers can globally characterize genes expressed in normal and various pathologic states. To accurately assess the differences between normal and pathologic states, one derives cDNA from control and diseased tissue specimens for genes expression profiling. For these reasons, microarray technology may be of particular interest to dermatopathologists and dermatologists interested in understanding cutaneous disease because these physicians have access to tissue specimens. In addition, microarray technology is an efficient way of identifying molecules expressed in a cell population; therefore, it can be used to search for unique immunohistologic markers. To this end, we have used microarray technology to define differences in the gene expression profile of nevi and melanomas. In this manuscript, we discuss the results of our study, which confirm previously known differences in gene expression between melanoma and nevi. While a few genes appear slightly overexpressed in nevi, a number of genes involved in regulating cell proliferation were upregulated in melanoma, such as cyclin D1, cdc2-related protein kinase, c-Myc binding protein, early growth response protein 1, and pleiotrophin. "Housekeeping" genes such as glyceraldehyde 3-phosphate dehydrogenase were expressed at similar levels in melanoma and nevi. Surprisingly, a majority of genes were expressed at similar levels in both nevi and melanoma. Based on this study, DNA microarray technology appears to be a valuable tool for identifying genes that may be specifically expressed in cutaneous lesions.

Biomarkers, Tumor↗
PubMed2003

Reliability and validity of a histologic score as a marker for skin cancer chemoprevention studies.

OBJECTIVE: To develop a reliable and valid scoring system for grading skin biopsies from actinic keratosis (AK) and sun-damaged skin for use in evaluating the efficacy of skin cancer chemopreventive agents. STUDY DESIGN: A panel of dermatopathologists developed histologic criteria and diagnostic definitions for the progression of lesions from early AK to AK. The criteria were then applied to a sample of 335 histologic slides from an ongoing chemoprevention study. A 10% sample of 35 slides was reread in order to assess intrarater reliability. RESULTS: Six of the 7 criteria demonstrated high reliability (> 85%). The total histologic score, calculated using the 6 criteria, was found to significantly differentiate between (blinded) biopsy location (normal, pre-AK, AK and adjacent to squamous cell carcinoma) and histologic diagnosis (normal, pre- or early AK, AK and squamous cell carcinoma). CONCLUSION: The total histologic score, having demonstrated reliability on repeated readings and validity in its association with biopsy location and histologic score, is a reliable and valid end point for judging the efficacy of agents in skin cancer chemoprevention studies. Additional interrater reliability tests utilizing larger test sets and a rigorous statistical design should be undertaken to establish its portability.

Biopsy↗
PubMed2002

Average midrange ultraviolet radiation flux and time outdoors predict melanoma risk.

Sunlight is the major environmental risk factor for melanoma. Descriptive studies have shown latitudinal variation in population incidence and mortality rates [D. C. Whiteman and A. C. Green, Int. J. Dermatol., 38: 481-489, 1999, and B. K. Armstrong, Australian J. Dermatol., 38 (Suppl. 1): 51-56, 1997]. In analytic studies, individual exposure has been particularly difficult to quantify. Lifetime residential history was coupled with levels of midrange UV radiation (UVB flux) to provide a measure of individual exposure to sunlight thought to be less subject to misclassification and recall bias. Data were analyzed from 718 non-Hispanic white patients with invasive cutaneous melanoma from melanoma clinics in Philadelphia and San Francisco. Matched controls were 945 patients from outpatient clinics with similar catchment areas. The association of melanoma risk and history of UVB flux along with the usual outdoor exposure risk factors were studied. A 10% increase in the average annual UVB flux was associated with a 19% [95% confidence interval (CI), 5-35%] increase in individual odds for melanoma for men and 16% (95% CI, 2-32%) for women. In men, a 10% increase in hours outdoors was associated with a 2.8% (95% CI, 1.2-4.5%) increase in odds. Even in women who could develop a deep tan, a 10% increase in hours outdoors was associated with a 5.8% increase in odds (95% CI, 1.4-10.4%). The association between melanoma risk and average annual UVB flux was strong and consistent for men and for women. The association with total adult hours outdoors was notable for men of all skin types and women who develop a suntan.

Adult↗
PubMed2002

Multiple primary melanoma revisited.

BACKGROUND: Incidence of cutaneous melanoma continues to increase in the Caucasian population worldwide. Approximately 5% of melanoma patients develop additional primary melanoma. This rate is significantly higher than the estimated lifetime risk of an individual for developing the disease (1.4%). These features suggest that a genetic predisposition may underlie multiple primary melanomas (MPMs). Prior studies had identified CDKN2A mutations in a few MPM individuals. The objectives of this study were to determine the frequency of family history of melanoma in MPM cases, to characterize other clinical features including history of other cancer, and to determine the association with functional CDKN2A mutations. METHODS: This study used a case series design. All living patients who had been seen in the Pigmented Lesion Clinic at the University of Pennsylvania and who had more than one primary invasive malignant melanoma or an invasive primary followed by an in situ melanoma were eligible for participation. RESULTS: Individuals with MPM frequently had a family history of melanoma, dysplastic nevi (DN), and/or another cancer including basal cell carcinoma (BCC), and squamous cell carcinoma breast cancer, and a personal history of DN, and basal cell carcinoma. Germline mutations in CDKN2A gene were identified in 8 of 96 MPM cases (8.3%, 95% confidence interval, 6.7-9.9%). CONCLUSIONS: These data indicate that the presence of MPM is associated with a modest incidence of a family history of melanoma, DN, or BCC and a small association with CDKN2A mutations. Therefore, in addition to the MPM index case, other family members can benefit from screening and regular surveillance for melanoma, DN, and BCC.

Adolescent↗
PubMed2002

Pathology review of cases presenting to a multidisciplinary pigmented lesion clinic.

OBJECTIVES: To determine if pathology review, within the context of a multidisciplinary pigmented lesion clinic, results in changes in diagnosis of melanocytic lesions and to ascertain if the change in diagnosis altered clinical management and outcome. METHODS: Retrospective review of pathology reports, progress notes, and diagnoses entered in the University of Pennsylvania (Philadelphia) Pigmented Lesion Clinic database. RESULTS: A total of 5136 primary melanocytic lesions from patients referred to the pigmented lesion clinic between 1991 and 1999 were reviewed by a single pathologist. Of these, 559 (11%) had diagnoses that were changed significantly from the submitting diagnosis, with 120 (2.3%) undergoing a "critical" revision, 63 (1.2%) defined as a change from malignant to benign, and 57 (1.1%) from benign to malignant; 171 (3.3%) remained within the same category (benign or malignant) but had a downgrade in diagnosis (less severe) that would have a significant impact on treatment, prognosis, and research. Likewise, 268 (5.2%) remained within the same category but had an upgrade in diagnosis (more severe) that would have a significant impact on the same parameters. In addition, 257 reexcisions of melanocytic lesions were reviewed, of which 15 (5.8%) were changed from clear to involved margins, while another 16 (6.2%) were changed from involved to clear margins, for a total of 12%. Of the lesions with a critical revision, follow-up was obtained in 98 (83%). The patients in the malignant-to-benign category were followed up for an average of 2.6 years while those in the benign-to-malignant category were followed up for an average of 4.2 years. The change of diagnosis from malignant to benign resulted in 9 patients (17%) being spared a reexcision while 12 patients (23%) were downgraded from a radical to moderate reexcision. The change in diagnosis from benign to malignant resulted in 45 patients (98%) requiring a reexcision after review. Twenty-five of these patients were found to have residual disease in their reexcision specimens or had already had recurrence at the excision site. Furthermore, 7 patients (15%) underwent lymph node dissection or sentinel lymph node biopsy after review. However, none of the nodes were positive for metastatic disease. During this time, 8 patients (17%) in the benign-to-malignant category, and 1 patient (1.9%) in the malignant-to-benign category (who had previously had 4 primary melanomas) developed metastatic disease. CONCLUSIONS: Pathology review of primary melanocytic lesions, within the context of a multidisciplinary pigmented lesion clinic, results in changes in diagnosis in a significant proportion of cases. These changes have important implications for clinical decision making, patient outcome, and research data collection.

Diagnosis, Differential↗
PubMed2002

Immunoprofile of MITF, tyrosinase, melan-A, and MAGE-1 in HMB45-negative melanomas.

A majority of desmoplastic melanomas and some of the other forms of melanomas are S-100 positive and HMB45 negative; this pattern of immunoreactivity is similar to certain nerve-derived tumors such as malignant peripheral nerve sheath tumor. In this study the immunostaining profile of HMB45-negative malignant melanomas was evaluated by a panel of antibodies against markers associated with melanoma and melanocytic differentiation, including microphthalmia transcription factor, tyrosinase, Melan-A, and MAGE-1. Immunodetection was performed on paraffin sections of 22 cases of HMB45-negative malignant melanomas (including 8 spindle cell melanomas, 8 desmoplastic melanomas, and 6 epithelioid melanomas), 8 HMB45-and S-100-positive malignant melanomas, 15 malignant peripheral nerve sheath tumors, 16 schwannomas, and 11 neurofibromas. Of eight HMB45-positive malignant melanomas, all were positive for Melan-A, tyrosinase, and melanocyte-specific transcription factor, and three were positive for MAGE-1. In the 14 HMB-45 negative, nondesmoplastic melanomas, melanocyte-specific transcription factor was positive in 9, Melan-A in 9, tyrosinase in 6, and MAGE-1 in 11. In eight desmoplastic malignant melanomas, MAGE-1 was positive in three, and all other markers were negative. The five markers tested were negative in all but two schwannomas, one with focal melanocyte-specific transcription factor and the other with tyrosinase and weak MAGE-1 reactivity. MAGE-1, melanocyte-specific transcription factor, tyrosinase, and Melan-A are useful markers in the diagnosis of malignant melanocytic lesions when HMB45 is negative. MAGE-1 may be useful in differentiating melanocytic lesions from nerve-derived lesions, but its sensitivity is relatively low. The immunostaining profile of desmoplastic malignant melanomas more closely resembles that of malignant peripheral nerve sheath tumor than that of other types of malignant melanoma. Melanocyte-specific transcription factor is not a useful marker for desmoplastic melanoma.

Antigens, Neoplasm↗
PubMed2002

P gene as an inherited biomarker of human eye color.

Human pigmentation, including eye color, has been associated with skin cancer risk. The P gene is the human homologue to the mouse pink-eye dilution locus and is responsible for oculocutaneous albinism type 2 and other phenotypes that confer eye hypopigmentation. The P gene is located on chromosome 15q11.2-q12, which is also the location of a putative eye pigmentation gene (EYCL3) inferred to exist by linkage analysis. Therefore, the P gene is a strong candidate for determination of human eye color. Using a sample of 629 normally pigmented individuals, we found that individuals were less likely to have blue or gray eyes if they had P gene variants Arg305Trp (P = 0.002), Arg419Gln (P = 0.001), or the combination of both variants (P = 0.003). These results suggest that P gene, in part, determines normal phenotypic variation in human eye color and may therefore represent an inherited biomarker of cutaneous cancer risk.

Carrier Proteins↗