James M. Grichnik

Guidelines of care for the management of primary cutaneous melanoma.

The incidence of primary cutaneous melanoma has been increasing dramatically for several decades. Melanoma accounts for the majority of skin cancer-related deaths, but treatment is nearly always curative with early detection of disease. In this update of the guidelines of care, we will discuss the treatment of patients with primary cutaneous melanoma. We will discuss biopsy techniques of a lesion clinically suspicious for melanoma and offer recommendations for the histopathologic interpretation of cutaneous melanoma. We will offer recommendations for the use of laboratory and imaging tests in the initial workup of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, we will provide recommendations for surgical margins and briefly discuss nonsurgical treatments. Finally, we will discuss the value and limitations of sentinel lymph node biopsy and offer recommendations for its use in patients with primary cutaneous melanoma.

Melanoma, Nevogenesis, and Stem Cell Biology

It is now well established that a subpopulation of tumor stem cells (TSCs) are present within cancer tissues. This suggests that tumors evolve from stem cells; however, the exact cell of tumor origin, the potential role of dedifferentiation, and the role of plasticity in tumor development are largely unknown. A model cancer for the study of the oncologic process is melanoma. The developmental biology of melanocytes is relatively well understood, the cells pigment as they differentiate making them easy to identify, and benign and malignant tumors develop on the skin surface allowing direct observation of growth features, early detection, and removal. This ready access to early-stage tumors will facilitate study of the early oncologic processes and the role of tissue stem cells. Melanomas, like other cancers, include a subpopulation of TSCs. These TSCs have access to embryologic developmental programs, including the capacity to differentiate along multiple cell lineages. For example, melanomas can activate germ-cell pathways with major implications for TSC self-renewal through the activation of telomerase and genomic instability through the collision of meiotic and mitotic pathways (meiomitosis). The TSC model is still evolving, but the existence of TSCs has significant ramifications for tumor development, diagnosis, prognosis, and treatment of melanoma and other cancers.

Murine dendritic cells transfected with human GP100 elicit both antigen-specific CD8(+) and CD4(+) T-cell responses and are more effective than DNA vaccines at generating anti-tumor immunity.

Dendritic cells (DCs) are potent inducers of cytotoxic T lymphocytes (CTLs) when pulsed with an antigenic peptide or tumor lysate. In this report, we have used liposome‐mediated gene transfer to examine the ability of plasmid DNA encoding the human melanoma‐associated antigen gp100 to elicit CD8+ and CD4+ T‐cell responses. We also compared the efficacy between gp100 gene–modified DCs and naked DNA (pCDNA3/gp100)–based vaccines at inducing anti‐tumor immunity. DCs were generated from murine bone marrow and transfected in vitro with plasmid DNA containing the gp100 gene. These gp100‐modified DCs (DC/gps) were used to stimulate syngeneic naive spleen T cells in vitro or to immunize mice in vivo. Antigen‐specific, MHC‐restricted CTLs were generated when DC/gps were used to prime T cells both in vitro and in vivo. Thus, these CTLs were cytolytic for gp100‐transfected syngeneic (H‐2b) tumor MCA106 (MCA/gp) and vaccinia‐pMel17/gp100‐infected syngeneic B16 and MCA106, but not parental tumor MCA106 and B16, or gp100‐transfected allogeneic tumor P815 (H‐2d). Immunization with DC/gp protected mice from subsequent challenge with MCA/gp but not parental MCA106. Antibody‐mediated T‐cell subset depletion experiments demonstrate that induction of CTLs in vivo is dependent on both CD4+ and CD8+ T cells. Furthermore, DC/gp immunization elicits an antigen‐specific CD4+ T‐cell response, suggesting that DC/gps present MHC class II epitopes to CD4+ T cells. In addition, our data show that gene‐modified, DC‐based vaccines are more effective than the naked DNA‐based vaccines at eliciting anti‐tumor immunity in both prophylactic and therapeutic models. These results suggest that the use of DCs transfected with plasmid DNA containing a gene for TAA may be superior to peptide‐pulsed DCs and naked DNA‐based vaccines for immunotherapy and could provide an alternative strategy for tumor vaccine design. Int. J. Cancer 83:532–540, 1999.

A pilot trial of digital imaging in skin cancer.

We have used inexpensive off-the-shelf equipment for store-and-forward teledermatology and compared the precision and accuracy of digital image consultations with conventional, clinic-based consultations. Thirteen lesions were studied on 12 patients referred to a dermatology clinic for a suspected skin cancer. Patients were examined by two dermatologists. Subsequently, digital images were examined by two different dermatologists. There was almost complete agreement, both among and between the clinical and digital examiners, on differential diagnosis and biopsy recommendations. Agreement on the single most likely diagnosis was also good. Digital imaging shows promise in teledermatology.

Human recombinant stem-cell factor induces melanocytic hyperplasia in susceptible patients☆

BACKGROUND Recombinant human stem-cell factor (SCF), a cytokine acting on hematopoietic progenitor cells, has potential for the treatment of several hematologic and oncologic disorders. In a hematology-oncology phase I trial of SCF, several patients had cutaneous hyperpigmentation at the SCF subcutaneous injection sites. OBJECTIVE Our purpose was to investigate the pathogenesis of this hyperpigmentation phenomenon. METHODS Skin biopsy specimens were obtained before, at the completion of, and after SCF therapy and were processed for histology, immunohistology, and electron microscopy. RESULTS Skin at the site of SCF injection had an increased number of melanocytes, increased melanocytic dendrite extension, and melanin as compared with noninjected tissue. Immunohistochemical stains revealed an increase in staining with melanocyte-specific monoclonal antibodies HMB-45 and NKI/beteb, and a monoclonal antibody to the receptor for SCF, c-kit. CONCLUSION Subcutaneous injection of SCF results in hyperplasia of melanocytes. SCF may be useful in the treatment of melanocytopenic disorders, but caution may be necessary in patients with disorders of melanocyte proliferation.

α-Melanocyte-Stimulating Hormone–Induced Eruptive Nevi

BACKGROUND Synthetic peptides that target proopiomelanocortin receptors are being investigated as a novel and safe way to tan. It has been postulated that synthetic alpha-melanocyte-stimulating hormone (alpha-MSH) peptides may have protective effects against the development of melanoma because of their melanogenic activity. Their ultimate biological effect, however, especially in patients with dysplastic nevi or previous melanoma, has yet to be determined. OBSERVATIONS A 40-year-old white man with a history of melanoma and multiple dysplastic nevi self-administered synthetic alpha-MSH. He developed crops of new pigmented nevi, many of which had atypical clinical and histopathologic features. The preexisting nevi became darker and acquired growth features. After alpha-MSH use was discontinued, the nevi progressively lightened and lost their growth features. CONCLUSIONS Synthetic alpha-MSH peptides can drive proliferation of neoplastic melanocytic cells in predisposed patients. This could present an increased risk for melanoma development.

Dermoscopy Key Points: Recommendations from the International Dermoscopy Society

J. Bowling G. Argenziano A. Azenha J. Bandic R. Bergman A. Blum H. Cabo A. Di Stephani J. Grichnik A. Halpern R. Hofman-Wellenhof R. Johr H. Kittler A. Kopf J. Kreusch D. Langford J. Malvehy A. Marghoob S. Menzies F. Ozdemir K. Peris D. Piccolo M.A. Pizzichetta D. Polsky S. Puig H. Rabinovitz P. Rubegni T. Saida M. Scalvenzi S. Seidenari H.P. Soyer M. Tanaka I. Zalaudek R.P. Braun

An improved objective evaluation measure for border detection in dermoscopy images

Background: Dermoscopy is one of the major imaging modalities used in the diagnosis of melanoma and other pigmented skin lesions. Owing to the difficulty and subjectivity of human interpretation, dermoscopy image analysis has become an important research area. One of the most important steps in dermoscopy image analysis is the automated detection of lesion borders. Although numerous methods have been developed for the detection of lesion borders, very few studies were comprehensive in the evaluation of their results.

Probing skin pigmentation changes with transient absorption imaging of eumelanin and pheomelanin

As some of the most ubiquitous and biologically important natural pigments, melanins play essential roles in the photoprotection of skin. Changes in melanin production could potentially be useful for clinical diagnosis of the progression stage of melanoma. Previously we demonstrated a new method for imaging melanin distribution in tissue with two-color transient absorption microscopy. Here we extend this study to longer wavelengths and show that we are able to image melanin in fixed thin skin slices with higher signal-to-noise ratios (SNRs) and demonstrate epimode imaging. We show that both photothermal effects and long-lived excited states can contribute to the long-lived signal. Eumelanin and pheomelanin exhibit markedly different long-lived excited state absorption. This difference should enable us to map out their respective distribution in tissue samples with subcellular resolution. This technique could provide valuable information in diagnosing the malignant transformation of melanocytes.

What is the oncologic risk of stem cell treatment for heart disease

See related article, pages 1340–1347 Every therapy has toxic and therapeutic windows, and defining the side effects of any new therapeutic modality is the first order of business in the development of a treatment. With transformative therapies such as cell-based approaches, treatment side effects can be unpredictable and unanticipated. In some cases, experimental data raise serious concerns that must be appropriately managed. In the face of the promise and enthusiasm for cell-based therapy for heart disease, results from rodent experiments have consistently raised the specter of a dreaded side effect—can the use of stem cells lead to cancer, either directly or through promotion of existing early-stage neoplasms? Mesenchymal stem cells (MSCs) are a multipotent immunotolerant cell source that can be readily expanded into therapeutic quantities from a variety of tissues such as the bone marrow, cord blood, and fat, and as such their use in cell-based therapeutic strategies holds great promise.1 With regard to heart disease, accumulating preclinical2–11 and clinical studies12–15 demonstrate that MSC transplantation may be salutary for both acute myocardial infarction and cardiomyopathy with an acceptable risk profile. The translational development of cell-based therapy has required rigorous large-animal experimentation, recognizing inherent limitations with rodent experimentation. In this context, more than 500 large animals (swine, canine, and sheep) have been tested to assess the safety and efficacy of MSC therapeutics for treating heart disease with the results demonstrating that MSC transplantation is a safe and durable approach that may be more effective than bone marrow mononuclear cells.16 Importantly, large-animal work provides a phenotyping opportunity not available in rodents, and rigorous cardiac MRI (CMR) and histological analysis in porcine hearts supported the regenerative effects subsequently demonstrated in the adult human heart.12,15 The mechanism of action appears multifaceted, involving direct …