Fluorescence in Situ Hybridization (FISH) for Distinguishing Nevoid Melanomas From Mitotically Active Nevi

Gerami, Pedram; Wass, Amanda; Mafee, Mariam; Fang, Yuaquin; Pulitzer, Melissa P.; Busam, Klaus J.

The American Journal of Surgical Pathology. 33(12):1783-1788, December 2009.:

Nevoid melanoma may resemble benign compound or intradermal nevi by their silhouette and profile on low power. Higher power usually reveals nuclear atypia, confluence of cells, incomplete maturation and dermal mitotic activity. However, to some extent all of these features maybe seen in benign compound or intradermal nevi and no single criteria can be used to differentiate nevoid melanoma from a benign nevus. The distinction can be particularly problematic in nevi that show mitotic activity and we have noted a recent trend in diagnosis of melanocytic neoplasms with dermal mitosis as nevoid melanoma despite the presence of normal maturation in the dermis and lack of significant nuclear atypia. Therefore in this study we evaluated 10 nevoid melanomas, 4 of which resulted in metastasis and 10 mitotically active nevi with fluorescence in situ hybridization targeting key chromosomal loci previously shown to effectively discriminate been malignant and benign melanocytic neoplasms. All 10 nevoid melanomas showed copy number abnormalities by fluorescence in situ hybridization in either chromosome 6 or 11 while none of the 10 mitotically active nevi did. The results demonstrate that fluorescence in situ hybridization targeting key chromosomal loci on chromosomes 6 and 11 can be effective in discriminating nevoid melanomas from mitotically active nevi. Additionally, our study presents further evidence that dermal mitoses alone without other diagnostic features such as nuclear atypia and lack of maturation does not constitute sufficient evidence alone for a diagnosis of melanoma.
(C) 2009 Lippincott Williams & Wilkins, Inc.

Atypical Spitzoid melanocytic tumours in children

Am J Surg Pathol. 2009 Sep;33(9):1386-95.

Atypical spitzoid melanocytic tumors with positive sentinel lymph nodes in children and teenagers, and comparison with histologically unambiguous and lethal melanomas.

Busam KJ, Murali R, Pulitzer M, McCarthy SW, Thompson JF, Shaw HM, Brady MS, Coit DG, Dusza S, Wilmott J, Kayton M, Laquaglia M, Scolyer RA.

Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. busamk@mskcc.org

Children and teenagers with a positive sentinel lymph node (SLN) after a prior diagnosis of an atypical spitzoid melanocytic tumor (ASMT) are usually cared for clinically in the same way as patients with melanoma. Little is known about long-term follow-up of these individuals to determine whether this practice is appropriate. To learn more about the biology of these tumors we retrospectively reviewed the clinical and pathologic findings of children and teenagers (<18 y of age at the time of diagnosis) with an ASMT, positive SLN and follow-up of at least 3 years. Their findings were compared with histologically unambiguous melanomas of children or teenagers, who had a positive SLN or died of metastatic melanoma. Eleven individuals, 6 girls and 5 boys, with primary ASMT and positive SLN were identified. The primary tumors ranged in thickness from 2.1 to 12 mm (median, 4.6 mm; mean, 5 mm). The tumor mitotic rate ranged from 1 to 10 mitoses/mm (median, 3/mm, median, 3/mm). The positive SLNs included 6 nodes with intranodal melanocytic aggregates measuring <1 mm in greatest dimension, and 5 nodes, in which the size of the melanocyte deposits was >/=1 mm. All the patients with ASMT and positive SLN remained free of disease with a median follow-up of 47 months (mean, 61 mo, range: 36 to 132 mo). In contrast, 2 of 5 patients <18 years of age with a histologically unambiguous melanoma and a positive SLN died of metastatic melanoma. The overall disease-specific mortality rate for all patients <18 years of age diagnosed with melanoma was 12%. Our findings confirm that children and teenagers with ASMTs and positive SLNs have a less aggressive clinical course than those with histologically unambiguous melanoma.

Heavily Pigmented Melanocytic lesions

Heavily Pigmented Melanocytic Lesions: A Spectrum of Lesions with a Different Prognosis

Are these lesions indeed a horse of a different color when it comes to outcomes?

Older gray horses frequently develop heavily pigmented lesions around the anus, lips, and eyelids. A human variant of malignant melanoma resembling these lesions is called "animal-type" or "equine-type melanoma." A small number of these lesions have been reported, with some authors indicating that the course is indolent compared with conventional melanoma. These authors examined the prognostic significance of the clinical and pathologic features of such lesions.
They identified 22 patients with a diagnosis of animal/equine/pigmented synthesizing melanoma or pigmented epithelioid melanocytomas from one institution. Diagnosis was unequivocal in 14 cases. Median patient age was 35. Dysplastic nevi were found in 41%; only 9% had blue nevi without evidence of Carney complex. Ulceration was unusual; 68% of the lesions were raised, and more than half were larger than 6 mm. The head, neck, trunk, and upper extremities were the most frequent sites. The median lesion depth was 2.22 mm; more than half were in the reticular dermis. Mitosis was seen in all lesions; more than one mitotic cell was found in 41%. Sentinel lymph node (SLN) biopsy samples were taken from 17 patients; eight were positive and involved more than 1% of the lymph node. These patients underwent complete lymph node excision, and only one had an additional positive nonsentinel lymph node. Lesion depth was not significantly associated with positivity, but the positive SLN patients were older. No histologic features predicted SLN involvement, distant metastasis, or death.
Comment: The differential diagnosis of a heavily pigmented melanocytic lesion is epithelioid blue nevus and animal-type melanoma. Histological overlap and wildly ranging behavior among these lesions prompts a suggestion that the term "pigmented epithelioid melanocytoma" be applied to the full spectrum of these tumors. Unlike in conventional melanoma, younger patients with heavily pigmented lesions have a lower risk for positive SLN, but with either lesion type, the low likelihood of distant metastasis confers a good prognosis for young patients. Whether dermatopathologists call heavily pigmented lesions in young patients animal-type melanoma or epithelioid melanocytomas, the evidence predicts an indolent course.
— Angelica Maria Selim, MD
Published in Journal Watch Dermatology January 22, 2010

Citation(s):

Ludgate MW et al. Animal-type melanoma: A clinical and histopathological study of 22 cases from a single institution. Br J Dermatol 2010 Jan; 162:129.

SLNB and thick melanomas

 Original Article

Is there a benefit to sentinel lymph node biopsy in patients with T4 melanoma?

Csaba Gajdos, MD 1, Kent A. Griffith, MPH, MS 2, Sandra L. Wong, MD 1, Timothy M. Johnson, MD 1 3, Alfred E. Chang, MD 1, Vincent M. Cimmino, MD 1, Lori Lowe, MD 4, Carol R. Bradford, MD 5, Riley S. Rees, MD 1, Michael S. Sabel, MD 1 *

1Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan 2Biostatistics Core, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 3Department of Dermatology, University of Michigan Health System, Ann Arbor, Michigan 4Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan 5Department of Otolaryngology, University of Michigan Health System, Ann Arbor, Michigan

email: Michael S. Sabel (msabel@umich.edu)

^*Correspondence to Michael S. Sabel, 304 Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0932

Fax: (734) 647-9647

KEYWORDS

Breslow depth • interferon • melanoma • sentinel lymph node biopsy

ABSTRACT

BACKGROUND:

Controversy exists as to whether patients with thick (Breslow depth >4 mm), clinically lymph node-negative melanoma require sentinel lymph node (SLN) biopsy. The authors examined the impact of SLN biopsy on prognosis and outcome in this patient population.

METHODS:

A review of the authors' institutional review board-approved melanoma database identified 293 patients with T4 melanoma who underwent surgical excision between 1998 and 2007. Patient demographics, histologic features, and outcome were recorded and analyzed.

RESULTS:

Of 227 T4 patients who had an SLN biopsy, 107 (47%) were positive. The strongest predictors of a positive SLN included angiolymphatic invasion, satellitosis, or ulceration of the primary tumor. Patients with a T4 melanoma and a negative SLN had a significantly better 5-year distant disease-free survival (DDFS) (85.3% vs 47.8%; P < .0001) and overall survival (OS) (80% vs 47%; P < .0001) compared with those with metastases to the SLN. For SLN-positive patients, only angiolymphatic invasion was a significant predictor of DDFS, with a hazard ratio of 2.29 (P = .007). Ulceration was not significant when examining SLN-positive patients but the most significant factor among SLN-negative patients, with a hazard ratio of 5.78 (P = .02). Increasing Breslow thickness and mitotic rate were also significantly associated with poorer outcome. Patients without ulceration or SLN metastases had an extremely good prognosis, with a 5-year OS >90% and a 5-year DDFS of 95%.

CONCLUSIONS:

Clinically lymph node-negative T4 melanoma cases should be strongly considered for SLN biopsy, regardless of Breslow depth. SLN lymph node status is the most significant prognostic sign among these patients. T4 patients with a negative SLN have an excellent prognosis in the absence of ulceration and should not be considered candidates for adjuvant high-dose interferon. Cancer 2009. © 2009 American Cancer Society.

Melanoma Excision Margins

Surgical excision margins for primary cutaneous melanoma

Whilst melanoma accounts for only 5% of skin cancers, it is important because it is the cause of 75% of all skin cancer deaths. For primary cutaneous melanoma, standard treatment is complete surgical removal of the melanoma with a safety margin some distance from the visible edges of the primary tumour. The purpose of the safety margin is to remove both the primary tumour and any melanoma cells that might have spread into the surrounding skin. However, the optimal width of the safety (excision) margin remains unclear.

This systematic review summarises the evidence about how much tissue (safety margin) should be removed for primary cutaneous melanoma (skin cancer). Excision margins are important because there could be a trade-off between a better cosmetic result but poorer long-term survival if excision margins become too narrow.

It is important to note that for the purposes of this review we consider only invasive melanoma - that has invaded into the deeper layer of the skin (dermis) - and not melanoma-in-situ where the melanoma cells are confined to the outermost layer of the skin (epidermis).

We found five published randomised trials, none of which showed a statistically significant difference in overall survival for patients who had either narrow or wide removal of the melanoma and surrounding tissue. Similarly, our meta-analysis showed there was no statistically significant difference in overall survival between the two groups treated with either narrow or wide excision.

The summary estimate for overall survival favoured wide excision by a small degree, but the result was not significantly different. This result is compatible with both a 5% relative reduction in overall mortality favouring narrower excision and a 15% relative reduction in overall mortality favouring wider excision.

Current randomised trial evidence is insufficient to address optimal excision margins for primary cutaneous melanoma.

The Cochrane Review on this issue can be downloaded here

Acral Lentiginous Melanoma removal

Acral lentiginous melanoma: conventional histology vs. three-dimensional histology
V. Lichte, H. Breuninger, G. Metzler, H.M. Haefner and M. Moehrle
Department of Dermatology, Universitätsklinikum Tübingen, Eberhard-Karls-Universität, Liebermeisterstr. 25, D-72076 Tübingen, Germany
British Journal of Dermatology
Volume 160 Issue 3, Pages 591 - 599
Correspondence to Verena Lichte.
E-mail: verena.lichte@med.uni-tuebingen.de

ABSTRACT
Background Patients with acral lentiginous melanoma (ALM) seem to have a poor prognosis. ALMs represent 4–10% of cutaneous melanomas in white populations. Surgery is mostly based on conventional histological evaluation. With micrographic surgery, continuously spreading tumours can be excised with smaller excision margins for better cosmesis and function.

Objectives Clinical parameters and surgical strategies influencing the prognosis of patients with ALM were evaluated.

Methods Two hundred and forty-one patients (44% male, 56% female) with stage I/II ALM were recorded during 1980–2006. One hundred and thirty-three patients underwent complete histology of three-dimensional excision margins (3D histology) using the paraffin technique. Risk factors for disease-specific and recurrence-free survival were estimated.

Results Patients were aged 26–87 years (median 63) with median tumour thickness of 2·0 mm. The median follow-up was 41 months. Multivariate analysis identified ulceration, conventional histology and tumour thickness as risk factors for recurrence-free and disease-specific survival. Using 3D histology, excision margins were significantly smaller (median 7 vs. 20 mm) without an increased risk of local recurrences. Patients with 3D histology had a 5-year survival of 81% compared with 63% with conventional histology. Retrospective analysis with immunohistological methods (anti-Melan-A) could improve the diagnostic specificity in detecting further melanocytic cell nests.

Conclusions Clinical and surgical risk factors seem to have different influences on the outcome of ALM. 3D histology allows reduction of excision margins by two-thirds without an increased risk of local recurrences and with better prognosis. 3D immunohistology could be a valuable diagnostic tool to reduce the rate of local recurrences.

Following up Spitz nevi

Spitz Nevus: Follow-Up Study of 8 Cases of Childhood Starburst Type and Proposal for Management
Massimiliano Ninoa, Bruno Brunettic, Sergio Delfinod, Beniamino Brunettid, Luigia Panarielloa, Daniela Russob
Dermatology 2009;218:48-51 (DOI: 10.1159/000161120)

Spitz nevus is an uncommon, benign melanocytic neoplasm that shares many clinical and histological features with melanoma. It presents clinical ambiguity that makes the diagnosis and management of the patient difficult. We present our experience in the management of Spitz nevus by rigorous dermoscopic long-term follow-up of 8 Spitz nevi in patients younger than 12 years. Dermoscopic images, acquired every 6 months, show evolution and modifications of these lesions. The aim of this paper is to better understand the long-term modifications of nevi with starburst pattern to avoid surgical excision of these lesions in the pediatric age group.

(I will try to get a copy of this article and post it in Skin Cancer Consult.)

Skin Cancer Research Review

The latest issue of Skin Cancer Research review by Prof Petyer Soyer can be viewed here. Some of the articles we have covered already but they are well presented in this Review. Get it here.

Risk factors and Prognosis of SCC

The Lancet Oncology Early Online Publication, 9 July 2008

Lancet Oncology DOI:10.1016/S1470-2045(08)70178-5

Articles


Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study
Kay D Brantsch MD a, Christoph Meisner PhD b, Birgitt Schönfisch PhD b, Birgit Trilling Dipl Inform Med c, Jörg Wehner-Caroli MD a, Prof Martin Röcken MD a and Prof Helmut Breuninger MD a

Summary
Background
Cutaneous squamous-cell carcinomas (SCC) are among the most common cancers capable of metastasis. Current Tumour Node Metastasis (TNM) staging includes horizontal tumour size, involvement of extradermal structures, and degree of differentiation. The aim of this study was to prospectively analyse the key factors predicting metastasis and local recurrence in cutaneous SCC.

Methods
We assessed prospectively investigated potential risk factors for metastasis or local recurrence of SCC, previously suggested by retrospective studies and small case series, in 615 white patients. Between Jan 1, 1990, and Dec 31, 2001, all patients underwent surgery for cutaneous SCC with complete histological examination of the three-dimensional excision margins (3D-histology) in one centre. Univariate and multivariate analysis included tumour thickness, horizontal size, body site, histological differentiation, desmoplastic growth, history of multiple SCC, and immunosuppression. Primary endpoints were time to metastasis and time to local recurrence, defined as the time from date of diagnosis of the primary tumour to the date of diagnosis of metastasis or local recurrence, respectively.

Findings
653 patients were enrolled in the study. 38 patients were lost to follow-up leaving 615 assessable patients (median age 73 years [range 27–98]). During a median follow-up period of 43 months (range 1–165), 26 (4%) of 615 patients developed metastases and 20 patients developed local recurrence (3%). Tumours 2·0 mm or less in thickness did not metastasise. Metastases occurred in 12 (4%) of 318 tumours between 2·1 mm and 6·0 mm in thickness, and in 14 (16%) of 90 tumours with a thickness greater than 6·0 mm. On multivariate analysis, key prognostic factors for metastasis were increased tumour thickness (hazard ratio 4·79 [95% CI 2·22–10·36]; p<0·0001), immunosuppression (4·32 [1·62–11·52]; p=0·0035), localisation at the ear (3·61 [1·51–8·67]; p=0·0040), and increased horizontal size (2·22 [1·18–4·15]; p=0·0128). The risk of local recurrence depended on increased tumour thickness (6·03 [2·71–13·43]; p<0·0001) and desmoplasia (16·11 [6·57–39·49]; p<0·0001).

Interpretation
Only SCC greater than 2·0 mm in thickness are associated with a significant risk of metastasis. Tumours greater than 6·0 mm are associated with a high risk of metastasis and local recurrence. Desmoplastic growth is an independent risk factor for local recurrence. Studies should assess the role of follow-up visits and sentinel-lymph-node biopsy in high-risk patients.

Also, This Summary of the article came from Journal Watch

Which Squamous Cell Carcinomas Are the Bad Actors?
Tumor thickness, immunosuppression, location on the ear, and horizontal size were associated with increased risk for metastasis in cutaneous SCC.


Squamous cell carcinoma (SCC) is seen daily in most dermatologists’ offices. Most are taken care of, never to be heard from again, but, occasionally, an SCC will recur or metastasize. In this prospective, longitudinal study from Germany, 615 white patients with primary SCC referred to a university dermatology department for definitive treatment were followed for at least 4 years. The tumors were resected using "3D-histology," which consists of en face examination of the peripheral and deep margins and vertical sections from the center of the specimen with examination of permanent sections. The data were subject to rigorous multivariate analysis.

Metastases developed in 4% of patients. The first metastatic focus was always in the regional draining lymph nodes. The risk for metastasis increased with tumor thickness, location on the ear, horizontal tumor size, and immunosuppression. No metastasis occurred in tumors that were 2.0 mm or thinner; 4% of tumors 2.1 mm to 6.0 mm thick metastasized, as did 16% of tumors thicker than 6.0 mm. Lip lesions and poorly differentiated lesions were not associated with increased risk for metastasis. Local recurrences developed in 3% of patients, all within 6 years. Recurrence developed in 12% of tumors thicker than 6 mm and 24% of tumors with a desmoplastic histologic pattern.

Comment: This study confirms what we see in practice: SCCs that are thick, large, desmoplastic, poorly differentiated, or present in immunosuppressed patients behave more aggressively. To the ear, I would add lip, temple, and genitals as locations of more-aggressive SCC lesions. The number of patients in the study may have been too small to detect differences for other anatomic sites.
— George J. Hruza, MD

IMP-3 as a marker of Melanoma

Modern Pathology (2008) 21, 431–437; doi:10.1038/modpathol.3801016; published online 18 January 2008

IMP-3 is a novel progression marker in malignant melanoma
Jennifer G Pryor1, Patricia A Bourne1, Qi Yang1, Betsy O Spaulding2, Glynis A Scott3 and Haodong Xu1

Abstract
Insulin-like growth factor-II messenger RNA (mRNA)-binding protein-3 (IMP-3), also known as K homology domain-containing protein overexpressed in cancer (KOC) and L523S, is a member of the insulin-like growth factor-II mRNA-binding protein family and is expressed during embryogenesis and in some malignancies. IMP-3 expression in melanocytic neoplasms has not been investigated. Fifty-six melanocytic neoplasms from 48 subjects were immunohistochemically studied using a monoclonal antibody against L523S/IMP-3. IMP-3 expression in melanoma was significantly higher than in Spitz nevi (P<0.05), and the staining intensity in the Spitz nevi was weak. IMP-3 expression in metastatic melanoma was significantly higher than in primary cutaneous melanoma with a Breslow depth 1 mm (P<0.01). None of the benign nevi and dysplastic nevi expressed IMP-3. Our study demonstrates that IMP-3 is expressed in malignant melanoma but not in benign nevi, even when dysplastic features are present; IMP-3 is expressed in a significantly higher proportion of melanomas than Spitz nevi; and IMP-3 is expressed in metastatic melanomas significantly more than in thin melanomas. In conclusion, IMP-3 appears to be involved in the progression of malignant melanoma and may play an important role in the regulation of the biologic behavior of this tumor. Additionally, IMP-3 may have diagnostic utility in distinguishing melanoma from benign nevic cells, dysplastic nevi, and Spitz nevi.

Stem Cells

Stem Cells 101
How these powerful entities operate and some recent developments in stem cell biology


REVIEW SUMMARY

1. Stem cells (SCs) are divided into two main types:


Embryonic stem cells derive from the blastocyst and can, in theory, give rise to all cell types in an organism.

Adult stem cells derive from mature tissue and usually have a restricted spectrum of possible differentiation (e.g., epidermal stem cells).


2. Stem cells have two cardinal features:


The ability to self-renew indefinitely through cell division

The ability to differentiate into varying cell types


3. Biologists have begun to unravel the genetic determinants that dictate "stemness."

4. Normal skin fibroblasts can be "reprogrammed" into a stem-cell–like phenotype (induced pluriopotent stem cells) through the introduction of a limited number of genes.

5. Stem cell therapy is theoretically ideal for degenerative human disorders; proof-of-principle has already been established in mice models of disease.

Stem cells have been a source of tremendous promise and controversy during the past decade. Some contention derives from conflicts between secular and religious definitions of life. Another source of controversy is the imprecise use of stem cell terminology and concepts. The purpose of this brief review is to clarify principles and showcase some recent advances in SC biology.

FUNCTIONAL ATTRIBUTES

SCs have traditionally been defined by their functional attributes. There are two cardinal features of all SCs. The first is self-renewal — the capacity to go through indefinite cycles of cell division while maintaining an undifferentiated state. To self-renew, SCs undergo either symmetric division or asymmetric division. In symmetric division, a stem cell gives rise to two identical daughter cells, both endowed with SC properties:

A A + A*
In asymmetric division, an SC gives rise to one stem cell and one progenitor cell with limited self-renewal potential:

A A + B*
Progenitor cells have the capacity to undergo several cycles of cell division,

B B + B*
but unlike stem cells, will eventually differentiate terminally.

B C + C*
(*A = adult stem cell; B = progenitor cell; C = terminal, differentiated cell)

The mechanisms that govern the activation of symmetric versus asymmetric division and that determine which daughter cells will be stem cells and which will be progenitor cells are still unclear.

The second cardinal feature of all SCs is potency — the ability to differentiate into specialized cell types. There are four major types of potency:


Totipotency is the ability of a single cell to expand in number, differentiate into embryonic and extraembryonic tissues, and develop into an organism.

Pluripotency is the ability to differentiate into any of the three germ layers: endoderm, mesoderm, or ectoderm.

Multipotency is the capacity to produce a related family of cells (e.g., hematopoietic SCs differentiate into various blood cell types).

Unipotency is the ability to differentiate into just one cell type (e.g., epidermal SCs generate only keratinocytes). Different sources and types of SCs may harbor different types of potency.


STEM CELL CLASSES
The two large classes of SCs are embryonic stem cells (ESCs), which are found in developing blastocysts, and adult stem cells (ASCs), which are found in mature tissues. ESCs derive from fertilized embryos; specifically, they are isolated from the epiblast tissue of the inner cell mass of a blastocyst or earlier morula. In humans, a blastocyst comprises about 50 to 150 cells and is approximately 4 to 5 days old. ESCs conform to the definition of pluripotency, in that they can develop as all three primary germ layers: ectoderm, endoderm, and mesoderm. ESCs do not contribute to the extraembryonic membranes or the placenta. Although there are phenotypic similarities between mouse and human ESCs, each requires very distinct experimental conditions for study.

ASCs can be found in the developed organism in both children and adults. ASCs are also known as somatic SCs and are often lineage-restricted (i.e., multipotent but not pluripotent). In the fully formed organism, ASCs are conventionally described according to the tissue of origin (e.g., epidermal SCs, adipose SCs, mesenchymal SCs). For instance, a certain type of ASC, the hematopoietic stem cell (HSC), has been used for decades in the treatment of certain bloodborne cancers. Bone marrow transplantation is successful because HSCs transfer and engraft. Michele De Luca and colleagues recently applied SC technology to treatment of junctional epidermolysis bullosa (JW Dermatol Jan 26 2007 and Nat Med 2006; 12:1397). From palmar skin, they isolated putative SCs, into which they introduced the defective laminin 5 (LAM5) subunit and used the engineered cells to prepare genetically corrected cultured epidermal grafts. The autologous grafts showed synthesis and proper assembly of normal levels of functional LAM5. Even after a year, the engineered epidermis remained stable and adherent without blisters, infections, inflammation, or immune response. Although longer-term follow-up with more patients is needed to validate this study, the use of ASCs for certain targeted tissues is appealing, as it does not involve embryos.

IDENTIFYING STEM CELLS AND STEM CELL UTILITY
The identification and isolation of SCs has been challenging. No single fixed criterion offers indisputable evidence of "stemness." The sine qua non of an SC is its ability to regenerate a certain tissue over the life of the organism; thus, SCs are particularly attractive therapeutic models for degenerative diseases, such as neuronal degeneration in Parkinson disease or pancreatic degeneration in diabetes. An extant example of SC utility is the reconstitution of a complete immune system from bone marrow, which, presumably, contains hematopoietic SCs. In vitro assays help us understand the cellular behavior of SCs. For example, in the well-established clonogenic assay, SCs are characterized by their capacity to form colonies in tissue culture plates when seeded at low density. By contrast, committed cells that have limited replicative or survival potential will not undergo enough rounds of cell division to form clonal colonies. More-recent work has attempted to identify SCs based on protein or RNA markers. For instance, ESCs have been isolated and found to express transcription factors that appear to maintain pluripotency (Cell 2005; 122:947). The ability to point to the master regulators of "stemness" has been leveraged to create a new generation of induced SCs from adult tissue.

STEM ALCHEMY: INDUCED PLURIPOTENT STEM CELLS
In the Middle Ages, the art of transforming common metals into gold became a source of great mystical enthusiasm (and ultimate disappointment). Given the controversial nature and rarity of ESCs, the transformation of somatic cells into ESCs has similarly engendered great excitement in the past few years. Unlike the alchemists, however, current researchers have had some successes in SC engineering that may eventually find a therapeutic outlet.

The theoretical framework for production of induced pluripotent stem cells (iPSCs) is relatively straightforward: Identify a set of genes that define the "stemness" of ESCs and then "reprogram" adult cells as ESC-like cells by introducing these genetic factors into the somatic cells. Induced PSCs were first generated in mice in 2006 (Cell 2006; 126:663). Initial observations showed that four key genes were essential for reprogramming differentiated cells into the pluripotent state: Oct-3/4, Sox2, c-Myc, and Klf4. Despite similarities with ESCs, early iPSC lines failed to produce viable chimeras when injected into mouse embryos; thus, they do not fulfill the in vivo criteria for ESCs. Chimeras are animals that develop from different genetic sources — in this case, animals derived from both the host and the iPSCs. Subsequent refinements in technique have led to the successful reprogramming of mouse fibroblasts into iPSCs that can, in fact, produce viable chimeras (Nature 2007; 448:313 and Nature 2007; 448:318), thereby fully substantiating their pluripotent nature.

Induced PSCs have been shown to be similar to ESCs in morphology, growth properties, and the expression of SC genes and SC markers. Most critically, iPSCs can be triggered to differentiate into cardiac and neural cells as well as form viable mouse chimeras. A major concern among iPSC investigators is the use of c-Myc — a known oncogene — in the reprogramming; in fact, a significant fraction of the derived mice later developed cancer. A more recent protocol may make it possible to dispense with c-Myc (Nat Biotechnol 2008; 26:101).

Figure 1: Skin fibroblasts as the source of pluripotent human stem cells of the future
Reprinted with permission from Macmillan Publishers Ltd: Nature Medicine copyright 2007.

Differentiated cells, such as skin fibroblasts, are isolated and genetically reprogrammed to become iPSCs via the introduction of certain genes such as POU5F1, MYC, KLF4, and SOX2. These genes in turn induce the expression of SC master regulators, POU5F1 and NANOG. The iPSCs can then be recovered and redifferentiated into therapeutically regenerative cells and tissue. For details, see Nat Med 2007; 13:783.

THERAPEUTIC IMPLICATIONS
So what are the potential therapeutic implications of iPSCs? No human trials of iPSCs are under way, but at MIT, Rudolf Jaenisch and colleagues have recently shown that fibroblasts can be reprogrammed into fully functional blood cells in a humanized mouse model of sickle cell anemia (Science 2007; 318:1917). The same group also showed that iPSCs can be efficiently differentiated into neural precursor cells; transplanted into the fetal mouse brain; and successfully form glia and neurons, including glutamatergic, GABAergic, and catecholaminergic subtypes. In addition, when transplanted into the adult brain in a rat model of Parkinson disease, these iPSCs were able to improve behavior (Proc Natl Acad Sci U S A 2008; 105:5856). Studies involving skin disease will undoubtedly be published over the course of the next few years.

The National Institutes of Health provide a good introductory discussion of stem cells and a useful glossary of related terms.

— Hensin Tsao, MD, PhD

Published in Journal Watch Dermatology June 13, 2008

UV Light and changes in nevi

This article looked at the changes in benign nevi after exposure to narrow band UVB and UVA. Both modalities caused significant dermatoscopic changes that should be taken into consideration if monitoring nevi in sun exposed areas.

J Am Acad Dermatol. 2008 May;58(5):763-8. Epub 2008 Jan 30.
Repeated equally effective suberythemogenic exposures to ultraviolet (UV)A1 or narrowband UVB induce similar changes of the dermoscopic pattern of acquired melanocytic nevi that can be prevented by high-protection UVA-UVB sunscreens.Manganoni AM, Tucci G, Venturini M, Farisoglio C, Calzavara-Pinton PG.
Department of Dermatology, University of Brescia, Brescia, Italy.

BACKGROUND: Sunlight modifies the size and the dermoscopic pattern of acquired melanocytic nevi (AMN). OBJECTIVE: We investigated whether repeated exposures to equally effective suberythemogenic doses of ultraviolet (UV)A or UVB can induce changes in the dermoscopic features of AMN. METHODS: Twenty volunteers received equally effective doses of narrowband UVB or UVA1. During exposures, an AMN was covered with an opaque tape, another was shielded with the sunscreen, and another was left unprotected.

RESULTS: Nevi exposed to either narrowband UVB and UVA1 showed statistically significant changes in their dermoscopic features: increased size, increase of pigment network, overall color darkening, formation of focal branched streaks, and increased number and size of brown dots and globules. LIMITATIONS: The study is a clinical cohort study on a small number of selected patients. CONCLUSION: AMN show similar changes in size and dermoscopic pattern after narrowband UVB and UVA1 exposures.

Blink versus Systematic examination in Dermoscopy

Melanoma mimicking seborrheic keratosis: an error of perception precluding correct dermoscopic diagnosis.Braga JC, Scope A, Klaz I, Mecca P, Spencer P, Marghoob AA.
Department of Dermatology, Memorial Sloan-Kettering Cancer Center, New York, New York 10022, USA.

Seborrheic keratosis is a common skin lesion that can usually be recognized either clinically or dermoscopically. However, melanomas mimicking seborrheic keratoses, as well as melanomas arising in association with seborrheic keratoses, have been described. We report the case of a patient with a lesion that initially revealed "classic" dermoscopic features of a seborrheic keratosis. However, during follow-up, changes in color developed within the center of the lesion that led the clinician to the correct diagnosis of melanoma. Upon retrospective evaluation of the baseline image of the lesion; the clinician was now able to "see" that which his brain could not appreciate on initial examination and to realize that the lesion had subtle features suspect for melanoma. This case represents a diagnostic pitfall due to errors in perception. Dermatologists should be cognizant of "errors in perception"; we suggest that a final dermoscopic judgment of a seborrheic keratosis be rendered by combining the gestalt diagnosis of the overall pattern, with deliberate dermoscopic analysis of all quadrants of the lesion.

PMID: 18328596 [PubMed - indexed for MEDLINE]
From Club Dermaweb
A dermatologist’s brain will always favour the overall impression of the right side of the brain over the detailed analysis of the left side of the brain, both with a dermoscope as well as with the naked eye. The first is intuitive, fast and often very beneficial and efficient. Detailed rational analysis, which involves looking at the tumour section by section and studying all the basic signs and dermoscopic patterns, is tedious and slow. It is therefore logical that the dermatologist’s first impression tends to influence the way he/she interprets the detailed analysis, or even convince them not to do it. In this example a pigmented lesion of the neck found during a routine examination was quickly identified as seborrheic keratosis because he/she found numerous pseudo-horny cysts. When the patient was seen a year later, the lesion was a lot darker and had a blue-white veil. Excision was performed and an SSM associated with seborrheic keratotic-like epidermal hyperplasia was found, even though it wasn’t possible to distinguish between a verrucous melanoma and a composite lesion. The dermatologist looked at the initial dermoscopic image again and noticed that some aspects which suggested MM were already present a year earlier in a limited area at the periphery of the lesion. Papillomatous epidermal hyperplasia with pseudo-horny cysts has already been found in a small number of cases of malignant melanomas and does not allow this diagnosis to be officially ruled out. The error in perception which makes dermatologists favour the overall picture in relation to detailed analysis should be kept in mind to avoid mistakes like this.

Sidedness and Melanoma

Left-Sided Excess in the Laterality of Cutaneous Melanoma
Jean-Luc Bulliard, PhD; Silvia Ess, MD; Andrea Bordoni, MD; Isabelle Konzelmann, MD; Fabio Levi, MD


Arch Dermatol. 2008;144(4):556-558.

An unequal distribution of cancer laterality, particularly in paired organs, has long been documented and generally thought to be related to asymmetries in organ size or behavioral factors such as handedness.1 Recently in a large series patients with cancers in the left testis, right lung, and left ovary were found to have a significantly better survival than those with contralateral cancers.2 Apart from anecdotal assertions and very sparse data that suggest asymmetrical differences in the frequency of cutaneous melanoma and photodamage,3-4 melanoma laterality has, to our knowledge, never been specifically studied. Investigation of laterality could thus contribute to a better understanding of cancer etiology and prognosis.

Methods

As part of a larger study,5 the laterality of 2143 first cutaneous melanomas was retrieved and clinically validated using a standardized body chart that allowed unequivocal marking of the location of the lesion.6 After excluding cases with unspecified laterality (n = 228 [11%]) or those on the midline (n = 254 [12%]), 1661 melanomas diagnosed between 1995 and 2002 in 5 Swiss population-based tumor registries (Neuchâtel, St Gallen/Appenzell, Vaud, Valais, and Ticino) were investigated. Results were expressed as left to right (L/R) ratios and stratified by cancer registration area, sex, age group, and subsite. Exact 2-sided 95% confidence intervals (95% CIs) were computed assuming that laterality was binomially distributed.


Results

This series included 890 left-sided and 771 right-sided melanomas, yielding an L/R ratio of 1.15 (95% CI: 1.05-1.27). The excess of left-sided lesions was consistently observed across all populations, sexes, age groups, body site, and categories of Breslow thicknesses (Table), although it only occasionally reached statistical significance. The upper limbs was the site with the greatest left-sided excess (27%). Left to right ratios higher than 1 were systematically found for clinical characteristics such as tumor behavior (invasive and in situ), skin type, and morphological type (data not shown).
Comment

This multicentric study suggests a moderate but consistently higher frequency of melanoma on the left side of about 15%. Four main potential explanations were identified and explored: chance finding, recording bias, differential sun exposure, and bilateral asymmetry in the number of melanocytes or tumor biological behavior.

Although chance finding cannot be excluded, we believe it is an unlikely explanation for our observation. The pattern was similar for every variable studied and, for instance, the probability of observing simultaneously an excess L/R ratio in all 5 populations was about 3% (1 in 32). The detailed site was thoroughly cross-validated from textual and pictorial support.6

Two nonmethodological explanations for a left-sided excess of melanoma can be speculated. Traveling in a motor vehicle is probably the only frequent human activity that results in side-specific UV exposure depending on the individual position in the car. Swiss drivers sit on the left side of the car and, until the recent availability of air conditioning, their left arm was more likely to be sun exposed through an open window, particularly in summertime. The largest left-sided excess observed for the upper limbs (an L/R ratio of 1.27, 95% CI: 1.05-1.54,Table) and the greater L/R ratio for men (an L/R ratio of 1.38, P = .02, data not shown) than women (an L/R ratio of 1.18, P = .22, data not shown) at this site supports this assumption and the known greater propensity for men to drive. Reports of a left-sided excess of facial photodamage lesions commensurate with time spent driving in the United States4 and the commoner occurrence of solar keratoses on the right upper limb among Australian men,3 where drivers sit on the right side of vehicles, concurred with our findings. This hypothesis, however, only partly explains our results, since it cannot account for the left-sided excess of melanomas observed at other body sites.

Several aspects in embryogenesis occur in asymmetric fashion. An asymmetry in the distribution of melanocytes favoring the left body side might occur when these cells migrate from the neural crest during embryonic development. This assumption could be challenged and eventually supported by investigating the laterality of nonmelanocytic skin cancers from the Vaud Cancer Registry database7 since L/R ratios computed for squamous and basal cell carcinomas registered over a 10-year period (1995-2004) were 1.03 (1286:1244) and 1.00 (2946:2939), respectively (F.L., oral communication, September 2007). An asymmetric development of the angiolymphatic system might lead to a higher progression of left-sided melanoma, which is compatible with our concomitant increase in L/R ratios and melanoma thickness.

This largest study to date to explore melanoma laterality suggests that an asymmetric, melanocytic distribution or, to a lesser extent, a differential sun exposure are plausible etiological explanations for the observed left-sided excess of melanomas but not of other types of skin cancers.


AUTHOR INFORMATION

Correspondence: Dr Bulliard, Unité d'épidémiologie du cancer, Institut universitaire de médecine sociale et préventive, rue du Bugnon 17, 1005 Lausanne, Switzerland (Jean-Luc.Bulliard@chuv.ch).

Variations in Management of Stage I to Stage III Cutaneous Melanoma

It is quite surprising how aggressive the French are in managing melanoma with much use of interferon, gretter scanning and investigation and use of sentinel lymph node biopsy examination.

Variations in Management of Stage I to Stage III Cutaneous Melanoma
A Population-Based Study of Clinical Practices in France

Florent Grange, MD, PhD; Fabien Vitry, MD; Florence Granel-Brocard, MD; Dan Lipsker, MD, PhD; Francois Aubin, MD, PhD; Guy Hédelin, PhD; Sophie Dalac, MD; François Truchetet, MD; Catherine Michel, MD; Marie-Laure Batard, MD; Béatrice Baury, PhD; Jean-Michel Halna, MD; Jean Luc Schmutz, MD; Christian Delvincourt, MD; Georges Reuter, MD; Stéphane Dalle, MD; Phillipe Bernard, MD, PhD; Arlette Danzon, MD


Arch Dermatol. 2008;144(5):629-636.

Objective To describe current management of cutaneous melanoma (CM) and identify factors accounting for disparities.

Design Retrospective population-based study using survey of cancer registries and pathology laboratories, and questionnaires to physicians.

Setting Five regions covering 19.2% of the French territory and including 8.2 million inhabitants.

Patients Incident cases of patients with stage I to stage II (hereinafter, stage I-II) tumors staged according to the American Joint Committee on Cancer Staging guidelines and nodal stage III CM in 2004.

Main Outcome Measures Modalities of diagnosis and excision, surgical margins, sentinel lymph node biopsy, adjuvant therapies and surveillance procedures, and their variations according to age, sex, residence, location of primary CM, Breslow thickness, type of physicians, modalities of decisions, and health care patterns.

Results Clinical stage I-II CMs (n = 710 cases) slightly predominated in females (53%), with a lower mean Breslow thickness (1.4 mm) than in males (1.9 mm). Initial excisions were most often performed by private dermatologists and wide excisions by surgeons. Narrow margins (8%) were associated with advanced age, higher Breslow thickness, and head location. Sentinel lymph node biopsy was performed in 34% of CMs thicker than 1.0 mm, depending on geographical regions, distance from reference centers, and health care patterns. Adjuvant therapies (mainly low-dose interferon) were proposed in 53% of thick CMs (>1.5 mm), depending on the patient's age and geographical region. In contrast with French recommendations, surveillance procedures frequently included systematic medical imaging. Stage III nodal CMs (n = 89 cases) predominated in males (62%). After lymphadenectomy, adjuvant therapies (including high-dose interferon in 32% of cases and chemotherapies in 24% of cases) were proposed in 68% of cases, depending on the patient's age and geographical region. A complete 1-year high-dose interferon regimen was administered in less than 10% of cases.

Conclusion Large disparities still exist in the management of CM in France, depending to a greater extent on medical and geographical environment than on the characteristics of either patients or tumors.

Utility of Lesion Diameter in the Clinical Diagnosis of Cutaneous Melanoma

Utility of Lesion Diameter in the Clinical Diagnosis of Cutaneous Melanoma
Naheed R. Abbasi, MPH, MD; Molly Yancovitz, MD; Dina Gutkowicz-Krusin, PhD; Katherine S. Panageas, DrPH; Martin C. Mihm, MD; Paul Googe, MD; Roy King, MD; Victor Prieto, MD; Iman Osman, MD; Robert J. Friedman, MD; Darrell S. Rigel, MD; Alfred W. Kopf, MD; David Polsky, MD, PhD


Arch Dermatol. 2008;144(4):469-474.

Objective To determine the utility of the current diameter criterion of larger than 6 mm of the ABCDE acronym for the early diagnosis of cutaneous melanoma.

Design Cohort study.

Setting Dermatology hospital-based clinics and community practice offices.

Patients A total of 1323 patients undergoing skin biopsies of 1657 pigmented lesions suggestive of melanoma.

Main Outcome Measure The maximum lesion dimension (diameter) of each skin lesion was calculated before biopsy using a novel computerized skin imaging system.

Results Of 1657 biopsied lesions, 853 (51.5%) were 6 mm or smaller in diameter. Invasive melanomas were diagnosed in 13 of 853 lesions (1.5%) that were 6 mm or smaller in diameter and in 41 of 804 lesions (5.1%) that were larger than 6 mm in diameter. In situ melanomas were diagnosed in 22 of 853 lesions (2.6%) that were 6 mm or smaller in diameter and in 62 of 804 lesions (7.7%) that were larger than 6 mm in diameter.

Conclusion The diameter guideline of larger than 6 mm provides a useful parameter for physicians and should continue to be used in combination with the A, B, C, and E criteria previously established in the selection of atypical lesions for skin biopsy.

Complex dermoscopic pattern: a potential risk marker for melanoma

Complex dermoscopic pattern: a potential risk marker for melanoma
J.B. Lipoff, A. Scope*, S.W. Dusza*, A.A. Marghoob*, S.A. Oliveria* and A.C. Halpern*
Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10022, U.S.A.
*Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, U.S.A.
BJD April 2008

Dysplastic naevi have repeatedly been shown to be an independent risk factor for melanoma; however, risk estimates vary. Dermoscopy has allowed for more elaborate classification of naevi based on global patterns.
Objectives To assess dermoscopic images of naevi from patients with melanoma and controls to explore dermoscopic patterns that are associated with melanoma risk.
Methods Dermoscopic images of naevi from the backs of 20 patients with melanoma and 20 age- and sex-matched controls were reviewed for dermoscopic patterns and structures. An unblinded review of 187 naevi of patients and 150 naevi of controls was completed. Complex global dermoscopic pattern was defined in naevi presenting both network and globules, with or without structureless areas.
Results Complex global dermoscopic pattern was observed more frequently in melanoma patients than controls (odds ratio, OR 2·9, P = 0·003). As for specific dermoscopic structures, presence of globules was observed more frequently in patients than controls (OR 2·3, P = 0·0001), whereas presence of dots was inversely associated with case status (OR 0·5, P = 0·002).
Conclusions These pilot data suggest that dermoscopic pattern may serve as a more robust and specific marker of melanoma risk than clinical naevus phenotype.

Metastatic melanoma of unknown origin

Dermoscopy of fully regressive cutaneous melanoma
N. Bories, S. Dalle, S. Debarbieux, B. Balme, S. Ronger-Savlé and L. Thomas
Department of Dermatology, Lyon 1 ‘Claude Bernard’ University, Hôtel Dieu, 69288 Lyon, CEDEX 02 France
BJD April 2008 Online posting

Metastatic melanoma of unknown origin is a difficult challenge diagnostically and therapeutically. Diagnosis of the putative primary lesion is difficult. This difficulty increases when the primary lesion has undergone complete regression.
Objective To define the dermocopic features of fully regressed melanoma.

Patients and methods A single-institution, register-based study of an unselected consecutive series of seven cases of metastatic melanoma in the lymph nodes with no known or visible primary lesion was carried out. Skin examination included dermoscopy; when a suspicious area was found, observed dermoscopic features were recorded and a biopsy was performed. Diagnosis of completely regressive cutaneous melanoma was based on clinical–pathological correlation according to widely accepted criteria.
Results Seven dermoscopic features were associated with completely regressive melanoma: scar-like depigmentation (100%); pink coloration of the background (100%); linear-irregular vessels (86%); globular pattern of the vessels (43%); remnants of pigmentation (86%), either macular (43%) or with a peppering aspect (43%); and white lighter transverse bands (43%). The last feature was only observed with polarized light dermoscopy devices.
Conclusion Dermoscopy more accurately distinguishes the vascular, pigmentary and scarring changes of fully regressive melanoma. We believe that dermoscopy should be included in the search for a regressive primary lesion in case of metastatic melanoma of unknown origin.

Putting the BITE on Melanoma

Highly efficient elimination of melanoma cells expressing melanoma-associated chondroitin sulfate proteoglycan (MCSP) by MCSP/CD3-bispecific chain antibody constructs: A 61.


An engineered antibody-like molecule that binds skin cancer cells to killer T cells, literally tying melanomas to the immune system, could provide a novel therapy for the disease, according to researchers at Micromet, a biotechnology company based in Bethesda, Md., and Munich, Germany. Melanomas are particularly sensitive to T-cell therapies, the researchers say, and their novel antibody construct could be a means of engaging some of the most effective cancer-killing cells in the immune system's arsenal.
These agents are new class of artificial antibodies - what Micromet researchers term a BiTE class (for bispecific T-cell engager) - that are T cell-recruiting antibodies. Essentially, the researchers have linked the binding regions of two specific antibodies together with a short peptide chain.
In this case, one antibody binds to an activating receptor on the surface of killer T cells, called CD3, and the other binds to a protein generally found on the surfaces of skin cancers, called melanoma-associated chondroitin sulfate proteoglycan (MCSP).
"Unlike regular monoclonal antibodies used in cancer therapies, BiTE antibodies can recruit killer T cells for redirected lysis of tumor cells," said Roman Kischel, M.D., director of immunotherapy at Micromet. "By this approach only cells expressing the antigen are attacked by T cells, and we can see target cell lysis at very low picomolar concentrations of BiTE antibodies."
When MCSP-BiTE binds to cancer cells, the cells become visible for any killer T cell passing by. "The T cell will briefly attach to the BiTE-decorated cancer cell and inject its deadly cocktail of killer proteins into the tumor cell," Dr. Kischel said. "This event gears up the T cell to produce more killer proteins and to go into melanoma serial killing mode."
According to Dr. Kischel, the BiTE antibodies do not require specific killer T cells, which may circumvent many limitations of T-cell therapies, such as the mechanisms that some tumors use to escape the immune system and defects in the ability of immune cells to recognize antigen, a frequent problem among cancer patients. Even on the cellular scale, BiTE antibodies are tiny, about a third of the size of conventional antibodies, which Micromet researchers believe may aid by improved tumor penetration in the effectiveness of the therapeutic.
Currently, Micromet researchers are studying similar antibodies specific for B-cell lymphomas in a Phase I trial. The MCSP-BiTE antibodies are now undergoing preclinical studies in cell cultures and animal models.

Daylight PDT for actinic keratoses

Continuous activation of PpIX by daylight is as effective as and less painful than conventional photodynamic therapy for actinic keratoses; a randomized, controlled, single-blinded study
Authors: Wiegell, S.R.; Hædersdal, M.; Philipsen, P.A.; Eriksen, P.1; Enk, C.D.2; Wulf, H.C.
Source: British Journal of Dermatology, Volume 158, Number 4, April 2008 , pp. 740-746(7)
Publisher: Blackwell Publishing
Abstract:
Summary Background
Photodynamic therapy (PDT) is a highly effective treatment for actinic keratoses (AK); however, it is time consuming and often painful for the patient. Daylight-PDT would make the treatment independent of the clinic and less painful due to the continuous activation of small amounts of porphyrins during its formation. Objectives
The objective of this randomized controlled study was to compare response rates and adverse effects after methyl aminolevulinate (MAL)-PDT using conventional red light-emitting diode (LED) light vs. daylight. Patients/methods
Twenty-nine patients with AK of the face and scalp were treated with MAL-PDT in two symmetrical areas. One area was illuminated by red LED light (37 J cm−2) after 3-h incubation with MAL under occlusive dressing. The other area was treated with daylight for 2·5 h after the MAL cream had been under occlusion for half an hour. Results
We found no significant difference in the treatment effect between the two treatments (P = 0·13), with a reduction of AK lesions of 79% in the daylight area compared with 71% in the LED area. Treatment response in the daylight area did not depend on the intensity of the daylight. Illumination with LED was more painful than daylight (P < 0·0001). Erythema and crusting occurred after both treatments and were similar in the two areas. Conclusions
PDT of AK by continuous activation of porphyrins by daylight proved to be as effective as conventional PDT. PDT using daylight activation will make the treatment of these extremely common premalignant tumours more time and cost effective, and more convenient for the patient.

Why dont all moles progress to melanoma

Why dont all moles progress to melanoma

University of Michigan Health System.
Oct 28, 2006 - 12:58:00 PM

ANN ARBOR, Mich. -- Everyone has moles. Most of the time, they are nothing but a cosmetic nuisance. But sometimes pigment-producing cells in moles called melanocytes start dividing abnormally to form a deadly form of skin cancer called melanoma. About one in 65 Americans born this year will be diagnosed with melanoma at some point during their lifetime.

Scientists know that 30 percent of all melanomas begin in a mole. They know that 90 percent of moles contain cancer-causing mutations. What scientists didn't know is how melanocytes stop these mutations from triggering the development of cancer.

Maria S. Soengas, Ph.D., and other scientists in the Multidisciplinary Melanoma Clinic at the University of Michigan Comprehensive Cancer Center, have found the answer to this important question in an unexpected place – a structure inside cells called the endoplasmic reticulum, or ER.

"Our results support the direct role of the endoplasmic reticulum as an important gatekeeper of tumor control," says Soengas, who is an assistant professor of dermatology in the U-M Medical School. "Until now, no one knew there was a connection between ER stress and the very early stages of tumor initiation."

Results of the U-M study – involving melanocytes from normal human skin and biopsies of non-malignant human moles – are being published in the October issue of Nature Cell Biology.

The endoplasmic reticulum is the cell's protein production factory. The process begins when chains of amino acids are deposited in the ER membrane in response to coded instructions from genes. Chaperone proteins fold these amino acids into specific shapes. When too many of them build up in the membrane, or when something goes wrong with the folding process, the system gets bogged down. This can stress or even kill the cell.

To prevent this, the ER sends out distress signals to activate what scientists call the unfolded protein response (UPR). This slows the protein production process and gets rid of excess incoming amino acids, giving the ER a chance to catch up. If that doesn't work, the UPR causes the cell to destroy itself in a process called apoptosis.

"Traditionally, the ER's role was considered to be limited to protein folding or protein modification," Soengas says. "But scientists like Randal Kaufman, a U-M professor of biological chemistry and co-author on our paper, have found that the ER can sense changes in glucose, nutrients, oxygen levels and other aspects of cellular physiology associated with diseases like diabetes and Alzheimer's disease."

"In our study, we found that the ER senses the activity of certain oncogenes in the melanocyte and triggers a response that prevents the malignant transformation of these cells," Soengas adds.

According to Soengas, the tumor suppressive mechanism induced by the ER in melanocytes with these cancer-causing mutations is premature senescence – a form of "suspended animation" that stops the cell cycle and keeps cells from dividing, but doesn't kill them.

"The cells are held in check – they don't die, but they don't proliferate either," Soengas explains. "In the case of moles, melanocytes can stay this way for 20 to 40 years or even your whole life. For most of us, just holding cells in an arrested state is sufficient to prevent the development of cancer. That's why so many people have moles, but few have melanoma."

In the study, U-M scientists found that the tumor suppressive response in melanocytes varied depending on the type of oncogene being expressed in the cell.

"We found that some oncogenes activated the endoplasmic reticulum, while other oncogenes didn't," Soengas says.

In a previous study, Soengas and colleagues found that certain oncogenes use a different senescence mechanism, which doesn't activate the ER, to block the transformation of melanocytes. Both these mechanisms work in addition to or independent from other well-known tumor suppressor mechanisms involving apoptosis.

Soengas says the results of the study will be important in helping scientists understand all the different mechanisms melanocytes use to protect themselves against oncogenes. But she cautions that there are no immediate clinical applications for the study and additional research will be required.

In future research, Soengas will attempt to determine exactly how oncogenes trigger the unfolded protein response in malignant and non-malignant skin cells. "By comparing what happens in normal melanoctyes with what happens in melanoma, we may be able to come up with events that are specific for tumor cells, which could be used for future drug development," she says.

Source:

University of Michigan Health System.

Overcalling of Genital Nevi as Melanomas.

Atypical Genital Nevi
Awareness of a unique subtype of pigmented vulvar lesion will prevent misdiagnosis of melanoma.
Gleason BC et al. Atypical genital nevi. A clinicopathologic analysis of 56 cases. Am J Surg Pathol 2008 Jan; 32:51.

The incidence of pigmented lesions and diffuse hyperpigmentation involving the genitalia is difficult to ascertain, but such lesions can be found in about 10% of white women. Approximately 2% of these are nevocellular nevi (other benign pigmented lesions found here include seborrheic keratoses, melanoses, lentigines, warts, and postinflammatory hyperpigmentation). In general, nevi on the vulva are identical in morphology and histopathology to nevi elsewhere on the body, except for a small subset of nevi in younger women that have the unusual feature of enlarged junctional nests varying in size, shape, and position. Their long-term biologic behavior has not been determined. The histologic and clinical features of these "atypical melanocytic nevi of the genital type" or "atypical genital nevi" (AGN) are the subject of this study.
The authors reviewed hematoxylin- and eosin-stained sections and medical records from 56 cases of AGN. Mean patient age was 26, but four patients were younger than 10 years. Nearly half the lesions were atypical on clinical exam (mean diameter, 6 mm). More than half arose in hair-bearing skin, the rest in glabrous skin or mucosa. In the pediatric group, juxtamucosal or glabrous surfaces (clitoris and labium minus) were the most frequently affected.

The mean follow-up period was 3.5 years. Ten of 17 cases with positive margins had follow-up data available; only 1 of these persisted or recurred, with no further recurrence after complete excision. About 80% of lesions were compound; more than two thirds showed moderate-to-severe cytologic atypia. Ten cases were focal but had pagetoid spread. Adnexal spread and nuclear atypia of the melanocytes situated in the superficial dermis were relatively common. Rare mitoses were identified (maximum, 2 per section). Dermal fibrosis was seen in 45%.

Comment: Melanocytic lesions in the genitalia and along the milk line (axillae, breasts, periumbilical region, and groin) have a tendency to be overdiagnosed as malignant melanomas, a pitfall ascribable to the presence of histologic features usually associated with aggressive biologic behavior. Awareness of this distinct subgroup of pigmented lesions affecting women of reproductive age is essential to avoid unnecessary surgery and patient distress. Although follow-up data on these lesions are limited, among 63 cases in the literature, no metastases have been reported to date.

Primary Dermal Melanoma

This is a lesion I am not familiar with. If I saw one with no overlying epidermal component and well separated from the overlying epidermis, I would think it was a metastasis! However this was excluded in these cases. The interesting thing is the thickness of the lesions but how accurate this is without overlying epidermal involvement I just dont know! The important message was the long survival time despite the thickness of the lesions.(IMCC)
Primary Dermal Melanoma
Distinct Immunohistochemical Findings and Clinical Outcome Compared With Nodular and Metastatic Melanoma

David S. Cassarino, MD, PhD; Erik S. Cabral, BS; Reena V. Kartha, PhD; Susan M. Swetter, MD


Arch Dermatol. 2008;144(1):49-56.

Objective To provide an updated and expanded analysis of clinical outcome and immunohistochemical (IHC) findings unique to primary dermal melanoma (PDM) that may be used to differentiate this entity from primary nodular melanoma (PNM) and cutaneous metastatic melanoma (MM).

Design Cohort analysis and extensive IHC panel comparing PDM with PNM and cutaneous MM.

Setting Melanoma clinics and pathology departments of academic and VA medical centers.

Patients Thirteen patients with a solitary dermal or subcutaneous nodule of histologically proven melanoma, prospectively followed through April 30, 2007.

Interventions Clinical, pathologic, and IHC assessment of patients diagnosed as having PDM.

Main Outcome Measures Long-term clinical outcome and determination of unique clinical and IHC features in the study cohort compared with other melanoma subtypes.

Results Histologically, there was no evidence of an overlying in situ component, ulceration, or regression, and there was no associated nevus in any cases. Clinical history and findings from workup, including imaging studies, skin examination, and sentinel lymph node biopsy, were negative for evidence of melanoma elsewhere. The mean Breslow depth was 9.6 mm. Two patients developed satellite or in-transit recurrences, 1 developed pulmonary metastasis, and another died of liver metastases. Overall, the cohort showed a 92% melanoma-specific survival rate at a mean duration of follow-up of 44 months. The IHC findings showed that PDM exhibited lower levels of staining for the antigens p53 (P = .02), Ki-67 (Mib-1) (P = .002), cyclin D1 (P = .001), and podoplanin (recognized by D2-40 antibody) lymphovascular staining (P <.001) compared with MM and PNM. All other markers were comparable.

Conclusions Patients with PDM have remarkably prolonged survival compared with patients with MM or PNM of similar thickness. Preliminary results suggest that PDM may be characterized by lower levels of p53, Ki-67, cyclin D1, and D2-40 compared with histologically similar MM and PNM.

Extramammary Paget's disease

Br J Dermatol. 2008 Feb;158(2):313-8.
Extramammary Paget's disease: treatment, prognostic factors and outcome in 76 patients.Hatta N, Yamada M, Hirano T, Fujimoto A, Morita R.Division of Dermatology, Toyama Prefectural Central Hospital, Nishinagae, Toyama 930-8550, Japan, and Department of Dermatology, Kanazawa University School of Medicine, Takara-machi, Kanazawa, Japan.

Background Extramammary Paget's disease (EMPD) is a rare cutaneous carcinoma usually presenting as a genital erythematous lesion in the elderly. Although most EMPD tumours are in situ, invasive EMPD has a poor prognosis. Objective To evaluate the clinical and pathological features of EMPD and determine prognostic factors for survival. Methods The medical records of 76 patients with EMPD were retrospectively reviewed. Results Of the 66 patients who underwent curative surgical excision, five (8%) developed local recurrence, but surgical margin ( 2 cm) was not correlated with local recurrence. Thirteen of the 76 patients (17%) developed systemic metastases and 10 of these died of disease. On univariate analysis, the presence of nodules in the primary tumour, clinical lymph node swelling, elevated serum carcinoembryonic antigen (CEA) levels, tumour invasion level and lymph node metastasis were significant prognostic factors. On multivariate analysis, invasion level and elevated serum CEA were the only factors that were significantly associated with reduced survival.

Conclusions Invasion level and lymph node metastasis are important prognostic factors in EMPD. In patients with in situ tumour, local tumour control is the major aim of treatment; however, wide surgical margins are not associated with a lower risk of local recurrence.

Polyoma virus and Merkel Cell Carcinoma

Researchers are unveiling a new virus in a report published online January 17 in Science. Dubbed the Merkel cell polyomavirus, it is the first to be strongly associated with a human tumor. Polyomaviruses have been shown to cause cancers in animals, but it is unclear what role, if any, they play in human cancer development. Although the important finding does not prove that the polyomavirus causes neuroendocrine cancer of the skin — also known as Merkel cell carcinoma — if confirmed, it might offer clues for future cancer treatment and prevention options.

Merkel cell carcinoma is a rare but extremely aggressive cancer that tends to spread rapidly. The incidence of this skin cancer has reportedly tripled over the past 20 years, to about 1500 cases a year. It tends to be seen in the elderly and in those with compromised immune systems, such as those with AIDS or patients taking transplant-related immunosuppressant drugs. About half of those with advanced Merkel cell carcinoma live 9 months or less.

"If these findings are confirmed, we can look at how this new virus contributes to a very bad cancer with high mortality and, just as important, use it as a model to understand how cancers occur and the cell pathways that are targeted," senior author Patrick Moore, MD, from the University of Pittsburgh School of Medicine, in Pennsylvania, said in a news release. "Information that we gain could possibly lead to a blood test or vaccine that improves disease management and aids in prevention."

Dr. Moore and his wife also discovered the cause of Kaposi's sarcoma. In 1993, the couple identified Kaposi's sarcoma–associated herpesvirus, the most common malignancy in AIDS patients and the most prevalent cancer in Africa.

During an interview with Medscape Oncology, Dr. Moore said his team was surprised by this latest finding. "We were certainly taken aback," he said. "I think anyone uncovering what could be a cause of cancer would be surprised by the finding," he laughed. A lot of work remains, but the Merkel cell polyomavirus might be an exciting clue.

Possible Cause of Rare Cancer Identified

Vaccines are now available against other causes of cancer, such as the human papillomavirus linked to cervical cancer. "The Merkel cell polyomavirus is another model that may increase our understanding of how cancers arise, with possibly important implications for nonviral cancers like prostate or breast cancer," coauthor Yuan Chang, MD, also from the University of Pittsburgh, pointed out in a news release.

Merkel cell polyomavirus, like the human papillomavirus, is said to integrate into the tumor cell genome, but not the genome of healthy cells. This integration destroys the virus's ability to replicate normally and might be the first step toward cancer.

Using a technique called digital transcriptome subtraction, the investigators looked at close to 400,000 messenger ribonucleic acid genetic sequences from 4 samples of Merkel cell carcinoma tumor tissue. They compared the sequences expressed by the tumor genome to gene sequences mapped by the Human Genome Project and systematically subtracted known human sequences to identify a group of genetic transcripts that might be from a foreign organism.

They found that 1 sequence was similar to, but distinct from, all known viruses. The team went on to show that this sequence belonged to a new polyomavirus present in 8 of 10 Merkel cell tumors they tested, but only 5 of 59 (8%) control tissues from various body sites and 4 of 25 (16%) control skin tissues.

"This is a rare cancer so it's hard to get enough tissue samples for large studies from just 1 center," Dr. Moore told Medscape Oncology. The group plans to continue collecting samples and will partner with others.

Even if the Merkel cell polyomavirus is proven to play a role in neuroendocrine cancer of the skin, Dr. Chang cautions that the virus is likely to be just part of a much larger picture.

Also Newly discovered virus, and strongly associated with Merkel cell carcinoma, is a member of the polyoma family. This cancer is most often found in immunocompromised persons, such as those afflicted by AIDS or taking organ transplant drugs which suppress the immune system.
According to the NY Times, this is the 7th virus linked to human cancers. (The others are Hep B & C with liver cancer, papilloma virus to cervical cancer, EBV with nose and pharynx cancer, and HTLV-1 to Human T cell leukemia.