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Management of primary cutaneous melanoma of the hands and feet: a clinicoprognostic study.
Rex J, Paradelo C, Mangas C, Hilari JM, Fernández-Figueras MT, Ferrándiz C. Dermatol Surg. 2009 Oct;35(10):1505-13.
BACKGROUND: Although acral lentiginous melanoma is the most common subtype of malignant melanoma in acral locations, the term acral melanoma (AM) has to be differentiated from the histopathologic description.
OBJECTIVES: To characterize the clinical and pathologic features of patients with a primary AM and to elucidate whether the prognosis of patients with AM differs from that of those with melanoma at other sites (nonacral melanoma; NAM).
PATIENTS AND METHOD: Over a 20-year period, a series of 822 consecutive patients with melanoma were recorded in the database. Clinical and follow-up data were retrieved from the melanoma register and prospectively analyzed.
RESULTS: Eighty-nine patients had a malignant melanoma located on the acral sites of extremities. Breslow thickness and Clark level were found to be related to specific and disease-free survival. Breslow thickness greater than 4 mm was associated with greater risk of recurrence, and amelanosis and age of 60 and older were significantly associated with greater risk of death. Comparison of survival of patients with AM with that of those with NAM clearly showed that disease-free survival and overall survival were significantly lower in the former.
CONCLUSION: Survival differences between patients with AM and NAM are due to differences in already known prognostic factors, probably as a consequence of a delay in the diagnosis in these locations.
Acral lentiginous melanoma of the foot is a relatively rare but often very aggressive variant of melanoma. More commonly identified in patients with darker skin, diagnosis of the lesions is often delayed because the area is not routinely examined by patients or primary care physicians. In addition, these lesions often mimic other entities, including vascular lesions and infections. Greater awareness of this entity and performing appropriate biopsies will result in more timely diagnoses and improved survival.
BACKGROUND: Malignant melanoma is a rare but potentially lethal form of cancer which may arise on the foot. Evidence suggests that due to misdiagnosis and later recognition, foot melanoma has a poorer prognosis than cutaneous melanoma elsewhere.
METHODS: A panel of experts representing podiatry and dermatologists with a special interest in skin oncology was assembled to review the literature and clinical evidence to develop a clinical guide for the early recognition of plantar and nail unit melanoma.
RESULTS: A systematic review of the literature revealed little high quality data to inform the guide. However a significant number of case reports and series were available for analysis. From these, the salient features were collated and summarised into the guide. Based on these features a new acronym "CUBED" for foot melanoma was drafted and incorporated in the guide.
CONCLUSIONS: The use of this guide may help clinicians in their assessment of suspicious lesions on the foot (including the nail unit). Earlier detection of suspicious pedal lesions may facilitate earlier referral for expert assessment and definitive diagnosis. The guide has been tested amongst practitioners and has been submitted for publication.
Malignant melanoma is a life threatening skin tumour which may arise on the foot. The prognosis for the condition is good when lesions are diagnosed and treated early. However, lesions arising on the soles and within the nail unit can be difficult to recognise leading to delays in diagnosis. These guidelines have been drafted to alert health care practitioners to the early signs of the disease so an early diagnosis can be sought.
Prognostic variables and surgical management of foot melanoma: review of a 25-year institutional experience.
Rashid OM, Schaum JC, Wolfe LG, Brinster NK, Neifeld JP. ISRN Dermatol. 2011;2011:384729.
Introduction. Cutaneous foot melanoma is rare, challenging to manage, and not adequately examined in the literature. This study evaluated the prognostic variables and surgical management of foot melanoma.
Materials and Methods. Foot melanoma cases managed at an academic center from 1985 to 2010 were retrospectively reviewed.
Results. 46 patients were identified with a broad range of demographic characteristics. Overall recurrence was 32.6%: 19% acral lentiginous, 57% nodular, 66% superficial spreading, 30% melanoma unspecified, 50% severely atypical; 53% ulcerated, 23% nonulcerated; 29% on the dorsum of the foot, 17% heel, 60% ankle, 22% toe, 50% plantar; 0% <1 mm thick, 47% 1-4 mm, 33% >4 mm. 13 had positive nodes, 4 (31%) of whom recurred. Prognostic factors and recurrence did not correlate, and survival was 96% with a median followup of 91 months.
Conclusions. Aggressive management of foot melanoma may result in excellent long-term survival even following disease recurrence.
A rare form of melanoma masquerading as a diabetic foot ulcer: a case report.
Thomas S, Meng YX, Patel VG, Strayhorn G. Case Report Endocrinol. 2012;
Background. Acral lentiginous melanoma (ALM) is a less-common form of melanoma in US, and it accounts for about 5% of all diagnosed melanomas in US. ALM is often overlooked until it is well advanced because of the lesion's location and its atypical appearance in the early stages. We present a case of ALM initially presented as a diabetic foot ulcer.
Case Report. An 81-year-old man initially presented to the primary care clinic with a right foot diabetic ulcer. There was a large plantar, dark-colored ulcer that bled easy. Initial excision biopsy revealed Clark's Level IV ALM. Subsequent definitive wide excision and sentinel node biopsy confirmed ALM with metastasis to inguinal lymph nodes (stage IIIb). The treatment included wide margin excision of the lesion with en bloc amputations of 4th and 5th toes, followed by adjuvant chemotherapy.
Discussion. The development of ALM may potentially relate to diabetes as a reported higher prevalence of diabetes with ALM patients.
Conclusion. The difficulty in early diagnosing of ALM remains as a formidable challenge particularly in diabetic patients who commonly develop plantar foot ulcers due to the diabetic neuropathy. This case reiterates the importance of a thorough foot exam in such patients.
The incidence of cutaneous malignant melanoma (MM) in the UK has notably increased over the last few decades. Despite recent improvements in the early diagnosis of the condition, the mortality rates are still high (UK Skin Cancer Mortality Statistics, SunSmart Campaign). Figures extracted from European studies also recognise that the stage (or thickness) at which the MM lesions are diagnosed has improved, leading to a slower increase in mortality compared to incidence rates (Grange, 2005, de Vries et al, 2003). These statistics are attributed to more and more people seeking professional advice at the early stages of MM presentation, as a result of increased public awareness and education programmes for both patients and practitioners (Schmid-Wendtner et al, 2002, Schwartz et al, 2002, Baumert et al, 2007, Russak, Rigel, 2012). The publicity surrounding the incidence and risk factor awareness of MM in the UK has been widespread over this past decade (UK Skin Cancer Mortality Statistics, SunSmart Campaign) and the publication of guidelines for both MM and subungual melanoma have contributed to the knowledge in this area (Bishop et al, 2007, Levit et al, 2000). Despite these positive outcomes, there are some MM on specific areas on the body that still have high mortality rates and therefore require further attention with regards to early diagnosis. One region in particular is the foot. This article will focus on this area, paying attention to the risk factors unique to foot MM (including the nail unit). Comparisons with other skin conditions and forms of MM will be made and new guidelines for assessment of MM on the foot introduced.
Press Release: Melanoma - The wolf in sheep's clothing
Researchers from the University of Bonn discover how melanoma cells circumvent the immune system
Melanoma is so dangerous because it tends to metastasize early on. New treatment approaches utilize, among other things, the ability of the immune defense to search out and destroy malignant cells. Yet this strategy is often only temporarily effective. A research team under the direction of Bonn University has discovered why this is the case: In the inflammatory reaction caused by the treatment, the tumor cells temporarily alter their external characteristics and thus become invisible to defense cells. This knowledge forms an important foundation for the improvement of combination therapies. The results have been published online in the renowned journal "Nature."
In Germany, approximately 15,000 people develop melanoma annually and approximately 2,000 people die from it every year. Malignant melanoma is the most frequently fatal skin diseases. The particular malignancy is based on the fact that small tumors can spread via the lymphatic vessels and the bloodstream. For many years, the working group under Prof. Dr. Thomas Tüting, Director of the Laboratory for Experimental Dermatology at the Bonn University Hospital, has investigated the effect of a targeted immune therapy with tumor-specific defense cells.
Tumor cells behave like a wolf in sheep's clothing
In trials on mice who congenitally develop melanoma, the researchers were able to destroy advanced tumors using so-called cytotoxic T-cells. "But they recover after some time - just as they do in patients in the hospital," explain Dr. Jennifer Landsberg and Dr. Judith Kohlmeyer, lead authors of the study. This form of therapy triggers inflammation. Now the researchers have discovered that the melanoma cells change their external characteristics precisely via this accompanying inflammatory reaction. "They behave like wolves in sheep's clothing and thus evade detection and destruction by defense cells," says Marcel Renn, also a lead author of the study.
The immune system can fight tumors – but it can also protect them
On the search for the underlying mechanisms, the researchers pointed histological investigations of tumors in the right direction: Therapy-resistant melanomas demonstrated a significantly stronger inflammatory reaction with many scavenger cells of the immune system, the so-called macrophages. A messenger primarily released from these immune cells - the tumor necrosis factor-alpha - was able to bring about the change in character of the melanoma cells directly in the Petri dish in the laboratory. Cells treated in this way were subsequently hardly detected by the defense cells. "The immune system is like a double-edged sword," explains Prof. Tüting. "It can fight the tumor – but it can also protect it." Such changes in the tumor tissue are probably of great importance for the formation of resistance to therapy. "According to more recent discoveries, treatment with inhibitors which prevent signal transmission in tumor cells is also affected by this," remarks Prof. Tüting.
Melanoma cells lose their typical characteristics
Molecular genetic investigations revealed that melanoma cells from therapy-resistant tumors had lost the characteristics typical for pigment cells. Instead, they demonstrated traits of connective tissue cells. "It is possible that melanoma cells undergo this change in character so easily because they originate from the embryonic development of cells in the neural crest which can also form connective tissue and nerve cells," says Prof. Dr. Michael Hölzel, co-author from the Institute for Clinical Pharmacology and Clinical Chemistry at the Bonn University Hospital.
Results can also be transferred to humans
Findings initially gained from laboratory mice were also able to be reproduced by the team of researchers with human melanoma cells and various associated defense cells in the Petri dish. The melanoma cells likewise reacted to the messenger tumor necrosis factor-alpha with a loss of pigment cell characteristics and could then no longer be detected by pigment-cell-specific defense cells. "Detection by other defense cells which can search out specific genetic changes in the melanoma cells was not affected by this, however," stresses Prof. Dr. Thomas Wölfel, director of a working group involved in the study at the Medical Clinic III of the Mainz University Hospital.
Important findings for new treatment strategies
As soon as the tumor necrosis factor alpha no longer had an effect on the human and mouse melanoma cells, however, the cells regained their pigment-cell characteristics. Then they were also able to be detected and fought against by all immune defense cells once more. All of these findings yield important information for new treatment strategies. Thus in the future, defense cells against antigens of various categories and specificity should be used and at the same time, the inflammation utilized by the tumor cells should be therapeutically inhibited. "Our experimental model system will help us to develop optimally effective combination therapies as rapidly as possible," says Prof. Tüting. "However, it will still take several years until the clinical application of strategies of this type."
The incidence of primary cutaneous malignant melanoma (MM) has been rapidly growing during the last decades with only a small rise in overall mortality. MM accounts for most of the deaths from skin malignancies due to its metastatic potential. However, early detection and wide surgical excision with histologically negative margins are nearly always curative for patients without micrometastatic disease. Although nonsurgical treatments have been increasingly used in recent years, surgery with standardized margins remains the only curative treatment modality for primary cutaneous MM. There are some special locations (e.g., the ear, nose, eyelid, genitalia, hand, or foot) where standardized wide surgery can not be completely achieved either for lack of tissue, ill-defined lesions, or cosmetic and functional reasons. Thus, skin surgeons dealing with these MMs should be well versed in new technologies such as confocal microscopy for the presurgical assessment of ill-defined lesions or the promising electrochemotherapy for nonsurgical tumors. Furthermore, a multidisciplinary melanoma team and a well-trained and experienced surgeon are mandatory to deal with these "out-of-the-guidelines" melanomas.
Melanomas on the foot are difficult to differentiate from diabetic foot ulcers (DFU). In particular, acral lentiginous and amelanotic melanomas have a high chance of being misdiagnosed. We present two patients with diabetes mellitus and malignant melanomas of the foot initially diagnosed as DFU. Both cases were treated with wide excision amputation and local dissection, without adjuvant chemotherapy or radiotherapy. Both patients remain disease-free up to the last follow-up visit. It is important to maintain a high index of suspicion and a skin biopsy should be done in any DFU with atypical features.
Background: Melanoma known to be common among Caucasians is increasingly getting more common among blacks in the tropics.
OBJECTIVE: To characterize the clinical and histological features of these tumours in adult Nigerians.
Methods: All cases of melanoma diagnosed between 2006 and 2010 in Aminu Kano Teaching Hospital, Kano, Nigeria were retrieved and their clinical and pathological features reviewed.
Results: Eighty five cases comprising 41 males and 44 females were diagnosed with mean age of 56±14.6 years. Mean duration before presentation was 2.3±0.8 years. Eighty five percent of cases were located in the foot, 8% with lymph node involvement and seventy eight of the 85 cases were of Breslow thickness >4mm. Fifty five cases were of Clark level V and 78% of Nodular variant. Prognostic features including ulceration, lymphocytic infiltration, significant mitotic activity, satellitosis and lymphovascular infiltration were present in 69%, 38%, 16%, 45% and 17% of cases respectively. Only three cases were amelanotic.
Conclusion: Melanoma in the Nigerians is predominantly of the nodular variant and located in the foot, is characterized by late presentation and is generally associated with adverse prognostic features.
Press release: Gene linked to worse outcomes for melanoma
Scientists at Queen Mary, University of London have identified a gene present in some melanoma which appears to make the tumour cells more resistant to treatment, according to research published today in the Journal of Experimental Medicine.
The scientists discovered that the gene TP63 is unexpectedly expressed in some melanoma and correlates significantly with a worse prognosis. It is hoped this new understanding of what makes some melanoma cells so difficult to kill will help inform the development of new therapies.
Melanoma is a form of skin cancer which usually appears on the body as a new or changing mole. Almost 13,000 people in the UK are diagnosed with melanoma each year. While it is less common than other forms of skin cancer – around five per cent of skin cancers are melanoma – it results in around 75 per cent of skin cancer related deaths (more than 2000 deaths a year in the UK).
The number of cases of melanoma is rising faster than almost any other cancer and one of the main risk factors is ultraviolet light, which comes from the sun or sunbeds. While early-stage melanomas can often be removed by surgery, more advanced melanomas are much harder to treat.
Dr Daniele Bergamaschi, a senior lecturer in cutaneous research at Queen Mary said: "For most patients where the melanoma has spread beyond the skin, there are few effective treatments and overall survival rates for this disease have not changed much over the past 30 years.
"To develop better treatments we need to understand the basic biology underpinning why these cells are so resistant to being killed."
The researchers analysed 156 melanoma tissue samples from 129 individuals for expression of the protein p63 – the protein encoded by the gene TP63. They found that p63 was expressed in more than 50 per cent of the samples (58% of primary metastatic samples, 53% of recurrent samples and 66% of metastatic samples) and correlated significantly with death from melanoma.
Dr Bergamaschi said: "We did not expect to find the TP63 gene expressed in melanoma. It is not usually found in the melanocytes (skin pigment cells), which are the cells from which melanomas develop. However, it appears in some cases this gene is turned on as the tumour forms, and when it does it is linked to a worse prognosis."
The researchers suggest that the TP63 gene, and the subsequent production of the protein p63 in some melanoma, is inhibiting the apoptotic function of the protein p53. One of the main activities mediated by p53 is apoptosis – the process of programmed cell death and one of the main mechanisms by which cancer cells die.
Dr Bergamaschi said: "The apoptotic pathway is often not working in melanoma. However this is not explained by mutations in the TP53 gene, which encodes for the p53 protein, as evidence suggests this is mutated in less than 10 per cent of melanoma.
"This work suggests that in a significant number of cases it is actually the protein p63 which is inhibiting p53's apoptotic function, making some tumours more resistant to treatment. We therefore suggest that p63 should be considered when designing new treatments for melanoma which are focused on re-activating the apoptotic pathway in order to make the cancer cells easier to kill."
Melanoma is a lethal skin cancer that occurs predominantly among Caucasians. In Malaysia, the incidence of melanoma is low. This is a retrospective study of clinical and histopathological features of patients with cutaneous melanoma who were seen at the University Malaya Medical Centre from 1998 to 2008. Thirty-two patients with cutaneous melanoma were recorded during that period. Of these, 24 had sought treatment at the onset of disease at our centre. Chinese patients constituted the largest group (19 cases). The median age of these 24 patients at the time of presentation was 62 years. 16 patients had melanoma involving the lower limb with 12 affecting the sole of the foot. None had melanoma arising from the face. Histopathology showed nodular melanoma in 22 cases (91.6%), with superficial spreading and acral lentiginous melanoma diagnosed in 1 case each. The majority of patients (62.5%) were found to be in Stage III of the disease at the time of diagnosis.
Since the discovery of activating mutations in the BRAF oncogene in melanoma, there has been remarkable progress in the development of targeted therapies for unresectable and metastatic melanoma. We review the latest developments in our understanding of the role of BRAF/MEK/ERK pathway signaling in melanoma, and the development of inhibitors of this pathway. We also explore alternative mutations seen in melanoma, such as NRAS, KIT, GNAQ, and GNA11, and the drug development that is ongoing based on this biology. Strategies for the management of the vexing clinical problem of BRAF inhibitor resistance, primarily via combination therapy, are outlined. With the recent approval of the BRAF inhibitor vemurafenib for stage IV metastatic melanoma, use of this agent is expanding in the United States. Thus, management of the skin toxicities of this agent, such as squamous cell carcinomas, "acneiform" eruptions, hand-foot syndrome, and panniculitis, will be a growing problem facing dermatologists today. We discuss the toxicities of targeted agents in use for melanoma, in particular the dermatologic effects and the management of these skin toxicities.
A new study has found that women who take aspirin have a reduced risk of developing melanoma—and that the longer they take it, the lower the risk. The findings suggest that aspirin's anti-inflammatory effects may help protect against this type of skin cancer. The study is published early online in CANCER, a peer-reviewed journal of the American Cancer Society.
In the Women's Health Initiative, researchers observed US women aged 50 to 79 years for an average of 12 years and noted which individuals developed cancer. At the beginning of the study, the women were asked which medications they took, what they ate, and what activities they performed.
When Jean Tang MD, PhD, of Stanford University School of Medicine in Palo Alto, and her colleagues analyzed available data from 59,806 Caucasian women in the study, they found that women who took more aspirin were less likely to develop melanoma skin cancer during the 12 years of follow up. Overall, women who used aspirin had a 21 percent lower risk of melanoma relative to non-users. Each incremental increase in duration of aspirin use (less than one year of use, one to four years of use, and five or more years of use) was associated with an 11 percent lower risk of melanoma. Thus, women who used aspirin for five or more years had a 30 percent lower melanoma risk than women who did not use aspirin. The researchers controlled for differences in pigmentation, tanning practices, sunscreen use, and other factors that may affect skin cancer risk.
"Aspirin works by reducing inflammation and this may be why using aspirin may lower your risk of developing melanoma," said Dr. Tang. Other pain medications, such as acetaminophen, did not lower women's melanoma risk. Dr. Tang noted that the findings support the design of a clinical trial to directly test whether aspirin can be taken to prevent melanoma.
Acral lentiginous melanoma affecting the nail is uncommon but carries a poor prognosis due to difficulties in early diagnosis. The gold standard of treatment for subungual melanoma is biopsy followed by wide local excision in form of amputation of the distal phalanx of the digit, in order to achieve at least 10 mm margin of clearance or by fixed tissue micrographic (Mohs') surgery. Here, we demonstrate a non-amputative approach for the excision of subungual melanoma in situ of the right great toe, involving removal of the nail unit with a layer of underlying bone before reconstruction with full thickness skin graft. This technique allows adequate excision margins to ensure full clearance of the lesion with satisfactory preservation of function