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Alfredo Di Leo. Annacinzia Amoruso. Domenico Piscitelli. Floriana Giorgio. A short summary of this paper. PDF Pack. People also downloaded these PDFs. People also downloaded these free PDFs. How our practice of histopathology, especially tumour pathology has changed in the last two decades: reflections from a major referral center in Pakistan by Romana Idrees and Syeda Fatima. Practical approach of a working group by Felix Herth. Urothelial carcinoma with plasmocytoid component by H.
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Neri I. Rubegni P. Bassi E. Human phthiriasis. Can dermoscopy really help dermatologists? Pilomatrixoma, a misdiagnosed lesion: two pediatric case reports Bilenchi R. The recognition of melanoma risk factors allows for the identification of a subgroup of high-risk patients that will likely benefit most from approaches aimed at minimizing exposure to ultraviolet radiation and from surveillance strategies geared towards finding melanomas while thin and easily curable. Herein, we will provide an overview of the most pertinent, novel and newly described melanoma risk factors and melanoma prognostic factors.
The potential benefits of skin cancer surveillance strategies including physician-based total body skin examination, total body photography, dermoscopy and patient-based self-skin examination will be examined. In addition, management of melanoma patients, focusing on prevention and early detection strategies will be discussed. Key words: Melanoma - Risk factors - Nevus - Ultraviolet rays.
C utaneous melanoma continues to be a public health problem worldwide. Corresponding author: A. E-mail: [email protected] Vol. Herein, we will review the melanoma risk factors, melanoma prognostic factors and discuss management of melanoma patients, focusing on prevention and early detection strategies.
Melanoma risk factors Recognizing risk factors for melanoma Table I allows for the identification of high-risk individuals that will benefit most from strategies aimed at preventing melanoma and detecting it while the tumor is confined to the skin. Preventive strategies, such as educational campaigns primary prevention and early-detection programs secondary prevention may help in curtailing melanoma related mortality.
The latter can be further sub-classified into genotypic and phenotypic factors. The phenotype of a person refers to the traits or observable characteristics that result from gene expression. Studies have shown that melanomas in the elderly are thicker, predominantly of the nodular type and often occur on the head and neck of males. Begg et al. Several pathways and genes have been associated with susceptibility to melanoma Figure 1.
Particularly, there are two recognized high-penetrance gene mutations CDKN2A and CDK4 , which are often found in familial cases and rarely in sporadic melanomas. Furthermore, with the emergence of targeted therapies for melanoma, this may be an appropriate time for physicians managing melanoma patients to become acquainted with the molecular pathways driving melanoma development and progression.
This knowledge will in turn assist ones understanding of the mechanism of action of many of the emerging targeted therapies directed against melanoma such as therapy targeting BRAF and Kit mutations. Signaling pathways altered in melanoma 1. These mutations are usually mutually exclusive, meaning that two different mutations are not present in the same cell, for example both RAS and BRAFVE mutations do not normally occur in the same cell.
Kit is important for the development of melanocytes, hematopoietic cells, mast cells, and primordial germ cells. Inactivating mutations in p16 also known as INK4a promotes the uncontrolled transition from G1 to S phase of the cell cycle. On the other hand, p14 also known as ARF , regulates the p53 tumor suppressor gene, which controls the transcription of numerous genes that ultimately lead to DNA repair and cell-cycle arrest, or leads to apoptosis.
Hence, p53 dysfunction can result in melanoma progression 25 Figure 1B. CDKN2A is the most well known high-risk melanoma susceptibility gene in the setting of familiar melanoma. Binding of ligands i. Phosporylated ERK ERK-p kinases translocates to the nucleus to activate transcription factors, which promote proliferation. Activated PI3K converts the plasma membrane lipid phosphatidylinositol 4,5-bisphosphonate to phosphatidylinositol triphosphate PIP3.
PIP3 leads to the phosphorylation of AKT and subsequent up-regulation of cell cycle, growth, and survival proteins. Furthermore, functional CDKN2A mutations are more common in individuals with multiple primary melanomas than in persons with single primary melanomas 2. These individuals are often younger, with more nevi and are more likely to have a family history of melanoma. Left: p14 can be induced by signals such as DNA damage.
This is important since p53 controls the transcription of numerous genes that ultimately results in cell-cycle arrest, DNA repair or apoptosis. Loss of PTEN decreases apoptosis. Melanocortin-1 Receptor MC1R gene, 16q It contributes to skin pigmentation by regulating the concentrations of eumelanin and pheomelanin. Its activation by ultraviolet radiation results in increased synthesis of eumelanin and increased melanocyte dendricity, proliferation, cell survival and DNA repair capability.
MC1R mutations associated with red hair phenotype increases the risk of developing melanoma, independent of pigmentation phenotype. Other genes. BRCA2, 13q The Breast Cancer Linkage Consortium reported a rel- 6 ative risk of 2. Two independent phenotypic traits that place individuals at higher risk for melanoma are fair skin see phototype below and the presence of a large number of melanocytic nevi see nevi 5 below.
Individuals with fair skin and poor ability to tan are classified having skin type I or II. Based on this scale, fairer skin types have an increased risk for melanoma. On the one hand, there is the observation that high nevus counts common and atypical are a risk marker for melanoma. In one study the lifetime risk of a nevus transforming into a melanoma was estimated to be approximately 0. Number of common melanocytic nevi Nevus counts are correlated with pigmentary traits, sun-exposure and history of sunburns.
However, the ultimate nevus count can be influenced by sun exposure. These families have one or more first- or second degree relatives with melanoma, multiple nevi and dysplastic nevi. FAMMM syndrome is also linked to the development of other cancers including breast cancer and pancreatic can- Vol. A, B Clinical and close up images. C Dermoscopy evaluation demonstrates a peripheral reticular with central hypopigmented nevus pattern in association with a focal atypical pigment network and blue-white veil at the periphery.
This lesion was biopsied revealing a melanoma in situ arising in association within a dysplastic nevus. Hence, these patients will benefit more from meticulous surveillance than they will from indiscriminate removal of their nevi. Furthermore, Lipoff et al.
In contrast, the lifetime risk for melanoma developing in a large They found that the estimated cumulative five-year risk to develop a second primary melanoma was Likewise, organ transplant recipients have a 3- to 5-fold increased risk for melanoma and these melanomas tend to be diagnosed at a mean of 5 years post-transplant.
This inability to repair the damaged DNA is due to defective nucleotide excision enzymes. These patients are at higher risk for developing melanoma. One study showed that the frequency of skin, eye and tongue cancers was increased fold or more in patients with XP who were younger than 20 years.
Although not all melanomas are related to sun exposure, most melanomas appear to be related to UVR exposure. In contrast, chronic sun exposure has been linked to the formation of lentigo maligna melanoma 16, 44, 73 Table II. The latency period from the time of the PUVA to the time of the melanoma diagnosis was reported to be as long as 15 years. The most important prognostic factors for localized melanoma Stage I and II are tumor thickness, mitotic rate and ulceration.
If feasible, an excisional biopsy with a narrow 1 to 2 mm margin is preferred to a shave or punch biopsy since this provides the necessary prognostic information and prevents histopathologic misdiagnosis. The number of regional lymph nodes harboring metastatic disease and the regional node tumor burden are also considered independent predictors of survival. Additionally, the number and location of metastases at distant sites is also an important prognostic factor.
Older age has been reported to be an independent adverse prognostic factor among patients with melanoma. Patients were randomly assigned to undergo excision with a 2 cm margin N. Thus, it was concluded that 2-cm margins are sufficient for patients with melanomas thicker than 2 mm 88 Table VI.
Sentinel lymph node biopsy is a procedure performed in patients with localized disease to identify those with nodal metastases with a high degree of accuracy. Candidates for sentinel lymph node biopsy include patients with melanomas that are 1. These new therapies include Vemurafenib, which is a selective BRAF inhibitor, and Ipilimumab, which is an IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte associated antigen-4, which in turn increases T-cell activation and proliferation.
However, it is clear that patients with a previous melanoma are at increased risk for developing subsequent new primary melanomas and thus, these patients are likely to benefit from the implementation of prevention strategies. Prevention strategies have been categorized into primary and secondary prevention.
Primary prevention entails the prevention of the disease via modifying melanoma risk factors. Secondary prevention involves early detection and treatment of melanoma or melanoma precursor lesions while the tumor is thin and easily curable by simple surgical excision.
One method to accomplish this task is the wearing of UV-blocking glasses or sunglasses. An added benefit of wearing UV protective eyewear is the lowering of the risk for cataract development. The wearing of a broad brimmed hat can also decrease the amount of UV reaching the eyes. Such hats have the added advantage of also protecting the scalp, ears, face and neck from UVR. The inorganic sunscreens, such as zinc oxide and titanium dioxide, reflect and scatter UVR and visible light.
The Sun Protection Factor SPF is used as the worldwide standard gauge for UVB protection and it is reported as a number, which is a proportion derived from measurements of the minimal erythema dose of sunscreen protected skin versus unprotected skin. Regarding UVA protection measurements, there is no one worldwide standard. Current labeling regulations of the European Commission , accepts two methods for measuring UVA protection i. A A new lesion on the face was observed on comparison with baseline images; B dermoscopy evaluation demonstrates a melanoma with a multicomponent pattern.
Lesion was biopsied revealing a melanoma without any associated nevus. The wavelength at which this is achieved is called the CW. However, for a sunscreen to be labeled as providing broad-spectrum coverage requires that the CW be at least nm. Green et al. The investigators randomly selected participants, who were randomly assigned to daily or discretionary sunscreen use to sun-exposed areas of their skin between the years to This is the only large randomized clinical trial on sunscreens that has 12 demonstrated that the regular use of sunscreen with an SPF of at least 15 reduces the incidence of new primary melanomas.
However, chemopreventive agents for melanoma remain under investigation and, to date, there are no drugs approved for this purpose. This endeavor can be accomplished by physician based periodic total body skin cancer surveillance examinations and patient monthly skin self-examination SSE.
Physician detection. It has been shown that physician screening is associated with higher rates of Vol. Any melanocytic neoplasm displaying any of the 10 melanoma specific structures highlighted in this figure should be considered for biopsy. A recent study on melanoma detection patterns in high-risk individuals under surveillance demonstrated that physician detected melanomas were thinner as compared to self-detected melanomas 0.
Two of the most commonly used techniques are dermoscopy and total body photography TBP. TBP consists of a set of clinical images of the entire skin surface. These images serve as a baseline to which subsequent skin examinations are compared. Dermoscopy evaluation of these lesions allowed the clinician to diagnose patient A with a benign growing nevus with a peripheral globular pattern, and a melanoma in patient B.
The lesion of patient A was followed over time and revealed symmetric growth until reaching senescence, at which time it revealed a reticular pattern only. The lesion of patient B was removed and revealed features of melanoma in situ. Dermoscopy on the other hand is used to evaluate individual lesions more closely to determine if a biopsy is warranted.
Numerous studies and meta-analyses have confirmed that dermoscopy provides improved diagnostic accuracy for the diagnosis of skin cancer as compared to the naked eye examination . It should be intuitively obvious to most that there exists a natural synergy between TBP and dermoscopy. Whereas TBP facilitates identifying subtly changing or new lesions, dermoscopy helps further evaluate these lesions to determine if a biopsy 14 is necessary Figures The combined use of TBP and dermoscopy is likely to translate into a much improved sensitivity and specificity for the detection of melanoma, which in turn results in the appropriate removal of skin cancers while at the same time minimizing the unnecessary removal of benign and biologically indolent lesions Figures 6, 7.
Some physicians have started advocating total body dermoscopy, which entails obtaining baseline dermoscopic imaging of all or almost all nevi in a given individual. These lesions can then be reimaged with dermoscopy in the future and compared to the baseline dermoscopic images. A Dermoscopy evaluation of the lesion on the abdomen revealed a benign reticular pattern nevus.
This nevus was followed and revealed no subsequent changes. Thus, the lesion was considered biologically indolent and subjected to continued follow-up; B Dermoscopy evaluation of the lesion on the back revealed a multicomponent pattern. This lesion was removed and revealed a microinvasive melanoma. Patient detection. To assist patients in their SSE some have advocated provided them with their own set of baseline TBP and perhaps even their own dermatoscope.
Baseline dermoscopic images of many nevi were obtained at baseline in row 1. Nevi were reimaged with dermoscopy two years later and the 4th and 5th lesion revealed changes that warranted a biopsy. The fourth lesion proved to be a dysplastic nevus and lesion number 5 proved to be a microinvasive melanoma.
The other lesions continued to be subjected to dermoscopic imaging and two years later remained unchanged. Secondary prevention by removing precursor lesions It is important to point out that there are no known obligate precursor lesions to melanoma. Although melanoma can arise in association with dysplastic nevi, congenital nevi and lentigines, these lesions are all considered potential non-obligate precursors to melanoma.
Unfortunately, there is currently no method available at our disposal that can reliably identify which of the benign lesions is destined to transform into melanoma. However, it is intriguing to speculate that while biologically indolent non-changing or senescent lesions are likely benign, some of the biologically dynamic changing, breaking out of senescence lesions that are found to be histologically benign may in fact be lesions that are on the road to melanoma.
What this implies is that some lesions that are histologically diagnosed as benign lesions may in fact be malignant when viewed on the molecular level. Attempts were made to focus on issues that are likely to be pertinent to busy practicing dermatologists such as awareness of variables that predispose an individual to skin cancer, strategies for UVR protection, and the importance of screening and surveillance of high-risk patients for the development of new primary melanomas.
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Screening for cutaneous melanoma by skin self-examination. Dermoscopy in skin self-examination: A useful tool for select patients. Arch Dermatol ; J Am Acad Dermatol [Epub ahead of print]. Lentigo maligna LM is LMM in situ, usually presenting an irregular tan colored or brownish pigmented macular lesion persisting for years on chronically sun-exposed skin.
It has been shown that chronically sun-damaged non-lesional skin can display some atypical features even in the absence of a melanocytic neoplasm. It is important for dermatopathologists to be aware of these findings so that such features are interpreted appropriately when making a histological assessment that may ultimately influence therapy and outcome. LMM is characterized by significant subclinical lesion extension which makes the treatment another challenge. Nowadays, a variety of therapeutic options are available in the treatment of LMM.
Surgery remains the mainstay of LMM therapy, however the treatment of LM remains controversial subject in the literature. These treatment options should be considered for a subset of patients with LM, especially in elderly patients with extensive or unresectable disease in difficult areas on the face or, as a second-line therapy if surgery is contraindicated. Surgical options include simple excision and margin-control techniques such as staged excision and Mohs micrographic surgery.
In this article, authors are reviewing the latest diagnostic and therapeutic advances in the management of LMM. Corresponding author: M. The age of onset has dropped over the past years and this tumour is nowadays also diagnosed in middle-aged individuals.
This lesion was first described by Hutchinson in as the presence and overgrowth of atypical melanocytes at the dermal-epidermal junction in chronically sun-damaged skin. Early diagnosis of LM requires a high index of suspicion for the often subtle atypical signs of pigmented lesions on sun-damaged skin. However, annular-granular structures and gray pseudo-network can also be found but usually more homogeneous in regressive areas of solar lentigo early stage of seborrheic keratosis , as well as in lichen planus-like keratosis and pigmented actinic keratosis.
For example, it has been reported that topical imiquimod may remove visible pigment while having no effect on the histological findings. Also, LM is a type of lesion in which a marked heterogeneity in the histological features in different portions of the same lesion can be found.
In a study conducted by Weyers et al. Hendi et al. This is because some pathologists make differentiation between LM as melanoma precursor and a true MIS according to the number of atypical melanocytes and the pattern of their arrangement in the basal epidermis. Surgery remains the mainstay of melanoma treatment at all sites. However, long-term follow-up and multiple post-treatment biopsies are strongly recommended, even in the absence of a clinical recurrence.
The excised tissue is then analyzed by the pathologist. Moreover, subclinical extension of tumour together with the poikilodermatous aspect of the solar damaged skin, make the border distinction difficult. Hence, the surgical challenge is to spare tissue while still achieving clear margins. Margin-control surgery offers the highest cure rate while minimizing loss of normal tissue. Numerous methods have been used to better visualize single melanocytes, with varying results.
The advent of rapid immunostains has made the use of MMS to treat melanoma more practical. Bhardwaj et al. The first Mohs layer was then taken, and staining with hematoxylin and eosin as well as Mel-5 immunostaining was performed. Frozen sections were confirmed by fixed histopathologic specimens. Subsequently these tissue blocks were examined with HMB monoclonal antibodies.
Patients were observed 5 to 9 years. Only one of the 16 patients had a recurrence 8 years after surgery. Staged excision procedures are specialized surgical techniques that focus on meticulous assessment of peripheral margins prior to closure staged margin control conducted with analysis of either frozen or permanent histologic sections.
Depending on the technique, primary tumour is excised with the initial margin specimens or left in place until margins are cleared. According to them, the main advantage of perimeter technique is that all margins are examined with permanent sections, whereas the main drawback is that multiple operative sessions are required to complete the procedure.
However, this technique does not require specific Mohs training and is therefore applicable to non-Mohs surgeons. Using staged excision, Two or more stages of excision were required in Invasive LMM was identified in There was one documented recurrence during a median 2. Any sites of tumor at resected margins were identified by a dermatopathologist and noted on the map of the excised specimen. Positive margins and areas with markedly atypical melanocytes were further resected, color-coded, mapped, and evaluated as previously described until margins free of tumor were attained.
The same procedure is repeated beyond the segments which are shown not to be tumour free and so forth until the minimal tumourfree perimeter is outlined. No operative wound is left between operative sessions. In the second phase, the melanoma resection and reconstruction are performed at the same time. In the study performed by GaudyMarqueste et al. The mean number of steps in the procedure was 1.
Grafts were used for reconstruction in all cases. After a median followup period of Unlike staged surgery, it does not leave patients with an open wound before the final reconstruction. However, this study was performed at a single centre and included a limited number of patients, with a relatively short follow-up period. However, the treatment of LM, remains controversial subject in the literature for over a decade.
When analyzing a lentiginous lesion in the area of chronically damaged skin, dermatopathologists should be aware of numerous pitfalls in the histologic and immunohistochemical analysis. Margin- control surgical techniques offer the highest cure rate while minimizing loss of normal tissue.
Nowadays, classical Mohs micrographic surgery is modified with the use of rapid intraoperative immunohistochemistry to identify melanocytes in frozen sections. Even though surgery is the treatment of choice, alternative options should also be considered, especially for the elderly for whom the need for efficiency and acceptability plays a significant role. La chirurgia rimane una pietra miliare per quanto riguarda la terapia del MLM, nonostante il trattamento della LM sia ancora un argomento controverso in letteratura.
Queste opzioni di trattamento dovrebbero essere considerate per un sottoinsieme di pazienti affetti da LM, specialmente nei pazienti anziani con malattia estesa o non resecabile in zone difficili del viso o come terapia di seconda linea nel caso in cui la chirurgia fosse controindicata.
Le opzioni chirurgiche includono escissione semplice e tecniche margine-controllo quali escissione a strati e chirurgia micrografica di Mohs. Nel presente articolo gli autori esaminano gli ultimi progressi diagnostici e terapeutici nella gestione del MLM.
Parole chiave: Macchia melanotica di Hutchinson - Melanoma - Diagnosi - Esame istologico - Trattamenti - Procedure chirurgiche mininvasive.
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