Overwhelming response to Dabrafenib in a patient with double BRAF mutation (V600E; V600M) metastatic malignant melanoma

ABSTRACT: The recent findings brought the necessity of testing the mutational status of a series of genes which had been already identified as responsible for melanomas development and progression, such as BRAF, CKIT and PTEN: the consequent results are, in fact, essential to guide the assessment of the novel treatment protocols based on tailored targeted therapies. We present here the case of a 66 year-old male patient, diagnosed with an advanced melanoma in June 2011, and treated with Dabrafenib for double mutant metastatic disease. The patient was referred to our attention for a large exophytic malignant melanoma on the left shoulder. After complete surgical excision and elective lymph node dissection for presence of metastatic sentinel lymph node, the patient has started high-dose interferon alfa- 2b injections as adjuvant therapy for a complete negative staging. The treatment was interrupted in August 2011 due to the appearance of metastatic lymph nodes. Tumor burden was rapidly growing reaching in few months the size of a tennis ball for the tumor mass located in the shoulder. Mutational study of the tumor revealed a double BRAF mutation on V-600E and V600M. This finding incited us to enroll the patient in compassionate Dabrafenib clinical trial. The therapy was started on may 2012 at 150 mg bid dosage. Almost surprisingly for the rapidity of the effect, one week later the lesion on the shoulder has reduced its size by 60% and one month later it has completely disappeared from sight. CT scan of June 2012 documented the astonishing clinical response

New investigative tools applied to the nail

Nail disorders can be very annoying for the patient and diagnostically challenging to the dermatologist. New investigative and noninvasive tools might be very useful in the diagnosis of nail disorders to reduce the number of nail biopsies and for follow up. Reflectance confocal microscopy is a high-resolution emerging imaging technique, with resolution at a cellular level, that can be used to explore the entire body surface, including skin, mucosa, hair and nails. Using the \u201cVivaStack\u201d function, the nail plate can be scanned from the surface to the transition of the plate to the underlying nail bed in horizontal images. According to the intensity of the reflection, three different layers can be differentiated with reflectance confocal microscopy. The superficial layer shows a brighter reflection, followed by a zone with slightly poorer signal, again followed by a brighter zone in the depth. The transition to the underlying nail bed is clearly visible only in thin nails (<500 \u3bcm) and displayed in wave-like structures, which are directed towards the fingertip. Reflectance confocal microscopy is able to display single corneocytes and the integrity of their borders. Optical Coherence Tomography is a non-invasive optical imaging technique that has the advantage of incredibly high spatial resolution compared to other clinically available methods. It provides images of the nail plate, the nail bed and the matrix up to a depth of 2 mm and a width of 6 mm, with a lateral resolution better than 7.5 \u3bcm and axial resolution better than 5 \u3bcm. The combination of these two investigative and noninvasive tools play an important role in the diagnosis and follow up of nail disorders such as onychomycosis, leukonychia, nail psoriasis and lichen planus. Moreover, they help to distinguish between benign and malignant causes of nail pigmentation

Role of microsatellite instability, immunohistochemistry and Mismatch Repair germline aberrations in immunosuppressed transplant patients: a phenocopy dilemma in Muir-Torre Syndrome.

Sebaceous tumours and keratoacanthomas are uncommon neoplasms that constitute important clinical criteria for Muir-Torre Syndrome (MTS) diagnosis. In MTS patients, the increased risk of developing synchronous or metachronous visceral malignancies is characterized by autosomal dominant inheritance. However, there are further conditions, other than MTS, that increase the risk of sebaceous neoplasms, e.g. iatrogenic immunosuppression. In this latter scenario, the sebaceous tumours can present Microsatellite instability (MSI) and loss of Mismatch-Repair (MMR) proteins, characteristic of hereditary syndromes, even in the absence of MMR germline mutations. In this paper we examine transplant probands in which the immunosuppressive therapies unmask the MTS cutaneous phenotypes, showing microsatellite instability (MSI) and loss of MMR protein expression, as demonstrated by immunohistochemistry (IHC). Furthermore, mismatch repair genes (MMR) sequencing analysis identified the presence of germline mutations in MTS-suspected individuals, in the absence of a visceral MTS phenotype. It is well known that immunosuppression plays a central role in the development of sebaceous tumours in both MTS and in non-syndromic settings. Sebaceous skin tumours MSI status and IHC profiles can be influenced by epigenetic or iatrogenic factors, however they constitute valuable tools and a cost-effective approach to screen individuals who otherways should undergo MMR genes direct sequencing in the context of immunosuppression. In this complex setting, the choice of the immunosuppressive drug becomes a critical decision for the management of both MTS and sporadic transplant patients, that may benefit from the administration of immunosuppressive drugs, resulting in a low impact on skin cancerogenesis

Skin Surface Reconstruction and 3D Vessels Segmentation in Speckle Variance Optical Coherence Tomography

In this paper we present a method for in vivo surface reconstruction and 3D vessels segmentation from Speckle-Variance Optical Coherence Tomography imaging, applied to dermatology. This novel technology allows to capture motion underneath the skin surface revealing the presence of blood vessels. Standard OCT visualization techniques are inappropriate for this new source of information, that is crucial in early skin cancer diagnosis. We investigate 3D reconstruction techniques for better visualization of both the external and internal structure of skin lesions, as a tool to help clinicians in the task of qualitative tumor evaluation

Skeletal stigmata as keys to access to the composite and ancient Gorlin-Goltz syndrome history: The Egypt, Pompeii and Herculaneum lessons

There are several genetic diseases with a wide spectrum of congenital bone stigmata in association to cutaneous and visceral benign and malignant neoplasms. Gorlin-Goltz syndrome, also named nevoid basal cell carcinoma syndrome, is an autosomal dominant systemic disease with almost complete penetrance and high intra-familial phenotypic variability, caused by germline mutations of the gene PTCH1. The syndrome is characterized by unusual skeletal changes and high predisposition to the development of multiple basal cell carcinomas, odontogenic keratocysts tumors and other visceral tumors. The Gorlin syndrome, clinically defined as distinct syndrome in 1963, existed during Dynastic Egyptian times, as revealed by a costellation of skeletal findings compatible with the syndrome in mummies dating back to 3000years ago and, most likely, in the ancient population of Pompeii. These paleogenetic and historical evidences, together with the clinical and biomolecular modern evidences, confirm the quite benign behavior of the syndrome and the critical value of the multiple and synchronous skeletal anomalies in the recognition of these rare and complex genetic disease

Microsatellite instability, immunohistochemistry and germline mismatch repair gene mutations for the diagnosis of Muir-Torre syndrome in immunosuppressed patients

Although rare sebaceous tumors and keratoacanthomas are clinical criteria for Muir-Torre syndrome (MTS), they can also be found in the context of immunosuppression. We present here two patients who underwent organ transplantation in which immunosuppression unmasked MTS through the early appearance of the cutaneous sebaceous neoplasms. In all of their sebaceous tumors we detected microsatellite instability (MSI) e loss of mutS protein homolog 2 (MSH2) and 6 (MSH6) expression at immunohistochemistry (IHC). Although in the absence of visceral MTS phenotype, we performed the sequencing analysis for mismatch repair genes (MMR) identifying two novel MSH2 and MSH6 germline mutations. The combination of MSI and IHC status can therefore be considered useful for the recognition of MTS, even in case of incomplete MTS phenotype and/or in immunosuppressed patients. It would allow a costeffective approach to identify individuals who should undergo MMR genes direct sequencing

Morphological features of Spitz naevus as observed by digital videomicroscopy

A characteristic epiluminescence pattern of pigmented epithelioid and/or spindle cell naevus, or Spitz naevus, has been described previously. The aim of this study was (i) to evaluate the characteristic morphological features both of pigmented and non-pigmented epithelioid and/or spindle cell naevi observed employing a videomicroscope, (ii) to identify their histopathological correlates and (iii) to assess the improvement in diagnostic accuracy for epithelioid and/or spindle cell naevi obtained by means of this new instrumental device. Clinical, videomicroscopic and histopathological diagnoses were performed on 26 epithelioid and/or spindle cell naevi. Moreover, the videomicroscopic pattern of each lesion was described using appropriate morphological parameters. Based on their morphological aspect detected by digital videomicroscopy, epithelioid and/or spindle cell naevi can be subdivided into three main groups: (i) darkly pigmented lesions, (ii) red or light brown ESC naevi, and (iii) lesions with dark or brown areas on a light-brown background. Whereas most epithelioid and/or spindle cell naevi of the spindle cell type belonged to the morphological group I and group 3, most epithelioid cell lesions appeared as red or light-brown coloured naevi. Finally, instrumental observation by means of a videomicroscope enabled an improvement in diagnostic accuracy with respect to the naked eye observation, with an increase in sensitivity from 15% to 58%

Fibroepithelioma of Pinkus: Solitary tumor or sign of a complex gastrointestinal syndrome

Fibroepithelioma of Pinkus (FEP), which is considered to be an uncommon variant of basal cell carcinoma, has been described in association with other systemic diseases. However, no specific studies are currently available on this subject. The aim of our study was to evaluate the clinical and morphological characteristics of FEP and investigate whether this rare tumor is a single entity or seen in the context of a more complex syndrome. We retrospectively analyzed 49 cases of FEP diagnosed and excised in a single academic institution from 1995 to 2011. The tumors were mainly located on the trunk (77.55%), followed by the lower extremities (12.20%) and the head and neck (10.20%). In 9 of the 49 cases (18%), FEP was associated with gastrointestinal tumors. The abovementioned cases are presented in an attempt to make clinicians more aware of a possible association between FEP and gastrointestinal cancer. Although a possible underlying common genetic background between FEP and gastrointestinal tumors was not provided, our study suggests that patients with FEP should be screened for the occurrence of gastrointestinal tumors

Desmoplastic melanoma: a challenge for the oncologist

To evaluate clinical, pathologic and genetic features of desmoplastic melanoma (DM).MATERIALS & METHODS: Analysis of all DM records from 1991 to 2015. RESULTS: The most common location of DMs was the head and neck (69%); median age and follow-up were 60.5 and 7.3 years, respectively. A familial predisposition for DMs and others malignancies was analyzed. Thin Breslow thickness (<4.5 mm) was associated with an intraepidermal component or a previous lentigo maligna, whereas high Breslow thickness (>4.5 mm) was observed in 'pure' DM. CONCLUSION: DM could progress from an early phase, characterized by an intraepidermal component, to late phase, characterized by a dermal nodule. This hypothesis correlates with melanoma genetic and NF1 mutation, which could be an early event in the progression of DM

The Impact of In Vivo Reflectance Confocal Microscopy for the Diagnostic Accuracy of Melanoma and Equivocal Melanocytic Lesions

In vivo confocal reflectance microscopy recently showed promising results for melanoma (MM) diagnosis on a limited series. The aim of the study was to evaluate the sensitivity and specificity of confocal features for the diagnosis of MM 351 equivocal melanocytic lesions (136 MMs and 215 nevi) were evaluated for 37 confocal features by two blinded expert observers. χ2 test, multivariate discriminant analysis and binary logistic regression were performed for the identification of the significant features and for testing newly created diagnostic models. Melanomas were mostly characterized by epidermal disarray and pagetoid cells in the epidermis, non-edged papillae, and cellular atypia at the junction, and atypical nests and bright nucleated cells in the upper dermis. On the other hand, regular dermal–epidermal architecture, and absence of pagetoid infiltration and atypical cells were suggestive of benign lesions. Five out of 136 melanomas, with mildly atypical melanocytes and occasional pagetoid cells at histopathology, were not diagnosed by confocal microscopy. Nevertheless, new diagnostic models showed no significant improvement compared with the previously proposed confocal microscopy algorithm. Owing to the visualization of cellular aspects, confocal microscopy seems useful for second level examination of clinically and dermoscopically equivocal lesions