Roberto Alfano

Atopy as a risk factor for thyroid autoimmunity in children affected with atopic dermatitis

As a result of several clinical reports addressing coincidence or coprevalence of atopy and autoimmune disease such as multiple sclerosis and type I diabetes mellitus, there has been considerable interest in defining the relationship between the expression of allergic and autoimmune disease in populations of patients. Although thyroid autoimmunity has been regularly associated with chronic urticaria in children, the cofrequency of thyroid autoimmunity and atopic dermatitis has not yet been investigated. The aim of the study was to describe our experience with children affected by atopic dermatitis and associated thyroid autoimmunity.

Update on dermoscopy of Spitz/Reed naevi and management guidelines by the International Dermoscopy Society

Spitzoid lesions represent a challenging and controversial group of tumours, in terms of clinical recognition, biological behaviour and management strategies. Although Spitz naevi are considered benign tumours, their clinical and dermoscopic morphological overlap with spitzoid melanoma renders the management of spitzoid lesions particularly difficult. The controversy deepens because of the existence of tumours that cannot be safely histopathologically diagnosed as naevi or melanomas (atypical Spitz tumours). The dual objective of the present study was to provide an updated classification on dermoscopy of Spitz naevi, and management recommendations of spitzoid‐looking lesions based on a consensus among experts in the field. After a detailed search of the literature for eligible studies, a data synthesis was performed from 15 studies on dermoscopy of Spitz naevi. Dermoscopically, Spitz naevi are typified by three main patterns: starburst pattern (51%), a pattern of regularly distributed dotted vessels (19%) and globular pattern with reticular depigmentation (17%). A consensus‐based algorithm for the management of spitzoid lesions is proposed. According to it, dermoscopically asymmetric lesions with spitzoid features (both flat/raised and nodular) should be excised to rule out melanoma. Dermoscopically symmetric spitzoid nodules should also be excised or closely monitored, irrespective of age, to rule out atypical Spitz tumours. Dermoscopically symmetric, flat spitzoid lesions should be managed according to the age of the patient. Finally, the histopathological diagnosis of atypical Spitz tumour should warrant wide excision but not a sentinel lymph‐node biopsy.

Eccrine poroma: the great dermoscopic imitator

1 Fanburg-Smith JC, Michal M, Partanen TA, Alitalo K, Miettinen M. Papillary intralymphatic angioendothelioma (PILA): a report of twelve cases of a distinctive vascular tumor with phenotypic features of lymphatic vessels. Am J Surg Pathol 1999; 23: 1004–1010. 2 McKee PH, Calonje E, Grantner SR, eds. Pathology of the Skin, 3rd edn. Elsevier Mosby, London, 2005: 1829–1830 3 Weedon D. Weedon’s Skin Pathology, 3rd edn. Churchill Livingstone Elsevier, London, 2010, 919 4 Neves RI, Stevenson J, Hancey MJ et al. Endovascular papillary angioendothelioma (Dabska tumor): underrecognized malignant tumor in childhood. J Pediatr Surg 2011; 46: e25–e28. 5 Dabska M. Malignant endovascular papillary angioendothelioma of the skin in childhood. Clinicopathologic study of 6 cases. Cancer 1969; 24: 503–510. 6 Quecedo E, Mart ınez-Escribano JA, Febrer I, Oliver V, Velasco M, Aliaga A. Dabska tumor developing within a preexisting vascular malformation. Am J Dermatopathol 1996; 18: 302–307. 7 Emanuel PO, Lin R, Silver L, Birge MB, Shim H, Phelps RG. Dabska tumor arising in lymphangioma circumscriptum. J Cutan Pathol 2008; 35: 65–69. 8 Takaoka K, Sakurai K, Noguchi K, Hashitani S, Urade M. Endovascular papillary angioendothelioma (Dabska tumor) of the tongue: report of a case. J Oral Pathol Med 2003; 32: 492–495. 9 Fiorillo A, DeRosa G, Giugliano F, DeLillo ML, Sabbatino MS, Veneziano A. Efficacy of pegylated lyposomal anthracyclines and of intra-arterial carboplatin and doxorubicin combined with local hyperthermia in a case of malignant endovascular papillary angioendothelioma. Curr Drug Deliv 2009; 6: 58–61. 10 Ward KA, Ecker PM, White RR et al. Papillary intralymphatic angioendothelioma of the thigh: a case report and review of the literature. Dermatol Online J 2010; 16: 4.

Unusual Dermoscopic Patterns of Seborrheic Keratosis

Background: Seborrheic keratoses (SKs) may sometimes mimic benign and malignant skin tumors, and a biopsy can be necessary in order to rule out malignancy. Methods: From the database of our pigmented lesion clinic, we evaluated the dermoscopic features of difficult-to-diagnose SKs that were biopsied between January 2010 and December 2014. Results: SKs represented 3.8% of all excised lesions (161/ 4,182). Specifically, 91 (56.5%) were excised to rule out melanoma, 63 (39.1%) to rule out squamous cell carcinoma and 7 (4.4%) to rule out basal cell carcinoma. The following 10 global dermoscopic patterns were identified: multicomponent (32; 19.9%); reticular (24; 14.9%), characterized by an irregular pigment network; bowenoid (21; 13.0%); hairpin (19; 11.8%); keratoacanthoma-like (16; 9.9%); blue-nevus-like (15; 9.3%); lichenoid (6; 3.7%); hyperkeratotic (6; 3.7%); clonal (5; 3.1%); spitzoid (5; 3.1%). Furthermore, 12 SKs (7.5%) were not included in any of such patterns (not classified). Conclusion: Our results are in line with previous studies highlighting the dermoscopic variability of SKs. Although excised SKs may be classified into 1 of 10 repetitive dermoscopic patterns, a biopsy remains mandatory for those that cannot be clearly differentiated from common skin malignancies.

Increased mortality for pregnancy‐associated melanoma: different outcomes pooled together, selection and publication biases

Editor We read with interest the systematic review–meta-analysis by Byrom et al. in the early view section of the Journal. This is an interesting study with clinically relevant conclusions. However, in our opinion, there are several methodological issues in their study that should be underlined. Specifically, the authors report that pooled hazard ratios (HRs) from four studies showed an increased risk of melanoma death for pregnancy-associated melanoma compared with other melanomas, after adjustment for patient age and stage of the disease (pooled HR 1.56, 95% CI: 1.23–1.99). According to the authors, a number of studies not reporting HRs were excluded from their analysis, while the results of these non-quantified, and thus excluded, studies did not support their pooled finding. Of note, the excluded study by O’Meara includes the highest number of pregnant patients. However, the authors do not comment why they did not attempt to calculate missing HRs from other reported data in the studies, according to the methods proposed by Parmar et al. This would minimize the selection bias of convenient sampling, namely including only the four studies that reported HRs, while failing to quantify data from all the studies. In one of the studies pooled by Byrom et al., MacKie et al. report a HR (1.30; 95% CI: 0.54–3.15) for delivery during melanoma (reference: non-delivery). Byrom et al. in their metaanalysis, include this HR for delivery during melanoma in a forest plot including other three HRs for melanoma death during pregnancy, which is obviously not the same. It would be appropriate if the authors had either excluded the latter study, or calculated death HRs for the group who developed melanoma during pregnancy as opposed to the other three groups in the MacKie study, who developed melanomas before, after or between pregnancies. In addition pertaining to the pooling of potentially different outcomes is the fact that Byrom et al. combine the results of the Stensheim et al. study that reports on cause specific survival, with the studies by Moller et al. and Lens et al. that report on overall survival, without discussing this limitation. In conclusion, we believe that the study by Byrom et al. deals with a very relevant topic, but the reported pooled HRs are not sufficiently justified by the evidence and the limitations of the review are not sufficiently discussed.

Pigmented epithelioid melanocytoma: clinical, dermoscopic and histopathological features.

DEAR EDITOR, Pigmented epithelioid melanocytoma (PEM) is a recently proposed term that encompasses melanocytic tumours showing overlapping features between an atypical epithelioid blue naevus (first described in Carney complex and then also as sporadic) and a low-grade ‘animal-type melanoma’ or ‘pigment-synthesizing melanoma’. Clinically, PEM occurs over a broad age range, with a predilection for children and young adults. Histopathologically, it is characterized by a dermal proliferation of heavily pigmented, both dendritic and spindle/epithelioid melanocytes, admixed with slightly larger, plumper and less pigmented epithelioid cells. Involvement of the regional nodes has been reported in up to 46% of cases, but usually with no further spread of the disease. No histological criteria are predictive of metastatic behaviour. Thus, the tumour could be a low-grade, lymphotropic variant of melanoma with frequent lymph node metastases but an indolent clinical course. The dermoscopic features of these uncommon skin tumours have not been described up to now. The aim of our study was to analyse the clinical, dermoscopic and histopathological features of a series of PEMs retrospectively collected, and to correlate the histological and dermoscopic features of these rare skin neoplasms. We retrospectively searched the image database of the ‘Gaetano Rummo’ General Hospital of Benevento, and Arcispedale Santa Maria Nuova, Reggio Emilia, Italy from 2004 to 2014 for images of excised tumours using ‘pigmented epithelioid melanocytoma’ as the keywords. All histopathological specimens were reviewed by two of us (R.R. and G.F.) on the basis of the criteria described by Zembowicz et al. Clinical and dermoscopic images were reviewed in agreement by two observers (E.M. and G.A.). Lesions were defined clinically as macular, papular and nodular. Dermoscopic criteria were evaluated on the basis of the most common dermoscopic criteria. Nine excised skin lesions with a histopathological diagnosis of pigmented epithelioid melanocytoma were found. The collected patients’ demographics and clinical information are summarized in Table 1. Their ages ranged from 3 to 57 years, mean 20 years. The majority of lesions were located on the head/neck area (n = 4), followed by lower limbs (n = 3), the upper limb (n = 1) and the dorsal aspect of the foot (n = 1). The majority of lesions were nodular (n = 6). Dermoscopically, all lesions showed a homogeneous blue pigmentation. Three cases presented blue and black colour (cases 3, 4 and 6). White colour, present as crystalline structures, was detected in cases 4 and 9. Brown colour and comedo-like openings were detected in case 3. The dermoscopic differential diagnosis was melanoma in six cases and blue naevus in three (cases 1, 5 and 9) (Fig. 1). Histopathologically, all of the neoplasms were dermal based, medium to large sized, more or less wedge shaped and heavily pigmented because of a proliferation of spindle/epithelioid and dendritic melanocytes admixed with many melanophages. No

Does pregnancy influence melanoma prognosis?: A meta-analysis

The literature has not been able to conclude whether pregnancy influences the prognosis of melanoma. The aim of this study was to explore the prognosis of melanoma diagnosed during pregnancy or post partum [pregnancy-associated melanoma (PAM)] compared with melanoma in female patients who were not pregnant. We systematically searched for studies of female patients with melanoma that reported outcomes related to survival. Fifteen eligible studies were found. Overall, PAM was associated with a 17% higher mortality compared with melanoma diagnosed in female patients who were not pregnant (hazard ratio=1.17, 95% confidence interval: 1.03–1.33, P=0.02). The heterogeneity associated with this test was moderate (P=0.07; I2=38%). PAM was also associated with a 50% higher recurrence rate compared with melanoma not associated with pregnancy (hazard ratio=1.50, 95% confidence interval: 1.19–1.90, P<0.001). The heterogeneity associated with this test was low (P=0.69; I2=0%). A limitation of this meta-analysis is the definition of PAM, which is not unanimous among the studies included. Our results indicate that PAM is associated with a worse prognosis than melanoma not related to pregnancy, both in terms of overall survival and disease-free survival. On the basis of our data, we anticipate that the survival difference we report here will be further amplified with the addition of future well-carried out studies. We suggest that detection of PAM requires particular awareness by healthcare professionals.

Predictive biomarkers along gastric cancer pathogenetic pathways

ABSTRACT Introduction: Gastric cancer is the second leading cause of cancer all over the world. Unfortunately, several gastric cancers are diagnosed in an advanced stage and chemotherapy and/or target therapies remain the only options to treat patients. Areas covered: Herein we evaluate the new molecular proposal of gastric cancer classification, offering the possibility to recognize different pathogenetic mechanisms and molecular biomarkers potentially useful for target therapies. Expert commentary: The possibility of introducing new specific tests for identification of molecular biomarkers critical for targeted therapies response represents the new frontier in the selection of gastric cancer patients to improve their survival. Besides HER2, already used in clinical settings as a target biomarker for biological therapy in gastric cancer patients with tissue cancer cells overexpressing HER2, other promising target biomarkers which are deregulated in gastric cancer, such as MET and FGFR, could be identified in tissue and then used for therapeutic purposes. In addition immunotherapy represents the most promising possibility of advanced gastric cancer treatment. In particular, as in other solid tumors, PD-1/PDL1 pathway has emerged in several clinical trials as an interesting therapeutic target.

Dabrafenib: a new opportunity for the treatment of BRAF V600-positive melanoma

Prior to 2011, the 1-year survival rates for patients suffering from advanced or metastatic melanoma was as low as 33%, with a median overall survival of about 9 months. Several chemotherapeutic regimens have been applied, either as monochemotherapy or as polychemotherapy, overall not resulting in an improvement of progression-free or overall survival. Novel insights into the epidemiology and biology of melanoma allowed the development of newer therapies. The discovery of mutations in BRAF, a part of the mitogen-activated protein kinase, allowed the development of two BRAF inhibitors, vemurafenib and dabrafenib, which significantly improved the outcome of metastatic melanoma treatment. This article reviews the mechanism of action, efficacy, and safety profile of dabrafenib. An in-depth knowledge of this medication will encourage clinicians to select the appropriate therapeutic strategy for each patient, as well as to prevent or adequately manage side effects, optimizing, thus, the drug’s applicability.

Are tumor-infiltrating lymphocytes protagonists or background actors in patient selection for cancer immunotherapy?

ABSTRACT Introduction: Tumor-infiltrating lymphocytes (TILs) are frequently observed in several tumors, reflecting the dynamic process of ‘“cancer immunoediting”’. Prognostic and predictive values of TILs have been demonstrated in different cancers, proving their pivotal role in clinical outcome. In recent years, new therapies targeting immune checkpoint inhibitors, especially CTLA-4 and PD-1/PDL-1 pathways, have been introduced into clinical practice. In this context, TILs may even have a possible utility as a predictive biomarker for immunotherapy response. Areas covered: In this review, the authors summarize the most relevant knowledge related to TILs. This includes their prognostic and predictive significance in various types of tumour and the recent findings about their potential role in the cancer immunotherapy. Expert opinion: TILs evaluation could lead to a predictive biomarker for immunotherapy effectiveness in several cancer types. Furthermore, typing of TILs subpopulation could have clinical relevance in patient selection for treatment with immune checkpoint inhibitors. However further studies are still needed.