Folliculotropism in Actinic Keratoses in Patients not Responding to Treatments: A Pilot Study.

Dear Editor, Actinic keratoses (AK) have a high prevalence in the general population, with greater rates in Caucasian patients after the fourth and fifth decades of life (37.5-60.0%) (1,2). Standard histopathologic reporting of AKs does not provide information on the presence of atypical keratinocytes extending to the hair follicle, also defined as folliculotropism (FLC). Commonly, atypical cells in AKs do not present FLC, but this feature can be observed in bowenoid AKs with full-thickness epidermal atypia (3,4). FLC has been considered a possible element enhancing the chances of a progression toward invasive SCC (iSCC). Fernandez-Figueras et al. (3) reported that the depth of FLC in AKs was correlated with the invasiveness of associated iSCC. Pandey et al. (5) reported a positive association between AKs with FLC and history of invasive cutaneous cancer or melanoma, more often in men at an older age. The role of FLC in cutaneous melanoma is still debated, but it is considered a parameter that may correlate with treatment response in lentigo maligna and disease progression or recurrences in invasive tumors (6,7). These studies draw particular attention to the potential role of hair bulge compartment stem cells in favoring tumor progression through the expression of adhesion molecules, cytokines, and growth factor receptors (8). Aks are known to have a high recurrence rate after topical treatment (1). The risk of evolution to an iSCC is not completely clear, but it has been estimated to be around 0.6% at 12 months and up to 2.5% at 48 months (1,3,7). Considering the possible progression and the heavy burden of AK treatments, including the economic burden, it is imperative to focus on histopathologic features associated with treatment failure. The aim of this preliminary study was to assess the histopathologic features, specifically FLC, of AK samples from patients considered "non-responders" to specific topical treatments. A secondary endpoint was to assess the clinical/dermoscopic features. Patients were considered "non-responders" if the lesions persisted after two alternated completed cycles of treatments with ingenol mebutate, imiquimod, diclofenac 3%, or 5-fluoruracil. Patients with a positive history of immunosuppression or genetic diseases were excluded. The study was approved by the local Ethics Committee. Slides of AKs diagnosed at the Laboratory of Dermatopathology, University of Bologna, Italy from January 2016 to October 2018 were reviewed by two dermatopathologists (CM, PAF). 155 "non-responder" AKs of five main histopathologic subtypes were included, classified from grade I to III according to the Roewert-Huber classification (9) (Table 1). The proliferative and atrophic histopathologic subtypes of AKs were detected in 33.6% and 30.4% samples, respectively. FLC was observed in 75.3% of the cases, subdivided into two categories, periadnexal (48.9%) and intraadnexal (26.4%). Periadnexal FLC was detected in 31.0% of atrophic and in 50.3% of proliferative AKs, while intraadnexal FLC was found in 48.7% and 29.2%, respectively (Figure 1, a, b). At dermoscopy, most lesions had been classified as grade I or II (38.8% and 45.8%), and only 15.4% as grade III, showing an unexpected non-response to treatment according to the dermoscopic criteria. In contrast, almost half of the AKs were classified as grade III at histology, revealing a discrepancy between the dermoscopic grading and histological findings in a majority of cases (77.4%) (Figure 2, c, d). Furthermore, atrophic and proliferative AKs accounted for 64.0% of total cases, and these are the variants associated with a higher probability of evolution toward an iSCC (10). The clinical/histological discrepancy has already been reported in the literature (9) and may represent a misleading factor for treatment choice and outcomes. We believe that a comparative analysis with dermoscopy and histology should be performed in non-responding AKs, in order to choose the best therapeutic option. In fact, some superficial treatments (such as cryotherapy) may not provide a good response in deep hair follicles (4). We also suggest encouraging greater focus on FLC and its description in pathology reports. This is a preliminary observational study, but it reinforces the need to further larger clinical studies investigating the role of specific histopathologic parameters in AKs, including FLC, that may correlate with treatment outcomes.

A Comparative Demographic Study of Atypical Spitz Nevi and Malignant Melanoma.

Spitz tumors are a subset of melanocytic neoplasms characterized by epithelioid or spindled melanocytes(1). The benign nature of the "Spitz nevus" has since been clarified, but the debate regarding Spitzoidtumors (STs) is still ongoing. Spitzoid tumors encompass a wide spectrum of cutaneous lesions ranging from benign Spitz nevus (SN) to Spitzoid melanoma (SM), the latter displaying capacity for widespread metastasis and a potentially lethal outcome (2). The term atypical Spitz tumors (ASTs) refers to melanocytic tumors exhibiting the morphological features of SN, as well as some features associated with malignancy, but not sufficient to classify them as SMs. Currently, histopathology is the gold standard for the diagnosis of STs and cutaneous MM. However, the differential diagnosis between benign and malignant melanocytic lesions with spitzoid features remains challenging (3-6). In order to facilitate the work of clinicians and pathologists, we attempted a comparative clinical and demographic study comparing ASTs and MMs of patients referred to two Italian institutes. Patient data were obtained from two different Italian dermatological centers (Melanoma Registry of the Instituto Dermopaticodell'Immacolata IDI-IRCCS Rome, Lazio and the Skin Cancer Unit of Dermatology, Hospital Sant'Orsola-Malpighi, University of Bologna), from January 2007 to December 2017. Histological reports presenting pre-operative queries of both "atypical Spitz nevi" or "malignant melanoma" and a final diagnosis confirming one of the queries were included in the study. The chi-square test or Mann-Whitney U-test were applied to analyze differences between the groups for categorical variables such as sex, diagnosis, and continuous variables (age). The "anatomic site" variable was classified into three categories as follows: the limbs, trunk, and head/neck. A multivariate binary logistic model was used to investigate if the anatomic site was an independent predictor of MM. Age and sex were considered confounding factors. A total of 504 patients (51.8% men; 48.2% women) met the inclusion study criteria (mean age 52 years, SD = 22.8) (Table 1). 373 were cases of MM and 131 were cases of AST. Mean age of MM cases and AST were 61.2 years old (SD = 17.6) and 25.8 years old (SD = 13.8), respectively. Subjects with MM were predominantly men (58.2% versus 33.6%) (P<0.0001) and older (median age 62 years versus 25 years) (P=0.0001) than subjects with AST. The most frequent anatomic site for MM was the trunk (39.7 %), while the lower limb was the most frequent anatomic site for AST (48.1 %) (P<0.0001). Table 2 shows the multivariable analysis used to assess if anatomic site was an independent predictor of cutaneous melanoma. Multivariate analysis confirmed an increased risk for MM in comparison with AST for both localization on the trunk (OR:2.78; 95 %CI: 1.74-4.45) (P<0.0001) and head/neck (OR:3.20; 95% CI: 1.60-6.38) (P=0.0001). After introducing age (model 1, OR: 2.11; 95% CI: 1.08-4.12) (P=0.003) and sex into the model, the only anatomic site that remained statistically significant was the trunk (model 2, OR: 2.03; 95% CI: 1.0.3-3.99) (P=0.04). The results show that if the lesion was located on the trunk, the probability of being a MM was two times higher than that of AST, independent of sex, age, or center. After stratifying for sex, the effect was stronger for women (OR: 2.72; 95% CI: 1.14-6.50). After stratifying for age, the effect was stronger for younger subjects (<40 years) (OR: 2. 59; 95% CI: 1.20-5.60) (P=0.02). In this study, we focused on the clinical-epidemiological data in an attempt to improve the identification of nodular melanocytic lesions by providing clinicians with further information in order to reduce the rate of misdiagnosis and assist in providing critical clinical information to surgeons and pathologists. Consistently with the literature, ASTs were mainly found in young-adult patients (mean age was 25.8 years), in the female sex (66.4%), and were typically located on the lower limbs (48.1%) (3,7-10). MM were found to be slightly more common in male patients (58.2%) in the overall patient group; the mean age at the time of the diagnosis was 61.2 years old, and the majority of lesions were located on the trunk (39.7%). These data were similar to those reported by other authors (11-13). ASTs cases were mainly women and younger than MM cases, and were typically located on the lower limbs (Figure 3 and Figure 4). Nodules located on the trunk resulted in a two times greater risk of MM in comparison with AST. In summary, distinguishing ASTs from MMs is often challenging, and histopathology remains the diagnostic gold standard for melanocytic neoplasms, but a specific clinical framework may help surgeons, pathologists, and clinicians to correctly diagnose and manage these lesions in children and adults.

Mucocutaneous pyoderma gangrenosum: a case report and literature review.

Pyoderma gangrenosum is an uncommon neutrophilic dermatosis that usually presents with rapidly growing, painful, undermined, and purulent ulcers that are more likely to develop at areas of trauma. It is associated with underlying systemic diseases in more than half of cases, most commonly with inflammatory bowel disease. Pyoderma gangrenosum has no specific clinical, histologic, or laboratory findings, and so the diagnosis is based on exclusion of all other diagnostic possibilities, especially infectious causes. Misdiagnoses are frequent, with systemic vasculitides representing one of the main imitators. Treatment of pyoderma gangrenosum usually requires a multidisciplinary approach, with infliximab emerging as the best treatment option for cases associated with inflammatory bowel disease. The prognosis of pyoderma gangrenosum remains unpredictable, and recurrences are common. Here, we report a case of mucocutaneous pyoderma gangrenosum as a preceding sign of ulcerative colitis that responded to treatment with methylprednisolone and infliximab.

Mycobacterium chelonae infection in an immunocompromised patient presenting as multiple papulonodules on the leg.

Mycobacterium chelonae is a rapidly growing nontuberculous mycobacteria that is a rare cause of cutaneous infections in both immunocompromised and immunocompetent patients. The clinical presentation is heterogeneous and non-specific, and therefore, despite an increasing incidence of these infections, patients are often misdiagnosed. Here we present the case of an immunocompromised 73-year-old female patient that developed tender, erythematous, violaceous to brownish papules and nodules on both the anterior and posterior aspects of her left lower leg. A histopathological examination revealed acid-fast bacilli, and a tissue culture identified M. chelonae. Disease resolution was achieved with long-term targeted antibiotic therapy based on susceptibility testing.

Matrix metalloproteinase (MMP)-1 and MMP-2, but not COX-2 serve as additional predictors for chronic venous ulcer healing.

Chronic venous ulcers affect 1% of the adult population and are associated with a marked reduction in quality of life, especially if healing is prolonged. Several matrix metalloproteinases (MMPs) appear to be involved in the pathophysiology of chronic venous ulcer healing, but their exact role is still unclear. Cyclooxygenase-2 (COX-2) is an important enzyme in prostanoid synthesis, induced during inflammation in chronic venous ulcer. The first aim of our study was to compare the expression of MMP-1, MMP-2, and COX-2 in wound tissue to that in normal skin. The second aim was to observe the expression of the above factors in 29 chronic venous ulcers in 22 patients at the beginning and 4 weeks later in relation to healing rates and final healing outcome after 24 weeks. The enrolled population was divided into two groups, healed and non-healed wounds after 24 weeks. The intensity of expression of MMP-1, MMP-2 and COX-2 was assessed for each ulcer in paired wound biopsy samples and wound size measurements using laser triangulation at the beginning and after 4 weeks of observation. Initial healing rates in the first 4 weeks were calculated and proved to be an important predictive factor of healing in 24 weeks. Decreases in MMP-1 and MMP-2 after 4 weeks of observation were distinct, positive predictors for ulcer healing. Healing odds were 3.7 times higher for a decrease in MMP-1 and 2.1 times higher for a decrease in MMP-2 compared to the healing odds for a non-decrease in MMP-1 and MMP-2. In conclusion, a decrease in MMP-1 and MMP-2, but not COX-2, in wound biopsy samples after 4 weeks of observation can predict better healing of chronic venous ulcer.

Psoriasis-like tinea incognita: a case report and literature review.

Tinea incognita is an atypical presentation of fungal infection of the skin, the clinical presentation of which has been modified by misuse of topical corticosteroids or calcineurin inhibitors. Such dermatophyte infections often have an atypical clinical presentation and are difficult to diagnose, but with the rise of immunosuppressive drugs and self-prescribed topical therapies, they are becoming increasingly prevalent. Here we report the case of a 68-year-old male patient with a history of psoriasis, presenting with erythematous scaly lesions, that did not respond to conventional treatment for psoriasis, as would be expected. A diagnosis of tinea incognita was made with histopathological examination with periodic acid-Schiff stain of a skin biopsy sample. This case highlights the fact that dermatophyte infections are widespread but sometimes neglected and can occur concomitantly with other dermatoses.

Epidermolysis bullosa simplex with mottled pigmentation: the first Slovenian case.

Epidermolysis bullosa simplex with mottled pigmentation is a rare subtype of epidermolysis bullosa simplex that is characterized by nonscarring blistering and reticulated hyperpigmentation. We report the first Slovenian case of a newborn with blisters, who later presented with hyperpigmented macules in the first year of life. A missense p.Pro25Leu mutation in the KRT5 gene was confirmed.