The association between clinical and laboratory findings of bullous pemphigoid and dipeptidyl peptidase-4 inhibitors in the elderly: a retrospective study.

AIM: To evaluate the association between the use of dipeptidyl peptidase-4 inhibitors (DPP4I) and clinical and laboratory findings of bullous pemphigoid (BP) in patients treated at the European Reference Network - Skin Reference Centre in Croatia. METHODS: This retrospective study enrolled 82 patients treated for BP at the Department of Dermatovenereology, University Hospital Center Zagreb from January 2015 to December 2019. Clinical features of BP, presence of comorbidities, and laboratory findings of anti-BP antibodies and eosinophilia were analyzed in three groups of BP patients: 1) diabetes mellitus (DM) type II patients treated with DPP4I, 2) DM type II patients not treated with DPP4I, and 3) non-DM type II patients. RESULTS: The average age and anti-BP180 titer were similar in all three groups. DPP4I group had a slightly lower eosinophil level in both peripheral blood (4.89%) and biopsy specimens (87.5%), but the difference was not significant. The prevalence of inflammatory BP in DPP4I group was 76.5%. DPP4I group had significantly higher percentage of patients with chronic renal failure and dementia (52.9% and 11.8%, respectively) compared with non-DPP4I DM (14.3% and 0%, respectively) and non-DM type II patients (15.7% and 0%, respectively). CONCLUSION: BP patients treated with DPP4I and those not treated with DPP4Is did not significantly differ in laboratory findings. However, DPP4I treatment was associated with an inflammatory subtype of BP and a higher prevalence of dementia and chronic renal failure. These findings warrant further research into the association of BP and DM with dementia and chronic renal failure.

Altered Levels of Sphingosine, Sphinganine and Their Ceramides in Atopic Dermatitis Are Related to Skin Barrier Function, Disease Severity and Local Cytokine Milieu.

Dysfunctional skin barrier plays a key role in the pathophysiology of atopic dermatitis (AD), a common inflammatory skin disease. Altered composition of ceramides is regarded as a major cause of skin barrier dysfunction, however it is not clear whether these changes are intrinsic or initiated by inflammation and aberrant immune response in AD. This study investigated the levels of free sphingoid bases (SBs) sphingosine and sphinganine and their ceramides and glucosylceramide in the stratum corneum (SC) and related them to skin barrier function, disease severity and local cytokine milieu. Ceramides were measured in healthy skin, and lesional and non-lesional skin of AD patients by a novel method based on deacylation of ceramides which were subsequently determined as corresponding sphingoid bases by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The cytokine levels were determined by multiplex immunoassay. Atopic skin showed increased levels of most investigated markers, predominantly in lesional skin. The largest difference in respect to healthy skin was found for glucosylceramide with respective median values of 0.23 (IQR 0.18-0.61), 0.56 (IQR 0.32-0.76) and 19.32 (IQR 7.86-27.62) pmol/g protein for healthy, non-lesional and lesional skin. The levels of investigated ceramide markers were correlated with disease severity (scoring atopic dermatitis, SCORAD) and skin barrier function (trans-epidermal water loss, TEWL) and furthermore with cytokines involved in innate, Th-1, and Th-2 immune response. Interestingly, the strongest association with SCORAD was found for sphinganine/sphingosine ratio (r = -0.69, p < 0.001; non-lesional skin), emphasizing the importance of SBs in AD. The highest correlation with TEWL was found for glucosylceramide (r2 = 0.60, p < 0.001), which was investigated for the first time in AD. Findings that the changes in SBs and ceramide levels were predominant in lesional skin and their association with disease severity and cytokine levels suggest an immune-system driven effect. a novel analysis method demonstrates a robust and simple approach that might facilitate wider use of lipid biomarkers in the clinics e.g., to monitor (immune) therapy or dissect disease endotypes.

[GIANT CELL TUMOR OF BONE: RESULTS AND TREATMENT COMPLICATIONS]. / GIGANTOCELULARNI TUMORI KOSTI: REZULTATI I KOMPLIKACIJE LIJECENJA.

Giant cell tumor of bone (GCT) is mostly benign, locally aggressive tumor with a high recurrence rate. GCT is treated primarily surgically, and the approach is determined according to localization and local tumor behavior. The aim of this study was to analyze results and complications of surgical treatment of GCT at atertiary orthopedic clinical center in Croatia. We analyzed all patients treated at University Department of Orthopedics, Zagreb University Hospital Center, during a 15-year period. From 1995 to 2009, 39 patients were surgically treated for GCT. Four patients were lost from follow up. In patients with low-grade GCT (n = 12, 34%), we performed marginal-intralesional resection, whereas in patients with locally aggressive GCT we performed en bloc resection and reconstruction with tumor endoprosthesis or bone allograft (n = 22, 63%). In one patient, the only treatment was tumor irradiation. Complications were evident in one-third of our patients. The most common complications were tumor recurrence (n = 6, 50% of all complications) and deep infection (n = 2, 17% of all complications). We performed amputation in two patients in whom osteosarcoma was revealed under GCT radiologic and histologic appearance. We performed 84 operations in 35 patients, not counting primary biopsy. In conclusion, treatment of GCT is complex, with a high incidence of tumor recurrence. Diagnosis and treatment are best provided through a multidisciplinary approach in highly specialized centers for orthopedic oncology.

The Role of Digital Dermoscopy and Follow-Up in the Detection of Amelanotic/Hypomelanotic Melanoma in a Group of High-Risk Patients-Is It Useful?

The prognosis, outcome, and overall survival of melanoma patients improve with early diagnosis which has been facilitated in the past few decades with the introduction of dermoscopy. Further advancements in dermoscopic research, coupled with skilled, educated dermatologists in dermoscopy, have contributed to timely diagnoses. However, detecting amelanotic and hypomelanotic melanoma remains a challenge even to the most skilled experts because these melanomas can mimic inflammatory diseases, numerous benign lesions, and non-melanoma skin cancers. The list of the possible differential diagnoses can be long. Melanoma prediction without the pigment relies only on vascular criteria, and all classic dermoscopic algorithms have failed to fulfill our expectations. In fact, the diagnosis of amelanotic and hypomelanotic melanomas is very challenging, which is why every tool in detecting these lesions is of significance. This review aims to explore the current knowledge and the literature on the possibility of detecting amelanotic/hypomelanotic melanomas using sequential monitoring with digital dermoscopy and total body skin photography.

Mycosis fungoides with large cell transformation (CD30+) and B-cell chronic lymphocytic leukemia.

Mycosis fugnoides (MF) is an indolent cutaneous T-cell lymphoma (CTLC) and is the most common of all cutaneous lymphomas. An increased risk for developing a second primary malignancy in patients with CTCL has been described in several studies, with a range from 1.04 to 2.4 (1-4). Caucasian males are at higher risk for MF development. MF is often diagnosed at ages between 55 and 67 years, and second malignancy usually occurs 5 or 6 years after the diagnosis of MF was established (5). The most common second primary malignancies include non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), lung carcinoma, bladder carcinoma, and melanoma. Even though a higher incidence rate of all NHL was described in patients with MF (15/1000) in comparison with the general population (0.32/1000), there are still only a few cases of B-cell NHL following MF described in the literature (6,7). We describe a rare case of a patient with MF and simultaneous large cell transformation (LCT) and a small B-cell lymphocytic lymphoma/chronic lymphocytic leukemia (B-CLL). In 2017, an 82-year-old man previously treated for MF presented with two fast growing tumorous lesions with ulceration on the right tight (Figure 1). A biopsy was performed, and a diagnosis of MF with LCT was established (Figure 2). During hospitalization, mild leukocytosis (12.2 x109 L-1), lymphocytosis (64%, total count of 7.81 x109 L-1), and anemia were found. Bone marrow biopsy was not performed due to low pain threshold. Bone marrow aspirate showed 70% of atypical lymphocytes and few "smudged" cells. Immunophenotyping by flow cytometry detected 49% monoclonal kappa+ B-cells with phenotypic features typical for B-CLL (CD5+, CD23+, kappa +). Of overall bone marrow cells, the ratio of monoclonal kappa + B-cells with the B-CLL phenotype was 21%. Immunophenotyping of peripheral blood showed up to 50% monoclonal kappa+ B-cells with phenotypic features typical for B-CLL (CD5+, CD23+, kappa +). Of overall peripheral blood cells, the ratio of monoclonal kappa+ B-cells with the B-CLL phenotype was 28%. Multi-sliced computed tomography was within normal ranges. A flow cytometry showed lymphocytes with phenotypic findings for CD20+ B-CLL. A diagnosis of MF with LCT (CD30+) clinical grade IIB (T3, N0, M0) and B-CLL was established. The patient was treated with fractionated superficial irradiation that resulted in applanation and regression of the tumorous lesions. No hematologic treatment was indicated other than regular follow-up. On dermatologic follow up for 2 years, the patient was stable, with no active skin lesions and no progression of MF. The patient was subsequently lost to follow-up. This is a rare case of MF with LCT and B-CLL occurring simultaneously. Large cell transformation in patients with MF can occur in 20-55% of advanced MF, as in our case, and this something physicians must be aware of, so repeated biopsies are advised (8). We also should keep in mind that patients with MF are at higher risk of developing a second malignancy. Of those second malignancies, a coexistence of lymphoproliferative disorders in two lineages, T-cell and B-cell, such as CTCL and B-CLL, is very uncommon, and only a few cases have been published (6,7,10). In most of these cases, CTCL preceded B-CLL, and with the only established explanation being increased risk of second malignancy in patients with CTCL (3,5,10). Other explanatory hypotheses include neoplastic stem cells, a genetic predisposition to malignancy, the use of immunosuppressive agents for the treatment for a first neoplasm, viral agents, and modulation of the B-cell system by monoclonal T-cell proliferation (1,5,6,9,10). Regular follow-up is mandatory for all patients with CTCL as well as MF, in order to identify the disease progression but for the timely detection of second malignancies.

Occupational Airborne Contact Dermatitis Caused by Omeprazole.

Airborne contact dermatitis (ACD) is a frequent condition, and there has been increasing recognition of the occupational origin of airborne contact dermatitis. ACD caused by drugs is often occupation-related and occurs mainly in healthcare workers who use the drugs for therapeutic aims and employees of pharmaceutical industries involved in the production of the drugs (1). Omeprazole (OM) is a proton pump inhibitor from the benzimidazole group used for treatment of gastric acid-related disorders (2). A 52-years-old female chemist had been working in a pharmaceutical company for 20 years. When working in the laboratory, she wore protective latex-free gloves, a mask, and glasses. Skin lesions started 6 months after she had started working in an analytic laboratory with omeprazole and azithromycin. Whenever omeprazole was being manufactured, the patient presented with eczema with scaling on the eyelids, face, and neck, with the hands subsequently being affected as well. The patient's skin lesions cleared during holidays and sick leave and worsened when she was working in omeprazole production. Topical corticosteroids were applied, which resulted in temporally regression of skin symptoms. We performed patch tests with the baseline series (Chemotechnique Diagnostics, Vellinge, Sweden, and Imunoloski zavod, Zagreb, Croatia) to materials in the patient's workplace and a lymphocyte transformation test (LTT) to omeprazole. All tests were negative, except the patch test to OM which showed a positive reaction (+) to 0.1% OM in saline solution on day (D) 2 and D3 and positive reaction (+) to 0.5% OM in saline solution on D2 and ++ on D3 (Figure 1). Hausen et al. performed experimental animal studies in which they concluded that OM and other proton pump inhibitors constitute a high-sensitizing-potential group (3). However, when administrated, orally or parenterally, the frequency of contact sensitization was low (3). Although direct contact with the skin was not always present, distribution of the dust containing OM through the air and deposition on exposed areas may result in ACD. The first two occupational cases of ACD caused by OM among pharmaceutical workers were reported in 1986 (4). Since then, ACD caused by OM in an occupational setting has been reported occasionally (2,4-6). Other proton pump inhibitors such as lansoprazole and pantoprazole have less pronounced potential to cause ACD (7,8). Ghatan et al. conducted a study in 2014 in an occupational setting with 97 workers and reported 31 positive LTT tests and 28 positive patch tests; these results confirm a high risk of sensitization to OM from occupational exposure (6). Although direct contact with the skin is not always present, it is important to bear in mind that distribution of dust containing OM through the air and deposition on exposed areas may result in ACD.

Nonsurgical treatment of nonmelanoma skin cancer in the mature patient.

Nonmelanoma skin cancer (NMSC) is the most common cancer, with the median age at NMSC diagnosis is 71 years. Treatment options for NMSC include surgical therapy, which is usually the first-choice treatment, and nonsurgical modalities. Therapeutic modalities depend on tumor localization, histologic type, and biologic behavior, as well as patient comorbidities, age, and life expectancy. Nonsurgical treatments include cryotherapy, local therapies (imiquimod, 5-fluorouracil, ingenol mebutate, and diclofenac), photodynamic therapy, radiotherapy, and hedgehog inhibitors. Some of these treatments can be combined with curettage and electrodesiccation for better outcomes. Every treatment modality has advantages and disadvantages that must be carefully considered individually. Because the facial area is the most common localization of NMSC, treatment modalities with better cosmetic outcome are preferred. Although NMSC mostly occurs in the elderly, this review is focused on the features and nonsurgical therapy of NMSC in deep old age (≥85) and long-lived persons (aged >95); however, clinical trials very rarely involve this population group due to poor cooperation or poor general condition of these patients; thus, the respective knowledge being generally based on clinical experience.

Nested Melanoma, a New Morphological Variant of Superficial Spreading Melanoma with Characteristic Dermoscopic Features.

A new morphological variant of superficial spreading melanoma (SSM) was first described by Kutzner et al. (1) and named "melanoma composed exclusively or predominantly of large nests"; it was later named "nested melanoma" (NM) (2,3). Clinically, lesions are larger in diameter (>6 mm), mostly showing typical clinical features of melanoma (the ABCD rule), and significantly different from all other pigmented lesions (the "ugly duckling sign") (1). The majority of NM is found on the trunk and limbs of patients older than 60 years (1-9). Dermoscopy shows typical features of melanoma (asymmetry, irregular blotches, atypical pigmented network, multicomponent structure, irregular dots, and globules) followed by the "typical" dermoscopic finding of a globular pattern with globules varying in shape, color, and distribution (1,3). It is known that flat nevi in the elderly present with a reticular or structureless dermoscopic global pattern, along with the fact that total nevi count decreases with advancing age due to involution of nevi (4,5). Therefore, a globular pattern is uncommon in the elderly, and this finding should always invoke a high suspicion of melanoma. Histological diagnosis may be difficult because of the predominantly nested pattern, and the condition may be confused histologically with a benign junctional nevus (6). However, these large junctional nests of different sizes, with bridging and cytonuclear atypias together with lesion asymmetry, are the hallmark of this special kind of melanoma (6). Pathologically, NM presents with large intraepidermal melanocytic nests, which are more or less the same size and shape and equally distributed along the dermoepidermal junction, with a focal tendency to confluence. Melanocytes in nests show moderate to significant cytological atypia (1). Since most NMs were found on sun-damaged skin, solar elastosis can be present. Pagetoid spread of atypical melanocytes along the epidermis is rare, but may be found (1-3). In most case reports there was discrepancy between clinical and dermoscopic features - both favoring melanoma - and histopathology, which at first glance appeared nevoid (9). Although the majority of analyzed NMs were in situ, an invasive dermal component was also found. The atypical nevus in the elderly is an unstable nevus, and one variation also observed is the hypercellular nested variant described by authors; these have been reported as in situ nevoid melanomas, with cellular morphology usually associated with crowded small-to-medium hyperchromatic melanocytes. The progression of these atypical nested melanomas is often to a small cell (nevoid) melanoma, which may become desmoplastic (9). Although the term "superficial spreading melanoma" is appropriate for NM from a clinical perspective, at least some of these tumors may be linked to an aberrant nevus pathway seen in elderly individuals, explaining their unusual pattern resembling a bizarre nevus (9). Additional tests can be performed due to clinicopathological discrepancy, including confocal microscopy, immunohistochemistry, array comparative genomic hybridization (aCGH), and in situ hybridization (FISH). Reflectance confocal microscopy may be useful in cases of such difficult lesions in order to proceed to surgical excision with more confidence, and can reveal the presence of dense nests at the dermo-epidermal junction with cytologic atypia and pagetoid cells (3,7). In confocal microscopy, a grossly regular clod pattern (at low magnification) with atypical cells within nests (at higher magnification) was found if the NM was in situ (3,7,9). aCGH showed multiple chromosomal aberrations in all cases (1,2). Processing with the FISH technique showed a variation in range from 40% to 87% FISH-positive NM, depending on different authors (1,2). Once the diagnosis of NM is established, further treatment, including re-excision, is highly recommended (2). All the authors who described NM consider NM a special variant of SSM in the elderly, and according to their opinion this should lead to modification of histopathological criteria for SSM. We would stress that the "elderly" criterion is not mandatory given the numerous cases reported in people under 60 years of age (6). This is important and should henceforth reduce misinterpretation of this variant of melanoma due to the lesion's nevoid appearance (9). Dermoscopic criteria for NM should also be established so clinicians consider NM in differential diagnosis, which would further help the pathologist establish the correct diagnosis, since it is crucial not to misdiagnose a malignant lesion. Dermoscopy is very helpful in all cases, and globules are typically found in conjunction with other melanoma-specific criteria (1,3).