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Open access

Željko P. Mijušković

Abstract

Basal cell carcinoma (BCC) is the most common cancer among Caucasians. It generally occurs on sun-exposed areas of the body, mostly on the head and neck (80%), trunk (15%), rarely on arms and legs. Basal cell carcinoma is a good example of a disease caused by a combination of genetic and environmental factors. Ultraviolet (UV) radiation plays a dual role in the development of BCC: it causes DNA damage and immunosuppression. UVA and UVB rays damage the DNA via various mechanisms. UVB radiation directly damages DNA within skin cells, causing cytosine → thymine mutations at dipyrimidine sites, whereas UVA radiation is 10.000 times less mutagenic, but it is significantly more present in the natural UV radiation. Also, UVA photons have lower energy than UVB photons and do not induce mutations. UV radiation exerts immune suppression by decreasing the antigen presenting cells ability and by producing immunosuppressive cytokines, such as interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-α). Mediators of UV-induced immunosuppression are DNA and cis-urocanic acid. Several studies showed a significant association between the development of BCC and sun-exposure during childhood and adolescence, and a strong relation with family history of skin cancer. Exposure to ionizing radiation increases the risk of nonmelanoma skin cancers by three times, while the risk is proportional to the radiation dose. Chemical carcinogens, such as arsenic, tar, psoralen, and pesticides, increase risks for nonmelanoma skin cancers, predominantly for squamous cell carcinoma (SCC). Regarding genetic predisposition, there is glutathione S-transferase (GST) as an important part of cellular defense against endogenous and exogenous chemicals. Several polymorphisms in GST family members have been associated with impaired detoxification, thus influencing the risk for some cancers, including nonmelanoma skin cancers. Cytochrome P450 enzymes are involved in detoxification of photosensitizing agents, and thus involved in BCC carcinogenesis. PTCH is a tumor suppressor gene first identified in patients with Gorlin syndrome. Abnormal activation of this gene and its pathways result in various types of tumorigenesis. BCC is associated with homozygous PTCH gene deletion. With regard to acquired genetic mutations, it was found that aggressive BCCs are significantly associated with increased p53 protein expression, probably representing the mutated form, although that assertion could not be established with certainty. Considering the apparently limited contribution of DNA damage and chromosome instability to the expression of BCC phenotype, the relevance of p53 mutations for BCC growth remains to be demonstrated. Data on the role of Bcl-2 gene family in the development of BCC are scarce. It is unclear whether Bcl-2 has a functional role in the development of BCC, or it only indicates the level of gene expression in tumor stem cells. Activation of Ras gene may play an important role during early stages in the development of nonmelanoma skin cancers, and it is often found on UV-exposed skin in BCC, actinic keratosis and SCC. Concerning immunologic factors, studies have shown that tumor necrosis factor-α (TNF-α) is the critical mast cell product involved in ultraviolet-induced immunosuppression: mast cells contain high quantities of TNF-α which is released after activation; the level of TNF-α is increased in the skin exposed to UV radiation disrupting the morphology and function of Langerhans cells, the principal antigen-presenting cells of the skin. An animal study suggests that the degree of susceptibility to ultraviolet-B-induced local immunosuppression depends on TNF-α level within the epidermis after UVB. It has been established that mast cell-derived histamine stimulates prostaglandin E2 (PGE2) production from keratinocytes. PGE2 alters the cytokine balance in favor of the immunosuppressive interleukin-10 (IL-10) against the immunostimulatory IL-12; histamine also increases suppressor T-cell function by binding to the H2 receptors, which in turn release higher levels of immune suppressive cytokines including IL-10 and induce apoptosis of antigen-presenting cells. All this results in a shift of the immune response from T helper 1 (Th1) cytokine profile to T helper 2 (Th2) cytokine profile, inhibiting antigen-presenting cells to induce antitumor activity.

Open access

Željko P. Mijušković, Lidija Kandolf-Sekulović, Danica Tiodorović, Miloš Nikolić, Marina Jovanović, Dušan Škiljević, Zorica Gajinov and Radoš D. Zečević

Open access

Željko P. Mijušković, Lidija Kandolf Sekulović and Radoš D. Zečević

Abstract

Molluscum contagiosum is a very common, benign, often self-limiting skin disease caused by Molluscum contagiosum virus, member of the poxvirus family. Genital ulcers in HIV positive women are usually acute or subacute, mostly idiopathic or aphtous. Sixty percent of cases are caused by herpes simplex virus syphilis or chancroid. We present a 31-yearold woman with a 2.5 month history of vulval ulceration and a several month history of molluscum contagiosum in the pubic region, neck and face. After she was admitted to our department, the patient underwent physical examination using enzyme-linked immunosorbent assay, and an immunoblot test for HIV 1/2. Both tests were positive. Thereafter, the patient was referred to an infectologist who recommended application of 5% imiquimod cream 3 times per week for molluscum contagiosum and acyclovir 3x400 mg/day. Considering that there are more accepted indications for HIV testing, we agree with other authors that all adults with molluscum contagiosum or chronic genital ulceration should be tested for HIV serology.

Open access

Tatjana Vukanović, Željko Mijušković, Lidija Kandolf-Sekulović, Lidija Zolotarevski and Radoš Zečević

Abstract

Porphyria cutanea tarda is a metabolic disorder that results from a reduced enzymatic activity of uroporphyrinogen decarboxylase. It is the commonest chronic porphyria. Two types of this disease have been reported up to now: acquired (Type 1, 80%) and inherited (Type 2, 20%) an autosomal dominant pattern with low clinical penetrance. Both types are associated with haemochromatosis, alcohol abuse, estrogens, iron overload, hepatitis C virus infection, and halogenated aromatic hydrocarbons causing deficiency of the uroporphyrinogen decarboxylase enzyme in the liver. In this case report we described a 23-year-old woman with increased hair growth on the face and neck, who visited an outpatient dermatology clinic for laser hair removal due to excessive hair growth on the face and neck during the last eight years (Figures 1, 2). Four laser treatments were carried out with incomplete effects. After the fourth laser hair removal treatment, a small sore on the tip of the nose was observed. The patient used oral contraceptive pills during the past 8 months. No additional medications were taken. The diagnosis of porphyria cutanea tarda was confirmed by specific biochemical analyses, since increased excretion of uroporphyrin and coproporphyrin were detected. After discontinuation of drospirenone and ethinyl estradiol (YazÒ tablets) a gradual clinical and laboratory improvement was noticed suggesting a causative role of this drug. There are many published reports discussing and describing estrogens as contraceptive agents, hormone supplements for postmenopausal replacement therapy in females, and adjunctive hormonal therapy in males with prostatic carcinoma, being the probable trigger of porphyria cutanea tarda. However, the mechanisms by which estrogens exert their effects on disease expression have not yet been fully clarified. Conclusion: this case report points to the importance of hypertrichosis as the first manifestation of porphyria cutanea tarda, since it may be a long lasting sign before the onset of other clinical symptoms of the disese

Open access

Lidija Cvetković Jordanov, Lidija Kandolf Sekulović, Željko Mijušković, Lidija Zolotarevski and Radoš Zečević

Abstract

Concomitant occurrence of psoriasis and bullous pemphigoid was described in less than 100 cases in the literature. The co-occurrence affects the treatment approach of patients. We present a case of a 58-year-old man with psoriasis presenting with erythematous plaques, tense bullae, erosions and fever up to 39°C. Direct and indirect immunofluorescence and histopathological examination confirmed the diagnosis of bullous pemphigoid. In our case, bullous eruptions were successfully treated with oral methylprednisolone and dapsone, and psoriasis with narrowband ultraviolet B phototherapy and acitretin.

In conclusion, the etiopathogenesis of the coexistence of these two entities remains unknown, but it may be related to relatively high incidence of psoriasis and bullous pemphigoid, respectively. Both conditions are immunologically mediated and combined immunosuppressive regimens, directed at cellular and humoral immune responses, usually result in clinical improvement.

Open access

Zorana Kremić, Željko P. Mijušković and Lidija Kandolf-Sekulović

Abstract

The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an adverse drug-induced reaction that occurs most commonly after exposure to drugs, most frequently anticonvulsants, sulfa derivates, antidepressants, nonsteroidal anti-inflammatory drugs, and antimicrobials. We present a 61-year-old male, with a generalized maculopapular exanthema on the trunk, face, extremities, palms, soles, palate, and fever (38°C). His medical history was notable for generalized epilepsy, treated with carbamazepine during 1 month. The diagnosis of DRESS syndrome was confirmed by specific RegiSCAR criteria. In our case, skin eruptions were successfully treated with oral methylprednisolone, cephalexin, and topical corticosteroid ointment.

In conclusion, although the mechanisms of this syndrome are not completely understood, numerous cases were reported in children and adults. This syndrome should be considered in every patient with skin eruption, fever, eosinophilia, liver and hematological abnormalities. Prompt recognition, supportive therapy and initiation of corticosteroids may prevent systemic manifestations.

Open access

Ivana Ilijin, Željko Mijušković, Dimitrije Brašanac and Lidija Kandolf Sekulović

Abstract

Mycosis fungoides (MF) belongs to a group of primary cutaneous T-cell lymphomas, with characteristic small- to medium-sized neoplastic T-lymphocytes with hyperchromatic and cerebriform nuclei. Folliculotropic mycosis fungoides (FMF) represents a variant of mycosis fungoides, which is histologically characterized by folliculotropic T-cell infiltrates, with or without mucinous degeneration of the hair follicles. Clinical features of FMF are characterized by appearance of grouped follicular papules, acneiform lesions, indurated plaques, sometimes tumors, which usually involve the head and neck region. The diagnosis is based on clinical presentation, histopathological and immunohistochemical (IHC) findings of skin biopsy specimens. The treatment of FMF, and generally MF, should be stage-adapted. Case report: We present a case of a 33-year-old male with an eight-month history of erythematous papules on his forehead accompanied by intense pruritus. Histopathological findings showed folliculotropic and perivascular lymphocytic infiltrates. An increased CD4/CD8 ratio of interfollicular lymphocytes with accumulation of Langerhans cell confirmed the diagnosis of FMF. Our patient was diagnosed with an early stage - IA, and P-UVA phototherapy was recommended due to ineffectiveness of prescribed topical corticosteroids that had shortterm effects. Conclusion: Folliculotropic mycosis fungoides represents a diagnostic challenge due to the great diversity of clinical manifestations. We presented a rare case of folliculotropic mycosis fungoides in a young adult, who presented with erythematous papules, accompanied by intense pruritus on the forehead, which lasted for several months. Histopathological and IHC analysis confirmed the diagnosis of folliculotropic mycosis fungoides stage IA. Due to an inadequate response to a topical corticosteroid, P-UVA phototherapy was administered, as well as close follow-up, essential for timely treatment of this frequently therapy-resistant disease.

Open access

Tijana Boljević, Željko Mijušković, Lidija Kandolf Sekulović and Biserka Vukomanović-Đurđević

Abstract

Swimming-pool granuloma and fish tank granuloma refer to the infections caused by Mycobacterium marinum. After having been discovered in salt water fish in Philadelphia Aquarium and described in 1926, this skin infection was first reported in humans in 1951. It developed in people who had swum in contaminated swimming pools. M. marinum is a non-tuberculous, atypical mycobacterium, which is found on plants, soil and fish in freshwater and salt water worldwide. Humans become infected usually after trauma and contact with an aquatic environment. Infection is limited to the skin and usually occurs in healthy individuals, but in immunocompromised patients the infection may disseminate or spread to the subcutis and bone. The lesions usually appear as solitary nodules or plaques that may lead to suppurative ulcers after 2-3 weeks of incubation. Occasionally, there may be sporotrichoid spread along lymphatics. Its diagnosis is frequently delayed, probably because the infection is very rare and a history of aquatic exposure, which is present in the majority of cases, is often overlooked. Common misdiagnoses include fungal and parasitic infection, cellulitis, verrucous tuberculosis of the skin, gout, rheumatoid arthritis, a foreign body and a skin tumour. We present a case of a 39-year-old Caucasian male with a 12-month history of a single erythematous tender nodule on the right dorsal aspect of the right hand. Histopathological examination revealed longstanding suppurated granulomatous inflammation. The infection was not responsive to several courses of antibiotics until we introduced doxycycline capsules as monotherapy which led to complete remission after 5 months.

Open access

Jelena Pantic Bisevac, Ivan Stanojevic, Zeljko Mijuskovic, Tatjana Banovic, Mirjana Djukic and Danilo Vojvodic

Summary

Background: The immune response in patients with melanoma is an important focus of research due to the tumor’s resistance and immunotherapy possibilities. IL-27 is one of the cytokines with antitumor properties. The role of IL-27 in the pathogenesis of melanoma is still unclear. The aim of this study was to examine the association between serum IL-27 levels and the clinical parameters of melanoma patients.

Methods: The IL-27 concentration was determined by commercial ELISA in serum samples from melanoma patients (n=72) and healthy control subjects (n=44). Patients were classified according to AJCC clinical stage, TNM stage, the length of progression-free interval (PFI) and the extent of the disease (localized or widespread).

Results: Average IL-27 values were increased in patients with early stages of melanoma compared to patients with terminal stages and control values. The highest IL-27 concentration was found in stage IIa. Patients in stages III and IV had significantly lower values of IL-27 compared to control. Patients with localized melanoma and shorter PFI had insignificantly increased IL-27 levels compared to patients with widespread disease and longer PFI. Patients with metastatic disease and stage TNM4 had significantly lower average IL-27 values compared to control. Patients with high production of IL-27 (>1000 pg/mL) were most numerous in IIa AJCC stage, with initial tumor size TNM2 and in the group of patients with localized disease.

Conclusions: High levels of IL-27 in patients with melanoma are associated with the initial stages and localized disease.

Open access

Kristina Kostić, Miroslav Dinić, Željko Mijušković, Lidija Zolotarevski, Lidija Kandolf-Sekulović and Radoš Zečević

Abstract

Neurofibromatosis type I (NF1) is an autosomal dominant, multisystemic disease that usually affects the skin, nervous system and bones. Diagnosis is made by matching at least two of the following 7 diagnostic criteria: six or more caféau- lait macules over 15 mm in diameter, two or more neurofibromas, axillary and/or inguinal freckles, optic glioma, two or more Lisch’s nodules (iris hamartoma), changes in the bones in the form of sphenoid dysplasia, thinning of the cortex of long bones and existence of neurofibromatosis in the first degree relatives. We report three patients, two men and a woman aged 18 to 33 years, in whom the first changes occurred at puberty, and there was no positive family history in any of them. All three patients had café-au-lait spots over 15 mm in diameter and numerous localized neurofibromas on the skin of the trunk and extremities that were histologically verified. In two patients, ophthalmic examinations recorded Lisch’s nodules in the iris. In one of the patients, MRI of the head, revealed presence of oval lesions with diameters of 10-15 mm, which may correspond to neurofibromas, and in the other patient fibrous dysplasia of the femur and tibia were observed. Psychological testing in one patient revealed IQ at the lower limits of average (IQ 68). After the diagnosis of neurofibromatosis type I, the patients were given advice about the disease and a plan for the monitoring and control of possible symptoms, and also the possibility of genetic testing during pregnancy. A multidisciplinary approach is required for diagnosing and monitoring of patients with neurofibromatosis type 1.