Tanja Batinac

p53 protein expression and cell proliferation in non-neoplastic and neoplastic proliferative skin diseases.

Aims and background The p53 protein is essential for the regulation of cell proliferation and its aberrant accumulation is usually seen in malignant tumors but also occurs in squamous epithelium of inflammatory skin diseases characterized by hyperproliferation. The aim of this study is to elucidate the role of the p53 tumor suppressor protein in the pathogenesis of different hyperproliferative, non-malignant and malignant skin diseases, and to determine the association between p53 overexpression and cell proliferation. We also investigated the influence of aging on p53 and Ki-67 protein expression. Methods One hundred and fifty skin specimens divided into 30 samples each of normal skin (NS), psoriatic skin (PS), keratoacanthomas (KA), basal cell carcinomas (BCC), and squamous cell carcinomas (SCC) were examined immunohistochemically to assess p53 and Ki-67 protein expression. Results p53 immunostaining of NS, PS, KA, BCC and SCC was detected in 39.0%, 46.7%, 66.7%, 80% and 86.7% of cases, respectively. Median values and ranges of p53 protein expression were as follows: 0.0% (range, 0.0–1.8%) in NS, 0.0% (range, 0.0–6.5%) in PS, 9.2% (range, 0.0–24.0%) in KA, 19.3% (range, 0.0–48.1%) in BCC and 30.1% (range, 0.0–68.1%) in SCC. p53- and Ki-67-positive cells were present in basal (NS) and suprabasal layers (PS), and not only in cancer nests of KA, BCC and SCC but also in dysplastic and even morphologically normal epidermis adjoining cancers. The positivity of p53 and Ki-67 proteins differed significantly among the groups, with no differences in p53 expression between NS and PS and in Ki-67 expression between PS and KA. Within all groups there was a significant correlation between p53 and Ki-67 expression. Lesion location and patient age, with the exception of location in PS and age in BCC, were significantly related to p53 and Ki-67 expression in all groups. Conclusions Our findings suggest that p53 overexpression occurs mainly in neoplastic skin lesions, although it may also occur in squamous epithelium of inflammatory skin diseases such as PS, as well as in normal skin epithelium. It is associated with cell proliferation in normal as well as altered epithelium. p53 protein overexpression is an age-related process and significantly associated with sun exposure, especially in NS and PS but also in KA and SCC. Our findings suggest that Ki-67 rate and p53 protein expression reflect the degree of malignancy in the examined cutaneous neoplasms.

Adverse reactions and alleged allergy to local anesthetics: analysis of 331 patients.

The aim of this study was to determine the prevalence of true local anesthetic (LA) allergy among patients referred for suspected hypersensitivity and to describe the main characteristics of adverse drug reactions (ADR) induced by LA in our population. We retrospectively analyzed the medical files of patients referred to the Department of Dermatovenereology, University Hospital Center Rijeka, Rijeka, Croatia, for the investigation of LA hypersensitivity in the period between January 2000 and December 2012. A total of 331 patients underwent skin testing and, in cases of negative results, subcutaneous exposition to LA. In patients with suspected delayed reaction, patch test was performed. Altogether, 331 patients reported 419 independent ADR occurring during 346 procedures. Most commonly, patients reported having only one ADR, but 41 (12.4%) of them had two reactions, 14 (4.2%) had three, five (1.5%) had four and in one patient (0.3%) five ADR to LA were observed. The majority of reactions occurred during dental procedures when most commonly lidocaine and articaine were used. Local reactions were reported in 44 patients, whereas 490 general symptoms occurred during 375 independent ADR in 287 patients. The most common symptoms were cardiovascular system reactions in 89 patients (18.2%). Allergic reaction was detected in three patients (0.91%). One patient showed immediate‐type reaction to bupivacaine and two patients had a delayed‐type reaction to lidocaine. Adverse reactions to LA are common and are mostly due to their pharmacological properties and drug combinations or psychogenic origin. Allergic accidents to LA are rare.

The distinction between lesional and non-lesional skin in psoriasis vulgaris through expression of adhesion molecules ICAM-1 and VCAM-1

Psoriasis vulgaris [pv] is a systemic inflammatory skin disease affecting 2-4% population. It is well known that pv affects some parts of the skin and also whole skin as in erythrodermic form. We still do not know why in pv some parts of the skin are affected and others are not. In our hypothesis we assumed that the whole skin is in <<stand by>> position and non-lesional skin could become in every moment lesional. According to our hypothesis and also other authors research, high expression of adhesion molecules ICAM-1 and VCAM-1 in lesional as well as non-lesional skin in pv, supports this hypothesis, suggesting a significance of these molecules in pathogenesis of pv. Our hypothesis could be proved by immunohistochemical stain of ICAM-1 and VCAM-1 in lesional and non-lesional skin of pv patient in comparison with healthy skin.

HPV 6-positive giant keratoacanthoma in an immunocompetent patient.

Keratoacanthoma (KA) is a clinically distinct, rapidly growing lesion that generally presents as a solitary crateriform nodule in sun-exposed areas in elderly, fair-skinned individuals. A KA larger than 20-30 mm is referred to as giant keratoacanthoma, a relatively rare lesion especially in young patients. Such lesions grow rapidly with possible destruction of underlying tissues. In addition to ultraviolet exposure, KAs have also been associated with chemical carcinogens, chemical peels, genetic factors, chronic skin conditions that produce scarring, trauma and thermal burns. Immunosuppressed patients, especially after transplantation, also develop KAs. A viral etiology has been suggested but not confirmed. We encountered a case of giant keratoacanthoma (greater than 50 mm in diameter) with induration of underlying structures on the upper lip of a 39-year-old male sailor. The patient reported sudden appearance and rapid enlargement of the lesion in only three weeks. Biopsy of the cutaneous lesion and the characteristic clinical history suggested the diagnosis of keratoacanthoma. Total excision with primary closure of the defect by a nasolabial advancement flap was performed. Histological examination of the tumor mass confirmed the diagnosis of KA with infiltrative growth and perineural invasion. Immunosuppression was excluded by blood analyses, as were HIV, syphilis and hepatitis infections. Only low-risk genital HPV type 6 was detected in the lesion, suggesting a possible cocarcinogenic effect of HPV and UV light in a chronically sun-exposed patient.

Angioimmunoblastic lymphadenopathy with dysproteinemia following doxycycline administration

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a primary lymphoproliferative T-cell disorder, currently classified as a peripheral T-cell non-Hodgkins lymphoma. AILD is characterized by generalized lymphadenopathy, hepatosplenomegaly, immunological abnormalities, polyclonal hypergammaglobulinemia and anemia. We report a case of AILD in an 80-year-old male who presented with a generalized pruritic maculopapular eruption and fever following doxycycline administration. The maculopapular rash progressed to formation of confluent nodules, plaques and finally erythroderma with lymphadenopathy and hepatosplenomegaly. Blood analysis revealed an elevated erythrocyte sedimentation rate and polyclonal hypergammaglobulinemia. Lymph node biopsy showed almost complete effacement of the nodal architecture with diffuse proliferation of small vessels forming an arborizing network, surrounded by atypical lymphocytes, usually CD3+ CD4+ and occasionally CD3 + CD8+. There were also larger cells (immunoblastic shape) that displayed CD20 positively, some scattered plasma cells, and eosinophils. Histology of a cutaneous lesion showed spongiosis and infiltration of the epidermis by atypical lymphocytes with large hyperchromatic nuclei, perivascular dermal lymphocytic infiltrate (CD3+) mixed with plasma cells and occasional large immunoblasts (CD20+). During hospitalization the patient developed hemolytic anemia (Coombs positive) and lung metastases. The prognosis of AILD is generally poor, with a median survival of less than 20 months. Our patient died two and a half months after the diagnosis was made due to sepsis caused by Staphylococcus aureus isolated in hemoculture.

Pityriasis rubra pilaris in association with laryngeal carcinoma

Pityriasis rubra pilaris (PRP) is a rare group of hyperkeratotic, papulosquamous diseases that can be acquired or inherited. Cases of PRP associated with malignancy have been rarely reported. We report a case of 46‐year‐old man who presented with rapidly progressing PRP as a possible initial cutaneous symptom of a previously undiagnosed laryngeal carcinoma. Microlaryngoscopy was performed because of the patient’s hoarseness, and this revealed leucoplakia on the left vocal cord. Histopathological examination led to the diagnosis of squamous cell carcinoma in situ. After surgical treatment, the clinical signs of PRP began to resolve, and the patient was free of skin lesions at follow‐up. This case represents a rare coexistence of PRP with malignancy, and indicates that PRP can occur as paraneoplastic dermatosis associated with laryngeal cancer.

Invasive carcinoma developing in condylomata gigantea Buschke-Löwenstein

A 65-year-old male patient presented at the department of dermatology with a self-reported three to four year history of nodular changes on his penis. For the last two weeks he had been receiving anti-inflammatory therapy by his general practitioner, without much success. The diagnosis of Buschke-Löwenstein tumor, with focal malignant transformation to verrucous carcinoma, was put on the basis of clinical and histolopathological features. Physical examination revealed verrucous, exophytic, partially ulcerated lesions all over the glans and the shaft of the penis with subsequent inflammation (Fig. 1), together with smooth, nontender palpable lymph nodes in the inguinal region (measuring up to 0.5 cm in diameter). We excluded other lymph node involvement, immunosupression, as well as hepatitis, HIV (Human Immunodeficiency Virus) and other sexually transmitted infections. Histopathology showed atypical epithelial cells with acanthosis and hyperkeratosis, showing predominantly expansive growth with a focal invasion to sub epithelial tissue (Fig. 2). There was an abundant peritumoral mononuclear infiltration. The variety of treatment regimens currently applied does not allow formulation of the definitive therapeutic guidelines [1, 2]. We performed a complete penectomy and lymph node resection. Lymph nodes showed no detectable tumor cells. HPV (Human PapillomaVirus) types 6 and 11 were detected and types 16, 18, 31, 33, 35, 52 and 58 were excluded by PCR (Polymerase Chain Reaction) analysis. Buschke-Löwenstein tumor arises on the external genitals and perianal region and is usually large, with the propensity to ulcerate, but without histomorphological criteria for malignancy [1, 2]. It is often referred to as a borderline malignant tumor because of its malignant transformation potential, including invasion and recurrence after treatment, but not metastatic potential [1, 2]. Malignant transformation is usually associated with oncogenic HPV 16/ 18 [3]. However, the absence of these “high-risk” HPV types (as in our case) obviously does not exclude focally invasive squamous cell carcinoma.

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