The immune system, natural autoantibodies and general homeostasis in health and disease

Hippokratia 2011; 15 (4): 295-298

A. Poletaev, P. Boura

Abstract

It is generally accepted that the destination of the immune system is not only to discriminate between self and non-self but also to mount responses against non-self. During the last decades, it became evident that weak self-reactivity is a necessary condition for immune homeostasis. Natural self reactivity and the internal image created by autoantibodies, participate greatly to the maintenance of homeostasis. Under conditions of increased or altered antigenic pressure, the homeostatic status is disrupted and the organism becomes vulnerable to the emergence of diseases. "Immunculus" is the self-reactive and interconnected entity of the immune system, provided by a complicated network of natural autoantibobies of different specificity, as a mosaic picture. Quantitative changes in each part of the image are related to variations of expression of relative antigens. The immune system takes in account image information from the continuous screening of the antigenic status and compares between presented state and the desired (optimal) one. Substantial and prolonged deviations from the optimal state, triggers the induction of compensatory and reparative processes, aiming to restore molecular and functional homeostasis. So, natural autoimmunity through the ability of natural a-Abs to induce mechanisms of natural and acquired immunity, aims to prevent pathogenic processes and maintain or restore health status.

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CD4+/CD25+ T-Lymphocytes and Th1/Th2 regulation in dilated cardiomyopathy

Hippokratia 2011; 15 (4): 335-342

I. Efthimiadis, P. Skendros, A. Sarantopoulos, P. Boura

Abstract

Objective: Autoimmune mechanisms are often involved in the pathogenesis of Dilated Cardiomyopathy (DCM) and Th1 immune response against cardiac antigens plays a pivotal role in disease development.
Methods: IL-2 receptor (CD4+/CD25+) and cytokines IL-2, IFN-ã, IL-10 were studied in 42 patients (17 with DCM - DCM group, 10 patients with hypertrophic cardiac disease - HCD group, and 15 healthy volunteers - Control group). DCM group was subdivided in: DCM-1 (9 patients with recent disease onset) and DCM-2 (8 patients with chronic DCM). The % CD4+/CD25+ T-lymphocytes were analyzed by double fluorescence flow cytometry both ex vivo and after phytohaemagglutinin (PHA)-cultures with/without 5 and 10 microgr of human cardiac myosin. The cytokines were measured using Enzyme-Linked Immunosorbant Assay (ELISA) method.
Results: Ex vivo analysis: In DCM group, CD4+/CD25+ T-cells significantly increased compared to other groups (p<0.05), due exclusively to DCM-2 subgroup (p=0.019). In PHA cultures in DCM-2 subgroup CD4+/CD25+ T-lymphocytes were significantly increased compared to all other groups (p<0.001). The addition of myosin in the cultures of DCM-2 subgroup maintained the same result. In cultures supernatants in DCM-2 subgroup, IL-2 levels were impressively increased compared to DCM-1 subgroup (p=5.91x10-6), HCD and Control groups (p<0.001). Addition of antigen decreased significantly IL-2 levels in DCM-2 subgroup (p=0.01). IFN- ã levels followed the same pattern of alterations.IL-10 levels were significantly increased in both DCM subgroups compared to HCD and Control groups (p<0.05).
Conclusions: Increased peripheral CD4+/CD25+ T-cells found in chronic DCM could be a useful prognostic marker in DCM progress. Increased synthesis of IL-2 and IFN - ã and varying IL-10 levels reflects a Th1 pattern of immune response during chronic disease and implies active cellular immunity process, related to poor prognosis. Thus, analysis of the Th1/Th2 phenotype may be useful in disease monitoring in patients with DCM.

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Human papilloma virus (HPV) vaccination in childhood: challenges and perspectives

Hippokratia 2011; 15 (4): 299-303

I. Mammas, F. Maher, M. Theodoridou, D. Spandidos

Abstract

Vaccination against human papilloma virus (HPV) in childhood is a significant step forward in the reduction of HPVassociated
morbidity and mortality and a considerable scientific achievement. However, many challenges remain to be overcome if an effective HPV vaccine programme is to be successfully introduced worldwide. The aim of this review is to identify and summarize the new issues concerning HPV vaccination that have emerged since its introduction into clinical practice in school-aged girls. According to the literature, the overall impact of HPV vaccination on cervical cancer is unlikely to be apparent for the next decade. Cost-effectiveness is of particular importance, particularly in developing countries. Determining the age at which the vaccine should be administered, whether to include boys in addition to girls, the costs and the implications for cervical screening are issues that need to be addressed by conducting further research.

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Quality of nutritional information on the Internet in health and disease

Hippokratia 2011; 15 (4): 304-307

K. Gkouskou, A. Markaki, M. Vasilaki, A. Roidis, I. Vlastos

Abstract

Background: Quality assessment of nutritional information on the internet may prove vital prior to providing public guidance on searching relative information.
Methods: The most popular web sites on four different topics ("Mediterranean diet", "sports nutrition", "nutrition, dysphagia and children" and "herbs and common cold") were assessed with the use of two validated questionnaires (EQIP and DISCERN).
Results: Medical categories produced significantly lower total quality scores when compared to "Mediterranean diet" and "sports nutrition" categories. (F=7.189, P<0.001). Commercial web pages had a significantly lower credibility score compared to institutional and other web page types (H=17.987, P<0.001). Ranking order of each web page was related to its total quality score (P=0.04) but not to its credibility (P=0.241).
Conclusions: Monitoring the accuracy, comprehensiveness and consistency of health-related information on the internet is an important public health issue since there are popular web pages that are regarded as of high quality but they do not always provide reliable information. Health professionals and especially dieticians should provide consumer training on how to search for and appraise nutritional information from the internet.

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Renoprotective effects of Vitamin D and renin-angiotensin system

Hippokratia 2011; 15(4):308-311

A. Koroshi, A. Idrizi

Abstract

Vitamin D has many physiological functions. First it is a primary regulator of calcium homeostasis. Beyond that, vitamin D and its receptors (VDR) play important role in the immune system, cardiovascular system, reproductive system and insulin resistance. An important aspect of vitamin D pleiotropic effects is the interaction with components of the renin-angiotensin system (RAS). It was demonstrated that vitamin D-null mice have a sustained elevation of renin expression. The combination of both the AT1 blockers and the vitamin D analogues, leads to a marked amelioration of the molecular and clinical markers of diabetic nephropathy. This combination may protect the kidney through the effects on both the glomerular and the tubulointerstitial compartments. There are different studies that corroborate the renoprotective action of vitamin D in CKD. In fact the renoprotective mechanisms in humans remain to be assessed, but these are realized through reduction of proteinuria, high blood pressure, inflammation as well as hemodynamic effects. An important mechanism is the role of vitamin D as a potent negative endocrine regulator of renin expression. It was shown that low levels of vitamin D represent a novel risk factor for the progression of renal disease but it is not demonstrated yet that vitamin D can prolong the time to end-stage renal disease. This question remains to be answered in other future controlled clinical trials.

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Flexible fiberoptic bronchoscopy in Greek children

Hippokratia 2011; 15 (4): 312-315

F. Kirvassilis, D. Gidaris, M. Ventouri, A. Zampouri, M. Mylona, A. Keramidiotis, Th. Kontakiotis, I. Tsanakas

Abstract

Background and aim: Flexible fiberoptic bronchoscopy (FFB) is one of the most important procedures in paediatric pulmonology. To the best of our knowledge there is no review - audit summarising the experience with FFB in children in Greece. We therefore analysed retrospectively all FFBs performed by the paediatric pulmonology team in our hospital in order to analyse indications for bronchoscopy in our population, explore diagnostic yield for each indication and highlight potential complications..
Material - Methods: Three hundred and sixteen (316) diagnostic FFBs performed in 305 children during a six years period were retrospectively analysed.
Results: Seventy five (75) % of bronchoscopies had a meaningful outcome. Diagnostic yield for individual indications ranged from 41% to 91%. Stridor was the most rewarding indication (91%). Fever was the most common side effect (7%). The rest of complications were in small numbers and easily reversible.
Conclusions: Bronchoscopy is a safe procedure and in our diverse population the overall diagnostic yield was 75%.

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Demographic profile and outcome analysis of pediatric intensive care patients

Hippokratia 2011; 15 (4): 316-322

E. Volakli, M. Sdougka, M. Tamiolaki, C. Tsonidis, M. Reizoglou, M. Giala

Abstract

Background: Demographic profile and outcome can vary in pediatric intensive care unit (PICU) patients. The aim of our study was to analyze demographic profile and outcome in a Greek PICU.
Methods: Prospective observational study. Data collected: demographic profile; co morbidities; source and diagnosis at admission; Pediatric Risk of Mortality (PRISM III-24); Glasgow Coma Scale (GCS, pediatric); Injury Severity Score (ISS); procedures; treatment; mechanical ventilation (MV); MV days; length of stay (LOS) and the outcome at PICU discharge. Statistical analysis: Student's t-test; Mann-Whitney U test; Kruskall-Wallis test; X2 criterion with relative risk (RR) estimation; Cox regression analysis; as appropriate. Values are mean ± SD, p < 0.05.
Results: 300 patients (196 boys/104 girls), aged 54.26 ± 49.93 months, were admitted due to respiratory failure (22.3%), head trauma (15.3%), seizures (13.7%), coma (9.7%), postoperative care (7.7%), polytrauma (7%), accidents (5.3%), sepsis-septic shock (5.3%), cardiovascular diseases (4.7%), metabolic diseases (3.3%), multiple organ failure syndrome (3%) and miscellaneous diseases (2.7%). PRISM III-24 score was 8.97 ± 7.79 and predicted mortality rate was 11.16% ± 18.65. MV rate was 67.3% (58.3% at admission) for 6.54 ± 14.45 days, LOS 8.85 ± 23.28 days and actual PICU mortality rate 9.7%. Patients who died had statistically worse severity scores. Significant mortality risk factors were inotropic use, PRISM III-24 > 8, MV, arterial and central venous catheterization, nosocomial infections, complications, and cancer. COX regression analysis showed that PRISM III-24 score and inotropic use were independent predictors of mortality.
Conclusions: Demographic profile followed similar patterns to relevant studies while there were major differences in case mix and the severity of the disease. Mortality rate (9.7%) was relatively high but better than predicted and in accordance with the characteristics of our population.

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Increased serum C-reactive protein levels in normal weight women with polycystic ovary syndrome

Hippokratia 2011; 15 (4): 323-326

A. Makedos, DG. Goulis, M. Arvanitidou, G. Mintziori, A. Papanikolaou, A. Makedou, D. Panidis

Abstract

Background: The clinical spectrum of polycystic ovary syndrome (PCOS) includes components of the metabolic syndrome, such as central obesity, insulin resistance, dyslipidemia, arterial hypertension and, even, disturbances of the clotting mechanism. All these disorders are pidemiologically related to cardiovascular disease, most probably through low-grade intravascular chronic inflammation. The aim of this study was to evaluate the serum concentrations of high sensitivity C-reactive protein (hsCRP), a non-specific marker of low-grade inflammation and a predictive marker for cardiovascular disease, in normal weight women with (PCOS).
Patients and Methods: One hundred and eighty-eight (188) normal weight [body mass index (BMI) < 25 kg/m2] women with PCOS were included in the study. Forty-three (43) normal weight women without PCOS (normal ovulation without clinical or biochemical hyperandrogenemia) served as controls. Serum samples for luteinizing hormone, folliclestimulating hormone, prolactin, total testosterone, Ä4-androstenedione, 17á-hydroxy-progesterone, sex hormone-binding globulin (SHBG), insulin, glucose and hsCRP were collected in early follicular phase (third to sixth day) of a menstrual cycle in the control group or during a spontaneous bleeding episode in the PCOS group.
Results: Normal weight women with PCOS had higher concentrations of serum hsCRP as compared to normal weight women without PCOS (mean ± standard error of the mean 0.55 ± 0.08 versus 0.27 ± 0.08 mg/dL, p = 0.001).
Conclusions: As normal weight women with PCOS are characterized by elevated serum concentrations of hsCRP, they have to be considered as carrying at least one marker of low-grade inflammation.

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The results of surgical treatment for hepatic hydatid disease

Hippokratia 2011; 15 (4): 327-329

S. Sozen, S. Emir, M. Tukenmez, O. Topuz

Abstract

Abstract: Background: Hydatid disease is an important health problem worldwide and surgery remains the gold standard in terms of treatment for patients with echinococcosis of the liver. In this study we aimed to present our recent surgical experience in treating patients with hepatic hydatidosis.
Patients and Methods: Fourty-eight patients with Liver Echinococcosis (LE) who were operated in our department between 2007 and 2008 were reviewed retrospectively. It was observed that cystectomy or hepatectomy had been preferred in certain patients with cysts of small size or subcapsular location.
Results: There was no significant difference in the type of surgical procedures and early post-operative complications. Recurrence rates and mean duration of hospitalization were significantly lower in patients treated by radical procedures than the patients in drainage and obliteration group. Conclusion: Radical operations for hydatid cyst disease are safe methods and may be preffered in selected cases.

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Trends of mortality in Greece 1980-2007: a focus on avoidable mortality

Hippokratia 2011; 15(4):330-334

M. Ollandezos, Th. Constantinidis, K. Athanasakis, CH. Lionis, J. Kyriopoulos

Abstract

Background: Avoidable mortality (AM) refers to deaths from certain conditions considered avoidable given timely and effective health care. AM rates in Greece between 1980 and 2007 were examined in order to investigate the extent to which health care has contributed to the decline in mortality rates in Greece over recent decades and detect possible shortcomings in the Greek healthcare system.
Methods: Mortality data from the General Secretariat of the National Statistic Service were used. The list of avoidable conditions was the basis of the analysis in which avoidable deaths were classified into conditions amenable to medical care (treatable avoidable mortality) and conditions responsive to health policy (preventable avoidable mortality). Ischaemic heart disease (IHD) was examined separately following relevant studies. Age standardized mortality rates were calculated according to the European Community standard population.
Results: A steady decline of the percentage of AM over all-cause mortality was documented (1980-1984:27%; 2000-2007:22.9%). AM rate fell by 30.5% (1980-1984:217.4/100,000 population; 2000-2007: 151.1/100,000). Treatable mortality rate fell by 48.1%, marking the largest contribution to the decline in AM (1980-1984:110.9/100,000; 2000- 2007:57.5/100,000). Ischaemic heart disease death rate fell by 13.1% (1980-1984:52.7/100,000; 2000 2007:45.8/100,000). Preventable mortality rates fell by 11%, marking a modest contribution to the decline in AM (1980-1984: 53.7/100,000; 2000-2007: 47.8/100,000).
Conclusions: Trends in AM in Greece between 1980-2007 were similar to those of other European countries, with Greece performing particularly well with respect to treatable mortality. Although the decline in AM may also reflect changes in factors that influence mortality, such as disease occurrence, environment and socioeconomic conditions, they are suggestive of the health care system being an important determinant of health improvements in Greece during the recent decades. Further studies are needed in order to access the quality of care and to examine the structure and adequacy of health care in Greece.

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Trends in the molecular epidemiology of carbapenem resistant acinetobacter baumannii in a tertiary Greek hospital

Hippokratia 2011; 15 (4):343-345

V. Koulourida, E. Martziou, K. Tsergouli, A. Papa

Abstract

Background: Acinetobacter baumannii is responsible for a variety of nosocomial infections, especially in intensive care unit patients. Nosocomial outbreaks due to carbapenem resistant A. baumannii strains have been reported in many countries, including Greece. The aim of the present study was to determine the trends of molecular epidemiology of carbapenem-resistant A. baumannii isolates in a 750-bed hospital in Thessaloniki, Greece, during 2009.
Methods: The study included 39 carbapenem-resistant A. baumannii isolates collected from patients hospitalized in the General Hospital Papageorgiou during 2009. They were tested for the presence of Ambler class D carbapenemases and class 1 integrons, and they were typed by pulsed-field gel electrophoresis.
Results: The blaOXA-58 gene was detected in all A. baumannii isolates. Among the 39 isolates, 18 were carrying a 2.2 kb integron, 18 were carrying a 2.5 kb integron, and 3 isolates had no class 1 integrons. Two different clones, each divided further into two subclones, were observed. Comparing the clones detected in 2009 with those of former years (2001- 2008), a significant difference was observed: three clones have disappeared, two clones continued to circulate in the hospital, while a new subclone emerged in February 2009.
Conclusions: A change was seen in the molecular epidemiology of carbapenem-resistant A. baumannii isolates during 2009. Molecular epidemiology studies provide useful data for the distribution of resistant bacteria in order to design effective prevention and control measures.

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Participation rates in cervical cancer screening: experience in rural Northern Greece

Hippokratia 2011; 15 (4): 346-352

A. Vakfari, M. Gavana, S. Giannakopoulos, E. Smyrnakis, A. Benos

Abstract
Background and aim: Cervical cancer is one of the most common causes of cancer mortality among women worldwide but it is one of the most preventable cancers due to the Pap smear test. The aim of this study was to estimate the participation rate of females in screening of cervical cancer with Pap smear test.
Methods: The study took place in a hospital in Rural Northern Greece during April and May 2007. Convenience sampling was performed and questionnaires were completed by 214 eligible females aged 20???64 years.
Results: One hundred and twenty four (57.9%) of the participants had had a Pap-test at some point in their lifetime. 72 of them (33.65%) had the test performed for the first time according to current guidelines. 13.6% were unaware about the recommended onset age of the test, 16.4% did not know the proper intervals, while 22.4% did not know the recommended upper age limit. 32.6% were informed by mass media, family members and friends. The take-up rates, the source of information and the setting where the examination was performed were related to age, origin, income, educational status, type of occupation and place of residence. Disparities in participation rates were detected.
Conclusions: Special efforts should be made by National Health Services towards enhancing secondary prevention of cervical cancer by increasing participation rates of older women, those with lower educational background, females with low income, Roma, retired or unemployed and residents of rural areas.

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Anterior clinoidal meningioma coincidental with bilateral intracranial aneurysms

Hippokratia 2011; 15(4):353-355

D. Paraskevopoulos, I. Magras, I. Balogiannis, K. Polyzoidis

Abstract

Coexistence of aneurysms and brain tumors is a rare occurrence. Coincidence is highest in patients with meningiomas rather than other types of tumors. We report a case in which a meningioma of the left anterior clinoid process was coexisting with a right middle cerebral artery (MCA) and a left anterior cerebral artery (ACA) aneurysm. While the right MCA aneurysm was detected preoperatively, the left ACA aneurysm was not detectable, being concealed by the major finding of the region. This report focuses on pitfalls of diagnosis and questions the surgical planning in aneurysms concealed by coincidental brain tumors.

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Nephrogenic diabetes insipidus : Old deletion, new effect. A case report of a family from Greece

Hippokratia 2011; 15 (4): 356-357

D. Tramma, S. Kalamitsou

Abstract

Congenital, X-linked, Nephrogenic Diabetes Insipidus (NDI) is a rare disorder in which the kidney is insensitive to the antidiuretic hormone, vasopressin. The gene responsible for this type of NDI, the V2 vasopressin receptor, has been cloned and mapped to Xq28. We report the case of a boy, 2.5 month old, who presented with nephrogenic diabetes insipidus (NDI). The mother and the 7 year old sister of the boy also had the NDI phenotype but did not seek medical attention until the presentation of the boy to our department. The mutational analysis of the patient showed the R337stop mutation, also founded to the mother's genotype analysis. The allele separation in mother revealed the second X chromosomal allele with a 12-bp in-frame deletion. The same in-frame deletion was also found in his sister's genotype. This deletion of four amino acids (Arg-247 to Gly-250) has been previously described but was suggested not to be linked with the NDI phenotype. However, in our case, the only possible cause of NDI phenotype in the boy's sister was the 12-bp in-frame deletion.

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A "sweet" hydrothorax in a child on peritoneal dialysis

Hippokratia 2011; 15 (4): 358-360

D. Gidaris, N. Printza, S. Batzios, AM. Belechri, F. Papachristou

Abstract

Peritoneal dialysis (PD) is an established, effective long term renal replacement treatment modality for children with end stage renal disease (ESRD). A rarely reported complication of PD in children is the development of hydrothorax1. We report the case of an 8-year-old boy that developed a right-sided pleural effusion during automated PD (APD), in order to raise awareness amongst paediatricians; we also review the diversity of clinical presentation and the available diagnostic tools, discuss theories regarding aetiology and highlight the available treatment options.

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Posterior mediastinal Castelman's disease presented as hypervascular lipomatous tumor

Hippokratia 2011; 15(4):361-362

M. Michaelides, A. Nikolaidou, D. Konstantinou, GC. Balis, I. Tsitouridis

Abstract

Castelman's disease (CD) is a rare lymphoproliferative disorder most often found in the chest. Herein we describe the imaging findings of a histologically proven case of CD involving the posterior mediastinum in a 41-year-old asymptomatic man presented as a well-defined hypervascular lipomatous tumor. To our knowledge less than 10 cases of posterior mediastinal CD have been reported so far and this is the first case of CD mimicking mediastinal lipomatous tumor.

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A case of extraskeletal Ewing sarcoma originating from the visceral pleura.

Hippokratia 2011; 15 (4): 363-365

C. Karatziou, X. Pitta, T. Stergiouda, V. Karadimou, G. Termentzis

Abstract

Extra skeletal Ewing Sarcoma (EES) is a rare entity which predominantly occurs in adolescents and young adults. It usually arises from the soft tissues of the trunk or the extremities. We present a case of EES arising from the left visceral pleura in a 21 year old female patient who presented to the emergency room of our institution with fever, productive cough and sternal pain radiating to the back for the last 3 days. Chest radiograph was firstly performed, followed by chest CT examination. Finally open lung biopsy revealed a small round cell malignancy. The mass was resected and the histological examination revealed Extra skeletal Ewing Sarcoma (EES) of the visceral pleura without involvement of the adjacent lung. Secondary multiple nodules at the lateral wall of the pleura were also noticed and so postoperative multiagent chemotherapy was performed. EES should be considered in the differential diagnosis of any patient, especially adolescents or young adults, with a soft tissue mass of the trunk or the extremities.

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Sacral nerve stimulation for fecal incontinence. First successful case in Greece

Hippokratia 2011; 15(4):366-369

C. Spanos, Th. Mikos, C. Constantogiannis, G. Georgantis, D. Kiskinis

Abstract

Introduction: Sacral nerve modulation (SNM) is an established and successful treatment for fecal incontinence. We present the first successful case in Greece, performed in our department.
Patients and Methods: A 60-year-old female patient presented with a 5-year-old history of fecal incontinence. The Cleveland Clinic Florida (CCF) Incontinence Score was 15. Endoanal ultrasound did not show defects of the internal or external anal sphincter. Conservative and pharmacological therapy was unsuccessful. The patient subsequently underwent a total pelvic floor repair, which was also unsuccessful. After discussing further options, the patient gave consent for percutaneous nerve evaluation (PNE), for possible permanent stimulator implantation.
Results: A quadripolar lead was placed percutaneously through the dorsal S3 foramen under local anesthesia. This was connected to a test stimulator (Medtronic Interstim Model 3625, Minneapolis, MN). The stimulator was activated for a period of 4 weeks. At the end of the test period, the CCF Incontinence score was 5. This was considered successful. A permanent stimulator (Medtronic Interstim Implantable Pulse Generator Model 3058, Minneapolis, MN) was then implanted under local anesthesia. Two months after permanent implantation, the Wexner Score has not increased.
Conclusion: SNM is a relatively simple, safe and minimally invasive technique for the treatment of fecal incontinence.

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Cerebellar hemorrhage after supratentorial burr hole drainage of a chronic subdural hematoma

Hippokratia 2011; 15 (4): 370-372

C. Kollatos, D. Konstantinou, S. Raftopoulos, G. Klironomos, L. Messinis, P. Zampakis, P. Papathanasopoulos, V. Panagiotopoulos

Abstract

Cerebellar hemorrhage is an unusual, but increasingly recognized complication after supratentorial surgery. Even rarer are the cases of cerebellar hemorrhage after supratentorial burr-hole drainage of a chronic subdural hematoma (CSDH). The pathophysiology of this rare complication still remains unclear. Hypertension and overdrainage of cerebrospinal fluid seem to be causative factors of postoperative cerebellar hemorrhage. The most important key to minimize this hazardous sequel is to be aware of this potential complication and its pathogenetic mechanisms. We report our case of a 43-year old man who developed cerebellar hemorrhage after burr hole trephination for supratentorial CSDH.

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Naevus-associated lentigo maligna: coincidence or continuum?

Hippokratia 2011; 15 (4): 373-375

A. Lallas, I. Zalaudek, C. Cota, E. Moscarella, D. Tiodorovic-Zivkovic, C. Catricala, G. Argenziano

Abstract

Despite the high frequency of intradermal facial nevi in adults, the development of lentigo maligna (LM) within a preexisting nevus is considered exceptionally rare. Herein we describe an emblematic case of nevus associated facial LM and discuss whether such "collision" is coincidental or a consequence of malignant transformation.

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