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Adverse reactions to psychotropic medication can be considered as risk indicators for an unfavorable evolution of patients with schizophrenia, based on particular pathogenic mechanisms that can be used in the personalized therapeutic approach. The combination of antidepressants with antipsychotic drugs in schizophrenia has a risk of synergistic action of excessive blockade of dopamine receptors, which causes hyperprolactinemia. Primary hyponatremia occurs during pregnancy and can be an important marker for signaling neurodevelopmental abnormalities, while secondary hyponatremia has a major clinical dimension and is induced by psychotropic drugs. The pathogenic mechanisms presented can be objectified by neuroimaging examinations that bring benefits in the diagnostic accuracy and re-evaluation of the therapeutic approach, especially in correlation with the severity of biological markers such as prolactin and sodium. The persistence of high prolactin and low sodium levels is an alarm signal that announces a negative evolution of the patient or a major risk of severe cardiac, metabolic, vascular or renal comorbidities. Recognition of pathogenic mechanisms of neurodevelopment, including ventriculomegaly, hyponatremia, focal cortical dysplasia, hippocampal or temporal lobe lesions, in association with a positive history of neonatal or febrile seizures, requires prophylaxis due to high risk of onset of schizophrenia in childhood. Fetal cortical dysplasia is associated with the risk of neonatal seizures. This vulnerability favors the appearance of febrile convulsions or enuresis with changes in brain structure. Enuresis may be an important marker of neurodevelopmental potential for schizophrenia. Neonatal seizures are correlated with hyponatremia and severe hypertension, which appeared in the third trimester of pregnancy, can trigger eclampsia. Neuroimaging monitoring in patients with neurodevelopmental abnormalities, hyperprolactinemia and primary or secondary hyponatremia, acquires a major importance, being able to delimit the boundary between a functional lesion, potentially reversible, with an irreversible lesion.

Psychological evaluation of women with suspected or diagnosed breast cancer can provide psychooncological elements for predicting the evolution of the disease and imperative customization of specific oncological therapies. In this study, we assessed the psychological status in terms of depression, anxiety and dysfunctional attitudes in both the group of patients with a confirmed diagnosis of breast cancer and that of patients with suspected breast cancer who are in the stage of histopathological evaluation of the diagnosis. The results of the psychometric evaluations allowed the development of a common neurobiological model for the two categories of patients. Given the staging model of breast cancer, the clinical and psychometric data obtained through our study allowed us to develop an integrative neurobiological model based on the evolutionary staging of anxiety and depressive disorders (Zhao et al., 2013). Based on these hypotheses, we argue that the staging of psychological disorders, the customization of specific psychotherapeutic prophylaxis strategies and the prudent pharmacological approach to these psychological changes can significantly improve the evolution and prognosis of cancer and the quality of life of patients. The state of relative psychoemotional balance (objectified by psychometric scales), without its validation by normalizing multisystemic biological indicators of depression (C-reactive protein, proinflammatory cytokines, blood-brain barrier disruption and cerebral blood flow decrease), suggests the risk of progression of the neoplastic process. We argue that when communicating the diagnosis and the therapeutic plan, a special methodology (specific protocol) must be applied to reduce distress, correct emotional balance and improve cognitive dysfunction by supporting the motivation to survive, as well as increasing patients' self-esteem.

Atypical antipsychotics have numerous benefits compared to conventional ones in respect to the possible adverse effects. However, like the other ones, they may induce direct cardiovascular alterations, probably through the apoptotic effect of dopamine receptor D2 (DRD2) blockade. The main objective of the study was to assess the cardiac ejection fraction (EF) using transthoracic speckle tracking echocardiography (TSTE) in patients treated with long-acting injectable (LAI) atypical antipsychotics.This cross-sectional study was conducted on 123 patients with schizophrenia or schizoaffective disorder divided in four samples according to their treatment: Aripiprazole, Olanzapine, Paliperidone and Risperidone. We analyzed socio-demographic data, the intensity of psychiatric symptoms, the duration of psychosis and of LAI treatment, and the cardiac EF measured with TSTE.We found no statistically significant differences between the four antipsychotics regarding the values of the EF. Nevertheless, we observed a trend indicating that patients treated with an antipsychotic associated with a lower affinity for the DRD2, such as Olanzapine, have higher EF values than patients treated with antipsychotics with a stronger binding to the DRD2, such as Paliperidone and Risperidone. Patients receiving Aripiprazole, which has the strongest affinity for the DRD2 from all four antipsychotics but is also a partial DRD2 agonist, display higher EF values than those on Paliperidone and Risperidone.Antipsychotics with a lower affinity for the DRD2 or a partial agonism for it may be associated with higher EF. Cardiac monitoring should be performed periodically in patients on LAI antipsychotic therapy.

Patients with serious mental illness are a high-risk category of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients with schizophrenia are not participatory and have increased mortality and morbidity, patients with dementia cannot be cared for while depression, anxiety, bipolar tubing are associated with low immune status. Social stress is amplified by social isolation, amplifying depression and the mechanisms of decreased immunity. Hygiene measures and prophylactic behavior are impossible to put into practice in conditions of chronic mental illness. In coronavirus disease 2019 (COVID-19), the risk for severe development is associated with the presence of comorbidities and immune system deficiency. Prothrombotic status, cytokine storm and alveolar destruction are mechanisms that aggravate the evolution of patients, especially in the context in which they have dysfunction of the autonomic system. The activity of proinflammatory cytokines is accentuated by hyperglutamatergia, which potentiates oxidative stress and triggers the mechanisms of neural apoptosis by stimulating microglial activation. Activation of M1-type microglia has an important role in pathogenesis of major psychiatric disorders, such as major depression, schizophrenia or bipolar disorder, and may associate hippocampal atrophy and disconnection of cognitive structures. Memantine and Amantadine, N-methyl-D-aspartate (NMDA) glutamate receptor inhibitors, have demonstrated, through their pharmacological profile, psychotropic effects but also antiviral properties. In the conditions of the COVID-19 pandemic, based on these arguments, we suggest that they can be associated with the therapy with the basic psychotropics, Memantine or Amantadine, for the control of neuropsychiatric symptoms but also as adjuvants with antiviral action.

Giant cell tumor of bone (GCTB) is a benign neoplasia more frequently encountered in young females. The pathogenic and evolutionary dynamics of the disease is strongly influenced by the presence of depression and cellular mechanisms, especially proinflammatory and immune. Although it is not a malignant tumor, it is often recurrent, which determines a high level of depression, anxiety, and fear of the patients. Cytokine mechanisms, especially through increased tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6), as well as the involvement of the receptor activator of nuclear factor-kappa B (RANK)–RANK ligand (RANK-L) system, can be correlated with the risk of malignancy. Unfavorable evolution is associated with persistent pain, difficulties of movement and body dysmorphic symptoms. The diagnosis is based mainly on histopathological (HP) assessment. The patients can be treated with pharmacological agents (Denosumab), surgery with tumor excision, reconstruction or osteosynthesis, and radiotherapy. Patients with GCTB require HP and imaging evaluations, especially of relapses, to detect the risk of metastasis or malignancy, simultaneously with psychological and psychiatric monitoring to detect depression, addictive behaviors, and suicide risk. It is necessary to evaluate in a multidisciplinary team to avoid unfavorable oncological and psychiatric developments. Through its clinical, HP, and therapeutic features, GCTB has multiple connections with the psychological and psychopathological dimension.

Gastric cancer represents a real public health problem as far as incidence, aggressiveness and unfavorable prognosis are concerned. The autonomous nervous system might be one of the major factors involved in the onset, progression, and metastasis, both sympathetically and parasympathetically. The increased activation of the M3 muscarinic acetylcholine receptors (mAChRs) triggers pro-oncogenic mechanisms, especially at a gastric level, through the activation of the Hippo signaling pathway and the increase of the nerve growth factor.In this study, biopsy or postoperative gastric resection pieces have been evaluated by histopathological (HP) and immunohistochemical (IHC) examination in a group of 77 gastric patients and 23 patients without an oncological diagnosis. To quantify the IHC signal, also considering the HP aspect, light microscopy images were obtained.The M3 mAChR expression analysis has been correlated with the different gastric adenocarcinoma differentiation degrees (G1-G3). M3 mAChR presence has been observed also in the non-malignant gastric tissue, but it was significantly increased in the tumor tissue. The highest receptor expression was recorded in patients with a poorly-differentiated (G3) adenocarcinoma, these expressions decreasing with the increase of the differentiation degree towards moderately-differentiated (G2) and well-differentiated (G1).Surgical or pharmacological parasympathetic activity inhibition could decrease the development and progression of gastric tumors and could improve the gastric cancer patient's prognosis.

In recent decades, traumatic brain injury (TBI) has become one of the most important health problems worldwide and is a major cause of morbidity, mortality and economic losses. Mild traumatic brain injury (mTBI) is less considered, with clinical underestimation leading to an epidemiological underevaluation of its incidence. Many of the signs and symptoms induced by mTBI are difficult to highlight clinically, especially those related to cognitive, behavioral, or emotional impairment. The complexity of the biological mechanisms induced by mTBI in the elderly determines synchronous pathogenic actions in which the vascular, inflammatory and neurodegenerative elements are intertwined. It is difficult to highlight a major pathogenic factor, since they act simultaneously, multimodally, in a real pathogenic cascade. The identification of mTBI and cerebral vascular changes by neuroimaging techniques, transcranial Doppler (TCD) or biological markers, suggests a potential prophylactic intervention by using neuroprotective factors as early as possible. Proper prophylaxis measures with neurotrophic treatment, rebalancing the gamma-aminobutyric acid (GABA)∕glutamate balance and combating the chronic inflammatory process, can become important pharmacological therapeutic targets.

In the context of the traumas suffered by patients following the oncological diagnosis and the expectation of the surgical intervention, it is important to unitary and multidimensional identify the psychological status, using a single interview structured to cover these psychological vulnerabilities. The overall psychological picture can help the psycho-oncologist to adapt his psychotherapeutic interventions to relieve the stress caused by the oncological diagnosis and specific treatment. 58 patients with a breast cancer diagnosis and 61 patients with breast lumps diagnosis who were waiting for the histopathological result, received several scales for assessing emotional distress, the level self-esteem, depression, anxiety and cognitive dysfunctions levels. The analysis of the answers led to the multidimensional identification of differences between the two categories of patients and establishing correlations between personality traits and the development of certain psychological changes. Statistically significant differences (p 0.05) were observed between patients with breast cancer and those with breast lumps awaiting histopathological diagnosis, in the areas of self-esteem, depression and cognitive schemas. Diagnosed patients have predominantly dysfunctional attitudes such as negative emotions and cognitive schemas related to catastrophe and self-deprecation, while undiagnosed patients, have cognitive schemas related to low tolerance for frustration and absolutist requirements and lower dysfunctional attitudes. A global assessment with a single psychological tool can capture the overall picture of the cancer patient, including possible triggers and maintenance of symptoms, with the psychological consequences of the disease that are reflected somatically, as well as predisposing factors in the history that generates these feelings.

Depression represents a public health issue because it significantly increases the risk of disabilities and premature mortality, decreases the quality of life, and increases the costs of care. The incomplete remissions favor the aggravation of neurobiological dysfunctions and pathogenesis of severe somatic comorbidities. The etiopathogenic mechanisms of depression are complex and involve multisystemic risk factors (genetic, neuroanatomic, neurobiochemical, neuroendocrine and psychosocial). Cognitive behavioral therapy (CBT) is used in all the stages of depression, as independent therapeutic method or as support of pharmacotherapy.This study has evaluated the therapeutic response of depression in M (medication) group with 136 patients under pharmacotherapy, compared with P (psychotherapy and medication) group with 137 patients treated simultaneously with medication and CBT, and the factors that can improve therapeutic management.Patients with depression had predominantly a reactive onset, recurrent evolution of at least four episodes, and frequent somatic comorbidities. After treatment, a significant improvement of depressive symptomatology was recorded especially in M group (72.06%), compared to P group (88.32%), p0.01, as well as a significant difference in regaining functional skills (69.12% - M group, 93.43% - P group; p0.001). The therapeutic response was significantly correlated with age (p0.01), social-economical involvement and education level.CBT demonstrated efficiency in the treatment of major depressive disorder in association with pharmacotherapy. The therapeutic approach should rely on the pathogenic biological models that would highlight the prediction indicators for the therapeutic response and for the evolution of depression, as well as considering the psychological profile of each patient.

Psychosocial factors are correlated with the risk of breast cancer, by the lack of externalization of feelings and aggressive tendencies, or with a negative prognosis, by the presence of a high level of stress and reduced coping abilities. Impairment of psychological status should be assessed early to identify quantifiable psychooncological changes, such as depression, anxiety, and self-esteem. These indicators, measured in this study, may become psychometric markers for predicting the existence of the neoplastic process, prior to histopathological evaluations.58 patients diagnosed with breast cancer and in different stages of evolution and 61 breast lumps patients were evaluated for depression, anxiety and self-esteem.The correlation of depression and anxiety levels according to the evolutionary stage of the disease was as follows: in stage I cases of severe depression with significant anxiety predominate, in stage II mild depression predominates with insignificant anxiety, in stage III depression predominates moderate with significant anxiety, while in stage IV moderate depression with significant anxiety predominates.The presence of significant anxiety in the uncertainty phase and the anxious-depressive clinical picture can be an alarm signal for the initiation of specific psychotherapeutic strategies, to increase the adaptive potential and resilience to the disease to ensure a therapeutic collaboration of the patient by increasing adherence and compliance. the proposed therapeutic plan. Relatively sudden anxiety in a young woman, risk factors for breast cancer, and deficient cognitive impairment require intensified clinical and paraclinical investigations to confirm early oncological diagnosis.

Frequent association of depressive disorder with clinical manifestations in prostate cancer patients raises problems with therapeutic response and adherence to treatment. Androgen deprivation therapies exacerbate depression and cause somatic adverse reactions, mainly represented by obesity, anemia, osteoporosis, muscle atrophy, gynecomastia. Depressive disorders correlate with activation of the hypothalamic-pituitary-adrenal axis (HPA), which induces high cortisol levels. The structural similarity between cortisol and testosterone suggests possible associations with their side effects. Decreased testosterone levels amplify the risk of developing or exacerbating depressive disorders. It is important the early identification of sexual identity and body perception disorders, as well as the interdisciplinary assessment of cognitive status and depression. The direct relationship between elevated PSA and testosterone levels and high depression scores suggests the unfavorable evolution of non-metastatic prostate cancer. It is necessary to evaluate depression from the diagnosis of prostate cancer as well as its dynamic monitoring. Therapeutic resistance raises the issue of early oncologic therapeutic switch and the combination of pharmacological and non-pharmacological antidepressant therapies.

Supersensitivity psychosis is a subdiagnosed clinical reality. This entity, however, is insufficiently elucidated from the point of view of the neurobiochemical mechanisms involved in the pathogenesis. The combination of an antipsychotic with a high D2 receptor blocking capacity and a neuroleptic-like substance such as cinnarizine trigger the dopaminergic hypersensitivity mechanisms. This stimulates the sensitivity for dopamine in the prefrontal cortex, ameliorating the negative and cognitive symptoms at the thalamic level, remodeling sensory integration and decreasing tinnitus, as well as in the cerebral tonsil, consequently decreasing the risk of antisocial behavior.

Schizophrenia is a major health problem in which diversification and increase in the quality of antipsychotic molecules did not yield the anticipated results. that the etiopathogenesis of schizophrenia accounts for a combination of genetic factors forming the genetic spectrum of vulnerability for schizophrenia. The neurodevelopmental anomalies correlated with the gestational period and obstetric traumatisms raises major pharmacological management issues. The two levels of vulnerability (genetic and neurodevelopmental) are the basis of the pathogeny of side effects induced by antipsychotic medication. The most severe side effects are related to extrapyramidal symptoms, hyperhomocysteinemia, hypofrontality, impairment of the neurovascular unit and neuronal metabolic processes. Understanding these particular mechanisms will allow the clinician to identify the pathogenic model of schizophrenia, customized for each specific case. The adverse drug reaction decreases the compliance and adherence to the treatment, determining repeated discontinuations with psychotic relapses, and may trigger psychopathogenic bursts deteriorating the structural and cerebral functional balance. The type of psychotropic medication must be taken into account, as well as the concomitant medication administered for comorbidities associated with schizophrenia. The cerebral vascular modifications are correlated with the metabolic syndrome induced by antipsychotic medication. This complex syndrome, associated also with modifications in the homocysteine metabolism, determines weight gain, obesity, high blood pressure, ischemic cardiopathy, hyperglycemia and dyslipidemia. Identification of possible biological or neuroimaging markers helps and their early correction may prevent the onset of neurodegenerative evolution and irreversible cerebral atrophies, as well as decrease the risk of side effect that may endanger the life of the schizophrenic patient. The complexity of the pathogenic mechanisms requires a prophylactic behavior, not based on therapeutic switch, but on the proactive, customized pharmacologic intervention, addressing the pathogenic chains.

The aim of our study was to assess the sympathetic nervous system’s involvement in the evolution of gastric carcinoma in patients by analyzing the mediators of this system (epinephrine and norepinephrine), as well as by analyzing the histological expression of the norepinephrine transporter (NET). We conducted an observational study including 91 patients diagnosed with gastric carcinoma and an additional 200 patients without cancer between November 2017 and October 2018. We set the primary endpoint as mortality from any cause in the first two years after enrolment in the study. The patients were monitored by a 24-h Holter electrocardiogram (ECG) to assess sympathetic or parasympathetic predominance. Blood was also collected from the patients to measure plasma free metanephrine (Meta) and normetanephrine (N-Meta), and tumor histological samples were collected for the analysis of NET expression. All of this was performed prior to the application of any antineoplastic therapy. Each patient was monitored for two years. We found higher heart rates in patients with gastric carcinoma than those without cancer. Regarding Meta and N-Meta, elevated levels were recorded in the patients with gastric carcinoma, correlating with the degree of tumor differentiation and other negative prognostic factors such as tumor invasion, lymph node metastasis, and distant metastases. Elevated Meta and N-Meta was also associated with a poor survival rate. All these data suggest that the predominance of the sympathetic nervous system’s activity predicts increased gastric carcinoma severity.

Background The coronavirus disease 2019 (COVID-19) pandemic outbreak forced cancer care providers to face different challenges in terms of prevention and treatment management due to specific precautions implemented for oncological patients. We aimed to describe the level of knowledge, attitude and practices (KAP) among cancer patients, with the purpose to provide an image of the impact of COVID-19 and evaluate the effectiveness of pandemic response measures. Patients and methods We developed a cross-sectional multicentric study that targeted adults with active cancer during the COVID-19 outbreak, aiming to describe KAP related to COVID-19 among Romanian oncological patients. A questionnaire investigating 64 items on KAP related to the novel coronavirus was designed and applied in seven Romanian hospitals. The group of participants consisted of 1585 oncological patients who completed the questionnaire during the outbreak (April-May 2020). Results Only 172 patients (10.8%) had very good knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection symptoms, treatment options and incubation period. Only 44.3% of patients identified diarrhoea as a sign of COVID-19. About one-third of patients (32.6%) declared that they are ‘very worried’ about getting infected with the novel coronavirus. More than two-thirds of participants (68%) considered that having cancer represents an additional risk for infection with SARS-CoV-2, but 27.8% would rather not vaccinate against SARS-CoV-2 should a vaccine be available. A small percentage (8.8%) believed that the risk of infection justifies delaying/stopping oncological treatment until after the pandemic. Around half of the participants (55.5%) declared being compliant with all the protective measures against coronavirus infection listed in the questionnaire. Conclusion Romanian oncological patients have a less than expected knowledge about SARS-CoV-2, appropriate prevention behaviours, with limited trust in their efficacy, optimistic attitudes towards COVID-19 and low level of trust in information sources. Good COVID-19 knowledge was associated with appropriate practices towards COVID-19 and optimistic attitudes., Highlights • Romanian oncological patients included in the study had a less than expected knowledge about coronavirus. • Appropriate prevention behaviours were noted among patients, but with limited trust in their efficacy. • Some patients would rather stop the oncological treatment for the duration of the pandemic. • Patients with low socioeconomic status or higher education were more worried that they might get infected with SARS-CoV-2. • The results suggest the need for implementation of better health education programs aimed at improving COVID-19 knowledge.

Schizophrenia is a functional psychosis with a multifactorial etiopathogeny involving genetic, endocrine and immunological risk factors. The main pathogenic hypothesis involves dopamine dysregulation, with hyperfunction in the limbic system and hypofunction in the prefrontal cortex. Normal dopamine activity is critical for cognitive and emotional processing, but also for autonomic and immune regulation. Co-morbidity between schizophrenia and cardiovascular anomalies is complex. Genetic factors influence the development of brain, cardiac and vascular structures, as well as the activity of enzymes involved in dopamine synaptic turnover. Autoimmunity triggered by infections or related to systemic diseases affects both brain and heart in a direct manner through autoantibodies and/or indirectly through microvascular injury. In most cases, the co-morbidity between schizophrenia and cardiac diseases is secondary to metabolic dysfunctions induced by psychotropic medication or psychosis itself. Because of their diverse pharmacodynamic profiles, antipsychotics differ in their propensity to facilitate the development of the metabolic syndrome. The distress associated with acute psychotic symptoms or a sedentary lifestyle due to negative symptoms may have a negative impact on the energetic metabolism or cardiac function. Conclusions: An interdisciplinary approach is required between neurosciences and cardiology not only at the research level, but also in the clinical practice. Cardiac co-morbidity in subjects with schizophrenia may critically affect the survival rates of these patients. Moreover, the nature of the cardiac co-morbidity may guide the clinician in better understanding and differentiating functional psychoses from organic ones. The multifactorial approach can identify cardiovascular risk factors based on clinical, biological and neuroimaging markers.

The aim of this study was to assess the cognitive decline in patients with Parkinson’s disease and to study its correlation with their depression. We studied 64 consecutive patients (30 men and 34 women), mean education level 11.2±1 years and mean age 72.3±3.5 years. These patients were admitted to Clinic of Neuropsychiatry Craiova between January 2016 and October 2016. They underwent a neurological and neuropsychological examination at baseline, after 6 months and 12 months later. For the cognitive assessment we used the revised version of the Addenbrooke′s Cognitive Examination (ACE-R) and Montreal Cognitive Assessment (MoCA) and for the evaluation of depression we used Hamilton Depression Rating Scale (HDRS). We have also included in our study a control group composed of 76 control subjects with the same range of educational level and age. All the patients met the diagnostic criteria for Parkinson′s Disease. In this study we included patients in stage I and II on Hoehn and Yahr scale. Twenty-six patients were in stage I and 38 patients in stage II. The patients were treated with levo-dopa monotherapy, dopaminergic agonists monotherapy, or levodopa associated with dopaminergic agonists. At baseline the patients in stage I showed a mean MoCA score 26.8 and a mean ACE-R score 89.6. The patients in stage II had a mean MoCA score 26.5 and a mean ACE-R score 89.4 at baseline. The control subjects showed a mean MoCA score 27.06 and a mean ACE-R score 90.3. One year later the patients group I showed a mean MoCA score 19.8 and 84.7 mean ACE-R score. The groups of patients in stage II had a mean MoCA score 18.3 and ACE-R score 84.2. The control group the mean MoCA values was 22.56 and ACE-R 87.1. Regarding asssessment of depression, we obtained the next scores: at baseline, patients in stage I showed a mean HDRS score of 14.6; the patients in stage II a mean HDRS score 14.8 and the control group a HDRS mean score of 8. One year later group I showed a mean HDRS score of 18.8; the group II 19.9 and the control group 9.7. For the statistical analyse, we used Student test (p

Pancreatic cancer represents one of the most aggressive types of cancer, resulting in a late diagnosis and rapid death (poor overall survival). After adenocarcinoma (counting almost 80% of cases of pancreatic cancer), the second category, as frequency, is represented by the family of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Pancreatic cancer is characterized by genetic heterogeneity and may results in different evolution among metastases, which may acquire driver mutations with the ability to transform under the action of several cancer treatments. Here we report a case of a 64-year-old patient diagnosed with pancreatic tumor localized on the body and tail, invasive in the splenic and portal vein, pT3pN0M0 (adenocarcinoma pancreatic cancer), treated with a multimodal approach: surgery (splenectomy and distal pancreatectomy, with suture of the portal vein), chemotherapy, in 2010, that relapsed in 2015, with local recurrence that was resected and distant liver metastases. Immunohistochemistry of the recurrence tumor showed a neuroendocrine transformation of the tumor, with major implications in treatment and prognosis. Computed tomography examination, as well as histopathological and immunohistochemically testing, sustained positive and differential diagnosis.