Bridging the Gap with Clinicians: The Issue of Underrecognition of Pathologists and Radiologists as Scientific Authors in Contemporary Medical Literature.

The purpose of this study was to evaluate recognition of pathologists and radiologists as coauthors in case reports in the field of surgical oncology. The MEDLINE database was searched for all full free text case reports involving human material published from April 1, 2011 until March 31, 2016, using search terms: "case report" + "tumors" + "surgery" + "malignant". The search strategy identified a total of 1427 case reports of which 907 were included in this analysis. Of 807 articles with histopathological images and/or descriptions, 352 (43.6%) did not acknowledge or include the pathologist as a coauthor. Of 662 case reports with radiographic images and/or their description, 537 (81.1%) did not list the radiologist as coauthor nor acknowledge them. In case reports containing histopathological images, significantly more pathologists were either listed as coauthors or acknowledged compared to those who were not (Z = 5.128; p = 0.001). However, among case reports containing radiographic images, there were significantly less articles either listing radiologists as coauthors or acknowledging them compared to a larger proportion of articles in which radiologists were omitted (Z = - 22.646; p = 0.001). In conclusion, pathologists and radiologists are underrecognized as coauthors in surgical oncology case reports in spite of obvious proof of their contribution to manuscript preparation. When involved in research and publishing, all physicians should be aware of fair and honest collaboration with specialists in other clinical and non-clinical disciplines to better serve the scientific community.

Management and treatment of children with medulloblastoma in Serbia, a middle-income country.

PURPOSE: The aim of this study was to present the management and treatment of children with medulloblastoma in Serbia, a middle-income country (MIC). METHODS: The data of 87 children diagnosed with medulloblastoma and treated at the Institute for Oncology and Radiology of Serbia from 2000 to 2013 were analyzed. RESULTS: The children's median age was 8.3 years (range 2.5-17.3). Eighty-two (94.2%) were 3 years or older. Sixtytwo (71.3%) patients had stage M0 medulloblastoma, 12 (13.8%) had stage M1 and 13 (14.9%) had stage M2 or M3. As of October 2015, 51 (58.6%) patients were alive and 31 (35.6%) had died. Five patients (5.7%) were lost to followup. Twenty-six patients relapsed. The median follow-up time was 58 months (range 4-187). Mean overall survival (OS) was 76.4% at 3 years, 66.2% at 5 years and 59.2% at 10 years. Mean disease-free survival (DFS) was 75.8% at 3 years, 62.8% at 5 years and 56.6% at 10 years. Mean OS of stage M0 patients was 86.4% at 3 years, 74% at 5 years and 63.1% at 10 years. The OS of stage M1, M2 and M3 patients combined was 48.9% at 3 years, 44.0% at 5 years and 37.7% at 10 years. CONCLUSION: In Serbia, a MIC, it is possible to achieve good treatment results in children with medulloblastoma using international treatment guidelines and recommendations, available resources and an experienced team of professionals dedicated to pediatric neurooncology.

The impact of TP53 and RAS mutations on cerebellar glioblastomas.

Cerebellar glioblastoma (cGBM) is a rare, inadequately characterized disease, without detailed information on its molecular basis. This is the first report analyzing both TP53 and RAS alterations in cGBM. TP53 mutations were detected in more than half of the samples from our cohort, mainly in hotspot codons. There were no activating mutations in hotspot codons 12/13 and 61 of KRAS and HRAS genes in cGBM samples but we detected alterations in other parts of exons 2 and 3 of these genes, including premature induction of STOP codon. This mutation was present in 3 out of 5 patients. High incidence of RAS mutations, as well as significantly longer survival of cGBM patients compared to those with supratentorial GBM suggest that cGBM may have different mechanisms of occurrence. Our results suggest that inactivation of TP53 and RAS may play an important role in the progression of cerebellar GBM.

Genomic instability and p53 alterations in patients with malignant glioma.

The purpose of this study was to detect the level of genomic instability and p53 alterations in anaplastic astrocytoma and primary glioblastoma patients, and to evaluate their impact on glioma pathogenesis and patients outcome. AP-PCR DNA profiling revealed two types of genetic differences between tumor and normal tissue: qualitative changes which represent accumulation of changes in DNA sequence and are the manifestation of microsatellite and point mutation instability (MIN-PIN) and quantitative changes which represent amplifications or deletions of existing chromosomal material and are the manifestation of chromosomal instability (CIN). Both types of alterations were present in all analyzed samples contributing almost equally to the total level of genomic instability, and showing no differences between histological subtypes. p53 alterations were detected in 40% of samples, predominantly in anaplastic astrocytoma. The higher level of genomic instability was observed in elderly patients (>50 years) and patents with primary glioblastoma. Level of genomic instability had no impact on patients' survival, while presence of p53 alterations seemed to be a favorable prognostic factor in this case. Our results indicate that extensive genomic instability is one of the main features of malignant gliomas.

Intraorbital ganglioglioma of optic nerve in a patient with neurofibromatosis type 1.

We report the case of an orbital optic nerve gangliogoma in a 55-year-old woman with neurofibromatosis type 1 (NF1). Clinical course neuroimaging findings, pathology, and treatment options of gangliogloma are discussed and contrasted with pilocytic astrocytomas of the optic nerve, a much more frequent visual pathway neoplasm in NF1 patients.

Expression of kisspeptin and KISS1 receptor in pituitary neuroendocrine tumours - an immunohistochemical study.

INTRODUCTION: Pituitary neuroendocrine tumours (PitNETs), traditionally designated as pituitary adenomas, show elatively frequent invasive growth with exceptional metastatic potential, the causes of which are not entirely elucidated. Kisspeptins, which perform their activity through KISS1 receptor (KISS1R), are recognised as metastatic suppressors in many malignant tumours. This study aimed to investigate the immunohistochemical expression of kisspeptin and KISS1R in different types of PitNETs and to compare it with the expression in the normal anterior pituitary, using tissue microarray. MATERIAL AND METHODS: The experimental group consisted of 101 patients with PitNETs, with 45 (37.3%) being of gonadotroph, 40 (33.9%) somatotroph, 4 (3.4%) corticotroph, 4 (3.4%) thyrotroph, 3 (2.5%) lactotroph, and 6 (5.1%) null-cell type. The control group consisted of anterior pituitary tissue accidentally removed during the surgery for PitNETs in 17 patients. RESULTS: Kisspeptin expression was observed in both experimental and control groups, without statistically significant differences in the staining intensity. Negative kisspeptin staining was detected in 10 (9.9%), weak in 79 (78.2%), and moderate in 12 tumours (11.9%); none of the tumours had strong staining intensity. The weak staining intensity was predominant in all PitNET types except thyrotroph tumours. Significant statistical difference in terms of kisspeptin expression between types of PitNET and the control group was not observed. Immunohistochemical expression of KISS1R was not observed in the control group or in the experimental group. CONCLUSIONS: We conclude that immunohistochemistry, as a method, cannot confirm the involvement of kisspeptin in tumourigenesis and aggressiveness of PitNETs, but potentially supports its antimetastatic role. The absence of KISS1R immunohistochemical expression in all anterior pituitaries and PitNETs in our cohort needs verification through the use of different procedures designed for the detection of the presence and localisation of proteins in the cell.

Lymphocytic Hypophysitis Successfully Treated with Stereotactic Radiosurgery: Case Report and Review of the Literature.

Lymphocytic hypophysitis (LH) is an autoimmune inflammatory infiltration of the pituitary gland, usually with a benign evolution. In rare circumstances the inflammatory process may extend beyond the pituitary and infiltrate the surrounding structures. We present a 42-year-old woman affected by an aggressive form of LH with extension to the cavernous sinus causing internal carotid artery occlusion and right sixth cranial nerve palsy. Prednisone therapy caused severe iatrogenic Cushing's syndrome, and the patient underwent transsphenoidal decompression. The histopathology report was consistent with LH. The patient was symptom free for a short period with reappearance of severe headache, diplopia, and hearing loss (middle ear inflammation) 3 months after surgery. Corticosteroids were reintroduced with the addition of azathioprine, but there was no regression of the pituitary mass. The patient was referred for stereotactic radiosurgery (SRS) using Gamma Knife (15 Gy to the margin). After 26 months, azathioprine was stopped, and the dose of prednisone was gradually tapered to 7.5 mg/day. Sellar magnetic resonance imaging showed regression of the pituitary mass. After follow-up for > 3 years after SRS, there was no clinical or radiologic evidence of the disease, but carotid arteries remained occluded. The patient developed secondary hypothyroidism and hypogonadism as consequences of SRS. An aggressive form of LH extending beyond the pituitary gland infiltrating surrounding structures is described. It was successfully treated with SRS after failure of transsphenoidal surgery and combined immunosuppressive therapy (prednisone, azathioprine). The review of the literature presents timely information concerning treatment with azathioprine and SRS of patients with an aggressive form of LH.

A large sellar granular cell tumor in a 21-year-old woman.

We report here the case of a 21-year-old woman with a large sellar tumor, extending to the suprasellar area associated with growth hormone deficiency, hypogonadism, hypocorticism, and hyperprolactinemia. Transsphenoidal surgery was performed, and histologic, immunohistochemical, and electron microscopic study lead to the diagnosis of granular cell tumor. These tumors are, in most cases, very small and are found incidentally at autopsy of older patients. Our case is exceptional because the tumor developed in a young woman, extended to the suprasellar region, and caused clinical symptoms.

All that glitters on PET is not cancer! 18F-deoxy-glucose avidity versus tumor biology: pituitary incidentaloma in a survivor of two previous unrelated malignancies.

INTRODUCTION: 18F-deoxy-glucose positron emission tomography combined with computed tomography (18F-FDG PET/CT) is routinely used in the detection of malignant disease based on the property of malignant cells to fuel their growth and replication by increased glucose uptake. Malignant lesions are rare in the sellar region, while pituitary adenomas are the most common pathology. These are benign neoplasms with insidious onset and low proliferation activity, and therefore are only exceptionally detected by 18F-FDG PET/CT. Studies that compare the biology of pituitary adenomas and their radiological properties using PET/CT are still lacking. CASE REPORT: We investigate and discuss tumour biology in light of increased 18F-FDG avidity in a symptom-free, 70-year-old male patient, previously treated for two different malignancies (lung and rectal). Increased tracer accumulation in the sellar region was incidentally detected on a follow-up 18F-FDG PET/CT scan. Additional MRI disclosed pituitary adenoma. Normal hormonal status was found, consistent with the diagnosis of non-functioning pituitary adenoma. Analysis of tumour tissue after pituitary surgery confirmed a silent gonadotroph adenoma with low proliferation index. Low expression of oncogene-induced senescence markers did not support senescence as the explanation for the tumour's low proliferative activity although it was in consonance with the hormonal activity. CONCLUSIONS: Pituitary adenomas can manifest as hypermetabolic foci on 18F-FDG PET/CT imaging with increased tracer uptake even in indolent, clinically silent pituitary adenomas with low mitotic activity. Special attention should be paid to evaluation of 18F-FDG avid pituitary adenomas in patients with multiple malignancies, bearing in mind that avidity does not always mirror its biological behaviour.

Oncogene-Induced Senescence in Pituitary Adenomas--an Immunohistochemical Study.

Oncogene-induced senescence (OIS) serves as an initial barrier to cancer development, being proposed as a possible explanation for the usually benign behavior of the pituitary adenomas. We aimed to explore the immunohistochemical expression of the OIS markers, senescence-associated lysosomal ß-galactosidase (SA-ß-GAL), p16, and p21 in different types of 345 pituitary adenomas and compared it with the expression in the normal pituitary and in the specimens from the repeated surgeries. SA-ß-GAL was overexpressed in the pituitary adenomas, compared to the normal pituitaries. Growth hormone (GH) producing adenomas showed the strongest SA-ß-GAL, with densely granulated (DG)-GH adenomas more reactive than the sparsely granulated (SG). Nuclear p21 was decreased in the adenomas, except for the SG-GH adenomas that had higher p21 than the normal pituitaries and the other adenomas. p16 was significantly lower in the adenomas, without type-related differences. SA-ß-GAL was slightly lower and p16 slightly higher in the recurrences. Our findings indicate alterations of the senescence program in the different types of pituitary adenomas. Activation of senescence in the pituitary adenomas presents one possible explanation for their usually benign behavior, at least in the GH adenomas that show a synchronous increase of two OIS markers. However, subdivision into GH adenoma subtypes reveals differences that reflect complex regulatory mechanisms influenced by the interplay between the granularity pattern and the hormonal factors, with possible impact on the different clinical behavior of the SG- and DG-GH adenoma subtypes. p16 seems to have a more prominent role in the pituitary tumorigenesis than in the senescence. Recurrent growth in a subset of the pituitary adenomas is not associated with consistent changes in the senescence pattern.

Intramedullary Spinal Cord Germinoma: A Case Report and Review of Literature.

Primary spinal cord germinomas are an extremely rare group of tumors, most commonly reported as single cases in young Japanese adults. They usually present as intramedullary lesions located in the thoracic and thoracolumbar spine. The importance of preoperative diagnosis lies in the fact that by using radiotherapy and chemotherapy, even without surgery, a good cure rate can be achieved in patients with spinal cord germinoma. These tumors, however, demonstrate unspecific imaging characteristics, and only some secrete tumor markers. Therefore, a diagnosis of these lesions before biopsy or resection with pathohistologic examination can be difficult. We present a case of a 28-year-old white man with intramedullary spinal cord germinoma. The tumor was resected completely with electrophysiological monitoring, without a biopsy and frozen section analysis. Postoperative radiotherapy also was part of the treatment. The patient has had no relapse 4.5 years after diagnosis; however, significant neurologic deficits remain. Although not as frequent in white patients, germinoma should be considered as differential diagnosis in cases of young adult patients with intramedullary tumor in the thoracic or thoracolumbar spine. Therefore, spinal mass surgery should commence with a biopsy and intraoperative frozen section analysis. In this way, attempting a gross total resection becomes unnecessary. With an approach of intraoperative biopsy and frozen section analysis, a considerable amount of postoperative neurologic deficits can be reduced.

Primary lymphoma of the brain in a young man whose brother died of hemophagocytic lymphohistiocytosis: case report.

INTRODUCTION: We represent the unique occurrence of primary central nervous system lymphoma (PCNSL) in a patient whose brother died of genetically confirmed hemophagocytic lymphohistiocytosis (HLH). CASE OUTLINE: We report a case of a 25-year-old male patient with primary aggressive diffuse large B-cell lymphoma affecting the brain and PCNSL. Despite one year of medical treatment outcome was lethal. However, our patient had a relatively longer survival compared to median survival time for PCNSL. Additionally, he had two older brothers who died at the age of about 11 years. One died of fulminate malignancy, shortly after pediatric admission, before the diagnosis could be established. The other one died from genetically confirmed (perforin mutation/PRF1) HLH. Our patient was heterozygous carrier of perforin mutation representing the genetic marker for HLH. Our patient's father was the carrier of the same mutation but had no symptoms of any disease. CONCLUSION: This case points at the presence of HLH and diffuse large B-cell PCNSL in brothers. Extensive assessment of patients with probable PCNSL and familial HLH is necessary, including genetic analysis for HLH.

Immunohistochemical Expression of p16 and p21 in Pituitary Tissue Adjacent to Pituitary Adenoma versus Pituitary Tissue Obtained at Autopsy: Is There a Difference?

Normal pituitary tissue is frequently used for comparison with protein expression in tumor tissue, being obtained either at surgery or at autopsy. p16 and p21 proteins are cyclin-dependent kinase inhibitors, belonging to INK4 and Cip/Kip family, respectively. Their expression is increased in response to DNA damage or other cellular stressors, resulting in the activation of cell cycle checkpoints. They also play important roles in cellular senescence. The purpose of this study was to investigate differences in p16 and p21 immunohistochemical expression in normal pituitary tissue adjacent to pituitary adenoma obtained during neurosurgical procedure with pituitary tissue obtained at autopsy, from patients who died from non-endocrinological diseases. Our results show significant difference in p16 nuclear and p21 cytoplasmic immunohistochemical expression between two types of normal pituitary tissues. One of the reasons for this difference could be the age of subjects because those who underwent autopsy for a non-endocrinological disease were significantly older than subjects who underwent neurosurgery for a pituitary adenoma. Our finding that differences are probably not influenced by postmortem changes is supported by no significant correlation between postmortem interval and immunohistochemical p16 and p21 expression. The influence of the presence of a pituitary adenoma could not be evaluated in these specimens.

Identification of novel genetic alterations in samples of malignant glioma patients.

Glioblastoma is the most frequent and malignant human brain tumor. High level of genomic instability detected in glioma cells implies that numerous genetic alterations accumulate during glioma pathogenesis. We investigated alterations in AP-PCR DNA profiles of 30 glioma patients, and detected specific changes in 11 genes not previously associated with this disease: LHFPL3, SGCG, HTR4, ITGB1, CPS1, PROS1, GP2, KCNG2, PDE4D, KIR3DL3, and INPP5A. Further correlations revealed that 8 genes might play important role in pathogenesis of glial tumors, while changes in GP2, KCNG2 and KIR3DL3 should be considered as passenger mutations, consequence of high level of genomic instability. Identified genes have a significant role in signal transduction or cell adhesion, which are important processes for cancer development and progression. According to our results, LHFPL3 might be characteristic of primary glioblastoma, SGCG, HTR4, ITGB1, CPS1, PROS1 and INPP5A were detected predominantly in anaplastic astrocytoma, suggesting their role in progression of secondary glioblastoma, while alterations of PDE4D seem to have important role in development of both glioblastoma subtypes. Some of the identified genes showed significant association with p53, p16, and EGFR, but there was no significant correlation between loss of PTEN and any of identified genes. In conclusion our study revealed genetic alterations that were not previously associated with glioma pathogenesis and could be potentially used as molecular markers of different glioblastoma subtypes.

What's in the Image? Pituitary Metastasis from Papillary Carcinoma of the Thyroid: A Case Report and a Comprehensive Review of the Literature.

A 67-year-old female patient presented with visual field impairment and hyperprolactinemia. Imaging revealed a sellar and suprasellar mass and during the evaluation of the sellar lesion, papillary thyroid carcinoma (PTC) was diagnosed by fine-needle aspiration biopsy in a long-standing euthyroid multinodular goiter. The patient did not have a previous history of PTC. Total thyroidectomy confirmed the diagnosis of PTC. Due to progressive visual loss, she underwent transcranial surgery for decompression of the optic chiasm. Pituitary metastasis from PTC was confirmed, histologically and immunohistochemically. In literature, overall 13 cases, including ours, with PTC metastasis to the sellar region have been reported. Most were women, with a median age of 56 years. Two thirds of patients were previously diagnosed with PTC. The presence of other distant metastases was confirmed in less than half of the patients. Only 2 and our patient had immunohistochemical confirmation of PTC metastasis to the sellar region. The presenting signs and symptoms included: visual field defects, ophthalmoplegia, and anterior pituitary hormone deficiencies. In conclusion, this is a rare case of metastatic PTC to the sellar region unequivocally confirmed by immunohistochemistry in whom the disease first presented with a sellar and suprasellar mass.

Multiple cavernous hemangiomas of the orbit: separate occurrence within a 24-year period.

BACKGROUND: Cavernous hemangioma is a frequent and the most common, primary, benign tumor of the orbit in adults. It is typically single and unilateral, considered not to recur after having been completely excised. Multiple orbital cavernous hemangiomas without signs of hemangiomatosis are rare. Multiple cavernous hemangiomas may recur after a complete excision and may exist with concurrent systemic tumors. Tumor recurrence is supposed to develop from vasculature that is present already in response to a proliferate stimulus. CASE REPORT: A 39-year-old female with painless proptosis of the right orbit was found to have four orbital tumors. The first orbitotomy was performed in 1984 by excising four cavernous hemangiomas. Six years later, another, the fifth one cavernous hemangioma was totally excised from the same orbit. Nine years after the first operation, reorbitotomy was performed because of positive radiological and clinical signs of de novo tumor in the orbit. The operation did not confirm the tumorous tissue. The fourth orbitotomy was performed 24 years after the first operation and two cavernous hemangiomas were totally excised. CONCLUSION: This case show the possibility of cavernous hemangioma recurrence after a previously totally excised tumor, separated more than two decades. A very long follow-up of the patients operated for these benign tumor lesions is recommended.