Browsing by Author "Manojlovic-Gacic, Emilija (36439877900)"

The emergence of de novo or recurrent cutaneous eruptions in individuals with hematological diseases presents a challenge when determining whether they indicate secondary dissemination or an unrelated diagnosis. Eosinophilic eruption of hematoprolif-erative disease is a rare nonspecific manifestation accompanying lymphoproliferative disorders, including chronic lymphocytic leukemia (CLL). We present the case of a 70-year-old man with CLL in remission (previously treated with two 6-month cycles of fludarabine-cyclophosphamide plus rituximab, 2 and 5 years earlier) with an acute, disseminated polymorphic skin eruption. Skin biopsies from two sites (bulla and infiltrated nodule) were taken for histopathological examination. The pathologist reported giant spongiform vesicle formation with eosinophils with dermal and hypodermal inflammatory infiltrate composed of lymphocytes (pre-dominantly T cells, fewer B cells) and eosinophils. Secondary neoplasm dissemination and sarcoidosis were excluded by means of immunohistochemistry. A diagnosis of eosinophilic eruption of hematoproliferative disease in the CLL patient post-chemotherapy and without active disease was established. Two weeks after skin remission, the patient worsened with enlarged lymph nodes and a leukocyte count of 291 × 109/l. CLL relapse was confirmed. Leukocytapheresis was performed and ibrutinib 140 mg three times daily was prescribed. Our case underscores the importance of recognizing this relatively common but underreported eosinophilic eruption associated with hematoproliferative diseases. © 2023, Slovene Medical Society. All rights reserved.

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. © 2019, Springer Nature B.V.

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. © 2019, Springer Nature B.V.

Background: Intracranial germinomas (ICG) are uncommon brain neoplasms with extremely rare familial occurrence. Because ICG invades the hypothalamus and/or pituitary, endocrine dysfunction is one of the common determinants of these tumours. We present two brothers with a history of ICG. Patient 1 is a 25-year-old male who suffered from weakness of the right half of his body at the age of 18 years. Cranial MRI revealed a mass lesion in the left thalamus. He underwent neurosurgery, and the tumour was removed completely. Histopathological (HP) and immunohistochemical analyses verified the diagnosis of pure germinoma. He experienced complete remission of the tumour after radiation therapy. At the age of 22 years a diagnosis of isolated growth hormone deficiency (IGHD) was established and GH replacement was initiated. Molecular genetic analysis of the tumour tissue detected the mutation within exon 2 in KRAS gene. Patient 2 is a 20-year-old man who presented with diabetes insipidus at the age of 12 years. MRI detected tumour in the third ventricle and pineal region. After endoscopic tumour biopsy the HP diagnosis was pure germinoma. He received chemotherapy followed by radiotherapy and was treated with GH during childhood. At the age of 18 years GH replacement was reintroduced. A six-month follow-up during the subsequent two years in both brothers demonstrated the IGF1 normalisation with no MRI signs of tumour recurrence. Conclusion: To the best of our knowledge, so far only six reports have been published related to familial ICG. The presented two brothers are the first report of familial ICG case outside Japan. They have been treated successfully with GH therapy in adulthood. © 2018 Via Medica. All rights reserved.

Background: Intracranial germinomas (ICG) are uncommon brain neoplasms with extremely rare familial occurrence. Because ICG invades the hypothalamus and/or pituitary, endocrine dysfunction is one of the common determinants of these tumours. We present two brothers with a history of ICG. Patient 1 is a 25-year-old male who suffered from weakness of the right half of his body at the age of 18 years. Cranial MRI revealed a mass lesion in the left thalamus. He underwent neurosurgery, and the tumour was removed completely. Histopathological (HP) and immunohistochemical analyses verified the diagnosis of pure germinoma. He experienced complete remission of the tumour after radiation therapy. At the age of 22 years a diagnosis of isolated growth hormone deficiency (IGHD) was established and GH replacement was initiated. Molecular genetic analysis of the tumour tissue detected the mutation within exon 2 in KRAS gene. Patient 2 is a 20-year-old man who presented with diabetes insipidus at the age of 12 years. MRI detected tumour in the third ventricle and pineal region. After endoscopic tumour biopsy the HP diagnosis was pure germinoma. He received chemotherapy followed by radiotherapy and was treated with GH during childhood. At the age of 18 years GH replacement was reintroduced. A six-month follow-up during the subsequent two years in both brothers demonstrated the IGF1 normalisation with no MRI signs of tumour recurrence. Conclusion: To the best of our knowledge, so far only six reports have been published related to familial ICG. The presented two brothers are the first report of familial ICG case outside Japan. They have been treated successfully with GH therapy in adulthood. © 2018 Via Medica. All rights reserved.

In the original publication of this article, upper and lower part of Table 2 was incorrectly formatted. The incorrect and correct version of Table 2 are shown in this correction article. The original article has been corrected. Relevant significantly enriched gene sets associated with the DMPs that differed between aggressive and metastatic PitNETs in the first surgery specimens (upper table) and in the entire cohort (lower table) Hypermethylated and positive enriched in PC pval padj NES size KEGG cell adhesion molecules CAMS 6.26E-07 5.63E-05 1.65 122 KEGG axon guidance 6.51E-07 5.63E-05 1.65 122 KEGG pathways in cancer 1.43E-06 8.24E-05 1.44 313 KEGG neuroactive ligand receptor interaction 6.39E-06 0.00028 1.44 249 KEGG focal adhesion 7.16E-05 0.0015 1.44 191 KEGG adherens junction 8.97E-05 0.0017 1.64 67 KEGG calcium signaling pathway 0.00025 0.0039 1.40 166 KEGG leukocyte transendothelial migration 0.0019 0.019 1.43 108 KEGG ECM receptor interaction 0.0019 0.019 1.49 83 KEGG gap junction 0.0063 0.036 1.40 83 KEGG axon guidance 1.60E-06 0.00028 1.53 122 KEGG calcium signaling pathway 3.22E-06 0.00028 1.44 166 KEGG neuroactive ligand receptor interaction 0.00010 0.0045 1.31 249 KEGG regulation of actin cytoskeleton 0.00013 0.0045 1.34 197 KEGG MAPK signaling pathway 0.00030 0.0066 1.29 251 KEGG cell adhesion molecules cams 0.0018 0.035 1.33 122 KEGG ECM receptor interaction 0.0034 0.049 1.36 83 KEGG Wnt signaling pathway 0.0052 0.064 1.27 145 KEGG Hedgehog signaling pathway 0.0057 0.064 1.40 55 KEGG leukocyte transendothelial migration 0.011 0.10 1.28 108 Relevant significantly enriched gene sets associated with the DMPs that differed between aggressive and metastatic PitNETs in the first surgery specimens (upper part of the table) and in the entire cohort (lower part of the table) Hypermethylated and positive enriched in PC pval padj NES size KEGG Cell adhesion molecules CAMS 6.26E-07 5.63E-05 1.65 122 KEGG Axon guidance 6.51E-07 5.63E-05 1.65 122 KEGG Pathways in cancer 1.43E-06 8.24E-05 1.44 313 KEGG Neuroactive ligand receptor interaction 6.39E-06 0.00028 1.44 249 KEGG Focal adhesion 7.16E-05 0.0015 1.44 191 KEGG Adherens junction 8.97E-05 0.0017 1.64 67 KEGG Calcium signaling pathway 0.00025 0.0039 1.40 166 KEGG Leukocyte transendothelial migration 0.0019 0.019 1.43 108 KEGG ECM receptor interaction 0.0019 0.019 1.49 83 KEGG Gap junction 0.0063 0.036 1.40 83 Hypermethylated and positive enriched in PC pval padj NES size KEGG Axon guidance 1.60E-06 0.00028 1.53 122 KEGG Calcium signaling pathway 3.22E-06 0.00028 1.44 166 KEGG Neuroactive ligand receptor interaction 0.00010 0.0045 1.31 249 KEGG Regulation of actin cytoskeleton 0.00013 0.0045 1.34 197 KEGG MAPK signaling pathway 0.00030 0.0066 1.29 251 KEGG Cell adhesion molecules cams 0.0018 0.035 1.33 122 KEGG ECM receptor interaction 0.0034 0.049 1.36 83 KEGG Wnt signaling pathway 0.0052 0.064 1.27 145 KEGG Hedgehog signaling pathway 0.0057 0.064 1.40 55 KEGG Leukocyte transendothelial migration 0.011 0.10 1.28 108 © The Author(s) 2024.

In the original publication of this article, upper and lower part of Table 2 was incorrectly formatted. The incorrect and correct version of Table 2 are shown in this correction article. The original article has been corrected. Relevant significantly enriched gene sets associated with the DMPs that differed between aggressive and metastatic PitNETs in the first surgery specimens (upper table) and in the entire cohort (lower table) Hypermethylated and positive enriched in PC pval padj NES size KEGG cell adhesion molecules CAMS 6.26E-07 5.63E-05 1.65 122 KEGG axon guidance 6.51E-07 5.63E-05 1.65 122 KEGG pathways in cancer 1.43E-06 8.24E-05 1.44 313 KEGG neuroactive ligand receptor interaction 6.39E-06 0.00028 1.44 249 KEGG focal adhesion 7.16E-05 0.0015 1.44 191 KEGG adherens junction 8.97E-05 0.0017 1.64 67 KEGG calcium signaling pathway 0.00025 0.0039 1.40 166 KEGG leukocyte transendothelial migration 0.0019 0.019 1.43 108 KEGG ECM receptor interaction 0.0019 0.019 1.49 83 KEGG gap junction 0.0063 0.036 1.40 83 KEGG axon guidance 1.60E-06 0.00028 1.53 122 KEGG calcium signaling pathway 3.22E-06 0.00028 1.44 166 KEGG neuroactive ligand receptor interaction 0.00010 0.0045 1.31 249 KEGG regulation of actin cytoskeleton 0.00013 0.0045 1.34 197 KEGG MAPK signaling pathway 0.00030 0.0066 1.29 251 KEGG cell adhesion molecules cams 0.0018 0.035 1.33 122 KEGG ECM receptor interaction 0.0034 0.049 1.36 83 KEGG Wnt signaling pathway 0.0052 0.064 1.27 145 KEGG Hedgehog signaling pathway 0.0057 0.064 1.40 55 KEGG leukocyte transendothelial migration 0.011 0.10 1.28 108 Relevant significantly enriched gene sets associated with the DMPs that differed between aggressive and metastatic PitNETs in the first surgery specimens (upper part of the table) and in the entire cohort (lower part of the table) Hypermethylated and positive enriched in PC pval padj NES size KEGG Cell adhesion molecules CAMS 6.26E-07 5.63E-05 1.65 122 KEGG Axon guidance 6.51E-07 5.63E-05 1.65 122 KEGG Pathways in cancer 1.43E-06 8.24E-05 1.44 313 KEGG Neuroactive ligand receptor interaction 6.39E-06 0.00028 1.44 249 KEGG Focal adhesion 7.16E-05 0.0015 1.44 191 KEGG Adherens junction 8.97E-05 0.0017 1.64 67 KEGG Calcium signaling pathway 0.00025 0.0039 1.40 166 KEGG Leukocyte transendothelial migration 0.0019 0.019 1.43 108 KEGG ECM receptor interaction 0.0019 0.019 1.49 83 KEGG Gap junction 0.0063 0.036 1.40 83 Hypermethylated and positive enriched in PC pval padj NES size KEGG Axon guidance 1.60E-06 0.00028 1.53 122 KEGG Calcium signaling pathway 3.22E-06 0.00028 1.44 166 KEGG Neuroactive ligand receptor interaction 0.00010 0.0045 1.31 249 KEGG Regulation of actin cytoskeleton 0.00013 0.0045 1.34 197 KEGG MAPK signaling pathway 0.00030 0.0066 1.29 251 KEGG Cell adhesion molecules cams 0.0018 0.035 1.33 122 KEGG ECM receptor interaction 0.0034 0.049 1.36 83 KEGG Wnt signaling pathway 0.0052 0.064 1.27 145 KEGG Hedgehog signaling pathway 0.0057 0.064 1.40 55 KEGG Leukocyte transendothelial migration 0.011 0.10 1.28 108 © The Author(s) 2024.

Context: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. Objective: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. Design: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. Results: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. Conclusion: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors. © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.

Context: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. Objective: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. Design: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. Results: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. Conclusion: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors. © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.

Background Actinic keratosis (AK) and Bowen's disease (squamous cell carcinoma in situ, SCCIS) are pre-invasive stages in the development of squamous cell carcinoma (SCC). Methods Immunohistochemical study of cyclin D1, cyclin E, p16INK4a and p21Cip1/Waf1 in AK (53 cases), SCCIS (16 cases) and SCC (40 cases), in relation to the type of the lesion and SCC prognostic parameters (grade, diameter and thickness). Results Diffuse cyclin D1 distribution was more frequent in SCCIS and SCC than in AK (p = 0.03) and similar pattern was observed for p16INK4a. For cyclin E, central distribution dominated in SCC compared with the AK (p = 0.001) and SCCIS (p = 0.03). p21Cip1/Waf1 displayed suprabasal distribution more frequently in AK than in SCCIS (p = 0.001) and SCC (p = 0.0004). Semiquantitative assessment showed more positive cells in AK (p = 0.04) and SCCIS (p = 0.04) than in SCC for cyclin E. SCC with diameter over 20 mm and those thicker than 6 mm revealed higher labeling index with p16INK4a and p21Cip1/Waf1, respectively. Conclusions Our results suggest different alterations for p16INK4a and p21Cip1/Waf1 in AK, SCCIS and SCC. Immunostaining distribution showed closer correlation with the type of the lesion, whereas percentage of positive cells displayed better association with the SCC prognostic parameters. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Introduction: Pituitary neuroendocrine tumours (PitNETs), traditionally designated as pituitary adenomas, show relatively 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. (Endokrynol Pol 2021; 72 (2): 91-96). © 2021 Via Medica. All rights reserved.

Introduction: Pituitary neuroendocrine tumours (PitNETs), traditionally designated as pituitary adenomas, show relatively 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. (Endokrynol Pol 2021; 72 (2): 91-96). © 2021 Via Medica. All rights reserved.

Aggressive pituitary neuroendocrine tumors (PitNETs)/adenomas are characterized by progressive growth despite surgery and all standard medical therapies and radiotherapy. A subset will metastasize to the brain and/or distant locations and are termed metastatic PitNETs (pituitary carcinomas). Studies of potential prognostic markers have been limited due to the rarity of these tumors. A few recurrent somatic mutations have been identified, and epigenetic alterations and chromosomal rearrangements have not been explored in larger cohorts of aggressive and metastatic PitNETs. In this study, we performed genome-wide methylation analysis, including copy-number variation (CNV) calculations, on tumor tissue specimens from a large international cohort of 64 patients with aggressive (48) and metastatic (16) pituitary tumors. Twelve patients with non-invasive pituitary tumors (Knosp 0–2) exhibiting an indolent course over a 5 year follow-up served as controls. In an unsupervised hierarchical cluster analysis, aggressive/metastatic PitNETs clustered separately from benign pituitary tumors, and, when only specimens from the first surgery were analyzed, three separate clusters were identified: aggressive, metastatic, and benign PitNETs. Numerous CNV events affecting chromosomal arms and whole chromosomes were frequent in aggressive and metastatic, whereas benign tumors had normal chromosomal copy numbers with only few alterations. Genome-wide methylation analysis revealed different CNV profiles and a clear separation between aggressive/metastatic and benign pituitary tumors, potentially providing biomarkers for identification of these tumors with a worse prognosis at the time of first surgery. The data may refine follow-up routines and contribute to the timely introduction of adjuvant therapy in patients harboring, or at risk of developing, aggressive or metastatic pituitary tumors. © The Author(s) 2024.

Aggressive pituitary neuroendocrine tumors (PitNETs)/adenomas are characterized by progressive growth despite surgery and all standard medical therapies and radiotherapy. A subset will metastasize to the brain and/or distant locations and are termed metastatic PitNETs (pituitary carcinomas). Studies of potential prognostic markers have been limited due to the rarity of these tumors. A few recurrent somatic mutations have been identified, and epigenetic alterations and chromosomal rearrangements have not been explored in larger cohorts of aggressive and metastatic PitNETs. In this study, we performed genome-wide methylation analysis, including copy-number variation (CNV) calculations, on tumor tissue specimens from a large international cohort of 64 patients with aggressive (48) and metastatic (16) pituitary tumors. Twelve patients with non-invasive pituitary tumors (Knosp 0–2) exhibiting an indolent course over a 5 year follow-up served as controls. In an unsupervised hierarchical cluster analysis, aggressive/metastatic PitNETs clustered separately from benign pituitary tumors, and, when only specimens from the first surgery were analyzed, three separate clusters were identified: aggressive, metastatic, and benign PitNETs. Numerous CNV events affecting chromosomal arms and whole chromosomes were frequent in aggressive and metastatic, whereas benign tumors had normal chromosomal copy numbers with only few alterations. Genome-wide methylation analysis revealed different CNV profiles and a clear separation between aggressive/metastatic and benign pituitary tumors, potentially providing biomarkers for identification of these tumors with a worse prognosis at the time of first surgery. The data may refine follow-up routines and contribute to the timely introduction of adjuvant therapy in patients harboring, or at risk of developing, aggressive or metastatic pituitary tumors. © The Author(s) 2024.

Non-functioning pituitary neuroendocrine tumors do not cause endocrine symptoms related to hypersecretion of adenohypophyseal hormones and are clinically characterized by symptoms due to growing sellar tumor mass. Histopathological classification of this tumor group has always been challenging due to their heterogeneity, limited knowledge on their biology, and diverse methodological problems. We have searched PubMed database for data related to the histopathological classification of non-functioning pituitary tumors and methods for its application. Principles of the classification and grading presented in the recently released 4th edition of the World Health Organization classification of endocrine tumors have been summarized. Based on the expression of anterior pituitary hormones and pituitary specific transcription factors, gonadotroph tumors dominate within the group of clinically non-functioning tumors, followed by corticotroph type; however, other less common types of the non-functioning tumors can be identified. Assessment of tumor cell proliferation is important to identify “high-risk adenomas.” A few subtypes of non-functioning tumors belong to the category of potentially aggressive tumors, independent of the cell proliferation rate. Here, we present up to date criteria for the classification of clinically non-functioning pituitary tumors, offer a diagnostic approach for the routine clinical use, and emphasize a need for inclusion of prognostic and predictive markers in the classification. © 2017, The Author(s).

Non-functioning pituitary neuroendocrine tumors do not cause endocrine symptoms related to hypersecretion of adenohypophyseal hormones and are clinically characterized by symptoms due to growing sellar tumor mass. Histopathological classification of this tumor group has always been challenging due to their heterogeneity, limited knowledge on their biology, and diverse methodological problems. We have searched PubMed database for data related to the histopathological classification of non-functioning pituitary tumors and methods for its application. Principles of the classification and grading presented in the recently released 4th edition of the World Health Organization classification of endocrine tumors have been summarized. Based on the expression of anterior pituitary hormones and pituitary specific transcription factors, gonadotroph tumors dominate within the group of clinically non-functioning tumors, followed by corticotroph type; however, other less common types of the non-functioning tumors can be identified. Assessment of tumor cell proliferation is important to identify “high-risk adenomas.” A few subtypes of non-functioning tumors belong to the category of potentially aggressive tumors, independent of the cell proliferation rate. Here, we present up to date criteria for the classification of clinically non-functioning pituitary tumors, offer a diagnostic approach for the routine clinical use, and emphasize a need for inclusion of prognostic and predictive markers in the classification. © 2017, The Author(s).

The anatomical and histological complexity of the parasellar region as well as the presence of embryonic remnants determine the huge diversity of parasellar neoplasms. Some of them are only located in the parasellar region, whereas others can occur elsewhere, within or outside the central nervous system. Their spectrum ranges from histologically benign and low-grade malignant to high-grade malignant tumours. Although rare, metastases can pose differential diagnostic dilemmas. The severity of the clinical picture, the challenges of surgery and the risk of adverse sequelae related to surgery or radiotherapy make parasellar tumours interesting entities for the clinicians irrespective of their histological malignancy grade. Due to the different cell origins of parasellar tumours, the World Health Organization classification system does not categorise them as a distinct group. Detailed criteria for classification and malignancy grading are presented in the classification systems covering central nervous system tumours, haematological malignancies and tumours of the soft tissue and bone. In the last few years, molecular genetic features have been integrated into the diagnosis of several types of the parasellar tumours enhancing diagnostic accuracy and providing information of the value for targeting therapies. In this review, we will present histopathological and molecular genetic features, updated classification criteria and recent advances in the diagnostics and rationale for novel pharmacological therapies of selected types of parasellar neoplasms. © 2020 S. Karger AG, Basel. All rights reserved.

The anatomical and histological complexity of the parasellar region as well as the presence of embryonic remnants determine the huge diversity of parasellar neoplasms. Some of them are only located in the parasellar region, whereas others can occur elsewhere, within or outside the central nervous system. Their spectrum ranges from histologically benign and low-grade malignant to high-grade malignant tumours. Although rare, metastases can pose differential diagnostic dilemmas. The severity of the clinical picture, the challenges of surgery and the risk of adverse sequelae related to surgery or radiotherapy make parasellar tumours interesting entities for the clinicians irrespective of their histological malignancy grade. Due to the different cell origins of parasellar tumours, the World Health Organization classification system does not categorise them as a distinct group. Detailed criteria for classification and malignancy grading are presented in the classification systems covering central nervous system tumours, haematological malignancies and tumours of the soft tissue and bone. In the last few years, molecular genetic features have been integrated into the diagnosis of several types of the parasellar tumours enhancing diagnostic accuracy and providing information of the value for targeting therapies. In this review, we will present histopathological and molecular genetic features, updated classification criteria and recent advances in the diagnostics and rationale for novel pharmacological therapies of selected types of parasellar neoplasms. © 2020 S. Karger AG, Basel. All rights reserved.

Twenty years after the first description of combined hypopituitarism (CPHD) caused by PROP1 mutations, the phenotype of affected subjects is still challenging for clinicians. These patients suffer from pituitary hormone deficits ranging from IGHD to panhypopituitarism. ACTH deficiency usually develops later in life. Pituitary size is variable. PROP1 mutation is the most frequent in familial congenital hypopituitarism (CH). Reports on initiation of hormonal replacement including growth hormone (GH) in adults with CH are scarce. We identified 5 adult siblings with CPHD due to PROP1 mutation (301-302delAG), aged 36–51 years (4 females), never treated for hormone deficiencies. They presented with short stature (SD from − 3.7 to − 4.7), infantile sexual characteristic, moderate abdominal obesity and low bone mineral density in 3 of them. Complete hypopituituitarism was confirmed in three siblings, while two remaining demonstrated GH, TSH, FSH and LH deficiencies. Required hormonal replacement including rhGH was initiated in all patients. After several months necessity for hydrocortisone replacement developed in all patients. After 2 years of continual replacement therapy, BMD and body composition (measured by DXA—dual X-ray absorptiometry) improved in all subjects, most prominently in two younger females and the male sibling. Besides rhGH therapy, these three patients have received sex hormones contributing to the favorable effect. The male sibling was diagnosed with brain glioblastoma two years following complete hormonal replacement. This report provides important experience regarding hormonal replacement, particularly rhGH treatment, in adults with long-term untreated CH. Beneficial effect of such therapy are widely acknowledged, yet these subjects could be susceptible to certain risks of hormonal treatment initiated in adulthood. Careful and continual clinical follow-up is thus strongly advised. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Twenty years after the first description of combined hypopituitarism (CPHD) caused by PROP1 mutations, the phenotype of affected subjects is still challenging for clinicians. These patients suffer from pituitary hormone deficits ranging from IGHD to panhypopituitarism. ACTH deficiency usually develops later in life. Pituitary size is variable. PROP1 mutation is the most frequent in familial congenital hypopituitarism (CH). Reports on initiation of hormonal replacement including growth hormone (GH) in adults with CH are scarce. We identified 5 adult siblings with CPHD due to PROP1 mutation (301-302delAG), aged 36–51 years (4 females), never treated for hormone deficiencies. They presented with short stature (SD from − 3.7 to − 4.7), infantile sexual characteristic, moderate abdominal obesity and low bone mineral density in 3 of them. Complete hypopituituitarism was confirmed in three siblings, while two remaining demonstrated GH, TSH, FSH and LH deficiencies. Required hormonal replacement including rhGH was initiated in all patients. After several months necessity for hydrocortisone replacement developed in all patients. After 2 years of continual replacement therapy, BMD and body composition (measured by DXA—dual X-ray absorptiometry) improved in all subjects, most prominently in two younger females and the male sibling. Besides rhGH therapy, these three patients have received sex hormones contributing to the favorable effect. The male sibling was diagnosed with brain glioblastoma two years following complete hormonal replacement. This report provides important experience regarding hormonal replacement, particularly rhGH treatment, in adults with long-term untreated CH. Beneficial effect of such therapy are widely acknowledged, yet these subjects could be susceptible to certain risks of hormonal treatment initiated in adulthood. Careful and continual clinical follow-up is thus strongly advised. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.