Emilija Manojlovic-Gacic

Histopathological classification of non-functioning pituitary neuroendocrine tumors

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.

Expression of G1/S‐cyclins and cyclin‐dependent kinase inhibitors in actinic keratosis and squamous cell carcinoma

Actinic keratosis (AK) and Bowens disease (squamous cell carcinoma in situ, SCCIS) are pre‐invasive stages in the development of squamous cell carcinoma (SCC).

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 β-galactosidase (SA-β-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-β-GAL was overexpressed in the pituitary adenomas, compared to the normal pituitaries. Growth hormone (GH) producing adenomas showed the strongest SA-β-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-β-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.

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.

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.

Clinical case seminar: Familial intracranial germinoma

BACKGROUND Intracranial germinomas (ICG) are uncommon brain neoplasms with extremely rare familial occurance. Since ICG invades hypothalamus and/or pituitary, the endocrine dysfunction is one of the common determinants of these tumors. We presented two brothers with the history of ICG. Patient 1 is a 25-year-old male who had been suffering from the weakness of the right half of his body at the age of 18. Cranial MRI revealed mass lesion in the left thalamus. He underwent neurosurgery, tumor was removed completely. Histopathological (HP) and immunohistochemical analyses verified the diagnosis of pure germinoma. He experienced complete remission of the tumor after a radiation therapy. At the age of 22 the diagnosis of isolated growth hormone deficiency (IGHD) was established and GH replacement was initiated. Patient 2 is a 20-year old boy who was presented with diabetes insipidus at the age of 12. MRI detected tumor in the third ventricle and pineal region. After the endoscopic tumor biopsy the HP diagnosis was pure germinoma. He received chemotherapy followed by radiotherapy, and treated with GH during childhood. At the age of 18 GH replacement was reintroduced. A six month follow-up during the next two years in both brothers demonstrated the IGF1 normalization with no MRI signs of tumor 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 of Japan. They are treated successfully with GH therapy in adult period. < /p > < p >.

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 tumours 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.

Contents Vol. 1, 2012

Maria Alevizaki, Athens Ana Aranda, Madrid Rebecca Bahn, Rochester, Minn. Paul Banga, London Luigi Bartalena, Varese Bernadette Biondi, Naples Anita Boelen, Amsterdam Georg Brabant, Lubeck Henning Dralle, Halle Murat Erdogan, Ankara Creswell J. Eastman, Westmead, N.S.W. Valentin Fadeyev, Moscow Ulla Feldt-Rasmussen, Copenhagen Laszlo Hegedus, Odense George J. Kahaly, Mainz Rui Maciel, São Paolo Ana Luiza Maia, Porto Alegre Jens Mittag, Stockholm Ralf Paschke, Leipzig Simon Pearce, Newcastle-upon-Tyne Robin Peeters, Rotterdam Kris Poppe, Bruxelles Samuel Refetoff , Chicago, Ill. Jacques Samarut, Lyon Pilar Santisteban, Madrid YoungKee Shong, Seoul Jan Smit, Leiden Mark Vanderpump, London Th eo Visser, Rotterdam Paolo Vitti, Pisa Graham Williams, London Shunichi Yamashita, Nagasaki Mariastella Zannini, Naples Luca Persani, Milan (Translational Th yroidology)