Category Archives: Cranial Base

Update: GH secreting pituitary adenoma

Growth hormone-secreting functioning pituitary adenoma (GHPA) is a rare, chronic, systemic disease that is associated with premature death and significant morbidity 1).

75 % are > 10 mm at time of diagnosis.

Epidemiology

An increased rate of acromegaly was reported in industrialized areas, suggesting an involvement of environmental pollutants in the pathogenesis and behavior of GH secreting pituitary adenoma2).

Etiology

The aim of a study was to evaluate the effects of some widely diffused pollutants (i.e. benzene, BZ; bis(2-ethylhexyl) phthalate, DEHP and polychlorinated biphenyls, PCB) on growth hormone secretion, the somatostatin and estrogenic pathways, viability and proliferation of rat GH-producing pituitary adenoma (GH3) cells. All the pollutants induced a statistically significant increase in GH secretion and interfered with cell signaling. They all modulated the expression of SSTR2 and ZAC1, involved in the somatostatin signaling, and the expression of the transcription factor FOXA1, involved in the estrogen receptor signaling. Moreover, all the pollutants increased the expression of the CYP1A1, suggesting AHR pathway activation. None of the pollutants impacted on cell proliferation or viability. Present data demonstrate that exposure to different pollutants, used at in vivo relevant concentrations, plays an important role in the behavior of GH3 pituitary adenoma cells, by increasing GH secretion and modulating several cellular signaling pathways. These observations support a possible influence of different pollutants in vivo on the GH-adenoma aggressiveness and biological behavior 3).

Types

Giant GH-secreting adenomas are invasive, uncontrolled by surgery, and respond poorly to medical treatment. Aggressive multimodal therapy is critical for their management, enhancing control rate and biochemical remission 4).


Co-secretion of growth hormone (GH) and prolactin (PRL) from a single pituitary adenoma is common. In fact, up to 25% of patients with acromegaly may have PRL co-secretion. The prevalence of acromegaly among patients with a newly diagnosed prolactinoma is unknown. Given the possibility of mixed GH and PRL co-secretion, the current recommendation is to obtain an insulin-like growth factor-1 (IGF-1) in patients with prolactinoma at the initial diagnosis. Long-term follow-up of IGF-1 is not routinely done 5).

Clinical Features

Excessive growth hormone (GH) is usually secreted by GH-secreting pituitary adenomas and causes gigantism in juveniles or acromegaly in adults.

Diagnosis

It is related to high levels of growth hormone (GH) and insulin-like growth factor-I (IGF-1).

MRI

The enhancement was significantly lower in GH secreting pituitary adenoma than in non-secreting ones. 6).

T2 weighted image differentiates GH secreting pituitary adenomas into subgroups with particular behaviors. This raises the question of whether T2-weighted signal could represent a factor in the classification of acromegaly in future studies 7).

In patients with acromegalyT2 weighted image signal intensity at diagnosis correlates with histological features and predicts biochemical outcome of first-line somatostatin analogues (SA) treatment 8).

Biomarkers

Each of the biomarkers, Ki-67 and p53, along with patient’s age and mixed GH-prolactin secretion showed a kind of correlation with each of aspects of the clinical, hormonal and radiologic outcome of GH-secreting pituitary adenomas 9).

Treatment

see Growth hormone secreting pituitary adenoma treatment

Surgery is the first-line therapy.

Surgery

The resection via a transsphenoidal approach is able to induce a long-term remission of acromegaly, with low risk of recurrence and complications. Endoscopic endonasal transsphenoidal approach is more suitable than microscopic technique in macroadenomas and adenomas with suprasellar extension 10).

Medical therapy

The cost of treatment including medications and the possibility of major side effects represent important limitations of the medical therapy 11) 12).

The most widely used criteria for neurosurgical outcome assessment were combined measurements of IGF-1 and GH levels after oral glucose tolerance test (OGTT) 3 months after surgery. Ninety-eight percent of respondents stated that primary treatment with somatostatin receptor ligands (SRLs) was indicated at least sometime during the management of acromegaly patients. In nearly all centers (96%), the use of pegvisomant monotherapy was restricted to patients who had failed to achieve biochemical control with SRL therapy. The observation that most centers followed consensus statement recommendations encourages the future utility of these workshops aimed to create uniform management standards for acromegaly 13)

Current pharmacotherapy includes somatostatin analogs (SAs) and GH receptor antagonist; the former consists of lanreotide Autogel (ATG) and octreotide long-acting release (LAR), and the latter refers to pegvisomant. As primary medical therapy, lanreotide ATG and octreotide LAR can be supplied in a long-lasting formulation to achieve biochemical control of GH and IGF-1 by subcutaneous injection every 4-6 weeks. Lanreotide ATG and octreotide LAR provide an effective medical treatment, whether as a primary or secondary therapy, for the treatment of GH-secreting pituitary adenoma; however, to maximize benefits with the least cost, several points should be emphasized before the application of SAs. A comprehensive assessment, especially of the observation of clinical predictors and preselection of SA treatment, should be completed in advance. A treatment process lasting at least 3 months should be implemented to achieve a long-term stable blood concentration. More satisfactory surgical outcomes for noninvasive macroadenomas treated with presurgical SA may be achieved, although controversy of such adjuvant therapy exists. Combination of SA and pegvisomant or cabergoline shows advantages in some specific cases. Thus, an individual treatment program should be established for each patient under a full evaluation of the risks and benefits 14).

Somatostatin treatment can induce extensive fibrosis in GH secreting pituitary adenoma 15).

Outcome

The standardised mortality index (the ratio of observed mortality in the acromegalic population to expected mortality in the general population) ranged from 1.2 to 3.3. If left untreated, patients with acromegaly can die approximately 10 years earlier than the healthy subjects. According to prior studies, approximately 60, 25 and 15% of the patients die from cardiovascular disease, respiratory complications and cancer, respectively 16)17).

Control of serum GH and insulin-like growth factor (IGF) 1 hypersecretion by surgery or pharmacotherapy can decrease morbidity.

Remission rates for micro- and macroadenomas were 81.8% and 45.8%, respectively. Patients of older age, with a smaller tumor, lower Knosp grade, lower preoperative GH, and insulinlike growth factor 1 levels were more likely to achieve remission. Remission rate decreased significantly with repeat surgeries. Those patients with adenomas that stained positive for somatostatin receptor subtype 2A were less likely to experience tumor recurrence and more likely to respond to medical treatment with persistent or elevated GH hypersecretion 18).

A retrospective review of 53 patients who had follow up endocrinologic data at least 3 months post-surgery was performed among patients who were treated by EEA between 1998 and 2012. Data were analyzed for remission using GH and IGF-I levels based on 2010 consensus criteria. We also analyzed the outcomes using 2000 consensus criteria for ease in comparison to prior studies of outcomes of surgery for acromegaly. In this series of mostly large (88.2% macroadenomas), invasive (46.9% Hardy-Wilson C, D, E) adenomas, there were 27 patients (50.9%) who achieved remission after EEA only. For patients who had no remission with EEA alone, RS and/or medical therapy were used and 37 patients (69.8 %) achieved remission overall. Statistical analysis showed larger tumor size, Hardy Stages C, D, E and Knosp Scores 3, 4 to be predictive against remission for EEA only and EEA with other modalities. The volume of residual tumor after EEA was not found to be predictive of remission with additional therapies. We used stringent consensus criteria from 2010 in a series which included a high proportion of invasive GH secreting adenomas to show that EEA alone or combined with other modalities results in comparable remission rates to earlier studies which used less strict criteria, while retaining low complication rates 19).

Each of the biomarkers, Ki-67 and p53, along with patient’s age and mixed GH-prolactin secretion showed a kind of correlation with each of aspects of the clinical, hormonal and radiologic outcome of GH-secreting pituitary adenomas in the series of Alimohamadi et al. 20).

Case reports

2015

A 37-year-old woman has presented with complaints of headacheamenorrhea and acromegaly.

Her laboratory studies showed markedly elevated levels of Insulin like Growth Factor 1 (IGF-1), and low levels of follicle stimulating hormone and luteinizing hormone. Computerized tomography has revealed a pituitary tumor without extra-sellar extension. The tumor has completely excised via Endoscopic transsphenoidal approach. Histologically, the tumor has diagnosed as a pituitary adenoma with GH positive cells. The serum IGF1 levels have gradually decreased to the normal range and the patient was symptom free for three and a half years when she has returned with complaint of visual impairment. The brain MRI that time has shown a supra-sellar mass growing independently into the remaining sellar part. Subsequently, surgical operation has performed via trans-nasal endoscopic approach. Histopathological and immunohistochemistry examination have revealed a rare case of growth hormone producing pituitary adenoma with brain invasion and lymphocytic infiltration.

The aim of this publication was to present a rare case of growth hormone producing pituitary adenoma with brain invasion and lymphocytic infiltration 21).

1)

Ayuk J, Clayton RN, Holder G, Sheppard MC, Stewart PM, Bates AS. Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly. J Clin Endocrinol Metab. 2004;89:1613–7.
2) , 3)

Fortunati N, Guaraldi F, Zunino V, Penner F, D’Angelo V, Zenga F, Pecori Giraldi F, Catalano MG, Arvat E. Effects of environmental pollutants on signaling pathways in rat pituitary GH3 adenoma cells. Environ Res. 2017 Jul 18;158:660-668. doi: 10.1016/j.envres.2017.07.015. [Epub ahead of print] PubMed PMID: 28732322.
4)

Shimon I, Jallad RS, Fleseriu M, Yedinak CG, Greenman Y, Bronstein MD. Giant GH-secreting pituitary adenomas: management of rare and aggressive pituitary tumors. Eur J Endocrinol. 2015 Jun;172(6):707-713. Epub 2015 Mar 19. PubMed PMID: 25792375.
5)

Manuylova E, Calvi LM, Hastings C, Vates GE, Johnson MD, Cave WT Jr, Shafiq I. Late presentation of acromegaly in medically controlled prolactinoma patients. Endocrinol Diabetes Metab Case Rep. 2016;2016. pii: 16-0069. PubMed PMID: 27855229.
6)

Lundin P, Bergström K. Gd-DTPA-enhanced MR imaging of pituitary macroadenomas. Acta Radiol. 1992 Jul;33(4):323-32. PubMed PMID: 1633042.
7)

Potorac I, Petrossians P, Daly AF, Schillo F, Ben Slama C, Nagi S, Sahnoun Fathallah M, Brue T, Girard N, Chanson P, Nasser G, Caron P, Bonneville F, Ravérot G, Lapras V, Cotton F, Delemer B, Higel B, Boulin A, Gaillard S, Luca F, Goichot B, Dietemann J, Beckers A, Bonneville J. Pituitary MRI characteristics in 297 acromegaly patients based on T2-weighted sequences. Endocr Relat Cancer. 2015 Jan 2. pii: ERC-14-0305. [Epub ahead of print] PubMed PMID: 25556181.
8)

Heck A, Ringstad G, Fougner SL, Casar-Borota O, Nome T, Ramm-Pettersen J, Bollerslev J. Intensity of pituitary adenoma on T2-weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly. Clin Endocrinol (Oxf). 2012 Jul;77(1):72-8. doi: 10.1111/j.1365-2265.2011.04286.x. PubMed PMID: 22066905.
9)

Alimohamadi M, Ownagh V, Mahouzi L, Ostovar A, Abbassioun K, Amirjmshidi A. The impact of immunohistochemical markers of Ki-67 and p53 on the long-term outcome of growth hormone-secreting pituitary adenomas: A cohort study. Asian J Neurosurg. 2014 Jul-Sep;9(3):130-6. doi: 10.4103/1793-5482.142732. PubMed PMID: 25685203; PubMed Central PMCID: PMC4323896.
10)

Lenzi J, Lapadula G, D’amico T, Delfinis CP, Iuorio R, Caporlingua F, Mecca N, Mercuri V, Bassotti G, Rillo M, Santoro F, Tamburrano G, Santoro A, Gargiulo P. Evaluation of trans-sphenoidal surgery in pituitary GH-secreting micro- and macroadenomas: a comparison between microsurgical and endoscopic approach. J Neurosurg Sci. 2015 Mar;59(1):11-8. PubMed PMID: 25658052.
11) , 16)

Chanson P, Salenave S, Kamenicky P, Cazabat L, Young J. Pituitary tumours: Acromegaly. Best Pract Res Clin Endocrinol Metab. 2009;23:555–74.
12)

Gondim JA, Ferraz T, Mota I, Studart D, Almeida JP, Gomes E, et al. Outcome of surgical intrasellar growth hormone tumor performed by a pituitary specialist surgeon in a developing country. Surg Neurol. 2009;72:15–9.
13)

Giustina A, Bronstein MD, Casanueva FF, Chanson P, Ghigo E, Ho KK, Klibanski A, Lamberts S, Trainer P, Melmed S. Current management practices for acromegaly: an international survey. Pituitary. 2011 Jun;14(2):125-33. doi: 10.1007/s11102-010-0269-9. PubMed PMID: 21063787.
14)

Wang JW, Li Y, Mao ZG, Hu B, Jiang XB, Song BB, Wang X, Zhu YH, Wang HJ. Clinical applications of somatostatin analogs for growth hormone-secreting pituitary adenomas. Patient Prefer Adherence. 2014 Jan 6;8:43-51. Review. PubMed PMID: 24421637.
15)

Kerschbaumer J, Pinggera D, Moser P, Hofmann A, Thomé C, Freyschlag CF. Somatostatin treatment can induce extensive fibrosis in growth hormone-producing adenoma. Acta Neurochir (Wien). 2016 Mar;158(3):441-3. doi: 10.1007/s00701-016-2714-7. Epub 2016 Jan 23. PubMed PMID: 26801514.
17)

Holdaway IM, Rajasoorya C. Epidemiology of acromegaly. Pituitary. 1999;2:29–41.
18)

Sun H, Brzana J, Yedinak CG, Gultekin SH, Delashaw JB, Fleseriu M. Factors associated with biochemical remission after microscopic transsphenoidal surgery for acromegaly. J Neurol Surg B Skull Base. 2014 Feb;75(1):47-52. doi: 10.1055/s-0033-1354578. Epub 2013 Sep 9. PubMed PMID: 24498589; PubMed Central PMCID: PMC3912146.
19)

Shin SS, Tormenti MJ, Paluzzi A, Rothfus WE, Chang YF, Zainah H, Fernandez-Miranda JC, Snyderman CH, Challinor SM, Gardner PA. Endoscopic endonasal approach for growth hormone secreting pituitary adenomas: outcomes in 53 patients using 2010 consensus criteria for remission. Pituitary. 2013 Dec;16(4):435-44. doi: 10.1007/s11102-012-0440-6. PubMed PMID: 23179961.
20)

Alimohamadi M, Ownagh V, Mahouzi L, Ostovar A, Abbassioun K, Amirjmshidi A. The impact of immunohistochemical markers of Ki-67 and p53 on the long-term outcome of growth hormone-secreting pituitary adenomas: A cohort study. Asian J Neurosurg. 2014 Jul-Sep;9(3):130-6. doi: 10.4103/1793-5482.142732. PubMed PMID: 25685203; PubMed Central PMCID: PMC4323896.
21)

Bidari-Zerehpoosh F, Sharifi G, Novin K, Mortazavi N. Invasive Growth Hormone Producing Pituitary Adenoma With Lymphocytic Infiltration: A Case Report and Literature Review. Iran J Cancer Prev. 2015 Dec;8(6):e3504. Epub 2015 Dec 23. PubMed PMID: 26855718.

Samuel Thomas von Sömmerring

Samuel Thomas von Sömmerring (28 January 1755 – 2 March 1830) was a German physician, anatomist, anthropologist, paleontologist and inventor. Sömmerring discovered the macula in the retina of the human eye. His investigations on the brain and the nervous system, on the sensory organs, on the embryo and its malformations, on the structure of the lungs, etc., made him one of the most important German anatomists.

Sömmerring was born in Thorn, Royal Prussia (Toruń, Poland) as the ninth child of the physician Johann Thomas Sömmerring. In 1774 he completed his education in Thorn and began to study medicine at the University of Göttingen. He visited Petrus Camper lecturing at the University in Franeker. He became a professor of anatomy at the Collegium Carolinum (housed in the Ottoneum, now a Natural History Museum) in Kassel and, beginning in 1784, at the University of Mainz. There he was for five years the dean of the medical faculty. Due to the fact that Mainz became part of the French Republic under the French Directory, Sömmerring opened up a practice in Frankfurt in 1795. As one of his many important enterprises, Sömmerring introduced against many resistances the vaccination against smallpox and became one of the first members of the Senckenbergische Naturforschende Gesellschaft and was nominated as counselor. He received offers of employment by the University of Jena and the University of St. Petersburg, but accepted in 1804 an invitation from the Academy of Science of Bavaria, in Munich. In this city, he became counselor to the court and was led into the Bavarian nobility.

He published many writings in the fields of medicine, anatomy and neuroanatomy, anthropology, paleontology, astronomy and philosophy. Among other things he wrote about fossil crocodiles and in 1812 he described Ornithocephalus antiquus now known as Pterodactylus. He was also the first to accurately draw a representation of the female skeleton structure.

In addition, Sömmerring was a very creative inventor, having designed a telescope for astronomical observations and an electrical telegraph in 1809. He worked on the refinement of wines, sunspots and many diverse other things. In 1811 he developed the first telegraphic system in Bavaria, which is housed today in the German Museum of Science in Munich. In 1823, he was elected a foreign member of the Royal Swedish Academy of Sciences.

Sömmering was married to Margarethe Elizabeth Grunelius (deceased 1802), and had a son, Dietmar William, and a daughter, Susanne Katharina. Due to bad weather, Sömmering left Munich in 1820 and returned to Frankfurt, where he died in 1830. He is buried at the city’s main cemetery 1) 2).


When Sömmerring was 23 years old he described the organization of the cranial nerves as part of this doctoral work: its study is valid until today.

The enumeration of the cranial nerves is traced briefly from Galen’s seven to Willis’ ten and to von Sömmerring’s twelve. The system of von Sömmerring, which has been followed for some 200 years, is a useful convention, although it is merely one of several possibilities. The naming of the cranial nerves was standardized nearly 100 years ago 3).

Virtually all contemporary atlases show the abducens, facial, and vestibulocochlear nerves (CNs VI–VIII) all emerging from the pontomedullary groove, as originally depicted by Soemmerring in 1778.

Direct observation at microsurgery of the cerebellopontine angle reveals that CN VII emerges caudal to the CN VIII root from the lower lateral pons rather than the pontomedullary groove. Additionally, the CN VI root lies in the pontomedullary groove caudal to both CN VII and VIII in the vast majority of cases.

In a high-resolution 3D MRI study, the exit location of CN VI was caudal to the CN VII/VIII complex in 93% of the cases. Clearly, Soemmerring’s rostrocaudal numbering system of CN VI-VII-VIII (abducens-facial-vestibulocochlear CNs) should instead be VIII-VII-VI (vestibulocochlear- facial-abducens CNs). While the inaccuracy of the CN numbering system is of note, what is remarkable is that generations of authors have almost universally chosen to perpetuate this ancient error. No doubt some did this through faithful copying of their predecessors. Others, it could be speculated, chose to depict the CN relationships incorrectly rather than run contrary to long-established dogma.

This study is not advocating that a universally recognized numbering scheme be revised, as this would certainly create confusion. The authors do advocate that future depictions of the anatomical arrangements of the brainstem roots of CNs VI, VII, and VIII ought to reflect actual anatomy, rather than be contorted to conform with the classical CN numbering system 4).

1)

Bachmann R. [Samuel Thomas von Sömmerring – 18 January 1755 to 2 March 1830. In memory of the 150th anniversary of his death]. Verh Anat Ges. 1981;75(Pt 1):33-46. German. PubMed PMID: 7046280.

2)

Jay V. A portrait in history. The anatomical legacy of Dr Sömmerring. Arch Pathol Lab Med. 1999 Sep;123(9):762. PubMed PMID: 10458819.

3)

O’Rahilly R. On counting cranial nerves. Acta Anat (Basel). 1988;133(1):3-4. PubMed PMID: 3063049.

4)

Eduardo Corrales C, Mudry A, Jackler RK. Perpetuation of errors in illustrations of cranial nerve anatomy. J Neurosurg. 2017 Jul;127(1):192-198. doi: 10.3171/2015.12.JNS151203. Epub 2016 Oct 28. PubMed PMID: 27791521.

Transsphenoidal Surgery: Complication Avoidance and Management Techniques

Transsphenoidal Surgery: Complication Avoidance and Management Techniques

Transsphenoidal Surgery: Complication Avoidance and Management Techniques

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This work details contemporary clinical knowledge on the multidisciplinary management of pituitary and other sellar/parasellar tumors, with a focus on surgical techniques and a particular emphasis on complication avoidance and management. International experts provide guidance on natural history, radiologic and clinical aspects, surgical indications, and resection techniques.In addition, case presentations and clinical photographs help the reader reduce the risk of error and advance their own surgical skills. Readers also have access online to streaming videos of key procedures to help them provide the best possible outcomes for every patient.

Transsphenoidal Surgery: Complication Avoidance and Management Techniques will be of great value to Neurosurgeons, Otolaryngologists, Endocrinologists, Radiation Oncologists, and residents and fellows in these specialties.


Product Details

  • Published on: 2017-06-13
  • Original language: English
  • Number of items: 1
  • Dimensions: 9.30″ h x .0″ w x 6.10″ l,
  • Binding: Hardcover
  • 641 pages