Pituitary adenoma classification

Pituitary adenoma classification

They are classified based on size or cell of origin. Pituitary adenoma can be described as microadenomamacroadenoma, and giant tumors based on size. Microadenoma is tumors less than 10 mm, while macroadenoma includes tumors larger than 10mm. Giant pituitary adenomas are more than 40 mm. There are functional pituitary adenomas in which the cell type that composes them causes increased secretion of one or multiple hormones of the anterior pituitary. Alternatively, there are Non-Functioning Pituitary Adenomas that do not secrete hormones, but they can compress the surrounding areas of the anterior pituitary leading to hormonal deficiencies 1).

see The 2017 World Health Organization classification of tumors of the pituitary gland.

In the fourth edition of the World Health Organization classification of endocrine tumors, are two critical changes to the classification for pituitary adenomas.

One is that the term “atypical adenoma,” which was characterized based on highly proliferative properties to predict adenomas that carry a poor prognosis, was completely eliminated due to the lack of definitive evidence. The other change is the introduction of more precise cell lineage-based classification of pituitary adenoma that is defined based on lineage-specific transcription factors and hormones produced. Accordingly, null cell adenomas have been re-defined as those that show completely negative immunostaining either for hormones or for adenohypophyseal transcription factors 2).

Somatotroph adenoma.

Lactotroph adenoma.

Tyrotroph adenoma.

Corticotroph adenoma.

Gonadotroph adenoma.

Null cell adenoma

Plurihormonal pituitary adenoma and double adenomas.


The classification is based upon the size, invasion of adjacent structures, sporadic or familial cases, biochemical activity, clinical manifestations, morphological characteristics, response to treatment, and recurrence 3).

Current classification systems for PAs are based primarily on secretory characteristics of the tumor but are also classified on the basis of phenotypical characteristics, including tumor size, degree of invasiveness (e.g., Knosp grade), and immunohistological findings 4).

The anterior WHO classification system for PAs was refined to include designations for benign adenoma, atypical adenoma, and pituitary carcinoma on the basis of p53 immunoreactivity, MIB-1 indexmitotic activity, and the absence/presence of metastases 5) 6).

These tumor types can be microadenomas or macroadenomas and can either be functional or non-functional.

By Size

Pituitary microadenoma

Pituitary macroadenoma

Giant pituitary adenoma

Volume can be calculated using MRI-guided volumetrics and an ellipsoid approximation (TV × AP × CC/2) transverse (TV), antero-posterior (AP) and cranio-caudal (CC).

By Function

Functioning pituitary adenoma

Nonfunctioning pituitary adenoma

Pituitary adenomas with gangliocytic component are rare tumors of the sellar region that are composed of pituitary adenoma cells and a ganglion cell component. Their histogenesis and hence nosology is not yet resolved because of the small number of cases reported and lack of large series in the literature 7).

Invasive pituitary adenomas and pituitary carcinomas are clinically indistinguishable until the identification of metastases.

Consistency

Although most authors differentiate easily aspirated (soft) tumors from those that are not (fibrous, might require prior fragmentation), there is no universally accepted PA consistency classification. Fibrous PA tends to be hypointense on T2WI and has lower apparent diffusion coefficient (ADC) values. Fibrous tumors seemed to present higher invasion into neighboring structures, including the cavernous sinus. Several articles suggest that dopamine agonists could increase PA consistency and that prior surgery and radiotherapy also make PA more fibrous. The anatomopathological studies identify collagen as being mainly responsible for fibrous consistency of adenomas.

Conclusions: Preoperative knowledge of PA consistency affords the neurosurgeon substantial benefit, which clearly appears to be relevant to surgical planning, risks, and surgery outcomes. It could also encourage the centralization of these high complexity tumors in reference centers. Further studies may be enhanced by applying standard consistency classification of the PA and analyzing a more extensive and prospective series of fibrous PA. 8).

Knosp Grade.

Hardy’s Classification of Pituitary Adenomas.


1)

Russ S, Shafiq I. Pituitary Adenoma. 2020 Feb 4. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK554451/ PubMed PMID: 32119338.
2)

Inoshita N, Nishioka H. The 2017 WHO classification of pituitary adenoma: overview and comments. Brain Tumor Pathol. 2018 Apr;35(2):51-56. doi: 10.1007/s10014-018-0314-3. Epub 2018 Apr 23. Review. PubMed PMID: 29687298.
3)

Syro LV, Rotondo F, Ramirez A, Di Ieva A, Sav MA, Restrepo LM, Serna CA, Kovacs K. Progress in the Diagnosis and Classification of Pituitary Adenomas. Front Endocrinol (Lausanne). 2015 Jun 12;6:97. doi: 10.3389/fendo.2015.00097. eCollection 2015. Review. PubMed PMID: 26124750; PubMed Central PMCID: PMC4464221.
4)

Knosp E, Steiner E, Kitz K, Matula C: Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33:610–618, 1993
5)

Barnes L, Eveson JW, Reichart P, David Sidransky: World Health Organization Classification of Tumours: Pathology and Genetics of Head and Neck Tumours Lyon, IARC Press, 2005
6)

Zada G, Woodmansee WW, Ramkissoon S, Amadio J, Nose V, Laws ER Jr: Atypical pituitary adenomas: incidence, clinical characteristics, and implications. J Neurosurg 114:336–344, 2011
7)

Balci S, Saglam A, Oruckaptan H, Erbas T, Soylemezoglu F. Pituitary adenoma with gangliocytic component: report of 5 cases with focus on immunoprofile of gangliocytic component. Pituitary. 2014 Jan 16. [Epub ahead of print] PubMed PMID: 24430434.
8)

Acitores Cancela A, Rodríguez Berrocal V, Pian H, Martínez San Millán JS, Díez JJ, Iglesias P. Clinical relevance of tumor consistency in pituitary adenoma. Hormones (Athens). 2021 Jun 19. doi: 10.1007/s42000-021-00302-5. Epub ahead of print. PMID: 34148222.

Brain death

Brain death

The published World Brain Death Project aims in alleviating inconsistencies in clinical guidelines and practice in the determination of death by neurologic criteria. However, critics have taken issue with a number of epistemic and metaphysical assertions that critics argue are either false, ad hoc, or confused.

Lazaridis disscussed the nature of a definition of death; the plausibility of neurologic criteria as a sensible social, medical, and legal policy; and within a Rawlsian liberal framework, reasons for personal choice or accommodation among neurologic and circulatory definitions. Declaration of human death cannot rest on contested metaphysics or unmeasurable standards, instead it should be regarded as a plausible and widely accepted social construct that conforms to best available and pragmatic medical science and practice. The definition(s) and criteria should be transparent, publicly justifiable, and potentially allow for the accommodation of reasonable choice. This is an approach that situates the definition of death as a political matter. The approach anticipates that no conceptualization of death can claim universal validity, since this is a question that cannot be settled solely on biologic or scientific grounds, rather it is a matter of normative preference, socially constructed and historically contingent 1).

The concept of brain death has periodically come under criticism 2).

Confirmatory tests for the diagnosis of brain death in addition to clinical findings may shorten observation time required in some countries and may add certainty to the diagnosis under specific circumstances.

The current U.S. approach to determining death was developed in response to the emergence of technologies that made the traditional standard of cardiopulmonary death problematic. In 1968, an ad hoc committee at Harvard Medical School published an influential article arguing for extending the concept of death to patients in an “irreversible coma.“ 3). The emerging neurologic criteria for death defined it in terms of loss of the functional activity of the brain stem and cerebral cortex. Although clinical criteria were developed in the 1960s, it took more than a decade for consensus over a rationale for the definition to emerge. In 1981, the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research provided a philosophical definition of brain death in terms of the loss of the critical functions of the organism as a whole 4).

Shortly thereafter, the National Conference of Commissioners on Uniform State Laws produced the Uniform Determination of Death Act, which has been adopted in 45 states and recognized in the rest through judicial opinion 5).

see Computed tomography angiography for brain death.

Changes in S100B protein, especially the levels of this dimer 48 hours after trauma can be used as marker to predict brain death. Alongside other known prognostic factors such as age, GCS and diameters of the pupils, however, this factor individually can not conclusive predict the patient’s clinical course and incidence of brain death. However, it is suitable to use GCS, CT scan, clinical symptoms and biomarkers together for a perfect prediction of brain death 6).

Near-Infrared Spectroscopy for Brain death

The practicability of Gadolinium-enhanced magnetic resonance angiography to confirm cerebral circulatory arrest was assessed after the diagnosis of brain death in 15 patients using a 1.5 Tesla MRI scanner. In all 15 patients extracranial blood flow distal to the external carotid arteries was undisturbed. In 14 patients no contrast medium was noted within intracerebral vessels above the proximal level of the intracerebral arteries. In one patient more distal segments of the anterior and middle cerebral arteries (A3 and M3) were filled with contrast medium. Gadolinium-enhanced MRA may be considered conclusive evidence of cerebral circulatory arrest, when major intracranial vessels fail to fill with contrast medium while extracranial vessels show normal blood flow 7).

The level of knowledge of medical students at Centro Universitário Lusíada – UNILUS- Santos (SP), Brazil, regarding brain death and transplantation is limited, which could be the result of inadequate education during medical school 8).

Brain death criteria.

In a editorial, Hibi et al., aimed to provide an outline of the world history of liver transplantation (LT), with a special focus on the innovation, development, and current controversies of living donor (LD) LT from East Asian and Western perspectives. In 1963, Starzl et al. (University of Colorado, U.S.) performed the world’s first human LT for a 3-year-old child with biliary atresia. The donor was a 3-year-old patient who had suffered from brain death following neurosurgery9).


1)

Lazaridis C. Defining Death: Reasonableness and Legitimacy. J Clin Ethics. 2021 Summer;32(2):109-113. PMID: 34129526.
2)

Truog RD, Miller FG, Halpern SD. The dead-donor rule and the future of organ donation. N Engl J Med 2013;369:1287-1289
3)

A definition of irreversible coma: report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 1968;205:337-340
4)

President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Defining death: a report on the medical, legal and ethical issues in the determination of death. Washington, DC: Government Printing Office, 1981.
5)

National Conference of Commissioners on Uniform State Laws. Uniform Determination of Death Act, 1981 (http://www.uniformlaws.org/shared/docs/determination%20of%20death/udda80.pdf).
6)

Shakeri M, Mahdkhah A, Panahi F. S100B Protein as a Post-traumatic Biomarker for Prediction of Brain Death in Association With Patient Outcomes. Arch Trauma Res. 2013 Aug;2(2):76-80. doi: 10.5812/atr.8549. Epub 2013 Aug 1. PubMed PMID:24396798.
7)

Luchtmann M, Beuing O, Skalej M, Kohl J, Serowy S, Bernarding J, Firsching R. Gadolinium-enhanced magnetic resonance angiography in brain death. Sci Rep. 2014 Jan 13;4:3659. doi: 10.1038/srep03659. PubMed PMID: 24413880.
8)

Reis FP, Gomes BH, Pimenta LL, Etzel A. Brain death and tissue and organ transplantation: the understanding of medical students. Rev Bras Ter Intensiva. 2013 Oct-Dec;25(4):279-283. Portuguese, English. PubMed PMID: 24553508.
9)

Hibi T, Eguchi S, Egawa H. Evolution of living donor liver transplantation: A global perspective. J Hepatobiliary Pancreat Sci. 2018 Jun 28. doi: 10.1002/jhbp.571. [Epub ahead of print] PubMed PMID: 29953731.

Anterior Thalamic Stimulation

Anterior Thalamic Stimulation

Deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) is a novel and promising treatment method for patients with drug-resistant epilepsy.

More than 70% of patients implanted with ANT-DBS benefit significantly from this method, i.e., they report seizure-reduction rates higher than 50%

The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate (≥50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years. In the 5 years of follow-up, 16% of subjects were seizure-free for at least 6 months. There were no reported unanticipated adverse device effects or symptomatic intracranial hemorrhages. The Liverpool Seizure Severity Scale and 31-item Quality of Life in Epilepsy measure showed statistically significant improvement over baseline by 1 year and at 5 years (p < 0.001).

Long-term follow-up of ANT deep brain stimulation showed sustained efficacy and safety in a treatment-resistant population.

Classification of evidence: This long-term follow-up provides Class IV evidence that for patients with drug-resistant partial epilepsy, anterior thalamic stimulation is associated with a 69% reduction in seizure frequency and a 34% serious device-related adverse event rate at 5 years. 1).

When focusing on the adverse events reported in a study of stimulation of the anterior nuclei of thalamus (SANTE study), the patients reported paresthesia (18% patients), pain in the implant side (10.9% patients), and infection at the implant site (9.1% patients) 2)

Sobstyl et al. performed a literature search regarding the clinical efficacy of ANT DBS. They discussed the surgical technique of the implantation of DBS electrodes with special attention paid to the targeting methods of the ANT. Moreover, they present in detail the clinical efficacy of ANT DBS, with a special emphasis on the stimulation parameters, a stimulation mode, and polarity. They also report all adverse events and present the current limitations of ANT DBS.

In general, the safety profile of DBS in intractable epilepsy patients is good, with a low rate of surgery, hardware-related, and stimulation-induced adverse events. No significant cognitive declines or worsening of depressive symptoms was noted. At long-term follow-up, the quality-of-life scores have improved. The limitations of ANT DBS studies include a limited number of patients treated and mostly open-label designs with only one double-blind, randomized multicenter trial. Most studies do not report the etiology of intractable epilepsy or they include nonhomogeneous groups of patients affected by intractable epilepsy. There are no guidelines for setting initial stimulation parameters. All the variables mentioned may have a profound impact on the final outcome.

ANT DBS appears to be a safe and efficacious treatment, particularly in patients with refractory partial seizures (three-quarters of patients gained at least 50% seizure reduction after 5 years). ANT DBS reduces most effectively the seizures originating in the temporal and frontal lobes. The published results of ANT DBS highlight promise and hope for patients with intractable epilepsy 3).


A literature review discusses the rationale, mechanism of action, clinical efficacy, safety, and tolerability of ANT-DBS in drug-resistant epilepsy patients. A review using systematic methods of the available literature was performed using relevant databases including Medline, Embase, and the Cochrane Library pertaining to the different aspects ANT-DBS. ANT-DBS for drug-resistant epilepsy is a safe, effective and well-tolerated therapy, where a special emphasis must be given to monitoring and neuropsychological assessment of both depression and memory function. Three patterns of seizure control by ANT-DBS are recognized, of which a delayed stimulation effect may account for an improved long-term response rate. ANT-DBS remotely modulates neuronal network excitability through overriding pathological electrical activity, decrease neuronal cell loss, through immune response inhibition or modulation of neuronal energy metabolism. ANT-DBS is an efficacious treatment modality, even when curative procedures or lesser invasive neuromodulative techniques failed. When compared to VNS, ANT-DBS shows slightly superior treatment response, which urges for direct comparative trials. Based on the available evidence ANT-DBS and VNS therapies are currently both superior compared to non-invasive neuromodulation techniques such as t-VNS and rTMS. Additional in-vivo research is necessary in order to gain more insight into the mechanism of action of ANT-DBS in localization-related epilepsy which will allow for treatment optimization. Randomized clinical studies in search of the optimal target in well-defined epilepsy patient populations, will ultimately allow for optimal patient stratification when applying DBS for drug-resistant patients with epilepsy 4).

Bilateral ANT electrodes were implanted into 18 patients suffering from focal, pharmacoresistant epilepsy. Antiepileptic treatment was kept unchanged from three months prior to operation. The Liverpool seizure severity scale (LSSS) was used to measure the burden of epilepsy.

Results: There was no significant difference between the 2 groups at the end of the blinded period at 6 months. However, when considering all patients and comparing 6 months of stimulation with baseline, there was a significant, 22% reduction in the frequency of all seizures (P = 0.009). Four patients had ≥50% reduction in total seizure frequency and 5 patients ≥50% reduction in focal seizures after 6 months of stimulation. No increased effect over time was shown. LSSS at 6 months compared to baseline showed no significant difference between the 2 groups, but a small, significant reduction in LSSS was found when all patients had received stimulation for 6 months.

Conclusions: Our study supports results from earlier studies concerning DBS as a safe treatment option, with effects even in patients with severe, refractory epilepsy. However, our results are not as encouraging as those reported from many other, mainly unblinded, and open studies 5).

A case of relapsing herpes simplex encephalitis (HSE) as a newly reported and potentially fatal stimulation-related adverse effect following stimulation of the anterior thalamic nucleus (ANT-DBS) accompanied by fever, confusion, and cognitive impairment in a 32-year-old epileptic patient with a history of herpes meningoencephalitis 31 years earlier. The T2-weighted/FLAIR high-signal intensity in the temporal lobe developed at a “distance” from the stimulation target. The positive polymerase chain reaction of herpes virus deoxyribonucleic acid in the cerebrospinal fluid confirmed the diagnosis. The condition improved partially on acyclovir and stimulation stopped. Seizures disappeared and then returned after few months. The unique case report presents a rationale for considering history of herpes encephalitis as a relative contraindication for ANT-DBS, and HSE relapse should be suspected in patients with post-stimulation fever and/or altered consciousness 6).


1)

Salanova V, Witt T, Worth R, Henry TR, Gross RE, Nazzaro JM, Labar D, Sperling MR, Sharan A, Sandok E, Handforth A, Stern JM, Chung S, Henderson JM, French J, Baltuch G, Rosenfeld WE, Garcia P, Barbaro NM, Fountain NB, Elias WJ, Goodman RR, Pollard JR, Tröster AI, Irwin CP, Lambrecht K, Graves N, Fisher R; SANTE Study Group. Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology. 2015 Mar 10;84(10):1017-25. doi: 10.1212/WNL.0000000000001334. Epub 2015 Feb 6. PMID: 25663221; PMCID: PMC4352097.
2)

Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, Oommen K, Osorio I, Nazzaro J, Labar D, Kaplitt M, Sperling M, Sandok E, Neal J, Handforth A, Stern J, DeSalles A, Chung S, Shetter A, Bergen D, Bakay R, Henderson J, French J, Baltuch G, Rosenfeld W, Youkilis A, Marks W, Garcia P, Barbaro N, Fountain N, Bazil C, Goodman R, McKhann G, Babu Krishnamurthy K, Papavassiliou S, Epstein C, Pollard J, Tonder L, Grebin J, Coffey R, Graves N; SANTE Study Group. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia. 2010 May;51(5):899-908. doi: 10.1111/j.1528-1167.2010.02536.x. Epub 2010 Mar 17. PMID: 20331461.
3)

Sobstyl M, Stapińska-Syniec A, Iwański S, Rylski M. Clinical Efficacy and Safety Profile of Anterior Thalamic Stimulation for Intractable Epilepsy. J Neurol Surg A Cent Eur Neurosurg. 2021 Jun 14. doi: 10.1055/s-0041-1725954. Epub ahead of print. PMID: 34126641.
4)

Bouwens van der Vlis TAM, Schijns OEMG, Schaper FLWVJ, Hoogland G, Kubben P, Wagner L, Rouhl R, Temel Y, Ackermans L. Deep brain stimulation of the anterior nucleus of the thalamus for drug-resistant epilepsy. Neurosurg Rev. 2019 Jun;42(2):287-296. doi: 10.1007/s10143-017-0941-x. Epub 2018 Jan 6. PMID: 29306976; PMCID: PMC6502776.
5)

Herrman H, Egge A, Konglund AE, Ramm-Pettersen J, Dietrichs E, Taubøll E. Anterior thalamic deep brain stimulation in refractory epilepsy: A randomized, double-blinded study. Acta Neurol Scand. 2019 Mar;139(3):294-304. doi: 10.1111/ane.13047. Epub 2018 Dec 11. PMID: 30427061.
6)

Hamdi H, Robin E, Stahl JP, Doche E, Azulay JP, Chabardes S, Bartolomei F, Regis J. Anterior Thalamic Stimulation Induced Relapsing Encephalitis. Stereotact Funct Neurosurg. 2019;97(2):132-136. doi: 10.1159/000499072. Epub 2019 May 3. PMID: 31055582.
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