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Journal ArticleDOI

From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal

TL;DR: A new terminology, pituitary neuroendocrine tumor (PitNET), is proposed, which is consistent with that used for other neuro endocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.
Abstract: The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

Content maybe subject to copyright    Report

DOI: 10.1530/ERC-17-0004
http://erc.endocrinology-journals.org © 2017 Society for Endocrinology
Printed in Great Britain
Published by Bioscientica Ltd.
Endocrine-Related Cancer
24:4
Commentary
S L Asaetal. Nomenclature revision for
pituitary tumors
10.1530/ERC-17-0004
From pituitary adenoma to pituitary
neuroendocrine tumor (PitNET): an
International Pituitary Pathology
Club proposal
S L Asa
1
, O Casar-Borota
2
, P Chanson
3
, E Delgrange
4
, P Earls
5
, S Ezzat
6
,
AGrossman
7
, H Ikeda
8
, N Inoshita
9
, N Karavitaki
10
, M Korbonits
11
, E R Laws Jr
12
,
MBLopes
13
, N Maartens
14
, I E McCutcheon
15
, O Mete
1
, H Nishioka
16
, G Raverot
17
,
FRoncaroli
18
, W Saeger
19
, L V Syro
20
, A Vasiljevic
21
, C Villa
22
, A Wierinckx
23
,
JTrouillas
24
, and the attendees of 14th Meeting of the International Pituitary
Pathology Club, Annecy, France, November 2016
1
Department of Pathology and Endocrine Oncology Site Group, Princess Margaret Cancer Centre,
University Health Network, Department of Laboratory Medicine and Pathobiology, University of
Toronto, Toronto, Ontario, Canada
2
Department of Pathology, Uppsala University Hospital, Uppsala, Sweden
3
Service of Endocrinology and Reproductive Diseases, Bicêtre Hospital, Paris, France
4
Department of Medicine, University of Louvain, Mont-sur-Meuse, Belgium
5
Department of Anatomical Pathology, St Vincent’s Hospital, Sydney, Australia
6
Department of Medicine and Endocrine Oncology Site Group, Princess Margaret Cancer Centre,
University Health Network and University of Toronto, Toronto, Ontario, Canada
7
Department of Endocrinology, University of Oxford, Oxford, UK
8
Research Institute for Pituitary Disease, Southern Tohoku General Hospital, Fukushima, Japan
9
Department of Pathology, Toranomon Hospital, Tokyo, Japan
10
Department of Endocrinology, Queen Elizabeth Hospital, University of Birmingham, Birmingham, UK
11
Division of Endocrinology, Queen Mary Hospital, Barts and the London School of Medicine, London,UK
12
Department of Neurosurgery, Harvard Medical School, Brigham & Women’s Hospital, Boston, Massachusetts,USA
13
Departments of Pathology and Neurological Surgery, University of Virginia, Charlottesville, Virginia,USA
14
Department of Neurosurgery, Royal Melbourne Hospital, The University of Melbourne, Melbourne,Australia
15
Department of Neurosurgery, UT MD Anderson Cancer Center, Houston, Texas, USA
16
Department of Neurosurgery, Toranomon Hospital, Tokyo, Japan
17
Department of Endocrinology, Groupement Hospitalier EST, Hospices Civils de Lyon,
UniversityofLyon, Lyon, France
18
Department of Neuropathology, Imperial College, London, UK
19
Institute of Neuropathology of the University of Hamburg, Hamburg, Germany
20
Department of Neurosurgery, Hospital Pablo Tobon Uribe, Medellin, Colombia
21
Department of Pathology, Groupement Hospitalier EST, Hospices Civils de Lyon, University of Lyon, Lyon, France
22
Department of Pathology, Hôpital Foch, Suresnes, France
23
INSERM U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France
24
Faculty of Medicine Lyon-Est, University of Lyon, Lyon, France
244
C5–C8
Correspondence
should be addressed
to S L Asa or J Trouillas
Email
sylvia.asa@uhn.ca or
Jacqueline.trouillas@
univ-lyon1.fr
Downloaded from Bioscientifica.com at 08/26/2022 11:18:13AM
via free access

C6
Commentary
S L Asaetal. Nomenclature revision for
pituitary tumors
Endocrine-Related Cancer
DOI: 10.1530/ERC-17-0004
http://erc.endocrinology-journals.org © 2017 Society for Endocrinology
Printed in Great Britain
Published by Bioscientica Ltd.
24:4
Abstract
The classication of neoplasms of adenohypophysial cells is misleading because of the
simplistic distinction between adenoma and carcinoma, based solely on metastatic spread
and the poor reproducibility and predictive value of the denition of atypical adenomas
based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current
classication of neoplasms of the anterior pituitary does not accurately reect the clinical
spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of
hormone hypersecretion cause signicant morbidity and mortality. We propose a new
terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used
for other neuroendocrine neoplasms and which recognizes the highly variable impact of
these tumors on patients.
Since the early work of Minkowski, who attributed
acromegaly to a pituitary tumor (Minkowski 1887),
neoplasms composed of pituitary adenohypophysial cells
have been recognized as the cause of significant illness.
However, Harvey Cushing attributed the term ‘adenoma’
even to patients who died of their disease (Cushing 1932).
We now recognize that these neoplasms are complex
and heterogeneous; they present multiple clinical
manifestations, including a wide range of proliferative and
invasive behaviors (Asa 2011). Some are slowly growing
small lesions that are clinically insignificant, some are
small or large hormonally active lactotroph tumors that
respond to medical therapy with shrinkage and reduced
hormone secretion, whereas other small and minimally
proliferative lesions cause the severe metabolic dysfunction
of Cushing’s disease or acromegaly. Many are large and
invasive neoplasms that cause significant morbidity due to
mass effects, with or without hormone excess syndromes.
Traditional classifications only recognize malignancy,
denoted as pituitary carcinoma, when there is evidence of
distant metastasis or cerebrospinal spread (DeLellisetal.
2004). The attempt to classify a subgroup as ‘atypical
adenomas’ based on the detection of mitoses or expression
of Ki-67 or p53 (DeLelliset al. 2004) has proven to lack
reproducibility and does not accurately predict recurrence
or resistance to medical therapy (Miermeisteretal. 2015).
Recently, a clinicopathological classification with five
grades identified Grade 2b tumors as those with a high
risk of recurrence or progression (Trouillas et al. 2013,
Raverot et al. 2015). However, prediction of clinically
aggressive behavior of these neoplasms, which occurs in
approximately 10% of these tumors, remains debatable
(Asa & Ezzat 2016). The term ‘adenoma’, which defines
a tumor as benign, does not seem appropriate to define
aggressive and invasive pituitary tumors that cannot be
resected and are refractory to therapy.
Patients and health care providers have long
expressed frustration that these lesions are considered
rare, benign and inconsequential. In most jurisdictions,
they are not reported in cancer registries. Pituitary
patients are often denied access to and/or health
insurance coverage for therapies that would be provided
for ‘cancers’.
The International Pituitary Pathology Club, created in
1981, is a group of expert pathologists, endocrinologists,
neurosurgeons and scientists who meet on a regular basis
to discuss challenges and advances in the pituitary field.
At the14th meeting in Annecy, France in November 2016,
the subject of classification of these lesions was, as usual,
controversial. However, there was consensus on one
important aspect: pituitary endocrine neoplasms exhibit
a spectrum of behaviors that are not entirely benign
and can cause significant morbidity, even when they are
notmetastatic.
We therefore propose a reclassification of these tumors
to apply terminology that has been widely accepted in
other neuroendocrine tumors (NETs) (DeLellis et al.
2004). Pituitary hormone-producing cells are members
of the family of neuroendocrine cells, similar to those of
pancreatic islets, as well as dispersed endocrine cells of
the gastrointestinal and respiratory tracts. Over the last
two decades, there have been terminology shifts that
reflect the potential for malignant behavior of even
the most bland of those neuroendocrine neoplasms.
They evolved from ‘adenoma’ to ‘tumor’ to recognize
the lack of predictability. We therefore propose that
neoplasms of adenohypophysial cells be termed ‘pituitary
neuroendocrine tumors’.
Endocrine-Related Cancer
(2017) 24, C5–C8
Key Words
f pituitary tumors
f nomenclature
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C7
Commentary
S L Asaetal. Nomenclature revision for
pituitary tumors
Endocrine-Related Cancer
DOI: 10.1530/ERC-17-0004
http://erc.endocrinology-journals.org © 2017 Society for Endocrinology
Printed in Great Britain
Published by Bioscientica Ltd.
24:4
Like other neuroendocrine neoplasms, many
primary adenohypophysial tumors are indolent;
they may be controlled by long-term pharmacologic
treatment (e.g. dopamine-agonist therapy in the case
of lactotroph tumors) or are non-invasive and cured
by surgery. However, a variable proportion may recur
despite remission. In addition, a large proportion (40%)
is invasive into the cavernous or sphenoid sinuses
or cranial bones and cannot be totally removed by
surgery. Moreover, some are resistant to the multiple
medical treatments available and are considered to be
clinically ‘aggressive’. The features distinguishing these
behaviors are not entirely clear at this time, and there
is still no consensus on this matter. Moreover, there is
no biomarker that can reliably predict malignancy as
defined by metastatic spread. There is evidence that
some morphologic subtypes of pituitary neoplasms of
the various cell lineages exhibit more aggressive behavior
(Asa & Ezzat 2016). It is also clear that invasive lesions,
which cannot be surgically resected are likely to result in
considerable morbidity (Raverot et al. 2015); some may
require radiotherapy or are rapidly proliferative despite
surgery, radiotherapy and/or medical therapy, requiring
chemotherapy, for example temozolomide or molecular
targeted therapies. Accordingly, indications for novel
therapies require elucidation of biomarkers that can guide
personalizedstrategies.
This revision of nomenclature is not intended to
negate the classification by morphologic cell type,
but instead is intended to change the classification to
‘tumor’ rather than ‘adenoma’; for example, a ‘sparsely
granulated somatotroph tumor’ rather than ‘sparsely
granulated somatotroph adenoma’. The classification by
morphologic cell type has been adopted by the World
Health Organization (WHO) (DeLellisetal. 2004) and will
remain in the next WHO classification that is underway.
Although the new terminology of ‘tumor’ replacing
‘adenoma’ will not be incorporated in the 2017 WHO
book, this change, as with previous terminologies that
transitioned to ‘NETs’, will be gradually adopted to be
included in the next edition. We hope that clarification
of additional appropriate biomarkers will ultimately
allow further refinement of the classification of pituitary
neuroendocrine tumors.
The authors of this statement feel strongly that the
time has come to reclassify clonal adenohypophysial
proliferations under the umbrella of ‘pituitary
neuroendocrine tumor’ (PitNET), a term that emphasizes
the biological spectrum of these common endocrine
neoplasms. Importantly, by analogy with other NETs,
we encourage tumor registries to capture data on these
tumors, thereby assisting efforts to clarify clinical and
pathological features that can appropriately guide patient
management. Pituitary neuroendocrine tumors are not
simply endocrine diseases, but should be considered as
tumors with endocrine manifestations within the context
of oncology.
Declaration of interest
The authors declare that there is no conict of interest that could be
perceived as prejudicing the impartiality of this commentary.
Funding
This work did not receive any specic grant from any funding agency in
the public, commercial, or not-for-prot sector.
Acknowledgement
The authors acknowledge the participation and wise counsel of Prof.
Günter Klöppel in the discussions that led to this manuscript. Attendees
of the 14th Meeting of the International Pituitary Pathology Club,
Annecy, France, November 2016 were: O Capraru, University of Medicine
and Pharmacy, Tirgu Mures, Romania; L Chinezu, Department of
Histology, University of Medicine and Pharmacy, Tirgu Mures, Romania;
H Dufour, Department of Neurosurgery, La Timone Hospital, Marseille,
France; NFukuhara, Department of Hypothalamic and Pituitary Surgery,
Toranomon Hospital, Tokyo, Japan; S Gaillard, Department of Surgery,
Hôpital Foch, Suresnes, France; F Guaraldi, Division of Endocrinology,
University of Turin, Turin, Italy; P E Harris, IPSEN, Paris, France; MLJaffrain-
Rea, University of L’Aquila, Coppito, L’Aquila, Italy; E Jouanneau,
Department of Neurosurgery, Groupement Hospitalier EST, Hospices
Civils de Lyon, University of Lyon, Lyon, France; I Kraljevic, Department
of Endocrinology, University Center, Zagreb, Croatia; E Manojlović-Gačić,
Institute of Pathology,Medical Faculty, University of Belgrade, Belgrade,
Serbia; O Tachibana, Department of Neurosurgery, Kanazawa Medical
University, Ishikawa, Japan; and M Theodoropoulou, Ludwig Maximilians
Universität München, Munich, Germany.
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Downloaded from Bioscientifica.com at 08/26/2022 11:18:13AM
via free access

C8
Commentary
S L Asaetal. Nomenclature revision for
pituitary tumors
Endocrine-Related Cancer
DOI: 10.1530/ERC-17-0004
http://erc.endocrinology-journals.org © 2017 Society for Endocrinology
Printed in Great Britain
Published by Bioscientica Ltd.
24:4
MinkowskiO 1887 Ueber einen fall von akromegalie. Klinische
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clinicopathologic classification of pituitary endocrine tumors.
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Received in final form 31 January 2017
Accepted 1 February 2017
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Citations
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TL;DR: This work believes this conceptual approach can form the basis for the next generation of NEN classifications and will allow more consistent taxonomy to understand how neoplasms from different organ systems inter-relate clinically and genetically.

688 citations


Cites background or result from "From pituitary adenoma to pituitary..."

  • ...PitNET prognosis and prediction relies more on cell type and degree of cell differentiation than on proliferative markers [10]....

    [...]

  • ...It was noted that the recently proposed new terminology for pituitary tumors is more in line with this proposal than the current 2017 WHO terminology [10]....

    [...]

Journal ArticleDOI
TL;DR: This review focuses on discussing the main changes on the upcoming fourth edition of the WHO Classification of Tumors of the Pituitary Gland emphasizing histopathological and molecular genetics aspects of pituitary neuroendocrine tumor aspects and some of the non-neuroendocrine tumors involving the pituitsary gland.
Abstract: This review focuses on discussing the main changes on the upcoming fourth edition of the WHO Classification of Tumors of the Pituitary Gland emphasizing histopathological and molecular genetics aspects of pituitary neuroendocrine (i.e., pituitary adenomas) and some of the non-neuroendocrine tumors involving the pituitary gland. Instead of a formal review, we introduced the highlights of the new WHO classification by answering select questions relevant to practising pathologists. The revised classification of pituitary adenomas, in addition to hormone immunohistochemistry, recognizes the role of other immunohistochemical markers including but not limited to pituitary transcription factors. Recognizing this novel approach, the fourth edition of the WHO classification has abandoned the concept of “a hormone-producing pituitary adenoma” and adopted a pituitary adenohypophyseal cell lineage designation of the adenomas with subsequent categorization of histological variants according to hormone content and specific histological and immunohistochemical features. This new classification does not require a routine ultrastructural examination of these tumors. The new definition of the Null cell adenoma requires the demonstration of immunonegativity for pituitary transcription factors and adenohypophyseal hormones Moreover, the term of atypical pituitary adenoma is no longer recommended. In addition to the accurate tumor subtyping, assessment of the tumor proliferative potential by mitotic count and Ki-67 index, and other clinical parameters such as tumor invasion, is strongly recommended in individual cases for consideration of clinically aggressive adenomas. This classification also recognizes some subtypes of pituitary neuroendocrine tumors as “high-risk pituitary adenomas” due to the clinical aggressive behavior; these include the sparsely granulated somatotroph adenoma, the lactotroph adenoma in men, the Crooke’s cell adenoma, the silent corticotroph adenoma, and the newly introduced plurihormonal Pit-1-positive adenoma (previously known as silent subtype III pituitary adenoma). An additional novel aspect of the new WHO classification was also the definition of the spectrum of thyroid transcription factor-1 expressing pituitary tumors of the posterior lobe as representing a morphological spectrum of a single nosological entity. These tumors include the pituicytoma, the spindle cell oncocytoma, the granular cell tumor of the neurohypophysis, and the sellar ependymoma.

283 citations


Cites methods from "From pituitary adenoma to pituitary..."

  • ...Subsequent to the WHO endocrine bluebook preparation, a group of experts and attendees of the 14th meeting of the International Pituitary Pathology Club (November 2016, France) have challenged the concept of pituitary adenomas by proposing the term Bpituitary neuroendocrine tumor (PitNET)^ in order reflect better the biological aggressiveness of some of the non-metastatic pituitary adenomas as well as the lack of reliable morphological criteria in the distinction of tumors that will present later on with metastatic disease [35]....

    [...]

Journal ArticleDOI
TL;DR: A concise review of the clinical and pathological aspects of silent pituitary adenomas was conducted in view of the new World Health Organization classification of pituitaries, which needs to be evaluated to better serve this unique group of patients.
Abstract: Context Silent pituitary adenomas are anterior pituitary tumors with hormone synthesis but without signs or symptoms of hormone hypersecretion. They have been increasingly recognized and represent challenging diagnostic issues. Evidence acquisition A comprehensive literature search was performed using MEDLINE and EMBASE databases from January 2000 to March 2018 with the following key words: (i) pituitary adenoma/tumor and nonfunctioning; or (ii) pituitary adenoma/tumor and silent. All titles and abstracts of the retrieved articles were reviewed, and recent advances in the field of silent pituitary adenomas were summarized. Evidence synthesis The clinical and biochemical picture of pituitary adenomas reflects a continuum between functional and silent adenomas. Although some adenomas are truly silent, others will show some evidence of biochemical hypersecretion or could have subtle clinical signs and, therefore, can be referred to as clinically silent or "whispering" adenomas. Silent tumors seem to be more aggressive than their secreting counterparts, with a greater recurrence rate. Transcription factors for pituitary cell lineages have been introduced into the 2017 World Health Organization guidelines: steroidogenic factor 1 staining for gonadotroph lineage; PIT1 (pituitary-specific positive transcription factor 1) for growth hormone, prolactin, and TSH lineage, and TPIT for the corticotroph lineage. Prospective studies applying these criteria will establish the value of the new classification. Conclusions A concise review of the clinical and pathological aspects of silent pituitary adenomas was conducted in view of the new World Health Organization classification of pituitary adenomas. New classifications, novel prognostics markers, and emerging imaging and therapeutic approaches need to be evaluated to better serve this unique group of patients.

108 citations

Journal ArticleDOI
TL;DR: The term “metastatic PitNET” is advocated to replace the previous terminology “pituitary carcinoma” in order to avoid confusion with neuro endocrine carcinoma (a poorly differentiated epithelial neuroendocrine neoplasm).

107 citations

References
More filters
Book
01 Jan 2004
TL;DR: Pathology and Genetics of Tumours of Endocrine OrgansMolecular Pathology of Breast CancerWho Classification of TUMoursPathology & Genetics of Surgical Tissues, Haematopoietic and Lymphoid Tissues and Soft Tissue Pathology.
Abstract: Pathology and Genetics of Tumours of Endocrine OrgansMolecular Pathology of Breast CancerWho Classification of Tumours of the Lung, Pleura, Thymus and HeartPathology and Genetics of Tumours of the Nervous SystemWHO Classification of Skin TumoursThe Molecular Basis of CancerMolecular Genetics of Lung CancerPathology and Genetics of Tumours of the Digestive SystemPathology and Genetics of Tumours of Head and Neck TumoursFemale Genital Tumours: Who Classification of TumoursPathology & Genetics of Tumours of Haematopoietic and Lymphoid TissuesModern Soft Tissue PathologyPathology and Genetics of Tumours of Endocrine OrgansWHO Classification of Tumours of the Digestive SystemPathology and Genetics of Tumours of the SkinWHO Classification of Tumours of the Urinary System and Male Genital OrgansWHO Classification of Tumours of the Central Nervous SystemPathology and Genetics of Tumours of the Breast and Female Genital OrgansWHO Classification of Tumours of Haematopoietic and Lymphoid TissuesWHO Classification of Tumours of Female Reproductive OrgansWHO Classification of Head and Neck TumoursPathology and Genetics of Tumours of the Nervous SystemPathology and Genetics of Tumours of Haematopoietic and Lymphoid TissuesPathology and Genetics of Tumours of the Nervous SystemWHO Classification of Tumours of Soft Tissue and BonePathology and Genetics of Tumours of the Urinary System and Male Genital OrgansSoft Tissue

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"From pituitary adenoma to pituitary..." refers background or methods in this paper

  • ...2004) and will remain in the next WHO classification that is underway....

    [...]

  • ...Although the new terminology of ‘tumor’ replacing ‘adenoma’ will not be incorporated in the 2017 WHO book, this change, as with previous terminologies that transitioned to ‘NETs’, will be gradually adopted to be included in the next edition....

    [...]

  • ...The classification by morphologic cell type has been adopted by the World Health Organization (WHO) (DeLellis et al....

    [...]

  • ...Traditional classifications only recognize malignancy, denoted as pituitary carcinoma, when there is evidence of distant metastasis or cerebrospinal spread (DeLellis et al. 2004)....

    [...]

  • ...The classification by morphologic cell type has been adopted by the World Health Organization (WHO) (DeLellis et al. 2004) and will remain in the next WHO classification that is underway....

    [...]

Journal ArticleDOI

870 citations


"From pituitary adenoma to pituitary..." refers background in this paper

  • ...However, Harvey Cushing attributed the term ‘adenoma’ even to patients who died of their disease (Cushing 1932)....

    [...]

Journal ArticleDOI
TL;DR: A new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operation therapy.
Abstract: Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case-control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.

358 citations

Book
01 Apr 1990
TL;DR: Anterior pituitsary tumors are clonal proliferation of pituitary cells that usually consist of one cell type, although some adenomas consist of more than one celltype.
Abstract: Anterior pituitary tumors are clonal proliferation of pituitary cells. They usually consist of one cell type, although some adenomas consist of more than one cell type.

283 citations

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