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## **Meet the editor**

Professor Vafa Rahimi-Movaghar was Neurosurgeon-in-Chief at Khatam-ol-anbia Hospital of Zahedan University Medical Sciences in Iran from 1994 to 2006 and then moved to the Sina Trauma & Surgery Research Center in Tehran University of Medical Sciences. Since 2010 he is Vice-Chairman of the research centre. Since January 2012, he has started to be the guide for PhD by

research in Neurotrauma. He has written in neurosurgical topics, with over 100 publications; 61 in SCOPUS and EMBASE; 59 in PUBMED, 54 of them in ISI. He has written 6 books and 8 chapters. He also has operative experience, which includes over 2700 neurosurgical operations. His major research interest is epidemiological, etiological, experimental and therapeutic aspects of neurotrauma especially spinal cord injury.

Contents

**Preface VII** 

Chapter 2 **Diagnostic Imaging of** 

Chapter 1 **Pituitary Adenomas and Ophthalmology 1** 

Chapter 3 **Functioning Pituitary Adenoma 33** 

and Vafa Rahimi-Movaghar

Chapter 4 **Pituitary Adenomas – Clinico-Pathological,** 

Ricardo H. Brau and David Lozada

Santiago Ortiz-Perez and Bernardo Sanchez-Dalmau

**Immunohistochemical and Ultrastructural Study 49**  Alma Ortiz-Plata, Martha L. Tena-Suck, Iván Pérez-Neri, Daniel Rembao-Bojórquez and Angeles Fernández

Chapter 5 **Stereotactic Radiosurgery for Pituitary Adenomas 67** 

**the Pituitary and Parasellar Region 13**  Joanna Bladowska and Marek Sąsiadek

Mahdi Sharif-Alhoseini, Edward R. Laws

### Contents

#### **Preface XI**


Preface

them.

The purpose of this book is to review all types of pituitary adenoma and describe the symptoms, epidemiology, diagnosis, management, outcome and complications of

Pituitary adenomas are typically benign, slow-growing tumors that arise from cells in the pituitary gland. The pituitary gland lies below the optic system, primarily the optic chiasm, and below the optic nerves and optic tracts. Thus, pituitary adenomas, the most common tumors of the hypophysis, can compress optic system and some of the main symptoms and signs in patients are visual. Therefore, measurement of visual acuity, visual fields, ophthalmoscopy and the use of Optical Coherence Tomography

Pituitary adenomas are classified based on hormone secretory products. But nonfunctioning adenomas are endocrine-inactive tumors. Because of physiologic effects of excess hormones, the functioning tumors present earlier than non-functioning adenomas. On the other hand, the mass effect from large pituitary adenomas may lead to the pressure symptoms, such as headaches, visual field defects, cranial nerve

The molecular mechanisms underlying the development and progression of pituitary adenoma have not yet been clearly defined. However, immunohistochemistry and ultrastructural analysis developed new insights into the pathogenesis of these tumors. The finding of specific serum markers in patients with pituitary adenoma will help physicians in the accurate diagnosis and specific treatment of patients in the future.

Diagnostic MRI of the sellar region constitutes one of the most challenging subjects in neurooncology. T1- and T2-weighted MRI in coronal and sagittal planes with and without paramagnetic contrast medium is the method of choice for imaging of the

During the past two decades, a number of new procedures for radiation dose delivery and fractionation have become extensively accessible. The most important progress has been in the use of stereotactic procedures to make radiotherapy targeting relatively simple and very precise. This has permitted the application of single fraction

has a significant role in diagnosis and periodic evaluation of the patient.

deficits, hypopituitarism, pituitary apoplexy or stalk effect.

pituitary gland and the perisellar area.

## Preface

The purpose of this book is to review all types of pituitary adenoma and describe the symptoms, epidemiology, diagnosis, management, outcome and complications of them.

Pituitary adenomas are typically benign, slow-growing tumors that arise from cells in the pituitary gland. The pituitary gland lies below the optic system, primarily the optic chiasm, and below the optic nerves and optic tracts. Thus, pituitary adenomas, the most common tumors of the hypophysis, can compress optic system and some of the main symptoms and signs in patients are visual. Therefore, measurement of visual acuity, visual fields, ophthalmoscopy and the use of Optical Coherence Tomography has a significant role in diagnosis and periodic evaluation of the patient.

Pituitary adenomas are classified based on hormone secretory products. But nonfunctioning adenomas are endocrine-inactive tumors. Because of physiologic effects of excess hormones, the functioning tumors present earlier than non-functioning adenomas. On the other hand, the mass effect from large pituitary adenomas may lead to the pressure symptoms, such as headaches, visual field defects, cranial nerve deficits, hypopituitarism, pituitary apoplexy or stalk effect.

The molecular mechanisms underlying the development and progression of pituitary adenoma have not yet been clearly defined. However, immunohistochemistry and ultrastructural analysis developed new insights into the pathogenesis of these tumors. The finding of specific serum markers in patients with pituitary adenoma will help physicians in the accurate diagnosis and specific treatment of patients in the future.

Diagnostic MRI of the sellar region constitutes one of the most challenging subjects in neurooncology. T1- and T2-weighted MRI in coronal and sagittal planes with and without paramagnetic contrast medium is the method of choice for imaging of the pituitary gland and the perisellar area.

During the past two decades, a number of new procedures for radiation dose delivery and fractionation have become extensively accessible. The most important progress has been in the use of stereotactic procedures to make radiotherapy targeting relatively simple and very precise. This has permitted the application of single fraction

#### VIII Preface

high-dose irradiation entitled stereotactic radiosurgery for brain tumors which can be given as an adjuvant or as a specific treatment modality for pituitary adenomas in patients who have had recurrence after microsurgery, or if complete tumor removal has not been possible.

Finally, visual testing, endocrine evaluation and MRI are three main tools in the pre and post treatment assessment of patients with pituitary adenoma. Considering all modalities of treatment (medical, surgical, or radiotherapy) selected for management of patients, visual assessment together with endocrine and imaging is essential in short and long term evaluation of tumors of the hypophysis.

I want to thank Ms Maja Bozicevic for helping me trough the process, InTech for giving me opportunity to work as an Editor and Prof. Ed Laws for his support.

#### **Vafa Rahimi-Movaghar, MD**

Associate professor of Neurosurgery Vice-Chairman of Sina Trauma and Surgery Research Center, Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran Research Centre for Neural Repair, University of Tehran, Tehran, Iran

VIII Preface

has not been possible.

high-dose irradiation entitled stereotactic radiosurgery for brain tumors which can be given as an adjuvant or as a specific treatment modality for pituitary adenomas in patients who have had recurrence after microsurgery, or if complete tumor removal

Finally, visual testing, endocrine evaluation and MRI are three main tools in the pre and post treatment assessment of patients with pituitary adenoma. Considering all modalities of treatment (medical, surgical, or radiotherapy) selected for management of patients, visual assessment together with endocrine and imaging is essential in short

I want to thank Ms Maja Bozicevic for helping me trough the process, InTech for

Vice-Chairman of Sina Trauma and Surgery Research Center, Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran,

Research Centre for Neural Repair, University of Tehran, Tehran,

**Vafa Rahimi-Movaghar, MD** Associate professor of Neurosurgery

Iran

Iran

giving me opportunity to work as an Editor and Prof. Ed Laws for his support.

and long term evaluation of tumors of the hypophysis.

**1** 

*Spain* 

**Pituitary Adenomas and Ophthalmology** 

*Hospital Clinic, University of de Barcelona, Ophthalmology department* 

Pituitary gland, also called hypophysis, is a neuroendocrine organ placed in the "sella turcica" in the skull base. This gland consists of 2 main areas, the anterior and medial part constitute the adenohypophysis, the posterior part is called neurohypophysis. Pituitary gland is in charge of the internal constancy, homeostasis and reproductive function; this is

Pituitary adenomas are a common pathology; they represent about 10% of all intracranial tumours and between 50-80% of pituitary tumours. Necropsy and imaging studies estimate an incident of 20-25% of pituitary adenomas in general population; however, only about 1/3 of them are clinically evident (Asa & Ezzat, 2009). The majority of these tumours have monoclonal origin (mutation of a single gonadotropic cell), but there are still some discrepancies about the pathogenesis of these neoplasms. The most common mutations seem in other human neoplasms are not frequent in pituitary adenomas, and only a minimum proportion of them are associated to other genetic disorders, such as MEN1 syndrome (multiple endocrine neoplasms type 1) or the Carney complex, due to mutations of the genes MEN1 and PRKAR1A (protein kinase A regulatory subunit 1A) respectively (Beckers & Daly, 2007). Hormones and growth factors involve in normal pituitary function can be also related to the growth of these tumours, although evident connection with the

Symptoms related to pituitary tumours are secondary to several factors. On the one hand, many of them are *non-secreting tumours*, they can be asymptomatic or cause compression symptoms if they are big enough; on the other hand, other are *secreting tumours* and they can cause clinical syndromes derivate from the hormone activity in different target organs. Hormones secreting by these tumours are the same that the physiologic hypophysis produces. According to frequency, the most frequent tumours are prolactin (PRL)-secreting pituitary adenomas, non secreting pituitary adenomas are in second position, growth hormone (GH)-secreting tumours in third, adrenocorticotropic hormone (ACTH)-secreting tumours in fourth, and the rarest are thyroid stimulating hormone (TSH)-secreting adenomas. There are also tumour secreting different combinations of hormones, mainly GH and PRL (Table 1). In cases of fast growing or big tumours affecting surrounding structures,

Two types of adenomas can be described depending on the size of the tumour, macroadenomas with more than 1 centimeter and microadenomas measuring less than 1 cm

why pituitary abnormalities cause a wide spectrum of signs and symptoms.

**1. Introduction** 

pathogenesis has not been demonstrated.

chiasmatic or cavernous sinus syndrome can be seen.

Santiago Ortiz-Perez and Bernardo Sanchez-Dalmau

## **Pituitary Adenomas and Ophthalmology**

Santiago Ortiz-Perez and Bernardo Sanchez-Dalmau *Hospital Clinic, University of de Barcelona, Ophthalmology department Spain* 

#### **1. Introduction**

Pituitary gland, also called hypophysis, is a neuroendocrine organ placed in the "sella turcica" in the skull base. This gland consists of 2 main areas, the anterior and medial part constitute the adenohypophysis, the posterior part is called neurohypophysis. Pituitary gland is in charge of the internal constancy, homeostasis and reproductive function; this is why pituitary abnormalities cause a wide spectrum of signs and symptoms.

Pituitary adenomas are a common pathology; they represent about 10% of all intracranial tumours and between 50-80% of pituitary tumours. Necropsy and imaging studies estimate an incident of 20-25% of pituitary adenomas in general population; however, only about 1/3 of them are clinically evident (Asa & Ezzat, 2009). The majority of these tumours have monoclonal origin (mutation of a single gonadotropic cell), but there are still some discrepancies about the pathogenesis of these neoplasms. The most common mutations seem in other human neoplasms are not frequent in pituitary adenomas, and only a minimum proportion of them are associated to other genetic disorders, such as MEN1 syndrome (multiple endocrine neoplasms type 1) or the Carney complex, due to mutations of the genes MEN1 and PRKAR1A (protein kinase A regulatory subunit 1A) respectively (Beckers & Daly, 2007). Hormones and growth factors involve in normal pituitary function can be also related to the growth of these tumours, although evident connection with the pathogenesis has not been demonstrated.

Symptoms related to pituitary tumours are secondary to several factors. On the one hand, many of them are *non-secreting tumours*, they can be asymptomatic or cause compression symptoms if they are big enough; on the other hand, other are *secreting tumours* and they can cause clinical syndromes derivate from the hormone activity in different target organs. Hormones secreting by these tumours are the same that the physiologic hypophysis produces. According to frequency, the most frequent tumours are prolactin (PRL)-secreting pituitary adenomas, non secreting pituitary adenomas are in second position, growth hormone (GH)-secreting tumours in third, adrenocorticotropic hormone (ACTH)-secreting tumours in fourth, and the rarest are thyroid stimulating hormone (TSH)-secreting adenomas. There are also tumour secreting different combinations of hormones, mainly GH and PRL (Table 1). In cases of fast growing or big tumours affecting surrounding structures, chiasmatic or cavernous sinus syndrome can be seen.

Two types of adenomas can be described depending on the size of the tumour, macroadenomas with more than 1 centimeter and microadenomas measuring less than 1 cm

Pituitary Adenomas and Ophthalmology 3

The wide spectrum of clinical syndromes including endocrinological, cardiovascular, neurological, ophthalmological, determine the needed of a multidisciplinary management between different specialists. Early diagnosis is very important in order to establish a proper

In this review, a comprehensive description about the ophthalmological syndromes associated to pituitary adenomas is presented. The suspicion of these syndromes by the doctors facing patients with pituitary tumours will allow earlier diagnostic and better treatments for them. Despite the general ophthalmic examination including visual field tests, we describe the Optical Coherence Tomography (OCT) as a new tool that must be

The most common neuro-ophthalmological syndrome associated to pituitary adenomas is due to compression of the central part of the optic chiasm; this produces the classic bitemporal hemianopia in the visual field. That was the onset manifestation in up to 80% of pituitary adenomas several years ago, but nowadays, the advantages in the hormone detection tests and neuroimaging have changed this trend, and headache and systemic clinical syndromes related to hormone production are the commonest onset manifestations. Neuro-ophthalmological manifestations are the debut syndrome in less than 10% of cases (Table 2); they are due to the anatomical relations between the gland and the optic chiasm,

> **Headache (%)**

(156;<1955) -- -- 86 50 5

1974-76) 21 24 31 19 4

(200; 1976-1981) 70 46 9 2 1

Table 2. Debut signs and symptoms in pituitary adenoma patients (Chhabra & Newman,

Optic nerves enter the intracranial space through the *optic foramen* in the sphenoid bones, after 8-15 mm up and backwards they join together to constitute the optic chiasm. There are anatomical variations in the length of the intracranial optic nerve and the position of the

(51; 1967-74) 45 69 47

**2.1 Anatomy of the pituitary area (Rouvière & Delmas, 1996)** 

**Visual dysfunction (%)** 

5 14 70 34 6

**Optic atrophy (%)** 

**EOM impairment** 

therapeutic plan and achieve the best prognosis for these patients.

**2. Ophthalmic manifestations of pituitary adenomas** 

the optic nerves and the III, IV and VI nerves in the cavernous sinus.

**Amenorrhea/ Impotence(%)**

performed in all these patients.

**Study. No of patients Year** 

Chamblin et al

Hollenhorst and younge (1000;1940-62)

Klauber et al

Wray (100;

Anderson et al

2006)

EOM: extraocular muscle

in size (figure 1). A low percentage of tumours have a malign behaviour producing metastases, central nervous system invasion and even death; nevertheless, this is very uncommon and the majority of the problems related to these tumours are due to the morbidity that they produce.


Table 1. Pituitary cells, hormones, tumours and associated clinical syndromes (Asa & Ezzat, 2002)

Fig. 1. Magnetic resonance imaging showing a pituitary macroadenoma.

in size (figure 1). A low percentage of tumours have a malign behaviour producing metastases, central nervous system invasion and even death; nevertheless, this is very uncommon and the majority of the problems related to these tumours are due to the

**function** 

Adrenal cortex; glucocorticoid metabolism

IGF-1 production. Muscle and bone

growth

Lactation

See above

Sexual development. Sexual steroids metabolism

Table 1. Pituitary cells, hormones, tumours and associated clinical syndromes (Asa & Ezzat,

**Tumour incidence** 

10 – 15%

35%

5%

35%

metabolism 2% Hypo -

**Clinical syndromes** 

Nelson syndrome

Cushing syndrome

Gigantism

Amenorrhea Galactorrhea Sexual dysfunction

Acromegaly Gigantism with hyper-PRL

hyperthyroidism

Hypogonadism Mass effect Hypopituitarism

10 – 15% Acromegaly

morbidity that they produce.

Somatotropic

Lactotropic

Mammo-

Gonadotropic

2002)

Adrenocorticotropic ACTH and

somatotropic GH , PRL

Thyrotropic TSH Thyroid

**Cell type Hormones Hormone** 

other peptides

GH

PRL

FSH, LH

Fig. 1. Magnetic resonance imaging showing a pituitary macroadenoma.

The wide spectrum of clinical syndromes including endocrinological, cardiovascular, neurological, ophthalmological, determine the needed of a multidisciplinary management between different specialists. Early diagnosis is very important in order to establish a proper therapeutic plan and achieve the best prognosis for these patients.

In this review, a comprehensive description about the ophthalmological syndromes associated to pituitary adenomas is presented. The suspicion of these syndromes by the doctors facing patients with pituitary tumours will allow earlier diagnostic and better treatments for them. Despite the general ophthalmic examination including visual field tests, we describe the Optical Coherence Tomography (OCT) as a new tool that must be performed in all these patients.

#### **2. Ophthalmic manifestations of pituitary adenomas**

The most common neuro-ophthalmological syndrome associated to pituitary adenomas is due to compression of the central part of the optic chiasm; this produces the classic bitemporal hemianopia in the visual field. That was the onset manifestation in up to 80% of pituitary adenomas several years ago, but nowadays, the advantages in the hormone detection tests and neuroimaging have changed this trend, and headache and systemic clinical syndromes related to hormone production are the commonest onset manifestations. Neuro-ophthalmological manifestations are the debut syndrome in less than 10% of cases (Table 2); they are due to the anatomical relations between the gland and the optic chiasm, the optic nerves and the III, IV and VI nerves in the cavernous sinus.


EOM: extraocular muscle

Table 2. Debut signs and symptoms in pituitary adenoma patients (Chhabra & Newman, 2006)

#### **2.1 Anatomy of the pituitary area (Rouvière & Delmas, 1996)**

Optic nerves enter the intracranial space through the *optic foramen* in the sphenoid bones, after 8-15 mm up and backwards they join together to constitute the optic chiasm. There are anatomical variations in the length of the intracranial optic nerve and the position of the

Pituitary Adenomas and Ophthalmology 5

Fig. 2. Anatomy of the cavernous sinus and surrounding structures. Relation between the

This is the most frequent syndrome; the damage involving mainly the crossed fibers produces bitemporal hemianopia with possible central visual field affectation (figure 3).

If the compression affects predominantly the inferior part of the chiasm the visual field

pituitary gland and the chiasm, cranial nerves and internal carotid arteries.

This syndrome is seen in lesions that damage the body of the optic chiasm.

Fig. 3. Visual field showing a bitemporal hemianopia.

**2.2.3 Inferior chiasmal syndrome** 

defects are temporal and superior.

**2.2.2 Central chiasmal syndrome** 

optic chiasm, this is extremely important with respect to the visual deficits caused by tumours in the suprasellar region. In 75-80% of people optic chiasm is placed just above the *diaphragma sellae*; when the intracranial optic nerve is shorter than about 12 mm (about 10% of people), the optic chiasm is positioned anteriorly, or "pre-fixed", and it sits above the *tuberculum sellae,* when the intracranial optic nerve is long, over 18 mm (10-15% of people), the chiasm is positioned posteriorly to the *dorsum sellae* or "post-fixed" (Chhabra & Newman, 2006; Miller N, et al, 2008).

Fibers running from the nasal retinal nerve cells (about 53% of fibers) cross in the chiasm to join the fibers from the temporal retinal nerve cells of the opposite side. However, as they enter the chiasm, some ventral crossed fibers, primarily from the inferonasal retinal of the contralateral eye and serving the superotemporal portion of the contralateral visual field, where historically believed to loop anteriorly 1 to 2 mm into the terminal portion of the opposite optic nerve before turning posteriorly to continue through the chiasm and into the optic tract. This loop is called Willebrand's Knee (Miller N, et al, 2008; Muñoz-Negrete & Rebolleda, 2002). There is some controversy about the real anatomical existence of this structure, however Willebrand's knee clearly exists from a clinical point of view, as it is described below. In cases of chiasm compression the crossed fibers are more likely to be damaged as they support the same quantity of pressure in less space (Kosmorsky, et al, 2008). This is the reason for the bitemporal hemianopia (crossed nasal fibers compression) as the more frequent syndrome in cases of chiasm compression. Fibers leave the chiasm backwards in both sides of the hypophysis as the optic tracts; in cases of pre-fixed chiasms is more likely to see damaged of these tracts.

The pituitary gland lies between the two paired cavernous sinuses. An abnormally growing adenoma will expand in the direction of least resistance and eventually compress the cavernous sinus (figure 2). The cavernous sinus receives blood via the ophthalmic vein through the superior orbital fissure and from superficial cortical veins, and is connected to the basilar plexus of veins posteriorly. The internal carotid artery (carotid siphon), and cranial nerves III, IV, V1, V2 and VI all pass through this blood filled space. The cavernous sinus drains by two channels, the superior and inferior petrosal sinuses, ultimately into the internal jugular vein. These nerves, with the exception of V2, pass through the cavernous sinus to enter the orbital apex through the superior orbital fissure. The maxillary nerve, division V2 of the trigeminal nerve travels through the lower portion of the sinus and exits via the foramen rotundum (Miller N, et al, 2008; Frank, et al, 2006).

#### **2.2 Clinical syndromes**

There are different syndromes that can be seen in cases of pituitary adenomas:

#### **2.2.1 Anterior chiasmal syndrome**

This is more common in post-fixed chiasms. The compression in the anterior angle of the optic chiasm affect the *Willbrandt's knee* fibers and produces temporal and superior visual field defects affecting one or both eyes. In cases of non-centred tumours the anterior junction syndrome of Traquair (junctional scotoma) can be observed, characterized by advanced visual field loss affecting the visual field centre in one eye and (possibly subtle) defects respecting the vertical midline in the fellow eye (Muñoz-Negrete & Rebolleda, 2002).

optic chiasm, this is extremely important with respect to the visual deficits caused by tumours in the suprasellar region. In 75-80% of people optic chiasm is placed just above the *diaphragma sellae*; when the intracranial optic nerve is shorter than about 12 mm (about 10% of people), the optic chiasm is positioned anteriorly, or "pre-fixed", and it sits above the *tuberculum sellae,* when the intracranial optic nerve is long, over 18 mm (10-15% of people), the chiasm is positioned posteriorly to the *dorsum sellae* or "post-fixed" (Chhabra &

Fibers running from the nasal retinal nerve cells (about 53% of fibers) cross in the chiasm to join the fibers from the temporal retinal nerve cells of the opposite side. However, as they enter the chiasm, some ventral crossed fibers, primarily from the inferonasal retinal of the contralateral eye and serving the superotemporal portion of the contralateral visual field, where historically believed to loop anteriorly 1 to 2 mm into the terminal portion of the opposite optic nerve before turning posteriorly to continue through the chiasm and into the optic tract. This loop is called Willebrand's Knee (Miller N, et al, 2008; Muñoz-Negrete & Rebolleda, 2002). There is some controversy about the real anatomical existence of this structure, however Willebrand's knee clearly exists from a clinical point of view, as it is described below. In cases of chiasm compression the crossed fibers are more likely to be damaged as they support the same quantity of pressure in less space (Kosmorsky, et al, 2008). This is the reason for the bitemporal hemianopia (crossed nasal fibers compression) as the more frequent syndrome in cases of chiasm compression. Fibers leave the chiasm backwards in both sides of the hypophysis as the optic tracts; in cases of pre-fixed chiasms is

The pituitary gland lies between the two paired cavernous sinuses. An abnormally growing adenoma will expand in the direction of least resistance and eventually compress the cavernous sinus (figure 2). The cavernous sinus receives blood via the ophthalmic vein through the superior orbital fissure and from superficial cortical veins, and is connected to the basilar plexus of veins posteriorly. The internal carotid artery (carotid siphon), and cranial nerves III, IV, V1, V2 and VI all pass through this blood filled space. The cavernous sinus drains by two channels, the superior and inferior petrosal sinuses, ultimately into the internal jugular vein. These nerves, with the exception of V2, pass through the cavernous sinus to enter the orbital apex through the superior orbital fissure. The maxillary nerve, division V2 of the trigeminal nerve travels through the lower portion of the sinus and exits

via the foramen rotundum (Miller N, et al, 2008; Frank, et al, 2006).

There are different syndromes that can be seen in cases of pituitary adenomas:

This is more common in post-fixed chiasms. The compression in the anterior angle of the optic chiasm affect the *Willbrandt's knee* fibers and produces temporal and superior visual field defects affecting one or both eyes. In cases of non-centred tumours the anterior junction syndrome of Traquair (junctional scotoma) can be observed, characterized by advanced visual field loss affecting the visual field centre in one eye and (possibly subtle) defects

respecting the vertical midline in the fellow eye (Muñoz-Negrete & Rebolleda, 2002).

Newman, 2006; Miller N, et al, 2008).

more likely to see damaged of these tracts.

**2.2 Clinical syndromes** 

**2.2.1 Anterior chiasmal syndrome** 

Fig. 2. Anatomy of the cavernous sinus and surrounding structures. Relation between the pituitary gland and the chiasm, cranial nerves and internal carotid arteries.

#### **2.2.2 Central chiasmal syndrome**

This is the most frequent syndrome; the damage involving mainly the crossed fibers produces bitemporal hemianopia with possible central visual field affectation (figure 3). This syndrome is seen in lesions that damage the body of the optic chiasm.

#### **2.2.3 Inferior chiasmal syndrome**

If the compression affects predominantly the inferior part of the chiasm the visual field defects are temporal and superior.

Pituitary Adenomas and Ophthalmology 7

Fig. 4. Patient affected by a III nerve palsy. Observe the eyelid ptosis due to affectation of the levator muscle. These patients also have pupillary dilation and extraocular movements

or damage to the interstitial nucleus of Cajal or adjacent structures of the tumour (Miller, et al, 2008). In cases of big tumours compressing the brainstem is also possible, although

This can be observed as a sign of visual pathway damage in different conditions, including

Some authors suggest that persistent photophobia of unknown aetiology should arise the

Defined as a sudden neurologic impairment, usually due to a vascular process. It is characterized by a sudden onset of headache, visual symptoms, altered mental status, and hormonal dysfunction due to acute hemorrhage or infarction of a pituitary gland. An existing pituitary adenoma is usually present. The incidence of this phenomenon has been described up to 10% in some series (Wakai, 1981). The visual symptoms may include both visual acuity impairment and visual field impairment from involvement of the optic nerve or chiasm and ocular motility dysfunction from involvement of the cranial nerves traversing the cavernous sinus (more frequent III nerve). Other less common symptoms are related to possible brainstem damage, such as light-near dissociation or convergence retraction nystagmus.

Most of the cases show normal optic discs in fundus examination. If altered, it can be a diffuse atrophy, or more typically the "band" or "bow-tie" atrophy that occupies a more or less horizontal band across the disc with relative sparing of the superior and inferior portions where the majority of spared temporal fibers enter (figure 5). Some cases can develop papilledema, this is more frequently associated with suprachiasmal tumours that can invade

and compress the 3rd ventricle, ultimately obstructing the flow of cerebrospinal fluid.

impairment

exceptional, the presence of nystagmus.

suspicion of pituitary pathology (Kawasaki & Purvin, 2002).

**2.2.11 Colour vision impairment** 

cases of pituitary adenomas.

**2.2.13 Pituitary apoplexy** 

**2.2.12 Photophobia** 

**2.2.14 Funduscopy** 

#### **2.2.4 Superior chiasmal syndrome**

Compression of the superior part of the chiasm is not a frequent condition in cases of pituitary adenomas; it is more likely to see this clinical picture in other tumours arising from the base of the brain, mainly the craniopharyngioma. In these cases the visual field defects are temporal and inferior.

#### **2.2.5 Posterior chiasmal syndrome**

More frequent in pre-fixed chiasms. It produces characteristic bitemporal hemianopic scotomas in the visual field.

#### **2.2.6 Lateral chiasmal syndrome**

This syndrome can be observed in tumours compressions or carotid pathology that pushes the chiasm laterally. Contralateral homonymus quadrantanopic or hemianopic defects can be assessed; much less frequent is the binasal hemianopia in these cases.

#### **2.2.7 Optic tract compression**

This is also more frequent in cases of post-fixed chiasms. Contralateral homonymus defects can be observed. Optic tract damage is more frequent in other neurological conditions, such as vascular processes, demyelinating diseases or trauma. Another pupillary phenomenon that is sometimes associated with lesions of the optic tract that produce a complete or nearly complete homonymus hemianopia is pupillary hemiakinesia (hemianopic pupillary reaction or Wernicke's pupil) (Miller N, et al, 2008).

#### **2.2.8 Neuro-ophthalmological signs and symptoms associated with the chiasmal syndrome**

The presence of visual field defect can associate different manifestations, such as the *hemifield slide phenomenon* that produces fluctuating diplopia with no oculomotor impairment due to anomalous retinal correspondence. It is also common a *disturbance of depth perception*. These two phenomenons are associated to bitemporal hemianopia (Chhabra & Newman, 2006; Miller N, et al, 2008).

#### **2.2.9 Ocular motility disorders**

Patients with pituitary pathology can refer diplopia related to the mentioned hemifield slide phenomenon, or due to cranial nerves damage in the cavernous sinus; the most frequently affected is the third nerve leading to an eyelid ptosis, pupillary dilation, and ocular motility disorders (figure 4). The rarest of those syndromes is the VI nerve palsy.

#### **2.2.10 Nystagmus**

In cases of tumours of the diencephalon and chiasmal regions the rare phenomenon of the "see-saw" nystagmus may occur. This condition is characterized by synchronous alternating elevation and incyclotorsion of one eye and depression and excyclotorsion of the opposite eye. The pathogenesis of this phenomenon is not well understood but it is thought to be related to perception impairment connected with hemianopia (Chhabra & Newman, 2006)

Compression of the superior part of the chiasm is not a frequent condition in cases of pituitary adenomas; it is more likely to see this clinical picture in other tumours arising from the base of the brain, mainly the craniopharyngioma. In these cases the visual field defects

More frequent in pre-fixed chiasms. It produces characteristic bitemporal hemianopic

This syndrome can be observed in tumours compressions or carotid pathology that pushes the chiasm laterally. Contralateral homonymus quadrantanopic or hemianopic defects can

This is also more frequent in cases of post-fixed chiasms. Contralateral homonymus defects can be observed. Optic tract damage is more frequent in other neurological conditions, such as vascular processes, demyelinating diseases or trauma. Another pupillary phenomenon that is sometimes associated with lesions of the optic tract that produce a complete or nearly complete homonymus hemianopia is pupillary hemiakinesia (hemianopic pupillary reaction

**2.2.8 Neuro-ophthalmological signs and symptoms associated with the chiasmal** 

The presence of visual field defect can associate different manifestations, such as the *hemifield slide phenomenon* that produces fluctuating diplopia with no oculomotor impairment due to anomalous retinal correspondence. It is also common a *disturbance of depth perception*. These two phenomenons are associated to bitemporal hemianopia (Chhabra

Patients with pituitary pathology can refer diplopia related to the mentioned hemifield slide phenomenon, or due to cranial nerves damage in the cavernous sinus; the most frequently affected is the third nerve leading to an eyelid ptosis, pupillary dilation, and ocular motility

In cases of tumours of the diencephalon and chiasmal regions the rare phenomenon of the "see-saw" nystagmus may occur. This condition is characterized by synchronous alternating elevation and incyclotorsion of one eye and depression and excyclotorsion of the opposite eye. The pathogenesis of this phenomenon is not well understood but it is thought to be related to perception impairment connected with hemianopia (Chhabra & Newman, 2006)

disorders (figure 4). The rarest of those syndromes is the VI nerve palsy.

be assessed; much less frequent is the binasal hemianopia in these cases.

**2.2.4 Superior chiasmal syndrome** 

**2.2.5 Posterior chiasmal syndrome** 

**2.2.6 Lateral chiasmal syndrome** 

**2.2.7 Optic tract compression** 

**syndrome** 

or Wernicke's pupil) (Miller N, et al, 2008).

& Newman, 2006; Miller N, et al, 2008).

**2.2.9 Ocular motility disorders** 

**2.2.10 Nystagmus** 

are temporal and inferior.

scotomas in the visual field.

Fig. 4. Patient affected by a III nerve palsy. Observe the eyelid ptosis due to affectation of the levator muscle. These patients also have pupillary dilation and extraocular movements impairment

or damage to the interstitial nucleus of Cajal or adjacent structures of the tumour (Miller, et al, 2008). In cases of big tumours compressing the brainstem is also possible, although exceptional, the presence of nystagmus.

#### **2.2.11 Colour vision impairment**

This can be observed as a sign of visual pathway damage in different conditions, including cases of pituitary adenomas.

#### **2.2.12 Photophobia**

Some authors suggest that persistent photophobia of unknown aetiology should arise the suspicion of pituitary pathology (Kawasaki & Purvin, 2002).

#### **2.2.13 Pituitary apoplexy**

Defined as a sudden neurologic impairment, usually due to a vascular process. It is characterized by a sudden onset of headache, visual symptoms, altered mental status, and hormonal dysfunction due to acute hemorrhage or infarction of a pituitary gland. An existing pituitary adenoma is usually present. The incidence of this phenomenon has been described up to 10% in some series (Wakai, 1981). The visual symptoms may include both visual acuity impairment and visual field impairment from involvement of the optic nerve or chiasm and ocular motility dysfunction from involvement of the cranial nerves traversing the cavernous sinus (more frequent III nerve). Other less common symptoms are related to possible brainstem damage, such as light-near dissociation or convergence retraction nystagmus.

#### **2.2.14 Funduscopy**

Most of the cases show normal optic discs in fundus examination. If altered, it can be a diffuse atrophy, or more typically the "band" or "bow-tie" atrophy that occupies a more or less horizontal band across the disc with relative sparing of the superior and inferior portions where the majority of spared temporal fibers enter (figure 5). Some cases can develop papilledema, this is more frequently associated with suprachiasmal tumours that can invade and compress the 3rd ventricle, ultimately obstructing the flow of cerebrospinal fluid.

Pituitary Adenomas and Ophthalmology 9

indicates that there must be other factors that determine different degrees of axonal affectation in different patients. One of the main current research lines in this field is actually seeking the diagnostic tools that allow us to predict the degree of axonal loss, and

During the last years, OCT has been used to establish and quantifying the axonal loss in several neurological disorders. OCT is a non-invasive tool that allows the retina to be directly approached as an appendix of the central nervous system. We can measure peripapillary retinal nerve fiber layer (RNFL) thickness, a parameter which has been found to be reproducible and useful for the diagnosis, prognosis and follow-up of optic nerve axonal damage in several neurological diseases, including pituitary adenomas (Moura, et al, 2007; Parisi, 2003; Sergott, et al, 2007; Kallenbach & Frederiksen, 2007; Toledo, et al, 2008; Noval, et al, 2006; Vessani, et al, 2009). (figure 6). OCT can be useful predicting

Fig. 6. Optical Coherence Tomography. Observe the retinal nerve fiber layer (RNFL) measurement in microns. A diagram is included to analyze the different sectors of the optic disc and peripapillar area. This example shows thinning of the RNFL affecting the right eye (OD) predominantly in the superior and temporal quadrants, the left eye (OS) shows normal results. The bottom of the image shows funduscopy of both eyes and demonstrates the optic

disc atrophy of the right eye (A) while the left eye is normal (B).

so the possibility of visual function recovery after the treatment.

Fig. 5. Schematic representation of retinal nerve fibers (A). Optic disc of a patient with a pituitary adenoma showing atrophy of the nasal and temporal areas ("band" atrophy) and relative spare of the superior and inferior areas of the disc (B).

#### **2.2.15 Other neuro-ophthalmological manifestations**

Apart from the syndromes derivated from the tumour itself, the treatments used in these patients can produce neuro-ophthalmological side-effects:


#### **3. Visual recovery prediction factors**

During the last years different specialists involve in the management of pituitary adenomas have tried to establish prognostic factors of visual recovery after the treatment of these patients. To date there are several well recognize prognostic factors, such as the age of patients (the older the worse prognostic), the duration of the symptoms before the surgery, the size of the tumour (better prognostic in microadenomas) and the presence of pituitary apoplexy, which is a bad prognostic factor. From the ophthalmology point of view, several factors such as visual acuities less than 20/100 or a pale optic disc have been reported to determine a worse prognostic (Chhabra & Newman, 2006).

Although some cases show a severe visual impairment, it is not unusual to observe important early recoveries (1st week), intermediate recoveries (1-4 months) or even late recoveries in some patients (up to 36 months after surgery) (Kerrison, et al, 2000). This

8 Pituitary Adenomas

Fig. 5. Schematic representation of retinal nerve fibers (A). Optic disc of a patient with a pituitary adenoma showing atrophy of the nasal and temporal areas ("band" atrophy) and

Apart from the syndromes derivated from the tumour itself, the treatments used in these

 Toxic dopaminergic psychosis caused by *Bromocriptine*. Treatment with this drug can also produce a quick tumour regression leading to an *empty sella syndrome* due to a

 The surgical treatment most frequently performed today for these patients is the endoscopic trans-sphenoidal surgery. This technique can be also responsible for some ophthalmological side effects, mainly for damaging the optic nerves or the chiasm; nevertheless, the increasingly improvement in the equipment and surgical techniques

 Post-radiotherapy optic neuropathy. This is a minor problem nowadays because radiotherapy is an unusual treatment for these tumours, and also because of the improvement in the techniques using fractioned radiotherapy and protecting important

During the last years different specialists involve in the management of pituitary adenomas have tried to establish prognostic factors of visual recovery after the treatment of these patients. To date there are several well recognize prognostic factors, such as the age of patients (the older the worse prognostic), the duration of the symptoms before the surgery, the size of the tumour (better prognostic in microadenomas) and the presence of pituitary apoplexy, which is a bad prognostic factor. From the ophthalmology point of view, several factors such as visual acuities less than 20/100 or a pale optic disc have been reported to

Although some cases show a severe visual impairment, it is not unusual to observe important early recoveries (1st week), intermediate recoveries (1-4 months) or even late recoveries in some patients (up to 36 months after surgery) (Kerrison, et al, 2000). This

allows treatments with much less complications (Cappabianca, et al, 2002).

structures such as the optic discs (Van den Bergh, et al, 2007).

determine a worse prognostic (Chhabra & Newman, 2006).

relative spare of the superior and inferior areas of the disc (B).

**2.2.15 Other neuro-ophthalmological manifestations** 

patients can produce neuro-ophthalmological side-effects:

herniation of the chiasm.

**3. Visual recovery prediction factors** 

indicates that there must be other factors that determine different degrees of axonal affectation in different patients. One of the main current research lines in this field is actually seeking the diagnostic tools that allow us to predict the degree of axonal loss, and so the possibility of visual function recovery after the treatment.

During the last years, OCT has been used to establish and quantifying the axonal loss in several neurological disorders. OCT is a non-invasive tool that allows the retina to be directly approached as an appendix of the central nervous system. We can measure peripapillary retinal nerve fiber layer (RNFL) thickness, a parameter which has been found to be reproducible and useful for the diagnosis, prognosis and follow-up of optic nerve axonal damage in several neurological diseases, including pituitary adenomas (Moura, et al, 2007; Parisi, 2003; Sergott, et al, 2007; Kallenbach & Frederiksen, 2007; Toledo, et al, 2008; Noval, et al, 2006; Vessani, et al, 2009). (figure 6). OCT can be useful predicting

Fig. 6. Optical Coherence Tomography. Observe the retinal nerve fiber layer (RNFL) measurement in microns. A diagram is included to analyze the different sectors of the optic disc and peripapillar area. This example shows thinning of the RNFL affecting the right eye (OD) predominantly in the superior and temporal quadrants, the left eye (OS) shows normal results. The bottom of the image shows funduscopy of both eyes and demonstrates the optic disc atrophy of the right eye (A) while the left eye is normal (B).

Pituitary Adenomas and Ophthalmology 11

Kerrison, JB., Lynn, MJ., Baer, CA., Newman, SA., Biousse, V. & Newman, NJ. (2000). Stages

Kosmorsky, GS., Dupps, WJ Jr. & Drake, RL. (2008). Nonuniform pressure generation in the

Miller, NR., Newman, NJ., Biousse, V. & Kerrison, JB. *Walsh and Hoyt's Clinical Neuro-*

Moura, FC., Medeiros, FA. & Monteiro, ML. (2007). Evaluation of macular thickness

coherente tomography. *Ophthalmology*. Vol. 114, 1, (Jan 2007), pp. (175-181). Muñoz-Negrete, FJ. & Rebolleda, G. (2002). Automated perimetry and neuro-

Noval, S., Contreras, I., Rebolleda, G. & Muñoz-Negrete, FJ. (2006). Optical coherence

Ortiz-Pérez, S., Sánchez-Dalmau, BF., Molina-Fernández, JJ. & Adán-Civera, A. (2009).

optical coherence tomography. *Rev Neurol*. Vol. 48, 2, (Jan 2009), pp. (85-90). Parisi, V. Correlation between morphological and functional retinal impairment in patients

Alzheimer's disease. *Semin Ophthalmol*. Vol. 18, 2, (Jun 2003), pp. (50-57). Rouvière, H. & Delmas, A. (1996). *Anatomía Humana. Descriptiva, topográfica y funcional* (9th

Sergott, RC., Frohman, E., Glanzman, R. & Al-Sabbagh, A. (2007). The role of optical

Toledo, J., Sepulcre, J., Salinas-Alaman, A. Garcia-Layana, A,. Murie-Fernandez, M,.

Van den Bergh, AC., Van den Berg, G., Schoorl, MA., Sluiter, WJ., Van der Vliet, AM.,

Vessani, RM., Moritz, R., Batis, L., Zagui, RB., Bernardoni, S. & Susanna, R. (2009).

eyes. *J Glaucoma*. Vol. 18, 3, (Mar 2009), pp. (253-261).

*Ophthalmol Scand*. Vol. 84, 6, (Dec 2008), pp. (790-794).

ed), Masson, ISBN 84-458-0506-1, Barcelona.

Vol. 263, 1-2, (Dec 2007), pp. (3-14).

(Aug 2008), pp. (906-912).

2007), pp. (863-869).

Vol. 130, 6, (Dec 2000), pp. (813-820).

2008), pp. (560-565).

2002), pp. (413-428).

7817-6379-0, Philadelphia.

of improvement in visual fields after pituitary tumors resection. *Am J Ophthalmol*.

optic chiasm may explain bitemporal hemianopsia*. Ophthalmology*. Vol. 115, 3, (Mar

*Ophthalmology: the essentials* (2nd ed), Lippincott Williams & Wilkins, ISBN-13: 978-0-

measurements for detection of band atrophy of the optic nerve using optical

ophthalmology. Topographic correlation. *Arch Soc Esp Oftalmol*, Vol. 77, 8, (Aug

tomography versus automated perimetry for follow-up of optic neuritis. *Acta* 

Neuro-ophthalmological manifestations of pituitary adenomas. The usefulness of

affected by ocular hypertension, glaucoma, demyelinating optic neuritis and

coherence tomography in multiple sclerosis: expert panel consensus. *J Neurol Sci*.

Bejarano, B. & Villoslada, P. (2008). Retinal nerve fiber layer atrophy is associated with physical and cognitive disability in multiple sclerosis. *Mult Scler*. Vol. 14, 7,

Hoving, EW., Szabó, BG,. Langendijk, JA,. Wolffenbuttel, BH. & Dullart, RP. (2007). Immediate postoperative radiotherapy in residual nonfunctioning pituitary adenoma: beneficial effect on local control without additional negative impact on pituitary function and life expectancy*. Int J Radiat Oncol Biol Phys*. Vol. 67, 3, (Mar

Comparison of quantitative imaging devices and subjective optic nerve head assessment by general ophthalmologists to differentiate normal from glaucomatous

the visual function recovery in patients with pituitary adenomas by measuring the axonal damage in the retina during the evolution of the disease (Ortiz-Perez, et al, 2009; Jacob, et al, 2008).

#### **4. Conclusions**

Pituitary adenomas are a frequent pathology with a wide spectrum of clinical features. These tumours should be managed between different specialists including general practitioners, endocrinologists, neurologists, neurosurgeons and ophthalmologists. Neuroophthalmological manifestations of pituitary adenomas are frequent and varied. They represent sometimes the onset symptoms in these patients. Many of the syndromes described above have an important diagnostic value due to their localizing information. Physicians must be aware about these syndromes in order to refer patients for ophthalmological assessments and establish an early diagnosis.

OCT is a new device used daily in ophthalmology clinics to study the retina and optic disc. This tool gives unique and new information about the axonal loss in patients with neurological disorders, including pituitary adenomas. OCT is easily performed, it has no side effects or contraindications, so it must be included in the routine examination of patients with hypophysis tumours.

#### **5. References**


the visual function recovery in patients with pituitary adenomas by measuring the axonal damage in the retina during the evolution of the disease (Ortiz-Perez, et al, 2009; Jacob, et al,

Pituitary adenomas are a frequent pathology with a wide spectrum of clinical features. These tumours should be managed between different specialists including general practitioners, endocrinologists, neurologists, neurosurgeons and ophthalmologists. Neuroophthalmological manifestations of pituitary adenomas are frequent and varied. They represent sometimes the onset symptoms in these patients. Many of the syndromes described above have an important diagnostic value due to their localizing information. Physicians must be aware about these syndromes in order to refer patients for

OCT is a new device used daily in ophthalmology clinics to study the retina and optic disc. This tool gives unique and new information about the axonal loss in patients with neurological disorders, including pituitary adenomas. OCT is easily performed, it has no side effects or contraindications, so it must be included in the routine examination of

Asa, SL. & Ezzat, S. (2009). The pathogenesis of pituitary tumors*. Annu Rev Pathol,* Vol. 4

Beckers, A. & Daly, AF. (2007). The clinical, pathological, and genetic features of

Cappabianca, P., Cavallo, LM., Colao, AM. & de Divitiis, E. (2002). Surgical complications

Chhabra, VS. & Newman, NJ. (2006). The neuro-ophthalmology of pituitary tumors. *Compr* 

Frank, G., Pasquini, E., Farneti, G., Mazzatenta, D., Sciarretta, V., Grasso, V. & Faustini, M.

Jacob, M., Joaunneau, E. & Raverot, G. (2008). Value of optical coherence tomography (OCT)

Kallenbach, K. & Frederiksen, J. (2007). Optical coherence tomography in optic neuritis and multiple sclerosis: a review. *Eur J Neurol*. Vol. 14, 8, (Aug 2007), pp. (841-849). Kawasaki, A. & Purvin, VA. (2002). Photophobia as the presenting visual symptom of chiasmal compression. *J Neuroophthalmol*. Vol. 22, 1, (Mar 2002), pp. (3-8).

adenomas*. J Neurosurg*. Vol. 97, 2, (Aug 2002), pp. (293-298).

*Ophthalmol Update,* Vol. 7, 5, (Oct 2006), pp. (225-240).

*Neuroendocrinology*. Vol. 83, 3-4, (2006), pp. (240-248).

familial isolated pituitary adenomas. *Eur J Endocrinol*, Vol. 157, 4, (Oct 2007), pp.

associated with the endoscopic endonasal transsphenoidal approach for pituitary

(2006). The endoscopic versus the traditional approach in pituitary surgery.

in predicting visual outcome after treatment of pituitary adenoma. In: *North American Neuro-Ophthalmology Society (NANOS) congress*. Orlando, EEUU, March

ophthalmological assessments and establish an early diagnosis.

2008).

**4. Conclusions** 

**5. References** 

patients with hypophysis tumours.

(2009), pp. (97-126)

(371-82).

2008.


**Diagnostic Imaging of** 

*Wroclaw Medical University* 

*Poland* 

Joanna Bladowska and Marek Sąsiadek

**the Pituitary and Parasellar Region** 

*Department of General Radiology, Interventional Radiology and Neuroradiology* 

Pituitary (*hypophysis*), the secreting gland located in the sella turcica, has fascinated the scientists since ages. In 1543 the Belgian scientist Andreas Vesalius described the anatomy of pituitary gland for the first time. He believed that pituitary produces mucus, which is secreted from the brain into the nasal cavity. This is why pituitary was called the mucous gland (*glandula pituitaria; pituita = mucus*). Pituitary gland, also called as "master gland" plays the special role in the body. There are plenty of pathological changes with different clinical and radiological appearances of lesions located in sellar and parasellar region. The knowledge of pituitary anatomy and function, as well as of the characteristic changes in size and shape of the pituitary throughout the life and special physiologic conditions, is mandatory for the correct diagnosis and therefore these factors have to be taken into account

Introduction of imaging modalities, especially magnetic resonance (MR), and of modern methods of neurosurgery and pharmacotherapy revolutionised diagnosis and therapy of pituitary tumours. Currently, MR is the method of choice for imaging of the pituitary gland and the parasellar area. Advanced MR techniques – MR diffusion, MR spectroscopy and MR perfusion – have been increasingly applied (Boxerman et al., 2010; Chernov et al., 2009).

MR imaging protocol of pituitary and sellar region including postoperative studies should consist of unenhanced T1- and T2-weighted images in coronal and sagittal planes (slice thickness 3mm, field of view FOV=16x16). Paramagnetic contrast medium is administrated intravenously at the standard dose of 0.1 ml/kg BM and post-contrast T1-weighted images

MR examination enables visualization of many anatomic details of pituitary gland, such as: the anterior lobe (adenohypophysis), the posterior lobe (neurohypophysis), pituitary infundibulum, parasellar structures (cavernous sinuses, sphenoid sinus, suprasellar cisterns)

The normal pituitary gland shows the homogenous signal intensity, which is isointense compared to the white matter signal on T1-weighted as well as on T2-weighted images

are taken in coronal and sagittal planes (Bladowska et al., 2004, 2011).

**1. Introduction** 

before assessing pituitary abnormalities.

and optic chiasm (Bladowska et al., 2004).

**2. Imaging of pituitary gland** 

Wakai, S., Fukushima, T., Teramoto, A. & Sano, K. (1981). Pituitary apoplexy: its incidence and clinical significance*. J Neurosurg*. Vol. 55, 2, (Aug 1981), pp. (187-193). **2** 

## **Diagnostic Imaging of the Pituitary and Parasellar Region**

Joanna Bladowska and Marek Sąsiadek

*Department of General Radiology, Interventional Radiology and Neuroradiology Wroclaw Medical University Poland* 

#### **1. Introduction**

12 Pituitary Adenomas

Wakai, S., Fukushima, T., Teramoto, A. & Sano, K. (1981). Pituitary apoplexy: its incidence

Pituitary (*hypophysis*), the secreting gland located in the sella turcica, has fascinated the scientists since ages. In 1543 the Belgian scientist Andreas Vesalius described the anatomy of pituitary gland for the first time. He believed that pituitary produces mucus, which is secreted from the brain into the nasal cavity. This is why pituitary was called the mucous gland (*glandula pituitaria; pituita = mucus*). Pituitary gland, also called as "master gland" plays the special role in the body. There are plenty of pathological changes with different clinical and radiological appearances of lesions located in sellar and parasellar region. The knowledge of pituitary anatomy and function, as well as of the characteristic changes in size and shape of the pituitary throughout the life and special physiologic conditions, is mandatory for the correct diagnosis and therefore these factors have to be taken into account before assessing pituitary abnormalities.

#### **2. Imaging of pituitary gland**

Introduction of imaging modalities, especially magnetic resonance (MR), and of modern methods of neurosurgery and pharmacotherapy revolutionised diagnosis and therapy of pituitary tumours. Currently, MR is the method of choice for imaging of the pituitary gland and the parasellar area. Advanced MR techniques – MR diffusion, MR spectroscopy and MR perfusion – have been increasingly applied (Boxerman et al., 2010; Chernov et al., 2009).

MR imaging protocol of pituitary and sellar region including postoperative studies should consist of unenhanced T1- and T2-weighted images in coronal and sagittal planes (slice thickness 3mm, field of view FOV=16x16). Paramagnetic contrast medium is administrated intravenously at the standard dose of 0.1 ml/kg BM and post-contrast T1-weighted images are taken in coronal and sagittal planes (Bladowska et al., 2004, 2011).

MR examination enables visualization of many anatomic details of pituitary gland, such as: the anterior lobe (adenohypophysis), the posterior lobe (neurohypophysis), pituitary infundibulum, parasellar structures (cavernous sinuses, sphenoid sinus, suprasellar cisterns) and optic chiasm (Bladowska et al., 2004).

The normal pituitary gland shows the homogenous signal intensity, which is isointense compared to the white matter signal on T1-weighted as well as on T2-weighted images

Diagnostic Imaging of the Pituitary and Parasellar Region 15

Fig. 3. MR imaging of normal pituitary gland in sagittal planes before contrast

administration: A. T1-weighted image. B. T2-weighted image. The high signal intensity of

Fig. 4. MR imaging in sagittal planes before contrast administration, a 36-y.o. man with central diabetes insipidus. A. T1-weighted image. B. T2-weighted image. The high signal

signal of the posterior lobe, therefore its absence cannot be taken as an absolute sign of

The normal pituitary gland undergoes the characteristic changes in size and shape throughout

In neonates, the pituitary gland is typically convex and shows a higher signal intensity compared to the brain stem on T1-weighted images (Fig.5). This appearance persists for about 2 months, after which the pituitary will present with a flat superior surface and a signal intensity similar to the signal of the pons, what is typical for the older children.

Throughout childhood, the pituitary reveals a slight but definite growth in all dimensions. The upper surface is flat or mildly concave and the height of the pituitary in the sagittal

the life, which have to be taken into account before assessing pituitary abnormalities.

plane is about 2-6mm (Fig.6a,b), there are no differences between girls and boys.

A B

the posterior lobe is clearly visible.

A B

intensity of the posterior lobe is not visible.

pituitary disease or dysfunction (Evanson, 2002).

(Fig.1a,b). After contrast administration pituitary gland presents the homogenous strong enhancement (Fig.2a,b).

The posterior lobe of the pituitary demonstrates the characteristic high signal intensity on T1- and T2-weighted images, seen just in front of the sellar dorsum and clearly differentiated from the anterior pituitary lobe. The high signal intensity of the posterior lobe is especially clearly visible on the sagittal planes (Fig. 3a,b) and it is called "posterior pituitary bright spot". This high intensity signal observed in the posterior lobe is believed to be related to intracellular droplets of lipid or lipidlike material in pituicytes (astrocytic glial cells). However, the recent studies using the sequences with fat suppression have not confirmed the presence of fat tissue within the neurohypophysis (Arslan et al., 1999).

Absence of this high intensity signal have been reported in patients with central diabetes insipidus (Fig.4a.b). It has to be stressed that some normal subjects lack this hyperintense

Fig. 1. MR imaging of normal pituitary gland in coronal planes before contrast administration: A. T1-weighted image. B. T2-weighted image.

Fig. 2. MR imaging of normal pituitary gland, T1-weighted images after contrast administration: A. Coronal plane. B. Sagittal plane.

(Fig.1a,b). After contrast administration pituitary gland presents the homogenous strong

The posterior lobe of the pituitary demonstrates the characteristic high signal intensity on T1- and T2-weighted images, seen just in front of the sellar dorsum and clearly differentiated from the anterior pituitary lobe. The high signal intensity of the posterior lobe is especially clearly visible on the sagittal planes (Fig. 3a,b) and it is called "posterior pituitary bright spot". This high intensity signal observed in the posterior lobe is believed to be related to intracellular droplets of lipid or lipidlike material in pituicytes (astrocytic glial cells). However, the recent studies using the sequences with fat suppression have not

confirmed the presence of fat tissue within the neurohypophysis (Arslan et al., 1999).

Fig. 1. MR imaging of normal pituitary gland in coronal planes before contrast

Fig. 2. MR imaging of normal pituitary gland, T1-weighted images after contrast

administration: A. T1-weighted image. B. T2-weighted image.

A B

administration: A. Coronal plane. B. Sagittal plane.

A B

Absence of this high intensity signal have been reported in patients with central diabetes insipidus (Fig.4a.b). It has to be stressed that some normal subjects lack this hyperintense

enhancement (Fig.2a,b).

Fig. 3. MR imaging of normal pituitary gland in sagittal planes before contrast administration: A. T1-weighted image. B. T2-weighted image. The high signal intensity of the posterior lobe is clearly visible.

Fig. 4. MR imaging in sagittal planes before contrast administration, a 36-y.o. man with central diabetes insipidus. A. T1-weighted image. B. T2-weighted image. The high signal intensity of the posterior lobe is not visible.

signal of the posterior lobe, therefore its absence cannot be taken as an absolute sign of pituitary disease or dysfunction (Evanson, 2002).

The normal pituitary gland undergoes the characteristic changes in size and shape throughout the life, which have to be taken into account before assessing pituitary abnormalities.

In neonates, the pituitary gland is typically convex and shows a higher signal intensity compared to the brain stem on T1-weighted images (Fig.5). This appearance persists for about 2 months, after which the pituitary will present with a flat superior surface and a signal intensity similar to the signal of the pons, what is typical for the older children.

Throughout childhood, the pituitary reveals a slight but definite growth in all dimensions. The upper surface is flat or mildly concave and the height of the pituitary in the sagittal plane is about 2-6mm (Fig.6a,b), there are no differences between girls and boys.

Diagnostic Imaging of the Pituitary and Parasellar Region 17

high signal intensity on T1-weighted images (Fig.7), like in the neonate period (Bladowska

Fig. 7. MR imaging of the pituitary gland in 24-y.o. woman 5 days after delivery, T1 weighted image in axial plane. The pituitary gland demonstrated the characteristic high

From young adulthood until middle age, the pituitary glands of both sexes show usually stable appearance. Beyond age of 50 years, progressive involution of the gland is observed, what is probably related to the decrease in pituitary activity during menopause and andropause period. It has to be emphasized that in about 30% of this population the high signal intensity of the posterior pituitary lobe is not visible, as well as the empty sella syndrome is more commonly noted, but these changes are typical signs of normal aging

Pituitary adenomas constitute approximately 10 to 15% of all primary intracranial neoplasms and are the most common causes of pituitary function disorders and field of view deficits. Therefore, early diagnosis and therapy of patients with pituitary tumors are of

Pituitary adenomas are the most common pathology encountered in the sellar region. They are usually benign and slow growing tumors, but up to 50% reveal histological evidence of capsule invasion, furthermore less than 0.2% could be malignant, causing local spread into

About 70% of pituitary adenomas are diagnosed in patients aged 30-50-y.o., while subjects in age below 20-y.o. constitute only 3 to 7% of all patients with pituitary tumors. Besides,

pituitary adenomas are more common in women than in men (Daly et al., 2009).

et al., 2004; Elster, 1991, 1993).

signal intensity.

process (Bladowska et al., 2004; Elster, 1993).

high importance in clinical practice (Bladowska et al., 2010a).

the central nervous system. Pituitary carcinoma is exceedingly rare.

**3. Imaging of pituitary adenomas** 

Fig. 5. MR imaging in neonate, T1-weighted image in axial plane. The pituitary gland demonstrates the characteristic high signal intensity.

Fig. 6. MR imaging of normal pituitary gland in 5-y.o. boy, T1-weighted images.: A. Sagittal plane B. Coronal plane after contrast administration.

At puberty the pituitary gland demonstrates the huge changes in size and shape, becoming larger than at any other time of the whole life. In girls the gland can reach the height of 10mm, while in boys it may measure 7-8mm. Furthermore, in pubertal girls the gland can also project above the sella and present with a marked convexity of its superior surface (Elster, 1990, 1993).

Physiologic hypertrophy of the pituitary can be observed during pregnancy, when the gland may increase in weight by 30%-100%. By the third trimester the pituitary usually measures even 10mm of height and shows the typical convex superior surface. It has to be stressed that during pregnancy and the 1st postpartum week, the pituitary gland demonstrates the

Fig. 5. MR imaging in neonate, T1-weighted image in axial plane. The pituitary gland

Fig. 6. MR imaging of normal pituitary gland in 5-y.o. boy, T1-weighted images.: A. Sagittal

At puberty the pituitary gland demonstrates the huge changes in size and shape, becoming larger than at any other time of the whole life. In girls the gland can reach the height of 10mm, while in boys it may measure 7-8mm. Furthermore, in pubertal girls the gland can also project above the sella and present with a marked convexity of its superior surface

Physiologic hypertrophy of the pituitary can be observed during pregnancy, when the gland may increase in weight by 30%-100%. By the third trimester the pituitary usually measures even 10mm of height and shows the typical convex superior surface. It has to be stressed that during pregnancy and the 1st postpartum week, the pituitary gland demonstrates the

demonstrates the characteristic high signal intensity.

plane B. Coronal plane after contrast administration.

(Elster, 1990, 1993).

A B

high signal intensity on T1-weighted images (Fig.7), like in the neonate period (Bladowska et al., 2004; Elster, 1991, 1993).

Fig. 7. MR imaging of the pituitary gland in 24-y.o. woman 5 days after delivery, T1 weighted image in axial plane. The pituitary gland demonstrated the characteristic high signal intensity.

From young adulthood until middle age, the pituitary glands of both sexes show usually stable appearance. Beyond age of 50 years, progressive involution of the gland is observed, what is probably related to the decrease in pituitary activity during menopause and andropause period. It has to be emphasized that in about 30% of this population the high signal intensity of the posterior pituitary lobe is not visible, as well as the empty sella syndrome is more commonly noted, but these changes are typical signs of normal aging process (Bladowska et al., 2004; Elster, 1993).

### **3. Imaging of pituitary adenomas**

Pituitary adenomas constitute approximately 10 to 15% of all primary intracranial neoplasms and are the most common causes of pituitary function disorders and field of view deficits. Therefore, early diagnosis and therapy of patients with pituitary tumors are of high importance in clinical practice (Bladowska et al., 2010a).

Pituitary adenomas are the most common pathology encountered in the sellar region. They are usually benign and slow growing tumors, but up to 50% reveal histological evidence of capsule invasion, furthermore less than 0.2% could be malignant, causing local spread into the central nervous system. Pituitary carcinoma is exceedingly rare.

About 70% of pituitary adenomas are diagnosed in patients aged 30-50-y.o., while subjects in age below 20-y.o. constitute only 3 to 7% of all patients with pituitary tumors. Besides, pituitary adenomas are more common in women than in men (Daly et al., 2009).

Diagnostic Imaging of the Pituitary and Parasellar Region 19

Fig. 9. T1-weighted image in coronal plane after contrast administration. The hypointense

It has to be emphasized, as mentioned above, the contrast-enhancement images may be normal in case of the extremely small tumor (picoadenoma). When the plain MR images are not convincing, other techniques can be also used. The delayed images taken about 30-40 minutes after contrast administration may reveal late enhancement of the microadenoma itself (Bonneville et al., 2005). In our own material of pituitary adenomas we have noticed microadenomas, which show contrast-enhancement just about 10 minutes after injection of

Fig. 10. T1-weighted sagittal images, before (A) and about 10 minutes after contrast administration. On the delayed image the enhancing microadenoma is clearly visible.

administration seem to be more useful in inconclusive cases.

The ACTH-secreting microadenomas associated with Cushing's disease tend to be very small (typical feature of picoadenomas) and more often occult on MR imaging (Bonneville et al., 2005; Evanson, 2002). Dynamic imaging can be recommended in the diagnosis of ACTHsecreting microadenomas, when the clinical symptoms are highly suggesting of pituitary pathology, but the plain MR imaging is normal. Dynamic imaging can evidence a lack or a temporary delay of enhancement in the microadenoma compared to the unaffected pituitary gland. However, the delayed images taken at least about 10 minutes after contrast

microadenoma is visible on the right side of the pituitary gland.

A B

contrast (Fig.10a,b).

Pituitary adenomas can be classified on the basis of their size: microadenomas are less than 10mm in diameter and macroadenomas are greater than 10mm. It has to be stressed that the separate term "picoadenomas" should be used for describing the tumors smaller than 3mm, because these lesions are posing special diagnostic problems – it is often impossible to visualize the picoadenomas on MR imaging (Bonneville et al., 2000, 2005).

Furthermore, clinically adenomas are classified depending upon the presence or absence of specific hormonal activity. They are divided into two groups: functioning pituitary adenomas and non-functioning adenomas. Functioning adenomas usually secrete a single hormone causing a well recognised endocrine syndrome like e.g. acromegaly (GH - growth hormone-secreting adenomas).

In MR imaging, on T1-weighted images, about 80-90% of pituitary microadenomas present with lower signal intensity compared to the normal anterior pituitary lobe – they are hypointense. The other cases of microadenomas could be isointense and therefore they will be not visible on T1-weighted images before contrast administration. Pituitary microadenomas can also reveal high signal intensity on T1-weighted images, what may be caused by hemorrhagic transformation of the adenoma and this is a frequent sign in prolactinomas (PRL - prolactine-secreting adenomas). On T2-weighted images, about 1/3 to ½ of microadenomas demonstrate high signal intensity (Fig.8), what is especially helpful in making the correct diagnosis of pituitary pathology. Increased signal intensity on T2 weighted images is noted in over 80% of microprolactinomas. The other types of pituitary microadenomas can present different signal intensity on T2- weighted images, iso or hypointense signal occurs in about 2/3 cases of GH-secreting microadenomas (Bonneville et al., 2005).

Fig. 8. MR imaging in coronal planes before contrast administration. A. T2-weighted image. B. T1-weighted image. On the right side of the pituitary gland there is a microadenoma, which shows the high signal intensity on T2- weighted image, making the correct diagnosis easy, while it is almost not visible on T1-weighted image.

On the contrast-enhanced T1-weighted images microadenomas can show typically low signal intensity compared to the intense enhancement of the unaffected pituitary gland (Fig.9) (Bladowska et al., 2004).

Pituitary adenomas can be classified on the basis of their size: microadenomas are less than 10mm in diameter and macroadenomas are greater than 10mm. It has to be stressed that the separate term "picoadenomas" should be used for describing the tumors smaller than 3mm, because these lesions are posing special diagnostic problems – it is often impossible to

Furthermore, clinically adenomas are classified depending upon the presence or absence of specific hormonal activity. They are divided into two groups: functioning pituitary adenomas and non-functioning adenomas. Functioning adenomas usually secrete a single hormone causing a well recognised endocrine syndrome like e.g. acromegaly (GH - growth

In MR imaging, on T1-weighted images, about 80-90% of pituitary microadenomas present with lower signal intensity compared to the normal anterior pituitary lobe – they are hypointense. The other cases of microadenomas could be isointense and therefore they will be not visible on T1-weighted images before contrast administration. Pituitary microadenomas can also reveal high signal intensity on T1-weighted images, what may be caused by hemorrhagic transformation of the adenoma and this is a frequent sign in prolactinomas (PRL - prolactine-secreting adenomas). On T2-weighted images, about 1/3 to ½ of microadenomas demonstrate high signal intensity (Fig.8), what is especially helpful in making the correct diagnosis of pituitary pathology. Increased signal intensity on T2 weighted images is noted in over 80% of microprolactinomas. The other types of pituitary microadenomas can present different signal intensity on T2- weighted images, iso or hypointense signal occurs in about 2/3 cases of GH-secreting microadenomas (Bonneville et

Fig. 8. MR imaging in coronal planes before contrast administration. A. T2-weighted image. B. T1-weighted image. On the right side of the pituitary gland there is a microadenoma, which shows the high signal intensity on T2- weighted image, making the correct diagnosis

On the contrast-enhanced T1-weighted images microadenomas can show typically low signal intensity compared to the intense enhancement of the unaffected pituitary gland

visualize the picoadenomas on MR imaging (Bonneville et al., 2000, 2005).

hormone-secreting adenomas).

A B

easy, while it is almost not visible on T1-weighted image.

(Fig.9) (Bladowska et al., 2004).

al., 2005).

Fig. 9. T1-weighted image in coronal plane after contrast administration. The hypointense microadenoma is visible on the right side of the pituitary gland.

It has to be emphasized, as mentioned above, the contrast-enhancement images may be normal in case of the extremely small tumor (picoadenoma). When the plain MR images are not convincing, other techniques can be also used. The delayed images taken about 30-40 minutes after contrast administration may reveal late enhancement of the microadenoma itself (Bonneville et al., 2005). In our own material of pituitary adenomas we have noticed microadenomas, which show contrast-enhancement just about 10 minutes after injection of contrast (Fig.10a,b).

Fig. 10. T1-weighted sagittal images, before (A) and about 10 minutes after contrast administration. On the delayed image the enhancing microadenoma is clearly visible.

The ACTH-secreting microadenomas associated with Cushing's disease tend to be very small (typical feature of picoadenomas) and more often occult on MR imaging (Bonneville et al., 2005; Evanson, 2002). Dynamic imaging can be recommended in the diagnosis of ACTHsecreting microadenomas, when the clinical symptoms are highly suggesting of pituitary pathology, but the plain MR imaging is normal. Dynamic imaging can evidence a lack or a temporary delay of enhancement in the microadenoma compared to the unaffected pituitary gland. However, the delayed images taken at least about 10 minutes after contrast administration seem to be more useful in inconclusive cases.

Diagnostic Imaging of the Pituitary and Parasellar Region 21

Intratumoral hemorrhage is very often found in prolactinomas, especially after the treatment with bromocriptine. However, the hemorrhage may be revealed on MR images within adenomas in patients, who have not been treated (Bonneville et al., 2005). The hemorrhage shows the characteristic high intensity signal on T1-weighted images (Fig.13). A "fluid-fluid level" can be seen within the hemorrhage, and this feature is typical and more

common in adenomas compared to other tumors, such as craniopharyngiomas.

Fig. 13. T1-weighted coronal unenhanced image. The high intensity area of hemorrhage

Fig. 14. T1-weighted coronal contrast-enhanced image. The complete encasement of the

intracavernous part of the left internal carotid artery by the adenoma is visible.

of involvement of the cavernous sinus (Fig.14) (Bladowska et al., 2004).

Macroadenomas are intrasellar masses usually with extrasellar extension. They may grow upwards causing the optic chiasm compression and indent the floor of the third ventricle. These tumors can also extend downward into the sphenoid sinus, back into the dorsum sellae or laterally into the cavernous sinus. Involvement of the cavernous sinus can modify the prognosis, therefore the correct diagnosis is of high clinical importance, although it may remain difficult to differentiate compression and involvement. The complete encasement of the intracavernous part of the internal carotid artery (ICA) by the adenoma is the best sign

within prolactine-secreting macroadenoma is visible.

The diagnosis of macroadenoma in MR imaging is usually simple because of the tumor size over 10mm, making the adenoma clearly visible, even in the computed tomography (CT). However, the other tumors may also be located in the sellar region and they can mimic pituitary adenomas. Therefore, the precise knowledge of the MR appearance of the macroadenomas is of high importance in the clinical practice.

Macroadenomas are usually isointense on T1-weighted images, and after contrast administration they show different enhancement patterns (Fig.11, 12). On T2-weighted images they may be often inhomogenous, with disseminated high intensity areas of cystic degeneration or necrotic regions. About 18% of macroadenomas reveal the cystic components, while about 20% show features of haemorrhage, usually clinically asymptomatic and diagnosed incidentally in MR imaging. Large pituitary adenomas are prone to develop infarction or haemorrhage, because of their tenuous blood supply.

Fig. 11. T1-weighted coronal images before (A) and after contrast administration (B). The sellar-suprasellar macroadenoma shows strong contrast-enhancement. There is evidence of the optic chiasm and the third ventricle compression.

Fig. 12. T1-weighted coronal images before (A) and after contrast administration (B). The macroadenoma does not enhance after contrast injection. The compressed pituitary gland, showing the high signal intensity, is displaced to the left side of the sella. There is also the right cavernous sinus involvement.

The diagnosis of macroadenoma in MR imaging is usually simple because of the tumor size over 10mm, making the adenoma clearly visible, even in the computed tomography (CT). However, the other tumors may also be located in the sellar region and they can mimic pituitary adenomas. Therefore, the precise knowledge of the MR appearance of the

Macroadenomas are usually isointense on T1-weighted images, and after contrast administration they show different enhancement patterns (Fig.11, 12). On T2-weighted images they may be often inhomogenous, with disseminated high intensity areas of cystic degeneration or necrotic regions. About 18% of macroadenomas reveal the cystic components, while about 20% show features of haemorrhage, usually clinically asymptomatic and diagnosed incidentally in MR imaging. Large pituitary adenomas are

prone to develop infarction or haemorrhage, because of their tenuous blood supply.

Fig. 11. T1-weighted coronal images before (A) and after contrast administration (B). The sellar-suprasellar macroadenoma shows strong contrast-enhancement. There is evidence of

Fig. 12. T1-weighted coronal images before (A) and after contrast administration (B). The macroadenoma does not enhance after contrast injection. The compressed pituitary gland, showing the high signal intensity, is displaced to the left side of the sella. There is also the

macroadenomas is of high importance in the clinical practice.

A B

the optic chiasm and the third ventricle compression.

A B

right cavernous sinus involvement.

Intratumoral hemorrhage is very often found in prolactinomas, especially after the treatment with bromocriptine. However, the hemorrhage may be revealed on MR images within adenomas in patients, who have not been treated (Bonneville et al., 2005). The hemorrhage shows the characteristic high intensity signal on T1-weighted images (Fig.13). A "fluid-fluid level" can be seen within the hemorrhage, and this feature is typical and more common in adenomas compared to other tumors, such as craniopharyngiomas.

Fig. 13. T1-weighted coronal unenhanced image. The high intensity area of hemorrhage within prolactine-secreting macroadenoma is visible.

Macroadenomas are intrasellar masses usually with extrasellar extension. They may grow upwards causing the optic chiasm compression and indent the floor of the third ventricle. These tumors can also extend downward into the sphenoid sinus, back into the dorsum sellae or laterally into the cavernous sinus. Involvement of the cavernous sinus can modify the prognosis, therefore the correct diagnosis is of high clinical importance, although it may remain difficult to differentiate compression and involvement. The complete encasement of the intracavernous part of the internal carotid artery (ICA) by the adenoma is the best sign of involvement of the cavernous sinus (Fig.14) (Bladowska et al., 2004).

Fig. 14. T1-weighted coronal contrast-enhanced image. The complete encasement of the intracavernous part of the left internal carotid artery by the adenoma is visible.

Diagnostic Imaging of the Pituitary and Parasellar Region 23

Furthermore, they present with different histological structure compared to craniopharyngiomas - Rathke's cysts are lined by a single layer of epithelium, while craniopharyngiomas have thick walls composed of squamous or basal cells (Bladowska et

Rathke's cleft cysts are relatively common incidental findings, usually remaining

In MR imaging Rathke's cleft cysts display variable signal intensity. Cysts containing serous fluid are typically hypointense on T1-weighted images and hyperintense on T2-weighted images (Fig.16), while mucoid cyst reveal high signal intensity on T1-weighted images and often characteristic very low signal on T2-weighted images (Fig.17). After contrast administration they usually do not enhance, although sometimes they can show very thin

Fig. 16. MR imaging in coronal planes before contrast administration. A. T1-weighted image. B. T2-weighted image. Rathke's cleft cyst containing serous fluid – it is hypointense on T1

Fig. 17. MR imaging in sagittal planes before contrast administration. A. T1-weighted image. B. T2-weighted image. Rathke's cleft cyst containing mucoid fluid – it is hyperintense on T1

al. 2004; Doerfler & Richter, 2008).

A B

and hyperintense on T2-weighted image.

and hypointense on T2-weighted image.

A B

asymptomatic.

rim enhancement.

### **4. Imaging of other pituitary tumors and parasellar lesions**

The most common pituitary tumors are adenomas, the other tumors constitute approximately 5 to 10% of all sellar and parasellar lesions. The precise knowledge of the MR appearance of these lesions is of high importance in clinical practice, because they can mimic pituitary adenomas. In this subsection we describe the characteristic imaging features of these tumors.

#### **4.1 Craniopharyngiomas**

Craniopharyngiomas are the most common suprasellar lesions. They account for approximately 3% of all intracranial neoplasms and are slow-growing, benign tumors, which arise from squamous epithelial cell rests of Rathke's pouch. These tumors are frequent in children and young adults, but they also can be found in older adults. Craniopharyngiomas may be divided into two histological types: adamantinomatous and squamous-papillary (Doerfler & Richter, 2008).

In MR imaging the signal intensity of craniopharyngioma varies with cyst contents. High T1 signal is the results of high protein content (Fig.15). The classic adamantinomatous type usually consists of hyperintense cysts and heterogeneous nodules. The less common papillary type is presented with isointense solid component. On T2-weighted images cysts are predominantly hyperintense, while the solid components show heterogeneous signal. After contrast administration the solid portions enhance heterogeneously, as well as cysts walls reveal strong enhancement (Bladowska et al. 2004; Doerfler & Richter, 2008).

Fig. 15. MR imaging in coronal planes before contrast administration. A. T1-weighted image. B. T2-weighted image. The sellar-suprasellar craniopharyngioma presents with high signal intensity on both T1- and T2-weighted images.

#### **4.2 Rathke's Cleft Cyst**

Rathke's cleft cysts account for approximately 1.5% of all sellar and parasellar lesions. They, like craniopharyngiomas, are also derived from the Rathke's pouch, but are usually smaller and almost always located intrasellar, between the anterior and posterior pituitary lobe.

The most common pituitary tumors are adenomas, the other tumors constitute approximately 5 to 10% of all sellar and parasellar lesions. The precise knowledge of the MR appearance of these lesions is of high importance in clinical practice, because they can mimic pituitary adenomas. In this subsection we describe the characteristic imaging features of these tumors.

Craniopharyngiomas are the most common suprasellar lesions. They account for approximately 3% of all intracranial neoplasms and are slow-growing, benign tumors, which arise from squamous epithelial cell rests of Rathke's pouch. These tumors are frequent in children and young adults, but they also can be found in older adults. Craniopharyngiomas may be divided into two histological types: adamantinomatous and

In MR imaging the signal intensity of craniopharyngioma varies with cyst contents. High T1 signal is the results of high protein content (Fig.15). The classic adamantinomatous type usually consists of hyperintense cysts and heterogeneous nodules. The less common papillary type is presented with isointense solid component. On T2-weighted images cysts are predominantly hyperintense, while the solid components show heterogeneous signal. After contrast administration the solid portions enhance heterogeneously, as well as cysts

Fig. 15. MR imaging in coronal planes before contrast administration. A. T1-weighted image. B. T2-weighted image. The sellar-suprasellar craniopharyngioma presents with high signal

Rathke's cleft cysts account for approximately 1.5% of all sellar and parasellar lesions. They, like craniopharyngiomas, are also derived from the Rathke's pouch, but are usually smaller and almost always located intrasellar, between the anterior and posterior pituitary lobe.

walls reveal strong enhancement (Bladowska et al. 2004; Doerfler & Richter, 2008).

**4. Imaging of other pituitary tumors and parasellar lesions** 

**4.1 Craniopharyngiomas** 

squamous-papillary (Doerfler & Richter, 2008).

A B

intensity on both T1- and T2-weighted images.

**4.2 Rathke's Cleft Cyst** 

Furthermore, they present with different histological structure compared to craniopharyngiomas - Rathke's cysts are lined by a single layer of epithelium, while craniopharyngiomas have thick walls composed of squamous or basal cells (Bladowska et al. 2004; Doerfler & Richter, 2008).

Rathke's cleft cysts are relatively common incidental findings, usually remaining asymptomatic.

In MR imaging Rathke's cleft cysts display variable signal intensity. Cysts containing serous fluid are typically hypointense on T1-weighted images and hyperintense on T2-weighted images (Fig.16), while mucoid cyst reveal high signal intensity on T1-weighted images and often characteristic very low signal on T2-weighted images (Fig.17). After contrast administration they usually do not enhance, although sometimes they can show very thin rim enhancement.

Fig. 16. MR imaging in coronal planes before contrast administration. A. T1-weighted image. B. T2-weighted image. Rathke's cleft cyst containing serous fluid – it is hypointense on T1 and hyperintense on T2-weighted image.

Fig. 17. MR imaging in sagittal planes before contrast administration. A. T1-weighted image. B. T2-weighted image. Rathke's cleft cyst containing mucoid fluid – it is hyperintense on T1 and hypointense on T2-weighted image.

Diagnostic Imaging of the Pituitary and Parasellar Region 25

Fig. 19. MR imaging in coronal planes of the pituitary abscess. A. T2-weighted unenhanced

**5. Postoperative MR imaging of pituitary and sellar region – own experience**  Post-surgical evaluation of the pituitary gland in MR is difficult because of a change in anatomical conditions. Interpretation of MR images taken after surgical therapy of pituitary tumors depends also on numerous other factors, including: size and expansion of a tumor before operation, type of surgical access, quality and volume of filling material and time of its resorption. Proper evaluation of post-surgical MR images is crucial for determination of completeness of the resection. Therefore neuro-radiologists face a responsible and difficult task of evaluation of structures present in the surgical area, and especially of differentiation of residual tumor from the implanted material and from post-surgical changes (fibrous and

cicatrical), or even from a part of normal gland left at site (Bladowska et al., 2010a,b).

In general, the residual tumors could be differentiated from postoperative changes by means of location, characteristic signal intensity and enhancing pattern, which should be similar to those in the preoperative MR imaging of the tumor. The infundibulum tilt could be additional factor suggesting the presence of residual adenoma. The endocrine studies are very helpful in postoperative diagnosis of hormone-secreting residual pituitary adenomas and are regarded as a method of choice in postoperative management of these tumors. It is especially difficult to evaluate the effectiveness of the surgical treatment of the nonfunctioning pituitary tumors, these tumors require a postsurgical MR follow-up

The basic therapeutic method of pituitary tumors (apart from microprolactinoma) is surgery. Among several operation methods of the sellar region, the most frequently applied is the one with transnasal transsphenoidal approach. This method has widely forced out craniotomy and is now concerned the method of choice in the treatment of the majority of pituitary adenomas, both the hormonally active and inactive ones (Bladowska et al.,

image. B. T1-weighted contrast-enhanced image. There is characteristic strong rim

A B

enhancement visible.

examinations.

2010b).

Other cysts located in the sellar and parasellar region include: arachnoid, dermoid, epidermoid and colloid cysts (Bladowska et al., 2010c; Doerfler & Richter 2008).

#### **4.3 Meningiomas**

Meningiomas of the sellar region (cavernous sinus, planum sphenoidale, diaphragm sellae and clinoid process) account for about 11% of all sellar and parasellar tumors and for 20- 30% of all intracranial meningiomas (Doerfler & Richter 2008). They are slow-growing, usually benign tumors.

Fig. 18. T1-weighted coronal contrast-enhanced image. The meningioma of the left cavernous sinus is visible.

In MR imaging meningiomas are isointense compared to grey matter on T1-weighted images and isointense or slightly hyperintense on T2-weighted images. After contrast administration they reveal homogeneous enhancement (Fig.18). Often they present with characteristic so-called "dural tail sign", what can help in differential diagnosis, but it has to be stressed that the "dural tail sign" is a nonspecific feature and may also be visible in other intracranial tumors.

#### **4.4 Other rare sellar and parasellar lesions**

Rare primary neoplasm of the pituitary and sellar region include: melanoma, intrasellar meningioma, germinoma, choristoma, glioma and metastases (Elster 1993; Ruscalleda 2005). Inflammatory and infectious lesions of pituitary and sellar region include: abscess (Fig.19) (Bladowska et al., 2010d), sarcoidosis, cysticercosis, Langerhans cell histiocytosis, blastomycosis, Wegener granulomatosis, Tolosa-Hunt syndrome, lymphocytic adenohypophysitis, giant cell granuloma and tuberculosis (Elster 1993; Doerfler & Richter 2008).

Other cysts located in the sellar and parasellar region include: arachnoid, dermoid,

Meningiomas of the sellar region (cavernous sinus, planum sphenoidale, diaphragm sellae and clinoid process) account for about 11% of all sellar and parasellar tumors and for 20- 30% of all intracranial meningiomas (Doerfler & Richter 2008). They are slow-growing,

epidermoid and colloid cysts (Bladowska et al., 2010c; Doerfler & Richter 2008).

Fig. 18. T1-weighted coronal contrast-enhanced image. The meningioma of the left

In MR imaging meningiomas are isointense compared to grey matter on T1-weighted images and isointense or slightly hyperintense on T2-weighted images. After contrast administration they reveal homogeneous enhancement (Fig.18). Often they present with characteristic so-called "dural tail sign", what can help in differential diagnosis, but it has to be stressed that the "dural tail sign" is a nonspecific feature and may also be visible in other

Rare primary neoplasm of the pituitary and sellar region include: melanoma, intrasellar meningioma, germinoma, choristoma, glioma and metastases (Elster 1993; Ruscalleda 2005). Inflammatory and infectious lesions of pituitary and sellar region include: abscess (Fig.19) (Bladowska et al., 2010d), sarcoidosis, cysticercosis, Langerhans cell histiocytosis, blastomycosis, Wegener granulomatosis, Tolosa-Hunt syndrome, lymphocytic adenohypophysitis, giant cell granuloma and tuberculosis (Elster 1993; Doerfler & Richter

**4.3 Meningiomas** 

usually benign tumors.

cavernous sinus is visible.

intracranial tumors.

2008).

**4.4 Other rare sellar and parasellar lesions** 

Fig. 19. MR imaging in coronal planes of the pituitary abscess. A. T2-weighted unenhanced image. B. T1-weighted contrast-enhanced image. There is characteristic strong rim enhancement visible.

#### **5. Postoperative MR imaging of pituitary and sellar region – own experience**

Post-surgical evaluation of the pituitary gland in MR is difficult because of a change in anatomical conditions. Interpretation of MR images taken after surgical therapy of pituitary tumors depends also on numerous other factors, including: size and expansion of a tumor before operation, type of surgical access, quality and volume of filling material and time of its resorption. Proper evaluation of post-surgical MR images is crucial for determination of completeness of the resection. Therefore neuro-radiologists face a responsible and difficult task of evaluation of structures present in the surgical area, and especially of differentiation of residual tumor from the implanted material and from post-surgical changes (fibrous and cicatrical), or even from a part of normal gland left at site (Bladowska et al., 2010a,b).

In general, the residual tumors could be differentiated from postoperative changes by means of location, characteristic signal intensity and enhancing pattern, which should be similar to those in the preoperative MR imaging of the tumor. The infundibulum tilt could be additional factor suggesting the presence of residual adenoma. The endocrine studies are very helpful in postoperative diagnosis of hormone-secreting residual pituitary adenomas and are regarded as a method of choice in postoperative management of these tumors. It is especially difficult to evaluate the effectiveness of the surgical treatment of the nonfunctioning pituitary tumors, these tumors require a postsurgical MR follow-up examinations.

The basic therapeutic method of pituitary tumors (apart from microprolactinoma) is surgery. Among several operation methods of the sellar region, the most frequently applied is the one with transnasal transsphenoidal approach. This method has widely forced out craniotomy and is now concerned the method of choice in the treatment of the majority of pituitary adenomas, both the hormonally active and inactive ones (Bladowska et al., 2010b).

Diagnostic Imaging of the Pituitary and Parasellar Region 27

Fig. 20. T1-weighted contrast-enhanced coronal images. A. Before operation – on the left side of the pituitary the microadenoma is visible (arrow). B. Follow-up MRI performed 1 month after surgery – there is haemostatic material implanted into the operation site (arrow).

cistern, regions of necrosis within the tumor or cicatrical fibrous tissue with granulation

In our own material, as much as 85.61% of the patients had their first postoperative MRI examination performed after 3 months following the procedure, and only 14.39% of the studied individuals (20 patients) – during the first 3 months. There were no examinations carried out within 24–48 hours from the procedure. When we consider the date of MRI examinations and the fast degeneration of the filling material, it is then easy to explain the fact why the haemostatic material was identified in only two patients of the studied group. The analysis of the conducted examinations revealed that the implanted autogenic fat and muscle with fascia, located in the lumen of the sphenoid sinus, can be observed on MRI for

Fatty tissue is not too difficult to identify, as it provides a characteristic signal of high intensity on T1-weighted images (Fig.21). There were reported cases of residual fatty material present in the sphenoidal sinus examined at 1–2 years after the procedure or even 3–4 years afterwards. However, according to our assessments, the implanted fat may remain in place for much longer. The volume of the implanted fat influences the duration of its presence on MRI. Normally, the adipose tissue implanted in larger amounts (in case of macroadenoma resection) retains for much longer than the small amount of that material

As compared to other filling materials, identification of the fatty tissue in the MRI examination is easy thanks to the characteristic high signal intensity produced by the material, its longer persistence, but also the absence of adjacent contrast-enhanced areas

In the studied material, the implanted fatty tissue was identified in as many as 86 patients after pituitary tumour surgery. In the remaining 12 patients, who according to surgical reports were implanted fatty filling material, it was impossible to find that material on MRI. No fatty tissue found in these patients may result from a small amount of the implanted material, from its fast

(implanted after microadenoma resection), absorbed within 9–12 months.

absorption, as well as from a longer postoperative time to MRI examination.

A B

around it (Bladowska et al., 2010b; Bonneville et al., 2003).

much longer (Bladowska et al., 2010b).

formed by the granulation tissue.

A characteristic feature of transsphenoidal surgery is the necessity of applying different filling materials to obtain haemostasis, to fill the resection site within the sella, and to inhibit the outflow of the CSF (cerebrospinal fluid).

Filling materials are foreign or autogenic bodies that do not become vascularised. To sustain haemostasis, the following materials are used: oxidized cellulose (Oxycel or Surgicel), spongostan (Gelfoam), tissue glue (Tissucol or Beriplast), bone wax (to restrain bleeding from bone). Liquorrhoea requires a reconstructive operation of sella, with the use of autogenic fascia, lyophilisated dura mater or tissue glue. Next, the sella is sealed with a muscle or flakes of oxidized cellulose. To close the bottom of the sella, it is necessary to use a fragment of the collected cartilaginous septum from the nose, the vomer, or a silicon plate. To protect the postresection site and to reinforce the bottom of the sella, an autogenic fat graft is implanted in the sphenoid sinus. The graft is collected from the fatty tissue of the lateral part of the thigh or from the patient's abdomen (Bladowska et al., 2010b).

Application of the filling materials constitutes a considerable challenge in interpretation of the MR imaging results in patients who underwent surgery of the pituitary tumors. This can also lead to misdiagnosis. The knowledge of MR characteristics of the implanted materials is very important in postoperative diagnosis of pituitary tumors and may help to discriminate between tumorous and non-tumorous involvement of the sellar region (Bladowska et al., 2010b).

In the MRI examination, on T1-weighted images, Surgicel (Oxycel) is represented by a heterogeneous structure with a regular, oval shape, low signal intensity, surrounded by a hyperintense rim. Examinations performed in the first days after the procedure, frequently reveal the presence of small air bubbles closed in the strips of Surgicel, in the hypointense central part of the filling material (Bladowska et al., 2010b; Bonneville et al., 2003).

Spongostan (gelfoam) is represented in the MRI examination by an intrasellar mass of signal intensity similar to that of the grey matter. In rare cases, spongostan may produce a heterogeneous high signal caused most probably by the presence of methemoglobin (Bladowska et al., 2010b; Bonneville et al., 2003).

The similarity between signal intensity of the filling material, of the anterior pituitary lobe, and of a potential residual tumour often makes it difficult to interpret the image in an unequivocal way and to carry out a correct differential diagnosis. However, according to T. Kilic et al., spongostan and Surgicel (Oxycel) may be recognised only on an early performed MRI, i.e. within 24–48 hours after the procedure, because afterwards, the materials begin to undergo a progressive degeneration and their radiological identification becomes harder (Kilic et al., 2001). E. Steiner et al reported that these materials are normally recognisable on MRI for up to 3–6 months after the procedure (Steiner et al., 1992). Our studies showed that haemostatic materials may be identified only in the early postoperative period – in own material is was 1 month (Fig.20) (Bladowska et al., 2010b).

After contrast administration, the central part of the haemostatic material remained hypointense, with peripheral rim of enhancement. This peripheral enhancement is caused by granulation tissue forming around the implanted material. Filling materials undergo changes which surely inhibit their identification. It should be underscored that a hypointense mass with peripheral enhancement after contrast administration is not characteristic for the filling material only. It may also correspond to the presence of a fluid

A characteristic feature of transsphenoidal surgery is the necessity of applying different filling materials to obtain haemostasis, to fill the resection site within the sella, and to inhibit

Filling materials are foreign or autogenic bodies that do not become vascularised. To sustain haemostasis, the following materials are used: oxidized cellulose (Oxycel or Surgicel), spongostan (Gelfoam), tissue glue (Tissucol or Beriplast), bone wax (to restrain bleeding from bone). Liquorrhoea requires a reconstructive operation of sella, with the use of autogenic fascia, lyophilisated dura mater or tissue glue. Next, the sella is sealed with a muscle or flakes of oxidized cellulose. To close the bottom of the sella, it is necessary to use a fragment of the collected cartilaginous septum from the nose, the vomer, or a silicon plate. To protect the postresection site and to reinforce the bottom of the sella, an autogenic fat graft is implanted in the sphenoid sinus. The graft is collected from the fatty tissue of the

Application of the filling materials constitutes a considerable challenge in interpretation of the MR imaging results in patients who underwent surgery of the pituitary tumors. This can also lead to misdiagnosis. The knowledge of MR characteristics of the implanted materials is very important in postoperative diagnosis of pituitary tumors and may help to discriminate between tumorous and non-tumorous involvement of the sellar region (Bladowska et al.,

In the MRI examination, on T1-weighted images, Surgicel (Oxycel) is represented by a heterogeneous structure with a regular, oval shape, low signal intensity, surrounded by a hyperintense rim. Examinations performed in the first days after the procedure, frequently reveal the presence of small air bubbles closed in the strips of Surgicel, in the hypointense

Spongostan (gelfoam) is represented in the MRI examination by an intrasellar mass of signal intensity similar to that of the grey matter. In rare cases, spongostan may produce a heterogeneous high signal caused most probably by the presence of methemoglobin

The similarity between signal intensity of the filling material, of the anterior pituitary lobe, and of a potential residual tumour often makes it difficult to interpret the image in an unequivocal way and to carry out a correct differential diagnosis. However, according to T. Kilic et al., spongostan and Surgicel (Oxycel) may be recognised only on an early performed MRI, i.e. within 24–48 hours after the procedure, because afterwards, the materials begin to undergo a progressive degeneration and their radiological identification becomes harder (Kilic et al., 2001). E. Steiner et al reported that these materials are normally recognisable on MRI for up to 3–6 months after the procedure (Steiner et al., 1992). Our studies showed that haemostatic materials may be identified only in the early postoperative period – in own

After contrast administration, the central part of the haemostatic material remained hypointense, with peripheral rim of enhancement. This peripheral enhancement is caused by granulation tissue forming around the implanted material. Filling materials undergo changes which surely inhibit their identification. It should be underscored that a hypointense mass with peripheral enhancement after contrast administration is not characteristic for the filling material only. It may also correspond to the presence of a fluid

central part of the filling material (Bladowska et al., 2010b; Bonneville et al., 2003).

lateral part of the thigh or from the patient's abdomen (Bladowska et al., 2010b).

the outflow of the CSF (cerebrospinal fluid).

(Bladowska et al., 2010b; Bonneville et al., 2003).

material is was 1 month (Fig.20) (Bladowska et al., 2010b).

2010b).

Fig. 20. T1-weighted contrast-enhanced coronal images. A. Before operation – on the left side of the pituitary the microadenoma is visible (arrow). B. Follow-up MRI performed 1 month after surgery – there is haemostatic material implanted into the operation site (arrow).

cistern, regions of necrosis within the tumor or cicatrical fibrous tissue with granulation around it (Bladowska et al., 2010b; Bonneville et al., 2003).

In our own material, as much as 85.61% of the patients had their first postoperative MRI examination performed after 3 months following the procedure, and only 14.39% of the studied individuals (20 patients) – during the first 3 months. There were no examinations carried out within 24–48 hours from the procedure. When we consider the date of MRI examinations and the fast degeneration of the filling material, it is then easy to explain the fact why the haemostatic material was identified in only two patients of the studied group.

The analysis of the conducted examinations revealed that the implanted autogenic fat and muscle with fascia, located in the lumen of the sphenoid sinus, can be observed on MRI for much longer (Bladowska et al., 2010b).

Fatty tissue is not too difficult to identify, as it provides a characteristic signal of high intensity on T1-weighted images (Fig.21). There were reported cases of residual fatty material present in the sphenoidal sinus examined at 1–2 years after the procedure or even 3–4 years afterwards. However, according to our assessments, the implanted fat may remain in place for much longer. The volume of the implanted fat influences the duration of its presence on MRI. Normally, the adipose tissue implanted in larger amounts (in case of macroadenoma resection) retains for much longer than the small amount of that material (implanted after microadenoma resection), absorbed within 9–12 months.

As compared to other filling materials, identification of the fatty tissue in the MRI examination is easy thanks to the characteristic high signal intensity produced by the material, its longer persistence, but also the absence of adjacent contrast-enhanced areas formed by the granulation tissue.

In the studied material, the implanted fatty tissue was identified in as many as 86 patients after pituitary tumour surgery. In the remaining 12 patients, who according to surgical reports were implanted fatty filling material, it was impossible to find that material on MRI. No fatty tissue found in these patients may result from a small amount of the implanted material, from its fast absorption, as well as from a longer postoperative time to MRI examination.

Diagnostic Imaging of the Pituitary and Parasellar Region 29

In 3 individuals, an implanted muscle with fascia was identified. It was represented by a round, isointense structure, filling nearly the whole sphenoidal sinus on T1-weighted MRI images. After intravenous contrast administration, the structure was becoming slightly enhanced in its peripheral part, with a central round area of lower signal intensity (Fig.23a). Such an image of the implanted muscle was found in 2 patients after 4 months following the procedure, and in 1 patient after 5 months from surgery. The follow-up MRIs (beginning approx. from the 12th postoperative month) were revealing a gradual change in the image of that material. After contrast administration, the previously distinct border between the enhanced peripheral part and the central hypointense part of the implanted muscle became indistinct. In further MRI examinations, performed approx. 25 months after surgery or later, the structure present in the lumen of the sphenoidal sinus remained hypointense after contrast administration. Without the analysis of previous images and the knowledge of patient's history, the correct diagnosis of that mass on T1-weighted images was impossible (especially its differentiation from e.g. fluid cistern). The implanted muscle with fascia produced a very characteristic and almost stable image in T2-weighted sequence (Fig.23b), for at least 31 months following the procedure. In the T2-weighted sequence, the material is represented by a hyperintense mass with a linear structure, of a very low signal intensity, corresponding to fascia (Fig.23b). It should also be pointed out that fascia was not identified

on T1-weighted images (Fig.23a) (Bladowska et al., 2010b, 2011).

Fig. 23. MR imaging of muscle with fascia implanted into the sphenoid sinus. A. T1 weighted enhanced coronal image. B. T2- weighted unenhanced coronal image – the linear structure, of a very low signal intensity, corresponding to fascia is very well visible.

These tumors require a postsurgical endocrinological and MRI follow-up.

The final diagnosis and evaluation of the surgical completeness on the basis of the performed MRI is often equivocal, in spite of the presence of the above mentioned criteria. It is especially hard to evaluate the effectiveness of the surgical treatment of the hormonally inactive tumors on the basis of the MRI examination results and their interpretation only.

Follow-up of abnormal structures present in the postsurgical area may allow for their verification. If in the following examinations there is a complete absorption of the focal

A B

Fig. 21. T1-weighted unenhanced sagittal images. A. MRI performed 10 months after transsphenoidal operation reveals the implanted fatty material inside the sphenoid sinus – it presents with high signal intensity. B. Follow-up MRI performed 23 months after surgery – there is no implanted material visible.

The earliest total absorption of the fatty material was observed 11 months after the procedure. In most of the cases, residues of the adipose tissue were present for a long time, for even up to 112 months (nearly 10 years) after the procedure, while in one patient, there was a large amount of the fatty material still present in the lumen of the sphenoidal sinus after 348 months (29 years) (Bladowska et al., 2010b).

In 2 patients, it was possible to visualise the implanted titanium mesh (Fig.22). On MRI, the titanium mesh was represented by a linear area producing no signal and located in the bottom of the sella (Bladowska et al., 2010b).

Fig. 22. MR imaging of implanted titanium mesh. A. T1-weighted coronal image. B. T2 weighted coronal image. A linear area producing no signal and located in the bottom of the sella is visible.

In 3 individuals, an implanted muscle with fascia was identified. It was represented by a round, isointense structure, filling nearly the whole sphenoidal sinus on T1-weighted MRI images. After intravenous contrast administration, the structure was becoming slightly enhanced in its peripheral part, with a central round area of lower signal intensity (Fig.23a). Such an image of the implanted muscle was found in 2 patients after 4 months following the procedure, and in 1 patient after 5 months from surgery. The follow-up MRIs (beginning approx. from the 12th postoperative month) were revealing a gradual change in the image of that material. After contrast administration, the previously distinct border between the enhanced peripheral part and the central hypointense part of the implanted muscle became indistinct. In further MRI examinations, performed approx. 25 months after surgery or later, the structure present in the lumen of the sphenoidal sinus remained hypointense after contrast administration. Without the analysis of previous images and the knowledge of patient's history, the correct diagnosis of that mass on T1-weighted images was impossible (especially its differentiation from e.g. fluid cistern). The implanted muscle with fascia produced a very characteristic and almost stable image in T2-weighted sequence (Fig.23b), for at least 31 months following the procedure. In the T2-weighted sequence, the material is represented by a hyperintense mass with a linear structure, of a very low signal intensity, corresponding to fascia (Fig.23b). It should also be pointed out that fascia was not identified on T1-weighted images (Fig.23a) (Bladowska et al., 2010b, 2011).

28 Pituitary Adenomas

Fig. 21. T1-weighted unenhanced sagittal images. A. MRI performed 10 months after

transsphenoidal operation reveals the implanted fatty material inside the sphenoid sinus – it presents with high signal intensity. B. Follow-up MRI performed 23 months after surgery –

The earliest total absorption of the fatty material was observed 11 months after the procedure. In most of the cases, residues of the adipose tissue were present for a long time, for even up to 112 months (nearly 10 years) after the procedure, while in one patient, there was a large amount of the fatty material still present in the lumen of the sphenoidal sinus

In 2 patients, it was possible to visualise the implanted titanium mesh (Fig.22). On MRI, the titanium mesh was represented by a linear area producing no signal and located in the

Fig. 22. MR imaging of implanted titanium mesh. A. T1-weighted coronal image. B. T2 weighted coronal image. A linear area producing no signal and located in the bottom of the

A B

there is no implanted material visible.

after 348 months (29 years) (Bladowska et al., 2010b).

A B

bottom of the sella (Bladowska et al., 2010b).

sella is visible.

Fig. 23. MR imaging of muscle with fascia implanted into the sphenoid sinus. A. T1 weighted enhanced coronal image. B. T2- weighted unenhanced coronal image – the linear structure, of a very low signal intensity, corresponding to fascia is very well visible.

The final diagnosis and evaluation of the surgical completeness on the basis of the performed MRI is often equivocal, in spite of the presence of the above mentioned criteria.

It is especially hard to evaluate the effectiveness of the surgical treatment of the hormonally inactive tumors on the basis of the MRI examination results and their interpretation only. These tumors require a postsurgical endocrinological and MRI follow-up.

Follow-up of abnormal structures present in the postsurgical area may allow for their verification. If in the following examinations there is a complete absorption of the focal

Diagnostic Imaging of the Pituitary and Parasellar Region 31

Pituitary adenomas are common neoplasm, they account for 10-15% of all diagnosed intracranial tumors. The proper diagnosis and management of patients with pituitary lesions are of high importance in the clinical practice. Currently, MR is the method of choice for imaging of the pituitary gland and the parasellar area. MR imaging protocol of pituitary and sellar region including postoperative studies should consist of unenhanced T1- and T2 weighted images in coronal and sagittal planes, followed by T1-weighted images after contrast administration. Because of so many pathological changes with different clinical and radiological appearances of the lesions located in sellar and parasellar region, the precise knowledge of pituitary lesions is mandatory for the correct diagnosis and management of

I would like to thank my dear husband Maciej, my lovely daughters Justynka and Hania, and my all family for the patience, they have given me during the time I was writing this

"There is no greater treasure, nor any wealthier trove, than the company of my family, and

Arslan A., Karaarslan E., Dincer A. (1999) High intensity signal of the posterior pituitary. A

Bladowska J., Sokolska V., Czapiga E., Badowski R., Koźmińska U., Moroń K. (2004)

*Advances in Clinical and Experimental Medicine*, Vol. 13, (2004) pp. 709-717. Bladowska J, Sokolska V, Sozański T et al. (2010) Comparison of post-surgical MRI

Bladowska J, Bednarek-Tupikowska G, Sokolska V et al. (2010) MRI image characteristics of

Bladowska J, Bednarek-Tupikowska G, Biel A, Sąsiadek M. (2010) Colloid cyst of the

Bladowska J, Bednarek-Tupikowska G, Sokolska V, Czapiga E, Czapiga B, Sąsiadek M.

literature review. *Neuroradiology Journal*, Vol.23, (2010), pp. 547-553. Bladowska J, Biel A, Zimny A et al. (2011) Are the T2-weighted images more useful than T1-

techniques. *Acta Radiologica*, Vol. 40, (1999) pp. 142-145.

tumours. *Polish Journal of Radiology*, Vol.75, (2010), pp. 46-54.

study with horizontal direction of frequency-encoding and fat suppression MR

Advances in diagnostics imaging of the pituitary and the parasellar region.

presentation of the pituitary gland and its hormonal function. *Polish Journal of* 

materials implanted at sellar region after transsphenoidal resection of pituitary

pituitary gland: Case report and literature review. *Polish Journal of Radiology*, Vol.75,

(2010) Unusual presentation of recurrent pituitary abscess – a case report and

weighted contrast-enhanced images in assessment of postoperative sella and parasellar region? *Medical Science Monitor*, Vol. 17, no 10 (October 2011), pp. MT83-

Joanna Bladowska

**6. Conclusion** 

patients with pituitary diseases.

chapter. I will use the words of Robert C. Martin:

*Radiology*, Vol. 75, (2010) pp. 29-36.

(2010), pp. 92-97.

MT90.

**7. Acknowledgment** 

the comfort of their love".

**8. References** 

lesion, this excludes the presence of a residual tumor and indicates to the filling material or postoperative changes.

If the size and volume of the pathological structure increases, this points to the presence of a residual tumor. On the other hand, it should be remembered that pituitary tumors grow slowly, so in a long-term follow-up, the tumor may seem stable, which does not facilitate the final diagnosis in unclear cases of hormonally inactive tumors.

As mentioned above, the transsphenoidal approach is currently the method of choice in treatment of most of pituitary tumors. There are characteristic changes inside the sphenoid sinus after the surgery (Connor & Deasy, 2002). MRI findings of sphenoid sinus filling (opacification) are present in approximately 37% of examinations performed more than 12 months after transsphenoidal surgery. The contrast enhancement at the margins of the sphenoid sinus, called as Rodriguez's changes (Fig.24), is always apparent in cases of hypervascularized and swollen mucosa (Rodriguez et al., 1996) and could persist even 10 years after surgery.

Fig. 24. MR imaging of Rodriguez's changes, T1-weighted sagittal images: unenhanced (A), contrast-enhanced (B). There are hypointense masses inside the sphenoid sinus, which show the characteristic rim contrast enhancement.

The special attention should be also paid to usefulness of T2-weighted images in assessment of postoperative sella and sellar region. T2-weighted images may help to discriminate between tumorous and non-tumorous involvement of the postoperative sella and the sphenoid sinus especially in cases, in which the signal intensity and enhancement pattern of pituitary gland and tumor are the same on T1-weighted images. T2-weighted images are also very useful in the postoperative evaluation of the implanted muscle with fascia, especially during long term follow-up. The best protocol for the postoperative imaging after pituitary tumor resections should include both T1- and T2-weighted imaging, because T1 and T2-weighted images supplement each other in the postoperative examination of the sella and sellar region. However, in some cases T2 could replace post-contrast T1, especially in patients with high risk of Nephrogenic Systemic Fibrosis (NSF) (Bladowska et al., 2011).

#### **6. Conclusion**

30 Pituitary Adenomas

lesion, this excludes the presence of a residual tumor and indicates to the filling material or

If the size and volume of the pathological structure increases, this points to the presence of a residual tumor. On the other hand, it should be remembered that pituitary tumors grow slowly, so in a long-term follow-up, the tumor may seem stable, which does not facilitate the

As mentioned above, the transsphenoidal approach is currently the method of choice in treatment of most of pituitary tumors. There are characteristic changes inside the sphenoid sinus after the surgery (Connor & Deasy, 2002). MRI findings of sphenoid sinus filling (opacification) are present in approximately 37% of examinations performed more than 12 months after transsphenoidal surgery. The contrast enhancement at the margins of the sphenoid sinus, called as Rodriguez's changes (Fig.24), is always apparent in cases of hypervascularized and swollen mucosa (Rodriguez et al., 1996) and could persist even 10

Fig. 24. MR imaging of Rodriguez's changes, T1-weighted sagittal images: unenhanced (A), contrast-enhanced (B). There are hypointense masses inside the sphenoid sinus, which show

The special attention should be also paid to usefulness of T2-weighted images in assessment of postoperative sella and sellar region. T2-weighted images may help to discriminate between tumorous and non-tumorous involvement of the postoperative sella and the sphenoid sinus especially in cases, in which the signal intensity and enhancement pattern of pituitary gland and tumor are the same on T1-weighted images. T2-weighted images are also very useful in the postoperative evaluation of the implanted muscle with fascia, especially during long term follow-up. The best protocol for the postoperative imaging after pituitary tumor resections should include both T1- and T2-weighted imaging, because T1 and T2-weighted images supplement each other in the postoperative examination of the sella and sellar region. However, in some cases T2 could replace post-contrast T1, especially in patients with high risk of Nephrogenic Systemic Fibrosis (NSF) (Bladowska et al., 2011).

final diagnosis in unclear cases of hormonally inactive tumors.

A B

the characteristic rim contrast enhancement.

postoperative changes.

years after surgery.

Pituitary adenomas are common neoplasm, they account for 10-15% of all diagnosed intracranial tumors. The proper diagnosis and management of patients with pituitary lesions are of high importance in the clinical practice. Currently, MR is the method of choice for imaging of the pituitary gland and the parasellar area. MR imaging protocol of pituitary and sellar region including postoperative studies should consist of unenhanced T1- and T2 weighted images in coronal and sagittal planes, followed by T1-weighted images after contrast administration. Because of so many pathological changes with different clinical and radiological appearances of the lesions located in sellar and parasellar region, the precise knowledge of pituitary lesions is mandatory for the correct diagnosis and management of patients with pituitary diseases.

#### **7. Acknowledgment**

I would like to thank my dear husband Maciej, my lovely daughters Justynka and Hania, and my all family for the patience, they have given me during the time I was writing this chapter. I will use the words of Robert C. Martin:

"There is no greater treasure, nor any wealthier trove, than the company of my family, and the comfort of their love".

Joanna Bladowska

#### **8. References**


**3** 

*1,3,4Iran 2USA* 

**Functioning Pituitary Adenoma** 

*2Department of Neurosurgery, Brigham & Women's Hospital,* 

*4Research Centre for Neural Repair, University of Tehran, Tehran,* 

*1Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran,* 

*Harvard Medical School, Boston, Massachusetts, 3Sina Trauma and Surgery Research Center,* 

Mahdi Sharif-Alhoseini1, Edward R. Laws2 and Vafa Rahimi-Movaghar3,4

Pituitary adenomas are typically benign, slow-growing tumors that arise from cells in the pituitary gland. Those are classified based on secretory products (1). The functioning (endocrine-active) tumors include almost 70% of pituitary tumors which produce 1 or 2 hormones that are measurable in the serum and cause definite clinical syndromes that are classified based on their secretory product(s). Non-functioning adenomas are endocrineinactive tumors (2). Because of the physiologic effects of excess hormones, functioning tumors usually present earlier than non-functioning adenomas (3). On the other hand, mass effect from large pituitary adenomas (often due to endocrine-inactive tumors) may lead to pressure symptoms such as headaches, visual field defects (typically loss of peripheral vision), cranial nerve deficits, hypopituitarism (compression of normal pituitary gland), pituitary apoplexy (sudden bleeding or infarction from outgrowing tumor blood supply), or stalk dysfunction (4). Compression of pituitary stalk is termed "stalk effect" which can cause

a mild elevation in prolactin, and must be differentiated from a prolactinoma (5).

The purpose of this chapter is to review all types of functioning pituitary adenoma (prolactin, ACTH, GH, TSH, LH and FSH secreting) from studies indexed in PubMed. We describe the symptoms, epidemiology, diagnosis, management, outcome and complications

This type of pituitary adenoma arises from neoplastic transformation of anterior pituitary lactotrophs and produces an excessive amount of hormone prolactin. A prolactinoma is the most common cause of chronic hyperprolactinemia once pregnancy, primary hypothyroidism, and drugs that elevate serum prolactin levels have been excluded (6).

**1. Introduction** 

of each.

**2. Prolactinoma** 

*Department of Neurosurgery, Tehran University of Medical Sciences, Tehran,* 


## **Functioning Pituitary Adenoma**

Mahdi Sharif-Alhoseini1, Edward R. Laws2 and Vafa Rahimi-Movaghar3,4

*1Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, 2Department of Neurosurgery, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, 3Sina Trauma and Surgery Research Center, Department of Neurosurgery, Tehran University of Medical Sciences, Tehran, 4Research Centre for Neural Repair, University of Tehran, Tehran, 1,3,4Iran 2USA* 

#### **1. Introduction**

32 Pituitary Adenomas

Bonneville JF. (2000) Pituitary adenomas: value of MR imaging. *Journal of Radiology,* Vol.81,

Bonneville JF, Bonneville F, Schillo F, Cattin F, Jacquet G. (2003) Follow-up MRI after transsphenoidal surgery. *Journal of Neuroradiology,* Vol.30, (2003), pp. 268-279. Bonneville JF, Bonneville F, Cattin F. (2005) Magnetic resonance imaging of pituitary

Boxerman JL, Rogg JM, Donahue JE et al. (2010) Preoperative MRI evaluation of pituitary

Chernov MF., Kawamata T., Amano K. et al. (2009) Possible role of single-voxel 1H-MRS in

Connor SEJ. & Deasy NP. (2002) MRI appearances of the sphenoid sinus at the late follow-

Daly AF, Tichomirowa MA, Beckers A. (2009) The epidemiology and genetics of pituitary

Doerfler A. & Richter G. (2008) Lesions within and around the pituitary. *Clinical* 

Kilic T, Ekinci G, Seker A et al. (2001). Determining optimal MRI follow-up after

Rodriguez O, Mateos B, de la Pedraja R et al. (1996) Postoperative follow-up of pituitary

Ruscalleda J. (2005) Imaging of parasellar lesions. *European Radiology*, Vol.15, (2005), pp. 549-

Steiner E, Knosp E, Herold ChJ et al (1992): Pituitary adenomas: Findings of postoperative

Elster A.D. (1993) Modern imaging of the pituitary. *Radiology,* Vol.187, (1993), pp. 1-14. Elster A.D., Chen M.Y.M., Williams D.W., Key L.L. (1990) Pituitary gland: MR imaging of physiologic hypertrophy in adolescence. *Radiology,* Vol.174, (1990), pp. 681-685. Elster A.D., Sanders T.G., Vines F.S., Chen M.Y.M. (1991) Size and shape of the pituitary

Evanson J. (2002) Imaging the pituitary gland. *Imaging*, Vol.14, (2002), pp. 93-102.

macroadenoma: imaging features predictive of successful transsphenoidal surgery.

differential diagnosis of suprasellar tumors. *Journal of Neurooncology,* Vol.91, (2009),

up of trans-sphenoidal surgery for pituitary macroadenoma. *Australasian Radiology*,

adenomas. *Best Practice & Research Clinical Endocrinology & Metabolism*; Vol.23,

gland during pregnancy and post partum: measurement with MR imaging.

transsphenoidal surgery for pituitary adenomas: scan at 24 hours postsurgery provides reliable information. *Acta Neurochirurgica* (Wien), Vol.143, (2001), pp.

adenomas after transsphenoidal resection: MRI and clinical correlation.

adenomas. *European Radiology*, Vol. 15, (2005) pp. 543-548.

*American Journal of Radiology AJR,* Vol.195, (2010), pp. 720-728.

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1103–26.

559.

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*Radiology*, Vol.181, (1991), pp. 531-535.

*Neuroradiology*, Vol.38, (1996), pp. 747–54.

MR imaging. *Radiology*, Vol.185, (1992), pp. 521–27.

(2009), pp. 543–554.

Pituitary adenomas are typically benign, slow-growing tumors that arise from cells in the pituitary gland. Those are classified based on secretory products (1). The functioning (endocrine-active) tumors include almost 70% of pituitary tumors which produce 1 or 2 hormones that are measurable in the serum and cause definite clinical syndromes that are classified based on their secretory product(s). Non-functioning adenomas are endocrineinactive tumors (2). Because of the physiologic effects of excess hormones, functioning tumors usually present earlier than non-functioning adenomas (3). On the other hand, mass effect from large pituitary adenomas (often due to endocrine-inactive tumors) may lead to pressure symptoms such as headaches, visual field defects (typically loss of peripheral vision), cranial nerve deficits, hypopituitarism (compression of normal pituitary gland), pituitary apoplexy (sudden bleeding or infarction from outgrowing tumor blood supply), or stalk dysfunction (4). Compression of pituitary stalk is termed "stalk effect" which can cause a mild elevation in prolactin, and must be differentiated from a prolactinoma (5).

The purpose of this chapter is to review all types of functioning pituitary adenoma (prolactin, ACTH, GH, TSH, LH and FSH secreting) from studies indexed in PubMed. We describe the symptoms, epidemiology, diagnosis, management, outcome and complications of each.

#### **2. Prolactinoma**

This type of pituitary adenoma arises from neoplastic transformation of anterior pituitary lactotrophs and produces an excessive amount of hormone prolactin. A prolactinoma is the most common cause of chronic hyperprolactinemia once pregnancy, primary hypothyroidism, and drugs that elevate serum prolactin levels have been excluded (6).

Functioning Pituitary Adenoma 35

imaging should be organized (6, 16). Most prolactinomas can be effectively treated with dopaminergic drugs as primary management. For most patients, medical therapy produces normalization of prolactin secretion, gonadal function, and considerable tumor shrinkage in the majority (16). The most commonly used dopamine agonists are bromocriptine, cabergoline (ergot derivatives) as well as quinagolide (a non-ergot derivative) (4, 18). Bromocriptine (D2 receptor agonist and D1 receptor antagonist) is the oldest drug for medical treatment of prolactinomas, and normalizes prolactin levels in 80-90% of microprolactinomas and 70% of macroprolactinomas. Tumor-mass shrinkage and improvement of visual-field deficits are commonly achieved in macroprolactinomas. Bromocriptine frequently can cause several side effects such as nausea, vomiting, postural hypotension, headache and dizziness (12). Cabergoline (a selective D2 receptor agonist) is very effective and well tolerated in more than 90% of the patients with either microprolactinomas or macroprolactinomas. Cabergoline treatment also induces tumor shrinkage in most macroprolactinomas. If patients have not previously been treated with other dopamine agonists, tumor shrinkage is more evident (17). When comparing the plasma half-life, efficacy and tolerability of these drugs, cabergoline seems to have the most favorable profile, followed by quinagolide (16). As a well tolerated and effective therapy and a simple dosing regimen, quinagolide (selective D2 receptor agonist) can also be considered a first-line therapy in the treatment of hyperprolactinaemia (19). Pergolide (a D1 and D2 agonist) normalizes prolactin excess and reduces tumor size in recently diagnosed patients with macroprolactinomas with a potency of about 100-fold that of bromocriptine (20). However pergolide as approved treatment for prolactinomas was withdrawn in 2007

If prolactin levels are well controlled with dopamine agonist therapy, gradual tapering of the dose to the lowest effective amount is recommended, and in some cases medication can be stopped after several years. Evidence to date suggests that cabergoline and quinagolide appear to have a good safety profile for women who wish to conceive, but hard evidence proving that dopamine agonists do not provoke congenital malformations when taken during early pregnancy is currently only available for bromocriptine. Once pregnant, dopamine agonist therapy should be immediately stopped, unless the growth of a macroprolactinoma or pressure symptoms is likely to occur (4, 16). Hyperprolactinemia may recur after dopamine agonist withdrawal in a considerable proportion of patients. The probability of successful treatment was highest when cabergoline was used for at least two

Surgery is generally used as second-line treatment in prolactinomas (22). Transsphenoidal surgery is an alternative for patients who are intolerant of or resistant to dopamine agonists or when hyperprolactinemia is caused by non-prolactin-secreting tumors compressing the

Because pituitary adenomas respond well to radiation, radiotherapy has been a part of their management for the past three decades (23). Radiotherapy is given if both pharmacologic therapy and surgery fail (4, 16). However, Sasaki et al. reported that the local control rate for

Gamma knife radiosurgery can be offered as a safe and effective treatment option especially for those patients with recurrent or residual pituitary adenoma after surgical removal. The

because of adverse effects on cardiac valves (12).

secreting adenomas by radiotherapy is unsatisfactory (23).

years (21).

pituitary stalk (4).

#### **2.1 Symptoms**

In female patients, even small prolactinomas can cause irregular menstrual periods or complete loss of menses. Higher prolactin levels lead to galactorrhea in women, whereas men may experience gynecomastia. In male patients, altered spermatogenesis with oligospermia and infertility may be found; galactorrhea and gynaecomastia are much less frequent. Hypogonadism, reduced libido and infertility are the most frequent symptoms in both genders. Patients can also present with osteopenia and osteoporosis (due to estrogen and testosterone deficiency, not due to the elevated prolactin itself). Large prolactinomas, more commonly found in men, may cause mass effect from the tumor (5-9).

#### **2.2 Epidemiology**

The estimated prevalence of prolactinoma is 100 per million adults (10). Prolactinomas are the most common hormone-secreting pituitary tumors, representing approximately 40% of all pituitary tumors (8, 11, 12). Recent data show a high prevalence of prolactinoma in the general population, 3-5 times more than the previously reported ones (13). The incidence of prolactinomas varies with age and sex; these tumors occur with the highest frequency in women aged 20–50 years, at which point the ratio between the sexes is estimated to be 10:1. In adults aged >60 years, prolactinomas occur with a similar frequency in both sexes (12). Men generally have macroadenomas (≥10mm diameter) whereas women generally have microadenomas (<10mm) (6, 13, 14). The mean age at diagnosis is 10 years greater in men. This delay possibly accounts for their greater incidence of macroprolactinomas with visual field defects and hypopituitarism at first presentation (15).

#### **2.3 Diagnosis**

A serum prolactin level is acquired in response to a specific presentation, including symptoms of hyperprolactinemia (such as amenorrhea and galactorrhea) it may also be an integral part of an infertility assessment. An initial level above the normal range should be followed by a repeat level from a blood sample drawn in the morning with the patient in a fasting state. When hyperprolactinemia is confirmed, a cause for the disorder needs to be sought. This involves a careful history and examination, followed by laboratory tests and diagnostic imaging of the sella turcica. If serum prolactin levels are above 200 µg/L, a prolactinoma is almost certainly the underlying cause, but if levels are lower, the differential diagnoses include pregnancy, treatment with drugs (such as neuroleptics) that reduce dopaminergic effects on the pituitary, compression of the pituitary stalk by other pathology, primary hypothyroidism, renal failure, cirrhosis, chest wall lesions, or idiopathic hyperprolactinemia. In the absence of such causes, radiologic imaging of the sella turcica is necessary to establish whether a prolactinoma or other lesions are present (4, 6, 16).

#### **2.4 Management**

The main purpose of treating prolactinomas, both micro- and macroprolactinomas, are to suppress excess hormone secretion and its clinical effects, to remove the tumor mass, and to prevent disease return or progression (16, 17). If there is no indication for therapy (such as amenorrhea, infertility or bothersome galactorrhea), microadenomas may be followed conservatively, and regular follow-up with serial prolactin measurements and pituitary

In female patients, even small prolactinomas can cause irregular menstrual periods or complete loss of menses. Higher prolactin levels lead to galactorrhea in women, whereas men may experience gynecomastia. In male patients, altered spermatogenesis with oligospermia and infertility may be found; galactorrhea and gynaecomastia are much less frequent. Hypogonadism, reduced libido and infertility are the most frequent symptoms in both genders. Patients can also present with osteopenia and osteoporosis (due to estrogen and testosterone deficiency, not due to the elevated prolactin itself). Large prolactinomas,

The estimated prevalence of prolactinoma is 100 per million adults (10). Prolactinomas are the most common hormone-secreting pituitary tumors, representing approximately 40% of all pituitary tumors (8, 11, 12). Recent data show a high prevalence of prolactinoma in the general population, 3-5 times more than the previously reported ones (13). The incidence of prolactinomas varies with age and sex; these tumors occur with the highest frequency in women aged 20–50 years, at which point the ratio between the sexes is estimated to be 10:1. In adults aged >60 years, prolactinomas occur with a similar frequency in both sexes (12). Men generally have macroadenomas (≥10mm diameter) whereas women generally have microadenomas (<10mm) (6, 13, 14). The mean age at diagnosis is 10 years greater in men. This delay possibly accounts for their greater incidence of macroprolactinomas with visual

A serum prolactin level is acquired in response to a specific presentation, including symptoms of hyperprolactinemia (such as amenorrhea and galactorrhea) it may also be an integral part of an infertility assessment. An initial level above the normal range should be followed by a repeat level from a blood sample drawn in the morning with the patient in a fasting state. When hyperprolactinemia is confirmed, a cause for the disorder needs to be sought. This involves a careful history and examination, followed by laboratory tests and diagnostic imaging of the sella turcica. If serum prolactin levels are above 200 µg/L, a prolactinoma is almost certainly the underlying cause, but if levels are lower, the differential diagnoses include pregnancy, treatment with drugs (such as neuroleptics) that reduce dopaminergic effects on the pituitary, compression of the pituitary stalk by other pathology, primary hypothyroidism, renal failure, cirrhosis, chest wall lesions, or idiopathic hyperprolactinemia. In the absence of such causes, radiologic imaging of the sella turcica is

necessary to establish whether a prolactinoma or other lesions are present (4, 6, 16).

The main purpose of treating prolactinomas, both micro- and macroprolactinomas, are to suppress excess hormone secretion and its clinical effects, to remove the tumor mass, and to prevent disease return or progression (16, 17). If there is no indication for therapy (such as amenorrhea, infertility or bothersome galactorrhea), microadenomas may be followed conservatively, and regular follow-up with serial prolactin measurements and pituitary

more commonly found in men, may cause mass effect from the tumor (5-9).

field defects and hypopituitarism at first presentation (15).

**2.1 Symptoms** 

**2.2 Epidemiology** 

**2.3 Diagnosis** 

**2.4 Management** 

imaging should be organized (6, 16). Most prolactinomas can be effectively treated with dopaminergic drugs as primary management. For most patients, medical therapy produces normalization of prolactin secretion, gonadal function, and considerable tumor shrinkage in the majority (16). The most commonly used dopamine agonists are bromocriptine, cabergoline (ergot derivatives) as well as quinagolide (a non-ergot derivative) (4, 18). Bromocriptine (D2 receptor agonist and D1 receptor antagonist) is the oldest drug for medical treatment of prolactinomas, and normalizes prolactin levels in 80-90% of microprolactinomas and 70% of macroprolactinomas. Tumor-mass shrinkage and improvement of visual-field deficits are commonly achieved in macroprolactinomas. Bromocriptine frequently can cause several side effects such as nausea, vomiting, postural hypotension, headache and dizziness (12). Cabergoline (a selective D2 receptor agonist) is very effective and well tolerated in more than 90% of the patients with either microprolactinomas or macroprolactinomas. Cabergoline treatment also induces tumor shrinkage in most macroprolactinomas. If patients have not previously been treated with other dopamine agonists, tumor shrinkage is more evident (17). When comparing the plasma half-life, efficacy and tolerability of these drugs, cabergoline seems to have the most favorable profile, followed by quinagolide (16). As a well tolerated and effective therapy and a simple dosing regimen, quinagolide (selective D2 receptor agonist) can also be considered a first-line therapy in the treatment of hyperprolactinaemia (19). Pergolide (a D1 and D2 agonist) normalizes prolactin excess and reduces tumor size in recently diagnosed patients with macroprolactinomas with a potency of about 100-fold that of bromocriptine (20). However pergolide as approved treatment for prolactinomas was withdrawn in 2007 because of adverse effects on cardiac valves (12).

If prolactin levels are well controlled with dopamine agonist therapy, gradual tapering of the dose to the lowest effective amount is recommended, and in some cases medication can be stopped after several years. Evidence to date suggests that cabergoline and quinagolide appear to have a good safety profile for women who wish to conceive, but hard evidence proving that dopamine agonists do not provoke congenital malformations when taken during early pregnancy is currently only available for bromocriptine. Once pregnant, dopamine agonist therapy should be immediately stopped, unless the growth of a macroprolactinoma or pressure symptoms is likely to occur (4, 16). Hyperprolactinemia may recur after dopamine agonist withdrawal in a considerable proportion of patients. The probability of successful treatment was highest when cabergoline was used for at least two years (21).

Surgery is generally used as second-line treatment in prolactinomas (22). Transsphenoidal surgery is an alternative for patients who are intolerant of or resistant to dopamine agonists or when hyperprolactinemia is caused by non-prolactin-secreting tumors compressing the pituitary stalk (4).

Because pituitary adenomas respond well to radiation, radiotherapy has been a part of their management for the past three decades (23). Radiotherapy is given if both pharmacologic therapy and surgery fail (4, 16). However, Sasaki et al. reported that the local control rate for secreting adenomas by radiotherapy is unsatisfactory (23).

Gamma knife radiosurgery can be offered as a safe and effective treatment option especially for those patients with recurrent or residual pituitary adenoma after surgical removal. The

Functioning Pituitary Adenoma 37

Cushing's syndrome refers to clinical manifestations induced by chronic exposure to excess glucocorticoids. The most common symptom of glucocorticoid excess is centripetal fat

Fat accumulates in the face as well as supraclavicular and dorsocervical fat pads, resulting in a typical moon face and buffalo hump, which is most often accompanied by facial plethora. Fat also accumulates over the thorax and the abdomen, which becomes

Other symptoms and signs include obesity; protein-wasting features such as skin thinning, large and purple abdominal striae, multiple ecchymotic lesions or purpura generated by minimal trauma, lower limb edema, spontaneous ruptures of tendons, slow healing of minor wounds, muscle atrophy, particularly in the lower limbs; bone wasting such as osteoporosis, pathological fractures, kyphosis and loss of height (34, 35); impaired protection mechanism against infections (36); high blood pressure and cardiovascular complications (37, 38); hirsutism; gonadal dysfunction (39); psychic disturbances such as anxiety, irritability, sleep disorders, depression, maniac disorders, delusions and/or

The prevalence of Cushing's disease is approximately 40 per million. ACTH-producing adenomas comprise 10-20% of pituitary adenomas (42). Cushing's disease is nine times

The clinical history is important to assess the general impact of hypercortisolism on organs and systems as well as to guide suspicion toward more aggressive entities such as the ectopic ACTH syndrome or to detect an iatrogenic etiology of Cushing's syndrome (43). Initial diagnosis is performed using tests such as urinary free cortisol, nocturnal salivary cortisol and 1 mg dexamethasone suppression that are sensitive but not specific, and still require established assessment criteria(44). A dexamethasone- corticotrophin releasing hormone (CRH) test can discriminate between Cushing's syndrome and pseudo-Cushing's syndrome. If ACTH is elevated, combinations of high-dose dexamethasone tests, CRH/desmopressin tests, and pituitary magnetic resonance imaging can indicate a pituitary source. Discrimination from an ectopic ACTH tumor often requires inferior petrosal sinus sampling to confirm the source of ACTH. If ACTH is low, adrenal computed tomography will identify the adrenal lesion(s) implicated. Some cortisol-producing adrenal tumors or, more frequently, bilateral macronodular hyperplasia, are under the control of aberrant membrane hormone receptors, or the altered activity of ectopic receptors (43-46). Sophisticated imaging and isotopic techniques play a significant role in locating the source of ACTH in ectopic syndromes but are not always effective. In general, biochemical and imaging tests should be combined in order to assess different mechanisms and perspectives of the syndrome. Rigorous methodology is essential to obtain accurate results, allowing a correct diagnosis and in improving therapeutic performance in this devastating disease (43).

deposition which is frequently the initial symptom of the patient.

hallucinations (40); and decreased short-term memory and cognition (41).

**3.1 Symptoms** 

protuberant (33).

**3.2 Epidemiology** 

**3.3 Diagnosis** 

more common in women than men(2).

tumor control rate after gamma knife radiosurgery for pituitary adenomas is equivalent to fractionated radiation therapy (24).

Some experimental treatments have been attempted, such as somatostatin analogues, hybrid molecules (both somatostatin and a dopamine agonist in a single molecule), selective estrogen receptor modulators, prolactin-receptor antagonists, and temozolomide are utilized in selected case reports or in trial settings. These have not yet been included in standard medical practice (12).

#### **2.5 Outcome**

The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass (11). Medical and surgical therapies generally have excellent results, and most prolactinomas are well controlled or even cured in some cases (19). Dopamine agonists are the preferred therapy for prolactinomas because of the risk of recurrent hyperprolactinemia that accompanies transsphenoidal surgery (25, 26). Dopamine agonists are the first line of therapy for macroprolactinomas, resulting in normalizing prolactin levels in 85%, inducing tumor shrinkage in 57%, and long-term remission rates in 22% of the patients (11, 27).

Surgery should be reserved for patients with dopamine agonist resistance or intolerance. Success rates after surgical treatment of microadenomas range from 73–90% and 30–50% for macroadenomas, with little morbidity and near zero mortality (28). However, subsequent relapse is possible in up to 20% of the cases (22). Surgical outcomes are highly dependent upon the expertise and experience of the neurosurgeon (11, 22).

Following radiotherapy the prevalence of subsequent hypopituitarism is high; therefore, this therapy should be carefully considered, and rather be indicated for mass control than for hyperprolactinemia (27).

Overall, patients with pituitary adenoma treated with surgery and radiotherapy have an increased risk of cerebrovascular motrtality compared to the general population, which mirrors the increased incidence of stroke (29).

#### **2.6 Complications**

As mentioned in the symptoms section, prolactinomas left untreated may lead to various complications. In both women and men, prolactinoma can cause reduced libido, infertility and osteoporosis. Women with prolactinoma may experience complications during pregnancy. A woman who has a large prolactinoma and becomes pregnant may experience additional pituitary growth and associated mass effect. Prolactinoma may also lead to impaired glucose tolerance and diabetes. If tumor grows large enough, prolactinoma may cause visual loss, headache and hypopituitarism. Disturbances of the haemostatic system and dyslipidemia may lead to excess mortality in patients with prolactinoma (5-9, 30, 31).

#### **3. ACTH secreting PA**

Approximately 80% of the cases of Cushing's syndrome are due to the excessive secretion of adrenocorticotropic hormone (ACTH). This is usually (60-80%) due to a pituitary corticotroph adenoma and is defined as Cushing's disease (2, 32).

#### **3.1 Symptoms**

36 Pituitary Adenomas

tumor control rate after gamma knife radiosurgery for pituitary adenomas is equivalent to

Some experimental treatments have been attempted, such as somatostatin analogues, hybrid molecules (both somatostatin and a dopamine agonist in a single molecule), selective estrogen receptor modulators, prolactin-receptor antagonists, and temozolomide are utilized in selected case reports or in trial settings. These have not yet been included in standard

The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass (11). Medical and surgical therapies generally have excellent results, and most prolactinomas are well controlled or even cured in some cases (19). Dopamine agonists are the preferred therapy for prolactinomas because of the risk of recurrent hyperprolactinemia that accompanies transsphenoidal surgery (25, 26). Dopamine agonists are the first line of therapy for macroprolactinomas, resulting in normalizing prolactin levels in 85%, inducing tumor

Surgery should be reserved for patients with dopamine agonist resistance or intolerance. Success rates after surgical treatment of microadenomas range from 73–90% and 30–50% for macroadenomas, with little morbidity and near zero mortality (28). However, subsequent relapse is possible in up to 20% of the cases (22). Surgical outcomes are highly dependent

Following radiotherapy the prevalence of subsequent hypopituitarism is high; therefore, this therapy should be carefully considered, and rather be indicated for mass control than

Overall, patients with pituitary adenoma treated with surgery and radiotherapy have an increased risk of cerebrovascular motrtality compared to the general population, which

As mentioned in the symptoms section, prolactinomas left untreated may lead to various complications. In both women and men, prolactinoma can cause reduced libido, infertility and osteoporosis. Women with prolactinoma may experience complications during pregnancy. A woman who has a large prolactinoma and becomes pregnant may experience additional pituitary growth and associated mass effect. Prolactinoma may also lead to impaired glucose tolerance and diabetes. If tumor grows large enough, prolactinoma may cause visual loss, headache and hypopituitarism. Disturbances of the haemostatic system and dyslipidemia may lead to excess mortality in patients with prolactinoma (5-9, 30, 31).

Approximately 80% of the cases of Cushing's syndrome are due to the excessive secretion of adrenocorticotropic hormone (ACTH). This is usually (60-80%) due to a pituitary

shrinkage in 57%, and long-term remission rates in 22% of the patients (11, 27).

upon the expertise and experience of the neurosurgeon (11, 22).

corticotroph adenoma and is defined as Cushing's disease (2, 32).

fractionated radiation therapy (24).

medical practice (12).

for hyperprolactinemia (27).

**2.6 Complications** 

**3. ACTH secreting PA** 

mirrors the increased incidence of stroke (29).

**2.5 Outcome** 

Cushing's syndrome refers to clinical manifestations induced by chronic exposure to excess glucocorticoids. The most common symptom of glucocorticoid excess is centripetal fat deposition which is frequently the initial symptom of the patient.

Fat accumulates in the face as well as supraclavicular and dorsocervical fat pads, resulting in a typical moon face and buffalo hump, which is most often accompanied by facial plethora. Fat also accumulates over the thorax and the abdomen, which becomes protuberant (33).

Other symptoms and signs include obesity; protein-wasting features such as skin thinning, large and purple abdominal striae, multiple ecchymotic lesions or purpura generated by minimal trauma, lower limb edema, spontaneous ruptures of tendons, slow healing of minor wounds, muscle atrophy, particularly in the lower limbs; bone wasting such as osteoporosis, pathological fractures, kyphosis and loss of height (34, 35); impaired protection mechanism against infections (36); high blood pressure and cardiovascular complications (37, 38); hirsutism; gonadal dysfunction (39); psychic disturbances such as anxiety, irritability, sleep disorders, depression, maniac disorders, delusions and/or hallucinations (40); and decreased short-term memory and cognition (41).

#### **3.2 Epidemiology**

The prevalence of Cushing's disease is approximately 40 per million. ACTH-producing adenomas comprise 10-20% of pituitary adenomas (42). Cushing's disease is nine times more common in women than men(2).

#### **3.3 Diagnosis**

The clinical history is important to assess the general impact of hypercortisolism on organs and systems as well as to guide suspicion toward more aggressive entities such as the ectopic ACTH syndrome or to detect an iatrogenic etiology of Cushing's syndrome (43). Initial diagnosis is performed using tests such as urinary free cortisol, nocturnal salivary cortisol and 1 mg dexamethasone suppression that are sensitive but not specific, and still require established assessment criteria(44). A dexamethasone- corticotrophin releasing hormone (CRH) test can discriminate between Cushing's syndrome and pseudo-Cushing's syndrome. If ACTH is elevated, combinations of high-dose dexamethasone tests, CRH/desmopressin tests, and pituitary magnetic resonance imaging can indicate a pituitary source. Discrimination from an ectopic ACTH tumor often requires inferior petrosal sinus sampling to confirm the source of ACTH. If ACTH is low, adrenal computed tomography will identify the adrenal lesion(s) implicated. Some cortisol-producing adrenal tumors or, more frequently, bilateral macronodular hyperplasia, are under the control of aberrant membrane hormone receptors, or the altered activity of ectopic receptors (43-46). Sophisticated imaging and isotopic techniques play a significant role in locating the source of ACTH in ectopic syndromes but are not always effective. In general, biochemical and imaging tests should be combined in order to assess different mechanisms and perspectives of the syndrome. Rigorous methodology is essential to obtain accurate results, allowing a correct diagnosis and in improving therapeutic performance in this devastating disease (43).

(55, 56).

**4.1 Symptoms** 

cardiomyopathy) (57-59).

hours will exclude acromegaly (60, 61).

**4.2 Epidemiology** 

**4.3 Diagnosis** 

**4.4 Management** 

Functioning Pituitary Adenoma 39

progressively acquired somatic disfigurement (primarily involving the face and extremities) and leads to acromegaly: a disorder of disproportionate tissue, skeletal, and organ growth

Because of the insidious onset and slow progression, acromegaly is frequently diagnosed from four to more than ten years after its onset (57). Patients usually display coarsened facial appearance, acral enlargement, increased skin thickness and soft tissue hyperplasia. Other manifestations include increased sweating, goiter, joint involvement, carpal tunnel syndrome, visual abnormalities, headache, colon polyps, sleep apnea, reproductive disorders, metabolic disturbances (hypertriglyceridemia, reduced insulin sensitivity), and cardiovascular disease (cardiac hypertrophy, hypertension, arrhythmias, and

The prevalence is estimated to be 40-130 per million inhabitants, with 3-4 new cases per million populations per year (55, 58). It is most often diagnosed in middle-aged adults

The measurement of fasting or random GH and of Insulin-like Growth Factor 1 (IGF-1) are baseline biochemical criteria for the diagnosis of acromegaly. A random GH level lower than 0.4 μg/l and an IGF-1 value in the age- and sex-matched normal range exclude the diagnosis of acromegaly. When these two parameters are dissonant, a 75 gram oral glucose tolerance test (OGTT) should be performed: a fall of serum GH to 1 μg/l or less within two

Measurement of circulating GH-releasing hormone (GHRH) is the preferred test for the differential diagnosis between GH-secreting pituitary adenoma and ectopic GHRH secretion. Stimulatory tests (thyroid releasing hormone (TRH) stimulation test or gonadotropin releasing hormone (GnRH) stimulation test) provide no advantage over

Acromegaly is caused by an adenoma of the pituitary gland in more than 98% of all patients. The size of the tumor and its expansion should be documented by MRI. If the tumor expands into the suprasellar space and/or laterally beyond the cavernous sinus, an ophthalmological assessment is suggested to determine the possible impairment of the

The goal of treatment is to relieve symptoms, to obtain control of local tumor mass, and to reduce morbidity and mortality. Treatment options include surgery, medical therapy and radiotherapy. Transsphenoidal surgery is the first choice of treatment when a definitive cure can be achieved, mainly in the cases of microadenomas and when decompression of surrounding structures (optic chiasm, ophthalmic motor nerves) is indicated. This treatment

(average age 40 years). Men and women are equally affected (57).

OGTT, and their use is not recommended for diagnosis (58).

visual field and function of oculomotor nerves (58).

#### **3.4 Management**

The best treatment option for Cushing's disease is when the responsible corticotroph adenoma can be entirely removed surgically by the trans-sphenoidal approach, with sufficient skill to preserve normal anterior pituitary function (32, 46). This induces remission in approximately 80% of the patients, but long-term relapse occurs in up to 30% of these cases (45). The choice of second-line therapy remains controversial (46). Repeat surgery can be successful when residual tumor is detectable on magnetic resonance imaging; however, it carries a high risk of hypopituitarism. The histological pseudocapsule of a pituitary adenoma is a layer of compressed normal anterior lobe that surrounds the adenoma and can be used during surgery to identify and guide the removal of the tumor. With this approach, the overall remission rate is high and the rate of complications is low (47). Radiotherapy combined with ketoconazole or radiosurgery was recently found effective, but a longer-term evaluation of hypopituitarism and brain function is required. As soon as residual tumor progresses, surgery and radiotherapy should be initiated. Various drugs which inhibit steroid synthesis (ketoconazole, metyrapone, aminoglutethimide, mitotane) are sometimes temporarily effective for rapidly controlling hypercortisolism either in preparation for surgery, after the unsuccessful removal of the etiologic tumor, or while awaiting the full effect of radiotherapy or more definitive therapy (45). Other modes of radiotherapy (heavy particles, stereotactic radiosurgery with gamma knife) are limited to specialized centers. Despite initial enthusiasm for gamma knife (48), a relapse rate of up to 20% has been reported following treatment. It may, however, be more rapid than conventional radiotherapy in onset of lowering cortisol levels (49).

#### **3.5 Outcome**

The long-term follow-up of patients treated for Cushing's disease should include the adequate replacement of glucocorticoids and other hormones, treatment of osteoporosis, and detection of long-term relapse of Cushing's disease (45). Following pituitary surgery, careful ongoing expert endocrine assessment is mandatory, as the incidence of relapse increases with time and also with the increasing rigor of the endocrine evaluation. (50).

#### **3.6 Complications**

Today, cardiovascular and psychiatric co-morbidities still remain the major life-threatening complication. The final prognostic criterion for Cushing's syndrome lies in the severity of the hypercortisolism and the aggressiveness of the responsible tumor (37, 46). Bone wasting results in generalized osteoporosis. The prevalence of bone demineralisation assessed by bone mineral density using dual energy X-ray absorptiometry is about 40% (51). Compression fractures of the spine are evident on plain radiographs in about 20% - 80% of the patients, depending on the studies, and almost half the patients complain about backache. Kyphosis and loss of height, sometimes dramatic, are frequent. Pathological fractures can occur elsewhere, particularly in the ribs, feet and pelvis (36). Transient features of brain atrophy can disappear after cure (52). Impaired quality of life may persist years after controlling hypercortisolism (53).

#### **4. GH secreting PA**

Excessive secretion of growth hormone (GH) is responsible for acromegaly (54). This disease is almost always due to a GH-secreting pituitary adenoma. It is distinguished by a gradual progressively acquired somatic disfigurement (primarily involving the face and extremities) and leads to acromegaly: a disorder of disproportionate tissue, skeletal, and organ growth (55, 56).

#### **4.1 Symptoms**

38 Pituitary Adenomas

The best treatment option for Cushing's disease is when the responsible corticotroph adenoma can be entirely removed surgically by the trans-sphenoidal approach, with sufficient skill to preserve normal anterior pituitary function (32, 46). This induces remission in approximately 80% of the patients, but long-term relapse occurs in up to 30% of these cases (45). The choice of second-line therapy remains controversial (46). Repeat surgery can be successful when residual tumor is detectable on magnetic resonance imaging; however, it carries a high risk of hypopituitarism. The histological pseudocapsule of a pituitary adenoma is a layer of compressed normal anterior lobe that surrounds the adenoma and can be used during surgery to identify and guide the removal of the tumor. With this approach, the overall remission rate is high and the rate of complications is low (47). Radiotherapy combined with ketoconazole or radiosurgery was recently found effective, but a longer-term evaluation of hypopituitarism and brain function is required. As soon as residual tumor progresses, surgery and radiotherapy should be initiated. Various drugs which inhibit steroid synthesis (ketoconazole, metyrapone, aminoglutethimide, mitotane) are sometimes temporarily effective for rapidly controlling hypercortisolism either in preparation for surgery, after the unsuccessful removal of the etiologic tumor, or while awaiting the full effect of radiotherapy or more definitive therapy (45). Other modes of radiotherapy (heavy particles, stereotactic radiosurgery with gamma knife) are limited to specialized centers. Despite initial enthusiasm for gamma knife (48), a relapse rate of up to 20% has been reported following treatment. It may, however, be

more rapid than conventional radiotherapy in onset of lowering cortisol levels (49).

The long-term follow-up of patients treated for Cushing's disease should include the adequate replacement of glucocorticoids and other hormones, treatment of osteoporosis, and detection of long-term relapse of Cushing's disease (45). Following pituitary surgery, careful ongoing expert endocrine assessment is mandatory, as the incidence of relapse increases with time and also with the increasing rigor of the endocrine evaluation. (50).

Today, cardiovascular and psychiatric co-morbidities still remain the major life-threatening complication. The final prognostic criterion for Cushing's syndrome lies in the severity of the hypercortisolism and the aggressiveness of the responsible tumor (37, 46). Bone wasting results in generalized osteoporosis. The prevalence of bone demineralisation assessed by bone mineral density using dual energy X-ray absorptiometry is about 40% (51). Compression fractures of the spine are evident on plain radiographs in about 20% - 80% of the patients, depending on the studies, and almost half the patients complain about backache. Kyphosis and loss of height, sometimes dramatic, are frequent. Pathological fractures can occur elsewhere, particularly in the ribs, feet and pelvis (36). Transient features of brain atrophy can disappear after cure (52). Impaired quality of life may persist years

Excessive secretion of growth hormone (GH) is responsible for acromegaly (54). This disease is almost always due to a GH-secreting pituitary adenoma. It is distinguished by a gradual

**3.4 Management** 

**3.5 Outcome** 

**3.6 Complications** 

after controlling hypercortisolism (53).

**4. GH secreting PA** 

Because of the insidious onset and slow progression, acromegaly is frequently diagnosed from four to more than ten years after its onset (57). Patients usually display coarsened facial appearance, acral enlargement, increased skin thickness and soft tissue hyperplasia. Other manifestations include increased sweating, goiter, joint involvement, carpal tunnel syndrome, visual abnormalities, headache, colon polyps, sleep apnea, reproductive disorders, metabolic disturbances (hypertriglyceridemia, reduced insulin sensitivity), and cardiovascular disease (cardiac hypertrophy, hypertension, arrhythmias, and cardiomyopathy) (57-59).

#### **4.2 Epidemiology**

The prevalence is estimated to be 40-130 per million inhabitants, with 3-4 new cases per million populations per year (55, 58). It is most often diagnosed in middle-aged adults (average age 40 years). Men and women are equally affected (57).

#### **4.3 Diagnosis**

The measurement of fasting or random GH and of Insulin-like Growth Factor 1 (IGF-1) are baseline biochemical criteria for the diagnosis of acromegaly. A random GH level lower than 0.4 μg/l and an IGF-1 value in the age- and sex-matched normal range exclude the diagnosis of acromegaly. When these two parameters are dissonant, a 75 gram oral glucose tolerance test (OGTT) should be performed: a fall of serum GH to 1 μg/l or less within two hours will exclude acromegaly (60, 61).

Measurement of circulating GH-releasing hormone (GHRH) is the preferred test for the differential diagnosis between GH-secreting pituitary adenoma and ectopic GHRH secretion. Stimulatory tests (thyroid releasing hormone (TRH) stimulation test or gonadotropin releasing hormone (GnRH) stimulation test) provide no advantage over OGTT, and their use is not recommended for diagnosis (58).

Acromegaly is caused by an adenoma of the pituitary gland in more than 98% of all patients. The size of the tumor and its expansion should be documented by MRI. If the tumor expands into the suprasellar space and/or laterally beyond the cavernous sinus, an ophthalmological assessment is suggested to determine the possible impairment of the visual field and function of oculomotor nerves (58).

#### **4.4 Management**

The goal of treatment is to relieve symptoms, to obtain control of local tumor mass, and to reduce morbidity and mortality. Treatment options include surgery, medical therapy and radiotherapy. Transsphenoidal surgery is the first choice of treatment when a definitive cure can be achieved, mainly in the cases of microadenomas and when decompression of surrounding structures (optic chiasm, ophthalmic motor nerves) is indicated. This treatment

Functioning Pituitary Adenoma 41

cardiovascular disease represents the cause of death in 60%, respiratory disease in 25% and malignancies in 15% of the cases. High GH levels, high blood pressure and heart disease represent the major negative survival determinants in acromegaly, whereas symptom duration, diabetes mellitus and cancer play a minor role in determining mortality (54, 58). If the condition is untreated, enhanced mortality due to cardiovascular, cerebrovascular, and

Thyroid stimulating hormone (TSH) secreting pituitary adenomas are a rare cause of secondary or central hyperthyroidism (68, 69). The pathogenesis of TSH-secreting-adenomas is indefinite and no definite role for various oncogenes has been demonstrated (70). Based on the Clarke et al. study, these tumors are often delayed in diagnosis, are frequently macroadenomas and plurihormonal in terms of their pathological characteristics, have a heterogeneous clinical picture, and are difficult to treat (71). Sometimes mixed pituitary

Because of the long standing duration of the disease, patients present mild or moderate signs of hyperthyroidism and can rarely be asymptomatic (68, 72, 73). In addition, mass effects of the pituitary tumor such as loss of vision and visual field defects may be occurred (70, 73). Moreover, hyperthyroid features can be eclipsed by those of acromegaly in patients with mixed TSH/GH adenomas, thus emphasizing the importance of systematic

TSH secreting tumors account for 0.9 to 2.8% percent of all pituitary adenomas. The diagnosis of these tumors has been increasing in the past 20 years (69). Most patients have

Hormonal evaluation shows increased free thyroid hormone concentration with detectable, normal or increased serum TSH level, raising the differential diagnosis of pituitary resistance to thyroid hormone (72). Ultrasensitive TSH assays allow a clear distinction between patients with suppressed and those with non-suppressed circulating TSH concentrations, i.e. between patients with primary hyperthyroidism (Graves' disease or toxic nodular goiter) and those with central hyperthyroidism (TSH-secreting adenomas or pituitary resistance to thyroid hormone action) (73). The MRI discloses the pituitary adenoma (72). A (99 m) Tc-octreotide scan can be a useful tool for confirming diagnosis of

Therapy of TSH-secreting adenomas can be accomplished by surgery, radiation therapy,

and medical treatment with somatostatin analogs or dopamine agonists (70).

measurement of TSH and free thyroxin (FT4) in patients with pituitary tumor (74).

pulmonary dysfunction is associated with a 30% decrease in life span (56).

tumors co-secrete TSH, growth hormone and prolactin (70).

macroadenomas, and microadenomas are exceptional (75).

**5. TSH secreting PA** 

**5.1 Symptoms** 

**5.2 Epidemiology** 

**5.3 Diagnosis** 

TSH-secreting adenoma (76).

**5.4 Management** 

is the first-line therapy except when the macroadenoma is giant or if surgery is contraindicated. Primary medical therapy should be conducted in patients bearing macroadenomas with significant lateral extension. In addition, preoperative primary medical therapy may result in tumor shrinkage, facilitating tumor resection, and may reduce preoperative complications due to GH excess. Within the spectrum of medical therapy, long-acting somatostatin analogues (somatostatins) are considered as primary therapy. Treatment with somatostatins results in GH control in about 60% of the cases. Somatostatins also induce tumor contraction in 30-50% of the patients, most effectively when applied as first-line treatment. Prolonged treatment with somatostatins is safe and well tolerated. Octreotide and lanreotide (two currently available somatostatins) appear to have equal effectiveness. In patients with suboptimal clinical and biochemical response to somatostatins, combination therapy with dopamine receptor agonists or pegvisomant (a new GH-receptor antagonist) typically leads to effective disease control. New developments in the medical therapy of acromegaly include the universal somatostatin receptor agonist pasireotide, and chimerical compounds that interact with both somatostatin and dopamine receptors with synergizing effects on GH secretion (54, 58, 62, 63).

If surgery fails, medical therapy should be started or reinstated. Dopaminergic drugs might be considered for a small group of patients with mildly elevated GH/IGF-1 levels or harboring GH-prolactin co-secreting adenomas (64, 65). The use of radiotherapy (fractionated, or by gamma-knife) appears to be justified as a treatment of last resort in patients with tumors progressively growing and unresponsive to somatostatins, and in a small group of patients who bear aggressive pituitary adenomas invasive of local structures including the cavernous sinus and even the temporal lobes. These tumors occur more frequently in younger patients, for whom the concerns about radiation-dependent hypopituitarism and second tumor formation are higher. Therefore several considerations must be taken into account when choosing an individualized treatment program for each patient (63, 66).

#### **4.5 Outcome**

Rheumatologic, cardiovascular, respiratory and metabolic consequences are major factors that determine the prognosis (55). The control of GH and IGF-1 secretion is the main goal of treatment, since normalization of these two parameters is the most significant determinant of reversing the increased mortality rate of the patients. The outcome of transsphenoidal surgery is far better for microadenomas (80-90%) than for macroadenomas (less than 50%), which unfortunately represent more than 70% of all GH-secreting pituitary tumors. Therefore, pituitary surgery is the first line treatment for microadenomas (58). Indeed, survival in acromegaly is restored to that observed in the general population after correction of GH/IGF-1 hypersecretion, while morbidity (obstructive sleep apnea, carpal tunnel syndrome, cardiac dysfunction, and diabetes mellitus) is markedly improved by lowering IGF-1 levels(67).

#### **4.6 Complications**

Acromegaly is a slowly progressive disease characterized by a 30% increase of mortality rate for cardiovascular disease (atherosclerosis, cardiomyopathy), respiratory complications, arthrosis and malignancies. Patients with acromegaly display an enhanced mortality rate,

is the first-line therapy except when the macroadenoma is giant or if surgery is contraindicated. Primary medical therapy should be conducted in patients bearing macroadenomas with significant lateral extension. In addition, preoperative primary medical therapy may result in tumor shrinkage, facilitating tumor resection, and may reduce preoperative complications due to GH excess. Within the spectrum of medical therapy, long-acting somatostatin analogues (somatostatins) are considered as primary therapy. Treatment with somatostatins results in GH control in about 60% of the cases. Somatostatins also induce tumor contraction in 30-50% of the patients, most effectively when applied as first-line treatment. Prolonged treatment with somatostatins is safe and well tolerated. Octreotide and lanreotide (two currently available somatostatins) appear to have equal effectiveness. In patients with suboptimal clinical and biochemical response to somatostatins, combination therapy with dopamine receptor agonists or pegvisomant (a new GH-receptor antagonist) typically leads to effective disease control. New developments in the medical therapy of acromegaly include the universal somatostatin receptor agonist pasireotide, and chimerical compounds that interact with both somatostatin and dopamine

If surgery fails, medical therapy should be started or reinstated. Dopaminergic drugs might be considered for a small group of patients with mildly elevated GH/IGF-1 levels or harboring GH-prolactin co-secreting adenomas (64, 65). The use of radiotherapy (fractionated, or by gamma-knife) appears to be justified as a treatment of last resort in patients with tumors progressively growing and unresponsive to somatostatins, and in a small group of patients who bear aggressive pituitary adenomas invasive of local structures including the cavernous sinus and even the temporal lobes. These tumors occur more frequently in younger patients, for whom the concerns about radiation-dependent hypopituitarism and second tumor formation are higher. Therefore several considerations must be taken into account when choosing an individualized treatment program for each

Rheumatologic, cardiovascular, respiratory and metabolic consequences are major factors that determine the prognosis (55). The control of GH and IGF-1 secretion is the main goal of treatment, since normalization of these two parameters is the most significant determinant of reversing the increased mortality rate of the patients. The outcome of transsphenoidal surgery is far better for microadenomas (80-90%) than for macroadenomas (less than 50%), which unfortunately represent more than 70% of all GH-secreting pituitary tumors. Therefore, pituitary surgery is the first line treatment for microadenomas (58). Indeed, survival in acromegaly is restored to that observed in the general population after correction of GH/IGF-1 hypersecretion, while morbidity (obstructive sleep apnea, carpal tunnel syndrome, cardiac dysfunction, and diabetes mellitus) is markedly improved by lowering

Acromegaly is a slowly progressive disease characterized by a 30% increase of mortality rate for cardiovascular disease (atherosclerosis, cardiomyopathy), respiratory complications, arthrosis and malignancies. Patients with acromegaly display an enhanced mortality rate,

receptors with synergizing effects on GH secretion (54, 58, 62, 63).

patient (63, 66).

**4.5 Outcome** 

IGF-1 levels(67).

**4.6 Complications** 

cardiovascular disease represents the cause of death in 60%, respiratory disease in 25% and malignancies in 15% of the cases. High GH levels, high blood pressure and heart disease represent the major negative survival determinants in acromegaly, whereas symptom duration, diabetes mellitus and cancer play a minor role in determining mortality (54, 58). If the condition is untreated, enhanced mortality due to cardiovascular, cerebrovascular, and pulmonary dysfunction is associated with a 30% decrease in life span (56).

#### **5. TSH secreting PA**

Thyroid stimulating hormone (TSH) secreting pituitary adenomas are a rare cause of secondary or central hyperthyroidism (68, 69). The pathogenesis of TSH-secreting-adenomas is indefinite and no definite role for various oncogenes has been demonstrated (70). Based on the Clarke et al. study, these tumors are often delayed in diagnosis, are frequently macroadenomas and plurihormonal in terms of their pathological characteristics, have a heterogeneous clinical picture, and are difficult to treat (71). Sometimes mixed pituitary tumors co-secrete TSH, growth hormone and prolactin (70).

#### **5.1 Symptoms**

Because of the long standing duration of the disease, patients present mild or moderate signs of hyperthyroidism and can rarely be asymptomatic (68, 72, 73). In addition, mass effects of the pituitary tumor such as loss of vision and visual field defects may be occurred (70, 73). Moreover, hyperthyroid features can be eclipsed by those of acromegaly in patients with mixed TSH/GH adenomas, thus emphasizing the importance of systematic measurement of TSH and free thyroxin (FT4) in patients with pituitary tumor (74).

#### **5.2 Epidemiology**

TSH secreting tumors account for 0.9 to 2.8% percent of all pituitary adenomas. The diagnosis of these tumors has been increasing in the past 20 years (69). Most patients have macroadenomas, and microadenomas are exceptional (75).

#### **5.3 Diagnosis**

Hormonal evaluation shows increased free thyroid hormone concentration with detectable, normal or increased serum TSH level, raising the differential diagnosis of pituitary resistance to thyroid hormone (72). Ultrasensitive TSH assays allow a clear distinction between patients with suppressed and those with non-suppressed circulating TSH concentrations, i.e. between patients with primary hyperthyroidism (Graves' disease or toxic nodular goiter) and those with central hyperthyroidism (TSH-secreting adenomas or pituitary resistance to thyroid hormone action) (73). The MRI discloses the pituitary adenoma (72). A (99 m) Tc-octreotide scan can be a useful tool for confirming diagnosis of TSH-secreting adenoma (76).

#### **5.4 Management**

Therapy of TSH-secreting adenomas can be accomplished by surgery, radiation therapy, and medical treatment with somatostatin analogs or dopamine agonists (70).

(85).

**6.3 Diagnosis** 

**6.4 Management** 

investigation (81).

**8. References** 

**6.5 Outcome & Complications** 

functioning pituitary adenomas.

May;64(5):713-9.

**7. Acknowledgements** 

Functioning Pituitary Adenoma 43

adenomas are gonadotrope-derived and recently recognized as gonadotropinomas, which account for as many as 40 to 50% of all pituitary macroadenomas (81, 84). Gonadotropinomas have been reported with increasing frequency in middle-aged men, but they are less frequently recognized in women. This could be the result of greater difficulty in diagnosis due to the normal increase in serum gonadotropins in postmenopausal women

Both clinical and hormonal characteristics of gonadotropinomas usually make them readily distinguishable from pituitary enlargement due to long-standing primary hypogonadism (86). A careful analysis of hormone assay results show that baseline concentrations of gonadotrophin or their free sub-units are elevated in 30 to 50% of the cases. The GnRH test is positive in 75 to 100% of the cases (84). The majority of the cases can be recognized, even in postmenopausal women, by the serum LH beta responses to TRH, and some can be

Most gonadotropinomas are now first treated by transsphenoidal surgery, to make an attempt to restore vision as quickly as possible, and then by radiation therapy to prevent the regrowth of any remaining adenomatous tissue. Radiosurgery using gamma knife, the linear accelerator, or proton beam therapy showed promising results, especially for controlling residual or recurrent tumors (63, 81). Medical therapy for a gonadotrope adenoma with a somatostatin analogs, dopamine agonists, or GnRH agonists and antagonists has limited utility but is employed in patients who are unable to undergo surgery. They may delay or prevent additional tumor growth (64, 84, 89, 90). Experimental therapy with intraoperative local chemotherapy or potential gene therapy requires further

Long-term outcomes and complications of gonadotropinomas are similar to those of non-

[1] McDowell B, Wallace R, Carnahan R, Chrischilles E, Lynch C, Schlechte J. Demographic differences in incidence for pituitary adenoma. Pituitary. 2011;14(1):23-30. [2] Greenberg MS. Handbook of Neurosurgery. 7 ed. New York: Thieme Medical Pub; 2010. [3] Ebersold MJ, Quast LM, Laws ER, Jr., Scheithauer B, Randall RV. Long-term results in

transsphenoidal removal of nonfunctioning pituitary adenomas. J Neurosurg. 1986

recognized by the responses of serum FSH and LH (87, 88).

The authors thank Mrs. Bita Pourmand for her edit of the chapter.

The major aim is to remove the pituitary tumor and restore euthyroidism. Thus, the first therapeutic approach to TSH-secreting pituitary microadenomas should be the transsphenoidal or subfrontal adenomectomy, the choice of the route depending on the tumor volume and its suprasellar extension. This may be complex because of the occasional marked fibrosis of these tumors, possibly related to high expression of basic fibroblast growth factor (68, 77). In patients with macroadenomas or invasive pituitary tumors, long-acting somatostatin analogs may be an effective therapeutic measure to decrease TSH and thyroid hormone secretion (72, 78). Octreotide can control central hyperthyroidism, induce tumor shrinkage, and it can be a satisfactory method of preoperative preparation for TSH-secreting adenoma (73, 76). Aberrant expression of TRβ4 (a novel thyroid hormone receptor β isoform) could possibly contribute to the aberrant secretion of TSH in a TSH-secreting adenoma (79).

#### **5.5 Outcome**

In the past, about one third of the patients were diagnosed as having a primary hyperthyroidism (Graves' disease) and thus mistakenly were treated with thyroid ablation (thyroidectomy and/or radioiodine) (73).

The increasing frequency and early diagnosis of TSH secreting pituitary adenoma may be explained by ultrasensitive methods now used for TSH measurement and progress in pituitary imaging, mainly with MRI. This change in the presentation and the state of disease at diagnosis and the excellent response to somatostatins has improved the prognosis for this uncommon disease (70, 80).

#### **5.6 Complications**

Failure to recognize the presence of a TSH-secreting adenoma may result in dramatic consequences, such as improper thyroid ablation that may cause the pituitary tumor volume to further expand (73).

#### **6. LH and FSH secreting PA**

Recent studies have found that a high proportion of clinically non-functioning pituitary adenomas are largely gonadotrope-derived, i.e. produce and secrete low levels of intact follicle-stimulating hormone (FSH), luteinizing hormone (LH) or only biologically inert alpha- or beta-subunits of these hormones (81, 82).

#### **6.1 Symptoms**

Gonadotroph adenomas are not typically associated with a clinical syndrome (2). They are almost always discovered in patients presenting with mass effect, including visual field loss and headache, hypogonadism, and hypopituitarism (81). Anterior pituitary insufficiency is much more frequent than gonadal hyperstimulation such as ovarian hyperstimulation (83), testicular enlargement (82), and precocious puberty (81, 84).

#### **6.2 Epidemiology**

Advances in immunocytochemistry, electron microscopy, cell culture, and molecular techniques have demonstrated that 80 to 90% of the clinically nonfunctioning pituitary adenomas are gonadotrope-derived and recently recognized as gonadotropinomas, which account for as many as 40 to 50% of all pituitary macroadenomas (81, 84). Gonadotropinomas have been reported with increasing frequency in middle-aged men, but they are less frequently recognized in women. This could be the result of greater difficulty in diagnosis due to the normal increase in serum gonadotropins in postmenopausal women (85).

#### **6.3 Diagnosis**

42 Pituitary Adenomas

The major aim is to remove the pituitary tumor and restore euthyroidism. Thus, the first therapeutic approach to TSH-secreting pituitary microadenomas should be the transsphenoidal or subfrontal adenomectomy, the choice of the route depending on the tumor volume and its suprasellar extension. This may be complex because of the occasional marked fibrosis of these tumors, possibly related to high expression of basic fibroblast growth factor (68, 77). In patients with macroadenomas or invasive pituitary tumors, long-acting somatostatin analogs may be an effective therapeutic measure to decrease TSH and thyroid hormone secretion (72, 78). Octreotide can control central hyperthyroidism, induce tumor shrinkage, and it can be a satisfactory method of preoperative preparation for TSH-secreting adenoma (73, 76). Aberrant expression of TRβ4 (a novel thyroid hormone receptor β isoform) could possibly contribute to the aberrant secretion of TSH in a TSH-secreting adenoma (79).

In the past, about one third of the patients were diagnosed as having a primary hyperthyroidism (Graves' disease) and thus mistakenly were treated with thyroid ablation

The increasing frequency and early diagnosis of TSH secreting pituitary adenoma may be explained by ultrasensitive methods now used for TSH measurement and progress in pituitary imaging, mainly with MRI. This change in the presentation and the state of disease at diagnosis and the excellent response to somatostatins has improved the prognosis for this

Failure to recognize the presence of a TSH-secreting adenoma may result in dramatic consequences, such as improper thyroid ablation that may cause the pituitary tumor volume

Recent studies have found that a high proportion of clinically non-functioning pituitary adenomas are largely gonadotrope-derived, i.e. produce and secrete low levels of intact follicle-stimulating hormone (FSH), luteinizing hormone (LH) or only biologically inert

Gonadotroph adenomas are not typically associated with a clinical syndrome (2). They are almost always discovered in patients presenting with mass effect, including visual field loss and headache, hypogonadism, and hypopituitarism (81). Anterior pituitary insufficiency is much more frequent than gonadal hyperstimulation such as ovarian hyperstimulation (83),

Advances in immunocytochemistry, electron microscopy, cell culture, and molecular techniques have demonstrated that 80 to 90% of the clinically nonfunctioning pituitary

**5.5 Outcome** 

(thyroidectomy and/or radioiodine) (73).

uncommon disease (70, 80).

**5.6 Complications** 

to further expand (73).

**6.1 Symptoms** 

**6.2 Epidemiology** 

**6. LH and FSH secreting PA** 

alpha- or beta-subunits of these hormones (81, 82).

testicular enlargement (82), and precocious puberty (81, 84).

Both clinical and hormonal characteristics of gonadotropinomas usually make them readily distinguishable from pituitary enlargement due to long-standing primary hypogonadism (86). A careful analysis of hormone assay results show that baseline concentrations of gonadotrophin or their free sub-units are elevated in 30 to 50% of the cases. The GnRH test is positive in 75 to 100% of the cases (84). The majority of the cases can be recognized, even in postmenopausal women, by the serum LH beta responses to TRH, and some can be recognized by the responses of serum FSH and LH (87, 88).

#### **6.4 Management**

Most gonadotropinomas are now first treated by transsphenoidal surgery, to make an attempt to restore vision as quickly as possible, and then by radiation therapy to prevent the regrowth of any remaining adenomatous tissue. Radiosurgery using gamma knife, the linear accelerator, or proton beam therapy showed promising results, especially for controlling residual or recurrent tumors (63, 81). Medical therapy for a gonadotrope adenoma with a somatostatin analogs, dopamine agonists, or GnRH agonists and antagonists has limited utility but is employed in patients who are unable to undergo surgery. They may delay or prevent additional tumor growth (64, 84, 89, 90). Experimental therapy with intraoperative local chemotherapy or potential gene therapy requires further investigation (81).

#### **6.5 Outcome & Complications**

Long-term outcomes and complications of gonadotropinomas are similar to those of nonfunctioning pituitary adenomas.

### **7. Acknowledgements**

The authors thank Mrs. Bita Pourmand for her edit of the chapter.

#### **8. References**


Functioning Pituitary Adenoma 45

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Quality of Life in Patients after Long-Term Biochemical Cure of Cushing's Disease.

al. Medical Therapy of Acromegaly: Efficacy and Safety of Somatostatin Analogues.

diagnosis, and management. Neurosurg Focus. 2007;23(3):E13.

Research Clinical Endocrinology & Metabolism. 2009;23(5):607-23.

disease: long-term results. J Neurosurg. 2002;97(5 Suppl):422-8.

disease. J Neurosurg. 2009;111(3):531-9.

Journal of Endocrinology. 2007;156(1):91-8.

2002;87(5):1949-54.

202.

Drugs. 2009;69(16):2207-26

Metabolism. 2000;85(2):526-9.

surveillance. Clin Endocrinol (Oxf). 2005;63(5):549-59.

[47] Jagannathan J, Smith R, DeVroom HL, Vortmeyer AO, Stratakis CA, Nieman LK, et al.

[48] Kobayashi T, Kida Y, Mori Y. Gamma knife radiosurgery in the treatment of Cushing

[49] Castinetti F, Nagai M, Dufour H, Kuhn J-M, Morange I, Jaquet P, et al. Gamma knife

[50] Atkinson AB, Kennedy A, Wiggam MI, McCance DR, Sheridan B. Long-term remission

[51] Ohmori N, Nomura K, Ohmori K, Kato Y, Itoh T, Takano K. Osteoporosis is more

[52] Bourdeau I, Bard C, Noël B, Leclerc I, Cordeau M-P, Bélair M, et al. Loss of Brain

[53] van Aken MO, Pereira AM, Biermasz NR, van Thiel SW, Hoftijzer HC, Smit JWA, et al.

[55] Chanson P, Salenave S, Kamenicky P, Cazabat L, Young J. Acromegaly. Best Practice &

[56] Melmed S. Acromegaly pathogenesis and treatment. J Clin Invest. 2009;119(11):3189-

[60] Giustina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Ho K, et al. Criteria for

[61] Trainer PJ. Acromegaly—Consensus, What Consensus? Journal of Clinical

Cure of Acromegaly: A Consensus Statement. Journal of Clinical Endocrinology &

Journal of Clinical Endocrinology & Metabolism. 2005;90(6):3279-86. [54] Feelders RA, Hofland LJ, van Aken MO, Neggers SJ, Lamberts SWJ, de Herder WW, et

Research Clinical Endocrinology & Metabolism. 2009;23(5):555-74.

[57] Chanson P, Salenave S. Acromegaly. Orphanet J Rare Dis. 2008;3:17. [58] Scacchi M, Cavagnini F. Acromegaly. Pituitary. 2006;9(4):297-303.

[59] Chanson P. [Acromegaly]. Presse Med. 2009;38(1):92-102.

Endocrinology & Metabolism. 2002;87(8):3534-6.


**4** 

*México City México* 

**Pituitary Adenomas – Clinico-Pathological,** 

Alma Ortiz-Plata, Martha L. Tena-Suck, Iván Pérez-Neri,

Daniel Rembao-Bojórquez and Angeles Fernández

*National Institute of Neurology and Neurosurgery* 

**Immunohistochemical and Ultrastructural Study** 

Pituitary adenomas (PA) constitute about 10% of intracranial neoplasm. Most of them have its origin in adenohypophysis (Cury et al., 2009; Rosai, 1989). They occur most often in adults between the ages of 30 and 60 years, and may have slightly higher incidence in females in early life (20-45 years) and in males in later life (35-60 years) (Davis et al., 2001; McDowell et al., 2011). The majority of pituitary adenomas have a sporadic origin; familial cases represent 5% of all pituitary tumors (Vandeva et al., 2010; Tichomirowa et al., 2009). Couldwell and Cannon (2010) report strong evidence of genetic contribution for

Pituitary adenomas clinically manifest by signs of hypopituitarism, this is caused by the compression of the gland by the tumor which may affect fertility, the compression of other adjacent structures may cause headache and if the optic chiasm is affected visual alterations; secretion of one or more specific hormones can take place (Galland & Chanson, 2009; Melmed, 2010). However, up to 30% of adenomas do not secrete hormones (Cury et al.,

Pituitary adenomas have been classified as: microadenomas (<10mm diameter) and macroadenomas (> 10 mm diameter), according to its size assessed by tomography and magnetic resonance; staining affinity (acidophilic, chromophobic or basophilic); hormonal activity or secretion of growth hormone (GH), prolactin (PRL), thyroid stimulating hormone(TSH), adrenocorticotrophin hormone (ACTH), follicle stimulating hormone (FSH), and luteinizing hormone (LH); and ultrastructural characteristics (Galland & Chanson, 2009; Nosé, 2011). Hardy (1973) classified pituitary adenomas in four grades according to its size

Grade I: Microadenomas, measuring less than 10mm in diameter, they minimally alter the

Grade II: Macroadenomas are bigger than 10mm in diameter, they enlarge the sella or

Grade III: Invasive adenomas, locally eroded the sella, and show suprasellar outgrowth. Grade IV: Strongly invasive adenomas, that destroys adjacent bony structures and with suprasellar outgrowth, including bone, hypothalamus, and the cavernous sinus.

exhibit suprasellar expansion, but not cause destruction.

**1. Introduction** 

predisposition to symptomatic pituitary tumors.

radiographic appearance of the sella.

2009; Martinez, 1986; Moreno, 2005).

and local invasion degree:


## **Pituitary Adenomas – Clinico-Pathological, Immunohistochemical and Ultrastructural Study**

Alma Ortiz-Plata, Martha L. Tena-Suck, Iván Pérez-Neri, Daniel Rembao-Bojórquez and Angeles Fernández *National Institute of Neurology and Neurosurgery México City México* 

#### **1. Introduction**

48 Pituitary Adenomas

[79] Tagami T, Usui T, Shimatsu A, Beniko M, Yamamoto H, Moriyama K, et al. Aberrant

[80] Latrech H, Rousseau A, Le Marois E, Billaud L, Bertagna X, Azzoug S, et al.

[81] Chaidarun SS, Klibanski A. Gonadotropinomas. Semin Reprod Med. 2002;20(4):339-48. [82] Dahlqvist P, Koskinen L-O, Brännström T, Hägg E. Testicular enlargement in a patient with a FSH-secreting pituitary adenoma. Endocrine. 2010;37(2):289-93. [83] Cooper O, Geller JL, Melmed S. Ovarian hyperstimulation syndrome caused by an FSHsecreting pituitary adenoma. Nat Clin Pract Endocrinol Metab. 2008;4(4):234-8. [84] Chanson P. [Gonadotroph pituitary adenomas]. Ann Endocrinol (Paris). 2000;61(3):258-

[85] Hattori N, Ishihara T, Moridera K, Ikekubo K, Hino M, Saiki Y, et al. LH- and FSH-

[86] Snyder PJ. Gonadotroph cell adenomas of the pituitary. Endocr Rev. 1985;6(4):552-63. [87] Daneshdoost L, Gennarelli TA, Bashey HM, Savino PJ, Sergott RC, Bosley TM, et al.

[88] Gruszka A, Kunert-Radek J, Pawlikowski M. Serum alpha-subunit elevation after TRH

[89] Berezin M, Olchovsky D, Pines A, Tadmor R, Lunenfeld B. Reduction of follicle-

[90] Chanson P, Brochier S. Non-functioning pituitary adenomas. J Endocrinol Invest.

bromocriptine. J Clin Endocrinol Metab. 1984;59(6):1220-3.

secreting pituitary adenoma in a postmenopausal woman. Endocrinol Jpn.

Recognition of gonadotroph adenomas in women. N Engl J Med. 1991;324(9):589-

administration: a valuable test in presurgical diagnosis of gonadotropinoma?

stimulating hormone (FSH) secretion in FSH-producing pituitary adenoma by

observations. La Revue de Médecine Interne. 2010;31(12):858-62.

2011;96(6):E948-52.

68.

94.

1991;38(4):393-6.

Endokrynol Pol. 2005;56(1):14-8.

2005;28(11 Suppl International):93-9.

expression of thyroid hormone receptor beta isoform may cause inappropriate secretion of TSH in a TSH-secreting pituitary adenoma. J Clin Endocrinol Metab.

Présentation et pronostic des adénomes thyréotropes : à propos de trois

Pituitary adenomas (PA) constitute about 10% of intracranial neoplasm. Most of them have its origin in adenohypophysis (Cury et al., 2009; Rosai, 1989). They occur most often in adults between the ages of 30 and 60 years, and may have slightly higher incidence in females in early life (20-45 years) and in males in later life (35-60 years) (Davis et al., 2001; McDowell et al., 2011). The majority of pituitary adenomas have a sporadic origin; familial cases represent 5% of all pituitary tumors (Vandeva et al., 2010; Tichomirowa et al., 2009). Couldwell and Cannon (2010) report strong evidence of genetic contribution for predisposition to symptomatic pituitary tumors.

Pituitary adenomas clinically manifest by signs of hypopituitarism, this is caused by the compression of the gland by the tumor which may affect fertility, the compression of other adjacent structures may cause headache and if the optic chiasm is affected visual alterations; secretion of one or more specific hormones can take place (Galland & Chanson, 2009; Melmed, 2010). However, up to 30% of adenomas do not secrete hormones (Cury et al., 2009; Martinez, 1986; Moreno, 2005).

Pituitary adenomas have been classified as: microadenomas (<10mm diameter) and macroadenomas (> 10 mm diameter), according to its size assessed by tomography and magnetic resonance; staining affinity (acidophilic, chromophobic or basophilic); hormonal activity or secretion of growth hormone (GH), prolactin (PRL), thyroid stimulating hormone(TSH), adrenocorticotrophin hormone (ACTH), follicle stimulating hormone (FSH), and luteinizing hormone (LH); and ultrastructural characteristics (Galland & Chanson, 2009; Nosé, 2011). Hardy (1973) classified pituitary adenomas in four grades according to its size and local invasion degree:


Grade III: Invasive adenomas, locally eroded the sella, and show suprasellar outgrowth.

Grade IV: Strongly invasive adenomas, that destroys adjacent bony structures and with suprasellar outgrowth, including bone, hypothalamus, and the cavernous sinus.

Pituitary Adenomas – Clinico-Pathological, Immunohistochemical and Ultrastructural Study 51

In other sections, immunohistochemistry (Bratthauer et al., 1994) was performed. Slides of each case were deparaffinized, rehydrated, and rinsed in PBS. Later on, endogenous peroxidase was blocked with 0.25 % H2O2/distilled water for 15 min., and blocking with 3% BSA in PBS (Albumin, Bovine, Sigma-AldrichCo. St. Louis USA). The slides were incubated for 1 h in ready to use monoclonal antibodies of pituitary hormones: prolactin, growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid stimulating hormone (TSH) (BioGenex, San Ramón, CA) and adrenocorticotropic hormone (ACTH, DAKO, Carpinteria, Ca, at a 1;100 dilution). Normal postmortem pituitaries were used as positive controls for pituitary hormones. To assess the proliferative index of pituitary adenomas Ki-67 antibody was used (Santa Cruz Biotechnology, inc. Santa Cruz CA. USA at 1:100 dilution). After that the sections were washed, and incubated for 30 min. with the secondary antibody (biotinylated anti-Ig, BioGenex, San Ramón, CA). After washing in PBS the sections were incubated for 30 min with peroxidase-conjugated streptavidina complex (BioGenex, San Ramón, CA). The reaction was developed with diaminobenzidine (DAB) using a Dako kit detection system (Dako enVision System Peroxidase. Dako Carpinteria, CA) according to manufacturer's instructions and the sections were hematoxylin counterstained. The immunodetection was analyzed under a wide-field microscope Olympus H2 (Tokyo, Japan). The immunoreactivity to different hormones in tumor cells were estimated as positive or negative, and the Ki-67 labeled index (LI) was assessed by counting the percentage of number of positive / nuclear cells in five 40x fields. Statistics analysis were done to associate Ki-67 labeling index (LI), disease evolution time, and outcome, in functional PA and in non-functional PA, hormone secretion, invasion

The second part of biopsy was processed for its use in electron microscopy to assess the fine structure of PA. The tissues were fixed in 2.5% glutaraldehyde in 0.1 M phosphate-buffersaline (PBS pH 7.4) and postfixed in 1% tetroxide osmium in the same buffer, dehydrated in alcohol, and embedded in Epon. One-micron thick sections were stained with toluidine blue and examined by light microscopy. Ultrathin sections at the silver/grey area of the spectrum of interference colors were stained with uranyl acetate and lead citrate and

Statistical analysis was performed by using the SPSS 13.0 software. ANOVA test and X2, Kurskal-Wallis were used to evaluate differences and association respectively, among evolution time and follow up with grades of invasion. Bivariate analysis was accomplished by means of Fisher's exact test for association among functional and non-functional PA, or hormonal immunodetection with recurrences. U Mann-Whitney's test was used to assess evolution time and follow up differences among functioning and non-functioning PA. To evaluate differences in Ki-67-LI detection among invasion grades, X2 Kurskal-Wallis test was done; among functioning and non-functioning PA with recurrences U Mann-Whitney's test was used; and the association of Ki-67-LI detection with hormonal immunodetection, U Mann-Whitney's test was accomplished. P value less than .05 were considered significant.

examined under Zeiss EM 10 transmission electron microscopy.

**2.2 Immunohistochemistry** 

degree, and tumor regrowth.

**2.3 Ultrastructural analysis** 

**2.4 Statistical analysis** 

This classification remains valid using computed tomography scanning and magnetic resonance imaging.

Histologically pituitary adenomas are dense cellular tumors, composed by cells with solid nuclei, rounded and uniform. These cells can be arranged in big groups (diffused pattern), around sinusoidal vessels (sinusoidal pattern), or covering connective-vascular axes (papillary pattern). In all PA types, atypia and mitotic cells are rare. Despite the histologically benign aspect, pituitary adenomas may have an invasive behavior (Chang, 2010; Lau, et al., 2010; Li-Ng, 2008; Melmed, 2010; Scheithauer, 1986; Zada et al., 2011;). This factor is not necessarily indicative of malignancy, because tumor growth is slow and metastases are rare. The histological aspect is not different from the rare carcinoma cases (Colao et al., 2010; Crocker, 1978; Kaltsas et al., 2005; Schteithauer et al., 2005; Tena-Suck et al., 2006;).

In most patients the pathologist cannot provide information about the PA behavior, if will be aggressive based on the histological appearance of adenomas, this is because tumors with variations in the size, shape and nuclear density and the presence of bi-or multinucleated cells do not necessarily had a poor prognosis.

The functional classification of pituitary adenomas based on its hormonal activity, assessed by immunohistochemistry technique, and associated with the transmission electron microscopy analysis, has allowed the characterization of neoplastic cells in detail and proposes the classification of the adenomas in 14 different types, this allows a better correlation with the clinical manifestations that the old classification of chromophobe, acidophilic and basophilic pituitary adenomas (Horvath & Kovacs, 1992; Horvath, 1994; Kovacs & Horvath, 1986).

The aim of this investigation is to present a review of different cases of pituitary adenomas studied in the Laboratory of Experimental Neuropathology of National Institute of Neurology and Neurosurgery, correlating the local invasion degree, clinical manifestations, histological aspects, immunohistochemical and ultrastructural features, with the biological behavior, especially with the invasive potential.

#### **2. Methods**

One hundred and twenty two cases of pituitary adenomas were studied. They were classified by their local invasion degree according with Hardy classification (Hardy, 1973), endocrine symptoms (clinically functioning and clinically non functioning pituitary adenomas) and by their hormonal secretion, assessed by immunohistochemistry. The evolution of the disease at the time of diagnosis, tumor regrowth, bromocriptine treatment, and time of outcome of the patients, were evaluated to analyze the PA biological behavior.

#### **2.1 Histopathological analysis**

The biopsies were divided in two parts; the first one was fixed in phosphate-buffer saline (PBS)-formalin solution, alcohol dehydrated and paraffin-embedded. Five µm sections were stained with hematoxilyn-eosin and Masson's trichrome (Prophet & Arrington, 1992) for PA treated with bomocriptine. In each hematoxylin-eosin stained section was analyzed nuclear pleomorphism and mitosis figures.

#### **2.2 Immunohistochemistry**

50 Pituitary Adenomas

This classification remains valid using computed tomography scanning and magnetic

Histologically pituitary adenomas are dense cellular tumors, composed by cells with solid nuclei, rounded and uniform. These cells can be arranged in big groups (diffused pattern), around sinusoidal vessels (sinusoidal pattern), or covering connective-vascular axes (papillary pattern). In all PA types, atypia and mitotic cells are rare. Despite the histologically benign aspect, pituitary adenomas may have an invasive behavior (Chang, 2010; Lau, et al., 2010; Li-Ng, 2008; Melmed, 2010; Scheithauer, 1986; Zada et al., 2011;). This factor is not necessarily indicative of malignancy, because tumor growth is slow and metastases are rare. The histological aspect is not different from the rare carcinoma cases (Colao et al., 2010; Crocker, 1978; Kaltsas et al., 2005; Schteithauer et al., 2005; Tena-Suck et

In most patients the pathologist cannot provide information about the PA behavior, if will be aggressive based on the histological appearance of adenomas, this is because tumors with variations in the size, shape and nuclear density and the presence of bi-or multinucleated

The functional classification of pituitary adenomas based on its hormonal activity, assessed by immunohistochemistry technique, and associated with the transmission electron microscopy analysis, has allowed the characterization of neoplastic cells in detail and proposes the classification of the adenomas in 14 different types, this allows a better correlation with the clinical manifestations that the old classification of chromophobe, acidophilic and basophilic pituitary adenomas (Horvath & Kovacs, 1992; Horvath, 1994;

The aim of this investigation is to present a review of different cases of pituitary adenomas studied in the Laboratory of Experimental Neuropathology of National Institute of Neurology and Neurosurgery, correlating the local invasion degree, clinical manifestations, histological aspects, immunohistochemical and ultrastructural features, with the biological

One hundred and twenty two cases of pituitary adenomas were studied. They were classified by their local invasion degree according with Hardy classification (Hardy, 1973), endocrine symptoms (clinically functioning and clinically non functioning pituitary adenomas) and by their hormonal secretion, assessed by immunohistochemistry. The evolution of the disease at the time of diagnosis, tumor regrowth, bromocriptine treatment, and time of outcome of the patients, were evaluated to analyze the PA biological behavior.

The biopsies were divided in two parts; the first one was fixed in phosphate-buffer saline (PBS)-formalin solution, alcohol dehydrated and paraffin-embedded. Five µm sections were stained with hematoxilyn-eosin and Masson's trichrome (Prophet & Arrington, 1992) for PA treated with bomocriptine. In each hematoxylin-eosin stained section was analyzed nuclear

resonance imaging.

al., 2006;).

cells do not necessarily had a poor prognosis.

behavior, especially with the invasive potential.

Kovacs & Horvath, 1986).

**2.1 Histopathological analysis** 

pleomorphism and mitosis figures.

**2. Methods** 

In other sections, immunohistochemistry (Bratthauer et al., 1994) was performed. Slides of each case were deparaffinized, rehydrated, and rinsed in PBS. Later on, endogenous peroxidase was blocked with 0.25 % H2O2/distilled water for 15 min., and blocking with 3% BSA in PBS (Albumin, Bovine, Sigma-AldrichCo. St. Louis USA). The slides were incubated for 1 h in ready to use monoclonal antibodies of pituitary hormones: prolactin, growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid stimulating hormone (TSH) (BioGenex, San Ramón, CA) and adrenocorticotropic hormone (ACTH, DAKO, Carpinteria, Ca, at a 1;100 dilution). Normal postmortem pituitaries were used as positive controls for pituitary hormones. To assess the proliferative index of pituitary adenomas Ki-67 antibody was used (Santa Cruz Biotechnology, inc. Santa Cruz CA. USA at 1:100 dilution). After that the sections were washed, and incubated for 30 min. with the secondary antibody (biotinylated anti-Ig, BioGenex, San Ramón, CA). After washing in PBS the sections were incubated for 30 min with peroxidase-conjugated streptavidina complex (BioGenex, San Ramón, CA). The reaction was developed with diaminobenzidine (DAB) using a Dako kit detection system (Dako enVision System Peroxidase. Dako Carpinteria, CA) according to manufacturer's instructions and the sections were hematoxylin counterstained. The immunodetection was analyzed under a wide-field microscope Olympus H2 (Tokyo, Japan). The immunoreactivity to different hormones in tumor cells were estimated as positive or negative, and the Ki-67 labeled index (LI) was assessed by counting the percentage of number of positive / nuclear cells in five 40x fields. Statistics analysis were done to associate Ki-67 labeling index (LI), disease evolution time, and outcome, in functional PA and in non-functional PA, hormone secretion, invasion degree, and tumor regrowth.

#### **2.3 Ultrastructural analysis**

The second part of biopsy was processed for its use in electron microscopy to assess the fine structure of PA. The tissues were fixed in 2.5% glutaraldehyde in 0.1 M phosphate-buffersaline (PBS pH 7.4) and postfixed in 1% tetroxide osmium in the same buffer, dehydrated in alcohol, and embedded in Epon. One-micron thick sections were stained with toluidine blue and examined by light microscopy. Ultrathin sections at the silver/grey area of the spectrum of interference colors were stained with uranyl acetate and lead citrate and examined under Zeiss EM 10 transmission electron microscopy.

#### **2.4 Statistical analysis**

Statistical analysis was performed by using the SPSS 13.0 software. ANOVA test and X2, Kurskal-Wallis were used to evaluate differences and association respectively, among evolution time and follow up with grades of invasion. Bivariate analysis was accomplished by means of Fisher's exact test for association among functional and non-functional PA, or hormonal immunodetection with recurrences. U Mann-Whitney's test was used to assess evolution time and follow up differences among functioning and non-functioning PA. To evaluate differences in Ki-67-LI detection among invasion grades, X2 Kurskal-Wallis test was done; among functioning and non-functioning PA with recurrences U Mann-Whitney's test was used; and the association of Ki-67-LI detection with hormonal immunodetection, U Mann-Whitney's test was accomplished. P value less than .05 were considered significant.

Pituitary Adenomas – Clinico-Pathological, Immunohistochemical and Ultrastructural Study 53

I 2 1 (50) 33/31 1.5 1 0

Table 2. Pituitary adenomas classification by grades of invasion according to Hardy (1973).

Prolactin was the most frequent hormone detected by immunohistochemistry (54 cases, 44.2%) (Table 3). Prolactin hormone expression was found in combination with others hormones: 10 were in combination with GH (8.1%), 4 (3.2%) with TSH; 3 (2.4%) with ACTH, and 1 (0.81%) with LH. Fifteen (12.3%) cases were positive for gonadotroph hormones, 5 (4%) for growth hormone, 2 (1.6%) for ACTH, 1 (0.82%) for TSH, 1 (0.82%) multihormonal

Fig. 1. Pituitary adenoma classification according to their hormonal content assessed by

Growth hormone; TSH= Thyroid stimulating hormone; ACTH= adrenocorticotropin hormone; LH= luteinizing hormone; FSH= follicle stimulating hormone; MH=

Prolactin hormone expression was the most frequent detected. Prl= prolactin hormone; GH=

Disease evolution time, follow up time, and recurrences in each grade are shown.

(HC-FSH-TSH), and 26 (21.3%) cases were negative for all hormones (Fig. 1).

Evolution Time Years (mean)

Follow up time Years (range)

Recurrences

(%) 1 2

Cases n

(1m-20yr) 6 (15.3%) 6

(2-20) 10 (25.6%) 7 3

(1-27) 23 (58.9%) 21 2

Grade Cases n

Gender Female n(%)

F= females; M= males; m= month.

**3.1 Immunohistochemistry** 

immunohistochemistry.

multihormonal; Neg= negative.

Mean Age F/M

II 20 4 (20%) 39/45 2.1 10.6

III 34 23 (67%) 40/34 3.4 12.1

IV 66 29 (44%) 39/44 3 10.3

#### **3. Results**

One hundred and twenty two pituitary adenomas were studied between 1988 and 1992. They were organized according to their characteristics, by means of transsphenoidal or transcranial-frontal technique, and the tumors were removed in 60 to 100%. Tumors mainly affected young adult population with a mean age of 41.4 yr. Sixty five (53.3%) were male, mean age of 43.6±14.8 yr (range, 17-71 yr) and 57 (46.7%) were female, mean age of 39.3±14.4 yr (range, 13-75 yr). Twelve patients were under 20 yr (9.8%). Six males with mean age of 18.8 ± 2.4 yr, and 6 females with mean age of 16.1 ± 2.5 yr. Clinically they were 11 functioning PA and 1 non-functioning PA (Table 1).


F= functioning pituitary adenoma; NF= non-functioning pituitary adenoma; VA= visual alterations; Ha= headache; Am= amenorrhea; Gal= Galactorrhea; Gig= gigantism; Ac= acromegaly; IHQ= immunohistochemical detection.

Table 1. Pituitary adenomas in young cases under 20 years old at the onset of symptoms. The age column is the age at diagnosis.

Twenty two cases (18%) were classified as I and II invasion grades tumors, and 66 cases (54.1%) were in extensive invasion phase (IV grade). The disease evolution time before the first surgery was 2.9±2.3 yr (range, 2 months to 10 years). Of the 122 patients thirty eight patients continued to attend their review appointments (31%). The average follow up time of the patients was 11±7.4 yr (range, 1-27 yr); from 1 to 5 yr, and from 15 to 20 yr, were the most frequent. Only one patient (0.8%) was considered healthy; four deaths have been reported. The remaining patients stopped coming to the Institute to control appointments. Thirty nine (31.9%) cases out of the 122 had recurrence; 23 (58.9%) belong to grade IV PA. In grade III and IV, two patients with recurrences were observed (Table 2).


Table 2. Pituitary adenomas classification by grades of invasion according to Hardy (1973). Disease evolution time, follow up time, and recurrences in each grade are shown. F= females; M= males; m= month.

#### **3.1 Immunohistochemistry**

52 Pituitary Adenomas

One hundred and twenty two pituitary adenomas were studied between 1988 and 1992. They were organized according to their characteristics, by means of transsphenoidal or transcranial-frontal technique, and the tumors were removed in 60 to 100%. Tumors mainly affected young adult population with a mean age of 41.4 yr. Sixty five (53.3%) were male, mean age of 43.6±14.8 yr (range, 17-71 yr) and 57 (46.7%) were female, mean age of 39.3±14.4 yr (range, 13-75 yr). Twelve patients were under 20 yr (9.8%). Six males with mean age of 18.8 ± 2.4 yr, and 6 females with mean age of 16.1 ± 2.5 yr. Clinically they were 11

II M 17 1 X Hypogonadism Prl II M 20 2 X VA Ha Ac GH II F 23 4 X VA Ha Am-Gal Prl-TSH II M 24 6 X Cush Neg II M 18 4 X VA Ha Prl III F 14 2 X VA Am Prl III M 20 8 X Gal-Am Gig Prl-GH III F 23 8 X VA Ha Am-Gal Prl-ACTH IV F 18 4 X VA Ha Am Prl IV F 18 4 X VA Ha Am-Gal Neg IV F 13 2 X VA Am Prl IV M 20 2 X VA Ac Prl-GH

F= functioning pituitary adenoma; NF= non-functioning pituitary adenoma; VA= visual alterations; Ha= headache; Am= amenorrhea; Gal= Galactorrhea; Gig= gigantism; Ac= acromegaly; IHQ=

Table 1. Pituitary adenomas in young cases under 20 years old at the onset of symptoms.

grade III and IV, two patients with recurrences were observed (Table 2).

Twenty two cases (18%) were classified as I and II invasion grades tumors, and 66 cases (54.1%) were in extensive invasion phase (IV grade). The disease evolution time before the first surgery was 2.9±2.3 yr (range, 2 months to 10 years). Of the 122 patients thirty eight patients continued to attend their review appointments (31%). The average follow up time of the patients was 11±7.4 yr (range, 1-27 yr); from 1 to 5 yr, and from 15 to 20 yr, were the most frequent. Only one patient (0.8%) was considered healthy; four deaths have been reported. The remaining patients stopped coming to the Institute to control appointments. Thirty nine (31.9%) cases out of the 122 had recurrence; 23 (58.9%) belong to grade IV PA. In

Time (yr) F NF Symptoms IHQ

functioning PA and 1 non-functioning PA (Table 1).

Grade Gender Age (yr) Evolution

immunohistochemical detection.

The age column is the age at diagnosis.

**3. Results** 

Prolactin was the most frequent hormone detected by immunohistochemistry (54 cases, 44.2%) (Table 3). Prolactin hormone expression was found in combination with others hormones: 10 were in combination with GH (8.1%), 4 (3.2%) with TSH; 3 (2.4%) with ACTH, and 1 (0.81%) with LH. Fifteen (12.3%) cases were positive for gonadotroph hormones, 5 (4%) for growth hormone, 2 (1.6%) for ACTH, 1 (0.82%) for TSH, 1 (0.82%) multihormonal (HC-FSH-TSH), and 26 (21.3%) cases were negative for all hormones (Fig. 1).

Fig. 1. Pituitary adenoma classification according to their hormonal content assessed by immunohistochemistry.

Prolactin hormone expression was the most frequent detected. Prl= prolactin hormone; GH= Growth hormone; TSH= Thyroid stimulating hormone; ACTH= adrenocorticotropin hormone; LH= luteinizing hormone; FSH= follicle stimulating hormone; MH= multihormonal; Neg= negative.

Pituitary Adenomas – Clinico-Pathological, Immunohistochemical and Ultrastructural Study 55

Photomicrograph of pituitary adenomas stained with immunohistochemical technique. Antibodies against prolactin hormone (A), and Ki-67 (B). Prolactin detection is present in the cytoplasm and Ki-67 can be seen in nucleus. Arrows show the immunodetection. (original

**A B** 

There was no significative statistic difference in disease evolution time (F=1.0, p=0.351) and follow up (F=0.1, p=0.885), compared between invasion degrees. Neither the evolution time (p=0.146) nor the follow-up time (p=0.678) differed between functioning PA and nonfunctioning PA, however disease evolution time was lightly higher in III and IV invasion degrees. Evolution time (X2=2.4, p=0.287) and follow up time (X2=0.1, p=0.939) did not have

No association was found among recurrence and functioning PA (p=0.526), and with

Ki-67-LI was higher in IV grade (median value: 24.5%; range 2-35) in comparison with grade II (median value 6.8%; range 1-20; X2=6.4, p=0.029); Grade III PA has an intermediate value (median value 10.7%; range 10-16). There was no statistic difference of Ki-67-LI between functioning PA and non-functioning PA (p=0.893) or between PA with recurrence and PA without recurrence (p=0.253). There was no association of Ki-67-LI with hormone secretion

Histologically 98.4% show high cellular density, discrete nuclear pleomorphism, and dense nuclei, between 7 and 10 µ of diameter (Fig. 4A). Neither necrosis areas nor mitotic figures were observed. Only two cases of IV grade invasion degree, which were prolactin secretor PA, show nuclear pleomorphism, pseudoinclusions, bi- or multinucleated cells, and mitotic

There were 11 prolactinomas (15.2%) treated with bromocriptine before surgery for a period of 2 months to 3 years. The drug decreased tumor size and serum prolactin levels, the menstruation was restored, galactorrhea stopped and fertility returned. Histologically interstitial fibroses was observed in these tumors (Fig. 4D). Ultrastructuraly the cells showed

hormone immunodetection (Prl p=0.595; GH p=0.377; FSH p=0.635).

Fig. 3. Immunohistochemical detection

association with the invasion grade.

type (Prl p=0.121; GH p=0.100; FSH p=0.5).

**3.3 Histopathological analysis** 

figures (Fig. 4B and 4C).

magnification X 400).

**3.2 Statistical analysis** 

Fig. 2. Classification of non-functioning pituitary adenomas.

Immunohistochemical detection of hormonal expression in non-functioning pituitary adenomas. Prl= prolactin hormone; GH= Growth hormone; TSH= Thyroid stimulating hormone; ACTH= adrenocorticotropin hormone; LH= luteinizing hormone; FSH= follicle stimulating hormone; Neg= negative.

There were 51 (41.8%) non-functioning PA, 17 (33%) were Prl positive by immunohistochemistry, 15 (29%) were negative, and 10 (19.6%) were positive for gonadotrophic hormones (Fig. 2).

Non-functioning PA presented visual alterations and headache as clinical manifestations. There was 58.2% of clinically functioning pituitary adenomas. The most frequent clinical manifestations were: amenorrhea, galactorrhea, and libido diminished. Acromegaly was found in GH positive pituitary adenomas and one patient with gigantism was found (Table 1). Ki-67-LI was high in IV grade tumors (Table 3, Fig. 3).


Table 3. Pituitary adenomas classification according to their endocrine symptoms: Clinically functioning pituitary adenomas (F) and clinically non-functioning pituitary adenomas (NF). Prolactin hormone expression detected by immunohistochemistry (Prl). Number and percentage of positive cases, in each grade. Ki-67 Labeled Index (Ki-67-LI) in each grade. ND= No determined.

Fig. 3. Immunohistochemical detection

Photomicrograph of pituitary adenomas stained with immunohistochemical technique. Antibodies against prolactin hormone (A), and Ki-67 (B). Prolactin detection is present in the cytoplasm and Ki-67 can be seen in nucleus. Arrows show the immunodetection. (original magnification X 400).

#### **3.2 Statistical analysis**

54 Pituitary Adenomas

Fig. 2. Classification of non-functioning pituitary adenomas.

1). Ki-67-LI was high in IV grade tumors (Table 3, Fig. 3).

Grade Cases # F NF Prl

stimulating hormone; Neg= negative.

gonadotrophic hormones (Fig. 2).

ND= No determined.

Immunohistochemical detection of hormonal expression in non-functioning pituitary adenomas. Prl= prolactin hormone; GH= Growth hormone; TSH= Thyroid stimulating hormone; ACTH= adrenocorticotropin hormone; LH= luteinizing hormone; FSH= follicle

There were 51 (41.8%) non-functioning PA, 17 (33%) were Prl positive by immunohistochemistry, 15 (29%) were negative, and 10 (19.6%) were positive for

Non-functioning PA presented visual alterations and headache as clinical manifestations. There was 58.2% of clinically functioning pituitary adenomas. The most frequent clinical manifestations were: amenorrhea, galactorrhea, and libido diminished. Acromegaly was found in GH positive pituitary adenomas and one patient with gigantism was found (Table

I 2 2 - 2 (100) ND II 20 10 10 11 (55) 10.7 (10-16) III 34 21 13 22 (64.7) 6.8 (1-20) IV 66 38 28 37 (56) 25.4 (2-35) Table 3. Pituitary adenomas classification according to their endocrine symptoms: Clinically functioning pituitary adenomas (F) and clinically non-functioning pituitary adenomas (NF). Prolactin hormone expression detected by immunohistochemistry (Prl). Number and percentage of positive cases, in each grade. Ki-67 Labeled Index (Ki-67-LI) in each grade.
