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Chapter 11b. Pituitary-Hypothalamic Tumor Syndromes: Adults

Richard Clayton, MD, FRCP, Dept of Endocrinology, Nines Block, City Gen Ward 60, Stoke-on-Trent, ST4 6QG, UK <r.n.clayton@med.keele.ac.uk>

Updated: March 30, 2010
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Space Occupying Lesions in the hypothalamic/pituitary region include tumors derived from endocrine or neural tissues, metastatic tumors, chronic inflammatory processes, cystic lesions or vascular aneurysms (Table 1). These lesions may be clinically silent, i. e. do not cause any endocrine, visual or other neurological disturbances, though they often lead to pituitary enlargement and are therefore discovered accidentally when skull X-ray, cranial CT, or MRI is performed for other reasons. These tumors are called pituitary incidentalomas. Management, i. e. therapy and follow up depends on the nature and position of the lesion (1).

More frequently, a variety of endocrine, ophthalmological, or neurological symptoms lead the clinician to the diagnosis of a space occupying lesion within the sellar or supra-sellar region, i. e. a pituitary tumor with intra-, supra-, and para-sellar extension or a primary hypothalamic tumor which also may extend into the sellar cavity (Fig. 1).

Figure 1. Schematic presentation of endocrine, visual, and neurological symptoms as they may occur in patients with pituitary (left) and suprasellar, hypothalamic lesions (right).

Schematic presentation of endocrine, visual, and neurological symptoms as they may occur in patients with pituitary (left) and suprasellar, hypothalamic lesions (right).

When there are no typical endocrine features suggesting hormonally active pituitary tumors, the differential diagnosis of the various causes of space occupying lesions in the pituitary-hypothalamic area can be difficult and often impossible without biopsy, which may be hazardous(2).

SPACE OCCUPYING LESIONS OF THE PITUITARY

Autopsy studies show that about 11% of pituitaries harbour small lesions up to 6mms in diameter with no known antemortem clinical suspicion of pituitary disease. This must be born in mind as increasing use of cranial CT and MRI scanning for CNS symptoms reveals a small mass lesion which requires hormonal evaluation. What proportion of these so-called incidentalomas increase in size and how rapidly is not known, but these masses do require radiological and sometimes endocrinological follow-up. The most common cause of a tumorous expanding lesion within the sella turcica is a pituitary adenoma (3, 4). The mean annual incidence of pituitary adenomas of all sizes and secretory activities is about two cases per 100 000 population. The prevalence of these tumors is tenfold higher. Although prolactin-secreting adenomas are the most common pituitary tumors, only 20% lead to overall enlargement of the sella turcica.

Table 1. Space occupying lesions in the pituitary-hypothalamic region

1. Pituitary lesions

1.1. Endocrine active pituitary adenoma


1.1.1.Prolactinoma


1.1.2.Somatotropinoma


1.1.3.Corticotropinoma


1.1.4.Thyrotropinoma


1.1.5.Gonadotropinoma


1.1.6.Somatomammotropinoma


1.1.7. Other mixed endocrine active adenomas


1.2. Non-Functioning Pituitary Adenomas (NFPA)


1.2.1. Null cell adenoma


1.2.2. Non-secreting adenoma (silent corticotropinoma, gonadotropinoma, somatotropinoma)


1.2.3. Biologically inactive sub-unit-secreting adenoma (α-subunits, β-subunits)


1.3. Malignant pituitary tumors


1.3.1. Corticotropin secreting carcinoma


1.3.2. Prolactin-secreting carcinoma


1.3.3. GH-secreting carcinoma


1.3.4. Endocrine inactive pituitary carcinoma


1.3.5.Sarcoma


1.4. Metastases in the pituitary (breast, lung, stomach, kidney)


1.5. Pituitary cysts


1.5.1. Rathke's cleft cyst


1.5.2.Mucocoeles


1.5.3. Arachnoid cysts


1.6. Empty sella syndrome


1.6.1. Primary empty sella


1.6.2. Secondary empty sella


1.7. Hypophysitis

2. Hypothalamic lesions

2.1. Developmental abnormalities cysts


2.1.1. Craniopharyngioma (occasionally intrasellar location)


2.1.2.Germinoma


2.1.3.Hamartoma


2.1.4.Chordoma


2.1.5.Epidermoid and Dermoid


2.2. Primary Tumors of the central nervous system


2.2.1.Perisellarmeningioma


2.2.2.Optic glioma


2.2.3. Ependymoma


2.3. Vascular tumors


2.3.1. Haemangioblastoma


2.3.2. Cavernous haemangioma


2.3.3. Haemangiopericytoma


2.4. Malignant systemic diseases of the central nervous system


2.4.1. Hodgkin's disease


2.4.2. Non-Hodgkin lymphoma


2.4.3. Leukaemic infiltration


2.4.4. Histiocystosis X


2.4.5. Eosinophilic granuloma


2.4.6. Giant cell granuloma (tumor)


2.5. Granulomatous diseases


2.5.1. Neurosarcoidosis


2.5.2. Wegner's granulomatosis


2.5.3. Tuberculoma


2.5.4. Syphilis


2.6. Vascular aneurysms (also intrasellar location)


2.7. Increased intracranial pressure (brain tumors outside the sellar/suprasellar region

The separation into pituitary and hypothalamic lesions is based on the observation that these lesions occur predominantly but not exclusively in the respective region. Thus, metastases are also found in the hypothalamic area and hypophysitis can take place in the pituitary stalk. On the other hand one can have a craniopharyngioma with a purely intrasellar location.


Eighty per cent are microadenomas, which are often discovered only in patients with hyperprolactinemia by performing magnetic resonance imaging (MRI) showing the lesion with lower signal intensity or by computerized tomography (CT) with an intra hypophyseal hypodense lesion. MRI should be performed with contrast enhancement and dynamic very early (minutes after contrast) images may be required to identify some small lesions. Other causes of hyperprolactinaemia should be excluded before proceeding to expensive imaging studies.

Non-functioning pituitary adenomas

The most common macroadenomas are non functioning pituitary adenomas (NFPA) followed again by macroprolactinomas (4). GH-, and ACTH-secreting adenomas (the latter are usually microadenomas) occur more rarely and TSH- and gonadotropin-secreting adenomas are even more rare. Prolactinomas, somatotropinomas and corticotropinomas all lead to characteristic clinical features. The detailed pathophysiology, clinical picture , and therapy of patients with pituitary adenomas and hormone hypersecretion are discussed elsewhere and will not be discussed in this chapter. This pertains also for tumors secreting TSH and gonadotropins in vivo.

Subtypes of NFPAs

All tumors in patients in whom no enhanced biological activity of anterior pituitary hormones can be clinically detected, are called non-functioning pituitary adenomas (NFPA). These tumors do not represent a single biological entity (4). A minority of the NFPAs show no evidence of hormone production whatsoever using immunostaining and in situ hybridisation with pituitary hormone RNA or measuring secretory products in the medium when the tumor has been taken into culture after surgery. These adenomas are called null cell adenomas. However, 80% of the NFPAs show at least positive immunostaining for one glycoprotein hormone, mostly gonadotropins. In 10% of the tumors proopiomelanocortin derived products can be documented, and 2% stain positive for growth-hormone. Since the majority of the NFPAs contain gonadotropins it has been speculated that they originally derive from gonadotroph cells. These "silent" gonadotropinomas, corticotropinomas and somatotropinomas may secrete their stored hormones into the medium when they are taken into tissue culture.

Non functioning adenomas which are clinically endocrine inactive since they do not secrete intact, biologically active glycoprotein hormones may however secrete α or β subunits in vivo (5). It is of interest, that NFPAs show on electron microscopy secretory granules. Even the null cell adenomas have a few granules with a diameter of 100 to 250 nm.

Molecular Pathology of NFPAs

Pathogenesis of NFPAs

Pathogenesis of pituitary tumors, including NFPA, is a multi-step process with genetic and epigenetic events conferring a growth advantage to a particular cell type which then increase by clonal expansion. These tumors are generally monoclonal, that is derive from a single abnormal cell, although there is some evidence to suggest that recurrent tumors may have a different clonal origin from the original tumors (5.1). Stimulatory factors either from the hypothalamus (releasing factors) or locally produced by the tumor cells themselves (growth factors) may act as progression factors rather than initiators of tumorigenesis. Since pituitary tumors from part of the MEN1 syndrome sporadic tumors have been analysed for mutations in the MENIN gene. To date no such mutations have been found. There are a few NFPAs showing activating mutations in the GS alpha subunit gene but these are rare (<10%) compared to the relatively high frequency (up to 40%) in somatotrophinomas.

Of the classical oncogenes responsible for tumorigenesis in other tissues (eg. breast, colon, leukaemias) no mutations, deletions or gene rearrangements have been described in NFPAs. Loss of heterozygosity in the region of tumor suppressor genes is frequent, especially in invasive NFPAs but whether these are pathogenetic or merely epiphenomena is not clear (5.2). Cell cycle regulatory proteins and apotosis are critical to the process of tumor formation. Whilst mutations in the genes are rare, some of these genes, (Retinoblastoma, GADD45, p16, p27), are inactivated by the epigenetic phenomenon of methylation on CpG islands (reviewed in 5.3), and are very likely to play a rôle as tumor initiators. Two “new” genes have been isolated from pituitary tumors that may contribute to the pathogenesis. The first to be identified is pituitary tumor transforming gene (PTTG) (Melmed) which is an oncogene and functions to regulate spindle alignment at mitosis. The second, pituitary tumor apotosis gene (PTAG) (5.4), was isolated from human pituitary tumors by differential methylation display and appears to be deficient in pituitary tumors leading to abrogation of the normal apotosis pathway. Failure to eliminate cells containing potentially tumorigenic genetic abnormalities by the normal gate keeping apototic process could enable expansion of an abnormal clone into a definitive tumor. Despite much research there is no single molecular abnormality in NFPAs that can predict tumor behaviour or recurrence or serve as a target for gene therapy.

Clinical signs and symptoms

In the absence of hormone hypersecretion NFPAs lead only to clinical symptoms when they cause visual field defects or endocrine disturbances. In very large tumors, ophthalmoplegia as well as frontal headaches are common non endocrine symptoms due to lateral extension of the tumor and pressure on the 3rd, 4th and 6th nerves in the wall of the cavernous sinus. Concerning anterior pituitary failure, hypogonadism is the most frequently observed clinical endocrine dysfunction in adults (table 2). The causes of the latter are multifactorial. Thus, hypogonadism may be due to compression of the normal pituitary or the pituitary stalk, which can also cause hyperprolactinemia and contribute to the manifestation of hypogonadism by itself. Thus, galactorrhea is observed in 15% of women with large NFPAs. Though menstrual disturbances in females and decline of libido and sexual potency in men are the first obvious clinical events, it is actually the impairment of growth hormone secretion leading to subnormal age related IGF-1 levels which is the first anterior pituitary hormone deficiency (table 2). However, in contrast to children in whom GH deficiency (GHD) leads to growth failure the symptoms of GHD in adults are more subtle and not easily recognized by clinical observation alone (7). Often these symptoms become apparent only when these patients have received substitution therapy with growth hormone, which changes their body composition and makes them feel better subjectively (8).

Secondary hypothyroidism and adrenal failure occur only in the more advanced cases. However, the latter may become clinically important in acute stress situations like severe infection, hemorrhage, and surgery. In these patients acute adrenal failure may develop though they had previously adequate adrenocortical function under basal conditions.

The diagnosis of NFPAs is made using imaging techniques such as MRI or CT scan, and endocrine evaluation. The latter serves to document the degree of pituitary insufficiency, and possible hypersecretion of biologically inactive hormones such as ? - or ? -subunits (see chapter 3.3.). In addition, ophthalmological evaluation examining visual fields and function of ocular nerves must be preformed.

Table 2. Prevalence of Hypopituitarism (%) in 26 patients with large NFPAs before and 2 - 3 months after transsphenoidal surgery.

Hormone function

Preoperative

Postoperative*

GH-deficiency

100

85

Hypogonadism

96

65

Hypothyroidism

81

35

Adrenal insufficiency

62

46

* The improvement of hormone function after surgery was usually observed in those patients who had hyperprolactinemia and responded with a rise of the anterior pituitary hormone after administration of the respective releasing hormone. Both observations point to pituitary stalk compression as a cause of pituitary hormone deficiency (from Arafah, B. M.: J. clin. Endoc. Metab., 62: 1173 - 9, 1986(9)).


Therapy

Surgical resection of the tumor is the treatment of choice (10, 11). Tumor removal leads to normalization or at least improvement of visual field defect in those cases in which chiasma compression had occurred only recently and the optic papilla has not become atrophic. Whenever anterior pituitary failure was mainly caused by compression of the pituitary stalk, surgery may lead to improvement of anterior pituitary function (table 2). This is not the case when anterior pituitary failure was caused by compression of the pituitary gland. In this situation endocrine dysfunction is usually irreversible even when surgery has led to resolution of the visual field defects (10).In patients in whom the tumor has grown into the cavernous sinus or in other structures of the brain, and could therefore not be resected totally, postoperative radiotherapy should be considered.

Radiotherapy (DXT) is not without its side effects which includes a high frequency of new hypopituitarism, if not already present. In a comparative study between 2 centres the one routinely employing post-operative radiotherapy to NFPA remnants had a much lower incidence of re-operation for recurrence (10.1). There has been concern whether pituitary DXT leads to a higher incidence of new brain tumors and visual impairment but this is minimal if at all (10.1). Of perhaps more concern is whether DXT leads to neuropsychological changes but currently there is insufficient data to establish a direct causal role of DXT compared to hormone deficiency or surgery (10.1). From retrospective epidemiological studies patients with NFPAs who became hypopituitary do appear to have an increased mortality risk from cerebrovascular events. If this is substantiated in prospective studies this would be a good reason to withhold routine post-operative DXT and reserve this for the small number of cases in whom a second operation for recurrence fails to relieve recurrent symptoms or restrain tumor growth. (10.2).

In selected patients with residual tumour laterally in the cavernous sinus away from the optic chiasma highly focused radiotherapy (gamma-knife or linac) may be superior to conventional three field radiotherapy. The advantage of these techniques, apart from patient convenience of a ‘one-shot’treatment, is the ability to deliver a higher radiation dose to a smaller field increasing the likelihood of tumour control and minimizing damage to residual normal pituitary tissue.(12.1). Since control of tumor growth can not be monitoredmeasuring secretory product, this will be difficult to evaluate (13). Post-operative treatment of clinically non-functioning pituitary adenomas with dopamine agonists decreases tumor remnant growth (13.1). Medical treatment with Somatostatin analogues does not reduce the risk of regrowth/recurrence. However, dopamine agonist therapy has been reported to increase the tumor enlargement free time when initiated on detection of residual tumor post-operatively. Although this data requires confirmation the use of newer dopamine agonists is simple, free of side-effects and merits consideration in any patient with residual tumor post-operatively. SomeNFPA’sexpress somatostatin subtype 2 and 5 receptors and although current somatostatinanalogues are not generally effective at controlling tumour growth the new combined D2 receptor/somatostain receptor agonists may have potential.(13.2,13.3)


Pituitary carcinoma

Though many of the non functioning pituitary adenomas are invasive, i. e. they are not following tissue boundaries, they are by definition not considered to be malignant as there are no metastases. However, the rare true pituitary carcinomas usually present as invasive macroadenomas in the early stage and only later develop metastases distant from the pituitary site (15). Occasionally local tumor growth may be so massive leading to destruction of the skull base and other vital centers causing early death of the patient not allowing the development of distant metastases (Fig. 2).

Figure 2. MRI of a 58 years old patient with an invasive, cystic giant prolactinoma, which has destroyed the base of the scull, caused blindness, and infiltrated the lateral ventricle. He did not respond to DA-agonists and died because of the local tumor complications, though he had no distant metastases, in the CNS or elsewhere

Using strict critera for making the diagnosis of a pituitary carcinoma, i. e. presence of central- and spinal nervous system or systemic metastases, less than 100 cases have been reported. One third were non functioning whereas 25% were either prolactin or ACTH-secreting, and 10% secreted growth-hormone (table 3). Particularly likely to become aggressive are the so-called ‘silent’ corticotroph adenomas which clinically present as NFPAs but immunostain positive for ACTH. These may subsequently develop frank Cushing's syndrome. This particular sub-group requires more frequent follow-up scanning than null-cell adenomas.

Typically, pituitary cancers develop from invasively growing macroadenomas. They present with anterior pituitary failure or symptoms and signs of hormone hypersecretion, i.e. Cushing's syndrome, rarely acromegaly. In patients with prolactin secreting carcinomas the diagnosis of a macroprolactinoma had usually been made some years before. These tumors were often already partially dopamine agonist resistant. In the course of the development of the disease they lost responsiveness to dopamine agonists completely, though in some patients dopamine receptors can still be documented in vivo.

Malignancies in the pituitary fossa may also be metastases from breast, bronchial, renal, or gastric cancers leading to similar symptoms to those caused by NFPAs. However, in contrast to benign NFPAs, which rarely lead to diabetes insipidus preoperatively, pituitary cancers and metastases may cause posterior pituitary failure before surgery or radiotherapy due to extensive suprasellar invasion of the tumor. Though patients with pituitary carcinomas have been treated aggressively with surgery, conventional and highly focussed radiotherapy, interstitial application of radioisotopes, and medical treatment including cytotoxic chemotherapy, the prognosis of these patients is overall unfavourable (15), although temozolomide has been reported to be of benefit in isolated cases (15.1).

Benign Cysts

The most common non-neoplastic cystic lesions in the sellar/suprasellar region are Rathkes's pouch or cleft cysts, mucocoeles and arachnoid cysts, which all can cause headaches, visual disturbances and pituitary failure (16). Rathke's cleft cysts derive from remnants of Rathke's pouch and are pathologically indistinguishable from mucocoeles which are expansions from the paranasal sinuses. Arachnoid cysts develop from a duplication of the arachnoid and can develop anywhere in the brain, also intrasellarly and in the suprasellar area. Arachnoid cysts represent less than 1% of all space occupying lesions in the brain and occur mainly in children, whereas Rathke's cysts occur more frequently in adult females (70%) compared to adult males (30%).

Typically,Rathke's cleft cysts lead to amenorrhea/galactorrhea by causing hyperprolactinemia due to impingement on the pituitary stalk and visual disturbances and headaches. Though MRI after gadolinium adminstration may lead to rim enhancement (Fig. 3) the diagnosis of an intrasellar Rathke's cleft cyst can not be made with absolute certainty. Thus, it is not unusual that in a patient operated for a presumed NFPA the diagnosis of Rathke's cleft cyst is made histologically after surgery.

Table 3. Pituitary Carcinomas

Metastases

Secretory Function

Number of Cases

In the Cerebral Spinal Axis

Outside CNS

Both

Non functioning

29

13

12

4

PRL

27

17

9

1

ACTH

24

8

11

5

GH

12

7

4

1

TSH

1

--

--

1

Gonadotrophins

1

--

--

1

Plurihormonal

1

--

--

1

Total

95

45

35

14

Modified after Kaltsas and Grossman. The Pituitary, 1998 (15)


Figure 3. MRI of a 34 years old patient with a surgically confirmed Rathke's cleft cyst. The MRI above suggests a NFPA, the enhanced rim seen after gadolinium administration (below) however, raises the suspicion of a cystic intrasellar, suprasellar extending lesion.

Treatment of choice is surgical total removal of the cyst (17). If this is not possible, drainage of the cyst content should be attempted. Particularly, in large mucocoeles drainage into the nasal sinuses can be achieved with good therapeutic results. Rathke's cleft cysts are related to craniopharyingiomas and epidermoid cysts concerning their origin. The latter two are mainly located in the suprasellar space, though intrasellar manifestations are also observed.

Empty Sella syndrome

Aneurysms of branches of the internal carotid artery may mimic a pituitary tumor. Vascular aneurysms can be easily demonstrated by digital or MRI angiography. Nuclear magnetic imaging may also reveal cerebrospinal fluid within the sella due to herniation of the sellar diaphragm with invagination of the third ventricle into the sella, i. e. empty sella syndrome. The latter may be caused by previous surgery or radiotherapy of a pituitary adenoma leading to shrinkage of the sella content (secondary empty sella) or may be due to transmission of intracranial pressure in the presence of an incompetent diaphragm (primary empty sella). A primary empty sella syndrome is often discovered accidentally since it is usually not associated with any clinical symptoms (18). In more pronounced cases, however, visual disturbances and anterior pituitary failure may be encountered (19). Auto-apoplexy of an intrasellar pituitary macroadenoma is also a possible cause of the empty sella syndrome (Fig. 4).

Figure 4. Empty sella: MRI of a 40 years old female patient with acromegalic features but a GH-level below 1 μg/l and an IGF-1-level below the normal age matched range. She had hypogonadotropic hypogonadism and her enlarged sellar cavity is filled with CSF with a rim of pituitary tissue, suggesting that she had an apoplexy of a somatotroph tumor.

Hypophysitis

Inflammatory lesions of the pituitary gland may clinically and radiologically mimic tumors of the sellar region, causing mass effects like headaches and visual impairment and endocrine symptoms such as hyperprolactinemia, diabetes insipidus, and anterior pituitary failure. Since CT- or MRI-scans produce images which are not significantly different from those of other space occupying lesions, the diagnosis of hypophysitis is often made only after transsphenoidal surgery has been performed (20). We differentiate primary from secondary hypophysitis, the latter being composed of inflammatory lesions induced by defined pathogens or as a manifestation of distinct diseases such as sarcoidosis, Wegner's granulomatosis, etc. (see Chapter 2.5).

The aetiology of primary hypophysitis is not known, though an autoimmune pathology is most likely. The most common form of primary hypophysitis is lymphocytic hypophysitis. Since its first description 40 years ago more than one hundred cases have been reported (20). It occurs more frequently in females mainly around late pregnancy or early postpartum. It has been speculated that pituitary failure occurring postpartum, which has been attributed to Sheehan's syndrome, may in fact have been caused by lymphocytic hypophysitis (21).

Another diagnosis of an enlarging pituitary mass in the peri-partum period may be an estrogen stimulated prolactinoma. However, though hyperprolactinemia is often observed in lymphocytic hypophysitis, PRL-levels are only slightly elevated compared to the size of the pituitary tumor.

Anterior pituitary failure occuring in patients with hypophysitis differs from that observed in patients with other space occupying lesions. In the latter, loss of growth hormone followed by gonadotropin deficiency with later failure of TSH and ACTH secretion is the expected sequence of events. In patients with hypophysitis however, secondary adrenal failure due to isolated ACTH deficiency, sometimes combined with TSH deficiency is the hallmark of anterior pituitary dysfunction, while growth hormone and gonadotropin secretion are often only slightly impaired (22). Occasionally, hypophysitis occurs in the area of the pituitary stalk and presents as infundibulitis, which invariably leads to clinically apparent diabetes insipidus (23). Histologically, lymphocytic hypophysitis is characterised by diffuse infiltation of the pituitary gland by lymphocytes which have formed lymphoid follicles. Since the histopathology resembles other autoimmune endocrine disorders an autoimmune pathology seems to be very likely. Thus 20 % of patients with hypophysitis have other autoimmune disorders.

Furthermore, antibodies against pituitary cells have been detected in a few patients (20).

Granulomatous hypophysitis has to be differentiated from lymphocytic hypophysitis. In contrast to the latter there is no female predominance. The diagnosis of this rare disorder is never made clinically but most cases are diagnosed at autopsy. In addition to the endocrine symptoms, affected patients have clinical symptoms like nausea, vomiting, and meningeal irritation (20).

In 1987 a rare form of hypophysitis was described which histologically presents with lipid rich foamy histiocytes resembling xanthomatous inflammatory processes which occur elsewhere in the body. This so called xanthomatous hypophysitis leads to cystic degeneration of the pituitary gland. The aetiology is unknown. Whether the 3 forms of hypophysitis are distinct entities or only different manifestations of the same disease is not clear. The clinical and radiological presentation of the 3 forms is identical, and only histological examination allows the differential diagnosis (20).

Though conservative management may lead to resolution of clinical symptoms caused by hypophysitis, many patients have been subjected to transsphenoidal surgery because a pituitary tumor had been suspected. Transsphenoidal surgery seems to be indicated also in those patient in whom progression of visual field defects is noted or further derangement of pituitary function is observed.

In those cases in which the diagnosis has been made on account of astute clinical observation, i.e. postpartum occurrence, diabetes insipidus, evidence for secondary adrenal insufficiency and persistently elevated prolactin levels, conservative management is justified. Spontaneous resolution of the abnormal endocrine function has been observed. In some patients glucocorticoid treatment has been shown to be effective to reduce the inflammatory process (20). However, since the development of the disease is unpredictable, patients with diagnosed or only suspected hypophysitis have to be followed up carefully.

SPACE OCCUPYING LESIONS IN THE HYPOTHALAMIC REGION

An enlarged pituitary fossa may also be caused by primary hypothalamic tumors extending into the pituitary fossa.(table 1).

Hypothalamic tumors may extend into the pituitary fossa thereby leading to endocrine, visual, and neurological symptoms similar to those observed in patients with primary pituitary tumors. Furthermore, in contrast to primary pituitary tumors, hypothalamic tumors may cause posterior pituitary failure. Thus, diabetes insipidus is not seen in patients with pituitary tumors before surgery, though it is frequently observed in patients with primary suprasellar tumors in the pituitary stalk- or hypothalamic region (Fig. 1). Furthermore, hypothalamic tumors can cause disturbances of thirst control and dysregulation of osmolality, may lead to massive obesity by abnormal control of satiety, or to dysregulation of body temperature control. Extension of the hypothalamic tumor into upper parts of the brain may lead to blockage of the foramen of Monroe , internal hydrocephalus, and at the end, coma. Many hypothalamic tumors are developmental tumors, the most common is the craniopharyngioma followed by the rare germinomas, chordomas and hamartomas (Table 1). Furthermore, whereas metastases of solid cancers usually develop within the pituitary, systemic malignant diseases such as Hodgkin's disease, leukemia, histiocytosis X (Langherhan's cell histiocytosis), and Wegner's granulomatosis manifest as space occupying lesions of the basal hypothalamus. In addition, benign granulomatous or infectious diseases such as neurosarcoidosis, tuberculosis, syphilis, and cysticercosis are rare causes of a suprasellar mass.

Craniopharyngioma

Craniopharyngiomas which derive from remnants of Rathke's pouch account for about 1% of all intracranial tumors in adults. They are more frequent in children were they represent about 10% of all intracranial tumors (24). Though craniopharyngiomas are benign, and grow rather slowly, they frequently infiltrate surrounding structures.

Histology shows adamantinous epithelial pallisades frequently with cyst formation and calcification. In adults about one third of the craniopharyngiomas show a squamous papillary pattern without calcification and without local infiltration. Adult patients with craniopharyngiomas usually have a better prognosis in respect to endocrine, visual and other neurological deficits than children with these tumors (25).

Craniopharyngiomas can be differentiated from epidermoid and dermoid cysts, which are much rarer than craniopharyngiomas, and Rathke's cleft cysts, though they are related embryologically. Fifteen percent of the epidermoids are located around the pituitary fossa in adults, whereas dermoid cysts are more frequently found in children.

Table 4. Clinical and biochemical features of patients with craniopharyngioma. (From Braunstein, G. D. The hypothalamus. In: The pituitary, S. Melmed (Ed.) Blackwell, London, 1995 (24))

Feature

Number abnormal/ number studied

Percentage

Anterior pituitary dysfunction

269/296

91.0

Gonadotropin deficiency *

39/42

93.0

Clinical hypogonadism

39/191

20.4

Growth hormone deficiency*

37/44

84.1

Short stature/delayed bone age

168/609

27.6

Adrenocorticotropic hormone deficiency

34/44

77.3

Thyroid-stimulating hormone deficiency

20/46

53.5

Multiple hormone deficiency

246/296

83.0

Hyperprolactinemia*

116/296

39.2

Galactorrhea

12/296

4.0

Precocious puberty

21/363

5.8

Decreased visual acuity/visual field defect

468/639

73.2

Headache

314/449

69.9

Obesity

207/489

42.3

Vomiting

103/367

28.1

Mental deterioration

106/382

27.7

Diabetes insipidus

215/902

23.8

Papilledema

33/149

22.1

Hydrocephalus

16/102

15.7

Somnolence

6/67

8.9

Ataxia

9/149

6.0

Pyramidal tract signs

4/67

6.0

*Result from biochemical testing.


The clinical presentation of craniopharyngiomas in adults depends on the location of the tumor. Intrasellar craniopharyngiomas cause mainly endocrine symptoms similar to those seen in patients with NFPAs. Patients with suprasellar invasive craniopharyngiomas may present with endocrine abnormalities, visual problems from visual field defects up to loss of vision, and neurological defects such as cranial nerve palsy, ataxia, and convulsions. Raised intracranial pressure can lead to headache, somnolence, and a comatous state (table 4). However, such severe craniopharyngioma induced symptoms are mainly seen in children, less often in adults.

The diagnosis, which is often suspected on clinical grounds in growth retarded children, is made on account of plane radiographs of the skull showing often an enlarged pituitary fossa and suprasellar calcification. The imaging technique of choice is the MRI or CT which shows the extension of the usually cystic space occupying lesion. The fluid in these cysts have been shown to contain high concentrations of immunoreactive b -hCG. The latter can also be found in the CSF. This brings up the differential diagnosis of germinomas, in which measurable b -hCG levels are often found in the CSF and occasionally also in the general circulation Some cells in the epithelial wall of the cyst can be positively immunostained for b-hCG(26).

The treatment of craniopharyngiomas is with surgery, though particularly in children it is difficult to obtain radical removal of the tumor. Postoperative external radiation, interstitial irradiation with radioactive isotope instilled into the cyst fluid, and shunting to relieve the hydrocephalus are therapeutic options to alleviate the symptoms (25). Despite intensive treatment mortality from craniopharyngioma is much higher than for NFPA’s, with an SMR of around 9.0 versus 2.0.(ref Tomlinson J et al 2001)

Endocrine management is not different from those of other hypothalamic pituitary deficiencies. However, non-endocrine hypothalamic disturbances of fluid balance due to disturbances of thirst- and osmotic control, hyperphagia, hyperthermia and somnolence, may be life threatening and extremely difficult to control.

Germ cell tumors

Germ cell tumors are differentiated into germinomas, which represent 65% of intracranial germ cell neoplasms, and non-germinomatous germ cell tumors (NGGCT) such as terratomas, embryonal carcinomas and chorioncarcinomas. The incidence of these neoplasms is rather low in western countries but is much higher in Japan (27).

Germinomas and non-germinomatous germ cell tumors (NGGCT) differ with regard to their age of onset, location and prognosis. Germ cell tumors may secrete b -hCG and alpha -fetoprotein which can be found in the CSF and the peripheral circulation (28).

NGGCTs occur in children whereas germinomas are more frequently observed in adult males. Germ cell tumors are usually found in the region of third ventricle between the suprasellar space (mainly germinomas) and the pineal gland (mainly NGGCTs). The clinical presentation in younger patients includes precocious puberty which may occur due to pressure on the median eminence or as a consequence of the elevated hCG levels which may directly stimulate Leydig cells of the testes.

The clinical features of these tumors, which may spread by direct invasion or via the CSF into the ventricles or suparachnoid pathways down to the spinal cord, are anterior pituitary failure, diabetes insipidus, visual disturbances, and other neurological deficits.

Radiotherapy is the treatment of choice after tumor extension has been delineated carefully by appropriate imaging techniques. Germinomas have a better prognosis than NGGCTs of which chorioncarcinomas have the worst prognosis. Chemotherapy is also used, particularly in patients with wide spread disease whereas surgery is only reserved for those patients with radiotherapy resistant tumors (29). The efficacy of therapy can be monitored by measuring ? -hCG or ? -fetoprotein in the circulation when they are produced and secreted by these tumors (28).

Chordoma

Chordomas are very rare neoplasms representing less than 0,5 % of primary intracranial tumors. First described by Rudolf Virchow 1856, it was believed that they were of cartilaginous origin. At present it is thought that the chordoma derives from remnants of the embryonic notocord, the precursor of the intraspinal nucleus pulposus which extends up to the sphenooccipital suture (30). They can present any time in life with symptoms of headaches, diplopia and palsies of the 6th, the 9th, the 10th and the 11th nerves. In addition, when the tumor mass is located in sellar area near the clivus, endocrine symptoms with hypogonadism, hypothyroidism and adrenal failure, hyperprolactinemia and diabetes insipidus may occur. Chordomas do not only occur intracranially. If they occur in the spinal cord they are more likely to give rise to distant metastases, which occur rarely when they are located in the pituitary hypothalamic area.

The diagnosis is made by MRI. A chordoma is suspected whenever the clivus is involved. However, the diagnosis of an isolated intrasellar chordoma is usually made only on account of the histology after surgery has been performed (31).Surgery is the established treatment. Whereas surgery can be performed in purely intrasellar chordomas and in extra cranial sacral chordoma, larger skull base chordomas are subjected to radiotherapy which has been shown to extend survival. Without treatment intracranial chordomas have an unfavourable prognosis (30).

Hypothalamic hamartomas (HH) are hyperplastic formations consisting of foci, of neurons and glia. HH are rare tumors which have profound influence on endocrine function since they may secret gonadotropin releasing hormone (GnRH) or growth hormone releasing hormone (GHRH). Since they occur exclusively in children they can cause precocious puberty and gigantism in addition to neurological complications such as intractable seizures. Diagnosis and treatment will be discussed in the chapter Pituitary - Hypothalamic Tumor Syndromes: Children.

Malignant systemic diseases of the central nervous system

Hodgin's disease, lymphomas, leukaemic infiltration, Langerhan's cell histiocytosis (histiocystosis X), eosinophilic granuloma and giant cell tumors can occur in the suprasellar area. They lead to the classical triad of anterior pituitary failure, diabetes insipidus and visual disturbances, which can be accompanied with other neurological deficits and symptoms due to the original disease (32, 33, 34, 35). Treatment depends on the diagnosis, the extent of endocrine dysfunction, the space occupying lesion and staging of the disease. The reversibility of endocrine dysfunctions, i. e. hyperprolactinemia or diabetes insipidus can be used as an indicator for the effectiveness of the respective therapy.

Neurosarcoidosis and other granulomatous diseases

Sarcoidosis of the nervous system can lead to peripheral and central manifestations (32, 34). When granulomatous disease in the CNS leads to local infiltration of brain substance and impedes the flow of CSF giving rise to increased intracranial pressure, diabetes insipidus, hyperprolactinemia and anterior pituitary failure as well as other hypothalamic disturbances like somnolence, disturbance of water balance, food intake, and temperature regulation are observed (36). Hypothalamic involvement is the most common feature of neurosarcoidosis though other neurological symptoms like seizures and psychiatric disturbances are also encountered. The diagnosis can not be made by MRI or CT alone. Determination of angiotensin converting enzyme is usual not helpful though analysis of the CSF may reveal an elevated protein content or an increase of CSF lymphocytes. Lymph node enlargement and pulmonary sarcoid disease are seldom present. Often the diagnosis is made only after a pituitary biopsy reveals the classical granulomas. Treatment of choice is prednisone (1,5 mg/kg body weight) which usually rapidly normalizes endocrine disturbances. However, other diseases should be excluded, before steroid treatment is considered (34).

Other rare differential diagnoses include hypophysitis (see above), infectious diseases at the base of the skull like tuberculosis, syphilis, fungal infections, and cysticercosis, and Wegner's granulomatosis which may all lead to endocrine and ophthalmological symptoms. In patients with HIV, manifestations of opportunistic infections may occur in the pituitary-hypothalamic area (37). CSF-examination may be helpful in making the differential diagnosis.

EVALUATION OF PATIENTS WITH PITUITARY/ HYPOTHALAMIC SPACE OCCUPYING LESIONS

There are 3 reasons why patients need special investigation of their pituitary/hypothalamic axis (Fig. 5).

1. Disturbance of pituitary hormone secretion.

2. Visual field defects due to compression of optic chiasm.

3. Incidental finding of a sellar or suprasellar space occupying lesion by MRI or CT

Figure 5. Assessment of enlarged pituitary fossa (38).

Insufficiency of GH secretion followed by secondary hypogonadism, followed by secondary thyroid and adrenal failure is the same regardless whether patients suffer from a primary pituitary or primary hypothalamic lesion. Typical for hypothalamic involvement however, is hyperprolactinemia, diabetes insipidus and behavioural symptoms such as increased appetite with pathological weight gain, somnolence, disturbances of temperature regulation etc.Furthermore, the clinical manifestation of hypopituitarism depends not only on the type and the degree of hormone deficiency but whether it is an acute or chronic deficiency. Patients with chronic hypopituitarism are often hypogonadal and have partial secondary hypothyroidism and hypoadrenalism, whereas in acute pituitary failure, such as that caused by tumor apoplexy the clinical picture is dominated by the consequence of acute cortisol deficiency with severe headaches, hypotension, prostration and coma.

The diagnostic work-up of pituitary or hypothalamic tumor patients should therefore answer the following questions:

1. What is the nature of the pituitary or hypothalamic space-occupying lesion?

2. Is there hormone hypersecretion?

3. Is there impairment of pituitary function?

4. Is there involvement of the optic pathways with visual field defects or other cranial nerve abnormalities?

Imaging studies

Though the lateral skull x-ray will show gross changes of the sella turcica indicating a pituitary space occupying lesion or show suprasellar calcification suggesting a suprasellar craniopharyngioma, the MRI is the imaging technique of choice for demonstrating an intra- or suprasellar mass. In addition, the MRI when used with gadolinium enhancement can show the relation of the supra- and para-sellar tumor extension to neural tissue. In this respect the MRI is clearly superior to the CT, which can be useful in those patients in whom the bony structures of the skull base need to be examined. Unlike CT however, MRI will not show the calcification associated with craniopharyngioma. Digital or MRI angiography can show vascular abnormalities, i. e. intrasellar aneurysms (see chapter 4, Radiology of the Hypothalamus and Pituitary).

Ophthalmology

Since changes in vision are often early signs of tumor progression, ophthalmological investigations are useful in the primary diagnosis as well as during follow up. Goldmann perimetry is most frequently performed to document visual field defects though computerized perimetry (Octopus) is more reliable. Sometimes visual evoked potentials (VEP) can be helpful in demonstrating lesions located along the optic pathways. VEPs may be useful in discriminating simple compression from severe demyelinating lesions of the optic pathways.

Endocrine evaluation

Full evaluation of pituitary function is needed in all patients with a pituitary hypothalamic tumor (7). The latter can often not be preformed by measuring basal hormones only. Thus, stimulation tests may be required (table 5), (38)). These tests are designed to assess target gland function and pituitary hormone reserve, ie. for hypopituitarism.

Table 5. Summary of assessment of anterior pituitary function

Basal pituitary hormones

ACTH

TSH

LH, FSH

GH

PRL

Target gland hormones

Cortisol (circardian)

Thyroxine

T3

Testosterone

IGF-1

Stimulation tests (suspect anterior pituitary failure)

Stimulation of the hypothalamus

Insulin hypoglycaemia

Clomiphene

Insulin hypoglycaemiaClonidineArginine

Insulin hypoglycaemia †

Metoclopramide

Stimulation of the anterior pituitary with hypophysiotropic hormones

CRH

TRH*

GnRH

GHRH

TRH †*

Stimulation of the target gland with tropic hormones

Synacthen Test

hCG test

*not to be performed in supra- and parasellar extending tumors. † Theoretical, rarely of practical clinical significance.


Tests which asses the hypothalamic-pituitary-target gland axis, particularly adrenal axis are most important. The insulin hypoglycaemia test, which stimulates ACTH, GH, and PRL secretion, is still the gold standard for testing anterior pituitary function (39). However, this test should not be performed in patients more than 65 years of age, or those with coronary disease, uncontrolled hypertension or epilepsy, because of the high risk of complications.

Alternatives to the IST

The short synacthen test with 250 mcg ACTH 1-24 is used in many centres as an alternative to the IST. There is still debate about the accuracy of this test, its sensitivity and positive and negative predictive value. (39.1). This has again been addressed in a large retrospective survey from UK and deemed to be a safe reliable replacement test for the IST (39.2). With excellent long-term predictive accuracy for assessment of the hypothalamic – pituitary – adrenal axis this test should now replace the IST, although it cannot assess growth hormone reserve for which other tests are required.

Stimulation of the anterior pituitary with a combination of all releasing hormones is almost as effective as the hypoglycaemia test, though this global test is at present very labor intensive and is not often necessary. Patients with pituitary tumors and hypopituitarism (no rise during insulin hypoglycaemia and subnormal target gland hormone levels) who have a normal hormone rise after administration of releasing hormones usually have stalk compression. In contrast, patients with pituitary tumors unresponsive to releasing hormones, often normalize their pituitary function after removal of the pituitary mass (9). Impingement on the pituitary stalk or hypothalamic involvement is also indicated by hyperprolactinemia and diabetes insipidus. Tests for diabetes insipidus are frequently indicated in patients with suprapituitary masses and not uncommonly in NFPA patients after pituitary surgery, especially when urine volume exceeds 3 litres/day.

The classical triad pointing to a hypothalamic lesion is hyperprolactinemic anterior pituitary failure, diabetes insipidus and visual field defects (Tab. 6).

Table 6. Triad of symptoms in hypothalamic tumor patients

1. Hyperprolactinaemic anterior pituitary failure (at least hypogonadism)

2. Diabetes insipidus

3. Visual disturbances.


In aIn addition to the measurement of pituitary hormones during stimulation tests (table 5) target gland hormones (thyroid, adrenal and sex hormones) need to be measured. (Table 7)

Table 7. Simplified diagnostic procedure of pituitary insufficiency needing substitutional therapy

1. Adrenal axisCortisol before and after250 mcg

2. Thyroid axisBasal TSH and T4

3. Gonadal axisFSH, LH and sex steroids

4.Growth-HormoneGH-+IGF-1 determinationBefore Therapy:GH-stimulation test (GHRH, Arginine, hypoglycemia)

5. ProlactinBasal PRL determination is helpful for determining the cause of pituitary failure

6. Antidiuretic hormone24 hour urine collectionserum sodium and chlorideserum- and urine osmolality


For example the pituitary thyroid axis can be assessed by free T4 and TSH levels. In those institutions where TSH is the single screening test of thyroid function it is essential to request free Thyroxine level. The pituitary gonadal axis can be assessed by testosterone, oestradiol and basal gonadotrophin levels and the GnRH stimulation test is reserved for those patients in whom fertility induction with pulsatile GnRH is contemplated.

Posterior pituitary function is evaluated by measuring daily urine output and serum and urine osmolality, and is tested formally by the water deprivation/desmopressin test. Often partial diabetes insipidus becomes manifest only after appropriate hydrocortisone substitution therapy in ACTH deficient patients.

In patients with intra, supra- and para-sellar tumor, PRL must be measured. When serum PRL-concentration is over 5000 mU/l, the diagnosis is most likely a prolactinoma. Moderately elevated serum PRL in the presence of a large space occupying lesion is often due to stalk compression rather than a true prolactinoma, but this cannot be excluded. When measurement of PRL is performed by immunoradiometric assay high PRL-levels may be missed due to the "hook effect" (40). Thus, a macroprolactinoma may be diagnosed as a NFPA, which would have serious therapeutical consequences. This can be avoided when the serum samples are measured in several dilutions.

Supplementary test

TRH stimulation test with measuring of ? -subunits and gonadotropins may be of importance in classifying endocrine inactive adenomas as silent gonadotropinomas (see table 5). However, a TRH-test should not be done in a patient with a macroadenoma, because of serious side effects which have been reported, i. e. pituitary apoplexy, sudden visual loss, etc. (41). beta -hCG and alpha -fetoprotein in the peripheral circulation or the CSF may help to identify a suprasellar mass as a germ cell tumor (28).

Therapy and follow-up

Pituitary hypothalamic space occupying lesions need to be treated, either by surgery, radiotherapy or both. In special situations medical therapy may be indicated.

A more complex problem is presented by the accidentally discovered pituitary mass (incidentaloma). Clinical judgement is needed not only in determining the extent of evaluation but also in respect to therapy and follow-up. In the absence of visual field abnormalities and endocrine dysfunction, an expectant policy of no intervention andperiodic follow-up is indicated (MRI scan at 12 month intervals) in order to detect whether the tumor will develop into a larger space occupying lesion. Limited information suggest that this will occur rarely in patients with microadenomas but in up to 25% of larger tumors (1). Timing of surgical intervention depends on several factors including patient’s general medical fitness, development of headache or visual symptoms, or hypopituitarism.

Since patients with pituitary or hypothalamic tumors are rarely cured completely or at least harbor one or several hormonal deficits needing substitution therapy, lifelong follow-up of these patients is warranted, though this may be at extended intervals (2-3 yearly) if patient’s tumour is stable..