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).
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).
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 |
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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. |
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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.
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.
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.
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.
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 5th 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)). |
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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).
Whether highly focused radiotherapy (gamma-knife or linac) is superior to conventional three field radiotherapy is not yet clear. Since control of tumor growth can not be monitored measuring 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 (Greenman Y Clin Endo 2005, 63: 39-44). 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
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).
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 |
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|---|---|---|---|---|
|
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) |
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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.
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.
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.