Primary ES may be an incidental radiologic finding. It has been variably associated to different clinical conditions (headache, obesity, hypertension, menstrual disturbances, and endocrine dysfunctions), even though a selection bias cannot be ruled out and a causal relation is far from being demonstrated. Compression of the pituitary gland and stretching of the pituitary stalk may sometimes trigger mild hyperprolactinemia (10-12%) and/or various degrees of hypopituitarism (mostly GH deficiency). DI and panhypopituitarism are very rare (Del Monte et al., 2006). On the other hand ES has been reportedly associated with active Cushing's disease (16%) or acromegaly (5%). Hypopituitarism and visual abnormalities are more frequent in children (where ES is less frequent) than in adults, regardless of the size of residual pituitary gland (Yamada et al., 2005). In this setting it was reported a strong association with defects in specific genes controlling the hypothalamopituitary development during fetal life (Naing & Frohman, 2007). CSF rhinorrhea is very

On imaging (figure 17) ES can be conventionally classified as complete or partial, when less than half of the sellar cavity is occupied by CSF and pituitary thickness is still > 2 mm (De Marinis et al., 2005). Sellar size in primary ES may be normal or enlarged with symmetrical ballooning, usually without lateral displacing of the pituitary stalk, features allowing the differential diagnosis with secondary ES in which the dorsum sellae is usually posteriorly displaced. The radiological and clinical findings of primary ES generally remain constant over time (De Marinis et al., 2005). Surgical treatment is generally not necessary except

Fig. 17. Empty sella. Contrast-enhanced T1 MRI demonstrates CSF-arachnoid spaces protruding inferiorly through diaphragma sellae, compressing pituitary gland, enlarging

sella without eroding sellar floor. The stalk is thin and centrally located.

when clear-cut campimetric or visual defects are present.

intermittent) or secondary to any cause, mainly necrosis of pituitary adenoma.

uncommon.

examination or on in vivo imaging, mainly in obese females (De Marinis et al., 2005).

There is usually no indication to surgical resection. The only treatment is aimed to control precocious puberty or seizures.

Fig. 16. Hamartomas. MRI on T1 shows a well delineated, nodular, not enhancing mass, isointense to the gray matter lesions, close to the pituitary stalk (a and b) or to the tuber cinereum (c). The pituitary gland appears normal and the "bright spot" in posterior pituitary gland is present.

#### **3.6.4 Arachnoid cyst**

Arachnoid cysts, arising from herniation of an arachnoid diverticulum through an incomplete diaphragma sellae, may be suprasellar or intrasellar. While the formers usually present in children with symptoms due to local mass effect, the latters are regarded as acquired and may become symptomatic later in life (Rennert & Doerfler, 2007).

Clinical symptoms may include increased intracranial pressure up to hydrocephalus, hormone deficiency, gait disturbance and visual impairment.

On MRI, arachnoid cysts appear as smooth, contoured, well-marginated lesions that are isointense to CSF on all sequences. Calcifications are absent, and these cysts do not exhibit central or rim enhancement with contrast. Although usually indistinguishable from RCCs, they typically displace anteriorly the adeno-hypophysis and posteriorly the infundibulum (Freda & Post, 1999; Nomura et al., 1996.). If needed, surgical treatment (either fenestration or derivation of the cyst) is the only therapeutic option.

#### **3.6.5 Pars intermedia cyst**

The pars intermedia is rudimentary in humans after fetal life. One or more small cysts (usually < 3 mm), regarded as embryological remnants of the Rathke's cleft, can be seen microscopically in pituitary specimens, coated by a single layer of cuboidal or columnar epithelium and filled with proteinaceous fluid or cellular debris. Occasionally, they can enlarge and become detectable on imaging within the pituitary gland (Spampinato & Castillo, 2005). No treatment is usually necessary.

#### **3.6.6 Empty sella syndrome**

Empty sella (ES) is defined as a herniation of the subarachnoid space into the sella turcica, associated with stretching of the pituitary stalk and flattening of the pituitary gland against the sellar floor (Giustina et al., 2010).

There is usually no indication to surgical resection. The only treatment is aimed to control

Fig. 16. Hamartomas. MRI on T1 shows a well delineated, nodular, not enhancing mass, isointense to the gray matter lesions, close to the pituitary stalk (a and b) or to the tuber cinereum (c). The pituitary gland appears normal and the "bright spot" in posterior

Arachnoid cysts, arising from herniation of an arachnoid diverticulum through an incomplete diaphragma sellae, may be suprasellar or intrasellar. While the formers usually present in children with symptoms due to local mass effect, the latters are regarded as

Clinical symptoms may include increased intracranial pressure up to hydrocephalus,

On MRI, arachnoid cysts appear as smooth, contoured, well-marginated lesions that are isointense to CSF on all sequences. Calcifications are absent, and these cysts do not exhibit central or rim enhancement with contrast. Although usually indistinguishable from RCCs, they typically displace anteriorly the adeno-hypophysis and posteriorly the infundibulum (Freda & Post, 1999; Nomura et al., 1996.). If needed, surgical treatment (either fenestration

The pars intermedia is rudimentary in humans after fetal life. One or more small cysts (usually < 3 mm), regarded as embryological remnants of the Rathke's cleft, can be seen microscopically in pituitary specimens, coated by a single layer of cuboidal or columnar epithelium and filled with proteinaceous fluid or cellular debris. Occasionally, they can enlarge and become detectable on imaging within the pituitary gland (Spampinato &

Empty sella (ES) is defined as a herniation of the subarachnoid space into the sella turcica, associated with stretching of the pituitary stalk and flattening of the pituitary gland against

acquired and may become symptomatic later in life (Rennert & Doerfler, 2007).

precocious puberty or seizures.

pituitary gland is present.

**3.6.5 Pars intermedia cyst**

**3.6.6 Empty sella syndrome**

the sellar floor (Giustina et al., 2010).

**3.6.4 Arachnoid cyst**

**a b c**

hormone deficiency, gait disturbance and visual impairment.

or derivation of the cyst) is the only therapeutic option.

Castillo, 2005). No treatment is usually necessary.

ES has been classified as either primary (attributed to congenital incomplete formation of the sellar diaphragm and/or increase in intracranial pressure, either unremitting or intermittent) or secondary to any cause, mainly necrosis of pituitary adenoma.

ES is a frequent finding, observed in up one third of subjects either at post-mortem examination or on in vivo imaging, mainly in obese females (De Marinis et al., 2005).

Primary ES may be an incidental radiologic finding. It has been variably associated to different clinical conditions (headache, obesity, hypertension, menstrual disturbances, and endocrine dysfunctions), even though a selection bias cannot be ruled out and a causal relation is far from being demonstrated. Compression of the pituitary gland and stretching of the pituitary stalk may sometimes trigger mild hyperprolactinemia (10-12%) and/or various degrees of hypopituitarism (mostly GH deficiency). DI and panhypopituitarism are very rare (Del Monte et al., 2006). On the other hand ES has been reportedly associated with active Cushing's disease (16%) or acromegaly (5%). Hypopituitarism and visual abnormalities are more frequent in children (where ES is less frequent) than in adults, regardless of the size of residual pituitary gland (Yamada et al., 2005). In this setting it was reported a strong association with defects in specific genes controlling the hypothalamopituitary development during fetal life (Naing & Frohman, 2007). CSF rhinorrhea is very uncommon.

On imaging (figure 17) ES can be conventionally classified as complete or partial, when less than half of the sellar cavity is occupied by CSF and pituitary thickness is still > 2 mm (De Marinis et al., 2005). Sellar size in primary ES may be normal or enlarged with symmetrical ballooning, usually without lateral displacing of the pituitary stalk, features allowing the differential diagnosis with secondary ES in which the dorsum sellae is usually posteriorly displaced. The radiological and clinical findings of primary ES generally remain constant over time (De Marinis et al., 2005). Surgical treatment is generally not necessary except when clear-cut campimetric or visual defects are present.

Fig. 17. Empty sella. Contrast-enhanced T1 MRI demonstrates CSF-arachnoid spaces protruding inferiorly through diaphragma sellae, compressing pituitary gland, enlarging sella without eroding sellar floor. The stalk is thin and centrally located.

Diagnostic Evaluation of the Lesions of the Sellar and Parasellar Region 131

(reflecting extension of the process towards the pituitary stalk) along with enhancement of the diaphragma sellae (possibly reflecting inflammation by contiguity), although described in a few cases only, and a tongue-like extension towards the hypothalamus (Honegger et al., 1997) seem to be particularly specific of lymphocytic hypophysitis. A ring-like enhancement is consistent with central necrosis (Rivera, 2006), a feature that may account for some cases of sterile pituitary abscesses (see below) in which no species are cultured and only inflammation is seen (Perez-Nunez et al., 2005). Dynamic MRI documented a hypothalamicpituitary vasculopathy in some cases (Sato et al., 1998), showing delayed enhancement of

the whole pituitary and doubling of peak time of posterior pituitary enhancement.

**a b c**

Fig. 18. Lymphocytic hypophysitis in a young female a few weeks after delivery. MRI on coronal (a) and sagittal (c) T1 shows an enlarged, uniformly enhancing pituitary gland and infundibulum. On coronal T2 (b) the characteristic central, triangular signal hyperintensity

Although the autoimmune nature of lymphocytic hypophysitis is well established, the pathogenic autoantigens targeted in this disease remain to be identified (Caturegli et al., 2005). PRL cell autoantibodies were the first to be detected, followed by antibodies to other pituitary hormone-producing cells (often, however, with low sensitivity and specificity) (Carpinteri et al., 2009). The role of anti-pituitary antibodies in this disease has yet to be clarified (Bellastella et al., 2003). Currently, a reliable serologic test based on implicated autoantibodies is not yet available for routine diagnostic purposes (Caturegli, 2007). Consequently, a diagnosis of lymphocytic hypophysitis can only be achieved with certainty by histological examination of the pituitary gland. Anyway, at present, approximately 40% of patients undergo surgery for a presumptive diagnosis of pituitary adenoma (Gutenberg et al., 2009). A diffuse polyclonal lymphocytic infiltration with predominance of T cells, particularly CD4 cells, is characteristic. Scattered plasma cells, a few eosinophils, edema, and fibrosis replacing pituitary acini are also commonly present. Electron microscopy has shown interdigitation of inflammatory cells with pituicytes and the presence of lysosomal

The natural history of lymphocytic hypophysitis is thought to progress from inflammation (with enlargement of the gland corresponding to the period of mass-effect symptoms and often, subclinical hormone deficits) to fibrosis and subsequent tissue destruction and atrophy associated with permanent hypopituitarism, which can later present as an ES in imaging studies (Bellastella et al., 2003). In some cases the course of the disease can be rather insidious, and relapsing remitting cases have been reported (Matta et al., 2002). The

bodies and oncocytic changes in some pituitary cells (Rivera, 2006).

is shown.

## **3.7 Granulomatous, infectious and inflammatory lesions**

#### **3.7.1 Hypophysitis**

Primary hypophysitis is isolated to the gland, whereas secondary hypophysitis is usually associated with an underlying systemic disorder (Lury et al., 2005)(table 2).

Table 2. Classification of hypophysitis (modified from Lury et al., 2005)

**Lymphocytic hypophysitis** is an autoimmune disorder frequently (20-25%) associated with other autoimmune diseases, most commonly autoimmune thyroiditis (about 75%), but also adrenalitis, ovarian failure, atrophic gastritis, pernicious anemia, or systemic lupus erythematosus.

It occurs mostly in women, and in 60% to 70% of cases it presents in the last two trimesters of pregnancy or until 6 months after delivery (Caturegli et al., 2005).

Headache and visual disturbances due to compression of adjacent structures are the most common (56-70%), and usually the initial, complaints. Other common symptoms are due to partial or complete deficiency of anterior pituitary hormones (66–97%). Secretion of ACTH is the most frequently affected, reported in 60–65% of cases (Rivera, 2006). In order of frequency, secretion of TSH (47%), gonadotropins (42.2%), and GH (36.7%) are then impaired. PRL may be increased (38%) or decreased (33.7%), with inability to lactate. It is worth underlining that hypopituitarism often appears disproportionate to the extent of changes on pituitary MRI, especially when compared with what usually happens in pituitary adenomas. DI (50%) corresponds well to pituitary stalk thickening on MRI and can be attributed either to direct immune destruction or to compression of the posterior lobe and infundibular stem (PRL levels are increased in the latter case) (Gutenberg et al., 2006). Occasionally presentation can resemble apoplexy (Dan et al., 2002).

The typical (95% of cases) MRI findings of lymphocytic hypophysitis include a symmetric enlargement of a homogeneous pituitary gland, a thickened stalk (rarely displaced, with a greater diameter > 3.5 mm at the level of the median eminence, and loss of the normal smooth tapering), a non specific loss of bright spot, and an usually intact sellar floor (Gutenberg et al., 2006, Lury et al., 2005)(figure 18). The lesion is contrast enhancing (70%)(Heinze & Bercu, 1997), often with suprasellar extension (62–75%) in some cases into the hypothalamus (Freda & Post, 1999). A triangular enhancement of the anterior pituitary

Primary hypophysitis is isolated to the gland, whereas secondary hypophysitis is usually

Lymphocytic autoimmune

Infectious Tubercular

Non infectious Wegener's

**Lymphocytic hypophysitis** is an autoimmune disorder frequently (20-25%) associated with other autoimmune diseases, most commonly autoimmune thyroiditis (about 75%), but also adrenalitis, ovarian failure, atrophic gastritis, pernicious anemia, or systemic lupus

It occurs mostly in women, and in 60% to 70% of cases it presents in the last two trimesters

Headache and visual disturbances due to compression of adjacent structures are the most common (56-70%), and usually the initial, complaints. Other common symptoms are due to partial or complete deficiency of anterior pituitary hormones (66–97%). Secretion of ACTH is the most frequently affected, reported in 60–65% of cases (Rivera, 2006). In order of frequency, secretion of TSH (47%), gonadotropins (42.2%), and GH (36.7%) are then impaired. PRL may be increased (38%) or decreased (33.7%), with inability to lactate. It is worth underlining that hypopituitarism often appears disproportionate to the extent of changes on pituitary MRI, especially when compared with what usually happens in pituitary adenomas. DI (50%) corresponds well to pituitary stalk thickening on MRI and can be attributed either to direct immune destruction or to compression of the posterior lobe and infundibular stem (PRL levels are increased in the latter case) (Gutenberg et al., 2006).

The typical (95% of cases) MRI findings of lymphocytic hypophysitis include a symmetric enlargement of a homogeneous pituitary gland, a thickened stalk (rarely displaced, with a greater diameter > 3.5 mm at the level of the median eminence, and loss of the normal smooth tapering), a non specific loss of bright spot, and an usually intact sellar floor (Gutenberg et al., 2006, Lury et al., 2005)(figure 18). The lesion is contrast enhancing (70%)(Heinze & Bercu, 1997), often with suprasellar extension (62–75%) in some cases into the hypothalamus (Freda & Post, 1999). A triangular enhancement of the anterior pituitary

Bacterial Fungal Viral

Sarcoidosis Crohn's Takayasu's Ruptured cyst

Granulomatous Xanthomatous

associated with an underlying systemic disorder (Lury et al., 2005)(table 2).

Table 2. Classification of hypophysitis (modified from Lury et al., 2005)

of pregnancy or until 6 months after delivery (Caturegli et al., 2005).

Occasionally presentation can resemble apoplexy (Dan et al., 2002).

**3.7 Granulomatous, infectious and inflammatory lesions**

**Primary**

**Secondary**

**3.7.1 Hypophysitis**

erythematosus.

(reflecting extension of the process towards the pituitary stalk) along with enhancement of the diaphragma sellae (possibly reflecting inflammation by contiguity), although described in a few cases only, and a tongue-like extension towards the hypothalamus (Honegger et al., 1997) seem to be particularly specific of lymphocytic hypophysitis. A ring-like enhancement is consistent with central necrosis (Rivera, 2006), a feature that may account for some cases of sterile pituitary abscesses (see below) in which no species are cultured and only inflammation is seen (Perez-Nunez et al., 2005). Dynamic MRI documented a hypothalamicpituitary vasculopathy in some cases (Sato et al., 1998), showing delayed enhancement of the whole pituitary and doubling of peak time of posterior pituitary enhancement.

Fig. 18. Lymphocytic hypophysitis in a young female a few weeks after delivery. MRI on coronal (a) and sagittal (c) T1 shows an enlarged, uniformly enhancing pituitary gland and infundibulum. On coronal T2 (b) the characteristic central, triangular signal hyperintensity is shown.

Although the autoimmune nature of lymphocytic hypophysitis is well established, the pathogenic autoantigens targeted in this disease remain to be identified (Caturegli et al., 2005). PRL cell autoantibodies were the first to be detected, followed by antibodies to other pituitary hormone-producing cells (often, however, with low sensitivity and specificity) (Carpinteri et al., 2009). The role of anti-pituitary antibodies in this disease has yet to be clarified (Bellastella et al., 2003). Currently, a reliable serologic test based on implicated autoantibodies is not yet available for routine diagnostic purposes (Caturegli, 2007). Consequently, a diagnosis of lymphocytic hypophysitis can only be achieved with certainty by histological examination of the pituitary gland. Anyway, at present, approximately 40% of patients undergo surgery for a presumptive diagnosis of pituitary adenoma (Gutenberg et al., 2009). A diffuse polyclonal lymphocytic infiltration with predominance of T cells, particularly CD4 cells, is characteristic. Scattered plasma cells, a few eosinophils, edema, and fibrosis replacing pituitary acini are also commonly present. Electron microscopy has shown interdigitation of inflammatory cells with pituicytes and the presence of lysosomal bodies and oncocytic changes in some pituitary cells (Rivera, 2006).

The natural history of lymphocytic hypophysitis is thought to progress from inflammation (with enlargement of the gland corresponding to the period of mass-effect symptoms and often, subclinical hormone deficits) to fibrosis and subsequent tissue destruction and atrophy associated with permanent hypopituitarism, which can later present as an ES in imaging studies (Bellastella et al., 2003). In some cases the course of the disease can be rather insidious, and relapsing remitting cases have been reported (Matta et al., 2002). The

Diagnostic Evaluation of the Lesions of the Sellar and Parasellar Region 133

Although most patients with hypothalamic-pituitary tuberculosis have signs of active tuberculosis elsewhere, this is not invariably true. As a result, the diagnosis of a tuberculoma in the region may, in some cases, be made only histologically after TSS (Freda

Imaging studies show involvement of pituitary fossa, along with thickening of the pituitary stalk. Simultaneous involvement of the clivus may be an additional unspecific feature. MRI shows a hypointense pituitary mass on T2, with or without an absent posterior pituitary bright signal. Tubercular pituitary abscesses appear isointense to hypointense on T1 (occasionally hyperintense owing to high protein/lipid content) and hyperintense on T2. Tuberculomas show strong enhancement with contrast and are often accompanied by thickening and enhancement of the stalk and dura. These signal characteristics are nonspecific and overlap those of pituitary adenomas. Tubercular abscesses may show peripheral contrast enhancement and adjacent meningeal enhancement on contrast-

Fungal (Histoplasma, Coccidioides, Cryptococcus, Candida, and Aspergillus), parasitic (Cysticercus) and opportunistic (Toxoplasma, Pneumocystis Carinii, Mucor) infections may rarely develop in the sellar region, particularly in immunocompromised patients, and may

**Aspergillosis** is a mycotic disease of paranasal sinuses, frequently extending into the orbital region, or invading the skull base. The organism has a typical tropism for vascular intimamedia layer, thus enabling hematogenous spreading to basal nuclei, occasionally until hemorrhagic vasculitis. The invasive forms are usually observed in immunocompromised patients (Pinzer et al., 2006). Aspergillosis of the sphenoid sinus extending into the sellar region and simulating a pituitary tumor is extremely rare, but it was reported even in immunocompetent patients. Imaging studies show lesions moderately hyperintense on T1, hypointense on T2 and brightly enhancing. The diagnosis can be achieved only as a result of

Another rare fungal infection to be considered when evaluating patients with a pituitary mass and ophthalmoplegia is **coccidioidomycosis**, where unilateral ophthalmoplegia may acutely appear and radiological studies show a mass lesion involving the pituitary gland

Sarcoidosis involves the CNS in 5-15% of patients with this disease. Neurosarcoidosis is usually associated with systemic sarcoidosis: only 5% of cases have no disease elsewhere. In rare cases neurosarcoidosis is the initial or only sign of the disease (Freda & Post, 1999).

Neurosarcoidosis has a predilection for the hypothalamic-pituitary region and therefore DI and headache are common, hyperprolactinemia and cranial neuropathy may be present.

On MR imaging, the intraparenchymal, meningeal, or sellar lesions of sarcoidosis appear isointense on T1 and variable on T2, and are contrast-enhancing. The stalk may be thickened and also enhancing. Very rarely a cystic appearance has been reported. Leptomeningeal

& Post, 1999).

enhanced MR (Lury et al., 2005).

simulate a pituitary adenoma (Freda & Post, 1999).

and cavernous sinus (Scanarini et al., 1991).

**3.7.4 Sarcoidosis**

surgical exploration of the invaded areas (Carpinteri et al., 2009).

**3.7.3 Other infections**

inflammatory process can also be self-limited, spontaneously or with conservative corticosteroid and hormone replacement therapy, and radiological follow-up can show regression of the sellar mass in about 2 years. However, complete or partial DI may be permanent, probably because of neuronal destruction (Caturegli et al., 2005; Rivera, 2006).

Idiopathic **granulomatous hypophysitis**, a rare chronic inflammatory condition, is distinct from secondary granulomatous hypophysitis associated with systemic disorders (Caturegli et al., 2005). It is not yet definitely established whether lymphocytic and idiopathic granulomatous hypophysitis are different diseases or opposite ends of the spectrum of the same disease, with fibrosis representing the end stage of the inflammatory process (Flanagan et al., 2002). Granulomatous hypophysitis however lacks the key epidemiological features that are present in lymphocytic hypophysitis, such as the female preponderance, the occasional spontaneous resolution, the association with pregnancy and other autoimmune diseases (Caturegli et al., 2005; Cheung et al., 2001).

Granulomatous hypophysitis usually occurs in older patients and is characterized histologically by multinucleated giant cells, epithelioid histiocytes and true granulomas (Rivera, 2006).

Clinical presentation consists of headache, visual disturbances, nausea, vomiting, DI, and hyperprolactinemia, and pituitary function is severely impaired (Caturegli et al., 2005; Cheung et al., 2001).

The striking CT features are an intrasellar mass with cystic areas and ring enhancement. On MRI, the diffusely enlarged gland is usually isointense to gray matter on T1-weighted images (but also hyperintense due to hemorrhage) and heterogeneous on T2 sequences, with abnormal thickening of the infundibulum. Contrast enhancement is frequently homogeneous, occasionally extending to the optic chiasm, but cystic areas with ring enhancement may be seen. Findings suggesting inflammation, such as linear enhancement of the dura, sphenoid mucosal thickening, and adjacent bone marrow abnormality, may be also observed. These findings are nonspecific and indistinguishable from those caused by other neoplastic or inflammatory pituitary processes (Lury et al., 2005).

**Xanthomatous hypophysitis** is rare and can be considered an inflammatory response to ruptured cysts components (Glezer et al., 2008; Roncaroli et al., 2004). Cystic-like areas of liquefaction, infiltrated by lipid-rich foamy histiocytes and lymphocytes, are present in the pituitary gland (Caturegli et al., 2005).

Immunosuppression with high-dose glucocorticoids or other drugs, such as azathioprine, methotrexate and cyclosporin, have been reported effective in reducing pituitary mass, and improving pituitary function and DI (Rivera, 2006).

#### **3.7.2 Tuberculosis**

Pituitary tuberculosis is rare. It may present with meningitis, a dense plaque-like exudate mostly at the base of the brain, involving the sellar and parasellar region, or as a tuberculoma (suprasellar or intrasellar). Signs of mass lesion, and possible impairment of hypothalamic or pituitary function and involvement of the optic chiasm may be present (Domingues et al., 2002; Freda & Post, 1999).

Although most patients with hypothalamic-pituitary tuberculosis have signs of active tuberculosis elsewhere, this is not invariably true. As a result, the diagnosis of a tuberculoma in the region may, in some cases, be made only histologically after TSS (Freda & Post, 1999).

Imaging studies show involvement of pituitary fossa, along with thickening of the pituitary stalk. Simultaneous involvement of the clivus may be an additional unspecific feature. MRI shows a hypointense pituitary mass on T2, with or without an absent posterior pituitary bright signal. Tubercular pituitary abscesses appear isointense to hypointense on T1 (occasionally hyperintense owing to high protein/lipid content) and hyperintense on T2. Tuberculomas show strong enhancement with contrast and are often accompanied by thickening and enhancement of the stalk and dura. These signal characteristics are nonspecific and overlap those of pituitary adenomas. Tubercular abscesses may show peripheral contrast enhancement and adjacent meningeal enhancement on contrastenhanced MR (Lury et al., 2005).

## **3.7.3 Other infections**

132 Explicative Cases of Controversial Issues in Neurosurgery

inflammatory process can also be self-limited, spontaneously or with conservative corticosteroid and hormone replacement therapy, and radiological follow-up can show regression of the sellar mass in about 2 years. However, complete or partial DI may be permanent, probably because of neuronal destruction (Caturegli et al., 2005; Rivera, 2006). Idiopathic **granulomatous hypophysitis**, a rare chronic inflammatory condition, is distinct from secondary granulomatous hypophysitis associated with systemic disorders (Caturegli et al., 2005). It is not yet definitely established whether lymphocytic and idiopathic granulomatous hypophysitis are different diseases or opposite ends of the spectrum of the same disease, with fibrosis representing the end stage of the inflammatory process (Flanagan et al., 2002). Granulomatous hypophysitis however lacks the key epidemiological features that are present in lymphocytic hypophysitis, such as the female preponderance, the occasional spontaneous resolution, the association with pregnancy and other

Granulomatous hypophysitis usually occurs in older patients and is characterized histologically by multinucleated giant cells, epithelioid histiocytes and true granulomas

Clinical presentation consists of headache, visual disturbances, nausea, vomiting, DI, and hyperprolactinemia, and pituitary function is severely impaired (Caturegli et al., 2005;

The striking CT features are an intrasellar mass with cystic areas and ring enhancement. On MRI, the diffusely enlarged gland is usually isointense to gray matter on T1-weighted images (but also hyperintense due to hemorrhage) and heterogeneous on T2 sequences, with abnormal thickening of the infundibulum. Contrast enhancement is frequently homogeneous, occasionally extending to the optic chiasm, but cystic areas with ring enhancement may be seen. Findings suggesting inflammation, such as linear enhancement of the dura, sphenoid mucosal thickening, and adjacent bone marrow abnormality, may be also observed. These findings are nonspecific and indistinguishable from those caused by

**Xanthomatous hypophysitis** is rare and can be considered an inflammatory response to ruptured cysts components (Glezer et al., 2008; Roncaroli et al., 2004). Cystic-like areas of liquefaction, infiltrated by lipid-rich foamy histiocytes and lymphocytes, are present in the

Immunosuppression with high-dose glucocorticoids or other drugs, such as azathioprine, methotrexate and cyclosporin, have been reported effective in reducing pituitary mass, and

Pituitary tuberculosis is rare. It may present with meningitis, a dense plaque-like exudate mostly at the base of the brain, involving the sellar and parasellar region, or as a tuberculoma (suprasellar or intrasellar). Signs of mass lesion, and possible impairment of hypothalamic or pituitary function and involvement of the optic chiasm may be present

autoimmune diseases (Caturegli et al., 2005; Cheung et al., 2001).

other neoplastic or inflammatory pituitary processes (Lury et al., 2005).

(Rivera, 2006).

Cheung et al., 2001).

**3.7.2 Tuberculosis**

pituitary gland (Caturegli et al., 2005).

improving pituitary function and DI (Rivera, 2006).

(Domingues et al., 2002; Freda & Post, 1999).

Fungal (Histoplasma, Coccidioides, Cryptococcus, Candida, and Aspergillus), parasitic (Cysticercus) and opportunistic (Toxoplasma, Pneumocystis Carinii, Mucor) infections may rarely develop in the sellar region, particularly in immunocompromised patients, and may simulate a pituitary adenoma (Freda & Post, 1999).

**Aspergillosis** is a mycotic disease of paranasal sinuses, frequently extending into the orbital region, or invading the skull base. The organism has a typical tropism for vascular intimamedia layer, thus enabling hematogenous spreading to basal nuclei, occasionally until hemorrhagic vasculitis. The invasive forms are usually observed in immunocompromised patients (Pinzer et al., 2006). Aspergillosis of the sphenoid sinus extending into the sellar region and simulating a pituitary tumor is extremely rare, but it was reported even in immunocompetent patients. Imaging studies show lesions moderately hyperintense on T1, hypointense on T2 and brightly enhancing. The diagnosis can be achieved only as a result of surgical exploration of the invaded areas (Carpinteri et al., 2009).

Another rare fungal infection to be considered when evaluating patients with a pituitary mass and ophthalmoplegia is **coccidioidomycosis**, where unilateral ophthalmoplegia may acutely appear and radiological studies show a mass lesion involving the pituitary gland and cavernous sinus (Scanarini et al., 1991).

#### **3.7.4 Sarcoidosis**

Sarcoidosis involves the CNS in 5-15% of patients with this disease. Neurosarcoidosis is usually associated with systemic sarcoidosis: only 5% of cases have no disease elsewhere. In rare cases neurosarcoidosis is the initial or only sign of the disease (Freda & Post, 1999).

Neurosarcoidosis has a predilection for the hypothalamic-pituitary region and therefore DI and headache are common, hyperprolactinemia and cranial neuropathy may be present.

On MR imaging, the intraparenchymal, meningeal, or sellar lesions of sarcoidosis appear isointense on T1 and variable on T2, and are contrast-enhancing. The stalk may be thickened and also enhancing. Very rarely a cystic appearance has been reported. Leptomeningeal

Diagnostic Evaluation of the Lesions of the Sellar and Parasellar Region 135

patients present with a chronic and indolent course with few infective manifestations, thus mimicking a pituitary tumor (Glezer et al., 2008). DI and headache are the most common presenting complaint (70%) (Fuyi et al., 2010), and over half of the patients complain of visual disturbances. Most patients (85%) have partial or total hypopituitarism (including PRL deficiency). In a recently reported series (Fuyi et al., 2010) the median time between the onset of symptoms and diagnosis was 6 months. Mortality can reach 30% to 50% of cases

Fig. 19. Pituitary abscess in a patient with staphylococcal sepsis. Coronal T1 (a) and sagittal T1 enhanced (b) MRI shows an intra/suprasellar cystic lesion, isointense to the brain, with thin regular rim enhancement. Coronal CT after contrast (c) depicts a homogeneously hypodense lesion, with rim enhancement, sparing cavernous sinus. Note non pneumatized

The typical MR features of an abscess are the presence of a round cystic or partially cystic sellar mass that appears as hypo- or isointense on T1 and hyper- or isointense on T2, with an enhanced rim after Gd injection and a central cavity that is isointense to the brain (Freda & Post, 1999; Glezer et al., 2008; Rennert & Doerfler, 2007)(figure 19). The sella may be

Surgical resection and appropriate long-term antibiotic coverage is the choice treatment.

Primary mucocele is a congenital mucous retention cyst expansion, whereas the commoner secondary mucocele results from a chronic obstruction of the sinus that leads to accumulation and dehydration of secretions. Predisposing factors are inflammatory

Mucocele can rarely extend to the pituitary fossa, parasellar and suprasellar regions, nasopharynx, orbits, clivus, or ethmoid air cells. A cystic accumulation of secretions expands and erodes the sinus walls, eventually compressing surrounding structures such as the cavernous sinus, the pituitary gland, the cranial nerves I through VI, and the carotid arteries. Sphenoid mucoceles usually evolve over a long period, often years, with nonspecific, usually severe, headaches and atypical facial pain with paresthesias secondary to trigeminal nerve irritation. Visual loss owing to direct nerve compression by the mass or

conditions, tumors, trauma, and previous surgery in the sphenoid sinus.

when it is complicated by meningitis (Glezer et al., 2008).

**a b c**

enlarged and, occasionally, extensively eroded.

Abscesses may recur requiring further surgery.

**3.7.7 Sphenoid sinus mucocele**

There is no specific age preponderance.

sphenoidal sinus.

involvement in the region of the hypothalamus and pituitary infundibulum may be seen as an isolated finding or associated with involvement of the basilar leptomeninges (Lury et al., 2004).

When neurosarcoidosis is suspected, CSF examination is indicated, evaluating angiotensinconverting enzyme, and cytology. In some patients, the diagnosis is made only by biopsy of the granulomatous lesion (Glezer et al., 2008).

Corticosteroids are the therapy of choice, but various adjuvant immunosuppressant drugs have been reportedly employed (Glezer et al., 2008).

## **3.7.5 Other systemic diseases**

Pituitary granulomatous involvement has been described in isolated case reports with other systemic diseases (Carpinteri et al., 2009):

## **3.7.6 Pituitary abscess**

Pituitary abscess is a rare potentially life-threatening disease, occurring in all age groups, estimated to account for less than 1% of clinically apparent pituitary disease and 0.27% of pituitary surgeries (Famini et al., 2011; Vates et al., 2001).

In most cases, it develops from direct extension of an adjacent infection (sphenoid sinus meningitis, contaminated CSF fistula or very rarely cavernous sinus thrombophlebitis) or is caused by hematogenous seeding. The infection source cannot occasionally be identified (Glezer et al., 2008).

Abscess can be primary (in two thirds of the cases), occurring in a previously normal pituitary, or secondary, arising in glands that harbor a pre-existing lesion (adenoma, craniopharyngioma or RCC). Other risk factors include an underlying immunocompromised condition, previous pituitary surgery, CSF rhinorrhea with recurrent meningitis and irradiation of the pituitary gland (Freda & Post, 1999; Liu et al., 2011).

Isolated organisms are typically gram-positive cocci; fungi, such as Aspergillus, Cryptococcus or Candida Albicans, and other organisms (Mycobacterium Tuberculosis, Toxoplasma, Clostridium Difficile, Staphylococcus or Pseudomonas) have been reported as well (Famini et al., 2011; Freda & Post, 1999; Glezer et al., 2008; Liu et al., 2011). In at least half of cases pituitary abscesses are reported to be sterile.

Fever, meningism and leukocytosis have been reported in one third of cases only, in spite of the presence of meningitis along with the abscess in approximately 60% of patients. Most

involvement in the region of the hypothalamus and pituitary infundibulum may be seen as an isolated finding or associated with involvement of the basilar leptomeninges (Lury et al., 2004). When neurosarcoidosis is suspected, CSF examination is indicated, evaluating angiotensinconverting enzyme, and cytology. In some patients, the diagnosis is made only by biopsy of

Corticosteroids are the therapy of choice, but various adjuvant immunosuppressant drugs

Pituitary granulomatous involvement has been described in isolated case reports with other

Wegener's granulomatosis, with central DI usually occurring after pulmonary or

 Erdheim–Chester disease, with DI, hypopituitarism and hyperprolactinemia, cerebellar syndromes, orbital lesions, and extra-axial masses involving the dura (Kovacs et al., 2004); Crohn's disease, with hypopituitarism, progressive bitemporal haemianopsia and

Pituitary abscess is a rare potentially life-threatening disease, occurring in all age groups, estimated to account for less than 1% of clinically apparent pituitary disease and 0.27% of

In most cases, it develops from direct extension of an adjacent infection (sphenoid sinus meningitis, contaminated CSF fistula or very rarely cavernous sinus thrombophlebitis) or is caused by hematogenous seeding. The infection source cannot occasionally be identified

Abscess can be primary (in two thirds of the cases), occurring in a previously normal pituitary, or secondary, arising in glands that harbor a pre-existing lesion (adenoma, craniopharyngioma or RCC). Other risk factors include an underlying immunocompromised condition, previous pituitary surgery, CSF rhinorrhea with recurrent

Isolated organisms are typically gram-positive cocci; fungi, such as Aspergillus, Cryptococcus or Candida Albicans, and other organisms (Mycobacterium Tuberculosis, Toxoplasma, Clostridium Difficile, Staphylococcus or Pseudomonas) have been reported as well (Famini et al., 2011; Freda & Post, 1999; Glezer et al., 2008; Liu et al., 2011). In at least half of cases

Fever, meningism and leukocytosis have been reported in one third of cases only, in spite of the presence of meningitis along with the abscess in approximately 60% of patients. Most

meningitis and irradiation of the pituitary gland (Freda & Post, 1999; Liu et al., 2011).

 Takayasu's disease, with pituitary mass, hypopituitarism and DI (Toth et al., 1996); Cogan's syndrome, with pituitary enlargement, DI and secondary hypothyroidism

kidney lesions in less than 1% of affected subjects (Goyal et al., 2000);

the granulomatous lesion (Glezer et al., 2008).

**3.7.5 Other systemic diseases**

(Kanatani et al., 1991).

**3.7.6 Pituitary abscess**

(Glezer et al., 2008).

systemic diseases (Carpinteri et al., 2009):

intrasellar mass (de Bruin et al., 1991);

pituitary surgeries (Famini et al., 2011; Vates et al., 2001).

pituitary abscesses are reported to be sterile.

have been reportedly employed (Glezer et al., 2008).

patients present with a chronic and indolent course with few infective manifestations, thus mimicking a pituitary tumor (Glezer et al., 2008). DI and headache are the most common presenting complaint (70%) (Fuyi et al., 2010), and over half of the patients complain of visual disturbances. Most patients (85%) have partial or total hypopituitarism (including PRL deficiency). In a recently reported series (Fuyi et al., 2010) the median time between the onset of symptoms and diagnosis was 6 months. Mortality can reach 30% to 50% of cases when it is complicated by meningitis (Glezer et al., 2008).

Fig. 19. Pituitary abscess in a patient with staphylococcal sepsis. Coronal T1 (a) and sagittal T1 enhanced (b) MRI shows an intra/suprasellar cystic lesion, isointense to the brain, with thin regular rim enhancement. Coronal CT after contrast (c) depicts a homogeneously hypodense lesion, with rim enhancement, sparing cavernous sinus. Note non pneumatized sphenoidal sinus.

The typical MR features of an abscess are the presence of a round cystic or partially cystic sellar mass that appears as hypo- or isointense on T1 and hyper- or isointense on T2, with an enhanced rim after Gd injection and a central cavity that is isointense to the brain (Freda & Post, 1999; Glezer et al., 2008; Rennert & Doerfler, 2007)(figure 19). The sella may be enlarged and, occasionally, extensively eroded.

Surgical resection and appropriate long-term antibiotic coverage is the choice treatment. Abscesses may recur requiring further surgery.

## **3.7.7 Sphenoid sinus mucocele**

Primary mucocele is a congenital mucous retention cyst expansion, whereas the commoner secondary mucocele results from a chronic obstruction of the sinus that leads to accumulation and dehydration of secretions. Predisposing factors are inflammatory conditions, tumors, trauma, and previous surgery in the sphenoid sinus.

There is no specific age preponderance.

Mucocele can rarely extend to the pituitary fossa, parasellar and suprasellar regions, nasopharynx, orbits, clivus, or ethmoid air cells. A cystic accumulation of secretions expands and erodes the sinus walls, eventually compressing surrounding structures such as the cavernous sinus, the pituitary gland, the cranial nerves I through VI, and the carotid arteries. Sphenoid mucoceles usually evolve over a long period, often years, with nonspecific, usually severe, headaches and atypical facial pain with paresthesias secondary to trigeminal nerve irritation. Visual loss owing to direct nerve compression by the mass or

Diagnostic Evaluation of the Lesions of the Sellar and Parasellar Region 137

calcification and thrombosis present within the aneurysm. Asymmetric enlargement and destruction of the sella turcica may occur in association with a giant aneurysm. CT cannot reliably distinguish an aneurysm from other pituitary lesion, but very intense, homogeneous blush with contrast may suggest an aneurysm (Rennert & Doerfler, 2007). On conventional spin-echo MRI, the aneurysm is contiguous to vessels, has well-defined margins, and appears heterogeneous (Glezer et al., 2008). Aneurysmatic sack may appear as a flow void or alternatively as a brightly enhancing spot corresponding to residual true lumen, according to vascular flow velocity. There may be variable amount of thrombosed lumen, which may contain crescent or ring shaped layers of different aged blood products or fibrosis, appearing heterogeneous on T1 and mostly hypointense on T2. There may be rings or arcs of calcification, especially at the periphery. A rim of calcification in the wall is

There have been many case reports of aneurysms associated with pituitary adenomas (Smith, 2005). In any case, if an aneurism is suspected, angiography should be immediately performed. Angio-CT, angio-MRI or digital subtraction angiography are all suitable. The last is the gold standard because it allows concomitant treatment by embolization if needed.

Thrombosis of the cavernous sinus is a very rare condition, often secondary to iatrogenic or septic etiologies. On MRI and CT, enlargement of the cavernous sinus with internal filling defects and incomplete enhancement of the sinus may be noted. MRI shows high signal thrombus within the cavernous sinus. Additionally, periorbital edema, exophthalmos or

Collision tumors represent two morphologically different tumors attached to each other. Extending this definition, collision lesions refer to histologically different pathological conditions found in combination and may include neoplastic, vascular, congenital, or infectious/inflammatory lesions. The presence of a collision sellar lesion represents a very uncommon event. Most include a pituitary adenoma coexisting with a second lesion like a craniopharyngioma, arachnoid cyst, epidermoid cyst, lymphocytic or granulomatous hypophysitis, as well as sarcoidosis within a pituitary adenoma and metastatic carcinoma to

Multiple pituitary adenomas are rarely encountered in patients undergoing pituitary surgery. In a large surgical cohort of more than 3,000 resected pituitary adenomas the percentage of double adenomas was 0.37% (Kontogeorgos et al., 1992). The same authors in the largest ever-reported autopsy study of more than 9,300 pituitary glands, identified 20

Double pituitary adenomas can be divided into contiguous and clearly separated double tumors. Most contiguous tumors are surgically removed as one tumor and the co-existence of different adenoma types is established by immunohistochemical and electron microscopic examination of the surgical specimen (Kim et al., 2004). The most common hormone-active adenoma identified in surgical series of double adenomas is GH-secreting, but also

dilatation of the superior ophthalmic vein can occur (Rennert & Doerfler, 2007).

characteristic but may resemble a craniopharyngioma.

a pituitary adenoma (Koutoroisiu et al., 2010)(figure 21).

cases of multiple adenomas (Kontogeorgos et al., 1991).

**3.8.2 Cavernous sinus thrombosis**

**3.9 Collision lesions**

ACTHomas are reported.

from scarring caused by an inflammatory reaction is usually slowly progressive but may be suddenly worsened by vascular compromise of the optic nerve. Optic neuropathy is most often unilateral, and visual field deficits are typically absent. Exophthalmos is present in about half of patients. Diplopia due to dysfunction of the third and, less often, the fourth cranial nerves is common (Freda & Post, 1999). Hypopituitarism is less common.

On CT, a non-destructive mass causing a thinning and bulging of the bone sinus walls may be seen, and the sellar contents can mimic a para- or suprasellar mass.

MRI appearance is variable. Expansion of the sphenoid sinus, usually with intact but occasionally eroded walls, and prominent opacification of its content is present in most patients, most often with a high signal on T2 images and, because of its high protein content, a homogeneously hyperintense T1 signal. After contrast administration it appears a thin regular rim of enhancement (Akan et al., 2004; Glezer et al., 2008; Rennert & Doerfler, 2007) (figure 20).

Surgical drainage is indicated only when the lesion is highly symptomatic or erosive of bone.

Fig. 20. Mucocele. Sagittal T1 (a) and axial T2 (c) MR show a cystic mass, filling and enlarging the left sphenoid sinus recess. The lesion appears homogeneously hyperintense on T1 (a) with rim enhancement (b). Chronic sinusitis is evident in the right sphenoidal recess.

#### **3.8 Vascular lesions**

#### **3.8.1 Aneurysm**

Aneurysms of the sellar region account for approximately 10% of all cerebral aneurysms. They usually originate from the cavernous, infraclinoid, or supraclinoid internal carotid arteries, but also from the anterior or posterior communicating arteries, or the ophthalmic arteries. Aneurysms in the parasellar and suprasellar region may sometimes reach great dimensions and compress the optic nerve, chiasm, or both and produce signs of visual loss. They may also extend into the sella, causing direct pituitary compression and thus modest hyperprolactinemia and hypopituitarism (Freda & Post, 1999).

Intrasellar aneurysm can mimic other parenchymal masses and imaging is essential to distinguish among the different disorders before surgery. If within the sella, aneurysms are usually eccentrically located. Their appearance is mostly affected by the amount of calcification and thrombosis present within the aneurysm. Asymmetric enlargement and destruction of the sella turcica may occur in association with a giant aneurysm. CT cannot reliably distinguish an aneurysm from other pituitary lesion, but very intense, homogeneous blush with contrast may suggest an aneurysm (Rennert & Doerfler, 2007). On conventional spin-echo MRI, the aneurysm is contiguous to vessels, has well-defined margins, and appears heterogeneous (Glezer et al., 2008). Aneurysmatic sack may appear as a flow void or alternatively as a brightly enhancing spot corresponding to residual true lumen, according to vascular flow velocity. There may be variable amount of thrombosed lumen, which may contain crescent or ring shaped layers of different aged blood products or fibrosis, appearing heterogeneous on T1 and mostly hypointense on T2. There may be rings or arcs of calcification, especially at the periphery. A rim of calcification in the wall is characteristic but may resemble a craniopharyngioma.

There have been many case reports of aneurysms associated with pituitary adenomas (Smith, 2005). In any case, if an aneurism is suspected, angiography should be immediately performed. Angio-CT, angio-MRI or digital subtraction angiography are all suitable. The last is the gold standard because it allows concomitant treatment by embolization if needed.

### **3.8.2 Cavernous sinus thrombosis**

Thrombosis of the cavernous sinus is a very rare condition, often secondary to iatrogenic or septic etiologies. On MRI and CT, enlargement of the cavernous sinus with internal filling defects and incomplete enhancement of the sinus may be noted. MRI shows high signal thrombus within the cavernous sinus. Additionally, periorbital edema, exophthalmos or dilatation of the superior ophthalmic vein can occur (Rennert & Doerfler, 2007).

#### **3.9 Collision lesions**

136 Explicative Cases of Controversial Issues in Neurosurgery

from scarring caused by an inflammatory reaction is usually slowly progressive but may be suddenly worsened by vascular compromise of the optic nerve. Optic neuropathy is most often unilateral, and visual field deficits are typically absent. Exophthalmos is present in about half of patients. Diplopia due to dysfunction of the third and, less often, the fourth

On CT, a non-destructive mass causing a thinning and bulging of the bone sinus walls may

MRI appearance is variable. Expansion of the sphenoid sinus, usually with intact but occasionally eroded walls, and prominent opacification of its content is present in most patients, most often with a high signal on T2 images and, because of its high protein content, a homogeneously hyperintense T1 signal. After contrast administration it appears a thin regular rim of enhancement (Akan et al., 2004; Glezer et al., 2008; Rennert & Doerfler, 2007)

Surgical drainage is indicated only when the lesion is highly symptomatic or erosive of

Fig. 20. Mucocele. Sagittal T1 (a) and axial T2 (c) MR show a cystic mass, filling and

hyperprolactinemia and hypopituitarism (Freda & Post, 1999).

enlarging the left sphenoid sinus recess. The lesion appears homogeneously hyperintense on T1 (a) with rim enhancement (b). Chronic sinusitis is evident in the right sphenoidal recess.

Aneurysms of the sellar region account for approximately 10% of all cerebral aneurysms. They usually originate from the cavernous, infraclinoid, or supraclinoid internal carotid arteries, but also from the anterior or posterior communicating arteries, or the ophthalmic arteries. Aneurysms in the parasellar and suprasellar region may sometimes reach great dimensions and compress the optic nerve, chiasm, or both and produce signs of visual loss. They may also extend into the sella, causing direct pituitary compression and thus modest

Intrasellar aneurysm can mimic other parenchymal masses and imaging is essential to distinguish among the different disorders before surgery. If within the sella, aneurysms are usually eccentrically located. Their appearance is mostly affected by the amount of

cranial nerves is common (Freda & Post, 1999). Hypopituitarism is less common.

be seen, and the sellar contents can mimic a para- or suprasellar mass.

**a b c**

(figure 20).

**3.8 Vascular lesions**

**3.8.1 Aneurysm**

bone.

Collision tumors represent two morphologically different tumors attached to each other. Extending this definition, collision lesions refer to histologically different pathological conditions found in combination and may include neoplastic, vascular, congenital, or infectious/inflammatory lesions. The presence of a collision sellar lesion represents a very uncommon event. Most include a pituitary adenoma coexisting with a second lesion like a craniopharyngioma, arachnoid cyst, epidermoid cyst, lymphocytic or granulomatous hypophysitis, as well as sarcoidosis within a pituitary adenoma and metastatic carcinoma to a pituitary adenoma (Koutoroisiu et al., 2010)(figure 21).

Multiple pituitary adenomas are rarely encountered in patients undergoing pituitary surgery. In a large surgical cohort of more than 3,000 resected pituitary adenomas the percentage of double adenomas was 0.37% (Kontogeorgos et al., 1992). The same authors in the largest ever-reported autopsy study of more than 9,300 pituitary glands, identified 20 cases of multiple adenomas (Kontogeorgos et al., 1991).

Double pituitary adenomas can be divided into contiguous and clearly separated double tumors. Most contiguous tumors are surgically removed as one tumor and the co-existence of different adenoma types is established by immunohistochemical and electron microscopic examination of the surgical specimen (Kim et al., 2004). The most common hormone-active adenoma identified in surgical series of double adenomas is GH-secreting, but also ACTHomas are reported.

Diagnostic Evaluation of the Lesions of the Sellar and Parasellar Region 139

personal experience DI is associated to pituitary adenomas mainly when apoplexy occurs. DI should always lead to consider alternative diagnoses. Craniopharyngioma, metastases, and sarcoidosis are the most frequent. Vasopressin deficiency may be partial or transient because of spontaneous regeneration (Freda & Post, 1999). DI may apparently improve in

The acute onset of cranial neuropathy often accompanies pituitary apoplexy, but the presence of ophtalmoplegia at presentation of a sellar/parasellar mass is suggestive of

Hypothalamic dysfunctions may be observed in large tumors (exceptionally rare in adenomas) leading to poor development and sexual immaturity in children and disruption

Intratumoral calcifications are observed mainly in craniopharyngiomas, but also in meningiomas, teratomas, gliomas, cartilagineous tumors, and even in aneurysms and

An enlarged pituitary stalk can be found in different diseases (hypophysitis, germinoma,

Neoplasms in the clival region include chordoma, chondrosarcoma, hemangiopericytoma, meningioma, lymphoma, plasmocytoma, paraganglioma, and metastasis (Rennert &

Location (midline vs. not midline) and consistence (mostly solid vs. cystic) of the lesion are

Tables 4 and 5 show synoptically key features of the different parasellar lesions (data are derived from the following references: Carpinteri et al., 2009; Famini et al., 2011; Freda & Post, 1999; Glezer et al., 2008; Huang & Castillo, 2005; Kaltsas et al., 2008; Karavitaki et al., 2006; Lury, 2005; Rennert & Doerfler, 2007; Ruscalleda, 2005; Smith, 2005; Spampinato &

**Midline Away from midline**

Meningioma Chondroma Schwannoma Glioma LCH (Metastases)

> (Abscess) Mycoses

Cartilagineous tumors and metastases typically destroy the bone of the skull base.

Adenoma Hypophysitis Germinoma Lymphoma Chordoma Metastases

Craniopharyngioma RCC Arachnoid cyst Abscess

Table 3. Classification of lesions according to consistence and location

lymphoma, tuberculosis, sarcoidosis, or LCH) (Gutenberg et al., 2009).

some patients when hypoadrenalism develops.

of the control of appetite in adults (Freda & Post, 1999).

alternative etiologies (Freda & Post, 1999).

pituitary adenomas (Freda & Post, 1999).

among the key imaging data to consider (table 3).

**Solid**

**Cystic**

**4.2 Imaging data**

Doerfler, 2007).

Castillo 2005).

Fig. 21. T1 enhanced MR shows an intrasellar nodular, relatively hypointense, right lesion, characteristic for a pituitary microadenoma, close to a suprasellar mass, with features of diaphragma sellae meningioma.

## **4. Differential diagnosis**

The differential diagnosis among the various neoplastic and non-neoplastic processes potentially involving the parasellar region is critical in the work-up of patients. It should always be performed jointly by the neurosurgeon, the endocrinologist and the neuroradiologist. The neuroradiological finding of a sellar mass may not always mean the presence of a pituitary adenoma, even though these are the great majority, and the correct screening among alternative diagnoses is crucial for an appropriate therapeutic planning. Some neoplasms should indeed not undergo surgery, unless requiring urgent decompression. A correct preoperative diagnosis allows to select the necessary treatment and eventually the correct surgical approach (trans-cranial vs. trans-sphenoidal) and strategy. Combining epidemiological, clinical and imaging data will allow progressively focusing of diagnosis.

## **4.1 Clinical data**

Headache and hormone dysfunction are not always helpful in the differential diagnosis of a sellar suprasellar lesion (Valassi et al., 2010), unless hypersecretory syndrome occurs. The neuro-ophthalmological examination is the basic investigation that allows to raise suspicion of a lesion, but it is of no practical value to establish a diagnosis of nature of a parasuprasellar lesion.

Some classical campimetric defects are related to the location of a given lesion and its relationships with the visual apparatus (Freda & Post, 1999):

DI at presentation is highly atypical for pituitary adenomas, occurring in 0.01-3% vs. 11% of non-adenomatous lesions according to a recent overview (Famini et al., 2011). In our personal experience DI is associated to pituitary adenomas mainly when apoplexy occurs. DI should always lead to consider alternative diagnoses. Craniopharyngioma, metastases, and sarcoidosis are the most frequent. Vasopressin deficiency may be partial or transient because of spontaneous regeneration (Freda & Post, 1999). DI may apparently improve in some patients when hypoadrenalism develops.

The acute onset of cranial neuropathy often accompanies pituitary apoplexy, but the presence of ophtalmoplegia at presentation of a sellar/parasellar mass is suggestive of alternative etiologies (Freda & Post, 1999).

Hypothalamic dysfunctions may be observed in large tumors (exceptionally rare in adenomas) leading to poor development and sexual immaturity in children and disruption of the control of appetite in adults (Freda & Post, 1999).

## **4.2 Imaging data**

138 Explicative Cases of Controversial Issues in Neurosurgery

**a b**

Fig. 21. T1 enhanced MR shows an intrasellar nodular, relatively hypointense, right lesion, characteristic for a pituitary microadenoma, close to a suprasellar mass, with features of

The differential diagnosis among the various neoplastic and non-neoplastic processes potentially involving the parasellar region is critical in the work-up of patients. It should always be performed jointly by the neurosurgeon, the endocrinologist and the neuroradiologist. The neuroradiological finding of a sellar mass may not always mean the presence of a pituitary adenoma, even though these are the great majority, and the correct screening among alternative diagnoses is crucial for an appropriate therapeutic planning. Some neoplasms should indeed not undergo surgery, unless requiring urgent decompression. A correct preoperative diagnosis allows to select the necessary treatment and eventually the correct surgical approach (trans-cranial vs. trans-sphenoidal) and strategy. Combining epidemiological, clinical and imaging data will allow progressively focusing of diagnosis.

Headache and hormone dysfunction are not always helpful in the differential diagnosis of a sellar suprasellar lesion (Valassi et al., 2010), unless hypersecretory syndrome occurs. The neuro-ophthalmological examination is the basic investigation that allows to raise suspicion of a lesion, but it is of no practical value to establish a diagnosis of nature of a para-

Some classical campimetric defects are related to the location of a given lesion and its

Lesions extending over the sella, such as adenomas and RCCs, produce the typical

Lesions arising in the suprasellar area, such as meningiomas, can present with

Lesions anterior to the chiasm, such as meningiomas of the optic nerve sheath, can

Lesions compressing the visual system more posteriorly along the optic tract, such as

DI at presentation is highly atypical for pituitary adenomas, occurring in 0.01-3% vs. 11% of non-adenomatous lesions according to a recent overview (Famini et al., 2011). In our

bitemporal hemianopsia due to chiasmal compression from below;

meningiomas or aneurysms, provoke homonymous hemianopsia.

bitemporal field cuts of the classic superior chiasmal compression variety;

relationships with the visual apparatus (Freda & Post, 1999):

produce unilateral visual loss;

diaphragma sellae meningioma.

**4. Differential diagnosis**

**4.1 Clinical data**

suprasellar lesion.

Intratumoral calcifications are observed mainly in craniopharyngiomas, but also in meningiomas, teratomas, gliomas, cartilagineous tumors, and even in aneurysms and pituitary adenomas (Freda & Post, 1999).

Cartilagineous tumors and metastases typically destroy the bone of the skull base.

An enlarged pituitary stalk can be found in different diseases (hypophysitis, germinoma, lymphoma, tuberculosis, sarcoidosis, or LCH) (Gutenberg et al., 2009).

Neoplasms in the clival region include chordoma, chondrosarcoma, hemangiopericytoma, meningioma, lymphoma, plasmocytoma, paraganglioma, and metastasis (Rennert & Doerfler, 2007).

Location (midline vs. not midline) and consistence (mostly solid vs. cystic) of the lesion are among the key imaging data to consider (table 3).

Table 3. Classification of lesions according to consistence and location

Tables 4 and 5 show synoptically key features of the different parasellar lesions (data are derived from the following references: Carpinteri et al., 2009; Famini et al., 2011; Freda & Post, 1999; Glezer et al., 2008; Huang & Castillo, 2005; Kaltsas et al., 2008; Karavitaki et al., 2006; Lury, 2005; Rennert & Doerfler, 2007; Ruscalleda, 2005; Smith, 2005; Spampinato & Castillo 2005).

\* Diabetes insipidus; ° Hypopituitarism; § PRL deficiency; # Cranial nerve palsies; + Hypersecretions Table 4. Clinical aspects of the different parasellar lesions

#### 140 Explicative Cases of Controversial Issues in Neurosurgery

Diagnostic Evaluation of the Lesions of the Sellar and Parasellar Region 141

\* Diabetes insipidus; ° Hypopituitarism; § PRL deficiency; # Cranial nerve palsies; + Hypersecretions

Table 4. Clinical aspects of the different parasellar lesions

SAH = subarachnoid hemorrhage; DWI: diffusion weighed images; NF = neurofibromatosis

Table 5. Imaging of the different parasellar lesions: for each lesion the most common picture is reported

Diagnostic Evaluation of the Lesions of the Sellar and Parasellar Region 143

Sellar enlargement is typical but not exclusive of macroadenomas because it can occur in half of non-adenomatous masses of the region, such as meningiomas, craniopharyngiomas, empty sella, and RCCs. Therefore, only the lack of sellar enlargement is helpful in diagnosis,

Bone erosion or invasion is not particularly helpful in the differential diagnosis because it can be seen with adenomas, chordomas, intracavernous aneurysms, meningiomas of the middle fossa, RCCs, arachnoid diverticula, and elevated intracranial pressure from any

The sudden onset of severe headache and ophthalmoplegia should always raise the suspicion of pituitary apoplexy. Since the presence of a pre-existing pituitary tumor is mostly unknown, diagnostic difficulties and delays can result in significant morbidity and rarely mortality. The diagnosis can often be difficult because patients may present in different clinical facilities, without immediate access to a skilled neuroradiologist. Clinical characteristics are not of help most of the times. On imaging CT and MRI will demonstrate an intrasellar mass and signs of bleeding or ischemia. Attention must be paid to the reported concomitant occurrence of pituitary adenomas and cerebral aneurysms (in 7%), requiring angiography. It must be pointed out that neuroradiology (CT scan and then MRI) is nowadays mandatory in every emergency case. Clinical data are of very little relevance in

On MRI lymphocytic hypophysitis appears as a symmetric enlargement of a homogeneous pituitary gland, with thickened but rarely displaced stalk and an intact sellar floor (Gutenberg et al., 2006; Lury, 2005), whereas macroadenomas are heterogeneous, frequently asymmetric lesions growing toward the suprasellar cistern and cavernous sinus, often displacing an intact stalk, depressing or eroding the sellar floor (Gutenberg et al., 2009; Lury, 2005). Intense and homogenous enhancement of the anterior pituitary, similar to that of the

It was suggested that hypophysitis should be suspected in a patient with pituitary dysfunction whenever there is the coexistence of 3 or more of the 9 following items (Rivera,

 acute onset of headache with ophthalmoplegia, visual field defects, nausea or vomiting (present also in pituitary apoplexy where presentation is more catastrophic and

acute onset of DI with headache and mass-effect symptoms (present also in sarcoidosis

 isolated, early or disproportionate impairment of ACTH secretion (usually the last hormone to be affected in patients with pituitary adenomas) and in general, disproportionate involvement of pituitary function for the magnitude of the changes on

**4.2.1 Solid lesions**

source (Freda & Post, 1999).

this setting.

2006):

young age;

MRI;

**NFPA vs. hypophysitis**

cavernous sinuses, is suggestive of hypophysitis.

women presenting during the peripartum period;

and LCH, with a more insidious presentation);

imaging shows bleeding or ischemia);

characteristic MRI findings;

pointing to a non-pituitary lesion (Freda & Post, 1999).

## **4.2.1 Solid lesions**

142 Explicative Cases of Controversial Issues in Neurosurgery

SAH = subarachnoid hemorrhage; DWI: diffusion weighed images; NF = neurofibromatosis

is reported

Table 5. Imaging of the different parasellar lesions: for each lesion the most common picture

Sellar enlargement is typical but not exclusive of macroadenomas because it can occur in half of non-adenomatous masses of the region, such as meningiomas, craniopharyngiomas, empty sella, and RCCs. Therefore, only the lack of sellar enlargement is helpful in diagnosis, pointing to a non-pituitary lesion (Freda & Post, 1999).

Bone erosion or invasion is not particularly helpful in the differential diagnosis because it can be seen with adenomas, chordomas, intracavernous aneurysms, meningiomas of the middle fossa, RCCs, arachnoid diverticula, and elevated intracranial pressure from any source (Freda & Post, 1999).

The sudden onset of severe headache and ophthalmoplegia should always raise the suspicion of pituitary apoplexy. Since the presence of a pre-existing pituitary tumor is mostly unknown, diagnostic difficulties and delays can result in significant morbidity and rarely mortality. The diagnosis can often be difficult because patients may present in different clinical facilities, without immediate access to a skilled neuroradiologist. Clinical characteristics are not of help most of the times. On imaging CT and MRI will demonstrate an intrasellar mass and signs of bleeding or ischemia. Attention must be paid to the reported concomitant occurrence of pituitary adenomas and cerebral aneurysms (in 7%), requiring angiography. It must be pointed out that neuroradiology (CT scan and then MRI) is nowadays mandatory in every emergency case. Clinical data are of very little relevance in this setting.

#### **NFPA vs. hypophysitis**

On MRI lymphocytic hypophysitis appears as a symmetric enlargement of a homogeneous pituitary gland, with thickened but rarely displaced stalk and an intact sellar floor (Gutenberg et al., 2006; Lury, 2005), whereas macroadenomas are heterogeneous, frequently asymmetric lesions growing toward the suprasellar cistern and cavernous sinus, often displacing an intact stalk, depressing or eroding the sellar floor (Gutenberg et al., 2009; Lury, 2005). Intense and homogenous enhancement of the anterior pituitary, similar to that of the cavernous sinuses, is suggestive of hypophysitis.

It was suggested that hypophysitis should be suspected in a patient with pituitary dysfunction whenever there is the coexistence of 3 or more of the 9 following items (Rivera, 2006):

Diagnostic Evaluation of the Lesions of the Sellar and Parasellar Region 145

Purely intrasellar meningiomas are extremely rare. They can be extremely difficult to distinguish from adenomas (Cappabianca et al., 1999). MRI is not different either on basal T1 or T2. However, post-contrast enhancement is marked, rapid and homogeneous in more than 90% of meningiomas, whereas adenomas generally enhance less intensely and more heterogeneously, with a longer time-to-peak enhancement on dynamic imaging (Huang & Castillo, 2005). Other features pointing to a meningioma (when present) are liquor cleft between the tumor and the gland, hyperostosis of the floor of the sella or adjacent bone structures, flow voids and prominent vessels, and calcifications (Huang & Castillo, 2005).

No radiological sign can accurately discriminate between the two conditions, even though

Posterior location, bone destruction with honeycomb aspect, and calcification as well as MR

Calcifications at CT are usually present in craniopharyngiomas. The apparent diffusion coefficient of craniopharyngiomas is higher than that of adenomas on average (Yamasaki et

On T2-weighed images meningiomas typically appear isointense, whereas

Patients with neurinoma usually complain of 5th nerve pain or numbness and deficit is usually present at the neurological examination. Schwannomas follow the expected course of a cranial nerve or its branches, occasionally enlarging the cranial nerve outlet foramen in the skull base, such as the foramen ovale or rotundum (Smith, 2005). Furthermore, on dynamic contrast enhancing MRI sequences meningiomas usually show early enhancement,

Lipomas can be distinguished from other lesions, similarly bright on precontrast T1 weighted images (such as hemorrhagic or proteinaceous lesions), by using suppressing fat

Tuber cinereum hamartoma can be differentiated from other pathologies in this region (gliomas, LCH, and germ cell tumors) by clinical presentation, absence of contrast enhancement, and unchanging appearance on follow-up without growth or invasion

craniopharyngiomas (and RCCs) typically look hyperintense (Freda & Post, 1999).

while neurinomas present gradual but brighter enhancement (Rennert et al., 2007).

**NFPA vs. metastasis**

**NFPA vs. chordoma**

**NFPA vs. solid craniopharyngioma**

**Meningioma vs. solid craniopharyngioma**

al., 2005; Zada et al., 2010).

**Meningioma vs. neurinoma**

**Lipoma vs. other tumors**

**Hamartoma vs. other tumors**

(Spampinato & Castillo, 2005).

Recently a case-control study was performed on 402 lesions (histological diagnosis was NFPA and autoimmune hypophysitis in 304 and 98, respectively) evaluating the predictive value of different features before surgery (Gutenberg et al., 2009). Authors concluded that no single radiologic sign had sufficient accuracy to distinguish with certainty hypophysitis from pituitary adenomas. In a multiple logistic regression model, however, some features contributed significantly to the correct classification of lesions: relation to pregnancy, pituitary symmetry, stalk size, signal intensity and homogeneity after contrast supported the diagnosis of hypophysitis, whereas greater pituitary mass volume and mucosal swelling in the sphenoid sinus supported the diagnosis of adenoma.

#### **NFPA vs. meningioma**

Meningiomas grow typically in the suprasellar space, with obtuse margins at the edge. In the vast majority of cases pituitary function is normal, the sella is not invaded and a normal pituitary is easily recognizable even in the rare instance of sellar invasion.

If cavernous sinus is invaded, meningiomas tend to narrow the carotid artery lumen more than any other tumors (Young et al., 1988).

The so-called dural tail, previously regarded as pathognomonic of a meningioma, is now considered nonspecific, because it can be seen in association with adenoma, metastases, lymphoma, and lymphocytic hypophysitis (even though DI is frequent in these last 3 cases and not in meningiomas). This asymmetric tentorial enhancement is thought to be caused by venous congestion due to compression or invasion of the ipsilateral cavernous sinus rather than to meningeal inflammation or tumor invasion (Guermazi et al., 2005; Nakasu et al., 2001; Rumboldt, 2005)(figure 22).

Fig. 22. Macroadenoma vs. meningioma (a vs. b): the former causes sellar enlargement and erodes sellar floor, the latter arising from planum sphenoidale, invades the sella that appears normal in size, and enhances strongly and homogeneously. In both cases dural tail is apparent.

Purely intrasellar meningiomas are extremely rare. They can be extremely difficult to distinguish from adenomas (Cappabianca et al., 1999). MRI is not different either on basal T1 or T2. However, post-contrast enhancement is marked, rapid and homogeneous in more than 90% of meningiomas, whereas adenomas generally enhance less intensely and more heterogeneously, with a longer time-to-peak enhancement on dynamic imaging (Huang & Castillo, 2005). Other features pointing to a meningioma (when present) are liquor cleft between the tumor and the gland, hyperostosis of the floor of the sella or adjacent bone structures, flow voids and prominent vessels, and calcifications (Huang & Castillo, 2005).

#### **NFPA vs. metastasis**

144 Explicative Cases of Controversial Issues in Neurosurgery

lymphomonocytic pleocytosis in the CSF, without clinical meningitis and antiviral

Recently a case-control study was performed on 402 lesions (histological diagnosis was NFPA and autoimmune hypophysitis in 304 and 98, respectively) evaluating the predictive value of different features before surgery (Gutenberg et al., 2009). Authors concluded that no single radiologic sign had sufficient accuracy to distinguish with certainty hypophysitis from pituitary adenomas. In a multiple logistic regression model, however, some features contributed significantly to the correct classification of lesions: relation to pregnancy, pituitary symmetry, stalk size, signal intensity and homogeneity after contrast supported the diagnosis of hypophysitis, whereas greater pituitary mass volume and mucosal swelling

Meningiomas grow typically in the suprasellar space, with obtuse margins at the edge. In the vast majority of cases pituitary function is normal, the sella is not invaded and a normal

If cavernous sinus is invaded, meningiomas tend to narrow the carotid artery lumen more

The so-called dural tail, previously regarded as pathognomonic of a meningioma, is now considered nonspecific, because it can be seen in association with adenoma, metastases, lymphoma, and lymphocytic hypophysitis (even though DI is frequent in these last 3 cases and not in meningiomas). This asymmetric tentorial enhancement is thought to be caused by venous congestion due to compression or invasion of the ipsilateral cavernous sinus rather than to meningeal inflammation or tumor invasion (Guermazi et al., 2005; Nakasu et al.,

Fig. 22. Macroadenoma vs. meningioma (a vs. b): the former causes sellar enlargement and erodes sellar floor, the latter arising from planum sphenoidale, invades the sella that appears normal in size, and enhances strongly and homogeneously. In both cases dural tail

presence of other autoimmune conditions and/or autoantibodies;

presence of circulating antipituitary antibodies, where available.

in the sphenoid sinus supported the diagnosis of adenoma.

**a b**

than any other tumors (Young et al., 1988).

2001; Rumboldt, 2005)(figure 22).

is apparent.

pituitary is easily recognizable even in the rare instance of sellar invasion.

antibodies;

**NFPA vs. meningioma**

No radiological sign can accurately discriminate between the two conditions, even though bone lytic reactions usually accompany the latter (Komninos et al., 2004).

#### **NFPA vs. chordoma**

Posterior location, bone destruction with honeycomb aspect, and calcification as well as MR signal characteristics usually point to chordoma (Glezer et al., 2008).

## **NFPA vs. solid craniopharyngioma**

Calcifications at CT are usually present in craniopharyngiomas. The apparent diffusion coefficient of craniopharyngiomas is higher than that of adenomas on average (Yamasaki et al., 2005; Zada et al., 2010).

#### **Meningioma vs. solid craniopharyngioma**

On T2-weighed images meningiomas typically appear isointense, whereas craniopharyngiomas (and RCCs) typically look hyperintense (Freda & Post, 1999).

#### **Meningioma vs. neurinoma**

Patients with neurinoma usually complain of 5th nerve pain or numbness and deficit is usually present at the neurological examination. Schwannomas follow the expected course of a cranial nerve or its branches, occasionally enlarging the cranial nerve outlet foramen in the skull base, such as the foramen ovale or rotundum (Smith, 2005). Furthermore, on dynamic contrast enhancing MRI sequences meningiomas usually show early enhancement, while neurinomas present gradual but brighter enhancement (Rennert et al., 2007).

#### **Lipoma vs. other tumors**

Lipomas can be distinguished from other lesions, similarly bright on precontrast T1 weighted images (such as hemorrhagic or proteinaceous lesions), by using suppressing fat sequences, which obtain their disappearance (Smith, 2005).

#### **Hamartoma vs. other tumors**

Tuber cinereum hamartoma can be differentiated from other pathologies in this region (gliomas, LCH, and germ cell tumors) by clinical presentation, absence of contrast enhancement, and unchanging appearance on follow-up without growth or invasion (Spampinato & Castillo, 2005).

Diagnostic Evaluation of the Lesions of the Sellar and Parasellar Region 147

depending on the nature of the cyst contents, making the differential diagnosis challenging

Imaging parameters that can be used to support a diagnosis of craniopharyngioma over RCC include: presence of calcification, greater tumor diameter (> 2 cm), suprasellar location with superior tumor lobulation, and compression of the third ventricle (Choi et al., 2007). Radiological parameters supporting a diagnosis of RCC are an ovoid shape, small cyst

Suprasellar calcification in a child is highly suggestive of the diagnosis of craniopharyngioma. Although the presence of calcifications may be helpful in the differential diagnosis, it is not specific. On CT scanning 42–87% of craniopharyngiomas exhibited calcification, compared with only 0–13% of RCCs. It is important to note, however, that several cases of RCCs have been reported to occur with ossification and no evidence of neoplastic features, and that the presence of calcium is not necessarily pathognomonic for

Arachnoid cyst typically contains CSF, while the content of RCC (and its imaging characteristics) is variable. RCC exhibits some degree of rim enhancement, as opposed to

Neither epidermoids nor arachnoid cysts enhance but epidermoids are usually bright on FLAIR and DW images, while the arachnoid cyst is dark on both sequences. Furthermore, epidermoids tend to insinuate between vessels and other adjacent structures, while

The 55 yo woman with headache and visual troubles needs a careful ophthalmologic, neuroradiological and endocrine evaluation. Initially, visual troubles must be better defined by performing a complete examination, including formal visual field testing. Bitemporal hemianopsia is shown together with previously unknown decreased left visual acuity. MRI shows a solid mass isointense on T1, hyperintense on T2, heterogeneously enhancing after Gd administration. The lesion enlarges the sella, extends in the suprasellar region impinging on the optic chiasm, while apparently sparing the cavernous sinuses. The patient denies polydipsia and polyuria. No clinical sign of hypersecretion is present. Screening of hypersecretions is negative: PRL is 88 ng/mL (no change after serum dilution 1:10 to rule out hook effect), IGF-I is 120 ng/mL (that is normal for her age range), and morning cortisol is normally suppressed after overnight dexamethasone suppression test (0.5 µg/dL). Screening of hypopituitarism is negative as well: morning cortisol, FT4, and FSH are 10 µg/dL, 1 ng/dl, and 45 U/L, respectively. All data (epidemiologic, clinical, endocrine and imaging) thus point to a diagnosis of NFPA. The patient is operated on by a transsphenoidal endoscopic approach, without perioperative steroid coverage (Cozzi et al., 2009b). Headache disappears and visual field normalizes. Histological evaluation confirms

minimal or no enhancement in arachnoid cyst (Valassi et al., 2010).

arachnoid cysts displace them (Spampinato & Castillo, 2005).

in some cases.

volume, and thin or no cyst wall enhancement.

craniopharyngiomas (Zada et al., 2010).

**Epidermoid cyst vs. arachnoid cyst**

**RCC vs. arachnoid cyst**

**5. Back to clinics**

**5.1 Patient 1**

## **4.2.2 Cystic lesions**

The spectrum of cystic pathologies occurring in the sellar region includes craniopharyngiomas, RCCs, arachnoid cysts, cystic pituitary adenomas, epidermoid cysts, dermoid cysts, and several others (Laws, 2008). A firm diagnosis is easily reached in most cases, while in others a diagnosis can be established only at surgery, when it is clinically indicated (Harrison et al., 1994; Zada et al., 2010).

## **Cysts vs. ES**

Arachnoid cysts or RCCs may simulate ES, but in the latter the pituitary stalk remains usually in the median position and can be visualized down to the sellar floor (Giustina et al., 2010).

#### **Cystic NFPA vs. RCC**

Both intrasellar and suprasellar cysts can produce signs and symptoms similar to those of adenomas, such as visual impairment or hypopituitarism (Freda & Post, 1999).

Presence of a fluid-fluid level on sagittal or axial images is highly indicative of adenomas, representing intratumoral degeneration and hemorrhage, which almost never occur in cysts (Rumboldt, 2005).

RCCs are located in the center of the gland, have complete absence of contrast enhancement, and may contain characteristic nodules of low T2 signal or be completely hypointense on T2-weighted images (Byun et al., 2000).

#### **Cystic NFPA vs. craniopharyngioma**

Cystic pituitary adenomas are located within the anterior pituitary lobe, are surrounded by normal pituitary tissue, and the cyst wall consists of enhancing tumor tissue. Cystic craniopharyngiomas are more commonly suprasellar and located superior to the pituitary gland and show enhancing solid components and calcifications (Spampinato & Castillo, 2005).

## **Cystic NFPA vs. abscess**

In contrast to adenomas, abscesses typically show ring enhancement and high signal intensities on diffusion weighted (DW) images together with a reduction in the apparent diffusion coefficient (ADC), whereas necrotic tumors display a hypointensity on DW images and higher ADC values (Takao et al., 2006). Furthermore, meningeal enhancement due to concurrent meningitis may be observed in pituitary abscess (Vates et al., 2001).

#### **RCC vs. cystic craniopharyngioma**

Presenting clinical features are not reliable in this differentiation.

The two lesions can be classically distinguished on MRI: craniopharyngiomas typically show prominent cystic components and calcifications, may be multilobulated or with an irregular shape or rim enhancement, with heterogeneous T1 signal demonstrating heterogeneous or strong homogeneous enhancement as well as solid enhancing nodules in the cyst; RCCs are typically small, round, purely cystic lesions lacking calcification with homogenous hypointense T1 signal intensity and midline anterior infundibular displacement (Famini et al., 2011). RCC may however have a variable imaging appearance depending on the nature of the cyst contents, making the differential diagnosis challenging in some cases.

Imaging parameters that can be used to support a diagnosis of craniopharyngioma over RCC include: presence of calcification, greater tumor diameter (> 2 cm), suprasellar location with superior tumor lobulation, and compression of the third ventricle (Choi et al., 2007). Radiological parameters supporting a diagnosis of RCC are an ovoid shape, small cyst volume, and thin or no cyst wall enhancement.

Suprasellar calcification in a child is highly suggestive of the diagnosis of craniopharyngioma. Although the presence of calcifications may be helpful in the differential diagnosis, it is not specific. On CT scanning 42–87% of craniopharyngiomas exhibited calcification, compared with only 0–13% of RCCs. It is important to note, however, that several cases of RCCs have been reported to occur with ossification and no evidence of neoplastic features, and that the presence of calcium is not necessarily pathognomonic for craniopharyngiomas (Zada et al., 2010).

#### **RCC vs. arachnoid cyst**

146 Explicative Cases of Controversial Issues in Neurosurgery

The spectrum of cystic pathologies occurring in the sellar region includes craniopharyngiomas, RCCs, arachnoid cysts, cystic pituitary adenomas, epidermoid cysts, dermoid cysts, and several others (Laws, 2008). A firm diagnosis is easily reached in most cases, while in others a diagnosis can be established only at surgery, when it is clinically

Arachnoid cysts or RCCs may simulate ES, but in the latter the pituitary stalk remains usually in the median position and can be visualized down to the sellar floor (Giustina et al.,

Both intrasellar and suprasellar cysts can produce signs and symptoms similar to those of

Presence of a fluid-fluid level on sagittal or axial images is highly indicative of adenomas, representing intratumoral degeneration and hemorrhage, which almost never occur in cysts

RCCs are located in the center of the gland, have complete absence of contrast enhancement, and may contain characteristic nodules of low T2 signal or be completely hypointense on

Cystic pituitary adenomas are located within the anterior pituitary lobe, are surrounded by normal pituitary tissue, and the cyst wall consists of enhancing tumor tissue. Cystic craniopharyngiomas are more commonly suprasellar and located superior to the pituitary gland and show enhancing solid components and calcifications (Spampinato & Castillo,

In contrast to adenomas, abscesses typically show ring enhancement and high signal intensities on diffusion weighted (DW) images together with a reduction in the apparent diffusion coefficient (ADC), whereas necrotic tumors display a hypointensity on DW images and higher ADC values (Takao et al., 2006). Furthermore, meningeal enhancement due to

The two lesions can be classically distinguished on MRI: craniopharyngiomas typically show prominent cystic components and calcifications, may be multilobulated or with an irregular shape or rim enhancement, with heterogeneous T1 signal demonstrating heterogeneous or strong homogeneous enhancement as well as solid enhancing nodules in the cyst; RCCs are typically small, round, purely cystic lesions lacking calcification with homogenous hypointense T1 signal intensity and midline anterior infundibular displacement (Famini et al., 2011). RCC may however have a variable imaging appearance

concurrent meningitis may be observed in pituitary abscess (Vates et al., 2001).

Presenting clinical features are not reliable in this differentiation.

adenomas, such as visual impairment or hypopituitarism (Freda & Post, 1999).

**4.2.2 Cystic lesions**

**Cystic NFPA vs. RCC**

(Rumboldt, 2005).

**Cystic NFPA vs. abscess**

**RCC vs. cystic craniopharyngioma**

T2-weighted images (Byun et al., 2000). **Cystic NFPA vs. craniopharyngioma**

**Cysts vs. ES**

2010).

2005).

indicated (Harrison et al., 1994; Zada et al., 2010).

Arachnoid cyst typically contains CSF, while the content of RCC (and its imaging characteristics) is variable. RCC exhibits some degree of rim enhancement, as opposed to minimal or no enhancement in arachnoid cyst (Valassi et al., 2010).

#### **Epidermoid cyst vs. arachnoid cyst**

Neither epidermoids nor arachnoid cysts enhance but epidermoids are usually bright on FLAIR and DW images, while the arachnoid cyst is dark on both sequences. Furthermore, epidermoids tend to insinuate between vessels and other adjacent structures, while arachnoid cysts displace them (Spampinato & Castillo, 2005).

## **5. Back to clinics**

## **5.1 Patient 1**

The 55 yo woman with headache and visual troubles needs a careful ophthalmologic, neuroradiological and endocrine evaluation. Initially, visual troubles must be better defined by performing a complete examination, including formal visual field testing. Bitemporal hemianopsia is shown together with previously unknown decreased left visual acuity. MRI shows a solid mass isointense on T1, hyperintense on T2, heterogeneously enhancing after Gd administration. The lesion enlarges the sella, extends in the suprasellar region impinging on the optic chiasm, while apparently sparing the cavernous sinuses. The patient denies polydipsia and polyuria. No clinical sign of hypersecretion is present. Screening of hypersecretions is negative: PRL is 88 ng/mL (no change after serum dilution 1:10 to rule out hook effect), IGF-I is 120 ng/mL (that is normal for her age range), and morning cortisol is normally suppressed after overnight dexamethasone suppression test (0.5 µg/dL). Screening of hypopituitarism is negative as well: morning cortisol, FT4, and FSH are 10 µg/dL, 1 ng/dl, and 45 U/L, respectively. All data (epidemiologic, clinical, endocrine and imaging) thus point to a diagnosis of NFPA. The patient is operated on by a transsphenoidal endoscopic approach, without perioperative steroid coverage (Cozzi et al., 2009b). Headache disappears and visual field normalizes. Histological evaluation confirms

Diagnostic Evaluation of the Lesions of the Sellar and Parasellar Region 149

treatment with desmopressin, hydrocortisone and thyroxine. Follow-up is scheduled with MRI, to evaluate the radicality of resection. Metabolic and weight control is of particular concern. GH treatment is started. Puberty induction will be postponed until attainment of

In the 45 yo male with the incidental finding of microlesion in the pituitary, the first task is screening of hypersecretory syndromes. PRL is 13 ng/mL, IGF-I 150 ng/mL, FT4 1 ng/dL, TSH 1 mU/L, and morning cortisol after overnight dexamethasone suppression test 1 µg/dL (all within normal limits). The 7-mm lesion is located in the left inferior portion of the gland, is hypointense on T1, hyperintense on T2, and moderately enhancing. All data point to a non-functioning microadenoma. On the basis of clinics (non functioning), size (micro) and location (far from critical structure), watchful waiting is an appropriate choice. MRI control is scheduled at 12 and 24 months, without any hormonal control. Size is unchanged and the patient is reassured about the lack of evolutivity of the lesion. There is disagreement between the neurosurgeon and the endocrinologist about further follow-up: it is to be prolonged life-long for the former (with MRI at 2-year intervals), and it is redundant for the

Most lesions are pituitary adenomas but alternative diagnoses must always be

A screening of hypersecretory syndromes and hormonal deficiencies is mandatory. This

Take always into account comorbidities: a hypothalamic-pituitary lesion can be a local

The flow-chart in figure 23 is a simple but not exhaustive guide to diagnostic reasoning.

A plausible diagnosis is possible in many cases of parasellar lesions on the basis of epidemiological, clinical and neuradiological data. This involves a multidisciplinary collaborative effort among the endocrinologist, the neuroradiologist, and the neurosurgeon. Skilled individuals in an organized team, the pituitary unit, better perform this task. In cases of doubt, a histological diagnosis may still be required for a correct diagnosis and to allow appropriate treatment planning. Although most parasellar tumors are slow growing and benign, it is important to identify on the basis of clinical context, laboratory data, and serial imaging those which exert a strong malignant potential or are malignant. Treatment as well involves a joint effort requiring the collaboration of different specialists: the neurosurgeon, the endocrinologist, and the radiotherapist, with the neuro-oncologist and the nuclear

satisfactory height for the genetic target.

**6. Expert suggestions and conclusions**

manifestation of a systemic disease.

physician entering as a second-line in a few cases.

can be accomplished by a few focused hormonal assays. In diagnostic reasoning, consider epidemiological factors.

 Imaging must be critically reviewed together with the radiologist.

A few key-points are to be kept in mind.

**5.4 Patient 4**

latter.

considered.

pituitary adenoma. Immunohistochemistry is negative for pituitary hormones, and Ki67 is 0.5%. Post-operative course is uneventful. At 4 months, a radical resection is shown on MRI, as well as normalization of visual acuity and visual fields; morning cortisol and FT4 are 12 µg/dL and 1.1 ng/dL, respectively. Follow-up is scheduled with yearly evaluation of MRI for 3 years, thereafter progressively lengthening intervals.

## **5.2 Patient 2**

In the 34 yo woman with amenorrhea since 8 months work-up must start from endocrine evaluation. PRL is 850 ng/mL. This value is diagnostic of prolactinoma, because no other disease is associated to such high values. It is useful to evaluate IGF-I levels, to rule out a concomitant GH hypersecretion (210 ng/mL, that is normal for her age range), and pituitary function to screen for hypopituitarism. Morning cortisol and FT4 are within normal limits (13 µg/dL and 1.2 ng/dL, respectively), whereas estradiol, LH and FSH are low as expected (40 pg/mL, 0.7 U/L, and 3.5 U/L, respectively). Visual field examination shows superolateral bilateral quadrantopsia and MRI demonstrates a large mass, hypointense on T1, hyperintense on T2, heterogeneously enhancing after Gd administration due to multiple cysts, with irregular extrasellar extension up to optic chiasm, and in the sphenoid and cavernous sinuses. Macroprolactinoma is the only clinical situation where neurosurgery is not the first line therapeutic option in spite of visual pathways compression. Cabergoline, a selective dopamine agonist drug, is started at 0.25 mg/week at at bedtime, obtaining visual field normalization within one week. Follow-up is scheduled with clinical and PRL evaluation monthly for the first 3 months, at 3-month intervals in the first year, and at 6 month intervals in the following two years. PRL levels progressively decrease until normalization in 6 months, with menses restoration. After the first control at 3 months, MRI should be repeated at 6 and 12 months. If there is progressive shrinkage (in this patient it is substantial), successive controls can be performed yearly or even at more prolonged intervals, provided that PRL levels are still suppressed.

#### **5.3 Patient 3**

The 8 yo boy with growth arrest and mass in the sellar region needs a thorough evaluation. On physical examination height is at the 25th centile (genetic target over 50th), weight at the 75th centile, puberty at Tanner stage I. Adenoma is not the most frequent diagnosis in this age group, nonetheless the screening for prolactinoma and Cushing's disease (even though macroadenoma would be exceptionally rare) is warranted. PRL is 60 ng/mL and morning cortisol is normally suppressed after overnight dexamethasone suppression test (basal 9 µg/dL, after dexamethasone 0.8 µg/dL). Beyond growth arrest and worsening of school results, weight increase and excessive thirst are reported. Serum sodium is 148 mEq/L and glucose 65 mg/dL. Thyroid function is slightly impaired (FT4 0.7 ng/dL, with normal values 0.8-2.2). On the basis of history and sodium values, partial central DI is diagnosed and desmopressin is started. On MRI a heterogeneous intra and suprasellar mass is observed, with mottled appearance on T1, heterogeneously hyperintense on T2. Multicystic appearance is evident after Gd administration, with rim enhancement. CT scan shows multiple calcifications. Epidemiologic, clinical and radiological data point to craniopharyngioma. The patient undergoes neurosurgery by trans-sphenoidal approach. Post-operatively, DI worsens and panhypopituitarism develops, requiring full substitutive treatment with desmopressin, hydrocortisone and thyroxine. Follow-up is scheduled with MRI, to evaluate the radicality of resection. Metabolic and weight control is of particular concern. GH treatment is started. Puberty induction will be postponed until attainment of satisfactory height for the genetic target.

## **5.4 Patient 4**

148 Explicative Cases of Controversial Issues in Neurosurgery

pituitary adenoma. Immunohistochemistry is negative for pituitary hormones, and Ki67 is 0.5%. Post-operative course is uneventful. At 4 months, a radical resection is shown on MRI, as well as normalization of visual acuity and visual fields; morning cortisol and FT4 are 12 µg/dL and 1.1 ng/dL, respectively. Follow-up is scheduled with yearly evaluation of MRI

In the 34 yo woman with amenorrhea since 8 months work-up must start from endocrine evaluation. PRL is 850 ng/mL. This value is diagnostic of prolactinoma, because no other disease is associated to such high values. It is useful to evaluate IGF-I levels, to rule out a concomitant GH hypersecretion (210 ng/mL, that is normal for her age range), and pituitary function to screen for hypopituitarism. Morning cortisol and FT4 are within normal limits (13 µg/dL and 1.2 ng/dL, respectively), whereas estradiol, LH and FSH are low as expected (40 pg/mL, 0.7 U/L, and 3.5 U/L, respectively). Visual field examination shows superolateral bilateral quadrantopsia and MRI demonstrates a large mass, hypointense on T1, hyperintense on T2, heterogeneously enhancing after Gd administration due to multiple cysts, with irregular extrasellar extension up to optic chiasm, and in the sphenoid and cavernous sinuses. Macroprolactinoma is the only clinical situation where neurosurgery is not the first line therapeutic option in spite of visual pathways compression. Cabergoline, a selective dopamine agonist drug, is started at 0.25 mg/week at at bedtime, obtaining visual field normalization within one week. Follow-up is scheduled with clinical and PRL evaluation monthly for the first 3 months, at 3-month intervals in the first year, and at 6 month intervals in the following two years. PRL levels progressively decrease until normalization in 6 months, with menses restoration. After the first control at 3 months, MRI should be repeated at 6 and 12 months. If there is progressive shrinkage (in this patient it is substantial), successive controls can be performed yearly or even at more prolonged

The 8 yo boy with growth arrest and mass in the sellar region needs a thorough evaluation. On physical examination height is at the 25th centile (genetic target over 50th), weight at the 75th centile, puberty at Tanner stage I. Adenoma is not the most frequent diagnosis in this age group, nonetheless the screening for prolactinoma and Cushing's disease (even though macroadenoma would be exceptionally rare) is warranted. PRL is 60 ng/mL and morning cortisol is normally suppressed after overnight dexamethasone suppression test (basal 9 µg/dL, after dexamethasone 0.8 µg/dL). Beyond growth arrest and worsening of school results, weight increase and excessive thirst are reported. Serum sodium is 148 mEq/L and glucose 65 mg/dL. Thyroid function is slightly impaired (FT4 0.7 ng/dL, with normal values 0.8-2.2). On the basis of history and sodium values, partial central DI is diagnosed and desmopressin is started. On MRI a heterogeneous intra and suprasellar mass is observed, with mottled appearance on T1, heterogeneously hyperintense on T2. Multicystic appearance is evident after Gd administration, with rim enhancement. CT scan shows multiple calcifications. Epidemiologic, clinical and radiological data point to craniopharyngioma. The patient undergoes neurosurgery by trans-sphenoidal approach. Post-operatively, DI worsens and panhypopituitarism develops, requiring full substitutive

for 3 years, thereafter progressively lengthening intervals.

intervals, provided that PRL levels are still suppressed.

**5.2 Patient 2**

**5.3 Patient 3**

In the 45 yo male with the incidental finding of microlesion in the pituitary, the first task is screening of hypersecretory syndromes. PRL is 13 ng/mL, IGF-I 150 ng/mL, FT4 1 ng/dL, TSH 1 mU/L, and morning cortisol after overnight dexamethasone suppression test 1 µg/dL (all within normal limits). The 7-mm lesion is located in the left inferior portion of the gland, is hypointense on T1, hyperintense on T2, and moderately enhancing. All data point to a non-functioning microadenoma. On the basis of clinics (non functioning), size (micro) and location (far from critical structure), watchful waiting is an appropriate choice. MRI control is scheduled at 12 and 24 months, without any hormonal control. Size is unchanged and the patient is reassured about the lack of evolutivity of the lesion. There is disagreement between the neurosurgeon and the endocrinologist about further follow-up: it is to be prolonged life-long for the former (with MRI at 2-year intervals), and it is redundant for the latter.

## **6. Expert suggestions and conclusions**

A few key-points are to be kept in mind.

The flow-chart in figure 23 is a simple but not exhaustive guide to diagnostic reasoning.

A plausible diagnosis is possible in many cases of parasellar lesions on the basis of epidemiological, clinical and neuradiological data. This involves a multidisciplinary collaborative effort among the endocrinologist, the neuroradiologist, and the neurosurgeon. Skilled individuals in an organized team, the pituitary unit, better perform this task. In cases of doubt, a histological diagnosis may still be required for a correct diagnosis and to allow appropriate treatment planning. Although most parasellar tumors are slow growing and benign, it is important to identify on the basis of clinical context, laboratory data, and serial imaging those which exert a strong malignant potential or are malignant. Treatment as well involves a joint effort requiring the collaboration of different specialists: the neurosurgeon, the endocrinologist, and the radiotherapist, with the neuro-oncologist and the nuclear physician entering as a second-line in a few cases.

Diagnostic Evaluation of the Lesions of the Sellar and Parasellar Region 151

Arena S, Barbieri F, Thellung S, Pirani P, Corsaro A, Villa V, Dadati P, Dorcaratto A,

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