(%)

Ki-67-LI Median (range) There was no significative statistic difference in disease evolution time (F=1.0, p=0.351) and follow up (F=0.1, p=0.885), compared between invasion degrees. Neither the evolution time (p=0.146) nor the follow-up time (p=0.678) differed between functioning PA and nonfunctioning PA, however disease evolution time was lightly higher in III and IV invasion degrees. Evolution time (X2=2.4, p=0.287) and follow up time (X2=0.1, p=0.939) did not have association with the invasion grade.

No association was found among recurrence and functioning PA (p=0.526), and with hormone immunodetection (Prl p=0.595; GH p=0.377; FSH p=0.635).

Ki-67-LI was higher in IV grade (median value: 24.5%; range 2-35) in comparison with grade II (median value 6.8%; range 1-20; X2=6.4, p=0.029); Grade III PA has an intermediate value (median value 10.7%; range 10-16). There was no statistic difference of Ki-67-LI between functioning PA and non-functioning PA (p=0.893) or between PA with recurrence and PA without recurrence (p=0.253). There was no association of Ki-67-LI with hormone secretion type (Prl p=0.121; GH p=0.100; FSH p=0.5).

#### **3.3 Histopathological analysis**

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

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

Pituitary Adenomas – Clinico-Pathological, Immunohistochemical and Ultrastructural Study 57

observed, some of them with secretory granules inside it, whose size was between 221 nm

Fig. 5. Electronmicrographs of sparsely granulated prolactin adenoma grade II. (A) Lamellar endoplasmic reticulum (arrow). X 6,076; (B) fused secretory granules (black arrow) and

**A B**

Ten cases (8%) of pituitary adenomas with prolactin hormone and growth hormone secretion were found. Ultrastructuraly it was observed a monomorphous tumor, formed by only one cell type. All cells were scarcely granulated with secretory granules with 178 nm of diameter, few mitochondrias, lamellar endoplasmic reticulum and folded cell membranes;

Fig. 6. Electronmicrograph of grade IV, GH PA, with their hall-mark fibrous body (arrow) X10,350. (A); grade III PA, prolactin and GH secreting, with lamellar endoplasmic reticulum (black arrow), crescent moon nuclei (curved arrow), and fibrous body of type II filaments

**A B**

(white arrow). X5,137. (B). Uranyl acetate-lead citrate.

misplaced exocytosis (white curved arrow). X9,750. Uranyl acetate-lead citrate.

**3.4.3 GH secreting adenoma and prolactin hormone adenoma** 

and up to 769 nm in diameter (Fig. 6A).

smaller endoplasmic reticulum and Golgi complex; lysosomes were more frequent observed and there were scarce secretory granules.

Fig. 4. Photomicrograph of pituitary adenomas with hematoxilyn-eosin stain (A-C), and with Masson's trichrome stain for collagen fibers (D). (A) PA showing solid pattern with homogeneous size cells. (B-C) PA showing nuclear pleomorphism (asterisk) and pseudoinclusions (arrow). (D) Bromocriptine treated PA which shows interstitial fibrosis (arrow). (Original magnification: X400).

#### **3.4 Ultrastructure**

#### **3.4.1 Prolactin adenomas**

The most frequent type of pituitary adenomas was the prolactinoma (59%). All prolactinomas were sparsely granulated. The tumor show polyhedral cells with irregular nucleus, and prominent nucleolus. In the cytoplasm abundant, lamellar, rough endoplasmic reticulum and well development Golgi complex, was observed. There were scarce secretory granules, with size between 100-300 nm in diameter; some of them were localized between lateral cell surfaces which are known as misplaced exocytosis, the morphologic mark of prolactin secretor PA (Fig. 5).

#### **3.4.2 Growth hormone adenomas**

Adenoma secreting only growth hormone had an incidence of 4%. Ultrastructuraly this tumor was sparsely granulated. The cells showed pleomorphic and eccentric nucleus, with scarce and dilated endoplasmic reticulum. Fibrous bodies with type II filaments were

smaller endoplasmic reticulum and Golgi complex; lysosomes were more frequent observed

**A B** 

**C D** 

Fig. 4. Photomicrograph of pituitary adenomas with hematoxilyn-eosin stain (A-C), and with Masson's trichrome stain for collagen fibers (D). (A) PA showing solid pattern with

pseudoinclusions (arrow). (D) Bromocriptine treated PA which shows interstitial fibrosis

The most frequent type of pituitary adenomas was the prolactinoma (59%). All prolactinomas were sparsely granulated. The tumor show polyhedral cells with irregular nucleus, and prominent nucleolus. In the cytoplasm abundant, lamellar, rough endoplasmic reticulum and well development Golgi complex, was observed. There were scarce secretory granules, with size between 100-300 nm in diameter; some of them were localized between lateral cell surfaces which are known as misplaced exocytosis, the morphologic mark of

Adenoma secreting only growth hormone had an incidence of 4%. Ultrastructuraly this tumor was sparsely granulated. The cells showed pleomorphic and eccentric nucleus, with scarce and dilated endoplasmic reticulum. Fibrous bodies with type II filaments were

homogeneous size cells. (B-C) PA showing nuclear pleomorphism (asterisk) and

**\***

and there were scarce secretory granules.

(arrow). (Original magnification: X400).

**3.4 Ultrastructure** 

**3.4.1 Prolactin adenomas** 

prolactin secretor PA (Fig. 5).

**3.4.2 Growth hormone adenomas** 

observed, some of them with secretory granules inside it, whose size was between 221 nm and up to 769 nm in diameter (Fig. 6A).

Fig. 5. Electronmicrographs of sparsely granulated prolactin adenoma grade II. (A) Lamellar endoplasmic reticulum (arrow). X 6,076; (B) fused secretory granules (black arrow) and misplaced exocytosis (white curved arrow). X9,750. Uranyl acetate-lead citrate.

#### **3.4.3 GH secreting adenoma and prolactin hormone adenoma**

Ten cases (8%) of pituitary adenomas with prolactin hormone and growth hormone secretion were found. Ultrastructuraly it was observed a monomorphous tumor, formed by only one cell type. All cells were scarcely granulated with secretory granules with 178 nm of diameter, few mitochondrias, lamellar endoplasmic reticulum and folded cell membranes;

Fig. 6. Electronmicrograph of grade IV, GH PA, with their hall-mark fibrous body (arrow) X10,350. (A); grade III PA, prolactin and GH secreting, with lamellar endoplasmic reticulum (black arrow), crescent moon nuclei (curved arrow), and fibrous body of type II filaments (white arrow). X5,137. (B). Uranyl acetate-lead citrate.

Pituitary Adenomas – Clinico-Pathological, Immunohistochemical and Ultrastructural Study 59

secretory granules were scarce and small (104 nm). In one case proliferation of type I

N

**B**

**C**

Fig. 8. (A) Electronmicrography of grade IV immunonegative PA. This tumor showed sparsely granulated cells with abundant mitochondria (arrow). X9,900 ; (B) Corticotroph cell adenoma grade III which consist of closely-apposed, angular cells, with marked cell boundaries (arrow), and nucleus with irregular shape (N). X6,370 ; (C) Cytoplasm with abundant type I filaments were observed (arrow). X8760. Uranyl acetate and lead citrate.

**A**

Pituitary adenomas are heterogeneous tumors, this is because their different types of cells. The analysis of them had take into account several characteristic, the aim of these is to

Pituitary adenomas comprise nearly 15% of intracranial neoplasms and are the most common lesions in the sellar region (Valassi et al., 2010). There is a report of 84.6% PA in a study of 4,122 tumors of sellar region (Saeger et al., 2007). In a 10-year study conducted at the National Institute of Neurology and Neurosurgery, in Mexico City, from 2,041 central nervous system tumors and covers, 26.2% were PA (personal communication). Here we present a study of 122 case of PA which occurred between 13 and 75 yr old, with peak of incidence from 20 and 60 years (100 cases; 81.9%), 10 yr earlier than other series (Davis et al., 2001). There was a slightly higher incidence in men; however women had earlier age at diagnosis (since 13 yr) than men (since 17), with higher frequency between 20 and 48 yr (men between 30 and 60 yr; 68%).

Pituitary adenomas incidence are rare in young people under 20 yr and mostly are prolactinomas (86%) or corticotropinomas (10%) (Mindermann & Wilson, 1994). In this study was found 12 patients under 20 yr (9.8%); Nine (75%) were prolactinomas, one of which was Prl-ACTH positive, two Prl-GH, one Prl-TSH. From these 12 cases, one (8.3%) was GH immunopositive and in 2 PA the hormone expression was no detected. In table 1 it can be

explain its behavior, although until now, has not been understood.

**4. Discussion** 

filaments were perceive with secretory granules inside it (Fig. 8C).

nucleus show rounded or crescent moon shape in which concave area fibrous bodies were observed (Fig. 6B).

#### **3.4.4 Gonadotroph adenomas**

These adenomas were the most abundant (12%) after prolactinomas (44%) and the negative types for immunohistochemistry (21%). This tumor was formed by polyhedral cells, with poorly developed cytoplasm. Nuclei had rounded contours, some of them with irregular shapes and eccentric nucleoli attached to the electron-dense perinuclear chromatin. Rough endoplasmic reticulum was scarce and dilated, and secretory granules were few and small (153 nm in diameter). Big Golgi complex was observed with dilated cisterns (Fig. 7A). In two IV grade cases, smooth endoplasmic reticulum, mixed with mitochondria and pleomorphic secretory granules were detected; there was a vacuolated Golgi complex which was arranged in a honey comb complex, the hall-mark of this adenoma type (Fig. 7B).

Fig. 7. Electronmicrograph of grade III gonadotroph PA. (A) This tumor showed big Golgi complex with dilated cisterns (arrow), small secretory granules located along the cell membrane (thin arrow). X 6,370; (B) Golgi shows a honey comb complex (arrow). X15,600. Uranyl acetate-lead citrate.

#### **3.4.5 Negative pituitary adenomas**

This type of tumors was negative for all hormones with the immunohistochemistry technique. Under transmission electron microscopy, poorly developed cells were observed with scarce rough endoplasmic reticulum, few secretory granules with 100-200 nm of diameter and small Golgi complex. In some cases it was observed numerous mitochondria, which is known as oncocytic transformation (Fig. 8A).

#### **3.4.6 Corticotroph adenoma**

There were 2 cases (1.6%) of ACTH secreting pituitary adenomas. This tumor showed polyhedral or elongated cells with poorly developed cytoplasm. The cell boundaries were clearly marked, elongated nuclei with irregular contours, and prominent nucleoli (8B); secretory granules were scarce and small (104 nm). In one case proliferation of type I filaments were perceive with secretory granules inside it (Fig. 8C).

Fig. 8. (A) Electronmicrography of grade IV immunonegative PA. This tumor showed sparsely granulated cells with abundant mitochondria (arrow). X9,900 ; (B) Corticotroph cell adenoma grade III which consist of closely-apposed, angular cells, with marked cell boundaries (arrow), and nucleus with irregular shape (N). X6,370 ; (C) Cytoplasm with abundant type I filaments were observed (arrow). X8760. Uranyl acetate and lead citrate.

### **4. Discussion**

58 Pituitary Adenomas

nucleus show rounded or crescent moon shape in which concave area fibrous bodies were

These adenomas were the most abundant (12%) after prolactinomas (44%) and the negative types for immunohistochemistry (21%). This tumor was formed by polyhedral cells, with poorly developed cytoplasm. Nuclei had rounded contours, some of them with irregular shapes and eccentric nucleoli attached to the electron-dense perinuclear chromatin. Rough endoplasmic reticulum was scarce and dilated, and secretory granules were few and small (153 nm in diameter). Big Golgi complex was observed with dilated cisterns (Fig. 7A). In two IV grade cases, smooth endoplasmic reticulum, mixed with mitochondria and pleomorphic secretory granules were detected; there was a vacuolated Golgi complex which was

arranged in a honey comb complex, the hall-mark of this adenoma type (Fig. 7B).

Fig. 7. Electronmicrograph of grade III gonadotroph PA. (A) This tumor showed big Golgi complex with dilated cisterns (arrow), small secretory granules located along the cell membrane (thin arrow). X 6,370; (B) Golgi shows a honey comb complex (arrow). X15,600.

**A B**

This type of tumors was negative for all hormones with the immunohistochemistry technique. Under transmission electron microscopy, poorly developed cells were observed with scarce rough endoplasmic reticulum, few secretory granules with 100-200 nm of diameter and small Golgi complex. In some cases it was observed numerous mitochondria,

There were 2 cases (1.6%) of ACTH secreting pituitary adenomas. This tumor showed polyhedral or elongated cells with poorly developed cytoplasm. The cell boundaries were clearly marked, elongated nuclei with irregular contours, and prominent nucleoli (8B);

observed (Fig. 6B).

**3.4.4 Gonadotroph adenomas** 

Uranyl acetate-lead citrate.

**3.4.6 Corticotroph adenoma** 

**3.4.5 Negative pituitary adenomas** 

which is known as oncocytic transformation (Fig. 8A).

Pituitary adenomas are heterogeneous tumors, this is because their different types of cells. The analysis of them had take into account several characteristic, the aim of these is to explain its behavior, although until now, has not been understood.

Pituitary adenomas comprise nearly 15% of intracranial neoplasms and are the most common lesions in the sellar region (Valassi et al., 2010). There is a report of 84.6% PA in a study of 4,122 tumors of sellar region (Saeger et al., 2007). In a 10-year study conducted at the National Institute of Neurology and Neurosurgery, in Mexico City, from 2,041 central nervous system tumors and covers, 26.2% were PA (personal communication). Here we present a study of 122 case of PA which occurred between 13 and 75 yr old, with peak of incidence from 20 and 60 years (100 cases; 81.9%), 10 yr earlier than other series (Davis et al., 2001). There was a slightly higher incidence in men; however women had earlier age at diagnosis (since 13 yr) than men (since 17), with higher frequency between 20 and 48 yr (men between 30 and 60 yr; 68%).

Pituitary adenomas incidence are rare in young people under 20 yr and mostly are prolactinomas (86%) or corticotropinomas (10%) (Mindermann & Wilson, 1994). In this study was found 12 patients under 20 yr (9.8%); Nine (75%) were prolactinomas, one of which was Prl-ACTH positive, two Prl-GH, one Prl-TSH. From these 12 cases, one (8.3%) was GH immunopositive and in 2 PA the hormone expression was no detected. In table 1 it can be

Pituitary Adenomas – Clinico-Pathological, Immunohistochemical and Ultrastructural Study 61

There were no adenomas classified in grades I and II. In our case, in women non-

In pituitary adenomas recurrences are common problems. The large size and the invasive behavior of these tumors cause difficulties in their removal (Paek et al., 2005). It has been reported that about 50% of patients have tumor remnants, and tumor re-growth can be presented at 10 years after neurosurgery (Reddy, 2011; Sassolas et al., 1993). Generally larger tumors recurred more frequently than smaller adenomas after surgery (Gopalan et al., 2011; Saeger et al., 2007). In our work the tumors were removed between 60% and 100%, by means of transcranial-frontal or transsphenoidal technique, and in III and IV grades the recurrences were higher, with secondary recurrences in 5 patients (three in III grade and 2 in IV grade). The time of interval between surgery and recurrence ranged from 1 to 11 years in both clinically functioning PA and non-functioning PA. In non-functioning pituitary adenomas Reddy et al. (2011) showed relapse/re-growth in 10 or more years after the initial surgery, and found significant increase in re-growth rates when remnant pituitary tumors are observed on the first post-operative scan or if the patient is younger age at initial surgery. The follow up time of the patients is an important factor for their outcome (Dekkers et al., 2008). In our work 38 (31%) patients were found with a mean of 11 yr of follow up (range 1-27 yr), 12 of them were non-functioning PA with 10.3 yr of follow up (range, 1-27 yr). Reddy et.al. (Reddy, 2011) reports an average of 6.1 yr (range, 1-25.8) of follow up in 29 patients with non-functioning PA out of 155, of which 54 (34.8%) had recurrence, with 20% of relapse after

10 years of surgery; they suggest that it is necessary to track patients beyond this time.

their vision with a second surgery (Chang et al., 2010; Müslüman et al., 2011).

2007).

In this study, few patients continued to attend for monitoring appointments. This could be because the patients who come to this health institution live outside of Mexico city, and sometimes it is difficult for them to travel to the city. Other patients are sent to other hospitals for continue their treatment, or they have no financial means for the follow up. Patients, who maintain their treatment and attendance to appointments for periodic reviews, have good outcome, with a improve of their visual impairments and hormonal levels, treated by hormonal substitution. It has been observed that patients with pre-operative anterior dysfunction recover function after surgery and the cases who presented with visual disturbance improve

An important factor in the biological behavior of pituitary adenomas is their proliferative capacity, which could be assessed by counting mitoses and the immunostaining of nuclei for proliferation markers as Ki-67. Mitoses figures are rare in non-invasive pituitary adenomas (3.9% of cases), they are more frequent in invasive PA (21.4%) and are greater in carcinomas (66.7%) (Pernicope et al., 2001). In our study there were found 2 cases (1.6%) with mitoses, which is not different from that reported in other studies, including the recently established rare subtype spindle cell oncocytoma of the pituitary gland (Matyja et al., 2010; Saeger et al.,

Ki-67 is the most important proliferation marker; it is expressed in early G1, S, G2, and M phases of the cell cycle. This marker is associated with tumor proliferation, invasiveness, and prognosis (Cattoretti et al., 1992; Petrowsky et al., 2001). In pituitary adenomas the value of Ki-67 is controversial, in relation to the aggressive behavior (de Aguiar et al., 2010; Zhao et al., 1999), and in pituitary carcinoma appear to predict rapid disease progression (Dudziak et al., 2011). In a study performed in 44 pituitary macroadenomas, visual field defect and recurrence show correlation with Ki-67 LI, no statistical differences were

functioming pituitary adenomas could be related with the size.

observed, that in some patients the age at diagnosis (age column) is over 20 yr, although the patients reported that the beginning of the symptoms was some years before (evolution time).

In general, tumor size correlates with functional activity (clinically functioning and clinically non-functioning pituitary adenomas), and in women has been observed that, prolactinomas and also in ACTH clinically functioning pituitary adenomas, the diagnosis is carry out at early stages. (Kontogeorgos, 2006). In our work we found 71 (58.1%) functioning PA; 44 (61.9%) were in female of which only 5 (11%) were grade I and II PA and 39 (88.6%) were classified in III and IV grades. Out of this 39 PA, 29 (74%; 13 in grade III and 16 in grade IV) were prolactin immunopositive. In this case, women functioning adenomas, which produced prolactin hormone, were detected at an advance stage of invasion.

In this study must of the PA were in a invasive phase (grade III and IV), and the disease evolution time in these patients was higher than in I and II grades, even though there was no statistical association with clinical manifestation (functioning or non-functioning PA) or hormonal activity assessed by immunohistochemistry. Similar long evolution time (from 10 days to 20 years), has been reported in a Brazilian serie which was greater than the Italian and US series (Drange et al, 2000; Ferrante et al., 2006). This may be due to the class of population that assist to this Institute, which are used to endure the symptoms of the disease for a long time before seeking medical treatment, or do not have the right information to perceive them at an early stage, also before turning to adequate health service they look for alternative therapies. As it has been suggested by other authors, the clinical signs might be underestimated or not correctly diagnosed (Drange et al., 2000; Ferrate et al., 2006). In our experience, patients as first choice went to the ophthalmologist, because of the visual alterations, and by the computed tomography or magnetic resonance imaging scans, sellar alterations were observed. Nowadays incidental detection of PA tumors has been increased due to radiological evaluations performed for unrelated reasons (Saeger et al., 2007). In this analysis we can observed that the functionality was not related to tumor size, but with time the patient will assit to the health center.

Non-functioning pituitary adenomas are a diverse and heterogeneous group, where glycoprotein hormones, null cell adenoma and oncocytoma are included (Laws et al., 1982; Moreno et al., 2005). They are usually diagnosed as macroadenomas due to absence of clinical manifestations, which cause tumor growth in long time. Non-functioning PA account between 15% and 45% of pituitary tumors (Asa & Kovacs, 1992; Milker-Zabel et al., 2005). It has been reported that 95-100% of non-functioning pituitary adenomas are macroadenomas, and the frequency of recurrence varies between 19% and 34.8% in different studies (Aurer & Clarici, 1985; Reddy et al., 2011); up to 79% has hormone expression, evaluated by immunohistochemistry (Moreno et al., 2005), being gonadotroph hormones and/or their α- β- subunits the most common (Cury et al., 2009, Hanson et al., 2005). In our study 51 (42%) tumors were non-functioning PA, of which 38 (74.5%) were men, this is consistent with other studies (Asa & Kovacs, 1992; Cury et al., 2009; Ferrante et al., 2006; Milker-Zabel et al., 2005). Out of 51 non-functioning pituitary adenomas, 15 (29.4%) showed recurrence and 41 (80%) were macroadenomas. In 71% of non-functioning PA hormone expression was found, being prolactin the most frequent hormone detected by immunohistochemistry (33%), followed by gonadotroph hormones (20%); there were 29% of immunonegative PA in accordance with Turner report (Turner et al., 1999). It is important to point out that 13 cases of non-functionig PA were female, 7 of grade III and 6 of grade IV.

observed, that in some patients the age at diagnosis (age column) is over 20 yr, although the patients reported that the beginning of the symptoms was some years before (evolution time). In general, tumor size correlates with functional activity (clinically functioning and clinically non-functioning pituitary adenomas), and in women has been observed that, prolactinomas and also in ACTH clinically functioning pituitary adenomas, the diagnosis is carry out at early stages. (Kontogeorgos, 2006). In our work we found 71 (58.1%) functioning PA; 44 (61.9%) were in female of which only 5 (11%) were grade I and II PA and 39 (88.6%) were classified in III and IV grades. Out of this 39 PA, 29 (74%; 13 in grade III and 16 in grade IV) were prolactin immunopositive. In this case, women functioning adenomas, which

In this study must of the PA were in a invasive phase (grade III and IV), and the disease evolution time in these patients was higher than in I and II grades, even though there was no statistical association with clinical manifestation (functioning or non-functioning PA) or hormonal activity assessed by immunohistochemistry. Similar long evolution time (from 10 days to 20 years), has been reported in a Brazilian serie which was greater than the Italian and US series (Drange et al, 2000; Ferrante et al., 2006). This may be due to the class of population that assist to this Institute, which are used to endure the symptoms of the disease for a long time before seeking medical treatment, or do not have the right information to perceive them at an early stage, also before turning to adequate health service they look for alternative therapies. As it has been suggested by other authors, the clinical signs might be underestimated or not correctly diagnosed (Drange et al., 2000; Ferrate et al., 2006). In our experience, patients as first choice went to the ophthalmologist, because of the visual alterations, and by the computed tomography or magnetic resonance imaging scans, sellar alterations were observed. Nowadays incidental detection of PA tumors has been increased due to radiological evaluations performed for unrelated reasons (Saeger et al., 2007). In this analysis we can observed that the functionality was not related to tumor size, but with time

Non-functioning pituitary adenomas are a diverse and heterogeneous group, where glycoprotein hormones, null cell adenoma and oncocytoma are included (Laws et al., 1982; Moreno et al., 2005). They are usually diagnosed as macroadenomas due to absence of clinical manifestations, which cause tumor growth in long time. Non-functioning PA account between 15% and 45% of pituitary tumors (Asa & Kovacs, 1992; Milker-Zabel et al., 2005). It has been reported that 95-100% of non-functioning pituitary adenomas are macroadenomas, and the frequency of recurrence varies between 19% and 34.8% in different studies (Aurer & Clarici, 1985; Reddy et al., 2011); up to 79% has hormone expression, evaluated by immunohistochemistry (Moreno et al., 2005), being gonadotroph hormones and/or their α- β- subunits the most common (Cury et al., 2009, Hanson et al., 2005). In our study 51 (42%) tumors were non-functioning PA, of which 38 (74.5%) were men, this is consistent with other studies (Asa & Kovacs, 1992; Cury et al., 2009; Ferrante et al., 2006; Milker-Zabel et al., 2005). Out of 51 non-functioning pituitary adenomas, 15 (29.4%) showed recurrence and 41 (80%) were macroadenomas. In 71% of non-functioning PA hormone expression was found, being prolactin the most frequent hormone detected by immunohistochemistry (33%), followed by gonadotroph hormones (20%); there were 29% of immunonegative PA in accordance with Turner report (Turner et al., 1999). It is important to point out that 13 cases of non-functionig PA were female, 7 of grade III and 6 of grade IV.

produced prolactin hormone, were detected at an advance stage of invasion.

the patient will assit to the health center.

There were no adenomas classified in grades I and II. In our case, in women nonfunctioming pituitary adenomas could be related with the size.

In pituitary adenomas recurrences are common problems. The large size and the invasive behavior of these tumors cause difficulties in their removal (Paek et al., 2005). It has been reported that about 50% of patients have tumor remnants, and tumor re-growth can be presented at 10 years after neurosurgery (Reddy, 2011; Sassolas et al., 1993). Generally larger tumors recurred more frequently than smaller adenomas after surgery (Gopalan et al., 2011; Saeger et al., 2007). In our work the tumors were removed between 60% and 100%, by means of transcranial-frontal or transsphenoidal technique, and in III and IV grades the recurrences were higher, with secondary recurrences in 5 patients (three in III grade and 2 in IV grade). The time of interval between surgery and recurrence ranged from 1 to 11 years in both clinically functioning PA and non-functioning PA. In non-functioning pituitary adenomas Reddy et al. (2011) showed relapse/re-growth in 10 or more years after the initial surgery, and found significant increase in re-growth rates when remnant pituitary tumors are observed on the first post-operative scan or if the patient is younger age at initial surgery.

The follow up time of the patients is an important factor for their outcome (Dekkers et al., 2008). In our work 38 (31%) patients were found with a mean of 11 yr of follow up (range 1-27 yr), 12 of them were non-functioning PA with 10.3 yr of follow up (range, 1-27 yr). Reddy et.al. (Reddy, 2011) reports an average of 6.1 yr (range, 1-25.8) of follow up in 29 patients with non-functioning PA out of 155, of which 54 (34.8%) had recurrence, with 20% of relapse after 10 years of surgery; they suggest that it is necessary to track patients beyond this time.

In this study, few patients continued to attend for monitoring appointments. This could be because the patients who come to this health institution live outside of Mexico city, and sometimes it is difficult for them to travel to the city. Other patients are sent to other hospitals for continue their treatment, or they have no financial means for the follow up. Patients, who maintain their treatment and attendance to appointments for periodic reviews, have good outcome, with a improve of their visual impairments and hormonal levels, treated by hormonal substitution. It has been observed that patients with pre-operative anterior dysfunction recover function after surgery and the cases who presented with visual disturbance improve their vision with a second surgery (Chang et al., 2010; Müslüman et al., 2011).

An important factor in the biological behavior of pituitary adenomas is their proliferative capacity, which could be assessed by counting mitoses and the immunostaining of nuclei for proliferation markers as Ki-67. Mitoses figures are rare in non-invasive pituitary adenomas (3.9% of cases), they are more frequent in invasive PA (21.4%) and are greater in carcinomas (66.7%) (Pernicope et al., 2001). In our study there were found 2 cases (1.6%) with mitoses, which is not different from that reported in other studies, including the recently established rare subtype spindle cell oncocytoma of the pituitary gland (Matyja et al., 2010; Saeger et al., 2007).

Ki-67 is the most important proliferation marker; it is expressed in early G1, S, G2, and M phases of the cell cycle. This marker is associated with tumor proliferation, invasiveness, and prognosis (Cattoretti et al., 1992; Petrowsky et al., 2001). In pituitary adenomas the value of Ki-67 is controversial, in relation to the aggressive behavior (de Aguiar et al., 2010; Zhao et al., 1999), and in pituitary carcinoma appear to predict rapid disease progression (Dudziak et al., 2011). In a study performed in 44 pituitary macroadenomas, visual field defect and recurrence show correlation with Ki-67 LI, no statistical differences were

Pituitary Adenomas – Clinico-Pathological, Immunohistochemical and Ultrastructural Study 63

have, a natural evolution, a potential to invasion, sparing the nervous tissue and without

Although there are no parameters or experimental tests that serve as clear markers of disease progression, the data that have been obtained as a result of the evaluation of hormone expression and clinical evaluation, have important information that can be associated with pathogenicity of PA. Currently, there are new molecular techniques, as proteomic technique

The setup of registry on pituitary tumours constitutes a useful tool to analyze clinical experience, improve therapeutic strategies and patient's care. It also contributes for teaching

Asa, S.L. & Kovacs, K. (1992). Clinically non-functioning human pituitary adenomas. *Can J* 

Bratthauer G.L, Adams L.R. (1994). Immunohistochemistry: Antigen detection in tissue. In:

Chacko, G.; Chacko, A.G.; Kovacs, K.; Scheithauer, B.W.; Mani, S.; Muliyil, J.P. & Seshadri,

Chang, E.F.; Sughrue, M.E.; Zada, G.; Wilson, C.B.; Blevins, L.S. Jr. & Kunwar, S. (2010).

Colao, A.; Ochoa, A.S.; Auriemma, R.S.; Faggiano, A.; Pivonello, R. & Lombardi G. (2010). Pituitary carcinomas. *Front Horm Res*, Vol.38, pp. 94-108, ISSN 1662-3762. Couldwell, W.T. & Cannon-Albright, L. (2010). A heritable predisposition to pituitary tumors. *Pituitary*, Vol.13, No.2, (June), pp. 130–137, ISSN 1573-7403. Crocker, D.W. (1978). The pituitary gland. En: Coulson W.F. (Ed): *Surgical Pathology*, pp. 878-

Cury, M.L.; Fernandes, J.C.; Machado, H.R.; Elias, L.L.; Moreira, A.C. & Castro, M. (2009).

Davis, J.R.; Farrell, W.E. & Clayton, R.N. (2001). Pituitary tumours. *Reproduction* Vol.121,

de Aguiar, P.H.; Aires, R.; Laws, E.R.; Isolan, G.R.; Logullo, A.; Patil, C. & Katznelson L.

Non-functioning pituitary adenomas: clinical feature, laboratorial and imaging assessment, therapeutic management and outcome. *Arq Bras Endocrinol Metabol*,

(2010). Labeling index in pituitary adenomas evaluated by means of MIB-1: is there a prognostic role? A critical review. *Neurol Res,* Vol.32, No.10, (Dec), pp. 1060-1071,

Mikel UV (ed) Advanced laboratory methods in histology and pathology. Armed Forces Institute of Pathology, American Registry of Pathology, Washington DC. Cattoretti, G.; Becker, M.H.; Key, G.; Duchrow, M.; Schlüter, C.; Galle, J. & Gerdes, J. (1992).

Monoclonal antibodies against recombinant parts of the ki-67 antigen (MIB1 and MIB3) detect proliferating cells in micro-wave-processed formalin-fixed paraffin

M.S. (2010). The clinical significance of MIB-1 labeling index in pituitary adenomas.

Long term outcome following repeat transsphenoidal surgery for recurrent endocrine-inactive pituitary adenomas. *Pituitary*, Vol.13, No.3, (Sep), pp. 223-229,

*Neurol Sci,* Vol.19, No.2 (May), pp.228–35, ISSN: 0317-1671.

sections. *J Pathol,* Vol.168, No.4, (Dec), pp. 357-363, ISSN 1096-9896.

*Pituitary*, Vol.13, No.4, (Dec), pp. 337-344. ISSN 1573-7403.

that allows us to investigate the proteins involved in the disease process.

medical students and develops clinical research.

ISSN 1573-7403.

ISSN 1743-1328.

898, Lippincott, Philadelphia, 1978.

Vol.5, No.1, (Feb), pp. 31-39, ISSN 1677-9487.

No.3, (Mar), pp. 363-371, ISSN 1741-7899.

seeding to distant organs.

**6. References** 

observed in Ki-67 LI in relation to the Hardy´s classification (Paek et al., 2005). In other study in a series of 20 radically resected pituitary macroadenomas (11 functioning, 9 nonfunctioning) MIB-1(antibody of Ki-67 antigen) did not show a significant difference of expression between recurrent and non-recurrent adenomas (Ruggeri et al., 2011). Yarman (2010) assessed Ki-67 expression in growth hormone-secreting pituitary adenomas and showed no correlation with the invasive character. In other study it has been observed that Ki-67 LI was marginally higher in clinically functioning adenomas than clinically nonfunctioning adenomas. They also found significant difference in the MIB-1 LI in tumors with a maximum diameter of more than 4cm at a MIB-1 LI of ≥2%, however this difference was not statistically significant at a higher MIB-1 LI cut off value of >3% (Chacko et al., 2010). On the other hand, there is other report in which no significant difference in MIB-1 LI was found between functioning and non-functioning PA (Scheithauer et al., 2006). In our results, Ki-67 LI was significantly higher in IV grade PA than those of II grade which is different to that reported by Paek (2005); however there was no statistic difference of Ki-67 LI between pituitary adenomas with recurrence or without recurrence. About functionality we did not found differences between functioning and non-functioning pituitary adenomas which differs with Scheithauer report (2006).

Ultrastructural analysis of pituitary adenomas is an important tool for the detailed characterization of this type of tumors, particularly in problematic cases, because it is the initial basis of adenoma classification. With transmission electron microscopy it can be confirmed the endocrine nature of PA and their functional differentiation, which can be identified based on their ultrastructural markers of each hormonal type. Despite the utility of electron microscopy analysis in the evaluation of these tumors, diagnostic cannot be made on ultrastructural grounds alone, it should be done taking into consideration histology, immunohistochemistry and electron microscopical morphologic features, as well as findings from imaging studies and the symptoms (Kontogeorgos, 2006). Both clinical and histopathological factors are important for the diagnostic and outcome of patients.

In our study we observed the ultrastructural features of the different types of PA according to their hormonal expression, and in relation to clinical manifestations. Ultrastructural analysis was very useful in mixed secretory adenomas, as growth hormone and prolactin secreting PA where cells with fibrous bodies, hall-mark of GH pituitary adenoma. In this way, ultrastructural findings of most PA are consistent with the immunophenotype, however there are occasional cases with ultrastructural features less well differentiated like the rare carcinomas (Scheithauer et. al., 2001).

#### **5. Conclusion**

Pituitary adenomas are a heterogeneous group whose behavior has not been understood yet. In our study must of the tumors were in a extensive invasive phase, they affected young adult population and in this series of cases people under 20 years were founded. The disease evolution time and recurrence frequency was high in the advanced grades. The diagnosis of these tumors was not related with the clinical manifestations, according to the time taken by the patients to consult a doctor. The good outcome of patients depends on the follow-up, which has a very low rate for different reasons.

Pituitary adenomas have benign histological aspect, however can be aggressive, and may have one or more recurrences, as has been shown in this analysis. These neoplasms seem to have, a natural evolution, a potential to invasion, sparing the nervous tissue and without seeding to distant organs.

Although there are no parameters or experimental tests that serve as clear markers of disease progression, the data that have been obtained as a result of the evaluation of hormone expression and clinical evaluation, have important information that can be associated with pathogenicity of PA. Currently, there are new molecular techniques, as proteomic technique that allows us to investigate the proteins involved in the disease process.

The setup of registry on pituitary tumours constitutes a useful tool to analyze clinical experience, improve therapeutic strategies and patient's care. It also contributes for teaching medical students and develops clinical research.

#### **6. References**

62 Pituitary Adenomas

observed in Ki-67 LI in relation to the Hardy´s classification (Paek et al., 2005). In other study in a series of 20 radically resected pituitary macroadenomas (11 functioning, 9 nonfunctioning) MIB-1(antibody of Ki-67 antigen) did not show a significant difference of expression between recurrent and non-recurrent adenomas (Ruggeri et al., 2011). Yarman (2010) assessed Ki-67 expression in growth hormone-secreting pituitary adenomas and showed no correlation with the invasive character. In other study it has been observed that Ki-67 LI was marginally higher in clinically functioning adenomas than clinically nonfunctioning adenomas. They also found significant difference in the MIB-1 LI in tumors with a maximum diameter of more than 4cm at a MIB-1 LI of ≥2%, however this difference was not statistically significant at a higher MIB-1 LI cut off value of >3% (Chacko et al., 2010). On the other hand, there is other report in which no significant difference in MIB-1 LI was found between functioning and non-functioning PA (Scheithauer et al., 2006). In our results, Ki-67 LI was significantly higher in IV grade PA than those of II grade which is different to that reported by Paek (2005); however there was no statistic difference of Ki-67 LI between pituitary adenomas with recurrence or without recurrence. About functionality we did not found differences between functioning and non-functioning pituitary adenomas which

Ultrastructural analysis of pituitary adenomas is an important tool for the detailed characterization of this type of tumors, particularly in problematic cases, because it is the initial basis of adenoma classification. With transmission electron microscopy it can be confirmed the endocrine nature of PA and their functional differentiation, which can be identified based on their ultrastructural markers of each hormonal type. Despite the utility of electron microscopy analysis in the evaluation of these tumors, diagnostic cannot be made on ultrastructural grounds alone, it should be done taking into consideration histology, immunohistochemistry and electron microscopical morphologic features, as well as findings from imaging studies and the symptoms (Kontogeorgos, 2006). Both clinical and

In our study we observed the ultrastructural features of the different types of PA according to their hormonal expression, and in relation to clinical manifestations. Ultrastructural analysis was very useful in mixed secretory adenomas, as growth hormone and prolactin secreting PA where cells with fibrous bodies, hall-mark of GH pituitary adenoma. In this way, ultrastructural findings of most PA are consistent with the immunophenotype, however there are occasional cases with ultrastructural features less well differentiated like

Pituitary adenomas are a heterogeneous group whose behavior has not been understood yet. In our study must of the tumors were in a extensive invasive phase, they affected young adult population and in this series of cases people under 20 years were founded. The disease evolution time and recurrence frequency was high in the advanced grades. The diagnosis of these tumors was not related with the clinical manifestations, according to the time taken by the patients to consult a doctor. The good outcome of patients depends on the follow-up,

Pituitary adenomas have benign histological aspect, however can be aggressive, and may have one or more recurrences, as has been shown in this analysis. These neoplasms seem to

histopathological factors are important for the diagnostic and outcome of patients.

differs with Scheithauer report (2006).

the rare carcinomas (Scheithauer et. al., 2001).

which has a very low rate for different reasons.

**5. Conclusion** 


Pituitary Adenomas – Clinico-Pathological, Immunohistochemical and Ultrastructural Study 65

Martínez A.J. (1986). The pathology of nonfunctional pituitary adenomas. *Semin Diag Pathol*,

Matyja, E.; Maksymowicz , M.; Grajkowska, W.; Olszewski, W.; Zieliński, G. & Bonicki, W.

McDowell, B.D.; Wallace, R.B.; Carnahan, R.M.; Chrischilles, E.A.; Lynch, C.F. & Schlechte,

Milker-Zabel, S.; Debus, J.; Thilmann, C.; Schlegel, W. & Wannenmacher M. (2001).

*Radiat Oncol Biol Phys* Vol.50, No.5, (Aug), pp.1279-1286. ISSN: 1879-355X. Mindermann, T. & Wilson C.B. (1994). Age-related and gender-related occurrence of pituitary adenomas. *Clinical Endocrinology,* Vol.41, No.3, (Sep), pp.359-364. ISSN: 0300-0664. Moreno, C.S.; Evans, Chheng-Orn; Zhan, X.; Okor, M.; Desiderio, D.M. & Oyesiku, N M.

Müslüman, A.M.; Cansever, T.; Ylmaz, A.; Kanat, A.; Oba, E.; Çavuşoğlu, H.; Sirinoğlu, D.

Nosé, V.; Ezzat, S.; Horvath, E.; Kovacs, K.; Laws E., Lloyd, R.; Lopes, B. & Asa S. (2011)

tumors. *Arch Pathol Lab Med* Vol.135, No.5, (May), pp.640-646, 1543-2165. Paek, K.I.; Kim, S.H.; Song, S.H.; Choi, S.W.; Koh, H.S.; Youm, J.Y. & Kim, Y. (2005). Clinical

Pernicope, P.J. & Scheithauer, B.W. (2001). Invasive pituitary adenoma and pituitary

Petrowsky, H.; Sturm, I.; Graubitz, O.; Kooby, D.A.; Staib-Sebler, E.; Gog, C.; Köhne, C.H.;

Prophet, E. & Arrignton J. (Eds.). (1992). Histotechnologyc methods. USA Armed Forces

Reddy, R.; Cudlip, S.; Byrne, J.V.; Karavitaki, N. & Wass, J.A. (2011). Can we ever stop imaging

adenoma? *Eur J Endocrinol,* Vol.165, No.5, (Nov), pp. 739-44, ISSN 1479-683X. Rosai, J. (1989). Pituitary adenomas. In: *Ackerman´s Surgical Pathology*. Volume 2. 7th ed.

Ruggeri, R.M.; Costa, G.; Simone, A.; Campennì, A.; Sindoni, A.; Ieni, A.; Cavallari, V.;

(2010). Spindle cell oncocytoma of the adenohypophysis - a clinicopathological and ultrastructural study of two cases. *Folia Neuropathol*, Vol.48, No.3, pp.175-184, ISSN

J.A. (2011). Demographic differences in incidence for pituitary adenoma. *Pituitary*,

Fractionated stereotactically guided radiotherapy and radiosurgery in the treatment of functional and nonfunctional adenomas of the pituitary gland. *Int J* 

(2005). Novel molecular signaling and classification of human clinically nonfunctional pituitary adenomas identified by gene expression profiling and proteomic analyses. *Cancer Res,* Vol.65, No.22, (Nov), pp.10214-10222, ISSN 1538-7445.

& Aydn Y. (2011). Surgical results of large and giant pituitary adenomas with special consideration of ophthalmologic outcomes. *World Neurosurg,* Vol.76, No.1-2,

Protocol for examination of specimens from patients with primary pituitary

significance of Ki-67 laveling index in pituitary macroadenoma. J *Korean Med Sci*,

carcinoma. In Diagnosis and management pituitary tumors. pp 369-386. Eds K Thapar, K.; K. Kovacs, B.W., Scheithauer and K.V Lloyd, Totowa N.J: Humana

Hillebrand, T.; Daniel, P.T.; Fong, Y. & Lorenz, M. (2001). Relevance of Ki-67 antigen expression and K-ras mutation in colorectal liver metastases. *Eur J Surg* 

in surgically treated and radiotherapy-naive patients with non-functioning pituitary

Trimarchi, F. & Curtò, L. (2011). Cell proliferation parameters and apoptosis indices in pituitary macroadenomas. *J Endocrinol Invest*, Sep 6. [Epub ahead of print] ISSN

Vol.3, No.1, (Feb), pp.83-94, ISSN 0740-2570.

Vol.14, No.1, (Mar), pp.23-30, ISSN 1573-7403.

(Jul-Aug), pp. 141-148, ISSN 1878-8750.

Vol.20, No.3, (Jun), pp. 489-494, ISSN 1598-6357.

*Oncol*, Vol.27, No.1, (Feb), pp. 80-87, ISSN 1532-2157.

Edited by Rosai J. St. Louis: C. V. Mosby;:1779-1789.

Institute of Pathology, ISBN 1-881041-00-X, Washington, D. C.

1509-572X.

press 2001.

1720-8386.


Dekkers, O.M.; Pereira, A.M. & Romijn, J.A. (2008). Treatment and follow-up of clinically

Drange, M.R.; Fram, N.R.; Herman-Bonert, V. & Melmed, S. (2000). Pituitary tumour

Dudziak, K.; Honegger, J.; Bornemann, A.; Horger, M. & Müssig K. (2011). Pituitary

Ferrante, E.; Ferraroni, M.; Castrignanò, T.; Menicatti, L.; Anagni, M.; Reimondo, G.; Del

(Oct), pp. 3717-3726, ISSN 1945-7197.

No.9, (Sep), pp. 2665-2669, ISSN 1945-7197.

168-174, ISSN 1945-7197.

nonfunctioning pituitary macroadenomas. *J Clin Endocrinol Metab*, Vol.93, No.10,

registry: anovel clinical resourse. *J Clin Endocrinol Metab*, Vol.85, No.1, (Jan), pp.

carcinoma with malignant growth from first presentation and fulminant clinical course--case report and review of the literature. *J Clin Endocrinol Metab*, Vol. 96,

Monte, P.; Bernasconi, D.; Loli, P.; Faustini-Fustini, M.; Borretta, G.; Terzolo, M.; Losa, M.; Morabito, A.; Spada, A.; Beck-Peccoz, P. & Lania, AG. (2006). Non-functioning pituitary adenoma database: a useful resourse to improve the clinical management of pituitary tumors. *Eur J Endocrinol,* Vol.155, No.6, (Dec), pp.823-829, ISSN 1479-683X. Galland, F. & Chanson, P. 2009. Classification and pathophysiology of pituitary adenomas. *Bull Acad Natl Med*, Vol.193, No.7, (Oct), pp. 1543-1556, ISSN 0001-4079. Gopala, R.; Schlesinger, D; Vance, M. L.; Laws, E. & Sheehan, J. (2011). Long-term outcomes

after Gamma Knife radiosurgery for patients with a nonfunctioning pituitary

in vivo and in vitro in patients with non-functioning pituitary adenomas. *European* 

and treatment of pituitary tumors*.* Int Congress Series No. 303. Edited by Kohler

Clinical review: diagnosis and management of pituitary carcinmomas. *J Clin* 

Edited by Washington: Armed Forces Institute of Pathology; 1986:57-93. Hartmann

specific clinical entities. In: Laws E.R, Randall R.V, Kern E.B, et.al. Manegement of pituitary adenomas and related lesions with emphasis on transsphenoidal

immunoexpression in aggressive pituitary adenoma and carcinoma. *Pituitary*,

adenoma. Neurosurgery, Vol.69, No.2, (Aug), pp. 284-93, ISSN 1524-4040. Hanson, P.L.; Aylwin, S.J.B.; Monson, J.P,; Burrin, J.M. (2005). FSH secretion predominates

Hardy, J. (1973). Transsphenoidal surgery of hypersecreting pituitary tumors, In: Diagnosis

Horvath, E. & Kovacs K. (1992). Ultrastructural diagnosis of human pituitary adenomas.

Horvath, E. (1994). Ultrastructural markers in the pathologic diagnosis of pituitary adenomas. Ultrastruct Pathol, Vol.18, No.1-2, (Jan-Apr), pp. 171-179, ISSN 1521-0758. Kaltsas, G.A.; Nomikos, P.; Kontogeorgos, G.; Buchfelder, M. & Grossman AB. (2005).

*Endocrinol Metab*, Vol.90, No.5, (May), pp. 3089-3099, ISSN 1945-7197. Kovacs, K. & Horvath E. (1986). Pituitary adenomas. In Tumors of the pituitary gland*.*

W.H, Sobin L.H. Second Series: Atlas of tumor Pathology, Fascicle 21. Kontogeorgos, G. (2006). Predictive markers of pituitary adenoma behavior. *Neuroendocrinology* Vol.83, No.3-4, (Oct), pp.179–188, ISSN: 1423-0194. Laws, E.R.; Ebersold, M.J. & Piepgras DG. (1982).The results of transsphenoidal surgery in

microsurgery. New York, Appleton-Century-Crofts pp. 277-305.

Vol.13, No.4, (Dec), pp. 367-79, ISSN 1573-7403.

No.9, (Sept), pp. 3284-3285, ISSN 1945-7197.

Lau, Q.; Scheithauer, B.; Kovacs, K.; Horvath, E.; Syro, L.V. & Lloyd R. (2010). MGMT

Li-Ng, M. & Sharma M. (2008). Invasive pituitary adenoma*. J Clin Endocrinol Metab,* Vol.93,

*J of Endocrinol*, Vol.152, No.3, (Mar), pp.363–370, ISSN:1479-683X.

*Microsc Res Tech*, Vol.20, No.2, (Jan), pp. 107-35, ISSN 1097-0029.

PO, Ross GT. Excerpta Medica; pp. 179-98. Amsterdam.


**5** 

**Stereotactic Radiosurgery for** 

*University of Puerto Rico / Medical Sciences Campus/ Department of Surgery/* 

Stereotactic Radiosurgery (SRS) is a technology that utilizes externally generated ionizing radiation to treat (a) defined target(s) in the head or spine without the need to make an incision. The target is defined by high-resolution stereotactic imaging. It uses multiple convergent beams aimed to the target. The beams deliver a maximal dose to the target (with precision of less than 1mm), while minimizing irradiation of the surrounding tissues. The treatment is performed in a single session. The procedure requires a multidisciplinary team consisting of a neurosurgeon, radiation oncologist and medical physicist. Technologies that are used to perform SRS include linear accelerators, particle beam accelerators and multisource Cobalt 60 units. In order to enhance precision, various devices may incorporate robotics and real time digital imaging. (*Stereotactic Radiosurgery Task Force* 

"Stereotactic Radiosurgery" was invented by the Swedish neurosurgeon Lars Leksell in 1951. Since its introduction, stereotactic radiosurgery (SRS) has evolved from an investigational concept into a recognized neurosurgical procedure for the management of a wide variety of brain disorders. Currently, radiosurgery can be employed as an adjuvant or

The three major sources of radiation used today to perform SRS are the multi-source Cobalt 60 units, modified linear accelerators and the particle beam accelerators. These machines provide extremely accurate targeting and precise treatment for brain tumors. They treat brain tumors and other cerebral conditions in a one-day treatment. The original system is the Gamma Knife® System (GKS). Its clinical efficacy has been well documented, with more than 550,312 cases treated worldwide by December 2009 providing the data for over 2,500 publications in peer-reviewed medical literature. The GKS is ideal for tumors less than 3.5

The modified linear accelerator (m-LINAC) based radiosurgery machines are prevalent throughout the world. The modified linear accelerator systems use similar principles as the GKS to treat the patient, but the source of the radiation is a linear accelerator. Modified Linear accelerator-based radiosurgery generally utilizes a stereotactic head-frame, floorstand and a 6-megavolt (MV) linear accelerator. The linear accelerator systems utilize

**1. Introduction** 

*AANS/CNS/ASTRO, March 20, 2006)*.

definite treatment modality for pituitary adenomas.

cm, and functional disorders of the brain.

**Pituitary Adenomas** 

*Neurosurgery Section* 

*Puerto Rico* 

Ricardo H. Brau and David Lozada


## **Stereotactic Radiosurgery for Pituitary Adenomas**

Ricardo H. Brau and David Lozada

*University of Puerto Rico / Medical Sciences Campus/ Department of Surgery/ Neurosurgery Section Puerto Rico* 

#### **1. Introduction**

66 Pituitary Adenomas

Saeger, W.; Lüdecke, D.K.; Buchfelder, M.; Fahlbusch, R.; Quabbe, H-J. & Petersenn, S.

Sassolas, G.; Trouillas,J.; Treluyer, C.; Perrin,G. (1993). Management of non-functioning

Scheithauer B.W, Kovacs K.T, Laws Jr E.R, Randall R.V. (1986) Pathobiology of invasive

Scheithauer, B.W.; Fereidooni, F.; Horvath, E.; Kovacs, K.; Robbins, P.; Tews, D.; Henry, K.;

Scheithauer, B.W. ; Kurtkaya-Yapicier, O. ; Kovacs, K.T. ; Young, Jr. W.F. & Lloyd R.V.

Scheithauer, B.W.; Gaffey, T.A.; Lloyd, R.V.; Sebo, T.J.; Kovacs, K.T.; Horvath, E.; Yapicier,

Tena-Suck, M.L.; Salinas-Lara, C.; Sánchez-García, A.; Rembao-Bojórquez, D. & Ortiz-Plata

Tichomirowa, M.A.; Daly, A.F. & Beckers, A. (2009). Familial pituitary adenomas. *J Intern* 

Turner, H.E.; Stratton, I.M.; Byrne, J.V.; Adams, C.B. & Wass J.A. (1999). Audit of selected

Vandeva, S.; Jaffrain-Rea, M.L.; Daly, A.F.; Tichomirowa, M.; Zacharieva, S. & Beckers, A.

Yarman, S.; Kurtulmus, N.; Canbolat, A.; Bayindir, C.; Bilgic, B. & Ince, N. (2010). Expression

behavior ? *Neuro Endocrinol Lett*, Vol.31, No.6, pp. 823-828, ISSN 0172-780X. Yu R, Melmed S. (2010).Pathogenesis of pituitary tumors. *Prog Brain Res*, Vol.182, pp. 207-27,

Zada, G.; Woodmansee, W.W.; Ramkissoon, S.; Amadio, J.; Nose, V. & Laws E.R. (2011).

Zhao, D.; Tomono, Y. & Nose, T. (1999). Expression of P27, Kip 1 and Ki-67 in pituitary

*Neurosurg*, Vol. 114, No.2, (Feb), pp. 336-44, ISSN 1933-0693.

*(Wien)*, Vol.141, No.2, pp. 187-192, ISSN 0942-0940.

pituitary adenomas. Acta Endocrinol (Copenh), Vol.129, pp. 21-26.

(Feb), pp.203-216, ISSN 0804-4643.

(May), pp. 1066-1074, ISSN 1524-4040.

(Aug), pp. 341-353, ISSN 1524-4040.

(Dec), pp.798-807, ISSN 1423-0194.

1879-3339.

ISSN 1875-7855.

Vol.65, No.6, (Dec), pp. 733-744, ISSN 1933-0693.

*Med*, Vol.266, No.1, (Jul), pp. 5–18, ISSN 1365-2796.

Vol.24, No.3, (Jun), pp. 461-76, ISSN 1532-1908.

(2007). Pathohistological classification of pituitary tumors: 10 years of experience with the German pituitary tumor registry. *European J Endocrinol* Vol.156, No.2,

pituitary tumors with special reference to functional classification. *J Neurosurg*

Pernicone, P.; Gaffrey, T.A. Jr.; Meyer, F.B..; Young, W.F. Jr.; Fahlbusch, R.; Buchfelder, M. & Lloyd, R.V. (2001). Pituitary carcinoma: an ultrastructural study of eleven cases. *Ultrastruct Pathol*, Vol.25., No.3, (May-Jun), pp. 227-242., ISSN 1521-0758.

(2005). Pituitary carcinoma: a clinicopathologycal review. Neurosurg, Vol.56, No.5,

O.; Young, W.F. Jr.; Meyer, F.B.; Kuroki, T.; Riehle, D.L. & Laws, E.R Jr. (2006). Pathobiology of pituitary adenomas and carcinomas. *Neurosurgery*, Vol.59, No.2,

A. (2006). Late development of intraventricular papillary pituitary carcinoma after irradiation of prolactinoma. *Surgical Neurol*, Vol.66, No.5, (Nov), pp. 527-533, ISSN

patients with nonfunctioning pituitary adenomas treated without irradiation- a follow-up study. *Clin Endocrinol,* Vol.51, No.3, (Sep), pp.281-284, ISSN 1365-2265. Valassi, E.; Biller, B.M.; Klibanski, A. & Swearingen, B. (2010). Clinical features of non-

pituitary sellar lesions in a large surgical series. *Clin Endocrinol (Oxf)*, Vol.73, No.6,

(2010). The genetics of pituitary adenomas. *Best Pract Res Clin Endocrinol Metab*,

of Ki-67, p53 and vascular endothelial growth factor (VEGF) concomitantly in growth hormone-secreting pituitary adenomas; which one has a role in tumor

Atypical pituitary adenomas: incidence, clinical characteristics, and implications. *J* 

adenomas: An investigation of marker of adenoma invasiveness. *Acta Neurochir* 

Stereotactic Radiosurgery (SRS) is a technology that utilizes externally generated ionizing radiation to treat (a) defined target(s) in the head or spine without the need to make an incision. The target is defined by high-resolution stereotactic imaging. It uses multiple convergent beams aimed to the target. The beams deliver a maximal dose to the target (with precision of less than 1mm), while minimizing irradiation of the surrounding tissues. The treatment is performed in a single session. The procedure requires a multidisciplinary team consisting of a neurosurgeon, radiation oncologist and medical physicist. Technologies that are used to perform SRS include linear accelerators, particle beam accelerators and multisource Cobalt 60 units. In order to enhance precision, various devices may incorporate robotics and real time digital imaging. (*Stereotactic Radiosurgery Task Force AANS/CNS/ASTRO, March 20, 2006)*.

"Stereotactic Radiosurgery" was invented by the Swedish neurosurgeon Lars Leksell in 1951. Since its introduction, stereotactic radiosurgery (SRS) has evolved from an investigational concept into a recognized neurosurgical procedure for the management of a wide variety of brain disorders. Currently, radiosurgery can be employed as an adjuvant or definite treatment modality for pituitary adenomas.

The three major sources of radiation used today to perform SRS are the multi-source Cobalt 60 units, modified linear accelerators and the particle beam accelerators. These machines provide extremely accurate targeting and precise treatment for brain tumors. They treat brain tumors and other cerebral conditions in a one-day treatment. The original system is the Gamma Knife® System (GKS). Its clinical efficacy has been well documented, with more than 550,312 cases treated worldwide by December 2009 providing the data for over 2,500 publications in peer-reviewed medical literature. The GKS is ideal for tumors less than 3.5 cm, and functional disorders of the brain.

The modified linear accelerator (m-LINAC) based radiosurgery machines are prevalent throughout the world. The modified linear accelerator systems use similar principles as the GKS to treat the patient, but the source of the radiation is a linear accelerator. Modified Linear accelerator-based radiosurgery generally utilizes a stereotactic head-frame, floorstand and a 6-megavolt (MV) linear accelerator. The linear accelerator systems utilize

Stereotactic Radiosurgery for Pituitary Adenomas 69

irreparable damage to DNA, proteins, membranes, and lipids that can evolve into the cell's

Radiation damages the cell's structures of tumor cells as well of normal cells in the radiation beam path. Normal tissue, however, is generally more proficient repairing sublethal damage than tumors cells. In general terms, tumors cells have altered repair mechanisms tolerating less irradiation damage than normal cells. Cells require time to repair DNA damage and one of the normal responses of the cell is delaying the cell cycle, delaying G2 phase. In radiotherapy where daily treatments with sublethal doses of radiation are given for several days, the difference in proficiency to repair the damage between normal and tumoral tissues is essential. Therefore, the radiobiology of the cell cycle and differences in cell repair are of great importance for fractionated radiotherapy. In radiosurgery, were a lethal dose of radiation is given in a single treatment, the repairing capacity of different tissues play a less critical role. Radiosurgery in many instances activates the apoptosis cascade resulting in cell death. The rate of proliferation of cells can determine the response to radiation, resulting in increased sensitivity of endothelial, glial and subependymal cells. Vascular endothelial cell damage tends to produce vessels obliteration that could play a role in the death of tumor

The radiation doses prescribed for radiotherapy have been developed from decades of clinical experience. However, the radiobiological principles of multifraction treatments do not necessarily apply to high dose ionizing beams as used in radiosurgery. Radiosurgery specifies a precise delivery of a high single fraction dose of ionizing beams to a defined

death. The radiation effects can be seen in the order of minutes to years (Figure 1).

Fig. 1. Effects of Ionizing radiation over time.

cells as well.

radiation beams that are redirected in many "arcs" centered over an isocenter to lessen the adverse effects on healthy tissue. These machines can perform radiosurgery on tumors smaller than 3.5cm in diameter with the same range of precision of the GKS. Most of the GKS and m-LINAC systems employ a stereotactic head frame (ring). The head frame allows a precise localization of the lesion to be treated. The head frame, which is attached to the skull with four small screws, ensures that the radiation beams are precisely targeted. The frame also prevents head motion during the treatment procedure, which ensures that only the target area receives the prescribed radiation. However, modern localization techniques using bony landmarks identified by diagnostic X-Rays system has allowed some systems of m-LINAC to avoid the use of the stereotactic head frame. One of the advantages of these systems is that patients can be treated over more than one day without the need of wearing a head frame over extended periods of time, and in a few special situations can treat tumors slightly larger than 3.5 cm in diameter with this hypofractionating technique. Another advantage of the m-LINAC system is that they can use Intensity-Modulated Radiation Therapy (IMRT) and Image Guided Radiotherapy (IGRT) dosimetries algorithms to treat critically located lesions. In IMRT, the intensity of the radiation beam is non-uniform (i.e., modulated) across the treatment field, rather than producing a single, uniform, intensity beam. When combining this technique with the imaging done in the pre-plan, it further improves the delivery of radiation. These systems can provide treatment to lesions outside the brain.

A special type of m-LINAC is the CyberKnife® Robotic Radiosurgery System. It utilizes a 6 MV compact linear accelerator mounted on a computer-controlled six-axis robotic manipulator that permits a wide range of beam orientations and takes advantage of intelligent robotics to enable the effective treatment of tumors in the brain and anywhere in the body. To date, an estimated over 80,000 patients have been treated with the CyberKnife® System and currently more than 50 percent of all CyberKnife® procedures in the United States are extra cranial.

The proton beam radiosurgery systems employ a stream of protons to treat lesions. As of June 2011, there were a total of 37 proton therapy centers in Canada, China, England, France, Germany, Italy, Japan, Korea, Poland, Russia, South Africa, Sweden, Switzerland, and USA and more than 73,800 patients had been treated (Particle Therapy Co-Operative Group, 2011). One hindrance to universal use of the proton in cancer treatment is the size and cost of the cyclotron or synchrotron equipment necessary to produce the protons.

The authors have used a modified linear accelerator-based system to provide radiosurgery treatment to pituitary adenomas. The initial radiosurgery system installed in 1999 was manufactured by Radionics®. In 2003 this system was upgraded to a Brain Lab System® that incorporated a multileaf collimator.

#### **2. The radiobiology of radiosurgery**

The basic principle of ionizing radiation is the creation of ions or free radicals in the irradiated tissues. This ions or free radicals interact with the cell's molecules producing damage to them. The radiation dose is usually measured in grays, where one gray (Gy) is the absorption of one joule per kilogram of mass. These ions and radicals, which may be formed from the water and oxygen in the cell or from the tissue substance, can produce

radiation beams that are redirected in many "arcs" centered over an isocenter to lessen the adverse effects on healthy tissue. These machines can perform radiosurgery on tumors smaller than 3.5cm in diameter with the same range of precision of the GKS. Most of the GKS and m-LINAC systems employ a stereotactic head frame (ring). The head frame allows a precise localization of the lesion to be treated. The head frame, which is attached to the skull with four small screws, ensures that the radiation beams are precisely targeted. The frame also prevents head motion during the treatment procedure, which ensures that only the target area receives the prescribed radiation. However, modern localization techniques using bony landmarks identified by diagnostic X-Rays system has allowed some systems of m-LINAC to avoid the use of the stereotactic head frame. One of the advantages of these systems is that patients can be treated over more than one day without the need of wearing a head frame over extended periods of time, and in a few special situations can treat tumors slightly larger than 3.5 cm in diameter with this hypofractionating technique. Another advantage of the m-LINAC system is that they can use Intensity-Modulated Radiation Therapy (IMRT) and Image Guided Radiotherapy (IGRT) dosimetries algorithms to treat critically located lesions. In IMRT, the intensity of the radiation beam is non-uniform (i.e., modulated) across the treatment field, rather than producing a single, uniform, intensity beam. When combining this technique with the imaging done in the pre-plan, it further improves the delivery of radiation. These systems can provide treatment to lesions outside

A special type of m-LINAC is the CyberKnife® Robotic Radiosurgery System. It utilizes a 6 MV compact linear accelerator mounted on a computer-controlled six-axis robotic manipulator that permits a wide range of beam orientations and takes advantage of intelligent robotics to enable the effective treatment of tumors in the brain and anywhere in the body. To date, an estimated over 80,000 patients have been treated with the CyberKnife® System and currently more than 50 percent of all CyberKnife® procedures in

The proton beam radiosurgery systems employ a stream of protons to treat lesions. As of June 2011, there were a total of 37 proton therapy centers in Canada, China, England, France, Germany, Italy, Japan, Korea, Poland, Russia, South Africa, Sweden, Switzerland, and USA and more than 73,800 patients had been treated (Particle Therapy Co-Operative Group, 2011). One hindrance to universal use of the proton in cancer treatment is the size and cost of the cyclotron or synchrotron equipment necessary to produce the protons.

The authors have used a modified linear accelerator-based system to provide radiosurgery treatment to pituitary adenomas. The initial radiosurgery system installed in 1999 was manufactured by Radionics®. In 2003 this system was upgraded to a Brain Lab System®

The basic principle of ionizing radiation is the creation of ions or free radicals in the irradiated tissues. This ions or free radicals interact with the cell's molecules producing damage to them. The radiation dose is usually measured in grays, where one gray (Gy) is the absorption of one joule per kilogram of mass. These ions and radicals, which may be formed from the water and oxygen in the cell or from the tissue substance, can produce

the brain.

the United States are extra cranial.

that incorporated a multileaf collimator.

**2. The radiobiology of radiosurgery** 

irreparable damage to DNA, proteins, membranes, and lipids that can evolve into the cell's death. The radiation effects can be seen in the order of minutes to years (Figure 1).

Fig. 1. Effects of Ionizing radiation over time.

Radiation damages the cell's structures of tumor cells as well of normal cells in the radiation beam path. Normal tissue, however, is generally more proficient repairing sublethal damage than tumors cells. In general terms, tumors cells have altered repair mechanisms tolerating less irradiation damage than normal cells. Cells require time to repair DNA damage and one of the normal responses of the cell is delaying the cell cycle, delaying G2 phase. In radiotherapy where daily treatments with sublethal doses of radiation are given for several days, the difference in proficiency to repair the damage between normal and tumoral tissues is essential. Therefore, the radiobiology of the cell cycle and differences in cell repair are of great importance for fractionated radiotherapy. In radiosurgery, were a lethal dose of radiation is given in a single treatment, the repairing capacity of different tissues play a less critical role. Radiosurgery in many instances activates the apoptosis cascade resulting in cell death. The rate of proliferation of cells can determine the response to radiation, resulting in increased sensitivity of endothelial, glial and subependymal cells. Vascular endothelial cell damage tends to produce vessels obliteration that could play a role in the death of tumor cells as well.

The radiation doses prescribed for radiotherapy have been developed from decades of clinical experience. However, the radiobiological principles of multifraction treatments do not necessarily apply to high dose ionizing beams as used in radiosurgery. Radiosurgery specifies a precise delivery of a high single fraction dose of ionizing beams to a defined

Stereotactic Radiosurgery for Pituitary Adenomas 71

reserved for tumor residuals or recurrences. For tumors that cannot be removed completely depending on the size, location, and invasiveness of surrounding tissues by the tumor, one surgical goal could be to create a safe distance of 2 to 5 mm between the lesion and optic apparatus so that an adequate radiosurgery dose can be delivered to the adenoma with

**Hormone Test Results and Additional Evaluations** 

function Serum Levels Elevated prolactin, usually with serum

Patients harboring secretory pituitary tumors warrant a special consideration regarding radiosurgery pre-planning. Since 2000, several studies have documented that cessation of suppressive medication before radiosurgery is recommended to offer the best normalization of hormone values after the treatment (Landolt 2000a, 2000b; Pouratian et al., 2006; Pollock et al., 2007). The optimal time period to temporarily halt anti-secretory medications is unclear and class I evidence is sill unavailable to support temporary cessation of

When medical and surgical treatments are not curative or cannot control the tumor growth or symptoms, radiosurgery needs to be considered. Prior to considering radiosurgery, the neurosurgeon and the radiation oncologist of the radiosurgery team evaluate the patient, both need to agree that radiosurgery is an optimal option. Then, the patient is scheduled for the procedure. On the day of the treatment or the day before, a MR study is obtained, with 3 mm thick slices of the brain including the sella and skull base. On the day of treatment a stereotactic head frame is applied under local anesthesia and/or IV sedation. Subsequently, stereotactic CT scanning is performed with the CT scan localizer on. Three-millimeter thick slices are obtained throughout the entire head. The stereotactic CT scan and MR images are transferred to the treatment-planning computer. The CT scan and MR images are fused electronically. The tumor, optic apparatus and critical surrounding structures are delineated in the planning computer. (Figure 2) The plan is carefully examined and adjusted to generate the actual treatment plan, maximizing the dose delivery to the tumor and

The radiation oncologist and the neurosurgeon review and approve the plan. Four or more sagittally oriented irradiation arcs are typically delivered using multileaf collimators. The

minimizing irradiation of the optic apparatus and the surrounding tissues.

levels > 75 ng/ml

In Cushing's syndrome, a 24 h urine free cortisol and a dexamethasone suppression test.

Oral glucose tolerance test with growth hormone measurements for GH secreting tumors.

minimal risk of radiation injury to the optic pathways.

Free thyroxine and thyroid stimulating hormone

Morning fasting and afternoon serum cortisol and ACTH level. Salivary cortisol levels.

Growth hormone and insulin-like growth factor (IGF)-1.

Table 1. Minimal basic endocrine workup for pituitary adenomas.

antisecretory medications as a standard of care.

**5. Radiosurgery procedure** 

Prolactin

Thyroid function

Adrenal function

Growth Hormone (GH)

target volume. Normal tissue is excluded from the target as much as possible and a steep dose gradient at the margin of the target volume assures that the surrounding tissue receives a minimal dosage. Therefore, repair capacity of normal tissue during treatment is less critical in radiosurgery.

#### **3. Pituitary adenomas**

Pituitary adenomas represent nearly 10-20% of all intracranial tumors. Multimodal treatment includes microsurgery, medical management, radiotherapy and radiosurgery. Pituitary adenomas are broadly classified into two groups—functioning (secretory) and nonfunctioning. Microsurgery is the primary recommendation for nonfunctioning and most of functioning adenomas, except for prolactinomas that are usually managed with dopamine agonist drugs. Long-term tumor control rates after microsurgery alone range from 50 to 80%. For both functioning and nonfunctioning pituitary adenomas, incomplete tumor resection or recurrence because of tumor invasion into surrounding structures (for example, the dura mater or cavernous sinus) is common. Postsurgical residual secretory adenoma results in the persistence of a hypersecretory state and the associated deleterious clinical features. Moreover, about 30% of patients require additional treatment after microsurgery for recurrent or residual tumors. In patients with recurrent or residual pituitary adenomas, treatment options include repeat resection, radiation therapy, medical management, and radiosurgery. More recently, radiosurgery has been established as a treatment option. Radiosurgery allows the delivery of prescribed dose with high precision strictly to the target and spares the surrounding tissues. Therefore, the risks of hypopituitarism, visual damage and vasculopathy are significantly lower. Furthermore, the latency of the radiation response after radiosurgery is substantially shorter than that of fractionated radiotherapy.

#### **4. Planning and technique**

All patients suspected of harboring a pituitary tumor should undergo a complete neurologic, ophthalmologic, endocrinologic, and radiologic work-up (Laws & Sheehan, 2006; Laws & Thapar 1996). This includes formal visual fields, an acuity testing and a detailed fundoscopic examination. Each facet of the hypothalamic-pituitary-end organ axis should be assessed by an endocrinologist and re-assessed by the neurosurgeon. (Table 1)

Evaluation of the sellar region is best accomplished by using a thin slice pre- and postcontrast magnetic resonance (MR) imaging. When there is a contraindication to MR or is not available, a computed tomography (CT) imaging can be useful (Jagannathan et al., 2005; Kanter et al., 2005).

If a patient has a neurological deficit attributable to an adenoma, surgery is the initial treatment of choice for all tumors except prolactinomas. Transsphenoidal microsurgery (endoscopic or microscopic) affords the best chance of rapid relief of mass effect and reduction in excessive hormone levels in patients with Cushing's disease and acromegaly (Laws & Sheehan, 2006; Laws & Thapar 1996; Laws et al., 1985a, 1985b, 2000). This approach is associated with a low rate of complications in the hands of experienced neurosurgeons (Ciric, 1997). For this reason, tumors located in areas such as the sellar floor or sphenoid that can be safely accessed surgically should undergo surgical removal, with radiosurgery being

target volume. Normal tissue is excluded from the target as much as possible and a steep dose gradient at the margin of the target volume assures that the surrounding tissue receives a minimal dosage. Therefore, repair capacity of normal tissue during treatment is

Pituitary adenomas represent nearly 10-20% of all intracranial tumors. Multimodal treatment includes microsurgery, medical management, radiotherapy and radiosurgery. Pituitary adenomas are broadly classified into two groups—functioning (secretory) and nonfunctioning. Microsurgery is the primary recommendation for nonfunctioning and most of functioning adenomas, except for prolactinomas that are usually managed with dopamine agonist drugs. Long-term tumor control rates after microsurgery alone range from 50 to 80%. For both functioning and nonfunctioning pituitary adenomas, incomplete tumor resection or recurrence because of tumor invasion into surrounding structures (for example, the dura mater or cavernous sinus) is common. Postsurgical residual secretory adenoma results in the persistence of a hypersecretory state and the associated deleterious clinical features. Moreover, about 30% of patients require additional treatment after microsurgery for recurrent or residual tumors. In patients with recurrent or residual pituitary adenomas, treatment options include repeat resection, radiation therapy, medical management, and radiosurgery. More recently, radiosurgery has been established as a treatment option. Radiosurgery allows the delivery of prescribed dose with high precision strictly to the target and spares the surrounding tissues. Therefore, the risks of hypopituitarism, visual damage and vasculopathy are significantly lower. Furthermore, the latency of the radiation response after radiosurgery is substantially shorter than that of

All patients suspected of harboring a pituitary tumor should undergo a complete neurologic, ophthalmologic, endocrinologic, and radiologic work-up (Laws & Sheehan, 2006; Laws & Thapar 1996). This includes formal visual fields, an acuity testing and a detailed fundoscopic examination. Each facet of the hypothalamic-pituitary-end organ axis should be assessed by an endocrinologist and re-assessed by the neurosurgeon. (Table 1)

Evaluation of the sellar region is best accomplished by using a thin slice pre- and postcontrast magnetic resonance (MR) imaging. When there is a contraindication to MR or is not available, a computed tomography (CT) imaging can be useful (Jagannathan et al., 2005;

If a patient has a neurological deficit attributable to an adenoma, surgery is the initial treatment of choice for all tumors except prolactinomas. Transsphenoidal microsurgery (endoscopic or microscopic) affords the best chance of rapid relief of mass effect and reduction in excessive hormone levels in patients with Cushing's disease and acromegaly (Laws & Sheehan, 2006; Laws & Thapar 1996; Laws et al., 1985a, 1985b, 2000). This approach is associated with a low rate of complications in the hands of experienced neurosurgeons (Ciric, 1997). For this reason, tumors located in areas such as the sellar floor or sphenoid that can be safely accessed surgically should undergo surgical removal, with radiosurgery being

less critical in radiosurgery.

**3. Pituitary adenomas** 

fractionated radiotherapy.

Kanter et al., 2005).

**4. Planning and technique** 

reserved for tumor residuals or recurrences. For tumors that cannot be removed completely depending on the size, location, and invasiveness of surrounding tissues by the tumor, one surgical goal could be to create a safe distance of 2 to 5 mm between the lesion and optic apparatus so that an adequate radiosurgery dose can be delivered to the adenoma with minimal risk of radiation injury to the optic pathways.


Table 1. Minimal basic endocrine workup for pituitary adenomas.

Patients harboring secretory pituitary tumors warrant a special consideration regarding radiosurgery pre-planning. Since 2000, several studies have documented that cessation of suppressive medication before radiosurgery is recommended to offer the best normalization of hormone values after the treatment (Landolt 2000a, 2000b; Pouratian et al., 2006; Pollock et al., 2007). The optimal time period to temporarily halt anti-secretory medications is unclear and class I evidence is sill unavailable to support temporary cessation of antisecretory medications as a standard of care.

#### **5. Radiosurgery procedure**

When medical and surgical treatments are not curative or cannot control the tumor growth or symptoms, radiosurgery needs to be considered. Prior to considering radiosurgery, the neurosurgeon and the radiation oncologist of the radiosurgery team evaluate the patient, both need to agree that radiosurgery is an optimal option. Then, the patient is scheduled for the procedure. On the day of the treatment or the day before, a MR study is obtained, with 3 mm thick slices of the brain including the sella and skull base. On the day of treatment a stereotactic head frame is applied under local anesthesia and/or IV sedation. Subsequently, stereotactic CT scanning is performed with the CT scan localizer on. Three-millimeter thick slices are obtained throughout the entire head. The stereotactic CT scan and MR images are transferred to the treatment-planning computer. The CT scan and MR images are fused electronically. The tumor, optic apparatus and critical surrounding structures are delineated in the planning computer. (Figure 2) The plan is carefully examined and adjusted to generate the actual treatment plan, maximizing the dose delivery to the tumor and minimizing irradiation of the optic apparatus and the surrounding tissues.

The radiation oncologist and the neurosurgeon review and approve the plan. Four or more sagittally oriented irradiation arcs are typically delivered using multileaf collimators. The

Stereotactic Radiosurgery for Pituitary Adenomas 73

toxicity of fractionated external beam radiotherapy is low; with 1.5% risk of radiation optic neuropathy (Brada et al., 1993; Tsang et al*.*, 1994) and 0.2% risk of necrosis of normal brain structures (Becker et al*.*, 2002). The most frequent late consequence of radiation is hypopituitarism likely to be primarily due to hypothalamic injury or primary pituitary gland injury. In patients with normal pituitary function around the time of radiotherapy, hormone replacement therapy is required in 20–40% of patients at 10 years. A rare late effect of radiation for pituitary adenoma is the development of second radiation-induced brain tumor. The reported frequency is in the region of 2% at 10–20 years (Brada et al., 1992; Tsang et al., 1993; Erfurth et al., 2001). Although there is an increased incidence of cerebrovascular accidents and excess cerebrovascular mortality in patients with pituitary adenoma treated with radiation, the influence of radiation on its frequency is not well

The radiation effects on the optic apparatus, other cranial nerves and brainstem are of critical importance. Most of the damage is thought to be a result of secondary damage of the endothelium of small vessels and protective Schwann cells or oligodendroglia. There is a difference in the tolerance of different cranial nerves; with sensory nerves (optic and acoustic) tolerating the least radiation. The nerves in the parasellar region, the facial nerves and the lower cranial nerves usually tolerate higher doses. Clinical experience suggests that these specialized sensory nerves do not show a great capacity to recover from injury. Although the precise dose tolerance of the cranial nerves is unclear, the anterior visual pathways seem to be the least radio-resistant, and single doses above 8 Gy should be avoided (Jagannathan et al., 2007; Leber et al., 1995, 1998). To minimize the risk of irradiation injuries to the optic apparatus, the distance between optic nerves and chiasm and the lesion being treated should be carefully assessed. A distance of 5 mm between the tumor and the optic apparatus is ideal, but a distance of as little as 2 mm may be acceptable. It appears that the risk may be related to the volume of the optic apparatus receiving the dose (Chen et al., 2001; Lim et al., 1998; Sheehan et al., 2000; Witt et al., 1998). However, a specific critical volume has not been agreed. This distance is critical to design a dose plan that delivers a lethal radiation dose to the tumor yet spare the optic apparatus. When all these

defined (Brada et al., 1999, 2002; Tomlinson et al*.*, 2001; Erfurth et al., 2002).

precautions and considerations are taken care the patient is treated accordingly.

The goals of radiosurgery for pituitary tumors are control of tumor growth, and in secretory adenomas to normalize hormonal hypersecretion. In addition to the above mention, these goals need to be carried out avoiding acute and delay radiation injury to neural structures

In our experience of twelve patients treated for nonfunctioning pituitary tumors (with mean follow-up of 47 months), tumor volume decreased in three patients (25%), remained unchanged in eight (66%), and there was no increased in size. One patient was lost to follow-up. Regarding tumor control, eleven patients achieved tumor control (91%) except for the patient who was lost to follow-up. All of our patients were treated with LINAC Radiosurgery as secondary therapy. The average prescription peripheral dose (Gy) was 15.8Gy with a range from 8 to 22.5Gy. This is similar to previously published data. The

**7. Radiosurgery for pituitary adenomas** 

and preventing secondary tumor formation.

**7.1 Non-secreting tumors** 

multileaf collimator is adjusted every 15 degrees to achieve a conformal treatment to the lesion. The head ring is removed on the same day of treatment. After a short observation period, the patient is discharged. Close clinical and radiological neuroimaging follow-up examination is arranged at appropriate intervals depending on the entity treated and the condition of the patient.

Fig. 2. Radiosurgical planning which includes protection of important structures and inclusion of treatment area.

#### **6. Toxicity and side effects**

Like any other medical intervention radiosurgery has side effects. The main concern is radionecrosis of structures adjacent to the pituitary gland; optic apparatus, cranial nerves within the cavernous sinus, hypothalamus, brainstem and medial temporal lobes. The

multileaf collimator is adjusted every 15 degrees to achieve a conformal treatment to the lesion. The head ring is removed on the same day of treatment. After a short observation period, the patient is discharged. Close clinical and radiological neuroimaging follow-up examination is arranged at appropriate intervals depending on the entity treated and the

Fig. 2. Radiosurgical planning which includes protection of important structures and

Like any other medical intervention radiosurgery has side effects. The main concern is radionecrosis of structures adjacent to the pituitary gland; optic apparatus, cranial nerves within the cavernous sinus, hypothalamus, brainstem and medial temporal lobes. The

condition of the patient.

inclusion of treatment area.

**6. Toxicity and side effects** 

toxicity of fractionated external beam radiotherapy is low; with 1.5% risk of radiation optic neuropathy (Brada et al., 1993; Tsang et al*.*, 1994) and 0.2% risk of necrosis of normal brain structures (Becker et al*.*, 2002). The most frequent late consequence of radiation is hypopituitarism likely to be primarily due to hypothalamic injury or primary pituitary gland injury. In patients with normal pituitary function around the time of radiotherapy, hormone replacement therapy is required in 20–40% of patients at 10 years. A rare late effect of radiation for pituitary adenoma is the development of second radiation-induced brain tumor. The reported frequency is in the region of 2% at 10–20 years (Brada et al., 1992; Tsang et al., 1993; Erfurth et al., 2001). Although there is an increased incidence of cerebrovascular accidents and excess cerebrovascular mortality in patients with pituitary adenoma treated with radiation, the influence of radiation on its frequency is not well defined (Brada et al., 1999, 2002; Tomlinson et al*.*, 2001; Erfurth et al., 2002).

The radiation effects on the optic apparatus, other cranial nerves and brainstem are of critical importance. Most of the damage is thought to be a result of secondary damage of the endothelium of small vessels and protective Schwann cells or oligodendroglia. There is a difference in the tolerance of different cranial nerves; with sensory nerves (optic and acoustic) tolerating the least radiation. The nerves in the parasellar region, the facial nerves and the lower cranial nerves usually tolerate higher doses. Clinical experience suggests that these specialized sensory nerves do not show a great capacity to recover from injury. Although the precise dose tolerance of the cranial nerves is unclear, the anterior visual pathways seem to be the least radio-resistant, and single doses above 8 Gy should be avoided (Jagannathan et al., 2007; Leber et al., 1995, 1998). To minimize the risk of irradiation injuries to the optic apparatus, the distance between optic nerves and chiasm and the lesion being treated should be carefully assessed. A distance of 5 mm between the tumor and the optic apparatus is ideal, but a distance of as little as 2 mm may be acceptable. It appears that the risk may be related to the volume of the optic apparatus receiving the dose (Chen et al., 2001; Lim et al., 1998; Sheehan et al., 2000; Witt et al., 1998). However, a specific critical volume has not been agreed. This distance is critical to design a dose plan that delivers a lethal radiation dose to the tumor yet spare the optic apparatus. When all these precautions and considerations are taken care the patient is treated accordingly.

#### **7. Radiosurgery for pituitary adenomas**

The goals of radiosurgery for pituitary tumors are control of tumor growth, and in secretory adenomas to normalize hormonal hypersecretion. In addition to the above mention, these goals need to be carried out avoiding acute and delay radiation injury to neural structures and preventing secondary tumor formation.

#### **7.1 Non-secreting tumors**

In our experience of twelve patients treated for nonfunctioning pituitary tumors (with mean follow-up of 47 months), tumor volume decreased in three patients (25%), remained unchanged in eight (66%), and there was no increased in size. One patient was lost to follow-up. Regarding tumor control, eleven patients achieved tumor control (91%) except for the patient who was lost to follow-up. All of our patients were treated with LINAC Radiosurgery as secondary therapy. The average prescription peripheral dose (Gy) was 15.8Gy with a range from 8 to 22.5Gy. This is similar to previously published data. The

Stereotactic Radiosurgery for Pituitary Adenomas 75

Most published results on radiosurgery for secretory adenomas have differed based on methodology, endocrine criteria for remission, the study population and length of followup. Most series typically report a higher prescription (margin) dose to patients with functioning adenomas, with a range between 20 Gy and 25 Gy in most reports (Jagannathan et al., 2007; Kim et al., 1999a, 1999b; Pouratian et al., 2006). Because hormone normalization has been followed in some cases by relapse, we prefer the term ''remission'' to ''cure.''

In our experience of fifteen patients treated for acromegaly (with mean follow-up of 37.2 months), tumor volume decreased in five patients (33.3%), remained unchanged in nine (60%), and there was one (6.6%) patient that showed an increase in tumor size. Tumor control was achieved in fourteen (93.3%) patients. All of our patients were treated with LINAC Radiosurgery as secondary therapy. The average prescription peripheral dose (Gy) was 19.4Gy with a range from 12 to 25Gy. In our experience, the rate of hormone normalization after radiosurgery for Acromegaly was seen in six (41.6%) patients. Hormone normalization in these five patients was observed at mean follow-up of 28 months. Tumor control was achieved in most patients correlating with hormone remission, except for one

patient, which despite hormone remission there was a slight increase in tumor size.

when matched for age [Giustina et al., 2000; Vance, 1998).

**Unit Pt No F/U** 

**(mos)** 

The most widely accepted guidelines for endocrine remission in acromegaly consist of a GH level less than 1 ng/ml in response to an oral glucose challenge and a normal serum IGF-1

Published remission rates following radiosurgery for acromegaly vary widely from 0% to 100%, with the majority of patients achieving tumor growth control (Table 3) (Buchfelder et al., 1991; Cozzi et al., 2001; Freda, 2003; Fukuoka et al., 2001; Horvath et al., 1983; Landolt et al., 1998, 2000; Pouratian et al., 2006; Witt et al., 1998). Jezkova et al. reported a remission rate of 50% at 42 months follow-up in 96 patients with acromegaly who received

> **Peripheral Dose (Gy)**

<sup>2003</sup>LINAC 4 30 15 50 100 Attanasio 2003 GK 30 46 20 23 100 Castinetti 2005 GK 82 49.5 12-40 40 NR Voges 2006 LINAC 64 54.3 15.3 49.8 97 Jezkova 2007 GK 96 53.7 32 50 100 Pollock 2007 GK 46 63 20 50 100 Vik-Mo 2007 GK 53 66 26.5 58 89 Losa 2008 GK 83 69 21.5 60.2 98

<sup>2008</sup>GK 95 57 22 53 98 Brau 2011\* LINAC 15 37.2 19.4 41.6 93.3

Table 3. Summary of cases treated with Radiosurgery for Acromegaly. (\*Unpublished

**IGF-1 Normalization (%)** 

**Tumor Control (%)** 

**7.2 Secretory tumors** 

**7.2.1 Acromegaly** 

**Author and Year RSx** 

Muramatsu,

Jagannathan

manuscript in writing)

median time of tumor shrinkage on MR-imaging was 12 months (range, 8-68 months) following radiosurgery. This is consistent with a recently published series that demonstrated pituitary adenomas were 90%, 80%, and 70% of their initial volume at 1, 2, and 3 years post-GK radiosurgery (Sheehan et al., 2002). Tumors involving the parasellar space require special consideration, as they would be otherwise untreatable.

Most other contemporary series involving stereotactic radiosurgery for non-functioning tumors (Table 2) have demonstrated excellent control of tumor growth, with a mean tumor control rate of 95.6% (range, 87%–100%) (Hayashi et al., 1999; Losa et al., 2004; Mitsumori et al., 1998; Morky et al., 1999; Muramatsu et al., 2003; Pollock & Carpenter, 2003; Pollock et al., 2008; Sheehan et al., 2002; Witt et al., 1998;).

In patients with four or more years of follow-up, the reported mean control rate is 95% (range, 83–100%) (Yoon et al., 1998; Morky et al., 1999; Feigl et al., 2002; Hoybye et al., 2001; Ikeda et al., 2001; Kobayashi et al., 2002; Shin et al., 2000; Wowra et al., 2002). Some series have even demonstrated improvement in visual function following radiosurgery after shrinkage of the tumor (Abe et al., 2002; Chen et al., 2001; Hayashi et al., 2005; Yoon et al., 1998). Nevertheless, prevention of tumor growth, without volume reduction, is still considered a radiosurgical goal.

The CyberKnife (Accuray, Calif., USA), is a newer radiosurgical device that is mounted on a maneuverable robotic manipulator and tracks the target with the aid of real-time guidance (Adler et al., 1997; Chang et al., 1998). Early experience with the Cyberknife has been promising for nonfunctioning adenomas, with a growth control rate of 95%, and lower prescription doses (14–16 Gy) than described for the Gamma Knife, although long-term clinical follow-up is still lacking (Kajiwara et al., 2005).


Table 2. Summary of cases treated with Radiosurgery on Non-functioning pituitary adenomas. (\*Unpublished manuscript in writing)

#### **7.2 Secretory tumors**

74 Pituitary Adenomas

median time of tumor shrinkage on MR-imaging was 12 months (range, 8-68 months) following radiosurgery. This is consistent with a recently published series that demonstrated pituitary adenomas were 90%, 80%, and 70% of their initial volume at 1, 2, and 3 years post-GK radiosurgery (Sheehan et al., 2002). Tumors involving the parasellar

Most other contemporary series involving stereotactic radiosurgery for non-functioning tumors (Table 2) have demonstrated excellent control of tumor growth, with a mean tumor control rate of 95.6% (range, 87%–100%) (Hayashi et al., 1999; Losa et al., 2004; Mitsumori et al., 1998; Morky et al., 1999; Muramatsu et al., 2003; Pollock & Carpenter, 2003; Pollock et al.,

In patients with four or more years of follow-up, the reported mean control rate is 95% (range, 83–100%) (Yoon et al., 1998; Morky et al., 1999; Feigl et al., 2002; Hoybye et al., 2001; Ikeda et al., 2001; Kobayashi et al., 2002; Shin et al., 2000; Wowra et al., 2002). Some series have even demonstrated improvement in visual function following radiosurgery after shrinkage of the tumor (Abe et al., 2002; Chen et al., 2001; Hayashi et al., 2005; Yoon et al., 1998). Nevertheless, prevention of tumor growth, without volume reduction, is still

The CyberKnife (Accuray, Calif., USA), is a newer radiosurgical device that is mounted on a maneuverable robotic manipulator and tracks the target with the aid of real-time guidance (Adler et al., 1997; Chang et al., 1998). Early experience with the Cyberknife has been promising for nonfunctioning adenomas, with a growth control rate of 95%, and lower prescription doses (14–16 Gy) than described for the Gamma Knife, although long-term

> **No. of Patients**

Mitsumori, et al., 1998 LINAC 7 47 19 15 100 Witt, et al., 1998 GK 24 32 38 19 94 Yoon, et al., 1998 LINAC 8 49 21 17 96 Hayashi, et al., 1999 GK 18 16 NR 20 92 Mokry, et al., 1999 GK 31 21 28 14 98 Sheehan, et al., 2002 GK 42 31 32 16 98

<sup>2003</sup>LINAC 8 30 26.9 15 100

<sup>2003</sup>GK 33 43 36 16 97 Losa, et al., 2004 GK 54 41 33 17 96 Iwai 2004 GK 34 60 14 87 Mingione 2006 GK 90 45 18.5 92 Pollock 2008 GK 62 45 16 97 Brau 2011\* LINAC 12 47 21.7 15.8 91

Table 2. Summary of cases treated with Radiosurgery on Non-functioning pituitary

**Mean/Median FU (months)**

**Max Dose (Gy)**

**Tumor Margin Dose(Gy)**  **Growth Control (%)** 

space require special consideration, as they would be otherwise untreatable.

2008; Sheehan et al., 2002; Witt et al., 1998;).

clinical follow-up is still lacking (Kajiwara et al., 2005).

adenomas. (\*Unpublished manuscript in writing)

**Unit** 

**Authors and Year Radiosurgery** 

Muramatsu, et al.,

Pollock & Carpenter,

considered a radiosurgical goal.

Most published results on radiosurgery for secretory adenomas have differed based on methodology, endocrine criteria for remission, the study population and length of followup. Most series typically report a higher prescription (margin) dose to patients with functioning adenomas, with a range between 20 Gy and 25 Gy in most reports (Jagannathan et al., 2007; Kim et al., 1999a, 1999b; Pouratian et al., 2006). Because hormone normalization has been followed in some cases by relapse, we prefer the term ''remission'' to ''cure.''

#### **7.2.1 Acromegaly**

In our experience of fifteen patients treated for acromegaly (with mean follow-up of 37.2 months), tumor volume decreased in five patients (33.3%), remained unchanged in nine (60%), and there was one (6.6%) patient that showed an increase in tumor size. Tumor control was achieved in fourteen (93.3%) patients. All of our patients were treated with LINAC Radiosurgery as secondary therapy. The average prescription peripheral dose (Gy) was 19.4Gy with a range from 12 to 25Gy. In our experience, the rate of hormone normalization after radiosurgery for Acromegaly was seen in six (41.6%) patients. Hormone normalization in these five patients was observed at mean follow-up of 28 months. Tumor control was achieved in most patients correlating with hormone remission, except for one patient, which despite hormone remission there was a slight increase in tumor size.

The most widely accepted guidelines for endocrine remission in acromegaly consist of a GH level less than 1 ng/ml in response to an oral glucose challenge and a normal serum IGF-1 when matched for age [Giustina et al., 2000; Vance, 1998).

Published remission rates following radiosurgery for acromegaly vary widely from 0% to 100%, with the majority of patients achieving tumor growth control (Table 3) (Buchfelder et al., 1991; Cozzi et al., 2001; Freda, 2003; Fukuoka et al., 2001; Horvath et al., 1983; Landolt et al., 1998, 2000; Pouratian et al., 2006; Witt et al., 1998). Jezkova et al. reported a remission rate of 50% at 42 months follow-up in 96 patients with acromegaly who received


Table 3. Summary of cases treated with Radiosurgery for Acromegaly. (\*Unpublished manuscript in writing)

Stereotactic Radiosurgery for Pituitary Adenomas 77

Jagannathan et al., 2007; Kobayashi et al., 2002; Morange-Ramos et al., 1998; Petrovich et al., 2003; Witt et al., 1998). In series with at least ten patients and a median follow-up of 2 years, endocrine remission rates range from 17% to 83% (Kobayashi et al., 2002; Mahmoud-Ahmed & Suh, 2002; Morange-Ramos et al., 1998, Petrovich et al., 2003). Rähn and associates (Flickenger et al., 1992) reported their experience at the Karolinska Institute involving 59 patients with Cushing's disease who were treated using the Gamma Knife and followed for 2–15 years. The efficacy rate of the initial treatment was 50%, with retreatment eventually

We use radiosurgery as a treatment for prolactinomas after failure of medical and/or surgical treatment. Ideally most of the prolactinomas should be treated with medication. Prolactinomas tumor control with medications has been reported around 80-90% (Ferone et al., 2007). Despite having good control, some patients do not tolerate the medications due to

In our series two patients were treated as primary therapy for medical reasons. Most of the patients were treated following microsurgery. Of the seven patients treated at our institution, complete normalization of prolactin levels occurred in only 14.2%, at an average time of 22 months, with a mean prescription dose of 18.7Gy. Tumor control was achieved in

In published studies of radiosurgery for prolactinomas, the mean prescription dose has varied from 13.3 Gy to 33 Gy, and remission rates varied from 0% to 84% (Table 5) (Kim et al., 1999, 2007; Landolt & Lomax, 2000; Laws & Vance, 1999; Post & Habas, 1990; Pouratian et al., 2006; Yildiz et al., 1999). Variations in success rate are likely related to the dose delivered to the tumor as well as other factors. Witt et al. noted no remissions with a prescription dose of 19 Gy (Witt et al., 1998; Witt, 2003). Pan et al. (Pan et al., 2000) reported a 52% endocrine ''cure'' rate in a retrospective study of 128 patients in whom GKRS was used as first-line treatment for prolactinomas with a prescription dose of 30 Gy. This study is on a large sample size, and is interesting in that GKRS was used as a first-line treatment

> **Peripheral Dose (Gy)**

**Hormone Normalization (%)** 

**Tumor Control (%)** 

providing normalization of cortisol production in 76% of patients (Rahn et al, 1980).

**7.2.3 Prolactin-secreting adenomas** 

before medical therapy.

**RSx** 

(\*Unpublished manuscript in writing)

**Unit Pt No F/U** 

**(mos)** 

Mitsumori 1998 LINAC 4 47 15 0 100 Yoon 1998 LINAC 11 49 17 84 96 Mokry 1999 GK 21 31 14 21 NR Pan 2000 GK 128 33 31.5 52 98.4 Choi 2003 GK 21 42.5 28.5 24 100

<sup>2003</sup>LINAC 1 30 15 0 100 Pouratian 2006 GK 23 58 18.6 24 89 Brau 2011\* LINAC 7 35.7 18.7 14.2 100

Table 5. Summary of cases involving Radiosurgery in patients with prolactinomas.

**Author and Year** 

Muramatsu

side effects and other turnout to be allergic to it.

100% of the cases, but did not correlate with hormone remission.

radiosurgery (Jezkova et al., 2006). Nearly one-third of these patients, however, had radiosurgery as primary treatment, without surgical extirpation of the adenoma. Pollock et al., (2007) demonstrated a remission rate of 50% in 46 patients with a higher remission rate in patients who were off suppressive medications at the time of radiosurgery. Pollock's group also stated that maximal radiosurgery effects may be delayed up to 5 years after treatment, therefore no other surgical treatment or additional radiosurgery should be considered within that period unless there is unequivocal evidence of tumor enlargement and progressive elevation of HGH and ILGF-1.

#### **7.2.2 Cushing's disease**

Cushing's disease is one of the most devastating pituitary disorders, and is associated with significant morbidity and premature death. Even after transsphenoidal surgery, up to 30% of patients may have persistent o recurrent disease (Ciric et al., 1997; Laws & Thapar, 1996; Mampalam et al., 1988). Most centers define an endocrine remission as a urine free-cortisol (UFC) level in the normal range associated with the resolution of clinical stigmata or a series of normal post-operative serum cortisol levels obtained throughout the day (Nieman, 2002; Sheehan et al., 2000). We have treated ten patients with Cushing's disease, with 40% of patients achieving normalization of hormones levels with a mean margin dose of 20.7Gy. The rate of remission statistically correlated with tumor volume, but not with tumor invasion into the cavernous sinus or the suprasellar region.

In our experience, the rate of hormone normalization after radiosurgery for Cushing's disease is difficult to predict, with remission occurring as early as 17months and as late as five years after LINAC Radiosurgery. Most patients who have remission, however, will do so within the first 2-3 years following radiosurgery. Patients with persistent disease should thus consider alternative treatments such as repeat TSS, or repeat radiosurgery (although this may be associated with a higher rate of cranial nerve damage) (Jagannathan et al., 2007).

Published endocrine remission rates following radiosurgery (Table 4) vary considerably, from 10% to 100%, with higher remission rates when radiosurgery follows surgical debulking (Arnaldi et al., 2003; Chu et al., 2001; Izawa et al., 2000; Jackson & Noren, 1999;


Table 4. Summary of cases involving Radiosurgery in patients with Cushing's disease. (\*Unpublished manuscript in writing)

radiosurgery (Jezkova et al., 2006). Nearly one-third of these patients, however, had radiosurgery as primary treatment, without surgical extirpation of the adenoma. Pollock et al., (2007) demonstrated a remission rate of 50% in 46 patients with a higher remission rate in patients who were off suppressive medications at the time of radiosurgery. Pollock's group also stated that maximal radiosurgery effects may be delayed up to 5 years after treatment, therefore no other surgical treatment or additional radiosurgery should be considered within that period unless there is unequivocal evidence of tumor enlargement

Cushing's disease is one of the most devastating pituitary disorders, and is associated with significant morbidity and premature death. Even after transsphenoidal surgery, up to 30% of patients may have persistent o recurrent disease (Ciric et al., 1997; Laws & Thapar, 1996; Mampalam et al., 1988). Most centers define an endocrine remission as a urine free-cortisol (UFC) level in the normal range associated with the resolution of clinical stigmata or a series of normal post-operative serum cortisol levels obtained throughout the day (Nieman, 2002; Sheehan et al., 2000). We have treated ten patients with Cushing's disease, with 40% of patients achieving normalization of hormones levels with a mean margin dose of 20.7Gy. The rate of remission statistically correlated with tumor volume, but not with tumor

In our experience, the rate of hormone normalization after radiosurgery for Cushing's disease is difficult to predict, with remission occurring as early as 17months and as late as five years after LINAC Radiosurgery. Most patients who have remission, however, will do so within the first 2-3 years following radiosurgery. Patients with persistent disease should thus consider alternative treatments such as repeat TSS, or repeat radiosurgery (although this may be associated with a higher rate of cranial nerve damage) (Jagannathan et al., 2007). Published endocrine remission rates following radiosurgery (Table 4) vary considerably, from 10% to 100%, with higher remission rates when radiosurgery follows surgical debulking (Arnaldi et al., 2003; Chu et al., 2001; Izawa et al., 2000; Jackson & Noren, 1999;

> **Peripheral Dose (Gy)**

Laws 1999 LINAC 50 --- 22 58 --- Izawa 2000 GK 12 28 22 17 94 Sheehan 2000 GK 43 44 20 63 100 Hoybye 2001 LINAC 18 204 --- 83 83 Kobayashi 2003 --- 20 64 29 35 100 Devin 2004 GK 35 42 15 49 91 Castinetti 2007 GK 40 55 29.5 42 100

<sup>2007</sup>GK 90 45 25 42 100 Brau 2011\* LINAC 10 50 20.7 40 90 Table 4. Summary of cases involving Radiosurgery in patients with Cushing's disease.

**Hormone Normalization (%)** 

**Tumor Control (%)** 

and progressive elevation of HGH and ILGF-1.

invasion into the cavernous sinus or the suprasellar region.

**Unit Pt No F/U** 

**(mos)**

**7.2.2 Cushing's disease** 

**Author and Year RSx** 

Jagannathan

(\*Unpublished manuscript in writing)

Jagannathan et al., 2007; Kobayashi et al., 2002; Morange-Ramos et al., 1998; Petrovich et al., 2003; Witt et al., 1998). In series with at least ten patients and a median follow-up of 2 years, endocrine remission rates range from 17% to 83% (Kobayashi et al., 2002; Mahmoud-Ahmed & Suh, 2002; Morange-Ramos et al., 1998, Petrovich et al., 2003). Rähn and associates (Flickenger et al., 1992) reported their experience at the Karolinska Institute involving 59 patients with Cushing's disease who were treated using the Gamma Knife and followed for 2–15 years. The efficacy rate of the initial treatment was 50%, with retreatment eventually providing normalization of cortisol production in 76% of patients (Rahn et al, 1980).

#### **7.2.3 Prolactin-secreting adenomas**

We use radiosurgery as a treatment for prolactinomas after failure of medical and/or surgical treatment. Ideally most of the prolactinomas should be treated with medication. Prolactinomas tumor control with medications has been reported around 80-90% (Ferone et al., 2007). Despite having good control, some patients do not tolerate the medications due to side effects and other turnout to be allergic to it.

In our series two patients were treated as primary therapy for medical reasons. Most of the patients were treated following microsurgery. Of the seven patients treated at our institution, complete normalization of prolactin levels occurred in only 14.2%, at an average time of 22 months, with a mean prescription dose of 18.7Gy. Tumor control was achieved in 100% of the cases, but did not correlate with hormone remission.

In published studies of radiosurgery for prolactinomas, the mean prescription dose has varied from 13.3 Gy to 33 Gy, and remission rates varied from 0% to 84% (Table 5) (Kim et al., 1999, 2007; Landolt & Lomax, 2000; Laws & Vance, 1999; Post & Habas, 1990; Pouratian et al., 2006; Yildiz et al., 1999). Variations in success rate are likely related to the dose delivered to the tumor as well as other factors. Witt et al. noted no remissions with a prescription dose of 19 Gy (Witt et al., 1998; Witt, 2003). Pan et al. (Pan et al., 2000) reported a 52% endocrine ''cure'' rate in a retrospective study of 128 patients in whom GKRS was used as first-line treatment for prolactinomas with a prescription dose of 30 Gy. This study is on a large sample size, and is interesting in that GKRS was used as a first-line treatment before medical therapy.


Table 5. Summary of cases involving Radiosurgery in patients with prolactinomas. (\*Unpublished manuscript in writing)

Stereotactic Radiosurgery for Pituitary Adenomas 79

these studies are limited by follow-up of 12 months and less in some cases (Adler et al.,

Ultimately, total dose prescribed and the prescription (margin) doses are likely the major factors determining the risk and onset of radiation induced hypopituitarism. The sequence of hormone loss following pituitary radiosurgery is unknown. The difficulty with determining the exact incidence of radiosurgery-induced hypopituitarism stems in part from the fact that many of the patients have previously undergone resection and some fractionated radiotherapy. In addition, pituitary deficiencies may results in part from aging. Thus, it is likely that hypopituitarism in the post-radiosurgical population is multifactorial in cause and related to radiosurgery as well as age-related changes and previous treatments (for example, microsurgery and radiotherapy). In spite of this, however, some have argued that the GH axis is the most sensitive to the late effects of radiation, with the radiation induced defect likely occurring at the hypothalamic level (Blacklay et al., 1986; Shalet, 1993). The gonadotropin and corticotrophin axes are also thought to be sensitive to radiation damage. Diabetes insipidus appears to be uncommon after radiosurgery with only sporadic case reports (Piedra et al., 2004). A well-controlled, long-term study focusing on this issue is needed to determine definitively the incidence of radiosurgery-induced hypopituitarism. Cranial neuropathies following radiosurgery are exceedingly rare following the first procedure, although the incidence may increase on re-treatment (Jagannathan et al., 2007). Visual injury in general can be avoided if the dose to the optic apparatus is restricted to less

Injury to the cavernous segment of the carotid artery or brain parenchyma is uncommon following radiosurgery. Pollock and associates have recommended that the prescription dose should be limited to less than 50% of the intracavernous CA vessel diameter (Pollock & Carpenter, 2003). Shin recommended restricting the dose to the internal CA to less than 30

Parenchymal brain injury can be present especially in the hypothalamic and temporal regions. Patients with injuries to medial temporal lobes can present with complex partial seizures or if the injury is bilateral with recent memory impairment. Induction of cavernous malformations following radiosurgery to the sellar region is also theoretically possible but

The exact incidence of radiosurgical-induced neoplasm is unknown at present, although we have not seen one in our series of pituitary patients treated with m-LINAC system. Loeffler and colleagues recently reported on 6 patients, including 2 patients with pituitary adenomas who developed new tumors following radiosurgery (Loeffler et al., 2003). They concluded that although the risk of new tumor formation after radiosurgery appears to be significantly less than that seen following fractionated radiotherapy, new tumors can develop in the full dose region as well as in the low-dose periphery of the radiosurgical field. The latency to new tumor formation in this small series (between 6 years and 20 years) was similar to that

Prognosis for pituitary adenoma patients is largely dependent upon the adenoma size and functionality as well as the patients' pre-radiosurgical status. Patients being treated for

2006; Kajiwara et al., 2005; Pham et al., 2004).

than 8 Gy (see previous discussion).

Gy (Shin et al., 2000).

thus far has not been reported.

seen after conventional radiation therapy.

**9. Prognosis and follow-up** 

#### **7.2.4 Nelson's syndrome**

Compared with nonfunctioning and other functioning pituitary adenomas, much less information is available about the efficacy of stereotactic radiosurgery for the treatment of Nelson syndrome. A subset of Cushing's patients do not achieve hormone normalization following microsurgery and radiosurgery, and undergo adrenalectomy as a ''salvage'' treatment for their disease. Although adrenalectomy is the definitive treatment for cortisol overproduction, a subset of patients may develop Nelson's syndrome, characterized by rapid adenoma growth, hyper-pigmentation and tumor invasion into the parasellar structures (Nagesser et al., 2000). This is thought to be related to the lack of feedback on the hypothalamus and the pituitary gland by the lack of cortisol.


Table 6. Endocrine and radiographic outcomes of GKRS for Nelson's syndrome. (a) Mean imaging follow-up/mean endocrine follow-up (b)ACTH levels decreased/ACTH reduced to normal values (50 pg/ml)

Pollock and Young reported on 11 patients who underwent GKRS for Nelson's syndrome. They reported control of tumor growth in 9 of 11 patients, with ACTH normalization in four patients (36%) (Pollock & Young, 2002).

There are relatively few studies detailing the results of radiosurgery for Nelson's syndrome (Table 6) ( Ganz, 2000; Ganz et al., 1993; Kobayashi et al., 2002; Laws & Vance, 1999; Levy et al., 1991; Mauermann et al., 2007; Pollock & Wolffenbuttel et al., 1998; Young, 2002). These studies report a mean tumor dose from between 12 Gy to 28.7 Gy, and an endocrine remission rate ranging from 0% to 36%, although only a minority of these studies defined what was meant by endocrine remission. Even cases where endocrine remission was not achieved, tumor growth control rates were favorable, ranging from 82% to 100%.

#### **8. Complications following radiosurgery for pituitary adenomas**

As previously stated, the most common problem after radiosurgery is development of hypopituitarism. Several groups have reported a low incidence (0–36%) of pituitary dysfunction following radiosurgery (Jagannathan et al., 2007; Jane et al., 2003; Sheehan et al., 2006; Pollock et al., 1994). This incidence is likely higher when patients are followed longterm, with the Karolinska Institute reporting a 72% incidence of hypopituitarism when patients were followed over 10 years (Hoybye et al., 2001). We have observed an overall risk of 20–30% for development of new hormone deficiency following radiosurgery without a significant difference across tumor pathologies. Recent studies using the Cyberknife for secretory adenomas, points to a significantly lower (9.5%) rate of endocrinopathy, although

Compared with nonfunctioning and other functioning pituitary adenomas, much less information is available about the efficacy of stereotactic radiosurgery for the treatment of Nelson syndrome. A subset of Cushing's patients do not achieve hormone normalization following microsurgery and radiosurgery, and undergo adrenalectomy as a ''salvage'' treatment for their disease. Although adrenalectomy is the definitive treatment for cortisol overproduction, a subset of patients may develop Nelson's syndrome, characterized by rapid adenoma growth, hyper-pigmentation and tumor invasion into the parasellar structures (Nagesser et al., 2000). This is thought to be related to the lack of feedback on the

> **Peripheral Dose (Gy)**

**Hormone Normalization (%)** 

**Tumor Control (%)** 

hypothalamus and the pituitary gland by the lack of cortisol.

**Unit Pt No F/U** 

**(mos)** 

Ganz 1993 GKS 3 18 NR 0 100

<sup>1998</sup>GKS 1 33 12 0 100 Kobayashi 2002 GKS 6 63 28.7 33 100 Pollock 2002 GKS 11 37 20 24 82 Vogues 2006 LINAC 9 63/47a 15.3 16.7 89 Mauerman 2007 GKS 23 20/50a 25 17/60b 91 Table 6. Endocrine and radiographic outcomes of GKRS for Nelson's syndrome. (a) Mean imaging follow-up/mean endocrine follow-up (b)ACTH levels decreased/ACTH reduced

Pollock and Young reported on 11 patients who underwent GKRS for Nelson's syndrome. They reported control of tumor growth in 9 of 11 patients, with ACTH normalization in four

There are relatively few studies detailing the results of radiosurgery for Nelson's syndrome (Table 6) ( Ganz, 2000; Ganz et al., 1993; Kobayashi et al., 2002; Laws & Vance, 1999; Levy et al., 1991; Mauermann et al., 2007; Pollock & Wolffenbuttel et al., 1998; Young, 2002). These studies report a mean tumor dose from between 12 Gy to 28.7 Gy, and an endocrine remission rate ranging from 0% to 36%, although only a minority of these studies defined what was meant by endocrine remission. Even cases where endocrine remission was not

As previously stated, the most common problem after radiosurgery is development of hypopituitarism. Several groups have reported a low incidence (0–36%) of pituitary dysfunction following radiosurgery (Jagannathan et al., 2007; Jane et al., 2003; Sheehan et al., 2006; Pollock et al., 1994). This incidence is likely higher when patients are followed longterm, with the Karolinska Institute reporting a 72% incidence of hypopituitarism when patients were followed over 10 years (Hoybye et al., 2001). We have observed an overall risk of 20–30% for development of new hormone deficiency following radiosurgery without a significant difference across tumor pathologies. Recent studies using the Cyberknife for secretory adenomas, points to a significantly lower (9.5%) rate of endocrinopathy, although

achieved, tumor growth control rates were favorable, ranging from 82% to 100%.

**8. Complications following radiosurgery for pituitary adenomas** 

**RSx** 

**7.2.4 Nelson's syndrome** 

**Author and Year** 

Wolffenbuttel

to normal values (50 pg/ml)

patients (36%) (Pollock & Young, 2002).

these studies are limited by follow-up of 12 months and less in some cases (Adler et al., 2006; Kajiwara et al., 2005; Pham et al., 2004).

Ultimately, total dose prescribed and the prescription (margin) doses are likely the major factors determining the risk and onset of radiation induced hypopituitarism. The sequence of hormone loss following pituitary radiosurgery is unknown. The difficulty with determining the exact incidence of radiosurgery-induced hypopituitarism stems in part from the fact that many of the patients have previously undergone resection and some fractionated radiotherapy. In addition, pituitary deficiencies may results in part from aging. Thus, it is likely that hypopituitarism in the post-radiosurgical population is multifactorial in cause and related to radiosurgery as well as age-related changes and previous treatments (for example, microsurgery and radiotherapy). In spite of this, however, some have argued that the GH axis is the most sensitive to the late effects of radiation, with the radiation induced defect likely occurring at the hypothalamic level (Blacklay et al., 1986; Shalet, 1993). The gonadotropin and corticotrophin axes are also thought to be sensitive to radiation damage. Diabetes insipidus appears to be uncommon after radiosurgery with only sporadic case reports (Piedra et al., 2004). A well-controlled, long-term study focusing on this issue is needed to determine definitively the incidence of radiosurgery-induced hypopituitarism.

Cranial neuropathies following radiosurgery are exceedingly rare following the first procedure, although the incidence may increase on re-treatment (Jagannathan et al., 2007). Visual injury in general can be avoided if the dose to the optic apparatus is restricted to less than 8 Gy (see previous discussion).

Injury to the cavernous segment of the carotid artery or brain parenchyma is uncommon following radiosurgery. Pollock and associates have recommended that the prescription dose should be limited to less than 50% of the intracavernous CA vessel diameter (Pollock & Carpenter, 2003). Shin recommended restricting the dose to the internal CA to less than 30 Gy (Shin et al., 2000).

Parenchymal brain injury can be present especially in the hypothalamic and temporal regions. Patients with injuries to medial temporal lobes can present with complex partial seizures or if the injury is bilateral with recent memory impairment. Induction of cavernous malformations following radiosurgery to the sellar region is also theoretically possible but thus far has not been reported.

The exact incidence of radiosurgical-induced neoplasm is unknown at present, although we have not seen one in our series of pituitary patients treated with m-LINAC system. Loeffler and colleagues recently reported on 6 patients, including 2 patients with pituitary adenomas who developed new tumors following radiosurgery (Loeffler et al., 2003). They concluded that although the risk of new tumor formation after radiosurgery appears to be significantly less than that seen following fractionated radiotherapy, new tumors can develop in the full dose region as well as in the low-dose periphery of the radiosurgical field. The latency to new tumor formation in this small series (between 6 years and 20 years) was similar to that seen after conventional radiation therapy.

#### **9. Prognosis and follow-up**

Prognosis for pituitary adenoma patients is largely dependent upon the adenoma size and functionality as well as the patients' pre-radiosurgical status. Patients being treated for

Stereotactic Radiosurgery for Pituitary Adenomas 81

Adler JR Jr, Chang SD, Murphy MJ, Doty J, Geis P, Hancock SL (1997) The Cyberknife: a frameless robotic system for radiosurgery. *Funct Neurosurg* 69: 124–128. Adler JR Jr, Gibbs IC, Puataweepong P, Chang SD (2006) Visual field preservation after

Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA,

Becker, G., Kocher, M., Kortmann, R.D., Paulsen, F., Jeremic, B., Muller, R.P. & Bamberg, M.

Blacklay A, Grossman A, Ross RJ, Savage MO, Davies PS, Plowman PN, Coy DH, Besser

Brada, M., Burchell, L., Ashley, S. & Traish, D. (1999) The incidence of cerebrovascular

Brada, M., Ford, D., Ashley, S., Bliss, J.M., Crowley, S., Mason, M., Rajan, B. & Traish, D.

Brada, M., Rajan, B., Traish, D., Ashley, S., Holmes-Sellors, P.J., Nussey, S. & Uttley, D.

Brada, M., Ashley, S., Ford, D., Traish, D., Burchell, L. & Rajan, B. (2002) Cerebrovascular mortality in patients with pituitary adenoma. *Clinical Endocrinology*, 57, 713–717. Buchfelder M, Fahlbusch R, Schott W, Honegger J (1991) Long term follow-up results in

Chang SD, Murphy M, Geis P, Martin DP, Hancock SL, Doty JR, Adler JR Jr (1998) Clinical

Chen JC, Giannotta SL, Yu C, Petrovich Z, Levy ML, Apuzzo ML (2001) Radiosurgical

Chu JW, Matthias DF, Belanoff J, Schatzberg A, Hoffman AR, Feldman D (2001) Successful

Ciric I, Ragin A, Baumgartner C, Pierce D (1997) Complications of transsphenoidal surgery:

treatment of brain and spinal cord tumors. *Neurol Med Chir* 38:780–783. Chen JC, Giannotta SL, Yu C, Petrovich Z, Levy ML, Apuzzo ML (2001) Radiosurgical

complications. *Neurosurgery* 48:1022–1030 discussion 1030–1022

complications. *Neurosurgery* 48:1022–1030 discussion 1030–1022

adenoma. *Strahlentherapie und Onkologie*, 178, 173–186.

pituitary adenoma. *British Medical Journal*, 304, 1343–1346.

control of pituitary adenomas. *Clinical Endocrinology*, 38, 571–578.

discussion 244–254

*Endocrinol* 108:25–29

*Endocrinol Metab* 88:5593–5602.

*Oncology, Biology, Physics*, 45, 693–698.

surgery. *Acta Neurochir Suppl (Wien)* 53:72–76

(RU 486). J *Clin Endocrinol Metab* 86:3568–3573.

*Neurosurgery* 40:225–236 discussion 236–227

multisession cyberknife radiosurgery for perioptic lesions. *Neurosurgery* 59:244–254

Findling JW, Gaillard RC, Grossman AB, Kola B, Lacroix A, Mancini T, Mantero F, Newell-Price J, Nieman LK, Sonino N, Vance ML, Giustina A, Boscaro M (2003) Diagnosis and complications of Cushing's syndrome: a consensus statement. J *Clin* 

(2002) Radiation therapy in the multimodal treatment approach of pituitary

GM (1986) Cranial irradiation for cerebral and nasopharyngeal tumors in children: evidence for the production of a hypothalamic defect in growth hormone release. *J* 

accidents in patients with pituitary adenoma. *International Journal of Radiation* 

(1992) Risk of second brain tumor after conservative surgery and radiotherapy for

(1993) The long-term efficacy of conservative surgery and radiotherapy in the

hormonally active pituitary adenomas after primary successful transsphenoidal

experience with image-guided robotic radiosurgery (the Cyberknife) in the

management of benign cavernous sinus tumors: dose profiles and acute

management of benign cavernous sinus tumors: dose profiles and acute

long-term treatment of refractory Cushing's disease with high-dose mifepristone

results of a national survey, review of the literature, and personal experience.

pituitary adenomas must be followed long-term with serial clinical, ophthalmological, endocrine and radiological evaluations.

Serial visual field examinations and hormonal screening should be performed. In the majority of cases serial testing of adrenal, thyroid function and GH reserves may be required as well. Patients receiving hormone replacement should have their replacement therapy adjusted as necessary.

Finally, serial MR imaging should be performed to assess for tumor recurrence. It is our practice to perform an initial post-radiosurgical MRI at 6 months after treatment with follow-up MRI's yearly thereafter, unless otherwise indicated. Endocrine and ophthalmologic follow-up should typically occur at the same time to provide adequate correlation with the treatment. There should be a good communication with every discipline involved in the treatment of these patients.

### **10. Conclusions**

Multimodality treatment is often used to manage pituitary adenomas. Therapeutic options include medical management, microsurgery, radiosurgery, and radiotherapy. Except for prolactinomas, microsurgery remains the primary treatment for sellar lesions in surgically fit patients, particularly when the lesion is exerting a mass effect on the optic apparatus or producing hormone overproduction. Nevertheless, 20 to 50% of patients experience recurrence of their adenomas, and adjuvant treatment is recommended for these patients.

Stereotactic radiosurgery has been demonstrated to be a safe and highly effective treatment for patients with recurrent or residual pituitary adenomas. Radiosurgery affords effective growth control and hormone normalization for patients and has a generally shorter latency period than that of fractionated radiotherapy. This shorter latency period with radiosurgery can typically be managed with hormone-suppressive medications. Furthermore, the complications (for example, radiation-induced neoplasia and cerebral vasculopathy) associated with radiosurgery appear to occur less frequently than those associated with radiotherapy. Radiosurgery may even serve as a primary treatment for those patients deemed unfit for microsurgical tumor removal because they have other co morbidities or demonstrable tumors in a surgically inaccessible location. Radiosurgery can frequently preserve and, at times, even restore neurological and hormone function.

Radiosurgery is a useful tool in the treatment of both secretory and non-secretory pituitary adenomas. In most patients, radiosurgery controls adenoma growth. However, normalization of hormone overproduction can vary considerably depending on the patients' presenting condition. Challenges for the future include delineating the optimal timing for the administration of antisecretory medications and identifying factors that can improve the response of pituitary adenomas to radiosurgery. Finally, physicians caring for patients with pituitary disorders should establish uniform endocrinological criteria and diagnostic testing for pre- and post-radiosurgical evaluations.

#### **11. References**

Abe T, Yamamoto M, Taniyama M, Tanioka D, Izumiyama H, Matsumoto K (2002) Early palliation of oculomotor nerve palsy following gamma knife radiosurgery for pituitary adenoma. *Eur Neurol* 47:61–63.

pituitary adenomas must be followed long-term with serial clinical, ophthalmological,

Serial visual field examinations and hormonal screening should be performed. In the majority of cases serial testing of adrenal, thyroid function and GH reserves may be required as well. Patients receiving hormone replacement should have their replacement

Finally, serial MR imaging should be performed to assess for tumor recurrence. It is our practice to perform an initial post-radiosurgical MRI at 6 months after treatment with follow-up MRI's yearly thereafter, unless otherwise indicated. Endocrine and ophthalmologic follow-up should typically occur at the same time to provide adequate correlation with the treatment. There should be a good communication with every discipline

Multimodality treatment is often used to manage pituitary adenomas. Therapeutic options include medical management, microsurgery, radiosurgery, and radiotherapy. Except for prolactinomas, microsurgery remains the primary treatment for sellar lesions in surgically fit patients, particularly when the lesion is exerting a mass effect on the optic apparatus or producing hormone overproduction. Nevertheless, 20 to 50% of patients experience recurrence of their adenomas, and adjuvant treatment is recommended for these patients. Stereotactic radiosurgery has been demonstrated to be a safe and highly effective treatment for patients with recurrent or residual pituitary adenomas. Radiosurgery affords effective growth control and hormone normalization for patients and has a generally shorter latency period than that of fractionated radiotherapy. This shorter latency period with radiosurgery can typically be managed with hormone-suppressive medications. Furthermore, the complications (for example, radiation-induced neoplasia and cerebral vasculopathy) associated with radiosurgery appear to occur less frequently than those associated with radiotherapy. Radiosurgery may even serve as a primary treatment for those patients deemed unfit for microsurgical tumor removal because they have other co morbidities or demonstrable tumors in a surgically inaccessible location. Radiosurgery can frequently

Radiosurgery is a useful tool in the treatment of both secretory and non-secretory pituitary adenomas. In most patients, radiosurgery controls adenoma growth. However, normalization of hormone overproduction can vary considerably depending on the patients' presenting condition. Challenges for the future include delineating the optimal timing for the administration of antisecretory medications and identifying factors that can improve the response of pituitary adenomas to radiosurgery. Finally, physicians caring for patients with pituitary disorders should establish uniform endocrinological criteria and diagnostic testing

Abe T, Yamamoto M, Taniyama M, Tanioka D, Izumiyama H, Matsumoto K (2002) Early

palliation of oculomotor nerve palsy following gamma knife radiosurgery for

preserve and, at times, even restore neurological and hormone function.

endocrine and radiological evaluations.

involved in the treatment of these patients.

for pre- and post-radiosurgical evaluations.

pituitary adenoma. *Eur Neurol* 47:61–63.

**11. References** 

therapy adjusted as necessary.

**10. Conclusions** 


Stereotactic Radiosurgery for Pituitary Adenomas 83

Ikeda H, Jokura H, Yoshimoto T (2001) Transsphenoidal surgery and adjuvant gamma knife

Izawa M, Hayashi M, Nakaya K, Satoh H, Ochiai T, Hori T, Takakura K (2000) Gamma knife

Jackson IM, Noren G (1999) Gamma knife radiosurgery for pituitary tumors. *Best Pract Res* 

Jagannathan J, Dumont AS, Jane JA Jr, Laws ER Jr (2005) Pediatric sellar tumors: diagnostic

Jagannathan J, Sheehan JP, Pouratian N, Laws ER, Steiner L, Vance ML (2007) Gamma knife

Jane JA Jr, Vance ML, Woodburn CJ, Laws ER Jr (2003) Stereotactic radiosurgery for

Jezkova J, Marek J, Hana V, Krsek M, Weiss V, Vladyka V, Lisak R, Vymazal J, Pecen L

Kajiwara K, Saito K, Yoshikawa K, Kato S, Akimura T, Nomura S, Ishihara H, Suzuki M

Kajiwara K, Saito K, Yoshikawa K, Kato S, Akimura T, Nomura S, Ishihara H, Suzuki M

Kanter AS, Diallo AO, Jane JA Jr, Sheehan JP, Asthagiri AR, Oskouian RJ, Okonkwo DO,

Kim MS, Lee SI, Sim JH (1999) Gamma Knife radiosurgery for functioning pituitary

Kim SH, Huh R, Chang JW, Park YG, Chung SS (1999) Gamma Knife radiosurgery for functioning pituitary adenomas. *Stereotact Funct Neurosurg* 72(Suppl 1):101–110. Kobayashi T, Kida Y, Mori Y (2002) Gamma knife Radiosurgery in the treatment of Cushing

Landolt AM, Haller D, Lomax N, Scheib S, Schubiger O, Siegfried J, Wellis G (2000)

Landolt AM, Haller D, Lomax N, Scheib S, Schubiger O, Siegfried J, Wellis G (1998)

Landolt AM, Lomax N (2000) Gamma knife radiosurgery for prolactinomas. J Neurosurg

Laws ER Jr, Ebersold MJ, Piepgras DG, Randall RV, Salassa RM (1985) The results of

Laws ER Jr, Fode NC, Redmond MJ (1985) Transsphenoidalsurgery following unsuccessful

Octreotide may act as a radio protective agent in acromegaly. *J Clin Endocrinol* 

Stereotactic radiosurgery for recurrent surgically treated acromegaly: comparison

transsphenoidal surgery in specific clinical entities. In: *Management of pituitary adenomas and related lesions with emphasis on Transsphenoidal microsurgery.* Laws ER Jr, Randall RV, Kern EB et al (eds) Appleton-Century-Crofts, New York, pp 277–305

prior therapy. An assessment of benefits and risks in 158 patients. *J Neurosurg*

hypersecreting pituitary tumors: part of a multimodality approach. *Neurosurg Focus*

(2006) Gamma knife Radiosurgery for acromegaly – long-term experience. *Clin* 

(2005) Image-guided stereotactic radiosurgery with the CyberKnife for pituitary

(2005) Image-guided stereotactic radiosurgery with the CyberKnife for pituitary

Sansur CA, Vance ML, Rogol AD, Laws ER Jr (2005) Single-center experience with

radiosurgery for pituitary adenomas. *J Neurosurg* 93(Suppl 3):19–22

procedures and management. *Neurosurg Focus* 18:6.

adenomas. *Minim Invasive Neurosurg* 48:91–96.

adenomas. *Minim Invasive Neurosurg* 48:91–96.

pediatric Cushing's disease. *J Neurosurg* 103:413–420

disease: long-term results. *J Neurosurg* 97:422–428

with fractionated radiotherapy. *J Neurosurg* 88:1002–1008

microadenoma. *Stereotact Funct Neurosurg* 72(Suppl 1):119–124.

surgery for Cushing's disease. *J Neurosurg* 106:980–987.

*Clin Endocrinol Metab* 13:461–469.

14:e12.

*Endocrinol* 64:588–595.

*Metab* 85:1287–1289.

93(Suppl 3):14–18.

63:823–829

treatment for growth hormone-secreting pituitary adenoma. *J Neurosurg* 95:285–291


Cozzi R, Barausse M, Asnaghi D, Dallabonzana D, Lodrini S, Attanasio R (2001) Failure of

Erfurth, E.M., Bulow, B., Mikoczy, Z., Svahn-Tapper, G. & Hagmar, L. (2001) Is there an

Erfurth, E.M., Bulow, B., Svahn-Tapper, G., Norrving, B., Odh, K., Mikoczy, Z., Bjork, J. &

Feigl GC, Bonelli CM, Berghold A, Mokry M (2002) Effects of gamma knife radiosurgery of

Ferone D, Pivonello R, Resmini E, Boschetti M, Rebora A, Albertelli M, Albanese V, Colao A,

Flickinger JC, Lunsford LD, Kondziolka D (1992) Dose prescription and dose-volume effects

Freda PU (2003) How effective are current therapies for acromegaly? *Growth Horm IGF Res*

Fukuoka S, Ito T, Takanashi M, Hojo A, Nakamura H (2001) Gamma knife radiosurgery for

Ganz JC (2002) Gamma knife radiosurgery and its possible relationship to malignancy: a

Ganz JC, Backlund EO, Thorsen FA (1993) The effects of Gamma Knife surgery of pituitary

Giustina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Ho K, Veldhuis J, Wass J,

Hayashi M, Izawa M, Hiyama H, Nakamura S, Atsuchi S, Sato H, et al: Gamma knife

Hayashi M, Taira T, Ochiai T, Chernov M, Takasu Y, Izawa M, Kouyama N, Tomida M,

Horvath E, Kovacs K, Scheithauer BW, Randall RV, Laws ER Jr, Thorner MO, Tindall GT,

Hoybye C, Grenback E, Rahn T, Degerblad M, Thoren M, Hulting AL (2001)

pituitary adenomas on pituitary function. *J Neurosurg* 97:415–421

increase in second brain tumours after surgery and irradiation for a pituitary

Hagmar, L. (2002) Risk factors for cerebrovascular deaths in patients operated and irradiated for pituitary tumors. *Journal of Clinical Endocrinology and Metabolism*, 87,

Culler MD, Minuto F. Preclinical and clinical experiences with the role of dopamine receptors in the treatment of pituitary adenomas. *Eur J Endocrinol*. 2007 Apr; 156

growth hormone-secreting pituitary adenomas invading the cavernous sinus.

adenomas on tumor growth and endocrinopathies. *Stereotact Funct Neurosurg*

Von Werder K, Melmed S (2000) Criteria for cure of acromegaly: a consensus

radiosurgery for pituitary adenomas. *Stereotact Funct Neurosurg* 72 (Suppl 1):111–

Tokumaru O, Katayama Y, Kawakami Y, Hori T, Takakura K (2005) Gamma knife surgery of the pituitary: new treatment for thalamic pain syndrome. *J Neurosurg*

Barrow DL (1983) Pituitary adenomas producing growth hormone, prolactin, and one or more glycoprotein hormones: a histologic, immunohistochemical, and ultrastructural study of four surgically removed tumors. *Ultrastruct Pathol* 5:171–

Adrenocorticotropic hormone-producing pituitary tumors: 12- to 22-year follow-up after treatment with stereotactic radiosurgery. *Neurosurgery* 49:284–291 discussion

radiotherapy in acromegaly. *Eur J Endocrinol* 145:717–726.

tumour? *Clinical Endocrinology*, 55, 613–616.

in radiosurgery. *Neurosurg Clin N Am* 3:51–59

statement. *J Clin Endocrinol Metab* 85:526–529

*Stereotact Funct Neurosurg* 76:213–217.

review. *J Neurosurg* 97:644–652

4892–4899.

Suppl 1:S37-43.

13(Suppl A): S144–S151

61(Suppl 1):30–37.

118, 1999

183.

291–282

102:38–41 Suppl


Stereotactic Radiosurgery for Pituitary Adenomas 85

Nagesser SK, van Seters AP, Kievit J, Hermans J, Krans HM, van de Velde CJ (2000) Long-

Pan L, Zhang N, Wang EM, Wang BJ, Dai JZ, Cai PW (2000) Gamma knife radiosurgery as a primary treatment for prolactinomas. *J Neurosurg* 93(Suppl 3):10–13 Petrovich Z, Yu C, Giannotta SL, Zee CS, Apuzzo ML (2003) Gamma knife radiosurgery for pituitary adenoma: early results. *Neurosurgery* 53:51–59 discussion 59–61 Pham CJ, Chang SD, Gibbs IC, Jones P, Heilbrun MP, Adler JR Jr (2004) Preliminary visual

Piedra MP, Brown PD, Carpenter PC, Link MJ (2004) Resolution of diabetes insipidus

Pollock BE, Carpenter PC: Stereotactic radiosurgery as an alternative to fractionated

Pollock BE, Cochran J, Nat N, Brown PD, Erickson D, Link MJ, Garces YI, Foote RL, Stafford

Pollock BE, Jacob JT, Brown PD, Nippoldt TB (2007) Radiosurgery of growth hormone-

Pollock BE, Kondziolka D, Lunsford LD, Flickinger JC (1994) Stereotactic radiosurgery for

Pollock BE, Young WF Jr (2002) Stereotactic radiosurgery for patients with ACTH-

Post KD, Habas JE (1990) Comparison of long term results between prolactin secreting adenomas and ACTH secreting adenomas. *Can J Neurol Sci* 17:74–77 Pouratian N, Sheehan J, Jagannathan J, Laws ER Jr, Steiner L, Vance ML (2006) Gamma knife

Rahn T, Thoren M, Hall K, Backlund EO (1980) Stereotactic radiosurgery in Cushing's

Sheehan JM, Vance ML, Sheehan JP, Ellegala DB, Laws ER Jr (2000) Radiosurgery for Cushing's disease after failed transsphenoidal surgery. *J Neurosurg* 93:738–742 Sheehan JP, Jagannathan J, Pouratian N, Steiner L (2006) Stereotactic radiosurgery for

Sheehan JP, Kondziolka D, Flickinger J, Lunsford LD (2002) Radiosurgery for residual or recurrent nonfunctioning pituitary adenoma. J Neurosurg 97:408–414 Sheehan JP, Kondziolka D, Flickinger J, Lunsford LD (2002): Radiosurgery for residual or recurrent nonfunctioning pituitary adenoma. *J Neurosurg* 97 (Suppl 5):408–414

syndrome: acute radiation effects. *Surg Neurol* 14:85–92 Shalet SM (1993) Radiation and pituitary dysfunction. *N Engl J Med* 328:131–133.

Nieman LK (2002) Medical therapy of Cushing's disease. Pituitary 5:77–82.

*Neurosurgery* 54:799–810 discussion 810–812

adenomas. *Neurosurgery* 53: 1086–1094, 2003

report. *J Neurosurg* 101:1053–1056

*Oncol Biol Phys*. 70(5): 1325-9.

59:255–266 discussion 255–266.

*Neurosurg* 106:833–838.

(Wien) 62:33–38

*Phys* 54:839–841.

34:185–205

term results of total adrenalectomy for Cushing's disease. *World J Surg* 24:108–113.

field preservation after staged CyberKnife radiosurgery for perioptic lesions.

following gamma knife surgery for a solitary metastasis to the pituitary stalk. Case

radiotherapy for patients with recurrent or residual nonfunctioning pituitary

SL, Shomberg PJ. (2008) Gamma knife Radiosurgery for patients with nonfunctioning pituitary adenomas: results from a 15 year experience. *Int J Radiat* 

producing pituitary adenomas: factors associated with biochemical remission. *J* 

pituitary adenomas: imaging, visual and endocrine results. *Acta Neurochir Suppl*

producing pituitary adenomas after prior adrenalectomy. *Int J Radiat Oncol Biol* 

radiosurgery for medically and surgically refractory prolactinomas. *Neurosurgery*

pituitary adenomas: a review of the literature and our experience. *Front Horm Res*


Laws ER Jr, Thapar K (1996) Recurrent pituitary adenomas. In: *Pituitary adenomas.* Landolt AM, Vance ML, Reilly PL (eds) Churchill-Livingtone, Edinburgh, pp 385–394 Laws ER Jr, Vance ML (1999) Radiosurgery for pituitary tumors and craniopharyngiomas.

Laws ER, Sheehan JP (2006) Pituitary surgery: a modern approach. *Front Horm Res.* Basel,

Laws ER, Vance ML, Thapar K (2000) Pituitary surgery for the management of acromegaly.

Leber KA, Bergloff J, Langmann G, Mokry M, Schrottner O, Pendl G (1995) Radiation

Leber KA, Bergloff J, Pendl G (1998) Dose-response tolerance of the visual pathways and

Levy RP, Fabrikant JI, Frankel KA, Phillips MH, Lyman JT, Lawrence JH, Tobias CA (1991)

Lim YL, Leem W, Kim TS, Rhee BA, Kim GK (1998) Four years' experiences in the treatment

Loeffler JS, Niemierko A, Chapman PH (2003) Second tumors after radiosurgery: tip of the iceberg or a bump in the road? *Neurosurgery* 52:1436–1440 discussion 1440–1432 Losa M, Valle M, Mortini P, Franzin A, Da Passano CF, Cenzato M, et al. (2004) Gamma

Mahmoud-Ahmed AS, Suh JH (2002) Radiation therapy for Cushing's disease: a review.

Mampalam TJ, Tyrrell JB, Wilson CB (1988) Transsphenoidal microsurgery for Cushing

Mauermann WJ, Sheehan JP, Chernavvsky DR, Laws ER, Steiner L, Vance ML (2007)

Mitsumori M, Shrieve DC, Alexander E III, Kaiser UB, Richardson GE, Black PM, et al.

Mokry M, Ramschak-Schwarzer S, Simbrunner J, Ganz JC, Pendl G (1999): A six year

Morange-Ramos I, Regis J, Dufour H, Andrieu JM, Grisoli F, Jaquet P, Peragut JC (1998)

Muramatsu J, Yoshida M, Shioura H, Kawamura Y, Ito H, Takeuchi H, et al. (2003): [Clinical

disease. A report of 216 cases. *Ann Intern Med* 109:487–493

adenomas. *Stereotact Funct Neurosurg* 72 (Suppl 1):88–100

*Igaku Hoshasen Gakkai Zasshi* 63:225–230

adenomas after bilateral adrenalectomy. *J Neurosurg* 106:988–993.

sensitivity of visual and oculomotor pathways. *Stereotact Funct Neurosurg* 64(Suppl

cranial nerves of the cavernous sinus to stereotactic radiosurgery. *J Neurosurg*

Heavy-charged-particle Radiosurgery of the pituitary gland: clinical results of 840

of pituitary adenomas with gamma knife radiosurgery. *Stereotact Funct Neurosurg*

Knife surgery for treatment of residual nonfunctioning pituitary adenomas after

Gamma Knife surgery for adrenocorticotropic hormone-producing pituitary

(1998): Initial clinical results of LINAC-based stereotactic radiosurgery and stereotactic radiotherapy for pituitary adenomas. *Int J Radiat Oncol Biol Phys* 42:573–

experience with the postoperative radiosurgical management of pituitary

Gamma-knife surgery for secreting pituitary adenomas. *Acta Neurochir* (Wien)

results of LINAC-based stereotactic Radiosurgery for pituitary adenoma.] *Nippon* 

*Neurosurg Clin N Am* 10:327–336

*Horm Res* 53(Suppl 3):71–75.

patients. *Stereotact Funct Neurosurg* 57:22–35.

surgical debulking. *J Neurosurg* 100:438–444

Karger vol 34, pp I-X

1):233–238

88:43–50.

70(Suppl1):95–109.

*Pituitary* 5:175–180.

580

140:437–443.

Nagesser SK, van Seters AP, Kievit J, Hermans J, Krans HM, van de Velde CJ (2000) Longterm results of total adrenalectomy for Cushing's disease. *World J Surg* 24:108–113.

Nieman LK (2002) Medical therapy of Cushing's disease. Pituitary 5:77–82.


Shin M, Kurita H, Sasaki T, Tago M, Morita A, Ueki K, Kirino T (2000) Stereotactic

Tomlinson, J.W., Holden, N., Hills, R.K., Wheatley, K., Clayton, R.N., Bates, A.S., Sheppard,

Tsang, R.W., Brierley, J.D., Panzarella, T., Gospodarowicz, M.K., Sutcliffe, S.B. & Simpson,

Witt TC, Kondziolka D, Flickinger JC, Lunsford LD (1998) Gamma knife radiosurgery for

Wowra B, Stummer W (2002) Efficacy of gamma knife Radiosurgery for nonfunctioning

Yildiz F, Zorlu F, Erbas T, Atahan L (1999) Radiotherapy in the management of giant

Yoon SC, Suh TS, Jang HS, Chung SM, Kim YS, Ryu MR, et al. 1998 Clinical results of 24

Lunsford LD, Kondziolka D, Flickinger J (eds) Karger, Basel, pp114–127. Wolffenbuttel BH, Kitz K, Beuls EM (1998) Beneficial gammaknife radiosurgery in a patient

Vance ML (1998) Endocrinological evaluation of acromegaly. *J Neurosurg* 89:499–500 Witt TC (2003) Stereotactic radiosurgery for pituitary tumors. *Neurosurg Focus* 14:e10.

with Nelson's syndrome. *Clin Neurol Neurosurg* 100:60–63.

based volumetric analysis. *J Neurosurg* 97:429–432

pituitary adenomas. *Radiother Oncol* 52:233–237.

*Onc Biol Phys* 41:849–853

93(Suppl 3):2–5

357, 425–431.

557–565

radiosurgery for pituitary adenoma invading the cavernous sinus. *J Neurosurg*

M.C. & Stewart, P.M. (2001) Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. *Lancet*,

W.J. (1994) Radiation therapy for pituitary adenoma: treatment outcome and prognostic factors. *International Journal of Radiation Oncology, Biology, Physics*, 30,

pituitary tumors. In: *Gamma knife brain surgery progress in neurological surgery*.

pituitary adenomas: a quantitative follow up with magnetic resonance imaging-

pituitary macroadenomas with linac based stereotactic radiosurgery. *Int J Radiat* 

### *Edited by Vafa Rahimi-Movaghar*

Pituitary Adenomas is a comprehensive book about the most common pathology of the pituitary gland in the sellar region. The book chapters include epidemiology, symptoms and signs, clinical, imaging, immunohistochemical and ultrastructural pathological diagnosis, therapeutic approaches and outcome of the functional and non-functional pituitary tumors. Therapies include medications, endoscopic transphenoidal and open surgeries; radiotherapy includes gamma knife radiosurgery. Visual symptoms has important and characteristic patterns which has discussed in one specific chapter. Endocrine secretion is another characteristic in 40% of pituitary adenomas. Therefore, another chapter presents it. Stereotactic radiosurgery and endoscopic surgery both have special role in recent decades. Thus, they have considered specifically, too. Authors expect to give excellent insight in pituitary adenoma to the book readers.

Photo by SubstanceP / iStock

Pituitary Adenomas

Pituitary Adenomas

*Edited by Vafa Rahimi-Movaghar*