pituitary adenomas
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Pituitary AdenomasPituitary Adenomas
Chien Wei OMS IVChien Wei OMS IV
September 14, 2006September 14, 2006
OverviewOverviewBackgroundBackgroundClinical PresentationClinical PresentationClassificationClassificationIs it beneficial to give RT after Is it beneficial to give RT after transsphenoidal resectiontranssphenoidal resectionHow much time post-RT should pt. be How much time post-RT should pt. be followed?followed?Is there benefit to GKS?Is there benefit to GKS?General ManagementGeneral ManagementComplicationsComplications
AnatomyAnatomy
60 mg midline structure in sella turcica60 mg midline structure in sella turcica
Bordered by diaphragma sellae, Bordered by diaphragma sellae, tuberculum sellae, dorsum sellae, lateral tuberculum sellae, dorsum sellae, lateral sinuses, and sphenoid sinusessinuses, and sphenoid sinuses
Anterior and posterior lobesAnterior and posterior lobes
FunctionFunction
Anterior Lobe:Anterior Lobe: FSHFSH LHLH ACTHACTH TSHTSH ProlactinProlactin GHGH
Posterior Lobe:Posterior Lobe: ADHADH OxytocinOxytocin
EpidemiologyEpidemiology
Etiology is unknownEtiology is unknownNot associated with environmental factorsNot associated with environmental factors10-15% of all primary brain tumors10-15% of all primary brain tumors20-25% of pituitary glands at autopsy 20-25% of pituitary glands at autopsy found to have adenomasfound to have adenomas70% of adenomas are endocrinogically 70% of adenomas are endocrinogically secretingsecreting25% of those with MEN-I develop pituitary 25% of those with MEN-I develop pituitary adenomasadenomas
Natural HistoryNatural History
Pituitary adenomas have long natural Pituitary adenomas have long natural historyhistory
Vary in size and direction of spreadVary in size and direction of spread
Microadenomas < 10 mm – may cause Microadenomas < 10 mm – may cause focal bulgingfocal bulging
Macroadenomas > 10 mm – cause Macroadenomas > 10 mm – cause problems due to mass effectproblems due to mass effect
Clinical PresentationClinical Presentation
Most common are endocrine abnormalities Most common are endocrine abnormalities – hyper-/hyposecretion of ant. pituitary – hyper-/hyposecretion of ant. pituitary hormoneshormones
HAHA
Vision changes – bitemporal hemianopsia Vision changes – bitemporal hemianopsia and superior and superior
temporal defectstemporal defects
Endocrine-Active Pituitary Endocrine-Active Pituitary AdenomasAdenomas
Prolactin – Amenorrhea, galactorrhea, Prolactin – Amenorrhea, galactorrhea, impotenceimpotence
Growth hormone – Gigantism and Growth hormone – Gigantism and acromegalyacromegaly
Corticotropin – Cushing’s disease, Corticotropin – Cushing’s disease, Nelson’s syndrome post adrenalectomyNelson’s syndrome post adrenalectomy
TSH - HyperthyroidismTSH - Hyperthyroidism
Non-functioning AdenomasNon-functioning Adenomas
25-30 % of patients do not have classical 25-30 % of patients do not have classical hypersecretory syndromeshypersecretory syndromes
May grow to a large size before they are May grow to a large size before they are detecteddetected
Present due to mass effectPresent due to mass effect Visual deficitsVisual deficits HAHA Hormone deficiencyHormone deficiency
EvaluationEvaluation
MRIMRI
Visual field assessmentVisual field assessment
Endocrine evaluationEndocrine evaluation Tests of normal gonadal, thyroid, and adrenal Tests of normal gonadal, thyroid, and adrenal
functionfunction Radioimmunoassays – for hormone levelsRadioimmunoassays – for hormone levels
Classifying Classifying
Imaging/surgical classificationImaging/surgical classification
Clinical/endocrine – functional vs. Clinical/endocrine – functional vs. nonfunctionalnonfunctional
Pathological classificationPathological classification
WHO classification – reconciles the three WHO classification – reconciles the three systems abovesystems above
ClassificationClassification
Microadenomas – Grades 0 and IMicroadenomas – Grades 0 and IMacroadenomas – Grades II to IVMacroadenomas – Grades II to IVGrade 0: Intrapituitary microadenoma with Grade 0: Intrapituitary microadenoma with normal sellar appearancenormal sellar appearanceGrade I: Nml-sized sella with asymmetric Grade I: Nml-sized sella with asymmetric floorfloorGrade II: Enlarged sella with an intact floorGrade II: Enlarged sella with an intact floorGrade III: Localized erosion of sellar floorGrade III: Localized erosion of sellar floorGrade IV: Diffuse destruction of floorGrade IV: Diffuse destruction of floor
ClassificationClassification
Type A: Tumor bulges into the chiasmatic Type A: Tumor bulges into the chiasmatic cisterncisternType B: Tumor reaches the floor of the 3Type B: Tumor reaches the floor of the 3rdrd ventricleventricleType C: Tumor is more voluminous with Type C: Tumor is more voluminous with extension into the 3extension into the 3rdrd ventricle up to the ventricle up to the foramen of Monroforamen of MonroType D: Tumor extends into temporal or Type D: Tumor extends into temporal or frontal fossafrontal fossa
Pathologic ClassificationPathologic Classification
Benign or malignantBenign or malignant
Chromophobic – Non-functioningChromophobic – Non-functioning
Basophilic – Cushing’s Basophilic – Cushing’s
Acidophilic - AcromegalyAcidophilic - Acromegaly
MixedMixed
WHO ClassificationWHO Classification
Five-tiered systemFive-tiered system Clinical presentation and secretory activityClinical presentation and secretory activity Size and invasiveness (e.g. Hardy)Size and invasiveness (e.g. Hardy) Histology (typical vs. atypical)Histology (typical vs. atypical) Immunohistologic profileImmunohistologic profile Ultrasturctural subtypeUltrasturctural subtype
The long-term efficacy of conservative The long-term efficacy of conservative surgery and radiotherapy in the control surgery and radiotherapy in the control
of pituitary adenomasof pituitary adenomasRetrospective study of 411 patients Retrospective study of 411 patients treated with EBRT for pituitary adenomastreated with EBRT for pituitary adenomas
Goal is to assess both long-term efficacy Goal is to assess both long-term efficacy and toxicity of conservative surgery and and toxicity of conservative surgery and RT in the management of pituitary RT in the management of pituitary adenomasadenomas
M. Brada et al, Clinical Endocrinology (1993) 38, 571-578
MethodMethod252 of 411 pts with non-functioning pituitary 252 of 411 pts with non-functioning pituitary adenomas adenomas 131 of 411 pts had functional pituitary adenomas 131 of 411 pts had functional pituitary adenomas (62 acromegaly, 60 prolactinomas, 7 Cushing’s, (62 acromegaly, 60 prolactinomas, 7 Cushing’s, 1 TSH, 1 Gn secreting)1 TSH, 1 Gn secreting)338 had surgical intervention; 11 with complete 338 had surgical intervention; 11 with complete resectionresection187 transfrontal approach, 24 trans-sphenoidal 187 transfrontal approach, 24 trans-sphenoidal approach, 35 had no surgeryapproach, 35 had no surgeryMedian f/u of 10.5 yrsMedian f/u of 10.5 yrs
M. Brada et al, Clinical Endocrinology (1993) 38, 571-578
Radiation TherapyRadiation Therapy
Post-op RT to prescribed dose of 45-50 Post-op RT to prescribed dose of 45-50 Gy in 25-30 fxs delivered at Gy in 25-30 fxs delivered at ≤ 1.8Gy/fx≤ 1.8Gy/fx
Three-field technique aimed at a target Three-field technique aimed at a target volume encompassing the tumor and a 1-volume encompassing the tumor and a 1-2cm margin2cm margin
Patient treated in supine positionPatient treated in supine position
M. Brada et al, Clinical Endocrinology (1993) 38, 571-578
ResultsResults
Years after RTYears after RT Progression free survivalProgression free survival
55 96%96%
1010 94%94%
2020 88%88%
M. Brada et al, Clinical Endocrinology (1993) 38, 571-578
ResultsResults
Extent of surgical resection did not correlate with Extent of surgical resection did not correlate with outcomeoutcomeRelative risk of death compared with normal Relative risk of death compared with normal population was 1.76 (p<0.001) population was 1.76 (p<0.001) No prognostic factors for survival were identifiedNo prognostic factors for survival were identifiedMorbidity of RT was lowMorbidity of RT was low1.5% of pts had assumed radiation induced 1.5% of pts had assumed radiation induced visual deteriorationvisual deteriorationCumulative risk for 2Cumulative risk for 2ndnd brain tumor at 20 yrs was brain tumor at 20 yrs was 1.9%1.9%
M. Brada et al, Clinical Endocrinology (1993) 38, 571-578
ConclusionsConclusions
High tumor control rate and low toxicity in High tumor control rate and low toxicity in nonfunctional pituitary adenomas suggests nonfunctional pituitary adenomas suggests that limited surgical approach and post-that limited surgical approach and post-surgical conventional fractionated EBRT surgical conventional fractionated EBRT should be the treatment of choiceshould be the treatment of choice
M. Brada et al, Clinical Endocrinology (1993) 38, 571-578
Results of surgery and irradiation or Results of surgery and irradiation or irradiation alone for pituitary irradiation alone for pituitary
adenomasadenomas
Retrospective review of all patients with Retrospective review of all patients with pituitary adenoma treated with RT alone, pituitary adenoma treated with RT alone, surgery and RT, or RT following surgical surgery and RT, or RT following surgical failurefailure
Grigsby et al, J of Neuro-Oncology 6: 129-134 (1988)
MethodsMethods
212 patients with pituitary adenoma 212 patients with pituitary adenoma underwent treatment between 1954 and underwent treatment between 1954 and 19821982Median f/u was 11.9 yrsMedian f/u was 11.9 yrsRadiologic evaluation consisted of skull Radiologic evaluation consisted of skull films, angiography, films, angiography, pneumoenchephalography, pneumoenchephalography, ventriculgraphy, CT and MRIventriculgraphy, CT and MRI73% had transfrontal approach73% had transfrontal approach
Grigsby et al, J of Neuro-Oncology 6: 129-134 (1988)
Radiation TherapyRadiation Therapy
Grigsby et al, J of Neuro-Oncology 6: 129-134 (1988)
RTRT Number of PatientsNumber of Patients
Orthovoltage X-raysOrthovoltage X-rays 1212
Cobalt 60Cobalt 60 88
4 MV X-rays4 MV X-rays 1313
18-25 MV X-rays18-25 MV X-rays 175175
Radiation TherapyRadiation Therapy
Most patients treated with parallel-opposed Most patients treated with parallel-opposed portalsportals
Mean field sizes: 32.1 cm2 for EBRT alone, 45.3 Mean field sizes: 32.1 cm2 for EBRT alone, 45.3 cm2 for surgery and EBRT, and 40.3 cm2 for cm2 for surgery and EBRT, and 40.3 cm2 for EBRT for surgical failuresEBRT for surgical failures
Median dose for all patients is 4967 cGy Median dose for all patients is 4967 cGy
Pts receiving EBRT only had a mean dose of Pts receiving EBRT only had a mean dose of 3989 cGy; post-op EBRT 4493 cGy, and 4553 3989 cGy; post-op EBRT 4493 cGy, and 4553 for EBRT salvage of surgical failuresfor EBRT salvage of surgical failures
Grigsby et al, J of Neuro-Oncology 6: 129-134 (1988)
Grigsby et al, J of Neuro-Oncology 6: 129-134 (1988)
Grigsby et al, J of Neuro-Oncology 6: 129-134 (1988)
Grigsby et al, J of Neuro-Oncology 6: 129-134 (1988)
ConclusionConclusion
Overall survival after treatment for all Overall survival after treatment for all patients is not significantly different from patients is not significantly different from an age, sex, and race matched populationan age, sex, and race matched populationPatients receiving surgery and post-op RT Patients receiving surgery and post-op RT had a greater control of local disease had a greater control of local disease EBRT salvage of surgical failures is EBRT salvage of surgical failures is possiblepossibleEBRT treatment results in a low EBRT treatment results in a low complication ratecomplication rate
Grigsby et al, J of Neuro-Oncology 6: 129-134 (1988)
Gamma-Knife RadiosurgeryGamma-Knife Radiosurgery
Gamma knife radiosurgery for Gamma knife radiosurgery for pituitary adenomaspituitary adenomas
Retrospective review of 79 pts treated with Retrospective review of 79 pts treated with GKS for pituitary adenomasGKS for pituitary adenomas
Purpose: To look at the clinical results of Purpose: To look at the clinical results of GKS and both its efficacy and safety in GKS and both its efficacy and safety in treatment of pituitary adenomastreatment of pituitary adenomas
Masahiro et al, J of Neurosurgery (Suppl 3) 93:19-22,2000
MethodsMethods
79 of 108 pts treated between 1993 to 79 of 108 pts treated between 1993 to 1999 with GKS whom f/u exceeded 6 mo.1999 with GKS whom f/u exceeded 6 mo.
56 FAs ( 29 acromegaly, 15 56 FAs ( 29 acromegaly, 15 prolactinomas, 12 Cushing’s) and 23 prolactinomas, 12 Cushing’s) and 23 NFAsNFAs
Mean age 50.2 yrs (26 y/o – 82 y/o)Mean age 50.2 yrs (26 y/o – 82 y/o)
49 female and 30 male49 female and 30 male
Mean tumor vol. 7.1 cm3Mean tumor vol. 7.1 cm3
Masahiro et al, J of Neurosurgery (Suppl 3) 93:19-22,2000
Radiosurgical TreatmentRadiosurgical Treatment40 pts (24 FAs and 16 NFAs) underwent 40 pts (24 FAs and 16 NFAs) underwent pre-GKS surgical resectionpre-GKS surgical resectionMean margin dose – 22.5 Gy (FA 24.2 Gy, Mean margin dose – 22.5 Gy (FA 24.2 Gy, NFA 19.5)NFA 19.5)Highest possible isodose (50-70%) usedHighest possible isodose (50-70%) usedMean f/u period of 26.4 monthsMean f/u period of 26.4 monthsTumor control= decreasing or unchanged Tumor control= decreasing or unchanged tumor vol.tumor vol.Endocrinologic improvement=fall in elev. Endocrinologic improvement=fall in elev. hormone levelhormone level
Masahiro et al, J of Neurosurgery (Suppl 3) 93:19-22,2000
ResultsResults
Tumor control – 93.6% (NFA 95.6%, FA Tumor control – 93.6% (NFA 95.6%, FA 92.8%)92.8%)Tumor shrinkage – 24.1% (NFA 26.1%, Tumor shrinkage – 24.1% (NFA 26.1%, FA 23.2%)FA 23.2%)Endocrinological improvement – 80.3%Endocrinological improvement – 80.3%Endocrinological normalization – 30.3%Endocrinological normalization – 30.3%5/6 pts with preexisting visual field showed 5/6 pts with preexisting visual field showed improvementimprovement3 pts. developed complications3 pts. developed complications
Masahiro et al, J of Neurosurgery (Suppl 3) 93:19-22,2000
ConclusionConclusion
Tumor growth control results achieved Tumor growth control results achieved with GKS is similar to those for with GKS is similar to those for fractionated RTfractionated RT
GKS may produce better results than GKS may produce better results than conventional RT in tx of pituitary adenoma conventional RT in tx of pituitary adenoma produced endocrinopathiesproduced endocrinopathies
GKS seems to be safer than fractionated GKS seems to be safer than fractionated RT in terms of complicationsRT in terms of complications
Masahiro et al, J of Neurosurgery (Suppl 3) 93:19-22,2000
Pituitary Adenoma: The efficacy of RT Pituitary Adenoma: The efficacy of RT as the sole treatmentas the sole treatment
Retrospective study of 29 patients with Retrospective study of 29 patients with nonfunctional or prolactin secreting nonfunctional or prolactin secreting macroadenomasmacroadenomas
Tumor dose – 4500 cGy in 4-5 wksTumor dose – 4500 cGy in 4-5 wks
Tumor controlled in 93% of ptsTumor controlled in 93% of pts
Conclusion: RT is effective for improving vision Conclusion: RT is effective for improving vision and can normalize hyperprolactinemiaand can normalize hyperprolactinemia
Doses need not exceed 4500 cGy in 25 fxsDoses need not exceed 4500 cGy in 25 fxs
Rush SC, Newall J., Int J Radiat Oncol Biol Phys 1989; 17:165
General ManagementGeneral Management
Pituitary adenoma management is complex Pituitary adenoma management is complex and is dictated by size, symptoms, and and is dictated by size, symptoms, and character of tumorcharacter of tumor
Treatment options require multiple Treatment options require multiple modalities, including: Surgery, RT, SRS, modalities, including: Surgery, RT, SRS, and medical managementand medical management
General ManagementGeneral Management
Multidisciplinary approachMultidisciplinary approach
Goals:Goals: Define tumor extentDefine tumor extent Evaluate hormone activityEvaluate hormone activity Remove tumor massRemove tumor mass Control hypersecretionControl hypersecretion Correct endocrine deficienciesCorrect endocrine deficiencies
General ManagementGeneral Management
Microadenomas: transsphenoidal surgery Microadenomas: transsphenoidal surgery or RTor RT
Macoradenomas: initial surgery with post-Macoradenomas: initial surgery with post-op RTop RT
Medical ManagementMedical Management BromocriptineBromocriptine SomatostatinSomatostatin
Pre-treatment MRI
Close to Chiasm?
yes no
SurgeryEBRTSRS/gamma-knife
Visual fieldtesting
Deficit
yes no
Surgery SurgeryEBRT
Treatment Algorithm
Appropriate for GKSAppropriate for GKS
Contraindication for GKSContraindication for GKS
RT Dosing GuidelinesRT Dosing Guidelines
EBRTEBRT
(1.8Gy/fx)(1.8Gy/fx)
Radio-Radio-surgerysurgery
(optic chiasm (optic chiasm dose < 9 Gy)dose < 9 Gy)
Local Local
Tumor Tumor
ControlControl
Biochemical Biochemical ControlControl
Nonfunctioning Nonfunctioning tumorstumors
45-50.4 45-50.4 GyGy
12-24 Gy 12-24 Gy to marginto margin
95%95% NANA
Functioning Functioning tumorstumors
45-54 Gy45-54 Gy 25-30 Gy 25-30 Gy to marginto margin
90-90-95%95%
33-95%33-95%
ComplicationsComplications
HypopituitarismHypopituitarism
Vision lossVision loss
CarcinogenicCarcinogenic
Radiation necrosisRadiation necrosis
Cerebral InfarctionCerebral Infarction
Future DirectionsFuture Directions
Profiles of toxicity in the 2-D vs. 3-D eraProfiles of toxicity in the 2-D vs. 3-D era
Thank YouThank You
FacultyFaculty
ResidentsResidents
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