Pituitary Adenomas

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


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


ResultsResults

Years after RTYears after RT Progression free survivalProgression free survival

55 96%96%

1010 94%94%

2020 88%88%


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%


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


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




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


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





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


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


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


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


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


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


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


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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Pituitary Adenomas