CLASSIFICATION OF PITUTARY TUMOR & THEIR MANAGEMENT

By

Dr.Anand kumar Jha

RIMS RANCHI

Tumor in the sellar and parasellar regions constitute 12-15% of all brain tumors

The most common of these are pitutary tumours,whichconstitute 8-12% of all intracranial neoplasms

Incidentalomas or lesions of the pituitary, picked up by imaging in assymptomatic patients, have been reported in10-37% of patients and on a follow up,40% of these increased in size ,20% become symptomatic and 9% of these incidental tumours developed apoplexy.

Most primary pituitary tumours are benign adenomas which arise from the anterior pituitary gland.

Neurohypophyseal tumors are rare

CLASSIFICATION OF PITUTARY TUMOURS

Adenomas may be classified by a number of schemes, including by endocrine function(aided by immunostaining) by light microscopy with routine histological staining, and by electron microscopic appearance.

Microadenoma: A pitutary tumour <1cm diameter.

Macroadenomas: A pitutary tumours >1cm diameter.

Light microscopicchromophobe: may produce

prolactine,GH,or TSHAcidophil:produce prl,TSH or

usually GHBasophil:gonadotrophins,b-lipotropin,or usually ACTH

Based on secretory productsEndocrine-active tumours: these are classified

based on their secretory products• prolactin cell adenoma

•Prolactin cell adenomas

sparsely granulateddensely granulated

•Growth hormone cell adenomassparsely granulateddensely granulated

•Mixed prolactin cell-growth hormone cell adenomas•Acidophilic stem cell adenomas•Mammosomatotroph cell adenomas•Corticotroph cell adenomas

sparsely granulateddensely granulated

•Gonadotroph cell adenomas•Thyrotroph cell adenomas•Plurihormonal adenomas

Endocrine-inactive(nonfunctional) tumours

A. null cell cytomaB. oncocytomaC. gonadotropin-secreting adenomaD. silent corticotropin secreting adenomaE. glycoprotein-secreting adenoma

MANAGEMENT OF PITUTARYTUMOR

Hormonally inactive macroadenomasdue to poor response rates to medication, surgery and /or XRT are usually the initial treatment of choice

Medical managementBromocriptineOctreotide

Surgical managementsurgical indications for hormanally inactive tumors:

•Tumors causing symptoms by mass efects

•Macroadenomas that elevate the chiasm

•Acute and rapid visual or other neurologicdeterioration.

•To obtain tissue for pathological diagnosis inquestionable cases

• Nelson’s syndrome

PROLACTINOMAS

Prolactin level<500ng/ml: PRL may be normalized with surgery

Prolactin level >500ng/ml:the chances of normalizing PRLsurgically are very low

Medical managementDopamine agonistsbromocriptine :start with 1.25mg PO q hs. Add additi-

onal 2.5 mg per day as necessary(based on PRL le-vels), making a dosage change every 2-4 weeks for microadenomas,or every 3-4 days for macroadeno-mas causing mass effect.

Cabergoline:start with 0.25mg PO twice weekly,andincrease each dose by 0.25mg every 4 weeksas needed to control PRL(maximum of 3mg)

Pergolide : Start with 0.05mgPO q hs,and increase by 0.025-0.05 mg(up to a maximum of 0.25mg/

day) until desired PRL levels are achieved.

Response to medical treatment:treatment response to DA is assesed with serial prolactin levels as shown in table

PRLlevel(ng/ml)

Recommendation

<20 20-50

>50

MaintainReassess dose

Consider surgery

Recommendations:if response to DA is satisfactory ,treat for 1-4 years

adenomas that are notlonger visible on MRI are candidate for DA agonist withdrawal.for microadenomas discontinue the drug;for macoadenomas slowly taper the drug then discntinue

Recurrence rate is highest during 1st year check prolactinlevels and clinical symptoms every 3 months during the

1st year. Long term follow up is required, especially for macroadenomas.

pe of adenoma Secretion Staining Pathology Percentage of hormone production cases

lactotrophic adenomas(prolactinomas) secrete prolactin acidophilicgalactorrhea, hypogonadism,amenorrhea, infertility, and impotence

30%[11]

somatotrophicadenomas secrete growth hormone (GH) acidophilic acromegaly in adults; gigantism in children 15%[11]

corticotrophicadenomas secrete adenocorticotropic hormone (ACTH) basophilic Cushing's disease

gonadotrophicadenomassecrete luteinizing hormone (LH), follicle-stimulating hormone (FSH) and their subunits

basophilic usually doesn't cause symptoms 10%[11]

thyrotrophic adenomas(rare) secrete thyroid-stimulating hormone (TSH) basophilic to chromophobicoccasionally hyperthyroidism,[12] usually doesn't cause symptoms

Less than 1%[11]

null cell adenomas do not secrete hormones may stain positive forsynaptophysin 25% of pituitary adenomas are nonsecretive[11]

Type of adenoma Secretion Staining Pathology Percentage of hormone production cases

lactotrophic adenomas(prolactinomas) secrete prolactin acidophilicgalactorrhea, hypogonadism,amenorrhea, infertility, and impotence

30%[11]

somatotrophicadenomas secrete growth hormone (GH) acidophilic acromegaly in adults; gigantism in children 15%[11]

corticotrophicadenomas secrete adenocorticotropic hormone (ACTH) basophilic Cushing's disease

gonadotrophicadenomassecrete luteinizing hormone (LH), follicle-stimulating hormone (FSH) and their subunits

basophilic usually doesn't cause symptoms 10%[11]

thyrotrophic adenomas(rare) secrete thyroid-stimulating hormone (TSH) basophilic to chromophobicoccasionally hyperthyroidism,[12] usually doesn't cause symptoms

Less than 1%[11]

null cell adenomas do not secrete hormones may stain positive forsynaptophysin 25% of pituitary adenomas are nonsecretive[11]

ACROMEGALY: Surgery is the primary t/t modality when t/t is indicated

assymptomatic elderly patients do not require t/tif no contraindications, surgery is currently the best initial therapy. Surgery is not recommended for elderly patients

Medical therapy: reserved for - patients not cured by surgery-for those who can’t tolerate surgery-for recurrence after surgery or XRT

XRT: for failure of medical therapy.not recommended asinitial t/t

MEDICAL THERAPYDopamine agonists(DAs): if responsive DAs are

especially well suited for GH tumors that cosecrete PRLbromocriptine 20-60mg/day ,maximal dose is 100mg/dycabergolinepergolideothers : lisuride, depo-bromocriptine

Somatostatin analoguesas initial medical therapy,or if no response to Das

Octreotide& octreotide-LAR start with 50-100ugSQ q 8hLanreotide

GH antagonist:Pegvisomant 5-40 mg/daySQ

Combination therapy: pegvisomant or octreotideplus DAs if no response to 1 drug alone

CUSHINGS DISEASE:-If pituitary MRI shows a mass: trans-sphenoidal surgery

If pituitary MRI is negative perform IPS samplingif IPS sampling is positive: surgeryif IPS sampling is negative : look for source of ACTH

If biochemical cure is not obtained with surgery:consider re-exploration if pituitary source is still suspectedstereotactic radiosurgery or medical therapyadrenalectomy in appropriate patients

Transsphenoidal surgeryit is the t/t of choice for mostcure rates are 85% for microadenomas, but are lower for larger tumors.

Stereotactic radiosurgeryoften normalizes serum cortisol level s. Useful for recurre-nce after surgery, inaccesible tumors(eg. cavernous sinus)

Adrenalectomytotal bilateral adrenalectomy corrects hypercortisolismin 96-100% but lifelong corticoid replacement are required and up to 30% develop Nelson’s syndrome

Medical therapy for patients who fail surgical therapy or for whom surgerycannot be tolerated , medical therapy and/or utilized .

Ketokonazole start with 200mg PO BID , usual maintenance doses 400-1200mg daily in divided doses

Aminoglutethimide 125-250 mg PO BID .do not exceed 1000mg/day

Metyrapone; 750-6000mg/day usually tid with meals Mitotane: 250-500mg PO q hsCyproheptadine: 8-36mg/d divided TID

Thyrotropin(TSH) secreting adenomas:-transsphenoidal surgery has been the traditional first linetreatment .these tumour may be fibrous and difficult toremovefor incomplete resection :post op XRT is employedif hyperthyroidism persists: medical therapy is added with agents including octreotide ,bromocriptine and oralcholecystographic agents eg.iopanoic acid

Medical therapyOctreotide ; start with 50-100ugSQ 8hrs

RADIATION THERAPY FOR PITUTARY ADENOMAS Conventional EBXRT usually consists of 40-50 Gy administered

over 4-6 weeks . Radiation therapy should not be routinely used following surgical

removal. Follow patients with yearly MRI. Treat recurrence with repeat operation .

Consider radiation if recurrence cannot be removed and tumor continue to grow. Table: Recurrence rate of pituitary

tumors removed by transsphenoi-dally

Extent of removal

Post op XRT Recurrencerate

subtotal no 50%

Gross total no 21%

subtotal yes 10%

Gross total yes 0

Surgical Treatment for pituitary adenomas: Medical preparation for surgery

stress dose steroids: given to all patients during and immediately after surgeryhypothyroidism: ideally , hypothyroid patients should have>4 weeks of replacement to reverse hypothyroidism

*donot replace thyroid hormone until the adrenal axis is assesed; if hypoadrenal, begin cortisolreplacement first, may begin thyroid hormone replacement after 24 hrs of cortisolSurgery is done frequently on patients with hypo

thyroidism and appears to be tolerated well in dvast majority of cases

Surgical approaches• Trans sphenoidal:

usually the procedure of choice.indicated for microadenoma, macroadenomas withoutsignificant extension laterally beyond the confines of the sella,patients with csf rhinorrhea, and tumors extension into sphenoid air sinus

A. sublabialB. trans-nares

• Trans ethmoidal approach• Trans cranial approaches;

Indications:-1.minimal enlargement of the sella with a large supra

sellar mass.2. extrasellar extension into the middle fossa i,e

larger than the intrasellar component.

3. Unrelated pathology may complicate a trans sphenoidalapproach : rare ,eg a parasellar aneurysm

4. unusually fibrous tumor that could not be completelyremoved on a previous transsphenoidal approaches

5. recurrent tumor following a previous transsphenoidalresection

B. Choices of approach• Subfrontal: provide access to both optic nerves • Frontotemporal:( pterional): good access for tumors with

significant lateral extrasellar extension• Subtemporal: usually not a viable choice. Does not allow

total removal of intrasellar component

TRANS SPHENOIDAL SURGERY

• Position:- supine, horseshoe head rest

or pin headholder

• Equipment:

Microscope

C-arm

image guided navigation system

Endoscopy cart

• Instrumentation: usually includes speculum, curetts

long instruments including bipolars

• Some surgeons use ENT to perform the approach and • closure and for follow up• post op ICU• consent

TECHNIQUE

• Lumbar drain: may be used with some macroadenomas toinject fluid to bring the tumor down ,also may be use for

p post-op CSF drainage following transsphenoidal repair of Csf fistula

• Medications: introperatively 100mg hydrocortisone IV q8hrs

• Positioning: elevate thorax 10-15 degree reduces venous pressureshoulder-roll

Top of head canted slightly to leftExtended neck slightly ET tube positioned down and to patients left Microscope: observer’ eyepiece on the left

• Abdomen or right thigh is prepped for fat graft• C-arm fluoro• After approach to floor of sella is complete outline, complet

outline the upper and lower boundaries of sella using an instrument under C-arm

•Opening the sellar floor:open exactly in midline using the nasal septum as a land-mark use a Kerrison rongeur to expand the opening

*stay away from the extreme lateral sella to avoid entering the cavernous sinus or injuring the carotid artery

•Coagulate the dura centrally in an X pattern with bipolar cautery

•Consider aspirating through dura with a 20 gauge spinal needle to rule out large venus sinus,aneurysm or emptysella

• Incise the dura in the X pattern • Tumor removal

Macroadenoma:gently bring tumor into the field with ring curettes and remove with pituitary rongeurs or aspirate with suction

Microadenoma: If the side of the tumor is known , begin exploration of the gland on that side by making incision with #11bladeand using a dissector to try and locate the tomor

•After removal of macroadenoma , check depth of tumor bed on fluoro or image guidence, and make sure it correlates with approximate tumor volume on MRI

• The sella may be packed in a number of ways - place muscle or fat in defect within sella- recreate the floor of the sella using nasal cartilage placed

within the sella- pack sphenoid sinuse with fat from abdomen-fibrin glue may optionally be used to help hold any of

these components in place

Intra operative disasters:• entry into carotid artery• opening through the clivus and erroneous biopsy of the

pons• opening through the floor of the frontal fossa with

into inferior frontal lobes

Perioperative complications1. hormonal imbalance

acute post-op concerns alterations in ADHcortisol deficiency-hypocortisolism-Addisoniancrisis

longterm: hypopituitarismTSH deficiency

Adrenal insufficiencyDeficiency of sex hormones

2.Secondry empty sella syndrome3.Hydrocephalus with coma4. Infection

pituitary abscessmeningitis

5. CSF rhinorrhea6. Carotid artery rupture7.Entry into cavernous sinus with possible injury of any

structure within8. Nasal septum perforation

Perioperative managementPre-op orders- Polysporin oinment applied in both nostrils the night

before surgery- Antibiotics;

chloramphenicol 500mg IV at 11PM& 6AMor chloramphenicol 500 po at MN & iv at 6 AM; ampicillin

1gm PO at MN &IV at 6 AM Ampicillin1 gm+0.5 gm sulbactum IVPB at MN &6 Am

-Steroid :- hydrocortisone sodium succinate 50mg im at 11PM & 6AM

Or hydrocortisone 100 mg PO at MN &IV at 6 AM - Intra op: continue 100 mg hydrocortisone IV q8 hrs

l

Post-op Orders:-1. intake and out put q 1 hr; urine specific gravity q 4 hrs

and anytime urine output >250ml/hr2. activity: BR with HOB @30 degree3.diet: ice chips PRN .patient is not to drink through straw4. no incentive spirometry5. IVF: base IV D5 ½ NS +20meq Kcl/L at rate of 75-100ml

per hour plus replace UO > base IV rate ml for ml with ½ NS

6. Medicins: Antibiotics: continue chloramphenicol 500 mg IVPB q

6hrs; change to PO when toleratedSteroid: hydrocortisone 50mg IM/IV q 6 hrs , on

POD #2 change to pednisone 5mg po q 6hrsfor 1 day, then 5 mg PO BID, D/c on POD#6

Diabetes Insipidus:Criteria: U.O >250ml/hr for 1-2 hrs and SG <1.005If DI develops , attempt to keep up with fluid loss with IVF if rate is too high for IV or PO replacement ,check urine SG

and if<1.005 then give a vasopressin preparation5U aqueous vasopressin (pitressin) IVP/IM/SQ q 6 hrs

ORDesmopressin (DDAVP) injection SQ/IV titrated to UO.

usual adult dose : 0.5- 1 ml daily in 2 divided dosesTHEN: when nasal pack out , either

intranasal DDAVP(100ug/ml) ;0.2 ml BIDOR Clofibrate 500mg PO QID

7. Labs: renal profile with osmolarity q 6hrs 8 AM serum cortisol

8. Nasal packs :remove on post-op day 3-6

Urinary out put: patterns of post op DIPost op DI generally follows one of three patterns

1. Transient DI: lasts until 12-36hrs post op2. Prolonged DI: lasts months, or may be permanent3. Triphasic response

DI – normalisation or SIADH like picture – DI again

Assesment for post op ACTH reserveIf patient was not hypocortisolemic pre op:

taper and stop hydrocortisone24-48 hrs post-op.Thencheck 6AM serum cortisol level after discontinuinghydrocortisone and interpret the results as shown in

table:-

6AMcortisol

Interpretation

Management

>9ug/dl Normal No further tests or t/t

3-9ug/dl PossibleACTH deficiency

Place patient on hydrocortisone

<3ug/dl ACTHdeficient

TABLE:- Interpretation of 6AM cortisollevels

Post op CT/MRI scan:The optimal timing of the initial post-op CT or MRI tofunction as a baseline to rule out future recurrence aftertrans sphenoidal surgery is 3-4 months post-op.

OUTCOMEFollowing transsphenoidal surgery In cases with compression of the optic apparatus ,there

can be significant improvement in vision followingsurgery

Endocrinogic cure was attained in 25% of prolactin secreting tumors, and in 20% of growth hormone secreting tumors

Gross total removal was unusual in tumors wiyh>2cm suprasellar extension

Recurrence incidence: 12% with most recurring 4-8 yrspost-op

Cushing disease: surgical cure rates are 85% for micro-adenomas but are lower for larger tumors

Management of recurrent pituitary adenomas For tumors demonstrating significant regrowth or

symptoms following initial resection, consideration forre- resection may be given .

Once the tumor is debulked ,consideration should be given to XRT, either immediately following the second operation or, if recurrence after a second operation thenalmost certainly after a third debulking

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