Radiation Oncology/CNS/Pituitary adenoma
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Pituitary Adenoma
Epidemiology
edit- Comprise ~10% of intracranial tumors
- On autopsy found in 5-25%
- Male:female 1:1
- Majority present between 30 and 50 years old
- Genetic predisposition in MEN-1
- Benign histologically
- Nonsecretory ~25%
- Secretory (hormonally active) ~75%
- Typically slow growth with insidious onset of symptoms
Anatomy
edit- Pituitary gland is confined within the sella turcica, part of the sphenoid bone.
- It measures ~1.5 cm
- Divisions
- Anterior pituitary (from Rathke's pouch): prolactin, growth hormone, ACTH, TSH, FSH, LH, and beta endorphin
- Intermediate lobe (from Rathke's pouch): MSH
- Posterior pituitary (from 3rd ventricle): oxytocin, ADH
- Due to the bony sella enclosure, growth of pituitary tumors is upward
Clinical presentation
edit- Incidental imaging finding
- Local compression
- Pituitary stalk: disruption of prolactin suppression from hypothalamus, leading to PRL overproduction
- Optic chiasm: visual symptoms, including bitemporal hemianopsia and loss of color discrimination
- Cavernous sinus: cranial nerve palsies, particularly ocular palsies
- 3rd ventricle: hydrocephalus
- Headaches
- Functional secretory symptoms
- Prolactin (~50%)
- Women: galactorrhea and hypoestrogenism, including decreased menstruation, anovulatory infertility, loss of libido, vaginal dryness
- Men: loss of libido, erectile dysfunction, infertility
- Growth hormone (~25%)
- Acromegaly: bone enlargement in hand/feet/skull, prominent jaw, cardiomegaly, heat intolerance, weight gain
- ACTH (~20%)
- Cushing's disease: central obesity (moon facies, buffalo hump), thin skin with striae, hirsutism
- Nelson's syndrome: hyperpigmentation and muscle weakness
- TSH (<1%)
- Other hormonal tumors are rare
- Prolactin (~50%)
Diagnosis
edit- MRI
- Endocrine evaluation
- Prolactin level (>100 ng/ml)
- Basal GH level (>10 ng/ml), IGF-1 level, glucose suppression
- Serum ACTH, free cortisol, dexamethasone suppression (>10 ug/ml after 8 hours)
- TSH, T3, T4
- FSH, LH, plasma estradiol, testosterone
- Skeletal survey in acromegaly
Staging
edit- By tumor size
- Microadenoma (<1 cm)
- Macroadenoma (>1 cm)
- By expansion or erosion of the sella (PMID 945663), not uniformly accepted
- Grade 0: Intrapituitary microadenoma with normal sellar appearance
- Grade I: Normal-sized sella (15 × 12 mm) with asymmetry of the floor
- Grade II: Enlarged sella with an intact floor
- Grade III: Localized erosion or destruction of the sellar floor
- Grade IV: Diffusely eroded or destroyed floor
Treatment Overview
edit- Observation for select nonsecreting microadenomas and small prolactinomas
- Microadenoma, not secreting prolactin: surgery
- Microadenoma, secreting prolactin: bromocriptine
- Macroadenoma: multimodality approach, typically surgery, if failed to suppress biochemically, then adjuvant/salvage RT
Medical Management
edit- Primary approach for prolactinomas
- Dopamine agonists - bromocriptine, cabergoline
- Salvage approach for acromegaly, if inadequate control after surgery
- Somatostatin analogues - octreotide, lanreotide
- Symptomatic management for Cushing's disease
- Ketoconazole to suppress cortisol secretion in adrenal glands
Surgery
edit- Goal:
- Decompress local symptoms
- Normalize endocrine function for secreting tumors
- Standard surgical approach is a transsphenoidal resection, either microsurgical or transsphenoidal
- For localized secretory tumors, surgical cure rate is 80-90%
- With biochemical failure, on second surgery tumor often found extending through dura into cavernous sinus. Success rate on reoperation tends to be lower
- Mortality 0.5%, significant morbidity ~1.5%
Conventional External Beam
edit- Control of hypersecretion (Perez & Brady)
- Acromegaly ~80%
- Cushing's disease 50-80%
- Hyperprolactinemia ~30%
Stereotactic Radiosurgery (SRS)
edit- Multi-Institutional; 2005 PMID 15871511 -- "Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium." (Sheehan JP, J Neurosurg. 2005 Apr;102(4):678-91.)
- Systematic literature review. 35 studies, 1621 patients treated with SRS.
- Outcome: Tumor size control ~90%; wide variability in endocrine control
- Toxicity: Risk of hypopituitarism, 2nd tumors, and cerebral vasculopathy appeared less than fractionated RT
- Conclusion: SRS offeres both safe and effective treatment for recurrent or residual pituitary adenomas; in rare instances it may be the best initial treatment
Proton Therapy
edit- Harvard
- GH; 1968 (1963–1967) PMID 4966299 -- "Proton-beam therapy in acromegaly." (Kjellberg RN, N Engl J Med. 1968 Mar 28;278(13):689-95.)
- Retrospective. 14/22 patients with acromegaly. Median time from onset to treatment 11.8 years. 5 prior RT therapy (36-40 rads). Proton dose typically 100-120 Gy (60-140 Gy), given 12 portals.
- Outcome: 7/12 improved clinically, 3/12 unchanged, 2/12 worse.
- Complications: Transient diplopia, H/A, anterior pituitary insufficiency
- GH; 2007 (1992–2003) PMID 18194929 -- "Proton stereotactic radiosurgery in management of persistent acromegaly." (Petit JH, Endocr Pract. 2007 Nov-Dec;13(7):726-34.)
- Retrospective. 22 patients, persistent acromegaly, at least 1 transsphenoidal surgery without biochemical cure. Median dose 20/1 CGE (15-24). Median F/U 6.3 years
- Outcome: CR (≥ 3 month normalization of IGF-1 without medical suppression) in 59%; median time to CR 3.5 years.
- Toxicity: New pituitary deficits 38%; no visual complications, seizures, brain injury or secondary tumors
- Conclusion: Proton SRS effective for persistent acromegaly, with low morbidity
- ACTH; 2008 (1992–2005) PMID 18029460 -- "Proton stereotactic radiotherapy for persistent adrenocorticotropin-producing adenomas." (Petit JH, J Clin Endocrinol Metab. 2008 Feb;93(2):393-9. Epub 2007 Nov 20.)
- Retrospective. 38 patients (33 Cushing's disease and 5 Nelson's syndrome), all with prior transsphenoidal surgery without biochemical cure, treated with proton SRS. Patients with NS underwent bilateral adrenalectomy median 40 months before SRS. Median F/U 5.2 years
- Outcome: CR (≥ 3 month normalization of urinary free cortisol without medical therapy) in Cushing's 52% and Nelson's 100%. Median time to CR 1.5 years
- Toxicity: New pituitary deficits 52%; no optic nerve damage, seizure or brain injury
- Conclusion: Proton SRS effective for persistent ACTH-secreting adenomas, with low morbidity
- GH; 1968 (1963–1967) PMID 4966299 -- "Proton-beam therapy in acromegaly." (Kjellberg RN, N Engl J Med. 1968 Mar 28;278(13):689-95.)
- Loma Linda; 2006 (1991–2001) PMID 16257131 -- "Fractionated proton beam irradiation of pituitary adenomas." (Ronson BB, Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):425-34. Epub 2005 Oct 27.)
- Retrospective. 47 patients with pituitary adenomas. 42 prior resection, 5 primary RT. Functional 49% (n=23). Median dose 54 CGE in 30 fractions, mean target volume 8 cm3
- Outcome: Stabilization in 100% with visible tumor, resolution 24%, regression 29%, stabilization 46%. If functional, biochemical control 86%, normalization 38%. OS 89%, due to disease progression 2 patients (Cushings)
- Toxicity: Temporal lobe necrosis with headaches 1 patient (2%), new visual deficits 3 patients (23%), hypopituitarism 11 patients (30%), panhypopituarism 2 patients (5%)
- Conclusion: Fractionated proton RT achieved effective radiologic, endocrinological, and symptomatic control; significant morbidity uncommon
- Saint Petersburg, Russia
- 1988 PMID 2848234 -- "[Effect of proton irradiation of the hypophysis on its gonadotropic and thyrotropic functions in patients with prolactinoma][Article in Russian]" (Isakov AV, Probl Endokrinol (Mosk). 1988 Jul-Aug;34(4):28-32.)
- Retrospective. 16 women, prolactin-secreting adenoma. Narrow beam proton therapy (1000 MeV) 40-120 Gy. Tested 2 month-2 years with IV TRH and LH-RH
- Outcome: Low reproductive function recover, lower functional reserves of hypophyseal thyrotrophs and gonadotrophs
- Conclusion: Refractivity to radiation exposure, and hypothalamic level of disorder of ovarian function regulation
- 1993 PMID 7801584 -- "[Results of proton therapy in the treatment of pituitary prolactin-secreting adenomas][Article in Russian]" (Konnov BA, Vestn Rentgenol Radiol. 1993 Sep-Oct;(5):46-9.)
- Retrospective. 75 female patients, prolactin-secreting pituitary adenomas. Narrow beam proton therapy (1000 MeV)
- Outcome: Response rate 96% in adenoma stage I-IIIa
- Conclusion: Outcomes superior to other treatment modalities
- 1988 PMID 2848234 -- "[Effect of proton irradiation of the hypophysis on its gonadotropic and thyrotropic functions in patients with prolactinoma][Article in Russian]" (Isakov AV, Probl Endokrinol (Mosk). 1988 Jul-Aug;34(4):28-32.)
- Lawrence Berkeley Laboratory
- 1991 PMID 1808652 -- "Heavy-charged-particle radiosurgery of the pituitary gland: clinical results of 840 patients." (Levy RP, Stereotact Funct Neurosurg. 1991;57(1-2):22-35.)
- Retrospective. 840 patients, 30 treated with protones, and 810 with helium ion. Pituitary tumors n=475 (59%), systemic disease treatment by inducing hypopituitarism n=365 (41%).
- Outcome: Great majority marked and sustained biochemical and clinical improvement
- Toxicity: Hypopituitarism in ~30%, focal temporal lobe necrosis ~1%
- 1980 (1957–1978) PMID 7415170 Full paper -- "Treatment of acromegaly, Cushing disease and Nelson syndrome." (Lawrence JH, West J Med. 1980 Sep;133(3):197-202.)
- Retrospective. 429 patients (acromegaly 72%, Cushing's disease 13%, chromophobe adenoma 8%, prolactin-secreting adenoma 4%, Nelson's syndrome 4%). Treated with alpha particles or protons. Dose ~60 Gy
- Outcomes reported
- 1991 PMID 1808652 -- "Heavy-charged-particle radiosurgery of the pituitary gland: clinical results of 840 patients." (Levy RP, Stereotact Funct Neurosurg. 1991;57(1-2):22-35.)
- ITEP, Russia; 1983 PMID 6314085 -- "[Proton therapy of pituitary adenomas][Article in Russian]" (Minakova EI, Med Radiol (Mosk). 1983 Oct;28(10):7-14.)
- Retrospective. 59 patients. Beam energy 200 MeV, beam diameter 7-15mm
- Outcome: Results reported. Least favorable results in prolactinomas
- Toxicity: No marked radiation reactions, neurological complications, or hypopituitarism
Radiotherapy vs Observation
edit- Netherlands (1979–98) PMID 17197121 -- "Immediate postoperative radiotherapy in residual nonfunctioning pituitary adenoma: beneficial effect on local control without additional negative impact on pituitary function and life expectancy." (van den Bergh AC, Int J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):863-9.)
- Cohort study. 122 pts with nonfunctioning adenomas. 1) Group 1 (Radiotherapy) / residual disease - 76 pts (62%), immediate postoperative radiotherapy at a median of 5.8 months. 2) Group 2 (Observation) / residual disease - 28 pts (23%). 3) Group 3 (No Residual) - 18 pts (15%). 3 pts in group 3 received immediate post-op RT.
- Median f/u 93 months (Group 1), 71 months (Group 2).
- Group 1 (RT): progression in 3 of 76 pts (4%). Local control rate 95% at 5 and 10 years.
- Group 2 (Obs): progression in 16 of 28 pts (57%). Local control rate 49% and 22% at 5 and 10 years. 14 of the 16 pts received RT for salvage (6 RT only, 8 RT + surgery). Control rate after salvage RT 95%.
- Group 3 (No Residual): progression in 1 of 18 pts (6%).
- Endocrine function: no difference between Groups 1 and 2.
- Conclusion: "Immediate postoperative radiotherapy provides a marked improvement of local control among patients with residual NFA compared with surgery alone, without an additional deleterious effect on pituitary function and life expectancy."