Non-PET Tumor Imaging p6_I-131 MIBG

Jiraporn Sriprapaporn, M.D.

Nuclear Medicine

Siriraj Hospital

Mahidol University

Non-PET Oncologic Imaging_Jiraporn

Radiopharmaceuticals for Non-PET Oncologic Applications

Nonspecific

• Ga-67 citrate:

– Lymphoma

• Tl-201 chloride:

– Bone sarcomas

– Brain tumors

– Thyroid cancer

• Tc-99m sestamibi:

– Breast cancer

– Parathyroid adenoma

– Thyroid cancer

• Tc-99m tetrofosmin: Similar to sestamibi

Tumor-Type Specific

• I-131: Diff thyroid cancer (PTC, FTC)

• I-131 MIBG: Neural crest tumors (adrenal medullary imaging)

• Radiolabeled peptides, Somatostatin receptors:

– In-111 pentetreotide (OctreoScan): Neuroendocrine tumors

– Tc-99m HYNIC-TOC: NETs

– Tc-99m depreotide*: Lung cancer

• Radiolabeled monoclonal antibodies:

– Tc-99m arcitumomab (CEA-Scan)*: Colorectal cancer

– In-111 capromab pendetide (ProstaScint): Prostate cancer

REF : modified from The Requisites


• I-131 or I-123 Metaiodobenzylguanidine

• Noradrenaline analog

• Localizes in adrenergic tissues, catecholamine-producing tumors & their metastases

• First synthesized by Wieland et al. In 1979

• Also known as adrenal medullary imaging


• Patient Preparation:

– Withdrawal of drugs interfering MIBG uptake

– Lugol’s solution to block thyroid uptake of free iodide

• I-131 MIBG: 0.5-1 for PED, 1-2 mCi for adults, slowly injected

• Imaging at 24,48, (72) hrs pi.

• Normal uptake: Liver, spleen, salivary gls, myocardium, adrenal medulla, colon, bladder, (thyroid)

• Excretion: Kidneys, large bowel


2010 EANM/SNMMI Guideline


Thyroid Blockade in Adults

Compound Formulation Daily dose

Potassium iodate Capsules 170 mg

Potassium iodide Capsules 130 mg

1% Lugol’s Solution 1 drop/kg to a maximum of 40

drops (20 drops twice a day)

Potassium perchlorate Capsules 400 mg

2010 EANM Guideline


Drug interaction with MIBG uptake

• Cardiovascular & Sympathomimetic drugs

– Antiarrhythmics

– Combined /β blockers

– Adrenergic neurone blockers

– Ca channel blockers

– Inotropic sympathomimetics

– Vasoconstrictors symp.

– Β stimulants

– Nasal decongestants

• Neurological drugs

– Antipsychotics

– Tricyclic antidepressants

– Sedating antihistamine

– Opioid analgesics

– CNS stimulants

2010 EANM Guideline

√ Prazosin (-1 antagonist)


• Pheochromocytoma/Paraganglioma*

• Neuroblastoma*

• Medullary thyroid carcinoma (MTC)

• Carcinoid tumor

• The specificity in diagnosis has remained above 95%.

• The sensitivity has varied with the nature of the tumor: close to 90% for intra-adrenal pheochromocytomas but 70% or less for PGLs. [SNM 2012, PMID: 22475426]


Incidence of Pheochromocytomas

• Any age, male ~ female

• It is estimated that 1 to 8 (0.0001%–0.0008%) cases of pheochromocytoma occur per million persons annually;

– The incidence of pheo increases with advancing age, with the prevalence approaching 0.1% in elderly persons.

– The prevalence of pheo is about 4%-6.5% in patients who have an incidental adrenal tumor.

– The incidence of genetic predisposition to pheo is between 10% and 20% in patients diagnosed with an apparent pheochromocytoma.

– This tumor is found in up to 5% of patients evaluated for hypertension with suggestive clinical symptoms (eg, headache, diaphoresis, palpitations).

Mary Ann Nguyen & Martin, Gary D. Hammer, 2006 - file:///D:/1_ACAD%203/2006_Pheo_Update.pdf


Pheochromocytoma (A disease of 10%)

• Malignant (90% are benign)

• Bilateral (90% are arise in just one of the two adrenal glands)

• Extra-adrenal (90% occurs in the adrenal gland)

• In Children (90% are in adults)

• Familial (10% will have a family member)

• Recur (10% or slightly less, will come back 5 to 10 years later)

• Associated with MEN syndromes (patients with rare syndromes of endocrine tumors.)

• Present with a stroke (10% of these tumors are found after the patient has a stroke)

[Classic Sx or TRIAD : Headache, palpitation, sweating]

http://www.endocrineweb.com/


Multiple Endocrine Neoplasia

MEN MEN 1 (Wermer syndrome)

MEN 2

Mutation MEN1 gene RET proto-oncogene

Prevalence 1 in 30,000 individuals 1 in 30,000 to 1 in 35,000 individuals.

Inherited AD AD

http://www.cancer.gov/types/thyroid/hp/medullary-thyroid-genetics-pdq

MEN2- 3 subtypes • MEN2A • MEN2B • Familial MTC (FMTC)


MEN Syndrome_WIKI

• MEN I (3 Ps) -Pituitary, -Parathyroid, -Pancreatic

• MEN 2A (1M,2Ps) -MTC -Pheochromocytoma -Parathyroid

• MEN 2B (2Ms,1P) -MTC, -Marfanoid habitus/Mucosal neuroma -Pheochromocytoma

3P 2P 1M 1P 2M


Pheo & associated hereditary syndromes

von Hippel-Lindau Syndrome (vHL)***

• Autosomal dominant (AD)

• Patients with vHL can develop pheochromocytomas (often bilateral), paragangliomas, retinal angiomas, CNS hemangioblastomas (brain tumors), RCC, renal and pancreatic cysts, pancreatic endocrine tumors, and epididymal cystadenoma.

• Mutations in the vHL gene, on chromosome 3.

• In some families with vHL, pheochromocytoma is the only sign of the syndrome.

• Overall, about 10 to 20% of vHL patients will develop pheochromocytomas.

• Bilateral tumors may present synchronously (i.e. at the same time) or separately over the course of many years.

MEN2A and 2B syndrome***

• AD

• Mutations in the RET gene are responsible for tumor development in

MEN2. 2 forms

• MEN 2A, pheochromocytomas are usually bilateral but may be

asynchronous (i.e. develop separately over time). They occur in

about 50% of MEN2A patients and are associated with MTC and

hyperparathyroidism

• MEN2B (accounts for 5% of MEN2 cases) includes

pheochromocytomas (usually bilateral), MTC, mucosal neuromas

(bumps on the lips, tongue, and eyelids), thickened corneal nerves

over the front of the eye, intestinal ganglioneuromatosis, and a

marfanoid body habitus

Neurofibromatosis type 1 (NF1)

• NF1 is also known as von Recklinghausen's disease.

• Mutation in chromosome 17

• NF1 is characterized by café au lait lesions (i.e. coffee-colored skin spots)

and tumors arising from nerve cells in the skin.

• Pheochromocytoma can occur in up to 5% of cases.

• They can be both in the adrenal and outside of the adrenal, but are rarely

bilateral.

Familial Paraganglioma Syndrome

• Pheochromocytomas can also occur (albeit rarely) in association with

familial paraganglioma syndromes

• Mutations in the succinate dehydrogenase (SDH) gene.

• Mutations in the B, C, and D parts of the SDH gene lead to different forms

of the disease.


Genetic testing should be considered if ..

a patient has one or more of the following:

• Diagnosis at younger than 50 years old

• Bilateral pheochromocytomas

• Paraganglioma

• Family history of pheochromocytoma or paraganglioma

• Family history of the syndromes previously described

• Other signs or symptoms of the syndromes previously described


LAB Investigations

• Plasma metanephrine testing has the highest sensitivity (96%) for detecting a pheochromocytoma, but it has a lower specificity (85%).[28]

• In comparison, a 24-hour urinary collection for catecholamines and metanephrines has a sensitivity of 87.5% and a specificity of 99.7%.[29]

http://emedicine.medscape.com/article/124059-workup


Biochemical diagnosis of pheochromocytoma

Tests Sensitivity Specificity

Plasma free metanephrine1 96% 85%

24-hr urine metanephrine2 87.5% 99.7%

Plasma normetanephrine

24-hr normetaneohrine

24-hr urine VMA

http://emedicine.medscape.com/article/124059-workup

1. Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, et al. Biochemical diagnosis of pheochromocytoma: which test is best?. JAMA. 2002 Mar 20. 287(11):1427-34. 2. de Jong WH, Eisenhofer G, Post WJ, Muskiet FA, de Vries EG, Kema IP. Dietary influences on plasma and urinary metanephrines: implications for diagnosis of catecholamine-producing tumors. J Clin Endocrinol Metab. 2009 Aug. 94(8):2841-9.


Biochemical Diagnosis of Pheochromocytoma: Which Test is Best?

Lenders JW, Et Al. JAMA 2002 PubMed PMID: 11903030

Tests Sensitivity [95% CI] Specificity [95% CI]

Plasma free metanephrines 99% [96%-100%] 89% [87%-92%]),

Urinary fractionated

metanephrines 97% [92%-99%] 69% [64%-72%]

Plasma catecholamines 84% [78%-89%] 81% [78%-84%]

Urinary catecholamines 86% [80%-91%] 88% [85%-91%]),

Urinary total metanephrines 77% [68%-85%] 93% [89%-97%]);

Urinary VMA 64% [55%-71%] 95% [93%-97%]

Catecholamines & metabolites


Detecting Pheochromocytoma: Defining the most sensitive test.

Guller U et al. 2006


Pheochromocytoma, An Update

• The “rule of 10s” is an outdated axiom that can no longer be used as an epidemiologic guide to pheochromocytomas.

• Genetic testing should be performed in the following groups:

– patients with a family history of pheochromocytoma,

– patients with bilateral or multifocal tumors or malignant or extra-adrenal pheochromocytoma, and

– patients who are aged 50 years or younger when diagnosed with pheochromocytoma.

• Plasma free metanephrine levels are the biochemical test of choice for excluding pheochromocytomas. (sen 99%)

• CT and MRI should be used as first-line imaging modalities for localizing pheochromocytomas.

• Radiolabelled MIBG radionuclide scan is useful for confirmation of pheochromocytoma and evaluate the extent of disease.

Mary Ann Nguyen & Martin, Gary D. Hammer, 2006 - file:///D:/1_ACAD%203/2006_Pheo_Update.pdf


Interpretation-Pitfalls

• Causes of false-negative results

– Lesion size,

– Tumor biology ( radiotracer avidity),

– Physiological uptake masking cancer lesions,

– Pharmaceutical interference, etc.

• Causes of false-positive results

– Artifacts (eg. contamination-planar images),

– Uptake due to physiological processes (misleading),

– Benign uptake, etc.


I-131 MIBG Scan in Right Pheochromocytoma

A. Whole-body I-131 MIBG images

B. I-131 MIBG static images with renal ROIs (Tc-99m DMSA)

• Typical location of adrenal mass = superomedial aspect of the kidney

24 hrs 48 hrs

Anterior Posterior Anterior Posterior

160905

A

Anterior Posterior

B


I-131 MIBG SPECT/CT Images in Right Pheochromocytoma

Anterior Posterior

SPECT/CT

071011


21 F, VHL with Family Hx of Pheo (Dad) Bilateral Pheochromocytoma

APD 3-7-15


70 M, Paraganglioma Retroperitoneal nodule, 3x3x2 cm.

CW 28-4-15


Malignant Paraganglioma with Multiple Liver and Bone Metastases, preop

I-131 MIBG Scan

Anterior Posterior

SPECT/CT images-Preop

CL 3-12-2009


Malignant Paraganglioma w Multiple Liver & Bone Metastases, postop.

[Before & After 1st I-131 MIBG Rx]

20-1-2010 15-2-2010

Diagnostic I-131 MIBG scan Posttherapeutic I-131 MIBG scan


• Neuroblastoma (NBM) is an embryonal malignancy of the sympathetic nervous system, typically occurring in children younger than 4 years of age.

• 70% of tumors originate in the retroperitoneal region, from the adrenal or the abdominal sympathetic chain, and 20% occur in the chest, derived from the thoracic sympathetic chain.

• At the time of Dx, > 50% of patients present with metastatic disease typically involves LN, liver, bone, and bone marrow.

[common locations of bone metastases are in the metaphyseal area of long bones]

The Requisites


Sen & spec

• Radiolabelled MIBG sensitivity for detection of neuroblastoma is > 90%, with specificity of 95%.

• MIBG is much more specific than bone scan

• Can evaluate both bony and soft tissue (solid organ) metastases.

• Combined bone scan and MIBG scan highest sensitivity for

metastatic disease.

Clinical Indications

• The study is used for staging, detecting metastatic disease, restaging, and determining patient response to therapy. (MIBG is very sensitive)

The Requisites


• Girl, 3 yo.

• Neuroblastoma stage IV with multiple bone metastases 2-44

• Pretreatment

• Staging

ANT POST


• Girl, 3 yo.

• Neuroblastoma stage IV with multiple bone metastases (2-44)

• S/P 4 courses of chemotherapy (induction)

• F/U after Rx

ANT POST ANT POST

28-2-44 (PreRx) 6-6-44 (PostRx)


I-123 MIBG SPECT/CT & Bone Metastasis in NBM

• Axial I-123 MIBG SPECT/CT

images demonstrating focal

uptake in a metastatic focus

in the T12 pedicle. (A: SPECT,

B: Fused SPECT/CT, C: CT )

B C

Sharp SE et al. SNM 2011

Health & Medicine

Non-PET Tumor Imaging p6_I-131 MIBG