MedullaryMedullary Thyroid CancerThyroid Cancer

Manuel Molina, MDManuel Molina, MDLutheran Medical CenterLutheran Medical Center

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Case PresentationCase Presentation

57y/o 57y/o chinesechinese female complaining of right anterior neck female complaining of right anterior neck mass, progressively enlarging over the past 4 years mass, progressively enlarging over the past 4 years without hoarseness, without hoarseness, dysphagiadysphagia, , dyspneadyspnea, weight loss or , weight loss or palpitations. Presented to the surgery clinic referred by palpitations. Presented to the surgery clinic referred by her PMD for evaluation.her PMD for evaluation.PMH: PUDPMH: PUDPSH: NonePSH: NoneMed: NoneMed: NoneAllergy: NoneAllergy: NoneSocial: No smoking, Social: No smoking, EtOHEtOH, IVDU, IVDUFamily Family HxHx: mother=rectal cancer: mother=rectal cancer

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Physical ExamPhysical Exam

VS T=98VS T=9800 BP=94/56BP=94/56 HR=77 RR=18HR=77 RR=18Neck: enlarged right thyroid gland, nonNeck: enlarged right thyroid gland, non--tender, solid tender, solid texture, bilateral palpable nodes in both jugular chains.texture, bilateral palpable nodes in both jugular chains.Lung: CTALung: CTACardiac: RRR, no murmurCardiac: RRR, no murmurAbdomen: soft, NT, ND, +BSAbdomen: soft, NT, ND, +BSReflex: 2+Reflex: 2+

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LaboratoriesLaboratories

5.814

43301

1394.1

10724

8180.7

Ca =8.4 Free T4 = 1.23TSH = 2.1

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SurgerySurgery

Total Total thyroidectomythyroidectomy and bilateral modified and bilateral modified radical lymph node dissection. Reradical lymph node dissection. Re--implantation implantation right inferior parathyroid in SCM muscle.right inferior parathyroid in SCM muscle.

Finding: Frozen sectionRight thyroid mass: medullary carcinomaRight and left nodes: positive

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Pathology FindingPathology Finding

Right thyroid:Right thyroid:Gland: Gland: medullarymedullary carcinomacarcinoma

Left thyroid: Left thyroid: Gland: Gland: medullarymedullary carcinomacarcinomaNode: Node: metastaticmetastatic medullarymedullary carcinomacarcinoma

Neck dissection: Neck dissection: Right: 12/25 nodes positiveRight: 12/25 nodes positiveLeft: 16/16 nodes: negativeLeft: 16/16 nodes: negative

Superior Superior mediastinalmediastinal nodesnodes1/1 positive1/1 positive

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Hospital CourseHospital CoursePOD #1: hoarse voice, unable to swallow liquids, POD #1: hoarse voice, unable to swallow liquids, hypocalcemiahypocalcemia to 6.5 responding to Ca drip and to 6.5 responding to Ca drip and popo calciumcalciumPOD #3: ENT consult=b/l vocal cord paralysis, watchful POD #3: ENT consult=b/l vocal cord paralysis, watchful waiting.waiting.POD #6: modified barium swallow: laryngeal penetration POD #6: modified barium swallow: laryngeal penetration with puree; tube feed started. with puree; tube feed started. HypocalcemiaHypocalcemia resolved, pt on resolved, pt on popo calcium.calcium.POD #12: Tolerating antiPOD #12: Tolerating anti--aspiration dietaspiration dietPOD #20: Discharge homePOD #20: Discharge home

Head CT = No Head CT = No metsmets. . Chest CT = No chest mass/nodeChest CT = No chest mass/nodeAbd/PelAbd/Pel CT = No CT = No metsmets..Bone scan = No Bone scan = No metsmets..

CalcitoninCalcitonin = 1310= 1310 CEA= 55CEA= 55 24hr urine VMA = 7.324hr urine VMA = 7.3

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Outpatient Follow upOutpatient Follow up

63Gy external beam radiation.63Gy external beam radiation.Labs:Labs:

DateDate CalcitoninCalcitonin CEACEA7/18/047/18/04 >528>528 30.730.78/10/048/10/04 18301830 20.520.59/15/049/15/04 18101810 16.716.7

PET scan increase uptake in central and left PET scan increase uptake in central and left neck.neck.CTscanCTscan Abdomen and chest, Bone scan: Abdomen and chest, Bone scan: negative for metastasis.negative for metastasis.

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PET ScanPET Scan

MedullaryMedullary Thyroid Thyroid CancerCancer

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MedullaryMedullary CarcinomaCarcinoma

NeuroNeuro endocrine tumor of the endocrine tumor of the parafollicularparafollicularC cells and produce C cells and produce calcitonincalcitonin..33--5% of all thyroid carcinomas.5% of all thyroid carcinomas.Inheritance: 80% sporadic, 20% hereditary Inheritance: 80% sporadic, 20% hereditary MEN 2A and MEN 2B MEN 2A and MEN 2B CharacteristicsCharacteristics

Solitary neck noduleSolitary neck noduleSpread to regional lymph nodesSpread to regional lymph nodesDistant metastasis: liver, lung, bone, brainDistant metastasis: liver, lung, bone, brainSporadic: often unilateralSporadic: often unilateralMENMEN’’ss: always bilateral and : always bilateral and multicentricmulticentric

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MedullaryMedullary CarcinomaCarcinoma

Spreads to central nodes (hyoid bone to Spreads to central nodes (hyoid bone to innominateinnominate veins and medial to the jugular veins and medial to the jugular veins). Seen in 50% of MTC. veins). Seen in 50% of MTC. Metastasis to Metastasis to ipsilateralipsilateral jugulojugulo--carotid chain: carotid chain: 57% sporadic and 28% hereditary. 57% sporadic and 28% hereditary. ContralateralContralateraljugulojugulo--carotid chain: 36% sporadic and 19% carotid chain: 36% sporadic and 19% hereditary.hereditary.

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MedullaryMedullary CarcinomaCarcinoma

Peak incidencePeak incidencesporadic=50sporadic=50--6060’’s y.o.s y.o. familial=20familial=20--3030’’s y.os y.o

Mutation in Ret protoMutation in Ret proto--oncogene (6oncogene (6--7%), tyrosine7%), tyrosine--kinasekinase receptor on chromosome 10. Almost 100% receptor on chromosome 10. Almost 100% develop develop medullarymedullary carcinoma. carcinoma. High risk, screening and early treatment has High risk, screening and early treatment has potential to improve outcome.potential to improve outcome.PrognosisPrognosis

86% at 5 yrs 86% at 5 yrs 65% at 10 yrs65% at 10 yrs

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DiagnosisDiagnosis

Fine needle aspirationFine needle aspirationUltrasoundUltrasoundCTscanCTscan, MRI (, MRI (locoregionallocoregional or distant metastasis)or distant metastasis)111111--InIn--octreotide or 99moctreotide or 99m--TcTc--DMSA scan for distal DMSA scan for distal metastasis.metastasis.AntiAnti--CEA monoclonal antibodies for localization or CEA monoclonal antibodies for localization or recurrencerecurrenceCalcitoninCalcitonin and Ca stimulated and Ca stimulated calcitonincalcitonin levelslevels24h urine for 24h urine for metanephrinemetanephrine, VMA, Ca level. (40% of , VMA, Ca level. (40% of cases have cases have pheochromocytomapheochromocytoma and should undergo and should undergo adrenalectomyadrenalectomy first)first)Genetic testing (RET mutation)Genetic testing (RET mutation)

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TNM StagingTNM StagingT1T1: <2 cm: <2 cmT2T2: : 22--4 cm4 cmT3T3: > 4 cm +/: > 4 cm +/-- minimal minimal extrathyroidextrathyroid extension (e.g., extension to extension (e.g., extension to sternothyroidsternothyroid muscle or muscle or perithyroidperithyroid soft tissues) soft tissues) T4aT4a: beyond capsule: SQ soft tissues, larynx, trachea, esophagus, r: beyond capsule: SQ soft tissues, larynx, trachea, esophagus, recurrent ecurrent laryngeal nervelaryngeal nerveT4bT4b: : prevertebralprevertebral fascia or encases carotid artery or fascia or encases carotid artery or mediastinalmediastinal vessels vessels

N0N0: No regional lymph node : No regional lymph node N1N1: Regional lymph node (central compartment, lateral cervical, an: Regional lymph node (central compartment, lateral cervical, and upper d upper mediastinalmediastinal lymph nodes)lymph nodes)N1aN1a: to level VI (: to level VI (pretrachealpretracheal, , paratrachealparatracheal, and , and prelaryngealprelaryngeal/ / DelphianDelphian lymph lymph nodes) nodes) N1bN1b: to unilateral or bilateral cervical or : to unilateral or bilateral cervical or superior superior mediastinalmediastinal lymph nodes lymph nodes

M0M0: No distant metastasis : No distant metastasis M1M1: Distant metastasis : Distant metastasis

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AJCC StagingAJCC StagingStage 0Stage 0: occult disease (biochemical screening): occult disease (biochemical screening)Stage IStage I: < 2 cm. : < 2 cm. Stage IIStage II: 2: 2--4 cm4 cmStage IIIStage III: > 4 cm with minimal : > 4 cm with minimal extrathyroidextrathyroid extension extension or or metsmets limited to limited to pretrachealpretracheal, , paratrachealparatracheal, or , or prelaryngeal/Delphianprelaryngeal/Delphian lymph nodeslymph nodes. . Stage IVAStage IVA: : resectableresectable +/+/-- lymph node metastases [for lymph node metastases [for T4a] but no distant T4a] but no distant metsmetsStage IVBStage IVB: locally : locally unresectableunresectable +/+/-- lymph node lymph node metastases but no distant metastases but no distant metsmetsStage IVCStage IVC: distant : distant metsmets

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TreatmentTreatment

50% with metastasis at the time of initial surgery50% with metastasis at the time of initial surgerySporadic, palpable thyroid noduleSporadic, palpable thyroid nodule

Total Total thyroidectomythyroidectomyNonNon--palpable, found by screening palpable, found by screening

Central neck dissection:Central neck dissection:ResectResect nodes between hyoid bone and nodes between hyoid bone and sternalsternal notch and notch and internal jugular veininternal jugular vein

Palpable nodesPalpable nodesModified radical neck dissectionModified radical neck dissection (preservation of (preservation of sternocleidomastoidsternocleidomastoid muscle)muscle)

+/+/-- autograftautograft inferior parathyroid gland in forearm inferior parathyroid gland in forearm or or sternocleidomastoidsternocleidomastoid..

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TreatmentTreatment

MEN 2A + preclinical MEN 2A + preclinical medullarymedullary Ca (DNA ret Ca (DNA ret analysis, normal analysis, normal calcitonincalcitonin, normal U/S), normal U/S)

Simple total Simple total thyroidectomythyroidectomy w/o lymph node w/o lymph node dissectiondissection

Otherwise: total Otherwise: total thyroidectomythyroidectomy w/ central neck w/ central neck or modified radical neck dissectionor modified radical neck dissection

ComplicationsComplicationsPermanent Permanent hypoparathyroidismhypoparathyroidism and recurrent and recurrent laryngeal nerve palsy: <2%laryngeal nerve palsy: <2%

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TreatmentTreatment

HypercalcitoninemiaHypercalcitoninemia after initial surgery:after initial surgery:US of neck and CT of chest and abdomenUS of neck and CT of chest and abdomenBone scanBone scanLocalization of the disease by catheterization of Localization of the disease by catheterization of hepatic, IJ, and hepatic, IJ, and innominateinnominate veins with measurements veins with measurements of of calcitonincalcitonin level.level.Laparoscopic examination of the liver if no evidence Laparoscopic examination of the liver if no evidence of distal metastasis.of distal metastasis.Meticulous Meticulous microdissectionmicrodissection of all local and regional of all local and regional lymph node if no evidence of disease in neck or lymph node if no evidence of disease in neck or superior superior mediastinummediastinum

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Adjunctive TherapyAdjunctive Therapy

Positive surgical margin, Positive surgical margin, mediastinalmediastinal extension, extension, recurrencerecurrenceExternal beam radiation: palliative recurrent, External beam radiation: palliative recurrent, postpost--op gross residual, or inoperable tumor. op gross residual, or inoperable tumor. 86% control rate with residual microscopic neck 86% control rate with residual microscopic neck disease disease vsvs 52% in patients without treatment.52% in patients without treatment.40Gy radiation with 10Gy boosts40Gy radiation with 10Gy boostsPalliative chemotherapy: Palliative chemotherapy: metastaticmetastatic diseasedisease

No standard protocolNo standard protocolNo benefit in survival has been shownNo benefit in survival has been shown

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LongLong--term Prognosisterm Prognosis

Age at the time of diagnosisAge at the time of diagnosisHigher rate of disease free survival if <40yr. Higher rate of disease free survival if <40yr. (95 % (95 % vsvs 65%)65%)Familial and sporadic similar prognosis. MEN Familial and sporadic similar prognosis. MEN 2B likely invasive disease, worst prognosis.2B likely invasive disease, worst prognosis.BergholmBergholm, et. al., , et. al., CancerCancer, Jan. 1, 1997., Jan. 1, 1997.

Sweden, 1959Sweden, 1959--19811981113 males, 134 females113 males, 134 femalesSurvival at 10 yrs: 69%, at 15 yrs: 65%Survival at 10 yrs: 69%, at 15 yrs: 65%Familial:10 yrs: 61%, at 15 yrs: 54%Familial:10 yrs: 61%, at 15 yrs: 54%

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PrognosisPrognosis

Factors that predict poor prognosis:Factors that predict poor prognosis:Cellular heterogeneityCellular heterogeneityPaucity of tumor Paucity of tumor immunostainingimmunostaining for for calcitonincalcitoninProminent tissue Prominent tissue immunostainingimmunostaining for galectinfor galectin--33ImmunostaningImmunostaning for CEA associated scan or absence staining for CEA associated scan or absence staining for for calcitonincalcitonin..

CalcitoninCalcitonin and CEA levels should be measured 6 and CEA levels should be measured 6 months after surgery to detect residual diseasemonths after surgery to detect residual diseasePatient with normal Patient with normal calcitonincalcitonin and CEA are considered and CEA are considered biochemicallybiochemically cured and have the best prognosis. cured and have the best prognosis. Recurrence rate 5%.Recurrence rate 5%.

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PrognosisPrognosis

CalcitoninCalcitonin >100 pg/ml should be evaluated for >100 pg/ml should be evaluated for residual residual resectableresectable disease in the neck or distal disease in the neck or distal metastases (liver).metastases (liver).CalcitoninCalcitonin >1000 pg/ml, with no obvious neck >1000 pg/ml, with no obvious neck and upper and upper mediastinummediastinum, most likely have distant , most likely have distant metastases to liver.metastases to liver.10 yr survival if <20yr 98% and >60yr 41%10 yr survival if <20yr 98% and >60yr 41%10 yr survival if 10 yr survival if biochemicallybiochemically cured is 98% and cured is 98% and residual disease 69%.residual disease 69%.

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Adjuvant RadiationAdjuvant Radiation

BrierleyBrierley, et. al, , et. al, ThyroidThyroid, 1996., 1996.40 patients with high risk for recurrence40 patients with high risk for recurrence

Extra glandular invasionExtra glandular invasionLymph node involvementLymph node involvementChemical residual diseaseChemical residual disease

10 year local/regional relapse10 year local/regional relapse--freefree25 pt with post25 pt with post--op radiation: 86%op radiation: 86%15 pt without radiation: 52%15 pt without radiation: 52%

No role for radioactive Iodine because tumor No role for radioactive Iodine because tumor cells do not concentrate Iodine.cells do not concentrate Iodine.

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Chemotherapy: dacarbazine+5FUChemotherapy: dacarbazine+5FU

OrlandiOrlandi, et. al., , et. al., Ann. Ann. OncolOncol.,., Oct. 1994Oct. 1994..5 patients (225 patients (22--71 71 yoyo) with stage IV (locally ) with stage IV (locally advanced or metastasisadvanced or metastasis--unresectableunresectable))5 days 5 days dacarbazinedacarbazine + 12 hr 5FU, every 4 weeks. + 12 hr 5FU, every 4 weeks. 6 cycles to 4 pt. and 4 to 1 pt.6 cycles to 4 pt. and 4 to 1 pt.4 pt. had stable disease (chemical or clinical) 4 pt. had stable disease (chemical or clinical) after 8 months, 1 had progressive disease after 8 months, 1 had progressive disease

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SomatostatinSomatostatin Analogs and InterferonAnalogs and Interferon

Produces significant tumor shrinkage in Produces significant tumor shrinkage in advanced MTCadvanced MTC

RadioimmunotherapyRadioimmunotherapyRadiolabelledRadiolabelled antianti--CEA antibodiesCEA antibodies131131--II--Labelled antiLabelled anti--CEA.CEA.

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1.1. In a patient with sporadic In a patient with sporadic medullarymedullary carcinoma of the carcinoma of the thyroid without palpable nodes, the best surgical thyroid without palpable nodes, the best surgical treatment is:treatment is:

a.a. Total Total thyroidectomythyroidectomyb.b. Total Total thyroidectomythyroidectomy with central neck dissectionwith central neck dissectionc.c. Total Total thyroidectomythyroidectomy with with ipsilateralipsilateral radical neck dissectionradical neck dissectiond.d. Total Total thyroidectomythyroidectomy with bilateral modified radical neck with bilateral modified radical neck

dissections.dissections.

2.2. Gene associated with hereditary Gene associated with hereditary medullarymedullary carcinoma carcinoma of the thyroid is: of the thyroid is:

a.a. RETRETb.b. MycMycc.c. HerHerd.d. P53P53

3.3. For recurrent local or residual disease the best results For recurrent local or residual disease the best results are achieved with: are achieved with:

a.a. RadiationRadiationb.b. ReRe--resectionnofresectionnof involved lymph node levelsinvolved lymph node levelsc.c. ReRe--resection and radiotherapyresection and radiotherapyd.d. chemotherapychemotherapy