87 year old female with dyspneaRommel R Geronimo MDPGY-3June 11, 2014

HPI87-year old female presented with 2 day history of dyspnea Several months of nonproductive coughIntermittent dyspnea, mostly on exertion but sometimes even at restHas occasional wheezing

HPINo fever or chillsNo night sweatsNo hemoptysisNo chest painNo palpitationsNo recent travel or exposure to sick contacts

Review of SystemsNo nausea, vomiting or abdominal painNo diarrhea or constipationNo dysuria or hematuriaNo headache, dizziness or numbnessNo significant changes in weight

Past Medical HistoryAllergic rhinitis takes Loratadine prnDenies history of asthma, COPD or PTBNo history of cancer, heart disease or DMNo known drug allergies

Past Surgical HistoryHysterectomyAppendectomy

Family HistoryAsthmaBreast cancer Coronary artery diseaseNo family history of kidney disease, thyroid disease or DM

Social HistoryNonsmokerNon-alcohol drinkerNo history of illicit drug useLives at home by herself

Initial PET: 36.8, BP: 146/77, HR: 90, RR: 14, Sats: 93% on room airAlert, oriented x 3, in no distressSkin: warm, dry, no rash or lesions, good skin turgorHEENT: moist oral mucosa, anicteric, supple neck, no JVD, no LAD, no neck masses

Initial PELungs: Expiratory wheezing, no cracklesHeart: Normal rate, regular rhythm, no murmurs/rubs/gallopsAbdomen: Soft, nontender, bowel sounds present in all quadrantsExtremities: No edema, no cyanosis, no clubbing, good peripheral pulsesNeuro: Awake, alert, oriented x 3, no focal deficits

Initial Labs

CXR

Chest CT AngiogramNo evidence of PE or aortic dissection.Multiple nodules and calcifications in the thyroid glandNoncalcified nodules in the posterior RUL (9mm, 5mm, 3mm)Multiple nodules in the anterior right lung base (largest at 1cm)Confluent area of density in the lingula measuring 1.7 x 1.2 cm

Chest CT Angiogram1.9 cm LN in the right hilum1.3 cm LN in the aorticopulmonary windowMultiple small paratracheal nodes3-mm calcified granuloma left anterior lung base Interstitial infiltrates at the posterior lung bases bilaterally may be due to fibrosis or streaky inflammatory infiltrates.

CT Abdomen/Pelvis with IV contrastNo significant pelvic or retroperitoneal lymphadenopathySigmoid colon diverticulosis

Thyroid USThyroid gland is mildly enlarged.Right nodule measures 2.3 x 1.9 x 1.6 cm and appears solid with numerous internal areas of calcification.Left nodule measures 1.9 x 1.8 x 1.4 cm and contains more coarse calcifications with posterior acoustic shadowing which limits visualization of the entire left thyroid nodule.

Differentials

DifferentialsThyroid CancerFollicular, Papillary, Medullary, AnaplasticMultinodular Toxic GoiterBenign Thyroid NodulesPulmonary NodulesInfectious Neoplastic primary vs metastatic

Approach to thyroid noduleswww.aafp.org

www.aafp.org

Additional LabsTSH: 2.540 (0.358-3.740) T4: 8.8 (4.7-13.3)T3: 1.0 (0.7-1.9)25, OH Vitamin D: 24 (30-100)ESR: 4 (0-21)Hepatic panel: Normal

The patient underwent FNAB of the thyroid nodules

FNA Cytology

FNA Cytology

FNA Cytology with Calcitonin IHC stain

FNA Left ThyroidPositive for malignant cells. FEATURES COMPATIBLE WITH MEDULLARY CARCINOMA. A calcitonin stain is positive.

FNA Right thyroidPositive for malignant cells. FEATURES COMPATIBLE WITH MEDULLARY CARCINOMA.

Additional LabsCalcitonin: 2583 pg/mL (

Additional Labs

The patient underwent Total Thyroidectomy with Central Neck Dissection

Thyroid Surgical Histopathology (Medullary)

Thyroid Surgical Histopathology (Medullary)

Thyroid Surgical Histopathology (Medullary)

Lymph Node

Lymph Node

Lymph Nodewith Calcitonin IHC stain

Thyroid Surgical Histopathology (Papillary)

Thyroid Surgical Histopathology (Papillary)

Total Thyroidectomy + Central Lymph Node DissectionBilateral medullary carcinomas confined within the thyroid tissue (2.2 cm and 2 cm)Incidentally discovered papillary thyroid carcinoma (1.75 cm), also contained within the thyroid tissueSmall benign perithyroidal lymph node present Single lymph node with metastatic medullar carcinoma present

Final DiagnosisBilateral Medullary Thyroid Carcinoma (T2N1)Papillary Thyroid Carcinoma (T1N0)

Medullary Thyroid Carcinoma

Medullary Thyroid Carcinoma (MTC)First described by Jaquet in the German literature as malignant goiter with amyloid.1In 1959, Hazard et al provided a definitive histological description.1Williams suggested that MTC originated from the calcitonin-secreting parafollicular C cells, derived from the neural crest1,2

MTCAccounts for < 5% of thyroid cancers3Most aggressive form of well-differentiated thyroid carcinoma, being responsible for 8 to 15% of all thyroid cancer-related deaths3In about 20% of cases, it is part of an autosomal dominant inherited disorder (MEN 2A and 2B).3In about 80% of cases, it presents sporadically.3

Clinical SyndromesSporadic MTCInherited MTCMEN 2AMEN 2BFamilial MTC

Sporadic MTCAccounts for about 80% of all cases4Patients usually in the 5th to 6th decades of life4Slight female preponderance4Most common presentation is a palpable neck massSolitary thyroid noduleEnlarged lymph node

Sporadic MTCGenerally unifocal5Tend to arise in the posterior thyroid, often invading the surrounding structures and causing dysphagia, hoarseness and/or respiratory difficulty5High levels of calcitonin leading to symptoms of flushing, diarrhea, and/or weight loss

Sporadic MTC10-15% of patients can present with distant metastases at the time of diagnosis5Most common sites:MediastinumLiver LungsBone

Sporadic MTCMost MTCs also secrete carcinoembryonic antigen (CEA)Occasional tumors secrete corticotropin (ACTH), causing ectopic Cushing's syndrome6Choi HS, Kim MJ, Moon CH, et al. Medullary thyroid carcinoma with ectopic adrenocorticotropic hormone syndrome. Endocrino Metab (Seoul). 2014 Mar; 29(1): 96-100.

Choi HS, Kim MJ, Moon CH, et al. Medullary thyroid carcinoma with ectopic adrenocorticotropic hormone syndrome. Endocrino Metab (Seoul). 2014 Mar; 29(1): 96-100.

Inherited MTCCaused by germline mutations in the RET proto-oncogene located in chromosome 10Transmitted in an autosomal dominant fashionTypically multifocal and bilateral5Usually preceded by premalignant C-cell hyperplasia7

MEN 2AAssociated with MTC, pheochromocytoma and primary parathyroid hyperplasiaSipple syndrome

MEN 2BAssociated with MTC, pheochromocytoma, mucosal neuromas and intestinal neurogangliomatosis

Familial MTCVariant of MEN 2AStrong predisposition to MTC but not to other clinical manifestations of MEN 2A5Strict definition:Absence of pheochromocytoma and hyperparathyroidism in 2 or more generations7Presentation must be after age 50 in multiple family members affected5

MENen.wikipedia.org

en.wikipedia.org

Fine-needle Aspiration BiopsySensitivity of 50-80%Increased sensitivity with addition of immunohistochemical staining for calcitonin8.

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Calcitonin9Measurement of serum calcitonin has not been part of the routine evaluation of pts with thyroid nodules in the USHigh sensitivity but poor specificityUsually correlates with tumor massUsually elevated in patients with palpable tumorPost op values may provide a prognostic factor or indicate biochemical cure.

False-positive CalcitoninHypercalcemiaHypergastrinemiaNeuroendocrine tumorsRenal insufficiencyPapillary thyroid CaFollicular thyroid CaGoiterAutoimmune thyroiditisMedicationsOmeprazoleBeta-blockersGlucocorticoids

CalcitoninCalcitonin measurement in FNAB washout fluid can help identify MTC in those diagnosed as benign, inadequate or indeterminate by FNAB cytology.3Threshold > 39.6 pg/mLThis method can reach 100% accuracy

Carcinoembryonic Antigen (CEA)Found in > 50% of patients with MTC5Can be used as a tumor marker> 30 ng/mL is suggestive of poor prognosis > 100 ng/mL suggests extensive LN involvement and distant metastasis.Anti-CEA antibodies for immunotherapy

Radiologic EvaluationWhen MTC is diagnosed by FNAB, US of the neck is indicated to look for cervical LN involvementMTC can spread by local invasion or mets within the neck or distantly10For pts with local LN mets or pre-op calcitonin > 400 pg/ml, additional imaging is required to assess for metastatic diseaseChest CT, Neck CT, CE Liver CT or Liver MRIMRI for suspected skeletal mets

Genetic ScreeningGermline testing of RET sporadic vs inherited MTCApproximately 95% of patients with MEN 2A and MEN 2B, and 88% of those with FMTC will have an identifiable RET mutationSomatic RET mutations are identified in only 30-50% of sporadic cases7

Genetic ScreeningAll patients with a personal medical history of primary C cell hyperplasia, MTC, or MEN 2 should be offered germline RET testing. (Grade: A Recommendation from ATA)1Appropriate genetic counsellingWhen the index patient is positive for a germline mutation, family members should be screened.

Prophylactic Thyroidectomy in CarriersPenetrance of familial MTC is almost 100%7All carriers of RET proto-oncogene mutation should be evaluated and treated surgically for MTC7Goal is to identify asymptomatic carriers of the mutation who will benefit from early thyroidectomy

Preoperative EvaluationCalcitonin and CEA levelsNeck USSerum calcium and PTH (hyperparathyroidism)Plasma fractionated metanephrines, 24 hour urine for fractionated metanephrines and catecholamines (pheochromocytoma)In a patient with negative RET proto-oncogene testing and no family history of MEN2 syndrome, biochemical testing for coexisting tumors is typically not required.

Surgical TherapyTotal thyroidectomy with central neck dissection is the procedure of choice for MTC7MTC usually spread to central neck nodesRequired fewer reoperationsIndication for lateral neck dissection is controversialRadioguided sentinel lymph node biopsy technique could be useful11Dissection is performed only in patients with proven lateral neck LN involvement

pTNM Staging (UICC and AJCC)

MortalityStage I< 2cm without evidence of extrathryoidal disease0Stage II2-4 cm without evidence of extrathyroidal disease13%Stage IIIAny tumor > 4 cm, Level VI nodal mets, microscopic extrathyroidal invasion regardless of tumor size56%Stage IVAny distant mets, LN involvement outside of level VI, gross soft tissue extension100%

Cervical LN Levelswww.aboutcancer.com

www.aboutcancer.com

Postoperative ManagementComplicationsHypoparathyroidismInjury to recurrent or superior laryngeal nervesThyroxine TherapyMeasurement of calcitonin and CEAResidual and recurrent disease

Thyroxine Therapy12Thyroxine replacement should be started immediately after surgeryInitial dose of 1.6 mcg/kg of body weightMeasurement of serum TSH in 1 monthGoal is to restore and maintain euthyroidismC cells are not TSH responsiveTSH suppression to less than normal is not indicated in MTCC cells do not concentrate iodineAdjuvant therapy with radioiodine is not approriate

Calcitonin and CEAMeasured 2-6 months after surgery to detect presence of residual diseaseNormal CEA and undetectable calcitoninBiochemically curedBest prognosis

Long-term Monitoring1For pts with undetectable post-op calcitonin and normal CEA levels:Twice yearly PE and measurement of calcitonin and CEA x 2 years then annuallyNeck US 6-12 month post-op to establish a baselineAdditional imaging not required unless calcitonin and CEA levels rise during ff up

Residual and Recurrent DiseasePersistent HypercalcitonemiaSurgeryRadiotherapy

Persistent Hypercalcitonemia1Calcitonin < 150 pg/mLPersistent loco-regional diseaseNeck US +/- cross-sectional imaging (CT or MRI)Monitoring of calcitonin and CEA every 6-12 monthsIf imaging is positive for persistent macroscopic metastatic disease consider meticulous dissection of all local and regional nodal tissue.

Persistent Hypercalcitonemia1Calcitonin > 150 pg/mLLikely to have distant metastasesAdditional imaging (CT/MRI of neck, chest, abdomen, bone scan)

Surgery for residual diseaseRe-operation is usually not curative and can be associated with significant morbidity Biochemical cure in only 25%Active surveillance observation optionSerial cross-sectional imaging q 6-12 monthsSurgical intervention if with structural disease progression

Radiotherapy for residual diseaseMay prolong the interval of disease progression or recurrenceRecommended for patients with evidence of extrathyroidal disease or extensive nodal metastases who did not undergo curative surgery Also used for palliation of painful bone metastases

ChemotherapyProgressive metastatic disease, cannot be treated by surgery or radiotherapyTyrosine Kinase Inhibitors (TKI)VandetanibCabozantinibSorafenibSunitinibCytotoxic AgentsDacarbazine-based chemotherapyVincristine, 5-FU, Cyclophosphamide, Streptozocin or Doxorubicin

Tyrosine Kinase Inhibitors

Vandetanib (ZD6474)13Approved for use in the USTargets VEGFR2, RETR and EGFRSE: diarrhea, colitis, rash, dermatitis, nausea, hypertension, headache, abdominal pain, hypocalcemia, ALT, QTRecommended starting dose of 300 mg daily

Cabozantinib14Approved by FDA for first-line treatment of advanced MTC in 2012Active against MET, VEGFR2, FLT3, c-KIT and RETA phase II trial with cabozantinib also showed promising response rates in patients with metastatic prostate cancer.

Investigational TherapyImmunotherapyTumor vaccinesRadioimmunotherapyRadiolabelled octreotide

Mixed / Collision Tumor15Thyroid tumors with both papillary and medullary carcinoma features are rare and represent < 1% of all thyroid malignanciesLess than 40 cases reported in literatureMixed tumor dual differentiationCollision tumor tumor with 2 separate and different componentsKataria K, Yadav R, Sarkar C, Karak AK. Simultaneous medullary carcinoma, papillary carcinoma and granulomatous inflammation of the thyroid. Singapore Med J. 2013; 54(7): 146-148

Kataria K, Yadav R, Sarkar C, Karak AK. Simultaneous medullary carcinoma, papillary carcinoma and granulomatous inflammation of the thyroid. Singapore Med J. 2013; 54(7): 146-148

Back to the casePt was started on levothyroxine therapy after the thyroidectomyNormal TSHLow calcitonin and CEA levels

Back to the casePulmonary nodules waxing and waning on serial CT ChestRUL nodule slightly increased in sizeSpiculated 1.0 x 1.1 cm 1.6 x 1.5 cmBronchoscopy with bronchial washingsNo evidence of endobronchial lesionsCytology: negative malignant cellsCultures: S. aureus, A. fumigatusTreated with course of Doxycycline

Back to the caseSecond bronchoscopy with bronchial washing and TBLBNo evidence of endobronchial lesionsAFB culture: Mycobacterium sp and Nocardia sp Fungal culture: Aspergillus fumigatusCytology: Negative for malignant cellsStarted on Bactrim DS and referred to IDID continued her on Bactrim DS x 3 months

Back to the caseOn follow up, still with chronic cough and exertional dyspneaStarted on Ciprofloxacin and Azithromycin for NTM

AcknowledgmentsDr. CilteaDr. SpeakmanDr. LeanoDr. TewariDr. Powell

ReferencesKloos RT, Eng C, Evans DB, et al. Medullary Thyroid Cancer: Management Guidelines of the American Thyroid Association. Thyroid. 2009; 19: 565-613.Trimboli P, Giovanella L, Crescenzi A, et al. Medullary thyroid cancer diagnosis: An appraisal. Head & Neck. 2013. doi: 10.1002/hed.23449.Pusztaszeri MP, Bongiovanni M, Faquin WC. Update on the cytologic and molecular features of medullary thyroid carcinoma. Adv Anat Pathol. 2014; 21: 26-35Saad MF, Ordonez NG, Rashid RK, et al. Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients. Medicine. 1984; 63: 319.Roy M, Chen H, Sippel R. Current understanding and management of Medullary Thyroid Cancer. The Oncologist. 2013. 1093-1100.

ReferencesChoi HS, Kim MJ, Moon CH, et al. Medullary thyroid carcinoma with ectopic adrenocorticotropic hormone syndrome. Endocrino Metab (Seoul). 2014 Mar; 29(1): 96-100.Griebeler ML, Gharib H, Thompson GB. Medullary Thyroid Carcinoma. Endocrine Practice. 2013; 19 (4): 703-711Bhanot P, Yang J, Schnadig VJ, Logrono R. Role of FNA cytology and immunochemistry in the diagnosis and management of medullary thyroid carcinoma: report of six cases and review of the literature. Diagn Cytopathol. 2007; 35 (5): 285-292.Costante G. Filetti S. Early diagnosis of medullary thyroid carcinoma: is systematic calcitonin screening appropriate in patients with nodular thyroid disease? Oncologist. 2011; 16: 49.Pacini F, Castagna MG, Cipri C, Schlumberger M. Medullary thyroid carcinoma. Clin Oncol. 2010. 22: 475

ReferencesBoni G, Mazarri S, Grosso M, et al. Sentinel node radioguided biopsy in surgical management of the medullary thyroid carcinoma. A case report. Ann Ital Chir. 2014 Jan 21; 85 (epub).Saad et al. Radioactive iodine in the treatment of medullary carcinoma of the thyroid. J Clin Endocrinol Metab. 1983; 57:124.Karras S, Anagonistis P, Krassas GE. Vandetanib for the treatment of thyroid cancer: an update. Expert Opin Drug Metab Toxicol. 2014 Mar; 10(3): 469-481 Grullich C. Cabozantinib: A MET, RET and VEGFR2 tyrosine kinase inhibitor. Recent Results Cancer Res. 2014; 201: 207-214.Kataria K, Yadav R, Sarkar C, Karak AK. Simultaneous medullary carcinoma, papillary carcinoma and granulomatous inflammation of the thyroid. Singapore Med J. 2013; 54(7): 146-148

Questions / Comments

*AAFP.org**TrimboliPusztaszeri et al. Adv Anat Pathol. 2014 Jan; 21(1):26-35*We describe a case of Cushing syndrome due to ectopic ACTH production from MTC in a 48-year-old male. He was diagnosed with MTC 14 years ago and underwent total thyroidectomy, cervical lymph node dissection and a series of metastasectomies. MTC was confirmed by the pathological examination of the thyroid and metastatic mediastinal lymph node tissues. Two years after his last surgery, he developed Cushingoid features, such as moon face and central obesity, accompanied by uncontrolled hypertension and new-onset diabetes. The laboratory results were compatible with ectopic ACTH syndrome. A bilateral adrenalectomy improved the clinical and laboratory findings that were associated with Cushing syndrome. This is the first confirmed case of ectopic ACTH syndrome caused by MTC in Korea.*RET proto-oncogene germline mutations were identified in MEN2a, MEN2b and FMTC in 1993.*RoyGriebler*Controversial*

9. Castro. Ann Intern Med. 2005;142(11):926.64. Toledo. Clinics (Sao Paulo). 2009;64(7):699-706.65. Endrogan. J Endocrinol Invest. 2006 Oct;29(9):771-5.*ATA 2009 guidelineGriebeler et al. Endocr Pract. 2013; 19(4)*ATA 2009

*Griebeler*Should be done before surgery*GriebelerBoni*Unfortunately, LN mets are already present in approximately 50% of patients at the time of initial surgery.*I submandibular, submentalII- upper jugularIII middle jugularIV lower jugularV posterior triangleVI - anterior compartment group comprises lymph nodes surrounding the midline structures of the neck extending from the level of the hyoid bone superiorly to the suprasternal notch inferiorly.

*Saad et al. Radioactive iodine in the treatment of medullary carcinoma of the thyroid. J Clin Endocrinol Metab. 1983; 57:124.*2-6 months post op**Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation). Numerous TKIs aiming at various tyrosine kinases have been generated by the originators of these compounds and proven to be effective anti-tumor agents and anti-leukemic agents. TKIs operate by four different mechanisms: they can compete with adenosine triphosphate (ATP), the phosphorylating entity, the substrate or both or can act in an allosteric fashion, namely bind to a site outside the active site, affecting its activity by a conformational change*Vandetanib targets multiple cell-signaling pathways involved in the molecular pathogenesis, namely VEGFR-2, EGFR and Rearranged during transfection recepor (RET)Karras et al. Expert Opin Drug Metab Toxicol. 2014 Mar; 10(3): 469-481.*Grullich C. Recent Results Cancer Res. 2014; 201:2017-214.*Kataria et al. Singapore Med J. 2013.*