Diagnostic and surgical dilemmas in hereditary medullary thyroid carcinoma

The LaryngoscopeVC 2009 The American Laryngological,Rhinological and Otological Society, Inc.

Diagnostic and Surgical Dilemmas inHereditary Medullary Thyroid Carcinoma

Shawn M. Allen, MD; Donald Bodenner, MD; James Y. Suen, MD; Gresham T. Richter, MD

Medullary thyroid carcinoma (MTC) is a raremalignancy arising from the parafollicular C cellswithin the thyroid gland. The majority of cases aresporadic, but at least 30% are hereditary in nature.Inherited forms of MTC occur as familial MTC or asa manifestation of multiple endocrine neoplasia type2. Early diagnosis and aggressive surgical manage-ment, including prophylactic thyroidectomy, improvethe prognosis of patients with hereditary MTC. Sev-eral issues regarding the diagnosis and treatment ofMTC remain controversial. Genetic penetrance andvirulence are variable. We present an index case offamilial MTC to illustrate common difficulties in theinitial diagnosis and dilemmas in the surgicalapproach, followed by a review of current literaturerelevant to the management of hereditary MTC.

Key Words: Medullary thyroid carcinoma, familialmedullar thyroid carcinoma, hereditary medullarythyroid carcinoma, diagnosis, therapy, dilemmas.

Laryngoscope, 119:1303–1311, 2009

INTRODUCTIONMedullary thyroid carcinoma (MTC) is a rare malig-

nancy arising from parafollicular C cells that comprises3% to 10% of all thyroid cancers. MTC occurs predomi-nantly as a sporadic, nonhereditary lesion. However,inherited forms of MTC occur in at least 30% of cases.Hereditary MTC (HMTC) is autosomal dominant andoccurs in multiple endocrine neoplasia type 2 syndromes(MEN2A or MEN2B) or familial MTC (fMTC). Morethan 90% of genetic carriers will eventually develop thedisease.1 HMTC is attributed to germ-line mutations inthe rearranged during transfection (RET) proto-oncogeneon chromosome 10. Testing family members for thesemutations has been shown to identify those at risk forMTC with nearly 100% accuracy.1,2 Recently, a relation-

ship between genotype and tumor virulence has beenelucidated with evidence of more aggressive forms ofMTC in patients with MEN2B and MEN2A syndromes.In contrast, patients with fMTC tend to display an indo-lent course without additional endocrinopathies. Todistinguish fMTC from other MEN2 syndromes, a kin-dred must include at least 10 members with a commonRET mutation, have multiple affected members or car-riers over the age of 50 years, and must not presentwith any associated endocrinopathies such as pheochro-mocytoma or hyperparathyroidism.3,4

Refined genotype-phenotype relationships havehelped investigators identify specific mutations inHMTC that lead to later disease onset, reduced diseaseprogression, and improved survival. This informationhas impacted decisions regarding the timing and extentof neck surgery for subsets of individuals and their fam-ily members at risk for HMTC.5–9 Despite recent geneticadvances, there continues to be diagnostic uncertaintywhen encountering index cases of HMTC. Most probandspresent with palpable thyroid disease. However, mis-diagnosis can occur when fine needle aspiration (FNA),pathologic diagnosis, or family history are misleading. Inthe following case report we describe an index patientwith an unusual presentation of HMTC that led to aninitial misdiagnosis. By investigating this case, potentialdiagnostic errors and specific diagnostic dilemmas inidentifying index patients with HMTC are addressed.Genetic testing revealed a mutation at codon 618 of theRET proto-oncogene in this patient and his family mem-bers. Variations in the observed virulence of certainHMTC mutations are addressed, along with a specificdiscussion of controversies surrounding the surgicalmanagement of familial cases of MTC.

CASE PRESENTATIONThe index case is a 57-year-old male referred to the

endocrine clinic with a history of frequent flushing ofthe face and trunk over the past 5 years to 6 years. Hereported an increase in severity and frequency over thepast 6 months with witnessed events occurring after eat-ing and lasting approximately 15 minutes to 20 minutes.Light-headedness and heart palpitations during theseevents required him to remain seated. Aside from thesesymptoms, the patient was in good medical condition

From the Department of Otolaryngology–Head and Neck Surgery(S.M.A., J.Y.S., G.T.R.), Department of Geriatrics (D.B), University of ArkansasMedical Sciences, and Central Arkansas VA Medical Center (D.B.), LittleRock, Arkansas, U.S.A.

Editor’s Note: This Manuscript was accepted for publication onMarch 2, 2009.

Send correspondence to Gresham T. Richter, MD, Arkansas Child-ren’s Hospital, 800 Marshall St. S3109, Little Rock, AR 72205.E-mail: [email protected]

DOI: 10.1002/lary.20299

Laryngoscope 119: July 2009 Allen et al.: Dilemmas in HMTC

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with no other past medical or surgical history, and wasnot currently taking any medications. Review of systemswas negative for headaches, blurred vision, chest pain,diarrhea, shortness of breath, wheezing, orthopnea,dysuria, fevers, chills, new masses, or skin lesions. Hewas a nonsmoker, but admitted to using alcohol occa-sionally. The patient denied any known hazardous ortoxic exposures. The patient reported a history of headand neck irradiation as a child for adenoid hypertrophy.Family history was noncontributory, and negative forparaneoplasms, cardiac arrhythmias, thyroid tumors, orflushing.

Physical examination revealed a slightly overweightmale with an erythematous, easily blanching hue to hisskin primarily over his upper extremities. A 2-cm thy-roid nodule was palpated right of the midline, and noother physical abnormalities were discovered. Vital signswere as follows: blood pressure 127/72, heart rate 76,and weight 215 lb. Ultrasound of the thyroid revealed amultinodular gland. The left lobe contained an 8-mmsolid nodule with multiple smaller nodules in the infe-rior portion of the gland. The right lobe waspredominantly replaced by two 2.5-cm solid nodules withmicrocalcifications.

After informed consent, FNA was performed usingthree needle passes in each nodule of the right thyroid.FNA specimens were sent for cytological analysis, whichrevealed highly cellular aspirate smears composed ofpoorly cohesive, moderately pleomorphic cell populationswith some cells displaying prominent nucleoli. Rare pap-illary clusters and multinucleated giant cells wereobserved, and the morphology was interpreted by pathol-ogy as most consistent with papillary carcinoma. Frozensection at the time of surgical resection was recom-mended. Twenty-four hour urine analysis for 5-Hydroxyindoleacetic acid, catecholamines, and meta-nephrines was within normal limits. Serum serotonin,thyroid-stimulating hormone (TSH), thyroxine, and gly-cosylated hemoglobin were also within normal limits.

The patient was then referred to the head and necksurgery clinic for definitive management of a supposedpapillary thyroid carcinoma. Signs, symptoms, and phys-ical exam at this time were unchanged. Based upon thehistory of neck irradiation and cytologic diagnosis ofpapillary thyroid carcinoma, the patient was brought tothe operating room, where he underwent a right hemi-thyroidectomy. As recommended by pathology, thesurgical specimen was immediately sent for frozen sec-tion analysis and was found to contain some cellssuspicious for MTC. Intraoperative basal calcitonin mea-surement revealed a level of 4,057.6 pg/mL (normal, 0.7–11.5 pg/mL). With a presumed diagnosis of MTC, the de-cision was made to proceed with a total thyroidectomyand right paratracheal lymph node dissection.

Postoperatively, the final pathologic diagnosisrevealed bilateral MTC (right 2.5 cm, left 0.6 cm) withboth right paratracheal lymph nodes testing positive fordisease. All margins were clear at the time of resection.The patient’s postoperative course was unremarkable,with normal voice and serum calcium levels. The calcito-nin level one week postoperatively was 18.5 pg/mL.

Following discussion with the patient regarding hisdiagnosis and chance for cure, he returned to the operat-ing room 3 weeks later for more extensive surgicalintervention. A central and lateral compartment selectiveneck dissection was performed on the right, includinglevels II through VII. The patient’s postoperative coursewas again unremarkable, with a stable recovery andwithout complications. All of the excised lymph nodeswere pathologically negative for malignancy.

The index patient elected to undergo genetic screen-ing for mutations of the RET proto-oncogene.Polymerase chain reaction-based assay and DNAsequence analysis were used to search for mutations inexons 10, 11, 13, 14, and 16 of the RET proto-oncogene.A mutation was identified in exon 10, specifically atcodon 618 (Cys!Gly) of the RET proto-oncogene. Todetermine if this patient’s MTC was sporadic or heredi-tary in nature, 15 family members spanning fourgenerations were subsequently tested for RET proto-oncogene mutations (Table I). Eleven members, includ-ing the index patient, tested positive for the codon 618(Cys!Gly) mutation, and another family member whodid not undergo genetic testing was found to have MTCat surgery. In addition, eight of these patients presentedwith elevated basal calcitonin measurements. To date,eight of the 12 RET mutation carriers have undergonetotal thyroidectomies, seven of whom were positive for

TABLE I.Familial MTC Kindred.

Patient RET Mutation Thyroid Involved Calcitonin

Generation I

1 C618 n/a 15 :

2 (�) n/a n/a

Generation II

Index C618 (þ) Bilateral 4057 :

2 C618 (þ) Bilateral 773 :

3 * (þ) Bilateral 2800 :

4 C618 (þ) Ipsilateral 31 :

Generation III

1 C618 (þ) Ipsilateral 16 :

2 (�) n/a 1.3

3 (�) n/a 0.6

4 (�) n/a 1



7 C618 n/a 3

8 C618 n/a 2

Generation IV

1 C618 n/a 11

2 C618 n/a 8.6

Totals 11/16 (þ) 7/16 (þ) 8/16 (:)

Familial MTC kindred of index patient and four generations of hisfamily. Extent of thyroid disease identified pathologically at surgery and cal-citonin levels are revealed for each patient.

MTC ¼ medullary thyroid carcinoma; n/a ¼ not available; þ ¼ posi-tive; (�) ¼ negative; * ¼ genetic testing not performed, but MTC confirmedat surgery; : ¼ elevated above normal.


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pathologically confirmed MTC, and three of whom hadlymph node metastases at the time of surgery. Interest-ingly, the 89-year-old proband of the kindred testedpositive for the RET mutation, but had not undergonethyroid surgery and had no overt thyroid nodules. Ourindex case was the first family member to be diagnosedwith MTC. Consistent with the classification of fMTC,no family member has shown evidence of endocrinopa-thies related to MEN2A and MEN2B syndromes.

DISCUSSION

Diagnostic DilemmasCarcinomas of the thyroid typically present as

asymptomatic central neck masses. Nearly 80% of MTCpresents with palpable neck nodules. Locoregional symp-toms such as hoarseness, dysphagia, or painful neckmasses are uncommon. Even rarer are systemic manifes-tations such as Cushing syndrome, flushing, or diarrhea,which more often represent extensive metastatic dis-ease.10,11 Thus, the lack of characteristic symptomsmakes the diagnosis of sporadic or index cases of heredi-tary MTC difficult by history alone. Prognosis has beenshown to depend upon disease stage at diagnosis.12 Inthe absence of reliable symptomatic indicators, ultra-sound-guided FNA, family history, and serum calcitoninmeasurements have become the primary modalities indistinguishing MTC from various other thyroid patholo-gies. Unfortunately, these techniques are not failsafe,and can lead to diagnostic dilemmas in unusual cases.

Our index patient presented to the endocrine clinicwith a history of flushing, and was incidentally discov-ered to have a thyroid nodule. Although rare, elevatedcalcitonin and calcitonin-gene-related peptide levelshave been reported to cause vasodilation and flushing.13

Other neuroregulatory peptides arising from parafollicu-lar cells have also been connected to flushing anddiarrhea in MTC patients, including vasoactive intesti-nal polypeptide and serotonin.14 The FNA results led toan initial misdiagnosis of papillary thyroid carcinoma,which was consistent with his history of neck irradiationas a child. In addition, his family history and laboratorydata failed to suggest any alternative thyroid or MENpathology. An accurate diagnosis was not achieved untilthe results of frozen section analysis and basal calcitoninmeasurements were obtained at the time of his surgicalintervention, which then necessitated a more extensiveoperation than was originally planned. Genetic testingsubsequently identified a RET (618) mutation in theindex patient and 10 other family members. Taking intoaccount the lack of additional endocrinopathies, the kin-dred was diagnosed with fMTC. This case exemplifiespotential diagnostic pitfalls when dealing with indexcases of HMTC, and suggests the need for a careful diag-nostic approach when attempting to identify and classifycases of MTC.

Fine needle aspiration. The diagnosis and surgi-cal management of MTC often depends upon FNAresults. The cytologic diagnosis of MTC is based uponthe following characteristics: a dispersed cell pattern orloosely cohesive groups of plasmacytoid, spindle, and/or

epitheliod cells, two or more eccentrically located nuclei,a neuroendocrine chromatin pattern, azurophilic cyto-plasmic granules, and the presence of stromalamyloid.15–17 Unfortunately, inconsistencies in cell type,architecture, and surrounding material make somelesions difficult to analyze. Studies have demonstratedthat cytological analysis of an FNA specimen can beinaccurate in up to 78% of MTC cases.18–21 Several fea-tures have been subject to misinterpretation. Forexample, MTC tumor cells can cluster in folliculararrangements, resembling follicular neoplasms. In addi-tion, amyloid may or may not be present, and can bemistaken for colloid when surrounded by small groups oftumor cells mimicking colloid-containing follicles. Intra-nuclear or cytoplasmic inclusions, representingdisturbances in mitotic activities that are routinely seenin papillary thyroid carcinoma, have been described inMTC as well. Although amyloid and azurophilic gran-ules are specific to MTC, Papaparaskeva et al. reportedthat only 34% and 64% of 128 histologically confirmedcases of MTC display these features, respectively. Thediagnostic accuracy of FNA for MTC in their study was89%, with a positive predictive value of 85%.16

The specificity of FNA cytology for diagnosing MTCis inconsistent in the literature. However, several stud-ies have reported FNA sensitivity for MTC ranging from85% to 99%.16,22,23 This indicates a false-negative ratefor FNA cytology (mistakenly read as benign) from 1%up to 15%, suggesting a need for additional testing toensure adequate management of those patients requir-ing surgical therapy. Repeated FNA has been found toonly slightly enhance the sensitivity for detecting MTCfrom 70% to 74%.22 When a lesion is suspicious formalignancy and typical cytological features are absent,immunocytochemistry can be used to detect the presenceor absence of calcitonin, carcinoembryonic antigen(CEA), thyroglobulin, and other neuroendocrine markersto enhance diagnostic accuracy.17,24 Other diagnosticadjuncts include testing for elevated levels of calcitoninin serum or FNA washout fluid, and electron microscopyof the FNA aspirate to uncover MTC tumor cells exhibit-ing membrane-bound neurosecretory granules withelectron-dense cores.15,23,25–28

Family history. A thorough family history is criti-cal for any patient presenting with a thyroid nodule,especially for those diagnosed with MTC. Unfortunately,even careful questioning can fail to identify hereditaryforms of MTC in 5% of cases.29,30 Mobile western soci-eties, fragmented family structures, and adoptionundoubtedly contribute to this effect. However, variablegenetic penetrance is the most important confoundingfactor when attempting to identify HMTC by historyalone.

As many as 30% of MEN2A mutation carriers ex-hibit no signs of disease expression by age 70.1 Thisvariable late onset is likely even more prevalent infMTC, as the virulence of the disease is thought to bereduced. This was true of our kindred, in which theindex case presented with MTC at 58 years old, whereasthe father (proband) had no clinical evidence of diseaseby the age of 89 years. Unidentified carriers of fMTC


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mutations, therefore, may manifest disease later in lifedespite having no reported family history of the disease.In fact, an estimated 7% to 30% of sporadic cases arelater diagnosed as HMTC.31,32 It is thereby recom-mended that practitioners maintain high levels ofsuspicion for MTC in atypical cases of thyroid disease,and that all index cases receive genetic testing of theRET proto-oncogene regardless of the presence of knownthyroid pathology among family members.

Preoperative calcitonin measurements. Hyper-secretion of calcitonin, a weak paracrine regulator ofcalcium homeostasis, frequently accompanies MTC withrare exception. Thus, calcitonin represents a unique andsensitive biological serum marker for MTC screeningand monitoring patients for persistent or recurrent dis-ease. Basal or stimulated calcitonin levels arerecommended in patients newly diagnosed with MTC toestablish a baseline level for long-term follow-up,although the limited availability of pentagastrin in theUS limits access to stimulation testing. In the US, serialcalcitonin measurements are routinely performed in thepostoperative period. Universal calcitonin screening forevery patient with nodular thyroid disease, however, iscontroversial.

Basal calcitonin levels >100 pg/mL are highly sug-gestive of either C cell hyperplasia or MTC.33,34

However, mild elevations in serum calcitonin levels canoccur in controls, in patients with Hashimoto’s thyroidi-tis or benign nodular thyroid disease, and in patientswith MTC.35 Despite the relatively low incidence ofMTC, studies have demonstrated a high level of sensitiv-ity for detecting MTC using universal calcitoninscreening. A large prospective study of 1,385 patientswith thyroid nodules demonstrated that eight patients(0.57%) had calcitonin levels >55 pg/mL and had MTCconfirmed at surgery.18 In a similar study of 657patients with multinodular goiter and non-nodular con-trols, four (0.84%) of the nodular and none of the non-nodular patients had elevated calcitonin levels. All fourpatients with elevated calcitonin had surgically con-firmed MTC.36 Several other studies have reportedcomparable observations, identifying patients with MTCin 0.5% to 1.37% of patients with nodular thyroid dis-ease using routine screening of serum calcitonin.21,34,37

Karanikas et al. reported on routine basal andstimulated calcitonin measurements in a series of 414patients with suspected thyroid disease, as well as 362healthy controls. They found only 1 out of 28 patients(3.6%) with elevated basal serum calcitonin (using alower threshold of >10 pg/mL) to have histological evi-dence of MTC. Interestingly, this was the only patientwith a pentagastrin-stimulated calcitonin measurement>500 pg/mL. Selective calcitonin stimulation tests weretherefore recommended in patients with basal calcitoninlevels >10 pg/mL to improve the specificity for detectingMTC.35

The cost-effectiveness of universal calcitonin screen-ing for nodular thyroid disease is a current topic ofinterest. One recent US study postulated that routineserum calcitonin screening in patients with thyroid nod-ules could offer a cost-effectiveness comparable to that of

screening with TSH, colonoscopy, or mammography. Theresults were based upon a hypothetical model, however,and no prospective studies are available in the literaturesupporting a cost-effective calcitonin screening strat-egy.38 Although calcitonin screening is clearly of benefitin confirming the presence of MTC in patients withinconclusive or suspicious FNA results, the exact criteriafor a cost-effective screening approach remain in ques-tion. The current approach of the thyroid clinic at ourinstitution, which has been adopted since the indexpatient was seen in the clinic, is to measure basal calci-tonin levels for all patients who undergo FNA. Theincidence of MTC is expected to be higher amongpatients biopsied for suspicious nodules; however, thishas not been validated in a prospective study.

Surgical ManagementTherapeutic modalities for MTC are limited. Unlike

other differentiated thyroid cancers, parafollicular Ccells in MTC arise from neuroendocrine precursors andare unable to sequester iodine. This has eliminated radi-oactive iodine ablation as an adjunct for managing MTC.In addition, debate continues over the efficacy of chemo-therapy and external beam radiation therapy for MTC.Thus, precise and aggressive surgical managementremains the best therapeutic option for potential cure inthe management of MTC. However, the timing andextent of surgery remain controversial.

RET mutations and levels of risk. With modernadvances in genetic research, genetic testing has becomethe standard of care for diagnosing HMTC in familymembers at risk. In fact, genetic testing has a reportedaccuracy of nearly 100% for detecting more than 30 var-iations of RET mutations.1,2,7 Germ-line mutations inthe RET proto-oncogene cause a genetic predispositionfor all C cells within the thyroid to eventually developthe disease. Thus, total thyroidectomy is widely advo-cated for patients and family members with a geneticpredisposition for HMTC, whether diagnosed by clinicalevidence or by genetic screening. Consistency in the vir-ulence of specific RET mutations has led some cliniciansto tailor the timing of prophylactic surgery in diseasecarriers based upon genetic risk stratification of diseaseonset and progression (Table II).6,7,39,40 The RET muta-tions may be divided according to three classificationsbased upon the level of risk they entail.

Level 3 (highest risk) RET mutations cause earlyand aggressive MTC, and manifest clinically as MEN2Bsyndrome. Mutations on codon 918 of the RET proto-oncogene are found in more than 95% of MEN2B cases,and mutations on codon 883 comprise most of theremaining cases.4 In addition, codon 922 mutations anddual mutations involving codons 804/806 or 804/904 arerare causes of MEN2B syndrome.4,27 Subjects with codon918 RET mutations can develop MTC as early as 9months of age, with lymph node metastases or distantmetastatic disease observed in early childhood.41 Accord-ingly, prophylactic total thyroidectomy is recommendedwithin the first month of life, and is necessary by 6months of age if a level 3 RET mutation is present.


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Some authors suggest including prophylactic centralcompartment lymph node dissections at the time of thy-roidectomy,4,41 whereas others maintain that the risks ofhypoparathyroidism or recurrent laryngeal nerve injuryoutweigh the potential benefits in cases with normalpreoperative ultrasound, serum calcitonin, and CEAlevels.27

Level 2 (high risk) RET mutations manifest asMEN2A or fMTC syndromes. The most common level 2mutation involves codon 634 of the RET proto-oncogene,and is present in 80% to 85% of MEN2A cases 27,42 and30% of fMTC cases.4 Among the various genetic causesof MEN2A syndrome, codon 634 mutations carry thehighest rates of pheochromocytoma and hyperparathy-roidism, and cause MTC to develop at an earlier agerelative to other level 2 RET mutations.41 Thus, prophy-lactic total thyroidectomy before the fifth year of life isrecommended when a codon 634 mutation is present. Se-rious consideration should be given to including acentral compartment lymph node dissection at the timeof surgical prophylaxis, especially in subjects >5 years ofage.4,41 Other level 2 RET mutations involve codons 609,611, 618, 620, and 630.41,42 These mutations can causeMTC to develop as early as age 5, and prophylactic totalthyroidectomy before the fifth year is again recom-mended. However, inclusion of a central compartmentlymph node dissection at the time of surgical prophy-laxis is less urgent unless the subject is older than 10years of age.4,41

Level 1 (least high risk) RET mutations occur pre-dominately in fMTC, but have been found in some casesof MEN2A. Mutations of RET codons 790, 791, 804, and891 have been noted in both fMTC and MEN2A,whereas codons 635 and 637 are rare and less aggressivemutations observed in MEN2A only. Mutations at manyother RET codons are strictly associated with fMTC,including 532, 533, 600, 603, 606, 649, 768, 778, 781,806, 819, 844, 852, and 912.4,40,41,43 Subjects with level 1RET mutations rarely develop MTC before the seconddecade of life, and prophylactic total thyroidectomy isappropriate at 5 years to 10 years of age. One notableexception has been reported, in which a 6-year-old witha level 1 RET mutation at codon 804 died of metastaticMTC.41 However, the majority of cases involving theselevel 1 RET mutations tend to present with MTC laterin life, and the disease tends to take a less aggressivecourse. In particular, fMTC secondary to a mutation atRET codon 768 has been described as having a variable

age of onset, incomplete penetrance, and a better prog-nosis in comparison to other inherited causes of MTC.Some clinicians have relied upon careful clinical moni-toring for the development of MTC among young familymembers carrying this mutation, followed by total thy-roidectomy in adulthood.3

Cervical lymphadenectomy. Cervical lymphade-nectomy has traditionally been reserved for patientswith clinical evidence of lymphadenopathy on neckultrasound, highly elevated basal calcitonin levels, orabnormal calcitonin-stimulation testing. Debate hasrecently centered on the extent and timing of lymphade-nectomy in patients without obvious nodal involvementand in RET mutation carriers undergoing prophylacticthyroidectomy who may be harboring cervical lymphnode metastases. It is now clear that the majority ofpatients presenting with clinically apparent MTC havelymph node metastases at the time of diagnosis. Dralleet al. coined the term compartment-oriented lymphade-nectomy in 1994, and described the systematicdissection of cervical lymph nodes and connective tissueen bloc during total thyroidectomy for MTC. This aggres-sive surgical approach stemmed from early evidence ofhigh rates of cervical recurrence in patients undergoingthyroidectomy alone for MTC. They described four ana-tomically distinct compartments for locoregionalmetastasis of MTC, including central (level VI), lateral(levels III and IV bilaterally), and mediastinal (level VII)lymph node groups. In their retrospective review of 142cases of MTC, they demonstrated a reduced recurrenceand improved survival in patients undergoing systematicversus selective lymphadenectomy (10% vs. 48%).44

More recently, however, a number of studies have out-lined specific indications for compartmental neckdissection at the initial operation for MTC (Table III).

Central compartment lymph node dissections(CLND) should be included during thyroidectomy forany clinically evident MTC disease.27 More than 80% ofcases involving palpable MTC lesions were found toinvolve lymph node metastases in the central compart-ment.4 In particular, MTC has a predilection forinvolving sites along the tracheoesophageal groove.45 Inthe absence of a palpable or confirmed MTC lesion, thedecision to include CLND can be based upon elevatedpreoperative stimulated calcitonin levels, even if the ba-sal calcitonin level is within normal limits.46 Genetictesting also helps guide the surgical approach, as alllevel 3 RET mutations (codons 918, 883, 922) and level 2

TABLE II.Surgical Prophylaxis in HMTC.

Genetic Risk Classification Timing of Prophylactic Total Thyroidectomy Prophylactic CLND

Level 3 RET mutations (MEN2B) Preferably in 1st month, necessary by 6 months of age �

Level 2 RET mutations (MEN2A, fMTC) Before 5th year �*

Level 1 RET mutations (MEN2A, fMTC) 5–10 years of age

*Prophylactic CLND should be considered if a subject with RET codon 634 mutation is older than 5 years at the time of surgical intervention, or if a sub-ject with another level 2 RET mutation is older than 10 years at the time of surgical intervention.

CLND ¼ central compartment lymph node dissection; fMTC ¼ familial hereditary medullary thyroid carcinoma; HMTC ¼ hereditary medullary thyroid car-cinoma; MEN ¼ multiple endocrine neoplasia; RET ¼ rearranged during transfection.


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RET mutations past certain ages (codon 634 carriersolder than 5, or codon 609/611/618/620/630 carriers olderthan 10 years) should receive prophylactic CLND.41

Lateral compartment lymph node dissections ipsi-lateral to the MTC lesion (ILND) are mandatory if anypositive central compartment lymph nodes are discov-ered.27,47 More than 70% of cases with positive centrallymph nodes, and even 10% of cases with negative cen-tral compartments, demonstrated MTC metastases inthe ipsilateral lymph node bed.47 In addition, ILNDshould be included if preoperative ultrasound or physicalexam suggest ipsilateral lymph node involvement or ifthe primary tumor is larger than 1 cm to 1.5 cm.27,48

Some authors even suggest mandatory CLND þ ILNDfor any confirmed case of MTC based upon a high inci-dence of lymph node metastases observed and arelatively low morbidity involved with a unilateral neckdissection.49

Bilateral lateral compartment lymph node dissec-tions (BLND) should be included if the MTC lesioninvolves both sides of the thyroid gland.27 The presenceof 10 or more positive central compartment lymph nodescarries a 77% risk of contralateral lymph node involve-ment, and is also an indication for BLND. Morespecifically, the presence of a single positive central com-partment lymph node on the side contralateral from aunilateral thyroid lesion carries a 64% risk of contralat-eral compartment involvement, and is an indication forBLND.47 Other indications for BLND include extensiveipsilateral compartment lymphadenopathy,27 elevatedpreoperative basal calcitonin levels,46 obvious contralat-eral lymphadenopathy, and suspicion for residual orrecurrent disease.49 Scollo et al. noted positive lymphnode metastases in both central and lateral compart-ments irrespective of tumor size, ability to palpate thelesion, or laterality of the lesion within the thyroidgland, and recommended CLND þ BLND in all known

cases of sporadic or hereditary MTC unless the patienthas received adequate surgical prophylaxis.50 There issome consensus, however, that in cases with negativecentral and ipsilateral compartments, the contralateraldissection is unnecessary.47,50

Mediastinal lymph node dissection (MLND) at thetime of the initial surgery is indicated in the presence ofcomputed tomography or magnetic resonance imagingevidence of mediastinal lymph node enlargement.46,51 DeGroot et al. advocate an aggressive initial surgicalapproach to any palpable MTC lesion involving CLND,BLND, and inclusion of an upper MLND performedthrough a cervical incision. They recommend using amedian sternotomy approach to MLND in revision sur-geries for symptomatic patients with persistentpostoperative hypercalcitoninemia and suspicious media-stinal lesions on radiography to avoid rapid invasion ofthe disease into vital structures.52 Extrathyroidal tumorextension with positive lymph node metastases in theneck at the time of revision surgery is also an indicationfor MLND. Alternatively, in such patients without radio-graphic evidence of mediastinal lymphadenopathy at thetime of revision surgery, close follow-up with serialmediastinal imaging may suffice.51

Revision surgery should be considered for anypatient with persistent or recurrent disease followingtheir initial surgery. Secondary operations have beennoted to lead to biochemical cure (a normalized calcito-nin level) in up to 30% to 40% of cases.4,53 Morespecifically, a revision contralateral neck dissectionshould be considered if initially spared in the event thatpositive lymph node metastases were discovered in theside of the central compartment contralateral to theMTC lesion, or if postoperative calcitonin levels fail tonormalize.45

Post-operative monitoring. Calcitonin and CEAare the most accurate markers for persistent or

TABLE III.Neck Dissection in MTC.

Clinical Indications CLND* ILND* BLND MLND

Clinically negative MTC: Elevated preoperative stimulated calcitonin levels �

Clinically evident MTC: palpable lesion, positive imaging, or positive FNA �

Suspicious ipsilateral LNs on US or PE � �

Primary tumor >1 cm � �

1–9 positive central compartment LNs � �

Lesion involves both sides of thyroid � �

�10 positive central compartment LNs � �

Positive central compartment LNs contralateral to a unilateral thyroid lesion � �

Multiple positive ipsilateral compartment LNs � �

Suspicious contralateral LNs on US or PE � �

Elevated preoperative basal calcitonin levels � �

Residual or recurrent disease � �

Mediastinal LN enlargement on CT/MRI � � �

Extrathyroidal tumor extension with positive LNs in the neck at revision surgery � � �

*Some authors recommend a minimum of CLND þ ILND for any confirmed case of MTC.BLND ¼ bilateral lateral compartment lymph node dissection; CLND ¼ central compartment lymph node dissection; CT ¼ computed tomography; ILND

¼ ipsilateral compartment lymph node dissection; LN ¼ lymph node; MLND ¼ mediastinal compartment lymph node dissection; MRI ¼ magnetic resonanceimaging; MTC ¼ medullary thyroid carcinoma; PE ¼ physical exam; US ¼ ultrasound.


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recurrent MTC. Serial measurements of serum calcito-nin and CEA should begin 2 months to 3 monthsfollowing surgery, and should be followed annually evenif levels are initially undetectable.27 Biochemical curebased upon normal postoperative basal and stimulatedcalcitonin levels has proven difficult to achieve and sus-tain. Only 25% to 43% of MTC patients presenting withclinically apparent disease have long-term normal calci-tonin levels following total thyroidectomy and cervicallymphadenectomy.12,54 The percentage of patients withnormalized calcitonin is generally lower following revi-sion surgery for persistent disease.54,55 Modigliani et al.observed a survival advantage in patients with biochem-ical cure. They predicted survival rates of >95% at 10years in patients with sustained normal calcitonin lev-els, and related the prognosis to the disease stage andthe extent of surgery at presentation.12

A worse prognosis is expected when the serummarker doubling time is <2 years, and when calcitonindecreases late in advanced MTC, which suggests dedif-ferentiation of the tumor. Postoperative calcitonin levels>5,000 pg/mL suggest metastatic disease outside of theneck. In contrast, postoperative levels <100 pg/mL arerarely associated with radiographically demonstrabledisease, and should be followed closely with periodicultrasound of the neck.56

Long-term survival. Clinical studies of MTCpatients with long-term (at least 5 years to 10 years) fol-low-up periods have shown the disease-specific survivalto depend upon the following factors: age at presenta-tion, disease stage at presentation, extrathyroidalextension of primary tumor, extent of primary surgicalresection, postoperative serum calcitonin doubling time,association with MEN2B syndrome, and the presence ofa RET mutation on codon 918 in cases of sporadicMTC.57–61 Table IV summarizes the clinical characteris-tics of both hereditary and nonhereditary MTCclassifications. Reported disease-specific, 10-year sur-vival rates range from 40% for subjects with distantmetastases at presentation, up to 75.5% for subjectswith regional and/or lymphatic involvement, and as highas 95.6% for subjects with localized tumors involvingonly thyroid tissue at presentation.58,60 An elevatedpostoperative serum calcitonin level (biochemical persist-

ence) is observed in the majority of MTC patients, andhas been shown not to accurately predict long-term prog-nosis. In fact, 24% of MTC patients with persistentlyelevated calcitonin levels remained clinically negativefor disease in a long-term follow-up study, whereas 3%of MTC patients in another study developed a clinicalrecurrence despite initial biochemical cure.62,63 Postoper-ative serum calcitonin doubling time is a useful andstatistically significant indicator of prognosis, with dou-bling times >2 years associated with 100% survival at10 years, doubling times ranging 0.5 years to 2 yearsassociated with 37% survival at 10 years, and doublingtimes <0.5 years associated with 8% survival at10 years.58

CONCLUSIONHereditary MTC presents an interesting diagnostic

challenge when faced with indeterminate FNA results,frequently misleading family histories, and uncertaintysurrounding calcitonin screening. As seen in our indexcase, a definitive diagnosis can be difficult to achievebefore surgical pathology results. Thus, a high index ofsuspicion should be maintained, and cautious counselingshould be included for any patient with atypical thyroidpathology. Genetic testing is essential in patients withconfirmed MTC, and should be extended to all firstdegree relatives when a RET proto-oncogene mutation isdiscovered. Early prophylactic surgery is the definitivetreatment for carriers of RET mutations. The timingand extent of prophylactic surgical intervention is de-pendent upon specific codons and their reported risks forearly disease progression. The extent of cervical lymph-adenectomy for MTC remains a source of controversy.However, reliable and evidence-based indications forselective, compartmental neck dissections have emergedin the literature and serve to guide the surgicalapproach based upon known genetic and pathologicalrisks.

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TABLE IV.MTC Classifications and Clinical Characteristics.

Sporadic FMTC MEN2A MEN2B HMTC (Combined)

Overall % of MTC cases64,65 60.1%-61.9% 5.1%–18.7% 17.3%–30.6% 2.1%–4.1% 38.1%–39.9%

Age at diagnosis66 40–50 years 45–55 years 25–35 years 10–20 years –

Multifocality within gland65 8.9% – – – 45.5%

Advanced disease stage (pT3/pT4) at diagnosis65 36% 13% 16% 16.7% 14.5%

Lymph node metastases50,67 45.3%–63% – – – 37.5%–47%

Distant metastases57,67 10.3%–29.4% – 37.5% 100% (3/3) 12.5%

5-year survival64 90.8% 100% 96.9% 73.8% –

10-year survival66,67 50%–70% 65–95% 50–95% 40%–80% 83%

Commonly involved RET mutation codons4,27,59 43% on 918 30% on 634 80%–85% on 634 >95% on 918 –

FMTC ¼ familial medullary thyroid carcinoma; HMTC ¼ hereditary medullary thyroid carcinoma; MTC ¼ medullary thyroid carcinoma; MEN ¼ multipleendocrine neoplasia; RET ¼ rearranged during transfection.


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Diagnostic and surgical dilemmas in hereditary medullary thyroid carcinoma