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Pathology – Research and Practice 210 (2014) 182– 185

Contents lists available at ScienceDirect

Pathology – Research and Practice

jo u r n al hom epage: www.elsev ier .com/ l ocate /prp

riginal Article

he variable pathologic presentations of medullary andicro-medullary thyroid carcinoma: An institutional experience

. Danielle Samulski ∗, Virginia A. LiVolsi, Kathleen Montone, Zubair Balochospital of the University of Pennsylvania, Pathology, Philadelphia, PA, United States

r t i c l e i n f o

rticle history:eceived 29 July 2013eceived in revised form7 November 2013ccepted 11 December 2013

eywords:edullary thyroid carcinoma

hyroid

a b s t r a c t

Medullary thyroid carcinoma (MTC) is a rare tumor; its pathologic diagnosis can be difficult due to vari-ability in its clinical presentation, size, morphology, and follow-up. We report our institutional experiencewith 45 cases of MTC diagnosed at University of Pennsylvania Medical Center between 2000 and 2007.

The collected data points included patient’s age, sex, family history, tumor size, method of diagnosis,calcitonin and CEA levels, presence of concomitant follicular derived thyroid carcinoma (FDTC), lymphnode (LN) status, and clinical follow-up.

The cohort included 17 males and 28 females (average age 53 years); 6 had a history of multipleendocrine neoplasia II (MENII). Pre-operative FNA was performed in 33/45 cases (33%); 23/33 were diag-

izeine needle aspiration

nosed as MTC or suspicious for MTC. Of 45 cases 20 were micro-MTC; 15 occurred with other thyroidmalignancies. LN metastases were present at primary resection in 18/45 cases. Calcitonin levels rose orremained elevated postoperatively in 4 cases; of these, 2 had regional LN recurrence and 1 developeddistant metastases and subsequently died of disease.

MTC is a heterogeneous disease. Sporadic micro-MTC carcinoma is an indolent tumor and can occurwith other malignant tumors of the thyroid gland.

© 2013 Elsevier GmbH. All rights reserved.

ntroduction

Medullary thyroid carcinoma (MTC) is a rare, yet clinically sig-ificant thyroid tumor. While accounting for only 3–10% of thyroidarcinomas, it is responsible for approximately 13% of patienteaths related to thyroid cancer, thus considered to be more clini-ally aggressive than follicular derived neoplasms (FDN) [1].

The vast majority of MTC are sporadic in nature, however, upo 25% are associated with one of three familial syndromes (Multi-le Endocrine Neoplasia type 2A and 2B-MEN2A, MEN2B; Familialedullary Thyroid Carcinoma-FMTC); attributed to germline gain

f function autosomal-dominant mutations in the RET proto-ncogene. Sporadic MTC tend to present with a palpable thyroidodule in the 5th to 6th decade of life, the familial cases typicallyccur at a younger age, and their presentation varies within theontext of the associated syndrome (MEN2A-pheochromocytoma,

yperparathyroidism; MEN2B pheochromocytoma, mucosal neu-omas, marfinoid habitus), often occurring multifocally or bilater-lly in association with C-cell hyperplasia [2].

∗ Corresponding author at: Hospital of the University of Pennsylvania, 3400pruce Street, Philadelphia 19104, United States.

E-mail address: teresa.samulski@uphs.upenn.edu (T.D. Samulski).

344-0338/$ – see front matter © 2013 Elsevier GmbH. All rights reserved.ttp://dx.doi.org/10.1016/j.prp.2013.12.004

Medullary thyroid carcinoma does not respond significantlyto chemotherapy and radiation therapy, and its clinical manage-ment rests largely on the surgical excision of the thyroid withlymph node dissection [3]. Lymph node involvement is presentin a considerable proportion of cases (up to 90% of patients withT3–T4 tumors) [4]. Therefore, based on the aggressive natureof this tumor, it is important to diagnose this tumor preoper-atively so that appropriate management can be planned. Thisis commonly accomplished through pre-operative fine needleaspiration analysis in conjunction with measurements of serumcalcitonin.

The natural history of MTC has been challenging to define dueto the rarity of this tumor. Even more elusive is the significanceof medullary microcarcinomas (those tumors measuring <1.0 cm),which are detected frequently, in part due to calcitonin screeningprograms, although these screening programs are not practicedworldwide. Much debate exists over the clinical significance andappropriate management of micro MTC, especially within the spo-radic and occult setting [5–8]. In addition, the recognition of smallMTC in conjunction with follicular derived neoplasms (FDN) within

the same gland has become an increasingly common phenomenon;yet its significance remains largely uncharacterized [9–12]. Wepresent here our institutional experience with MTC, specificallyexamining the diagnostic accuracy of cytologic diagnosis and the

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linico-pathologic characteristics of macro- and micro-MTC, as wells of MTC arising in association with FDNs.

aterials and methods

The MTC patients were identified and surgical pathology reportsere retrieved from the electronic pathology database at Univer-

ity of Pennsylvania Medical Center employing the search termsf “medullary”, “carcinoma” and “thyroid”. From January 2000o December of 2007, 45 cases of medullary thyroid carcinomaMTC) were diagnosed at our institution. All cases were diagnosedy senior pathologists according to well-established diagnosticriteria for medullary thyroid carcinoma. All cases classified asicro-MTC were those cases diagnosed as medullary thyroid car-

inoma at the time of resection that measured ≤1.0 cm. C-cellyperplasia was excluded from this analysis based on the appli-ation of appropriate diagnostic criteria (i.e. presence or absence oftromal invasion) by the primary pathologist at the time of resec-ion. For this analysis, no additional slide review was performedfter review by the primary pathologist at the time of resection. Aetrospective medical record review was performed to collect dataoints on patient age, sex, family history, size of tumor, method(s)f diagnosis (fine-needle aspiration and/or surgical resection), pre-nd post-operative calcitonin and CEA levels, presence of concomi-ant follicular derived thyroid carcinoma (FDTC), lymph node statust the time of resection, and clinical follow-up.

Family history, results of genetic testing for MENII (when avail-ble), and pre- and post-operative calcitonin and CEA levels wereecorded. Clinical-pathologic follow-up included initial surgicalreatment, initial and subsequent neck dissection and/or lymphode biopsy results, as well as the development of local recurrencend/or distant metastasis. Clinical and radiographic follow-upnvestigations, including ultrasonographic examination of the neck,omputed tomography (CT) scans, and magnetic resonance imag-ng (MRI) results, were recorded. Finally, survival data was collectedincluding those patients who died of disease and those patientsho were alive with and without disease at last recorded follow-p).

esults

Forty-five patients with MTC were diagnosed at our institutionuring a seven-year period (2000–2007). The cohort included 17ales and 28 females (Male:Female, 1:1.7), with an average age of

3 years (median age 51 years; range). Pre-operative fine-needlespiration (FNA) was performed in 33/45 cases (73%). Of these, theiagnosis was consistent with “medullary thyroid carcinoma” in5/33 (45.5%) cases and “suspicious for medullary thyroid carci-oma” in 8/33 (24.2%); in the remaining 10 cases, the preoperativeNA diagnosis was “follicular neoplasm”.

The average size of the 45 tumors was 1.68 cm (range:.1 cm–7.5 cm; median: 1.1 cm). When segregated based on size

nto macro- (>1.0 cm) and micro-MTC (<1.0 cm), 25/45 (56%) caseseasured >1.0 cm (average size 2.8 cm) and 20/45 (44%) cases mea-

ured <1.0 cm (average size 0.35 cm). Bilateral disease was noted in1 cases (24%). A confirmed diagnosis of MENII was available in

patients (6/45, 13%) and four of these presented with bilateralisease.

A concomitant follicular derived thyroid carcinoma (FDTC)as identified in 15/45 (33%) patients; of these 9/15 (60%) were

n patients with micro-MTC. The most common FDTC identified

as papillary thyroid carcinoma (PTC) (12/15, 80%), followed by

ollicular carcinoma (2/15, 13%) and 1 case of anaplastic carci-oma. Lymph node metastases of MTC were present at the timef diagnosis in 16/45 (35.5%) cases, and 6 of these patients had

and Practice 210 (2014) 182– 185 183

micro-MTC. Two patients presented with lymph node metastasesfrom only PTC at the time of primary resection. Clinical follow-upranging from 1 month to 146 months was available in 21/45 (47%)cases. Pre-operative CEA levels were available in two (3.49 mg/Land 20.9 mg/L, respectively) and calcitonin levels were available in17/45 (38%) patients (ranging from 4.1 to 1709 mg/L). In 13 cases,post-operative calcitonin levels fell or remained low and patientsremained disease-free at the last follow-up. In 4 patients, calci-tonin levels rose or remained elevated post-operatively. Of these,2 patients developed lymph node recurrence and 1 developeddistant metastases to the lung and liver. The patient with distantmetastases eventually died of disease eighteen months afterdiagnosis. No tumor recurrence or distant metastases occurred inpatients with a diagnosis of micro-MTC.

Discussion

In a seven year period at our institution, we diagnosed 45cases of MTC. Our cohort had a female predominance (male:femaleratio 1:1.7), with the majority of patients presenting early in thesixth decade. These demographics are comparable to other cohortswithin the literature, although the age at presentation of ourpatients is slightly older than those reported in recently publishedseries (mean – 53 years compared to 38–45 years [1,13–15]). Afraction (13.3%) of patients with MTC had a documented historyof MENII. This proportion falls somewhat short of that describedin the recent literature, which approaches 30% of cases in someseries [1,13,14]. The observation that many patients with familialsyndromes are diagnosed with MTC at an earlier age than sporadiccases, along with the fact that our proportion of familial cases isslightly lower than commonly reported, may help to explain ourincreased average age at presentation when compared to the cur-rent literature.

However, while we recommend genetic testing for mutationsin the RET proto-oncogene in all newly diagnosed cases of MTC, asa referral center, many of our patients present for primary resec-tion and receive clinical follow-up in community hospitals closer tohome. This may also explain the lack of complete clinical and familyhistory in patients undergoing primary resection at our institution.Therefore, it is possible that our proportion of cases attributed tofamilial syndromes could be higher than we have reported.

MTC lymph node metastases were present at the time of pri-mary resection in 35.5% of cases, a rate corroborated by some [16],but lower than reported in other series [1,13–15]. It is well knownthat the rate of MTC lymph node metastasis at diagnosis increaseswith increasing tumor size [9,12]; most recent studies [1,13–15]reported average tumor sizes larger than our cohort (∼2.5 cm com-pared to 1.68 cm, respectively). This may explain the decreased rateof lymph node metastasis in our series at the time of diagnosis.

Clinical follow-up, ranging from 1 month to 146 months, wasavailable in 47% of our cases. Pre-operative measurements ofcalcitonin and CEA were not available in all patients; 76.5% ofpatients experienced a fall or stabilization of their calcitonin lev-els after tumor resection, and these patients remained disease-freeat their last follow-up. In 23.5% of patients with available pre-operative calcitonin levels, calcitonin rose or remained elevatedpost-operatively. Two of these patients developed lymph noderecurrence, and 1 patient developed distant metastases to the lungand liver; this patient ultimately died of disease. These trendsrelated to post-operative calcitonin levels and associated rates ofrecurrence, metastasis and survival are comparable to known case

cohorts [1,13–16]. However, our overall rate of local recurrence,distant metastasis, and patient death are lower than experiencedat other institutions [1,13,14,16]. We believe that this is due to theoverall smaller tumor size in our cohort as compared to recently

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ublished series, however, large tumor size as a poor prognosticndicator has not been confirmed in all available series [1,13].

he accuracy and validity of fine needle aspiration analysisn cases of MTC

Pre-operative FNA was performed in 73% of cases; 69.7% of theseere classified as “consistent with” or “suspicious for MTC”. In

hose cases in which we did not suggest the diagnosis of MTC, diagnosis prompting surgical resection was still rendered i.e.follicular neoplasm”. None of the cases undergoing FNA were diag-osed as benign.

The diagnostic pitfall of MTC mistakenly classified as “follic-lar neoplasm” on FNA has been well characterized [17–19]. Inytologic preparation, the MTC cells can appear to form loosemicro-follicles” rather than the characteristic dispersed pattern,ontain oncocytic cytoplasm to be mistaken for oncocytic folliculareoplasm, and amyloid can be mistaken for thick colloid. How-ver, even though cases diagnosed as follicular neoplasm are notfforded the certainty of a pre-operative diagnosis of MTC, theyost likely will undergo resection, thus avoiding an unaccept-

ble false negative result. It has been shown that pre-operativecreening for calcitonin can confirm the diagnosis of MTC whichre unable to be classified by FNA [20]. However, this screening isften times prompted by suspicious cytologic findings and morearely is performed in all patients with thyroid nodules labeleds follicular neoplasm or suspicious for malignancy. In the currenttudy, eight cases were classified as suspicious for MTC on FNA andorrelation with serum calcitonin levels was recommended in fiveases.

he clinico-pathologic characteristics of micro-MTC

Micro-medullary carcinomas are defined as tumors measuring1.0 cm. Not surprisingly, these tumors were often originally rec-gnized in patients with known familial predisposition to MTC, andere typically discovered after prophylactic thyroidectomy. How-

ver, with the increase in the ability of ultrasound to detect smallernd smaller nodules, and with the evolving institution of calcitonincreening programs in patients with nodular goiter, sporadic casesf micro-MTC are becoming increasingly recognized.

In our 45 cases, there was an even split between MTC measuring1.0 cm and >1.0 cm. These rates are similar to those published inecent series that have examined both familial and sporadic cases ofTC [1,14]. While lymph node (LN) metastases at the time of resec-

ion were more likely to occur in cases of tumors measuring >1.0 cm,pproximately 30% of cases of micro-MTC did display LN metastasist the time of primary resection; of these, only one was a familialase. This proportion of micro-MTC presenting with LN metastasesas been reported by some [5], but not all [6–8] series to date. Noumor recurrence or distant metastases occurred in patients with

diagnosis of micro-MTC during clinical follow-up.The general notion that micro-MTC have higher cure rates and

ower risk of metastases and death than their larger counterpartsas been well established in the current literature [5–8], with very

ew clinically aggressive cases reported [5,8]. Based on our cohort,icro-MTC appears to be a common presentation. Our findings

onfirm that, given the real possibility of aggressive pathologicehavior at diagnosis, early detection and treatment of micro-MTC

s beneficial. In addition, there is a significant possibility of curefter primary resection in micro-MTC. While many countries have

stablished calcitonin screening programs for this purpose, theretill remain significant uncertainties surrounding the true malig-ant potential of these tumors which has prevented the institutionf this practice within the United States [21].

and Practice 210 (2014) 182– 185

MTC arising in the context of concomitant FDTC

Despite the distinct origin of MTC and FDTC, the simultane-ous occurrence of these two neoplasms within the same gland hasbecome increasingly recognized. Given the rarity of MTC alone, thisphenomenon is rarer still, again limiting our understanding of thesignificance and pathogenesis of these curious patient presenta-tions. Several varying hypotheses have been proposed to explainthe concomitant nature of these tumors ranging from a commonstem cell theory, to shared neoplastic stimuli within the harboringpatient, to simply coincidence [9].

In our population of MTC, concomitant FDTC was seen in15/45 cases. The most common associated FDTC was papillarythyroid carcinoma. By far, concomitant PTC has been most fre-quently encountered in similar series, with many reports focusingsolely on MTC/PTC presentations [10–12]. Our rate of concomi-tant MTC/FDTC is slightly higher than the rates reported in thesepapers (Biscolla-13.8%, Machens-3.6%, Kim-19%) in addition tobeing higher than those published in series examining micro-MTC/FDTC only [5,6].

In our series, micro-MTC was more commonly associated withan FDTC than macro-MTC. Wong et al. [9] reported in a largepopulation-based study that, overall, MTC occurring with concomi-tant FDTC were of small size compared to MTC discovered alone.Similar findings have been reported by Machens and Dralle [11].We believe that our findings along with the evidence in the cur-rent literature [9–12] support that concomitant MTC/FDTC is mostlikely an incidental phenomenon.

Conclusions

In our experience, MTC is a heterogeneous disease due to its clin-ical presentation, pathology, and follow-up. We demonstrate thatMTC often has a variable presentation with the majority of patientsachieving cure through surgical resection, despite the propensityfor early lymph node metastasis. In addition, preoperative diag-nosis can readily be accomplished by FNA. Based on our findings,micro-MTC is an indolent tumor, although it can display aggressivepathologic characteristics at diagnosis. Finally, with regard to con-comitant FDTC, our data support the hypothesis that concomitantMTC/FDTC is an incidental phenomenon.

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