prognostic implications of papillary thyroid carcinoma with tall-cell features

THYROID CANCER AND NODULES

Prognostic Implications of PapillaryThyroid Carcinoma with Tall-Cell Features

Ian Ganly,1 Tihana Ibrahimpasic,1 Michael Rivera,2 Ian Nixon,1 Frank Palmer,1 Snehal G. Patel,1

R. Michael Tuttle,3 Jatin P. Shah,1 and Ronald Ghossein2

Background: The prognostic implications of the diagnosis of a papillary thyroid carcinoma (PTC) with tall-cellfeatures are unknown.Methods: All PTC patients identified between 1985 and 2005 were analyzed histologically. Classical PTC caseswere defined as having < 30% tall cells, PTC with tall-cell features (PTC TCF) as 30%–49% tall cells, and tall-cellvariant of PTC (TCV) as ‡ 50% tall cells. All classical PTC, PTC TCF, and TCV ‡ 1 cm in size were included.Results: A total of 453 patients satisfied the inclusion criteria (288 classical PTC, 31 PTC TCF, and 134 TCV).Classical PTC patients were younger than their PTC TCF and TCV counterparts ( p < 0.0002). There was an increasein tumor size from classical PTC to PTC TCF and TCV ( p = 0.05). Extensive extrathyroid extension and positivemargins were more often present in TCV and PTC TCF than in classical PTC ( p = 0.0001 and p = 0.03 respectively).Overall pathologic tumor (pT) stage was more advanced in TCV and PTC TCF than in classical PTC ( p < 0.0001).Total thyroidectomy and radioactive iodine therapy were more often performed and administered in TCV patientsthan in their PTC TCF and classical PTC counterparts ( p = 0.001 and p = 0.0001 respectively). Median follow-upwas 9.3 years. Ten-year disease-specific survival (DSS) was lower in TCV (96%) and PTC TCF (91%) than inclassical PTC (100%; p < 0.001). Ten-year distant recurrence-free survival (RFS) was higher in classical PTC (98%)than in PTC TCF (89%) and TCV (96%; p = 0.03). In multivariate analysis, the presence of more than five positivenodes and extranodal extension were the only independent prognostic factors of neck and distant RFS respectively.Four (2.4%) of 165 PTC TCF and TCV developed poorly differentiated or anaplastic carcinoma in their recurrence,while none of the 288 classical PTC transformed into higher grades ( p = 0.017).Conclusions: PTC TCF and TCV have similar clinicopathologic features that are more aggressive than classicalPTC. PTC TCF and TCV have similar DSS and distant RFS but poorer outcomes than classical PTC. PTC TCF arecurrently being treated like classical PTC, that is, less aggressively than TCV. PTC TCF and TCV have higher ratesof high-grade transformation than classical PTC. Consideration should be given to using a 30% tall-cell thresholdto diagnose TCV.

Introduction

The tall-cell variant of papillary thyroid carcinoma(TCV) was initially described by Hawk and Hazard as a

distinctive subtype of papillary thyroid carcinoma (PTC)harboring cells whose height is twice their width (1). Ac-cording to their original description, these cells are oftenfound in highly papilliferous areas and can have a strikinglyeosinophilic cytoplasm. Hawk and Hazard noted the ag-gressive behavior of that subtype of papillary carcinomacompared to other histologic forms of PTC, as well as anolder age at presentation and a larger size. (1). While almostall authors agree on the fact that TCV is more aggressive as agroup than classical PTC, there is still considerable disagree-ment as to the independent prognostic value of TCV (2,3). For

some investigators, the worse prognosis of TCV is related toolder age at presentation, larger tumor size, and high fre-quency of extrathyroid tumor extension (ETE) (4), whileothers have shown that TCV histology is an independentpredictor of poor outcome (5,6). There is also considerabledebate in regard to the number of tall cells needed to reach aTCV diagnosis, with the threshold ranging from 30% to75% according to various studies (2,7). More confusion wasadded in the last decade by a higher reporting of low-stageTCV (i.e., confined to the thyroid without nodal metastases)and the frequent use of the term ‘‘papillary carcinoma withtall-cell features.’’ The latter tumor has noticeable tall cellsbut lacks the required percentage for the TCV diagnosis.The prognostic significance of a papillary carcinoma withtall-cell features (PTC TCF) is unknown.

Departments of 1Surgery, 2Pathology, and 3Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.

THYROIDVolume 24, Number 4, 2014ª Mary Ann Liebert, Inc.DOI: 10.1089/thy.2013.0503

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The above controversies create therapeutic dilemmas andsignificant anxiety for patients and their physicians. In orderto address these issues, we undertook a clinical and meticu-lous pathologic examination of a large cohort of classicalPTC, TCV, and PTC TCF treated at our institution over a 20-year period.

Materials and Methods

Patient selection

The hospital database was searched for all cases diagnosed asPTC and treated at the Memorial Sloan-Kettering CancerCenter(MSKCC), New York, between 1985 and 2005. After sub-centimeter tumors were excluded, all remaining PTC with ad-equate histologic slides were submitted to re-review by at leastone of two head and neck pathologists with special expertise inthyroid neoplasia (R.G. and M.R.). The pathologists wereblinded to the clinical outcome of all patients studied. The studywas approved by the Institutional Review Board of MSKCC.

Tumor definition

The tumors were defined as follows:

TCV. A tumor was classified as TCV if it contained 50%or more tall cells without tumor necrosis or marked mitoticactivity (‡5 mitoses/10 high-power fields, 400·). The tallcells were defined as cells with their height twice their widthand having an eosinophilic cytoplasm with a low nuclear–cytoplasmic ratio and the characteristic nuclear features ofPTC (i.e., irregular enlarged clear nuclei with grooves andpseudo-inclusions). The required percentage of tall cells andtheir height–width ratio matched the criteria used for the di-agnosis of TCV by the Cancer Genome Atlas Project WorkingGroup (TCGA).

PTC TCF. A tumor was defined as PTC TCF if it har-bored between 30% and 50% tall cells (i.e., 30% to < 50%).The tumor was not considered a PTC TCF if associated withtumor necrosis or marked mitotic activity (‡5 mitoses/10high-power fields, 400·).

Classical PTC. A tumor was classified as classical PTC ifit showed >1% papillary formations and was composed ofcells having the characteristic nuclear features of papillarycarcinoma. The classical cases had to contain < 30% tall cellsand be devoid of tumor necrosis or marked mitotic activity(‡5 mitoses/10 high-power fields, 400·).

Inclusion criteria

Tumors were included in the study if they fulfilled theabove definitions and were ‡1 cm in size.

Histopathologic analysis

The largest dimension of the carcinoma was based on re-view of the gross pathology report and direct microscopicmeasurement of the tumor on the slides. The mitotic rate ofthe tumor was determined by counting 10 contiguous high-power fields (400·) using an Olympus microscope (U-DOmodel BX-40; Olympus America Inc., Melville, NY). Using

that microscope type, these 10 high-power fields correspondto 2.4 mm2. Tumor necrosis was defined by a ‘‘comedo-like’’appearance composed of degenerating cytoplasm and punc-tate, karyorrhectic nuclear debris. Vascular invasion wascategorized as present or absent. Invasion of the tumor cap-sule defined as transcapsular penetration was recorded. ETEwas defined as tumor cells invading beyond the thyroidcapsule into perithyroid soft tissue or organs. ETE was sub-divided into: (i) none; (ii) focal: presence of one or two mi-croscopic foci of ETE measuring £ 1 mm each; (iii) extensive:presence of more than two microscopic foci of ETE ( £ 1 mmin size each) or any foci > 1 mm in size. The type of peri-thyroid tissue or organ invaded by the tumor was recorded(e.g., adipose tissue, skeletal muscle, recurrent nerve, trachea,and esophagus). The status of the resection margins was re-ported as positive (tumor present at the surgical margin) ornegative (no tumor at surgical margin). The number of lymphnodes examined microscopically, as well as the number ofnodes with metastatic carcinoma, were recorded. On the basisof gross and microscopic examination of the surgical specimenby the pathologist, the greatest diameter of the largest meta-static node was measured, as well as the largest size of thelargest metastatic tumor focus. A PTC was defined as trans-formed if it displayed foci of poorly differentiated or anaplasticthyroid carcinoma in the recurrence. Poorly differentiatedcarcinoma was defined as a tumor having follicular cell dif-ferentiation at the histological or immunohistochemical levelwith marked mitotic activity (‡5 mitoses/10 high-powerfields, 400·) and/or tumor necrosis. Anaplastic carcinoma wasdefined as a tumor composed of undifferentiated tumor cellslacking follicular cell differentiation at the morphologic andimmunohistochemical level.

Clinical parameters

The patient’s electronic medical records were reviewed forthe age at diagnosis, type of surgery, and adjuvant treatmentincluding radioactive iodine (RAI) therapy. Staging wasperformed according to the AJCC Cancer Staging Manual 7thedition (8). In view of the fact that many cases from the 1980sdid not have adequate biochemical data, the patient diseasestatus at recurrence or follow-up was based on a combinationof clinical and imaging assessments. These evaluations in-clude history taking, physical examination, RAI scanning,cross-sectional imaging, and/or positron emission tomogra-phy (PET) scanning. Thus, biochemical recurrence was notassessed. The type of cervical lymph node dissection/biopsywas recorded as central, lateral, central and lateral, or other.The latter category consists solely of perithyroidal lymphnodes removed with the thyroid specimen or superior medi-astinal lymph nodes. The date of initial surgery and last dateof follow-up were documented. The status at last follow-upwas recorded as follows: no evidence of disease; alive withdisease; dead of other causes, and dead of disease (DOD).

Statistical analysis

Pearson’s chi-square test was used to assess the relationbetween categorical variables. Survival probabilities wereestimated by the Kaplan–Meier method and compared usingthe log-rank test. A p-value £ 0.05 was considered as signif-icant. Recurrence free survival (RFS) was defined as the timeinterval between the date of initial surgery and date of first

PAPILLARY CARCINOMA WITH TALL-CELL FEATURES 663

Table 1. Clinicopathologic Features at Presentation According to the Subtype

of Papillary Thyroid Carcinoma

Classical PTC TCF TCVVariable PTC (n = 288) (n = 31) (n = 134) p

Age (years)< 45 180 (62%) 12 (39%) 58 (43%)‡ 45 108 (38%) 19 (61%) 76 (57%) 0.0002*

SexMale 77 (27%) 10 (32%) 45 (34%)Female 211 (73%) 21 (68%) 89 (66%) 0.33

pT stagea,b

1 126 (44%) 8 (26%) 25 (19%)2 40 (14%) 2 (6%) 15 (11%)3 102 (35%) 14 (45%) 68 (51%)4 20 (7%) 7 (22%) 26 (19%) < 0.0001*

Tumor size (cm)£ 2 190 (66%) 19 (61%) 72 (54%)> 2 98 (34%) 12 (39%) 62 (46%) 0.05*

Margin statusNegative 263 (91%) 26 (84%) 111 (83%)Positive 25 (9%) 5 (16%) 23 (17%) 0.03*

Extrathyroid extensionc

None 166 (58%) 13 (42%) 45 (34%)Focal 26 (9%) 2 (6%) 15 (11%)Extensive 96 (33%) 16 (52%) 74 (55%) 0.0001*

Vascular invasionAbsent 267 (93%) 31 (100%) 124 (92%)Present 21 (7%) 0 (0%) 10 (8%) 0.29

pN statusb

N0 73 (32%) 8 (32%) 34 (29%)N1 152 (68%) 17 (68%) 82 (71%) 0.84

No. of positive lymph nodes£ 3 133 (59%) 17 (68%) 78 (67%)> 3 92 (41%) 8 (32%) 38 (33%) 0.28

No. of positive lymph nodes< 5 147 (65%) 20 (80%) 88 (76%)> 5 78 (35%) 5 (20%) 28 (24%) 0.07

Extranodal extensionAbsent 100 (67%) 12 (70%) 54 (68%)Present 49 (33%) 5 (30%) 25 (32%) 0.94

ThyroidectomyTotal 203 (70%) 21 (68%) 116 (87%)Less than total 85 (30%) 10 (32%) 18 (13%) 0.001{

Neck dissectiond

Central 68 (24%) 8 (26%) 30 (22%)Lateral 15 (5%) 0 (0%) 13 (10%)Central and lateral 60 (21%) 7 (23%) 23 (17%)Other 82 (28%) 10 (32%) 50 (37%)Not performed 63 (22%) 6 (19%) 18 (13%) 0.02{

RAI treatmente

Absent 137 (48%) 13 (42%) 34 (26%)Present 150 (52%) 18 (58%) 98 (74%) 0.0001{

aIn this calculation, pT4 was compared to pT1–3.bTNM staging as per Edge et al. (8).cAnalysis compared extensive to focal/no extrathyroid extension.dThe analysis compared the presence to absence of lymphadenectomy.eIn three cases, RAI therapy status was not available.PTC, papillary thyroid carcinoma; RAI, radioactive iodine; PTC TCF, PTC with tall-cell features; TCV, tall-cell variant of PTC.*TCV/PTC TCF vs. Classical PTC.{Classical PTC/PTC TCF vs. TCV.PTC, papillary thyroid carcinoma; RAI, radioactive iodine; PTC TCF, PTC with tall-cell features; TCV, tall-cell variant of PTC.

664 GANLY ET AL.

recurrence. Disease-specific survival (DSS) was calculatedfrom the date of initial surgery to last follow-up. DSS statuswas defined as the presence or absence of DOD at lastfollow-up. Multivariate analysis was performed using aCox regression model and log-rank statistics. Statisticalanalysis was carried out using JMP statistical package (SASInstitute Inc., Cary, NC) and SPSS version 19.0 (IBMCorp., Chicago, IL).

Results

Clinicopathologic features accordingto the subtype of PTC

Table 1 displays the clinicopathologic features of thetumor according to the subtype of PTC. Patients withclassical PTC are younger, have smaller tumor size,lower stage, less positive margins, and less extensive ETE

Table 2. Univariate Analysis of Prognostic

Factors for Neck Recurrence–Free Survival

VariableNo.

patients10-yearNRFS p

Age (years)< 45 250 88%‡ 45 203 83% 0.29

SexMale 132 75%Female 321 90% 0.004

PathologyClassical PTC 288 88%TCV 134 84%PTC TCF 31 83% 0.16

pT stagea

1 159 87%2 57 81%3 184 88%4 53 87% 0.53

Tumor size£ 2 cm 281 89%> 2 cm 172 80% 0.13

Margin statusNegative 400 86%Positive 53 87% 0.56

Extrathyroid extensionNone 224 94%Focal 43 91%Extensive 186 78% 0.01*

Vascular invasionNo 422 86%Yes 31 84% 0.42

pN statusa

N0 115 97N1 251 80 0.001

Positive lymph nodes£ 3 228 93%> 3 138 74% 0.0002

Positive lymph nodes< 5 255 92%> 5 111 70% < 0.0001

Largest positive lymph node£ 1 cm 68 93%> 1 cm 66 73% 0.01

Extranodal extensionAbsent 166 84%Present 79 71% 0.12

RAI treatmentb

Absent 184 96%Present 266 80% 0.001

aTNM staging as per Edge et al. (8).bIn three cases, RAI therapy status was not available.*Extensive vs. focal/none.NRFS, neck recurrence-free survival.

Table 3. Univariate Analysis of Prognostic

Factors for Distant Recurrence–Free Survival

VariableNo.

patients10-yearDRFS p

Age (years)< 45 250 98%‡ 45 203 91% 0.06

SexMale 132 94%Female 321 95% 0.15

PathologyClassical PTC 288 98%TCV 134 96%PTC TCF 31 89% 0.05*

pT stagea

1 159 97%2 57 100%3 184 95%4 53 87% 0.01{

Tumor size£ 2 cm 281 96%> 2 cm 172 94% 0.06


Extrathyroid extensionNone 224 98%Focal 43 100%Extensive 186 91% 0.002{

Vascular invasionNo 422 95%Yes 31 93% 0.28

pN statusa

N0 115 94%N1 251 94% 0.37




Extranodal extensionNo 166 99%Yes 79 86% < 0.0001

RAI treatmentb

Absent 184 100%Present 266 94% 0.03

aTNM staging as per Edge et al. (8).bIn three cases, RAI therapy status was not available.*TCV/PTC TCF vs. Classical PTC.{pT4 vs pT1–3.{Extensive vs. focal/none.DRFS, distant recurrence–free survival.


FIG. 1. (A) Distant recurrence-free survival (DRFS) according to papillary thyroid carcinoma (PTC) subtype. ClassicalPTC patients have a better DRFS rate than patients with either PTC with tall-cell features (PTC TCF) or tall-cell variant ofPTC (TCV). (B) Disease-specific survival (DSS) according to PTC subtype. Classical PTC patients have a better DSS ratethan patients with either PTC TCF or TCV.

FIG. 2. A 64-year-old female with PTC TCF that transformed as anaplastic carcinoma in the pleura seven years afterdiagnosis and resulted in death. (A) Medium-power view (100 · ) of the primary PTC TCF. Area with high concentration oftall cells. Arrows indicate elongated follicles typically seen in tall-cell rich tumors. (B) High-power view (400·) of the sametumor in (A) showing tall cells (arrow) with a height at least twice their width. (C) Medium-power view (100 · ) of pleuralrecurrence as anaplastic carcinoma. The tumor grows in large sheets with squamoid morphology and keratin pearl formation(arrow) resembling squamous cell carcinoma. This growth pattern is typically seen in anaplastic carcinoma arising from tall-cell rich tumors. (D) High-power view (400·) of the same tumor in (C). Nuclear pleomorphism, spindle cells, and mitosis(arrow) typical of anaplastic carcinoma.

666 GANLY ET AL.

than those with TCV and PTC TCF ( p £ 0.05). There wereno differences between TCV and PTC TCF in regard to theabove parameters. In contrast, TCV were more often treatedwith total thyroidectomy, RAI therapy, and lymphade-nectomy than the cohort of patients with classical PTC andPTC TCF ( p £ 0.05). There were no differences in treatmentmodalities between those who harbored classical PTC andthose with PTC TCF.

Anaplastic and poorly differentiated carcinomatransformation in the recurrence sites

Four (2.4%) out of a group of 165 patients with PTC TCFand TCV developed poorly differentiated or anaplastic car-cinoma in their recurrence. In contrast, none of the 288classical PTC transformed into poorly differentiated or ana-plastic carcinoma ( p = 0.017). Three PTC TCF cases har-bored anaplastic (n = 2) and poorly differentiated carcinoma(n = 1) in their recurrence sites. One TCV case relapsed asanaplastic carcinoma.

Outcome of the whole patient population

The median follow-up was 112 months (range 4–291months). The 10-year DSS was 98% with only six patientsDOD. Overall, 45 patients recurred with a RFS of 84% at 10years. Forty-one patients recurred in the neck, and 13 atdistant sites with a 10-year neck RFS of 86% and a 10-yeardistant RFS of 95%.

Prognostic factors of recurrence-free survival

Tables 2 and 3 list the variables affecting neck and distantRFS respectively. Male sex, extensive ETE, the presence ofpositive nodes, a high number of nodal metastasis, and a largesize metastatic node ( > 1 cm) conferred worse neck RFS( p £ 0.05). The subtype of PTC did not influence neck RFS.In contrast, patients with TCV and PTC TCF had a poorerdistant RFS in comparison to those with classical PTC( p = 0.03; Fig. 1A). Other factors predicting worse distantRFS were pT4 tumor, positive margins, extensive ETE, ahigh number of nodal metastasis, a large size metastatic node( > 1 cm), and extranodal extension ( p £ 0.05). In multivariateanalysis (Table 4), the presence of more than five positivenodes and extranodal extension were the only independentprognostic factors of neck and distant RFS respectively.

Prognostic factors of DSS

Table 5 lists the variables affecting DSS. Older age patients,those with pT4 tumor, positive margins, or extranodal ex-tension had worse 10-year DSS ( p £ 0.05). Individuals withTCV and PTC TCF had a higher risk of dying from thyroid

carcinoma than those with classical PTC ( p < 0.001; Fig. 1B).It was not possible to perform multivariate analysis for DSS,since only six patients died of disease.

Clinicopathologic characteristicsof patients who died of disease

Table 6 shows the clinicopathologic characteristics of thesix patients who died of thyroid carcinomas. All patients hadnodal metastasis at presentation. Five (83%) of the six

Table 5. Prognostic Factors

for Disease-Specific Survival

VariableNo.

patients10-year

DSS p

Age (years)< 45 250 100%‡ 45 203 96% 0.002

SexMale 132 100%Female 321 98% 0.25

PathologyClassical PTC 288 100%TCV 134 96%PTC TCF 31 91% 0.004*

pT stagea

1 159 98%2 57 100%3 184 100%4 53 92% 0.03{

Tumor size£ 2 cm 281 99%> 2 cm 172 98% 0.51


Extrathyroid extensionNone 224 98%Focal 43 100%Extensive 186 98% 0.56

Vascular invasionAbsent 422 98%Present 31 100% 0.44

pN statusa

N0 115 100%N1 251 97% 0.21




Extranodal extensionAbsent 166 100%Present 79 96% 0.04

RAI treatmentb

Absent 184 100%Present 266 97% 0.08

aTNM staging as per Edge et al. (8).bIn three cases, RAI therapy status was not available.*TCV/PTC TCF vs. Classical PTC.{pT4 vs. pT1–3.

Table 4. Multivariate Analysis

for Recurrence-Free Survival

Recurrencesite

Independentvariable RR [CI] p

Neck > 5 positive nodes 3.2 [1.7–6.0] < 0.0001

Distant Extranodalextension

21.0 [2.6–166.2] < 0.0001

RR, relative risk; CI, confidence interval.


patients harbored TCV or PTC TCF in the primary tumor. Infour (67%) of six patients, the tumor transformed to a highergrade (anaplastic or poorly differentiated thyroid carcino-mas) in the recurrence site (Fig. 2).

Discussion

In the current series, patients with TCV presented at anolder age and higher stage than their classical PTC counter-parts. This is in agreement with the large amount of literatureon the subject (1–4,9–14). Similar to patients with TCV,those with PTC TCF were significantly older and harboredmore aggressive tumor features (e.g., higher stage, extensiveETE) than patients with classical PTC. There was no differ-ence in lymph node positivity rate between the three subtypesof PTC. This is in disagreement with some publications thatdemonstrated a higher rate of nodal metastases in the TCV(2,4). However, other authors did not find a significant dif-ference in node positivity between TCV and classical PTC(3,7). The use of a different percentage of tumor cells for theTCV diagnosis does not seem to be a factor. Indeed, thoseauthors who found a higher rate of nodal positivity in TCVused a much lower threshold of tall cells (30%) (2) than thosewho did not demonstrate a significant difference in nodalmetastases between TCV and classical PTC. The latter in-vestigators required 70%–75% tall cells for the TCV diagnosis(3,7). Clearly, other unknown factors are responsible for theseresults. The aggressive clinicopathologic features of PTC TCFat presentation are translated into worse outcomes with a dis-ease-specific and distant recurrence-free survival similar tothose of TCV and worse than classical PTC. Despite the factthat PTC TCF is as aggressive as TCV, the former is treatedlike classical PTC. Indeed, we found that total thyroidectomywas performed less often in classical PTC (70%) and PTC TCF(68%) than in TCV (87%; p = 0.001). Similarly, RAI was moreoften administered in patients with TCV (74%) than in thosewith classical PTC (52%) and PTC TCF (58%; p = 0.0001). Itappears that the inclusion of the term ‘‘tall-cell features’’ is notperceived by the treating physicians as evidence of a moreaggressive phenotype. In view of the above, it may be moreprudent to avoid the term PTC TCF and lower the threshold forthe diagnosis of TCV to 30%, as was used in the study ofJohnson et al. 25 years ago (2).

One of the most interesting findings in this study is a higherproportion of transformation to anaplastic and poorly differ-entiated thyroid carcinomas in the TCV and PTC TCF groups.Four of 165 (2.4%) TCV and PTC TCF transformed to thesehigher-grade tumors when compared to none of 288 classical

PTC ( p = 0.017). This is another example of the higher ag-gressive biological behavior of TCV, as well as PTC TCF, andshould prompt the pathologist to sample these tumors gener-ously for microscopic examination in search of an anaplastic orpoorly differentiated component, especially in older patients.Indeed, all the transformed cases occurred in individuals whowere over the age of 50 years. Many molecular factors havebeen incriminated as responsible for the aggressive behavior ofTCV. MUC1 was often shown to be amplified at the DNA leveland overexpressed at the transcript and protein levels in TCV(15). In a previous study, we detected MUC1 by immu-nostaining in a significantly higher proportion of TCV thanclassical PTC (15). The overexpression of this transmembraneepithelial cell surface glycoprotein in many carcinomas inter-feres with integrin-mediated adhesion to the extracellular ma-trix and with cadherin-mediated cell–cell adhesion. This couldlead to cellular dissociation and oncogenic progression (16,17)contributing to the biologic behavior of TCV. The 72-kd typeIV collagenase (matrix metalloproteinase-2; MMP-2) wasshown to be overexpressed in TCV compared to a group ofclassical, follicular variant, and microcarcinoma PTC (18).This neutral metalloproteinase initiates the degradation of typeIV collagen in basement membranes. Its production by tumorcells has been correlated with invasion and metastasis. Theaggressive behavior of TCV may also be related to a higherprevalence of BRAF V600E point mutations in TCV whencompared to classical PTC (19). Finally, c-MET was shown tohave a higher rate of overexpression by immunostaining inTCV than in classical PTC (20). The proto-oncogene cMETencodes the tyrosine kinase receptor for hepatocyte growthfactor/scatter factor, and its overexpression is speculated toresult in increased motility and invasiveness in PTC (21). TheThyroid Cancer Genome Atlas (TCGA) program is now un-dertaking the comprehensive genotyping of 500 PTC usingvarious platforms (e.g., exome sequencing, expression arrays,gene methylation, and microRNA arrays). Many TCV are in-cluded in this analysis, and their histologic definition ( ‡ 50% oftumor cells) is similar to the one used in this study. This deepsequencing study will help to characterize the molecular profileof TCV better.

One of the most important controversies in the assessmentof PTC relates to the independent prognostic value of a di-agnosis of TCV. This has practical implications, since thereseems to be a recent increase in the number of TCV diagnosedat a lower stage in young patients. While some authors believethat TCV is more aggressive than classical PTC only becauseof its higher stage and older age at presentation (4), othersconsider it as an independent prognostic factor of outcome

Table 6. Clinicopathologic Characteristics of Patients Who Died of Disease

CaseAge

(years)Primary PTC

histologyTumor

size (cm) pT pN MResection

marginExtranodalextension

High-grade transformationin recurrence

#1 77 PTC TCF 2.0 T4a N1b M0 Positive Present Poorly differentiated Ca#2 75 TCV 4.5 T4a N1b M1 Positive Present None#3 64 PTC TCF 4.0 T4a N1b Mx Positive Present Anaplastic Ca#4 56 PTC TCF 2.5 T2 N1a Mx Negative Present Anaplastic Ca#5 55 Classical PTC 1.7 T1 N1a M1 Negative Absent None#6 67 TCV 1.5 T1 N1b M0 Negative N/A Anaplastic Ca

TNM staging as per Edge et al. (8).Ca, carcinoma.

668 GANLY ET AL.

(5,6,13,22). In the current study, PTC subtype was not anindependent predictor of RFS. The disparate results betweenseveral publications could be related to the definition utilizedfor the diagnosis of the TCV and to the presence or absence ofa meticulous histologic analysis. In our study, we excluded alltumors with high mitotic activity and/or tumor necrosis, whilea matched paired analysis using the Surveillance, Epide-miology, and End Results (SEER) database could not controlfor these pathologic variables, since no re-review of the his-tologic slides is possible with SEER cases (22). In the latterstudy, the presence of high-grade TCV tumors could haveimparted an independent prognostic value to the diagnosis ofTCV. In that regard, Akslen and Livolsi found a higher fre-quency of tumor necrosis in TCV compared to other subtypesof PTC (7). Furthermore, they found that the histologic grade(defined as nuclear atypia, tumor necrosis, and vascular in-vasion) and tumor size, rather than PTC subtype, were inde-pendent prognostic factors (7). Multivariate analysis could notbe performed for DSS, since only six patients died of thyroidcarcinoma. This low death rate could also be attributed to theabsence of PTC with high-grade proliferative features in ourpatient cohort. Alternatively, the discrepant results betweeninvestigators could be simply related to variation in samplesize and outcome measures. In a previous publication on TCVand classical PTC without ETE, we found that there was ahigher but not statistically significant rate of recurrence anddistant metastasis in TCV than in classical PTC using histo-logical definitions similar to the one utilized in the currentstudy (23). However, in contrast to the current investigation,the sample size was much smaller, and recurrence was as-sessed using not only clinical but also biochemical parameters.Clearly, there is a need for larger studies on the subject with re-review of the histology slides, and clear definitions of PTCsubtypes and outcome measures. Because of these controver-sial data regarding the independent prognostic value of TCVand PTC TCF and their lack of independent predictive powerfor clinical recurrence in that study, we recommend at thepresent time refraining from aggressive treatment in low-stageTCV and PTC TCF that do not display any worrisome features(i.e., high mitotic rate, tumor necrosis, angioinvasion, cervicalnode involvement, and ETE).

In conclusion, this study confirms the aggressive nature ofTCV as a group of tumors compared to classical PTC. It alsoshows that PTC TCF behave like TCV. However, they arecurrently treated like classical PTC. Therefore, PTC TCFshould be considered as TCV, and the threshold for the diag-nosis of TCV should be lowered to 30% of tall cells in thetumor. The independent prognostic value of TCV and PTCTCF at least in regard to RFS is still subject to debate. TCV aswell as PTC TCF have a higher risk of transformation to higher-grade tumors. This should prompt generous tissue sampling ofthese carcinomas in search for anaplastic and poorly differen-tiated foci, especially in patients over 50 years old.

Author Disclosure Statement

The authors have nothing to disclose.

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Address correspondence to:Ronald Ghossein, MD

Department of PathologyMemorial Sloan-Kettering Cancer Center

1275 York AvenueNew York, NY 10065

670 GANLY ET AL.

prognostic implications of papillary thyroid carcinoma with tall-cell features

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