Macrofollicular Variant ofPapillary Carcinoma:A Potential Thyroid FNA PitfallDaniel Chung, M.D., Ronald A. Ghossein, M.D., and Oscar Lin, M.D., Ph.D.*

Macrofollicular variant of papillary carcinoma (MFPC) is arare variant of papillary carcinoma in which over 50% of thefollicles are represented by macrofollicles. The cytologic fea-tures from 7 cases of histologically confirmed MFPC were eval-uated. The cytology specimens were evaluated for the followingcriteria: cellularity, cluster arrangement (micro and macrofollic-ular), chromatin pattern, nuclear grooves, pseudonuclear inclu-sions, nuclear shape, nuclear overlap, nucleoli, presence oflymphocytes, macrophages and Hurthle cell, amount and char-acteristics of background colloid. Most cases were moderatelyto highly cellular with presence of both microfollicles as well asmacrofollicles, but nuclear features of papillary thyroid carci-noma were absent or focal in all cases. MFPC is a variant ofpapillary carcinoma that can be extremely difficult to diagnosecytologically. The presence of abundant colloid, macrophages,macrofollicular follicular cell arrangement and/or absence ofwidespread cytologic features associated with papillary carci-noma can lead to an erroneous diagnosis of goiter. Diagn. Cyto-pathol. 2007;35:560–564. ' 2007 Wiley-Liss, Inc.

Key Words: papillary; carcinoma; macrofollicular; cytology;aspiration

Follicular variant of papillary carcinoma (FVPC) is a vari-

ant of papillary carcinoma characterized by a follicular

architecture and cytomorphologic features of papillary

carcinoma. Usually, the follicles are small in size and are

associated with thick dense colloid.1,2 It behaves, clini-

cally, as any other variant of papillary carcinoma with

disease localized to the neck with involvement of the thy-

roid and local lymph node metastases. The accurate diag-

nosis of FVPC by fine-needle aspiration biopsy (FNA)

can be difficult and some authors even question the ability

to make it on cytology material.3,4 The lack of papillary

structures, psammoma bodies, intranuclear cytoplasmic

inclusions and multinucleated giant cells associated with

the presence of a predominant microfollicular pattern can

hinder the recognition of these neoplasms as papillary car-

cinomas. This difficulty was nicely demonstrated in the

series by Kesmodel et al., in which only 9% of pre-opera-

tive FNAs of FVPC were correctly diagnosed as papillary

carcinoma.5

Macrofollicular variant of papillary carcinoma (MFPC)

is a rare variant of FVPC, first described by Albores-

Saavedra et al. in 1991.6 They described a variant of the

usual follicular variant of papillary carcinoma character-

ized by an encapsulated follicular variant of papillary

carcinoma in which over 50% of the cross-sectional

area was composed of macrofollicles. Macrofollicles

were defined as follicles measuring more than 250 lmacross. The follicular cells in MFPC have been de-

scribed as large cuboidal cells with ground glass chroma-

tin pattern, cuboidal cells with more stippled chromatin

and/or hyperchromatic small follicular cells. The histo-

logic hallmark of this tumor, macrofollicular pattern

could lead to an erroneous diagnosis of goiter in histo-

logic sections.6

The objective of this study was to evaluate the preoper-

ative FNAs findings of a new series of MFPC, their cyto-

logic findings and discuss potential implications regarding

quality assurance and clinical impact.

Material and Methods

The surgical pathology files of the Department of Pathol-

ogy were searched for cases of FVPC of the thyroid with

corresponding preceding FNAs. The search was approved

by the Institutional Review Board. Tumors were reviewed

by a surgical pathologist with expertise in thyroid

(R.A.G.) and classified as FVPC if they were composed

completely or almost entirely (99% of the tumor) of fol-

licles lined by cells that had the nuclear features of papil-

lary carcinoma (i.e., irregular, enlarged, clear nuclei with

grooves, pseudoinclusions, and overlapping).Only cases of

Department of Pathology, Memorial Sloan-Kettering Cancer Center,New York, New York

*Correspondence to: Oscar Lin, M.D., Ph.D., Department of Pathol-ogy, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NewYork, NY 10021. E-mail: lino@mskcc.org

Received 26 June 2006; Accepted 19 June 2007DOI 10.1002/dc.20702Published online in Wiley InterScience (www.interscience.wiley.com).

560 Diagnostic Cytopathology, Vol 35, No 9 ' 2007 WILEY-LISS, INC.

FVPC meeting the criteria described by Albores-Saavedra

et al. such as encapsulated lesion with over 50% of the

cross-sectional area composed of macrofollicles (>250

lm) were included in this study.6 All cases were encapsu-

lated and capsular invasion was noted only in once case.

Seven cases with corresponding pre-operatory FNAs were

selected. The preparations available included direct

smears and Thinprep1 slides. The slides were stained

with modified Giemsa stain (Quik-Dip stain, Mercedes

Medical, Sarasota, FL), H.E. and Papanicolaou stains. The

following cytology criteria were evaluated in each case:

cellularity, cluster arrangement (micro and macrofollicular

pattern), chromatin pattern, nuclear grooves, nuclear chro-

matin pattern, pseudonuclear inclusions, nucleoli, nuclear

shape, nuclear overlap, nucleoli, and the presence or ab-

sence of lymphocytes, macrophages and Hurthle cells.

The amount and characteristics of background colloid

were also analyzed.

Results

The patient population was composed of 7 patients rang-

ing in age from 22 to 78 years, with a mean age of 47

years. Two patients were male and five were female. The

thyroid nodules sampled ranged in size from 1 to 4 cm.

One of 7 specimens was hypocellular, displaying rare

clusters of follicular cells arranged in a macrofollicular

pattern (Fig. 1). The remaining 6 cases displayed moder-

ate to high cellularity with follicles of different sizes

including microfollicles (Fig. 2). Pseudonuclear inclusions

and nuclear grooves were identified in 6 of 7 cases. Nu-

clear grooves were rare in 2 cases, and easily identified in

the remaining 4 cases. Ground glass chromatin pattern

was noted in 5 of 7 cases, while nuclear overlap and

small peripheral nucleoli were noted in all 7 cases (Fig.

3). Hurthle cells were seen in 3 of 7 cases. Macrophages

were noted in 6 of 7 cases and were abundant in 4 of

these 6 cases. All cases contained mostly thin colloid

(Fig. 4), but focal thick dense colloid was noted in 5 of 7

cases (Fig. 5). A summary of the cytologic findings can

be seen in Table I.

The histologic sections in all cases demonstrated encap-

sulated lesions with a predominant macrofollicular pat-

tern, some showing a mixture of macrofollicular and

microfollicular pattern (Figs. 6a and b). There were at

least focal areas with nuclear changes suggestive of papil-

lary carcinoma, such as, ground glass chromatin pattern,

grooves, pseudonuclear inclusions, and overlapping

nuclei. One case showed capsular invasion.

Five of the seven cases had an intraoperative frozen

section performed. All of them were interpreted as follic-

ular lesion, favoring a benign lesion. None of the cases

evaluated intraoperatively were correctly diagnosed as fol-

licular variant of papillary carcinoma.

Fig. 1. Clusters of follicular cells arranged in flat sheets and macrofol-licular pattern.

Fig. 2. Clusters of follicular cells presenting with follicles of differentsizes, including microfollicles (arrow).

Fig. 3. Clusters of follicular cells with nuclear overlap.

MACROFOLLICULAR VARIANT OF PAPILLARY CARCINOMA

Diagnostic Cytopathology, Vol 35, No 9 561

Diagnostic Cytopathology DOI 10.1002/dc

Discussion

MFPC is defined as a tumor in which more than 50% of

the follicles are larger than 250 lm and they are lined at

least focally by cells with nuclear features consistent with

papillary carcinoma.6 These features include nuclear

grooves, pseudonuclear inclusions, nuclear overlap, and

ground glass chromatin pattern. Less than 50 cases have

been described in the literature.6–15 This lesion has been

described predominantly in female patients, and is consid-

ered to be less aggressive than conventional papillary car-

cinoma due to its lower rate of lymph node metastases.6

The histologic differential diagnoses of MFPC often

include goiter and macrofollicular adenoma due to the

large size of the follicles. Macrofollicular adenomas are

encapsulated nodules composed of large follicles lined by

flat epithelial cells with hyperchromatic nuclei, but none

of the nuclear features suggestive of papillary carcinoma

are present. Nodular goiter displays follicles of varying

Fig. 4. Watery colloid.

Fig. 5. Focal thick dense colloid.

Table

I.Cytologic

Findingsin

MFPC

Cellularity

Cluster

arrang

ement

Nuclear

overlap

Nuclear

shape

Chrom

atin

Nuclear

grooves

Nuclear

pseudo-inclusion

sNucleoli

Lym

phocytes

Hurthle

cells

Macrophag

esColloid

1H

Ma/mi

YRO

GR

RSp

YY

AM,W

2L

Ma

NRO

G;FGG

NN

Sp

NN

NA,W,FT

3H

Ma/mi

YRO

G;FGG

RR

Sp

YN

AM,W,FT

4L

Ma

YRO

GN

NSp

NN

NA,W

5M

Ma/mi

YRO

G;FGG

FR

Sp

NY

MM,W,FT

6M

Ma/mi

YRO

G;FGG

FF

Sp

NN

FM,W,FT

7M

Ma/mi

YRO

G;FGG

FR

Sp

NN

AA,W,FT

8H

Ma/mi

YRO

G;FGG

FF

Sp

NY

AA,W,FT

9H

Ma/mi

YRO

G;FGG

FF

Sp

YN

FA,W,FT

H,high;M,moderate;

Ma,

macrofollicular;mi,microfollicular;Y,yes;N,no;RO,roundandovoid;G,granular;FGG,focallygroundglass;R,rare;F,focal;sp,sm

allandperipheral;W,watery;

FT,focallythick.

CHUNG ET AL.

562 Diagnostic Cytopathology, Vol 35, No 9

Diagnostic Cytopathology DOI 10.1002/dc

sizes but the follicular epithelium also lacks the nuclear

changes seen in papillary carcinoma. MFPC, on the other

hand, is an encapsulated lesion with at least focal cellular

changes of follicular variant of papillary carcinoma. In

fact, Albores-Savedra described a heterogeneous appear-

ance of the follicle lining in MFPC. The follicular cells in

MFPC have been described as large cuboidal cells with

ground glass chromatin pattern, cuboidal cells with more

stippled chromatin and/or hyperchromatic small follicular

cells. Nuclear grooves were only noted in cells with

ground glass chromatin pattern.6

The heterogeneous appearance of MFPC, both in fine-

needle aspiration specimens as well as in histologic sec-

tions, is probably the main reason for low sensitivity of

FNA for MFPC. It is important to remember that these

lesions can present only focal morphologic features of

papillary carcinoma, but the entire encapsulated lesion is

considered papillary carcinoma, as recommended by

Baloch and LiVolsi.16 In our study, three cases were

interpreted as benign changes and/or suggestive of nodu-

lar goiter and four cases were interpreted as suspicious

for papillary carcinoma. Factors which most likely con-

tributed to a false negative diagnosis in three cases

included low cellularity, predominance of macrofollicular

pattern, presence of macrophages, paucity or absence of

nuclear inclusions and/or nuclear grooves, and presence

of moderate to abundant thin watery colloid. Interestingly,

2 of these 7 cases did not reveal any nuclei with ground

glass chromatin pattern. Sampling was probably one of

the causes for the false negative diagnosis since the nu-

clear changes suggestive of papillary carcinoma, while

undoubtedly present in the histologic sections, were often

focal in nature. Unfortunately, the presence of few

grooves is not particularly helpful in the achieving the

correct diagnosis. The presence of few grooves can be

focally seen in a variety of lesions including goiter and

Hurthle cell lesions. Hypochromatic nuclei with oval

shape, a finding in MFPC previously described by Meso-

nero et al.13 was only noted focally in 5 of 7 cases in our

series. These changes are probably too subtle to suggest a

malignancy, since they can also be present in cells with

Hurthle cell changes or in association with Hashimoto’s

thyroiditis. The abundant watery colloid seen in all cases

might also have contributed to a false negative diagnosis,

since it is usually associated with goiter. In retrospect, the

accurate diagnosis could only be suggested through a

combination of subtle criteria. In our study, nuclear over-

lap, small peripheral nucleoli in atypical follicular cells

with grooves and presence of focal abnormal dense col-

loid (present in a background of watery and thin colloid)

were the most common features in the FNA of MFPC.

These findings are similar to findings by Mesonero

et al.13 and Fadda et al.8

The complexity in making this diagnosis raises another

issue. How should these lesions be dealt in a cytology-

histology correlation quality assurance evaluation?

Renshaw et al.17 studied the ability of cytologists to make

the correct diagnosis of papillary carcinoma in the pres-

ence of certain morphologic features. They evaluated

which cytologic features of histologically proven papillary

thyroid carcinoma performed poorly were compared with

those of 15 cases that performed well based on data from

the College of American Pathologists Nongynecologic

Cytology Program. They concluded that cases of papillary

thyroid carcinoma that lack marked nuclear enlargement,

pale chromatin, and intranuclear inclusions are signifi-

cantly more difficult to recognize when compared to cases

displaying these features. Fadda et al. concluded in their

study that the right diagnosis could not have been made

pre-operatively in some of these cases.8 These findings

appear to justify the low sensitivity of cytology in the

diagnosis of MFPC. It is important to note that in our

Fig. 6. Histologic sections of macrofollicular variant of papillary carci-noma. (a) Low power magnification of lesion surrounded by capsule(arrow) displaying macrofollicles; (b) high power magnification display-ing nuclear changes.

MACROFOLLICULAR VARIANT OF PAPILLARY CARCINOMA

Diagnostic Cytopathology, Vol 35, No 9 563

Diagnostic Cytopathology DOI 10.1002/dc

series, the diagnosis was also very difficult in histologic

sections. All 5 cases submitted to frozen section were

also misdiagnosed as ‘‘follicular lesion, favor benign’’ and

in none of the cases the possibility of papillary carcinoma

was raised. Based on this data, a false negative diagnosis

of MFPC should be considered a difficult case in the

quality assurance analysis and should be approached in

this context.

Up to this date, no marker for papillary carcinoma has

been studied in MFPC and resulted in consistent results.

Fortunately, recent studies by Liu et al. have showed that

encapsulated lesions without invasion, as 6 of 7 cases in

our study were, have an excellent prognosis. These encap-

sulated lesions have a clinical behavior very similar to

follicular neoplasms of the thyroid.18

In summary, MFPC is a variant of papillary carcinoma

that can be extremely difficult to diagnose cytologically.

The specimens might be hypocellular and the presence of

abundant watery colloid, macrophages, macrofollicular cell

arrangement and/or absence of widespread classic cyto-

logic features associated with papillary carcinoma can lead

to an erroneous diagnosis of goiter. Presence of subtle

changes, such as areas of dense colloid, nuclei with grooves

and small peripheral nucleoli, and nuclear overlap associ-

ated to a strong degree of clinical suspicion (dominant nod-

ule) may be needed to arrive at the correct diagnosis.

References

1. Chem KT, Rosai J. Follicular variant of thyroid papillary carci-

noma: A clinicopathologic study of six cases. Am J Surg Pathol1977;1:123–130.

2. Rosai J, Zampi G, Carcangiu ML. Papillary carcinoma of the thy-

roid. A discussion of its several morphologic expressions, with par-ticular emphasis on the follicular variant. Am J Surg Pathol 1983;7:809–817.

3. Leung CS, Hartwick RW, Bedard YC. Correlation of cytologic and

histologic features in variants of papillary carcinoma of the thyroid.Acta Cytol 1993;37:645–650.

4. Martinez-Parra D, Campos Fernandez J, Hierro-Guilmain CC, Sola

Perez J, Perez-Guillermo M. Follicular variant of papillary carci-

noma of the thyroid: to what extent is fine-needle aspiration reli-able? Diagn Cytopathol 1996;15:12–16.

5. Kesmodel SB, Terhune KP, Canter RJ, et al. The diagnostic di-lemma of follicular variant of papillary thyroid carcinoma. Surgery2003;134:1005–1012; discussion 1012.

6. Albores-Saavedra J, Gould E, Vardaman C, Vuitch F. The macro-follicular variant of papillary thyroid carcinoma: a study of 17cases. Hum Pathol 1991;22:1195–1205.

7. Albores-Saavedra J, Housini I, Vuitch F, Snyder WH, III. Macrofol-licular variant of papillary thyroid carcinoma with minor insularcomponent. Cancer 1997;80:1110–1116.

8. Fadda G, Fiorino MC, Mule A, LiVolsi VA. Macrofollicular encap-sulated variant of papillary thyroid carcinoma as a potential pitfallin histologic and cytologic diagnosis. A report of three cases. ActaCytol 2002;46:555–559.

9. Gamboa-Dominguez A, Vieitez-Martinez I, Barredo-Prieto BA,Richaud-Patin Y, Herrera ME, Angeles-Angeles A. Macrofollicularvariant of papillary thyroid carcinoma: A case and control analysis.Endocr Pathol 1996;7:303–308.

10. Hernandez-Ortiz MJ, Amengual-Antich I, Canet-Ribas de Pina R.Fine needle aspiration cytology of macrofollicular variant of thyroidpapillary carcinoma in a male. Acta Cytol 2001;45:483–486.

11. Hirokawa M, Shimizu M, Terayama K, Kanahara T, Sonoo H, Man-abe T. Macrofollicular variant of papillary thyroid carcinoma.Report of a case with fine needle aspiration biopsy findings. ActaCytol 1998;42:1441–1443.

12. Lugli A, Terracciano LM, Oberholzer M, Bubendorf L, Tornillo L.Macrofollicular variant of papillary carcinoma of the thyroid: a his-tologic, cytologic, and immunohistochemical study of 3 cases andreview of the literature. Arch Pathol Lab Med 2004;128:54–58.

13. Mesonero CE, Jugle JE, Wilbur DC, Nayar R. Fine-needle aspiration ofthe macrofollicular and microfollicular subtypes of the follicular variantof papillary carcinoma of the thyroid. Cancer 1998;84:235–244.

14. Nakamura T, Moriyama S, Nariya S, Sano K, Shirota H, Kato R.Macrofollicular variant of papillary thyroid carcinoma. Pathol Int1998;48:467–470.

15. Woyke S, Al-Jassar AK, Al-Jazzaf H. Macrofollicular variant ofpapillary thyroid carcinoma diagnosed by fine needle aspiration bi-opsy: a case report. Acta Cytol 1998;42:1184–1188.

16. Baloch ZW, LiVolsi VA. Encapsulated follicular variant of papillarythyroid carcinomawith bone metastases.Mod Pathol 2000;13:861–865.

17. Renshaw AA, Wang E, Haja J, Wilbur D, Henry MR, Hughes JH.Fine-needle aspiration of papillary thyroid carcinoma: Distinguish-ing between cases that performed well and those that performedpoorly in the College of American Pathologists Nongynecologic Cy-tology Program. Arch Pathol Lab Med 2006;130:452–455.

18. Liu J, Singh B, Tallini G, et al. Follicular variant of papillary thy-roid carcinoma. A clinicopathologic study of a problematic entity.Cancer 2006;107(6):1255–1264.

CHUNG ET AL.

564 Diagnostic Cytopathology, Vol 35, No 9

Diagnostic Cytopathology DOI 10.1002/dc