Nodule Heterogeneity as Shown by Size Differences
Between the Targeted Nodule and the Tumor in
A Cause for a False-Negative Diagnosis of Papillary Thyroid Carcinoma
on Fine-Needle Aspiration
Masood A. Siddiqui, MD1
Kent A. Griffith, MPH, MS2
Claire W. Michael, MD1
Robert T. Pu, MD, PhD1
1Department of Pathology, University of Michi-
gan, Ann Arbor, Michigan.
2Biostatistics Unit, University of Michigan, Com-
prehensive Cancer Center, Ann Arbor, Michigan.
BACKGROUND. Missed papillary thyroid carcinoma (PTC) diagnoses on fine-nee-
dle aspiration (FNA) can result from many causes. To the authors’ knowledge,
the issue of whether the detection of PTC is correlated with nodule heterogeneity
has not been studied to date.
METHODS. The authors identified all thyroidectomy specimens with a diagnosis
of PTC that had undergone at least 1 prior FNA in the study institution between
1998 and 2003. The tumor size at the time of the resection, the ultrasound (US)-
determined nodule size, and other parameters were compared between the 2
groups in which PTC was or was not diagnosed on FNA.
RESULTS. Of a total of 89 specimens, 47 were diagnosed on FNA with an average
tumor size of 1.7 cm and an US-determined nodule size of 2.1 cm (a difference
of 0.4 cm). Forty-two specimens with a smaller average tumor size of 0.9 cm
(P \.0001) and a US-determined nodule size of 2.4 cm (a difference of 1.5 cm)
were missed. The differences with regard to the US-determined nodule size and
tumor size between the 2 groups were significant (0.4 cm vs 1.5 cm; P \.0001).
In the missed group, 29 specimens were found to have PTC foci that measured
?1.0 cm and 26 had a reasonable size difference (RSD; defined as a PTC size out-
side the range of ?50% of the US-determined nodule size) as the indicator of the
mixed nature of nodules targeted for FNA, whereas in the diagnostic group, 9
foci measured ?1.0 cm and 6 had RSD. There was no cytologic evidence with
which to render a diagnosis of PTC on further review in the missed group.
CONCLUSIONS. The major reason for a missed diagnosis of PTC on FNA is
because of inadequate tumor sampling due to the heterogeneity of the nodule
targeted for FNA. This is illustrated by the RSD noted between the targeted nod-
ule and the actual PTC tumor focus in the resection specimen. Cancer (Cancer
Cytopathol) 2008;114:27–33. ? 2007 American Cancer Society.
KEYWORDS: thyroid, fine-needle aspiration, papillary thyroid carcinoma, missed
diagnosis, nodule heterogeneity, reasonable size difference.
diagnostic modalities, including ultrasound (US)guided-fine-needle
aspiration (FNA) has made it possible to detect even the smallest of
lesions. Papillary thyroid microcarcinoma (PTMC) is defined by the
World Health Organization (WHO) as those PTC that measure ?1.0
cm in greatest dimension and are found incidentally.1To our knowl-
edge, the biology of PTMC is not well understood, but several
apillary thyroid carcinomas (PTC) represent 75% to 80% of all
malignant thyroid neoplasms.1Increasing sensitivities of various
Address for reprints: Robert T. Pu, MD, PhD,
Department of Pathology, University of Michigan
Hospitals, 1500 East Medical Center Drive,
Ann Arbor, MI 48109-0054; Fax: (734) 763-4095;
October 12, 2007; accepted October 31, 2007.
June 4,2007; revisionreceived
ª 2007 American Cancer Society
Published online 17 December 2007 in Wiley InterScience (www.interscience.wiley.com).
‘‘atypical’’ cells.16In addition, a cystic mass also gen-
erates RSD, an indicator of nodule heterogeneity, thus
affecting tumor sampling. In Figure 3, at the 2.5-cm
cutoff point, there was a counterintuitive decrease in
the probability of a correct diagnosis to 50%. This is
in part because of the finding that 2 cases in this
group were diagnosed as ‘‘cyst contents’’ on FNA but
subsequently were found to demonstrate cystic PTC
(3.0 cm) at the time of surgical resection because
thyroid lobectomy is advocated for large cystic
lesions.17,18In addition, 2 missed cases with multifo-
cal but small PTC foci that might be more difficult to
sample were included in this[2.5-cm group.
In conclusion, the major reason for a false-nega-
tive diagnosis of PTC on FNA is because of inade-
quate tumor sampling due to the mixed nature
of the lesion/heterogeneity of the nodule. This is
illustrated by the RSD between the targeted nodule
and the actual PTC tumor focus in the resection
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Nodule Heterogeneity Limiting PTC Diagnosis on FNA/Siddiqui et al. 33