2008;84;78-82 Postgrad. Med. J.
A Salajegheh, E B Petcu, R A Smith and A K-Y Lam
diagnostic challenge for clinicians and
Follicular variant of papillary thyroid carcinoma: a
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on 10 September 2008
Follicular variant of papillary thyroid carcinoma: a
diagnostic challenge for clinicians and pathologists
A Salajegheh, E B Petcu, R A Smith, A K-Y Lam
Discipline of Pathology (School
of Medicine), Griffith University,
Gold Coast, Queensland,
Professor A Lam, Department of
Pathology, Griffith Medical
School, Gold Coast Campus,
Gold Coast, Queensland, 4222,
Received 27 September 2007
Accepted 15 January 2008
The follicular variant of papillary thyroid carcinoma
(FVPTC) presents a type of papillary thyroid cancer that
has created continuous diagnosis and treatment con-
troversies among clinicians and pathologists. In this
review, we describe the nomenclature, the clinical
features, diagnostic problems and the molecular biology
of FVPTC. It is important for clinicians to understand this
entity as the diagnosis and management of this group of
patient may be different from other patients with
conventional PTC. The literature suggests that FVPTC
behaves in a way similar, clinically, to conventional
papillary thyroid carcinoma. However, there are some
genotypic differences which may characterise this
neoplasm. These parameters may account for the
phenotypic variation described by some scientists in this
type of cancer. Further understanding can only be
achieved by defining strict pathological criteria, in-depth
study of the molecular biology and long term follow-up of
the optional patients with FVPTC.
Papillary thyroid carcinoma (PTC) is the most
common histological type of thyroid cancer and
accounts for more than 70% of primary thyroid
malignancies.1–5Recently, its incidence has been
increasing, which is believed to be partly related to
the detection of small early lesions by ultrasono-
graphy and fine needle aspiration biopsy.6 7The
diagnosis of the follicular variant of papillary
thyroid carcinoma (FVPTC) also adds to the
Although FVPTC has been recognised for more
than 50 years, its diagnostic features, molecular
biology and prognosis are still debatable.2 8It is
important for clinicians to understand this entity
as the diagnosis and management of this group of
patients may be different from other patients with
conventional PTC. In this review, the current
knowledge of FVPTC will be evaluated.
THE MILESTONES OF FVPTC
FVPTC was first described in 1953 by Crile and
Hazard who named this lesion alveolar variant of
PTC.9The identification was confirmed by Lindsay
in 1960.10The author observed that although the
neoplasm had a follicular architectural pattern, the
nuclear features were that of the conventional
PTC. Therefore, the tumour should be designated
as a FVPTC. Also, the author hypothesised that the
biological behaviour of this condition should be
similar to that of conventional PTC.10In 1976,
Hawk and Hazard performed a study of 300
consecutive cases of PTC and noted significant
diagnostic problems.11In 1977, Chen and Rosai
stressed the importance of nuclear rather than
architectural pattern in making a diagnosis of PTC.
They showed that FVPTC behaves similarly to the
conventional variant of PTC.12Thereafter, the
FVPTC was diagnosed with greater frequency.
Most frequently, FVPTC presents as a thyroid
nodule that is discovered incidentally or on routine
examination. Sometimes, patients present with
metastasis in a neck lymph node or with hoarse-
ness of voice caused by involvement of the
recurrent laryngeal nerve. Rarely, FVPTC gives rise
to lung metastases in the absence of lymph node
Ultrasound imaging and fine needle aspiration
biopsy are common tools necessary for investiga-
tion of patients suspected of having thyroid cancer.
The ultrasound makes a clear differentiation
between solid and cystic lesions and also identifies
calcifications.14Fine needle aspiration biopsy is also
useful in the diagnosis of papillary carcinoma.1
However, some studies have reported a very low
sensitivity with fine needle aspiration for the
identification of FVPTC. It is accepted that the
only reliable way to diagnose this tumour is
histological examination of the thyroidectomy
The main differential diagnoses of this tumour
are follicular adenoma or follicular carcinoma.
Morphologically, FVPTC may appear partially or
completely encapsulated.15 16This is very impor-
tant to know since FVPTC can be misdiagnosed as
follicular adenoma or as follicular thyroid carci-
noma if capsular or vascular invasion are present.15
Also, conventional PTC with follicular pattern and
papillary microcarcinoma may be misdiagnosed as
LiVolsi and Baloch have suggested that the
challenge posed by an FVPTC diagnosis can be
explained by the following: (1) large numbers of
this malignancy arise in a background of nodular
goitre, resembling adenoma
nodules which mostly lack of capsular and vascular
invasion; (2) some tumours show multifocal rather
than diffuse distribution of typical nuclear features
of papillary thyroid carcinoma; (3) the majority of
the encapsulated FVPTCs are solitary, lack any
invasive characteristics, are confined to the thyroid
and behave in an indolent fashion.17In a multi-
centric study, experienced thyroid pathologists
were asked to make a diagnosis of this papillary
variant. Surprisingly, the concordance rate was
only 40%. Nevertheless, the authors concluded
that cytoplasmic invagination into the nucleus,
abundant nuclear grooves, ground glass nuclei,
psammoma bodies, enlarged overlapping nuclei
78 Postgrad Med J 2008;84:78–82. doi:10.1136/pgmj.2007.064881
on 10 September 2008
and irregularly shaped nuclei were the most important criteria
for diagnosis of FVPTC. Dark staining colloid, irregular contours
of follicles, scalloping of colloid, elongated follicles and multi-
nucleated macrophages in the lumen of follicles were viewed as
less important diagnostic parameters.8
It has been always difficult to document the clinical behaviour
and long term outcome of FVPTC. Many published series
evaluating clinicopathologic features and outcome of this
tumour lack a clear definition of this condition. Some studies
also evaluate relatively few cases, and no long term follow-up
was included in the assessment.3 5 18 19Many authorities believe
that FVPTC has the same prognosis as conventional PTC.3 18 19
FVPTC patients present with larger tumour size and younger
age groups.3 18 20 21However, in some reports, FVPTC was found
to mimic the pathologic features and clinical behaviour of
follicular neoplasms.2 20Some encapsulated FVPTC metastasise
to distant sites in the absence of lymph node metastases,
mimicking the behaviour of follicular carcinoma.13Also, some
FVPTC cases demonstrated a significantly higher prevalence of
angiovascular and capsular invasion, distant metastases and
poorly differentiated areas.19 22 23However, it was noted on
histological examination that FVPTC has significantly lower
rates of lymph node metastases, is more often encapsulated and
shows extra-thyroidal invasion less often than conventional
PTC.2 5 18 19 22Furthermore, FVPTC showed less calcification,
psammoma bodies and bone formation in comparison with
In a recent study that involved more than 500 thyroid cancer
patients and with more than 15 years of follow-up, FVPTC was
concluded to have more favourable clinicopathological features
and a better tumour risk group profile. However, long term
outcome was similar to conventional PTC patients.5
In recent years, advances in molecular biology have shed some
light on the diagnosis and prognosis of thyroid cancer. The
controversial issues related to the follicular variant of PTC could
be explained by molecular biology. In papillary thyroid cancer,
the three most commonly reported genetic alterations in the
carcinogenesis are the BRAF, RAS and RET/PTC oncogenes.24
All these genes are involved in the control of cellular growth and
differentiation, occupying various positions in the major cell
growth signalling pathway, and the most common genetic
abnormalities in PTC are located at this level.
RET is a proto-oncogene located on chromosome 10q11.2
that encodes a protein tyrosine kinase receptor with an
extracellular domain, a transmembrane domain, and an
intracytoplasmic kinase domain.25There are a number of
RET/PTC gene rearrangements, all produced by the fusion of
the tyrosine kinase portion of RET with 59-portions of different
genes. RET/PTC1 and RET/PTC3 are the most common types,
making up more than 90%, whereas RET/PTC2 and several
other types are uncommon.26–32The rearrangement is considered
to be an early event in thyroid tumourogenesis. While in some
studies it has been reported that the prevalence of RET/PTC
rearrangements was similar in CPTC and FVPTC (40–45%), it
has been shown that FVPTC has lower frequencies of RET/PTC
rearrangements than conventional PTC.29 33–35
BRAF is a protein kinase that has an important role in cell
proliferation, differentiation, and programmed cell death.
Initially, activating mutations of BRAF were found in malig-
nant melanomas, and colorectal and ovarian carcinomas.36Now,
it is recognised that BRAF is also mutated in PTC with high
frequency, between 29–69% of cases.37 38The most common
mutation is characterised by a change of a valine amino acid to
glutamate in codon 600 (BRAF mutation V600E, previously
labelled V599E) which causes increased kinase activity.37–41The
prevalence of BRAF mutations has been shown to correlate
positively with age and it has been shown that BRAF mutation
may be related to prognosis.38 42 43
A distinct BRAF mutation (K601E) has been detected in
FVPTC.38Trovisco et al claimed that this mutation is typical of
FVPTC. However, it is less frequent than BRAF V600E in CPTC.
The substitution of a lysine by a glutamate in codon 601 (BRAF
K601E) in the FVPTC causes increased kinase activity and
resembles the BRAF V600E mutation found in CPTC.44It is
worth noting that BRAF V600E has about 2.56 the kinase
activity of BRAF K601E.36 45
Ras proto-oncogenes, known individually as H-ras, K-ras and
N-ras are members of the large family of guanosine triphosphate
(GTP) binding proteins. The proteins are associated with the
cellular membrane and are bound to guanosine diphosphate
Scientific advances that have allowed development of
understanding of the clinical aspects of FVPTC
c The concordance rate of diagnosing FVPTC in the hands of
experts was only 40%.
c FVPTC patients present with larger tumour size and younger
age groups than conventional PTC.
c FVPTC shows less calcification, psammoma bodies and bone
formation in comparison with PTC.
c FVPTC has more favourable clinicopathological features (lower
rates of lymph node metastases, more often encapsulated and
shows extra-thyroidal invasion less often than conventional
c FVPTC has a better tumour risk group profile than conventional
c The long term outcome of patients with FVPTC was similar to
patients with conventional PTC.
Outstanding research questions or things we need to
c The three most commonly reported genetic alterations in PTC
are the BRAF, RAS and RET/PTC oncogenes.
c FVPTC has lower frequencies of RET/PTC rearrangements than
c FVPTC can have a different mutation (K601E) from
c Ras mutation pattern in FVPTC is similar to that of follicular
c PAX8-PPARc gene fusion is mostly seen in follicular
carcinomas but can be seen in FVPTC.
c Cylcooxygenase-2 was often positive in conventional PTC but
negative in FVPTC.
c There was a frequent lack of p16 protein expression and
promoter methylation in FVPTC when compared with
c Caution is needed in interpreting the literature of molecular
biology in thyroid carcinoma.
Postgrad Med J 2008;84:78–82. doi:10.1136/pgmj.2007.064881 79
on 10 September 2008
(GDP) when inactive. They have been shown to play a key role
in signal transduction as molecular switches modulating
proliferation and malignant transformation. Activating point
mutations of the ras genes arise in codons 12, 13, or 61. They are
usually found in follicular carcinomas, at frequencies of between
18–52%.23 46 47
Their existence has been reported with a
significantly lower frequency in PTC.23 48Interestingly, PTC
and follicular carcinoma have different patterns of ras oncogene
activating mutations. However, it has been reported that the ras
mutation pattern in FVPTC is similar to that of follicular
carcinoma.23 49There is a possibility of a strong correlation
between ras mutation and follicular differentiation in thyroid
Changes to these three prototype genes above have been
found in approximately 70% of PTC.24In other words,
approximately 30% of thyroid cancers may have other genetic
alterations. Some of the observed candidates for these genetic
changes are detailed below.
PAX8-PPARc gene fusion is mostly seen in follicular
carcinomas (53–63%) and in some follicular adenomas (8–
13%).50–55It has been cytogenetically identified as translocation t
(2;3) (q13;p25).55Its prevalence in follicular carcinomas may be
higher in tumours associated with radiation exposure as it has
been seen in Belarusian citizens exposed to ionising radiation
after the Chernobyl nuclear accident in 1986. It is also believed
that the existence of this rearrangement may be involved in the
invasive behaviour of the follicular neoplasm.50 54 56–58Roque et al
found PAX8-PPARc gene fusion in a case of FVPTC by using
conventional cytogenetics.59Furthermore, there is an associa-
tion between PAX8-PPARc and the presence of multifocality
and vascular invasive characteristics in FVPTC.60Thus, this
rearrangement may have a possible role in promoting metas-
Cylcooxygenases are known to play a role in the formation of
prostaglandins and consist of two identified isoforms, COX-1
and COX-2. Cyclooxygenase-2 (COX-2) has a role in the
carcinogenesis of PTC. Expression of COX-2 has been mostly
observed in PTC but not in benign thyroid nodules. Previous
studies have revealed that COX-2 expression was significantly
lower in anaplastic and follicular carcinomas than in PTC.61–63It
was also shown that COX-2 expression in PTC was noticeably
reduced in elderly patients, large sized tumours and in cases
associated with advancedstageand satellitetumours.
Therefore, there was a suggestion that COX-2 may be
important in the early phase of pathogenesis of thyroid
carcinoma.61 62The gene may therefore represent a useful target
for the identification of thyroid tissue transitioning from a
benign to a malignant state. Lo and colleagues demonstrated a
significant difference in the level of COX-2 mRNA in PTC
compared with adjacent non-tumorous and benign thyroid
tissues. This study has also investigated the expression of COX-
2 in the FVPTC. It was shown that most FVPTC cases are
negative for COX-2.63
The p16 gene encodes the p16 protein, which competes with
cyclin D for binding to CDK4. This inhibits the ability of the
cyclin D–CDK4 complex to phosphorylate RB (retinoblastoma),
thus causing cell cycle arrest in the late G1 phase. The roles of
this gene in PTC have been investigated in a few studies.64–68
Studies indicated that different types of p16 alterations are
present in approximately 80% of patients with PTC. It is worth
noting that there was a frequent lack of p16 protein expression
and promoter methylation in FVPTC when compared with
The limited data available in the literature suggest that
FVPTC has different molecular alterations compared to
conventional papillary thyroid carcinoma. However, we should
be cautious in interpreting the literature. Firstly, the number of
follicular variant tumours described in some studies was small.
Secondly, due to the difficult morphological assessment, some
cases of follicular neoplasm, papillary microcarcinoma or
conventional PTC may have been misdiagnosed as FVPTC.
Nevertheless, we believe that FVPTC has some genotypic
differences compared with conventional PTC which lead to
the phenotypic difference between these two entities. More
studies are necessary to address those issues.
As the long term outcome of FVPTC is similar to conventional
PTC patients, FVPTC may be managed similarly to conven-
tional PTC.5Surgery as a standard preferred procedure of choice
has been performed for many years. Patients would undergo
total or near total thyroidectomy. The decision to perform a
total thyroidectomy mostly depends on the patient’s risk
factors, tumour characteristics, the presence or absence of nodal
metastases and the patient’s choice.5 18 69Decisions on the
subsequent management after surgery are often made by
oncologists and surgeons. Postoperative radioactive iodine
c Papillary thyroid carcinoma (PTC) is the most common
histological type of thyroid cancer.
c Increasing incidence of PTC is related to the detection of small
early lesion and increased diagnosis of the follicular variant of
papillary thyroid carcinoma (FVPTC).
c Nuclear features rather than architectural pattern are important
in making a diagnosis of PTC.
c The only reliable way to diagnose FVPTC is histological
examination of the thyroidectomy specimen.
c The main differential diagnoses of FVPTC are follicular
adenoma, follicular carcinoma, conventional papillary
carcinoma and papillary microcarcinoma.
c The decision to perform a total thyroidectomy mostly depends
on the patient’s risk factors, tumour characteristics, the
presence or absence of nodal metastases, and the patient’s
c Lloyd RV, Erickson LA, Casey MB, et al. Observer variation in
the diagnosis of follicular variant of papillary thyroid
carcinoma. Am J Surg Pathol 2004;28:1336–40.
c Lang BH, Lo CY, Chan WF, et al. Classical and follicular variant
of papillary thyroid carcinoma: a comparative study on
clinicopathologic features and long-term outcome. World J
c LiVolsi VA, Baloch ZW. Follicular neoplasms of the thyroid
view, biases, and experiences. Adv Anat Pathol 2004;11:279–
c Lam AKY, Lo CY, Lam KSL. Papillary carcinoma of thyroid: a
30-yr clinicopathological review of the histological variants.
Endocr Pathol 2005;16:323-30.
c Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer
80Postgrad Med J 2008;84:78–82. doi:10.1136/pgmj.2007.064881
on 10 September 2008
(I131) ablation (dose 80–100 mCi), followed by whole body
scintigraphy and thyroxin suppression therapy, should be given
to patients with high risk factors. Follow-up examinations may
include clinical investigations, chest x ray, cervical ultrasono-
graphy or magnetic resonance image (MRI) scan and measure-
ment of thyroglobulin levels without thyrotropin stimulation.5
Furthermore, radioactive iodine (I131) whole body scintigraphy
should be repeatedly performed for the detection of suspicious
recurrences and for patients with an elevated thyroglobulin
level.3–5 18 19 69In addition, pathological consultation may be
needed on follow-up if the patient develops features suggestive
of follicular neoplasm rather than papillary carcinoma (for
example, vascular metastases). In this circumstance the initial
diagnosis needs to be reviewed as follicular neoplasms may be
misdiagnosed as FVPTC.
FVPTC has distinct clinicopathological characteristics. The
correct histopathological diagnosis of this entity is difficult.
Moreover, some of the molecular features of FVPTC may differ
from those of conventional PTC. Nevertheless, it is likely that
some specimens of FVPTC may mimic the pathologic features
and clinical behaviour of follicular adenoma or carcinoma.
Further understanding of this malignancy can only be achieved
by attention to pathological criteria, in-depth study of the
carcinoma’s molecular biology and long term follow-up of
MULTIPLE CHOICE QUESTIONS (TRUE (T)/FALSE (F); ANSWERS
AFTER THE REFERENCES)
1. Epidemiology of papillary thyroid carcinoma and its follicular
(A)Papillary thyroid carcinoma (PTC) is the most common
histological type of thyroid cancer
PTC’s increasing incidence is partly related to the
detection of small early lesions by ultrasonography and
fine needle aspiration biopsy
FVPTC accounts for .70% of primary thyroid malig-
FVPTC accounts partly for the increasing number of PTC
cases recorded worldwide in the recent years
FVPTC is mostly discovered as a thyroid nodule on
2. Pathological characteristics of FVPTC:
FVPTC is often smaller than conventional PTC
FVPTC often occurs in the elderly groups
FVPTC has nuclear grooves and intranuclear inclusions
FVPTC does not metastasise to lymph node
FVPTC has the tumour cells arranged in follicles
3. Diagnosis of FVPTC:
(A) Ultrasound imaging and fine needle aspiration biopsy are
necessary tools for the investigation of patients suspected
of having FVPTC
In pathological diagnosis of FVPTC, the cytoplasmic
features are more critical than nuclear features of the
The most reliable way to diagnose FVPTC is histological
examination of the thyroidectomy specimen
(D)FVPTC is the neoplasm that has a follicular architectural
pattern but the nuclear features of the conventional
papillary thyroid carcinoma
Most physicians now believe that FVPTC behaves
similarly to the classic variant of papillary thyroid
4. Molecular biology of papillary thyroid carcinoma:
(A) The BRAF, RAS and RET/PTC are the most common
genetic alterations in papillary thyroid cancer
(B) RET/PTC rearrangement is an early event in thyroid
(C) The BRAF mutation pattern of FVPTC is different from
that in conventional papillary thyroid carcinoma
(D) RAS mutation pattern in FVPTC is similar to that of
follicular carcinoma of thyroid
(E) The expression of COX-2, p16 protein expression and
promoter methylation are more frequent in FVPTC when
compared with conventional PTC
5. Management of FVPTC:
(A)Total or near total thyroidectomy is the standard
preferred procedure of choice in the management of
(B) The management of the patient depends on the patient’s
risk factors, tumour characteristics, the presence or
absence of nodal metastases and the patient’s choice
(C) Postoperative radioactive iodine ablation, followed by
whole body scintigraphy and thyroxin suppression
therapy, should be given to patients with low risk factors
(D)Clinical investigations, chest x ray, cervical ultrasonogra-
phy or MRI scan and measurement of thyroglobulin levels
are performed as the follow-up examinations of patients
(E)Pathological consultation on follow-up is necessary if the
patient develops features suggestive of follicular neoplasm
such as vascular metastases
Competing interests: None.
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82Postgrad Med J 2008;84:78–82. doi:10.1136/pgmj.2007.064881
on 10 September 2008