Metastatic Minimally Invasive (Encapsulated)
Follicular and Hurthle Cell Thyroid Carcinoma:
A Study of 34 Patients
Neal S. Goldstein, M.D., Peter Czako, M.D., James S. Neill, M.D.
Departments of Anatomic Pathology (NSG, JSN) and General Surgery (PC), William Beaumont Hospital,
Royal Oak, Michigan
Most studies that have examined minimally inva-
sive, encapsulated, follicular carcinoma (FC) or
Hurthle cell carcinomas (HCs) have contained only
a few metastatic neoplasms. We studied 34 patients
with a single, minimally invasive, metastatic FC or
HC and compared them with 38 patients with sim-
ilar, nonmetastatic FCs or HCs. The numbers of
incomplete capsular penetration (neoplasm into
but not through the capsule), complete capsular
penetration (neoplasm through the capsule), and
vascular invasion foci were quantified. The median
number (three), range, and distribution of complete
capsular penetration and vascular invasion foci
were similar in the nonmetastatic and metastatic
carcinomas. All of the metastatic FCs and HCs had
at least one vascular invasion or complete capsular
penetration focus. Sixty-two percent of the meta-
static carcinomas had two to four complete capsu-
lar penetration foci, and 60% had two to four vas-
cular invasion foci. Two metastatic neoplasms had
incomplete capsular penetration but had one and
two vascular invasion foci, respectively. One tumor
had no vascular invasion but had four complete
capsular penetration foci. No metastatic neoplasms
had incomplete capsular penetration only. There
were no differences in the number of vascular inva-
sion or complete capsular penetration foci between
metastatic and nonmetastatic FCs and HCs and be-
tween metastatic FCs and HCs. Most metastatic
neoplasms had vascular space invasion and com-
plete capsular penetration. The number of com-
plete capsular penetration or vascular invasion foci
was not associated with the initial site of metastasis
or the interval between the surgery and the metas-
KEY WORDS: Capsular invasion, Encapsulated, Fol-
licular carcinoma, Hurthle cell carcinoma, Metasta-
ses, Thyroid, Vascular invasion.
Mod Pathol 2000;13(2):123–130
There are two major types of intrathyroidal, low
grade follicular carcinomas (FCs) and Hurthle cell
carcinomas (HCs): widely invasive and minimally
invasive (1–12). The latter type forms a solitary le-
sion in the thyroid and is almost always encapsu-
lated. Extratumoral capsular extension, if present, is
usually only several millimeters beyond the outer
edges of the capsule.
The histologic features of vascular space invasion
and capsular penetration as criteria for distinguish-
ing follicular adenoma from minimally invasive car-
cinoma were first noted by Graham (2) in 1914
(Case 11074). Graham (2, 3) and Coller (4) formally
established these features as criteria of malignancy
in the early 1920s, and Warren (5) confirmed them
in the early 1930s. Studies on the histopathologic
criteria of minimally invasive, encapsulated HCs
concluded that the histologic criteria for carcinoma
in the minimally invasive HCs are the same as for
FCs (10, 13–24).
The focus of this large body of studies has been
on identifying the histologic features that predict
for metastases or soft-tissue recurrences. One lim-
itation of most of these studies is that the number
of patients who develop metastases is few. A large
number of metastatic noninvasive or minimally in-
vasive neoplasms have been available only to a few
authors. We identified 58 studies, other than case
reports, that reported the number of patients with
recurrent or metastatic intrathyroidal, minimally
invasive FCs or HCs. Fourteen percent of these
studies had no patients who developed a metastasis
or soft-tissue neck recurrence, and 42% of the stud-
ies had five or fewer patients. There have been
Copyright © 2000 by The United States and Canadian Academy of
VOL. 13, NO. 2, P. 123, 2000 Printed in the U.S.A.
Date of acceptance: August 24, 1999.
Address reprint requests to: Neal S. Goldstein, M.D., Department of An-
atomic Pathology, William Beaumont Hospital, 3601 West 13 Mile Road,
Royal Oak, MI 48073; e-mail: firstname.lastname@example.org; fax: 248-551-
several studies that have addressed the range of
pathologic features in metastatic minimally inva-
sive FCs and HCs (21, 25–32).
We studied 34 patients who developed metasta-
ses or soft-tissue recurrences from a solitary, intra-
thyroidal, minimally invasive, encapsulated thyroid
FC or HC. We compared them with 38 nonmeta-
static, histologically identical FCs and HCs and ex-
plored associations between the follicular and
Hurthle cell morphology.
MATERIALS AND METHODS
The William Beaumont Tumor Registry and An-
atomic Pathology files were searched from January
1972 through October 1998 and June 1955 through
October 1998, respectively, for patients with thyroid
FC or HC or follicular and Hurthle cell lesions (ad-
enomas or carcinomas of all grades). Patients were
excluded from the search results if they had the
following: thyroid adenomas without metastases;
diffusely invasive FC or HC; extrathyroidal exten-
sion; multiple carcinomas; or insular, trabecular,
medullary, anaplastic, or follicular variant of papil-
lary carcinomas. All patients included in the study
had follow-up information, including the time and
location of the development of a metastasis or soft-
tissue neck recurrence that was provided by the
William Beaumont Tumor Registry. This registry
tracks all patients with a malignancy treated at Wil-
liam Beaumont Hospital and records subsequent
hospital, clinic, and William Beaumont Hospital–
associated primary medical physician visits. There
was insufficient follow-up information after a pa-
tient’s local metastasis or soft-tissue recurrence de-
veloped to determine the efficacy of various thera-
The control cases were selected from a pool of
patients who had a single, nonmetastatic, encapsu-
lated FC or HC and that were identified from our
files during the time period of June 1955 through
October 1998. The morphology of these neoplasms
were identical to the metastatic neoplasms. All neo-
plasms had at least one focus of complete capsular
penetration or vascular space invasion. Consecu-
tive nonmetastatic cases equal to the number of
metastatic cases from that decade plus an addi-
tional nonmetastatic case were selected for the
study. This totaled 38 nonmetastatic FCs and HCs.
Twenty-seven patients were female. Thirty-five pa-
tients were treated with complete thyroidectomy.
All 34 patients with metastatic FCs or HCs and 38
patients with nonmetastatic FCs or HCs had a sin-
gle, grossly encapsulated carcinoma that was con-
fined to the thyroid. Three patients from the 1960s
were initially diagnosed as having an adenoma that
The following features of the thyroid specimen
1. Maximum dimension of the carcinoma
2. Number of blocks submitted from the carci-
3. Number of slides made from the carcinoma
4. Number of foci of complete capsular penetra-
tion, defined as tumor extension completely
through the capsule. The criteria for complete
capsular penetration are those defined by
Lang et al. (26) and Franssila et al. (29) (Fig. 1).
Complete capsular penetration was consid-
ered present only when there was total pene-
tration of the tumor capsule by neoplastic tis-
sue so that there was contact between tumor
tissue and adjacent thyroid tissue. A thin
pseudocapsule around the leading edge of the
invasive focus was occasionally observed.
Sharp projections of thyroid neoplasm that
extended into but not through the capsule
were not complete capsular penetration (33).
5. Number of foci of incomplete capsular pene-
tration, defined as carcinomatous extension
into but not through the capsule (Fig. 2) (26,
29). Incomplete capsular penetration included
irregular nests or fingers of tumor cells within
the tumor capsule, beyond the outer circum-
ferential edge of most of the neoplasm (27). It
smoothly contoured, discrete, often almond-
shaped tumor islands within but not through
the tumor capsule (33).
6. Number of vascular invasion foci subjacent to,
in, or beyond the tumor capsule (Figs. 3 and 4)
(27, 29, 33). The most common pattern of vas-
cular invasion was subendothelial tumor cell
clusters or sheets that often formed polypoid
projections into vessel lumina (33). Other pat-
terns of vascular invasion included polypoid
lesions described as
FIGURE 1. Complete capsular penetration. A tongue of follicular
carcinoma has extended through the capsule of the neoplasm
(hematoxylin and eosin, 76.8?).
tumor thrombi or large clusters of tumor cells
that protruded into a large or moderate-sized
vessel. Small tumor nests that slightly bulged
into small, thin-walled vessels were not re-
garded as vascular invasion (27, 29). The tu-
mor thrombi were usually covered by an en-
thrombi that bulged into large veins that were
not covered by endothelial layer were also
considered as vascular invasion (27, 29). Tu-
mor thrombus attachment to a vessel wall was
not a prerequisite of vascular invasion (27, 29).
Observing the actual point of vascular inva-
sion into the vessel wall was also not required
to diagnose vascular invasion (1, 27, 29). Elas-
tic stains were not used to diagnose vascular
space invasion (29).
7. Hurthle or follicular subtype. Hurthle cell car-
cinoma was defined as having 75% or more of
the neoplastic cells be of Hurthle cell type (15).
One patient had a mixture of Hurthle cells and
clear cells. Electron microscopy identified nu-
merous mitochondria in the clear cells, and it
was classified as an HC (34).
The amount of incomplete and complete capsu-
lar penetration and vascular invasion was scored
independently by two of the authors (NSG and
JSN), and the mean value for each case was used in
the final analyses. Also recorded for each patient
were the date of surgery, age at the time of surgery,
interval between the thyroid surgery and when clin-
ical identification of the thyroid neoplasm metas-
tasis or soft-tissue neck recurrence was detected,
and location of the initial metastasis or soft-tissue
neck recurrence. Fisher’s exact t test was used for
Twenty-seven of the 34 patients (79%) who de-
veloped metastases were female. Thirty patients
were treated by total thyroidectomy or lobectomy
followed by contralateral completion lobectomy.
The other four patients, who were operated on be-
fore 1966, underwent only a lobectomy. Three of
these patients initially were diagnosed as having an
adenoma. The mean and median follow-up periods
were 11.5 and 6.1 years, respectively (range, 140
days to 36.6 years; SD, 11.5 years). The median age
at diagnosis was 53.5 years (range, 27.4 to 86.2
years; SD, 14.9 years). The mean and median inter-
val until the first metastasis was detected were 3.2
and 1.6 years, respectfully. Twenty of the 34 pa-
tients (59%) had FCs, and the other 14 patients
(41%) had HCs. Five patients (15%) presented with
their metastasis before the primary thyroid tumor
was detected. Four of these five patients had distant
metastases (bone ? 4 patients, lung ? 1 patient); all
four had FCs. The other patient had a neck lymph
FIGURE 3. Vascular space invasion by follicular carcinoma in a vein
immediately outside the neoplasm’s capsule (hematoxylin and eosin,
FIGURE 2. Incomplete capsular penetration by follicular carcinoma
that extends into but not through the neoplasm’s capsule. A thin rim of
capsule remains between the front edge of the neoplasm and the
adjacent thyroid parenchyma (hematoxylin and eosin, 76.8?).
FIGURE 4. Vascular space invasion, higher magnification of Figure 3.
The carcinoma embolus is attached to the vessel wall. There is a thin
endothelium covering the embolus in the right half of the photograph
(hematoxylin and eosin, 576?).
Follicular and Hurthle Cell Thyroid Carcinoma (N.S. Goldstein et al.) 125
node metastasis from an HC. Another four patients
had their metastasis detected at the time of thyroid
surgery, two of which were HCs. Three of these four
patients had neck lymph node metastases, and one
had a bone metastasis. Of the 25 patients who de-
veloped their first metastasis after the thyroid sur-
gery, the mean and median interval until the me-
tastasis was first detected was 4.5 and 3.6 years,
respectively (range, 74 days to 13.7 years; SD, 3.8
Twenty-one patients (62%) developed their first
metastasis in a distant site. The first metastasis was
to the bone in 12 patients, lung in 6 patients, liver in
2 patients, and lung and brain in 1 patient. The
median age at the time of diagnosis was 48.9 years.
The mean and median time periods from the thy-
roid surgery until the first metastasis was identified
was 4.3 and 4.1 years, respectively. Thirteen of the
21 patients (62%) had FCs, and the other 14 patients
(38%) had HCs. Seven patients (21%) developed
their first recurrence in the soft tissues of the neck.
The median age at diagnosis in this patient group
was 47.8 years, and the mean and median time
periods from thyroid surgery until their neck soft-
tissue metastasis was identified was 1.7 and 1.6
years, respectively. Six of the seven patients (86%)
had FCs, and one patient (14%) had an HC. Six
patients (18%) had their initial metastasis to a neck
lymph node. The median age at diagnosis in this
patient group was 72.8 years, and the mean and
median time periods from thyroid surgery until
their neck lymph node metastasis was found was
1.3 and 0.43 years, respectively. One patient (17%)
had FC, and the other five patients (83%) had HCs.
The mean and median follow-up period of the 38
patients with nonmetastatic FC or HC was 17 and
14 years, respectively (range, 1.1 years to 45 years;
SD, 7.0 years). The median age at diagnosis was 41
years (range, 18 to 70 years; SD, 10.5 years).
Table 1 lists tumor size and number of slides and
blocks examined. The mean maximum tumor di-
mension in nonmetastatic and metastatic FCs and
HCs was 4.9 and 4.6 cm, respectively. There were no
significant differences in the number of blocks or
slides examined per patient between the patients
who developed metastases and those who did not
develop metastases. The carcinomas from seven
metastatic and four nonmetastatic specimens were
completely embedded. All of these specimens were
from the 1980s or 1990s.
The mean, median, and ranges of complete cap-
sular penetration foci, vascular invasion foci, and
incomplete capsular penetration foci per neoplasm
in the nonmetastatic and metastatic groups were
almost identical (Table 2). The median number of
complete capsular penetration foci for these two
patient groups were 3.4 and 3.0, respectively, and
the median number of vascular invasion foci was
2.7 and 3.0, respectively.
Sixty-six percent of the nonmetastatic carcino-
mas and 62% of the metastatic carcinomas had two
to four foci of complete capsular penetration (Table
3). Only five (13%) of the nonmetastatic carcinomas
and six (17%) of the metastatic carcinomas had five
or more complete capsular penetration foci. The
majority of neoplasms in both groups had two to
four foci of vascular invasion. One nonmetastatic
carcinoma had no capsular penetration (incom-
plete or complete), but it had two foci of vascular
invasion, both of which were within the thick tumor
capsule. One nonmetastatic carcinoma also had no
vascular invasion, but it had one focus of complete
Five metastatic carcinomas had one focus of
complete capsular penetration, all of which had
between two and four foci of vascular invasion. Two
metastatic carcinomas, both FCs, had no complete
capsular penetration but had one focus and two
TABLE 1. Tumor Size and Numbers of Blocks and Slides Submitted
Blocks per cm
Slides per cm
0.6–6.2 (1.0) (5.3) (5.8)
TABLE 2. Histologic Parameters of Malignancy in
Metastatic and Nonmetastatic Minimally Invasive
Follicular Thyroid Carcinoma
Nonmetastatic carcinomas (N ? 38)
Metastatic carcinomas (N ? 34)
foci of vascular invasion, respectively. These neo-
plasms also had three and four foci of incomplete
capsular penetration, respectively. Both of these
neoplasms were initially diagnosed as adenoma.
One HC that produced metastases had no vascular
invasion but had four foci of complete capsular
penetration. None of the metastatic carcinomas
had only incomplete capsular penetration.
Follicular versus Hurthle Cell Morphology
among Metastatic Carcinomas
Of the 34 patients who developed metastases, 20
patients (59%) had FC and 14 (41%) had HC mor-
phology (Table 4). The mean and median number
of incomplete and complete capsular penetration
and vascular invasion foci were almost identical
between the two tumor types. The location of the
initial metastasis was significantly different be-
tween the two groups (P ? .037). Of the 20 FCs, 6
(30%) initially developed neck soft-tissue metasta-
ses compared with only 1 of 14 (7%) patients with
HC. Conversely, only 1 of the 20 FCs (5%) initially
developed neck lymph node metastases compared
with 5 of 14 (36%) patients with HC. A similar ma-
jority of patients with FCs (65%) and HCs (57%)
initially developed distant metastases.
The histologic criteria of minimally invasive FC
and HC are well established; complete capsular
penetration or vascular invasion identifies a group
of neoplasms that have the potential to metastasize
or recur (1–6, 8, 13–15, 17, 18, 20, 21, 24–29, 33–43).
Despite the large number of studies that have ex-
amined the histologic features associated with me-
tastases or recurrences in minimally invasive FC
and HC, the number of patients who develop me-
tastases in most of these studies is small. We iden-
tified 58 studies, other than case reports, that re-
ported the number of patients with intrathyroidal,
minimal (encapsulated) FCs or HCs who developed
metastases (1, 2, 5, 7, 9, 13–16, 20, 21, 25–28, 31–33,
40–79). Fourteen percent of these studies included
no patients who developed metastases, and 42% of
the studies had one to five patients. To our knowl-
edge, there are only three studies, in addition to
ours, that have examined more than 30 patients
with metastatic carcinoma (27, 31, 79). Two of these
studies are by the same group of authors. None of
these studies quantified the number of vascular,
incomplete, or complete penetration foci.
We found that there were no significant differ-
ences in the number of complete capsular penetra-
tion and vascular invasion foci between metastatic
and nonmetastatic tumors. The median number of
complete capsular penetration or vascular invasion
foci in metastatic carcinomas was three. Sixty-two
percent of neoplasms had two to four foci of com-
plete capsular penetration, and 60% had two to four
foci of vascular invasion. Almost all of the meta-
static FCs and HCs had at least one vascular inva-
sion and complete capsular penetration focus,
three had one feature, and none had incomplete
capsular penetration only. These values are identi-
cal to the mean number of vascular invasion foci of
36 encapsulated FCs reported by Lang et al. (21, 26),
of which only 2 produced metastases. In one of
their studies, 25% of encapsulated FCs had one
vascular invasion focus in 10 tissue blocks, 47% had
two to four vascular invasion foci, and the remain-
ing 39% had five or more foci (26). Thirty-nine
percent of cases had no complete capsular pene-
tration foci, 6% had one complete capsular pene-
tration focus, 22% had two to four foci, and 33%
had five or more foci (26). In another study by the
TABLE 3. Distribution of Capsular Penetration and Vascular Invasion Foci in Nonmetastatic and Metastatic
Complete Capsular Penetration FociVascular Invasion Foci
TABLE 4. Metastatic Follicular versus Hurthle Cell Carcinomas
Number of patients
Complete capsular penetration foci mean/median
Vascular invasion foci mean/median
Incomplete capsular penetration foci mean/median
Neck lymph node metastases
Patient age mean/median
Follicular and Hurthle Cell Thyroid Carcinoma (N.S. Goldstein et al.) 127
same group of authors, 53 of 106 (50%) encapsu-
lated FCs had invaded one to three small blood
vessels, and the other 53 (50%) had invaded a few
thick-walled vessels. Complete capsular penetra-
tion was rare (21). Another group of authors re-
ported that two minimally invasive FCs had two
and seven foci of complete capsular penetration
and many sites of vascular invasion, respectively,
and in another seven FCs that had no complete
capsular penetration, there were at least seven foci
of vascular invasion identified in each case (30).
Hazard and Kenyon (33) identified vascular space
invasion in 2 to 100% of the countable vessels in 32
encapsulated angioinvasive neoplasms.
There is debate in the literature regarding the
prognostic significance of complete capsular pene-
tration versus vascular invasion. Our study suggests
that there is no difference in their predictive ability;
most metastatic neoplasms had both histologic fea-
tures, two had vascular space invasion only, and
one had complete capsular penetration only. Some
authors found that vascular space invasion has
stronger association with metastases than capsular
invasion (2, 5, 21, 26, 33, 37, 39, 65). Other authors
have found a compounding effect for the associa-
tion of these features with metastases (27, 63).
Pathologists should be aware that metastases can
develop in FCs and HCs that have only a few foci of
complete capsular penetration or vascular invasion.
A careful search, with the numerous blocks, of all
encapsulated follicular or Hurthle cell neoplasms
for these histologic features is mandatory.
The median and mean interval between thyroid
surgery and when the initial metastasis developed
was 1.6 and 3.2 years, respectively. These results
confirm the results of other authors that recur-
rences and metastases by FC and HC are usually
within the first 5 years after surgery, although oc-
casionally they may develop many years after the
initial thyroid surgery (10, 11, 21, 26, 27, 33, 59,
63–65, 74, 79, 80).
We found no difference in the median number of
complete capsular penetration or vascular invasion
foci between FC and HC. These results differ from
the recent study by Evans et al. (43), who found vein
invasion to be significantly more common in FC
than in HC. Despite this difference, they were not
able to demonstrate a significantly different clinical
course in noninvasive FC and HC neoplasms.
We also found that the number of complete cap-
sular penetration and vascular invasion foci were
similar among the patients who initially developed
local recurrence, neck lymph node, or distant me-
tastases. These results support previous findings
that one cannot predict the most likely site of me-
tastasis in a minimally invasive, encapsulated FC or
HC on the basis of the number of vascular space
invasion or complete capsular penetration foci (15).
The prognostic significance of a metastasis to
these sites may be different. We had insufficient
follow-up information to compare the patient’s
overall survival, initial metastasis location, and the
type of postmetastasis adjuvant therapy or addi-
tional surgery. Finally, because of the retrospective
nature of the study, we cannot be assured that there
was no capsular invasion in the nonsampled cap-
sular tissue in those cases with no vascular space
invasion and in which the entire capsule was not
sampled. The results of this study reflect relation-
ships based on routine sectioning of practice stan-
dards over time.
In summary, we found that all of the encapsu-
lated metastatic FCs and HCs had at least one focus
of vascular invasion or complete capsular penetra-
tion, most had both, and none had capsular inva-
sion only. There was no difference in the number of
complete capsular penetration or vascular invasion
foci between metastatic and nonmetastatic carci-
nomas or between metastatic FCs and HCs.
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