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CANCER
196
CYTOPATHOLOGY
Cytopathology of Insular Carcinoma of the Thyroid
Gerardo E. Guiter, M.D.1
Manon Auger, M.D.2
Syed Z. Ali, M.D.3
Elizabeth A. Allen, M.D.3
Maureen F. Zakowski, M.D.1
1
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
2
Department of Pathology, McGill University, Montreal, Province of Quebec, Canada.
3
Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland.
BACKGROUND. Insular carcinoma of the thyroid (ICT) first was reported in 1984. To
the authors’ knowledge, few cytology reports have been published since that time.
The authors describe the cytologic features of six tissue-proven ICTs and propose
criteria that suggest its diagnosis.
METHODS. Four cases were thyroid fine-needle aspiration (FNA) samples. Two
cases were FNAs of metastases. All cases were found to be classic ICT on examination of primary or metastatic surgical specimens.
RESULTS. Three cases originally were diagnosed as carcinoma, including two FNAs
of metastatic sites and one thyroid FNA. Two additional thyroid FNAs were diagnosed as suspicious for malignancy, favor follicular neoplasm. One case was
termed a neoplasm, favor follicular type. Smears showed high cellularity and
scanty colloid. Three cases were found to contain some microfollicles. One case
showed a few papillae. Necrosis and mitosis were rare. Cells were round with pale,
poorly defined cytoplasm. Nuclei were round and monomorphic with finely granular chromatin, mild hyperchromasia, smooth nuclear membranes, and small
nucleoli. Nuclear grooves and inclusions were rare.
CONCLUSIONS. Three cases were diagnosed as suspicious for follicular neoplasm,
the main differential diagnosis of ICT. Both tumors exhibited high cellularity and
scanty colloid. However, ICT showed a predominance of single cells whereas
follicular neoplasms reveal microfollicles with more nuclear atypia. There is cytologic overlap between these two neoplasms. Papillary thyroid carcinoma should be
distinguished from ICT easily because the latter usually does not reveal the classic
cytologic features associated with the former. ICT should be considered in the
differential diagnosis of follicular neoplasms. Features favoring ICT are predominance of single cells, small loose nests of cells with few microfollicles, and little
nuclear atypia. Cancer (Cancer Cytopathol) 1999;87:196 –202.
© 1999 American Cancer Society.
KEYWORDS: cytology, fine-needle aspiration, insular carcinoma, thyroid.
P
Abstract presented at the United States and Canadian Academy of Pathology Annual Meeting, San
Francisco, California, March 21–26, 1999.
Address for reprints: Maureen F. Zakowski, M.D.,
Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York,
NY 10021.
Received September 4, 1998; revision received
January 11, 1999; accepted January 20, 1999.
© 1999 American Cancer Society
oorly differentiated “insular” carcinoma of the thyroid originally
was reported in 1984 by Carcangiu et al.,1 who defined its histopathologic diagnostic criteria. The tumor was so named because of
its growth pattern of solid clusters or nests of cells reminiscent of
what is observed in the majority of examples of carcinoid tumor,
occasionally referred to as insular.
Intermediate in aggressiveness between well differentiated (follicular and papillary) and anaplastic thyroid carcinomas, insular carcinoma of the thyroid (ICT) subsequently has been well documented
both as a discrete tumor entity and as a component of other, better
differentiated thyroid neoplasms.2– 4 To our knowledge, few cytology
reports have been published.2,5– 8 This neoplasm appears to be less
common in the Americas than in Europe.1 The ability to recognize
ICT in cytologic material may be important in devising an appropriate
therapy, which would be more aggressive than that for the more
Cytology of Insular Carcinoma of Thyroid/Guiter et al.
197
TABLE 1
Clinicopathologic Data
Patient
Age (yrs)
Gender
Clinical Hx
FNA site
Original cytologic diagnosis
1
60
F
Goiter 1 ICT
Liver
2
77
F
Goiter
Thyroid
3
18
M
Thyroid
4
37
F
Thyroid
Suspect follicular neoplasm
5
58
M
Mass on physical
examination
Hashimoto’s
thyroiditis 3 3 yrs
Thyroid tumor
Poorly differentiated
carcinoma c/w thyroid
origin
Poorly differentiated thyroid
carcinoma
Suspect follicular neoplasm
6
62
M
Goiter
Cervical lymph
nodes
Thyroid
Poorly differentiated
carcinoma
Suspect follicular neoplasm
Hx: history; FNA: fine-needle aspiration; F: female; ICT: insular carcinoma of the thyroid; c/w: consistent with; M: male.
TABLE 2
Cytopathologic Features of ICT
Background
Cell pattern
Cell shape
Nuclear features
Cytoplasm
Bloody but clean, no necrosis, no debris, no psammoma
bodies, scant colloid
Well formed nests, loose clusters, acinar structures,
many single cells
Mostly round to oval, pleomorphism, occasional
syncytial arrangements
High N:C, fine to coarse chromatin, hyperchromasia,
prominent overlapping, some nuclear grooves and
inclusions, rare mitosis, occasional atypia
Scant to moderate, usually eosinophilic on Pap stain,
occasional small vacuoles, no Hürthle change
ICT: insular carcinoma of the thyroid; N:C: nuclear-cytoplasmic ratio; Pap: Papanicolaou.
common well differentiated carcinomas and may include total thyroidectomy and radioiodine, external
beam radiotherapy, and chemotherapy.2,4
In the current study we describe the cytologic
features in fine-needle aspiration (FNA) material from
six cases of histologically proven ICT and expand the
cytologic criteria that may suggest a preoperative diagnosis of this unusual tumor type.
MATERIALS AND METHODS
Surgically resected cases of ICT in which there was a
previous or concomitant FNA were collected from several institutions. Six specimens from six patients were
identified and constituted the basis of our study. One
case previously was published as a case report.7 The
patient profiles, along with the original cytologic diagnoses, are presented in Table 1. At least two patients
(Patients 2 and 3) were found to have lymph node
involvement at the time of initial surgery. In five cases,
alcohol-fixed, Papanicolaou-stained smears were
available for review. In one case air-dried Giemsa-
FIGURE 1. Cellular smear of insular carcinoma of the thyroid showing cells
with round, regular nuclei with marked overlap.
stained smears were available for review. All cases
were determined to be classic examples of ICT on
examination of the primary thyroid surgical pathology
198
CANCER (CANCER CYTOPATHOLOGY) August 25, 1999 / Volume 87 / Number 4
FIGURE 2. Low power magnification of cellular aspirate demonstrating large
clusters and single cells. Insert: finely vacuolated cytoplasm stained with
DiffQuik (Scientific Products, McGaw Park, IL).
specimen. All cases were reviewed by at least two of
the authors.
RESULTS
All cases originally were diagnosed on cytologic material as favoring a neoplasm or suspicious or positive
for malignancy. There were no false-negative or falsepositive results. In only one case (Patient 2) was the
diagnosis of poorly differentiated ICT considered
based on review of the cytologic material alone. In the
remaining three cases of primary thyroid masses, follicular neoplasm was suspected and surgery recommended. FNA confirmed the suspected thyroid metastases to the cervical lymph nodes and liver in the
remaining two patients (Patients 1 and 5).
Examination of the smears revealed high cellularity in all six cases with very scanty colloid. Cells were
arranged in well formed nests and single cells. The
FIGURE 3. Papanicolaou staining demonstrating cellular nest of loosely
cohesive tumor cells.
single cell pattern predominated. In three cases a focally well developed microfollicular pattern was evident. In one case papillary structures were identified
as a minor component. Blood was present significantly in the background of all cases. Necrosis was
minimal. Mitoses were present in low numbers. No
psammoma bodies were observed in any of the cases.
The cells were round with scant to moderate
amounts of pale cytoplasm that was eosinophilic on
Papanicolaou stain and poorly defined. Slight vacuolization could be observed. Overlapping of the cells
was a common feature. Nuclei were round and monomorphic with finely granular chromatin, mild to moderate hyperchromasia, and smooth nuclear membranes. Nucleoli were small. In two cases (Patients 2
and 3) focal nuclear atypia, both mild and extreme
(represented by enlarged pleomorphic hyperchromatic nuclei), was evident.
Nuclear grooves and intranuclear inclusions, features usually associated with papillary thyroid carci-
Cytology of Insular Carcinoma of Thyroid/Guiter et al.
FIGURE 4. Small microfollicle-like cluster of cells in insular carcinoma of the
199
FIGURE 5. Larger cluster of insular carcinoma of the thyroid showing that the
nesting of the insular pattern is easily observed in the cell block.
thyroid.
noma, were observed focally in two cases. Cell blocks
were prepared in one case and revealed classic features of insular carcinoma with a very well formed
nesting pattern.
In the two cases in which lymph node involvement by ICT was found at the time of surgery, the
tumors demonstrated ICT identical to that in the primary tumor in one case and only papillary carcinoma
without an insular component in the other case. The
cytopathologic features of ICT are presented in Table
2. The morphologic features are presented in Figures
1–7.
DISCUSSION
ICT is an unusual primary thyroid neoplasm that to
our knowledge only was described in the modern pathology literature in 1984.1 Since that time there have
been various studies confirming the initial findings
and expanding the description and experience with
this tumor, with the majority of the reported work
performed on resected surgical material.3,4 Histologically, these tumors have a characteristic pattern with
small malignant cells, some in microfollicles, arranged
in nests surrounded by stroma.9 Patients with this
“poorly differentiated” malignancy usually are older10
and do clinically worse than their counterparts with
papillary and follicular carcinomas but better than
those with anaplastic carcinoma.9 The follicular cell of
origin in ICT is supported by immunohistochemical
staining for thyroglobulin8 and its association with
goiter.1,4,5,8 Because this tumor represents only approximately 4 –7%9 of all primary thyroid neoplasms
and appears to be more common in some parts of
Europe and South America than in the U.S.,10 to our
knowledge the total number of cases described remains few. Fewer still are the reports in the cytology
literature.2,4,5,6 – 8 Generally, the cytologic findings
200
CANCER (CANCER CYTOPATHOLOGY) August 25, 1999 / Volume 87 / Number 4
FIGURE 6.
High power Papanicolaou stain of mostly regular-shaped cells
with finely vacuolated cytoplasm and round to oval, regular nuclear contours.
have been similar, including cellular smears, single
cells, and a common overlapping cell pattern,5 although the cytologic features are not uniform.11
The specimens in the current series were characterized by similar high cellularity with scanty colloid
present. Overall, our cytologic findings correlated well
with those described in the literature.5– 8 Three of our
six patients had histories of goiter, for which an association with ICT already has been noted. Although
nuclear atypia was not striking, it was observed in two
of the cases, similar to a reported case12 in which
considerable pleomorphism was found in the cytology
smear. Although the presence of necrosis is believed
to be useful in making the diagnosis of ICT11 because
it is not often absent in other, better differentiated
neoplasms, it is interesting to note that it was nearly
completely absent in our series.
Three of our cases were diagnosed as suspicious
for follicular neoplasm, which is the main cytologic
FIGURE 7. Cellular smear showing overlapping, scant cytoplasm, and, in this
case, slight nuclear atypia.
differential consideration of ICT. Both neoplasms are
characterized in general by high cellularity and scanty
colloid. However, ICT shows a predominance of single
cells whereas follicular neoplasms reveal a predominance of syncytial-type tissue fragments as well as
microfollicles that may be bland or can show nuclear
atypia.13 Nevertheless, there is a considerable cytologic overlap between these two tumors and making a
distinction based on cytologic material may be difficult. The arrangement of small cells in nests with
cellular overlap of ICT and not the predominately
microfollicular pattern of follicular carcinoma was a
helpful feature in our series.
The differential diagnosis of ICT also includes
papillary carcinoma. Nuclear grooves and intranuclear inclusions as well as papillary formations in ICT
have been described,7,8 although in only a minority of
the cases reported. Nuclear pleomorphism and
multinucleation also are unusual in this tumor.1,12 ICT
also lacks the characteristic fine powdery nuclear
Cytology of Insular Carcinoma of Thyroid/Guiter et al.
201
TABLE 3
Comparative Cytologic Features of Thyroid Tumors
Insular
carcinoma
Follicular
neoplasm
Papillary carcinoma
Medullary carcinoma
Cellularity
Single cells
High
Many
Moderate to high
Few
Moderate to high
Few
Microfollicles
Papillae
Cytoplasm
Many
None
Scant to moderate
and poorly
defined
Mild to moderate
Few to many
Present
Moderate and poorly
or well defined
Nuclear atypia
Few
Rare
Moderate and
poorly
defined
Mild
High
Many with small clusters
and variable shape
None
None
Variable
Chromatin
Finely granular
Coarsely granular
Nucleoli
Grooves and inclusions
Necrosis
Small
Few
Reported5,11
Small to medium
Very rare
Rare
chromatin of papillary carcinoma. However, papillary
carcinoma may coexist with insular carcinoma.1 In
those cases, FNA smears may reveal features of papillary carcinoma, at least focally. We have not examined cases in which ICT formed a minor component of
an otherwise better differentiated tumor. However, because these cases have been described histologically,3 it may be interesting to study their cytologic
features. Cellular thyroid aspirates with scanty colloid,
predominance of single cells, and little nuclear atypia
but without the classic features of papillary carcinoma
should raise the possibility of a diagnosis of ICT. Medullary carcinoma of the thyroid may be included in the
differential diagnosis of ICT. It can have a prominent
single cell pattern with high cellularity. The background usually is clean without necrosis but amyloid
deposition may be observed. Binucleation and
multinucleation and spindled cells can be present.
Although ICT generally lacks the multinucleation that
can be present in medullary carcinoma, the single
small cell pattern could be misleading. The presence
of cytoplasmic granules and calcitonin positivity help
to distinguish it from ICT.14
Anaplastic carcinoma can be distinguished from
ICT based on the presence of a necrotic background
and widespread marked nuclear atypia, including
spindle and giant cells. The specific features of ICT
compared with papillary and follicular carcinoma are
presented in Table 3.
Fine powdery
chromatin
Small
Common
Rare
Small round to
binucleate
Coarsely granular
Prominent
Present
Rare
ever, a definitive FNA diagnosis of ICT may be difficult
due to overlapping of cytologic features with follicular
neoplasms. Careful attention to the cytologic criteria
should allow for better categorization. Features that
favor ICT are many single cells and nests with little
nuclear atypia and finely granular nuclear chromatin.
Cell blocks may be helpful in establishing specific
preoperative diagnosis. Further studies need to be
performed to assess accuracy in applying the proposed cytologic criteria for ICT in a prospective fashion.
REFERENCES
1.
2.
3.
4.
5.
6.
CONCLUSIONS
ICT should be considered in the differential diagnosis
of thyroid lesions sampled by FNA when a small cell
pattern without pleomorphism predominates. How-
Moderate
7.
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Pereira EM, Maeda SA, Alves F, Schmitt FC. Poorly differentiated carcinoma (insular carcinoma) of the thyroid diagnosed
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