A 27 year-old woman presents with a palpable 3.0 cm mass in the
right thyroid gland that had been slowly enlarging over the past six months. An FNAB was performed.
Direct smears stained with Papanicolaou and Diff-Quik
stains were hypercellular and contained large, loosely cohesive clusters of crowded follicular cells in a
background of blood, scattered single follicular cells, and absent colloid. Some groups of follicular
cells were surrounded by bands of dense stroma and suggested a nested or insular architecture.
Individual follicular cells had scant cytoplasm and were uniform in size, but at higher magnification,
the round to oval nuclei were moderately pleomorphic, chromatin was slightly clumped, and occasional
mitotic figures were seen. Immunocytochemical stains performed on this specimen showed that the tumor
cells were strongly positive for thyroglobulin and negative for calcitonin, thus excluding medullary
carcinoma from the differential diagnosis. The FNA was diagnosed as "suspicious for a follicular
neoplasm, with features suggestive of insular carcinoma" and surgical excision was recommended.
Figure 2A - Hypercellular smears containing large loosely cohesive clusters of crowded follicular cells with a "nested" appearance. (Papanicolaou stain, low power)
Figure 2B - The individual follicular cells had scant cytoplasm and were uniform in size with round to oval nuclei. (Papanicolaou stain, medium power)
Figure 2C - At higher magnification the individual follicular cell nuclei were moderately pleomorphic with slightly clumped chromatin. (Papanicolaou stain, high power)
Histology and Clinical Follow-Up:
A total thyroidectomy was performed and
revealed a circumscribed, tan-white nodule measuring 3.0 cm within the right thyroid lobe. Histologic
examination showed an encapsulated microfollicular neoplasm that was partially replaced by discrete solid
clusters of crowded, small, hyperchromatic follicular cells in a nested or insular architectural
arrangement. Groups of follicular cells were surrounded by bands of sclerotic stroma; mitotic activity
was brisk and focal individual cell necrosis was present. A diagnosis of an encapsulated insular
carcinoma (poorly differentiated thyroid carcinoma) was made.
Clinical follow-up was uneventful until at
two years post-surgery, when a routine CT scan revealed the presence of multiple liver nodules. A liver
FNA performed under CT guidance demonstrated metastatic insular carcinoma.
Discussion: Insular carcinoma
raises two important issues in the evaluation of thyroid nodules by FNA: 1) The limits of FNA as a
screening test for follicular carcinoma, and 2) the clinicopathologic significance of insular carcinoma .
The extremely large number of benign thyroid lesions (up to 7% of the population have palpable thyroid
nodules) relative to the small number of admixed malignant ones creates a clinical dilemma - how to
manage patients with a detectable thyroid nodule that statistically is more likely to be benign. Over
the past two decades,FNA has become the single most important first step in the evaluation of a thyroid
nodule. Thyroid FNA is widely accepted as a highly cost-effective, safe, and accurate technique, and it
is also considered by many to be the most sensitive and most specific non-surgical thyroid cancer test
- Thyroid FNA is >95% accurate for satisfactory specimens
- Reduced the number of patients requiring thyroid surgery by approximately 50%
- Increased the yield of thyroid malignancy at thyroidectomy by 2-3x
- Decreased the cost of managing thyroid nodules by over 25%.
While the above facts about thyroid FNA sound very good, the truth is that thyroid
FNA has severe limitations when applied as a screening test for follicular carcinoma.
In general, thyroid lesions to be evaluated by FNA can be divided into two groups: 1) those lesions
for which FNA is primarily a screening procedure (follicular and oncocytic
neoplasms) and 2) those lesions for which FNA is a diagnostic test
(thyroiditis, papillary thyroid carcinoma, anaplastic carcinoma, medullary carcinoma, malignant
lymphoma, and metastatic disease). The first group, where FNA is a screening procedure, consists of
follicular and oncocytic lesions of the thyroid including multinodular goiter, follicular adenoma,
follicular carcinoma, and oncocytic (Hurthle cell) neoplasms. As a screening test, FNA is able to
identify a majority of thyroid nodules which can be diagnosed as "benign" and which in many instances can
be managed without direct surgical intervention. The remainder of the cases fall into a category of
follicular neoplasm where histologic evaluation is necessary to distinguish a benign follicular lesion
from a malignant one. These cases are diagnosed as "suspicious for a follicular neoplasm."
The cytologic criteria used to distinguish "benign" from "suspicious" thyroid lesions include the
follicular group architecture, smear cellularity, and amount of colloid; cytologic atypia is generally
not a useful feature. Among the most important of these criteria is follicular architecture,
specifically whether the lesion is composed predominantly of macrofollicles, or microfollicles,
trabeculae, and crowded groups. This approach works because follicular carcinomas are virtually never
composed of predominantly normal-sized or macrofollicles. In smears of thyroid aspirates, macrofollicles
are recognized as colloid-filled spheres usually with numerous follicular cells, or as flat sheets of
evenly spaced follicular cells. The flat sheets result from fragmentation of macrofollicles with
extrusion of colloid during the smear preparation. Smears with a predominance of macrofollicles and flat
orderly honyecomb sheets of follicular cells are diagnosed as "benign" thyroid
nodules by FNA. In contrast, thyroid aspirates composed of microfollicles (small follicular groups of
6-12 follicular cells in a ring with or without a small amount of central colloid) or crowded trabeculae
and groups of overlapping follicular cells are a feature of follicular carcinomas as well as some
follicular adenomas. These aspirates are diagnosed as "suspicious for a follicular
neoplasm," and it is this group of patients for whom surgical removal of the lesion is generally
FNA As A Screening Test For Follicular Carcinoma:
CYTOLOGIC FEATURE ||
FNA Diagnosis ||
HISTOLOGIC Diagnosis |
MULTINODULAR GOITER & SOME FOLLICULAR ADENOMAS |
SUSPICIOUS FOR A
FOLLICULAR NEOPLASM ||
FOLLICULAR CARCINOMAS & SOME FOLLICULAR ADENOMAS |
While thyroid FNA is associated with an overall very low false negative (approx. 0.7%) and false
positive rate (approx. <6%), the severe limitation of thyroid FNA as a screening test is in the fact
that 75-85% of thyroid aspirates diagnosed as "suspicious for a follicular neoplasm" are actually benign
nodules when surgically resected. Since cytologic features can only take us so far in the evaluation of
this group of thyroid FNAs, clearly what is needed is a biologic marker that could distinguish the many
resected follicular adenomas from the few follicular carcinomas. Unfortunately, no ancillary markers
(immunohistochemical or molecular) have been identified to date that can do this with high sensitivity
and specificity. Some candidate biologic markers being studied in both histologic and cytologic
specimens include: HBME-1, galectin-3, CD44v6, PPAR-gamma rearrangements, as well as various
proliferation markers (Ki-67, p27, topoII-alpha). Until a single marker or panel of markers is
demonstrated to be effective at differentiating follicular carcinomas from adenomas, FNA as a screening
test will continue to have severe limitations.
With regard to the specific diagnosis of insular carcinoma in this case,
insular carcinoma is considered the classic form of "poorly differentiated" thyroid carcinoma. It is a
rare neoplasm, representing approximately 4% of all thyroid cancers. Patients are typically older,
presenting at a mean age of 55 years. A majority of insular carcinomas exhibit a high stage at
presentation due to extrathyroidal extension or distant metastases, especially to lung and bone. The
long-term mortality for patients with insular carcinoma is thought to be as high as 50%, considerably
greater than for most well-differentiated papillary and follicular carcinomas. Importantly, the presence of an insular histologic pattern, even if only a small component
of an otherwise well-differentiated carcinoma, is considered a strong independent aggressive prognostic
As in the case presented here, FNA of insular carcinoma is characterized by cellular smears comprised
of monomorphic-appearing small follicular cells singly and in crowded clusters, as well as in intact
insulae. Nuclei are round and variably hyperchromatic with mild to moderate nuclear irregularities.
Mitotic activity and individual cell necrosis distinguish this neoplasm from most other microfollicular
and benign macrofollicular lesions but these two features may be sparse. In addition, colloid is
typically scant to absent. In most cases, an FNA diagnosis of "suspicious for a follicular neoplasm" is
appropriate since it may be cytologically difficult if not impossible to accurately distinguish insular
carcinoma from other benign follicular neoplasms. Again, no ancillary marker is available to help
The cytologic differential diagnosis of insular carcinoma includes medullary carcinoma, the solid
variant of papillary carcinoma, and anaplastic thyroid carcinoma. Insular carcinoma can be distinguished
from medullary carcinoma by the absence of stippled neuroendocrine-type chromatin as well as the lack of
immunohistochemical staining for calcitonin. Although occasional nuclear grooves or rare intranuclear
pseudoinclusions may be found, insular carcinoma lacks the classic nuclear features of papillary
carcinoma such pale chromatin, papillary architecture, and extensive nuclear grooving, and the nuclear
atypia of insular carcinoma is much less pronounced than is seen in anaplastic carcinomas.
Imunohistochemically, insular carcinomas are positive for keratin, thyroglobulin and TTF-1, and negative
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