An 86 year-old woman presents with an 8.0 cm right thyroid mass.
An FNAB was performed. (Images 6A-6C)
The smears, stained with rapid H&E and Papanicolaou
stains, are cellular and consist of a pure population of predominantly dispersed follicular cells with
oncocytic features (Hurthle cells). Individual cells have enlarged round nuclei, fine chromatin,
prominent nucleoli, and abundant finely granular eosinophilic cytoplasm. Nuclei are centrally to
eccentrically placed, and some cells are binucleated. Occasional scattered Hurthle cells have markedly
enlarged nuclei greater than twice the diameter of others. Some crowded clusters of Hurthle cells are
seen as well as focal groups with transgressing blood vessels. The background contains blood and scant
naked nuclei. Focally, a crowded group of hyperchromatic spindle cells is present.
Figure 6A - Aspirate smears were cellular and composed of a pure population of follicular cells with oncocytic features (Hurthle cells). Individual cells were large with enlarged, round nuclei, fine chromatin and prominent nucleoli. (H&E stain, high power)
Figure 6B - Occasional scattered Hurthle cells have markedly enlarged nuclei, greater than twice the diameter of others. (H&E stain, high power)
Figure 6C - Crowded clusters of Hurthle cells are seen as well as individual cells. Focally a crowded group of hyperchromatic spindle cells is present. (H&E, medium power)
Histology and Clinical Follow-Up:
The patient had a total
thyroidectomy which revealed a mass that completely replaced the right thyroid lobe with extension into
extrathyroidal soft tissues. Histologic examination revealed a widely invasive Hurthle cell carcinoma,
and focally (less than 5% of the tumor), a markedly atypical spindle cell component representing
anaplasic transformation was present. The patient died of local disease recurrence approximately 2
months after surgery.
Discussion: Hurthle cell carcinoma with focal anaplastic carcinoma
illustrates two important issues in thyroid aspiration cytology: 1) The limits of FNA as a screening
test for Hurthle cell carcinoma, and 2) the clinical importance of recognizing an anaplastic
Hurthle cell neoplasms are composed of follicular cells where over 75% have oncocytic or oxyphilic
features. These neoplasms comprise approximately 3% of all thyroid cancers and about 20% of all
follicular tumors. Based upon their clinical behavior and molecular marker studies, Hurthle cell
carcinomas may merit placement into a separate category of follicular neoplasms, although this is
controversial. Relative to non-Hurthle cell neoplasms, a greater percentage of Hurthle cell neoplasms
are malignant (10-32%). Also, Hurthle cell carcinomas relative to standard follicular carcinomas show a
higher tendency to metastasize to lymph nodes (21%), and in some studies appear to be more clinically
aggressive with a 5-year mortality rate as high as 50-60%.
As with non-oncocytic follicular neoplasms of the thyroid, Hurthle cell adenomas and Hurthle cell
carcinomas cannot be distinguished by FNA, since like other follicular lesions of the thyroid, the
histologic diagnosis depends upon recognizing the presence or absence of capsular and/or vascular
invasion. Therefore both of these neoplasms are diagnosed by FNA as "suspicious for
an oncocytic (Hurthle cell) neoplasm," and surgical excision is indicated. FNA correctly
identifies the vast majority of Hurthle cell neoplasms as neoplastic. In addition, FNA distinguishes
between true Hurthle cell neoplasms and other benign conditions with Hurthle cell changes such as
Hashimoto's thyroiditis or multinodular goiter which can be accurately diagnosed as "benign" and for
which surgical excision is not indicated. In general, cells from non-neoplastic Hurthle cell nodules
form orderly flat sheets, and they often lack extensive distinct nucleoli. The typical cytologic
features of true Hurthle cell neoplasms include a cellular smear with a uniform population of dyshesive
cells with abundant granular cytoplasm, distinct red nucleoli, and finely granular chromatin. Nuclei are
often eccentrically placed giving a plasmacytoid appearance, and binucleation is common. Colloid tends
to be scant, and chronic inflammation is absent or sparse. The cells can appear bland, and often form
crowded three-dimensional aggregates as well as occasional sheets with well-defined cell borders and
follicles; transgressing vessels may be present within groups of cells. Important entities to exclude
from the differential diagnosis of Hurthle cell neoplasms include: medullary carcinoma, oncocytic
variant of papillary carcinoma, metastatic renal cell carcinoma, and parathyroid adenoma.
Unfortunately, as with non-oncocytic follicular lesions, FNA as a screening test for Hurthle cell
carcinoma is markedly limited in its application by the fact that over 70-90% of lesions diagnosed as
"suspicious" are in fact benign when surgically resected - A sensitive and specific
ancillary marker for Hurthle cell carcinomas has yet to be identified. Recently, Dr. Renshaw
identified a "new and improved" set of cytologic criteria for diagnosing Hurthle cell neoplasms. He
suggests that by using a more specific set of 5 criteria, an improved specificity without loss of
sensitivity can be obtained in the cytologic diagnosis of Hurthle cell neoplasms. These 5 criteria
include: predominantly Hurthle cells and scant colloid, and at least one of either small cell dysplasia,
large cell dysplasia, crowding, and dyshesion.
With regard to the anaplastic component present in the current case, the cytologic
diagnosis of anaplastic carcinoma has extremely critical implications for the clinical management of a
thyroid nodule since it may dictate whether or not surgical intervention will be used. The rare
cases of anaplastic carcinoma associated with longer term survival (and where surgery may be considered
as a therapeutic option) are usually those where the anaplastic carcinoma is small or forms a minor
component of a well differentiated tumor.
Anaplastic carcinoma is among the most aggressive human malignancies with greater than 90% mortality
and a dismal median survival of approximately 4-7 months. This carcinoma can arise de novo but in up to
80% of cases is associated with dedifferentiation of a precursor thyroid lesion such as in this case
where it arose from de-differentiation of the Hurthle cell carcinoma. Anaplastic carcinoma represents
approximately 2-5% of all thyroid carcinomas, and typically occurs in older patients (mean age 66 years),
more commonly in women. At presentation, most tumors are large, and widely invasive with extension into
extrathyroidal soft tissue, tracheal involvement, regional spread to lymph nodes, and sometimes distant
metastasis. More than 50% of cases are inoperable at presentation.
Given adequate clinical and radiologic information, FNA of anaplastic carcinoma is highly accurate
owing to its obvious malignant cytologic features. The cytologic appearance includes a cellular smear
with malignant-appearing, sometimes bizarre, spindled and multinucleated tumor giant cells in groups and
as single cells in a background of tumor diathesis (blood, fibrin, acute inflammation, necrotic cells,
and debris). The nuclei of undifferentiated thyroid carcinoma are highly pleomorphic with dark,
irregular chromatin clumping, macronucleoli, and occasional intranuclear pseudoinclusions. Numerous
mitoses and abnormal mitotic figures may be seen.
At times the diagnosis of anaplastic carcinoma can be challenging since in some cases, only portions
of the aspirate will show the anaplastic cyto-phenotype, while other portions of the cytologic specimen
will consist of conventional well- or poorly differentiated carcinoma as in the case presented here.
Clearly, thorough sampling of clinically suspicious lesions is important to avoid missing an anaplastic
component. Fortunately, these are the rare cases where surgical intervention may be warranted to attempt
a cure. When focal, anaplastic carcinoma must be distinguished from other spindled and atypical cells
especially reactive elements. Immunocytochemical stains are helpful when adequate material is available
for study. Most cases will exhibit keratin positivity helping to exclude a reactive fibroblastic,
histiocytic, or vascular component of an otherwise well-differentiated thyroid neoplasm. In addition,
anaplastic carcinomas will usually lack thyroglobulin and TTF-1 immunoreactivity that are seen in an
adjacent well- or poorly-differentiated follicular carcinoma, and they will often exhibit overexpression
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