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Fine Needle Aspiration Cytology of Selected Thyroid lesions With Discussion of Participant performance in The Interlaboratory Comparison Program in Non Gynecologic Cytopathology Of The College of American Pathologists Theodore R. Miller, MD Director of Cytology University of California at San Francisco

Fine Needle Aspiration Cytology of Selected Thyroid Lesions · Diffuse, Multinodular, and Uninodular Goiter (FIG. 1) Diffuse and nodular goiters have similar cytologic pictures. In

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Page 1: Fine Needle Aspiration Cytology of Selected Thyroid Lesions · Diffuse, Multinodular, and Uninodular Goiter (FIG. 1) Diffuse and nodular goiters have similar cytologic pictures. In

Fine Needle Aspiration Cytology of Selected Thyroid lesions

With Discussion of Participant performance in

The Interlaboratory Comparison Program in Non Gynecologic Cytopathology

Of

The College of American Pathologists

Theodore R. Miller, MD Director of Cytology

University of California at San Francisco

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Introduction

The Interlaboratory Comparison Program in Non-Gynecologic Cytology (ICP in N-G) for

thyroid FNA material confirms the excellent triage nature of this procedure. For benign conditions,

non-neoplastic goiter and Hashimoto’s, the lab response was negative in 80% and 84% of the

challenges respectively. The lab response rate for nodular goiter and Hashimoto’s has remained

stable for the past several years. Papillary carcinoma cases performed well in the triage mode with

lab responses of positive for Papillary carcinoma 78%, positive for a neoplastic condition 84%, and

12% suspicious. The following material should be useful in arriving at a more specific diagnosis.

Fine needle aspiration biopsy (FNAB) has become an accepted tool in the initial evaluation

of palpable and nonpalpable thyroid masses. In the hands of experienced individuals, FNAB is

extremely sensitive and specific. It can be performed as an outpatient procedure and is minimally

discomforting to the patient both in terms of physical pain and in cost. For the clinician, the

procedure allows for rapid turnaround time from biopsy to diagnosis and features high positive and

negative predicative values. In the era of managed care, the low cost of fine needle aspiration will

likely drive up the demand for this technique and thus, pathologists will be asked to perform and

interpret more and more of them.

Optimal performance and interpretation of FNABs of the thyroid requires both good

technical and interpretive skills. The technical component of FNAB includes not only the

performance of the biopsy, but also the processing and staining of the slides; this aspect cannot be

overemphasized. If adequate material is not harvested from a lesion, or if the smears are technically

deficient, the ability to make an informative diagnosis is markedly diminished. Smears should be

prepared on clean, partially frosted slides and both air-dried and alcohol-fixed material should be

available for May-Grünwald-Giemsa and Papanicolaou stains, respectively. When FNAB of the

thyroid is carried out under optimal conditions, accuracy exceeds 95% and inadequacy rates are

usually less than 10% [2,9,14].

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Overview

Although fine needle aspiration is widely viewed as a screening tool for malignant neo-

plasms, it is important to bear in mind that the majority of lesions evaluated by this technique are

benign. It is equally important to remember that for most malignant cases, this is not merely a

screening test, but it can provide a definitive and accurate diagnosis. Although it is difficult to give

accurate numbers because of differences in both geography and medical practices, approximately 80

to 85% of all thyroid aspirates are for benign conditions [2,11,21], including, most frequently,

colloid and degenerative cysts, benign thyroid nodules (goitrous nodules), and chronic thyroiditis.

Follicular lesions, which comprise both follicular adenoma and well-differentiated follicular

carcinoma, represent approximately 5% of all thyroid aspirates. Papillary carcinoma, the most

frequently encountered malignancy, accounts for 2 to 3% of cases. Hürthle cell lesions make up

between 1 and 3% of cases. The "grey zone" or "suspicious for malignancy" category accounts for

approximately 1 to 10% of cases and nondiagnostic aspirates account for 2 to 21%. Less common

entities, such as lymphoma, medullary carcinoma, anaplastic carcinoma, and metastatic

malignancies, account for less than 1% of all thyroid aspirates [9].

Diffuse, Multinodular, and Uninodular Goiter (FIG. 1)

Diffuse and nodular goiters have similar cytologic pictures. In most cases, aspirates of these

lesions contain abundant colloid and benign thyroid epithelium. Grossly, colloid is typically shinny

and may be light tan to dark brown. Microscopically, it is watery blue with MGG and blue-green to

eosinophilic with the Papanicolaou stain. When aspirates are overly bloody, serum may be mistaken

for colloid, especially on Pap stains. Features that can help to identify the colloid component include

the presence of cracking artifact, rouleaux formation, and "colloid tide" at the edge of the smear.

"Colloid tide" refers to the sharp, irregular border of colloid at the edge of the slide. Serum, in

contrast, blends imperceptibly with the edge of the smear. The thyroid epithelium has uniform round

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nuclei that are approximately the size of a red blood cell with scanty delicate cytoplasm. The

epithelial cells are arranged in small groups or flat sheets with evenly spaced nuclei, which impart a

honeycomb appearance. Hürthle cell change may also be present; however, in contrast to Hürthle

cell neoplasms, aspirates of these lesions lack cellular homogeneity and demonstrate groups of

Hürthle cells admixed with otherwise typical thyroid epithelium. Involutional changes are common

and may include old blood, foamy macrophages, and iron-laden macrophages.

Goitrous thyroids may occasionally contain nodules that demonstrate a predominantly

microfollicular structure. Aspirates of these cellular nodules may be very difficult to differentiate

from follicular neoplasms. In many cases, groups or sheets of normal thyroid epithelium with

uniform cellular polarity and a honeycomb pattern may be identified, which helps identify the lesion

as benign. However, 10-15% of aspirates from goitrous thyroids may demonstrate a microfollicular

pattern similar to that seen in both follicular adenoma and follicular carcinoma [3,14].

Table I 2003 Interlaboratory Comparison Program in Non-Gynecologic Cytopathology

Site, General and Reference Diagnosis Specific Evaluation of Participant Responses Dx Groups w/>100 lab responses only

Table I FNA Thyroid/Parathyroid General Diagnosis: Negative Reference Diagnosis: Nodular/non-neoplastic goiter (adenomatous nodule)

Pathologist Cytotech-nologist

Laboratory

Participant responses N % N % N % General Diagnosis Negative 933 80.9% 657 78.2% 460 80.3% Uspicious 119 10.3% 115 13.7% 61 10.7%Positive 50 4.3% 32 3.8% 23 4%Unsatisfactory 51 4.4% 36 4.3% 29 5.1%Specific Diagnosis Nodular/non-neoplastic goiter (adenomatous nodule)

734 63.7% 475 56.6% 351 61.3%

Follicular neoplasm 93 8.1% 94 11.2% 48 8.4%Correct general and specific diagnosis are highlighted Only most frequent specific diagnosis are included in table

FIG. I: MNG with large follicular structures and watery colloid.

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Chronic Thyroiditis (Fig. 2)

Chronic thyroiditis or Hashimoto's thyroiditis is usually a disease of middle aged women

who present with a history of hypothyroidism. The thyroid in these patients is diffusely enlarged in

most cases but may present as a uninodular goiter. Aspiration of these thyroids demonstrates a het-

erogeneous population of lymphocytes and Hurthle cells. The lymphoid component is composed

predominantly of small round lymphocytes but may also include plasma cells, immunoblasts, large

lymphocytes, and macrophages. Often these are seen as "lymphoid tangles", an amorphous stretched

out conglomerated of fragile lymphocytes. In some cases the lymphoid component is scant or mixed

with peripheral blood. Finding lymphoid tangles, macrophages, or plasma cells may help identify the

inflammatory nature of this lesion. In other cases, the lymphoid component may predominate

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prompting the differential of lymphoma or lymph node. The Hurthle cell change may be a minor

component admixed with unremarkable thyroid epithelium or may be the predominant component.

In the latter case, the differential includes a Hurthle cell neoplasm [12,14].

TABLE II 2003 Interlaboratory Comparison Program in Non-Gynecologic Cytopathology

Site, General and Reference Diagnosis Specific Evaluation of Participant Responses Dx Groups w/>100 lab responses only

Table II FNA Thyroid/Parathyroid General Diagnosis: Negative Reference Diagnosis: Lymphocytic thyroiditis (Hashimoto's)

Pathologist Cytotech-nologist

Laboratory

Participant Responses N % N % N % General Diagnosis Negative 536 82.7% 317 73.6% 275 84.1%Suspicious 59 9.1% 50 11.6% 26 8.0%Positive 48 7.4% 63 14.6% 24 7.3%Unsatisfactory 5 0.8% 1 0.2% 2 0.6%Specific Diagnosis Lymphocytic thyroiditis (Hashimoto's) 484 74.7% 267 62.0% 239 73.1%Hurthle cell neoplasm 18 2.8% 20 4.6% 7 2.1%Follicular neoplasm, suspicious for malignancy 30 4.6% 32 7.4% 17 5.2%Lymphoma 21 3.2% 13 3.0% 7 2.1%

Correct general and specific diagnosis are highlighted Only most frequent specific diagnosis are included in table

Fig. 2: Chronic thyroiditis with Hurthle cells and lymphocytes

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Follicular Neoplasms (fig. 3)

The spectrum of follicular lesions consists of cellular adenomatoid nodules, follicular

adenomas, follicular carcinoma, and the follicular variant of papillary carcinoma. The classification

of follicular adenomas includes the trabecular (embryonal), microfollicular, normofollicular

(simple), and macrofollicular subtypes. In general terms, the cytologic pattern of cellular

adenomatoid nodules, trabecular adenomas, microfollicular adenomas, parathyroid adenomas, and

well-differentiated follicular carcinoma is very similar. Given that the diagnosis of follicular

carcinoma depends largely on the presence of vascular or capsular invasion, it is generally not

possible to discriminate between follicular adenoma and well-differentiated follicular carcinoma

[3,17]. At the other end of the spectrum, cellular adenomatoid nodules are often indistinguishable

from follicular neoplasms. Thus, all follicular lesions are lumped into one diagnostic and surgical

management group. Normofollicular and macrofollicular adenomas are cytologically

indistinguishable from goitrous nodules.

Follicular lesions are cellular and contain groups of thyroid epithelial cells arranged in small

microfollicles, which have a uniform appearance throughout the smear. These microfollicles may be

monolayered and have a central lumen or they may be three-dimensional. Inspissated, thick colloid,

which stains dark green or red with the Pap stain and dark blue with MGG, may sometimes be seen

within the microfollicles. However, the abundant watery colloid seen in colloid and goitrous nodules

is not present. In lesions containing trabecular and/or microfollicular components, serpiginous

tissue fragments composed of thyroid epithelial cells are also seen [19]. In contrast to the

monolayered pattern of goitrous nodules, these tissue fragments demonstrate crowded and

overlapping cells (i.e., a "syncytia" of cells). Within this syncytia of cells occasional microfollicles

can sometimes be identified. As a rule it is not possible to distinguish benign from malignant

follicular tumors; however, carcinoma should be suspected in cases that demonstrate marked nuclear

enlargement, pleomorphism, and necrosis. The relationship of neoplasia with the amount of

microfollicular or solid growth has been described [3,15,18].

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TABLE III

1999,2000, & 2001 Interlaboratory Comparison Program in Non-Gynecologic Cytopathology Site, General and Reference Diagnosis Specific Evaluation of Participant Responses

Total lab responses >100

Table III - FNA Thyroid/Parathyroid General Diagnosis: Suspicious Reference Diagnosis: Follicular neoplasm

Pathologist Cytotech-nologist

Laboratory

Participant Responses N % N % N % General Diagnosis Negative 35 11 48 23 16 9Suspicious 185 59 100 48 111 64Positive 94 30 62 29 46 27Specific Diagnosis Follicular neoplasm 171 55 88 43 105 63Papillary carcinoma 67 21 35 17 40 23

Correct general and specific diagnosis are highlighted Only most frequent specific diagnosis is included in table

Fig. 3: Follicular neoplasm with microfollicular pattern.

Papillary Carcinoma (Figs. 4&5)

Papillary carcinoma is the most common malignant thyroid tumor. Of the many well-

described cytologic features of papillary carcinoma, the three most important for making the

diagnosis are intranuclear inclusions, metaplastic cytoplasm, and avascular papillary structures [16].

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Intranuclear inclusions are evident, as a protrusion of the cytoplasmic contents into, but not

through, the cytoplasmic membrane. These protrusions deform the nuclear membrane in such a way

that they appear to enter the nucleus; thus, they are actually pseudoinclusions. The inclusions have a

sharp, well-circumscribed border whose edge is darker than the surrounding chromatin. The contents

of the inclusions are the same as in the cell's cytoplasm. Occasionally, cytoplasmic vacuoles may

overlay the nucleus and give the appearance of an inclusion. These vacuoles are usually clear and

irregular, lacking both the sharp circumscription and dense border of an inclusion.

Metaplastic cytoplasm is dense and "waxy" and is a near facsimile of the metaplastic cells of

the endocervix. This is in contrast to the well-defined cytoplasm that can be seen not only in

papillary carcinoma but in several other thyroid conditions as well. Well-defined cytoplasm is more

dense than normal thyroid epithelium but not as dense as metaplastic cytoplasm. It also has a

granular texture, which contrasts with the "waxy" cytoplasm of metaplastic cells. Well-defined

cytoplasm is found in Hürthle cell lesions, chronic thyroiditis, follicular lesions, medullary

carcinoma, and goitrous nodules. It can be misinterpreted as metaplastic cytoplasm, especially if

slides are overstained.

The avascular papillae in papillary carcinoma consist of bluntly rounded fragments of tissue.

Occasionally, these fragments have a filiform configuration with multiple papillae. In other cases,

the papillae are small and singular. These fragments are multilayered and overall, the cells are

arranged in a disorderly fashion; however, they often demonstrate polarity towards the edge of the

papilla. Focusing in and out of multiple planes will demonstrate the multilayered avascular nature of

the papilla. In contrast, fragments of tissue from a goitrous nodule demonstrate flat sheets of cells,

many of which have a follicular configuration.

The finding of any two of these three features is highly suggestive of papillary carcinoma.

However, intranuclear inclusions, although a sensitive indicator of papillary carcinoma and present

in approximately 90% of cases, are not specific for papillary carcinoma since they can also be seen

in follicular lesions, medullary carcinoma, parathyroid adenomas, Hürthle cell tumors, and chronic

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thyroiditis. The inspissated thick colloid commonly seen in papillary carcinoma (“sticky colloid”),

while a specific cytologic feature, is usually only found in less than 20% of cases. Other features that

may be seen in papillary carcinoma include psammoma bodies, vascular papillae, septate vacuoles,

and epithelial giant cells. These minor features may be seen in up to 60% of papillary carcinomas

but may also be identified in other thyroid lesions, including multinodular goiter, follicular adenoma,

chronic thyroiditis, and follicular carcinoma. Nuclear grooves, a common histological feature of

papillary carcinoma, can also be found in up to 100% of papillary carcinoma FNABs [1,7].

Unfortunately, nuclear grooves are not a specific finding as they are also seen in a number of thyroid

conditions, including follicular neoplasms, Hürthle cell tumors, medullary carcinoma, Hashimoto's

thyroiditis, subacute thyroiditis, and multinodular goiters. Some investigators have claimed that

nuclear grooves are present in greater numbers in papillary carcinoma and that a nuclear groove

index of >20% can reliably distinguish papillary carcinoma from other thyroid lesions [7]. However,

nuclear grooves can be subtle and their identification depends greatly on staining types and methods.

Thus, while nuclear grooves may help raise the suspicion of papillary carcinoma, the diagnosis

should rest on the finding of at least two of the three major features: intranuclear inclusions,

metaplastic cytoplasm, and avascular papillae.

A stepwise logistic regression analysis of the three major cytologic features of papillary

carcinoma demonstrated that 87% of lesions have at least two of the three major cytologic features

and 53% of papillary carcinomas have all three [16]. Using these criteria, the sensitivity for

papillary carcinoma is 95% with a positive predictive value approaching 100%. An occasional

papillary carcinoma will be missed due to inadequate sampling or the presence of atypical features

(discussed below).

There are several atypical variants of papillary carcinoma that may be encountered in fine

needle aspiration material. These include the follicular, sclerosing [5], and tall cell variants [13].

These variants of papillary carcinoma usually demonstrate at least some of the typical cytological

features of papillary carcinoma. In the case of follicular papillary carcinoma, lesions lack the

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avascular papillae but they may have intranuclear inclusions and metaplastic cytoplasm. In tall cell

papillary carcinomas, intranuclear inclusions, metaplastic cytoplasm, and avascular papillae can all

be identified. In most instances, these unusual variants of papillary carcinoma are recognizable

cytologically because they retain the typical features of papillary carcinoma, but their "variant"

nature is not often detected on the cytologic material.

Given the cytologic criteria for papillary carcinoma, the diagnosis is often apparent with ade-

quate sampling. However, several diagnostic pitfalls may be encountered by both inexperienced and

experienced cytologists [4,12]. These pitfalls include interpretive and diagnostic errors. The former

category includes such errors as the misinterpretation of various cytologic changes as nuclear inclu-

sions, metaplastic cytoplasm, or avascular papillae. In the latter category are the rare and atypical

variants of thyroid neoplasia, which may be misinterpreted as papillary carcinoma.

Occasionally, thyroid cysts will possess an epithelial lining with metaplastic cytoplasm.

Aspiration of these cysts will yield small groups of cells with metaplastic-like cytoplasm and ovoid

nuclei. For the uninitiated, these cells may present a diagnostic dilemma. However, these cells are

few in number and the nuclei tend to be arranged in one direction in a "flowing" pattern similar to

that described for reparative changes in cervical smears. Moreover, the cytoplasm of these cells is

much less dense than that of a papillary carcinoma and other features of papillary carcinoma, such as

intranuclear inclusions and avascular papillae, are absent.

False positive diagnoses of papillary carcinoma can occur in follicular adenomas, goitrous

nodules [6], and hyalinizing trabecular adenomas [18]. Misinterpretation of these lesions as papillary

carcinoma usually occurs because of an overreliance on one or two major, or multiple minor

cytologic features to establish a diagnosis of papillary carcinoma. Identifying all three major

cytologic features before calling a lesion papillary carcinoma will avoid overdiagnosis. Rare and

unusual thyroid neoplasms may also be a potential source of confusion because they are poorly

defined cytologically and yet may possess one or more cytologic features of papillary carcinoma.

Hyalinizing trabecular adenoma is a rare thyroid neoplasm, which, if encountered in fine needle

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aspirates, can be easily confused with papillary carcinoma. These lesions may demonstrate

intranuclear inclusions, metaplastic type cytoplasm, and psammoma bodies [20].

TABLE IV

2003 Interlaboratory Comparison Program in Non-Gynecologic Cytopathology Site, General and Reference Diagnosis Specific Evaluation of Participant Responses

Dx Groups w/>100 lab responses only Table IV - FNA Thyroid/Parathyroid

General Diagnosis: Positive Reference Diagnosis: Papillary carcinoma

Pathologist Cytotech-nologist

Laboratory

Participant responses N % N % N % General diagnosis Positive 644 80.7% 391 79.3% 340 83.7%Suspicious 98 12.3% 61 12.4% 47 11.6%Negative 54 6.8% 39 7.9% 19 4.7%Unsatisfactory 2 0.3% 2 0.4% 0 0.0%Specific Diagnosis Follicular Neoplasm 72 9.0% 51 10.3% 30 7.4%Papillary carcinoma 611 76.6% 358 72.6% 317 78.1%

Correct general and specific diagnosis are highlighted Only most frequent specific diagnosis is included in table

Fig. 4: Papillary structure without a visible vessel.

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Fig. 5: Papillary carcinoma showing metaplastic cells and a nuclear inclusion.

Hurthle cell tumors (Fig. 6)

Hurthle cell neoplasms include both benign Hurthle cell adenomas and Hurthle cell carcinomas.

Although Hurthle cell carcinomas may demonstrate significant nuclear pleomorphism, there are no

cytologic features, which reliably distinguish, benign from malignant tumors. Hurthle cell tumors

are therefore regarded as one surgical management group. Hurthle cell tumors are usually cellular

and composed of a monomorphic population of oval to polygonal shaped Hurthle cells. The Hurthle

cells characteristically have abundant granular cytoplasm which stains either cyanophilic or

eosinophilic on the pap stain and light to dark blue on the MGG stain. The nuclei tend to be round,

eccentrically placed and contain a large macronucleolus. Cells may be arranged in small clusters, but

have a tendency to be dispersed singly throughout the smear.

The differential diagnosis of Hurthle cell tumors includes chronic thyroiditis and Hurthle cell

metaplasia in goitrous nodules. It is important to distinguish both goitrous lesions and chronic thy-

roiditis from Hurthle cell tumors because the former group of lesions may be managed medically. In

contrast to Hurthle cell neoplasms, both chronic thyroiditis and goitrous nodules demonstrate a

heterogeneous population of cells and the Hurthle cells are almost always in cohesive groups.

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Moreover, the Hurthle cell change in chronic thyroiditis and goitrous nodules if often less well de-

veloped compared to Hurthle cell tumors. Chronic thyroiditis is characterized by the presence of

chronic inflammation and Hurthle cells. The inflammatory component may consist of lymphocytes

and/or plasma cells. Lymphocytes are often crushed in smear preparations and appear as "tangles" of

cells on the smear. The Hurthle cell component may consist of only a few groups of cells admixed

with otherwise benign appearing thyroid epithelium or may be quite cellular. Goitrous nodules may

also contain significant numbers of Hurthle cells, however these cells are cohesive and are usually

admixed with otherwise benign appearing thyroid epithelium [10].

Table V 1999 Interlaboratory Comparison Program in Non-Gynecologic Cytopathology

Site, General and Reference Diagnosis Specific Evaluation of Participant Responses Dx Groups w/>100 lab responses only

Table V - FNA Thyroid/Parathyroid General Diagnosis: Suspicious Reference Diagnosis: Hurthle cell neoplasm

Pathologist Cytotech-nologist

Laboratory

Participant Responses N % N % N % General diagnosis Negative 25 10.6 19 10.6 13 8.6Suspicious 158 67 68 38 96 63.6Positive 53 22.5 92 51.4 41 27.2Specific* Diagnosis Negative - Hurthle cell neoplasm 10 4.2 9 5.0 7 4.6Negative - Lymphocytic thyroiditis (Hashimoto's)

14 5.9 8 4.5 6 4.0

Suspicious - Follicular neoplasm 4 1.7 2 1.1 4 2.6Suspicious - Hurthle cell neoplasm 154 65.3 63 35.2% 90 59.6Positive - Hurthle cell neoplasm 14 5. 46 25.7 16 10.6

*Includes combination of general and reference diagnosis Correct general and specific diagnosis are highlighted Only most frequent specific diagnosis is included in table

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.

Fig. 6: Hurthle cell tumor with numerous single oncocytic cells.

Medullary Carcinoma (Fig. 7)

Medullary carcinoma is among the rarer lesions encountered in both surgical and cytology

specimens representing approximately 5% of all thyroid carcinomas and comprising no more than

.2% to .4% of all thyroid aspirates [14,22]. In other words, medullary carcinoma is diagnosed on

average in one out of every 250 fine needle biopsies of the thyroid. Despite these reassuring

numbers, medullary carcinoma is frequently considered in thyroid fine needle biopsies and may be

over diagnosed.

The most characteristic feature of medullary carcinoma is a variable cytologic pattern. The

aspirates are often cellular and composed of spindle cells and polygonal cells, which are usually

dispersed singly throughout the smear, but also may appear in irregular disorganized groups.

Frequently the polygonal cells are multinucleated with eccentrically placed nuclei. Amyloid may be

observed in approximately 50%-60% of cases and appears as faint eosinophilic hyaline material on

Papanicolaou stain and light blue hyaline material on May-Grunwald Giemsa stain [8,22]. Amyloid

may be readily mistaken for inspissated colloid, however it characteristically occurs as irregular

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amorphous material in the background of the slide and may be identified definitively with Congo red

stains. Cytoplasmic granules which characteristically stain red with the MGG stain and blue with the

Papanicolaou stain are another feature which may be seen in up to 30% of cases.

The differential diagnosis includes papillary carcinoma, Hurthle cell tumors, and anaplastic

carcinoma. Papillary carcinoma is occasionally a consideration when intranuclear inclusions are

identified in addition to the other features listed above. However, papillary fragments and meta-

plastic type cytoplasm are not characteristic features of medullary carcinoma. Moreover, a variable

cell pattern with both spindle and polygonal cells, which are predominantly dispersed singly

throughout and aspirate, are uncommon features in a papillary carcinoma. Hurthle cell tumors are a

primary consideration in lesions composed predominantly of polygonal cells, which are dispersed

singly throughout the smear. However, Hurthle cells typically have fine densely granular cytoplasm

with uniform nuclei and prominent round nucleoli. In contrast, medullary carcinoma cells usually

have very course, evenly distributed nuclear chromatin with or without nucleoli and variable

cytoplasmic granularity. Anaplastic carcinoma is a consideration in any lesion with large

pleomorphic multinucleated giant cells. However, anaplastic carcinomas demonstrate greater de-

grees of anaplasia that are more uniformly expressed in all the tumor cells. In difficult cases,

calcitonin immunoperoxidase stains may be invaluable. These may be performed on alcohol fixed

Papanicolaou stained slides or cellblocks.

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TABLE VI 2003 Interlaboratory Comparison Program in Non-Gynecologic Cytopathology

Site, General and Reference Diagnosis Specific Evaluation of Participant Responses Dx Groups w/>100 lab responses only

Table VI - FNA Thyroid General Diagnosis: Positive Reference Diagnosis: Medullary carcinoma

Pathologist Cytotech-nologist

Laboratory

Participant responses N % N % N % General diagnosis Positive 185 84.5% 139 80.4% 101 82.8%Suspicious 13 5.9% 17 9.8% 10 8.2%Negative 21 9.6% 17 9.8% 11 9.0%Unsatisfactory Specific Diagnosis Follicular neoplasm 11 5.0% 15 8.7% 6 4.9%Medullary carcinoma 157 71.7% 87 50.3% 79 64.8%Lymphoma 10 4.6% 12 6.9%

Correct general /specific diagnosis are highlighted, Only most frequent specific diagnosis is included in table

Fig. 7: Medullary carcinoma with spindle and epitheloid cells.

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© College of American Pathologists 2004. Materials are used with the permission of Theodore R. Miller, MD, FCAP.

References

1. Bhambani S, Kashyap V, Das DK: Nuclear grooves: Valuable diagnostic features in May-

Grünwald-Giemsa stained fine needle aspirates of papillary carcinoma of the thyroid. Acta

Cytol 34:809-812, 2990.

2. Bisi H, Asato de Camargo RY, Filho AL: Role of fine needle aspiration cytology in the

management of thyroid nodules: Review of experience with 1925 cases. Diagn Cytopathol

8:504-510, 1992.

3. Busseniers AE, Ortel YC: “Cellular adenomatoid nodules” of the thyroid: Review of 219 fine

needle aspirates. Diagn Cytopathol 9:581-589, 1993.

4. Caraway NP, Sneige N, Samaan NA: Diagnostic pitfalls in thyroid fine needle aspiration:,

Review of 394 cases. Diagn Cytopathol 9:345-350, 1993

5. Caruso G, Tabarri B, Lucchi I, Tison V: Fine needle aspiration cytology in a case of diffuse

sclerosing carcinoma of the thyroid. Acta Cytol 34:352-354, 1990.

6. Fiorella RM, Isley W, Miller LK, Kragel PJ: Multinodular goiter of the thyroid mimicking

malignancy: Diagnostic pitfalls in fine needle aspiration biopsy. Acta Cytol 9:351-357, 1963.

7. Francis IM, Das DK, Sheikh ZA, et al: Role of nuclear grooves in the diagnosis of papillary

thyroid carcinoma. Acta Cytol 39:409-415, 1995.

8. Geddie WR, Bedard YC, Strawbridge HT. Medullary carcinoma of the thyroid in fine needle

aspiration biopsies. Am J Clin Pathol 1984; 82: 552-558

9. Gharib H,Goellner JR: Fine-needle aspiration biopsy of the thyroid: An appraisal. Ann Int Med

118:282-289, 1993.

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cytomorphologic approach to diagnosis. Amer J Clin Pathol 1993; 100:231-5.

11. Hawkins F, Bellido D, Bernal C, et al: Fine needle aspiration biopsy in the diagnosis of thyroid

cancer and thyroid disease. Cancer 59:1206-1209, 1987.

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12. Jeffrey PB, Miller TR: Fine-needle aspiration cytology of the thyroid. In: Ljung BM (ed), Fine

Needle Aspiration Biopsy. Pathology: State of the Art Reviews Vol 4, Philadelphia, Hanley &

Belfus, Inc., 1996. pp 319-335.

13. Kaw YT: Fine needle aspiration cytology of the tall cell variant of papillary carcinoma of the

thyroid (letter). Acta Cytol 38:282-283, 1994.

14. Kini SR (ed): Guides to Clinical Aspiration Biopsy: Thyroid. New York: Igaku-Shoin, 1987.

15. Miller JM, Hamburger JI: The diagnosis of malignant follicular neoplasms of the thyroid by

needle biopsy. Cancer 55:2812-2817, 1985.

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intermediate smear. Acta Cytol 34:813-820, 1990.

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aspiration biopsy of the thyroid in an endemic area. Pathol Res Pract 181:308-310, 1986.

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Acta Cytol 36:435-439, 1992.

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A flow chart is provided to indicate helpful diagnostic points and considerations as well as areas of

overlap.

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DIAGNOSTIC FLOW CHARTFine Needle Aspiration of the Thyroid

Colloid (protein)

MacrophageDominance

Follicular Cells(few)

Follicular Cells(numerous)

Papillary Groups

IntranuclearInclusions (INC)

Calcified Bodies

Hurthle Cells(distinct cell borders,granular cytoplasm,prominent single nucleoli)

InflammatoryDominance

1. Abundant watery colloid + phagocytic cells , normal follicular cells in sheets or 3D spheres2. Inspissated colloid in small microfollicles3. Bubblegum colloid

1. BTN, involutional type, lesser degrees of cellular and colloid components can be seen2. Papillary carcinoma, involutional pattern3. Thyroglossal duct cyst (+ squamous or metaplastic cells & debris)

Lymphocyte-sized nuclei with scanty to absentcytoplasm. Small clusters may be seen

Nuclear enlargement & variable oxyphilic changeof cytoplasm

1. Hyperplastic papillations as in Graves ' disease, chronic thyroiditis , or MNT2. Papillary carcinoma

1. Papillary carcinoma2. Radiation to thyroid3. Neoplasm reported to have INC4. MNT (rare)

1. Calcium oxylate (geometric)2. Dystrophic calcifications (aggregates of micropheroids)3. Psammoma bodies (concentrically laminated)

1. Pure Hurthle cell tumor2. Hurthle cell change in

1. Lymphocytes2. Granulomatous

Benign Thyroid Nodule (BTN)

Follicular NeoplasmPapillary Carcinoma

Often seen in BTN or T4-treated patient

1. Trabecular or microfollicular pattern

2. Macrofollicles (BTN)3. Mixed follicular pattern (BTN)

a. Hurthle cell tumorb. Follicular adenomac. Medullary carcinomad. Parathyroid adenomae. Metastatic disease

a. Papillary carcinomab. Intrafollicular psammoma bodies as seen in toxic goiter

a. Papillary carcinomab. Chronic thyroiditisc. MNT

a. Chronic thyroiditisb. Lymph nodec. R/O lymphoma, subacute thyoiditis

a. Follicular adenomab. Follicular carcinomac. Follicular variant of papillary carcinomad. Chronic thyroiditise. Parathyroid adenoma

a. MNTb. Benign macro- follicular adenomaa. MNTb. Follicular adenoma

Cells with "Malignant" Nuclear Features, not just Variations in Size

1. Small cell anaplastic (R/O lymphoma)2. Large cell anaplastic carcinoma, often few cells per case with large amounts of necrosis and blood3. Less than well-differentiated thyroid carcinoma4. Metastatic carcinoma5. Medullary carcinoma (red granules in cytoplasm on Wright's stain)6. Ablative 131I or other radiotherapy