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nodule. The follicular adenomas are classically defined as

solitary encapsulated nodules arising in an otherwise normal

thyroid that lacks evidence of capsular or vascular invasion

(Fig.1). It is well understood that the concept of the normal

thyroid is withering in the current era of enhanced imaging

where thyroid nodules are detected in >60 % of the US

population. Thus, it is not uncommon to find nodules that

match all descriptors of an adenoma in a multinodular thyroidgland. They are characterized microscopically by encapsula-

tion, a homogenous internal pattern of growth, lack of or

minimal mitotic activity, and lack of necrosis and are

surrounded by normal-appearing thyroid. The patterns may

be macro- or microfollicular, trabecular, or mixed. Some

examples will show oncocytic cytology [4,8,9]. Pure papil-

lary growth pattern has been reported in follicular adenoma;

some authors have termed this as papillary adenoma.

However, usage of such terminology may be more confusing

to the clinicians as the term papillary can be mistaken for a

carcinoma. The presence of a capsule, no matter how thin, is

used by most pathologists as a necessary feature to consider anodule as an adenoma. Some prefer to diagnose those homo-

geneous lesions without a capsule as benign follicular

nodule.Most of these lesions have been shown to be clonal

proliferations [10].

The diagnosis of follicular adenoma may present difficul-

ties for the pathologist because of the changes that may occur

in those lesions which have undergone fine-needle aspiration

(FNA) preoperatively. These histologic alterations can range

from linear areas of granulation tissue to tracking of lesional

follicles into and through its capsule or even infarction of the

nodule [11]. Histological criteria useful for distinguishing

these changes from true invasion have been described and

published [11, 12]; however, pathologists who do not examine

large numbers of thyroid cases may still encounter difficulties

with these tumors.

Follicular carcinoma represents only about 5 % of thyroid

cancers in areas of the world in which adequate iodine is

present in the diet due to natural resources or due to fortifica-

tion [13,14]. It is unclear if the frequency of follicular carci-

noma in endemic goiter areas (iodine deficient diets) as re-

ported for decades is as high as cited (since the encapsulated

follicular variant of papillary carcinoma was not well recog-

nized in past decades).Clinically, follicular carcinoma presents as a solitary mass

and can resemble an adenoma grossly. FNA or even core

biopsy of such lesions is unable to distinguish the nature of

such nodule, i.e., whether it is benign or malignant [15]. The

determination of malignancy in this type of tumor rests on the

demonstration of invasion at the edges (capsule) of the nodule,

and since a biopsy samples the center, a definitive diagnosis

cannot be rendered [15,16].

The distinction between follicular adenoma and carcinoma

is solely based on demonstration of capsular and/or vascular

invasion. Therefore, one must histologically examine the tu-

mor and its capsule interface with the surrounding thyroidgland [4, 8, 13, 1620]. These lesions avoid lymphatics

hence, follicular thyroid carcinoma is unifocal in the gland,

and true embolic lymph node metastases are exceedingly rare.

Follicular carcinoma disseminates hematogenously and me-

tastasizes characteristically to the bone, lungs, brain, and liver

[4,8,17,19].

The treatment of follicular carcinoma remains controver-

sial; many surgeons consider total thyroidectomy as appropri-

ate therapy for encapsulated follicular cancers because radio-

active iodine therapy (to treat potential circulating tumor cells

or metastatic deposits) is only effective when all normal

thyroid tissue has been removed from the neck. Some experts

believe that since the diseasefree interval after lobectomy

and/or cure of these encapsulated lesions is excellent,

completion thyroidectomy may represent overtreatment

in a large percentage of these patients. Lymph node dissec-

tion is not warranted since these tumors do not spread to

nodes [21,22].

Traditionally, two main types of follicular carcinoma are

recognized: the so-called minimally invasive and widely in-

vasive. In contrast, others believe that there should be three

categories: widely invasive, grossly encapsulated minimally

invasive, and grossly encapsulated angioinvasive types.

The widely invasive follicular carcinoma is a tumor that is

clinically and surgically recognized as a cancer; the role of the

pathologist in its diagnosis is to confirm that it is of follicular

origin. These lesions are often large, involve much of the

thyroid, and usually have obvious extraglandular spread and

adhesion/invasion of the neighboring neck structures (recur-

rent laryngeal nerves, skeletal muscle, carotid artery sheath,

esophagus, and trachea). Gross venous invasion may be noted

surgically. The prognosis is guarded (less than 20 % survival

rate at 5 years) [19,2326].

Fig. 1 Encapsulated follicular-patterned neoplasm without capsular and/or vascular invasion compatible with follicular adenoma (hematoxylinand eosin stain 20)

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Grossly, the minimally invasive follicular carcinoma re-

sembles a follicular adenoma; the lesion is encapsulated.

The gross appearance may differ slightly from the benign

nodule because of the thickness of the capsule. Microscopic

examination is needed however to diagnose the lesion as

malignant or benign. Capsular invasion is usually seen as a

rounded fragment of tumor cells, attached to the main tumor

mass penetrating in a hook-like fashion or mushrooming intothe tumor capsule; this can be limited and only involve the

inner or mid portion of the capsule, or tumor may extend

through the capsule into the surrounding thyroid parenchyma.

In most cases, there are multiple foci of capsular invasion; one

can rarely encounter a single focus of capsular invasion in a

well-sampled or totally submitted tumor [15,16].

The definition and degree of capsular invasion for the

diagnosis of minimally invasive follicular carcinoma remain

controversial. Some authors require penetration through the

entire thickness of the tumor capsule, and others consider

invasion into the capsule enough for a malignant diagnosis.

At the same time, others have even questioned if capsularinvasion without vascular invasion justifies a malignant diag-

nosis [16,27,28].

Is capsular invasion insufficient for the diagnosis of follic-

ular cancer? What follow-up is available in series in which

such lesions are diagnosed as cancer? Some authors have

reported metastases in cases diagnosed as follicular carcinoma

based on capsular invasion only [16,18,29]. Interestingly, a

study by Yamashina about encapsulated follicular patterned

have shown that cases with capsular invasion also only dem-

onstrated vascular invasion on deeper sectioning of the tumor

blocks. Therefore, the question arises whether limited sam-

pling had missed the foci of angioinvasion, if the tumor

capsule was not sampled in its entirety in cases of follicular

carcinoma with capsular invasion only and distant metastasis.

On the other hand, those authors who diagnose tumors with

capsular invasion only as atypical adenomas indicate a

benign clinical course after thyroid lobectomy. The question

arises: Is there enough follow-up available in the literature

which can be used to justify the diagnosis of atypical follicular

adenoma for such cases? Periods of follow-up differ among

various series [30,31]. Data are not available in the literature

on 2030-year follow-up of large numbers of patients diag-

nosed with atypical adenoma of the thyroid.

Currently, in our practice, uni- or multifocal invasion into

or through the capsule without vascular invasion is sufficient

to render a diagnosis of minimally invasive follicular carcino-

ma [15]. The invading tumor nests should show a connection

with the main tumor mass; free floating islands of cells within

the tumor capsule may represent entrapped tumor cells due to

preoperative trauma (FNA, core biopsy) [12]. Such minimally

invasive follicular carcinomas with only capsular invasion

have a very low risk of recurrence and/or metastases. For

those follicular carcinomas in which vascular invasion is

found, our preferred diagnostic term is grossly encapsulated

angioinvasive follicular carcinoma since this group has a

significant propensity for clinically malignant behavior; about

50 % of patients with angioinvasive follicular cancers have

recurrence including metastatic disease with follow-up pe-

riods of ten or more years [3235]. A study by Goldstein

et al. evaluated the clinicopathologic features of encapsulated

features with or without metastases. These authors found thatcomplete tumor capsule penetration was seen in all cases;

however, vascular invasion was a common factor among all

encapsulated follicular pattern associated with metastases

[36].

The criterion for vascular invasion applies solely and strict-

ly to the vessels in the tumor capsule or in the surrounding

thyroid or extrathyroidal soft tissue (Fig. 2). Tumor plugs

within capillaries in the substance of the tumor have no

apparent diagnostic and prognostic importance, i.e., this find-

ing alone is not associated with malignant behavior. Vascular

invasion is defined as the presence of tumor cells intermixed

with fibrin and red blood cells within the capsular vesselsattached to the vessel wall, and endothelial cells should line

at least three sides of the tumor thrombus [16].

Regardless of the large body of literature available on

immunohistochemical, proliferation, and molecular profile

of follicular carcinoma, the distinction between a benign en-

capsulated follicular nodule and follicular carcinoma can only

be accomplished by examination of the H&E sections. A

majority of follicular thyroid carcinomas demonstrate aneu-

ploidy and a high prevalence of rat sarcoma (Ras) gene

mutations and of paired box gene 8 (PAX8)-peroxisome

proliferator-activated receptor gamma (PPAR) rearrange-

ments (2;3 translocation). However, this molecular profile

can also be seen in histologically classified follicular adeno-

mas [37].

Fig. 2 Follicular carcinoma showing invasion into the vessels within thetumor capsule (hematoxylin and eosin stain 20)

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Many Faces of Follicular Variant of Papillary Thyroid

Carcinoma

Probably the most difficult and controversial diagnostic area

in follicular-patterned thyroid lesions is follicular variant of

papillary carcinoma. This tumor is composed exclusively of

follicles lined by cells with nuclear features of papillary car-

cinoma (some authors use less strict criteria and allow for rarefoci of papillary growth) (Fig.3). Originally, it was believed

that tumors with the characteristic nuclear features of papillary

carcinoma would behave clinically as classic papillary carci-

noma [2,5,6,38].

However, as more cases and series of cases were examined,

it became clear that follicular variant of papillary thyroid

carcinoma (FVPTC) is a heterogeneous group of tumors.

The infiltrating variety is unencapsulated (or has a minor

component with a capsule); it invades lymphatic spaces,

may show multiple foci in different areas of the thyroid, and

may have psammoma bodies. It has a similar metastatic po-

tential for nodal metastases as classic papillary carcinomadoes [39]. Such tumors should be expected to behave as usual

papillary carcinoma and have similar metastatic patterns and

rare extracervical metastases [4043].

The encapsulated FVPTC has proven to be the most diffi-

cult and controversial diagnosis in thyroid tumor pathology.

The reasons for difficulty in diagnosing these lesions include

tumors showing multifocal rather than diffuse distribution of

nuclear features of papillary thyroid carcinoma and the lack of

invasive features, i.e., capsular and/or vascular invasion in

majority of cases of FVPTC. Hence, some authors believe

that diagnosing these tumors as carcinoma justifies treatment,

which may be excessive, i.e., total thyroidectomy and radio-

active iodine ablation [3, 7, 44]. This controversy is further

complicated by studies reporting a great interobserver vari-

ability in diagnosing encapsulated FVPTC even among thy-

roid pathology experts [5,6,38].

The encapsulated FVPTC can be divided into those lesions

which have invasion of capsule and/or vascular invasion most

pathologists would diagnose as carcinoma, although some

would consider them follicular carcinoma or well-

differentiated tumor not otherwise specified (NOS) or hybrid

tumors [13, 28] and cases that show either well-developed

diffuse or only focal features of papillary carcinoma (Fig. 4).

Whether the nuclei are present throughout the lesion or aremultifocal, if invasion is present, it is carcinoma [7,15].

Tumors with no capsular or vascular invasion but with

diffuse nuclear features of papillary carcinoma would be

considered as FVPTC by many but not all pathologists

(Fig. 4). Those lesions with multifocal nuclear change are

diagnosed as either FVPTC, atypical adenoma, borderline

lesion, or tumor of uncertain malignant potential [57]

(Fig.5a, b). The cases in which one encounters multiple foci

of FVPTC intermixed with benign-appearing follicles within

an encapsulated nodule can be diagnosed as multiple foci of

papillary microcarcinoma arising within adenoma. If one

looks into how such cases will be managed clinically, thetreatment of multiple foci of papillary microcarcinoma is

similar to that of clinical papillary carcinoma (measuring

greater than 1.0 cm), i.e., total thyroidectomy and radioactive

iodine ablation. It has been shown that multifocal papillary

thyroid microcarcinoma is a significant risk factor associated

with bilateral thyroid lobe involvement at presentation as

compared with unifocal papillary microcarcinoma [45].

Hence, some experts pursue a practical approach and classify

the entire tumor nodule as FVPTC leading to subsequent

completion of thyroidectomy as a part of oncologic

management.

This above-mentioned approach of classifying the entire

tumor nodule demonstrating multifocal nuclear features as

FVPTC may be perceived as overdiagnosis; however, some

studies employing ancillary studies have supported this. Stud-

ies on rearrangements of the rearranged during transfection

Fig. 3 Follicular variant of papillary thyroid carcinoma, follicles withthick luminal colloid, and cells linning these demonstrating nuclearfeatures of papillary thyroid carcinoma (hematoxylinand eosin stain 40)

Fig. 4 Enncapsulated follicular variant of papillary thyroid carcinomademonstrating diffuse distribution of nuclear features of papillary thyroidcarcinoma (hematoxylin and eosin stain, 10, inset60)

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(RET) proto-oncogene in papillary thyroid carcinoma (RET/

PTC) in cases of FVPTC, which show multiple rather than

diffuse diagnostic foci of papillary carcinoma, have demon-

strated that RET/PTC is expressed in areas which are mor-

phologically diagnosable as papillary carcinoma [46, 47].

Similar findings have been reported by immunohistochemical

studies employing antibodies to CK-19 and HBME-1 [48] In

addition, cases that were diagnosed as follicular adenoma due

to the lack of diffuse distribution of nuclear features of papil-

lary carcinoma, in which lymph node and bone metastasis

developed later, have been reported [49].

The thought-provoking work of Nikiforova et al. has

shown that a significant number of FVPTC have muta-

tions in N-Ras rather than RET/PTC, and

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and/or architectural atypia [56]. The former is usually seen as

focal presence of either nuclear pleomorphism characterized

by hyperchromasia and nuclear enlargement or nuclear fea-

tures suspicious for papillary carcinoma. The latter occurs

when a portion of specimen shows microfollicles or well-

formed papillary architecture. It is prudent to understand that

majority of these nuclear and architectural atypical features

are due to benign thyroid conditions such as degeneratinghyperplastic/adenomatoid nodule, chronic lymphocytic thy-

roiditis, and toxic adenomas [56]. It is recommended that

nodules with this classification undergo repeat FNA, since

the repeat cytology result is benign in 5060 % of cases,

preventing surgical intervention. The reported thyroid cancer

rate is 15 % for all nodules with an initial AUS/FLUS cytol-

ogy, which increases to 27 % for surgically excised nodules

with repeat AUS/FLUS cytology [57].

The FNA specimens from both follicular adenomas and

carcinomas are cellular with scant to absent colloid. The

follicular epithelium appears in syncytial fragments with

microfollicular or trabecular patterns (Fig.6). Both morpho-logic and morphometric studies have emphasized the features

of increased nuclear size, nuclear pleomorphism, and

crowding as helpful in the specific cytologic diagnosis of

follicular carcinoma [58, 59]. However, in routine practice,

most follicular carcinomas and follicular adenomas have a

similar cytologic pattern. This pattern may be indistinguish-

able, in 1525 % of cases, from hyperplastic nodule in goiter

[58,60] . Similarly, overlapping cytologic criteria occur be-

tween follicular neoplasms and follicular variant of papillary

carcinoma, particularly when the characteristic nuclear chang-

es are focal and not adequately sampled or are poorly visual-

ized in the aspirated material. Generous sampling and optimal

specimen preparation minimize these limitations of FNA in

distinguishing among follicular lesions. Overall, the incidence

of malignancy in nodules with a cytologic diagnosis of follic-

ular neoplasm ranges from 1530 % [61].

The needle aspirates of FVPTC in cytology show follicle

formation, cohesive cell groups with nuclear overlapping, and

crowding and monolayer sheets. Some cases may demonstrate

readily identifiable nuclear features of PTC leading to a diag-nosis of PTC while others contain few but not all nuclear

features (Fig.7a, b). The latter scenario can cause these cases

to be diagnosed as suspicious for malignancy (malignancy

risk 6075 %), follicular neoplasm (malignancy risk 20

30 %), or AUS/FLUS malignancy risk (1015 %) [62,63].

The use of molecular testing for somatic mutations in FNA

specimens diagnosed as AUS/FLUS, follicular neoplasm, and

Fig. 6 Fine-needle aspiration specimen diagnosed as suspicious for/consistent with follicular neoplasm.It shows a monotonous populationof follicular cells arranged in cohesive follicular groups. No nuclearfeatures of papillary carcinoma are seen (ThinPrep preparation, 60)

Fig. 7 Fine-needle aspiration specimen diagnosed as suspicious forfollicular variant of papillary thyroid carcinoma. This case showsmicrofollicle formation on alcohol-fixed smear (a papanicolaou stain,60). The ThinPrep preparation from the same cases highlights theatypical nuclei with nuclear enlargement, elongation, nuclear chromatinclearing, eccnetrically placed nuclei and delicate intranuclear grooves,and lack of intranuclear inclusions (bpapanicolaou stain 100)

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