Benign

Elsheikh, Tarik M.; Cochand-Priollet, Béatrix; Hong, Soon Won; Sidawy, Mary K.

doi:10.1007/978-3-319-60570-8_3

Tarik M. Elsheikh³,
Béatrix Cochand-Priollet⁴,
Soon Won Hong⁵ &
…
Mary K. Sidawy⁶

3825 Accesses
2 Citations

Abstract

Thyroid fine needle aspiration (FNA) derives much of its clinical value from its ability to reliably identify benign thyroid nodules, thus sparing many patients with nodular thyroid disease unnecessary surgery. Because most thyroid nodules are benign, a benign result is the most common FNA interpretation (approximately 60–70% of all cases). The term “Benign” is recommended to report benign thyroid cytopathology results. These are further sub-classified as benign follicular nodule, thyroiditis, or other less common entities. The designation “benign follicular nodule” applies to a cytologic sample that is adequate for evaluation and consists predominantly of colloid and benign-appearing follicular cells in varying proportions. The designation “lymphocytic thyroiditis” applies to a cytologic sample composed of many polymorphic lymphoid cells associated with benign thyroid follicular cells and/or Hürthle (oncocytic) cells. Benign cytopathology is associated with a very low risk of malignancy (<3%), and patients are usually followed conservatively with periodic clinical and radiologic examinations.

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Core Needle Biopsy for the Diagnosis of Thyroid Nodules: Pathologic Aspects

Thyroid Fine Needle Aspiration Cytology

Fine Needle Aspiration of Benign Thyroid Nodules

Keywords

Thyroid fine needle aspiration (FNA) derives much of its clinical value from its ability to reliably identify benign thyroid nodules, thus sparing many patients with nodular thyroid disease unnecessary surgery. Because most thyroid nodules are benign, a benign result is the most common FNA interpretation (approximately 60–70% of all cases) [1, 2].

To report benign thyroid cytopathology results, the term “Benign” is preferred over other terms such as “Negative for malignancy” and “Non-neoplastic” [3, 4]. Benign cytopathology is associated with a very low risk of malignancy, and patients are usually followed conservatively with periodic clinical and radiologic examinations [2, 5, 6]. Benign results are further sub-classified as benign follicular nodule, thyroiditis, or other less common entities. Nodular goiter (NG) is the most commonly sampled lesion by FNA, and chronic lymphocytic or Hashimoto thyroiditis is the most commonly encountered form of thyroiditis.

Benign Follicular Nodule

Background

Benign follicular nodule (BFN) is the most commonly encountered entity in thyroid cytopathology and encompasses a group of benign lesions with similar cytologic features that are classified histologically as nodular hyperplasia in nodular goiter (NG), hyperplastic (adenomatoid) nodules, colloid nodules, nodules in Graves’ disease, and an uncommon subset of follicular adenomas composed predominantly of macrofollicular or normofollicular architecture. The distinction among these different histologic entities may not be possible by FNA, but this is of little importance because they are all benign, and can be managed in a similar, conservative manner. In surgical pathology, the noncommittal term BFN has been suggested for benign cellular nodules where distinction between follicular adenoma and hyperplastic nodule (HN) is not possible on histologic examination [7]. Cytologically, BFNs are characterized by variable amounts of colloid, benign-appearing follicular cells, oncocytic (Hürthle) cells, and macrophages.

Definition

The designation “benign follicular nodule ” applies to a cytologic sample that is adequate for evaluation and consists of colloid and benign-appearing follicular cells in varying proportions. The general term BFN may be utilized in cytology reporting; subclassification as a more specific benign diagnosis such as colloid nodule, nodular goiter, hyperplastic/adenomatoid nodule, or Graves’ disease may also be used, depending on the cytomorphologic findings and associated clinical presentation (see Sample Reports).

Criteria

Specimens are sparsely to moderately cellular.

Colloid is viscous, shiny, and light yellow or gold in color (resembling honey or varnish) on gross examination. It is dark blue-violet-magenta with Romanowsky-type stains and green or orange-pink with the Papanicolaou stain (Figs. 3.1a, b and 3.2a, b). It may be thin or thick in texture (Fig. 3.3a, b).

Thin, watery colloid often forms a “thin membrane/cellophane” coating or film with frequent folds that impart a “crazy pavement,” “chicken wire,” or mosaic appearance (see Fig. 3.1a, b). At times, it forms lacunae (Fig. 3.4b).

Thick (dense, “hard”) colloid has a hyaline quality and often shows cracks (see Fig. 3.2a).

Follicular cells are arranged predominantly in monolayered sheets and are evenly spaced (“honeycomb-like ”) within the sheets (Figs. 3.3a, b and 3.4a).

Occasional follicular cells are arranged in intact, three-dimensional, variably-sized balls/spheres, and microtissue fragments (Figs. 3.5 and 3.6a).

Hürthle cells (oncocytes) are sometimes present, in flat sheets and/or as isolated cells (Fig. 3.6b).

Microfollicles may be present but comprise a minority of the follicular cell population.

The follicular cells have scant or moderate amounts of delicate cytoplasm (Figs. 3.7a, b and 3.8a, b).

Green-black cytoplasmic granules may be seen, representing lipofuscin or hemosiderin pigment (see Fig. 3.7b).

Follicular cell nuclei are round to oval, approximately the size of a red blood cell (7–10 μ in diameter), and show a uniformly granular chromatin pattern (Figs. 3.7b, 3.8a, b).

Minimal nuclear overlapping and crowding can occur (Fig. 3.9a). Anisonucleosis is appreciated in some cases, but there is no significant nuclear pallor or nuclear membrane irregularity.

Small flat sheets of follicular cells without nuclear overlapping or atypia may be present and do not represent neoplastic microfollicles (Fig. 3.9b).

Follicular cell nuclei may be stripped of cytoplasm and mistaken for lymphocytes (Fig. 3.10).

Papillary hyperplasia is occasionally seen (Fig. 3.11).

Follicular cells may appear shrunken, spindled, and degenerated when associated with abundant colloid (Fig. 3.12a, b).

Macrophages are commonly present and may contain hemosiderin pigment (Fig. 3.13).

Focal reparative changes are sometimes observed, especially in cystic lesions, including cyst lining cells with enlarged nuclei, finely granular chromatin, and a squamoid or spindle-shaped (“tissue-culture cell”) appearance (Fig. 3.14a, b, c).

Explanatory Notes

The major differential diagnosis of a circumscribed follicular-patterned nodule in surgical resection specimens is hyperplastic/adenomatoid nodule (HN) , follicular adenoma (FA), follicular carcinoma (FC), follicular variant of papillary thyroid carcinoma (FVPTC), and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). FVPTC and NIFTP are recognized primarily by their characteristic nuclear features. The great majority of FAs and FCs are solitary nodules and completely encapsulated, with a predominantly trabecular/solid or microfollicular architecture, and, therefore, when aspirated they are most likely to be reported cytologically as FN/SFN or AUS/FLUS. Less frequently, a FA or FC may display a prominent macrofollicular or normofollicular pattern. Therefore, in surgical pathology specimens most nodules with a trabecular, solid, or microfollicular growth pattern are diagnosed as either FA or FC , depending on the absence or presence of invasion, respectively, whereas most nodules with a normofollicular or macrofollicular pattern are called HN [7]. The noncommittal term BFN has been suggested when the histologic distinction between HN and FA is not possible [7].

The term BFN is especially apt for cytology reporting because many of the histologic distinctions described above (solitary vs. multiple nodule, encapsulated vs. not) are not apparent on an aspiration sample. Thus BFN conveniently describes a morphologically diverse group of benign histologic lesions, ranging from the colloid nodule or nodular goiter with minimal cellularity and abundant colloid to the hyperplastic (adenomatoid) nodule with moderate cellularity and scant colloid [8,9,10,11]. The predominance of honeycomb-like sheets of benign follicular cells, admixed in some cases with Hürthle (oncocytic) cells (see Figs. 3.3–3.8), and variable amount of colloid is the hallmark of BFN.

Cytoplasmic lipofuscin and hemosiderin pigment granules (paravacuolar granules) are more commonly associated with benign nodules (Fig. 3.7b), but they can be found in malignant neoplasms and so have no diagnostic significance [12].

Watery colloid is most apparent with one of the Romanowsky-type stains like the commonly used Diff-Quik stain ; it is less conspicuous but still visible with Papanicolaou-stained preparations (Figs. 3.1, 3.2, 3.3, and 3.4) and can be confused with serum in bloody specimens. Helpful clues to recognizing watery colloid on smears are the presence of cracking and folding in colloid, as well as its tendency to surround follicular cells and occasionally form lacunae (Fig. 3.4), whereas serum accumulates at the edges of the slide and around platelets, fibrin, and blood clots. Specimens consisting of abundant colloid only (e.g., colloid covering the majority of the surface of a smear), with rare or no follicular cells, are considered BFNs, reported as “Benign,” and may be further described as “suggestive of...” or “consistent with colloid nodule” (Fig. 3.2)b. Occasionally, the benign thyroid follicular cells are spindled and show evidence of dissociation when suspended in abundant colloid (Fig. 3.12a, b). If colloid is abundant, a diagnosis of BFN is appropriate, even if one cannot find six groups of well-preserved, well-visualized follicular cells, each with at least ten follicular cells.

The cytologic features and diagnostic accuracy of BFNs are generally similar between smears and liquid-based preparations, but there are a few differences [13, 14]. The amount of colloid is diminished in liquid-based preparations when compared with smears, but nuclear detail may be superior [15, 16]. Benign-appearing follicular cells are arranged in relatively smaller monolayer sheets, usually with less than 20–25 cells per sheet. The cells have pale cytoplasm and smaller and darker nuclei (Fig. 3.15a, b). Thick colloid appears as dense, dark blue-orange droplets; and watery colloid as thin, tissue paper-like sheets (Fig. 3.16a, b) [14]. Macrophages may have more abundant pale cytoplasm, enlarged, pale nuclei, and prominent nucleoli. Hürthle cells (oncocytes) may be arranged in a more dissociative pattern and appear shrunken compared to conventional smears, with irregularly shaped, variably sized nuclei and more prominence of the nucleoli (Fig. 3.26b).

Thyroid cysts with an inadequate number of follicular cells should be interpreted as “Nondiagnostic” or “Unsatisfactory,” with a comment pertaining to the “cyst fluid only” nature of the aspirate (see Chap. 2) [17].

Thyroglossal duct cyst enters in the differential diagnosis of thyroid cystic lesions when an aspirate consists predominantly of proteinaceous material, inflammatory cells, and rare degenerated squamous or ciliated columnar cells (Fig. 3.17a, b). The diagnosis can be suggested in the appropriate clinical presentation (anterior midline neck cyst, usually above the thyroid isthmus and below the hyoid bone, or rarely just lateral to midline). Mature squamous cells and anucleated squames rarely predominate. If they do, the cyst may be indistinguishable from branchial cleft cyst [18]. Occasional benign-appearing squamous cells may also result from squamous metaplasia associated with lesions such as lymphocytic thyroiditis and cystic papillary thyroid carcinoma.

A cellular sample comprised almost exclusively of mature, benign-appearing squamous cells has been associated with benign follow-up in the available but limited literature, and such cases may be reported as benign in the appropriate clinical setting (Fig. 3.17c) [19].

A not infrequently encountered cystic lesion is the parathyroid cyst, which may be clinically and cytologically mistaken for a thyroid cyst. Aspirated fluid from a parathyroid cyst, however, has a characteristic watery, clear gross appearance, is often acellular or hypocellular, and may show rare cohesive groups of small round cells with dark nuclei and scant cytoplasm, arranged in sheets or microfollicles (Fig. 3.18). The diagnosis of a parathyroid cyst can be established by immunohistochemistry (positive staining for parathormone and chromogranin, negative for thyroglobulin) and/or demonstration of elevated parathormone levels in the cyst fluid [20].

Moderately cellular BFNs may prompt consideration of a follicular neoplasm, but cellularity alone is not enough to merit the interpretation “Follicular neoplasm/Suspicious for a follicular neoplasm (FN/SFN).” Follicular cell crowding, overlapping, and microfollicle formation affecting a majority of the follicular cell population are the important features of the FN/SFN specimen [21]. Some BFNs do contain a minor component of microfollicles , but these tend to show no significant nuclear enlargement or nuclear overlapping and crowding. When microfollicles comprise a minority of the sample and are accompanied by a predominance of macrofollicle fragments, the sample is interpreted as a BFN. Macrofollicle fragments range in size from small to large. A small fragment of benign-appearing follicular cells should not be misconstrued as a neoplastic microfollicle (Fig. 3.9b); an important defining feature of the neoplastic microfollicle is the significant crowding and overlapping of the follicular cells, sometimes accompanied by nuclear enlargement.

Papillary hyperplasia is defined histologically as a benign proliferation (either hyperplasia or adenoma) notable for the arrangement of follicular cells, usually in a single layer, around fibrovascular cores. Fortunately, papillary hyperplasia in the form of true papillae (defined as having fibrovascular cores) is rarely eoncountered in aspirates, but when it is it can be a diagnostic challenge [22]. More commonly, one sees large fragments of follicular cells associated with stromal tissue that only raises the question of a fibrovascular core. If there are no nuclear features of PTC, the case can be reported as benign (Fig. 3.11).

Hürthle (oncocytic) cells per se should not prompt the interpretation “Follicular neoplasm, Hürthle cell type/Suspicious for a follicular neoplasm, Hürthle cell type (FNHCT/SFNHCT).” A minor population of Hürthle (oncocytic) cells is a common finding in BFNs. Not uncommonly, Hürthle cells can be a prominent or even the predominant component of a BFN (Fig 3.6b), and in some cases there can be significant anisonucleosis and hyperchromasia of the Hürthle (oncocytic) cells. The interpretation FNHCT/SFNHCT should be reserved for cases that consist exclusively (or almost exclusively) of Hürthle cells [23] (see Chap. 6). An aspirate with a significant amount of colloid and a predominant but not exclusive Hürthle cell population is consistent with BFN in the appropriate clinical setting [23].

It is important to evaluate even colloid-rich aspirates for the presence of nuclear features of papillary thyroid carcinoma so as not to miss a macrofollicular variant of papillary carcinoma. This variant often presents with flat sheets without significant nuclear overlapping, resembling benign thyroid follicular cells on low magnification. Occasionally, an aspirate with the features of a BFN will contain a subpopulation of cells with reparative changes, and it is important not to confuse those changes with those of papillary carcinoma (Fig. 3.14a, b, c). When nuclear atypia (e.g., pallor, irregularity) goes beyond what is accepted for reactive/reparative changes, such cases are interpreted as “Suspicious for malignancy” or “Atypia of Undetermined Significance (AUS/FLUS),” depending on the extent and degree of the atypia (see Chaps. 4 and 7).

“Black thyroid ” is a benign pigmentation of thyroid follicular cells in patients on chronic treatment with antiobiotics of the tetracycline family (e.g., minocycline) for conditions like acne. Follicular cells show abundant dark brown cytoplasmic pigment. It is darker than hemosiderin and likely represents a form of melanin (Fig. 3.19) [24, 25].

Amyloid goiter is a rare pathologic entity defined as a clinically apparent thyroid enlargement due to amyloid deposition. It is associated with both primary and secondary amyloidosis and results in a diffuse/bilateral involvement of the thyroid gland. Many patients present with symptoms of compression such as hoarseness, dysphagia, and dyspnea. FNA reveals abundant purple to pink/orange amorphous material morphologically similar to colloid but recognizable due to the presence of embedded fibroblasts (Fig. 3.20a, b) [26]. Focal amyloid deposits are also seen in medullary thyroid carcinoma and primary amyloidosis of the thyroid.

Graves’ Disease

Graves’ disease (GD) is an autoimmune diffuse hyperplastic thyroid disorder , commonly seen in middle-aged women and usually diagnosed clinically due to hyperthyroidism. Most patients have a diffuse rather than nodular enlargement of the thyroid gland and do not require FNA for diagnosis [27]. Occasionally, however, large and/or cold nodules develop that raise the suspicion of a co-existing malignancy and thus prompt FNA. The cytologic features of GD are non-specific, and clinical correlation is needed for a definitive diagnosis. Aspirates are often cellular and show similar features to non-Graves’ BFNs, including abundant colloid and a variable number of follicular cells. Occasionally, lymphocytes and Hürthle cells (oncocytes) may be seen in the background.

Follicular cells are arranged in flat sheets and loosely cohesive groups, with abundant delicate, foamy cytoplasm [28] (Figs. 3.21 and 3.22). Nuclei are often enlarged, vesicular, and show prominent nucleoli. Few microfollicles may be observed. Distinctive “flame cells ” may be prominent and are represented by marginal cytoplasmic vacuoles with red to pink frayed edges (best appreciated with Romanowsky-type stains) [27, 29] (Fig. 3.21). Flame cells, however, are not specific for GD and may be encountered in other non-neoplastic thyroid conditions, follicular neoplasms, and papillary carcinoma. Occasionally the follicular cells display focal chromatin clearing and rare intranuclear grooves (Fig. 3.23a). These changes are not diffuse, however, and other diagnostic nuclear features of papillary carcinoma are commonly absent. [30] Occasionally, treated GD shows prominent microfollicular architecture, significant nuclear overlapping and crowding, and considerable anisonucleosis. Care must be taken not to over-interpret these changes as malignant or neoplastic, and inquiry should be made regarding prior radioactive iodine therapy [31, 32] (Fig. 3.23b). Lymphocytes are usually not prominent in GD, but in some cases they may be present in significant numbers and mimic lymphocytic thyroidits [29, 31].