What Does Scattered Cytologically Bland Follicular Cells In A Background Of Abundant Colloid.

Clinical aspects

In the past five or six decades, fine needle aspiration (FNA) cytology of the thyroid has been increasingly utilized for the investigation of thyroid lesions.¹ ^– ⁵ The prevalence of thyroid nodules is 4–eight% in Western populations.⁶ Since cancer is more common in lonely cold nodules, they are conventionally viewed with suspicion. While most thyroid cancers are cold on scintiscanning, the antipodal is not truthful. The prevalence of malignancy in solitary cold nodules ranges from 10% to 44.7%.^vii Besides, not-palpable thyroid nodules are existence increasingly detected by scanning techniques.⁸ Preoperative distinction of benign lesions is of paramount importance to avoid unnecessary surgery. Simplicity, diagnostic accurateness and most of all cost effectiveness^four, ^9, ¹⁰ have given FNA the status of the starting time-line diagnostic examination in the preoperative evaluation of thyroid lesions. With increasing experience, FNA has been shown to be able to categorise many beneficial and malignant lesions and thereby guide therapeutic protocols. It is as well useful in the diagnosis and monitoring of autoimmune thyroid lesions, especially in clinically equivocal cases and cases where biochemical and immunological parameters are normal or marginally aberrant.

The principal indications of FNA in thyroid lesions are the following:

FNA has been shown to be the safest and nigh accurate of diagnostic tools in thyroid lesions^11, ¹² with a sensitivity equally high as 93.4%, a positive predictive value of malignancy of 98.6%, and a specificity of 74.9%; its employ has simultaneously diminished the number of surgeries washed for benign lesions and increased the proportion of malignancies in surgically resected thyroids. Cytological reports can and have been used to program definitive surgery, although some surgeons nonetheless need frozen department or alkane-section confirmation to overcome cytological error. Frozen section has trivial to offer over cytology in the cess of follicular neoplasms (FNs), as these crave all-encompassing sampling to place capsular and/or vascular invasion. Imprints during frozen section could be very useful in the identification of follicular variant of papillary carcinoma (FV-PC)¹³ as the characteristic nuclear morphology is brought out to advantage in cytologic smears and is easier to identify than in frozen sections.

The accuracy of FNA is distinctly higher in centers where not only the interpretation simply the needling besides is carried out by the pathologist.¹² Ultrasonography (Usa), thyroid function tests, antibody profiles and FNA, used in conjunction in selected cases, complement i another. US-guided FNA of thyroid is useful, especially in cystic and multinodular lesions harboring malignancy.¹⁴ Its value in clinically impalpable nodules has been questioned (see Affiliate 2 and iii) due to the insignificant percent of cancers in this setting.¹⁵ Recent guidelines recommending The states exam in patients with palpable nodules¹⁶ accept led to an emerging trend in Usa-guided FNA. Published data indicate reduced not-diagnostic and false-negative rates with United states evaluation and US guidance.^17, ^eighteen

Several studies take compared the accuracy and complications of core needle biopsy with that of FNA¹⁹ that has increased adequacy charge per unit but reduced sensitivity, especially for PC.^xx Combination of core needle biopsy with FNA increases diagnostic accuracy but the trouble of distinguishing benign and cancerous FNs remains. In general, safety and ease of utilise of FNA outweigh the slight increment in accuracy achieved past core needle biopsy.

The inability of FNA to distinguish follicular adenoma (FA) from follicular carcinoma (FC) has been debated at length²¹ ^– ²³ and in plow has led to the apply of ancillary techniques to resolve this problem. Marked reduction in the incidence of FC (from 20% of thyroid cancers to less than 2%) since the practice of iodide supplementation of food supplies^22, ²⁴ has, all the same, shifted the focus to other follicular lesions such as cellular nodular goiter (NG) and FV-PC.¹²

Nomenclature used in reporting

Reporting of thyroid FNA specimens should follow a standard format that is clinically relevant in gild to direct management. At the National Cancer Institute sponsored thyroid country of the science conference in Bethesda in October, 2007, consensus was reached regarding indications, pre-FNA requirements, FNA techniques, diagnostic terminology, etc.²⁵ The Bethesda System reporting terminology includes six categories: non-diagnostic, beneficial, atypia of undetermined origin, FN/suspicious of FN, suspicious for malignancy and malignant.²⁶ Every category carries with it the unsaid risk for malignancy. Each category should be further qualified as to the possible pathological entity.

If an indeterminate diagnosis is being made due to features suspicious but not diagnostic of a neoplasm, it should be so qualified, since echo FNA may enable definitive diagnosis. If, on the other manus, it is being fabricated for FN, qualifying it as such will analyze that stardom of benign from cancerous cannot be achieved past echo FNA, and either coincident techniques or histological study are required. To simplify the issue, nosotros suggest that in the onetime, a diagnosis of 'indeterminate (suspicious)' be given and in the latter 'indeterminate (FN)'. We suggest the revised Papanicolaou system of reporting¹⁰ which is unproblematic and easily reproducible with the following vi categories that are useful in triaging patients for either clinical follow-up or surgery:

Accurateness and limitations of cytodiagnosis

In experienced hands, and in situations where the pathologist performs the needling, cytology can exist a very sensitive tool with sensitivity and specificity of up to 94% and 98% for the diagnosis of malignant lesions^ten and almost 90% accurateness rates for the identification of malignancy if follicular lesions are excluded.^27, ²⁸ Cytologic diagnosis is generally accurate in thyroiditis, usual blazon of PC, medullary carcinoma (MC), anaplastic carcinoma (AC) and high-grade lymphoma. False negatives generally occur in cystic lesions harboring malignancy, in depression-course or intermediate-grade lymphomas occurring in a background of Hashimoto's thyroiditis (HT), in Ac with necrosis, in focal involvement of the gland past thyroiditis and in cases with dual pathology where the dominant not-neoplastic lesion overlies or obscures a small-scale carcinoma.²⁹ ^– ³¹ Fake negatives accept been shown to exist minimized by using The states-guided FNA. The false-positive rate tin be reduced further by excluding indeterminate follicular lesions.

Complications

There are no contraindications to thyroid FNA. Local hemorrhage may be caused past needling, occasionally causing a hematoma in the anterior neck³² that in turn may crusade airway pinch.³³ Carotid hematoma is an extremely rare complication.³⁴ Transient song cord paralysis,³⁵ acute transient goiter,³⁶ acute suppurative thyroiditis³⁷ and chemical neuritis³⁸ accept been noted occasionally. Puncture of the trachea during needling usually causes cough. Small amounts of blood may be coughed upward but recovery is rapid. Needling may convert a hot nodule to a common cold one and vice versa, therefore scans (and in general, all noninvasive investigations) should be washed before FNA. Mail service-FNA infarction is an uncommon complication and most reported cases have been Hurthle cell nodules, followed past PC and FNs.³⁹ Hemorrhage, necrosis or infarction caused by needling may occasionally obscure the histological pattern of thyroid neoplasms. Cellular and vascular granulation tissue of organising hematoma or necrosis tin mimic sarcoma or angiomatous tumors. Fibrosis, papillary hyperplasia, calcification, cholesterol clefts, vascular thrombosis and capsular baloney simulating invasion are other worrisome histological alterations that occasionally follow needling.^forty Changes are, in general, proportionate to the size of the needle used and the number of needle passes.⁴¹ Mail-needling alterations are generally less with the fine needle capillary sampling technique⁴¹ described below. Aggressive and repeated needling and using needles thicker than 22 gauge should exist avoided at all times. In cases where needling is to exist repeated for inadequate or inconclusive cytology, information technology is wise to allow an interval of a calendar week to 10 days for any artifacts of initial needling to minimize.⁴² Rare cases of tumor implantation forth the needle rails have been documented⁴³ ^– ⁴⁵. Use of fine-caliber needles (24 gauge or less) and gentle needling technique are stressed to avert complications and to maximize patient comfort.

Technical considerations

After examining the thyroid with the patient sitting upright, the patient should be made to lie supine with a pillow behind the neck for hyperextension, which makes the lesion more obvious. The fine needle capillary sampling technique is eminently more suitable in vascular structures similar thyroid as it provides cellular cloth with minimal dilution by claret. After instructing the patient to refrain from swallowing, the lesion is needled with a fine needle (gauge 25–27), speedily and gently at dissimilar angles and points of entry. Needling should be concluded before or equally soon as textile appears at the hub of the needle, the needle and so fastened to an air-filled syringe, and material deposited and smeared on to clean glass slides. Half of the smears tin be air-dried for May Grünwald Giemsa (MGG) or Diff-Quik stain while the rest should be wet-fixed in ethanol for Papanicolaou (PAP) stain (that brings out nuclear details to advantage). If the aspirate is scanty, air-drying with Diff-Quik or MGG stain is ameliorate equally information technology ensures retention of 100% of cells on the slide. Rapid smearing is important in bloody samples, as clotting of blood will entangle diagnostic cells and distort morphology. Irksome drying of wet samples causes nuclear shrinkage and loss of cytological characteristics. A hair-dryer can be used for rapid drying but should be avoided in samples that may be infectious, to avert aerosols. Despite cost and bounty issues, bedside evaluation of a Diff-Quik or ultrafast PAP-stained smear is advantageous to ascertain acceptable cellularity and representative sampling and to select cases for ancillary studies.^42, ^46, ⁴⁷

In cystic lesions where fluid appears at the hub of the needle, the needle should be withdrawn and FNA done using a 22-gauge needle attached to a syringe that will enable aspiration and possible evacuation of cyst contents. After evacuation, any palpable lesion remaining should be needled to minimize chances of missing a neoplasm in the cyst wall. Needling sometimes causes the cyst to make full up with blood and The states-guided repeat needling can be done after resorption of claret. Surgical excision can be postponed until after repeat needling of cytologically indeterminate lesions (done after 7–10 days), which often gives a definitive diagnosis. The states-guided needling improves the diagnostic yield, especially in very small nodules, retrosternal or mediastinal lesions and enlarged parathyroid glands.^48, ⁴⁹ In all US-guided cases, pathologist and radiologist should work together with modest-caliber needles, completing the procedure quickly to minimise dilution with blood and reduce chances of the sample clotting within the needle. Rapid bedside evaluation of smears is mandatory to ensure representative sampling. In situations where Us-guided FNA yields hemorrhagic cloth and an on-site pathologist is not available, cell blocks may requite amend results than direct smears.^l

Poor smearing technique and problems involving specimen transportation to the laboratory accept led to increasing use of liquid-based processing (LBP) at some centers.⁸ While LBP has the advantage of enabling ancillary tests such equally immunostains and molecular techniques,⁵¹ specific tumor categorization was found to be less frequent as compared to conventional smears.⁵² While LBP is a practiced option in situations where the needling and smearing are performed by a variety of personnel, the importance of training the operator in the technique of optimal smear-making cannot be overemphasized. Increasing utilise of LBP may also lead to diminishing skills in direct smear reading, which is required for on-site assessment. On-site assessment not only helps decide specimen capability but helps triage the specimen to methods that optimize its diagnostic value.^eight, ⁴⁶

Cytological features

Unless otherwise stated, the appearances described refer to MGG/Unequal-Quik stained smears.

Normal structures

Follicular epithelial cells and colloid are regular features in normal thyroids and in colloid goiter. Follicular cells show delicate grayness-bluish or pale-blue cytoplasm with indistinct or fuzzy cell borders. Fibroid bluish (paravacuolar) cytoplasmic granules may be seen (Fig. half dozen.1). Bare nuclei, similar in shape and size to normal lymphocytes, are common. Some cells may testify pocket-sized nucleoli.

In non-bloody specimens, thin colloid stains blue, violet or pinkish and forms a sparse membrane-similar coating or moving-picture show, with folds and cracks due to drying of colloid on the slide (Fig. vi.2A,B). Colloid may wash off from the slide while staining simply the parched-earth or crazy-pavement antiquity of colloid remains and follicular cells are often seen at the smear margins. Thick colloid appears as round, dense clumps of deep blue, violet or magenta-colored acellular material, or as globular masses with superimposed follicular cells, specially in samples from NG. Colloid can exist mistaken for hyalinized collagenous stroma (collagenous spherules) or amyloid. Skeletal muscle fragments appear as straps of nighttime-blueish material with stake ovoid nuclei and cantankerous-striations visible in higher magnification. In PAP-stained smears, thin colloid stains stake dark-green or orange, with not bad artifacts seen. Thick colloid appears as clumps of nighttime green or orangish material (Fig. six.2C,D). The blue violet color and hyaline texture of colloid announced to reward in MGG-stained smears and distinction from fibrillary collagen and deep magenta staining amyloid is easier (Fig. 6.iii). In bloody smears, colloid resembles other protein-rich fluids, including serum.

Fig. 6.2 Colloid

(A, B) Sparse colloid forms a varnish-like coat of relatively homogenous material, characteristic 'crazy pavement' and cracking artifacts (A, MGG IP; B, Pap, IP); (C, D) Thick colloid forms irregular dense clumps of material; homogeneous and violet in MGG; variable density and staining in Pap. Compare with Figure 6.3 A and B (C, MGG, IP; D, Pap, IP).

C-cells resemble medullary thyroid carcinoma cells and need immunocytochemical stains for identification, except in C-cell hyperplasia, where they are nowadays in large numbers. Accidental puncturing of the trachea or larynx during FNA can be suspected if the patient coughs and air enters the syringe. Smears show mucus, respiratory cells and carbon-laden macrophages. Cartilage may be seen, appearing every bit bright magenta flecks with fibrillary edges.

Nodular goiter (Figs half dozen.4-6.7)

Smears evidence arable thick or thin colloid, follicular cells in monolayered sheets, poorly cohesive groups and as unmarried cells, globular colloid masses with superimposed follicular cells, blank nuclei and pigment-laden histiocytes (foam cells) in varying proportions. Involutional follicular cells with modest round night nuclei and fragile, feathery cytoplasm besides as larger, hyperplastic cells with arable vacuolated cytoplasm or with marginal vacuoles (fire-flares) are seen (see Fig 6.9). The latter may show anisonucleosis. Oxyphilic (Hurthle) cells may be seen.

Macrofollicles disrupted by needling flatten on the slide to grade monolayered sheets of epithelial cells. These accept a honeycomb structure due to distinct jail cell membranes (Fig. vi.6A)³ and frayed edges. Focally, the cytoplasm is indistinct, forming a web-like background to the nuclei. Smaller follicles may be removed intact past the needle. They appear as spherical prison cell clusters resembling multinucleate giant cells (Fig. six.6B), that may be enveloped by a basement membrane. Macrofollicles are evidence of benignity and are of diagnostic significance. Hyperplastic papillae containing follicles and intact dilated follicles in cell-block preparations are supportive evidence of a benign nodule. Foam cells, often hemosiderin-laden, suggest degeneration, commonly seen in NG (Fig. 6.5A). Distinction between degenerate epithelial cells and true macrophages is not always possible as transitional forms occur that show epithelioid as well as histiocytoid features and focal atypia. Hyalinized stroma presents as irregular pink/red frayed fragments of vaguely fibrillar material, some with adherent epithelial cells (encounter Fig. 6.3A).

Inadequate samples may exist obtained from colloid nodules due to low cellularity and degenerative change. If smears contain few or no well-preserved follicular cells, the specimen should be reported every bit not-diagnostic, unsatisfactory, and repeated.

The cytological appearances of NG tin overlap with FN and cytological criteria alone cannot ever reliably distinguish between the two. Selective sampling of a microfollicular focus in NG leads to a repetitive design of microfollicles or rosettes with no colloid, and distinction from FN may be impossible.⁶⁷ However, since this is a focal phenomenon, samples from other areas are likely to bear witness macrofollicles, abundant colloid and degenerative changes recognizable equally colloid goiter. In the cytological spectrum of follicular nodules, a big canvass pattern of follicular cells with sparse colloid in the background indicates a macrofollicular pattern suggestive of benignity while syncytial clusters with nuclear crowding and overlapping suggest a tumour.⁶⁸

Cystic PCs often contain abundant colloid. This can cause diagnostic difficulties if smears are poor in cells, but a close look at the nuclear features should allow a right diagnosis in near cases, as detailed below. Smears in FV-PC may evidence well-formed follicles containing colloid.

Groups of large cells with irregular nuclei, non infrequently found in NG, are probably related to degenerative alter. Their origin is uncertain; they may be histiocytes or regenerating epithelial cells consistent with repair (Fig. 6.seven). Prominent aggregates of histiocytes can in some cases mimic cells of PC due to similar nuclear features.⁶⁹

The value of cytology in hyperfunctioning nodules has been disputed merely recent reports propose that there may be an increased incidence of malignancy in hyperthyroidism and that FNA is a reliable diagnostic method in these cases. It appears reasonable, therefore, to evaluate these lesions cytologically prior to radioactive iodine treatment or surgical intervention.⁷⁰

Cystic nodules

Thyroid cysts are most unremarkably due to retrogressive changes in NG where they may be small-scale, yielding a few drops of fluid or larger cysts yielding substantial quantities. FNA yields chocolate-brown colloid-like fluid with altered blood. Smears show foam cells that may contain hemosiderin and thin degenerating follicular epithelium (see Fig six.5).^31, ⁷¹

Cystic change and/or hemorrhage occur in thyroid tumors (25% of PCs, and 20% of FNs in ane series).⁷² Prevalence of malignancy in resected cystic nodules is 10–fifteen%.^4, ³¹ Partly solid and cystic nodules may also harbor malignancy.

A definitive diagnosis of cystic NG requires adequate sampling of any solid component. Cystic fluid containing only macrophages and no epithelial cells does non dominion out a cystic neoplasm. The gross appearance of cyst fluid is non helpful.³¹ Presence of atypical cells in a 'cyst fluid merely' sample should lead to a 'suspicious' diagnosis (not not-diagnostic).⁷³ A cystic lesion that can be completely evacuated with no palpable nodule remaining and no epithelial atypia indicates benignity.⁷¹ While 4–40% of cystic lesions can be permanently cured by FNA, others need repeated evacuations. False-negative cytological diagnosis is most mutual in cystic carcinomas, especially PC, where just upwards to sixty% can be correctly diagnosed.^71, ⁷⁴ Re-biopsy of the cyst bed and of any residual or recurrent swelling, preferably with US-guidance, is advisable. Recurrent cysts, lesions greater than 3–4 cm in diameter and lesions in immature males are indications for surgical excision.

Thyroglossal cysts yield clear or mucoid fluid and smears may incorporate squamous or respiratory epithelium associated with colloid.⁷⁵ Foregut cyst of thyroid yields yellowish fluid and smears testify detached ciliary tufts and macrophages.⁷⁶ Rare epidermoid cysts of thyroid have been described.⁷⁷

Clear fluid aspirated from a lateral cystic lesion suggests a parathyroid cyst and parathormone estimation of the fluid is advised.⁷⁸ Thymic cysts yield clear fluid containing lymphocytes.

Acute suppurative thyroiditis

This is an uncommon but potentially life-threatening condition⁷⁹ occurring mostly in devitalized or immunosuppressed individuals.⁴² Patients present with extremely tender thyroid enlargement, fever and loftier ESR. Smears show neutrophils, necrotic cells and debris. Intracellular bacteria, (normally Gram-positive cocci), may be nowadays. Less commonly, mycobacteria, viruses, aspergillus, actinomycosis, cryptococcosis and pneumocystis have been observed.⁴² Cytologic material can also exist sent for culture and sensitivity.

Autoimmune thyroid disease

The syndromes comprising autoimmune thyroid affliction are many intimately related illnesses, the two most mutual being Graves' disease (GD) (with goiter, hyperthyroidism and, in many patients, associated ophthalmopathy) and Hashimoto's thyroiditis (HT) (with goiter and euthyroidism or hypothyroidism). Immunological mechanisms in these diseases are closely related and the syndromes are connected together past like thyroid pathology, co-occurrence in family groups, and transition from one clinical picture to another inside the same private over time. Antibodies to thyroid peroxidase (TPO-Ab), produced mainly by intrathyroidal lymphocytes, are the hallmark of autoimmune thyroid affliction and are nowadays in most patients with HT and in 75% of patients with Graves' hyperthyroidism.^fourscore

Graves' disease (master hyperplasia) (Figs vi.viii and 6.ix)^81, ⁸²

Cytological study is not normally sought in GD every bit the clinical and biochemical profile are feature in almost cases. Nevertheless, cytology aids distinction from other weather condition that nowadays with thyrotoxicity, such as toxic NG, de Quervain'due south thyroiditis, HT presenting in toxic stage and rarely in thyroid carcinomas.⁷⁰

Smears are bloody with scant colloid. Cellularity is moderate to high with follicular epithelium present equally monolayered sheets, rings or follicular structures with suggestion of columnar shape (Fig. 6.8A). Cytoplasm is abundant and cobweb-like and delicately vacuolated, with larger marginal vacuoles giving a characteristic 'burn down-flare' advent.⁸² 'Fire-flares' are pale pinkish/reddish clumps of material measuring 1–7 µm in diameter, often with a stake center, mainly seen at the rim of the cytoplasm around the edges of aggregates of follicular cells (Fig. 6.9). They may correspond to colloid droplets seen ultrastructurally or to dilated cisternae of endoplasmic reticulum, and are indicative of cellular hyperactivity. They are present in toxic NG, and may be seen in a smaller percentage of cells in HT, diffuse or nodular goiter, and occasionally in neoplasms, including carcinoma.^83, ⁸⁴ In untreated GD, however, upwardly to 100% of cells may show fire-flares. Paravacuolar granules may be seen. There may be moderate to marked nuclear atypia, specially in cases treated with radioactive iodine or neomercazole (Fig vi.8B).⁸⁵ Papillary structures may be seen, occasionally resembling PC. Hurthle cells and lymphocytes and rarely multinucleate behemothic cells or epithelioid cells may be seen.⁸²

Autoimmune thyroiditis (Hashimoto'southward thyroiditis/lymphocytic thyroiditis) (Figs 6.10-6.thirteen)^81, ⁸⁶ ^– ⁸⁹

Lymphocytic thyroiditis and HT stand for different phases or manifestations of an organ-specific immunologically mediated inflammatory disease. A defect in suppressor T cells makes the gland vulnerable to cytotoxic T cells and stimulates T-helper cells to induce autoantibody product.^ninety Patients usually nowadays with diffuse or nodular thyroid enlargement and contradistinct thyroid role caused by gradual immunologically mediated destruction of the gland. Antithyroid antibodies (especially microsomal/TPO-Ab) are significantly elevated in most cases. HT is one of the major manifestations of autoimmune thyroid disease, the other being GD.⁹¹ It is more than common in Asians.⁹² In multiethnic Malaysia, a report of 88 cases of HT showed it to be more common in Indians than Chinese or Malays, and nodular presentation was seen in about one-third of cases.⁹³

A bloody background with lymphoid cells, degenerative changes in follicular cells and infiltration of follicular cells by lymphoid cells are characteristic features of HT. Variable features include oxyphilic cells (Hurthle cells), plasma cells, epithelioid jail cell granulomas and multinucleated behemothic cells.

The 'lymphocytic' pattern of HT occurs in children and young adults with a shorter history of the illness and absent or low antibiotic titers.⁸⁸ Smears are dominated by a mixed population of lymphoid cells including centroblasts, immunoblasts and dendritic reticulum cells from germinal centers characteristic of a reactive lymphoid proliferation (Fig. 6.12). Germinal center histiocytes have plentiful pale cytoplasm and oval or indented histiocytoid nuclei with granular chromatin. They are often clustered and associated with lymphoid cells, some of which prevarication within their cytoplasm. Histiocyte-lymphocyte rosettes or lympho-histiocytic clusters may be seen. Lymphoid : follicular cell ratios are frequently equally high as 10 : 1 with epithelial cells so inconspicuous that smears resemble reactive lymphoid hyperplasia (Fig 6.12 A).

'Classic' or 'florid' HT occurs in older patients (usually women), who are more oft hypothyroid and have raised TPO-Ab. The smear background shows lymphocytes with a variable number of plasma cells. There is prominent oxyphilic (Hurthle cell/Askanazy jail cell) modify with single and syncytial aggregates of cells showing abundant, dumbo, finely granular, gray-blue cytoplasm (MGG), and well-defined cell borders. Nuclei are 2–4 times the size of normal follicular cell nuclei (Figs half dozen.10 and half-dozen.11) and may show atypia and prominent nucleoli. Normal-appearing follicular cells may be nowadays, showing features of hyperactivity. A characteristic feature is that of lymphocytes (and occasionally plasma cells) seeming to adhere to or infiltrate follicular cells, supporting the theory of direct epithelial damage past lymphocytes. Multinucleated behemothic cells and epithelioid cells can be seen in up to 40% of cases.^87, ⁹³ Neutrophils and eosinophils may be seen adhering to or infiltrating follicular cells in early stages.^42, ⁹³

Seven to 30-iii percent of cases are antibody negative.^87, ^90, ⁹³ In a study of 150 cases of HT, overall Ab positivity was found to be 88.67%.⁹⁴ TPO-Ab showed significant correlation with high lymphoid : epithelial ratios but non with cases showing follicular hyperplasia or hashitoxicosis (see beneath). It appears that antibiotic positivity may depend on the phase of the affliction. Absenteeism of serum antibodies tin can besides be explained on the basis of local antibody production by intrathyroidal lymphocytes.⁹³

Stripped follicular cell nuclei resemble lymphocyte nuclei in size and shape. All the same, they have more homogenous chromatin and denser nuclear rim and lack the basophilic rim of cytoplasm seen in lymphocytes. Smears in HT prove a polymorphous population of lymphoid cells (including mature and transformed lymphocytes) with lymphoglandular bodies in the backgound.

Lymphoid cells are often seen in smears from PC, particularly the diffuse sclerosing and Warthin-like variants.^95, ⁹⁶ Multiple sampling is important to ensure representative sampling so that neoplastic cells are not missed. Histological sections from thyroids resected for NG oft show focal collections of lymphoid cells or lymphoid follicles. This does non imply a diagnosis of thyroiditis and review of cytologic smears from such cases rarely show lymphoid cells.⁸¹

Some cases of HT may present in a hyperthyroid state with increased T3 and T4 levels (hashitoxicosis).⁸⁷ In these cases, TPO-Ab are oftentimes negative.⁹⁴ Smears are highly cellular with hyperplastic follicular cells showing fire-flares. Lymphoid and Hurthle cells may be few or focal, and stardom from GD is frequently difficult or impossible. Vi monthly follow-up of these cases with cytological monitoring and thyroid function tests have shown the patients becoming euthyroid within a few months to 2 years, with concurrently changing smear pattern to reflect the usual features of HT.⁴² Sensation of the close kinship between various forms of autoimmune thyroid disease (GD, HT and postpartum thyroiditis – described later) facilitates diagnosis and management.

While high-class not-Hodgkin'due south lymphoma is easily identified on cytological preparations, depression-grade and MALT lymphomas are often difficult to distinguish from reactive lymphoid populations seen in thyroiditis. Approximately 75% of lymphomas ascend in a background of HT. Focal involvement tin cause sampling problems. The smear pattern may be of HT in ane function of the gland, that of obvious lymphoma in some other (come across Fig. 6.65). The 'florid lymphocytic' blazon of thyroiditis with scant epithelial cells, common in immature patients, should be viewed with suspicion if found in elderly individuals, and efforts fabricated to rule out lymphoma. Catamenia cytometry and molecular assessment of lymphoid infiltrates in fine needle samples are being increasingly used for the stardom of lymphoma from thyroiditis.⁹⁷

Follicular and Hurthle cells in HT may show atypia significant enough to cause concern to the inexperienced observer (Fig. six.11A). Sometimes, and more often in younger patients with florid lymphocytic thyroiditis, abundant agile-looking epithelium may exist aspirated, leading to a suspicion of neoplasia. While Hurthle cell atypia in a groundwork of lymphoid cells is recognized as part of the diagnostic spectrum of the illness, selective sampling of lesions of focal nodular hyperplasia constituted by atypical Hurthle or follicular cells (seen in early on phase of some cases of HT) with scanty or no lymphoid populations tin be easily mistaken for neoplasia.^42, ⁸⁷ In so-chosen 'burnt-out' HT simply oxyphilic cells may be present in smears.^89, ^98, ⁹⁹ This problem is more than pronounced when such a case has a nodular presentation. Multiple sampling offers the best chance of finding evidence of lymphoid infiltration. Disorganized, poorly cohesive masses of oxyphilic cells with prominent nucleoli are more indicative of neoplasia, sheet-similar structures infiltrated by lymphocytes of hyperplasia.¹⁰⁰ All the same, this distinction is non always obvious. Some authors propose against making a diagnosis of follicular/oxyphilic tumour in the presence of pleomorphism and arable lymphoid cells.^82, ^101, ¹⁰² The possibility of a tumour with surrounding HT should be considered if abundant epithelium and lymphocytes are aspirated.^98, ^101, ¹⁰³ Coexistence of HT with differentiated thyroid carcinoma (four%) or lymphoma (1%)⁴² may have to exist considered, especially in cases with nodular presentation, observed in 22–80% cases in diverse series.^104, ¹⁰⁵

Many 'hypertrophic epithelial cells' with abundant cytoplasm are present in early stages of thyroiditis. These lack the dense cytoplasm and well-defined cytoplasmic borders of Hurthle cells. Some may even have 'burn down flares' and presumably represent TSH-stimulated cells. Epithelioid-like cells with elongated, spindle-shaped cytoplasm and elongated or bean-shaped nuclei may be seen. These may resemble oxyphilic cells and forms morphologically intermediate between these two types occur (Fig. half-dozen.13). Histiocytes or dendritic reticulum cells from germinal centers could be confused with oxyphilic cells, but lack the characteristic cytoplasmic density.

Cases of HT showing behemothic cells and/or epithleioid cells⁹³ may be confused with granulomaotus thyroiditis (GT).⁸¹ The inflammatory infiltrate in GT is not uniformly lymphocytic simply is mixed, with evidence of more severe tissue devastation. The smear pattern is dominated by multinucleated giant cells surrounding extruded colloid and epithelioid cell collections. A few cases have showed overlap in cytological features with HT,¹⁰⁶ and thryoid role tests and antibodies are required to clarify the diagnosis.

Fibrosing variant of HT may be confused with Riedel's struma,⁴² a rare thyroid manifestation of systemic collagenitis occurring in euthyroid heart-aged women. Smears yield paucicellular material containing collagenous fragments, bland or plump spindle cells and myofibroblasts.¹⁰⁷

Psammoma bodies have been described in association with HT¹⁰⁸ and in other beneficial processes. Their presence in smears probably warrants surgical biopsy considering of close association with PC. Clan of HT per se with PC is too reported.¹⁰⁹

de Quervain's thyroiditis (subacute thyroiditis; granulomatous thyroiditis) (Figs 6.xiv-six.17)^42, ^81, ⁸⁷

This is a spontaneously remitting granulomatous inflammation of the thyroid, of possible viral etiology, occurring predominantly in females from the second to the fifth decades. Patients unremarkably nowadays with chills, fever, fatigue and a painful tender goiter that may be unilateral or spread from one lobe to the other.

Smears in GT are dominated by the presence of large multinucleate giant cells with numerous nuclei, granulomatous aggregates of epithelioid cells, degenerating follicular cells, neutrophils, macrophages and lymphocytes in a dirty smear background that shows debris and colloid.

The follicular cells ofttimes show degenerative features and comprise dark-blue (golden in PAP-stained smears) cytoplasmic 'paravacuolar' granules representing lipofuscin or lysosomal debris. These granules are not a specific feature of this condition and may exist seen in involutional follicular cells of NG, in GD and occasionally in PC and FNs.¹¹⁰ Stripped or crushed nuclei may be present. The giant cells are the hallmark of the illness and are characteristically very large, containing up to 200 nuclei (Figs 6.14 and 6.fifteen), but fifty-fifty without them the diagnosis may be suggested if the other features of the disease are present (Fig. 6.16). Hurthle cells may be seen in some cases.

The overlap with cases of HT showing multinucleate giant cells and granulomas has already been discussed. Epithelioid and giant cells may rarely be seen in GD. Giant cells are often seen in PC in association with lymphocytes and therefore PC must be considered in the differential diagnosis.¹¹¹ Rarely, the thyroid may exist the site of mycobacterial infection, sarcoidosis or other infectious granulomatous processes.⁴²

Cases showing Hurthle cells may be dislocated with HT.¹⁰⁶

A small follicle withdrawn intact may simulate a multinucleate giant cell. The spherical nature and singled-out outline of the structure in contrast with the irregular, flat form of truthful histiocytic behemothic cells should prevent confusion (Fig. 6.17A).

Cases with nodular presentation may simulate a lymph node or a tumour. Conversely, carcinomatous involvement of thyroid can mimic GT^112, ¹¹³ or simulate silent thyrotoxic thyroiditis (hyperthyroiditis).

Characteristic cytological features of GT may be absent in the resolving phase of the affliction.

Vigorous palpation of the gland may cause extrusion of follicular colloid, inciting a giant cell reaction. These granulomas are scanty, minute and clinical and functional profiles of GT are absent.¹¹⁴

Silent thyrotoxic thyroiditis (painless thyroiditis, subacute lymphocytic thyroiditis)^88, ^115, ¹¹⁶ normally occurs in women as a sporadic or mail service-partum condition (post-partum thyroiditis), presenting with a minor, diffuse, painless goiter. The disease may go through hyperthyroid, euthyroid, hypothyroid and recovery phases like to GT. Low titers of TPO Ab are transiently present in two-thirds of cases. Smears show scattered lymphoid cells and behemothic cells in occasional cases. Unlike GT, in that location is no hurting or any show of preceding viral infection and granulomas are uncommon. Rare cases have shown cytologic similarity to HT.¹¹⁶

Follicular neoplasms (Figs 6.18-half-dozen.24)^23, ^29, ^68, ¹¹⁷ ^– ¹²⁰

FNs are classified as benign (FA) and malignant (FC). FAs and well-nigh FCs are encapsulated tumors, occurring in one of the lobes. Histological diagnosis of a well-differentiated FC requires sit-in of capsular and/or vascular permeation. Well-nigh FNs, specially adenomas, accept a uniform internal construction that is reflected in the cytological smears. FAs are more common in women and microscopically prove a variety of histological patterns such as microfollicular (fetal), normofollicular, macrofollicular, trabecular, solid (embryonal), Hurthle jail cell and atypical adenomas.⁴² Cytologically, follicular lesions include FA, FC, cellular NG and FV-PC.¹²¹

Smears in FN are cellular in a bloody background that is usually devoid of colloid. Many uniform-sized follicular cell clusters, microfollicles and rosette formations are nowadays. Syncytial aggregates, nuclear crowding and overlapping are also often seen.

The repetitive smear pattern with compatible cell population is in contrast to the variable pattern of different jail cell types seen in colloid and hyperplastic nodules. Microacinar clusters with a key lumen (that may incorporate a drop of colloid) stand for microfollicles (Figs six.18, 6.19 and half-dozen.21B). These are characteristic of FN but may be found focally in NG. Rosette-like groupings without a lumen (Fig. half-dozen.20) suggest a more solid growth pattern. A trabecular pattern is represented by rows and elongated aggregates of epithelial cells that resemble papillary structures when they adhere to strands of vascular stroma (see Fig. 6.33B,C). Small blood vessels with adherent epithelial cells tin exist found in any type of follicular neoplasm (come across Fig. 6.25A).

The stardom between FN and NG is the about common differential diagnostic problem in solitary nodules as cytological appearances overlap (Fig. vi.22). A microfollicular focus in a colloid nodule cytologically resembles a microfollicular tumour, while smears from a macrofollicular (colloid) adenoma resemble a ascendant nodule in multinodular goiter. Jaffar¹²² indicated that the presence of hemosiderin within macrophages and follicular cells excludes FN. The faux-negative rate of cytology in FN may exist 30% or more because of the inability to recognize normofollicular neoplasms.¹²³ All the same, these distinctions are of little clinical importance every bit long as the nodule is recognized as benign and spared from unnecessary surgery.

Near FCs are microfollicular, trabecular or solid, contain little colloid, and will be reported every bit 'FN' by cytology. Although the failure to recognize FC every bit neoplastic has been surprisingly loftier in some series,⁷ other studies show high diagnostic sensitivity, with false-negative rates as depression as 0–two%.^11, ^thirteen, ²⁸

Cytological features in FA and FC are similar, with cellular smears composed of syncytial clusters of crowded cells. There is a tendency for uniform nuclear enlargement in FC, whereas FA may evidence small or big nuclei.¹²⁴ These differences are oftentimes subtle, with much overlapping (Fig. half-dozen.20).^3, ^68, ¹²⁵ Cells from a well-differentiated but clinically aggressive FC may not appear plainly singular or enlarged in smears (Figs 6.23, 6.24B). Anisokaryosis per se is more a feature of non-neoplastic lesions such as NG and thyroiditis.⁴²

Most authors are content to use cytology to select cellular FNs for follow-up or surgical excision, and to get out a diagnosis of malignancy to histological assessment of capsular and vascular invasion. Reporting cytological atypia and any suspicion of malignancy, although non diagnostic, may exist of some use in making the choice betwixt follow-upwardly and immediate surgical excision. The ultimate prognosis of microfollicular, solid or trabecular adenomas is uncertain and these should probably be excised anyway.

FC has been considered the second most common thyroid cancer, accounting for 10–twenty% of all thyroid malignancies.¹²⁶ The proportion of carcinoma in lesions designated equally FN has been reported as ranging from 14% to 44% in previous series.^three, ¹¹⁹ In a large series of operated cases from 1994 to 2002 from Bethesda,¹²⁷ an 18.2% charge per unit of malignancy was found in cases in which a cytological diagnosis of 'possible FN' was given and 20.9% in cases with a definitive cytological categorization of 'FN'.

Clinicians (and cytopathologists) are conventionally preoccupied with the disability of cytologically distinguishing FA from FC, leading to numerous ancillary investigations to assist make this distinction. Figurer assisted cell morphometry, ploidy assay and determination of AgNORs in cytological smears have been tried with variable success.^61, ^128, ¹²⁹ Results of proton magnetic resonance spectroscopy accept been encouraging.¹³⁰ However, the most promising technique for the future is probably immunocytochemical demonstration of molecular markers.¹³¹ Positive immunostaining with CD44v6 or galectin 3 (with a score of G2) in combination with FNA^54, ⁵⁵ have been noted to be useful in cases with indeterminate cytology.⁵⁶ Telomerase activity⁵⁸ and microarray assay of cytologic samples⁵⁹ are other ancillary tests that may aid in distinguishing benign from malignant follicular lesions.

Interestingly, there are studies indicating that FC is gradually becoming a rare entity.^18, ^22, ^24, ^132, ¹³³ Prevalence of malignancy in operated cases of FN¹¹⁸ was 31%, and 9% of these were follicular or Hurthle cell carcinomas. The incidence of FC was only 2% of thyroid cancers in LiVolsi'south series²⁴ and 1% at the University of Chicago Medical Center.²² Discussing the gradual demise of FC, De May²² opined that independent of the quality of any diagnostic examination employed, statistically speaking, its predictive value would exist affected past the prevalence of the disease in question. It stood to reason therefore that, if the prevalence of FC is depression, the predictive value of cytology for FC would also tend to be low, although cytology is otherwise an excellent diagnostic modality.

Atypical adenomas prove foci of extremely pleomorphic cells that cytologically simulate malignancy (Fig. 6.24A). These are designated as carcinoma only if there is capsular or vascular invasion. Nuclear pleomorphism is not a common feature of well-differentiated FC and is non considered a cytological criterion of malignancy. On the other hand, it is frequent in dyshormonogenetic goiter, treated GD, and following chemotherapy and radiotherapy.^42, ⁸⁵

In recent years, FV-PC has attracted much attention. Due to the presence of follicular groupings and colloid in these tumors (see Fig. half-dozen.43), it constitutes a generous proportion of malignancies reported equally FN.^21, ^22, ¹¹⁸ However, a proportion of nuclei brandish typical cytological features of PC (described beneath in section on PC). In some series, loftier cytologic accuracy rates for FV-PC¹³⁴ with 93–94% sensitivity, specificity, positive and negative predictive values have been demonstrated using ultrafast PAP stain.¹³⁵

No cytological criteria conspicuously distinguish parathyroid from follicular thyroid neoplasms.¹³⁶ Agarwal et al.,¹³⁷performing US-guided FNA of 53 parathyroid adenomas, reported low sensitivity as a major limitation. Smears showed moderate cellularity with monomorphous, round to slightly oval cells predominantly bundled in loose two-dimensional clusters with occasional papillary fragments. The majority of them exhibited stippled nuclear chromatin and bare nuclei were seen in the groundwork. There was no pregnant pleomorphism, mitotic activeness, or prominent nucleoli. Parathyroid adenomas are usually not palpable simply radiological examination is capable of locating most non-palpable parathyroid lesions. However, the occasional parathyroid adenoma may be intrathyroidal.¹³⁸ Cytohistological overlap in parathyroid and thyroid follicular lesions can exist a problem at the fourth dimension of frozen department evaluation, and intraoperative parathyroid hormone monitoring may exist required. In parathyroid carcinomas, clinical, biochemical and radiological findings are usually feature. Cytology, combined with clinical, radiological and immunocytochemical findings can enhance diagnostic accuracy.¹³⁹ Tseleni-Balafouta¹⁴⁰ felt that due to overlapping morphological features, in social club to avert surgical mismanagement, the possibility of a parathyroid lesion should be stated conspicuously in cytology reports in all colloid-gratuitous cellular follicular lesions. Parathyroid incidentalomas comprise 0.4% of lesions in patients referred for suspected thyroid nodules, and parathyroid hormone assay in FNA washouts has been found to exist a diagnostic aid.¹⁴¹

FNs are oftentimes highly vascular and aspiration of blood may obscure neoplastic cells. It should be understood that excessively blood-stained smears are not necessarily related to poor technique but may signal the possibility of a tumour. Repeat needling using the fine needle capillary sampling technique with a 26 or 27-gauge needle subsequently a gap of a week or 2 oftentimes yields diagnostic material.

Colloid in small follicles is often very dense and may exist laminated, merely the regular border is unlike that of a psammoma body.