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M. Sakr

Fig. 13.14 CT neck showing right-sided thyroid neoplastic lesion with query invasion of paravertebral muscles

Fig. 13.15 CT neck showing enlarged right upper deep cervical LN (level II)

Limitations

Both CT scan and MRI are relatively expensive and have a limited role in the initial evaluation of thyroid nodules as they have a limited ability in distinguishing benign from malignant lesions. However, they are necessary in some cases to determine the staging and extent of the disease and in planning surgery since CT scan can pro-

Fig. 13.16 CT neck showing enlarged left middle deep cervical LN (level III)

Fig. 13.17 CT neck showing enlarged right middle deep cervical LN (level III) (blue arrow), prelaryngeal (Delphic) LN (level VI) (orange arrow), and goiter (green arrow)

vide structural information about the gland and its relationship to adjacent structures as well as detection of cervical LNs with high sensitivity [179]. Unlike contrast media used with CT scan, contrast media (Gadolinium) used in MRI does not inuence thyroid function.

13.3.8.5 Positron Emission

Tomography (PET)

18F-2-uoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) and PET-CT are nuclear medicine imaging tests that use a small amount of radiolabeled glucose to identify can-

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13 Malignant Thyroid Disease

Fig. 13.18 CT neck showing bilateral enlarged middle deep cervical LN (level III) (arrows)

cer. Since cancer cells are more metabolically active than normal cells, the cancer cells take up more of the radiolabeled glucose than normal cells and show up on the FDG-PET scan. FDGPET scans are frequently combined with computerized tomography (CT) scans (PET-CT) to accurately identify where in the body a cancer is located.

A recent meta-analysis conrmed that approximately one-third 18FDG-PET positive thyroid nodules proved to be cancerous [180], with higher mean maximum standardized uptake value in malignant compared to benign nodules (6.9 vs. 4.8, P<0.001).

13.3.8.6 Fine-Needle Aspiration

Cytology (FNAC)

In malignant conditions of LNs, US- or CT-guided FNA enjoys a high sensitivity and specicity, the average being 95% [181–187]. It virtually has eliminated the need for open biopsy of metastatic cervical lymphadenopathy and the sequela of violating tissue planes prior to denite treatment [185, 186]. In addition, FNA is quite helpful in differentiating metastatic squamous cell adenopathy from metastatic thyroid malignancy and even from enlarged LNs secondary to lympho- proliferative and reactive adenopathy [187]. The high sensitivity of FNA for PTC is strongly correlated with tumor size.

357

Tumors smaller than 0.5 cm and those larger than 3cm may be more difcult to successfully aspirate on FNA [188].

Ultrasound (US)-Guided FNA

The use of US-guided FNA can improve the diagnostic accuracy and should be considered whenever confronted with a patient whose thyroid nodule is difcult to palpate on physical examination or in whom the initial FNAB was nondiagnostic [189]. Still however, interpretation of the aspirate for denitive diagnosis may still not be possible.

A study by Yuan etal. on 78 patients, however, indicated that the patterns of enhancement differ signicantly between benign and malignant solitary thyroid nodules (STNs) examined with realtime, “contrast-enhanced” US, with most malignant lesions showing irregular shape, unclear boundary, and nonhomogeneous and incomplete enhancement [190]. In addition, the combination of the newer US techniques with “molecular markers” now available for FNAB may be able to accurately distinguish malignant from benign thyroid nodules.

To date, FNAB remains unpopular in “children” because of their smaller neck sizes, the need for heavier amounts of anesthesia and sedation, and the amount of specimen needed. Furthermore, because the higher rates of malignancy in children, denitive pathological diagnosis is much more in demand. Despite of the difculties associated with FNAB, in a series involving 41 children, Al-Shaikh et al. reported 100% sensitivity, 86% specicity, and a 59% decrease in surgery rates [191].

Cytology Categories ofFNAC (Bethesda System)

The recently issued Bethesda System for Reporting Thyroid Cytopathology (BSRTC) [192], based on an NCI-sponsored conference (2007), is currently considered to be the most suitable for communicating ndings from thyroid smears. The cytodiagnostic categories of Besthesda Classication [192], with the corresponding estimated risk of malignancy, are listed in Table13.8.

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Table 13.8 The Bethesda system for reporting thyroid cytopathology recommended diagnostic categories [192]

Risk of

Category Description I Non-diagnostic or

unsatisfactory: Cyst uid only—Virtually acellular specimen, other (obscuring blood, clotting artifact)

II Benign: Consistent with a benign

follicular nodule, Hashimoto’s thyroiditis or granulomatous thyroiditis

III Atypia of undetermined

signicance (AUS) or follicular lesion of undetermined signicance (FLUS)

IV Follicular neoplasm (FN) or

suspicious for a follicular neoplasm (SFN)

V Suspicious for malignancy

(SUSP)

VI Malignant 97–99%

cancer 1–4%

0–3%

5–15%

15–30%

60–75%

13.3.9 Surgery forPTC

13.3.9.1 Elective Surgical Treatment

Management ofthePrimary Tumor (Thyroid Surgery)

The terms “subtotal lobectomy” and “subtotal thyroidectomy” are imprecise and should be avoided. They are inappropriate for the treatment of thyroid cancer. The following terms should be used (Table13.9).

The RLNs should be identied and preserved in virtually all instances. Permanent damage to a RLN should occur in <5% of thyroid cancer but are higher after re-operative surgery [108]. Inltration by cancer contributes to RLN palsy rates [193]. Attempts should also be made to preserve the ELN by ligation of the STA at the capsule of the gland. Injury rates may be higher than for RLN damage [194]. The parathyroid glands (PTGs) should whenever possible be identied and preserved. If their vascular supply is compromised, the gland/s should be excised and re- implanted into muscle [195, 196]. LN dissection (level VI) results in increased risk of postoperative hypoparathyroidism [197].

Table 13.9 Terms used in thyroid surgery

Term Description Lobectomy Complete removal of one thyroid

lobe including the isthmus

Near-total lobectomy

Near-total thyroidectomy

Total thyroidectomy

Table 13.10 Levels of lymph nodes in thyroid surgery

Lateral compartment of neck

Level I Submental (Ia) and submandibular

Level II Deep cervical chain skull base to

Level III Deep cervical chain level of hyoid

Level IV Deep chain from cricoid to

Level V Posterior triangle nodes, divided by

Central compartment of neck

Level VI Pretracheal and paratracheal nodes

Mediastinal nodes

Level VII Superior mediastinal nodes superior

Compartment 4

LNs between the brachio-cephalic vein and tracheal bifurcation within the anterior mediastinum

Total lobectomy leaving behind only the smallest amount of thyroid tissue (signicantly <1g) to protect the RLNs

Complete removal of one thyroid lobe (lobectomy) with a near-total lobectomy on the contralateral side or a bilateral near-total procedure

Removal of both lobes, isthmus, and pyramidal lobe

nodes (Ib)

hyoid. Divided spinal accessory nerve to IIa (medial) and IIb (lateral)

to level of cricoid

supra-sternal notch

omohyoid muscle into Va (above) and Vb (below)

from hyoid to sternal notch, and to the carotid arteries laterally

aspect to brachiocephalic vein

Management oftheNodal Spread

The levels of LNs in the thyroid surgery are listed in Table13.10, and types of neck dissections are summarized in Table13.11.

Differences exist regarding the procedure of choice for addressing the neck in PTC, from (1) a prophylactic ND in a clinically negative neck [147, 198, 199], to (2) expectant management with resection limited to palpable LN metastases that is selective removal or berry picking [200,

201] based on the view that nodal disease is clini-

cally insignicant and unlikely to inuence sur-

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13 Malignant Thyroid Disease

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Table 13.11 Types of neck dissection (ND)

Type Description Selective

neck dissection

Radical neck dissection (RND)

Modied RND (MRND)

Extended neck dissection

Cervical lymphadenectomy of less than levels I–V.The spinal accessory nerve (SAN), internal jugular vein (IJV) and sternocleidomastoid muscle (SCM) are preserved

A classical RND removes all the lymphatic tissue in levels I–V plus SAN, SCM, and IJV

Removal of LNs I–V+preservation of one or more non-lymphatic structures as follows:

1. MRND type I: Preservation of the SAN

2. MRND type II: Preservation of the SAN and IJV

3. MRND type III (functional): Preservation of the SAN, IJV and SCM

Removal of one or more additional LN groups for example Para-pharyngeal, and superior mediastinal nodes and/or non-lymphatic structures

vival [202], or (3) a formal comprehensive dissection of all lateral LNs (MRND) [203–205] in a clinically positive neck, based on the consensus of the high frequency of occult nodal disease with reduced recurrence-free survival.

Surgical Decision forTreatment ofPTC

Patients with a node-negative cancer of <1 cm (pT1) can be adequately treated by lobectomy [39, 40]. For tumors >1cm, multifocal disease, extra-thyroidal spread, familial disease, clinically involved nodes, and children with history of previous neck irradiation, TT is indicated [206].

If the diagnosis of thyroid cancer is made after thyroid lobectomy and completion (contralateral) lobectomy is required, it should be offered within 8weeks of histological diagnosis of cancer.

In patients with no clinical LNs, but who are high risk (male, >45years, tumors >4cm, extracapsular, or extra-thyroidal disease), TT and central node dissection should be considered [108].

Palpable disease in level VI nodes discovered at surgery is treated by a level VI node dissection. When suspicious/clinically involved nodes are apparent preoperatively or are encountered

at surgery in the lateral neck, and conrmed by needle biopsy or frozen-section, then a selective neck dissection (levels IIa–Vb) is recommended, preserving the SAN, SCM, and IJV [207].

Surgery forPapillary (or Follicular) Micro-carcinoma

Patients with WDTCs <1cm have an extremely low risk of death from thyroid cancer (0.1%) [68] and hence can be treated adequately by thyroid lobectomy provided that the tumor does not extend beyond the thyroid capsule, and there is no evidence of metastases, vascular invasion, multifocality, or contralateral disease. Otherwise, completion of thyroidectomy and RAI is necessary. Future treatment involves TSH suppression with thyroxin and measurement of the serum Tg.

13.3.9.2 Emergency Surgery

It is rare for emergency surgery to be needed in PTC. However, acute presentation of a patient with thyroid cancer and severe airway compromise requires urgent/immediate surgery.

13.3.9.3 Surgery forLocally Advanced Disease

When preoperative vocal cord (VC) examination shows no sign of RLN palsy, every attempt should be made to dissect the tumor from the nerve/s. In patients with unilateral nerve involvement and extensive extra-thyroidal disease, the nerve may have to be sacriced to achieve a curative procedure. It may not be possible to remove the entire tumor without damaging both RLNs. A small residue of tumor may be left behind to protect the nerve/s and be subsequently dealt with by

131

I ablation and -thyroxin with or without

EBRT [193].

In individual patients with locally advanced disease involving the upper aerodigestive tract and/or one or both RLNs, curative excisional surgery of the tracheal wall and/or esophagus should be considered. When radical curative surgery is not possible or agreed to by the patient, treatment with radical radiotherapy

131

I should be

considered.

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13.3.10 Prognostic Indicators

In general, survival for patients with PTC is believed to be relatively good, especially when compared with that of patients with other thyroid and non-thyroid malignancies. However, not all patients with PTC fare well, and one of the major challenges is to identify patients with poor prognosis to offer more aggressive and efcacious treatment [68].

13.3.10.1 Factors Aecting Prognosis andSurvival

– Age: Nearly all the deaths from PTCs occur

when the tumor manifests itself after the age of 40years.

– Gender: Women are said to have a better prog-

nosis than men, although in some series the difference was not signicant.

– Extra-thyroidal extension: This feature

adversely affects the prognosis in a very signicant manner and has have been incorporated into the staging system of thyroid carcinoma.

– Microscopic variant: Among the different

variants of PTC, the diffuse sclerosing, tall/ columnar cell, and diffuse follicular variants have the worst prognosis.

– Poorly differentiated, squamous or anaplastic

foci: These features have a markedly detrimental effect on prognosis. Fortunately, they are present in <5% of cases.

– History of previous irradiation: Contrary to

previous statements, the prognosis of tumors in which this antecedent is present does not seem to differ signicantly from the others.

– Tumor size: A rough inverse correlation is

present between tumor size and prognosis.

– Capsule and margins: Tumors that are encap-

sulated and/or have pushing margins have a better outcome than the others.

– Multicentricity: Patients in whom this is a

prominent feature have a greater incidence of metastasis and a lesser chance of disease-free survival.

– Distant metastases: Prognosis is adversely

affected by metastases to the lungs and is

more inuenced by metastases to other sites, such as the skeletal system.

– Grading: This parameter bears a denite rela-

tionship with prognosis that has been underestimated. However, it needs to be clearly dened in terms of criteria (necrosis, mitotic activity, etc.) and properly standardized for it to reach its full potential.

– Circulating tumor cells: The presence of cir-

culating tumor cells (as determined with an RT-PCR assay for thyroglobulin (Tg) mRNA) seems to be associated with a higher likelihood of metastatic disease but may not play a practical role in clinical management.

13.3.10.2 Prognostic Scales/Scores

– AGES Scale: This is a postoperative prognos-

tic scale originated in Mayo clinic. It is an acronym standing for Age, pathologic tumor Grade, Extent of disease, and Size of tumor [208].

– MACIS Scale: This more sophisticated post-

operative scale is a modication of the AGES system. Factors assessed are distant Metastases, Age at presentation (<40 or>40years), Completeness of original surgi- cal resection, extra-thyroidal Invasion, and Size of original lesion (in cm) [208].

– AMES Score: Cady and Rossi described a

prognostic scoring system, originating in Lahey clinic, based on Age, Metastases, Extent, and Size of tumor. Stage for stage and risk of death are mostly related to age and gender [209–211]. Age limits were dened as older than 40 years in men but older than 50years in women. Patients <45years of age without distant metastases usually are considered to be at low risk [208]. Distant metastasis at the time of diagnosis was the greatest predictor of survival [212]. The extent of tumor indicated extra-capsular tumor invasion, and size limits were greater than 5cm.

– The most signicant single prognostic indica-

tor overall is distant metastases, especially to bone. Local invasion of the primary tumor through the thyroid capsule into the adjacent

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13 Malignant Thyroid Disease

Table 13.12 Stratication of patients and differentiated thyroid tumors

Risk Description Low-risk

patients High-risk

patients

Low-risk tumors

High-risk tumors

Females under the age of 45years

All males and females over 45years (patients under 16years should be regarded as high-risk and are usually best treated aggressively)

PTC <1cm in size and minimally invasive FTC <1cm in size

PTC and FTC >1cm in size, any tumor associated with signicant multifocality, local, or distant spread

361

Fig. 13.19 FTC consisting of fairly uniform cells forming small follicles containing colloid

Table 13.13 The 5-year survival of PTC according to stage

Stage 5-Year survival rate I Near 100% II Near 100% III 93% IV 51%

structures increases the mortality ten-fold over matched patients with intra-thyroidal tumors [213].

From these different systems, patients as well as differentiated thyroid tumors are nally stratied into low-risk and high-risk patients and tumors as shown in Table13.12. The 5-year survival rate (SR) of PTC according to stageof diseae is listed in Table13.13.

13.4 Follicular Thyroid Cancer

(FTC)

Follicular thyroid carcinomas (FTCs) account for 5–15% of primary thyroid cancers but constitute 25–40% in areas with dietary I2 deciency.

13.4.1 Gross Features

Follicular carcinomas appear as single nodules that may be well-circumscribed or widely inltrative. Sharply demarcated lesions may be exceedingly difcult to distinguish from follicular adenomas by gross examination. Larger

lesions may penetrate the capsule and inltrate well beyond the thyroid capsule into the adjacent neck structures. They are gray to tan pink on cut section and may be somewhat translucent due to the presence of large, colloid-lled follicles. Degenerative changes such as center brosis and foci of calcication are sometimes present.

13.4.2 Microscopic Appearance

Microscopically, most FTCs composed of fairly uniform cells forming small follicles containing colloid (Fig.13.19). In other cases, follicular differentiation may be less apparent, and there may be nests or sheets of cells without colloid. Occasional tumors are dominated by cells with abundant granular, eosinophilic cytoplasm (Hurthle cell or oncocytic variant of FTC). Whatever the pattern, the nuclei lack the features typical of PTC, and psammoma bodies are not present.

While nuclear features (optically clear nuclei, nuclear grooves) are helpful in distinguishing papillary from follicular neoplasms, there are no reliable cytological difference between follicular adenomas and minimally invasive follicular carcinomas. Making this distinction requires extensive histological sampling of tumor–capsule– thyroid interface to exclude capsular and/or vascular invasion [214]. The criterion for vascular invasion applies solely and strictly to “veins” in or beyond the capsule; the presence of tumor

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362

plugs within intra-tumoral blood vessels has little prognostic signicance, whereas the denition of capsular invasion is controversial [214,

215]. Some authors require penetration of the

capsule to diagnose a follicular carcinoma, while others need tumor invasion through the capsule into the surrounding normal thyroid [215, 216].

Distant metastases have been reported in follicular carcinoma diagnosed only on the basis of capsular and not vascular invasion; however, in some cases, metastases were already present at initial diagnosis [217]. Unlike in papillary cancers, lymphatic spread is uncommon in follicular cancers.

In contrast to minimally invasive follicular carcinoma, the diagnosis of carcinoma is obvious in widely invasive follicular carcinomas, which inltrate the thyroid parenchyma and extrathyroidal soft tissue. Histologically, these cancers tend to have a greater proportion of solid or trabecular growth pattern, less evidence of follicular differentiation, and increased mitotic activity. Up to 80% of patients with widely invasive follicular cancer can develop metastases with a mortality rate of approximately 50%.

13.4.3 Clinical Aspects

Follicular thyroid carcinomas (FTCs) are more common in women (3:1) and occur more in older patients than do PTCs; with the peak incidence between 40 and 60years of age [218]. Symptoms suggesting carcinoma include hoarseness of voice, rapid growth of a thyroid nodule, dysphagia, hemoptysis, or pain in the neck. Uncommon presentations include cervical lymphadenopathy, symptomatic bone pain from metastatic disease to the spine, pelvis or ribs, asymptomatic lung metastases found radiographically, and focal neurological abnormalities from distant spread to the brain.

Physical examination may reveal a hard, irregular, solitary, xed thyroid mass causing local compressive symptoms with or without associated cervical lymphadenopathy (Fig. 13.20). Direct laryngoscopy should be performed to detect a vocal cord paresis or, rarely, tracheal

M. Sakr

Fig. 13.20 A 41-year-old lady with a large, hard, irregular thyroid mass that proved by histology to be a follicular carcinoma. Note the dilated veins over the sternum

invasion when present. A thyroid mass with an associated ipsilateral vocal cord paresis contains carcinoma until proven otherwise.

Multicentricity and LN involvement are less frequent (10–20%) in FTC than in PTC [219], and metastasis to the lungs and bones results from a tendency of these tumors to spread by hematogenous pathways instead of lymphatic channels.

13.4.4 Surgical Decision

forTreatment ofFollicular Carcinoma

At present, FNAC cannot distinguish follicular adenoma or benign hyperplastic nodules from carcinoma [220]. Thy three cytology usually mandates lobectomy as the least surgical procedure. Frozen-section is unhelpful when the FNAC diagnosis is that of a follicular lesion (Thy3). If denitive histology reveals a follicular adenoma (Fig.13.21) or a hyperplastic nodule, no further teratment is required.

A “FTC”<1 cm with minimal capsular invasion should be treated by lobectomy [221].

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13 Malignant Thyroid Disease

Table 13.14 The 5-year survival according to stage

5-year survival

Stage Description I Intra-thyroidal disease Near 100% II With cervical LN

metastases

III With extra-thyroidal

extension

IV With distant metastases 50%

rate

Near 100%

71%

13.5 Hurthle Cell (Oncocytic)

Tumors

363

Fig. 13.21 Follicular adenoma with regular cells and no capsular or vascular invasion

Patients with FTC showing evidence of vascular invasion should be treated with TT and those with FTC >4cm should be treated with TT.Lowrisk patients (women, patients <45 years with tumors <2 cm) may be treated by lobectomy alone and -thyroxin [222].

Clear recommendations for otherwise lowrisk patients with tumors 2–4cm showing minimal capsular invasion only cannot be made [205].

Palpable/suspicious cervical LNs are dealt with in a similar manner to PCT.If the diagnosis of thyroid cancer has been made after thyroid lobectomy and completion, (contra-lateral) thyroid lobectomy is required; the latter should be offered within 8weeks of histological diagnosis of cancer.

13.4.5 Prognostic Factors

The outcome of patients with FTC is generally worse than that of PTC and is directly related to the stage of disease at the time of diagnosis. Patients are divided into four clinical stages based on the extent of disease at presentation as shown in Table13.14.

Independent prognostic factors that inuence survival in follicular carcinoma include (1) age > 45 years, (2) extra-thyroidal extension (capsular invasion and angioinvasion), (3) distant metastases, (4) lymph node involvement, (5) tumor size >4cm, and (6) an aneuploid DNA pattern [223].

13.5.1 Introduction

Hürthle cell neoplasms (HCNs) are an uncommon group of thyroid epithelial tumors that generate much controversy and have additional names in the literature such as Ashkenazy cell or Langhans tumors. There is ongoing disagreement, regarding the cell of origin of these neoplasms; follicular versus para-follicular. Furthermore, some surgeons consider all Hürthle cell neoplasms to be potentially malignant and therefore warrant aggressive surgical therapy [224], while others believe that certain histopathological features can predict the biological behavior of HCNs and consequently can identify patients for whom a more conservative treatment is appropriate [225].

There is an increased incidence of malignancy with increasing age, prior exposure to radiation, and concomitant PTC or FTC at a site different from the index nodule [224, 226]. Once a Hürthle cell neoplasm is proven to be malignant, surgery is the only effective therapy.

13.5.2 Clinical Presentation

The incidence of Hurthle cell neoplasm (HCN) varies between 3 and 10% in all thyroid nodules [224–230]., of which 10–35% is Hürthle cell carcinoma (HCC) [225, 227]. At the time of diagnosis of Hürthle cell carcinoma, approximately 75% are conned to the thyroid gland, 15% have distant metastases, and 10% have LN metastases [224, 226].

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M. Sakr

The clinical presentation of HCNs is similar

13.5.3 Pathology

to that of follicular neoplasms, appearing mostly as a solitary, nonfunctioning nodule. The presence of symptoms should raise the suspicion of carcinoma, which may be aggressive in nature, grow rapidly, and cause compressive symptoms (Fig. 13.22). However, about 30% of patients with HCNs will have an additional benign thyroid disease such as Graves’ disease, MNG, or Hashimoto’s thyroiditis (HT); and accordingly, may present with symptoms of hyperthyroidism.

13.5.3.1 Adenoma or Carcinoma?

HCNs have been classied into Hurthle cell adenoma (HCA) and Hurthle cell carcinoma (HCC) [231]. In the absence of metastasis, a controversy arises regarding the nature of HCN as whether it is benign or malignant since cytological criteria diagnostic of malignancy on FNA, like cellular atypia and architectural distortion, may be found in benign HCNs [232]. In this context, FNAB usually reports “BHCL/HCN” [233].

Hürthle cell neoplasms generally present later in life than papillary and follicular tumors, most commonly appearing in the sixth decade of life and are more common in females, though malignant lesions are more common in men [224].

characterized by large polygonal cells, distinct cell borders, and voluminous granular cytoplasm because of huge number of mitochondria lling the cell,in addition to a large nucleus and prominent nucleolus (Fig.13.23) [234]. However, these

Hurthle cell neoplasms of the thyroid gland is

Fig. 13.22 A 53-old-gentleman with a huge thyroid gland, more on the right side, and retro-sternal extension. Biopsy proved to be a Hurthle cell carcinoma (a). Lateral view of the same patient. Note the huge size and dilated veins (b)

Fig. 13.23 Hürthle cells arranged in loosely cohesive clusters and single cells. The cells are polyhedral and have abundant granular cytoplasm with well-dened cell borders. Nuclei are enlarged and have a central prominent macro-nucleolus

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13 Malignant Thyroid Disease

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features can also be found in nodular goiter, foci of nonspecic chronic thyroiditis, long-standing hyperthyroidism, and HT [235].

Thus, the mere presence of Hürthle cells does not necessarily signify a neoplastic process. The presence of a capsule surrounding Hürthle cells, on the other hand, is the dening characteristic of Hürthle cell neoplasms, which contain at least a 75% Hürthle cell component.

Hurthle cell tumors are generally believed to be a variant of follicular neoplasms [226]. However, other authors believe that they represent a distinct entity, citing the unique oncogenic expression and the relative inability of Hürthle cells to absorb radioiodine [225].

13.5.3.2 Cytological/Histopathological

Features

Diagnosis of a HCN by FNA can typically be classied as a follicular lesion of undetermined signicance (FLUS) or atypia of undetermined signicance (AUS) with Hürthle cell features (AUS/FLUS/Hürthle cell lesion of undetermined signicance [HLUS], Bethesda III). Both benign and malignant oncocytic lesions can demonstrate marked cytological atypia, complicating the process of diagnosis on biopsy alone. Overall, the projected risk of malignancy for this diagnostic category is 5–15%. A cytological diagnosis of suspicious for HCN (Bethesda IV) carries a projected 15–30% risk of malignancy [236].

The diagnostic category “AUS” should be reserved for thyroid FNAs containing cells with architectural and/or nuclear atypia that is not sufcient to classify as suspicious for neoplasm, suspicious for malignancy, or malignancy; however, atypia is more marked than can be designated as benign [237, 238]. Thus, AUS is a heterogeneous category with different cytological scenarios. It is suggested to use the AUS category if there is a predominance of Hurthle cells in a sparsely cellular FNA with scant colloid or when there is a moderately or markedly cellular sample composed of a virtually exclusive population of Hurthle cells yet the clinical setting suggests a benign Hurthle cell nodule, especially

lymphocytic thyroiditis and multinodular goiter [239].

Unfortunately, intra-operative frozen-section examination was consistently reported to be unhelpful in discriminating benign from malignant HCNs [240–243]. Thus, the sole distinction is based on the presence or absence of capsular invasion (CI) and vascular invasion (VI), which can only be reliably identied in parafn-section. Therefore, in patients with FNAC demonstrating an HCN, diagnostic surgical excision should be performed if molecular testing is not done or if it is inconclusive [244].

Given the aggressive behavior of histologically proven malignant HCN reported by some investigators, such indeterminate ndings impose a challenging situation in which clinicians tend to follow a more aggressive surgical approach. However, the incidence of malignancy among nodules, cytologically suspicious HCN, was found, by histopathology, to range from 5% to 35% only [241, 245]. Thus, a considerable proportion of these patients are unnecessarily exposed to the risk of surgical complications.

13.5.3.3 Stratication ofHurthle Cell

Carcinoma Risk

Hurthle cell carcinoma (HCC) is currently designated by the World Health Organization (WHO) as a histopathological variant of FTC, and this is echoed in the American Thyroid Association (ATA) and National Comprehensive Cancer Network (NCCN) treatment guidelines, with HCC following the same risk stratication as that of follicular carcinoma. For the ATA, intrathyroidal encapsulated tumors with minor capsular or vascular invasion (<4foci) or≤5 metastatic LNs where the foci of metastases are <0.2cm are considered to be “low risk.” The “intermediate risk” is dened by vascular invasion, minimal extra-thyroidal extension (ETE), or>5 metastatic LNs (0.2–3 cm). “High-risk” patients include those with macroscopic ETE, incomplete tumor resection, distant metastases, or metastatic LNs >3cm [246].

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