Tumors of the Thyroid and Parathyroid Glands

Cytologic Features.

The nuclei of papillary carcinoma are typically large, crowded, ovoid, ground glass–like (“Orphan Annie” eye) and grooved, with small distinct nucleoli. The cellular crowding results in an up-and-down placement of the nuclei ( Fig. 18A.8 ). Sometimes the nuclei may assume a crescent shape (see Fig. 18A.8A ).

Ground-glass change refers to the empty-looking nuclei with scanty, marginated dusty chromatin (see Fig. 18A.8B ), believed to be an artifact of formalin fixation because it is usually not evident in frozen sections or cytologic preparations. While this feature is observed in paraffin sections in more than 80% of papillary carcinomas, it is not pathognomonic because benign lesions such as nodular hyperplasia, follicular adenoma, Graves disease, and Hashimoto thyroiditis can exhibit clear nuclei focally.

Another characteristic feature is the nuclear groove formed by deep folding of the nuclear membrane (see Fig. 18A.8B ), observed in almost all cases of papillary carcinoma, at least focally. The grooved nuclei can be well appreciated in cytologic preparations. However, nuclear grooving can also be observed in solid cell nests, some follicular neoplasms (especially Hurthle cell type), hyalinizing trabecular adenomas, poorly differentiated thyroid carcinomas, and adenocarcinomas of nonthyroid origin.

Nuclear pseudoinclusions, which represent intranuclear herniation of pockets of cytoplasm, appear as pale-staining membrane-delineated vacuoles. They are typical but not pathognomonic of papillary carcinoma and are usually found in only a minority of the tumor cells (see Fig. 18A.8A ).

In some papillary carcinomas, the nuclear features as described here are not well developed or occur only focally. The nuclei may not be ground glass but are simply pale or show evenly distributed fine chromatin. Occasionally, the nuclei may even exhibit coarse chromatin and considerable pleomorphism. In such cases, the diagnosis of papillary carcinoma would have to rest more on the architectural features and presence of more diagnostic nuclear features in other areas.

Mitotic figures are generally absent or sparse, but they can be more easily found in some highly invasive tumors or recurrences.

The neoplastic cells are polygonal to cuboidal but can be attenuated, dome-shaped, hobnailed, or columnar. The cytoplasm is lightly eosinophilic to amphophilic but can be oncocytic or clear (see Fig. 18A.8 ). Cytoplasmic mucin can sometimes be demonstrated ( Fig. 18A.9 ). Squamous differentiation occurs in approximately half of the cases and is accompanied by loss of the typical nuclear features of papillary carcinoma ( Fig. 18A.10 ).

Architectural Features.

Papillary carcinomas are usually infiltrative ( Fig. 18A.11 ), but some may be circumscribed or encapsulated. Some tumors can exhibit cystic change, a feature which is particularly common in the metastatic deposits in lymph nodes (see Fig. 18A.3 ). Lymphatic permeation is not uncommon.

The papillae usually are arborizing ( Fig. 18A.12 ), with delicate fibrovascular cores. However, the papillae can be broad, with the cores being formed by fibrocellular, edematous, or hyalinized tissue, which may contain foamy macrophages, adipose cells, or small neoplastic follicles (see Fig. 18A.12B ). Sometimes micropapillae comprising cellular tufts are formed (see Fig. 18A.9 ).

Follicles are frequently present. They vary in size and contour but are commonly elongated or irregular shaped and contain dark-staining colloid ( Fig. 18A.13 ). Some follicles can be distended with colloid. Intrafollicular hemorrhage is common. Very often there is an intricate blending of the follicles with papillae, resulting in a complex tubulopapillary pattern (see Fig. 18A.13B ). Less common patterns include microglandular, garland-like, cribriform, anastomosing tubular, trabecular, and solid ( Fig. 18A.14 ).

Stroma.

Papillary carcinoma is frequently accompanied by an abundant sclerotic stroma, which may show calcification or ossification (see Fig. 18A.11 ). Cellular desmoplastic stroma can be present at the invasive fronts. There is commonly a patchy infiltrate of lymphocytes, plasma cells, and macrophages.

Multinucleated histiocytes, often with dark-staining cytoplasm, are present in the luminal space of some follicles and papillae in 46% of cases (see Fig. 18A.8B ). They can be of diagnostic value because they are rare in benign lesions and other tumor types.

Psammoma bodies, which are laminated calcified structures, are found in approximately half of the cases. They occur in the stalks of the papillae, fibrous stroma, or among the tumor cells (see Fig. 18A.12A ). In the thyroid, they are practically pathognomonic of papillary carcinoma. Whenever psammoma bodies are identified, a diligent search must be made for papillary carcinoma. Calcified colloid materials, which are fairly common in Hurthle cell neoplasms and hyalinizing trabecular adenoma, are distinguishable from psammoma bodies by their exclusive location in the follicular lumens.

Follicular Variant.

This variant is composed entirely of follicles. The follicles vary in size and shape but are often elongated or irregular shaped, with abortive papillary formation, and the colloid is usually deep staining and scalloped ( Fig. 18A.15 ). Psammoma bodies and sclerosis may be present. The diagnosis rests on identification of the typical nuclear features of papillary carcinoma.

This variant has evoked intense controversies, in particular the highly variable threshold in histologic diagnosis, the low interobserver reproducibility in diagnosis, and its biologic nature. However, it is now clear that follicular variant of papillary carcinoma encompasses two entities: infiltrative type and encapsulated type ( Table 18A.5 ).

The infiltrative type shows obvious infiltration of the thyroid parenchyma, often accompanied by sclerosis, similar to conventional papillary carcinoma, except that papillae are absent. For this type, there should be no difficulty in recognizing its malignant nature, and the interobserver reproducibility in diagnosis is high. The clinicopathologic and biologic features are no different from classic papillary carcinoma (see Table 18A.5 and Fig. 18A.15 ).

The clinical features (low frequency of lymph node metastasis and lack of adverse events in the absence of invasion), pathologic features (encapsulated solitary tumor and infrequent intratumoral sclerosis), and molecular features (presence of RAS mutation or PAX8/PPARγ translocation, but not BRAF mutation or RET/PTC translocation) of the encapsulated type are much more akin to follicular adenoma/carcinoma ( Table 18A.6 ; also see Table 18A.5 ). In the 2017 WHO classification, the designation invasive encapsulated follicular variant of papillary carcinoma is reserved for cases that exhibit capsular or vascular invasion (see Fig. 18A.15C and D ), while cases lacking invasion are categorized as noninvasive follicular thyroid neoplasm with papillary-like nuclear features or NIFTP .

Encapsulated Variant.

This variant constitutes 4% to 14% of all papillary carcinomas. The fibrous capsule may or may not show invasion by tumor ( Fig. 18A.16 ), but lymph node metastasis can occur even in the absence of capsular or vascular invasion. The patients tend to be younger, compression symptoms are most uncommon, and the frequency of lymph node metastasis (12%–38%) is lower compared with conventional papillary carcinoma. The prognosis is excellent, with all patients remaining disease free after treatment. According to one series comparing encapsulated classic papillary carcinoma (comprising papillae or a mixture of papillae and follicles) with encapsulated follicular variant of papillary carcinoma, the former is more likely to show capsular invasion (65% vs 38%), less likely to show vascular invasion (5% vs 25%), and more likely to show lymph node metastasis (26% vs 3%). The findings indicate that the encapsulated follicular variant of papillary carcinoma behaves more like follicular adenoma or carcinoma; cases lacking invasion are recategorized as NIFTP in the 2017 WHO classification.

Solid Variant.

This variant is defined by presence of more than 50% to 70% areas exhibiting solid, packeted or trabecular growth. The tumor is often traversed by delicate capillaries, and the nuclear features of conventional papillary carcinoma are retained ( Fig. 18A.17 ). There should not be tumor necrosis. This variant occurs with a disproportionate frequency among nuclear accident-associated papillary thyroid carcinomas. The tumor is often large and shows extrathyroidal extension. It is associated with a higher frequency of pulmonary metastasis and less favorable prognosis compared with conventional papillary carcinoma. It is most important not to mistake this variant for poorly differentiated thyroid carcinoma (in which nuclei are more hyperchromatic and mitotic figures more readily identified).

Diffuse Sclerosing Variant.

This variant mostly affects children and young adults, who present with unilateral or bilateral symmetric thyroid swelling. Tests for serum antithyroglobulin or antimicrosomal antibodies may be positive, increasing the mimicry of thyroiditis. Most studies have shown this variant to be biologically more aggressive than conventional papillary carcinoma, as manifest by a higher incidence of extrathyroidal extension, lymph node metastasis (nearly 100%), and frequent distant metastasis. There is a high recurrence rate. Most studies report a low mortality rate, presumably related to the favorable impact of young age, but some have reported a worse 5-year survival (87.5%) compared with conventional papillary carcinoma.

The thyroid shows diffuse replacement of the parenchyma by white firm tissue, which is often gritty on cutting. The typical histologic features include :

• 1.

  Diffuse involvement of one or both lobes ( Fig. 18A.18A )

  

• 2.

  Sclerosis

• 3.

  Heavy lymphoplasmacytic infiltrate

• 4.

  Abundant psammoma bodies

• 5.

  Scattered small islands of papillary carcinoma with prominent squamous or squamoid differentiation (see Fig. 18A.18B ), although a discrete tumor can sometimes be found in addition

• 6.

  Extensive lymphatic permeation

On casual examination, the histologic picture may mimic that of thyroiditis, but the psammoma bodies should provide a strong clue to the diagnosis of papillary carcinoma. Loss of the characteristic nuclear features of papillary carcinoma in the areas of squamous differentiation further increases the difficulties in diagnosis.

Diffuse Follicular Variant.

This is a rare aggressive form of papillary carcinoma occurring in young patients (mean age 21.3 years), characterized by diffuse involvement of the entire thyroid without formation of discernible nodules, exclusive or predominant follicular pattern, and absence of fibrosis. Since the follicles are often large or even cystic, distinction from colloid-adenomatous goiter may be difficult ( Fig. 18A.19 ). Careful attention to nuclear details, in particular in the smaller follicles, and clinical features (such as evidence of metastatic disease) is required for making the diagnosis. The diffuse follicular variant shows a high frequency of lymph node (87.5%), pulmonary (75%), and bone (25%) metastasis. However, the outcome is still favorable because of the excellent response to radioactive iodine therapy and the favorable impact of young age.

Tall Cell Variant.

This variant is composed predominantly of cells that are two to three times as tall as they are wide, and accounting for 30% or more of the tumor ( Fig. 18A.20 ). Compared with conventional papillary carcinoma, the tall cell variant shows the following features ^a

a References .

:

• 1.

  Slightly older age group (mean 50–57 years)

• 2.

  More bulky tumors

• 3.

  Higher frequency of BRAF mutation (60%–95%)

• 4.

  Frequent nodal metastasis (67%)

• 5.

  Frequent extrathyroidal extension (42%–82%)

• 6.

  More aggressive (recurrence in 18%–58%; mortality 9%–25%)

Nonetheless, there are studies that have shown the tall cell variant not to differ in behavior from conventional papillary carcinoma except for a higher rate of extrathyroidal extension. Some cases can dedifferentiate into a spindle cell squamous or anaplastic carcinoma.

The tall cell variant is usually highly papilliferous and invasive. The nuclei, which are typical of those of papillary carcinoma, are mostly basally located. The cytoplasm is often plentiful and oncocytic due to accumulation of mitochondria. Focal clearing of the cytoplasm, particularly subnuclear, is sometimes observed. The tall cell variant has to be distinguished from the columnar cell variant (see next section).

Columnar Cell Variant.

The columnar cell variant was first reported by Evans as a rare thyroid neoplasm (columnar cell carcinoma) that was much more aggressive than the differentiated thyroid carcinomas. Subsequent studies, however, have shown that only cases showing obvious invasive growth pursue an aggressive course, while the encapsulated ones have a favorable prognosis.

For tumors that are invasive, there is male predilection, with a mean age of 57 years. There is a high frequency of distant metastases (especially to lung and vertebra) and regional lymph node metastases. The tumor-associated mortality rate is high (>50%).

On the other hand, for encapsulated tumors, there is marked female predominance. The mean age is 43.8 years, and no patients died from the tumor.

Tumors that are invasive often show extrathyroidal extension. The encapsulated tumors may show capsular, and sometimes vascular, invasion. The columnar cell variant of papillary carcinoma is characterized by mixed papillary, complex glandular, cribriform, and solid patterns ( Fig. 18A.21 ). The papillae and glands are lined by tall columnar cells with pseudostratified hyperchromatic oval or elongated nuclei (see Fig. 18A.21 ). Subnuclear vacuoles and cytoplasmic clearing may be present ( Fig. 18A.22 ). The cells in the solid areas are often smaller and polygonal. Fascicles of spindle cells can also be present. The tumor is positive for thyroid transcription factor 1 (TTF1), and 10% to 50% of cases are positive for CDX2. BRAF mutation is demonstrable in 10% to 33% of cases.

The columnar variant differs from the tall cell variant in the greater height of the cells, striking nuclear pseudostratification and nuclear hyperchromasia, and lack of oncocytic change in the cytoplasm. Stated simply, columnar cell carcinoma is histologically reminiscent of colorectal carcinoma or endometrioid adenocarcinoma, while tall cell papillary carcinoma looks more like conventional papillary carcinoma.

Occasional cases show coexistence and merging with tall cell papillary carcinoma. ^b

b References .

There is some morphologic overlap with the cribriform-morular variant of papillary carcinoma and familial adenomatous polyposis (FAP)–associated thyroid carcinoma. In fact, one case reported by Evans as occurring in a patient with FAP probably represents such a case.

Oncocytic (Oxyphilic) Variant.

It is formed predominantly by cells with abundant eosinophilic granular cytoplasm due to accumulation of mitochondria ( Fig. 18A.23 ). There may be partial or total cytoplasmic clearing caused by ballooning of the mitochondria. The nuclei are otherwise typical of papillary carcinoma, although some may show hyperchromasia and distinct nucleoli. The behavior and molecular features are no different from conventional papillary carcinoma. It is important to distinguish this neoplasm from Hurthle cell neoplasms.

Warthin Tumorlike Variant.

Rare cases of papillary carcinoma resemble Warthin tumor of the salivary gland by virtue of a papillary pattern and a rich lymphoplasmacytic infiltrate in the cores of the papillae. The cells that cover the papillae have an oncocytic appearance and can be tall ( Fig. 18A.24 ). This variant often occurs in a background of Hashimoto thyroiditis, and immunoglobulin G4 (IgG4) ⁺ plasma cells may be increased.

Clear Cell Variant.

Rare cases of papillary carcinoma exhibit extensive cytoplasmic clearing, usually due to accumulation of glycogen. In those cases with admixed oncocytic tumor cells, the clear cell change may be confined to the apical portion of the cells and results from ballooning of mitochondria.

Macrofollicular Variant.

This refers to tumors with more than a 50% area composed of large follicles. This variant may be mistaken for nodular goiter or macrofollicular adenoma, but attention to the nuclear features will permit the correct diagnosis to be made ( Fig. 18A.25 ). The cells that line the macrofollicles are attenuated and thus may not display the characteristic nuclear features of papillary carcinoma. Assessment is therefore best made on the smaller follicles. Uncommonly, dedifferentiation to anaplastic carcinoma can occur.

Cribriform-Morular Variant (Including FAP-Associated Thyroid Carcinoma).

This is an uncommon variant characterized by a prominent cribriform pattern, with interspersed squamoid islands (morules) that frequently harbor nuclei filled with lightly eosinophilic, homogeneous, biotin-containing inclusions ( Fig. 18A.26 ). Closely packed follicles, papillae, and trabeculae are commonly admixed. Characteristically, the luminal spaces are devoid of colloid. The tumor cells are columnar, cuboidal, or attenuated. The nuclei are often chromatin rich, but nuclear features typical of papillary carcinoma can often be seen focally. Some tumor cells can be plump spindled, forming fascicles or whorls. The tumor is often circumscribed or even encapsulated, with or without capsular and vascular invasion. Nuclear staining for β-catenin is characteristic ( Fig. 18A.27 ). The neoplasm can potentially be mistaken for tall cell and columnar cell variants of papillary carcinoma, as well as hyalinizing trabecular adenoma/carcinoma.

About half of all cases occur as a sporadic tumor (often solitary) and half occur in the setting of familial adenomatous polyposis (often multifocal). In fact, most thyroid carcinomas occurring in patients with familial adenomatous polyposis exhibit this histologic pattern. The implication of a diagnosis of this variant of papillary carcinoma is that the clinician should be alerted to the possible association with familial adenomatous polyposis.

The cribriform-morular variant occurs almost exclusively in females, and the mean age at diagnosis of the thyroid tumor is 24 years, sometimes predating the diagnosis of familial adenomatous polyposis. There is a low frequency of lymph node metastasis at presentation, and the clinical outcome is highly favorable.

The tumors commonly show RET/PTC rearrangement as characteristic of papillary carcinoma. The APC gene has also been implicated, either through germline mutation (sometimes accompanied by somatic mutation) in familial adenomatous polyposis-associated cases or somatic mutation in some sporadic cases. Somatic mutations in CTNNB1 (β-catenin gene) and PIK3CA are common, while BRAF mutation is not found.

Papillary Carcinoma With Lipomatous Stroma.

In rare cases, adipose cells are interspersed within the papillary carcinoma.

Variant With Fibromatosis-Like Stroma.

Rarely, papillary carcinoma is associated with such an abundant nodular fasciitis or fibromatosis-like stroma that the neoplastic nature of the lesion may be obscured ( Fig. 18A.28A ). The interaction between the stroma and tumor results in unusual histologic patterns reminiscent of fibroadenoma, phyllodes tumor, or fibrocystic disease of the breast. The tumor islands can also be dispersed and subtle. The stroma is composed of spindled myofibroblastic cells lying in a vascularized fibromyxoid matrix, with extravasated red cells (see Fig. 18A.28B ). The spindle cells have been postulated to represent an exaggerated stromal reaction to the infiltrative neoplasm, but recent studies suggest that they represent desmoid fibromatosis as evidenced by nuclear staining for β-catenin (and hence the proposed revised terminology of papillary carcinoma with desmoid-type fibromatosis ). However, CTNNB1 (β-catenin) gene mutation has been found in only 3 of 10 cases.

Variant With Spindle Cell Metaplasia.

Rare examples of papillary carcinoma can exhibit a component of spindle tumor cells, which can constitute a minor to major proportion of the entire tumor. The bland-looking spindle cells form short fascicles and merge into the papillary carcinoma component. They are epithelial in nature, and they stain for both cytokeratin and TTF1.

Hobnail Variant.

This is a rare aggressive variant in which more than 30% of the tumor cells exhibit hobnail and/or micropapillary features. Cervical lymphadenopathy is common at presentation. During the course of disease, distant metastases are common. According to one series, 6 of 12 patients died of disease after a mean of 45 months. The tumor is usually multifocal, with variably sized papillae covered by cells with apically placed nuclei that produce a surface bulge ( Fig. 18A.29 ). BRAF and TP53 mutations are detected in 58% to 80% and 17% to 56% of cases, respectively.

Adenoid Cystic Carcinoma-Like Variant.

Rare cases of papillary carcinoma may show abundant deposits of globular hyaline material in focal areas of the tumor, reminiscent of the architectural features of adenoid cystic carcinoma. This morphologic feature apparently does not define a specific subtype of papillary carcinoma but can be seen in usual papillary carcinoma, follicular variant, columnar variant, and cribriform-morular variant.

Dedifferentiated Papillary Carcinoma.

This refers to the coexistence of papillary carcinoma with an anaplastic or poorly differentiated thyroid carcinoma ( Fig. 18A.30 ). The latter component may appear at presentation of the papillary carcinoma or with subsequent recurrence. The transformation can occur either in the primary tumor or in metastatic deposits. The prognosis is bad because it is dictated by the higher-grade component, except when the dedifferentiated component constitutes only a tiny focus of the entire tumor.

Activation of the Protooncogene RET, TRK, or ALK by Intrachromosomal Inversion or Chromosomal Translocation.

This occurs in 10% to 30% of cases. The frequency of RET/PTC rearrangements has dropped over the past 15 years (from 33% to 10% according to a study from Italy). Of interest, transfection of primary cultures of human thyroid cells with a RET/PTC retroviral construct results in nuclear changes, including irregular nuclear contour and euchromatic appearance, suggesting that the genetic alteration may underlie the observed nuclear features characteristic of papillary carcinoma. Oligoclonal RET/PTC rearrangement can be found in nonneoplastic thyroid tissues such as Hashimoto thyroiditis and benign nodules.

The tyrosine kinase region of RET gene can be fused with a number of genes constitutively expressed in thyroid epithelial cells, such as PTC1 through inv(10)(q11.2q21) , PTC2 through t(10;17)(q11.2;q23), PTC3 through cytogenetically undetectable paracentric inversion within 10q11.2, PTC4, and PTC5 . The fusion contributes a dimerization domain to the RET protein, leading to constitutive activation of the tyrosine kinase. The frequency of RET/PTC gene fusion is higher among children and young patients (50%–60%), Chernobyl accident–associated papillary carcinomas (60%–80%, most commonly RET/PTC3 ), and patients who had received external radiation therapy during childhood (60%–70%, most commonly RET/PTC1 ). RET/PTC fusion is also correlated with locally advanced disease, lymph node metastasis, low proliferative activity, and low tendency for dedifferentiation. RET/PTC1 is correlated with papillary carcinoma with predominant papillary architecture and papillary microcarcinoma, and RET/PTC3 the tall cell and solid variants. RET/PTC fusion is not found in follicular adenoma/carcinoma, poorly differentiated thyroid carcinoma, or anaplastic carcinoma.

Less commonly, NTRK1 gene, which encodes a receptor for the nerve growth factor, is fused with TPM3, TPR, or TFG. NTRK3 can be fused with ETV6 or other genes; ETV6-NTRK3 is one of the most common oncogenic rearrangements in radiation-associated papillary thyroid carcinomas. ETV6-NTRK3 positive papillary carcinomas occurring in adults without radiation exposure are locoregionally aggressive and can metastasize distantly.

ALK gene translocation (most commonly STRN-ALK ) occurs in 2.2% of papillary carcinomas, and is more common in young females, diffuse sclerosing variant, and radiation-related tumor. Its occurrence is mutually exclusive with BRAF mutation and is not associated with aggressive clinicopathologic features.

BRAF Mutation.

BRAF belongs to the RAF family of protein kinases that play a central role in transduction of signals along the RAS/RAF/MEK/MAPK pathway, mediating cell growth, differentiation, and survival. BRAF mutation, which causes constitutive activation of BRAF kinase, occurs in approximately 50% of cases and up to 88% in some series. The most common mutation is a missense mutation at nucleotide 1799, with T→A transversion that results in substitution of valine by glutamic acid (V600E mutation). Interestingly, the frequency of BRAF V600E mutation in papillary carcinoma has gradually increased over the past 20 years (e.g., from 28% to 58% in a study from Italy and from 51% to 88% in a study from the United States). BRAF V600E mutation is much less frequent in papillary carcinomas of children and young patients (0%–13%). BRAF mutation is more prevalent in classic papillary carcinoma, tall cell variant, Warthin tumorlike variant, and oncocytic variant, but is very rare in the follicular variant. The prognostic significance of BRAF mutation is controversial, but most studies report this feature to be correlated with aggressive features such as older age, extrathyroidal extension, more advanced stage (III and IV), lymph node metastasis, and tumor recurrence, BRAF mutation can be detected in one-third to one-half of cases of anaplastic carcinoma and 0% to 13% of poorly differentiated thyroid carcinoma; however, it is absent in follicular adenoma/carcinoma and medullary carcinoma. Thus at least some cases of anaplastic carcinoma appear to have transformed from papillary carcinoma.

Other Molecular Alterations.

Mutation of the RAS gene is very rare in papillary carcinomas. The previously reported 15% prevalence is attributable to inclusion of the encapsulated follicular variant of papillary carcinomas, most cases of which are now reclassified as NIFTP. TERT promoter mutations are found in 5% to 15% of cases and are associated with a worse prognosis.

Follicular Adenoma.

Follicular adenoma occurs mostly in adults aged 20 to 50 years, but no age is exempt. It is more common in females (M:F ratio 1 : 6). Most patients present with a solitary thyroid nodule noticed for variable periods. The adenomas usually lack uptake on iodine scans (“cold” nodules), but rare ones may be “hot” and can cause hyperthyroidism (so-called toxic adenoma). They are totally benign and are adequately treated by lobectomy.

Follicular Carcinoma.

Follicular carcinoma generally affects patients with a higher mean age compared with follicular adenoma ( Table 18A.7 ; see also Table 18A.4 ). Most patients present with a thyroid mass, but up to 11% of patients present initially with distant metastasis such as bone pain, fracture, or pulsatile mass in soft tissue. In contrast to papillary carcinoma, the main mode of spread is hematogenous (predilection sites being bone and lung) rather than lymphatic. The likelihood of metastasis and survival probability depend greatly on the extent of local disease (see Table 18A.7 ). The natural history of follicular carcinoma is depicted in Fig. 18A.35 . For patients who present initially with metastasis, it can be surprisingly difficult to ascertain a diagnosis of malignancy in the subsequently excised thyroid gland—in some cases, the follicular neoplasm shows no vascular invasion and only equivocal capsular invasion.

Vascular Invasion.

To qualify for vascular invasion, the involved blood vessels have to be located within or outside the fibrous capsule ( Figs. 18A.41 and 18A.42 ), and the intravascular polypoid tumor growth must be covered by endothelium (see Fig. 18A.42B ). The only situation whereby the requirement for endothelialization of the tumor island can be waived is when the intravascular tumor cluster is attached to the wall and associated with thrombus formation. Mete and Asa have redefined vascular invasion as tumor cells invading through a vessel wall and endothelium, and associated with thrombus adherent to intravascular tumor, but such criteria are too strict and not widely accepted.

Collections of follicles bulging slightly into the thin-walled capsular vessels can be disregarded if deeper cuts and further sampling fail to reveal more convincing vascular invasion ( Fig. 18A.43 ). Retraction artifacts around tumor islands can be distinguished from vascular invasion by absence of endothelial lining in the space ( Fig. 18A.44 ). Sometimes irregular clusters of nonendothelialized tumor with ragged borders and not conforming to the contour of blood vessels may be seen inside the capsular vessels; they result from artifactual dislodgment of the tumor during cut-up of the specimen and should not be counted as vascular invasion ( Fig. 18A.45 ).

A rare occurrence that may simulate vascular invasion is intravascular endothelial hyperplasia occurring in capsular blood vessels. Careful scrutiny will reveal that the intravascular polypoid plug is formed by plump spindled endothelial cells and pericytes, which are quite different from neoplastic follicular epithelial cells ( Fig. 18A.46 ). Nonetheless, although intravascular endothelial hyperplasia per se does not constitute vascular invasion, this finding warrants more careful sampling and examination to look for genuine vascular invasion elsewhere.

Capsular Invasion.

To qualify for capsular invasion, there must be complete transgression of the fibrous capsule— that is, the tumor bud has to extend beyond an imaginary line drawn through the external contour of the capsule ( Fig. 18A.47 ). The problems in assessment of capsular invasion are explained in Figs. 18A.48 and 18A.49 . Tumors exhibiting features short of complete capsular transgression after extensive sampling and careful assessment should not be given a label of carcinoma, although some authors accept incomplete capsular invasion as being sufficient for the diagnosis of follicular carcinoma. One major differential diagnosis is capsular rupture due to prior fine-needle aspiration ( Fig. 18A.50 ).

Vascular invasion and capsular invasion are in fact closely related phenomena. Tumors showing vascular invasion frequently show capsular invasion. A tumor bud not uncommonly invades into or through the capsule to extend directly into a vascular space.

Minimally Invasive Follicular Carcinomas.

They are grossly encapsulated tumors showing focal capsular invasion that is usually apparent only on histologic examination (see Figs. 18A.42 and 18A.47 ). These tumors have practically zero risk of metastasis.

Encapsulated Angioinvasive Follicular Carcinomas.

They are encapsulated tumors with vascular invasion; capsular invasion may or may not be present. It is preferable to further assess the degree of vascular invasion:

• 1.

  Invasion of less than four blood vessels is associated with a very low rate of metastasis (~5%).

• 2.

  Invasion of four or more blood vessels is associated with a higher risk of metastasis. The cumulative event rate is approximately 18%.

In view of the excellent prognosis, lobectomy with or without suppressive thyroxine therapy is adequate treatment for low-risk patients (see Fig. 18A.5 for risk-group assignment), ^f

f References .

although some investigators recommend total thyroidectomy for all patients. Total thyroidectomy and radioactive iodine therapy should be considered for high-risk patients; the purpose of total thyroidectomy is to remove all normal thyroid tissue that may compete with any residual or metastatic follicular carcinoma to effectively take up radioactive iodine.

Widely Invasive Follicular Carcinomas.

They show widespread infiltration of the thyroid parenchyma and blood vessels, and they often lack complete encapsulation ( Figs. 18A.51 and 18A.52 ). At least a proportion of cases of widely invasive follicular carcinomas reported in the literature represent poorly differentiated thyroid carcinomas. At presentation, regional lymph node metastasis and distant metastasis are already found in 7% and 29% to 66% of cases, respectively. On follow-up, more patients will develop further metastases, especially to the bone and lung. According to one long-term follow-up study, 29% of patients died of disease, 41% were alive with disease, and only 22% were alive without disease. Extension of the tumor into the soft tissues of the neck imparts an unfavorable influence on the survival (event rate 53% at 6 years, compared with 28% for carcinomas confined to the thyroid gland). Widely invasive carcinomas are aggressive neoplasms and thus have to be treated by total thyroidectomy, radioactive iodine, and suppressive thyroxine.

Hyalinizing Trabecular Adenoma and Carcinoma.

Hyalinizing trabecular adenoma is an unusual variant of follicular adenoma, which may be mistaken for paraganglioma, medullary carcinoma, or papillary carcinoma. There is an association with chronic lymphocytic thyroiditis. Long-term follow-up shows that the tumor does not recur or metastasize. The hyalinizing trabecular pattern is not totally specific for follicular neoplasm and can be observed focally in colloid nodule, thyroiditis, and otherwise typical papillary carcinoma.

The exceptionally rare examples of hyalinizing trabecular carcinoma are distinguished from hyalinizing trabecular adenoma by the presence of vascular and/or capsular invasion. However, some cases reported as such might have represented FAP-associated cribriform-morular variant of papillary carcinoma instead.

Hyalinizing trabecular adenoma is characterized by long wavy and coiled trabeculae or packets of elongated to polygonal cells with lightly eosinophilic cytoplasm ( Fig. 18A.53 ). The elongated tumor cells are aligned perpendicularly in the trabeculae. There are frequently interspersed microcysts and larger cystic spaces representing abortive or true follicle formation. The oval nuclei exhibit fine chromatin, and some degree of pleomorphism may be present. Nuclear grooves, pseudoinclusions, and perinucleolar halo are frequent findings (see Fig. 18A.53B ). There are unique cytoplasmic yellow bodies, which are often perinuclear, pale yellow, spherical, and refractile, measuring up to 5 µm; they are surrounded by a clear halo, and are shown ultrastructurally to represent giant lysosomes ( Fig. 18A.54 ). The delicate fibrovascular stroma tends to undergo hyalinization, sometimes in the form of lumpy eosinophilic deposits merging with the tumor cells. Calcified colloid, usually associated with the abortive follicles, may be seen. The tumor shows thyroglobulin immunoreactivity, which may be confined to the microcysts and follicles. TTF1 is expressed by most tumor cells. Hyalinizing trabecular adenoma frequently shows a unique pattern of cytoplasmic granular and cell membrane staining with MIB1 antibody, but not the polyclonal Ki67 antibody.

The nosologic nature of hyalinizing trabecular adenoma/carcinoma has been controversial, leading to the noncommittal designation hyalinizing trabecular tumor adopted in the 2017 WHO classification. Some authors believe that this tumor represents an unusual variant of papillary carcinoma, based on the following observations: (1) merging with or coexistence with typical papillary carcinoma in some cases, (2) focal hyalinizing trabecular neoplasm–like areas that can be seen in some typical papillary carcinomas, (3) striking similarities in nuclear features to papillary carcinoma, (4) similarities in immunohistochemical profile (such as high molecular weight cytokeratin, CK19, basement membrane deposition) in at least a proportion of cases, and (5) demonstration of RET/PTC translocation in a proportion of cases. However, there are stronger arguments against this postulation: (1) Other studies have not found expression of high molecular weight cytokeratin and CK19 (hallmarks of papillary carcinoma). (2) The frequency of galectin-3 expression is much lower than in papillary carcinoma (40% vs 83%). (3) The diagnosis of some cases of hyalinizing trabecular tumor included in studies that have demonstrated RET/PTC translocation may not be reliable, and another study fails to detect RET/PTC in hyalinizing trabecular adenoma. (4) HBME1 is consistently negative. (5) BRAF mutation, a characteristic molecular feature of papillary carcinoma, is not found. (6) The microRNA (miRNA) expression pattern is significantly different from that of papillary carcinoma. (7) Hyalinizing trabecular adenoma has been shown to exhibit a distinctive PAX8-GLIS3 gene fusion, and less commonly PAX8-GLIS1 gene fusion, as the genomic hallmark.

Signet Ring Cell Variant.

It exhibits discrete cytoplasmic vacuoles, which displace the nuclei to one side ( Fig. 18A.55 ). The cytoplasmic vacuoles often show the staining properties of mucosubstances and are furthermore immunoreactive for thyroglobulin. They correspond ultrastructurally to intracellular lumens lined by microvilli. Signet ring cell changes can be focal or diffuse, and this pattern may merge into microcystic spaces filled with extracellular mucin.

Mucinous Variant.

This variant shows accumulation of abundant extracellular basophilic mucinous material, often accompanied by a microcystic, reticular, or even multicystic growth pattern. Some large mucinous pools can also be produced ( Fig. 18A.56 ). In some cases, signet ring cell change may be observed in the neoplastic epithelium.

Clear Cell Follicular Neoplasm, Including Lipid-Rich Adenoma.

Clear cell change can occur in a wide variety of tumors in the thyroid (follicular neoplasm, papillary carcinoma, medullary carcinoma, intrathyroid parathyroid tumor, metastatic renal cell carcinoma) as well as in the normal or hyperplastic thyroid gland (see Table 18A.8 ). The mechanisms include ballooning of mitochondria, accumulation of lipid (lipid-rich adenoma), accumulation of glycogen, or deposition of intracellular thyroglobulin.

Clear cell follicular neoplasms are composed of follicles, trabeculae, or solid sheets ( Fig. 18A.57 ); vascular/capsular invasion is the only criterion to distinguish carcinoma from adenoma. Should there be any doubt about the line of differentiation, immunostaining for thyroglobulin or TTF1 will be confirmatory.

Follicular Adenoma With Papillary Hyperplasia (Papillary Variant of Follicular Adenoma).

This is a benign tumor occurring predominantly in children and adolescents. It is encapsulated, partially cystic, and composed of papillae and follicles ( Fig. 18A.58 ). The nuclei are round, hyperchromatic, and regularly aligned at the base of the cells. By definition they lack the nuclear features of papillary carcinoma. Hemosiderin deposition is common in the luminal macrophages and follicular epithelium.

Encapsulated Papillary Oncocytic Neoplasm (Follicular Adenoma/Carcinoma, Oncocytic Variant With Papillary Growth).

This is a controversial entity, in particular whether it is a form of papillary carcinoma or a follicular neoplasm. Woodford et al have shown that it should be considered a follicular neoplasm. The tumor is defined as an encapsulated thyroid tumor composed of oncocytic cells, with more than 50% papillary architecture and lacking the typical nuclear features of papillary carcinoma, although rare nuclei reminiscent of papillary carcinoma are allowable. True arborizing papillae are covered by oncocytic cells, often with hobnail appearance ( Fig. 18A.59 ). About half of the cases show capsular or vascular invasion (with such cases being considered minimally invasive or encapsulated angioinvasive follicular carcinomas). There is no immunohistochemical or molecular evidence to suggest a relationship with papillary carcinoma (HBME1−, CK19−, CD56+, no BRAF mutation, and no RET/PTC rearrangement). On follow-up of 3 months to 13 years, 12 patients were alive with no local recurrence, and 1 patient developed cervical nodal metastasis at 1 year.

Hyperfunctioning Adenoma.

Rare follicular adenomas are hyperfunctioning (also known as hot or toxic adenomas), with autonomous production of thyroxine. The tumor appears as a hot nodule on radioactive iodine scan. It comprises normal-sized or small follicles, lined by tall columnar cells that form papillary infoldings, reminiscent of the follicles seen in Graves disease ( Fig. 18A.60 ). Activating somatic mutations of the genes encoding the thyroid-stimulating hormone receptor or α−subunit of stimulatory G protein are commonly found.

Follicular Neoplasm With Lipomatous Stroma or Cartilaginous Metaplasia.

The rare adenolipoma (lipoadenoma) is a follicular adenoma containing interspersed mature fat cells. Even more rarely, fat cells can occur inside follicular carcinoma. Exceptional examples of follicular adenoma with extensive chondroid metaplasia have been reported.

Infarcted Follicular Neoplasm Following Fine-Needle Aspiration.

Partial or complete infarction of follicular neoplasms sometimes occurs after fine-needle aspiration. The main findings are coagulative necrosis, hemorrhage, accumulation of macrophages, and variable degrees of organization by fibrogranulation tissue ( Fig. 18A.61 ), depending on the time interval between the needle aspiration and the excision. A peripheral thin rim of viable tumor may still be present in some cases. Interestingly, for follicular carcinomas showing total infarction, the invasive buds often remain viable, probably because the infarction results from compromise of the blood supply to the intracapsular portion of the tumor through increased intralesional tension resulting from the hemorrhage. Infarction may create problems in diagnosis:

• 1.

  Difficulties may occur in recognizing the true nature of the tumor.

• 2.

  Exuberant granulation tissue (plump stromal cells with vesicular nuclei) mixed with macrophages may invite an erroneous diagnosis of anaplastic carcinoma ( Fig. 18A.62 ). The subsequent fibrosis may break up the residual tumor into irregular islands, creating a pseudoinfiltrative pattern ( Fig. 18A.63 ).

  
  

• 3.

  The islands of residual tumor around the infarct may show striking reactive nuclear atypia, leading to an erroneous diagnosis of high-grade carcinoma. Follicular dilatation may also result in an angiosarcoma-like pattern.

Follicular Neoplasm With Spindle Cell Metaplasia.

Rarely, a follicular neoplasm can show a variable component of bland-looking neoplastic spindle cells, forming short fascicles or even perivascular whorls ( Fig. 18A.64 ). The chromatin is fine, and nucleoli are inconspicuous. The metaplastic nature of the spindle cells can be confirmed by positive staining for cytokeratin, thyroglobulin, and TTF1; the proliferative fraction is very low.

Atypical Adenoma.

Follicular neoplasms showing generalized nuclear atypia, giant cells, or coagulative necrosis but that lack vascular/capsular invasion after thorough sampling are labeled atypical adenoma ( Fig. 18A.65 ). They pursue a benign course, as has been documented by long-term follow-up studies.

Follicular Adenoma With Bizarre Nuclei.

This variant refers to an otherwise typical follicular adenoma, which contains interspersed huge cells with bizarre hyperchromatic nuclei.

Exceptionally Rare Morphologic Variants.

A follicular carcinoma comprised of unusual glomeruloid follicles has been reported. A follicular carcinoma has been reported to have abundant extracellular amorphous globular structures made up of basement membrane materials, mimicking adenoid cystic carcinoma. We have encountered a hyalinizing follicular carcinoma with abundant hyaline deposits, resulting in an intracanalicular or phyllodes growth pattern in areas.