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Five Top Stories in Thyroid Pathology.

Thyroid disorders are among the most common endocrine abnormalities encountered in surgical pathology practice. In the category of nonneoplastic lesions, patients with Hashimoto thyroiditis (HT) often undergo surgical resection for investigation of a masslike lesion. A subset of fibrosing variant of HT shows characteristic clinicopathologic features, which are usually associated with increased numbers of immunoglobulin (Ig) G4 immunoreactive plasma cells in tissue. This has been referred to as IgG4-related thyroiditis. During the past decade there have been several reports describing clinical and pathologic features of this entity. Among the neoplastic lesions, thyroid lesions with follicular pattern pose the greatest challenge for pathologists and the treating physicians. Therefore, this subset of follicular cell-derived thyroid tumors remains a controversial area in thyroid pathology with significant interobserver variability; newer ancillary tests have been tried with the hope of being helpful in their classification into benign and malignant categories. The concept of microcarcinoma, based on the tumor size, is unique to thyroid and has been applied to both follicular cell and C-cell-derived tumors. The latter group of tumors, especially in the familial setting, may show precancerous lesions referred to as "hyperplasia" in thyroid gland as opposed to dysplasia or intraepithelial neoplasia as is commonly recognized in some other organs. Finally, with the evolution of newer molecular diagnostic techniques, there has been great interest in the application of these tests in thyroid pathology, both on cytology and surgical pathology specimens, with diagnostic and potential therapeutic implications. In this review we have selected these "5 hot topics in thyroid pathology" and discuss the recent advances in each of these areas.

This article is part of the Five Top Stories in Anatomic Pathology special series, organized by Armando E. Fraire, MD.

THYROID LESIONS WITH FOLLICULAR PATTERN

More than 35 000 new cases of thyroid carcinoma are diagnosed each year in the United States. (1,2) Even though almost 10% to 15% of thyroid carcinomas are of follicular pattern, (2) not all follicular-patterned lesions of thyroid are carcinomas. More interestingly, not all follicular-patterned carcinomas are follicular carcinomas (FCs). (3) Follicular pattern in thyroid lesions is a common and well-known pattern and by definition encompasses thyroid follicular cells organizing around a central lumen filled with colloid material. (3,4) The differential diagnoses of a lesion with this pattern include, but are not limited to, FC, follicular adenoma (FA), goiter or hyperplasic nodule, follicular variant of papillary thyroid carcinoma (FVPTC), and Hurthle cell tumor. (3,5-7) The distinction between these entities, based on the morphologic and immunohistochemical (IHC) characteristics, is not always easy and even more disappointingly, there is no general consensus about the criteria based on which a pathologist could make the appropriate diagnosis. (4) No wonder some have referred to these lesions as "bane of the pathologist." (3)

In this section we review the common follicular-patterned lesions of the thyroid gland and discuss our institutional approach including use of specific morphologic features and IHC staining toward making a final diagnosis.

In the benign category of follicular-patterned thyroid lesions, the 2 entities commonly encountered in surgical pathology practice include hyperplastic colloid nodule (HCN) and FA. These 2 entities sometimes look very similar to the extent that some authors refer to them as "adenomatoid thyroid lesions." (8) Hyperplastic nodule usually arises in the background of multinodular goiter, is composed of a mixture of small and large follicles, and is partially or completely encapsulated. (9) Interestingly, HCN has been shown to be a clonal neoplastic lesion. (10,11) Follicular adenoma, on the other hand, is usually a solitary nodule discovered in a euthyroid gland. It is most commonly encapsulated and may be microfollicular, normofollicular, or macrofollicular. The microfollicular variant shows paucity of colloid. (12) At our institution, a solitary encapsulated lesion, which is distinct from the rest of the thyroid parenchyma, is diagnosed as an FA, while a dominant nodule in the background of a multinodular goiter is referred to as an adenomatoid nodule.

The malignant category of follicular-patterned thyroid lesions includes FC (including its oxyphilic variant, also known as Hurthle cell carcinoma) (13) and FVPTC. (3,7) Follicular carcinomas represent approximately 5% of all thyroid malignancies in the United States. (14) On gross examination and fine-needle aspiration (FNA) biopsy there is no definitive diagnostic criteria differentiating FC from FA. (7) Therefore, resection of the tumor is warranted for the appropriate diagnosis, as the presence of capsular and/or vascular invasion is the only criterion to differentiate FC from FA (7,12) approximately 20% of cases that are classified as indeterminate on FNA biopsy turn out to be malignant). (15,16) As a result, distinction between FA and FC requires thorough sampling and careful histologic examination of the entire lesional capsule. Multiple levels of selected sections may be needed, particularly in cases with a thick capsule. (3,17,18) Based on the extent of capsular invasion, there are 2 types of FC: minimally invasive (mostly encapsulated) and widely invasive carcinoma. (14,17) Although some pathologists still believe that minor capsular invasion may not be a true indicator of invasive behavior, (19-21) the general consensus is that the capsular microinvasion is enough to call a follicular neoplasm a carcinoma owing to its potential to metastasize. (17,22-27) It might be an indicator of vascular invasion as well, a characteristic feature solely restricted to carcinomas. (24,28,29) Distinction between minimally versus widely invasive FC is important as both their clinical behavior and management are different. (25) Diagnosis of widespread invasion, however, is not usually difficult. Nonetheless, diagnosis of minimally invasive FC harbors the most trouble in this field and often lacks consensus among endocrine pathologists, endocrine surgeons, and endocrinologists. (24) By definition, minimally invasive FC should demonstrate a full-thickness invasion and/or vascular invasion within or outside the capsule. (25) According to the World Health Organization (WHO) criteria, capsular invasion is defined as penetration through the capsule that is not associated with the previous FNA biopsy site (30) (Figure 1, A). What constitutes vascular invasion has also been a subject of debate among pathologists, and some advocate to follow strict histologic criteria for this feature in order to have meaningful clinical significance. (31) Vascular invasion is described as presence of tumor cells with attachment to the endothelial surface in a vascular lumen within or immediately outside the capsule (32) (Figure 1, B and C). To complicate matters further, we may at times encounter cases with questionable capsular invasion without any discernible vascular invasion. These have been referred to as follicular tumor of uncertain malignant potential (FTUMP) by some authors. (33) FTUMP has not been universally accepted as an entity owing to lack of long-term follow-up data and therefore there is uncertainty in its clinical significance. (34) The importance of histologic demonstration of capsular or vascular invasion is more obvious when we realize that more than 85% of all intraoperative consultations (frozen section [FS]) are not useful and some are even inaccurate for the diagnosis of FC; therefore, the role of FS in the diagnosis of FC is very limited. (35,36) In our practice we limit the use of FS examination in diagnosis of FC. We, instead, perform a thorough gross examination and extensively submit the lesional capsule for permanent sections. If we find a thick capsule or other suspicious features but without an unequivocal evidence of capsular or vascular invasion in initial sections, we submit the whole capsule and check multiple deeper recuts on selected sections showing suspicious areas, as morphology is the only way, in our opinion, to make a diagnosis of minimally invasive FC.

Papillary thyroid carcinoma (PTC) is by far the most common malignancy in the thyroid gland. (37) These tumors have characteristic diagnostic nuclear features such as nuclear crowding and enlargement, chromatin clearing, nuclear grooves, and sometimes intranuclear pseudoinclusions and prominent nucleoli. (3,34) Psammoma bodies, a feature commonly associated with conventional PTC, may rarely be seen in FVPTC. In conventional PTC where there are widespread characteristic nuclear changes along with papillary architecture, the diagnosis is straightforward. (34) In contrast to classical PTC, FVPTC, which is the second most common type of thyroid malignancy, shows multifocal rather than diffuse distribution of nuclear changes with an overall follicular architecture and often encapsulation, making the diagnosis more challenging at times. (38,39) Owing to the patchy and multifocal nuclear changes in FVPTC, which are commonly interspersed with benign-looking thyroid follicles, there is a tendency to diagnose these as multiple foci of papillary microcarcinoma arising within an FA or HCN. (40) However, when they are all confined within an encapsulated lesion we tend to consider them as 1 PTC nodule. FVPTC shares some morphologic and molecular features with both PTC and FC and may indeed represent a hybrid tumor. In addition to focal nuclear features, architectural features resembling PTC, including an infiltrative pattern, may be seen in a subset of these tumors. Encapsulation and angioinvasion are histologic features more commonly associated with FC. At the molecular level, BRAF mutation and RET/PTC gene rearrangement, seen in most classical PTCs, are only seen in a small minority of FVPTCs; and RAS mutations, a feature of FCs, are commonly seen in FVPTCs and not in classical PTCs. (41) Molecular alterations in thyroid tumor are discussed in more detail in the last section of this article. The reclassification of thyroid lesions with follicular pattern, solely based on their molecular signature in the future, is an intriguing concept that is not unlikely when more data emerge from future studies. FVPTC has been classified on morphologic grounds into 2 groups: infiltrative and encapsulated types. There is significant difference in clinical behavior and potential therapeutic implications of these 2 groups. (42) The infiltrative type shows an ill-defined follicular pattern lesion with PTC nuclear features and desmoplastic stroma (Figure 2, A), while the encapsulated type shows an encapsulated follicular pattern lesion with similar nuclear changes (Figure 2, B and C). In our practice we use the above classification for FVPTC and discuss these terminologies with our clinical colleagues at multidisciplinary endocrine conferences in order to prevent any potential misinterpretation.

The role of ancillary studies, such as IHC and molecular diagnostics, in the classification of follicular pattern thyroid lesion into benign and malignant categories is also debatable. It will not be wrong to say there is no single "magic marker" with high degree of sensitivity and specificity that may aid in this differential diagnosis. Therefore, an approach using a panel of antibodies has been suggested and found to be useful. Some of these useful antibodies in the diagnosis of FVPTC include cytokeratin 19 (CK19), Hector Battifora mesothelial 1 (HBME1), CREB-binding protein/p300-interacting transactivator with Asp/Glu-rich C-terminal domain 1 (CITED1), galactoside-binding lectin soluble 3 (Galectin-3), CD57, retinoblastoma (Rb) protein, and p27, among others (31,43-46) (Table). Recently, we have shown that the expression of insulin-like growth factor messenger RNA-binding protein-3 (IMP3) is seen only in malignant follicular pattern lesions including FC and FVPTC and is always negative in the benign lesions (FA and HC). (6) However, while IMP3 expression has 100% specificity for diagnosis of malignancy, the sensitivity is low (69% for FC and 38% for FVPTC); therefore, it is not appropriate to be used as a standalone antibody although it may be helpful as part of a panel with other antibodies. (6) Our approach when having a follicular-patterned thyroid lesion, with some suspicious PTC-like nuclear features, is to use a panel of immunostains including CK19, HBME1, CITED1, Galectin-3, and IMP3. We have found this approach to be quite useful in differentiating FVPTC from benign lesions such as FA and HCN. Our algorithmic approach is outlined in Figure 3.

Although medullary thyroid carcinomas can also present with a follicular pattern, the cells usually possess distinct neuroendocrine features along with calcitonin expression, making their distinction from other types more straight-forward. (47)

Notwithstanding all these recent improvements in the diagnostic approach toward follicular-patterned thyroid lesions, they continue to pose diagnostic problems for pathologists and it should be emphasized that in order to reach a proper diagnosis, morphology should always be correlated with IHC and molecular studies.

PAPILLARY THYROID MICROCARCINOMA

Incidence and Epidemiology

Papillary thyroid carcinoma is the most common tumor of thyroid and its incidence has increased almost 2.3-fold in the past several decades. (48) Papillary thyroid microcarcinoma (PTMC) is defined by size of 1 cm or less in greatest dimension. According to a recent study, PTMC constitutes approximately half of papillary thyroid carcinomas in patients older than 45 years. (30,49) The increase in incidence has been partly attributed to the increased detection by widespread use of ultrasonography and FNA to diagnose and monitor thyroid nodules. In autopsy studies, incidental PTMC incidence has been reported to be in the range of 6% to 36%. (50,51)

Pathologic Features

A microcarcinoma can be detected during ultrasonographic examination of thyroid gland or it could be an incidental finding in the thyroid gland resected for other conditions such as goiter. When large enough to be detected by gross examination, the microcarcinoma may appear as a well circumscribed or irregular tan-white area, which may be located in the peripheral (Figure 4, A) or central part of the gland. Microscopically, these tumors may show classic papillary architecture as well as follicular growth pattern. The classic architecture shows fibrovascular cores lined by tumor cells with characteristic PTC nuclear features including enlarged, oval overlapping nuclei, clear chromatin, irregular nuclear membranes, nuclear grooves, and nuclear pseudoinclusions. Microcarcinoma may be associated with psammoma bodies, stromal reaction including fibrosis, sclerosis (Figure 4, B and C), and/or desmoplasia and chronic inflammatory infiltrate.

Most PTMCs show excellent behavior but a small subset may recur or even metastasize. Traditionally, older age, male sex, tumor size, tumor multifocality, vascular invasion, extrathyroidal invasion, and lymph node metastasis have all been linked to the high-risk behavior. (52-55) In the past decade or so, several studies have tried to identify high-risk features and improved risk stratification in PTMC for optimal management. Extrathyroidal extension and lymph node metastasis have been shown to be important predictors of locoregional recurrence in PTMC. (56,57) In some studies, (58-60) extrathyroidal extension has been reported in up to 52% of PTMCs. In our experience, extrathyroidal extension was seen relatively more commonly in microcarcinoma located at the periphery, involving the pseudocapsule of the thyroid gland. Niemeier et al (61) also noted peripheral location of the tumor as one of the aggressive features. Recently, Piana et al (62) described a case series of 3 cases of fatal PTMC with distant metastasis; all 3 PTMCs were superficially located. Lymph node metastases have been reported in up to 66% of microcarcinomas. (55,63) So et al (64) demonstrated that almost 37% of clinically node-negative PTMCs in 551 total thyroid resections harbored subclinical central lymph node metastasis. Another unfavorable histologic feature is the presence of aggressive variants; for example, tall cell variant of microcarcinoma appears to show aggressive features at presentation when compared with PTMCs with classic features. (57,65) Although the current WHO classification of papillary thyroid carcinoma does not recommend subclassification of PTMC, we believe that the tall cell variant should be differentiated from other PTMCs.

Using the size of PTMC to predict biologic behavior has produced variable results. Zhou et al (56) demonstrated that PTMCs that are 7 mm or smaller were less likely to be associated with aggressive features including lymph node metastasis or extrathyroidal extension when compared with PTMCs greater than 7 mm. However, Lee et al (66) reported that PTMCs that are 5 mm or smaller were associated with central as well as lateral lymph node metastasis in 42% and 3.8% of cases, respectively.

[BRAF.sup.V600E] gene mutation has emerged as an important molecular marker and leading genetic event in papillary thyroid carcinoma. (67-69) It has been used as a diagnostic marker in thyroid cytology and proposed to be a possible negative prognostic indicator. (70,71) [BRAF.sup.V600E] gene mutation has been reported in PTMC in the range of 40% to 70%, similar to PTC greater than 1 cm. (72-74)

In a genotype-phenotype correlation study, Virk et al (72) found that [BRAF.sup.V600E]-mutated PTMCs have distinct morphologic features when compared with [BRAF.sup.V600E] wild-type PTMCs. Mutated tumors are more likely to have infiltrative interface with nonneoplastic thyroid parenchyma and tumor-associated stromal reaction including fibrosis and/or desmoplastic reaction. These authors further subtyped PTMC in their study and found [BRAF.sup.V600E] mutation to be least common in follicular variant compared to classic and tall cell variants.

Xing et al (75) demonstrated [BRAF.sup.V600E] mutation to be significantly associated with cancer-related mortality in PTC in a retrospective multicenter study, but the significance was lost on multivariate analysis. Gouveia et al (74) did not find significant association of [BRAF.sup.V600E] mutation with aggressive features in PTC. Niemeier et al (61) proposed a scoring system based on histologic and molecular features for risk stratification that included superficial tumor location, intraglandular spread, and tumor fibrosis with [BRAF.sup.V600E] status. While the association between [BRAF.sup.V600E] mutation and aggressive histopathologic features such as microscopic extrathyroidal extension and lymph node metastasis is appreciable, prospective randomized studies are needed to establish an association with poor outcome.

MEDULLARY THYROID MICROCARCINOMA

Inheritable C-Cell Neoplasia: Medullary Thyroid Microcarcinoma and Neoplastic C-Cell Hyperplasia

C cells originate in the neural crest and reach their usual anatomic location as parafollicular cells in the thyroid via the ultimobranchial bodies that migrate to fuse with the lateral lobes of thyroid. The C cells are located in the upper two thirds of the thyroid lobes. (76) In our practice, thyroid lobes in patients with germline mutation in the RET proto-oncogene that are grossly unremarkable are serially sectioned at 2 to 3 mm and submitted entirely for microscopic examination. (76) C-cell proliferations are frequently noted on hematoxylineosin (H&E) staining. If no C-cell proliferations are seen on initial sections, multiple levels of H&E-stained sections may be examined from the upper two-thirds of the lobes. In the presence of germline mutation in the RET proto-oncogene, all C-cell proliferations are neoplastic and may range from the preinvasive C-cell hyperplasia (CCH or medullary carcinoma in situ) to medullary thyroid carcinoma (MTC); in this situation the term hyperplasia is a misnomer. (76-78) Neoplastic C-cell proliferations are usually multifocal and bilateral, involving both lobes, and can be detected by H&E stain by their large size and nuclear atypia (Figure 5, A through F). These atypical C cells are morphologically similar to the tumor cells in MTC, and therefore, consistent with medullary carcinoma in situ. (78) Architecturally, the atypical C cells can be focal, diffuse, or nodular. In focal CCH, the C cells focally involve a thyroid follicle, whereas complete ringlike involvement of the follicle without obliteration of its lumen is seen in diffuse CCH. Complete obliteration of the follicle by nodules of C cells with intact basement membrane is consistent with nodular hyperplasia. (76) Others have simply divided them as nodular and nonnodular CCH. (79) In contrast to neoplastic CCH, physiologic or reactive CCH may be seen as increased numbers of scattered C cells secondary to an underlying thyroid disease such as thyroiditis, goiter, or tumor. They are also associated with older age and male sex. (76,78) Reactive C cells are not easily recognizable on H&E staining as the cells are not atypical; however, they may be detected by immunohistochemistry. (78) Albores-Saavedra et al (80) defined reactive CCH as 50 or more C cells per low-power field (X10 objective). In contrast, neoplastic CCH is defined by morphology, that is, cellular atypia and not by the number of C cells. Reactive or physiologic CCH has no demonstrable malignant potential. (81)

Presence of complex architecture, stromal fibrosis, C cells infiltrating the stroma outside of the basement membrane of thyroid follicle, and presence of amyloid are hallmarks of medullary carcinoma. (76,79) It is important to differentiate microcarcinoma (size [less than or equal to] 1 cm) from neoplastic CCH owing to the metastatic potential of the former. (30) We recently had a 10-year-old asymptomatic male patient with bilateral medullary microcarcinoma (microMTC) with extensive nodal metastasis to central compartment and lateral cervical lymph nodes. The child had de novo mutation in codon 918 associated with multiple endocrine neoplasia 2B (MEN2B).

Bilateral and multifocal microMTC associated with CCH is pathognomonic of heritable MTC seen in MEN2 and familial MTC, and is caused by gain-of-function mutations in the RET proto-oncogene on 10q11.2. (82) These mutations have an autosomal dominant pattern of inheritance with extremely high penetrance. The gene encodes a transmembrane receptor tyrosine kinase protein. The mutations are limited to relatively few codons that are associated with distinctive phenotypes. The American Thyroid Association (ATA) has assigned 4 risk levels for developing MTC, determined by the type of mutation; the highest risk of MTC is associated with level D (codons 883 and 918) and the "least high" risk is associated with level A. (83) The youngest reported patient with mutation in codon 634 who developed medullary thyroid carcinoma was 15 months old. (84) Therefore, the ATA has placed codon 634 mutations in the "higher" risk level (level C) and recommends prophylactic thyroidectomy before the age of 5 years. Indeed, Pelizzo et al (85) reported microMTC in 100% of prophylactic thyroidectomies performed on patients with codon 634 mutation with a mean age of 17 years. As point mutations in codon 634 are strongly linked to pheochromocytoma and hyperparathyroidism, these patients need lifelong screening.

The microMTC appears to have a good prognosis. Extrathyroidal extension, size of the microcarcinoma, and the patient's age appear to be independently associated with risk of metastasis. (86) Kazaure et al (86) reported lymph node and distant metastasis in 37% and 5% of patients, respectively; however, most patients were older than 45 years. Thus, central neck dissection is recommended in older patients at the time of prophylactic thyroidectomy but its value in children has remained controversial.

IgG4-RELATED THYROID DISEASE

There has been a major interest in the IgG4-related diseases (IgG4-RDs) in recent years. (87-89) Since the first description of IgG4-RD in 2003, (90) this entity has been reported in almost every organ system. (88,91-96) Many diseases such as Riedel thyroiditis (RT), Mikulicz syndrome, periaortitis, multifocal fibrosclerosis, retroperitoneal fibrosis, and idiopathic membranous glomerulonephritis, described as separate entities previously, have now been categorized as part of the IgG4-RD spectrum. (87,97-103) Irrespective of the affected sites in this disease, there are markedly similar histopathologic characteristics of the lesion, which include intense lymphoplasmacytic infiltration, dense fibrosis with storiform or a perivascular onion skin pattern, obliterative phlebitis, and increased numbers of polyclonal IgG4-producing plasma cells. (87,88,104) Serum IgG4 levels are frequently high; however, approximately 30% of individuals may have near-normal serum levels. (105) The presence of IgG4-producing plasma cells in the tissue, though, is essential for the diagnosis of IgG4-RD. (87,94) Considering the fact that IgG4 immunoglobulin typically functions as an anti-inflammatory immunoglobulin, along with the absence of IgG4 autoantibodies in IgG4-RD, the current accepted paradigm is that these antibodies are produced in response to an inflammatory stimulus. (87,94) The affected organ usually has an admixture of different inflammatory cells such as B cells in germinal centers and diffusely distributed T cells. (87,106) Although eosinophils are commonly found in the affected sites, the presence of neutrophils is only restricted to some rare cases. (87,94,106,107) There are some proposed theories about the pathogenesis of the IgG4-RDs. In several studies, different mechanisms have been suggested such as autoimmunity, (108-110) genetic factors, (111-113) and bacterial molecular mimicry (114) (Figure 6).

Thyroid gland is one of the organs frequently involved in IgG4-RD. (93,115,116) Thyroid involvement in IgG4-RD can be in the form of HT. (116) Hashimoto thyroiditis is subclassified to IgG4-thyroiditis (with increased numbers of IgG4-positive plasma cells) and non-IgG4-thyroiditis (no or few IgG4-positive plasma cells). (116) Although in general, patients with IgG4-RD have a subacute course of disease, and mostly without any constitutional symptoms, (87) IgG4-thyroiditis nevertheless has a more progressive course. (109) It still displays a female predilection, however, with lower female to male ratio than that typically seen in other thyroid disorders. It affects patients in younger age groups and has a higher level of circulating thyroid autoantibodies than non-IgG4 type. (109) The other type of thyroiditis, which has been suggested to be part of IgG4-RD, is RT, which occurs less commonly in this setting. (93) Riedel thyroiditis is a chronic form of thyroid inflammation with diffuse fibrosis in parenchyma and also in surrounding perithyroidal tissues. (115) Obliterative phlebitis, which is one of the main features of IgG4-RD, is only seen in RT and not in HT. (89) It has also been suggested that RT is more commonly seen in systemic pattern of IgG4-RD, while HT is more of an organ-specific type of this disease; this was supported by a dramatic reduction in serum IgG4 levels after thyroidectomy only in HT subtypes. (89) Dahlgren et al (93) have postulated that the presence of obliterative phlebitis is therefore essential for having systemic pattern of IgG4-RD, as the fibroinflammatory changes of IgG4-HT are totally confined to the thyroid gland with no vascular changes as opposed to phlebitis in RT.

Diagnosis of IgG4-related thyroiditis is mainly established through histopathologic analysis of the specimens. (87,89,117) As explained earlier, the pathologic features of thyroid involvement are very similar to those of other organs affected in the systemic form of IgG4-RD, (90) especially autoimmune pancreatitis (as more than one-third of affected patients (118) have some form of thyroiditis as well, (90,119) and include diffuse lymphoplasmacytic infiltration, lymphoid follicle formation with germinal centers, dense stromal fibrosis, and follicular cell destruction (Figure 7, A through C). Increased numbers of IgG4-positive plasma cells are usually observed in IgG4-related thyroiditis (109,116) (Figure 8, A through C). An important distinction to make is the lack of fibroinflammatory elements outside the thyroid gland and no vascular changes in HT as compared with RT subtype. (89) Some studies (89,109,116) used immunohistochemical staining to determine the ratio of IgG4-positive plasma cells to total IgG-producing plasma cells in the tissue as a diagnostic tool to differentiate between IgG4-related HT and conventional HT. They suggested a cutoff value of more than 30% for IgG4 to IgG ratio, or more than 20 per high-power field of IgG4-producing plasma cells, for diagnosis of IgG4-related thyroiditis. (89,106,109,116)

Treatment of IgG4-RD is essential as without treatment the disease progresses frequently to an extensive fibrosis and loss of function in the affected organs. (94,95,120) Glucocorticoids are the cornerstone of treatment in IgG4-RD (87,121-123) and particularly, an aggressive treatment is crucial when vital organs are involved. (95) Glucocorticoid-sparing agents such as azathioprine, (124,125) methotrexate, (126,127) and rituximab (128,129) have been used with variable success. For patients who have IgG4-RD confined to the thyroid gland, there is limited use of glucocorticoids (130) and thyroidectomy with thyroid-replacement therapy has been used more frequently. (89) In one small study, (128) rituximab was used in IgG4-related RT without significant effect.

In summary, IgG4-related thyroiditis should be considered when dense fibrosis is appreciated with diffuse lymphoplasmacytic infiltration. Immunohistochemical staining for IgG and IgG4 should be performed in these cases for the diagnosis of IgG4-related thyroiditis as affected patients may require a systemic clinical evaluation.

MOLECULAR TESTS IN THYROID LESIONS

Several molecular pathways are involved in the tumorigenesis of different types of thyroid neoplasms. Molecular analysis can provide useful information for both diagnostic and prognostic purposes, and may also guide targeted therapy based on individual tumor characteristics. Most molecular alterations found in thyroid neoplasms are due to 1 of 2 main mechanisms: point mutations, such as RAS and BRAF gene mutations, and gene rearrangements, such as RET/PTC and PAX8/PPARG. The commonly found mutations in thyroid neoplasms are typically mutually exclusive. (69,131,132) Here we review the most commonly studied molecular alterations in follicular cell-derived thyroid neoplasms.

BRAF Gene Mutations

[BRAF.sup.V600E] gene mutation is the most commonly observed genetic alteration in PTC, which is found in almost half of the classic PTC cases, (133,134) whereas it is rarely detected in well-differentiated follicular neoplasms. (69) BRAF gene mutations are more often seen in the tall cell variant of PTC (70%-80%), and have shown some correlation with extrathyroidal invasion, cervical lymph node and distant metastases, resistance to radioactive iodine treatment, (135,136) and possibly with worse prognosis although this remains controversial. (137) BRAF gene mutations are also commonly found in anaplastic thyroid carcinoma (ATC). (133) It is also notable that the inversion of chromosome arm 7q with AKAP9/BRAF rearrangement, a rare molecular alteration involving the BRAF gene, has been reported in PTC associated with ionizing radiation exposure. (138)

The clinical utility of BRAF IHC has been studied by different groups, which showed that BRAF IHC staining with antibody against mutant [BRAF.sup.V600E] (clone VE1) has both a sensitivity and negative predictive value (NPV) of 100% and a variable specificity ranging from 61.5% to 98.7%. (139-141) Thus, BRAF IHC utilization may add more value to the previously proposed IHC panel for the diagnosis of conventional PTC in indeterminate thyroid FNA or in difficult surgical cases. Furthermore, BRAF IHC is a valuable screening tool to select patients for confirmatory molecular testing who may benefit from targeted therapy.

RAS Gene Mutations

RAS gene mutations (NRAS, HRAS, and KRAS) are associated with follicular-patterned thyroid lesions. NRAS is present in 20% to 50% of follicular thyroid carcinomas (FTCs) (142) and in up to 40% of FAs, suggesting an early role for RAS gene mutations in promoting tumorigenesis of follicular neoplasms. (136) Surprisingly, RAS mutations are found more commonly in FVPTC than in other histologic types of PTC, suggesting that FVPTC might be a separate class of thyroid tumors with overlapping features of both PTC and FTC. Recent studies (143) even advocate reclassification of PTC into [BRAF.sup.V600E]-like PTC and RAS-like PTC, based on the histomorphologic and molecular characteristics of the tumor. In addition, RAS gene mutation is the predominant oncogenic defect in poorly differentiated thyroid carcinoma (PDTC), found in 20% to 55% of cases, while it is only found in approximately 12% to 17% of ATCs. (133)

RET/PTC Gene Rearrangement

RET/PTC1 and RET/PTC3 are the most common types of the RET/PTC gene rearrangement (133) and are found in 10% to 20% of PTCs. (132) They can be associated with ionizing radiation exposure and are more commonly seen in the pediatric population. (144,145) Whether the presence of the RET/ PTC rearrangement infers a better prognosis is not clear; however, it is typically absent in PDTC and ATC. (133)

PAX8-PPARG Gene Rearrangements

PAX8/PPARG gene rearrangement t(2; 3)(q13; p25) is prevalent in FTC (variably reported in 36%-63% of cases) (134,146) as well as in FVPTC, FA, and a small proportion of Hurthle cell carcinomas. (146) It is typically associated with microfollicular and solid histologic patterns, thick capsule, and capsular and vascular invasion. Therefore, FA with PAX8/ PPARG rearrangement needs thorough sampling of the specimen to rule out capsular and vascular invasion. (145)

Other Molecular Alterations

Mutations in complex-1[alpha] mitochondrial DNA (also known as NDUFA13 or GRIM19) are found in 10% to 20% of Hurthle cell carcinomas, oncocytic FTCs, and the oncocytic variant of PTCs. (132,136) Recently, ETV6-NTRK3 rearrangement has been shown in pediatric and adolescent PTC, which was associated with radiation exposure and more aggressive disease. (147) Interestingly, anaplastic lymphoma kinase (ALK) fusions such as STRN-ALK fusion have been found in PDTC and ATC, which may work as a potential target for therapy with ALK inhibitors (ie, crizotinib). (148)

In addition, there are a few other mutations, such as TP53 and [beta]-atenin gene (CTNNB1) mutations, that are more commonly seen in PDTC and ATC, rarely identified in well differentiated thyroid carcinomas, (136,149,150) and are associated with more advanced disease. (133,136)

Clinical and Diagnostic Applications of Thyroid Molecular Testing

Cytologic examination of thyroid FNA is currently the most accurate and cost-effective approach for the evaluation of thyroid nodules. (151) The Bethesda system for reporting thyroid cytopathology (BSRTC) has been developed to bring a more uniform approach in thyroid cytology and therefore to improve the diagnostic utility of FNA. Based on BSRTC, 6 diagnostic categories exist for thyroid FNA evaluation: nondiagnostic, benign, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), follicular neoplasm or suspicious for a follicular neoplasm (FN/SFN), suspicious for malignancy (SM), and malignant. Fine-needle aspiration is capable of distinguishing between benign versus malignant lesions in most cases. However, up to 25% to 30% of the thyroid nodule FNAs are diagnosed as indeterminate (AUS/FLUS and FN/SFN). (41,134) Recently, the utility of molecular testing has been extensively reviewed by different groups to aid in the appropriate management of patients in this category. (41,152,153) The goal is to prevent unnecessary resection of benign thyroid lesions by exploiting an ancillary test with a high NPV and to obviate the need for a second surgery (completion thyroidectomy) by implementing a test with high positive predictive value (PPV) (154,155) (Figure 9). (156) Molecular testing using panels targeting different alterations is now available and includes BRAF and RAS gene point mutations and RET/PTC and PAX8/PPARG gene rearrangements. Overall, the presence of any of these alterations is a robust predictor of a neoplastic process with 78%, 93%, and 98% PPV for FLUS, FN, and SM, respectively. (153,157) Thus, a total thyroidectomy is probably recommended in cases with a high PPV test, such as BRAF gene mutation. In addition, patients with BRAF-mutated PTC may benefit from lymph node dissection. (154,158)

Commercially Available Thyroid Molecular Tests

Implications of the molecular studies in cytology samples have led to development of a few commercially available molecular tests for thyroid FNA evaluation. A direct mutation testing with high PPV has been developed by Asuragen, Inc (Austin, Texas). Asuragen miRInform thyroid test is a panel of 9 molecular alterations, which is performed on a minimum of 50 ng of tissue in RNA preservative. (154) A prospective study done by Nikiforov et al (153) using the similar panel on 513 indeterminate thyroid nodules with consequent histologic correlation revealed that the presence of any type of mutations in the panel contributed to the increased risk of malignancy, with an overall sensitivity of 89% for indeterminate thyroid nodules on cytology specimens. (153) This test appears as a promising diagnostic tool to rule in malignancy. As a result, total thyroidectomy is recommended in cases with positive result with the intent to avoid an extra cost of unnecessary diagnostic lobectomies. (159)

The Veracyte Afirma Gene Expression Classifier (South San Francisco, California) is a multigene expression profiling assay that is performed on messenger RNA extracted from needle wash and measures expression levels of 167 genes. This test was mainly designed to distinguish benign thyroid nodules in suspicious cases with sensitivity of 92% and specificity of 52% (160) and a high NPV of 95% and 94% for AUS/FLUS and FN/SFN, respectively. (161) This makes the test a valuable tool in ruling out malignancy and therefore preventing unnecessary surgeries in cases where a more conservative approach can be used. (155,159)

Cost-efficacy analyses showed that molecular testing followed by total thyroidectomy ($16 414, including the added cost of molecular testing) costs less than diagnostic lobectomy followed by completion total thyroidectomy ($19 638). (153)

Quest Diagnostics (Chantilly, Virginia) also provides a thyroid cancer mutation panel assay on needle wash specimens fixed in CytoLyt (Hologic Inc, Bedford, Massachusetts) or formalin, as well as formalin-fixed paraffin-embedded samples. The details about the performance characteristics of this test have not been published yet. (152,154)

Therapeutic Implications

Although some of the thyroid tumors with known mutational changes, especially BRAF-mutated PTC, tend to behave aggressively and therefore may benefit from tyrosine kinase inhibitor therapy, therapeutic utility of thyroid molecular testing has only been studied by a few researchers so far. (162,163) In a phase I clinical trial, vemurafenib, a tyrosine kinase inhibitor targeting mutant BRAF gene, showed some promising results in patients with metastatic PTC. (164)

Future Directions

Next-generation (massive parallel) sequencing technology may prove to be a powerful diagnostic tool with advantages for testing mutational analysis in much more limited samples and may increase both the PPV and NPV of the current common mutational panels. (165) Based on the 2009 revised ATA guidelines for management of patients with thyroid nodule, none of these molecular tests are entirely accurate, and there is as yet no generally accepted protocol for their use in the diagnosis of thyroid neoplasms. (151) Various studies, however, are being undertaken and new PTC driver gene mutations such as EIF1AX have been introduced, so that existence of PTC with no oncogenic driver is close to extinction. (143) Moreover, a new system of thyroid neoplasm categorization has recently been suggested, based on the molecular subtypes, to predict their clinical behavior and consequently manage them appropriately. (143)

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Parnian Ahmadi Moghaddam, MD; Renu Virk, MD; Ali Sakhdari, MD, MSc; Manju L. Prasad, MD; Ediz F. Cosar, MD; Ashraf Khan, MD

Accepted for publication May 6, 2015.

From the Department of Pathology, University of Massachusetts Memorial Medical Center, Worcester (Drs Moghaddam, Sakhdari, Cosar, and Khan); and the Department of Pathology, Yale School of Medicine, New Haven, Connecticut (Drs Virk and Prasad).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Ashraf Khan, MD, Department of Pathology, UMass Memorial Medical Center, 3 Biotech, One Innovation Dr, Worcester, MA 01605 (e-mail: ashraf.khan@umassmemorial.org).

Figure 1. Follicular carcinoma. A, Microinvasion with capsule breeching in a mushroomlike pattern. B and C, Vascular invasion (hematoxylin-eosin, original magnifications X100 [A and C] and X40 [B]).

Caption: Figure 2. Follicular variant of papillary thyroid carcinoma. A, Infiltrative pattern. B, Encapsulated pattern. C, Higher magnification of the same tumor as in (A) showing the cytologic features of papillary thyroid carcinoma (hematoxylin-eosin, original magnifications X100 [A and B] and X400 [C]).

Caption: Figure 3. Our institute's approach to follicular-patterned lesions of the thyroid gland. Abbreviations: CITED1, CREB-binding protein/ p300-interacting transactivator with Asp/Glu-rich C-terminal domain 1; CK19, cytokeratin 19; FA, follicular adenoma; FC, follicular carcinoma; FTUMP, follicular tumor of undetermined malignant potential; FVPTC, follicular variant of papillary thyroid carcinoma; Galectin-3, galactoside-binding lectin soluble 3; HBME1, Hector Battifora mesothelial 1; IMP3, insulin-like growth factor II messenger RNA binding protein 3; PTC, papillary thyroid carcinoma.

Caption: Figure 4. Papillary thyroid microcarcinoma (PTMC). A and B, Peripherally located 0.5-cm PTMC with associated stromal infiltration and sclerosis. C, Cytologic features of papillary thyroid carcinoma. Psammoma bodies are also noted. This tumor was found to be metastatic to 2 level VI cervical lymph nodes and was [BRAF.sup.V600E] wild type (hematoxylin-eosin, original magnifications X20 [A], X100 [B], and X400 [C]).

Caption: Figure 5. C-cell hyperplasia (CCH). A, Nodular and diffuse. Solid nodules of C cells as well as a complete ringlike proliferation of C cells are seen between the basement membrane and the follicular epithelium with preservation of the follicular lumen. B, Medullary thyroid microcarcinoma. C cells are outside the follicular basement membrane infiltrating the fibrous stroma in small nests and single files. Focal and diffuse CCH are also noted at the periphery. C and D, Focal CCH. Atypical C cells (arrow) are seen scattered around the follicles within the basement membrane. E and F, The C cells are atypical and malignant, even when within the basement membrane (carcinoma in situ). Association with amyloid and fibrosis favors microcarcinoma (hematoxylin-eosin, original magnifications X200 [A and B] and X400 [C and E]; immunohistochemistry for calcitonin, original magnification X400 [D]; Congo red, original magnification X400 [F]).

Caption: Figure 6. The skewed activation of immune system toward Th2 cells leads to higher levels of IL-4 and IL-13 in the serum. These cytokines activate B cells and Tregs, which consequently increase the production of IgG4/IgE and TGF[beta] followed by a high serum level of IgG4, eosinophilia, and tissue fibrosis. Abbreviations: Ig, immunoglobulin; IL, interlukin; TGF[beta], transforming growth factor [beta]; Th2, T cell helper 2; Tregs, regulatory Tcells. Data derived from Stone et al. (87)

Caption: Figure 7. Immunoglobulin G4-related thyroiditis. A, Lymphoid follicles with germinal centers and squamous metaplasia. In this case, it was scattered throughout the thyroid gland. B and C, Follicular cell destruction and replacement of the thyroid tissue by dense stromal fibrosis (hematoxylin-eosin, original magnifications X100 [A and B] and X200 [C]).

Caption: Figure 8. The same case as shown in Figure 7. A, Lymphoplasmacytic infiltration of the sclerotic thyroid tissue. B, Immunoglobulin G (IgG) immunohistochemical stain (IHC) highlights the plasma cells. C, The IgG4 IHC reveals more than 20 IgG4-producing plasma cells per high-power field (hematoxylin-eosin, original magnification X200 [A]; original magnification X400 [B and C]).

Caption: Figure 9. Shown is an algorithm for the management of FNA of thyroid lesions, based on the cytologic findings. For the category of follicular lesions, application of a test with a higher NPV is recommended and for the category of papillary thyroid carcinoma, using a test with higher PPV is preferred. Abbreviations: AUS, atypia of undetermined significance; FLUS, follicular lesion of undetermined significance; FN, follicular neoplasm; FNA, fine-needle aspiration; LND, lymph node dissection; NPV, negative predictive value; PPV, positive predictive value; PTC, papillary thyroid carcinoma; SFN, suspicious for follicular neoplasm. Adopted by permission from Elsevier Publishers Ltd: Lancet volume 381, Copyright [C] 2013 Elsevier Lt from Xing et al. (156)

Please Note: Illustration(s) are not available due to copyright restrictions.
Our Institutional Immunohistochemistry Panel and Its
Utility in Differentiation Between Follicular-Patterned
Thyroid Lesions

Immunostain   Follicular   Follicular       FVPTC
               Adenoma     Carcinoma

CK19          Usually -    Usually -      Usually +
HBME1         Usually -     May be +      Usually +
Galectin-3    Usually -    Usually +      Usually +
IMP3              -         May be +      May be +
CITED1            -        Usually -    + in a subset
P27               +        Focally +      Focally +
Rb protein        +            -              -

Abbreviations: CITED1, CREB-binding protein-p300-interacting
trans-activator with Asp-Glu-rich C-terminal domain 1; CK19,
cytokeratin 19; FVPTC, follicular variant of papillary thyroid
carcinoma; Galectin-3, galactoside-binding lectin soluble 3; HBME1,
Hector Battifora mesothelial 1; IMP3, insulin-like growth factor II
messenger RNA binding protein 3; P27, protein 27; Rb,
retinoblastoma protein; +, positive; usually +, majority positive;
may be +, positive reports in literature; usually -, majority
negative; -, negative.
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Author:Moghaddam, Parnian Ahmadi; Virk, Renu; Sakhdari, Ali; Prasad, Manju L.; Cosar, Ediz F.; Khan, Ashraf
Publication:Archives of Pathology & Laboratory Medicine
Date:Feb 1, 2016
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