, Haiyan Liu1 and Jun Zhang2
(1)
Department of Laboratory Medicine, Geisinger Health System, Danville, PA, USA
(2)
Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA
Keywords
ThyroidParathyroidAcute thyroiditisGranulomatous thyroiditisSubacute thyroiditisNodular goiterGraves’ diseaseAtypical follicular cells of undetermined significanceFollicular neoplasmsFollicular adenomaFollicular carcinomaHurthle cell neoplasmsHurthle cell adenomaHurthle cell carcinomaPapillary carcinoma (follicular variant, tall cell variant, columnar cell variant, diffuse sclerosing variant, cribriform variant, Warthin-like variant, macrofollicular variant, oncocytic variant)Papillary microcarcinomaPoorly differentiated (insular) carcinomaMedullary carcinomaUndifferentiated (anaplastic) carcinomaHyalinizing trabecular neoplasmCarcinomaSarcomaLymphomaPlasmacytomaMelanomaMetastasisCK7CK20CK19HBME1TROP2Galectin-3ChromograninSynaptophysinMIB-1 (Ki67)PTHGATA3CalcitoninCEATTF1PAX8Beta-cateninBRAFSummary of Pearls and Pitfalls
Based on the Bethesda System for Reporting Thyroid Cytopathology, the terminology “follicular lesion” is no longer recommended in routine practice. Instead, a distinct subcategory of “Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance” (AUS/FLUS) was recommended.
Focal nuclear pleomorphism of the follicular cells is frequently seen in a lymphocytic/Hashimoto’s thyroiditis; one should avoid overdiagnosing this change as “Atypia of Undetermined Significance.”
When a fine-needle aspiration (FNA) smear is composed of a mixture of epithelioid and spindle cells singly and in loosely cohesive groups, and absence of colloid, regardless of the cellularity, a medullary carcinoma should be included in the diagnostic consideration.
Hyalinizing trabecular neoplasm is an uncommon lesion and shares many important cytological features with papillary carcinoma of the thyroid, including nuclear grooves and intranuclear pseudoinclusions. When the follicular cells appear to be elongated and a hyaline matrix-like material between cellular components is present, it is necessary to exclude a hyalinizing trabecular neoplasm before a definitive diagnosis of papillary carcinoma is rendered. An immunostain for mindbomb E3 ubiquitin protein ligase 1 (MIB-1 clone[Ki-67]) with distinctive membranous staining pattern is useful in confirming the diagnosis.
If abundant acute inflammation is present, in addition to an acute inflammatory process, undifferentiated (anaplastic) carcinoma of the thyroid should be included in the diagnostic consideration. Paired box gene 8 (PAX8 ) is positive in 50% of the tumors; in contrast, both thyroid transcription factor 1 (TTF1 ) and thyroglobulin are usually negative.
The vast majority of cystic lesions of the thyroid are benign; however, cystic papillary carcinoma of the thyroid or metastatic squamous cell carcinoma with cystic degeneration may mimic a benign cystic lesion.
Parathyroid adenoma/neoplasm should be excluded if colloid is absent and numerous small naked nuclei and vascular-rich stroma are seen. Clear cell or oncocytic changes are common.
If the neoplastic cells are morphologically unlike follicular cells and colloid is absent in the background, a rare primary tumor or a metastasis should be considered. The most common metastases in the thyroid are renal cell (clear cell) carcinoma, melanoma , and adenocarcinoma of the lung, breast, and stomach.
If a mixture of histiocyte-like cells and lymphoid cells is present, Langerhans cell histiocytosis, follicular dendritic cell tumors, and other rare histiocytic lesions should be considered.
Modified from the 2004 World Health Organization (WHO) Classification of Thyroid and Parathyroid Tumors1
Thyroid
Benign Nonneoplastic Lesions
Acute thyroiditis
Granulomatous thyroiditis/subacute thyroiditis
Hashimoto’s thyroiditis/lymphocytic thyroiditis
Nodular goiter
Graves’ disease
Neoplasms
Follicular Neoplasms
Follicular adenoma
Follicular carcinoma
Hurthle Cell Neoplasms
Hurthle cell adenoma
Hurthle cell carcinoma
Other Neoplasms
Papillary carcinoma
Medullary carcinoma
Poorly (insular) differentiated carcinoma
Undifferentiated (anaplastic) carcinoma
Hyalinizing trabecular neoplasm
Uncommon and Rare Lesions
Squamous cell carcinoma
Mucoepidermoid carcinoma
Sclerosing mucoepidermoid carcinoma with eosinophilia
Mucinous carcinoma
Spindle cell tumor with thymus-like differentiation
Carcinoma showing thymus-like differentiation
Lymphoma and plasmacytoma
Angiosarcoma
Smooth muscle tumor
Peripheral nerve sheath tumor
Solitary fibrous tumor
Follicular dendritic cell tumor
Langerhans cell histiocytosis
Teratoma
Ectopic thymoma
Second tumors
Kidney
Skin (melanoma )
Lung adenocarcinoma
Breast carcinoma
Gastric adenocarcinoma
Squamous cell carcinoma of the head and neck
Parathyroid
Parathyroid adenoma
Parathyroid carcinoma
The Bethesda System for Reporting Thyroid Cytopathology
FNA biopsy plays a crucial role in the assessment and triage of a thyroid nodule, and it has resulted in a significant reduction in unnecessary surgeries for patients with a benign lesion. However, some of the diagnostic categories and terminologies are inconsistent from one laboratory to another, which has created ambiguity and confusion among pathologists and clinicians. To clarify the potential misunderstanding and improve clarity of communication, the Bethesda System for Reporting Thyroid Cytopathology was introduced and published as an atlas in 2010. Six diagnostic categories and the associated risk of malignancy and recommended clinical management for each category were recommended as summarized in Table 3.1 below.
Table 3.1
Summary of the Bethesda System for Reporting Thyroid Cytopathology
Diagnostic category | Diagnosis | Risk of malignancy (%) | Recommended management |
|---|---|---|---|
Non-diagnostic or unsatisfactory | Cyst fluid only aVirtually acellular specimen | – | Repeat FNA with ultrasound guidance |
Benign | Benign follicular nodule Lymphocytic (Hashimoto’s) thyroiditis Granulomatous thyroiditis | 0–3 | Clinical follow-up |
Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance | Atypical follicular cells | 5–15 | Repeat FNA |
Follicular neoplasm or suspicious for follicular neoplasm | Follicular neoplasm Hurthle cell neoplasm | 15–30 | Lobectomy |
Suspicious for malignancy | Suspicious for papillary carcinoma, medullary carcinoma, metastatic carcinoma, lymphoma, and others | 60–75 | Lobectomy or near-total thyroidectomy |
Malignant | Papillary thyroid carcinoma (PTC) Medullary thyroid carcinoma Poorly differentiated thyroid carcinoma Anaplastic thyroid carcinoma Squamous cell carcinoma Non-Hodgkin’s lymphoma Metastatic carcinoma Others | 97–99 | Near-total thyroidectomy |
Perhaps the most important change was to introduce a distinct subcategory of “Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance.” This subcategory of lesions was defined as cellular components (follicular cells, lymphoid cells, and others) with architectural and/or nuclear atypia that is not sufficient to be classified as suspicious for a follicular neoplasm/Hurthle cell neoplasm, suspicious for malignancy, or malignancy. Also, the atypia cannot be confidently classified as benign change. The risk of malignancy in this category is about 5–15%, and a repeat FNA in a reasonable interval was suggested.
Normal Thyroid
Colloid
Colloid is the key diagnostic component for thyroid disease. Colloid appears to be light blue or blue-purple on a Diff-Quik (DQ)-stained slide (Fig. 3.1) and light purple to pink on Papanicolaou (Pap) stain (Fig. 3.2). Comparing the two staining methods, colloid is easier to observe on DQ stain. In the presence of blood and the absence of follicular cells, thin colloid can be difficult to differentiate from serum. The finding of even few follicular cells is an important clue to confirm the presence of thin or watery colloid. In general, two types of colloid are seen: one is thin or watery colloid (Fig. 3.3) and the other is thick or inspissated colloid (Fig. 3.4). When watery colloid falls off the slide, it resembles a spider web (Fig. 3.5).
Fig. 3.1
Watery colloid on DQ stain
Fig. 3.2
Watery colloid on Pap stain
Fig. 3.3
Colloid on DQ stain with cracked glass window appearance
Fig. 3.4
Thick colloid with dark blue staining on DQ stain
Fig. 3.5
Colloid fell off the slide, with spiderweb appearance on DQ stain
Follicular Cells
Follicular cells are cuboids and uniform in size, with a honeycomb arrangement. Nuclei are round, 6–9 um, with small to inconspicuous nucleoli, fine nuclear chromatin with even distribution, and a smooth nuclear contour (Fig. 3.6).
Fig. 3.6
Benign follicular cells with uniform size and orderly arrangement on DQ stain
In general, an adequate specimen should contain a minimum of six groups of well-visualized follicular cells with at least ten cells per group, preferably on a single slide, with the exception of these special circumstances: (1) colloid nodule, (2) solid nodules with cytologic atypia, and (3) solid nodules with inflammation such as lymphocytic thyroiditis or abscess .
Hurthle Cells
A subtype of follicular cells, slightly larger than normal follicular cells, with abundant granular cytoplasm, small to conspicuous nucleoli, and binucleation; they appear light purple on DQ stain and orange to pink on Pap stain (Fig. 3.7).
Fig. 3.7
Hurthle cells with large nuclei and abundant eosinophilic granular cytoplasm
Flame Cells
A subtype of follicular cells, with abundant cytoplasm with cytoplasmic fine vacuoles; they appear purple-pink on DQ stain (Fig. 3.8). They reflect the hyperfunctional status of the thyroid, such as in Graves’ disease . They can be seen in nodular goiter and subacute thyroiditis as well .
Fig. 3.8
Flame cells frequently seen in nodular goiter with hyperthyroid function
Respiratory Epithelial Cells
During the aspiration procedure, the needle may accidentally enter the trachea, and the aspirate may contain respiratory epithelial cells (Fig. 3.9).
Fig. 3.9
Ciliated columnar respiratory epithelial cells when a needle accidentally enters the trachea
Benign Thyroid Lesions
Acute Thyroiditis
Clinical Features
Rare, caused by bacteria and fungus.
Fever and neck pain.
Biopsy is generally unnecessary because of the obvious clinical presentation. If a nodular lesion is formed, then a neoplastic lesion, especially an anaplastic carcinoma, should be included in the diagnostic consideration.
Cytological Features
Numerous acute inflammatory and histiocytes (Fig. 3.10a, b)
Fig. 3.10
Acute inflammatory cells , histiocytes, and necrotic debris in acute thyroiditis (Pap stain)
Only few follicular cells
Necrotic debris or granulomatous inflammation
Fungus or bacteria can be seen on a special stain (Fig. 3.11)
Fig. 3.11
Fungal elements in acute thyroiditis (Grocott’s methenamine silver [GMS] stain)
Histologic Features
Acute inflammation with abscess formation and tissue necrosis
Differential Diagnosis
Anaplastic carcinoma
Granulomatous (de Quervain) Thyroiditis/Subacute Thyroiditis
Clinical Features
Caused by viral infection and a self-limiting process
More common in young female
Painful or painless diffuse thyroid enlargement
Cytological Features
Granulomatous inflammation with multinucleated giant cells; some giant cells may engulf colloid.
Many giant cells may contain many nuclei (many more nuclei than multinucleated giant cells seen in PTC).
Acute and chronic inflammatory cells.
Few follicular cells.
Histologic Features
Usually multiple non-caseating granulomas associated with marked inflammation
Granulomas containing foreign-body giant cells, which may engulf colloid (Figs. 3.12 and 3.13)
Fig. 3.12
A large multinucleated giant cell in subacute thyroiditis
Fig. 3.13
Epithelioid histiocytes in chronic granulomatous inflammation (DQ stain)
Thyroid follicles surrounded by granulomas and inflammation
Patchy fibrosis
Differential Diagnosis
Tuberculosis
Sarcoidosis
Mycoses
Hashimoto’s Thyroiditis/Lymphocytic Thyroiditis
Clinical Features
An autoimmune-related disease.
More common in middle-aged women.
Present with firm and diffuse enlargement of the thyroid.
Normal thyroid function in early stage and hypothyroidism in late stage.
Serological tests are positive for anti-thyroglobulin, anti-mitochondrial antibody, and anti-oxidase antibody.
Cytological Features
Infiltration of lymphocytes in Hurthle cells (Fig. 3.14a, b).
Fig. 3.14
Infiltration of lymphoid cells within Hurthle cells in Hashimoto’s thyroiditis (Pap stain and DQ stain)
Acute and chronic inflammatory cells with plasma cells.
Multinucleated giant cells.
Granulomatous inflammation.
Reduced numbers of follicular cells dependent upon of the stage of the disease. It can be divided into three phases: (1) florid lymphoid phase, predominately a mixed population of lymphoid cells with sparse Hurthle cells and follicular cells; (2) cellular phase, proliferation of Hurthle cells; and (3) fibrotic phase, fibrotic tissue, scant Hurthle cells and lymphoid cells, and squamous cells (squamous metaplasia).
Reactive atypical follicular cells /Hurthle cells; may mimic papillary carcinoma.
May coexist with papillary carcinoma, especially papillary microcarcinoma .
Histologic Features
Typically diffuse involvement of the thyroid both grossly and microscopically but can be a localized process with a distinct nodular involvement.
Thyroid follicles with oncocytic changes and epithelial atrophy.
Lymphoplasmacytic infiltration of the stroma with many large lymphoid follicles, which contain prominent germinal centers (Fig. 3.15a–c).
Fig. 3.15
Histologic sections of Hashimoto’s thyroiditis with oncocytic follicular cells with lymphoid cell infiltration (a, b), prominent germinal center (c) and Hurthle cell/follicular cells with reactive atypia (d)
Lymphoplasmacytic cells infiltrating oncocytic follicular cells.
Lymphoid cells, plasma cells, histiocytes, and scattered granulomas.
Patchy fibrosis or extensive fibrosis with dense hyaline-type collagens.
Squamous metaplasia is common.
Cystic formation may be present.
Immunohistochemistry
Reactive oncocytic follicular cells may be positive for galectin-3 and Hector Battifora mesothelial epitope-1 (HBME-1) but usually negative for cytokeratin (CK) 19 and tumor-associated calcium signal transducer 2 (TROP2 ).
Differential Diagnosis
Papillary carcinoma
Hurthle cell neoplasm
Lymphoma
Riedel’s thyroiditis
Nodular Goiter
Clinical Features
The most common benign lesion
More common in middle-aged women
Normal thyroid function; sometimes hyper- or hypothyroidism
Goiter with multiple nodules
Cytological Features
Abundant colloid and small amount of follicular cells (Figs. 3.16, 3.17, 3.18, 3.19, 3.20, and 3.21).
Fig. 3.16
Nodular goiter /hyperplasia with abundant watery colloid, benign follicular cells, and histiocytes (Pap stain)
Fig. 3.17
Benign follicular cells in a nodular goiter/hyperplasia (DQ stain)
Fig. 3.18
Hurthle cells in a nodular goiter/hyperplasia (Pap stain)
Fig. 3.19
Hurthle cells in a nodular goiter (Pap stain)
Fig. 3.20
Hurthle cells in a nodular goiter/hyperplasia (DQ stain)
Fig. 3.21
Histiocytes in a nodular goiter/hyperplasia with degenerative change (DQ stain)
Mixed population of follicular cells, Hurthle cells, and histiocytes.
Pigment-laden histiocytes, foamy histiocytes, and stromal cells.
Follicular cells are arranged in a honeycomb pattern with follicles of variable sizes.
Focal reactive atypical follicular cells can be seen .
Histologic Features
A wide spectrum of histologic changes can be seen (Fig. 3.22a–c).
Fig. 3.22
Histologic sections of nodular goiter with Hurthle cells changes, calcification, and degenerative and regenerative changes
Multiple nodules, some surrounded by partial or even complete capsules.
Huge follicles lined by flattened follicular epithelium, a mixture of follicles of variable sizes, cellular nodules with microfollicles, or cellular nodules with hyperplastic changes, including papillary formations.
Focal or diffuse Hurthle cell changes.
Secondary changes such as hemorrhage, cystic degeneration, fibrosis, calcification, or even ossification.
Rupture of follicles with granulomatous reaction, foreign body-type multinucleated giant cells, and variable numbers of chronic inflammatory cells .
Differential Diagnosis
Follicular neoplasm
Hurthle cell neoplasm
Papillary carcinoma
Neoplastic Thyroid Lesions
Follicular Neoplasm
Including follicular adenoma and follicular carcinoma
Follicular Adenoma
Clinical Features
Common benign neoplasm
More common in women
Usually present with a solitary, well-circumscribed, mass
Cytological Features
Hypercellular specimen with numerous groups of follicular cells and little or no colloid (Figs. 3.23 and 3.24).
Fig. 3.23
Follicular neoplasm (DQ stain) with microfollicular growth pattern and lack of colloid in the background
Fig. 3.24
Follicular neoplasm (DQ stain) with microfollicular growth pattern, nuclear enlargement, and nuclear crowding
Microfollicular growth pattern (defined as 6–12 crowded follicular cells in a ring or rosette-like structure, with or without colloid in the center).
Relatively uniform population of follicular cells without other types of cells, such as Hurthle cells and histiocytes.
Follicular cells are enlarged in size with round nuclei.
Focal nuclear atypia can be present .
Histologic Features
A follicular nodule enclosed by a fibrous capsule of variable thickness (Fig. 3.25a).
Fig. 3.25
Histologic sections of follicular adenoma with thin fibrous capsule (a), microfollicular and solid pattern (b), trabecular pattern (c), macrofollicular (d), clear cell changes (e), and bizarre nuclei (f)
Absence of capsular or vascular invasion.
The architectural patterns may include microfollicular and solid (Fig. 3.25b), trabecular (Fig. 3.25c), normofollicular, and macrofollicular architectures (Fig. 3.25d).
The tumor cells are cuboidal, columnar or polygonal, and frequently with uniform, dark, round nuclei.
Foci of large nuclei or atypical nuclei with degenerative changes can be seen.
Mitotic figures are rare.
Many histologic variants have been described, such as clear cell follicular adenoma (Fig. 3.25e), oncocytic follicular adenoma, signet-ring cell follicular adenoma, lipoadenoma, mucinous follicular adenoma, follicular adenoma with bizarre nuclei (Fig. 3.25f), follicular adenoma with papillary hyperplasia, and hyperfunctioning follicular adenoma.
Secondary changes, such as myxoid change, cyst formation, fibrosis, hyalinization, hemorrhage, cartilaginous metaplasia, ossification, and calcifications, can be seen .
Immunohistochemistry
Positive for TTF1 , PAX8 , and thyroglobulin
Negative for calcitonin and neuroendocrine markers
Can be positive for HBME-1 and galectin-3 ; usually negative for CK19 and TROP2
Differential Diagnosis
Cellular nodular goiter
AUS/FLUS
Follicular variant of papillary carcinoma
Follicular Carcinoma
Clinical Features
More common in 40- to 60-year-old women.
Accounts for 10% of thyroid carcinomas.
A slow-growing neoplasm.
Can be divided into two types: minimally invasive type which is rarely going for distant metastasis ; another type is widely invasive type which is frequently goes for a distant metastasis and has a worse prognosis than papillary carcinoma of the thyroid .
In general, there are no definitive criteria to separate follicular adenoma from follicular carcinoma on an FNA sample.
Crowded and three-dimensional follicular structures.
Microfollicles with irregular shapes and many single cells.
Nuclear pleomorphism.
Nuclear enlargement (three to four times that of normal follicular cells).
Coarse and irregular nuclear chromatin.
High nuclear-to-cytoplasmic ratio.
Prominent and multiple nucleoli.
Mitoses can be seen .
Fig. 3.26
Nuclear enlargement , crowding, and pleomorphism, suggestive of follicular carcinoma
Fig. 3.27
Marked nuclear atypia , suggestive of follicular carcinoma (DQ stain)
Fig. 3.28
Follicular carcinoma on Pap stain
Histologic Features
A follicular nodule enclosed by a thick fibrous capsule showing definite capsular and/or vascular invasion.
Lack of diagnostic nuclear features of PTC.
Can have variable architectural patterns and cytological features.
Classically, it can be divided into two categories: (1) minimally invasive follicular carcinoma with limited capsular invasive and vascular invasion (less than four vessels) and (2) widely invasive follicular carcinoma with widespread capsular and vascular invasion (greater than four vessels).
Fig. 3.29a–g shows some examples of capsular and vascular invasion.
Fig. 3.29
Histology section of follicular carcinoma with capsular invasion (e) and vascular invasion (f, g)
Oncocytic variant and clear cell variant have been described .
Immunohistochemistry
Similar to follicular adenoma
Can be positive for HBME-1 and galectin-3 ; usually negative for CK19 and TROP2
Differential Diagnosis
Follicular adenoma
Follicular variant of papillary carcinoma
Hurthle Cell Neoplasm (Figs. 3.30, 3.31, 3.32, and 3.33a–c)
May be considered a subtype of follicular neoplasm
Uniform population of Hurthle cells in small clusters and single cells
Little or no colloid
Prominent or small nucleoli
Three-dimensional or crowded structures
Features suggestive for Hurthle cell carcinoma , including nuclear pleomorphism, multiple and prominent nucleoli, high nuclear-to-cytoplasmic ratio, nuclear crowding, and mitoses
Fig. 3.30
Hurthle cell neoplasm with groups of Hurthle cells and absence of colloid in the background (DQ)
Fig. 3.31
Histology section of Hurthle cell adenoma
Fig. 3.32
Hurthle cell carcinoma on FNA smear (DQ)
Fig. 3.33
Histologic sections of Hurthle cell carcinoma (a) with capsular (b) and vascular invasion (c)
Hyalinizing Trabecular Neoplasm
Clinical Features
A rare tumor of follicular cell origin.
The nuclear features of the tumor suggest that it may be related to PTC.
Rearranged during transfection (RET)/PTC rearrangements have been reported in some tumors.
Much more common in middle-aged women .
Cytological Features (Fig. 3.34a–d)
Similar cytological features to papillary carcinoma.
Hyalinizing material may be present between tumor cells.
Tumor cells may be more elongated or even spindle.
Nuclear grooves and intranuclear inclusions are frequent findings.
Psammoma bodies can be seen .
Fig. 3.34
Hyalinizing trabecular adenoma with many cytological features of PTC, including intranuclear inclusion. Note that eosinophilic hyalinizing material between cells (a, DQ) and cellblock (d)
Histologic Features
A solid neoplasm with or without thin fibrous capsule.
Trabecular or alveolar growth pattern.
Polygonal or spindle tumor cells, with granular to clear cytoplasm, with a prominent hyaline stroma between nests or trabeculae of tumors.
Elongated nuclei, centrally located, with nuclear grooves and intranuclear pseudoinclusion (Fig. 3.35a, b).
Fig. 3.35
Hyalinizing trabecular adenoma . Histologic sections showing elongated nuclei, centrally located with nuclear grooves and intranuclear pseudoinclusion (a, b). Note that MIB-1 (Ki-67) immunostain on histology section showing distinct membranous staining pattern (c)
Mitotic figures are rarely seen; psammoma bodies may be present.
Usually absence of colloid .
Immunohistochemistry
MIB-1 (a specific clone for Ki-67) staining showing distinctive membranous staining pattern in the majority of cases (Fig. 3.35c)
Frequently positive for galectin-3 ; can be positive for CK19
Positive for TTF1 and PAX8 and negative for calcitonin and neuroendocrine markers
Differential Diagnosis
Papillary carcinoma
Medullary carcinoma
Table 3.2 below summarizes useful markers for the distinction among these three tumors.
Table 3.2
Differentiation of hyalinizing trabecular neoplasm, papillary carcinoma, and medullary carcinoma by immunostains
Marker
Hyalinizing trabecular neoplasm
Papillary carcinoma
Medullary carcinoma
Thyroglobulin
+
+
−
Calcitonin
−
−
+
MIB-1 (Ki-67)
Membranous
Nuclear
Nuclear
PTC (Papillary Thyroid Carcinoma)
Clinical Features
Accounts for about 70% of malignant thyroid neoplasms.
More common in young females, with female-to-male ratio of 4:1, especially under age 40.
Slow growing; patient may survive for many years even after local lymph node metastasis .
Papillary microcarcinoma is defined as a tumor 1 cm or less in diameter.
Tall cell variant , columnar cell variant , diffuse sclerosing variant , and solid variant tend to show a more aggressive clinical behavior than a conventional PTC .
Cytological Features of Conventional PTC (Figs. 3.36, 3.37, 3.38, 3.39, 3.40, 3.41, 3.42, 3.43, 3.44, 3.45, 3.46, 3.47, and 3.48)
Hypercellular specimen with three-dimensional or two-dimensional papillary structures
Nuclear enlargement, overlapping, open nuclear chromatin, small and marginated nucleoli, nuclear grooves, and intranuclear cytoplasmic inclusions
Squamoid cytoplasm, oncocytic cytoplasm, or cytoplasm with small vacuoles
Thick colloid or gummy colloid
Multinucleated giant cells
Psammoma bodies
Fig. 3.36
Papillary carcinoma with two-dimensional papillary structure (DQ stain)
Fig. 3.37
Papillary carcinoma with three-dimensional papillary fronds (DQ stain)
Fig. 3.38
Papillary carcinoma with nuclear enlargement and squamoid cytoplasm (DQ stain)
Fig. 3.39
Papillary carcinoma with nuclear enlargement, overlapping, nuclear grooves, and intranuclear inclusions (Pap stain)
Fig. 3.40
Papillary carcinoma with squamoid cytoplasm and septated cytoplasmic vacuoles and intranuclear cytoplasmic inclusion (DQ stain)
Fig. 3.41
Papillary carcinoma with open nuclear chromatin, grooves, and intranuclear cytoplasmic inclusions (Pap stain)
Fig. 3.42
Papillary carcinoma . Cytoplasmic vacuoles (Pap stain)
Fig. 3.43
Papillary carcinoma . Squamoid cytoplasm (Pap stain)
Fig. 3.44
Papillary carcinoma . Multinucleated giant cells (Pap stain)
Fig. 3.45
Papillary carcinoma . Psammoma body (Pap stain)
Fig. 3.46
Papillary carcinoma . Psammoma body (DQ stain)
Fig. 3.47
Papillary carcinoma . Gummy/sticky colloid (DQ stain)
Fig. 3.48
Papillary carcinoma . Multinucleated giant cells (DQ stain)
Cytologic Features for Variants of PTC
Follicular Variant
Resembles an FNA smear of follicular neoplasm.
Tumor cells mostly arranged in microfollicles with absence or near absence of papillary structures.
Nuclear features for PTC tend to be subtle when comparing to a classical PTC.
Less intranuclear pseudoinclusions.
Multinucleated giant cells, psammoma bodies, and cystic changes are usually absent.
Follicular neoplasm and parathyroid neoplasm are included in the diagnostic consideration .
Tall Cell Variant
Resembles a classic PTC.
The tumor cells have an elongated shape, with a height-to-width ratio of 3:1 or greater (Fig. 3.49a, b).
Fig. 3.49
Cytologic features of some variants, tall cell variant (a, b), cystic variant (c), and Warthin-like variant (d)
Classic nuclear features are needed to render a definitive diagnosis.
Columnar Cell Variant
The neoplastic cells are arranged in papillae, groups, and sheets.
The nuclei are elongated and stratified.
The nuclear chromatin tends to be more hyperchromatic than open chromatin.
The intranuclear inclusions are less prominent.
Definitive nuclear changes for PTC are required to render a diagnosis.
Macrofollicular Variant
Resembles a benign colloid nodule on a low-power view with a mixture of sheets of follicular cells, some with microfollicular patterns, and abundant colloid.
Diagnosis is based on the observation of nuclear changes for PTC at higher magnification. In general, these tend to be subtle.
Oncocytic Variant
Resembles Hurthle cell proliferation, including Hurthle cell neoplasm.
The majority of tumor cells contain abundant oncocytic cytoplasm and are isolated or arranged in sheets or papillae.
Classic nuclear changes for PTC, including intranuclear inclusions.
Absence of lymphoid cells.
Nucleoli tend to be more conspicuous than in a conventional PTC; however, prominent nucleoli, frequently seen in a Hurthle cell neoplasm, are not typical features for an oncocytic variant of PTC .
Cystic Variant
Resembles a colloid cyst with very low cellularity or mainly hemosiderin-laden histiocytes and clear background.
Only a few groups of neoplastic follicular cells are present, and they are usually arranged in a small groups, sheets, papillae, or follicles (Fig. 3.49c).
The tumor cells may show “histiocytoid” features with cytoplasmic vacuoles.
Identification of diagnostic nuclear features for PTC, including intranuclear inclusions, is required to render a diagnosis .
Warthin-Like Variant
Resembles Hashimoto’s thyroiditis.
Oncocytic tumor cells arranged in sheets, groups, and papillary and follicular structures.
Lymphoplasmacytic background with lymphoid cells and plasma cells intimately associated with tumor cells (Fig. 3.49d).
Classic nuclear features for PTC are required to render a diagnosis .
Histologic Features
The characteristic nuclear features mentioned above are the key to making a diagnosis.
Complex papillary architectures with branching and squamous metaplasia are commonly seen.
The papillae may have markedly edematous changes.
Cystic changes are frequent.
Psammoma is frequently present.
Many histologic variants are present: (1) follicular variant (Fig. 3.50a), (2) oncocytic variant , (3) tall cell variant (Fig. 3.50b, c), (4) columnar cell variant , (5) diffuse sclerosing variant , (6) clear cell variant, (7) solid variant, (8) cystic variant (Fig. 3.50d, e), (9) cribriform variant (Fig. 3.50f, g), (10) macrofollicular variant , and (11) Warthin-like variant (Fig. 3.50h).
Fig. 3.50
Histologic sections of follicular variant (a), tall cell variant (b, c), cystic variant (d, e), cribriform variant (f, g), and Warthin-like variant (h)
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