Thyroid carcinomas
Other thyroid tumors
Papillary carcinoma
Teratoma
Follicular carcinoma
Primary lymphoma and plasmacytoma
Poorly differentiated carcinoma
Ectopic thymoma
Undifferentiated (anaplastic) carcinoma
Angiosarcoma
Squamous cell carcinoma
Smooth muscle tumors
Mucoepidermoid carcinoma
Peripheral nerve sheath tumors
Sclerosing mucoepidermoid carcinoma with eosinophilia
Paraganglioma
Mucinous carcinoma
Solitary fibrous tumor
Medullary carcinoma
Follicular dendritic cell tumor
Mixed medullary and follicular carcinoma
Langerhans cell histiocytosis
Spindle cell tumor with thymus-like differentiation
Secondary tumors
Carcinoma showing thymus-like differentiation
Parathyroid tumors
Thyroid adenoma and related tumors
Parathyroid carcinoma
Follicular adenoma
Parathyroid adenoma
Hyalinizing trabecular tumor
Secondary tumors
Pediatric thyroid nodules have been reported to be more frequent in females, with a female-to-male ratio of 3:1 or more [10, 20, 21]. This ratio is markedly lower under the age of 10 years, at 1.5:1, and male children younger than 12 years (prepubertal) are more likely to have malignancy [21].
Age is an important factor in the incidence and recurrence of pediatric thyroid carcinoma. Thyroid carcinoma is more common in adolescents, although there are reports of such cases in the neonatal period [8]. Children under 10 years are more likely to have a recurrent carcinoma [1, 22]. The peak incidence of thyroid carcinoma in children is noted between the ages of 12 and 16, with the average age being 12–13 years [1].
Thyroid carcinoma in children usually manifests as an asymptomatic neck mass, but often the first manifestation of a tumor is cervical lymphadenopathy, which occurs in 35–80% of cases [9, 15]. A considerable number of children with thyroid carcinoma have a genetic predisposition [19]. Approximately 25% of medullary carcinomas are hereditary, while more than 75% are sporadic [18, 19]. A family history of MTC, pheochromocytoma, or hyperparathyroidism may indicate multiple endocrine neoplasia 2A (MEN2A) or multiple endocrine neoplasia 2B (MEN2B) . The disease is caused by germline mutation in the RET gene, and has an autosomal dominant inheritance with variable expressivity. Children with MEN2B usually present at an earlier age than children with MEN2A, and have a higher risk for aggressive forms of medullary carcinoma [11, 18]. Approximately 5% of the follicular cell carcinomas also have a hereditary origin. The main types are familial papillary and Hürthle cell thyroid carcinomas. Familial nonmedullary thyroid carcinoma may include Carney’s complex (PPKAR1A gene mutation), with a multiple neoplasia and lentiginosis syndrome that affects endocrine glands, including the pituitary, adrenals, and testes [17]. Familial nonmedullary thyroid carcinoma may be a part of Cowden’s syndrome (PTEN gene mutation), also known as multiple hamartoma syndrome, with a cancer-associated dermatosis. It is characterized by hamartomas of the gastrointestinal tract and cancer of the breast, endometrium, brain, and thyroid [23]. From 67 to 85% of patients with these syndromes have multiple thyroid nodules that are associated with a risk of malignancy. Familial nonmedullary thyroid tumors are noted as a component of familial adenomatous polyposis (FAP) (APC gene mutation). In 1–2% of patients with FAP, thyroid carcinoma is also observed [18, 19].
Ultrasonography (US) of the thyroid gland is an important part of the diagnostic algorithm. In children, as in adults, a number of characteristics seen in US are associated with a higher risk of malignancy: solitary solid lesion, hypoechogenic and heterogeneous echostructure, subcapsular localization, irregular margins, calcifications [24–26]. Solid nodules are associated with a higher risk of thyroid carcinoma, although the presence of a cyst does not exclude malignancy. Color-Doppler sonography indicates an intensive intranodular flow within a highly vascularized lesion [27]. One of the most important functions of ultrasonography is the ability to perform fine needle aspiration biopsy (FNAB) of the thyroid gland [28].
Thyroid scintigraphy is most useful in revealing tissue function in thyroglossal duct cysts and in diagnosing ectopic thyroid, but is not helpful indistinguishing malignant from benign disease [29].
Noncontrast CT scans can be used in children with substernal location, local invasion, or lymph node metastasis [3].
8.2 Cytomorphology
Nodules of the thyroid gland may be successfully diagnosed cytologically using palpatory technique or by guided ultrasound [2]. In children, Bethesda criteria seem to accurately identify benign nodules, but other categories have a very high rate of malignancy and require more histological evaluation (Bethesda System for Reporting Thyroid Cythopathology-BSRTC) (Table 8.2) [14].
I | Nondiagnostic or unsatisfactory |
Cyst fluid only | |
Virtually accellular specimen | |
Other (blood, artifact, etc.) | |
II | Benign |
Benign follicular nodule (adenomatoid nodule, colloid nodule, etc.) | |
Lymphocytic (Hashimoto) thyroiditis | |
Granulomatous (subacute) thyroiditis | |
Other (blood, artifact, etc.) | |
III | Atypia of undetermined significance or follicular lesion of undetermined significance |
IV | Follicular neoplasm or suspicious for a follicular neoplasm |
Specify if Hürthle cell (oncocytic) type | |
V | Suspicious for malignancy |
Suspicious for papillar carcinoma | |
Suspicious for medullary carcinoma | |
Suspicious for metastatic carcinoma | |
Suspicious for lymphoma | |
Other | |
VI | Malignant |
Papillary thyroid carcinoma | |
Poorly differentiated carcinoma | |
Medullary thyroid carcinoma | |
Undifferentiated (anaplastic) carcinoma | |
Squamous cell carcinoma | |
Carcinoma mixed features (specify) | |
Metastatic carcinoma | |
Non-Hodgkin lymphoma | |
Other |
8.3 Thyroglossal Duct Cyst
Remnants of the thyroglossal duct can develop into cyst. Approximately half of thyroglossal duct cysts manifest during childhood and adolescence, commonly before the age of 5, and a significant number are evident at the time of birth [3, 31]. Specimens obtained by fine needle aspiration of thyroglossal duct cysts have scant cellularity with macrophages, inflammatory cells, and outnumber epithelial cells in a background of amorphous proteinaceous material and cholesterol crystals. Ciliated columnar, squamous cells may be combined with anucleated squames. Thyroid follicles are seen rarely.
The differential diagnosis of thyroglossal duct cysts includes dermoid and epidermoid cysts, midline cervical cleft, cystic degeneration of colloid nodule, lymph node metastasis with cystic degeneration, branchial cleft cyst, and teratoma. Malignant transformation occurs in 1% or fewer of thyroglossal duct cysts. In most cases this is papillary carcinoma, which has the same histological features as in the thyroid gland.
8.4 Benign Follicular Nodule
Benign follicular nodule is the general cytopathologic description of condition clinically known as goiter. It combines the benign lesions with similar cytological features such as colloid nodules hyperplastic nodules, nodules in Graves’s disease and macrofollicular types of follicular adenomas [9, 16, 30].
Specimens are sparsely to moderately cellular. Follicular cells can be present in monolayer sheets and/or singly, three-dimensional spheres, and, rarely, in microfollicles. Follicular cells nuclei are oval-to-round with uniformly granulated chromatin. Minimal nuclear crowding and light anisonucleosis can occur in some cases. Oncocytes, multinucleated giant cells, and macrophages also can be seen in the background of colloid, which may be thin and watery or thick and dense. It is dark blue with Romanowsky-type stain or green-to-orange-pink with Papanicolaou stain.
Hyperplastic (adenomatoid) nodules may have moderate-to-high cellularity and scanty colloid. In such cases, smears consist of spheres and large monolayer sheets of follicular cells without significant overlapping and atypia. In patients with Grave’s disease, large sheets of “flame” cells have abundant cytoplasm with marginal cytoplasmic vacuoles and red edges. Occasionally the follicular cells have rare intranuclear grooves and focal chromatin clearing. Sometimes follicular cells show microfollicular architecture, significant nuclear overlapping, and crowding and atypia.
8.4.1 Ancillary Techniques
In Grave’s disease , cells typically reveal proliferative activity under 5% as measured by Ki-67 and retain p27 immunoreactivity in most nuclei [18].
8.4.2 Differential Diagnosis
Morphologically , the differential diagnosis includes follicular tumors (follicular adenoma and carcinoma), papillary carcinoma, particularly the follicular variant, and chronic lymphocytic thyroiditis.
8.5 Chronic Lymphocytic Thyroiditis
Chronic lymphocytic thyroiditis is the most frequent form of thyroiditis among children and adolescents. The juvenile variant is an ill-defined form of chronic lymphocytic thyroiditis that occurs in younger individuals and histologically shows little or no follicular atrophy. Chronic lymphocytic thyroiditis is usually associated with circulated antibodies to thyroglobulin, thyroperoxidase (microsomal antigen) colloid antigen, and thyroid hormones. Autoimmune thyroiditis is considered to be a condition preventing the expansion of neoplasm. Individuals with chronic lymphocytic thyroiditis have an increased risk of primary thyroid lymphoma. A nodule in lymphocytic thyroiditis may progress to carcinoma (Fig. 8.1), especially papillary thyroid carcinoma, but also can be associated with benign tumor [9, 10].
Fig. 8.1
Papillary thyroid carcinoma associated with chronic lymphocytic thyroiditis. A cluster of tumor cells and scant lymphocytic infiltration, May-Grünwald-Giemsa (MGG)
Aspirates are usually hypercellular and consist of polymorphic lymphoid cells and oncocytic cells. The lymphoid population includes small lymphocytes, reactive lymphoid cells, and plasma cells. Oncocytes (Hürthle cells) are arranged in layers and separately. Oncocytes have abundant granular cytoplasm and large nuclei with prominent nucleoli. Follicular cells and oncocytes can occasionally demonstrate reactive changes and mild atypia, including nuclear enlargement, grooves, and chromatin clearing. Occasional squamous metaplasia may be seen in chronic lymphocytic thyroiditis.
8.5.1 Differential Diagnosis
The differential diagnosis includes papillary carcinoma, malignant lymphoma, and follicular neoplasm, oncocytic type. In lymphocytic thyroiditis nodules, oncocytes usually form small cohesive clusters of cells with large nuclei and sometimes glassy chromatin. This nuclear atypia can mimic changes in papillary carcinoma, and it is not typical of the Hürthle cell type of follicular neoplasm. In these cases it is necessary to use ancillary techniques, such as molecular diagnostics, to detect the presence of BRAF mutation, RET/PTC, and some types of mRNA.
8.6 Follicular Adenoma
Follicular adenoma is a benign, encapsulated, noninvasive tumor of thyroid follicular cells. Oncocytic follicular adenoma is the most common variant of follicular adenoma [3, 12].
Cytologic specimens are markedly cellular with numerous microfollicular structures. Microfollicles are composed of 6–12 follicular cells arranged in small spherical structures. Dense colloid may be seen in the center of the microfollicle. Microfollicles tend to be relatively uniform in size. Rare macrofollicles and a small amount of colloid may be present in specimens. Follicular cells in follicles are round-to-polygonal, with uniform round-to-oval nuclei. An important defining feature of microfollicles is the crowding and overlapping of follicular cells. The nuclear membranes are smooth and without significant irregularities. Nuclear grooves—intranuclear pseudoinclusions associated with papillary carcinoma—are absent. Erythrocytes and a small amount of colloid are present in the background of smears (Fig. 8.2).
Fig. 8.2
Follicular neoplasm: follicular adenoma , MGG
Cytological samples of oncocytic (Hürthle cell type) follicular adenomas contain sheets of large cells with a relatively low nuclear-to-cytoplasmic ratio and abundant finely granular chromatin, enlarged central or eccentrically located round nuclei, and prominent nucleoli. Hürthle cells are typically variable in size, from small to large. Occasional cells may show nuclear membrane irregularities, grooves, and chromatin clearing. There is usually little or no colloid. In some cases, vessels are visible.
8.6.1 Ancillary Techniques
The immunohistochemistry profile of follicular adenoma cells is similar to those of normal thyroid. The cells are reactive for thyroglobulin, TTF-1, PAX8, low-molecular-weight cytokeratins, and some intermediate-molecular-weight cytokeratins [18, 32].
Clonal cytogenetic aberrations have been detected in about 45% of thyroid adenomas. Chromosome 7 is most frequently affected with gains of one or more copies, followed by gains of chromosomes 12 and 5. RAS mutations have been detected in follicular adenomas, follicular carcinomas, and multinodular goiter, but not in toxic adenomas [18].
8.6.2 Differential Diagnosis
Because of the same cytological features, follicular adenoma belongs to “Follicular neoplasm/Suspicious for Follicular neoplasm” category in BSRTC terminology, which includes also follicular carcinoma and nodular hyperplasia. It is impossible to cytologically distinguish follicular adenoma from follicular carcinoma. The final diagnosis depends on the presence or absence of capsular and/or vascular invasion. In some cases, parathyroid adenoma can mimic follicular neoplasm. Follicular neoplasm, Hürthle cell type, must first be differentiated from oncocytes hyperplasia in lymphocytic thyroiditis [30].
8.7 Follicular Carcinoma
Follicular carcinoma is a malignant well-differentiated tumor of thyroid follicular cells that lacks the diagnostic nuclear features of papillary carcinoma. The main histopathologic variant of follicular carcinoma is oncocytic (Hürthle cell) follicular carcinoma [11]. Most of the tumors are well-differentiated and represent minimally invasive follicular carcinoma. There are several rare microscopic variants of follicular carcinoma: clear cell variant, mucinous variant, and follicular carcinoma with signet-ring cells. The cytological features of follicular carcinoma and Hürthle cell follicular carcinoma are similar to those of the follicular adenomas (Fig. 8.3). For this reason, carcinoma is classified as “Follicular neoplasm/Suspicious for Follicular neoplasm” in BSRTC [30].
Fig. 8.3
Follicular neoplasm: follicular carcinoma , MGG
In some cases there are a small proportion of microfollicles with crowded and overlapping cells in the sparsely cellular aspirate. Such cases can be classified as Atypia of Undetermined Significance (BSRTC). If the follicular cells show features of papillary thyroid carcinoma, the specimen should be interpreted as “Malignant, Papillary thyroid carcinoma” or “Suspicious for Malignancy, suspicious for papillary thyroid carcinoma.”
8.7.1 Ancillary Techniques
The cells of follicular carcinoma are reactive for thyroglobulin, TTF-1, and PAX8. This makes it possible to detect the thyroid follicular cell origin of distant metastases. The pattern of reactivity for cytokeratins in follicular carcinoma is similar to normal thyroid cells. Significant negative markers are calcitonin, CEA, and neuroendocrine markers (chromogranin, synaptophyisin, CD56, NSE). Oncocytic carcinomas show a similar pattern of immunoreactivity.
Some types of follicular carcinomas can be positive for Galectin-3, HMBE, and CITED1, but these markers are not specific for malignancy. Ten to thirty percent of follicular adenomas demonstrate positivity for any one of these markers. The proliferative index detected by Ki-67 immuno-staining varies from 5 to 20% depending on the degree of invasiveness and metastasis. Most follicular carcinomas reveal to TP53 staining and preserve Bcl-2 and E-cadherin immunoreactivity [11, 30, 32].
8.7.2 Molecular Diagnostics
The finding of PAX8/PRAPy can be used to assist in the diagnosis of malignancy, but it also can be seen in 5% of adenomas. RAS mutations are found in 40–50% of follicular carcinomas, in 40% of follicular variant of papillary carcinoma, and in 30% of follicular adenomas. Detection of RAS mutation can be used in thyroid FNA samples.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
