Cytodiagnosis and Its Limitations
a. overlap of cytological patterns between neoplastic and non-neoplastic lesions.
b. overlap of cytological features between various neoplasms.
c. coexistence of non-neoplastic and neoplastic processes and multiple malignancies in the same gland.
For a practical diagnostic approach, the cytological findings of thyroid lesions may be divided into seven main groups, as recommended by the Papanicolaou Task Force on Standard of Practice. These groups are heterogenous and consist of both neoplastic and non-neoplastic lesions that may show either similar or specific cytological manifestations. A non-diagnostic group is added as some TNs yield inadequate or non-specific cytological findings. The above-mentioned groups with their commonly encountered thyroid lesions are tabulated in Table 1.
1. Benign Colloid Nodule
This group includes solitary benign colloid nodules and prominent benign colloid nodules in a multinodular colloid goiter. These lesions arecharacterized by abundant, thick colloid material with cracking or bubble pattern (Figs. 1 and 2) and sheets of benign follicular epithelial cells in honeycomb arrangement (Fig. 3). Clusters of slightly hyperplastic Hurthle cells may be present. The cytological differential diagnosis between a benign colloid nodule and a macrofollicular adenoma of the thyroid is extremely difficult if not impossible, as the two lesions usually show abundant, thick colloid and similar follicular cells.
2. Cellular Microfollicular Lesion
This group includes hyperplastic microfollicular nodules in a multinodular colloid goiter or Hashimoto thyroiditis, a microfollicular adenoma, and a well-differentiated follicular carcinoma. These lesions are the most challenging ones to diagnose cytologically. They are commonly reported as a microfollicular lesion or tumor with a recommendation for surgical excision. FNA from a microfollicular lesion usually reveals abundant follicular cells in clusters, acini and small monolayered sheets (Figs 4 and 5). The individual cells show scanty, ill-defined cytoplasm and oval nuclei with regular nuclear contours and inconspicuous or prominent nucleoli.
Cellular microfollicular lesions of the thyroid fall into the diagnostic category of indeterminate or suspicious lesions, and in one large series 14% of microfollicular lesions were malignant.
3. Hurthle Cell Lesion
Diagnosis of Hurthle cell lesions is a challenge in thyroid cytology. A hyperplastic Hurthle cell nodule in a Hashimoto thyroiditis or in a multinodular colloid goiter and a Hurthle cell neoplasm display similar cytologic findings. The presence of numerous lymphocytes or a large amount of thick colloid material in the needle aspirate may indicate a hyperplastic Hurthle cell nodule in Hashimoto disease or a multinodular colloid goiter, respectively. Hurthle cell adenoma and carcinoma usually show similar cytologic findings that are characterized by sheets and clusters of polygonal epithelial cells with abundant, granular, eosinophilic or basophilic cytoplasm, oval nuclei with regular nuclear contours and conspicuous or inconspicuous nucleoli (Figs. 6 and 7). The presence of syncytial clusters of Hurthle cells with or without prominent nuclei and abundant naked tumor cell nuclei has been reported to be a feature of Hurthle cell carcinoma.
When a Hurthle cell lesion is detected by FNA, surgical excision is usually indicated for further histologic study. Thyroid Hurthle cell lesions fall into the cytodiagnostic category of indeterminate lesions or suspected malignant lesions, and 13% of Hurthle cell lesions were malignant in one large series.
4. Primary Malignant Lesions
This group includes papillary, high-grade follicular, insular, medullary and anaplastic carcinomas, and lymphoma. These lesions commonly show distinctive cytologic features that permit a correct identification in the majority of cases. An insular carcinoma, or poorly differentiated carcinoma yields small cells in clusters, similar to those of a high-grade microfollicular carcinoma.
4a. Papillary carcinoma (PC). The conventional PC is characterized in FNA by the presence of thick or thin papillary tissue fragments with fibrovascular cores, sheets of tumor cells showing focal nuclear crowding and overlapping, irregular nuclear contours, intranuclear cytoplasmic inclusions (INCI) and nuclear grooves (NG). Psammoma bodies and metaplastic squamous cells may also be present (Figs. 8, 9, 10, 11, 12, 13). These nuclear changes are recognized with less difficulty in Papanicolaou-stained cell samples, but they may be difficult to identify in cell samples stained with the Romanowsky staining method. However, a presence of minute true papillary tissue fragments with fibrous vascular cores even without the identifiable above-mentioned nuclear changes is indicative of a PC. These papillary tissue fragments should be differentiated from thick and large follicular epithelial cell clusters with vascular transgression that may be found in FNA from different types of non-papillary epithelial neoplasms of the gland.
- Micro- and macrofollicular PCs constitute a diagnostic challenge. A microfollicular PC may show in FNA follicular cells forming acini similar to those seen in the aforementioned cellular microfollicular lesions, and a macrofollicular PC may be easily mistaken for a macrofollicular adenoma or a benign colloid nodule cytologically, as nuclear changes characteristic for a thyroid PC may not be seen (Fig. 14).
- Hyalinizing trabecular adenoma is indistinguishable from a PC cytologically, as these two lesions yield cells with similar nuclear features 44. Recent molecular studies have suggested that this tumor is actually an encapsulated trabecular variant of thyroid PC.
- Other PC carcinoma subtypes. Tall-cell PC is characterized by the presence of tall tumor cells with well-defined, granular cytoplasm and nuclei with NGs and single or multiple INCIs, making at least 30% of the aspirated cells (Fig. 15). Columnar-cell variant shows no classic cytologic features of thyroid PC, but presence of clusters of columnar cells with palisading nuclei and the absence of classic nuclear changes of thyroid PC are cellular features of this neoplasm. Diffuse sclerosing variant can be confidently suggested when abundant squamous cells admixed with lymphocytes, follicular epithelial cells with nuclear features of papillary carcinoma and a few psammoma bodies are noted (Fig. 16).
4b. A high-grade follicular carcinoma and insular carcinoma are characterized by sheets and acinar clusters of pleomorphic epithelial cells with prominent nucleoli.
4c. A medullary carcinoma shows in FNA a mixture of single and clustered polygonal cells and spindle tumor cells that may display INCIs (Figs. 17 and 18). The tumor cells cytoplasm may show intracytoplasmic pink azurophil granules that are well-visualized by MGG or Diff-Quik? stain and stain positively with calcitonin antibody. Amyloid material that stains positively with Congo red may be seen (Fig. 19).
4.d. Anaplastic thyroid carcinoma consists of two main histologic variants: Giant cell and spindle cell-subtypes. Depending on the histologic subtype, an anaplastic thyroid carcinoma may display in FNA pleomorphic large, bizarre cancer cells with prominent nucleoli or spindle cancer cells admixed with a variable amount of necrotic debris (Figs. 20 and 21).
4.e. A primary thyroid non-Hodgkin lymphoma is usually of large cell type and yields in FNA cells similar to those of a lymph node involved by the same neoplastic process. A thyroid Hodgkin disease is characterized by Reed-Sternberg? cells admixed with benign lymphoid cells and eosinophils.
5. Cystic Lesion
Benign cysts account for the majority of thyroid cystic lesions. They are formed as the result of hemorrhagic degeneration of a benign colloid nodule. FNA from a benign colloid cyst may show colloid material admixed with benign follicular epithelial cells and hemosiderin laden macrophages. However, any thyroid neoplasm may undergo hemorrhagic necrosis and become a cystic lesion . Of the thyroid neoplasms, PC tends to undergo marked hemorrhagic degenerative change. FNA from the tumor commonly shows a large amount of blood and the cystic lesion tends to recur rapidly. Cytological examination of the aspiration smears usually reveals a large amount of blood and rarely tumor cells. However, sections from the cell block prepared from the needle aspirate may show diagnostic papillary tissue fragments with fibrovascular cores or nuclear features of a PC while that of a benign colloid nodule will show no true papillary tissue fragments with fibrovascular cores or nuclear features of a thyroid PC (Figs. 22 and 23).
Hashimoto thyroiditis and subacute thyroiditis commonly have fairly distinctive clinical findings. Rarely, these lesions may present as a nodular lesion mimicking a thyroid neoplasm. Hashimoto thyroiditis is characterized by the presence of numerous benign lymphoid cells admixed with benign follicular cells and Hurthle cells, (Figs. 24 and 25). A subacute thyroiditis may yield clustered epithelioid cells, scattered lymphocytes and a few multinucleated giant cells containing up to one hundred nuclei (Figs. 26 and 27). It should be born in mind that Hashimoto thyroiditis may harbor hyperplastic follicular and Hurthle cell nodules, and these two nodules are cytologically indistinguishable from a cellular follicular neoplasm and a Hurthle cell neoplasm, respectively. Surgical excision of these lesions is usually required for histologic confirmation.
7. Other Lesions
Graves disease may rarely present as a nodular thyroid lesion. It yields non specific cytologic findings.
Metastatic cancers to the thyroid are common in patients with advanced cancers arising from other body sites. However, metastatic cancer to the thyroid gland presenting as a palpable TN is uncommon. For unknown reasons, renal cell carcinoma is the most common metastatic neoplasm to the thyroid, and cases of clinically occult renal cell carcinoma presenting initially as a large thyroid mass have been documented. Cytodiagnosis of metastatic cancer to the thyroid is relatively straightforward as metastatic cancer usually displays a cytologic pattern distinctive from those of a primary thyroid carcinoma. However, a cytological differential diagnosis between a metastatic renal cell carcinoma of clear cell type and a primary thyroid carcinoma with clear cell change may be difficult, and immunocytochemical staining of aspirated tumor cells with thyroglobulin antibody will be helpful to identify the aforementioned primary thyroid cancer.
8. Non-Diagnostic? CategoryThe lesions in this category are highly diversified and may be any lesions listed in the above seven categories. In this category the FNA yields non-diagnostic or inadequate cellular materials. In one study, cystic thyroid lesions yielded non-diagnostic cell samples at initial FNA in about 50% of cases. In the Mayo Clinic experience, repeating the FNA in the cases with initial non-diagnostic needle aspirates revealed diagnostic material in 30 to 80% of cases. Other investigators found that thyroid re-FNA was of limited value. If the re-aspiration is still non-diagnostic, ultrasound-guided FNA should be performed. Ultrasound-guided FNAs yield adequate cytologic materials in about 91% of cases. Patients with no specific risk factors for thyroid malignancy and a non-diagnostic FNA who refuse a re-biopsy may be managed conservatively. While patients in the high-risk group should have their TNs removed for histologic study, an increase in nodule volume alone is not a reliable predictor of malignancy, as most solid and benign TNs grow in size.
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