Extrathyroidal extension is noted in up to 20% of patients.⁴,¹³,¹⁷ The tumors can be as large as 10 cm in their greatest dimension, and they feature a firm cut surface with a tan-brown to yellow-white mass. Although they are well demarcated, they are seldom encapsulated (Fig. 15.1). Cystic degeneration, sometimes with a myxoid-mucoid appearance, and necrosis are sometimes identified.¹,⁴

The tumor is infiltrative, demonstrating intertwined cords and nests of epidermoid cells and mucocytes in a stroma of fibrous connective tissue (Fig. 15.2). The epidermoid component may appear as sheets of atypical cells, sometimes with keratinization (Fig. 15.3). Keratin pearl formation is noted. Cystic spaces may be present; when they are, they frequently contain keratinaceous and mucinous debris with inflammatory cells (Fig. 15.3). The goblet-like cells may be seen within the cystic spaces, lining the cords of epidermoid cells, or within gland-like lumina (Fig. 15.4). The cytoplasm of the mucocyte may be clear to foamy or vacuolated. Mucin can be intra- and/or extracellular (Fig. 15.5). Ciliated cells may be seen.¹,⁴ Hyaline bodies (positive with periodic acid-Schiff [PAS] staining) resembling colloid may be seen in the cytoplasm of mucocytes.¹² The cells are intermediate in size. Their nuclei have pale nuclear chromatin similar to papillary thyroid carcinoma. Nuclear grooves and intranuclear cytoplasmic inclusions can be seen.¹ Psammoma bodies are occasionally present.⁹,¹² Lymphocytic thyroiditis is usually present in the surrounding thyroid parenchyma, and although germinal center formation is common, oncocytic metaplasia of the follicular epithelium is not.¹,⁴,¹⁰,¹²,¹⁶ Squamous metaplasia is seen in lymphocytic thyroiditis (Hashimoto thyroiditis) and is present in papillary thyroid carcinoma. Areas of transition between MEC and papillary thyroid carcinoma can be seen.¹,⁶,⁸,¹⁸,¹⁹ Concurrent papillary carcinoma has been identified in up to 50% of cases (Fig. 15.6).⁴,¹⁰,¹²,¹⁹ In rare cases, anaplastic (undifferentiated) carcinoma may develop, a finding that often alters the prognosis.¹⁰,¹¹,¹²,²⁰

The mucinous material is highlighted with PAS (Fig. 15.4), mucicarmine, and Alcian blue pH 2.5.¹² The tumor cells are positive with keratins (high and low molecular weight), with polyclonal carcinoembryonic antigen (CEA) (mucocytes only), and focally with thyroglobulin and TTF1 (Fig. 15.7).¹,⁴,⁹,¹⁶,¹⁹,²⁰ p63 and CK5/6 may be of value in highlighting the epidermoid epithelium (Fig. 15.7). P-cadherin neoexpression and E-cadherin abnormalities are seen in the epidermoid tumor cells.²¹ Calcitonin is negative.⁴,¹⁶,¹⁹ Expression of thyroid-specific genes (TTF1, TTF2, PAX8, and thyroid peroxidase) detected by RT-PCR supports a follicular epithelial derivation,⁹ although BRAF (V600E) mutation is not detected.¹⁴,²² The CRTC1/MAML2 fusion is detected in about one-third of cases.¹⁵

Smears are cellular, with cohesive monolayered and syncytial sheets of cells within a background of amorphous debris and necrotic and mucinous material. A dual cell population of mucocytes (vacuolated to foamy cytoplasm compressing the nucleus) and epidermoid cells (polygonal cells with distinct cell borders and round nuclei, vesicular nuclear chromatin, prominent nucleoli, and opaque, homogeneous eosinophilic cytoplasm) are intermingled.¹,³,²⁰,²³,²⁴ In rare cases, anaplastic cells may also be present.¹¹,²⁰

Tumor size ranges from 1 to 13 cm. Tumors usually appear as ill-defined, white to yellow, firm, solid masses.²⁷,³⁴ Cystic change may occur, but this is uncommon.²⁸

Anastomosing cords, strands, and nests of tumor cells are identified in a stroma of very sclerotic fibrohyaline connective tissue (Fig. 15.8). Innumerable eosinophils are seen throughout (Fig. 15.9). The neoplastic cells are biphasic, with cohesive nests of epidermoid, polygonal cells with well-developed cell borders. Intercellular bridges are noted, with opacified, thick eosinophilic cytoplasm. Keratin pearls and keratin debris can be identified (Figs. 15.9 and 15.10) There is only mild to moderate pleomorphism. Nucleoli are prominent. Occasionally, clear cells are present.²⁹ Mucocytes with squashed nuclei are intermingled in the epidermoid sheets, highlighted with mucicarmine stain or PAS with diastase (Fig. 15.10). Mucus pools are uncommon.²⁷ In rare cases, the tumor cells may grow in a pseudoangiomatous pattern. Extrathyroidal extension is seen in as many as one-half of all cases, with lymph node metastasis in about one-third.¹⁰,²⁷,²⁸,³⁶,³⁷ Perineural and vascular invasion is common. Lymphoid infiltration (lymphocytes and plasma cells), including a finding of lymphocytic thyroiditis (Hashimoto thyroiditis), is seen in the adjacent thyroid parenchyma in nearly all cases. Squamous metaplasia is also seen in the areas of lymphocytic thyroiditis.¹⁰,²⁷,³³,³⁵ Papillary carcinoma is identified in a few cases, although transition between the two is less common than it is in MEC.

Cytokeratins are positive in the tumor cells (Fig. 15.11); TTF1 is identified less often. CEA is sometimes expressed in the mucocytes but not in the areas of squamous differentiation. Calcitonin and thyroglobulin immunoreactive is not present.¹⁰,²⁷,²⁸,²⁹ p63 strongly stains the epidermoid tumor cells (Fig. 15.11),³⁰ a finding that is also seen in the basaloid cells of squamous metaplasia.³¹ TP53 staining is occasionally seen in the epidermoid cells. BRAF mutations are not identified.²²

In general, a definitive diagnosis by fine needle aspiration cytology is difficult because of the nonspecific nature of the findings. There tends to be a combination of malignant epithelial cells set
in a mucinous and debris-filled background with eosinophils. Cohesive clusters of cells with either epidermoid or glandular differentiation are present. These findings suggest malignancy, but they may also raise the possibility of metastatic tumor or Hashimoto thyroiditis.³⁵,³⁸

Like undifferentiated carcinomas, SCCs are usually large (up to 8 cm), firm, tan-white masses, often involving one or both lobes of the thyroid gland. Additional nodules of tumor are frequently identified, and extrathyroidal extension is frequent. Necrosis is common (Fig. 15.12).⁴¹,⁵²,⁵⁶,⁵⁷

Before making a diagnosis of a primary thyroid SCC, direct extension from the larynx or esophagus (clinically, radiographically, or operatively) must be excluded. A primary SCC is an invasive neoplasm with extensive destruction, composed entirely of squamous cells (Fig. 15.13).⁶³ Vascular and perineural invasion, as well as extensive local extension, is common. The cells are cohesive and arranged in sheets, ribbons, and nests (Fig. 15.14) of pleomorphic cells with a variable nucleus-to-cytoplasm ratio (Fig. 15.15). Tumor cell spindling can be seen. Keratinization is frequently present, with keratin pearl formation (Fig. 15.15). Mitotic figures are common, including atypical forms. Tumors are graded as well differentiated, moderately differentiated, and poorly differentiated. They are also classified as keratinizing or nonkeratinizing; most thyroid tumors are poorly differentiated. An inflammatory infiltrate and stromal fibroplasia are frequently present (Fig. 15.16), sometimes in association with mucin production.⁴¹,⁴⁴,⁴⁶,⁴⁹,⁵²,⁵⁶,⁵⁸ It is important to note that papillary carcinoma and undifferentiated carcinoma can both exhibit areas of squamous differentiation,⁴⁷,⁵⁶,⁵⁹,⁶⁴,⁶⁵,⁶⁶,⁶⁷,⁶⁸,⁶⁹,⁷⁰ and these are much more common than in primary thyroid SCC. Fine needle aspiration may induce squamous metaplasia in the tumor.⁶⁷ Therefore, although rare cases of SCC associated with follicular neoplasms have been reported,⁴⁴,⁶⁴,⁷¹ by definition and convention, a primary SCC of the thyroid gland must be a pure tumor without any other type of differentiation. If other differentiation is present, the primary tumor is diagnosed and coupled with a statement about squamous differentiation—for example, anaplastic carcinoma with squamous differentiation. Collision tumors (from different lobes) have been reported.⁷²

Pankeratin, CK19, and p63 are strongly positive within the neoplastic cells. CK7 and CK18 are focally immunoreactive, whereas epithelial membrane antigen (EMA) is occasionally reactive.²⁵,⁵³,⁵⁷,⁷⁰,⁷³ CK1, CK4, CK6, CK10/13, CK20, and CD5 are nonreactive.⁵⁷,⁷³,⁷⁴ S-100A9 is highlighted in a diffuse, laminated reaction that is different from the reaction seen with thymus-derived tumors.⁷⁵ Diffusion artifacts may cause a falsepositive thyroglobulin reaction, but TTF1 immunoreactivity has been reported.⁵³ The tumor cells usually demonstrate a high proliferation index with MIB-1 antibodies.²⁵,⁴¹,⁵³,⁵⁶ Although only a few cases have been studied, abnormal p53 expression and loss of p21 expression have been reported.²⁵,⁵³,⁵⁶,⁵⁷ TP53 expression becomes greater as the neoplasm exhibits less squamous differentiation.⁵⁷ Epidermal growth factor receptor (EGFR) may be overexpressed in these tumors (which showed gene polysomy), possibly providing a therapeutic alterative for these tumors.⁵⁴,⁷⁶