Endocrine pathology

Clinical features

The diffuse sclerosing variant of papillary thyroid carcinoma (PTC) is recognized to exhibit specific clinical characteristics including female predominance and younger age at presentation (mean age, 18–29 years). Compared with classical PTC, this variant tends to be characterized by more aggressive biological behavior as evidenced by involvement of both thyroid lobes, extrathyroidal extension, higher rates of lymph node metastasis, and greater incidence of pulmonary involvement.

Pathologic features

Microscopic findings

The tumor background exhibits dense fibrosis and marked lymphoplasmacytic infiltrate similar to that seen in CLT. In this setting, there are scattered islands and clusters of epithelial cells that demonstrate cytologic and architectural features typical of classical PTC ( Fig. 10.1 ). Multifocal lymphovascular invasion along with abundant psammoma bodies are typical features as well. Squamous morular metaplasia is also a common finding in these tumors.

Ancillary studies

The diffuse sclerosing variant of PTC demonstrates the typical immunophenotype characteristic of PTC in general. Specifically, the tumor cells should be positive for thyroid transcription factor-1 (TTF1), paired box gene 8 ( PAX8 ), and thyroglobulin. The most common molecular alteration seen in these tumors is the RET/PTC rearrangement.

Differential diagnosis

While the diffuse sclerosing variant of PTC may mimic multinodular goiter and CLT on gross examination, histologic studies will confirm the malignant nature of the neoplasm. Microscopically, the tumor demonstrates abundant evidence of lymphovascular space invasion and due to this appearance, the differential diagnosis can include metastatic carcinoma. This differential diagnostic consideration is more likely to be entertained in the setting of a thyroid tissue biopsy. In Fig. 10.2 , a case of metastatic breast carcinoma is illustrated in which an inflammatory background is appreciable and tumor clusters are seen within lymphovascular spaces. Morphologic assessment is often sufficient in distinguishing the diffuse sclerosing variant of PTC as this tumor is often associated with psammoma bodies and demonstrates nuclear features in keeping with PTC. In more challenging cases, immunohistochemistry can be helpful in distinguishing metastasis from a PTC. Immunoreactivity for PAX8, TTF1, and thyroglobulin would favor the diagnosis of PTC. Absence of staining for all three markers would lend support for metastasis. As a cautionary note, it should be noted that carcinomas of renal and female genital tract origin are often positive for PAX8 and pulmonary adenocarcinomas are often TTF1 positive ( Table 10.1 ).

Prognosis and therapy

Patients with diffuse sclerosing variant of PTC are often treated with aggressive surgical intervention. Specifically, surgical treatment consists of total thyroidectomy, central compartment lymph node dissection, and bilateral cervical lymph node dissections. Although the incidence of pulmonary metastasis is higher in these patients, the mortality associated with this tumor is lower than expected. Long-term survival and prognosis remain very good, with a mortality rate of less than 2%. Postoperative radioiodine treatment improves disease-free survival.

Clinical features

Secretory carcinoma (also known as mammary analogue secretory carcinoma) presents as a thyroid mass with a reported age range of 36–74 years of age. Extrathyroidal extension and lymph node metastases at presentation have been reported.

Pathologic features

Ancillary studies

The tumor cells of secretory carcinoma may express mammaglobin, GCDFP-15, and S100. Expression of PAX8 and TTF1 may be seen but is usually weak or focal. Immunostaining for thyroglobulin is negative. Molecular analysis reveals the presence of an ETV6-NTRK3 gene fusion.

Differential diagnosis

The architectural and cytologic features of secretory carcinoma share some similarities with conventional PTC ( Table 10.2 ). Both tumors can show papillary architecture, nuclear clearing, and nuclear membrane irregularities. Rare nuclear pseudoinclusions may be seen in secretory carcinoma. Despite these similarities, a few distinguishing differences can be seen. Coarsely vacuolated cytoplasm imparting a microcystic appearance is a common feature of secretory carcinoma and is unusual to see in conventional PTC ( Fig. 10.3 ). While vesicular chromatin imparting nuclear clearing can be seen in secretory carcinoma, the chromatin is usually coarser than conventional PTC. In addition, conspicuous central nucleoli are frequently present in secretory carcinoma. PTC typically has a fine powdery chromatin distribution and nucleoli are sparse to absent. It should be noted that secretory carcinoma is not always mutually exclusive from conventional PTC. Cases of secretory carcinoma arising in conjunction with PTC have been described. Immunostains are helpful to distinguish secretory carcinoma from conventional PTC. Thyroglobulin positivity is characteristic of conventional PTC, while negative in secretory carcinoma. While some cases of secretory carcinoma express TTF1 and PAX8, the staining is usually weak and focal. In contrast, conventional PTC is strongly positive for both TTF1 and PAX8. ETV6-NTRK3 gene fusion is present in secretory carcinoma. Since secretory carcinoma can arise at other sites, such as the breast or salivary glands, correlation with clinical and imaging findings is needed to exclude a metastasis.

Prognosis and therapy

As only a small number of case reports have been documented, the overall prognosis of secretory carcinoma is not well elucidated. Local regional lymph node metastases and extrathyroidal extension can be seen. Some tumors show frequent recurrences but favorable long-term survival. However, rare fatal cases with distant metastases have been reported. The primary treatment is surgical excision.

Clinical features

The cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) occurs mostly in females, with only rare cases reported in male patients. The tumor usually occurs in the third decade of life, presenting as an incidental nodule or mass detected by palpation or imaging. Multiple nodules may be seen, especially in syndromic cases. The CMV-PTC is associated with familial adenomatous polyposis (FAP) in about half of the cases.

Pathologic features

Microscopic findings

The tumor is frequently encapsulated, showing of a combination of cribriform, follicular, papillary, trabecular, and solid growth patterns. While follicular and cystic growth is frequently present, colloid secretions are sparse to absent. The follicles and papillae are lined by columnar-appearing cells, which may show some nuclear stratification. Variable nuclear clearing, nuclear grooves, and pseudoinclusions can be identified. A characteristic feature is the presence of morules, which may appear squamoid, containing optically clear nuclei or nuclear pseudoinclusion-like bodies that result from biotin accumulation ( Fig. 10.4 ).

Ancillary studies

Immunohistochemical expression of TTF1 is a consistent feature in CMV-PTC, while staining for thyroglobulin is frequently weak or focal. β-catenin immunohistochemistry shows strong nuclear staining reflecting abnormalities in the Wnt signaling pathway. APC mutations have been reported in 64% of cases and CTNNB1 mutations in 32% of cases. While BRAFV600E mutations are not seen, RET/PTC rearrangements may be present. Rare cases showing immunohistochemical expression of neuroendocrine markers have been reported.

Differential diagnosis

The differential diagnosis of CMV-PTC includes variants of PTC. The most common considerations include classical PTC, the tall cell variant of papillary thyroid carcinoma (TCV-PTC), and the columnar cell variant of papillary thyroid carcinoma (CCV-PTC) ( Fig. 10.5 and Table 10.3 ). CMV-PTC shows similar cytologic features to conventional PTC including nuclear grooves and pseudoinclusions. In general, the degree of nuclear clearing is more pronounced in classical PTC. The CMV-PTC frequently contains back-to-back follicular spaces that impart a cribriform appearance. The presence of squamoid morules, containing cells with nuclear incisions from biotin accumulation, is characteristic of CMV-PTC. In addition, the conspicuous near-total absence of colloid seen in CMV-PTC is usually quite striking, serving as a clue for the diagnosis of CMV-PTC.

The CMV-PTC may contain columnar-shaped tumor cells lining the follicles and papillae, which shows morphologic overlap with the CCV-PTC and TCV-PTC. In addition, CCV-PTC can also have solid areas of growth causing further confusion with CMV-PTC. In contrast to CMV-PTC, CCV-PTC is composed of tumor cells containing relatively dark nuclei with a stratified appearance. Typical features of PTC, including pseudoinclusions, are generally not seen. In addition, subnuclear vacuolization is a frequent feature of CCV-PTC, imparting an endometrioid appearance. TCV-PTC usually shows conspicuous nuclear features of PTC, including marked nuclear clearing and easily identifiable pseudoinclusions. The classic nuclear features of PTC are more difficult to appreciate in CMV-PTC. An abundance of granular oncocytic cytoplasm is identified in TCV-PTC, causing the tumor cells to appear two to three times tall as they are wide. In addition, many of the infiltrating tumor follicles comprising TCV-PTC have elongated and sometimes serpiginous contours. This is accompanied by a more conspicuous pattern of infiltration seen with TCV-PTC. These features impart a distinctive low-power appearance to TCV-PTC compared with CMV-PTC, appearing as a tumor with a radial infiltrative growth pattern composed of elongated follicular structures containing abundant oncocytic cytoplasm and conspicuous nuclear features of PTC.

Immunohistochemically, CMV-PTC shows nuclear β-catenin staining reflecting abnormalities of the Wnt signaling pathway. In conjunction with the histologic features, this excludes other variants of PTC. Investigation of the clinical history, to determine if the patient has FAP, can also be useful to corroborate the diagnosis.

Prognosis and therapy

Patients diagnosed with CMV-PTC have a favorable prognosis. Approximately 10% of patients recur in the form of regional neck lymph node metastases. Distant metastases have been reported but are uncommon. Rare reports of aggressive behavior have been identified with tumors showing neuroendocrine differentiation. Patients are treated with total thyroidectomy and may be treated with radioactive iodine. External beam radiation has been used in patients with locally advanced disease.

Clinical features

NIFTP, formerly classified as noninvasive encapsulated follicular variant of PTC, usually presents as solitary painless nodule. In some cases, when presenting as a large mass, may cause compressive symptoms.

Pathologic features

Ancillary studies

Molecular analysis has revealed NIFTP to share similar genetic abnormalities to follicular neoplasia including RAS mutations. RET fusions and BRAFV660E mutations are absent. CK19, HBME-1, and Galectin-3 can be positive in NIFTP. However, as these stains can also be positive in classical PTC and sometimes in follicular neoplasia, interpretation for classification should not be done independently from the morphologic features.

Differential diagnosis

The main differential diagnosis is with the invasive encapsulated follicular variant of papillary thyroid carcinoma (EN-FVPTC), encapsulated papillary thyroid carcinoma (EN-PTC), and follicular adenoma (FA) as seen in Fig. 10.6 and listed in Table 10.4 . FAs are typically composed of tumor cells containing uniform round nuclei without significant nuclear enlargement, clearing, or nuclear membrane irregularities. The presence of papillary architecture or psammoma bodies excludes the diagnosis of NIFTP and instead indicates the diagnosis of EN-PTC. Caution should be exercised in cases showing conspicuous cytologic features of PTC including intranuclear pseudoinclusions and marked nuclear clearing. Such cases often show papillary architecture, in keeping with PTC. Therefore, tumors should be generously sampled to exclude conventional PTC with a predominant follicular growth pattern. If features typical of other variants of PTC are present, then NIFTP is also excluded. Any invasive features exclude the possibility of NIFTP, and the diagnosis of invasive EN-FVPTC (or other thyroid carcinoma) should be rendered. This underscores the need for generous or complete sampling of the tumor capsule to ensure that invasion has been unequivocally excluded. Regarding invasion, keep in mind that papillary microcarcinomas can have circumscribed, noninfiltrative appearance. Therefore, the diagnosis of NIFTP should be rendered cautiously in tumors less than 1.1 cm in size, especially when multifocal lesions are present. Other features which can exclude the diagnosis of NIFTP include increased mitotic activity (>3 mitoses/10 HPF), solid/ trabecular/insular growth (>30% of the tumor area), and tumor necrosis (excluding FNA-induced necrosis) as these are features more frequently observed with higher-grade thyroid carcinomas.

Prognosis and therapy

NIFTP is a clinically indolent tumor which rarely causes metastatic disease. Indeed, according to some studies, no metastatic cases were reported. Since the tumor behaves in a clinically benign fashion in most cases, NIFTP is generally treated in a similar fashion to FA, with lobectomy alone sufficing in the majority of cases.

Clinical features

Follicular neoplasms can occasionally demonstrate cytoplasmic clear cell change. Clear cell change, in isolation, does not necessarily equate to malignancy as this can be seen to varying degrees in both benign and malignant follicular neoplasms. Clear cell change can be seen in up to 3% of primary thyroid carcinomas including follicular carcinoma and PTC.

Pathologic features

Microscopic findings

Clear cell change can occur in both FAs as well as malignant follicular epithelial-derived tumors ( Fig. 10.7 and Table 10.5 ). This can be seen to varying degrees within the tumor. Ultrastructurally, the cytoplasmic clearing has been attributed to a variety of etiologies such as intracellular accumulation of glycogen, lipid, or colloid vacuoles. Diagnostic criteria for distinguishing between FAs and follicular carcinomas with clear cell change are identical to those for their counterparts without clear cell change; the presence of capsular and/or vascular invasion is necessary for diagnosis of malignancy in this context. If nuclear features in keeping with PTC are seen in a follicular epithelial tumor with clear cell change that fulfills criteria for PTC, then a diagnosis of PTC is rendered.

TABLE 10.5

Histologic and Immunohistochemical Features of Follicular Neoplasms With Clear Cell Change Versus Metastatic Renal Cell Carcinoma

Follicular Neoplasms With Clear Cell Change	Metastatic Renal Cell Carcinoma
Chromatin can vary from granular to vesicular depending on tumor type	In low-grade tumors, the nuclei are small and hyperchromatic. In higher-grade tumors, prominent nucleoli are visible.
Immunoreactive for TTF1 and PAX8	Immunoreactive for PAX8 but negative for TTF1
Immunoreactive for thyroglobulin	Negative for thyroglobulin

Ancillary studies

Follicular neoplasms of the thyroid gland that demonstrate clear cell change should exhibit the typical immunophenotype as conventional follicular neoplasms. Specifically, they should demonstrate nuclear immunoreactivity for TTF1 and PAX8 as well as cytoplasmic immunoreactivity for thyroglobulin.

Differential diagnosis

Metastatic carcinoma to the thyroid gland is a rare phenomenon; however, renal cell carcinoma (RCC) represents one of the more common neoplasms to involve the thyroid gland ( Fig. 10.8 ). The clearing of cytoplasm in occasional thyroid follicular neoplasms, especially if the clear cell changes are diffusely present throughout the nodule, can occasionally raise the possibility of metastatic RCC to the thyroid gland. Nonetheless, the presence of follicular architecture would argue against metastatic RCC. Metastatic RCC typically demonstrates a more packeted, nested pattern associated with delicate capillary vasculature. In case of PTCs that demonstrate clear cell change, the chromatin clearing can lead to easier visualization of nucleoli. Thus, the nuclear features in this context can overlap with the nuclear features of metastatic RCC. Immunohistochemical distinction between follicular neoplasms with clear cell change from metastatic RCC should be straightforward. The former should demonstrate immunoreactivity for TTF1, PAX8, and thyroglobulin. In contrast, the latter should immunostain only for PAX8 and be negative for TTF1 and thyroglobulin.

Prognosis and therapy

Surgical excision represents the mainstay of treatment of these tumors. The prognosis of follicular neoplasms that exhibit clear cell change is similar to follicular neoplasms for which clear cell change is absent.