Thyroid Tumors

Here we'll learn about thyroid tumors with epithelial origins; we'll use terminology from the 2017 WHO classification scheme. Thyroid tumors can be benign (these are called adenomas) or malignant (these are called carcinomas).

• We use capsular and vascular invasion as key indicators of malignancy.

Thyroid cancer is the most common endocrine cancer and is in the top 10 of all cancers. Demographics: Thyroid tumors are more common in women over 40 years old. The majority of thyroid tumors are sporadic. Key risk factors include:

• Pre-existing thyroid disease
• Goiter (but be aware that not all studies support this association)
• Exposure to radiation (including x-rays and gamma rays)
• Iodine deficiency (although an important exception to this is papillary thyroid cancer, which is associated with too much iodine!)

Early and late driver mutations are also predictive of thyroid cancer, and helps us link precursor tumors (adenomas) with progression to specific carcinomas.

• We'll call out key genetic associations as we learn about the different tumor types. Because thyroid tumors more often appear in women, a hormonal association is expected, but has yet to be verified.

Treatment: In cases of suspected malignancy or other complications, tumor removal is recommended; the need for additional treatment, such as radiation, depends on the malignancy. The gland lies in the neck, wrapping around the trachea/larynx. When large enough, thyroid tumors can compress these structures and the associated nerves and vessels, and cause hoarseness and difficulty breathing and swallowing. We draw some thyroid follicles with colloid to remember that follicular cells make up the bulk of the gland and make thyroid hormone. Follicular thyroid adenomas Comprise a thin-to-medium thickness capsule with potentially visible blood vessels. The architectural pattern of the thyroid follicles can vary, but we'll show the microfollicular pattern (this is sometimes called the "fetal" pattern because it resembles the follicular architecture of the fetal thyroid gland). The follicles surround small pools of colloid. See more examples of follicular adenoma architecture, including solid, normofollicular, and macrofollicular. Note that a single tumor may comprise multiple areas with different architectural types. Genetics: Follicular adenomas are associated with point mutations in RAS genes; adenomas are also associated with PTEN harmatoma tumor syndrome, which results from germline mutations in the PTEN tumor suppressor gene (PHTS includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, multiple harmatoma syndrome, and proteus-like syndrome). Rarely, follicular adenomas are hyperproductive, aka, toxic, and produce high levels of thyroid hormone. Toxic adenomas are associated with mutations in the thyroid-stimulating hormone receptor gene and GNAS gene. Although follicular adenomas are benign, genetic associations tell us they are likely precursors for follicular thyroid carcinomas. Hürthle cell adenomas Similar to follicular adenomas, but comprise 75% or more oncocytic cells (thus, these are sometimes referred to as oncocytic adenomas). Hürthle cell adenomas were historically a sub-set of follicular adenomas; however, advances in our understanding of their distinct genetic and pathologic profiles warrants an independent category. Oncocytic cells of Hürthle cell adenomas are polygonal with eosinophilic granular cytoplasm due to a large number of accumulated mitochondria. They have dark, centrally located nuclei with prominent nucleoli.

• Oncocytic cells are also referred to as Askanazy or oxyphilic cells.

Other morphological features (capsule, architectural variants, etc.) are similar to follicular adenomas. Genetics: RAS and EIF1AX point mutations and a high number of somatic copy number alterations. Hürthle cell adenomas are likely precursors to Hürthle cell carcinomas. NIFTP Noninvasive follicular neoplasm with papillary-like nuclear features. This is a category created in 2017 to include tumors that have a low potential for malignancy, despite having features associated with papillary thyroid carcinoma. We can classify a tumor as NIFTP if it is encapsulated (or has clear demarcation), a follicular growth pattern, and has nuclear features of papillary carcinoma (and also meets certain exclusion criteria, including invasiveness, true papillae, necrosis, and other features of carcinomas). Nuclear features of papillary carcinoma can be broken down into three key categories: 1. Enlarged/elongated nuclei that appear jumbled or otherwise crowded. 2. Nuclear membrane with irregularities, including irregular contours, grooves, or pseudo-inclusions (these look like clear bubbles). 3. Chromatin clearing with margination – this makes the nuclei look "glassy." Genetics: RAS point mutations and PPARG and THADA gene fusions are associated with NIFTP; some authors argue that these genetic associations make NIFTP a likely precursor for the follicular variant of papillary thyroid carcinoma. Follicular tumor of uncertain malignant potential & Well-differentiated tumor of uncertain potential: These categories are associated with uncertain invasiveness, and, therefore, give little direction for treatment strategy. Thus, some authors argue that we should avoid this terminology and instead strive to determine the invasiveness and nuclear feature scoring in all tumors. Hyalinizing trabecular thyroid tumor These tumors are indolent but have PTC nuclear features. Rare. Papillary thyroid carcinoma (PTC) PTC accounts for 85% of all thyroid cancers. These tumors are characterized by finger-like projections of branching papillae comprised of a fibrovascular core and epithelial covering. Papillary nuclear features (as we discussed in NIFTP): Large, jumbled nuclei, irregular nuclear membranes, nuclear grooves, nuclear pseudo-inclusions, and chromatin clearing (sometimes called Orphan Annie eye). Psammoma bodies between the papillae. These purple-black glassy swirls are unique to PTC and are thought to reflect layers of calcium deposited around a small group of necrotic tumor cells. Be aware that pseudo-psamomma bodies may be seen in follicular and Hürthle cell adenomas – but these will be visible within the follicles, which is a sign that we're dealing with fake outs. Lastly, show that tumor fibrosis is common. Genetics: Point mutations in BRAF and RAS genes. We'll see classic, follicular, and other variants in the cell architecture – let the nuclear features, psammoma bodies, irregular tumor border, and genetics guide you in your designation of PTC. These tumors grow slowly and spread in the lymph with metastasis to nearby lymph nodes. Follicular thyroid carcinoma This is the second most common thyroid cancer – it accounts for approximately 10% of all cases. The presence of capsular or vascular invasiveness is key to separating follicular adenomas from carcinomas; their cell architecture is otherwise very similar. We can broadly categorize these carcinomas by degree of invasiveness:

• Minimally invasive tumors will fully penetrate the capsule – look for various shapes, including mushroom and hooks of follicular cells growing into the capsule.

• Encapsulated angioinvasive means that blood vessels have been invaded – look for a vessel in the capsule or just outside of it, and be sure that the invaded vessel is lined by endothelium. The tumor itself will be attached to the vessel wall and/or covered by a layer of endothelial cells. Be aware that "free-floating" tumor cells within the vessel do NOT count as angioinvasive – these cells could have been displaced to this location during sampling or processing.

• Widely invasive follicular thyroid carcinoma comprises nonencapsulated tumors that extend into thyroid and even extra-thyroidal tissues.

Follicular thyroid carcinoma - cells invading capsule: These tumors do not have papillary nuclear features. Genetics: Point mutations in RAS, DICER, EIF1AAX genes and the PTEN-Harmatoma Tumor syndrome). Metastasis: These tumors spread in the blood vessels and are prone to metastasis in the lungs and bone. Hürthle cell carcinomas These are similar to follicular thyroid carcinomas, but with at least 75% oncocytic cells. We measure tumor invasiveness like we do follicular carcinomas, and these tumors also spread in the blood vessels. However, Hürthle cell carcinomas are thought to be more aggressive with more metastases to the lungs, lymph, and bones. Although more common in women, males seem to have worse prognosis. These tumors are associated with a high number of somatic mutations in mitochondrial DNA. The carcinomas we've learned so far well-differentiated – that is, they look similar to normal thyroid cells and tend to grow slowly. Poorly differentiated thyroid tumors These tumors represent the next step on a continuum – these rare tumors can arise via de-differentiation of other tumors or de novo. Genetics: mutations in TP53 or TERT are later driver mutations that fuel de-differentiation. Cell architecture varies; here we'll show the insular pattern, in which nests of cells are separated by interweaving fibrovascular stroma. The nuclei vary, and can be small and round, or elongated, or even convoluted (these are said to have a "raisin-like" appearance, and may reflect dedifferentiation from papillary carcinoma origins); tumor necrosis and high mitotic activity are common. These tumors are aggressive, and often extend beyond the thyroid; vascular invasion and metastasis to local lymph nodes or distant sites is common. Tumors may comprise both well-differentiated tissue and poorly differentiated tissue. Anaplastic Aka, undifferentiated thyroid cancer completes the continuum. This is a rare but highly aggressive form with a 90% mortality rate. Mortality is highest in poor areas, in part due to delayed diagnosis of well-differentiated precursor cancers. Masses grow quickly and invade local tissues of the neck and throat in most patients with metastasis to the lungs, brain, and bones; cells are spindle-shaped. Be aware that tumors may present with areas of well, poorly, and undifferentiated tissue. Demographics: Women 60 years and older are most affected. Genetics: mutations in TP53 and TERT genes; they are also associated with a high number of somatic copy alterations. These tumors arise from the c-cells aka, parafollicular cells, which are neuroendocrine cells that lie outside of the thyroid follicles. Medullary carcinoma is rare, but we can recognize it by the nests of cells with "salt & pepper" or stippled chromatin; these small groups of cells are surrounded by fibrovascular stroma, and amyloid deposits are commonly seen. Be aware that architectural patterns vary (we've shown round, here). Genetics: medullary carcinoma is often sporadic but inherited forms are associated with MEN2A and MEN2B syndromes, and with germline RET mutations. C-cell hyperplasia is a precursor, and calcitonin levels may be elevated. Medullary carcinoma spreads via lymphatic and vascular routes; metastasis to the lymph nodes is common, and the lungs, liver, bone, and brain are the most common sites of distant metastasis. Review Multiple Endocrine Neoplasia; some forms are associated medullary thyroid cancer.

• For full references, please see tutorial on Thyroid Tumors