Pathology of Thyroid TumorsCHAPTER 1

Thyroid tumors account to 1% of all malignancies in developed countries and 0.2% of cancer deaths. They are the most common malignancies of the endocrine system and pose a significant challenge to pathologists, surgeons and oncologists. Most of the carcinomas affect young and middle aged adults and are indolent malignancies with a 10 year survival that exceeds 90%. There has been an increase in the incidence rate of these tumors worldwide which can be largely attributed to more sophisticated diagnostic methods and a change in diagnostic practices with an increasing number of smaller tumors being detected of late. Thyroid tumor pathology is an area replete with diagnostic challenges. Though there are typical morphological patterns described, overlaps with non-neoplastic entities pose diagnostic difficulties. Updates in this field include ancillary and research aiming at techniques that can further narrow down our diagnosis from the different ‘indeterminate/grey zone’ lesions detected on screening.

The conventional classification based on morphology and clinical features is largely supported by molecular data currently available. Genetic profiles of four main categories appear distinctly different from each other with a few areas of overlap.

Fine needle aspiration (FNA) still remains the mainstay for screening and diagnosis of thyroid lesions.

There are several reporting systems which are being used to guide further management of the lesions. Most widely used one is that of Bethesda system. The system divides the lesions in to six diagnostic categories.

Borderline lesions (category 3) make up to 10–15% of the cases. Overlapping cytological features of thyroiditis with papillary carcinomas and cellular colloid nodules with follicular neoplasms are particularly troublesome.

This is the most common malignant tumor of the thyroid gland and comprises 80–85% of all 5malignancies. It is common in countries having iodine sufficient or iodine excess diets.

They tend to be biologically indolent and have an excellent prognosis. Papillary carcinoma can occur at any age, but most of them are diagnosed in third and fifth decades of life. Women are more frequently affected (2–4: 1). Multifocality is common. Most important etiological role is that of radiation. It was frequently diagnosed in patients who are treated with low dose radiation to head and neck for benign diseases. It was also recognized in survivors of atomic bomb explosion in Japan. Survivors of other cancers who were treated with radiation were also found to develop papillary carcinomas as second primaries. Dietary iodine concentration appears to influence incidence and in some cases, the morphology of papillary carcinomas.

Papillary carcinoma shows varied gross features. Majority of the cases present as a solid irregular and firm grey white growth with granular cut surface. Scarring may be very prominent in some of the cases. Calcification is a common finding. It can also present as a small scar in the subcapsular location. Some lesions may be completely cystic with a solid mural nodule attached.

It is not a specific variant but includes all papillary carcinomas that measure one cm or less in dimension (stage IA).

Prognosis of papillary carcinoma is excellent.10 year survival rate is over 90% and for young patients, over 98%. Tall cell and columnar cell variants have a less favorable prognosis than conventional papillary carcinomas.

It is a malignant epithelial tumor showing follicular cell differentiation and lacking diagnostic nuclear features of papillary carcinoma. It accounts for 10–15% of thyroid malignancies. It is more common in women in the fifth decade. Incidence is higher in iodine deficient areas. Follicular carcinomas most commonly present as large asymptomatic thyroid nodules which are typically cold on scintigraphy. Distant metastasis is seen in up to 20% during presentation. Oncocytic variants typically occur ten years later than the conventional types and show greater propensity for recurrence and local invasion. Follicular carcinomas are usually encapsulated with grey tan to brown bulging cut surface. Widely invasive carcinomas may show extensive permeation of the capsule.

Rarely thyroid veins and superior vena cava may be involved. Multifocality is uncommon. Distal metastasis to the lung and bones are common.

Aspirates will be hypercellular and show repetitive microfollicles and scant colloid. Atypical nuclear features do not denote malignancy. Demonstration of capsular or vascular invasion is needed for the diagnosis of follicular carcinoma.

Follicular carcinomas show variable morphology with cells arranged in follicles, solid or trabecular patterns. They are divided into two major categories—minimally invasive and widely invasive. While conceptually simple, there is no consensus as to the definition of capsular invasion. Some authorities require complete transgression of the capsule, while other authorities do not require complete transgression of the capsule. Minimally invasive carcinomas have limited capsular and/or vascular invasion. Widely invasive carcinomas have widespread invasion of thyroid tissue and/or blood vessels. The probability of aggressive behavior increases with the extent of vascular invasion.

The term ‘grossly encapsulated 8angioinvasive follicular carcinoma’ has been suggested for those tumors that demonstrate vascular invasion only.

Minimally invasive follicular carcinomas have very low long-term mortality (3–5%). Widely invasive carcinomas have 50% mortality. Oncocytic carcinoma behaves more aggressively than conventional types with higher frequencies of extrathyroidal extension, local recurrence and nodal metastasis. Adverse prognostic factors include age >45 years, oncocytic tumor type, extrathyroidal extension, tumor size >4 cm and presence of distant metastasis.

They are defined as follicular cell neoplasms that show limited evidence of follicular cell differentiation and occupy both morphologically and behaviorally an intermediate position between differentiated and undifferentiated carcinomas. Turin proposal (2006) remains so far the most accepted criteria for diagnosing this entity. According to this proposal PDTCs are defined by: (1) Presence of TIS (trabecular/insular/solid) architecture, with (2) At least one of the following features—convoluted nuclei, mitotic figures of >3/hpf, or coagulative necrosis; (3) Absence of conventional nuclear features of papillary carcinoma. PTDCs can be seen as component of well-differentiated carcinomas and as little as 10% is sufficient to confer an aggressive biological behavior. Most tumors present as cold nodules with or without enlarged lymphadenopathy. Lung and bone metastases are also relatively frequent at the time of diagnosis. Extrathyroidal extension is less commonly seen than in anaplastic carcinomas.

Anaplastic carcinomas are highly malignant tumors that histologically appear wholly or partially composed of undifferentiated cells that exhibit immunohistochemical or ultrastructural features indicative of epithelial differentiation. It affects mainly the elderly age group with higher incidence reported in endemic goiter regions. It has a high mortality rate (90%) with a median survival rate of up to 6 months after diagnosis.

Patients typically present with rapidly expanding neck mass 9with pressure symptoms like hoarseness and dysphagia. Tumors are hard and fixed and frequently invade the surrounding structures. Lymph node involvement as well as distant metastasis is seen in up to 40% of cases. All anaplastic carcinomas are staged as T4 (T4a-intrathyroidal, T4b—extrathyroidal extension).

Medullary thyroid carcinoma is a malignant tumor showing C cell differentiation. It constitutes 5–10% of all thyroid malignancies. Up to 25% cases are heritable, caused by germ-line mutations in RET proto-oncogene. Mean age at presentation is 50 years for sporadic cases. MEN II B patients present in infancy or early childhood while MEN IIA associated tumors occur in late adolescence or early adulthood. Patients with FMTC present at an age of 50 years.

Tumors typically 10are located in the middle third of the lobes. They present as cold nodules with more patients presenting with nodal metastasis (50%) and up to 15% with distant metastasis. Virtually all MTCs produce calcitonin and serum levels are typically increased. Paraneoplastic syndromes may occur due to production of other peptides and amines. Cytologically smears show loosely cohesive cells with polygonal, bipolar, or spindle shapes. Plasmacytoid cells are common and multinucleated giant cell morphology is occassionally encountered. MGG stains show characteristic red cytoplasmic granules. Amyloid may be found in 50–70% of the cases.

Alterations of follicular cells that lead to carcinogenesis are caused by unopposed activation of either the mitogen-activated protein (MAP) kinase pathway or the phosphatidylinositol-3-kinase (PI3K)/AKT pathway. Specifically, the MAP kinase pathway (encompassed by the MEK and ERK kinase cascade) is regulated by the RET, RAS, and BRAF genes. Point mutations in the BRAF and RAS genes or RET/PTC translocation can lead to unopposed cellular proliferation and to a carcinogenic environment via the MAP kinase pathway.

Ancillary testing can be used for diagnostic, prognostic, and, to some extent, therapeutic purposes in thyroid cancer. While several markers are now commonly used in patient management, they are not yet a “universal standard of care.”