Neoplasms of the thyroid

Nodules are more likely to be neoplastic if they occur;

• Singly rather than multiple
• In younger rather than older patients
• In men rather then women
• Following a history of radiation treatment to the head and neck
• Nodules which take up radioactive iodine are more likely to be benign than malignant

Diagnosis can only be formally made histologically using a fine needle aspiration biopsy 

 

Adenomas

 

• Discrete solitary masses and with rare exception are derived from follicular epithelium
• Adenomas are not forerunners of cancer except in rare circumstances
• May resemble normal thyroid tissue(simple colloid adenomas) or various stages in the embryogenesis of the thyroid
• The majority are non-functional although a small number produce thyroid hormones and can result in thyrotoxicosis
• In this case the hormone production is independent of TSH

 

Pathogenesis

• The TSH receptor signalling pathway plays an important role in the pathogenesis of toxic adenomas
• Activating somatic mutations in one of two components of the signalling system, most commonly the TSH receptor itself and then α-subunit of Gs causes chronic overproduction of cAMP
• This results in clonal expansion of follicular epithelial cells that autonomously produce thyroid hormone
• Pathogenesis of non-functioning adenoma is unclear

 

Morphology

• Solitary, spherical, encapsulated, well demarcated lesion
• Average size is 3cm
• Colour ranges from white to brown depending on the colloid content
• Can be distinguished from multinodular goiters which show less compression of the adjacent thyroid parenchyma and lack a well formed capsule
• There are commonly areas of haemorrhage, fibrosis, calcification and cystic change
• Histologically, mitotic figures are rare, papillary changes is not a feature
• Occasionally the epithelial cells may become Hürthle like in nature in which case the lesion is called a Hürthle cell adenoma (no different from a conventional adenoma)
• Other features may include clear cell change of the cytoplasm and adenomas with ‘signet ring’ features
• The hallmark of all follicular adenomas is an intact, well formed capsule encircling the tumour therefore careful evaluation of the capsule is essential to distinguish follicular adenomas from follicular carcinomas

 

Clinical features

• Most commonly present as a unilateral painless mass, large masses may cause swallowing difficulties
• Most adenomas take up less radioactive iodine than the normal thyroid tissue
• In the minority of cases they may be hyperfunctional producing signs of hyperthyroidism. These lesions may be hot on radionuclide imaging and may show some dependence on TSH
• Definitive diagnosis can only made following histological examination of a carefully resected specimen
• Adenomas have an excellent prognosis and don’t recur or metastase

 

• Some solitary nodules may turn out to be cysts, the majority are due to cystic degeneration of a follicular adenoma and the remainder arise from multinodular goiters
• They are filled with a turbid, brown substance containing blood, haemosiderin and cell debris
• Additional benign lesions include, dermoid cysts, lipomas, haemangiomas and teratomas (seen mainly in infants)

 

Carcinomas

 

• Rare cancer accounting for 1.5% of all cancers
• More common in adults, particularly female in the early and middle adult years (due to expression of oestrogen receptor on neoplastic thyroid epithelium)
• Some forms, particularly papillary may present in childhood
• Most are well differentiated
• The major subtypes are;
  • Papillary carcinoma (75-85% of cases)
  • Follicular carcinoma (10-20%)
  • Medullary carcinoma (5%)
  • Anaplastic carcinoma (< 5%)
• All are derived from follicular epithelium apart from medullary carcinoma which is derived from parafollicular or C cells

 

Pathogenesis

• Several factors are implicated in the pathogenesis of thyroid cancer;
  • Genetic factors
    • Familial medullary carcinomas account for most inherited cases of thyroid cancer
    • Papillary and follicular variants are rare
    • Distinct genes are involved in the histological variants of thyroid cancer
  • Follicular thyroid carcinomas
    • Important mutations include members of the RAS family of oncogenes
    • Also involved is a translocation between PAX8 (a paired homeobox gene that is important in thyroid development) and PPARg1 (peroxisome proliferator-activated receptor g1, a nuclear hormone receptor involved in the terminal differentiation of cells)
  • Papillary thyroid carcinomas
    • Again, multiple non-overlapping genetic pathways are involved;
    • Rearrangement of the tyrosine kinase receptors RET or NTRK1 (neurotrophic tyrosine kinase receptor 1)
    • Activating mutations in the BRAF oncogene
    • RAS mutations
  • Medullary thyroid carcinomas
    • Arise from parafollicular C cells
    • Familial medullary thyropid carcinomas occur in multiple endocrine neoplasia type 2 and are associated with germ-line RET protooncogenes
    • RET mutations are also seen in non-familial forms of medullary thyroid cancer
    • The RET mutations of medullary carcinoma differ from those of papillary carcinoma
  • Anaplastic carcinoma
    • Highly aggressive, lethal tumours can arise from a ‘de-differentiation’ of a well differentiated papillary or follicular carcinoma
    • Commonly associated with point mutations in p53 which are rare in other thyroid carcinomas
  • Environmental factors
    • Major risk is ionising radiation particularly in the first two decades of life
    • Long standing multinodular goiters may be a predisposing factor
    • While most thyroid lymphomas arise from pre-existing Hashimoto thyroiditis, there is no conclusive evidence to suggest that thyroiditis is associated with increased risk of thyroid epithelial carcinomas

 

Papillary carcinoma

• Most common form of thyroid cancer
• Account for the majority of cancers seen after ionising radiation
• Occurs most commonly between 20 and 40

 

Morphology

• Can be solitary or multifocal lesions
• Histological hallmarks include;
  • Branching papillae consisting of a fibrovascular stalk covered by a single to multiple layers of cuboidal epithelial cells. Epithelium may be well differentiated or anaplastic but can be differentiated from hyperplastic lesions as they are more complex and have denser fibrovascular cores
  • The nuclei of papillary carcinoma contains finely dispersed chromatin, which results in an empty appearance. The nuclei are called ground glass or Orphan Annie nuclei. Invaginations of the cytoplasm also give the appearance of inclusions within the cell
  • Concentrically calcified structures called psammoma bodies may be present. They are never present in follicular or medullary carcinoma and so are specific for papillary carcinoma. They are generally found in the cores of the papillae
• There are different histological variants which are important to recognise;
  • Encapsulated variant – constitutes 10% of all papillary carcinomas. Confined to the thyroid, rarely presents with vascular or lymph node dissemination so can be confused with a benign adenoma. Generally it has an excellent prognosis
  • Follicular variant – has nuclei which are characteristic of papillary carcinoma but have a follicular architecture. As long as they are definitely not follicular carcinomas they have a good prognosis
  • Tall cell variant – marked by tall columnar cells with eosinophilic cytoplasm lining the papillary structure. They tend to occur in older people and are associated with vascular invasion, extrathyroid involvement and cervical and distant metastases. Around half harbour a ret/PTC translocation conferring greater mitogenic potential. This may explain their aggressive nature
  • Diffuse sclerosing variant – seen in younger patients. Don’t present with a single mass but rather with a bilateral goiter. There is abundant psammoma bodies and a diffuse fibrosis throughout the thyroid gland. Propensity to invade the intrathyroidal lymphatics hence there are metastases in most cases
  • Hyalinising trabecular tumours – have an ‘organoid’ growth patternwith nests and trabeculae of elongated tumour cells in a fibrovascular stroma. There is intracellular and extracellular hyalinisation resulting in a generalised ‘pinkish’ colouration on microscopic examination. May be encapsulated (adenomas) or infiltrative (carcinoma)

 

Clinical course

• May present as an asymptomatic thyroid nodule which cant be distinguished from a benign nodule
• The presence of isolated cervical node metastases doesn’t appear to have a significant influence on the generally good prognosis of these lesions
• In the minority haematogenous spread results in lung metastases at presentation
• Most lesions are ‘cold’ on scintiscans

 

Prognosis

• 10 year survival rate of 95%
• Dependant on the patient being less than 40, presence of extrathyroidal extension and the staging

 

Follicular carcinoma

• Tends to present in women, with a peak incidence at age 40 to 50
• Incidence of follciualr carcinoma is increased in areas of dietary iodine deficiency suggesting nodular goiter may predispose
• The high frequency of RAS mutations in follicular adenomas and carcinomas suggest the two may be related

 

Morphology

• Single nodules that may be well circumscribed or widely infiltrative
• Microscopically, most are composed of fairly uniform cells forming small follicles containing colloid, closely resembling normal thyroid tissue
• In other cases the follicular differentiation may be less apparent and there may be nests or sheets of cells without colloid
• There may be Hürthle cells but not psammoma bodies
• Lymphatic spread is uncommon

 

Clinical course

• Present as slowly enlarging nodules
• Most frequently they are cold lesions on scintigrams
• Regional lymph nodes are rarely invaded but vascular invasion is common with spread to the bones, lungs and liver
• Widely invasive follicular carcinoma has a 50% 10 year survival rate
• Minimally invasive follicular carcinoma has a 90% 10 year survival rate
• Treatment is generally via total thyroidectomy followed by administration of radioactive iodine
• In order to suppress endogeneous TSH, as any residual follicular carcinoma may be TSH responsive, the patient may also be treated with thyroid hormone after surgery

 

Medullary carcinoma

• Neuroendocrine carcinomas derived from parafollicular or C cells
• These cells secrete calcitonin, measurement of which can be used for diagnosis and postoperative follow up
• In some cases the tumours may also produce somatostatin, serotonin and VIP
• The tumours arise spontaneously in 80% of patients

 

Morphology

• Can arise as a solitary lesion or as multiple lesions involving both lobes of the thyroid
• Sporadic neoplasms tend to be singular whereas familial forms tend to multiple
• Microscopically composed of polygonal, spindle shaped cells which may form nests, trabeculae or follicles
• Acellular amyloid deposits derived from altered calcitonin molecules may be present in the stroma
• Cytoplasmic calcitonin may be demonstrated immunohistologically
• A particular feature of familial medullary carcinoma is foci of C cell hyperplasia (which are believed to be the precursors from which medullary carcinoma arise

 

Clinical course

• Most often present as a mass in the neck and may be associated with dysphagia or hoarseness
• May present as a paraneoplastic syndrome owing to the secretion of a peptide hormone
• Hypocalcaemia is not a prominent feature despite the high levels of calcitonin
• Suspected familial cases are detected via screening for calcitonin levels
• Familial medullary thyroid carcinoma lesions are fairly indolent
• Sporadic medullary carcinomas and those associated with MEN-2A are of intermediate aggressiveness
• MEN-2B have a poor outcome due to their propensity for early metastases via the bloodstream

 

Anaplastic carcinoma

• Undifferentiated tumours of follicular epithelium
• Aggressive – mortality rate approaching 100%
• Account for less than 5% of all thyroid tumours
• Mean age of 65

 

Morphology

• Highly anaplastic cells, histological patterns include;
• Large pleomorphic giant cells with occasional osteoclast-like multinucleate giant cells
• Spindle cells with sarcomatous appearance
• Mixed spindle and giant cells
• Small cells resembling small cell carcinomas arising at other sites

 

Clinical course

• Present as rapidly enlarging bulky neck mass
• By the time of presentation the lesion may have spread beyond the capsule and be involving other neck structures and the lungs
• There is no effective therapy and disease is normally fatal within 1 year

Although metastases occur, death is generally due to its aggressive growth compromising the vital structures in