Case 1

Group 1 Click to edit Master subtitle style secB

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Scenario:

50-year-old female, presents with enlargement of alongstanding neck mass.

Physical examination reveals amultinodular thyroid gland, all of which moves with swallowing. There is a dominant, left-lobe,6-cm nodule, which the patient said hadenlarged abruptly10 days before. Her thyroid gland extends below the sternal notch 3/14/12 into the anterior mediastinum, so the

The patient is taken to surgery because of her sensation oflaryngeal compression, and a total thyroidectomy is performed. The pathologist notes amultinodular goiterand confirms the largehemorrhagic cyst, but also finds asolid 2.5-cmnodule in the mediastinal portion of the thyroid gland. This mass ispartially encapsulated, but enlarged follicular cells forming small follicles are seen topenetrate the capsuleand toinvade vascular channelsaround the nodule. The cells have round, euchromatic nuclei without inclusions, grooves, or papillae. The patient does not return for follow-up visits until one year later, when she 3/14/12 notespainin herleft humerus. On x-ray

Differential Diagnosis
Follicular carcinoma Multinodular Goiter Peak of Onset Gender Predilection Higher in females

Medullary Carcinoma

Bet. Ages of 40 and 60 Older than 50 yrs 40s and 50s 3-4 times common No predilection for in women gender (+) multiple nodules Presence of one or more palpable nodules in a gland

solitary

One lobe involvement Involve one lobe Bilateral and Click to edit Master subtitle stylemore than the multicentric far other (-) hemorrhage in lesion (-) laryngeal compression Hyperchromatic and prominent nuclei 3/14/12 Nuclear features Euchromatic Inclusions and pleomorphic (+) hemorrhage in (+) hemorrhage in lesion lesion (+) layrngeal compression (+) laryngeal compression

Follicular Ca Capsular feature Infiltrate well beyond the capsule

Mutinodular goiter

Medullary ca

non-encapsulated Infiltrate well beyond the capsule

metastasis

(+)

(-)

(+)

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What is the most likely DIAGNOSIS?

Follicular thyroid carcinoma(stage IV) complicating multinodular goiter

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Multinodular Goiter

Gross findings. The normal thyroid gland weighs up to40 g. Simple goiters usually weigh more than 40 g.

Simple goiters are firm and diffusely enlarged. The cut surface shows a uniform amber color with a translucent appearance.
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Multinodular goiters are of varying sizes and often weigh from 60 to 1000 g or more. The gland has a distorted shape and is nodular. Some nodules may be partially or completely separated from the gland, constituting sequestered or parasitic nodules.Cut sections of the multinodular goiter show areas with degenerative changes (such as 3/14/12 scarred areas, fibrosis, old and recent

Microscopic findings.

The histology of multinodular goiter parallels the macroscopic features, with nodules consisting of irregularly enlarged follicles of variable size with flattened epithelium and abundant colloid, adjacent to smaller follicles with a taller, more active epithelium. There may be evidence of old and recent hemorrhage with 3/14/12 hemosiderin-laden macrophages,

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The concept of areas of hyperplasia coupled with areas of involution. In the pathogenesis of simple and multinodular goiters, it is assumed that there is initially diffuse hyperplasia which becomes nodular with increasing size, fibrosis, and distortion of the vascular supply of the thyroid gland.
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Why a long-standing nontoxic goiter becomes nodular?

Not surprisingly, mutations affecting proteins of the TSH-signaling pathway that lead to constitutive activation of this pathway have been identified in a subset of autonomous thyroid nodules.

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Clinical

Multinodular goiter is the end stage in the evolution of simple goiter. The most obvious feature of a goiter is the enlargement of the thyroid, that can often be seen and palpated. Extreme enlargement of the thyroid can give rise to pressure symptoms on both the trachea and the esophagus.

Most patients with multinodular goiter are euthyroid; however, in endemic areas, where the disease is a result of insufficient iodine in the salt, many children are 3/14/12

The incidence of malignancy in longstanding multinodular goiters is low(less than 5%) but not zero, and concern for malignancy arises in goiters that demonstrate sudden changes in sizes or symptoms(e.g hoarseness of voice).

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Management

Surgical resection:

Total thyroidectomy

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Follicular Carcinoma

Follicular thyroid carcinoma (FTC) is a well-differentiated tumor. In fact, FTC resembles the normal microscopic pattern of the thyroid. FTC originates in follicular cells and is the second most common cancer of the thyroid, after papillary carcinoma.

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Despite its well-differentiated characteristics, follicular carcinoma may be overtly or minimally invasive. In fact, FTC tumors may spread easily to other organs. Life expectancy of affected patients is related to their age; the prognosis is better for younger patients than for patients who are older than 45 years. 3/14/12

Pathophysiology

Activating point mutations in therasoncogene are well known in patients with follicular adenoma and carcinoma,[2, 3, 4]especially in poorly differentiated (55%) and anaplastic carcinoma (52%). As a result of such mutations, p21-RAS becomes locked in its active conformation, leading to the constitutive activation of the protein and tumor development.[5]The biochemical 3/14/12 pathways that this process follows may

Accidental (not diagnostic) x-ray exposure may influence both occurrence and pattern ofrasmutation. A study of differential gene expression profiling of aggressive and nonaggressive follicular carcinomas identified 94 genes that distinguish follicular carcinomas from follicular adenomas (includingPBPandCKS2) and 4 3/14/12 genes that distinguish aggressive

Although follicular cancer is frequently present in goitrous thyroids, the relationship between prolonged elevation of thyroidstimulating hormone (TSH) and follicular carcinoma is not known. Several reports have shown a relationship between iodine deficiency and the incidence of thyroid carcinoma. 3/14/12

Histologic Findings
On gross examination, FTC appears encapsulated and solitary and is often found in necrotic and/or hemorrhagic areas.

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The right lobe of the thyroid was sectioned and reveals a large solid nodule with necrotic and hemorrhagic areas. Histologic diagnosis is follicular thyroid carcinoma
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Histologically, the lesion may be encapsulated and may demonstrate well-defined follicles containing colloid, making its distinction from follicular adenoma difficult.

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diagnosis is made by finding pseudocapsule and/or blood vessel invasion, High magnification of the abortive follicles may demonstrate atypia of the follicular epithelium and intervening stroma. Thyrocytes are large and show an abnormal nuclear/cytoplasmic ratio with several mitoses. Presence of colloid-rich follicles lined by flattened follicular cells that are occasionally accompanied by several histiocytes is maintained in a benign lesion. Definitive diagnosis is often not possible with samples obtained from FNAB because accurate distinction between benign and malignant lesions cannot be made.
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Figure 1:Follicular Carcinoma. H and E staining showing characteristic features for follicular carcinoma. a) (3.76X magnification) Thyroid nodule showing thickened capsule and a nodule composed of small thyroid follicles. Notice that the edges of the follicle are irregular and appear to infiltrate into the fibrous capsule. b) (9.4X magnification) and d) (37.6X magnification) Tumour cells within the vascular space confirming vascular invasion. c) (56.4X magnification) Shows the morphology of the carcinoma 3/14/12 of relatively small follicular architecture with somewhat enlarged cells.

RET Mutation

More than 25 mutations in the RET gene are known to cause multiple endocrine neoplasia type 2. Most of these mutations change single protein building blocks (amino acids) in the RET protein. The most common mutation responsible for multiple endocrine neoplasia type 2A substitutes the amino acid arginine for the amino acid cysteine at position 634 (written as Cys634Arg or C634R). Another 3/14/12 mutation causes more than 90 percent of

Mutations responsible for multiple endocrine neoplasia type 2 result in an overactive RET protein that can transmit signals without first attaching to growth factors outside the cell. The overactive protein likely triggers cells to grow and divide abnormally, which can lead to the formation of tumors in the endocrine system and other tissues.
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Schematic representation of the RET gene showing the codons involved in germline mutation in MEN 2. 3/14/12

Management

The most common sites of metastases are lymph nodes, lung, and bone. Treatment of lymph node metastases alone is often curative. Treatment of distant metastases is usually not curative but may produce significant palliation.

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Standard treatment options:

I131: Metastases that demonstrate uptake of this isotope may be ablated by therapeutic doses of I131. External-beam radiation therapy for patients with localized lesions that are unresponsive to I131.

Resection of limited metastases, 3/14/12 especially symptomatic metastases,

The prognosis for patients with distant metastases is poor.

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Learning Objective Questions:

In a patient with a solitary thyroid nodule, list at least four clinical features favoring carcinoma over goitrous nodule.

Prior history of radiation exposure should be ascertained in all patients presenting with solitary thyroid nodule.

Past medical history or family history of pheochromocytoma, hyperparathyroidism, chronic constipation and diarrhea, hypertension, and episodes of nervousness or excitability should alert the clinician of the possibility of familial MEN 3/14/12 2a or 2b syndrome.

Fixation to or invasion of surrounding structures and the presence of palpable lymph nodes in the neck are also highly suggestive of malignancy. preexisting benign thyroid disease, irregular menstruation, bilateral oophorectomy, family history of thyroid malignancy, certain inherited syndromes, and residence in endemic goiter areas.
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Others include:

sex and age of the patient

Although solitary thyroid nodules are found more frequently in women, incidence of carcinoma in solitary thyroid nodules is increased in men. Several studies have reported a bimodal age distribution of thyroid carcinoma in solitary thyroid nodules.

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