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8/2/2019 Genpath Case 1
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Case 1
Group 1secB
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Scenario:•
50-year-old female, presents with• enlargement of a longstanding neck
• mass.
Physical examination revealsa multinodular thyroid gland, all of which moves with swallowing. There is a
dominant, left-lobe, 6-cm nodule, whichthe patient said had enlargedabruptly 10 days before. Her thyroid
gland extends below the sternal notchinto the anterior mediastinum so the
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The patient is taken to surgery because of her sensation oflaryngeal compression, and atotal thyroidectomy is performed. Thepathologist notes a multinodular goiter andconfirms the large hemorrhagic cyst, but alsofinds a solid 2.5-cm nodule in the mediastinalportion of the thyroid gland. This massis partially encapsulated, but enlargedfollicular cells forming small follicles are seento penetrate the capsuleand to invadevascular channels around the nodule. The cells
have round, euchromatic nuclei withoutinclusions, grooves, or papillae.
The patient does not return for follow-up
visits until one year later, when shenotes ain in her left humerus. On x-ra
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Differential DiagnosisFollicular carcinoma Multinodular
GoiterMedullaryCarcinoma
Peak of Onset Bet. Ages of 40 and 60 Older than 50 yrs 40s and 50s
GenderPredilection
Higher in females 3-4 times commonin women
No predilection forgender
solitary (+) multiple
nodules
Presence of one or
more palpablenodules in a gland
One lobe involvement Involve one lobefar more than theother
Bilateral andmulticentric
(-) hemorrhage inlesion (+) hemorrhage inlesion (+) hemorrhage inlesion
(-) laryngealcompression
(+) layrngealcompression
(+) laryngealcompression
Hyperchromatic andprominent nuclei
Nuclear features Euchromatic Inclusions and pleomorphic
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Follicular Ca Mutinodulargoiter
Medullary ca
Capsular feature Infiltrate well
beyond thecapsule
non-encapsulated Infiltrate well
beyond thecapsule
metastasis (+) (-) (+)
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What is the most likelyDIAGNOSIS?
• Follicular thyroid carcinoma(stage IV)complicating multinodular goiter
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Multinodular Goiter
• Gross findings.
• The normal thyroid gland weighs up
to 40 g. Simple goiters usually weighmore than 40 g.
Simple goiters are firm and diffusely
enlarged. The cut surface shows auniform amber color with a translucentappearance.
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• Multinodular goiters are of varyingsizes and often weigh from 60 to1000 g or more. The gland has a
distorted shape and is nodular. Somenodules may be partially orcompletely separated from the
gland, constituting sequestered orparasitic nodules. Cut sections of themultinodular goiter show areas withdegenerative changes (such asscarred areas, fibrosis, old and recent
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Microscopic findings.
• The histology of multinodular goiterparallels the macroscopic features,
with nodules consisting of irregularlyenlarged follicles of variable size withflattened epithelium and abundantcolloid, adjacent to smaller follicleswith a taller, more active epithelium.
• There may be evidence of old andrecent hemorrhage withhemosiderin-laden macro ha es
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y a ong-s an ngnontoxic goiter becomes
nodular?• The concept of areas of hyperplasiacoupled with areas of involution. Inthe pathogenesis of simple and
multinodular goiters, it is assumedthat there is initially diffusehyperplasia which becomes nodular
with increasing size, fibrosis, anddistortion of the vascular supply of the thyroid gland.
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• Not surprisingly, mutations affectingproteins of the TSH-signalingpathway that lead to constitutive
activation of this pathway have beenidentified in a subset of autonomousthyroid nodules.
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Clinical
• Multinodular goiter is the end stage inthe evolution of simple goiter.
• The most obvious feature of a goiter is theenlargement of the thyroid, that can often
be seen and palpated.• Extreme enlargement of the thyroid can
give rise to pressure symptoms on boththe trachea and the esophagus.
• Most patients with multinodular goiter areeuthyroid; however, in endemic areas,where the disease is a result of insufficient
iodine in the salt, many children are
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• The incidence of malignancy in long-standing multinodular goiters islow(less than 5%) but not zero, and
concern for malignancy arises ingoiters that demonstrate suddenchanges 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 awell-differentiated tumor. In fact, FTCresembles the normal microscopic
pattern of the thyroid. FTC originatesin follicular cells and is the secondmost common cancer of the thyroid,
after papillary carcinoma.
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• Despite its well-differentiatedcharacteristics, follicular carcinomamay be overtly or minimally invasive.
In fact, FTC tumors may spread easilyto other organs.
• Life expectancy of affected patients
is related to their age; the prognosisis better for younger patients thanfor patients who are older than 45
years.
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Pathophysiology • Activating point mutations in
the ras oncogene are well known inpatients with follicular adenoma andcarcinoma,[2, 3, 4] especially in poorlydifferentiated (55%) and anaplasticcarcinoma (52%).
• As a result of such mutations, p21-RASbecomes locked in its activeconformation, leading to the constitutiveactivation of the protein and tumordevelopment.[5] The biochemical
pathways that this process follows may
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• Accidental (not diagnostic) x-ray
exposure may influence bothoccurrence and patternof ras mutation.
•
A study of differential geneexpression profiling of aggressiveand nonaggressive follicular
carcinomas identified 94 genes thatdistinguish follicular carcinomas fromfollicular adenomas(including PBP and CKS2) and 4
genes that distinguish aggressive
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• Although follicular cancer isfrequently present in goitrousthyroids, the relationship between
prolonged elevation of thyroid-stimulating hormone (TSH) andfollicular carcinoma is not known.
• Several reports have shown arelationship between iodinedeficiency and the incidence of
thyroid carcinoma.
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Histologic Findings
On gross examination, FTCappears encapsulated and solitary andis often found in necrotic and/or
hemorrhagic areas.
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The right lobe of the thyroid was sectionedand reveals a large solid nodule withnecrotic and hemorrhagic areas. Histologicdiagnosis is follicular thyroid carcinoma
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• Histologically, the lesion may beencapsulated and may demonstratewell-defined follicles containingcolloid, making its distinction fromfollicular adenoma difficult.
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• diagnosis is made by finding pseudocapsuleand/or blood vessel invasion,
• High magnification of the abortive follicles may
demonstrate atypia of the follicular epithelium andintervening stroma.
• Thyrocytes are large and show an abnormalnuclear/cytoplasmic ratio with several mitoses.
• Presence of colloid-rich follicles lined by flattenedfollicular cells that are occasionally accompaniedby several histiocytes is maintained in a benignlesion.
• Definitive diagnosis is often not possible withsamples obtained from FNAB because accuratedistinction between benign and malignant lesionscannot be made.
• - - -
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Figure 1: Follicular Carcinoma. H and E staining showing characteristicfeatures for follicular carcinoma. a) (3.76X magnification) Thyroid noduleshowing thickened capsule and a nodule composed of small thyroidfollicles. Notice that the edges of the follicle are irregular and appear toinfiltrate into the fibrous capsule. b) (9.4X magnification) and d) (37.6Xmagnification) Tumour cells within the vascular space confirming vascularinvasion. c) (56.4X magnification) Shows the morphology of the carcinomaof relatively small follicular architecture with somewhat enlarged cells.
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RET Mutation
• More than 25 mutations in the RET geneare known to cause multiple endocrineneoplasia type 2. Most of these mutations
change single protein building blocks(amino acids) in the RET protein. Themost common mutation responsible for
multiple endocrine neoplasia type 2Asubstitutes the amino acid arginine forthe amino acid cysteine at position 634(written as Cys634Arg or C634R). Another
mutation causes more than 90 percent of
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Mutations responsible for multipleendocrine neoplasia type 2 result inan overactive RET protein that cantransmit signals without firstattaching to growth factors outsidethe cell. The overactive proteinlikely triggers cells to grow anddivide abnormally, which can lead
to the formation of tumors in theendocrine system and other tissues.
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Schematic representation of the RET geneshowing the codons involved in germline
mutation in MEN 2.
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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 demonstrateuptake of this isotope may beablated by therapeutic doses of I131.
•
External-beam radiation therapy forpatients with localized lesions that
are unresponsive to I131.•
Resection of limited metastases,
especially symptomatic metastases,
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The prognosis for patients withdistant metastases is poor.
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Learning Objective Questions:
• In a patient with a solitary thyroid nodule, listat least four clinical features favoringcarcinoma over goitrous nodule.
– Prior history of radiation exposure should
be ascertained in all patients presentingwith 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 theclinician of the possibility of familial MEN2a or 2b syndrome.
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Fixation to or invasion of surroundingstructures and the presence of palpable lymph nodes in the neck arealso highly suggestive of malignancy.
preexisting benign thyroid disease,irregular menstruation, bilateraloophorectomy, family history of
thyroid malignancy, certain inheritedsyndromes, and residence in endemicgoiter areas.
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• Others include:
– sex and age of the patient
• Although solitary thyroid nodules arefound more frequently in women,incidence of carcinoma in solitarythyroid nodules is increased in men.
Several studies have reported abimodal age distribution of thyroidcarcinoma in solitary thyroid nodules.