Transcript Endocrinology

Endocrinology CPC
History/Findings:
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The patient is a 25 year old concert violinist from
Drogheda who presented with a 5 cm x 4 cm x 3 cm
mass in the left mid jugular area.
Other small nodes were palpated in the remainder of
the left neck, as well. There was a hard 2 cm in
diameter mass located in the left lobe of the thyroid
gland and the remainder of the gland was palpable
and slightly firm.
Clinical History
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He underwent 5 fine needle aspirations, a CT
scan, and a MRI at his local hospital.
He was told he needed a thyroidectomy and
radical neck dissection. (Please note a
radical neck dissection would sacrifice the
spinal accessory nerve which would paralyze
the left trapezius muscle, a catastrophic
deficit to a concert violinist.)
The patient elected to come to SJH for
additional consultation and treatment.
Lab/Imaging
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FNA #1 on 23-12-08 Left Neck – Apparent cyst with
fragments of epithelium.
FNA #2 on 16-01-09 Left thyroid – Atypical cellular
fragments, suspicious for papillary carcinoma.
FNA #3 on 24-01-03 Left thyroid – Consistent with
colloid nodule.
FNA #4 Left neck cyst – Histiocytes with epithelial
cells.
FNA #5 Solid neck mass – Consistent with papillary
carcinoma.
FNA
 FNA showing follicular
cells.
 The follicles are
composed of small
clusters of cells.
 The colloid cannot be
identified easily in this
preparation.
 The nuclei are
monotonous without
obvious atypia.
http://pathweb.uchc.edu
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MRI – Described the palpable masses and
some calcification of the left thyroid lobe.
CAT scan – Describes the palpable left neck
mass but “no significant lymphadenopathy”;
incidental note was made of a polyp in the left
maxillary sinus.
TFT’s within normal limits.
CT Scan
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This CT scan of the upper
chest (thorax) shows a
malignant thyroid tumour.
The dark area around the
trachea (marked by the
white U-shaped tip of the
respiratory tube) is an area
where normal tissue has
been eroded and died
(necrosis) as a result of
tumour growth.
Clinical Course:
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The patient was taken to the operating room where a total thyroidectomy in
continuity with a left paratracheal and pretracheal lymph node dissection was
performed along with a modified radical neck dissection.
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The jugular vein was sacrificed due to the surrounding lymphadenopathy, but
the spinal accessory nerve was preserved.
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His post operative course was uneventful and he left the hospital after a brief
inpatient stay.
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He and his family returned home.
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His TSH was 90 at 3 weeks post-op.
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He was given an ablative dose of 150 mc of radioactive iodine.
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A total body scan done at that time was negative. He will continue in follow-up,
and his prognosis remains good.
Final Pathology:
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The final pathology report revealed the primary
tumour to be papillary carcinoma, 2.5 cm to 3 cm in
greatest dimension.
The tumour was well differentiated.
Additional foci of tumour were encountered in the
isthmus of the gland.
The right lobe was negative for tumour. Six out of
seven paratracheal lymph nodes were found to be
positive for metastatic papillary cancer and an
additional 15 positive lymph nodes were
encountered in the left neck dissection specimen.
All in all, 32 lymph nodes were resected.
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Lymph node with metastasis of
papillary thyroid carcinoma
(middle/bottom of image).
The papillary thyroid carcinoma
(thyroid cancer) shown here has the
classically described appearance
(papillary architecture -- papillae
with fibrovascular cores).
The diagnostic nuclear features for
papillary thyroid carcinoma (nuclear
inclusions, nuclear grooves, nuclear
clearing, overlap of nuclear
membranes/crowding) are present
but not seen well at this
magnification.
The lymph node has several
germinal centers (left, top/right of
image). Adipose tissue (fat) is seen
at the edge of the image (bottom
and left).
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Papillary tumours are the most common of all thyroid
cancers (>70%). Papillary carcinoma typically arises as an
irregular, solid or cystic mass that arises from otherwise normal
thyroid tissue.
This cancer has a high cure rate with ten year survival rates for
all patients with papillary thyroid cancer estimated at 80-90%.
Cervical metastasis (spread to lymph nodes in the neck) are
present in 50% of small tumours and in over 75% of the larger
thyroid cancers.
The presence of lymph node metastasis in these cervical areas
causes a higher recurrence rate but not a higher mortality rate.
Distant metastasis (spread) is uncommon, but lung and bone are
the most common sites.
Tumours that invade or extend beyond the thyroid capsule have
a worsened prognosis because of a high local recurrence rate.
Characteristics of Papillary Thyroid
Cancer
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Peak onset ages 30 through 50
Females more common than males by 3 to 1 ratio
Prognosis directly related to tumour size [less than 1.5 cm (1/2
inch) good prognosis]
Accounts for 85% of thyroid cancers due to radiation exposure
Spread to lymph nodes of the neck present in more than 50% of
cases
Distant spread (to lungs or bones) is very uncommon
Overall cure rate very high (near 100% for small lesions in young
patients)
Foundations of Molecular Diagnostics
Cell
protein
RNA
DNA
Pathological Pathways
Papillary Thyroid Carcinoma
Follicular Epithelial Cell
Follicular Carcinoma
Oncogenes in thyroid carcinomas
RAS proto oncogenes
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commonly mutated in many
different types of human cancers.
three main RAS genes,
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Point mutations common
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H-RAS (chromosome 11p15.5),
N-RAS (chromosome 1p13.2)
K-RAS (chromosome 12p12.1).
usually occur in the GTP-binding
domain (codons 12 and 13), and in
the
GTPase domain (codon 61),
though other types of mutations,
including amplifications and
acquired polymorphisms have also
been detected.
N-RAS mutations may be more
frequent than K-RAS and H-RAS
point mutations.
Hunt J. Expert Review of Molecular Diagnostics, Volume 5, Number 5,
September 2005, pp. 725-734
BRAF
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located on chromosome 7q34.
Point mutations in BRAF occur in
multiple tumor types.
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melanoma,
cholangiocarcinoma
papillary thyroid carcinoma.
common point mutation is a T -A
transversion at nucleotide 1796 in
exon 15 (V599E) .
BRAF mutations have been
reported in between 35% and 69%
of papillary thyroid carcinomas.
given its high prevalence and the
high specificity for papillary thyroid
carcinoma, it may be useful as a
diagnostic marker, either in FNA
specimens or in surgical
specimens.
Hunt J. Expert Review of Molecular Diagnostics, Volume 5, Number 5,
September 2005, pp. 725-734
PAX 8-PPAR g
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Chromosomal translocation present
in approximately 40% of follicular
thyroid carcinomas.
PAX8 - thyroid transcription factor
critical for thyroid regulation of
growth, differentiation and function.
PPARγ (peroxisome proliferatorsactivated receptor γ)
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nuclear receptor
ligand dependent transcription factor
highly expressed in adipose tissue.
translocation may also be present in
benign lesions, (follicular
adenomas),
Hunt J. Expert Review of Molecular Diagnostics, Volume 5, Number 5,
September 2005, pp. 725-734
ret/PTC -1, -3
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translocation is between the tyrosine
kinase domain of the RET protooncogene on chromosome 10 and
multiple different partner genes.
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most common partner genes are ELE1
(PTC3) and
H4 (PTC1),
both located on chromosome 10.
Both translocations are more
frequently seen in radiation-induced
tumours,
ret-PTC3 translocation may be more
common in solid variant of papillary
carcinomas.
ret/PTC rearrangements found in
approximately 30-40% of papillary
carcinomas.
Hunt J. Expert Review of Molecular Diagnostics, Volume 5, Number 5,
September 2005, pp. 725-734
Molecular markers in PTC
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ret/PTC
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To date 15 chimeric mRNAs involving 10 different
genes have been described
Ret/PTC-1 and ret/PTC-3 are the most common
types, accounting for 90%.
Morphological variants are likely to reflect
variations in tumour biology which have yet to be
fully defined.
ret/PTC and BRAF in an Irish PTC cohort
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7
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5
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3
2
1
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ret/PTC
Year
19
94
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6
19
97
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9
20
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-0
2
19
82
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4
19
85
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7
19
88
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0
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91
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3
T1799A mutation
Sorafenib (Nexavar)
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Inhibits tumor cell proliferation and angiogenesis by
targeting RAF KINASES and VEGF RECEPTORS;
multikinase inhibitor that targets serine/threonine
and receptor tyrosine kinases to decrease tumour
growth and angiogenesis; FDA approved orphan
drug indication for hepatocellular carcinoma in
2006.
Sunitinib
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Description: Inhibits VEGF-R2 and PDGF-R beta
tyrosine kinase; has antineoplastic activity.
Sunitinib is in a class of medications called
multikinase inhibitors. It works by blocking the action
of the abnormal protein that signals cancer cells to
multiply. This helps stop or slow the spread of
cancer cells and may help shrink tumours.
Comments:
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A 25 year old male with a very hard left
thyroid mass and massive left sided cervical
lymphadenopathy has thyroid cancer until
proven otherwise.
We need to be prudent and selective in our
employment of pre-operative testing.
This will save a lot of money, avoid significant
patient discomfort, and expedite the patient’s
diagnosis and treatment.