Follicular carcinoma

Cytopathology of the Thyroid
Helsinki 21 11 2012
Akif Demir
Sahlgrenska University Hospital Clnical Pathology & Cytology
Gothenburg-Sweden
Cytology (Archeology)
Histopathology (Architecture)
Thyroidea
Follicle
Functional unit,
follicular cells, C cells
Lobule
20-30 follicle
Classification
(based on WHO book published in 2004)
Primary
Epithelial tumours
Follicular cell tumors
C cell tumours (Medullary Carcinoma)
Mixed follicular and C cell tumours
Others
Metastatic
Classification…
BENIGN
Thyroid adenoma and related tumours
Follicular Adenoma (+Onkocytic Adenoma)
Hyalinizing trabecular tumor
Classification…
MALIGNANT
Papillary carcinoma (and variants)
Follicular carcinoma (+ Onkocytic
carcinoma)
Poorly differentiated carcinoma
Undifferentiated (Anaplastic) carcinoma
Classification, malignant tumours
Squamous cell carcinoma
Mucoepidermoid carcinoma
Sclerosing mucoepidermoid carcinoma with
eosinophilia
Mucinous carcinoma
Medullary carcinoma
Mixed medullary and follicular cell carcinoma
Spindle cell tumor with thymus-like differentiation
Carcinoma showing thymus-like differentiation
Classification…
OTHER THYROID TUMOURS
Teratoma
Primary lymphoma and plasmacytoma
Ectopic thymoma
Angiosarcoma
Smooth muscle tumours
Peripheral nerve sheet tumours
Paraganglioma
Solitary fibrous tumour
Follicular dendritic cell tumour
Langerhans cell histiocytosis
Secondary tumours
Variants of papillary carcinoma
Follicular variant
Macrofollicular variant
Oncocytic variant
Clear cell variant
Diffuse sclerosing variant
Tall cell variant
Columnar cell variant
Solid variant
Cribriform carcinoma (FAP)
Variants of follicular carcinoma
Oncocytic variant
Clear cell variant
Variants of medullary carcinoma
Papillary or pseudopapillary , characterized by the presence of true papillae or
artefactual pseudopapillae, caused by tissue fragmentation.
Glandular (tubular or follicular)
Giant cell
Spindle cell
Small cell and Neuroblastoma-like
Paraganglioma-like
Oncocytic cell
Clear cell
Angiosarcoma-like
Squamous cell
Melanin-producing
Amphicrine
Encapsulated tumours/lesions
Dominant or adenomatous nodules (Nodular goitre)
Follicular adenom
Follicular carcinom
Follicular Variant Papillary carcinom (FVPC)
Well differentiated tumour of uncertain malignant
potential
Follicular tumour of uncertain malignant potential
Well differentiated carcinom
Preoperative Diagnosis
Conventional FNA
Immunocytochemistry
Cell-block
Immunohistochemistry
Molecular pathologic analysis
Papillary
Poorly
differentiated
Follicular
Anaplastic
Oncocytic
Medullary
ICC:
ImmunoCytoChemistry
TTF-1
THYROGLOBULIN
ImmunoCytoChemistry
TTF1 and TG: Primary/thyrocyte
Galectin 3: Malignant potential?
HBME-1: Malignant potential?
HMWCK: Papillary carcinoma
CK 19: Papillary carcinoma, more or less the other
follicular tumours.
Calcitonin: Medullary carcinoma
Chromogranin-A: Medullary carcinoma
CEA: Medullary carcinoma (+ onco. tm.)
PanCK: Pancytokeratin
CD56 Follicular X Papillary ??
Ki 67: Proliferative marker
CELL BLOCK
Cell Block Haematoxylin & Eosin
AE1/AE3
CK19
Galectin 3
anaplastic cells
Galectin 3
Clear cells
CK7
CARBA
CELL BLOCK-IHC
Ki67
p53
SYNAPTOPHYSIN
CHROMOGRANIN (-)
CD56 (-)
THYROGLOBULIN
TTF-1
CELL BLOCK-IHC
Surgical material
THYROGLOBULIN –surgical material
P53 ANAPLASTIC AREA
TTF-1 NEGATIVE
A few nuclei with
weak positivity
BRAF NEGATIVE
P53 FOCAL POSITIVITY
THE BETHESDA SYSTEM FOR
REPORTING THYROID
CYTOPATHOLOGY
http://papsociety.org/atlas.html
The benefits of a uniform reporting system for
thyroid cytopathology
Improved communication
Facilitated cytologic & histologic correlation
Facilitated research into the epidemiology,
molecular biology, pathology, and diagnosis of
thyroid diseases
Easy and reliable sharing of data from different
laboratories
Easy to follow algorithms
Economical aspects
Local, national & international standardisation
of reporting terminology is essential
Quality control of outcomes via local, national
& international audits of PPV & NPV for
malignancy, inadequate rates, rates for follicular
neoplasm & AFUS is required
Good training in FNA technique & smear
preparation
Use of LBC if problems with direct smear
making & specimen collection
Molecular techniques very exciting but not as yet
widely implemented.
Implied risk of malignancy and recommended
clinical management
Diagnostic category
Risk of
malignancy (%)
I-Nondiagnostic or
unsatisfactory
Usual management
Repeat FNA with
ultrasound guidance
II-Benign
0-3
Clinical follow-up
III-AUS/FLUS
5-15
Repeat FNA
IV-Follicular neoplasm or
suspicious for a follicular
neoplasm
15-30
Surgical lobectomy
V-Suspicious for malignancy
60-75
Near-total thyroidectomy or
surgical lobectomy
VI-Malignant
97-99
Near total thyroidectomy
Adequacy
Minimum of six groups of well-visualized
follicular cells, with at least ten cells per group,
preferably on a single slide.
Exceptions:
Solid nodules with cytologic atypia
Solid nodules with inflammation
Colloid nodules
Adequacy; exceptions…
Solid nodules with cytologic atypia
Mandatory to report any significant atypia
A minimum number of follicular cells is not
required
Solid nodules with inflammation
A minimum number of follicular cells is not
required
Colloid nodules
A minimum number of follicular cells is not
required if easily-identifiable colloid
predominates.
I. Nondiagnostic/Unsatisfactory
1.
2.
3.
Fewer than six groups of well-preserved, wellstained follicular cell groups with ten cells
each.
Poorly prepared, poorly stained, or obscured
follicular cells
Cyst fluid, with or without histiocytes, and
fewer than six groups of ten benign follicular
cells
http://papsociety.org/atlas.html
Non-diagnostic…
Management
Should be re-aspirated but no sooner than 3
months later (to prevent false positive
interpretations due to reactive/reparative
changes)
US-guided re-aspiration with on-site adequacy
evaluation (especially for solid nodules)
Repeating FNA results in a diagnostic
interpretation up to 60% of cases
Non-diagnostic/management…
After 2 successive ND/UNS specimens close
clinical follow up with US or surgery should be
considered
Risk of malignancy is low for cystic lesions if
they are simple/unilocular and <3 cm. In proper
clinical setting these lesions may be considered
clinically adequate, even though they are
reported as non-diagnostic. Repeat FNA should
be performed only if the ultrasound findings are
suspicious
Non-diagnostic management
ND
re-aspiration
60% diagnoses
ND
follow up with US
Surgery
Non-diagnostic management
ND, Cyst fluid only
<3 cm
Not suspicious US
simple/unilocular
Suspicious US
Clinically adequate
Repeat FNA
Cystic lesion in thyroid region: Cystic parathyroid adenoma /Chromogranin A +
II. Benign follicular nodule (BFN)
Without atypia
II. Benign follicular nodule (BFN)
The most common diagnose in FNA
interpretation (approx. 65% of all cases)
Benign results are further sub-classified as
Benign follicular nodules
Nodular goiter, hyperplastic (adenomatoid) nodules,
colloid nodules, nodules in Grave’s disease, and subset of
follicular adenomas (those of macrofollicular type)
Thyroiditis
Lymphocyic (Hashimoto’s), Granulomatous, Acute,
Riedel’s
Benign…
Specimens consisting of abundant colloid only,
with a very few or no follicular cells, are
considered BFNs and may be reported as
“suggestive of…” or “consistent with colloid
nodule”
Colloid must be distinguished from serum and
should cover a significant portion of the glass
slide surface.
Benign…
Cellularity alone is not enough to merit the
interpretation “Follicular Neoplasm/Suspicious
for FN”
“Flame cells” may be encountered in Grave’s
Disease but also in other non-neoplastic
conditions, follicular neoplasm and papillary
carcinoma.
Treated Grave’s Disease may show
microfollicular architecture, nuclear overlapping
and considerable atypia.
III. Atypia of undetermined significance
(AUS) or Follicular lesion of undetermined
significance (FLUS)
Atypi av oklar signifikans eller follikulär resistens av oklar signifikans
(oklar follikulär förändring)
III. Atypia of undetermined significance
(AUS) or Follicular lesion of undetermined
significance (FLUS)
Cases that do not fulfill the criteria of other
categories
Heterogeneous category (9 scenarios)
AUS/FLUS…
Definition: “This category is reserved for
specimens that contain cells (follicular , lymfoid,
or other) with architectural and/or nuclear
atypia that is not sufficient to be classified as
suspicious for malignancy or malignant. On the
other hand, the atypia is more marked than can
be ascribed to benign changes.
AUS/FLUS…
!!! Low cellularity, poor fixation, obscuring
elements by themselves NOT sufficient for
AUS/FLUS
AUS/FLUS…
7%?
“The frequency of AUS interpretations should
be in the range of approximately 7 % of all
thyroid FNA interpretations.
This figure may be further refined as more
laboratories report their experiences using the
AUS designation within the context of these
criteria.”
AUS/FLUS…
7%
Based on 2 large studies
Yang et al, Cancer cytopathol 2007: 11: 306-15
4703 thyroid FNAs
Atypical AUS = 3%
Yassa et al, Cancer Cytopathol 2007; 111: 508-16
3589 thyroid FNAs
Atypical (AUS) = 6%
AUS/FLUS…
Scenarios
1. AUS:
Sparsely cellular aspirate comprised of follicular cells
with architectural atypia. Colloid is absent.
Note: A repeat aspirate after an appropriate interval of
observation may be helpful if clinically indicated.
2. AUS
Follicular cells with focal cytologic and architectural
atypia, but obscuring blood and clotting artifact
preclude definitive evaluation.
Note: …
AUS/FLUS…
Scenarios
3. AUS
Follicular cells, predominately benignappearing, with focal cytologic atypia.
Note: A repeat aspirate after an appropriate
interval of observation may be helpful if clinically
indicated.
4. AUS
Predominantly benign appearing follicular
cells; some show focal cytologic and
architectural atypia.
Note: …
AUS/FLUS, Scenarios…
5. FLUS
Follicular lesion of undetermined significance
6. (FNA of a nodule in the right lobe in a patient with
multiple nodules)
AUS: The specimen is moderately cellular and consists almost
exclusively of Hurtle cells. Colloid is scant, and there is no
apparent increase in lymphoid cells.
Note: In a patient with multiple nodules, the findings likely represent
a Hurtle cell hypeplasia in the setting of multinodular goiter, but a
Hurtle cell neoplasm cannot be entirely excluded. Clinical correlation
is adviced.
7. (FNA of a nodule in a patient with a history of
Hashimoto thyroiditis)
AUS: The sample consists exclusively of Hurtle cells.
Note: in a patient with Hashimoto thyroiditis, the findings likely
represent a Hurtle cell hyperplasia, but a Hurtle cell neoplasm cannot
be entirely excluded. Clinical correlation advised.
AUS/FLUS, Scenarios…
8. (FNA of a nodule in a patient treated with I)
131
AUS: Marked cytologic atypia of follicular cells
Note: In a patient treated with radioiodine, the findings
likely represent reactive, treatment-related changes, but a
neoplasm cannot be entirely excluded. Clinical correlation
is advised.
9. AUS
Numerous, relatively momomorphic lymphoid cells
Note: the findings are atypical and raise the possibility of a
lymphoproliferative lesion, but immunophenotyping
studies could not be performed because of insufficient
material. An additional aspiration, with apportioning of
fresh needle-rinse fluid for flow cytometry, might be
helpful if clinically indicated.
AUS/FLUS…
Management
Clinical correlation
For most cases, repeat FNA
After an appropriate interval
Surgery considered for “repeat atypicals”
Only 20-25% of nodules are repeatedly AUS
The risk for malignancy: difficult to ascertain / a subset
of theese nodules have surgical follow up.
Cancer risk for selected population 20-25%
with repeatedly AUS results or
patients with worrisome clinical or sonographic findings
Cancer risk for all AUS nodules is probably 5-15%
Preliminary conclusions from recent
studies in the USA
The AUS/FLUS rate is variable (2-20%)
Currently many labs are exceeding the recommended
7% AUS-FLUS frequency
Malignancy rate for AUS-FLUS cases is variable,
generally in keeping with Bethesda guideline
Data support repeat FNA as initial management for
AUS-FLUS
Repeat FNA resolves the diagnosis in most AUS-FLUS
cases
Validity of the AUS-FLUS category re-affirmed
Molecular features
Common molecular changes of thyroid malignancies
Papillary Thyroid Carcinoma
BRAF mutation, RET/PTC, H-, K-, and NRAS mutations
Follicular Carcinoma
PAX8/PPAR
Medullary Thyroid Carcinoma
Familial: RET
Sporadic: RET and RAS
Anaplastic carcinoma
TP53, beta-catenin, BRAF, PTEN
BRAF mutations in PTC
T-A substitution at nucleotide 1799 (V600E)
MEK signal pathway
Very specific not seen in follicular carcinoma, MTC or
benign nodules
Applied to thyroid FNA
Found in 44% PTC in western countries
Conventional 60%
FVPTC 12%
Tall cell 77%
BRAF mutation tested on FNA is associated with poor
clinical outcome of PTC
BRAF positive (n=73)
BRAF negative (n=117)
p
N
%
N
%
Extranodal
extension
17
23.3
13
11.1
0.039
Capsule
invasion
21
28.8
19
16.2
0.045
Lymph node
metastases
28
38.4
21
18.0
0,002
Xing M. J Clin Oncol 2009; 27: 2977-82
None of the genetic changes is 100% sensitive
and specific for thyroid malignancies
Some of the genetic changes are “mutually
exclusive”
Nikiforov and Xing, J Endocrin Metabolism, 2003
Combining reviewed cytology and BRAF Mutational Analysis
BRAF
Reviewed
cytology
Reviewed
cytology +
BRAF
Sensitivity
63.3
78.9%
91.1%
Specifity
100%
100%
100%
Accuracy
67.7%
81.4%
92.2%
•Up to 86% of PTC patients in Korea have BRAF mutation
•Most atypical cases (90/102) were “suspicious” cases
•Kang G. Cancer (cytopathology), 2011
PCR versus Direct DNA Sequencing
Allele-specific PCR
Direct sequencing
Sensitivity
74,6%
59,5%
Specificity
85,7%
100%
Accuracy
75,1%
61,3%
•Kang G. Cancer (cytopathology), 2011
Diagnostic Significance of a Panel of
Mutational Tests in Thyroid FNA with
AUS/FLUS
513 thyroid FNA
with FLUS
(20,5%)
117 cases accepted
for molecular testing
and had surgical
follow-up
A panel of molecular testing
(BRAF, RAS, RET/PTC, and
PAX8/PPAR
Carcinoma on
surgical pathology
follow-up
Positive
n=12
10%
n=12
100%
Negative
n=105
90%
n=8
7,6%
Ohori et al. Cancer (cytopath) 2010: 118:17-23
Cantara J Clin Endocrin Metab, 2010; 95:1365-69
Cytology
Mutation on FNA
Histology
Indeterminate
(n=41)
BRAF (2)
PTC (2)
RET/PTC (2)
PTC (2)
RAS (5)
PTC (2) FA (3)
None (34)
PTC (1)
BRAF (21)
PTC (21)
RET/PTC (6)
PTC (6)
RAS (10)
PTC (10)
None (17)
PTC (9)
Sensitivity
Specifity
Cytology alone
59%
95%
Cytology + Molecular
91%
99%
Suspicious for cancer
(n=53)
Cancer risk in thyroid nodules with indeterminate cytology
and molecular testing performed on FNA
Cancer risk
AUS/FLUS
N=247
FN/SFN
N=214
SMC
N=52
Cytology only
14%
27%
54%
Any Mutation
identified
88%
87%
95%
No mutation
identified
6%
14%
28%
Nikiforov Y. J Clin Endocrin Metab August 2011
Proposed clinical algorithm for management
with indeterminate thyroid FNA
Cyto diagnose
AUS/FLUS
SFN/FN
Susp. Malign.
Cancer risk
14%
27%
54%
A panel of molecular testing
Mutational status
Cancer risk
Management
+
88%
Total
6%
FNA+/-
+
87%
Total
14%
+
95%
28%
Partial
Total
Partial
Nikiforov Y. J Clin Endocrin Metab August 2011
Differential miRNA expression profiles in variants of
papillary thyroid carcinoma and encapsulated
follicular thyroid tumours.
Analysis of a set of five selected miRNAS
distinguish common variants of PTC from
FA/MNG but failed to be a useful diagnostic
method in individual and doubtful cases,
especially in the differential diagnosis of
encapsulated follicular thyroid tumours.
Sheu SY, Grabellus F, Schwertheim S, Worm K, Broecker-Preuss M, Schmid
KW. Br J Cancer. 2010 Jan 19;102(2):376-82. Epub 2009 Dec 22.
IV. Follicular Neoplasm/Suspicious
for a Follicular Neoplasm (FN/SFN)
IV. Follicular Neoplasm/Suspicious
for a Follicular Neoplasm (FN/SFN)
Some laboratories prefer SFN because up to 35% of
cases prove not to be neoplasms but rather hypeplastic
nodules in nodular goiter.
Cytologic-histologic correlation for the follicular
patterned thyroid nodules is hindered somewhat by the
imperfect reproducibility among histopathologists in
the diagnosis of nodular hyperplasia, follicular
adenoma, follicular carcinoma, and follicular variant
papillary carcinoma.
IV. Follicular Neoplasm/Suspicious for a Follicular
Neoplasm (FN/SFN)…
Definition: Cellular aspirate comprised of
follicular cells most of which are arranged in an
altered architectural pattern characterized by
significant cell crowding and/or microfollicle
formation. Cases that demonstrate the nuclear
features of papillary carcinoma are excluded
from this category.
IV. Follicular Neoplasm/Suspicious for a Follicular Neoplasm
(FN/SFN)…
Moderately or markedly cellular preparations.
Presence of significant architectural alteration
in the majority of the follicular cells: crowding
and overlapping of follicular cells.
”Microfollicle”: crowded, flat groups of less
than 15 follicular cells arranged in a circle that
is at least two-thirds complete.
A small amount of kolloid in the microfollicle
Microfollicles are relatively uniform in size
In some cases ribbons of overlapping cells
(trabeculae)
IV. Follicular Neoplasm/Suspicious for a Follicular
Neoplasm (FN/SFN)…
The likelihood that the nodule is neoplastic is
65-85%
The rate of malignancy, 12-32%
27-68% of the malignant cases are interpreted
histopathologically as papillary carcinomas
Imperfect reproducibility of the histologic
diagnoses of follicular carcinoma and FVPTC
HBME-1
CD56
Galectin 3
CK 19
IV. Follicular Neoplasm/Suspicious for a Follicular Neoplasm (FN/SFN)…
Management
Hemithyroidectomy or lobectomy.
Follicular neoplasm, Hurtle Cell
Type/Suspicious for a Follicular Neoplasm,
Hurtle Cell Type
Follicular neoplasm, Hurtle Cell
Type/Suspicious for a Follicular Neoplasm,
Hurtle Cell Type
Striking morphological differences between FN/SFN
and FN/FSN Hurtle cell type
Data suggesting that follicular and Hurtle cell
carcinomas may be genetically different neoplasms.
(PAX8-PPAR rearrangement is seen in 26-53% of
Follicular carcinomas but virtually never in Hurtle cell
carcinomas)
If Hurtle cell differentiation is clear-cut but only focal,
>75% rule of WHO should be considered.
<75% FN/SFN
Follicular neoplasm, Hurtle Cell Type/Suspicious for a Follicular Neoplasm, Hurtle Cell Type…
Cellular aspirate that consists exclusively (or
almost exclusively) of Hurtle cells.
”Suspicious for a follicular neoplasm, Hurtle cell
type Hurtle cell neoplasm (SFNHCT) is
preferred:
16-25% of cases prove not to be neoplasms but
rather hyperplastic proliferations.
Oncocytic cells with nuclear features of papillary
carcinoma are excluded from this category.
Follicular neoplasm, Hurtle Cell Type/Suspicious for a Follicular Neoplasm,
Hurtle Cell Type…
Patient known to have multiple nodules and
exclusively Hurtle cell specimen:
FNHCT/SFNHCTor
AUS + an explanatory note that raises the possibility
of a Hurtle cell hyperplasia
The goal is to provide clinician with the
opportunity to avoid an unnecessary lobectomy.
Repeat aspiration unlikely to add any helpful
information
Follicular neoplasm, Hurtle Cell Type/Suspicious for a Follicular Neoplasm,
Hurtle Cell Type…
Patients with lymfocytic/Hashimoto thyroiditis
that shows exclusively Hurtle cell specimen:
FNHCT/SFNHCT or
AUS + note: benign Hurtle cell hyperplasia is
favored
The goal is to provide clinician with the
opportunity to avoid an unnecessary lobectomy.
Repeat aspiration unlikely to add any helpful
information
Follicular neoplasm, Hurtle Cell Type/Suspicious for a Follicular Neoplasm,
Hurtle Cell Type…
Hurtle cell specimen with some architectural and
nuclear features of papillary carcinoma:
FNHCT/SFNHCT, or
Suspicious for malignancy + explanatory note:
differential diagnose between PTC and HCN
Management: Candidate for lobectomy with frozen
section
Follicular neoplasm, Hurtle Cell Type/Suspicious for a Follicular Neoplasm,
Hurtle Cell Type…
Differentell diagnose with Medullary Carcinoma
Immunocytochemistry is helpful
Serum calcitonin level
Differentiell diagnose with oncocytic
parathyroidea adenoma
Immunocytochemistry
Correlation with clinical findings, imaging findings
and serologic testing results
V. Suspicious for malignancy
V. Suspicious for malignancy
“Some features raise the possibility of
malignancy, but the findings are not sufficient
for a conclusive diagnosis. Cases suspicious for a
follicular or Hurthle cell neoplasm are excluded.
The changes are such that malignancy is
considered more likely than not”
V. Suspicious for malignancy (SFM)…
The positive predictive value of the SFM
category should be greater than 50% and ideally
in the range of 65-85% especially at the
institutions where surgeons are likely to perform
a total thyroidectomy based on SFM
interpretation.
V. Suspicious for malignancy (SFM)…
Subtypes
Suspicious for papillary carcinoma
Pattern A: Patchy nuclear changes
Pattern B: Incomplete nuclear changes
Pattern C: Sparcely cellular specimen
Pattern D: Cystic degeneration pattern.
Suspicious for medullary carcinoma
Suspicious for lymphoma
Suspicious for malignancy, NOS.
V. Suspicious for malignancy (SFM)…
Management
Surgical lobectomy or total thyroidectomy
Contribution of intraoperative frozen section and/or
touch imprint after a SFM diagnosis is unclear
Total thyroidectomy is considered for >4 cm tumors
Suspicious for medullary carcinoma
Repeat FNA & Immunostains, serum calcitonin can convert
diagnosis to malignant/medullary carcinoma category
Suspicious for lymphoma
Repeat FNA for flow cytometry
VI. Malignant
VI. Malignant
Papillary Carcinoma
Lobectomy versus total thyroidectomy? The
American Thyroid Association recommends total or
near total thyroidectomy if any of the following is
present:
The malignant nodule is more than 1-1,5 cm
Contralateral thyroid nodules
Regional or distant metastases
Patient has a personal history of radiation therapy to the
head and neck
First degree family history of differentiated thyroid cancer.
Older age>45 years may also be criterion
Papillary carcinoma
Classics!
Cabernet sauvignon
Papillary carcinoma
46 year old
3 cm tumour
right lobe of the thyroid
Follicular
neoplasia,
consistent with
columnar
variant of
papillary
carcinoma
Columnar Variant Papillary
Carcinoma /Histopathology
Thyroglobulin
VI. Malignant…
Medullary thyroid carcinoma
Total extracapsular thyroidectomy
Poorly Differentiated Thyroid Carcinoma
Surgery + I and external beam radiotherapy for T3 & T4
Diagnostic categories:
131
Malignant
Suspicious for Follicular Neoplasm + note: mitosis, necrosis, TG &
TTF-1 (+), Calcitonin (-); suggesting poorly differentiated thyroid
carcinoma.
Undifferentiated (Anaplastic) Carcinoma
Complete surgical resection with or without pre- operative
hyperfractionated radiotherapy and/or chemotherapy
Diagnose: Malignant cytology/Consistent
with medullary carcinoma
Diagnose: Anaplastic
carcinoma
Diagnose: Malignant cytology/Consistent
with medullary carcinoma
Second opinion: Anaplastic carcinoma
(confirmed histopath.)
Diagnose: Anaplastic
carcinoma
Second opinion: Giant cell
v. Medullary Thyroid
Carcinoma (confirmed
histopath.)
Ki 67
ICC
Anaplastic carcinoma
Medullary carcinoma
Calcitonin
Cytokeratin MNF116
Chromogranin A
72 year old
, 2 cm tumour in the thyroid
Alc. Congo /Polarized
MNF116
CK7
Mc Manus
Synaptophysin
Calcitonin
N
E
G
A
T
I
V
E
CEA
Negative markers: TTF-1, TG, CK20, CK19, p53, Tag72, S-100, Ki 67
Ki 67
cellblock
AE1/AE3
Calcitonin
CEA
TTF1
Chromogranin A
Synaptophysin
Cell block from FNAC
Ki 67: 27%
Thyroidektomi material
Ki 67: 46%
NEUROENDOCRINE TUMOR
METASTASES
Metastases from the head and neck
organ tumors
Larynx: Local lymph node metastases are seen in moderately
and poorly differentiated (small and large cell) NECs of the
larynx.
Salivary gland small cell carcinoma: Cervical lymph node
involvement is less common than haematogegenous
metastasis. Lymph node metastases are common in large cell
NE carcinoma
Medullary thyroid carcinoma tends to metastasize cervical
lymph nodes early.
Malignant paraganglioma may show lymph node metastases
Metastases from the other organs to
the head and neck region
Lung
Gastrointestinal system
Pancreas
Metastases…
Lung
In the head and neck region the most common site of
metastasis is the brain; but it can also metastasize to
the oral cavity, gingiva, tongue, parotid gland and
lymph nodes.
Typical carcinoid
Atypical carcinoid
Large cell neuroendocrine carcinoma
Small cell carcinoma
Non-small cell carcinoma with neuroendocrine
differentiation
Synaptophysin
Cytokeratin
MNF116
Small cell cancer metastasis in the thyroid
Metastases…
Gastrointestinal system
WHO 2010 classification of the primary neuroendocrine
tumors of the gastrointestinal system
NET G1 (carcinoid) (Neuroendocrine Tumor Gr-1)
NET G2 (Neuroendocrine Tumor Gr-2)
NEC (Neuroendocrine Carcinoma, large cell or small cell
type)
MANEC (Mixed Adenoneuroendocrine Carcinoma)
Hyperplastic and preneoplastic lesions.
NETs usually show local metastases but NECs
are usually much more aggressive tumors and
can show widespread metastases
Serotonin + midgut carcinoid, Ki 67: 1%
Chromogranin A
Serotonin + midgut carcinoid /ileum
FNA from lymph node/neck
Chromogranin A
Somatostatin positive abdominal NEC (PDEC) Ki67 >50%,
GIS? Pancreas?
FNA from lymph node/neck
28 year old ,
rethroperitoneal
tumour (NEC,
Ki67: 30%),
lymph node
metastasis/neck
Metastases…
Pancreas
Almost the same classification and grading system as
in gastrointestinal system
“Pancreatic small cell NECs may not express
neuroendocrine markers and this does not preclude
the diagnosis so long as alternative diagnostic
considerations are excluded”.
NET usually p53(-), NEC usually p53(+)
NET can be positive for CD99. t(11;22) translocation
can be helpful in differential diagnosis of PNET.
CASE: 49 year old , left/lower neck, 4x2 cm hard, rounded
tumour. Vaccination (bird flu) anamnesis 1 week before the
lesion.
CASE: 49 year old , left/lower neck…
CASE: 49 year old , left/lower neck…
CASE: 49 year old , left/lower neck…
CK20
CASE: 49 year old , left/lower neck…ImmunoCytoChemistry
VMAT 2 Nuclear staining ???
MNF116
Ki67 index FNA: 20%
SYNAPTOFYSIN
Negative markers: calcitonin, ttf-1, estrogen & progesteron receptors,
thyroglobulin, CK7, VMAT-1 and serotonin. VMAT2 unusual staining.
CASE: 49 year old , left/lower neck…
Cytologic Diagnose: NEUROENDOCRINE
CARCINOMA (NEC) METASTASIS Intermediate
Grade (Gr 2)
Suggestions for primary tumor: Most probably pancreas
and alt. stomach.
CT: Pancreas tumour and metastatic lymph nodes
around pancreas.
CASE: 49 year old , left/lower neck…lymph node biopsy
CK8/18
CASE: 49 year old , left/lower neck…ImmunoHistoChemistry
Synaptofysin
CDX2
VMAT2
Ki67 index: 35%
Negative markers: gastrin, insulin, glukagon, somatostatin, pancreaspolypeptid,
calcitonin, serotonin, ACTH, thyroglobulin, TTF-1, VMAT-1, VMAT-2.
CASE: 49 year old , left/lower neck…
Diagnose: NEUROENDOCRINE CARCINOMA
(NEC) Grade 3
Suggestions for primary tumor: Gastrointestinal system,
gallblader, pancreas.
Childhood tumors in differential
diagnosis
Small round cell tumors
Ewing sarcoma / Primitive Neuroectodermal Tumor
(ES/PNET)
Aerodigestive tract or head and neck region is the third
anatomic site for ES/PNET
Children or adolescents
Fusion of EWS/FLI-1 genes, t(11:22)
Melanotic Neuroectodermal Tumor of Infancy
Metastatic Neuroblastoma
Rhabdomyosarcoma
15 year old
, proximal clavicula
CD99 Cell block
FISH: rearrangement of
EWS (22q12)
Fusion transcript for EWS/FLI1 typ2.
FFPE RNA extraction/One step RTPCR.
CYTOMORPHOLOGY
Summary and future
Bethesda System for Reporting Thyroid Cytopathology
has been widely adopted in many countries
Questions remain regarding optimal AUS-FLUS rate
Current efforts focus on minimizing AUS-FLUS rate
Don’t call something AUS/FLUS if it is really
“nondiagnostic”
Likely future role for reflex molecular testing of AUSFLUS
Try to use the suggested SNOMED codes
In the country
of white lillies
Kiitos huomiota!