Cytopathology of the ThyroidII. Benign follicular nodule (BFN) The most common diagnose in FNA...

Cytopathology of the ThyroidHelsinki 21 11 2012

Akif DemirSahlgrenska University Hospital Clnical Pathology & Cytology

Gothenburg-Sweden

Cytology (Archeology) Histopathology (Architecture)

FollicleFunctional unit, follicular cells, C cells

Lobule20-30 follicle

Thyroidea

Classification (based on WHO book published in 2004)

PrimaryEpithelial tumours

Follicular cell tumorsC cell tumours (Medullary Carcinoma)Mixed follicular and C cell tumours

Others

Metastatic

BENIGN

Thyroid adenoma and related tumoursFollicular Adenoma (+Onkocytic Adenoma)Hyalinizing trabecular tumor

Classification…

MALIGNANT

Papillary carcinoma (and variants)Follicular carcinoma (+ Onkocytic carcinoma)Poorly differentiated carcinomaUndifferentiated (Anaplastic) carcinoma

Classification…

Squamous cell carcinomaMucoepidermoid carcinomaSclerosing mucoepidermoid carcinoma with eosinophiliaMucinous carcinomaMedullary carcinomaMixed medullary and follicular cell carcinomaSpindle cell tumor with thymus-like differentiationCarcinoma showing thymus-like differentiation

Classification, malignant tumours

OTHER THYROID TUMOURSTeratomaPrimary lymphoma and plasmacytomaEctopic thymomaAngiosarcomaSmooth muscle tumoursPeripheral nerve sheet tumoursParagangliomaSolitary fibrous tumourFollicular dendritic cell tumourLangerhans cell histiocytosisSecondary tumours

Classification…

Variants of papillary carcinoma

Follicular variantMacrofollicular variantOncocytic variantClear cell variantDiffuse sclerosing variantTall cell variantColumnar cell variantSolid variantCribriform carcinoma (FAP)

Variants of follicular carcinoma

Oncocytic variantClear cell variant

Variants of medullary carcinomaPapillary or pseudopapillary , characterized by the presence of true papillae or artefactual pseudopapillae, caused by tissue fragmentation.Glandular (tubular or follicular)Giant cellSpindle cellSmall cell and Neuroblastoma-likeParaganglioma-likeOncocytic cellClear cell Angiosarcoma-likeSquamous cellMelanin-producingAmphicrine

Encapsulated tumours/lesions

Dominant or adenomatous nodules (Nodular goitre)Follicular adenomFollicular carcinomFollicular Variant Papillary carcinom (FVPC)Well differentiated tumour of uncertain malignant potentialFollicular tumour of uncertain malignant potentialWell differentiated carcinom

Preoperative Diagnosis

Conventional FNAImmunocytochemistryCell-blockImmunohistochemistryMolecular pathologic analysis

Papillary Follicular Oncocytic

Poorly differentiated

Anaplastic Medullary

ICC: Immuno-

CytoChemistry

TTF-1

THYROGLOBULIN

ImmunoCytoChemistryTTF1 and TG: Primary/thyrocyteGalectin 3: Malignant potential?HBME-1: Malignant potential?HMWCK: Papillary carcinomaCK 19: Papillary carcinoma, more or less the otherfollicular tumours. Calcitonin: Medullary carcinomaChromogranin-A: Medullary carcinomaCEA: Medullary carcinoma (+ onco. tm.) PanCK: PancytokeratinCD56 Follicular X Papillary ??Ki 67: Proliferative marker

CELL BLOCK

Cell Block Haematoxylin & Eosin

AE1/AE3 CK19 CK7

Galectin 3 anaplastic cells

Galectin 3

Clear cells

CARBA

CELL BLOCK-IHC

Ki67 p53 SYNAPTOPHYSIN

THYROGLOBULIN TTF-1

CHROMOGRANIN (-)

CD56 (-)

CELL BLOCK-IHC

Surgical material

THYROGLOBULIN –surgical material

TTF-1 NEGATIVE

A few nuclei with weak positivity

BRAF NEGATIVE

P53 ANAPLASTIC AREA

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 communicationFacilitated cytologic & histologic correlationFacilitated research into the epidemiology, molecular biology, pathology, and diagnosis of thyroid diseasesEasy and reliable sharing of data from different laboratoriesEasy to follow algorithmsEconomical aspects

Local, national & international standardisationof reporting terminology is essentialQuality control of outcomes via local, national & international audits of PPV & NPV for malignancy, inadequate rates, rates for follicular neoplasm & AFUS is requiredGood training in FNA technique & smear preparationUse of LBC if problems with direct smear making & specimen collectionMolecular techniques very exciting but not as yet widely implemented.

Implied risk of malignancy and recommended clinical management

Diagnostic category Risk of malignancy (%)

Usual management

I-Nondiagnostic or unsatisfactory

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 follicularneoplasm

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-visualizedfollicular cells, with at least ten cells per group, preferably on a single slide.

Exceptions:Solid nodules with cytologic atypiaSolid nodules with inflammationColloid nodules

Adequacy; exceptions…

Solid nodules with cytologic atypiaMandatory to report any significant atypiaA minimum number of follicular cells is notrequired

Solid nodules with inflammationA minimum number of follicular cells is notrequired

Colloid nodulesA minimum number of follicular cells is notrequired if easily-identifiable colloidpredominates.

I. Nondiagnostic/Unsatisfactory

1. Fewer than six groups of well-preserved, well-stained follicular cell groups with ten cells each.

2. Poorly prepared, poorly stained, or obscuredfollicular cells

3. Cyst fluid, with or without histiocytes, and fewer than six groups of ten benign follicularcells

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 consideredRisk 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 Suspicious USsimple/unilocular

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 nodulesNodular goiter, hyperplastic (adenomatoid) nodules, colloid nodules, nodules in Grave’s disease, and subset of follicular adenomas (those of macrofollicular type)

ThyroiditisLymphocyic (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-neoplasticconditions, 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 categoriesHeterogeneous 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 studiesYang et al, Cancer cytopathol 2007: 11: 306-15

4703 thyroid FNAsAtypical AUS = 3%

Yassa et al, Cancer Cytopathol 2007; 111: 508-163589 thyroid FNAsAtypical (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. AUSFollicular cells with focal cytologic and architecturalatypia, but obscuring blood and clotting artifactpreclude definitive evaluation.

Note: …

AUS/FLUS… Scenarios

3. AUSFollicular cells, predominately benign-appearing, with focal cytologic atypia.

Note: A repeat aspirate after an appropriateinterval of observation may be helpful if clinicallyindicated.

4. AUSPredominantly benign appearing follicularcells; some show focal cytologic and architectural atypia.

Note: …

AUS/FLUS, Scenarios…5. FLUS

Follicular lesion of undetermined significance6. (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 representa Hurtle cell hypeplasia in the setting of multinodular goiter, but a Hurtle cell neoplasm cannot be entirely excluded. Clinical correlationis 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 likelyrepresent a Hurtle cell hyperplasia, but a Hurtle cell neoplasm cannotbe entirely excluded. Clinical correlation advised.

AUS/FLUS, Scenarios…

8. (FNA of a nodule in a patient treated with 131I)AUS: Marked cytologic atypia of follicular cells

Note: In a patient treated with radioiodine, the findingslikely represent reactive, treatment-related changes, but a neoplasm cannot be entirely excluded. Clinical correlationis advised.

9. AUSNumerous, relatively momomorphic lymphoid cells

Note: the findings are atypical and raise the possibility of a lymphoproliferative lesion, but immunophenotypingstudies 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 correlationFor most cases, repeat FNA

After an appropriate interval

Surgery considered for “repeat atypicals” Only 20-25% of nodules are repeatedly AUSThe 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 frequencyMalignancy rate for AUS-FLUS cases is variable, generally in keeping with Bethesda guidelineData support repeat FNA as initial management for AUS-FLUSRepeat FNA resolves the diagnosis in most AUS-FLUS casesValidity 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 N-RAS mutations

Follicular Carcinoma PAX8/PPAR

Medullary Thyroid Carcinoma Familial: RETSporadic: RET and RAS

Anaplastic carcinoma TP53, beta-catenin, BRAF, PTEN

BRAF mutations in PTC

T-A substitution at nucleotide 1799 (V600E)MEK signal pathwayVery specific not seen in follicular carcinoma, MTC or benign nodulesApplied to thyroid FNAFound 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 %

Extranodalextension

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 malignanciesSome of the genetic changes are “mutually exclusive”

Nikiforov and Xing, J Endocrin Metabolism, 2003

Combining reviewed cytology and BRAF Mutational Analysis

BRAF Reviewedcytology

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%)

A panel of molecular testing (BRAF, RAS, RET/PTC, and

PAX8/PPAR

Carcinoma on surgical pathology

follow-up

117 cases accepted for molecular testing

and had surgical follow-up

Positive n=1210%

Negative n=10590%

n=12 100%

n=87,6%

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)

Suspicious for cancer(n=53)

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%

Cancer risk in thyroid nodules with indeterminate cytology and molecular testing performed on FNA

Cancer risk

AUS/FLUSN=247

FN/SFNN=214

SMCN=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

A panel of molecular testing

Cyto diagnose

Cancer risk

AUS/FLUS SFN/FN Susp. Malign.

14% 27% 54%

Mutational status

Cancer risk+

88%-

6%+

87%-

14%+

95%-

28%

Management Total FNA+/- Total 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.


Moderately or markedly cellular preparations.Presence of significant architectural alteration in the majority of the follicular cells: crowdingand 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 microfollicleMicrofollicles are relatively uniform in sizeIn some cases ribbons of overlapping cells (trabeculae)


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 carcinomasImperfect reproducibility of the histologic diagnoses of follicular carcinoma and FVPTC

HBME-1 CD56

Galectin 3 CK 19


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 typeData 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 butrather hyperplastic proliferations.

Oncocytic cells with nuclear features of papillarycarcinoma are excluded from this category.


Patient known to have multiple nodules and exclusively Hurtle cell specimen:

FNHCT/SFNHCTorAUS + an explanatory note that raises the possibilityof a Hurtle cell hyperplasia

The goal is to provide clinician with the opportunity to avoid an unnecessary lobectomy.Repeat aspiration unlikely to add any helpfulinformation


Patients with lymfocytic/Hashimoto thyroiditisthat shows exclusively Hurtle cell specimen:

FNHCT/SFNHCT orAUS + 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 helpfulinformation


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 HCNManagement: Candidate for lobectomy with frozensection


Differentell diagnose with Medullary CarcinomaImmunocytochemistry is helpfulSerum 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)…

SubtypesSuspicious for papillary carcinoma

Pattern A: Patchy nuclear changesPattern B: Incomplete nuclear changesPattern C: Sparcely cellular specimenPattern D: Cystic degeneration pattern.

Suspicious for medullary carcinomaSuspicious for lymphoma Suspicious for malignancy, NOS.

V. Suspicious for malignancy (SFM)… Management

Surgical lobectomy or total thyroidectomyContribution of intraoperative frozen section and/or touch imprint after a SFM diagnosis is unclearTotal thyroidectomy is considered for >4 cm tumorsSuspicious for medullary carcinoma

Repeat FNA & Immunostains, serum calcitonin can convert diagnosis to malignant/medullary carcinoma category

Suspicious for lymphomaRepeat FNA for flow cytometry

VI. Malignant

VI. MalignantPapillary 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 cmContralateral thyroid nodulesRegional or distant metastasesPatient has a personal history of radiation therapy to the head and neckFirst degree family history of differentiated thyroid cancer.Older age>45 years may also be criterion

Papillary carcinoma

Cabernet sauvignon

Papillary carcinoma

Classics!

46 year old

3 cm tumour

right lobe of the thyroid

Follicular neoplasia, consistent with columnar variant of papillary carcinoma

Thyroglobulin

Columnar Variant PapillaryCarcinoma /Histopathology

VI. Malignant…

Medullary thyroid carcinomaTotal extracapsular thyroidectomy

Poorly Differentiated Thyroid CarcinomaSurgery + 131I and external beam radiotherapy for T3 & T4Diagnostic categories:

MalignantSuspicious for Follicular Neoplasm + note: mitosis, necrosis, TG & TTF-1 (+), Calcitonin (-); suggesting poorly differentiated thyroidcarcinoma.

Undifferentiated (Anaplastic) CarcinomaComplete surgical resection with or without preoperative 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

Cytokeratin MNF116 Chromogranin ACalcitonin

72 year old , 2 cm tumour in the thyroid

Alc. Congo /Polarized Mc Manus

CEACalcitoninCK7MNF116 Synaptophysin

NEGATIVE

Ki 67

Negative markers: TTF-1, TG, CK20, CK19, p53, Tag72, S-100, Ki 67

AE1/AE3 CEA Chromogranin A

Calcitonin TTF1 Synaptophysin

cellblock

Thyroidektomi materialKi 67: 46%

Cell block from FNACKi 67: 27%

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 haematogegenousmetastasis. 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 tothe head and neck region

LungGastrointestinal systemPancreas

Metastases… LungIn 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 carcinoidAtypical carcinoidLarge cell neuroendocrine carcinomaSmall cell carcinomaNon-small cell carcinoma with neuroendocrine

differentiation

Synaptophysin

Cytokeratin MNF116

Small cell cancer metastasis in the thyroid

Metastases… Gastrointestinal systemWHO 2010 classification of the primary neuroendocrine

tumors of the gastrointestinal systemNET 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 , rethroperitonealtumour (NEC, Ki67: 30%), lymph nodemetastasis/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, roundedtumour. Vaccination (bird flu) anamnesis 1 week before the lesion.

CASE: 49 year old , left/lower neck…


CK20

VMAT 2 Nuclear staining ??? Ki67 index FNA: 20%

MNF116 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…ImmunoCytoChemistry

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.


CK8/18

CASE: 49 year old , left/lower neck…lymph node biopsy

Synaptofysin

CDX2

VMAT2

Ki67 index: 35%

CASE: 49 year old , left/lower neck…ImmunoHistoChemistry

Negative markers: gastrin, insulin, glukagon, somatostatin, pancreaspolypeptid, calcitonin, serotonin, ACTH, thyroglobulin, TTF-1, VMAT-1, VMAT-2.

Diagnose: NEUROENDOCRINE CARCINOMA (NEC) Grade 3

Suggestions for primary tumor: Gastrointestinal system, gallblader, pancreas.


Childhood tumors in differential diagnosis

Small round cell tumorsEwing sarcoma / Primitive Neuroectodermal Tumor (ES/PNET)

Aerodigestive tract or head and neck region is the third anatomic site for ES/PNETChildren or adolescentsFusion of EWS/FLI-1 genes, t(11:22)

Melanotic Neuroectodermal Tumor of InfancyMetastatic NeuroblastomaRhabdomyosarcoma

CD99 Cell block

15 year old , proximal clavicula

FISH: rearrangement of EWS (22q12)

Fusion transcript for EWS/FLI1 typ2. FFPE RNA extraction/One step RT-PCR.

CYTOMORPHOLOGY

Summary and future

Bethesda System for Reporting Thyroid Cytopathologyhas been widely adopted in many countriesQuestions remain regarding optimal AUS-FLUS rateCurrent efforts focus on minimizing AUS-FLUS rateDon’t call something AUS/FLUS if it is really “nondiagnostic”Likely future role for reflex molecular testing of AUS-FLUSTry to use the suggested SNOMED codes

In the country of white lillies

Kiitos huomiota!

Cytopathology of the ThyroidII. Benign follicular nodule (BFN) The most common diagnose in FNA...

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Transcript of Cytopathology of the ThyroidII. Benign follicular nodule (BFN) The most common diagnose in FNA...