What's Wrong with FNA of Thyroiddistribute.cmetoronto.ca/LMP1201/10_1000_Borner.pdf ·...
Transcript of What's Wrong with FNA of Thyroiddistribute.cmetoronto.ca/LMP1201/10_1000_Borner.pdf ·...
Thyroid Cytology
Scott Boerner MD FRCPC Head, Division Cytopathology, University Health Network
Associate Professor, University of Toronto [email protected]
UNIVERSITY of TORONTO
Presentation Objectives
Review “Thyroid Bethesda” terminology.
Illustrate the cytoarchitecture of the thyroid.
Investigate the diagnostic features of papillary thyroid carcinoma.
Develop an approach to follicular patterned lesions and Hürthle cell (oncocytic) lesions.
Communication - The Thyroid Bethesda
6 tiered scheme Nondiagnostic or Unsatisfactory
Benign
Follicular lesion (Atypia) of undetermined significance
Neoplasm (or suspicious for neoplasm) • Follicular neoplasm
• Hürthle cell neoplasm
Suspicious for malignancy
Malignant
Communication - The Thyroid Bethesda
Benign Low risk of malignancy (0-3%)
Subcategories: • “Consistent with benign follicular nodule”
– Nodular goiter, colloid nodule, hyperplastic/adenomatoid nodule
• “Consistent with lymphocytic (Hashimoto) thyroiditis in proper clinical context”
• “Consistent with granulomatous (subacute) thyroiditis”
• Other
At UHN we use the terms: • “Benign thyroid tissue” and “Lymphocytic thyroiditis” and etc.
– “Follicular nodule” is too close to “follicular lesion” and “follicular neoplasm” – confuses the clinicians
Communication - The Thyroid Bethesda
Follicular Lesion of Undetermined Significance – This abbreviates as “FLUS”
» I prefer Follicular Lesion of Uncertain Finding (FLUF)
» Or Follicular Lesion of Undetermined Significance, Help! (FLUSH)
Alternative name “Atypia of Undetermined Significance (AUS)
Cytomorphology
• “Not benign” or “not neoplasm” or “not suspicious”
Communication - The Thyroid Bethesda
Follicular Lesion of Undetermined Significance
Situations in which it may be used
• I endorse this:
– Samples with technically compromised morphology
» Nuclear morphology is not discernible
» Much of the epithelium is obscured by blood or other artefact
• Of course this means, if it is your lab, you must do something to eliminate the compromising issue.
Communication - The Thyroid Bethesda
Follicular Lesion of Undetermined Significance
Situations in which it may be used
• I am not a fan of these:
– Microfollicular predominant pattern, but not enough for follicular neoplasm (i.e. in sparsely cellular FNA)
– Predominance of Hürthle cells in sparsely cellular FNA with scant colloid
– Moderate to marked cellularity, exclusively Hürthle cells, yet clinical setting suggests benign Hürthle cell nodule (Hash or multinodular goiter)
– Focal features of papillary carcinoma (grooves, enlarged nuclei, pale chromatin, altered nuclear contour/shape) in an otherwise benign appearing sample
» Especially in Hashimoto or with abundant colloid
Communication - The Thyroid Bethesda
Follicular Lesion of Undetermined Significance
Situations in which it may be used
• I am not a fan of these:
– Cyst-lining cells with grooves, prominent nucleoli, nuclear elongation and/or intranuclear inclusions (WHAT!!!) in an otherwise predominantly benign appearing sample
– Minor population of follicular cells with nuclear enlargement and prominent nucleoli
– Atypical lymphoid infiltrate, (in which repeat aspirate for flow cytometry is desirable) but not sufficient to consider suspicious for malignancy
Communication - The Thyroid Bethesda
Follicular Lesion of Undetermined Significance
Used in approximately 3-18% of reports
• But varies widely
• Recommendations to:
– “Try to limit its use to approximately 7% or fewer of all thyroid FNA”
– Or AUS/malignant ratio between 1.0 to 3.0
Risk of malignancy 5-15%
• Some reports 20-25%
– Variability to be expected, because of the wide variation in definitions used.
Communication - The Thyroid Bethesda
Follicular neoplasm / Hürthle cell neoplasm In my opinion, this term is trying to identify follicular-
patterned carcinomas
Things that trigger the diagnosis “follicular neoplasm” • Non-neoplastic
– Hyperplasia / goiter – we should be trying to avoid this
• Benign neoplasia – Adenomas – this is OK, they should come out, need to examine
capsule » I think many follicular adenoma are not recognizable on cytology
• Malignant neoplasia – Follicular variant of papillary carcinoma
– Follicular (Hürthle cell) carcinoma
• Risk of malignancy estimated 15-30%
Communication - The Thyroid Bethesda
Suspicious for malignancy
Suspicious for papillary carcinoma
• The bulk of cases will be suspicious for papillary ca
Suspicious for ___________
• Medullary carcinoma
• Lymphoma
• Metastasis
• Others
Risk of malignancy: 50-75%
• I would hope for 85+%
Communication - The Thyroid Bethesda
Malignant
Risk of malignancy 97-99%
Communication - The Thyroid Bethesda
Nondiagnostic or Unsatisfactory For application to:
• Limited cellularity • Poor fixation and preservation • Cyst contents
– BUT, unsatisfactory with cyst contents to be separated from the unsatisfactory due to low cellularity (but not cystic)
Ed Cibas (AJCP 2009;132:658-665 & Thyroid 2009;19:1159-1165)
• Strong advocate of epithelial quantitation – 6 groups each composed of at least 10 cells
Cytoarchitecture of Thyroid
There are 5 cytoarchitectures in thyroid
Monolayered sheets
Syncytial clusters (aggregates)
Epithelium with transgressing vessels
Microfollicular structures
Papillary structures
Cytoarchitecture of Thyroid
Monolayered sheets
Normal thyroid follicle histology
• Variably sized but large (100 to 1,000 epithelial cells)
• Single layer of epithelial cells
• Central colloid
• Separated and supported by a delicate fibrovascular stroma
FNA ruptures the follicle liberating the epithelial cells as variably sized flat sheets
• “Monolayered sheets”
Cytoarchitecture of Thyroid
Monolayered sheets = macrofollicles In many cases – but not always
• Macrofollicles are benign – Usually – but not always
Cytology • Simple sheet, composed of one cell layer
• May fold on itself, generating 2 or rarely 3 layers – Folding identified by the distinct layers found when
changing focal planes
• “Honeycomb” appearance may be seen – Cell boundaries often can be resolved
• Nuclei are well spaced with intervening cytoplasm
Cytoarchitecture of Thyroid
Monolayered sheets
Sometimes represent denuded papillae
• De-gloving injury to the papillary epithelium
Even when a monolayered sheets truly represents a macrofollicle
• Macrofollicles are occasionally present in neoplasms.
Cytoarchitecture of Thyroid
Monolayered sheets are
Usually macrofollicles Benign (usually)
Sometimes papillae Could be malignant
How do you tell?
The monolayered sheet itself is not unique
• Look at the nuclei – for features of papillary carcinoma
• Look for fibrovascular stalks
Cytoarchitecture of Thyroid
Syncytial clusters
Represent the disordered growth of the epithelium
• Increased cell layers from the normal 1 cell layer
• Increase N/C ratio in the cells
• Colloid depletion
Neoplastic Character
Neoplastic Character
But may also be seen in reactive conditions - thyroiditis
Cytoarchitecture of Thyroid
Syncytial clusters
Cytology
• Disorganized group of nuclei (haphazardly arranged)
– Inconstant distance between nuclei
– Inconstant focal planes in which nuclei are found
• Apparent loss of cell boundaries
• The apparent syncytial nature is not important
– It is the loss of ordered structure that is important
Cytoarchitecture of Thyroid
Transgressing vessels Really an extension from the syncytial clusters
Represents • “Neo-vascularization” of thick epithelial structures
• Abnormal vessels occurring in neoplasms
Cytology • Vascular structures (capillary size or larger) with loosely
adherent epithelial cells arranged around the vessels – Appears as if the vessels “transgresses” or course through
the epithelial cells
• Dissociated epithelial cells in background
Cytoarchitecture of Thyroid
Transgressing vessels
Originally described as a feature to aid in the distinction of Hürthle nodule from Hürthle neoplasm
• Transgressing vessels Hürthle neoplasm
• No transgressing vessels Hürthle cell nodule
Not restricted to Hürthle cell lesions
• But not generally noted in textbooks
Cytoarchitecture of Thyroid
Microfollicular structures Can occur normally or as a neoplastic growth
pattern • Normal macrofollicles & microfollicles
• Neoplastic predominance of microfollicles
It is not the finding of microfollicles that is important
• It is when microfollicles take over the sample!! – Must weigh the microfollicles against the monolayered
sheets
Cytoarchitecture of Thyroid
Microfollicular structures
Are not just small follicles!
Cytology
• 6 to 18 epithelial cells radially arranged around small droplet of colloid or a central clear space
I consider microfollicles significant if 30-40% of the epithelium is present in this architecture
Cytoarchitecture of Thyroid
Papillary structures
I am a rigid pathologist and do not accept what some cytologists call a “papillary structure”
A papillary structure must have a fibrovascular core
• Actually in cytology we usually have denuded or partially denude fibrovascular cores
– True intact papillary structures are less frequent.
Cytoarchitecture of Thyroid
Papillary structures
Occur in
• Papillary carcinoma (common entity)
• Papillary hyperplasia (rare entity)
To identify that this papilla is from a papillary carcinoma, you must find the nuclear features of papillary carcinoma in the epithelial cells
Papillary Carcinoma
Malignancy defined by a constellation of cytologic findings
Architectural
• Syncytial clusters of epithelial cells
Nuclear
• Enlarged & oval nuclei
• Powdery (fine pale) chromatin
• Nucleoli
• Nuclear grooves
• Intranuclear cytoplasmic pseudo-inclusions
Papillary Carcinoma
Malignancy defined by a constellation of cytologic findings
Architectural
• Syncytial clusters of epithelial cells
Nuclear
• Enlarged oval nuclei
• Powdery (fine pale) chromatin
• Nucleoli
• Nuclear grooves
• Intranuclear cytoplasmic pseudo-inclusions
? Specific to papillary carcinoma ?
Frequently, but not always a marker of a follicular epithelial neoplasia
Papillary Carcinoma
Nuclear enlargement
Enlargement is asymmetrical resulting in ovoid nuclei
Results in increased N/C ratio, manifest as:
• Nuclear crowding
• Nuclear overlapping
• Syncytial architecture of epithelial tissue fragments
– i.e. syncytial clusters
Papillary Carcinoma
Changes in chromatin texture
More pale with increase granularity
Prone to areas of chromatin clearing
• Appear as “holes” in the nucleus
– Must differentiate from inclusions
Susceptible to development of “Orphan Annie” or optically clear nuclei if:
• Formalin fixed
• Air-dried, rehydrated and UltraFast Pap stained
• Not evident in most cases of routinely prepared FNA
Papillary Carcinoma
Nucleoli
Usually of micronucleoli variety and not macronucleoli
Eosinophilic
Frequently multiple, but may be single
Often eccentrically place along nuclear membrane
“Bare” nucleoli found
• Clearing of chromatin around nucleolus
– Appears as if it is sitting within a hole in the nucleus
Papillary Carcinoma
Nuclear irregularities
Nuclear membranes in papillary carcinoma are variable
• Fairly smooth contoured
• Minor wavy or saw tooth nuclear membrane irregularities
• Profoundly irregular membranes (raisinoid)
Reflect deranged nuclear skeletal elements
• Also predisposes to development of
– Nuclear grooves
– Intranuclear inclusions
Papillary Carcinoma
Nuclear Grooves
Multiple names
• Lineage chromatin ridge, nuclear crease, nuclear fold, etc.
Represents linear invagination of nuclear membrane parallel to the long axis of the nucleus
• Seen as a “line” running along the axis of the nucleus
• If nuclear orientation optimal
– Forms a “notch” as the groove crosses over the nuclear horizon.
Papillary Carcinoma
Nuclear grooves Visualization is dependent on nuclear orientation
• As is true of any nuclear cleft
Nuclear grooves occasionally lead to debate • “Is it real or not?”
• The notch is very evident and not a feature open to challenge
The groove must be within an epithelial cells • Histiocytes have elongated and “groove” nuclei that may
be mistaken as abnormal epithelial cells
Papillary Carcinoma
Nuclear grooves
Are seen in air dried Romanowsky stained material
• “Finger nail scratches” across surface of nucleus
I find them more difficult to appreciate than alcohol fixed material
Papillary Carcinoma
Intranuclear inclusion
Full name:
• Cytoplasmic intranuclear pseudoinclusion
• Shortened to “intranuclear inclusion”
A profound invagination of cytoplasm into the nucleus
• Kind of an exaggerated nuclear groove
Papillary Carcinoma
Intranuclear inclusion
Cytologic criteria
• Diameter of the inclusion must be at least ¼ of the nuclear diameter
• Edges of the inclusion must be sharply defined
– As sharply defined as the remainder of the nuclear membrane
• Inclusion must be round and regular
• Inclusion must look the same as the cytoplasm
– In colour and density – it contains cytoplasm after all
• Inclusion must be found in an epithelial cell
Papillary Carcinoma
Intranuclear inclusions
The same criteria for intranuclear inclusions are applied to:
• Alcohol fixed pap stained material
– Direct smears
– ThinPrep
– Cytocentrifuge preps
• Air-dried, Romanowsky stained material
Papillary Carcinoma
Intranuclear inclusions Mimics of intranuclear inclusions:
• Air drying induced “hole” – Tend to be small
– Fuzzy edges
– Spherical (the same as a true inclusion)
– Appear empty (white)
– Any cell type
• Chromatin pallor – Variable size, often small
– Fuzzy edges
– Irregular outline, not spherical
– Appear pale (similar to a true inclusion)
– Usually epithelial cells
Papillary Carcinoma
Specificity of grooves
Nuclear grooves are not specific to papillary carcinoma
• Seen in a number of conditions, notably lymphocytic thyroiditis
Weak relationship between the number of grooves and papillary carcinoma
• More grooves – more likely to be papillary carcinoma
Be cautious with grooves alone
Papillary Carcinoma
Specificity of inclusions Much greater specificity than grooves, but not
pathognomic
May also be seen in • Medullary carcinoma
• Lymphocytic thyroiditis – I question this. How have we established it is not
carcinoma? – usual answer – an expert’s opinion.
• Hyalinizing trabecular tumour
Must not be seen in papillary hyperplasia
Papillary Carcinoma
“Unique” features of papillary carcinoma
Nuclear grooves
Nuclear inclusions
Are NOT unique or specific to, nor pathognomic of papillary carcinoma
Papillary Carcinoma
Can you have a papillary carcinoma that does not have intranuclear inclusions?
Yes – but be cautious
• Intranuclear inclusions are an excellent predictor that the surgical pathology will be called papillary carcinoma.
– It is as much a predictor of a surgical pathologist’s behavioural pattern as it is a predictor of a specific pathologic entity.
Suspicious for PTC
I usually use in the context of:
All the cytologic features of papillary carcinoma, but lacking definitive intranuclear inclusions
• Look very hard before you say there are no inclusions
• Most are follicular variant of PTC, in which intranuclear inclusions are less frequent
• Occasionally a benign mimic of PTC
The presence of psammoma bodies without epithelium or epithelium lacks the features of PTC.
Psammoma bodies
Calcified, concentrically laminated, spherical bodies Calcospherites
• “Naked” psammoma bodies
Psammoma bodies • Calcospherites surrounded by cells
May coalescence into concretions and lose their spherical structure
They are NOT the tombstone of dead cells / infarcted papillae
Psammoma bodies
Mimics of psammoma bodies
Inspissate (dense) colloid
• Lacks laminations
Amyloid
• Lacks laminations
• May appear fibrillary and / or waxy
Dystrophic calcifications
• Lacks laminations
• Irregular masses
Psammoma bodies
Diagnostic significance
Literature states 50% positive predictive value
• I think this is an under-estimate
A 50% PPV indicates the nodule must be examined
• Diagnosis: Suspicious for papillary carcinoma
Caveat
• Look carefully at the epithelium present
– It likely has nuclear features of papillary carcinoma
Follicular Neoplasms
Unlike papillary carcinoma, follicular neoplasms do not have “unique” nuclear features
They do have “neoplastic” nuclei
• Enlarged, somewhat ovoid nuclei
• Increased N/C ratio (syncytial clusters)
• Altered chromatin structure
• Increased prominence of nucleoli
Follicular Neoplasms
The clue to diagnosis:
Altered cytoarchitecture
• Syncytial clusters
• Transgressing vessels
• Microfollicular structures
Exclusion of nuclear features of PTC
Hürthle Cell Neoplasm
What are Hürthle cell neoplasms?
In my mind, they are the same as their “follicular” counterparts except that they show Hürthle cell differentiation
I think the most common lesion called a “Hürthle cell neoplasm” on FNA turns out to be:
• A Hürthle cell (oncocytic) variant of papillary carcinoma.
– Look hard at the nuclei of Hürthle cell neoplasms for intranuclear inclusions
Hürthle Cell
What is a Hürthle cell?
Large cell (larger than normal follicular epithelial cells)
Abundant cytoplasm
• Cyanophilic cytoplasm
• Numerous cytoplasmic granules (mitochondria)
– Eosinophilic, imparting eosinophilic tinge to cytoplasm
• Moderate to marked cytoplasmic vacuolation
• Eccentrically placed nucleus
– Enlarged, but round nucleus
– Regular, smooth nuclear membranes
– Increased chromatin chromaticity and more granular
– Prominent (single) eosinophilic nucleolus
Hürthle Cell
What is a Hürthle cell?
Normal Hürthle cells maintain a monolayered sheet architecture in FNA
• Syncytial clusters are concerning
• Transgressing vessels very disturbing
The presence of nuclear grooves is of little predictive value
The presence of intranuclear inclusions is very disturbing
Hürthle Cell Lesion?
Are Hürthle cells evil?
No - Hürthle cells can be your friend
• The combination of Hürthle cells and regular follicular cells represent a “polyclonal” population – benign
Hürthle cells are common and almost expected in most cases of thyroiditis
Hürthle Cell Lesion?
Are numerous Hürthle cells evil?
I do not like any cell when they seem to “gang-up” on me, but…
• A predominance of Hürthle cells is NOT a strong predictor of a Hürthle cell neoplasm
– It is something to precipitate careful examination to try to determine if the lesion is neoplastic
How do you tell if it is a Hürthle cells lesion / neoplasm?
Hürthle Cell Lesion?
I try at all costs to avoid “Hürthle cell lesion”, I will use Hürthle cell neoplasm
Look at the cytoarchitecture of the Hürthle cells
• Monolayered sheets Benign
• Syncytial clusters Neoplasm
• Transgressing vessels Neoplasm
Look for intranuclear inclusions
• Must exclude a papillary carcinoma, knowing it is the most common Hürthle cell neoplasm I will see
My Approach to Hürthle Cells
Nuclear Features of papillary carcinoma present
Yes
Hürthle cell variant papillary
carcinoma present
No
Complex Architectural Features*
Yes
No
Hürthle cell neoplasm
Benign thyroid tissue
* Transgressing vessels, microfollicular dominance, complex syncytial aggregates