the diagnosis of papillary thyroid...

THE DIAGNOSIS OF PAPILLARY THE DIAGNOSIS OF PAPILLARY THYROID CARCINOMA:THYROID CARCINOMA:

How much (or how little) is enough?How much (or how little) is enough?

Virginia A. LiVolsi, MDVirginia A. LiVolsi, MDUniversity of PennsylvaniaUniversity of Pennsylvania

PAPILLARY THYROID PAPILLARY THYROID CARCINOMACARCINOMA

�� Most common type of thyroid Most common type of thyroid malignancymalignancy--85% of thyroid cancers85% of thyroid cancers

�� Most common endocrine malignancyMost common endocrine malignancy


�� ClinicalClinical

•• Any ageAny age

•• Microscopic to largeMicroscopic to large

•• Female: Male= 2Female: Male= 2--4:14:1•• Female: Male= 2Female: Male= 2--4:14:1

•• Radiation historyRadiation history

•• Lymph nodesLymph nodes

•• Prognosis 95% at 25 yearsPrognosis 95% at 25 years


�� GrossGross

•• Any sizeAny size

•• Confined or extrathyroidalConfined or extrathyroidal

•• May show capsule (especially follicular May show capsule (especially follicular •• May show capsule (especially follicular May show capsule (especially follicular variant)variant)

•• May be cysticMay be cystic

•• May note gross calcification or even May note gross calcification or even bonebone


�� PathologyPathology

•• Papillae and/or folliclesPapillae and/or follicles

•• Can be totally follicularCan be totally follicular

•• SclerosisSclerosis•• SclerosisSclerosis

•• Calcification (psammoma bodies)Calcification (psammoma bodies)

•• NUCLEINUCLEI


�� Psammoma bodiesPsammoma bodies

•• GHOSTS of dead PapillaeGHOSTS of dead Papillae

•• In stroma or lymphaticsIn stroma or lymphatics

•• Importance in lymph nodesImportance in lymph nodes•• Importance in lymph nodesImportance in lymph nodes


�� PATHOLOGYPATHOLOGY•• Lymphatic invasion early onLymphatic invasion early on

•• May show vascular invasion alsoMay show vascular invasion also

•• Lymph nodes positive over 50% at Lymph nodes positive over 50% at •• Lymph nodes positive over 50% at Lymph nodes positive over 50% at diagnosisdiagnosis

•• May present as nodal metastasis in neck May present as nodal metastasis in neck especially cystic (confused with especially cystic (confused with branchial cleft cyst)branchial cleft cyst)


�� The characteristic morphologic feature The characteristic morphologic feature was historically : was historically : PAPILLAEPAPILLAE

�� In older literature, if greater than 50% of In older literature, if greater than 50% of a tumor was follicular in pattern, it was a tumor was follicular in pattern, it was a tumor was follicular in pattern, it was a tumor was follicular in pattern, it was classified as either:classified as either:

�� MIXED PAPILLARYMIXED PAPILLARY--FOLLICULAR CA FOLLICULAR CA OROR

�� FOLLICULAR CAFOLLICULAR CA


�� In 1960s, some authors (notably Stuart In 1960s, some authors (notably Stuart Lindsay) began to pay attention to the Lindsay) began to pay attention to the nuclear features.nuclear features.

�� Hence over time, the nuclear Hence over time, the nuclear �� Hence over time, the nuclear Hence over time, the nuclear morphology became the most morphology became the most overriding diagnostic consideration.overriding diagnostic consideration.

�� It no longer mattered how much of the It no longer mattered how much of the tumor was papillary or even if all of it tumor was papillary or even if all of it was follicular in pattern.was follicular in pattern.


�� In 1977, Chen and Rosai described the In 1977, Chen and Rosai described the FOLLICULAR VARIANT OF PAPILLARY FOLLICULAR VARIANT OF PAPILLARY CARCINOMACARCINOMA

�� Over 30 years we have witnessed Over 30 years we have witnessed �� Over 30 years we have witnessed Over 30 years we have witnessed debate and dispute about this tumor; debate and dispute about this tumor; panels of experts have been shown to panels of experts have been shown to have wide diagnostic variations have wide diagnostic variations ranging from adenoma to carcinoma.ranging from adenoma to carcinoma.


�� WHAT ARE THE QUESTIONS TODAY?WHAT ARE THE QUESTIONS TODAY?

�� MORE IMPORTANTLY WHAT ARE THE MORE IMPORTANTLY WHAT ARE THE ANSWERS?ANSWERS?


�� If we rely solely on nuclear criteria, If we rely solely on nuclear criteria, then many lesions would be considered then many lesions would be considered FVPTCFVPTC

�� SUCH AS: Chronic sialadenitis, SUCH AS: Chronic sialadenitis, �� SUCH AS: Chronic sialadenitis, SUCH AS: Chronic sialadenitis, chronic endometritis, etc.chronic endometritis, etc.


�� THE NUCLEITHE NUCLEI

ElongatedElongatedEnlargedEnlargedEnlargedEnlargedCleared out centerCleared out centerThick nuclear Thick nuclear membranemembraneGroovesGroovesInclusionsInclusionsTiny nucleoliTiny nucleoli


�� In the thyroid the nuclei that are In the thyroid the nuclei that are excellent mimics of the PTC nuclei excellent mimics of the PTC nuclei include those in:include those in:

�� Hashimoto thyroiditisHashimoto thyroiditis�� Hashimoto thyroiditisHashimoto thyroiditis

�� Graves’ diseaseGraves’ disease

�� Some nodular goitersSome nodular goiters


�� So perhaps the nuclei alone are not So perhaps the nuclei alone are not enough.enough.

�� I personally require the nuclei be I personally require the nuclei be present in a “mass” lesion.present in a “mass” lesion.present in a “mass” lesion.present in a “mass” lesion.

�� This is especially true in Hashimoto This is especially true in Hashimoto disease.disease.


�� I do not believe that one can have a I do not believe that one can have a diffuse papillary cancer of the thyroid.diffuse papillary cancer of the thyroid.

�� In some Hashimoto or Graves’ glands, In some Hashimoto or Graves’ glands, every follicular epithelial cell had a every follicular epithelial cell had a every follicular epithelial cell had a every follicular epithelial cell had a nucleus with features of PTC. nucleus with features of PTC.

�� THIS IS NOT CANCER.THIS IS NOT CANCER.


�� From molecular analysis it has been From molecular analysis it has been shown that in Hashimoto diseaseshown that in Hashimoto disease

�� 1. Areas of epithelium with abnormal 1. Areas of epithelium with abnormal nuclei show nuclei show LOH andLOH andnuclei show nuclei show LOH andLOH and

�� 2. Low levels of ret/PTC translocation2. Low levels of ret/PTC translocation

�� 3. 3. ButBut almost no cases of Braf almost no cases of Braf mutations.mutations.


�� So the question raised isSo the question raised is

�� Is the epithelium in Hashimoto disease Is the epithelium in Hashimoto disease “DYSPLASTIC”, “PRENEOPLASTIC”?“DYSPLASTIC”, “PRENEOPLASTIC”?


�� From an epidemiologic and clinical From an epidemiologic and clinical viewpoint, the incidence of clinical viewpoint, the incidence of clinical papillary carcinoma in Hashimoto papillary carcinoma in Hashimoto disease appears slightly increased over disease appears slightly increased over disease appears slightly increased over disease appears slightly increased over background background BUTBUT

�� The frequency of microptc is really The frequency of microptc is really elevated.elevated.


�� The problems with these data are myriad but The problems with these data are myriad but a few are:a few are:

�� The definition (clinically, serologically and The definition (clinically, serologically and histopathologically) of Hashimoto thyroiditis.histopathologically) of Hashimoto thyroiditis.histopathologically) of Hashimoto thyroiditis.histopathologically) of Hashimoto thyroiditis.

�� The definition of the background population.The definition of the background population.

�� Most patients with thyroiditis do not have Most patients with thyroiditis do not have surgery (if there is no nodule) so it surgery (if there is no nodule) so it impossible to know the true incidence of impossible to know the true incidence of cancer (microptc).cancer (microptc).


�� Data for Graves’ disease are even Data for Graves’ disease are even sparser, since it is unusual to have sparser, since it is unusual to have surgery for this disorder. surgery for this disorder.

�� Clinical cancer in Graves’ disease is Clinical cancer in Graves’ disease is �� Clinical cancer in Graves’ disease is Clinical cancer in Graves’ disease is unusual.unusual.


�� NOW Let us turn attention to nodules NOW Let us turn attention to nodules (mass lesions).(mass lesions).

�� We consider mass lesions as any size We consider mass lesions as any size nodule that appears at low power nodule that appears at low power nodule that appears at low power nodule that appears at low power magnification as a lesion and different magnification as a lesion and different from whatever is going on in the diffuse from whatever is going on in the diffuse background disease.background disease.


�� If such a nodule has a papillary If such a nodule has a papillary architecture and nuclei as previously architecture and nuclei as previously defined, it is papillary cancer no matter defined, it is papillary cancer no matter what its size.what its size.what its size.what its size.

�� If such a nodule has a totally follicular If such a nodule has a totally follicular architecture and nuclei as previously architecture and nuclei as previously defined, is it papillary cancer?defined, is it papillary cancer?

�� MY ANSWER IS MY ANSWER IS YESYES..


�� We need to recognize that there are We need to recognize that there are different patterns of the different patterns of the

�� FOLLICULAR VARIANT OF PAPILLARY FOLLICULAR VARIANT OF PAPILLARY CARCINOMACARCINOMACARCINOMACARCINOMA


�� FOLLICULAR VARIANT OF PAPILLARY FOLLICULAR VARIANT OF PAPILLARY CARCINOMACARCINOMA

�� The easiest to recognize is the The easiest to recognize is the �� The easiest to recognize is the The easiest to recognize is the infiltrative pattern.infiltrative pattern.

PAPILLARY THYROID PAPILLARY THYROID CARCINOMA, FOLLICULAR CARCINOMA, FOLLICULAR

VARIANTVARIANTTYPETYPE Dx: CANCERDx: CANCER Dx: OTHERDx: OTHER

InfiltrativeInfiltrative YESYES

Encapsulated; Encapsulated; YESYESEncapsulated; Encapsulated; invasive; nuclei invasive; nuclei diffuse or multifocaldiffuse or multifocal

YESYES

Encapsulated; diffuse Encapsulated; diffuse nucleinuclei

Most YESMost YES Atypical adenoma; Atypical adenoma; UMPUMP

Encapsulated; Encapsulated; multifocal nuclei or multifocal nuclei or equivocal nucleiequivocal nuclei

Few YESFew YES Many atypical Many atypical adenoma; few UMPadenoma; few UMP

Encapsulated; one Encapsulated; one focus nucleifocus nuclei

Many microPTC in Many microPTC in adenomaadenoma

Many just adenomaMany just adenoma

WHY?WHY?

ENCAPSULATED FVPTC ENCAPSULATED FVPTC (Per Baloch ZW)

FVPTC FVPTC

FVPTC WITH CAP & VAS INV PTC MCA IN ADENOMA


�� THE NUCLEITHE NUCLEI�� ElongatedElongated

�� EnlargedEnlarged

�� Cleared out centerCleared out center�� Cleared out centerCleared out center

�� Thick nuclear membraneThick nuclear membrane

�� GroovesGrooves

�� InclusionsInclusions

�� Tiny nucleoliTiny nucleoli


�� BACK TO THE NUCLEIBACK TO THE NUCLEI

�� My reasoning for considering My reasoning for considering encapsulated follicular tumors with encapsulated follicular tumors with multifocal nuclei as FVPTCmultifocal nuclei as FVPTCmultifocal nuclei as FVPTCmultifocal nuclei as FVPTC

�� Sometimes in node and/or bone Sometimes in node and/or bone metastases, the nuclei look normal and metastases, the nuclei look normal and not like PTC nuclei, yet these are not like PTC nuclei, yet these are metastases.metastases.

�� Thus, if can happen in mets, why not in Thus, if can happen in mets, why not in the primary site?the primary site?


VARIANTVARIANT�� A little Molecular data.A little Molecular data.

�� The follicular variant (the encapsulated The follicular variant (the encapsulated varieties) tend to fall somewhere in between varieties) tend to fall somewhere in between classic papillary carcinoma and classic classic papillary carcinoma and classic classic papillary carcinoma and classic classic papillary carcinoma and classic follicular carcinomafollicular carcinoma

�� Thus they have less ret/PTC rearrangements, Thus they have less ret/PTC rearrangements, rarely Braf mutations ( as does classic PTC) rarely Braf mutations ( as does classic PTC) and more ras mutations (similar to follicular and more ras mutations (similar to follicular carcinoma).carcinoma).


VARIANTVARIANT�� A little Clinicopathologic data.A little Clinicopathologic data.

�� The follicular variant (the encapsulated The follicular variant (the encapsulated varieties) tend to show fewer nodal varieties) tend to show fewer nodal metastases (about 20metastases (about 20--25%) than 25%) than metastases (about 20metastases (about 20--25%) than 25%) than classical PTC.classical PTC.

�� They show more bony metastases and They show more bony metastases and often have vascular invasion in the often have vascular invasion in the primary.primary.


�� BACK TO THE NUCLEIBACK TO THE NUCLEI

�� NOW FOR THE CYTOPATHOLOGISTNOW FOR THE CYTOPATHOLOGIST

�� WHY IS IT SO DIFFICULT TO WHY IS IT SO DIFFICULT TO �� WHY IS IT SO DIFFICULT TO WHY IS IT SO DIFFICULT TO DIAGNOSE FOLLICULAR VARIANT DIAGNOSE FOLLICULAR VARIANT PTC ON FNA?PTC ON FNA?



�� WHY IS IT SO DIFFICULT TO WHY IS IT SO DIFFICULT TO DIAGNOSE FOLLICULAR VARIANT DIAGNOSE FOLLICULAR VARIANT DIAGNOSE FOLLICULAR VARIANT DIAGNOSE FOLLICULAR VARIANT PTC ON FNA?PTC ON FNA?

�� I think it is because although the nuclei I think it is because although the nuclei are enlarged oval and have grooves, are enlarged oval and have grooves, they rarely show intranuclear they rarely show intranuclear inclusionsinclusions and so the FNA diagnosis is and so the FNA diagnosis is often suspicious but not definitive.often suspicious but not definitive.


�� FOLLICULAR VARIANTFOLLICULAR VARIANT

�� Sometimes there are undercallsSometimes there are undercalls

Best nuclei tend to be under capsule of Best nuclei tend to be under capsule of �� Best nuclei tend to be under capsule of Best nuclei tend to be under capsule of lesion, not usually sampled by the FNA lesion, not usually sampled by the FNA (tends to sample center where nuclei (tends to sample center where nuclei may not be well developed).may not be well developed).


�� NOW BACK TO THE CYTOPATHOLOGISTNOW BACK TO THE CYTOPATHOLOGIST

�� Sometimes there are “overcalls” although Sometimes there are “overcalls” although these are rare.these are rare.these are rare.these are rare.

�� Grooves can be seen in other nuclei in the Grooves can be seen in other nuclei in the thyroid.thyroid.

�� One can get squamous metaplasia One can get squamous metaplasia (spontaneous) in(spontaneous) in benign benign conditions and this conditions and this can be overdiagnosed.can be overdiagnosed.



�� There is a possible marker that may be There is a possible marker that may be usefuluseful——EMERINEMERIN

�� As shown by Bussolati’s group this As shown by Bussolati’s group this �� As shown by Bussolati’s group this As shown by Bussolati’s group this marker shows nuclear irregularities in marker shows nuclear irregularities in histological and cytological preps of histological and cytological preps of papillary carcinoma but not in nonptc papillary carcinoma but not in nonptc lesions.lesions.

�� HISTOPATH April 2009HISTOPATH April 2009



�� Sometimes there are “overcalls” Sometimes there are “overcalls” although these are rare.although these are rare.although these are rare.although these are rare.

�� Beware of Beware of oncocyticoncocytic cells which can be cells which can be large and have nuclear grooves, large and have nuclear grooves, especially in hyperfunctioning glands especially in hyperfunctioning glands and nodules. If the nucleus has a and nodules. If the nucleus has a nucleolus and/or is round, do not make nucleolus and/or is round, do not make a diagnosis of PTC.a diagnosis of PTC.

THE DIAGNOSIS OF PAPILLARY THE DIAGNOSIS OF PAPILLARY THYROID CARCINOMA:THYROID CARCINOMA:

How much (or how little) is enough?How much (or how little) is enough?

Virginia A. LiVolsi, MDVirginia A. LiVolsi, MDUniversity of PennsylvaniaUniversity of Pennsylvania

THE DIAGNOSIS OF PAPILLARY THYROID CARCINOMA: HOW MUCH OR

HOW LITTLE IS ENOUGH?

Virginia A. LiVolsi, MD.

University of Pennsylvania

Department of Pathology and Laboratory Medicine

Philadelphia, Pennsylvania

Address for Correspondence:

Virginia A. LiVolsi, M.D.

University of Pennsylvania

Department of Pathology and Laboratory Medicine

3400 Spruce Street, Sixth Floor, Founders Pavillion

Philadelphia, Pennsylvania 19104

Joint ASC-PAP Society Meeting, USCAP, Washington, DC 2010

SALIENT POINTS

At the conclusion of this lecture, the members of the audience should:

1. Understand the subtypes of follicular variant of papillary carcinoma

(currently a controversial diagnosis).

2. Recognize that certain benign reactive conditions can demonstrate

nuclear changes that simulate papillary cancer nuclei.

3. Learn the diagnostic clues that are helpful in dividing these lesions into

clinically relevant entities.

4. Appreciate the applications of the diagnostic criteria to the cytological

diagnosis of papillary thyroid carcinoma.

Keywords: Papillary thyroid carcinoma, follicular variant, nuclear features, diagnostic

criteria

The entity of follicular variant of papillary thyroid carcinoma (FVPC) which had

been recognized in the 1960s by Lindsay 1was elegantly defined in 1977 by Chen and

Rosai.. Until that time, most textbooks and review articles on the pathology of papillary

thyroid carcinoma (PTC) classified follicular patterned thyroid tumors as “follicular

carcinoma” without reference to nuclear features or growth pattern.3

In a short time, the pathology community noticed the importance of nuclear

characteristics in the classification of, and biological behavior of well differentiated

thyroid carcinoma. The AFIP fascicle and the WHO defined lesions as papillary

carcinoma solely on the basis of “peculiar nuclear morphology without regard to

architectural growth, i.e. whether or not papillary structures were present.

Over the past 30 years, many follicular patterned tumors of the thyroid were

diagnosed as papillary carcinoma based on these nuclear features (enlargement,

elongation (oval rather than rounded shape), nuclear clearing, intranuclear grooves and

inclusions, and small nucleoli with thickened nuclear membranes). Lesions which were

infiltrative and those which were partially or completely encapsulated were included in

this category.

Problems arose in the diagnosis of completely en capsulated tumors since even

so-called “experts” in endocrine pathology showed very poor agreement among

themselves in defining the nuclei of papillary carcinoma. Lloyd et al evaluated inter-

observer variability in the diagnosis of FVPC; 87 cases were reviewed 10 experienced

endocrine pathologists.

The cohort included cases with one or more diagnostic nuclear features of

papillary carcinoma and some with capsular (67%) and vascular invasion (5.7%). A

concordant diagnosis of FVPCA was made by all 10 reviewers with a cumulative

frequency of 39%. In this series, 24.1% of the patients had metastatic disease, in this

group a diagnosis of FVPCA was made by all 10 reviewers with a cumulative frequency

of 66.7%, and 7 of the reviewers made a diagnosis of FVPCA with a cumulative

frequency of 100%.

Hirokawa et al submitted 21 encapsulated follicular patterned thyroid lesions to

four American and four Japanese pathologists for expert review. There was unanimous

agreement among all pathologists in 2 (10%) cases, 7 of 8 pathologists agreed in 29% and

6 of 8 pathologists in 76% of cases. All pathologists, however, agreed on the diagnosis of

benign vs. malignant lesion in 13(62%) of 21 cases. Interestingly, the American

pathologists frequently made the diagnosis FVPC as compared to Japanese pathologists

(25% vs. 4%).9 Elsheikh et al assessed inter and intra-observer agreement among 6

thyroid experts by using 15 cases in which the original pathologists considered the

differential diagnosis of FVPC vs. follicular adenoma (FA). There was complete

agreement in the diagnosis of FVPC in 2 (13%), complete agreement on benign and

malignant diagnoses in 4 (27%) and majority agreement in 8 (53%) cases.

Several authors agree that this variability in the diagnosis of FVPC is due to the

lack of agreement on the minimal diagnostic criteria. The diagnosis of papillary cancer is

established by examining the nucleus. Most often the cytopathologists will not render the

diagnosis of papillary carcinoma in thyroid fine needle aspiration specimens until all

major diagnostic features are evident. Any specimens which fell short of this are

diagnosed as suspicious for papillary carcinoma. Numerous studies have shown that that

rate of malignancy in cases diagnosed as such is 60-75% and interestingly most cases on

histologic examination are found to FVPC. Verhulst et al employed a scoring system for

the diagnosis of PTC. In this study the 132 thyroid tumors (66 PTC and 66 follicular

adenoma) were used as a training set to establish the scoring system which was tested on

a validation set of 58 thyroid tumors (29 PTC and 29 FNA) to assess its efficacy in the

diagnosis of PTC. Theses authors found that the microscopic criteria for PTC were highly

variable among cases and ranged from 0% to 75%, nuclear enlargement was the only

feature that was present in 75% of the tumor cells in 94% of cases. Interestingly, in the

validation part of the study eight cases of PTC majority of which were follicular

patterned were in gray zone i.e. at or below the threshold score for the diagnosis of PTC.

The hope for a marker that may help define the nuclei of papillary carcinoma

remains to be fulfilled. At least one marker may show some promise but more work

needs to be done to confirm it. The group from the University of Turino has studied

Emerin a nuclear membrane component and found that immunohistochemical staining

shows differences between papillary carcinomas and benign mimics, normal thyroid and

nonmalignant lesions. The staining is applicable to both cytologic and histologic

preparations.

The considerable inter and intra-observer variability in the diagnosis of FVPC

which often creates treatment dilemmas among clinicians i.e. whether to treat or not i.e.

completion thyroidectomy (in cases where lobectomy is done as the initial procedure)

and/or radioiodine ablation. The result of this confusion is that many cases of FVPC

(especially encapsulated lesions) are sent to thyroid pathology experts for second opinion

Due to this controversy the Chernobyl Pathologist group have proposed the term

“well-differentiated thyroid tumor of uncertain malignant potential” for encapsulated

follicular patterned tumor that only shows some or unconvincing features of PTC.

We recognize that the follicular variant of papillary carcinoma represents a

heterogeneous group of tumors due to its variable growth patterns (architectural) and

distribution of nuclear features of papillary carcinoma.

The un-encapsulated invasive tumor is a lesion which grows in an infiltrative

pattern and is without question therefore a carcinoma. In its growth pattern resembles

classical papillary carcinoma. However, the lesion demonstrates no papillae and is

composed exclusively of follicles. The nuclei throughout the lesion are the characteristic

nuclei of papillary carcinoma. These lesions may show lymphatic invasion, multifocal

growth within the thyroid, and on occasion psammoma bodies; lymph node metastases

are not unusual and may even demonstrate papillary growth. These cases do not usually

produce difficulties in diagnosis

The encapsulated tumor represents the group that may cause diagnostic

disagreements. In encapsulated tumors which show invasion of the tumor capsule or

capsular blood vessels, most pathologists will consider these cancers; the diagnostic issue

is whether these should be classified as follicular or papillary carcinoma. We consider

these papillary carcinomas if the nuclear features are present, whether these are diffuse

throughout the tumor or are present in multiple locations within the neoplasm. The

encapsulated FVPC without invasion and showing diffuse nuclear changes of PTC will

be classified by many experienced pathologists as FVPTC; however, problems exist in

those encapsulated noninvasive lesions with multifocal nuclear change but in which the

nuclei do not show all of the characteristic features listed above of papillary cancer i.e.

unconvincing.. Most often, there are few if any nuclear inclusions.

Finally there are lesions that contain a sub-centimeter area of follicles with papillary

nuclei that if present in the normal thyroid would be diagnosed as a papillary

microcarcinoma; such rare lesions should be diagnosed as papillary microcarcinoma

arising in and confined within a follicular adenoma. These have the biologic

characteristics and probably better clinical outlook than identical lesions of intra-

glandular incidentally found microcarcinoma; i.e., very small to almost nonexistent risk

of metastatic potential.

REFERENCES

1. Lindsay S. Carcinoma of the thyroid gland: a clinical and pathologic

study of 239 patients at the University of California Hospital. Sprigfield, IL; 1960.

2. Chen KT, Rosai J. Follicular variant of thyroid papillary carcinoma: a

clinicopathologic study of six cases. Am J Surg Pathol. 1977;1:123-30.

3. Meissner WA. Follicular carcinoma of the thyroid; frozen section

diagnosis. Am J Surg Pathol. 1977;1:171-175.

4. DeLellis RA, Lloyd RD, Heitz PU, Eng C, eds. WHO: Pathology and

Genetics. Tumours of Endocrine Organs. Lyon, France: IARC Press; 2004.

5. Rosai J, Carcangui ML, DeLellis RA. Tumors of The Thyroid Gland. 3rd

Series, Fascicle 5 vol. Washington, DC: Armed Forces Institute of Pathology; 1992.

6. LiVolsi VA. Surgical Pathology of The Thyroid. Philadelphia, PA: WB.

Saunders; 1990.

7. LiVolsi VA, Asa SL. The demise of follicular carcinoma of the thyroid

gland. Thyroid. 1994;4:233-6.

8. Lloyd RV, Erickson LA, Casey MB et al. Observer variation in the

diagnosis of follicular variant of papillary thyroid carcinoma. Am J Surg Pathol.

2004;28:1336-40.

9. Hirokawa M, Carney JA, Goellner JR et al. Observer variation of

encapsulated follicular lesions of the thyroid gland. Am J Surg Pathol. 2002;26:1508-14.

10. Renshaw AA, Gould EW. Why there is tendency to "overdiagnose" the

follicular variant of papillary thyroid carcinoma. Am J Clin Pathol. 2002;117:19-21.

11. Chan JK. Strict criteria should be applied in the diagnosis of encapsulated

follicular variant of papillary thyroid carcinoma. Am J Clin Pathol. 2002;117:16-18.

12. Baloch ZW, Livolsi VA. Follicular-patterned lesions of the thyroid: the

bane of the pathologist. Am J Clin Pathol. 2002;117:143-50.

13. Elsheikh TM, Asa SL, Chan JK et al. Interobserver and intraobserver

variation among experts in the diagnosis of thyroid follicular lesions with borderline

nuclear features of papillary carcinoma. Am J Clin Pathol. 2008;130:736-44.

14. Logani S, Gupta PK, LiVolsi VA, Mandel S, Baloch ZW. Thyroid nodules

with FNA cytology suspicious for follicular variant of papillary thyroid carcinoma:

follow-up and management. Diagn Cytopathol. 2000;23:380-5.

15. Zacks JF, de las Morenas A, Beazley RM, O'Brien MJ. Fine-needle

aspiration cytology diagnosis of colloid nodule versus follicular variant of papillary

carcinoma of the thyroid. Diagn Cytopathol. 1998;18:87-90.

16. Baloch ZW, Livolsi VA, Asa SL et al. Diagnostic terminology and

morphologic criteria for cytologic diagnosis of thyroid lesions: A synopsis of the

National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science

Conference. Diagn Cytopathol. 2008;36:425-37.

17. Verhulst P, Devos P, Aubert S et al. A score based on microscopic criteria

proposed for analysis of papillary carcinoma of the thyroid. Virchows Arch.

2008;452:233-40.

18. Baloch ZW, LiVolsi VA. Our approach to follicular-patterned lesions of

the thyroid. J Clin Pathol. 2007;60:244-50.

19. Williams ED, Abrosimov A, Bogdanova TI, Roasi J, Sidorov Y, Thomas

GA. Two proposals regarding the terminology of thyroid tumors. Guest Editorial. Int J

Surg Pathol. 2000;8:181-183.

20. Baloch ZW, LiVolsi VA. Pathologic diagnosis of papillary thyroid

carcinoma: today and tomorrow. Expert Rev Mol Diagn. 2005;5:573-84.

21. Kaur A, Jayaram G. Thyroid tumors: cytomorphology of follicular

neoplasms. Diagnostic Cytopathology. 1991;7:469-72.

22. Baloch ZW, Fleisher S, LiVolsi VA, Gupta PK. Diagnosis of "follicular

neoplasm": A gray zone in thyroid fine-needle aspiration cytology. Diagn Cytopathol.

2002;26:41-4.

23. LiVolsi VA, Baloch ZW. Follicular neoplasms of the thyroid: view,

biases, and experiences. Adv Anat Pathol. 2004;11:279-87.

24. Nayar R, Ivanovic M. The indeterminate thyroid fine-needle aspiration:

experience from an academic center using terminology similar to that proposed in the

2007 National Cancer Institute Thyroid Fine Needle Aspiration State of the Science

Conference. Cancer Cytopathol. 2009;117:195-202.

25. Rivera M, Tuttle RM, Patel S, Shaha A, Shah JP, Ghossein RA.

Encapsulated papillary thyroid carcinoma: a clinico-pathologic study of 106 cases with

emphasis on its morphologic subtypes (histologic growth pattern). Thyroid. 2009;19:119-

27.

26. Baloch ZW, LiVolsi VA. Encapsulated follicular variant of papillary

thyroid carcinoma with bone metastases. Mod Pathol. 2000;13:861-865.

27. Mizukami Y, Nonomura A, Hayashi Y, et.al. Late bone metastasis from an

encapsulated follicular carcinoma of the thyroid without capsular and vascular invasion.

Pathol Internat. 1996;46:457-461.

28. Goldstein NS, Czako P, Neill JS. Metastatic minimally invasive

(encapsulated) follicular and Hurthle cell thyroid carcinoma: a study of 34 patients.

Modern Pathology. 2000;13:123-30.

29. Hunt JL, Dacic S, Barnes EL, Bures JC. Encapsulated follicular variant of

papillary thyroid carcinoma. Am J Clin Pathol. 2002;118:602-3; author reply 605-6.

30. Giordano TJ, Kuick R, Thomas DG et al. Molecular classification of

papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene

expression profiles discovered by DNA microarray analysis. Oncogene. 2005;24:6646-

56.

31. Nikiforov YE, Nikiforova MN, Gnepp DR, Fagin JA. Prevalence of

mutations of ras and p53 in benign and malignant thyroid tumors from children exposed

to radiation after the Chernobyl nuclear accident. Oncogene. 1996;13:687-93.

32. Zhu Z, Gandhi M, Nikiforova MN, Fischer AH, Nikiforov YE. Molecular

profile and clinical-pathologic features of the follicular variant of papillary thyroid

carcinoma. An unusually high prevalence of ras mutations. Am J Clin Pathol.

2003;120:71-7.

33. Pizzolanti G, Russo L, Richiusa P et al. Fine-needle aspiration molecular

analysis for the diagnosis of papillary thyroid carcinoma through BRAF V600E mutation

and RET/PTC rearrangement. Thyroid. 2007;17:1109-15.

34.. Nikiforov YE, Steward DL, Robinson-Smith TM et al. Molecular testing

for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J Clin

Endocrinol Metab. 2009;94:2092-8.

35. Asioli S, Bussolati G. Emerin immunohistochemistry reveals diagnostic features

of nuclear membrane arrangement in thyroid lesions.Histopathology;54:571-9, 2009.

36. LiVolsi VA and Baloch ZW. The many faces of follicular variant of papillary thyroid

carcinoma. Path Case Rev 2010 (in press).

the diagnosis of papillary thyroid...

Documents