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, MD Virginia A. LiVolsi, MD University of Pennsylvania University of Pennsylvania
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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
•• 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•• 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
�� 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.
�� 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.
�� 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:
�� 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.
�� 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.
�� 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?
�� 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.
�� 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.
�� 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?
�� NOW FOR THE CYTOPATHOLOGISTNOW FOR THE CYTOPATHOLOGIST
�� 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.
�� 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.
�� NOW FOR THE CYTOPATHOLOGISTNOW FOR THE CYTOPATHOLOGIST
�� 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.
�� NOW FOR THE CYTOPATHOLOGISTNOW FOR THE CYTOPATHOLOGIST
�� 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