Papillary thyroid carcinoma

Papillary thyroid carcinoma
Diagnosis in short
Papillary thyroid carcinoma. H&E stain.
LM	nuclear changes: nuclear membrane irregularities (e.g. raisinoid shape), +/-nuclear grooves, +/-nuclear pseudoinclusions, +/-nuclear clearing, nuclear enlargement (usu. mild), nucleoli; architectural changes: overlap of nuclei, papillae (not required), +/-psammoma bodies
Subtypes	tall cell variant, columnar cell variant, follicular variant, cribriform-morular variant, diffuse sclerosing variant, Warthin-like variant, solid variant, oncocytic variant, others
LM DDx	lymphocytic thyroiditis (Graves disease, Hashimoto thyroiditis), solid cell nest of thyroid, follicular thyroid carcinoma, follicular thyroid adenoma, adenomatoid nodule, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)
IHC	HBME-1 +ve, CK19 +ve, Galectin-3 +ve, thyroglobulin +ve, TTF-1 +ve
Molecular	BRAF mutation - commonly
Staging	thyroid cancer staging
Site	thyroid gland
Syndromes	familial adenomatous polyposis (cribriform-morular variant)
Signs	thyroid mass
Prevalence	very common
Prognosis	usu. good
Clin. DDx	other thyroid gland tumours

Papillary thyroid carcinoma, abbreviated PTC, is the most common thyroid gland malignancy. It usually has an indolent course.

General

Medical school memory device P's:

• Palpable lymph nodes.
• Popular - most common malignant neoplasm of the thyroid.
• Prognosis is good.
• Pre-Tx iodine scan.
• Post-Sx iodine scan.
• Psammoma bodies.

Notes:

• PTC is associated with radiation exposure.
• Papillary thyroid microcarcinoma is defined as a tumour with a maximal dimension of 1.0 cm or less.

Prognosis

Prognosis can be predicted by MAICS score. It which includes:

• Metastases.
• Age.
• Invasion of surround tissues.
• Completeness of excision.
• Size of tumour.

Microscopic

Features:

• Nuclear changes - key feature.
  1. "Shrivelled nuclei"/"raisin" like nuclei, nuclei with a wavy ("textured", convoluted) nuclear membrane -- usu. easy to find.
  2. Nuclear pseudoinclusions -- usu. harder to find; have high specificity (nuclear pseudoinclusions appear as a result of the very convoluted nuclear membrane wrapping around parts of the cytoplasm; true nuclear inclusions in contrast are seen only in viral infections).
  3. Nuclear grooves, seen as a result of the highly "textured" nuclear membrane.
  4. Nuclear clearing (only on permanent section) - also known as "Orphan Annie eyes".
• Overlap of nuclei - "cells do not respect each other's borders" (easy to see at key feature at low power).
• Classically has papillae (nipple-like shape); papilla (definition): epithelium on fibrovascular core.
  • Absence of papillae does not exclude diagnosis.
• Psammoma bodies.
  • Circular, acellular, eosinophilic whorled bodies.
  • Not necessary to make diagnosis - but very specific in the context of a specimen labeled "thyroid".
  • Arise from infarction & calcification of papilla tips.

Notes:

• Psammoma bodies are awesome if you see 'em, i.e. useful for arriving at the diagnosis.
  • If there are no papillae structures -- you're unlikely to see psammoma bodies.
• At low power look for cellular areas/loss of follicles.
• Nuclear clearing seen in:
  • Hashimoto's and papillary thyroid carcinoma.
  • May be an artifact of fixation/processing.
• Nuclear overlapping is easy to see at lower power-- should be the tip-off to look at high power for nuclear features.
• Nuclear inclusions are quite rare and not required to make the diagnosis -- but a very convincing feature if seen.
• Papillae may be seen in Graves disease.
• Thyroid tissue lateral to the jugular vein (often referred to as lateral aberrant thyroid tissue) is generally considered metastatic thyroid carcinoma (papillary thyroid carcinoma) even if it looks benign.
  • This dictum is disputed.
  • The level VI and VII lymph nodes are medial to the jugular.

DDx:

• Lymphocytic thyroiditis:
  • Graves disease.
  • Hashimoto thyroiditis.
• Solid cell nest of thyroid.

Subtypes of papillary thyroid carcinoma

There are many.

Poor prognosis variants:

• Tall cell variant.
• Columnar cell variant.
• Solid variant.
• Diffuse sclerosing variant.

Papillary thyroid carcinoma tall cell variant

General

• ~10% of PTC.
• Often large > 6 cm.

Microscopic

Features:

• 50% of cells with height 2x the width.
  • There is some disagreement on these criteria; Raphael believes the height ought to be ~3x width, for 50% of the cells.
• Eosinophilic cytoplasm.
• Well-defined cell borders.
• Nucleus stratified; basal location, i.e. closer to the basement membrane.

Negative:

• Nuclei not pseudostratified, if pseudostratified consider columnar cell variant.

Images:

• 

  PTC tall cell variant - intermed. mag. (WC)

• 

  PTC tall cell variant - high mag. (WC)

Papillary thyroid carcinoma columnar cell variant

General

Epidemiology:

• Poor prognosis.
• Very rare.

Microscopic

Features:

• Elongated nuclei (similar to colorectal adenocarcinoma) - key feature.
• +/-Pseudostratification of the nuclei (like in colorectal adenocarcinoma), differentiates from tall cell variant.
• Nuclear stratification - key feature.
• "Minimal" papillary features.
• "Tall cells".
• Clear-eosinophilic cytoplasm.
• Mitoses common.

Image: Columnar variant PTC (wiley.com).

Papillary thyroid carcinoma follicular variant

General

• May be confused with follicular carcinoma or follicular adenoma.
• Pathologists often disagree about this diagnosis.

Microscopic

Features:

• Small tightly packed follicles - key feature.
• Hypereosinophilic colloid.
• Nuclear features of PTC.
  • Large nuclei.
  • Typically have less nuclear pseudoinclusions than the conventional type.
• +/-Fibrous capsule (common).

DDx:

• Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).
• Follicular thyroid carcinoma - has a fibrous capsule and invasion though it.
• Follicular thyroid adenoma - surrounded by a fibrous capsule.
• Adenomatoid nodule - round nuclei, no nuclear features of PTC.

Images:

Papillary thyroid carcinoma cribriform-morular variant

General

• Associated with familial adenomatous polyposis (FAP).

Microscopic

Features:

• Circumscribed or even encapsulated neoplasm.
• Morules - interspersed balls of squamoid cells
  • No keritinization or intercellular bridges.
  • Homogenous, lightly eosinophilic glassy nuclei (biotin accumulation).
• Follicles
  • Cribriform, papillary, trabecular and solid patterns.
  • Columnar or cuboidal cells.
  • Little colloid
  • Papillary carcinoma nuclear features.

• 

  Thyroid - Papillary Carcinoma Cribriform Morular Variant - Medium power (SKB)

• 

  Thyroid - Papillary Carcinoma Cribriform Morular Variant - High power (SKB)

• 

  Thyroid - Papillary Carcinoma Cribriform Morular Variant - high power]]

• 

  Thyroid - Papillary Carcinoma Cribriform Morular Variant - High power (SKB)

• 

  Thyroid - Papillary Carcinoma Cribriform Morular Variant - CDX2 (SKB)

• 

  Thyroid - Papillary Carcinoma Cribriform Morular Variant - p16 (SKB)

• 

  Thyroid - Papillary Carcinoma Cribriform Morular Variant - ER (SKB)

• 

  Thyroid - Papillary Carcinoma Cribriform Morular Variant - beta catenin (SKB)

DDX:

• Papillary thyroid carcinoma
• Papillary thyroid carcinoma, tall cell variant

IHC

• CDX2 - Highlights the morules (CDX2 is positive in the biotin rich nuclei associated with morule formation in a variety of situations)
• CD10 - Highlights the morules
• Beta-catenin - nuclear and cytoplasmic - all tumour cells.
• Estrogen receptor - positive
• TTF-1 - positive

Molecular

• Up-regulating disturbances in the Wnt signaling pathway promote formation of morules with optically clear biotin rich nuclei
  • Mutation of the beta-catenin gene
  • Mutation in APC
• Examples
  • • Well-differentiated fetal adenocarcinoma
    • Papillary thyroid carcinoma, cribriform morular variant (mutation in APC in familial variants)
    • Pancreatoblastoma

Papillary thyroid carcinoma diffuse sclerosing variant

General

• Usually young adults, children.

Microscopic

Features:

• Papillae - usu. prominent.
• Squamous morules - key features.
• Lymphocytes - abundant.
• Fibrosis.

DDx:

• Lymphocytic thyroiditis (esp. Hashimoto's thyroiditis).

Papillary thyroid carcinoma Warthin-like variant

• Resembles Warthin tumour.

Microscopic

Features:

• Eosinophilic cytoplasm.
• Lymphocytic thyroiditis.
• Papillae.

Papillary thyroid carcinoma solid variant

Features:

• Some studies suggest this has a poor prognosis.
• More common in children.
• Associated with Chernobyl nuclear accident.

Microscopic

Features:

• Solid sheets >50% of tumour mass.

Papillary thyroid carcinoma oncocytic variant

Features:

• Possible association with autoimmune thyroiditis.

Microscopic

Features:

• Abundant oncocytic tumour cells with apical nuclei.
• Classic features of PTC:
  • Grooves and and abundant pseudoinclusions.
• >70% papillary architecture.
• +/-Degenerative changes.

Note:

• CK19 +ve -- though not specific or sensitive.

• 

  PTC oncocytic - low mag. (WC)

• 

  PTC oncocytic - intermed mag. (WC)

• 

  PTC oncocytic - high mag. (WC)

• 

  PTC oncocytic - very high mag. (WC)

IHC

Thyroid versus something else:

• Thyroglobulin +ve.
• TTF-1 (thyroid transcription factor-1) +ve.
• CD15 +ve.^{[citation needed]}

PTC versus benign:

• HBME-1 +ve (strong, diffuse).
• CK19 +ve (strong, diffuse).
• Galectin-3 +ve (strong, diffuse).

Molecular

• BRAF mutation.

Tabular summary

Molecular changes in papillary thyroid carcinoma as per Adeniran et al:

Molecular change	Frequency	Histology	Notes
BRAF point mutations	~ 40%	tall cell variant	poorer prognosis, older individuals
RET/PTC rearrangments	~ 20%	papillary architecture, psammoma bodies	younger individuals
RAS point mutations	~ 15%	exclusively follicular variant	-

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HEMITHYROID, RIGHT, COMPLETION OF TOTAL THYROIDECTOMY:
- PAPILLARY THYROID CARCINOMA, FOLLICULAR VARIANT.
-- TUMOUR SIZE: 4 MM (MAXIMAL).
-- ARCHITECTURE: FOLLICULAR.
-- CYTOMORPHOLOGY: CLASSICAL.
-- HISTOLOGIC GRADE: G1 (WELL DIFFERENTIATED).
-- NO TUMOUR CAPSULE IDENTIFIED.
-- NEGATIVE FOR LYMPHOVASCULAR INVASION.
-- NEGATIVE FOR PERINEURAL INVASION.
-- NEGATIVE FOR EXTRATHYROIDAL EXTENSION.
-- SURGICAL MARGINS NEGATIVE FOR MALIGNANCY.

Note:

• If it is a completion thyroidectomy and the staging changes one should do a full synoptic report.

Microcarcinoma

A. LEFT HEMITHYROID, THYROIDECTOMY COMPLETION:
- PAPILLARY THYROID MICROCARCINOMA.
-- MARGINS NEGATIVE FOR MALIGNANCY.
-- TUMOUR SIZE ~ 1 MILLIMETRE.
-- NEGATIVE FOR LYMPHOVASCULAR INVASION.
-- NEGATIVE FOR PERINEURAL INVASION.
- PALPATION THYROIDITIS, FOCAL.
- NODULAR HYPERPLASIA.

B. LYMPH NODES, LEVEL 6 AND 7, LYMPH NODE DISSECTION:
- TWO LYMPH NODES, NEGATIVE FOR MALIGNANCY ( 0 POSITIVE / 2 ).

THYROID GLAND, TOTAL THYROIDECTOMY:
- INCIDENTAL PAPILLARY THYROID MICROCARCINOMA.
-- MARGINS NEGATIVE FOR MALIGNANCY.
-- TUMOUR SIZE ~ 1 MILLIMETRE.
-- NEGATIVE FOR LYMPHOVASCULAR INVASION.
-- NEGATIVE FOR PERINEURAL INVASION.
- NODULAR HYPERPLASIA.
- ONE PARATHYROID GLAND.

Lymph node dissection

A. NECK, RIGHT LEVEL 2 AND 3, LYMPH NODE DISSECTION:
- ONE LYMPH NODE POSITIVE FOR PAPILLARY THYROID CARCINOMA ( 1 POSITIVE / 4 ).

B. NECK, RIGHT LEVEL 4, LYMPH NODE DISSECTION:
- TWO LYMPH NODES, NEGATIVE FOR MALIGNANCY ( 0 POSITIVE / 2 ).

C. NECK, RIGHT LEVEL 6 AND 7, LYMPH NODE DISSECTION:
- ONE LYMPH NODE POSITIVE FOR PAPILLARY THYROID CARCINOMA ( 1 POSITIVE / 3 ).

Micro

The sections show lymph nodes with tumour that has a papillary architecture. The tumour cell nuclei are enlarged and overlap. They also have nuclear grooves, nucleoli and abundant pseudoinclusions. The chromatin of the tumour cells has a powdery appearance.

See also

• Thyroid gland.