Papillary Carcinoma

Slide 1 · Papillary Carcinoma of the Thyroid

Morphology • molecular pathogenesis • clinicopathologic reasoning

Thyroid pathology: a structured diagnostic and molecular approach

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Recognize the nuclear and architectural hallmarks of conventional PTC.

Connect BRAF and kinase-fusion drivers to MAPK signaling.

Explain lymphatic dissemination, clinical presentation and prognosis.

Distinguish conventional PTC from key follicular-patterned mimics.

Slide 3 · PTC is a follicular epithelial malignancy

Arises from thyroid follicular epithelium, not parafollicular C cells.

Belongs to the differentiated thyroid carcinomas.

Characteristic nuclear changes are central to recognition.

Right lobe

Left lobe

Thyroid anatomy — simplified schematic

Slide 4 · Thyroid carcinoma: Diagnostic context

Tumor family

Differentiation / origin

Key distinction

Papillary

Follicular epithelial

Papillae; defining nuclear features

Follicular / oncocytic

Follicular epithelial

Capsular or vascular invasion

High-grade / anaplastic

Follicular epithelial

High-grade morphology / dedifferentiation

Medullary

Parafollicular C cell

Neuroendocrine; calcitonin

Slide 5 · Papillary carcinoma dominates thyroid malignancies

Accounts for nearly 85% of thyroid cancers in the United States.

Its high frequency largely determines the clinical face of thyroid cancer.

Small, localized PTCs contribute to overall favorable thyroid cancer outcomes.

Slide 6 · PTC can occur throughout life

Occurs across the age spectrum.

Most often presents between 25 and 50 years of age.

Age also informs prognosis: Outcomes are generally less favorable after 55.

Slide 7 · Ionizing radiation is an important risk exposure

PTC predominates among thyroid cancers associated with prior radiation.

Exposure in the first two decades of life is particularly relevant.

Historical radiation-related childhood PTC provides etiologic evidence.

Ionizing radiation

Childhood thyroid exposure

Exposure association — conceptual

Slide 8 · A plausible mechanism for radiation-associated fusions

DNA double-strand breaks

Chromosomal rearrangement

Oncogenic kinase fusion

MAPK activity

The text proposes that radiation-related DNA breaks may help explain the increased fusion frequency in radiation-associated PTC.

Conceptual mechanism — editable schematic

Slide 9 · PTC development involves oncogenic driver events

Conventional PTC is associated with activating BRAF point mutations.

Rearrangements involving RET, NTRK or BRAF are another driver class.

These pathways promote growth signaling in follicular epithelial cells.

Slide 10 · BRAFV600E activates a signaling kinase

BRAF V600E in up to 80% of conventional PTCs.

The alteration substitutes glutamate for valine at codon 600.

It produces gain of function in a serine/threonine kinase.

BRAF (wild type)

BRAF V600E

Increased downstream MAPK signaling

Driver-mutation schematic

Slide 11 · BRAF lies within the MAPK signaling pathway

The canonical cascade links upstream receptor/RAS signaling to BRAF.

BRAF activates MEK, which activates ERK.

The downstream response influences proliferation and differentiation.

RTK / RAS

BRAF

MEK

ERK

Schematic MAPK signaling

Slide 12 · A driver mutation is not a histologic diagnosis

BRAF V600E occurs in PTC and in other malignancies.

Molecular evidence should be interpreted with cytomorphology and clinical context.

PTC recognition remains anchored in its characteristic nuclear changes.

Slide 13 · BRAF is linked to altered thyroid differentiation

The source associates BRAF-mutant conventional PTC with reduced differentiation markers.

Examples include thyroglobulin and thyroid peroxidase.

This association helps connect oncogenic signaling with tumor phenotype.

Slide 14 · BRAF status and adverse behavior: Interpret cautiously

A possible association with extrathyroidal extension.

A possible association with recurrence is also noted.

These are probabilistic associations, not deterministic outcome predictions.

Slide 15 · RET fusions create constitutive kinase signaling

Genomic rearrangement

RET fusion gene

Active RET kinase

Growth signaling

The rearrangement produces a fusion kinase active without normal physiological regulation.

Conceptual mechanism — editable schematic

Slide 16 · RET is an unusual oncogenic kinase in follicular cells

Normal thyroid follicular cells do not usually express RET.

Rearrangements can activate the RET tyrosine kinase in PTC.

CCDC6 is a common RET fusion partner.

Follicular epithelial cell

RET fusion rearrangement

Oncogenic RET kinase activity

Molecular schematic

Slide 17 · NTRK rearrangements form another driver class

NTRK1 and NTRK3 encode receptor tyrosine kinases.

Gene rearrangements can produce constitutively active fusion proteins.

The source notes these rearrangements particularly in some childhood PTCs.

Slide 18 · Conventional PTC: Two driver patterns

Molecular pattern

Example

Functional interpretation

Activating point mutation

BRAF V600E

Activated BRAF serine/threonine kinase

Oncogenic gene fusion

RET fusion

Constitutively active receptor tyrosine kinase

Oncogenic gene fusion

NTRK1 / NTRK3

Constitutively active fusion kinase

Oncogenic gene fusion

BRAF fusion

BRAF pathway deregulation

Slide 19 · BRAF-like versus RAS-like follicular neoplasms

Conventional PTC

Follicular-patterned neoplasms

Frequently BRAF V600E or kinase fusions

Often RAS mutations or related alterations

Conventional papillary architecture is common

Follicular architecture may predominate

Thyroid differentiation markers may be reduced with BRAF

RAS-associated tumors often retain differentiation markers

Lymphatic spread characteristic

Vascular spread important when invasive

Slide 20 · Additional mutations underlie higher-grade progression

Differentiated carcinoma

Additional genetic hits

High-grade transformation

The source names TERT promoter and TP53 alterations in aggressive thyroid carcinomas. This is context, not a defining step for conventional PTC.

Conceptual mechanism — editable schematic

Slide 21 · Conventional PTC may be solitary or multifocal

Some glands contain a single dominant primary lesion.

Others show multiple geographically separate foci.

Multifocality is a gross distribution, not proof of extrathyroidal invasion.

Right lobe

Left lobe

Multifocal nodules — schematic

Slide 22 · Tumor margins may be circumscribed or infiltrative

Well-circumscribed lesions can have recognizable borders.

Other PTCs permeate adjacent thyroid parenchyma.

Margin assessment requires examination of tumor–thyroid interfaces.

Perithyroid tissue

Simplified tissue schematic

Slide 23 · Gross appearance can include secondary changes

Areas of fibrosis may be present.

Calcification is common enough to be a characteristic gross feature.

Cystic change may alter the tumor’s apparent architecture.

Papillary foci may be visible on the cut surface.

Slide 24 · True papillae have fibrovascular stalks

Branching epithelial projections contain a central fibrovascular core.

The epithelial covering may range from one to several cell layers.

Branching complexity distinguishes the pattern from a simple follicle.

Fibrovascular core

Epithelial lining

Schematic, not H&E micrograph

Slide 25 · Architecture alone does not fully define PTC

Well-formed branching papillae strongly support conventional PTC.

Characteristic nuclear morphology remains essential.

Papillary-type nuclear changes also occur in follicular-patterned lesions.

Slide 26 · Optically clear nuclei are a defining feature

Chromatin appears finely dispersed and pale.

The empty-looking nucleus is termed ground-glass or Orphan Annie eye.

Assess nuclear clearing alongside other nuclear membrane changes.

Pale, finely dispersed chromatin

Schematic cell nuclei — not histology

Slide 27 · Nuclear grooves reflect membrane irregularity

Nuclear contours show folds or longitudinal indentations.

Grooves may create a coffee-bean appearance.

They form part of a constellation of diagnostic nuclear changes.

Longitudinal nuclear membrane infolding

Schematic cell nuclei — not histology

Slide 28 · Intranuclear pseudoinclusions are cytoplasmic invaginations

Cytoplasm appears to extend into the nucleus.

Pseudoinclusions are enclosed by the nuclear membrane.

They support PTC when accompanied by the expected nuclear phenotype.

Cytoplasm appears invaginated into nucleus

Schematic cell nuclei — not histology

Slide 29 · Interpret nuclear features as a combined pattern

Nuclear enlargement, overlap and clearing occur together.

Nuclear membrane wrinkling and grooves add specificity.

Pseudoinclusions provide a further characteristic clue.

Clearing • groove • pseudoinclusion

Schematic cell nuclei — not histology

Slide 30 · Psammoma bodies show concentric calcification

Round, laminated calcifications are characteristic of PTC.

They often lie within papillary cores or adjacent stroma.

Their microscopic organization differs from coarse nonspecific calcification.

Concentric lamellated calcification

Schematic psammoma body

Slide 31 · Psammoma bodies have diagnostic utility in FNA

Their identification supports PTC in thyroid aspirates.

Their rarity in follicular and medullary thyroid carcinomas.

They supplement rather than replace the full cytologic assessment.

Slide 32 · Microscopic hallmarks: Structure and nuclei

Architectural clues

Nuclear clues

Stromal / invasive clues

Complex branching papillae

Fine chromatin clearing

Psammoma bodies

Fibrovascular papillary cores

Nuclear grooves / wrinkling

Lymphatic involvement

Cuboidal epithelial covering

Cytoplasmic pseudoinclusions

Variable stromal fibrosis

Slide 33 · Lymphatic invasion is common in PTC

Tumor cells may enter intrathyroidal lymphatics.

Regional lymphatic dissemination explains frequent cervical nodes.

The pattern differs from the blood-borne spread of follicular carcinoma.

Primary thyroid tumor

Lymphatic invasion

Cervical lymph node

Common route in conventional PTC

Slide 34 · Blood-vessel invasion is less frequent

Conventional PTC preferentially involves lymphatic channels.

Blood-vessel invasion is uncommon, particularly in smaller tumors.

The route of invasion predicts the usual pattern of dissemination.

Slide 35 · Regional cervical nodal metastasis is common

Adjacent cervical nodes may harbor metastatic tumor.

Nodal involvement in up to one-half of cases.

A palpable node may be the first sign of the primary carcinoma.

Primary thyroid tumor

Lymphatic invasion

Cervical lymph node

Common route in conventional PTC

Slide 36 · PTC versus follicular carcinoma: Spread

Feature

Papillary carcinoma

Follicular carcinoma

Preferred route

Lymphatic

Hematogenous

Regional nodes

Often involved

Uncommon

Blood vessels

Less common in small PTC

Important diagnostic feature

Distant spread

May occur

Characteristic when invasive

Slide 37 · Follicular growth does not exclude papillary-type nuclei

Some encapsulated lesions show an entirely follicular pattern.

Their nuclei nevertheless resemble those of PTC.

Invasion determines whether some lesions belong to an invasive category.

Intact boundary

Encapsulated noninvasive pattern — schematic

Slide 38 · NIFTP is noninvasive by definition

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features.

Strict criteria are required for this designation.

The source describes essentially absent recurrence or metastatic risk in correctly defined lesions.

Intact boundary

Encapsulated noninvasive pattern — schematic

Slide 39 · Invasive encapsulated FV-PTC breaches boundaries

Capsular, vascular or intrathyroidal invasion indicates invasive disease.

This category differs from NIFTP despite similar papillary-type nuclei.

Invasive follicular-patterned tumors may disseminate hematogenously.

Breach in capsule / vessel → invasion

Invasion concept — schematic

Slide 40 · Follicular-patterned tumors: Boundary assessment

Entity

Nuclear appearance

Invasion

Follicular adenoma

Lacks PTC-type nuclei

Absent

NIFTP

PTC-like nuclear changes

Absent; strict criteria apply

Invasive encapsulated FV-PTC

PTC-like nuclear changes

Capsular / vascular / intrathyroidal

Follicular carcinoma

Lacks classic PTC-type nuclei

Capsular and/or vascular

Slide 41 · Most patients present with a thyroid nodule

Conventional PTC is often asymptomatic at discovery.

The lesion may be found during examination or neck imaging.

Clinical palpation alone cannot reliably label the nodule benign or malignant.

Slide 42 · A cervical lymph node can be the first clue

PTC sometimes declares itself through regional lymph node enlargement.

The thyroid primary may be clinically inconspicuous.

Node pathology must be interpreted alongside thyroid examination.

Primary thyroid tumor

Lymphatic invasion

Cervical lymph node

Common route in conventional PTC

Slide 43 · Movement with swallowing is not a benign sign

Many PTC nodules move with the thyroid during deglutition.

This finding establishes thyroid attachment rather than histologic behavior.

Benign and malignant nodules may be indistinguishable clinically.

Slide 44 · Compressive symptoms raise concern for advanced disease

Hoarseness may signal involvement of nearby vocal structures.

Dysphagia suggests disturbance of swallowing structures.

Cough or dyspnea can occur in locally advanced neck disease.

Slide 45 · Nodule assessment combines function and morphology

Recognize nodule

Assess thyroid function

Fine-needle aspiration

Cytologic interpretation

Scintigraphy is generally reserved for low TSH; Structural and cytologic findings carry the malignant/benign assessment.

Conceptual mechanism — editable schematic

Slide 46 · Fine-needle aspiration evaluates cell morphology

FNA is a major tool to separate benign from malignant thyroid nodules.

Papillary cellular arrangements can appear in aspirates.

Nuclear clearing, grooves and pseudoinclusions guide interpretation.

Clearing • groove • pseudoinclusion

Schematic cell nuclei — not histology

Slide 47 · Fine-needle aspirates can reveal stromal clues

Psammoma bodies support the diagnosis of PTC.

Papillary fragments may accompany the nuclear features.

Sampling variation makes pattern recognition more reliable than a single clue.

Slide 48 · TSH determines whether scintigraphy is informative

The source generally reserves scintigraphy for a low TSH concentration.

Functioning “hot” nodules produce excess thyroid hormone.

PTCs are usually nonfunctioning (“cold”) lesions.

Low TSH

Consider thyroid scintigraphy

Source-based diagnostic principle, not full algorithm

Slide 49 · Cold versus hot nodules

Scintigraphic finding

Interpretation

Malignancy implication

Cold

Reduced tracer uptake

PTC usually appears cold

Hot

Excess thyroid hormone production

Hot nodules are almost never malignant

Slide 50 · Molecular testing complements indeterminate cytology

Not every aspiration is unequivocally benign or malignant.

Ancillary molecular diagnostics can help resolve indeterminate cases.

Results must be integrated with cytology, not viewed in isolation.

Thyroid nodule

TSH assessment

FNA cytology

Morphology ± molecular testing

Simplified diagnostic elements, not a complete guideline

Slide 51 · Clinical decisions should integrate multiple domains

Clinical symptoms and examination define immediate concerns.

TSH/scintigraphy provide functional context when relevant.

FNA supplies morphologic evidence; Molecular assays may clarify ambiguity.

Extent and recurrence risk inform treatment selection.

Slide 52 · The overall prognosis of PTC is excellent

10-year survival exceeding 95%.

Excellent disease-specific outcomes coexist with frequent nodal spread.

Prognosis is heterogeneous and depends on stage and other risk factors.

Slide 53 · Recurrence is distinct from disease-specific survival

Local or regional recurrence occurs in approximately 5%–20% in the source.

A patient may experience recurrence despite an excellent long-term survival outlook.

Risk-based follow-up is therefore clinically meaningful.

Slide 54 · Distant metastases are less frequent but important

Distant metastatic disease in 10%–15% of patients.

Distant spread contributes importantly to stage and prognosis.

The lungs are a recognized distant metastatic site in thyroid carcinoma.

Slide 55 · Prognostic variables emphasized by Robbins

Factor

Direction of concern

Reason for importance

Age older than 55 years

Less favorable prognosis

Patient-level risk context

Extrathyroidal extension

Adverse

Local anatomical spread

Distant metastases

Adverse

Advanced stage / systemic disease

Recurrence-risk profile

Guides management intensity

Selection of surgery ± radioiodine

Slide 56 · Recurrence risk drives treatment intensity

Some favorable-risk tumors have excellent outcomes after lobectomy alone.

Higher-risk cases may require total thyroidectomy followed by radioiodine.

Surgery must balance oncologic control against endocrine and nerve injury.

Low recurrence risk

Lobectomy may suffice

Higher recurrence risk

Total thyroidectomy ± radioiodine

Conceptual risk-adapted strategy; Not a guideline algorithm

Slide 57 · Thyroid-sparing surgery has functional benefits

Preserving thyroid tissue may preserve endogenous hormone production.

Less extensive surgery may lower some treatment-associated harms.

Recurrent laryngeal nerve injury can produce vocal cord palsy.

Slide 58 · Radioiodine is selected according to recurrence risk

Radioiodine ablation following total thyroidectomy in higher-risk PTC.

It is not presented as mandatory for all PTCs.

Treatment choices require individual risk assessment beyond morphology alone.

Slide 59 · Papillary versus medullary thyroid carcinoma

Feature

Papillary carcinoma

Medullary carcinoma

Cell of origin

Follicular epithelium

Parafollicular C cell

Microscopic hallmark

PTC-type nuclei ± papillae

Neuroendocrine cells; stromal amyloid

Typical molecular change

BRAF V600E; kinase fusions

RET activating point mutations

Serum marker

Thyroglobulin in post-thyroidectomy context

Calcitonin; CEA

Slide 60 · Conventional PTC versus aggressive thyroid cancers

Dimension

Conventional PTC

High-grade / anaplastic

Differentiation

Usually well differentiated

High-grade or undifferentiated

Architecture

Papillae; defining nuclei

Necrosis / mitoses; solid or pleomorphic

Molecular setting

BRAF and kinase fusions

Additional TP53 / TERT promoter hits

Clinical course

Frequently favorable

Greater aggressiveness

Slide 61 · Clinical reasoning exercise: A cervical node

A hypothetical 37-year-old has a painless thyroid nodule and an enlarged ipsilateral cervical lymph node. Cytology from the thyroid shows crowded pale nuclei with grooves and pseudoinclusions.

Interpretation task

Which thyroid neoplasm is most likely?

Which dissemination route best explains the cervical node?

Slide 62 · Interpretation: Nuclear phenotype plus lymphatic spread

Papillary thyroid carcinoma is favored by the combined nuclear features.

Lymphatic dissemination provides a coherent explanation for cervical nodal disease.

Neither the nodule’s mobility nor nodal involvement alone establishes prognosis.

Slide 63 · Clinical reasoning exercise: Follicular pattern

A hypothetical encapsulated follicular-patterned thyroid lesion has enlarged pale nuclei with grooves. Extensive histologic sampling shows no capsular, vascular or intrathyroidal invasion.

Interpretation task

Why does conventional papillary architecture not apply?

Which noninvasive category should be considered if strict criteria are satisfied?

Slide 64 · Interpretation: Distinguish noninvasive follicular tumors

PTC-type nuclei can occur in an entirely follicular growth pattern.

If strict requirements are met, the noninvasive lesion is designated NIFTP.

Capsular, vascular or intrathyroidal invasion instead supports invasive encapsulated FV-PTC.

Slide 65 · Integrative pathology summary

Conventional PTC is defined by papillary architecture and a distinctive nuclear phenotype.

BRAF V600E and kinase fusions converge on oncogenic growth signaling.

Lymphatic dissemination and cervical nodal disease are common.

Excellent overall prognosis requires stage- and risk-aware interpretation.

Slide 66 · Primary reading and source scope

Core textbook

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th ed. (2026).

Chapter 24, The Endocrine System — Thyroid carcinomas and Papillary carcinoma.

Main lesion: printed pages 989–990. Molecular parent context and adjacent differential material: pages 988–992.

Illustrations throughout this lecture are native-editable conceptual schematics, not diagnostic photomicrographs.