Follicular Carcinoma

Slide 1 · Follicular Carcinoma

Thyroid pathology: molecular context, invasive morphology and clinical correlation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain the morphologic basis for diagnosing follicular carcinoma.

Relate RAS-pathway alterations to follicular differentiation.

Distinguish follicular carcinoma from adenoma and follicular-patterned PTC.

Connect vascular invasion to spread, prognosis, and follow-up.

Molecular context

Tumor architecture

Capsular / venous invasion

Clinical consequences

Schematic

Slide 3 · The decisive distinction is invasion

Follicular carcinoma may closely resemble a benign follicular adenoma.

The malignant diagnosis requires capsular and/or vascular invasion.

Cytologic blandness and follicular formation do not exclude carcinoma.

Capsule crossed

Follicular tumor

Fibrous capsule

Schematic—capsular interface, not a histologic section

Slide 4 · A follicular-cell–derived malignancy

Follicular carcinoma arises from thyroid follicular epithelial cells.

It is generally a well-differentiated thyroid malignancy.

Tumor cells often retain follicles and colloid production.

Colloid-containing follicles (native schematic)

Schematic—not an H&E photomicrograph

Slide 5 · Position among major thyroid cancers

Papillary carcinoma is the predominant follicular-cell–derived thyroid cancer.

Follicular carcinoma represents a smaller but important subset.

Medullary carcinoma originates from parafollicular C cells—not follicular cells.

Thyroid malignancy

Follicular-cell lineage

C-cell lineage

Papillary and follicular

Medullary

Schematic

Slide 6 · Frequency varies with iodine nutrition

Follicular carcinoma accounts for 5%–15% of primary thyroid cancers.

In iodine-deficient settings, it may account for 25%–40%.

These percentages describe different populations, not competing estimates.

Share of primary thyroid cancers

General setting

5%–15%

Iodine-deficient setting

25%–40%

Bars are illustrative; Labels give source-reported ranges

Conceptual display; Numeric estimates where shown

Slide 7 · Age at presentation

Follicular carcinoma generally presents later than papillary carcinoma.

Peak incidence in the source is 40–60 years.

Age is a clinical context clue, not a diagnostic criterion.

Peak occurrence

40–60 years

Age profile differs from papillary carcinoma

Conceptual display; Numeric estimates where shown

Slide 8 · Iodine deficiency: Population association

Dietary iodine deficiency and associated goiter correlate with more follicular neoplasms.

The association is epidemiologic; An individual nodule still requires morphologic diagnosis.

Do not infer histologic malignancy solely from geographic exposure.

FNA: Follicular cells

Invasion not represented

Surgical tissue / capsule

Assess capsule + veins

Schematic

Slide 9 · The relevant follicular-neoplasm spectrum

Follicular adenoma is benign despite a clonal follicular proliferation.

Follicular carcinoma may show the same architecture but invades capsule and/or vessels.

Follicular-patterned lesions with papillary-type nuclei require a separate classification pathway.

Noninvasive follicular tumor

Capsular ± vascular invasion

Infiltration beyond capsule

Illustrative progression of invasive extent; Not inevitable tumor evolution

Slide 10 · Molecular drivers: Signaling pathways

Follicular-derived thyroid tumors often alter growth signaling pathways.

Follicular neoplasms particularly involve RAS-associated signaling.

Molecular alterations help explain biology but do not replace invasion assessment.

RAS activation

MAPK signaling

PI3K / AKT

Growth and differentiation

Schematic—simplified pathway relationships

Slide 11 · RAS mutations in follicular neoplasms

Gain-of-function RAS alterations occur in follicular adenomas and carcinomas.

RAS mutations occur in up to 50% of these lesions overall.

Shared driver mutations limit their specificity for a benign-versus-malignant distinction.

RAS activation

MAPK signaling

PI3K / AKT

Growth and differentiation

Schematic—simplified pathway relationships

Slide 12 · RAS-associated differentiated phenotype

RAS-mutated follicular neoplasms retain thyroid differentiation markers.

Examples include thyroglobulin and thyroid peroxidase.

Retention may contribute to histology that resembles normal follicles.

Colloid-containing follicles (native schematic)

Schematic—not an H&E photomicrograph

Slide 13 · PAX8::PPARG fusion

A subset of follicular neoplasms has t(2;3)(q13;p25).

The rearrangement joins PAX8 and PPARG gene regions.

PAX8 relates to thyroid development; PPARG encodes a nuclear hormone receptor.

Chromosomes 2 and 3

PAX8::PPARG fusion

Follicular-neoplasm subset

Schematic—simplified pathway relationships

Slide 14 · PI3K-pathway alterations

Up to 10% of follicular carcinomas harbor PIK3CA activation or PTEN loss.

PTEN is a negative regulator of PI3K-pathway signaling.

Changes in this axis favor proliferative and survival signaling.

PIK3CA gain of function

PTEN loss of function

PI3K → AKT axis

Proliferation / survival

Schematic—simplified pathway relationships

Slide 15 · Genetic overlap with follicular adenoma

Finding

Adenoma

Carcinoma

Follicular architecture

Often

Often

RAS alteration

Possible

Possible

PAX8::PPARG fusion

Subset

Subset

Capsular / vascular invasion

Absent

Present

RAS and PAX8::PPARG alterations occur in follicular neoplasms, not solely carcinomas.

Follicular adenomas generally are not regarded as obligatory carcinoma precursors.

A subset may share a biological lineage; This remains an inference, not a required sequence.

Slide 16 · Why the genotype cannot establish carcinoma

A molecular result may help characterize follicular lineage or neoplastic risk.

It does not visualize histologic penetration of a capsule or vessel.

The definitive adenoma–carcinoma distinction remains a tissue-based assessment.

Follicular neoplasm

Evaluate nuclear phenotype

Assess capsule + veins

Diagnose from proven invasion

Schematic

Slide 17 · Gross presentation: Usually solitary

The typical lesion is a solitary thyroid nodule.

Some tumors are sharply circumscribed; Others infiltrate widely.

Clinical palpation or gross inspection may not separate adenoma from carcinoma.

Original gross-cut schematic: Tan nodule with follicles

Schematic—not an authentic surgical specimen

Slide 18 · Well-demarcated carcinoma can mimic adenoma

A circumscribed carcinoma may appear encapsulated and benign.

The capsule must be examined histologically for microscopic invasion.

This explains why gross appearance alone cannot establish tumor behavior.

Follicular tumor

Fibrous capsule

Schematic—capsular interface, not a histologic section

Slide 19 · Widely infiltrative gross pattern

More extensive tumors can extend through the capsule.

They may penetrate adjacent thyroid and infiltrate soft tissues of the neck.

Macroscopic invasion can make the malignant nature apparent.

Grossly infiltrative extension

Follicular tumor

Fibrous capsule

Schematic—capsular interface, not a histologic section

Slide 20 · Cut surface reflects retained follicles

Follicular carcinoma is commonly gray, tan, or pink on cut section.

Colloid-containing follicles can make tissue appear translucent.

Colour or translucency does not determine whether invasion is present.

Original gross-cut schematic: Tan nodule with follicles

Schematic—not an authentic surgical specimen

Slide 21 · Secondary gross changes

Central fibrosis and coarse calcification can occur.

Degenerative changes may modify an otherwise follicular cut surface.

These changes are ancillary rather than defining carcinoma criteria.

Original gross-cut schematic: Tan nodule with follicles

Schematic—not an authentic surgical specimen

Slide 22 · Follicular microarchitecture

Most tumors comprise relatively uniform epithelial cells.

Cells organize into small follicles with variably recognizable colloid.

At routine magnification, this may closely resemble native thyroid.

Colloid-containing follicles (native schematic)

Schematic—not an H&E photomicrograph

Slide 23 · Colloid does not imply benign behavior

Some malignant follicles retain colloid-filled lumens.

Well-differentiated structure can coexist with true invasion.

Assess architecture and the tumor–host interface, not colloid alone.

Colloid-containing follicles (native schematic)

Schematic—not an H&E photomicrograph

Slide 24 · Uniform nuclei are compatible with carcinoma

Cells can be cytologically bland with minimal pleomorphism.

Follicular carcinoma lacks the characteristic nuclei of papillary carcinoma.

An apparently bland aspirate therefore cannot exclude follicular carcinoma.

Uniform follicular cells ≠ absence of invasion

Schematic—not an H&E photomicrograph

Slide 25 · Features absent in conventional follicular carcinoma

Feature

Follicular carcinoma

Papillary carcinoma

Follicular growth

Usually present

Possible

PTC-type nuclei

Absent

Defining

Psammoma bodies

Absent

May occur

Typical spread

Hematogenous

Lymphatic

Typical papillary-type nuclear clearing, grooves, and pseudoinclusions are absent.

Psammoma bodies are not a usual feature of follicular carcinoma.

If papillary-type nuclei are present, reconsider classification.

Slide 26 · Oncocytic morphology requires recognition

A subset of follicular-derived carcinomas contains abundant granular eosinophilic cytoplasm.

This oncocytic morphology alongside follicular carcinoma.

The invasive interface remains important; Oncocytic appearance alone is not proof of carcinoma.

Colloid-containing follicles (native schematic)

Schematic—not an H&E photomicrograph

Slide 27 · Two morphologic routes to malignant diagnosis

Evidence of capsular invasion can establish carcinoma.

Evidence of vascular invasion can independently establish carcinoma.

Widely invasive tumors are usually evident through destructive tissue infiltration.

Nuclear phenotype

No PTC-like nuclei

PTC-like nuclei

Check invasion

Check invasion

Adenoma / carcinoma

NIFTP / invasive FV-PTC

Schematic

Slide 28 · Intact capsule: A benign pattern

Adenoma has a circumferential fibrous capsule without tumor penetration.

Compressed non-neoplastic follicles can lie outside the capsule.

Careful orientation is essential to interpret the interface.

Follicular tumor

Fibrous capsule

Schematic—capsular interface, not a histologic section

Slide 29 · Capsular invasion: Tumor crossing the boundary

Tumor penetrates through the capsule into tissue beyond its outer boundary.

A small focus may be the only malignant feature.

The pathologist must evaluate the full capsule interface.

Capsule crossed

Follicular tumor

Fibrous capsule

Schematic—capsular interface, not a histologic section

Slide 30 · Why partial protrusion needs caution

A focus near the outer capsule contour may be difficult to orient.

Limited sections can obscure whether invasion is complete.

When uncertain, more complete capsule sampling can clarify the interface.

Indeterminate contour

Follicular tumor

Fibrous capsule

Schematic—capsular interface, not a histologic section

Slide 31 · Vascular invasion: A second decisive route

Vascular invasion occurs in venous channels.

Relevant vessels lie within the capsule or just beyond it.

Intravenous tumor provides an anatomic route for distant metastasis.

Capsule-associated vein

Tumor within lumen

Blood-vessel wall

Schematic—venous invasion; Not a micrograph

Slide 32 · Vascular invasion is not simple congestion

A vessel must contain neoplastic tissue, not only erythrocytes.

The tissue relationship to a bona fide venous lumen must be interpretable.

Indeterminate artifacts should not be overcalled as definite invasion.

Capsule-associated vein

Tumor within lumen

Blood-vessel wall

Schematic—venous invasion; Not a micrograph

Slide 33 · Why the capsule needs extensive sampling

Microscopic invasion may be focal despite an otherwise complete capsule.

A few representative sections may miss the diagnostic focus.

Histology must sample enough of the tumor–capsule interface to assess invasion.

Serial blocks evaluate the interface

Schematic—capsule sampling, not a universal block count

Slide 34 · Sampling begins with correct orientation

Examine the relationship among tumor, fibrous capsule, and surrounding thyroid.

Direct attention to suspicious breaks, protrusions, and capsule-associated vessels.

Preserve the spatial relationship in histologic sections.

Serial blocks evaluate the interface

Schematic—capsule sampling, not a universal block count

Slide 35 · Widely invasive carcinoma

Invasion into native thyroid parenchyma can be conspicuous.

Extrathyroidal soft tissue extension indicates local infiltrative behavior.

This morphology contrasts with a solitary focal microscopic invasion.

Grossly infiltrative extension

Follicular tumor

Fibrous capsule

Schematic—capsular interface, not a histologic section

Slide 36 · Invasion categories have prognostic meaning

Minimal invasion and widespread infiltration indicate different behaviors.

The extent of invasion is central to prognosis.

Report the observed pattern rather than relying on bland-looking cells.

Noninvasive follicular tumor

Capsular ± vascular invasion

Infiltration beyond capsule

Illustrative progression of invasive extent; Not inevitable tumor evolution

Slide 37 · A practical histology decision sequence

First establish a follicular-patterned neoplasm and examine the nuclear phenotype.

Then assess the complete relevant capsule and vascular interface.

Definite capsular/vascular invasion supports follicular carcinoma if PTC-type nuclei are absent.

Follicular neoplasm

Evaluate nuclear phenotype

Assess capsule + veins

Diagnose from proven invasion

Schematic

Slide 38 · Fine-needle aspiration cannot assess the capsule

An aspirate samples cells, not the entire tumor–capsule boundary.

Adenoma and minimally invasive follicular carcinoma share cytologic appearances.

A follicular-patterned aspirate may therefore remain indeterminate for malignancy.

FNA: Follicular cells

Invasion not represented

Surgical tissue / capsule

Assess capsule + veins

Schematic

Slide 39 · Why benign-appearing cells are insufficient

A cytology slide may demonstrate orderly follicular epithelial groups.

Neither the presence nor absence of capsular penetration is visible.

The diagnostic question is fundamentally architectural and invasive.

Uniform follicular cells ≠ absence of invasion

Schematic—not an H&E photomicrograph

Slide 40 · Molecular testing: Informative but limited

Molecular analysis may assist assessment of indeterminate thyroid nodules.

RAS positivity can occur in both adenoma and follicular carcinoma.

Do not label a cytologic sample carcinoma based on a shared driver alone.

Chromosomes 2 and 3

PAX8::PPARG fusion

Follicular-neoplasm subset

Schematic—simplified pathway relationships

Slide 41 · Distinguish papillary nuclear phenotype

Nuclear feature

Follicular carcinoma

PTC

Optically clear chromatin

Not typical

Characteristic

Nuclear grooves

Not typical

Common

Pseudoinclusions

Not typical

Can occur

Psammoma bodies

Absent

May occur

Conventional PTC exhibits chromatin clearing, nuclear grooves, and pseudoinclusions.

Follicular carcinoma lacks these characteristic nuclear changes.

The differential hinges on nuclear phenotype and invasion pattern.

Slide 42 · Growth pattern alone does not define PTC

Follicular growth is shared by carcinoma, adenoma, and follicular-patterned PTC.

Papillary carcinoma can adopt predominantly follicular architecture.

Nuclear findings are essential to the distinction.

Thyroid malignancy

Follicular-cell lineage

C-cell lineage

Papillary and follicular

Medullary

Schematic

Slide 43 · NIFTP: Noninvasive, but papillary-like nuclei

NIFTP shows follicular growth with PTC-like nuclear features.

Strictly noninvasive lesions meet distinct diagnostic criteria.

Its very low recurrence/metastatic risk supports the non-carcinoma designation.

Follicular tumor

Fibrous capsule

Schematic—capsular interface, not a histologic section

Slide 44 · Invasive encapsulated follicular variant of PTC

Follicular growth and papillary-type nuclei can coexist with invasion.

Invasive encapsulated follicular variant of PTC is distinguished from NIFTP by invasion.

RAS-like biology and hematogenous spread may overlap with follicular carcinoma.

Capsule crossed

Follicular tumor

Fibrous capsule

Schematic—capsular interface, not a histologic section

Slide 45 · A two-axis classification framework

First axis: Follicular carcinoma nuclei versus PTC-like nuclear features.

Second axis: No demonstrated invasion versus proven invasion.

The combination directs classification, not follicular pattern alone.

Nuclear phenotype

No PTC-like nuclei

PTC-like nuclei

Check invasion

Check invasion

Adenoma / carcinoma

NIFTP / invasive FV-PTC

Schematic

Slide 46 · Core differential diagnoses

Entity

PTC-like nuclei

Invasion

Follicular adenoma

Absent

Absent

Follicular carcinoma

Absent

Present

NIFTP

Present

Absent (strict criteria)

Invasive encapsulated FV-PTC

Present

Present

Follicular adenoma: No capsular or vascular invasion.

Follicular carcinoma: Invasive lesion without typical PTC-type nuclear features.

NIFTP or invasive encapsulated follicular variant PTC: Follicular growth plus PTC-type nuclei.

Slide 47 · Why lymph nodes are usually not involved

Follicular carcinoma has relatively little tendency to enter lymphatic channels.

Cervical nodal metastases are therefore less typical than in papillary carcinoma.

Absence of involved nodes does not imply absence of systemic spread.

Thyroid follicular carcinoma

Venous invasion → bloodstream

Distant organ deposits

Schematic—hematogenous route; Not a measured risk model

Slide 48 · Hematogenous dissemination

Vascular invasion enables venous access by malignant follicular cells.

Tumor cells may travel through the bloodstream to distant tissues.

This is the characteristic metastatic pathway emphasized in the source.

Thyroid follicular carcinoma

Venous invasion → bloodstream

Distant organ deposits

Schematic—hematogenous route; Not a measured risk model

Slide 49 · Common distant metastatic sites

Bone and lungs are important metastatic destinations.

Liver and brain may also be involved.

These sites reflect a systemic route of dissemination.

Thyroid follicular carcinoma

Venous invasion → bloodstream

Bone

Lung

Liver

Brain

Schematic—hematogenous route; Not a measured risk model

Slide 50 · Compare dissemination with papillary carcinoma

Feature

Follicular

Papillary

Route emphasized

Hematogenous

Lymphatic

Regional nodes

Typically spared

Often involved

Distant spread

Bone / lung etc.

May occur

Nuclear morphology

No PTC nuclei

PTC nuclei

Papillary thyroid carcinoma often exhibits lymphatic invasion and cervical nodal deposits.

Follicular carcinoma more characteristically spreads through blood vessels.

The patterns overlap; They are tendencies, not absolute prohibitions.

Slide 51 · Typical clinical presentation

The nodule is usually painless and slowly enlarging.

Local examination may not reveal benign versus malignant histology.

Asymptomatic disease is entirely possible.

Original gross-cut schematic: Tan nodule with follicles

Schematic—not an authentic surgical specimen

Slide 52 · Thyroid scintigraphy: Often a cold nodule

Most follicular carcinomas appear nonfunctioning (“cold”) on scintigraphy.

Cold status does not establish carcinoma—it identifies functional behavior.

Morphologic evidence remains required for definitive classification.

Nonfunctioning / cold: Usual

Warm / functioning: Very rare

Conceptual display; Numeric estimates where shown

Slide 53 · Rare functioning follicular carcinomas

Better-differentiated lesions can very rarely be hyperfunctional.

Such tumors may concentrate radioiodine and appear warm.

Functional activity should not be used as an absolute benignity rule.

Nonfunctioning / cold: Usual

Warm / functioning: Very rare

Conceptual display; Numeric estimates where shown

Slide 54 · Imaging and cytology answer different questions

Scintigraphy characterizes thyroid nodule function.

FNA examines sampled cellular morphology.

Histology of the interface establishes capsular or vascular invasion.

Scintigraphy → function

FNA → cytology

Resection → interface

Histology → invasion

Schematic

Slide 55 · What determines prognosis?

Extent of invasion is an important prognostic determinant.

Stage at presentation, particularly systemic metastasis, is crucial.

Do not infer risk from a single bland cytology field.

Minimally invasive

10-year survival >90%

Widely invasive

Up to half die within 10 years

Conceptual display; Numeric estimates where shown

Slide 56 · Minimally invasive carcinoma: Favorable prognosis

Ten-year survival exceeds 90% estimate.

This estimate pertains to minimally invasive disease.

It must not be generalized to widely invasive tumors.

Minimally invasive

10-year survival >90%

Widely invasive

Up to half die within 10 years

Conceptual display; Numeric estimates where shown

Slide 57 · Widely invasive carcinoma: A different course

Widely invasive tumors often present with distant metastases.

As many as one-half die of disease within 10 years.

These figures reflect a high-risk subgroup, not all follicular carcinomas.

Minimally invasive

10-year survival >90%

Widely invasive

Up to half die within 10 years

Conceptual display; Numeric estimates where shown

Slide 58 · Avoid mixing prognosis measures

Clinical setting

10-year statement in source

Interpretation

Minimally invasive

>90% survival

Favorable subgroup

Widely invasive

Up to 50% death

High-risk subgroup

“Survival over 90%” and “up to half die” refer to different invasion groups.

Their denominators and clinical populations are not interchangeable.

A pathology report should communicate the invasion findings underpinning risk.

Slide 59 · Surgery is the treatment foundation

Most cases in the source are managed by thyroidectomy, tailored to risk.

Selected minimally invasive carcinomas have sufficiently low recurrence risk for less aggressive management.

Surgical extent should not be decided from this deck alone.

Pathologic risk assessment

Surgery for local control

Selected radioactive iodine

TSH suppression / follow-up

Schematic

Slide 60 · Radioactive iodine: Selected patients

After thyroidectomy, radioactive iodine may reveal metastatic disease.

It can also ablate radioiodine-avid residual deposits.

Use is risk-dependent and is not implied for every minimally invasive tumor.

Pathologic risk assessment

Surgery for local control

Selected radioactive iodine

TSH suppression / follow-up

Schematic

Slide 61 · TSH suppression addresses stimulation

Residual differentiated follicular carcinoma may respond to TSH.

Thyroid hormone treatment can suppress endogenous TSH after surgery.

The therapeutic rationale is reduced trophic stimulation of residual cells.

Pathologic risk assessment

Surgery for local control

Selected radioactive iodine

TSH suppression / follow-up

Schematic

Slide 62 · Thyroglobulin in postoperative surveillance

Thyroglobulin reflects thyroid follicular-cell differentiation.

Following total thyroidectomy, a disease-free patient is expected to have very low thyroglobulin.

Interpret surveillance in the context of treatment and clinical evaluation.

Thyroidectomy

Assess thyroid differentiation

Serial thyroglobulin context

Investigate suspected recurrence

Schematic

Slide 63 · Case 1 — a follicular aspirate

A patient has a slowly enlarging, nonfunctioning thyroid nodule.

FNA shows uniform follicular cells without PTC-type nuclei.

Question: Can carcinoma be confirmed from this aspirate?

What is the decisive next inference?

Identify the finding that changes classification

Hypothetical educational case; No patient data

Slide 64 · Case 1 — the missing information

No: Cytology cannot establish the tumor–capsule interface.

Adenoma and minimally invasive carcinoma may have indistinguishable aspirates.

Tissue evaluation for capsular and vascular invasion is required.

FNA: Follicular cells

Invasion not represented

Surgical tissue / capsule

Assess capsule + veins

Schematic

Slide 65 · Case 2 — one microscopic breach

An encapsulated follicular tumor has one confirmed focus crossing its capsule.

Cells elsewhere look uniform and colloid-rich.

Question: What makes this lesion malignant?

What is the decisive next inference?

Identify the finding that changes classification

Hypothetical educational case; No patient data

Slide 66 · Case 2 — invasion overrides bland cytology

Demonstrated capsular invasion establishes malignant behavior.

The bland follicular architecture does not negate invasion.

Document the location and extent of the confirmed invasive focus.

Capsule crossed

Follicular tumor

Fibrous capsule

Schematic—capsular interface, not a histologic section

Slide 67 · Case 3 — a bone lesion years later

A treated patient develops a destructive bone lesion compatible with thyroid origin.

A history of follicular carcinoma makes hematogenous spread biologically plausible.

Question: Which initial histologic feature explains that route?

What is the decisive next inference?

Identify the finding that changes classification

Hypothetical educational case; No patient data

Slide 68 · Case 3 — venous invasion links pathology to spread

Neoplastic entry into venous vessels enables distant dissemination.

Bone and lung are characteristic systemic metastatic destinations.

Regional lymph-node sparing cannot exclude distant involvement.

Thyroid follicular carcinoma

Venous invasion → bloodstream

Bone

Lung

Liver

Brain

Schematic—hematogenous route; Not a measured risk model

Slide 69 · Integrated diagnostic synthesis

Recognize follicular growth and evaluate nuclear phenotype.

Sample the capsule and associated veins for definite invasion.

Combine observed invasion, local extension, and stage for risk communication.

Follicular nodule

Evaluate PTC-like nuclei

Sample capsule and veins

Classify invasion + extent

Schematic

Slide 70 · Five points to retain

Follicular carcinoma is diagnosed by invasion, not by bland follicular cytology.

RAS-related molecular overlap does not prove malignant behavior.

Capsular and venous interfaces require extensive sampling.

Hematogenous spread, especially to bone or lung, is characteristic.

Invasion extent and stage strongly influence prognosis.

Molecular context

Tumor architecture

Capsular / venous invasion

Clinical consequences

Schematic