Melanocytic Nevus Pigmented Nevus Mole

Slide 1 · Melanocytic Nevus

Pigmented nevus (mole)

Pathogenesis • Morphology • Diagnostic interpretation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain why nevi are benign melanocytic neoplasms despite oncogenic pathway activation.

Recognize junctional, compound, and intradermal growth patterns.

Describe maturation with depth and its diagnostic significance.

Compare representative nevus variants and distinguish risk markers from ordinary nevi.

Slide 3 · The essential definition of a melanocytic nevus

A common benign neoplasm of melanocytic lineage.

Usually associated with acquired activating mutations in RAS-pathway components.

Encompasses clinically and histologically diverse lesions rather than one uniform appearance.

The ordinary acquired nevus is the most frequent form.

Slide 4 · Pigmentation is not synonymous with a nevus

Pigmented skin lesion

Melanocytic nevus

Describes color, not its cause.

May reflect pigment within keratinocytes.

Requires an architectural diagnosis.

Benign melanocytic neoplasm.

Nevus-cell aggregates or nests.

May show junctional and/or dermal components.

Slide 5 · Why nevi are considered neoplastic

Many harbor acquired mutations that constitutively stimulate RAS or BRAF.

Clonal signaling activation provides a proliferative stimulus.

Their benignity reflects subsequent growth restraint, not absence of oncogenic signaling.

Morphology remains essential; A mutation alone does not establish melanoma.

Slide 6 · Ordinary acquired nevi are ubiquitous

The usual acquired melanocytic nevus is extremely common.

Most individuals have at least a few moles.

Routine nevi are generally small and clinically regular.

Biologic diversity becomes important when assessing an atypical lesion.

Slide 7 · The core biologic paradox

Activated RAS / BRAF

Transient nevus-cell proliferation

P16-associated cell-cycle arrest

Benign stable nevus

An oncogenic driver may initiate a lesion without producing sustained malignant growth.

Slide 8 · RAS-pathway activation initiates nevus formation

The RAS signaling pathway is a frequent molecular target in acquired nevi.

Activating mutations sustain signaling in affected melanocytes.

The signal initially drives a limited proliferative phase.

A built-in antiproliferative response subsequently constrains lesion growth.

Slide 9 · BRAF lies immediately downstream of RAS

RAS signaling

BRAF kinase

Melanocyte proliferation

The source identifies BRAF as a serine/threonine kinase immediately downstream of RAS.

Slide 10 · Activated signaling: Driver versus phenotype

Genetic event

Observed phenotype

Acquired activating mutation.

RAS or BRAF can signal constitutively.

Provides proliferative drive.

Growth does not continue indefinitely.

Most lesions remain benign.

Growth arrest changes the biological outcome.

Slide 11 · Oncogene-induced senescence

Activated RAS or BRAF stimulates a limited proliferative interval.

The same stimulus is followed by a relatively permanent growth arrest.

This as oncogene-induced senescence.

The response helps explain why ordinary nevi rarely become melanoma.

Slide 12 · P16 constrains the cell cycle

Oncogenic RAS / BRAF stimulus

Accumulation of p16

Inhibition of CDK4 and CDK6

Growth arrest

The source specifies p16 as an inhibitor of cyclin-dependent kinases, including CDK4 and CDK6.

Slide 13 · The role of p16

P16 is a cell-cycle inhibitor that contributes to nevus-cell growth arrest.

Its accumulation follows ectopic or acquired activation of RAS/BRAF signaling.

By inhibiting CDK4/CDK6, p16 counteracts proliferative drive.

This is a protective barrier, not an assurance that progression is impossible.

Slide 14 · Why most nevi do not progress

Initiating signal

Progression restraint

Mutations promote proliferation.

Constitutive RAS/BRAF activity.

Can occur in benign nevi.

P16 rises.

Senescence interrupts cell cycling.

Further alteration is needed to escape restraint.

Slide 15 · Melanoma disrupts this protective restraint

Senescence disruption in melanoma and some precursor lesions.

Loss of the growth barrier permits continued expansion.

A shared initiating driver does not imply equivalent biological behavior.

Interpret mutation findings in their morphological and clinical context.

Slide 16 · Molecular-to-morphologic integration

Oncogenic initiation

Benign expansion

Senescence / maturation

Stable architectural nevus

The model links molecular arrest to the observed maturation of nevus cells with depth.

Slide 17 · What does a typical acquired nevus look like?

Usually tan to brown and relatively uniformly pigmented.

Typically small, generally less than 6 mm across.

Well-defined and rounded in outline.

May be a flat macule or elevated papule.

Slide 18 · Flat nevus: A macular phenotype

Relatively flat surface.

Uniform brown pigmentation.

Well-defined rounded border.

Schematic surface profile — not a clinical photograph

Slide 19 · Elevated nevus: A papular phenotype

Raised surface contour.

May retain pigment uniformity.

Common in later morphologic stages.

Schematic surface profile — not a clinical photograph

Slide 20 · Symmetry and pigment uniformity

Ordinary acquired nevus

Diagnostic interpretation

Often symmetric shape.

Relatively uniform pigment.

Smooth, circumscribed margin.

Consistent with a benign pattern.

Does not independently prove benignity.

Must be considered with histologic architecture.

Slide 21 · Size and border in conventional nevi

Ordinary acquired lesions are usually less than 6 mm in diameter.

A well-demarcated, rounded margin is typical.

These are descriptive tendencies rather than absolute diagnostic cutoffs.

Atypical features should trigger broader morphologic evaluation.

Slide 22 · Pregnancy-related prominence

Nevi may become more prominent during pregnancy.

This observation supports a degree of hormonal sensitivity.

Prominence alone does not establish malignant transformation.

Morphological context is more informative than isolated change.

Slide 23 · A proposed morphologic sequence

Junctional nevus

Compound nevus

Intradermal nevus

This is a typical conceptual progression, not a mandatory timeline for every lesion.

Slide 24 · Junctional nevus: The earliest common pattern

Epidermis

Dermis

Nests cluster at junction.

Dermis lacks a nevus-cell component.

Often clinically flat.

Schematic: Round nests at the dermoepidermal junction

Slide 25 · Why junctional nevi are called “junctional”

Nevus cells collect along the epidermal–dermal interface.

Rounded nests are seen near tips of rete ridges.

This distribution defines the architectural compartment.

Recognition begins at low magnification with the lesion location.

Slide 26 · Cytology of ordinary nevus cells

Nuclei tend to be uniform and rounded.

Nucleoli are generally inconspicuous.

Little or no mitotic activity is expected.

The orderly pattern complements the architectural diagnosis.

Slide 27 · Architecture and cytology are complementary

Architecture

Cytology

Junctional nests.

Symmetric lesion organization.

Subsequent dermal components in compound nevi.

Uniform rounded nuclei.

Subtle nucleoli.

Minimal mitotic activity.

Slide 28 · Compound nevus: Junctional plus dermal elements

Epidermis

Dermis

Persistent junctional nests.

Nests and cords in dermis.

Often dome-shaped and raised.

Schematic: Junctional nests coexist with dermal growth

Slide 29 · How a compound nevus forms

Nevus cells extend from the junction into the underlying dermis.

Dermal cells aggregate as nests and cords.

Some junctional nests remain visible.

The resulting lesion has two recognizable compartments.

Slide 30 · Why compound nevi tend to be elevated

Dermal cell volume adds bulk.

Surface may become dome-shaped.

Symmetry remains a useful clue.

Schematic surface profile — not a clinical photograph

Slide 31 · Compound nevus: An architectural checklist

Identify intraepidermal or junctional nevus-cell nests.

Identify dermal nests or cords beneath those nests.

Examine change in cell size and pigmentation with depth.

Assess overall organization together with bland cytology.

Slide 32 · Intradermal nevus: Epidermal nests have disappeared

Epidermis

Dermis

Nevus cells restricted to dermis.

No remaining epidermal nests.

Typically more elevated.

Schematic: Nevus cells entirely below the junction

Slide 33 · Understanding the intradermal stage

Older lesions may lose their junctional nests entirely.

Residual nevus cells are then confined to the dermis.

These lesions are termed pure intradermal nevi.

Like compound nevi, they are commonly raised.

Slide 34 · Three principal acquired nevus architectures

Type

Junctional nests

Dermal nevus cells

Clinical contour

Junctional

Present

Absent

Often relatively flat

Compound

Present

Present

Frequently elevated

Intradermal

Absent

Present

Frequently elevated

Slide 35 · Maturation with depth: A benign pattern

Superficial nevus cells tend to be larger and more pigmented.

Deeper nevus cells progressively decrease in size and pigment.

Growth shifts from nests toward cords and individual cells.

This patterned transition is characteristic of ordinary nevi.

Slide 36 · Maturation: Cell size decreases with depth

Superficial

Deep

Increasing depth

Progressive reduction in cell size supports benign nevus maturation.

Slide 37 · Maturation: Pigment production diminishes

Superficial

More melanin

Intermediate

Less melanin

Deep

Little or no pigment

Slide 38 · Maturation: Nesting shifts to cords and single cells

Superficial nests

Deeper cords

Deep single cells

Architecture changes with depth; This is a conceptual drawing, not H&E.

Slide 39 · Neurotization at the deepest aspect

Deep nevus cells may become fusiform or spindle-shaped.

They may be arranged in fascicles resembling neural tissue.

Robbins refers to this morphological pattern as neurotization.

It represents deep maturation rather than a separate neural neoplasm.

Slide 40 · Neurotization: A schematic of deep spindle-cell change

Superficial rounded nevus cells

Deep spindle-shaped fascicles

Schematic cellular transformation; Proportions are illustrative

Slide 41 · Tyrosinase activity parallels nevus-cell maturation

Tyrosinase activity decreases in progressively deeper nevus cells.

Deep nonpigmented cells often appear nerve-like.

Decreased enzyme activity correlates with reduced pigment formation.

Biochemical and microscopic maturation therefore align.

Slide 42 · Pigment and cell form: Linked changes

Superficial larger cells

Diminishing tyrosinase activity

Reduced melanin in deeper cells

Neurotized / spindle-like cells

A correlation, not proof that enzyme loss causes neurotization.

Slide 43 · Benign maturation versus failure of maturation

Typical benign nevus

Concerning interpretation

Smaller deep cells.

Reduced deep pigmentation.

Cords / single cells / neurotization.

Little or no mitotic activity.

Absent orderly maturation is a warning clue.

Evaluate architecture and cytology together.

Do not diagnose malignancy from one feature.

Escalate to full clinicopathologic assessment.

Slide 44 · What histology explains about clinical evolution

Junctional nests tend to correspond to flatter lesions.

Addition of dermal cells increases lesion bulk.

Loss of junctional nests can leave an elevated intradermal lesion.

Maturation may occur as the lesion ages.

Slide 45 · The term “nevus” covers biologic diversity

Acquired nevi are only one part of the category.

Congenital, blue, Spitz, and halo nevi show distinctive patterns.

The same clinical color may reflect different architectural forms.

Subtype recognition prevents misclassification.

Slide 46 · Congenital melanocytic nevus

Present at birth rather than newly acquired later.

Histologically may extend deeply around skin adnexa and vessels.

Lesional cells may involve deep dermis or subcutis.

Large congenital forms have increased melanoma risk.

Slide 47 · Congenital nevus: Deeper anatomic involvement

Epidermis

Dermis

Around adnexa

Around neurovascular bundles

Along vessel walls

May reach subcutis

Schematic anatomy; No specimen image used

Slide 48 · Congenital nevus: Clinical risk is size-dependent

Large congenital nevi as carrying increased melanoma risk.

The source does not supply an absolute risk percentage for this entry.

Ordinary acquired nevi should not be assigned the same risk profile.

Architecture and clinical history help distinguish congenital from acquired forms.

Slide 49 · Blue nevus: Why the lesion appears striking

The clinical lesion may be a black-blue nodule.

Dermal nevus cells can be strongly pigmented and dendritic.

Histology shows nonnested infiltration within the dermis.

Associated fibrosis is common in the source description.

Slide 50 · Blue nevus: A clinical mimic of melanoma

Blue-black nodule.

Deeply pigmented dermal cells.

May appear alarming clinically.

Schematic surface profile — not a clinical photograph

Slide 51 · Spitz nevus: Distinctive cellular morphology

Spitz nevus is a spindle and epithelioid cell nevus.

Histologic architecture may show fascicular growth.

Cells can be large and plump with pink-blue cytoplasm.

Fusiform cells may coexist with epithelioid cells.

Slide 52 · Spitz nevus: Often an erythematous nodule

Common in children.

Frequently a red-pink nodule.

Can resemble hemangioma clinically.

Schematic surface profile — not a clinical photograph

Slide 53 · Halo nevus: A host immune response

Nevus cells can be surrounded by a lymphocytic infiltrate.

The host response targets nevus cells and adjacent normal melanocytes.

Loss of surrounding pigment produces the characteristic halo phenotype.

The central nevus cells may otherwise resemble ordinary nevi.

Slide 54 · Halo nevus: Depigmentation around a central mole

Central nevus.

Pale surrounding zone.

Lymphocyte-mediated response.

Schematic surface profile — not a clinical photograph

Slide 55 · Nevus variants: Architecture and clinical clue

Variant

Distinctive histologic pattern

Practical clinical clue

Congenital

Deep periadnexal / neurovascular growth

Present at birth; Large lesions carry risk

Blue

Dendritic, pigmented cells; Dermal infiltration

Black-blue nodule

Spitz

Spindle / epithelioid cells; Fascicles

Childhood red-pink nodule

Halo

Lymphocytes around nevus cells

Depigmented surrounding halo

Slide 56 · Clinical similarity does not equal same histology

Blue nevus

Spitz nevus

Black-blue nodule.

Dendritic pigmented cells.

Diffuse nonnested dermal architecture.

Red-pink nodule.

Plump spindle / epithelioid cells.

Fascicular architecture.

Slide 57 · Dysplastic nevus: Related but distinct entity

A dysplastic nevus is not identical to an ordinary acquired nevus.

The adjacent Robbins section notes coalescent intraepidermal nests.

Cytologic atypia can be present.

Recognizing the distinction matters because dysplastic nevi mark melanoma risk.

Slide 58 · Ordinary nevus versus dysplastic nevus

Ordinary acquired nevus

Dysplastic nevus

Common symmetrical pattern.

Bland uniform nevus nuclei.

Maturation with dermal depth.

Coalescent intraepidermal nests.

Cytologic atypia.

May indicate increased melanoma risk.

Slide 59 · Risk marker versus direct precursor

Most dysplastic nevi remain clinically stable.

Some can be direct precursors of melanoma, but progression is uncommon.

Multiple dysplastic nevi may indicate a heightened melanoma risk background.

A risk marker does not imply every nevus becomes malignant.

Slide 60 · How the ordinary nevus is distinguished from melanoma

Orderly and well-circumscribed growth supports nevus architecture.

Uniform nuclear appearance and sparse mitoses are reassuring findings.

Progressive maturation with depth is a key benign pattern.

Melanoma generally lacks such characteristic maturation.

Slide 61 · Nevus–melanoma distinction: Integrated clues

Nevus-favoring

Features that warrant concern

Symmetry and uniform pigment.

Maturing cells with depth.

Small inconspicuous nucleoli.

Minimal mitoses.

Irregular overall architecture.

Failure of ordered maturation.

Marked cytologic atypia.

Proliferation incongruent with a banal nevus.

Slide 62 · Diagnostic pitfall: Overinterpreting RAS or BRAF

An activating pathway mutation is compatible with a benign nevus.

The biologic context includes p16-mediated senescence.

Mutation presence alone is not equivalent to melanoma diagnosis.

Histopathologic pattern remains the central diagnostic evidence.

Slide 63 · Diagnostic pitfall: Judging a nevus by color alone

Blue nevi can be intensely dark but benign.

Spitz nevi may be pink rather than brown.

Halo nevi may lose surrounding pigmentation.

Clinical color is insufficient to infer the underlying subtype.

Slide 64 · Diagnostic pitfall: Treating all nevus types alike

Ordinary acquired nevi are common and predominantly benign.

Large congenital nevi have a different stated risk profile.

Dysplastic nevi may mark an increased melanoma-risk background.

Clinical history and subtype should shape interpretation.

Slide 65 · A morphology-first reading sequence

Clinical contour and symmetry

Junctional versus dermal distribution

Cytologic blandness

Maturation with depth

Read the entire lesion: No single favorable feature replaces integrated assessment.

Slide 66 · Case 1 — identify the architectural nevus

A small, symmetric, flat brown macule shows round melanocyte nests limited to the dermoepidermal junction.

Junctional nevus

Compound nevus

Intradermal nevus

Slide 67 · Case 2 — explain a raised benign mole

A dome-shaped mole contains junctional nests plus cords of melanocytes in the upper dermis.

Junctional nevus

Compound nevus

Pure intradermal nevus

Slide 68 · Case 3 — interpret deep spindle-shaped cells

A dermal nevus has progressively smaller, less pigmented cells; Its deepest cells are spindle-shaped in fascicles.

Maturation and neurotization

Evidence of a neural tumor

Proof of melanoma

Slide 69 · Case 4 — a red-pink lesion in a child

A child has a red-pink skin nodule. Histology shows large epithelioid and spindle-shaped nevus cells with fascicular growth.

Spitz nevus

Blue nevus

Halo nevus

Slide 70 · Case 5 — oncogenic mutation in a benign lesion

Molecular analysis of a bland melanocytic nevus identifies an activating BRAF alteration. Which conclusion is supported?

The mutation can initiate nevus growth.

The lesion must be melanoma.

The lesion cannot undergo growth arrest.

Slide 71 · Three anchors for accurate interpretation

Biology

RAS/BRAF activation initiates growth.

P16-associated senescence restrains growth.

Mutations alone do not define melanoma.

Architecture

Junctional nests first.

Compound lesions contain dermal growth.

Older lesions may be intradermal.

Maturation

Deep cells become smaller.

Pigment and tyrosinase decline.

Neurotization may occur.

Slide 72 · Key morphologic conclusions

A nevus is a benign melanocytic neoplasm, not merely a pigmented macule.

Junctional, compound, and intradermal patterns describe cell location.

Nevus cells typically mature as they extend more deeply.

Recognize distinct variants and the separate significance of dysplastic nevi.

Slide 73 · Selected source and illustration status

Primary textbook

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026. Chapter 25: The Skin. “Melanocytic Nevus,” printed p. 1031.

Parent-context material

Table 25.2 (representative nevus variants), adjacent Dysplastic Nevi section; Freckle / Lentigo neighboring text.

Visual disclosure

All tissue, cell, and clinical morphology drawings are original native PowerPoint schematics, not specimen photographs.