Familial Tumor Syndromes

Slide 1 · Familial Tumor Syndromes

Inherited predisposition to tumors of the nervous system

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Inherited predisposition, distinctive tumor spectra

Inherited syndromes increase risk of characteristic neoplasms rather than one uniform “brain tumor.”

Tumor type and anatomic location often suggest the underlying syndrome.

Major examples in the CNS chapter: NF1, NF2, schwannomatosis, TSC and VHL.

Inherited predisposition

Syndrome-linked tissue lesions

Recognizable clinical pattern

Slide 3 · The four major clinicopathologic patterns

NF1: Neurofibromas, optic pathway gliomas and pigmentary findings.

NF2 / schwannomatosis: Schwann-cell tumors with different distributions.

TSC: Cortical and subependymal hamartomas; SEGA.

VHL: Hemangioblastomas with systemic tumor and cyst associations.

NF1

Neurofibroma + glioma

NF2 / schwannomatosis

Schwannoma pattern

TSC

Hamartoma + SEGA

VHL

Hemangioblastoma

Slide 4 · Why family history cannot be the only clue

Autosomal dominant inheritance characterizes NF1, NF2, TSC and VHL.

NF1 has high penetrance but variable expressivity; Limited distribution may reflect mosaicism.

Schwannomatosis may be familial or sporadic description.

Inherited syndrome

Variable phenotype

Mosaic presentation

Familial or sporadic pattern

Slide 5 · Genotype links to an altered cellular restraint

NF1: Loss of neurofibromin removes a restraint on RAS activation.

TSC1/TSC2: Loss of hamartin–tuberin control elevates mTOR activity.

VHL: Impaired HIF down-regulation favors angiogenic signaling.

NF2: Merlin loss affects growth, cell shape and adhesion pathways.

NF1

RAS

TSC1/TSC2

MTOR

VHL

HIF / VEGF

NF2

Merlin-regulated signaling

Slide 6 · A benign mass may be neurologically dangerous

Cortical tubers can be epileptogenic despite their hamartomatous nature.

Subependymal giant cell astrocytoma may obstruct ventricular CSF flow.

Vestibular schwannoma may compromise hearing or compress adjacent neural tissue.

Hemangioblastoma may cause mass effect in the cerebellum.

Cortex: Seizures

Ventricle: Obstruction

CN VIII: Hearing

Cerebellum: Mass effect

Slide 7 · The central diagnostic task: Recognize the pattern

Synthesize tumor histology with the number and distribution of lesions.

Assess accompanying skin, eye, renal and other systemic manifestations.

Separate a solitary sporadic tumor from a syndromic constellation.

Tumor morphology

Distribution + associated lesions

Syndrome-level inference

Slide 8 · NF1 combines nerve sheath tumors and developmental signs

Autosomal dominant syndrome occurring in approximately 1 in 3,000 individuals.

Associated tumors include neurofibromas, optic nerve gliomas, other gliomas and MPNST.

Pigmentary, ocular, skeletal and neurologic changes complete the phenotype.

NF1 phenotype

Nerve sheath tumors

Optic glioma

Cutaneous / ocular signs

Slide 9 · NF1 is a RAS-pathway tumor suppressor disorder

NF1 maps to chromosome 17q11.2 and encodes neurofibromin.

Neurofibromin limits active RAS signaling through GTPase-related regulation.

Its loss permits prolonged RAS activation and growth signaling.

NF1 loss → neurofibromin deficiency

RAS activity persists

Growth advantage

Slide 10 · Biallelic NF1 loss identifies neoplastic Schwann cells

The inherited NF1 defect alone does not make all tissue cells neoplastic.

Schwann cells of NF1-related neurofibromas show complete loss of neurofibromin.

Other tumor components can retain one functional allele and participate in the microenvironment.

NF1 neurofibroma

Neoplastic Schwann cells

Stromal fibroblasts

Mast / perineurial-like cells

Slide 11 · Variable expressivity is part of NF1 pathology

Some patients have subtle disease while others show extensive lesions.

Mosaic NF1 can produce a phenotype restricted to a body region.

Large deletions involving NF1 and adjacent genes correlate with greater severity.

Broad phenotype

Generalized lesions

Mosaic phenotype

Region-restricted lesions

Slide 12 · Cutaneous signs provide clues beyond the tumor

Café-au-lait macules are hyperpigmented cutaneous patches.

Superficial cutaneous neurofibromas may be multiple.

Other affected tissues should be evaluated when these findings coexist.

Skin findings

Café-au-lait macules

Cutaneous neurofibromas

Systemic assessment

Slide 13 · The eye may show both pigmentary and neoplastic lesions

Iris Lisch nodules are pigmented nodules linked to NF1.

Optic nerve gliomas are a prominent neoplastic manifestation.

The combination connects a visible ocular clue with a CNS tumor predisposition.

Lisch nodules

Iris pigmentation

Optic glioma

Optic pathway tumor

Slide 14 · Neurofibromas are heterogeneous nerve sheath tumors

Neoplastic Schwann cells coexist with fibroblasts, perineurial-like cells and mast cells.

CD34-positive spindle cells also contribute to the admixture.

The variable extracellular matrix helps explain their diverse patterns.

Schwann cells

Fibroblasts

Mast cells

Other stromal cells

Schematic — cell types / morphology

Slide 15 · Three growth patterns of neurofibroma

Localized cutaneous: Well-delineated dermal/subcutaneous nodule.

Diffuse: Plaque-like infiltration through skin and deeper tissue.

Plexiform: Expansion of multiple nerve fascicles along a nerve.

Localized cutaneous

Nodular

Diffuse

Plaque-like, infiltrative

Plexiform

Multiple enlarged fascicles

Slide 16 · Localized cutaneous neurofibroma: Low-cellularity lesion

Small, unencapsulated nodules in the dermis or subcutaneous fat.

Bland Schwann cells intermingle with stromal elements and loose collagen.

Adnexal structures may become entrapped near the lesion edge.

Localized nodular growth

Schematic — not a histologic specimen

Slide 17 · Diffuse neurofibroma spreads through tissue planes

Infiltrates dermis, subcutaneous connective tissue or deeper soft tissue.

Entraps adipose tissue and skin appendages as it expands.

Pseudo-Meissner corpuscles may occur within the lesion.

Diffuse infiltration / entrapment

Schematic — not a histologic specimen

Slide 18 · Plexiform neurofibroma expands nerve fascicles

Arises in association with large nerves or nerve roots.

Multiple fascicles enlarge, producing a rope-like “bag of worms” mass.

This pattern is strongly linked to NF1.

Enlarged nerve fascicles

Schematic

Slide 19 · Plexiform neurofibroma: Microscopic architecture

Tumor cells permeate and expand individual nerve fascicles while entrapping axons.

Perineurial coverings can remain recognizable around expanded fascicles.

Collagen bundles may appear reminiscent of shredded carrots.

Enlarged nerve fascicles

Schematic

Slide 20 · The tumor microenvironment matters in NF1

NF1-haploinsufficient mast cells may respond strongly to KIT ligand from Schwann cells.

Mast-cell factors can then stimulate Schwann-cell growth.

Tumor–stroma signaling may reinforce growth of the lesion.

Schwann-cell KIT ligand

Mast-cell response

Growth-promoting signals

Slide 21 · Plexiform lesions carry an important malignant risk

MPNST can arise by malignant transformation of a preexisting neurofibroma.

Transformation is most often associated with the plexiform variant.

MPNST occurs in approximately 5%–10% of patients with NF1.

Plexiform neurofibroma

Additional malignant changes

MPNST

Slide 22 · MPNST differs fundamentally from benign neurofibroma

High-grade MPNST shows infiltrative growth into neighboring soft tissue.

Mitoses, necrosis and nuclear anaplasia are common.

A fascicular spindle-cell pattern may retain evidence of nerve sheath origin.

Benign neurofibroma

Bland mixed cells

Loose collagen

MPNST

Anaplasia / mitoses

Invasion / necrosis

Slide 23 · Histologic clues to MPNST in an NF1 patient

A mass may appear variably cellular and “marbleized” at low power.

Spindled tumor cells form infiltrative fascicles with malignant cytology.

Nerve association and prior neurofibroma help distinguish it from other sarcomas.

Architecture

Infiltrative fascicles

Cytology

Anaplasia, mitoses

Context

Nerve / neurofibroma association

Slide 24 · MPNST progression may involve further suppressor loss

NF1 loss is a founding feature in syndromic tumors.

High-grade MPNST may show PRC2 pathway disruption and CDKN2A/B deletion.

Malignancy therefore reflects additional alterations beyond the original predisposition.

Inherited NF1 susceptibility

Neurofibroma formation

Additional changes in MPNST

Slide 25 · NF1: Link the clinical clue to the tissue lesion

Multiple pigmentary findings plus nerve sheath nodules favor syndromic evaluation.

A plexiform lesion requires different risk interpretation from a small cutaneous nodule.

Pathology reports should specify neurofibroma subtype and any concerning malignant features.

Skin / ocular phenotype

Neurofibroma subtype

Risk-oriented interpretation

Slide 26 · NF2 has a distinct tumor distribution

Autosomal dominant syndrome occurring in approximately 1 in 40,000–50,000 people.

Typical neoplasms: Vestibular schwannomas, meningiomas and spinal ependymomas.

Neurofibromas are not the defining tumor of NF2.

NF2

Vestibular schwannomas

Meningiomas

Spinal ependymomas

Slide 27 · NF2 encodes the cytoskeletal regulator merlin

NF2 maps to 22q12 and encodes merlin.

Merlin participates in signaling controlling cell growth, shape and adhesion.

Somatic NF2 alterations also occur in sporadic schwannomas, meningiomas and spinal ependymomas.

NF2 gene loss

Merlin dysfunction

Abnormal growth regulation

Slide 28 · Bilateral vestibular schwannomas suggest NF2

The vestibular division of cranial nerve VIII is a characteristic tumor origin.

Bilateral lesions are a hallmark of the syndromic pattern.

Associated intracranial and spinal tumors strengthen the interpretation.

Right CN VIII

Left CN VIII

Other CNS tumors

Slide 29 · Vestibular schwannoma causes symptoms by location

Tumors commonly arise near the cerebellopontine angle.

Tinnitus and hearing loss may be presenting symptoms.

Larger tumors may compress neighboring CNS structures.

Vestibular nerve mass

Auditory / local compression

Tinnitus, hearing loss

Slide 30 · Schwannomas grow beside rather than through the nerve

Most are circumscribed and encapsulated, attached loosely to the associated nerve.

They often produce a firm gray mass.

This pattern contrasts with fascicular infiltration by plexiform neurofibroma.

Encapsulated mass abutting nerve

Schematic

Slide 31 · Antoni A and Antoni B are complementary patterns

Antoni A areas are cellular and architecturally organized.

Antoni B areas are looser, more myxoid and less structured.

Their juxtaposition is a characteristic histologic feature of schwannoma.

Antoni A

Antoni B

Schematic patterns

Slide 32 · Verocay bodies arise from nuclear palisading

Aligned Schwann-cell nuclei create palisading rows in Antoni A tissue.

A central anuclear zone separates the parallel rows.

The pattern is named a Verocay body.

Palisaded nuclei

Central anuclear zone

Schematic — Verocay body

Slide 33 · Schwann-cell lineage markers aid interpretation

Schwannomas typically express S100 and SOX10.

Continuous basement membrane material surrounds tumor cells.

Marker expression supports lineage but must be interpreted with architecture.

S100 / SOX10

Schwann differentiation

Basement membrane

Continuous pericellular pattern

Architecture

Antoni A / B, palisading

Slide 34 · Degenerative atypia does not automatically mean malignancy

Schwannomas may show pleomorphic nuclei, hyalinized vessels and cystic change.

Xanthomatous change and necrosis are also described.

Interpret atypical changes alongside mitotic activity, architecture and clinical behavior.

Degenerative schwannoma

Hyalinization

Cystic / nuclear change

Malignant concern

Invasive growth

Malignant cytology

Slide 35 · Schwannomatosis differs from NF2 by tumor distribution

The textbook characterizes non-NF2 schwannomatosis by multiple nonvestibular schwannomas.

Distribution may be generalized or restricted to one body region.

Cases may be familial or sporadic.

NF2 pattern

Vestibular schwannomas

Meningioma / ependymoma

Schwannomatosis pattern

Nonvestibular schwannomas

Generalized or localized

Slide 36 · Three diagnoses, three nerve sheath patterns

NF1 chiefly links neurofibromas with pigmentary and optic pathway findings.

NF2 prominently links vestibular schwannomas to additional CNS neoplasms.

Schwannomatosis centers on multiple nonvestibular schwannomas.

NF1

Neurofibromas + optic glioma

NF2

Vestibular schwannomas

Schwannomatosis

Nonvestibular schwannomas

Slide 37 · Neurofibroma versus schwannoma: Read the anatomy

Neurofibroma: Mixed cellular composition and variable nerve infiltration.

Schwannoma: Circumscribed, usually encapsulated, predominantly Schwann cells.

Antoni A/B and Verocay bodies favor schwannoma over neurofibroma.

Neurofibroma

Mixed cells

Often unencapsulated

Schwannoma

Schwann cells

Antoni A/B

Slide 38 · Clinical application: Bilateral VIII-nerve tumors

A young patient has bilateral vestibular nerve masses and a meningioma.

The lesion constellation supports NF2 rather than isolated sporadic schwannoma.

The strongest clue is distribution, not a single slide’s histology.

Bilateral CN VIII masses

Additional meningioma

NF2 pattern

Slide 39 · TSC unites developmental lesions and neoplasia

Autosomal dominant disorder affecting roughly 1 in 6,000 births.

CNS manifestations include cortical tubers, subependymal nodules and SEGA.

Systemic hamartomas and benign neoplasms involve several other organs.

TSC

Cortical tubers

Subependymal nodules

SEGA

Slide 40 · Hamartin and tuberin restrain mTOR activity

TSC1 at 9q34 encodes hamartin; TSC2 at 16p13.3 encodes tuberin.

Their protein complex suppresses mTOR signaling.

Loss of complex function permits excessive anabolic and growth signaling.

TSC1 / TSC2 loss

Hamartin–tuberin restraint lost

MTOR overactivity

Slide 41 · MTOR dysregulation explains enlarged lesional cells

MTOR regulates protein synthesis and cell size.

Increased mTOR activity contributes to cell growth and hamartomatous lesions.

SEGA cells frequently display strikingly voluminous cytoplasm.

Unregulated mTOR

Increased cellular growth

Large lesional cells

Slide 42 · Cortical tubers disturb normal cortical architecture

Cortical hamartomas form firm, disorganized regions (“tubers”).

Neurons lose the orderly laminar arrangement of normal cortex.

This disturbed architecture contributes to epileptogenic activity.

Disrupted cortical lamination

Schematic

Slide 43 · Cortical tubers: Histology is disorganization

Haphazard neuronal distribution replaces normal layered cortical structure.

Abnormal large cells can combine glial and neuronal features.

Recognition depends on architecture as well as lesional cell cytology.

Normal cortex

Organized laminae

Ordered neurons

Cortical tuber

Disordered laminae

Dysplastic giant cells

Slide 44 · Dysplastic cells show mixed neuronal and glial traits

Large vesicular nuclei with nucleoli can resemble neurons.

Abundant eosinophilic cytoplasm can resemble gemistocytic astrocytes.

Cells may express both neurofilament and GFAP.

Large vesicular nucleus

Abundant cytoplasm

Neurofilament + GFAP expression

Schematic — not a histologic specimen

Slide 45 · Cortical tubers explain common neurological findings

Seizures are prominent and tubers can act as seizure foci.

Autism and intellectual disability are frequent clinical manifestations.

In difficult epilepsy, resection of an epileptogenic tuber may help.

Cortical structural abnormality

Abnormal network excitability

Seizure phenotype

Slide 46 · Subependymal nodules border the ventricle

Hamartomatous nodules lie beneath the ependymal surface.

Large astrocyte-like cells form clustered subependymal lesions.

Protrusion into the ventricle creates the “candle gutterings” appearance.

Nodules beneath ventricular lining

Schematic

Slide 47 · SEGA is a larger related subependymal tumor

Subependymal giant cell astrocytoma resembles the cellular pattern of nodules.

The mass is larger and behaves as a benign neoplasm.

Its clinical importance lies particularly in ventricular obstruction.

Larger mass near CSF pathway

Schematic

Slide 48 · How SEGA produces obstructive hydrocephalus

A subependymal mass may narrow a ventricular CSF pathway.

Obstruction leads to upstream ventricular enlargement.

Clinical impact reflects location even without high-grade cytology.

SEGA near ventricle

CSF outflow obstruction

Hydrocephalus

Slide 49 · Systemic hamartomas offer diagnostic corroboration

Renal angiomyolipomas and retinal glial hamartomas are recognized associations.

Cardiac rhabdomyomas and pulmonary lymphangioleiomyomatosis may occur.

Cysts may involve kidney, pancreas or liver.

Kidney

Angiomyolipoma; Cysts

Retina / heart

Glial hamartoma; Rhabdomyoma

Lung

Lymphangioleiomyomatosis

Liver / pancreas

Cysts

Slide 50 · The skin provides high-yield syndrome clues

Facial angiofibromas are recognized cutaneous lesions.

Hypopigmented “ash-leaf” macules and shagreen patches are characteristic.

Subungual fibromas may also occur.

Pigment

Ash-leaf macules

Dermis

Angiofibromas; Shagreen patches

Nail region

Subungual fibromas

Slide 51 · MTOR inhibitors target the causal signaling axis

Conventional treatment includes anticonvulsants for seizure control.

MTOR inhibitors can reduce the consequences of pathway hyperactivity.

Selected patients may show marked improvement with pathway-directed therapy.

TSC1/TSC2 loss

MTOR overactivity

MTOR-directed intervention

Slide 52 · Different lesions create different clinical problems

Cortical tuber: Network dysfunction and refractory epilepsy.

Subependymal nodule: Often a recognizable ventricular hamartoma.

SEGA: Larger mass with potential CSF-flow obstruction.

Cortical tuber

Epileptogenic cortex

Subependymal nodule

Ventricular hamartoma

SEGA

Obstructive mass effect

Slide 53 · Clinical application: Epilepsy with ventricular lesion

A patient has seizures, hypopigmented macules and a ventricular mass.

The combined phenotype raises TSC with possible SEGA.

Assess whether ventricular enlargement suggests an obstructive consequence.

Seizures + skin signs

Subependymal tumor

TSC / SEGA pattern

Slide 54 · VHL links vascular CNS neoplasia to systemic tumors

Autosomal dominant syndrome present in roughly 1 in 30,000–40,000 people.

Hemangioblastomas favor the cerebellum and retina.

Renal cell carcinoma, pheochromocytoma and visceral cysts also occur.

VHL disease

Hemangioblastoma

Renal cell carcinoma

Pheochromocytoma / cysts

Slide 55 · VHL is a tumor suppressor at chromosome 3p25.3

VHL protein participates in a ubiquitin ligase complex.

The complex normally down-regulates hypoxia-inducible factors (HIFs).

Loss of VHL function leads to inappropriate persistence of HIF-dependent signaling.

VHL loss

HIF down-regulation fails

HIF transcriptional activity

Slide 56 · HIF drives an angiogenic and metabolic program

HIFs control expression of VEGF, erythropoietin and other factors.

VEGF increases vascular growth, contributing to hemangioblastomas.

HIF also regulates genes involved in cellular metabolism and growth.

HIF activity

VEGF → angiogenesis

EPO → erythropoiesis

Growth / metabolism genes

Slide 57 · VEGF explains the dense vascularity of hemangioblastoma

Excess VEGF promotes extensive capillary formation.

The lesional vasculature consists of numerous thin-walled vessels.

Highly vascular morphology is therefore mechanistically linked to VHL loss.

VHL deficiency

HIF → VEGF excess

Capillary-rich tumor

Slide 58 · Erythropoietin can explain secondary polycythemia

Hemangioblastoma stromal cells may express erythropoietin.

Excess erythropoietin stimulates red-cell production.

Polycythemia in about 10% of hemangioblastoma patients.

Tumor-derived erythropoietin

Increased red-cell production

Polycythemia

Slide 59 · Hemangioblastoma has a characteristic distribution

The cerebellum is a common CNS location.

Retinal hemangioblastomas are another major syndrome manifestation.

Other CNS locations may also be involved.

Cerebellum

Retina

Other CNS sites

Slide 60 · Hemangioblastoma may form a cyst with a mural nodule

A solid vascular nodule can lie along the wall of a large fluid-filled cyst.

The cyst can dominate gross lesion size and contribute to mass effect.

Recognition of the cyst–nodule configuration helps connect imaging and gross pathology.

Fluid-filled cyst

Mural nodule

Schematic

Slide 61 · Hemangioblastoma histology: Capillaries plus stromal cells

Numerous thin-walled capillary-sized vessels traverse the lesion.

Intervening neoplastic stromal cells have vacuolated, lipid-rich cytoplasm.

The mixed vascular–stromal architecture is a key diagnostic clue.

Thin vessels + lipid-rich stromal cells

Schematic — not a histologic specimen

Slide 62 · Inhibin is a useful stromal-cell marker

The neoplastic stromal component expresses inhibin.

The same cells may express VEGF and erythropoietin.

Diagnostic interpretation must distinguish stromal cells from the prominent vasculature.

Stromal cells

Lipid-rich cytoplasm

Inhibin expression

Vascular component

Thin-walled capillaries

Angiogenic response

Slide 63 · Systemic tumor spectrum distinguishes VHL

Renal cell carcinomas and renal cysts are important extracranial lesions.

Pheochromocytomas are part of the syndrome.

Cysts may involve pancreas and liver as well as kidney.

CNS / retina

Hemangioblastomas

Kidneys

RCC; Cysts

Adrenal

Pheochromocytoma

Viscera

Pancreatic / hepatic cysts

Slide 64 · Hemangioblastoma care is lesion-directed

Symptomatic cerebellar lesions may be surgically resected.

Retinal hemangioblastomas can be treated with laser methods.

Systemic evaluation is essential because the predisposition affects several organs.

Define affected organs

Treat threatening lesions

Assess systemic manifestations

Slide 65 · Clinical application: Vascular cerebellar mural nodule

A cystic cerebellar mass contains a mural nodule rich in capillaries.

Vacuolated stromal cells and inhibin expression support hemangioblastoma.

The associated syndrome to consider is VHL, especially with visceral lesions.

Cyst + mural nodule

Hemangioblastoma histology

Consider VHL

Slide 66 · Each syndrome disrupts a different cell-growth control

NF1: RAS activation persists without neurofibromin restraint.

NF2: Merlin-dependent growth and adhesion control is disturbed.

TSC: MTOR signaling is overactive.

VHL: HIF-driven angiogenic signaling is excessive.

NF1

Neurofibromin → RAS

NF2

Merlin → growth/adhesion

TSC

Hamartin/tuberin → mTOR

VHL

VHL → HIF/VEGF

Slide 67 · Tumor phenotype provides a practical syndrome index

Plexiform neurofibroma strongly favors NF1.

Bilateral vestibular schwannomas strongly favor NF2.

SEGA with cortical tubers favors TSC.

Cystic vascular cerebellar tumor with mural nodule favors VHL.

Plexiform neurofibroma

NF1

Bilateral vestibular schwannoma

NF2

SEGA + cortical tubers

TSC

Hemangioblastoma

VHL

Slide 68 · Location can matter as much as cell phenotype

A benign nerve sheath tumor can impair cranial nerve VIII function.

A benign SEGA can obstruct a ventricle.

A cerebellar vascular lesion can produce clinically important compression.

CN VIII / hearing

Ventricle / CSF

Cerebellum / compression

Slide 69 · Morphologic differentials rely on architecture

Schwannoma: Circumscription, Antoni A/B architecture and Verocay bodies.

Neurofibroma: Mixed cells and variable infiltration through nerve structures.

Hemangioblastoma: Capillary-rich stroma with vacuolated neoplastic cells.

Schwannoma

Antoni A/B

Neurofibroma

Mixed nerve sheath cells

Hemangioblastoma

Vessels + lipid-rich stromal cells

Slide 70 · A diagnostic sequence for multifocal nervous-system tumors

First identify a dominant tumor type and its histologic architecture.

Next map its anatomic distribution and count synchronous lesions.

Then seek the characteristic skin, eye and systemic clues.

Histology

Multiplicity / locations

Syndrome pattern

Slide 71 · Case comparison: Pigmentary signs or bilateral vestibular masses?

Patient A: Café-au-lait macules, Lisch nodules and a plexiform neurofibroma.

Patient B: Bilateral vestibular schwannomas with a meningioma.

Distinctive associated features distinguish NF1 from NF2.

Patient A

Pigmentary + plexiform

NF1

Patient B

Bilateral vestibular

NF2

Slide 72 · Case comparison: SEGA or hemangioblastoma?

Patient C: Cortical tubers, seizures and a subependymal ventricular tumor.

Patient D: Cerebellar cyst with a highly vascular mural nodule.

Cellular and anatomic patterns favor TSC and VHL, respectively.

Patient C

Tuber + ventricular mass

TSC

Patient D

Cystic vascular mass

VHL

Slide 73 · Four high-yield pathology-to-mechanism links

NF1 neurofibromas: Biallelic neurofibromin loss in neoplastic Schwann cells.

NF2 schwannomas: Merlin pathway dysfunction in nerve sheath tumors.

TSC giant cells: Loss of mTOR restraint favors enlargement.

VHL hemangioblastoma: HIF/VEGF excess explains vascularity.

NF1

Schwann-cell tumor → RAS

NF2

Schwannoma → merlin

TSC

Giant cells → mTOR

VHL

Capillaries → HIF/VEGF

Slide 74 · What pathology can and cannot establish alone

Characteristic histology helps identify a lesion but may not prove hereditary disease.

Multiple characteristic tumors and nonneoplastic findings raise syndrome-level confidence.

Genetic diagnosis and clinical classification require appropriate contextual assessment.

Lesion diagnosis

Multisystem phenotype

Syndrome-level assessment

Slide 75 · Synthesis: Hereditary tumor syndromes of the nervous system

Recognize each characteristic tumor distribution and its distinctive microscopy.

Connect the lesion to NF1/RAS, NF2/merlin, TSC/mTOR or VHL/HIF signaling.

Explain symptoms through lesion location, not grade alone.

Use systemic manifestations to recognize a syndrome beyond a solitary tumor.

NF1

Neurofibroma; Optic glioma

NF2

Vestibular schwannoma

TSC

Cortical tuber; SEGA

VHL

Hemangioblastoma

Slide 76 · Primary textbook source

Robbins, Cotran & Kumar: Pathologic Basis of Disease

11th edition (2026)

Chapter 28: The Central Nervous System — Familial Tumor Syndromes, pp. 1185–1186

Related context: Chapter 27, Peripheral Nerves and Skeletal Muscles, pp. 1125–1127