Adrenal Medulla

Slide 1 · Adrenal Medulla

Normal neuroendocrine tissue, pheochromocytoma and clinicopathologic correlations

Pathology lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish chromaffin tissue from the adrenal cortex and extra-adrenal paraganglia.

Explain the inherited molecular pathways associated with pheochromocytoma and paraganglioma.

Interpret characteristic gross, microscopic and immunophenotypic findings.

Link catecholamine release to cardiovascular manifestations and diagnostic investigation.

Explain why metastatic behavior cannot be determined reliably by histology alone.

Slide 3 · Medulla and cortex: Two distinct compartments

Adrenal medulla

Adrenal cortex

Specialized neural-crest neuroendocrine cells

Developmentally distinct adrenal compartment

Chromaffin and sustentacular cells

Cortical cells (different cellular lineage)

Source of epinephrine and norepinephrine

Not the major catecholamine-producing compartment

Characteristic neoplasm: Pheochromocytoma

Distinct group of cortical neoplasms

Slide 4 · Chromaffin cells and supporting cells

Adrenal cortex

Medulla

Chromaffin cells are the catecholamine-producing population.

Sustentacular cells form a supporting network.

The two cell populations reappear in the histology of pheochromocytoma.

Schematic – not a histologic specimen

Slide 5 · Catecholamine output of the adrenal medulla

Chromaffin cells

Neuroendocrine medullary cells

Catecholamines

Epinephrine + norepinephrine

Circulation

Systemic catecholamine effects

Clinical relevance

Excess release produces cardiovascular symptoms

Slide 6 · Norepinephrine has two physiological contexts

Adrenal endocrine source

Sympathetic nervous system

Medullary chromaffin cells release catecholamines into circulation.

Norepinephrine also acts as a neurotransmitter.

Part of systemic catecholamine physiology.

Particularly important in sympathetic nerves.

Tumor hypersecretion creates an endocrine syndrome.

Neural function must not be confused with tumor secretion.

Slide 7 · Adrenal and extra-adrenal paraganglia

Neural crest–related cells

Neuroendocrine lineage

Adrenal medulla

Chromaffin cell compartment

Extra-adrenal clusters

Paraganglion system

Neoplasms

Pheochromocytoma / paraganglioma

Slide 8 · Neoplastic spectrum of adrenal medullary tissue

Adrenal medulla / related neuroendocrine cells

Chromaffin-cell tumors

Pheochromocytoma

Extra-adrenal related tumors

Paraganglioma

Neuronal neoplasms

Neuroblastic tumors (Chapter 10)

Slide 9 · What defines pheochromocytoma?

A neoplasm composed of chromaffin cells.

Neoplastic cells synthesize and release catecholamines.

Some tumors also secrete peptide hormones.

Recognition matters because it can cause surgically correctable hypertension.

Slide 10 · Anatomic terminology has diagnostic consequences

Pheochromocytoma

Paraganglioma

Chromaffin-cell tumor in adrenal medulla.

Related neoplasm in extra-adrenal paraganglia.

May be unilateral or bilateral.

May arise in sites such as carotid body or organ of Zuckerkandl.

Can cause catecholamine excess.

Some extra-adrenal tumors also secrete catecholamines.

Potential for metastatic disease.

Metastatic behavior is particularly important in selected sites and genotypes.

Slide 11 · Why pheochromocytoma is clinically important

Medullary tumor

Chromaffin-cell neoplasm

Intermittent hormone output

Catecholamine release

Hemodynamic response

Hypertension and tachycardia

Potential emergency

Arrhythmia, infarction or stroke

Slide 12 · A substantial fraction has a germline predisposition

30%–40%

Individuals with pheochromocytoma or paraganglioma may harbor an oncogenic germline mutation.

Mutations in at least a dozen genes; Inherited disease cannot be dismissed as exceptional.

Slide 13 · Inherited tumors have recognizable patterns

Individuals with germline mutations typically present at younger ages than sporadic cases.

Bilateral adrenal tumors occur more often in inherited settings.

Bilateral pheochromocytomas may occur in up to 50% of patients with a familial tumor syndrome.

A tumor phenotype should trigger attention to accompanying syndromic lesions.

Slide 14 · Two broad molecular classes

Growth signaling

Pseudohypoxia

Genes exemplified by RET and NF1.

Genes include VHL, EPAS1 and SDH subunits.

Increased growth factor receptor pathway signaling.

Increased activity or stability of HIF transcription factors.

Altered proliferative signaling is central.

Altered oxygen-sensing machinery creates a pseudohypoxic state.

Slide 15 · RET-associated tumor susceptibility

RET alteration

Oncogenic signaling

Growth factor pathway

Increased activity

Chromaffin proliferation

Pheochromocytoma risk

Syndromic context

MEN type 2

Slide 16 · NF1-associated tumor susceptibility

NF1 alteration

Growth pathway regulation disturbed

Enhanced signaling

Growth factor pathway activity

Tumor predisposition

Pheochromocytoma

Clinical context

Neurofibromatosis type 1

Slide 17 · Pseudohypoxia: The central idea

Oxygen-sensing disturbance

VHL / EPAS1 / SDH pathway

HIF stabilization

Activity persists

Pseudohypoxic program

Hypoxia-associated signals without the usual trigger

Tumor predisposition

Pheochromocytoma / paraganglioma

Slide 18 · VHL loss alters HIF turnover

Normal VHL product

Required for oxygen-dependent HIF-1α degradation

Loss-of-function VHL

Normal HIF destruction disrupted

HIF-1α persists

Pseudohypoxia-associated signaling

Susceptibility

VHL-related PPGL

Slide 19 · EPAS1 mutation stabilizes HIF-2α

EPAS1

Encodes HIF-2α

Gain-of-function mutation

Impaired degradation sites

HIF-2α stabilization

Persistent HIF activity

Clinical association

Polycythemia–paraganglioma syndrome

Slide 20 · Succinate dehydrogenase genes

Inherited predisposition may involve components of the succinate dehydrogenase complex.

The Robbins table identifies SDHB, SDHC and SDHD.

This mitochondrial complex participates in electron transport and oxygen sensing.

Impaired function is believed to up-regulate HIF proteins and promote pseudohypoxia.

Slide 21 · Contrasting the inherited molecular routes

RET / NF1

Growth-factor signaling

Enhanced proliferative input

VHL / EPAS1 / SDHx

HIF persistence

Pseudohypoxia phenotype

Slide 22 · Germline and sporadic disease share oncogenic genes

Genes implicated in inherited susceptibility can also be altered somatically.

NF1, VHL, EPAS1 and RET among such genes.

A sporadic presentation does not imply a completely distinct molecular pathway.

Distinguish a tumor’s somatic driver from an inherited pathogenic variant.

Slide 23 · Syndromic associations: Clinical map

Pheochromocytoma / paraganglioma

RET

MEN-2A / MEN-2B

NF1

Neurofibromatosis type 1

VHL

Von Hippel–Lindau

SDHB / SDHC / SDHD

Hereditary paraganglioma

EPAS1

Polycythemia–paraganglioma

Slide 24 · MEN-2A: The combination to recognize

RET is the implicated gene.

Pheochromocytoma or paraganglioma may coexist with medullary thyroid carcinoma.

Parathyroid hyperplasia is another associated feature.

This constellation places a medullary adrenal tumor in a multisystem hereditary syndrome.

Slide 25 · MEN-2B: Distinguishing accompanying lesions

RET-associated endocrine tumor syndrome.

Pheochromocytoma or paraganglioma and medullary thyroid carcinoma are associated lesions.

Marfanoid habitus and mucocutaneous ganglioneuromas are distinctive accompanying features.

Recognizing the nonadrenal phenotype can guide syndromic interpretation.

Slide 26 · NF1-related pheochromocytoma

The NF1 gene is part of the growth-signaling molecular group.

Pheochromocytoma can occur with characteristic neurofibromatosis.

The Robbins syndrome table identifies café-au-lait spots and optic nerve glioma.

A chromaffin tumor is one possible component of a wider hereditary phenotype.

Slide 27 · VHL syndrome: Endocrine and nonendocrine tumors

The VHL gene encodes a tumor suppressor required for regulated HIF-1α degradation.

Pheochromocytoma or paraganglioma may arise in VHL syndrome.

Associated lesions include renal cell carcinoma and hemangioblastoma.

Pancreatic neuroendocrine neoplasms also appear in the Robbins table.

Slide 28 · Hereditary paraganglioma: SDH associations

Hereditary syndrome

Gene

Adrenal / extra-adrenal association

Paraganglioma 1

SDHD

Pheochromocytoma, paraganglioma

Paraganglioma 3

SDHC

Paraganglioma

Paraganglioma 4

SDHB

Pheochromocytoma, paraganglioma

Robbins also lists gastrointestinal stromal tumors as associated lesions.

Slide 29 · EPAS1 and polycythemia–paraganglioma

EPAS1 encodes hypoxia-inducible factor HIF-2α.

Gain-of-function changes can stabilize HIF-2α.

Associated phenotype includes pheochromocytoma and paraganglioma.

Polycythemia is the systemic clue captured in the syndrome name.

Slide 30 · Hereditary syndromes: A comparison

Gene

Tumor syndrome

A distinguishing nonadrenal clue

RET

MEN-2A

Medullary thyroid carcinoma; Parathyroid hyperplasia

RET

MEN-2B

Medullary thyroid carcinoma; Mucocutaneous ganglioneuromas

NF1

NF1

Café-au-lait spots; Optic nerve glioma

VHL

VHL

Renal cell carcinoma; Hemangioblastoma

Slide 31 · Pseudohypoxia syndromes: A comparison

Gene

Tumor predisposition

Associated feature

SDHD

Hereditary paraganglioma 1

Gastrointestinal stromal tumor

SDHC

Hereditary paraganglioma 3

Gastrointestinal stromal tumor

SDHB

Hereditary paraganglioma 4

Gastrointestinal stromal tumor

EPAS1

Polycythemia–paraganglioma

Polycythemia

Slide 32 · Clinical reasoning from an inherited phenotype

Medullary tumor

Adrenal or extra-adrenal

Age and laterality

Younger or bilateral clues

Associated findings

Thyroid / kidney / cutaneous / hematologic

Syndrome recognition

Interpret tumor in genetic context

Slide 33 · Gross appearance spans a wide spectrum

Small

Large / heterogeneous

Small, circumscribed lesions may remain confined to the adrenal.

Large masses may become hemorrhagic, necrotic or cystic.

Size and appearance alone do not definitively establish metastatic behavior.

Gross-appearance schematic – not a clinical specimen

Slide 34 · Tumor mass can vary dramatically

A mean weight of approximately 100 g.

Published examples extend from slightly more than 1 g to almost 4000 g.

Larger tumors may compress surrounding adrenal tissue.

Lesion dimensions are descriptive—not a stand-alone classification of malignancy.

Slide 35 · Smaller pheochromocytomas on cut section

Adrenal rim

Circumscribed tumor

Well-circumscribed lesion within the adrenal gland.

Cut surfaces of smaller tumors are typically yellow-tan.

A residual rim of adrenal tissue may remain visible.

Gross-appearance schematic – not a clinical specimen

Slide 36 · Larger lesions remodel the adrenal gland

Hemorrhage / cystic change

Often well-demarcated by fibrous tissue or compressed adrenal elements.

Hemorrhage, necrosis and cystic degeneration are common in larger tumors.

The normal gland may be effaced or stretched over one pole.

Gross-appearance schematic – not a clinical specimen

Slide 37 · Fibrovascular trabeculae shape gross architecture

Rich vascularity

Prominent intratumoral vessels

Fibrous trabeculae

Partition tumor parenchyma

Lobular pattern

Recognizable gross organization

Slide 38 · Chromaffin: Origin of the name

Catecholamines

Stored in tumor cells

Potassium dichromate

Oxidation of stored catecholamines

Dark-brown change

Classical chromaffin reaction

Slide 39 · Zellballen architecture of pheochromocytoma

Nests of chief cells are separated by a rich vascular network.

Sustentacular cells lie around the nests.

Architecture is characteristic but tumor patterns are variable.

Cell-nest schematic – not a histologic specimen

Slide 40 · Chief-cell cytology

Chief (chromaffin) tumor cells range from polygonal to spindle-shaped.

Their cytoplasm is often finely granular because of catecholamine-containing granules.

Small nests or alveoli are typically richly vascularized.

A single tumor may contain more than one growth pattern.

Slide 41 · Neuroendocrine nuclear chromatin

Nuclei are usually round to oval.

Fine stippling creates a “salt-and-pepper” chromatin pattern.

This is a neuroendocrine cytologic clue, not a prediction of metastasis.

Cell-nest schematic – not a histologic specimen

Slide 42 · Morphologic variation within one tumor

Typical nesting is not the only possible architecture.

Spindle-cell or small-cell patterns can predominate occasionally.

A variety of patterns may coexist in a single lesion.

Interpret atypical patterns in conjunction with site, clinical history and neuroendocrine differentiation.

Slide 43 · Catecholamine secretory granules

Chief-cell cytoplasm

Fine cytoplasmic granularity

Silver stains

May highlight the granules

Electron microscopy

Membrane-bound electron-dense granules

Functional implication

Secretory storage of catecholamines

Slide 44 · Chromogranin and synaptophysin

Chief cells are immunoreactive for neuroendocrine markers.

Chromogranin and synaptophysin highlight neoplastic chief-cell differentiation.

The staining distribution must be interpreted in the correct cellular compartment.

These markers confirm neuroendocrine character; They do not determine metastatic potential.

Slide 45 · S-100 highlights sustentacular cells

Sustentacular cells occupy the periphery of chief-cell nests.

They express S-100 in the Robbins description.

The peripheral network differs from chromogranin/synaptophysin-positive chief cells.

Cell-nest schematic – not a histologic specimen

Slide 46 · Tumor cells versus sustentacular cells

Chief / chromaffin cells

Sustentacular cells

Form the bulk of tumor nests.

Peripheral supporting cells around nests.

Catecholamine secretory granules.

Supporting structural network.

Chromogranin and synaptophysin.

S-100 immunoreactivity.

Neuroendocrine nucleus and granular cytoplasm.

Best recognized by their position and IHC.

Slide 47 · Morphology cannot certify a benign course

Pheochromocytomas and paragangliomas are regarded as potentially metastatic.

Histologic scoring for malignancy has proven unreliable as a definitive test.

Tumors with bland morphology may metastasize.

Highly pleomorphic tumors may remain confined to the adrenal gland.

Slide 48 · Features associated with aggressive behavior

A larger number of mitotic figures has been linked to increased risk.

Confluent tumor necrosis has been associated with aggressive behavior.

Spindle-cell morphology may also correlate with risk.

None of these findings establishes metastasis by itself.

Slide 49 · Why pleomorphism is a diagnostic trap

An alarming appearance

What it does not establish

Marked nuclear size variation

Metastatic disease by itself

Bizarre or giant tumor cells

An inevitable aggressive clinical course

Mitotic figures

A sufficiently reliable binary benign/malignant distinction

Bland cytology

A guarantee against future metastasis

Slide 50 · Capsular and vascular invasion have limits

Capsular invasion may be seen in these tumors.

Vascular invasion also may be encountered.

Even these findings do not independently provide a definitive metastatic classification.

Documented metastases for definitive malignant behavior.

Slide 51 · Defining metastatic pheochromocytoma

Primary chromaffin tumor

Adrenal medulla / paraganglion

Documented spread

Regional or distant tumor deposits

Clinical classification

Metastatic pheochromocytoma / paraganglioma

Slide 52 · Metastatic distribution: Where to look

Documented metastatic deposits

Regional

Lymph nodes

Distant solid organ

Liver

Distant solid organ

Lung

Skeletal

Bone

Slide 53 · Extra-adrenal tumors may have higher metastatic risk

20%–40%

Metastatic behavior in this range for extra-adrenal paragangliomas.

The text also emphasizes greater risk with certain germline mutations; Do not extrapolate this range to every adrenal tumor.

Slide 54 · Catecholamine secretion produces hypertension

Tumor output

Catecholamine release

Vascular / cardiac response

Hemodynamic stimulation

Clinical finding

Elevated arterial pressure

Potential complication

Acute cardiovascular injury

Slide 55 · Hypertension is the dominant clinical feature

90%

Proportion of pheochromocytoma patients reported to present with hypertension.

The remaining approximately 10% may not show hypertension—absence of the finding does not exclude a tumor.

Slide 56 · The paroxysmal catecholamine syndrome

Abrupt blood-pressure elevation is accompanied by tachycardia or palpitations.

Headache, sweating, tremor and apprehension are characteristic associated symptoms.

Chest or abdominal pain, nausea and vomiting may occur.

Among hypertensive patients, approximately two-thirds have paroxysmal episodes.

Slide 57 · Sustained hypertension often coexists with paroxysms

Isolated episodic attacks

Sustained elevation plus attacks

Occurs in fewer than half of patients.

More common pattern.

Sudden hypertension may dominate the history.

Baseline hypertension is punctuated by surges.

A normal reading between episodes can obscure detection.

Both chronic hypertension and attacks require explanation.

Slide 58 · Patterns of symptoms are mechanistically linked

Sudden catecholamine surge

Abrupt secretory episode

Cardiovascular activation

Tachycardia + sharp pressure rise

Associated systemic symptoms

Sweating, tremor, apprehension

Possible end-organ impact

Ischemia or arrhythmia

Slide 59 · What can precipitate a paroxysm?

Emotional stress and physical exercise.

Changes in posture.

Palpation in the region of the tumor.

In urinary-bladder paraganglioma, micturition may precipitate an episode.

Slide 60 · Micturition-associated hypertension as a clue

Bladder paraganglioma

Extra-adrenal chromaffin tumor

Micturition

Possible precipitating event

Catecholamine surge

Paroxysmal blood-pressure elevation

Site-specific clue

Consider extra-adrenal disease

Slide 61 · Potential cardiovascular and neurologic emergencies

Severe catecholamine surge

Cardiac failure

Congestive heart failure

Pulmonary

Pulmonary edema

Ischemic

Myocardial infarction

Electrical

Ventricular fibrillation

Neurologic

Cerebrovascular accident

Slide 62 · Catecholamine cardiomyopathy

Excess catecholamines can create myocardial instability and ventricular arrhythmias.

Myocardial injury may reflect catecholamine-related vasospasm and ischemia.

Direct catecholamine toxicity is an additional proposed mechanism.

The cardiac presentation can be more consequential than the adrenal mass itself.

Slide 63 · Myocardial tissue correlates of injury

Focal myocardial necrosis.

Mononuclear inflammatory infiltrates may be present.

Interstitial fibrosis may develop.

These changes are nonspecific and require clinical correlation with catecholamine excess.

Slide 64 · Peptide hormone secretion can broaden presentation

Some pheochromocytomas secrete hormones other than catecholamines.

Corticotropin and somatostatin are examples.

Associated clinical effects may reflect the secreted peptide rather than catecholamine excess alone.

Variable secretory behavior explains some atypical clinical presentations.

Slide 65 · Biochemical evidence is central to diagnosis

Urinary measurements

Plasma measurements

Increased excretion of free catecholamines.

Elevated plasma metanephrines.

Increased urinary metanephrine metabolites.

Provides biochemical evidence of catecholamine metabolism.

Interpreted in the appropriate clinical context.

A biochemical approach complements tumor morphology.

Slide 66 · Why metanephrines matter

Chromaffin-cell secretion

Catecholamines

Metabolism

Metanephrine products

Testing

Urine or plasma measurements

Interpretation

Biochemical support for a secreting tumor

Slide 67 · Resection requires adrenergic preparation

Functional chromaffin tumor

Risk of hormone-release crisis

Adrenergic blockade

Preoperative / intraoperative medication

Surgical excision

Treatment for an isolated localized lesion

Clinical rationale

Avoid a hypertensive crisis

Slide 68 · Multifocal disease may require continuing management

Treatment approach differs from excision of an isolated tumor.

Multifocal lesions may require long-term medical control of hypertension.

Clinical management must account for tumor distribution and catecholamine output.

Inherited predisposition can influence the interpretation of multifocal disease.

Slide 69 · Diagnostic synthesis: Four connected domains

Suspected medullary neoplasm

Clinical

Hypertension, attacks, extra-secretory features

Biochemical

Catecholamines and metanephrines

Pathologic

Chromaffin cells, zellballen, neuroendocrine markers

Risk / context

Anatomic site, metastasis, germline syndrome

Slide 70 · Case: Episodic hypertension and an adrenal mass

A patient has sudden episodes of headache, sweating, palpitations and marked hypertension. Imaging detects an adrenal mass.

Questions for interpretation

Which adrenal compartment is most relevant?

What biochemical measurements are supported by Robbins?

Why is preparation before surgery important?

Slide 71 · Case interpretation: A functional chromaffin tumor

A medullary chromaffin-cell neoplasm is a major consideration.

Catecholamine and metanephrine testing provides biochemical support.

Abrupt catecholamine secretion explains paroxysmal tachycardia and hypertension.

Adrenergic blockade is used around surgery to reduce hypertensive-crisis risk.

Slide 72 · Case: Bilateral tumors with syndromic findings

A younger patient presents with bilateral adrenal medullary masses. Family history and clinical examination reveal other endocrine or systemic lesions.

Questions for interpretation

Why is inherited susceptibility particularly relevant?

Which gene groups are implicated?

What concurrent findings might distinguish RET, NF1 or VHL?

Slide 73 · Case interpretation: Inherited molecular context

Younger presentation and bilateral involvement increase suspicion for germline predisposition.

RET and NF1 represent growth-signaling susceptibility.

VHL, EPAS1 and SDH subunits participate in pseudohypoxia-related susceptibility.

Associated thyroid, parathyroid, renal, neural or hematologic features refine syndromic interpretation.

Slide 74 · Five diagnostic principles to retain

The adrenal medulla is neural-crest-derived chromaffin tissue with supporting sustentacular cells.

Pheochromocytoma is a catecholamine-secreting chromaffin neoplasm; Some paragangliomas are related extra-adrenal tumors.

Hereditary predisposition often maps to growth-signaling or pseudohypoxia pathways.

Zellballen nests, chromogranin/synaptophysin and sustentacular S-100 define a recognizable pathologic pattern.

Clinical danger arises from catecholamine crises; Documented metastasis—not bizarre cytology—defines metastatic behavior.

Slide 75 · References and image provenance

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th edition (2026). Chapter 24, The Endocrine System.

Lecture content is based on the supplied Chapter 24 text under “Adrenal Medulla” and “Pheochromocytoma.”

All medullary, tumor, molecular and histoarchitectural drawings in this deck are original editable schematics—not histologic specimens.

No textbook photomicrographs or externally sourced clinical images are reproduced in this version.