Definition/General
Introduction:
Pheochromocytoma is a neuroendocrine tumor arising from adrenal medulla chromaffin cells
FNAC is generally contraindicated due to risk of hypertensive crisis
When performed, shows uniform neuroendocrine cells with abundant granular cytoplasm
Part of paraganglioma family of tumors.
Origin:
Arises from chromaffin cells of adrenal medulla
Derived from neural crest cells
Produces catecholamines (epinephrine, norepinephrine)
10% rule: 10% bilateral, 10% extra-adrenal, 10% malignant, 10% pediatric, 10% familial
Hereditary syndromes in 40% cases.
Classification:
Location-based: Adrenal pheochromocytoma vs extra-adrenal paraganglioma
Hereditary syndromes: VHL disease
MEN 2A/2B
NF1
Succinate dehydrogenase mutations
Sporadic vs hereditary
Functional vs non-functional.
Epidemiology:
Incidence: 0.1-0.6% of hypertensive patients
Peak incidence: 4th-5th decades
Equal gender distribution
Rule of 10s: classical teaching
Hereditary cases: younger age, bilateral, multifocal
Malignant potential: 5-10% adrenal, 15-20% extra-adrenal.
Clinical Features
Presentation:
Hypertension (90% cases): sustained or paroxysmal
Classic triad (50% cases): headache, sweating, palpitations
Hypertensive crisis (life-threatening)
Diabetes mellitus (catecholamine effect)
Weight loss despite good appetite
Anxiety and panic attacks.
Symptoms:
Headache (severe, throbbing)
Excessive sweating (diaphoresis)
Palpitations and chest pain
Tremor and anxiety
Nausea and vomiting
Visual disturbances
Abdominal pain
Heat intolerance
Constipation.
Risk Factors:
Hereditary syndromes: VHL, MEN2, NF1, PGL syndromes
Family history of pheochromocytoma
Previous pheochromocytoma
Young age onset (<20 years)
Bilateral disease
Extra-adrenal location
Malignant behavior.
Screening:
CONTRAINDICATION: FNAC should not be performed without alpha-blockade
Biochemical diagnosis first: plasma metanephrines, 24-hour urine catecholamines
Imaging: CT, MRI, MIBG scan
Genetic testing for hereditary syndromes
Alpha-blockade essential before any intervention.
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Gross Description
Appearance:
FNAC (when performed with precautions) shows highly cellular aspirate
Uniform neuroendocrine cells
Abundant granular cytoplasm
Salt-and-pepper chromatin pattern
Minimal blood if technique optimal
May show binucleated cells
Necrosis rare in benign cases.
Characteristics:
Cellular smears with dispersed cells and clusters
Polygonal to spindle cells
Abundant cytoplasm (eosinophilic to amphophilic)
Fine granular texture (chromaffin granules)
Eccentric nuclei with fine chromatin
Prominent nucleoli may be seen
Plasmacytoid appearance.
Size Location:
Variable size: 2-10 cm diameter
Adrenal medulla location (90%)
Extra-adrenal paraganglia (10%)
Bilateral in hereditary syndromes
Unilateral in sporadic cases
Well-circumscribed lesions typically.
Multifocality:
Solitary in sporadic cases (90%)
Bilateral/multifocal in hereditary syndromes
Synchronous vs metachronous presentation
Extra-adrenal sites: organ of Zuckerkandl, bladder, thorax
Familial clustering in hereditary cases.
Microscopic Description
Histological Features:
Uniform neuroendocrine cells in clusters and dispersed pattern
Polygonal cells with abundant cytoplasm
Salt-and-pepper chromatin (neuroendocrine pattern)
Binucleated cells common
Sustentacular cells may be present
Rich vascular pattern.
Cellular Characteristics:
Medium to large cells
Abundant granular cytoplasm (chromaffin granules)
Eccentric nuclei
Fine chromatin with small nucleoli
Binucleation frequent
Plasmacytoid morphology
Mitotic activity variable
Nuclear pleomorphism may be present.
Architectural Patterns:
Zellballen pattern (classic): cell nests surrounded by sustentacular cells
Trabecular pattern
Solid pattern
Alveolar pattern
Spindle cell pattern (rare)
Mixed patterns common
Rich vascular stroma.
Grading Criteria:
GAPP score (Grading system for Adrenal Pheochromocytoma and Paraganglioma)
Parameters: histologic pattern, cellularity, comedo necrosis, capsular/vascular invasion, Ki-67 index, catecholamine type
Well-differentiated neuroendocrine tumor classification.
Immunohistochemistry
Positive Markers:
Chromogranin A (95-100% positive)
Synaptophysin (90-95% positive)
CD56/NCAM (neuroendocrine marker)
GFAP (sustentacular cells)
S-100 (sustentacular cells)
Tyrosine hydroxylase (catecholamine synthesis)
PNMT (epinephrine-producing).
Negative Markers:
Cytokeratins (usually negative)
EMA (negative)
Inhibin (negative, excludes adrenal cortical)
Melan-A (negative, excludes cortical)
RCC marker (negative)
TTF-1 (negative)
Calcitonin (negative, excludes medullary thyroid).
Diagnostic Utility:
Confirms neuroendocrine differentiation
Chromogranin A + synaptophysin diagnostic combination
GFAP/S-100 highlights sustentacular cells (zellballen pattern)
Ki-67 for proliferation assessment
Excludes other tumors (cortical, metastatic)
Prognostic markers: SDHB loss.
Molecular Subtypes:
Cluster 1: pseudohypoxia (VHL, SDH mutations)
Cluster 2: kinase signaling (RET, NF1, TMEM127, MAX)
Cluster 3: Wnt signaling (somatic mutations)
Noradrenergic vs adrenergic phenotype
Hereditary vs sporadic molecular profile.
Molecular/Genetic
Genetic Mutations:
Hereditary syndromes (40%): VHL (25%), SDHB (20%), SDHA, SDHC, SDHD, SDHAF2
RET mutations (MEN 2)
NF1 mutations
MAX mutations
TMEM127, TMEM127 mutations
Somatic mutations in sporadic cases.
Molecular Markers:
Succinate dehydrogenase pathway alterations
Hypoxia-inducible factor pathway
mTOR pathway activation
Wnt signaling alterations
Catecholamine biosynthesis enzymes
VEGF overexpression (angiogenesis).
Prognostic Significance:
SDHB mutations: higher malignant potential
Extra-adrenal location: increased risk
Large size (>5 cm): higher risk
Young age: often hereditary
GAPP score: risk stratification
Ki-67 >3%: increased risk.
Therapeutic Targets:
Alpha-adrenergic blockade (phenoxybenzamine)
Beta-blockade (after alpha-blockade)
Tyrosine hydroxylase inhibitors (metyrosine)
mTOR inhibitors (experimental)
Anti-angiogenic therapy (sunitinib)
Radionuclide therapy (MIBG, DOTATATE).
Differential Diagnosis
Similar Entities:
Adrenal cortical adenoma
Adrenal cortical carcinoma
Metastatic neuroendocrine tumor
Ganglioneuroma
Neuroblastoma (pediatric)
Medullary thyroid carcinoma metastasis
Renal cell carcinoma metastasis.
Distinguishing Features:
Pheochromocytoma: chromogranin+, synaptophysin+, catecholamine excess
Cortical tumors: inhibin+, melan-A+, steroid excess
Metastatic NET: primary site evidence
Ganglioneuroma: ganglion cells present
Neuroblastoma: small blue cells, pediatric age.
Diagnostic Challenges:
Benign vs malignant pheochromocytoma distinction
Cortical vs medullary origin
Primary vs metastatic NET
Hereditary syndrome identification
FNAC limitations vs histology
Hypertensive crisis risk during procedure.
Rare Variants:
Malignant pheochromocytoma
Composite pheochromocytoma (with ganglioneuroma)
Pigmented pheochromocytoma
Cystic pheochromocytoma
Multiple endocrine neoplasia associated
Familial paraganglioma syndromes.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Clinical Information
Patient with [hypertension, catecholamine excess], biochemical studies: [results]
Procedure Note
FNAC performed with appropriate alpha-blockade precautions
Specimen Adequacy
Adequate with neuroendocrine cells present
Cytomorphological Features
Shows [neuroendocrine cells] with [granular cytoplasm, salt-pepper chromatin]
Neuroendocrine Features
Cells show [chromaffin morphology, zellballen pattern, binucleation]
Immunocytochemistry
Chromogranin A, Synaptophysin: [positive]
Inhibin, Melan-A: [negative]
Ki-67: [percentage]
Risk Assessment
Benign vs malignant assessment limited in cytology
Final Cytological Diagnosis
Neuroendocrine tumor consistent with Pheochromocytoma
Recommendations
Recommend [surgical resection, genetic counseling, family screening]