Paraganglioma and Phaeochromocytoma
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Direct answer
Zellballen — rounded nests of polygonal neuroendocrine chief cells cradled by a rim of S100-positive sustentacular cells — are the architectural signature of paraganglioma, a neoplasm of neural-crest-derived paraganglia from the carotid body, jugulotympanic region, vagal bodies and sympathetic chain; the adrenal medullary counterpart is phaeochromocytoma. Tumour cells express chromogranin and synaptophysin while the sustentacular rim highlights with S100, and immunohistochemical loss of succinate dehydrogenase B flags an underlying SDHx germline mutation, now routine in workup because heritable disease accounts for a far larger share than the old "rule of 10s" ever conceded. Benign and malignant tumours are histologically indistinguishable: malignancy is declared only by metastasis to non-chromaffin sites, which is why SDHB-mutated tumours — the highest-risk genotype — demand long surveillance.
What you must remember
- Sites and behaviour: parasympathetic head-and-neck paragangliomas (carotid body is the classic) are usually non-secretory; sympathetic abdominal and thoracic ones, like adrenal phaeochromocytomas, secrete catecholamines.
- Immunoprofile: chief cells positive for chromogranin, synaptophysin, GATA3 and often tyrosine hydroxylase; sustentacular cells S100 and SOX10 positive — the nested pattern with the peripheral rim is the diagnosis.
- Hereditary panel: SDHD (paraganglioma syndrome 1, paternal transmission with parent-of-origin effect), SDHAF2, SDHC, SDHB (syndrome 4 — highest metastatic risk), plus RET, VHL, NF1 and MAX.
- SDHB immunohistochemistry: loss of granular staining in tumour cells indicates SDHx mutation and mandates genetic testing; retained staining does not fully exclude it.
- Malignancy definition: only proven metastases at non-chromaffin sites (bone, lung, liver, lymph nodes) define malignancy — no combination of atypia, necrosis or mitoses suffices.
- Adrenal risk scores: the PASS score (phaeochromocytoma of the adrenal gland scale) totals twelve histological features, with scores of four or more prompting closer follow-up; GAPP grading similarly stratifies risk.
- Clinical rule that never changes: suspected catecholamine-secreting tumours are confirmed biochemically (plasma or urinary metanephrines) and imaged — never diagnosed by biopsy, which can provoke a hypertensive crisis.
From a neck lump to a family study
A 34-year-old woman presents with a slowly growing, painless submandibular swelling; examination finds a firm mass with transmitted pulsation and carotid bruit — imaging shows a mass splaying the carotid bifurcation (the Lyre sign), the carotid body paraganglioma in its classic position. Biopsy is contraindicated; catecholamine metabolites are normal, consistent with a parasympathetic tumour, and embolisation followed by surgical excision removes a Zellballen-rich tumour whose sustentacular rim glows with S100. Because she is young, SDHB immunohistochemistry is performed and is lost; germline testing confirms an SDHD mutation, and cascade testing identifies her father as an unaffected carrier — the paternal transmission that makes SDHD pedigrees skip generations through mothers. Her surveillance now pairs periodic imaging with metanephrines, since a second primary is a real lifetime risk. The histology was the start of the story, not the end.
Where candidates slip
The rule of 10s — 10 per cent bilateral, familial, malignant, extra-adrenal — is still recited as current, but heritable disease now explains roughly 30-40 per cent of apparently sporadic tumours, so the modern answer is genetic testing by phenotype plus SDHB stain. The second slip is calling a histologically alarming tumour malignant: necrosis, mitoses and capsular invasion raise suspicion and scores, but only metastasis certifies. The third, most dangerous at the bedside: biopsying an undiagnosed retroperitoneal or adrenal mass that turns out to be a catecholamine producer — biochemical evaluation precedes any needle in every suspected paraganglioma, a rule that protects patients and earns its marks.
Frequently asked questions
What is the Zellballen pattern?
Nests of neuroendocrine chief cells enclosed by fibrovascular stroma and a rim of S100-positive sustentacular cells — the defining architecture of paraganglioma.
Which mutation carries the highest metastatic risk?
SDHB germline mutations, associated with extra-adrenal, often noradrenaline-secreting tumours with the greatest metastatic potential among the paraganglioma syndromes.
Why does SDHD show parent-of-origin inheritance?
SDHD tumours develop only when the mutation is paternally inherited, so the defect is silent when passed through carrier mothers but expressed when transmitted by fathers.
How is malignancy diagnosed in these tumours?
Solely by metastasis to non-chromaffin sites such as bone, lung or liver; histological atypia alone cannot establish it.
Which tumour should never be biopsied before biochemistry?
Any suspected catecholamine-secreting paraganglioma or phaeochromocytoma — biopsy risks a hypertensive crisis; plasma or urinary metanephrines and imaging come first.
What does loss of SDHB staining on immunohistochemistry mean?
Loss of granular cytoplasmic staining in tumour cells suggests an underlying SDHx germline mutation and triggers formal genetic testing.