# Paraganglioma and Phaeochromocytoma > Paraganglioma for NEET-PG Pathology: Zellballen architecture, S100 sustentacular cells, SDHB loss by immunohistochemistry, PASS scoring and why the rule of 10s is obsolete. - Canonical URL: https://prepelephant.com/topics/neet-pg/pathology/paraganglioma-pathology - Exam / course: NEET-PG · Subject: Pathology - Publisher: PrepElephant (https://prepelephant.com) — Prepared and reviewed by the PrepElephant Academic Review Team - First published: 2026-10-02 - Last updated: 2026-10-02 - How to cite: "Paraganglioma and Phaeochromocytoma", PrepElephant, https://prepelephant.com/topics/neet-pg/pathology/paraganglioma-pathology ## 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.