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Microscopic features of paraganglioma

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Here is a thorough summary of the microscopic features of paraganglioma, drawn from Robbins, Cotran & Kumar Pathologic Basis of Disease and Cummings Otolaryngology.

Microscopic Features of Paraganglioma

Gross Appearance (context)

Tumor tissue is red-pink to brown. Most tumors are well-circumscribed, rarely exceeding 6 cm (e.g., carotid body tumors).

Hallmark Architecture: Zellballen Pattern

The defining microscopic feature is the Zellballen (German: "cell balls") pattern - discrete nests or clusters of tumor cells separated by a delicate fibrovascular stroma with prominent capillaries (Fig. 16.17A above).

Cell Types

Cell TypeLocationMorphologyStaining
Chief cells (type I)Within the nestsRound to oval, abundant clear or granular eosinophilic cytoplasm; round to ovoid, sometimes vesicular nucleiChromogranin +, Synaptophysin +, INSM1 +, CD56 +
Sustentacular cells (type II)Periphery/edges of nestsSpindle-shaped stromal cells forming a supporting networkS-100 protein +

Cytological Details

  • Cellular pleomorphism: Little to absent in most tumors
  • Mitoses: Scant
  • Nuclei: Round to ovoid, uniform; sometimes with vesicular (open) chromatin
  • Cytoplasm: Abundant, clear or finely granular eosinophilic

Vascularity

  • Tumor nests are separated by delicate vascular septae marked by capillaries (the septae contain red cells, visible on H&E)
  • Tumors are highly vascular - this is why biopsy can cause excessive hemorrhage

Immunohistochemistry Summary

MarkerChief CellsSustentacular Cells
ChromograninPositiveNegative
SynaptophysinPositiveNegative
INSM1PositiveNegative
CD56PositiveNegative
S-100NegativePositive
Keratins (AE1/AE3)NegativeNegative
Keratin negativity is important for distinguishing paraganglioma from carcinoid/neuroendocrine carcinoma, which are keratin-positive.

Electron Microscopy

  • Well-demarcated neuroendocrine (dense-core) granules are found in the cytoplasm of chief cells, especially in paravertebral (sympathetic) tumors
  • These granules are variable in number and tend to be scant in non-functioning tumors

Histologic Features and Malignancy

This is a key point: standard histologic features do NOT reliably predict malignancy.
  • Mitoses, pleomorphism, and even vascular invasion are not reliable indicators of malignant behavior
  • Malignancy is defined only by the presence of metastases (to lymph nodes or distant sites)
  • SDHB gene mutation is the strongest predictor of malignancy, with metastasis rates of 30-50%

Histology Image (Carotid Body Tumor - Robbins Pathology)

Carotid body tumor: (A) H&E showing zellballen pattern with vascular septae; (B) Chromogranin IHC showing strong positivity in tumor nests
Fig. 16.17 - Carotid body tumor. (A) Low-power H&E view showing tumor clusters (zellballen) separated by capillary-containing septa. (B) Chromogranin immunohistochemistry showing strong positivity in the chief cell nests.

Key Points Summary

  1. Zellballen - nests of chief cells in a rich vascular stroma - is the hallmark pattern
  2. Two cell populations: neuroendocrine chief cells (chromogranin/synaptophysin/INSM1+) and peripheral sustentacular cells (S-100+)
  3. Minimal pleomorphism and rare mitoses despite occasional aggressive behavior
  4. Dense-core neurosecretory granules visible on EM
  5. Histologic features alone cannot predict malignancy - only metastasis confirms it
  6. SDHB mutation = highest metastatic risk
Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 1049-1058; Cummings Otolaryngology Head and Neck Surgery, p. 528-529
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