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GLOMUS TUMORS (PARAGANGLIOMAS OF THE HEAD AND NECK)

A Comprehensive 50-Mark Answer

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1. INTRODUCTION & HISTORICAL PERSPECTIVE

"These tumours arise from paraganglia associated with the jugular bulb and the tympanic branch of the glossopharyngeal nerve (Jacobson's nerve)." — Scott-Brown's Otorhinolaryngology, Head and Neck Surgery, 7th ed.

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2. APPLIED ANATOMY

Paraganglia of the Temporal Bone

ANATOMICAL DIAGRAM – GLOMUS TUMOR SITES

Temporal Bone (Coronal Section)
┌─────────────────────────────────────────────┐
│  External Auditory Canal                    │
│         │                                   │
│  [Middle Ear / Tympanic Cavity]             │
│    ●  GLOMUS TYMPANICUM                     │
│       (on Promontory — Jacobson's nerve)    │
│         │                                   │
│  ═══════════════════════════  Jugular Fossa │
│    ●  GLOMUS JUGULARE                       │
│       (Jugular Bulb adventitia)             │
│         │                                   │
│  Internal Jugular Vein                      │
│         │                                   │
│  Carotid Artery    ── ● GLOMUS VAGALE       │
└─────────────────────────────────────────────┘

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3. CLASSIFICATION SYSTEMS

A. Glasscock–Jackson Classification (Most Widely Used)

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B. Fisch Classification (Temporal Bone Paragangliomas)

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C. McCabe & Fletcher Classification (Cummings Otolaryngology)

• Glomus tympanicum
• Glomus jugulare
• Glomus jugulotympanicum (most common combined form)
• Glomus vagale

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4. EPIDEMIOLOGY

• Incidence: 1 per 1.3 million population/year; second most common benign tumor of the middle ear (after acoustic neuroma in the temporal bone region)
• Age: Peak incidence: 5th–6th decade
• Sex: Female predominance (F:M = 6:1) (Dhingra, Hazarika)
• Bilateral/multicentric: 3–10% of sporadic cases; 25–50% in familial cases
• Malignancy: Only 3–5% are malignant (defined by metastases, not histology)
• Familial: Autosomal dominant with genomic imprinting; SDHB, SDHC, SDHD mutations (succinate dehydrogenase subunit genes — WHO Classification 2017, p. 28)

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5. PATHOLOGY

Gross Appearance

• Lobulated, highly vascular, reddish-brown mass
• Encapsulated but not truly so — infiltrates surrounding structures
• "Sunrise appearance" — reddish pulsatile mass behind intact tympanic membrane

Microscopic Appearance

• Zellballen pattern — nests of chief cells (type I / glomus cells) surrounded by sustentacular cells (type II) and an elaborate vascular sinusoidal stroma
• Chief cells: Large, polygonal, eosinophilic cytoplasm, granular — contain catecholamine-secreting dense core vesicles
• Sustentacular cells (type II): Spindle shaped, at periphery of nests, S-100 positive
• IHC markers: Chromogranin A, synaptophysin, neuron-specific enolase (NSE) positive; S-100 in sustentacular cells

Functional Status

• Majority (>95%) are non-secretory (no catecholamine excess)
• ~1–3% secrete catecholamines → hypertensive crises, flushing, palpitations
• Always check 24-hour urinary VMA, metanephrines, catecholamines before surgery

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6. GENETICS (Recent Advances)

GENETIC FLOWCHART – HEREDITARY PARAGANGLIOMA
                                        
Succinate Dehydrogenase (SDH) Complex
(Mitochondrial Krebs Cycle)
           │
    ┌──────┴──────┐
   SDHA          SDHB ──→ High malignancy risk
    │             │
   SDHC          SDHD ──→ Head/neck paragangliomas
    │                      (Genomic imprinting:
    │                       paternal transmission)
    ▼
Pseudohypoxia → HIF-1α upregulation
    │
    ▼
VEGF ↑ → Neoangiogenesis → Tumor growth

• MEN2A/2B: RET proto-oncogene mutations
• NF1: Neurofibromatosis type 1
• VHL: Von Hippel-Lindau (HIF2A/EPAS1)
• Hereditary PGL syndromes (PGL1–PGL5): SDHx mutations (Andrews et al., J Med Genet 2018)

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7. CLINICAL FEATURES

SYMPTOM FLOWCHART

GLOMUS TUMOR – CLINICAL PRESENTATION FLOWCHART

                 GLOMUS TUMOR
                     │
        ┌────────────┴────────────┐
        │                         │
  GLOMUS TYMPANICUM        GLOMUS JUGULARE
        │                         │
  ┌─────┴──────┐           ┌──────┴──────────────┐
  │             │           │                     │
EARLY        LATE        LOCAL              CRANIAL NERVE
  │             │        SYMPTOMS           INVOLVEMENT
  │             │           │                     │
Pulsatile    Conductive   Pulsatile           CN IX, X, XI, XII
tinnitus     hearing      tinnitus            (Jugular Foramen
  │          loss         + HL                Syndrome)
  │             │           │                     │
Bluish-red   Otalgia      Otalgia            Dysphonia
pulsatile    Ear          Aural fullness     Dysphagia
mass behind  bleeding     Vertigo            Shoulder weakness
TM           Vertigo      CN involvement     Tongue atrophy
             (rare)       Horner's syndrome  Hoarseness

Symptom Summary by Tumor Type

1. Pulsatile tinnitus (most common, synchronous with pulse)
2. Conductive hearing loss
3. Bluish-red pulsatile mass visible behind intact tympanic membrane
4. "Brown's sign" / "Rising sun sign" — pulsatile reddish mass in hypotympanum
5. Aquino's sign (Pulsatile tinnitus ceases on compressing ipsilateral carotid) — actually seen in vascular tumors
6. Schwartze sign — reddish tinge through tympanic membrane (also seen in otosclerosis — differentiation needed)

1. Pulsatile tinnitus + conductive hearing loss
2. Jugular foramen syndrome (Vernet's syndrome): CN IX, X, XI palsy
3. Collet-Sicard syndrome: CN IX, X, XI, XII
4. Villaret's syndrome: CN IX, X, XI, XII + Horner's (sympathetic chain)
5. Facial nerve palsy (CN VII) — late feature
6. Sensorineural hearing loss (cochlear/labyrinthine extension)
7. Neck mass (extension into neck)

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Clinical Signs

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8. INVESTIGATIONS

FLOWCHART: DIAGNOSTIC WORKUP

SUSPECTED GLOMUS TUMOR
         │
         ▼
HISTORY + CLINICAL EXAMINATION
(Otoscopy, cranial nerve examination, neck)
         │
         ▼
AUDIOLOGICAL ASSESSMENT
(Pure tone audiogram, tympanogram — Type B flat curve)
         │
         ▼
BIOCHEMICAL SCREEN (all cases)
• 24-hr urine VMA, metanephrines, catecholamines
• Serum chromogranin A
• (Rule out functional tumor → avoid hypertensive crisis at surgery)
         │
    ┌────┴────┐
Negative    Positive → Alpha-blockade (Phenoxybenzamine)
    │                   before any intervention
    ▼
IMAGING
    │
    ├─── CT TEMPORAL BONE (HRCT) ──→ Bone detail
    │    • Erosion of jugular plate
    │    • "Moth-eaten" jugular foramen
    │    • Carotid canal involvement
    │
    ├─── MRI WITH GADOLINIUM ──────→ Soft tissue extent
    │    • "Salt and pepper" pattern (flow voids)
    │    • Intracranial/intradural extension
    │    • Dural sinus involvement
    │
    ├─── MR ANGIOGRAPHY / CT ANGIOGRAPHY → Vascular anatomy
    │
    ├─── FOUR-VESSEL ANGIOGRAPHY ──→ Pre-op embolization
    │    (DSA – digital subtraction angiography)
    │    • Feeding vessels (ascending pharyngeal artery)
    │    • Venous drainage
    │    • Contralateral ICA assessment (balloon occlusion)
    │
    └─── NUCLEAR MEDICINE
         • 68Ga-DOTATATE PET-CT (best for multicentric disease)
         • 123I-MIBG scintigraphy (functional tumors)
         • Octreotide scan (somatostatin receptor scintigraphy)

Radiological Features

• Soft tissue density in middle ear/jugular fossa
• "Moth-eaten" or "permeative" destruction of jugular fossa
• Erosion of caroticojugular spine
• Destruction of jugular plate separating carotid artery from jugular vein

• T1: Isointense to muscle with multiple signal voids (flow voids from vessels)
• T2: Hyperintense
• Post-Gad T1: Intense homogeneous enhancement
• "Salt and Pepper" sign: Pathognomonic — high-signal foci (hemorrhage/slow flow = "salt") alternating with low-signal flow voids (rapid flow = "pepper")

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CT AND MRI IMAGING — GLOMUS TYMPANICUM

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9. DIFFERENTIAL DIAGNOSIS

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10. MANAGEMENT

TREATMENT FLOWCHART

CONFIRMED GLOMUS TUMOR
         │
         ▼
ASSESS: Age, fitness, tumor grade, bilateral disease,
        only hearing ear, CN status, intracranial extension
         │
         ├─────── ELDERLY / HIGH SURGICAL RISK / ASYMPTOMATIC
         │               └──→ WATCHFUL WAITING (Active Surveillance)
         │                    Serial MRI every 12–24 months
         │
         ├─────── SURGICAL CANDIDATE
         │               │
         │        PRE-OPERATIVE EMBOLIZATION
         │        (24–72 hrs before surgery)
         │        • Ascending pharyngeal artery
         │        • Occipital artery branches
         │        • Reduces intraoperative bleeding
         │               │
         │               ▼
         │        SURGERY (based on grade)
         │        │           │
         │   GLOMUS          GLOMUS
         │  TYMPANICUM       JUGULARE
         │  (Grade I–II)     (Grade III–IV)
         │       │                 │
         │  Transcanal/     Infratemporal
         │  Endaural        Fossa Approach
         │  approach        Type A (Fisch)
         │  Tympanoplasty   ± Craniotomy
         │                  (Di grades)
         │
         └─────── NOT SUITABLE FOR SURGERY / RECURRENCE
                         └──→ RADIOTHERAPY
                              • Stereotactic Radiosurgery (SRS)
                                - Gamma Knife
                                - CyberKnife
                                - LINAC-based SRS
                              • Fractionated Stereotactic RT
                              • Conventional RT (palliative)

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A. Surgical Approaches (Detailed)

1. Glomus Tympanicum

2. Glomus Jugulare — Fisch Infratemporal Fossa Approach Type A (IFTA-A)

1. C-shaped post-auricular incision with inferior cervical extension
2. Cervical dissection — exposure of ICA, IJV, CN IX–XII
3. Subtotal petrosectomy — mastoidectomy + removal of EAC posterior wall
4. Blind sac closure of EAC
5. Anterior transposition of facial nerve (CN VII) — out of fallopian canal
6. Ligation/resection of sigmoid sinus and IJV
7. Skeletonization and resection of jugular bulb/tumor
8. Intracranial extension addressed with neurosurgical assistance

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SURGICAL APPROACH DIAGRAM — GLOMUS JUGULARE

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B. Pre-operative Embolization

• Performed 24–72 hours before surgery
• Route: Transarterial — microcatheter superselective embolization
• Agents: PVA particles, Onyx, n-BCA glue, coils
• Reduces blood loss by 40–60%
• Risk: Stroke (ICA/vertebral involvement), CN palsy, skin necrosis
• Contraindication: Dangerous anastomoses between external and internal carotid circulation

C. Radiotherapy

• Elderly/medically unfit patients
• Residual/recurrent tumor
• Intracranial extension
• Bilateral tumors
• Patient refusal of surgery
• Glomus vagale (CN X sacrifice unacceptable)

• Dose: 12–15 Gy (single session)
• Tumor control rate: 90–95% at 5 years
• Does NOT cure the tumor — causes fibrosis, arrest of growth
• Preferred for small–medium tumors (<3 cm)

• Total dose: 45–54 Gy in 1.8–2 Gy fractions
• Larger tumors / proximity to critical structures

D. Watchful Waiting (Active Surveillance)

• Growth rate: 0.8–1.7 mm/year (very slow)
• Appropriate for: Asymptomatic elderly patients, bilateral tumors, only hearing ear, poor surgical candidates
• Serial MRI every 12–24 months
• Intervention triggered by: Symptomatic progression, significant growth, new CN deficits

E. Pharmacological (Functional Tumors)

• Alpha-adrenergic blockade (Phenoxybenzamine 10–40 mg/day) — 2 weeks pre-op
• Followed by beta-blockade after adequate alpha-blockade
• Metyrosine (tyrosine hydroxylase inhibitor) — reduces catecholamine synthesis
• For metastatic/inoperable functional tumors: Sunitinib, Temozolomide (recent advances)

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11. COMPLICATIONS

Intraoperative

• Massive hemorrhage (ECA/ICA branches)
• CN VII–XII injury
• ICA injury → stroke
• CSF leak (intradural extension cases)
• Air embolism (open sinuses/veins)

Post-operative

• CN VII palsy (anterior transposition in IFTA) — usually temporary
• Lower cranial nerve deficits (CN IX, X, XI, XII) → aspiration, dysphonia, dysphagia
• CSF leak
• Meningitis
• Residual/recurrent tumor
• Conductive hearing loss (canal wall down procedures)

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12. PROGNOSIS

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13. SPECIAL SITUATIONS

Bilateral / Multicentric Disease

• Occurs in PGL1 (SDHD), PGL4 (SDHB) mutation carriers
• Pre-operative 68Ga-DOTATATE PET-CT essential to exclude multicentric disease
• Staged surgery; hearing preservation prioritized
• SRS preferred for bilateral cases

Pregnancy

• Surgery postponed until after delivery if possible
• Embolization may be considered for symptomatic relief
• Avoid ionizing radiation (MRI preferred for surveillance)

"Wait and Scan" Policy

• Endorsed by Zanoletti & Mazzoni (Skull Base 2006) for elderly patients
• Annual/biennial MRI
• Intervention if growth >3 mm/year or new CN deficits

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14. RECENT ADVANCES

1. Genetics & Molecular Pathology

• SDHx mutation testing now standard in all paraganglioma patients (WHO 2017)
• HIF2A mutations — cluster 1B tumors with polycythemia
• TMEM127, MAX gene mutations identified
• Liquid biopsy — cell-free DNA for monitoring

2. Imaging

• 68Ga-DOTATATE PET-CT: Superior sensitivity (>95%) over conventional scintigraphy for detecting multicentric/metastatic paragangliomas (Timmers et al., J Nucl Med 2012)
• 3T MRI with time-resolved MR angiography — better delineation of carotid involvement
• 4D-CT angiography for dynamic vascular assessment

3. Endoscopic Surgery

• Endoscopic transcanal approach for glomus tympanicum Class A1/A2
• Minimally invasive; reduced morbidity; superior visualization of protympanum
• Championed by Marchioni, Presutti et al. (European skull base centers)

4. Radiosurgery

• Long-term data (10–15 years) confirming >90% tumor control with SRS
• Hypofractionated SRT (3–5 fractions) for intermediate-size tumors
• Combination: Embolization + SRS (for residual tumor)

5. Systemic Therapy (Metastatic Disease)

• Sunitinib (VEGFR inhibitor) — phase II trials showing partial responses
• Temozolomide + Capecitabine (TEMCAP)
• 177Lu-DOTATATE PRRT (Peptide Receptor Radionuclide Therapy) — promising for SSTR-positive metastatic paragangliomas
• Cabozantinib — ongoing trials (CABOPARA study)

6. Immunotherapy

• Checkpoint inhibitors (PD-1/PD-L1) under investigation
• Tumor microenvironment rich in M2 macrophages — potential therapeutic target

7. Robotic Surgery

• Da Vinci robotic assistance for carotid body tumors and glomus vagale resection in select centers

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15. SUMMARY FLOWCHART — COMPLETE MANAGEMENT ALGORITHM

PULSATILE TINNITUS + REDDISH MIDDLE EAR MASS
                    │
                    ▼
         OTOSCOPY + PNEUMATIC OTOSCOPY
              Brown's sign (+)?
                    │
             YES ───┤───── NO ────→ Consider other causes
                    │
                    ▼
         AUDIOGRAM + TYMPANOGRAM
         (CHL + flat curve common)
                    │
                    ▼
         BIOCHEMISTRY (24h urine VMA,
         metanephrines, Chromogranin A)
                    │
                    ▼
         HRCT TEMPORAL BONE + MRI GADOLINIUM
         ("Salt and pepper" + intense enhancement)
                    │
         ┌──────────┴──────────┐
   GLOMUS TYMPANICUM    GLOMUS JUGULARE
   (Fisch A/B)          (Fisch C/D)
         │                    │
    Transcanal/          Fisch IFTA-A
    Endaural             ± Pre-op embolization
    surgery              ± Craniotomy (Di)
         │                    │
         └──────────┬──────────┘
                    │
         Poor candidate/Elderly?
                    │
              ┌─────┴─────┐
          SRS/SRT      Watchful Waiting
          (Gamma         (Serial MRI)
           Knife)
                    │
                    ▼
         FOLLOW-UP (Annual MRI × 5 years,
         then biennial)
         Screen family (SDHx mutations)

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16. KEY POINTS SUMMARY (Exam Quick Reference)

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REFERENCES

1. Scott-Brown's Otorhinolaryngology, Head and Neck Surgery, 7th/8th ed. — Browning, Luxon et al. Chapters on Paragangliomas of the Temporal Bone
2. Cummings Otolaryngology: Head & Neck Surgery, 6th/7th ed. — Flint et al. Chapter: Glomus Tumors
3. Stell & Maran's Head and Neck Surgery, 4th/5th ed. — Watkinson, Gaze, Wilson. Chapter: Paragangliomas
4. Zakir Hussain — Textbook of Ear, Nose and Throat Diseases, relevant chapters on middle ear tumors
5. Dhingra PL — Diseases of Ear, Nose and Throat, 7th ed. — Glomus tumors, pp. 90–96
6. Hazarika P — Textbook of ENT and Head-Neck Surgery, 3rd ed. — Tumors of middle ear and temporal bone
7. Fisch U, Mattox D. Microsurgery of the Skull Base. Stuttgart: Thieme; 1988
8. Glasscock ME, Jackson CG. Surgery of the Skull Base. Lippincott; 1988
9. WHO Classification of Tumours of Endocrine Organs, Vol 10, 4th ed. Lyon: IARC, 2017
10. Andrews KA et al. Tumour risks and genotype-phenotype correlations — J Med Genet, 2018;55:384–394
11. Timmers HJ et al. 68Ga-DOTATATE PET imaging. J Nucl Med 2012
12. Fishbein L. Pheochromocytoma and paraganglioma: genetics, diagnosis, and treatment. Hematol Oncol Clin North Am. 2016;30:135–150
13. Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and pheochromocytoma: from genetics to personalized medicine. Nat Rev Endocrinol. 2015;11:101–111
14. Gruber LM et al. Pheochromocytoma and paraganglioma in patients with neurofibromatosis type 1. Clin Endocrinol (Oxf). 2017;86:141–149

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