Lymphangiosarcoma (Stewart-Treves Syndrome)

Definition

Pathogenesis & Etiology

• Prolonged lymphatic stasis creating an immunologically impaired microenvironment
• Local tissue hypoxia and chronic inflammation promoting malignant endothelial transformation
• The tumor arises from lymphatic endothelium and proliferates rapidly with early systemic spread

Clinical Features

• Acute worsening of pre-existing chronic lymphedema
• Appearance of bluish or reddish-purple subcutaneous nodules on the affected extremity (typically the arm in postmastectomy cases)
• Nodules have a propensity toward hemorrhage and ulceration
• Multiple lesions are common
• Rapid proliferation with early systemic metastasis

Immunohistochemistry (Pathology)

• Positive markers: CD34, CD31, Ulex europaeus lectin (endothelial markers)
• Negative: Antikeratin antibodies (useful to exclude metastatic breast carcinoma, which stains keratin-positive)

Prognosis

• Average survival after diagnosis: ~19 months
• Early and aggressive metastatic spread is the rule
• Schwartz's Principles of Surgery reports the tumor is "generally aggressive"

Treatment

1. Radical surgery - often requires radical amputation of the affected extremity; this may be lifesaving if performed early
2. Preoperative chemotherapy - used in the multimodal approach, as for other high-grade sarcomas
3. Radiation therapy - combined with surgery in a multimodal approach
4. The standard sarcoma approach: neoadjuvant chemoradiation followed by surgical excision is the framework - Sabiston Textbook of Surgery

Related/Differential Entities

Key Facts Summary

• First described: Stewart & Treves, 1948 (6 cases of postmastectomy lymphangiosarcoma)
• Incidence: ~0.07% after axillary node dissection
• Latency: Usually >10 years of chronic lymphedema before malignant transformation
• Site: Most common in the upper extremity (postmastectomy), but can occur in any chronically lymphedematous region
• Predisposing conditions listed by Washington Manual: Age, prior radiation, chemical/chemotherapy exposure, genetic syndromes, Paget's disease of bone, HIV/HHV-8 (Kaposi), and chronic lymphedema (lymphangiosarcoma/Stewart-Treves)

Multinodular Goitre (MNG)

Definition

Figure: Large multinodular goitre (Bailey & Love's Short Practice of Surgery, 28e)

Classification

Pathogenesis

1. Iodine deficiency (or goitrogenic substances, genetic enzyme defects) → low circulating thyroid hormones → raised TSH
2. TSH drives diffuse follicular hyperplasia (parenchymatous/hyperplastic goitre)
3. With fluctuating TSH levels, some lobules remain active, others become inactive - creating areas of active and inactive tissue
4. Inactive follicles fill with colloid → colloid goitre
5. Repeated cycles of hyperplasia, necrosis, haemorrhage, fibrosis → multinodular stage (irreversible)

• Goitrogenic substances: cabbage, turnips, brassica vegetables, soya, antithyroid drugs, para-aminosalicylates
• Physiological demands: puberty, pregnancy (increased metabolic demand)
• Genetic mutations within specific nodules can drive clonal expansion and autonomous function (in toxic MNG) - Scott-Brown's ENT HNS, Vol 1

Epidemiology

• 6 times more common in females than males (oestrogen receptors in thyroid tissue)
• In endemic areas: nodulation appears early, ages 20-30 years
• In sporadic areas: nodulation appears later, ages 30-40 years (patient may be unaware until their 40s or 50s)
• Approximately 50% of patients who present with a "solitary nodule" actually have MNG on further evaluation

Clinical Features

Symptoms

• Slowly enlarging, painless lump in the neck
• Sudden pain and enlargement if haemorrhage occurs into a nodule
• Pressure symptoms when the goitre becomes large:
  • Dyspnoea (tracheal compression/deviation)
  • Dysphagia to solids
  • Stridor
  • Engorged neck veins (superior mediastinal compression)
  • Symptoms worse at night or in the recumbent position

Signs

• Gland has an asymmetrical shape with a smooth, nodular surface
• Nodule consistency varies: soft to hard (hard nodules = calcification or tense haemorrhage)
• Moves upwards on swallowing (confirming thyroid origin)
• Hardness and irregularity due to calcification can simulate carcinoma

Functional Status

• Most patients are euthyroid (non-toxic MNG)
• Secondary thyrotoxicosis occurs in ~25% of long-standing cases (autonomous nodule function)
• In very long-standing disease, most nodules become inactive → myxoedema may develop by age 60-70

Toxic Multinodular Goitre

• Occurs when two or more autonomously functioning nodules secrete excess thyroid hormone
• The most common cause of hyperthyroidism in the elderly in iodine-replete areas; in iodine-deficient areas it is the most common cause of hyperthyroidism overall
• Thyroid hyperfunction is less marked than in Graves' disease
• Cardiovascular effects predominate: palpitations, atrial fibrillation, other tachyarrhythmias
• Classical eye signs (exophthalmos), tremor may be absent
• Jod-Basedow effect: pharmacological iodine doses (e.g., IV contrast media) can precipitate acute thyrotoxicosis in MNG, especially in iodine-deficient areas
• Definitive treatment with radioiodine is required

Complications of MNG

Investigations

1. Thyroid function tests (TFTs) - to exclude hypo- or hyperthyroidism
2. Thyroid antibodies - to differentiate from autoimmune (Hashimoto's) thyroiditis (the two can coexist)
3. Ultrasound - gold standard for nodule assessment; multiple isoechoic nodules with varying cystic change throughout both lobes = almost certainly benign; US outperforms CT/MRI for nodule characterisation
4. FNAC (Fine Needle Aspiration Cytology) - only required for nodules with suspicious ultrasonographic features (not necessarily the largest/dominant nodule); must be US-guided
5. CT scan of chest and neck - if swallowing or breathing symptoms are present; best to assess tracheal/oesophageal compression or retrosternal extension
6. MRI - can identify cystic/solid components and haemorrhage in retrosternal goitre
7. Radionuclide scan (¹³¹I) - helpful for retrosternal extension; hot vs cold nodule determination

Treatment

Non-Toxic MNG

• Features suggesting underlying malignancy
• Pressure symptoms (after excluding other causes)
• Tracheal compression
• Cosmetic reasons (patient preference)
• FNAC suspicious of malignancy

• Iodised salt - primary prevention in endemic areas; dramatically reduces incidence
• Thyroxine suppression therapy - now considered outdated; leads to subclinical hyperthyroidism with risks of reduced bone mineral density and cardiovascular disease; nodules often regrow on discontinuation
• Radioactive iodine (¹³¹I) - used when surgery is refused or contraindicated by age/frailty/comorbidities; can reduce goitre volume by up to 60%, with most shrinkage occurring soon after treatment; better outcomes in younger patients with smaller goitres receiving higher doses

• More than half of benign nodules regress over 10 years without surgery
• Reoperation for recurrent goitre is more difficult and hazardous - hence preference for total thyroidectomy in younger patients at first operation
• Total thyroidectomy requires lifelong thyroxine replacement

Toxic MNG

• Antithyroid drugs (carbimazole/propylthiouracil) - initial medical control
• Definitive treatment: radioiodine (¹³¹I) - treatment of choice; older patients respond well
• Surgery if radioiodine contraindicated or goitre is large

Key Points Summary