Thymic Neuroendocrine Tumour

Thymic neuroendocrine tumours are rare neoplasms of the thymus with neuroendocrine differentiation. They range from typical and atypical carcinoids to the high grade large cell neuroendocrine carcinoma and small cell carcinoma, and they behave more aggressively than their pulmonary counterparts.

They form under 5% of thymic epithelial tumours. Median age is in the 40s to 60s, with a male predominance of about 3 to 1 (higher in multiple endocrine neoplasia type 1). About one quarter to one third are associated with multiple endocrine neoplasia type 1 (MEN1), and smoking raises risk in MEN1.

Ectopic ACTH secretion with Cushing syndrome occurs in about 30% of cases, usually in atypical carcinoids. Carcinoid syndrome and hypercalcaemia are uncommon.

Pathophysiology. Tumour cells express chromogranin A, synaptophysin, CD56 and INSM1, and often somatostatin receptors. Grade is set by mitotic count and necrosis: typical carcinoid has under 2 mitoses in 2 mm2 and no necrosis, atypical carcinoid has 2 to 10 mitoses in 2 mm2 or focal necrosis, and the high grade carcinomas have over 10.

MEN1 association. Germline MEN1 variants (menin loss) cause parathyroid, pancreatic and pituitary tumours. Thymic carcinoid develops in about 5% of patients with MEN1, almost always men.

Behaviour. Nodal metastasis occurs in 30% to 50% and distant metastasis (bone, liver, lung) in 20% to 40%. Recurrence reaches about 50%. Five year survival is about 50% to 70% and ten year survival about 30% to 40%. Cushing syndrome and high grade worsen outcome.

• Anterior mediastinal mass: cough, chest pain, dyspnoea, hoarseness, and superior vena cava obstruction. About one third are asymptomatic.
• Ectopic ACTH: rapid weight gain, hypertension, hypokalaemia, hyperglycaemia, proximal myopathy, bruising, striae and psychiatric symptoms. The course is often rapid and the classical features may be absent.
• MEN1 features: hypercalcaemia (primary hyperparathyroidism), pancreatic neuroendocrine tumour, pituitary adenoma.

Red flags.

• Severe hypokalaemia, uncontrolled hypertension or sepsis in a patient with hypercortisolism.
• Superior vena cava syndrome, stridor or respiratory compromise.
• Acute psychosis or severe myopathy with ectopic ACTH.

• CT or MRI of the chest: lobulated anterior mediastinal mass, often with vessel invasion and necrosis in high grade tumours.
• 68Ga-DOTATATE PET-CT (high sensitivity, defines receptor status and metastases). FDG-PET for high grade tumours.
• CT-directed core biopsy with immunohistochemistry (chromogranin A, synaptophysin, INSM1, cytokeratin, TTF1 and ACTH staining) and proliferation index.
• Biochemistry: 24-hour urinary free cortisol, late night salivary cortisol, morning ACTH and cortisol, and potassium. Dexamethasone 8 mg suppression and inferior petrosal sinus sampling when the source is uncertain. Calcium, PTH, prolactin, IGF-1, fasting gastrin and glucose for MEN1.
• MEN1 gene testing, with pituitary MRI and abdominal imaging (CT or MRI of the pancreas).
• Staging: CT of chest, abdomen and pelvis, bone scan or DOTATATE PET, and MRI brain for symptoms.

Differential diagnosis.

• Thymoma and thymic carcinoma
• Lymphoma and mediastinal germ cell tumour
• Small cell lung cancer and metastatic neuroendocrine tumour (lung, gastrointestinal)
• Intrathoracic goitre and Castleman disease
• Ectopic ACTH from lung, pancreas or medullary thyroid carcinoma

Surgery. Complete en bloc resection by median sternotomy, with thymectomy, resection of involved pericardium, pleura and vascular structures, and mediastinal lymph node dissection, is the mainstay. Hypercortisolism is medically controlled first.

MEN1. Transcervical thymectomy is added at the time of parathyroid surgery in men, since it lowers later thymic carcinoid risk. Genetic counselling and family screening.

Radiotherapy. Adjuvant 50 to 60 Gy in 25 to 30 fractions for microscopic or macroscopic residual disease, nodal involvement or high grade histology, with doses set by tolerance.

Hypercortisolism control.

• Metyrapone: 250 mg orally three times daily at the start, titrated every 3 to 7 days by 250 to 500 mg to a 24-hour urinary free cortisol or mean serum cortisol in the normal range, with hydrocortisone replacement if overcorrected; maximum 6 g daily; monitoring: potassium, blood pressure, androgens (hirsutism in women), cortisol profile, adrenal insufficiency symptoms; adjustment: lower doses in hepatic impairment, correct hypokalaemia before and during treatment, no routine renal adjustment.

Advanced or unresectable disease.

• Lanreotide (somatostatin receptor positive, indolent disease): 120 mg deep subcutaneously every 28 days until progression; maximum 120 mg every 28 days; monitoring: glucose and HbA1c, gallbladder ultrasound, thyroid function, heart rate; adjustment: start at 60 mg in moderate to severe renal or hepatic impairment.
• Lutetium (177Lu) dotatate (progressive somatostatin receptor positive disease): 7.4 GBq IV over 30 minutes every 8 weeks for 4 doses, with an amino acid infusion for renal protection starting 30 minutes before; maximum 4 doses; monitoring: FBC, creatinine and liver tests before each dose, delayed myelodysplasia; adjustment: withhold for grade 2 or worse toxicity and resume at 3.7 GBq, avoid when creatinine clearance is under 30 mL/min, contraception during and for 7 months after treatment (4 months for men).
• Capecitabine with temozolomide (atypical carcinoid): capecitabine 750 mg/m2 orally twice daily on days 1 to 14 with temozolomide 200 mg/m2 orally once daily on days 10 to 14, every 28 days for 4 to 6 months or until progression; maximum capecitabine 1500 mg/m2 daily and temozolomide 200 mg/m2 daily; monitoring: FBC, creatinine, liver tests, hand foot syndrome, diarrhoea; adjustment: reduce capecitabine to 75% when creatinine clearance is 30 to 50 mL/min and avoid under 30, test DPYD before starting, avoid warfarin, caution with temozolomide when creatinine clearance is under 36 mL/min.
• Cisplatin with etoposide (high grade carcinoma): cisplatin 75 mg/m2 IV on day 1 with etoposide 100 mg/m2 IV daily on days 1 to 3, every 21 days for 4 to 6 cycles; maximum cisplatin 100 mg/m2 each cycle; monitoring: FBC, creatinine, potassium, magnesium, audiometry, neuropathy; adjustment: give cisplatin only when creatinine clearance is 60 mL/min or more (carboplatin AUC 5 is the alternative), etoposide 75% of the dose when creatinine clearance is 15 to 50 mL/min and 50% when under 15, reduce for hepatic impairment.
• Radiotherapy or surgery for symptomatic bone or limited metastases.

Monitoring. CT of the chest every 3 to 6 months for 2 years, then annually for at least 10 years because of late recurrence. 24-hour urinary free cortisol for ACTH-secreting tumours, and MEN1 surveillance (calcium, PTH, pituitary and pancreatic imaging).

Referral and escalation.

• Endocrinology, thoracic surgery, oncology and nuclear medicine multidisciplinary review at diagnosis.
• Urgent admission for superior vena cava syndrome, severe hypokalaemia or sepsis with hypercortisolism.

Special groups.

• MEN1: family screening, and surgery with perioperative cortisol cover.
• Pregnancy: Cushing syndrome carries high foetal risk. Radiolabelled therapy is contraindicated, and surgery is timed with the multidisciplinary team.
• Kidney impairment: avoid lutetium and cisplatin, and adjust capecitabine.