small cell carcinoma of the lung (SCLC, oat cell carcinoma)

Etiology

• tumor originates from neuroendocrine cells
• Kulchitsky cell hypothesized cell of origin, although not proven

Epidemiology

• 25% of bronchogenic carcinomas
• smokers & uranium miners are at risk

Pathology

• generally metastatic cancer at the time of diagnosis
• histologic classification:
  • small cell carcinoma
  • mixed small & large cell carcinoma
  • combined small cell carcinoma (neoplastic squamous &/or glandular components)
• histological features
  • scant cytoplasm
  • small, hyperchromatic nuclei with fine chromatin
  • indistinct nucleoli
  • diffuse sheets of cells
• invades tracheobronchial tree
• spreads submucosally & later breaks through mucosa
• < 20% of tumors are peripheral
• brain metastases (30%)

Genetics

• rearrangement 1p32 RLF with L-MYC
• chromosomal deletion 3p13-23
• other implicated genes
  • ROBO1, HTATIP2, ITGA9, c-MYC, INSM1, CCKBR, USP4

Clinical manifestations

• cough
• hemoptysis
• chest pain
• hoarseness
• dyspnea
• associated syndromes:
  • SIADH
  • Cushing syndrome
  • Lambert-Eaton myasthenic syndrome
  • superior vena cava syndrome
  • cortical cerebellar degeneration (rare)
  • limbic encephalitis (rare)
  • peripheral neuropathy (rare)
• hyperpigmentation from melanocyte-stimulating hormone (MSH)

Laboratory

• serum chemistries:
  • chem 7
    • serum K+: hypokalemia (increased ACTH)
    • serum Na+: hyponatremia (SIADH)
  • serum Ca+2: NOT associated with hypercalcemia
  • serum phosphorous
  • liver function tests (LFTs)
• serum osmolality & urine osmolality
• complete blood count (CBC)
• serum calcitonin & serum procalcitonin
  • increased secretion of calcitonin (70%)
• serum ACTH: increased ACTH
• 24 hour urinary free cortisol (Cushing syndrome)
• antineuronal nuclear antibody (ANNA-1) may be positive
• bone marrow biopsy & aspiration
• immunohistochemistry:
  • NSE: + in 95% of pulmonary neuroendocrine tumors of all types
  • chromogranin A: + 20-50% of small cell carcinomas
  • synaptophysin: + 80-100%
  • CK7: + 10%
  • CD57: + 20-50%
  • CEA: + 100%
  • low molecular weight keratins (CAM5.2, 34betaH11, AE1/AE3): + 90%
  • high molecular weight keratins: -

Diagnostic procedures

• bronchoscopy may show thickened mucosa
• biopsy of metastatic deposits identified on radiographs establishes diagnosis*
• skin test for tuberculosis
• barium swallow if esophageal symptoms are present
• pulmonary function studies including arterial blood gas (ABG) if signs/symptoms of respiratory insufficiency are present
• electrocardiogram
• overnight dexamethasone suppression test (Cushing syndrome)

* needle aspiration rather than biopsy of lymph node diagnostic according to ref

Radiology

• chest X-ray
  • unilateral, rapidly enlarging hilar or peripheral mass
  • widening of mediastinum
• computed tomography of thorax & abdomen & pelvis (chest CT, abdominal CT, CT of pelvis)
  • hilar hilar or peripheral mass confirming chest X-ray finding
  • mediastinal lymphadenopathy
• MRI of brain (even if no symptoms)
• whole body radionucliide bone scan or positron emission tomography (PET scan)

Staging

• limited: no universal definition
  • includes confined to one hemithorax/mediastinum/supraclavicular nodes or limited to one radiation field
• extensive: distant metastases
  • TNM staging system for non-small cell carcinomas not commonly used
  • survival not usually affected by small differences in amount of local/regional tumor
  • ref recommends TNM staging system
• defer further staging procedures if distant metastasis is documented
• see pretreatment staging for patients with lung cancer

Differential diagnosis

• neuroendocrine neoplasms encompass a spectrum:
  • bronchial carcinoid with excellent prognosis after resection
  • malignant/atypical carcinoid or well-differentiated neuroendocrine carcinoma
  • small cell carcinoma

Management

• tumor responds to radiation & chemotherapy
• even patients with poor performance status benefit from chemotherapy
  • effect of chemotherapy on quality of life & in patients with poor prognosis is unknown
• early palliative care consult for metastatic lung cancer
  • concurrent chemotherapy & palliative care can improve quality of life & increase life expectancy 20%
• platinum-based combination chemotherapy
  • 5-6 cycles of chemotherapy suggested
• active chemotherapeutic agents:
  • carboplatin or cisplatin (carboplatin with favorable toxicity profile)
  • etoposide
  • cyclophosphamide
  • doxorubicin
  • vincristine
  • oral topotecan may be an option for relapse (do not use IV topotecan) (NGC NICE)
  • addition of lurbinectedin (Zepzelca) to atezolizumab (Tecentriq) as 1st-line maintenance therapy for advanced-stage small cell lung cancer improves progression-free & overall survival
• surgical candidates (rare to uncommon)
  • single small primary tumor
  • absence of lymph node involvement
  • invasive staging of the mediastinum with endobronchial ultrasound vs mediastinoscopy to rule out occult disease
  • adjuvant chemotherapy (without radiation if surgical margins negative)
• limited stage disease
  • combination chemotherapy (cisplatin + etoposide) + radiation therapy
• if complete clinical response to chemotherapy, add prophylactic cranial irradiation; decreases frequency of brain metastases & prolongs survival
• extensive stage disease: combination chemotherapy
  • carboplatin or cisplatin + etoposide + immunotherapy
  • cisplatin + ironotecan (conflicting reports)
  • radiation therapy of no benefit
• whole brain radiation therapy
  • prophylaxis for patients who respond to chemotherapy
  • symptomatic brain metastases
• routine chest radiation therapy does not improve survival
• monthly intravenous bisphosphonate (pamidronate, zoledronate) decreases skeletal-related events

see National Cancer Institute - Small Cell Lung Cancer Treatment

Prognosis:

• most aggressive of pulmonary tumors without treatment: median survival ~2-4 months

More general terms

• neuroendocrine carcinoma
• carcinoma of the lung
• small cell carcinoma

Additional terms

• chromosomal deletion 3p13-23 (SCC lung)
• distinguishing features of small cell carcinoma
• pretreatment staging for patients with lung cancer

Database

• OMIM: https://mirror.omim.org/entry/182280