Paraneoplastic Syndromes & Cancer-Related Hypercalcemia

Lung Tumours: General Information

• Lung cancer is the third most common cancer in the UK, following breast and prostate cancer.
• Lung cancer is the biggest cancer killer in the UK.
• Lung cancer kills more than breast, prostate, and pancreatic cancers combined.
• Approximately 36,000 people die each year from lung cancer in the UK
• About 98 people die of lung cancer every day
• There is currently no national lung cancer screening program in the UK.
• One-year lung cancer survival rate is 37%.
• Five-year lung cancer survival rate is 10%.
• Ten-year lung cancer survival rate is 5%.
• It is vital to correctly classify lung tumours as benign or malignant, primary or secondary, and identify the common types that metastasize to the lungs.

Metastases

• Metastases to the lungs are as common or more common than primary malignant lung tumours.
• Metastatic lung tumours are multiple and bilateral.
• Haematogenous spread can result in impressive "cannonball" tumours from sarcomas, melanomas, malignant testicular germ cell tumours, and carcinomas like renal cell carcinoma.
• Lymphatic spread can result in a more diffuse pattern of involvement: e.g., Lymphangitis carcinomatosa from breast carcinoma
• Malignant pleural effusions can occur.
• Common malignancies that present with pulmonary metastases consist of lung, colorectal, renal cell, pancreatic, & breast carcinoma
• Primaries that most frequently metastasize to the lungs consist of choriocarcinoma, Ewing's sarcoma, malignant melanoma, osteogenic sarcoma, testicular germ cell tumours, thyroid carcinoma, and pancreatic carcinoma

Primary Lung Tumours

• Primary (benign) lung tumours include pulmonary hamartoma/chondroma.
• Primary (malignant) lung tumours consist of (pulmonary carcinoid), bronchogenic carcinoma, malignant mesothelioma, malignant lymphoma, and certain types of soft tissue (mesenchymal) sarcoma
• Pulmonary chondroma/hamartoma: There is a disordered proliferation of mature cartilage, fat, smooth muscle with entrapped respiratory epithelial lined clefts. It is more frequent in males than females. Common in Central>periphery & is solitary

Primary Lung Carcinoma Classification

• Primary lung carcinomas are classified based on histology.
• Squamous carcinoma makes up 20-30%
• Adenocarcinoma makes up 30-40%
• Large cell (undifferentiated carcinoma) makes up 10-15%
  • Large cell is also anaplastic
• The 3 above are sometimes classified together as "Non-small cell carcinoma"
• Small cell carcinoma makes up 15-20%.
• Histological features:
  • Squamous carcinoma has keratin pearls and intercellular bridges.
  • Adenocarcinoma has gland formation and moderate differentiation.
  • Large cell (undifferentiated) carcinoma is anaplastic/poorly differentiated with a high grade.
  • Small cell carcinoma is very malignant, characterized by a high proliferation fraction and increased apoptosis and neuroendocrine differentiation.
• Pathogenesis:
  • Cigarette smoking and other causes of repeated injury to bronchial epithelium (e.g., bronchiectasis) lead to metaplasia: a permanent change from a respiratory ciliated bronchial epithelial lining to an abnormal squamous epithelium.
  • Dysplastic change progresses to carcinoma in situ and eventually invasive squamous carcinoma, often centrally located near the lung hilum.
  • Adenocarcinomas often develop more peripherally and are associated with fibrous scarring.
  • The precursor lesion for adenocarcinomas is atypical adenomatous hyperplasia and occurs in pneumocytes
• Classification of primary lung carcinoma include by central (hilar) or peripheral tumor
  • Central tumours are most often squamous cell carcinoma
  • Peripheral tumors are most often adenocarcinoma.
  • Bronchoscopy with cytology and bronchial biopsy is used for diagnosis

Anatomy Review

• Hilar anatomy includes bronchi, pulmonary artery & vein, and bronchial artery & vein
• The vagus nerve is also a key anatomical feature of the hilar region

Complications of Lung Tumours

• Local effects of lung tumors involve mass effect and ulceration.
• Superior vena cava obstruction causes fixed elevated JVP
• Masses obstruct a bronchus and cause collapse of the lung distal to the tumour, leading to atelectasis and infection.
• Ulceration of a pulmonary artery or veins/branches causes haemoptysis.
• Recurrent laryngeal nerve damage causes hoarseness.
• Phrenic nerve damage elevations of the hemidiaphragm
• Pericardium involvement could cause a malignant pericardial effusion, atrial fibrillation, and other arrhythmias
• Pleura involvement could lead to malignant pleural effusion
• Carina, oesophagus, and vertebra invasion can also occur due to local effects
• The growing tumour can cause compression of the superior vena cava, leading to a fixed elevated jugular venous pressure. Compression/infiltration of the sympathetic/stellate ganglion can cause Horner's syndrome: miosis, ptosis, and anhidrosis.

TNM Staging

• TNM stands for (Tumour size, Lymph Nodes, Metastases)
• The TNM system is used to stage most malignant tumours
• Staging is informed by clinical examination, radiological investigations.
• Staging is also informed by pathological examination of specimens (p prefix used).

The TNM Descriptors

• Primary Tumour (T):
  • TX: Primary tumour cannot be assessed, or tumour proven by the presence of malignant cells in sputum or bronchial washings but not visualised by imaging or bronchoscopy
  • T0: No evidence of primary tumour
  • Tis: Carcinoma in situ
    • Tis (AIS) for adenocarcinoma in situ
    • Tis (SCIS) for squamous cell carcinoma in situ
  • T1: Tumour 30 mm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal that the lobar bronchus
    • T1mi: Minimally invasive adenocarcinoma
    • T1a: Tumour 10 mm or less in greatest dimension
    • T1b: Tumour more than 10 mm but not more than 20 mm in greatest dimension
    • T1c: Tumour more than 20 mm but not more than 30 mm in greatest dimension
  • T2: Tumours more than 30 mm but not more than 50 mm in greatest dimension; or tumours with any of the following features (T2 tumours with these features are classified as T2a if 40 mm or less, or cannot be determined, or T2b if more than 40 mm but not more than 50 mm):
    • Involves the main bronchus
    • Invades visceral pleura
    • Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, either involving part of the lung or the whole lung.
    • T2a: Tumour more than 30 mm but not more than 40 mm in greatest dimension
    • T2b:Tumour more than 40 mm but not more than 50 mm in greatest dimension.
  • T3: Tumour more than 50 mm but not more than 70 mm in greatest dimension, or one that directly invades one of the following: parietal pleura (PL3), chest wall (including superior sulcus tumours), phrenic nerve, parietal pericardium; or associated separate tumour nodule(s) (intra-pulmonary metastases) in the same lobe as the primary.
  • T4: Tumour more than 70 mm in greatest dimension or one that directly invades one of the following: diaphragm, mediastinum, heart, great vessels, recurrent laryngeal nerve, carina, trachea, oesophagus, vertebra; or separate tumour nodule(s) (intra-pulmonary metastases) in different ipsilateral lobe to that of the primary.
• Regional Lymph Nodes (N):
  • NX: Regional lymph nodes cannot be assessed
  • N0: No regional node involvement
  • N1: Metastasis in ipsilateral peribronchial and/or ipsilateral hilar nodes and/or intrapulmonary nodes (node stations 10–14), including involvement by direct extension
  • N2: Metastasis in ipsilateral mediastinal and/or subcarinal node(s) (node stations 1–9)
  • N3: Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular nodes
• Distant Metastasis (M):
  • M1: Distant metastasis
    • M1a: Separate tumour nodule(s) in a contralateral lobe; tumour with pleural nodules or malignant pleural or pericardial effusion
    • M1b: Single extrathoracic metastasis in a single organ and involvement of a single distant (non-regional) lymph node
    • M1c: Multiple extrathoracic metastases in one or several organs
• Staging via TNM 8 is now recommended for *small cell carcinomas and carcinoid tumours, especially for those with limited disease

Metastatic Lung Carcinoma

• It is sometimes described as Stage IV disease.
• It is not curable by conventional treatments.
• Lung cancer can spread to other lung, pleural cavity, liver, bones, and brain, and adrenal glands.

Clinical Effects of Malignant Lung Tumours

• Can cause persistent cough, haemoptysis, dyspnoea, pleuritic chest pain, weight loss/cachexia, fatigue, and finger clubbing.
• Clinical indications of locally irresectable/incurable lung cancer include:
  • Horner's syndrome and involvement of left recurrent laryngeal nerve.
  • Scalene lymph node enlargement and hepatic or bone metastases are signs
• Syndromes not explained by local effect or metastases, or by the production of hormones indigenous to the tissue from which the tumour arose.

Paraneoplastic Syndromes

• Occur in about 10% of patients with malignancy.
• They arise from tumour secretion of hormones, peptides, or cytokines, or from immune cross-reactivity between malignant and normal tissues.
• Most commonly associated malignancies for concern include small cell lung cancer, breast, gynaecological, and haematological.
• Recognition of these syndromes may offer permit diagnosis of cancer in patients with confusing symptoms and Signs
• Examples include:
  • Neurologic can include Eaton-Lambert syndrome (immune mediated myasthenia).
  • Endocrine can include Cushing's syndrome
  • Musculoskeletal like Hypertrophic osteoarthropathy
  • Other Paraneoplastic Syndromes could consist of Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH)

Cushing's Syndrome:

• Approximately 5-10% of cases are paraneoplastic.
• Up to 50-60% of these paraneoplastic cases are lung tumours (small cell lung cancer and bronchial carcinoids).
• Patients often present with symptoms of paraneoplastic Cushing syndrome before a cancer diagnosis is made.

Hypertrophic Osteoarthropathy

• Prominent clinical feature of certain lung cancers.
• Includes painful swelling of the joints (knees, ankles, wrists, elbows, and metacarpophalangeal joints) as finger-clubbing.
• The Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH) leads in some cases to hypo-osmotic, euvolemic hyponatremia
• Affects 1-2% of all patients with cancer
• approximately 10% to 45% of all patients with small cell lung cancer can develop SIADH
• Arises from tumour cell production of antidiuretic hormone (ADH) and atrial natriuretic peptide.
• It occurs in up to 30% of patients with malignancy
• Severe cases are associated with severe neurocognitive dysfunction, volume depletion and renal insufficiency/failure
• Common associated malignancies are lung, multiple myeloma and renal carcinoma
• Humoral hypercalcaemia
  • Pathophys: PTHrP mediated hypercalcaemia:
  • Associated with squamous cell carcinoma of the head and neck, oesophagus, or lung
• Local osteolytic hypercalcaemia, extensive boney metastases, multiple myeloma, breast cancer, etc. occurs due to cytokine release from tumours

Malignant Mesothelioma

• Arises from mesothelial lining cells of pleura
• Strongly associated with exposure to asbestos; calcified pleural plaques may be seen on CXR or CT.
• Most commonly seen in shipyard workers, electricians, and plumbers.
• Notifiable to coroner: Coroner's autopsy required in all cases to confirm cause of death/diagnosis
• Conventional treatments for cancer, chemotherapy, and non-small cell lung carcinoma are options
• Small cell carcinoma is generally not treated by surgery because of high rates of metastasis.
• Poor prognoses: Overall, the prognosis is poor due to other factors.

Molecular Pathology

• Molecular pathology classifications may be more relevant than histology in lung cancer.
• This has driven the development and adoption of innovative targeted treaments.
• Targets may include EGFR; ALK; BRAF; ROS1; RET; NTRK1; and NRG1.
• Other treatments such as drivers not being found yet, a high mutational load & PD-L1 high expression can lead to consideration of Immunotherapy
• A soft-tissue mass in the right mediastinum can come from SCLC, which can show itself as a mediastinal mass or mediastinal lymphadenopathy with/without visualization of a primary lung tumour.

Glossary of Terms:

• Anaplastic: poorly differentiated or no discernible differentiation
• Atelectasis: collapse of part of the lung
• Cushing's syndrome: Clinical syndrome caused by excess cortisol secondary to excess ACTH production or exogenous steroid treatment or overproduction of cortisol because of adrenal disease (Cushing's disease)
• Cachexia: weight loss and muscle wasting secondary to cancer or other serious chronic diseases
• Dyspnoea: air hunger/shortness of breath
• Haemoptysis: blood in sputum
• Horner's syndrome: Ptosis (drooping of eyelid), miosis (constricted pupil), anhidrosis (lack of sweating). Due to interruption of sympathetic innervation
• Hyponatraemia: Low serum sodium
• Hypercalcaemia: High serum calcium

Explore cancer-related hypercalcemia, focusing on the percentage of cancer patients affected and the mechanisms behind it, including humoral and local osteolytic hypercalcemia. Also, learn about paraneoplastic syndromes, their underlying mechanisms, and specific syndromes like Lambert-Eaton myasthenic syndrome.