7.7 about 24 minDeep Learning viewL7 p.24–25

Effects on the host and paraneoplastic syndromes

A tumor harms its host by occupying space, by consuming and inflaming the whole body, and by secreting substances that act far from the tumor. Paraneoplastic syndromes are the third kind, and they can be the first sign of the cancer.

Local effects: pressure, obstruction, bleeding

L7 p.22, 24

The simplest harm a tumor does is mechanical, and even a benign tumor can kill this way if the site is critical. A pituitary adenoma compresses the optic chiasm; a benign meningioma raises intracranial pressure. The pattern of symptoms follows the anatomy, not the biology.

Local effects and their classic presentationsL7 p.22, 24Ref. · Robbins: clinical effects of tumors

  • Obstruction

    Mechanism
    A mass fills a lumen
    Example
    Bronchial carcinoma → collapse and post-obstructive pneumonia; colon carcinoma → bowel obstruction; pancreatic head carcinoma → obstructive jaundice

  • Compression

    Mechanism
    A mass presses on a neighbor
    Example
    Pituitary adenoma → bitemporal hemianopia; lung apex tumor → Horner syndrome; mediastinal tumor → superior vena cava syndrome

  • Bleeding

    Mechanism
    The tumor ulcerates or outgrows its vessels
    Example
    Colon carcinoma → occult blood and iron deficiency anemia; gastric or renal carcinoma → hematemesis or hematuria

  • Perforation and infection

    Mechanism
    Necrotic tumor breaks down
    Example
    Perforated colon carcinoma; infected necrotic lung tumor

  • Pain

    Mechanism
    Stretch, invasion of nerves, bone destruction
    Example
    Perineural invasion (pancreas, prostate); pathologic fracture

  • Hormone excess from a functioning tumor

    Mechanism
    The tumor's own cell type secretes too much
    Example
    Adrenal adenoma → Cushing syndrome; insulinoma → hypoglycemia

Cachexia and the systemic effects

L7 p.24

Cachexia is progressive loss of body fat and lean muscle with weakness and anorexia, out of proportion to how much the patient eats and to the size of the tumor. It is not simple starvation: in starvation the body lowers its metabolic rate and spares muscle, whereas in cachexia basal metabolic rate stays high and muscle protein is broken down. The lecture names two tumor products, proteolysis-inducing factor (PIF) and lipolysis-mobilizing factor (LMF); cytokines from the tumor and the host, above all TNF (originally called cachectin), with IL-1 and IL-6, drive the same response and suppress appetite.

Systemic effects the lecture listsL7 p.24

  • Cachexia

    Mechanism
    TNF, IL-1, IL-6, PIF and LMF: ↑ metabolic rate, proteolysis, lipolysis, anorexia
    Clue
    Weight loss with preserved or raised metabolic rate; not reversed by feeding alone

  • Anemia of chronic disease

    Mechanism
    Inflammatory cytokines → hepcidin → iron trapped in macrophages; ↓ erythropoiesis
    Clue
    The commonest anemia in cancer: low serum iron with normal or high ferritin

  • Iron deficiency anemia

    Mechanism
    Chronic blood loss from the tumor
    Clue
    Low iron and low ferritin

  • Myelophthisic anemia

    Mechanism
    Marrow replaced by tumor
    Clue
    Leukoerythroblastic blood film: nucleated red cells and immature granulocytes

  • Hypercoagulability

    Mechanism
    Tumor procoagulants and tissue factor; thrombocytosis; raised clotting factors
    Clue
    Venous thrombosis; pancreatic carcinoma is notorious; can progress to DIC

  • Fever

    Mechanism
    Usually infection; sometimes tumor pyrogens (IL-1)
    Clue
    Investigate for infection first (the lecture's point)

Ectopic hormones

L7 p.25

A paraneoplastic syndrome is caused by a substance the tumor secretes, not by the tumor's bulk or its metastases. It can appear before the tumor is detectable, mimic metastatic disease, or be the thing that is actually killing the patient. Many are ectopic hormones, and small cell carcinoma of the lung produces more of them than any other tumor.

Teaching schematic

  • Small cell carcinoma of lung

    • ACTH → Cushing syndrome (hypokalemic alkalosis)
    • ADH → SIADH, hyponatremia
    • Anti-calcium-channel antibodies → Lambert–Eaton

  • Squamous cell carcinoma of lung

    • PTHrP → hypercalcemia with suppressed PTH

  • Renal cell / hepatocellular carcinoma

    • Erythropoietin → secondary polycythemia
    • HCC: IGF-2 → hypoglycemia

  • Pancreatic carcinoma

    • Procoagulants → Trousseau migratory thrombophlebitis
    • Nonbacterial thrombotic endocarditis (mucin-secreting)

  • Gastric carcinoma

    • Growth factors → acanthosis nigricans
    • Sudden seborrheic keratoses (Leser–Trélat)

  • Others

    • Lymphoma: calcitriol → hypercalcemia
    • Germ-cell tumors: hCG → gynecomastia
    • Medullary thyroid carcinoma: calcitonin
    • Bronchogenic carcinoma: clubbing, hypertrophic osteoarthropathy
Where the ectopic hormones come from and what they do: ACTH and ADH from small cell carcinoma, PTHrP from squamous carcinoma, erythropoietin from renal cell carcinoma, insulin-like factors from large tumors, hCG from germ-cell and trophoblastic tumors.L7 p.25

Ectopic hormone syndromesL7 p.25

  • Cushing syndrome

    Mediator
    ACTH
    Classic tumor
    Small cell carcinoma of lung; medullary thyroid carcinoma; pancreatic carcinoma
    Findings
    Hypertension, hyperglycemia, hypokalemic metabolic alkalosis, weakness; muscle wasting more than the classic habitus

  • SIADH (hyponatremia)

    Mediator
    ADH
    Classic tumor
    Small cell carcinoma of lung
    Findings
    Euvolemic hyponatremia, concentrated urine, confusion, seizures

  • Hypercalcemia (humoral)

    Mediator
    PTHrP; calcitriol in lymphomas
    Classic tumor
    Squamous cell carcinoma of lung; renal cell carcinoma; breast carcinoma; adult T-cell leukemia/lymphoma
    Findings
    Thirst, polyuria, constipation, confusion. PTHrP raises calcium but PTH is suppressed

  • Secondary polycythemia

    Mediator
    Erythropoietin
    Classic tumor
    Renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma
    Findings
    High hematocrit with a low serum erythropoietin in polycythemia vera, high here

  • Hypoglycemia

    Mediator
    Insulin-like growth factor 2
    Classic tumor
    Hepatocellular carcinoma, ovarian carcinoma, fibrosarcoma
    Findings
    Low glucose with low insulin and C-peptide

  • Gynecomastia

    Mediator
    hCG
    Classic tumor
    Choriocarcinoma of testis, seminoma
    Findings
    Breast enlargement in a man; β-hCG raised

  • Hypocalcemia

    Mediator
    Calcitonin
    Classic tumor
    Medullary carcinoma of the thyroid
    Findings
    The lecture's pairing; in practice calcitonin is mostly a marker, as clinically significant hypocalcemia is rare

Core activity · One Fact Changes

One Fact Changes

Answer a case and name the decisive clue. Then exactly one fact changes. Decide whether the answer moves, and why.

1 · The original case

A 64-year-old man who has smoked for 40 years has a central lung mass and weight loss. Serum calcium is 3.4 mmol/L (13.6 mg/dL), phosphate is low and intact PTH is undetectable; a bone scan shows no metastases. Biopsy of the mass is pending.

Which tumor and mediator best explain the laboratory findings?

Which fact decided it?

Neurologic, skin, clotting and kidney syndromes

L7 p.25

Non-endocrine paraneoplastic syndromesL7 p.25

  • Lambert–Eaton myasthenic syndrome

    Mechanism
    Antibodies against presynaptic voltage-gated calcium channels → less acetylcholine released
    Tumor
    Small cell carcinoma of lung
    Recognize it by
    Proximal weakness that improves with repeated use; dry mouth; reflexes return after exercise (the opposite of myasthenia gravis)

  • Acanthosis nigricans

    Mechanism
    Tumor-derived growth factors (TGF-α, EGF) stimulate keratinocytes
    Tumor
    Gastric adenocarcinoma (other GI carcinomas)
    Recognize it by
    Velvety, hyperkeratotic, hyperpigmented thickening of axilla, neck, flexures, anogenital skin

  • Leser–Trélat sign

    Mechanism
    Same growth factors
    Tumor
    Gastric and other carcinomas
    Recognize it by
    Sudden eruption of many seborrheic keratoses

  • Hypertrophic osteoarthropathy and clubbing

    Mechanism
    Unclear; growth factors (PDGF, VEGF) bypassing the lung
    Tumor
    Bronchogenic carcinoma
    Recognize it by
    Clubbing plus painful periosteal new bone at the distal phalanges and long bones

  • Trousseau syndrome (migratory thrombophlebitis)

    Mechanism
    Tumor procoagulants and mucins activate coagulation
    Tumor
    Pancreatic carcinoma; also lung, GI
    Recognize it by
    Superficial venous thromboses that appear in one site, resolve, then appear in another

  • Nonbacterial thrombotic (marantic) endocarditis

    Mechanism
    Sterile platelet-fibrin vegetations on a hypercoagulable, damaged endocardium
    Tumor
    Mucin-secreting pancreatic and colorectal carcinoma
    Recognize it by
    Small, friable, sterile vegetations on the mitral valve; emboli to brain and kidneys; blood cultures negative

  • Membranous nephropathy (nephrotic syndrome)

    Mechanism
    Subepithelial immune complexes in the glomerular capillary wall
    Tumor
    Lung, breast and stomach carcinoma
    Recognize it by
    Nephrotic-range proteinuria, edema; thickened capillary walls without hypercellularity

Worked case · Which syndrome, which tumor?

A 59-year-old woman has velvety, dark, thickened skin in both axillae, on her neck and in the anogenital region. Serum cortisol and other adrenal steroids are normal. She has lost weight.

If this is paraneoplastic, where is the tumor, and why does the normal cortisol matter?

Ch. VII cases p.7L7 p.25

Knowledge check · 7.7

Answer, read why, and try again whenever you like. Answers are kept in both study modes.

0 of 6 correct
  1. Q1Acanthosis nigricans and gastric carcinomaCh. VII cases p.7L7 p.25

    A 59-year-old woman has increasing skin pigmentation. Examination shows hyperkeratosis and hyperpigmentation of the axilla, neck, flexures and anogenital region. Serum adrenal corticosteroids and glucocorticoids are normal.

    If this represents a paraneoplastic syndrome, where is the primary tumor most likely to be?

  2. Q2Humoral hypercalcemia of malignancyL7 p.25

    A 64-year-old smoker has a 5-cm central lung mass. Serum calcium is 3.4 mmol/L (13.6 mg/dL), phosphate is low, intact PTH is undetectable, and a bone scan shows no metastases. Biopsy shows nests of keratinizing cells.

    What is causing the hypercalcemia?

  3. Q3SIADH from small cell carcinomaL7 p.25L4 p.19

    A 68-year-old man with a hilar lung mass is confused. Serum sodium is 116 mmol/L, serum osmolality 245 mOsm/kg and urine osmolality 580 mOsm/kg. He is euvolemic, with normal thyroid and adrenal function.

    Which tumor and mediator explain this picture?

  4. Q4Trousseau syndromeL7 p.24–25

    A 61-year-old man has had three episodes of tender, red, cord-like swellings in different superficial veins of his legs and left arm over 2 months. Each resolved and another appeared elsewhere. He has lost 9 kg and has epigastric pain radiating to the back.

    Which tumor is most likely, and what causes the thromboses?

  5. Q5Lambert–Eaton syndromeL7 p.25

    A 58-year-old woman with small cell lung carcinoma has difficulty rising from a chair. On testing, her proximal muscle strength improves after repeated contractions. She also has a dry mouth. Reflexes are reduced at rest.

    What is the mechanism?

  6. Q6Nonbacterial thrombotic endocarditisL7 p.25

    A 70-year-old man with widely metastatic colorectal carcinoma develops sudden right-sided weakness. Echocardiography shows small, friable vegetations on the mitral valve; three sets of blood cultures are negative and he has no fever.

    What is the most likely diagnosis?

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