OzEMedicine - Wiki for Australian Emergency Medicine Doctors

see also:

• neoplasia / cancer / tumours

• A dominant clone forms in tumours (selected by microevolutionary process) & this is the sole clone is present in the tumour & in metastases but there may be phenotypic heterogeneity with different receptors, etc. expressed.
• For a tumour to spread it must have clones with a metastatic phenotype (“seed”) that allows metastasis, a suitable tissue (“soil”) to metastasize in & a mechanism of getting there without destruction by the immune system;
• Metastases may occur early in tumor development, & the constant shedding of cells is irrelevant to metastasis.
• There is nothing that a metastatic cell can do that is not a routine task for normal cells such as lymphocytes, monocytes & neutrophils except normal cells don't appear to migrate & invade by the same mechanisms as tumour metastases;

• direct infiltration of surrounding tissues - all malignant tumours;
• tend to follow natural clefts or tissue planes & move in line least resistance;
• may be held up for some time by dense fascial sheaths;
• cartilage is resistant to tumour invasion → i/vert disc & epiph. v.late;
• may infiltrate into:
  • striated muscle cell fibres;
  • epidermis (eg. Paget's of nipple, malig. melanoma)
  • BCC spread entirely local;

• carcinomas » sarcomas have tendency to invade lymphatics
• ⇒ cord-like “permeation” within lymphatics
• ⇒ block channel
• ⇒ retrograde diversion of lymph & Ca cells
• ⇒ outlying malig. nodules (eg. skin over breast Ca);
• ⇒ local oedema (peau-d'orange in breast Ca);
• eg. lymphangitis carcinomatosa - in lung usually due to 2° (breast);

• esp. pancreas Ca & adenoid cystic Ca parotid, many other Ca → pain;

• esp. lung Ca as many vessels available, but may be missed as often covered with thrombus;
• also clear-cell Ca kidney → renal V (→ L. varicocoele);

• generally, thick elastic wall prevents invasion but:
  • lung → pulm A (may → tumour necrosis, lung infarct);

• probably invaded in every case of malignant dis., esp sarcoma;

• once mesothelium eroded, the space may be traversed by tumour cells:
  • some periph. lung Ca → directly to chest wall;

• emboli of permeated tumour cells (mainly Ca rarely sarcoma) → LN's
  • ⇒ may pass into blood via thoracic duct, etc;
• retrograde embolism to other LN's may occur if lymph blocked:
  • eg. gastric Ca blocking thor.duct @ entry into L.subclavian V
    • ⇒ spread to L. cervical nodes (Virchow's node);
• early LN involement in: breast, lung, tongue Ca;
• late LN involvement in: skin, lip Ca;

• NB. also after lymph spread into subclavian Vv (Ca » sarcoma);
• emboli after venous/small vessel invasion (sarcoma » Ca) then impact on (most die) & then penetrate a distant capillary network to proliferate, acquire own blood supply & develop into secondary tumours, mainly at following sites in order frequency:
  • liver esp. if tumour invades portal V - GIT, breast, lungs, gen/urin; sarcoma;
  • lung - breast, kidney, thyroid, sarcomata;
  • bones (red marrow) - lung (esp. oat-cell ), breast, prostate, kidney (clear-cell),
  • thyroid (foll.cell mainly); neuroblastoma;
  • osteoplastic lesions - prostate (occas. breast, colon, neuroblastoma);
  • brain - lung, breast, melanoma;
  • adrenal (med>cort) - lung (esp. oat-cell), breast,
  • skin (face, scalp) - lung, breast, melanoma;
• NB. sarcomata metastasise early, mainly → lung » liver/brain » bone;
• NB. malignant brain tumours rarely → outside cranial cavity (no lymph);
• NB. these metastases may lie dormant for a long time & although may have occurred prior to lymph node involvement, the LN's may become evident 1st !!

• when tumour invades a serosal layer of a viscus → inflamm. response → effusion, & may allow malig. cells to detach & be swept away in effusion & set up seedlings elsewhere on serosal wall:
• peritoneal: stomach, colon, ovary → greater omentum, Pouch of Douglas; ovaries;
  • NB. Krukenberg bilat. ov. tumour - ? from perit. or lymphatics;
  • usually 1° mucoid tumour - stomach»colon/breast;
• pleural: lung, breast , lung 2°'s → pericardium;
  • NB. Meig's synd.: benign ov. fibroma → ascites + pleural effusion!!
• CSF: 1° cerebral tumours → subarachnoid space → spinal theca;
  • esp. medulloblastoma, oligodendroglioma, ependymoma;
• Spread along epithelial-lined spaces:
  • papillary tumours renal pelvis → scattered tumours along ureter & bladder;
  • surgical implantation of tumour cells at incisions or along needle tracks;

• Growth: overcome allogeneic inhibition by nearby tissue cells, etc.;
• Angiogenesis if > 2mm (similar to wound healing):
  • degree of angiogenesis often predictive of metastatic disease;
  • degradation of basement membrane, extracellular matrix;
  • endothelial migration & proliferation, then organisation & maturation;
  • needs:
    • proteolysis (see under tissue invasion)
    • stimulation of new capillaries, etc
  • regulated by balance between:
    • fibroblast growth factors;
    • transforming growth factors;
    • inhib. by high dose steroid & heparin;
    • inhib. factors;
• Tissue invasion:
  • tissue matrix proteolysis
  • balance b/n:
    • matrix metalloproteinases (released as zymogens, best @ pH7)
    • interstitial collagenases (collagen I/II/III);
    • gelatinases (gelatin & collagen IV)
    • stromelysins (collagen IV & proteoglycans)
    • tissue inhib. of metalloproteinases (TIMPs)
  • cell detachment from main mass (ie. homophilic cell/cell interactions decr.);
  • down regulation of cadherin expression esp. if loss of differentiation;
    • ⇒ increased migratory & invasiveness;
  • increased cell-matrix interactions
    • correlates with tumour progression in some tumours;
    • assists in providing traction at migrating front of tumour cell & is released from hind part to allow movement;
    • up-regulation of fibronectin & vitronecton receptors (integrins) that bind to Arg-Gly-Asp (RGD) tripeptide sequences in extracellular matrices;
  • cell motility increased
    • due to cell receptor binding motility stimulating factors (motogenic cytokines):
      • scatter factor produced by fibroblasts
        • same as hepatocyte growth factor (HGF);
        • receptor is a transmemb. tyr. kin. encoded by c-MET oncogene!
        • autocrine motility factor (AMF) from cell itself → acts via G protein;
        • migration stimulating factor (MSF)

• Survival - Host interactions ( with cytotoxic T cells, etc):
  • down regulation of expression of MHC class I molecules, or,
  • lack of surface neoantigens (tumour-specific antigens)
    • tumour-spec. transplantation Ags (TSTAs)
      • rejection via cytotox. T cells &/or Ig/compl-mediated cytotoxicity;
      • occas. protection “immunol. enhancement” as Ig hide Ag from T cells;
    • oncofetal antigens (tumour markers in blood but not involved in rejection)
      • carcinoembryonic Ag (CEA) - some colon Ca in tumour mass;
      • alpha-fetoprotein - liver Ca, germ-cell tumours; stomach/pancreas;
    • other antigens, often tumour specific
      • T antigen - nucleus od DNA-virus induced tumours;
      • Ca antigen - many malignant tumours;
  • lack of expression of ICAM-1 (needed for stable binding to T cell LFA-1 integrin)
  • release of soluble forms of ICAM-1 that would bind T cells & thus decr. T cell availability to bind ICAM-I on the tumour cell;
  • NB. circulating Ig seems to have little restraint on tumours but NK cells may do.
  • spontaneous regression may occur due to immune response to some tumours:
    • Burkitt's, chorioCa, melanoma (before metastasis); clear-cell kidney (rarely);
  • immunosuppressed & immunocompromised are @ incr. risk of neoplasia;
  • immune-complexes formed may → nephrotic synd., arthralgia, skin eruptions;

• adherence to endothelial cell via:
  • VLA-4/V-CAM - melanoma
  • CD44/??
  • sialylLex antigen/ELAM-1 - colorectal Ca
  • CD44-hyaluronate-CD44
• emigration out of blood vessel via:
  • retraction of endothelial cell exposes basement membrane receptors;

• May be that parental populations of tumour cells contain clones of varying metastatic capacity depending on the presence/abscence of the above qualities;
• Possible metastogenes are:
  • nm23:
    • appears to be a metastasis suppressor gene with loss of expression correlating with poor survival in breast cancer & converse true;
    • considerable homology with abn. wing disc gene of fruit fly!!
    • ? codes for a nucleoside diphosphate (NDP) kinase which may be involved in microtubule assembly/disassembly & signal transduction through G proteins
      • ie. cell adhesion & motility!

• As important causal factor:
  • unopposed oestrogen (Rx or granulosa cell tumour ovary) → uterine Ca
  • high doses oestrogen → breast Ca
  • ? OCP → hepatic adenoma & focal nodular hyperplasia liver occas. & rarely hep. Ca;
  • maternal diethylstilboestrol 1st TM → clear-cell adenoCa vagina in daughters (9 per 1000);
  • androgen Rx → hepatocellular Ca & hepatic adenoma (rarely);
• Hormone dependent tumours - important in maintaining growth:
  • prostate Ca:
    • androgens → Rx of Ca: castration, DES, GnRH analogue → decr.FSH/LH
    • ketoconazole → decr.FSH/LH; anti-androgens;
  • 30% breast Ca:
    • oestrogens, prog, PRL, GH, plac. lactogen (esp. in pre-menopausal);
      • ⇒ Rx of Ca: oophorectomy; tamoxifen; bilat. adrenalectomy;
      • glucocorticoids → decr. adrenal; high dose E??;
  • thyroid Ca (usually well-diff.):
    • TSH → Rx of Ca by thyroxine → decr. TSH;
  • metastatic endometrial Ca & renal Ca may respond to Rx with prog.
  • clear-cell Ca kidney sometimes responds to Rx with oestrogen;
• pregnancy accelerates: breast Ca, Cx Ca, melanotic & neurofibroma hamartomata;