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neoplasia_spread

neoplastic spread

introduction

  • 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 spread

local spread

  • 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;

invasion of lymphatics

  • 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);

perineural invasion & spread

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

venous invasion

  • 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);

arterial invasion

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

small vessels

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

serous spaces

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

embolic spread

lymphatic

  • 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;

blood spread

  • 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 !!

transcoelomic spread

  • 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;

Molecular Biological Theoretical Basis Of Tumour Spread:

local spread

  • 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)

intravasation & release in lymph/blood vessels

  • 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;

intravascular arrest & extravasation (similar to neutrophils)

  • 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;

genes for controlling metastatic phenotype "metastogenes"

  • 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!

hormonal stimulation ("promotion" not "initiation" ?) of tumours

  • 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;
neoplasia_spread.txt · Last modified: 2009/10/22 18:22 (external edit)