Therapeutic Ultrasound and Tumour Metastasis

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REVIEW PAPER

Therapeutic Ultrasound and Tumour Metastasis Linda Maxwell

primary tumour ofbone. Thew t u m o m a r k moet

often in adoleecente and young adulte, and malee are ntkted more commonly than females, by a ratio of 2:1. The tumow commonly arieee in the medullary cavity of the metaphyeie of long bones, particularly the lower end of femur, upper end of the tibia and upper h u m e m . They are extremely aggressive tumoure with a poor prognoeie (5-205 five year survival rate), and frequently extend into soft tieeue. Metaetaeie via the bloodstream ie to the lunge, viecera and other bonee. Clinically, there ie ueually a hietory of pain, limitation of movement aseociated with ewelling and increaeed local heating. Other malignant mueculoekeletal tumoute include chondmmuwm and rhabdomye sarcomas. ChondroMrcomae in contrast to oeteomarcoman grow more elowly and are rare before Introduction skeletal maturity, while rhnbdomyoearcoma The most insidiom ampeict of neoplastic disease ie accounta for 19% of all malignant eoft tieeue the dimemination of the primary tumour and the tumoure) (Enzinger and Weiee, 1983) and ie the formation of secondary growths or metretases at mock common malignant eoR tieeue tumour in dintant mites (Poete and Fidler, 1980). In eome children. orgum local invanion may in ibelf be sufficient to The clinical behaviour of the majority of produg fatal clinical eventa (egCNS tumourn), but mueculoskeletal tumoure is euch t h a t the with most tumoun death usually reoulte from widespread mehstasis and secondary invaeion (Root and Isvin, 1992). The application of therapeutic ultramud over tumoura b mntraindicated, pmmmably because it is believed that there is a n increased risk of metastasis (ter Haar d a& 1888). However, experimental evidence directly to support the hypohain that therapeutic ulfammundp m m o t ~ rneta&uia ~~ is lacking. Neverthele~,such a contra-indication seem prudent given the biology of tumour metadusis and the tivw and cellular effecta of ultramud. Despite thir gemad caution there am timea when tumoure Munknowingly sonicated by a therapiat, much M when tumoun ofthc murcul<#lelet.l sysbm are midi8gnoBed.

Tumounoftha rnuruloaeleW yetam encompw a vuiety of benign and malignant neoplaema h i n g !?om and involving muacle, bone, fibroue

ti-, cartilage, blood veuels and fat. While benign murulorlelet.1 tumours are common, primuy malignant tumoun (aee~ table) are

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symptoms are shared with a wide range of nontumorous orthopaedic disorders. Pain, swelling, and local heat are also common to inflammatory conditions. In addition, the most likely sites for musculoskeletal tumours are regions frequently involved in sports injuries (Lewis and hilly, 1987). Occasionally the patient does recall some sort of injury at the site of a previously unsuspected tumour and this further confuses the relationship between trauma and malignancy. Tumours may elude early accurate diagnosis and become refemed for physiotherapy where they are inadvertently treated with ultrasound. In view of the poor prognosis such a delay in diagnosis is seldom forgiven. In addition, the application of ultrasound to these tumours may indwd accelerate their spread.

For tumour growth and dissemination it is essential that a primary tumour has a blood supply. New capillary blood vessel formation (angiogenesis) is needed if a tumour is to expand beyond 2 mm in diameter (Folkman et aZ,1989)and angiogenesis has been correlated with metastatic disease (Weidner et al, 1991).New capillariesarise from pre-existing capillaries or venules by ingrowth of columns of aligned endothelial cells. Adjacent columns contact to form loops which then develop a lumen and permit blood flow (Hart and Saini, 1992).These delicate new vessels provide a route of dissemination for cancer cells. Whether or not ultrasound stimulates tumour angiogenesis is unknown, but Hogan et a2 (1982) have demonstrated that an increase in capillary density occurs in rat cremaster muscle exposed to ultrasound at 2.5 W/cm*,1 MH,for five minutes, three times a week for three weeks. These authors conclude that ultrasound can stimulate angiogenesis.

MallQnantmuoculdrektrl tumoun

Mwle Rhabdomyosarcoma Cartilage Chondrosarcoma Bone Osteosarcoma Giant cell tumom Ewing’s tumour Fibrous tissue Hietiocytoma Fibmsarcoma Joints Synovial gareoma Adipose tissue Liposarcoma Blood veseels Angiosarcoma

The mechanisms of detachment of tumour cells from the primary neoplasm are poorly understood (weiss and Ward, 19831,but in general, tumour cells are thought to be more easily separable from each other than normal cells. Liolta et aZ(1974) have demonstrated that tumour trauma can produce a marked increase in the density of tumour cells in venous blood draining the tumour site. Furthermore, manipulation of the tumour, such as occurs in surgical procedures or for the purpose of diagnosis, results in tumour cell release (Sherbet, 1982). Thus mechanical forces can initiate and enhance metastasis.

Metastasis and Ultrasound A metastasis is defined as a neoplastic lesion arising from another neoplasm with which it is no longer in contiguity (Poste and Fidler, 1980).It is a complex process which occurs in several progressive stages (fig 2). tumour cell detachment

v

invasion and entry of cells into B ve&l V passag; through lymphatic or blood vessels

V

stasis in a vessel tn the recipient organ

V adhesion and eatravasation

V

proliferation to form metastasis v

’

Fb 2 The ooquenco of wenta Invoked In tha Ckvetapnwnt oftumour mtasmoa.

Therapeutic ultrasound has the potential mechanically to disrupt tumours in several ways and thus increase the possibility of metastasis. The application of ultrasound usually requires direct contact via a coupling agent and it is recommended that the transducer should be moved continuously throughout the treatment in small overlapping circles(McDiarmid and Burns,1987).This in effect acts as a ‘superficial massage’. While such gentle movements are very unlikely to alter normal tissue, the stroma of tumours is fragile with little connective tissue supporting the tumour cells. In addition, ultrasound itself is a mechanical wave where energy is transmitted by the vibration of molecules (ter Ham, 1987). When ultrasound waves are absorbed in the tissue the alternate positive and negative pressures at the frequency of the machine causes a ‘micro massage’ effect. This effect hae been suggested to result in depolymerisation of connective tissue ground substance. Consequently, therapeutic ultrasound is recommended in the treatment of adhesions to hasten the breakdown of fibrous tissue (Oakley, 1982).Clearly therapeutic ultrasound could caw

the separation of weakly bound tumour cells and the disruption of delicate tumour vessels.

0- a k ; l m r w d haa become dehcbsd it is able to invade local tissues or lymphatic and blood VBBBela A three-step hypothesis of tissue invasion has been propoeed that includes attachment, enzymatic degradation and movement. Tumour cells adhere to specific tissue components, including Btromal fibronectin in the tissue matrix and laminin in the basement membranes of blood veseels, v i a specific receptors on the tumour cell surface. Some highly aggressive tumours express laminin receptors in quantities that are 50 times normal (Wewer et al, 19871, and when these are blocked tumour cells fail to metaetaai fMcCarthy et al, 1988). Recently ultrasound has been demonstrated to augment the adhesion of leucocytesto endothelial cells ovlaxwell et al, 1994). Adhesion molecules expressed by normal endothelial cells recognise surface receptors expressed on tumour cells (Hart and Saini, 1992). Once adhered, the cells secrete a variety of hydrolytic enzymes (eg elastase and collagenase) which degrade the matrix locally (Md=arthy et al, 1988; Liolta et al, 1980), and allow the movement of cells through the tiseue or into blood lympathic vessels. Generally detached tumour celle are disseminated by three major routes. Tumoura growing in body cavities may show transcoelomic spread in which shed fragments attach to and become implanted into apposing s e r d m u c o s a l surfaces to form secondary tumours. The second is spread by the lymphatic system (carcinomastend to be disseminated by this route). Access to the lymphatic system is generally by means ofthe small lymphaticvessels which possess structural features that allow permeation. They lack a basement membrane and have a high proportion of incomplete junctions between endothelial cells. Tunour cells easily enter and are then carried to regional lymph nodes. Since involvement of regional lymph nodes is an indication of tumour spread, nodal status is one of the criteria assessed in the clinical staging of malignant disease. The third route is uiu the blood stream and the importance of vascularisation in musculoskeletal tumours was alluded to earlier. Experimental studies have demonstrated the amount of tumour material escaping into the bloodstream is related to the size of vessels in the tumour (Kleinerman and Liotta, 1977). Vessels larger than 30 pm seem to be critical to the dissemination process as these thin-walled vessels offer little resistance to invading cells. Furthermore, these vessels are often defective with gaps between endothelial cells making them more susceptible to invasion @id'ler

and Balch, 1987). Ultrasound treatment is known to af€ect blood vessels in several ways. Direct endothelial damage can occur during ultrasound (Dyson, 1987) and mast cell degranulation and histamine release can also be induced Wyfe and Chahl, 1982). While direct damage to the vessel wall usually results in increased permeability, histamine stimulates endothelial cell contraction and the formation of gape between cells. Such gaps would facilitate tumour cell intravasation and hence dissemination.

Conclusions This review has discussed some of the biological mechanisms involved in tumour metastasis. Theoreticallytherapeutic ultrasound does have the potential to augment metaetaeis in several ways. However, there is a lack of direct experimental evidence to support the hypothesis. Until there is research to the contrary, physiotherapists should be aware of the differential diagnosis of musculoskeletal tumours, and the possibility that some malignant musculoskeletal tumours mimic conditions for which therapeutic ultrasound is beneficial. Constant vigilance is required if these tumours are not to be mismanaged. Author and Addmss for Correspondence Dr Linda MameN PhD 6Sc MCSP is a senior lecturer in the Department of Pathology, University of Auckland School of Medicine, Private Bag, Auckland, New Zealand.

Refmnces Chalmers, J (1988). 'Tumours of the musculoskeletal system: Clinical presentation'. Current OrthqJaedics. 2, 135 140. Dyson. M (1987). 'Mechanismsirm0)Ved in thempatic ultrasound: P h y s i o h ~73, , 116-120.

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Enringer, F M and Weirs, S W (1983). Soft Tissue Turnours. C V Mosby, St Louia.

Fidler. I J and Balch. C M (1987). 'The biology of cancer metastasis and implications for therapy', Current Problems in Sufwfy, 24. 129-209. Folkman. J. Watson, K, Ingber. D and Hanahan, D (1989). 'Inductionof angiogenesisduringthe transition from hyperplasia to neoplasia. Nature, 339, 58-61. Frost, P and Levin, B (1992). 'Clinical implications of the metastatic process', Lancet. 339, 1458- 61. Fyfe, M C and Chahl, L A (1982). 'Mast cell degranulation: A possible mechanism of action of therapeutic ultrasound: Ultrasound in Medicine and Biology, 8, suppl 1. 62. Hart, I h and Saini. A (1992). 'Blology of tumour metastasis', Lancet, 339, 1453-57. Hogan, R 0 , Burke, K M and Franklin, T 0 (1982). 'The effect of ultrasound on microvascular haemodynamics in skeletal muscle: Effects during ischaemia', Microvascular Research. 23. 370 - 379. Homa. D N (1991). 'Incidence and survival rate in children and young adults with osteogenic sarcoma', Cancer, 67.2219- 23. Kleinerman. J and Liotta, L (1977). In: Day, S B, Laird Myers, W P, Stansley, P, Garattini. S and Lewis, M G (eds), Cancer lnvesion

and Metastasis: Bidagc mechanismsand t h e m (lsn). Raven Press, New York.

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Lewis, M M and Reilly, J F (1987). ‘Sportstumours’. American Journal of Sports Medicine. 15. 362- 365. Liolta. L A, Tryggvason. K, Garbisa. S, Hart, I. Foltz. C M and Shafie, S (1980). ‘Metastaticpotential correlates with enzymatic degradation of- basement membrane collagen’. Nature. 284, 67 - 68.

Poste, G and Fidler, I J (1980). ‘The pathogenesis of cancer metastasis’, Nature, 283. 139- 146. Sherbet, G V (1982). ‘The biology of tumour malignancy’, Academic Press, London. ter Haar. G (1987). ‘Basic physics of therapeutic ultrasound‘,

Maxwell. L. Collecutt. T, Gledhill, M, Sharma. S. Edgar, S and Gavin, J (1994). ‘The augmentation of leucccyte adhesion to endothelium by therapeutic ultrasound’, Ultrasoundin Medicine and Biology, 20, 383- 390. McCarthy, J B, Skubitz, A P, Palm. S L and Furcht, L T (igse). ‘Metastasisinhibition of different tumour types by purified laminin fragmentsand heparin-bindingfragmentof flbronectin’, Natlonal Cancer institute 80, 108-116. McDiarmid. T and Burns, P N (1987). ‘Clinical applications of therapeutic ultrasound’, Physiotherapy. 73355 - 162. Oakiey. E M (1982). ‘Evidencefor effectiveness of ultrasound treatment in physical medicine’, British Journal of Cancer, 45,

ter Haar, G. Dyson, M and Oakley. S (1988). ‘Ultrasound in physiotherapy in the UnWed Kingdom: Resultsof a questionnaire’, Physiotherapy Practice. 4, 69 - 72. Weidner. N, Semple, J P, Welch. W R and Folkman, J (1991). ‘Tumourangiogenesisand metastasis - correlationin invasive breast carcinoma’,New €*/and Journa/ of Medicine, 324, 1 - 8. Weiss, L and Ward, P M (1983). ‘Cell detachment and in cancer’, Metastasis Review, 2. 111 - 127. Wewer, U M. Taraboletti, 0 , Sobel, M E. Albrechteen, R and Liolta, L A (1987). ‘Role of laminin receptors k\ tumour cell migration’,Cancer Research, 47, 5691 - 98.

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Abstract of Higher Degree Thesis An Investigation into the Sit-stand-sit Activity in Normal Subiects and Patients with Total HiD Rerdacement Kate Kerr P ~ MW D Course: Doctor of Philosophy, Queen’s University of Belfaet, 1995

Housed at: Queen’s University of Belfast,department of orthopaedic surgery, and University library

A measurement system was developed conaiding of vector stereography, accelerometry and electrogoniometry, to analyee the sit-stand-sit movement activity in normal subjects and patients admitted for total hip replacement. Data derived from the measurement system were passed through a sevenchannel amplifier and recorded using an analogue to digital converter on a computer. The validity, accuracy and repeatability of individual elements of the system were established, and the reliability of the system as a whole, when applied in repeated trials within a single subject, demonstrated coefficients of variance of less than 5% over a number of spatial and temporal parameters extracted from the data. A definitive hmework for the analysis of the sit-standsit movement cycle was proposed, based on events identified from the spatial and temporal data. The movement cycle was defined in terms of phases (rising and descending), eomponenta (forward lean, vertical displacement, knee angular displacement and recovery) and events, based on changes in displacement parameters. Within this definitiveh e m o r k statistical analysis of numerical data extracted from the recorded movement patterns was carried out on a number d specifk temporal and spatial parametem to determine both abaolute values, and temporal relatiomhipbetween phaeee, components and events.

Data derived from 50 normal healthy subjecta, 25 men

and 25 women, aged between 20.1 and 78.3 yeam (mean age 46.8) were a n a l w to provide normative data for the sit-stand-sit movement cycle, and to identify where differences existed in the selected parametem due to BB. and age In general, there was consistency in the pattern

ofaseociationbetweenthephaaes,componeutsandwents both within individual groups and within the tdal combined group, and where Merencee emerged among groups, these tended to involve the elderly groups, and occur during the rising phaee of the cycle Data from a total of 30 patients, 17 women and 13 men, aged between 35.0 and 79.3 years (mean age 65.5 m) admitted for total hip replacement were analysed during the sibstand-sit movement cycle, prior to surgery. Eleven women and 12 men performed the activity in a manner similar to the normal pattern of movement, with a general trend towards slower movement times than those exhibited by normal subjecta Two alternative compensatory strategies were demonetrated by the remaining patients, namely a ‘slow ridslow descent’ strategy, and a ‘multiple attempts’ strategy. Fourteen af these patients were re-analyeed six weehe after surgery, of whom 11 performed the movement in a manner similar to the normal pattern, and temporal parametem approached values from normal subjects. The remaining three subjects again demonstrated the same compensatory strategies. Compariaonabetween the findings ofthis study and those from previous studies were made, and explanationa for findings propoeed. It was generally concluded that the meaeurementeyrhem developed in thie study was capable of providing accurate and reliable informationon the sib stand-sit movement cycle, and that the definitive framework p r o p o d enabled a stanapproachto the analysis of the movement activity in normal aubjecte and thoae with pathology affecting the lower limb. Recommendationsfor further research were made.