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The mechanism of metastasis in the so-called “benign giant cell tumor of bone”
in place. T h e disc variance was associated with e m b o l i z a t i o n o f t h e e r o d e d T e f l o n material to the lungs w h e r e it p r o d u c e d a f o r e i g n .body t y p e o f g r a n u l o m a t o u s r e a c t i o n a r o u n d the foreign material. References I. Chun, P. K. C., and Nelson, W. P.: Common cardiac prosthetic vah'es. Radiologlc identification and associated complications. J.A.M.A., 238:401, 1977. 2. Roberts, W. ('., Fishbein, M. C., and Golden. A.: Cardiac pathology after valve replacement by disc prosthesis. A study of 61 necropsy patients. Am. J. Cardiol.,35:7-t0, 1975. 3. Silver, M. D., and Wilson, J. G.: The pathology of wear in the Beall model 104 heart vah'e prosthesis. Circulation, 56:617, 1977. 9t. Ridolfi, R. L., and tlutchins, G. M.: Detection of ball variance in prosthetic heart valves by liver biopsy. Johns tlopkins Med. J., 134:131, 1074. 5. Aquino. T. I., and Skinsnes, O. K.: Teilon embolism of coronary arteries. A case rct:x~rt. Arch. Palhol., 80:625, 1965. 6. Gonzalez-Crussi, F., Mandy, S.,Johnson. I. E.. and Grccn,J. R.: Teflon emtxmsm of coronary arteries. J. Thnrac. Cardinvasc. Surg., 54:53, 1967. 7. Hameed, K., and Waugh, D. O. W.: Ball fracture and extrusion in the Starr-Ed~vards aortic vah~zprosthesis ",vithdissemination of ball material. Arch. Pathol., 86:520, 1968. 8.. Roberts, W. C., and Morrow, A.G.: Fatal degeneration of the silicon rubbcr ball of the Starr-Edwards prosthetic aortic valve. Ann J. CardiuLo22:614, 1968. 9. Niles. N. R., and Sandilands, J. R.: Pathology of heart valve rcplacemcnt surgery. Autopsies of 62 paticnts ,,vith Starr-Edwards prostheses. Dis. Chest, 56:373, 1969. 10. Niles, N. R.: Teflon eml~)lism from Starr-Edwards valves. J. Thorac. Cardinvasc. Surg., 59:794, 1970. I I. Silver, M.D.: Late complications ,ff prosthetic heart valves. Arch. Pathol., Lab. Med., 102:281, 1978. 12. Thomassen, R. W., lto~'bert, J. P., winn, D. F., and Thompson, S. W.: The otcurrence anti characterization of cmboli associated ~'ith the use ,ff a silicon aniifoaming agent. J. "I'librac~('ardiovasc~ Surg., 41:61 I, 1961. 13. Helmsworth, J. A., Gall, E. A., Perrin, E. V., Braley, S. A., Flege, J. B., Kaplan, S., and Keirle, A. M.: Occurrence of emboli during prnfusion with an oxygenatnr pump. Surgery, 53:177, 1963.
Department of Pathology and Laboratory Medidne Mount Sinai Medical Center 4300 Alton Road Miami Beach, Florida 33 I-t0 (Dr. Robinson)
THE MECHANISM OF METASTASIS IN THE SO-CALLED "BENIGN G I A N T CELL TUMOR OF BONE" ROMEO L. CABALLES,M.D.*
Abstract
A case of so-called "benign giant cell tumor of bone" with an incidental histologic finding of intratumor vascular invasion is reported. The me[hanism and biology of metastasis are briefly discussed. For the purposes of this presentation, the mechanism of metastasis is divided into two types---active and passive. An active type of metastasis indicates maligTmncy, whereas a passive type denotes a benign process. The malignant features of the conventional or typical giant cell tumor of bone are demonstrated. It is proposed that this neoplasm be labeled malignant despite its seem-
Accepted fi~r puhllcatioILJuly 2 I, 1980. *Clinical Assistant Professor o f Pathology, College of Medicine and Dentistry of NcwJcrscy, NcwJersey Medical School. l)ircctor of Orthopedic Pathology, Dcparnncnls of Pathology and Orthopedic Surgery, United Hospitals Medical Center and United Hospitals Orthopedic Center, Newark, New Jersey.
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ingly benign histologic appearance. Relative to the degree of malignanc)', a lesion of this nature may be classified as either a low or a high grade type of malignant giant cell tumor. T h e r e a r e certain n e o p l a s m s that a r e classified as benign and yet a significant n u m b e r o f these lesions have metastasized and on occasion have even caused d e a t h o f the patient. 3a~176 E x a m p l e s o f t u m o r s b e l o n g i n g in this c a t e g o r y are the " b e n i g n " giant cell t u m o r Of bone, u t e r i n e l e i o m y o m a , a n d h y d a t i d i f o r m mole. In p u b l i s h e d cases o f metastatic " b e n i g n " giant cell t u m o r o f b o n e a n d u t e r i n e leiomyoma, the h m g has b e e n the target o r g a n in almost every instance, t2a3a~ O n t h e o t h e r band, a l t h o u g h p u l m o nary metastasis is n o t u n c o m m o n in h y d a t i d i f o r m mole, a considerable n u m b e r o f these patients have vaginal and u r e t h r a l i n v o l v e m e n t . I~ R a r e o c c u r r e n c e o f e x t r a p u i m o nary s p r e a d f r o m u t e r i n e l e i o m y o m a has likewise b e e n rep o r t e d in o r g a n s a n d s t r u c t u r e s such as the ovary, spinal cord, r e t r o p e r i t o n e a l l y m p h nodes, and p e r i t o n e u m . 7'23a7 So far t h e r e has h e e n only o n e r e c o r d e d case o f l y m p h n o d e metastasis in a " b e n i g n " giant cell t u m o r o f b o n e ? A l t h o u g h relatively little attention has b e e n d i r e c t e d toward these obviously v e r y i m p o r t a n t a n d r a t h e r interesting p h e n o m e n a , the m e c h a n i s m o f metastasis in m a l i g n a n t t u m o r s has been extensively investigated and r e p o r t e d by m a n y authors, a2m A s u r v e y o f the English literature failed to yield any acceptable o r logical e x p l a n a t i o n r e g a r d i n g the f o r m a t i o n o f metastasis in this small g r o u p o f " u n u s u a l " tumors. T o characterize the m e c h a n i s m by which the t u m o r cells have r e a c h e d t h e i r sites o f implantation, s o m e writers have used such terms as " e m b o l i s m " and "deportation," sugg e s t i n g t h a t t h e p r o c e s s was p a s s i v e r a t h e r t h a n active.4.6.~o,24,29.at F o r the p u r p o s e s o f this stud)', t h e m e c h a n i s m o f metastasis has been d i v i d e d into two t y p e s - - a c t i v e a n d passive. T h e process is c o n s i d e r e d active w h e n the defect in the vessel wall t h r o u g h which the neoplastic cells e n t e r the circulation has been c r e a t e d by the destructive effect o f the t u m o r cells themselves, w h e r e a s w h e n the e n t r a n c e o f the t u m o r cells into the circulation is t h r o u g h a vascular wall d e f e c t tlaat has b e e n c a u s e d by any o t h e r means, the process is c o n s i d e r e d passive. T h e majority o f a u t h o r s , however, have r e f e r r e d to the process o f distant i m p l a n t a t i o n as an active f o r m o f s p r e a d , but no tenable e x p l a n a t i o n has b e e n o f f e r e d as to how the t u m o r cells w e r e a b l e to g a i n access into t h e v a s c u l a r circulat ion.n~,s.7a2-~s,20.2~.2a.2s-z7 It is the intention in this c o m m u n i c a t i o n to describe and illustrate the m e c h a n i s m o f metastasis in the so-called " b e n i g n giant cell t u m o r o f b o n e " and to p r o p o s e that such lesion be labeled m a l i g n a n t regardless o f its s e e m i n g l y benign histologic pattern. CASE REPORT A 20 year old black w o m a n was a d m i t t e d to the hospital for the first time on J u l y 7, 1978, because o f pain in t h e left knee, which started a f t e r she fell oil that knee six m o n t h s p r i o r to admission. X-ray films taken at tltat t i m e s h o w e d a n o n e x p a n s i l e lytic l e s i o n w i t h all ill d e f i n e d b o r d e r , m e a s u r i n g 5.5 by 3.5 ~:m., ill the u p p e r e n d o f the left tibia. Several weeks b e f o r e admission she had noticed progressive swelling a r o u n d t h e affected knee. O n admission, the swollen a r e a was f o u n d to be h a r d a n d t e n d e r . A slight j o i n t effusion and i n c r e a s e d skin t e m p e r a t u r e w e r e als0 noted. She walked with a limp, but no limhation o f m o t i o n was detected. R a d i o g r a p h s s h o w e d an 8 by 7.5 cm., completely lytic a n d e x p a n s i l e lesion with f a i n t i r r e g u l a r
ttUMAN PATltOI.OGY--VOLUME 12, NUMBER 8August 1981
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MEDICAL INTELLIGENCE trabeculation forming a multiloculated pattern in the u p p e r end o f the left tibia (Figs. 1, 2). T h e process a p p e a r e d to involve a portion o f the shaft and the entire epiphyseal and metaphyseal areas. T h e r e was considerable thinning o f the cortex, but no evidence of cortical destruction was noted. A thin shell o f cortical bone outlined the lateral borders o f the lesion. Chest x-ray views were r e p o r t e d as normal. T h e only pertinent laboratory finding was an elevated sedimentation rate (31 ram. p e r hr.). Surgery was p o s t p o n e d owing to lack o f compatible bank blood. O n the second day o f the second admission (August 17, 1978), the growth in the u p p e r e n d o f the left tibia was excised and the surgical defect packed with bone chips. T h e
Figure I . Roentgenogram'(anteroposterior view), taken o n admission shows a large, totaIl)' ostcolytic and expansile lesion ill the upper end of the left tibia inw~lving the entire epiph)'seal and metaphyseal areas and a l~Jrtion of tlie diaph)sis. A thin shell of cortical lxme outlines its lateral margins.
gross specimen consisted o f several i r r e g u l a r pieces o f brownish to d a r k p u r p l e and partly hemorrhagic soft tissue, measuring from 3.5 by 1.8 by I cm. up to 8 by 4 by 3 cm. T h e microscopic a p p e a r a n c e was typical o f the socalled conventional o r benign giant cell t u m o r o f bone. T h e proliferating neoplastic cells were either spindle shaped (fibrobastic type) o r ovoid (histiocytic type), interspersed in many places with collections o f muhinucleated giant cells (Fig. 3). T h e nuclei o f the giant cells were often n u m e r o u s and indistinguishable from the nuclei o f the histiocytic type o f cell. Mitotic figures were few and somewhat difficult to find. Portions o f cyst wall containing some muhinucleated giant ceils were recognized. Also present were multiple foci o f scarring and fairly large areas o f acute h e m o r r h a g e . A few spicules o f reactive osteoid were likewise noted.
Figure 2. Lateral view showing faint irregular trat.x:culation fi)rming a muhiloculated pattern.
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H U M A N P A T H O L O G Y - - V O L U M E 12, N U M B E R 8 August 1981
Figure 3. Medium power view of a typical ct;nventional giant cell tumor showing characteristic proliferation of both spindle and ovoid neoplastic cells, interspersed with many muhinuclcatcd giant cells. (Hcmatoxylin and eosin stain. • 100.)
A very interesting incidental finding was the presence o f blood vessel invasion in every section examined. T h e portion o f the wall involved in the early stage o f vascular invasion was rather limited o r localized, and before complete penetration took place, progressive thinning o f the area accompanied by disintegration o f muscle wall components was noted (Figs. 4, 5). T h e diagnosis was malignant (low grade) giant cell t u m o r o f bone. THE BIOLOGY OF METASTASIS Theoretically three distinct stages have been recognized in the formation o f metastases in malignant neoplasms. 9 In r e g a r d to the first stage there are several theories that have been proposed, some o f whiclt relate specifically to the process~ o f invasion--the initial stage o f metastasis. T h e designation "biological p r e d e t e r m i n i s m " has been coined by some investigators to emplmsize the characteristic invasiveness o f t u m o r cells and the lack o f this distinct feature in normal cells) 6 According to Fisher a n d Fisher, 9 " A t t e m p t s to explain divergence o f such determinism have been related to features o f cell motility, differences in mut u a l adhesiveness o f malignant neoplastic cells, related to their surface changes and or calcium content, and the loss o f contact inhibition, a p h e n o m e n o n r e g a r d e d as accounting for the lack o f invasiv/zness o f normal ceils." Roberts et al., ~2 on the o t h e r hand, p r o p o s e d that t u m o r cells reach the circulation by way o f vascular defects when the extravascular pressure exceeds that within a vessel, a process r e f e r r e d to as intravasation. Probably the most tenable idea is the
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possibility that t u m o r cells could elaborate a s p r e a d i n g factor (probably hyaluronidase) capable o f altering the g r o u n d substances o f the connective tissues to pave the way for their invasion and p r o m o t e distant implantation by destroying vascular walls. Is Dissemination, the second stage in the d e v e l o p m e n t o f metastasis, commences with the intravascular release o f neoplastic cells from the p r i m a r y growth. T u m o r cells most probably are continuously invading the circulation in large quantity. However, it has been estimated that only a very small n u m b e r (0.01 p e r cent) o f these circulating t u m o r ceils ultimately survive to initiate distant implantation, aa .Until recently the circulatory route (either lymphatic o r hematogenous) t h r o u g h which t u m o r cells disseminate was thought to be the d e t e r m i n a n t o f the means by which certain organs and structures become the sites o f metastasis. An interesting e x p e r i m e n t by Fisher and Fisher s has demonstrated that t u m o r cells are capable o f crossing interstitial barriers and a p p e a r quite readily in the thoracic lymph following blood vessel injection. T h e third and final stage ifi the formation o f metastasis involves t h r e e distinct processes, namely, l o d g m e n t , attachment, and growth o f cancer cells at distant sites. T o be effective in initiating~implantation the cancer cells must inevitably attach themselves to vascular endothelium. Very soon after attachment, the cells become e n t r a p p e d within fibrin clot where they may either survive for a length o f time o r proliferate and, subsequently, p e n e t r a t e t h e vascular wall and invade perivascular tissues. During the period o f cell proliferation, vascularization and connective tissue formation are taking place simultaneously. Vasctdar con-
Figure 4. Low power magnification showing vascular invasinn, with fncal complete penetration of the wall causing extravasatinn of red blond cells into perivascular tissues. (Hcmatnxyli n and eosin stain, x40.)
Figure 5. Low power view showing vascular invasion occurring simultaneously in two different areas of the wall. (ttematnxylin and eosin stain, x40.)
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H U M A N P A q ' t l O L O G Y - - V O L U M E 12, NUMBER 8 August 1981 nections are believed to be accomplished through elaboration o f an angiogcnesis factor by tumor cells? From this secondary growth, metastasis may also develop. DISCUSSION In view of its frequently unusual clinical behavior, the so-called "benign giant cell tumor o f bone" has always been regarded as one o f the UlOSt unpredictable neoplastic lesions o f the skeletal system. This is in part attributable to its remarkably high incidence o f recurrence after either curettage or local resection of the basic lesion, usually occurring within two )'ears after the initial surgery. More remarkable than its propensity to recur, however, is the capacity of this neoplasm to metastasize, despite its innocent looking histologic pattern. Both recurrent and metastatic lesions commonly retain their original benign microscopic features. Occasionally the hstologic features o f tile recurrent tumor are obviously malignant. T h e site o f nletastasis is almost invariably the lung. Lymphatic spread in a case of "benign" giant cell tumo'r o f the distal etad of the femur was reported by Budzilovich et al. 5 T h e occurrence of tumor thrombi in venous channels adjacent to a "benign" giant cell tumor of bone is not unusual? z However, the question regarding its pathogenesis has not yet been fully resolved. Obviously the solution depends chiefly on tile documentation o f a case with intratumor vascular (venous) invasion. Recognizing the preceding information as factual and essential to a discussion relevant to a better understanding o f how and why metastasis develops from a tumor that has been classified as benign, I shall now proceed to discuss its mechanism o f invasion by utilizing the histopathologle findings in a "benign" giant cell tumor r e m o v e d front the proximal end of the tibia of the 20 )'ear old black woman just presented. MECHANISM OF VASCULAR I N V A S I O N T h e incidental microscopic finding o f vascular invasion in this tumor was the main object and motivating factor i n this study. As far as could be determined in the English literature, intratumor vascular invasion in prinmry "benign" giant cell tumor o f bone has never been reported. Tile radiographic and microscopic features o f the lesion under discussion may be best characterized as being typical of a conventional type o f giant cell tumor. Radiologically it presents a totally lytic process with faint irregular trabeculation, forming a mvltiloculated pattern and expanding the upper end o f the tibia. T h e growth appears to involve the entire epiphyseai and metaphyseal areas and a portion of the diaphysis. T h e r e is no evidence of tumor penetration through the cortex, and a thin shell of cortical bone outlines its lateral margins. Except for the interesting finding o f blood vessel invasion in this lesion, the overall histologic appearance, as previously indicated, is distinctly that o f a conventional giant cell tumor. As usual, the growth is quite cellular and the component cells are either ovoid (histiocytic type) or spindle shaped (fibroblastic type), interspersed in many areas with collections o f multinucleated giant cells. T h e nuclei o f the giant cells are often ntnnerous, and they resemble very closely the nuclei of the ovoid or histiocytic type o f cell. Dividing cells are scanty'and inconspicuous. . Fairly large areas o f acute hemorrhage and multiple foci of scarring are noted. Also recognized are portions o f cyst wall, consisting o f thin strips of fibrocollagenous tisst, c, containing some multinucleated giant cells. A small amount o f reactive os-
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teoid is likewise present. In addition, every representative histologic section examined shows invasion o f several blood vessels by tumor cells. T h e vessels involved are usually small to medium sized arteries and veins. Initially the destruction of a blood vessel by t u m o r cells appears to involve a rather linlited or localized portion o f the wall, creating a seemingly progressive thinning o f tile area, accompanied by disintegration of muscle wall components. Finally, complete penetration takes place. While observing the different stages o f vascular invasion, it became obvious tlmt the nluhinucleated giant cells are most probably actively participating in the process. They are often present in the advancing masses o f tt, mor cells, destroying vascular walls and also within h, mina of involved vessels. Extravasated blood has formed fairly large areas of acute hemorrhage, usually occurring around vessels with completely penetrated walls, and seepage of red blood cells through these defects has become apparent. The foregoing information, evidence of an active type of metastasis, indicates that the designation "benign giant cell tumor of bone" is realistically a misconception, and therefore warrants redefinition and reclassification. A suggestion was made earlier that this neoplasm be labeled malignant, despite its seemingly benign lfistologic appearance. It is further proposed that relative to the degree o f malignancy, a lesion of this nature be classified as either a low or a high grade type of malignant giant cell tumor. A high grade type o f tumor must contain, within a setting o f t typical giant cell tumor, a fibrosarcomatous component. The labeling o f a low grade type of lesion, on the other hand, simply requires tile usual criteria in diagnosing a typical or conventional giant cell tumor. References
1. Ackerman, 1- V., and Rosai,J.: Surgical Pathology. Ed. 5. st. Louis, The C. V. Mosby Company, 197.t.p. 818. ,'2. Ariel, I. M., and Trinidad, S.: Pulmonary metastasis from a uterine "leinm)oma.'" Relx)rt of a case----evaluation of differential diagnosis and treatment ~)licies. Am. J. Obstet. G)nec., 94:110-116, 1960. 3. Arnold, H. A.. and Bainborough, A. R.: Subacute cor pulmonale following trophoblastic pulmonary emb~)lism. Canad. Med. Assn. J., 76:478, 1957. 4. Bardawil. A.. and Toy, B. L: The natural history of choriocarcinoma; problems of immunity and spontaneous regres'slon. Ann. N.Y. Acad. Sci., 80:197, 1959. 5. Budzilovich, G. N., Truchly, GI, and Wilens. S. I..: T u m o r giant cells in regional lymph nodes of a case t)f recurrent glant-ccll tumor of l~me. Clin. Orthop., 30:182-187, 1963. 6. Canlas, B. D.: Benign lesions ofa|n_'rrant trophoblast in the hmg. Obstet. Gynec., 20:602, 196,'2. 7. Fallahzadeh, It., Dockerty, M. B., and l.ee. R. A.: Leir ~)f the ovary--re~)rt of five cases and review of the literature.'-Am.J. Obstet. Gynec., 113:39-t-398, 1972. 8. Fisher, B., and Fisher, E. R.: Biological aspects nf cancer-cell spread. In Fifth National Cancer Conferance Proceedings. Philadell)hia, J. B. Lippincott Company, 196-1, p. 105. 9. Fisher, B., and Fisher, E. R.: Metaslasis reGsitcd. In Weiss, L. (Editor): Fundamenlal Aspects of Metastasis. New York. Elsevier-North tlolland Publishing Company, 1976, pp. -127-435. 10. llsu, C . T . , ltuang, L.C, and Chen, T.Y.: Metastasis in benign hydatidiform mole and cborioadenoma destruens. Am. J. Obstet. Gynec., 84: !.t 12, i 962. II. Jac~)bson, F.J., and Enzen, N.: II)datidiform mole with "'benign'" metastasis to lung--Ifistological ek'idence of regressing lesion in lung. Am. J. Obstet. Gyncc.. 78:868, 1959. 12. Jaffe, il. L.: Giant-cell tumor. In Jaffe, tl. L.: Tumors and Tumorous Conditicms ~f Bcmes and Joints. Philadelphia, Lea & Febigcr, 1958. pp. 18-43. 13. Je~'ell, J. I1., anti Bush, L. F.: Benign giant-ten tum~w ~f b~me x~ith a s(~litary pulmonary metastasis. A case report. J. B~me Joint Surg., 46A:848-852, 1964. 14. Johnson, E.W.: Adjacent and di:stant spread of giant-cell tumors. Am.J. Surg.. 109:163, 1965. 15. I~_'feb~re. R., ec al.: Leinmyoma of the uterus with bilateral pulmonary metastases. Canad. Meal. Assn. J., 105:501-503, 1971. 16. MacDonald. !. G.: Bic~logical predeterminism in human cancer. Surg. Gynec. Obstet., 92:443. 1951.
MEDICAL INTELLIGENCE 17. Marcuse, P. M.: Pulmonary syncytial giant cell embolism. Report ofmaternal death. J. Obstet. G) nec., 3:210, 1954. 18. McCutcheon, M., and Cumao, D. R.: Spreading factor in human carcinomas.-Cancer Res., 7:379-382, 1947. 19. Neumann, J.: Beitireg zur lehre yon malignen deciduom. Monatsschr. Geburtsh. Gynak., 3:387-412, 1896. 20. Pan, P., Dahlin, D. C., Lipscomb, P. R., and Bernatz, P. E.: Benign giaut cell tumor of the radius with pulmonary metastasis. Mayo Clin. Proc., 39:344-349, 1964. 21. Pocock, E., Craig, J . R , and Bullock, W.K.: Metastatic uterine leiomyomata. Cancer, 38:2096-2100, 1976. 22. Roberts, S. In Cole, H. W., et al. (Editors): Dissemination of Cancer-Prevention and Therapy. New York, Appleton-Century-Crofts, 1961. 23. Rogers, L., and Thomas, L.: Paraplegia caused by extraspinal metastasis from a uterine fibroid. J. Neurol. Neurosurg. Psychiat., 22:141 - 142, 1959. 24. Schmorl, C. G.: Patologisch-Anatomische Untersuchungen tiber Pnerperale Eklampsie, Leipzig, Vogel, 1893. 25. Spiro, R. tl., and McPeak, C.J.: On the so-called metastasizing leiomyoma. Cancer, 19:544-548, 1060. 26. Steiner, P. E.: Metastasizing fibroleiomyoma of the uterus. Report of a case and review of the literature. Am. J. Pathol., 15:89-109, 1939.
27. Taubert, I1., Wissncr, S. E., and tlaskins, A.L.: Leitml)omatosis peritoncalis disseminata. An unusual complication of genital lelomyomata. J. Obstet. Gynec., 25:561-574, 1965. 28. Tedeschi, L. G., and Toy, B. L.: Experimental transpuhllonary migration of trophoblast. J. Obstet. Gynec., 21:55, 1962. 29. To}', B. L., and Tedcschi, L. G.: Emlx~lic trophoblast in peripheral circulatlon during pregnancy. Proc. 8oc. Exper. Biol. Med., 106:865, 1961. 30. Trotter, R. F, and Tieche, it. L.: Maternal death due to pulmtmar)' embolism of trophoblastlc cells. Am.J. Obstet. Gynec., 71: I 114, 1956. 31. Viet,J.: Ueber Deportation yon chorionzotten (Verschleppungs'on Votten in mutterliche Blutbahnan). Z. Geburtsh. Gynfk., 44:466-5Ot, 1901. 32. Weiss, L. (Editor): Fundamental Aspects of Metastasis. North Holland Publishing Co. 1976, Ch. 1, p. 25. 33. Weiss, L.: Dynamic aspects ofcancer cell population in metastasis. Am.J. Path., 97:601-608, 1979. 34_ Willis, R. A.: The Spread of Tumors in the Human Body. Ed. 3. l.~mdon, Butterwortlt & Co. (Publishers) Ltd., 1973, Ch. I, p. 29. Department of Pathology United Hospitals Medical Center 15 South 9th Street Newark. New Jersey 07107
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Department of Pathology and Laboratory Medidne Mount Sinai Medical Center 4300 Alton Road Miami Beach, Florida 33 I-t0 (Dr. Robinson)
THE MECHANISM OF METASTASIS IN THE SO-CALLED "BENIGN G I A N T CELL TUMOR OF BONE" ROMEO L. CABALLES,M.D.*
Abstract
A case of so-called "benign giant cell tumor of bone" with an incidental histologic finding of intratumor vascular invasion is reported. The me[hanism and biology of metastasis are briefly discussed. For the purposes of this presentation, the mechanism of metastasis is divided into two types---active and passive. An active type of metastasis indicates maligTmncy, whereas a passive type denotes a benign process. The malignant features of the conventional or typical giant cell tumor of bone are demonstrated. It is proposed that this neoplasm be labeled malignant despite its seem-
Accepted fi~r puhllcatioILJuly 2 I, 1980. *Clinical Assistant Professor o f Pathology, College of Medicine and Dentistry of NcwJcrscy, NcwJersey Medical School. l)ircctor of Orthopedic Pathology, Dcparnncnls of Pathology and Orthopedic Surgery, United Hospitals Medical Center and United Hospitals Orthopedic Center, Newark, New Jersey.
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ingly benign histologic appearance. Relative to the degree of malignanc)', a lesion of this nature may be classified as either a low or a high grade type of malignant giant cell tumor. T h e r e a r e certain n e o p l a s m s that a r e classified as benign and yet a significant n u m b e r o f these lesions have metastasized and on occasion have even caused d e a t h o f the patient. 3a~176 E x a m p l e s o f t u m o r s b e l o n g i n g in this c a t e g o r y are the " b e n i g n " giant cell t u m o r Of bone, u t e r i n e l e i o m y o m a , a n d h y d a t i d i f o r m mole. In p u b l i s h e d cases o f metastatic " b e n i g n " giant cell t u m o r o f b o n e a n d u t e r i n e leiomyoma, the h m g has b e e n the target o r g a n in almost every instance, t2a3a~ O n t h e o t h e r band, a l t h o u g h p u l m o nary metastasis is n o t u n c o m m o n in h y d a t i d i f o r m mole, a considerable n u m b e r o f these patients have vaginal and u r e t h r a l i n v o l v e m e n t . I~ R a r e o c c u r r e n c e o f e x t r a p u i m o nary s p r e a d f r o m u t e r i n e l e i o m y o m a has likewise b e e n rep o r t e d in o r g a n s a n d s t r u c t u r e s such as the ovary, spinal cord, r e t r o p e r i t o n e a l l y m p h nodes, and p e r i t o n e u m . 7'23a7 So far t h e r e has h e e n only o n e r e c o r d e d case o f l y m p h n o d e metastasis in a " b e n i g n " giant cell t u m o r o f b o n e ? A l t h o u g h relatively little attention has b e e n d i r e c t e d toward these obviously v e r y i m p o r t a n t a n d r a t h e r interesting p h e n o m e n a , the m e c h a n i s m o f metastasis in m a l i g n a n t t u m o r s has been extensively investigated and r e p o r t e d by m a n y authors, a2m A s u r v e y o f the English literature failed to yield any acceptable o r logical e x p l a n a t i o n r e g a r d i n g the f o r m a t i o n o f metastasis in this small g r o u p o f " u n u s u a l " tumors. T o characterize the m e c h a n i s m by which the t u m o r cells have r e a c h e d t h e i r sites o f implantation, s o m e writers have used such terms as " e m b o l i s m " and "deportation," sugg e s t i n g t h a t t h e p r o c e s s was p a s s i v e r a t h e r t h a n active.4.6.~o,24,29.at F o r the p u r p o s e s o f this stud)', t h e m e c h a n i s m o f metastasis has been d i v i d e d into two t y p e s - - a c t i v e a n d passive. T h e process is c o n s i d e r e d active w h e n the defect in the vessel wall t h r o u g h which the neoplastic cells e n t e r the circulation has been c r e a t e d by the destructive effect o f the t u m o r cells themselves, w h e r e a s w h e n the e n t r a n c e o f the t u m o r cells into the circulation is t h r o u g h a vascular wall d e f e c t tlaat has b e e n c a u s e d by any o t h e r means, the process is c o n s i d e r e d passive. T h e majority o f a u t h o r s , however, have r e f e r r e d to the process o f distant i m p l a n t a t i o n as an active f o r m o f s p r e a d , but no tenable e x p l a n a t i o n has b e e n o f f e r e d as to how the t u m o r cells w e r e a b l e to g a i n access into t h e v a s c u l a r circulat ion.n~,s.7a2-~s,20.2~.2a.2s-z7 It is the intention in this c o m m u n i c a t i o n to describe and illustrate the m e c h a n i s m o f metastasis in the so-called " b e n i g n giant cell t u m o r o f b o n e " and to p r o p o s e that such lesion be labeled m a l i g n a n t regardless o f its s e e m i n g l y benign histologic pattern. CASE REPORT A 20 year old black w o m a n was a d m i t t e d to the hospital for the first time on J u l y 7, 1978, because o f pain in t h e left knee, which started a f t e r she fell oil that knee six m o n t h s p r i o r to admission. X-ray films taken at tltat t i m e s h o w e d a n o n e x p a n s i l e lytic l e s i o n w i t h all ill d e f i n e d b o r d e r , m e a s u r i n g 5.5 by 3.5 ~:m., ill the u p p e r e n d o f the left tibia. Several weeks b e f o r e admission she had noticed progressive swelling a r o u n d t h e affected knee. O n admission, the swollen a r e a was f o u n d to be h a r d a n d t e n d e r . A slight j o i n t effusion and i n c r e a s e d skin t e m p e r a t u r e w e r e als0 noted. She walked with a limp, but no limhation o f m o t i o n was detected. R a d i o g r a p h s s h o w e d an 8 by 7.5 cm., completely lytic a n d e x p a n s i l e lesion with f a i n t i r r e g u l a r
ttUMAN PATltOI.OGY--VOLUME 12, NUMBER 8August 1981
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MEDICAL INTELLIGENCE trabeculation forming a multiloculated pattern in the u p p e r end o f the left tibia (Figs. 1, 2). T h e process a p p e a r e d to involve a portion o f the shaft and the entire epiphyseal and metaphyseal areas. T h e r e was considerable thinning o f the cortex, but no evidence of cortical destruction was noted. A thin shell o f cortical bone outlined the lateral borders o f the lesion. Chest x-ray views were r e p o r t e d as normal. T h e only pertinent laboratory finding was an elevated sedimentation rate (31 ram. p e r hr.). Surgery was p o s t p o n e d owing to lack o f compatible bank blood. O n the second day o f the second admission (August 17, 1978), the growth in the u p p e r e n d o f the left tibia was excised and the surgical defect packed with bone chips. T h e
Figure I . Roentgenogram'(anteroposterior view), taken o n admission shows a large, totaIl)' ostcolytic and expansile lesion ill the upper end of the left tibia inw~lving the entire epiph)'seal and metaphyseal areas and a l~Jrtion of tlie diaph)sis. A thin shell of cortical lxme outlines its lateral margins.
gross specimen consisted o f several i r r e g u l a r pieces o f brownish to d a r k p u r p l e and partly hemorrhagic soft tissue, measuring from 3.5 by 1.8 by I cm. up to 8 by 4 by 3 cm. T h e microscopic a p p e a r a n c e was typical o f the socalled conventional o r benign giant cell t u m o r o f bone. T h e proliferating neoplastic cells were either spindle shaped (fibrobastic type) o r ovoid (histiocytic type), interspersed in many places with collections o f muhinucleated giant cells (Fig. 3). T h e nuclei o f the giant cells were often n u m e r o u s and indistinguishable from the nuclei o f the histiocytic type o f cell. Mitotic figures were few and somewhat difficult to find. Portions o f cyst wall containing some muhinucleated giant ceils were recognized. Also present were multiple foci o f scarring and fairly large areas o f acute h e m o r r h a g e . A few spicules o f reactive osteoid were likewise noted.
Figure 2. Lateral view showing faint irregular trat.x:culation fi)rming a muhiloculated pattern.
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Figure 3. Medium power view of a typical ct;nventional giant cell tumor showing characteristic proliferation of both spindle and ovoid neoplastic cells, interspersed with many muhinuclcatcd giant cells. (Hcmatoxylin and eosin stain. • 100.)
A very interesting incidental finding was the presence o f blood vessel invasion in every section examined. T h e portion o f the wall involved in the early stage o f vascular invasion was rather limited o r localized, and before complete penetration took place, progressive thinning o f the area accompanied by disintegration o f muscle wall components was noted (Figs. 4, 5). T h e diagnosis was malignant (low grade) giant cell t u m o r o f bone. THE BIOLOGY OF METASTASIS Theoretically three distinct stages have been recognized in the formation o f metastases in malignant neoplasms. 9 In r e g a r d to the first stage there are several theories that have been proposed, some o f whiclt relate specifically to the process~ o f invasion--the initial stage o f metastasis. T h e designation "biological p r e d e t e r m i n i s m " has been coined by some investigators to emplmsize the characteristic invasiveness o f t u m o r cells and the lack o f this distinct feature in normal cells) 6 According to Fisher a n d Fisher, 9 " A t t e m p t s to explain divergence o f such determinism have been related to features o f cell motility, differences in mut u a l adhesiveness o f malignant neoplastic cells, related to their surface changes and or calcium content, and the loss o f contact inhibition, a p h e n o m e n o n r e g a r d e d as accounting for the lack o f invasiv/zness o f normal ceils." Roberts et al., ~2 on the o t h e r hand, p r o p o s e d that t u m o r cells reach the circulation by way o f vascular defects when the extravascular pressure exceeds that within a vessel, a process r e f e r r e d to as intravasation. Probably the most tenable idea is the
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possibility that t u m o r cells could elaborate a s p r e a d i n g factor (probably hyaluronidase) capable o f altering the g r o u n d substances o f the connective tissues to pave the way for their invasion and p r o m o t e distant implantation by destroying vascular walls. Is Dissemination, the second stage in the d e v e l o p m e n t o f metastasis, commences with the intravascular release o f neoplastic cells from the p r i m a r y growth. T u m o r cells most probably are continuously invading the circulation in large quantity. However, it has been estimated that only a very small n u m b e r (0.01 p e r cent) o f these circulating t u m o r ceils ultimately survive to initiate distant implantation, aa .Until recently the circulatory route (either lymphatic o r hematogenous) t h r o u g h which t u m o r cells disseminate was thought to be the d e t e r m i n a n t o f the means by which certain organs and structures become the sites o f metastasis. An interesting e x p e r i m e n t by Fisher and Fisher s has demonstrated that t u m o r cells are capable o f crossing interstitial barriers and a p p e a r quite readily in the thoracic lymph following blood vessel injection. T h e third and final stage ifi the formation o f metastasis involves t h r e e distinct processes, namely, l o d g m e n t , attachment, and growth o f cancer cells at distant sites. T o be effective in initiating~implantation the cancer cells must inevitably attach themselves to vascular endothelium. Very soon after attachment, the cells become e n t r a p p e d within fibrin clot where they may either survive for a length o f time o r proliferate and, subsequently, p e n e t r a t e t h e vascular wall and invade perivascular tissues. During the period o f cell proliferation, vascularization and connective tissue formation are taking place simultaneously. Vasctdar con-
Figure 4. Low power magnification showing vascular invasinn, with fncal complete penetration of the wall causing extravasatinn of red blond cells into perivascular tissues. (Hcmatnxyli n and eosin stain, x40.)
Figure 5. Low power view showing vascular invasion occurring simultaneously in two different areas of the wall. (ttematnxylin and eosin stain, x40.)
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H U M A N P A q ' t l O L O G Y - - V O L U M E 12, NUMBER 8 August 1981 nections are believed to be accomplished through elaboration o f an angiogcnesis factor by tumor cells? From this secondary growth, metastasis may also develop. DISCUSSION In view of its frequently unusual clinical behavior, the so-called "benign giant cell tumor o f bone" has always been regarded as one o f the UlOSt unpredictable neoplastic lesions o f the skeletal system. This is in part attributable to its remarkably high incidence o f recurrence after either curettage or local resection of the basic lesion, usually occurring within two )'ears after the initial surgery. More remarkable than its propensity to recur, however, is the capacity of this neoplasm to metastasize, despite its innocent looking histologic pattern. Both recurrent and metastatic lesions commonly retain their original benign microscopic features. Occasionally the hstologic features o f tile recurrent tumor are obviously malignant. T h e site o f nletastasis is almost invariably the lung. Lymphatic spread in a case of "benign" giant cell tumo'r o f the distal etad of the femur was reported by Budzilovich et al. 5 T h e occurrence of tumor thrombi in venous channels adjacent to a "benign" giant cell tumor of bone is not unusual? z However, the question regarding its pathogenesis has not yet been fully resolved. Obviously the solution depends chiefly on tile documentation o f a case with intratumor vascular (venous) invasion. Recognizing the preceding information as factual and essential to a discussion relevant to a better understanding o f how and why metastasis develops from a tumor that has been classified as benign, I shall now proceed to discuss its mechanism o f invasion by utilizing the histopathologle findings in a "benign" giant cell tumor r e m o v e d front the proximal end of the tibia of the 20 )'ear old black woman just presented. MECHANISM OF VASCULAR I N V A S I O N T h e incidental microscopic finding o f vascular invasion in this tumor was the main object and motivating factor i n this study. As far as could be determined in the English literature, intratumor vascular invasion in prinmry "benign" giant cell tumor o f bone has never been reported. Tile radiographic and microscopic features o f the lesion under discussion may be best characterized as being typical of a conventional type o f giant cell tumor. Radiologically it presents a totally lytic process with faint irregular trabeculation, forming a mvltiloculated pattern and expanding the upper end o f the tibia. T h e growth appears to involve the entire epiphyseai and metaphyseal areas and a portion of the diaphysis. T h e r e is no evidence of tumor penetration through the cortex, and a thin shell of cortical bone outlines its lateral margins. Except for the interesting finding o f blood vessel invasion in this lesion, the overall histologic appearance, as previously indicated, is distinctly that o f a conventional giant cell tumor. As usual, the growth is quite cellular and the component cells are either ovoid (histiocytic type) or spindle shaped (fibroblastic type), interspersed in many areas with collections o f multinucleated giant cells. T h e nuclei o f the giant cells are often ntnnerous, and they resemble very closely the nuclei of the ovoid or histiocytic type o f cell. Dividing cells are scanty'and inconspicuous. . Fairly large areas o f acute hemorrhage and multiple foci of scarring are noted. Also recognized are portions o f cyst wall, consisting o f thin strips of fibrocollagenous tisst, c, containing some multinucleated giant cells. A small amount o f reactive os-
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teoid is likewise present. In addition, every representative histologic section examined shows invasion o f several blood vessels by tumor cells. T h e vessels involved are usually small to medium sized arteries and veins. Initially the destruction of a blood vessel by t u m o r cells appears to involve a rather linlited or localized portion o f the wall, creating a seemingly progressive thinning o f tile area, accompanied by disintegration of muscle wall components. Finally, complete penetration takes place. While observing the different stages o f vascular invasion, it became obvious tlmt the nluhinucleated giant cells are most probably actively participating in the process. They are often present in the advancing masses o f tt, mor cells, destroying vascular walls and also within h, mina of involved vessels. Extravasated blood has formed fairly large areas of acute hemorrhage, usually occurring around vessels with completely penetrated walls, and seepage of red blood cells through these defects has become apparent. The foregoing information, evidence of an active type of metastasis, indicates that the designation "benign giant cell tumor of bone" is realistically a misconception, and therefore warrants redefinition and reclassification. A suggestion was made earlier that this neoplasm be labeled malignant, despite its seemingly benign lfistologic appearance. It is further proposed that relative to the degree o f malignancy, a lesion of this nature be classified as either a low or a high grade type of malignant giant cell tumor. A high grade type o f tumor must contain, within a setting o f t typical giant cell tumor, a fibrosarcomatous component. The labeling o f a low grade type of lesion, on the other hand, simply requires tile usual criteria in diagnosing a typical or conventional giant cell tumor. References
1. Ackerman, 1- V., and Rosai,J.: Surgical Pathology. Ed. 5. st. Louis, The C. V. Mosby Company, 197.t.p. 818. ,'2. Ariel, I. M., and Trinidad, S.: Pulmonary metastasis from a uterine "leinm)oma.'" Relx)rt of a case----evaluation of differential diagnosis and treatment ~)licies. Am. J. Obstet. G)nec., 94:110-116, 1960. 3. Arnold, H. A.. and Bainborough, A. R.: Subacute cor pulmonale following trophoblastic pulmonary emb~)lism. Canad. Med. Assn. J., 76:478, 1957. 4. Bardawil. A.. and Toy, B. L: The natural history of choriocarcinoma; problems of immunity and spontaneous regres'slon. Ann. N.Y. Acad. Sci., 80:197, 1959. 5. Budzilovich, G. N., Truchly, GI, and Wilens. S. I..: T u m o r giant cells in regional lymph nodes of a case t)f recurrent glant-ccll tumor of l~me. Clin. Orthop., 30:182-187, 1963. 6. Canlas, B. D.: Benign lesions ofa|n_'rrant trophoblast in the hmg. Obstet. Gynec., 20:602, 196,'2. 7. Fallahzadeh, It., Dockerty, M. B., and l.ee. R. A.: Leir ~)f the ovary--re~)rt of five cases and review of the literature.'-Am.J. Obstet. Gynec., 113:39-t-398, 1972. 8. Fisher, B., and Fisher, E. R.: Biological aspects nf cancer-cell spread. In Fifth National Cancer Conferance Proceedings. Philadell)hia, J. B. Lippincott Company, 196-1, p. 105. 9. Fisher, B., and Fisher, E. R.: Metaslasis reGsitcd. In Weiss, L. (Editor): Fundamenlal Aspects of Metastasis. New York. Elsevier-North tlolland Publishing Company, 1976, pp. -127-435. 10. llsu, C . T . , ltuang, L.C, and Chen, T.Y.: Metastasis in benign hydatidiform mole and cborioadenoma destruens. Am. J. Obstet. Gynec., 84: !.t 12, i 962. II. Jac~)bson, F.J., and Enzen, N.: II)datidiform mole with "'benign'" metastasis to lung--Ifistological ek'idence of regressing lesion in lung. Am. J. Obstet. Gyncc.. 78:868, 1959. 12. Jaffe, il. L.: Giant-cell tumor. In Jaffe, tl. L.: Tumors and Tumorous Conditicms ~f Bcmes and Joints. Philadelphia, Lea & Febigcr, 1958. pp. 18-43. 13. Je~'ell, J. I1., anti Bush, L. F.: Benign giant-ten tum~w ~f b~me x~ith a s(~litary pulmonary metastasis. A case report. J. B~me Joint Surg., 46A:848-852, 1964. 14. Johnson, E.W.: Adjacent and di:stant spread of giant-cell tumors. Am.J. Surg.. 109:163, 1965. 15. I~_'feb~re. R., ec al.: Leinmyoma of the uterus with bilateral pulmonary metastases. Canad. Meal. Assn. J., 105:501-503, 1971. 16. MacDonald. !. G.: Bic~logical predeterminism in human cancer. Surg. Gynec. Obstet., 92:443. 1951.
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27. Taubert, I1., Wissncr, S. E., and tlaskins, A.L.: Leitml)omatosis peritoncalis disseminata. An unusual complication of genital lelomyomata. J. Obstet. Gynec., 25:561-574, 1965. 28. Tedeschi, L. G., and Toy, B. L.: Experimental transpuhllonary migration of trophoblast. J. Obstet. Gynec., 21:55, 1962. 29. To}', B. L., and Tedcschi, L. G.: Emlx~lic trophoblast in peripheral circulatlon during pregnancy. Proc. 8oc. Exper. Biol. Med., 106:865, 1961. 30. Trotter, R. F, and Tieche, it. L.: Maternal death due to pulmtmar)' embolism of trophoblastlc cells. Am.J. Obstet. Gynec., 71: I 114, 1956. 31. Viet,J.: Ueber Deportation yon chorionzotten (Verschleppungs'on Votten in mutterliche Blutbahnan). Z. Geburtsh. Gynfk., 44:466-5Ot, 1901. 32. Weiss, L. (Editor): Fundamental Aspects of Metastasis. North Holland Publishing Co. 1976, Ch. 1, p. 25. 33. Weiss, L.: Dynamic aspects ofcancer cell population in metastasis. Am.J. Path., 97:601-608, 1979. 34_ Willis, R. A.: The Spread of Tumors in the Human Body. Ed. 3. l.~mdon, Butterwortlt & Co. (Publishers) Ltd., 1973, Ch. I, p. 29. Department of Pathology United Hospitals Medical Center 15 South 9th Street Newark. New Jersey 07107
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