[CANCER RESEARCH 32, 983-987, May 1972] Anastomotic Sarcoma of Irradiated Parabiont Rats ' S. Warren, E. E. Hurst, Jr., C. E. Brown, and R. IM. Chute Cancer Research Institute, New England Deaconess Hospital, Boston, Massachusetts 02215 fS. W., C. E. B., R. N. C./, and University of Chicago, Chicago, Illinois 60637 (E. E. H.] SUMMARY In a series of 1003 pairs of parabiosed rats, in which the right partner of each pair received 1000 rads total-body irradiation, the incidence of soft-part sarcomas at the anastomotic site was 8.7%. The incidence in other parts of the irradiated partner was 5.8%, and in the nonirradiated partner it was 0.3%. A combination of whole-body irradiation plus local factors of continuing trauma and scar formation is thought to account for the higher incidence of sarcomas in the anastomotic region. Systemic factors such as the endocrines may also play a secondary role. INTRODUCTION An excess incidence of sarcomas appeared in the connective tissue and muscle of the anastomotic region of long-term parabiosed rats, in which 1 partner had received supralethal total-body radiation (1000 rads) (Fig. 1). Sarcomas of these tissues were less frequent in unirradiated parabiont pairs and even less so in single animals. In addition to describing these sarcomas, we will discuss factors involved in their pathogenesis and localization within and outside the anastomotic region of the irradiated and nonirradiated rats. While osteogenic sarcomas and fibrosarcomas sometimes arose at the scapular union, these have been excluded because of the differences in tissue environment. MATERIALS AND METHODS The anastomotic sarcomas in this report occurred among 1003 parabiont pairs, with radiation of the right partner, and among 128 unirradiated pairs. Excluded from the present series were 44 sarcomas, mostly osteogenic, occurring around the wire at the scapular anastomosis of the experimental 1003 pairs, and 9 similarly located sarcomas of the 128 nonirradiated control pairs. Although many of the same etiological factors were no doubt present here, the foreign body reaction to the wire, as well as chemical factors, may have introduced changes not present elsewhere in the anastomoses. The incidence of mesenchymal 'Presented at the American Association for Cancer Research 1971 meeting, Chicago, 111.,April 10, 1971. This investigation was supported by United States Atomic Energy Commission Contract AT(30-l)-3777 with the New England Deaconess Hospital and by USPHS Grant RR 5591 from the General Research Support Branch, Division of Research Resources. Received December 10, 1971; accepted February 8, 1972. sarcomas in 362 single, unirradiated rats of similar age is also presented (Fig. 2). All of the rats were of the NEDH Slonaker strain, either inbred or penbred. In each series, the proportion of male and female rats was the same. Only animals living over 230 days were included, none of the mesenchymal tumors having appeared before that time. Minor modifications in the methods of Bunster and Meyer (1) and of Sauerbruck and Heyde (15) were used to perform the parabioses. Our procedure has been to anesthetize, with Nembutal, 1-month-old littermate pairs of rats of the same sex. The operational fields were shaved, and aqueous Zephiran was applied. A cutaneous incision was made along adjacent lateral body walls of each rat from the iliac crest to the base of the ear, curving slightly ventrally. The ventral margins were sutured with continuous atraumatic 4-0 chromic catgut. The abdominal muscles and peritoneum were then incised from the inguinal region to the lowest rib of each animal. A large peritonea] fistula was made by suturing opposing muscles and peritoneal margins ventrally, then dorsally. Adjacent scapulae were fixed together with a nonabsorbable suture of either tantalum or stainless steel wire. The dorsal skin margins were then sutured. Each animal received about 10,000 units of penicillin i.p. The great majority of the parabioses were perfomed by 1 operator and, hence, were technically uniform. However, minor variations in technique may be important since, in a group parabiosed by another operator, numerous sarcomas developed along the anastomosis. Sixty to 90 days after operation, the right partners of healthy, healed pairs received 1000 rads of 250 kV X-rays at 15 ma with only intrinsic filtration. The scatter to the immediately adjacent tissue of the left, lead-shielded partner at the anastomosis was about 10% of the full dose. For the purposes of this study, the anastomotic region is defined as approximately 2 cm either side of the suture line in adult animals. To gain some idea of the amount of soft tissue in the anastomotic region compared with the amount elsewhere in parabiosed rats, we dissected out and weighed the skin, s.c. tissue, and muscles for 2 cm on each side of the anastomotic scar. The remaining soft tissue of the pair was likewise dissected and weighed. In addition to the parabiosed rats, 362 single, comparable, control rats were maintained until their natural death. RESULTS Occasionally, parabiont pairs attained an age of over 800 days. The average age was 562 ±129 days for all experimental MAY 1972 983 Research. on August 18, 2021. © 1972 American Association for Cancer cancerres.aacrjournals.org Downloaded from
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[CANCER RESEARCH 32, 983-987, May 1972]
Anastomotic Sarcoma of Irradiated Parabiont Rats '
S. Warren, E. E. Hurst, Jr., C. E. Brown, and R. IM. Chute
Cancer Research Institute, New England Deaconess Hospital, Boston, Massachusetts 02215 fS. W., C. E. B., R. N. C./, and University of Chicago,Chicago, Illinois 60637 (E. E. H.]
SUMMARY
In a series of 1003 pairs of parabiosed rats, in which theright partner of each pair received 1000 rads total-bodyirradiation, the incidence of soft-part sarcomas at theanastomotic site was 8.7%. The incidence in other parts of theirradiated partner was 5.8%, and in the nonirradiated partner itwas 0.3%.
A combination of whole-body irradiation plus local factorsof continuing trauma and scar formation is thought to accountfor the higher incidence of sarcomas in the anastomotic region.Systemic factors such as the endocrines may also play asecondary role.
INTRODUCTION
An excess incidence of sarcomas appeared in the connectivetissue and muscle of the anastomotic region of long-termparabiosed rats, in which 1 partner had received supralethaltotal-body radiation (1000 rads) (Fig. 1). Sarcomas of thesetissues were less frequent in unirradiated parabiont pairs andeven less so in single animals. In addition to describing thesesarcomas, we will discuss factors involved in their pathogenesisand localization within and outside the anastomotic region ofthe irradiated and nonirradiated rats. While osteogenicsarcomas and fibrosarcomas sometimes arose at the scapularunion, these have been excluded because of the differences intissue environment.
MATERIALS AND METHODS
The anastomotic sarcomas in this report occurred among1003 parabiont pairs, with radiation of the right partner, andamong 128 unirradiated pairs.
Excluded from the present series were 44 sarcomas, mostlyosteogenic, occurring around the wire at the scapularanastomosis of the experimental 1003 pairs, and 9 similarlylocated sarcomas of the 128 nonirradiated control pairs.Although many of the same etiological factors were no doubtpresent here, the foreign body reaction to the wire, as well aschemical factors, may have introduced changes not presentelsewhere in the anastomoses. The incidence of mesenchymal
'Presented at the American Association for Cancer Research 1971meeting, Chicago, 111.,April 10, 1971. This investigation was supportedby United States Atomic Energy Commission Contract AT(30-l)-3777with the New England Deaconess Hospital and by USPHS Grant RR5591 from the General Research Support Branch, Division of ResearchResources.
Received December 10, 1971; accepted February 8, 1972.
sarcomas in 362 single, unirradiated rats of similar age is alsopresented (Fig. 2). All of the rats were of the NEDH Slonakerstrain, either inbred or penbred. In each series, the proportionof male and female rats was the same. Only animals living over230 days were included, none of the mesenchymal tumorshaving appeared before that time.
Minor modifications in the methods of Bunster and Meyer(1) and of Sauerbruck and Heyde (15) were used to performthe parabioses. Our procedure has been to anesthetize, withNembutal, 1-month-old littermate pairs of rats of the samesex. The operational fields were shaved, and aqueous Zephiranwas applied. A cutaneous incision was made along adjacentlateral body walls of each rat from the iliac crest to the base ofthe ear, curving slightly ventrally. The ventral margins weresutured with continuous atraumatic 4-0 chromic catgut. Theabdominal muscles and peritoneum were then incised from theinguinal region to the lowest rib of each animal. A largeperitonea] fistula was made by suturing opposing muscles andperitoneal margins ventrally, then dorsally. Adjacent scapulaewere fixed together with a nonabsorbable suture of eithertantalum or stainless steel wire. The dorsal skin margins werethen sutured. Each animal received about 10,000 units ofpenicillin i.p. The great majority of the parabioses wereperfomed by 1 operator and, hence, were technically uniform.However, minor variations in technique may be importantsince, in a group parabiosed by another operator, numeroussarcomas developed along the anastomosis.
Sixty to 90 days after operation, the right partners ofhealthy, healed pairs received 1000 rads of 250 kV X-rays at15 ma with only intrinsic filtration. The scatter to theimmediately adjacent tissue of the left, lead-shielded partner atthe anastomosis was about 10% of the full dose. For thepurposes of this study, the anastomotic region is defined asapproximately 2 cm either side of the suture line in adultanimals.
To gain some idea of the amount of soft tissue in theanastomotic region compared with the amount elsewhere inparabiosed rats, we dissected out and weighed the skin, s.c.tissue, and muscles for 2 cm on each side of the anastomoticscar. The remaining soft tissue of the pair was likewisedissected and weighed.
In addition to the parabiosed rats, 362 single, comparable,control rats were maintained until their natural death.
RESULTS
Occasionally, parabiont pairs attained an age of over 800days. The average age was 562 ±129 days for all experimental
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Warren, Hurst, Brown, and Chute
pairs, approximately the same as that for rats bearinganastomotic sarcomas. At times, the irradiated partnerdeveloped as many as 4 individual primary benign or malignanttumors in different organs. Many of these occurred inendocrine organs such as the pituitary (23), adrenals (22),ovaries (6), and pancreas (20). The first evidence ofmesenchymal tumor, some 7 to 8 months after parabiosis, wasthe appearance of a small firm nodule in the anastomoticregion. In some instances, the diffuse nature of the growthprecluded exact definition of its point of origin in relation tothe scar. Most of the anastomotic tumors grew rapidly,attaining a diameter of 5 to 6 cm within 4 to 6 weeks (Fig. 1).The virulence of the tumors was expressed by early andextensive infiltration leading to ulcérationof the skin andenvelopment of abdominal organs, and also by a 33%incidence of metastasis, which was high, based on ourexperience with rat sarcomas. Métastasesappeared mostfrequently in lungs and lymph nodes of either partner.Metastasis could have occurred by direct invasion of veinsdraining the tumor, since the tumor was supplied byvasculature derived from each animal as demonstrated byradiography after jugular injection. Metastasis could also haveoccurred from tumor tissue that had spread transperitoneally.Twenty-nine % of the extraanastomotic sarcomas in theirradiated partner also metastasized but, unlike theanastomotic sarcomas, they were restricted to the partner inwhich the tumor originated.
A number of anastomotic sarcomas have been transplantedsuccessfully.
The 87 anastomotic sarcomas were classifiedmicroscopically as follows: 64 fibrosarcomas, 10undifferentiated sarcomas, 8 rhabdomyosarcomas, 3extraosseous osteogenic sarcomas, 1 angiosarcoma, and 1myxosarcoma.
The fibrosarcomas were composed of fusiform cellsinterspersed through variable amounts of collagen (Fig. 3). Thewell-differentiated tumors contained occasional mitoses andmuch collagen, while the less differentiated ones exhibitedmany mitoses and scant collagen. Myxomatous areas werenoted occasionally. Peripheral invasion was alwaysdemonstrable.
The cells of the rhabdomyosarcomas were larger and usuallyliad an abundance of pink amorphous or fibrillar cytoplasm.Myofibrils and, more rarely, cross-striations could be identifiedin the cytoplasm. Large pleomorphic nuclei contained coarsedark chromatin, and mitoses were fairly numerous (Fig. 4).
The undifferentiated sarcomas were composed of plump,single or polygonal cells with large hyperchromatic nuclei,often in mitosis. Except where necrosis was present, the tumorcells were crowded into sheets with little intercellularsubstance (Fig. 5). Myxoid changes were seen occasionally.
Preliminary electron microscopic studies on a singlefibrosarcoma by Dr. Micheline Federman have demonstratedthe complexly folded cell membrane and abundant organellesoften seen in tumor cells (Fig. 6). Secondary lysosomescontaining laminated phospholipid bodies were frequentlypresent, probably representing beginning autolysis of thecytoplasmic structures. These cells are now being studied indetaU and will be reported upon later. Recognizable virusbodies have not been encountered. Survey immunological
studies, for which we are indebted to the National CancerInstitute, demonstrated that the colony was free of polyomavirus. There was evidence of the occasional presence of theToolan HI or Kilham rat virus.
The distribution of soft-part sarcomas in 1003 irradiatedparabionts was as follows: 8.7 ±0.28% occurred in theanastomotic region, 5.8 ±0.25% occurred elsewhere in theirradiated partner, and 0.3 ±0.06% occurred in thenonirradiated partner, exclusive of the anastomotic region. Incontrast to the 1003 experimental pairs, the 128 nonirradiatedcontrol pairs showed an incidence of 3.1*0.17% in theanastomotic region (Fig. 2) and 2.3 ±0.15% elsewhere in thesoft tissues of each member of the control pairs. The soft-parttissues of the anastomotic region weighed less than one-fourththat of the soft parts of the pair outside the anastomosis.
The 362 nonirradiated single control rats had an incidenceof 1.9% soft-part sarcomas.
DISCUSSION
At least 3 factors may account for the development andlocalization of mesenchymal sarcomas predominantly in theright partner and in the anastomotic regions, namely,hormonal environment, irradiation, and regional conditions atthe anastomotic site which contributed to the density andextent of scar formation.
Evidence for the role of the endocrine factor present iscoincidental rather than direct. An increase in circulatinggonadotropins in parabiotic rodents, 1 partner of which hadbeen castrated, has been reported (7, 9). In many of ourirradiated parabiosed rats, the pituitary gland of one or theother partner showed hyperplasia or adenoma formation (23).This probably resulted from altered feedback from irradiatedend organs such as gonads, adrenals, and pancreas, withsubsequent increased stimulation of these organs byappropriate pituitary hormones. We have noted a modestpreponderance of anastomotic tumors in males (11.4%) ascompared with 6% in females. Some endocrine tumors occurpredominantly in males, for example, adrenal medullary (22)and insular tumors (20). The marked deficiency of sarcomas inthe shielded partners (0.3%) raised the question as to whytheir mesenchymal cells respond differently from those of theanastomotic site and of the irradiated partner. Certainly,hormonal imbalance is present in these animals, but whetherthis exerts a neoplastic effect on the mesenchymal cells of theanastomotic site or on the cells of the irradiated partner ishypothetical.
The increased incidence of mesenchymal sarcomas in theirradiated partners of 1003 parabiosed rats seems to establishirradiation as an etiological factor. Excluding for a momentthe anastomotic site, 5.8% of the mesenchymal sarcomasoccurred in the irradiated partner as against 0.3% in thenonirradiated partner. This also exceeds the 2.3% in eachcontrol parabiont and the 1.9% in the single controls. Theseresults are similar to those of Koletsky and Gustafson (10)who found a 7.3% incidence of fibrosarcomas in skin and s.c.tissue of single, Wistar male rats following whole-bodyX-radiation with 660 R.
The greatest number of sarcomas arose in the anastomotic
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region (8.7%). The right half of this region received the fulldose of 1000 rads, and the left half received a diminishingamount of irradiation. In this region, additional factors werepresent, namely, chronic irritation, continuing stress frommovement, and alterations in histocompatibility, all of whichcontribute to scar formation. The possible effect of localfactors at the anastomotic site, uncomplicated by irradiation,were shown in the control series of 128 parabionts. Here, anincidence of 3.1% compares with 2.3% in each of the partner's
soft tissues outside the anastomosis. The incidence of sarcomasin the anastomotic region of both the experimental andcontrol parabionts becomes more impressive, since we haveshown that the mass of soft tissue in the anastomotic regionwas less than one-fourth of that outside it. There is also somesupport in the literature for assigning etiological significance tolocal factors operative at the anastomosis site.
The general incidence of soft-part sarcomas in rats is low. In1 series of Sprague-Dawley rats, the incidence was reported as1.6% (18). In 2 series of Wistar rats (3, 14), in 1 of theOsborne-Mendel strain (16), and in other strains (4), it wasreported as less than 1%.
Under appropriate chemical stimulation, the connectivetissue of the rat has a considerable propensity to developsarcomas (8). This is also true for mice (2) and guinea pigs (17,21).
A more subtle etiology is apparently operative in the genesisof mesenchymal sarcomas arising in scar tissue around insertedplastic films. In 1941, Turner (19) produced fibrosarcomas inthe scar tissue around Bakelite disks implanted in the s.c. tissueof rats. Seven years later, Oppenheimer étal.(13) reported theoccurrence of fibrosarcomas around cellophane film, andfollowed this with reports of s.c. sarcomas occurring adjacentto such plastic films as Dacron, nylon, Sarán,and polyethylene(12), as well as around metal foils (11) and glass coverslips (5).Analysis of the scar tissue around cellophane has shown anincrease in insoluble collagen around the films prior to thedevelopment of sarcoma (5).
The operation of some regional factor at the anastomoticsite in our parabionts and related to scar formation was furthersuggested by a group of 172 rats not included in the presentseries. Here the incidence of anastomotic sarcomas in thehands of 1 operator reached 42% in contrast to the usualincidence of 7 to 9% in the hands of others. At present thereason for this unusual increase is not apparent, and furtherexperiments are being conducted in attempts to producedenser and more extensive scars by wider incisions, vascularocclusion, and increased local trauma.
A review of the lineage of tumor-bearing rats showed noconsistent pattern.
Subtle differences in the histocompatibility of the 2partners might produce imperfect continuity ofmesenchymally derived cells and cause the cells of 1 animal toact as an impenetrable film to the cells of the other animal,thus stimulating scar tissue reaction and ultimate neoplasia.
REFERENCES
1. Bunster, E., and Meyer, R. K. An Improved Method of Parabiosis.Anat. Record, 57: 339-343, 1933.
Rat Anastomotic Sarcoma
1. Burrows, H., Hieger, J., and Kennaway, E. L. The ExperimentalProduction of Tumors of Connective Tissue. Am. J. Cancer, 16:57-67,1932.
3. Crain, R. C. Spontaneous Tumors in the Rochester Strain of WistarRats. Am. J. Pathol., 34: 311-335, 1958.
4. Curtis, M. R., Bullock, F. D., and Dunning, W. F. A StatisticalStudy of the Occurrence of Spontaneous Tumors of the Rat. Am.J. Cancer, ¡5:67-121, 1931.
5. Danishefsky, I., Oppenheimer, E. T., Heritier-Watkins, O., Bella,A., Jr., and Willhite, M. Biochemical Changes in the ConnectiveTissue Pocket Surrounding Subcutaneously Imbedded Films.Cancer Res., 27: 833-837, 1967.
6. Friede!!, G. H., Sommers, S. C., Chute, R. N., and Warren, S.Ovarian Tumorigenesis in Irradiated Parabiotic Rats. Cancer Res.,26:427-434, 1966.
7. Fuson, R. B. Bibliography of Parabiosis. ExperimentalEndocrinology Section. Transplantation Bull., 27: 112, 1961.
8. Hartwell, J. L. Survey of Compounds Which Have Been Tested forCarcinogenic Activity. Ed. 2, USPHS Publication No. 149.Washington D. C.: United States Government Printing Office,1951.
9. Johnson, D. C., and Witschi, E. Endocrinology of Ovarian TumorFormation in Parabiotic Rats. Cancer Res., 21: 784-789, 1961.
10. Koletsky, S., and Gustafson, G. E. Whole-Body Radiation as aCarcinogenic Agent. Cancer Res., 15: 100-104, 1955.
11. Oppenheimer, B. S., Oppenheimer, E. T., Danishefsky, I., andStout, A. P. Carcinogenic Effect of Metals in Rodents. Cancer Res.,16: 439-441, 1956.
12. Oppenheimer, B. S., Oppenheimer, E. T., Danishefsky, I.. Stout, A.P., and Eirich, F. R. Further Studies of Polymers as CarcinogenicAgents in Animals. Cancer Res., /5: 333-340, 1955.
13. Oppenheimcr, B. S., Oppenheimer, E. T.. and Stout, A. P.Sarcomas Induced in Rats by Implanting Cellophane. Proc. Soc.Exptl. Biol. Med., 67: 33-34, 1948.
14. Ratcliffe, H. L. Spontaneous Tumors in Two Colonies of Rats ofthe Wistar Institute of Anatomy. Am. J. Pathol., 16: 237-254,
1940.15. Sauerbruck, F., and Heyde, M. ÜberParabiosc Künstlichvereinigter
Warmblüter.Muench. Med. Wochschr., 55: 153-156, 1908.16. Saxton, J. A., Jr., Sperling, G. A., Barnes, L. L., and McCay, C. M.
The Influence of Nutrition upon the Incidence of SpontaneousTumors of the Albino Rat. Acta UnióIntern. Contra Cancrum, 6:423-431, 1948.
17. Shimkin, M. B., and Mider, G. B. Induction of Tumors in GuineaPigs with Subcutaneously Injected Methylcholanthrene. J. Nati.Cancer Inst., 1: 707-725, 1941.
18. Thompson, S. W., Huseby, R. A., Fox, M. A., Davis, C. L., andHunt, R. D. Spontaneous Tumors in the Sprague-Dawley Rat. J.Nati. Cancer Inst., 27: 1037-1051, 1961.
19. Turner, F. C. Sarcoma at Sites of Subcutaneously ImplantedBakelite Disks in Rats. J. Nati. Cancer Inst., 2: 81 83, 1941.
20. Warren, S., Carlstein, R. G., Steinke, J., and Chute, R. N.Island-Cell Tumors in Irradiated Rats in Parabiosis. Proc. Soc.Exptl. Biol. Med., 115: 910-912, 1964.
21. Warren, S., and Gates, O. Spontaneous and Induced Tumors of theGuinea Pig. Cancer Res., 1: 65-68, 1941.
22. Warren, S., Grozdev, L., Gates, O., and Chute, R. N.Radiation-Induced Adrenal Medullary Tumors in the Rat. Arch.Pathol., 82: 115-118, 1966.
23. Warren, S., and Imai, T. Pituitary Changes in Parabiosed andIrradiated Rats. Professor Khanolkar Felicitation Volume, pp.106-111. Bombay, India: Bombay University Press, 1963.
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1003 Experimental Pairs 128 Control Pairs 362 Single Controls
Fig. 1. Characteristic location of anastomotic sarcomas.Fig. 2. Diagrammatic representation of the location of mesenchymal sarcomas in experimental parabiont pairs, control parabiont pairs, and
single control rats. The region considered to be anastomotic is stippled. The highest incidence of sarcomas is in the anastomotic region of thosepairs in which the righthand animal received 1000 R. The irradiated member of the pair shows a greater incidence of sarcomas than does theshielded partner. The incidence in control parabiont pairs is somewhat larger than in control single animals.
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Fig. 3. Well-differentiated fibrosarcoma; fairly abundant collagen; rare mitoses. H & E, X 500.Fig. 4. Rhabdomyosarcoma with tumor giant cells, myofibrils, and cross-striations. Phosphotungstic acid-hematoxylin, X 600.Fig. 5. Undifferentiated sarcoma with poorly defined cytoplasmic boundaries and numerous mitoses. H & E, X 600.Fig. 6. Portion of typical tumor cell representing characteristic findings as seen in 1 sarcoma. Note the secondary lysosomes containing
laminated phospholipid bodies, probably the result of autolytic digestion of mitochondria (Rat PRA 73). Electron photomicrograph, x 40,000.(Courtesy of Dr. Micheline Federman.)
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1972;32:983-987. Cancer Res S. Warren, E. E. Hurst, Jr., C. E. Brown, et al. Anastomotic Sarcoma of Irradiated Parabiont Rats
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