[CANCER RESEARCH 44, 2608-2615, June 1984]

Transplantability of Naturally Occurring Benign and Malignant Neoplasmsand Age-associated Nonneoplastic Lesions of the Aging F344 Rat asBiological Evidence for the Histological Diagnosis of Neoplasms1

Jerrold M. Ward2 and Peter H. Lynch

Tumor Pathology and Pathogenesis Section, Laboratory of Comparative Carcinogenesis, Division of Cancer Etiology, National Cancer Institute, NIH,Frederick, Maryland 21701

ABSTRACT

Portions of 162 naturally occurring neoplasms and 26 nonneo-

plastic lesions from 93 aged male or female F344/NO rats wereimplanted into the left inguinal mammary fat pads of weanlingsyngeneic recipients. As controls, 95 normal tissues were implanted to the right inguinal fat pad. Transplant recipients weremaintained for up to 1 year. Essentially, all types of naturallyoccurring benign and malignant tumors were successfully transplanted, i.e., grew progressively forming nodules and masses.For the transplants, the latency period preceding palpablegrowth, tumor growth rate, invasiveness, metastatic rate, andtime to death were associated with the degree of histologicalmalignancy of the primary tumor. The tumors which were themost malignant based on these criteria included large granularlymphocyte leukemia, sarcomas, and carcinomas. Fibromas,mammary fibroadenomas, and papillomas were easily transplanted but were not invasive. Endocrine tumors generally werethe slowest-growing tumors. This study provides evidence that

successful tumor transplantation is only evidence of neoplasiaand does not distinguish whether a primary tumor is benign ormalignant.

INTRODUCTION

Tumor transplantation has been utilized to study the autonomous growth of neoplasms and to differentiate neoplastic fromnonneoplastic lesions (4, 7, 13, 14, 23, 24, 35). Transplantedtumors grow progressively and may kill the host. Some investigators believe transplantation of a tumor is the ultimate proof ofmalignancy (4, 23, 24, 35), while others provide evidence thattransplantation is proof of neoplasia but does not distinguishbenign from malignant tumors (1, 7,11).

Descriptive terminology for neoplasms has evolved since the19th century (6, 25, 34, 35). Benign tumors, which grow autonomously and progressively, must be distinguished from hyper-

plastic lesions which are reaction to injury or which may precedeneoplasia and are reversible. Benign tumors are histologicallywell differentiated, are delineated from adjacent normal tissue,and do not invade or metastasize (6, 7, 18, 20, 34). Clinically,such tumors may be removed surgically with an excellent prognosis but if not removed may cause death, usually by mechanicalinterference with adjacent normal tissues. Malignant tumors mayarise de novo, from benign neoplasia or from hyperplastic lesions(7, 23, 26, 31, 32). They are defined as tumors with histological

1This project has been supported in part by USPHS Contracts N01-CO-21910

to Program Resources, Inc., and N01-CO-23912 to LJtton Bionetics, Inc.2To whom requests for reprints should be addressed.

Received November 15, 1983; accepted February 27, 1984.

characteristics of poorly to well-differentiated tumor cells; inva

sion of adjacent tissues, blood vessels, or lymphatics; and ultimately métastases.Often the extent to which these features areevident is associated with tumor size and histological type (6,18,20,34). Clinically, the prognosis for malignant tumors is moreguarded than for benign tumors. These definitions are at leastpartly subjective and have been developed by pathologists foruse in everyday practice or research.

In F344 rats, tumors are seen which occur spontaneously andfit the description of "benign" tumors given above (3, 8, 10, 26,

27, 31 ). These include fibromas in dermal areas of the mammaryfat pads, mammary fibroadenomas, certain endocrine tumors,cutaneous papillomas, and uterine stromal polyps. Several isolated reports have indicated the transplantability of at least somehistologically benign tumors in rodents including mammary fibroadenomas (11, 24) and skin papillomas (1). There are nostudies on the transplantability of representative naturally occurring tumors of all sizes and the association of transplantationwith histological appearance and biological behavior in the primary host. The study described herein attempts to define transplantation characteristics of histologically benign and malignanttumors occurring naturally in the aging F344 rat in an effort toprovide a biological basis for histological tumor diagnosis.

MATERIALS AND METHODS

Ninety-three male and female retired breeder F344/NCr rats were

obtained from the National Cancer Institute Animal Genetics and Production Branch and Animal Program, Frederick, MD, and maintained 3/cagein polycarbamate cages with hardwood bedding until 20 to 38 monthsold. They were fed Wayne Sterilizable Lab-Blox (Allied Mills, Inc., Chi

cago, IL) and water ad libitum. They were sacrificed at various ages, anda selective necropsy was performed on each rat.

Two- to 3-mm-square portions of grossly visible tumors, nonneoplastic

lesions, or grossly normal tissues were transplanted into the inguinalmammary fat pad of normal weanling (4- to 5-week-old) male or female

F344/NCr according to the method of Williams er al. (15, 16, 32, 33).Ketamine hydrochloride (Ketaset; Bristol Laboratories, Syracuse, NY)anesthesia was used at a dosage level of 50 mg/kg i.m. A small pocketwas prepared in the left or right inguinal fat pad; one tissue implant wasplaced in each pocket. The pocket was closed with a purse string sutureof 4-0 surgical silk to enclose the implant and provide a gross and

histological marker of the implant site. The skin was closed with stainlesssteel clips that were removed 1 week later. Usually, tumor tissue wasplaced in the left inguinal fat pad, and a normal portion of the sametissue was placed in the right inguinal fat pad of the same rat. Eachtumor was implanted in only one rat. Transplant sites were palpated,and rats were weighed weekly. When tumors appeared, they weremeasured weekly and their progression was recorded. Rats died or weresacrificed only when moribund or when the transplant became largeenough to interfere with the rat's normal functions. All surviving rats

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Transplantation of Benign and Malignant Tumors

were sacrificed 1 year after transplantation. Selected tumors werepassed into second- and third-generation recipients.

All donor rats and transplant recipients were necropsied, and selectedtissues fixed in 10% neutral buffered formalin or Bouin's solution. Por

tions of primary and transplanted tumors, regional lymph nodes adjacentto the primary tumor or tumor transplant, and lungs were fixed fromeach rat. For diagnosis of LGL3 leukemia in donor or recipient rats, spleen

and liver were fixed from the majority of the rats. Tissues were embeddedin paraffin, sectioned at 4 to 6 /¿m,and stained with hematoxylin andeosin. Selected tumors were stained by one of the following methods:periodic acid-Schiff; Masson's trichrome; or Wilder's reticulin. Tumors

from donor rats were classified by conventional histological criteria.Primary benign neoplasms were well differentiated and well circumscribed and did not invade adjacent normal tissues. Benign tumors ofrats, however, usually have no capsule. These tumors grow by expansion. Primary malignant neoplasms were usually less differentiated orhad areas of various degrees of differentiation, had more mitotic figuresthan did benign tumors, and invaded adjacent normal tissues to varyingdegrees. Some malignant neoplasms metastasized to distant tissues.

For immunoperoxidase localization of a cell surface antigen reactingwith monoclonal OX-8 antibody, the avidin-biotin-peroxidase complexmethod was used (12, 22, 29). The mouse monoclonal OX-8 antibodywas obtained from Sera-Lab, Sussex, United Kingdom, and the Vectas-

tain ABC Kit was used (Vector Laboratories, Inc., Burlingame, CA).

RESULTS

Tumor Transplantation. Results of tumor transplantation areshown in Tables 1 to 3. Successful transplantation of a tumorwas defined as progressive nodular or massive growth of thetransplant by expansion or invasion. Transplants were successfulfrom almost every type of tumor. The transplants appeared togrow in the recipient as they did in the donor. There was anassociation between tumor latency (time to clinical appearanceof the tumor by palpation or body weight loss) and the histologiedegree of malignancy. If the primary tumor was histologicallyinvasive (e.g., all sarcomas and carcinomas) or metastatic (e.g.,mesothelioma or leukemia), latency of the transplant was short,usually 1 to 2 months. These tumors also had more mitoticfigures than did benign tumors. Growth of malignant tumorsusually resulted in death of the recipient from 1 to 8 weeks aftertumor appearance because of tumor métastases, hemorrhageinto the tumor and subsequent anemia, or invasion and interference with organ function. The LGL leukemias frequently hadonly small tumors at the transplant site, but recipient rats diedfrom disseminated leukemia, anemia, and occasionally braininvolvement (22,30). If primary tumors were histologically benign(e.g., adenomas, endocrine tumors), tumor latency was longer,usually 3 to 12 months. These benign tumors grew slower thandid malignant tumors, and they interfered with host survival onlyby mechanical means, especially those that reached 40 to 60mm in diameter after 6 to 12 months. Several tumors types(fibroma, preputial gland adenoma, LGL leukemia, malignantfibrous histiocytoma, pulmonary alveolar type II cell carcinoma,mesothelioma) were transplanted for 2 or more passages. Allgrew well in the second and later passages and generally maintained their original histological characteristics.

Histological Appearances of Transplanted Tumors. In general, the histological appearance of the first passage of each

3The abbreviations used are: LGL, large granular lymphocyte; NK, natural killer

cell.

tumor was identical or similar to that of the primary tumor.Histologically malignant primary neoplasms including sarcomasand carcinomas usually were invasive when transplanted. LGLleukemias disseminated quickly from the transplant site (22, 30).The site usually was only slightly enlarged while the spleen, liver,lungs, and other organs were severely infiltrated by leukemiccells. Only 4 transplants other than LGL leukemias metastasizedto the lungs. These included one each of the following tumortypes: fibrosarcoma; carcinoma of the auditory sebaceousglands; pheochromocytoma; and mesothelioma.

Many transplant recipients died of LGL leukemia. Aged F344/NCr rats (2 to 3 years) have a 65% incidence of LGL leukemia(28). The aged rat donors usually had typical lesions of fulminating LGL leukemia (30, 31). Some donor rats had evidence of theearly stage of LGL leukemia (12, 31) and a few donor ratsappeared histologically normal without evidence of early or lateLGL leukemia. The stroma of some primary tumors which weretransplanted into weanling recipients was composed of bloodvessels or connective tissue containing LGL leukemia cells, asshown by the OX-8 cell surface antigen marker (22, 29, 30) (Fig.

1). Some primary epithelial and endocrine tumors were transplanted with leukemia cells growing within the transplant in therecipient rat (Fig. 2). In some rats that died with leukemia, themammary fat pad site of tumor implantation contained foci ofresting or degenerative nonleukemic tumor cells or small epithelial or endocrine tumors in an early stage of growth. Characteristicresting tumors were composed of an island of cells similar tothose in the primary tumor but which were atrophied, degenerative, or well differentiated (Fig. 3). Early tumors appear to arisefrom these resting cells (Fig. 4). These small implants had fewreactive lymphocytes and scant connective tissue stroma orcapsule. Histologically, transplanted tumors were nodules ormasses, sometimes with areas of connective tissue capsuleformation. They usually were identical in morphology to theprimary tumor (Figs. 5 to 10). Some tumors had variable patternswhich were different than those of the primary tumor. Theprimary pulmonary adenocarcinoma (composed primarily of alveolar type II cells by ultrastructural examination) had foci ofsquamous metaplasia while the transplant did not. The 2 skinpapilloma transplants formed cystic tumors with papillary, acan-

thotic, and normal squamous lining epithelium (Figs. 5 and 6).Benign tumors were not invasive (Fig. 7), but a few formedmultiple lobules or nodules (Fig. 8). Transplanted tumors of mixedepithelial and mesenchymal elements such as the uterine stremaipolyp maintained both their epithelial and their stromal components. The mesothelioma formed solid sheets of poorly differentiated cells.

Hepatocellular neoplasms were difficult to transplant, in partbecause the majority of recipients died from LGL leukemia. In 4recipients, foci of hepatocytes with chronic inflammatory cellswere seen within the implant sites up to 1 year later.

Nonneoplastic Lesions and Normal Tissues. Nonneoplasticlesions did not form tumors at implant sites except for theappearance of a transplantable transitional cell carcinoma froma kidney implant with lesions of aging nephropathy (Table 4). Notumor was seen in the donor kidney. The common nodularlesions of epidermal inclusion cyst, abdominal fat necrosis, andherniated hepatic nodule (at diaphragm) did not form tumors.Normal tissues did not produce tumors (Table 4), but 26 of 92implants (effective number) yielded nonneoplastic lesions composed of tissues resembling the implanted tissue (Figs. 11 and

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J. M. Ward and P. H. Lynch

Table 1Transplantationcharacteristics of naturally occurring endocrine, hematopoietic,and other tumors in F344 rats

TumortypeEndocrinePituitary

adenomaTesticularinterstitial cell ade

nomaPancreaticIslet

cell adenomaor carcinomaAcinar

adenomaAdrenalpheochromocytomaThyroid

adenocarcinomaHematopoieticLGL

leukemiafromA.SpleenB.

LiverOtherUterine

stromalpolypMesotheliomaPulmonary

adenocarcinomaHepatocellularadenomaHepatocellular

carcinomaNO.trans

planted24314261910942121No.

thatdied of

leukemia11153021910201110Effectiveno."1716425191094211No.

ofrecipients

with tumors105204191042200Diameter

ofprimary tumors trans

planted(mm)2-84-103-4NA"5-1110NANA6-24NA3.5-20NANAMeandays to pal

pabletransplant141

(72-227)"284

(284)>365NA252(228-277)NA41120200(112-330)58

(29-88)30NANAMean

daysto 20-mmtumor187(3)c>365>365NA>365NANANA>36586(2)87NANAMean

daysto death

fromtumor>365>365>365NA228>36570147>365121161>365>365No.

of tumorsfound

only at1yr440NA100010000No.

withnonneo-plastic lesions at

site56001NA0021031

"Rats living more than 250 days after transplantation or developinga tumor transplant prior to 250 days even if developing leukemia."Numbers in parentheses, range.cNumbers in parentheses, number of tumors."NA, not applicable (no tumors found, or leukemiatransplants did not grow to 20 mm at transplant site).

Table 2Transplantationcharacteristics of naturally occurring skin and adnexalgland tumors in F344ratsTumor

typeSupporting

tissuesFibrosarcomaMalignant fibrous histiocytomaSchwannomaMyxosarcomaFibromaNo.

transplanted2

1319No.

thatdied of

leukemia00104Effective no."2

1318No.

of recipientswith tu

mors2

13

17Diameter

range of primary tu

mors transplanted(mm)2030

4-655013-40Mean

days topalpabletrans

plant30(26-38)"

1493(57-129)29

126(71-164)Mean

daysto 20mm4728120(2)c

49141 (6)Mean

daysto death

from tumor82

3421884268No.

oftumorsfound

only at1y0

0000No.

withnonneo-plasticlesionsat site0

0000

Epithelial tissuesPreputial or clitoral gland

Adenoma 7Carcinoma 1

Auditory sebaceous gland cara- 2noma

Papilloma 2

Epithelial tissuesMammary fibroadenoma 14Mammary adenoma 3

133

6-601020

6-16

15-4030-35

120(26-252)8854

97(62-132)

>365308

153(3)10391

84(1)

>365365

249186260

>365

>365>365

"Rats living more than 250 days after transplantation or developinga tumor transplant prior to 250 days even if developing leukemia.6Numbers in parentheses, range.cNumbers in parentheses, number of tumors.

Table 3Summaryof the transplantability of tumors of F344 rats

Mean latentperiod (days to

No. tumor takes/no. palpabletrans-Histotogicaltumor type transplanted plant)

LGL leukemiaSarcomasCarcinomas

FibromaBenign epithelialBenign endocrineMammary fibroadenoma9/9

(100)"

7/7 (100)6/7 (84)7/8 (87)

12/21 (57)22/42 (52)

6/13 (46)41

4857

126158

>250>365

Numbers in parentheses, percentage.

12). These tissues were often degenerative, inactive, or atrophied.

Suture granulomas were usually seen at the implant site forup to 1 year after surgery. These lesions were used as markersto help find the implants, which were usually nearby.

DISCUSSION

Our study showed that histologically malignant naturally occurring neoplasms were transplantable at a higher rate and witha shorter latent period than were benign tumors. Benign tumors,

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Transplantation of Benign and Malignant Tumors

Table4Transplantation characteristics of nonneoplastic lesions and normal tissues of

F344 rats

LesionEpidermalinclusioncystAging

nephropathyMammarycystichy-perplasiaAbdominal

fatHerniatedhepaticnoduleNormal

tissuePituitaryglandTestesPancreasAdrenalThyroidSpleenAged

ratsWeanlingratsLiverMammary

glandSkinFatKidneyPreputial

glandLungUterusNo.

oftransplants548727913722518161879No.

of recipientswhichdied of

leukemia4312156622102130141Effectiveno."23851568502516051749No.

of recipientswith tu

mors0100000000000000000No.

ofnonneo

plastic lesions atsite im

plant0100033111203000236

"Rats living more than 250 days after transplantation or developing a tumor

transplant prior to 250 days even if developing leukemia.

however, were consistently transplantable from most tissueswith the exception of the liver. Our results agree with conceptspromoted by Foulds (7) and others; i.e., progressive growth ontransplantation is evidence of neoplasia but does not provemalignancy as has been proposed by some pathologists (4, 17,19, 24, 35). The histological appearance of the primary tumorsin our study correlated well with the transplantability, latentperiod, growth rate, histology, and invasiveness of the transplants in tumor recipients. Similar findings have been reported inliver tumor transplant studies (15, 16, 21, 32, 33). The highsuccess rate in our experiment is related to the use of an inbredstrain. Spontaneous tumors have been shown to be easily transplanted in syngeneic hosts and evoke little immune response (5,10,13,36).

The finding that most types of benign neoplasms are transplantable is of no surprise. Some benign tumors were shownpreviously to be transplantable (1, 11, 24). By definition, aneoplasm is a progressive growth of cells generally not undernormal cell control mechanisms in the host. Although the neoplasm should grow in a syngeneic recipient, however, not allbenign or malignant tumors are transplantable (1,10,13,17,21,32, 36). Factors other than tumor morphology appear to play arole in successful tumor transplantation. Benign tumors in recipients resembled those in primary donors in lack of invasivenessand métastases and morphological appearance. The fact thattransplanted malignant tumors other than LGL leukemia rarelymetastasized is not surprising. Few spontaneous tumors of theF344 rat metastasize (3, 8, 10, 31). Specific types of chemicallyinduced primary and transplantable tumors have high metastaticrates, while others have low metastatic rates (2, 21, 24).

The LGL leukemia occurs in high incidence in F344 rats (8,26, 28, 30) and less commonly in other rat strains. Some caseshave leukemic cells with high NK activity (22, 30). Similar diseases have recently been found in humans (9). It is tempting tospeculate that the LGL leukemia cells had NK activity againstthe spontaneous tumors in the donor F344 rats. Thus, whentumors were implanted into recipient rats, some LGL leukemiacells were also implanted from those donor rats with LGL leukemia, explaining the appearance of leukemia in recipient rats. Itmay also be possible that LGL leukemia cells were present indonor tumors because of the vascularity of the primary tumors,since only 20 to 30% of primary LGL leukemias have high NKactivity as measured in vitro (22, 30). We found no evidence forNK activity against natural primary tumors in aged F344 ratswith LGL leukemia (27). Since we did not perform a completepathology survey of all tissues of donor rats, we cannot evaluatethe possibility that transplanted tumors stimulated the development of leukemia in recipient rats. The vast majority of recipientrats which developed leukemia received tumors or tissues fromdonors which had lesions of leukemia.

ACKNOWLEDGMENTS

The authors are grateful for the aid of Drs. Amos Palmer, Donald Fish, andDraginja Djurickovic, Fred Argilan, Bill Danner, Robert Payne, Tom Tyler, Lee Dove,Lam/ Ostby, Gary Best, Kevin Beali, Jeannie Huntzberry, and Marcha Gamber.

REFERENCES

1. Andrews, E. J. The morphological, biological, and antigenic characteristics oftransplantable papillomas and keratinous cysts induced by methylcholan-threne. Cancer Res., 34: 2842-2851,1974.

2. Becker, F. F. Patterns of spontaneous metastasis of transplantable hepato-cellular carcinomas. Cancer Res., 38:163-167,1978.

3. Coleman, G. L, Barthold, S. W., Osbaldiston, G. W., Foster, S. J., and Jonas,A. M. Pathological changes during aging in barrier-reared Fischer 344 malerats. J. Gerontol., 32. 258-278,1977.

4. Dunn, T. B. The Unseen Fight against Cancer, 204 pp. Charlottesville, VA:Batt Bates and Company, 1975.

5. Embleton, M. J., and Middle, J. G. Immune responses to naturally occurringrat sarcomas. Br. J. Cancer, 43: 44-52, 1981.

6. Ewing, J. Neoplastic Disease: a Treatise on Tumors, Ed. 2,1054 pp. Philadelphia: W. B. Saunders Co., 1922.

7. Foulds, L. Neoplastic Development, Vol. 1, 439 pp. New York: AcademicPress, Inc., 1969.

8. Goodman, D. G., Ward, J. M., Squire, R. A., Chu, K. C., and ünhart,M. S.Neoplastic nonneoplastic lesions in aging F344 rats. Toxicol. Appi. Pharmacol.,48:237-248, 1979.

9. Itoh, K., Tsuchikawa, K., Awataguchi, T., Shiiba, K., and Kunagai, K. A caseof chronic lymphocytic leukemia with properties characteristic of natural killercells. Blood, 6i: 940-948, 1983.

10. Jacobs, B. B., and Huseby, R. A. Neoplasms occurring in aged Fischer rats,with special reference to testicular, uterine, and thyroid tumors. J. Nati. CancerInst., 39: 303-309,1967.

11. Loeb, L., and Fleisher, M. S. Transplantation of benign tumors. J. Cancer Res.,J: 427-459, 1916.

12. Losco, P., and Ward, J. M. The early stage of large granular lymphocyteleukemia. Vet. Pathol., in press, 1984.

13. Middle, J. G., Robinson, G., and Embleton, M. J. Naturally arising tumors ofthe inbred WAB/not rat strain. I. Classification, age and sex distribution andtransplantation behavior. J. Nati. Cancer Inst., 67: 629-636, 1981.

14. Money, W. L., and Rawson, R. W. The experimental production of thyroidtumors in the rat exposed to prolonged treatment with thiouracil. Cancer(Phila.), 3:321-335, 1950.

15. Mori, H . Furuya. K., and Williams, G. M. Enhanced survival and absence ofprogressive growth of transplanted rat liver altered eosinophilic foci andneoplastic nodules in phenobarbital-treated rats. J. Nati. Cancer Inst., 71:849-

854. 1983.16. Ohmori, T., Watanabe, K., and Williams, G. M. Absence of uniform progressive

growth of long-term transplants of rat liver neoplastic nodules. J. Nati. CancerInst., 65: 485-490, 1980.

17. Percy, D. Comparison of biologic behavior and histology of transplantedmammary tumors in GR mice. J. Nati. Cancer Inst., 69: 933-938. 1982.

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J. M. Ward and P. H. Lynch

18. Pierce, G. G., Shikes, R., and Fink, L. M. Cancer, a Problem of DevelopmentalBiology, 242 pp. Engtewood Cliffs, NJ: Prentice-Hall, Inc., 1975.

19. Pierce, G. G., and Wallace, C. Differentiation of malignant to benign cells.Cancer Res., 31: 127-134, 1971.

20. Pilot, H. C. Fundamentals Of Oncology, 192 pp. New York: Marcel Dekker,Inc., 1978.

21. Reuber, M. D., and Firminger, H. I. Morphologic and biologic correlation oflesions obtained in hepatic carcinogenesis in AXC rats given 0.025 percent N-2-fluorenyldiacetamide. J. Nati. Cancer Inst., 37: 1407-1429,1963.

22. Reynolds, C. W., Bere. E. W., Jr., and Ward, J. M. Natural killer activity in therat. IV. Characterization of transplantable large granular lymphocyte (LGL)leukemias in the F344 rat. J. Immunol., 732: 534-540,1984.

23. Stewart, H. L. Comparative aspects of certain cancers. In: F. F. Becker (ed.),Cancer: a Comprehensive Treatise, pp. 303-374. New York: Plenum Publishing Corp., 1975.

24. Stewart, H. L., Snell, K. C., Dunham, L. J., and Schiyen, S. M. Transplantableand Transmissible Tumors of Animals, 378 pp. Washington, DC: Armed ForcesInstitute of Pathology, 1959.

25. Virchow, R. Cellular Pathology. Translated from the second edition of theoriginal by F. Chance, pp. 529-532. Philadelphia: J. B. Uppincott and Co.,

1863.26. Ward, J. M. Background data and variation in tumor rates of control rats and

mice. Prog. Exp. Tumor Res., 26: 241-258,1983.

27. Ward, J. M. Background variations of tumor incidence in rodent populations.In: F. Homburger (ed.), Safety Evaluation and Regulation of Chemicals, pp.

210-216. Basel: S. Karger AG, 1983.28. Ward, J. M. Increased susceptibility of livers of aged F344/NCr rats to the

effects of phénobarbital on the incidence, morphology and histochemistry ofhepatocellular foci and neoplasms. J. Nati. Cancer Inst., 77: 815-823,1983.

29. Ward, J. M., Argilan, F., and Reynolds, C. W. Immunoperoxidase localizationof large granular lymphocytes in normal tissues and lesions of athymic nuderats. J. Immunol., 737. 132-139,1983.

30. Ward, J. M., and Reynolds, C. W. Large granular lymphocyte leukemia. Am.J.Pathol., 777:1-10,1983.

31. Ward, J. M., Sagartz, J. W., and Casey, H. W. Pathology of the Aging F344Rat, 33 pp. Washington, DC: Armed Forces Institute of Pathology, 1980.

32. Williams, G. M., Hirota, N., and Rice, J. M. The resistance of spontaneousmouse hepatocellular neoplasms to iron accumulation during rapid iron loadingby parenteral administration and their transplantability. Am. J. Pathol., 94: 65-74,1979.

33. Williams, G. M., Ohmori, T., and Watanabe, K. The persistence and phenotypicstability of transplanted rat liver neoplastia nodules. Am. J. Pathol., 99:1-12,1980.

34. Willis, R. A. Pathology of Tumors, Ed. 4, 1019 pp. New York: Appleton-Century-Crofts, 1967.

35. Yoshida, T. Problems in the pathological evaluation of malignancy. GannMonogr., 7:21-28, 1965.

36. Zoller, M., Matzku, S., and Goerttler, K. High incidence of spontaneoustransplantable tumors in BOX rats. Br. J. Cancer, 37: 61-66, 1978.

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Fig. 1. Portion of primary preputial gland adenoma showing infiltration of LGL leukemia cells which are reactive with OX-8 monoclonalantibodies (dark cells). Avidin-biotin-peroxidasecomplex immunocytochemicaltechnique, hematoxylin, x 130.

Fig.2. Portion of transplanted pituitary adenoma (pale areas),with outgrowth of LGL leukemia(dark cells). H & E, x 80.Fig.3. Plaqueat fat pad implant site from testicular interstitial cell adenoma.Tumor cells are inactive and nondividing.H & E, x 80.Fig.4. Portion of nodule at implant site showing growth of large neoplastiainterstitial cells and smaller degenerativeinactive implantedcells. H & E, x 220.

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Fig. 5. Primary papilloma in aged F344 rat which was successfully transplanted to weanling recipient. H & E, x 27.Fig.6. Transplanted papilloma in the mammary fat pad. The tumor is cystic and contains papillary areas resembling papillomaand squamous areas resembling the

histological appearanceof the epidermal inclusioncyst. H & E, x 27.Fig. 7. Portion of transplanted fibroma. Note absence of invasion. H & E, x 80.Fig.8. Transplanted uterine stromal polyp showing polypoid tumors and the absenceof invasion into fat pad. H & E, x 38.

2614

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Fig. 9. Primary preputial gland adenoma in aged F344 rat. H & E, x 130.

Fig. 10. Transplanted preputial gland adenoma in recipient showing granularity of tumor cells and localized growth without invasion. Note similarity to primary tumorFig. 9. H & E. x 330.

Fig. 11. Island of hepatocytes and lymphocytes in mammary fat pad. Primary tumor was a hepatocellular adenoma. H & E, x 130.

Fig. 12. Thyroid follicles in fat pad after implantation of normal thyroid gland. Suture granuloma at lower portion of figure. H & E, x 54.

2615

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Fig. 11

Fig. 12.

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1984;44:2608-2615. Cancer Res   Jerrold M. Ward and Peter H. Lynch  Diagnosis of NeoplasmsAging F344 Rat as Biological Evidence for the HistologicalNeoplasms and Age-associated Nonneoplastic Lesions of the Transplantability of Naturally Occurring Benign and Malignant

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