Botts, S, Jokinen, MP, Isaacs, KR, Meuten, DJ, Tanaka, N (1991). Proliferative lesions of the and parathyroid glands, E-3. In: Guides for Toxologic Pathology. STP/ARP/AFIP, Washington, DC.

Proliferative Lesions of the Thyroid and Parathyroid Glands

1 2 3 S. Borrs , M.P. JoKINEN , K.R. lsAAcs , D.J. MEUTEN4, N. TANAKA5 'Experimental Pathology Laboratories, Inc., RTP, NC 2National Institute of Environmental Health Sciences, RTP, NC 3EPL Scientific Limited, Harrogate, England 4North Carolina State University School of Veterinary Medicine, Raleigh, NC 50tsuka Pharmaceutical Company, Tokushima, Japan

THYROID GLAND MORPHOLOGY

INTRODUCTION FOLLICULAR CELL HYPERTROPHY (Figure 1) Activity of the thyroid gland varies between indi­ Neoplasms can potentially arise within the thyroid viduals of the same sex, age, and strain; males and gland from any of several cell types including the two females; and animals of different ages (12, 13, 21, 26). glandular parenchymal cells, parafollicular (C-cells) and This variation reflects complex multifactorial interac­ follicular cells, as well as those associated with lymphatic tions which increase or decrease with changes in thyroid or blood vessels, nerves, and the stromal fibrous connec­ stimulating hormone (TSH) production by the pituitary tive tissue. Spontaneous and induced proliferative gland. Increases in this hormone result in diffuse lesions of the thyroid gland are more common in rats physiologic changes seen morphologically as increased than mice (1, 12. 13. 20, 28, 35). vascularity, which is the first change observed, and Hyperplastic or neoplastic changes may involve increased height of the follicular from the thyroid unilaterally or bilaterally. Most focal cuboidal to tall columnar. Both of these changes are the hyperplastic lesions and small adenomas of follicular or most consistent histological indicators of thyroid C-cell origin are not grossly visible. Diffuse hyperplasia follicular epithelial activity. Decreased staining intensity may be seen as bilateral enlargement accompanied by of colloid, in which it appears pale or slightly basophilic darker red coloration. Large follicular adenomas are as compared to the usual brightly eosinophilic appear­ reddish to yellow-grey nodules and may be multiple. ance, is associated with utilization of in Visible C-cell adenomas are white and also may be thyroid hyperactivity. multiple. Fluid-filled cysts large enough to be seen grossly may occur in follicular adenomas or carcinomas of the macrofollicular pattern. Usually other types of FOLLICULAR CELL HYPERPLASIA (Figures 2, 3, 4) cystic lesions are microscopic. Generally, hyperplasia occurs as a diffuse or follicular carcinomas are very vascular, soft, and focal change, often involving multiple sites in one or resemble the normal red-brown coloration of the thyroid both lobes of the thyroid gland. Diffuse hyperplasia fre­ gland while C-cell carcinomas are pale tan to yellow, quently is microfollicular in appearance, and the lobes firm and less vascularized. Both may efface the gland are grossly enlarged and assume a more lobulated shape and/or invade the thyroid capsule. rather than being smoothly ovoid. Follicular epithelium is hyperchromatic, cuboidal to flattened cuboidal, or may appear more active with tall columnar epithelium having large basophilic ovoid nuclei. There is no cellular atypia or invasion. Follicular cell number per unit area may be increased either by papillary infoldings of epithelium or Address correspondence to: Society of Toxicologic stratification of follicular lining cells. Follicular lumens Pathologists, P.O. Box 368, Lawrence, KS 66044 in focal hyperplastic lesions may contain an increased 2 amount of colloid which can cause compression or ad­ vessels. necrosis. and distant mctasUL'iCS may be seen. jacent parcnchyma. but there is minimal architectural distinction from adjacent thyroid parenchyma and no C-CELL HYPERPLASIA (Figures 9. 10) encapsulation. Hyperplastic foci blend with the Prolifcrntion or C-cells is common in the rnt but adjacent gland and are poorl y demarcated. Follicular quite rare in the mouse (7). Diffuse lesions arc cysts. in contrast to foca l hyperplasia. arc sharply common in aging rats and arc composed of nom1al demarcated and may be distended with colloid. but are appearing C-cclls surrounding follicles, giving the lined by a single layer of nauencd epithelium. The impression or increased intcrfollicular ti ssue. Rarely thyroid capsular connective ti ssue may increase in do C-cclls accumulate more than two cells deep in thickness in rats with hypcrplastic lesions (34). The diffuse hyperplasia. Transverse sectioning or the lesions arc considered to be incapable or autonomous thyroid gland result in fewer ec ti ons containing growth and may retain the potential for regression fol­ proliferati ve C-cells than longitudinal sectioning when lowing the wi thdrawal or the inciting stimulus (4. 12. embedded nut. Consistc111 sampling is imperative to 13. 21. 26. 30. 3 1. 35). accurately evaluate incidences of C-ccll lesions ( 16). Small foca l hypcrplasti c lesions occur in the FOLLICULAR CELL ADENOMA (Figures 5. 6) parafollicular area with liulc compression or distortion Adcnomas arc well delineated. minimally to of the adjacent follicles. In larger lesions there may be noncncapsulated. cxpansile and compressive masses (5. compression or follicl es with follicular atrophy and 20. 2 1. 26. 30. 3 1. 35). There may be homogeneous filling or follicles wi th C-cclls. There is no invasion or cellular morphology and architecture within an acle­ encapsulation. Nom1al C-cells are polyhedral to noma. but both differ from the adjacent thyroid gland spherical wi th pale cosinophilic cytoplasm and a parenchyma. Adenomas exhibit three paucms or com­ centrally located nucleus. C-cells forming hypcrplastic bination or patterns: cystic, papillary. or solid. Solid foc i arc morphologically indistinguishable from nomml pauerns include macro- or microfollicular types. C-cclls and these foci or hyperplasia do not exceed five Colloid is often prominent in the macrofollicular type. average follicular diameters (13. I 6. 17). Follicular size is variable. The epithelial lining may be si ngle or multiple layers of cuboidal to columnar cells. C-CELLADENOMA (Figures 11.12) with an increased nuclear to cytoplasmic ratio. uclear C-cell masses greater than live average follicular hypcrchromasia. cytoplasmic basophilia, and nuclear diameters have been designated acl enomas ( 12, 14. 16. crowding arc variably present. Mi totic fi gures are 17. 20). These neoplasms are frequently coinprcssivc generally not present. but do not invade. They arc rarely encapsulated. have scant stroma, :111d are usually discrete. we ll-circum­ FOLLICULAR CELL CARCINOlvlA (Figures 7, 8) scri bed masses. Neoplastic C-cclls arc usually indistin­ Pauems of cellular arrangement within follicu lar guishable from nomial C-cells having unifom1 pale. cell carcinomas include papillary, cystic, macrofollicu­ slightly eosinophilic cytoplasm and spherical centrally lar. solid (microfollicular). scirrhous or a mixture of located nuclei. Less rrequently. the cytoplasm may be patterns within a single mass (6. 20. 26. 30. 3 1. 35). more basophilic. Tumor cells are round to oval but may Solid and follicular areas may appear in the same be fosironn in an expanding mass if they arc com­ tumor. Neoplastic follicular cells have large nuclei pressed by surrounding cells. Cells may spill over into with prominent nucleoli and usually appear well differ­ contiguous follicles or expand a single follicl e. The entiated. Small solid nests and/or sheets or fo llicular presence of nmyloid wi thin the neoplasm i infrequent. cells may be intcnninglcd with areas of fibrosis or. oc­ casionally. the follicular cells may be highly pleomor­ C-CELL CARCINOMA (Figures 13, 14) phic and occur in small nests or individualized cells Cells in C-ccll carcinomas (9. 12. 13, 20) arc which incite a marked scirrhous reaction. Vascularity variably arranged in solid sheets to irregular groups wi thin the neoplasm often is a prominent feature separated by fibrovascular stroma which may have although not diagnostic for carcinomas. Necrosis is amyloid present. Cellular morphology of the neoplas­ common. The mitotic index is variable but may be tic cells depends on the degree of differentiation. They quite high. Variable features include focal mineraliza­ may be well differentiated with round to polygonal tion. brown (iron and PAS positive) pigment (32), and cells having abundant lightly eosinophilic cytoplasm cholesterol cleft format ion. Encapsulation is variable and round to oval nuclei containing finely stippled and the tumor may have a scirrhous capsule with tumor chromatin. Alternati vely, less differentiated cells cells penetrating through the capsule. Invasion of the capsule, adjacent tissues, lymphatic and/or blood 3

exhibiting more nuclear plcomorphi i.m may be the PARATHYROID GLAN D predominant cell type. Many C-cell carcinomas have markedly pleornorphic cells with increased cytoplasmic basophilia. fusifonn shape and many mitoti c figures. Hemorrhage in solid tumors is sometimes pre, cn1. I NTROD CTION Criteria for malignancy may include invasion of the capsule, adjacc r11 tissue. lymphatic and/or blood ves­ The only parenchymal cell in the rat parathyroid is the sels. necrosis and dis1an1 metastases. These fcawres :lre chief cell ( I. I 0. 14. 23). The gland is surrounded by a critical 10 assess malignancy in we ll-diffcret11 ia1ed delicate librous cap ule and is composed of 1igh1ly C-ccll carci nomas. packed nests of chief cells separ:11ed by fine fibrovas­ cular connecti ve tis ue scptae. o oxyphilic cells arc present a:. in other species ( I 0). Mitoti c activity is DISCUSS ION present in nonnal parathyroid glandular epitheli um. Muhinuclea1c. yncytial chief cells have been reponcd Borderline prolifcr:Hivc lesions present the most as a nomial linding in untreated rats ( I 0). Syncytial difficully in the thyroid gland. panicularly. when distin­ cells arc present in variable numbers in different areas guishing between C-cell hypcrplasiu and adenoma. II is of the gland but arc most numerous near the periphery. necessary 10 c:,tablish arbitra rily a si1.c criteria 10 P;m11 hyroid neoplasms arc mre in rats ( I 0. 11. 14. 22. maintain consistency in diagnosis of these two lesions. 24. 33). Compression is not a reliable charnc1cri s1i c 10 di 1in­ I lyperplas1ic le ions and acl enonwo; arc similar in guish C-cell adenomas. however. it is the key feat ure 10 color gro. sly and arc white 10 light grey. In diffuse ca1cgori1.c follicular cell hyperplasia and adenoma with hyperplasia. the parJthyroid glands may be bilater.illy the caveat 1h:11 colloid-filled follicular cysts may be enlarged and elevated above the surface of the thyroid. compressive. For very anaplastic ncopbsms. immu­ Only in foca l hyperplasia may the lesion be unilateml. nohis1ochcmis1ry and electron microscopy may be Adenomas arc usually small. nodular, solitary masses necessary 10 detcm1i nc the cell of origin. originating in nonnnl or hyperplas1ic parathyroid Goitrogcnic compounds. such as ethylthiourea or glands. The con1r:1la1cral glnnd may be hypcrplas1ic. ami trole, admi nistered 10 rats have been shown to normal or atrophic. Carcinomas of the parathyroid are induce follicular cell hyperplasia which may progress 10 extre mely rare in rat ( I 0, 22. 33). They may efface follicular cell adenomas and carcinomas (2 1. 29. 30. the entire parathyroid and/or th yroid gland. They are 3 1, 35). Amitrolc. for example. inhibits peroxidase pale grey-white and may have central necrosi . activi ty as do many goitrogenic compounds. This inhibition prevents one step in the synthesis of T3 and T4 causing release of excessive thyroid stimulating MORPHOLOGY honnone by the pituitary via a negati ve feedback loop ( 12, 13. 2 1. 29). Compounds such ns phenobarbital llYP£RPLASIA (Figures 15. 16. 17) which induce hep:11ic microsomal enzymes may in­ Cells within the may increase crease the number of induced thyroid neoplasms by in­ in number and become quite large in conditions in directly increasing release of TSH in response 10 more which calcium homeostasis is di !> rupted (23. 24). Chief rapid removal of thyroid hom1 ones from the plasma by cells arc polygonal and ha ve pale eosinophilic cyto­ enhanced catnbolism and excretion ( 18. 19. 21 ). Simi­ plasm. The nuclei range from round 10 fusifom1 and larl y. a lcukotriene antagonist (L-649.923) has been have finely stippled chromatin. The cellular popula­ rcponcd 10 cau ·c increased metabolism of plasma thy­ tion is generally homogeneous and the glands arc roxine result ing in stimulation of TS I I and thyroid bilatemlly enlarged in diffuse hyperplasia which may hyperplasia in Sprague-Dawley rats experimentally rcsull in compression of adjacent thyroid parcnchyma (27). These and other various mnnipula1ions of or protrusion above the capsular surface. Occasionally. experimental design 10 delineate the imemc1i ons of the fibrous capsule may be thickened. Cells may goitrogens. thyroid honnonc supplemcn1:11ion, thyroid nppcar dark or cle:lr depending on the fun ctional state. carcinogens. and microsomal enzyme inducers provide however. the c differences in 1inc1orial stai ni ng quality evidence that prolonged folli cular hypenrophy and TSH do not represent two di 1inc1 cell types. Focal hyper­ stimulation of the thyroid may progress 10 folli cular plasia exhibits similar cellular feature with no hyperplasia and neoplasia. compression of adjacent parcnchyma. There are no distinguishable boundaries and the lesion i unencapsu­ latcd. 4

AD£NOMA (Figure/8) NOMENCLATURE ANU 011\GNOSTJ C C RITERIA Adenomas may appear i.i milar to focal hyperpla­ sia bu1 arc well demarcated from the bordering tis uc and arc compressive (22). The cellular morphology T llYROJU GLAND and/or pattern wi 1hin the neoplasm is distincl from that of surrounding parathyroid gland. Pattern are varied wi1h solid tumors being most common. 01her patterns FOLLICULAR CELL 1IYP ERTROPHY arc papillary or acinar arrangement of cells. Encapsu­ I. Diffuse. bilateral lation may be present. Cytologic features include clear 2. Decreased diameter of follicular lumens or vacuolated cytopla m with distinct cellular border . 3. Large cuboidal to tall columnar epithelial cells plcomorphic nuclei and variable number of mitotic 4. Decreased eosi nophilia of colloid figures. A rim of normal or a1rophic parathyroid tissue 5. Increased vascu larity may be present. 6. Increased number of foll icles 7. Physiologic response to Thyroid Stimulating CARCINOMA llormone Paraihyroid carcinomas occur so rarely (3.22,33) Jhnl none have been reported and confinned by immu­ FOLLICULAR CELL 1IYP ERPLASIA nohistochemis1ry in 1he Nmional Toxicology Program I. Focal or diffuse. unilateral or bilateral Data Base. Presumably charac1eristics of malignancy 2. Noninvasive. nonencupsu lated. noncompressive including anaplasia. necrosis. cap s ul ~1r penetralion or and poorly demarcated distanl metaslasis as seen wi1h 01her neoplasms would 3. Follicle si?.e variable. enlarged follicles may cause be applicable 10 the para1hyroicl gland carcinomas. compression One para1hyroid carcinoma was reported and described 4. lncrca. ed numbers of cuboidal to columnar. in an OF/\ rat by Pour ct al.. 1983 (22). The neoplastic cells in this carcinoma were anaplas1ic and oval to hyperchrommic to vacuolated epithelial cell . sometimes wi1h papillary infolding or slight fu . ifom1 in shape. TI1ese cells occurred in sheet. or strati ficution nodules wi1 hin a variable amount of fibrous connective 5. Increased vascularity ti ssue. Criteria for carcinomas of parathyroid were developed from that single clescrip1ion. FOLLICULAR CELL ADE OMA

Disc ss10 N I. Single or multiple. unilateral or bilateral 2. Well-demarcated. non- or minimally encapsulated. Two neoplasms diagnosed as parnth yroid carcino­ compression of adjacent follicles mus in TP studies have been shown by immunohisto­ 3. Papillary. follicular. cystic. or solid chemistry to be thyroid follic ular cell carcinomas. (microfollicular) p:merns often with mixture of two Additi onal sections of one of 1hcse tumors cxhibi1ed or more puttem follicular fonn:uion which was not present in 1he 4. Cells usually in n single layer. sometimes in original section thereby strongly suggesting 1hyroid multiple layers rather 1han parmhyroid gland origin. 5. Cells cuboidal to columnar with eosinophilic to Aged nus with chronic nephropathy frequently basophilic cytoplasm, low mi1otic index. increased may have diffuse bilatcml parathyroid hyperplasia. nuclear 10 cytoplasmic ratio, nuclear Unilateral and/or focal hyperplasia of the parathyroid hyperchromasia :111d/or crowding sometimes does occur but must be diagno ed only after examina­ present tion of both parathyroids ince often only one gland or only a ·mall area of the contralatcral gland may be FOLLICULAR CELL CARCINOMA presem in a rou1ine transverse section. Adenomas may be functionally active causing the adjacent or opposite I. UnilaterJI or bilateral gland to sometimes become atrophic. Discrimination 2. Papillary. follicular. solid (microfo llicular) and between focal hyperplasia and adenoma is difficuh and cystic patterns often wi1 h mixture of 1wo or more often the key feature sepan11ing the two entities is paucms compression which is exhibited by adenomas. 5

3. Cells may fonn multiple layen.. solid nests and/or P ARAT llYROID GI.AND sheets 4. Minimal to marked cellular pleomorphism. usually a high mitotic index. prominent vascularity. necrosis and mincrali1.ation may be prese nt HYPERPLASIA 5. Fibroplasia. penetration of thyroid gland capsule. I. Focal or diffuse. unilateral or bilateral local invasion of adjacc111 tissue and/or vcs els. 2. In diffuse lesions. bilateral glandular enlargement and metastasis indicate malignancy is present. compression is sporadic. and encapsulation occurs occa ionally C-CELL HYPERPLAS IA 3. Increase in cell number. cellular size may be variable. cytoplasm may be clear or eosinophilic I. Focal or diffuse. unilateral or bilateral 4. Focal lesions blend with ndjacc111 gland. arc 2. Increased numbers of C-cells prcse 111 in clusters unencapsulated and noncornprcssivc less than five average foll icular diameters or sca11crcd in intcrfollicular space 3. Minimal compression or distonion of thyroid ADE OMA follic les I . Solirnry. well -delineated. compress adjacc n1 tissue, 4. C-cclls large and round to polyhedral with may be encapsulated abundant pale cosinophilic cytoplasm nnd cc111rally 2. Solid. papillary. or acinar pancms located round nuclei 3. Cells may have clear to vacuolated cytoplasm and 5. Diffuse lesions surround follicles resembling pleomorphic nuclei. variable mitotic index incrcm.cd intcrfollicular tissue CARCINOMA C-CELL ADE 0 tA I. Solital)' masses of oval to fu sifom1 cells arranged I. Single or multiple. unilateral or bilateral in heets or nodules separated by fibrous tissue. 2. Di crctc mass greater than fi ve average follicular variable mitotic index, necrosis may be pre ent diameters 2. Penetration of cap ulc. local invasion of adjacent 3. Noninvasive. rarely encapsulated. scam stroma. tissues and/or vesse l ~. and metastasis may occur may contain i.cattercd follicles. amyloid pre e111 rarely 4. Solid sheets of round to oval to fusifonn cells wi th pale eosinophilic cytoplasm or. infrequently. basophilic cytoplasm. and round to oval centrally R EFERENCES located nuclei

I. Anderson MP and Capen CC ( 1978). The C-CELL CARCINOMA . In : Pmlto/ogy of laboratory I . Unilateral or bilatcrnl a11i111als. \lo/umc I. K Oenirschke. r=M Gamer. and 2. Solid sheets or irregular nests of cells separJtcd by TC Jones (eds). Springer-Verlag. New York. pp. fibrovascular stroma. necrosis may be prese 111. 443-499. amyloid pre. e111 rarely 2. Anvcr MR and Cohen BJ ( 1979). Lesions 3. Cells vary from round to polygonal with abundant associated with aging. In: Tlte Lt1boratory Rat. pale eosinophilic cytoplasm and round to oval \lo/11111c I. New York. Academic Press. p. 393. nuclei to markedly pleomorphic highly fusifonn basophilic cells with high mitotic index 3. Berdjis CC ( 1972). Parathyroid diseases and 4. Penetration of thyroid gland capsule. local invasion irradiation. Stmltle111!terapie 143:48-62. of adjacent tissues and/or vessel . and metastasi 4. Boom1an GA ( 1983). Follicular cell hyperpla ia. indicate malignancy thyroid. rat. In: E11docri11e system. Monograplts of pathology of laboratory a11i111als. TC Jones. U Mohr. and RD Hunt (eel ). Springer-Verlag. Berlin. pp. 176-177. 5. Boonnan GA ( 1983). Follicular cell adcnoma. thyroid. ra t. In: £11docri11e system. Monographs of 6

pathology of laborato1y animals. TC Jones. U press). Mohr. and RD Hun1 (eds). Springer-Verlng. 17. Kadudo K. Uemn1su K. Suehiro M nnd Fukuchi M Berlin. pp. 77- 180. ( 1984). Primary C-cell hyperplasia of the 1hyroid 6. Boorman GA ( 1983). Follicular cell carcinoma. in Fischer 344 rais. An immuno-histochemical 1hyroid. rat. In: Endocrine system. Monographs of study. Aclll Pat/wt. Jpn. 34(5):947-955. pathology of laboratory animals. TC Jones. U 18. McClain RM {1 989). The significance of hepatic Mohr, and RD Hun1 (eds). Springer-Verlag. microsomnl enzyme induction and ahered thyroid Berlin. pp. 180-184. func ti on in rats: implicntions of 1hyroid neoplasia. 7. Boorman GA and DeLell is RA ( 1983). C-cell Toxicol. Pathol. 17:294-306. hyperplasia. th yroid. rat. In: Endocrine system. 19. McClain RM . Posch RC, Bosakowski T and Monographs of patlw/ogy of laboratory animals. Arm trong JM ( 1988). Studies on 1he mode of TC Jones. U Mohr. and RD Hun1 (ed ~) . Springer­ action for 1hyroid gland wmor promotion in rats by Verlag. Berlin. pp. 192- 197. phenobarbital. Tnx. and Appl. Plwrmaco/. 8. Boorman GA nnd DeLcllis RA ( 1983). C-cell 94:254-265. adenoma. 1hyroid, rat. In: Endocrine system. 20. Napalkov NP ( 1976). Tumors of 1hc thyroid Monographs of pmhology of la/Jora1tJ1)' onimols, gland. In: Pathology of 111111m·s in la/Jomtory TC Jones. U Mohr. and RD Hun1 (eds). Springer­ animals. Volume I - Tumors of tile rot. Parr 2. VS Verlag. Berlin. pp. 197-200. Turusov (ed). International Agency for Research 9. Boorman GA and Delellis RA ( 1983). on Cancer. Lyon, pp. 239-271. Medullary carcinoma. thyroid. rat. In: £ 11docri11e 2 1. Paynter OE. Burin GJ. Jaeger RB. and Gregorio system. Monoxmphs of pothology of lnborato1)' CA ( 1988). Goitrogens and 1hyroid follicular cell animals, TC Jones, U Mohr, and RD Hum (eds). neoplasia: evidence for a threshold process. 200-203. Springer-Verlag, Berlin. pp. f~eg 11/ato 1 y Toxicol. 8: I 02-119. I0. Capen CC ( 1983). Structu ral and biochemical 22. Pour PM. Wilson JT. and Salrnasi S {1 983). aspects of para1hyroid gland functi on. In: Adenoma. carcinoma. parathyroid. rat. In: £11tlo c:ri11e system. Monograph ~ 011 pmlwlogy of £11docri11e .\)'Stem. Mo11ograplls 0 11 pathology of laboratory animals. TC Jones. U Mohr. and RD laboratory animals, TC Jones. U Mohr, and RD Hunt (eel s). Springer-Verl ag. Berlin, pp. 2 17-247. Hunt (eel s). Springer-Verlag. Berlin. pp. 28 1-287. 11 . Capen CC ( 1990). Neoplasms of 1he punuhyroid 23. Pour PM . Wilson JT. and Salmasi S ( 1983). gland . In: Atlas of Tumor Pathology of the FJ././ Ana1orny. histology. uhrnstruc1urc. parathyroid. Rat, SF Sti n on and G Reznik (eds). CRC Press. rat. In: £11docri11e system. Monogrnphs 011 Inc .. Boca Raton. Florida. pp. 367-378. pathology of /abomtm)' animals. TC Jones. U 12. Capen CC nnd Manin SL ( 1989). Mechanisms Mohr. and RD Hunt (eds). Springer-Verlag. 1ha1 lead 10 disease of 1he endocrine system in Berlin. pp. 257-262. animals. Toxicol. Parhol. 17:233-249. 24. Pour PM. Wilson JT. and Salmasi S ( 1983). 13. Capen CC and Manin. SL ( 1989). The effects of Hyperplasia pnrathyroid. rat. In: Endocrine xenobiotics on the struc1urc and func1ion of thyroid system. Monographs 011 pathology of laboratory follicular and c-cells. Toxic:ol. Pm/wt. 17:266- animals. TC Jones. U Mohr. and RD Hunt (ed ). 293. Springer-Verlag. Berlin. pp. 268-274. 14. Capen CC and Rosol TJ ( 1989). Rccen1 advances 25. Rosol TJ and Capen CC ( 1989). Tumors of the in the struc1ure and func1i on of the parathyroid parn1hyroid gland and circulnting para1hyroid gland in animals and 1he effec1s of xenobiotic . horn1one-rela1ed pro1ein associated with pcrsis1en1 Toxic:ol. Pathol. 17:333-345. hypercalccmia. Toxicol. Pat/wt. 17:346-356. 15. Green WL ( 1978) Mechanisms of action of 26. Ru field AB ( 1967). Pathology of the endocrine an1i1hyroid compound . In: The Thyroid. SC glands. and tes1is of rats and mice. In: Werner. and SI I lngbar (eds) . H ~1rpc r and Row, Pm/10/o1:y of laboratory rats and mice, E Co1chin. New York. pp. 77-87. and FJC Roe (eds). Blackwell Scientific 16. Hardisty JF. Boorman GA. ( 1990). Thyroid gland. Publica1ions. Oxford and Edinburgy. pp. 391-467. In: Patholo1:y of the FJ././ rat. GA Boorman. SL 27. Sanders JE. Eigcnbcrg DA . Brac ht U. Wang WR. Eus1is. CA Montgomery. MR Elwell. and WF and V:mZwietcn MJ { 1988). Thyroid and liver MacKenzie {ed). Academic Press. New York. (In trophic changes in rats secondary to leukotriene 7

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Fig. I Folliculur Ccll Hypcnrophy • Diffu-.c hypcnropy of folliculnr Fig. 2. Follicular Cyst ·Cy~• diMcndcd wi1h colloid nnd lined b)' cells wi1h decreased lumen diamc1crs. (H&E. 205x) naucncd epithelium. CH&E. 82x)

Fig. 3. Follicular Cell llyperplasia - Focal hyperplasia with incensed Fig. 4. Follicular Cell Hyperplasia • Diffuse hyperplasia with increased colloid and papillary infoldings of lining epi1hclium. (H&E. 4 Ix) numbers nnd papillary infolcling of lining epithelium. (H&E. 205x) 9

Fig. 5. Folliculur Cell Adcnoma • Noncncnp,ulu1cd well· Fis. 6. Folli cular Cell Adcnoma • I fighcr magnificmion of Figure 5 dcmarcmcd prolifcm1ion of follicular cpi1hclium wi1h co 111prc ~~ion of Cll&E. :?05it) adjaccn1 follicle\. (ll&E. 13.5x)

Fig. 7. Folhcular Cell Carcinom.s • PJp1llal) paucm \\1lh cellular Fig. !I. Folhcul:ir Cell Carcinoma · I fisher magmficauon of Figure plcomorplmm and fibropl:t~i:i.

Fig. 9. C·Ccll llypcrplu.,i:i • Foc11I h) pcrplru.it1 of C·ccll' wilh Fig. 10. C-Ccll llypcrplasia • D1flu,c hypcrplu\iu of C·c:clh minimal comprc"ion of thyroid follicle,, Cll&E. 102.Sx) 'urroundin& follicle ~ rc~cmblins incrcn,cc.l in1crfollicular th>uc. CH&E. 51.25>.)

Fig. 11. C·Ccll J\dcnomn • 01-.cn.:tc, noncncnp,ulnlcd, noni nvasive Fig. 12. C-Ccll Ac.lcnoma • Higher nmgnilic:ation of Figure 11 prolifcrJtion ofC-cclh with re\idual fo lh clc~. (H&E. 16.4't) Cll&E. 102.Sxl J 1

Fig. 13. C-Cell Carcinoma - Solid ~ hee l\ of pmlifcmting C.)

Fig. 15. P:trJth)roid. H}licrpla,i:i - D1ffu\e h)pcrpla<;1:1 "11h Fag. 16. Pamth)ro1d. H)pcrpln_,ia - ll1gl1er 111ag111!icat1on of Figure 1ncn:a-cd nurnbc,... of enlarged p:tlc co,1noph1lic chief cell~ . 15 (ll&E. 205\) (H&E. :?0.5>.) 12

Fig. 17. Pnmthyroid. llypcrpla,iu · focal hypcrpln~ia or chief ce ll ~ Fig. 18. Panuhyroid. Adcnoma • Solilnry. \\Cll·clclincatcd wi th no co111prc"ion of \Urrounding purcnch)•mu. (ll&E. 205x) prolifcmtion of chief cells with comprc.,.,ion of ndjaccrn th~uc. (ll&E. 205")