M form of true thymic hyperplasia [l], in which the
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1 ssive Thymic Hyperplsi Anthony G. Linegr, B, ChB, John A. Odell, RCS(Edin), W.. Pitt ennell, RCS(Eng), Puline. Close, RCPth, rk K. De Groot, RCS(C), Dennis R. Csserly, Ch, nd Joss I. Perold, ed(pth) Deprtment of Crdiothorcic Surgery nd Deprtment of Pthology, University of Cpe Town, Cpe Town, nd rere Hospitl, Est London, South Afric ssive thymic hyperplsi is n extremely rre form of true thymic hyperplsi most often described in infnts nd children. Hyperplsi of this order is not known to occur in ny other orgn, nd its etiology nd prognostic significnce remin unknown. As there is no ccurte wy of preopertively differentiting mssive thymic hyperplsi from other tumors of the thymus nd nterior medistinum, we dvise excision in ll cses for histologicl nlysis nd relief of medistinl compression. This description of 4 cses updtes the 0 previously reported cses, nd includes literture review. (Ann Thorc Surg ) ssive thymic hyperplsi (TH) is n idiopthic form of true thymic hyperplsi [l], in which the glnd chieves mssive proportions fr exceeding those usully seen in the norml thymic hyperplstic response to development or fter severe systemic stress. It is chrcterized by generlized hyperplsi with preservtion of the norml thymic rchitecture, nd, unlike rebound thymic hyperplsi, it occurs in the bsence of known provoctive systemic stress. The immunohistologicl ppernce is similr to tht of norml thymus [2], but cytoenzymtic studies hve shown quntittive reduction in mture T cells in both corticl nd medullry res []. urthermore, TH is distinct from lymphoid folliculr hyperplsi of mystheni grvis, from thymom, nd from thymic lymphom by the bsence of germinl centers, the bsence of neoplstic cells, nd the preservtion of norml thymic histology [l, 21. This report updtes nd reviews the 0 cses previously reported [2-161 (Tble 1). Cse Reports Two ptients (ptients 1 nd 2) were treted t Red Cross Childrens' Hospitl, tertiry cre, mjor teching hospitl of the University of Cpe Town. These 2 children presented in 1990 nd 1974, respectively, nd represent the only such cses on record t the hospitl. Ptients nd 4 were treted during 1990 t rere Hospitl Est London, which is mjor referrl center serving lrge popultion of the Estern Cpe province. Ptient 1 A 2-month-old femle infnt weighing.6 kg ws seen with chest infection nd respirtory distress. There ws 2-cm splenomegly, but no lymphdenopthy ws plpble. Peripherl blood smer reveled of 76% of 28.8 x loyl leukocytes. Chest rdiogrphs Accepted for publiction Sep 1, Address reprint requests to Dr Linegr, Deprtment of Crdiothorcic Surgery, University of Cpe Town, edicl School, Observtory 7925, Cpe Town, Republic of South Afric. nd computed tomogrphic (CT) scn demonstrted well-defined, lrge nterior medistinl mss. During the course of dmission she experienced n episode of cute irwy obstruction but recovered spontneously when plced in the left lterl position. At right posterolterl thorcotomy, lrge mss of thymic tissue weighing 220 g ws excised from the nterior medistinum. Histologicl exmintion showed norml thymic tissue with preservtion of norml thymic rchitecture. Postopertively the lymphocyte count dropped to third of the preopertive vlue by dy 2, nd the spleen becme implpble. She ws dischrged weeks lter. At follow-up months lter she ws noted to be cliniclly well. Ptient 2 A -yer-old mle child weighing 18 kg ws referred from Nmibi with history of recurrent chest infections nd lrge nterior medistinl mss on chest rdiogrph. Lymphocytosis of 77% of 15.4 x 10y/L leukocytes ws present in the peripherl blood smer. A right posterolterl thorcotomy ws performed, nd n encpsulted mss of thymic tissue weighing 855 g nd mesuring 18 X 10 X 6 cm ws removed from the nterior medistinum. Histologicl nlysis demonstrted norml lobulr rchitecture with prominent dipose tissue between the lobules, consistent with thymic hyperplsi in the presence of lipomtous involution. He recovered from the opertion without incident, nd the postopertive immunologicl profile ws norml. He returned home to Nmibi nd ws subsequently lost to follow-up. Ptient A 6-yer-old mle child ws seen with persistent wheeze nd recurrent bouts of severe dyspne. Chest rdiogrph (igs 1, 2) nd CT scn (ig ) reveled mssive nterior medistinl mss, extending into the left hemithorx. His prents initilly refused consent for thorcotomy, nd needle biopsy ws performed, which showed norml thymic tissue by The Society of Thorcic Surgeons /9/$6.00
2 1198 LINEGAR ET AL ASSIVE THYIC HYPERPLASIA Ann Thorc Surg Tble I. Cse Reports of ssive Thymic Hyperplsi Ptient No. Age (Y) Birth Body ss Thymic Sex Clinicl etures 0%) ss (g) Yer & Reference, Respirtory distress,, Respirtory distress Beckwith-W eidemnn, respirtory distress, died Respirtory distress, dysphgi Cough Cough Respirtory distress, Respirtory distress, pulmonry infection,, Respirtory distress,, Dyspne Respirtory distress, pulmonry infection,, irwy obstruction, Respirtory distress, irwy obstruction B Biopsy Biopsy =100b 1971 [4] 1971 [4] 1971 [5] 1971 ( [] 1978 [9] 1979 [lo] [ll] 198 [12] 1985 [1] 1986 [14] 1986 [] 1986 [] 1986 [] 1986 ( [16] 1989 (21 (ptient 1) (ptient 2) (ptient ) (ptient 4) Tumor msses reported to be between 47 nd 92 g. Estimted tumor mss. He presented 1 yer lter with severe respirtory distress, which rpidly progressed to complete irwy obstruction requiring intubtion nd ventiltion. There ws no rdiogrphic chnge in the size of the mss reltive to the chest size over the yer of observtion. At medin stemotomy, n enormously enlrged thymus weighing 1,260 g ws excised (ig 4). The cut surfce showed homogeneous ple pink tissue. Histologicl exmintion showed well-defined medullry res with prominent Hssll's corpuscles nd discernible lobules, in which the norml rchitecturl reltionship of cortex to medull ws mintined. However, there ws mssive corticl expnsion with blurring of the lobulr pttern due to incresed numbers of lymphocytes. Occsionl foci with incresed numbers of epithelil cells nd reltively few lymphocytes, reminiscent of thymom, were noted, but even
3 Ann Thorc Surg LINEGAR ET AL 1199 ASSIVE THYIC HYI'ERPLASIA ig I. Anteroposterior chest rdiogrph (ptient ). these res contined distinct medull with well-defined Hssll's corpuscles. On the bsis of these fetures, thymom ws excluded nd dignosis of TH ws mde. He ws subsequently lost to follow-up. Ptient 4 A -yer-old child ws investigted for recurrent respirtory infections nd tuberculosis contct. Chest rdiogrph showed very lrge thymic shdow with clssic sil ig. Computed tomogrphic scn showing mssive thymus (ptient ). sign. He ws observed for period of 9 months, during which time the mss remined rdiologiclly unchnged. At right posterolterl thorcotomy lrge hyperplstic thymus ws excised. It ws estimted to weigh pproximtely 100 g. Histologicl nlysis showed recognizble lobulr pttern consistent with thymic hyperplsi, with expnsion of the corticl res by numerous lymphocytes nd thymic epithelil cells. The medullry regions were well defined with isolted Hssll's corpuscles. His recovery ws uncomplicted, nd he ws not seen gin fter his erly postopertive follow-up visit. Comment Our 4 cses nd the 0 previously described cses re reviewed in Tble 1. ig 2. Lterl chest rdiogrph (ptient ). ig 4. ssively hyperplstic thymus weighing 1,260 g excised from ptient.
4 1200 LINEGAR ET AL ASSIVE THYIC HYI'ERPLASIA Ann Thorc Surg 199;55: Tble 2. Clinicl Chrcteristics on Presenttion ~ ~~ ~~~ eture No. of Ptients Percentge Pulmonry infection Respirtory distress Airwy obstruction Coughing Dysphgi Chest discomfort Lymphocytosis Splenomegly /4 1/ / Clinicl etures nd Preopertive Dignosis There were 19 mle (56%) nd 15 femle ptients (44%). Age t presenttion rnged from birth to 15 yers. Ten ptients (29%) were 1 yer old or younger, nd 24 ptients (71%) were less thn 10 yers of ge. Clinicl presenttion ws vrible (Tble 2), with ptients presenting in three wys: (1) no symptoms, with the incidentl finding of n nterior medistinl mss on chest rdiogrph (reported in 8% of cses); (2) the clinicl effects of medistinl compression, ie, respirtory distress (reported in 29% of cses), dysphgi (1 report), or irwy obstruction (ptients 1 nd of this report); () cute or recurrent pulmonry infection (reported in 5% of cses). In ddition, there is 1 report of TH dignosed t birth in child with the Beckwith-Weidemnn syndrome [1]. The most disturbing clinicl feture is respirtory distress, which ws present in 29% of ptients. This my progress, without wrning, to complete irwy obstruction, which occurred in 6% of ptients. Although irwy obstruction is common in nterior medistinl msses [17], our 2 ptients re pprently the only ones with TH to hve experienced this compliction. Immedite positioning of the ptient in the lterl position my temporrily ttenute compression nd obvite endotrchel intubtion. The well-known difficulties of intubting nd ventilting ptients who hve suffered cute irwy obstruction from nterior medistinl msses questions the wisdom of conservtive mngement of very lrge tumors [17]. Preopertive peripherl ws documented in 29% of ptients, with counts decresing to norml fter thymectomy. Lymphocyte subpopultion studies showed 2 ptients [8, 91 to hve 90% T cell predominnce, but this ws not found in 4 others who were studied [15]. One ptient ws found to hve hypogmmglobulinemi 2 yers fter thymectomy but ws reported to be helthy [8]. The significnce of ssocited bnormlities of the lymphoid system remins uncler. The chest rdiogrph typiclly revels well-defined, mssive nterior medistinl soft tissue mss occupying most of one hemithorx, with no evidence of clcifiction. Occsionlly tringulr sil sign my be seen. This describes the thymic silhouette, which my resemble the sil of ycht when contrsted ginst the djcent lung tissue. The thymus, thus silhouetted, my lso show n irregulr wvy border known s the thymic wve sign. However, none of these rdiologicl signs re pthognomonic for TH. Computed tomogrphic scn is helpful for locliztion nd for defining reltionships to other structures. There re no pthognomonic CT scn fetures ttributed to TH, nd the hyperplstic thymus retins the fetures of norml thymus on CT scn irrespective of size [5, 161. Steroid dministrtion yields inconsistent results in shrinking the hyperplstic thymus glnd, nd is therefore not sufficiently relible for dignostic purposes [12, 151. Attempts to differentite thymic tumors from norml thymus with pneumomedistinogrphy, internl mmmry rteriogrphy, nd thymic venogrphy hve lso proved unrelible [I. There is, therefore, no relible wy of preopertively differentiting TH from other potentilly more serious cuses of nterior medistinl msses. P thology The weights of the resected thymic specimens (see Tble 1) vried from 80 to 1,260 g. The norml pttern of thymic growth [19, 201 is one of progressive enlrgement from birth weight of 22 f 1 g, with mximl weight occurring during puberty, fter which the glnd regresses in size to weight of 4 f 10 g by 26 to 1 yers of ge. The body weight to thymic weight rtio, expressed s percentge, is gretest t birth t 0.76% nd decreses to 0.19% between 1 nd 6 yers of ge. As there re no generlly ccepted criteri defining "mssive", we suggest the following guidelines: (1) It should be greter thn the hert shdow on posterontenor chest rdiogrph. (2) The thymus should weigh severl times the expected weight for the ge of the ptient [14]. () It should represent more thn 2% of the body mss. In those cses where the body mss nd tumor mss ws provided, it is noted tht the tumor represented 2% to 6% of the body mss (see Tble 1). We hve differentited rebound thymic hyperplsi nd TH cliniclly by noting the bsence of systemic stress s provoctive stimulus in TH. urthermore, rebound hyperplsi is not, to our knowledge, reported to chieve the sme proportions s seen in TH. However, conclusions regrding definitive seprtion of the two conditions wit further investigtion of their pthogenesis. Histologicl nlysis typiclly revels norml thymic tissue with preservtion of the norml corticl nd medullry rchitecture [l,, 211. yoid cells hve been found in TH [14] but re believed to represent norml component of thymic tissue [2]. The immunohistologicl ppernce is lso similr to tht of norml thymus [2]. Nezelof nd Normnd [], using cytoenzymtic techniques to mrk mture T cells, hve shown quntittive reduction in mture T cells in corticl nd medullry res, nd hve suggested tht TH represents n intrthymic ccumultion of immture T cells. ngement ngement is directed t estblishing histologicl dignosis, s there is no other relible method of differ-
5 Ann Thorc Surg LINEGAR ET AL 1201 ASSIVE THYIC HYERPLASIA entiting TH from the other cuses of mssive nterior medistinl mss, prticulrly thymom nd lymphom. This is best performed by posterolterl thorcotomy with complete excision of the mss, thereby lso relieving the effects of medistinl compression. It is evident from the literture tht most ptients re mnged surgiclly. Twenty-eight ptients (82%) underwent thorcotomy for excision of their msses, nd there re no reports of surgicl complictions. Two other ptients underwent medistinoscopic biopsy for histologicl dignosis nd did not undergo thorcotomy []. However, this method hs previously proved unrelible fter biopsy dignosis of thymic hyperplsi ws lter revised to thymom on complete excision of the thymus [22]. A further 4 ptients were mnged conservtively without histologicl dignosis [ 151. Dignoses were presumed on the bsis of chest rdiogrph nd CT scn ppernces, in ssocition with peripherl. Although steroids were dministered to ptients, only l showed reduction in the size of the glnd. Respirtory distress, which ws present in ll 4 ptients, disppered without obvious reduction in thymic size. The rte of trophy of the mssively hyperplsic thymus is often very slow, with reports of little or no chnge in size fter months [15], or fter 2 yers [16]. Two of our ptients (ptients nd 4) were observed for 12 nd 9 months due to prentl reluctnce regrding opertion, during which no chnge in size ws noted, thereby emphsizing the very slow rte of chnge in size nd, in ptient, the ever-present potentil for cute irwy obstruction. Conclusion The dignosis of TH is therefore bsed on the very lrge size of the glnd, the bsence of preceding severe systemic stress or withdrwl of steroids, nd microscopic ppernce of norml thymus, with exclusion of thymom, lymphom, nd lymphoid hyperplsi of mystheni grvis. It is our opinion tht the preferred opertive pproch to the excision of very lrge msses of the medistinum is through posterolterl thorcotomy performed on the side contining the lrgest mount of tumor. Vsculr control nd the delivery of the lrge mss from the chest re chieved more esily by this pproch thn by medin sternotomy. The etiology nd prognostic significnce of TH remin unknown. As there is no ccurte wy of preopertively differentiting TH from other tumors of the thymus nd nterior medistinum, we dvise excision in ll cses for histologicl dignosis nd relief of medistinl compression. References 1. Levine GD, Rosi J. Thymic hyperplsi nd neoplsi: review of current concepts. Hum Pthol 1978;9: Ruco LP, Rosti S, Plmieri B, Pescrmon E, Rendin EA, Broni CD. True thymic hyperplsi: histologicl nd immunohistochemicl study. Histopthology 1989;15: Nezelof C, Normnd C. Tumor-like mssive thymic hyperplsi in childhood: possible defect of T-cell mturtion, histologicl nd cytoenzymtic studies in three cses. Thymus 1986;8: Kook Sng Oh, Weber AL, Borden S. Norml medistinl mss in lte childhood. Peditr Rdiol 1971;101: Prker LA, Gisie G, Sctliff H. Computerized tomogrphy nd ultr-sonogrphic findings in mssive thymic hyperplsi. Cse report nd review of current concepts. Clin Peditr 1985;24: Brci PJ, Nelson TG. Hyperplsi of the thymus nd thymic neoplsms in children. ilit ed 1979;144: Rsore-Qurtino A, Rebizzo, Romgnoli G. Iperplsi gignte del timo nell'infnzi. Pthologic 1979;71: Ktz S, Chtten J, Bishop HC, Rosemblum H. ssive thymic enlrgement. Report of cse of gross thymic hyperplsi in child. Am J Clin Pthol 1977;68: OShe PA, Boonchin P, mes P. Gint thymic hyperplsi in infncy: immunologic, histologic, nd ultrstructurl observtions. Lb Invest 1978;8: Lee Y, ollem S, Cluss RH. ssive hyperplstic thymus in 22-month-old infnt. Ann Thorc Surg 1979;27: Lck EE. Thymic hyperplsi with mssive enlrgement. J Thorc Crdiovsc Surg 1981;81: Lmesch AJ. ssive thymic hyperplsi in infnts. Z Kinderchir 198;8: Blcolm RJ, Hknson D, Werner A, Gordon P. ssive thymic hyperplsi in n infnt with Beckwith-Wiedemnn syndrome. Arch Pthol Lb ed 1985;109: Judd RL. ssive thymic hyperplsi with myoid cell differentition. Hum Pthol 1987;18: Kobyshi T, Hirbyshi Y, Kobyshi Y. Dignostic vlue of plin chest roentgenogrm nd CT scn findings in four cses of mssive thymic hyperplsi. Peditr Rdiol 1986;16: Arliss J, Scholes J, Dickson P, essin J. ssive thymic hyperplsi in n dolescent. Ann Thorc Surg 1988;45: ckie A, Wtson CB. Anesthesi nd medistinl msses. A cse report nd review of literture. Anesthesi 1984;9: Yune HY, Kltte EC. Thymic venogrphy. Rdiology 1970; 96: Boyd E. Weight of the thymus nd its component prts nd number of Hssel corpuscles in helth nd in disese. Am J Dis Child 191;51: Young, Turnbull H. An nlysis of the dt collected by the sttus lymphticus investigtion committee. J Pthol 191;4:21> Hofmnn WJ, oller P, Otto H. Thymic hyperplsi. I. True thymic hyperplsi. Review of the literture. Klin Wochenschr 1987;65: Blsimnn B, Kuffer, Bettex. Chirurgische Betrchtungen uber die Thymushyperplsie. Z Kinderchir 1977;71:
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