Document a4q0k436KDn5RE5Om4oQL31oy

( Si 'to. I RETICULUM CELL SARCOMA IN CHILDREN lyntpf >vett fcarly Incut! Kttl"H |igtf-. rimary malignant tumors of lymphoid Tabi.r 1 Al"' PR oiigin are usually considered to be fatal in children; in addition, these diseases usually AGE AT ONSET, SEX, RACE, AND ANATOMIC SITE OF TUMOR IN 45 PATIENTS WITH RETICULUM bf onllwb'ii have a more rapid and difficult course in the CELL SARCOMA In the c younger age group than that seen in adults. The problems of diagnosis, treatment, and Case ptognosis as related to morphology are ob no. Pt. Ft. ago, Pt. Pt. init. yr. sex race Anatomic site tumor pable, peiidii lit aih scured by the multiple classifications in differ ent institutions; attempts have been made to achieve a standard classification applicable to all cases, but these have not been successful. One pathological diagnosis that has been con stant in most classifications is that cf reticulum cell sarcoma (RCS) and studies cf prognosis indicate that this is the most malignant cf all tfie lymphoid tumors. Due to the paucity of studies limited specifically to RCS in children, this study cf 45 cases is presented in the hope that it will provide a better understanding of the clinical picture, treatment, and prog nosis, as well as an increased awareness of this specific disease process. Case M/ Ti'.RiAL This series of 45 cases of RCS is composed of children with that diagnosis admitted to (tie Pediatric Service cf Memorial Hospital for Cancer and Allied Diseases from 1933 through 1961, Some have been previously reported in general studies of lymphosarcoma in chil dren.4'5'7'8 The group includes 35 male and 10 female patients: the youngest at the time of diagnosis was 15 months of age and the old est 14 years, with a mean age of 7.4 years. The composition cf the group is shown in Table 1. Cases cf RCS of bone have been excluded because of site of origin. This may be an over sight because cf similarity cf progression cf disease, brit all cases included have arisen in 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 IS 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 S.M. 11 C.A. 2 M F W W Cervical Cervical ItmtHi lion (<: B.S. B.M. 2 2 M M W W Nasopharyngcall Nasophnryng<.il| (.1! t G.R. 3 M W Mediastinal llOlf I S.B. 3 A4 W Subcutaneous If cm S.M. T.B. 3 3 F C Cervical M W Abdominal louipl < C.l\ 3 F W Abdominal ltalilv C.S. 3h M W Abdominal L.J. 4 M W Abdominal v.ll. 4 M W Abdominal li,ielKi> \,IG> iR.L. B.A. .C. o.r. W.E. B,|. K.T. B.T. S.J. 11.11. R.G. F.B. H.M. HAV. M.B. B.D. L.L. M.A. M.D. E.L. 41 4j 6 6 6i 61 7 7 8 8 8 8 8 8 9 9 9 9 91 10 M M M M F M F M F M M M ic M M M M M hi F M W w w w w w w w w \v vv w w w w w w w w c w Abdominal Generalized Abdominal Subcutaneous Generalized Cervical Mediastinal Abdominal Cervical Nasopharynx . Abdominal Nnsopbaryng*. Cervical Abdominal Cervical Generalized Cerviral Abdominal Abdominal Cervical Subcutaneous If ,1 II Ini' d Itlf I .i " h|( M ||' pi'C'vr, . u sec! tun di I i jnin.il d (.'tin Idriioj): ,K SCi dl an nvk' M.M. S.L. T.M. M.J. W.M. W.F. L.A. G.R. M.L. C.D. M.M. D.R. 10 10 11 11 11 12 13 13 13 13 14 14 M M F M M F M M M M M M W w w w w w w w w w w w Nasopharynx Cervical Abdominal Nasopharyng' Nasopharyng'; Cervica I Generalized Subcutaneous Abdominal Nasopharyng1 Abdominal Cervical "t. and /r lymphoid tissue. Tissue biopsy and/or post- From the Department of Pediatrics, Memorial Hos pital for Cancer and Allied Diseases, 444 E. 68th St,, New York 21, N.Y. The author expresses his appreciation to Dr. C. T. Tan, Dr. H. W. Dargeon, ana Dr. W. G, Thurman for their encouragement in the preparation of this manuscript. Present address: Department of immunology, St. ]ude Hospital, Memphis, Tcnn. Received for publication June <5, 1P6.1. mortem examination established the histoh r** marrow cal diagnosis in all cases. Subsequent coul both as inpatients and outpatients, has bn documented by members of the staff of d Hospital. Clinical Manifestations. Vague symptof f^OUS Sy-sti such as low grade fever, anorexia, generati/i weakness, an-d loss of weight were the umi 26 im s i-i.i .1! h u ir,1' !l 11 I wii'il ni-i ii ihiiiii ill1 1 ,ii ill.11 \ ' nin 1 ih.,i 1., ,il llni.ll ' it ,li 111.11 I I Reticulum cell sarcoma in children liorella 27 |y,,iproms noted initially. Anemia and/or manifestations of bleeding were not Seen :ir!v in the disease. In addition to the afotc:nni tinned vague symptoms, 6 major classifi, 1,, ms of symptoms, with or without physical jj.rn were apparent, i\lxlomina]. This was the commonest form onset; 15 children (33.3%) presented with >1 dominal pain; 10 had, in association, amass g,, tin abdomen. This mass was usually pal- ,1, !e, but the possible diagnosis of acute ap|,rin I iritis was the presenting complaint in 3. , addition, 4 children developed acute inIn^iisception necessitating surgical interveniiiin (case 15). t 11 viral Adenopathy. Enlargement of 1 or ,,ni cervical lymph nodes, in tlie absence * 1 neralized adenopathy, was tlie primary plaint in 12 (25.0%). No specific abnoric.l.iv of clinical appearance suggested tlie jn"ito,sis, which was made only after biopsy. \ isopharyngcal Symptoms. Tlie appearance h 1 nasophatyngeal mays was usually pre<i<d by iliinorrhea, obstructive breathing, n! 1 "persistent cold.'' These symptoms were mi for a vaiiablc period c time prior io Miner) of the mass, and this clinical picture n eon in 8 (17.7%) of the children. As otic mild expect, a dental root abscess was tlie im d diagnos s in 2 of tlie children. (.1 ncralizcc Adenopathy. J11 comparison to j! nopal by limited to the cervical area alonr, !s%) presented with enlargement of nodes li ill nreai Subcutaneous Nodules, The presence c a subcutaneous mass was the presenting prob lem in 4 (8.87,) children; all had accompany ing regional adenopathy. Mediastinal Mass. The continuing presence of a cough associated with weight loss led to roentgenographic examination cf the chest, which demonstrated mediastinal enlargement. This presentation was seen in 2 (4.4%) of the 45 children. These clinical patterns are relatively non specific in most instances, and it is again em phasized that tissue diagnosis is necessary. Figure 1 illustrates the relative incidence cf involvement of various tissues. In 8 (17.7%) of these children, the disease remained local ized to tlie site of origin (and initial diagnosis), hut tire majority had generalized extension of tlie tumor process. Hepatomegaly was a find ing in 27 (60%) of the children at sonie dine during tlie course of tlie disease, usually late; in contrast, only 17 (37.7%) had clinically documented splenomegaly. Urinary tract involvement was another fre quent compiicatioh. Intrinsic disease, later demonstrated to be bilateral at postmortem examination, was seen as frequently as was extrinsic disease, secondary to compression from abdominal or retroperitoneal masses. The major difference was that the extiinsic form was most frequently unilateral with secondaiY hyclronephtosis on the affected side. The kid ney involvement was cf clinical significance in 10 (42%) of tlie children. til .1 and 'or 111111111 . and /or HI Generalized involvement CZD Regional involvement inadequate study I if >" system Kir.. I. Systems involved with disease. 1_.I --1 ll .II llil ill ill 1 Lj 1 I I 1 I 1 I 1 111111 1ij 0 5 10 15 20 25 30 35 40 Number of rases 28 Canckr January 1964 Table 2 SURVIVAL AS RELATED TO INITIATION OF THERAPY AFTER DIAGNOSIS Ti from onset ilis. to treat. 0-15 dav 15-30 dav 1-2 mo. 2-3 mo. 3-6 mo. 6-9 mo. 9-12 mo. > 12 mo. Survival, 0-6 6-12 12-24 24-60 >60 t 000 1 91 223 53002 21 101 03 200 0 1 1 00 00020 00000 Tot. no. pAl 2 17 10 5 5 2 2 0 Total 17 9 6 4 7 * l\vn patients have ina< lequntc follow--up. 4.1 I Ik: leukemic phase of UGS is assuming a imnh moje iniportant role than previously recognized; 14 of 34 (11 patients did not have hone mat row examination) of the children de veloped bone mat row changes compatible with a diagnosis of acute leukemia. The time fiont onset of symptoms to the appearance oi leukemic changes in the bone marrow and potiphcrnl blood ranged from 1 toll months with a mean of 3.9 months; survival, aficr tlic leukemic conversion occunetl, averaged 2.2 months. Hematological and othei data for these cases ale in preparation lor subsequent publhalion. Mediastinal and bone involvement are tlir other frequently occurring clinical problems. Mediastinal disease, present in 16 (35.5%), was usually found only by roentgenogram; clinical symptoms necessitating cmetgcnc.y therapy early in the disease did noi occur. A superior vena caval syndronie (cyanosis, dysp nea, edema cf upper part of body, and venous engorgement) occurred in only 1 patient; prompt lelicf was obtained with the combinalion of radiotherapy and nitrogen mustard; 13 (28.8%) children had osteolytic bone lesion-psually generalized; 3 had localized areas cf bone involvement; all of these occurred subsequent to origin in a lymphoid site. All children did not have bone surveys, so this figure is not accurate. There was no absolute coirelation between bone lesions and bone marrow involvement. Neurological symptoms were noietl in 7 (15.5%) cf the children. These were both pe ripheral nerve and central nenropathies, re lated to either meningeal or cortex invasion. This complication is illustrated by case 28 and will be discussed later. 'V'.w.vwpy was inVdV.'.VM'. \n 70% of v.w| within 2 months after the onset of symptoms! No correlation between survival and tinn institution of therapy after onset of symptom could be demonstrated; however, as is show in Table 2, no 5-year survivals were d<vu men ted in those whose treatment was delate 3 or more months after the onset of symptoms kadiotherapy, surgery, and chemothei.ip were all used, singly and in combination, vitl no definite plan. The results are shown ii Table 3. Again, no definite conclusions oh Ire derived, the number of patients in ( id group being too small. It would appear, hov ever, that neither radiotherapy nor clunv therapy alone should Ire used in RCS; radii therapy with or without surgery lias hen 111., 2. A. M.i mi 1 loin j.muary 16 <" 1 considered standard therapy and a transim luc occurs mm response may be obtained as illustrated vinphos.iKoni, I'ig. 2A, B, and C. The addition of clicnw therapy to either surgery or radiotherapy til'- have been ated with tadii both has now become standard; the clTeciius ness of this is yet to be determined. The c>nih moil mode of therapy in all but 1 of tin 3j; year survivors is surgery, indicating that i complete excision is possible, this is out Ixu iisioit would he Iditive rather th.i Comparably, K* me resistant lie uilable cheinoibt form of therapy. The extent of surgery neir sary for control is demonstrated by the pi'in tigs evaluated h [nieiraptopui inc. that the procedures done include radical unf dissection, hemicolectomy, ileal resection, pit (), vincristine, . yju il, and steroids. tial pneumonectomy, and splenectomy. The rifecfivriK As has been shown for oilier tumors <> lymphoid origin, most cases of RCS arcscnsimi Bust rated in the b to radiotherapy initially; it is om experienn !l Case 28. M.lt. that subsequent development of unhoicmi loped the follow Taiii.ic 3 3year aficr the on . eyes, hendac he. SURVIVAL AS RELATED TO THERAPY "pistons, and. final Survival, mo. 11 dilation rcve.iln ittia. The hone m. Therapy 0-6 6-12 12-24 24-60 >60 itirture yielded a Chemothcr. only .1 0 0 Radiothcr. only Surg. only 40 1 0 00 0 0 Rndiother. & chemothcr. 12 .1 5 3 Surg.&radio- tfier, 01 0 1 Sure. & chemothcr. 0 t 0 0 Surg., radio- ther., & chemother. - 1 0 0 eu. mm., all m otein was 280 mg hcrapy of 4 doses i *25 mg. per kg. | |dintherapy to th 1 niid-plane tissue i is instituted. Ain neurological syn Te within normal showed marked |ed 2 months Ian 'foa with no rcru Total 17 9 6 4 s system disease. *Two patients have inadequate follow-up. This approach \ i* d and tilth e 'm'.ci of symptom v< viT, as is shmvr. Rivals were doui i mi ni was del:i\r> i of symptom* d (linnollici.i))' M n f tin at ion, v ill Mi', .no shown << inclusions < at I patients in c.ul| >!]!'! apprar, Imv > apv nor (linn. ln A, Mass on roentgenogram at time nf diagnosis, ft, Post-treatment roentgenogram taken after treatment in RCS; radii a'f.;OIV has lien Idin [miliary Iti to l elimary .`I n idi a 2.a.'ifi i mid-plane tumor dose. Ci. Roentgenogram showing rcrimeiue. \ ami a ttansi<r tie ocons more quickly in ihis group than ... illustrated f Iwnphosamima or other tumors. No survi- ddition of (hrni'i; s leave been doonneuted in the group .. i adiot hn a]>\ % eated with radiotherapy alone, and the coll 1; iho effected usion would he that radiotherapy should he a m il. The i "in lilitive lather than the only inode of therapy. !i hut 1 of till Comparably, RCS lias been shown to he *ri<!ii at inn; thni i me resistant than the other lymphomas to i his is our hr ; ailahle chemotherapeutic agents. Among the ! ' .<1 snt gci y l)( i r ugs evaluated have been nitrogen mustard, nod liv the JinilV mcrcaptopurinc, nmolhoptcrin (Mctholrex- huh' i adiral m d e). vincristine, cyclophosphamide, chloram- h al jcsecliou, p,n tril, and steroids. a lirnortomv. 'The effectiveness or combined therapy is hi Illinois JJtisiralcd in the following case. )' < i.S are sensii m - one experienn | Case 28. M.B., a 9-ycar-old white boy, de- i of t atlior(.is! lupcd (he following neurological symptoms |ycar after the onset of tlie disease: pain over 6e eyes, headache, blindness, generalized con- ment of the immediate problem, hut no effect was demonstrated on the systemic disease. Similarly, those children developing RCS leu kemia responded for short periods of time to folic acid antagonists, 6-mercaptopurine, and steroids. Clinical experience with the newer compounds (cyclophosphamide and vincris tine) is too limited and too short to establish airy conclusions. Discussion Reticulum cell sarcoma is a rare tumor, as are all the lymphosarcomas in children. Any attempt to determine the exact incidence is doomed to failure because of the multiplicity of pathological classifications utilized. The Pathology Department of Memorial Hospital utilizes the following classification for lympho 1| !') TUKRARY JBilsions, and, finally, eonta. Rctinoscopic cx- sarcoma; (1) giant follicular lymphosarcoma; Jnination revealed 4 phis bilateral papillc- (2) reticulum cell sarcoma (RCS); and (3) lym l.'l >60 #m'i. The hone marrow was normal. Lumbar lit' Ifcnriure yielded a spinal fluid with 5,000 cells cu. mm., all mononuclear leukocytes; the otein was 280 mg.: and glucose 5 mg. ChctnIherapy of 4 doses of intrathecal Methotrexate m2:> tng. per kg. per dose every 5 days) and ^(h'oiherapy to the whole brain and orbit _j rnid-plane tissue dose of 1,091 r over 12 days) instituted. After 20 days, the patient had phosarcoma. By this classification and others, lympho sarcoma occurs most frequently, with RCS next in frequency.7 It is estimated that 3.5 to fi.3% of. childhood cancels are lymphomas; RCS is the pathological diagnosis in 0.8 to 3.19% of the reported scries. Tt is most fre quent in boys, with a sex ratio of 3.5 to 1: neurological symptoms; spinal fluid studies no rare predilection has been described. The ere within normal limits, and his visual aeu- association of RCS of bone to RCS of the f showed marked improvement. The child lymphoid grotip has not been defined pathologi led 2 months later with reticulum cell sar- cally, but both are known to convert to leu 7 with no recurrence of the central nervl,s system disease. kemia, as w'ell as to metastasize and dis seminate. If a close relationship is estab tll.lt*' follow-tip. s'! his approach was successful in manage lished, this will not markedly increase the Cancer January 1964 JJVi I N<> 1 0 Nasopharyngeal H Abdominal Cervical formed. The pathological diagnosis was RCT diffusely infiltrating the bowel. Periphenll blood and bone marrow were within.norm;!' limits. No other physical abnormalities weie noted. After operation the patient received actinomycin D orally; 6 weeks later this was discontinued when lie developed partial ob struction clue to fibrous bands that was te- lieved by a second surgical procedure. Hepa tomegaly and cervical adenopathy were notu'f at this time. After dircharge he received d |i mercaptopurine orall^y (2.5 --m; .p--er kg. .p..c..t.|i day) in a cyclic pattern (3 weeks bn and oil). 3 none suivive ! kemia develo months. The > iiing oT RC.S ip ) , Despite th'- 1 the chihhen I Common chat as follows: 1. Except ii sinned within !' 2. All preset) 0-6mos. 6-l?mos. 12-24mos. 2-5yrs. 5yrs. * tic. Clinical forms of onset ami survival. Two tnonths later liver and lymph nodes wclc|'J ailiv or an abd< not palpable. None had Three and a half years postdiagnosis aii,lf|s I. A radical while still on therapy, the patient developc'l" ,n |)llt one. 1C swelling of the upper jaw anti submaxillai' rA ,.nu(,tr, ised i< fymph nodes and was treatrd by his denti<,;:/'" I't is i- nteresti for dental caries. Because of lack of impros1'.' ment he was examined under anesthesia, "b 3-cm., grayish, soft mass -was found occludi"f the posterior nasopharynx. Biopsy tcvcal"1 hVed dfir have sui vi til of more i RCS. He received a 1,500-rtumor dose over d" ( ><dining ffrt.om nasophatyngoal and submandibulai areas w'll innd. imidciKc in that reticulum cell sarcoma of bone is also rare. The beginning symptoms are usually local ized, and the form cf onset appears to be ielated to survival. Patients presenting with (Civiral lympliadenopathy or an abdominal mass have a better prognosis than those seen with a nasopharyngeal mass, generalized lymphadenopathy, or mediastinal involvement (Fig. 3). Ptevious studies have shown that this is true for the entire group of lymphosarcomas: Bailey et al.,1 Munson and Marx," arid Charache2 all reportctl cares of lymphosarcoma of the ccivical and abdominal type in which the paticntssuivived 5 years or longer. Zuelzer and Flatz10 discussed the problem ot surgical lesions as a complication of acute leukemia and management of the emergency situation. In RCS, a surgical emergency may lead to the pathological diagnosis, often pre viously unsuspected. This is illustrated in the following case, which emphasizes that the nec essary surgical procedure ran be tolerated and often piovides specific pathological diagnosis. As discussed earlier, surgical excision is still the best therapy. Case IS, J.C., a 5i/>-year-olct white boy, was referred to Memorial Hospital with a chief complaint of vomiting and abdominal pain cf 2 months' duration. Barium enema revealed an intussusception. At operation, a mass in total regression of the tumor mass. The l,a,u m remains well; he was seen last in SePtemhn 1962, 5 years and 9 months after t'le on-e of the disease. Flic (1 iitir al tusis of |ri chii The incidence of leukemic conversion :om.i ,'RC.S) has RCS in this series is more frequent than 1 >1 Rt.'.S in chib beeft reported.8 This probably can be atti I, V 'tiM'i is abdomii uted to the more frequent use of bone min (incision doc row examination (Tabled), From 1933 to Iria none of the patients showed leukemic corn0 sion; in the last 9 years, however, of 35 path nl' months. Tl f' usion rises (o iliiv is investi' admitted to Memorial Hospital with a diat '.i nosjs cf RCS, 14 developed leukemia (40' f1 s i Bone marrow studies were not clone in 5 >' the 35. The reported incidence cf leukei"" conversion in lymphosarcoma tanged fi"" 5a I I', mi rv. R. J,, ! < M(lljf>IKItlt |. iooi. 15% f8 to 37%.s In children with lymph - t ii\rAcur, It sarcoma who develop leukemia, the dural"'1 of illness is similar to that of patients v'l! 'g | iil(|iirI, inclndm (ioic;c,i,,t. 7Ci: 5'M acute leukemia (median 44 weeks, averagi Vy .n f t'MICFON, II. \ ,c, ,'x Pfaint. 0: I weeks).9 This has not been the pattern cf sl"| lUk'itON, II. Vi vival in the group of children reportctl hi:tb All with leukemic conversion showed bun'] marrow changes within the first 12 mon I usilise. New |' :i'29. livur.roN, II \ Table 4 BONF. MARROW STUDIES I I fi Ml s'som. c. I, Jj-rj Milrslim* in r? Bone marrow studios, no r . Period No. pt the terminal ileum was intussuscepting into the colon, and a right hemicolectomy was per- kdni;i developed and the mean was 2.2 months. The mean survival from the beginjuing of RCS in this group was 8.6 months (Fig. IV Despite the generally grave prognosis, 7 of >,)!( children have survived more than 5 years, {common characteristics in these patients are f*IS Inllows: I. Except in 1 instance, treatment was |5i o ted within 2 months of diagnosis. . All presented with either cervical adenop|aihv or an abdominal mass. None had leukemic conversion. I A radical surgical procedure was done in ,|| hut one. Radiotherapy and/or chemother,|)\ were used in addition. It is interesting to note that 1 patient, with generalized disease and 1 with regional dis use have survived 5 years or longer. The re- (i111 of more intensive therapy in the cases i, dining from 19!r7-l%2 cannot yet be evalit'd. Summary I lie clinical picture, management, and prog nosis of 1.r> children with reticulum cell sartom.i ;RCS) has been presented. The prognosis RCS in children is better if the form of JJiim i is abdominal or cervical, and if leukemic goiiwisinn does not develop within the first months. The incidence of leukemic conleisioti rises to at least. 10% when this possiiiliis is investigated. In these cases, the re- > IC 10 ,S 1 -e& IS u < 4 6 8 10 Tim in months from onset of R.c. S. leukemia to death Fig. 4. Time from diagnosis of reticulum cell sarcoma until development of leukemia and survival after con version. The mean time from onset of symptoms to leukemia involvement was 3.9 months. The mean sur vival time after the conversion to leukemia was 2.2 months. sponse to the usual treatment is poor, and the median duration of life is shorter than in children with acute stem cell leukemia. Alteration of prognosis (mean survival or 5year cures) may be provided by early diagnosis, surgical resection when feasible, and the addi tion of radiotherapy and/or chemotherapy. More controlled studies are necessary. RF.FF.RF.NCK.S !' 'a i v. R. J., Jr.; Bvrcirt, F. O., Jr., and Daiilin. Malignant lvmphoma in children. Pediatiics 28: .1961. ' iiiMtAeiiR, if.; I.ymphosarcoma in infancy and I! "oil, including case of 22 years' survival. Am. J. ; ,wl. 76; 591-598, J956. ' luncroN, H. W.: Lymphosarcoma in childhood. I',,lint. 6: 13-32, 1953. I'uiiaoN, JL IV.: Tumors of Childhood; a Cliuil".illse. New Yoik, N.Y. Paul B. Hocber, Inc. e ".29. UuicrnN, II. W.: Lymphosarcoma in childhood. I Itnnugmol. 85; 729-732, 1961. 'li \son, C. L.. and Marx. H. F..: Lymphoma of I niicstinc in childhood. Delaware Stale M. /. 18: 153-155, 1916. 7. Rosenkerg, Sr A.; Diamond, H. W., and Craver, L. F.: I.ymphosarcoma; effects of therapy and survival in 1.269 patients in review of 30 years' experience. Ann. hit. Med. 53: 877-897, I960. 8. Rosenherg, S. A.; H.Diamond, D.; Dargeon. H. W,, and Craver, L. Fd Lymphosarcoma in childhood. New England J. Med. 259: 505-512,1958. 9. Sullivan, M. D.: Malignant lymphomas in chil dren. In Clark. R. I... Jr., F.d.: Cancer Chemo therapy. Springfield, 111. Charles C, Thomas, 1961; pp. 79-83. 10. Zuelzer, W. W,, and Flatz, G.: Acute childhood leukemia; 10-year study. A. M. A. Ant. J. Dis. Child. 100: 886-907. I960.