Document RjEgvp8OYE5ZGNMjdm0arGDXE

The Development of Hodgkin's Disease and Lymphoina during Anticonvulsant Therapy D URING By GEORGE A. HYMAN AND SHELDON C. SOMMERS THE PERIOD from 1958 to 1964, 85 cases of so-called pseu- dolymphoma following anticonvulsant therapy have been reported mdi- eating that this entity is not rare.14,t#{176},'2,14 However, the unexpected occur- rence of true malignant with Hodgkin's disease lymphoma in 6 patients and 3 with lymphosarcoma on anticonvulsant therapy ) within a 4-year period (3 in one medical center has prompted this report. This finding may imidicate that patients with lymphoma and Hodgkin's disease superimposed on a seizure disorder actually may outnumber those in whom a pseudolymphomatous adenopathy is provoked by antiseizure therapy. In addition, this association suggests that anticonvulsant therapy may have been an inducing factor in the neoplastic transformation. The pertinent case histories, clinicopathologic findings and therapeutic man- agement in 6 patients, all recently seen at Presbyterian Hospital and Francis Delafield Hospital in New York City, will be summarized hriefly to explore thie problem of the development of lymphoma and Hodgkin's disease during ther- apy with anticonvulsant drugs. lines for the future management In addition, of similar such an analysis patients. Details may yield guideare presemited in Table 1. REPORT OF CASES Case 1 A 24-year-old white woman was first admitted in 1958 to the Neurological Institute. New York City, for treatment of severe psychomotor seizures which started in 1950 following an injury' to the left temple. Since October 1950 she had been treated with Dilantin. 0.5 Cm./day. In October 1952 phenobarbital, 30 mug., and Mysoline, 250 tug., 3 tinies (lailv were added; in 1961. Celontin was also added. In October 1961 a right scalene lymph node biopsy revealed Hodgkin's disease (Figs. 1 and 2). The blood counts and general physical examination tumor (lose were entirely normal. From May 16 to June 13, 1962. to the right hilar area using the Betatron, with complete she was given disappearance 3000 r of the shadow seen by x-ray. In 1963 and 1964, because of pain in the distribution of the left sciatic nerve, she From Columbia University College of Physicians and Surgeons, and Francis Delafield Hospital, New York, N. 1. This investigation was supported in part by U. S. Public Health Service Grants CAM2332 and CA-04346 from the National Cancer Institute, the Hyman Goldhurg Memorial Fund, and the Irvng Wershaw Memorial Fund. First submitted July 30, 1965; accepted for publication Jan. 31, 1966. GEORGE A. HYMAN, M.D.: Associate in Medicine, Columbia University College of Physi- (.ft.Jp,#{23a1n}d Surgeons; Visiting in Medicine and Hematologist, Francis Delafield Hospital; Assistant Physician in Medicine, Presbyterian Hospital, New York, N. 1. SHELDON C. Soss- MERS, M.D.: Professor of Pathology, Columbia University College of Physicians and Stir- geons; Associate Director of Laboratories, Department of Pathology, Francis Dela field Hospital, New York, N. 1'. 416 BLOOD, VOL. 28, No. 3 (SEPTEMBER), 1966 HODGKIN'S DISEASE AND LYMPHOMA 417 required radiotherapy to the left hemipelvis and to the area of emergence of the 2nd and 3rd left lumbar nerve roots. X-rays, including myelogram and lymphangiogram, were negative. When last seen on February 24. 1965, she continued to have deep left groin and left-sided pain. The Dilantin was discontinued in 1962 and she is receiving Mysoline. 250 111g.. phenobarhital, 30 mg.. benzedrine, 5 mg., an(l Thorazine, 25 mg., 3 times daily. Case 2 A Negro girl at the age of 10 years seizure 1 year later. In June 1953 she j)liemiobarbital. 30 nig. daily'. was added. ing. (laih and continued through 1958, first had psychomotor epilepsy with a grand nial was started on Dilantin. 0.3 Cm. daily. to which On June 17, 1954, Dilantin was increased to 400 at which time it was increased to 500 mg. In 1957. l)lie1ilarbital was increased to 30 lug. 4 times (lady. On February 15. 1965. at age 23, when 5 months pregnant, she presented at Presbyterian Hospital in New York City with a right cervical adenopathy of 3 months' duration. The chest x-ray was negative. There was fever up to 100 F. Hemoglobin was 10 Cm. per cent; white count. 6500 with a normal differential; ESR, 36. A biopsy of the right cervical lymph nodes on March 2, 1965 disclosed Hodgkin's disease (Figs. 3 and 4). The lymph nodes enlarged rapi(lly to 6 X 8 cm. in size and cobalt-60 teleotherapy was instituted on March 16, 1965. to the cervical nodes with good effect. She has been maintained on Dilantin to the present. Case 3 In NIav 1964 this 23-year-old s('en at Francis Delafleld hospital white housewife and mother of a 3-month-old child was because of decreased appetite. weight loss of 15 pounds. peripheral receiving lymphadenopathv. and night sweats with onset in November Dilantin. 0.3 Cm. daily', since July 1962 for petit mal with 1963. She had been good effect. A right cervical lymph node biopsy in December 1963 was interpreted as Hodgkin's disease (Figs. 5 and 6). She had received 20 mg. of nitrogen mustard (0.4 mg./Kg.) at an outside hospital and 8 mg of Leukeran a day, intermittentl'. on December 15. 1963. until May 13. 1964, with a transient weight gain and return of a general feeling of well-being. A course of Peripheral supervoltage radiotherapy was given at Francis Delafleld Hospital. On July 31, 1964, splenic enlargement was noted. The hemoglobin level progressively declined from 10.6 to 7.9 Cm. with a reticuloc'te count of 0.5 per cent, white cell count of 6500 with a normal differential. platelets of 314.000, ESR of 1 17 ( Westergren ). and a 2+ positive direct Coombs test. Mesantoin. 0.1 Cnm. 3 tinmes daily. was introduced in September 1964 to replace the Dilantin. This was completel' effective. hut there was progressive anemia. weight loss. fever. and further painful enlargement of the spleen to 6 cm. below the left costal margin. \Vhen a course of Velban. started in October 1964. was unsuccessful, she was adiiiitted to Francis Delafleld Hospital for the first tinie on December 2, 1964. Phenobarbital was Slml)Stitllted for sIesantoin, successfully. Intravenous pyelograph demonstrated involvement of the left retroperitoneal h'mph nodes and she was given radiotherapy to this area and then to the spleen, with relief of pain. During the succeeding 8 months there has been a rise in henioglobin level to 13.0 Cm. per cent. a 15-pound weight gain, and cessation of SVimiI)tOIi'Is. Case 4 A 63-year-old white man had always l)een healthy. with semiannual normal physical examinations a!1(l normal blood counts. through 1961. On October 15, 1962, because of his first generalized seizure, he was admitted to the Neurological Institute in New York City, at which time no etiolog' could be determined. Dilantin therapy was started, 0.3 Gm. daily through March 1 1, 1964. when it was reduced to 0.2 Gm. daily. On February 7, 1964. the splenic tip was palpable for the first time. The physical examination was otherwise negative and there was a normal complete blood count, On May 5, 1964, the first 418 HYMAN AND SOMMERS Table 1.-AnticonvuL,ant Case and Sex K. Z. F Race and Present Age W im B. M. F N 2:3 Therapy Age at Onset and Type of Epilepsy 1 (1950) Psychomotor (after head injury) 10 (1952) Psychomotor and Grand Mal Followed by Lymphoma. Age at Onset of Lymphoma and Type and Site of Biopsy Diagnosis 27 (i961) Hodgkin's R. scalene disease node 22 (Nov. 1964) Hodgkin's disease R. cervical node Summary of Data (6 Patients) Anticonvulsant Therapy prior to and after Diagnoaia of Lymphoma --_______________________________ Pr DX Post DX DiIantin*195O + Phenobarbital-1952 + Mysohne-1954 -I- Celontin- 1961 Dilantin to 1962 Phenobarbital `I- Mysolinet Dilantin-1953 + Phenobarbital 1953 1)ilantin to present 1965 J. A. F W 19 (1959) 24 Psychomotor 23 (Nov. 1963) Hodgkin's disease R. cervical node Dilantin July. July. 19621964 Mesantoin Sept.-Dec. 1964 Phenobarbitalt since Dec. I 964 A. 0. M W 61 (Oct. 1962) 63 Grand Mal J. D. M S. S. M W 48 (1936) 73 Grand Mal (after head injury) w 54 (1954) 65 Grand Mat (vascular) `No change in tymphoma after tAdequate control of seizures. withdrawal 62 (Feb. 1964) with splenomegaly Aug. 1964 lymphocytic lymphosarcoma L. inguinal node 67 (Nov. 1955) Iymphoytic lymphosarcoma R.scalenenode 65 (Aug. 1965) reticulum cell lymphosarcoma retroperitoneal node of Dilantin. Dilantin' Oct. 1962-. Jan. 1965 Phenobarbital'-1938 Dilantin 1941 (?) to 1948 1951-1961 Mebaral-1951-1956 Ditantin and Phenobarbital Sept. 1962 Phenobarbitalt from Jan. 1965 Dilantin until death Dilantin and Phenobarbital abnornial leukocyte count was obtained, a total of 8250 with 63 per cent mature lympho- cytes and 35 per cent polymorphs. On July 21. 1964, an asymptomatic left inguinal lymph node was palpated. This was hiopsied on August 7, 1964; the diagnosis was lymphocytic lymphosarconia (Figs. 7 and 8). The chest x-ray was negative. The only other abnormality found was a small homogeneous electrophoretic spike in the serum gamma globulin. Leukeran therapy was introduced in August 1964 but was ineffective. On December 21, 1964, the hemoglobin had fallen to 8.4 Gm. per cent with a further enlargement of the spleen to 16 cm. below the costal margin. A trial of prednisone, 30 ing. daily. was given without improvement. In January 1965 he received two transfusions and splenic radiotherapy to a total of 550 r. HODGKINS DISEASE AND LYMPHOMA Abnormalities at Time of Diagnosis of Lymphoma Px Hematotogic Negative Noce Table 1.-Continued X-:ay R. hitar node Therapy of Lymphoma Agents X-ray (1) (2) RX to: chest (1962) L. iliac area (1963-1964) Results (I) Excellent (2) Poor 419 Notes II, cervical adenopathy fib- 11) ESR-36 ILL. cervical It. axiltary adet, opathy H b-- I 0 ESR-S0 Splenomegaly None Ncgative None I.. thyroid and LLQ mass None Chest x-ray Chest x-ray negative IvP I,.. retropenitoneal nodes Hitar a(lenopathy Chest x-ray negative L. thyroid Chest x-ray negative mass X-ray RX to R. cervical (Mar. 1965) area Nitrogen mustard (Dec. 1961) Leukeran 1964) (Jan-May Vetban (Oct-Nov. 1964) X-ray RX to bilateral cervical and R. axit- lary nodes X-ray RX to retro- peritoneat and spleen (Dec. 1964) Leukeran (Aug-Dec. 1964) Prednisone (Nov. 1964-Jan. 1965) X-ray RX to spleen (Jan. 1965) X-ray RX to penned area X-ray RX to thyroid RX incom- Ptete Poor Poor None Good Good Pregnant (onset Sept. 1964) at time of diagnosis of Hodgkin's disease; nocardia cut. tured from cervical biopsy. node Poor None Good Good Died in 1961 of generalized arteriosctero4is at age 73 Tre'itment progress in The prednisone was canceled. By' April 1965 the spleen had decrease(l by' two-thirds. the henioglobin had risen to 1 1 Cm. per cent, the platelet count to 50.000 from 20,000, and the white count had returned to normal. Dilantin therapy was stopped and phenobarbital started. 150 lug. daily'. on Januar' 30, 1965, without a s111)se(luent recurrence of the seizures until por. \Vork-up June 1965. when he was readniitted to the Neurological Institute in semistu- disclosed a large 111SS cortical lesion, presumably due to lymphosarcoma. The patient was started on radotherap' to the brain with Decadron as supportive therapy, but he died 10 clays later in coma. Autops' perlnission was refused. Case 5 A 68-vear-oI(l white because of a 30-pound man was first admitted to Francis Delafield Hospital weight loss in 8 months, intermittent fever, and in May weakness 1956 for 2 420 HYMAN AND SOMMERS Fig. 1-Coarse scarring with foci of atypical and anaplastic multinucleated reticulum cells are indicative of Hodgkin's disease, nodular sclerosing type. Case 1, x 200. All slides stained with hematoxvhin and eosin. Fig. 2.-Typical x500. Reed-Sternberg cells of Hodgkin's disease were present. Case 1, Fig. 3.-Discrete foci of necrosis and fibrosis were found, surrounded by a mixture of lymphoid cells, including Reed-Sternberg cells. Case 2, X 200. Fig. 4.-Reed-Sternberg cells were identified characteristic of Hodgkin's disease, graimloma type. Case 2, X 500. HODGKIN'S DISEASE AND LYMPHOMA 421 Fig. 5.-A granulomatous type of reaction with many Reed-Sternberg cells and less necrosis x 100. or fibrosis suggests an earlier stage of Hodgkin's disease. Case 3, Fig. 6.-Mixed lymphoid cells, including typical Reed-Sternberg cells, were evident as well as some eosinophilic leukocytes Case 3, X 500. Fig. 7.-The lymph node capsule was infiltrated by lymphoid cells, the peripheral sinusoids were obliterated and the follicular pattern of the cortex was replaced by a monotonous cellular lymphosarcomatous growth. Case 4, X 100. Fig. 8.-Cells infiltrating the capsule and sinusoids were immature to represent predominantly immature lymphocytes. Case 4, X 600. and appeared 422 HYMAN AND SThIMER5 Fig. 9.-The first biopsy of lymph node showed a blurred nodal architecture with predominant overgrowth of immature lymphoid cells, but the diagnosis of lymphoma was questionable. Case 5, X 600. Fig. 10.-In the second biopsy, the lymph node capsule, peripheral sinusoids, and vein walls were clearly infiltrated by lymphoblasts typical of lymphosarcoma. Case 5, X 600. months. I Ic was found to have 1)net111init afl(l h'poganuuaglobn1ineinia, vith a history of grand nial seizures following a head injur' in 1935. In 1938 lie hd l)een startv(l on phenoharl)ital, 45 lug. twice (lady. to which Dilantin. 0.1 Ciii. twice daily'. was a(l(led when it hecanie available. In 1948. due to "intoxication" 1951 . At that time, because of increased seizures, by' this treatment. it WaS stopped until Dilantin and I)lieliobanl)it1tl were resumed and Mebaral, 0.1 nightl'. was added. His seizures had been nio(leratelv well con- trolled. On Januar'' 17. 1957, a hiops' of the scalene lyniph node was diagnosed as lvmphocvtic linphosarconia. This had l)een snspecte(I clinically. although the physical eXt1fliI1ttiO11, chest x-ray, and complete 1)lood counts were normal. On review, some garded the nodes as probabl' a Dilantin-tvpe at'pical hvperplasia (Fig. 9). pathologists re- Fronl 1957 to 1960. the patient had niultiple episodes of fnrnncnlosis tn(l skin abscesses. On July 16. 1959, a further biopsy' showed definite because of lymph node pressure in the perinetlni. lvmphosarcoma he received (Fig. 10). In 1960. local radiothenap'. In October 1960 the cervical and axillarv lymph nodes first hecanie enlarged. followed by all the other peripheral nodes. The blood count remained normal except for hemoglobin of 1 1.2 Cm. per cent. Continuing seizures did not periiiit the withdrawal of Dilantin an(l phenobarbital. Because of progressive mental (leterioration. believed due to cerebral arterio- sclerosis. he was transferred to a nursing home where lie died in July 1961. No autopsy was performed. Case 6 (This patient original paper.) to arteriosclerotic was ii new case presenting A 65-year-old man develope(l cerebrovascular disease. in December 1965 grand mal seizures He was started on after the in 1954 l)ilaiitin prepanmtin thought to (0.3 GIll/dat') of the l)e due and HODCKINS DISEASE AND LYMPHOMA 423 plet1ol)1trl)ital (45 mg./da') on September 24. 1962. In August 1965 he presented with low back pain and was found to have a mass in the left lower quadrant and left thyroid region. Rapid enlargement of the abdominal mass le(l to a laparotoniv on Deceniher 9. 1965, and the biopsy of a retroperitoneal node revealed reticulum cell sarcoma. The p;mtient has responded to a course of radiotherap'. PATHOLOGIC FINDINGS Tiw ls'mph node architecture was conipletely' obliterated in the biopsies fronl the first 3 cases 111i(l was partially' obliterated in the other 2. Case 1 had niatte(l lvnmph nodes with a loss of the capsular l)oundaries. nlnltiple fibrous an1 hvaline no(ltIles (Fig. 1 ). This is so- called nodular sclerosing Hodgkin's (lisease. The other 2 instances of Hodgkin's disease were of the granulomatous e(lellla, necrosis, an(l infiltrates of histiocvtes and plasma cells. All 3 had Reed-Sternberg cells. as well as anaplastic mononuclear and multimicleated type, with foci of t'pical hinucleate cells (Figs. 2, 4 and 6). Eosinophils were present in Case 3. In Case 2, there was less fibrosis (Fig. 3) and the alterations ap)eared relatively' early'. Case :3 had a rather nodular. granuloniatotis apearance (Fig. 5). Ctse 4 ha(l unusually' large l'nmpli nodes with a nodular architecture 1(11(1 infiltrations )enetraing lymphocytes. the capsule consistent into the perinolal with ly'mphocvtic fat (Figs. 7 and 8). The preclominmtnt cells were lymphosarcoma. Some aspects resembled the so- called polvmo#{231}phous-cell sarcoma of mm4 Case 5 had two biopsies. In the first biopsy, several lymph nodes ( less than 5 mm. in (lianleter) were removed. Their capsules were intact, the cortex and me(lulla were poorl' demtrcated, and the nodes had a solid appearance. On higher power examination. there were close-packed immature lymphoc'tes and occasional reticuluni cells. 500W with atVl)ical nticlei 111(l pronlinent nucleoli (Fig. 9). A definite diagnosis of lynm})luJnla was difficult to make and the appearance was more consistent with at'pical hy'perplasia secondary' to Dilantin. Other observers had considered this to be a lvmphoc'tic lvmphosarcoma. The second biopsy 30 months later yielded several abnormally large. matted lymph nodes. Microscopically the normal structures uniform l'niphoblastic cells typical of lymphosarcoma an(l infiltrated the capsules. Similar cells were infiltrating had replaced the walls of "ellis (Fig. 10). DIScuSsIoN The entity of pseudolymphoma following Dilantin and other anticonvulsive therapy was given emphasis following the articles of Saltzstein, Ackerman, and co-workers.111 It is worthwhile to define this entity and compare it to true lymphioma-thiat is, lymphosarcoma amid Hodgkin's disease. Pseudolymphoma may be defined as a localized enlargement of lymph nodes that simulates malignant lymphoma clinically and grossly, but which lacks the necessary histologic diagnostic criteria. Obliteration of architectural features, invasion of the peripheral node capsule and blood vessel walls, and clearly recognizable malignant mieoplastic cells are generally not Ol)served with pseudolymphoma. Lymphocytic and lymphoblastic lymphosarcoma present a "monotonous" pat- tern, whereas Hodgkin's disease is characterized microscopically by necrosis, fibrosis, amid Reed-Sternberg cells. Typical Reed-Stemberg cells are binucleate or multimiucleated with large, pale, overlapping notched or reniform nuclei that contain prominent following entities: nucleoli. We include in the term "maligmiant lymphoma" (1 ) giant follicle lymphoma, (2) stem cell lymphoma, the (3) lmphosarcoma, (4) reticulum cell sarcoma, and (5) Hodgkin's disease. 424 IIYMAN AND SOMMEFIS Pseudolymphoma may appear grossly indistinguishable from genuine lymphoma but it fails to meet the histologic criteria. The nodal architecture may be distorted but it is not destroyed, and no architectural or cytologic attributes of malignant neoplasia are clearly identified. Pseudolymphioma is not a specific histologic entity. As a histopathologic diagnostic term it refers to those lymph nodes in which the extent and degree of atypical hyperplasia present either simulate or may be confused with malignant lymphoma. Cy- tologically there are bizarre reticulum cells, lymphoblasts and unclassifiable lymphoid cells in abundance, but they are not sufficiently anaphastic to be recognizable as lymphoma cells. Early papers emphasized the presence of mononuclear or binucleate cells that simulated, but lacked, the essential fea- tures of Reed-Sternberg cells. Thus, lymphosarcoma, lymphocytoma, or giant follicle hymphoma may often be imitated by pseudolymphoma. It should miot be considered merely a synonym of so-called atypical Hodgkin's disease. The clinical picture of pseudohymphoma consists of lymphadenopathy, fever and a morbilhiform rash; joint pain and swelling occur often. The spleen and liver may be enlarged, and eosinophilia may occur. There is a short, latent period of days to a few weeks after administration of the offending drug0 and rapid improvement in the same period of time after withdrawal of the agent. Repeat administration of the drug precipitates the syndrome again. Admittedly, malignant lymphoma is more difficult to diagnose pathologically than many other neoplasms. Therefore, a history of anticonvulsant administra- tion may help to forestall erroneous diagnosis of camicer. Even the positive history of the administration of anticonvulsant drugs is not definitive, since in the first series of 32 pseudolymphoma cases at least one patient subsequently developed malignant lymphoma.4 The presemit report describes 6 patients with typical Hodgkins disease or other types of malignant lymphoma who had been receiving therapy with anticonvulsants. The anticonvulsants used were Dilantin, used in all 6 patients, plus phenobarbital used in 3 of the patients, Mysoline and Celontin used in I patiemit, and Mebaral used in 1 patient (see Table 1 ). Pathologically all the biopsies were typical of malignant lymphoma. The only exception was Case 5, since the first specimen obtained was interpreted as pseudolymphoma by some pathologists and as lymphocytic lymphosarcoma by others. All subsequent biopsies were clearly lymphomatous. This situation exemplifies the difficult differential diagnosis of an atypical lymph node hyperplasia from early lymphoma. The knowledge of anticonvulsant therapy in such an individual may sometimes sway opinion toward pseudolymphoma.4"#{176}'12 Whether the atypical hyperplasia of lymph nodes sometimes observed dur- ing anticonvulsant drug therapy is a precancerous state, and whether Dilantin and related agents sometimes act as carcinogens cannot be answered from the present information. In almost all the previously reported cases when the initial biopsy showed pseudolymphoma, this diagnosis persisted throughout the #{176}Drugsimplicated to date include Dilantin (diphenyihydantoin), Tridione (trimethadione), Mesantoin, Methoin, Milontin (phonsuximide), Mysohine (primidone), and Peganone. HODGKIN'S DISEASE AND LYMPHOMA 425 course. In 5 of the present 6 cases the diagnosis of lymphoma was made initially on th#{236f}irest biopsy and remained the diagnosis thereafter. In addition, there is no evidence from animal studies to show that anticonvuhsant agents are carcinogenic.5 However, it is entirely possible that the anticonvulsant drugs are carcinogenic in certain sensitive individuals or act as the inciting factor for lymphoma in these persons. The fact that 6 patients on amiticonvulsant therapy were found to have lymphoma in one medical center, in a short period of time, led to a review of the incidence of the diagnosis of atypical lymph node hyperplasia during a 5-year period in this medical center. The diagnosis was only made 8 times in the period in nearly 200 lymph node biopsies. It was found that there were fewer positive biopsies of atypical lymph node hyper- plasia ( pseudolymphoma ) than of true lymphoma in patients receiving anti- comivulsant agents. Thus, it appears that lymphoma may occur at least as often in association ing ( 1 ) a lymphoma, with anticonvulsant relationship between and ( 2 ) the possibility therapy as pseudolymphoma, administration of anticonvulsant that anticonvulsant drugs again suggestdrugs and may be carcino- genic in certain susceptible hosts rather than simply allergenic. These possibihi- ties must be borne in mind in persons receiving Dilantin or other anticonvuh- sants. It is hoped this paper will stimulate other clinical and research reports on this sul)jcct. The management of patients with lymphoma or lymphomatous disorders during the course of anticonvulsant therapy is more complex than in lymphio- ma developing de novo, because of the constant concern that the pathologist may be in error, and the desire to avoid cancer drug therapy for pseudo- lymphoma, a benign condition. However, if a carefully studied lymph node l)iopsy in conjunction with the clinical findings and course indicates a true lymphoma, appropriate therapy for this disorder should be administered with- out delay. In the uncommon instance when a clear diagnosis is not possible, a trial with the substitution of another agent such as phenobarbital for the original anticonvulsant drug is warranted. Should this fail to yield clinical improvement, such as subsidence of fever and involution of the lymphadeno- pathy within several weeks, a repeat biopsy is indicated. This may yield proof of lymphoma. The patient should then receive therapy for lymphoma, prefer- ably with radiotherapy, based on the experience in this group of 6 patients. It is worthy of note, even in this small series, that the response to all of the other agents ( nitrogen mustard, Leukeran, Velban, and prednisomie ) was poor, suggesting that chemotherapy is inferior to radiotherapy in this group of pa- tients. An unnecessary delay in biopsy may allow a true lymphoma that is early and radiation-responsive to progress to an advanced and poorly responsive stage in the interim. Recent reports of supervoltage technics employed in lymphoma, treated at an early stage, were associated with the highest 5-year arrest rate.7'5 One cannot anticipate what the response might have been if there had been a delay in treatment, but in the group of patients in this paper early radio- therapy was effective. In almost all instances, managememit should include replacement rather than 426 HYMAN AND SOMMEIIS withdrawal of the anticonvulsant in use. Although elimination of the offending agent may lead to a rapid subsidence of a nonneoplastic has not led to a remission of the lymphomatous process adenopathy,1'1 ( once established it ) in the patients being presented. Withdrawal of these antiseizure agents may I)c harmful to the patient's neurologic status, simice actual brain damage may result in patients with seizures who are deprived of anticonvulsant therapy.2 A general withdrawal of these agents is also unnecessary, as indicated by our cases K. Z., J. A. and A. G. (see Table 1 ), who had completely satisfactory control of seizures following the substitution of phenobarbital for Dihantin, a result also reported imi the literature.1#{176} Occasionally the original anticonvulsant may have to lie continued if the other agents fail to comitrol the seizures. SUMMARY 1 . Six I)atients in whom Hodgkin's disease or during the use of anticonvulsant agents ( Dilantin, Celontin ) are reported. lymphosarcoma phenobarbital, developed Mysoline, 2. The differential diagnosis from pseudolvmphoma, the course of these malignant lymphomas, and their therapeutic management are discussed. 3. Based upomi information presently available, it could not be determined whether the atypical hyperplasia sometimes observed during anticonvulsant drug therapy is precamicerous, or whether these agents may be carcinogenic in certain sensitive individuals. 4. Patients with a seizure disorder who develop lymphoma require standard therapy for both conditions. The anticonvulsant drugs had no evident adverse effect on the course of the lymphoma, although substitution of another agent seems warranted, if possible, for the offending drug. Su\rIA1uo lx INTEHLINGUA 1. Es reportate le casos de 6 patientes in (IUi I'norl)o sarcoma se disveloppava durante he uso de pharmacos de Ilodgkin anticonvulsive o lympho- (Dilan- tina, phenobarbital, Mysolina, Celontina). 2. Es commentate le diagnose differemitial relative a pscudolvmphoma, Ic curso de iste mahigne lymphomas, e br manipulation therapeutic. 3. A base del imiformationes curremitemente disponibile, il non esseva possibile determinar si Ic hyperplasia atypic que es occasionalmemite observate durante chimotherapia anticonvulsive es de character precancerose o si iste agentes es carcinogene in certe susceptibile sul)jectos. 4. Patientes con un disordine convulsive qui disveloppa lmphoma require le therapia standard pro le un e Ic altere condition. Le pharmacos anti- convulsive habeva nulle evidente effecto adverse super le curso del lmphoma, sed le substitution de un altere agente pare justificabile imi tamito que possihile in loco del pharmaco incriminate. A 30-year-old white male was nervousness, night sweats. anorexia, 0 examine(l in January' 1966 with coniplaints and a 25-pound weight loss. Since May of fatigue, 1965 he had #{176}Cassuemmary kindly supplied by Dr. Herman A. Freckman of Cincinnati. Ohio. HODGKINS DISEASE AND LYMPHOMA 427 noted a cough and progressive swelling in the right cervical left axillary and, eventually, left supraclavicular regions. The patient had been receiving Dilantin, 0.1 Cm. 4 times daily', since November 1959 for the control of grand mal seizures following a head injury in August 1959. In addition to the l'iimphadenopathy described above, a mediastinal mass was seen on chest x-ray. A left cervical node biopsy reviewed by the authors revealed the architecture to he obliterated by' l'mphoc'tes, bizarre reticulum cells antI occasional plasiia cells. A few foci appear fibrotic. Sternherg cells are noted in abundance. Necrosis is not evident. Cells identifiable The section was interpreted as Hodgkin's At l)reseflt the latiet is receiving combined Velban and I eukeran therapy' with lwnefit, and has l)een continue(l on Dilantin. as Reeddisease. apparent REFERENCES 1 . Anonymous. : Drug-induced psendoly'm- plioma. Med. Letter 4:56, 1962. 2. Carter, S.. and Merritt. H. II.: Convul- sive seizures. Lippincott's Med. Sci. 6:713, 1959. 3. hanson, T. A. S.: histological classifica- tiOti an(l survival in I Iodgkin's disease. Cancer 17:1595. 1964. 4. Ilarrington. \V. j., Kissane. J.. Saltz- stein. S. L.. et al.: Clinicopathologic Conference. Amer. J. Med. 32: 286. 1962. 5. IItiel)er. \V. C., an(l Conway, W. D.: In Chem ical Carcinogenesis antI Cancers ( I. N. Kugelmass. Ed.). Springfield. Ill., Charles C Thomas. 1964. pp. 6- 14. 6. Ih'nman. (;. A.: Hodgkin's disease. In Current Therapy L(l. ) . Philadelphia, (Howard F. Conn. W. B. Saunders Company. 1965, pp. 210-217. 7. Kaplan. H. S.: Radical radiotherapy of regionall' localized Hodgkin's (lisease. Radiology 78:553. 1962. 8. Peters. NI. V. : The contribution of ra(li- ation therap in the control of early lvmphoma. Amer. J. Roentgen. 90:5: 956. 1963. 9. Rosenfield, S.. Swiller, A. I.. Shenov, M. V.. an(l Morrison. A. N.: Syndrome sininlating liuphosarconma in(luced b' Diphenvlhvdantoin 5O(litIm. j.A.M.A. 176:491. 1961. 10. Saltzstein, S. L.. and Ackerman, L. V.: Lvmphadenopathv md uiced 1w anti- con'uIsant drugs and nmimicking cliii- ically' and pathologicall malignant lniphonias. 1 1 . Saltzstein, Cancer 12: 164, 1959. S. L., Jandon. J. C.. Lose, S. A., anl Ackerman. L. V. : Lvnipha- (lenopath' in(luce(l h' Ethotoin (Peganone). J.A.M.A. 167:1618. 1958. 12 Sommers, S. C.: Proc. Seminar Amer. Soc. Clin. Path.. Chicago, 1964. Case 16. p. 47. 13. Sparberg. M.: Diagnostically confusing complications of Diphenvlhvdantoin therapy. Ann. Intern. Me(l. 59:914. 1963. 14. Svmmers. D.: Giant follicular lmph- adenopath with or without spleno- megal. Arch. Path. 26:603. 1938.