288 2 November 1968

Burkitt's Lymphoma: Remissions Following Seemingly Non-specificTherapy

JOHN DAVID,* F.R.C.S.ED.; DENIS BURKITT,t M.D., F.R.C.S.ED.

Brit. med. J., 1968, 4, 288-291

Summary: Long-term remissions observed in four out

of eight unselected patients with Burkitt's lymphomafollowing seemingly non-specific treatment with Septi-cemine, are described. This is regarded as strong

evidence of an effective immunological response.

Introduction

In 1924 Dr. R. A. Hoyte arrived in the Gold Coast fromTrinidad and practised near Accra for 43 years, initially in-partnership with Dr. F. M. Simmonds, who had worked inAshanti since 1895. Both doctors used a medicine namedSepticemine for a wide variety of conditions, including yaws,

typhus, gonorrhoea, tropical ulcers, and meningitis, withapparent benefit in many unrelated diseases. This medicine was

first prescribed in France in 1921 and subsequently marketed byLaboratoires Cortial Ltd. under the name " Septicemine." Itwas composed of the following ingredients: Hexamine iodo-methylate 6.3 g., hexamine 1 g., sodium benzoate 1 g., saccharose5 g., distilled water 100 ml. It was given either intramuscularlyor intravenously.

Professor Lewis, of the Department of Pharmacology in theGhana Medical School, considers that hexamine is the onlyactive principle, the other ingredients merely representing a

former popularity of multiple pharmacy.Hoyte and Simmonds used Septicemine to treat a number of

children with swellings of the maxilla and orbit which theybelieved to be neoplastic, and recorded marked temporary remis-sions in most cases. This response to treatment caused them todoubt the diagnosis of malignancy, and a tentative diagnosis ofsepsis, actinomycosis, or cavernous sinus thrombosis was sub-stituted for that of cancer. In retrospect they were almostcertainly treating patients with Burkitt's lymphoma.The use of Septicemine was virtually abandoned when

sulphonamides became available in the late 'thirties.

Case 1.-In 1961 a boy of 11 was admitted to Korle Bu Hospital,Accra, with a tumour invading the left side of the nose which was

histologically diagnosed as a lymphoma or reticulosarcoma. Theswelling of the palate and orbital involvement characteristic of Bur-kitt's lymphoma developed subsequently. The tumour enlargedrapidly and the child was discharged as inoperable. The parents indesperation consulted Dr. Hoyte, who once again resorted to hisformer treatment and gave the child Septicemine. After one month'streatment the tumour began to regress and a month later the boyreturned to school. He was seen by one of us (J. D.) a year laterwith no clinical evidence of tumour, and he was well seven yearslater.

This remarkable success from unorthodox therapy coincidedwith a period of financial stringency during which no cytotoxicdrugs were available. It was therefore decided to test the effectof Septicemine on other patients with Burkitt's tumours.

The next nine patients admitted with Burkitt's lymphoma ofthe jaw were treated with Septicemine. Two are not includedin this series. One, a girl aged 6 years with a jaw tumour andabdominal masses, was removed from hospital after three weeks'

*Ear, Nose, and Throat Specialist, Ghana Government Medical Service,Korle Bu Hospital, Accra, Ghana.

t Medical Research Council, London W.1.

treatment without improvement. The effect of therapy couldnot be assessed in this case. The other patient was treated withSepticemine and methotrexate. In view of the known efficacyof the latter in the treatment of this tumour, the marked response

recorded must be assumed to be due to the methotrexate therapy,and so this case has not been included.With the exception of these two patients, this series consists

of unselected cases treated as they were seen (see Table).

Summary of Patients

Case Age Sex

1 11 M2 9 M

3 6 M

9 M'

D 6 F

6I 7 F

7 15 M

8 9 M

Site ofLesion

L. maxillaR. maxilla.L. orbit.Intracranial

L. maxilla.Abdomen

L. maxilla

R. maxilla.AbdomenL. maxilla.Abdomen

L. maxilla.L. orbit

R. maxilla.R. orbit.Intracranial

Response Histology

Well seven years laterGood response. Death six months

later from intracranial involve-ment

Delayed response two monthsafter beginning " treatment."Died two and a half years laterfrom unknown cause

Delayed response two monthsafter beginning treatment.Death over a year later frombowel perforation throughnecrotic tumour

Little if any response

Little if any response

Response delayed two months.Well three years later

Remission. Recurrence. Furtherremission. Death six monthslater from intracranial com-plications

+

Clinical Trial

Dose and Administration.-The dosage and mode ofadministration originally used by Hoyte were adopted-3-4 ml.intramuscularly on alternate days for six to eight weeks. Thedose was then reduced to twice weekly and subsequently to once

weekly, treatment being continued for three to four months.Since Hoyte used to give a single dose of Acetylarsan, as hemight be dealing with a case of yaws, his example was followedin this matter to make the treatment resemble as nearly as

possible the original.

Case Reports

Case 2.-A boy aged 9 was admitted to hospital with a largelymphoma of the right maxilla invading the orbit. The diagnosiswas confirmed histologically. There was also evidence of intracranialinvolvement and his general condition was very poor. The tumour

was partially removed surgically and treatment with Septicemine was

begun. After two months' treatment the tumour mass remain-

ing after surgery had shrunk considerably in size, and histologyshowed massive tumour necrosis, though apparently viable turnourcells were also present. The boy's general condition had greatlyimproved. Intracranial complications caused the death of the child

a month later.Case 3.-A boy aged 6 was admitted with a malignant lymphoma

involving the left maxilla. The loose teeth, some of which had

already fallen out, expanded alveolus, and bulging palate were

characteristic of Burkitt's lymphoma. An abdominal mass was also

detected and the diagnosis was confirmed histologically. During two

months' treatment with Septicemine the tumour continued to grow to

an enormous size with gross distortion of the face, and a further

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2 November 1968 Burkitt's Lymphoma-David and Burkitt BarrmsUMEDICAL JOURNAL 289

biopsy showed areas of living and of necrotic tumour tissue. Thelatter was at the time believed to reflect faulty fixation or stainingrather than tumour necrosis. Since the medication was apparentlyproving ineffective, injections of Septicemine were reduced to one aweek. Two months later the abdominal swellings were no longerpalpable. Nine months after admission the teeth in the involved jawhad become re-embedded in bone and appeared to be growing nor-mally. The lamina dura round involved teeth had again becomeradiologically visible. Two months later he developed chicken-pox.Nearly two years later he was symptom-free except for a purulentdischarge from his left nostril. This was reminiscent of a patientseen by one of us (D. B.) several years after successful treatment fora maxillary tumour, with necrosis of the previously involved maxilla.The boy died " in the bush " two and a half years after his admissionto hospital. There is no evidence that death was related to histumour.

Case 4.-A boy aged 9 was admitted with a very large tumourof the left maxilla, with dislodged teeth and gross distortion of hisface (Fig. 1). Within three weeks the palatal swelling filled themouth. As much as possible of the tumour was removed througha modified Caldwell-Luc approach, and the diagnosis was confirmedhistologically (Fig. 2). Treatment with Septicemine was begun.The tumour, however, rapidly recurred, surpassing its original sizewithin a few weeks. There was rapid and gross deterioration inthe patient's general condition. The injections of Septicemine,which had been given thrice weekly, were reduced to biweekly,being continued for a further six weeks. By this time markedtumour remission (Fig. 3) and improvement in the patient's generalcondition, with much recovery of lost weight, had taken place.Histological examination of the shrunken tumour mass showedalmost complete necrosis (Fig. 4). Death occurred from bowelperforation. At' necropsy (performed by a military pathologist nolonger in the country) it was reported that " the left kidney wasoverlain by an encapsulated smooth mass . . . incorporating theadrenal." " A tumour mass apparently arising from the bowelwall," and about 3 in. (7.5 cm.) in diameter, was found on theascending colon. On histological section the tumour involving theadrqnal showed viable lymphoma cells scattered among necrotictissue. The bowel tumour showed only necrotic tissue. Thoughit was stated that " the cause of death in my opinion was peritonitissecondary to a metastatic tumour in the bowel," no mention wasmade of a demonstrable perforation. The possible significance ofthis spontaneously necrosing tumour undetected in life is discussedbelow.

effect on the tumour. As in the previous case death occurred threemonths after admission.

FIG. 2.-Case 4. Histological appearances, low-power and high-power.'

Case 7.-A boy aged 15 had a tumour of the upper part of theleft maxilla involving the orbit. Though attempts at biopsy failedto secure tumour tissue, the clinical features and progression ofgrowth precluded any diagnosis other than a malignant neoplasm.The clinical and radiological appearances strongly suggested a diag-nosis of Burkitt's tumour. Septicemine was given, but tumourgrowth continued for two months. A sudden change then occurredwith rapid and complete tumour remission. Three years later heremained well. Though this tumour was not histologically con-

FIG. I FIG. 3

FIG. 1.-Case 4. Massive left maxillary tumour invading the orbit.FIG. 3-Case 4. Appearance five months later.

Case 5.-A girl aged 6 was admitted with a right maxillarytumour and abdominal masses. Histology confirmed the diagnosisof Burkitt's tumour. She was treated with Septicemine withoutany obvious effect on the tumour, and died three months afteradmission.

Case 6.-A girl aged 7 was admitted with a left maxillary andabdominal tumours. The diagnosis was confirmed histologically.The patient was given a course of Septicemine without any obviousD

FIG. 4.-Case 4. Histological appearances of tumour necrosis afterbeginning clinical remission.

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Burkitt's Lymphoma-David and Burkitt

firmed, the eventual remission would be extremely unlikely in any

other clinically similar neoplasm.Case 8.-A boy aged 9 had a massive tumour of his right maxilla

with advanced orbital invasion and extension into the mouth. Hisgeneral condition was extremely poor, He was treated with metho-

trexate in a dose of 10 mg. a day for one week and Septicemine.Marked tumour remission and improvement in his general conditionoccurred within this period. Six weeks later as much as possibleof the residual mass was excised. Two months later marked tumourrecurrence was noted. Treatment with Septicemine was again begun.After a further two months almost complete remission occurred.Subsequently he developed intracranial complications and died sixmonths later, 10 months after his initial admission.

Discussion

Evidence has been submitted that in six out of eight patientssuffering from Burkitt's lymphoma marked remission followedtreatment with Septicemine, a preparation containing hexamine.In six patients tumour tissue was histologically examined andthe appearances were considered to be diagnostic of Burkitt'slymphoma or consistent with this conclusion. In the remainingtwo patients the diagnosis was thought to be almost indisputableon clinical grounds.When considering reports of isolated cases of this tumour

the question naturally arises whether the histological featureswere in fact diagnostic of Burkitt's lymphoma or whether thepatient might have suffered from some other form of malignantlymphoma. Spontaneous and sustained remission of any othertumour clinically and histologically resembling Burkitts.lymphoma would be most unusual.

In seeking an explanation for these remissions it must bequestioned whether the treatment was in any way specific orwhether the response was attributable to immunologicalmechanisms. No cytotoxic action has hitherto been attributedto hexamine, and in no case did tumour regression begin untilmany weeks after the commencement of therapy. In contrastthe effect of cytotoxic agents has usually been dramatic withina few days.

Considerable clinical and laboratory evidence has beenaccumulated which indicates a particularly strong immuno-logical mechanism operating in Burkitts lymphoma. Burkittet al. (1965) and Burkitt (1967b) suggested that the long-termremissions following sometimes single non-toxic doses of cyto-toxic therapy must be in part attributable to host response.Moreover, remissions occurring after diagnostic biopsy (Burkittand Kyalwazi, 1967) but without therapy must be attributedto an immunological response possibly initiated by the traumaof surgical biopsy liberating cell-bound antigens and thusinitiating tumour-antibody formation. Three patients inUganda are known to be alive and well two to five years afterbeing discharged from hospital with tumours failing to respondto therapy.

This evidence of host defence mechanisms can best beexplained on a basis of tumour antigenicity, a contention whichis supported by Osunkoya's (1967) observation that whereas theserum from patients with active Burkitt lymphomas acceleratesthe growth of tumour cells in tissue culture, serum frompatients in long-term remission or from indigenous adults hasthe opposite effect.

Klein et al. (1968) showed that when antibodies tumour-specific to Burkitt cells can be demonstrated in patients' serathe clinical response to treatment is likely to be good, and viceversa.

In the treatment of this tumour with cytotoxic agents it isthe long-term and not the initial response that has beenattributed to host defence mechanisms.

In Case 4 it is particularly interesting to note the necrosisof the bowel and adrenal tumours associated with peritonitis

BRITIH

MEDICAL JOURNAL

and death over a year after successful treatment of a maxillarytumour. This strongly argues a " subsequent" tumour beingdealt with immunologically in a similar manner to the original

jaw tumour. Ngu (1967), referring to his Ibadan experience,remarked: " Rapid tumour destruction with cyclophosphamidecan lead to complications; for example, rapid necrosis of

tumour in the bowel may lead to a perforation and peritonitis."The bowel "tumour" could have been a totally necrotic

lymphoma, but, alternatively, it could have been inflammatory

in origin. In East Africa a number of cases of peritonitishave resulted from a worm (Oesophagostomum) penetrating the

wall of the ascending colon and resulting in an inflammatory

mass (helminthoma) and eventually diffuse peritonitis

(McAdam, 1968).Whether or not this bowel lesion was a tumour which had

regressed spontaneously, the adrenal mass, which consisted of

a few viable tumour cells scattered throughout otherwise necrotic

tissue, at least suggests that these tumours can regress

spontaneously before becoming clinically detectable.

It is possible that spontaneous remission of early tumours

might often occur. These patients would never be medically

examined and the event would pass unrecorded.

The particular combination of circumstances that made this

trial possible were fortuitous and unique. In the temporary

absence of conventional cytotoxic agents Hoyte's recollection

of successful treatment with Septicemine of apparently malig-

nant tumours in children, and in particular the first recorded

case in this series, prompted a further trial with this drug.

Confidence in the efficacy of a drug, though in retrospect

unfounded, provided an opportunity to withhold specific

therapy in good faith, an attitude which in other circumstances

would be unjustifiable. Hitherto, refusal of treatment has

afforded the only occasional opportunity to witness spontaneousremission.

This series of eight cases was unselected, and thus indicates

the possibility of temporary remission and even long-term sur-

vival in untreated patients. Though it would appear that these

results are better than what would normally be expected in

untreated cases, they underline not only the possibility of

spontaneous recovery but a possibility that this might be far

in excess of that ever reported in any other tumour.

A survey of patients treated in East Africa (Pike, 1966;

Morrow et al., 1967) has shown that patients surviving for

over 15 months are unlikely to succumb to the tumour subse-

quently and may thus be considered potential cures.

Cases 1, 3, and 7 of the present series fall into this category,

since there is no evidence that death two and a half years after

treatment in Case 3 was connected with the tumour. In Case 4

death occurred over a year after treatment without recurrence

of the maxillary tumour.

The therapy response shown by Burkitt's lymphoma has been

compared with that of acute leukaemia (Burchenal, 1967;

Burkitt, 1967). It has been pointed out that, although the

initial response to therapy in both diseases is dramatic, recur-

rence is almost invariable in acute leukaemia, whereas a high

proportion of long-term remissions, believed to be possible

cures, has been reported in Burkitt's lymphoma.

In view of the evidence here presented it is suggested that

the factor responsible for the significant proportion of long-

term remissions observed in this tumour, in contrast to their

paucity in acute leukaemia, is immunological. In both condi-

tions therapy greatly reduces tumour mass, but only in the

lymphoma is there strong host reactivity to tip the balance in

favour of recovery.

The high degree of antigenicity suggested by this evidence

provides further support for a viral aetiology, particularly when

coupled with the group specificity of the tumour demonstrated

by Klein et al. (1968) and the time-space clustering shown by

Pike et al. (1967).

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2 November 1968 Burkitt's Lymphoma-David and Burkitt BRIT= 291

We wish to acknowledge Figs. 2 and 4 to the National CancerInstitute, Washington, D.C. We are grateful to Miss Ella Wrightfor much secretarial and other assistance.

Reprints should be ordered from Mr. D. P. Burkitt, MedicalResearch Council, 172 Tottenham Court Road, London W. 1.

REFERENCES

Burchenal, J. H. (1967). Cancer Res., 26, 2393.Burkitt, D. P. (1967a). Possible Relationships between the African

Lymphoma and Acute Leukaemia. London.Burkitt, D. P. (1967b). The Treatment of Burkitt Tumour. UICC

Monograph Series, No. 8, edited by J. H. Burchenal and D. P.Burkitt, p. 94. Heidelberg.

Burkitt, D., Hutt, M. S. R., and Wright, D. H. (1965). Cancer (Philad.),I 18, 399.

Burkitt, D. P., and Kyalwazi, S. K. (1967). Brit. 7. Cancer, 21, 14.Klein, G., Klein, E., and Clifford, P. (1968). Search for host defences in

Burkitt lymphoma: Membrane immunofluorescence tests on biopsiesand tissue culture lines. In press.

McAdam, I. W. J. (1968). In W. W. Davey's Companion to Surgery inAfrica, p. 93. Edinburgh and London.

Morrow, R. H., Pike, M. C., and Kisuule, A. (1967). Brit. med. 7., 4,323.

Ngu, V. A. (1967). The Treatment of Burkitt Tumour. UICC Mono-graph Series, No. 8, edited by J. H. Burchenal and D. P. Burkitt,p. 204. Heidelberg.

Osunkoya, B. 0. (1967). The Treatment of Burkitt Tumour, UICCMonograph Series, No. 8, edited by J. H. Burchenal and D. P.Burkitt, p. 233. Heidelberg.

Pike, M. C. (1966). Lancet, 2, 856.Pike, M. C., Williams, E. H., and Wright, B. (1967). Brit. med. 7., 2,

395.

Sleep and Barbiturates: some Experiments and Observations*

J. I. EVANS,t M.B., CH.B., D.P.'M.; S. A. LEWIS4 B.SC.; I. A. M. GIBB,§ M.B., CH.B., D.P.M.

MARY CHEETHAM,JJ M.B., CH.B., D.A.

Brit. med. J., 1968, 4, 291-293

Summary: To determine the effect of barbiturates onsleep two subjects, after a control period, received

200 mg. of sodium amylobarbitone for 26 nights. Allnight sleep records taken during this period showed thatthe barbiturate shortened the delay to sleep, increasedthe total sleep period, lengthened the delay to rapid eyemovement (R.E.M.) sleep, and depressed R.E.M. sleep.After five nights R.E.M. sleep returned to baseline values

-that is, showed tolerance. On stopping the drug with-drawal phenomena were seen, even to this small dose ofthe drug.

In a second experiment a subject dependent on 600 mg.of Tuinal was found to have low normal R.E.M. sleepwhile on drugs. On withdrawal, delay to sleep increasedand total sleep time fell. R.E.M. sleep was doubled andthe delay to R.E.M. became abnormally short.These findings suggest that hypnotics allow sleep to be

"borrowed," and that patients should be supported whilethey are being withdrawn.

Introduction

In the past decade drugs have become the focus of attentionof many groups in society. Doctors have become more awareof their side-effects, prolonged actions, effects on foetal develop-ment, and the possibility of addiction and overdose. Societyhas become anxious over the questions of abuse and addiction,and these anxieties have produced a number of standing com-mittees in an effort to control this complex problem.The need for such control is apparent even when the quantity

of drugs consumed for therapeutic reasons is appreciated.Ministry of Health (1964) statistics show that hypnotics, anal-gesics, and tranquillizers constitute 22.6% of all prescriptions.Of this group barbiturates are the largest contributors, makingup 8.1% of all prescriptions, and the amount increasesannually. Other indices confirm the increasing use and abuseof these drugs. Overdosage by hypnotics has increased

steadily as a means of attempting suicide (Kessel, 1965), anddelirium due to abrupt withdrawal is a frequent hazard (James,1963).Many doctors were taught that whatever else they could not

do for their patients they could at least provide sleep. Thisexpectation seems to have passed on to the patients, as doctorsoften complain that they feel under pressure to prescribehypnotics.

In the past decade knowledge about sleep has also greatlyincreased. It has been found to consist of two regularlyalternating states (Aserinsky and Kleitman, 1953, 1955), whichdiffer drastically in many physiological criteria.At the beginning of the night the normal subject enters a

cycle of sleep which is characterized by slow waves andspindling activity in the E.E.G., slow rolling/absent eye move-ments, the presence of muscle activity, and regularity of pulserate, blood pressure, and respiration. After about an hour ofthis slow wave or " orthodox sleep " there is an abrupt change.Spindles disappear from the E.E.G., muscle tone drops pre-cipitately in the submental region (Berger, 1961), the E.E.G.becomes low-voltage, and runs of sharp waves appear-the" saw tooth" frontal activity which is followed by bursts ofjerking synchronous eye movements (Dement and Kleitman,1957). Respiration and pulse rate become irregular and bloodpressure is variable (Snyder et at., 1963, 1964). After 10 to20 minutes the eye movements disappear, often after a bodymovement, and spindles reappear as another cycle of slow wavesleep begins. This second type of sleep has been called " para-doxical" or rapid eye movement (R.E.M.) sleep.

In the normal night five or six cycles of orthodox sleep withan equivalent number of periods of paradoxical sleep occur.Paradoxical (R.E.M.) sleep usually occupies about 24% of thetotal sleep. Normally, orthodox sleep takes precedence overR.E.M. sleep, and the first R.E.M. period of the night doesnot occur until after at least 45 minutes of orthodox sleep(Rechtschaffen and Verdone, 1964; Oswald and Priest, 1965).Mental activity differs in these two types of sleep. In

orthodox sleep mental activity is variable, often fragmentary,and more reality-orientated. During R.E.M. sleep disorienta-tion in time and place is common and dreams are reported(Aserinsky and Kleitman, 1953; Goodenough et al., 1959;Monroe et ad., 1965). To determine the effect of drugs on

e From the Sleep Laboratory, University Department of Psychiatry,(Royal Edinburgh Hospital), Edinburgh 10.

t Lecturer, University Department of Psychiatry, Edinburgh.t Medical Research Council Scholar, University Department of Psychiatry,

Edinburgh.s Late Registrar, Royal Edinburgh Hospital.n Late Senior House Officer, Royal Edinburgh Hospital.

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