Kaposi's Areview of 136 Rhodesian cases

Postgrad. med. J. (August 1967) 43, 513-519.

Kaposi's sarcoma:

A review of 136 Rhodesian African cases

JoHN A. GORDONM.B., Ch.B.(Cape Town), F.R.C.S.(Edin.)

Surgeon, Harari Central Hospital, Salisbury, Rhodesia;Cancer Association Fellow of the Cancer Association of

Rhodesia to the Westminster Hospital, London

KAPosi's syndrome was originally described byMoricz Kaposi, Professor of Dermatology in theUniversity of Vienna in 1872. The condition wasthought to be rare and virtually confined toCentral European Jews, although later it was alsodescribed in Mediterranean peoples. There waseven evidence that amongst the Jews the con-dition was confined to the Ashkenazic sect(Rothman, 1962). Early reports were often basedon small series of cases, rarely numbering morethan a dozen.

Since the original masterly description of thedisease (Kaposi, 1872) there has been much con-fused discussion on all aspects of the tumour.Today it is recognized that Kaposi's sarcoma ismore common than was at first thought, particu-larly in some parts of Africa. The realization ofthe importance of the disease led to a symposiumon Kaposi's sarcoma held at Makerere College,Uganda, in May 1961. It is to this symposium thatthe current upsurge of interest and increase inresearch is primarily due.

IncidenceAt the Harari Hospital histological laboratory,

Rhodesia, Ross (1966) found 136 cases whichconformed to the criteria of Kaposi's sarcoma andwhich represented 3-3% of all malignant tumoursseen between 1955 and 1965. Between 1961 and1966 the author, a general surgeon, observedthirteen cases of the disease at Harari CentralHospital. Cook (1966) quotes an incidence in theCongo of 12% of all cancers and Davies & Lothe(1962) in Uganda found a figure of 3 % of allcancers or 6-4% of all tumour cases in males. Thisis in contrast with the experience among the whiteraces. For example, the records of the radiotherapyunit, Westminster Hospital, reveal only three casesfrom 1949 to 1965, during which time nearly16,000 patients were treated for malignant disease,and Rothman (1962) reported that search of the

University of Chicago cancer registry from 1946to 1960 showed eight cases of Kaposi's sarcoma in13,700 malignancies.

AgeThe original and subsequent 'European' des-

cription stressed that the patient would be in thesixth or seventh decades. However, Oettle (1962)found that the African patients were between 35and 44 years. At Harari Hospital some difficultyhas been experienced in establishing ages but nonein the series was over 50 years and this seems tocorrespond closely with Oettle's figures though atleast one patient was 24 years of age.

In contrast, at the Westminster Hospital, thethree patients were 76, 78 and 83 years old,respectively.

SexMales predominate in all series and Ross (1966)

reported 128 males, four females and four whereno sex was indicated in his 136 records.

RaceAll the Harari patients were Bantu. At West-

minster there were two Jews of Central Europeanorigin. The third case occurred in an Englishmanborn of an English father and a Welsh mother.Series from Europe and America conform to theoriginal description of a preponderance of CentralEuropean Jews or Mediterranean peoples. Of greatinterest is the fact that the disease is unusual inthe Jews of Israel but is becoming commoner inGermany where the Jewish population is greatlyreduced (Oettle, 1962).

Clinical featuresThe Harari Bantu cases were typical of the

original description of European patients given byKaposi. The skin changes were not as obvious inthe dark skin, and patients tended to present rather

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John A. Gordon

later in the course of the disease. One hundredand twenty-eight cases in the series were maleswho were surprisingly young, appearing to be intheir later thirties or early forties. Age is still adifficult thing to determine in the African and onehas to obtain an approximation on past events inmany people over 35.The history was of nodules developing upon

the limbs accompanied by some discomfort inthe form of itching or pricking. Swelling andsometimes haemorrhage from the nodule afterslight trauma was also noted.

FIG. 2. Foot of an African patient with Kaposi'ssarcoma. The Kaposi nodule is present with earlyulceration. The lymphoedema is producing an elephan-tiasis of the foot. (Dr J. Forbes' case.)

FIG. 1. Kaposi's sarcoma: nodules on the forearm ofan African patient. The early changes in lymphaticflow produce a shiny watered silk appearance. (Mr B.Hammar's case.)

The nodule of Kaposi's sarcoma in our patientsoccurred on the hands or feet and often furthernodules were found over the forearms or lowerleg. These varied in size from a few millimetres toa centimetre, but large nodules were encounteredof 2-3 cm in size. Ulceration occurred in thenodules often irrespective of size, and might spreadto involve other nodules.The skin around the nodule and the skin in

apparently uninvolved areas may show interestingsequential changes. It may become turgid andshiny, often resembling watered silk in the earlystages and eventually the skin becomes coarse andpachydermatous. Elephantiasis may be the finalresult. These changes are probably due to theenormously increased lymph flow in the involvedarea. With the multicentric sarcomatous changesoccurring in the soft tissues, and the inordinateincrease in lymph flow, it would be logical toexpect tissue changes from simple oedema throughto a form of elephantiasis.

Overt oedema occurs in over 60% of cases andis not a mere central lymphatic obstruction but a

lymphatic venous shunt with an enormous quan-

tity of lymph shunting through widely dilatedlymphatics. Palmer (1962) showed this con-vincingly in a limb involved by Kaposi's sarcomawhen he demonstrated increased lymphatic flow inthe shunt using diodone as his contrast medium.

Davies & Lothe (1962) describe the disease inwomen and children. Women have classical lesionsbut the course is shorter and the prognosis worse.In children, the disease is manifest in alymphadenopathy of the lymph glands of neck,axilla and groin rather than in nodule formation.There may also be involvement of salivary tissue.

In the present series visceral lesions have beenencountered definitely in one case and pre-sumptively in a second case. In one young male,histology of the appendix revealed the diseaseafter he had undergone laparotomy for anapparently acute abdomen. The second case had atypical presentation with widespread nodules of allfour limbs. While undergoing therapy he com-plained of abdominal pain and a clinical diagnosisof visceral involvement was made. Visceral lesionsare common and they have been described inevery organ with the exception of the brain(Lothe & Murray, 1962).

Differential diagnosisThe clinical diagnosis should always be con-

firmed by biopsy. Kaposi's sarcoma may beconfused with a simple ganglion, an angioma,neurofibromatosis, melanoma (often found on thesole of the foot in Africans), nodular leprosy,granuloma pyogenicum, lymphangiosarcoma,onchocerciasis, filarial elephantiasis, madura-mycosis, syphilis, sarcoidosis of the skin and post-mastectomy lymphangiosarcoma.

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Kaposi's Sarcoma

FIG. 3. A nodule in Kaposi's sarcoma in cross section. This figure demonstrates the epi-thelium stretched over the tumour. On each side are normal rete pegs. The tumour hasnot involved the epithelium but is obviously malignant on the deep aspect.

V

FIG. 4. High-power magnification (x l600) of Kaposi's sarcoma. Note the strands of mature connectivetissue, the vascularity and the malignant fibroblasts. (Section by kind permission of Dr C. M. D. Ross.)

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John A. Gordon

further areas of involvement appeared, all ofwhich required repeated therapy. One has died at83 years of age while two still attend the follow-upclinic, 2 years after being diagnosed.

Radiological featuresSoft tissue films may reveal extensive changes

that are not clinically obvious. Palmer (1962) hasmade an extensive study of the radiologicalchanges in Kaposi's sarcoma and has shown thatthe nodule is merely the 'tip of the malignant ice-berg'. Further, there may be bone changes

~associated with soft tissue involvement. There maybe generalized rarefaction and the head or base ofa phalanx or metacarpal or metatarsal may appear

K .... ~ ~....... ..........

to have been 'rubbed out'.Localized rarefaction with a loss of trabecula-

tion of the bone or cortical erosion may occur insome, while infiltration of the bone can produce'cysts' as opposed to rarefaction which is due tolocal hyperaemia.

AngiogrphyThis is a most interesting investigation since it

demonstrates the surprisingly extensive involve-ment of the soft tissues. The skin nodule is merely

i t; 0 0#Xt1X a small part of extensive tissue change. Thearteries to involved tissues may demonstrate asharp 'cut off' effect.

FIG. 5. Radiograph of the foot in a patient withKaposi's sarcoma. The metatarsal heads appear to havebeen 'rubbed out. There is generalized rarefaction dueto gross soft tissue oedema and poor blood supply inthe foot. There is increased density of the shafts of thebone together with small soft tissue nodules, rarefactionof the tarsus, metatarsal heads and phalanges. Somecortical destruction and central deposits are present.(Professor P. Palmer's case: by kind permission ofProfessor Palmer and S. Karger AG, Basel.)

Spontaneous regressionCook (1966) has suggested that spontaneous ; ,

regression may be expected in perhaps 2% ofpatients. No patient in this series has shown com-plete regression.

... .

The Westminster cases _The three elderly males treated at Westminster

Hospital were typical examples of Kaposi'ssarcoma. Two were Central European Jews. Thelesions demonstrated slow progression with exten- FIG. 6. Soft tissue tumours of the foot and ankle insive tissue involvement. There was a satisfactory advanced Kaposi s sarcoma. Note the extent of the softtissue involvement. (By kind permission of Professorresponse to radiotherapy and chemotherapy, but P. Palmer and S. Karger AG, Basel.)

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Kaposi's sarcoma

HistologyMicroscopic examination shows large spindle

cells with numerous mitotic figures associated witha varying proportion of new blood vessels. Strandsof mature connective tissue penetrate the tumourand there is a sparse infiltration of plasma cellsand histocytes in these strands. The lymphaticsmay show a striking dilatation, indicatingincreased lymphatic flow in keeping with Palmer'slymphangiographic observations. Over a typicalnodule the epidermis may be stretched withflattening of the rete pegs or there may be infiltra-tion of the dermis with direct extension of thetumour and the blood vessels may show invasionby the tumour.The examination of multiple sections taken at

widely separated sites demonstrates the multifocalorigin of the tumour. The maturity and autonomyof the tumour in each section favours a multi-centric origin rather than direct or metastaticinvolvement.

TreatmentIn the treatment of Kaposi's sarcoma radio-

therapy, chemotherapy or a combination of bothmethods has been employed. Both methods areavailable in Rhodesia, but in Uganda there is noradiotherapy unit and it is to the credit ofclinicians there that such excellent results havebeen obtained by chemotherapy alone. Kaposi'ssarcoma is extremely radiosensitive and radio-therapy, coupled with the long natural history ofthe disease, has proved to be the most effectiveweapon in treatment.Where facilities for radiotherapy are available,

all obviously involved areas are treated and it maybe necessary subsequently to treat any other areathat becomes involved later in the disease. It mustbe borne in mind that the apparently superficiallesion is only a small part of the disease and thatsuperficial therapy will be inadequate.

ChemotherapyIt has been the author's practice to use nitrogen

mustard to treat Kaposi's sarcoma, which corre-sponds to the technique used at Mulago. Eightpatients were treated in this manner where therewas either a very localized lesion and one hadtime to review the treatment and employ sub-sequent radiotherapy if necessary, or where thepatient had very extensive disease and it was feltthat a systemic drug would be preferable to veryextensive radiotherapy.The route of the nitrogen mustard administra-

tion was both arterial and intravenous. Isolatedperfusion of a limb was considered but rejected onthe following grounds:

(i) The disease is multicentric and cytotoxic

agents must reach involved areas not as yetclinically or radiologically apparent. The danger tothe haemopoietic tissue was considered to be out-weighed by the gravity of the condition, alwaysprovided that careful clinical and laboratorymonitoring was carried out before, during andafter cytotoxic therapy.

(ii) The rapidity with which nitrogen mustardis fixed within the tissues favours intra-arterialinjection of the drug without involving a majorvascular dissection.

After the initial arterial injection the drug wasadministered by the intravenous route in anattempt to deal with active cellular division occur-ring after the initial injection.

Nitrogen mustard was administered at an initialdosage of 0-4 mg/kg body weight using a per-cutaneous arterial puncture into the major arteryof the limb. This was always carried out underanaesthesia to ensure the patient's comfort and tofacilitate the procedure. The injection was madeover about 10 min using a dilution of 1 mgmustine hydrochloride in 1 ml normal saline. Atthis dilution the average volume given was 20 mlcontaining 20 mg mustine hydrochloride. It is nowour policy to use percutaneous arterial cannulationrather than direct arterial puncture, injecting thedrug into the lumen of the artery at a distance of5-10 cm from the puncture wound, thus avoidingthe possibility of perivascular spill of the drug.

Following the initial dosage mustine hydro-chloride, 10 mg twice weekly, is administered bythe intravenous route in dilution of 20 ml by slowinjection. Should the patient not tolerate the druga higher dilution of 10 mg in 200 ml saline is used.All cases are given thiethylperuzine dihydrogenmaleate (10 mg three times a day) or similar anti-emetic prior to therapy and for the day oftherapy. A full blood count including plateletcount is carried out before administering mustinehydrochloride. If the haemoglobin falls below80% (11 6 g/100 ml), the white blood count below3000 cells/mm3 or the lymphocytes below 10% ofthe differential count or the platelet count below100,000/mm3 treatment is suspended. The treat-ment is continued until clinical regression isevident, usually within 2 or 3 weeks. Our policy isto wait 2-3 months before repeating the courseunless new lesions appear.At Mulago, Cook (1966), using nitrogen

mustard, reported that 8-2% of his series showedcomplete regression and 42% showed some im-provement. Follow-up of Harari patients left muchto be desired as most patients returned to theirown districts and, despite an out-patient appoint-ment, would not re-attend unless there was furtherprogression of the tumour.

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Theoretically the most effective therapy wouldappear to be radiotherapy and cytotoxic drugs. Allovert lesions are treated by radiotherapy and thepatient is given a course of mustine hydrochlorideto treat the deep-seated and as yet unapparentareas. However, cytotoxic drugs may interfere withthe response to radiotherapy. This therapy hasbeen used in two of the author's cases withapparent initial success.At the Harari Hospital from 1957 to 1966,

forty-nine cases have been treated by radiotherapy(Greig) in the following annual distribution:1957 1958 1959 1960 1961 1962 1963 1964 1965 1966

1 1 6 6 8 7 2 6 11 1These patients were given radiotherapy for 6

weeks at a dose rate of 150 r / week on a 50-kVunit. There has been a response to therapy withthe disappearance of local lesions. O'Brien &Brasfield (1966) treated the superficial lesions withlow voltage radiotherapy on a 50-80-kV machine,giving a total of 500-2000 r. For deeper lesionsthey used 200-250-kV orthovoltage equipment. Atthe Westminster Hospital therapy is given on an80-kV unit, giving 3000-3500 r over 3-4 weeks, thedosage being dependent upon the volume of thelimb or anatomical site receiving therapy.Where radiotherapy has been combined with

nitrogen mustard therapy at Harari Hospital thedose of radiotherapy has been cut to 50 r on a50-kV machine to clinically involved areas.McWhirter (1967, personal communication)

describes a case with involvement of both legs inwhich he treated the whole thickness of the left legby the use of two opposed fields and gave a dosageof 1250 rad in a period of 1 week using 250 kV.This limb has remained free from recurrence for1 year. The patient's right leg was perfused with30 mg nitrogen mustard. A transient response wasobtained and radiotherapy was used at the samedosage as in the left leg with a less dramatic result.There seems to be little doubt that the nitrogenmustard therapy has interfered with the responseto radiotherapy.

DiscussionThe interest in Kaposi's sarcoma was initially

due to its rarity and to its apparent confinementto Mediterranean or Central European Jews. Thecurrent interest in the disease centres upon themulticentric origin, the racial differences and thefact that it is far commoner than expected. Thereis a high incidence in Bantu, and the Congolesehave the highest incidence of the disease, while theBantu of Kenya, Rhodesia and South Africa havea lower incidence than in the Congo. This varia-tion is also geographical, the incidence beinggreatest in hot, humid climates and tending to

decrease towards temperate zones. It may thus bethat there is no racial variation but an environ-mental factor. This theory is further enhanced bythe low incidence among Jews in Israel and therising incidence among German Jews.The diagnosis of Kaposi's sarcoma is being

made with greater frequency in African territories.The disease has only recently been investigated inAfrica and there are insufficient records uponwhich to form an opinion of the apparently risingincidence. Accurate records are now being keptand trends in incidence will become apparent inthe near future.There are at present few pointers to the

aetiology. It would appear that some environ-mental factor is of major importance while geneticfactors are far less important than at first thought.The possibility of a geographical factor is greatlydiminished when it is realized that the immigrantcommunities of Africa are not liable to developKaposi's sarcoma. It occurs in the African but notto any extent in the Asian or European immigrantsto Africa.Trauma (Oettle, 1962) has been said to have no

part in the aetiology of the disease nor has ultra-violet irradiation, as Kaposi's sarcoma is not seenin the albino or in association with xerodermapigmentosum. The sites affected do not correspondwith those usually involved in basal cell carcinomaor squamous cell carcinoma. Infective causes suchas a virus, unless one postulates an associatedhygienic factor, are not likely as the immigrantcommunity is free of the disease. The fact thatmales are numerically at risk leaves the avenue ofhormonal factors open to investigation.

It is certain that the lymphoedema associated withKaposi's sarcoma occurs as part of the diseaseand there is no question of its being a sarcomatouschange occurring in previously lymphangiomatoustissue similar to the lymphangiosarcoma of thePost-mastectomy case.

O'Brien & Brasfield (1966) have reviewed aseries of sixty-three patients with Kaposi's sarcomain which eighteen died of a second primaryneoplasm. Included were five cases of Hodgkin'sdisease, three lymphosarcoma, three carcinoma ofthe colon and one each of multiple myeloma,malignant melanoma, carcinoma of the prostate,carcinoma of the tongue, carcinoma of the tonsil,carcinoma of the pancreas and carcinoma of thebreast. These authors state that the mortality fromthese second primary neoplasms was higher thanthat of the Kaposi sarcoma. No second primaryneoplasms have been reported in the Rhodesiancases and the author had not encountered anycase with a second primary neoplasm among hispatients.

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Kaposi's sarcoma 519

The presence of angiomatous vessels has led tothe belief that the disease is a form of angio-sarcoma (Roulet, 1962; Dupont, 1951), but thework of Cook and his associates had centred atten-tion upon the spindle cell component. Cook (1962)considers the spindle cell to be the prime elementand, by a process of exclusion, suggests that thiscell originates in the connective tissue rather thanthe vascular endothelium, smooth muscle or neuralsheath. In his tissue cultures the spindle cellbehaved as a fibroblast, and it could producereticulin and collagen but did not differentiate intoany distinctive cells such as the Schwann cell. Thecurrent view is therefore that the spindle cell ofKaposi's sarcoma is a malignant fibroblast arisingwith new vessels from a primitive mesenchymalcell which may be located in the loose adventitialcoat of small blood vessels. Histiocytes which arevery commonly associated with the tumour maybe part of the stromal reaction of the tumour orhave arisen from the original mesenchymal cell.

SummaryKaposi's sarcoma is a well-documented tumour.

It was thought to be rare and confined to MiddleEuropean Jews and Mediterraneans. It has, how-ever, been found to be surprisingly common incertain parts of Africa.

Attention is drawn to the early changes in theskin of the African, manifest as a shiny wateredsilk appearance, which will progress to elephan-tiasis. The nodule is typical but is seen later in theAfrican. Radiology is of interest in the detectionof soft tissue and typical bony change.Recent research into the origin of the tumour

suggests that the malignant fibroblast originates inthe adventitia of small blood vessels and that thetumour is a fibrosarcoma rather than a haemangio-sarcoma.The current view on therapy is that radiotherapy

is curative but may have to be used at multiplesites. Chemotherapy has been successfully employedwhere radiotherapy has not been available and inSalisbury, Rhodesia, chemotherapy has proved to beof value.

Interest in this tumour is increasing in view ofthe success of various forms of therapy andbecause of its potential in the field of research.Links must be sought in racial, environmental andgeographical influence on this tumour.

AcknowledgmentsI wish to thank Professor Harold Ellis for his advice and

constructive criticism of the paper and for permission to usehis case history from Westminster Hospital; Mr T. M.Prossor, Dr K. A. Newton and Mr G. Westbury forpermission to examine and use the Westminster Hospitalradiotherapy records; Dr C. M. D. Ross and Dr A. Greigfor their information and comments; Dr M. Webster,O.B.E., Secretary for Health, Rhodesia, for permission topublish this paper; and Mr John Cook of Edinburgh andformerly of Makerere College for his help and advice inwriting this article. My thanks are due also to Professor R.McWhirter for information on his case of Kaposi's syndrome;Professor Philip Palmer for the use of Figs. 5 and 6 fromhis paper; S. Karger AG, Arnold-Bocklin-Strasse 25, Basel,Switzerland for permission to use Figs. 5 and 6 originallyprinted in Acta Unio Internationalis contra Cancrum, Vol.18, No. 3, 1962, now published in book form as Symposiumon Kaposi's Sarcoma, edited by Ackerman and Murray;and Miss H. Osgood, Miss M. Bird and Miss A. Hodsonfor typing numerous drafts of this paper.

ReferencesCOOK, J. (1966) Kaposi's sarcoma. J. roy. Coll. Surg. Edinb.

ii, 185.DAVIES, J.N.P. & LOTHE, F. (1962) Kaposi's sarcoma in

African children. Acta Un. int. Cancr. 18, 394.DUPONT, A. (1951) L'Angio-reticulomatose Cutanee (Sar-

comatose Multiple Idiopathique Pigmentaire de Kaposi).I. Duculot, Gembloux.

KAPOSI, M. (1872) Idiopathisches Multiples Pigments, Sar-kom der Haut. Arch. Derm. Syph. (Wein), 4, 256.

LOTHE, F. & MURRAY, J. (1962) Kaposi's sarcoma. Autopsyfindings in the African. Acta Un. int. Cancr. 18, 116.

O'BRIEN, P. & BRASFIELD, R. (1966) Kaposi's sarcoma.Cancer, 19, 1497.

OETTLE, A. (1962) Geographical and racial differences in thefrequency of Kaposi's sarcoma as evidence of environ-mental or genetic causes. Acta Un. int. Cancr. 18, (No. 3).

PALMER, P. (1962) The radiological changes of Kaposi'ssarcoma. Acta Un. int. Cancr. 18, (No. 3).

Ross, C.M.D. (1966) Personal communication on materialsubmitted for publication in Cent. Afr. J. Med.

ROTHMAN, S. (1962) Some clinical aspects of Kaposi's sarcomain the European and North American population. ActaUn. int. Cancr. 18, 362.

ROULET, R. (1962) Comments on the possible histogenesisof the cellular components of the so-called "haeman-giosarcoma Kaposi." Acta Un. int. Cancr. 18, 147.



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Kaposi's Areview of 136 Rhodesian cases