J. cliii. Path. (1969), 22, 573-578

Recent views on Buerger's diseaseGEORGE WILLIAMS

From the Department ofPathology, University of Manchester

SYNOPSIS Eighty-two biopsy specimens of vessels from 37 patients with clinical Buerger's diseasewere examined histologically and classified. The aetiology of this vascular disorder is discussedand a basis suggested for its pathogenesis as primarily a thrombotic disorder complicated byvasculitis. Thus both acute and chronic lesions are acceptable as entities.

Thromboangiitis was established as a clinico-pathological entity by Buerger in the early part ofthis century. Despite the extensive literature whichhas accumulated around this disease, its aetiologyremains unknown, its pathogenesis controversial,and its clinical course unpredictable. In this paper,some aetiological factors long associated withBuerger s disease are considered in the light of themore recent literature and its pathology is studiedin 82 biopsy specimens from clinically affectedpatients.

CONTRIBUTORY AETIOLOGICAL FACTORS

Sex, age, race, tobacco, and infection have allreceived attention as contributory factors.

Thromboangiitis is predominantly a disease ofmales. Buerger (1924) recorded only two females in500 cases and this bias has been maintained in everymajor series. A few cases have been recorded inwomen (Poteete and Lynch, 1956; Montorsi andGhiringhelli, 1961). Gaylis (1957) reckoned that of4,467 cases collected from the literature, probablyfewer than 10 could be regarded as genuine occur-rences in women, an assessment reinforced byKaiser, Musser, and Shumacker (1960). The agegroup mainly involved is between 25 and 50 years,although patients well outside this range have beenrecorded (Allen, Barker, and Hines, 1962).

Buerger's view of the disorder as being largelyrestricted to the Jewish race reflected a strong racialbias in the population from which his own patientswere drawn; this view is no longer tenable. Over theyears a wider incidence has been recorded: McKusickand Harris (1961) and Inada, Hayashi, and Okatani(1964) have described the disease in Japan. In 120Cases Lynn and Burt (1949) recorded only fiveJewish patients; Hershey, Pareira, and Ahlvin

Received for publication 31 December 1968.

(1962) found none, and Szilagyi and Elliott (1964)only one in their respective series of seven and 22cases. Studies of the disorder in an almost exclusivelyJewish population in Israel (Goodman, Elian, Mozes,and Deutsch, 1965) showed an 800% incidence inAshkenazim as opposed to Sephardic stock.The harmful effects of cigarette smoking on the

course of the disease, emphasized by Silbert (1935,1945, and 1948), have been substantiated by morerecent studies (McKusick and Harris, 1961; Hersheyet al, 1962). Goodman et al, however, found that theconsumption of tobacco of patients with arterio-sclerosis and of those classified as having Buerger'sdisease did not differ significantly and that cessationof smoking was beneficial only if maintained for atleast 12 months. The collective evidence shows thatchronic vascular insufficiency is aggravated bytobacco consumption, an effect to which patientsin the Buerger category seem particularly sus-ceptible.The striking inflammatory component of the

active phase of the disease has prompted severalworkers to seek an infective cause. In this contextthe most significant association has been betweenBuerger's disease and fungal infection as indicatedby Thompson (1941) and Naide (1941), and laterby Boyd, Ratcliffe, Jepson, and James (1949) andBoyd (1950). The latter emphasized that the patchy,superficial phlebitis which may precede involvementof larger vessels was commonly associated withdermophytosis of the interdigital folds. The role offungi is difficult to assess; in the present study aminority of patients had fungal infections but theirvascular lesions differed in no way from the largernon-infected group.

PATHOLOGICAL STUDY

In this study, a specimen was defined anatomically573

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TABLEDISTRIBUTION AND TYPE OF LESIONS

Upper Limb Vessels

Digital Others

Lower Limb Vessels

Digital Popliteal Tibial

I (radial) I2 3 1

2

9 1

in terms of its vessel of origin. Thus, in someinstances, for example, from amputated limbs oras a result of repeated biopsies, several specimenswere obtained from individual patients. A total of82 specimens (Table I)-10 from upper limbs, 72from lower limbs-were examined from 37 patients(34 males, three females). Microscopically, fourupper limb specimens were normal, the remainingsix were abnormal. Of the lower limb specimens,four were normal and 68 abnormal. The lesions wereclassified as acute, subacute, or chronic in terms ofthe tissue changes. Arteries and veins were commonlyboth involved though not necessarily at the samestage of the process. Different stages were occasion-ally seen in one group of vessels or in differentvessel groups from individual patients. In this series,66% of all specimens showed chronic lesions, 15%acute or subacute, the remaining 19% showingeither bland thrombosis in normal vessels, atheroma(one case), or simply normal vessels.

Macroscopically longstanding lesions showedarteries, veins, and sometimes nerve trunks boundtogether as fibrous cords. Multiple transverse sec-tions showed obliteration of the vascular luminaby dense grey tissue with variable canalization.Acute and subacute lesions appeared as friablebrown-red thrombus occupying short lengths of thevessels, either as isolated occlusions or as termina-tions of more chronic obliterated segments.

Microscopically, the acute stage showed luminalobstruction by thrombus containing dense aggre-gates of polymorph leucocytes. the vessel wallsshowed infiltration with polymorph leucocytes, an

intact, elastic lamina, and no significant muscledamage. In the subacute stage, mononuclear as wellas polymorphonuclear leucocytes contributed to thecell infiltrates, and foamy giant cells were presentwithin the lumen, usually at the cell-fibrin interface(Fig. 1). Chronic lesions evinced a wide spectrum offibrous occlusions with variable chronic inflam-matory infiltrates, lymphoid aggregates, and peri-vascular fibrosis (Figs. 2, 3, 4, and 5); arterial musclecoats were penetrated by extensions of the vasa

2

38

2 311 14 44

1 8(peroneal)

37

1 5(femoral)1 54(peroneal)

53 82

vasorum linking up with the luminal canalizing-vessels. Superficial thrombophlebitis (Fig. 6) was

seen in three cases. The acute phases may occur interminal portions of occluded vessels or occasionallyin isolated segments, sometimes in superficial veins,a point which Buerger emphasized. The acute lesionin both arteries and veins consists of a thrombusassociated with an intense inflammatory reactioninvolving the vessel coats and frequently adjacentvascular channels and nerves. In the materialunder study I have not seen vasculitis in the absenceof thrombosis, though the reverse may occur, forexample, at the extremity of a recent occlusion.

DISCUSSION

Acute and subacute lesions are relatively rare andtheir significance has been questioned. Gery,Fontaine, and Branzeu (1939) found none in arteri-ectomy specimens and amputated limbs from 14patients. However, Schatz, Fine, and Eyler ((1966)described inflammatory vessel changes in nine of the12 cases they studied pathologically, and McKusick,Harris, Ottesen, and Goodman (1962) describedmicro-abscess formation as a feature of the acutelesions affecting many vessels in four of their patients.The intens_ inflammatory reaction in the acutelesions and their subacute counterparts is not a

feature of ordinary thrombi; their appearancessuggest an inflammatory response to constituents ofthe thrombus, at first limited to the vascular lumen,then later spreading to involve the vessel coats andadjaceat structures.Emphasis on the distinctive nature of the active

lesions does not detract from the concept ofBuerger's disease as primarily a thrombotic disorder.Indeed, there is considerable evidence in support ofsuch a view. De Takats (1943) and Hagedorn andBarker (1948) found increased tolerance of heparinin patients with Buerger's disease and arterioscler-otics as compared with controls. Eisen, Tyson,Michael, and Baumann (1951) showed that plateletadhesiveness was markedly increased during active

574

Nature of Process

4Normal

Recent thrombus onlyAcute thromboangiitisSubacute thromboangiitis

Chronic occlusion

Atherosclerosis

2 1

Totals

Others

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Recent views on Buerger's disease

AV ~ 4-

FIG. 2.

FIG. 1. Subacute lesion showing polymorph and mono-nuclear leucocytes, fibrin, and giant cells in vessel lumen.x 120.

FIG. 2. Popliteal artery showing recurrence of subacutelesion (fibrin and giant cells) within a recanalized oldthrombus. x 50.

FIG. 3. Posterior tibial artery showing recanalizedthrombus, lymphocyte infiltration, and penetrating muralcapillaries. x 40.

FIG. 3.

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.,A\

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q f*|* .da*¶> .; ppt S.##'

| w . w ' wFIG.

FIG. 4. Popliteal vein showing recanalized thrombus con-taining lymphoid aggregates. x 35.

FIG. 5. Lymphocytic aggregates surround collateral ad-ventitial vessels. x 100.

J. *:# i FIG. 6. Thrombophlebitis in a superficial vein. x 120.

OrJX^9:R

FIG. 4

FIG. 6

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phases of thromboangiitis, and remained higherthan that of control patients during quiescentperiods of the disease. By studying a range ofcoagulation factors Craven and Cotton (1967)showed that in contrast to atherosclerotic andcontrol groups, patients with Buerger's disease haveraised plasma levels of heparin-precipitable fibrino-gen, indicating a hypercoagulable state.The chronic lesions of Buerger's disease comprise

organized recanalized thrombi within muscularwalls frequently distorted by fibrosis and ingrowthsof adventitial vessels. As such they represent theend products of vascular injury or occlusion. Thedegree of perivascular fibrosis and of lymphoidinfiltration of the luminal tissue varies throughoutthe obliterated vessel segments. These features are

consistent with a disease process in which focal oI

segmental vasculitis, combined with thrombosis andpossible end-arteritic changes, effect a variablepattern of vascular obliteration quite distinct fromthat of atherosclerosis.

In recent times it has been argued that Buerger'ssyndrome is not a distinct entity. Fisher (1957)studied its cerebrovascular manifestations in fivecases and concluded that they resulted from 'stagna-tion thrombosis' complicating proximal occlusionsof the carotid or midcerebral arteries. By applyingthis hypothesis to lesions of the major limb vesselshe viewed the latter as secondary to obstruction ofthe proximal arterial trunks by atherosclerosis. Goreand Burrows (1958) drew similar conclusions fromtheir review of necropsy and amputation specimens.Ming, Wessler, Gurewich, and Freiman (1959)examined pathological specimens from 26 patientsand concluded that the lesions of Buerger s diseasecould be explained in terms of multiple emboliza-tion, thrombosis, and atheroma. Later studies by thesame group of workers (Wessler, Ming, Gurewich,and Freiman, 1960; Wessler, 1961) reinforced theirconclusions. However, others, including Horwitz(1961), Barker (1962), Ishikawa, Kawase, andMishinia (1962) and particularly McKusick and hiscolleagues (1961, 1962a and b), have rejected thisconcept. The latter group, after extensive studies inJapan and the Orient, failed to demonstrate emboliza-tion, atheroma, or thromboses as the basis ofBuerger's disease which they viewed as a distinct clini-copathological entity. Clinical and angiographic diff-erences between Buerger's disease and arteriosclerosishave also been indicated. McPherson, Juergens, andGifford (1963) found that survival times for patientswith Buerger's disease were comparable to those ofthe normal population, indicating a self-limiting dis-order, whereas arteriosclerosis, on account of itsprogressive nature, killed at least 300% of patientswithin 10 years of diagnosis. Angiographically, in

Buerger's disease, the main arterial trunks proximalto occluded segments have a smooth lining (Steiner,1956) with regular, tapered outlines (Hershey et al,1962) in contrast to the irregular lining and serpi-ginous outlines of arteriosclerotic vessels.

This dichotomy of views regarding the nature ofBuerger's disease may be partly reconciled byaccepting it as an episodic thrombotic disorderwhich produces, possibly on an allergic basis, focalor segmental vasculitis in response to the thrombusor its breakdown products. Thus the acute lesionwould be acceptable as an entity. The variablepatterns of luminal obliteration, chronic inflam-matory infiltration, and vascular distortion whichcharacterize the chronic lesions could logicallyrepresent the long-term residue left by repeatedacute episodes, thrombosis, and end-arteritic change.

I am indebted to Dr J. Davson for reading the manu-script and to Mr N. Mowat and Mr J. T. Stopford forthe photomicrographs.

REFERENCES

Allen, E. V., Barker, N. W., and Hines, E. A. (1962). PeripheralVascular Diseases. 3rd ed. Saunders, Philadelphia.

Barker, N. W. (1962). Circulation, 25, 1.Boyd. A. M., Ratcliffe, A. H., Jepson, R. P., and James, G. N. H.

(1949). J. Bone Jt. Surg., 31-B, 325.(1950). Angiology, 1, 373.

Buerger, L. (1924). The Circulatory Disturbances of the Extremities.Saunders, Philadelphia and London.

Craven, J. L., and Cotton, R. C. (1967). Brit. J. Surg., 54, 862.De Takats, G. (1943). Surg. Gynec. Obstet., 77, 31.Eisen, M. E., Tyson, M. C., Michael, S. R., and Baumann, F. (1951).

Circulation, 3, 271.Fisher, C. M. (1957). Medicine, 36, 169.Gaylis, H. (1957). Angiology, 8, 259.Gery, L., Fontaine, R., and Branzcu, P. (1939). J. int. Chir., 4, 427.Goodman, R. M., Elian, B., Mozes, M., and Deutsch, V. (1965).

Amer. J. Med., 39, 601.Gore, J., and Burrows, S. (1958). Amer. J. cdin. Path., 29, 319.Hagedorn, A. B., and Barker, N. W. (1948). Amer. Heart J., 35, 603.Hershey, F. B., Pareira, M. D., and Ahlvin, R. C. (1962). Circulation,

26, 1261.Horwitz, 0. (1961). Ann. intern. Med., 55, 341.Inada, K., Hayashi, M., and Okatani, T. (1964) Arch. Surg., 88, 454.Ishikawa, K., Kawase, S., and Mishima, Y. (1962). Angiology, 13,

398.Kaiser, G. C., Musser, A. W., and Shumacker, H. B., Jr (1960).

Surgery, 48, 133.Lynn, R. B., and Burt, C. C. (1949). Edinb., med. J., 56, 422.McKusick, V. A., and Harris, W. S. (1961). Bull. Johns Hopk. Hosp.,

109, 241., Ottesen, 0. E., and Goodman, R. M. (1962a). Ibid,

110, 145.Shelley, W. M., and Bloodwell, D. B. (1962b).

J. Amer. med. Ass.. 181, 93.McPherson, J. R., Juergens, J. L., and Gifford, R. W., Jr (1963).

Ann. intern. Med., 59, 288.Ming S. -C., Wessler, S., Gurewich, V., and Freiman, D. G. (1959).

Amer. J. Path., 35, 676.Montorsi, W., and Ghiringhelli, C. (1961). Angiology, 12, 376.Naide, M. (1941). Amer. J. Med. Sci., 202, 822.Poteete, F. H., Jr, and Lynch, R. C. (1956). Surgery, 39, 340.Schatz, 1. J., Fine, G., and Eyler, W. R. (1966). Brit. Heart J., 28, 84.Silbert, S. (1935). Ann. Surg., 101, 324.

(1945). J. Amer. med. Ass., 129, 5.(1948). Amer. Heart. J., 36, 757.

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Szilagyi, D. E., DeRusso, F. J., and Elliott, J. P., Jr (1964). Arch. New. EngI. J. Med, 262, 1149.Surg., 88, 824. - (1961). Circulation, 23, 165.

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