pulmonale due to tumour embolism derived from intrasinusoidal … · cancerous emboli, usually with secondary throm-bosis and/orendarteritis. Considerable overlap may be present between

J. clin. Path., 1975, 28, 457-464

Cor pulmonale due to tumour embolism derivedfrom intrasinusoidal metastatic liver carcinomaR. A. BURNETT

From the University of Glasgow, Department of Pathology, Western Infirmary, Glasgow GIl 6NT

SYNOPSIS Two cases of primary breast carcinoma are described, both terminating in acute cardio-respiratory failure due to multiple tumour micro-embolism. In both cases the source of the emboliwas extensive metastatic intrasinusoidal carcinomatous infiltration of the liver. The associationof these two uncommon conditions has not previously been reported. A brief review of the liter-ature pertaining to diffuse intrasinusoidal metastatic carcinoma of the liver and to carcinomatouspulmonary embolism is included. The latter condition may be commoner and of greater clinicalsignificance than has hitherto been appreciated. Some of the factors which may be responsible forthis peculiar type of tumour dissemination are discussed.

Intrasinusoidal metastatic carcinoma of the liveris a relatively rare condition. In 1955, Watsonreviewed the 13 cases then in the literature andadded five of his own. All his cases were of broncho-genic origin. A further review by Smith (1961)expanded the number to 26 and included primarytumours from the following sites-melanocarcinoma(8), breast (7), lung (6), stomach (3), pancreas (1),and uterus (1).

In diffuse intrasinusoidal metastatic carcinomathe liver is enlarged, although the shape and archi-tecture may be well preserved. The tumour cellsdiffusely infiltrate the hepatic sinusoids and areusually present in branches of the hepaticand hepatic portal veins; the liver parenchymamay be destroyed by pressure atrophy. If discretetumour nodules. are present also, the conditionis said to be of 'mixed' type (Watson, 1955). Smith(1961) noted that many of these cases showed asilent and often substantial interval between thetreatment of the primary tumour and the terminalillness as well as an unusually rapid terminal course,these features being particularly prominent incases of malignant melanoma and breast carcinoma.The diagnosis was rarely made before necropsy.

Metastatic tumour in the lungs is exceedinglycommon but the development of cor pulmonaleon such a basis is comparatively rare. In 1961,Durham et al reviewed the 17 cases then reportedand added one of their own. Three main groups

Received for publication 13 December 1974

were delinieated as previously described by Storstein(1951).Type a: lymphangitis carcinomatosa, the pul-monary lymphatic vessels being extensivelyinvaded by tumour with compression of alveoliand capillaries and loss of lung complianceType b: lymphangitis carcinomatosa with com-pression and invasion of small arteries andarterioles producing thrombosis and/or endar-teritisType c: a purely embolic form in which the pul-monary arteriks and arterioles are occluded bycancerous emboli, usually with secondary throm-bosis and/or endarteritis.Considerable overlap may be present between

these three types but essentially two main groups,the lymphatic and the embolic, may be distinguished.Stomach (Morgan, 1949) and breast (Mason,1940) were the commonest primary sites, accountingbetween them for the majority of the reports inthe literature at that time. More recently, othertumours have been implicated, particularly chorion-epithelioma (Bagshawe and Brooks, 1959) andhepatoma (Winterbauer et al, 1968).The embolic group (type c) in its pure form is

the most clear cut entity, not requiring the presenceof previous lung tumour or lymphatic spread andresulting in a dramatic clinical picture becauseof its purely vascular involvement. Of the 18 cases ofDurham et al (1961), eight were purely or pre-dominantly of this type. Winterbauer et al (1968)assembled 35 cases all of the embolic form (type c),

457

on March 10, 2020 by guest. P

rotected by copyright.http://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.28.6.457 on 1 June 1975. Dow

nloaded from

http://jcp.bmj.com/

R. A. Burnett

in each of which the tumour embolism was con-sidered to be the immediate cause of death. Theseincluded stomach, breast, chorionepithelioma, hepa-toma, and one case each with thyroid and parotidprimaries. Unfortunately, these authors also inclu-ded entities of doubtful malignancy in their series,including a case of trophoblastic embolism andseveral of hydatidiform mole.Although fatal cor pulmonale due to tumour

embolism is rare, minor degrees of embolism arenot uncommon. Willis (1952, p. 39) points out that'Frequently in cases with disseminated tumours,microscopical study of apparently unaffected areasof lung discloses pulmonary arterioles occluded bytumour thrombi'. The findings of Winterbaueret al (1968) support this observation and also suggestthat the incidence of clinically significant degrees ofembolism is much greater than has been previouslyappreciated. The consequences of tumour impactionin the pulmonary circulation, namely thrombosisand reactive endarteritis, are described by Saphir(1947), and the entire subject is reviewed in RevistaClinica Espanola (Editorial, 1969).

Case reports

CASE 1The patient presented in September 1972 at the

age of 41 years with a six-week history of a painfullump in the left breast. Her past medical historyincluded negative investigations for thyrotoxicosisin 1969 and a history of infertility; she also sufferedfrom severe congenital kyphoscoliosis. She smoked60 cigarettes per day.The mass was excised three days later and frozen

section confirmed the clinical diagnosis of car-cinoma. Simple mastectomy was performed underthe same anaesthetic, the axilla being left undis-turbed and a course of postoperative radiotherapygiven. Microscopy of the tumour mass showedextensive intraduct carcinoma of comedo typeand infiltrating, moderately differentiated, meta-plastic squamous cell carcinoma (fig 1). Kera-tinization was evident in the tumour, and in a fewareas intercellular bridges could be demonstrated.Extensive lymphatic invasion was evident.The patient remained well for 15 months, until

January 1974 when she was readmitted in extremis.Five days before admission she had experienceddyspnoea of sudden onset. This was at first ratherintermittent but became progressively worse untilshe was severely and continuously breathless at rest.On examination she was pale, slightly jaundiced,and extremely dyspnoeic. The pulse was 120 perminute and regular, and the jugular venous pressurewas markedly raised. There was no clinical evidence

Fig 1 Case 1. The primary breast tumur Haematoxyjl*nand eosin x-60.

Fig 1 Case 1. The primiary breast tumour. Haematoxylin and eosin x 60.

458



j.com/

J Clin P


nloaded from

http://jcp.bmj.com/

Cor pulmonale due to tumour embolism

of metastatic disease. Chest radiography showed nochange from the previous films of 1972. She diedshortly afterwards.

NecropsyThe body was that of a slightly icteric adult female.An old left mastectomy scar was present, andkyphoscoliosis affecting the lumbar and dorsalspine was noted. The heart (230 g) showed right-sided dilatation but no hypertrophy. The leftpleural space was obliterated by dense old adhesions,possibly relating to her radiotherapy. The lungs(right, 600 g; left, 480 g) were congested and showedpatchy areas of collapse. The large pulmonaryarteries were patent throughout. The liver (1430 g)appeared pale and firm. A large proportion of thisorgan was streaked with haemorrhagic areas andappeared necrotic. Numerous small whitish nodulesof secondary tumour were present, particularly in theright lobe. Tumour metastases were present in thelumbar spine and also within mediastinal lymphnodes. There were no other significant findings.

MicroscopyAs well as the tumour nodules noted at necropsy,the liver showed extensive intrasinusoidal infiltrationby anaplastic carcinoma, almost the whole liversubstance being involved (figs 2 and 3). The appear-ances were consistent with a breast carcinoma but,unlike the primary tumour showed little tendencytowards squamous differentiation. In many areasthere was only mild parenchymal damage withintrasinusoidal tumour columns infiltrating throughan intact liver architecture. Elsewhere compressionand atrophy of the liver cords had occurred to thepoint where they could be recognized only aslinear deposits of lipofuscin pigment lying betweenparallel tumour columns, the reticulin frameworkbeing preserved. Little desmoplastic reaction waspresent in these areas of intrasinusoidal tumourbut this became more prominent with the coalescenceof the tumour to form the macroscopically identi-fiable nodules. There was widespread involvementof branches of both the hepatic and hepatic portalveins by tumour plugs, sometimes with associatedthrombus. Invasion of branches of the hepaticartery was not seen. Haemorrhagic areas were alsopresent, particularly in the coalescing intrasinusoidaltumour areas. Inflammatory cell response was notprominent, being restricted to areas of tumournecrosis and to occasional foci of round cells,particularly around vessels.The lungs showed a striking picture of vascular

occlusion by anaplastic tumour. The majority of thesmall pulmonary arteries in both lungs contained

viable tumour emboli, and tumour was also exten-sively present in arterioles, venules, and, lessfrequently, in larger veins. Occasionally singletumour cells or short columns were seen in alveolarcapillaries. Very little thrombosis or reactiveendarteritis was present in the pulmonary vesselsbut accumulations of fibrin were frequently seen,particularly in the arterioles, either related totumour cells or occluding the vessel in the absenceof demonstrable tumour. There was no parenchymalinvasion but occasional lymphatic vessels con-taining tumour plugs were noted. The intravasculartumour plugs showed occasional mitotic figures,and in the larger ones some central necrosis waspresent. The lungs were markedly congested withdilatation of the larger arteries and veins and areasof lung collapse. In addition to the acute changesnoted above there was evidence of chronic pul-monary hypertension, and much dust was alsopresent. These changes may be related respectivelyto the patient's kyphoscoliosis and to her smoking.The metastases in the mediastinal lymph nodes andlumbar spine were confirmed and they consisted ofsimilar anaplastic carcinoma.

CASE 2The patient first presented in April 1972, aged 35years, with discrete lumps in the left breast. Excisionbiopsy was performed and rather unexpectedlyhistology revealed a primary anaplastic breastcarcinoma (fig 4) with evidence of lymphaticinvasion. She was seen again two months laterwhen induration below the scar and a hard, mobilelump in the left axilla were noted. Simple mastect-omy with axillary clearance was performed inAugust 1972, and a course of postoperative radio-therapy was given.The mastectomy specimen contained a 2 cm

diameter tumour nodule close to the nipple andadjacent to a haematoma which had formed deepto the original biopsy scar. Several lymph nodeswere included with axillary fat. Microscopy showedextensive cribriform intraduct carcinoma andscirrhous infiltrating carcinoma, a few areas of whichshowed attempts at adenocarcinomatous differen-tiation. The lymph nodes showed almost completereplacement by similar tumour.The patient remained well until February 1974,

when she returned with two small firm swellingsin the left side of the neck. Excision biopsy wasperformed and frozen section confirmed that theywere lymph nodes which had been replaced byanaplastic tumour. On the basis of the frozensection reports, bilateral oophorectomy was per-formed, and in the abdomen the surgeon noted the

459



j.com/

J Clin P


nloaded from

http://jcp.bmj.com/

R. A. Burnett

*1.-4. .. ., pr w, "- m, z

Fig 2 Case 1. Low-power view of the liver showing intrasinusoidal tumour. Note the extensivevenous invasion. H and E x 24.

*ttt+>w -&*F*78*><gX < 3 S t*.it 4

;mw ~ ~ *.xii.<& } . t . t > <: i tw'

* A+ N4,g.I,: ,

~ ~ ~ j4n't

Fig 3 Case 1. Higher-power view of a similar area to that shown in fig 2 shows diffuseintrasinusoidal tumour. H and E x 60.

460

v

r,

A

.1

i



j.com/

J Clin P


nloaded from

http://jcp.bmj.com/


9.'

__

*^, ~~~~.

Fig 4 Case 2. The primary breast tumour. HandE x 240.

AP

absence of any tumour in either the peritonealcavity or liver. When next seen in April 1974, thepatient was complaining of back pain and radio-graphy showed secondary tumour in the lumbarspine and pelvis. She was treated with palliativespinal radiotherapy followed by a course of cytotoxic

chemotherapy. At that time the liver was thoughtto be enlarged. She was finally admitted in June1974 with a four-day history of increasing dyspnoeaand also anorexia, nausea, and vomiting, which sheattributed to the chemotherapy. On examinationshe was distressed and markedly breathless at rest.

Fig 5 Case 2. Close-up of the grossappearance ofthe liver. The lighterarea corresponds to intrasinusoidalspread withparenchymal atrophy; thedarker area is less heavily involvedand atrophy is minimal. Note thepreservation ofarchitectural markingsin both areas.

A61



j.com/

J Clin P


nloaded from

http://jcp.bmj.com/

R. A. Burnett

v'x;

A~~~~~~~~~~~~~~~~~A

.29~~~~~~~~~~~~~~~4IJ

Fig 6 Case 2. Almost all the arterial vessels in this lung field are occluded by tumour plugs.There is neither thrombosis nor endarteritis. H and E x 23

A degree of jaundice was noted. Examination of thelung fields revealed no abnormality but a degree ofsmooth hepatomegaly was present. A chest radio-graph was entirely normal. She rapidly becamehypotensive and died shortly after admission.

NecropsyThe body was that of an adult female. Old leftmastectomy and transverse suprapubic scars werepresent. The heart (300 g) showed right-sideddilatation but no hypertrophy. The lungs (left,500 g; right, 500 g) were congested but showed noother abnormality. The pulmonary arteries appearedpatent throughout. The liver (2600 g) (fig 5) wasenlarged, pale, and smooth. The right lobe wascompletely replaced by whitish tumour with smallareas of infarction. The left lobe was markedlycongested with accentuation of the lobular patternand contained occasional tumour nodules. Theintrahepatic branches of the portal vein appearedto be thrombosed, and the major hepatic veinswere also occluded. Small nodules of tumour werepresent in the right adrenal gland and in the cortexof the left kidney. Extensive metastatic tumourwas present in the lumbar spine.

HistologyThe right lobe of the liver showed almost completecarcinomatous replacement by intrasinusoidal ana-plastic tumour, the liver parenchyma being des-troyed but the lobular and reticulin architectureremaining. The left lobe showed patchy intra-sinusoidal spread without significant parenchymalatrophy or destruction but with marked vascularinvasion. No desmoplastic reaction was present ineither lobe. Numerous branches of the hepaticportal and hepatic veins contained tumour plugs,sometimes associated with thrombus. Tumour wasnot seen within branches of the hepatic artery.Mitoses were quite frequent but tumour necrosiswas not present and the inflammatory cell responsewas minimal. Cholestasis was marked. The lungsshowed a histological picture of carcinomatousembolism virtually identical with that of case 1(fig 6). These lungs however showed no evidenceof pre-existing disease, and no tumour was presentin the pulmonary lymphatic vessels. A slightlygreater degree of fibroblastic endarteritis waspresent in the pulmonary arterioles than in case 1,although this was still not marked and quite difficultto find. No thrombosis was present. Metastatic

4.

.

462

.,V..



j.com/

J Clin P


nloaded from

http://jcp.bmj.com/


tumour was confirmed in the lumbar spine, rightadrenal, and left kidney, and in these sites theadenocarcinomatous component of the tumour wasmore prominent with areas of mucin production.No desmoplastic reaction was noted in thesemetastases.

Discussion

Metastatic intrasinusoidal liver carcinoma and corpulmonale due to tumour micro-embolism arerare conditions. Primary carcinomata of the stomachand breast are capable of giving rise to both. Theoccurrence together of these two conditions hasnot previously been reported but the associationdoes not seem particularly surprising-especiallywhen associated with a primary from one of theabove sites-because invasion of the hepatic veinsis almost invariable in intrasinusoidal carcinoma ofthe liver (Watson, 1955). Willis (1952, p. 186)states: 'In nearly all cases in which I have observedhepatic venous invasion, numerous pulmonarymetastases also were present. In one such instance,in which the lungs apppeared normal, microscopicalsearch revealed cancerous thrombi in pulmonaryarterioles'. The embolic nature of this phenomenonis well illustrated in the report of Storey and Gold-stein (1962), in which invasion of the main hepaticveins by a malignant hepatoma was followed bymassive tumour embolism to the lungs. Winterbaueret al (1968) present a good case for relating theincidence of tumorous embolism to the degree ofliver involvement by metastatic carcinoma andparticularly to the degree of hepatic venous invasion.

Excluding the melanocarcinomas, all of the 17cases of intrasinusoidal liver carcinoma reported bySmith (1961) were undifferentiated tumours, and thiscorrelates well with the work of Densert andSoderstrom (1965), who reviewed diffuse metastasesfrom primary bronchogenic carcinoma to the liverand spleen in a necropsy series. These workersfound an overall incidence of 2.6% of diffuse liverinvolvement but this occurred only with 'small-celled' types of bronchial carcinoma.

Oertel (1935) described a case (type c) of gastriccarcinoma in which infiltration of the hepaticsinusoids was associated with widespread pluggingof pulmonary and peribronchial arteries, veins,and lymphatics by tumour emboli, but he makesno mention of cor pulmonale.The first specific reports of cor pulmonale caused

by tumour were those of Brill and Robertson(1937) (type b) and Mason (1940) (type c), theprimary sites being in the stomach and breastrespectively. In both these papers the term'subacute

cor pulmonale' was used to delineate this apparentlyspecific clinicopathological entity, and Morgan (1949)also used the term in this way in his review oflymphangitis carcinomatosa. This view was chal-lenged by Durham et al (1961), who argued that thepathogenesis of cor pulmonale due to carcinomatousembolism was in no way different from the morecommon forms of pulmonary embolism. Altemusand Lee (1967) commented that subsequent reportshave emphasized that non-malignant emboli, origi-nating from systemic veins or uterine trophoblasticelements, may initiate an identical clinical picture.Certainly neither of the cases reported here, withterminal illnesses of five and four days respectively,could be included under this heading becauseMason (1940) defined subacute cor pulmonale ashaving a course of between nine days and twomonths.The case reported by Durham et al (1961) was

similar in most respects to the two reported here(type c). Their patient, a 39-year-old woman whohad undergone radical mastectomy and radio-therapy for carcinoma nine months previously,presented with a three-week history of progressivedyspnoea. There was extensive tumour embolismto the smaller pulmonary arterial vessels, some ofwhich also contained thrombus. Others showed afibroblastic intimal proliferation around clumpsof degenerating tumour cells. The liver weighed2000 g, and most of the parenchyma was replacedby irregular greyish to yellowish white tumourtissue with areas of necrosis. Microscopy showedextensive invasion of hepatic veins by tumour.There was no mention of an intrasinusoidal mode ofspread within the liver, although this seems possiblefrom the description.The two cases described in this paper show

remarkable similarities, particularly in the acutenessof the terminal illnesses. Th. histology of the lungs,particularly the absence of thrombosis and thescanty and poorly developed reactive endarteritis,correlates well with the duration of dyspnoea. Inmost of the cases previously described these latterchanges were more prominent because the patientssurvived for much longer. The absence of rightventricular hypertrophy also supports the conceptof a shower of emboli occurring over a few days,rather than a gradual process which would haveresulted in chronic pulmonary hypertension. Adegree of pulmonary hypertension was present inthe first case, being almost certainly related to thekyphoscoliosis (Bergofsky et al, 1959) and not to thetumour embolism, but there was no evidence ofprevious episodes of cardiac decompensation.The paucity of clinical signs in the chest and the

463



j.com/

J Clin P


nloaded from

http://jcp.bmj.com/

R. A. Burnett

absence of radiological changes in both cases arein accord with the findings of previous workers intype (c) cases (Altemus and Lee, 1967; Winterbaueret al, 1968).

Neither of these cases showed the epigastricpain and abdominal swelling which Watson (1955)described as being frequently seen in intrasinusoidalliver carcinoma, but both were jaundiced, this beingmore common than with the nodular forms ofmetastatic liver tumour. Clinically, in both cases,the cause of the terminal cardiorespiratory failurewas completely obscure, and in the first case necropsydid not elucidate the problem as the gross appear-ances were misinterpreted. Oertel (1935) alsofailed to diagnose intrasinusoidal hepatic tumouron the gross appearances in his case, and Watson(1955) comments on the problem. The case ofintrasinusoidal carcinoma reported by Craciumet al (1931), where the primary was a scirrhousbreast tumour, is of interest. Apparently the diffuselyinfiltrating tumour cells in the liver had retainedtheir capability to stimulate a desmoplastic reaction,and the gross appearance of the liver was indis-tinguishable from that of diffuse hepatic fibrosis.Micolonghi et al (1958) reported a similar case,and again the necropsy diagnosis was 'cirrhosis',the presence of tumour being found only on micro-scopical examination. That the cirrhotic appearanceofthe liver was due to the tumour and had not precededit was excluded by these authors on morphologicalgrounds. Lieber (1957) pointed out that tumourmetastasis to a cirrhotic liver is unusual, and in hisseries of 24 329 cancer deaths it occurred in only0.12%o of cirrhotic livers, compared to 28.6% ofnon-cirrhotic organs. A cirrhotic appearance wasseen in neither of the present cases. In case 2 thepresence of diffuse hepatic tumour was appreciatedat necropsy and the invasion of the hepatic veinswas correctly interpreted. It was then possible topredict with some confidence the histologicalappearance of the lungs, in view of the clinicalhistory and in the absence of any naked-eye changes.Four months previously, during the oophorectomyoperation, this liver had been visualized by thesurgeon and was considered to be free of tumour.It is worth mentioning that in the absence ofspecific contraindications the diffuse nature ofintrasinusoidal metastatic carcinoma makes this

condition highly susceptible to diagnosis by needlebiopsy of the liver.

References

Altemus, L. R. and Lee, R. E. (1967). Carcinomatosis of thelung with pulmonary hypertension. Arch. intern. Med.,119, 32-38.

Bagshawe, K. D. and Brooks, W. D. W. (1959). Subacutepulmonary hypertension due to chorionepithelioma.Lancet, 1, 653-658.

Bergofsky, E. H., Turino, G. M., and Fishman, A. P. (1959).Cardiorespiratory failure in kyphoscoliosis. Medicine(Baltimore), 38, 263-317.

Brill, I. C. and Robertson, T. D. (1937). Subacute corpulmonale. Arch. intern. Med., 60, 1043-1057.

Cracium, E.C., Asian, A., and Caffe, L. (1931). Cirrhoseatrophique neoplasique secondaire. (Quoted by Smith,1961). Ann Anat. path., 8, 1089-1112.

Densert, 0. and Soderstrom, J. (1965). Diffuse metastasesin bronchial cancer. Acta path. microbiol. scand., 64,477-484.

Durham, J. R., Ashley, P. F., and Dorencamp, D. (1961).Cor pulmonale due to tumor emboli. J. Amer. med. As.s.,175, 757-760.

Editorial 1969. Tumoral pulmonary embolism. Rev. clin.Esp., 113, 540-541.

Lieber, M. M. (1957). The rare occurrence of metastaticcarcinoma in the cirrhotic liver. Amer. J. med. Sci., 233,145-152.

Mason, D. G. (1940). Subacute cor pulmonale. Arch.intern. Med., 66, 1221-1229.

Micolonghi, T., Pineda, E., and Stanley, M. M. (1958).Metastatic carcinomatous cirrhosis of the liver: report of acase in which death followed hemorrhage from esophagealvarices and hepatic coma. Arch. Path., 65, 56-62.

Morgan, A. D. (1949). The pathology of subacute cor pul-monale in diffuse carcinomatosis of the lungs. J. Path.Bact., 61, 75-84.

Oertel, H. (1935). On a peculiar vascular transportation andgeneralization of carcinoma without local metastases.J. Path. Bact., 40, 323-334.

Saphir, 0. (1947). The fate of carcinoma emboli in the lungs.Amer. J. Path., 23, 245-253.

Smith, J. C. (1961). Diffuse intrasinusoidal metastaticcancer of the liver. Ann. intern. Med., 54, 104-113.

Storey, P. B. and Goldstein, W. (1962). Pulmonary embo-lization from primary hepatic carcinoma. Arch. intern.Med., 110, 262-269.

Storstein, 0. (1951). Circulatory failure in metastaticcarcinoma of the lung: a physiologic and pathologicstudy of its pathogenesis. Circulation, 4, 913-919.

Watson, A. J. (1955). Diffuse intra-sinusoidal metastaticcarcinoma of the liver. J. Path. Bact., 69, 207-217.

Willis, R. A. (1952). The Spread of Tumours in the HumanBody. 2nd edition. Butterworth, London.

Winterbauer, R. H., Elfenbein, I. P., and Ball, W. C. Jr.(1968). Incidence and clinical significance of tumorembolisation to the lungs. Amer. J. Med., 45, 271-290.

464



j.com/

J Clin P


nloaded from

http://jcp.bmj.com/

Documents

pulmonale due to tumour embolism derived from intrasinusoidal … · cancerous emboli, usually with secondary throm-bosis and/orendarteritis. Considerable overlap may be present between