Br. J. Surg. Vol. 61 (1974) 76-80

Short notes on rare or obscure cases

Postmastectomy lymphangiosarcoma-temporary response to cyclophosphamide chemotherapy in 2 cases D A V I D T O N G A N D J O H N W I N T E R *

SUMMARY Two cases of lymphangiosarcoma developing in oedematous arms following radical mastectomy (Stewart-Treeoes syndrome) are reported. Both patients showed marked symptomatic improvement and tumour regression on cyclophosphamide therapy nlthough remission was only temporary.

LYMPHANGIOSARCOMA is a rare malignant tumour of connective tissue which occurs in the extremities in the presence of chronic lymphoedema. Most commonly it arises in a chronic lymphoedematous arm as a rare complication of radical mastectomy. Since the original description by Stewart and Treeves (1948) the exact incidence has been investigated by Shirger (1962) and Fitzpatrick (1969). Shirger (1962) reported anincidence of 0.45 per cent (4 cases in a series of 894 patients surviving 5 years or more after radical mastectomy), but Fitzpatrick (1969) encountered only 7 cases in over 9000 patients (0.07 per cent) followed up after treatment for early carcinoma of the breast. He reviewed another 76 cases which had been described in the world literature. Reviews of the pathology and treatment have been made by Herrmann and Gruhn ( 1 957), Hope-Stone and Bence (1959), McConnell and Haslam (1959), McSwain and Stephenson (1960), Taswell et al. (19621, Eby et al. (1967), Herrmann and Ariel (19671, Tragus and Wagner (19681, Barnett et al. (1969) and Haagensen (1971).

The prognosis of this condition is usually poor and in most recorded cases the tumour has proved resistant to all forms of treatment and rapidly lethal. Radiotherapy to the involved limb has been widely used with some subsequent regression of the tumour, but there are only 3 recorded cases of long-term survival after such treatment (Rawson and Frank, 1953; Southwick and Slaughter, 1955; Herrmann and Ariel, 1967). Local excision of an early lesion (with or without skin grafting) and forearm amputation have also been recommended, but the prognosis after surgery is equally bad with only isolated cases surviving for more than 3 years (McCarthy and Pack, 1950; Bowers et al., 1955; Taswell et al., 1962; Barnett et al., 1969; Fitzpatrick, 1969). The results of chemotherapy on the established tumour have not been well documented, but they also appear to be discouraging. Fitzpatrick (1969) was unable to detect any response to treatment with nitrogen mustard, Thiotepa or vinblastine sulphate. Eby et a]. (1967)

and Tragus and Wagner (1968) have reviewed the effectiveness of chemotherapy in cases of lymphangio- sarcoma described in the literature. They reported failures or only short-lived improvement with a variety of cytotoxic drugs, including dactinomycin, melphalan, Thiotepa, nitrogen mustard, chlorambuci! or triethylenemelamine. Tragus and Wagner them- selves were unable to show any tumour response to cyclophosphamide, methotrexate or vincristine but induced a temporary remission in 1 case by perfusion with nitrogen mustard (mustine hydrochloride).

Two cases of lymphangiosarcoma occurring in lymphoedematous arms 16 and 10 years after radical mastectomy in which temporary responses to cyclo- phosphamide occurred are described.

Case histories Case 1 : Mrs M. B., aged 65 years, had a left radical mastectomy in October, 1952, for intraduct and infiltrating carcinoma of the breast showing tubular differentiation. After postoperative radiotherapy the left arm became slightly oedematous but did not cause her concern until 15 years later (May, 1968), when there was a transient increase in swelling followed 6 months later by the appearance of skin lesions around the elbow, which were first attributed to mosquito bites. Two months later (February, 1969) raised nodules and blisters covered much of the left arm and extended on to the chest around the mastectomy scar.

The lesions were first treated as recurrent breast carcinoma with a course of stilboestrol which failed to halt their progress to ulceration 1 month later, by which time the arm was very painful and the limb useless. On 17 March the patient was admitted with a grossly oedematous arm infiltrated by haemor- rhagic growth, associated with purple vesicles extending across the chest nearly to the midline (Fig. 1).

In spite of a report of anaplastic carcinoma from a biopsy of the left forearm the clinical diagnosis favoured lymphangio- sarcoma (which was subsequently confirmed by a further biopsy), and since the condition was too far advanced for surgi- cal treatment or radiotherapy, chemotherapy was started. Vinblastine sulphate, 10-mg i.v. injections, was given once weekly for 7 weeks, with transient slight improvement in the skin of the upper arm but with progression of the lesions of the forearm. The lesions became infected with Staphylococcus a u r a s and haemolytic streptococci. The infection was cleared by a course of ampicillin but the patient’s general condition deteriorated. The arm continued to exude large quantities of bloodstained fluid and was the site of considerable pain. A further complication arose: the development of massive left leg oedema, thought to be due to deep venous thrombosis, which was treated by anticoagulant therapy. Associated with the copious serous sanguineous exudate and vinblastine chemo- therapy there was a fall in the total plasma proteins with reversal of the albumin : globulin ratio and moderate anaemia and

~~

* Breast Clinic and Department of Radiotherapy, Guy’s Hospital, London.

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lymphangiosarcoma. No autopsy was performed, but a t no stage during her illness was there any clinical or radiological evidence of recurrent carcinoma or dissemination of lymphangio- sarcoma. Case 2: Mrs H. B., aged 62 years, had a left radical mastectomy in September, 1959, for scirrhous carcinoma of the breast with extensive axillary node metastases. After postoperative radiotherapy she developed lymphoedema of the arm, and after 8 years’ disability sought further surgical advice. The axillary vein was decompressed from a surrounding bed of thick fibrous tissue. However, there was recurrence of lymph- oedema within a few months, followed a year later by the appearance of a subcutaneous lump over the triceps muscle which was excised and histologically was reported as an anaplastic secondary deposit. The site of the lump was treated by a short course of radiotherapy and subsequent treatment with drostanolone propionate. Within a few weeks small bluish nodules appeared in the skin of the left arm and over the sternum (Fig. 7) and progressed rapidly.

The patient was referred to Guy’s Hospital in April, 1970, with considerable discomfort in the arm, which was the site Of massive lymphoedema and induration. The skin was yellow and covered with numerous bluish nodules and haemorrhagic vesicles ranging in size from 0.3 to 3.0 cm in diameter (Fig. 8). There was a similar purple vesicle in the skin over the lower end of the sternum. Culture of the lower arm lesions grew a coagulase-positive Staph. aureus and a haernolytie strepto- coccus which were sensitive to tetracycline. An irregular hard mobile mass appeared in the right breast, two large nodes in the ipsilateral axilla and multiple hard nodes in the supraclavicular fossa and along the border of the sternomastoid.

Fig. 1. case 1 . Ulcerating vesicles and nodules on the upper arm and above the mastectomy scar before cyc~ophospham~de,

Fig. 2. Case 1 . Fungating tumour on the left forearm before starting cyclophosphamide.

leucopenia which was corrected by transfusions of 6 pints of blood.

Her condition continued to deteriorate with fungation and foul-smelling exudate of the whole forearm (Fig. 2) and pain which was only relieved by large doses of opiates.

Two weeks after the end of her course of vinblastine she was given 200 mg cyclophosphamide a day by mouth for 2 months, interrupted briefly on two occasions because of leucopenia. The drug was well tolerated and produced relief of pain after 3 weeks, followed soon after by reduction in the skin lesions with some healing of areas of ulceration in the upper arm and re-epithelization (Figs. 3 , 4). After a month her general condition had improved, she was able to sit up in bed and needed only occasional analgesia. On 27 June the lesions over the chest and left arm had almost disappeared, there was reduction in arm oedema and her general condition had improved enough to allow her out of bed. However, there remained an area of fungation on the left forearm. The condition of the arm deteriorated after two interruptions of cyclophosphamide chemotherapy because of leucopenia (Fig. 5), and localized oedema was accentuated by continuing hypo-albuminaemia (1.8 g/lOO ml), which was not influenced by diuretic drugs.

In spite of further cyclophosphamide chemotherapy she deteriorated rapidly, and large discharging nodules spread over the left forearm (Fig. 6) and became infected with Staph. aureus and later Proteus, neither of which was influenced by ampicillin o r cloxacillin. Cyclophosphamide was stopped (after a total dose of 10.5 g over 68 days) and as a last resort radiotherapy (two doses of 1000 r) was given 1 week and 2 Fig. 4. Case 1 . The left forearm after 40 days’ cyclophosphamide weeks after stopping chemotherapy. The patient died on 19 therapy. There is extensive re-epithelization and marked August, 8 months after the appearance of the lesions of turnour regression.

Fig. 3. Case 1. Appearance after 40 days’ cyclophosphamide therapy. The nodules have disappeared. Note particularly the upper arm and mastectomy scar.

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Fig. 5. Case 1. Tumour of the upper arm 10 days after stopping cyclophosphamide.

Fig. 6. Case 1. The left forearm 10 days after stopping cyclo- phosphamide.

A radiograph of the chest showed pulmonary metastases and a large opacity at the right hilum (Fig. 9) but no apparent skeletal involvement by metastasis. However, the texture of the second and fifth lumbar vertebrae was abnormal and associated with a complaint of severe lumbago, which was controlled only by strong analgesics. The histological appearances of biopsies from both the xiphisternum and the right mammary lesions were of angiosarcoma, and the previous biopsy from the left triceps region was reassessed as lymphangiosarcoma or haemangiosarcoma.

The patient was treated with cyclophosphamide, initially by the intravenous route (200mg a day), to a total of 2.9 g in 2 weeks. There were no side-effects, other than leucopenia with a WBC of 1600/mm3. A week after starting the drug her back pain disappeared and she was able to get up. There was marked reduction of lymphoedema (by 3 cm at the wrist and 4 cm a t the forearm), considerable relief of pain and healing of the skin lesions, some of which disappeared completely (Fig. 10). Three weeks after starting cyclophosphamide there was marked regression of the lung lesions on the radiograph (Fig. l l) , and regression of some of the involved cervical lymph-nodes but persistence of others.

Cyclophosphamide chemotherapy was stopped, but 5 days later the patient had fever associated with severe pain in the left arm and transient increase in swelling which subsided after 2 days’ tetracycline treatment. Cyclophosphamide was started again when the WBC climbed above 4000/mm3 since there was some progression of the angiosarcomatous condition with the appearance of nodules on the left hypothenar eminence and fungation of lesions near the elbow (Fig. 12). There was improvement in the patient’s general condition, but cyclo- phosphamide had to be withdrawn again because of leucopenia. However, she was well enough to be discharged from hospital. At the time of discharge there was an overall improvement in the appearance of the left arm, the residual lymphoedema was slight, the back pain had disappeared and the arm pain was considerably less. She had no respiratory symptoms.

Oral cyclophosphamide maintenance was started again in the second week after discharge when the WBC had returned to normal, but again chemotherapy was followed by pyrexia which resolved after a course of penicillin. A fortnight later improvement was maintained in the appearance of the arm but her general condition had deteriorated.

A chest radiograph in June showed overall improvement although a number of new opacities could be seen in the right upper lobe. The persistent fungating tumour on the arm remained localized. She continued to take cyclophosphamide as an outpatient but again developed pyrexia associated with leucopenia and increase in pain. She was successfully treated with ampicillin as an inpatient but cultures of the lesions and of the blood were negative. At the beginning of July after a further short course ofcyclophosphamide the localized lesion of the left arm was treated by radiotherapy to a total skin dose of 1500 r. Her general condition deteriorated rapidly, the arm became more painful and she developed fever, in spite of antibiotics. However, the local lesions were halted and began to dry up.

Terminally, multiple skin nodules spread rapidly over the trunk, left forearm and hand; there was collapse and consoli- dation of the left lower lobe and right mid-zone associated with left pleural effusion, and the patient became breathless and cyanosed. She died on 11 July 1 week after starting radio- therapy and 12 months after the first appearance of the tumour.

Post-mortem examination revealed a necrotic lesion in the right cerebral hemisphere and metastases in the thoracolumbar spine, in addition to the multiple skin nodules of the left arm and chest wall and lesions in the lung. The pulmonary deposits were small and there was no evidence of the large lung metastases that had been demonstrated in the earlier radio- graphs. Involved right axillary and cervical nodes contained well-differentiated haemangiosarcoma; metastases from the skin and lungs had similar histological appearances. There was evidence of tumour regression at the site of radiotherapy. There was no evidence of residual or recurrent breast cancer.

Fig. 7. Case 2. The oedematous arm before treatment, showing typical vesicles and nodules over the arm and one over the lower sternum.

Fig. 8. Case 2. Ulcerating nodules over the lateral aspect of the left forearm before treatment.

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Both of our cases had very extensive disease when they presented. In Case 1, who had advanced local disease, the major problems were pain, massive sero- sanguineous exudation leading to hypoproteinaemia and anaemia and fungation and local infection which resulted in a long-standing pyrexia and toxaemia.

In Case 2, who had widespread metastases from the lymphangiosarcoma, the dominant problems were again the pain (in the involved arm and from the metastases in the spine) and recurrent bouts of fever. The latter was presumed to be due to secondary infection in the arm in view of the rapid response to antibiotics. Jn this patient exudation from the fungating lesions great enough to cause a fall in the plasma proteins was only present in the later stages of the illness.

Fig. 9. Case 2 . Chest radiograph before cyclophosphamide therapy showing multiple pulmonary metastases one of which is adjacent to the right hilum.

Fig. 10. Caw 2 . Fifteen days after commencing cyclophospha- mide therapy the arrowed lesions have regressed and are flatter compared with those in Fi,?. 8.

Fig. 11. Case 2. Chest radiograph 20 days after commencing cyclophosphamide therapy. The lung opacities have almost disappeared, especially the one adjacent to the right hilum.

Discussion Most authors agree that lymphangiosarconia of the classic Stewart-Treeves syndrome is a highly malignant turnour with a hopeless prognosis. The typical bluish and purple nodules appear insidiously in the skin of a lymphoedeniatous arm about 10-1 5 years (mean 12.5 years) after radical mastectomy (Fitzpatrick, 1969). At this time the patient is apparently cured of the original mammary carcinoma and probably only attends annual follow-up clinics. The clinical and histological diagnosis is often delayed and difficult (Herrmann and Gruhn, 1957; Hope-Stone and Bence, 1959; Fitzpatrick, 1969). Only isolated cases have been apparently cured by radiotherapy Or amputation (Cutler, 1962; Taswell et al., 1962; Herrmann, 'g65; Tragus and Wagner, 1968).

Fig. 12. Case 2. The left forearm after 11 weeks, showing that the lesions have enlarged and become necrotic after temporarily stopping cyclophosphamide for several days.

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The response to cyclophosphamide in both patients was dramatic though temporary. There was both symptomatic improvement and tumour regression in each case. In Case 1 cyclophosphamide was employed at a late stage in the disease when there were con- siderable secondary complications. Other chemo- therapy had failed. Cyclophosphamide was given by mouth because veins were not easily accessible, and in relatively small dosage. In Case 2 cyclophosphamide was given intravenously and the response was more rapid and tumour regression more marked.

In both cases there was prompt reactivation of tumour as soon as cyclophosphamide was stopped because of leucopenia.

The successful use of cyclophosphamide in the treatment of lymphangiosarcoma does not appear to have been previously recorded. Tragus and Wagner (1968) were unable to influence postmastectomy lymphangiosarcoma in 2 patients treated with cyclo- phosphamide orally and intravenously. However, Greenspan (1961) reported cyclophosphamide- induced temporary regression in angiosarcoma which had metastasized to the lungs after failure of a Thiotepa/methotrexate combination. Nielsen (1 967) and Kitchen and Garrett (1971) reported the effective- ness of intralymphatic injection of cyclophosphamide in improving massive lymphoedema of the arm secondary to local spread of carcinoma of the breast.

The cases reported here suggest that lymphangio- sarcoma may be sensitive to cyclophosphamide, and that this cytotoxic agent either alone or in combina- tion with other agents should be considered in patients whose tumours are too advanced for palliative treat- ment with either surgery or radiotherapy. The cases also illustrate the importance of early diagnosis and the need for effective treatment of this appalling condition.

Acknowledgements We are grateful to Mr J. L. Hayward and Mr J . M. McArthur for permission to publish these cases. We are also indebted to Dr Michael Simister of W.B. Pharmaceuticals Ltd for his considerable technical assistance and encouragement in the publication of this article. We acknowledge the help and advice given by the late Professor S. E. de Nevasquez, Dr G. A. K. Missen and Dr A. Stevens in their interpretation of the pathological specimens.

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