SKELETAL MUSCLE NECROSIS ASSOCIATED WITH CARCINOMA

BARBARA SMITH Department of Pathology, St Bartholomew’s Hospital, London

PLATES LXXXII AND LXXXIII

M USCLE weakness and wasting may occur in patients with carcinoma in the absence of metastases. This weakness may be due to anterior horn cell damage with consequent denervation atrophy (Brain, Croft and Wilkinson, 1965) or to lesions in the muscle itself. This muscle lesion has usually been described as polymyositis (Walton and Adams, 1958), myopathy (Henson, Russell and Wilkinson, 1954) or neuromyopathy (Shy and Silverstein, 1965). Two cases are presented here that show a histological picture somewhat different from that usually seen in polymyositis, and it is suggested that they may have a different pathogenesis.

CASE REPORTS

Case I A woman of 54 had a hemicolectomy at another hospital for carcinoma of the hepatic

flexure. Soon after the operation she noticed that her legs were heavy and she had difficulty in raising her right arm above her head to comb her hair. On examination, there was weakness but no wasting of her shoulder girdle muscles, more marked on the right than the left, and some weakness of the hip flexors. There was no pain, no peripheral weakness and no sensory disturbance. An electromyograph (EMG) showed a myopathic pattern. A motor-point biopsy of the right triceps was done at that time. Fluorescent antibody studies with the patient’s serum against her own muscle and rat muscle were negative. She was treated with 12.5 mg prednisolone daily for 4 mth, but her weakness became progressively worse. The steroids were tailed off, but her condition continued to deteriorate and she died elsewhere from carcinomatosis 4 mth later. A necropsy was not performed.

Histology of muscle. Three or four whole muscle bundles were necrotic, the fibres being replaced by empty tubes containing sarcolemmal nuclei and histiocytes (fig. 1). Lying in this mass were a number of fine regenerating fibres with rows of large vesicular nuclei and prominent nucleoli. A number of similar nuclei lying singly, with shreds of blue cytoplasm attached, were free in the tubes. The rest of the muscle contained a number of hyaline eosinophilic fibres and others in a more advanced stage of necrosis with some ‘‘ break-up ” of the fibres and histiocytic invasion. A small number of lymphocytes were scattered through the necrotic areas but not in aggregates. The blood vessels were normal and there was no perivascular inflammation. A methylene blue preparation showed a normal terminal innervation.

Case 2 The patient was a woman of 60 who complained of weakness of both hands, which she

had had for 2 mth. It was initially mainly in her fingers, but had spread to involve her arms. Recently aching pain had developed in the muscles of her arms and in her calves and

Received 23 Oct. 1967; accepted 11 July 1968. 1. PATH.-VOL. 97 (1969) 207

208 BARBARA SMITH

she had noticed a rash on her arms, legs and trunk. On examination there was weakness of both hands and the muscles of her arms were tender. The rash was livido reticularis and in addition she had ulcerating papules on the tips of her fingers. There was a firm mass in her left axilla, her blood pressure was 205/110 mm Hg and her ESR was 6 mni in the 1st hr. The EMG showed myopathic changes. Fluorescent antibody studies using the patient’s serum against rat muscle were negative. The mass in her axilla was removed and a biopsy taken of the left triceps. The mass was an anaplastic carcinoma and was thought to arise from the axillary tail of the breast. Two weeks later a local mastectomy was performed on that side and the specimen showed no residual growth. Following operation the papules and the livido reticularis disappeared and her muscle strength improved. Two and a half years later her muscles are normal clinically and there is no recurrence of her carcinoma. The EMG still shows some myopathic abnormality.

Histology of muscle. There were extensive areas of fibre necrosis with marked regeneration (fig. 2). The appearances were similar to thosein the previous case, but even fewer lymphocytes could be found. A number of muscle fibres with an apparently intact sarcolemma contained nuclei, with portions of sarcoplasm attached, lying within the tube (fig. 3). There was no vasculitis or perivascular inflammation.

DISCUSSION The histological features of the muscle in these two cases are very extensive

fibre necrosis involving whole bundles with a histiocytic response but minimal lymphocytic infiltration. In some places there is evidence of “ break-up ” of fibre contents, each sarcolemmal nucleus being surrounded by a fragment of sarcoplasm. This appears to progress to a total loss of sarcoplasm, the empty tube containing initially sarcolemmal nuclei and later histiocytes as well. There is marked muscle fibre regeneration often proceeding directly in the empty tubes.

Polymyositis is characterised by a perivascular and interstitial inflammation, mainly lymphocytes and plasma cells with muscle fibre necrosis, often of single fibres or small bundles in close relation to the inflammatory exudate. Frequently this appears to be invading the fibres (fig. 4). The question is, are these two patterns the two ends of a spectrum or do they signify two different pathogenetic processes? Many workers think that the condition of polymyositis is a hyper- sensitivity phenomenon allied to the collagen diseases (Garcin, 1955). The histological picture is very similar to that which can occur in polyarteritis nodosa and systemic lupus erythematosus, and it could be that the object of the immune attack is the perimysial collagen rather than the muscle fibre itself.

Of the large number of cases of dermatomyositis and polymyositis that have been reported in association with malignancy, only twelve have been described or illustrated in sufficient detail to assess the histological changes in the muscle (Sheldon, Young and Dyke, 1939; McCombs and MacMahon, 1947; Cottel, 1952; Walton and Adams, 1958; Scherbel et al., 1964). Of these, nine would appear to be similar to those described above. Of the other three, one (Scherbel et al.) was described as having a few small areas of inflammatory cells and two (Walton and Adams, 1958) may, as the authors suggest, have been coincidental. This may not be a true picture of the condition as the rather striking histology of these nine cases may have inspired the writers to give more histological detail. The case described very fully by McCombs and MacMahon showed areas of

SMITH PLATE LXXXII

CARCINOMA AND SKELETAL MUSCLE NECROSIS

FIG. 1 .-Case 1 . Muscle bundle showing almost complete necrosis with small dark regenerating fibres. Most of the nuclei are sarcolemmal or histiocytic in type. There are a few lymphocytes but no aggregations. Haemotoxylin and eosin. x 150.

FIG. 2.-Cuse 2. Similar muscle bundIes showing considerable destruction. An artery close to the necrotic tissue has no perivascular inflainmatory exudate. HE. X 150.

SMITH

CARCINOMA AND SKELETAL MUSCLE NECROSIS

PLATE LXXXIII

FIG. 3.-Cuse 2. Two necrotic segments, in one of which the fibre has broken up and the sarcolernmal nuclei are surrounded by a portion of cytoplasm. HE. x 300.

FIG. 4.-Polymyositis not associated with malignant disease. There is extensive inflammatory exudate between the fibres and it appears to be '" eating its way " into the fibre. HE. x 300.

CARCINOMA AND SKELETAL MUSCLE NECROSIS 209

necrosis, with vacuolation and fragmentation of every fibre and very few in- flammatory cells. This case also showed a vasculitis and case 2 described here had livido reticularis, which is usually considered to be a vasculitis, although not proved histologically in this instance. Sheldon et al. described fragmenta- tion with muscle giant cells and only a secondary inflammatory response. Both Walton and Adams, and Shy and Silverstein (1965) comment on the relative paucity of the inflammation. There seems little doubt that if there are two different types of muscle damage involved in these cases the clinical picture is similar if not identical, but this does not necessarily mean that they are the same disease. Coers (1956) in a discussion of the same problem in cases of polymyositis not associated with malignancy makes the same point. A tissue as specialised as muscle can manifest only a limited number of clinical signs and symptoms. The histological difference between muscle destruction brought about from without by an inflammatory exudate and one resulting from disintegration from within, with an initially intact sarcolemma, appears valid and might imply a different pathogenesis. The latter process seems to be seen in association with malignancy, but also occurs independently of it, as described by Coers. It is also probable that the more usual picture of polymyositis may occur in patients with cancer.

One can only speculate on the cause of the muscle destruction. It could be produced by a substance secreted by the carcinoma or it could be caused by an antibody directed against some constituent of the muscle fibre other than collagen. In the latter case, one might expect a more impressive lymphocyte response. The first case described here did not respond to steroids although some cases have been reported to do so. The improvement in the muscle weakness after removal of the carcinoma in the second case is interesting but inconclusive, since the disease fluctuates normally in the absence of treatment. If there are two pathogenetic mechanisms involved, it is not just of academic interest, since it is possible that the response to steroids, which is rather variable, may depend on the aetiology of the necrosis.

SUMMARY Two cases of extensive skeletal muscle necrosis associated with carcinoma

are described. It is suggested that the histology can be distinguished from the more usual

variety of polymyositis associated with an " immune " inflammatory response. The two types of muscle damage may have a different aetiology and respond differently to treatment.

This work was assisted by a grant from the Muscular Dystrophy Group of Great Britain. I am grateful to Dr J. Aldren Turner and Dr H. Wykeham Balme for access to their case records. The photographs were taken by Mr P. Crocker.

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WILKINSON, MARCIA

210 BARBARA SMITH

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