CHANGES IN SKELETAL MUSCLE ASSOCIATED WITH CACHEXIA OSCAR S. M. MARIN, M.D.,* AND D. DENNY.BROWN, M.D. From the Neurological Unit, Boston City Hospital, and the Department of Neurology, Harvard Medical School, Boston, Mass. The atrophy and friability of skeletal muscles in states of cachexia are well known. The classic descriptions of diseases of muscle not only mention the progressive atrophy of muscle, but also note fatty granular changes in many of the muscle fibers."2 Deposits of lipochrome have also been noted, but their greater prominence in older patients has led them to be regarded as a senile alteration.3 4 Increasing awareness of states of "polymyositis" in relation to carcinomatosis in recent years,5'6 and the intriguing problem as to the relationship of simple reversible atrophy and the degeneration of muscle fibers in these states has led us to investigate this problem. We have examined the skeletal muscles in a series of i8 consecutive necropsy cases where cachexia was a prom- inent feature. In most such material simple atrophy was the prominent finding, but in 3 cases degenerative changes were generalized and severe, and these are the subject of this report. METHODS Samples of many muscles, usually including sternocleidomastoid, diaphragm, deltoid, psoas, abdominal wall, quadriceps, adductor of thigh and gastrocnemius, were taken at necropsy and fixed in Zenker's solution. Pieces of muscular nerve were also obtained. After paraffin embedding, these tissues were sectioned and stained with hematoxylin and eosin, phosphotungstic acid hematoxylin (PTAH), or eosin- methylene blue. When degenerative changes were present, periodic acid-Schiff (PAS), Feulgen, Turnbull, and von Kossa reactions were done on the relevant material, and frozen sections were stained for fat by oil red 0. Tables I and II summarize the relevant data, including the nature of the verified cause of cachexia, and the chief histologic features in the skeletal muscles. Any muscular change related to denerva- tion or to direct invasion by carcinoma or other pathologic alteration are excluded. The first 4 cases are reported in detail below. Since it was necessary to relate the degenerative changes to those of nutritional atrophy, we made counts of fiber area in ioo fibers in representative transverse sec- tions in each of the 4 most remarkable cases, and in 2 control cases-a normal 35-year-old man without nutritional impairment, killed by subarachnoid hemorrhage, and a woman of 78 years who died of acute cerebral hemorrhage without nutritional disorder. The estimations of area were made by planimeter on an enlargement of Accepted for publication, February 6, I962. *Research Fellow in Neurology, Harvard Medical School; Senior Trainee, National Institute of Neurological Diseases and Blindness, National Institutes of Health, United States Public Health Service. Present address: Department of Medicine (Neurology), Catholic University School of Medicine, Santiago, Chile. 23 24 MARIN AND DENNY-BROWN Vol. 4z, No. I C.) co .g Cu Cua I + + + I I I I + I I I 400 + S X Eo + u : + co +) E) 100 cqU) v 14 ae 4) CU I + + + + + + I I + + ' 0Cr I +I .0 co toq + + + I++I I 0Cu r0£ + + UO£4 4) + CU >z. Cu 4)0 toS. C) cis .4) + + U) -4 +) < +4 . 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U P~~ 'IQU O ~, CU O Cl C) if) 0 4"- 00 0' 0 l C , H 4 * July, Z962 SKELETAL MUSCLE IN CACHEXIA 25 0 0 .4) ;3 r. o oo Q S .0 + + + + Uco4 Le + + + + -U S0 0 -000oL) bO 545o 0 cd 0 ul0 Ca 0o 0en 0~ I I~~~~~~~~~~~~~~~~~~~~~~~ 64 4) bo Oo 0 140 0 00 00"0 ._0 .60 I 4) 54. :: + + + + .0 + 0 0 .0 td 4 1. od 0 n o 0 0 0 .0 0 0 F N- N N .0 C o48 o0 co 080 4) to o 0%00 ao :0. 00 00 00 ax 0go fI ea r CaLd C' a *Uco U m ._I N o~~~1 14 164 26 MARIN AND DENNY-BROWN Vol. 4I, No. z transverse sections. Since we shall be chiefly concerned with the smallest fibers, the distribution of fiber size in these 6 cases was plotted in semi-logarithmic paper (Text- figs. i and 2). REPORTS OF CASES The general observations in all cases examined are set out in Table I. Degeneration of muscular or intramuscular nerve bundles was not pres- (0 m- ILL o 0 z 4 6 8 1 2 4 6 8 1 2 4 6 8 10 100 AREA OF CROSS SECTION IN TEXT-FIGURE I. Frequency curves of muscle fiber size in a normal man aged 35 years, a woman aged 78 without cachexia, and case i, on semilogarithmic scale, to show the shift to smaller fiber size. ent in any of the material reported. Mild arteriosclerotic vascular lesions were present in cases i, 2, 6, 8, 9, I3, 14, I5 and i6. The atrophic and degenerative lesions were generalized in all muscles examined in every instance except case I5, where the alterations were more pronounced in distal muscles. The 4 cases, I3 to i6 (Table II), were controls for age without cachexia, and all presented a mild atrophy with slight increase in the number of sarcolemmal nuclei per low power field, but without degenerative change in muscle fibers. A plot of the fiber area scatter in cross section from case I 5, a woman 78 years of age who died of a cere- July, Z962 SKELETAL MUSCLE IN CACHEXIA 27 bral hemorrhage, is compared in Text-figure i with that of a normal man aged 35 years. Whereas the normal adult muscle shows the great majority of fibers between 200 and 700 square t,f with few fibers ranging down to 40 to ioo square jp (Fig. iA), senile muscle exhibits a large peak at 50 square ,. and a few fibers up to i00 square , (Fig. iB). Simple atrophy of this type presents a shift of frequency from large fiber size 50 40 Cn 30 I- 0 20 z 10 4 6 8 1 2 4 681 2 4 6 8 10 100 AREA OF CROSS SECTION IN p t TEX-FIGURE 2. Frequency curves of muscle fiber size in cases 2, 3 and 4, to be com- pared with Text-figure i. to smaller, without other significant change. In the presence of cachexia, additional changes were found; these will be described in relation to 4 cases typifying different degrees of further alteration. Case I W.M., 63 years of age, had suffered from a squamous cell carcinoma in the middle third of the esophagus, which had caused progressive dysphagia for 8 months. At necropsy the tumor was found to have caused a tracheo-esophageal fistula. There were metastases to the right lung and to both kidneys. There was extreme emaciation and cachexia, with a weight-height ratio of 0.62 (Table I). 28 8MARIN AND DENNY-BROWN Vol. 4z, No. z The microscopic appearance was the same in all muscles examined. A typical low power view, Figure IC, presented a remarkable mixture of fibers of two predominant types. The plot of fiber size frequency (Text-fig. I) showed wide separation of the groups with one distinct peak at ioo square ,1, and another at 20 square ,&. The smaller fibers stood out by reason of their dark staining with all stains used and their prismatic shape in cross section (Fig. 2). Yet in longitudinal section these small fibers exhibited normal myofibrils and general architecture (Fig. 2 B). Their muscle nuclei were of normal appearance, and the ap- parent increase in number could be accounted for by the reduction in fiber size. The myofibrils were of natural appearance, though so closely packed that it was not possible to count them in cross section. Under oil immersion, groups of 6 or more myofibrils commonly appeared to be fused into one dark mass in which the exact number of components was uncertain. The appearance could be accounted for by the almost total disappearance of sarcoplasm. An early granular change was found in the myofibrils of only one or two of these small muscle fibers out of many hundreds examined. There was no evidence of fragmentation of muscle fibers or of the clumping of nuclei or nuclear remnants found in degen- eration of muscle. No abnormality was detected in the endomysium. Case 2 P.F., a 77-year-old man who had been a stonecutter for over 30 years, was admitted to the hospital because of cough and dyspnea on exertion. Repeated sputum and gastric cultures were negative for tubercle bacilli. Pulmonary silicosis was diagnosed. In spite of various treatments, his general health deteriorated in the last 6 months of life. Necropsy examination, restricted to the chest, revealed extremely severe cachexia, severe pulmonary silicosis with bronchiectasis and emphysema, and ter- minal acute bronchitis.