[CANCER RESEARCH (SUPPL.) 44, 4826s-4835s, October 1984] Pathological Effects of Hyperthermia in Normal Tissues1 Luis Felipe Fajardo L-G Department ol Pathology, Stanford University School of Medicine, Stanford, California 94305, and Veterans Administration Medical Center, Palo Alto, California 94304 Abstract alterations, serum enzyme abnormalities, and symptoms of var iable severity have been described (7, 44) [see also article by L. This is a brief review of the major pathological alterations H. Cronau in this issue (11)]. It appears that, by the current produced by hyperthermia in normal tissues of humans and other methods used for TBH, fatalities directly attributed to the hyper mammals. Whole-body hyperthermia, spontaneous or artificially thermia are rare; autospy descriptions are rather difficult to find. induced, can produce severe lesions that have been best de What we know about the pathology of systemic hyperthermia scribed in humans: necropsies, of fatal cases of heatstroke or of comes mostly from observations made in fatal cases of heat individuals treated in the 1940s by hyperpyrexia, have demon stroke (30, 36), or from deaths in patients treated by "hyperpy strated important lesions in the central nervous system, liver, rexia" for conditions other than cancer (23) (see Table 1). These kidney, heart, adrenal, testis, and bone marrow. All cases have 2 situations are somewhat different from current TBH (because shown hemorrhagic diathesis affecting many tissues, and in of the methodology, intensive care, and careful monitoring in some the hemorrhages may have directly contributed to death. TBH), but the pathology of the fatal cases is probably comparable The information on the pathology of localized hyperthermia and, at the present, is the best material available. One of the comes mainly from experimental studies in mammals. Pathology most informative morphological studies was made during the descriptions are available mainly for skin, mesenchymal tissues 1940s in patients subjected to "systemic hyperpyrexia." In their (skeletal muscle and adipose tissue), liver, small intestine, brain, publication, Gore and Isaacson (23) described meticulously the kidney, urinary bladder, prostate, and cartilage. In several of findings in 17 necropsies of individuals who died of TBH induced these tissues, however, the morphological data are incomplete, (by the Kettering cabinet, by i.v. injection of typhoid vaccine, by and very few have sequential observations. Thus, the ultimate hot baths, etc.) in an attempt to treat gonorrhea, nonsuppurative (delayed) result of the acute lesions of focal hyperthermia is arthritis, etc. The temperatures (p.o. or rectal) reached were unknown for most tissues. 40.5-43°, and the duration of hyperthermia was 3 to 11 hr (23). Clearly, more information is needed in order to define the Unfortunately, the total number (the denominator) of patients range of safety for clinical hyperthermia. treated by such a method was not stated, and probably was not available to the authors. Thus, although stated as low (23), one Introduction cannot decide from their paper the incidence of complications or fatalities of that unusual treatment. Unquestionably, hyperthermia has an important role in cancer One other thorough and extensive clinicopathological study therapy today. Also, unquestionably, hyperthermia can affect the was made by Malamud et al. (36) on fatal cases of heatstroke.3 normal tissues adjacent to the treated tumor or, in the case of These pathologists described the findings in 125 necropsies of TBH,2 many normal tissues. Therefore, to apply this modality United States Army personnel who died between 1941 and 1944. judiciously one must know, and weigh, these possible deleterious In their series, the p.o. or rectal temperatures registered at effects. admission to hospitals were 38-44°; in 107 of these patients the In this article I describe the pathological effects of both whole- temperature range was 41.5-44° (36). In 70% of these cases body (systemic), and localized hyperthermia on tissues of several death occurred in less than 24 hr, and in the rest between 1 and mammals, including humans. The scope of this publication does not allow an extensive review of "thermal pathology." Therefore, 12 days from initiation of illness (36). The following is a description of the alterations observed in I limit it to outlines of the morphological findings in selected the most affected organs or tissues (in order of severity), follow tissues. The descriptions of organs and tissues are organized ing spontaneous (30, 36) or induced hyperthermia. not along conventional organ systems but according to the quantity of pathology data available (Tables 1 and 2). Liver Whole-Body Hyperthermia The most severe and consistent injuries observed in the Gore This was the initial form of therapeutic hyperthermia. It was and Isaacson (23) series occurred in the liver: initially there was based on reports of spontaneous cures of tumors following high vacuolization of hepatocytes (8 to 16 hr after the end of therapy); (erysipelas-associated) fever, in the mid-19th century. Clinical then progressive necrosis of cells in the center of the lobules occurred, reaching a maximum ("60% of the central part of the TBH is used nowadays only in carefully controlled trials at a few lobule") by 60 hr. At 7 days necrotic debris was removed by institutions (8, 43). In such clinical trials, fluid loss, hemodynamic macrophages. Regeneration from peripheral hepatocytes, and 1 Presented at the Workshop Conference on Hyperthermia in Cancer Treatment, proliferation of bile ducts was active in those who died late; March 19 to 21, 1984, Tucson, AZ. The experiments described here have been supported by Veterans Administration Research Funds (MRIS 2735-01), and 3 Heatstroke must be distinguished from malignant hyperthermia, a genetically USPHS Grants CA 04542, CA 19386, and CA 34686 of the National Cancer determined myopathy with fever. The latter is often accompanied by metabolic Institute, NIH. acidosis, hyperkalemia, muscle rigidity, etc. This condition may be precipitated by 2 The abbreviations used are: TBH, total-body hyperthermia; TER, thermal anesthesia and, if unrecognized, is often fatal. The pathology of malignant hyper enhancement ratio; LDay,, 50% lethal dose at 7 days. thermia is not within the scope of this article. 4826s CANCER RESEARCH VOL. 44 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1984 American Association for Cancer Research. Pathological Effects of Hyperthermia Table 1 Heart Whole-body hyperthermia Tissues most affected in fatal cases of heatstroke or therapeutic hyperpyrexia8 The most conspicuous lesions in spontaneous (36) or induced Liver Adrenal (23) hyperthermia have been hemorrhages: subepicardial, intra Central nervous system Testis muscular, subendocardial, or even intravalvular. Some hemor Kidney Bone marrow Heart rhages are massive (36), enough to produce ventricular failure. * Hemorrhages in many tissues and cavities. Various degrees of individual myocytolysis and myocyte necrosis have been described, from mild to extensive, but generally focal (23,36). Fragmentation and fatty degeneration of myocytes have fibrosis, however, was not seen in the longest (14 days) survivor. been observed (36). Jaundice (interpreted as a sign of liver failure) was observed in all patients surviving more than 49 hr (23). Similar but less striking liver alterations were described by Adrenal Malamud ef al. (36). Additional information comes from Kew ef Both heatstroke and induced hyperthermia produce adrenal al. (30), who studied 18 liver biopsies and 8 necropsies from 39 lesions, limited to the cortex. Pericortical hemorrhage is common Bantu miners afflicted by heatstroke. The biopsies showed usu (36), but intraparenchymal hemorrhage is rare. Separation of ally mild lesions; 6 of the necropsies revealed structural altera cortical cells (artifactual?) from their basement membrane and tions similar to those described above. Portal inflammatory infil from each other results in a tubular-like arrangement (23, 36). trate and fatty changes were also noted (30). Focal necrosis is variable (23, 36). Gore and Isaacson (23) Pettigrew ef a/. (44) have described alterations of serum liver describe an early coalescence of lipid droplets in the zona function tests in patients subjected to TBH by the paraffin bath method: patients who reached temperatures of 41.8-42.2° fasciculata which results in large irregular vacuoles as early as 3 hr after heat induction. showed elevation of lactic dehydrogenase (2-fold), aspartate Interestingly enough, no alterations of other endocrine organs aminotransferase (25-fold), alanine aminotransferase (8-fold), are described in whole-body hyperthermia. and bilirubin (modest, to 1.56 mg/dl) (44). Higher levels of bilirubin have been reported by Wills ef al. (54), up to 18.5 mg/dl 5 days after treatment of 42°for 8 hr. In vitro studies have indicated 7esf/s that increase in ammonia production by liver tissue (accumulation in the medium) is a sensitive indicator of hyperthermic injury and As expected, the seminiferous tubules are affected, although becomes detectable at 42°(9). only in patients dying after 8 hr of induction of hyperthermia (23). The lesions consist of severe decrease in spermatogenesis, with formation of multinucleated cells in the germinal layers, Central Nervous System which desquamate into the lumen. Later there is loss of germinal cells. Interstitial cells are not affected