- Email: [email protected]
AIDS autopsies: Has the risk been established?
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logic, a n d clinical studies that d e m o n s t r a t e d its specificity. T h e y can be s u m m a r i z e d as follows: (1) I n t h e i r original d e s c r i p t i o n o f this m o n o c l o n a l antibody, H o r a n H a n d et al 2 d e m o n s t r a t e d that RAP-5 specifically r e a c t e d with ras p21 in i m m u n o b l o t as well as solid phase r a d i o i m m u n o a s s a y (RIA) e x p e r i m e n t s . (2) Similar quantitative a n d qualitative i m m u n o h i s t o chemical staining p a t t e r n s h a v e b e e n d e m o n s t r a t e d w h e n RAP-5 was c o m p a r e d with a n o t h e r p21 specific a n t i b o d y (Y13-259) in the study o f n u m e r o u s cancers a n d n o r m a l tissues. 3-~ R A P - 5 staining also correlates with solid p h a s e R I A u s i n g Y13-259 antibody. 5 (3) T h e intensity o f i m m u n o h i s t o c h e m i c a l staining by RAP-5 was s h o w n to c o r r e l a t e with steady-state ras-specific R N A levels d e t e c t e d by in situ hybridization. 5 (4) Finally, indirect e v i d e n c e o f the specificity o f RAP-5 is p r o v i d e d by studies assessing the p r o g n o s t i c significance o f p21 in p r i m a r y breast cancers. D i f f e r e n t studies u s i n g i m m u n o h i s t o c h e m i s t r y with b o t h R A P - 5 a n d Y13-259, 6 RAP-5 alone, 7 o r i m m u n o b l o t assays with Y13-259 s c a m e to similar conclusions a n d d e m o n s t r a t e d the usefulness o f tum o r p21 levels. Because o f the h e a t lability o f the p21 protein, a req u i r e m e n t f o r s t a n d a r d i z e d fixation t e c h n i q u e in such studies, a n d the necessity to use e n d p o i n t titration assays in studies o f this type, in which b e n i g n a n d m a l i g n a n t tissues are b e i n g c o m p a r e d , it is n o t s u r p r i s i n g that conflicting d a t a may arise.
CORRESPONDENCE p21 Expression in the Progression of Breast Cancer ras
To the E d i t o r : - - T h e m o n o c l o n a l a n t i b o d y RAP-5 was u s e d by F r o m o w i t z et al t to investigate ras p21 e x p r e s s i o n in breast cancer, as r e p o r t e d in the D e c e m b e r 1987 issue o f the Journal. T h e r e is r e a s o n to suspect that this r e a g e n t m a y n o t be suitable for such a study. It is clear that RAP-5 shows i n t e r e s t i n g staining p a t t e r n s on i m m u n o h i s t o c h e m i s t r y , but a l t h o u g h these m a y h a v e biological significance, we wish to p o i n t o u t that t h e r e is serious d o u b t as to t h e i r relationship with e x p r e s s i o n o f ras genes. RAP-5 was p r o d u c e d by i m m u n i z a t i o n o f a m o u s e with a synthetic o c t a p e p t i d e c o n t a i n i n g the 10-17 a m i n o acid s e q u e n c e o f the m u t a t e d Ha-ras o n c o p r o t e i n p21, c o u p l e d to t h y r o g l o b u l i n . 2 T h e h y b r i d o m a was selected o n the basis o f a p p a r e n t l y h i g h d i f f e r e n t i a l reactivity for the m u t a t e d p e p t i d e s e q u e n c e c o m p a r e d with the n o n m u t a t e d h o m o logue. It has b e e n a s s u m e d by the originators o f the antib o d y a n d o t h e r s that cross-reactivity occurs with the n o n m u t a t e d p21, as RAP-5 reacts with e p i t o p e s in n o r m a l tissues a n d t u m o r s in w h i c h a c t i v a t e d ras w o u l d n o t be e x p e c t e d . T h i s a n o m a l y has not b e e n a d e q u a t e l y e x p l a i n e d . I m p o r t a n t claims w e r e m a d e for RAP-5; notably, its p u t a t i v e ability to b i n d p r e f e r e n t i a l l y to e p i t o p e s e x p r e s s e d in infiltrative areas o f tumors. W e p u b l i s h e d an e v a l u a t i o n o f R A P - 5 ~ in which we d e m o n s t r a t e d that the a n t i b o d y was u n a b l e to distinguish o n i m m u n o h i s t o c h e m i s t r y b e t w e e n a n o n - r a s - e x p r e s s i n g e m b r y o n i c fibroblast cell line a n d a derivative line genetically m a n i p u l a t e d to express the m u t a t e d T 2 4 Ha-ras o n c o g e n e at h i g h levels. W e were u n a b l e to c o n f i r m reactivity o f RAP-5 with p21 on i m m u n o b l o t s . I n contrast, the rat m o n o c l o n a l antibody YI3-2594 to ras p 2 i clearly distinguishes b e t w e e n these cell lines a n d identifies a single 21kDa b a n d o n i m m u n o b l o t s o f p r o t e i n extracts o f ras-expressing cells. W e are s u r p r i s e d that F r o m o w i t z et al chose to i g n o r e this i n f o r m a t i o n w i t h o u t c o m m e n t , as it has f u n d a m e n t a l implications for t h e i r w o r k a n d to that o f o t h e r s c o n t i n u i n g to use RAP-5 for i m m u n o h i s t o c h e m i c a l d e t e c t i o n o f the ras p21 p r o d u c t .
JOEL LUNDY, M D MICHAEL VIOLA, M D FRANK FROMOWlTZ, MD State U n i v e r s i t y o f N e w Y o r k at Stony B r o o k Stony B r o o k , N Y
ALISTAIR R. W. WILLIAMS, MRCPATH JUAN PIRIS, DPHIL, MRCPATH ANDREW H. WYLLIE, PHD, FRCPATH University Medical School E d i n b u r g h , Scotland 1. Fromowitz FB, Viola MV, Chao S, et al: ras p21 expression in the progression of breast cancer. HuM PATHOL18:1268, 1987 2. Horan Hand P, Thor A, Wunderlich D, et al: Monoclonal antibodies of predefined specificity detect activated ras gene expression in human mammary and colon carcinomas. Proc Natl Acad Sci USA 81:5227, 1984 3. Robinson A, Williams ARW, Piris J, et al: Evaluation of a monoclonal antibody to ras peptide, RAP-5, claimed to bind preferentially to cells of infiltrating carcinomas. Br J Cancer 54:877, 1986 4. Furth ME, Davis LJ, Fleurdelys B, et at: Monoclonal antibodies to the p21 products of the transforming gene of Harvey nmrine sarcoma virus and of the cellular ras gene family. J Viro143:294, 1982 T h e above letter was r e f e r r e d to the a u t h o r s o f the article in question, w h o o f f e r the following reply: To the E d i t o r : - - W e w e r e n e g l i g e n t in not r e f e r r i n g to the r e p o r t o f Williams a n d colleagues, which q u e s t i o n s w h e t h e r t h e r e a c t i v e a n t i g e n to R A P - 5 is t h e ras p21 p r o t e i n . 1 W e chose to use RAP-5 in the study o f invasive breast c a n c e r based on a n u m b e r o f biochemical, i m m u n o -
1. Robinson A, Williams ARW, Piris J, et al: Evaluation ofa monoclonal antibody to a ras peptide, RAP-5, claimed to bind preferentially to cells of infiltrating carcinomas. Br J Cancer 54:877, 1986 2. Horan Hand P, Thor A, Wunderlich D, et ah Monoclonal antibodies of predefined specificity detect activated ras gene expression in human and mammary colon carcinomas. Proc Natl Acad Sci USA 81:5227, 1986 3. Ohuchi N, Thor A, Page DL, et al: Expression of the 21,000 molecular weight ras protein in a spectrum of benign and malignant mammary tumors. Cancer Res 46:2511, 1986 4. Thor A, Ohuchi N, Horan Hand P, et al: ras gene alterations and enhanced levels of ras p21 expression in a spectrum of benign and malignant human mammary tissues. Lab Invest 55:603, 1986 5. Ohuchi N, Horan Hand P, Merto G, et al: Enhanced expression of c-Ha-ras p21 in human stomach adenocarcinomas defined by immunoassays using monoclonal antibodies and in situ hybridization. Cancer Res 47:1413, 1987 6. Querzoli P, Marchetti E, Baghi A, et al: Expression of p21 ras gene products in breast cancer relates to histological types, receptorial and nodal status. Breast Cancer Res Treat (in press) 7. Lundy J, Mishricky Y, Chao S, et al: Elevated ras oncogene expression correlates with lymph node metastases in human breast cancer. J Clin Oncol 4:1321, 1986 8. Clair T, Miller WR, Cho-Chung YS: Prognostic significance of the expression of a ras protein with a molecular weight of 21,000 by human breast cancer. Cancer Res 47:5290, 1987 AIDS Autopsies: Has t h e Risk B e e n Established? To the Editor:--HUMAN PATHOLOGY has d r a w n o u r attention to t h e quite serious p r o b l e m o f the d e c l i n i n g n u m b e r o f autopsies p e r f o r m e d in the U n i t e d States a n d o t h e r countries.t-3 T h i s is quite a w o r r i s o m e t r e n d since autopsy d a t a are necessary for the a d v a n c e m e n t o f t h e medical sciences, the d e v e l o p m e n t o f public h e a l t h m e a s u r e s , a n d the i m p r o v e m e n t o f patient care. 2,~ H o w e v e r , despite the technical safety p r o c e d u r e s issued by d i f f e r e n t sources, 4-7 m o s t pathologists face difficulties in p e r f o r m i n g autopsies o n A I D S cases, It is i m p o r t a n t to p o i n t o u t t h a t safety is an
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HUMAN PATHOLOGY
Volume 19, No. 9 [September 1988]
issue not only relevant to the team p e r f o r m i n g the autopsy, but also has direct implications r e g a r d i n g the protection o f the whole environment. This is particularly true in community-based hospitals all over the world. For instance, how m a n y o f these hospitals pay sufficient attention to the issue o f not using r u n n i n g water d u r i n g the autopsy o f an AIDS case or o f decontaminating the water used d u r i n g such a p r o c e d u r e before it enters the sewage system4-6? As a pathologist who has worked in Brazil, the United States, and J a p a n , I can attest to the fact that not all pathologic services have suitable facilities for p e r f o r m i n g autopsies o f patients who die from a highly infectious disease, like AIDS. A l t h o u g h there is no question of the scientific merit o f such a p r o c e d u r e , we can easily raise ethical questions about the m e a n i n g o f an act for which the risk/benefit ratio is not absolutely clear at the moment. Some services are finding themselves in the paradoxic situation o f trying to increase the n u m b e r o f autopsies p e r f o r m e d on the one hand, but, on the other hand, they are unofficially refusing to do autopsies o f those cases that may fall into the "high risk" category. This question has led to conflict between pathologists, their clinical colleagues, and hospital and gove r n m e n t officers. Declining to p e r f o r m an autopsy is probably also a matter o f Hippocratic ethics and, as such, the medical c o m m u n i t y should face this issue as soon a n d as clearly as possible. A feasible solution would be to authorize only those hospital centers currently providing AIDS treatm e n t to p e r f o r m AIDS autopsies, provided their autopsy r o o m s ( a n d this is a very h i g h p r i o r i t y ) a r e suitably equipped. O f course, all the above considerations are personal and not necessarily shared by my c u r r e n t host institution. j . L. V. DE CAMARGO, MD, PHD Nagoya City University Medical School Japan 1. Wagner BM: Mortality statisticswithout autopsies: Wonderland revisited. HuM PAWIqOL18:875, 1987 (editorial) 2. Anderson RE: Autopsy-related initiativesin the United States: Current status and suggestions for the future. HuM PATHOL18:977, 1987 3. StevanovicG, Tucakovic G, Dotlic R, et al: Correlation of clinical diagnosis with autopsy findings: A retrospective study of 2,145 consecutive autopsies. HUMPATHOL17:1225, 1986 4. Orenstein JM: Guidelines for high risk or potentially high risk autopsy cases. Pathologist 38:33, 1984 5. Centers for Disease Control: Acquired immunodeficiencysyndrome (AIDS): Precautious for clinicaland laboratory staffs. MMWR31:577, 1982 6. Reichert CM, O'Leary TJ, LevensDL, et al: Autopsypathologyin the acquired immunodeficiencysyndrome. Am J Pathol 112:357, 1983 7. Brynes RK, Ewing EP Jr: Is the autopsy of AIDS patients a safe procedure in the community hospital setting? Pathologist39:32, 1985
Response To the Editor:--Dr de Camargo's letter raises again one o f the i m p o r t a n t problems facing Pathology and Medicine, which we have taken the liberty of rephrasing: Is it acceptable to not p e r f o r m autopsies on patients dying from AIDS? T h e answer requires addressing at least three related, but distinct, issues: (1) W h a t is the risk to the pathologist and s u p p o r t staff if an autopsy is p e r f o r m e d on an AIDS patient? Autopsies were p e r f o r m e d on AIDS patients for years in New York, San Francisco, and Los Angeles, before the pathogenesis of the d i s o r d e r was understood. I n d e e d , GRID ("gay-related i m m u n e deficiency"), as AIDS was known before transmissibility to non-male homosexuals became recognized, was at one time t h o u g h t to be a toxin-induced disease possibly caused by aphrodisiac inhalants r a t h e r than an infective
agent. Pathologists, autopsy assistants, f u n e r a l directors, and others involved with tissues from these patients took no special precautions. Since there are no known cases o f AIDS in pathologists o t h e r than in those who belong to recognized high-risk groups, 1 we can suspect that infectivity is not high at the time o f autopsy. I n d e e d , neither pathologists n o r autopsy technicians are listed a m o n g those health care workers who have d e m o n s t r a t e d seropositivity.2 Alt h o u g h a definitive study o f infectivity has not yet been p e r f o r m e d on bodies o f AIDS patients, u n p u b l i s h e d data o f a few such cases suggests that the virus is p r e s e n t in very low concentrations by the time someone dies f r o m AIDS, if it is present at all? T h e greatest c o n c e r n remains the u n d i a g n o s e d patient. I n one o n g o i n g study at a busy medical examiner's office, as many as 85% o f those bodies whose sera was shown to have antibodies to the h u m a n immunodeficiency virus ( H I V ) h a d not b e e n clinically s u s p e c t e d to have AIDS. 4 In summary, there is no evidence that there is great risk in p e r f o r m i n g autopsies on patients dying from AIDS. Hepatitis continues to be the most significant infectious risk to the pathologist, and practice patterns that protect against hepatitis will be effective against AIDS. 5 A n a p p r o a c h to the autopsy that regards every patient as potentially infectious is certainly r e c o m m e n d e d , since t h e r e could be risk in perf o r m i n g autopsies on patients who have H I V viremia which is not recognized either because they have not yet develo p e d antibody or because there were no clinical indications for H I V antibody testing. (2) Can an autopsy be p e r f o r m e d safely on an AIDS patient in the average hospital without risk to the community? W h a t should be d o n e with the body fluids and tissues? T h e r e is absolutely no evidence that hospital waste has caused disease in the community because o f usual disposal methods. 2 It is entirely reasonable, however, to identify wastes with the potential for causing infection and develop methods o f handling t h e m that are practical a n d effective. In general, infectious waste should be incinerated or autoclaved before disposal in a sanitary landfill. 2,6 Fluids, including blood, may be p o u r e d down a d r a i n connected to a sanitary sewer if allowed by local health codes. 2,6 H I V has been shown to be effectively inactivated by a variety of comm o n disinfectants at concentrations usually below those usually used for laboratory disinfection. 7,8 A f t e r use, all laboratory surfaces, including those in the autopsy facility, should be d e c o n t a m i n a t e d with an a p p r o p r i a t e chemical germicide after a spill o f blood or bloody fluids and when all work is completed. 2 T h e most i m p o r t a n t factor in insuring the well-being o f the pathologist a n d coworkers remains the pathologist! Sensible a n d aesthetic d i s c r e t i o n with blood, feces, and body fluids can insure safety. T h e greatest d a n g e r in most settings is not the autopsy facility but the pathologists' lack o f r e g a r d for potential risk. T h e classical techniques o f the autopsy, which were d e v e l o p e d when tuberculosis and hepatitis were greatly feared, need to be rei n t r o d u c e d into residency p r o g r a m s a n d into the practice o f pathology. (3) W h y p e r f o r m autopsies on A I D S patients? Perhaps we should just ask why p e r f o r m autopsies? Regrettably, more a n d more physicians and pathologists r e g a r d this as a reasonable question. It is, rather, a reflection of a significant lack o f u n d e r s t a n d i n g about the i n n u m e r a b l e benefits o f the autopsy to quality medical care, to society, to student and physician education, a n d to family members. 9 This is especially true in the setting o f AIDS. No two AIDS deaths are identical. T h e r e is m u c h to be l e a r n e d f r o m the AIDS death: the specific cause o f death is often unsuspected, all
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logic, a n d clinical studies that d e m o n s t r a t e d its specificity. T h e y can be s u m m a r i z e d as follows: (1) I n t h e i r original d e s c r i p t i o n o f this m o n o c l o n a l antibody, H o r a n H a n d et al 2 d e m o n s t r a t e d that RAP-5 specifically r e a c t e d with ras p21 in i m m u n o b l o t as well as solid phase r a d i o i m m u n o a s s a y (RIA) e x p e r i m e n t s . (2) Similar quantitative a n d qualitative i m m u n o h i s t o chemical staining p a t t e r n s h a v e b e e n d e m o n s t r a t e d w h e n RAP-5 was c o m p a r e d with a n o t h e r p21 specific a n t i b o d y (Y13-259) in the study o f n u m e r o u s cancers a n d n o r m a l tissues. 3-~ R A P - 5 staining also correlates with solid p h a s e R I A u s i n g Y13-259 antibody. 5 (3) T h e intensity o f i m m u n o h i s t o c h e m i c a l staining by RAP-5 was s h o w n to c o r r e l a t e with steady-state ras-specific R N A levels d e t e c t e d by in situ hybridization. 5 (4) Finally, indirect e v i d e n c e o f the specificity o f RAP-5 is p r o v i d e d by studies assessing the p r o g n o s t i c significance o f p21 in p r i m a r y breast cancers. D i f f e r e n t studies u s i n g i m m u n o h i s t o c h e m i s t r y with b o t h R A P - 5 a n d Y13-259, 6 RAP-5 alone, 7 o r i m m u n o b l o t assays with Y13-259 s c a m e to similar conclusions a n d d e m o n s t r a t e d the usefulness o f tum o r p21 levels. Because o f the h e a t lability o f the p21 protein, a req u i r e m e n t f o r s t a n d a r d i z e d fixation t e c h n i q u e in such studies, a n d the necessity to use e n d p o i n t titration assays in studies o f this type, in which b e n i g n a n d m a l i g n a n t tissues are b e i n g c o m p a r e d , it is n o t s u r p r i s i n g that conflicting d a t a may arise.
CORRESPONDENCE p21 Expression in the Progression of Breast Cancer ras
To the E d i t o r : - - T h e m o n o c l o n a l a n t i b o d y RAP-5 was u s e d by F r o m o w i t z et al t to investigate ras p21 e x p r e s s i o n in breast cancer, as r e p o r t e d in the D e c e m b e r 1987 issue o f the Journal. T h e r e is r e a s o n to suspect that this r e a g e n t m a y n o t be suitable for such a study. It is clear that RAP-5 shows i n t e r e s t i n g staining p a t t e r n s on i m m u n o h i s t o c h e m i s t r y , but a l t h o u g h these m a y h a v e biological significance, we wish to p o i n t o u t that t h e r e is serious d o u b t as to t h e i r relationship with e x p r e s s i o n o f ras genes. RAP-5 was p r o d u c e d by i m m u n i z a t i o n o f a m o u s e with a synthetic o c t a p e p t i d e c o n t a i n i n g the 10-17 a m i n o acid s e q u e n c e o f the m u t a t e d Ha-ras o n c o p r o t e i n p21, c o u p l e d to t h y r o g l o b u l i n . 2 T h e h y b r i d o m a was selected o n the basis o f a p p a r e n t l y h i g h d i f f e r e n t i a l reactivity for the m u t a t e d p e p t i d e s e q u e n c e c o m p a r e d with the n o n m u t a t e d h o m o logue. It has b e e n a s s u m e d by the originators o f the antib o d y a n d o t h e r s that cross-reactivity occurs with the n o n m u t a t e d p21, as RAP-5 reacts with e p i t o p e s in n o r m a l tissues a n d t u m o r s in w h i c h a c t i v a t e d ras w o u l d n o t be e x p e c t e d . T h i s a n o m a l y has not b e e n a d e q u a t e l y e x p l a i n e d . I m p o r t a n t claims w e r e m a d e for RAP-5; notably, its p u t a t i v e ability to b i n d p r e f e r e n t i a l l y to e p i t o p e s e x p r e s s e d in infiltrative areas o f tumors. W e p u b l i s h e d an e v a l u a t i o n o f R A P - 5 ~ in which we d e m o n s t r a t e d that the a n t i b o d y was u n a b l e to distinguish o n i m m u n o h i s t o c h e m i s t r y b e t w e e n a n o n - r a s - e x p r e s s i n g e m b r y o n i c fibroblast cell line a n d a derivative line genetically m a n i p u l a t e d to express the m u t a t e d T 2 4 Ha-ras o n c o g e n e at h i g h levels. W e were u n a b l e to c o n f i r m reactivity o f RAP-5 with p21 on i m m u n o b l o t s . I n contrast, the rat m o n o c l o n a l antibody YI3-2594 to ras p 2 i clearly distinguishes b e t w e e n these cell lines a n d identifies a single 21kDa b a n d o n i m m u n o b l o t s o f p r o t e i n extracts o f ras-expressing cells. W e are s u r p r i s e d that F r o m o w i t z et al chose to i g n o r e this i n f o r m a t i o n w i t h o u t c o m m e n t , as it has f u n d a m e n t a l implications for t h e i r w o r k a n d to that o f o t h e r s c o n t i n u i n g to use RAP-5 for i m m u n o h i s t o c h e m i c a l d e t e c t i o n o f the ras p21 p r o d u c t .
JOEL LUNDY, M D MICHAEL VIOLA, M D FRANK FROMOWlTZ, MD State U n i v e r s i t y o f N e w Y o r k at Stony B r o o k Stony B r o o k , N Y
ALISTAIR R. W. WILLIAMS, MRCPATH JUAN PIRIS, DPHIL, MRCPATH ANDREW H. WYLLIE, PHD, FRCPATH University Medical School E d i n b u r g h , Scotland 1. Fromowitz FB, Viola MV, Chao S, et al: ras p21 expression in the progression of breast cancer. HuM PATHOL18:1268, 1987 2. Horan Hand P, Thor A, Wunderlich D, et al: Monoclonal antibodies of predefined specificity detect activated ras gene expression in human mammary and colon carcinomas. Proc Natl Acad Sci USA 81:5227, 1984 3. Robinson A, Williams ARW, Piris J, et al: Evaluation of a monoclonal antibody to ras peptide, RAP-5, claimed to bind preferentially to cells of infiltrating carcinomas. Br J Cancer 54:877, 1986 4. Furth ME, Davis LJ, Fleurdelys B, et at: Monoclonal antibodies to the p21 products of the transforming gene of Harvey nmrine sarcoma virus and of the cellular ras gene family. J Viro143:294, 1982 T h e above letter was r e f e r r e d to the a u t h o r s o f the article in question, w h o o f f e r the following reply: To the E d i t o r : - - W e w e r e n e g l i g e n t in not r e f e r r i n g to the r e p o r t o f Williams a n d colleagues, which q u e s t i o n s w h e t h e r t h e r e a c t i v e a n t i g e n to R A P - 5 is t h e ras p21 p r o t e i n . 1 W e chose to use RAP-5 in the study o f invasive breast c a n c e r based on a n u m b e r o f biochemical, i m m u n o -
1. Robinson A, Williams ARW, Piris J, et al: Evaluation ofa monoclonal antibody to a ras peptide, RAP-5, claimed to bind preferentially to cells of infiltrating carcinomas. Br J Cancer 54:877, 1986 2. Horan Hand P, Thor A, Wunderlich D, et ah Monoclonal antibodies of predefined specificity detect activated ras gene expression in human and mammary colon carcinomas. Proc Natl Acad Sci USA 81:5227, 1986 3. Ohuchi N, Thor A, Page DL, et al: Expression of the 21,000 molecular weight ras protein in a spectrum of benign and malignant mammary tumors. Cancer Res 46:2511, 1986 4. Thor A, Ohuchi N, Horan Hand P, et al: ras gene alterations and enhanced levels of ras p21 expression in a spectrum of benign and malignant human mammary tissues. Lab Invest 55:603, 1986 5. Ohuchi N, Horan Hand P, Merto G, et al: Enhanced expression of c-Ha-ras p21 in human stomach adenocarcinomas defined by immunoassays using monoclonal antibodies and in situ hybridization. Cancer Res 47:1413, 1987 6. Querzoli P, Marchetti E, Baghi A, et al: Expression of p21 ras gene products in breast cancer relates to histological types, receptorial and nodal status. Breast Cancer Res Treat (in press) 7. Lundy J, Mishricky Y, Chao S, et al: Elevated ras oncogene expression correlates with lymph node metastases in human breast cancer. J Clin Oncol 4:1321, 1986 8. Clair T, Miller WR, Cho-Chung YS: Prognostic significance of the expression of a ras protein with a molecular weight of 21,000 by human breast cancer. Cancer Res 47:5290, 1987 AIDS Autopsies: Has t h e Risk B e e n Established? To the Editor:--HUMAN PATHOLOGY has d r a w n o u r attention to t h e quite serious p r o b l e m o f the d e c l i n i n g n u m b e r o f autopsies p e r f o r m e d in the U n i t e d States a n d o t h e r countries.t-3 T h i s is quite a w o r r i s o m e t r e n d since autopsy d a t a are necessary for the a d v a n c e m e n t o f t h e medical sciences, the d e v e l o p m e n t o f public h e a l t h m e a s u r e s , a n d the i m p r o v e m e n t o f patient care. 2,~ H o w e v e r , despite the technical safety p r o c e d u r e s issued by d i f f e r e n t sources, 4-7 m o s t pathologists face difficulties in p e r f o r m i n g autopsies o n A I D S cases, It is i m p o r t a n t to p o i n t o u t t h a t safety is an
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HUMAN PATHOLOGY
Volume 19, No. 9 [September 1988]
issue not only relevant to the team p e r f o r m i n g the autopsy, but also has direct implications r e g a r d i n g the protection o f the whole environment. This is particularly true in community-based hospitals all over the world. For instance, how m a n y o f these hospitals pay sufficient attention to the issue o f not using r u n n i n g water d u r i n g the autopsy o f an AIDS case or o f decontaminating the water used d u r i n g such a p r o c e d u r e before it enters the sewage system4-6? As a pathologist who has worked in Brazil, the United States, and J a p a n , I can attest to the fact that not all pathologic services have suitable facilities for p e r f o r m i n g autopsies o f patients who die from a highly infectious disease, like AIDS. A l t h o u g h there is no question of the scientific merit o f such a p r o c e d u r e , we can easily raise ethical questions about the m e a n i n g o f an act for which the risk/benefit ratio is not absolutely clear at the moment. Some services are finding themselves in the paradoxic situation o f trying to increase the n u m b e r o f autopsies p e r f o r m e d on the one hand, but, on the other hand, they are unofficially refusing to do autopsies o f those cases that may fall into the "high risk" category. This question has led to conflict between pathologists, their clinical colleagues, and hospital and gove r n m e n t officers. Declining to p e r f o r m an autopsy is probably also a matter o f Hippocratic ethics and, as such, the medical c o m m u n i t y should face this issue as soon a n d as clearly as possible. A feasible solution would be to authorize only those hospital centers currently providing AIDS treatm e n t to p e r f o r m AIDS autopsies, provided their autopsy r o o m s ( a n d this is a very h i g h p r i o r i t y ) a r e suitably equipped. O f course, all the above considerations are personal and not necessarily shared by my c u r r e n t host institution. j . L. V. DE CAMARGO, MD, PHD Nagoya City University Medical School Japan 1. Wagner BM: Mortality statisticswithout autopsies: Wonderland revisited. HuM PAWIqOL18:875, 1987 (editorial) 2. Anderson RE: Autopsy-related initiativesin the United States: Current status and suggestions for the future. HuM PATHOL18:977, 1987 3. StevanovicG, Tucakovic G, Dotlic R, et al: Correlation of clinical diagnosis with autopsy findings: A retrospective study of 2,145 consecutive autopsies. HUMPATHOL17:1225, 1986 4. Orenstein JM: Guidelines for high risk or potentially high risk autopsy cases. Pathologist 38:33, 1984 5. Centers for Disease Control: Acquired immunodeficiencysyndrome (AIDS): Precautious for clinicaland laboratory staffs. MMWR31:577, 1982 6. Reichert CM, O'Leary TJ, LevensDL, et al: Autopsypathologyin the acquired immunodeficiencysyndrome. Am J Pathol 112:357, 1983 7. Brynes RK, Ewing EP Jr: Is the autopsy of AIDS patients a safe procedure in the community hospital setting? Pathologist39:32, 1985
Response To the Editor:--Dr de Camargo's letter raises again one o f the i m p o r t a n t problems facing Pathology and Medicine, which we have taken the liberty of rephrasing: Is it acceptable to not p e r f o r m autopsies on patients dying from AIDS? T h e answer requires addressing at least three related, but distinct, issues: (1) W h a t is the risk to the pathologist and s u p p o r t staff if an autopsy is p e r f o r m e d on an AIDS patient? Autopsies were p e r f o r m e d on AIDS patients for years in New York, San Francisco, and Los Angeles, before the pathogenesis of the d i s o r d e r was understood. I n d e e d , GRID ("gay-related i m m u n e deficiency"), as AIDS was known before transmissibility to non-male homosexuals became recognized, was at one time t h o u g h t to be a toxin-induced disease possibly caused by aphrodisiac inhalants r a t h e r than an infective
agent. Pathologists, autopsy assistants, f u n e r a l directors, and others involved with tissues from these patients took no special precautions. Since there are no known cases o f AIDS in pathologists o t h e r than in those who belong to recognized high-risk groups, 1 we can suspect that infectivity is not high at the time o f autopsy. I n d e e d , neither pathologists n o r autopsy technicians are listed a m o n g those health care workers who have d e m o n s t r a t e d seropositivity.2 Alt h o u g h a definitive study o f infectivity has not yet been p e r f o r m e d on bodies o f AIDS patients, u n p u b l i s h e d data o f a few such cases suggests that the virus is p r e s e n t in very low concentrations by the time someone dies f r o m AIDS, if it is present at all? T h e greatest c o n c e r n remains the u n d i a g n o s e d patient. I n one o n g o i n g study at a busy medical examiner's office, as many as 85% o f those bodies whose sera was shown to have antibodies to the h u m a n immunodeficiency virus ( H I V ) h a d not b e e n clinically s u s p e c t e d to have AIDS. 4 In summary, there is no evidence that there is great risk in p e r f o r m i n g autopsies on patients dying from AIDS. Hepatitis continues to be the most significant infectious risk to the pathologist, and practice patterns that protect against hepatitis will be effective against AIDS. 5 A n a p p r o a c h to the autopsy that regards every patient as potentially infectious is certainly r e c o m m e n d e d , since t h e r e could be risk in perf o r m i n g autopsies on patients who have H I V viremia which is not recognized either because they have not yet develo p e d antibody or because there were no clinical indications for H I V antibody testing. (2) Can an autopsy be p e r f o r m e d safely on an AIDS patient in the average hospital without risk to the community? W h a t should be d o n e with the body fluids and tissues? T h e r e is absolutely no evidence that hospital waste has caused disease in the community because o f usual disposal methods. 2 It is entirely reasonable, however, to identify wastes with the potential for causing infection and develop methods o f handling t h e m that are practical a n d effective. In general, infectious waste should be incinerated or autoclaved before disposal in a sanitary landfill. 2,6 Fluids, including blood, may be p o u r e d down a d r a i n connected to a sanitary sewer if allowed by local health codes. 2,6 H I V has been shown to be effectively inactivated by a variety of comm o n disinfectants at concentrations usually below those usually used for laboratory disinfection. 7,8 A f t e r use, all laboratory surfaces, including those in the autopsy facility, should be d e c o n t a m i n a t e d with an a p p r o p r i a t e chemical germicide after a spill o f blood or bloody fluids and when all work is completed. 2 T h e most i m p o r t a n t factor in insuring the well-being o f the pathologist a n d coworkers remains the pathologist! Sensible a n d aesthetic d i s c r e t i o n with blood, feces, and body fluids can insure safety. T h e greatest d a n g e r in most settings is not the autopsy facility but the pathologists' lack o f r e g a r d for potential risk. T h e classical techniques o f the autopsy, which were d e v e l o p e d when tuberculosis and hepatitis were greatly feared, need to be rei n t r o d u c e d into residency p r o g r a m s a n d into the practice o f pathology. (3) W h y p e r f o r m autopsies on A I D S patients? Perhaps we should just ask why p e r f o r m autopsies? Regrettably, more a n d more physicians and pathologists r e g a r d this as a reasonable question. It is, rather, a reflection of a significant lack o f u n d e r s t a n d i n g about the i n n u m e r a b l e benefits o f the autopsy to quality medical care, to society, to student and physician education, a n d to family members. 9 This is especially true in the setting o f AIDS. No two AIDS deaths are identical. T h e r e is m u c h to be l e a r n e d f r o m the AIDS death: the specific cause o f death is often unsuspected, all
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