PERITONEAL MESOTHELIOMA* Milton Kannerstein, M.D.,~ and Jacob Churg, M.D.~
Abstract T h e cytohistology in 82 cases diagnosed as tnalignant peritoneal inesotheliotna was correlated with available clinical and gross pathologic information. T h e cases were then evahtated as to certainty of diagnosis. T h e material had come from a large n u t n b e r of sources, most o f it having been traced by a history o f occupational exposure to asbestos. A relatively short interval of significant symptoms, with already existent diffuse peritoneal involvetnent and ascites, a n d an average survival time of less than a year characterized the group. T h e microscopic morphology f o r m e d a spectrum from highly cimracteristic, pure epithelial a n d mixed epithelial and sarcomatoid types, t h r o u g h nonspecific although relatively differentiated appearances, to pleontorphic anaplastic proliferations. Local invasion and metastasis were colfimon but much more limited than witlt tuntors of otlter.itistogenesis showing contl)arable serotts mentbrane involventent. Autopsy was of considerable exchtsionary wtlue altliottgh n o t in itself always determinative, and mucopolysacclmride histoclmmistry was occasionally decisive in diagnosis. Because of tlte microscopic versatility of ntesothelionm and the clinical attd gross nmrpltologic overlap with other neol)lasnts, all available data must be taken into consideration in arriving at a diagnosis. We believe that the degree of certainty of diagnosis should be indicated by a succinct but reasonably explicit terminology.
Diffuse malignant peritoneal tnesothelioma, although pet'lmps not as extensively investigated as mesothelioma of the pleura, has been the subject of numerotis reports. These date back, at least, to 1908 t .but have been ntore frequent in the last two decades, especially after 1960 when tim relationship to asbestos exposnre was established3 -x~ Most o f the reports lmve consisted of groups o f cases selected because o f the relative certainty of diag-
nosis in order to assist in tlm delineation of tim clinical and pathologic features o f this neoplasm. This would appear to ltave been largely accoml)lished. However, it is evident that the diagnosis is lnade erroneously in ntany instances, t~ just as it is certain that it is missed in an u n d e t e r m i n e d proportion. TM Although the increased incidence in recent )'ears is certaildy not a diagnostic artefact,as, t4 ntore precise epidemiologic information is highly desir-
*.Study supported by U.S. Public tiealdl Service research grants AM-00918 from the National Institute of Arthritis and Metabolic Diseases and ES-00238 fronl tile National Institute of Environmetatal ! lealth Sciences. tAssistant Clinical Professor of Pathology, Mount Sinai School of Medicine, New York, New York. Consuhant in Pathology, Barnert Memorial llospital Center, l'atcrson, New Jersey. +Professor of Pathology, M o u n t Sinai School of Medicine, New York, New York. Pathologist, Bm'nert Memorial ttospital Center, l'aterson, New Jersey.
83
HUMAN I'ATHOLOGY--VOLUME 8, NUMBER 1 Janumy 1977 able, and this d e p e n d s in large part o n reliable diagnosis. It is o u r p u r p o s e to present some generalizations relevant to the m o r p h o l o g y and behavior o f peritoneal mesothelioma derived f r o m a fairly large g r o u p o f cases, and to offer some opinions c o n c e r n i n g the evahmtion o f the diagnosis.
MATERIAL AND METHODS
84
O f a series o f 187 cases diagnosed as diffuse malignant mesotheliomas with varying degrees o f certainty, 83 (44 per cent) were primary in the peritoneum. T h e material came f r o m man)' sources t h r o u g h out the United States over a period o f years. T h e majority o f cases were traced t h r o u g h occupational e x p o s u r e to asbestos and were drawn from files dating back to 1949. In 69 (84 per cent) o f the peritoneal cases the patient came to biopsy or autopsy in the )'ears 1964 to 1974. I n f o r m a t i o n varied in quality and quantity, being quite deficient in many cases. Autopsy findings were available in only 36, but a description o f the peritoneal cavity at l a p a r o t o m y was given in a n o t h e r 26. Histologic sections were seen by us in all cases, although i n some a greater sampling o f the t u m o r would have been desirable. Basic histochemical tests for mucosubstances were carried out in 28 instances. In a few others a section stained only for neutral (i.e., epithelial) mucin was a v a i l a b l e - t h e PAS reaction or mucicarmine stain. Sections o f lung were obtained in 32 cases for examination for asbestos bodies and the grading o f fibrosis. Cytologic preparations o f fluid were available in too few instances to permit significant analysis o f the modality, and this is not discussed in this report. Electron microscopic study was p e r f o r m e d in only a small n u m b e r o f instances and has been the subject o f a separate report.~5 T h e microscopic features were characterized and evaluated according to established histologic criteria. ~6-~s Clinical and gross pathologic information was abstracted, summarized, and tabulated as p r e s e n t e d u n d e r the resuhs section. Microscopic and o t h e r findings were correlated and the case classified as to
certainty o f diagnosis as discussed in the section on diagnostic evaluation.
RESULTS
Only six patients were female. Ages r a n g e d f r o m 38 to 82 )'ears; 58 (75 per cent o f the 77 whose ages were known) were between 50 and 69 )'ears o f age. Sixty-eight patients (83 per cent) were known to have had occupational e x p o s u r e to asbestos. T h e clinical symptomatology most f r e q u e n t l y r e c o r d e d was abdominal discomfort o r pain, distention, digestive distnrbances, and weight loss. Palpable abdominal masses were described in some. l'eripheral e d e m a was a c o m m o n finding. Ascites was r e f e r r e d to in 49 cases. In only several was the statement m a d e that at autopsy t h e r e was no fluid in the peritoneal cavity. T h e viscosity o f the fluid varied, in a few being r e f e r r e d to as mucinous. Variations in history ilacluded first detection in a hernial sac (five cases) or partial intestinal obstruction. T h e d u r a t i o n o f life after the onset of symptoms was calculable in 61. It ranged f r o m o n e m o n t h to almost six )'ears. Only 15 patients were known to have survived for m o r e than one year, and 44 per cent were d e a d in six months. T h e description o f the abdominal cavity c o n f o r m e d to several patterns, almost all showing extensive t u m o r involvem e n t o f both visceral and parietal peritoneum. " S t u d d e d with t u m o r nodules" was a c o m m o n descriptive phrase. T h e nodules were o f varying size, f r o m a few millimeters to 5 cm. in diameter. In 26 cases t h e r e were descriptions o f massive accumulations u p to 25 cm., most often in the o m e n t u m and next most f r e q u e n t l y in the lower a b d o m e n and pelvis. Diffuse thickening o f the p e r i t o n e u m u p to 5 or 6 cm. a n d plaques were f r e q u e n t l y mentioned. Adhesions o f varying e x t e n t were c o m m o n , and agglutination o f the entire intestinal tract or obliteration o f the peritoneal cavity with complete i n c o r p o r a t i o n o f all viscera in t u m o r was described in a n u m b e r o f instances. "Encasement o f liver a n d spleen" was often r e f e r r e d to. In only two cases was the t u m o r limited in extent, o n e o f these a laparotomy finding. In this case the t u m o r was situated chiefly be-
PERITONEAL MESOTHELIOMA--KAxxERSTEIN, CHORG tween one lobe of the liver and the diaphragm. In the other, a male, it involved chiefly the pelvis with massive metastasis to the liver. T h e effect of prior laparotomy a n d of radiation or local c h e m o t h e r a p y on the appearance at autopsy must be taken into consideration. T h e microscopic findings encompassed the established diversity o f cell forms and histologic patterns that is virtually unique a m o n g neoplasms originating from a single cell line. Sixty-two (75 per cent) of the cases were designated as epithelial, 18 (22 per cent) as mixed (epithelial and sarcomatoid), and only two as entirely" sarcomatoid. Wide variations in cytohistologic features were present in individual cases, often in adjacent areas. In the epithelial tumors, and the epithelial element o f the tumors of mixed type, cytologic variation ranged from those resembling hyperplastic mesothelium to anaplastic cells, often in a pleomorphic context, that bore no resemblance to mesothelial cells. Over three-fifths o f the epithelial tunaors could be categorized as predominantly" moderately' to well differentiated, although many of these also had areas o f variable anaplasia and pleomorphism. Tubulopapillary, papillary, or tubular patterns, entirely" or predominant1)', characterized about one-third o f the cases (Fig. IA, B, C). In almost half the cases a sheetlike or more or less solidly massed, patternless structure predominated (Fig. 2A). However, more than twothirds of these contained tubular or papillary elements to a greater or lesser extent. Papillations were sometimes only a surface p h e n o m e n o n on the solid masses. T h e cells in the solid formations varied in degree of differentiation and uniformity. R o u n d or polygonal forms, sometimes producing a pavement-like effect, were seen. Occasionally epithelial cells became elongated, assuming an ahnost fl~siform shape but retaining their el)ithelial character. Nuclei varied in appearance, often having a vesiculous character and, as in any anaplastic tunaor, showing irregtdarity in shape and size and large nucleoli. Mitoses increased in fi'equency and a t y p i s m in less differentiated areas. Altlmugh often obviously' consistent
with a mesothelial origin, a degree o f specificity was i m p a r t e d to the appearance of tile less differentiated tumors only with the finding of tubules, papillae, or a sarcomatoid element. Vacuolation, prominent in about one-fourth of tile epithelial tumors, ranged f r o m single cytoplasmic vacuoles, sometimes large enough to produce a signet ring effect, to confluence, with tlle formation o f large intercelhdar spaces. This gave an adenomatoid or even "lacy" appearance (Fig. 1D). Ill tltese vacuoles and spaces hyaluronic acid could be demonstrated. A relatively" small n u m ber of tumors grew in solid cellular cords or clumps e m b e d d e d in stroma. Stroma varied in qtmntity a n d cellularity, from a delicate fibrillar to a more typical copious collagenous, sometimes hyaline form. A myxoid stroma was quite distinctive in a n u m b e r o f tumors (Figs. 1, 2). T h e sarcomatoid component of tumors of the mixed type usually took the form o f spindle or fusiform cells with elongated or oval nuclei (Figs. 1F, 2E). Parallel orientation was frequent, but well developed fasciculation was rare. In some tumors the sarcomatoid cells showed degrees of anaplasia with giant bizarre nuclei. Some tumors of the mixed type even with a lesser degree of cellular differentiation were so characteristic in pattern as to be quite convincing (Fig. 2E). In mixed tumors one could observe in many" instances cells representing a transition from the epithelial c o m p o n e n t to the distinctly sarcomatoid form (Fig. 1F). In several tumors, areas composed of large bizarre multinucleated cells, some reminiscent o f rhabdomyoblasts, were present. O f the two sarcomatoid tumors, one was composed of slender uniform spindle cells and was poor in collagen. T h e other consisted of plumper, r o u n d e r cells that were of a more intermediate type, i.e., with ahnost epithelioid features in some areas. Local invasion occurred in 28 cases, as shown in Table 1, most often into the wall of the gastrointestinal tract. Invasion of the liver capsule was often mentioned, but in five c~ises intraparenchymal extension was specified. Invasion of the abdominal wall was essentially into the scars of previous laparotomies. T h e undersurface of the diaphragm was characteristically covered by nodules, but only
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86
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Figure 2. Mesotheliomas of acceptable but less characteristic pauern and variable differentialion. A , Monotmmus sheet-like strtzcture. Cells are well differentiated. (x400.) B, Elongated, parallel, relativel)' unifornl tubules. Identification of cell type and other parameters ma)" be required for distinction fi'om adenocarcinoma. (x400.) C, Pure papillary form, not in itself distinguishable from papillary carcinoma. (x500.) D, l.oosel)" dispose0 cells in a myxomatous stroma. This is a faMy characteristic type. (x.t00.) E, Mixed form of rather characteristic pattern but less well differentiated. (x500.)F, Pure sarcomatoid fi)rm without distinct pattern, resembling a fibrosarcoma. (x400.)
87
HUMAN I'ATIIOI.OGY--VOLUME 8, NUMBER 1 Jamm U 1977 TABLE 1.
LOCALINVASION* NO. of
Tissues Invaded
Cases
Gastrointestinal tract (to submucosa-5; to m t , c o s a - 4 ) I.iver parenchyma Abdominal wall Diaphragm Retroperito,mum (massive) Bladder Pancreas (massive)
22 5 6 5 5 2 '2
*Total: 28 cases (22 autopsies).
occasionally was invasion into the diap h r a g m specifically described. In the five cases o f significant retroperltoneal extension, t u m o r s u r r o u n d e d the kidneys in three, involving tim renal capsule but not the kidney itself. In eight cases tim pancreas was described as being s u r r o u n d e d by t u m o r . In m a n y instances f r e e d o m o f the pancreas from t u m o r was explicitly stated. In two cases invasion o f tim pancreas was massive. Invasion o f adipose tissue alone, presumably most often tlm o m e n t u m , the favorite site o f biopsy, was d e m o n s t r a t e d in 32 cases and conceivably o c c u r r e d to a d e g r e e in virtually all cases (Table 1). Metastasis was known to have taken place in 18 o f the autopsy cases (50 per cent). T i m sites o f metastasis are listed in T a b l e 2. Involvement o f lymph nodes was i n t e r p r e t e d as lymphatic metastasis, altlmugh in some instances direct extension fl'om s u r r o u n d i n g t u m o r may have been the route. T h e l y m p h nodes involved were most often the mesenteric and peripan-
creatic. In three cases thoracic nodes, and in t h r e e also inguinal nodes, contained t u m o r (Table 2). T h e r o u t e o f pleural a n d p n l m o n a r y spread has been attributed principally o r entirely to direct extension througll tim d i a p h r a g m , a= Tiffs was true in at least one case o f the seven in tiffs series showing involvement o f the pleura or hmg, and possibly in t h r e e others. In tim r e m a i n i n g cases no continuity or d i a p h r a g m a t i c im'olvement was mentioned. Ptflnmnary blood vessel metastasis was seen ill one case. O f tim 28 cases in which tissue was subjected to the colloidal iron reaction, 11 gave positive staining that was negated or diminished by llyaluronidase. Nine o f these were histologically characteristic in hematoxylin and eosin stained sections. T h e reaction for neutral mucosubstance disclosed n o clearcut positives, several instances being equivocal. P s a m m o m a bodies were present in three cases having a papillary structure. Asbestos bodies were f o u n d in tim h m g sections in 31 of the 32 cases in which this tissue was available. T h e y varied fl'om a few to m a n y in 6 micron hematoxylin and eosin stained sections. Eight o f these disclosed no fibrosis, 15 minimal to mild fibrosis, seven m o d e r a t e fibrosis, and only one severe fibrosis. Hyaline pleural plaques were r e f e r r e d to in 16 cases, in 13 of wlfich lung sections were available. All 13 contained asbestos bodies. T i m o t h e r three patients lind histories o f occupational exposure.
DIAGNOSTIC TABLE 2.
METASTASIS* NO. of
Organs Lymph nodes only (abdominal--5: inguinal-3) Viscera and lymph nodes (viscera and thoracic n o d e s - 3 ) Viscera alone I.iver Ltmg Pleura Pericardium Heart Adrenal 88
EVALUATION
*Total: 18 autopsy cases.
Cases
6 6 6 8 5 6 2 i I
As indicated, tile microscopic features r a n g e d fi'om highly characteristic, p a t t e r n e d , p u r e epithelial and mixed epithelial and mesencilymal forms, througll sheetlike, regular, and p e r h a p s differentiated but nonspecific epithelial and sarcomatoid appearances to poorly differentiated a n d - a t least in a r e a s - w i l d l y pleotnorphic proliferations that are unclassifiable structurall)'. Figure 1 slmws several characteristic mesotheliomas. T h e s e lead to a high d e g r e e o f diagnostic conviction even in tim total absence o f an)" data. In Figure 2 are seen levels o f con-
I'ERITONEAL MESOTI1ELIOMA--KA,~,~ERSTEtN, CnuRc,
9
siderable differentiation with a lack o f specificity that requires the consideration of other entities of visceral or connective tissue o r i g i n - a variety o f carcinomas and sarcomas. Reactive p r o c e s s e s mesothelial o r fibrous tissue h y p e r p l a s i a are also differential problems. In these cases one must know the source o f the specimen, the gross pathologic findings, and sometimes even clinical features. H e r e also m o r e extensive sampling may be required. In this study, starting in most cases with tile knowledge that tile p r o b l e m was tile diagnosis o f mesothelionm, we attempted to maintain a critical approacll to avoid bias. This attitude o f reserve was also a compensation for the deficiencies in data and nmterials ah'eady mentioned. T h e p r o c e d u r e , in essence, was to examine the histologic material, review the gross pathologic and clinical findings, and g r a d e the case as to certainty o f diagnosis. I f the cytohistologic findings c o n f o r m e d closely to characteristic morphologic variants o f the level o f those illustrated in Figure 1, and clinical and gross m o r p h o l o g y was concordant, the case was categorized as definite. I f a case was deficient in o n e or a n o t h e r element (e.g., a less than characteristic microscopic m o r p h o l o g y or lack o f or a p p a r e n t l y inconsistent o r complex gross pathology o r history), it was classified, at most, as probable. T h u s in the absence o f autopsy findings, even when the microscopic a p p e a r a n c e was characteristic, the case was placed in the probable category. Conversely, even if autopsy findings were quite consistent but the microscopic features were poorly differentiated, the grading was r e d u c e d proportionately. (These j u d g m e n t s will be analyzed f u r t h e r in the discussion.) In addition, certain complications, such as the presence o f a second t u m o r o r the history o f s u r g e r y for cause tmknown when tiffs may have been a neoplasm, led to evaluation with caution as to the certainty o f diagnosis o f mesothelioina. T h o s e rated as merely possible--and this category itself includes a span o f e v a l u a t i o n - w e r e essentially o f an atypical or poorly differentiated m o r p h o l o g T. In the course o f collection o f this series a n u m b e r o f cases were received tlmt were rejected unequivocally. Titese
were r e g a r d e d as t u m o r s o f other histog e n e s i s - usually c a r c i n o m a s - o n the basis o f histology. In some a llistochemical reaction favoring c a r c i n o m a was the decisive factor in such exclusion (Fig. 3). In o t h e r c a s e s - a n d this was the difficult or gray a r e a - t h e possibility o f a mesothelioma could not be categorically denied. T h e s e fell into two subgroups: those in which o u r own considered j u d g m e n t based on histologic study and in some cases also gross nlorphologic o r clinical features favored a n o t h e r origin, and those in which we were unable to make any d i s t i n c t i o n - a position o f neutrality. Such cases were not included in tiffs report. T a b l e 3 presents a g r o u p i n g by estimated degrees o f certainty o f diagnosis, based u p o n the f o r e g o i n g considerations. It will be noted that only 22 (27 per cent) met all the criteria previously established for a definite diagnosis, whereas 51 (62 per cent) were r e g a r d e d as probable. However, 20 o f the probable cases showed characteristic histologic features and were d o w n g r a d e d because o f lack o f an autopsy, o r in o n e case because o f the presence o f a n o t h e r tumor. I f these histologically typical cases were a d d e d on the basis o f histologic findings to the definite g r o u p , 42 (51 per cent) could be r e g a r d e d as established. It may be pointed out that the probable categorization in general implies a high d e g r e e o f p r e f e r e n c e for the diagnosis o f mesothelioma. T h e s e two categ o r i e s - definite and p r o b a b l e - combined account for 89 p e r cent of the series. In the nine cases g r a d e d as possible, the diagnosis was favored o v e r that of any o t h e r type o f t u m o r (Table 3). O f the 14 autopsy cases that were not unequivocally accepted, six had a consistent gross a p p e a r a n c e but poorly differentiated histologic features. Table 4 lists these less than totally accepted cases and the reasons for the reservations (Table 4).
D I S C U S S I O N
T h e paucity o f females and the high incidence o f asbestos e x p o s u r e in tiffs series are, o f course, attributable to occupational selection. T h e relatively small m n n b e r o f patients with reasonable certainty o f no asbestos e x p o s u r e frustrates
89
HUMAN PATHOLOGY--VOI,U*IE 8, NUMBER 1 Jamm~3" 1 9 7 7 TABLE 4.
T A B L E 3. DIAGNOSIS BY DEGREE OF CERTAINTY
Definite mesothclioma Probable (histologically typical but n o autopsy--20 cases) l'ossible mesothelioma
AUTOpS'cCASES NOT IN
DEFINI I-E GROUP
'2'2 cases
51 cases 9 cases
No. of Cases A u t o p s y c o n s i s t e n t btlt t u m o r
poorly differentiated Autopsy consistent but second tl.III]or p r e s e n t
any a t t e m p t to find distinctions between exposed and n0nexposed. T h e clinical a n d gross pathologic findings parallel those n o t e d in the literature dealing with peritoneal mesothelioma. 2-~~ ra Althougll nonspecific with respect to these features and indistinguishable in general f r o m certain carcinomas w h e n these are widely d i s s e m i n a t e d in the p e r i t o n e u m , cases o f ntesothelioma a r e very similar to each other. Considerable d e p a r t u r e f r o m these p a t t e r n s - p a r t i c u larly in the gross m o r p h o l o g y - s l m u l d occasion careful scrutiny o f the case a n d weighing o f the diagnosis o f mesotheliOllla.
It is o f interest that we were not presented in this series with a single instance o f localized m e s o t h e l i o m a o f the fibrous type described by Stout -~~ a n d others, TM z., a n d that we lmve seen in the l)eritoneum in o n e instance in a n o t h e r series, a n d m u c h m o r e fi'equently in the pleura. O f the two cases o f limited e x t e n t o f growth in the p r e s e n t g r o u p , o n e can be r e g a r d e d as being representative m e r e l y o f an earlier stage in the course o f s p r e a d and the o t h e r as b e i n g atypical. In all o t h e r cases the t u m o r was widely distributed when s y m p toms c o m m e n c e d . In this series we were not able to arrive at any consistent correlation between cell type, histologic p a t t e r n , or overall d e g r e e o f differentiation a n d length o f survival. H o w e v e r , the cases o f patients surviving f o r o v e r one year w e r e in ahnost all instances r a t e d as microscopically characteristic, whereas the cytohistologic features in
Autopsy findings atypical l'revious orchiectomy for unknown diagnosis
those s u r v i v i n g three m o n t h s o r less were onl)' m o d e r a t e l y differentiated. T h e bulk o f the cases, falling between these time limits, were essentially m o d e r a t e l y or well differentiated. Since most patients with m e s o t h e l i o m a , particularly o f the perit o n e u m , are d e a d within o n e )'eat" a f t e r the onset o f s y m p t o m s , r~ this f e a t u r e c a n n o t be used to distinguish m e s o t h e l i o m a f r o m visceral c a r c i n o m a , even c a r c i n o n m o f the pancreas..~.~.:24 Carcinomas o f the o v a r y and stonmch are subject to m o r e variables. 25' 26 Only the relatively few patients with mesothelioma surviving for o v e r two )'ears with a k n o w n a b d o m i n a l tnnlor a n d ascites can b e said to be d e m o n s t r a t i n g a biologic distinctiveness. T h e classification as to cell type is also subject to observer variability. Differences in i n t e r p r e t a t i o n m a y exist as to w h e t h e r a fibrous c o m p o n e n t is truly neoplastic o r m e r e l y a cellular stronta. In o u r study a t u m o r was r e g a r d e d as m i x e d only if the m a l i g n a n t clmracter o f the mesenchymal e l e m e n t s e e m e d unequivocal. A point w o r t h y o f mention is the a p p a r e n t l o w e r f i e q u e n c y o f p u r e sarcontatoid growths in the p e r i t o n e u m as c o m p a r e d with the pleura. T h e value o f histochemical study for m u c o s u b s t a n c e s as an objective aid in the diagnosis o f m e s o t h e l i o m a has often b e e n c o n m t e n t e d u p o n with diverse conclusions. Such m e t h o d s are o f least assistance in es-
Figure 3. Tu,nors simulating mesotheliomas by extensive serosal growth. ,'1.Adenocarcinoma of u,adetermined origin. Tumor, in general, sttggested an adenocarcinoma cytologically. (x.t00.) II, Same case as in A. Section stained with PAS, after diastase, disclosing neutral mucin secretion in h, mina as seen in adenocarcinoma (arrows). (• C, Growth of small cells on peritoneal surface, metastatic fiom an undifferentiated gastric carcinoma. (• D, Same case as in C. Section stained with PAS, after diastase, showing nmrked cytoplasmic granular fuchsinophilia indicating neutral mucin. (x640.) E, Somewhat papillary tumor, apparently from ovary. (x400.) F, Metastasis fi'om cystosarcoma phyllodes resembling a sarcomatoid mesothelioma. (x400.) 9
90
I'ERITONEAL MESOTHEIJOMA--KANNFRSTEIN, CIiURG
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91
HUMAN I'ATHOLOGY--VOLUME 8, NUMBER 1 Janumy 1977
92
tablishing the identity o f a poorly differentiated mesothelioma in which acid mucosubstance may not be p r o d u c e d , but can be o f distinct help in m a n y m o r e highly differentiated tumors. A negative PAS reaction with a positive colloidal iron reaction r e m o v e d by lwaluronidase, following criteria set down elsewhere, may be conclusive in the diagnosis o f a mesothelioma that is difficult to distinguish otherwise from an a d e n o c a r c i n o m a Y A definitely positive PAS reaction in a poorly differentiated t u m o r established the diagnosis o f carcinoma, and this is helpful when there is extensive serous m e m b r a n e involvement a n d the existence o f a p r i m a r y t u m o r has not been clearly d e m o n s t r a t e d . It may be pointed out that acquired j u d g m e n t is helpful when only small a m o u n t s of mucosubstance are present or when o t h e r tissue elements, for example, projections o f s t r o m a or necrotic cellular material, simulate secretion. A n u m b e r o f writers have noted tlmt autopsy is f r e q u e n t l y not essential in nmking a definite diagnosis. 5" ~s In individual cases, and fox" practical purposes, such confirmation may not be necessary, especiall), for those familiar with the diversity o f cytohistologic expressions of this neoplasm. In man)' instances, however, a carefnlly p e r f o r m e d autopsy is o f great exclusionary value. T h e r e may o f course be limitations to the informational value o f an autopsy. In cases o f very advanced and extensive t u m o r growth it may be difficult to distinguish p r i m a r y fi'om secondary o r g a n invoh'ement. A tiny or even possibly involuted prinmry t u m o r or one concealed by secondary growth may escape identification. 2s A r e p o r t o f previous surgical extirpation with findings u n k n o w n confuses some cases. In any event an apparently c o n c o r d a n t autopsy is meaningful only to the extent tlmt the histologic findings are consistent with mesothelioma. In this series f o u r cases were known to have been associated with primary visceral tumors. O n e was an oat cell carcin o m a o f the lung, a n o t h e r an adenocarcin o m a o f the prostate. T h e accompanying mesotheliomas were so typical and so diff e r e n t from the carcinomas that no problena o f distinction existed. In the o t h e r cases the mesotbeliomas were less clmracteristic. In one t h e r e was said to have been
a large a d e n o n m o f the adrenal cortex, no section o f which was available to us; this case was c o n s i d e r e d as merely probable. Examination in the fourth case was said to have shown bilateral plleocllromocytomas of the adrenals. Although no confusion of t u m o r s was considered likely, this case also was less characteristic in its gross manifestations. As to the identity o f t u m o r s that simulate a mesothelioma grossly--and often m i c r o s c o p i c a l l y - i n the pleura, they appear most often to be p e r i p h e r a l puhnonary adenocarcinomas. 16, ''~ In the periton e u m , in females, certain ovarian tumors may play a sinfilar role, even t h o u g h an ovarian t u m o r would seem to be m o r e easily detectable grossly. T h e recently detined papillary surface t u m o r s o f the ovary of so-called borderline nmlignancy, particularly, might u n d e r some circumstances cause diagnostic difficult)'. T h e s e tumors have a t e n d e n c y to disseminate by seeding the p e r i t o n e u m ? ~ 3~ T h e potentialities o f cells in the pelvis of women, perhaps o f p a r a m e s o n e p h r i c or m e s o n e p h r i c type, and their relationslfip to the mesothelinm have been discussed? -~ 33 One might revive the c o n c e p t o f embryonal r e m n a n t s o f the paranaesonephros or m e s o n e p h r o s as the source o f carcinomas that grossly resemble a mesothelioma but show a p r e d o m i n a n c e in the pelvis? 4 In the male no one organ has been indicted as the p r e d o m i n a n t site of origin o f a carcinoma that yields diffuse, often massive peritoneal spread yet remains so occult as to escape detection. l'resunmbly a carcinoma o f the body o r tail o f the pancreas o r o f the stonmch migl!t belmve in tiffs way. 23' as-at However, in some cases abdominal carcinomatosis that imitates mesoti~elioma does so apparently even to the extent o f following the restrained visceral metastatic behavior o f the mesothelioma rather titan the m o r e florid metastatic proclivity o f typical pancreatic or gastric carcinoma. F u r t h e r study in this area is requisite. T h e diagnosis o f mesothelioma should not be a repository for t u m o r s in wlfich a prinmry site cannot be d e m o n s t r a t e d . It is a specific identifi.cation, its origin limited to a single cell species, despite the versatility o f expression o f tlmt cell. M cCat , i ghey 3s lms succinctl)' s u m m a r i z e d the basis f o r accurate histologic diagnosis:
PERITONEAL
recognition o f the capacity of the malignant mesothelial cell to form~ widely different types of neoplastic tissue, famili~irity .with t h e more specific structural patterns of the tumor, and a good knowledge of general tumor pathology. This statement incorporates a considerable number of variables. Thus despite a reluctance to be less than categorical, it is believed that a grading system such as that employed in this report is realistic.
14. 15.
16. 17.
ACKNO~VLEDGMENTS 18.
Most of the cases associated with asbestos exposure were obtained through the courtesy o f Dr. I.J. Selikoff. Appreciation is also expressed to a number of physicians who submitted their cases for consultation. Excellent technical assistance was given by Mr. A. l'rado. REFERENCES 1. Miller, J., a n d Wynn, W. H.: A malignant tumor arising from the endothelium of the peritoneum and producing a mucoid ascitic fluid. J. Path. Bact., 12:267, 1908. 2. Godwin, M. C.: Diffuse mesotlleliomas. Cancer, 10:298, 1957. 3. Winslow, D. J., and Taylor, It. B.: Malignant peritoneal mesothelionms. Cancer, 13:127, 1960. 4. Keal, E. E.: Asbestosis and abdominal neoplasms. Lancet,2:1211, 1960. 5. Bolio-Cicero, A., Aguirre, J., and l'erez-Tamayo, R.: Malignant peritoneal mesothelioma. Amer. J. Clin. Path.,36:417, 1961. 6. Enticknap, J. B., a n d Smitber, W. J.: Peritoneal tulnors in asbestosis. Brit. J. had. Med., 21:20,
1964. 7. Hourihane, D. O.: T h e pathology o f mesotheliomata and an analysis of their association with asbestos exposure. Thorax, 19:268, 1964. 8. Mann, R. H., Grosh,J. L., and O'Donnell, W. M.: Mesothelioma associated with asbestos. Cancer, 19:521, 1966. 9. Smith, I'. G., Higgins, P. McR., and Park, W. D.: Peritoneal mesothefioma presenting surgically. Brit.J. Surg.,55:681, 1968. 10. Roberts, G., and Irvine, R. W.: Peritoneal mesuthelioma. Brit.J. Surg.,57:645, 1970. 11. McDonald, A. D., Magner, D., and Eyssen, G.: Primary malignaut mesothelial tumors in Canada, 1960-1968. Cancer, 31:869, 1973. 12. Thomson, J. G.: T h e pathological diagnosis of malignant mesothelioma of pleura and peritoneum. In Shapiro, H. A. (Editor): Proceedings of lnternatioual Conference on l'neumoconiosis. Cape Town, Oxford University Press, 1970, p. 150. 13. Selikoff, I.J., Hammond, E. C., and Seidman, ti.:
19. 20. 21.
22. 23. 24.
25.
26.
27.
28. 29.
30. 31. 32.
33.
MESOTHELIOMA~KAX:~ERSTEIX,
CnURG
Cancer risk o f iusulation workers in the United States. In Biological Effects of Asbestos. Lyon, I.A.R.C., 1973, p. 209. Newhouse, M. L.: Cancer among workers ill the asbestos textile industry. In Biological Effects o f Asbestos. I.yon, I.A.R.C., 1973, p. 203. Suzuki, Y., Kannerstein, M., aqd Clmrg, J.: Electron microscopy of normal, hyperplastic and neoplastic mesotllelium. In Biological Effects of Asbestos. I.yon, I.A.R.C., 1973, p. 80. McCaughey, W. T. E.: Criteria for diagnosis o f diffuse mesothelial tumors. Ann. N.Y. Aead. Sci., 132:603, 1965. Churg, J., Rosen, S. H., and Moolten, S. E.: Histological characteristics of mesothelioma associated with asbestos. Ann. N.Y. Acad. Sci., 132: 614, 1965. Hourihane, D. O.: A biopsy series of mesotheliomata and attempts to identify asbestos within some of the tumors. Ann. N.Y. Acad. Sci., 132:647, 1965. Ehnes, P. C.: T h e natural history ofdiffose mesothelioma. In Biological Effects of Asbestos. Lyon, I.A.R.C., 1973, p. 267. Stout, A. P.: Solitary fibrous mesothelioma of peritonetnn. Cancer,3:820, 1950. Nevius, D. B., and Friedman, N. B.: Mesotheliomas and extraovarian thecmnas with Iffpogl)cemia and nepllrotic syndrome. Cancer, 12:1263, 1959. Lowbeer, L.: Extrapancreatic tumors and hypoglycemia. Amer. J. Clin. Path., 35:233, 1961. Duff, G. L.: Clinical and pathological features of carcinoma of the body and tail of the pancreas. Bull. Johns Hopkins Hosp., 65:69, 1939. Glenn, F., and Throbjarnarson, B.: T h e pancreas. In Nealon, T. F. (Editor): The Managemeat of the Patient with Cancer. Philadelphia, W. B. Saunders Company, 1965, p. 604. Munnell, E. W., and Taylor, tt. C.Jr.: T h e ovary. In Nealon, T. F. (Editor): T h e Management of the Patient with Cancer. Philadelplfia, W. B. Saunders Company, 1965, p. 719. McNeer, G.: T h e stomach. In Nealon, T. F. (Editor): T h e Management of the Patient with Cancer. l'hiladelphia, W. B. Saunders Company, 1965, p. 561. Kannerstein, M , , Churg, J., and Magner, D.: Histochemistry in the diagnosis of malignant mesothelioma. Ann. Clin. Lab. Sci., 3:207, 1973. Willis, R. A.: l'athology of Turnouts. Ed. 4. London, Butterworth & Co. (l'ublisllers) Ltd., 1967, p. 181. ltarwood, T. R., Grace)', D. R., and Yokoo, tt.: l'seudomesotheliomatous carcinoma of the lung. A variant of peripheral hmg cancer. Amer. J. Clin. Path., 65:159, 1976. Scully, R. E.: Recent progress in ovarian cancer. Hum. l'atlml., 1:73, 1970. Julian, G. J., and Woodruff, J. D.: Biologic belmvior of low-grade papillary serous carcinoma of ovary. Obstet. Gynec., 40:860, 1972. Swerdlow, M.: Mesothelioma of the peh'ic peritoneum resembling papillary cystadenocarcinoma of the ovary. Amer. J. Obstet. Gynec., 77:197, 1959. Parmley, T. tt., and Woodruff, J. D.: T h e ovarian mesothelioma. Amer. J. Obstet. Gynec,, 120: 234, 1974.
93
HUMAN
PATHOLOGY-VOLUME
8, N U M B E R
34. Changns, G. W.: Fine structure of so-called mesonephric carcinoma. Lab. Invest., 20:579, 1969 (abstr.). 35. Bell, E. T.: Carcinoma of the pancreas. Amer. J. Path.,33:497, 1957. 36. Ackerman, L. V., and Rosai, J.: Surgical Pathology. Ed. 5. St. Louis, The C. V. Mosby Co., 1974, p. 1176.
1 Janualy 1977
37. Morson, B. C., and Dawson, I.M.P.: Gastrointestinal Pathology. Oxford, Blackwell Scientific Publications, 1970, p. 154. 38. McCaughey, W. T. E.: Morbid anatomical and histological criteria for the diagnosis of diffuse mesothelioma. Conference on the Biological Effects of Asbestos, Lyon, 1972 (unpublished communication). Department of Pathology Baruert Memorial Hospital Center 680 Broadway Paterson, New Jersey 07514 (Dr.
94
Kannerstein)
Abstract T h e cytohistology in 82 cases diagnosed as tnalignant peritoneal inesotheliotna was correlated with available clinical and gross pathologic information. T h e cases were then evahtated as to certainty of diagnosis. T h e material had come from a large n u t n b e r of sources, most o f it having been traced by a history o f occupational exposure to asbestos. A relatively short interval of significant symptoms, with already existent diffuse peritoneal involvetnent and ascites, a n d an average survival time of less than a year characterized the group. T h e microscopic morphology f o r m e d a spectrum from highly cimracteristic, pure epithelial a n d mixed epithelial and sarcomatoid types, t h r o u g h nonspecific although relatively differentiated appearances, to pleontorphic anaplastic proliferations. Local invasion and metastasis were colfimon but much more limited than witlt tuntors of otlter.itistogenesis showing contl)arable serotts mentbrane involventent. Autopsy was of considerable exchtsionary wtlue altliottgh n o t in itself always determinative, and mucopolysacclmride histoclmmistry was occasionally decisive in diagnosis. Because of tlte microscopic versatility of ntesothelionm and the clinical attd gross nmrpltologic overlap with other neol)lasnts, all available data must be taken into consideration in arriving at a diagnosis. We believe that the degree of certainty of diagnosis should be indicated by a succinct but reasonably explicit terminology.
Diffuse malignant peritoneal tnesothelioma, although pet'lmps not as extensively investigated as mesothelioma of the pleura, has been the subject of numerotis reports. These date back, at least, to 1908 t .but have been ntore frequent in the last two decades, especially after 1960 when tim relationship to asbestos exposnre was established3 -x~ Most o f the reports lmve consisted of groups o f cases selected because o f the relative certainty of diag-
nosis in order to assist in tlm delineation of tim clinical and pathologic features o f this neoplasm. This would appear to ltave been largely accoml)lished. However, it is evident that the diagnosis is lnade erroneously in ntany instances, t~ just as it is certain that it is missed in an u n d e t e r m i n e d proportion. TM Although the increased incidence in recent )'ears is certaildy not a diagnostic artefact,as, t4 ntore precise epidemiologic information is highly desir-
*.Study supported by U.S. Public tiealdl Service research grants AM-00918 from the National Institute of Arthritis and Metabolic Diseases and ES-00238 fronl tile National Institute of Environmetatal ! lealth Sciences. tAssistant Clinical Professor of Pathology, Mount Sinai School of Medicine, New York, New York. Consuhant in Pathology, Barnert Memorial llospital Center, l'atcrson, New Jersey. +Professor of Pathology, M o u n t Sinai School of Medicine, New York, New York. Pathologist, Bm'nert Memorial ttospital Center, l'aterson, New Jersey.
83
HUMAN I'ATHOLOGY--VOLUME 8, NUMBER 1 Janumy 1977 able, and this d e p e n d s in large part o n reliable diagnosis. It is o u r p u r p o s e to present some generalizations relevant to the m o r p h o l o g y and behavior o f peritoneal mesothelioma derived f r o m a fairly large g r o u p o f cases, and to offer some opinions c o n c e r n i n g the evahmtion o f the diagnosis.
MATERIAL AND METHODS
84
O f a series o f 187 cases diagnosed as diffuse malignant mesotheliomas with varying degrees o f certainty, 83 (44 per cent) were primary in the peritoneum. T h e material came f r o m man)' sources t h r o u g h out the United States over a period o f years. T h e majority o f cases were traced t h r o u g h occupational e x p o s u r e to asbestos and were drawn from files dating back to 1949. In 69 (84 per cent) o f the peritoneal cases the patient came to biopsy or autopsy in the )'ears 1964 to 1974. I n f o r m a t i o n varied in quality and quantity, being quite deficient in many cases. Autopsy findings were available in only 36, but a description o f the peritoneal cavity at l a p a r o t o m y was given in a n o t h e r 26. Histologic sections were seen by us in all cases, although i n some a greater sampling o f the t u m o r would have been desirable. Basic histochemical tests for mucosubstances were carried out in 28 instances. In a few others a section stained only for neutral (i.e., epithelial) mucin was a v a i l a b l e - t h e PAS reaction or mucicarmine stain. Sections o f lung were obtained in 32 cases for examination for asbestos bodies and the grading o f fibrosis. Cytologic preparations o f fluid were available in too few instances to permit significant analysis o f the modality, and this is not discussed in this report. Electron microscopic study was p e r f o r m e d in only a small n u m b e r o f instances and has been the subject o f a separate report.~5 T h e microscopic features were characterized and evaluated according to established histologic criteria. ~6-~s Clinical and gross pathologic information was abstracted, summarized, and tabulated as p r e s e n t e d u n d e r the resuhs section. Microscopic and o t h e r findings were correlated and the case classified as to
certainty o f diagnosis as discussed in the section on diagnostic evaluation.
RESULTS
Only six patients were female. Ages r a n g e d f r o m 38 to 82 )'ears; 58 (75 per cent o f the 77 whose ages were known) were between 50 and 69 )'ears o f age. Sixty-eight patients (83 per cent) were known to have had occupational e x p o s u r e to asbestos. T h e clinical symptomatology most f r e q u e n t l y r e c o r d e d was abdominal discomfort o r pain, distention, digestive distnrbances, and weight loss. Palpable abdominal masses were described in some. l'eripheral e d e m a was a c o m m o n finding. Ascites was r e f e r r e d to in 49 cases. In only several was the statement m a d e that at autopsy t h e r e was no fluid in the peritoneal cavity. T h e viscosity o f the fluid varied, in a few being r e f e r r e d to as mucinous. Variations in history ilacluded first detection in a hernial sac (five cases) or partial intestinal obstruction. T h e d u r a t i o n o f life after the onset of symptoms was calculable in 61. It ranged f r o m o n e m o n t h to almost six )'ears. Only 15 patients were known to have survived for m o r e than one year, and 44 per cent were d e a d in six months. T h e description o f the abdominal cavity c o n f o r m e d to several patterns, almost all showing extensive t u m o r involvem e n t o f both visceral and parietal peritoneum. " S t u d d e d with t u m o r nodules" was a c o m m o n descriptive phrase. T h e nodules were o f varying size, f r o m a few millimeters to 5 cm. in diameter. In 26 cases t h e r e were descriptions o f massive accumulations u p to 25 cm., most often in the o m e n t u m and next most f r e q u e n t l y in the lower a b d o m e n and pelvis. Diffuse thickening o f the p e r i t o n e u m u p to 5 or 6 cm. a n d plaques were f r e q u e n t l y mentioned. Adhesions o f varying e x t e n t were c o m m o n , and agglutination o f the entire intestinal tract or obliteration o f the peritoneal cavity with complete i n c o r p o r a t i o n o f all viscera in t u m o r was described in a n u m b e r o f instances. "Encasement o f liver a n d spleen" was often r e f e r r e d to. In only two cases was the t u m o r limited in extent, o n e o f these a laparotomy finding. In this case the t u m o r was situated chiefly be-
PERITONEAL MESOTHELIOMA--KAxxERSTEIN, CHORG tween one lobe of the liver and the diaphragm. In the other, a male, it involved chiefly the pelvis with massive metastasis to the liver. T h e effect of prior laparotomy a n d of radiation or local c h e m o t h e r a p y on the appearance at autopsy must be taken into consideration. T h e microscopic findings encompassed the established diversity o f cell forms and histologic patterns that is virtually unique a m o n g neoplasms originating from a single cell line. Sixty-two (75 per cent) of the cases were designated as epithelial, 18 (22 per cent) as mixed (epithelial and sarcomatoid), and only two as entirely" sarcomatoid. Wide variations in cytohistologic features were present in individual cases, often in adjacent areas. In the epithelial tumors, and the epithelial element o f the tumors of mixed type, cytologic variation ranged from those resembling hyperplastic mesothelium to anaplastic cells, often in a pleomorphic context, that bore no resemblance to mesothelial cells. Over three-fifths o f the epithelial tunaors could be categorized as predominantly" moderately' to well differentiated, although many of these also had areas o f variable anaplasia and pleomorphism. Tubulopapillary, papillary, or tubular patterns, entirely" or predominant1)', characterized about one-third o f the cases (Fig. IA, B, C). In almost half the cases a sheetlike or more or less solidly massed, patternless structure predominated (Fig. 2A). However, more than twothirds of these contained tubular or papillary elements to a greater or lesser extent. Papillations were sometimes only a surface p h e n o m e n o n on the solid masses. T h e cells in the solid formations varied in degree of differentiation and uniformity. R o u n d or polygonal forms, sometimes producing a pavement-like effect, were seen. Occasionally epithelial cells became elongated, assuming an ahnost fl~siform shape but retaining their el)ithelial character. Nuclei varied in appearance, often having a vesiculous character and, as in any anaplastic tunaor, showing irregtdarity in shape and size and large nucleoli. Mitoses increased in fi'equency and a t y p i s m in less differentiated areas. Altlmugh often obviously' consistent
with a mesothelial origin, a degree o f specificity was i m p a r t e d to the appearance of tile less differentiated tumors only with the finding of tubules, papillae, or a sarcomatoid element. Vacuolation, prominent in about one-fourth of tile epithelial tumors, ranged f r o m single cytoplasmic vacuoles, sometimes large enough to produce a signet ring effect, to confluence, with tlle formation o f large intercelhdar spaces. This gave an adenomatoid or even "lacy" appearance (Fig. 1D). Ill tltese vacuoles and spaces hyaluronic acid could be demonstrated. A relatively" small n u m ber of tumors grew in solid cellular cords or clumps e m b e d d e d in stroma. Stroma varied in qtmntity a n d cellularity, from a delicate fibrillar to a more typical copious collagenous, sometimes hyaline form. A myxoid stroma was quite distinctive in a n u m b e r o f tumors (Figs. 1, 2). T h e sarcomatoid component of tumors of the mixed type usually took the form o f spindle or fusiform cells with elongated or oval nuclei (Figs. 1F, 2E). Parallel orientation was frequent, but well developed fasciculation was rare. In some tumors the sarcomatoid cells showed degrees of anaplasia with giant bizarre nuclei. Some tumors of the mixed type even with a lesser degree of cellular differentiation were so characteristic in pattern as to be quite convincing (Fig. 2E). In mixed tumors one could observe in many" instances cells representing a transition from the epithelial c o m p o n e n t to the distinctly sarcomatoid form (Fig. 1F). In several tumors, areas composed of large bizarre multinucleated cells, some reminiscent o f rhabdomyoblasts, were present. O f the two sarcomatoid tumors, one was composed of slender uniform spindle cells and was poor in collagen. T h e other consisted of plumper, r o u n d e r cells that were of a more intermediate type, i.e., with ahnost epithelioid features in some areas. Local invasion occurred in 28 cases, as shown in Table 1, most often into the wall of the gastrointestinal tract. Invasion of the liver capsule was often mentioned, but in five c~ises intraparenchymal extension was specified. Invasion of the abdominal wall was essentially into the scars of previous laparotomies. T h e undersurface of the diaphragm was characteristically covered by nodules, but only
85
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Figure 1. Mesothdiomas of characteristic pattern and well differentiated cell type. il, Tubules lined by ct,boidal epithelium in a myxoid stroma. (x~00.) B, Papillae with cuboidal epithelium covering m)'xoid cores. (x-t00.) C, Tubulol~apillary structures in a collagenous sLroma. (• D, "'Adenomatoid" form with promixmnt vacuolation. (x400.) E, Section stained with colloidal iron stain showing intracytoplasmic acid mucosut)stance (hyaluronic acid; arrows). (x040.) F , Mixed type with el)ithelial tubulopal~illary formations in a sarcomatoid
86
stroma. (x400.)
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Figure 2. Mesotheliomas of acceptable but less characteristic pauern and variable differentialion. A , Monotmmus sheet-like strtzcture. Cells are well differentiated. (x400.) B, Elongated, parallel, relativel)' unifornl tubules. Identification of cell type and other parameters ma)" be required for distinction fi'om adenocarcinoma. (x400.) C, Pure papillary form, not in itself distinguishable from papillary carcinoma. (x500.) D, l.oosel)" dispose0 cells in a myxomatous stroma. This is a faMy characteristic type. (x.t00.) E, Mixed form of rather characteristic pattern but less well differentiated. (x500.)F, Pure sarcomatoid fi)rm without distinct pattern, resembling a fibrosarcoma. (x400.)
87
HUMAN I'ATIIOI.OGY--VOLUME 8, NUMBER 1 Jamm U 1977 TABLE 1.
LOCALINVASION* NO. of
Tissues Invaded
Cases
Gastrointestinal tract (to submucosa-5; to m t , c o s a - 4 ) I.iver parenchyma Abdominal wall Diaphragm Retroperito,mum (massive) Bladder Pancreas (massive)
22 5 6 5 5 2 '2
*Total: 28 cases (22 autopsies).
occasionally was invasion into the diap h r a g m specifically described. In the five cases o f significant retroperltoneal extension, t u m o r s u r r o u n d e d the kidneys in three, involving tim renal capsule but not the kidney itself. In eight cases tim pancreas was described as being s u r r o u n d e d by t u m o r . In m a n y instances f r e e d o m o f the pancreas from t u m o r was explicitly stated. In two cases invasion o f tim pancreas was massive. Invasion o f adipose tissue alone, presumably most often tlm o m e n t u m , the favorite site o f biopsy, was d e m o n s t r a t e d in 32 cases and conceivably o c c u r r e d to a d e g r e e in virtually all cases (Table 1). Metastasis was known to have taken place in 18 o f the autopsy cases (50 per cent). T i m sites o f metastasis are listed in T a b l e 2. Involvement o f lymph nodes was i n t e r p r e t e d as lymphatic metastasis, altlmugh in some instances direct extension fl'om s u r r o u n d i n g t u m o r may have been the route. T h e l y m p h nodes involved were most often the mesenteric and peripan-
creatic. In three cases thoracic nodes, and in t h r e e also inguinal nodes, contained t u m o r (Table 2). T h e r o u t e o f pleural a n d p n l m o n a r y spread has been attributed principally o r entirely to direct extension througll tim d i a p h r a g m , a= Tiffs was true in at least one case o f the seven in tiffs series showing involvement o f the pleura or hmg, and possibly in t h r e e others. In tim r e m a i n i n g cases no continuity or d i a p h r a g m a t i c im'olvement was mentioned. Ptflnmnary blood vessel metastasis was seen ill one case. O f tim 28 cases in which tissue was subjected to the colloidal iron reaction, 11 gave positive staining that was negated or diminished by llyaluronidase. Nine o f these were histologically characteristic in hematoxylin and eosin stained sections. T h e reaction for neutral mucosubstance disclosed n o clearcut positives, several instances being equivocal. P s a m m o m a bodies were present in three cases having a papillary structure. Asbestos bodies were f o u n d in tim h m g sections in 31 of the 32 cases in which this tissue was available. T h e y varied fl'om a few to m a n y in 6 micron hematoxylin and eosin stained sections. Eight o f these disclosed no fibrosis, 15 minimal to mild fibrosis, seven m o d e r a t e fibrosis, and only one severe fibrosis. Hyaline pleural plaques were r e f e r r e d to in 16 cases, in 13 of wlfich lung sections were available. All 13 contained asbestos bodies. T i m o t h e r three patients lind histories o f occupational exposure.
DIAGNOSTIC TABLE 2.
METASTASIS* NO. of
Organs Lymph nodes only (abdominal--5: inguinal-3) Viscera and lymph nodes (viscera and thoracic n o d e s - 3 ) Viscera alone I.iver Ltmg Pleura Pericardium Heart Adrenal 88
EVALUATION
*Total: 18 autopsy cases.
Cases
6 6 6 8 5 6 2 i I
As indicated, tile microscopic features r a n g e d fi'om highly characteristic, p a t t e r n e d , p u r e epithelial and mixed epithelial and mesencilymal forms, througll sheetlike, regular, and p e r h a p s differentiated but nonspecific epithelial and sarcomatoid appearances to poorly differentiated a n d - a t least in a r e a s - w i l d l y pleotnorphic proliferations that are unclassifiable structurall)'. Figure 1 slmws several characteristic mesotheliomas. T h e s e lead to a high d e g r e e o f diagnostic conviction even in tim total absence o f an)" data. In Figure 2 are seen levels o f con-
I'ERITONEAL MESOTI1ELIOMA--KA,~,~ERSTEtN, CnuRc,
9
siderable differentiation with a lack o f specificity that requires the consideration of other entities of visceral or connective tissue o r i g i n - a variety o f carcinomas and sarcomas. Reactive p r o c e s s e s mesothelial o r fibrous tissue h y p e r p l a s i a are also differential problems. In these cases one must know the source o f the specimen, the gross pathologic findings, and sometimes even clinical features. H e r e also m o r e extensive sampling may be required. In this study, starting in most cases with tile knowledge that tile p r o b l e m was tile diagnosis o f mesothelionm, we attempted to maintain a critical approacll to avoid bias. This attitude o f reserve was also a compensation for the deficiencies in data and nmterials ah'eady mentioned. T h e p r o c e d u r e , in essence, was to examine the histologic material, review the gross pathologic and clinical findings, and g r a d e the case as to certainty o f diagnosis. I f the cytohistologic findings c o n f o r m e d closely to characteristic morphologic variants o f the level o f those illustrated in Figure 1, and clinical and gross m o r p h o l o g y was concordant, the case was categorized as definite. I f a case was deficient in o n e or a n o t h e r element (e.g., a less than characteristic microscopic m o r p h o l o g y or lack o f or a p p a r e n t l y inconsistent o r complex gross pathology o r history), it was classified, at most, as probable. T h u s in the absence o f autopsy findings, even when the microscopic a p p e a r a n c e was characteristic, the case was placed in the probable category. Conversely, even if autopsy findings were quite consistent but the microscopic features were poorly differentiated, the grading was r e d u c e d proportionately. (These j u d g m e n t s will be analyzed f u r t h e r in the discussion.) In addition, certain complications, such as the presence o f a second t u m o r o r the history o f s u r g e r y for cause tmknown when tiffs may have been a neoplasm, led to evaluation with caution as to the certainty o f diagnosis o f mesothelioina. T h o s e rated as merely possible--and this category itself includes a span o f e v a l u a t i o n - w e r e essentially o f an atypical or poorly differentiated m o r p h o l o g T. In the course o f collection o f this series a n u m b e r o f cases were received tlmt were rejected unequivocally. Titese
were r e g a r d e d as t u m o r s o f other histog e n e s i s - usually c a r c i n o m a s - o n the basis o f histology. In some a llistochemical reaction favoring c a r c i n o m a was the decisive factor in such exclusion (Fig. 3). In o t h e r c a s e s - a n d this was the difficult or gray a r e a - t h e possibility o f a mesothelioma could not be categorically denied. T h e s e fell into two subgroups: those in which o u r own considered j u d g m e n t based on histologic study and in some cases also gross nlorphologic o r clinical features favored a n o t h e r origin, and those in which we were unable to make any d i s t i n c t i o n - a position o f neutrality. Such cases were not included in tiffs report. T a b l e 3 presents a g r o u p i n g by estimated degrees o f certainty o f diagnosis, based u p o n the f o r e g o i n g considerations. It will be noted that only 22 (27 per cent) met all the criteria previously established for a definite diagnosis, whereas 51 (62 per cent) were r e g a r d e d as probable. However, 20 o f the probable cases showed characteristic histologic features and were d o w n g r a d e d because o f lack o f an autopsy, o r in o n e case because o f the presence o f a n o t h e r tumor. I f these histologically typical cases were a d d e d on the basis o f histologic findings to the definite g r o u p , 42 (51 per cent) could be r e g a r d e d as established. It may be pointed out that the probable categorization in general implies a high d e g r e e o f p r e f e r e n c e for the diagnosis o f mesothelioma. T h e s e two categ o r i e s - definite and p r o b a b l e - combined account for 89 p e r cent of the series. In the nine cases g r a d e d as possible, the diagnosis was favored o v e r that of any o t h e r type o f t u m o r (Table 3). O f the 14 autopsy cases that were not unequivocally accepted, six had a consistent gross a p p e a r a n c e but poorly differentiated histologic features. Table 4 lists these less than totally accepted cases and the reasons for the reservations (Table 4).
D I S C U S S I O N
T h e paucity o f females and the high incidence o f asbestos e x p o s u r e in tiffs series are, o f course, attributable to occupational selection. T h e relatively small m n n b e r o f patients with reasonable certainty o f no asbestos e x p o s u r e frustrates
89
HUMAN PATHOLOGY--VOI,U*IE 8, NUMBER 1 Jamm~3" 1 9 7 7 TABLE 4.
T A B L E 3. DIAGNOSIS BY DEGREE OF CERTAINTY
Definite mesothclioma Probable (histologically typical but n o autopsy--20 cases) l'ossible mesothelioma
AUTOpS'cCASES NOT IN
DEFINI I-E GROUP
'2'2 cases
51 cases 9 cases
No. of Cases A u t o p s y c o n s i s t e n t btlt t u m o r
poorly differentiated Autopsy consistent but second tl.III]or p r e s e n t
any a t t e m p t to find distinctions between exposed and n0nexposed. T h e clinical a n d gross pathologic findings parallel those n o t e d in the literature dealing with peritoneal mesothelioma. 2-~~ ra Althougll nonspecific with respect to these features and indistinguishable in general f r o m certain carcinomas w h e n these are widely d i s s e m i n a t e d in the p e r i t o n e u m , cases o f ntesothelioma a r e very similar to each other. Considerable d e p a r t u r e f r o m these p a t t e r n s - p a r t i c u larly in the gross m o r p h o l o g y - s l m u l d occasion careful scrutiny o f the case a n d weighing o f the diagnosis o f mesotheliOllla.
It is o f interest that we were not presented in this series with a single instance o f localized m e s o t h e l i o m a o f the fibrous type described by Stout -~~ a n d others, TM z., a n d that we lmve seen in the l)eritoneum in o n e instance in a n o t h e r series, a n d m u c h m o r e fi'equently in the pleura. O f the two cases o f limited e x t e n t o f growth in the p r e s e n t g r o u p , o n e can be r e g a r d e d as being representative m e r e l y o f an earlier stage in the course o f s p r e a d and the o t h e r as b e i n g atypical. In all o t h e r cases the t u m o r was widely distributed when s y m p toms c o m m e n c e d . In this series we were not able to arrive at any consistent correlation between cell type, histologic p a t t e r n , or overall d e g r e e o f differentiation a n d length o f survival. H o w e v e r , the cases o f patients surviving f o r o v e r one year w e r e in ahnost all instances r a t e d as microscopically characteristic, whereas the cytohistologic features in
Autopsy findings atypical l'revious orchiectomy for unknown diagnosis
those s u r v i v i n g three m o n t h s o r less were onl)' m o d e r a t e l y differentiated. T h e bulk o f the cases, falling between these time limits, were essentially m o d e r a t e l y or well differentiated. Since most patients with m e s o t h e l i o m a , particularly o f the perit o n e u m , are d e a d within o n e )'eat" a f t e r the onset o f s y m p t o m s , r~ this f e a t u r e c a n n o t be used to distinguish m e s o t h e l i o m a f r o m visceral c a r c i n o m a , even c a r c i n o n m o f the pancreas..~.~.:24 Carcinomas o f the o v a r y and stonmch are subject to m o r e variables. 25' 26 Only the relatively few patients with mesothelioma surviving for o v e r two )'ears with a k n o w n a b d o m i n a l tnnlor a n d ascites can b e said to be d e m o n s t r a t i n g a biologic distinctiveness. T h e classification as to cell type is also subject to observer variability. Differences in i n t e r p r e t a t i o n m a y exist as to w h e t h e r a fibrous c o m p o n e n t is truly neoplastic o r m e r e l y a cellular stronta. In o u r study a t u m o r was r e g a r d e d as m i x e d only if the m a l i g n a n t clmracter o f the mesenchymal e l e m e n t s e e m e d unequivocal. A point w o r t h y o f mention is the a p p a r e n t l o w e r f i e q u e n c y o f p u r e sarcontatoid growths in the p e r i t o n e u m as c o m p a r e d with the pleura. T h e value o f histochemical study for m u c o s u b s t a n c e s as an objective aid in the diagnosis o f m e s o t h e l i o m a has often b e e n c o n m t e n t e d u p o n with diverse conclusions. Such m e t h o d s are o f least assistance in es-
Figure 3. Tu,nors simulating mesotheliomas by extensive serosal growth. ,'1.Adenocarcinoma of u,adetermined origin. Tumor, in general, sttggested an adenocarcinoma cytologically. (x.t00.) II, Same case as in A. Section stained with PAS, after diastase, disclosing neutral mucin secretion in h, mina as seen in adenocarcinoma (arrows). (• C, Growth of small cells on peritoneal surface, metastatic fiom an undifferentiated gastric carcinoma. (• D, Same case as in C. Section stained with PAS, after diastase, showing nmrked cytoplasmic granular fuchsinophilia indicating neutral mucin. (x640.) E, Somewhat papillary tumor, apparently from ovary. (x400.) F, Metastasis fi'om cystosarcoma phyllodes resembling a sarcomatoid mesothelioma. (x400.) 9
90
I'ERITONEAL MESOTHEIJOMA--KANNFRSTEIN, CIiURG
',~1v " C ' ~ + ~ " ~ ? * ++9
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91
HUMAN I'ATHOLOGY--VOLUME 8, NUMBER 1 Janumy 1977
92
tablishing the identity o f a poorly differentiated mesothelioma in which acid mucosubstance may not be p r o d u c e d , but can be o f distinct help in m a n y m o r e highly differentiated tumors. A negative PAS reaction with a positive colloidal iron reaction r e m o v e d by lwaluronidase, following criteria set down elsewhere, may be conclusive in the diagnosis o f a mesothelioma that is difficult to distinguish otherwise from an a d e n o c a r c i n o m a Y A definitely positive PAS reaction in a poorly differentiated t u m o r established the diagnosis o f carcinoma, and this is helpful when there is extensive serous m e m b r a n e involvement a n d the existence o f a p r i m a r y t u m o r has not been clearly d e m o n s t r a t e d . It may be pointed out that acquired j u d g m e n t is helpful when only small a m o u n t s of mucosubstance are present or when o t h e r tissue elements, for example, projections o f s t r o m a or necrotic cellular material, simulate secretion. A n u m b e r o f writers have noted tlmt autopsy is f r e q u e n t l y not essential in nmking a definite diagnosis. 5" ~s In individual cases, and fox" practical purposes, such confirmation may not be necessary, especiall), for those familiar with the diversity o f cytohistologic expressions of this neoplasm. In man)' instances, however, a carefnlly p e r f o r m e d autopsy is o f great exclusionary value. T h e r e may o f course be limitations to the informational value o f an autopsy. In cases o f very advanced and extensive t u m o r growth it may be difficult to distinguish p r i m a r y fi'om secondary o r g a n invoh'ement. A tiny or even possibly involuted prinmry t u m o r or one concealed by secondary growth may escape identification. 2s A r e p o r t o f previous surgical extirpation with findings u n k n o w n confuses some cases. In any event an apparently c o n c o r d a n t autopsy is meaningful only to the extent tlmt the histologic findings are consistent with mesothelioma. In this series f o u r cases were known to have been associated with primary visceral tumors. O n e was an oat cell carcin o m a o f the lung, a n o t h e r an adenocarcin o m a o f the prostate. T h e accompanying mesotheliomas were so typical and so diff e r e n t from the carcinomas that no problena o f distinction existed. In the o t h e r cases the mesotbeliomas were less clmracteristic. In one t h e r e was said to have been
a large a d e n o n m o f the adrenal cortex, no section o f which was available to us; this case was c o n s i d e r e d as merely probable. Examination in the fourth case was said to have shown bilateral plleocllromocytomas of the adrenals. Although no confusion of t u m o r s was considered likely, this case also was less characteristic in its gross manifestations. As to the identity o f t u m o r s that simulate a mesothelioma grossly--and often m i c r o s c o p i c a l l y - i n the pleura, they appear most often to be p e r i p h e r a l puhnonary adenocarcinomas. 16, ''~ In the periton e u m , in females, certain ovarian tumors may play a sinfilar role, even t h o u g h an ovarian t u m o r would seem to be m o r e easily detectable grossly. T h e recently detined papillary surface t u m o r s o f the ovary of so-called borderline nmlignancy, particularly, might u n d e r some circumstances cause diagnostic difficult)'. T h e s e tumors have a t e n d e n c y to disseminate by seeding the p e r i t o n e u m ? ~ 3~ T h e potentialities o f cells in the pelvis of women, perhaps o f p a r a m e s o n e p h r i c or m e s o n e p h r i c type, and their relationslfip to the mesothelinm have been discussed? -~ 33 One might revive the c o n c e p t o f embryonal r e m n a n t s o f the paranaesonephros or m e s o n e p h r o s as the source o f carcinomas that grossly resemble a mesothelioma but show a p r e d o m i n a n c e in the pelvis? 4 In the male no one organ has been indicted as the p r e d o m i n a n t site of origin o f a carcinoma that yields diffuse, often massive peritoneal spread yet remains so occult as to escape detection. l'resunmbly a carcinoma o f the body o r tail o f the pancreas o r o f the stonmch migl!t belmve in tiffs way. 23' as-at However, in some cases abdominal carcinomatosis that imitates mesoti~elioma does so apparently even to the extent o f following the restrained visceral metastatic behavior o f the mesothelioma rather titan the m o r e florid metastatic proclivity o f typical pancreatic or gastric carcinoma. F u r t h e r study in this area is requisite. T h e diagnosis o f mesothelioma should not be a repository for t u m o r s in wlfich a prinmry site cannot be d e m o n s t r a t e d . It is a specific identifi.cation, its origin limited to a single cell species, despite the versatility o f expression o f tlmt cell. M cCat , i ghey 3s lms succinctl)' s u m m a r i z e d the basis f o r accurate histologic diagnosis:
PERITONEAL
recognition o f the capacity of the malignant mesothelial cell to form~ widely different types of neoplastic tissue, famili~irity .with t h e more specific structural patterns of the tumor, and a good knowledge of general tumor pathology. This statement incorporates a considerable number of variables. Thus despite a reluctance to be less than categorical, it is believed that a grading system such as that employed in this report is realistic.
14. 15.
16. 17.
ACKNO~VLEDGMENTS 18.
Most of the cases associated with asbestos exposure were obtained through the courtesy o f Dr. I.J. Selikoff. Appreciation is also expressed to a number of physicians who submitted their cases for consultation. Excellent technical assistance was given by Mr. A. l'rado. REFERENCES 1. Miller, J., a n d Wynn, W. H.: A malignant tumor arising from the endothelium of the peritoneum and producing a mucoid ascitic fluid. J. Path. Bact., 12:267, 1908. 2. Godwin, M. C.: Diffuse mesotlleliomas. Cancer, 10:298, 1957. 3. Winslow, D. J., and Taylor, It. B.: Malignant peritoneal mesothelionms. Cancer, 13:127, 1960. 4. Keal, E. E.: Asbestosis and abdominal neoplasms. Lancet,2:1211, 1960. 5. Bolio-Cicero, A., Aguirre, J., and l'erez-Tamayo, R.: Malignant peritoneal mesothelioma. Amer. J. Clin. Path.,36:417, 1961. 6. Enticknap, J. B., a n d Smitber, W. J.: Peritoneal tulnors in asbestosis. Brit. J. had. Med., 21:20,
1964. 7. Hourihane, D. O.: T h e pathology o f mesotheliomata and an analysis of their association with asbestos exposure. Thorax, 19:268, 1964. 8. Mann, R. H., Grosh,J. L., and O'Donnell, W. M.: Mesothelioma associated with asbestos. Cancer, 19:521, 1966. 9. Smith, I'. G., Higgins, P. McR., and Park, W. D.: Peritoneal mesothefioma presenting surgically. Brit.J. Surg.,55:681, 1968. 10. Roberts, G., and Irvine, R. W.: Peritoneal mesuthelioma. Brit.J. Surg.,57:645, 1970. 11. McDonald, A. D., Magner, D., and Eyssen, G.: Primary malignaut mesothelial tumors in Canada, 1960-1968. Cancer, 31:869, 1973. 12. Thomson, J. G.: T h e pathological diagnosis of malignant mesothelioma of pleura and peritoneum. In Shapiro, H. A. (Editor): Proceedings of lnternatioual Conference on l'neumoconiosis. Cape Town, Oxford University Press, 1970, p. 150. 13. Selikoff, I.J., Hammond, E. C., and Seidman, ti.:
19. 20. 21.
22. 23. 24.
25.
26.
27.
28. 29.
30. 31. 32.
33.
MESOTHELIOMA~KAX:~ERSTEIX,
CnURG
Cancer risk o f iusulation workers in the United States. In Biological Effects of Asbestos. Lyon, I.A.R.C., 1973, p. 209. Newhouse, M. L.: Cancer among workers ill the asbestos textile industry. In Biological Effects o f Asbestos. I.yon, I.A.R.C., 1973, p. 203. Suzuki, Y., Kannerstein, M., aqd Clmrg, J.: Electron microscopy of normal, hyperplastic and neoplastic mesotllelium. In Biological Effects of Asbestos. I.yon, I.A.R.C., 1973, p. 80. McCaughey, W. T. E.: Criteria for diagnosis o f diffuse mesothelial tumors. Ann. N.Y. Aead. Sci., 132:603, 1965. Churg, J., Rosen, S. H., and Moolten, S. E.: Histological characteristics of mesothelioma associated with asbestos. Ann. N.Y. Acad. Sci., 132: 614, 1965. Hourihane, D. O.: A biopsy series of mesotheliomata and attempts to identify asbestos within some of the tumors. Ann. N.Y. Acad. Sci., 132:647, 1965. Ehnes, P. C.: T h e natural history ofdiffose mesothelioma. In Biological Effects of Asbestos. Lyon, I.A.R.C., 1973, p. 267. Stout, A. P.: Solitary fibrous mesothelioma of peritonetnn. Cancer,3:820, 1950. Nevius, D. B., and Friedman, N. B.: Mesotheliomas and extraovarian thecmnas with Iffpogl)cemia and nepllrotic syndrome. Cancer, 12:1263, 1959. Lowbeer, L.: Extrapancreatic tumors and hypoglycemia. Amer. J. Clin. Path., 35:233, 1961. Duff, G. L.: Clinical and pathological features of carcinoma of the body and tail of the pancreas. Bull. Johns Hopkins Hosp., 65:69, 1939. Glenn, F., and Throbjarnarson, B.: T h e pancreas. In Nealon, T. F. (Editor): The Managemeat of the Patient with Cancer. Philadelphia, W. B. Saunders Company, 1965, p. 604. Munnell, E. W., and Taylor, tt. C.Jr.: T h e ovary. In Nealon, T. F. (Editor): T h e Management of the Patient with Cancer. Philadelplfia, W. B. Saunders Company, 1965, p. 719. McNeer, G.: T h e stomach. In Nealon, T. F. (Editor): T h e Management of the Patient with Cancer. l'hiladelphia, W. B. Saunders Company, 1965, p. 561. Kannerstein, M , , Churg, J., and Magner, D.: Histochemistry in the diagnosis of malignant mesothelioma. Ann. Clin. Lab. Sci., 3:207, 1973. Willis, R. A.: l'athology of Turnouts. Ed. 4. London, Butterworth & Co. (l'ublisllers) Ltd., 1967, p. 181. ltarwood, T. R., Grace)', D. R., and Yokoo, tt.: l'seudomesotheliomatous carcinoma of the lung. A variant of peripheral hmg cancer. Amer. J. Clin. Path., 65:159, 1976. Scully, R. E.: Recent progress in ovarian cancer. Hum. l'atlml., 1:73, 1970. Julian, G. J., and Woodruff, J. D.: Biologic belmvior of low-grade papillary serous carcinoma of ovary. Obstet. Gynec., 40:860, 1972. Swerdlow, M.: Mesothelioma of the peh'ic peritoneum resembling papillary cystadenocarcinoma of the ovary. Amer. J. Obstet. Gynec., 77:197, 1959. Parmley, T. tt., and Woodruff, J. D.: T h e ovarian mesothelioma. Amer. J. Obstet. Gynec,, 120: 234, 1974.
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34. Changns, G. W.: Fine structure of so-called mesonephric carcinoma. Lab. Invest., 20:579, 1969 (abstr.). 35. Bell, E. T.: Carcinoma of the pancreas. Amer. J. Path.,33:497, 1957. 36. Ackerman, L. V., and Rosai, J.: Surgical Pathology. Ed. 5. St. Louis, The C. V. Mosby Co., 1974, p. 1176.
1 Janualy 1977
37. Morson, B. C., and Dawson, I.M.P.: Gastrointestinal Pathology. Oxford, Blackwell Scientific Publications, 1970, p. 154. 38. McCaughey, W. T. E.: Morbid anatomical and histological criteria for the diagnosis of diffuse mesothelioma. Conference on the Biological Effects of Asbestos, Lyon, 1972 (unpublished communication). Department of Pathology Baruert Memorial Hospital Center 680 Broadway Paterson, New Jersey 07514 (Dr.
94
Kannerstein)
