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Diffuse Malignant Mesothelioma

MARCELLA KLIMA, M.D., HARLAN J. SPJUT, M.D., AND WILLIAM D. SEYBOLD, M.D.

Veterans Administration Hospital, Houston, Texas 77211, St. Luke's Episcopal Hospital, and Kelsey-Seybold Clinic,
and Baylor College of Medicine, Houston, Texas 77025

ABSTRACT

Klima, Marcella, Spjut, Harlan J., and Seybold, William D.: Diffuse
malignant mesothelioma. Am J Clin Pathol 65: 583-600, 1976. Thirteen
cases of diffuse malignant mesothelioma, 12 pleural and one peritoneal,
were examined and reviewed from the clinical and morphologic points
of view. T h e most frequent symptom and sign were pain and effusion.
Periods of survival varied, with one patient surviving 11 years despite
morphologic features of the pleural tumor. T h e diagnosis can be made only
on the basis of excised tumor tissue. T h e best control of the tumor is at-
tained by repeated surgical removal. Neither radiation nor chemotherapy
altered significantly the growth of the tumors. (Key words: Mesothelioma,
diffuse, epithelial, sarcomatous; Clinical, diagnostic, histologic and electron
microscopic aspects.)

DURING the last two decades, interest in had experience widi 13 malignant meso-
diffuse malignant mesothelioma has in- theliomas over the past 15 years.
creased steadily. The tumor seems to occur,
or at least is diagnosed, more frequently Material and Methods
than in the past.22 Electron microscopy
and tissue cultures helped to establish that Our study group comprised 13 patients
these tumors originate from the meso- examined and treated in our hospital. T h e
thelium, 30 which is pluripotential, 15,20,29,33 clinical details are shown in Table 1. Twelve
and that they do not represent metastases of the lesions were primary pleural tumors,
from obscure tumors, as many investi- four extending into the peritoneum. One
gators believed.34 Also interesting are the was a primary peritoneal mesothelioma
epidemiologic aspects related to as- with a solitary metastasis in a mediastinal
bestos.4-6-18-26'28 lymph node.
Malignant mesothelioma is still un- Tissues for diagnosis and study were ob-
common. Thus, additional information tained from 31 operative procedures and
concerning morphologic features and bio- three autopsies. Ten patients had repeated
logical behavior is needed. At St. Luke's surgical operations (Table 2). Tissue from
Episcopal Hospital in Houston, we have eight patients was examined electronmicro-
scopically. One specimen from each of
four patients, two different specimens
Received February 27, 1975; received revised
manuscript J u n e 2, 1975; accepted for publication from three patients and four specimens
June 2, 1975. from one patient were available.
Address reprint requests to Dr. Klima: Department
of Pathology, Veterans Administration Hospital, Specimens for cytologic examination
Houston, Texas 77211. came from repeated thoracenteses of seven
583

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Table 1. Clinical Data 00

Age No. of

on 13 February 2018
(Yr.), Related Follow-up from first
Sex Occupation Initial Symptom Operations X-Ray Therapy Visit to Physician

Patient 1 49, M Lawyer Pleural pain Pleural fluid Irradiation (6,000 Died 11 yr.
(long-lasting) rads in 28 days)
Radioact. gold

Patient 2 46, M Petrol, engr. Acute pneumo- Pleural density Irradiation (6,000 Died 9 mo.
thorax rads in 42 days)
(4,000 rads in
14 days)
Hydroxyurea

Patient 3 28, M Geologist Pleural pain Intrapleural mass Irradiation (6,000 Died 10 mo. >
(short-lasting) rads) en
Actinomycin D
C
H
Patient 4 42, F Teacher Pleural pain Coin lesion Irradiation Alive 8 yr. >
2
(long-lasting) recently D

Patient 5 50, F Cook, later Pleural pain Pleural fluid Atabrine Died 2 mo. w
housewife (long-lasting) <

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Repeated effusion O

Patient 6 40, M Geologist Pleural effusion Pleural fluid No Died 2!4 yr.
Pleural thickening Autopsy
elsewhere

Patient 7 57, M Boiler rm. Pain in scapula Pleural fluid Thiotepa Died l'/2 yr.
engr. Shortness of Fluffy densities
breath

Patient 8 58, M Diff. unrrel. Back pain Bronchogenic No Died 11 mo. 4)


occupations Pleural effusion carcinoma
as mechanic Weight loss
£
May 1976 DIFFUSE MALIGNANT MESOTHELIOMA 585

patients and from bronchial washings and


sputum of two patients.
IM

Results

a a. a. Clinical Findings

live
uto
uto
ied
ied

•o 2
.£ 3 ied
a< a Q < Q < < Most patients were in the fifth or sixth
decade of life, with an age range of 2 8 - 6 9
years. Eleven have died and two are alive.
Cobalt
'toxin
phos.

One of the two women in our group is


1) >*
surviving in the eight year. T h e shortest
cil

a.
mycin

g ra .a O ra" ra
Q.
.9 « l; E E
fc- 3 p
OJ" V
Jj
survival from admission until death was 2
S °> c o
c
luoro
chr

'C 0
bri

0
c JS JS
_o months; the longest was 11 years.
xra •5
cti

S ra
g JS ft. h ra 0
T h e predominant symptom was pain
i h < < S u. 8 < os Z
localized to the thoracic region on the
60 bo
affected side; two patients had pain in other
C _C U
< locations—one in the shoulder on the same
>/~
) 3 tfl X,
u w c
leu ral thiceke

0S3
ELU

ro j3 •a t T3 1^- side, the other in the lumbar region. T h e


leu ral flui
t. mid. lo

ma (19
leural flui

leu ral flui

OSS ible m

latter (Patient 8) had undergone laminec-


toneal

assive
loll;apsed

973)

tomy before a diagnosis of pleural effusion


E ^. _o was made. In three instances a spontaneous
ft. OS ft.
•s
P. ft. ft. ft.
U
pneumothorax was the first clinical symp-
tom, preceding the diagnosis of pleural
tumor by several months in two patients.
An important symptom was persistent ef-
fusion, which was present in three of our
cases (Table 1). Two patients had histories
of chronic respiratory disease (asthma and
c
pneumonia), and two had significant
«5
o
3 § '35 V
weight losses during the illness.
o .E
rtn

2 5 U-i
JS
JS ra There did not appear to be any signifi-
JS u- OJ 0 ra
u
S u •5 . u o °- cant factor in the social and occupational
ra JS
3 -SP S
c i3
13 c
U •ra
o
UH
0
II histories of our patients. Almost all were
S £ 0- ft. A. aj 3
city dwellers, although their occupations
s ft. ft.
brought some of them into the rural areas.
For example, two were geologists and one a
a. school teacher from rural New Mexico.
3
While six patients could be considered as
-O ra
c <u
, u JS having possible exposure to asbestos, chem-
2 ~ CM
t/3
ra
(J
OS
I icals or dusts, others did not. Six of the pa-
tients smoked, but only one was considered
a heavy smoker. One was an alcoholic.
•o Seven of the eleven patients who died
were presumed to have died of tumor, as
autopsies were not done. Four patients
had autopsies; three in our hospital and the
fourth in another hospital in Houston.
All four had extensive tumors of the

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586 KLIMA, SPJUT AND SEYBOLD A.J.C.P.—Vol. 65

Table 2. Morphologic Features


Site Histologic types

Patient 1 Pleural Glandular, myxomatous stroma


Patient 2 Pleural Sarcomatous, myxo-fibromatous stroma
Patient 3 Pleural Sarcomatous, fibromatous vascular stroma
Patient 4 Pleural Sarcomatous, myxo-fibromatous stroma, vascular
Patient 5 Pleural Glandular, fibrous stroma
Peritoneal extension
Patient 6 Pleural Glandular (tubular), dense collagenous stroma
Patient 7 Pleural Glandular with sarcomatous areas, myxomatous stroma
Patient 8 Pleural Glandular, myxomatous stroma
Patient 9 Pleural Glandular, myxomatous stroma
Peritoneal extension
Patient 10 Pleural Glandular, myxo-fibromatous stroma
Peritoneal extension
Patient 11 Peritoneal Glandular, myxo-fibromatous stroma
Patient 12 Pleural Sarcomatous
Peritoneal extension
Patient 13 Pleural Sarcomatous with glandular foci

thoracic cavity widi spread to the ab- tablished by other means. Most of the
dominal cavity. No other tumor was found. cytologic reports were either inconclusive
or negative. Even a direct touch smear of a
Roentgenologic Findings tumor obtained during an operation did
not result in a positive diagnosis.
All patients had roentgenologic studies.
T h e basic morphologic changes, pleural
fluid and pleural thickening or intra- Surgical Findings
thoracic mass, were described, but the
Sooner or later, the patients underwent
diagnostic interpretations ranged from
thoracotomy and/or laparotomy. Three
adhesions to possible bronchogenic car-
had both procedures. In six patients the
cinoma. In only one case was a diagnosis
lesions were considered nonresectable
of mesothelioma suggested by the roent-
(Table 3).
genologist. However, the roentgenograms
In most of the patients, the tumor was
were helpful and were essential in the
nodular (Fig. 1) and diffuse. Where it was
differential diagnosis and in making the
possible, the parietal pleura with the tumor
decision for a surgical procedure.
was removed; however, in four patients
lung tissue was excised, ranging from
Cytology biopsy through hemilobectomy to lobec-
Some of the patients had repeated thor- tomy. In one patient who had thoracic
acenteses or abdominal paracenteses. T h e involvement the tumor extended into the
results of the examinations of four fluids abdominal cavity and was diagnosed by
in two patients were positive, but the biopsy of omentum (Patient 10). One pa-
diagnosis of mesothelioma had been es- tient initially had resection of pleural ad-

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May 1976 DIFFUSE MALIGNANT MESOTHELIOMA 587

hesions, but three years later the tumor Epithelial-like cells formed tubular, cystic
was nonresectable, extending through the or cystopapillary formations with a scant
chest wall (Patient 1). Another patient had myxoid and fibrous stroma (Fig. 2). In
recurrent tumor with seven local pleural only one case (Patient 6) was the stroma
resections and finally a lobectomy was densely fibrous (Fig. 3). Focal necrosis was
done; the patient is alive (Patient 4). found occasionally. There was no ap-
parent transition from stromal to glandular
cells. T h e tumor cells were 2 0 - 5 0 /u,m. in
Histologic Findings
diameter and were round to polygonal,
Eight of the mesotheliomas presented a distinctly outlined, and had abundant
predominantly pseudoglandular pattern. eosinophilic (with hematoxylin-eosin

Table 3. Surgical Review


Date of Interval from
First Visit First Visit to
to Physician Operations Diagnosis

'atient 1 12/1953 1954 dissection of adhesions 4 yr.


6/1957 thoracotomy (inoperable)*
'atient 2 2/1964 2/1964 lobectomy*
2wk.
6/1964 excision of tumor implant
'atient 3 12/1964 5 mo.
5/1965 hemilobectomy*
'atient 4 12/1966 3 mo.
3/1967 resection of pleural tumor*
7/1970 resection of recurrent tumor
4/1971 excision of tumor extending in chest wall
5/1972 resection of recurrent tumor
11/1972 pleurectomy
1/1973 pleurectomy
10/1973 pleurectomy (Waco, Texas)
5/1974 lobectomy
Patient 5 7/1970 9/1970 pleurax bx. (open) 2 mo.
9/1970 laparotomy*
Patient 6 11/1970 11/1970 pleural bx. (open) 8 mo.
7/1971 pleurectomy*
Patient 7 1/1971 2/1971 thoracotomy (inoperable)* 1 mo.
5/1971 excision of chest meta.
8/1971 excision of chest meta.
Patient 8 8/1971 1971 laminectomy (elsewhere)
4/1972 exploratory laparotomy
6/1972 thoracotomy (inoperable)* 10 mo.
Patient 9 12/1971 5/1972 RM lobectomy
9/1972 laparotomy (inoperable)* 9 mo.
Patient 10 9/1971 4/1973 exploratory laparotomy (inoperable)* 1 !4 yr.
Patient 11 3/1971 3/1971 exploratory laparotomy* 1 wk.
5/1972 omental bx.
Patient 12 1/1973 3/1974 excision of metastasis* 14 mo.
Patient 13 4/1974 3/1973 pleurodesis
1/1974 thoracotomy* 2yr.
* Diagnostic surgery.

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588 KLIMA, SPJUT AND SEYBOLD A,J.C.P.—Vol. 65

FIG. 1. Diffuse malig-


nant mesothelioma. Nodu-
lar spread of tumor over
the parietal pleura and
diaphragm. Inset. Close
view of the nodular tumor.
xl.5.

stain) cytoplasm with lighter paranuclear which, in some places, had an undulating
staining (Fig. 4). Occasionally, a large pattern. T h e tenuousness of the cellular
clear vacuole or foamy area was seen in the attachments was reflected by free-lying cells
cytoplasm (Fig. 5). T h e glandular struc- in the glandular lumina.
tures were formed by loosely arranged cells The nuclei were predominantly vesicu-

FIG. 2 (upper, left). Patient 9. Epithelial type of mesothelioma. Note the cystopapillary formations,
the tendency to separation of cells, and the scant, loose stroma. Hematoxylin and eosin. xlOO.

FIG. 3 (upper, right). Patient 6. Epithelial type of mesothelioma. Tubular (pseudoglandular) structures
and dense collagen. Hematoxylin and eosin. x 5 2 . Inset. Higher magnification of a pseudogland.
T h e area surrounded by tumor cells is also collagen. Hematoxylin and eosin. X 120.

FIG. 4 (second row, left). Patient 9. High magnification of tumor cells in the epithelial type of malig-
nant mesothelioma. Note the peripheral rim and the abundance of cytoplasm. T h e nuclei contain
small but prominent nucleoli. Hematoxylin and eosin. x650.

FIG. 5 (second row, right). Patient 9. High magnification of tumor cells in epithelial type of mesothelioma.
Note the perinuclear clearing of cytoplasm and peripheral vacuoles. Hematoxylin and eosin. X590.

FIG. 6 (third row, left). Patient 12. Sarcoma-like type of mesothelioma, showing the dense arrange-
ment and interweaving pattern of tissue. Note the resemblance to other mesenchymal tumors. Hematoxylin
and eosin. x280.

FIG. 7 (third row, right). Patient 12. Sarcoma-like type of mesothelioma, showing denser and looser
areas with some plump cells. Hematoxylin and eosin. x 9 8 .

FIG. 8 (lower, left). Patient 4. Sarcoma-like type of mesothelioma, showing the plump cells and thick
vascular walls. Note the pale nuclei and prominent nucleoli. Hematoxylin and eosin. x230.

FIG. 9 (lower, right). Patient 2. Sarcoma-like type of mesothelioma, showing the fibrosing pattern and
the vacuolated, plump tumor cells. Hematoxylin and eosin. X280.

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May 1976

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590 KLIMA, SPJUT AND SEYBOUD A.J.C.P. —Vol. 65

lar, rounded, sometimes with small in- found continuity between the luminal con-
dentations of the nuclear membrane. They tent and the surrounding stroma, suggest-
were not large in comparison with the ing that they were pseudoglands (Fig. 3,
amount of cytoplasm. Small but prominent, Table 2).
round, nucleoli were common. Mitoses Special stains, including Mallory's tri-
were rare. chrome, periodic acid-Schiff reaction, re-
In five cases, the tumor was predomi- ticulin, mucicarmine, and Alcian blue, were
nandy sarcoma-like. Densely arranged, done on most of the tissues. T h e sarcoma-
elongated cells were reminiscent of fibro- tous cells stained red with trichrome.
sarcoma or leiomyosarcoma. However, Mucin stains were negative in all of the
there were focally plump cells with dark cases, and reticulin was more abundant
eosinophilic cytoplasm, but no epithelial in the sarcomatous tumors than in the other
structures were present. The nuclei tended types. T h e PAS reaction was occasionally
to be rounded, vesicular and contained focally positive and reflected the glycogen
small prominent nucleoli (Figs. 6 - 9 ) . content in some of the tumors. Alcian blue
Mitoses were more frequent than in the stain showed blue-green vacuoles in the
glandular type, but still not abundant. large cells of glandular type.
T h e stroma varied from dense, collagenous We did not see transformation from one
to slightly myxoid. These sarcoma-like histologic type to another, nor was there a
tumors were richly cellular and could be change in tumor pattern following multiple
differentiated from the "solitary fibrous" resections or other therapy.
mesothelioma by this cellularity and by the
different gross pattern. Electronmicroscopic Findings
All of the tumors were very vascular. Of the eight cases studied electronmicro-
T h e vessels formed peculiar wide channels scopically, three were sarcomatous and five
with thick fibrous walls and occasional were epithelial mesotheliomas.
prominent endothelial cells (Figs. 7 and 8). T h e basic cell was large and polygonal.
In some parts of the tumor, the vessels T h e cytoplasm formed many slender
were dominant, suggesting a tumor of microvilli on part of the surface (Fig. 10).
vascular origin. Where the cells were more tightly packed,
In one of our cases (Patient 7), there the microvilli interlocked (Fig. 11). Some
was a mixed epithelial and sarcoma-like of the cellular surfaces were smooth with
pattern. However, the two were distinctly focal dark areas similar to those seen in
separate, with only a small area of transi- tight junctions and on the surface of
tion. In another (Patient 6) we noticed an smooth muscle cells. Occasional des-
interesting feature. T h e small gland-like mosomes were observed (Fig. 10). An
structures were lined by cuboidal, rather interesting and important feature was the
than polygonal, cells. Their lumina were formation of large intracellular vesicles
filled by dense material, with a staining lined by microvilli (Fig. 12, inset).
reaction of collagen. In some areas we The most prominent organelle in all
>
FIG. 10 (upper). Patient 7. Typical cell from epi thelial type of mesothelioma, showing slender long
abundant microvilli on the left and basal membrame on the right side of the surface. Note the row of
desmosomes in the left lower corner, x 12,000.

Fie. 11 (lower). Patient 9. A tumor cell from the epithelial type of mesothelioma. Note the interlocking
villi in right upper corner. T h e nucleus is pale with evenly distributed chromatin. X 12,000.

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May 1976 DIFFUSE MALIGNANT MESOTHELIOMA 591

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592 KLIMA, SPJUT AND SEYBOLD A.J.C.P. —Vol. 65

FIG. 12. Patient 8. T h e surface of


a tumorous mesothelial cell, showing
details of villous protrusions, des-
mosomes a n d tight j u n c t i o n s
(arrows), x 14,400. Inset at lower left
shows the large intracytoplasmic
vacuoles with scattered villi on the
inner surface. X 1,200.

cells was the mitochondrion. They were bodies limited by a single membrane and
rounded and/or elongated with irregu- lysosomal structures. Several of the cells
larly arranged cristae. T h e mitochondria showed dense bodies resembling secretory
formed groups in the paranuclear area, granules and scattered autophagic vacuoles
but were found in other parts of the cysto- (Fig. 14). The cytoplasmic background was
plasm also. Golgi apparatus was incon- formed by multiple thin, haphazardly
spicuous in some cells and abundant and arranged fibers and scattered small dark
rather large in others. Many small tubules bundles of fibrils similar to tonofilaments
and vesicles were associated with the Golgi (Fig. 17). Their relation to an occasional
apparatus (Fig. 13). In the large cells of desmosome was evident, but they were
the epithelial type, these vesicles were more frequent than the desmosomes. In a
gready distended (Fig. 11). T h e rough few tumor cells (especially in one of the
endoplasmic reticulum was fragmented sarcomatous tumors) glycogen deposits
and formed narrow undulating tubules were seen (Figs. 14 and 18).
that occasionally surrounded some of the T h e intercellular spaces were either
larger mitochondria (Fig. 14). empty or filled by finely fibrillar material
T h e cytoplasm in some instances con- and collagen fibers with typical periodic-
tained many small tubules and smooth ity. These were intimate with the cellular
vesicles, which were scattered throughout, membrane (Figs. 15, 19 and 20). T h e capil-
but were most frequently peripherally. No laries showed markedly thickened base-
clear transition of these tubules to pinocy- ment membranes and occasional promi-
totic vesicles was appreciated. Mingled with nent endothelial cells; they were otherwise
these vesicles were frequent multivesicular not remarkable.

' Fie. 13 (upper). Patient 8. Mesothelial tumor cell containing prominent number of mitochondria with
irregular cristae and Golgi apparatus with associated small tubules. X 15,000.

FIG. 14 (lower). Patient 4. A tumor cell from a sarcomatous type of mesothelioma with glycogen in
the cytoplasm and a dense body at the upper edge. Note the presence of villi at the left side. Rough
endoplasmic reticulum is noncontinuous. x 14,000.

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May 1976 DIFFUSE MALIGNANT MESOTHELIOMA 593

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594 KLIMA, SPJUT AND SEYBOLD A.J.C.P.—Vol. 65

Although the sarcoma-like mesothe-


lioma was suggestive of a mesenchymal
tumor by light microscopy, ultrastruc-
turally the cells had features of epithelial
cells. The two types of diffuse malignant
mesothelioma differed only in a few as-
pects. T h e sarcoma-like type was com-
posed mainly of closely packed cells, with
fewer organelles than the epithelial type.
Free ribosomes and few cytoplasmic fibrils
were present. In contrast, the epithelial
type differed more from cell to cell and
from case to case. Some possessed a promi-
nent brush border, others had prominent
desmosomes, but most had both. Cyto-
plasmic filaments were prominent, as were
distended vesicles, considered to be of
Golgi origin.
T h e nuclei in both types were large
and pale with dense nucleoli. T h e
chromatin congregated at the nuclear
membrane and in small clusters around the
nucleolus (Figs. 12 and 13). T h e nuclear
membrane produced shallow indentations
and deep invaginations. In three specimens
elongated or rounded filamentous and
crystalloid structures were present in the
nucleus. They were not bounded by a mem-
brane and faded into the nucleolemma
(Fig. 16).

Therapy
T h e therapeutic procedures are listed in
Table 1. Four of our patients were treated

FIG. 15 (upper). Patient 7. Detail of the surface of a


tumor cell with intimate contact of extracellular sub-
stance and collagen production, x 15,500.

FIG. 16 (middle). Patient 9. Detail of a crystal-


loid body in the nucleus of a malignant mesothelial
cell. x37,200.

FIG. 17 (lower). Patient 9. Detail of intracytoplasmic


tonofilaments. Upper part of the picture shows
degenerating changes in die cytoplasm. X 33,000.

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May 1976 DIFFUSE MALIGNANT MESOTHELIOMA 595

surgically only and survived 8 years, 2'/2 years, and 3 years, respectively. T h e poor
years, 2'/2 years, and 11 months. Although survival may be explained by the fact that
Patient 4 received irradiation recently, her many patients come to the physician with
tumor was controlled successfully for 7'/2 advanced disease, rendering the lesions
years with repeated pleural resections. nonresectable. Early diagnosis is im-
portant, but difficult to make. An example
Discussion is the case of Patient 1, who initially
had a diagnosis of pleural adhesions; three
In comparison with series published by years later the tumor was nonresectable.
other investigators, 18,23,24,26 our group of Review of the tissue obtained at the first
patients is small. However, some interest- thoracotomy failed to show mesothelioma
ing facts are worth noting. in retrospect. Malignant mesothelioma is
Along with the interest in diffuse malig- seldom suspected clinically.
nant mesothelioma goes the more pressing
question of the etiologic factors involved The main symptom, which should alert
in its development. There is abundant and the clinician, is persistent pain and/or
still growing evidence of a strong rela- effusion.5,24,25,27 These symptoms, together
tionship between inhaled asbestos fibers with the radiologic detection of pleural
and diffuse malignant mesothelioma. Re- thickening in the absence of intrapul-
cently, it has been suggested that the sig- monary disease, should lead to a considera-
nificance of asbestos might not be as over- tion of the diagnosis of mesothelioma.
whelming as heretofore considered. 18,23 From our experience and that of
Other studies suggest that, in fact, the as- others, 2,11,19,27 cytologic examination of the
bestos crystals and fibers are ubiquitous, fluid is rarely helpful. T h e fluid contains
since they are admixed in many insulation, mesothelial cells that are difficult to dis-
construction or electrical material. 32 It tinguish from proliferative mesothelial
must be assumed that if asbestos was an cells.3,16,17 We were not able to find the
important factor in the genesis of the nuclear changes described to occur in the
tumor in our cases, the patients must have malignant mesothelial cells by Morawetz, 21
been exposed to the asbestos particles in and in our experience, such changes are
the usual environment. None of our pa- more typical for adenocarcinomatous
tients worked in industries known to use cells, thus making it impossible to dis-
asbestos. Where possible, we reviewed the tinguish these two cells in the pleural or
lung tissue from the surgical or autopsy peritoneal fluids. However, when they are
material, but could not find any fer- mucin-positive, the questionable cells will
ruginous bodies, which is in contrast to be adenocarcinoma. In sarcomatous type
other studies. 8 of mesothelioma, the fluid is frequently
Diffuse malignant mesothelioma has cell-free.
been considered to be quickly fatal, with If clinical symptoms persist for more
the course rarely exceeding one year. 2,5,13,27 than four weeks, the most efficient means
For example, a case with survival for more of establishing the diagnosis is by thoracot-
than 4'/2 years has been published as being omy. However, even the pathologist faces
unusual. 9 In our series, five of the patients a dilemma. It is difficult for him to make a
died in short periods—a year or less; five diagnosis of diffuse malignant mesothe-
patients have survived 1 to 3 years, and lioma without clinical, radiologic and surgi-
three patients have survived 11 years, 7 cal information. Diffuse malignant meso-

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596 KLIMA, SPJUT AND SEYBOLD A.J.C.P.—Vol. 65

•:^W^
>,»•>-J .5 7 » . •* -J

.--.'S-

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May 1976 DIFFUSE MALIGNANT MESOTHELIOMA 597

Fie. 18 (upper). Patient 4. An area of malignant mesothelioma of sarcomatous type. Note the inter-
locking cellular protrusions in intercellular spaces (arrow), the glycogen content, and the typical
vesicular nuclei with a prominent nucleolus, which are seen usually in epithelial cells. x4,800.

FIG. 19 (lower). Patient 8. An area of an epitheliomatous type of malignant mesothelioma. T h e tissue


shows both abundant microvilli and collagen fibers. x4,000.

thelioma is easily mistaken for metastatic the two types. They are vesicular, lightly
adenocarcinoma when it has a glandular stained, rounded, and contain small, dark
pattern or for sarcoma when it is the nucleoli as a rule. In some cases, the vas-
sarcomatous form. 14 It may be errone- cularity is predominant, and some vessels
ously diagnosed as benign when col- are spacious and probably are an integral
lagenous tissue is prevalent in a biopsy. part of the mesothelioma. 2
T h e differentiation between diffuse malig- T h e stroma varies from myxoid to
nant mesothelioma and mesothelial pro- densely collagenous. T h e vasculature
liferation is difficult or impossible to make forms wide sinusoid-like channels or thick-
on the basis of a small biopsy specimen or walled vessels that appear hyalinized. T h e
by frozen-section examination. The use of amounts of stroma differ enormously from
electron microscopy aids in the solution of case to case and even from block to block
the problem. 17 in each tumor.
Nonetheless, there are some microscopic Only the mucin stain aids in routine
features that should be sought. In the differentiation of mesothelioma from
glandular form, the loose coherence of adenocarcinoma. Should the tumor be re-
epithelial cells,15 the free-lying cells or garded as mesothelioma, the mucin stain
groups of cells in luminal spaces, and the must be negative. 5,27 T h e results of PAS
absence of mucin are significant. T h e positivity are variable in different reports.
tumor cells are large, polygonal, but more We found that some of the tumors were
uniform than in adenocarcinoma. They weakly positive with focal granular PAS-
have distinct cytoplasmic borders. T h e positive material in some of the cells. This
cellular vacuoles and clear cytoplasmic corresponds to our electronmicroscopic
spaces are stained greenish by Alcian blue. findings of glycogen in some cells. T h e
This should be kept in mind in view of the reticulin was not helpful since in some
fact that these cells are able to produce cases it was almost absent, while in others
ground substance of mesenchymal tissue. it was dense and abundant.
In one of our cases (Patient 6) we showed In four cases (Patients 1,4,7 and 8), there
continuation between the pseudoluminal were extensions of the tumors through the
content and surrounding collagenous chest wall. In one (Patient 12), the tumor
stroma, similar to what has been described metastasized in the axilla and in another
to occur in adenoid cystic carcinomas. 7 (Patient 11), to a mediastinal lymph node.
T h e sarcomatous form presents a more The tumors spread from the thorax to the
difficult problem. In some cases, die tumor abdominal cavity, producing abdominal
has the appearance of smooth muscle symptoms, in four patients (Patients 5, 9,
tumor, even to the point of having similar 10 and 12).
staining properties. The tumor cells, even T h e epithelial mesotheliomas that ex-
when spindle-shaped, are plumper than tended into the abdominal cavity were
the slender smooth muscle cells. Almost composed of loosely arranged cells sus-
always an area of loose arrangement and pended in almost myxomatous stroma.
rounding of the isolated tumor cells can be Whedier this structure was the reason for
found. The nuclei seem to be similar in spread or the result of such extension

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598 KLIMA, SPJUT AND SEYBOLD AJ.C.P. —Vol. 65

FIG. 20. Patient 12. A tumor cell from a sarcoma-like mesothelioma. Note the intracytoplasmic fibrils,
the presence of glycogen, and the intimate relation to extracytoplasmic reticulin fibers. x25,000.

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May 1976 DIFFUSE MALIGNANT MESOTHELIOMA 599

cannot be determined from our study. diagnosis in cases of malignant meso-


In our experience, malignant meso- thelioma.
thelioma appeared more prone to invade At present no particularly effective
the thoracic or abdominal wall than to in- therapy is known. One of our patients
vade adjacent organs. 1 Only once did we see (Patient 4) has survived many years wim
questionable extension of tumor into the repeated surgical removal of the recurrent
lung tissue, but there had been previous tumor. It seems that operative intervention
segmental resection of lung in the region has some effect in controlling the tumor,
of invasion. whereas radiation and chemotherapy do
In accordance with another opinion, 3 not alter the course of the disease. 2,27
it is not possible to predict the prognosis Acknowledgments. Marilyn Smith aided with the
in relation to histologic type of tumor. electronmicroscopy and the interpretation of the
Neither the predominant cell type nor electron micrographs, and Alyce Haydon pro-
vided technical assistance.
the formation of collagen has any signifi-
cance. Two of our long-surviving patients References
had tumors of the glandular type, and one 1. Barrett NR: T h e pleura. With special reference
has a tumor of sarcomatous type. It should to fibrothorax. Thorax 25:515-524, 1970
be pointed out that none of the tumors we 2. Campbell WN: Pleural mesothelioma. Am J
Pathol 26:473-489, 1950
studied changed its histologic appearance 3. Castor CW, Naylor B: Characteristics of normal
during the course of the disease. and malignant h u m a n mesothelial cells
studied in vitro. Lab Invest 20:437-443, 1969
Our electronmicroscopic findings were 4. Churg J, Rosen SH, Moolten S: Histological
in accord with results in other studies 10,15,33 characteristics of mesothelioma associated
with asbestos. Ann NY Acad Sci 132:614-
i.e., the tumor cell has the morphologic 622, 1965
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19:298-319, 1957
casional features of a mesenchymal cell. 6. Harries PG, Jones JSP, Skidmore JW, et al:
This confirms the results of previous cul- Summary of Symposium on Diseases Asso-
ture studies 30,31 demonstrating the pluri- ciated with Asbestos Dust Exposure. Bull
Int Pathol 14:9-15, 1973
potentiality of the mesothelial cell. Our 7. Hoshino M, Yamamoto I: Ultrastructure of
studies showed the predominance of adenoid cystic carcinoma. Cancer 25:186-
198, 1970
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lesions indistinguishable from mesenchy- theliomata, and attempts to identify asbestos
mal tumors by light microscopy. From the within some of the tumors. Ann NY Acad Sci
132:647-673, 1965
diagnostic point of view, the most im- 9. Jordanoglou J, Lymberatos K, Arapakis G: An
portant features are the abundant micro- unusual case of mesothelioma of the pleura.
Am Rev Resp Dis 103:418-422, 1971
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the presence of reticulin and collagen fiber malignant fibrous mesothelioma of the pleura.
formation, and the formation of intracyto- Arch Pathol 92:449-455, 1971
11. Kn^lle H, Matzel W: Ein beitrag zur morphologie
plasmic secondary lumina. Also, in contrast und klinischen diagnostik der pleurameso-
to cytoplasm in some other epithelial cells, theliome. Z Erkr Atmungsorgane 136:26-27,
1972
cytoplasm in mesotheliomas contains fewer 12. Legrand M, Pariente R: Etude au microscope
organelles related to secretion. T h e pre- electronique de 18 mesotheliomes pleuraux.
dominant organelle is the mitochondrion. Pathol Biol 22:409-420, 1974
13. Lulenski GC, Pifarre R, Neville WE: Rapid
T h e sarcomatous types show cells with growth of a pleural mesothelioma. Chest
mesenchymal features having focal devel- 59:230-323, 1971
14. Magner D, McDonald AD: Malignant meso-
opment of microvilli and nuclei such as is thelial tumors—histologic type and asbestos
seen in epithelial cells.12 exposure. N Engl J Med 287:570-571, 1972
15. Manguikian B, Prior J T : Mesotheliomas of the
Electron microscopy was found helpful pleura. Arch Pathol 75:236-249, 1963
in confirming or establishing the proper 16. Marsan C, Cayphas Y: T h e aid of some histo-

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chemical stains in the identification of meso- Mesotheliomes pleuraux malins. Bull Cancer
thelial cells. Acta Cytol 18:252-258, 1974 56:265-308, 1969
17. McCaughey WTE: Criteria for diagnosis of dif- 26. Selikoff IJ, Churg J, Hammond EC: Relation
fuse mesothelial tumors. Ann NY Acad Sci between exposure to asbestos and meso-
132:603-613, 1965 thelioma. N Engl J Med 272:560-565, 1965
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Epidemiology of primary malignant tumors in thelioma. Acta Chir Scand 126:78-91, 1963
Canada. Cancer 26:914-919, 1970 28. Stanton MF, Wrench C: Mechanisms of meso-
19. McGowan L, Burmag B: Morphology of meso- thelioma induction with asbestos and fibrous
thelial cells in peritoneal fluid from normal glass. J Natl Cancer Inst 4 8 : 7 9 7 - 8 2 1 , 1972
women. Acta Cytol 18:205-209, 1974 29. Stoebner P, Miech G, Sengel A, et al: Notions
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